Macrocyclic compounds, medicinal agents based on them and their use

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

 

The technical field to which the invention relates.

The present invention relates to 12-membered cyclic macrolide compound, which can be used as a drug, its reception and its application.

Background of invention

Compounds with cytotoxicity, have already been used as anticancer agents, and already there have been many studies screening method using cytotoxicity as an indicator. The results showed that the majority of existing anticancer agents has an effect on cancer cells and normal tissue, in which the active proliferation of cells, such as bone marrow, intestinal epithelium, and the like. Thus, the improvement of QOL of patients are not adequately provided.

In addition, although it is hoped that therapy means treatment is quite effective for leukemia, it is not always possible to say that it will be effective for solenoi malignant tumors. So there was a great need for the creation of anticancer agents, effective against solenoi tumors and highly secure.

Already conducted studies on the screening method of fermentation products of microorganisms with the use of what Finance cytotoxicity in vitroas an indicator, in the hope that they can also be used as antitumor agents. It was found many compounds with cytotoxicity, but most of them showing cytotoxic activity onlyin vitro, a small part of these shows antitumor activityin vivoand among them very few are those compounds that are effective against solenoi malignant tumors.

The invention

The aim of the present invention to provide compounds exhibiting antitumor activity not onlyin vitrobutin vivoand with antitumor activity against solenoi malignant tumors of the fermentation products of the microorganism or their derivatives.

It is believed that the carcinogenesis of normal cells induce gene mutation in a cell and expression of the abnormal gene. Therefore, the authors of the present invention have conducted intensive studies on the basis of the conclusion that the growth of tumor cells can be suppressed by changing the gene expression of tumor cells, i.e. the growth of tumor cells can be adjusted by modifying the expression of an oncogene or suppressor gene tumor or changing the expression of a gene involved in the cell cycle. The inventors found that the compound that alters the expression of a gene, in particular the connection is out, dampening the production of VEGF (vascular endothelial growth factor in hypoxic conditions, could suppress induced tumor angiogenesis and possess antitumor activity against solenoi malignant tumors. Then they held a screening of fermentation products of the microorganism and their derivatives, using as indicator the production of VEGF by the U251 cell under conditions of hypoxic stimulation. In the found new physiologically active compounds, 12-membered cyclic macrolide compounds, called 11107 and their analogues, which inhibit the production of VEGF in hypoxic conditionsin vitroand, in addition, inhibit the growth solidnyh tumor cellsin vivo.

It was also found that 11107D analogues 11107 stable even in aqueous solution and that the compounds obtained by chemical modifications of 11107D (hereinafter called as derivative 11107D)inherit from 11107D property stability in aqueous solution and inhibit the growth of solidnyh tumor cells in experimentsin vivomany more. On the basis of these findings and was created by the present invention.

As related to 12-membered cyclic macrolide compounds, the most structurally similar to the compounds of the present invention, it is known 12-membered cyclic macrolide connection is giving FD-895 (JP-A 4-352783), represented by formula (XIV):

The publication revealed that FD-895 has inhibitory cell growth activityin vitroagainst cells R murine leukemia cells of L-1210 murine leukemia cells HL-60 human leukemia in the medium RPM-1640 (column 6, table 2). However, it was reported that FD-895 does not show antitumor activity in experimentin vivousing cells R murine leukemia (Seki-M. Asano et al., J. Antibiotics, 47, 1395-1401, 1994).

In addition, FD-895 is unstable in aqueous solution, as described later, and, as expected, are unsuitable for mixing with the infusion solution in the introduction. Thus, we cannot say that FD-895 possesses sufficient for antineoplastic properties.

Therefore, in accordance with the present invention proposed:

(1) the compound represented by formula (I):

(in the formula, R3, R6, R7and R21are the same or different from each other and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R3, R6, R7and R21provided that R6limited to hydroxyl groups,

2) optionally substituted C1-22alkoxygroup,

3) optional Zam is on unsaturated With 2-22alkoxygroup,

4) optionally substituted C7-22aralkylated,

5) optionally substituted 5 to 14-membered heteroeroticism,

6) RCO-O- (where R represents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

(C) optionally substituted unsaturated With2-22alkyl group,

d) optionally substituted C6-14aryl group,

e) optionally substituted 5-14 membered heteroaryl group,

f) optionally substituted C7-22aracelio group,

g) optionally substituted 5 to 14-membered heteroalkyl group,

h) optionally substituted C1-22alkoxygroup,

i) optionally substituted With unsaturated2-22alkoxygroup,

j) optionally substituted C6-14alloctype or

k) optionally substituted 5 to 14-membered heterokaryosis),

7) RS1RS2RS3SiO- (RS1, RS2and RS3are the same or different from each other and each of them represents a

a)1-6alkyl group, or

(b) (C6-14aryl group),

8) halogen atom,

9) RN1RN2N-RM- (where RMrepresents a

a) a single bond,

b) -CO-O-,

with) -SO2-O-,

d) -CS-O -, or

e) -CO-NRN3- (where RN3is an atom in which Orada or optionally substituted C 1-6alkyl group), provided that each of the leftmost bond in b)-e) attached to the nitrogen atom; and

RN1and RN2are the same or different from each other and each of them represents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

(C) optionally substituted unsaturated With2-22alkyl group,

d) optionally substituted aliphatic C2-22acyl group,

e) optionally substituted aromatic7-15acyl group,

f) optionally substituted C6-14aryl group,

g) optionally substituted 5-14 membered heteroaryl group,

h) optionally substituted C7-22aracelio group,

i) optionally substituted C1-22alkylsulfonyl group,

j) optionally substituted C6-14arylsulfonyl group,

k) optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed RN1and RN2together with the nitrogen atom that is attached to RN1and RN2and non-aromatic heterocyclic group may have substituents,

l) optionally substituted 5 to 14-membered heteroalkyl group,

m) optionally substituted C3-14cycloalkyl group or

n) optionally substituted 3-14 membered neuromotion is such a heterocyclic group),

10) RN4SO2-O- (where RN4represents a

a) optionally substituted C1-22alkyl group,

b) optionally substituted C6-14aryl group,

(C) optionally substituted C1-22alkoxygroup,

d) optionally substituted unsaturated With2-22alkoxygroup,

e) optionally substituted C6-14alloctype,

f) optionally substituted 5 to 14-membered heteroepitaxy,

g) optionally substituted C7-22aralkylated or

h) optionally substituted 5 to 14-membered heteroeroticism),

11) (RN5O)2RO-O- (where RN5represents a

a) optionally substituted C1-22alkyl group,

b) optionally substituted With unsaturated2-22alkyl group,

(C) optionally substituted C6-14aryl group,

d) optionally substituted 5-14 membered heteroaryl group,

e) optionally substituted C7-22aracelio group or

f) optionally substituted 5 to 14-membered heteroalkyl group)

12) (RN1RN2N)2RO-O- (where RN1and RN2have the same meanings as defined above), or

13) (RN1RN2N)(RN5O)RO-O- (where RN1, RN2and RN5have the same meanings as defined above), provided that the excluded compound is where R 3, R6, R7and R21all represent a hydroxyl group, and a compound in which R3, R6and R21all represent a hydroxyl group and R7is acetochlor), its pharmacologically acceptable salt or hydrate;

(2) the compound according to item (1)represented by formula (I-a):

(in the formula, R3A, R6A, R7aand R21Aare the same or different from each other and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R3A, R6A, R7aand R21Aprovided that R6Alimited to hydroxyl groups,

2) optionally substituted C1-22alkoxygroup,

3) RandCO-O- (where Randrepresents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

(C) optionally substituted unsaturated With2-22alkyl group,

d) optionally substituted C6-14aryl group,

e) optionally substituted 5-14 membered heteroaryl group,

f) optionally substituted C7-22aracelio group,

g) optionally substituted 5 to 14-membered heteroalkyl group,

h) optionally substituted C1-22and is oxygraph,

i) optionally substituted With unsaturated2-22alkoxygroup,

j) optionally substituted C6-14alloctype or

k) optionally substituted 5 to 14-membered heterokaryosis),

4) RaS1RaS2RaS3SiO- (RaS1, RaS2and RaS3are the same or different from each other and each of them represents a

a)1-6alkyl group, or

(b) (C6-14aryl group),

5) a halogen atom, or

6) RaN1RaN2N-RaM- (where RaMrepresents a

a) a single bond,

b) -CO-O-,

with) -SO2-O-,

d) -CS-O -, or

e) -CO-NRaN3- (where RaN3represents a hydrogen atom or optionally substituted C1-6alkyl group), provided that each of the leftmost bond in b)-e) attached to the nitrogen atom; and

RaN1and RaN2are the same or different from each other and each of them represents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

(C) optionally substituted unsaturated With2-22alkyl group,

d) optionally substituted aliphatic C2-22acyl group,

e) optionally substituted aromatic7-15acyl group,

f) optionally substituted C6-14aryl group,

g) optional samisen the Yu 5-14-membered heteroaryl group,

h) optionally substituted C7-22aracelio group,

i) optionally substituted C1-22alkylsulfonyl group,

j) optionally substituted C6-14arylsulfonyl group,

k) optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed RaN1and RaN2together with the nitrogen atom that is attached to RaN1and RaN2and non-aromatic heterocyclic group may have substituents,

l) optionally substituted 5 to 14-membered heteroalkyl group,

m) optionally substituted C3-14cycloalkyl group or

n) optionally substituted 3 to 14-membered non-aromatic heterocyclic group)), its pharmacologically acceptable salt or hydrate;

(3) the compound according to item (1)represented by formula (I-b):

(in the formula, R3b, R6b, R7band R21bare the same or different from each other and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R3b, R6b, R7band R21bprovided that R6blimited to hydroxyl groups,

2) optionally substituted C1-22alkoxygroup,

3) RbCO-O- (where Rbis Wal-Christ.

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

(C) optionally substituted unsaturated With2-22alkyl group,

d) optionally substituted C6-14aryl group,

e) optionally substituted 5-14 membered heteroaryl group,

f) optionally substituted C7-22aracelio group,

g) optionally substituted 5 to 14-membered heteroalkyl group,

h) optionally substituted C1-22alkoxygroup,

i) optionally substituted With unsaturated2-22alkoxygroup,

j) optionally substituted C6-14alloctype or

k) optionally substituted 5 to 14-membered heterokaryosis),

4) RbS1RbS2RbS3SiO- (RbS1, RbS2and RbS3are the same or different from each other and each of them represents a

a)1-6alkyl group, or

(b) (C6-14aryl group), or

5) RbN1RbN2N-RbM- (where RbMrepresents a

a) -CO-O - or

b) -CS-O-, provided that each of the leftmost bond in a) and b) attached to the nitrogen atom; and

RbN1and RbN2are the same or different from each other and each of them represents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

C) optional samewe the percent unsaturated With 2-22alkyl group,

d) optionally substituted aliphatic C2-22acyl group,

e) optionally substituted aromatic7-15acyl group,

f) optionally substituted C6-14aryl group,

g) optionally substituted 5-14 membered heteroaryl group,

h) optionally substituted C7-22aracelio group,

i) optionally substituted C1-22alkylsulfonyl group,

j) optionally substituted C6-14arylsulfonyl group,

k) optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed RbN1and RbN2together with the nitrogen atom that is attached to RbN1and RbN2and non-aromatic heterocyclic group may have substituents,

l) optionally substituted 5 to 14-membered heteroalkyl group,

m) optionally substituted C3-14cycloalkyl group or

n) optionally substituted 3 to 14-membered non-aromatic heterocyclic group)), its pharmacologically acceptable salt or hydrate;

(4) the compound according to item (1)represented by formula (I-c):

(in the formula, R3c, R6c, R7cand R21care the same or different from each other and each of them represents a

1) hydroxyl gr is foam or oxoprop, formed together with the carbon atom that is attached to each of R3c, R6c, R7cand R21cprovided that R6climited to hydroxyl groups,

2) optionally substituted C1-22alkoxygroup,

3) RcCO-O- (where Rcrepresents a

a) optionally substituted C1-22alkyl group,

b) optionally substituted C6-14aryl group,

c) optionally substituted C7-22aracelio group or

d) optionally substituted C6-14alloctype),

4) RS1RS2RS3SiO- (RS1, RS2and RS3are the same or different from each other and each of them represents a

a)1-6alkyl group, or

(b) (C6-14aryl group), or

5) RN1RN2N-RcM- (where Rsmrepresents a

a) -CO-O - or

b) -CS-O-, provided that each of the leftmost bond in a) and b) attached to the nitrogen atom; and

RN1and RN2are the same or different from each other and each of them represents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

(C) optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed RN1and RN2together with the nitrogen atom to which recognize the ENES R N1and RN2and non-aromatic heterocyclic group may have substituents,

d) optionally substituted 5 to 14-membered heteroalkyl group,

e) optionally substituted C3-14cycloalkyl group or

f) optionally substituted 3 to 14-membered non-aromatic heterocyclic group and non-aromatic heterocyclic group may have substituents)), its pharmacologically acceptable salt or hydrate;

(5) the compound according to item (1)represented by formula (I-d):

(in the formula, R3drepresents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to R3d,

2) optionally substituted C1-22alkoxygroup,

3) optionally substituted unsaturated With2-22alkoxygroup,

4) optionally substituted C7-22aralkylated,

5) RdCO-O- (where Rdrepresents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

(C) optionally substituted unsaturated With2-22alkyl group,

d) optionally substituted C6-14aryl group,

e) optionally substituted 5-14 membered heteroaryl group,

f) optionally substituted C7-22aracelio group,

g) NeoMaster is but substituted 5-14-membered heteroaryl group,

h) optionally substituted C1-22alkoxygroup,

i) optionally substituted With unsaturated2-22alkoxygroup,

j) optionally substituted C6-14alloctype or

k) optionally substituted 5 to 14-membered heterokaryosis) or

6) RdN1RdN2N-CO-O- (where RdN1and RdN2are the same or different from each other and each of them represents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

(C) optionally substituted unsaturated With2-22alkyl group,

d) optionally substituted C6-14aryl group,

e) optionally substituted 5-14 membered heteroaryl group,

f) optionally substituted C7-22aracelio group,

g) optionally substituted 5 to 14-membered heteroalkyl group,

h) optionally substituted C3-14cycloalkyl group,

i) optionally substituted 3 to 14-membered non-aromatic heterocyclic group, or

j) optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed RdN1and RdN2together with the nitrogen atom that is attached to RdN1and RdN2and non-aromatic heterocyclic group may have substituents),

and

R6d, R7dand R21dare the same or otlichayuschimisya from each other and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R6d, R7dand R21dprovided that R6dlimited to hydroxyl groups,

2) optionally substituted C1-22alkoxygroup,

3) optionally substituted unsaturated With2-22alkoxygroup,

4) optionally substituted C7-22aralkylated,

5) RdCO-O- (where Rdhas the same meaning as defined above),

6) RdN1RdN2N-CO-O- (where RdN1and RdN2have the same meanings as defined above)

7) RdN1RdN2N-SO2-O- (where RdN1and RdN2have the same meanings as defined above)

8) RdN1RdN2N-CS-O- (where RdN1and RdN2have the same meanings as defined above)

9) RdN3-SO2-O- (where RdN3represents a

a) optionally substituted C1-22alkyl group,

b) optionally substituted C1-22alkoxygroup,

(C) optionally substituted unsaturated With2-22alkoxygroup,

d) optionally substituted C6-14aryl group,

e) optionally substituted C6-14alloctype,

f) optionally substituted 5 to 14-membered heteroepitaxy,

g) optionally substituted C7-22aralkylated or

h) neoba is consequently substituted 5-14-membered heteroeroticism,

10) (RdN5O)2RO (where RdN5represents a

a) optionally substituted C1-22alkyl group,

b) optionally substituted With unsaturated2-22alkyl group,

(C) optionally substituted C6-14aryl group,

d) optionally substituted 5-14 membered heteroaryl group,

e) optionally substituted C7-22aracelio group or

f) optionally substituted 5 to 14-membered heteroalkyl group)

11) (RdN1RdN2N)2RO (where RdN1and RdN2have the same meanings as defined above), or

12) (RdN1RdN2N)(RdN5O)RO (where RdN1, RdN2and RdN5have the same meanings as defined above), provided that the excluded compound in which R3d, R6d, R7dand R21dall represent a hydroxyl group, and a compound in which R3d, R6dand R21dall represent a hydroxyl group and R7dis acetochlor), its pharmacologically acceptable salt or hydrate;

(6) the compound according to item (1), where R6and/or R7represent(et) a RN1RN2N-RM- (where RMrepresents a

a) -CO-O - or

b) -CS-O-; and

RN1and RN2have the same meanings as defined above, provided that each extreme lion which I link in a) and b) attached to the nitrogen atom), its pharmacologically acceptable salt or hydrate;

(7) the compound according to item (1), its pharmacologically acceptable salt or hydrate, where R21is oxoprop formed together with the carbon atom that is attached to R21;

(8) the compound according to item (5)represented by formula (I-e):

(in the formula, R3Eand REare the same or different from each other and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R3Eand RE,

2) optionally substituted C1-6alkoxygroup,

3) optionally substituted unsaturated With2-10alkoxygroup,

4) optionally substituted C7-10aralkylated,

5) optionally substituted aliphatic C2-6alloctype or

6) ReN1ReN2N-CO-O- (where ReN1and ReN2are the same or different from each other and each of them represents a

(A) a hydrogen atom, or

C) optionally substituted C1-6alkyl group); and

R6thand R7Eare the same or different from each other and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom, is that attached each of R 6thand R7Eprovided that R6thlimited to hydroxyl groups,

2) optionally substituted C1-6alkoxygroup,

3) optionally substituted unsaturated With2-10alkoxygroup,

4) optionally substituted C7-10aralkylated,

5) optionally substituted aliphatic C2-6alloctype or

6) ReC(=Ye)-O- (where Yerepresents an oxygen atom or a sulfur atom, and Rerepresents a

(a) a hydrogen atom,

b) optionally substituted C1-6alkyl group,

(C) optionally substituted C7-10aracelio group,

d) optionally substituted 5 to 14-membered heteroalkyl group,

e) a group of the formula (III):

(in the formula

A) n is an integer from 0 to 4;

Xerepresents a

(i)- (CHReN4-,

ii) -NReN5-,

iii) -O-,

iv) -S-,

v) -SO - or

vi) -SO2-;

RN1represents a

(i) a hydrogen atom, or

ii)1-6alkyl group;

RN2represents a

(i) a hydrogen atom, or

ii)1-6alkyl group;

RN3and ReN4are the same or different from each other and each of them represents a

(i) a hydrogen atom,

ii) optionally substituted C1-6alkyl group,

iii) optionally substituted unsaturated With2-10alkyl group,

iv) optionally substituted C6-14aryl group,

v) optionally substituted 5-14 membered heteroaryl group,

vi) optionally substituted C7-10aracelio group,

vii) optionally substituted C3-8cycloalkyl group,

viii) optionally substituted C4-9cycloalkylcarbonyl group,

(ix) optionally substituted 5 to 14-membered heteroalkyl group,

x) optionally substituted 5 to 14-membered non-aromatic heterocyclic group,

xi) -NReN6ReN7(where ReN6and ReN7are the same or different from each other and each represents a hydrogen atom or optionally substituted C1-6alkyl group), or

xii) optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed ReN3and ReN4together with the carbon atom that is attached to ReN3and ReN4and non-aromatic heterocyclic group may have substituents; and

RN5represents a

(i) a hydrogen atom,

ii) optionally substituted C1-6alkyl group,

iii) optionally substituted unsaturated With2-10alkyl group,

iv) optionally substituted C6-14aryl group,

v) neo is Astelin substituted 5-14-membered heteroaryl group,

vi) optionally substituted C7-10aracelio group,

vii) optionally substituted C3-8cycloalkyl group,

viii) optionally substituted C4-9cycloalkylcarbonyl group,

(ix) optionally substituted 5 to 14-membered heteroalkyl group,

x) optionally substituted 5 to 14-membered non-aromatic heterocyclic group, or

(xi) optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed ReN3and ReN4together with the nitrogen atom that is attached to ReN3and ReN4and non-aromatic heterocyclic group may have substituents,

In) Xe, n, ReN3, ReN4and ReN5represent each group as defined above, and ReN1and ReN2together form an optionally substituted 5 to 14-membered non-aromatic heterocyclic group,

(C) Xe, n, ReN2, ReN4and ReN5represent each group as defined above, and ReN1and ReN3together form an optionally substituted 5 to 14-membered non-aromatic heterocyclic group, or

D) Xe, n, ReN1, ReN4and ReN5represent each group as defined above, and ReN2and ReN3together form an optionally substituted 5 to 14-membered non-aromatic heterocyclic group) or

f) a group of the formula (V):

(in the formula, RN8and ReN9are the same or different from each other and each of them represents a

(i) a hydrogen atom,

ii) optionally substituted C1-6alkyl group,

iii) optionally substituted C6-14aryl group,

iv) optionally substituted 5-14 membered heteroaryl group,

v) optionally substituted C7-10aracelio group or

vi) optionally substituted 5 to 14-membered heteroalkyl group))), its pharmacologically acceptable salt or hydrate;

(9) the compound according to item (5), where R6dand/or R7drepresent(et) a Rd1C(=Yd1)-O- (where Yd1represents an oxygen atom or a sulfur atom, and Rd1represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted C7-10aracelio group or

4) optionally substituted 5 to 14-membered heteroaryl group), its pharmacologically acceptable salt or hydrate;

(10) the compound according to item (5), where R6dand/or R7drepresent(et) a Rd2C(=Yd2)-O- (where Yd2represents an oxygen atom or a sulfur atom, and Rd2represents a group of formula (III'):

(in the formula, n represents the th integer from 0 to 4, X1represents a

1) -CHRdN7-,

2) -NRdN8-,

3) -O-,

4) -S-,

5) -SO - or

6) -SO2-;

RdN4and RdN5are the same or different from each other and each of them represents a

1) a hydrogen atom, or

2)1-6alkyl group;

RdN6and RdN7are the same or different from each other and each of them represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted unsaturated With2-10alkyl group,

4) optionally substituted C6-14aryl group,

5) optionally substituted 5-14 membered heteroaryl group,

6) optionally substituted C7-10aracelio group,

7) optionally substituted C3-8cycloalkyl group,

8) optionally substituted C4-9cycloalkylcarbonyl group,

9) optionally substituted 5 to 14-membered heteroalkyl group,

10) optionally substituted 5 to 14-membered non-aromatic heterocyclic group,

11) -NRdN9RdN10(where RdN9and RdN10are the same or different from each other and each represents a hydrogen atom or optionally substituted C1-6alkyl group), or

12) optionally substituted 5 to 14-membered, neuromate the definition heterocyclic group, formed along RdN6and RdN7and non-aromatic heterocyclic group may have substituents; and

RdN8represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted unsaturated With2-10alkyl group,

4) optionally substituted C6-14aryl group,

5) optionally substituted 5-14 membered heteroaryl group,

6) optionally substituted C7-10aracelio group,

7) optionally substituted C3-8cycloalkyl group,

8) optionally substituted C4-9cycloalkylcarbonyl group,

9) optionally substituted 5 to 14-membered heteroalkyl group,

10) optionally substituted 5 to 14-membered non-aromatic heterocyclic group,

11) optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed RdN4, RdN5or RdN6together with the nitrogen atom that is attached to each of RdN4, RdN5and RdN6and non-aromatic heterocyclic group may have substituents, or

12) optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed by two substituents selected from the group consisting of RdN4, RdN5and RdN6together with the nitrogen atom, to cat the rum they are attached, moreover, non-aromatic heterocyclic group may have substituents)), its pharmacologically acceptable salt or hydrate;

(11) the compound according to item (10), its pharmacologically acceptable salt or hydrate, where X1represents-NRdN8- (where NRdN8has the same meanings as defined above);

(12) the compound according to item (5)represented by formula (I-f):

(in the formula, R7fis an RfC(=Yf)-O- (where Yfrepresents an oxygen atom or a sulfur atom, and Rfrepresents a group of formula (V):

(where n is an integer from 0 to 4,

RfN1represents a

1) a hydrogen atom,

2) methyl group, or

3) ethyl group, and

RfN2represents a

1) a hydrogen atom,

2) methylaminopropyl,

3) dimethylaminopropyl,

4) ethylamino,

5) diethylaminopropyl,

6) ethylmethylamino,

7) pyridinyl group,

8) pyrrolidin-1-ilen group,

9) piperidine-1-ilen group,

10) morpholine-4-ilen group or

11) 4-methylpiperazin-1-ilen group))), its pharmacologically acceptable salt or hydrate;

(13) the compound according to item (5), where R6dand/or R7drepresent(et) a Rd3CO-O- (where Rd3represents the Oh group of the formula (VI):

(where n1and n2are the same or different from each other and each represents an integer from 0 to 4,

X2represents a

1) -CHRdN13-,

2) -NRdN14-,

3) -O-,

4) -S-,

5) -SO - or

6) -SO2-;

RdN11represents a

1) a hydrogen atom, or

2) optionally substituted C1-6alkyl group;

RdN12represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted C6-14aryl group, or

4) optionally substituted C7-10aracelio group;

RdN13represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted unsaturated With2-10alkyl group,

4) optionally substituted C6-14aryl group,

5) optionally substituted 5-14 membered heteroaryl group,

6) optionally substituted C7-10aracelio group,

7) optionally substituted C3-8cycloalkyl group,

8) optionally substituted C4-9cycloalkylcarbonyl group,

9) optionally substituted 5 to 14-membered heteroalkyl group,

10) -NRdN15RdN16(where RdN15and RdN16are the same the mi or different from each other and each represents a hydrogen atom or optionally substituted C 1-6alkyl group), or

11) optionally substituted 5 to 14-membered non-aromatic heterocyclic group; and

RdN14represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted unsaturated With2-10alkyl group,

4) optionally substituted C6-14aryl group,

5) optionally substituted 5-14 membered heteroaryl group,

6) optionally substituted C7-10aracelio group,

7) optionally substituted C3-8cycloalkyl group,

8) optionally substituted C4-9cycloalkylcarbonyl group,

9) optionally substituted 5 to 14-membered heteroalkyl group or

10) optionally substituted 5 to 14-membered non-aromatic heterocyclic group)), its pharmacologically acceptable salt or hydrate;

(14) the compound according to item (5)represented by formula (I-g):

(in the formula, R7gis an RgCO-O- (where Rgrepresents a group of formula (VII):

(where n3is 1 or 2,

RdN17represents a

1) a hydrogen atom,

2) methyl group, or

3) ethyl group, and

RdN18represents a

1) a hydrogen atom,

2) methyl group, or

3) e the ilen group))), its pharmacologically acceptable salt or hydrate;

(15) the compound according to item (5), where R6dand/or R7drepresent(et) a Rd4CO-O- (where Rd4represents a group of formula (VIII):

(where n1and n2are the same or different from each other and each represents an integer from 0 to 4,

X3represents a

1) -CHRdN21-,

2) -NRdN22-,

3) -O-,

4) -S-,

5) -SO - or

6) -SO2-;

RdN19represents a

1) a hydrogen atom, or

2)1-6alkyl group;

RdN20represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted C6-14aryl group, or

4) optionally substituted C7-10aracelio group;

RdN21represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted unsaturated With2-10alkyl group,

4) optionally substituted C1-6alkoxygroup,

5) optionally substituted C6-14aryl group,

6) optionally substituted 5-14 membered heteroaryl group,

7) optionally substituted C7-10aracelio group,

8) optionally substituted C3-8cycle the alkyl group,

9) optionally substituted C4-9cycloalkylcarbonyl group,

10) optionally substituted 5 to 14-membered heteroalkyl group,

11) -NRdN23RdN24(where RdN23and RdN24are the same or different from each other and each represents a hydrogen atom or optionally substituted C1-6alkyl group), or

12) optionally substituted 5 to 14-membered non-aromatic heterocyclic group; and

RdN22represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted unsaturated With2-10alkyl group,

4) optionally substituted C6-14aryl group,

5) optionally substituted 5-14 membered heteroaryl group,

6) optionally substituted C7-10aracelio group,

7) optionally substituted C3-8cycloalkyl group,

8) optionally substituted C4-9cycloalkylcarbonyl group,

9) optionally substituted 5 to 14-membered heteroalkyl group or

10) optionally substituted 5 to 14-membered non-aromatic heterocyclic group)), its pharmacologically acceptable salt or hydrate;

(16) the compound according to item (5)represented by formula (I-h):

(in the formula, R7hthe submitted is an R hCO-O- (where Rhrepresents a group of formula (IX):

(where n4is an integer from 1 to 3 and

RdN25represents a

1) amino group,

2) methylaminopropyl,

3) dimethylaminopropyl,

4) pyrrolidin-1-ilen group,

5) piperidine-1-ilen group or

6) morpholine-4-ilen group))), its pharmacologically acceptable salt or hydrate;

(17) the compound according to item (5)represented by formula (I-i):

(in the formula, R7iis an RiCO-O- (where Rirepresents a group of formula (X):

(where n4is an integer from 1 to 3,

RdN26represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted C6-14aryl group, or

4) optionally substituted C7-10aracelio group;

RdN27represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted C3-8cycloalkyl group,

4) optionally substituted 3-8-membered non-aromatic heterocyclic group,

5) optionally substituted C6-14aryl group,

6) optionally substituted 5-can heteroaryl group,

7) optionally substituted C7-10aracelio group,

8) optionally substituted 5 to 14-membered heteroalkyl group or

9) optionally substituted C4-9cycloalkylcarbonyl group))), its pharmacologically acceptable salt or hydrate;

(18) the compound according to item (5)represented by formula (I-j):

(in the formula, R7jis an RjCO-O- (where Rjrepresents a group of formula (XI):

(where n4is an integer from 1 to 3 and

RdN28represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3)3-8cycloalkyl group,

4)4-9cycloalkylcarbonyl group,

5)7-10aracelio group,

6) pyridinyl group or

7) tetrahydropyranyloxy group))), its pharmacologically acceptable salt or hydrate;

(19) the compound according to item (5)represented by formula (I-k):

(in the formula, R7kis an RkCO-O- (where Rkrepresents a group of formula (XII):

(where m1, m2, m3and m4are the same or different from each other and each of them is equal to 0 or 1,

n4is the battle integer from 1 to 3 and

RdN29represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group,

3) optionally substituted unsaturated With2-10alkyl group,

4) optionally substituted C6-14aryl group,

5) optionally substituted 5-14 membered heteroaryl group,

6) optionally substituted C7-10aracelio group,

7) optionally substituted C3-8cycloalkyl group,

8) optionally substituted C4-9cycloalkylcarbonyl group,

9) optionally substituted 5 to 14-membered heteroalkyl group or

10) optionally substituted 5 to 14-membered non-aromatic heterocyclic group))), its pharmacologically acceptable salt or hydrate;

(20) the compound according to item (5)represented by formula (I-m):

(in the formula, R7mis an RmCO-O- (where Rmrepresents a group of the formula (XIII):

(where m5is an integer from 1 to 3 and n5is 2 or 3))), its pharmacologically acceptable salt or hydrate;

(21) the compound according to item (5)represented by formula (I-n):

(in the formula, R7nis an RnCO-O- (where Rnrepresents a group of the formula (XIV):

its pharmacologically acceptable salt or hydrate;

(22) the compound according to item (1), which is selected from:

(8E,12E,14)-7-(N-(2-(N',N'-dimethylamino)ethyl)-N-methylcarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 6);

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide (compound 9);

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide (compound 12);

(8E,12E,14)-7-((4-butylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 16);

(8E,12E,14)-7-((4-ethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 21);

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylpiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide (compound 25);

(8E,12E,14)-7-((4-cyclohexylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 26);

(8E,12E,14)-7-((4-(cyclopropylmethyl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 27);

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-papillomaviruses-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide (compound 31);

(8E,12E,14)-7-((4-(cyclopropylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 36);

(8E,12E,14)-7-((4-cyclopentylpropionyl-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 38);

(8E,12E,14)-3,6,16,21-tetrahydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 44);

(8E,12E,14)-7-((4-cycloheptatrien-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 45);

(8E,12E,14)-7-(N-(2-(N',N'-diethylamino)ethyl)-N-methylcarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 75);

(8E,12E,14)-3,6,16,21-tetrahydroxy-7-((4-isobutylpyrazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 54);

(8E,12E,14)-7-((4-acylhomoserine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 63);

(8E,12E,14)-7-((4-butyrometers-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 64);

(8E,12E,14)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-the Lede (compound 85);

(8E,12E,14)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(piperidine-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide (compound 109);

(8E,12E,14)-7-((4-(2,2-dimethylpropyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 69); and

(8E,12E,14)-3,6,16-trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide (compound 131);

(23) the compound according to item (1), which is selected from:

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide (compound 9);

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide (compound 12);

(8E,12E,14)-7-((4-cyclohexylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 26);

(8E,12E,14)-3,6,16,21-tetrahydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 44);

(8E,12E,14)-7-((4-cycloheptatrien-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 45); and

(8E,12E,14)-7-(N-(2-(N',N'-diethylamino)ethyl)-N-methylcarbamoyl)-3,6,16,21-Ter the hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (compound 75);

(24) a drug containing the compound according to any one of items (1)to(23), its pharmacologically acceptable salt or hydrate as an active ingredient;

(25) a pharmaceutical composition comprising a compound according to any one of items (1)to(23), its pharmacologically acceptable salt or hydrate as an active ingredient;

(26) the drug according to item (24), which is an agent for the prevention or treatment of diseases against which effective regulation of gene expression;

(27) the drug according to item (24), which is an agent for the prevention or treatment of diseases against which effective inhibition of VEGF production;

(28) the drug according to item (24), which is an agent for the prophylaxis or treatment of a disease against which an effective antiangiogenic effect;

(29) the drug according to item (24), which is an inhibitor of angiogenesis;

(30) the drug according to item (24), which is an antitumor agent;

(31) the drug according to item (24) as a therapeutic agent for the treatment of angiomas;

(32) the drug according to item (24), which is an inhibitor of cancer metastasis;

(33) the drug according to item (24), which is a therapeutic tool for the treatment of the Oia retinal revascularization or diabetic retinopathy;

(34) the drug according to item (24), which is a therapeutic tool for the treatment of inflammatory diseases;

(35) the drug according to item (24), which is a therapeutic agent for the treatment of inflammatory diseases, comprising deforming arthritis, rheumatoid arthritis, psoriasis and delayed-type hypersensitivity;

(36) the drug according to item (24), which is a therapeutic agent for the treatment of atherosclerosis;

(37) the drug according to item (24), which is a therapeutic tool for the treatment of solenoi malignant tumors;

(38) the drug according to item (37), where solenoi malignant tumor is lung cancer, brain tumor, breast cancer, prostate cancer, ovarian cancer, cancer of the colon or melanoma;

(39) the drug according to item (24), which is a therapeutic agent for the treatment of leukemia;

(40) the drug according to item (24), which is an antitumor agent based on the regulation of gene expression;

(41) the drug according to item (24), which is an antitumor agent based on the inhibition of VEGF production;

(42) the drug according to item (24), which is an antitumor among the STV, based on the effect of inhibition of angiogenesis;

(43) a method of preventing or treating a disease against which effective regulation of gene expression, containing the introduction to the patient a pharmacologically effective dose of the drug under paragraph (24);

(44) a method of preventing or treating a disease against which effective inhibition of VEGF production, containing the introduction to the patient a pharmacologically effective dose of the drug under paragraph (24);

(45) a method of preventing or treating a disease against which effective inhibition of angiogenesis, containing the introduction to the patient a pharmacologically effective dose of the drug under paragraph (24);

(46) use of the compound according to any one of items (1)to(23), its pharmacologically acceptable salt or hydrate to origin the funds for the prevention or treatment of diseases against which effective regulation of gene expression;

(47) use of the compound according to any one of items (1)to(23), its pharmacologically acceptable salt or hydrate to origin the funds for the prevention or treatment of diseases against which effective inhibition of VEGF production;

(48) use of the compound according to any one of items (1)to(23), its pharmacologically acceptable salt or hydrate to origin the funds for the prevention or treatment C the disease, against which effective inhibition of angiogenesis; and

(49) the use of compounds according to any one of items (1)to(23), its pharmacologically acceptable salt or hydrate to origin the funds for the prevention or treatment solidnyh malignant tumors.

Below is illustrated the terms, symbols and the like, used in this description.

In this description chemical formula of the compound of the present invention is shown for convenience in the form of planimetric formula, but the connection may include some isomers derived from a given chemical formula. The present invention may include all isomers and mixtures of isomers such as geometric isomers, generated by the connection configuration, optical isomers based on asymmetric carbon atom, rotamer, stereoisomer and tautomer. The present invention is not limited suitable for this case description chemical formula and may cover any isomers or mixtures thereof. Thus, when the compound of the present invention contains the formula asymmetric carbon atom and are its optically active substance and the racemate, the invention encompasses them. In addition, when there are polymorphic crystals, the crystalline form of the present invention are not particularly limited to any one form and any who I crystalline forms may exist separately or in a mixture of crystalline forms. The compound represented by formula (I) in accordance with the present invention, or its salt can be anhydrate or hydrate, and both are included in the present invention. The metabolites formedin vivoas a result of decomposition of the compounds of formula (I) according to the present invention, the prodrug compounds of the formula (I) according to the present invention or salts thereof are also included in the present invention.

The term "halogen atom"used in this description means a fluorine atom, chlorine atom, bromine atom and iodine atom. Among them, preferred is, for example, a fluorine atom, a chlorine atom or a bromine atom, typically preferred is a fluorine atom or a chlorine atom.

"C1-22alkyl group"used in this description of the present invention, represents an unbranched or branched alkyl group containing 1-22 carbon atoms, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, 1,1-dimethylpropylene group, 1,2-dimethylpropylene group, 2,2-dimethylpropylene group, 1-ethylpropyl group, n-exilda group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-popypropylene group, 1-methylbutyl the th group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, n-heptylene group, n-aktiline group, n-nanlina group or n-decile group; preferably an unbranched or branched alkyl group containing 1-6 carbon atoms, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, second-bucilina group, tert-bucilina group or n-pencilina group; more preferably, for example, methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, or tert-boutelou group.

"Unsaturated With2-22alkyl group"used in this description of the present invention, represents an unbranched or branched alkenylphenol group containing 2-22 carbon atoms, or an unbranched or branched alkylamino group containing 2-22 carbon atoms, such as vinyl group, allyl group, 1-protanilla group, Isopropenyl group, 2-methyl-1-protanilla group, 2-methyl-2-protanilla group, 1-bucinellina group, 2-bucinellina group, 3-buta is nilina group, 1-penttila group, 1-examilia group, 1,3-hexadienyl group, 1,5-hexadienyl group, etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group, 3-Butyrina group, 1-ethinyl-2-proponila group, 2-methyl-3-Butyrina group, 1-penicilina group, 1-hexylamine group, 1,3-hexadienyl group or 1.5-hexadienyl group. Preferably it represents an unbranched or branched alkenylphenol group containing 2-10 carbon atoms, or an unbranched or branched alkylamino group containing 2-10 carbon atoms, such as vinyl group, allyl group, 1-protanilla group, 2-protanilla group, Isopropenyl group, 3-methyl-2-bucinellina group, 3,7-dimethyl-2,6-octadienal group, etinilnoy group, 1-proponila group, 2-proponila group, 1-Butyrina group, 2-Butyrina group, 3-Butyrina group or 3-methyl-1-proponila group.

"C6-14aryl group"used in the description to this application, means an aromatic cyclic hydrocarbon group containing 6-14 carbon atoms, and includes monocyclic group and condensed cycles, such as bicyclic group and tricyclic group. Examples include phenyl group, angenlina group, 1-naftalina the group, 2-naftalina group, atulananda group, heptylaniline group, Indianola group, acenaphthylene group, fluoroaniline group, phenylaniline group, phenanthroline group and antarctilyne group, of which a preferred example is a phenyl group, 1-naftalina group or 2-naftalina group.

"5-14-Membered heteroaryl group"used in the description to this application, means a monocyclic, bicyclic or tricyclic 5 to 14-membered aromatic heterocyclic group containing one or more heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom. Preferred examples of the group include nitrogen-containing aromatic heterocyclic group such as pyrrolidine group, pyridinoline group, pyridazinyl group, pyrimidinyl group, piratininga group, thiazolidine group, tetrataenia group, benzotriazolyl group, pyrazolidine group, imidazolidinyl group, benzimidazolyl group, indayla group, isoindolyl group, indolizinyl group, polylina group, indazolinone group, hyalinella group, sochineniia group, hyalinella group, phthalazinone group, naphthyridinone group, khinoksalinona group, chinadaily group, indolenine groups who, pteridinyl group, imidazolidinyl group, pirazinamida group, accidenily group, phenanthridinone group, carbazolyl group, carbazolyl group, pyrimidinyl group, phenanthroline group, pensinula group, imidazopyridine group, imidazopyrimidines group or pyrazolopyrimidine group; sulfur-containing aromatic heterocyclic group such as thienyl group or benzothiazoline group; and oxygen-containing aromatic heterocyclic group such as furilla group, Pernilla group, cyclopentadienyl group, benzoperylene group or isobenzofuranone group; an aromatic heterocyclic group containing two or more different heteroatoms, such as thiazolidine group, isothiazolinone group, benzothiazolyl group, benzothiadiazole group, phenothiazinyl group, isoxazolyl group, furazolidine group, phenoxypyridine group, oxazoline group, isoxazolyl group, benzoxazolyl group, oxadiazolyl group, pyrazoloquinoline group, imidazothiazole group, thienopyridine group, properally group or pyridoxamine group, of which a preferred example is a thienyl group, furilla group, pyridinoline group is a, pyridazinyl group, pyrimidinyl group or piratininga group.

"3-14-Membered non-aromatic heterocyclic group"used in the description to this application, means a monocyclic, bicyclic or tricyclic 3-14-membered nonaromatic heterocyclic group that may contain one or more heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom. Preferred examples of it are aziridinyl group, azetidinone group, pyrrolidinyl group, pyrrolidine group, piperidinyl group, piperazinilnom group, homopiperazine group, homopiperazine group, imidazolidinyl group, pyrazolidinone group, imidazolidinyl group, morpholinyl group, thiomorpholine group, imidazolidine group, oxazolidine group, 2,5-diazabicyclo-[2.2.1]heptylene group, 2,5-diazabicyclo[2.2.2]anjilina group, 3,8-diazabicyclo[3.2.1]anjilina group, 1,4-diazabicyclo[4.3.0]Danilina group, hinkleyville group, tetrahydrofuranyl group and tetrahydrobiopterine group. Non-aromatic heterocyclic group includes a group derived from Spiridonovka cycle, and condensed nonaromatic cycle (for example, a group derived from phthalimide cycle or operations of the loop)

"C7-22kalkilya group"used in this description, means the appropriate group defined above With1-22alkyl group, the substituted part of which is defined above, substituted "6-14aryl group". Specific examples include benzyl group, penicilina group, 3-phenylpropionate group, 4-phenylbutyrate group, 1-naphthylmethyl group and 2-naphthylmethyl group, of which preferred is kalkilya group containing 7-10 carbon atoms, such as benzyl group or penicilina group.

"5-14-Membered heteroalkyl group"used in this description, means the appropriate group defined above With1-22alkyl group, the substituted part of which is defined above, substituted "5 to 14-membered heteroaryl group". Specific examples of it are thienylmethyl group, purimetla group, pyridinylmethyl group, pyridinylmethyl group, pyrimidinylidene group and personalitly group, of which a preferred example is thienylmethyl group, purimetla group or pyridinylmethyl group.

"C3-14cycloalkyl group"used in this description, means cycloalkyl group containing 3-14 carbon atoms, and suitable examples of it are clapapella group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, cycloheptyl group and cyclooctyl group, of which a preferred example is cyclopentenone group, tsiklogeksilnogo group, cycloheptyl group or cyclooctyl group.

"C4-9cycloalkylation group"used in this description, means the appropriate group defined above.

"C1-22alkyl group, the substituted part of which is defined above, substituted "3-14cycloalkyl group". Specific examples of it are cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group and cyclooctylmethyl group, of which a preferred example is cyclopropylmethyl group, cyclobutylmethyl group or cyclopentylmethyl group.

"C1-22alkoxygroup"used in this description, means the appropriate group defined above With1-22alkyl group", one end of which is attached to the oxygen atom. Suitable examples are methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, second-butoxypropan, tert-butoxypropan, n-pentyloxy, isopentylamine, second-pentyloxy is the SCP, n-hexyloxy, isohexadecane, 1,1-DIMETHYLPROPANE, 1,2-DIMETHYLPROPANE, 2,2-DIMETHYLPROPANE, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyramide, 1,2-dimethylbutyramide, 2,2-dimethylbutyramide, 2,3-dimethyl-butoxypropan, 1,3-dimethylbutyramide, 2-itivuttaka, 2-methylpentylamino, 3-methylpentylamino and hexyloxy, of which a preferred example is a methoxy group, ethoxypropan, n-propoxylate, isopropoxide, isobutoxy or 2,2-dimethylpropanoate.

"Unsaturated With2-22alkoxygroup"used in this description, means a group corresponding to a certain higher unsaturated With2-22alkyl group", one end of which is attached to the oxygen atom. Suitable examples of it are vinyloxy, alliancegroup, 1-propionyloksypo, 2-propionyloksypo, isopropenylacetate, 2-methyl-1-propionyloksypo, 2-methyl-2-propionyloksypo, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 1-pentyloxy, 1-hexaniacinate, 1,3-hexacyanochromate, 1,5-hexacyanochromate, propargyloxy and 2-butenyloxy, of which a preferred example is alliancegroup, propargyloxy the group or 2-butenyloxy.

"C6-14alloctype"used in this description, means the appropriate group defined above With6-14aryl group", one end of which is attached to the oxygen atom. Specific examples are fenoxaprop, ingenjorsfirma, 1-naphthyloxy, 2-naphthyloxy, aspleniaceae, heptylaniline, indatadialogruta, acenaphthylene, fluorenylacetamide, phenyleneoxy, fenantrenkhinona and anthranilamide, of which a preferred example is fenoxaprop, 1-naphthyloxy or 2-naphthyloxy.

"C7-22arancelaria"used in this description, means the appropriate group defined above With7-22aranceles group", one end of which is attached to the oxygen atom. Specific examples are benzyloxy, penetratiegraad, 3-phenylpropoxy, 4-phenylbutyraldehyde, 1-naphthalenyloxy and 2-naphthalenyloxy, of which a preferred example is benzyloxy.

"5-14-Membered heteroarylboronic"used in this description, means the appropriate group defined above "5 to 14-membered heteroaryl group", one end of which is attached to the oxygen atom. Specific examples are titelmelodie, furylmethyl xygraph, pyridylmethylamine, pyridinylmethyl, pyrimidinediamine and personalitytasha, of which a preferred example is titelmelodie, feniletilamina or pyridylmethylamine.

"5-14-Membered heteroanalogues"used in this description, means the appropriate group defined above "5 to 14-membered heteroaryl group", one end of which is attached to the oxygen atom. Specific examples are paralelograma, peridiniaceae, peridiniaceae, pyrimidinylidene, personalantispy, trisalicylate, tetraallyloxyethane, benzothiazolylthio, pyrazolylborate, imidazolylalkyl, benzimidazolylthio, indoleacetate, isoindolines, indolizinium, purinacare, Indaselassie, hinolincarbonova, izohinolinove, kinoliteratura, palatinolinotype, naphthyridinone, hinoksalinovym, ginasolinspu, sinolingua, peridiniaceae, imidazotriazine, pirazinoizohinolina, criminologica, phenanthridinone, carbazochrome, carbetopendecinia, pyrimidinylidene, fenantroliniya, panathiniakos, imidazopyridines the group, imidazopyrimidines, pyrazolopyrimidinones, taylortype, bestyrelsegruppen, ferrochrome, pyranyloxy, Cyclopentasiloxane, benzofuroxan, isobenzofuranyl, diazolidinylurea, isothiazolinones, benzothiazolylthio, benzothiazolylthio, fenotiazinas, isoxazolidine, puritanashttp, paroxetinetherapy, oxazolidones, isoxazolidine, benzoxazolinone, oxadiazolidine, pyrazolecarboxylate, imidazothiazoles, teenagersintokyo, fucopyranoside and pyridoxinhydrochloride, of which a preferred example is taylortype, peridiniaceae, pyrimidinylidene or personalantispy.

"Aliphatic C2-22acyl group"used in this description, means the appropriate group defined above With1-22alkyl group or unsaturated With2-22alkyl group", one end of which is attached a carbonyl group. Examples include acetyl group, propylaniline group, Butyrina group, isobutylene group, valerina group, isovaleryl group, pivellina group, Carolina group, dekheila group, Laurila group, Mirandolina group, palm is Tolna group, caarolina group, Archidona group, calolina group, Propylamine group, crotonoideae group, isotretinoina group, olaola group and linoleoyl group, of which a preferred example is an acyl group containing 2-6 carbon atoms, such as acetyl group, propylaniline group, Butyrina group, isobutylene group or calolina group.

"Aromatic With7-15acyl group"used in this description, means the appropriate group defined above With6-14aryl group or 5 to 14-membered heteroaryl group", one end of which is attached a carbonyl group. Examples of it are benzoline group, 1-napolina group, 2-napolina group, pokoleniya group, nicotinoyl group, isonicotinoyl group, frolina group and thiophenecarboxylate group, of which a preferred example is benzoline group, pokoleniya group, nicotinoyl group or isonicotinoyl group.

"C1-22alkylsulfonyl group"used in this description, means sulfonyloxy group, which is attached with defined above With1-22alkyl group". Specific examples of it are methanesulfonyl group, acanaloniidae group, n-propanesulfonyl group and isop Panalpina group, of which a preferred example is methanesulfonyl group.

"C6-14arylsulfonyl group"used in this description, means sulfonyloxy group, which is attached with defined above With6-14aryl group". Specific examples of it are benzolsulfonat group, 1-naphthalenesulfonyl group and 2-naphthalenesulfonyl group, of which a preferred example is benzolsulfonat group.

"Aliphatic C2-22alliancegroup"used in this description, means the appropriate group defined above "aliphatic C2-22acyl group", one end of which is attached to the oxygen atom. Specific examples are acetoxygroup, propionyloxy and akilattirattu, of which a preferred example is acetoxygroup or propionyloxy.

"C2-22alkoxycarbonyl group"used in this description, means the appropriate group defined above,

"C1-22alkoxygroup", one end of which is attached a carbonyl group. Examples of it are methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, solutionline group, sec-butoxycarbonyl the th group and tert-butoxycarbonyl group, of which a preferred example is ethoxycarbonyl group, isopropoxycarbonyl group or tert-butoxycarbonyl group.

"Unsaturated With3-22alkoxycarbonyl group"used in this description, means a group corresponding to a certain higher unsaturated With2-22alkoxygroup", one end of which is attached a carbonyl group. Examples of it are vinyloxycarbonyl group, allyloxycarbonyl group, 1-propanecarboxylate group, isopropoxycarbonyl group, propylenecarbonate group and 2-butyloxycarbonyl group, of which a preferred example is allyloxycarbonyl group.

"C1-22allylthiourea"used in this description, means the appropriate group defined above With1-22alkyl group", one end of which is attached to the sulfur atom. Examples of it are methylthiourea, ethylthiourea, n-PropertyGroup and isopropyltoluene, of which a preferred example is methylthiourea or ethylthiourea.

"C1-22alkylsulfonyl group"used in this description, means the appropriate group defined above With1-22alkyl group", one end of which is attached sulfonylurea group. Examples of it are methanesulfonyl the group, econsultancy group, n-propanesulfonyl group and isopropylaniline group, of which a preferred example is methanesulfonyl group or econsultancy group.

"C1-22alkylsulfonates"used in this description, means the appropriate group defined above With1-22alkylsulfonyl group", one end of which is attached to the oxygen atom. Examples of it are methysulfonylmethane, econsultancy, n-propanesulfonate and isopropylphenoxy, of which a preferred example is methysulfonylmethane.

Deputy expression "optionally substituted"used in this description, may represent one or more groups selected from:

(1) halogen atom,

(2) a hydroxyl group,

(3) thiol groups,

(4) nitro group,

(5) nitrosopropane,

(6) ceanography,

(7) a carboxyl group,

(8) hydroxysultaine group,

(9) amino group,

(10)1-22alkyl group (e.g. methyl group, ethyl group, n-sawn group, isopropyl group, n-butilkoi group, isobutylene group, sec-butilkoi group and tert-butilkoi group)

(11) unsaturated With2-22alkyl groups (for example, vinyl group, allyl group, 1-about Tilney group, 2-propenyloxy group, Isopropenyl group, etinilnoy group, 1-propanolol group, 2-propanolol group, 1-botinelli group, 2-botinelli group and 3-botinelli group)

(12)6-14aryl group (e.g. phenyl group, 1-naftilos group and 2-naftilos group)

(13) 5-14-membered heteroaryl group (for example, thienyl group, shriley group, pyridinoline group, pyridazinyl group, pyrimidinyl group and personalni group)

(14) 3-14-membered non-aromatic heterocyclic group (for example, aziridinyl group, azetidinone group, pyrrolidinyl group, pyrrolidino group, piperidinyl group, piperazinilnom group, homopiperazine group, homopiperazine group, imidazolidine group, pyrazolidinone group, imidazolidinyl group, morpholinyl group, thiomorpholine group, imidazolidine group, oxazolidine group and hinkleyville group)

(15)3-14cycloalkyl group (for example, cyclopropene group, cyclobutyl group, cyclopentyloxy group, tsiklogeksilnogo group, cycloheptyl group and cyclooctyl group)

(16)1-22alkoxygroup (for example, metoxygroup, ethoxypropan, n-propoxylate, isopropoxy, sec-propoxylate, n-butoxypropyl, isobutoxy, fret-butoxypropyl),

(17) unsaturated With2-22alkoxygroup (for example, vinyloxy, alliancegroup, 1-propenyloxy, 2-propenyloxy, isopropenylacetate, acidilactici, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy and 2-butenyloxy),

(18)6-14alloctype (for example, phenyloxy, 1-naphthyloxy and 2-naphthyloxy),

(19)7-22aralkylated (for example, benzyloxy, penetrometry, 3-phenylpropoxy, 4-phenylbutyraldehyde, 1-naphthalenyloxy and 2-naphthalenyloxy),

(20) 5-14-membered heteroarylboronic (for example, canimmediately, fullmetalchemy, pyridylmethylamine, pyridinylmethyl, pyrimidinediamine and personalantispy),

(21) 5-14-membered heterokaryosis (for example, taylortype, ferrochrome, pyridyloxy, peridiniaceae, pyrimidinamine and personalantispy),

(22) aliphatic C2-22acyl group (e.g. acetyl group, propionyloxy group, butyilkoy group, isobutyryloxy group, valurile group, isovaleryl group, pivaloyl group, Carolinas group, technoloy group, Eurolines group, myristoleic group, Palmitoyl group, stekolnii group, archeology group, crinolines group, propylamino group, crotonoyl group, isotretinoinsee group, OleOle group and linoleoyl group)

(23) aromatic C7-15acyl group (for example, bentilee group, 1-naftolin group and 2-naftolin group)

(24) aliphatic C2-22alloctype (for example, acetochlor, propionyloxy and akilattirattu),

(25)2-22alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxyethene group, sec-butoxycarbonyl group and tert-butoxycarbonyl group)

(26) unsaturated With3-22alkoxycarbonyl group (for example, vinyloxycarbonyl group, allyloxycarbonyl group, 1-propanecarboxylate group, 2-propanecarboxylate group, isopropoxycarbonyl group, propylenecarbonate group and 2-butyloxycarbonyl group)

(27)1-22allylthiourea (for example, methylthiourea, ethylthiourea, n-PropertyGroup and isopropylthio),

(28)1-22alkylsulfonyl group (for example, methanesulfonyl group, ethanolamines group, n-propanesulfonyl group and isopropanolamines group)

(29)1-22alkylsulfonyl the group (for example, methanesulfonyl group, acanaloniidae group, n-propanesulfonyl group and isopropanolamines group)

(30)6-14arylsulfonyl group (for example, benzolsulfonate group, 1-naphthalenesulfonyl group and 2-naphthalenesulfonyl group)

(31)1-22alkylsulfonates (for example, methanesulfonamido, econsultancy, n-propanesulfonate and isopropylphenoxy),

(32) carbamoyl group and

(33) formyl group.

Of them, preferred is an amino group, With1-22alkyl group, unsaturated With2-22alkyl group, a C6-14aryl group, a 5-14-membered heteroaryl group, a 3-14 membered non-aromatic heterocyclic group and C3-14cycloalkyl group, and more preferred is an amino group, With1-22alkyl group, 3-14-membered non-aromatic heterocyclic group and C3-14cycloalkyl group. Each of the above (9) amino and (31) carbamoyl group as a substituent in the "optionally substituted" group may be optionally substituted with one or two from C1-22alkyl groups, unsaturated With2-22alkyl group or6-14aryl group.

The compounds of formula (I) according to the present invention is explained below./p>

The compounds of formula (I) inhibit the production of VEGF in hypoxic conditions and possess inhibitory activity against cell growth solenoi tumorin vivo. Among them, preferred are the compounds of formula (I-a), of which more preferred compounds of formula (I-b), and the compounds of formula (I-C) are typical best connections.

The compounds of formula (I) is structurally characterized by a side chain at position 6 and/or the side chain in position 7, and a group of more preferred compounds can be defined as compounds of formula (I-d). In addition to compounds of the formula (I-d) to a group of compounds with good activity include compounds of formula (I)in which R21forms oxoprop together with the carbon atom that is attached to R21. As examples of specific options is more preferable compounds among the compounds of formula (I-d), you can specify connection points (5)-(19) of the present invention.

Preferred examples of compounds of formula (I) below. A preferred group of compounds, including compounds described in the examples below, includes, for example, compound 6, compound 9, compound 12, compound 15, compound 16, compound 20, compound 21, compound 22, compound 25, compound 26, compound 27, compound 31, compound 34, compound 36, Obedinenie 38, compound 39, compound 40, compound 41, compound 43, compound 44, compound 45, compound 48, compound 51, the connection 53, the connection 54, the connection 55, the connection 57, the connection 58, the connection 62, the connection 63, the connection 64, compound 65, compound 69, compound 70, compound 72, compound 74, 75 connection, the connection 77, compound 79, compound 85, compound 88, the connection 105, the connection 106, the connection 108, the connection 109 and the connection 131. Among them, examples of more preferred compounds are compound 6, compound 9, compound 12, compound 16, compound 21, compound 25, compound 26, compound 27, compound 31, compound 36, compound 38, compound 44, compound 45, compound 54, the connection 63, the connection 64, compound 69, compound 75, compound 85, compound 109 and compound 131, of which, for example, compound 9, compound 12, compound 26, compound 44, compound 45 and 75 connection are typical preferred compounds.

Next explained obtaining the compounds of formula (I) according to the present invention.

The compound of formula (I) can be obtained by cultivation of a strain belonging to the genus Streptomyces which is capable of producing bioactive substance 11107D [compound of formula (I)in which R3, R6and R21represent a hydroxyl group, and R7represents and what maxigrip] under aerobic conditions, collecting the compound from the cells of the microorganism and culture and chemical modification of the compounds obtained by the traditional method.

Hereinafter first described the method of obtaining 11107D.

Instead of microorganism for producing 11107D can be used following the Deposit of the microorganism. The strain was deposited at the international deposited in International Patent Organism Depositary (IPOD) National Institute of Advanced Industrial Science and Technology (Tsukuba Central 6, 1-1, Higashi 1-Chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan). In particular, Streptomyces sp. Mer-11107 was deposited as FERM P-18144 in the National Institute of Bioscience and Human-Technology Agency of Industrial Science and Technology (1-3, Higashi 1-chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan). Then he was transferred to the International Deposit FERM BP-7812 at International Patent Organism Depositary (IPOD) National Institute of Advanced Industrial Science and Technology (Tsukuba Central 6, 1-1, Higashi 1-Chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan).

The strain for the production of 11107D not particularly limited and includes options such strains, if only he belonged to the genus Streptomyces and had the ability to produce 11107D. Examples of the strain is Streptomyces sp. A-1532, Streptomyces sp. A-1533, and Streptomyces sp. A-1534 in addition to the above strain. These strains were put on the international deposited in International Patent Organism Depositary (IPOD) National Institute of Advanced Industrial Science and Technology (Tsukuba Central 6, 1-1, Higashi 1-Chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan) as FERM BP-7849, FERM BP-7850 and FERM BP-7851, respectively.

Below is a detailed description: 1. the properties of the selected mi is reorganize, 2. the method of fermentation of the microorganism and 3. method of purification of the active substance in obtaining 11107D.

1. Property of the selected microorganism

With regard to strain for use in the present invention, it is anticipated that can be used in any of the strains belonging to the genus Streptomyces and capable of producing 11107D. However, as typical of the strain used in the present invention, the authors suggest, for example, a strain called "strain Mer-11107". The specified strain has the following taxonomical properties.

(1) Morphological characteristics

In the specified strain from vegetative hyphae depart aerial hyphae in the form of a helical spiral. At the end of the Mature aerial hyphae formed a chain of argument, consisting of about 10-20 bar dispute. The size of the dispute is approximately 0.7 x 1.0 μm, the surface of spores smooth, and specific organs, such as the sporangium, the sclerotia and the flagellum are not observed.

(2) Cultural characteristics on various media

Below shows the cultural characteristics of the strain after incubation at 28°within two weeks on different environments. Hue describes the color name and codes are shown in parentheses in the Color Harmony Manual (Container Corporation of America).

1) Agar medium with yeast and malt extracts

Observed a well-grown strain, n is Jennie hyphae, having grown up on the surface, and light gray spores (Light gray; d). The opposite side of the colony had the yellow Light melon yellow (EA). Soluble pigment has not been developed.

2) Agar medium with oatmeal

Observed strain, grown at the average level, the aerial hyphae, slightly germinated on the surface, and gray spores (Gray; g). The opposite side of the colony had reddish-brown color Nude (DS) or color Putty (1 1/es). Soluble pigment has not been developed.

3) Agar medium with inorganic salt and starch

Observed a well-grown strain, aerial hyphae growing on the surface, and gray spores (Gray; e). The opposite side of the colony had color Fawn (4ig) or Gray (g). Soluble pigment has not been developed.

4) Agar medium with glycerol and asparagine

Observed a well-grown strain, aerial hyphae growing on the surface, and white spores White;). The opposite side of the colony had color Pearl pink (sa). Soluble pigment has not been developed.

5) Agar medium with peptone, yeast extract and iron

Growth of the strain was bad, and the aerial hyphae on the surface could not grow. The opposite side of the colony had the yellow Light melon yellow (EA). Soluble pigment has not been developed.

6) the tyrosine agar medium

Observed a well-grown strain, aerial hyphae grown on a surface is STI, and white spores White;). The opposite side of the colony had color Pearl pink (sa). Soluble pigment has not been developed.

(3) the Use of different carbon sources

Various carbon sources added to the agar medium Pridham-Gottlieb (Pridham-Gottlieb)below shows the growth of strain after incubation at 28°within two weeks.

1) L-arabinose±
2) D-xylose±
3) D-glucose+
4) D-fructose+
5) sucrose+
6) Inositol+
7) L-rhamnose-
8) D-mannitol+
9) D-raffinose+

(+: positive, ±: slightly positive, -: negative)

(4) Physiological properties

Physiological properties of the strain are as shown below.

(a) the temperature Interval of cultivation (agar medium with yeast and malt extracts, incubation for 2 weeks): 12°-37°

(b) the Interval of optimum temperature (agar medium with yeast and malt extracts, incubation for 2 weeks): 21°-33°

(C) Liquefaction of gelatin (agar medium with glucose, peptone and VC is Tina): negative

(d) the Coagulation of milk (agar medium with separated milk): negative

(e) Peptonize milk agar medium with separated milk): negative

(f) Hydrolysis of starch (agar medium with inorganic salt and starch): positive

(g) Education melanoides pigment (agar medium with peptone, yeast extract and iron): negative,

(the tyrosine Wednesday): negative

(h) Production of hydrogen sulfide (agar medium with peptone, yeast extract and iron): negative

(i) a Decrease in the content of nitrate (broth containing 0.1% potassium nitrate): negative

(j) Tolerance to sodium chloride (agar medium with yeast and malt extracts, incubation for 2 weeks): grew up in the salt content of 4% or below

(5) Chemotaxonomy

Were found LL-diaminopimelic acid and glycine from the cell wall of this strain.

Based on the above characteristics of the microorganism believe that this strain is a strain of the genus Streptomyces. Therefore, the authors of the present invention called the microorganism strain as Streptomyces sp. Mer-11107 and deposited as FERM P-18144 in the National Institute of Bioscience and Human-Technology Agency of Industrial Science and Technology.

2. The method of fermentation of the microorganism-producer

Physiologically active compound 11107D of the present invention can b the th obtained by the inoculation of strain in a nutrient medium and implementation of an aerobic fermentation. The strain for the production of physiologically active substances 11107D is not limited to the strain mentioned above, and any strain belonging to the genus Streptomyces and capable of producing the 11107D substance, can be used in the present invention.

The method of fermentation of the above microorganism corresponds to the usual method of fermentation of the microorganism, but preferably it is carried out in aerobic conditions, such as culturing with shaking or fermentation with aeration and stirring using a liquid medium. The medium used for cultivation, may be a medium containing a power source that can be used by the microorganism belonging to the genus Streptomyces, therefore, may be used any of the environments, synthetic, semi-synthetic, organic, and the like. As a carbon source in the medium composition can be used alone or in combination with glucose, sucrose, fructose, glycerol, dextrin, starch, molasses, soybean oil and the like. As the source of nitrogen can be used alone or in combination with organic sources of nitrogen, such as pharmaceutical environment, peptone, meat extract, soybean powder, casein, amino acid, yeast extract and urea, and inorganic nitrogen sources such as nitrate is the atrium and ammonium sulfate. In addition, for example, can be added and used salts such as sodium chloride, potassium chloride, calcium carbonate, magnesium sulfate, sodium phosphate, potassium phosphate and cobalt chloride, salts of heavy metals, vitamins, such as vitamin b or Biotin, if necessary. And yet, when during cultivation becomes noticeable foaming, if necessary, can be added to the various defoamers. When adding antifoam you want to assign a concentration that have no adverse impact on the production of the target substance, it is desirable, for example, a concentration of 0.05% or lower.

The cultivation conditions can be appropriately selected in the range in which the microbial strain grows well and can produce the above substance. For example, pH is equal to about 5-9 and preferably close, usually neutral. The temperature of the fermentation is kept usually in the range of 20°S-40°C, preferably 28°-35°C. the fermentation Time is about 2-8 days, usually about 3-5 days. These fermentation conditions can be appropriately changed in accordance with the type and properties of the used microorganism, external conditions and the like, not to mention the fact that can be selected optimal mode. Physiologically active compound 11107D accumulated in the LM is some nutrient medium, may be collected by conventional methods of separation using its properties, such as the method of extraction solvent and method of absorption resin.

Physiologically active compound 11107D can also be obtained, for example, by a microorganism belonging to the genus Streptomyces (e.g., the strain Streptomyces sp. AB-1704 (FERM P-18999) and use of substances W (compound described in example A4, WO 02/060890), as shown in the reference examples 6-10.

3. Method of purification of biologically active substances

To collect 11107D from the culture medium after fermentation can be used General methods of separation and purification used for the selection of microbial metabolites from a liquid nutrient medium. For example, it fits into all the appropriate methods, such as extraction with an organic solvent, usually methanol, ethanol, butanol, ethyl acetate or chloroform; various kinds of ion-exchange chromatography; gel filtration chromatography using Sephadex LH-20; treatment by adsorption and desorption using absorption chromatography, usually using active carbon or silica gel, or thin-layer chromatography; or high performance liquid chromatography, typically using a reversed-phase column. In addition, methods of cleaning the 11107D substance osobne limited to the above methods.

Compound 11107D can be isolated and purified by the application of these methods separately or in combination, or multiple use.

Next, explain the formation of compounds of formula (I), other than 11107D.

The compounds of formula (I) can be synthesized from the isolated and purified compound 11107D as source material by conversion of the hydroxyl group and/or acetochlor of the compounds according to the General methods of organic synthesis. Typical examples of methods of synthesis are: A. obtaining a derived urethane, C. derivatization of thiourethane, C. derivatization simple ether, D. derivatization of ester, that is, obtaining the derived complex ester of phosphoric acid or of ester aminophosphonic acids, F. obtaining a derived complex ester of sulfuric acid or of ester amigorena acid, G. obtaining halogenated derivative, N. derivatization of ester sulfonic acid, I. derivatization Amin and J. getting oxopropanal oxidation of the hydroxyl group. Introduction or removal of the protective group for the hydroxy-group can be carried out, if necessary, by the method described in the material (Protective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons, Inc. 3rd Edition), or an equivalent method depending on the tee is a protective group and the stability of connections participating in a specific receipt. The compounds of formula (I) can be obtained by using reactions introduction and removal hydroxylamino group and the above-described receiving in a suitable combination. In particular, the compounds of formula (I)in which R3, R6, R7and R21represent the substituents listed above in paragraph 9), can be obtained by the method of deriving urethane, derived thiourethane derived complex ester amigorena acid or amine derivative; a compound of formula (1)in which R3, R6, R7and R21represent the substituents listed above in paragraph 2)to (5)can be obtained by a method of deriving a simple ester; compound of formula (1)in which R3, R6, R7and R21represent the substituents listed above in paragraph 6), can be obtained by the method of obtaining the derived complex ester; compound of formula (1)in which R3, R6, R7and R21represent the substituents listed above in paragraph 11)-13), can be obtained by the method of obtaining the derived complex ester of phosphoric acid or of ester aminophosphonic acid; the compound of formula (1)in which R3, R6, R7and R21represent the substituents listed to enter is in paragraph 10), can be obtained by the method of obtaining the derived complex ester of sulfuric acid or of ester sulfonic acid; the compound of formula (1)in which R3, R6, R7and R21represent the substituents listed above in paragraph 8), can be obtained by the method of obtaining halogenated derivative; a compound of formula (1)in which R3, R6, R7and R21represent the substituents listed above in paragraph 7), can be obtained by applying reactions introduction or removal hydroxylamino group; and oxoproline, in which R3, R6, R7and R21represent the substituents listed above in paragraph 1)may be obtained by the method of obtaining oxopropanal oxidation of the hydroxyl group.

Next, explain the methods of synthesis used to obtain the compounds of formula (I).

A. derivatization urethane

In the formulas, each of R3A, R6A, R16Aand R21Arepresents a hydrogen atom or a protective group, provided that R3A, R6A, R16Aand R21Ado not represent hydrogen atoms all at the same time; each of R3B, R6V, R16Band R21Brepresents a hydrogen atom, a protective gr is foam or group, represented by the formula, RFO-CO- (where RFrepresents an optionally substituted C6-14aryl group, provided that R3B, R6V, R16Band R21Bdo not represent hydrogen atoms all at the same time; each of R3S, R6S, R16Cand RSrepresents a hydrogen atom, a protective group or a group represented by the formula, RN1RN2N-CO- (where each of RN1and RN2represents a group as defined previously), and each of R3D, R6D, R16Dand R21Drepresents a hydrogen atom or a group represented by the formula, RN1RN2N-CO- (where each of RN1and RN2represents a group as defined earlier).

Stage A1 is the stage of obtaining the compounds of formula (IA). This phase of the conduct, protecting a hydroxyl group(s) of the compound 11107D.

The reaction of the hydroxyl protecting group or groups carried out according to methods well known in the chemistry of organic synthesis, chosen depending on the type of the protective group.

Examples of protective groups are 1-ethoxyethyl, tetrahydropyranyl, 1-methyl-l-methoxyethyl, l-(2-chloroethoxy)ethyl, 1-methoxycyclohexyl, 4-methoxyestradiol, 4-methoxycarbonylaminophenyl, S,S-dioxide, 4-methoxycarbonylaminophenyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl is l, trichloroacetyl, trimethylsilylmethyl, trimethylsilyloxy, tert-butyldimethylsilyl, triethylsilyl, diethylenediamine, trimethylsilyl, triisopropylsilyl, methyldi-tert-Boticelli, diphenylmethylsilane, benzyl, p-methoxybenzyl, p-methylbenzyl, p-nitrobenzyl, p-Chlorobenzyl and triphenylmethyl. All or part of the hydroxyl groups can be appropriately protected these protective groups.

For example, derivatives with hydroxyl groups, protected 1-amoxicilan, tetrahydropyranyl, 1-methoxycyclohexyl, 4-methoxycarbonylpropionyl, 4-methoxycarbonylaminophenyl or S,S-dioxide 4-methoxycarbonylaminophenyl, can be synthesized by treating compound 11107D corresponding simple vinyl ether, such as ethylenically ether or dihydropyran, in the presence of acid. Examples of the acid are the usual acids, including organic acids such as p-toluene sulfonate pyridinium (PPTS), p-toluensulfonate acid, camphorsulfonic acid, acetic acid, triperoxonane acid or methansulfonate acid, and inorganic acids such as hydrogen chloride, nitric acid, chloromethane acid or sulfuric acid. Which one is preferable example is p-toluene sulfonate pyridinium (PPTS), p-toluensulfonate acid or camphorsulfonic acid. R is storytell, used in the reaction is not particularly restricted, but is desirable inert solvent which does not easily interact with the source material. Examples of such solvents are ethers, such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; hydrocarbons such as hexane, benzene and toluene; ketones such as acetone and methyl ethyl ketone; NITRILES, such as acetonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyridone and hexamethylphosphoramide, and sulfoxidov, such as dimethylsulfoxide, of which a preferred example is dichloromethane, chloroform or tetrahydrofuran. The reaction time is from 10 minutes to 5 hours, preferably 1-2 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably equal to room temperature. The number of vinyl ether and acid used in the reaction is in relation to the compound 11107D 1-200 equivalents and 0.05 to 2 equivalents, and preferably 30-50 equivalents and 0.1 to 0.3 equivalent, respectively.

Examples of other protective groups are methoxymethyl, methylthiomethyl, methoxyethoxymethyl, trichloroacetyl, trimethyl shall ilililil, trimethylsilyloxy, tert-butyldimethylsilyl, triethylsilyl, trimethylsilyl, diethylenediamine, triisopropylsilyl, di-tert-butylmethylether, diphenylmethylsilane, benzyl, p-methoxybenzyl, p-methylbenzyl, p-nitrobenzyl, p-Chlorobenzyl and triphenylmethyl. Such derivatives with protected hydroxyl groups can be synthesized by the interaction of the source material with chloride, bromide or triftoratsetata appropriate protective groups in the presence of a base. The base is an organic base or inorganic base. Examples of organic bases are aromatic base such as imidazole, 4-(N,N-dimethylamino)pyridine (4-dimethylaminopyridine, N,N-dimethylaminopyridine and dimethylaminopyridine mean the same thing), pyridine, 2,6-lutidine or kallidin; tertiary amine such as N-methylpiperidine, N-methylpyrrolidine, triethylamine, trimethylamine, diisopropylethylamine, cyclohexyldimethylamine, N-methylmorpholine or 1,8-bis(dimethylamino)naphthalene; secondary amine such as diisobutylamine or dicyclohexylamine; acility, such as motility or utility; a metal alkoxide, such as sodium methoxide or ethoxide sodium. Examples of inorganic bases are alkali metal hydride such as sodium hydride or potassium hydride; hydride, Melo rosemaling metal, such as calcium hydride; alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; a carbonate of an alkali metal such as sodium carbonate, potassium carbonate or cesium carbonate, and bicarbonate of an alkali metal such as sodium bicarbonate. Preferred examples of the base to protect the hydroxyl group of the silyl protecting group is an aromatic base such as imidazole or 4-dimethylaminopyridine, and tertiary amine, such as triethylamine. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples of such solvents are the above-described inert solvents, of which a preferred example is tetrahydrofuran, dichloromethane or N,N-dimethylformamide. The reaction time is from 10 minutes to 3 hours, preferably 1-2 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C. the Number of chloride, bromide or triftoratsetata and base used in the reaction is in relation to the compound 11107D 1-20 equivalents and 0.5 to 30 equivalents, preferably 1 to 15 equivalents and 0.5 to 20 equivalents, respectively.

The hydroxyl group of compound 11107D can be the ü selectively protected by the choice of the reagent and its equivalence used to protect hydroxyl groups. For example, a connection that selectively protect the hydroxyl group at position 3 and position 21 can be obtained by conducting the reaction at room temperature using chlorotriethylsilane, triethylamine and 4-dimethylaminopyridine in dichloromethane or tert-butylcholinesterase and imidazole in N,N-dimethylformamide. According to this method, for example, the hydroxyl group at position 3 can be selectively protected by regulation IFF chlorotriethylsilane or tert-butylcholinesterase. In addition, you can protect two or three of the four hydroxyl groups, silyl group, and then the other two or one hydroxyl group to protect the above amoxicillon or the like.

Stage A2 is the stage of obtaining the compounds of formula (IIA). This stage is performed by turning acetochlor the compounds of formula (IA) in the hydroxyl group processing base in an inert solvent.

Examples of the base used at this stage are inorganic bases including alkali metal hydride such as sodium hydride or potassium hydride; alkaline earth hydride metal, such as calcium hydride; alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali carbonate is about metal, such as lithium carbonate, sodium carbonate or potassium carbonate, a bicarbonate of an alkali metal such as sodium bicarbonate, and a metal alkoxide such as lithium methoxide, sodium methoxide, ethoxide or sodium tert-piperonyl potassium, and such grounds as guanidine or ammonia. Preferred examples of the base include potassium carbonate and guanidine.

Examples of the inert solvent used in the reaction include, in addition to the above solvents, alcohol solvents such as methanol, ethanol, isopropanol or tert-butanol, and water. These solvents may be used in combination as a mixture. The preferred solvent is an alcoholic solvent or mixture of alcohol and halogenated solvent. The reaction time is from 10 minutes to 5 hours, preferably from 30 minutes to 1 day. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably equal to room temperature. The amount of base used in the reaction, relative to the compound of formula (IA) is 1 to 10 equivalents, and preferably 2-5 equivalents.

Stage A3 is the stage of obtaining the compounds of formula (IIIA). This stage is realized by the processing of the hydroxyl group of the compounds of formula (IIA) derived chloroformiate or carbonylation what azolam in the presence of a base. Examples of the derived chloroformiate are 4-nitrophenylphosphate, vanillaroma, 4-chlorophenylalanine, 4-brompheniramine and 2,4-dinitrophenolate. Examples of the base are the aforementioned organic bases and inorganic bases, of which preferably use, for example, diisopropylethylamine, 4-dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples of such solvents are the above-described inert solvents, which are preferably used, for example, tetrahydrofuran, dichloromethane or N,N-dimethylformamide. The number derived chloroformate and base used in the reaction, relative to the compound of formula (IIA) is 1-10 equivalents and 1-20 equivalents, preferably 1-5 equivalents and 1 to 10 equivalents, respectively. The reaction time is from 10 minutes to 30 hours, preferably 1-4 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

As for the hydroxyl of compound (IA)in which one to three of the groups OR3A, OR6A, OR16Aand OR21Awas not the protected stage A1, the hydroxyl group can be converted into ester groups of carbonic acid at the stage A3. In particular, the hydroxyl group of compound (IA), other than a hydroxyl group at position 7 can be converted into ester groups of carbonic acid as a hydroxyl group in position 7, the processing of base and derived chloroformiate equivalents, corresponding to the number of hydroxyl groups into ester groups of carbonic acid.

Stage A4 stage is obtaining the compounds of formula (IVA). This stage is performed by treatment of ester of carbonic acid of the formula (IIIA) with the amine (RN1RN2H), which can form the desired compound of formula (I) in an inert solvent in the presence of a base or only one amine.

Examples of the amine used at this stage are methylamine, ethylamine, Propylamine, butylamine, octylamine, decylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, dimethylamine, diethylamine, ethylmethylamine, Ethylenediamine, 1,3-propandiamine, 1,4-butanediamine, N,N-dimethylethylenediamine, N,N-dimethyl-1,3-propandiamine, N,N-dimethyl-1,4-butanediamine, N,N-diethylethylenediamine, N,N-diethyl-1,3-propandiamine, N,N-diethyl-1,4-butanediamine, N,N,N'trimethylethylenediamine, N,N,N'-trimethyl-1,3-propandiamine, N,N,N'-trimethyl-1,4-butanediamine, N-ethyl-N',N'-dimethylethylene the min, N-ethyl-N',N'-dimethyl-1,3-propandiamine, N-ethyl-N',N'-dimethyl-1,4-butanediamine, N,N,N'-triethylammonium, N,N,N'-triethyl-1,3-propandiamine, N,N,N'-triethyl-1,4-butanediamine, N,N-diethyl-N'-methylethylenediamine, N,N-diethyl-N'-methyl-1,3-propandiamine, N,N-diethyl-N'-methyl-1,4-butanediamine, N,N'-dimethyl-N-phenylethylenediamine, N,N'-dimethyl-N-phenyl-1,3-propandiamine, N-benzyl-N,N'-dimethylethylenediamine, N-benzyl-N,N'-dimethyl-1,3-propandiamine, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, pyrrolidine, piperidine, piperazine, homopiperazine, 4-hydroxypiperidine, 4-methoxypiperidine, 1-methylpiperazine, 1-ethylpiperazine, 1-propylpiperazine, 1-butylpiperazine, 1-isopropylpiperazine, 1-cyclobutylmethyl, 1-cyclopentylpropionyl, 1-cyclohexylpiperazine, 1-cycloheptylmethyl, 1-cyclooctylmethyl, 1-(cyclopropylmethyl)piperazine, 1-benzylpiperazine, 1-methylhomopiperazine, 1-acylhomoserine, 1-(2-amino-ethyl)pyrrolidine, 1-(2-(N-methylamino)ethyl)pyrrolidin), 1-(3-aminopropyl)pyrrolidine, 1-(3-(N-methylamino)propyl)pyrrolidin), 1-(2-amino-ethyl)piperidine, 1-(2-(N-methylamino)ethyl)piperidine), 1-(3-aminopropyl)piperidine, 1-(3-(N-methylamino)propyl)piperidine), 4-(2-amino-ethyl)morpholine, 4-(2-(methylamino)ethyl)morpholine), 4-(3-aminopropyl)morpholine, 4-(3-(N-methylamino)propyl)morpholine), 1-(2-aminoethyl)-4-methylpiperazine, 1-(3-aminopropyl)-4-methylpiperazine, 1-(3-(N-methylamino)propyl)-4-methylpiperazine, 1-amino-4-methylpiperid the Dean, 1-methylamino-4-methylpiperidine, 1-ethyl-4-(N-methylamino)piperidine, 1-methylamino-4-propylpiperidine, 1-butyl-4-(N-methylamino)piperidine, 1-(N,N-dimethylamino)piperidine, 1-(N,N-diethylamino)piperidine, 4-(pyrrolidin-1-yl)piperidine, 4-(piperidine-1-yl)piperidine, 3-aminoquinuclidine, 3-(N-methylamino)Hinkley, aniline, N-methylaniline, N,N-dimethyl-p-phenylenediamine, N,N-dimethyl-m-phenylenediamine, N,N,N'-trimethyl-p-phenylenediamine, N,N,N'-trimethyl-m-phenylenediamine, 1-naphtylamine, 2-naphtylamine, benzylamine, N-methylbenzylamine, phenethylamine, N-methylpentylamino, 2-picolylamine, 3-picolylamine, 4-picolylamine, N-methyl-2-picolylamine, N-methyl-3-picolylamine, N-methyl-4-picolylamine, 2,5-diazabicyclo[2.2.1]heptane, 2-methyl-2,5-diazabicyclo[2.2.1]heptane, 3,8-diazabicyclo[3.2.1]octane and 1,4-diazabicyclo[4.3.0]nonan.

Examples of the base are the aforementioned organic bases and inorganic bases, of which preferably use, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples of such solvents are the above-described inert solvents, which are preferably used, for example, tetrahydrofuran, dichloromethane or N,N-dimethylformamide. Number is the number of amine and base, used in the reaction, relative to the compound of formula (IIIA) is 1-10 equivalents and 2 to 20 equivalents, preferably 1.5 to 5 equivalents and 2 to 10 equivalents, respectively. The reaction time is from 10 minutes to 30 hours, preferably 1-2 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

The compound of formula (IVA) can be obtained by treating compounds of formula (IIA) with the isocyanate in an inert solvent in the presence of a base and/or chloride of copper(1). The isocyanate is not particularly limited and includes, for example, utilitzant, methyl isocyanate and phenylisocyanate. Examples of the base are the aforementioned organic bases and inorganic bases, of which preferably use, for example diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples of such solvents are the above-described inert solvents, which are preferably used, for example, tetrahydrofuran, dichloromethane or N,N-dimethylformamide. The number of bases and isocyanate used in the reaction, attributed the Yu to the compound of formula (IIIA) is 3 to 100 equivalents and 1 to 20 equivalents, preferably 5-20 equivalents and 3-10 equivalents, respectively. In the case of chloride of copper(1) amount equal to 1-10 equivalents, preferably 2 to 6 equivalents. The reaction time is from 10 minutes to 30 hours, preferably 1-2 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

Hydroxyl compound in which one to three of the groups OR3A, OR6A, OR16Aand OR21Awere not protected at stage A1, can be converted into a derivative containing multiple urethane structures, by transformation of these hydroxyl groups to ester groups of carbonic acid at the stage A3 and then turning them into carbamoyloximes on stage A4.

Stage A5 is the stage of obtaining the compounds of formula (VA). This phase of the exercise, exposing derived urethane of the formula (IVA) described below, the processing for removing protection in an inert solvent. The reaction of removing the protective groups of hydroxyl groups varies depending on the type of protective group, but is carried out by a method well known in the chemistry of organic synthesis.

With regard to the corresponding hydroxyl group protected, for example, 1-amoxicilan, tetrahydropyranyl, 1-methoxycyclohexyl, 4-methoxyestradiol what piranian, 4-methoxycarbonylaminophenyl or 4-methoxycarbonylaminophenyl-S,S-dioxide, the reaction of removing the protection can be easily carried out by treatment with an acid in an inert solvent. Examples of acids are above organic acids and inorganic acids, of which preferred is, for example, p-toluensulfonate pyridinium, n-toluensulfonate acid or camphorsulfonic acid. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily interact with the source material. Preferred examples are alcohol solvent such as methanol, ethanol, isopropanol or tert-butanol, or a mixture of alcohol and the above inert solvent. The amount of acid used in the reaction, relative to the compound of formula (IVA) is 0.5-5 equivalents, preferably 1-3 equivalents. The reaction time is from 10 minutes to 10 hours, preferably 1-4 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

When a hydroxyl group protected by other protective group such as tert-butyldimethylsilyl, triethylsilyl, diethylenediamine, trimethylsilyl, triisopropylsilyl, di-tert-butylmethylether or the WPPT is ylmethylene, protection may be removed by treatment with Floridiana or acid. Examples of Floridiana are tetrabutylammonium, hydrogen fluoride, potassium fluoride and perevoditelis. Examples of acids are above organic acids and inorganic acids, of which a preferred example is acetic acid, formic acid, triperoxonane acid, p-toluensulfonate pyridinium or camphorsulfonic acid. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples of it include the abovementioned inert solvents, which are preferably used, for example, tetrahydrofuran, diethyl ether or water. The amount of fluoride anion and the acid used in the reaction, relative to the compound of formula (IVA) is 1-5 equivalents and 0.5 to 5 equivalents, preferably 1-4 equivalents and 0.5 to 3 equivalents, respectively. The reaction time is from 10 minutes to 30 hours, preferably 1-2 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

The combination of different methods of protection of hydroxyl groups as described in stage A1, and the different ways of protecting described on the stage A5 corresponding hydroxyl group in position 3, position 6 and position 21 can be selectively converted into derivatives of urethane. For example, the derived urethane containing a hydroxyl group in position 6 can be synthesized by exposure of the hydroxyl group in position 6 of the compound (IA)in which R3A, R16Aand R21Aare triethylsilyl group, the reactions at the stage A3 stage A4 stage A5, respectively.

Selective modification of the hydroxyl group in position 3, position 6 or position 21 is implemented by a combination of techniques to protect and unprotect, can also be applied to other methods of modification are described below.

C. derivatization of thiourethane

In the formulas, each of R3A, R6A, R16Aand R21Arepresents the same group as previously defined; each of R3E, R6TH, REand RErepresents a hydrogen atom, a protective group or a group represented by the formula, RN1RN2N-CS- (where each of RN1and RN2represents the same group as defined earlier), provided that R3E, R6TH, REand REdo not represent hydrogen atoms all at the same time; and each of R3F, R6F, R16Fand R21Frepresents a hydrogen atom or the group represented the military formula, R N1RN2N-CS- (where each of RN1and RN2represents the same group as defined earlier).

Stage B1 is the stage of obtaining the compounds of formula (IB) using thioisocyanate or thiocarbanilide instead of the isocyanate. This stage is carried out by treating compound of formula (IIA) isothiocyanato or thiocarbamoylation in an inert solvent in the presence of a base or bis(tributylamine)oxide. Isothiocyanate used in this reaction is not particularly limited and includes, for example, ethylisothiocyanate, methylisothiocyanate, phenylisothiocyanate, benzylisothiocyanate, allylisothiocyanate, 2-(N,N-dimethylamino)ethylisothiocyanate, 2-(N,N-diethylamino)ethylisothiocyanate, 3-(N,N-dimethylamino)propalestinian, 3-(N,N-diethylamino)propalestinian, 2-(morpholine-4-yl)ethylisothiocyanate, 2-(piperidine-1-yl)ethylisothiocyanate and 2-(pyrrolidin-1-Il)ethylisothiocyanate. Thiocarbamoylation used in this reaction is not particularly limited and includes, for example, N,N-dimethylthiocarbamate, N-phenyl-N-methylthiocarbamate, (morpholine-4-yl)thiocarbamoyl, (4-methylpiperazin-1-yl)thiocarbamoyl and (4-methylhomopiperazine-1-yl)thiocarbamoyl. Examples of the base are the aforementioned organic bases and inorganic bases, of which preferably are used, e.g. the, diisopropylethylamine, 4-dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples of such solvents are the above-described inert solvents, which are preferably used, for example, tetrahydrofuran, dichloromethane, N,N-dimethylformamide or toluene. The amount of base or bis(tributylamine)oxide and isothiocyanate or thiocarbanilide in relation to the compound of formula (IIA) is 1-5 equivalents and 1-10 equivalents, preferably 1-3 equivalents and 2 to 5 equivalents, respectively. The reaction time is from 10 minutes to 72 hours, preferably 1-24 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 70°C.

The compound of formula (IB)containing several thiocarbamoyl groups can be synthesized by conversion of the hydroxyl group or groups of the compounds represented by formula (IIA), where one to three of OR3A, OR6A, OR16Aand OR21Anot protected, in thiocarbamoylation(s) at stage B1.

Derived thiourethane formula (IIB) can be synthesized by removing the protective group of hydroxyl group in the accordance with the stage A5.

C. derivatization simple ether

In the formulas, each of R3G, R6G, R16Gand R21Grepresents a hydrogen atom or a protective group, provided that R3G, R6G, R16Gand R21Gdo not represent hydrogen atoms all at the same time and at least one of them represents a hydrogen atom and each of R3H, R6N, RNand RNrepresents a protective group, or optionally substituted C1-22alkyl group.

Stage C1 is the stage of synthesizing the compounds of formula (IC). This stage is carried out in the same manner as the reaction stage A1 receipt And, except for the fact that it is necessary to protect one or three hydroxyl groups.

In accordance with another option at this stage of the connection, which is in position 3, position 6 or position 21 is a hydroxyl group and the other hydroxyl group is protected, can be synthesized by the combination of different ways of protecting the hydroxyl group of the corresponding stage A1, and how to unprotect a protected hydroxyl group corresponding to the stage A5 is received.

Stage C2 is the stage of synthesizing the compounds of formula (IIC). This stage is carried out by alkylation of the unprotected hydroxyl group or groups connected to the I (IC).

The alkylation can be carried out by treatment with alkylating agent of formula Rm-X in the presence of a base. Deputy Rmrepresents a C1-22alkyl group which may have substituents, and includes, for example, methyl group, ethyl group and benzyl group. X represents a group to delete. Examples of the deleted group are chromium, bromine, iodine and trifloromethyl group. Examples of the base are above organic and inorganic bases, of which preferred examples are sodium hydride, bis(trimethylsilyl)amide lithium, diisopropylamide lithium, dicyclohexylamine lithium, potassium carbonate, cesium carbonate and 1,8-bis(N,N-dimethylamino)naphthalene. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples are the above-described inert solvents, which are preferably used, for example, diethyl ether, tetrahydrofuran, dimethoxyethane or toluene. The amount of alkylating agent and base used in the reaction, relative to the compound of formula (IC) is 3-20 equivalents and 5 to 30 equivalents, preferably 3 to 5 equivalents and 5-10 equivalents, respectively. The reaction time is from 10 minutes to 48 hours, predpochtitelno 1-24 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 70°C.

In the formulas, each of R3J, R6J, R16Jand R21Jrepresents an alkyl group or a protective group, each of R3K, R6K, R16Kand R21Krepresents an alkyl group or a hydrogen atom and R7Krepresents karbamoilnuyu group or thiocarbamoyl group, each of which may contain substituents at the nitrogen atom.

If required, a derivative containing karbamoilnuyu group entered into a hydroxyl group in position 7, and the alkyl group introduced into one or two hydroxyl group in position 3, position 6 and position 21 can be obtained by further exposure to the compounds of formula (IIC) reactions stages A2, A3, A4 and A5.

In accordance with another variant, derivative, containing thiocarbamoyl group entered into a hydroxyl group in position 7, and the alkyl group introduced into one or two hydroxyl group in position 3, position 6 and position 21 can be obtained by exposure to the compounds of formula (IIIC) reaction stage B1 and then the reaction stage A5.

In the formulas, each of R3A , R6A, R16Aand R21Arepresents the same group as defined previously, and each of R3L, R6L, R7LR16Land R21Lrepresents a hydrogen atom or alkyl group.

Derived simple ether represented by the formula (IIC'), where the hydroxyl group in position 7 is alkylated, can be obtained by exposure to the compounds of formula (IIA) reaction stage C2 and then the reaction stage A5 manner similar to that described above.

In addition, the corresponding derived simple ester can be obtained by using an alkylating agent with unsaturated alkyl, kalkiliya agent or heteroarylboronic agent instead of an alkylating agent that will give the desired compound of formula (I).

D. Obtaining a derived complex ester

In the formulas, each of R3G, R6G, R16Gand R21Grepresents the same group as defined previously, and each of R3M, R6M, R16and R21represents a hydrogen atom, a protective group or a group represented by the formula, RCOCO- (where RCOrepresents a hydrogen atom, optionally substituted C1-22alkyl group, optionally substituted With unsaturated2-22alkyl group, optionally substituted C6-14Ari is inuu group, optionally substituted 5 to 14-membered heteroaryl group, optionally substituted C7-22aracelio group or optionally substituted 5 to 14-membered heteroaryl group), provided that R3M, R6M, R16Mand R21Mdo not represent hydrogen atoms at the same time.

Stage D1 is the stage of transformation of an unprotected hydroxyl group in the ester group using the compounds of formula (IC), synthesized at the stage of CI, as the source material.

The etherification is carried out, for example, using the anhydride of the acid-base galogenangidridy with the base of the carboxylic acid with a condensing agent, or by conducting the reaction Mitsunobu (Mitsunobu). As the acid anhydride used various anhydrides of carboxylic acids. Examples are mixed anhydride containing, for example, acetic acid, propionic acid, butyric acid, valeric acid and benzoic acid; symmetrical anhydride; cyclic anhydride, such as succinoyl anhydride, glutaric anhydride or adipic anhydride. Preferred examples are acetic anhydride, propionic anhydride, butyric anhydride and benzoic anhydride. As gelegenheid use, for example, various acid chlorides and bromohydrin, of which predpochtitelnei is acetylchloride, propionate, benzoyl chloride or benzylbromide. Examples of the base are above organic and inorganic bases, of which a preferred example is imidazole, 4-dimethylaminopyridine, pyridine or sodium hydride. As the carboxylic acid using various carboxylic acids, of which a preferred example is acetic acid or propionic acid. Preferred examples of the condensing agent are, for example, dicyclohexylcarbodiimide, triperoxonane anhydride, carbonyldiimidazole, N,N-diisopropylcarbodiimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. In the reaction of Mitsunobu various carboxylic acids can be substituted in the presence of triphenylphosphine and diethylazodicarboxylate or diisopropylcarbodiimide. The solvent used in each of the reactions is not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples are the above-described inert solvents, which are preferably used, for example, dichloromethane, chloroform or tetrahydrofuran. The number of acid anhydride with a base, gelegenheid with the base and the carboxylic acid with a condensing agent relative to the compound of formula (IC) is equal to 1-10 equivalents with 3-20 equivalents is, 1-10 equivalents with 3-20 equivalents and 1 to 20 equivalents with 1-20 equivalents, preferably 1-5 equivalents with 2-10 equivalents, 1-5 equivalents with 2-10 equivalents and 1-5 equivalents of 1 to 5 equivalents, respectively. The reaction can be, when needed, accelerated by adding 0.2 to 2 equivalents of 4-dimethylaminopyridine. The reaction time is from 10 minutes to 30 hours, preferably 1-2 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

The compound of formula (ID) can be obtained by exposure synthesized in the manner described above ester derivative of the reaction, similar to that performed on stage A5 to remove the protective group of hydroxyl group.

You can also atrificial one to four hydroxyl groups, carrying out the esterification in a manner similar at the stage D1, using compound 11107D as source material.

In the formulas, each of R3A, R6A, R16Aand R21Arepresents the same group as defined previously, and each of R3N, R6N, R7NR16Nand R21Nrepresents a hydrogen atom or a group represented by the formula, RCOCO- (where RCOis the th same group, as defined earlier).

Derived complex ester represented by the formula (ID'), where the hydroxyl group in position 7 etherification, can be synthesized by exposure to the compounds of formula (IIA) reaction stage D1 and then the reaction stage A5 manner similar to that described above.

E. Obtaining a derived complex ester of phosphoric acid or of ester aminophosphonic acid

In the formulas, each of R3A, R6A, R16Aand R21Arepresents the same group as defined previously, each of R3, R6, RR16Rand R21Rrepresents a hydrogen atom, a group represented by the formula (RN3O)2PO, formula (RN1RN2N)2PO - or the formula (RN1RN2N)(RN3O)PO (where each of RN1, RN2and RN3represents the same group as defined above).

Stage E1 is the stage of transformation of the hydroxyl group of the compounds of formula (IIA) as a starting material in an ester of phosphoric acid or ester aminophosphonic acid.

The esterification of phosphoric acid is carried out, for example, using phosphorylcholine and base. You can use different phosphorylchloride, examples of which are dialkoxybenzene, diphenylacetonitrile arid, alkoxy(N,N-disubstituted amino)phosphorylchloride, allyloxy(N,N-disubstituted amino)phosphorylchloride, alkoxy(N-substituted amino)phosphorylchloride, allyloxy(N-substituted amino)phosphorylchloride. Examples of the base are above organic and inorganic bases, of which preferred examples are pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiethanolamine, sodium hydride, n-utility, potassium carbonate or sodium carbonate. The solvent used in each of the reactions is not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples are the above-described inert solvents, which are preferably used, for example, dichloromethane, chloroform, tetrahydrofuran or N,N-dimethylformamide. The reaction time is from 10 minutes to 72 hours, preferably 1-24 hours. The number of phosphorylchloride and base used in the reaction, relative to the compound of formula (IIA) is 1-10 equivalents and 2 to 20 equivalents, preferably 1-5 equivalents and 2 to 10 equivalents, respectively. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

The compound of formula (IE) can be obtained by exposure synthesized as described in the above way derived complex ester of phosphoric acid reaction, similar to that performed on stage A5 to remove the protective group of hydroxyl group.

You can also convert one to four hydroxyl groups in the esters of phosphoric acid by esterification of phosphoric acid compound 11107D as source material in a manner similar at the stage E1.

F. Obtaining a derived complex ester of sulfuric acid or of ester amigorena acid

In the formulas, each of R3A, R6A, R16Aand R21Arepresents the same group as defined previously, and each of R3Q, R7Q, R6Q, R16Qand R21Qrepresents a hydrogen atom or a group represented by the formula, RN1RN2N-SO2or the formula, RN3Oh-SO2(where each of RN1, RN2and RN3represents the same group as defined above).

The F1 stage is the stage of transformation of the hydroxyl group of the compounds of formula (IIA) as a starting material in an ester of sulphuric acid.

The esterification with sulfuric acid is carried out, for example, using sulfonylmethane and base. You can use different sulphonylchloride, examples of which are alkoxysilylated and N,N-disubstituted sulfhemoglobin. Examples of the base are specified in the above organic and inorganic bases, of which preferred examples are pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiethanolamine, sodium hydride, n-utility, potassium carbonate or sodium carbonate. The solvent used in each of the reactions is not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples are the above-described inert solvents, which are preferably used, for example, dichloromethane, chloroform, tetrahydrofuran or N,N-dimethylformamide. The number of sulphonylchloride and base used in the reaction, relative to the compound of formula (IIA) is 1-10 equivalents and 2 to 20 equivalents, preferably 1-5 equivalents and 2 to 10 equivalents, respectively. The reaction time is from 10 minutes to 72 hours, preferably 1-24 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

The compound of formula (IF) can be synthesized by exposure synthesized in the manner described above derived complex ester of sulfuric acid reaction, similar to that performed on stage A5 to remove hydroxylamino group.

You can also convert one to four hydroxyl groups in the esters of sulfuric acid, subjecting connected to the e 11107D as source material esterification with sulfuric acid to obtain ether sulfuric acid method, like at the stage F1.

G. Obtaining halogenated derivative

In the formulas, each of R3A, R6A, R16Aand R21Arepresents the same group as defined previously, each of R3R, R6R, R16Rand R21Rrepresents a hydroxyl group or a halogen atom.

Stage G1 is the stage of transformation of the hydroxyl group of the compounds of formula (IA) as a starting material in a halogen.

Halogenoalkane carried out, for example, processing diethylaminoacetate (DAST) or triphenylphosphine with tetrabromide carbon, bromine, tribromide phosphorus, iodine or carbon tetrachloride in the presence of a base. The base used in this reaction includes, for example, organic and inorganic bases, such as diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in each of the reactions is not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples are tetrahydrofuran, dichloromethane and N,N-dimethylformamide. Preferred is the fluoridation of diethylaminoacetate. The number of diethylaminoacetate (DAST) in relation to the compound of formula (IIA) RA is but 1-5 equivalents, preferably 1-3 equivalents. The reaction time is from 10 minutes to 10 hours. The reaction temperature ranges from -78°C to room temperature.

The compound of formula (IG) can be synthesized by exposure synthesized in the manner described above halogenated derivative procedure stage A5, to thereby remove the protective group of hydroxyl group.

N. Derivatization of ester sulfonic acid

In the formulas, each of R3A, R6A, R16Aand R21Arepresents the same group as defined previously, and each of R3S, R6S, R7S, R16Sand R21Srepresents a hydrogen atom or a group represented by the formula, RN3SO2- (where RN3represents the same group as defined earlier).

Stage N1 is the stage of sulfonylurea hydroxyl group of compounds of formula (IIA) as the starting material.

Sulfonylamine can be carried out, for example, by treatment with sulphonylchloride, such as p-toluensulfonate, methanesulfonate or benzosulphochloride, in the presence of a base. Examples of bases are, for example, organic and inorganic bases, such as diisopropylethylamine, dimethylaminopyridine, Tr is ethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in each of the reactions is not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples are tetrahydrofuran, dichloromethane and N,N-dimethylformamide. The number of sulphonylchloride and base used in the reaction, relative to the compound of formula (IIA) is 1-5 equivalents and 2 to 10 equivalents, preferably 1-3 equivalents and 2 to 6 equivalents, respectively. The reaction time is from 10 minutes to 30 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux.

Derivative represented by the formula (IH)in which sulfonylamino hydroxyl group in position 7, can be synthesized by exposure synthesized in the manner described above derived complex ester sulfonic acid reaction stage A5 to remove the protective group of hydroxyl group.

Can also be sulfonylamino compound 11107D as source material by the method similar to that described in stage N1 to sulfonylurea one to four hydroxyl groups.

I. derivatization Amin

In the formulas, each of R3A, R6A, R16Aand R21Arepresents the same group, ka is a previously defined, and each of R3T, R6T, R7T, R16Tand R21Trepresents a hydroxyl group or a group of the formula RN1RN2N- (where each of RN1and RN2represents the same group as defined above).

Stage I1 is the stage of transformation of the hydroxyl group of the compounds of formula (IIA) directly in the amine or in the right of the deleted group, then in azide and then by Amin recovery.

When the hydroxyl group is transformed into azide, examples of reagents used in the reaction are 1) diphenylphosphinite (DPPA), diethylazodicarboxylate and triphenylphosphine, 2) DPPA and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 3) hydrogen azide, diethylazodicarboxylate and triphenylphosphine, 4) DPPA, tetramethyldisiloxane (TMAD) and tributylphosphine and 5) sodium azide in the presence of a base. Examples of the base are above organic and inorganic bases, of which preferably use, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride. Specified hydroxyl group can also be converted into azide by treatment with sodium azide in the presence of palladium catalyst. An example of the catalyst is Pd(PPh3)4. The solvent used in the reaction are not particularly limited, but preferable solvent which cannot easily interact with the source material. Examples are tetrahydrofuran, dichloromethane, N,N-dimethylformamide, toluene and benzene. The reaction time is from 10 minutes to 30 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux.

The restoration of the azide to the amine can be carried out using, for example, triphenylphosphine or sociallyengaged. Azide can also be restored to the amine, for example, by using a catalyst such as palladium on carbon or Lindlar catalyst in hydrogen atmosphere. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples are tetrahydrofuran, diethyl ether and ethanol. The reaction time is from 10 minutes to 30 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux.

The transformation of the hydroxyl group at the right of the deleted group can be carried out by the method similar to that described in stage G1 (halogenoalkane) or at the stage N1 (sulfonylurea). Examples of suitable groups are removed chromium, bromine, iodine, methansulfonate group and p-toluensulfonyl group. In addition, the processing of the converted compounds containing a group to delete, Amin is m in an inert solvent in the presence of a base it is possible to synthesize the compound, in which the hydroxyl group is converted into the amino group or substituted in the amino group.

Examples of the amine used in the reaction, are methylamine, ethylamine, dimethylamine and diethylamine. Examples of the base are above organic and inorganic bases, of which preferably use, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily interact with the source material. Examples of it include the abovementioned inert solvents, which are preferably used, for example, tetrahydrofuran, dichloromethane or N,N-dimethylformamide. The reaction time is from 10 minutes to 30 hours, preferably 1-2 hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux, preferably from -10°C to 50°C.

The compound of formula (II) can be obtained by exposure synthesized in the manner described above amine derivative of the reaction of removing the protective group of hydroxyl group, such as those described in stage A5. You can turn one or two of the hydroxyl group of compound 11107D as source material in the amino group in a manner similar to op the sledge on stage I1.

The compound of formula (I) can also be obtained by alkylation, acylation, carbamoylethyl or sulfonylamine amino group of compounds of formula (II) by methods well known in the chemistry of organic synthesis, and methods described above.

J. Obtaining exocoetidae (oxidation of hydroxyl group)

In formulas or one of R3Jaand R3Jbrepresents a hydroxyl group and the other represents a hydrogen atom, or R3Jaand R3Jbtogether with the carbon atom to which R3Jaand R3Jbattached, represent oxoprop, or one of R21Jaand R21Jbrepresents a hydroxyl group and the other represents a hydrogen atom, or R21Jaand R21Jbtogether with the carbon atom to which R21Jaand R21Jbattached, represent oxoprop.

Stage J1 is the stage of synthesizing exocoetidae represented by the formula (IIJ), oxidation of the hydroxyl group of compound 11107D as source material.

Examples of the oxidizing agent used at this stage are manganese dioxide, chlorproma pyridinium, pyridinium dichromate, reagent dessa-Martin and reagents used in the oxidation will Roll. The solvent used in the reaction is not particularly restricted, but is desirable races is veritel, which cannot easily interact with the source material. Examples are tetrahydrofuran, dichloromethane, chloroform, and toluene. The reaction temperature ranges from -78°C to the boiling temperature under reflux. The reaction time is from 10 minutes to 78 hours. Among these reactions, it is preferable, for example, a reaction using a reagent dessa-Martin, manganese dioxide or reagents used in the oxidation will Roll, of which more preferred is a reaction using a reagent dessa-Martin. As a solvent for oxidation using reagent dessa-Martin usually preferred is dichloromethane or chloroform. The amount of oxidizing agent used in the reaction, relative to the specified connection (11107D) is 1-20 equivalents, preferably 1-5 equivalents. The reaction temperature is in the range from 0°C to room temperature. The reaction time is from 30 minutes to 24 hours, preferably 1-8 hours.

The compound in which a hydroxyl group in position 3 or position 21 of these derivatives are converted into exoframe, can be synthesized by exposure instead of 11107D, for example, urethane derivative, tourmanova derivative, ester derivative or alkyl derivatives, polucen the th earlier in the ways described, procedure stage J1. In addition, oxidation of the hydroxyl group in position 7 of the compound represented by formula (IIA)can be obtained 7-exocoetidae.

And yet, the hydroxyl group in position 3, position 7 and/or position 21 can be selectively converted into exoframe different combinations of reaction conditions protect and unprotect on stage A1 stage and A5 with the procedure stage J1. In addition, the connection that contains exoframe, and urethane, touracademy, ester or alkyl fragment, can be respectively obtained by the synthesis of compounds previously turned into exoframe, the methods described above in connection with obtaining a urethane derivative, tourmanova derivative, ester derivative or alkyl derivatives.

Compounds represented by formula (I)can be synthesized by an appropriate combination reactions A-J and reactions of protection and exemption from protection of the hydroxyl group.

Upon completion of the reaction, the target product of the corresponding reaction is recovered from the reaction mixture by conventional methods. For example, the target compound can be isolated by filtration if there insoluble material, and evaporating the solvent or by dilution of the reaction mixture with an organic solvent such as ethyl acetate, washing the organic slavedog, drying over anhydrous magnesium sulfate and evaporation of the solvent. The connection, if necessary, can then be purified by the conventional method, such as column chromatography, thin layer chromatography or high performance liquid chromatography.

To illustrate the usefulness of the present invention is defined, in particular, generally hopeless activity against VEGF transcription, inhibitory activity against the growth of human cells WiDr colon cancer, inhibitory activity against the growth solenoi malignant tumor, weight loss (acute toxicity) and stability in aqueous solution representative compounds of the compounds of formula (I) according to the present invention.

Example 1 tests. Construction of reporter system for screening compounds inhibiting the transcription of VEGF

To get a reporter system reflecting the transcription from the VEGF promoter, cloned sequence of the VEGF promoter and inserted it into the vector secretory alkaline phosphatase (PLAR) to construct reporter vector.

To obtain the promoter region of the human VEGF cloned from a library of phage VEGF genomic DNA. On the basis of the VEGF cDNA (GenBank accession number: H) was determined by PCR(PCR)primers containing the sequence described in Sequence Numbers 1 and 2, and the implementation of PCR Paul is the beginning of the fragment, containing approximately 340 BP were Selected genomic library of phages man (Human genomic library, Clontech Co.) and used it as a probe to obtain genomic DNA VEGF. Using EcoRI, were digested DNA, and the resulting fragments were inserted into the EcoRI-site of pUC18. Finally got pUC18-VEGFA, containing approximately 5,4 thus, the 5'-flanking region of VEGF. Using Cloned/NheI, were digested pUC18-VEGFA and received VEGF promoter region of about 2.3 thus inserted into multiclone site Cloned/NheI vector secretory alkaline phosphatase (PLAP) (Goto et al, Mol. Pharmacol., 49, 860-873, 1996), and thus designed vector VEGF-PLAP.

The resulting vector VEGF-PLAP was transfectional in the cell U251, cultivated in modified, Dulbecco environment Needle (DMEM; manufacturer SIGMA Co. Ltd.), containing 10% fetal calf serum, and the cells were cultured in the presence of 1 mg/ml G418 (Merck Co.), to create resistant to G418 stable clone (cell U251/1-8).

It was confirmed that the cell U251/1-8, secreted PLAP in hypoxic conditions (2% O2the incubator) as already described (Cell. Mol. Biol. Res. 40, 35-39, 1994), and was a reporter system reflecting the transcription from the VEGF promoter. Using the clone, then made the selection of compounds inhibiting the production of VEGF caused by hypoxic stimulation.

Example 2 tests. VEGF transcription oppressive activity of various analogs and derivatives 11107

Th is would be to eliminate the influence of alkaline phosphatase in serum, cells U251/1-8 washed two times sufficient amount of PBS (phosphate buffer solution), diluted in DMEM containing 10% serum, in which alkaline phosphatase iactiveaware treatment at 65°C for 20 min, and were distributed in 96-well tablets 4 x 104cells/180 μl.

After culturing at 37°overnight in CO2incubator (5% CO2) was added 20 μl of the above-described incubation solution containing the test compound, diluted 3-fold dilution, and then cells were incubated in hypoxic (2% CO2) incubator for 18 hours. As for the PLAP activity in the culture supernatant, then 50 μl of 0.28 M Na2CO3-NaHCO3buffer solution (pH of 10.0, 8.0 mm MgSO4) were added 10 μl of supernatant and then 50 μl molocnotsvetkovogo substrate (LUMISTEIN, Genomescience Co.). After the interactions within one hour was measured molochnotovarnuyu PLAP activity detection chemical luminescence using a microplate reader (Perkin Elmer Co.). PLAP activity in normoxia was set as 0%, PLAP activity of cells treated under hypoxic conditions were set as 100%, and the concentration, generally hopeless PLAP activity by 50% was set as the IC50-the value of the PLAP. Measured IC50values derived 11107D shown the examples, presented in table 1 IC50values representative of derivative 11107D. Derivatives 11107D showed high generally hopeless activity against VEGF transcription.

Table 1
ConnectionThe VEGF transciption oppressive activity (IC50: nm)
632,0
912,9
1210,2
163,1
17a 3.9
216,1
2225,6
245,5
252,9
262,8
273,7
44a 3.9
451,9
759,1
951,2
1093,3
1224,4
1272,4
1311,7
1361,2
14211,2

Example 3 tests. Inhibitory activity against the growth of human cells WiDr colon cancer

Human cells WiDr colon cancer, coltivirus is installed in the modified Dulbecco environment Needle (DMEM; manufacturer SIGMA Co. Ltd.), containing 10% fetal calf serum, penicillin (100 units/ml) and streptomycin (100 μg/ml)were distributed in 96-well tablets on h3cells/well. After culturing overnight in CO2the incubator was added 20 μl of the above-described incubation solution containing the test compound, diluted 3-fold dilution, and the cells are then incubated. Three days were added 50 μl of a solution of 3.3 mg/ml MTT, and then cultured for another one hour. Then formazan formed by recovery under the action of living cells, was extracted with 100 ál of DMSO, was determined by optical density (A/A) and was established as a measure of the number of living cells.

Determined concentration of the compounds of formula (I), in which the growth of human cells WiDr colon cancer Engibarov 50%. The values of the IC50for representative compounds are shown in table 2. The compounds of formula (I) showed high inhibitory activity against the growth of human cells WiDr colon cancer.

Table 2
ConnectionInhibitory activity to growth of human cells WiDr colon cancer

(IC50: nm)
612,5
95,5
162,0
172,6
213,2
2214,6
245,3
251,2
261,6
271,2
442,1
450,7
754,1
950,5
1091,5
1221,1
1270,7
1310,7
1360,8
142a 4.9

Example 4 tests. Inhibitory activity against the growth solenoi tumor

To investigate the inhibitory activity against the growth solenoi tumor compounds of formula (I)in vivosubcutaneously implanted human cells WiDr colon cancer in Boca exposed mice. Animals were divided into groups so that the average value of the volumes in the respective groups was the same, when it reached about 100 mm3. The control group consisted of 10 mice, and groups with the compounds 11107D from 5 mice. Derivatives were injected into mice in groups for introduction within 5 pic is dovetailing days intravenous injection with any of the doses of 0.625 mg, 1.25 mg, 2.5 mg, 5 mg and 10 mg/kg/day and the control group was injected media. Measured volumes of the tumors on day 15 and was determined by the relative ratios of the volume of tumors (T/C%)choose tumor volume of the control group as 100%. T/C% representative compounds of formula (I) shown in table 3. Measured body weight on day 1, day 5, day 8, day 12 and day 15 (or 16) and determined the relative changes in body weight, taking the body weight on day 1 for 100%. Was determined by the relative ratios of body weight on the day when the weight of the body has reached at least the minimum coefficients of body weight are shown in table 3.

Table 3
ConnectionDose (mg/kg)Growth inhibitory activity against model solenoi tumor man

(T/C%)
Minimum relative mass ratios
61,25350,81
95,0100,86
122,5210,85
152,5360,82
162,5280,90
212,5280,80
225,0390,74
262,5420,93
445,0190,89
455,0200,90
755,0170,82
109of 0.625360,89
1312,5280,83

The compounds of formula (I) showed a similar largest growth inhibitory activity against model tumor WiDr colon of a person without noticeable loss of body weight alsoin vivo.

Example 5 tests. Stability in aqueous solution

The compounds of formula (I) was dissolved in DMSO at concentrations of 10-20 mm, and the resulting solution was diluted to about 500-fold with buffer solution of Britton-Robinson with a pH of 7. Each of the solutions that serve as solutions of samples were incubated at 25°With within 24 hours.

Solution samples were analyzed by high-performance liquid chromatography before and after incubation and from peak areas obtained chromatograms were identified indicators of remnant subjects of substances in solutions of the samples after incubation.

Example The peak area (mAV x s)Rate balance (%)
InitialAfter 24 hours
FD895119799383,0
11107D3994381795,6
Connection 95690547696,2
Connection 125450516994,9
The connection 224713451495,8
The connection 444031382094,8
The connection 455291502495,0
Connection 752594247895,5
Connection 1092224211194,9
The connection 1224872462094,8
The connection 1304819458395,1
Connection 13116815793,2
Connection 1363750357995,4
Connection 1423916370564,6

The results show is live, the content FD895 decreased to 83% after 24 hours and the content of compounds 9, 12 and 22 as representative compounds of the compounds of formula (I) remained at the level of 95-96%, indicating that the derived 11107D stable in aqueous solution.

As can be seen from the examples, pharmacological test, the compounds of formula (I) according to the present invention, in particular, inhibit the production of VEGF by changing gene expression, and, as expected, can be used as anti-cancer drugs, in particular drugs for the treatment of solenoi malignant tumor, suppressor of metastasis of carcinoma, as well as funds for the treatment of diabetic retinopathy, rheumatoid arthritis and anghinoni. In addition, example 4 toxicity tests show that the compounds of formula (I) exhibit inhibitory growth activity in models of tumor WiDr colon of a person to such an extent that does not cause significant loss of body weight of the tested mouse, and are safe compounds. Therefore, they are effective as a means for prevention or treatment of diseases against which effective regulation of gene expression, diseases against which effective oppressive activity in relation to the production of VEGF, and the diseases against which an effective angiogenesis inhibiting activity. "Prevention or treatment" OSN which includes or prevention, or treatment or both. In particular, the compounds of formula (I) according to the present invention is effective as antitumor agents and especially as anti-cancer agents and suppressing metastasis of carcinoma to solenoi malignant tumors. As solenoi malignant tumors include, for example, pancreatic cancer, stomach cancer, cancer of the colon, breast cancer, prostate cancer, lung cancer, kidney cancer, brain tumor, head and neck cancer, esophageal cancer, skin cancer, liver cancer, uterine cancer, cervical cancer, bladder cancer, thyroid cancer, testicular cancer, horiokartsinoma, osteosarcoma, soft tissue sarcoma and ovarian cancer, of which preferred is a cancer, such as cancer of the colon, breast cancer, prostate cancer cancer, lung cancer, head and neck cancer or ovarian cancer. In addition, they are also effective as anti-cancer agents for the treatment of leukemia. They are effective as a treatment for bruises. And yet they are also effective as a treatment for diabetic retinopathy, rheumatoid arthritis, and bruises that are based on the inhibitory effect on the production of VEGF. In addition, it is also effective as a treatment for inflammatory diseases, including osteoarthritis, psoriasis and lergicescoe reaction of the delayed type, and atherosclerosis.

When the compounds prepared in the form of an injection solution, by main drug type, if necessary, a pH regulator, buffer, stabilizer, solubilizer and the like with the receipt by the traditional method of solution for subcutaneous, intramuscular, intra-articular or intravenous injection.

When the connection is used as a prophylactic or therapeutic agent against various diseases, it can be administered orally in the form of tablets, powders, granules, capsules, syrups and the like or parenterally in the form of an aerosol, suppository, injection solution, external drug or drops. The dose varies according to the severity of the symptom, age, type of liver disease, etc. and is in General from about 1 mg to 100 mg per day for adult with disposable or reusable introduction.

For the manufacture of medicines use conventional inert excipients and traditional methods of manufacture. That is, when they produce solid dosage form for oral administration, to the main medicinal ingredient is added a filler and, if necessary, binder, baking powder, grease, dye, corrective substance and the like and then make tablets, tablets with the opening, granules, powders, capsules and the like. Needless to say, that if necessary, on tablets and granules may be coated in sugar coating, gelatin coating or other suitable coating.

In accordance with the present invention the compounds of formula (I) according to the present invention inhibit, in particular, production of VEGF by modifying gene expression and exhibit high antitumor activity in models ofin vivosolidnyh tumors. In addition, the compounds of formula (I) according to the present invention are stable in aqueous solution and can provide, for example, for the treatment of cancer, in particular for the treatment Solidago cancer metastasis suppressor carcinoma, treatment for diabetic retinopathy, rheumatoid arthritis and angioma.

Examples

The present invention is described hereinafter in more detail by examples and reference examples, which should not be considered as limiting scope of the present invention.

Below shows the symbols used in the chemical structural formulas in the examples.

DEIPS: diethylethanolamine group

Et: ethyl group

HER: 1-amoxicilina group

Me: methyl group

TES: triethylsilyl group.

Example 1. Fermentation of strain Mer-11107 and cleaning 11107D

One full loop grown on stubble nutrient medium culture (ISP) strain Mer-11107 made in a 500 ml Erlenmeyer flask, containing 50 ml of medium for sowing (2% glycerol, 2% glucose, 2% soybean meal (ESUSAN-MEAT production Ajinomoto Co. Ltd.), 0,5% yeast extract, 0.25% sodium chloride, 0.32 per cent of calcium carbonate, of 0.0005% sulphate of copper, of 0.0005% chloride of manganese, of 0.0005% zinc sulfate, pH 7.4), and cultivated at 28°C for three days on the shaker, which gave the first seed culture. Seed culture (0.6 ml) were introduced into a 500 ml Erlenmeyer flask containing 60 ml of producing environment (5% soluble starch, 0.5% of the liquid corn extract, 0.5% of dried yeast, 0.5% of the flour from gluten, 0.1% calcium carbonate), and parenterally at 28°C for four days on a rotary shaker that gave cultured fermentation broth.

Cultured broth (10 l) was extracted with 1-butanol (10 l), then any resulting botanology layer was evaporated to dryness to obtain 100 g of the crude active fraction. The crude active fraction was applied to a Sephadex LH-20 (1500 ml; manufacturer Pharmacia Co. Ltd.) and suirable a mixture of tetrahydrofuran-methanol (1:1) as solvent. Elyuirovaniya fraction from 540 to 660 ml ml was concentrated to dryness to obtain a residue (660 mg). The obtained residue was dissolved in a mixture of ethyl acetate and methanol (9:1, vol/about.) and subjected to column chromatography on silica gel (WAKO GEL C-200, 50 g). The column was suirable mixture (2 l), consisting of n-hexane and ethyl acetate is (1:9, about./vol.), erwerbende fractions from 1440 ml to 1566 ml was collected and evaporated to obtain 15 mg of the crude active fraction.

The crude active fraction was subjected to preparative high performance liquid chromatography (HPLC) under the following conditions (A) preparative HPLC and the collected fractions, erwerbende at retention time of 17 minutes. After removal of acetonitrile appropriate fractions were absoluely by HPLC under the following conditions (C) preparative HPLC to obtain 11107D (retention time: 36 minutes, 1.8 mg).

Conditions (A) preparative HPLC:

Column: YMC-PACK ODS-AM F20 mm x 250 mm (manufacturer YMC Co.)

Flow rate: 10 ml/min

Detection: 240 nm.

Eluent: acetonitrile/0.15% aqueous potassium dihydrophosphate (pH 3.5) (2:8-8:2, vol/about., 0-50 min, linear gradient).

Conditions (C) preparative HPLC:

Column: YMC-PACK ODS-AM F20 mm x 250 mm (manufacturer YMC Co.).

Flow rate: 10 ml/min

Detection: 240 nm.

Eluent: methanol/water (2:8-10:0, from./about., 0-40 min, linear gradient).

Example 2. Physico-chemical properties of 11107D

Physico-chemical properties of 11107D shown below. Determined the structure of 11107D shown below.

1. Appearance: colorless powder.

2. Molecular weight: 552, ESI-MS m/z 551 (M-H)-, 575 (M+Na)+.

3. Molecular formula: C30H48About9.

4. Solubility:soluble in dimethyl sulfoxide, pyridine, methanol and acetone and slightly soluble in water.

5. Color reaction: positive for iodine and sulphuric acid.

6. Ultraviolet absorption spectrum (methanol, the maximum value) nm: 239 (ε 33100).

7. Infrared absorption spectrum (KBr) cm-1: 3417, 2967, 1732, 1714, 1455, 1372, 1248, 1176.

8.1H-NMR-spectrum (CD3OD, 500 MHz): δ ppm (integral intensity, multipletness, the binding constant J (Hz)): 0,93 (3H, d, J=7,0 Hz)of 0.95 (3H, d, J=6,8 Hz), and 0.98 (3H, t, J=8.0 Hz), of 1.23 (3H, s)of 1.30 (1H, m), 1,36-of 1.66 (9H, m)1,70 (1H, DD, J=6,4, of 14.2 Hz), 1,82 (3H, d, J=1.0 Hz), 1,90 (1H, DD, J=6,4, of 14.2 Hz), 2,10 (3H, s), 2,52 (2H, m), 2,62 (1H, m), of 2.72 (1H, DD, J=2,4, 8,3 Hz)to 2.94 (1H, dt, J=2,4, 5,7 Hz), 3,55 (1H, dt, J=8,3, 4,4 Hz), 3,82 (1H, m), 5,10 (1H, d, J=9.8 Hz), 5,11 (1H, d, J=10,8 Hz), the ceiling of 5.60 (1H, DD, J=9,8, 15.2 Hz), 5,74 (1H, DD, J=8,3, 15.2 Hz), of 5.92 (1H, d, J=15.2 Hz), 6,18 (1H, d, J=10,8 Hz), to 6.57 (1H, DD, J=10,8, 15.2 Hz).

9.13H-NMR-spectrum (CD3OD, 125 MHz): δ ppm (multipletness): 10,52 (kV)10,82 (kV)11,98 (kV)of 16.84 (kV), 21,07 (kV), 24,21 (kV), 28,62 (t), 28,79 (kV), 30,46 (t), 37,53 (t)40,10 (t), 41,80 (d), 42,58 (d), 45,97 (t), 55,99 (d), 62,53 (d), 70,42 (d), 73,09 (C), 74,11 (C), 75,30 (d), 80,31 (d), 84,19 (d), 123,64 (d), 127,10 (d), 131,76 (d), 133,81 (C), 141,61 (d), 143,22 (d), 171,75 (C), 172,18 (s).

Example 3. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 3)

Example 3-1. (8E,12E,14)-7-Acetoxy-3,6,16,21-Ter the keys(1 ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (formula XV) and (8E,12E,14)-7-acetoxy-3,16,21-Tris(1-ethoxyethoxy)-6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (formula XVI)

To a solution of (8E,12E,14)-7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (50 mg, 0.09 mmol) in dichloromethane (2.5 ml) was added a simple ethylenically ester (326 mg, 4.5 mmol) and p-toluensulfonate pyridinium (6,8 mg, 27 μmol) at room temperature, followed by stirring at the same temperature for 19 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=30:70) to obtain (8E,12E,14)-7-acetoxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (60 mg, 79%) as a colourless oil (formula XV).

ESI-MS m/z 863 (M+Na)+.

Then received (8E,12E,14)-7-acetoxy-3,16,21-Tris(1-ethoxyethoxy)-6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old (6 mg, 9%) as a colourless oil (formula XVI) of elyuirovaniya fraction of the mixture ethyl acetate:hexane=50:50.

ESI-MS m/z 791 (M+Na)+.

Example 3-2. (8E,12E,14)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old

To a solution of 8E,12E,14)-7-acetoxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (145 mg, 0,17 mmol) in methanol (2.5 ml) was added potassium carbonate (95 mg, 0.69 mmol) at room temperature, followed by stirring at the same temperature for two hours and 30 minutes. The reaction mixture was diluted with ethyl acetate and then washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=40:60) to obtain the specified title compound (128 mg, 93%) as a colourless oil.

ESI-MS m/z 821 (M+Na)+.

Example 3-3. (8E,12E,14)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxydecane-8,12,14-trien-11-old

To a solution of (8E,12E,14)-3,6,16,21-tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (139 mg, 0,17 mmol) in dichloromethane (2.5 ml) was added triethylamine (88 mg, 0.87 mmol), N,N-dimethylaminopyridine (64 mg, 0.52 mmol) and 4-nitrophenylphosphate (105 mg, 0.52 mmol) under ice cooling, followed by stirring at room temperature in nitrogen atmosphere for one hour. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous with what LifeCam magnesium, filtered and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=20:80) to obtain the specified title compound (134 mg, 80%) as a colourless oil.

ESI-MS m/z 986 (M+Na)+.

Example 3-4. (8E,12E,14)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-old

(8E,12E,14)-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxydecane-8,12,14-trien-11-olide (11.4 mg, 0.12 mmol) was added a solution of 4-(pyrrolidin-1-yl)piperidine (2.4 mg, 16 μmol) in tetrahydrofuran (0.5 ml) at room temperature. To the mixture was added triethylamine (2.3 mg, 24 μmol) at room temperature, followed by stirring at the same temperature for three hours. The reaction mixture was evaporated to obtain compound (11 mg) as a crude product (pale yellow oil).

Example 3-5. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 3)

To the crude product (8E,12E,14)-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-ol is DN (11 mg, 11 µmol) was added a solution of p-toluensulfonate pyridinium (11.4 mg, 45 μmol) in a mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (1 ml) at room temperature. To the mixture was added molecular sieves 4Å (10 mg) followed by stirring at room temperature for a period of 18.5 hours. Added p-toluensulfonate pyridinium (11.4 mg, 45 μmol), followed by stirring at room temperature for 72 hours. The reaction mixture was evaporated and the obtained residue was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel Plate, methanol:dichloromethane=1:19) to obtain specified in the connection header (2,88 mg, 35%, two stages) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6,8 Hz)to 0.92 (3H, t, J=7.2 Hz), to 1.21 (3H, s), 1,22 by 1.68 (8H, m)of 1.34 (3H, s), 1.77 in (3H, s), 1,78 is 2.00 (9H, m), 2,48-2,62 (3H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,68-2,92 (9H, m), 3.46 in-3,54 (1H, m), 3.72 points-is 3.82 (1H, m), 4,24-and 4.40 (1H, m)to 4.92 (1H, d, J=10,8 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 14,8 Hz), 5,72 (1H,DD, J=9,2, 14,8 Hz), 5,86 (1H, d, J=14,8 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 691(M+H)+.

Example 4. (8E,12E,14)-7-(N-Ethylcarbamate)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxidic the a-8,12,14-trien-11-OLED (compound 4)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,10 (3H, t, J=7,6 Hz)of 1.20 (3H, s), 1,22-1,62 (7H, m)of 1.34 (3H, s), of 1.65 (1H, DD, J=6,6, of 13.7 Hz), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,7, of 13.7 Hz), 2,50 of $ 2.53 (2H, m), 2,53-2,60 (1H, m)to 2.67 (1H, DD, J=2,4, a 7.6 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), of 3.12 (2H, q, J=7.2 Hz), 3,49-of 3.54 (1H, m), 3,74-3,81 (1H, m), 4,82-to 4.98 (1H covered the peak of the H2O)of 5.06 (1H, d, J=10,8 Hz), of 5.55 (1H, DD, J=9,6, 15.2 Hz), 5,69 (1H, DD, J=9,2, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 604(M+Na)+.

Example 5. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-(3-morpholine-4-yl)propyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 5)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.20 (3H, s), 1,26-1,73 (10H, m)of 1.34 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,4, 14.1 Hz), 2,35-2,60 (9H, m), to 2.67 (1H, DD, J=2,4, a 7.6 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz)and 3.15 (2H, t, J=7.2 Hz), 3,48-of 3.54 (1H, m), 3,68 (4H, t, J=4,8 Hz), 3,74-3,82 (1H, m), 4,82-to 4.98 (1H, overlapped with the peak of the H2O)of 5.06 (1H, d, J=10,8 Hz), of 5.55 (1H, DD, J=10,0, 15.2 Hz), 5,69 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10.4 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 681 (M+H)+.

When is EP 6. (8E,12E,14)-7-(N-(2-(N',N'-Dimethylamino)ethyl)-N-methylcarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 6)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,22 (3H, s), 1,24 by 1.68 (8H, m)of 1.34 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,28 (6H, s), 2,45-2,62 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,86-to 2.99 (4H, m), 3.49 points of 3.56 (1H, m), 3.75 to 3,82 (1H, m)to 4.92 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, the 15.6 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=14,8 Hz), 6,14 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 639 (M+H)+.

Example 7. (8E,12E,14)-(7-N-(3-(N',N'-Dimethylamino)propyl)-N-methylcarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 7)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)to 1.21 (3H, s), 1,24 is 1.75 (10H, m)of 1.34 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,9, of 13.7 Hz), 2,28 (6H, s), is 2.37 (2H, t, J=7,6 Hz), 2,48-2,62 (5H, m)to 2.67 (1H, DD, J=2,4, a 7.6 Hz), 2,86-to 2.99 (4H, m), 3,48-to 3.58 (1H, m), 3,74-3,82 (1H, m), is 4.93 (1H, d, J=10, 4 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H,DD, J=11,2, 15.2 Hz); ESI-MS m/z 653 (M+H)+.

Example 8. (8E,12E,14)-7-(N-(2-(N',N'-Dimethylamino)ethyl)carbanilate)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 8)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), to 1.21 (3H, s), 1,22 by 1.68 (8H, m)of 1.34 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,7, and 14.3 Hz), to 2.29 (6H, s), 2,44-2,62 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,49 of 3.56 (1H, m), 3,74-3,82 (1H, m), 4,82-to 4.98 (1H, overlapped with the peak of the H2About), is 5.06 (1H, d, J=10,8 Hz), of 5.55 (1H, DD, J=10,4, 15.2 Hz), 5,69 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 625 (M+H)+.

Example 9. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 9)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,887 (3H, d, J=6.6 Hz), 0,894 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), 1,23-of 1.27 (4H, m)of 1.33 (3H, s), 1,33-1,68 (7H, m), 1.77 in (3H, d, J=0.7 Hz), 1,82 is 1.91 (3H, m)to 2.35 (3H, ), 2,50-2,66 (7H, m)to 2.66 (1H, DD, J=2,2, 7,7 Hz), 2,89 (1H, dt, J=2,2, 5,5 Hz), 3,49 of 3.56 (3H, m), to 3.58-to 3.67 (2H, m), 3.75 to-3,81 (1H, m), 4,94 (1H, d, J=9.5 Hz), is 5.06 (1H, d, J=a 10.6 Hz), to 5.57 (1H, is d, J=9,9, 15,0 Hz), 5,72 (1H, DD, J=9,5, 15,0 Hz), 5,86 (1H, d, J=15,0 Hz), 6,13 (1H, d, J=9.9 Hz), of 6.52 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 651 (M+H)+.

Example 10. (8E,12E,14)-7-(N-(3-(N',N'-Dimethylamino)propyl)carbanilate)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 10)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,6 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz)of 1.20 (3H, s), 1,20-of 1.26 (1H, m)of 1.33 (3H, s), 1,33-1,71 (9H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,5, and 14.3 Hz in ), 2.25 (6H, s), a 2.36 (2H, t, J=7,3 Hz), 2,49-2,61 (3H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,89 (1H, dt, J=2,2, 5,5 Hz), of 3.13 (2H, t, J=6.6 Hz), 3,52 (1H, dt, J=4,4, 8.1 Hz), 3.75 to-3,81 (1H, m), 4,89 (1H, d, J=9.5 Hz), of 5.05 (1H, d, J=a 10.6 Hz), of 5.55 (1H, DD, J=9,5, to 15.4 Hz), 5,69 (1H, DD, J=9,5, to 15.4 Hz), 5,86 (1H, d, J=15,4 Hz), 6,13 (1H, d, J=a 10.6 Hz), of 6.52 (1H, DD, J=10,6, to 15.4 Hz); ESI-MS m/z 639 (M+H)+.

Example 11. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-((pyridin-4-yl)methyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 11)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=5,1 Hz)to 0.89 (3H, d, J=7,0 Hz)to 0.94 (3H, t, J=7,3 Hz)of 1.23 (3H, s), 1,23-of 1.27 (1H, m)of 1.33 (3H, s), 1,33-of 1.62 (6H, m), of 1.65 (1H, DD, J=6,2, and 14.3 Hz), 1.77 in (3H, ), to 1.86 (1H, DD, J=6,2, and 14.3 Hz), 2,4-to 2.65 (3H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,89 (1H, dt, J=2,2, 6.2 Hz), 3,52 (1H, dt, J=4,4, 8.1 Hz), 3,74-of 3.80 (1H, m), 4,35 (2H, s), is 4.93 (1H, d, J=9.5 Hz), is 5.06 (1H, d, J=10,6 Hz)to 5.56 (1H, DD, J=9,5, to 15.4 Hz), 5,73 (1H, DD, J=9,5, to 15.4 Hz), 5,86 (1H, d, J=15,0 Hz), 6,13 (1H, d, J=11.0 in Hz)of 6.52 (1H, d, J=of 11.0 to 15.0 Hz), 7,33 (2H, d, J=5,9 Hz), to 8.45 (2H, DD, J=1,5, and 4.4 Hz); ESI-MS m/z 645 (M+H)+.

Example 12. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 12)

The first stage

(8E,12E,14)-6-(1-Ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-3,6,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 12-1)

A solution of compound 46-4 (8E,12E,14)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,6,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (628 mg, 0,575 mmol)obtained in the fourth stage of example 46, in tetrahydrofuran (7 ml) was cooled to 5°and thereto was added dropwise a solution of 1-methylpiperazine (118 mg, 1,152 mmol) in tetrahydrofuran (1.5 ml) and a solution of triethylamine (236 mg, 2,305 mmol) in tetrahydrofuran (1.5 ml). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium bicarbonate and a saturated solution of salt. The organic layer was dried over without the one magnesium sulfate, filtered and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate:hexane:methanol, 1:1:0 4:1:0 9:1:0 1:0:0 39:0:1 19:0:1) obtaining specified in the title compound (514 mg, 85%) as a colourless oil.

The second stage

(8E,12E,14)-6-(1-Ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 12-2)

A solution of compound 12-1 (8E,12E,14)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-3,6,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (514 mg, 0,489 mmol)obtained in the first stage, in tetrahydrofuran (10 ml) was cooled to 5°and thereto was added dropwise tetrabutylammonium (1.0 M tertrahydrofuran ring solution of 1.62 ml, 1.62 millimole). The reaction mixture was stirred at room temperature for two hours. Added dropwise tetrabutylammonium (1.0 M tertrahydrofuran ring solution, 0.3 ml, 0.3 mmol) and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified column chromatography on si is imagele (Fuji Silysia, NH silica gel, 200-350 mesh; ethyl acetate:hexane:methanol, 1:1:0 4:1:0 1:0:0 49:0:1 19:0:1) obtaining specified in the title compound (364 mg, 99%) as a colourless oil.

ESI-MS m/z 709 (M+Na)+.

The third stage

(8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 12)

To a solution of compound 12-2 (8E,12E,14)-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide (364 mg, 0,489 mmol)obtained in the second stage, in a mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (10 ml) was added p-toluensulfonate pyridinium (184 mg, 0,734 mmol) and the reaction the mixture was stirred at room temperature for 19 hours. Then to the reaction mixture was added dropwise a triethylamine (75 mg, 0,374 mmol) and the mixture was evaporated. The obtained residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified column chromatography on silica gel (Fuji Silysia NH silica gel, 200-350 mesh; ethyl acetate:hexane:methanol, 1:1:0 > 2:1:0 > 4:1:0 > 1:0:0 > 39:0:1 > 29:0:1 > 19:0:1). The crude fraction was evaporated and the residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel Plate, methanol:D. harmatan=1:29) to obtain the specified title compound (286 mg, 92%) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19 of 1.28 (4H, m), 1,32 by 1.68 (10H, m), 1.77 in (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,6, 14.4 Hz), is 2.30 (3H, s), 2,36 is 2.44 (4H, m), 2,50-of 2.64 (3H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,38-3,70 (5H, m), 3.75 to-3,81 (1H, m), is 4.93 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 637 (M+H)+.

Example 13. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 13)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,20-1,30 (4H, m), 1,32 by 1.68 (10H, m), 1.77 in (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,6, 14.4 Hz), 2,50-of 2.64 (3H, m), to 2.67 (1H, DD, J=2,4, 8.0 Hz), was 2.76 (4H, t, J=5,2 Hz), 2,89 (1H, dt, J=2,4, 5,6 Hz), 3,34-3,68 (5H, m), 3.75 to-3,81 (1H, m), 4,94 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 623 (M+H)+.

Example 14. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(pyridin-4-yl)piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 14)

Specified in the header connect the tion (colorless oil) was synthesized by the method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,20-1,30 (4H, m), 1,32 was 1.69 (10H, m), 1.77 in (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,6, 14.4 Hz), 2,50-of 2.64 (3H, m), to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,38-of 3.46 (4H, m), 3,49-a-3.84 (6H, m), equal to 4.97 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), 5,59 (1H, DD, J=10,0, 15.2 Hz), 5,74 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz), 6,86 (2H, d, J=6.8 Hz), 8,13 (2H, d, J=6.8 Hz); ESI-MS m/z 700 (M+H)+.

Example 15. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-(methylpiperidin-4-yl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 15)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m), 1,32 was 1.69 (12H, m), 1,72-1,90 (6H, m), 2.06 to 2,22 (2H, m), of 2.28 (3H, s), 2,50-of 2.64 (3H, m), to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,7 6-2,98 (6H, m), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), 3.75 to 3,82 (1H, m), 3,85-to 4.14 (1H, m), of 4.95 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 665 (M+H)+.

Example 16. (8E,12E,14)-7-((4-Butylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 16)

Specified the title compound (colorless oil) was synthesized by the method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)to 0.94 (3H, t, J=7,6 Hz), 1,19-1,69 (18H, m), 1.77 in (3H, d, J=1.2 Hz), to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,34-2,64 (9H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6.4 Hz), 3,38-and 3.72 (5H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15,2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 17. (8E,12E,14)-7-((4-Benzylaminopurine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 17)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.85 to 0.92 (6H, m)to 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m), 1,32 was 1.69 (10H, m), of 1.78 (3H, s), 1,79-1,90 (3H, m), 2,50-of 2.72 (8H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,4 2-3,68 (7H, m), 3,75-3,82 (1H, m), 4,91 is equal to 4.97 (1H, m), is 5.06 (1H, d, J=10,8 Hz), of 5.53-5,62 (1H, m), 5,67 is 5.77 (1H, m), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz), 7,21-to 7.35 (5H, m); ESI-MS m/z 727 (M+H)+.

Example 18. (8E,12E,14)-7-((4-(3-Chlorpropyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 18)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in the ore 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m), 1,32 was 1.69 (10H, m), 1.77 in (3H, d, J=0.8 Hz), 1,80 is 1.96 (5H, m), 2,49-2,74 (10H, m), 2,89 (1H, dt, J=2,4, 6.4 Hz), 3,41-3,69 (7H, m), 3.75 to-3,81 (1H, m), 4.92 in-equal to 4.97 (1H, m), 5,07 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 713 (M)+.

Example 19. (8E,12E,14)-7-((4-(N,N-dimethylamino)piperidine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 19)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-1,68 (16H, m), 1.77 in (3H, d, J=0.8 Hz), 1,83-of 1.93 (3H, m), of 2.28 (6H, s), of 2.38 (1H, TT, J=3,6, and 11.6 Hz), 2,49-2,62 (3H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2.71 to is 2.88 (2H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), 3.75 to 3,82 (1H, m), 4,08 is 4.45 (2H, m)to 4.92 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 665 (M+H)+.

Example 20. (8E,12E,14)-7-((1,4-Diazabicyclo[4,3,0]nonan-4-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 20)

Specified in the title compound (colorless oil) was synthesized method is m, similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m), 1,32 was 1.69 (10H, m), 1,7 3-2,02 (6H, m), 2,09-2,22 (2H, m), 2,49-a 2.71 (6H, m), 2,87-of 3.12 (6H, m), 3,52 (1H, dt, J=4,4, 8.0 Hz), 3.75 to 3,82 (1H, m), 4,01-4,51 (2H, m), 4,88-4,99 (1H, m), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 14,8 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 663 (M+H)+.

Example 21. (8E,12E,14)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 21)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.11 (3H, t, J=7,6 Hz)to 1.21 (3H, s), 1,22-1,64 (7H, m), 1-34 (3H, s), of 1.65 (1H, DD, J=6,2, of 14.2 Hz), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,39-2,49 (6H, m), 2,50 of $ 2.53 (2H, m), 2,53-2,62 (1H, m)to 2.66 (1H, DD, J=2,4, a 7.6 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,34-and 3.72 (5H, m), 3,74-3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz), of 5.05 (1H, d, J=10.4 Hz), to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 651 (M+H)+.

Example 22. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(piperidine-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 22)

Specified in the header connect the out (colorless oil) was synthesized by the method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz)to 1.21 (3H, s), 1,20-1,69 (16H, m)of 1.34 (3H, s), 1.77 in (3H, s), 1,83-of 1.93 (3H, m), 2,45-to 2.65 (8H, m), 2,66 (1H, DD, J=2,4, a 7.6 Hz), 2,70-to 2.85 (2H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,51 (1H, TD, J=4,4, 8.0 Hz), 3,74-3,82 (1H, m), 4,12-of 4.25 (1H, m), 4,30-4,45 (1H, m)to 4.92 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), 5.56mm (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=10,0, the 15.6 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 705 (M+H)+.

Example 23. (8E,12E,14)-7-((Homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 23)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.4 Hz), of 1.23 (3H, s), 1,24 was 1.69 (8H, m)of 1.34 (3H, s), 1.77 in (3H, s)of 1.78-1.90 (3H, m), 2,48-2,62 (3H, m), 2,66 (1H, DD, J=2,4, 8.0 Hz), 2,72-of 2.93 (5H, m), 3.43 points-to 3.67 (5H, m), 3,74-3,82 (1H, m), 4,94 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,4, 15.2 Hz), 5,72 (1H, DD, J=9,8, to 15.4 Hz), 5,86 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 637 (M+H)+.

Example 24. (8E,12E,14)-7-((4-Benzylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 24)

Specified in the title compound (colorless oil) which was intesively way similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)to 0.89 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.20 (3H, s), 1,22-of 1.65 (7H, m)of 1.34 (3H, s), of 1.65 (1H, DD, J=6,2, of 14.2 Hz), 1.77 in (3H, s)to 1.87 (1H, DD, J=5,4, of 14.2 Hz), 2,39-2,49 (4H, m), 2,50-of 2.64 (3H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,0, 5.6 Hz), 3,36-3,72 (7H, m), 3,74-a 3.83 (1H, m)to 4.92 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz), 7,22-7,37 (5H, m); ESI-MS m/z 713 (M+H)+.

Example 25. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylpiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 25)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,86-0,97 (12H, m)to 1.21 (3H, s), 1,21 by 1.68 (10H, m)of 1.34 (3H, s), 1.77 in (3H, s)to 1.87 (1H, DD, J=5,2, of 14.0 Hz), 2,30-of 2.36 (2H, m), 2,38-2,47 (4H, m), 2,49-2, 63 (3H, m)to 2.66 (1H, DD, J=2,4, a 7.6 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,35-and 3.72 (5H, m), 3,74-a 3.83 (1H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=1,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10.0 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 665 (M+H)+.

Example 26. (8E,12E,14)-7-((4-Cyclohexylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 26)

Specified in the header of the compounds is their (colorless oil) was synthesized by the method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,10-1,69 (15H, m)to 1.21 (3H, s)of 1.34 (3H, s)of 1.78 (3H, s), 1,78-of 1.93 (4H, m), 2.26 and to 2.35 (1H, m), 2,47-2,64 (7H, m)to 2.67 (1H, DD, J=2,0, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,36-3,70 (5H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 705 (M+H)+.

Example 27. (8E,12E,14)-7-((4-(Cyclopropylmethyl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 27)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,12-0,17 (2H, m), 0,52-of 0.58 (2H, m)to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), from 0.90 to 0.97 (4H, m)to 1.21 (3H, s), 1,21 was 1.69 (8H, m)of 1.34 (3H, s)of 1.78 (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz)to 2.29 (2H, d, J=6.8 Hz), 2,47-2,64 (7H, m)to 2.67 (1H, DD, J=2,0, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,40-and 3.72 (5H, m), 3,74-3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), 5,57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 677 (M+H)+.

Example 28. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(morpholine-4-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 28)

Specified in the agolove compound (colorless oil) was synthesized by the method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m), 1,31 by 1.68 (12H, m), 1.77 in (3H, d, J=1.2 Hz), 1,83-of 1.95 (3H, m), 2,34 is 2.43 (1H, m), 2,50-2,64 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,73-2,89 (2H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,52 (1H, TD, J=4,4, 8.0 Hz), 3,66-and 3.72 (4H, m), 3.75 to-3,81 (1H, m), 4,07-of 4.44 (2H, m)to 4.92 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 707 (M+H)+.

Example 29. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(3,3,3-cryptochromes)piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 29)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m), 1,31 was 1.69 (10H, m), 1.77 in (3H, d, J=1.2 Hz), to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,35-2,66 (11H, m), to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,38-3,71 (5H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 719 (M+H)+, 741 (M+Na)+.

Example 30. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(4,4,4-trifloromethyl)piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 30)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m), 1,32 was 1.69 (10H, m), 1.70 to is 1.81 (5H, m)to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,14-of 2.28 (2H, m), 2,38-2,49 (6H, m), 2,50-of 2.64 (3H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,39-and 3.72 (5H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,72 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=10,8,15,2 Hz); ESI-MS m/z 733 (M+H)+, 755 (M+Na)+.

Example 31. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-papillomaviruses-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 31)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.87 to 0.92 (9H, m)to 0.94 (3H, t, J=7,6 Hz), 1,20-1,30 (4H, m), 1,32 was 1.69 (12H, m), 1.77 in (3H, d, J=0.8 Hz), 1,82 is 1.91 (3H, m), 2,41-2,49 (2H, m), 2,50-2,77 (8H, m), 2,89 (1H, dt, J=2,4 is 6.0 Hz), 3,42-to 3.67 (5H, m), 3.75 to 3,82 (1H, m), 4,94 (1H, d, J=9.6 Hz), 5,07 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 32. (8E,12E,14)-3,6,16,21-Tetrahydroxy-7-((4-(2-methoxyethyl)piperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 32)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m), 1,31 was 1.69 (10H, m), 1.77 in (3H, d, J=1.2 Hz), to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,44-2,64 (9H, m), to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz)to 3.33 (3H, s), 3,39-3,71 (7H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 681 (M+H)+.

Example 33. (8E,12E,14)-7-((4-Cyclobutylmethyl-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 33)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m), 1,32 was 1.69 (10H, m), 1.70 to is 1.81 (5H, m), 1,83-of 1.95 (3H, m), 2,02-2,11 (2H, m), 2,27-is 2.37 (4H, m), 2,49-of 2.64 (3H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,72-of 2.81 (1H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,37-3,71 (5H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz),by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 677 (M+H)+.

Example 34. (8E,12E,14)-7-((4-(1-Ethylpropyl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-old (compound 34)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.87 to 0.97 (15H, m), 1,19-1,69 (18H, m), 1.77 in (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,15-of 2.23 (1H, m), 2,45-2,64 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,34-the 3.65 (5H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 693 (M+H)+.

Example 35. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(tetrahydropyran-4-yl)piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 35)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)to 1.21 (3H, s), 1,21 was 1.69 (10H, m)of 1.34 (3H, s), 1.77 in (3H, s), 1.77 in-1,90 (3H, m), 2,42-2,62 (8H, m), 2,66 (1H, DD, J=2.0 a, 7,6 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,34-3,71 (7H, m), 3,74-3,82 (1H, m), 3,94-was 4.02 (2H, m), is 4.93 (1H, d, J=9.6 Hz), of 5.05 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10.4 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 707 (M+H)+.

Example 36. (8E,12E,14)-7-((4-(Cyclopropylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old (with the Association 36)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0.08 to 0.14 (2H, m), 0,48-of 0.54 (2H, m), or 0.83 (3H, d, J=6,8 Hz)to 0.88 (3H, d, J=7,2 Hz), 0,89-0,94 (4H, m), 1,20-to 1.67 (8H, m)to 1.21 (3H, s)is 1.31 (3H, s)of 1.75 (3H, s), 1,80-1,90 (3H, m), is 2.37 (2H, d, J=6,4), 2,47-2,61 (3H, m), 2,62-2,82 (5H, m), 2,87 (1H, dt, J=2,4, 6,0 Hz), 3.43 points at 3.69 (5H, m), of 3.73-of 3.80 (1H, m)to 4.92 (1H, d, J=9.6 Hz), 5,04 (1H, d, J=10,8 Hz), of 5.55 (1H, DD, J=10,0, 15.2 Hz), 5,70 (1H, DD, J=9,6, 15.2 Hz), of 5.84 (1H, d, J=15.2 Hz), 6,11 (1H, d, J=11.2 Hz), 6,50 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 691 (M+H)+.

Example 37. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(2,2,2-triptorelin)piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 37)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)to 1.21 (3H, s), 1,20 was 1.69 (8H, m)of 1.34 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, 14.4 Hz), 2,50-2,69 (8H, m), 2,86 of 2.92 (1H, m), 3,38-and 3.72 (2H, m), 3.04 from-3,14 (5H, m), 3,74-3,82 (1H, m), is 4.93 (1H, d, J=10.0 Hz), of 5.05 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 727 (M+Na)+.

Example 38. (8E,12E,14)-7-((4-Cyclopentylpropionyl-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-Tr is EN-11-OLED (compound 38)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)to 1.21 (3H, s), to 1.21 to 1.76 (14H, m)of 1.34 (3H, s), 1.77 in (3H, s), 1,83-of 1.95 (3H, m), 2,46-2,62 (8H, m), 2,66 (1H, DD, J=2,4, a 7.6 Hz), is 2.88 (1H, dt, J=2,4, 6.4 Hz), 3,34-and 3.72 (5H, m), 3,74-3,82 (1H, m), is 4.93 (1H, d, J=10.0 Hz), of 5.05 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 691 (M+H)+.

Example 39. (8E,12E,14)-7-((4-Isobutylpyrazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 39)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.87 to 0.97 (15H, m)to 1.21 (3H, s), 1,21 was 1.69 (8H, m)of 1.34 (3H, s), 1.77 in (3H, s)of 1.78-1.90 (2H, m), 2,11 (2H, d, J=7,2 Hz), 2,32-to 2.41 (4H, m), 2,50-2,63 (3H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,0,6,0 Hz), 3,38-3,70 (5H, m), 3,74-3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz), of 5.05 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,71 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 40. (8E,12E,14)-7-(((1S,4S)-5-Benzyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (Conn is out of 40)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,84 (3H, d, J=7,0 Hz)to 0.85 (3H, d, J=7,0 Hz)to 0.89 (3H, t, J=7,3 Hz), 1,14-of 1.27 (4H, m), 1,27-of 1.65 (7H, m)of 1.30 (3H, s), 1,65-of 1.92 (6H, m), 2,44-of 2.66 (5H, m), 2,79-is 2.88 (2H, m), 3,16 (0,6H, DD, J=1,8, 10,3 Hz), 3.25 to 3,31 (0,4H, m), 3.45 points-of 3.78 (6H, m), 4,29 (0,4H, Sirs), to 4.52 (0,6H, Sirs), 4,8 9 (1H, d, J=9.9 Hz), 5,02 (1H, d, J=a 10.6 Hz), 5,54 (1H, DD, J=9,9, 15,0 Hz), 5,68 (0,6H, DD, J=9,9, 15,0 Hz), 5,73 (0,4H, DD, J=9,9, 15,0 Hz), of 5.82 (1H, d, J=15,4 Hz)6,09 (1H, d, J=11,0 Hz), 6.48 in (1H, d, J=of 11.0 to 15.4 Hz), 7,16-to 7.32 (5H, m); ESI-MS m/z 725 (M+H)+.

Example 41. (8E,12E,14)-7-(N-(2-(N',N'-Dimethylamino)ethyl)-N-ethylcarbamate)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 41)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), 1,08-to 1.14 (3H, m), 1,20-of 1.29 (1H, m), 1,22 (3H, s), 1,31-1,68 (7H, m)of 1.33 (3H, s), 1.77 in (3H, d, J=0.7 Hz), to 1.86 (1H, DD, J=5,5, and 14.3 Hz), 2,28 (6H, s), 2,43-2,62 (5H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,89 (1H, dt, J=2,2, 5,5 Hz), 3,23-to 3.52 (4H, m), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), 3,74-3,82 (1H, m)to 4.92 (1H, d, J=9.9 Hz), is 5.06 (1H, d, J=10,6 Hz)to 5.56 (1H, DD, J=9,9, 15,0 Hz), 5,73 (1H, DD, J=9,9, 15,0 Hz), 5,86 (1H, d, J=15,0 Hz), 6,13 (1H, DD, J=1,1, and 11.0 Hz), of 6.52 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 653 (M+H)+.

Example 42. (8E,12E,14)-7-(N-(2-(N',N'-IER is ylamino)ethyl)-N-ethylcarbamate)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 42)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,6 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz)of 1.06 (6H, t, J=7.0 Hz), 1.06 a-1,15 (3H, m), 1,20-of 1.29 (1H, m), 1,22 (3H, s), 1,31-1,68 (7H, m)of 1.33 (3H, ), or 1.77 (3H, d, J=1.1 Hz), to 1.86 (1H, DD, J=5, 5,14, 3 Hz), 2,48-of 2.66 (5H, m), 2,59 (4H, q, J=7.0 Hz), to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,89 (1H, dt, J=2,2, 5,5 Hz), 3,21-of 3.60 (4H, m), 3,52 (1H, dt, J=4,4, 8,4 Hz), 3,74-3,81 (1H, m), is 4.93 (1H, d, J=9.9 Hz), is 5.06 (1H, d, J=a 10.6 Hz), to 5.57 (1H, DD, J=9,9, 15,0 Hz), 5,73 (1H, DD, J=9,9, 15,0 Hz), 5,86 (1H, d, J=15,4 Hz), 6,13 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 681 (M+H)+.

Example 43. (8E,12E,14)-7-Acetoxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 43)

(8E,12E,14)-7-Acetoxy-3,16,21-Tris(1-ethoxyethoxy)-6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old (34 mg, 44 μmol)obtained in example 3, and 1,8-bis(N,N-dimethylamino)naphthalene (57 mg, 266 μmol) was dissolved in toluene (2 ml). To the resulting solution was added methyltrichlorosilane (22 mg, 133 μmol) and the reaction mixture was stirred at 65°C for 11 hours. After removing the precipitate by filtration, the reaction mixture was diluted with ethyl acetate and was added an aqueous solution of ammonium chloride, followed by intensive stirring for 5 minutes. Organic is the cue layer was washed with saturated aqueous sodium bicarbonate solution and saturated salt solution, was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, neutral, 40-100 μm; hexane:ethyl acetate=1:1) to obtain (8E,12E,14)-7-acetoxy-3,16,21-Tris(1-ethoxyethoxy)-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (14 mg) as a colourless oil.

The compound obtained was subjected to the procedure of removal of the protective ethoxyethylene group method similar to that described in example 3, to obtain the specified title compound (5.7 mg, 22.9 per cent, two-stage) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.5 Hz), of 0.91 (3H, d, J=7.5 Hz), were 0.94 (3H, t, J=7.5 Hz), to 1.21 (3H, s), 1,22-1,32 (1H, m)of 1.34 (3H, s), 1,40-1,70 (7H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=5,5, 14,0 Hz), to 2.06 (3H, s), 2,46-2,63 (3H, m)to 2.67 (1H, d, J=8.5 Hz), 2,99 (1H, Sirs), to 3.33 (3H, s), 3,50 of 3.56 (1H, m), 3,78-3,86 (1H, m), is 5.06 (1H, d, J=10.5 Hz), 5,12 (1H, d, J=10.0 Hz), to 5.56 (1H, DD, J=10,0, 15,5 Hz), 5,72 (1H, DD, J=10,5, 15,5 Hz), by 5.87 (1H, d, J=15,5 Hz), 6,14 (1H, d, J=10.5 Hz), 6,53 (1H, DD, J=10,5, 15,5 Hz); ESI-MS m/z 589 (M+Na)+.

Example 44. (8E,12E,14)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 44)

The first stage

(8E,12E,14)-6-(1-Ethoxyethoxy)-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connected to the e 44-1)

To a solution of compound 46-4 (8E,12E,14)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (1.27 g, of 1.16 mmol)obtained in the fourth stage of example 46, in tetrahydrofuran (25 ml) was added triethylamine (470 mg, with 4.64 mmol) and isopropylpiperazine (298 mg, 2.32 mmol) at room temperature and the reaction mixture was stirred at the same temperature in for 1.5 hours. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; hexane:ethyl acetate=1:1 ethyl acetate ethyl acetate:methanol=97:3) to obtain the specified title compound (1.12 g, 89%) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,58-0,70 (27H, m), 0,80-1,72 (53H, m)of 1.76 (3H, s), 1,88-to 1.98 (1H, m), 2,33-of 2.64 (8H, m), 2,64 was 2.76 (1H, m), 2,80-2,90 (1H, m), 3,38-3,66 (6H, m), 3,68-3,7 8 (1H, m), 3,85-3,98 (1H, m,), 4,88-4,99 (2H, m), of 5.05 (0,4H, q, J=5,2 Hz), 5,13 (0,6H, q, J=5,2 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,72-5,80 (1H, m), of 5.82 (1H, d, J=14,8 Hz), 6,13 (1H, d, J=10,8 Hz), 6,50 (1H, DD, J=10,8, 15.2 Hz).

The second stage

(8E,12E,14)-6-(1-Ethoxyethoxy)-3,16,21-trihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,6,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 44-2)

To a solution of compound 44-1 (8E,12E,14)-6-(1-ethoxyethoxy)-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (1.12 g, of 1.03 mmol)obtained in the first stage, in tetrahydrofuran (20 ml) was added tetrabutylammonium (4,1 ml, 1.0 M tertrahydrofuran ring solution) at room temperature and the reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified column chromatography on silica gel (Fuji Silysia NH Silica gel, 200-350 mesh; ethyl > ethyl acetate:methanol=95:5) to obtain specified in the connection header (0,76 g, 99%) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.8 Hz), 0, 90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,0 6 (6H, d, J=6.4 Hz), 1,12-1,70 (20H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=2,4, a 7.6 Hz), 2,42-2,62 (7H, m), 2,64 was 2.76 (2H, m), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,38-3,66 (7H, m), 3.75 to-a-3.84 (1H, m), to 4.98 (1H, d, J=9.6 Hz), 5,02-5,16 (2H, m)to 5.56 (1H, DD, J=10,0, the 15.6 Hz), 5,72-5,80 (1H, m), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 737 (M+H)+.

The third stage

(8E,12E,14)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazine-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 44)

To a solution of compound 44-2 (8E,12E,14)-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (0,76 g of 1.03 mmol)obtained in the second stage, in a mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (20 ml) was added p-toluensulfonate pyridinium (0.39 g, 1.55 mmol) at room the temperature and the reaction mixture was stirred at the same temperature for 16 hours. To the reaction mixture were added at room temperature triethylamine (0.25 g, 3.10 mmol) and the organic solvent evaporated. The obtained residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified column chromatography on silica gel (Fuji Silysia NH Silica gel, 200-350 mesh; ethyl > ethyl acetate:methanol=95:5) to obtain specified in the connection header (0,76 g, 85%) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.6 Hz), of 0.90 (3H, d, J=6.9 Hz), were 0.94 (3H, t, J=7.4 Hz), with 1.07 (6H, d, J=6.4 Hz), 1,14-1,67 (14H, m), 1.77 in (3H, Sirs), to 1.86 (1H, DD, J=5,4, of 14.2 Hz), 2,46-2,63 (7H, m), of 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,64-and 2.79 (1H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,36-to 3.67 (5H, m), 3.72 points-3,81 (1H, m), is 4.93 (1H, d, J=9.7 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,7, 15.1 Hz),5,71 (1H, DD, J=9,7, 15.2 G is), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 665 (M+H)+.

Example 45. (8E,12E,14)-7-((4-Cycloheptatrien-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 45)

The first stage

(8E,12E,14)-7-((4-Cycloheptatrien-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 45-1)

To a solution of compound 46-4 (8E,12E,14)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (1,368 g, 1,254 mmol)obtained in the fourth stage of example 46, in tetrahydrofuran (20 ml), was added dropwise 1-cycloheptylmethyl (462 mg, 2.51 mmol) and triethylamine (513 mg, 5,02 mmol). Then to the mixture was added tetrahydrofuran (8 ml) and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium bicarbonate and a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; a mixture of ethyl acetate-hexane, 1:9 1:4 1:3) with the teachings specified in the connection header (1,455 g, 99%) as a colourless oil.

The second stage

(8E,12E,14)-7-((4-Cycloheptatrien-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 45-2)

A solution of compound 45-1 (8E,12E,14)-7-((4-cycloheptatrien-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (1,454 g, 1,254 mmol)obtained in the first stage, in tetrahydrofuran (30 ml) was cooled to 5°C, was added dropwise tetrabutylammonium (1.0 M tertrahydrofuran ring solution, 4.5 ml, 4.5 mmol) and the reaction mixture was stirred at room temperature for 1.5 hours. Added dropwise tetrabutylammonium (1.0 M tertrahydrofuran ring solution of 0.52 ml, 0.52 mmol) and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium bicarbonate and a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Fuji Silysia NH Silica gel, 200-350 mesh; a mixture of ethyl acetate-hexane, 1:1 4:1 9:1 1:0) obtaining specified in the connection header (965 mg, 97%) as a colourless oil.

ESI-MS m/z 791 (M+is) +.

The third stage

(8E,12E,14)-7-((4-Cycloheptatrien-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 45)

To a solution of compound 45-2 (8E,12E,14)-7-((4-cycloheptatrien-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (964 mg, 1,218 mmol)obtained in the second stage, in a mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (22 ml) was added p-toluensulfonate pyridinium (459 mg, 1,827 mmol) and the reaction the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium bicarbonate and a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Fuji Silysia NH Silica gel, 200-350 mesh; a mixture of ethyl acetate-hexane-methanol, 2:1:0 4:1:0 99:0:1 98:0:1 97:0:1) and the crude fraction was concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; a mixture of methanol-dichloromethane, 1:29 1:19 1:17 1:14 1:9) obtaining specified in the connection header (866 mg, 99%) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 G is), 1,10-1,77 (24H, m), 1.77 in (3H, Sirs), 1,79-1,90 (3H, m), 2,42-2,74 (9H, m), 2,85 of 2.92 (1H, m), 3,36-3,70 (5H, m), 3.72 points-of 3.84 (1H, m)to 4.92 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,71 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 719 (M+H)+.

Example 46. (8E,12E,14)-7-((4-Arylpiperazine-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 46)

The first stage

(8E,12E,14)-7-Acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 46-1)

To a solution of (8E,12E,14)-7-acetoxy-6,3,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (100 mg, 0.18 mmol) in dichloromethane (6 ml) was added N,N-dimethylaminopyridine (221 mg, 1.8 mmol) and chlorotriethylsilane (272 mg, 1.8 mmol) at room temperature and the reaction mixture was stirred at the same temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=20:80) to obtain the specified title compound (15 mg, 98%) as a colourless oil.

ESI-MS m/z 918 (M+Na)+.

The second stage

(8E,12E,14)-7-Acetoxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 46-2)

To a solution of compound 46-1 (8E,12E,14)-7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (1.6 g, 1.8 mmol)obtained in the first stage, in dichloromethane (35 ml) was added a simple ethylenically ether (2.6 g, 36 mmol) and p-toluensulfonate pyridinium (22 mg, 89 μmol) at room temperature and the resulting mixture was stirred at the same temperature for 19 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=10:90) to obtain the specified title compound (1.6 g, 93%) as a colourless oil.

ESI-MS m/z 990 (M+Na)+.

The third stage

(8E,12E,14)-6-(1-Ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 46-3)

To connect 46-2 (8E,12E,14)-7-acetoxy-6-(1-ethoxyethoxy)-6,10,12,1,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (1.6 g, 1.7 mmol)obtained in the second stage, was added guanidine/guanidine nitrate (41 ml, 0.2 M solution in a mixture of dichloromethane:methanol=10:90) at room temperature, followed by stirring at the same temperature for three hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=20:80) to obtain the specified title compound (1.3 g, 84%) as a colourless oil.

ESI-MS m/z 948 (M+Na)+.

The fourth stage

(8E,12E,14)-6-(1-Ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 46-4)

To a solution of compound 46-3 (8E,12E,14)-6-(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (1.3 g, 1.4 mmol)obtained in the third stage, in dichloromethane (30 ml) was added triethylamine (826 mg, 8.2 mmol), N,N-dimethylaminopyridine (831 mg, 6.8 mmol) and 4-nitrophenylphosphate (823 mg, 4.1 mmol) at room temperature and the resulting mixture was stirred at the same temperature for 1.5 hours. Reacts the traditional mixture was diluted with dichloromethane and washed with saturated aqueous solution of ammonium chloride, saturated aqueous sodium bicarbonate and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=10:90) to obtain the specified title compound (1.4 g, 97%) as a colourless oil.

ESI-MS m/z 1114 (M+Na)+.

Fifth stage

(8E,12E,14)-7-((Arylpiperazine-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 46-5)

To a solution of compound 46-4 (8E,12E,14)-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (37 mg, 34 μmol)obtained in the fourth stage, in tetrahydrofuran (2 ml) was added triethylamine (14 mg, 0.14 mmol) and arylpiperazine (8.5 mg, 68 μmol) at room temperature and the resulting mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N 40-100 μm; the ethyl acetate:hexane=30:70) to obtain the specified title compound (28 mg, 77%) as a colourless oil.

ESI-MS m/z 1078 (M+N)+.

Sixth stage

(8E,12E,14)-7-((4-Arylpiperazine-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 46)

To a solution of compound 46-5 (8E,12E,14)-7-((arylpiperazine-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (26 mg, 24 μmol)obtained in the fifth stage, in tetrahydrofuran (2.5 ml) was added tetrabutylammonium (79 μl, 1 M tertrahydrofuran ring solution) at room temperature and the resulting mixture was stirred at the same temperature for three hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel Plate; methanol:dichloromethane=5:95) to obtain specified in the title compound (13 mg, 72%) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.85-0.90 ( 6H, m)to 0.94 (3H, t, J=7,6 Hz), 1,12-1,68 (20H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=2,4, a 7.6 Hz), 2,38-2,62 (7H, m)to 2.67 (1H, DD, J=2,4, 8,0 Hz), 89 (1H, dt, J=2.0 a, 6,0 Hz), 3,03 (2H, d, J=6.4 Hz), 3,44-3,62 (7H, m), 3,76-a-3.84 (1H, m), 4,94-5,14 (3H, m), 5,16-of 5.26 (2H, m)to 5.56 (1H, DD, J=10,0, the 15.6 Hz), 5,70-of 5.82 (3H, m), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 735 (M+H)+.

Example 47. (8E,12E,14)-7-((4-Arylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 47)

To compound 46 (8E,12E,14)-7-((arylpiperazine-1-yl)carbonyl)oxy-6-(1-ethoxyethoxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (8,7 mg, 12 μmol)obtained in example 46 was added a solution of p-toluensulfonate pyridinium (3,3 mg, 13 µmol) in a mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (1 ml) at room temperature and the reaction mixture was stirred at the same temperature for 17 hours. The reaction mixture was concentrated. The obtained residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel Plate; methanol:dichloromethane=5:95) to obtain specified in the title compound (5.5 mg, 70%) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), to 1.21 (3H, s)of 1.34 (3H, s), 1,22 by 1.68 (8H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=2,4, a 7.6 Hz), 2,38 is 2.46 (4H, m), 2,48-2,60 (3H, m)to 2.67 (1H, DD, J=2,0, 8.0 Hz), 2,89 (1H, dt, J=2,0, 5.6 Hz), 3.04 from (2H, d, J=6.8 Hz), 3,42-of 3.64 (5H, m), 3,74-3,82 (1H, m)to 4.92 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), 5,16-5,2 6 (2H, m)to 5.57 (1H, DD, J=10,0, the 15.6 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), of 5.82-of 5.92 (2H, m), 6,13 (H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 663 (M+H)+.

Example 48. (8E,12E,14)-7-((4-(3,7-Dimethyl-2,6-octadien-1-yl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 48)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), to 1.21 (3H, s)of 1.34 (3H, s), 1,24 by 1.68 (8H, m)to 1.60 (3H, s)of 1.66 (6H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,04-of 2.16 (4H, m), 2.40 a is 2.46 (4H, m), 2,48-2,62 (3H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 5,2 Hz), to 3.02 (2H, d, J=6.8 Hz), 3,42-of 3.64 (5H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=10,0 Hz), 5,02-5,12 (2H, m), of 5.24 (1H, t, J=7.2 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,14 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 760 (M+H)+.

Example 49. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-pentylpyridine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 49)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=7,2 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz)to 1.21 (3H, s), 1,22-1,68 (20H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,6, of 13.7 Hz), 2,32-2,60 (9H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=1,6, 5.6 Hz), 3,40-3,70 (5H, m), 3,74-3,82(1H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,8, 15.2 Hz), 5,72 (1H, DD, J=10,8, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=9,2 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 693 (M+H)+.

Example 50. (8E,12E,14)-3,6,16,21-Tetrahydroxy-7-(((1S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 50)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1.06 a-1,12 (6H, m), 1.18 to 1,68 (16H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=5,7, of 13.7 Hz), 2,47-2,62 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6.4 Hz), 3,05 (1H, t, J=10.0 Hz), 3,19 (1H, DD, J=2,4, and 10.8 Hz), 3,48-3,68 (2H, m), of 3.78 (1H, Sirs), to 4.92 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.58 (1H, DD, J=9,6, 15.2 Hz), 5,68-5,78 (1H, m), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 677 (M+H)+.

Example 51. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(3-methyl-2-butene-1-yl)piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 51)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), to 1.21 (3H, s)of 1.34 (3H, s), 1,24-of 1.64 (8H, m)to 1.67 (3H, s), 1-75 (3H, s), 1.77 in (3H, what), to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,38-2,48 (4H, m), 2,50 of $ 2.53 (2H, m), 2,54-2,62 (1H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz)of 3.00 (2H, d, J=6.8 Hz), 3,42-3,66 (5H, m), 3,74-3,82 (1H, m), 4,93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), a 5.25 (1H, t, J=6.8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10.4 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 691 (M+H)+.

Example 52. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(morpholine-4-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 52)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), of 0.93 (3H, t, J=7.2 Hz), to 1.21 (3H, s)of 1.34 (3H, s), 1,24 is 1.70 (8H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,50-2,62 (3H, m), to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,86 of 2.92 (1H, m), 3,42 of 3.56 (5H, m), to 3.58-3,68 (4H, m), 3,76-3,82 (1H, m), of 4.95 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.58 (1H, DD, J=10,0, 15.2 Hz), 5,72 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 646 (M+Na)+.

Example 53. (8E,12E,14)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 53)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.4 Hz), 0,0 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), was 1.04 (6H, d, J=6,4 Hz)of 1.23 (3H, s), 1,23 was 1.69 (9H, m)of 1.34 (3H, s), 1.77 in (3H, s), 1.77 in-1,90 (2H, m), 2,47 was 2.76 (8H, m), 2,84 are 2.98 (2H, m), 3,42-3,68 (5H, m), 3,74-is 3.82 (1H, m), 4,94 (1H, d, J=9.6 Hz), of 5.05 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, the 15.6 Hz), 5,73 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, the 15.6 Hz); ESI-MS m/z 679 (M+H)+.

Example 54. (8E,12E,14)-3,6,16,21-Tetrahydroxy-7-((4-isobutylpyrazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 54)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.87 to 0.97 (15H, m)of 1.23 (3H, s), 1,23 was 1.69 (10H, m)of 1.34 (3H, s), 1.77 in (3H, s), 1,69-1,90 (2H, m), of 2.23 (2H, d, J=6.8 Hz), 2,50-2,70 (8H, m), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,43-3,66 (5H, m), 3,74-3,82 (1H, m), 4,94 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, the 15.6 Hz), 5,73 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, the 15.6 Hz); ESI-MS m/z 693 (M+H)+.

Example 55. (8E,12E,14)-7-((4-Cyclopentylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 55)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,15-2,20 (20H,m), of 1.23 (3H, s)of 1.34 (3H, s), 1.77 in (3H, s), 2,42 (2H, d, J=7,2 Hz), 2,46-2,74 (8H, m), 2,86 of 2.92 (1H, m), 3,40-3,68 (5H, m), 3.75 to 3,82 (1H, m), 4,94 (1H, d, J=9.6 Hz), 5,07 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, the 15.6 Hz); ESI-MS m/z 719 (M+H)+.

Example 56. (8E,12E,14)-7-(N-((3S)-1-Ethylpyrrolidin-3-yl)-N-methylcarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 56)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), of 1.12 (3H, t, J=7,6 Hz)of 1.23 (3H, s), 1,23 is 1.70 (9H, m)of 1.34 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,08-2,22 (1H, m), 2,38-2,90 (11H, m), 2,90 (3H, s), 3,28-to 3.33 (1H, overlapped CD3OD), 3,49 of 3.56 (1H, m), 3.75 to 3,82 (1H, m), 4,87-is 4.93 (1H, overlapped, H2O)of 5.06 (1H, d, J=10.4 Hz), to 5.58 (1H, DD, J=9,6, 15.2 Hz), 5,71 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, the 15.6 Hz); ESI-MS m/z 665 (M+H)+.

Example 57. (8E,12E,14)-7-((4-Cyclobutylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 57)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,89 (6H, q, j =6.8 Hz), of 0.94 (3H, t, J=7.2 Hz), of 1.23 (3H, s), 1,23-1,96 (16H, m)of 1.34 (3H, s), 1.77 in (3H, s), 2,02-2,12 (2H, m), 2,50-of 2.64 (8H, m), 2,64-2,70 (2H, m), 2,86 of 2.92 (1H, m), 3,40-3,68 (5H, m), 3.75 to 3,82 (1H, m), 4,94 (1H, d, J=9.6 Hz), 5,07 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz),5,72 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 705 (M+H)+.

Example 58. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(((2S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 58)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,20-2,03 (17H, m)of 1.23 (3H, s)of 1.34 (3H, s), 1.77 in (3H, s), 2,38-2,70 (10H, m), 2,85 of 2.92 (1H, m), 3.33 and-3,44 (1H, m), 3.49 points of 3.56 (1H, m), 3.75 to 3,82 (1H, m), 3,93-4,08 (2H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 691 (M+H)+.

Example 59. (8E,12E,14)-7-(((3S)-3,4-Dimethylpiperidin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 59)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t,J=7,6 Hz), a 1.08 (3H, d, J=6,4 Hz)to 1.21 (3H, s), 1,221 was 1.69 (8H, m)of 1.34 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,02-of 2.23 (2H, m), is 2.30 (3H, s), 2,46-2,84 (6H, m), 2,89 (1H, dt, J=2,0, 5.6 Hz), 2,94-of 3.12 (1H, m), 3,48-3,55 (1H, m), 3.75 to 3,82 (1H, m), 3,82-4,20 (2H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 651 (M+H)+.

Example 60. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(prop-2-in-1-yl)piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 60)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,22 (3H, s), 1,22 was 1.69 (8H, m)of 1.34 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,50-2,64 (7H, m), 2,64-2,70 (2H, m), 2,89 (1H, dt, J=2,0, 5.6 Hz), 3,30 (2H, d, J=2.4 Hz), 3,40-3,74 (5H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.58 (1H, DD, J=9,6, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 661 (M+H)+.

Example 61. (8E,12E,14)-7-((4-(But-2-in-1-yl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 61)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

1H-NMR spectra is R (CD 3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,22 (3H, s), 1,22 was 1.69 (8H, m)of 1.34 (3H, s), 1.77 in (3H, s), of 1.80 (3H, t, J=2,4 Hz)to 1.86 (1H, DD, J=14,0 of 5.6 Hz), 2,45-2,64 (7H, m)to 2.66 (1H, DD, J=2,0, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz)at 3.25 (2H, q, J=2,4 Hz), 3,40-and 3.72 (5H, m), 3,74-3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=10,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 675 (M+H)+.

Example 62. (8E,12E,14)-7-((4-Cyclobutylmethyl-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 62)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), of 1.23 (3H, s), 1,25-of 1.29 (1H, m)of 1.34 (3H, s), 1,34-1,71 (9H, m), 1.77 in (3H, Sirs), 1,80-1,90 (5H, m), 2,01-2,12 (2H, m), 2,38-2,62 (7H, m)to 2.66 (1H, DD, J=2.0 a, 7,6 Hz), 2,86-of 2.97 (2H, m), 3,42-to 3.67 (5H, m), 3.75 to 3,82 (1H, m), 4,94 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz),to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,72 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 691 (M+H)+.

Example 63. (8E,12E,14)-7-((4-Acylhomoserine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 63)

Specified in the title compound (colorless oil) was synthesized by the method is such described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.2 Hz), of 1.09 (3H, t, J=7.2 Hz), of 1.23 (3H, s), 1,23-of 1.30 (1H, m)of 1.34 (3H, s), 1,34 was 1.69 (7H, m), 1.77 in (3H, s), 1,83-of 1.92 (3H, m), 2,47-2,78 (10H, m), 2,89 (1H, dt, J=2,4, 6.4 Hz), 3,44-3,68 (5H, m), 3.75 to a 3.83 (1H, m), 4,94 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.58 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 665 (M+H)+.

Example 64. (8E,12E,14)-7-((4-Butyrometers-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 64)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz)of 0.95 (3H, t, J=7.2 Hz), of 1.23 (3H, s), 1,23-of 1.30 (1H, m), 1-34 (3H, s), 1.30 and 1.69 in (11H, m), 1.77 in (3H, s), to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 1,90-to 1.98 (2H, m), 2,47-2,62 (3H, m), 2,62-by 2.73 (3H, m), 2,78 are 2.98 (5H, m), 3,44-to 3.73 (5H, m), 3,76-3,82 (1H, m), of 4.95 (1H, d, J=10.4 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.58 (1H, DD, J=of 9.6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 693 (M+H)+.

Example 65. (8E,12E,14)-7-((4-Cyclohexylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 65)

Specified in the title compound (colorless oil) was synthesized what procedure, similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), the 1.06-1.69 in (20H, m), 1,74-1,90 (10H, m), 2,44-2,85 (9H, m), 2,89 (1H, dt, J=2,0, 5.6 Hz), 3,40-to 3.67 (5H, m), 3,74-a 3.83 (1H, m), 4,94 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 719 (M+H)+.

Example 66. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-(3-methyl-2-butene-1-yl)homopiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 66)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,16-1,67 (14H, m)to 1.67 (3H, s)of 1.76 (3H, s), 1.77 in (3H, s), 1,82-of 1.93 (3H, m), 2,44 is 2.80 (8H, m), 2,89 (1H, DD, J=2,4, 5,6 Hz), 3,17 (2H, d, J=7,2 Hz), 3,43-3,70 (5H, m), 3.72 points-a 3.83 (1H, m), of 4.95 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10.4 Hz), 5,20-and 5.30 (1H, m), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,72 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 705 (M+H)+.

Example 67. (8E,12E,14)-7-((4-(2-(N,N-Dimethylamino)ethyl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 67)

Specified in the title compound (colorless oil) was synthesized by the method of podobn the m described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), to 1.98-1.69 in (14H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=6,0, 15.2 Hz), of 2.33 (6H, s), 2.40 a-2,62 (11H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6.4 Hz), 3,38-3,70 (5H, m), 3,74-3,82 (1H, m), is 4.93 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=10,0, 15.2 Hz), 5,86 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 694 (M+H)+.

Example 68. (8E,12E,14)-7-((4-(2-(N,N-Diethylamino)ethyl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 68)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), a 1.08 (6H, t, J=7.2 Hz), to 1.21 (3H, s), 1,22-of 1.30 (1H, m)of 1.34 (3H, s), 1,34-1,68 (7H, m), 1.77 in (3H, s), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2.40 a-2,72 (16H, m), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,38-3,70 (5H, m), 3,74-3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), 5,86 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 722 (M+H)+.

Example 69. (8E,12E,14)-7-((4-(2,2-Dimethylpropyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 69)

Specified in the title compound (colorless oil) was synthesized SP is way similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,85 (6H, s)0,86 (3H, s)to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1.18 to 1,68 (14H, m), 1,72-1,82 (5H, m)to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,28 (2H, ), 2,46-2,62 (3H, m)to 2.66 (1H, DD, J=2,4,8,O Hz), 2,68 is 2.75 (2H, m), of 2.81 (2H, DD, J=5,2, 10.4 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,36-3,68 (5H, m), 3.72 points-is 3.82 (1H, m), 4,94 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=the 10.8 Hz), to 5.57 (1H, DD, J=9,6, 14,8 Hz), 5,73 (1H, DD, J=9,6, 14,8 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 707 (M+H)+.

Example 70. (8E,12E,14)-7-((4-Cyclopentylpropionate-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 70)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.2 Hz), 1.18 to 1,68 (18H, m), 1.70 to 1.77 in (2H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 1,88-2,02 (4H, m), 2,46-2,62 (3H, m)to 2.66 (1H, DD, J=2,0, 8.0 Hz), 2,82-to 3.02 (5H, m), is 3.08-up 3.22 (1H, m), 3,42-to 3.73 (5H, m), of 3.73-a-3.84 (1H, m), of 4.95 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.58 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=a 9.6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 705 (M+N)+.

Example 71. (8E,12E,14)-7-((4-Cyclopropylmethyl-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 71)

The criminal code is related to the title compound (colorless oil) was synthesized by the method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,34-0,52 (4H, m)to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,13-1,70 (15H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,35-of 2.72 (8H, m), 2,80-2,92 (1H, m), 3,30-3,68 (5H, m), 3,70-3,82 (1H, m)to 4.92 (1H, d, J=10.0 Hz), of 5.05 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,70 (1H, DD, J=9,6, 15.2 Hz), 5,86 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 663 (M+H)+, 685 (M+Na)+.

Example 72. (8E,12E,14)-7-((4-(1,1-Dimethylethyl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 72)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,10 (9H, s)to 1.22 (3H, s), 1,22-of 1.30 (1H, m)of 1.34 (3H, s), 1,35 was 1.69 (7H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,50-2,64 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,38-3,68 (5H, m), 3,74-3,82 (1H, m), is 4.93 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 73. (8E,12E,14)-7-((4-Cyclopropylmethyl-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 73)

Specified in the title compound (colorless is aslo) was synthesized by the method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,32-0,54 (4H, m)to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,14-1,68 (15H, m), 1,69-of 1.93 (6H, m), 2,42-2,62 (3H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,70 of 2.92 (5H, m), 3,38-3,68 (5H, m), 3,68-3,82 (1H, m), 4,94 (1H, d, J=10.4 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 677 (M+H)+.

Example 74. (8E,12E,14)-7-((4-(2,2-Dimethylpropyl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 74)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.87 to 0.92 (15H, m)to 0.94 (3H, t, J=7,6 Hz), 1,20-of 1.29 (4H, m), 1,31 was 1.69 (10H, m), 1.77 in (3H, d, J=1.2 Hz), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), is 2.09 (2H, s), 2,45-2,64 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,36-to 3.67 (5H, m), 3.75 to a 3.83 (1H, m)to 4.92 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, DD, J=1,6, and 10.8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 693 (M+H)+.

Example 75. (8E,12E,14)-7-(N-(2-(N',N'-Diethylamino)ethyl)-N-methylcarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 75)

Specified in the title compound (colorless oil) was synthesized by the method, the one described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,6 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz)of 1.06 (6H, shirt, J=7,0 Hz), 1,15-of 1.65 (7H, m)to 1.22 (3H, Sirs), of 1.33 (3H, s), of 1.65 (1H, DD, J=6,2, 14,3H), 1.77 in (3H, s)to 1.86 (1H, DD, J=6,2, and 14.3 Hz), 2,46-to 2.65 (5H, m), 2,59 (4H, q, J=7.0 Hz), to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,89 (1H, dt, J=2,2, 6.2 Hz), 2,92 (1,6H, s), 2,99 (1,4H, C), 3,28 is 3.40 (1H, m), 3,52 (1H, dt, J=4,0, 8,4 Hz), 3,52-3,62 (1H, m), 3,74-3,81 (1H, m)to 4.92 (1H, d, J=9.5 Hz), is 5.06 (1H, d, J=10,6 Hz)to 5.56 (1H, DD, J=9,9, 15,0 Hz), 5,72 (1H, DD, J=9,5, 15,0 Hz), 5,86 (1H, d, J=15,4 Hz), 6,13 (1H, d, J=of 11.0 Hz), of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 667 (M+H)+.

Example 76. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(morpholine-4-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 76)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,888 (3H, d, J=6.6 Hz), 0,894 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), 1,19-of 1.65 (7H, m), 1,22 (3H, s)of 1.33 (3H, s), of 1.65 (1H, DD, J=6,6, a 13.9 Hz), or 1.77 (3H, d, J=0.7 Hz), 1,86 (1H, DD, J=6,2, to 13.9 Hz), 2,45-2,61 (9H, m)to 2.66 (1H, DD, J=2,6, 7,7 Hz), 2,89 (1H, dt, J=2,6, 6.2 Hz), 2.91 in (1,6H, s), 2,98 (1,4H, C), 3,30 is-3.45 (1H, m), 3,52 (1H, dt, J=4,4, 8.1 Hz), 3,60-3,71 (5H, m), 3,74-3,81 (1H, m)to 4.92 (1H, d, J=9.9 Hz), is 5.06 (1H, d, J=a 10.6 Hz), 5,51-the ceiling of 5.60 (1H, m), 5,67 is 5.77 (1H, m), 5,86 (1H, d, J=15,0 Hz), 6,13 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 681 (M+H)+.

Example 77. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(piperidine-1-yl)ethyl)carbanilate)-18,19-epoxidic the for-8,12,14-trien-11-OLED (compound 77)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), 1,19-1,68 (17H, m)of 1.33 (3H, s), 1.77 in (3H, d, J=0.7 Hz), to 1.86 (1H, DD, J=5,5, to 13.9 Hz), 2,41-2,62 (9H, m), of 2.66 (1H, DD, J=2,6, 7,7 Hz), 2,87 of 2.92 (1H, m), 2,90 (1,6H, s), 2,98 (1,4H, C), 3,36 is-3.45 (1H, m), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), 3,55-3,62 (1H, m), 3,74-3,81 (1H, m), 4,86-is 4.93 (1H, m), of 5.05 (1H, d, J=10,6 Hz), to 5.56 (1H, DD, J=9,9, 15,0 Hz), 5,71 (1H, DD, J=10,6, 15,0 Hz), 5,86 (1H, d, J=15,4 Hz), 6,13 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 679 (M+H)+.

Example 78. (8E,12E,14)-7-(N-Ethyl-N-(2-(morpholine-4-yl)ethyl)carbanilate)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 78)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,886 (3H, d, J=6.6 Hz), 0,893 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), 1,08-1,17 (3H, m), 1,18-of 1.65 (7H, m), 1,22 (3H, s)of 1.33 (3H, s), of 1.65 (1H, DD, J=5,5, to 13.9 Hz), or 1.77 (3H, d, J=1.1 Hz), to 1.86 (1H, DD, J=5,5, to 13.9 Hz), 2,44-2,62 (9H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,89 (1H, dt, J=2,2, 5,5 Hz), 3,30-of 3.54 (3H, m), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), 3,54-3,71 (5H, m), of 3.73-3,81 (1H, m), 4.92 in (1H, sird, J=9.5 Hz), is 5.06 (1H, d, J=a 10.6 Hz), to 5.57 (1H, DD, J=9,9, 15,0 Hz), 5,67-5,78 (1H, m), 5,86 (1H, d, J=15,0 Hz), 6,13 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 695 (M+H)+.

Example 79. (8E,12E,14)-3,6,16,21-Tetrahed the hydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(pyrrolidin-1-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 79)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,6 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), 1,19-1,65 (10H, m)of 1.33 (3H, s), of 1.65 (1H, DD, J=5,5, and 14.3 Hz), 1,74-of 1.85 (4H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,5, and 14.3 Hz), 2,49 of 2.68 (10H, m), 2,86 of 2.92 (1H, m), 2.91 in (1,6H, s), 2,99 (1,4H, C), 3,39-of 3.60 (2H, m), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), to 3.73-3,81 (1H, m), 4,91 (1H, d, J=9.5 Hz), of 5.05 (1H, d, J=10,6 Hz), to 5.56 (1H, DD, J=9,9, to 15.4 Hz), 5,72 (1H, DD, J=9,5, to 15.4 Hz), 5,86 (1H, d, J=15,4 Hz), 6,13 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 665 (M+H)+.

Example 80. (8E,12E,14)-7-(N-(3-(N',N'-Diethylamino)propyl)-N-methylcarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 80)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,6 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz)of 1.05 (6H, t, J=7,3 Hz), 1,21-of 1.81 (10H, m)to 1.21 (3H, s)of 1.33 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,5, to 13.6 Hz), 2,46-2,62 (5H, m), 2,58 (4H, q, J=7,3 Hz)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,87-2,95 (1H, m), 2,89 (1,6H, s), 2,97 (1,4H, C), 3,20-of 3.32 (1H, m), 3,50-3,59 (1H, m), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), 3,74-is 3.82 (1H, m), is 4.93 (1H, d, J=9.9 Hz), is 5.06 (1H, d, J=10,6 Hz)to 5.56 (1H, DD, J=9,9, 15,0 Hz), 5,73 (1H, DD, J=9,9, 15,0 Hz), 5,86 (1H, d, J=15,4 Hz), 6,13 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 681 (M+H)+.

Example 81. (8E,12E,14)-3,6,6,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 81)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 3.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,6 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), 1,19 is 1.70 (7H, m), 1,20 (1,2H, C), 1,22 (1,8H, C)of 1.33 (3H, s), of 1.65 (1H, DD, J=6,2, and 14.3 Hz), 1,72-1,77 (1H, m), 1.77 in (3H, d, J=0.7 Hz), to 1.86 (1H, DD, J=6,2, and 14.3 Hz), 1,86-of 1.92 (1H, m), 2,38 (1,2H, s), 2.40 a (1,8H, s), 2,50-2,62 (3H, m), 2,63-2,7 0 (2H, m), 2,74-and 2.83 (1H, m), 2,89 (1H, dt, J=2,2, 6,2 Hz), 3,21 (0,6H, DD, J=1,8, a 10.6 Hz), 3,36 (0,4H, DD, J=1,8, a 10.6 Hz), 3,47-3,59 (3H, m), 3.75 to 3,82 (1H, m), 4,32 (0,4H, C), 4,55 (0,6H, s), 4,91 (1H, d, J=9.9 Hz), is 5.06 (1H, d, J=a 10.6 Hz), 5,68 is 5.77 (1H, m,), 5,51-5,61 (1H, m), 5,86 (1H, d, J=15,0 Hz), 6,13 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 649 (M+H)+.

Example 82. (8E,12E,14)-7-(((1S,4S)-5-Ethyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 82)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,93 (3H, d, J=6.8 Hz), were 0.94 (3H, d, J=6,8 Hz), and 0.98 (3H, t, J=7.2 Hz), 1,10-of 1.18 (3H, m), 1,22-1,74 (14H, m)1,80 (1H, Sirs), is 1.82 (3H, s), 1,87-of 1.95 (2H, m), of 2.51-2,77 (7H, m), 2,87-of 2.97 (2H, m), 3,23-3,29 (0,5H, m), 3,37-3,43 (0,5H, m), 3,51-3,63 (2H, m), 3,63 at 3.69 (1H, m), 3,79-a 3.87 (1H, m), 4,37 (0,5H, Sirs), 4,60 (0,5H, Sirs), 4,96 (1H, d, J=9.6 Hz), 5,11 (1H, d, J=10.4 Hz), 5,57-5,67 (1H, m), 5,72-5,67 (1H, m), 5,91 (1H, d, J=15.2 Hz), 6,18 (1H, d, J=11.2 Hz), to 6.57 (1H, DD, J=11,2, 15.2 Hz);ESI-MS m/z 663 (M+H) +.

Example 83. (8E,12E,14)-7-((4-Cyclooctylmethyl-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 83)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,94 (3H, d, J=6.8 Hz), were 0.94 (3H, d, J=6,8 Hz), and 0.98 (3H, t, J=7.2 Hz), 1,25 (3H, s), 1,25-1,87 (28H, m), 1,91 (1H, DD, J=5,6, 14.4 Hz), 2,50 was 2.76 (9H, m), with 2.93 (1H, dt, J=2.0 a, 6,0 Hz), 3,42-3,74 (5H, m), 3,78-3,88 (1H, m), equal to 4.97 (1H, d, J=9.6 Hz), 5,11 (1H, d, J=10.4 Hz), 5,61 (1H, DD, J=9,6, 15.2 Hz), USD 5.76 (1H, DD, J=9,6, 15.2 Hz), 5,91 (1H, d, J=15.2 Hz), 6,18 (1H, d, J=11.2 Hz), to 6.57 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 733 (M+H)+.

Example 84. (8E,12E,14)-7-((4-(Ethoxycarbonylmethyl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 84)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,20-of 1.42 (3H, m)to 1.21 (3H, s)of 1.26 (3H, t, J=7.2 Hz), of 1.34 (3H, s), 1,44-and 1.54 (2H, m), 1.56 to of 1.64 (2H, m,), of 1.65 (1H, DD, J=6,5, 14.4 Hz), of 1.78 (3H, s)to 1.86 (1H, DD, J=5,0, 14.4 Hz), 2,50-2,62 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,87-only 2.91 (1H, m), 3,26 (2H, s), 3,40-3,70 (4H, m), 3,50-3,55 (1H, m), 3.75 to-3,81 (1H, m)to 4.17 (2H, q, J=7.2 Hz), is 4.93 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,0, 15.2 G is), 5,71 (1H, DD, J=9,8, 15.2 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=10.0 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 731 (M+Na)+.

Example 85. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 85)

The first stage

(8E,12E,14)-7-Acetoxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 85-1)

To a solution of compound 46-1 (8E,12E,14)-7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (171 mg, 0,19 mmol)obtained in the first stage of example 46, in toluene (6 ml) was added methyltrichlorosilane (188 mg, to 1.14 mmol) and 1,8-bis(N,N-dimethylamino)naphthalene (368 mg, 1,71 mmol) at room temperature and the reaction mixture was stirred at 65°C for 14 hours. Then to the resulting mixture added methyltrichlorosilane (304 mg, 1.9 mmol) and 1,8-bis(N,N-dimethylamino)naphthalene (400 mg, 1.9 mmol) at room temperature and the reaction mixture was stirred at 65°C for 6 hours. The reaction mixture was diluted with diethyl ether and filtered through a glass filter. The filtrate was mixed with 28% aqueous ammonia (1 ml) and the reaction mixture was stirred at room temperature for one hour and consequently is washed with saturated salt solution, 0.1 M aqueous citric acid solution, saturated aqueous sodium bicarbonate and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=10:90) to obtain the specified title compound (141 mg, 84%) as a colourless oil.

ESI-MS m/z 932 (M+Na)+.

The second stage

(8E,12E,14)-7-Hydroxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 85-2)

To a solution of compound 85-1 (8E,12E,14)-7-acetoxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (158 mg, 0,17 mmol)obtained in the first stage, in methanol (5 ml) was added potassium carbonate (120 mg, 0.87 mmol) at room temperature, after which the reaction mixture was stirred at the same temperature for three hours. The reaction mixture was diluted with ethyl acetate and washed with saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude product was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=10:90) to obtain the specified title compound (91 mg, 61%) as a colourless what about the oil.

ESI-MS m/z 890 (M+Na)+.

The third stage

(8E,12E,14)-6-Methoxy-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 85-3)

To a solution of compound 85-2 (8E,12E,14)-7-hydroxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (91 mg, 0.11 mmol)obtained in the second stage, in dichloromethane (4 ml) was added triethylamine (64 mg, 0.52 mmol), N,N-dimethylaminopyridine (64 mg, 0.52 mmol) and 4-nitrophenylphosphate (63 mg, 0.31 mmol) at room temperature and the reaction mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=10:90) to obtain the specified title compound (97 mg, 89%) as a colourless oil.

ESI-MS m/z 1055 (M+Na)+.

The fourth stage

(8E,12E,14)-6-Methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 85-4)

The solution is connected to the I 85-3 (8E,12E,14)-6-methoxy-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (30 mg, 29 μmol)obtained in the third stage, in tetrahydrofuran (2 ml) was added triethylamine (11 mg, 0.12 mmol) and 1-methylpiperazine (5,8 mg, 58 μmol) at room temperature and the reaction mixture was stirred at the same temperature for one hour. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; methanol:dichloromethane=3:97) to obtain the specified title compound (26 mg, 89%) as a colourless oil.

ESI-MS m/z 994 (M+N)+.

Fifth stage

(8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 85)

To a solution of compound 85-4 (8E,12E,14)-6-methoxy-6,10,12,16,20-pentamethyl-7-(4-methylpiperazin-1-yl)carbonyl)oxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (25 mg, 25 μmol)obtained in the fourth stage, in tetrahydrofuran (3 ml) was added tetrabutylammonium (83 μl, 1.0 M tertrahydrofuran ring solution) at room temperature, after which the reaction mixture was stirred at the same temperature for 1.5 hours. The reactions is nnow mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel Plate; methanol:dichloromethane=5:95) to obtain specified in the title compound (11 mg, 67%) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), to 1.21 (3H, s)of 1.34 (3H, s), 1,22 was 1.69 (8H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=5,6, 14,0 Hz)to 2.29 (3H, s), 2,36 is 2.44 (4H, m), 2,45-2,60 (3H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,86 of 2.92 (1H, m)to 3.34 (3H, s), 3,44-to 3.58 (5H, m), 3,78-3,86 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=11.2 Hz), to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=9,2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 651 (M+H)+.

Example 86. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 86)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,22 (3H, s), 1,22-to 1.82 (8H, m)of 1.34 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=6,0, of 14.0 Hz), 2,44-2,62 (3H, m), to 2.66 (1H, DD, J=2,0, 8.0 Hz), 2,70-2,82 (4H, m), 2,89 (1H, dt, J=2,4, 5,6 Hz), of 3.25 to 3.36 (3H, overlapped CD3OD), 3,38-3,55 (5H, m), 3,78-3,86 (1H, m), 5,02 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, the 15.6 Hz), 5,73 (1H, DD, J=9,6, the 15.6 Hz), 5,86 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=11.2 G is), of 6.52 (1H, DD, J=11,2, the 15.6 Hz); ESI-MS m/z 637 (M+H)+.

Example 87. (8E,12E,14)-7-(N-(2-(N',N'-Diethylamino)ethyl)carbanilate)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 87)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.0 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.06 (6H, t, J=7.2 Hz), 1,22 (3H, s), 1,22 is 1.70 (8H, m)of 1.34 (3H, s)of 1.78 (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,44-2,64 (9H, m)to 2.66 (1H, DD, J=2,0, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,21 (2H, t, J=7.2 Hz), of 3.25 to 3.36 (3H, overlapped CD3OD), 3,48 of 3.56 (1H, m), of 3.77-of 3.85 (1H, m), equal to 4.97 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz)5,54 (1H, DD, J=10,0, 15.2 Hz), 5,71 (1H, DD, J=9,6, the 15.6 Hz), 5,86 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=11,2, the 15.6 Hz); ESI-MS m/z 667 (M+H)+.

Example 88. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-methylpiperidin-4-yl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 88)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,17-1,69 (16H, m), 1,72-1,90 (6H, m), 2,10-2,2 6 (2H, m), of 2.33 (3H, s), 2,44-2,62 (3H, m)to 2.66 (1H, DD, J=to 2.4, 8.0 Hz), 2,82 (3H, s), 2,89 (1H, dt, J=2,4, 6,0 Hz), 2.95 and-3,03 (2H, m)to 3.35 (3H, s), 3,52 (1H, dt, J=4,4,8,0 Hz), 3,78-of 3.85 (1H, m), 3,92-Android 4.04 (1H, m), of 5.03 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 89. (8E,12E,14)-7-((4-(N,N-dimethylamino)piperidine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 89)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.0 Hz), to 0.89 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,17-1,68 (16H, m), of 1.78 (3H, s), 1,81-of 1.94 (3H, m)to 2.29 (6H, s), 2,34-2,63 (4H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,73-2,89 (2H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz)to 3.33 (3H, s), 3,52 (1H, dt, J=4,4, 7,6 Hz), 3,78-of 3.85 (1H, m), 4,10-4,30 (2H, m), free 5.01 (1H, d, J=9,2 Hz), is 5.06 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 90. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-papillomaviruses-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 90)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): from 0.84 to 0.92 (9H, m)to 0.94 (3H, t, J=7.2 Hz), 1,24 (3H, s)of 1.34 (3H, s), 1,22 was 1.69 (10H, m), of 1.78 (3H, d, J=0.8 Hz), 1,82-1,90 (3H, m), 2,4 0-2,72 (10H, m), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,24-to 3.36 (3H, overlapped CD3OD), 3,44-of 3.60 (5H, m), 3,78-3,86 (1H, m), of 5.03 (1H, d, J=9.6 Hz), 5,07 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,74 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, the 15.6 Hz); ESI-MS m/z 693 (M+H)+.

Example 91. (8E,12E,14)-7-((4-Butyrometers-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 91)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,86-and 0.98 (12H, m)of 1.23 (3H, Sirs), of 1.34 (3H, s), 1,22 is 1.70 (12H, m), of 1.78 (3H, d, J=0.8 Hz), 1,82-1,89 (3H, m), 2,44-2,74 (10H, m), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,30 (3H, s), 3,42-to 3.58 (5H, m), 3,79-of 3.85 (1H, m), of 5.03 (1H, d, J=9,2 Hz), 5,07 (1H, d, J=10.4 Hz), to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,74 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 707 (M+H)+.

Example 92. (8E,12E,14)-7-((4-Cyclopropylmethyl-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 92)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,38 at 0.42 (2H, m), 0,47-0,52 (2H, m)to 0.88 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.2 Hz), of 1.23 (3H, s)of 1.34 (3H, s), 1,22 by 1.68 (9H, m), of 1.78 (3H, d, J0,8 Hz), 1,80-of 1.92 (3H, m), 2,44-2,60 (3H, m)to 2.66 (1H, DD, J=2.0 a, 7,6 Hz), 2,74-2,87 (4H, m), 2,89 (1H, dt, J=1,6, 5,6 Hz)to 3.33 (3H, s), 3,44-of 3.60 (5H, m), 3,78-3,86 (1H, m), of 5.03 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,4 Hz)to 5.56 (1H, DD, J=10,0, the 15.6 Hz), 5,74 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 691 (M+H)+.

Example 93. (8E,12E,14)-7-((4-Cyclobutylmethyl-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 93)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.23 (3H, s)of 1.34 (3H, s), 1,22-1,72 (10H, m), of 1.78 (3H, s), 1,80-1,90 (5H, m), 2,02 is 2.10 (2H, m), 2,41-2,60 (7H, m)to 2.67 (1H, DD, J=2,4,8,O Hz), 2,86-to 2.94 (2H, m), 3,24-to 3.36 (3H, overlapped CD3OD), 3,44-of 3.60 (5H, m), 3,78-3,86 (1H, m), of 5.03 (1H, DD, J=2,0, 9.6 Hz), 5,07 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,74 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,14 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 705 (M+H)+.

Example 94. (8E,12E,14)-7-((4-Cyclopentylpropionate-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 94)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (m is.): to 0.88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.23 (3H, s)of 1.34 (3H, s), 1,36-1,72 (16H, m), of 1.78 (3H, d, J=0.8 Hz), 1,82-1,90 (3H, m), 2,44-2,60 (3H, m), 2,64-2,70 (3H, m), 2,73-2,82 (2H, m), 2,84-to 2.94 (2H, m), 3,24-to 3.36 (3H, overlapped CD3OD), 3,44-of 3.60 (5H, m), 3,78-3,86 (1H, m), 5,04 (1H, d, J=11,6 Hz), 5,07 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=9,6, the 15.6 Hz), 5,74 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 719 (M+H)+.

Example 95. (8E,12E,14)-7-((4-Cyclohexylpiperazine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 95)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.0 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), of 1.23 (3H, s)of 1.34 (3H, s), 1,12-1,68 (18H, m), of 1.78 (3H, d, J=0.8 Hz), 1,75-1,89 (3H, m), 2,42-2,60 (4H, m), 2,64-of 2.72 (3H, m), 2,75-2,82 (2H, m), 2,89 (1H, dt, J=1,2, 5,2 Hz), 3,26-to 3.36 (3H, overlapped CD3OD), 3,42 of 3.56 (5H, m), 3,78-3,86 (1H, m), of 5.03 (1H, DD, J=3.2, and 9.6 Hz), 5,07 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,74 (1H, DD, J=10,0, 14,8 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 733 (M+H)+.

Example 96. (8E,12E,14)-3,16,21-Trihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 96)

Specified in the title compound (colorless oil) synthesisof is there any way similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.0 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.03 (6H, d, J=6.4 Hz), 1,24 (3H, s)of 1.34 (3H, s), 1,22 was 1.69 (8H, m), of 1.78 (3H, s), 1,76-1,90 (3H, m), 2,44-2,74 (8H, m), 2,86-to 2.94 (2H, m)to 3.33 (3H, s), 3,44-of 3.60 (5H, m), 3,79-3,86 (1H, m), of 5.03 (1H, DD, J=4,4, 9.6 Hz), 5,07 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=10,8, 16.0 Hz), 5,74 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11,6 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 693 (M+H)+.

Example 97. (8E,12E,14)-3,16,21-Trihydroxy-7-((4-isobutylpyrazine-1-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 97)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,84-0,95 (15H, m)of 1.26 (3H, s)of 1.34 (3H, s), 1,22 to 1.76 (9H, m), of 1.78 (3H, s)of 1.78-1.90 (3H, m), of 2.23 (2H, d, J=6.8 Hz), 2,44-of 2.72 (8H, m), 2,89 (1H, dt, J=2.0 a, 5,2 Hz), 3,24-3,38 (3H, overlapped CD3OD), 3,42-to 3.58 (5H, m), 3,78-3,86 (1H, m), of 5.03 (1H, d, J=9.6 Hz), 5,07 (1H, d, J=10.4 Hz), to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,74 (1H, DD, J=9,2, 14,8 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 707 (M+H)+.

Example 98. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(morpholine-4-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 98)

Specified in the title compound (colorless oil) sintesio the Ali method, similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=5,2 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz)to 1.21 (3H, s)of 1.34 (3H, s), 1,24 by 1.68 (10H, m), of 1.78 (3H, d, J=1.2 Hz), 1,82 is 1.96 (3H, m), 2,32 is 2.43 (1H, m,), 2,44-2,62 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,74 of 2.92 (3H, m), of 3.32 (3H, s), 3,52 (1H, dt, J=3,6, 8.0 Hz), 3,64-3,74 (4H, m), 3,78-3,86 (1H, m), 4,08-to 4.28 (2H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz)5,54 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 721 (M+H)+.

Example 99. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(pyrrolidin-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 99)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=5.6 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,22 (3H, s)of 1.34 (3H, s), 1,23 is 1.70 (10H, m), of 1.78 (3H, s), 1,79-1,90 (5H, m), 1,92 is 2.00 (2H, m), 2,20-2,30 (1H, m), 2,44 of 2.68 (8H, m), was 2.76 of 2.92 (3H, m), 3,24-to 3.36 (3H, overlapped CD3OD), 3,52 (1H, dt, J=4,8, 8.0 Hz), of 3.77-3,86 (1H, m), 4.04 the-4,24 (2H, m), free 5.01 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 705 (M+H)+.

Example 100. (8E,12E,14)-3,16,21-Trihydroxy-7-((4-(4-hydroxypiperidine-1-yl)piperidine-1-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old (with the Association 100)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.0 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz)to 1.21 (3H, s)of 1.34 (3H, s), 1,22 was 1.69 (12H, m), of 1.78 (3H, s), 1,82-of 1.93 (5H, m), 2,28-of 2.38 (2H, m), 2,43-2,58 (4H, m)to 2.67 (1H, DD, J=2.0 a, 7,6 Hz), 2,72-and 2.83 (5H, m), 3,24-3,39 (3H, overlapped CD3OD), 3,52 (1H, dt, J=4,8, 8.0 Hz), 3,56-of 3.64 (1H, m), 3,78-3,86 (1H,m), 4,10-4,30 (2H, m)5,00 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), of 5.55 (1H, DD, J=10,4, 15.2 Hz), 5,73 (1H, DD, J=10,0, the 15.6 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 735 (M+H)+.

Example 101. (8E,12E,14)-7-(N-(3-(N',N'-Dimethylamino)propyl)-N-methylcarbamoyl)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 101)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.0 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,22 (3H, s)of 1.34 (3H, s), 1,20-of 1.78 (10H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=6,3, 14,5 Hz), 2,24 (6H, s), 2,31 (2H, t, J=8,8 Hz), 2,44-2,60 (3H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,85-2,96 (4H, m), 3,22-to 3.38 (5H, blocked CD3OD), 3,52 (1H, DD, J=3,6, 8.0 Hz), 3,78-of 3.85 (1H, m), free 5.01 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10.4 Hz), of 5.55 (1H, DD, J=9,6, 15.2 Hz), 5,74 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 667 (M+H)+.

When the EP 102. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(morpholine-4-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 102)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,22 (3H, s)of 1.34 (3H, s), 1,23 was 1.69 (8H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=4,6, and 12.7 Hz), 2,44-2,56 (9H, m), to 2.66 (1H, DD, J=2,4, a 7.6 Hz), 2,86-2,96 (4H, m), 3,22-to 3.38 (2H, overlapped CD3OD), to 3.34 (3H, s), 3,52 (1H, dt, J=4,0, 8.0 Hz), 3,62-and 3.72 (4H, m), 3,78-a-3.84 (1H, m), free 5.01 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), of 5.55 (1H, DD, J=10,0, 15.2 Hz), 5,68-5,79 (1H, m), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10.4 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 695 (M+H)+.

Example 103. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(pyrrolidin-1-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 103)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,22 (3H, s)of 1.34 (3H, s), 1,23 by 1.68 (8H, m), of 1.78 (3H, d, J=0.8 Hz), 1,78 of-1.83 (4H, m)to 1.86 (1H, DD, J=5,4, 13.1 Hz), 2,44 of 2.68 (10H, m), 2,86-of 2.97 (4H, m)to 3.34 (3H, s), 3,40-of 3.48 (2H, m), 3,52 (1H, dt, J=4,0, a 7.6 Hz), 3,78-3,86 (1H, m)5,00 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), of 5.55 (1H, DD, J=10,0, 14,8 Hz), 5,74(1H, DD, J=9,6, 14,8 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 104. (8E,12E,14)-7-(N-(3-(N',N'-Diethylamino)propyl)-N-methylcarbamoyl)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 104)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.05 (6H, t, J=7.2 Hz), 1,22 (3H, s)of 1.34 (3H, s), 1,20-1,82 (10H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=5,6, 14.4 Hz), 2,42-2,60 (9H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,84-2,96 (4H, m), 3,22 is 3.40 (5H, blocked CD3OD), 3,52 (1H, dt, J=3,6, 8.0 Hz), 3,78-3,86 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), of 5.55 (1H, DD, J=10,0, the 15.6 Hz), 5,74 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10.0 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 695 (M+H)+.

Example 105. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 105)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.29 (4H, m)of 1.34 (3H, s), 1,38 was 1.69 (7H, m), of 1.78 (3H, d, J=0.8 Hz), 1,83-of 1.93 (3H, m)to 2.35 (3H, ), 2,45-to 2.65 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz),2,89 (1H, dt, J=2,4, 6,0 Hz), 3,32 (1,5H, s), 3.33 and (1,5H, s), 3.46 in-3,62 (5H, m), 3,79-3,86 (1H, m), 5,01-of 5.06 (1H, m), 5,07 (1H, d, J=10.4 Hz), to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,74 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, DD, J=1,2, 11.2 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 665 (M+H)+.

Example 106. (8E,12E,14)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 106)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.11 (3H, t, J=7,6 Hz), 1,20-of 1.29 (4H, m)of 1.34 (3H, s), 1,37 was 1.69 (7H, m), of 1.78 (3H, d, J=0.8 Hz), 1,86 (1H, DD, J=5,2, of 14.0 Hz), 2,41-2,63 (9H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,32 (3H, s), 3,43-3,59 (5H, m), 3,79-3,86 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), 5.56mm (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, DD, J=1,2, and 10.8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 665 (M+H)+.

Example 107. (8E,12E,14)-7-((4-Acylhomoserine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 107)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), a 1.08 (3H, t, J=7.2 for the TS) 1,19-of 1.29 (4H, m)of 1.34 (3H, s), 1,38 is 1.70 (7H, m), of 1.78 (3H, d, J=0.8 Hz), 1,82-1,90 (3H, m), 2,45-2,73 (10H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3.33 and (1,5H, s), 3.33 and (1,5H, s), 3.46 in-3,62 (5H, m), 3,79-3,85 (1H, m), 5,00-of 5.06 (1H, m), 5,07 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,74 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 108. (8E,12E,14)-7-(N-(2-(N',N'-Dimethylamino)ethyl)-N-methylcarbamoyl)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 108)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.29 (4H, m)of 1.34 (3H, s), 1,38 is 1.70 (7H, m), of 1.78 (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), of 2.27 (6H, s), a 2.45-2.63 in (5H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,87-of 2.97 (4H, m), 3,30-to 3.36 (3H, m), 3,37-of 3.46 (2H, m), 3,52 (1H, TD, J=4,4, 8.0 Hz), 3,78-of 3.85 (1H, m)5,00 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), of 5.55 (1H, DD, J=9,6, 15.2 Hz), 5,69-5,79 (1H, m), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 653 (M+H)+.

Example 109. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(piperidine-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 109)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR-spectrum CD 3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.29 (4H, m), 1,31-1,69 (18H, m), of 1.78 (3H, s), 1,83-of 1.93 (3H, m), 2,41-2,61 (8H, m)to 2.67 (1H, DD, J=the 2.4, 8.0 Hz), 2,70-is 2.88 (2H, m), 2,89 (1H, dt, J=2.0 a, 6,0 Hz)to 3.33 (3H, s), 3,52 (1H, TD, J=4,4, 8.0 Hz), 3,78-of 3.85 (1H, m), 4,11-the 4.29 (2H, m)5,00 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz),to 5.56 (1H, DD, J=of 9.6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 719 (M+H)+.

Example 110. (8E,12E,14)-3,16,21-Trihydroxy-7-((4-(isopropylpiperazine-1-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 110)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.07 (6H, d, J=6.8 Hz), 1,20-of 1.29 (4H, m), of 1.32 to 1.76 (10H, m), of 1.78 (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,6, of 14.0 Hz), a 2.45-2.63 in (7H, m), 2,64 is 2.75 (2H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,32 (3H, s), 3,42-3,59 (5H, m), 3,78-3,86 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 111. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-propylpiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 111)

Specified in the title compound (colorless oil) was synthesized SP is way similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), of 0.93 (3H, t, J=7.2 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,20-1,30 (4H, m)of 1.34 (3H, s), 1,39 was 1.69 (9H, m), of 1.78 (3H, d, J=1.2 Hz), 1,87 (1H, DD, J=5,2, of 14.0 Hz), 2,31-is 2.37 (2H, m), 2.40 a 2.63 in (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,90 (1H, dt, J=2.0 a, 6,0 Hz), 3,32 (3H, s), 3,42-of 3.60 (5H, m), 3,79-3,86 (1H, m), 5,02 (1H, d, J=9.6 Hz), 5,07 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,74 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,14 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 112. (8E,12E,14)-7-((4-Butylpiperazine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 112)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,19-of 1.29 (4H, m)of 1.29-1.69 in (14H, m), of 1.78 (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,34-2,39 (2H, m), 2.40 a 2.63 in (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,32 (3H, s), 3,41-of 3.60 (5H, m), 3,79-of 3.85 (1H, m), free 5.01 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 693 (M+H)+.

Example 113. (8E,12E,14)-3,16,21-Trihydroxy-7-((4-isobutylpyrazine-1-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 113)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6,8 Hz)of 0.91 (6H, d, J=6.4 Hz), were 0.94 (3H, t, J=7,6 Hz), 1, 19-1,29 (4H, m)of 1.34 (3H, s), 1,39 was 1.69 (7H, m), 1,76-1,90 (5H, m), 2,11 (2H,, d, J=7,2 Hz), 2,33-to 2.41 (4H, m), a 2.45-2.63 in (3H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,32 (3H, s), 3,40-to 3.58 (5H, m), 3,79-3,86 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=the 10.8 Hz), to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 693 (M+H)+.

Example 114. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-7-((4-(2-methoxyethyl)piperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 114)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.29 (4H, m)of 1.34 (3H, s), 1,38 was 1.69 (7H, m), of 1.78 (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,44-2,63 (9H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,32 (3H, s)to 3.33 (3H, s), 3,41-3,59 (7H, m), 3,78-of 3.85 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 695 (M+H)+.

Example 115. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(tetrahydropyran-4-yl)who piperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 115)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.29 (4H, m)of 1.34 (3H, s), 1,38 was 1.69 (9H, m), 1.77 in-of 1.85 (5H, m)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,43-2,63 (8H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,32 (3H, s), 3,35-of 3.43 (2H, m), 3,43-3,59 (5H, m), 3,78-of 3.85 (1H, m), 3,98 (2H, DD, J=4,4, 11.2 Hz), free 5.01 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, DD, J=1,2, 11.2 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 721 (M+H)+.

Example 116. (8E,12E,14)-7-((4-Cyclopropylmethyl-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 116)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,40-0,46 (2H, m), 0,46-of 0.53 (2H, m)to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.29 (4H, m)of 1.34 (3H, s), 1,38 is 1.70 (8H, m), of 1.78 (3H, d, J=0,8 Hz)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), a 2.45-2.63 in (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,32 (3H, s), 3,37 of 3.56 (5H, m), 3,78-of 3.85 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=the 10.8 Hz), to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, DD, J=1,2, and 10.8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 677 (M+H)+.

Example 117. (8E,12E,14)-7-((4-Cyclobutyl the piperazine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 117)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.29 (4H, m)of 1.34 (3H, s), 1,39-of 1.78 (9H, m), of 1.78 (3H, d, J=0.8 Hz), 1,83-of 1.95 (3H, m), 2,02 is 2.10 (2H,, m), 2,31 (4H, t, J=4,8 Hz), a 2.45-2.63 in (3H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,72-of 2.81 (1H, m), 2,89 (1H, dt, J=2.0 a, 6,0 Hz)and 3.31 (3H, s), 3,40-to 3.58 (5H, m), 3,78-of 3.85 (1H, m), free 5.01 (1H, d, J=9.6 Hz), 5,06 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 691 (M+H)+.

Example 118. (8E,12E,14)-7-((4-Cyclopentylpropionyl-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 118)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,19-of 1.29 (4H, m)of 1.34 (3H, s), 1,36-1,77 (13H, m), of 1.78 (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 1,86-of 1.95 (2H, m), 2,44-2,63 (8H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,32 (3H, s), 3,42-3,59 (5H, m), 3,78-of 3.85 (1H, m), free 5.01 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10.4 Hz), to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, DD, J=1,2, and 10.8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 705 (M+H)+.

Example 119. (8E,12E,14)-7-((4-Cyclohexylpiperazine--yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 119)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), of 1.09 and 1.33 (10H, m)of 1.34 (3H, s), 1,39 was 1.69 (7H, m), of 1.78 (3H, d, J=0.8 Hz), 1,78-of 1.93 (5H, m), and 2.27 to 2.35 (1H, m), 2,45-to 2.65 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,32 (3H, s), 3,39-to 3.58 (5H, m), 3,79-3,86 (1H, m), free 5.01 (1H, d, J=9.6 Hz), 5,07 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,74 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 719 (M+H)+.

Example 120. (8E,12E,14)-7-((4-Cycloheptatrien-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 120)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m)of 1.34 (3H, s), 1,38-1,75 (17H, m), of 1.78 (3H, d, J=0.8 Hz), 1,79 is 1.86 (2H, m)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,45-of 2.64 (8H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,32 (3H, s), 3,39 is 3.57 (5H, m), 3,78-of 3.85 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 733 (M+H)+.

Example 121. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-IU the Il-2,5-diazabicyclo[2.2.1]heptane-2-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 121)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,20-of 1.29 (4H, m)of 1.34 (3H, s), 1,40 was 1.69 (7H, m), 1,74-to 1.82 (4H, m), 1,83-of 1.93 (2H, m), 2,38 (1,2H, C), 2,41 (1,8H, s), 2,44-2,63 (3H, m), 2,65-a 2.71 (2H, m), of 2,75 2,85 (1H, m), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,20-3,30 (1H, m), 3.33 and (1,8H, s), 3,34 (1,2H, s), 3.46 in-3,59 (3H, m), 3,79-of 3.85 (1H, m), 4,32 (0,4H, s), 4,42 (0,6H, s), 4,98-5,04 (1H, m), is 5.06 (1H, d, J=10.4 Hz), to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,74 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 663 (M+H)+.

Example 122. (8E,12E,14)-7-(((1S,4S)-5-Ethyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 122)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), of 1.05 to 1.13 (3H, m), 1,20-1,30 (4H, m)of 1.34 (3H, s), 1,38 was 1.69 (7H, m), of 1.78 (3H, d, J=0.8 Hz), 1,83 is 1.91 (2H,, m), 2,45-of 2.72 (8H, m), 2,82-of 2.93 (2H, m), 3,20-of 3.31 (1H, m), 3.33 and (1,5H, s), 3,34 (1,5H, s), 3,50-of 3.64 (3H, m), 3,79-of 3.85 (1H, m), 4,32 (0,5H, s), 4,42 (0,5H, s), 4,98-5,04 (1H, m), is 5.06 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,74 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, DD, J=1,2, and 10.8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 677 (M+H)+.

Example 123. (8E,2E,14)-3,16,21-Trihydroxy-7-(((1S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)carbonyl)oxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 123)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), of 1.05 to 1.11 (6H, m), 1,19-of 1.30 (4H, m)of 1.34 (3H, s), 1,37 was 1.69 (7H, m), 1,73-1,90 (5H, m), 2,45-to 2.65 (6H, m), to 2.67 (1H, DD, J=2,4, 8,0), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,01-3,20 (1H, m), 3,18 to be 3.29 (1H, m), 3,32-to 3.35 (3H, m), 3,52 (1H, TD, J=a 4.4, and 8.4 Hz), 3,54-the 3.65 (1H, m), 3,76-3,86 (2H, m), 4,30 (0,5H, s), and 4.40 (0,5H, s), 4,98-5,09 (2H, m), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,70-5,79 (1H, m), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 691 (M+H)+.

Example 124. (8E,12E,14)-7-((4-(2-(N,N-Dimethylamino)ethyl)piperazine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 124)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m)of 1.34 (3H, s), 1,37 was 1.69 (7H, m), of 1.78 (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), of 2.27 (6H, s), 2,43-2,48 (4H, m), 2,48-2,62 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,32 (3H, s), 3,41-3,59 (5H, m), 3,78-of 3.85 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 708 (M+H)+.

Example 125. (8E,12E,14)-3,16,21-Trihydroxy-6-m the toxi-6,10,12,16,20-pentamethyl-7-((4-(1-methylpiperidin-4-yl)piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 125)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.30 (4H, m)of 1.34 (3H, s), 1,39 was 1.69 (9H, m), of 1.78 (3H, d, J=1.2 Hz), 1,83-1,90 (3H, m), 1,98-2,07 (2H,, m), 2,24 is 2.33 (1H, m), of 2.25 (3H, s), 2,45-2,62 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,87-2,96 (3H, m), of 3.32 (3H, s), 3,41-to 3.58 (5H, m), 3,79-3,86 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.56 (1H, DD, J=10,0, 15.2 Hz), 5,73 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, DD, J=1,2, and 10.8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 734 (M+H)+.

Example 126. (8E,12E,14)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(pyridin-4-yl)piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 126)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 1,19-of 1.29 (4H, m)of 1.34 (3H, s), 1,38 was 1.69 (7H, m), of 1.78 (3H, d, J=1.2 Hz), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), at 2.45 2.63 in (3H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz)to 3.34 (3H, s), 3,40-3,47 (4H, m), 3,52 (1H, TD, J=a 4.4, and 8.4 Hz), 3,56-and 3.72 (4H, m), 3,80-a 3.87 (1H, m), of 5.05 (1H, d, J=9,2 Hz), 5,07 (1H, d, J=10.4 Hz), to 5.58 (1H, DD, J=10,0, 15.2 Hz), USD 5.76 (1H, DD, J=10,0, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, DD, J=1,2, 11.2 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz), 6,86 (2H, d, J=6.4 Hz), 8,02-of 8.04 (2H, m); ESI-MS m/z 714 (M+H)+.

Example 127.(8E,12E,14)-6-Ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 127)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 85, except ethyltrichlorosilane in the first stage.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.16 (3H, t, J=7.2 Hz), 1,22 (3H, s), 1,22-to 1.60 (7H, m)of 1.34 (3H, s), of 1.65 (1H, DD, J=6,4, of 14.0 Hz), 1,78 (3H, s)to 1.86 (1H, DD, J=5,6, or 13.6 Hz), is 2.30 (3H, s), 2,36 is 2.43 (4H, m), 2,43-2,69 (4H, m), 2,89 (1H, dt, J=2,4, 5,6 Hz), 3,43-3,61 (7H, m), of 3.77-a-3.84 (1H, m), to 4.98 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), of 5.55 (1H, DD, J=10,0, 15.2 Hz), 5,7 6 (1H, DD, J=9,6, 15.2 Hz), 5,86 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 665 (M+H)+.

Example 128. (8E,12E,14)-6-Ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(piperidine-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 128)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 127.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.0 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.17 (3H, t, J=6.8 Hz), 1,22 (3H, s), 1,22-1,69 (16H, m)of 1.34 (3H, s)of 1.78 (3H, s), 1,83-of 1.93 (3H, m), 2,42-2,63 (8H, m)to 2.67 (1H, DD, J=2,4, a 7.6 Hz), 2.70 height of 2.92 (3H, m), 3,49-3,62 (3H, m), of 3.77-a-3.84 (1H, m), 4,13-4,27 (2H, m), to 4.98 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10.4 Hz), 5,54 (1H, DD, J=10,0, 15.2 Hz), USD 5.76 (1H, DD, J=9,6, the 15.6 Hz), 5,86 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10.0 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 733 (M+H)+.

A solution of (8E,12E,14)-7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (221 mg, 0.4 mmol), N,N-dimethylaminopyridine (25 mg, 0.2 mmol) and triethylamine (613 mg, 6 mmol) in dichloromethane (7 ml) was cooled to 5°C, was added dropwise thereto a solution of chlorotrimethylsilane (609 mg, 4 mmol) in dichloromethane (3 ml) and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:9 > 1:4 > 1:3) to obtain the specified title compound (320 mg, quantitative) as a colourless oil.

ESI-MS m/z 803 (M+Na)+.

Example 130. (8E,12E,14)-3,6,16-Trihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 130)

The first stage

(8E,12E,14)-7-Acetoxy-6,16-bis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,21-bis(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 130-)

To a solution of compound 129 (8E,12E,14)-7-acetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-3,21-bis(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (320 mg, 0.41 mmol)obtained in example 129, and simple etilenovogo ester (589 mg, 8 mmol) in dichloromethane (6 ml) was added a solution of p-toluensulfonate pyridinium (5 mg, 20 μmol) in dichloromethane (1 ml) at room temperature and the resulting mixture was stirred at the same the temperature during the night. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:9 1:7) to obtain the specified title compound (252 mg, 67%) as a colourless oil.

ESI-MS m/z 947 (M+Na)+.

The second stage

(8E,12E,14)-7-Acetoxy-6,16-bis(1-ethoxyethoxy)-3,21-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 130-2)

A solution of compound 130-1 (8E,12E,14)-7-acetoxy-6,16-bis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,21-bis(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (107 mg, 0,1156 mmol)obtained in the first stage, in tetrahydrofuran (6 ml) was cooled to 5°C, was added thereto dropwise, tetrabutyl IPTRID (1.0 M tertrahydrofuran ring solution, 0.25 ml, 0.25 mmol) and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and then washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:1 > 2:1) to obtain the specified title compound (81 mg, 100%) as a colourless oil.

ESI-MS m/z 719 (M+Na)+.

The third stage

(8E,12E,14)-7-Acetoxy-3-diethylazodicarboxylate-6,16-bis(1-ethoxyethoxy)-21-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 130-3)

A solution of compound 130-2 (8E,12E,14)-7-acetoxy-6,16-bis(1-ethoxyethoxy)-3,21-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (33,2 mg, or 47.6 mmol)obtained in the second stage, N,N-dimethylaminopyridine (3 mg, to 23.8 mmol) and triethylamine (49 mg, 0,476 mmol) in dichloromethane (1 ml) was cooled to -20°C, was added dropwise diethylazodicarboxylate (10,3 mg, 59.5 mmol) and the reaction mixture was stirred at a temperature of from -20°to 5°C for 1.2 hours. Then to the reaction mixture was added dropwise at the same temperature diethylazodicarboxylate (31 mg, 179 μmol), followed by stirring for 4.5 cha is impressive. Added to the reaction mixture dropwise at the same temperature diethylazodicarboxylate (41,2 mg, 238 mmol) followed by stirring for 1.3 hours and then stirring at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by thin-layer chromatography (Merck Art 1,05628; ethyl acetate-hexane, 1:2) to obtain the specified title compound (19.1 mg, 49%) as a colourless oil.

ESI-MS m/z 847 (M+Na)+.

The fourth stage

(8E,12E,14)-7-Acetoxy-3-diethylazodicarboxylate-6,16-bis(1-ethoxyethoxy)-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 130-4)

A solution of compound 130-3 (8E,12E,14)-7-acetoxy-3-diethylazodicarboxylate-6,16-bis(1-ethoxyethoxy)-21-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (33,2 mg, 40 μmol)obtained in the third stage, and 1,8-bis(N,N-dimethylamino)naphthalene (51,4 mg, 0.24 mmol) in toluene (),7 ml) was cooled to 5°and was added to the reaction mixture dropwise methyltrichlorosilane (20 mg, 0.12 mmol) followed by addition of 0.5 ml of toluene. The reaction mixture was stirred at 50°C for 12.5 hours. The reaction mixture was cooled whom to room temperature, was diluted with toluene and was added at 5°0,06 N. aqueous ammonia (5 ml) followed by stirring at room temperature for about 20 minutes. To the mixture was added ethyl acetate, water and saturated aqueous solution of ammonium chloride, the mixture is stirred for some time, and separated the organic layer. The organic layer was washed sequentially 0.05 M aqueous solution of citric acid and aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:9 > 1:7 > 1:4 > 1:3) to obtain the specified title compound (15.8 mg, 47%) as a colourless oil.

ESI-MS m/z 861 (M+Na)+.

Fifth stage

(8E,12E,14)-3-Diethylazodicarboxylate-6,16-bis(1-ethoxyethoxy)-7-hydroxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 130-5)

To connect 130-4 (8E,12E,14)-7-acetoxy-3-diethylazodicarboxylate-6,16-bis(1-ethoxyethoxy)-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (21,5 mg, 25.6 mmol)obtained in the fourth stage, was added a 0.2 M solution of guanidine/guanidine nitrate (methanol-dichloromethane, 9:1) (0,26 ml, 52 mmol), followed by stirring at room temperature for 12.5 hours. The reaction mixture once alali with ethyl acetate, washed with water and saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:7 > 1:5 > 1:4) to obtain the specified title compound (19.3 mg, 95%) as a colourless oil.

ESI-MS m/z 819 (M+Na)+.

Sixth stage

(8E,12E,14)-3-Diethylazodicarboxylate-6,16-bis(1-ethoxyethoxy)-21-methoxy-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 130-6)

A solution of compound 130-5 (8E,12E,14)-3-diethylazodicarboxylate-6,16-bis(1-ethoxyethoxy)-7-hydroxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (19.3 g, and 24.2 mmol)obtained in the fifth stage, N,N-dimethylaminopyridine (3 mg, and 24.2 mmol) and triethylamine (25 mg, 0,242 mmol) in dichloromethane (1.2 ml) was cooled to 5°added to it drops of a solution of 4-nitrophenylphosphate (25 mg, 121 μmol) in dichloromethane (0.3 ml) and then the resulting mixture was stirred at room temperature for three hours. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous solution of sodium bicarbonate. Then the organic layer was washed sequentially with an aqueous solution of ammonium chloride, aqueous solution of sodium bicarbonate and water in the specified by adca. The organic layer was dried over anhydrous magnesium sulfate and evaporated to obtain the residue specified in the connection header (40,7 mg) as a pale yellow solid.

The obtained solid substance was subjected to the subsequent reaction without purification.

The seventh stage

(8E,12E,14)-3-Diethylazodicarboxylate-6,16-bis(1-ethoxyethoxy)-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 130-7)

A solution of the crude compound 130-6 (8E,12E,14)-3-diethylazodicarboxylate-6,16-bis(1-ethoxyethoxy)-21-methoxy-7-(4-nitrophenoxy)carboxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (20.4 mg, 12.1 mmol)obtained in the sixth stage, in tetrahydrofuran (0.9 ml) was cooled to 5°and added thereto dropwise a solution of 1-isopropylpiperazine (2.4 mg, 18.2 mmol) in tetrahydrofuran (0.1 ml) and triethylamine (3.7 mg, 36,3 mmol) followed by stirring at room temperature for 6.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel plate; a mixture of ethyl acetate-hexane, 1:3) to obtain the specified title compound (10.0 mg, 87%, two hundred the AI) as a colourless oil.

ESI-MS m/z 951 (M+N)+.

The eighth stage

(8E,12E,14)-6,16-Bis(1-ethoxyethoxy)-3-hydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 130-8)

A solution of compound 130-7 (8E,12E,14)-3-diethylazodicarboxylate-6,16-bis(1-ethoxyethoxy)-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (10 mg, 10.5 μmol)obtained in the seventh stage, in tetrahydrofuran (1.0 ml) was cooled to 5°and added thereto dropwise tetrabutylammonium (1.0 M tertrahydrofuran ring solution of 11.6 ál, 11.6 mmol), then stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by thin-layer chromatography (Merck Art 1,05628; methanol-dichloromethane, 1:29) to obtain the specified title compound (7.4 mg, 86%) as a colourless oil.

ESI-MS m/z 823 (M+N)+.

Ninth stage

(8E,12E,14)-3,6,16-Trihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 130)

To a solution of compound 130-8 (8E,12E,14-6,16-bis(1-ethoxyethoxy)-3-hydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (7.4 mg, 9 μmol)obtained in the eighth stage, in a mixture of tetrahydrofuran:2-methyl-2-propanol=1:1 (0.7 ml) was added p-toluensulfonate pyridinium (6,8 mg, 27 mmol), then stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel plate, a mixture of methanol:dichloromethane=1:39) to obtain the specified title compound (4.2 mg, 69%) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=7,2 Hz)to 0.88 (3H, t, J=7,6 Hz)to 0.89 (3H, d, J=6,8 Hz)of 1.07 (6H, d, J=6,4 Hz)to 1.21 (3H, s), 1,28-1,70 (11H, m), 1.77 in (3H, d, J=1.2 Hz), of 1.85 (1H, DD, J=5,2, 14,0 Hz), 2,47-2,62 (7H, m)of 2.64 (1H, DD, J=2,4, 8.0 Hz), 2,67-to 2.74 (1H, m), is 2.88 (1H, dt, J=2,4, 6,0 Hz), 3,14-3,19 (1H, m)to 3.38 (3H, s), 3,42-3,70 (4H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 131. (8E,12E,14)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 131)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 130.

1H-NMR spectrum (CD3 OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=7,2 Hz)to 0.88 (3H, t, J=7,6 Hz)to 0.89 (3H, d, J=6,8 Hz)to 1.21 (3H, s), 1,29-1,70 (11H, m), 1.77 in (3H, d, J=1.2 Hz), of 1.85 (1H, DD, J=5,2, of 14.0 Hz), is 2.30 (3H, s), 2,35-2,63 (7H, m)of 2.64 (1H, DD, J=2,4, 8.0 Hz), is 2.88 (1H, dt, J=2,4, 6,0 Hz), 3,14-3,20 (1H, m)to 3.38 (3H, s), 3,39-3,71 (4H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=10.0 Hz), is 5.06 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, DD, J=1,2, and 10.8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 651 (M+H)+.

Example 132. (8E,12E,14)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 132)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 130.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=7,2 Hz)to 0.88 (3H, t, J=7,6 Hz)to 0.89 (3H, d, J=6.8 Hz), 1,22 (1,2H, C), 1,23 (1, 8H, s), 1,28-1,71 (11H, m), 1.77 in (3H, d, J=0.8 Hz), 1,81-of 1.93 (3H, m), 2,34 (1,2H, C), 2,35 (1,8H, s), 2,50-to 2.67 (8H, m), is 2.88 (1H, dt, J=2.0 a, 6,0 Hz), 3,14-3,20 (1H, m)to 3.38 (3H, s), 3,47 of 3.56 (2H, m), to 3.58-to 3.67 (2H, m), 3.75 to 3,82 (1H, m), of 4.95 (1H, d, J=10.0 Hz), 5,07 (1H, d, J=to 10.8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz),6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 665 (M+H)+.

Example 133. (8E,12E,14)-7-((4-Acylhomoserine-1-yl)carbonyl)oxy-3,6,16-trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 133)

Specified in the title compound (colorless oil which) was synthesized by the method similar to that described in example 130.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=7,2 Hz)to 0.88 (3H, t, J=7,6 Hz)to 0.89 (3H, d, J=6,8 Hz)1,08 (1,5H, t, J=7.2 Hz), 1,09 (1,5H, t, J=7.2 Hz), 1,22 (1,5H, s), 1,23 (1,5H, s), 1,28-1,70 (11H, m), 1.77 in (3H, d, J=1.2 Hz), 1,82 is 1.91 (3H, m), 2,47 was 2.76 (10H, m), is 2.88 (1H, dt, J=2,4, 6,0 Hz), 3,14-3,19 (1H, m)to 3.38 (3H, s), 3.45 points-to 3.67 (4H, m), 3.75 to 3,82 (1H, m), of 4.95 (1H, d, J=9.6 Hz), 5,07 (1H, d, J=10,8 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,73 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 134. (8E,12E,14)-7-Acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-6-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 134)

The first stage

(8E,12E,14)-7-Acetoxy-6,10,12,16,20-pentamethyl-6-(4-nitrophenoxy)carboxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 134-1)

To a solution of compound 46-1 (8E,12E,14)-7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (44 mg, 49 μmol)obtained in the first stage of example 46, in dichloromethane (2.0 ml) was added triethylamine (30 mg, 0.29 mmol), N,N-dimethylaminopyridine (90 mg, 0.73 mmol) and 4-nitrophenylphosphate (90 mg, 0.44 mmol) under ice cooling and the reaction the mixture was stirred at room temperature under nitrogen atmosphere for three days. The reaction mixture was diluted with ethyl is the Etat and washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=10:90) to obtain the specified title compound (19 mg, 36%) as a colourless oil.

ESI-MS m/z 1082 (M+Na)+.

The second stage

(8E,12E,14)-7-Acetoxy-6,10,12,16,20-pentamethyl-6-((4-methylpiperazin-1-yl)carbonyl)oxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 134-2)

To a solution of compound 134-1 (8E,12E,14)-7-acetoxy-6,10,12,16,20-pentamethyl-6-(4-nitrophenyl)carboxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (9 mg, 8,5 mcool)obtained in the first stage, in tetrahydrofuran (1 ml) was added triethylamine (8 mg, 85 μmol) and 1-methylpiperazine (1.7 mg, 17 μmol) at room temperature, followed by stirring at the same temperature under nitrogen atmosphere for 4 hours. The reaction mixture was diluted with ethyl acetate and then washed with a saturated solution of salt. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=50:50) to obtain the specified title compound (8.6 mg, 100%) as a colourless oil.

ESI-MS m/z 1021 (M+N) .

The third stage

(8E,12E,14)-7-Acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-6-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 134)

To a solution of compound 134-2 (8E,12E,14)-7-acetoxy-6,10,12,16,20-pentamethyl-6-((4-methylpiperazin-1-yl)carbonyl)oxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (9 mg, 8.5 μmol)obtained in the second stage, in tetrahydrofuran (1 ml) was added tetrabutylammonium (1.0 M tertrahydrofuran ring solution, 48 μl, 48 mmol) at room temperature and the reaction mixture was stirred at the same temperature under nitrogen atmosphere within 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated solution of salt. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; methanol:dichloromethane=5:95) to obtain specified in the title compound (4.4 mg, 77%) as a colourless oil.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (6H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,20 of 1.28 (1H, m)of 1.34 (3H, s), 1,38 is 1.70 (10H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,04 (3H, s), 2,31 (3H, s), 2,38-2,48 (4H, m), 2,48-2,52 (2H, m), 2,56-to 2.65 (1H, m)to 2.66 (1H, DD, J=2.0 a, 7,6 Hz), 2,89 (1H, dt, J=2,0, 6.4 Hz), 3,42-3,62 (5H, m), 3,76-a-3.84 (1H, m), free 5.01 (1H, d, J=9.6 Hz), is 5.06 (1H, d, J=10,8 Hz), 5,63 (1H, DD, J=a 9.6, 15.2 Hz), of 5.75 (1H, d is, J=9,2, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,14 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 679 (M+H)+.

Example 135. (8E,12E,14)-7-Acetoxy-6-((4-cycloheptatrien-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 135)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 134.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,22-1,32 (1H, m)of 1.34 (3H, m), 1,40-1,78 (20H, m)to 1.79 (3H, s), 1,82-of 1.93 (3H, m), is 2.05 (3H, s), 2,39-2,47 (1H, m), 2,50 (2H, d, J=3.6 Hz), 2,54-of 2.66 (6H, m), 2,89 (1H, dt, J=2,0, 6.4 Hz), 3,37-of 3.64 (5H, m), 3,76-a 3.83 (1H, m), 5,07 (1H, d, J=10,8 Hz), further 5.15 (1H, d, J=9,2 Hz), 5,63 (1H, DD, J=9,2, 15.2 Hz), 5,71 (1H, DD, J=9,2, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,14 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 761 (M+H)+.

Example 136. (8E,12E,14)-7-Acetoxy-6-((4-acylhomoserine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 136)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 134.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (6H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.2 Hz), a 1.08 (3H, t, J=7.2 Hz), 1,20 of 1.28 (1H, m)of 1.34 (3H, s), 1,38 is 1.70 (10H, m), of 1.78 (3H, s), 1,83 is 1.91 (3H, m), 2,03 (3H, s), 2,33-2,42 (1H, m), 2,50 (2H, d, J=3,9 Hz), 2,58 is 2.80 (7H, m), 2,89 (1H, dt, J=2,4, 6.4 Hz), 3.45 points-of 3.65 (5H, m), 3.75 to-a-3.84 (1H, m), 5,02(1H, d, J=9.6 Hz), 5,07 (1H, d, J=10.4 Hz), 5,63 (1H, DD, J=9,6, 15.2 Hz), USD 5.76 (1H, DD, J=9,6, the 15.6 Hz), by 5.87 (1H, d, J=15.6 Hz), 6,14 (1H, d, J=11.2 Hz), 6,53 (1H, DD, J=11,2, the 15.6 Hz); ESI-MS m/z 707 (M+H)+.

Example 137. (8E,12E,14)-3,6,16,21-Tetrahydroxy-7-(N-isopropylcarbamate)-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 137)

The first stage

(8E,12E,14)-3,6,16,21-Tetrakis(1-ethoxyethoxy)-7-(N-isopropylcarbamate)-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 137-1)

To a suspension of sodium hydride (60% oil dispersion, 2 mg, 0,052 mmol) in tetrahydrofuran (0.5 ml) was added dropwise a solution of (8E,12E,14)-3,6,16,21-Tetra(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (19 mg, 0.019 mmol)obtained in example 3-(2), in tetrahydrofuran (0.5 ml) under ice cooling and stirring and the reaction mixture was stirred at room temperature for 10 minutes. Then to the mixture was added dropwise isopropylethylene (6.6 mg, of 0.066 mmol) and the reaction mixture was stirred at room temperature for three hours. Was added to the reaction mixture water while cooling with ice to stop the reaction, after which the mixture was diluted with ethyl acetate and washed with saturated solution of salt. The organic layer was dried over anhydrous sodium sulfate and evaporated. P the obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; a mixture of ethyl acetate:hexane=25:75) to obtain the specified title compound (10 mg, 60%) as a colourless oil.

ESI-MS m/z 922 (M+Na)+.

The second stage

(8E,12E,14)-3,6,16,21-Tetrahydroxy-7-(N-isopropylcarbamate)-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 137)

Specified in the title compound (colorless oil) was obtained by the method similar to that described in example 3-5.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): to 0.89 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), 1,14-1,69 (20H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,48-2,60 (3H, m)to 2.66 (1H, DD, J=2.0 a, 8,0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,49-4,08 (1H, m), of 3.73-a 3.83 (1H, m), 4,23-4,34 (1H, m), of 4.95 (1H, d, J=9.6 Hz), 5,07 (1H, d, J=10.4 Hz), the ceiling of 5.60-of 5.92 (3H, m), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 634 (M+Na)+.

Example 138. (8E,12E,14)-7-(N-Butyldiethanolamine)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 138)

Specified in the title compound (colorless oil) was obtained by the method similar to that described in example 137.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=7,2 Hz), 0,937 (3H, t, J=7.2 Hz), 0,942 (3H, t, J=7.2 Hz), 1,19 (3H, s), 1,19-1,69 (15H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,49-2,62 (3H, m)to 2.66 (1H, DD, J=2,0, 8.0 Hz),2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,42 is 3.57 (3H, m), of 3.73-a 3.83 (1H, m), of 4.95 (1H, d, J=9.6 Hz), 5,07 (1H, d, J=10.4 Hz), 5,62-of 5.92 (3H, m), 6,14(1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 648 (M+Na)+.

Example 139. (8E,12E,14)-7-(N-(3-(N',N'-Diethylamino)propyl)thiocarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 139)

Specified in the title compound (colorless oil) was obtained by the method similar to that described in example 137.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.2 Hz), to 1.14 (6H, t, J=6.8 Hz), 1,19 (3H, s), 1,21-1,69 (13H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,48-2,61 (3H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 3,70-3,86 (6H, m),2,89 (1H, dt, J=2,4, 5,6 Hz), 3,44-to 3.58 (3H, m), 3.75 to a 3.83 (1H, m), 4,96 (1H, d, J=8,4 Hz), 5,07 (1H, d, J=10.4 Hz), 5,64-of 5.92 (3H, m), 6,14 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 683 (M+H)+.

Example 140. (8E,12E,14)-7-Benzoyloxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 140)

The first stage

(8E,12E,14)-7-Benzoyloxy-3,6,16,21-tetrakis(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 140-1)

To a solution of (8E,12E,14)-3,6,16,21-tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (10 mg, 12.5 μmol)obtained in example 3-2, in pyridine (0.5 ml) was added N,N-dimethylaminopyridine (8 mg, 62.5 mmol) and benzylchloride (17.6 mg, 125 μmol) at room temp is the temperature, and the reaction mixture was stirred at the same temperature under nitrogen atmosphere for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=25:75) to obtain the specified title compound (6 mg, 55%) as a colourless oil.

ESI-MS m/z 925 (M+Na)+.

The second stage

(8E,12E,14)-7-Benzoyloxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 140)

Specified in the title compound (colorless oil) was obtained by the method similar to that described in example 3-5.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)to 0.89 (3H, d, J=7,2 Hz), of 0.93 (3H, t, J=7.2 Hz), 1,20-1,76 (14H, m), of 1.78 (3H, s)to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 2,53-of 2.64 (3H, m)to 2.66 (1H, DD, J=2,4, 8,0 Hz), 2,89 (1H, dt, J=2,4, 5,6 Hz), 3,52 (1H, dt, J=4,8, 8.0 Hz), 3,78-of 3.85 (1H, m), 5,09 (1H, d, J=10,8 Hz), from 5.29 (1H, d, J=9.6 Hz), 5,69 (1H, DD, J=9,6, 15.2 Hz), of 5.83 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15,2 Hz), 6,14 (1H, d, J=10.4 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz), 7,47 (2H, DD, J=7,6, 7,6 Hz), 7,60 (1H, DD, J=7,6, 7,6 Hz)to 8.12 (2H, d, J=7,6 Hz); ESI-MS m/z 637 (M+Na)+.

Example 141. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-propenyloxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 141)

Specified in the header connection (best is to maintain oil) was obtained by way similar to that described in example 140.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz)to 0.89 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.2 Hz), is 1.11 (3H, t, J=8.0 Hz), of 1.18 (3H, s), 1,22-1,68 (11H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,28-of 2.45 (2H, m), 2,50-2,61 (3H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,52 (1H, dt, J=4,8, 8.0 Hz), 3.75 to 3,82 (1H, m), of 4.95 (1H, d, J=9.6 Hz), of 5.05 (1H, d, J=9.6 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,70 (1H, DD, J=9,6, 15.2 Hz), by 5.87 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 589 (M+Na)+.

Example 142. (8E,12E,14)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-(3-phenylpropenoyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 142)

Specified in the title compound (colorless oil) was obtained by the method similar to that described in example 140.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,86 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7.2 Hz), of 1.09 (3H, s), 1,20-1,69 (11H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,46 at 2.59 (3H, m), 2,62-2,70 (3H, m), 2,85-2,96 (3H, m), 3,48 of 3.56 (1H, m), 3.72 points-of 3.80 (1H, m), of 5.03 (1H, d, J=9,2 Hz), of 5.05 (1H, d, J=10,8 Hz)5,54 (1H, DD, J=9,6, 15.2 Hz), to 5.66 (1H, DD, J=9,2, 15.2 Hz), by 5.87 (1H, d, J=14,8 Hz), 6,13 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 14,8 Hz), 7,12-7,28 (5H, m); ESI-MS m/z 665 (M+Na)+.

Example 143. (8E,12E,14)-7-(Hexanoyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 143)

Specified in the title compound (colorless oil) was obtained in a manner similar to described the example 140.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,76-of 0.83 (9H, m), and 0.98 (3H, t, J=7.2 Hz), of 1.23 (3H, s), 1,24-1,74 (17H, m), equal to 1.82 (3H, Sirs), at 1.91 (1H, DD, J=5,6, 14.4 Hz), 2,32 is 2.44 (2H, m), 2,52-2,69 (3H, m), 2,71 (1H, DD, J=2,4, 8,0 Hz), to 2.94 (1H, dt, J=2,4, 6,0 Hz), 3,53-of 3.60 (1H, m), 3,78-3,86 (1H, m), 5,10 (1H, d, J=9.6 Hz), 5,11 (1H, d, J=9.6 Hz), 5,61 (1H, DD, J=9,6, 15.2 Hz), 5,74 (1H, DD, J=9,6, 15.2 Hz), 5,91 (1H, d, J=15.2 Hz), 6,18 (1H, d, J=11.2 Hz), to 6.57 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 631 (M+Na)+.

Example 144. (8E,12E,14)-7,21-Diacetoxy-3,6,16-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 144-1) and 8E,12E,14)-3,7,21-triacetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 144-2)

Connection 144-1

Connection 144-2

A solution of (8E,12E,14)-7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (276 mg, 0.5 mmol), N,N-dimethylaminopyridine (31 mg, 0.25 mmol) and triethylamine (256 mg, 2.5 mmol) in dichloromethane (15 ml) was cooled to -20°C, was added thereto dropwise over 30 minutes a solution of acetic anhydride (53 mg, 0.5 mmol) in dichloromethane (2 ml) and the reaction mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dropwise over 30 minutes a solution of acetic anhydride (10.5 mg, 0.1 mmol) in dichloromethane (1 ml), after which the reaction mixture was stirred at the same temperature for 2.5 hours. Yes is it again added dropwise to the reaction mixture over 30 minutes a solution of acetic anhydride (10.5 mg, 0.1 mmol) in dichloromethane (1 ml), after which the mixture was stirred at the same temperature for 30 minutes. And another was added to the reaction mixture dropwise over 5 minutes a solution of acetic anhydride (21 mg, 0.2 mmol) in dichloromethane (1 ml) followed by stirring at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; a mixture of ethyl acetate-hexane, 2:1 3:1 4:1 9:1) with receipt of the balance of the connection 144-1 in the form of a colorless oil and connections 144-2 (67,7 mg, 21%) as colorless crystals. The remainder of the connection 144-1 then purified by thin-layer chromatography (Merck Art 1,13792; ethyl acetate-hexane, 8:1 9:1) to obtain compound 144-1 (214,3 mg, 72%) as a colourless oil.

Connection 144-1

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.87 (3H, t, J=7,6 Hz)to 0.88 (3H, d, J=7,2 Hz)to 0.92 (3H, d, J=6,8 Hz)of 1.18 (3H, s), 1,31-1,68 (11H, m), 1.77 in (3H, d, J=0.8 Hz), 1,82 (1H, DD, J=5,2, of 14.0 Hz), was 2.05 (3H, s), 2.06 to (3H, s), 2,46-2,63 (4H, m), is 2.88 (1H, dt, J=2.0 a, 6,0 Hz), 3.75 to-3,81 (1H, m), 4,84 to 4.92 (1H, overlapped, H2O)5,04 (1H, d, J=9.6 Hz), of 5.05 (1H, d, J=10,8 Hz)to 5.56 (1H, DD, J=9,6, 15.2 Hz), 5,70 (1H, DD, J=9,6, 15.2 Hz), 5,86 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 617 (M+Na)+.

Connection 144-2

1H-NMR spectrum (CD3D, 400 MHz) δ (ppm): of 0.87 (3H, t, J=7,6 Hz)to 0.89 (3H, d, J=6,8 Hz)of 0.91 (3H, d, J=6,8 Hz)of 1.18 (3H, s)of 1.33 (3H, s), 1,34-of 1.73 (8H, m), 1.77 in (3H, d, J=0.8 Hz)and 1.83 (1H, DD, J=5,6, of 14.0 Hz), 2,04 (3H, C)is 2.05 (3H, s)to 2.06 (3H, s), 2,53 of 2.68 (4H, m), is 2.88 (1H, dt, J=2.0 a, 6,0 Hz), 4,78-4,96 (2H, overlapped, H2O), 4,99 (1H, d, J=10.4 Hz), 5,02 (1H, d, J=9.6 Hz), to 5.57 (1H, DD, J=9,6, 15.2 Hz), 5,72 (1H, DD, J=9,6, 15.2 Hz), 5,86 (1H, d, J=15.2 Hz), 6,14 (1H, DD, J=1,2, and 10.8 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 659 (M+Na)+.

Example 145. (8E,12E,14)-21-Acetoxy-3,6,16-trihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 145-1) and (8E,12E,14)-3,21-diacetoxy-6,16-dihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 145-2)

Connection 145-1

Connection 145-2

Listed in the connection header (each is a colorless oil) was synthesized by a method similar to that described in example 144 except for using compound 44, obtained in example 44.

Connection 145-1

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.91 (3H, t, J=7.2 Hz), of 0.93 (3H, d, J=6,8 Hz)to 0.96 (3H, d, J=7,2 Hz), of 1.12 (6H, d, J=6.4 Hz), 1.26 in (3H, s), 1.30 and of 1.56 (6H, m), was 1.58 to 1.76 (5H, m), equal to 1.82 (3H, s)to 1.87 (1H, DD, J=5,6, of 14.0 Hz), 2,10 (3H, s), 2,48-2,70 (8H, m), 2,70-2,82 (1H, m)of 2.93 (1H, dt, J=2,0, 5.6 Hz), 3,44 is 3.76 (4H, m), 3,78-3,88 (1H, m), 4,86-to 4.98 (1H, overlapped, H2O), equal to 4.97 (1H, d, J=9.6 Hz), 5,10 (1H, d, J=10,8 Hz), 5,62 (1H, DD, J=1,0, 15.2 Hz), USD 5.76 (1H, DD, J=9,6, 15.2 Hz), 5,90 (1H, d, J=15.2 Hz), 6,18 (1H, d, J=10,8 Hz), to 6.57 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 707 (M+H)+.

Connection 145-2

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.91 (3H, t, J=7,6 Hz)of 0.93 (3H, d, J=6,8 Hz)to 0.96 (3H, d, J=7,2 Hz), of 1.12 (6H, d, J=6.4 Hz), 1,25 (3H, s), 1.30 and 1,92 (15H, m), putting on 2,088 (3H, s)2,094 (3H, s), 2,50 is 2.80 (9H, m), of 2.93 (1H, dt, J=2.0 a, 6,0 Hz), 3,40 is 3.76 (4H, m), 4.80 to 4,96 (2H, overlapped, H2O)4,96 (1H, d, J=9.6 Hz), 5,04 (1H, d, J=10,8 Hz), 5,63 (1H, DD, J=10,0, 15.2 Hz), 5,78 (1H, DD, J=9,6, 15.2 Hz), 5,91 (1H, d, J=15.2 Hz), 6,18 (1H, d, J=10,8 Hz), 6,56 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 749 M+.

Example 146. (8E,12E,14)-6,16-Dihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,21-dioxo-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 146-1) and (8E,12E,14)-3,6,16-trihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-21-oxo-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 146-2)

Connection 146-1

Connection 146-2

To a solution of compound 44 (20 mg, 30 μmol)obtained in example 44, in dichloromethane (2.0 ml) was added a reagent dessa-Martin (43 mg, 0,101 mmol) under ice cooling and stirring and the reaction mixture was stirred at room temperature under nitrogen atmosphere for six hours. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate solution and saturated salt solution. Organic is the cue layer was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; dichloromethane:methanol=95:5 90:10) to obtain the specified header connections: connections 146-1 (9.6 mg, 48%) and connections 146-2 (8,9 mg, 45%) as a colourless oil each.

Connection 146-1

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.91 (3H, d, J=6,8 Hz), and 1.00 (3H, t, J=7.2 Hz), with 1.07 (3H, d, J=7,2 Hz), 1,10 (6H, d, J=6.4 Hz), of 1.30 (3H, s)of 1.33 (3H, s), and 1.63 (1H, DD, J=6,8, 14.4 Hz), 1,74 and 1.80 (1H, m)1,80 (3H, s), 1,89 (1H, DD, J=5,6, 14.4 Hz), 2.00 in of 2.08 (1H, m), 2,28-is 2.37 (1H, m), 2,46 (2H, d, J=12,4 Hz), 2,52-2,70 (7H, m), 2,72-2,84 (3H, m), of 2.92 (1H, dt, J=2,0, 6.4 Hz), 3,31-to 3.33 (1H, m), 3,42-of 3.64 (4H, m), 4,94 (1H, d, J=8.0 Hz), 4,96 (1H, d, J=10,8 Hz), 5,23 (1H, DD, J=8,8, 15.6 Hz), of 5.50 (1H, DD, J=8,4, the 15.6 Hz), 5,86 (1H, d, J=15.2 Hz), 6,10 (1H, d, J=10,8 Hz), is 6.54 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 661 (M+H)+, 683 (M+Na)+.

Connection 146-2

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,8 Hz), and 1.00 (3H, t, J=7.2 Hz),with 1.07 (3H, d, J=6.8 Hz), 1,10 (6H, d, J=7,2 Hz), to 1.21 (3H, s), 1,38-of 1.42 (5H, m), 1,54 by 1.68 (3H, m), 1.77 in (3H, s), 1,89 (1H, DD, J=4,8, of 14.0 Hz), 2,28-of 2.36 (1H, m), 2,50-of 2.64 (8H, m)of 2.75 (1H, DD, J=2.0 a, and 8.4 Hz), was 2.76-2,84 (1H, m), 2.91 in (1H, dt, J=2,4, a 7.6 Hz), 3,31-to 3.33 (1H, m), 3,42-of 3.64 (4H, m), 3.75 to 3,82 (1H, m), is 4.93 (1H, d, J=9.6 Hz)that is 5.06 (1H, d, J=10.4 Hz), to 5.57 (1H, DD, J=10,0, 15.2 Hz), 5,72 (1H, DD, J=10,0, 15.2 Hz), 5,86 (1H, d, J=15.2 Hz), 6,14 (1H, d, J=10,8 Hz), 6,53 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 663 (M+H)+, 685 (M+Na)+.

Example 147. (8E,12E,14)-7-Acetoxy-6-ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 147)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 43, except ethyltrichlorosilane.

1H-NMR spectrum (CD3OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=6.4 Hz), of 0.90 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz)of 1.17 (3H, t, J=7.2 Hz), 1,20 (3H, s), 1,22-to 1.60 (7H, m)of 1.34 (3H, s), of 1.65 (1H, DD, J=6,4, of 14.0 Hz), 1,78 (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 2,04 (3H, s), 2,44 of 2.68 (4H, m), 2,89 (1H, dt, J=2,4, 5,2 Hz), 3,49-3,66 (3H, m), of 3.77-a-3.84 (1H, m), is 5.06 (1H, d, J=10.4 Hz), 5,10 (1H, d, J=9.6 Hz), of 5.55 (1H, DD, J=9,6 and 15.6 Hz), of 5.75 (1H, DD, J=10,0, the 15.6 Hz), 5,86 (1H, d, J=15.2 Hz), 6,13 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, the 15.6 Hz); ESI-MS m/z 603 (M+Na)+.

Examples of the manufacture of dosage forms

Below shows examples of the manufacture of dosage forms of the compounds of the present invention, but these examples do not limit the manufacture of dosage forms of the compounds of the present invention.

Example 1 manufacture of dosage forms

The compound of example 44 45 (parts)

Heavy magnesium oxide 15

Lactose 75

were subjected to homogeneous mixing with the formation of the powdered drug in the form of a powder or fine granules with the size of 350 μm or less. The powdered drug was loaded into the capsule receiving encapsulated dosage forms.

Example 2 manufacture of dosage forms

The compound of example 75 45 (parts)

Krahm the l 15

Lactose 16

Crystalline cellulose 21

Polyvinyl alcohol 3

Distilled water 30

were subjected to homogeneous mixing, pulverization, granulation, drying and then screening with the formation of granules with the size 1410-177 microns.

Example 3 manufacture of dosage forms

Having granules manner similar to that described in example 2 manufacture of dosage forms, was added 4 parts of calcium stearate to 96 parts of the pellets, extruded and molded with obtaining tablets with a diameter of 10 mm

Example 4 manufacture of dosage forms

To 90 parts of the granules obtained by the method of example 2 manufacture of dosage forms, were added 10 parts of crystalline cellulose and 3 parts of calcium stearate, extruded and molded with obtaining tablets with a diameter of 8 mm and Then inflicted on them a mixed suspension syrup, gelatin and precipitated calcium carbonate, resulting in tablets with sugar coating.

Example 5 manufacture of dosage forms

The compound of example 45 0,6 (parts)

Nonionic surfactants 2,4

Isotonic solution of sodium chloride 97

were heated, mixed and loaded into vials, ampoules were sterilized with obtaining injectable dosage forms.

Reference examples

Compounds were obtained by the following three-stage synthesis.

Reference example 1-1

Benzyl 4-(qi is aproportional)piperazine-1-carboxylate

In 35 ml of N,N-dimethylformamide was dissolved benzyl 1-piperidinecarboxylate (of 5.00 g, 22.7 mmol) and cyclopropanecarbonyl acid (2,54 g, 29.5 mmol) and the resulting solution was added at room temperature, the hydrochloride of 1-ethyl-3-(3-(N,N-dimethylamino)propyl)carbodiimide (6,53 g, to 34.1 mmol), 1-hydroxybenzotriazole (4.52 g, 29.5 mmol) and triethylamine (of 3.60 g, or 35.9 mmol) followed by stirring at the same temperature for three hours. The reaction mixture was mixed with water and was extracted twice with ethyl acetate. The organic layer was washed successively with water two times, saturated aqueous sodium bicarbonate once and a saturated salt solution once, dried over anhydrous sodium sulfate. The organic layer was passed through a column of silica gel (Fuji Silysia NH Silica gel and evaporated to obtain specified in the connection header (6,10 g, 93.1%) are in the form of a white amorphous substance.

1H-NMR spectrum (CDCl3, 400 MHz) δ (ppm): 0.75 to 0,83 (2H, m), 0,95-of 1.03 (2H, m)of 1.65 and 1.75 (1H, m), 3,40-of 3.80 (8H, m), 5,16 (2H, s), 7,30-7,40 (5H, m).

Reference example 1-2. 1-(Cyclopropanecarbonyl)piperazine

In 100 ml of ethanol was dissolved benzyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate (3.00 g, 10.4 mmol) and the resulting solution was added 1.5 g of 10% palladium on carbon, followed by stirring PR is room temperature in hydrogen atmosphere overnight. Was removed by filtration palladium on carbon and the filtrate was evaporated to obtain specified in the title compound (1.50 g, 97,3%) as a colourless oil.

1H-NMR spectrum (CDCl3, 400 MHz) δ (ppm): 0,73-0,80 (2H, m), 0,96-of 1.03 (2H, m), 1,67-to 1.77 (1H, m), 2,82-of 2.97 (4H, m), 3,60-3,71 (4H, m).

Reference example 1-3. 1-(Cyclopropylmethyl)piperazine

Sociallyengaged (770 mg, 20.3 mmol) suspended in tetrahydrofuran (150 ml), the resulting suspension was gradually added 1-(cyclopropanecarbonyl)piperazine (1.56 g, 10.1 mmol) and the reaction mixture is boiled under reflux for 30 minutes. The reaction mixture was cooled to room temperature and slowly added thereto sequentially 0.8 ml of water, 0.8 ml of 15% aqueous sodium hydroxide solution and 2.3 ml of water. Precipitated precipitated insoluble material was removed by filtration through Celite and the filtrate was evaporated to obtain specified in the title compound (1.40 g) as a colourless oil. The product was used for the synthesis of (8E,12E,14)-7-((4-cyclopropylamines-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (the compound of example 27) without further purification.

1H-NMR spectrum (CDCl3, 400 MHz) δ (ppm): 0,09-0,15 (2H, m), 0,48-of 0.56 (2H, m), 0,82 with 0.93 (1H, m), of 2.25 (2H, d, J=7,2 Hz) 2,48-to 2.65 (4H, m), 2,90-to 2.99 (4H, m).

Referential example 2. 1 Isobutene erasin

Benzyl 1-piperidinecarboxylate (1.1 g, 5.00 mmol) and Isobutyraldehyde (of 0.91 ml, 10.0 mmol) was dissolved in 30 ml of tetrahydrofuran and the resulting solution was added acetic acid (or 0.57 ml, 10.0 mmol) and triacetoxyborohydride sodium (2,11 g, 10.0 mmol) and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was mixed with 1 N. aqueous sodium hydroxide solution was extracted with ethyl acetate twice and the combined organic layers were washed with a saturated solution of salt once. The mixture was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Fuji Silysia NH Silica gel; ethyl acetate:hexane=50:50) to give benzyl 4-isobutylpyrazine-1-carboxylate (of 1.05 g) as a colourless oil.

The resulting benzyl 4-isobutylpyrazine-1-carboxylate (of 1.05 g) was dissolved in 35 ml of ethanol, to the solution was added 10% palladium on carbon (750 mg) and the reaction mixture was stirred at room temperature in hydrogen atmosphere (1 ATM) for 12 hours. Was removed by filtration palladium on carbon and the filtrate was evaporated to obtain specified in the title compound (610 mg) as a colourless oil.

1H-NMR spectrum (CDCl3, 400 MHz) δ (ppm): of 0.90 (6H, d, J=6.8 Hz), 1,71 is 1.86 (1H, m)2,07 (2H, d, J=7,6 Hz), 2,33-2,4 3 (4H, m), 2,86-of 2.93 (4H, m).

Saloon the th example 3. 1-(Tetrahydropyran-4-yl)piperazine

Specified in the title compound was synthesized in a manner similar to that described for the compound of reference example 2 (1-isobutylpyrazine).

1H-NMR spectrum (CDCl3, 400 MHz) δ (ppm): 1,50-of 1.64 (2H, m), 1,72 and 1.80 (2H, m), 2,36 is 2.46 (1H, m), 2,54-of 2.64 (4H, m), 2.91 in-of 2.97 (4H, m), 3,37 (2H, dt, J=2.0 a, and 11.6 Hz), a 4.03 (2H, DD, J=4,4, to 11.6 Hz).

Reference example 4. 1-(Cyclopropylmethyl)homopiperazin

Benzyl 1-homopiperazines (1,95 g, 8,32 mmol) and cyclopropanecarboxaldehyde (700 mg, 10.0 mmol) was dissolved in 40 ml of tetrahydrofuran. To the solution was added acetic acid (600 mg, 10.0 mmol) and triacetoxyborohydride sodium (2,11 g, 10.0 mmol) and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was mixed with 1 N. aqueous sodium hydroxide solution was extracted with ethyl acetate twice and the combined organic layers were washed with a saturated solution of salt once. The mixture was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Fuji Silysia NH Silica gel; ethyl acetate:hexane=50:50) to give benzyl 4-(cyclopropylmethyl)homopiperazin-1-carboxylate (2.5 g) as a colourless oil.

The resulting benzyl 4-(cyclopropylmethyl)homopiperazin-1-carboxylate (2.5 g) was dissolved the 50 ml of ethanol, to the solution was added 10% palladium on carbon (500 mg) and the reaction mixture was stirred at room temperature in hydrogen atmosphere (1 ATM) for 12 hours. Was removed by filtration palladium on carbon and the filtrate was evaporated to obtain specified in the title compound (1.4 g) as a colourless oil.

1H-NMR spectrum (CDCl3, 400 MHz) δ (ppm): 0,08-0,15 (2H, m), 0,47-of 0.56 (2H, m), 0,82-of 0.95 (1H, m), 1,80-1,89 (2H, m)2,44 (2H, d, J=6,4 Hz) of 2,75 2,85 (4H, m), 2,94-3,03 (4H, m).

Reference example 5. 1-(2,2,2-Triptorelin)piperazine

Benzyl 1-piperidinecarboxylate (2.0 g, remaining 9.08 mmol), 2,2,2-triftoratsetilatsetonom (2.5 g, about 10.8 mmol) and triethylamine (1.9 ml, of 13.8 mmol) was dissolved in 50 ml of tetrahydrofuran and the reaction mixture was stirred at 60°C for two hours. After cooling to room temperature the reaction mixture was mixed with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate twice. The combined organic layers were washed successively with water and saturated saline solution in this order. The mixture was dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified column chromatography on silica gel (Fuji Silysia NH Silica gel; ethyl acetate:hexane=50:50) to give the benzyl ester of 4-(2,2,2-triptorelin)piperazine-1-carboxylic acid (3.1 g) as a colourless oil.

p> The resulting benzyl 4-(2,2,2-triptorelin)piperazine-1-carboxylate (3.1 g) was dissolved in 50 ml of ethanol and to the solution was added 10% palladium on carbon (900 mg), followed by stirring at room temperature in hydrogen atmosphere (1 ATM) overnight. Was removed by filtration palladium on carbon and the filtrate was evaporated to obtain specified in the title compound (1.4 g) as a colourless oil.

1H-NMR spectrum (CDCl3, 400 MHz) δ (ppm): 2,64-2,77 (4H, m), 2,90-a 3.01 (6H, m).

Reference example 6

One full loop grown on stubble nutrient culture [of 0.5% soluble starch, 0.5% glucose, 0.1% extract of meat fish (manufacturer Wako Pure Chemical Industries, Ltd.), 0.1% of yeast extract (manufacturer Oriental Yeast Co., Ltd.), 0,2% NZ-shell (the manufacturer Humko Sheffield Chemical Co.), 0.2% sodium chloride, 0.1% calcium carbonate and 1.6% agar (manufacturer Wako Pure Chemical Industries, Ltd.)] strain Streptomyces sp. AB-1704 (FERM P-18999), isolated from soil, was made in 65-ml test tube containing 7 ml of medium for planting [of 2.0% soluble starch, 1.0% glucose, 0.5% polypeptide (manufacturer Nihon Pharmaceutical Co., Ltd.), 0.5% of yeast extract (manufacturer Oriental Yeast Co., Ltd.) and 0.1% of calcium carbonate], and cultured at 28°C for three days in a shaking incubator with obtaining seed culture.

Then 0.5 ml of seed culture was inoculable in ml tube containing 7 ml of a production medium [2,0% soluble starch, 1.0% glucose, 0.5% polypeptide (manufacturer Nihon Pharmaceutical Co., Ltd.), 0.5% of yeast extract (manufacturer Oriental Yeast Co., Ltd.) and 0.1% of calcium carbonate], and cultured at 28°C for three days in a shaking incubator.

Next, the prepared solution (25 mg/ml) substrate substance B (compound of example A4 in WO 02/060890) in ethanol and 0.2 ml was added to the culture. After adding the culture was shaken at 28°C for 48 hours to perform the reaction conversion.

Upon completion of the reaction, the reaction mixture was analyzed by HPLC under the following conditions (a) analysis by HPLC to confirm the formation of 11107D substance in the reaction mixture.

Conditions (a) analysis by HPLC:

Column: CAPCELL PACK C18 SG120 ø4 (, 6 mm x 250 mm (manufacturer SHISEIDO Co.)

Temperature: 40°

Flow rate: 1 ml/min

Detection: 240 nm

Eluent: acetonitrile/0.15% of potassium dihydrophosphate (pH 3.5) (3:7-5:5, vol/about., 0-18 min, linear gradient), acetonitrile/0.15% of potassium dihydrophosphate (pH 3.5) (5:5-85:15, vol/about., 18-22 min, linear gradient)

Retention time: the 11107D substance - 9,9 min, substance P and 19.4 minutes

Reference example 7

One full loop grown on stubble nutrient medium culture (agar medium with yeast and malt) strain A-1545 (FERM P-1944), isolated from soil, was inoculable in 250-ml Erlenmeyer flask containing 20 ml of medium for seeding [2,4% soluble starch, 0.1% glucose, 0.5% of soybean meal (ESUSAN-MEAT, manufacturer Ajinomoto Co., Ltd.), of 0.3% beef extract (manufacturer Difco), 0.5% of yeast extract (manufacturer Difco), 0.5% tripton-peptone (manufacturer Difco) and 0.4% calcium carbonate], and cultured at 28°C for three days in a shaking incubator with obtaining seed culture.

Then 0.6 ml seed culture was inoculable in 500-ml Erlenmeyer flask containing 60 ml of a production medium [2% soluble starch, 2% glucose, 2% soybean meal (ESUSAN-MEAT, manufacturer Ajinomoto Co., Ltd.), 0.5% of yeast extract (manufacturer Oriental Yeast Co., Ltd.), 0.25% sodium chloride, 0.32 per cent of calcium carbonate, of 0.0005% sulphate of copper, of 0.0005% chloride of manganese, of 0.0005% zinc sulfate, pH 7.4 before sterilization], and cultured at 28°C for four days in a shaking incubator. Each 2 ml of the obtained culture was added into 15 ml tubes. Then prepared solution (20 mg/ml) substance-substrate V in dimethyl sulfoxide was added 0.05 ml of the obtained solution. After adding the culture was shaken at 28°C for 23 hours to perform the reaction conversion. Upon completion of the reaction, the reaction mixture was analyzed by HPLC under the following conditions is s (b) analysis by HPLC, to confirm the formation of 11107D substance in the reaction mixture.

Conditions (b) analysis by HPLC:

Column: CAPCELL PACK C18 SG120 ø4 (, 6 mm x 250 mm (manufacturer SHISEIDO Co.)

Temperature: 40°

Flow rate: 1 ml/min

Detection: 240 nm

Eluent: acetonitrile/water (50:50, vol/vol.), isocratic elution

Retention time: the substance V - 7,2 min, the 11107D substance - 3,6 minutes

Reference example 8

One full loop grown on stubble nutrient culture [of 0.5% soluble starch, 0.5% glucose, 0.1% extract of meat fish (manufacturer Wako Pure Chemical Industries, Ltd.), 0.1% of yeast extract (manufacturer Oriental Yeast Co., Ltd.), 0,2% NZ-shell (the manufacturer Humko Sheffield Chemical Co.), 0.2% sodium chloride, 0.1% calcium carbonate and 1.6% agar (manufacturer Wako Pure Chemical Industries, Ltd.)] strain Streptomyces sp. AB-1704 (FERM P-18999), isolated from soil, was made in 500-ml Erlenmeyer flask containing 100 ml of medium for planting [of 2.0% soluble starch, 1.0% glucose, 0.5% polypeptide (manufacturer Nihon Pharmaceutical Co., Ltd.), 0.5% of yeast extract (manufacturer Oriental Yeast Co., Ltd.) and 0.1% of calcium carbonate], and cultured at 28°C for three days in a shaking incubator with obtaining a seed culture. Then every 2 ml of seed culture was inoculable in 500-ml Erlenmeyer flask (150 flasks), each containing 100 ml productio the Noah environment [2,0% soluble starch, 1.0% glucose, 0.5% polypeptide (manufacturer Nihon Pharmaceutical Co., Ltd.), 0.5% of yeast extract (manufacturer Oriental Yeast Co., Ltd.) and 0.1% of calcium carbonate], and cultured at 28°C for two days in a shaking incubator.

To prepare solution (20 mg/ml) substance-substrate W in ethanol and every of 0.44 ml) was added to the culture (100 ml/500-ml Erlenmeyer flask, 150 flasks). After adding the culture was shaken at 28°C for 9 hours to perform the reaction conversion. Upon completion of the reaction, the culture was collected and divided into the culture supernatant and the precipitate mycelium by centrifugation at 2700 rpm for 10 minutes. Sediment mycelium was extracted with 5 l of methanol and filtered to obtain a methanol extract. The methanol extract was evaporated to remove methanol, combined with the supernatant of culture and was extracted with 10 l of ethyl acetate. Received an ethyl acetate solution was evaporated to obtain 2090 mg of the crude active fraction. The crude active fraction was dissolved in 4 ml of a mixture of tetrahydrofuran-methanol (1:1, vol/about.) and 6 ml of 50% aqueous solution of acetonitrile was subjected to chromatography on a column of ODS (manufacturer YMC Co., ODS-AM 120-S50 s,6 cm x 43 cm) and suirable 40% aqueous solution of acetonitrile. Elyuirovaniya fraction from 336 ml to 408 ml was concentrated to dryness under reduced pressure to obtain 560 megastate. Then the residue was dissolved in 10 ml of 50% aqueous solution of methanol, subjected to chromatography on a column of ODS (manufacturer YMC Co., ODS-AM 120-S50 s,6 cm x 40 cm) and suirable 50% aqueous solution of methanol. Elyuirovaniya fraction from 1344 ml to 1824 ml was concentrated to dryness under reduced pressure to obtain 252 mg of 11107D substance.

Reference example 9

One full loop grown on stubble nutrient medium culture (agar medium with yeast and malt) strain A-1544 (FERM P-18943), isolated from soil, was inoculable in 250-ml Erlenmeyer flask containing 25 ml of medium for seeding [2% soluble starch, 2% glucose, 2% soybean meal (ESUSAN-MEAT, manufacturer Ajinomoto Co., Ltd.), 0.5% of yeast extract (manufacturer Difco), 0.25% sodium chloride and 0.32% calcium carbonate, pH 7.4 before sterilization], and cultured at 28°C for two days in a shaking incubator with obtaining a seed culture. Every 0.75 ml of the culture were made in 2-ml tubes with serum (manufacturer Sumitomo Bakelite Co., Ltd.) and added an equal amount of 40% aqueous solution of glycerol. After mixing, the contents were frozen at -70°obtaining a frozen seed culture. Frozen seed culture was thawed, 0.25 ml it was inoculable in 250-ml Erlenmeyer flask containing 25 ml of medium for seeding [2% soluble starch, 2% glucose, 2% soy flour ESUSAN-MEAT, manufacturer Ajinomoto Co., Ltd.), 0.5% of yeast extract (manufacturer Oriental Yeast Co., Ltd.), 0.25% sodium chloride and 0.32% calcium carbonate, pH 7.4 before sterilization], and cultured at 28°C for two days in a shaking incubator with obtaining a seed culture. Then the sowing culture (0.5 ml) was inoculable in 500-ml Erlenmeyer flask containing 100 ml of production medium [2% soluble starch, 2% glucose, 2% soybean meal (ESUSAN-MEAT, manufacturer Ajinomoto Co., Ltd.), 0.5% of yeast extract (manufacturer Oriental Yeast Co., Ltd.), 0.25% sodium chloride and 0.32% calcium carbonate, pH 7.4 before sterilization] and cultured at 28°C for three days in a shaking incubator.

Each of the obtained cultures (100 ml/500-ml Erlenmeyer flask, 10 flasks) were subjected to centrifugation at 3000 rpm for 10 minutes to collect cells, and the cells suspended in 100 ml of 50 mm phosphate buffer solution (pH 6.0). Then prepared solution (100 mg/ml) substance-substrate V in dimethyl sulfoxide was added to each 0.5 ml of the obtained solution. After adding the culture was shaken at 28°within 24 hours for the implementation of the reaction conversion. Upon completion of the reaction, the reaction mixture was collected and separated into supernatant and precipitate mycelium by centrifugation at 5000 rpm for 20 minutes. The supernatant extragear the Wali 1 l of ethyl acetate. Sediment mycelium was extracted with 500 ml of methanol and then filtered to obtain a methanol extract. The methanol extract was evaporated to remove methanol and extracted with 1 l of ethyl acetate. Each of an ethyl acetate layers were washed with water, dried over anhydrous sodium sulfate and the combined layers were evaporated to obtain 937 mg of the crude active fraction. The crude active fraction was subjected to column chromatography on silica gel (Russ. name gel 60, 50 g) and suirable 1200 ml of a mixture of ethyl acetate and n-hexane (90:10, vol/about.) to obtain 234 mg of the active fraction. The obtained active fraction was subjected to preparative high performance liquid chromatography (HPLC) under the following conditions (C) preparative HPLC and the resulting eluate was analyzed by HPLC under the following conditions (c) analysis by HPLC. Solvent was removed from the fractions containing the 11107D substance, receiving 80 mg of 11107D substance.

Conditions (C) preparative HPLC:

Column: CAPCELL PACK C18 UG120 s x 250 mm (manufacturer SHISEIDO Co.)

Flow rate: 20 ml/min

Detection: 240 nm

Eluent: acetonitrile/water (30:70, about./vol.), isocratic elution

Conditions (c) analysis by HPLC:

Column: CAPCELL PACK C18 SG120 ø4 (, 6 mm x 250 mm (manufacturer SHISEIDO Co.)

Temperature: 40°

Flow rate: 1 ml/min

Detection: 240 nm

Eluent: acetonitrile/water (35:65, about./vol.), isocratic elution

Retention time: the 11107D substance - 7,8 minutes

Reference example 10

Each of the cultures of strain A-1545 (FERM P-18944), (100 ml/500-ml Erlenmeyer flask, 10 flasks)obtained by the method similar to that described in reference example 9 were subjected to centrifugation at 3000 rpm for 10 minutes to collect cells, and the cells suspended in 100 ml of 50 mm phosphate buffer solution (pH 6.0). Then prepared solution (100 mg/ml) substrate W in dimethyl sulfoxide was added to each 1 ml of the obtained solution. After adding the culture was shaken at 28°within 24 hours for the implementation of the reaction conversion. Upon completion of the reaction, the reaction mixture was collected and separated into supernatant and precipitate mycelium by centrifugation at 5000 rpm for 20 minutes. The supernatant was extracted with 1 l of ethyl acetate. Sediment mycelium was extracted with 500 ml of acetone and then filtered to obtain the acetone extract. The acetone extract was evaporated to remove acetone and was extracted with 1 l of ethyl acetate. Each of an ethyl acetate layers were washed with water, dried and dehydrational over anhydrous sodium sulfate and the combined layers were evaporated to obtain 945 mg of the crude active fraction. The crude active fraction was subjected to column chromatography on silica gel (Russ. name el 60, 50 g) and suirable 100 ml of a mixture of ethyl acetate and n-hexane (50:50, vol/vol.), 200 ml of a mixture of ethyl acetate and n-hexane (75:25, about./about.) and 600 ml of a mixture of ethyl acetate and n-hexane (90:10, vol/about.) obtaining 463 mg of the active fraction. The obtained active fraction was subjected to preparative high performance liquid chromatography (HPLC) under the conditions (C) preparative HPLC as described in example 4 and the obtained eluate was analyzed by HPLC under the following conditions analysis by HPLC as described in example 4. Solvent was removed from the fractions containing the 11107D substance, obtaining 304 mg 11107D substance.

1. The compound represented by formula (I)

(in the formula, R3, R6, R7and R21are the same or different from each other, and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R3, R6, R7and R21provided that R6limited to hydroxyl groups,

2) optionally substituted C1-22alkoxygroup,

3) optionally substituted unsaturated With2-22alkoxygroup,

4) RCO-O- (where R represents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkiline the group,

c) optionally substituted C6-14aryl group,

d) optionally substituted 5-14 membered heteroaryl group,

e) optionally substituted C7-22aracelio group,

f) optionally substituted 5 to 14-membered heteroalkyl group,

g) optionally substituted C6-14alloctype

5) RS1RS2RS3SiO - (RS1, RS2and RS3are the same or different from each other, and each of them represents a

a)1-6alkyl group, or

(b) (C6-14aryl group),

6) RN1RN2N-RM(where RMrepresents a

a) a single bond,

b) -CO-O-,

c) -CS-O -, or

d) -CO-NRN3- (where RN3represents a hydrogen atom or optionally substituted C1-6alkyl group), provided that each of the leftmost bond in b)to (e) attached to the nitrogen atom; and

RN1and RN2are the same or different from each other and each represents (a) hydrogen atom, b) optionally substituted C1-22alkyl group,

c) optionally substituted unsaturated C2-22alkyl group,

d) optionally substituted 5-14 membered heteroaryl group,

f) optional what about the substituted 3 to 14-membered non-aromatic heterocyclic group, formed RN1and RN2together with the nitrogen atom that is attached to RN1and RN2and non-aromatic heterocyclic group may have substituents, or

g) optionally substituted 5 to 14-membered heteroalkyl group,

i) optionally substituted 3 to 14-membered non-aromatic heterocyclic group),

provided that excluded the compound in which R3, R6, R7and R21all represent a hydroxyl group; a compound in which R3, R6and R21all represent a hydroxyl group and R7is acetochlor and the compound in which R3, R6represent a hydroxyl group, R7is acetoxy and R21represents an oxo group formed together with the carbon atom that is attached to R21), its pharmacologically acceptable salt or hydrate.

2. The compound according to claim 1, represented by formula (I-a)

(in the formula, R3A, R6A, R7aand R21aare the same or different from each other, and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R3a, R 6a, R7aand R21aprovided that R6alimited to hydroxyl groups,

2) optionally substituted C1-22alkoxygroup,

3) RaCO-O- (where Rarepresents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

c) optionally substituted C6-14aryl group,

d) optionally substituted 5-14 membered heteroaryl group,

e) optionally substituted C7-22aracelio group,

g) optionally substituted C6-14alloctype or

h) optionally substituted 5 to 14-membered heterokaryosis),

4) RaS1RaS2RaS3SiO- (RaS1, RaS2and RaS3are the same or different from each other, and each of them represents a

a) C1-6alkyl group, or

(b) (C6-14aryl group),

5) RaN1RaN2N-RaM- (where RaMrepresents a

a) a single bond,

b) -CO-O-,

c) -CS-O -, or

(e) -CO-NRaN3- (where RaN3represents a hydrogen atom or optionally substituted C1-6alkyl group, provided that each of the leftmost bond in b)to (e) attached to the nitrogen atom); and

RaN1and RaN2are the same or otlichayuschimisya from each other, and each of them represents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

c) optionally substituted unsaturated C1-22alkyl group,

d) optionally substituted 5-14 membered heteroaryl group,

f) optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed RaN1and RaN2together with the nitrogen atom that is attached to RaN1and RaN2and non-aromatic heterocyclic group may have substituents,

g) optionally substituted 5 to 14-membered heteroalkyl group, or

i) optionally substituted 3 to 14-membered non-aromatic heterocyclic group, its pharmacologically acceptable salt or hydrate.

3. The compound according to claim 1, represented by formula (I-b)

(in the formula, R3b, R6b, R7band R21bare the same or different from each other, and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R3b, R6b, R7band R21bprovided that R6blimited to hydroxyl groups,

2) optionally substituted C1-22alkoxygroup,

3) RbCO-O- (where Rbrepresents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

c) optionally substituted C6-14aryl group,

d) optionally substituted 5-14 membered heteroaryl group,

e) optionally substituted C7-22aracelio group,

g) optionally substituted C6-14alloctype,

4) RbS1RbS2RbS3SiO- (RbS1, RbS2and RbS3are the same or different from each other, and each of them represents a

a)1-6alkyl group, or

(b) (C6-14aryl group), or

5) RbN1RbN2N-RbM- (where RbMrepresents a

a) -CO-O - or

b) -CS-O-, provided that each of the leftmost bond in a) and b) attached to the nitrogen atom;

and

RbN1and RbN2are the same or different from each other, and each of them represents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

c) optionally substituted unsaturated C2-22alkyl group,

d) optionally substituted 5-14 membered heteroaryl group,

f) optionally substituted 3 to 14-membered non-aromatic g is teracycline group, formed RbN1and RbN2together with the nitrogen atom that is attached to RbN1and RbN2and non-aromatic heterocyclic group may have substituents,

g) optionally substituted 5 to 14-membered heteroalkyl group or

i) optionally substituted 3 to 14-membered non-aromatic heterocyclic group)), its pharmacologically acceptable salt or hydrate.

4. The compound according to claim 1, represented by formula (I-c)

(in the formula, R3c, R6cR7cand R21care the same or different from each other, and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R3c, R6c, R7cand R21cprovided that R6climited to hydroxyl groups,

2) optionally substituted C1-22alkoxygroup,

3) RcCO-O- (where Rcrepresents a

a) optionally substituted C1-22alkyl group,

b) optionally substituted C6-14aryl group,

e) optionally substituted C6-14alloctype),

4) RcS1RcS2RcS3SiO- (RcS1, RcS2and RcS3are the same or different is Rog from each other, and each of them represents a

a)1-6alkyl group, or

(b) (C6-14aryl group), or

5) RcN1RcN2N-RcM- (where RcMrepresents a

a) -CO-O - or

b) -CS-O-, provided that each of the leftmost bond in a) and b) attached to the nitrogen atom;

and

RcN1and RcN2are the same or different from each other, and each of them represents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

c) optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed RcN1and RcN2together with the nitrogen atom that is attached to RcN1and RcN2and non-aromatic heterocyclic group may have substituents,

d) optionally substituted 5 to 14-membered heteroalkyl group,

e) optionally substituted C3-14cycloalkyl group or

f) optionally substituted 3 to 14-membered non-aromatic heterocyclic group, its pharmacologically acceptable salt or hydrate.

5. The compound according to claim 1, represented by formula (I-d)

(in the formula, R3drepresents a

1) hydroxyl group, or oxoprop, formed the left together with the carbon atom, attached to R3d,

2) optionally substituted C1-22alkoxygroup,

3) optionally substituted unsaturated With2-22alkoxygroup,

4) RdCO-O- (where Rdrepresents a

(a) a hydrogen atom,

b) optionally substituted C1-22alkyl group,

(C) optionally substituted C6-14aryl group,

d) optionally substituted 5-14 membered heteroaryl group,

e) optionally substituted C6-14alloctype

or

5) RdN1RdN2N-CO-O- (where RdN1and RdN2are the same or different from each other, and each of them represents a

(a) a hydrogen atom,

b) optionally substituted C7-22alkyl group,

c) optionally substituted unsaturated C2-22alkyl group,

d) optionally substituted 5-14 membered heteroaryl group,

f) optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed RdN1and RdN2together with the nitrogen atom that is attached to RdN1and RdN2and non-aromatic heterocyclic group may have substituents), and

R6d, R7dand R21dare the same or different from each other, and what each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R6d, R7dand R21dprovided that R6dlimited to hydroxyl groups,

2) optionally substituted C1-22alkoxygroup,

3) optionally substituted unsaturated With2-22alkoxygroup,

5) RdCO-O- (where Rdhas the same meaning as defined above),

6) RdN1RdN2N-CO-O- (where RdN1and RdN2have the same meanings as defined above)

8) RdN1RdN2N-CS-O- (where RdN1and RdN2have the same meanings as defined above)

its pharmacologically acceptable salt or hydrate.

6. The compound according to claim 1, where R6and/or R7represent(et) a RN1RN2N-RM(where RMrepresents a

a) -CO-O - or

b) -CS-O-; and

RN1and RN2have the same meanings as defined above, provided that each of the leftmost bond in a) and b) attached to the nitrogen atom), its pharmacologically acceptable salt or hydrate.

7. The compound according to claim 1, its pharmacologically acceptable salt or hydrate, where R21is oxoprop formed together with the carbon atom that is attached to R21.

8. Soedinenie to claim 5, represented by formula (I-e)

(in the formula, R3eand R21eare the same or different from each other, and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R3eand R21eprovided that R6elimited to hydroxyl groups,

2) optionally substituted C1-6alkoxygroup,

3) optionally substituted unsaturated With2-10apaksalbumu,

4) optionally substituted aliphatic C2-6alloctype or

5) ReN1ReN2N-CO-O- (where ReN1and ReN2are the same or different from each other, and each of them represents a

(A) a hydrogen atom, or

B) optionally substituted C1-6alkyl group); and

R6eand R7eare the same or different from each other, and each of them represents a

1) hydroxyl group, or oxoprop formed together with the carbon atom that is attached to each of R6eand R7Eprovided that R6thlimited to hydroxyl groups,

2) optionally substituted C1-6alkoxygroup,

3) optionally substituted by nanasi the n 2-10alkoxygroup,

5) optionally substituted aliphatic C2-6alloctype,

its pharmacologically acceptable salt or hydrate.

9. The compound according to claim 5, where R6dand/or R7drepresent(et) a Rd1C(=Yd1)-O- (where Yd1represents an oxygen atom or a sulfur atom, and Rd1represents a

1) a hydrogen atom,

2) optionally substituted C1-6alkyl group, its pharmacologically acceptable salt or hydrate.

10. The compound according to claim 5, represented by formula (I-f)

(in the formula, R7fis an RfC(=Yf)-O- (where Yfrepresents an oxygen atom and R represents a group of formula (V)

(where n represents an integer of 0

RfN1represents a

1) a hydrogen atom,

2) methyl group, or

3) ethyl group, and RfN2represents 1) a hydrogen atom,

7) pyridinyl group,

8) pyrrolidin-1-ilen group,

9) piperidine-1-ilen group,

10) morpholine-4-ilen group or

11) 4-methylpiperazin-1-ilen group))), its pharmacologically acceptable salt or hydrate.

11. The compound according to claim 1, which is selected is C:

(8E,12E,14E)-7-(N-(2-(N',N'-dimethylamino)ethyl)-N-methylcarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-butylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-ethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylpiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-cyclohexylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-(cyclopropylmethyl)piperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-papillomaviruses-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-(cyclopropylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6,16,21-those whom rehydrate-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-cyclopentylpropionyl-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-3,6,16,21-tetrahydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-cycloheptatrien-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-(N-(2-(N',N'-diethylamino)ethyl)-N-methylcarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-3,6,16,21-tetrahydroxy-7-((4-isobutylpyrazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-acylhomoserine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-butyrometers-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(piperidine-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-(2,2-dimethylpropyl)homopiperazin the-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide; and

(8E,12E,14)-3,6,16-trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide.

12. The compound according to claim 1, which is selected from

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-cyclohexylpiperazine-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-3,6,16,21-tetrahydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide;

(8E,12E,14)-7-((4-cycloheptatrien-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide; and

(8E,12E,14E)-7-(N-(2-(N',N'-diethylamino)ethyl)-N-methylcarbamoyl)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide.

13. Drug, possess cytotoxic activity containing a compound according to any one of claims 1 to 12, its pharmacologically acceptable salt or hydrate as the active component.

14. Pharmaceutical composition having cytotoxic activity containing compound is of any one of claims 1 to 12, its pharmacologically acceptable salt or hydrate as the active component.

15. The drug is indicated in paragraph 13, which is an agent for the prevention or treatment of diseases against which effective regulation of gene expression.

16. The drug is indicated in paragraph 13, which is an agent for the prevention or treatment of diseases against which effective inhibition of VEGF production.

17. The drug is indicated in paragraph 13, which is an agent for the prophylaxis or treatment of a disease against which an effective antiangiogenic effect.

18. The drug is indicated in paragraph 13, which is an inhibitor of angiogenesis.

19. The drug is indicated in paragraph 13, which is an antitumor agent.

20. The drug is indicated in paragraph 13 as a therapeutic agent for the treatment of angiomas.

21. The drug is indicated in paragraph 13, which is an inhibitor of cancer metastasis.

22. The drug is indicated in paragraph 13, which is a therapeutic agent for the treatment of retinal revascularization or diabetic retinopathy.

23. The drug is indicated in paragraph 13, which is a therapeutic tool for the treatment of solid malignant tumors.

24. Drug for item 23, where a solid malignant tumor is a lung cancer, a tumor of the head is about the brain, breast cancer, prostate cancer, ovarian cancer, cancer of the colon or melanoma.

25. The drug is indicated in paragraph 13, which is a therapeutic agent for the treatment of leukemia.

26. The drug is indicated in paragraph 13, which is an antitumor agent based on the regulation of gene expression.

27. The drug is indicated in paragraph 13, which is an antitumor agent based on the inhibition of VEGF production.

28. The drug is indicated in paragraph 13, which is an antitumor agent based on the effect of inhibition of angiogenesis.

29. A method of preventing or treating a disease against which effective regulation of gene expression, containing the introduction to the patient a pharmacologically effective dose of the drug according to item 13.

30. A method of preventing or treating a disease against which effective inhibition of VEGF production, containing the introduction to the patient a pharmacologically effective dose of the drug according to item 13.

31. A method of preventing or treating a disease against which effective inhibition of angiogenesis, containing the introduction to the patient a pharmacologically effective dose of the drug according to item 13.

32. The use of compounds according to any one of claims 1 to 12, its pharmacologically acceptable salt or hydrate for izgotovleniia for the prevention or treatment of disease, against which effective regulation of gene expression.

33. The use of compounds according to any one of claims 1 to 12, its pharmacologically acceptable salt or hydrate for the manufacture of products for the prevention or treatment of diseases against which effective inhibition of VEGF production.

34. The use of compounds according to any one of claims 1 to 12, its pharmacologically acceptable salt or hydrate for the manufacture of products for the prevention or treatment of diseases against which effective inhibition of angiogenesis.

35. The use of compounds according to any one of claims 1 to 12, its pharmacologically acceptable salt or hydrate for the manufacture of products for the prevention or treatment of solid malignant tumors.

The priority of 23.05.2002 on PP,10,14-36

on the filing date from 29.05.2003 according to claims 1-8, 11-13.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new piperidine derivative, with the following general formula (I) where R1 - R4 each stands for any of the univalent groups, indicated below: R1 stands for a hydrogen atom, halogen atom, inferior alkyl, which can be substituted with a halogen atom or OH; -O-inferior alkyl, which can be substituted with a halogen atom; -O-aryl, aryl, -C(=O)-inferior alkyl, COOH, -C(=O)-O-inferior alkyl, -C(=O)-NH2, -C(=O)NH-inferior alkyl, -C(=O)N-(inferior alkyl)2, OH, -O-C(=O)-inferior alkyl, NH2, -NH-inferior alkyl, -N-(inferior alkyl)2, NH-C(=O)- inferior alkyl, CN or NO2; R2 and R3 each stands for a hydrogen atom; and R4 stands for any of the univalent groups (a), (b) and (c), shown below in formula 2 where in the above indicated groups (a), (b) and (c), A stands for a pyrrolidine, piperidine, morpholine, piperizine or oxazepane ring; B stands for a pyrrolidine or piperidine ring; R5 and R8-R11 can be identical or different from each other and each stands for a hydrogen atom, -C(=O)-O-inferior alkyl, cycloalkyl or tetrahydropyrane; R6 stands for a hydrogen atom, -C(=O)-O-inferior alkyl, OH, -inferior alkylene-OH or -C(=O)-pyridine; and R7 stands for a hydrogen atom. The invention also pertains to pharmaceutical salts of the piperidine derivative, as well as medicinal compositions.

EFFECT: obtaining new biologically active compounds and a medicinal composition, based on these compounds, which is a sodium channel inhibitor.

10 cl, 91 ex, 22 tbl

FIELD: chemistry.

SUBSTANCE: invention claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: chemistry.

SUBSTANCE: description is given of new diazabicyclic aryl derivatives, with general formula I: its enantiomers, or mixture of enantiomers, or its adjoining pharmaceutical salt, where X and Y independently represent CR2, CR3 or N, where R2 is hydrogen, C1-6alkyl or halogen; and R3 is hydrogen or halogen; and R1 is hydrogen or halogen, CF3, NO2 or phenyl, possibly substituted, group with formula phenyl-Z-(C1-6alkyl)m-, phenyl -C≡C- or pyridyl -Z-(C1-6alkyl)m-, where m equals 0 or 1; Z - O or S, where phenyl and pyridyl are possibly substituted, or R1 and R3 , together with carbon atoms to which they are bonded, form a benzocondensed aromatic carbocyclic ring, which can be substituted. The new compounds are cholinergic ligands of nicotinic acetylcholine receptors.

EFFECT: compounds can be useful for treating such diseases or disorders related to the cholinergic system of the central nervous system, peripheral nervous system etc.

11 cl, 3 ex, 1 tbl

FIELD: organic chemistry.

SUBSTANCE: invention relates to novel individual compounds of series 2,5a-methano[1,4]diazepino[1,7-a]-quinoxaline-5-carboxylates, namely, to isopropyl-12-aroyl-2-hydroxy-1,6-dioxo-4-(3-pyridinyl)-7-phenyl-1,3,6,7-tetrahydro-2,5a-methano[1,4]diazepino[1,7-a]-quinoxaline-5-carboxylates of the formula (1) wherein Ar means phenyl or p-methoxyphenyl, and to a method for their synthesis. Method for synthesis of compound of the formula (1) involves interaction of 3-aroyl-5-phenylpyrrolo[1,2-a]-quinoxaline-1,2,4(5H)-triones with isopropyl-3-amino-3-(3-pyridinyl)-2-propenoate in an inert aprotonic solvent medium and the following isolation of end substances. The proposed method provides synthesis of novel compounds of the formula (1) possessing antibacterial effect with high yield and selectivity.

EFFECT: improved method of synthesis.

4 cl, 1 tbl, 3 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to new biarylcarboxamides of the general formula (I): wherein A means compound of the formula (II): ; D means oxygen atom (O) or sulfur atom (S); E means a simple bond, oxygen atom, sulfur atom or NH; Ar1 means 5-membered heteroaromatic ring comprising one nitrogen atom (N) and one sulfur atom (S) or one oxygen atom (O), or one S atom, or one N atom; or 6-membered aromatic ring, or heteroaromatic ring comprising one N atom; Ar2 means 5-membered heteroaromatic ring comprising one S atom or on O atom, or one N atom and one O atom, or one N atom; or 6-membered aromatic ring or heteroaromatic ring comprising one N atom; or 9-membered condensed heteroaromatic ring system comprising one O atom, or 10-membered condensed aromatic ring system, or heteroaromatic ring system comprising one N atom wherein aromatic ring Ar2 is possibly substituted with one or two substitutes taken among halogen atom, (C1-C4)-alkyl, cyano-group (-CN), nitro group (-NO2), NR1R2, OR3, trihalogen-(C1-C4)-alkyl, (C1-C4)-acylamino-, hydroxy-, morpholino-, amino-, methylamino-group, amino-(C1-C4)-alkyl and hydroxymethyl but if Ar1-phenyl and Ar2 represent quinolinyl group then Ar2 is substituted with one or two (C1-C4)-alkyls, -CN, -NO2, NR1R2, OR3 wherein R1, R2 and R3 mean (C1-C4)-alkyl and compound of the formula (III) doesn't represent .

EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new individual compounds of azapentacycloeicosanes class. Invention describes 20-aroyl-12-hydroxy-17,17-dimethyl-3-phenyl3,10,13-triazapentacyclo[10.7.1.01,10.O4,9.O14,19]eicosa-4,6,14(19)-2,11,15-triones of the formula:

wherein R means hydrogen atom; Ar means phenyl; or R means benzyl and Ar means p-methoxyphenyl group. Also, the invention describes a method for preparing these compounds. Invention provides preparing new compounds that can be used as the parent substances for synthesis of new heterocyclic systems.

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

4 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new annelated azaheterocyclic amides, including a pyrimidine fragment, with the general formula 1, method of obtaining them and their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of P13K kinase, in compounds with the general formula 1: , where: X represents an oxygen atom, sulphur atom or not necessarily substituted at the nitrogen NH group, where the substitute is selected from lower alkyls and possibly a substituted aryl; Y represents an atom of nitrogen or substituted at the carbon atom CH group, where the substitute is selected from lower alkyls; Z represents an oxygen atom; R1 represents a hydrogen atom or not necessarily substituted C1-C6alkyl, or Z represents a nitrogen atom, which is together with a carbon atom, with which it is joined, form through Z and R1 annelated imidazole cycle; R2 and R3 independently from each other represent hydrogen, not necessarily substituted with C1-C6alkyl, C3-C6cycloalkyl, not necessarily substituted with phenyl, not necessarily substituted with 6-member aza-heteroaryl, under the condition, when Y represents a nitrogen atom, or R2 and R3 independently from each other represent not necessarily substituted C1-C6alkyl, not necessarily substituted with phenyl, not necessarily substituted with 5-7-member heterocycle with 1-2 heteroatoms, selected from nitrogen and oxygen, and possibly annelated with a phenyl ring, under the condition, when Y does not necessarily represent a substituted carbon atom at the CH group, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents a substituted aminoC1-C6alkyl and not necessarily substituted 5-6-member aza-heterocycloalkyl, under the condition, when Y represents a group which is substituted at the CH atom, and X represents an oxygen atom, sulphur atom, or R2 represents hydrogen, and R3 represents phenyl which is not necessarily substituted, pyridyl which is not necessarily substituted, pyrimidinyl which is not necessarily substituted, under the conditions, when R1 represents a substituted aminoC1-C6alkyl, substituted C2-C3hydroxyalkyl and aza-heterocycloalkyl not necessarily substituted, Y represents a group with CH substituted, and X represents an oxygen atom, sulphur, and the substitute of the above indicated substituted alkyl, phenyl, heterocycle, pyridyl, pyrimidyl are selected from groups of hydroxyl-, cyano-groups, hydrogen, lower alkyls, possibly mono- or di-substituted lower alkyl sulfamoyl, carbamoyl, C1-C6alkoxycarbonyl, amino, mono- or di-lower alkyl-amine, N-(lower alkyl), N-(phenylC1-C6alkyl)amine, phenyl, possibly substituted with a halogen atom, C1-C6alkyl, haloid-C1-C6alkyl; phenylC1-C6alkyl, saturated or non-saturated 5-6-member heterocycle containing 1-2-heteroatoms, selected from nitrogen, oxygen and sulphur, and possible condensation with a benzene ring R4 represents hydrogen or a lower alkyl.

EFFECT: obtaining new annelated aza-heterocyclic amides, including a pyrimidine fragment, with the general formula with the possibility of their application in the form of free bases or their pharmaceutically accepted salts as inhibitors of PI3K kinase.

16 cl, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to methane sulphonate of 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrazol[1,5-a]pyrimidine, its crystal and method of obtaining it. Methane sulphonate of 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrazol[1,5-a]pyrimidine has excellent thermal stability. The invention also relates to pharmaceutical compositions based on the above mentioned salt and its crystal. The compositions are CRF antagonists and can be used for treating neuropsychiatric disorders or alimentary system diseases. The invention also pertains to an efficient high output new method of making the intermediate compound 1-cyano-1-(2-chloro-4-methoxyphenyl)propan-2-one from 1-bromo-2-chloro-4-methoxybenzol.

EFFECT: obtaining intermediate compound with efficient high output.

16 cl, 6 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a new compound - acid mesylate of 4-(4-trans-hydroxycyclohexyl) amino-2-phenyl-7H-pyrrolo [2,3d]pyrimidine and its polymorphous α and β forms. The compound has agonistic activity towards adenosine-1 receptor and can be used for making medicinal preparations for treating hypertensive diseases, congestive heart failure and renal failure.

EFFECT: obtaining a compound with better bioavailability due to high solubility and which is more stable in ambient conditions.

17 cl, 6 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: described is 4-(4'-hydroxybutyl)-6-phenyl-1,2,4-triazolo[5,1-c] [1,2,4]triazin-7-on of formula (1) possessing anti-viral activity, , which can be applied in medicine and agriculture.

EFFECT: obtaining compound which possesses antiviral activity.

1 cl, 3 ex, 1 tbl

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diaminopyrrolo quinazoline of formula (I), which possess properties of protein tyrosine phosphatase PTP-1B inhibitors and can be used for reduction of glucose concentration in blood. In general formula (I) A stands for 5- or 6-member unsaturated or saturated hydrocarbon ring or 5- or 6-member unsaturated or saturated ring, which contains at least one heteroatom, selected from S, N or O, R1 represents hydrogen or lower alkyl; Ra represents hydrogen,

,

,

,

or lower alkyl , R1, Ra, Rb, Rc, Rd, Re, Rf are such as defined in invention formula.

EFFECT: obtaining derivatives of diaminopyrrolo quinazoline which possess properties of protein tyrosine phosphatase inhibitors.

32 cl, 5 dwg, 118 ex

FIELD: chemistry.

SUBSTANCE: this invention refers to new production method of composition of formula I where R1 represents: H; cyano; optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; or -C(O)-R5, where R5 represents H; optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; either OR6 or NR6R7 where each R6 and R7 independently represents H optionally unsubstituted or substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; R2 represents H; R3 represents H or alkyl; R4 represents H, halogen or alkyl including: a) Sonogashira coupling of formula II , where X represents halogen or CF3SO2-O- with compound of formula III to produce compound of formula IV ; b) reduction of connection of formula IV to produce compound of formula V ; c) transformation of compound of formula V into compound of formula VI ; d) N,N-dimethyl-2-nitroethylenamine treatment of compound of formula VI to produce compound of formula VII ; e) reduction of connection of formula VII to produce compound of formula VIII ; f) of compound of formula VIII by Raney-nickel reduction and subsequent base ring formation into compound of formula I. Besides described is production method of 8-fluorine-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indole-6-one through key Sonogashira coupling reaction and CuI-promotor indole production.

EFFECT: new production method of compounds of formulas I effective as poly(ADP-ribose)polymerase inhibitors is developed.

8 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazin-7-one, dehydrate of formula (1) is obtained by interaction of salt of 3-methylthio-1,2,4-triazol-5-yl-diazonium with diethylnitromalonate in presence of base at 0-25°C in water-alcohol medium.

EFFECT: compound possesses antivirus activity and can find application in medicine.

1 cl, 1 tbl, 1 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new condensed dicyclic nitrogen-containing heterocycles with the general formula (I), their pharmaceutically accepted salts and stereoisomers, possessing DGAT inhibiting action. In the compound of formula (I): , X is selected from a group, which consists of C(R1) and N; Y is selected from a group, which consists of C(R1), C(R2)(R2), N and N(R2); Z is selected from a group, which consists of O; W1 is selected from cyclo(C3-C6)alkyl, aryl and 5- or 6-member heteroaryl, containing 1-2 heteroatoms, selected from a group, which comprises of nitrogen and sulphur, W2 selected from cyclo(C3-C8)alkyl, (C5-C6)heterocycloalkyl, containing 1 or 2 heteroatoms, selected from groups, consisting of nitrogen or oxygen, benzol and 5-or 6-member heteroaryl, containing 1-2 nitrogen atoms as heteroatoms, L1 is the link; L2 is selected from a group consisting of links, 0, (C1-C4)alkylene and (C1-C4)oxyalkylene; m denotes 0 or 1; its not a must that when m denotes 1 and L2 denotes a link, the substitute for W2 can be integrated with the substitute for W1 forming a 5-or 6-member ring, condensed with c W1 forming a spiro-system or condensed with W2, where specified ring could be saturated or unsaturated and has 0 or 1 atom O, as a member of the ring R1 is H; R2 is H; R3 and R4 are independently selected from groups consisting of H and (C1-C8) alkyl; optionally, R3 and R4 can together form 3-, 4-, 5- or 6-member spirorings, R5 and R6 are independently H; optionally, when Y includes the group R1 or R2, R5 or R6 can be joined with R1 and R2 forming a 5- or 6-member condensate ring, containing a nitrogen atom, to which R5 or R6 are joined, and optionally containing an oxo-group; R7 is selected from a group, composed of H, (C1-C8) alkyl, halogen(C1-C4)alkyl, 0Ra and NRaRb ; Ra selected from groups composed of H and (C1-C8)alkyl; and Rb selected from groups consisting of H and (C1-C8)alkyl; a dotted line indicates a possible bond. The invention also relates to pharmaceutical compositions and applications of the compounds.

EFFECT: obtaining compounds which can be used for getting medicinal agents to treat or prevent diseases or a mediated action state of DGAT, such as obesity, diabetes, syndrome X, resistance of insulin, hyperglycemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, disease of non-alcoholic fatty infiltration of the liver, atherosclerosis, arteriosclerosis, coronary artery disease and myocardial infarction.

33 cl, 17 dwg, 11 tbl, 391 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new compounds with general formula (1), which includes compounds (VI), which relate to conformational stable compounds that imitate the secondary structures of parts of molecules of biologically active peptides and proteins with reverse configurations. The compounds can be used as antitumoral compounds for the treatment and prophylaxis of cancer such as, colorectal cancer, for treating rheumatoid arthritis and ulcerative colitis. The compound facilitates the increase of apoptosis and increases the proliferation of neurites, and inhibits survirin expression in the cell. In compounds, corresponding to the general formula (I) and (VI) , in formula (I) W denotes -Y(C=O)-, -(C=O)NH-, -(SO2)- or is absent, Y denotes an oxygen atom, Z denotes a nitrogen atom or CH, X denotes a nitrogen atom or CH, n=0 or 1, on the condition that when Z denotes CH, X denotes a nitrogen atom and n=1; and when Z denotes a nitrogen atom, then n=0; in formula (VI) X1 denotes a hydroxyl, and at least one of X2 is X3 is a hydroxyl, or X1 denotes hydrogen, and X2 and X3 can be similar of different and independently selected from hydrogen, hydroxyl and halogen. Other radicals have the value specified in the formula of the invention.

EFFECT: obtaining compounds which can be used as antitumoral compounds for the treatment and prophylaxis of cancer such as, colorectal cancer, for treating rheumatoid arthritis and ulcerative colitis.

26 cl, 33 dwg, 9 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

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