Condensed heterocyclic succinamide compounds

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

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

8 cl, 11 tbl, 463 ex

 

The scope of the invention

The present invention relates to a condensed cyclic compounds, to methods of using such compounds to treat diseases associated with nuclear receptor hormone, such as cancer, and to pharmaceutical compositions containing such compounds.

The level of technology

Receptors nuclear hormone (other) consists of numerous superfamily of ligand-dependent and specific to the sequence of transcription factors. Members of this superfamily have an effect on transcription, either directly through specific binding to the promoter of target genes (Evans, Science 240: 889-895 (1988)), or indirectly via protein-protein interactions with other transcription factors (Jonat et al., Cell 62: 1189-1204 (1990), Schuele et al., Cell 62: 1217-1226 (1990), and Yang-Yen et al., Cell 62: 1205-1215 (1990)). The superfamily of nuclear receptors hormone (also known as "the superfamily of receptors steroid/thyroid hormones") includes receptors for a variety of hydrophobic ligands, including cortisol, aldosterone, estrogen, progesterone, testosterone, vitamin D3, thyroid hormone and retinoic acid (Evans, 1988, supra). In addition to these common receptors nuclear hormone superfamily includes several proteins that have no known ligands, called ivanovii receptors nuclear hormone (Mangelsdorf et al., Cell 83: 35-839 (1995), O'malley et al., Mol. Endocrinol. 10: 1293 (1996), Enmark et al., Mol. Endocrinol. 10, 1293-1307 (1996) and Giguere, Endocrin. Rev. 20, 689-725 (1999)). Normal receptors nuclear hormone are generally transactivator in the presence of ligand and can be an active repressor substances or transcriptionally inert in the absence of ligand. Some of Ivanovych receptors manifest themselves as if they were transcriptionally inert in the absence of ligand. Others, however, manifest itself as an essential activator or repressor substances. These ivanovii receptors nuclear hormone under the control of ubiquitous ligands that are unidentified or do not require the binding of ligands for the manifestation of their activity.

At the same time with other transcription factors receptors nuclear hormone have a modular structural formula, including three separate areas: N is a finite domain variable length containing the transcriptional activation function AF-I highly preserved DNA-associated domain and moderately preserved ligand-associated domain. Ligand-associated domain responsible for binding of the specific ligand, but also contains a transcriptional activation function, called AF-2, and dimerization domain (Wurtz et al., Nature Struc. Biol. 3, 87-94 (1996), Parker et al. Nature Struc. Biol. 3, 113-115 (1996) and Kumar et al. Steroids 64, 310-319 (1999)). Although a complete protein and consequently the efficiency of these receptors can vary considerably, they all show how the General structural arrangement, showing the deviation from the generic archetype, as well as significant homology (especially the sequence identity) to the ligand-bound domain.

Associated with steroid receptors nuclear hormone (SB-other) constitute a superfamily of receptors nuclear hormone. These receptors are similar in that they are more strong sequence homology to each other, especially in the ligand-bound domain (LBD), compared with other with other members of the superfamily (Evans, 1988, supra), and they all use the ligands based on the steroid. Some examples of this superfamily are other androgeny receptor (AR), estrogen receptor (ER), progesterone receptor (PR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), aldosterone receptor (ALDR) and the receptor of the steroid and xenobiotic (SXR) (Evans et al, WO 99/35246). Based on the strong homology sequence of the LBD, some ivanovii receptors may also be members of the SB-other subfamilies.

According to high homologous sequence found in LBD for each SB-other, natural ligands for each descended from a common steroid nucleus. Some examples of ligands based on the steroid used by members of the SB-other include cortisol, aldosterone, estrogen, progesterone, testosterone and dihydrat stosterone. The specificity of a particular ligand-based steroid, one SB-other to the other, get a different substitution in the steroid nucleus. High affinity binding to specific SB-other, defined by a high level of specificity in relation to this particular SB-other, can be achieved only minor structural changes in the steroid nucleus (e.g., Waller et al., Toxicol. AppI Pharmacol. 137, 219-227 (1996) and Mekenyan et al., Environ. Sd. Technol. 31, 3702-3711 (1997), the affinity of binding to progesterone in relation to the androgen receptor in comparison with testosterone).

Described numerous synthetically derived steroid and non-steroid agonists and antagonists of the members of the SB-other family. Many of these ligands agonists and antagonists are used clinically for the treatment of many medical diseases in humans. RU486 is an example of a synthetic agonist of PR, which is used as a means of birth control (Vegeto et al., Cell 69: 703-713 (1992)), and Flutamide is an example of the AR antagonist, which is used for the treatment of prostate cancer (Neri et al, Endo. 91,427-437 (1972)). Tamoxifen is an example of a tissue-specific modulator of ER function, which is used to treat breast cancer (Smigel, J. Nati Cancer Inst. 90, 647-648 (1998)). Tamoxifen can act as an antagonist of ER in tone chest and both the ER agonist in bone (Grese et al., Proc. Natl. Acad. Sci. USA 94,14105-14110 (1997)). Because deniesbarcelona actions exhibited by Tamoxifen, the agent and other agents, called "partial agonist" or "partial antagonist". In addition to synthetically derived endogeny ligands, endogene ligands for other can be obtained from foods (Regal et al., Proc. Soc. Exp. Biol. Med. 223, 372-378 (2000) and Hempstock et al., J. Med. Food 2, 267-269 (1999)). The flavonoid phytoestrogens are an example of non-natural ligand for SB - other, which are easily obtained from foods such as soy (Quella et al., J. din. Oncol. 18, 1068-1074 (2000) and Banz et al., J. Med. Food 2, 271-273 (1999)). The ability to modulate the transcriptional activity of individual other by the addition of a small molecule ligand makes them ideal targets for the development of pharmaceutical products to many diseases.

As indicated above, non-natural ligands can be obtained synthetically for use as modulators of the function of the other. In the case of other receiving non-natural ligand may include the identification of the core structure, which simulates the system kernel of the natural steroid. This can be achieved by random screening against some or other directional approaches using available crystal structures of many other ligand-associated domains (Bourguet et al., Nature 375, 377-382 (1995), Brzozowski, et al., Nature 389, 753-758 (1997), Shiau et al., Cell 95, 927-937 (1998) and Tanenbaum et al., Proc. Natl. Acad. Sd. SA 95, 5998-6003 (1998)). Various substitution in this steroid-mimicking the kernel can lead to agents with selectivity for one receptor over the other.

In addition, such modifications can be used for agents with agonistic or antagonistic activity for a particular SB-other. Various substitution in steroid-mimicking the engine can produce a number of highly specific agonists and antagonists with specificity, for example, to ER with respect to PR, with respect to AR, with respect to GR, in relation to MR. This approach is different substitution was reported, for example, modulators, based on quinoline, for other steroid in J. Med. Chem., 41, 623 (1999); WO 9749709; US 5696133; US 5696130; US 5696127; US 5693647; US 5693646; US 5688810; US 5688808 and WO 9619458, all included in the present invention as references.

Compounds of the present invention include a core, which acts as a simulator steroid, and are useful as modulators of the function associated with the steroid receptor nuclear hormone as well as other other, described below.

The invention

The present invention relates to a condensed cyclic compounds of the formula I and their salts, are particularly useful as modulators of receptor function of nuclear hormone:

As used in f is rule I, and in the description, the radicals have the following meanings, unless otherwise indicated, and are in each case independently selected from:

G, which represents aryl or heterocycle (e.g., heteroaryl) group, where

this group is a mono - or polycyclic group, substituted at one or more positions, preferably with hydrogen, alkyl or substituted alkyl, alkenyl or substituted by alkenyl, quinil or substituted by quinil, halogen, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, arylalkyl or substituted by arylalkyl, heterocyclization or substituted by heterocyclization, CN, R1OC=O, R1C=O, R1C=S, R1HNC=O, R1R2NC=O, HOCR3R3', nitro, R1OCH2, R1O, NH2, NR4R5, SR1S=OR1, SO2R1, SO2OR1, SO2NR1R1', (R1O)(R1O)P=O, oxo, (R1)(R1')P=O, or R1')(Other1)P=O;

Z1represents O, S, NH or NR6;

Z2represents O, S, NH or NR6;

a1represents CR7or N;

And2represents CR7or N;

Y is J-J'-J"where J presented yet a (CR 7R7')n and n=0-3, J' is a bond or O, S, S=O, SO2, NH, NR7With=On, OS=O, NR1C=O, CR7R7'=CR8R8', R2P=O, R2P=S, R2OP=O, R2NHP=O, OP=OOR2, RR=ONHR2, OP=OR2, OSO2, C=NR7, NHNH, NHNR6, NR6NH, N=N, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle or aryl or substituted aryl, and J" is (CR7R7)n and n=0-3, where Y is not a bond;

W represents CR7R7'-CR7R7', CR8=CR8', CR7R7'-C=O, NR9-CR7R7'N=CR8N=N, NR9-NR9'S-CR7R7'That SO-CR7R7', SO2-CR7R7'cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle or aryl or substituted aryl, where W is NR9-CR7R7'N=CR8N=N, NR9-NR9'S-CR7R7', SO-CR7R7', SO2CR7R7or heterocycle or substituted heterocycle, then J' must be O, S, S=O, SO2, NH, NR7OS,=O, NR1C=O, OP=OOR2, RR=ONHR2, OSO2, NHNH, NHNR6, NR6NH, or n=N;

Q1represents H, alkyl or substituted alkyl, alkenyl or replaced alkenyl, the cycle is alkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, arylalkyl or substituted arylalkyl, quinil or substituted quinil, aryl or substituted aryl, heterocycle (for example, heteroaryl) or substituted heterocycle (for example, substituted heteroaryl), halogen, CN, R1OS=O, R4C=O, R5R6C=O, HOCR7R7', nitro, R1OCH2, R1O, NH2C=OSR1, SO2R1or NR4R5;

Q2represents H, alkyl or substituted alkyl, alkenyl or replaced alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, arylalkyl or substituted arylalkyl, quinil or substituted quinil, aryl or substituted aryl, heterocycle (for example, heteroaryl) or substituted heterocycle (for example, substituted heteroaryl), halogen, CN, R1OC=O, R4C=O, R5R6NC=O, HOCR7R7', nitro, R1OCH2, R1O, NH2C=OSR1, SO2Rlor NR4R5;

L is a bond, (CR7R7')n, NH, NR5, NH (CR7R7')n, or NR5(CR7R7')n, where n=0-3;

R1and R1each independently represent H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cyclea kenil or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl;

R2represents an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl;

R3and R3each independently represent H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, halogen, CN, hydroxylamine, hydroxamic, alkoxy or substituted alkoxy, amino, NR1R2, thiol, alkylthio or substituted, alkylthio;

R4represents H, alkyl or substituted alkyl, cycloalkyl or Deputy is on cycloalkyl, cycloalkene or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R1C=O, R1NHC=O, SO2OR1or SO2NR1R1';

R5represents an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R1C=O, R1NHC=O, SO2R1, SO2OR1or SO2NR1R1';

R6represents an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, CN, IT, OR1, R1C=O, R1NHC=O, SO 2R1, SO2OR1or SO2NR1R1';

R7and R7each independently represent H, alkyl or substituted alkyl, alkenyl or replaced alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, halogen, CN, OR1, nitro, hydroxylamine, hydroxylated, amino, other4, NR2R5, NOR1, thiol, alkylthio or substituted, alkylthio, R1C=O, R1OC=O, R1NHC=O, SO2R1,SOR1, RHO3R1R1', R1R1NC=O, C=OSR1, SO2R1, SO2OR1or SO2NR1R1'or, where

A1or a2contains the group R7and W contains the group R7specified R7groups A1or a2and W together form a heterocyclic ring;

R8and R8'each independently represent H, alkyl or substituted alkyl, alkenyl or replaced alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl Il is substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, nitro, halogen, CN, OR1, amino, other4, NR2R5, NOR1alkylthio or substituted, alkylthio,=OSR1, R1OC=O, R1C=O, R1NHC=O, R1R1'NC=O, SO2OR1S=OR1, SO2R1, PO3R1R1'or SO2NR1R1'; and

R9and R9'each independently represent H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, CN, IT, OR1, R1C=O, R1OC=O, R1NHC=O, SO2R1, SO2OR1or SO2NR1R1';

The compounds of formula I are new, preferred sub-group has the following formula Ia:

where G, L, Z1, Z2, A1, A2, Q1and Q2have the meanings defined above;

Y' represents a J-J'-J"where J is a (CR7R7' )n and n=0-3, J' is a bond or O, S, S=O, SO2, NH, NR7, CR7R7', R2P=O, R2P=S, R2OP=O, R2NHP-O, OP=OOR2OP=ONHR2, OSO2. NHNH, NHNR6, NR6NH, N=N, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl or heterocycle or substituted heterocycle and J" is (CR7R7')n and n=0-3, where Y is not a bond; and

W' represents CR7R7'-CR7R7', CR7R7'-C=O, NR9-CR7R7'- N=CR8N=N, NR9-

NR9'cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle or aryl or substituted aryl, where, when W is NR9-CR7R7'- N=CR8N=N, NR9-NR9' or heterocycle or substituted heterocycle, then J1may be O, S, S=O, SO2, NH, NR7, RR=OOR2, RR=ONHR2, OSO2, NHNH, NHNR6, NR6NH or N=N; or alternatively,

Y' represents NR7-CR7R7'and W represents CR8=CR8'; or alternatively,

Y' represents CR7R7'-C=O and W' represents NR9-CR7R7';

where R2, R6, R7, R7', R8, R9and R9' are as defined above, and provided that (1) when a is-O-, Q1and Q2are hydrogen, Z1and Z2are O, W' is CH2-CH2-and A1and a2are CH, then G-L is not phenyl, one-deputizing by phenyl or by phenyl which is substituted by two or more of the following groups: methoxy, halogen, NO2, stands, CH3-S-, HE, CO2H, trifluoromethyl, -C(O)-C6H5, NH2,4-7-epoxy, hexahydro-1N-isoindole-1,3(2H)dione or-C(O)-CH3;

(2) when Y1is-O-, Q1and Q2are hydrogen, Z1and Z2are O, W' is a CH2-CH2and one of the A1and a2represents CH and the other is CR7then G-L is not unsubstituted phenyl;

(3) when Y' is-O-, Q1and Q2are hydrogen, Z1and Z2are O, W' is CH2-CH2and one of the A1and a2is CH and the other is-CH3then G-L is not a phenyl substituted by chlorine and/or stands;

(4) when Y1is-O - or-S-, Q1and Q2are hydrogen, Z1and Z2are O, W' is CH2-CH2and one of the A1and a2is CH and the other is CH or C-alkyl, then G-L is not N-substituted piperazine-alkyl - or N-substituted imidazolidin-alkyl-;

(5) when Y' is a Ki is-O-; Q1and Q2are hydrogen, Z1and Z2are O, W' is CH2-CH2and A1and a2are CH, then G-L is not oxazole or triazole;

(6) when Y1is-O-; Q1and Q2are hydrogen or stands, Z1and Z2are O, W' is CH2-CH2and A1and a2are CH or-CH3then G-L is not a thiazole or substituted thiazole (in addition, such compounds where G-L is optionally substituted thiadiazole or partially saturated thiazole optionally removed when A1and a2both are SN);

(7) when Y' contains the J1selected from S, S=O, SO2, NH, NR7, R2P=O, R2P=S, R2OP=O, R2NHP=O, OP=OOR2, RR=ONHR2, OSO2, NHNH, other6, NR6NH or N=N, W is CR7R7'-CR7R7'and Z1and Z2are O, then G-L is not unsubstituted phenyl;

(8) when Y1is NR7W' is unsubstituted or substituted by phenyl, and Q1and Q2are hydrogen, then Z1and Z2are not About;

(9) when Y1is-O-, Q1and Q2are hydrogen, Z1and Z2are O, W is dihydroisoxazole bearing an optionally substituted phenyl group, and A1and the 2are CH, then G-L is not unsubstituted phenyl or dichlorophenyl;

(10) when Y' is Oh, Q1and Q2are hydrogen, Z1and Z2are O, W' is an ethylene oxide and A1and a2are CH, then G-L is not a were or chlorophenyl;

(11) when Y1is NR7-CR7R7'W is CR8=CR8', Q1and Q2are hydrogen, A1and A2are CH,-CH3,- CH2-C6H5or-CH2-CH3and Z1and Z2are O, then G-L is not unsubstituted phenyl, one-deputizing a phenyl or methylpyridinium;

(12) when Y1is CR7R7'-C=O, W' is NR9-CR7R7', Q1and Q2are hydrogen, A1and a2are CH, and Z1and Z2are O, then G-L is not unsubstituted phenyl;

(13) when Y' is CHR7-NR7'where R7is unsubstituted phenyl, methoxy or ethoxy and R7is unsubstituted phenyl, stands, or-C(O)-C6H5W is dimethoxyaniline or unsubstituted phenylene, Z1and Z2are O, Q1and Q2are hydrogen, and A1and a2are CH, C-CN,-C(O)-C6H5or-C(O)-acid, then G-L is not unsubstituted phenyl is m;

(14) the compound of formula Ia is not 6,10-epithio-4H-thieno-[3',4':5,6]cycloocta[1,2-f]isoindole-7,9(5H,8H)-dione, 8-(3,5-dichlorophenyl)-6,6A,9a, 10,11,12,hexahydro-1,3,6,10-tetramethyl-2,2,13-trioxide, (6R,6aR,9aS,10S);

(15) when Y' is O, W' is CH2-CH2-, Q1and Q2are the stands, Z1and Z2are On, and A1and a2are CH, then G-L is not unsubstituted phenyl, phenyl substituted methoxy, phenylalkyl-, or morpholinyl, and none of the connections is not attached itself to itself through the group L, which is alkalinous to form Basseinaya;

(16) when Y' is-O-, Q1and Q2are hydrogen, Z, and Z2are O, W' is CR7R7'-CR7R7'and A1and a2are CH, then G-L is not unsubstituted phenyl group; and

(17) when Y1is-O-, Q, and Q2are hydrogen, Z1and Z2are O, W' is cyclopentyl, cyclohexyl, 3-phenyl-2-isoxazoline or CR7R7'-

CR7R7'where R7and R7'each independently defined as Cl, Br, H and 4-butyrolactone and R7and R7'are not all simultaneously H and A1and a2are CH, then G-L is not unsubstituted naftilos ring or one-deputizing phenyl ring, where specified, the Deputy is IU is hydroxy, Br, Cl, NO2, stands, ethyl, CH2-phenyl, S-phenyl, or O-phenyl.

Preferably, the compounds of formula I are Monomeric and do not contain inside other oligomers or polymers.

Another new preferred subgroup are compounds of the following formula Ib:

where G, Z1, Z2, Q1and Q2are as defined above;

Y' represents a J-J'-J"where J is a (CR7R7')n and n=0-3, J' is a bond or O, S, S=O, SO2, NH, NR7, CR7R7'', R2P=O, R2P=S, R2OP=O, R2NHP=O, OP=OOR2OP=ONHR2, OSO2, NHNH, NHNR6, NR6NH, N=N, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl or heterocycle or substituted heterocycle and J" is (CR7R7')n and n=0-3, where Y is not a bond; and

W' represents CR7R7'-CR7R7', CR7R7'-C=O, NR9-CR7R7'- N=CR8N=N, NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle or aryl or substituted aryl, where

when W' is not a NR9-CR7R7'- N=CR8N=N, NR9-NR9' or heterocycle or zamesheny heterocycle, have a look at the J' can be Oh, S, S=O, SO2, NH, NR7, RR=OOR2, RR=ONHR2, OSO2, NHNH, NHNR6, NR6NH or N=N; or alternatively,

Y' represents CR7R7'-C=O and W represents NR9- CR7R7';

L is a bond; and

A1and a2are as defined above, in particular, when a and/or a2are alkyl or optionally substituted alkyl (preferably those optional substituents are one or more groups V1defined below), provided that when Y'=O and W'=-CH2-CH2-, then at least one of A1or A2is not CH;

when additional conditions(2), (3), (6), (7) and (8), as described above.

The compounds of formula I and their salts contain a kernel, which can serve as a simulator steroid, ( and does not require the presence of a typical steroid (for example, similar cyclopentanoperhydrophenanthrene structural analogue).

Detailed description of the invention

Following are the definitions of terms used in the description of the present invention. Initial definitions are intended for a group or for a term belonging to this group according to the present invention or to the term itself, used for describing or relating to or part of another group, unless otherwise indicated.

The terms "alkyl" and "ALK" refers to a straight or branched chain alonovoa (hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms. Examples of such groups include, without limitation, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. "Substituted alkyl" refers to an alkyl group substituted by one or more substituents, preferably from 1 to 4 substituents, at any available place of connection. Examples of substituents include, without limitation, one or more of the following groups: halogen (e.g. halogen Deputy or multiple halogen substituents forming, in the latter case, groups such as performanceline group or an alkyl group bearing Cl3or CF3), alkoxy, alkylthio, hydroxy, carboxy (i.e.,- COOH), alkoxycarbonyl, alkylcarboxylic, amino (i.e.,- NH2), carbarnoyl or substituted carbamoyl, carbamate or substituted carbamate, urea or substituted urea, amidine or substituted amidines, thiol (SH), aryl, heterocycle, cycloalkyl, heteroseksualci, -S-aryl, -S-heterocycle, -S=O-aryl, -S=O-heterocycle, arylalkyl-O-, -S(O)2-aryl, -S(O)2heteros is CL, -NHS(O)2-aryl, -NHS(O)2-heterocycle, -NHS(O)2NH-aryl, -NHS(O)2NH-heterocycle, -P(O)2-aryl, -P(O)2-heterocycle, -NHP(O)2-aryl, -NHP(O)2-heterocycle, -NHP(O)2NH-aryl, -NHP(O)2NH-heterocycle, -O-aryl, -O-heterocycle, -NH-aryl, -NH-heterocycle, -NHC=O-aryl, -NHC=O-alkyl, -NHC=O-heterocycle, -OC=O-aryl, -OC=O-heterocycle, -NHC=ONH-aryl, -NHC=ONH-heterocycle, -OC=OO-aryl, -OC=OO-heterocycle, -OS=ONH-aryl. OS=ONH-heterocycle, -NHC=OO-aryl, -NHC=OO-heterocycle, -NHC=OO-alkyl, -C=ONH-aryl, -C=ONH-heterocycle,- =OO-aryl,- =OO-heterocycle, -N(alkyl)S(O)2-aryl, -N(alkyl)S(O)2-heterocycle, -N(alkyl)S(O)2NH-aryl, -N(alkyl)S(O)2NH-heterocycle,-N(alkyl)P(O)2-aryl,-N(alkyl)P(O)2-heterocycle, -N(alkyl)P(O)2NH-aryl, -N(alkyl)P(O)2NH-heterocycle, -N(alkyl)-aryl, -N(alkyl)-heterocycle, -N(alkyl)C=O-aryl, -N(alkyl)C=O-heterocycle, -N(alkyl)C=ONH-aryl, -N(alkyl)C=ONH-heterocycle,-OC=ON(alkyl)-aryl,-OC=ON(alkyl)-heterocycle, -N(alkyl)C=OO-aryl, -N(alkyl)With=OO-heterocycle, -C=ON(alkyl)-aryl, -C=ON(alkyl)-heterocycle,-NHS(O)2N(alkyl)-aryl,-NHS(O)2N(alkyl)-heterocycle, -NHP(J)2N(alkyl)-aryl, NHP(O)2N(alkyl)-heterocycle, -NHC=ON(alkyl)-aryl, -NHC=ON(alkyl)-heterocycle,-N(alkyl)S(O)2N(alkyl)-aryl, (alkyl)S(O)2N(alkyl)-heterocycle, -N(alkyl)P(O)2N(alkyl)-aryl, N(alkyl)P(O)2N(alkyl)-heterocycle, -N(alkyl)C=ON(alkyl)-aryl, and-N(alkyl)C=ON(alkyl)-heterocycle. In the above definitions cover the oil, in each case, groups such as "alkyl", "aryl" and "heterocycle" may themselves be optionally substituted; for example, "alkyl" group "NCH=OO-alkyl"mentioned above, may be optionally substituted so that both "NHCOO-alkyl" and "NHC=OO-substituted alkyl" are examples of typical substituents. Examples of alkyl substituents include groups such as "T" and "T-R12" (defined below), in particular, for substituted alkyl groups inside A1or a2.

The term "alkenyl" refers to straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Examples of such groups include ethynyl, or allyl. "Replaced alkenyl" refers to alkenylphenol group, substituted by one or more substituents, preferably from 1 to 4 substituents, at any available place of connection. Examples of substituents include, without limitation, alkyl or substituted alkyl, as well as those groups which are mentioned above as examples of the alkyl substituents.

The term "quinil" refers to straight or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Examples of such groups include ethinyl. "Substituted quinil" refers to an alkyne is through the group, substituted by one or more substituents, preferably from 1 to 4 substituents, at any available place of connection. Examples of substituents include, without limitation, alkyl or substituted alkyl, as well as those groups which are mentioned above as examples of the alkyl substituents.

The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing from 1 to 4 rings and 3 to 8 carbons in the ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. "Substituted cycloalkyl" refers to cycloalkyl group, substituted by one or more substituents, preferably from 1 to 4 substituents, at any available place of connection. Examples of substituents include, without limitation, nitro, cyano, alkyl or substituted alkyl, as well as those groups which are mentioned above as examples of alkyl substituents, and as previously mentioned as preferred aryl substituents in the definition of G. Examples of the substituents also include Spiro-attached or condensed cyclic substituents, mainly cycloalkenyl or substituted cycloalkenyl.

The term "cycloalkenyl" refers to partially unsaturated cyclic hydrocarbon group containing. from 1 to 4 rings and 3 to 8 carbons in the ring. Examples of such groups include the up cyclobutenyl, cyclopentenyl, cyclohexenyl and so forth Substituted cycloalkenyl" refers to cycloalkenyl group, substituted by one or more substituents, preferably from 1 to 4 substituents, at any available place of connection. Examples of substituents include, without limitation, nitro, cyano, alkyl or substituted alkyl, as well as those groups which are mentioned above as examples of alkyl substituents, and as previously mentioned as preferred aryl substituents in the definition of G. Examples of the substituents also include Spiro-attached or condensed cyclic substituents, mainly cycloalkyl or substituted cycloalkyl.

The terms "alkoxy" or "alkylthio" refer to alkyl groups, as described above connected through an oxygen bridge (-O-) or the bridge of sulfur (-S -), respectively. The terms "substituted alkoxy" or "substituted alkylthio" refers to substituted alkyl groups as described above connected through an oxygen bridge or the bridge of sulfur, respectively.

The term "alkoxycarbonyl" refers to alkoxygroup connected via a carbonyl group.

The term "alkylaryl" refers to an alkyl group linked through a carbonyl group.

The term "alkylcarboxylic" refers to alkylcarboxylic group connected through an oxygen bridge.

The term is "arylalkyl", "substituted arylalkyl," "cycloalkyl," "substituted cycloalkyl," "cycloalkenyl", "substituted cycloalkenyl", "heteroseksualci" and "substituted heteroseksualci" refer to aryl, cycloalkyl, cycloalkenyl and heterostropha linked through alkyl groups, substituted aryl, cycloalkyl, cycloalkenyl or heterocycle and/or alkyl group, which is designated as "substituted."

The term "aryl" refers to a cyclic, aromatic hydrocarbon groups which have from 1 to 5 aromatic rings, mainly monocyclic or bicyclic groups such as phenyl, biphenylene or aftilova, which contains two or more aromatic rings (bicyclic, and so on), aromatic ring aryl groups may be combined at a single point (e.g., biphenyl) or condensed (for example, naphthyl, phenanthrene and the like). "Substituted aryl" refers to an aryl group substituted with one or more substituents, preferably 1, 2, 3, 4 or 5 substituents in any place of connection. Examples of substituents include, without limitation, nitro, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, cyano, alkyl-S(O)m(m=0,1 or 2), alkyl or substituted alkyl, as well as those groups which are mentioned above as examples of skilnik deputies and as previously mentioned as preferred aryl substituents in the definition of G. Examples of the substituents also include condensed "cyclic substituents, such as heterocycle or cycloalkenyl or substituted heterocycle or cycloalkenyl group (for example, the thus formed feranil, tetrahydronaphthalene or dihydroindolone group).

"Carbarnoyl" refers to the group-CONH-, which is connected at one end with the remainder of the molecule and the other is hydrogen or an organic component (such as alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, alkylaryl, hydroxyl, and substituted nitrogen). "Carbamate" refers to the group-O-CO-NH-, which is connected at one end with the remainder of the molecule and the other is hydrogen or an organic component (such as the one above). "Urea" refers to the group-NH-CO-NH-, which is connected at one end with the remainder of the molecule and on the other with hydrogen or organic component (such as the one above). "Amidine" refers to the group-C(= NH)(NH2). "Substituted carbarnoyl," "substituted carbamate," "substituted urea and substituted amidines" refer to carbamoyl, urethane, urea or Medininkai groups, as described above, in which one or more hydrogen groups are replaced with an organic component (such as the one above).

The terms "heterocycle", heterocyclic" and "heterocycle" refers to fully asystem or partially or fully unsaturated, including aromatic (i.e. "heteroaryl") cyclic groups (for example, from 3 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 16-membered tricyclic ring systems, which have at least one heteroatom in at least one carbon-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1,2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the heteroatoms nitrogen and sulfur may optionally be oxidized and the nitrogen heteroatoms may optionally be stereoselectivity. (The term "heteroaryl" refers to a heteroaryl group having stereoselectivity nitrogen atom and, thus, the positive charge.) Heterocyclic group may be attached to the remainder of the molecule via any heteroatom or carbon atom of the ring or ring system. Examples of monocyclic heterocyclic groups include ethylene oxide, azetidine, pyrrolidine, pyrrolyl, pyrazolyl, oxetanyl, pyrazolines, imidazoles, imidazolines, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, diazolidinyl, isothiazolin, isothiazolinones, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxo is zainil, azepines, hexahydroazepin, 4-piperidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfon, 1,3-dioxolane and tetrahydro-1,1-DIOXOLANYL, and the like. Examples of bicyclic heterocyclic groups include indolyl, isoindolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzoxadiazole, benzothiazyl, hinokitiol, chinoline, tetrahydroisoquinoline, ethenolysis, benzimidazolyl, benzopyranyl, indolizinyl, benzofuran, benzofurazanyl, chromones, coumarinyl, benzopyranyl, indolinyl, honokalani, imidazolyl, pyrrolopyridine, properidine (such as furo[2,3-C]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroergotoxine, dehydrodiconiferyl, dihydroisoquinolyl, dihydroindole, dihydroquinoline, dihydroquinazolines (such as 3,4-dihydro-4-oxo-hintline), trainersair, tetrahydropyranyl and the like. Examples of tricyclic heterocyclic groups include carbazolyl, benzhydryl, phenanthrolines, dibenzofurans, acridines, phenanthridines, xantener and the like.

"Substituted heterocycle" and "substituted heterocyclic" and "substituted heterocycle" (such as "substituted heteroaryl") refers to the heterocycles, geterotsiklicheskikh is or heterostropha, substituted by one or more substituents, preferably from 1 to 4 substituents, at any available place of connection. Examples of substituents include, without limitation, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, nitro, oxo (i.e. = O), cyano, alkyl-S(O)m(m=0, 1 or 2), alkyl or substituted alkyl, as well as those groups which are mentioned above as typical alkyl substituents, and as previously mentioned as preferred heterocyclization in the definition for G.

The term "Quaternary nitrogen" refers to a tetravalent positively charged nitrogen atom including, for example, positively charged nitrogen in tetraalkylammonium group (for example, Tetramethylammonium, N-methylpyridinium), positively charged nitrogen in protonated ammonium species (e.g., trimethylhydroquinone, N-hydropyridine), positively charged nitrogen in amino N-oxides (for example, N-methyl-morpholine-N-oxide, pyridine-N-oxide) and the positively charged nitrogen in the N-aminoaniline group (for example, N-aminopyridine).

The terms "gologergen" or "halo" refers to chlorine, bromine, fluorine or iodine.

The terms "customer" and "hydroxylated" refers to the groups OH-NH-and IT is-NH-CO -, respectively.

When the functional group is defined as a "protected", this means, Thu the group is in modified form converted, to soften, mainly to eliminate undesirable side reactions at the protected position. Suitable protective groups for methods and compounds described in the present invention include, without limitation, those described in the monographs, such as Greene, T. W. et al., Protective Groups in Organic Synthesis, Wiley, N.Y. (1991).

When using terms such as "(CRR)n, this means optionally substituted alkyl chain, located between the two fragments, with which it is associated, the length of which is determined by the interval that defines the term n. An example of this is a chain with n=0-3, containing from zero to three (CRR) links existing between the two fragments that are attached to the first and the last (CRR) link. In a situation where the term n has a value of zero (n=0), the relationship existing between the two fragments attached to (CRR).

Unless otherwise indicated, any heteroatom with unsaturated valency, as it is assumed that attaches the hydrogen atoms in a quantity sufficient to saturate all valences.

Divalent groups such as those defined as W (for example, NR-CR7R7')can be connected in any direction with the remainder of the molecule (for example,for the above-mentioned groups in the definition of W).

Carboxylate anion refers to the negatively charged the group-SOS -. The compounds of formula I form salts which are also within the present invention. Reference to the compounds of formula I in the present invention, as should be clear, includes a link to their salts, unless otherwise indicated. The term "salt(s)"as used in the present invention, means acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when the compound of formula I contains both a basic component, such as, without limitation, pyridine or imidazole, and an acidic component, such as, without limitation, carboxylic acids, can be formed zwitterions ("inner salts") and included in the term "salt(s)"as used in the present invention. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, when selecting or clearing in the process of producing compounds. Salts of the compounds of formula I can be formed, for example by reaction of compounds of formula I with a certain amount of acid or base, such as an equivalent amount, in such an environment, from which the salt precipitates or in an aqueous medium followed by lyophilization.

The compounds of formula I which contain a basic component, such as, without limitation, and is in or pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Examples of the acid additive salts include acetates (such as those formed with acetic acid or trigalogenmetany acid, for example, triperoxonane acid), adipate, alginates, ascorbates, aspartate, benzoate, bansilalpet, bisulfate, borates, butyrate, citrates, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, econsultancy, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonic (for example, 2-hydroxyethanesulfonic), lactates, maleate, methanesulfonate, naphthalenesulfonate (for example, 2-naphthalenesulfonate), nicotinate, nitrates, oxalates, pectinate, persulfates, phenylpropionate (for example, 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylates, succinate, sulfates (such as those formed with sulfuric acid), sulfonates (such as those referred to in the present invention), tartratami, thiocyanates, toluensulfonate, such as tozilaty, undecanoate, and the like.

The compounds of formula I which contain an acidic component, such as, without limitation, carboxylic acid, may form salts with a variety of organic and inorganic bases. Examples of basic salts on the Ute ammonium salts, alkali metal salts, such as salts of sodium, lithium and potassium, salts of alkaline earth metals such as calcium salts and magnesium salts, salts with organic bases (for example, organic amines)such as benzathine, dicyclohexylamine, geranamine (formed with N,N-bis(dehydroabietyl)Ethylenediamine), N-methyl-D-glucamine, N-methyl-O-glucoside, tert-butyl amines, and salts with amino acids such as agronin, lysine and the like. Basic nitrogen-containing groups can be stereoselectivity with agents such as lower alkylamide (for example methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), diallylsulfide (for example dimethyl, diethyl, dibutil and dimycolate), long-chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkylated (for example benzyl and phenetermine) and others.

Prodrugs and solvate compounds also described in the present invention. The term "prodrug", as used in the present invention means a compound, which upon introduction into a subject, undergoes chemical transformations with metabolic or chemical processes that gives compound of formula I or its salt and/or MES. The solvate of the compounds of formula I include, for example, hydrates.

The compounds of formula I and their salts may exist in their tautomeric form (EmOC is emer, as amido or iminoethyl). Such tautomeric forms are considered in the present invention as part thereof.

All stereoisomers of the compounds of the present invention (for example, those which may exist due to asymmetric carbons with various substituents, including enantiomeric and diastereomeric forms, considered in the framework of the present invention. Individual stereoisomers of the compounds according to the invention can, for example, to be substantially free of other isomers (for example, as a pure or substantially pure optical isomer having a specific activity) or can be mixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the compounds of the present invention can have the S or R configuration as determined IUPAC Recommendations, 1974. The racemic forms can be separated using physical methods, such as, for example, fractional crystallization, separation or crystallization diastereoisomeric derivatives or separation using chiral chromatography on a column. The individual optical isomers can be obtained from the racemate using any suitable method, including without limitation, ordinary methods, such as, for example, the formation of a salt with an optically active acid, and then crystallization.

All the config is operating isomers of the compounds of the present invention considered in any mixture, or in pure or substantially pure state. The definition of the compounds of the present invention includes both the CIS (Z) and TRANS (E) almansoori, as well as CIS and TRANS isomers of cyclic hydrocarbons or heterocyclochain. In some cases, for example, Exo - or anticonformal may be preferable to the condensed ring system associated with G-L in the formula I. for Example, antagonists androgenous receptor (or selective modulators androgenous receptor), where Y is O or NR7exconfederate may be preferable, while for other definitions Y, andconfiguration may be preferable. As can be appreciated, the preferred configuration may be a function of individual compounds and their preferred activity. The split configuration of the isomers may be achieved using any suitable method, such as chromatography on a column.

Throughout the description of the group and their alternates can be selected to ensure the stability of the components and connections.

The embodiment indicated in the present description as an exemplary or preferred, should serve only as illustration, but not limitation.

Ways to get

Compounds of the present invention can be obtained using methods such as those, which is depicted in the following schemes I to XI. Solvents, temperatures, pressures and other reaction conditions can be easily selected average specialist in this field of knowledge. The initial products are commercially available, or they can be obtained easily by using one of the conventional techniques in this field of knowledge. Combined techniques can be applied upon receipt of the compounds, for example, if the intermediate products are groups that are suitable for these techniques. See the following links that describe other ways that can be applied to obtain the compounds of the present invention: Li, et al., Eur. J. Org. Chem. 9, 1841-1850 (1998); Li, Y Q, Synlett. 5, 461-464 (1996); Thiemann et al., Bull. Chem. Soc. Jpn. 67, 1886-1893 (1994); Tsuge et al., Heterocydes 14, 423-428 (1980); Ward et al., Can. J. Chem. 75, 681-693 (1997); Ward et al, Can. J. Chem. 69, 1487-1497 (1991); Ward et al., Tetpahedron Lett. 31, 845-848 (1990); Fleming et al., J. Org. Chem. 44, 2280-2282 (1979); Jankowski et al., J. Were Obtained. Chem. 595, 109-113 (2000); Keglevich et al., J. Were Obtained. Chem. 579, 182-189 (1999); Keglevich et al, J. were obtained. Chem. 570, 49-539 (1998); Jankowski et al, Hetroat. Chem. 7, 369-374 (1996); Jankowski et al, J. Am. Chem. Soc. 113, 7011-7017 (1991); Quin et al, Tetrahedron Lett. 31,6473-6476 (1990); Quin et al, J. Org. Chem. 59, 120-129 (1994); Quin et al, J. Org. Chem. 58, 6212-6216 (1993); Quin et al, Phosphorous, Sulfur Silicon Relat. Elem. 63, 349-362 (1991); Quin et al, Hetroat. Chem. 2, 359-367 (1991); Hussong et al., Phosphorus Sulfur. 25, 201-212 (1985); Quin et al., J. Org. Chem. 51, 3341-3347 (1986); Myers et al, J. Am. Chem. Soc. 114, 5684-5692 (1992); Myers et al, J. Am. Chem. Soc. 113, 6682-6683 (1991); Shen et al., US Patent No. 5817679; Cordone et al, J. Am. Chem. Soc. I'll 5969-5970 (1989); Jung et al, J. Chem. Soc. Commun. 630-632 (1984); Lay et al, J Am. Chem. Soc. 104, 7658-7659 (1982); Gonzalez et al, J. Am. Chem. Soc. 117, 3405-3421 (1995); Kreher et al., Chem Ber. 125, 183-189 (1992); Simig et al, Synlett. 7, 425-426 (1990); Sha et al, J. Org. Chem. 55, 2446-2450 (1990); Drew et al, J. Chem. Soc., Perkin Trans. 17, 1277-1284 (1985); Kreher et al, Anorg. Chem., Org Chem. 31B, 599-604 (1976); Avalos et al, Tetrahedron Lett. 39, 9301-9304 (1998); Gousse et al, Macromolecules 31, 314-321 (1998); Mikhailyuchenko et al, Khim. Geterotsikl Soedin. 6, 751-758 (1993); Lubowitz et al, US Patent No. 4476184; Padwa et al., J. Org. Chem. 61, 3706-3714 (1996); Schlessinger et al, J. Org. Chem. 59, 3246-3247 (1994); Buchmeiser et al., WO Publication No. 9827423; Tanabe et al., Japanese Patent Document JP 07144477; Mochizucki et al, Japanese Patent Document JP 63170383; Hosoda et al, Japanese Patent Document JP 62053963; Onaka et al, Japanese Patent Document JP 62053964; Kato et al, Japanese Patent Document JP 53086035; Kato et al, Japanese Patent Document JP 51088631; Tottori et al, Japanese Patent Document JP 49124225; Augustin et al., German Patent Document DD101271; Named et al., French Patent Document FR 2031538; Gousse et al, Polym. Int. 48, 723-731 (1999); Padwa et al, J. Org. Chem. 62, 4088-4096(1997); Theurillampem-Moritz et al, Tetrahedron: Asymmetry 7, 3163-3168 (1996); Mathews et al., J. Carbohydr. Chem. 14, 287-97 (1995); Srivastava et al, Natl Acad. Sd. Lett. (India) 15, 41-44 (1992); Mayorga et al, Rev. Cubana Quim. 4, 1-6 (1988); Kondoli et al, J. Chem. Res., Synop. 3, 76 (1987); Primelles et al, Cent. Azucar 7-14 (1985); Solov'eva et al, Khim. Geterotsikl Soedin. 5, 613-15 (1984); Liu et al, Yaqxue Xuebao 18, 752-759 (1983); Joshi et al, Indian J. Chem, Sect. B. 22, 131-135(1983); Amos et al, WO Publication No. 9829495; Odagiri et al, US Patent No. 4670536; Gallucci et al, European Patent Document EP 355435; Redmore, D. US Patent No. 3821232; Nakano et al. Heterocycles 35, 37-40 (1993); Tomisawa et al, Chem. Pharm. Bull 36, 1692-1697 (1988); Krow et al, J. Heterocycl Chem. 22, 131-135 (1985); Krow et al, J. Org. Chem. 47, 1989-1993 (1982); Liu et al., Yaoxue Xuebao 18, 752-759 (1983); Nishikawa et al., Yaoxue Xuebao JP 01061457; and/or Rice et al, J. Med. Chem. 11, 183-185 (1968).

As depicted in Scheme I, d the EN formula II can react with a dienophile of formula III under conditions easily selected average person skilled in the art (for example, heating ("Δ"))to obtain the compound of formula IV, which is a compound of formula I. Intermediate diene of formula II can be obtained from commercial sources or readily prepared by a person skilled in the art, for example, in accordance with the following literary documents and links related to this process: Hofman et al., J. Agric. Food Chem. 45, 898-906 (1997); Baciocchi et al, J. Chem. Soc., Perkin Trans. 28, 821-824 (1975); Wu et al, J. Heterocycles 38, 1507-1518 (1994); Yin et al, Tetrahedron Lett. 38, 5953-5954 (1997); Mic'ovic' et al, Tetrahedron 20, 2279-2287 (1964); Gorbunova et al, J. Org. Chem.. 35, 1557-1566 (1999); Rassu et al, Chem. Soc. Rev. 29, 109-118 (2000); Kaberdin et al, Russ. Chem. Rev. 68, 765-779(1999); Barluenga et al., Aldrichimica Acta 32, 4-15 (1999); Bogdanowicz-Szwedefa et al., Wiad. Chem. 52, 821-842(1998); Casiraghi et al, Adv. Asymmetric Synth. 3, 113-189 (1998); and/or Baeckvall et al, Chem. Rev.98, 2291-2312 (1998). Intermediate dienophile of formula III can be obtained from commercial sources or readily prepared by the average person skilled in the art, for example, in accordance with the following found in literary references: Deshpande et al, Heterocycles 51, 2159-2162 (1999); Seijas et al, J. Chem. Res., Synop. 7, 420-421 (1999); Langer et al, Eur. J. Org. Chem. 7, 1467-1470 (1998); Kita et al, Japanese Patent Document JP 09194458; Lopez-Alvarado et al, J. Org. Chem. 61, 5865-5870 (1996); Condon et al, US Patent No. 5523277; Sasakihara et al, Japanese Patent Document JP 04290868; Igarashi et al, Japanese Patent Document JP 04149173; Aoyama et al, Japanese Patent Document JP 04134063; Aoyama et al, Japanese Patent Document JP 04134062; Pastor et al, J. Org. Chem. 53, 5776-5779 (1988); and/or Takahashi et al, Chem. Lett. 6, 1229-1232(1987).

As depicted in Scheme II, compounds of formula I can be obtained by reaction of a primary amine of the formula V with a substituted intermediate anhydride-like formula VI, for example in a solvent such as acetic acid, with or without heating, which gives the compound of formula IV, which is a compound of formula I. the Primary amines of the formula V can be obtained from commercial sources or readily synthesized with the help of a qualified specialist in this field. Anhydride-like agents of the formula VI can be obtained from commercial sources or readily synthesized with the help of a qualified specialist in this field. The documents included in the following list, describe typical approaches for the synthesis of the intermediate of formula VI, as well as methods of synthesis, which can be applied for the synthesis of compounds of formula IV (all included in the present invention as a reference fully): Kohler, ER; Tishler, M.; Potter, N.; Thompson, N.T. J. Am. Chem. Soc. 1939, 1057-1061; Yur'ev, UK; Zefirov, N.S. J. Gen. Chem. U.S.S.R. (Engl. Transl.) 1961, 31, 772-5; Norman G. Gaylord US Patent No. 3995099; Schueler, P.E.; Rhodes, Y.E. J. Org. Chem. 1974, 39. 2063-9; Ishitobi, H.; Tanida, H; Tsuji, T. Bull. Chem. Soc. Japan 1971, 44, 2993-3000; Stajer, G.; Virag, M.; Szabo, A.E.; Bemath, G.; Sohar, P.; Sillanpaa, R. Ada. Chem. Scand. 1996, 50, 922-30; Hart, H.; Ghosh, T. Tetrahedron Lett. 1988, 29,881-884; Kato, M.; Yamamoto, S.; Yoshihara, T.; Furuichi, K. Miwa, T. Chem. Lett. 1987, 1823-1826; Kottwitz, J.; Vorbruggen, H. Synthesis 1995, 636-37; Creary, X. J. Org. Chem. 1975, 40, 3326-3331; Alder, K.; Ache, H.-J.; Page, F.H. Chem. Ber. 1960, 93, 1888-1895; Toder, B.H.; Branca, S.J.; Dieter, R.K.; Smith, A.B. Ill Synth. Commun. 1975, 5, 435-439; Sprague, P.W.; Heikes, J.E.; Gougoutas, J.Z.; 'malley, M.F.; Harris, D.N.; and/or Greenberg, R. J. Med. Chem. 1985, 28, 1580-1590.

The above-mentioned(e) the approach(s) can be applied to combinatorial methods of producing compounds, for example, using the reaction block with many cells, such as described in Waldemar Ruediger, Wen-Jeng Li, John W., Alien Jr., and Harold N. Weller III, US Patent No. 5961925, Apparatus for Synthesis of Multiple Organic Compounds With Pinch Valve Block (included in the present invention by reference in their entirety entirety). When using the above reaction block with many cells can, for example, be performed in multiple 96 reactions simultaneously. The solvent can then be removed from the reaction tubes without removal from the reaction block and the crude products can be precipitated using such bases as sodium bicarbonate. The balance can be collected by filtering the reaction block, and then the desired products can be transferred directly into the chamber 96 plates for screening. In this way the numerous weight of compounds of formula I can be synthesized and tested, preferably using an automated approach.

Scheme III describes a method of obtaining the intermediate compounds is of formula VI, which can be used for the synthesis of compounds of formula I as described in Scheme II. As described in Scheme III, the diene of formula II can react with a dienophile of formula VII, which gives an intermediate compound of formula VI. The methods used to make this conversion, similar to those described in Scheme I.

Scheme IV describes a method of obtaining the intermediate compounds of formula VI, which can be used for the synthesis of compounds of formula I as described in Scheme II. As shown in Scheme IV, the diene of formula II can react with a dienophile of formula VIII, which gives an intermediate compound of formula IX. The intermediate compound of formula IX can be digidrirovanne to americaphobes intermediate compounds of formula VI. The dehydration of bis-acid intermediate of formula IX can be achieved using a variety of methods known to the skilled person skilled in the art and are described in the following documents and links: Sprague et al, J. Med. Chem. 28, 1580-1590 (1985); and/or Retemi et al, J. Org. Chem. 61, 6296-6301 (1996).

Scheme I no IV describe the General methods of synthesis of compounds of formula I and their intermediate, providing a direct substitution on the ring system, for example at the level of the intermediate diene, a dienophile, americaphobes intermediate and AMI is AGroup. In addition to these approaches further substitution can be performed on the already-obtained compound of formula I using a variety of approaches, which allow to obtain other compounds of formula I. Examples of ways to further substitution described in schemes V to XI.

Scheme V describes one such approach to the implementation of additional substitution in the compound of formula I. As shown in Scheme V, a compound of formula X, which is a compound of formula I, where A1and A2are CR7W is NH-CHR7and Y is CHR7-CHR7may be functionalized by free amino group W by using any of the reactions with a variety of electrophilic agents, such as galodamadruga acids or alkylhalides, in the presence of a base, for example, using methods known to a qualified specialist in this field. In Scheme V, X is a leaving group and a compound of formula XI is a compound of formula I, where A1and a2are CR7W is NR7-CHR7and Y is CHR7-CHR7.

Scheme VI describes an additional approach to the further implementation of the substitution of compounds of formula I. As shown in Scheme VI, the compound of formula XII, which is connected to is of formula I, where A1and a2are CR7W is S-CHR7and Y is CHR7-CHR7may be partially oxidized oxidizing agent such as mCPBA or other agents such as those known to a qualified specialist in this field, which gives sulfoxide analog of formula XIII, which is a compound of formula I, where A1and a2are CR7W are SO-CHR7and Y are CHR7-CHR7. Further processing of the compounds of formula XIII oxidizing agent such as mCPBA or other agents such as those known to a qualified specialist in this field, can give output sulfonovy similar formula XIV, which is a compound of formula I, where A1and a2are CR7W are SO-CHR7and Y are CHR7-CHR7. Alternatively, the compound of formula XII can be converted directly into a compound of formula XIV with a long processing oxidizing agent such as mCPBA or other agents such as those known to a qualified specialist in this field.

Scheme VII describes another approach is the introduction of additional substitution in the compound of formula I. As shown in Scheme VII, a diene of formula IIa may react with a dienophile of formula III, as described in Scheme I, gives the compound of formula IVa, which is a compound of formula I, where Y is O, a2is CR7and A1is-(CH2)q-So the Compound of formula IVa may react with the reagent of formula R12-T'to obtain a compound of formula IVb or IVc, which are compounds of formula I where Y is O, a2is CR and A1is-(CH2)q-T-R12or-(CH2)q-T-R12respectively. The reagent R12-T' can be obtained from commercial sources or can be easily derived by a skilled person in this field.

In the above Scheme, R12has the same meaning as R7defined previously, q is zero or an integer from 0 to 8, and T is defined as (1) nucleophilic center, such as, but without limitation, nitrogen, oxygen, or sulfur-containing group, able to enter into a nucleophilic substitution reaction with the leaving group T'; or (2) leaving the group is able to engage in a nucleophilic substitution reaction with the nucleophilic group T (such as, but without limitation, as nitrogen, oxygen or sulfur-containing nucleophilic group). T' has the same definition that, and So In this case, for example, nucleophilic substitution reaction occurs when the attacking reagent (nucleophile) brings an electron pair to the substrate, using this pair for which obrazovaniya new relationship and leaving group (nucleofug) goes to e-pair, leaving as anionic intermediate connection. A detailed discussion of the mechanism of aliphatic nucleophilic substitution and review specific aliphatic nucleophilic substitution reactions, see Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 4thAddition. Jerry March (Ed.), John Wiley & Sons, New York (1992) 293-500 and related to this, the reference relationship. Compounds of formula IVa, IVb or IVc can of course be used in the methods described in the present invention (mainly, the treatment associated with nuclear hormone receptors diseases)without further reaction T or T'.

An alternative approach to compounds of formula IVa, IVb and IVc is shown in Scheme VIII. For this approach, techniques such as those described in schemes II, III and IV can be applied to obtain the intermediate compounds of formula VIa where T and q have the meanings given in Scheme VII. The intermediate compound of formula VIa can react with substituted amine of the formula V, as described in Scheme II, which gives the compound of formula IVa, which is a compound of formula I, where Y is O, A2is CR7and A1is-(CH2)q-So the Compound of the formula IVa can be processed by the method described in Scheme VII, to obtain the compounds of formula IVb or IVc, which are compounds of formula I, where Y t is is About, And2is CR7and A1is-(CH2)q-T'-R12or-(CH2)q-T-R12respectively.

Scheme IX describes another approach to the introduction of one substitution in the compound of formula I. As shown in Scheme IX (where X is a leaving group), a diene of formula IIb can react with a dienophile of formula III, as described in Scheme I, which gives the compound of formula IVe, which is a compound of formula I, where Y is NH, and A1and a2are CR7. The compound of formula IVe can be functionalized according to the free amine by using reactions with a variety of electrophilic agents, such as galodamadruga acids or alkylhalides in the presence of a base, for example using methods known to the skilled person skilled in the art and described in Scheme V, which gives the compound of formula IVf, which is a compound of formula I, where Y is NR7and A1and a2are CR7.

An alternative approach to compounds of formula IVe and IVf is shown in Scheme X. For this approach, techniques such as those described in schemes II, III and IV can be applied to obtain the intermediate compounds of formula VIb. The intermediate compound of formula VIb can react with zameshannaya formula V, as described in Scheme II, which gives the compound of formula IVe, which is a compound of formula I, where Y is NH, and A1and a2are CR7. The last intermediate connection can be processed by the method described in Scheme V, to obtain the compound of formula IVf, which is a compound of formula I where Y is NR7and A1and a2are CR7.

Scheme XI describes another approach to the introduction of substitution in the compound of formula I. As shown in Scheme XI, the diene of formula IIc can react with a dienophile of formula III, as described in Scheme I, which gives the compound of formula IVg, which is a compound of formula I, where Y is SO, and A1and a2are CR7. The compound of formula IVg can be treated with an oxidizing agent such as mCPBA as described in Scheme VI, which gives the compound of formula IVh, which is a compound of formula I, where Y is the SO2and A1and a2are CR7.

Scheme XII describes another approach to the implementation of the additional substitution of compounds of formula I. As shown in Scheme XII, a compound of formula XV, which can be obtained in accordance with the above schemes, can be incubated in the presence of a suitable enzyme or microorganism, h is about leads to the formation of gidrauxilirovannogo analogue of formula XVI. This process can be applied to implement regiospecifically, as well as enantiospecific the introduction of a hydroxyl group in the molecule of formula XV with a specific microorganism or by using a series of different microorganisms. Such microorganisms can, for example, be natural bacteria, yeast or fungi and can be obtained from distributors, such as ATSS, or identified for use in this way, as well as using methods known to a qualified specialist in this field. Compound XVI is a compound of formula I, where Y has the meanings given above and A1and A2are preferably CR7.

Scheme XIII describes another approach to the implementation of the additional substitution of compounds of formula I. As shown in Scheme XIII, a compound of formula XVII, which can be obtained in accordance with the above schemes, can be incubated in the presence of a suitable enzyme or microorganism, which leads to the formation of diol analogue of formula XVIII. This process can be applied to implement regiospecificity, as well as enantiospecific the transformation of compounds of formula XVII in 1-2 diol of formula XVIII with a specific microorganism or by using a series of different what microorganismos. Such microorganisms can, for example, be natural bacteria, yeast or fungi and can be obtained from distributors, such as ATSS, or identified for use in this way, as well as using methods known to a qualified specialist in this field. Compound XVIII is a compound of formula I, where Y is as described above, and A1and a2are preferably CR7.

The present invention also provides methods described in schemes XII and XIII

Thus, in one embodiment, the present invention provides a method for obtaining compounds of the following formula XVI or salts thereof:

where the radicals defined in the present description,

including the stage of contacting the compounds of formula XV or its salt:

where the radicals defined above;

with an enzyme or microorganism capable of catalyzing hydroxylation of the specified compound XV with the formation of the compounds XVI and initiate the specified hydroxylation.

In another preferred embodiment, the present invention provides a method for obtaining compounds of formula XVIII, or its salt:

where the radicals defined in the present description,

includes article is Dios contacting the compounds of formula XVII, or its salt:

where the radicals defined above;

with an enzyme or microorganism capable of catalyzing the disclosure epoxy ring compounds XVII with the formation of the diol of the compounds XVIII and to initiate the disclosure of the specified ring and the formation of diol.

All stereoconfiguration nonspecific chiral centers of the compounds of formulas XV, XVI, XVII and XVIII considered in the methods of the present invention as an individual (generally available from other stereoisomers) or in a mixture with other stereoisomeric forms. Selective transformation of one isomer (for example, hydroxylation of antisolar preferably before hydroxylation of endosomes) in collaboration isomeric mixture is a preferred embodiment of the invention. Conversion selectively in one isomer (e.g., hydroxylation at extpoverty "antisolar" preferably before andpoverty "endosome" or regioselective disclosure of the epoxide with the formation of only one of the two possible regioisomers TRANS diol) is a preferred embodiment of the invention. Hydroxylation achiral intermediate compounds with the formation of simple optical isomer gidrauxilirovannogo product is also a preferred embodiment of the invention. The splitting of racemic with whom thou intermediate compounds selective hydroxylation or disclosure alexinho ring and the formation of diol to obtain one of two possible optical isomers is also a preferred embodiment of the invention. Used herein, the term "cleavage" refers to a partial, and, preferably, full cleavage.

Used herein, the term "enzymatic process" or "enzymatic method" refers to a process or method of the present invention, using an enzyme or microorganism. Used herein, the term "hydroxylation" means the introduction of a hydroxyl group in the methylene group described above. Hydroxylation may be performed, for example, the interaction of molecular oxygen in accordance with the methods of the present invention. Education diol may be, for example, by interaction with water in accordance with the methods of the present invention. Used in the present methods, the enzyme or microorganism" includes the use of two or more, and one enzyme or microorganism.

The enzyme or microorganism used in the present invention may be any enzyme or microorganism capable of catalyzing enzyme described here transformation. Enzyme or microbial material, regardless of origin or purity, can be used in free form or can be immobilized on a substrate, for example, physical adsorption or capture. Microorganisms or enzymes suitable for use in the present from which Britanie, can be selected by screening for the desired activity, for example, the interaction of the microorganism or enzyme with the reference compound XV or XVII or their salt, and determining the conversion into the corresponding compound XVI or XVIII or its salt. The enzyme may, for example, be a form of animal or vegetable enzymes or their mixtures, cells of microorganisms, crushed cells, extracts of cells or natural origin.

Examples of microorganisms include microorganisms of the class: Streptomyces or Amycolatopsis. Particularly preferred microorganisms are microorganisms type Streptomyces griseus, especially Streptomyces griseus ATCC 10137 and Amycolatopsis orientalis, such as ATCC 14930, ATCC 21425, ATCC 35165, ATCC 39444, ATCC 43333, ATCC 43490, ATCC 53550, ATCC 53630, and especially ATCC 43491. Used here, the term "ATCC" refers to the available number American Type Culture Collection, 10801 University Blvd., Manassas, Virginia 20110-2209, related to Depository microorganism. It is clear that mutants of these organisms are also planned by the present invention for use in the above methods, such as mutants, modified by the use of chemical, physical (e.g. X-rays) or biological means (e.g., methods in molecular biology).

Preferred enzymes include enzymes derived from microorganisms, especially pathogens described above. Enzymes can be the ü is selected, for example, extraction and purification methods, such as methods known to the person skilled in the art. The enzyme may, for example, be used in pure form or in an immobilized form. One of the embodiments of the invention is the enzyme adsorbed on a suitable carrier, for example, mountain flour (porous Celite Hyflo Supercel), microporous polypropylene (Enka Accurel® polypropylene powder) or non-ionic polymeric adsorbent such as Amberlite® XAD-2 (polystyrene) or XAD-7 (polyacrylate) from Rohm and Haas Co. When using immobilized enzyme carrier can determine the particle size of the enzyme and prevent the aggregation of particles of the enzyme when used in an organic solvent. Immobilization can be carried out, for example, by precipitation of an aqueous solution of the enzyme with cold acetone in the presence of Celite Hyflo Supercel, followed by vacuum drying, or when using non-ionic polymeric adsorbent, incubation of solutions of the enzyme with the adsorbent in the mixer, removing excess solution, and drying the enzyme-resin adsorbent in a vacuum. Although the use of the minimum possible amount of enzyme is desired, the required amount of enzyme is strongly dependent on the specific activity of the used enzyme.

Hydroxylation, described above, may occur in vivo. For example, EN zymes the liver can selectively, directly to endosomes, hydroxypyruvate ectosomal compounds of the present invention. When carrying out the methods of the present invention outside of the body as a catalyst can be used enzyme in the microsomal hydroxylase liver.

These methods can also be carried out using microbial cells containing the enzyme, which is able to catalyze transformation. When using microorganisms for conversion of these methods is usually carried out by adding cells and source of raw materials in the required reaction medium.

Where there are microorganisms, cells can be used in the form of intact wet cell or dry cell, for example liofilizovannyh, spray dried or heat dried cells, or treated cellular material, such as damaged cells or cell extracts. Can also be used in cell extracts immobilized on Celite® or Accurel® polypropylene, as described above. It is also possible the use of genetically engineered organisms. The host-cell can be any cell, such as Escherichia coli, modified by inclusion of a gene or genes for the expression of one or more enzymes capable of the above catalysis.

When using one or more microorganisms ferment the e methods of the present invention can be carried out consistently with the fermentation of the microorganism (two-stage fermentation and conversion) or competitive with it, in the latter case is the in situ fermentation and conversion (single-stage fermentation and conversion).

The growth of microorganisms can be performed by a specialist in the art using a suitable environment. Suitable environment for the growth of microorganisms include environments that include nutrients necessary for the growth of microbial cells. Usual environment for growth includes the required carbon sources, nitrogen sources and elements (e.g., in trace quantities). You can also add the inductors. Used here, the term "inductor" includes any compound that causes the appearance of the required enzyme activity in the microbial cell.

The carbon sources may include carbohydrates such as maltose, lactose, glucose, fructose, glycerol, sorbitol, sucrose, starch, mannose, propylene glycol and the like; organic acids such as sodium acetate, sodium citrate and the like; and alcohols such as ethanol, propanol and the like.

The nitrogen sources may include N-Z amine A, water corn extract, flour soybean, meat extracts, yeast extracts, molasses, Baker's yeast, tripton, nutrisol, peptone, yeast amine, amino acids such as sodium glutamate and the like, sodium nitrate, ammonium sulfate and the like.

Trace elements can be made with the Lee magnesium, manganese, calcium, cobalt, Nickel, iron, sodium and potassium. Phosphates can also be added in trace or, preferably, more than trace quantities.

Used environment may include more than one source of carbon or nitrogen or other nutrient.

The preferred environment for growth includes the aquatic environment.

Agitation and aeration of the reaction mixture makes available the amount of oxygen in the ongoing process of transformation, for example, in cultures, shaking the flask, or enzymatic tanks during the growth of microorganisms.

Incubation of the reaction medium takes place preferably at a temperature of between about 4 and about 60°C. the reaction Time may be selected depending on the quantity used of the enzyme and its specific activity. The reaction time can be reduced by increasing the reaction temperature and/or increasing the amount of enzyme added to the reaction solution.

Preferred is also the use of water as the reaction mixture, although it can also be used organic liquid that is miscible or immiscible (bi-phase) organic/aqueous liquid mixture. The amount of enzyme or microorganism used relative to the source of raw materials, chosen to provide the catalysis of enzymatic transformations this is the first invention.

Solvents for the organic phase of the biphasic system solvent may be any organic solvent immiscible with water such as toluene, cyclohexane, xylene, trichlorotrifluoroethane and the like. The aqueous phase is usually water, preferably deionized water or a suitable aqueous buffer solution, especially phosphate buffer solution. The bi-phase solvent system preferably contains between about 10 to 90 percent by volume of the organic phase and between about 90 to 10 percent by volume of the aqueous phase and preferably contains 20 percent or so by volume of the organic phase and 80 percent or so by volume of the aqueous phase.

Exemplary embodiments of such methods begin with the receipt of the used aqueous solution of enzyme(s) or microbes. For example, the preferred enzyme(s) or microbes can be added to a suitable amount of an aqueous solvent, such as phosphate buffer and the like. This mixture preferably lead and support when required pH.

Compounds XVI and XVIII, obtained by the methods of the present invention, can stand out and be purified, for example, various methods such as extraction, distillation, crystallization and column chromatography.

The preferred Connection

Preferred palpography connect the developments of the present invention, include the compounds of formula I or their salts in which one or more, preferably all, have the following substituents, which are defined below:

G is an aryl or heterocycle (e.g., heteroaryl) group, where the group is a mono - or polycyclic group which is optionally substituted by one or more positions, preferably with hydrogen, alkyl or substituted alkyl, alkenyl or substituted by alkenyl, quinil or substituted by quinil, halogen, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, arylalkyl or substituted by arylalkyl, heterocyclization or substituted by heterocyclization, CN, R1OC=O, R1C=O, R1HNC=O, R1R2NC=O, HOCR3R3', nitro, R1OCH2, R1O, NH2, NR4R5S=OR1, SO2R1, SO2NR1R1', (R1)(1R1')P-O or (R1')(Other1)P=O;

Z1represents O, S, NH or NR6;

Z2represents O, S, NH, or NR6;

A1represents CR7or N;

And2represents CR7or N;

Y is J-J'-J"where J is a (CR7R7')n and n=0-3, ' is a bond or O, S, S=O, SO2, NH, OS=O, C =O, NR7, CR7R7'. R2P=O, R2P=S, R2OP=O, R2NHP=O, OP=OOR2OP=ONHR2, OP=OR2, OSO2, NHNH, NHNR, NR6NH, N=N, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or heterocycle or substituted heterocycle, and J" is (CR7R7')n and n=0-3, where Y is not a bond;

W represents CR7R7'-CR7R7', CR7R7'-C=O, NR9-CR7R7'- N =CR8N =N,NR9-

NR9'cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle or aryl or substituted aryl, in this case, when W is NR9CR7R7'- N=CR8N=N, NR9-NR9' or heterocycle or substituted heterocycle, then J' must be O, S,S=O, SO2, NH, NR7, OP=OR2OP=ONHR2, OSO2, NHNH, NHNR6, NR6NH, or N=N;

Q1represents H, alkyl or substituted alkyl, alkenyl or substituted

alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, arylalkyl or substituted arylalkyl, quinil or substituted quinil, aryl or substituted aryl, heterocycle (for example, heteroaryl) or substituted heterocycle (e.g. the measures substituted heteroaryl), halogen, CN, R1OC=O, R4C=O, R5R6NC=O, HOCR7R7', nitro, R1OCH2, R1O, NH2or NR4R5;

Q2represents H, alkyl or substituted alkyl, alkenyl or replaced alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, arylalkyl or substituted arylalkyl, quinil or substituted quinil, aryl or substituted aryl, heterocycle (for example, heteroaryl) or substituted heterocycle (for example, substituted heteroaryl), halogen, CN, R1OC=O, R4C= O, R5R6NC=O, HOCR7R7', nitro, R1OCH2, R1O, NH2or NR4R5;

L is a bond, (CR7R7')n, NH, NR5or NR(CR7R7')n, where n =0-3;

R1and R1each independently is H, alkyl or substituted alkyl, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylation or substituted by cycloalkylation, cycloalkenyl or substituted by cycloalkylation, heterocyclization or substituted by heterocyclization, aryl or substituted aryl, arylalkyl or substituted by arylalkyl;

R2is the th alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl;

R3and R3'each independently is H, alkyl or zameshannym-alkyl, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylation or substituted by cycloalkylation, cycloalkenyl or substituted by cycloalkylation, heterocyclization or substituted by heterocyclization, aryl or substituted aryl, arylalkyl or substituted by arylalkyl, halogen, CN, hydroxylamine, hydroximino, alkoxy or substituted alkoxy, amino, NR1R2, thiol, alkylthio or substituted, alkylthio;

R4represents H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl,arylalkyl or substituted arylalkyl, R1C=O, R1NHC=O or SO2NR1R1';

R5represents an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R1C=O, R1NHC=O, SO2R1or SO2NR1R1';

R6represents an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, CN, IT, OR1, R1C=O, R1NHC=O, SO2R1or SO2NR1R1';

R7and R7each independently is H, alkyl or substituted alkyl, alkenyl or substituted by alkenyl, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylation or substituted qi is alkylalcohol, cycloalkylation or substituted by cycloalkylation, heterocyclization or substituted by heterocyclization, aryl or substituted aryl, arylalkyl or substituted by arylalkyl, halogen, CN, OR1, nitro, hydroxylamine, hydroxylamines, amino, other4, NR2R5, NOR1, thiol, alkylthio or substituted, alkylthio, R1C =O, R1OC=O, R1NHC=O, SOR1, PO3R1R1', R1R1'NC=O, C=OSR1, SO2R1or SO2NR1R1';

R8and R8each independently is H, alkyl or substituted alkyl, alkenyl or substituted by alkenyl, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylation or substituted by cycloalkylation, cycloalkenyl or substituted by cycloalkylation, heterocyclization or substituted by heterocyclization, aryl or substituted aryl, arylalkyl or substituted by arylalkyl, nitro, halogen, CN, OR1, amino, other4, NR2R5, NOR1alkylthio or substituted, alkylthio,=OSR1, R1OS=O, R1C=O, R1NHC=O, R1R1'NC=O, S=OR1, SO2R1, PO3R1R1' or SO2NR1R1';

R9and R9each independently is H, Alky the om or substituted by alkyl, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylation or substituted by cycloalkylation, cycloalkenyl or substituted by cycloalkylation, heterocyclization or substituted by heterocyclization, aryl or substituted aryl, arylalkyl or substituted by arylalkyl, CN, IT, OR1, R1C=O, R1OC=O, R1NHC=O or SO2NR1R1';

where, in particular, the groups W and Y in these preferred subgroups have values that are included in the definition of W' and Y' of the formula Ia, when the conditions from (1) to (14) for the indicated compounds of formula Ia, are appropriate for these groups, and most preferably, when (i) Y' represents-O -, and W' represents CR7R7'-CR7R7', A1and a2are not both CH; and (ii) when L is a bond, G is not an unsubstituted phenyl group.

Other more preferred subgroup of compounds of the present invention include compounds of formula I or their salts in which one or more, preferably all the substituents have the meanings are the same as defined below:

G is an aryl or heterocycle (e.g., heteroaryl) group, where the group is a mono - or polycyclic group, the which is optionally substituted by one or more of the provisions preferably hydrogen, alkyl or substituted alkyl, alkenyl or substituted by alkenyl, quinil or substituted by quinil, halogen, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, arylalkyl or substituted by arylalkyl, heterocyclization or substituted by heterocyclization, CN, R1C=O, R1HNC=O, R1R2NC=O, HOCR3R3', nitro, R1OCH2, R1O, NH2, NR4R5, SO2R1or SO2NR1R1';

Z1represents About;

Z2represents About;

A1represents CR7;

And2represents CR7;

Y is J-J'-J"where J is a (CR7R7')n and n=0-3, J' is a bond or O, S, S=O, SO2, NH, NR7, CR7R7', R2P=O, R2P=S, R2OP=O, R2NHP= O, OP=OOR2OP=ONHR2, OP=OR2, OSO2, NHNH, NHNR6, NR6NH, N=N, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, or heterocycle or substituted heterocycle, and J" is (CR7R7')n and n=0-3, where Y is not a bond;

W represents CR7R7'-CR7R7', CR7R7'=O, NR9-CR 7R7'- N=CR8N=N, NR9-NR9'cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, or aryl or substituted aryl, where, when W is NR9-CR7R7'- N=CR8N=N, NR9-NR9'or heterocycle or substituted heterocycle, then J' must be O, S, S=O, SO2, NH, NR7, RR=OOR2, RR=ONHR2, OSO2, NHNH, NHNR6, NR6NH, or N =N;

Q1represents H, alkyl or substituted alkyl, alkenyl or substituted

alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, arylalkyl or substituted arylalkyl, quinil or substituted quinil, aryl or substituted aryl, heterocycle (for example, heteroaryl) or substituted heterocycle (for example, substituted heteroaryl), halogen, CN, R4C=O, R5R6NC=O, HOCR7R7', nitro, R1OCH2, R1O, NH2or NR4R5;

Q2represents H, alkyl or substituted alkyl, alkenyl or replaced alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, arylalkyl or substituted arylalkyl, quinil or substituted quinil, aryl or for ewenny aryl, heterocycle (for example, heteroaryl) or substituted heterocycle (for example, substituted heteroaryl), halogen, CN, R4C=O, R5R6NC=O, HOCR7R7', nitro, R1OCH2, R1O, NH2or NR4R5;

L is a bond;

R1and R1' each independently is H, alkyl or substituted alkyl, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylation or substituted by cycloalkylation, cycloalkenyl or substituted by cycloalkylation, heterocyclization or substituted heterocycle the alkyl, aryl or substituted aryl, arylalkyl or substituted by arylalkyl;

R2represents an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl;

R3and R3' each independently is H, alkyl or substituted alkyl, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, heterocycle elizabetn heterocycle, cycloalkylation or substituted by cycloalkylation, cycloalkenyl or substituted by cycloalkylation, heterocyclization or substituted by heterocyclization, aryl or substituted aryl, arylalkyl or substituted by arylalkyl, halogen, CN, alkoxy or substituted alkoxy, amino, NR1R2alkylthio or substituted, alkylthio;

R4represents H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R1C=O, R1NHC=O, or SO2NR1R1';

R5represents an alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, R1C=O, R1NHC=O, SO2R1or SO2NR1R1';

R6represents lkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocycle or substituted heterocycle, cycloalkyl or substituted cycloalkenyl, cycloalkenyl or substituted cycloalkenyl, heteroseksualci or substituted heteroseksualci, aryl or substituted aryl, arylalkyl or substituted arylalkyl, CN, IT, OR1, R1C=O, R1NHC=O, SO2R1or SO2NR1R1';

R7and R7' each independently is H, alkyl or substituted alkyl, alkenyl or substituted by alkenyl, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylation or substituted by cycloalkylation, cycloalkenyl or substituted by cycloalkylation, heterocyclization or substituted by heterocyclization, aryl or substituted aryl, arylalkyl or substituted by arylalkyl, halogen, CN, OR1, nitro, amino, other4, NR4R5alkylthio or substituted, alkylthio, R1C=O, R1NHC=O, SO2R1, R1R1'NC=O, or SO2NR1R1';

R8and R8'each independently is H, alkyl or substituted alkyl, alkenyl or substituted by alkenyl, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or someseni what cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylation or substituted by cycloalkylation, cycloalkenyl or substituted by cycloalkylation, heterocyclization or substituted by heterocyclization, aryl or substituted aryl, arylalkyl or substituted by arylalkyl, nitro, halogen, CN, OR1, amino, other4, NR2R5alkylthio or substituted, alkylthio, R1C= O, R1NHC=O, R1R1'NC=O, SO2R1or SO2NR1R1'; and

R9and R9'each independently is H, alkyl or substituted alkyl, cycloalkyl or substituted by cycloalkyl, cycloalkenyl or substituted by cycloalkenyl, heterocycle or substituted heterocycle, cycloalkylation or substituted by cycloalkylation, cycloalkenyl or substituted by cycloalkylation, heterocyclization or substituted by heterocyclization, aryl or substituted aryl, arylalkyl or substituted by arylalkyl, CN, IT, OR1, R1C=O, R1NHC=O or SO2NR1R1';

in particular, where the groups W and Y of these preferred subgroups are also included in the definition of W' and Y' of the compounds of formula Ia, when the conditions from (1) to (14) for the indicated compounds of formula Ia, which correspond to these subgroups and most preferably, (i) when Y' represents-O -, and W' represents CR7/sup> R7'-CR7R7', A1and A2are not both CH; and (ii) When L is a bond, G is not an unsubstituted phenyl group.

Especially preferred subgroup of the compounds of the present invention includes compounds of formula I or their salts in which one or more, preferably all the substituents have the meanings are the same as defined below:

G represents aryl (especially phenyl or naftalina) or heterocycle (especially those heterologue G of the compounds listed in the examples of the present invention) group, where the group is a mono - or polycyclic group which is optionally substituted by one or more positions, preferably substituents, as illustrated on any sample for any of the compounds in the present invention;

L is a bond, (CR7R7' )n (where n is 1 and R7and R7' each independently is H, alkyl or substituted alkyl), or-CH2-NH-;

And1and a2each is independently CR7where R7(i) represents hydrogen, alkyl or substituted alkyl, arylalkyl or substituted arylalkyl, alkenyl or replaced alkenyl (for example, alkenyl, substituted aryl (mainly, phenyl or aftilova) or zames the config aryl or alkenyl, substituted heterocycle or substituted heterocycle), aryl or substituted aryl, heterocycle or substituted heterocycle, heteroseksualci or substituted heteroseksualci, where for each preferred substituents are one or more groups selected from V1(in particular, A1and a2group of the formula CR7where R7for each A1and/or And2is independently selected from C1-4of alkyl, which alkyl is substituted with one or more groups V1), or (ii) forms, together with R7from the group of W (in particular, where W represents CR7R7'-CR7R7'), heterocyclic ring;

V is a HE, CN, halogen, -O-aryl, -O-substituted aryl, -O-heterocycle,

-O - substituted heterocycle, -O-CO-alkyl, -O-CO-substituted alkyl, -O-(alkylsilane), -O-arylalkyl, -O-substituted arylalkyl, -O-CO-alkyl, -O-CO-substituted alkyl, -O-CO-arylalkyl, -O-CO-substituted arylalkyl, -O-CO-aryl, -O-CO-substituted aryl, -O-CO-heterocycle, -O-CO-substituted heterocycle, -S-(optionally substituted aryl)-NH-CO-(optionally substituted alkyl), -SO-(optionally substituted aryl)-NH-CO-(optionally substituted alkyl), -SO2-(optionally substituted aryl)-NH-CO-(optionally substituted alkyl), -NH-SO2-aryl, -NH-SO2-substituted aryl, -NH-CO-O-(optional someseni arylalkyl), -NH-CO-O-alkyl, -NH-CO-O-substituted alkyl, -NH-CO-alkyl, -NH-CO-substituted alkyl, -NH-CO-aryl, -NH-CO-substituted aryl, -NH-CO-(optionally substituted arylalkyl), -NH-CO-(optionally substituted alkyl)-O-(optionally substituted aryl), -N(optionally substituted alkyl)(optionally substituted aryl), -N(optionally substituted alkyl)(optionally substituted arylalkyl), -SLEEP, -COOH, -CO-O-alkyl, -CO-O-substituted alkyl, -CO-O-optionally substituted arylalkyl, -CO-aryl, CO-substituted aryl, -O-CO-NH-aryl, -O-CO-NH-substituted aryl, -CO-NH-aryl, -CO-NH-substituted aryl, -CO-NH-arylalkyl, -CO-NH-substituted arylalkyl, -O-(optional substituted aryl)-NH-CO-(optionally substituted alkyl);

Y represents-O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N(alkyl)-, -CH2-S-, -CH2-SO2-;

V2represents hydrogen, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl;

W represents CR7R7'-CR7R7' (where R7and R7' each represents independently selected from H, HE, alkyl or substituted alkyl (such as hydroxyalkyl) or, where R7forms a heterocyclic ring together with R7from A1or A2), CR8=CR8(where R8and R8' each represents independently selected from H, alkyl or substituted alkyl (such as hydroxyalkyl)), CR7R7'-C=O where R 7and R7' each is hydrogen or, where R7forms a heterocyclic ring together with R7from A1or a2), N=CR8(where R8represents alkyl), cycloalkyl or substituted cycloalkyl or heterocycle or substituted heterocycle;

Z1and Z2predstavljaet a; Q1and Q2predstavljaet a N.

Preferred G-L groups are optionally substituted naphthyl and optionally substituted condensed-bicyclic heterocyclic group such as optionally substituted benzo-condensed heterocyclic groups (for example, attached to the remainder of the molecule through the benzene portion), in particular such groups represent a group, where the heterocyclic ring associated with benzene has 5 members, such as benzoxazole, benzothiazole, benzothiadiazole, benzoxadiazole or benzothiophen, for example:

or

where X = halogen (especially F), OH, CN, NO2/sub> or

,or;

U represents O or S (where S may optionally be oxidized, for example, to SO);

U1represents CH3or CF3;

each U2independently is N, CH or CF;

U3represents N, O or S;

U4and U5together with the atoms to which they are linked, form an optionally substituted 5-membered heterocyclic ring which may be partially unsaturated or aromatic and which contains from 1 to 3 ring heteroatoms;

each U6independently represents CH or N; and

means optional(s) double(s) relationship(s) within the ring formed by using U3U4and U5.

Especially preferred subgroup includes the compounds of formula I of the following formula or its salt:

where G is an optionally substituted naphthyl or benzododecinium bicyclic heterocyclic group, R7represents CH3or1-4alkyl, substituted with V and R7'represents H or hydroxyl.

Compounds where R7'represents hydroxyl, can provide increased rastvorimost is in the water and metabolic stability, with respect to the corresponding compounds where R7'represents H, in addition to the good accessibility and high systemic levels of blood. These compounds carrying hydroxyl, can be obtained in vivo by metabolism of the corresponding compounds where R7'represents H, as well as using synthetic methods of preparation, such as those described in the present invention.

The use and usefulness

Compounds of the present invention modulate the function of receptors nuclear hormone (other) and include compounds which are, for example, agonists, partial agonists, antagonists or partial antagonists androgenous receptor (AR), estrogen receptor (ER), progesterone receptor (PR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), receptor of the steroid and xenobiotic (SXR), another steroid associated with other, Ivanovich receptors or other other. Preferred is a selective modulation of one of these other associated with the other of the other family. "Modulation" includes, for example, the activation (e.g., agonistic activity, such as selective agonistic activity towards androgenovmi receptor), or inhibition (e.g., antagonistic activity).

Compounds according to the invention, after vetelino, can be useful for the treatment connected with other States. "Associated with other condition", as used here, denotes a condition or disease that can be treated by modulating the functions of the other subject where treatment includes prevention (e.g., prophylactic treatment), partial relief or complete cure of the condition or disease. Modulation may occur locally, for example, in certain tissues of the subject, or more widely around the subject on the recovery from this state of the disease.

Compounds of the present invention are useful for treating many conditions and diseases, including, but not limited to, the following:

The compounds of formula I may be used as agonists, partial agonists, antagonists or partial antagonists of the estrogen receptor, preferably selectively in relation to this receptor, in many medical conditions which involve modulation of the path of the estrogen receptor. Applications of these compounds include, but are not limited to: osteoporosis, hot flashes, vaginal dryness, prostate cancer, breast cancer, endometrial cancer, cancers caused by the estrogen receptor, such as the aforementioned cancers and other, contraception, abortion, menopause, amenorrhea and dysmenorrhea.

Link the formula I can be used as agonists, partial agonists, antagonists or partial antagonists of the progesterone receptor, preferably selectively in relation to this receptor, in many medical conditions which involve modulation path progesterone receptor. Applications of these compounds include, but are not limited to: breast cancer, other cancers, including progesterone receptor, endometriosis, cachexia, contraception, menopause, cyclosiloxane, menigioma, dysmenorrhea, fibroids, abortion, induction of childbirth and osteoporosis.

The compounds of formula I may be used as agonists, partial agonists, antagonists or partial antagonists of the glucocorticoid receptor, preferably selectively in relation to this receptor, in many medical conditions which involve modulation of the path of the glucocorticoid receptor. Applications of these compounds include, but are not limited to: inflammatory diseases, autoimmune diseases, prostate cancer, breast cancer, Alzheimer's Disease, mental illness, drug dependency, insulin-independent diabetes mellitus, and as blocking agents dopamine receptor or as agents for the treatment of diseases mediated by the dopamine receptor.

The compounds of formula I can use is as agonists, partial agonists, antagonists or partial antagonists mineralocorticoid receptor, preferably selectively in relation to the receptor, in many medical conditions which involve modulation path mineralocorticoid receptor. Applications of these compounds include, but are not limited to: drug abstinence and inflammatory diseases.

The compounds of formula I may be used as agonists, partial agonists, antagonists or partial antagonists of aldosterone receptor, preferably selectively in relation to this receptor, in many medical conditions which involve modulation path aldosterone receptor. One of the applications of these compounds include, but are not limited to them: cumulative heart failure.

The compounds of formula I may be used as agonists, partial agonists, antagonists or partial antagonists androgenous receptor, preferably selectively in relation to this receptor, in many medical conditions which involve modulation path androgenous receptor. Applications of these compounds include, but are not limited to: hairiness, acne, seborrhea, Alzheimer's disease, androgenic alopecia, hypogonadism, hypergonadism, EXT is kachestvenna hypertrophy of the prostate, adenoma and neoplasia of the prostate (such as advanced metastatic prostate cancer), treatment of benign or malignant cancer cells containing androgeny receptor, such as with cancer of the breast, brain, skin, ovarian, bladder, lymphatic, liver and kidney, pancreatic modulation of VCAM expression and their application for the treatment of heart diseases, inflammatory and immune modulation, modulation of VEGF expression and their application for use in ambulatory patients as antiangiogenic agents for osteoporosis, suppressing sperm count, libido, cachexia, endometriosis, polycystina ovarian syndrome, anorexia, maintaining the level of androgen age-related decrease in testosterone levels in men, female menopause, male hormone replacement, male and female sexual dysfunction and inhibition of muscular atrophy. For example, it is assumed AR modulation, particularly preferably selective AR modulation of the prostate ("SARM"), such as in the treatment of early stage prostate cancer.

The compounds of formula I can be used as a (preferably selective) antagonists mutated androgenous receptor, for example, are found in many types of tumors. Examples of such mutants detected in cell lines representing prostate cancer, such as LCap, (T877A mutation, Biophys. Acta, 187, 1052 (1990)), PCa2b, (L701H and T877A mutation, J. Urol, 162, 2192 (1999)) and CWR22, (H874Y mutation, Mol. Endo., 11, 450 (1997)). Applications of these compounds include, but are not limited to: adenomas and neoplasias of the prostate, breast cancer and endometrial cancer.

The compounds of formula I may be used as agonists, partial agonists, antagonists or partial antagonists of the receptor of the steroid and xenobiotic, preferably selectively in relation to this receptor, in many medical conditions which involve modulation of the path of the receptor of the steroid and xenobiotic. Applications of these compounds include, but are not limited to: treatment of deregulirovania cholesterol homeostasis, impaired metabolism of pharmaceutical agents in the joint introduction of an agent (compound of the present invention), which modulates the P450 regulatory actions SXR.

Together with the above other there are also a number of other, which cannot be characterized by activating or deactivating the ligands. These proteins are classified as other because of their strong sequence homology with other other, and is known as ivanovii receptors. Because ivanovii receptors show strong sequence homology with other other, the compounds of formula I include those that act as modulators of the function of fanovich other. Ivanovii receptors that modulate other modulators, such as compounds within formula I are those, which are shown in Table 1, but not limited to. Examples of therapeutic applications of these modulators Ivanovich receptors are also presented in Table 1, but are not limited to these examples.

The present invention also relates to methods of treating conditions associated with other, including the stage of introduction to a subject in need this, at least one of the compounds of formula I in effective amounts. In these methods, the compounds according to the invention can be used with other therapeutic agents, such as agents, described below (e.g., separately or in the same composition as the fixed dose). In the methods of the present invention, such other therapeutic agent(s) may be entered in advance, together or after the introduction of compounds) of the present invention.

The present invention also relates to pharmaceutical compositions comprising at least one of the compounds of formula I, is able to treat the condition associated with the other, in effective amount, and a pharmaceutically acceptable carrier (binder or diluent). Compositions of the present invention may contain other therapeutic agents as described below, and may be, for example, using conventional solid or liquid binders or diluents, as well as pharmaceutical additives suitable for this route of administration (for example, excipients, fillers, preservatives, stabilizers, perfumes, etc. in accordance with methods well known in the field for the pharmaceutical the ski trains.

It should be noted that the compounds of the present invention, without limiting the mechanism of their action, are useful for treating any of the conditions or diseases or those listed here, such as inflammatory diseases or cancer, or other proliferative diseases, and in compositions for the treatment of such conditions or diseases. Such conditions and diseases include, without limitation, any previously described, and the conditions and diseases described later, such as: maintaining strength and muscle function (for example, during aging); treatment or prevention of frailty or functional disorders, age-related ("ARFD") in aging (e.g., sarcopenia); treatment of catabolic side effects of glucocorticoids; prevention and/or treatment to reduce bone mass, density or growth (e.g., osteoporosis and osteopenia); treatment of chronic fatigue syndrome (CFS); chronic malaria; treatment of syndrome acute fatigue and loss of muscle mass due to elective surgery (e.g., surgical rehabilitation); accelerating healing of wounds; the acceleration of the accretion of bone tissue (such as accelerating the recovery of patients with fractures of the hip); accelerate the treatment of complicated fractures, e.g. distraction osteogenesis; to replace joints; the prevention of the formation of p is chirurgicale adhesion; the accelerated restoration or tooth growth; maintenance of sensory function (e.g., hearing, sight, smell, and taste); treatment of periodontal disease; treatment of wasting caused by fractures, and cachexia associated with chronic obstructive pulmonary disease (COPD), chronic liver disease, AIDS, weight loss, cancer cachexia, recovery from burns and injuries, chronic catabolic state (e.g., coma), diseases associated with food intake (e.g., anorexia) and chemotherapy; treatment of cardiomyopathy; treatment of thrombocytopenia; treatment of growth deceleration associated with Crohn's disease; treatment short intestinal syndrome; treatment of irritable intestinal syndrome; treatment of inflammatory bowel disease; treatment of Crohn's disease and ulcerative colitis; treatment of complications associated with transplantation; treatment of physiological short, including growth hormone deficiency in children and small in stature associated with chronic illness; treatment of obesity and stunting associated with obesity; treatment of anorexia (e.g., associated with cachexia or age); treatment of hypercortisolism and syndrome Kushinga; disease Paget; treatment of osteoarthritis; strengthening the pulsating release of growth hormone treatment osteochondrodysplasias; treatment of depression, nervousness, sec is aiternate and stress; treatment of reduced mental energy and low self-esteem (e.g., motivation/statement); improvement of cognitive function (e.g., treatment of dementia, including Alzheimer's disease and short term memory loss); treatment of catabolism associated with pulmonary dysfunction and oxygen dependency; treatment of cardiac dysfunction (e.g., associated with disease blemish valves, heart attack myocardi, cardiac hypertrophy or congested heart failure); lowering blood pressure; protection against ventricular dysfunction or prevention of reperfusion; the treatment of the elderly chronic dialysis; cessation or slowing of the catabolic state of aging; attenuation or termination of protein catabolic responses due to injury (for example, stopping the catabolic state associated with surgery, congested heart failure, cardiac myopathy, burns, cancer, COPD etc); reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; treatment of hyperinsulinemia including nesidioblastosis; treatment immunosuppressing patients; treatment of wasting associated with multiple sclerosis or other neurodegenerative disease; increased allocation of myelin repair; maintenance of skin thickness; treatment of m is tablecache homeostasis and renal homeostasis (e.g., when painful aging); stimulation of osteoblasts, reverse engineering of bone and cartilage; the regulation of food intake; treatment of insulin resistance, including NIDDM, in mammals (e.g., humans); treatment of insulin resistance in the heart; improvement of sleep quality and correction of the relative senile hyposomatotropism, due to the strong increase in REM sleep and decreased REM flush status; treatment of hypothermia; treatment of congested heart failure; treatment of lipodystrophy (e.g., patients suffering from HIV or AIDS, such as protease inhibitors); treatment of muscular atrophy (e.g., due to physical inactivity, bed mode or condition of reduced weight); treatment of muscular-skeletal injuries (e.g., aging); the improvement of the overall pulmonary function; treatment of sleep and the treatment of the catabolic state of prolonged critical illness; treatment of polosatosti, acne, seborrhea, androgenic alopecia, anemia, hyperboloidal, benign hypertrophia prostate adenomas and neoplasias of the prostate (for example, extensive metastatic prostate cancer) and malignant tumor cells containing androgeny receptor, such as with cancer of the breast, brain, skin, ovarian, bladder, lymphatic, liver and kidney damage; skin cancer, pancreatic cancer, e is dometria, lung and colon; osteosarcoma; malignant hypercalcemia; metastasian bone disease; treatment of spermatogenesis, endometriosis and polycystinea ovarian syndrome; late toxemia, eclampsia of pregnancy and interruption of delivery; treatment of premenstrual syndrome; treatment of vaginal dryness; decreased levels of testosterone associated with age, male menopause, hypogonadism, the substitution of male hormones, male and female sexual dysfunction (e.g., erectile dysfunction, reduced sexual desire, sexual status, decreased libido), male and female contraception, hair loss syndrome Riven and increasing mobility/strength of bones and muscles and condition, disease and disorder, together called "syndrome X" or metabolic syndrome, described Johannsson.Z Clin. Endocrinol. Metab., 82, 727-34 (1997).

Compounds according to the invention have therapeutic activity in modulating the activation/proliferation of immune cells, such as competitive inhibitors of the reactions of the extracellular ligand/receptor binding, including HIMSELF (cell adhesion molecules) and LaMontagne. For example, the compounds of the invention modulate LFA-1 and ICAM are particularly useful as LFA-ICAM 1 antagonists for the treatment of all conditions associated with LFA-ICAM 1, such as immune the disease. The preferred use of the compounds according to the invention include, but are not limited to: inflammatory condition, such as the status in the response of non-specific immune system in a mammal (for example, age-related respiratory stress syndrome, shock, oxygen toxicity syndrome multiple damage to organs due to septicemia, a syndrome of multiple lesions of organs as a result of trauma, tissue damage due to cardiovascular bypass, heart attack myocardi or the use of thrombolytic agents, acute glomerulonephritis, vasculitis, reactive arthritis, dermatitis with acute inflammatory components, paralysis, thermal injury, hemodialysis, leikaferez, ulcerative colitis, necrotizing enterocolitis and syndromes, associated with the transfusion of granulocytes) and conditions resulting from a response of the specific immune system in a mammal (e.g., psoriasis, rejection of organ/tissue graft, a reaction against the graft and autoimmune diseases, including syndrome Raynaud, autoimmune thyroiditis, dermatitis, multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, uoit, inflammatory disease of the intestines, including Crohn's disease and ulcerative colitis and systemic lupus erythematosus). Connection to izopet the tion can be used to treat asthma or as a Supplement to reduce toxicity when phytocenology therapy in the treatment of cancer. Compounds according to the invention can be used for the treatment of all diseases that are currently treated with steroid therapy. Compounds according to the invention can be used to treat these and other diseases separately or together with other immunosuppressive or anti-inflammatory agents. In accordance with the invention, the compound of formula I may be administered prior to the beginning of the inflammation (the expected suppression of inflammation) or after the onset of inflammation. Prophylactic use of immunosuppressive compound(I) is preferably introduced to prevent any inflammatory response or symptom (e.g., pre, during or shortly after transplantation of an organ or tissue, but in order to prevent any symptoms or rejection). Prophylactic administration of compounds of formula I, prevents or reduces any subsequent inflammatory response (such as, for example, rejection of the transplanted organ or tissue, and so on). Introduction the compounds of formula I reduces any acute inflammation (such as, for example, rejection of the transplanted organ or tissue).

The compounds of formula I can be any described herein means any suitable means, for example, orally in the form of tablets, capsules, granules or powders; sublingually; buccal; paren eraldo, for example, subcutaneously, intravenously, intramuscularly, or intrasternally injection or infusion methods (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasal, including introduction to nasal membranes, for example, by inhalation spray; topically, in the form of a cream or ointment; or rectally, for example in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable binders or diluents. Compounds according to the invention can for example be in the form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising compounds according to the invention, or, especially in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. Compounds according to the invention can also be administered liposomal.

Examples of compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting volume, alginic acid or sodium alginate as a suspending agent, methylcellulose as an amplifier viscosity and sweeteners or flavors, known from the prior techniques is; and tablets of immediate release, which may contain, for example, microcrystalline cellulose, calcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, fillers, enlargers volume, disintegrating agents, diluents and lubricants known from the prior art. The compounds of formula I can also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or tablets obtained by freeze-drying are examples of forms that can be used. Examples of compositions include compositions containing compound(I) according to the invention with a rapidly dissolving diluents such as mannose, lactose, sucrose and/or cyclodextrins. In such compositions may include excipients with high molecular weight, such as cellulose (avicel) or polyethylene glycol (PEG). Such compositions can also include excipient that mediate through the mucous membrane, such as hydroxypropylcellulose (LDCs), hypromellose (receiver array), carboxymethylcellulose sodium (SCMC), a copolymer of maleic anhydride (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (for example Carbopol 934). Can also be added lubricants, agents for slide, perfumes, beautiful girl who ate and stabilizers for ease of manufacture and use.

Examples of compositions for nasal aerosol or inhalation include saline solutions, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solvent or dispersing agents known in the prior art.

Examples of compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannose, 1,3-butanediol, water, Ringer, isotonic solution of sodium chloride or other suitable dispersing or moisturizing and suspendresume agents, including synthetic mono - or diglycerides, and fatty acids, including oleic acid, or cremaphor.

Examples of compositions for rectal injection include candles, which can contain, for example, suitable non-irritating excipient, such as cocoa butter, synthetic glycerol esters or polyethylene glycols, which are solid at ordinary temperatures, but become liquid and/or dissolve in the rectal cavity to release the drug.

Examples of compositions for the local introduction include local media, such as Plastibase (mineral oil, gelatinizes the cell polyethylene).

An effective amount of the compounds of the present invention can be determined by a person skilled in the art, and includes exemplary dosage amounts for an adult human of from about 1 to 100 (e.g., 15) mg/kg of body weight of active compound per day, which can be administered in a single dose or in the form of individually divided doses, for example from 1 to 4 times a day. It is clear that the specific dose level and frequency of the dose for each individual entity can vary and depends on various factors including the activity of the specific compound, the metabolic stability and length of action of that compound, the type, age, body weight, General health, sex and diet of the subject, the mode and time of administration, rate of excretion, combination of drugs and the severity of the special conditions. Preferred subjects for treatment include animals, most preferably mammalian species such as human and domestic animals, such as dogs, cats and the like, subjects with conditions associated with with other.

As indicated above, the compounds of the present invention can be used alone or in combination with each other and/or other suitable therapeutic agents useful for treatment of conditions associated with other, for example, an antibiotic or other pharmaceutically active medium spans the PTO.

For example, the compounds of the present invention may be combined with the simulated growth agents such as, but not limited to, TRH, diethylstilbesterol, theophylline, enkephalins, E types of prostaglandins, compounds described in US 3239345, for example, zeranol, and compounds described in US 4036979, for example, solanax or peptides described in US 4411890.

Compounds according to the invention can also be used in combination with the means, amplifying secretion of growth hormone, such as GHRP-6, GHRP-1 (as described in US 4411890 and publications WO 89/07110 and WO 89/07111), GHRP-2 (as described in WO 93/04081), NN703 (Novo Nordisk), LY444711 (Lilly), MK-677 (Merck), CP424391 (Pfizer) and NT or factor for the release of growth hormone and its analogs or growth hormone and its analogs or somatomedins, including IGF-1 and IGF-2, or with alpha-adrenergic agonists, such as clonidine or serotoninovye S-HTDagonists, such as sumatriptan, or agents which inhibit somatostatin or its release, such as fissistigma and pyridostigmine. Another use of the described compounds according to the invention is the combination with parathyroid hormone, PTH(1-34) or bisphosphonates, such as MK-217 (alendronate).

Another use of the compounds according to the invention is the combination with estrogen, testosterone, a selective estrogen receptor modulator, such as is tamoxifen or raloxifene, or other modulators androgenous receptor, such as modulators described in Edwards, J.. etc., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamaim, L.G. and others, J. Med. Chem., 42, 210-212 (1999).

Another use of the compounds of the present invention is the combination with agonists, progesterone receptor ("PRA"), such as levonorgestrel, medroxyprogesterone acetate (MPA).

Compounds of the present invention can be used alone or in combination with each other and/or other receptor modulators of nuclear hormone or other suitable therapeutic agents suitable for treatment of the aforementioned disorders including: anti-diabetic agents; anti-osteoporosis agents; agents against obesity; anti-inflammatory agents; soothing agents; antidepressants; anti-hypertensive agents; antiagregaie agents; antithrombotic and thrombolytic agents; cardiac glycosides; agents that reduce cholesterol/lipids; antagonists mineralocorticoid receptor; phosphodiesterase inhibitors; inhibitors of protein tyrosine kinase; thyroid mimetics (including thyroid agonists of the receptor); anesthetic agents; drugs against HIV or AIDS; drugs used for the treatment of Alzheimer's disease and other known diseases; drugs used for the treatment of diseases of the dream; and theproliferation agents and agents against cancer.

Examples of suitable anti-diabetic agents for use in combination with compounds of the present invention include biguanides (e.g., Metformin), glucosidase inhibitors (e.g. acarbose), insulins (including tools that enhance insulin secretion or insulin sensitizers), meglitinides (for example, Repaglinide), sulfonylureas (e.g., glimepiride, glyburide and glipizide), combination biguanid/gliburid (e.g., Glucovance®)preparations, thiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitors of glycogen phosphorylase inhibitors of protein fatty acid binding (ar), such as described in US 09/519079 filed 06.03.2000, glucagon-like peptide-1 (GLP-I) and inhibitors dipeptidylpeptidase IV (DP4).

Examples of suitable anti-osteoporosis agents for use in combination with compounds of the present invention include alendronate, risedronate, PTH, PTH fragments, raloxifene, calcitonin, steroidal or non-steroidal agonists, progesterone receptor, RANK ligand antagonists, antagonists sensitive to the calcium receptor, TRAP inhibitors, selective modulators of estrogen receptor (SERM), estrogen and AP-1 inhibitors.

Examples of suitable agents against obesity is to use the education in combination with the compounds of the present invention include ar inhibitors, such as described in US 09/519079 filed 06.03.2000, PPAR gamma antagonists, PPAR Delta agonists, beta 3 adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355 (Merck) or SR (Pfizer) or other known beta 3 agonists as described in US 5541204, 5770615, 5491134, 5776983 and 5488064, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), an inhibitor of the capture of a serotonin (and dopamine), such as sibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron)the cure for beta thyroid receptor, such as a ligand thyroid receptor, as described in WO 97/21993 (U. Cal SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), and/or an agent that reduces the appetite, such as dexamfetamine, phentermine, phenylpropanolamine or mazindol.

Examples of suitable anti-inflammatory agents for use in combination with compounds of the present invention include prednisone, dexamethasone, Enbrel®, cyclo-oxygenase inhibitors (for example, inhibitors of MOR-1 and/or MOR-2, such as NSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen®, Celebrex®, Vioxx®), CTLA4-Ig agonists/antagonists, ligand CD40 antagonists, IMPDH inhibitors, such as mycophenolate (CellCept®) integranova antagonists, alpha-4 beta 7 integranova antagonists, inhibitors of cell adhesion, antagonists of interferon-gamma, ICAM-1, antagonists of tumor necrosis factor (TNF) (e.g., infliximab, OR1384), inhibitors of prostaglandin synthesis, budeso the ID, clofazimine, CNI-1493, CD4 antagonists (e.g., priliximab)inhibitors R mitogen-activated protein kinase inhibitors proteincontaining (RTC), IKK inhibitors and drugs for the treatment of syndrome of inflamed intestine (for example, open Zeimac® and Maxi-K®such as described in US 6184231 B1).

An example of a suitable sedative agents for use in combination with compounds of the present invention include diazepam, lorazepam, buspirone, oxazepam, and hydroxyzine, pamoat.

Examples of suitable antidepressant for use in combination with compounds of the present invention include italopram, fluoxetine, nefazodone, sertraline, and paroxetine.

Examples of suitable antihypertensive agents for use in combination with compounds of the present invention include beta-blockers, calcium channel (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mibefradil), diuretics (for example, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide, benzthiazide, ticrynafen etakrinova acid, chlorthalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g. captopril, zofenopril, fosinopril, enalapril, ceronapril, cyl is sobril, delapril, pentopril, quinapril, ramipril, lisinopril), antagonists at-1 receptor (e.g., losartan, irbesartan, valsartan), antagonists, ET receptor (e.g., sitaxsentan, atrasentan and compounds described in US 5612359 and 6043265), dual ET/AII antagonist (e.g., compounds described in WO 00/01389), inhibitors of neutral endopeptidase (NEP)inhibitors vasopeptidase (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat) and nitrates.

Examples of suitable antiagregaimi agents for use in combination with compounds of the present invention include GPIIb/IIIa blockers (e.g., abciximab, eptifibatide, tirofiban), P2Y12 antagonists (e.g., clopidogrel, ticlopidine, CS-747), antagonists thromboxane receptor (e.g., ferroban), aspirin and PDE-III inhibitors (e.g., dipyridamole) with aspirin or without it.

Examples of suitable cardiac glycosides for use in combination with compounds of the present invention include digitalis and ouabain.

Examples of suitable agents to reduce cholesterin/lipid for use in combination with compounds of the present invention include inhibitors of HMG-CoA reductase (e.g., pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, or nicastrin, or nicastrin) and ZD-4522 (a.k.a. rosuvastatin, or itavastatin, or in Salatin)), inhibitors salanova synthetase, fibrates, excretion of bile acids, ACAT inhibitors, MTP inhibitors, lipoxygenase inhibitors, inhibitors of cholesterol absorption and inhibitors of protein-Laden air cholesterine (e.g., CP-529414).

Examples of suitable antagonists mineralocorticoid receptor for use in combination with compounds of the present invention include spironolactone and eplerenone.

Examples of suitable phosphodiesterase inhibitors for use in combination with compounds of the present invention include PDEIII inhibitors such as Cilostazol, and PDE V inhibitors, such as sildenafil.

Examples of suitable thyroid mimetics for use in combination with compounds of the present invention include thyrotropin, politizoid, KV-130015, and dronedarone.

Examples of suitable anesthetic agents for use in combination with compounds of the present invention include testosterone, TRH diethylstilbesterol, estrogen, β-agonists, theophylline, anabolic steroids, dehydroepiandrosterone, enkephalins, E-type prostaglandins, retinoic acid and compounds described in US 3239345, for example, Zeranol®; US 4036979, for example, Solanax® or peptides described in US 4411890.

Examples of suitable medicines for HIV or AIDS for use in combination with connected the s of the present invention include indinavir sulfate, saquinavir, saquinavir mesilate, ritonavir, lamivudine, zidovudine, lamivudine/zidovudine, zalcitabine, didanosine, stavudine and megestrol acetate.

Examples of suitable medicines for the treatment of Alzheimer's disease and family of diseases for use in combination with compounds of the present invention include donepezil, taken, rivastigmin, NT, inhibitors of gamma secretase, inhibitors of beta secretase, blockers SK channel mask-blockers and K-CNQ blockers.

Examples of suitable drugs for the treatment of diseases sleep for use in combination with compounds of the present invention include analogs of melatonin antagonists melatonindosage receptor, L1 agonists and antagonists of GABA/NMDA receptor.

Examples of suitable anti-proliferative agents for use in combination with compounds of the present invention include cyclosporin a, paclitaxel, FK 506 and adriamed.

Examples of suitable anti-cancer agents for use in combination with compounds of the present invention include paclitaxel, adriamycin, epothilones, cisplatin and aroplatin.

Compounds of the present invention can also be used in combination with nutritional supports, such as described in US 5179080, especially in combination with whey protein or casein, amino acid and (such as leucine, branched amino acids and hydroxymethylbutyrate), triglycerides, vitamins (e.g., A, B6, 12, folate, C, D and E), minerals (such as selenium, magnesium, zinc, chromium, calcium and potassium), carnitine, lipoic acid, creatine and coenzyme Q-10.

In addition, the compounds of the present invention can be used in combination with therapeutic agents used for the treatment of sexual dysfunction, including, but not limited to the PDE5 inhibitors, such as sildenafil or IC-351; with antiresorptive agents, drugs for hormone replacement, vitamin D analogues, calcitonine, dopolnitelnye elemental calcium and calcium inhibitors of cathepsin K, MMP inhibitors, antagonists vitronektinove receptor, Src SH2antagonists, inhibitors vasculary-N+-Atras, agonists, progesterone receptor, ipriflavone, fluorine, RANK antagonists, PTH and its analogues and fragments, tibolona, inhibitors of HMG-COA reductase, SERM, R inhibitors, prostanoids, inhibitors of 17 beta hydroxysteroid dehydrogenase inhibitors and Src kinase.

Compounds of the present invention can be used in combination with male contraceptives, such as nonoxynol 9 or therapeutic agents for the treatment of hair loss, such as Minoxidil and finasteride or chemioterapico the mini-agents such as LHRH agonists.

For the preferred anticancer or use of antiangiogenic compounds of the present invention can be administered alone or in combination with other anti-cancer and cytotoxic agents and drugs useful for treating cancer or other proliferative diseases, for example, when the second drug has the same or a different mechanism of action, the compounds according to the invention of formula I. Examples of classes of anti-cancer and cytotoxic agents used in combination with the compounds according to the invention, include, but are not limited to: alkylating agents such as nitrogen mustard, alkyl sulphonates, nitrocefin, ethylenimine and triazine; antimetabolites such as folate antagonists, purine analogues, and pyrimidine analogues; antibiotics such as anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; enzymes such as L-asparaginase; inhibitors farnesyl-protein transferase; inhibitors 5α inhibitors; inhibitors of 17β-hydroxysteroid dehydrogenase type 3; hormonal agents such as glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progestins, and antagonists luteinizing-releasing hormone, Acireale acetate; microtubule-damaging agents, such as ecteinascidins or from the taxes and derivatives; microtubule-stabilizing agents such as taxanes, for example, paclitaxel (Taxol®), docetaxel (Taxotere®) and their analogues, and epothilones, such as epothilones A-F and their analogs; plant products, such as winninowie alkaloids, epipodophyllotoxins, taxanes; and topoisomerase inhibitors; inhibitors prenyl-protein transferase; and a variety of agents, such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, complexes of platinum, such as picoplatin and carboplatin; and other agents used as anti-cancer and cytotoxic agents such as biological modifiers of response, growth factors; immune modulators and monoclonal antibodies. Compounds according to the invention can also be used in combination with radiation therapy.

Representing examples of these classes of anti-cancer and cytotoxic agents include, but are not limited to, mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustin, lomustin, semister, streptozocin, thiotepa, dacarbazine, methotrexate, thioguanine, mercaptopurine, fludarabine, pentostatin, cladribine, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubitsin, bleomycin sulfate, mitomycin C, actinomycin D, saracini, saframycin, quinoxaline, discodermolide, vincristine, vinb Astin, vinorelbine tartrate, etoposide, etoposide phosphate, teniposide, paclitaxel, tamoxifen, estramustine, estramustine sodium phosphate, flutamide, buserelin, leuprolide, pteridine, dainty, levamisole, flacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethasone, gemcitabine hydrochloride, altretamine and topotecan and any of its analogs or derivatives.

Preferred representatives of these classes include, but are not limited to, paclitaxel, cisplatin, carboplatin, doxorubicin, karminomitsin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743 or porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or derivatives podofillotoksina, such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, laurasian, vindesine and neurotin.

Examples of anticancer and other cytotoxic agents include the following: epothilone derivatives described in DE 4138042.8; WO 97/19086, WO 98/22461, WO 98/25929. WO 98/38192, WO 99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO 99/27890, WO 99/28324, WO 99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO 99/65913, WO 99/67252, WO 99/67253 and WO 00/00485; inhibitors of cyclin-dependent kinases described in WO 99/24416 (see also US 6040321); and inhibitors prenyl-protein transferase described in WO 97/30992 and WO 98/54966; and agents, t is the cue as described generally and specifically in the US 6011029 (connection, which can be used in conjunction with any other modulators (including, but not limited to, compounds of the present invention), such as AR modulators, ER modulators, with LHRH modulator or surgical castration, especially in the treatment of cancer).

Compositions of the present invention can also be joined or be administered with other therapeutic agents that are selected depending on their specific suitability for the introduction of medicines associated with the above conditions. For example, the compounds according to the invention can communicate with agents to prevent nausea, hypersensitivity and irritation of the stomach, such as antiemetics and antihistamines H1and H2.

Suitable for cancer therapy compounds of the present invention is most preferably used alone or in combination with anti-cancer therapies, such as radiation therapy, and/or cytostatic and/or cytotoxic agents, such as, but not limited to, DNA interactive agents, such as cisplatin or doxorubicin; inhibitors farnesyl protein transferase, such as described in US 6011029; topoisomerase II inhibitors such as etoposide; topoisomerase inhibitors I, such as CPT-11 or topotecan; tubulin stabilizing agents, such as pacl taxel, docetaxel, other takanami, or epothilones; hormonal agents such as tamoxifen; inhibitors of thymidylate synthase, such as 5-perurail; antimetabolites, such as methoxtrexate; antiangiogenic agents, such as angiostatin, ZD6474, ZD6126 and Chamberlain A2; kinase inhibitors, such as her2 specific antibodies, inhibitors Iressa and CDK; inhibitors of histone deacetylase, such as CI-994 and MS-27-275. Such compounds can also be combined with agents that inhibit the secretion of circulating testosterone, such as LHRH agonists or antagonists, or with surgical castration.

For example, well-known therapy for extensive metastases prostate cancer include therapy with complete removal of androgen, where tumor growth inhibit for controlling flow of androgen to the tissues of the prostate through chemical castration (castration is used for inhibiting the selection of circulating testosterone (T) and dihydrotestosterone (DHT)) with the subsequent introduction of the antagonists androgenous receptor (AR) (which inhibit the function of T/DHT obtained by conversion of circulating androgen precursors in the T/DHT prostate tissue). Compounds of the present invention can be used as AR antagonists in full removes therapy, alone or in combination with other AR antagonists, such as F. alamid, casodex, nilutamide or cyproterone acetate.

Compounds of the present invention can be used in conjunction with surgery.

Another use of the compounds according to the invention is used in combination with antibody therapy, such as, but not limited to, treatment with antibodies against PSCA. Additional application relates to a vaccine/immune modulating agents for the treatment of cancer.

Compounds of the present invention can be used in accordance with the methods described in the application US 60/284,438, titled "Selective modulators androgenous receptor and methods for their identification, preparation and use", filed 18.04.2001 Mark E. Salvati, etc. (Attorney Docket No. LD0250(PSP)), which is incorporated fully herein by reference (including, but not limited to, links to all of the specific compounds of formula I of the present invention), and the application of US (not labeled), titled "Selective modulators androgenous receptor and methods for their identification, preparation and use", filed 20.06.2001 Mark E. Salvati, etc. (Attorney Docket No. LD0250(NP)), which is incorporated fully herein by reference (including, but not limited to, links to all of the specific compounds of formula I of the present invention).

In the case of racemates of compounds of the present invention, one enantiomer may, for example, be full AR antagonist, then ka is the other may be an AR antagonist in tumor tissue, although not have activity or agonistic activity in non-cancer tissues containing androgeny receptor.

The above other therapeutic agents when used in combination with the compounds of the present invention can be used, for example, in amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by the person skilled in the technical field.

The following tests can be used to confirm the activity of the compounds as other modulator. Preferred are those compounds whose activity is greater than 20 μm for binding or development in any of these trials. Using tests transactivation and standard tests for AR binding, described next, it is shown that various compounds of the present invention have the activity of AR modulator.

Transactivation tests:

AR specific experiment:

Compounds of the present invention are tested in transactivation trials with transfectional design transfer and using endogenous androgeny receptor cells of the host. Transactivational experiment relates to a method of identifying functional agonists and partial agonists that mimic, or antagonists, which inhibit the action of natural hormones, in this case, dihydrotestosterone (HT). This experiment can be used to predict in vivo activity, as there is a correlation in both types of data. See, for example, T. Berger, and others, J. Steroid Biochem. Molec. Biol. 773 (1992), the essence of which is given here as a reference.

In transactivational experiment reporter plasmid introduced by transfection (the procedure is the introduction into the cells of alien genes) in the respective cells. This reporter plasmid containing cDNA for a reporter protein, such as a dedicated alkaline phosphatase (SEAP), controlled by the previous downstream transcription by sequence-specific antigen of the prostate (PSA), containing the elements androgenous response (ARE). This reporter plasmid acts as a reporter for activity, modulating the transcription of AR. Therefore, the reporter acts as a surrogate for products (mRNA, then the protein), usually expressed gene under the control of AR and its natural hormone. In order to identify antagonists, transactivational experiment is carried out in the presence of constant concentration of natural AR of the hormone (DHT), which, as you know, helps to identify the reporter signal. Increasing concentrations of the supposed antagonist will lead to a decrease in reporter signal (e.g., SEAP production). On the other hand, exposure transfinitely cells to improve the structure of the estimated concentrations of agonist will lead to increased production of reporter signal.

For this experiment, LNCaP and MDA 453 cells obtained from American Type Culture Collection (Rockville, MD) and grown in RPMI 1640 or DMEM medium with addition of 10% bovine fetal serum (FBS; Gibco), respectively. The corresponding cells quickly transferout by electroporation in accordance with the optimal procedure described Heiser, 130 Methods Mol. Biol, 117 (2000), using the pSEAP2/PSA540/enhancer reporter plasmid. Reporter plasmid construct as follows: commercially available human placental genomic DNA used for polymerase cyclic reaction (PCR) fragment containing the Bg1II site (position 5284) and Hind III site at position 5831 human promoter specific antigen of the prostate (Accession # U37672), Schuur, etc., J. Biol. Chem., 271 (12): 7043-51 (1996). This fragment subcloning in rear/base (Clontech), with a pre-built Bg1II and HindIII to obtain the pSEAP2/PSA540 design. Then the fragment carrying the fragment of a human PSA prior to the downstream transcription sequence between positions -5322 and -3873, transferred to a PCR from human placental genomic DNA. Xhol and Bg1II sites introduced in the primers. The resulting fragment subcloning in the pSEAP2/PSA540, with built-Xhol and Bg1II, respectively, to obtain the pSEAP2/PSA540/enhancer constructs. LNCaP and MDA 453 cells are collected in a medium containing 10% deprived coal FBS. Each cell susp is SIU injected into two gene pulsating cuvette (Bio-Rad), which then contribute 8 µg reporter construct and use electroporation Bio-Rad gene pulser with 210 volts and 960 McGard. Received transfinitely cells are washed and incubated in medium containing devoid of coal bovine fetal serum in the absence (blank) or presence (control), 1 nm dihydrotestosterone (DHT; Sigma Chemical) and in the presence or in the absence of a standard antiandrogennogo bikalutamida or compounds of the present invention in concentrations ranging from 10-10 to 10-5 M (sample). For each sample using the duplicates. Dissolution of the compounds spend on a Biomek 2000 laboratory equipment. After 48 hours the supernatant fraction is examined for SEAP activity using the Phospha-Light Chemiluminescent Reporter Gene Assay System (Tropix, Inc). The viability of the remaining cells is determined using CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay (MTS Assay, Promega). Briefly, a mixture of tetrazole connection (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy)-2-(4-sulfophenyl)-2H-tetrazol, inner salt; MTS) and the electron binding reagent (fenesin methosulfate; PMS) is added to the cells. MTS (Owen's reagent) biopotentials cells in formazan, which is soluble in the environment of tissue culture, and, therefore, its absorption at 490 nm can be measured directly in 96-cell experimental substrates without additional processing. The number fo masonboro product, measured as the number at 490 nm the absorption is directly proportional to the number of living cells in culture. For each repetition, SEAP reading level on Abs490 the value obtained from MTS experiment. For antagonist % inhibition is calculated as:

% inhibition=100×(1-[average control-average net]/[average sample-average net])

According to the results data to build a graph and calculate the concentration of compound that inhibits 50% of the aligned SEAP (IC50).

For agonists % control is defined as the action of the test compound compared with the maximum effect observed for the natural hormone, in this case, DHT, and is calculated as:

% Control=100×[(average sample-average net)/(mean control-mean net)]

According to the results data to build a graph and calculate the concentration of compound that activates to 50% of level cleared SEAP in control (EC50).

GR specific experiment:

Used reporter plasmid contains the cDNA for SEAP reporter protein, as described for experiment specific AR TRANS-activation. The expression of the SEAP reporter protein control sequence with the long-term recurrence of the virus in breast tumor mice (MMTV LTR), which contains three item response hormone (HRE), which can be adjusted GR and PR, see, for example, . Chalepakis, etc.. Cell, 53(3), 371 (1988). This plasmid transferout in A cells, which Express endogenous GR, for the experiment, GR-specific TRANS-activation. A cells obtained from American Type Culture Collection (Rockville, MD) and grown in RPMI 1640 with 10% bovine fetal serum (FBS; Gibco). The definition of specific GR antagonist activity of compounds of the present invention were carried out as described for experiment specific AR TRANS-activation, except that DHT as opposed to 5 nm dexamethasone (Sigma Chemicals), a specific agonist for GR. The definition of specific GR agonist activity of the compounds of the present invention is carried out, as described for experiment AR TRANS-activation, where the measured activation of the GR-specific reporter system when adding the test compound, in the absence of a known ligand specific GR agonist.

PR Specific experiment:

Used reporter plasmid contains the cDNA for SEAP reporter protein, as described for experiment specific AR TRANS-activation. The expression of the SEAP reporter protein control sequence with the long-term recurrence of the virus in breast tumor mice (MMTV LTR), which contains three item response hormone (HRE), which can be adjusted GR and PR. This plasmid transferout in T47D, which expressio the t endogenous PR, for the experiment PR-specific TRANS-activation. T47D cells obtained from American Type Culture Collection (Rockville, MD) and grown in DMEM medium with 10% bovine fetal serum (FBS; Gibco). The definition of PR specific antagonistic activity of the compounds of the present invention were carried out as described for experiment specific AR TRANS-activation, except that DHT as opposed to 1 nm of promegestone (NEN), a specific agonist for PR. The definition of PR-specific agonistic activity of the compounds of the present invention is carried out, as described in experiment AR TRANS-activation, where they measure the activation of PR-specific reporter system when adding the test compound, in the absence of a known ligand PR specific agonists.

Experiment AR binding:

In the experiment linking all cells of the human LNCaP cells (THE mutant AR) or MDA 453 wild type AR) in 96-microtiter cell substrates containing RPMI 1640 or DMEM with 10% deprived coal CA-FBS (Cocaleco Biologicals), respectively, incubated at 37°to remove any endogenous ligand that can bind to the receptor in the cells. After 48 hours, conduct or analysis of saturation to determine the Kdsaturated with tritium dihydrotestosterone, [3H]-DHT, or a competitive binding experiment to determine the ability of those who together with compounds to compete with [ 3H]-DHT. In the analysis of saturation to cells add medium (RPMI 1640 or DMEM - 0.2% CA-FBS)containing [3H]DHT (in concentrations ranging from 0.1 nm to 16 nm) in the absence (total binding) or presence (nonspecific binding) of 500-fold molar excess of unlabeled DHT. After 4 hours at 37 With selected aliquot environment full binding at each concentration of [3H]-DHT to determine the amount of free [3H]-DHT. The remaining environment is separated, the cells washed with PBS three times and sown on UniFiker GF/B substrate (Packard), add microstent (Packard) and the substrate is placed in a top count (Packard) to determine the amount of bound peroxidase [3H]-DHT.

In the analysis of the saturation difference between total binding and nonspecific binding is defined as specific binding. Specific binding is determined by Scatchard analysis to calculate the Kdfor [3H]-DHT. See, for example, D. Rodbard, Mathematics and statistics ofligand assays: an illustrated guide: In: J. Langon and J.J. Clapp, eds., Ligand Assays, Masson Publishing U.S.A., Inc., New York, pp. 45-99, (1981), described here as references.

In the competitive tests to cells add a medium containing 1 nm [3H]-DHT and compounds according to the invention ("test compounds") in concentrations ranging from 10-10up to 10-5M Use two repetitions for each sample. After 4 hours at 37°cells are washed, high the claim and calculate, as explained above. According to the results data to build a graph of a response curve of the necessary quantity of [3H]-DHT (% of control in the absence of test compounds) on the level of dose for this connection. Calculate the concentration of test compound that inhibits 50% of the number associated with [3H]-DHT in the absence of a competitive ligand (IC50), after log-logit transformation. Values of K1determined using the Cheng-Prusoff equation for IC50values, where:

.

After clarification of non-specific binding determine the IC50value. IC50defined as the concentration of the competitive ligand required to reduce specific binding by 50%. Kds [3H]-DHT for MDA 453 and LNCaP are 0.7 and 0.2 nm, respectively.

The experiment of cell proliferation of human prostate;

Compounds of the present invention are tested ("test compounds") on the proliferation of cell lines of prostate cancer person. For this MDA 2b cell line derived from a metastasis of a patient subjected to castration, Navone and others, Clin. Cancer Res., 3, 2493-500 (1997), incubated with or without test compounds for 72 hours and calculate the number of [3H]-thymidine embedded in DNA, to determine the number of cells and hence proliferation. MDA PCa2b cell line expressed the more in BRFF-HPC1 environment (Biological Research Faculty & Facility, Inc., MD) with 10% FBS. In the experiment the cells are placed on biocrete 96-cell micropolicy and incubated at 37°With 10% FBS (without coal)/BRFF-BMZERO (without androgens). After 24 hours, cells treated in the absence (blank) or presence of 1 nm DHT (control) or test compounds (sample) of the present invention in concentrations ranging from 10-10up to 10-5M For each sample using the duplicates. Dilution connection spend on a Biomek 2000 laboratory working device. In seventy-two hours add 0.44 uCi. [3H]-thymidine (Amersham) per cell and incubated for another 24 h followed by trypsinization, growing cells on GF/B filters. The filters add microstent PS to measure them on a Beckman TopCount.% Inhibition is calculated as:

% Inhibition=100×(1-[averagecontrol-averagenet]/[averagesample-averageclean.])

According to the results data to build a graph and calculate the concentration of compound that inhibits 50% of the introduction of [3H]-thymidine (IC50).

Experiment development SS of mouse myoblasts:

Spend two functional transactivation tests to determine the effectiveness androgenetic agonists on the precursors of muscle cells using the luciferase reporter. The first experiment (ARTA stable 1) includes the use cleto the Noi line, stable 1 (clone #72), which stably expresses full length androgenous receptor of the rat, but requires the time of transfection enhancer/reporter. This cell line is obtained from SS cells of mouse myoblasts. The second experiment (ARTA stable 2) includes the use of cell lines, stable 2 (clone #133), obtained from the stable 1, which stably expresses and rAR and enhancer/reporter luciferase.

The enhancer/reporter construct used in this system is GL3/HVK-1/luciferase. It was reported that 2XDR-1 is an AR specific response element in CV-1 cells. Brown et. al. Journal of Biological Chemisty 272, 8227-8235, (1997). It was obtained by random mutagenesis AR/GR end enhancer sequence.

ART Stable 1:

1. The stable cells 1 are placed in 96 wells in the amount of 6,000 cells/cell in DMEM with high content of glucose without phenol red (Gibco BRL, Cat. No.: 21063-029)containing 10% FBS, treated with dextran and coal (HyClone Cat. No.:SH30068.02), 50 nm HEPES buffer (Gibco BRL, Cat. No.: 15630-080), IX MEM Na pyruvate (Gibco BRL, Cat. No.: 11360-070), 0.5X antifungal antibiotic and 800 μg/ml of geneticin (Gibco BRL, Cat. No.:10131-035).

2. After 48 hours cells transferout pGL3/2XDR-l/luciferase using LipofectAMINE Plus™ reagent (Gibco BRL, Cat. No.: 10964-013). More specifically, 5 μg/cell DNA, pGL3/2XDR-l/luciferase and 50 ng/cell Salmon Sperm DNA (as carrier) dilute 5 ál/I is a side Opti-MEMem medium (Gibco BRL, Cat. No.: 31985-070). To do this, add 0.5 μl/cell Plus reagent. This mixture is incubated for 15 minutes at room temperature. In a separate vessel 0.385 μl/cell LipofectAMINE reagent was diluted with 5 MK/cell Opti-MEM. The mixture of DNA and then unite with a mixture of LipofectAMINE and incubated for another 15 minutes at room temperature. During this time, remove the medium from the cells and replaced with 60 μl/cell Opti-MEM. To do this, add 10 μl/cell transfection mixture of DNA/LipofectAMINE. Cells incubated for 4 hours.

3. Transfection mixture is removed from the cells and replaced with 90 μl of medium, as described above in #1.

4. Place 10 μl/cell suitable diluted medicinal product in each cell.

5. After 24 hours, the experimental system Steady-Glo™ luciferase is used for determining the activity in accordance with the manufacturer's instructions (Promega, Cat. No.: E2520).

ARTA stable 2

1. Stable 2 cells are placed in 96 wells in the amount of 6,000 cells/cell in DMEM with high content of glucose without phenol red (Gibco BRL, Cat. No.: 21063-029) containing 10% FBS, treated with dextran and coal (HyClone Cat. No.: SH30068.02), 50 mm HEPES buffer (Gibco BRL, Cat. No.: 15630-080), IX MEM Na pyruvate (Gibco BRL, Cat. No.: 11360-070), 0.5X antifungal antibiotic, 800 μg/ml of geneticin (Gibco BRL, Cat. No.: 10131-035) and 800 μg/ml of hygromycin β (Gibco BRL, Cat. No.: 10687-010).

2. After 48 hours the medium from the cells remove and replace 90 MK is fresh environment. In each cell is placed 10 μl/cell suitable diluted medicinal product.

3. After 24 hours, the experimental system Steady-Glo™ luciferase is used for determining the activity in accordance with the manufacturer's instructions (Promega, Cat. No.: E2520).

Cm. US No. (not labeled), with the name "Cell Lines and Cell-BasedAssays for Identification ofAndrogen Receptor Modulators", filed 20.06.2001 Jacek Ostrowski and others (Attorney Docket No. DO 177), which is incorporated fully herein by reference.

Tests proliferation

The experiment on the proliferation of cells of murinova breast cancer:

The ability of the compounds of the present invention ("test compounds") to modulate the function of the AR is determined by testing these compounds in the experiment on the proliferation of using responsible for androgen cell lines murinova breast cancer, tumor-derived Shionogi, Hiraoka and others, Cancer Res., 47, 6560-6564 (1987). Stable AR-dependent clones kinship lines Shionogi defined by exposure of tumor fragments common procedures originally described in Tetuo, et. al., Cancer Research 25, 1168-1175 (1965). In accordance with the specified procedure one stable line, SC114, isolated, characterized and used to identify examples of compounds. SC114 cells incubated with or without test compounds for 72 hours and calculate the number of [MN]-thymidine embedded in DNA as the point is to determine the number of cells and therefore, the speed of cell proliferation, as described in Suzuki et. al, J. Steroid Biochem. Mol. Biol. 37, 559-567 (1990). SC114 cell line grown in MEM containing 10-8M testosterone and 2% FCS, treated with DCC. In the experiment the cells are placed in 96-cell micropolicy in a supported environment and incubated at 37°C. the next day, Wednesday, replace the medium without serum [Ham F-12-.MEM (1;1, vol/vol)containing 0.1% BSA] (antagonistic) or without (agonist mode) 10-8M testosterone and the tested compounds of the present invention in concentrations ranging from 10-10up to 10-5M For each sample using the duplicates. Dilution connection spend on a Biomek 2000 laboratory work equipment. In seventy-two hours add 0.44 uCi [3H]-thymidine (Amersham) per cell and incubated for another 2 h with subsequent trypsinization, growing cells on GF/B filters. The filters add microstent PS to measure them on a Beckman TopCount. For antagonistic way% inhibition is calculated as:

% Inhibition=100×(1-[averagesample-averagenet]/[averagecontrol-averagenet])

According to the results data to build a graph and calculate the concentration of a compound that inhibits by 50% the introduction of [3H]-thymidine (IC50).

For agonistic method% control is defined as the step test compound compared to the maximum effect, observed for the natural hormone, in this case, DHT, and is calculated as:

% Control=100×(averagesample-averagenet)/(averagecontrol-averagenet)

According to the results data to build a graph and calculate the concentration of a compound that inhibits by 50% the introduction of [3H]-thymidine (IC50).

In Vitro Experiment to determine the AR-1 transrepression caused GR:

AP-1 experiment is an experiment based on the cell luciferase reporter. A cells, which contain endogenous glucocorticoid receptor, stably transferout AP-1 DNA binding site attached to the luciferase gene. Cells are then grown in RPMI+10% fetal calf serum (processed coal)+Penicillin/streptomycin with mg/ml geneticin. Cells placed the day before the experiment in the amount of approximately 40,000 cells/cell. On the day of the experiment environment remove and add 20 ál of the experimental buffer (RPMI without phenol red+10% FCS (processed coal)+Pen/Strep) in each cell. At this point in each cell or add 20 ál of the experimental buffer (control experiments), compounds of the present invention ("test compounds") (dissolved in DMSO and added in various concentrations) or dexamethasone (100 nm in DMSO, positive counter is eh). The substrate then preincubated for 15 minutes at 37°With subsequent stimulation of the cells 10 ng/ml PMA. The substrate is then incubated for 7 hours at 37°that each cell add 40 ál of substrate reagent luciferase. Activity is measured by the analysis on the luminometer compared with the control experiments, treated with buffer or dexamethasone. The activity is indicated as % inhibition of reporter system compared with the buffer control with 10 ng/ml PMA separately. Control, dexamethasone at a concentration of <10 μm normally inhibits the activity of 65%. Test compounds that exhibit inhibition of PMA induction by 50% or more concentrations of the test compounds <10 μm, are considered to be active.

AR Antagonistic experiment wet weight of the prostate:

The activity of the compounds of the present invention as AR antagonists to determine the model of immature male rats, standard test antiandrogenov activity of this compound, as described in L.G.Hershberger and others, Proc. Soc. Expt. Biol. Med., 83,175 (1953); ..Walsh and R.F.Gittes, "Inhibition of extratesticular stimuli to prostate growth in castrated rat by antiandrogens". Endocrinology, 86, 624 (1970); and B. J. Furr and others, "ICI 176,334: novel non-steroid, peripherally selective antiandrogen", J. Endocrinol., 113, R7-9 (1987), described here as a reference.

The basis of this experiment lies in the fact that mu is ski genitals, such as the prostate and seminal vesicles play an important role in reproductive function. Stimulating growth of these organs and grown in size and renal function depends on the continuous presence of serum testosterone (T), which is the main androgen serum (>95%)produced by granulocyte eggs in the testes under the control of luteinizing hormone from the pituitary (LH) and follicle-stimulating hormone (FSH). Testosterone is transformed into a more active form, dihydrotestosterone, (DHT)in the prostate with 5α-reductase. Androgens of adrenal glands also make up about 20% of the total DHT in the prostate of rats compared with 40% of androgens in 65-year-old man. F.Labrie and other din. Invest. Med., 16, 475-492 (1993). However, this is not the main way, because of a mammal and people castration leads to almost complete degeneration of the prostate and seminal vesicles, without concomitant adrenalectomy. Therefore, in the normal state of the adrenal glands do not cause significant growth of prostate tissues. ..Luke and D.S.Coffey, " discrimination of Reproduction" ed. By E.Knobil and J.D.Neill, 1, 1435-1487 (1994). As the male sex organs are tissues which are most responsible for modulating androgenous activity, this model is used for determination of androgen-dependent growth of the reproductive organs in immature castrated rats.

Males immature rats (19-20 day the age of the Sprague-Dawley, Harlan Sprague-Dawely) castrated under anesthesia by metofane. Five days after surgery, these castrated rats (60-70 g, 23-25 days of age) give the medicine for 3 days. Animals injected medication subcutaneously (s.c.) 1 mg/kg testosterone propionate (TP) in the spanning peanut butter and antiandrogenov test compounds (compounds of the present invention) is administered orally through a feeding tube (r.o.) in solution/suspension of 80% PEG 400 and 20% Tween 80 (PEGTW). Animals injected (v/w) 0.5 ml resin /100 g body weight. Experimental groups are as follows:

1. The control binder

2. The testosterone propionate (TP) (3 mg/rat/day, subcutaneously)

3. TR plus Casodex (input r.o. in PEGTW, QD), known antiandrogen, as reference compounds.

4. To determine the antagonistic activity of the compound of the present invention ("test connection") enter (r.o. in PEGTW, QD) with TR (s.c., as introduced in group 2) in different doses.

5. To determine the agonistic activity of the compound of the present invention ("test connection") is administered separately (r.o. in PEGTW, QD) in various doses.

At the end of the 3-day treatment, the animals kill and ventral prostate weighed. To compare data from different experiments, the weight of the genital organs first, such as mg per 100 g of body weight, and increase the weight of the body, caused by TR, is the maximum magnification (100%). ANOVA followed odnostoechny Student or Fischer exact test used for statistical analysis.

The increase and decrease in the weight of the penis reflects changes in the number of cells (containing DNA) and cell mass (containing protein), depending on the concentration of androgen in serum. Cm. Y. Okuda and others, J. Urol., 145, 188-191 (1991). Consequently, the measurement of the weight of raw body can show the bioactivity of androgens and androgenetic antagonists. The undeveloped castrated rats substitution of exogenous androgens increases seminal vesicles (SV) and ventral prostate (VP), depending on the dose.

The maximum increase in the weight of the body is 4 or 5 times the dose of 3 mg/rat/day of testosterone (T) or 1 mg/rat/day of testosterone propionate (TP) for 3 days. EC50for T and TR is about 1 mg and 0.03 mg, respectively. the growing weight of the VP and SV also correlates with the increase in serum T and DHT concentrations. Although the introduction T has increased concentrations of T and DHT in serum in 5 times within 2 hours after subcutaneous injection compared to TR, then these high levels decrease very quickly. On the contrary, the concentration of serum T and DHT in TP-treated animals clearly standing for 24 hours, and therefore, TR are about 10-30 times more active is to be compared with the net So

In this immature castrated model rats known AR antagonist (casodex) also injected simultaneously with 0.1 mg TP (ED80), inhibiting testosterone-mediated increase in weight VP and SV depending on the dose. Antagonistic action is about the same when introduced orally or subcutaneously. Compounds according to the invention also exhibit AR antagonistic activity, inhibiting testosterone-mediated increase in weight VP and SV.

AR Agonistic experiment with levator muscle of the anus and wet weight of the prostate:

The activity of the compounds of the present invention as AR agonists examined on the model of immature male rats, known to test the analgesic action on the muscles and prolonged action on the sex organs for a given compound, as described in L.G. Hershberger and others, Proc. Soc. Expt. Biol. Med., 83, 175 (1953); .L. Beyler, etc, "Methods for evaluating anabolic and catabolic agents in laboratory animals", J. Amer. Med. Women's Ass., 23, 708 (1968); H. Fukuda and others, "Investigations of levator ani muscle as an anabolic steroid assay", Nago Dai. Yak. Ken. Nem. 14, 84 (1966).

The basis of this experiment lies in the well-studied action of androgenic agents on the maintenance and growth of muscle tissues and reproductive organs in animals and humans. Androgenic steroids, such as testosterone (T), is well characterized for their ability to maintain muscle mass. Treatment of animals or humans after castrations exogenous source Tperiodic to stop muscle atrophy.

The effect of T on muscle atrophy in the levator muscle of the anus rats are well known. .Masuoka and others, Constant cell population in normal, testosteron deprived and testosteron stimulated levator ani muscles" Am. J. Anat. 119,263 (1966); Z. Gori and others, "Testosteron hypertrophy of levator ani muscle of castrated rats. I. Quantitative data" Boll. - Soc. Ital. Biol. Sper. 42, 1596 (1966); Z. Gori and others, "Testosteron hypertrophy of levator ani muscle of castrated rats. II. Electron-microscopic observations" 5o//. - Soc. Ital. Biol. Sper. 42, 1600 (1966); A. Boris, etc.. Steroids 15, 61 (1970). As described above, the effect of androgens on the maintenance of male reproductive organs such as the prostate and seminal vesicles are well known. Castration leads to rapid degeneration and atrophy of the prostate and seminal vesicles. This action can be stopped by exogenous addition of androgens. As the levator muscle of the anus and the male sex organs are tissues that are most responsible for the action of androgenic agents, this model is used to determine the androgen-dependent atrophy of the levator muscle of the anus and genitals in undeveloped castrated rats. Mature rats (200-250 g, 6-8 weeks of age, Sprague-Dawley, Harlan) castrated by the manufacturer (Taconic). Rats are divided into groups and treated daily for 7 to 14 days in one of the following reagents:

1. The control binder

2. The testosterone propionate (TP) (3 mg/rat/day, subcutaneously)

3. TR plus Casodex (input r.o. in PEGTW, QD), known antiandrogen, the quality is TBE reference connection.

4. To determine the antagonistic activity of the compound of the present invention ("test connection") enter (r.o. in PEGTW, QD) with TR (s.c. as introduced in group 2) in different doses.

5. To determine the agonistic activity of the compound of the present invention ("test connection") is administered separately (r.o. in PEGTW, QD) in various doses.

At the end of the 7-14-day care of animals killed with carbon dioxide and levator muscle of the anus, seminal vesicle and ventral prostate weighed. To compare data from different experiments, the weight of the levator muscle of the anus and penis first, such as mg per 100 g of body weight, and increased body weight caused by TR, is the maximum magnification (100%). For statistical analysis using Super-anova (one-factor).

The increase and decrease in the weight of the penis reflects changes in the number of cells (containing DNA) and cell mass (containing protein), depending on the concentration of androgen in serum. Cm. Y. Okuda and others, J Urol, 145,188-191 (1991), described here as a reference. Consequently, the measurement of the weight of raw body can show the bioactivity of androgens and androgenetic antagonists. The undeveloped castrated rats substitution of exogenous androgens increases the levator muscle of the anus, seminal vesicles (SV) and the prostate depending the spine of the dose.

The maximum increase in the weight of the body is 4 or 5 times with the introduction of 3 mg/rat/day of testosterone (T) or 1 mg/rat/day of testosterone propionate (TP) for 3 days. EU50T and TR is about 1 mg and 0.03 mg, respectively. The growing weight of the VP and SV also correlated with increasing concentrations of T and DHT in serum. Although the introduction of the T shows increased concentrations of T and DHT in serum in 5 times within 2 hours after subcutaneous injection compared to TR, then these high levels decrease very quickly. On the contrary, the concentration of serum T and DHT in TP-treated animals clearly standing for 24 hours, and therefore, TR are about 10-30-fold greater activity compared to a net So

Stenograficheskii experiment MDA 2b a man's prostate:

In Vivo Antitumor test: tumor MDA-PCa-2b human prostate grown in Balb/c nu/nu deprived of wool mice. The tumor is administered as a subcutaneous transplants in adult males deprived of wool mice (4-6 weeks of age) using tumor fragments obtained from donor mice. Transplantation of the tumor spend every 5-6 weeks.

To test the antitumor effectiveness of the required number of animals in need in determining the response value, unite at the beginning of the experiment and each injected subcutaneously implanted tumor fragment (&x002DC; 50 mg) using a 13-block trocar. To allow tumors to grow to approximately 100-200 mg (tumors outside the scope excluded) and animals randomly divided into groups for different treatment and control. The treatment of each animal based on individual body weight. Processed animal control daily toxicity/mortality associated with treatment. Each group of animals are weighed before treatment (Wt1) and then again following the last treatment dose (Wt2). The difference of body weight (Wt2-Wt1) provides a measurement related to treatment toxicity.

Tumor response was measured by measurement of tumors with calipers twice a week until the tumor has not reached the "end" of 0.5 GM. The tumor weight (mg) determined by the formula: tumor Weight=(length×Sirina)÷2

The end point of tumor response is expressed as the inhibition of tumor growth (%T/C), defined as the ratio of the mean tumor weight of the treated tumors (T) to the average sowing the control group (C).

To determine the destruction of tumor cells, the doubling time of the tumor volume is first calculated according to the formula:

TVDT=Average time (days) for control tumors to reach target size-the Average time (days) for control tumors to reach half the target size s And Log destruction of cells=(T-S)-(3.32×TVDT).

The way the political processing of data is carried out with the help of test Wilcoxon signed, founded by Gehenom.

Long-term prostate cancer:

Long R3327H prostate cancer is a spontaneously emerging, distinct androgen-adenocarcinoma of the prostate (Smolev JK, Heston WD, Scott WW and Coffey DS, Cancer Treat Rep. 61, 273-287 (1977)). Growth R3327H subran for its high androgen and reproducible increase in intact male rats. Therefore, this model and other as compared to this tumor are widely used to determine the in vivo antitumor activity of anti-androgens such as flutamide and balloted/Casodex (Maucher, A., and von Angerer, J. Cancer Res. din. Oncol., 119, 669-674 (1993), B.J.A. Furr Euro. URL 18 (suppl. 3), 2-9 (1990), Cement S.A. and Huot Rl. J. Steriod Biochem. 31, 711-718 (1988)).

At the beginning of the study of long-term tumor fragments (about 4x4 mm) transplanted subcutaneously in the flank of Mature male rats from Copenhagen (6-7 weeks of age, Harlan-Sprague Daw-ley, Indianapolis, MD). After about 6 weeks after implantation, animals with tumors measured size (about 80-120 mm) is divided into treatment group (8-10 rats/group) and begin treatment. One group of rats castrated, which serves as the negative control tumor growth. The animals are treated daily by the compounds of the present invention, the standard anti-androgens, such as balloted or binder (control) average of 10 to 14 weeks. Test compounds are dissolved in a binder substance (2.5 ml/kg weight of the body), 10% peg and 0.05% Tween-80 in 1% carboxymethylcellulose, PEG/CMC (Sigma, St Louis, MO). Conventional therapeutic experiments include three groups of three increasing doses for each standard or test compounds (in the field 300-3 mg/kg).

Tumors in the group with the binder (control) reaches a size from 1500 to 2500 mm, whereas the group of castrated animals usually manifests stop tumors after 14 weeks of observation. It is expected that animals treated orally 20 mg/kg bikalutamida or flutamide, show a 40% reduction in tumor volume compared to control after 14 weeks of treatment. The size of the tumors are measured weekly of Vernier calipers (Froboz, Switzerland), spending perpendicular to measure the length and width. The volume of tumors is calculated in mm3according to the formula: Length x Width x Height=Volume. Statistical differences between the treatment groups and control are evaluated using multiple ANOVA analysis followed odnostoechny reparametrise Student t test.

The experiment the weight of the prostate Mature rats:

The activity of the compounds of the present invention is examined for Mature models male rats, which is a variant of the experiment levator muscle of the anus and wet weight of the prostate, as described above. The above in vivo tests are known tests for determination of anesthetic effects on the muscles and supporting effects on Polo who's bodies for this connection, as described in L.G.Hershberger etc., 83 Proc. Soc. Expt. Biol. Med., 175 (1953); .L.Beyler, etc, "Methods for evaluating anabolic and catabolic agents in laboratory animals", 23 J. Amer. Med. Women's Ass., 708 (1968); H.Fukuda and others, "Investigations of levator ani muscle as an anabolic steroid assay", 14 Nago Dai. Yak. Ken. Nem. 84 (1966), described here as a reference. The basis of this experiment lies in the well-known action of androgenic agents on the maintenance and growth of muscle tissues and reproductive organs in animals and humans.

The male sex organs such as the prostate and seminal vesicles play an important role in reproductive function. Stimulating growth of these organs and grown in size and renal function depends on the continuous presence of serum testosterone (T), which is the main androgen serum (>95%)produced by granulocyte eggs in the testes under the control of luteinizing hormone from the pituitary (LH) and follicle-stimulating hormone (FSH). Testosterone is transformed into a more active form, dihydrotestosterone, (DHT)in the prostate with 5α-reductase. Androgens of adrenal glands also make up about 20% of the total DHT in the prostate of the rat, compared with 40% of androgens in 65-year-old man. F.Labrie and other din. Invest. Med., 16, 475-492 (1993). However, this is not the main way, because of a mammal and people castration leads to almost complete degeneration of the prostate and seminal vesicles without the accompanying adramalech the myus. Therefore, in the normal state of the adrenal glands do not cause significant growth of prostate tissues. ..Luke and D.S.Coffey, "discrimination of Reproduction" ed. By E.Knobil and J.D.Neill, 1, 1435-1487 (1994). As the male sex organs and levator muscles of the anus are the tissues most responsible for the modulation androgenous activity, this model is used for determining the activity of compounds that modulate the path androgenous receptor in Mature rats.

Together with mitogenic activity in tissues such as the prostate, seminal vesicles and muscles, testosterone also acts as a negative regulator for its own biosynthesis. Production of testosterone in granulocyte eggs in the testes is controlled by the level of circulating LH secreted from the pituitary gland. LH levels themselves are controlled by the level of LHRH produced by the region of the hypothalamus. Testosterone levels in the blood are used for inhibiting the selection LHRH and significantly decreased levels of LH and alternative levels of circulating testosterone levels. By measuring the levels of LH in the blood, that is compounds of the present invention ("test compounds")may determine the level of agonistic or antagonistic activity of these compounds in the system of this hypothalamus endocrine cycle.

Selected groups Harlan Sprague-Dawely rats (40-42 day is on age, 180-220 g), administered orally through a feeding tube (r.o.) of the tested compounds in solution/suspension of 80% PEG 400 and 20% Tween 20 (PEGTW) within 14 days. Two control groups, one healthy and one neutered, administered orally only PEGTW binder. Animals injected (v/w) 0.5 ml resin /100 g body weight. Experimental groups are as follows:

1. Intact binding substance (r.o., PEGTW, QD)

2. The control binder (r.o., PEGTW, QD)

3. Bikalutamid (Casodex known antiandrogen, as a reference compound) or a compound of the present invention, R. O. in PEGTW QD (in different doses). At the end of the 14-day treatment of animals killed and the ventral prostate, seminal vesicles, and levator muscle of the anus surgically removed and weighed. To compare data from different experiments, the weight of the bodies first, such as mg per 100 g of body weight and expressed as a percentage of the value of the relevant body in the intact group.

Luteinizing hormone in rats (rLH) is quantitatively determined using Biotrak [125 I] equipment (Amersham Pharmacia Biotek), following the manufacturer's instructions. The experiment is based on a comparison of present in serum LH, bound [125I]rLH, suspension Amerlex-M bead/antibody. The radioactivity remaining after incubation with serum and posleduyuschiey, extra is alyout on the standard curve to obtain the values in ng/mg of

The increase and decrease in the weight of the penis and lifting the muscles of the anus reflects changes in the number of cells (containing DNA) and cell mass (containing protein), depending on the concentration of androgen in serum, see Y.Okuda etc., J. Urol., 145, 188-191 (1991), described here as a reference. Consequently, the measurement of the weight of raw body can show the bioactivity of androgens and androgenetic antagonists. In the experiment with rats developed active agonistic agents do not have steps or do not increase the weight of one or more androgen-dependent organs (levator muscle of anus, prostate, seminal vesicle) and not my actions or overwhelming effect on the secretion of LH. Compounds with antagonistic activity reduces the weight of one or more androgen-dependent organs (levator muscle of anus, prostate, seminal vesicle) and have no steps or reduce the inhibitory effect on secretion of LH.

Stenograficheskii experiment CWR22 human prostate;

In Vivo Antitumor test: Tumor CWR22 human prostate grown in Balb/c nu/nu deprived of wool mice. The tumor is administered as a subcutaneous grafts in adult males deprived of wool mice (4-6 weeks of age)using tumor fragments obtained from donor mice. Transplantation of the tumor spend every 5-6 weeks.

For the of spitoni on the antitumor effectiveness of the required number of animals, need to determine what response, unite at the beginning of the experiment and each injected subcutaneously implanted tumor fragment (˜50 mg) using a 13-block trocar. To allow tumors to grow to approximately 100-200 mg (tumors outside the scope excluded) and animals randomly divided into groups with different treatment and control. The treatment of each animal based on individual body weight. Processed animal control daily for toxicity and mortality associated with treatment. Each group of animals are weighed before treatment (Wt1) and then after the last therapeutic dose (Wt2). The difference of body weight (Wt2-Wt1) provides a measurement related to treatment toxicity.

Tumor response was measured by determination of the tumors with calipers twice a week until the tumor has not reached the "end" of size 0.5 GM. The tumor weight (mg) determined by the formula: tumor Weight = (length·Sirina)÷2.

The end point of tumor response is expressed as the inhibition of tumor growth (% T/C), defined as the ratio of the mean tumor weight of the treated tumors (T) to the average weight of the control group (C).

To determine the destruction of tumor cells first calculate the doubling time of the tumor volume using the formula:

TVDT = Average time (days) for control tumors to reach target size is a - Average time (days) for control tumors to reach half the target size And Log destruction of cells = (T-C)+(3.32×TVDT)

Statistical processing of data is carried out with the help of test Wilcoxon signed, founded by Gehenom.

The following examples illustrate embodiments of the present invention and do not limit the scope of the present invention.

Reduction

The following abbreviations are used:

DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

4-DMAP = 4-dimethylaminopyridine

it = enantiomeric excess

DMF = dimethylformamide

EtOAc = atlapetes

LDA = diisopropylamide lithium

Hunig's Base = N,N-diisopropylethylamine

Me = methyl

RT = retention time

TFA = triperoxonane acid

THF = tetrahydrofuran

TLC = thin layer chromatography

TMS = trimethylsilyl

pTSA = pair-toluensulfonate acid

Δ = heat

t-Bu = tert-butyl

PhCH3= toluene

Pd/C = palladium on charcoal

TsCl = taillored

TBSOTf = tert-butyldimethylsilyl triptorelin sulfonate

TBS = tert-butyldimethylsilyl

MeI = methyl iodide

(VOS)2About = di-tert-BUTYLCARBAMATE

TEA = triethylamine

n-BuLi = n-utility

room temperature = room temperature

LC = liquid chromatography

Ts = tosyl

Ph = phenyl

EtOH = ethanol

DCE = dichloroethane

DMSO = dimethyl sulfoxide

Ra-Ni = Nickel R is Ney

MS = molecular sieve

MS(EC) = electrospray massspectrometry

mCPB A = m-chloroperoxybenzoic acid

rich = rich

Asón = acetic acid

Meon = methanol

Et2O = diethyl ether

AC = acetyl

DEAD = diethyl-azodicarboxylate

h = hours

Et = ethyl

WSDCC = water-soluble dicarbonitrile, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

TBAF = tetrabutylammonium fluoride

DBAD = di-tert.-utilisationbased

DCC = Dicyclohexylcarbodiimide

Wilkinson''s catalyst = RhCl(PPh3)3(the catalyst of Wilkinson)

ADDP = 1,1-[azodicarbon]piperidin

DMA = dimethylacetamide

DME = 1,2-dimethoxyethane

THIEF = benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexaflurophosphate

TFA = triperoxonane acid

Example 1

(3Aα,4α,7α7aα)-2-(4-Bromo-3-were)tetrahydro-4,7-ethanediamine [3,4-C]pyrrol-1,3,8(2H,4H)-Trion(1C)

A. 4-(tert-Butyldimethylsiloxy)-2H-thiopyran (1A)

2,3-Dihydro-4H-thiopyran-4-one (1.50 g, 13.14 mol, synthesized as described in Richards et al, J. Org. Chem. 46, 4836-4842 (1981)), was dissolved in CH2Cl2(130 ml) and add triethylamine (5.47 ml, 39.41 mmol). Then add tert-butyldimethylsilyl triftorbyenzola (3.62 ml, 15.77 mmol). After 10 minutes, the volatile substances are removed from the SIP is using a rotary evaporator at 25° C. the Obtained yellow oil is passed through a short column with SiO2, elwira 3% TEA in hexane, giving 1.82 g of compound 1A in the form of an orange oil.

C. 1-[4-bromo-3-were]-1N-pyrrole-2,5-dione (IB)

4-Bromo-3-methylaniline (1.55 g, 8.33 mmol) and maleic anhydride (0.898 g, 9.16 mmol) was dissolved in acetic acid (10 ml) and heated at a temperature of 115°C for 12 hours. The reaction mixture is then cooled to a temperature of 25°C and acetic acid is removed in vacuo. The resulting residue is suspended in 5% To2CO3(100 ml), stirred for 25 minutes and then fillout and washed with water. The resulting product is then dried in a vacuum that gives compound 1B as a pale brown solid (1.65 g). HPLC: 100% within 2.96 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm).

S. (3Aα,4α,7α7aα)-2-(4-Bromo-3-were)tetrahydro-4,7-ethanediamine[3,4-C]pyrrol-1,3,8(2H,4H)-Trion (1C)

Compound 1A (0.313 g, 1.41 mmol) and compound 1B (0.250 g, 0.94 mmol) is dissolved in toluene and heated at the boil under reflux for 5 hours. Then the toluene is removed, blowing argon through the reaction flask. The residue is purified using flash chromatography on SiO2elwira 20% hexane in chloroform. This gives 0.168 g of intermediate Enola ether in a solid yellow color. Intermediate enol ether dissolved in dichloroethane (2.0 ml) and added TFA (0.25 ml). After 0.5 hours the reaction zakolerovat saturated aqueous NaHCO3and extracted with CH2Cl2(2×30 ml). The organics are dried over anhydrous sodium sulfate and evaporated, giving 0.079 g of compound 1C in the form of a solid white color. HPLC: 99% within 3.010 minutes (retention time) (YMC S5 ODS column C mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 396.9 [M+NH4]+.

Example 2

(3Aα,4α,7α7aα)-2-(4-Bromo-3-were)tetrahydro-4,7-ethanediamine[3,4-C]pyrrol-1,3,8(2H,4H)-Trion,5-dioxide (2)

Compound 1C (0.040 g, 0.105 mmol) was dissolved in CH2Cl2(4.0 ml) and cooled to a temperature of 0°C. Then add m-SRV (60% purity, 0.061 g, 0.210 mmol) and the reaction mixture is heated to a temperature of 25C. After one hour with vigorous stirring a mixture of 1:1 saturated NaHCO3and saturated sodium sulfate (20 ml). After 15 minutes the mixture is extracted with CH2Cl2(2×30 ml) and the organics dried over anhydrous sodium sulfate, which gives 0.031 g of compound 2 as a solid white color. Further cleanup does not t buesa. HPLC: 78% within 2.290 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 429.8 [M+NH4]+.

Example 3

(3Aα,4β,7β7aα)-2-(3-Chlorophenyl)hexahydro-4-methyl-4,7-epoxy-1N-isoindole-13(2H)-dione (3)

3-Chloroaniline (0.100 g, 0.787 mmol) and 3,6-endoxa-3-methylhexahydrophthalic anhydride (0.172 g, 0.945 mmol) was dissolved in Asón (2.0 ml) and heated to a temperature of 110°within hours. The reaction mixture is then cooled to a temperature of 25°and poured into cold saturated solution of K2CO3, and then vigorously stirred for 10 minutes. Then the solution is filtered and washed with water. The obtained filtrate is dried in vacuo, giving 0.118 g of compound 3 in the form of a solid white color. Further purification is not required. HPLC: 99% within 2.510 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 292.32 [M+H]+.

Example 4

(3Aα,4α,7α7aα)-and(3Aα,4β,7β7aα)-4-[(atomic charges)methyl]-3α4,7,7a-tetrahydro-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1N-isoindole-1,3(2H)-dione (4i and 4ii respectively)

2-Acetoxymethyl (0.599 ml, 4.78 mmol) and 1-[3-(trifluoromethyl)-phenyl]-1N-pyrrole-2,5-dione (0.500 g, 2.39 mmol) was dissolved in methylene chloride (3.0 ml) at 25°C. After 22 hours, volatiles are removed in vacuo and the resulting residue purified using flash chromatography on SiO2, elwira 0-15% acetone in methylene chloride, which gives 0.438 g of the yellow oil in a 2:1 mixture of compound 4i and the connection 4ii, which is not razdelyayut. HPLC: 100% within 3.093 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 398.9 [M+NH4]+.

Example 5

(3Aα,4α,7α7aα)- and (3Aα,4β,7β7aα)-4-[(atomic charges)methyl]-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1N-isoindole-1,3(2H)-dione (5i and 5ii, respectively)

A mixture of 2:1 compounds 4i and 4ii (0.361 g, from example 4) is dissolved in ethyl acetate (25 ml) and added Pd/C (10% Pd, 0.2 g). Hydrogen is injected through the balloon and the reaction mass is stirred at a temperature of 25°C for 4 hours, then filtered through celite and washed with ethyl acetate. Concentration in vacuo gives a yellow oil, which is defined as the mixture of 2:1 compounds 5i and connections 5ii (0.348 g) and which do not share. HPLC: 00% over 2.900 min (retention time) (YMC S5 ODS column 4.6× 50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 40 1.0 [M+NH4]+

Example 6

(3Aα,4α,7α7aα)- and (3Aα,4β,7β7aα)-3A,4,7,7a-Tetrahydro-5-(hydroxymethyl)-2-[3-(trifluoromethyl)(phenyl]-4,7-epoxy-1N-isoindole-1,3(2H)-dione (6i and 6ii, respectively)

1-[3-(Trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (0.500 g, 2.39 mmol) and 3-furanmethanol (0.412 ml, 4.78 mmol) was dissolved in methylene chloride (3.0 ml) and stirred at a temperature of 25°C for 20 hours. Volatiles are then removed in vacuum and the resulting product was then purified using flash chromatography on SiO2, elwira chloroform/acetone, which gives 0.379 g of compound 6i and 0.220 g of compound 6ii, both in the form of a solid white color. Compound 6i: HPLC: 100% within 2.197 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (ES): m/e 338.0 [M-H]-. Connection 611: HPLC: 100% within 2. minutes (retention time) (YMC S5 ODS column 4.6 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (ES): m/e 338.0 [M-N]-.

Example 7

(3Aα,4α,7α7aα)-3A,4,7,7 the-Tetrahydro-5-(hydroxymethyl)-4-methyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione

2-Methyl-3-furanmethanol (0.537 g, 4.78 mmol) and 1-[3-(trifluoromethyl)-phenyl]-1N-pyrrole-2,5-dione (0.500 g, 2.39 mmol) dissolved in dichloroethane (2.0 ml) and stirred at a temperature of 25°C for 20 hours. The reaction mixture was then concentrated in vacuo and purified using flash chromatography on SiO2, elwira with ethyl acetate/methylene chloride, which gives 0.317 g of compound 7 in the form of a solid white color. No other possible isomer not emit after chromatography. HPLC: 100% within 2.197 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 351.9 [M-N]-.

Example 8

(3Aα,4β,7β7aα)-2-[3,5-Bis(trifluoromethyl)phenyl]hexahydro-4,7-epoxy-1N-isoindole-1,3(2H)-dione(8)

3,5-Bis(trifluoromethyl)-aniline (0.017 g, 0.0075 mmol) dissolved in acetic acid (0.300 ml) and transferred into a conical vial with a volume of 1.5 ml with a partition. Solutions source additional 95 amines receive, as described above. In each of the above vials add 0.4 ml (0.12 mmol) of the original solution of Exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride acid in acetic acid. The ampoule is then sealed and heated at a temperature of 110°C for h is CA. After cooling to 25°With the ampoule is opened, and then removed with acetic acid under vacuum. To each vial was added 1 ml of a mixture of 2:1 acetone/methylene chloride and the vessel is heated at a temperature of 40°within hours. All the products in the solution, automatically transferred into tubes with filters, filled with large Frits, pre-moistened with 0.2 ml of water. Pass nitrogen through each tube until you remove organic volatiles. Then to each tube, add 1.5 ml of 10% solution To2CO3and then vigorously shaken at 25°C for 15 minutes. Then decanted from the tube, re-seal and add 1.0 ml of water in each tube, then shake. Again decanted and washed with water a second time. The obtained residues in each tube is dried in vacuum for 48 hours. After drying in each tube add 1.0 ml of 20% TFA in methylene chloride and the vessel shaken for 30 minutes. The tube is then poured into a 96-cellular plate with pre-made microtubuli. In each tube to check the purity of the product (analytical LC) and identity (LC-MS). The contents of the test tube is then concentrated in vacuo and weighed to determine yield. The tube, which carried out the reaction of 3,5-bistrifluormethylbenzene and Exo-7-oxabicyclo[2.2.1]heptane-2,3-and the hydride dicarboxylic acid, give 0.022 g of compound 8 in the form of a solid white color. HPLC: 94% within 4.03 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 434.2 [M+Na+MeOH]+. Implementation 95 additional reactions gives the total number of end connections equal to 80, with a purity of >70% and yield of >5 mg Some samples require further cleaning, which is done using short SiO2column elwira methylene chloride/acetone. See table 2 below.

Example 9

(3Aα,4α,7α7aα)-2-(4-Bromophenyl)octahydro-1,3-dioxo-4,7-etheno-5H-pyrrolo[3,4-C]pyridine-5-carboxylic acid phenyl ester(9)

1-[4-Bromophenyl]-1N-pyrrole-2,5-dione (0.250 g, 0.992 mmol, synthesized as described in example 1B) and 1 (2H)-pyridineboronic acid phenylmethylene ether (0.299 g, 1.49 mmol, synthesized as described by Richard et. al, J. Org. Chem. 46, 4836-4842 (1981)) is dissolved in toluene and heated to a temperature of 85°within hours. After cooling to 25°With toluene removed in vacuo. The resulting residue is dissolved in a minimal amount chloroform and the product precipitated by adding hexane. After one hour at 25°C, the product is filtered and washed with cold 20% geksanalem in chloroforme, floor the tea connection 9 in the form of a solid white color (0.243 g) in the form of a single isomer. HPLC: 100% within 3.393 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 run), MS (EC): m/e 454.98 [M+H]+.

Example 10

(3Aα,4α,7α7aα)-2-(4-Bromophenyl)octahydro-1,3-dioxo-4,7-etheno-5H-pyrrolo[3,4-C]pyridine-5-carboxylic acid fenilmetilovy ether(10)

1-[3-(Trifluoromethyl)phenyl]-1N-pyrrole-2,5-dione (3.78 g, 15.7 mmol) and 1(2H)-pyridineboronic acid fenilmetilovy ether (4.0 g, 18.8 mmol, synthesized as described in Richard et. al, J. Org. Chem. 46, 4836-4842 (1981)) is dissolved in toluene and heated at a temperature of 80°C for 3 hours. After cooling to 25°the toluene is removed in vacuo and the resulting residue purified using flash chromatography on SiO2, elwira methanol/methylene chloride, giving 3.2 g of compound 10 in the form of a yellow oil. HPLC: 95% within 3.510 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 457.2 [M+H]+.

Example 11

(3Aα,4α,7α7aα)-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1N-tirolo[3,4-C]pyridine-1,3(2H)-dione triptorelin (11)

Compound 10 (3.2 g) was dissolved in 100 ml Meon and we use the t 10% Pd/C catalyst Degussa (2 g). Then introduce hydrogen from a cylinder. After one hour the reaction mass is filtered through celite and washed with Meon. Volatiles are removed in vacuo and the obtained crude product was then purified using preparative HPLC with reversed phase, giving 2.5 g of compound (11) in the form of a salt with TFA (triperoxonane acid) (white solid). HPLC: 99% within 1.843 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 325.12 [M+H]+.

Example 12

(3Aα,4α,7α7aα)-5-Acetyltetrahydro-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1N-pyrrolo[3,4-C]pyridine-1,3(2H)-dione(12)

Compound 11 (0.100 g, 0.23 mmol) suspended in THF (5.0 ml) and added TEA (0.097 ml, 0.46 mmol)to give a homogeneous solution. Then add acetylchloride (0.033 ml, 0.46 mmol). After 2 hours the reaction mass zakolerovat saturated aqueous NaHCO3and extracted with methylene chloride (3×15 ml). The crude product is purified using preparative-TLC, elwira chlorform/acetone, which gives 0.099 g of compound 12 as a colorless oil. HPLC: 99% for 2.66 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EU): the/e 367.0 [M+H] +.

Example 13

(3Aα,4α,7α7aα)-5-Benzoylecognine-2-(3-(trifluoromethyl)phenyl]-4,7-ethano-1N-pyrrolo[3,4-C]pyridine-1,3(2H)-dione(13)

Compound 11 (0.100 g, 0.23 mmol) suspended in THF (5.0 ml) and added TEA (0.097 ml, 0.46 mmol)to give a homogeneous solution. Then add benzoyl chloride (0.05433 ml, 0.46 mmol). After 2 hours the reaction mass zakolerovat saturated aqueous NaHCO3and extracted with methylene chloride (3×15 ml). The crude product is purified using preparative HPLC with reversed phase that give 0.020 g of compound 13 as a white foam. HPLC: 99% within 3.183 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 429.1 [M+H]+.

Example 14

(3Aα,4α,7α7aα)-Hexahydro-5-methyl-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1N-pyrrolo[3,4-C]pyridine-1,3(2H)-dione(14)

Compound 11(0.100 g, 0.23 mol) is suspended in THF (5.0 ml) and added TEA (0.097 ml, 0.46 mmol)to give a homogeneous solution. Add dimethylsulfate (0.043 ml, 0.46 mmol) and the reaction mass is stirred at a temperature of 25°C. After 14 hours the reaction mass was concentrated in vacuo and the crude product purified using preparative-TLC, elwira 10% Meon chloride in which the ethene, that gives 0.030 g of compound 14 in the form of a solid white color. HPLC: 100% within 1.797 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 339.21

Example 15

(3Aα,4α,7α7aα)-Hexahydro-5-(phenylmethyl)-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione triptorelin(15)

Compound 11 (0.100 g, 0.23 mmol) dissolved in DMF (5.0 ml) and added To the2CO3(0.063 g, 0.46 mmol). Then add benzylbromide (0.041 ml, 0.35 mmol). The reaction mass is stirred at a temperature of 25°within an hour, and then filtered and concentrated. The crude product is purified using preparative HPLC with reversed phase that give 0.055 g of compound 15 in the form of a solid white color. HPLC: 100% within 2.31 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 415.36 [M+H]+.

Example 16

(3Aα,4α,7α7aα)-Hexahydro-5-propyl-2-[3-(trifluoromethyl)phenyl 1-4,7 ethano-1N-pyrrolo[3,4-C]pyridine-1,3(2H)-dione triptorelin(16)

Compound 11 (0.100 g, 0.23 mmol) dissolved in DMF (5.0 ml) and added To the2/sub> CO3(0.079 g, 0.57 mmol)and then 1-bromopropane (0.031 ml, 0.34 mmol). The reaction mass is stirred at a temperature of 25°C for 6 hours and then filtered and concentrated. The crude product is purified using preparative HPLC with reversed phase that give 0.070 g of compound 16 in the form of a solid white color. HPLC: 100% within 1.907 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 340.22 [M+H]+

Example 17

(3Aα,4α,4β5Aβ,6α6Aα)-2-[4-Cyano-3-(trifluoromethyl)phenyl]decahydro-1,3-dioxo-4,6-(aminomethane)cycloprop [f] isoindole-7-carboxylic acid fenilmetilovy ether(17)

1-Methyl-3-nitro-1-nitrosoguanidine (2.5 g, 17 mmol) is added in portions to a 40% solution of KOH/N2About (15 ml) and Et2O (25 ml) at 0°C. After the addition is complete, the ether layer becomes yellow. After 30 minutes at 0°the ether layer was poured into a solution of (3Aα,4α,7α7aα)-2-[4-cyano-3-(trifluoromethyl)phenyl]-octahydro-1,3-dioxo-4,7-etheno-5H-pyrrolo[3,4-C]pyridine-5-carboxylic acid phenylmethylene ester (0.50 g, 1.09 mmol, obtained as described in example 10) and Pd(OAc)2(0.010 g) in THF (10 ml) at 0°C. the Reaction mixture was then slowly heated to a temperature of 25°and peremeshivayte within 24 hours and then filtered through celite, washed with THF. The crude product is then purified using flash chromatography on SiO2, elwira Meon/CH2Cl2that gives 0.34 g of compound 17 in a solid white color and as a single isomer. HPLC: 100% within 3.61 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 496.25 [M+H]+.

Example 18

(3Aα,4α,4β5Aβ,6α6Aα)-4-[Decahydro-1,3-dioxo-4,6-(aminomethane)declared]isoindole-2-yl]-2-(trifluoromethyl)benzonitrile(18)

Compound 17 (0.200 g, 0.404 mmol) was dissolved in Meon (20 ml) and add 5% Pd/C (0.200 g). Then introduce hydrogen from a cylinder. After 3 hours the reaction mass is filtered through celite, washed with Meon and volatiles removed in vacuum that gives compound 18 (0.130 g) in the form of a solid white color. HPLC: 100% within 1.80 min (retention time) (YMC S5 ODS column 4.6 x 50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 362.09 [M+H]+.

Example 19

(3Aα,4α,4β5Aβ,6α6Aα)-4-[Decahydro-7-methyl-1,3-dioxo-4,6-(aminomethane)cycloprop[f]isoindole-2-yl]-2-trifluoromethyl)benzonitrile(19)

Compound 17 (0.100 g, 0.277 mmol) was dissolved in CH3CN (2.0 ml). TEA (0.19 ml, 1.39 mmol) and then add MeI (0.052 ml, 0.83 mmol) and the reaction mass is stirred at a temperature of 25°C for 14 hours. It is then concentrated and the crude product was dissolved in CH2Cl2/water and extracted with CHhCIa (3×15 ml). The combined organics dried over anhydrous Na2SO4. The crude product is purified using flash chromatography elwira 3% MeOH/CH2Cl2that gives 0.030 g of compound 19 in the form of a solid of light yellow color. HPLC: 100% within 1.720 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 376.11 [M+H]+.

Example 20

(3Aα,4α,7β7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile(20V)

A. (3Aα,4β,7β7aα)-Hexahydro-4,7-epoxidation-1,3-dione(20A)

Fresh dimethylfuran (1.60 ml, 15.3 mmol) was dissolved in CH2Cl2(2.0 ml) and added maleic anhydride (1.0 g, 10.2 mmol). The reaction mass is stirred at a temperature of 25°C for 16 hours and then concentrated in vacuo, giving a solid yellow color. Polucen the e solid is dissolved in ethyl acetate (30 ml) and added Pd/C (10% Pd, 0.200 g). Then injected hydrogen using a balloon and the reaction mass is stirred for 24 hours. Pd is removed by filtration through celite, rinsing EtOAc, then concentra vacuum that gives compound 20A (1.69 g) as a solid white color. 2-Dimensional NOE experiments confirmed the structural connection structure 20A.

Century (3Aα,4β,7β7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile(20V)

A solution of compound 20A (603 mg, 3.21 mmol, 1 EQ.), 5-amino-2-cyanobenzoate (640 mg, 3.44 mmol, 1.07 EQ.) and TsOH (10 mg, catalytic amount) in toluene (5 ml) is heated in a sealed tube for 2 days. The reaction mixture is cooled to room temperature, and then concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 50% EtOAc/hexane gives 400 mg (1.10 mmol, 34%) of compound 20B in the form of a solid white color. HPLC: 99% within 3.04 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 382.2 [M+NH4]+.

Example 21

(3Aα,4β,7β7aα)-N-[4-[[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]thio]phenyl] ndimethylacetamide (E)

Table 1
Approximate ivanovii receptors nuclear hormone form (M=monomer, D=heterodimeric, N=goodkarma), tissue expression and ultimate therapeutic applications. (CNS=Central nervous system)
ReceptorForm Tissue expressionThe ultimate therapeutic use
NURR1M/DDominatrices neuronsParkinson's disease
RZRβMThe brain (pituitary), musclesSleep disorders
RORαMThe cerebellum, Purkinje cellsArthritis, Cerebral ataxia
NOR-1MThe brain, muscles, heart,

The adrenal glands, the thymus
Central nervous system diseases, Cancer
NGFI-BβM/DThe brainis zabolevaniya CNS
COUP-TfαNThe brainDiseases of the Central nervous system
COUP-TFβNThe brainDiseases of the Central nervous system
COUP-TFγχHThe brainDiseases of the Central nervous system
Nur77NBrain, thymus, adrenal glandDiseases of the Central nervous system
Rev-ErbAαNMuscle, brain (whole)Obesity
HNF4αNLiver, kidney, intestineDiabetes
SF-1MThe sex glands, the pituitary glandMetabolic disorders
LXRα,βDKidney (whole)Metabolic disorders
GCNFM/NTesticles, ovariesInfertility
ERRα,βMPlacenta, boneInfertility, osteoporosis
FXRDThe liver, kidneysMetabolic disorders
CARαNThe liver, kidneysMetabolic disorders
PXR to define againstNLiver, intestineMetabolic disorders
A.5-Methyl-2-paranatural (21A)

A solution of n-BuLi (83 ml, 133.0 mmol, 1.2 EQ., 1.6 M in hexane) is added to a stirred solution of 2-methylfuran (10 ml, 1 10.8 mmol, 1 EQ.) in THF (85 ml) at 0°in an inert atmosphere. The reaction mixture is stirred for 4 hours at room temperature, then cooled to a temperature of 0°C. is Added dropwise ethylene oxide (8.3 ml, 166.3 mmol, 1.5 EQ.) and the reaction mixture was allow to warm to room temperature over night. After tahaliyani saturated aqueous NH4Cl the resulting layers are separated and the aqueous layer was extracted with Et2O (2). The combined organic layers dried over Na2SO4and concentrate under reduced pressure. Distillation at atmospheric pressure (-170-185° (C)gives 10.13 g (80.3 mmol, 72%) of compound 21A in the form of oil is light yellow in color. Century 2-(2-Bromacil)-5-methylfuran (21B)

Ph3Br2(3.68 g, 8.72 mmol, 1.1 EQ.) added to a solution of compound 21A (1 g, 7.93 mmol, 1 EQ.) in DMF (8 ml) and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was added to N2O and extracted with EtOAc (3x). The combined organic layers washed with N2On (2x), dried over Nasub> 2SO4and concentrate under reduced pressure. Purification using flash chromatography on silica gel, elwira 10% EtOAc/hexane, gives 0.507 g (2.68 mmol, 34%) of compound 21B.

C. N-[4-[[2-(5-Methyl-2-furanyl)ethyl)thio]phenyl]ndimethylacetamide(S)

To a solution of 4-acetamidophenol (442 mg, 2.64 mmol, 1 EQ.) in THF (1 ml) at 0°in an inert atmosphere add a solution of n-BuLi (2 ml, 3.17 mmol, 1.2 EQ., 1.6 M in hexane) in THF (1 ml). The reaction solution was stirred at room temperature for 10 minutes and add a solution of compound 21B (0.5 g, 2.64 mmol, 1 EQ.) in THF (3 ml). After all the initial product is consumed as determined by TLC, the reaction mass zakolerovat H2Oh and the mixture extracted with EtOAc (2x), dried over Na2SO4and concentrate under reduced pressure. Purification using flash chromatography on silica gel, elwira 50% EtOAc/hexane, gives 0.644 g (2.34 mmol, 88%) of compound 21 C. MS (ESI): m/e 276.09 [M+H]+.

D. (3Aα,4β,7β7aα)-N-[4-[[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]-1,2,3,3A,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]thio]phenyl]ndimethylacetamide (21D)

A solution of compound C (195 mg, 0.708 mmol, 1 EQ.) and 4-(2,5-dihydro-2,5-dioxo-1N-pyrrol-1-yl)-2-triftormetilfosfinov (377 mg, 1.416 mmol, 2 EQ., obtained as described in example 1B) in CH2 Cl2(1.5 ml) was stirred at room temperature for two days. The reaction mixture was concentrated under reduced pressure, which gives the connection 21D, as determined by NMR analysis. Connection 21D are used directly in the next step without purification.

That is, (3Aα,4β,7β7aα)-N-[4[[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]-octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]thio]-phenyl] ndimethylacetamide (E)

A solution of crude compound 21D (0.708 mmol) and 10% Pd/C (200 mg) in Meon (20 ml) is stirred in hydrogen atmosphere over night. Purification using preparative chromatography [HPLC for 34.4 minutes (retention time) (YMC S5 ODS column, 20 x 250 mm, 0-100% aqueous solution of methanol over 30 minutes containing 0.1% TFA, 10 ml/min, monitoring at 220 nm)] then flash chromatography on silica gel, elwira 1% Meon/CH2Cl2, give 29 mg (0.053 mmol, 7.5%) connection E in the form of a yellow powder. HPLC: 99% within 3.44 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 544.01 [M+H]+

Example 22

[3aα,4β,7β,7aα)-N-[4-[[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]sulfinil]phenyl]ndimethylacetamide(22)

mCPBA (12 mg, 0.05 mmol) is added by portions to a solution of crude compound A (65 mg, 0.12 mmol, 1 EQ.) in CH2Cl2(6 ml)until you have used up the original product. Purification using preparative chromatography [HPLC within 30.5 minutes (retention time) (YMC S5 ODS column 30×250 mm, 0-100% aqueous solution of methanol over 30 minutes containing 0.1% TFA, 25 ml/min, monitoring at 220 nm)] gives 27.5 mg (0.049 mmol, 41%) of compound 22 in the form of solid red (˜1:1 mixture of diastereomers). HPLC: 96% within 2.88 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 559.97 [M+H]+.

Example 23

(3Aα,4β,7β7aα)-N-[4-[[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]sulfonyl]phenyl] ndimethylacetamide

(23)

mCPBA (26 mg, 0.105 mmol, 3 EQ.) added to a solution of compound A (19 mg, 0.035 mmol, 1 EQ.) in CH2Cl2(6 ml) and the reaction mass stirred at room temperature until used the original product and the intermediate sulfoxide (compound 22), as determined by TLC. Purification using preparative chromatography [HPLC for 53.3 minutes (retention time) (YMC S5 ODS column 30×250 mm 0-70% in denim solution of methanol for more than 45 minutes, containing 0.1% TFA, 25 ml/min, monitoring at 220 nm)] gives 27.5 mg (0.049 mmol, 40%) of compound 23 in the form of a solid white color. HPLC: 99% within 2.94 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 575.95 [M+H]+.

Example 24

(3Aα,4β,7β7aα)- and (3Aα,4α,7α7aα)-N-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]benzosulfimide (24Ci and 24Cii respectively)

A. 5-Methyl-2-paranatural 4-methylbenzenesulfonate (24A)

4-Methylbenzenesulfonate (907 mg, 4.76 mmol) are added to a solution of compound 21A (500 mg, 3.96 mmol) in 6 ml of dry pyridine. The reaction mass was stirred at room temperature for 4 hours, then zakolerovat ice. The reaction mixture was extracted with CH2Cl2and the combined organic layers washed with saturated aqueous sodium bicarbonate and water, dried and concentrated under reduced pressure, giving 900 mg (81%) of compound 24 in the form of a yellow oil.

C. N-[2-(5-Methyl-2-furanyl)ethyl]benzosulfimide (24V)

Benzosulfimide (157 mg, 1 mmol) are added to 10% water is a sodium hydroxide solution (0.4 ml, 1 mmol). Then add a solution of compound 24A (280 mg, 1 mmol) in acetone (1 ml). The reaction mixture is heated at a temperature of 90°C for 8 hours, then cooled to room temperature. Add ice and the mixture extracted with CH2Cl2. The combined organic layers washed with water, dried and concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira CH2Cl2give 60 mg (23%) of compound 24 in the form of a yellow oil.

S. (3Aα,4β,7β7aα)- and (3Aα,4α,7α7aα)-N-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]benzene sulfonamide (24Ci and s respectively)

4-(2,5-Dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-cryptomathematical (129 mg, 0.45 mmol, obtained as described in example 1B) are added to a solution of compound 24 (60 mg, 0.23 mmol) in CH2Cl2(2 ml). The reaction mixture was stirred at room temperature for 2 days, concentrated under reduced pressure and purified using flash chromatography on silica gel, elwira 70% EtOAc/hexane, giving 20 mg (16%) unsaturated product Delta-alder reaction. Unsaturated product (20 mg) immediately dissolved in 2 ml ethanol and add 10 mg of 10% Pd/C. the Solution was stirred at room temperature overnight in a hydrogen atmosphere. The mixture is filtered and f is ltrate concentrated under reduced pressure. Purification using preparative HPLC with reversed phase give 7 mg of the compound 24Ci and 2 mg of compound 24Cii. Connection 24Ci: HPLC: 96% within 3.17 min (retention time) (YMC S5 ODSA CIS 4.6×50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.1% TFA defined at 220 nm), MS (EC): m/e: 533.99 [M+H]+. Connection 24Cii: HPLC: 99% within 38.95 minutes (retention time) (YMC S5 ODS 20×250 mm, 10%-90% aqueous solution of methanol over a 40 minute gradient with 0.1% TFA defined at 220 nm), MS (USA): m/e 533.99 [M+H]+

Example 25

(3Aα,4β,7β7aα)-4-[Octahydro-4-(2-hydroxyethyl-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (25V)

A. (3Aα,4β,7β7aα)- and (3Aα,4α,7α7aα)-4-[1,3,3A,4,7,7a-Hexahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (25Ai and 25Aii respectively)

A solution of compound 21A (252 mg, 2 mmol, 1 EQ.) and 4-(2,5-dihydro-2,5-dioxo-1N-pyrrol-1-yl)-2-triftormetilfosfinov (798 mg, 3 mmol, 1.5 EQ.) in CH2Cl2(10 ml) was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 65% EtOAc/hexane, to give 217 mg of pure compound 25Ai, 73 mg of pure compound 25Ai and 310 mg of the mixture of both compounds 25Ai and 25Aii. All three fractions isolated in the form of solids in white with a total yield 600 mg (1.53 mmol, 76.5%). Connection 25Ai: HPLC 90% within 2.56 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm). Connection 25AU: HPLC 90% within 2.56 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm).

Century (3Aα,4β,7β7aα)-4-[octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile(25V)

A solution of compound 25Ai (0.2 g, 0.51 mmol, 1 EQ.) and 10% Pd/C (43 mg, catalytic amount) in EtOH (12 ml) is stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction mixture is filtered through celite and concentrated under reduced pressure, giving 0.2 g (0.51 mmol, 100%) connection 25V in a solid white color. HPLC: 95% within 2.59 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 394.97 [M+H]+.

Example 26

(3Aα,4α,7α7aα)- and (3Aα,4β,7β7aα)-N-[4-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]Oct the Idro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethoxy]phenyl]ndimethylacetamide (26Ci and 26Cii respectively)

A. 2-[4-[2-(5-Methyl-2-furanyl)ethoxy]phenyl]ndimethylacetamide (26A)

Triphenylphosphine (681 mg, 2.6 mmol, 1.3 EQ.) added to a solution of compound 21A (252 mg, 2 mmol, 1 EQ.) and 4-acetamidophenol (302 mg, 2 mmol, 1 EQ.) in CH2Cl2(4 ml). TTF (5 ml) is added to make the reaction mixture homogeneous, and the mixture is then cooled to a temperature of 0°C. is Added dropwise DEAD (0.41 ml, 2.6 mmol, 1.3 EQ.) and the reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 60% EtOAc/hexane, then preparative HPLC with reversed phase give 270 mg (52%, 1.04 mmol) of compound 26A in the form of a solid light brown color. MS (ESI): m/e 260.09 [M+H]+.

Century (3Aα,4α,7α7aα)- and (3Aα,4β,7β7aα)-N-[4-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]-1,2,3,3A,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethoxy]phenyl]ndimethylacetamide (26Bi and 26Bii respectively)

A solution of compound 26A (40 mg, 0.154 mmol, 1 EQ.) and 4-(2,5-dihydro-2,5-dioxo-1N-pyrrol-1-yl)-2-triftormetilfosfinov (88 mg, 0.31 mmol, 2 EQ.) in CH2Cl2(2 ml) was stirred at room temperature for 2 days. actionnow the mixture is concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 75% EtOAc/hexane, to give 55 mg (0.105 mmol, 68%) from 5 to 1 mixture of compounds 26Bi and 26Bii in a solid white color, which is used directly in the next step. HPLC 90% within 3.28 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm).

S. (3Aα,4α,7α7aα)- and (3Aα,4β,7β7aβ)-N-[4-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethoxy]phenyl]ndimethylacetamide (26Ci and 26Cii respectively)

Solution mixture of compounds 26Bi and 26Bii (55 mg, 0.105 mmol, 1 EQ.) and 10% Pd/C (12 mg, catalytic amount) in EtOH (3 ml) is stirred under hydrogen atmosphere at room temperature overnight. The reaction mixture is filtered through celite and concentrated under reduced pressure, giving 50 mg of crude product. Purification using flash chromatography on silica gel, elwira 70% EtOAc/hexane, to give 18 mg (0.034 mmol, 32%) connection 26Ci [HPLC: 96% within 3.33 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm). MS (EU): m/e 528.01 [M+H]+]; and 2.3 mg (0.004 mmol, 4%, 85:15-endo:Exo) 85:15 mixture of compounds (with the aid of the d 1H NMR) 26Cii and connections 26Ci respectively [HPLC: 90% within 3.35 min (retention time) (YMC S5 ODS column C mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 528.12 [M+H]+].

Example 27

(3Aα,4α,7α7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-1N-isoindole-1,3(2H)-dione (27D)

A. (endo, endo)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (27A)

Compounds 27A, 27B and 27C are synthesized in accordance with techniques described in Sprague et al, J. Med. Chem. 28, 1580-1590 (1985). A mixture of furan (100 ml, 1.38 mol, 1 EQ.) and maleic acid (159.6 g, 1.38 mol, 1 EQ.) in N2(340 ml) was stirred at room temperature for 5 days. Place the mixture into a separating funnel and the aqueous layer was separated from the layer containing unreacted furan. The aqueous layer was treated with charcoal, filtered through celite and placed in the fridge. The desired product crystallized from solution after persecution, filtered off, washed with cold water and dried over P2O5that gives 70 g (0.38 mol, 28%) of compound 27A in the form of a solid white color.

C. (endo, endo)-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid (27B)

To a solution of connection is drop-27A (69 g, 0.375 mol, 1 EQ.) in EtOH (700 ml) is added 10% Pd/C (4.5 g, catalytic amount) and the mixture is shaken in an atmosphere of hydrogen at 55 psi until prekratila gas absorption. The mixture is filtered through celite and concentrated in vacuo, giving 66 g (0.355 mol, 95%) of compound 27B in a solid white color.

S. (3Aα,4β,7β7aα)-Hexahydro-4,7-epoxidation-1,3-dione (27)

A solution of compound 27B (66 g, 355 mol) in acetylchloride (300 ml) is heated at boiling under reflux for one hour. The reaction solution was concentrated in vacuo and the resulting residue is recrystallized from benzene, giving 49.2 g (0.292 mol, 82%) of compound 27 in the form of a solid white color (>99% endo with1H NMR).

D. (3Aα,4α,7α7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-1N-isoindole-1,3(2H)-dione (27D)

Compound 27C (45 mg, 0.30 mmol, 1 EQ.) combine with 2 naphthalenamine (47 mg, 0.33 mmol, 1.1 EQ.) in acetic acid (1 ml) and heated at a temperature of 115°With during the night. After the reaction mass is then cooled to room temperature, add a drop of water and the precipitate filtered off. The resulting product is washed with methanol and dried to obtain 65.7 mg (74.5%) of compound 27D in the form of a crystalline solid white. HPLC: 99% within 2.68 minutes (VRU is retention)-(YMC S5 ODS column 4.6× 50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 294.0 [M+H]+.

Example 28

(1Aα,2β2Aα5Aα,6β6Aα)-Hexahydro-4-(2-naphthalenyl)-2,6-epoxy-3H-oxirane[f]isoindole-3,5(4H)-dione(28V)

A. (1α,2β2Aα5Aα,6β6Aα)-Tetrahydro-2,6-amoxicilina[f]isobenzofuran-3,5(an,an)-dione (28A)

As described in Yur'ev, et al, J. Gen. Chem. U.S.S.R. (Engl. Transl.) 31, 772-775 (1961), a solution of anhydride Exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid (5 g, 30.09 mmol), formic acid (10 ml) and hydrogen peroxide (6 ml) was stirred at room temperature. After 30 minutes the reaction mass is placed in an ice bath (it becomes exothermic, together with gas evolution) and give the ability to slowly warm to room temperature. After stirring over night the precipitate is collected by filtration, washed with glacial acetic acid and dried, giving 3.02 g of white powder. The crude solid is boiled in acetylchloride (100 ml) for 10 hours and the mixture is concentrated -20 ml under reduced pressure. The precipitate is filtered off, washed with dioxane and dried, giving 2.37 g of compound 28A in the form of white powder.

Century (1Aα,2β,2a1 ,5aα,6β6Aα)-Hexahydro-4-(2-naphthalenyl)-2,6-epoxy-3H-oxirane [f] isoindole-3,5(4H)-dione (28V)

Compound 28A (100 mg, 0.520 mmol, 1.2 EQ.) mix with 2 naphthalenamine (0.434 mmol, 1 EQ.) in acetic acid (2 ml) and heated at a temperature of 115°With during the night. Then the reaction allow to cool to room temperature, water is added and the precipitate filtered off. The resulting product is washed successively with an aqueous solution To a2CO3and water, and then dried in a vacuum thermostat to get 113.7 mg (85.3%) of compound 28 in the form of a crystalline solid off-white color. HPLC: 99% within 1.76 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 308.0 [M+H]+.

Example 29

(3Aα,4α,7α7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-3A,4,7,7a-tetrahydro-4,7-dimethyl-4,7-epithio-1N-isoindole-1,3(2H)-dione 8-oxide (29)

2.5-Dimethylthiophene (0.048 ml, 0.42 mmol) and 4-(2,5-dihydro-2,5-dioxo-1N-pyrrol-1-yl)-2-cryptomathematical (0.290 g, 0.625 mmol) was dissolved in CH2Cl2(8.0 ml) and cooled to a temperature of -20 °C. Slowly add first BF3Et2O (0.412 ml, 3.36 mmol), and then mCPBA (-50%, 0.290 g, 0.84 mmol). After 2 hours, when the fact is the temperature value -20 ° With the reaction mass is then poured into a saturated solution of NaHCO3and extracted with CH2Cl2(3×20 ml), the organics dried over anhydrous Na2SO4. The crude product is purified using flash chromatography on SiO2, elwira 5%-10%-20% EtOAc in CH2Cl2that gives 0.119 g of compound 29 in the form of a solid white color. HPLC: 91% within 3.303 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution metaal for over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm). MS (ESI): m/e 480.2 [M+H]+.

Example 30

(3Aα,4α,7α7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]-3A,4,7,7a-tetrahydro-4,7-epithio-1N-isoindole-1,3(2H)-dione 8-oxide (30)

Thiophene (0.375 ml, 4.69 mmol) and 4-(2,5-dihydro-2,5-dioxo-1N-pyrrol-1-yl)-2-cryptomathematical (0.100 g, 0.313 mmol) dissolved in CH2Cl2(50 ml), added mCPBA (-50%, 1.62 g, 4.69 mmol) and stirred at a temperature of 25°C for 3 hours. Then add triphenylphosphine (2.0 g). After 15 minutes, the volatiles removed in vacuum and the obtained residue was dissolved in CH2Cl2(200 ml) and washed with saturated solution of NaHCO3(3×50 ml) and dried over Na2SO4. Then the crude product is purified using flash chromatography on SiO2, elwira 1%-3%-5% methanol in CH2Cl2that gives compound 30 as white powder (0.059 g). NMR spectroscopy and LC analysis shows a single diastereoisomer. HPLC: 100% within 3.437 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 443.2 [M+H]+

Example 31

(3Aα,4α,7α7aα)-Hexahydro-2-[3-(trifluoromethyl)phenyl-4,7-imino-1N-isoindole-1,3(2H)-dione (31D)

A. 7-Azabicyclo[2.2.1]hepta-2,5-diene-2,3,7-tricarboxylic acid, 2,3-dimethyl 7-(1,1-dimethylethyl) ether (31A)

Fresh acetylenedicarbonic acid dimethyl ester (6.7 ml, 54.0 mmol) and N-(tert-butyloxycarbonyl)-1N-pyrrole (9.0 ml, 54.0 mmol) are combined and heated at a temperature of 120°C for 3 hours. Purification using flash chromatography on SiO2, elwira EtOAc/CH2Cl2give 8.3 g of compound 31A in the form of a solid yellow color.

Century (Exo,endo)-7-Azabicyclo[2.2.1]hept-2,5-diene-2,3,7-tricarboxylic acid, 7-(1,1-dimethylethyl) ether (V)

Compound 31A (1.0 g, 3.5 mmol) dissolved in Meon (2.0 ml) and add a solution of KOH (1 g in 5 ml of N2O). The reaction mass is heated to a temperature of 50°within hours. The reaction mixture is then cooled to a temperature of 25 C and added Pd/C (0.5 g, 10% Pd), and the mixture is then placed in the apparatus is at Parra for 14 hours at 25° C. the Reaction mixture was then filtered over celite and washed with water. The aqueous solution is acidified to pH 2 by the addition of IN HCl and then extracted with EtOAc (2×100 ml). The concentration of the organic network connection V in the form of a solid pale yellow color.

S. (3Aα,4α,7α7aα)-Hexahydro-1,3-dioxo-4,7-aminoazobenzene-8-carboxylic acid 1,1-dimethylethylene ether (S)

The crude compound W heated to a temperature of 120°With vacuum in the chamber sublimation, getting sublimated connection S in a solid white color (0.051 g), which is collected directly used in the next step without further purification.

D. (3Aα,4α,7α7aα)-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-imino-1N-isoindole-1,3(2H)-dione (31D)

Connection S (0.050 g, 0.187 mmol) and 1-amino-3-(trifluoromethyl)benzene (0.030 g, 0.187 mmol) was dissolved in Asón (2.5 ml) and heated to a temperature of 115°C for 4.5 hours. The reaction mass zakolerovat by adding a saturated aqueous solution of NaHCO3and extracted with methylene chloride (3×15 ml). The crude product is purified using preparative HPLC with reversed phase that give 0.030 g of compound 31D in a solid white color. HPLC: 99% for 2.33 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution m is canola for more than 4 minutes, containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 311.15

Example 32

(3Aα,4β,7β7aα)- and (3Aα,4α,7α7aα)-3A,4,7,7a-Tetrahydro-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1N-isoindole-1,3(2H)-dione (32i and 32ii, respectively)

Fresh 2.5-dimethylfuran (0.32 ml, 2.6 mmol) dissolved in CH2Cl2(2.0 ml) and add 1-[3-(trifluoromethyl)phenyl]-1N-pyrrole-2,5-dione (0.5 g, 2.5 mmol). The reaction mass is stirred at a temperature of 25°C for 16 hours and then concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 0.5% Meon/CH2Cl2gives 50 mg connection 32i and 250 mg of compound 32ii, in the form of solids white. Connection 32i: HPLC: 92% within 3.047 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e: 338.75 [M+H]+Connection 32ii: HPLC: 98% within 3.08 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 338.30 [M+H].

Example 33

(3Aα,4α,7α7aα)-Hexahydro-4,7-dimethyl-2-[3-(triform the Teal)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione (33)

Connection 32ii (0.080 g, 0.237 mmol) dissolved in EtOAc (2 ml) and EtOH (1 ml) and added Pd/C (10% Pd, 0.050 g). From the container and then introducing hydrogen and the reaction mass is stirred for 24 hours. The mixture is filtered through celite, washed with EtOAc and concentrated in vacuo, giving compound 33 (0.075 g) as a solid white color. Further purification is not required. HPLC: 90% within 3.233 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 340.40 [M+H]+.

Example 34

(3Aα,4α,7α7aα)-Tetrahydro-5-methyl-2-(4-nitro-1-naphthalenyl)-4,7-etheno-1N-pyrrolo[3,4-C]pyridine-1,3,6(2N,,5H)-Trion(34B)

A. 4,5,7,7a-Tetrahydro-5-methyl-4,7-Adenophora[3,4-C]pyridine-1,3,6(an)-Trion (34A)

Compound 34A synthesized with the help of advanced methods in Tomisawa et al, Heterocycles 6, 1765-1766 (1977) and Tetrahedron Lett. 29, 2465-2468 (1969). Maleic anhydride and 1-methyl-2-pyridone suspended in 30 ml of anhydrous toluene. The reaction vessel was equipped with a trap Dean stark and heated at the boil under reflux for 48 hours. The solution is painted in a dark color, allow to cool to room temperature and then flying the substances removed in vacuum. The resulting paste is brown dissolved in 10 ml of boiling toluene and the hot solution is filtered under a stream of nitrogen to remove small particles. Leaving to stand at 25°C, the desired product precipitated from solution. Solid allocate filtration and washed with cold toluene, which gives the connection 34A, which is used without further purification.

Century (3Aα,4α,7α7aα)-tetrahydro-5-methyl-2-(4-nitro-1-naphthalenyl)-4,7-etheno-1N pyrrolo [3,4-C] pyridine-1,3,6(2H,5H)-Trion(34B)

1-Amino-4-nitronaphthalene (0.094 g, 0.5 mmol) and compound 34A (0.130 g, 0.63 mmol) dissolved in Asón (2.0 ml) and heated to a temperature of 110°within hours. The reaction mixture is then cooled to a temperature of 25°and poured into cold saturated aqueous solution of K2CO3, and then vigorously stirred for 10 minutes. The solution is filtered and washed with water. The obtained filtrate is dried in vacuo and purified by chromatography on silica gel using a solvent system of 4:6 EtOAc/hexane, giving 0.172 g of compound 34B in the form of a solid white color. HPLC: 92% within 2.472 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 378.29 [M+H]+

Example 35

(3Aα,4β,7β7aα)-4-[4-[2-(4-CFT is Hinoki)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile(35)

DEAD (0.06 ml, 0.380 mmol, 1.5 EQ.) added to a solution of triphenylphosphine (100 mg, 0.380 mmol, 1.5 EQ.) in THF (1.3 ml) at room temperature in an inert atmosphere. After stirring for 10 minutes, add one dose of 4-terfenol (43 mg, 0.380 mmol, 1.5 EQ.). The reaction mixture is stirred for 5 minutes add the connection 25V (100 mg, 0.254 mmol, 1 EQ.) and stirring is continued for 3.5 hours. Purification using flash chromatography on silica gel, elwira 50% EtOAc/hexane, then preparative chromatography [HPLC: 1 1.93 min (retention time) (YMC S5 ODS column 20×100 mm, 0-100% aqueous solution of methanol over 10 min containing 0.1% TFA, 20 ml/minute, monitoring at 220 nm)], to give 72 mg (58%) of compound 35 as a solid substance. HPLC: 99% within 3.74 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 487.1 [M-N]-.

Example 36

(3aα,4β,7β7aα)-4-[4-(2-Bromacil]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (36)

The solution 25V (495 mg, 1.26 mmol, 1 EQ.) and pyridine (0.1 ml, 1.26 mmol, 1 EQ.) in CH2Cl2(2 ml) was added to a solution of Ph3PBr2(636 mg, 1.51 mmol, 1.2 EQ.) in CH2C 2(2 ml) at 0°C. the Reaction mixture was stirred at room temperature for 3 hours, then the solvent is removed under reduced pressure. The obtained residue is washed twice with 10 ml doses EtOAc-hexane (6:4) and the joint remover purified using flash chromatography on silica gel, elwira 60% EtOAc/hexane, giving 390 mg (0.85 mmol, 67.7%) of compound 36 in the form of a solid white color. HPLC: 99% within 3.51 min (retention time) (YMC S5 ODS column 4.6 x 50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm). MS (ESI): m/e 456.7 [M-N]-.

Example 37

(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-(3-methyl-4-nitrophenyl)-4,7-epoxy-1N-isoindole-1,3(2H)-dione (37)

A mixture of 4-nitro-3-methylaniline (0.050 g, 0.33 mmol), compound 20A (0.083 g, 0.43 mmol), TEA (0.2 ml), MgSO4(0.075 g) and toluene (0.8 ml) are combined in a sealed tube and the mixture is heated to a temperature of 120°C for 14 hours. After cooling to 25 the reaction mass is filtered, washed with CH2Cl2and concentrate. The crude product is purified using preparative-TLC on SiO2, elwira CH2Cl2that gives 0.075 g of compound 37 in the form of a solid pale yellow color. HPLC: 100% within 2.733 minutes (retention time)-(YMC S5 ODS column, 4.6 is 50 mm; 10-90% MeOH/H2O gradient + 0.1% TFA; 4 ml/min, 220 nm), MS (EC): m/e 348.2 [M+NH4]+.

Examples 38 121

Additional compounds of the present invention are obtained by methods similar to those described above. The compounds of examples 38 121 have the following structural formula (L is a bond):

where the value of G, the connection name, retention time, molecular mass, and the production method, formulated in table 2. The chromatographic technique used to determine the retention time in table 2 is defined as follows: LCMS=YMC S5 ODS column, h mm, elwira 10-90% MeOH/H2O more than 4 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. The molecular weight of compounds in table 2, was determined using MS (EC) by the formula m/E.

Table 2
Ave. No.GThe connection nameRetention time (minutes)/ molecular weightThe process of example
38(3Aα,4β,7β7aα)-2-(2-Forfinal)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.72 LCMS/332.20 [M+H]+8
39(3Aα,4β,7β7aα)-2-[3-Chloro-4-(4-morpholinyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.20 LCMS/363.20 [M+H]+8
40(3Aα,4β,7β7aα)-2-Dihydro-1H-inden-5-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.26 LCMS/284.22 [M+H]+8

Ave. No.GThe connection nameRetention time (minutes)/ molecular. weightThe process of example
41(3Aα,4β,7β7aα)-2-(4-Bromo-1-naphthalenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.73 LCMS/404.11 [M+CH3HE+H]+8
42(3Aα,4β,7β7aα)-2-(4-Chloro-1-naphthalenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.63 LCMS/328.14 [M+H]+8
43(3Aα,4β,7β7aα)-2-(5-Amino-1-naphthalenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione1.64 LCMS/8
44(3Aα,4β,7β7aα)-Hexahydro-2-(7-hydroxy-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.54 LCMS/308.23 [M-H]-8
45(3Aα,4β,7β7aα)-Hexahydro-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.117 LCMS/404.11 [M+CH3HE+H]+8
46(3Aα,4β,7β7aα)-Hexahydro-2-(1H-indol-5-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.39 LCMS/283.23 [M+H]+8
47(3Aα,4β,7β7aα)-Hexahydro-2-(1H-indazol-6-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.35 LCMS/282.23 [M-N]-8
48(3Aα,4β,7β7aα)-2-(1,3-Benzodioxol-5-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.47 LCMS/288.20 [M+H]+8

Ave. No.GThe connection nameRetention time (minutes)/ molmass.The process of example
49 (3Aα,4β,7β7aα)-2-[4-Amino-3-(trifluoromethyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.71 LCMS/327.20 [M+H]8
50(3Aα,4β,7β7aα)-2-(3-Chloro-4-itfinal)hexahydro-4,7-epoxy-1H-isoindole-1,3 (2H)-dione3.70 LCMS/435.2 [M+CH3HE]+8
51(3Aα,4β,7β7aα)-Hexahydro-2-(8-chinoline)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.28 LCMS/295.22 [M+H]8
52(3Aα,4β,7β7aα)-2-(2,3-Dihydro-1,4-benzodioxin-6-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.55 LCMS/302.23 [M+H]+8
53(3Aα,4β,7β7aα)-Hexahydro-2-[2-oxo-4-(trifluoromethyl)-2H-1-benzopyran-7-yl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.38 LCMS/412.17 [M+CH3HE+H]+8
54(3Aα,4β,7β7aα)-Hexahydro-2-(4-methyl-2-oxo-2H-1-benzopyran-7-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.7 LCMS/326.20 [M+H] +8
55(3Aα,4β,7β7aα)-2-(2,5-Dimethoxy-4-nitrophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.70 LCMS/349.23 [M+H]+8
56(3Aα,4β,7β7aα)-2,3,5,6-Titrator-4-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzonitrile2.97 LCMS8

Ave. No.GThe connection nameRetention time (minutes)/mol. weightThe process of example
57(3Aα,4β,7β7aα)-Hexahydro-2-(2,4,5-tryptophanyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.90 LCMS8
58(3Aα,4β,7β7aα)-Hexahydro-2-(2,4,5-trichlorophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.64LCMS/346.39[M]+8
59(3Aα,4β,7β7aα)-2-(2-Amino-4,5-dichlorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.23 LCMS8
60(3Aα,4β,7β7aβ)-2-(3,4-Differenl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.91 LCMS/280.23 [M+H]+8
61(3Aα,4β,7β7aα)-1-Acetyl-2,3-dihydro-6-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-1H-indole2.43 LCMS/359.26 [M+CH3HE+H]+8
62(3Aα,4β,7β7aα)-2-(3-Chloro-4-forfinal)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.21 LCMS/328.14 [M+CH3HE+H]+8
63(3Aα,4β,7β7aβ)-2-(3,4-Dichlorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.54 LCMS/311.79 [M-H]+8
64(3Aα,4β,7β7aα)-Hexahydro-2-(3,4,5-trichlorophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.5 LCMS/378.10 [M+CH3OH+H]+8

8
Ave. No.GThe connection nameRetention time (minutes)/mol. mass.The process p is example
65(3Aα,4β,7β7aα)-2-(3-Chloro-4-methoxyphenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.99 LCMS/308.11 [M+H]+8
66(3Aα,4β,7β7aα)-2-(3-Chloro-4-were)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.39 LCMS/292.20 [M+H]+8
67(3Aα,4β,7β7aα)-Hexahydro-2-(2-methyl-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.28 LCMS/308.23 [M+H]+8
68(3Aα,4β,7β7aα)-2-(4-Chloro-3-were)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.40 LCMS/292.20 [M+H]8
69(3Aα,4β,7β7aα)-2-(3,4-Dimetilfenil)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.11 LCMS/272.23 [M+H]+8
70(3Aα,4β,7β7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.76 LCMS/421.98 [M+CH3HE+H]+
71(3Aα,4β,7β7aα)-2-(4-Bromo-3-were)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.50 LCMS/336.05 [M+H]+8
72(3Aα,4β,7β7aα)-2-(4-Fluoro-3-nitrophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.80 LCMS/305.25 [M-H]-8

Ave. No.GThe connection nameRetention time (minutes)/molmasseThe process of example
73(3Aα,4β,7β7aα)-2-[4-Fluoro-3-(trifluoromethyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.45LCMS/362.26 [M+CH3HE+H]+8
74(3Aα,4β,7β7aα)-2-(4-Chloro-3-nitrophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.19 LCMS/322.86 [M]+8
75(3Aα,4β,7β7aα)-2-[4-Chloro-3-(trifluoromethyl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.68 LCMS/345.83 [M]+/sup> 8
76(3Aα,4β,7β7aα)-2-(4-Chloro-2-methoxy-5-ethylphenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.31 LCMS/322.20 [M+H]+8
77(3Aα,4β,7β7aα)-2-(4-Amino-3-nitrophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.34 LCMS/302.27 [M-H]-8
78(3Aα,4β,7β7aα)-Hexahydro-2-(4-methyl-3-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.2 LCMS/335.20 [M+CH3HE+H]+8
79(3Aα,4β,7β7aα)-2-(3,4-Acid), hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.35 LCMS/304.25 [M+H]+8
80(3Aα,4β,7β7aα)-Hexahydro-2-(3-hydroxy-4-methoxyphenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione0.98 LCMS/321.19 [MN-SN3HE]+8

Ave. No.GThe connection nameThe retention time (m is chickpeas)/mol. weightThe process of example
81(3Aα,4β,7β7aα)-Hexahydro-2-(4-methyl-5-nitro-2-pyridinyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione0.54 LCMS/304.20 [M+H]+8
82(3Aα,4β,7β7aα)-2-Chloro-4-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-α-phenylbenzophenone3.67 LCMS/423.8 [M+CH3HE]+8
83(3Aα,4β,7β7aβ)-Hexahydro-2-(2-methoxy-3-dibenzofurans)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.66 LCMS/ 364.25 [M+H]+8
84(3Aα,4β,7β7aα)-Hexahydro-2-(2,3,4-tryptophanyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.06 LCMS/298.14 [M+H]+8
85(3Aα,4β,7β7aα)-2-(2,3-Dihydro-2-methyl-1,3-dioxo-1H-isoindole-5-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.70 LCMS/359.22 [M+CH3HE+H]+8
86(3Aα,4β,72 7aα)-2-(4-Bromo-2,3,5,6-tetrafluorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.72 LCMS/426.07 [M+CH3HE+H]+8
87(3Aα,4β,7β7aα)-Hexahydro-2-(2-hydroxy-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.52 LCMS/308.26 [M-N]+8
88(3Aα,4β,7β7aα)-2-[2,5-Dichloro-4-(1H-pyrrol-1-yl)phenyl]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.70 LCMS/376.64 [M-N]+8

8
Ave. No.GThe connection nameRetention time (minutes)/mol. weightThe process of example
89(3Aα,4β,7β7aα)-Hexahydro-2-[4-(methoxymethyl)-2-oxo-2H-1-benzopyran-7-yl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.79 LCMS/ 356.26 [M+H]+8
90(3Aα,4β,7β7aα)-2-(6-Benzothiazolyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.46 LCMS/301.19 [M+H]+8
91 (3Aα,4β,7β7aα)-2-Methoxy-4-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzoic acid methyl ester2.75 LCMS/332.25 [M+H]+8
92(3Aα,4β,7β7aα)-2-Methyl-5-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzonitrile2.80 LCMS/315.26 [M+CH3HE+H]+8
93(3Aα,4β,7β7aα)-Hexahydro-2-(2-oxo-2H-1-benzopyran-6-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.45 LCMS/312.20 M+H]+8
94(3Aα,4β,7β7aα)-Hexahydro-2-(2,3,5,6-tetramethyl-4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.59 LCMS/377.25 [M+CH3HE+H]+8
95(3Aα,4β,7β7aα)-Hexahydro-2-(2,4,5-trimetilfenil)-4,7-epoxy-1H-isoindole-1,3 (2H)-dione3.33 LCMS/286,30 [M+H]+8
96(3Aα,4β,7β7aα)-2-(4-Fluoro-3-were)hexahydro-4,7-epoxy-1H-isoindole-1,3 (2H)-dione3.00 LCMS/276.23 [M+H]+

Ave. No.GThe connection nameRetention time (minutes)/mol. weightThe process of example
97(3Aα,4β,7β7aα)-Hexahydro-2-(3-methoxy-4-were)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.5 LCMS/288.23 [M+H]+8
98(3Aα,4β,7β7aα)-1-Ethyl-2-methyl-5-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-N-vinylbenzenesulfonic3.56 LCMS/441.26 [M+H]+8
99(3Aα,4β,7β7aα)-2,6-Dibromo-4-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzosulfimide2.25 LCMS8
100(3Aα,4β,7β7aα)-2,4-Dimethyl-6-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-3-pyridylcarbonyl2.75 LCMS/298.23 [M+H]+8
101(3Aα,4β,7β7aα)-2-(2,3-Dimethyl-1H-indol-5-yl)hexahydro-4,7-epoxy-1 H-isoindole-1,3(2H)-dione8
102(3Aα,4β,7β7aα)-2-(3-Dibenzofurans)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.72 LCMS/366.23 [M+CH3HE+H]+8
103(3Aα,4β,7β7aα)-Hexahydro-2-(2'-hydroxy[1,1':3',1"-terphenyl]-5'-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.70 LCMS/412.23 [M+H]+8
104(3Aα,4β,7β7aα)-Hexahydro-2-(5,6,7,8-tetrahydro-3-hydroxy-2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.24 LCMS/312.32 [M+H]+8

Ave. No.The connection nameRetention time (minutes)/mol. weightThe process of example
105(3Aα,4β,7β7aα)-2-(2,3-Dihydro-1H-indol-6-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.42 LCMS/285.29 [M+H]+8
106(3Aα,4β,7β7aα)-2-(1,3-Dihydro-2,2-tioxidants]thiophene-5-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3 (2H)-dione 1.99 LCMS/366.26 [M+CH3HE+H]+8
107(3Aα,4β,7β7aα)-Hexahydro-2-(2-hydroxy-4,5-dimetilfenil)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.78 LCMS/286.32 [M-H]-8
108(3Aα,4β,7β7aα)-2-(2,3-Dihydro-2,2,3,3-titrator-1,4-benzodioxin-6-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.82 LCMS/406.19 [M+CH, OH+N]+8
109(3Aα,4β,7β,a)-Hexahydro-2-(1H-indazol-5-yl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.13 LCMS/284.23 [M+H]8
110(3Aα,4β,7β7aα)-2-(4-Amino-2,3,5,6-tetrafluorophenyl)-hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.60 LCMS/363.22 [M+CH3HE+H]+8
111(3Aα,4β,7β7aα)-2-(4-Bromo-3-chlorophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.64 LCMS/389.64 [M+CH3HE+H]+8
112(3Aα,4β,7β,7 theα )-Hexahydro-2-(5-hydroxy-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.48 LCMS/308.27 [M-H]-8

Ave. No.GThe connection nameRetention time (minutes)/mol. weightThe process of example
113(3Aα,4β,7β7aα)-4-(Octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile3.28 LCMS/337.16 [M+H]+8
114(3Aα,4β,7β7aα)-2-(4-Morpholinyl)-5-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzoic acid methyl ester2.72 LCMS/387.17 [M+H]+8
115(3Aα,4β,7β7aα)-2-Fluoro-5-(octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzonitrile2.69 LCMS/319.26 M+CH3HE+H]+8
116(3Aα,4β,7β7aα)-2-(4-Bromophenyl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione5.80 LCMS/393.0 [M+H]+8
117 (3Aα,4β,7β7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-1 H-isoindole-1,3(2H)-dione2.92 LCMS/333.7 [M+H]+8
118(3Aα,4β,7β7aα)-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.27 LCMS/312.2 [M+H]+8
119(3Aα,4β,7β7aα)-Hexahydro-2-(4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.88 LCMS/343.2 [M+H]+8
120(3Aα,4β,7β7aα)-2-(9-Ethyl-N-carbazole-3-yl)hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.73 LCMS/360.1 [M+H]+8

Ave. No.GThe connection nameRetention time (minutes)/mol. weightThe process of example
121(3Aα,4β,7β7aα)-2-[1,2-Dihydro-8-methyl-2-oxo-4-(trifluoromethyl)-7-chinoline]hexahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.11 LCMS/393.0 [M+H]+8

Examples 122 164

On the next connection of the present invention produced using the methods, similar to those described above. Table 3 shows the connection name and structural formula, the retention time, as well as the number of the example in which the described method, which is based on the formation of compounds in Table 3 for examples with 122 164. Chromatograph the Oia is used to determine the retention time of the compounds from Table 3, as follows:

LCMS=YMC S5 ODS column, 4.6×50 mm, eluent 10-90% MeO/N2Oh, more than 4 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LC=YMC S5 ODS column 4.6×50 mm, eluent 10-90% Meon/N2On over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm

Ave. No.The structural formula of the compoundThe connection nameThe hold time. Min./mol. weightThe process of example
122(3Aα,4β,7β7aα)-Hexahydro-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.66 LCMS27
123(3Aα,4β,7β7aα)-Hexahydro-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.76 LCMS27
124 (3Aα,4β,7β7aα)-2-(4-Bromo-3-were)-3A,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione6.36 LCMS8
125(3Aα,4β,7β7aα)-2-(4-Bromophenyl)-3A,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione5.72 LCMS8
126(3Aα,4β,7β7aα)-3A,4,7,7a-tetrahydro-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione5.92 LCMS8
127(3Aα,4β,7β7aα)-2-(9-Ethyl-N-carbazole-3-yl)-3A,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.73 LCMS8
128(3Aα,4β,7β7aα)-2-[4-Fluoro-3-(trifluoromethyl)phenyl]-3A,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.40 LCMS8

Ave. No.The structural formula of the compoundThe connection nameThe hold time. Min./mol. weightThe process of example
129(3A1 ,4β,7β7aα)-2-[1,2-Dihydro-8-methyl-2-oxo-4-(trifluoromethyl)-7-chinoline]-3A,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.14 LCMS8
130(3Aα,4β,7β7aα)-4-[(atomic charges)methyl]-2-(4-bromo-3-were)-3A,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.95 LC4
131(3Aα,4β,7β7aα)-4-[(atomic charges)methyl]-2-(4-bromo-3-were)-3A,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.97 LCMS5
132(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.08 LC20
133(3Aα,4β,7β7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-1-naphthaleneacetic3.00 LC20
134(3Aα,4β,7β7aα)-(Benzo[b]thiophene-3-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.61 LC20

Ave. No.The structural formula of the compoundThe connection nameThe hold time. Min./mol. weightThe process of example
135(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.21 LC20
136(3Aα,4β,7β7aα)-4-(1,3,3A,4,7,7a-Hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-1-naphthaleneacetic2.94 LC32
137(3Aα,4β,7β7aα)-Hexahydro-4-methyl-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.88 LC3
138(3Aα,4β,7β7aα)-2-(4-Bromo-3-were)hexahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.11 LC3
139(3Aα,4β,7β7aα)-Hexahydro-4-methyl-2- [3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.90 LC3
140 (3Aα,4β,7β7aα)-2-(3,5-Dichlorophenyl)hexahydro-4-methyl-4,7-epoxy-1 H-isoindole-1,3(2H)-dione3.31 LC3
141(3Aα,4β,7β7aα)-2-(3-Chloro-4-forfinal)-hexahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione2.72 LC3

Ave. No.The structural formula of the compoundThe connection nameThe hold time. Min./mol. weightThe process of example
142(3Aα,4β,7β7aα)-2-Methoxy-4-(octahydro-1,3-dioxo-4-methyl-4,7-epoxy-2H-isoindole-2-yl)-1-naphthaleneacetic2.72 LC3
143(3Aα,4β,7β7aα)-Hexahydro-4-methyl-2-[4-nitro-3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.10 LC3
144(3Aα,4β,7β7aα)-Hexahydro-2-[4-(1H-imidazol-1-yl)phenyl]-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione1.16 LC3
145 (3Aα,4β,7β7aα)-2-[3-Chloro-4-(2-thiazolyl)phenyl]hexage ro-4-methyl-4,7-epoxy-1 H-isoindole-1,3(2H)-dione2.81 LC3
146(3Aα,4β,7β7aα)-2-(3,5-Dichlorophenyl)hexahydro-4,7-imino-1H-isoindole-1,3(2H)-dione2.72 LC31
147(3Aα,4β,7β7aα)-2-(4-Bromo-1-naphthalenyl)hexahydro-4,7-imino-1H-isoindole-1,3(2H)-dione2.95 LC31
148(3Aα,4β,7β7aα)-2-(4-Bromo-3-were)hexahydro-4,7-imino-1H-isoindole-1,3(2H)-dione2.65 LC31

Ave. No.The structural formula of the compoundThe connection nameThe hold time. Min./mol weightThe process of example
149(3Aα,4β,7β7aα)-Hexahydro-2-(4-nitro-1-naphthalenyl)-4,7-imino-1H-isoindole-1,3(2H)-dione2.49 LC31
150(3Aα,4β,7β7aα)-8-Acetyl-2-(3,5-is chlorphenyl)hexahydro-4,7-imino-1H-isoindole-1,3(2H)-dione 3.53 LC31
151(3Aα,4β,7β7aα)-Octahydro-1,3-dioxo-2-[3-(trifluoromethyl)phenyl]-4,7-ethano-5H-pyrrolo[3,4-C]pyridine-5-carboxylic acid phenyl ester3.397 LC9
152(3Aα,4β,7β7aα)-4-(Octahydro-1,3-dioxo-4,7-ethano-2H-pyrrolo[3,4-C]pyridine-2-yl)-1-naphthaleneacetic1.74LC11
153(3Aα,4β,7β7aα)-4-(Octahydro-5-methyl-1,3-dioxo-4,7-ethano-2H-pyrrolo[3,4-C]pyridine-2-yl)-1-naphthaleneacetic1.71 LC14
154(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-1,3-dioxo-4,7-etheno-5H-pyrrolo[3,4-C]pyridine-5-carboxylic acid fenilmetilovy ether3.40 LC10

Ave. No.The structural formula of the compoundThe connection nameThe hold time. Min./ mol. weightThe process of example
155(3Aα,4β,β 7aα)-4-(Octahydro-1,3-dioxo-4,7-ethano-2H-pyrrolo[3,4-C]pyridine-2-yl)-2-(trifluoromethyl)benzonitrile1.74 LC11
156(3Aα,4β,7β7aα)-4-(Octahydro-5-methyl-1,3-dioxo-4,7-ethano-2H-pyrrolo[3,4-C]pyridine-2-yl)-2-(trifluoromethyl)benzonic Il1.65LC14
157(3Aα,4β,7β7aα)-2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-1,3-dioxo-4,7-etheno-5H-pyrrolo[3,4-C]pyridine-5-carboxylic acid fenilmetilovy ether3.53 LC10
158(3Aα,4β,7β7aα)-2-[4-Bromo-3-(trifluoromethyl)phenyl]tetrahydro-5-methyl-4,7-etheno-1H-pyrrolo[3,4-C]pyridine-1,3,6(2H,5H)-Trion2.95 LCMS34
159(3Aα,4β,7β7aα)-tetrahydro-5-methyl-2-[3-(trifluoromethyl)phenyl] -4,7-etheno-1H-pyrrolo[3,4-C]pyridine-1,3,6(2H,5H)-Trion2.53 LCMS34
160(3Aα,4β,7β7aα)-tetrahydro-5-methyl-2-(2-naphthalenyl)-4,7-etheno-1H-pyrrolo[3,4-C]pyridine-1,3,6(2H,5H)-Trion2.58 LCMS34

Ave. No.The structural formula of the compoundThe connection nameThe hold time. Min./ mol. weightThe process of example
161(1Aα,2β2Aα5Aα,6β6Aα)-Hexahydro-4-[3-(trifluoromethyl)phenyl]-2,6-epoxy-3H-oxirane[f]ISO-indole-3,5(4H)-dione1.80 LCMS28
162(1Aα,2β2Aα5Aα,6β6Aα)-4-(3,5-Dichlorophenyl)-hexahydro-2,6-epoxy-3H-oxirane[f]isoindole-3,5(4H)-dione1.45 LCMS28
163(1Aα,2β2Aα5Aα,6β6Aα)-Hexahydro-4-(4-nitro-1-naphthalenyl)-2,6-epoxy-3H-oxirane[f]isoindole-3,5(4H)-dione1.52 LCMS28
164(1Aα,2β2Aα5Aα,6β6Aα)-4-(3,4-Dichlorophenyl)-hexahydro-2,6-epoxy-3H-oxirane[f]isoindole-3,5(4H)-dione3.21 LCMS28

Examples 165 to 203

Additional compounds of the present invention obtained and are listed in the following Table 4. Table 4 shows the name of the program and its structural formula, as well as the number of the example in which the described method, which is based on the process of obtaining compounds of Table 4, with 165 at 203.

Table 4
Ave. No.The structural formula of the compoundThe connection nameThe process of example
1652-[4-(4-Bromo-phenoxy)phenyl]-3A,4,7,7a-tetrahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
1663A,4,7,7a-tetrahydro-2-(2-methoxyphenyl)-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
167[(1,2,3,3A,7,7a-Hexahydro-2-phenyl-4,7-epoxy-4H-isoindole-4-yl)methyl]karamanova acid(3,5-acid)methyl ester21-26
1682-(2,4-Dimetilfenil)-3A,4,7,7a-tetrahydro-4-(hydroxymethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione21-26
1692-(1,3-Benzodioxol-5-yl)-3A,4,7,7a-tetrahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
170 4-Bis(atomic charges)methyl]-2-(3-bromophenyl)-3A,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione21-26

Ave. No.The structural formula of the compoundThe connection nameThe process of example
171N-[[1,2,3,3a,7,7a-Hexahydro-2-(2,4,6-trimetilfenil)-4,7-epoxy-4H-isoindole-4-yl]methyl]-2,2-dimethylpropanamide21-26
1723A,4,7,7a-tetrahydro-4-(hydroxymethyl)-2-[2-(trifluoromethyl )phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione21-26
1733A,4,7,7a-tetrahydro-4-(hydroxymethyl)-2-(1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione21-26
1742-Chloro-5-(1,3,3A,4,7,7a-hexahydro-4,7-dimethyl-4, 7-epoxy-2H-isoindole-2-yl)benzoic acid methyl ester32
1754-[Bis(atomic charges)methyl]-2-(4-bromo-2-nitrophenyl)-3A,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione21-26

Ave. No.The structural formula of the compoundThe connection nameThe process of example
1763A,4,7,7a-tetrahydro-4-methyl-2-(4-methyl-3-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
1772-[2-Chloro-5-(trifluoromethyl)phenyl]-3A,4,7,7a-tetrahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
1782-[4-Chloro-3-(trifluoromethyl)phenyl]-3A,4,7,7a-tetrahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
1792-(1,3,3A,4,7,7a-Hexahydro-4-methyl-4,7-epoxy-2H-isoindole-2-yl)benzonitrile32
1802-(4-Forfinal)-3A,4,7,7a-tetrahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
1812,2,2-Cryptor-N-[(1,2,3,3A,7,7a-hexahydro-2-phenyl-4,7-epoxy-4H-isoindole-4-yl)methyl]ndimethylacetamide21-26

Ave. No.The structural formula of the compound The connection nameThe process of example
1823A,4,7,7a-tetrahydro-4,7-dimethyl-2-(4-methyl-3-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
1832-Chloro-5-[1,3,3A,4,7,7a-hexahydro-4-(hydroxy methyl)-4,7-epoxy-2H-isoindole-2-yl]benzoic acid21-26
1843A,4,7,7a-tetrahydro-4,7-dimethyl-2-(4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
1853A,4,7,7a-tetrahydro-2-(2-mercaptophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
1863A,4,7,7a-tetrahydro-2-[2-[(phenylmethyl)thio]phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione32
187[[2-(4-Chlorophenyl)-1,2,3,3A,7,7a-hexahydro-4,7-epoxy-4H-isoindole-4-yl]methyl]carbamino acid 2-methylpropyl ether21-26

Ave. No.The structural formula of the compoundThe connection nameThe process by which the Rimera
1884-(1,1-Dimethylethyl)-N-[[1,2,3,3a,7,7a-hexahydro-2-(4-were)-4,7-epoxy-4H-isoindole-4-yl]methyl]benzamide21-26
1892,4-Dichloro-N-[[1,2,3,3A,7,7a-hexahydro-2-(4-nitrophenyl)-4,7-epoxy-4H-isoindole-4-yl]methyl]benzamide21-26
190N-[[2-(4-Chlorophenyl)-1,2,3,3A,7,7a-hexahydro-4,7-epoxy-4H-isoindole-4-yl]methyl]-2,4,6-trimethylbenzenesulfonamide21-26
191N-[[1,2,3,3a,7,7a-Hexahydro-2-(4-nitrophenyl)-4,7-epoxy-4H-isoindole-4-yl]methyl]-2,2-dimethylpropanamide21-26
192N-[(1,2,3,3a,7,7a-Hexahydro-2-phenyl-4,7-epoxy-4H-isoindole-4-yl)methyl]-2-phenoxyacetamide21-26
193[(1,2,3,3A,7,7a-Hexahydro-2-phenyl-4,7-epoxy-4H-isoindole-4-yl)methyl]karamanova acid 1,1-dimethylethylene ether21-26

Ave. No.The structural formula of the compoundThe connection name% The SS for example
1942-(2,4-Dichlorophenoxy)-N-[[1,2,3,3A,7,7a-hexahydro-2-(4-nitrophenyl)-4,7-epoxy-4H-isoindole-4-yl]methyl]ndimethylacetamide21-26
195N-[[1,2,3,3a,7,7a-Hexahydro-2-(4-were)-4,7-epoxy-4H-isoindole-4-yl]methyl] - for 3,5-dimethoxybenzamide21-26
196N-[[2-(4-Chlorophenyl)-1,2,3,3A,7,7a-hexahydro-4,7-epoxy-4H-isoindole-4-yl]methyl]-2-nitrobenzenesulfonamide21-26
197(3Aα,4β,7β7aα)-Hexahydro-2-[(1S)-1-phenylethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.8
198(3Aα,4β,7β7aα)-Hexahydro-2-[(1S)-2-hydroxy-1-phenylethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.8
199(3Aα,4β,7β7aα)-2-[(1S)-2-(atomic charges)-1-phenylethyl]-3A,4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione.8

Ave. No.The structural formula of the compoundThe connection name The process of example
200(3Aα,4β,7β7aα)-3A,4,7,7a-tetrahydro-2-[(1S)-1-phenylethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.8
201(3Aα,4β,7β7aα)-Hexahydro-2-[(1R)-1-phenylethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.8
202(3Aα,4β,7β7aα)-4-[[[(Octahydro-1,3-dioxo-4,7-epoxy-2 H-isoindole-2-yl)methyl]amino]benzoic acid.8
203(3Aα,4β,7β7aα)-Hexahydro-2-(4-morpholinylmethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.8

Example 204

(3Aα,4β,7β7aα)-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (204D/25V)

2-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]-5-methylfuran (A)

To a solution of compound 21A (2.00 g, 15.9 mmol) in DMF (50 ml) was added imidazole (1.62 g, 23.9 mmol)and then tert-butyldimethylsilyl (2.63 g, 17.5 mmol). After 2 hours at 25°the reaction was poured into diethyl ether (300 ml) and washed with water (1&x000D7; 100 ml), 1 N HCl (1×100 ml), water (1×100 ml), brine (1×50 ml) and dried over anhydrous MgSO4. The crude compound A analyzed by LCMS and NMR to determine the adequacy of its purity to transfer directly to the next stage. HPLC: 100% within 4.347 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm).

Century (3Aα,4β,7β7aα)-4-[2-[[(1,1-Dimethylethyl)dimethylsilane]-oxy]ethyl]hexahydro-7-methyl-4,7-epoxy-1H-isobenzofuran-1,3(2H)-dione (V)

Connection A (4.0 g, 18.9 mmol) and maleic anhydride (1.42 g, 14.51 mmol) dissolved in dichloroethane (10 ml) and stirred at a temperature of 25°C for 60 hours. Volatiles are then removed in vacuum and the resulting orange oil was dissolved in absolute ethanol (50 ml) and added Pd/C (10% Pd, 1.00 g). Then introduce hydrogen from a cylinder. After 3 hours the reaction mass is filtered through celite, washed with EtOAc and concentrated in vacuo. The crude anhydride purified by repeated flash chromatography on SiO2, elwira acetone/chlorform (0-2-4% acetone)that give 1.30 g of compound B in the form of a colorless oil, in addition to 3.00 g of starting compound A. Characterization using proton NMR spectroscopy shows collextor. 1H NMR, 400 MHz, CDCl3, 3.83 (2H, t, J=6.0 Hz), 3.22 (1H, d, J=8.2 Hz), 3.06 (1H, d, J=8.2 Hz), 1.70-2.25 (6N, m), 1.55 (3H, s), 0.82 (S, s), 0.00 (6N, C).

S. (3Aα,4β,7β7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilane]-oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (S)

Connection V (0.250 g, 0.8 mmol) and 4-amino-2-cryptomathematical (0.124 g, 0.668 mmol) suspended in dry toluene (2.0 ml) in a sealed tube. Then add MgSO4(6.200 g) and triethylamine (0.5 ml), the tube is sealed and placed in an oil bath at 125°C. After 40 hours, the reaction mass is then cooled to a temperature of 25°, filtered and concentrated in vacuo. The crude product is purified using flash chromatography on SiO2, elwira CH2Cl2that gives 0.111 g of compound C in a solid yellow color. HPLC: 92% within 4.203 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm). MS (ESI): m/e 531.1 [M+Na]+.

D. (3Aα,4β,7β7aα)-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (V)

Connection S (0.031 g, 0.061 mmol) dissolved in THF (0.5 ml) and transferred into a container with propylene, and then cooled to ambient temperature the ry 0° C. Then add HP·pyridine (˜47% HF, 0.1 ml). After 15 minutes the reaction is complete as determined by LC, and poured into cold saturated aqueous solution of NaHCO3. The mixture is extracted with CH2Cl2(3×10 ml). The combined organic layers washed with 1 N HCl (1×20 ml) and dried over anhydrous Na2SO4. Connection 204D isolated in the form of butter yellow and compared with the product obtained in example 25. Further purification is not required.

Example 205

(3Aα,4β,7β7aα)- and (3Aα,4α,7α7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(phenylmethyl)-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (205Ci and 205Cii respectively)

A. 2-Methyl-5-(phenylmethyl)-furan (205A)

n-BuLi (1.8 ml, 4.51 mmol, 1.1 EQ., 2.5 M in hexane) are added to a solution of 2-methylfuran (0.37 ml, 4.10 mmol, 1 EQ.) in anhydrous THF (3 ml) at a temperature of -25°C. the resulting solution was stirred at room temperature for 3 hours, and then cooled to a temperature of -15°C. Add benzylbromide (0.59 ml, 4.92 mmol, 1.2 equiv.) which enters through the layer of aluminum oxide and the solution warmed to room temperature and stirred over night. Add a saturated solution of NH4Cl (5 ml) and the mixture is stirred for one hour. The reaction the mixture is then extrage the comfort with ether (2× ) and the combined organic extracts are dried and concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira hexane, give 323 mg (46%, 1.88 mmol) of compound 205A in the form of a colorless oil. HPLC: 95% within 3.72 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm) and approximately 400 mg of the mixture of product and benzyl bromide (˜2:1 by HPLC).

Century (3Aα,4β,7β7aα)- and (3Aα,4α,7α7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(phenylmethyl)-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (205 Bi and 205Bii respectively)

A solution of compound 205A (124 mg, 0.72 mmol, 1 EQ.) and 4-(2,5-dihydro-2,5-dioxo-1N-pyrrol-1-yl)-2-triftormetilfosfinov (290 mg, 1.09 mmol, 1.5 EQ.) in CH2Cl2(2 ml) was stirred at room temperature. After 4 days the reaction mixture was concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira CH2Cl2, give 62 mg (0.14 mmol, 20%) of a mixture of compounds 205Bi and 205Bii in a solid white color, which is used directly in the next step. HPLC: 93% within 3.69 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol within the m ore than 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm).

S. (3Aα,4β,7β7aα)- and (3Aα,4α,7α7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(phenylmethyl)-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)-benzonitrile (205Ci and s respectively)

Solution mixture of compounds 205Bi and 205Bii (62 mg, 0.14 mmol, 1 EQ.) and 10% Pd/C (12 mg, catalytic amount) in EtOH (3.5 ml) is stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction mixture is filtered through celite and concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 35% EtOAc/hexane, to give 22 mg (0.05 mmol, 35%) connection 205Ci and 12 mg (0.027 mmol, 19%) connection s. Connection 205Ci: HPLC: 98% for 3.75 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 458.2 [M+NH4]+. Connection s: HPLC: 97% within 3.78 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (ESI): m/e 473.45 [M+CH3HE]+.

Example 206

(3Aα,4β,7β7aα)-2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-propanenitrile (206)

A solution of compound 36 (34 mg, 0.074 mmol) and NaCN (24 mg, 0.49 mmol) in DMSO (1 ml) is heated at a temperature of 100°C for 0.5 hours. After cooling, the reaction mixture was poured into H2O and the aqueous layer was extracted with EtOAc (2×). The combined organic layers washed with N2About (2×), dried over Na2SO4and concentrate under reduced pressure. Purification using flash chromatography on SiO2, elwira 50% EtOAc/hexane, then preparative HPLC, 30.41 minutes (retention time) (YMC S5 ODS 30×250 mm, 10-90% aqueous solution of methanol over 30 minutes containing 0.1% TFA, 25 ml/min, monitoring at 220 nm), gives 6.6 mg (22%) of compound 206 in the form of a solid white color. HPLC: 99% within 2.89 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 402.1 [M-N]-

Example 207

(3Aα,4β,7β7aα)-[Octahydro-4-methyl-7-[2-(4-morpholinyl)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile, triptorelin(1:1) (207)

A solution of compound 36 (15.6 mg, 0.034 mmol) and morpholine (6 ml, 0.068 mmol) in toluene (1 ml) is heated at a temperature of 100°With during the night. After cooling, the reaction mixture was concentrated under reduced pressure. The sight of the TKA using flash chromatography on SiO 2, elwira 10% MeOH/CH2Cl2then preparative HPLC 23.96 minutes (retention time) (YMC S5 ODS 30×250 mm, 10-90% aqueous solution of methanol over 30 minutes containing 0.1% TFA, 25 ml/min, monitoring at 220 nm), gives 8.7 mg (55%) of compound 207 (TFA salt) as a solid white color. HPLC: 99% during 2.02 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 464.3 [M+H]+.

Example 208

(3Aα,4β,7β7aα)-2-(5-fluoro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (S)

A. 1-Fluoro-5-nitronaphthalene (A)

To a solution of 6N HCl (12 ml) was added 1.47 g (7.83 mmol) of dry powdered 5-nitro-1-naphtylamine, as described in J. Chem. Soc. 1187 (1949). The mixture is cooled to a temperature of 0°and slowly add cold solution of NaNO2(547 mg, 7.93 mmol) in 2 ml of H2O so that the temperature was kept at 0°C. After complete addition, the reaction mixture is stirred for 30 minutes and filtered. The filtrate is cooled to a temperature of 0°and treated With cold 4.5 M NaBF4a solution (5 ml), which gives the deposition of bordered the page. The mixture is left at 0°C for 30 minutes,then filtered and the residue washed with cold 4.5 M NaBF 4a solution (5 ml), ice cold ethanol (10 ml) and Et2O (20 ml). The obtained solid is dried in air, giving 1.74 g (77%) of the corresponding diazonium salts.

To 1.70 g (5.92 mmol) of the above-described bartered, page add 5 g of sand and the components are thoroughly mixed. The reaction mixture was gently heated at a temperature reduced pressure, until the decomposition. Until the end of the reaction the flask is heated within 30 minutes to 130°s that ensures a complete metamorphosis. After cooling, the reaction mixture is dissolved in acetone and the contents of the pre-adsorb on silica gel. Purification is achieved using flash chromatography (silica gel, EtOAc in hexane from 0 to 10%), which gives 449 mg (50%) of the compound A in a solid white color.

Century 1-Amino-5-fornatale (V)

A solution of compound A (62 mg, 0.32 mmol) in 1 ml EtOH containing 0.1 ml of 12 N HCl, heated at the boil under reflux. Add small doses of metal powder (62 mg, 1.11 mmol) and continue heating for 2 hours. The mixture is cooled, neutralized with a solution of 1 N NaOH and the aqueous layer was extracted with CH2Cl2. The combined organic phases are dried over MgSO4and concentrated, leaving a residue which is purified using flash chromatography (silica gel, EtOAc in hexane from 40 to 80%) is the best 42 mg (80%) of compound V in a solid yellow color.

S. (3Aα,4β,7β7aα)-2-(5-fluoro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (S)

Connection V (42 mg, 0.26 mmol), compound 20A (54 mg, 0.27 mmol), MgSO4(69 mg, 0.58 mmol) and triethylamine (191 μl, 1.37 mmol) bring in 2 ml of toluene and placed in a sealed tube. The sealed tube is heated to a temperature of 135°C for 14 hours. The cooled reaction mixture is filtered through a small layer of celite, elwira CH2Cl2and the solvent is removed under reduced pressure. The residue is purified using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, elwira 30-100% aqueous solution of methanol over 10 min containing 0.1% TFA, 20 ml/min), giving 15 mg (17%) connection S in the form of a solid of light yellow color. HPLC: 16% within 2.96 min; 77% within 3.06 min (retention time, atrophie isomers) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 340.2

Example 209

(3Aα,4β,7β7aα)-2-(5-fluoro-4-nitro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (209C)

A. N-(5-fluoro-1-naphthalenyl)ndimethylacetamide (A)

A solution of 141 mg (0.74 mmol) of the compound A in 2 ml of Asón heating the t at boiling under reflux and treated with small doses of metal powder (118 mg, 2.11 mmol). The mixture is refluxed for 15 minutes before add 73 μl (0.78 mmol) AU2O. After an additional 15 minutes of the boil under reflux the mixture is cooled and filtered, elwira CH2Cl2. The filtrate is then concentrated and the residue purified using flash chromatography (silica gel, EtOAc in hexane from 20 to 50%), which gives the connection A (145 mg, 97%) as a solid white color.

Century 1-Amino-5-fluoro-4-nitronaphthalene (V)

Connection A (133 mg, 0.66 mmol) dissolved in 1 ml of Asón and the resulting solution is cooled to a temperature of 10°C. At this temperature, add 80 ál (2.00 mmol) of steaming brown color HNO3and stirring is continued for 15 minutes before the reaction mass zakolerovat by adding crushed ice. The aqueous layer was extracted with CH2Cl2and the combined organic phases are dried over MgSO4and concentrate. The resulting residue is dissolved in 3 ml of EtOH is heated at the boil under reflux and treated with 0.5 ml of 40% aqueous NaOH solution. Stirring is continued for 15 minutes before the reaction mass is then cooled and diluted with N2O. the Aqueous layer was extracted with CH2Cl2and the combined organic phases are dried over MgSO4and concentrate. Received the STATCOM purified using flash chromatography (silica gel, EtOAc in hexane from 40 to 70%)to obtain 36 mg (27%) connection V in a solid yellow color.

C. 3Aα,4β,7β7aα)-2-(5-fluoro-4-nitro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (S)

Connection V (36 mg, 0.18 mmol) is reacted in a sealed tube with compound 20A (38 mg, 0.19 mmol), MgSO4(46 mg, 0.39 mmol) and Et3N (128 μl, 0.92 mmol) in 250 μl of toluene in accordance with the manner described in example C, which gives, after purification using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, elwira 30-100% aqueous solution of methanol over 10 min containing 0.1% TFA, 20 ml/min), 27 mg (40%) connection S in a solid yellow color. HPLC: 8% for 2.88 min; 84% within 3.06 minutes (atropisomers, retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 402.0 [M+H]+

Example 210

(3Aα,4β,7β7aα)-2-(1,1-Dioxides[b]thiophene-3-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (210)

mCPBA (160 mg, 0.641 mmol, 70% pure) are added to a solution of compound 134 (70 mg, 0.214 mmol) in CH2Cl2(2 ml) at room temperature. After the initial product is used up, reactio the percent mass zakolerovat a saturated solution of NaHCO 3and extracted with CH2Cl2. The organic layer was washed with 1N NaOH, dried over Na2SO4and concentrate under reduced pressure, giving 63.9 mg (83%) of compound 210 in the form of a solid white color. HPLC: 99% within 3.81 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 360.0 [M+H]+.

Example 211

4-(1,3,3A,4,7,7a-Hexahydro-4,6,7 there-trimethyl-1,3-dioxo-4,7-epoxy-2H-pyrrolo[3,4-c]pyridine-2-yl)-2-(trifluoromethyl)benzonitrile (211)

2,4,5-Trimethylhexanal (0.48 ml, 4.14 mmol) dissolved in toluene (2.0 ml) and add 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-cryptomathematical (1.0 g 3.76 mmol). The reaction mixture is stirred at a temperature of 75°C in nitrogen atmosphere for 2.5 hours. The solution is cooled to room temperature and the precipitate is filtered and washed with toluene, giving 0.51 g (35% yield) of compound 211 in the form of a solid light gray. NMR analysis shows that the connection 211 has one isomer (Exo/endo), however, the identity of the isomers could not be determined by NMR analysis. HPLC: 100% within 2.85 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 the minutes, containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 378.42 [M+H]+.

Example 212

(3Aα,4β,7β7aα)-Tetrahydro-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3,5(NN)-Trion and (3Aα,4α,7α7aα)-Tetrahydro-4,7-dimethyl-2-[3-(trifluoromethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3,5(2H,4H)-Trion (212i and 212ii respectively)

2,2-Dimethyl-3(H)-furanone (0.500 g, 4.46 mmol) and 1-[3-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (1.07 g, 4.46 mmol) suspended in toluene (20 ml) in a sealed tube. The mixture is heated at a temperature of 110°C for 4 hours and then cooled to a temperature of 25°and concentrated in vacuo. The resulting residue is purified using flash chromatography on SiO2, elwira methylene chloride, which gives 0.411 g of compound 212i in a solid white color and 0.193 g of compound 212ii in a solid white color. Structural imaging confirmed using 1-D NOE proton NMR experiments. Connection 212i: HPLC: 100% within 2.817 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 376.0 [M+Na]+. Connection 212ii: HPLC: 100% within 3.013 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution metasolv for more than 4 minutes, containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 354.02 [M+H]+.

Example 213

(3Aα,4β,7β7aα)-2-(5-Chloro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (V)

And 1-Amino-5-chloronaphthalene (213A)

To a solution of 1.74 g (6.06 mmol) of desomorphine (described in example A) in acetone (7 ml) is added in small doses 693 mg (7.00 mmol) of CuCl. After the evolution of nitrogen ceases, remove the acetone under reduced pressure and the residue is placed in CH2Cl2(30 ml). The organic phase is washed with N2O (30 ml), dried over MgSO4concentrate and in the end purify using flash chromatography (silica gel, EtOAc in hexane from 0 to 15%), which gives 754 mg (70%) of 1-chloro-5-nitronaphthalene.

The above synthesized 1-chloro-5-nitronaphthalene (540 mg, 2.6 mmol) dissolved in 10 ml of Asón, then treated 415 mg (7.43 mmol) of metallic powder and then acelerou AU2O (0.26 ml, 2.73 mmol) in accordance with the method described in example A that give 543 mg (95%) 1-atsetamino-5-chloronaphthalene.

The above synthesized solution of 1-atsetamino-5-chloronaphthalene (52 mg, 0.24 mmol) in 3 ml of EtOH is heated at the boil under reflux and treated with 0.5 ml of 40% aqueous NaOH solution. The mixture is heated at boiling with inverse x is Hladilnika, until the full amount of the original product, cooled and concentrated under reduced pressure. The residue is placed in CH2Cl2(50 ml) and washed with H2O (25 ml). The organic layer is dried over MgSO4and concentrated to leave 41 mg (98%) of compound 213A in a solid white color.

In (3Aα,4β,7β7aα)-2-(5-Chloro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (V)

Connection 213A (24 mg, 0.14 mmol) is reacted in a sealed tube with compound 20A (29 mg, 0.15 mmol), MgSO4(36 mg, 0.30 mmol) and Et3N (100 μl, 0.71 mmol) in 250 μl of toluene in accordance with the method described in example C, which gives, after purification using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, elwira 30-100% aqueous solution of methanol over 10 min containing 0.1% TFA, 20 ml/min), 27 mg (40%) connection V in a solid white color. HPLC: 98% within 1.82 minutes (retention time) (YMC S5 TurboPack Pro column 4.6×33 mm, elwira 10-90% aqueous solution of methanol over 2 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 356.4 [M+H]+.

Example 214

(3Aα,4β,7β7aα)-2-(5-Chloro-4-nitro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (V)

A. 1-Amino-5-chloro-4-nitronaphthalene (A)

1 Acetamino-5-chloronaphthalene (150 mg, 0.68 mmol, obtained as described in example 213A) dissolved in 1 ml of Asón and handle 82 μl, Smokey brown color HNO3and then decelerat 1 ml of 40% aqueous solution of NaOH in 3 ml of EtOH in accordance with the method described in example A that give 49 mg (32%) of compound A in a solid yellow color.

Century (3Aα,4β,7β7aα)-2-(5-Chloro-4-nitro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (V)

Connection A (27 mg, 0.12 mmol) is reacted in a sealed tube with compound 20A (26 mg, 0.13 mmol), MgSO4(32 mg, 0.27 mmol) and Et3N (88 μl, 0.63 mmol) in 250 μl of toluene in accordance with the method described in example C, which gives, after purification using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, elwira 30-100% aqueous solution of methanol over 10 min containing 0.1% TFA, 20 ml/min) 22 mg (45%) of compound V in a solid yellow color. HPLC: 24% within 3.06 minutes; 76% for 3.25 minutes (atrophie isomer, retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 418.0 [M+NH4]+.

Example 215

(3Aα,4β,7β7aα)-4-Ethylhexane-7-methyl-2-(4-nitro-1-NAF is linil)-4,7-epoxy-1H-isoindole-1,3(2H)-dione (V)

A. (3Aα,4β,7β7aα)-4-Ethylhexane-7-methyl-4,7-epoxidation-1,3-dione (A)

2-Ethyl-5-methylfuran (1.89 ml, 15.3 mmol) was dissolved in methylene chloride (10 ml) and added maleic anhydride (1.00 g, 10.2 mmol). The reaction mass is stirred at a temperature of 25°C for 18 hours and then concentrated in vacuo. The resulting crude bicikl dissolved in EtOAc (50 ml) and add 10% Pd/C (0.40 g). Then introduce hydrogen from a cylinder. After 4 hours the reaction mass is filtered through celite, washed with EtOAc. Concentration in vacuo gives the crude compound A (1.93 g) as a solid white color. The product obtained is used directly in the next stage without purification.

Century (3Aα,4β,7β7aα)-4-Ethylhexane-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione (V)

Connection A (0.168 g, 0.798 mmol) and 4-nitro-1-naphthalamine (0.10 g, 0.53 mmol) suspended in toluene (0.8 ml) and TEA (0.2 ml) and add magnesium sulfate (0.1 g). The mixture is heated at a temperature of 135°in a sealed tube for 18 hours. The reaction mixture is then cooled to room temperature, filtered and washed with chlorform. Concentration gives the crude product, which was purified using preparative TLC on SiO2, elwira chloride, methylene is. This gives the connection V (0.077 g) in a solid yellow color. HPLC: 100% within 3.260 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 381.05

Example 216

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)-N-(4-forfinal)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-ndimethylacetamide (V)

A. N-(4-Forfinal)-5-methyl-2-fornacette (A)

5-Methyl-2-furoxone acid (1.00 g, 7.14 mmol, synthesized as described in WO 9507893, Example 19) was dissolved in CH3CN/DMF (4:1, 25 ml); add 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (1.37 g, 7.14 mmol)and then 1-hydroxy-7-asobancaria (0.972 g, 7.14 mmol). And then 4-ftoranila (0.676 ml, 7.14 mmol). After 3 hours the reaction mass was diluted with EtOAc (150 ml) and washed with 1N HCl (1×30 ml), saturated aqueous NaHCO3(1×30 ml), brine (1×40 ml) and dried over sodium sulfate. Connection A (1.581 g) was isolated in the form of a yellow foam after concentration in vacuum. Further purification is not required. HPLC: 78% within 2.647 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min monitoring at 220 nm).

Century 3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)-N-(4-forfinal)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-ndimethylacetamide (V)

Connection A (0.200 g, 0.858 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-cryptomathematical (0.164 g, 0.66 mmol) dissolved in benzene and heated at a temperature of 60°C for 14 hours. The reaction mixture was then cooled and concentrated in vacuo. The resulting orange oil was dissolved in EtOAc (15 ml) and add 10% Pd/C (0.050 g). Then introduce hydrogen from a cylinder. After 3 hours the reaction mass is filtered through celite, washed with EtOAc and concentrated in vacuo. The resulting crude product was then purified using preparative TLC on silica, elwira 5% acetone in methylene chloride, which gives 0.166 g of compound V in a solid white color. NMR spectroscopy shows only a single isomer, which define the identity with the Exo isomer by using NOE experiments. HPLC: 95% within 3.200 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 484.0 [M+H]+.

Example 217

(3Aα,4β,7β7aα)-Hexahydro-4-methyl-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione, more quickly eluruumis enantiomer; (3Aα,4β,7β7aα)-Hexa is Idro-4-methyl-2-(2-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione, slowly eluruumis enantiomer (2171; 21711, respectively)

Racemic compound 137 is divided into individual antipodes by using chiral liquid chromatography with reversed phase. Using Chiralpak AD-R column (4.6×250 mm), elwira 70% acetonitrile/30% water at a rate of 1 ml/min. Use UV specified at 220 nm. Quickly eluruumis isomer, compounds 217i (retention time = 15.66 minutes), as shown, has a value of 99.9% and slowly eluruumis isomer, compound 217ii (retention time = 15.66 minutes) has a yield of 99.6% according to analytical chiral chromatography with reversed phase.

Example 218

(3Aα,4β,7β7aα)-4-[4-[[2-[[(4-Forfinal)methyl]methylamino]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (V)

A. (4-Terbisil)methylamine; Bis(4-terbisil)methylamine (218a Centralnaya street; 218a Centralnaya street')

Connection 218a Centralnaya street and 218a Centralnaya street' receive in accordance with the method described in Singer, ef. Al., J. Med. Chem. 29; 40-44 (1986). 4-Florantyrone (189 mg, 1.00 mmol) is heated at boiling under reflux in ethanol (1.5 ml) and methylamine (5 ml, 2 M solution in Meon) for 3 hours. Enter additional portion of methylamine (2 ml) and the mixture is heated at the boil under reflux for additionally the hour. The solution is cooled and concentrated in vacuo and the residue dissolved in a mixture of 2N HCl (3 ml) and ether (1.5 ml). The layers are separated and the aqueous layer was extracted with additional ether. The aqueous solution is cooled to a temperature of 0°, titrated to pH 11 with NaOH and extracted with CH2Cl2. The extracts are dried over MgSO4and concentrate, which gives 120 mg 2.5:1 mixture of compound 218a Centralnaya street and connection 218a Centralnaya street', respectively. The crude mixture was used without further purification.

Century (3Aα,4β,7β7aα)-4-[4-[2-[[(4-Forfinal)methyl]-methylamine]ethyl]octahydro-7-methyl-1,3-Dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (V)

A solution of compound 36 (34.3 mg, 0.075 mmol) and compounds 218a Centralnaya street and 218a Centralnaya street' (21 mg, ˜0.088 mmol (218a Centralnaya street)) in toluene (0.4 ml) is heated at a temperature of 100°With during the night. The reaction mixture is cooled to room temperature, and then concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 25% acetone/75% CH2Cl2give 30 mg (0.058 mmol, 77.7%) V in a solid yellow color. HPLC: 99% within 2.46 min (retention time) (YMC S5 ODS 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, monitoring at 220 nm), MS (USA): m/e 516.26 [M+H]+.

Example 219

(3Aα,4β,5β,6β,7β7aα)-4-(Octahydro-4,5,6,7-tetramethyl-1,3-dioxo-4,7-epoxy-2H-and indol-2-yl)-2-(trifluoromethyl)benzonitrile (219D)

A. 2,3,4,5-Tetramethylurea (A)

Connection I receive in accordance with the method described in Hancock et. Al, J. Org. Chem. 42, 1850-1856 (1977) & Amamath, et. Al., J. Org. Chem., 60, 301-307 (1995). 2-Propanone (100 ml, 1.1 mol) is heated at boiling under reflux over PbO2(26.7 g, 0.11 mol) for 28 hours. After cooling to room temperature the reaction mixture is filtered and the residue washed with acetone. The filtrate is concentrated under reduced pressure to remove acetone, and then distil at 20 Torr. Fractions that appeared in the temperature range between 100-120°collect that give 6.75 g (42.5%) 3,4-dimethylhexane-2,5-dione in the form of oil is light yellow in color.

A solution of 3,4-dimethylhexane-2,5-dione (3.00 g, 21.1 mmol) and n-toluensulfonate acid (401 mg, 2.11 mmol) in benzene (30 ml) is heated at boiling under reflux trapped in a Dean-stark during the night. The reaction mixture is distilled at atmospheric pressure to remove excess benzene. The remaining mixture is transferred to a small flask and distilled at atmospheric pressure. Fractions that appeared in the temperature range between 80-100°To collect, which gives 509 mg (19%) connection A in the form of oil is light yellow in color.

Century (3Aα,4β,7β7aα)-4-Ethyl-3A,4,7,7a-tetrahydro-4,5,6,7-tetramethyl-4,7-apoxie benzofuran-1,3-dione (V)

A solution of compound A (400 mg, 3.22 mmol) and maleic anhydride (442 mg, 4.51 mmol) in E2tO (1.5 ml) was stirred at room temperature overnight. The reaction the mixture is then placed in the freezer for 5 days, after this time the resulting crystals are collected and dried, giving 0.26 g (37%) of compound V in the form of crystals yellow - brown color. The crude compound V used in the next step without further purification.

S. (3Aα,4β,5α,6α,7β7aα)-4-Ethylhexane-4,5,6,7-tetramethyl-4,7-epoxidation-1,3-dione (S)

A solution of compound V (120 mg, 0.545 mmol) and 10% Pd/C (24 mg, catalytic amount) in EtOAc (2 ml) is stirred in the atmosphere of a balloon of hydrogen at room temperature overnight. The reaction mixture is filtered through celite and concentrated under reduced pressure, giving 100 mg (0.446 mmol, 81.9%) connection S in a solid white color, which is used without further purification.

D. (3Aα,4β,5β,6β,7β7aα)-4-(Octahydro-4,5,6,7-tetramethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile (219D)

A solution of compound C (44.4 mg, 0.2 mmol), 5-amino-2-cyanobenzaldehyde (45 mg, 0.24 mmol), TEA (0.04 ml) and MgSO4(20 mg) in toluene (0.2 ml) is heated at a temperature of 135#x000B0; With during the night. The reaction mixture is cooled to room temperature, filtered and then concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 40% EtOAc/hexane, then washing the obtained solid substance Meon give 17 mg (0.043 mmol, 21.7%) connection 219D in a solid white color. HPLC: 90% within 3.11 min (retention time) (YMC S5 ODS 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, monitoring at 220 nm), MS (USA): m/e 391.2 [M-N]-.

Example 220

(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile, quickly eluruumis antipode; (3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-β4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile, slowly eluruumis enantiomer (220i; 220ii, respectively)

Racemic compound 35 is divided into individual antipodes by using chiral liquid chromatography normal phase. Chiralpak AD column (50×500 mm) is used, elwira 85% hexane/7.5% methanol/7.5% ethanol, @ 50 ml/minute. Use UV specified at 220 nm. Quickly eluruumis isomer compounds 220i (retention time = 55.86 minutes), as the show is about, has a purity of 95.8% ([α]D25=-53.02°,=3.134 mg/cm3in CH2Cl2and slowly eluruumis isomer compounds 220M (retention time = 62.86 minutes) has a purity of 86% ([α]D25=+48.74°,=2.242 mg/cm3in CH2Cl2with the help of analytical chiral chromatography normal phase.

Example 221

(3Aα,4β,5β,7β7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile (V)

A. (3Aα,4β,7β7aα)-4-(hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile (221Ai); (3Aα,4β,7β7aα)-4-(hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile (a)

A solution of 2,5-dimethylfuran (0.8 ml, 7.51 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-triftormetilfosfinov (synthesized as described in example 1B) (1.00 g, 3.75 mmol) in benzene (4 ml) is heated at a temperature of 60°With during the night. The reaction mixture was concentrated under reduced pressure and placed in the rotor pump with high vacuum until the oil hardens, which gives a 3:1 mixture (determined using LC and NMR) compounds 221Ai and 221Aii respectively in the form of a solid brown color, which use neposredno is but the next step without further purification.

Century (3Aα,4β,5β,7β7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile (V)

NR3·THF (3.75 ml, 3.75 mmol, 1 M in THF) are added to a solution of crude compounds 221Ai and AN (3.75 mmol) in THF (12.5 ml) at 0°C. After the initial product is used up, the reaction mixture was concentrated under reduced pressure. Then the obtained residue is dissolved in toluene (12.5 ml), add Me3NO (845 mg, 11.25 mmol) and the mixture is heated at boiling under reflux overnight. The reaction mixture is then cooled to room temperature, add to H2O and extracted with EtOAc (three times). The combined organic layers dried over MgSO4and concentrate under reduced pressure. Purification using flash chromatography on SiO2, elwira 75% EtOAc/hexane, gives 0.354 g (25%) of compound 221 In the form of powder yellow-brown color. HPLC: 90% within 2.45 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 381.11

Example 222

(3Aα,4β,5β,7β7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile (222D)

A. 3-[[(1,1-Dimethylethyl)on methylsilyl]oxy]-2,5-dimethylfuran (A)

2,5-Dimethyl-3(3H)-furanone (2.00 g, 17.8 mmol) was dissolved in methylene chloride (180 ml). Add TEA (7.43 ml, 53.5 mmol), and then TBSOTf (4.92 ml, 21.4 mmol) at 25°C. After one hour the reaction mass is concentrated under vacuum and the resulting suspensio passed through the column on silica gel filled in 3% TEA in hexane. Product elute 3% tea/hexane, giving 3.6 g of compound A in the form of an orange oil, which was used directly in subsequent reactions.

Century (3Aα,4β,7β7aα)-4-[5-[[(1,1-Dimethylethyl)dimethylsilane]oxy]-1,3,3A,4,7,7a-hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (V)

4-(2,5-Dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-cryptomathematical (1.00 g, 3.85 mmol) dissolved in benzene (5.0 ml) and add connection A (1.30 g, 5.77 mmol). The reaction mixture is heated to a temperature of 60°C for 2 hours and then cooled to a temperature of 25°C. Then the solution was concentrated in vacuo, giving the connection V in the form of a yellow oil, which is transferred in the following reaction without purification. HPLC: 60% for 4.013 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm).

S. (3Aα,4β,α ,7β7aα)-4-[5-[[(1,1-Dimethylethyl)dimethylsilane]oxy]octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (S)

The crude compound V (3.85 mmol) was dissolved in ethyl acetate (75 ml) and add 10% Pd/C (1.20 g). Then introduce hydrogen from a cylinder. After 24 hours the reaction mass is filtered through celite, washed with ethyl acetate and concentrated in vacuo, giving a yellow oil. The crude product is purified using flash chromatography on silica gel, elwira methylene chloride/acetone (0%-1%-2% acetone), which gives the connection IS in a solid yellow color (0.710 g). HPLC: 100% within 4.160 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 517.6 [M+Na]+.

D. (3Aα,4β,5α,7β7aα)-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile (222D)

Connection S (0.040 g, 0.081 mmol) dissolved in THF (1.0 ml) and add HP·Pyridine (0.5 ml). After 2 hours the reaction mass is carefully poured into a cold saturated solution of NaHCO3. The mixture is then extracted with methylene chloride (3×10 ml). The combined organics are washed with 1N HCl (1×10 ml) and dried over anhydrous sulfate is the atrium. Concentration in vacuo gives compound 222D in a solid yellow color (0.031 g). NOE experiments confirmed the determination of the isomer. HPLC: 98% within 2.777 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 403.06 [M+Na]+.

Example 223

(αR-α-Methoxybenzyloxy acid, 2-[(3Aα,4β,7β7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl ester (223C)

A. (3Aα,4β,7β7aα)-[4-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (A)

A solution of 4-amino-1-naphthalenethiol (19.2 g, 114 mmol) and maleic anhydride (14.0 g, 1 13 mmol) in Asón (230 ml) is heated at a temperature of 115°C for 12 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure, then diluted with CH2Cl2(2.5 l). The organic layer is washed three times H2O (3 l), once with saturated aqueous Na2CO3(1 l) and once with brine (1 l), dried over MgSO4and concentrate to ˜200 ml under reduced pressure. Purification using flash is cromatografia on cation exchange resin (60 g, CUBX13M6 from United Chemical Technologies), elwira CH2Cl2gives 25.0 g (88%) of 4-(2,5-Dihydro-2,5-dioxo-1H-1-yl)-1-naphthaleneacetic in a solid yellow color. HPLC 96% within 2.48 min (Phenomenex-prime S5-C18 column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 249.25 [M+H]+.

4-(2,5-Dihydro-2,5-dioxo-1H-1-yl)-1-naphthaleneacetic (1.00 g, 4.03 mmol) is suspended in benzene (6.0 ml) in a sealed tube and add the connection A (1.11 g, 5.24 mmol). The reaction mass is heated at a temperature of 60°C for 16 hours and then cooled to a temperature of 25°C. the Benzene is removed in vacuo, giving a solid yellow color. Specified the solid is dissolved in ethyl acetate (40 ml) and added Pd/C (10% Pd, 0.300 g). Then introduce hydrogen from a cylinder. After 4 hours the reaction mass is filtered through celite and washed with ethyl acetate. Concentration in vacuo gives a solid light yellow color, which was purified using flash chromatography on silica gel, elwira acetone/chlorform (0%-1.5%-3% acetone), which gives the connection A (1.53 g) as a yellow foam. HPLC: 86% within 4.173 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/mi is ut, monitoring at 220 nm).

Century (3Aα,4β,7β7aα)-4-[Octahydro-4-(2-hydroxyacyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (V)

Connection A (1.37 g, 2.97 mmol) dissolved in THF (8.0 ml) and transferred into a test tube with polypropylene and cooled to a temperature of 0°C. Then add HF·Pyridine (2.0 ml). After 20 minutes the reaction mass is carefully poured into a cold saturated. The sodium bicarbonate solution and extracted with methylene chloride (3×30 ml). The organics are then washed with 1N HCl and dried over anhydrous sodium sulfate. Concentration in vacuo gives compound V (0.99 g) as a yellow foam, which is not purified further. HPLC: 96% within 2.443 and 2.597 (atrophie isomers) minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 399.02 [M+Na]+.

C. (αR-α-Methoxybenzyloxy acid, 2-[(3Aα,4β,7β7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl ester (S)

Connection V (0.200 g, 0.575 mmol) are added to a solution WSDCC (0.138 g, 0.719 mmol) and ®-almond acid (0.096 g, 0.575 mmol) in dichloromethane (6.0 ml). Then added 4-DMAP (0.005 g) and the reaction mass is stirred for p and a temperature of 25° C for 4 hours. The mixture is then diluted with dichloromethane and washed with 1N HCl (2×10 ml) and once with sodium bicarbonate (10 ml) and dried over anhydrous sodium sulfate. Concentration in vacuo gives compound C (0.220 g) in a solid yellow color, which does not require further purification. HPLC: 100% within 3.283 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 547.26 [M+Na]+.

Example 224

(3Aα,4β,7β7aα)-2-(Methylthio)-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzonitrile (224)

4-Amino-2-(methylthio)benzonitrile (100 mg, 0.61 mmol, synthesized as described in EP 40931 A1) is reacted in a sealed tube with compound 20A (131 mg, 0.67 mmol), MgSO4(161 mg, 1.34 mmol) and Et3N (0.44 ml, 3.17 mmol) in 0.50 ml of toluene in accordance with the method described in example C, which gives, after purification using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, elwira 30-100% aqueous solution of methanol over 10 min containing 0.1% TFA, 20 ml/min), 137 mg (0.40 mmol, 66%) of compound 224 in the form of a solid white color. HPLC: 100% within 2.73 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution is of ethanol for more than 4 minutes, containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 401.0 [M-H+SLA].

Example 225

(3Aα,4β,7β7aα)-2-(Methylsulfinyl)-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzonitrile (225)

To ice the suspension of compound 224 (30 mg, 0.09 mmol) in 2 ml of N2O/Meon (1:1) add Oxon (80 mg, 0.26 mmol) in one dose in the form of solids. The resulting mixture is stirred for 4 hours at 0°With, before it is diluted with N2About (10 ml) and extracted with CH2Cl2(2×20 ml). The combined organic layers are dried and concentrated to obtain the residue, which is purified by filtering the product through a small layer of silica gel, elwira CH2Cl2that gives 32 mg (0.09 mmol, 100%) of compound 225 as a colourless oil. HPLC: 99% during 2.01 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 376.0 [M+NH4]+.

Example 226

(3Aα,4β,7β7aα)-2-(Methylsulphonyl)-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzonitrile (226)

To a solution of compound 225 (48 mg, 0.14 mmol) in CH2Cl2(2 ml) is added mCPBA (145 mg, 50% see the camping, 0.42 mmol) in one portion as a solid substance. The mixture allow to warm to room temperature and then stirred for 60 hours, during which the original product is completely consumed, as determined using HPLC. The reaction mass zakolerovat the addition of a saturated aqueous solution of NaHCO3(5 ml), the layers separated and the aqueous layer was extracted with CH2Cl2(20 ml). The combined organic phases are dried over MgSO4and concentrate. Ostavshiisa the residue purified using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, elwira 30-100% aqueous solution of methanol over 10 min containing 0.1% TFA, 20 ml/min)to obtain 48 mg (0.13 mmol, 92%) of compound 226 in the form of a solid white color. HPLC: 100% within 2.07 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 392.0 [M+NH]+.

Example 227

(3Aα,4β,5β,7β7aα)-7-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]hexahydro-5-hydroxy-4-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione (V)

A. (3Aα,4β,7β7aα)-4-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]-3A,4,7,7a-tetrahydro-7-methyl-2-(4-nitro-1-naphtha is inil)-4,7-epoxy-1H-isoindole-13(2H)-dione (A)

A solution of compound A (455 mg, 1.894 mmol, 2 EQ.) and 1-[4-nitronaphthalene]-1H-pyrrole-2,5-dione (254 mg, 0.947 mmol, 1 EQ.) (receive, as described for 4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthalenethiol, Example A) in benzene (2 ml) is heated at a temperature of 60°With during the night. The reaction mixture was concentrated under reduced pressure, giving crude compound A in a solid brown color, which are used directly in the next step without further purification.

Century (3Aα,4β,5β,7β7aα)-7-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]hexahydro-5-hydroxy-4-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-13(2H)-dione (V)

NR3·THF (0.95 ml, 0.95 mmol, 1M in THF, 1 EQ.) added to a solution of crude compound A (0.95 mmol, 1 EQ.) in THF (2 ml) at 0°C. After the connection A used up, as explicitly defined by using HPLC, the reaction mixture was concentrated under reduced pressure. Then the obtained residue is dissolved in toluene (2 ml), add Me3NO (71 mg, 2.84 mmol, 3 EQ.) and the mixture is heated at boiling under reflux over night. The reaction mixture is then cooled to room temperature, add to H2O and extracted with EtOAc (3×). The combined organic layers dried over MgSO4and concentrate under reduced on the no. Purification using flash chromatography on SiO2, elwira a mixture of 75% EtOAc/hexane, gives 130.2 mg (26%) of compound V in a solid brown color. HPLC: 94% within 3.92 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 527.5 [M+H]+.

Example 228

(3Aα,4β,5β,7β7aα)-Hexahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione (228)

A mixture of TBAF (0.3 ml, 0.296 mmol, 1 M solution in THF) and HF (0.3 ml, 50% in H2O) CH3CN (6 ml) are added to a solution V (104 mg, 0.197 mmol) in THF (2 ml) at 0°C. the Reaction mixture was stirred over night at room temperature. After the initial product will be used up, as explicitly defined by using TLC, add H2O and EtOAc and the layers separated. The aqueous layer was extracted with EtOAc (1×) and the combined organic layers washed with N2O (1×) and brine (1×), dried over Na2SO4and concentrate under reduced pressure. Purification using flash chromatography on SiO2, elwira 5% Meon/CH2Cl2gives 61.2 mg (75%) of compound 228 in the form of a solid yellow color. HPLC: 99% within 2.47 min (retention time) (YMC S5 ODS column .6× 50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 411.2[M-N]-.

Example 229

(3Aα,4β,5β,7β7aα)-7-[2-(4-Pertenece)ethyl)hexahydro-5-hydroxy-4-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione (229)

DBAD (37.7 mg, 0.164 mmol) are added to a solution of PPh3(43 mg, 0.164 mmol) in THF (1 ml). After stirring for 10 minutes add 4-terfenol (18.3 mg, 0.164 mmol) and the reaction mixture is stirred for a further 5 minutes. Add a solution of compound 228 (45 mg, 0.109 mmol) in THF (1 ml) and the mixture is stirred at room temperature overnight. Using HPLC, analyze crude reaction mixture, which contains mainly original diol (compound 228), so that this mixture is added to pre-formed mixture, as to PPh3(86 mg), DBAD (75.4 mg) and phenol (36.6 mg) in THF (4 ml) at room temperature. Stirring is continued until it is completely spent connection 228. The reaction mixture was then concentrated under reduced pressure. Purification using preparative chromatography [HPLC for 15.2 minutes (retention time) (YMC S5 ODS column 20×100 mm, 10-90% aqueous solution of methanol over 15 minutes containing 0.1% TFA, 20 ml/min, control is the formation at 220 nm)] gives 25.0 mg (45%) of compound 229 in the form of a solid of light yellow color. HPLC: 99% within 3.53 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 505.2 [M-N]-

Example 230

(3Aα,4β,5β,6β,7β7aα)-4-(Octahydro-5.6-dihydroxy-4,7-dimethyl-13-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile; (3Aα,4β,5α,6α,7β7aα)-4-(Octahydro-5.6-dihydroxy-4,7-dimethyl-1,3-Dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile (230Bi and 230bii respectively)

A. (3Aα,4β,7β7aα)-4-(1,3,3A,4,7,7a-Hexahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile (230V)

3,5-Dimethylfuran (1.23 ml, 11.54 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-cryptomathematical (2.00 g, 7.69 mmol) dissolved in benzene (10 ml) and heated at a temperature of 60°C for 18 hours. Volatile organics are then removed in vacuum. The resulting crude compound 230V used without further purification. HPLC: 71% within 3.007 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm).

Century (3Aα,4β,5β,6β,7β7aα)-4-(Octahydro-56-dihydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile; ((3Aα,4β,5β,6β,7β7aα)-4-(Octahydro-5,6-dihydroxy-4,7-dimethyl-1,3-Dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile (230Bi and 230Bii)

Connection 230V (0.100 g, 0.281 mmol) was dissolved in acetone and added dropwise N-methylmorpholin-N-oxide (50% solution, 0.100 ml, 0.42 mmol). Then add OsO4(4% solution, 0.014 mmol). After 3 hours at 25°the reaction is complete and add sodium sulfate (0.250 g) with vigorous stirring. After 15 minutes add the brine (10 ml) and the solution extracted with EtOAc (3×15 ml). The organics are dried over anhydrous sodium sulfate and then concentrated in vacuo. A mixture of crude diol purified using preparative TLC, elwira 18% acetone in chloroform that give 0.038 g of compound 230Bi (beta side) and 0.012 g of compound 230Bii (alpha side) in the form of solids pale yellow color. Connection 230Bi: HPLC: 100% within 2.567 minutes (retention time) (YMC 85 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 397.08 [M+H]+. Connection 230Bii: HPLC: 100% within 2.417 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 397.08 [M+H]+.

Example 231

(3Aα,4β,5β,6β7β 7aα)-4-[Octahydro-5,6-dihydroxy-4-(hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (231C)

A. (3Aα,4β,7β7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]-1,3,3A,4,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (A)

Connection A (29.03 g, 120 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthaleneacetic (20.0 g, 80.6 mmol) is suspended in benzene (80 ml) and heated to a temperature of 60°C for 14 hours. The mixture is then concentrated in vacuo at a temperature of 40°C for 40 minutes. Received suspensio cooled to a temperature of 25°With, then suspended in the Meon (200 ml) and stirred at room temperature for 30 minutes. Then the solution is cooled to a temperature of 0°C for 30 minutes and then filtered and washed with cold Meon. The obtained solid is dried in vacuum, giving 26.1 g of crude compound A in a solid white color. A solution of methanol was concentrated in vacuo and re-suspended in the Meon (50 ml) and cooled to a temperature of -20°C for 4 hours. Then the solution is filtered and washed with cold Meon. The obtained solid is dried in vacuum, giving 3.8 g of compound A in a solid white color. HPLC: 95% at t the increase 4.227 minutes (retention time) (YMC S5 ODS column 4.6× 50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm)

Century (3Aα,4β,5β,6β,7β7aα)-4-[4-[2-[[(1,1-methylethyl)dimethylsilane]oxy]ethyl]octahydro-5,6-dihydroxy-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (V)

Connection A (0.400 g, 0.851 mmol) dissolved in acetone (9.0 ml) and add N-methylmorpholin-N-oxide (50% solution, 0.0.150 ml, 1.28 mmol). Then add OsO4(4% solution, 0.043 mmol). After 3 hours at 25°the reaction is complete and add sodium sulfate (1.0 g) with vigorous stirring. After 15 minutes add the brine (30 ml) and the solution extracted with EtOAc (3×50 ml). The organics are dried over anhydrous sodium sulfate and then concentrated in vacuo. The crude diol purified using flash chromatography on silica, elwira 5-25% acetone in chloroform that give 0.355 g of compound V in a solid yellow color. HPLC: 93% within 3.903 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 522.00 [M+H]+.

S. (3Aα,4β,5β,6β,7β7aα)-4-[Octahydro-5,6-dihydroxy-4-(hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-naphthaleneboronic (S)

Connection V (0.400 g, 0.766 mmol) dissolved in THF (5.0 ml) and transferred into a test tube with polypropylene and cooled to a temperature of 0°C. Then add HF·Pyridine (1.0 ml). After 20 minutes, the reaction mass is carefully poured into a cold saturated solution of sodium bicarbonate and extracted with methylene chloride (3×30 ml). The organics are then washed once with 1N HCl and dried over anhydrous sodium sulfate. Concentration in vacuo gives compound C (0.290 g) as a yellow foam, which does not require additional purification. HPLC: 92% within 2.273 and 2.423 (atrophie isomers) minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 409.10 [M+H]+.

Example 232

(3Aα,4β,5β,6β,7β7aα)-4-[Octahydro-5.6-dihydroxy-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile, (232C)

A. 2-Methyl-5-[2-[4-(trifluoromethyl)phenoxy]ethyl]furan (A)

To a solution of triphenylphosphine (1.56 g, 5.95 mmol) in THF (40 ml) add DBAD (1.37 g, 5.95 mmol). After 10 minutes add 4-triptoreline (0.964 g, 5.95 mmol). After another 10 minutes add the connection 21A (0.500 g, 3.97 mmol). After 14 hours at 25°Reaktsionnuyu mass was concentrated in vacuo and purified using flash chromatography on silica, elwira chlorform that gives 0.713 g of compound A in the form of a colorless oil.

Century (3Aα,4β,7β7aα)-4-[1,3,3A,4,7,7a-hexahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (V)

Connection A (0.301 g, 1.15 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-cryptomathematical (0.220 g, 0.846 mmol) is suspended in benzene (1.5 ml) and heated to a temperature of 60°C for 14 hours. The mixture is then concentrated in vacuo at a temperature of 40°C for 40 minutes. The crude product is purified using flash chromatography on silica, elwira 10-0% hexane in methylene chloride, which gives 0.199 g of compound V in a solid yellow color. Connection V characterized as exodusformer using NOE experiments. HPLC: 94% within 3.993 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm).

S. (3Aα,4β,5β,6β,7β7aα)-4-[Octahydro-5,6-dihydroxy-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (232C)

Connection V (0.075 g, 0.140 mmol) dissolved in acetone (2.0 ml) and add N-methylmorpholin-N-oxide (50% solution, 0.025 ml, 0.21 IMO is b). Then add OsO4(4% solution, 0.007 mmol). After 3 hours at 25°the reaction is complete and add sodium sulfate (0.25 g) with vigorous stirring. After 15 minutes, add the brine (5 ml) and the solution extracted with EtOAc (3×10 ml). The organics are dried over anhydrous sodium sulfate, and then concentrated in vacuo. The crude diol purified using preparative TLC on silica gel, elwira 10% acetone in chloroform that give 0.038 g of compound 232C in a solid yellow color. HPLC: 98% within 3.747 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 593.08 [M+Na]+.

Example 233

(3Aα,4β,5β5Aβ,8Aβ8bα)-4-(Decahydro-5-hydroxy-4-methyl-1,3-dioxo-4,8A-epoxy-2H-furo[3,2-e]isoindole-2-yl)-1-naphthaleneacetic, (233)

To a solution of triphenylphosphine (0.072 g, 0.276 mmol) in THF (3.0 ml) is added DBAD (0.063 g, 0.276 mmol). After 10 minutes add 4-cyanoprop (0.033 g, 0.276 mmol). After another 10 minutes add the connection C (0.075 g, 0.184 mmol). After 3 hours at 25°the reaction mass was concentrated in vacuo and purified using preparative TLC on silica gel, elwira 15% acetone in chloroform that give 0.068 g of compound 233 in the form of a solid white color. HPLC: 95% within 2.430 and 2.560 minutes (atrophie isomers) (retention time) (YMC S5 ODS column 4.6× 50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 391.09 [M+H]+.

Example 234

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-acetic acid, (V)

A. (3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)-1,2,3,3A,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-4h-isoindole-4-acetic acid (234A)

5-Methyl-2-furoxone acid (0.500 g, 3.57 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthaleneacetic (0.899 g, 3.57 mmol) dissolved in benzene (3.0 ml) and heated at a temperature of 60°C for 2 hours and then cooled to a temperature of 25°C. After 12 hours the white solid precipitated from solution, filtered and washed with diethyl ether, giving 1.20 g of compound 234A in a solid light yellow color. NMR shows the presence of only one diastereoisomer. HPLC: 86% within 2.767 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 389.45 [M+H]+.

Century (3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-Dioxo-4,7-epoxy-4H-isoindole-4-acetic sour is a (V).

Compound 234A (1.1 g, 2.82 mmol) was dissolved in EtOH/EtOAc (1:1, 50 ml) and added Pd/C (10% Pd, 0.4 g), then H2through the cylinder. After 5 hours at 25°C, the reaction mass is filtered through celite, washed with EtOAc and concentrated in vacuo, giving 1.00 g of compound V in a solid yellow color. HPLC: 80% within 2.84 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 391.1

Example 235

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-acetic acid, methyl ester (235)

Connection V (0.050 g, 0.125 mmol) was dissolved in acetonitrile (2.0 ml), then added DCC (0.025 g, 0.125 mmol), and then the SPLA (0.018 g, 0.125 mmol). Add 4-tormentingly alcohol (0.014 ml, 0.125 mmol) and the reaction mass is stirred for 3 hours. The reaction mixture was then concentrated in vacuo and purified using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, 10-90% aqueous solution of methanol over 15 minutes containing 0.1% TFA, 20 ml/min, monitoring at 220 nm). Cleaning give 0.040 g of compound 235 in the form of a solid white color, rather than the expected benzyl ether. No expected benzyl ether is not observed is t and using NMR or LC-MS. HPLC: 100% within 3.033 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 405.51 [M+H]+.

Example 236

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)-N-[(4-forfinal)methyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-ndimethylacetamide, (236)

Connection V (0.100 g, 0.256 mmol) was dissolved in acetonitrile (4.0 ml). Then add the SPLA (0.035 g, 0.256 mmol) and DCC (0.049 g, 0.256 mmol) and 4-forbindelsen (0.030 ml, 0.256 mmol). After 4 hours at 25°the reaction mass was concentrated in vacuo and purified using preparative HPLC (YMC S5 ODS 20×100 mm, 10-90% aqueous methanol over 15 minutes containing 0.1% TFA, 20 ml/min, monitoring at 220 nm), which gives 0.085 g of compound 236 in the form of a solid white color. HPLC: 100% within 3.277 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 498.43 [M+H]+.

Example 237

(3Aα,4β,7β7aα)-N-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]-4-perbenzoic. (V)

A. 4-Fluoro-N-[2-(5-methyl-2-furanyl)ethyl]benzamide (A)

4-Perforazione (0.29 ml, 2.44 mmol) is added dropwise to the solution-(5-methyl-2-furanyl)ethanamine (300 mg, 2.44 mmol, obtained in accordance with the method Yur'ev, Wik Et. Al. J. Gen. Chem. USSR (Engl. Transl.) 33, 3444-8 (1963)) in THF (2.5 ml) at room temperature, then added dropwise Et3N (0.34 ml, 2.44 mmol). When the initial product whole reacts, as explicitly defined by using HPLC, the reaction mass zakolerovat H2O and extracted with CH2Cl2. The combined organic layers dried over MgSO4and concentrate under reduced pressure. Purification using flash chromatography, elwira 0%-50% EtOAc/geksanalem gradient gives 523 mg (95%) of compound A in a solid white color. HPLC: 99% within 2.84 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 248.15 [M+H]+.

Century (3Aα,4β,7β7aα)-N-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]-4-perbenzoic, (V)

A solution of compound A (221.5 mg, 0.896 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthaleneacetic (222.4 mg, 0.896 mmol) in benzene (4 ml) is heated at a temperature of 60°With during the night. The reaction mixture was concentrated under reduced pressure and the solution is between EtOAc (30 ml). Add 10% Pd/C (50 mg) and the mixture is stirred atmophere balloon of hydrogen overnight. The reaction mixture is filtered through a bed of celite and concentrate under reduced pressure. Purification using flash chromatography, elwira 25%-75% EtOAc/hexane gradient, gives 160.3 mg (36%) of compound V in a solid off-white color. HPLC: 97% within 3.13; 3.23 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e' 498.11 [M+H].

Example 238

[3R-((3Aα,4β,7β7aα)-4-[Octahydro-4-[2-hydroxyethyl)-7-methyl-13-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic; [3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-4-[2-gidroksistil-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic. (238i and 238ii)

Racemic compound V share his inationary using preparative chiral HPLC (CHIRALPAK AD 5×50 cm column, elwira 20% MeOH/EtOH (1:1) heptane (isocratic) at 50 ml/minute, @ 220 nm), which gives fast aliremove connection 238i (chiral HPLC: 13.54 min; CHIRALPAK AD 4.6×250 mm column, elwira 20% MeOH/EtOH (1:1) in heptane at 1 ml/min) and slowly aliremove connection 238ii (chiral HPLC: 14.99 min; CHIRALPAK AD 4.6×250 mm column, elwira 20% MeOH/EtOH (1:1) what heptanol at 1 ml/min). The absolute configuration of compounds 238i and 238ii not set. For ease of nomenclature connection 238i identified in the present invention as having a "R" configuration and connection 238ii of the invention as having an "S" configuration. Enatiomers pure products derived from compound 238i identified in the present invention as having a "R" configuration and enatiomers pure products derived from compound 238ii identified in the present invention as having an "S" configuration.

Example 239

[3R-((3Aα,4β,7β7aα)-4-[2-(3-Pertenece)ethyl)octahydro-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic; [3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(3-Pertenece)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (239i and 239ii)

To a solution of triphenylphosphine (0.0524 g, 0.20 mmol) in THF (2.0 ml) is added DBAD (0.046 g, 0.2 mmol). After 10 minutes add 3-terfenol (0.018 ml, 0.2 mmol). After another 10 minutes add enatiomers net connection 238i (0.050 g, 0.133 mmol). After 3 hours at 25°the reaction mass was concentrated in vacuo and purified using preparative HPLC (YMC S5 ODS 20×100 mm, 10-90% aqueous solution of methanol over 15 minutes containing 0.2% TFA, 20 ml/min, monitoring at 220 nm), which gives 0.031 g of compound 239i in a solid white color. This is what the process is repeated with enatiomers net connection 238ii, that gives compound 239ii. Connection 239i: HPLC: 100% within 3.80 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 471.65 [M+H]+, [α]D25=-47.371 (=4.412 mg/cm3CH2Cl2). Connection 239ii: HPLC: 100% within 3.80 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 471.65 [M+H]+, [α]D25=+24.3 (C=4.165 mg/cm3CH2Cl2).

Example 240

(4-Forfinal)carbamino acid, 2-[(3aα,4β,7β7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl ester, (240)

Connection V (0.100 g, 0.279 mmol) dissolved in dichloroethane (3.0 ml) and add 4-forgenerations (0.048 ml, 0.419 mmol), then heated to a temperature of 60°C. After 2 hours the reaction mass is then cooled to a temperature of 25°and diluted with methylene chloride. The mixture is washed once with saturated sodium bicarbonate solution (20 ml) and then the organics dried over anhydrous sodium sulfate. The crude product is purified using flash chromatography on silica, elwira 15% acetone is in chloroforme, that gives 0.098 g of compound 240 in the form of a yellow foam. HPLC: 98% within 3.320 and 3.457 minutes (atrophie isomers) (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 514.13 [M+H]+.

Example 241

(3Aα,4β,7β7aα)-4-[Octahydro-4-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (241D)

A. 2-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]furan (A)

2-(2-Hydroxyethyl)furan (1.00 g, 8.93 mmol. Example A) is dissolved in DMF at a temperature of 25°and add imidazole (0.790 g, 11.61 mmol). Then the portions added TBSCl (1.35 g, 8.93 mmol) over 5 minutes. After 2 hours the reaction was poured into diethyl ether (300 ml) and washed successively with water (1×100 ml), 1N HCl (1×100 ml) and brine (1×100 ml). The combined organics are then dried over magnesium sulfate and concentrated in vacuo. Connection A isolated in the form of a colorless oil (1.77 g) and used without purification. HPLC: 100% within 4.233 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm).

Century (3Aα,4β,7β7aα)-4-[4-[2-[[(1,1-DIMET later)dimethylsilane]oxy]ethyl]-1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (V)

4-(2,5-Dihydro-2,5-dioxo-1H-1-yl)-1-naphthaleneacetic (0.721 g, 3.40 mmol) is suspended in benzene (5.0 ml) in a sealed tube and add the connection A (1.00 g, 4.42 mmol). The reaction mass is heated at a temperature of 60°C for 16 hours and then cooled to a temperature of 25°C. the Benzene is removed in vacuo, giving a solid yellow color. The crude product is purified using flash chromatography on silica, elwira 1-5% acetone in chloroform that give 1.37 g of compound V in a solid yellow color. The NMR data confirm exconfederate isomer. HPLC: 100% within 4.030 and 4.110 (atrophie isomers) minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm).

S. (3Aα,4β,7β7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]octahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (S)

Connection V (0.500 g, 1.14 mmol) dissolved in ethyl acetate (40 ml) and added Pd/C (10% Pd, 0.200 g). Then introduce hydrogen from a cylinder. After 4 hours the reaction mass is filtered through celite, washed with ethyl acetate and concentrated in vacuo, giving a solid light yellow color, which is purified by means of flash chromatography on silica gel, elwira acetone/chlorform (0%-1.5%-3% acetone), which gives the connection S (0.450 g) in the form of a yellow foam.

D. (3Aα,4β,7β7aα)-4-[Octahydro-4-(2-hydroxyethyl)-1,3-Dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (241D)

Connection S (0.283 g, 0.50 mmol) is dissolved in a solution of 2% of 12N HCl in absolute ethanol (10 ml). After one hour the reaction mass zakolerovat saturated sodium bicarbonate solution and extracted with methylene chloride (4×20 ml). The combined organics dried over sodium sulfate and concentrated in vacuo, giving 0.211 g of compound 241D in the form of a solid white color. HPLC: 100% within 2.14 min (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 363.45

Example 242

(3Aα,4β,6β,7β7aα)-4-[4-[2-(4-Cianfrocca)ethyl]octahydro-6-hydroxy-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (242C)

A. (3Aα,4β,6β,7β7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]octahydro-6-hydroxy-13-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (242A)

Connection V (1.00 g, 2.28 mmol) and the catalyst of Wilkinson (0.105 g, 0.114 mmol) is rapidly stirred under vacuum at 25°for Casai then blow N 2. After that add THF (30 ml), and then, after the olefin is completely dissolved - of catechol borane (0.487 ml, 4.57 mmol). After one hour the reaction mass is then cooled to a temperature of 0°and add phosphate buffer with pH 7.2 (33 ml), and then EtOH (13 ml) and N2O2(30% solution, 3.0 g). After 3 hours at 0°With response complete with LC and the mixture is extracted with methylene chloride (3×50 ml). The combined organics are washed with 1:1 mixture of 10% sodium sulfate/1N NaOH (50 ml) and once with brine (50 ml). All the aqueous phases are combined and extracted with methylene chloride (50 ml) and the organic phase is combined with the previous selections. Then the organics dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product is purified using flash chromatography on silica, elwira 10-20% acetone in chloroform that gives 0.634 g of compound 242A in the form of a white foam. HPLC: 96% within 3.797 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 493.13 [M+H]+.

Century (3Aα,4β,6β,7β7aα)-4-[Octahydro-6-hydroxy-4-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (242V)

Connection 242A (0.400 g, 0.813 mmol) is dissolved in a solution of 2% of 12N HCl in absolute floor is zero (10 ml). After one hour the reaction mass zakolerovat saturated sodium bicarbonate solution and extracted with EtOAc (4×20 ml). The combined organics dried over sodium sulfate and concentrated in vacuo, giving 0.305 g of compound 242V in a solid white color. HPLC: 90% within 2.043 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 379.09 [M+H]+.

S. (3Aα,4β,5β,7β7aα)-4-[4-[2-(4-Cianfrocca)ethyl]octahydro-6-hydroxy-13-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (S)

To a solution of triphenylphosphine (0.054 g, 0.207 mmol) in THF (2.0 ml) is added DBAD (0.048 g, 0.207 mmol). After 10 minutes add 4-cyanoprop (0.025 g, 0.207 mmol). After another 10 minutes add the connection 242V (0.050 g, 0.138 mmol). After 3 hours at 25°the reaction mass was concentrated in vacuo and purified using preparative TLC on silica, elwira 25% acetone/chlorform that give 0.056 g of compound C in a solid white color. HPLC: 90% within 2.987 minutes (retention time) (VMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 480.10 [M+H]+.

Example 243

[3aS-(3Aα,4β,5β,7β,7 theα )-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic; [3R-(3Aα,4β,5β,7β7aα)-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (243Di and 243Dii)

A. (3Aα,4β,7β7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]-1,3,3A,4,7,7a-hexahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (A)

4-(2,5-Dihydro-2,5-dioxo-1H-1-yl)-1-naphthaleneacetic (18.3 g, 68.7 mmol) are added to a solution of compound A (26.6 g, 110.6 mmol) in benzene (75 ml) and heated to a temperature of 60°With during the night. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The residue is treated Meon (250 ml) with stirring at a temperature of 0°C for 10 minutes. The obtained solid is filtered off, washed with cold Meon (2×10 ml) and dried, giving 26.7 g (79.5%) connection A in a solid yellow color. HPLC analysis described above, the solid shows that it has a 95% purity (HPLC conditions: 95% within 2.48 min (Phenomenex-prime S5-C18 column, 4.6×50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm)). The filtrate then close tryout under reduced pressure and the obtained solid substance chromatographic, elwira 3% acetone/CHCl3that gives advanced 4.36 g of compound A (13%), obtaining the total final output of 92.5%.

Century (3Aα,4β,5β,7β7aα)-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (V)

The mixture A (10 g, 20.46 mmol) and RhCl(PPh3)3(0.947 mg, 1.02 mmol) vacuum and filled with argon (3×). Add THF (200 ml) and simultaneously dissolve all small particles, then slowly added dropwise, catecholborane (4.4 ml, 40.93 mmol). When the formation of the product will end, as determined by HPLC, the reaction mixture is cooled to a temperature of 0°and zakolerovat phosphate buffer (330 ml, pH 7.2), then add EtOH (130 ml) and N2About2(300 ml, 30% solution). After boronat will enter into the reaction, the mixture is extracted with CH2Cl2(3×) and the combined organic layers are washed with 1N NaOH, 10% aqueous solution of NaHSO3(1:1, 1×) and brine (1×). The combined wash water is extracted with CH2Cl2(1×) and the combined organic layers dried over Na2SO4. Purification using flash chromatography on silica gel, elwira from 10% to 30% acetone/CHCl3gradient over 25 minutes, give 7.1 g (68%) V in the form of a solid of light yellow color. HPLC conditions: 98% at t the value of 3.82 min (Phenomenex-prime S5-C18 column 4.6× 50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm).

C. [3R-(3Aα,4β,5β,7β7aα)-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic; [3S-(3Aα,4β,5β,7β7aα)-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (243Ci and s)

Racemic compound V divided into separate inationary using chiral liquid chromatography normal phase. Using Chiralpak OD column (50×500 mm), elwira 13% EtOH/hexane for more than 99 minutes at 50 ml/min, determined at 220 to them. Quickly aliremove isomeric compound 243Ci has a retention time = 45 minutes and slowly aliremove isomeric compound 243Cii has a retention time = 66 minutes.

D. [3S-(3Aα,4β,5β,7β7aα)-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic; [3aR-(3Aα,4β,5β,7β7aα)-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (243Di and 243Dii)

Connection 243Ci (0.84 g, 2.14 mmol) dissolved in 2% of 12N HCl/EtOH (20 ml). stirred for 5 minutes and end tryout under reduced pressure. Purification using flash chromatography on silica gel, elwira 5-10% MeOH/CH2Cl2give 0.57 g (88%) 243Di. Connection 243Di, which appeared as quickly eluruumis isomer (243Ci), with enantiomeric excess of 99.7%as determined by analytical chiral chromatography normal phase. HPLC conditions: 99.7% within 2.17 min (Chiralcel OJ 44.6×250 mm, 10 micron, 40°, isocratic 80% heptane/20% EtOH/Meon (1:1), 1.0 ml/min, determined at 288 nm).

Connection 243Cii (0.86 g, 2.19 mmol) dissolved in 2% of 12N HCl/EtOH (20 ml), stirred for 5 minutes and concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 5-10% MeOH/CH2Cl2give 0.60 g (90%) 243Dii. Connection 243Dii, which appears as a slowly eluruumis isomer (243Cii)appears with enantiomeric excess 87.1%, as determined by analytical chiral chromatography normal phase. HPLC conditions: 87.1% for 18.4 min (Chiralcel OJ 44.6×250 mm, 10 micron, 40°, isocratic 80% heptane/20% EtOH/Meon (1:1), 1.0 ml/min, determined at 288 nm).

The absolute configuration of the compounds of the 243Di and 243DH not define. For ease of nomenclature connection 243Di identified in the present invention as having an "S" configuration and connection 243Dii in the present invention as having a "R" configuration. Enatiomers pure products derived from compound 243Di denoted by the present invention as having an "S" configuration and enatiomers friendly products, obtained from compound 243Dii identified in the present invention as having a "R" configuration.

Example 244

[3S-(3Aα,4β,5β,7β7aα)-4-[7-[2-(4-Cianfrocca)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic; [3aR-((3Aα,4β,5β,7β7aα)-4-[7-[2-[4-Cianfrocca)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (244! and 244ii)

DBAD (26 mg, 0.115 mmol) are added to a solution of PPh3(30 mg, 0.115 mmol) in THF (0.65 ml). After stirring for 10 minutes add 4-cyanoprop (13.6 mg, 0.115 mmol) and the reaction mixture is stirred for a further 5 minutes. Add connection 243Di (30 mg, 0.076 mmol) and the mixture is stirred at room temperature for one hour. The reaction mass is concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 30% acetone/70% CHCl3gives 23.1 mg (0.047 mmol, 61.7%) connection 244i. HPLC conditions: 95% within 3.06 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm). MS (EU): m/e 494.09 [M+H]+. [α]D=53.30°, C=4.5 mg/cm3in THF, @ 589 nm)

DBAD (26 mg, 0.115 mmol) are added to a solution of PPh3(30 mg, 0.115 mmol) in THF (0.65 ml). After stirring during the 10 minutes add 4-cyanoprop (13.6 mg, 0.115 mmol) and the reaction mixture is stirred for a further 5 minutes. Add connection 243Dii (30 mg, 0.076 mmol) and the mixture is stirred at room temperature for one hour. The reaction mass is concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 30% acetone/70% CHCl3gives 20.3 mg (0.041 mmol, 54.2%) connection 244ii. HPLC conditions: 90% within 3.07 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm). MS (EU): m/e 494.09 [M+H]. [α]D=-42.87°, C=6.6 mg/cm3in THF, @ 589 nm)

Example 245

(3Aα,4β,7β7aα)-4-[4-[2-(4-Cianfrocca)ethyl]-7-atelectasia-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic. (245D)

A. 2-Ethyl-5-(2-hydroxyethyl)furan (A)

n-BuLi (2.5 M in hexane, 4.4 ml, 11 mmol) are added to a solution of 2-ethylfuran (1.05 ml, 10 mmol) in THF (10 ml) at a temperature of -25°C. the Solution is heated at room temperature and stirred for 3 hours. Ethylene oxide (0.75 ml) is added at a temperature of -78°C. the Reaction mass is stirred for 0.5 hours at a temperature of -15°and over night at room temperature. Add saturated aqueous solution of NH4Cl and the mixture extracted with ether (3×). About the United extracts washed with water (1× ) and brine (1×) and dried over Na2SO4. Purification using flash chromatography on silica gel, elwira 30% EtOAc/70% hexane, to give 1.12 g (8.02 mmol, 80.2%) of compound 245 And in the form of a yellow oil.

Century (3Aα,4β,7β7aα)-4-[4-Ethyl-1,3,3A,4,7,7a-hexahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (245V)

A solution of compound A (280 mg, 2.00 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthaleneacetic (496 mg, 2.00 mmol) in benzene (2 ml) is stirred at a temperature of 60°C for 2 hours. The reaction mixture was concentrated under reduced pressure. Solid yellow, connection 245V, are used directly in the next step.

S. (3Aα,4β,7β7aα)-4-[4-Atelectasia-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (S)

The mixture of compounds 245V (764 mg, 1.97 mmol) and 10% Pd/C (115 mg, catalytic amount) in EtOAc (36 ml) is stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction mixture is filtered through celite and concentrated under reduced pressure, giving 779 mg of crude compound S. Purification of this crude product by flash chromatography on silica gel, elwira 70% EtOAc/30% hexane, to give 235 mg (0.6 mmol, 30.1%) connection S. HPLC condition is I: 99% within 2.84 min (YMC S5 ODS 4.6× 50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm). MS (EC): m/e 391.12 [M+H]+.

D. (3Aα,4β,7β7aα)-4-[4-[2-(4-Cianfrocca)ethyl]-7-atelectasia-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (245D)

DBAD (44.2 mg, 0.192 mmol) are added to a solution of PPh3(50.4 mg, 0.192 mmol) in THF (1 ml). After stirring for 10 minutes add 4-cyanoprop (23 mg, 0.192 mmol) and the reaction mixture stirred for an additional 5 minutes. Add connection C (50 mg, 0.128 mmol) and the mixture is stirred at room temperature for 2 hours. The reaction mass is concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 40% EtOAc/60% hexane, to give 43 mg (0.087 mmol, 68.4%) connection 245D in a solid white color. HPLC conditions: 99% within 3.65 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm). MS (EU): m/e 492.16 [M+H]+.

Example 246

(3Aα,4β,7β7aα)-4-[2-(atomic charges)ethyl]-2-(4-cyano-1-naphthalenyl)hexahydro-7-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione, (246)

Connection V (0.100 g, 0.279 mmol) was dissolved in methylene chloride (3.0 ml) at 25°and pyridine (0.071 ml, 0.837 mmol) and add the 4-DMAP (1.0 mg). Then add acetic anhydride (0.053 ml, 0.559 mmol) and the reaction mass is stirred for 20 hours at 25°C. After 20 hours, add a saturated solution of sodium bicarbonate and the reaction mass is still stirred for 30 minutes. The mixture is then extracted with methylene chloride (2×20 ml). Then the organics washed once with 1N HCl (10 ml)and then dried over anhydrous sodium sulfate. After concentration in vacuo the crude product is purified using preparative TLC on silica, elwira 12% acetone in chloroform that give 0.073 g of compound 246 in the form of a yellow foam. HPLC: 95% within 2.837 and 3.027 minutes (atrophie isomers) (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 441.10 [M+Na]+.

Example 247

(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(2-oxoethyl)-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (247)

Oxalicacid (2.0 M solution, 1.73 ml, 3.5 mmol) is added to a dry methylene chloride (10 ml) and cooled to a temperature of -78°C. Then added dropwise DMSO (0.283 ml, 3.99 mmol) vydelyaetsa gas. After 15 minutes add the connection V (1.00 g, 2.66 mmol) in methylene chloride (10 ml). After 15 minutes, add TEA (1.10 ml, 7.98 mmol) and p is a promotional mass is slowly heated to a temperature of 25° C. Then add water (30 ml) and the mixture is diluted with methylene chloride (100 ml). Organics washed once with 1N HCl (30 ml), once with water (30 ml) and once with brine (30 ml)and then dried over anhydrous sodium sulfate. The crude product is produce by concentration in vacuum that gives compound 247 in the form of an orange foam. The crude compound 247 are used directly in the next stage. HPLC: 100% within 2.70 min (retention time) (YMC 85 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 483.65

Example 248

[3Aα,4β(E),7α7aα]-4-[4-[3-(4-Cyanophenyl)-2-propenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic; [3aα,4β(E),7α,7aα]-4-[4-[3-(4-Cyanophenyl)-2-propenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (248i and 248ii)

(4-cyanobenzyl)-triphenylphosphonium chloride (0.072 g, 0.174 mmol) suspended in THF (2.0 ml) and cooled to a temperature of 0°C. Then added dropwise n-BuLi (1.6 M solution, 0.092 ml, 0.147 mmol)to give a homogeneous solution. The solution is heated to a temperature of 25°C for 15 minutes and then cooled to a temperature of 0°C. add the connection 247 (0.050 g, 0.134 mmol) in THF. After one hour the reaction mass zakolerovat nassen is m solution of ammonium chloride, and then extracted with methylene chloride (3×20 ml). The combined organics dried over anhydrous sodium sulfate, and then concentrated in vacuo. The crude product is purified using preparative TLC, elwira 5% acetone in chloroform that give 0.010 g of a mixture of compounds 248i and 248ii in a solid white color. A mixture of 1:1 isomeric olefins E and Z determined using NMR spectroscopy. HPLC: 100% within 3.517 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 474.2

Example 249

(3Aα,4β,7β7aα)-4-|4-[3-(4-Cyanophenyl)propyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (249)

The mixture of compounds 248i and 248ii (0.008 g, 0.017 mmol) was dissolved in EtOH (3.0 ml) and added Pd/C (10% Pd, 0.008 g). Then enter H2from the container. After 18 hours the reaction mass is filtered through celite, elwira EtOAc, then concentrated in vacuo. Compound 249 isolated in a solid white color (0.007 g). HPLC: 90% within 3.520 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 476.13 [M+H]+.

Example 250

(3Aα,4β ,7β7aα)-4-[4-[2-[(6-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (250)

To a solution of PPh3(52 mg, 0.20 mmol) in 0.5 ml THF added DBAD (46 mg, 0.20 mmol) in one portion as a solid substance. The resulting mixture was stirred for 10 minutes, before adding 6-chloro-3-hydroxy-1,2-benzisoxazol (34 mg, 0.20 mmol). Stirring is continued for 10 minutes before a solution of compound B (50 mg, 0.13 mmol) in 0.5 ml THF is injected through the cannula. The resulting mixture was stirred at ambient temperature for 24 hours, concentrated and purified using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm column, elwira 30-100% aqueous solution Meon, contains 0.1% TFA over 10 minutes at 20 ml/minute), which gives a solid white color. The obtained solid substance was dissolved in CH2Cl2, washed with saturated aqueous NaHCO3, dried over Na2SO4and concentrate that gives 50 mg (71%) of compound 250 in the form of a colorless oil. HPLC: 26% within 3.89 minutes and 74% within 4.02 minutes (mixture of atropisomers, retention time) (YMC S5 ODS column 4.6×50 mm Ballistic, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% N3PO4, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 528.4 [the+H] +.

Example 251

(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-7-[2-[(6-nitro-1H-indazol-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (251)

To a solution of compound B (50 mg, 0.13 mmol) in toluene (1 ml) was added ADDP (50 mg, 0.20 mmol), 6-nitro-3-indazolinone (36 mg, 0.20 mmol) and n-Bu3R (50 ál, 0.2 mmol). The resulting mixture is heated to a temperature of 80°within 24 hours, concentrated and purified using Raman preparative HPLC with reversed phase (YMC S5 ODS 20×100 mm column, elwira 30-100% aqueous solution Meon, contains 0.1% TFA over 10 minutes at 20 ml/minute) and flash chromatography (silica gel, 25% acetone in CHCl3)that give 17 mg (25%) of compound 251 in the form of a solid yellow color. HPLC: 24% during 3.60 minutes and 76% within 3.74 minutes (mixture of atropisomers, retention time) (YMC S5 ODS column 4.6×50 mm Ballistic, 10-90% aqueous solution of methanol over 4 minutes containing 0.2% N3PO4, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 537.6 [M+H]+.

Example 252

[3S-(3Aα,4β,5β,7β7aα)]-4-[7-[2-(1,2-Benzisoxazol-3-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (252)

PPh3(47 mg, 0.18 mmol), DBAD (41 mg, 0.18 mmol), 3-hydroxy-1,2-benzisoxazol (24 mg, 0.18 mmol) and compound 243Di (35 mg, 0.09 mmol) react in accordance with the method described for connection 250. Purification was achieved using HPLC with reversed phase (YMC S5 ODS 20×100 mm column, elwira 30-100% aqueous solution Meon, contains 0.1% TFA over 10 minutes at 20 ml/minute), which gives a solid white color. The obtained solid substance was dissolved in CH2Cl2, washed with saturated aqueous NaHCO3, dried over Na2SO4and concentrate, which gives 29 mg (64%) of compound 252 in the form of a colorless oil. HPLC: 96% within 3.29 minutes (mixture of atropisomers, retention time) (YMC S5 ODS column 4.6×50 mm Ballistic, 0-100% aqueous solution of methanol over 4 minutes containing 0.2% N3PO4, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 510.2 [M+H]+.

Example 253

[3aR-(3aα,4β,5β,7β7aα)]-4-[7-[2-(1,2-Benzisoxazol-3-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (253)

PPh3(47 mg, 0.18 mmol), DBAD (41 mg, 0.18 mmol), 3-hydroxy-1,2-benzisoxazol (24 mg, 0.18 mmol) and compound 243DH (35 mg, 0.09 mmol) react in accordance with the method described for connection 250. Purification was achieved using HPLC with reversed phase (YMC S5 ODS 20×100 mm column, elwira 30-100% aqueous solution Meon, contains 0.1% TFA over 10 minutes the ri 20 ml/minute), that gives a solid white color. The obtained solid substance was dissolved in CH2Cl2, washed with saturated aqueous NaHCO3, dried over Na2SO4and concentrate that provides 23 mg (51%) of compound 253 in the form of a colorless oil. HPLC: 95% within 3.29 minutes (mixture of atropisomers, retention time) (YMC S5 ODS column 4.6×50 mm Ballistic, 0-100% aqueous solution of methanol over 4 minutes containing 0.2% NSR, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 510.4 [M+H]+.

Example 254

(3Aα,4β,5β,7β7aα)]-4-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile; ((3Aα,4β,5β,7β7aα)]-(Octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(trifluoromethyl)benzonitrile, (254i and 254ii)

Racemic compound V divided into inationary using preparative chiral HPLC (CHIRALPAK AD 5×50 cm column, elwira 20% MeOH/EtOH (1:1) in heptane (isocratic) at 50 ml/minute), which gives fast aliremove connection 254i (chiral HPLC: 10.02 min; CHIRALPAK AD 4.6×250 mm column, elwira 20% MeOH/EtOH (1:1) in heptane at 1 ml/min) and slowly aliremove 254ii (chiral HPLC: 14.74 minutes; CHIRALPAK AD 4.6×250 mm column, elwira 20% MeOH/EtOH (1:1) in heptane at 1 ml/minute).

Example 255

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)oktay the ro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile; (3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile, (255Hi and n)

And 2-(2-Hydroxyethyl)furan (A)

2-(2-Hydroxyethyl)furan receive in accordance with the following methods described in the references: Harmata, M, et al. J. Org. Chem. 60, 5077-5092 (1995). To a solution of furan (8 ml, 1 10 mmol) in 100 ml THF at a temperature of -78°add H-BuLi (2.5 M in hexane, 44 ml, 1 10 mmol). The solution is stirred at a temperature of 0°C for 4 hours, and then adding ethylene oxide (7.5 ml) at a temperature of -78°C. the Reaction mixture was stirred at -15°C for one hour and then overnight at room temperature. The reaction mass zakolerovat saturated aqueous NH4Cl and extracted with ether (3×). The combined extracts washed with water (1×) and brine (1×). The ether solution is dried over Na2SO4and concentrate under reduced pressure. Purification using flash chromatography on silica gel, elwira 40% EtOAc/60% hexane, gives 5.4 g (48.2 mmol, 43.8%) connection A in the form of butter, light brown.

C. 2-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]furan (255V)

The imidazole (3.65 g, 53.6 mmol) and TBSC1 (6.47 g, 42.9 mmol) are added to a solution of compound 255 is (4.00 g, 35.7 mmol) in 50 ml of DMF. The mixture is stirred at room temperature for 2 hours and then the reaction mixture is poured into ether. The ether solution washed with water (1×), 1N HCl (1×), water (1×) and brine (1×). The organic layer is dried over Na2SO4and concentrate under reduced pressure. Purification using flash chromatography on silica gel, elwira 30% of CH2Cl2/70% hexane, gives 7.4 g (32.7 mmol, 9 1.7%) 255V in the form of a colorless oil.

C. 2-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]-5-(2-hydroxyethyl)furan (S)

r-BuLi (1.2 M in pentane, 10 ml, 16.99 mmol) is added dropwise to a stirred solution 255V (3.49 g, 15.44 mmol) in 13 ml of THF at a temperature of -78°C. the Mixture is stirred for 4 hours at 0°C. In the reaction solution is added ethylene oxide (1.05 ml) at a temperature of -78°C. the Mixture is heated to room temperature and stirred over night. Add saturated aqueous solution of NH4Cl and most of the THF is removed under reduced pressure. The mixture is extracted with ether (3×) and the combined organic layers washed with water (1×), brine (1×) and dried over Na2SO4. Purification using flash chromatography on silica gel, elwira 5% EtOAc/95% SN2Cl2gives 2.8 g (10.4 mmol, 67%) connection S in the form of a yellow oil.

D. 2-[2-[[(1,1-Dimethylethyl)on methylsilyl]oxy]ethyl]-5-[2-(phenylmethoxy)ethyl]furan (255D)

Alcohol S (1.00 g, 3.7 mmol) in 12 ml of THF is treated with 60% NaH (177.8 mg, 4.44 mmol), benzylbromide (0.53 ml, 4.44 mmol) and tetrabutylammonium the iodide (50 mg, 5%) for 3 hours at room temperature. Water is added and the mixture extracted with EtOAc (3×). The combined extracts washed with water (1×) and brine (1×) and dried over Na2SO4. Purification using flash chromatography on silica gel, elwira 20% hexane/80% CH2Cl2give 1.10 g (3.05 mmol, 82.6%) connection 255D in the form of a yellow oil.

E. 2-(2-Hydroxyethyl)-5-[2-(phenylmethoxy)ethyl]furan (E)

Tetrabutylammonium fluoride (1.0 M in THF, 3.06 ml, 3.06 mmol) are added to a solution of compound 255D (1.1 g, 3.06 mmol) in 10 ml THF at 0°C. the Reaction mixture was stirred at room temperature for 10 minutes, zakolerovat with a saturated aqueous solution of NH4Cl and extracted with ether (3×). The combined extracts dried over Na2SO4. Purification using flash chromatography on silica gel, elwira 10% EtOAc/90% CH2Cl2give 750 mg (3.05 mmol, 99.6%) connection E in the form of oil is light yellow in color.

F. 5-[2-(Phenylmethoxy)ethyl]furan-2-propenenitrile (255F)

DEAD (1.285 ml, 8.17 mmol) are added to stir the solution Ph3P (2.14 g, 8.17 mmol) in 12 ml of dry T is f at 0° C. the Solution is stirred for 30 minutes at room temperature and add the connection A (670 mg, 2.72 mmol). The reaction mass is stirred for 15 minutes and add acetonecyanohydrin (0.745 ml, 8.17 mmol) at -15°C. the Reaction mass is stirred for 30 minutes at a temperature of -15°C, then at room temperature overnight. The mixture is then concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 100% CH2Cl2give 180 mg (0.705 mmol, 26%) connection 255F in the form of a colorless oil.

G. (3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)-1,2,3,3A,7,7a-hexahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile (255G)

A solution of compound 255F (180 mg, 0.706 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthaleneacetic (263 mg, 1.06 mmol) in CH2Cl2(3 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 5% EtOAc/CH2Cl2give 318 mg (0.63 mmol, 89.6%) connection 255G in the form of a solid light grey color, which are used directly in the next step.

N. (3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-EPO is si-4H-isoindole-4-propanenitrile; (3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-13 dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile (255Hi and 255Hii)

The mixture of compounds 255G (318 mg, 0.63 mmol) and 10% Pd/C (64 mg) in EtOH (10 ml) and EtOAc (5 ml) is stirred under hydrogen atmosphere at room temperature overnight. The reaction mixture is filtered through celite and concentrated under reduced pressure, giving 320 mg of crude compound 255Hi and 255Hii. Cleaning 25 mg of this crude product by flash chromatography on silica gel, elwira 55% EtOAc/hexane, gives 6.5 mg (0.013 mmol, 26% (based on 25 mg)) connection 255Hi and 8.1 mg (0.016 mmol, 32.4% (based on 25 mg)) connection 255Hii. Connection 255Hi: HPLC conditions: 98% within 3.57 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm), MS (EC): m/e 506.15 [M+H]+. Connection 255Hii: HPLC conditions: 98% within 3.51 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm), MS (EC): m/e 506.15 [M+H]+.

Example 256

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-4H-isoindole-4-propanenitrile; (3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-4H-isoindole-4-propanenitrile, (256i and 256ii)

The mixture of compounds 255Hi and 255Hii (200 mg, 0.396 mmol) and PdCl2(8.4 mg, catalytic amount) in EtOH (1 ml) and EOAc (3 ml) is stirred in hydrogen atmosphere (30 psi) at room temperature over night. The reaction mixture is filtered through celite and concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 5% Meon/CH2Cl2then using the second column, elwira 100% EtOAc, gives 28.9 mg (0.0696 mmol, 17.6%) connection 256ii and 26.5 mg (0.0639 mmol, 16.1%) connection 256i. Connection 256ii: HPLC conditions: 90% within 2.44 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm.), MS (EU): m/e 416.11 [M+H]+. Connection 256i: HPLC conditions: 99% within 2.47 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm), MS (EC): m/e 416.11 [M+H]+.

Example 257

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)-7-[2-(4-pertenece)ethyl]octahydro-1,3-dioxo-4,7-epoxy-4H-isoindole-4-propanenitrile (257)

DBAD (15 mg, 0.065 mmol) are added to a solution of PPh3(17 mg, 0.065 mmol) in THF (0.3 ml). After stirring for 10 minutes add 4-terfenol (7.33 mg, 0.065 mmol) and the reaction mixture stirred for another 5 minutes. Add soy is inania 256i (18.1 mg, 0.044 mmol) and the mixture is stirred at room temperature for 3 hours. The reaction mass is concentrated under reduced pressure. Purification using flash chromatography on silica gel, elwira 60% EtOAc/30% hexane, gives 5.9 mg (0.0116 mmol, 26.34%) connection 257. HPLC conditions: 98% within 3.59 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous solution of methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm). MS (EU): m/e 510.14 [M+H]+.

Example 258

(3Aα,4β,7β7aα)-2-(7-Chloro-2,1,3-benzoxadiazole-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (258)

A. 4-Amino-7-chloro-2,1,3-benzoxadiazole (A)

A solution of 1.0 g (5.02 mmol) of 4-chloro-7-nitrobenzofurazan in 20 ml of Asón, 10 ml of EtOAc and 2 ml of N2About heated to a temperature of 50°and treated with iron powder (1.4 g, 251 mmol). The mixture is heated at a temperature of 80°C for 30 minutes and then give her a chance to cool to room temperature. The mixture is filtered through celite, elwira EtOAc. The filtrate was washed with saturated aqueous NaHCO3, dried over MgSO4and concentrate, which gives the connection A (0.80 g, 94%) as a solid red color.

Century (3Aα,4β,7β7aα)-2-(7-Chloro-2,1,3-benzoxadiazole-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (V)

Connection A (42 mg, 0.25 mmol) is reacted in a sealed tube with compound 20A (73.5 mg, 0.375 mmol), MgSO4(75 mg, 0.625 mmol) and Et3N (170 μl, 1.25 mmol) in 250 μl of toluene in accordance with the method described in example C, which gives, after purification using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, elwira 30-100% aqueous methanol, contains 0.1% TFA over 12 min, 20 ml/min) 23 mg (26%) connection V in a solid yellow color. HPLC: 97.6% within 2.87 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous methanol, contains 0.2% phosphoric acid over 4 min, 4 ml/min, monitoring at 220 nm), MS (DCl): m/e 347.9 [M]+.

Example 259

(3Aα,4β,7β7aα)-2-(7-Chloro-2-methyl-4-benzofuranyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione. (259).

7-Chloro-2-methyl-4-benzofuranyl (38 mg, 0.25 mmol, obtained in accordance with the method described Enomoto and Takemura in EP 0476697 A1) is reacted in a sealed tube with compound 20A (73.5 mg, 0.375 mmol), MgSO4(75 mg, 0.625 mmol) and Et3N (170 μl, 1.25 mmol) in 250 μl of toluene in accordance with the method described in example C, which gives, after purification using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, elwira 30-100 aqueous methanol, contains 0.1% TFA over 12 min, 20 ml/min is t), 42 mg (47%) of compound 259 in a solid white color. HPLC: 98% during 3.45 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (DCl): m/e 359.9 [M]+.

Example 260

(3Aα,4β,7β7aα)-2-(7-Chloro-2-methylbenzo[b]thiophene-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (260)

A. 1-Chloro-2-(2-chlorellales)-4-nitrobenzene (A)

A solution of 2-chloro-5-nitrobenzonitrile (1.0 g, 5.27 mmol, obtained in accordance with the method described by Still et. Al., Synth. Comm. 13, 1181 (1983)) in 15 ml DMF is treated with 2,3-dichloropropene (693 μl, 7.52 mmol) and K2CO3(433 mg, 3.13 mmol). The mixture is heated at a temperature of 80°C for 2 hours, and then give her a chance to cool to room temperature. Add EtOAc (200 ml) and H2O (100 ml). The organic phase is washed with N2About (2×250 ml), saturated aqueous NaCl (100 ml), dried over MgSO4and concentrate. The crude product is purified using flash chromatography on a column of silica gel, elwira 20% EtOAc in hexane, which gives the connection A (1.09 g, 89%) as orange oil.

Century 4-Amino-7-chloro-2-methylbenzo[b]thiophene (260V)

A solution of 1.09 g (4.67 shall mol) of the compound A in 20 ml of Asón with 10 ml of EtOAc and 2 ml of N 2About heated to a temperature of 80°and treated with iron powder (1.3 g, 23.4 mmol). The mixture is heated at a temperature of 80°C for 40 minutes and then give her a chance to cool to room temperature. The mixture is filtered through celite, elwira EtOAc. The filtrate was washed with saturated aqueous NaHCO3, dried over MgSO4and concentrated in vacuo. Add N,N-diethylaniline (10 ml) and the reaction mass is heated at a temperature of 215°C for 6 hours. After cooling to room temperature, add 1N aqueous HCl (20 ml) and the reaction mass stirred at room temperature for 2 hours. The mixture is extracted with EtOAc (3×30 ml). The organic phase is washed with saturated aqueous NaHCO3, dried over MgSO4and concentrate. The crude product is purified using flash chromatography on a column of silica gel elwira 25% EtOAc in hexane, which gives the connection 260V (320 mg, 35%) as a solid grayish-yellow color.

S. (3Aα,4β,7β7aα)-2-(7-Chloro-2-methylbenzo[b]thiophene-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (S)

Connection 260V (49 mg, 0.25 mmol) is reacted in a sealed tube with compound 20A (73.5 mg, 0.38 mmol), MgSO4(75 mg, 0.63 mmol) and Et3N (170 μl, 1.25 mmol) in 250 μl of toluene in accordance with the method described in example S that gives th the purification by using preparative HPLC with a reversed phase (YMC S5 ODS 20× 100 mm, elwira 30-100% aqueous solution of methanol for more than 12 minutes containing 0.1% TFA, 20 ml/min), 28 mg (30%) connection S in the form of a solid pale yellow color. HPLC: 96% during 3.18 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (DC1): m/e 376.0 [M]+.

Example 261

[3Aα,4β(E),7β7aα]-4-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]-2-butenova acid fenilmetilovy ether (261)

Compound 247 (0.500 g, 0.134 mmol) was dissolved in THF (20 ml) and added dropwise benzyl(triphenylphosphorane) (0.55 g, 0.134 mmol). The reaction mixture is stirred at a temperature of 67°C for 2 hours and then concentrated under reduced pressure. Purification using flash chromatography on SiO2, elwira 5% acetone/95% CHCl3give 0.65 g of compound 261 in a solid yellow color. HPLC: 99% within 3.717 minutes (retention time) (YMC S5 ODS column 4.6×50 mm elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 507.1 [M+H]+.

Example 262

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoing the l-4-butenova acid (262)

Compound 261 (0.60 g, 1.19 mmol) dissolved in EtOH/EtOAc (5 ml/5 ml) and add 10% Pd/C (0.30 g). Then introduce hydrogen from a cylinder. After 8 hours the reaction mass is filtered through celite, and then concentrated under reduced pressure, which gives compound 262 (0.47 g) as a solid white color. HPLC: 98% within 2.81 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 419.1 [M+H]+.

Example 263

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)-N-f4-forfinal)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-butanamide, (263)

Compound 262 (0.030 g, 0.072 mmol) was dissolved in CH3CN (1 ml). DCC (0.014 g, 0.072 mmol) and then add the SPLA (0.0098 g, 0.072 mmol)and then 4-ftoranila (0.007 ml, 0.072 mmol). The reaction mixture is stirred in an argon atmosphere for 14 hours, the crude product is dissolved in Meon and purified using preparative HPLC (YMC VP-ODS column, 20×100 mm, elwira from 20% to 100% In 15 minutes and golodny @ 100% for 10 minutes). Compound 263 (0.020 g) was isolated in a solid white color. HPLC: 100% within 3.217 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 the minutes, containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 512.1

Example 264

[3aS-(3aα,4β,5β,7β7aβ)]-4-[7-[2-[atomic charges)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic; [3aR-(3Aα,4β,5β,7β7aβ)]-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl]-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, (264Di and 243Dii)

Racemic mixture of compounds 243Di and 243Dii (1.90 g) was dissolved in 100 ml of anhydrous THF in a 2 l flask. Anhydrous tert-butyl methyl ether (900 ml) and vinyl acetate (40 ml) is transferred into the flask under stirring and add the lipase (20 g sample of the crude product from the pancreas of pigs; Sigma, Cat# L3126). The reaction mixture is stirred for 2 hours at room temperature, while adding another 5 grams of lipase and 20 ml of vinyl acetate. The reaction mass was stirred at room temperature for 19 hours, maintained at a temperature of 4°without stirring for 36 hours and then stirred at room temperature for the remaining 22 hours (until the desired % enantiomeres excess is reached, as will determine chiral HPLC). For analysis collect 200 units/ml of the mixture and centrifuged. Supernatant (100 uL) is dried in a nitrogen atmosphere and the resulting residue is dissolved in 100 units/ml EtOH and will versaut HPLC analysis:

1) HPLC with reversed phase: column YMC-ODS AQ 150×4.6; flow rate, 1.2 ml/min; sample volume, 10 ál

the solvent And,: 1 nm HCl in water; solvent B, MeCN; control at 300 nm

Gradient:
Time (minutes)088.59.51012
In %306085853030

2) Chiral-HPLC: Column, CHIRALCEL OJ 4.6×250 mm mobile phase, hexane/Meon/EtOH (8:1:1). A flow rate of 1 ml/min; sample size of 20 units/ml of control when values of 220 and 300 nm, performed at a temperature of 25°; 40°With (to determine enantiomeres excess in the reaction mixture)

The enzyme is removed by filtration and the filtrate concentrated in vacuo. The resulting mixture was dissolved in CHCl3and adsorb on silica gel (63-200 μm). These solids are used in VLC funnel (3 cm I.D., VLC is a vacuum liquid chromatography using a glass funnel, with 24/40 of the joint at the base), containing 5 cm of the substrate of silica gel (25-40 microns) and perform step gradient. The gradient is composed of 100% CHCl3in the first three fractions, then CHCl3-1% Meon (3 fractions), CHCl33-3% Meon (3 fractions), CHCl3-4% Meon (3 fractions) and, finally, CHCl3-5% Meon (3 fractions). The volume fractions was 100 ml to achieve CHCl3-3% Meon and at this point he was 200 ml. Connection 264 elute in the last two fractions of 100% CHCl3and before the first fraction CHCl3-2% of the Meon. Connection 243Dii eluted initially with the second fraction CHCl3-2% Meon and continues to buyouts to the first fraction CHCl3-5% of the Meon. The crude compound 243Dii contains a small amount of colored impurities, which are removed using a Sephadex column [LN-20, swollen in CHCl3-Meon (2:1), column (2.5 cm I.D.; 90 cm in length), which gives 632 mg connection 243Dii. Compound 264: HPLC conditions: 98% for 7.2 minutes (method 1), chiral HPLC conditions: 29.0 minutes @ 25° (method 2). Connection 243Dii: HPLC conditions: 98% for 4.6 minutes (method 1), chiral HPLC conditions: 96% EE in 25.7 minutes (@ 25° (C) and 19.8 minutes (@ 40° (C) (method 2).

Example 265

(3Aα,4β,7β7aαand(E)]-4-[Octahydro-4-methyl-1,3-dioxo-7-(4-oxo-4-phenyl-2-butenyl)-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (265)

Compound 247 (0.050 g, 0.134 mmol) was dissolved in THF (1.5 ml) and add (penacillin)triphenylphosphorane (0.051 g, 0.134 mmol). The reaction mixture is stirred at a temperature of 67°within 24 hours, and then cooled to a temperature of 23°and concentrated in Vacu the IU. The crude product is then purified using preparative HPLC. (YMC VP-ODS column, 20×100 mm, elwira from 20% to 100% within 15 minutes and cold @ 100% In for 10 minutes.), that gives compound 265 (0.040 g) as a solid white color. HPLC: 100% within 3.503 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 477.1 [M+H]+.

Example 266

(3Aα,4β,7β7aαand(E)]-4-[Octahydro-4-methyl-1,3-dioxo-7-(4-oxo-4-phenyl-butenyl)-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (266)

Compound 265 (0.010 g, 0.021 mmol) was dissolved in EtOH (2.0 ml) and added Pd/C (10% Pd, 0.005 g). Then introduce hydrogen from a balloon and the reaction mass is stirred at a temperature of 25°C for 3 hours. The reaction mixture was then filtered over celite, washed with EtOAc and concentrated in vacuo, giving the connection 266 in the form of a solid yellow-brown (0.009 g). Further purification is not required. HPLC: 100% within 3.38 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 503.2 [M+Na]+.

Examples from 267 to 378

Additional soedinyayuschayasya of the invention was produced using the techniques similar to those described above. Connection examples with 267 in 378 have the following structural formula (L is a bond):

where G, R7the connection name, retention time, molecular mass, and the production method, are given in table 5. The absolute configuration for the following compounds do not define. For simplicity in nomenclature, compound 238i identified as having an "R" configuration and the connection 238ii identified as having an "S" configuration. Enatiomers pure products derived from compound 238i identified in the present invention as having a "R" configuration and enatiomers pure products derived from compound 238ii identified in the present invention as having an "S" configuration.

Chromatographic techniques are used to determine the retention time of the compounds from table 5, as follows: LCMS=YMC S5 ODS column, 4.6×50 mm, elwira 10-90% Meon/N2O over 4 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column, 4.6×50 mm, elwira 10-90% Meon/N2About 2 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LC=YMC S5 ODS column 4.6×50 mm, elwira 10-90% Meon/N2On over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm. The molecular weight of compounds in table 5, the set is on with MS (EC) by the formula m/E.

Table 5.
Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
267(3Aα,4β,7β7aα)-(4-[7-[2-(4-Bromophenoxy)ethyl]octahydro-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.97 LCMS 549.0 [M+H]+204,35
268(3Aα,4β,7β7aα)-(4-[Octahydro-7-[2-(4-iodinase)ethyl]-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.4.09 LCMS 597.0 [M+H]+204,35
269(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.95 LC204,35

Ave. No.GR7Name the of connections The retention time Minutes./Molecular weightThe method according to example
270(3Aα,4β,7β7aα)-4-[Octahydro-7-[2-(4-methoxyphenoxy)ethyl]-4-methyl-1,3-dioxo-4,7-epoxy-2H-Isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.66 LC204,35
271(3Aα,4β,7β7aα)-4-[7-[2-(4-Ethoxyphenoxy)ethyl]octahydro-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.81 LC204,35
272(3Aα,4β,7β7aα)-4-[7-[2-(4-Chlorophenoxy)ethyl]octahydro-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.97 LCMS 522.2 [M+H]+204,35
273(3Aα,4β,7β7aα)-4-[2-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-Epoxy-4H-isoindole-4-yl]ethoxy]benzoni acid, methyl ester3.77 LCMS 529.12 [M+H]+24,35

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
274(3Aα,4β,7β7aα)-Hexahydro-4-(2-hydroxyethyl)-7-methyl-2-(3-methyl-4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.44 LC204,35
275(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(triptoreline)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.97 LC204,35
276CH3(3Aα,4β,7β7aα)-2-(3,5-Dichlorophenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.31 LCMS 341.2 [M+H]*20
277CH3(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.04 LCMS20

Ave. No.GR7Connection nameThe hold time min/mol. weightThe method according to example
278(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(phenylmethoxy)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.4.06 LC204,35
279(3Aα,4β,7β7aα)-Hexahydro-4-(2-hydroxyethyl)-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.607 and 2.743 rotary isomers LC204,35
280(3Aα,4β,7β7aα)-4-[2-(4-Pertenece)ethyl]hexahydro-7-methyl-2-(3-methyl-4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.68 LC204,35
281(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-[(trifluoromethyl)thio]phenoxy]ethyl]4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile. 4.11 LC204,35

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
282(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-7-[2-(4-nitrophenoxy)ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.68 LC204,35
283(3Aα,4β,7β7aα)-4-[2-(4-Pertenece)ethyl]hexahydro-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.68 and 3.80 rotational isomers LC204,35
284(3Aα,4β,7β7aα)-4-[Octahydro-7-methyl-1,3-dioxo-7-[2-[2-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.89 LC204,35
285(3Aα,4β,7β7a&x003B1; )-4-[4-[2-(2-Bromophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.91 LC204,35

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
286(3Aα,4β,7β7aα)-4-[4-[2-(3-Pertenece)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.78 LC204,35
287N(3Aα,4β,7β7aα)-Hexahydro-2-[4-(1H-imidazol-1-yl)phenyl]-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.16 LC3
288N(3Aα,4β,7β,7αand)-2-[3-Chloro-4-(2-thiazolyl)phenyl]hexahydro-4-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.81 LC3
289CH3(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-(3-methyl-4-nitrophenyl)-4,7-epoxy-1H and Jindal-1,3(2H)-dione. 2.74 LC20

3.25 LC
Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
290CH3(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-(2-methyl-4-nitrophenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.71 LC20
291(3Aα,4β,7β7aα)-2-(3,5-Dichlorophenyl)hexahydro-4-(2-hydroxyethyl)-7-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.98 LC204
292(3Aα,4β,7β7aα)-2-(3,5-Dichlorophenyl)-4-[2-(4-pertenece)ethyl]hexahydro-7-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.4.03 LC204,35
293(3Aα,4β,7β7aα)-4-[Octahydro-4-[2-(4-hydroxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.204,35

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
294(3Aα,4P,7đ,7aα)-4-[4-[2-(4-Cianfrocca)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.51 LC204,35
295(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[3-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.85 LC204,35
296(3Aα,4β,7β7aα)-4-[4-[2-(3-Bromophenoxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.84 LC204,35
297(3Aα,4β,7β7aα)-4-[4-[(4-Forfinal)methyl]octagen the-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile. 3.73 LC205

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
298CH33-pyridinyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.61 LC20
299CH3(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-(1-methyl-6-oxo-3-piperidinyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.73LC20
300(3Aα,4β,7β7aα)-4-[4-[2-(3-Cianfrocca)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.46 LC20
301(3Aα,4β,7β7aα)-4-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethoxy]benzoic acid, fenilmetilovy ether.4.01 LC 204,35

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
302(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-(2-phenoxyethyl)-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.57 LC204,35
303CH3(3Aα,4β,7β7aα)-2-(3,5-Dichloro-4-nitrophenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.40 LC20
304CH3(3Aα,4β,7β7aα)-2-(3,5-Dichloro-4-hydroxyphenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.58 LC20
305CH3(3Aα,4β,7β7aα)-2-(5-fluoro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.96 and 3.06 rotary isomers LC20

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
306CH3(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-(1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.60 and 2.73 rotary isomers LC20
307CH3(3Aα,4β,7β7aα)-Hexahydro-2-[3-methoxy-4-(5-oxazolyl)phenyl]-4,7-Dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.62 rotary isomers LC20
308(3Aα,4β,7β7aα)-Hexahydro-4-[2-(4-methoxyphenoxy)ethyl]-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.42 and 3.55 rotary isomers LC204,35
309(3Aα,4β,7β7aα)-Hexahydro-4-methyl-2-(4-nitro-1-naphthalenyl)-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.81 and 3.93 rotary isomers LC24,35
310(3Aα,4β,7β7aα)-Hexahydro-4-methyl-2-(4-nitro-1-naphthalenyl)-7-[2-(4-nitrophenoxy)3.61 3.48 and rotary isomers LC204,35

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
ethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.
311CH3(3Aα,4β,7β7aα)-2-(1,6-Dihydro-1,4-dimethyl-6-oxo-3-pyridinyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.89LC20
312(3Aα,4β,7β7aα)-4-[Octahydro-7-methyl-2-(4-nitro-1-naphthalenyl)-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethoxy]benzonitrile.3.63 LC204,35
313CH3(3aα,4β,7β7aα )-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-1,2-benzylcarbamoyl.2.38 LC20

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
314(3Aα,4β,7β7aα)-4-(2-Bromacil)hexahydro-7-methyl-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.52 LC36
315(3Aα,4β,7β7aα)-4-[4-[2-(4-Cianfrocca)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.19 and 3.35 rotary isomers LC223,35
316(3aα4β7β7aα)-4-[Octahydro-4-[2-(4-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.34 3.50 and rotary isomers LC223,35
317 (3Aα,4β,7β7aα)-4-[Octahydro-4-[2-(3-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.34 3.50 and rotary isomers LC223,35

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
318(3Aα,4β,7β7aα)-4-[4-[2-(3-Pertenece)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.And 3.61 3.46 rotary isomers LC223,35
319(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-7-[2-[3-(4-morpholinyl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.01 and 3.18 rotary isomers LC223,35
320(3Aα,4β,7β,7αand)-4-[Octahydro--methyl-7-[2-[4-nitro-3-(trifluoromethyl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic. 3.70 and 3.83 rotary isomers LC223,35
321(3Aα,4β,7β7aα)-4-[4-[2-(3-Cianfrocca)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-Isoindole-2-yl]-1-naphthaleneacetic.3.39 and 3.55 rotary isomers LC223,35

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
322CH3((3Aα,4β,7β7aα)-2-(2,3-Dihydro-3-methyl-2-oxo-6-benzothiazolyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.34 rotary isomers LC20
323CH3(3Aα,4β,7β7aα)-2-(2,3-Dihydro-2-oxo-6-benzothiazolyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.16 LC20
324(3Aα,4β,7β7aα)-4-[4-[2-[3-(Dimetilan the but)phenoxy]ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-Isoindole-2-yl]-1-naphthaleneacetic. 2.63 and 2.79 rotary isomers LC223,35
325(3Aα,4β,7β7aα)-4-[2-[4-Cyano-3-(trifluoromethyl)phenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethoxy]-1,2-benzylcarbamoyl.3.42 rotary isomers LC223,35

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
326CH3(3Aα,4β,7β7aα)-N-[2-Cyano-5-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)phenyl]ndimethylacetamide.1.94 LC20
327CH3(3Aα,4β,7β7aα)-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-2-(triptoreline)benzonitrile3.52 LC20
328CH3(3Aα,4β,7β7aα)-2-Methoxy-4-(octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzene the reel. 2.47 LC20
329CH3(3Aα,4β,7β7aα)-2-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione3.09 LC20

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
330CH3(3Aα,4β,7β7aα)-2-[4-(4-Bromo-1-methyl-1H-pyrazole-3-yl)phenyl]hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.04 LC20
331(3Aα,4β,7β7aα)-4-[Octahydro-4-(2-hydroxyethyl)-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.2.44 and 2.60 rotary isomers LC223,35
332CH3(3Aα,4β,7β7aα)-2-IDO-4-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)benzonitrile.2.78 rotary isomer is LC 20
333(3Aα,4β,7β7aα)-4-[4-[2-(4-Pertenece)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.39 and 3.53 rotary isomers LC223,35

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
334(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[4-(trifluoromethyl)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.And 3.78 3.66 rotary isomers LC223,35
335(3Aα,4β,7β7aα)-4-[4-[2-(4-Cyano-3-pertenece)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.26 and 3.41 rotary isomers LC223,35
336 (3aα4β7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[2,3,5,6-titrator-4-(trifluoromethyl)phenoxy] ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.94 4.01 and rotary isomers LC223,35
337CH3(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-[4-(1H-1,2,4-triazole-3-yl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.06 LC20

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
338CH3(3Aα,4β,7β7aα)-2-[4-(4,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)phenyl]hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.42 LC20
339CH3(3Aα,4β,7β7aα)-Hexahydro-2-[3-methoxy-4-(2-oxazolyl)phenyl]-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.51 LC20
340CH3((3Aα,4β7β 7aα)-Hexahydro-2-(4-hydroxy-1-naphthalenyl)-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.30 LC20
341CH3(3Aα,4β,7β7aα)-Hexahydro-2-(8-hydroxy-5-chinoline)-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione, triptorelin (1:1).1.49 LC20

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
342(3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-1,3-dioxo-7-[2-[methyl(phenylmethyl)amino]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.2.42 LC223,35
343CH3(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-(5-chinoline)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.69 LC20
344CH3(3Aα,4β,7β7aα)-5-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-EP is XI-2H-isoindole-2-yl)-2-pyridylcarbonyl 2.18 LC20
345CH3(3Aα,4β,7β7aα)-5-(Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl)-8-hinolincarbonova.2.31 LC20
346CH3(3Aα,4β,7β7aα)-2-(5-Bromo-4-nitro-3.10 and 3.29 rotary isomers LC20

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.
347CH3(3Aα,4β,7β7aα)-2-(5-Bromo-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.28 and 3.40 rotary isomers LC20
348CH3(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-[8-(triform the Teal)-4-chinoline]-4,7-epoxy-1H-isoindole-1,3(2H)-dione. 3.08 LC20
3494-Formentera acid, 2-[(3Aα,4β,7β7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl ester.3.64 and 3.77 rotary isomers LC223

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
350Venzolasca acid, 2-[(3Aα,4β,7β7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl ester.And 3.67 3.53 rotary isomers LC223
3514-forbestown acid, 2-[(3Aα,4β,7β7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl ester.3.53 and 3.66 rotary isomers LC223
352 (3Aα,4β,7β7aα)-Hexahydro-4-methyl-7-[2-[4-(methylsulfonyl)phenoxy]ethyl]-2-(4-nitro-1-naphthalenyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.31 LC223,35

Ave. No.GR7The connection nameThe retention time Minutes./Molecular weightThe method according to example
353CH3(3Aα,4β,7β7aα)-Hexahydro-2-{2-naphthalenyl)-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.94 LC20
354CH3(3Aα,4β,7β7aα)-2-(4-Chloro-1-naphthalenyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.34 3.22 and rotary isomers LC20
355(3Aα,4β,7β7aα)-N-[(4-Chlorophenyl)methyl]-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-ndimethylacetamide.3.52 LC237

Ave. No./td> GR7The connection nameThe hold time min/mol. weightThe method according to example
3564,7,7-Trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxylic acid,2-[(3Aα,4β,7β7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl ester3.45 LC223
357(αSα-Methoxy-α-(trifluoromethyl)venzolasca acid, 2-[(3Aα,4β,7β7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl ester.3.91 LC223
358(αR-α-Methoxy-α-(trifluoromethyl)venzolasca acid, 2-[(3Aα,4β,7β7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl ester.2.00 LC223

Ave. No.GR7The name with the unity The hold time min/mol. weightThe method according to example
359((3Aα,4β,7β7aα)-4-[Octahydro-4-methyl-7-[2-[(7-methyl-1,2-benzisoxazol-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.79 and 3.92 LC rotary isomers250
360(3Aα,4β,7β7aα)-4-[4-[2-(1,2-Benzisoxazol-3-yloxy)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.55 and 3.70 LC rotary isomers250
361(3Aα,4β,7β7aα)-4-[2-(Benzoyloxy)ethyl]-2-(4-cyano-1-naphthalenyl)hexahydro-7-Methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.51 3.66 LC Rotary isomers223
362(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)-4-[2-[(4-nitrobenzoyl)oxy]ethyl]hexahydro-7-methyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.3.67 3.52 and LC turning the isomers 223

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
3634 Chlorbenzoyl acid, 2-1[(3aα,4β,7β,7aα)-2-(4-cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl ester.3.79 LC223
3642-propenyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.4.14 LC 499.13 [M+H]+248
365(3Aα,4β,7β,7aα)-4-[Octahydro-4-methyl-7-[3-(1-naphthalenyl)propyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.4.14 LC 501.14 4.15 [M+H]+248,249
366CH3(3Aα,4β,7β,7aα)-Hexahydro-4,7-dimethyl-2-(2-methyl-6-chinoline)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.2 LC 337.0 [M+H] 20
367CH3(3Aα,4β,7β,7aα)-Hexahydro-2-(5-ethenolysis)-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.06 and 1.29 LC variables isomers 323.0 [M+H]+20

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
368CH3(3Aα,4β,7β7aα)-2-(6-Benzothiazolyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.2.15 LC 329.0 [M+H]+20
369[(3Aα,4β,7β7aαand(E)]-4-[Octahydro-4-methyl-1,3-dioxo-7-(4-oxo-4-phenyl-2-butenyl)-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.50 LC 482.14 [M+H]+248
370(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-N-(2-hydroxyphenyl)-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindol the-4-ndimethylacetamide. 3.07 LC 482.14 [M+H]+236
371[3Aα,4β(E),7β7aα]-4- [Octahydro-4-methyl-7-[3-(6-methyl-2-pyridinyl)-2-propenyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.2.28 LC 464.19 [M+H]+248

Ave. No.GR7The connection nameThe hold time Min./Mol. weightThe method according to example
372(3Aα,4β,7β7aα)-Octahydro-4-methyl-7-[3-(6-methyl-2-pyridinyl)propyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.2.19 LC 466.32 [M+H]248,249
373[3aR-(3Aα,4β,7β,7αand)-4-[Octahydro-4-[2-(3-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.73 LC 483.65 [M+H]+238i, 239i
374 [3aS-(3Aα,4β,7β7aα)]-4-[Octahydro-4-[2-(3-methoxyphenoxy)ethyl]-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.73 LC238ii, 239ii
375[3aR-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cianfrocca)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.33 and 3.49 LC variables isomers238i, 239i

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
376[3aS-(3aα,4β,7β,7aα)]-4-[4-[2-(4-Cianfrocca)ethyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.73 LC 483.65 [M+H]238ii, 239ii
377[3Aα,4β(E),7βR,7aα]-4-[4-[3-(1H-Benzimidazole-2-yl)-2-propenyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-Isoindole-2-yl]-1-naphthaleneacetic2.48 C 489.26 [M+H] +248
378(3Aα,4β,7β7aα)-4-[4-[3-(1H-Benzimidazole-2-yl)propyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic2.37 LC 491.26 [M+H]+249

Examples from 379 to 381

Additional compounds of the present invention are obtained by methods similar to those described above. Connection examples from 379 to 381 have the following structural formula (L is a bond):

where the values of G, R7the connection name, retention time, molecular mass, and the production method, are shown in table 6. The chromatographic technique used to determine the retention time in table 6, as follows: LCMS=YMC S5 ODS column, 4.6×50 mm, elwira 10-90% MeOH/H2O more than 4 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column, 4.6×50 mm, elwira 10-90% Meon/N2About for more than 2 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LC=YMC S5 ODS column 4.6×50 mm, elwira 10-90% Meon/N2On over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm.

The molecular weight compounds contained in the face 6, was determined using MS (EC) by the formula m/E.

Table 6
Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
379(3Aα,4α,7α7aα)-4-[4-[(4-Forfinal)methyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile.3.75 LC205
380CH3(3aα,4α,7α,7aα)-Hexahydro-4,7-dimethyl-2-(1-methyl-6-oxo-3-piperidinyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.88 LC27
381CH3(3Aα,4α,7α7aα)-2-(1,6-Dihydro-1,4-dimethyl-6-oxo-3-pyridinyl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione.1.91 LC27

Examples 382 on 383

Additional compounds of the present invention are obtained by methods similar to those described above. Connection examples with 382 in 383 have the structural formula, Naim is the commemoration of the connection, the retention time, molecular mass, and the production method, are shown in table 7. The chromatographic technique used to determine the retention time in table 7 are defined as follows: LCMS=YMC S5 ODS column, 4.6×50 mm, elwira 10-90% Meon/H2Oh, over 4 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column, 4.6×50 mm, elwira 10-90% MeOH/H2O more than 2 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LC=YMC S5 ODS column 4.6×50 mm, elwira 10-90% Meon/H2Oh, over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm. The molecular weight of the compounds listed in table 7, was determined by MS (EC) by the formula m/E.

Table 7
Ave. No.The structural formulaThe connection nameThe hold time minThe method according to example
382(3Aα,4β,7β7aα)-2-[4-Cyano-3-(trifluoromethyl)phenyl] octahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile.3.63 LC255
383(3Aα,4β,7β7aα)-2-[4-Cyano-3-(three is tormentil)phenyl]octahydro-1,3-dioxo-7-[2-(phenylmethoxy)ethyl]-4,7-epoxy-4H-isoindole-4-propanenitrile 3.64 LC255

Examples 384 at 418

Additional compounds of the present invention are obtained by methods similar to those described above. Connection examples with 384 at 418 have the following structural formula (L is a bond):

where G, R7the connection name, retention time, molecular mass, and the production method, are shown in table 8. The absolute configuration for the following compounds do not define. For simplicity, the item's connection 243Di identified in the present invention as having an "S" configuration and connection 243Dii the invention as having an "R" configuration. Enatiomers pure products derived from compound 243Di identified in the present invention as having an "S" configuration and enatiomers pure products derived from compound 243Dii identified in the present invention as having a "R" configuration.

The chromatographic technique used to determine the retention time in table 8, are defined as follows: LCMS=YMC S5 ODS column, 4.6×50 mm, elwira 10-90% MeOH/H2O more than 4 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column, 4.6×50 mm, elwira 10-90% Meon/N2O more than 2 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LC=YMC S5 ODS to Lanka 4.6× 50 mm, elwira 10-90% Meon/N2O more than 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm. The molecular weight of the compounds listed in table 8, was determined by MS (EC) by the formula m/E.

Table 8
Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
384(3Aα,4β,7β7aα)-4-[7-[2-(4-Cianfrocca)ethyl)octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.18 LC 494.40 [M+H]+227, 228, 229
385[3aS-(3Aα,4β,7β7aα)-4-[7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.19 LC 571.3 [M-H+SLA]'234Di, 243i
386[3aR-(3Aα,4β,7β7aα)-4-[7-[2-(1,3-Benzodioxol-5-yloxy)ethyl]OK what ahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic. 3.22 LC 571.2 [M-H+SLA]-234DH, 243ii
387[3aS-(3Aα,4β,7β7aα)-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-3.37 LC 562.2 [M-H+SLA]-234Di, 243i

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.
388[3aR-(3Aα,4β,7β7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.37 LC 504.0 [M+H]+234Dii, 243ii
389[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-(4-Chlorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthalenedione the reel. 3.51 LC 503.08 [M+H]+234Di,243i
390[3aR-(3Aα,4β,7β7aα)]-4-[7-[2-(4-Chlorophenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.51 LC 503.08 [M+H]+234Dii, 243ii

Ave. No.GR7The connection nameThe hold time min/mol weightThe method according to example
391[3aS-(3Aα,4β,7β7aα)]-4-[7-[2-(4-Acetylphenol)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.05 LC 511.13 [M+H]+234Di, 243i
392[3aR-(3Aα,4β,7β7aα)]-4-[7-[2-(4-Acetylphenol)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.05 LC 503.13 [M+H]+234Dii, 243ii
393 [3S-(3Aα,4β,7β7aα)]-4-[7-[2-(3-Cianfrocca)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.09 LC 494.13 [M+H]+234Di,243i

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
394[3aR-(3Aα,4β,7β7aα)]-4-[7-[2-(3-Cianfrocca)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.09 LC 494.13 [M+H]+234Dii, 243ii
395[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.85 LC 523.17 [M+H]+234Di, 243i
396[3aR-(3Aα,4β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindol the-2-yl]-1-naphthaleneacetic. 3.85 LC 523.17 [M+H]+234Dii, 243ii

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
397[3aS-(3Aα,4β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.29 LC 537.13 [M+H]+234Di, 243i
398[3aR-(3Aα,4β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[(5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.29 LC 537.13 [M+H]+234Dii, 243ii
399[3aS-(3Aα,4β,7β7aα)]-4-[7-[2-(4-Pertenece)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.28 LC 487.11 [M+H]+234Di, 243i

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
400[3aR-(3Aα,4β,7β7aα)]-4-[7-[2-(4-Pertenece)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.27 LC 487.11 [M+H]+234Dii, 243ii
401[3aS-(3Aα,4β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(4-methyl-2-oxo-2H-1-benzopyran-7-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.15 LC 551.15 [M+H]f234Di, 243i
402[3aR(3Aα,4β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-7-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.16 LC 551.10 [M+H]+234Dii, 243ii
403[3aS-(3Aα,4β,7β,7aα )]-4-[7-[2-(3,5-Dimethoxyphenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.28 LC 529.19 [M+H]+234Di, 243I

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
404[3aR-(3Aα,4β,7β7aα)]-4-[7-[2-(3,5-Dimethoxyphenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.26LC 529.12 [M+H]+234Dii, 243ii
405[3aR-(3Aα,4β,7β7aα)]-]-4-[7-[2-(4-Chloro-3-methylphenoxy)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.68 LC 517.33 [M+H]+234Dii, 243ii
406[3aR-(3aα,4β,7β,7aα)] -4-[7-[2-(4-Cyano-2,3-divergence)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphtha is uncarbonated. 3.23 LC 530.13 [M+H]+234Dii, 243ii

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
407[3aS-(3aα,4β,7β,7aα)]-4-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.59 LC 602.1 [M-H+SLA]-243Di, 252
408[SaR-(3Aα,4β,7β7aα)]-4-[7-[2-[(5-Chloro-1,2-benzisoxazol-3-yl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.3.57 LC 602.0 [M-H+SLA]-243Dii, 253
409[3aR-(3Aα,4β,7β7aα)]-3-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-6-hydroxy-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethoxy]-5-isoxazolidinone acid, acetic ether2.90 LC 518.27 [M+H]+243Dii, 253

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
410[3aR-(3Aα,4β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[4-(1H-1,2,4-triazole-1-yl)phenoxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic.2.93 LC 536.30 [M+H]+243Dii, 244ii
411[3aS-(3Aα,4β,7β7aα)]-4-[7-[2-[(7-Chloro-4-chinoline)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, triptorelin (1:1).2.52 LC 554.13 [M+H]+243Di, 244i
412[3aR-(3Aα,4β,7β7aα)]-4-[7-[2-[(7-Chloro-4-chinoline)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic, triptorelin (1:1).2.53 LC 554.27 [M+H]+243Dii, 244ii

tr>
Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
413[SaR-(3Aα,4β,7β7aα)}-4-[7-(2-(2-Benzoxazolinone)ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.13 LC 568.1 [M-H+SLA]-243Dii, 244ii
414[3aR-(3Aα,4β,7β7aα)-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(9-methyl-N-purine-8-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic2.34 LC 525.2 [M+H]+243Dii, 244ii
415[SaR-(3Aα,4β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(1-methyl-1H-indazol-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.33 LC251,253

Ave. No.GR7The connection nameTime is holding min/mol. weightThe method according to example
416[3aS-(3aα,4β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[4-(1,2,3-thiadiazole-5-yl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.17 LC 553.10 [M+H]+243Dii, 244ii
417[3aR-(3Aα,4β,7β7aα)N-[Octahydro-5-hydroxy-4-methyl-7-[2-[4-(1,2,3-thiadiazole-5-yl)phenoxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.20 LC 553.25 [M+H]+243Dii, 244ii
418[3aS-(3Aα,4β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.45 LC 538.23 [M+H]+243Dii, 244ii

Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
419 [3aR-(3Aα,4β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.45 LC 538.23 [M+H]+243Dii, 244ii
420[3aS-(3Aα,4β,7β7aα)]-4-[7-[2-[(6-Chloro-2-methyl-4-pyrimidinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.02 LC243Dii, 244ii
421[3aR-(3Aα,4β,7β7aα)]-4-[7-[2-[(6-Chloro-2-methyl-4-pyrimidinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.02 LC243Dii, 244ii

Example 422

(3Aα,4β,7β7aα)-2-(7-Bromo-2,1,3-benzoxadiazole-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (S)

A. 4-Bromo-7-nitrobenzofurazan (A)

To a solution of 2,6-dibromoanisole (1.0 g, 4.0 mmol) in CHCl3(8 ml) is added a suspension of mCPBA (70% according to HPLC, 1.4 g, 8.0 mmol) in CHCl3(8 ml) and received MES stirred for 24 hours at room temperature. The reaction mixture was diluted with CHCl3and washed successively with 2% solution of Na2S2About3a 5% solution of Na2CO3and brine. The organic layer is dried over Na2SO4and concentrate under reduced pressure before the formation of solids that are suspended in DMSO (15 ml). To the resulting suspension is added a solution of NaN3(272 mg, 4.19 mmol) in DMSO (15 ml) at room temperature. The resulting mixture was stirred at room temperature until you cease to be allocated nitrogen, and then quickly heated to a temperature of 120°C for 3 minutes. Then the reaction mixture is cooled and poured on crushed ice (100 g). After standing for one hour the precipitated residue is filtered off, dried in vacuum and re-dissolved in concentrated H2SO4(5 ml). To this solution add a solution of NaNO3(400 mg, 4.7 mmol) in 50% H2SO4(1.6 ml), the temperature of the support at 60°C. After complete addition, the mixture is heated to a temperature of 85°C for 30 minutes, cooled to room temperature and poured on crushed ice (40 g). Then add EtOAc, the layers separated and the aqueous layer was extracted with EtOAc. The combined organic layers dried over Na2SO4and concentrated to leave a solid, which was purified using flash chromatography (silica gel, EtOAc (20%)in hexane), receiving a connection A (785 mg, 81%) as a solid yellow-brown color.

C. 4-Bromo-7-aminobenzophenone (V)

A solution of compound A (563 mg, 2.31 mmol) in Asón (5 ml) is heated to a temperature of 70°and one portion add a powder of Fe0(258 mg, 4.62 mmol). Received the dark reaction mixture is stirred for 15 minutes, cooled to room temperature and concentrate under reduced pressure. The residue is placed in EtOAc and the resulting solution was washed with saturated aqueous Na2CO3. The organic layer is dried over Na2SO4concentrate and purify using flash chromatography (silica gel, EtOAc in hexane from 10 to 60%), receiving the connection V (470 mg, 95%) as a solid red color.

S. (3Aα,4β,7β7aα)-2-(7-Bromo-2,1,3-benzoxadiazole-4-yl)hexahydro-4,7-dimethyl-4,7-epoxy-1H-isoindole-1,3(2H)-dione (S)

The mixture of compounds V (43 mg, 0.20 mmol), compound 20A (45 mg, 0.23 mmol), MgSO4(60 mg, 0.50 mmol), Et3N (139 μl, 1.0 mmol) and 1,2-dimethoxyethane (300 μl) is placed in a hermetically closed tube and heated to a temperature of 135°C for 14 hours. After cooling to room temperature the mixture is filtered through celite, elwira Meon, which gives a dark solid dark color, which is purified using flash chromatography (forces the Kagel, EtOAc in hexane from 5 to 40%), which gives the connection C (42 mg, 54%) as a solid yellow color. HPLC: 99% within 2.96 min (retention time) (YMC S5 ODS column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 minutes containing 0.2% N3PO4, 4 ml/min, monitoring at 220 nm).1H NMR (acetone-d6, 400 MHz): δ=8.00 (d, J=7.5 Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 3.31 (s, 2H), 1.98-1.93 (m, 2H), 1.74-1.69 (m, 2H), 1.57 (s, 6N).

Example 423

(3Aα,4β,7β7aα)-7-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2,1,3-benzoxadiazole-4-carbonitrile (423)

To a solution of compound C (42 mg, 0.11 mmol) in DMA (1 ml) was added CuCN (20 mg, 0.22 mmol) and the resulting mixture is heated to a temperature of 150°C for 5 hours. Mixture is allowed to cool down to room temperature and then share it between EtOAc and aqueous NaCN solution (5 g/50 ml). The layers are separated and the aqueous layer was extracted once with EtOAc. The combined organic phases are dried over Na2SO4concentrate and purify using flash chromatography (silica gel, EtOAc in hexane from 20 to 70%)that gives compound 423 (13 mg, 35%) as a yellow oil. HPLC: 99% for 2.66 min (retention time) (YMC S5 ODS column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 minutes containing 0.2% N3PO4, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 39.9 [M-H+SLA] -.

Example 424

(3Aα,4β,7β7aα)-7-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile (V)

A. 4-Cyano-7-amino-benzothiadiazole (A)

A solution of 2-cyano-5-nitrophenylamino (78 mg, 0.44 mmol, obtained as described in WO 0076501) SOCl2(2 ml), heated at the boil under reflux for 3 hours. The obtained mixture is allowed to cool down to room temperature, and then placed in a bath of ice water. Add CH2Cl2, the layers separated and the aqueous layer was extracted twice, CH2Cl2. The combined organic phases are dried over MgSO4concentrate and purify using flash chromatography (silica gel, EtOAc in hexane 50%), giving 4-cyano-7-nitrobenzothiazole. This product is dissolved in Asón (2 ml)containing EtOAc (1 ml) and N2About (0.2 ml) and heated to a temperature of 70°C. At this temperature is added in one portion solid Fe0powder (78 mg, 1.41 mmol) and the mixture is dark color is stirred for 20 minutes and then cooled to room temperature. The reaction mixture was filtered through Celite, elwira EtOAc, washed with saturated aqueous Na2CO3, dried over MgSO4and concentrate. Purification using flash chromatography (silica gel, EtOAc hexane from 20 to 70%), network connection A (47 mg, 61%) as a solid brown color.

Century (3Aα,4β,7β7aα)-7-[Octahydro-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2,1,3-benzothiadiazole-4-carbonitrile (V)

A mixture of compound (35 mg, 0.20 mmol), compound 20A (45 mg, 0.23 mmol), MgSO4(60 mg, 0.50 mmol), Et3N (139 μl, 1.0 mmol) and DME (200 μl) is placed in a hermetically closed tube and heated to a temperature of 135°C for 14 hours. After cooling to room temperature the mixture is filtered through Celite, elwira Meon, which gives a solid dark color, which is cleaned by a combination of flash chromatography (silica gel, EtOAc in hexane from 10 to 50%) and preparative HPLC with reversed phase (YMC S5 ODS 20×100 mm, elwira 27-100% aqueous solution of methanol over 10 min containing 0.1% TFA, 20 ml/minute), which gives the connection V (36 mg, 51%) as a solid yellow color. HPLC: 98% within 2.45 minutes (retention time) (YMC S5 ODS column 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 minutes containing 0.2% N3PO4, 4 ml/min, monitoring at 220 nm), MS (DCl): m/e 355.0 [M+H]+.

Example 425

(3Aα,4β,7β,7aα)-N-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]-4-fluoro-N-methylbenzamide

A. 4-Fluoro-N-methyl-N-[2-(5-methylfuran-2-yl-ethyl]-benzamide (A)

To a solution of 4-fluoro-N-[2-(5-methyl-2-furanyl)ethyl]benzamide (269 mg, 1.09 mmol, U) in THF (5 ml) is added by portions NaH (60% dispersion in oil, 65 mg, 1.63 mmol). After the evolution of gas is added dropwise logmean (0.14 ml, 2.18 mmol). When HPLC analysis shows that the reaction of 50% has ended, the mixture is concentrated under reduced pressure and re-subjected to the above treatments. After the initial product will enter into the reaction, add H2O and the resulting mixture was extracted with EtOAc (2×5 ml). The combined organic layers dried over Na2SO4and concentrate under reduced pressure. Purification using flash chromatography, elwira 20% acetone/CHCl3give 238 mg (84%) of compound 425 A. HPLC: 98% within 2.94 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e [M+H] - 262.38.

Century (3Aα,4β,7β7aα)-N-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-yl]ethyl]-4-fluoro-N-methylbenzamide (V)

A solution of compound A (183 mg, 0.75 mmol) and 4-(2,5-dihydro-2,5-dioxo-1N-1-yl)-1-naphthaleneacetic (174 mg, 0.75 mmol) in benzene (1 ml) is heated at a temperature of 60°C for 15 hours. The reaction mixture is concentrated at the pony who hinnon pressure, that gives 357 mg of crude intermediate product. The crude intermediate product (156 mg) was dissolved in EtOAc (6 ml), add 10% Pd/C (16 mg) and the mixture is stirred atmophere hydrogen from a cylinder during the night. The reaction mixture is filtered through a bed of celite and concentrate under reduced pressure. Purification using preparative chromatography with reversed phase (YMC S5 ODS 20×100 mm, 20-100% aqueous methanol over 15 minutes containing 0.1% TFA, 20 ml/min, monitoring at 220 nm), gives 160.3 mg (72%) of compound 425 In the form of a solid off-white color. HPLC: 99% within 3.23 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e [M+H]=512.19.

Example 426

(3Aα,4β,7β7aα)-Hexahydro-4,7-dimethyl-2-[4-(2,2,2-Cryptor-1-hydroxyethyl)phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione (V)

1-(4-AMINOPHENYL)-2,2,2-triptoreline (A)

Connection I receive in accordance with the method described in Stewart, R. et. al. Can. J. Chem. 58, 2491-2496 (1980). NaBH4(47 mg, 1.235 mmol) are added to a solution of p-aminodiphenylamine (155.7 mg, 0.823 mmol, synthesized as described by Klabunde, .J. et. al., J. Org. Chem. 35, 1711-1712 (1970)) in isopropanol (3 ml) is ri room temperature. After 30 minutes the reaction mass zakolerovat phosphate buffer (pH 7.2), and diluted with N2O and extracted with EtOAc (2×10 ml). The combined organic layers dried over Na2SO4and concentrate under reduced pressure, giving 154 mg (98%) of compound A in the form of a solid yellow-brown color. The product obtained is used directly in the next step without purification. HPLC: 99% during 0.42 min (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e [M+H]=192.13.

Century (3Aα,4β,7β,aα)-Hexahydro-4,7-dimethyl-2-[4-(2,2,2-Cryptor-1-hydroxyethyl)phenyl]-4,7-epoxy-1N-isoindole-1,3(2H)-dione (V)

The mixture of compounds A (75.3 mg, 0.394), compound 20A (51.5 mg, 0.262 mmol), triethylamine (0.15 ml) and MgSO4(50 mg) in toluene (1 ml) is heated in a sealed tube to a temperature of 135°C for 15 hours. The mixture is filtered and concentrated under reduced pressure. Purification using preparative chromatography with reversed phase (YMC S5 ODS 20×100 mm, 20-100% aqueous methanol over 15 minutes containing 0.1% TFA, 20 ml/min, monitoring at 220 nm), gives 63.1 mg (65%) of compound V in a solid white color. HPLC: 98% for 2.49 min (retention time) (Phenomenex-prime S5-C18 to Lanka 4.6× 50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e [M+H]=370.16.

Example 427

(3Aα,4β,7β7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilane]axiety]-1,3,3A,4,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl]benzonitrile; (3Aα,4α,7α7aα)-4-[4-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]-1,3,3A,4,7,7a-hexahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (427i and 427ii)

Connection A (2.00 g, 8.50 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)-2-cryptomathematical (1.50 g, 5.60 mmol) is stirred in benzene (5.0 ml) and heated at a temperature of 60°C for 14 hours, then cooled to a temperature of 25°C. the Solvent is removed at 40°C in vacuum for one hour, giving the crude product, which was purified using flash chromatography on SiO2, elwira 0.5% EtOAc/CH2Cl2that gives 2.0 g of compound 427i and 1.3 g of compound 427ii, both in the form of solids in a light brown colour. Connection 427i: HPLC: 95% within 4.200 min (retention time) (YMC S5 ODS column 4.6 × 50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 507.1 [M+H]+. Connection 427ii: HPLC: 95% at t the value of 4.20 min (retention time) (YMC S5 ODS column 4.6 × 50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 507.1 [M+H]+.

Example 428

[3aR-(3aα,4β,5β,7β,7aα)]-4-[7-[2-[[1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile; [3aS-(3aα,4β,5β,7Bβ,7aaα)]-4-[7-[2-[[(1,1-Dimethylethyl)dimethylsilane]oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (428i and 428ii)

Connection 427i (1.40 g, 2.77 mmol) and RhCl(PPh3)3(0.128 g, 0.14 mmol) is stirred in the flask. Then vaccum flask and rinsed three times with argon, and then the syringe add THF (3.0 ml). At one time all the small particles dissolve and added dropwise catechol borane (0.59 ml, 5.54 mmol). The reaction mixture is stirred at a temperature of 25°C in argon atmosphere for 30 minutes, then cooled to a temperature of 0°C. Add phosphate buffer (pH 7,20 ml), and then EtOH (10 ml), 30% N2O2/N2O (2 ml). The reaction mixture is stirred at a temperature of 0°C for 3 hours, then extracted with dichloromethane (3×25 ml). The combined organic layers are washed with 1N NaOH (25 ml), 10% Na2SO3(25 ml) and brine (25 ml). The crude product is then concentrated and cleaned the Ute using flash chromatography on SiO 2, elwira from 2% EtOAc/CH2Cl2up to 10% EtOAc/CH2Cl2that give 0.63 g of racemic mixtures of compounds 428i and 428ii in the form of a solid of light yellow color. HPLC: 99% within 3.867 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 525.1 [M+H].

Racemic mixture of compounds 428i and 428ii separated using preparative chiral HPLC normal phase using a Chiracel OD column (5 cm×50 cm), elwira 13% of the solvent (EtOH) in a solvent (Hexane), flow rate: 50 ml/minute. Connection 428i elute from 34 minutes to 38 minutes and connection 428ii elute from 44 minutes to 49 minutes. The enantiomeric excess was determined by chiral HPLC. Connection 428i: >99% EE (12.576 minutes (retention time) (Chiralcel OJ column 4.6×250 mm, elwira isocratic 85% heptane/15% Meon/ethanol (1:1), 1 ml/min, monitoring at 220 nm, 40°). Connection 428ii: 99% within 18.133 minutes (retention time) (Chiralcel OJ column 4.6×250 mm, elwira isocratic 85% heptane/15% Meon/ethanol (1:1), 1 ml/min, monitoring at 220 nm, 40°).

The absolute configuration of compounds 428i and 428ii not installed. For ease of nomenclature connection 428i identified in the present invention as having a "R" configuration and connection 428ii as having the e "S" configuration. Enatiomers pure products derived from compound 428i identified in the present invention as having a "R" configuration and enatiomers pure products derived from compound 428ii identified in the present invention as having an "S" configuration.

Example 429

[3R-(3Aα,4β,5β,7β7aα)]-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile; [3S-(3Aα,4β,5β,7β7aα)]-4-[Octahydro-5-hydroxy-7-(2-hydroxyethyl)-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole]-2-yl]-2-(trifluoromethyl)benzonitrile (4291 and 429ii)

Connection 428i (180 mg, 0.34 mmol) dissolved in 2% HCl/EtOH (5.0 ml). After 30 minutes, add saturated aqueous solution of NaHCO3and the aqueous layer was extracted with dichloromethane (20 ml×3), washed with brine and dried over Na2SO4that give 135 mg of the compound 429i in a solid white color. HPLC: 99% within 2.257 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 411.1 [M+H]+.

The above-described method is repeated with the connection 428ii that gives the desired diol compound 429ii with the same output.

Example 430

[3R-(3Aα,4β,5β,7β7aα)]-4-[7-[2-[(5-Chloro-2-Piri is inil)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (430)

Triphenylphosphine (0.026 g, 0.098 mmol) and DBAD (0.023 g, 0.098 mmol) stirred in THF (0.5 ml). After the mixture allow to react for 15 minutes, add 2-hydroxy-6-chloropyridin (0.016 g, 0.100 mmol) and the newly formed mixture allow to mix for 10 minutes and then add the connection 429i (0.020 g, 0.049 mmol). The reaction mixture is stirred at a temperature of 25°C for 2 hours, and then the crude product is purified using preparative TLC, elwira 10% acetone/CHCl3that gives 0.014 g of compound 430 in the form of a solid light brown color. HPLC: 100% within 3.370 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 522.08 [M+H]+.

Example 431

[3S-(3Aα,4β,5β,7β7aα)]-4-[7-[2-[(5-Chloro-2-pyridinyl)oxy]ethyl]octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-2-(trifluoromethyl)benzonitrile (431)

Triphenylphosphine (0.026 g, 0.098 mmol) and DBAD (0.023 g, 0.098 mmol) stirred in THF (0.5 ml). After the mixture allow to react for 15 minutes, add 2-hydroxy-6-chloropyridin (0.016 g, 0.100 mmol), the mixture is allowed the opportunity to mix during the 10 minutes, and then add the connection 429ii (0.020 g, 0.049 mmol). The reaction mixture is stirred at a temperature of 25°C for 2 hours, and then the crude product is purified using preparative TLC, elwira 10% acetone/CHCl3that gives 0.015 g of compound 431 in the form of a solid light brown color. HPLC: 100% within 3.370 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 522.08 [M+H]+.

Example 432

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-N-(2-hydroxyphenyl)-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-butanamide (432)

Compound 262 (0.100 g, 0.239 mmol) was dissolved in DMF (anhydrous, 1.5 ml), THIEF (0.211 g, 0.478 mmol), then added 2-aminophenol (0.052 g, 0.478 mmol) and N-methylmorpholin (0.052 ml, 0.478 mmol). The reaction mixture is stirred at a temperature of 25°C in argon atmosphere for 3 hours, then the crude product is purified using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, 20-100% aqueous methanol over 15 minutes containing 0.1% TFA, 20 ml/min, monitoring at 220 nm), which gives 0.060 g of compound 432 in the form of a solid light brown color. HPLC: 100% within 3.037 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous what astora methanol over 4 minutes, containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 510.34 [M+H]+.

Example 433

(3Aα,4β,7β7aα)-4-[4-[3-(2-Benzoxazolyl)propyl]octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (433)

Triphenylphosphine (0.031 g, 0.118 mmol) and DBAD (0.027 g, 0.118 mmol) stirred in THF (0.5 ml). The previous mixture, allow to react for 15 minutes, then add the connection 432 (0.030 g, 0.059 mmol). The reaction mixture is stirred at a temperature of 25°C for 2 hours, and then the crude product is purified using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, 20-100% aqueous methanol over 15 minutes containing 0.1% TFA, 20 ml/min, monitoring at 220 nm), which gives 0.018 g of compound 433 in the form of a solid light brown color. HPLC: 100% within 3.357 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 492.37 [M+H]+.

Example 434

(3Aα,4β,5β,7β7aα)-4-[4-Atelectasia-5-hydroxy-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (S)

A. tert-Butyl[2-(5-ethylfuran-2-yl)-ethoxy]-dimethylsilane (A)

The imidazole (255 mg, 3.75 mmol) and TBSCl (414 mg, 2.75 mmol) are added to a solution A (350 mg, 2.5 mmol) in DMF (4 ml). The mixture is stirred at room temperature for 15 hours, and then add 100 mg (0.66 mmol) additional quantity of TBSCl to bring the reaction to completion. After stirring for a further hour, the reaction mixture was diluted with diethyl ether (100 ml) and washed with water (20 ml), 1N HCl (20 ml), water (20 ml) and brine (20 ml). The organic layer is dried over Na2SO4and concentrate under reduced pressure, giving 509 mg connection A (80.3%) as a yellow oil.

Century (3Aα,4β,7β7aα)-4-[4-[2-[[(1,1-Dimethylethyl)-dimethylsilane]oxy]ethyl]-4-ethyl-1,3,3A,4,7,7a-hexahydro-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (V)

A solution of compound A (509 mg, 2.00 mmol) and 4-(2,5-dihydro-2,5-dioxo-1H-1-yl)-1-naphthaleneacetic (498 mg, 2.00 mmol) in benzene (2 ml) is heated at a temperature of 60°C for 18 hours. The reaction mixture was concentrated under reduced pressure, giving 992 mg (99%) of crude compound V, which are used directly in the next step without further purification.

S. (3Aα,4β,5β,7β7aα)-4-[4-Atelectasia-5-hydroxy-7-(2-hydroxyethyl)-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (S)

The mixture of compounds V (992 mg, 198 mmol) and RhCl 2(PPh3)3(183 mg, 0.198 mmol) vacuum and filled with argon (3×). Add THF (20 ml) and once dissolve all the fine particles, and then slowly added dropwise, catecholborane (0.42 ml, 3.96 mmol). When product formation stopped, as determined by HPLC, the reaction mixture is cooled to a temperature of 0°and zakolerovat phosphate buffer (34 ml, pH 7.2), then add EtOH (19 ml) and H2O2(2.9 ml, 30% aqueous solution). After 2 hours, add phosphate buffer (6.8 ml, pH 7.2), EtOH (3.8 ml) and H2O2(0.6 ml). The reaction mixture was stirred at room temperature for 3 hours. When intermediate boronat consumed, the mixture is extracted with CH2Cl2(300 ml) and the combined organic layers are washed with 1N NaOH, 10% aqueous solution of NaHSO3and brine. The combined organic layers dried over Na2SO4. Purification using flash chromatography on silica gel, elwira 10% MeOH/CH2Cl2gives 75 mg (9.3%) connection S in a solid gray color. HPLC conditions: 97% within 2.43 min (Phenomenex-prime S5-C18 column 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm). MS (EU): m/e 407.18 [M-I-N]+.

Example 435

(3Aα,4β,5β,7β7aα)-4-[7-[2-(4-Cianfrocca)ethyl]-4-atelectasia-5-hydroxy-1,3-dioxo-4,7-e is the hydroxy-2H-isoindole-2-yl]-1-naphthaleneacetic (435)

DBAD (39.6 mg, 0.172 mmol) are added to a solution of PPh3(45.1 mg, 0.172 mmol) in THF (0.8 ml). After stirring for 10 minutes add 4-cyanoprop (20.5 mg, 0.172 mmol) and the reaction mixture is additionally stirred for 5 minutes. Add connection S (25.0 mg, 0.062 mmol) and the mixture is stirred at room temperature for 2 hours. The reaction mass is concentrated under reduced pressure. Purification using preparative TLC, elwira 10% acetone/CHCl3gives 18.1 mg (0.036 mmol, 57.6%) connection 435. HPLC conditions: 96% within 3.15 min (YMC S5 ODS 4.6×50 mm, 10%-90% aqueous methanol over 4 minute gradient with 0.2% N3PO4defined at 220 nm). MS (EC): m/e 508.14 [M+H].

Example 436

(3Aα,4β,7β7aα)-2-(4-Cyano-1-naphthalenyl)octahydro-N-(2-hydroxyphenyl)-7-methyl-1,3-dioxo-4,7-epoxy-4H-isoindole-4-ethanamide (436)

Connection V (0.100 g, 0.256 mmol) was dissolved in DMF (anhydrous, 1.5 ml), add THIEF (0.225 g, 0.51 mmol)and 2-aminophenol (0.056 g, 0.51 mmol) and N-methyl-morpholine (0.056 ml, 0.51 mmol). The reaction mixture is stirred at a temperature of 25°C in argon atmosphere for 3 hours, then the crude product is purified using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, 20-100% aqueous methanol over 15 minutes containing 0.1 TFA, 20 ml/min, monitoring at 220 nm), which gives 0.078 g of compound 436 in the form of a solid light brown color. HPLC: 100% within 3.037 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (USA): m/e 482.34 [M+H]+.

Example 437

(3Aα,4β,7β7aα)-4-[4-(2-Benzoxazolyl)octahydro-7-methyl-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic (437)

Triphenylphosphine (0.082 g, 0.312 mmol) and DBAD (0.072 g, 0.312 mmol) stirred in THF (0.5 ml). The mixture allow to react for 15 minutes, then add the connection 436 (0.075 g, 0.156 mmol). The reaction mixture is stirred at a temperature of 25°C for 2 hours, and then the crude product is purified using preparative HPLC with a reversed phase (YMC S5 ODS 20×100 mm, 20-100% aqueous methanol over 15 minutes containing 0.1% TFA, 20 ml/min, monitoring at 220 nm), which gives 0.052 g of compound 437 in the form of a solid light brown color. HPLC: 100% within 3.443 minutes (retention time) (YMC S5 ODS column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm), MS (EC): m/e 464.18 [M+H]+.

Example 438

(3Aα,4β,7β7aα)Hexahydro-4,7-dimethyl-2-[4-[2,2,2-Cryptor-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-4,7-epoxy-1H-isoindole-1,3(2H)-dione (438)

A mixture of 2-(4'-AMINOPHENYL)-1,1,1,3,3,3-hexamer-2-propanol (95.7 mg, 0.369), compound 20A (48.3 mg, 0.246 mmol), triethylamine (0.15 ml) and MgSO4(50 mg) in toluene (1 ml) is heated in a sealed tube to a temperature of 135°With during the night. The mixture is filtered and concentrated under reduced pressure. Purification using preparative chromatography with reversed phase (YMC S5 ODS 20×100 mm, 20-100% aqueous methanol over 15 minutes containing 0.1% TFA, 20 ml/min, monitoring at 220 nm), gives 44.0 mg (41%) of compound 438 in the form of a solid white color. HPLC: 99% during 3.10 min (retention time) (Phenomenex-prime S5-C18 column 4.6×50 mm, elwira 10-90% aqueous solution of methanol over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm), MS (USA): m/e [M+H]=438.14.

Examples 439 on 454

Additional compounds of the present invention are obtained by methods similar to those described above. Connection examples with 439 in 454 have the following structural formula (L is a bond):

where G, R7the connection name, retention time, molecular mass, and the production method, are shown in table 9. The absolute configuration for the following compounds do not define. For simplicity in nomenclature, compound 43Di identified in the present invention as having an "S" configuration and connection 243Dii the invention as having an "R" configuration. Enatiomers pure products derived from compound 243Di identified in the present invention as having an "S" configuration and enatiomers pure products derived from compound 243Dii identified in the present invention as having a "R" configuration. Also the connection 428i identified in the present invention as having an "S" configuration and connection 428ii of the invention as having an "R" configuration. Enatiomers pure products derived from compound 428i identified in the present invention as having an "S" configuration and enatiomers pure products derived from compound 428ii identified in the present invention as having a "R" configuration.

The chromatographic technique used to determine the retention time in table 9, as follows: LCMS=YMC S5 ODS column, 4.6×50 mm, elwira 10-90% Meon/N2O more than 4 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LCMS*=YMC S5 ODS column, 4.6×50 mm, elwira 10-90% MeOH/H2O more than 2 minutes containing 0.1% TFA; 4 ml/min, monitoring at 220 nm. LC=YMC S5 ODS column 4.6×50 mm, elwira 10-90% Meon/N2On over 4 minutes containing 0.2% phosphoric acid, 4 ml/min, monitoring at 220 nm. The molecular weight of the compounds listed in table 9, was determined by MS (EC) by the formula m/E.

Table 9
Ave. No.GR7The connection nameThe hold time min/mol. weightThe method according to example
439[3aR-(3Aα,4β,5β,7α7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(1-methyl-1H-indazol-3-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.33 LC 523.3 [M+H]+251,253
440[3aR-(3Aα,4β,5β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-7-[2-[(9-methyl-N-purine-8-yl)oxy]ethyl]-1,3-dioxo-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic2.34 LC

525.2 [M+H^
251,253
441[3aR-(3Aα,4β,5β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[1-(phenylmethyl)-1H-indazol-3-yl]oxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.73 LC243Dii, 244Dii

Ave. No.GRsup> 7The connection nameThe hold time min/mol. weightThe method according to example
442[3aR-(3Aα,4β,5β,7β,7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[1-(phenylmethyl)1H-pyrazole[3,4-d]pyrimidine-3-yl]oxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.37 LC251,253
443[3aS-(3Aα,4β,5β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.45 LC 538.23 [M+H]+243Di, 244Di
444[3aR-(3Aα,4β,5β,7β7aα)]-4-[Octahydro-5-hydroxy-4-methyl-1,3-dioxo-7-[2-[[5-(trifluoromethyl)-2-pyridinyl]oxy]ethyl]-4,7-epoxy-2H-isoindole-2-yl]-1-naphthaleneacetic3.46 LC 538.24 [M+H]+243Dii, 244Dii

Ave. No.GR7The connection name The hold time min/mol. weightThe method according to example
445[3aR-(3Aα,4β,5β,7β,7aα)]-N-[4-[2-[2-(4-Cyano-1-naphthalenyl)octahydro-5-hydroxy-4-methyl-1,3-dioxo-4,7-epoxy-7H-isoindole-7-yl]ethoxy]phenyl]ndimethylacetamide2.747 LC 526.28 [M+H]+243Dii, 244Dii
446[3aR-(3Aα,4β,5β,7β7aβ)]-4-[7-[2-(2,4-Dichlorophenoxy)ethyl]octahydro-5-hydr