New physiologically active substances

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula (I) , and their salts used in pharmacology, and their hydra as well as others, where W represents or and R³, R⁷, R¹⁶, R¹⁷, R²⁰, R²¹ and R²¹ are identical or different and each of them represents a hydrogen atom or assumes other values, given in the formula of invention. The invention also relates to pharmaceutical compositions and medicinal preparations based on these compounds, cultures, used for obtaining them, methods of inhibition and treatment and use.

EFFECT: formula (I) can be used as medicinal preparations for curing solid malignant tumours.

43 cl, 4 tbl, 60 ex

The technical field to which the invention relates

The present invention relates to 12-membered cyclic macrolide compound useful as a drug, the method of its production and its use.

Background of invention

Compounds with cytotoxicity, already used as anticancer agents, and more research is being conducted by the screening method using cytotoxicity as an indicator. The results show that, since the majority of existing anticancer agents has an effect on tumor cells and normal tissues with active cell proliferation, for example, bone marrow and intestinal epithelium, the improvement of QOL of patients are not adequately provided.

In addition, under the existing circumstances it happens that anti-cancer drugs have a beneficial effect in the treatment of leukemia, but not necessarily that they are effective for the treatment of solid malignant tumors. Therefore, there is a great need in antitumor tools that are effective against solid tumors and highly secure.

Already conducted studies on a method of screening fermentation products of microorganisms mainly using qi is otoxicity in vitroas an indicator, in order to use them as anticancer agents. In the result, it was found many cytotoxic compounds. However, as it turned out, most of these compounds exhibits cytotoxic activity onlyin vitroand found some compounds exhibiting anti-tumor activity ofin vivo.In addition, very few compounds have shown efficacy against solid malignant tumors.

Disclosure of the invention

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

It is believed that the carcinogenesis of normal cells cause mutations of the gene in the cell, the result is expressed abnormal gene. In this situation, the authors of the present invention have conducted extensive studies on the assumption that the change in gene expression in tumor cells may cause inhibition of proliferation of tumor cells, i.e. the proliferation of tumor cells can inhibit, for example, changes in gene oncogene or suppressor gene tumor or changing expre is this gene, involved in the cell cycle. The inventors have conducted a screening of fermentation products of various microorganisms and their derivatives using as an indicator the production of VEGF (vascular endothelial growth factor) U251 cells under conditions of hypoxic stimulation, expecting that compounds that alter gene expression, in particular compounds that inhibit the production of VEGF in low hypoxia will suppress induced tumor angiogenesis and, in addition, to exhibit antitumor activity against solid malignant tumors. The authors of the present invention opened a new physiologically active substance, a 12-membered cyclic macrolide compound called 11107 and its analogues, which inhibit the production of VEGF in low hypoxiain vitroand, in addition, inhibit the proliferation of cells in a solid tumorin vivo.

As a result of further extensive studies, the authors of the present invention found that among the analogs 11107 compound 6-deoxy 11107D, in which the hydroxyl group of compound 11107D in position 6 is replaced by hydrogen, and compounds obtained by chemical modification of the 6-deoxy 11107D (hereinafter called as "derivatives of 6-deoxy 11107D"), are stable in aqueous solution and that these derivatives are not only inherit the characteristic is cteristic stability from 11107D, but stronger inhibit the proliferation of cells in solid tumors in experimentsin vivo. On the basis of these findings and was created by the present invention.

As a related known compounds, the most structurally similar to the compound of the present invention, is FD-895, which is a 12-membered cyclic macrolide compound (JP-A-04-352783)represented by the formula (XIV):

In the above publication revealed that FD-895 has cytotoxic activityin vitroagainst cells R murine leukemia cells of L-1210 murine leukemia cells and HL-60 human leukemia in a nutrient medium RPM-1640 (column 6, table 2 of this publication). However, there is a message 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, as described later, since FD-895 is unstable in aqueous solution, it is expected that it is unsuitable for mixing with the infusion solution in the introduction. Thus, FD-895 has not enough for antineoplastic properties.

Therefore, in accordance with the present invention include:

1. The compound represented by formula (I):

where W is provided which allows a

and R³, R⁷, R¹⁶, R¹⁷, R²⁰, R²¹and R^21'identical or different, independently represent

1) a hydrogen atom,

2) a hydroxyl group, or oxoprop, provided that oxoprop limited oxopropoxy formed R³or R⁷together with the carbon atom that is attached to the group R³or R⁷and exography formed by groups of R²¹and R^21'together with the carbon atom that is attached to R²¹and R^21',

3)₁-C₂₂alkoxygroup, which may have a Deputy,

4) unsaturated With_2-22alkoxygroup, which may have a Deputy,

5)₇-C₂₂aralkylated, which may have a Deputy,

6) 5-14-membered heteroeroticism, which may have a Deputy,

7) RC(=Y)-O-, where Y represents oxygen atom or sulfur atom and R represents a

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

(C) unsaturated With₂-C₂₂alkyl group which may have a Deputy,

d)₆-C₁₄aryl group which may have a Deputy,

f) a 5-14-membered heteroaryl group which may have a Deputy,

f)₇-C₂₂aracelio group, which is may have a Deputy,

g) 5-14-membered heteroaryl group which may have a Deputy,

h)₁-C₂₂alkoxygroup, which may have a Deputy,

i) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

j)₆-C₁₄alloctype, which may have a Deputy,

k)₃-C₁₄cycloalkyl group which may have a Deputy,

l) 3-14-membered non-aromatic heterocyclic group which may have a Deputy, or

m) 5-14-membered heteroepitaxy, which may have a Deputy,

8) R^S1R^S2R^S3SiO-, where R^S1, R^S2and R^S3identical or different, independently represent

a)₁-C₆alkyl group, or

(b) (C₆-C₁₄aryl group,

9) a halogen atom,

10) R^N1R^N2N-R^M-where R^Mrepresents a

a) a single bond,

b) -CO-O-,

with) -SO₂-O-,

d) -CS-O -, or

e) -CO-NR^N3-where R^N3represents a hydrogen atom or a C₁-C₆alkyl group which may have a Deputy, provided that the leftmost bond in b)-e) attached to the nitrogen atom,

R^N1and R^N2identical or different, independently represent

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have the",

(C) unsaturated With₂-C₂₂alkyl group which may have a Deputy,

(d) aliphatic C₂-C₂₂acyl group which may have a Deputy,

(e) aromatic C₇-C₁₅acyl group which may have a Deputy,

f)₆-C₁₄aryl group which may have a Deputy,

g) 5-14-membered heteroaryl group which may have a Deputy,

h)₇-C₂₂aracelio group which may have a Deputy,

i)₁-C₂₂alkylsulfonyl group which may have a Deputy,

j)₆-C₁₄arylsulfonyl group which may have a Deputy,

k) 3-14-membered non-aromatic heterocyclic group formed R^N1and R^N2together with the nitrogen atom that is attached to R^N1and R^N2moreover , 3-14-membered non-aromatic heterocyclic group may have a Deputy,

l) 5-14-membered heteroaryl group which may have a Deputy,

m)₃-C₁₄cycloalkyl group which may have a Deputy, or

n) 3-14-membered non-aromatic heterocyclic group which may have a Deputy,

11) R^N4SO₂-O-, where R^N4represents a

a)₁-C₂₂alkyl group which may have a Deputy,

b ₆-C₁₄aryl group which may have a Deputy,

C)₁-C₂₂alkoxygroup, which may have a Deputy,

(d) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

e)₆-C₁₄alloctype, which may have a Deputy,

f) 5-14-membered heteroepitaxy, which may have a Deputy,

g)₇-C₂₂aralkylated, which may have a Deputy, or

h) 5-14-membered heteroeroticism, which may have a Deputy,

12) (R^N5O)₂RO-O-, where R^N5represents a

a)₁-C₂₂alkyl group which may have a Deputy,

b) unsaturated With₂-C₂₂alkyl group which may have a Deputy,

C)₆-C₁₄aryl group which may have a Deputy,

d) a 5-14-membered heteroaryl group which may have a Deputy,

e)₇-C₂₂aracelio group which may have a Deputy, or

f) 5-14-membered heteroaryl group which may have a Deputy,

13) (R^N1R^N2N)₂RO-O-, where R^N1and R^N2are the same as defined above, or

14) (R^N1R^N2N)(R^N5O)RO-O-, where R^N1, R^N2and R^N5are the same as defined above,

it pharmacolo the automatic acceptable salt or hydrate;

2. The compound according to 1, represented by formula (I-a):

where W is as defined above, and R^3A, R^7a, R^16A, R^17A, R^20A, R^21Aand R^21A'identical or different, independently represent

1) a hydrogen atom,

2) a hydroxyl group, or oxoprop, provided that oxoprop limited oxopropoxy formed R^3Aor R^7atogether with the carbon atom that is attached to the group R^3Aor R^7aand exography formed by groups of R^21Aand R^21A'together with the carbon atom that is attached to R^21Aand R^21A',

3)₁-C₂₂alkoxygroup, which may have a Deputy,

4) R^andC(=Y^and)-O-, where Y^andrepresents an oxygen atom or a sulfur atom, and R^andrepresents a

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

(C) unsaturated With₂-C₂₂alkyl group which may have a Deputy,

d)₆-C₁₄aryl group which may have a Deputy,

f) a 5-14-membered heteroaryl group which may have a Deputy,

f)₇-C₂₂aracelio group which may have a Deputy,

g) 5-14-membered heteroaryl group, which the traveler may have a Deputy,

h)₁-C₂₂alkoxygroup, which may have a Deputy,

i) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

j)₆-C₁₄alloctype, which may have a Deputy,

k)₃-C₁₄cycloalkyl group which may have a Deputy,

l) 3-14-membered non-aromatic heterocyclic group which may have a Deputy, or

m) 5-14-membered heteroepitaxy, which may have a Deputy,

5) R^aS1R^aS2R^aS3SiO-, where R^aS1, R^aS2and R^aS3identical or different, independently represent

a)₁-C₆alkyl group, or

(b) (C₆-C₁₄aryl group, or

6) R^aN1R^aN2N-R^aM-where R^aMrepresents a

a) -CO-O - or

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

R^aN1and R^aN2identical or different, independently represent

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

(C) unsaturated With₂-C₂₂alkyl group which may have a Deputy,

(d) aliphatic C₂-C₂₂acyl group which may have a Deputy,

(e) aromatic C₇-C₁₅acyl group, which can the be Deputy,

f)₆-C₁₄aryl group which may have a Deputy,

g) 5-14-membered heteroaryl group which may have a Deputy,

h)₇-C₂₂aracelio group which may have a Deputy,

i)₁-C₂₂alkylsulfonyl group which may have a Deputy,

j)₆-C₁₄arylsulfonyl group which may have a Deputy,

k) 3-14-membered non-aromatic heterocyclic group formed R^aN1and R^aN2together with the nitrogen atom that is attached to R^aN1and R^aN2moreover , 3-14-membered non-aromatic heterocyclic group may have a Deputy,

l) 5-14-membered heteroaryl group which may have a Deputy,

m)₃-C₁₄cycloalkyl group which may have a Deputy, or

n) 3-14-membered non-aromatic heterocyclic group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

3. The compound according to 1, represented by formula (I-b):

where W is as defined above, and R^3b, R^7b, R^16b, R^17b, R^20b, R^21band R^21'bidentical or different, independently represent

1) a hydrogen atom,

2) a hydroxyl group, or oxoprop, in terms of the AI, that oxoprop limited oxopropoxy formed R^3bor R^7btogether with the carbon atom that is attached to the group R^3bor R^7band exography formed by groups of R^21band R^21b'together with the carbon atom that is attached to R^21Aand R^21b',

3)₁-C₂₂alkoxygroup, which may have a Deputy,

4) R^bC(=O)-O-, where R^brepresents a

a)₁-C₂₂alkyl group which may have a Deputy,

b) unsaturated With₂-C₂₂alkyl group which may have a Deputy,

c₇-C₂₂aracelio group which may have a Deputy,

d) 5-14-membered heteroaryl group which may have a Deputy,

e)₆-C₁₄alloctype, which may have a Deputy,

f)₃-C₁₄cycloalkyl group which may have a Deputy,

g) 3-14-membered non-aromatic heterocyclic group which may have a Deputy,

5) R^bS1R^bS2R^bS3SiO-, where R^bS1, R^bS2and R^bS3identical or different, independently represent

a)₁-C₆alkyl group, or

(b) (C₆-C₁₄aryl group, or

6) R^bN1R^bN2N-R^bM-where R^bMrepresents a

a) -CO-O - or

b) -CS-O-, when y is and that the leftmost bond in a) or b) attached to the nitrogen atom, and

R^bN1and R^bN2identical or different, independently represent

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C) 3-14-membered non-aromatic heterocyclic group formed R^bN1and R^bN2together with the nitrogen atom that is attached to R^bN1and R^bN2moreover , 3-14-membered non-aromatic heterocyclic group may have a Deputy,

d)₃-C₁₄cycloalkyl group which may have a Deputy, or

e) 3-14-membered non-aromatic heterocyclic group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

4. The compound according to 1, represented by formula (I-c):

where W is as defined above, and R^3s, R^7C, R^16C, R^17c, R^20s, R^Sand R^21'sidentical or different, independently represent

1) a hydrogen atom,

2) a hydroxyl group, or oxoprop, provided that oxoprop limited oxopropoxy formed R^3sor R^7Ctogether with the carbon atom that is attached to the group R^3sor R^7Cand exography formed by groups of R^Sand R^S'in the natural with the carbon atom, attached to R^Sand R^S',

3) R^withC(=O)-O-, where R^withrepresents a C₁-C₂₂alkyl group which may have a Deputy,

4) R^S1R^S2R^S3SiO-, where R^S1, R^S2and R^S3identical or different, independently represent

a)₁-C₆alkyl group, or

(b) (C₆-C₁₄aryl group, or

5) R^N1R^N2N-R^cM-where R^cMrepresents-CO-O-, provided that the leftmost link attached to the nitrogen atom, and

R^N1and R^N2identical or different, independently represent

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C) 3-14-membered non-aromatic heterocyclic group formed R^N1and R^N2together with the nitrogen atom that is attached to R^N1and R^N2moreover , 3-14-membered non-aromatic heterocyclic group may have a Deputy,

d)₃-C₁₄cycloalkyl group which may have a Deputy, or

e) 3-14-membered non-aromatic heterocyclic group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

5. The compound according to 1, represented by formula (I-d):

1) hydroxyl group,

2)₁-C₂₂alkoxygroup, which may have a Deputy,

3) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

4)₇-C₂₂aralkylated, which may have a Deputy,

5) R^dC(=O)-O-, where R^drepresents a

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

(C) unsaturated With₂-C₂₂alkyl group which may have a Deputy,

d)₆-C₁₄aryl group which may have a Deputy,

f) a 5-14-membered heteroaryl group which may have a Deputy,

f)₇-C₂₂aracelio group which may have a Deputy,

g) 5-14-membered heteroaryl group which may have a Deputy,

h)₁-C₂₂alkoxygroup, which may have a Deputy,

i) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

j)₆-C₁₄alloctype, which may have a Deputy, or

k) 5-14-membered heteroepitaxy, which may have a Deputy, or

6) R^dN1R^dN2N-CO-O-, where R^dN1and R^dN2identical or different, independently represent

a) the atom odor is Yes,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

(C) unsaturated With₂-C_ALKilen group which may have a Deputy,

d)₆-C₁₄aryl group which may have a Deputy,

f) a 5-14-membered heteroaryl group which may have a Deputy,

f)₇-C₂₂aracelio group which may have a Deputy,

g) 5-14-membered heteroaryl group which may have a Deputy,

h)₃-C₁₄cycloalkyl group which may have a Deputy,

i) 3-14-membered non-aromatic heterocyclic group which may have a Deputy, or

j) 3-14-membered non-aromatic heterocyclic group formed R^dN1and R^dN2together with the nitrogen atom that is attached to R^dN1and R^dN2moreover , 3-14-membered non-aromatic heterocyclic group may have a Deputy, and

R^7dand R^21didentical or different, independently represent

1) hydroxyl group,

2)₁-C₂₂alkoxygroup, which may have a Deputy,

3) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

4)₇-C₂₂aralkylated, which may have a Deputy,

5) R^dC(=O)-O-, where R^dis the same as defined the above,

6) R^dN1R^dN2N-CO-O-, where R^dN1and R^dN2such as defined above,

7) R^dN1R^dN2N-SO₂-O-, where R^dN1and R^dN2such as defined above,

8) R^dN1R^dN2N-CS-O-, where R^dN1and R^dN2such as defined above,

9) R^dN4-SO₂-O-, where R^dN4represents a

a)₁-C₂₂alkyl group which may have a Deputy,

(b) (C₆-C₁₄aryl group which may have a Deputy,

C)₁-C₂₂alkoxygroup, which may have a Deputy,

(d) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

e)₆-C₁₄alloctype, which may have a Deputy,

f) 5-14-membered heteroepitaxy, which may have a Deputy,

g)₇-C₂₂aralkylated, which may have a Deputy, or

h) 5-14-membered heteroeroticism, which may have a Deputy,

10) (R^dN5O)₂RO-O-, where R^dN5represents a

a)₁-C₂₂alkyl group which may have a Deputy,

b) unsaturated With₂-C₂₂alkyl group which may have a Deputy,

C)₆-C₁₄aryl group which may have a Deputy,

d) a 5-14-membered heteroaryl group which may have a Deputy,/p>

e)₇-C₂₂aracelio group which may have a Deputy, or

f) 5-14-membered heteroaryl group which may have a Deputy,

11) (R^dN1R^dN2N)₂RO-O-, where R^dN1and R^dN2such as defined above, or

12) (R^dN1R^dN2N)(R^dN5O)RO-O-, where R^dN1, R^dN2and R^dN5such as defined above,

its pharmacologically acceptable salt or hydrate;

6. The compound according to 1, where R⁷and/or R⁶independently represent RC(=Y)-O-, where Y and R such as defined above, or R^N1R^N2N-R^M'-where R^M'represents a

a) -CO-O - or

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

R^N1and R^N2such as defined above,

its pharmacologically acceptable salt or hydrate;

7. The compound according to 1, represented by formula (I-e):

where R^3E, R^Eand R^Eidentical or different, independently represent

1) hydroxyl group,

2)₁-C₂₂alkoxygroup, which may have a Deputy,

3) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

4)₇-C₂₂aralkylated, which may have a Deputy,

5) aligations the Yu ₂-C₆acyl group which may have a Deputy, or

6) R^eN1R^eN2N-CO-O-, where R^eN1and R^eN2independently represent

(a) a hydrogen atom, or

(b) (C₁-C₆alkyl group which may have a Deputy, and

R^7Eis an R^eC(=Y^e)-O-, where Y^erepresents an oxygen atom or a sulfur atom, and R^erepresents a

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C)₆-C₁₄aryl group which may have a Deputy,

d) a 5-14-membered heteroaryl group which may have a Deputy,

e)₇-C₁₀aracelio group which may have a Deputy,

f) 5-14-membered heteroaryl group which may have a Deputy,

g) 3-14-membered non-aromatic heterocyclic group which may have a Deputy,

h) a group of the formula (III):

where (A) n is an integer from 0 to 4,

X_erepresents a

(i)- (CHR^eN4-,

ii) -NR^eN5-,

iii) -O-,

iv) -S-,

v) -SO - or

vi) -SO₂-,

R^N1represents a

(i) a hydrogen atom, or

ii)₁-C₆alkyl group which may have a Deputy,

R^N2represents a

i) atom is odorata or

ii)₁-C₆alkyl group which may have a Deputy,

R^N3and R^eN4identical or different, independently represent

(i) a hydrogen atom,

ii)₁-C₆alkyl group which may have a Deputy,

iii) unsaturated With₂-C₁₀alkyl group which may have a Deputy,

iv)₆-C₁₄aryl group which may have a Deputy,

v) 5-14-membered heteroaryl group which may have a Deputy,

vi)₇-C₁₀aracelio group which may have a Deputy,

vii)₃-C₈cycloalkyl group which may have a Deputy,

viii)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

ix) 5-14-membered heteroaryl group which may have a Deputy,

x) 5-14-membered non-aromatic heterocyclic group which may have a Deputy,

xi) -NR^eN6R^eN7where R^eN6and R^eN7identical or different, independently represent a hydrogen atom or a C₁-C₆alkyl group which may have a Deputy, or

xii) a 5 to 14-membered non-aromatic heterocyclic group formed R^eN3and R^eN4together with the nitrogen atom that is attached to R^eN3and R^eN4and 5-14 membered aeromatic the Skye heterocyclic group may have a Deputy, and

R^N5represents a

(i) a hydrogen atom,

ii)₁-C₆alkyl group which may have a Deputy,

iii) unsaturated With₂-C₁₀alkyl group which may have a Deputy,

iv)₆-C₁₄aryl group which may have a Deputy,

v) 5-14-membered heteroaryl group which may have a Deputy,

vi)₇-C₁₀aracelio group which may have a Deputy,

vii)₃-C₈cycloalkyl group which may have a Deputy,

viii)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

ix) 5-14-membered heteroaryl group which may have a Deputy,

x) 5-14-membered non-aromatic heterocyclic group which may have a Deputy, or

xi) 5-14-membered non-aromatic heterocyclic group formed R^eN3and R^eN5together with the nitrogen atom that is attached to R^eN3and R^eN5and 5-14 membered non-aromatic heterocyclic group may have a Deputy,

In) X_e, n, R^eN3, R^eN4and R^eN5independently represent a group as defined above, and R^eN1and R^eN2independently represent a 5 to 14-membered non-aromatic heterocyclic group formed together groups of R^eN1and R^{eN2 and 5-14 membered non-aromatic heterocyclic group may have a Deputy,}

^{(C) X_e, n, ReN2, ReN4and ReN5independently represent a group as defined above, and ReN1and ReN3independently represent a 5 to 14-membered non-aromatic heterocyclic group formed together groups of ReN1and ReN3and 5-14 membered non-aromatic heterocyclic group may have a Deputy, or}

D) X_e, n, R^eN1, R^eN4and R^eN5independently represent a group as defined above, and R^eN2and R^eN3independently represent a 5 to 14-membered non-aromatic heterocyclic group formed together groups of R^eN2and R^eN3and 5-14 membered non-aromatic heterocyclic group may have a Deputy, or

i) a group of the formula (IV):

where R^N8and R^eN9identical or different, independently represent

(i) a hydrogen atom,

ii)₁-C₆alkyl group which may have a Deputy,

iii)₆-C₁₄aryl group which may have a Deputy,

iv) a 5-14-membered heteroaryl group which may have a Deputy,

v)₇-C₁₀aracelio group which may have a Deputy, or

vi) 5-14-membered heteros who aracelio group, which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

8. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^E1C(=Y^E1)-O-, where Y^E1represents an oxygen atom or a sulfur atom, and R^E1represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3)₆-C₁₀aryl group which may have a Deputy,

4) 5-14-membered heteroaryl group which may have a Deputy,

5)₇-C₁₀aracelio group which may have a Deputy, or

6) 5-14-membered heteroaryl group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

9. Connection in accordance with 7, where R^7Eand/or R^Eare R^E2C(=Y^E2)-O-, where Y^E2represents an oxygen atom or a sulfur atom, and R^E2represents a group of formula (III'):

where (A) n is an integer from 0 to 4,

X₁represents a

1) -CHR^eN13-,

2) -NR^eN14-,

3) -O-,

4) -S-,

5) -SO - or

6) -SO₂-,

R^N10and R^N11identical or different, independently represent

1) a hydrogen atom, or

2) -C₆alkyl group which may have a Deputy,

R^N12and R^eN13identical or different, independently represent

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3) unsaturated With₂-C₁₀alkyl group which may have a Deputy,

4)₆-C₁₄aryl group which may have a Deputy,

5) 5-14-membered heteroaryl group which may have a Deputy,

6)₇-C₁₀aracelio group which may have a Deputy,

7)₃-C₈cycloalkyl group which may have a Deputy,

8)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

9) 5-14-membered heteroaryl group which may have a Deputy,

10) 5-14-membered non-aromatic heterocyclic group which may have a Deputy,

11) -NR^eN15R^eN16where R^eN15and R^eN16identical or different, independently represent a hydrogen atom or a C₁-C₆alkyl group which may have a Deputy, or

12) 5-14-membered non-aromatic heterocyclic group formed together groups of R^eN12and R^eN13and 5-14 membered non-aromatic heterocyclic group may have a Deputy, and

Rsup> N14represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3) unsaturated With₂-C₁₀alkyl group which may have a Deputy,

4)₆-C₁₄aryl group which may have a Deputy,

5) 5-14-membered heteroaryl group which may have a Deputy,

6)₇-C₁₀aracelio group which may have a Deputy,

7)₃-C₈cycloalkyl group which may have a Deputy,

8)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

9) 5-14-membered heteroaryl group which may have a Deputy,

10) 5-14-membered non-aromatic heterocyclic group which may have a Deputy,

11) 5-14-membered non-aromatic heterocyclic group formed together with the nitrogen atom that is attached to the group R^eN14and one Deputy selected from the group consisting of R^eN10, R^eN11and R^eN12and 5-14 membered non-aromatic heterocyclic group may have a Deputy, or

12) 5-14-membered non-aromatic heterocyclic group formed together with the nitrogen atom that is attached to the group R^eN14and the two substituents selected from the group consisting of R^eN10, R^eN1 and R^eN12and 5-14 membered non-aromatic heterocyclic group may have a Deputy, or

In) n, X₁, R^eN11, R^eN13and R^eN14are as defined above, and R^eN10and R^eN12together form a 5 to 14-membered non-aromatic heterocyclic group, and the 5-14 membered non-aromatic heterocyclic group may have a Deputy,

its pharmacologically acceptable salt or hydrate;

10. Connection in accordance with 9, where X₁represents-NR^dN14-where NR^dN14is the same as defined above, its pharmaceutically acceptable salt or hydrate;

11. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^E3C(=Y^E3)-O-, where Y^E3represents an oxygen atom or a sulfur atom, and R^E3represents a group of formula (V):

where n₁is an integer from 0 to 6,

R^N17represents a

1) a hydrogen atom, or

2)₁-C₆alkyl group which may have a Deputy, and

R^N18represents a

1) a hydrogen atom,

2) an amino group which may have a Deputy,

3) pyridyloxy group which may have a Deputy,

4) pyrrolidin-1-ilen group which may have replace the ü,

5) piperidine-1-ilen group which may have a Deputy,

6) morpholine-4-ilen group which may have a Deputy, or

7) piperazine-1-ilen group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

12. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^E4CO-O-, where R^E4represents a group of formula (VI):

where n₂and n₃identical or different, independently represent an integer from 0 to 4,

X₂represents a

1) -CHR^N21-,

2) -NR^N22-,

3) -O-,

4) -S-,

5) -SO - or

6) -SO₂-,

R^N19represents a

1) a hydrogen atom, or

2)₁-C₆alkyl group which may have a Deputy,

R^N20represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3)₆-C₁₄aryl group which may have a Deputy, or

4)₇-C₁₀aracelio group which may have a Deputy,

R^N21represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3) unsaturated With₂-C₁₀alkyl group which may have replaced the Titel,

4)₆-C₁₄aryl group which may have a Deputy,

5) 5-14-membered heteroaryl group which may have a Deputy,

6)₇-C₁₀aracelio group which may have a Deputy,

7)₃-C₈cycloalkyl group which may have a Deputy,

8)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

9) 5-14-membered heteroaryl group which may have a Deputy,

10) -NR^N23R^N24where R^N23and R^N24identical or different, independently represent a hydrogen atom or a C₁-C₆alkyl group which may have a Deputy, or

11) 5-14-membered non-aromatic heterocyclic group which may have a Deputy, and

R^N22represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3) unsaturated With₂-C₁₀alkyl group which may have a Deputy,

4)₆-C₁₄aryl group which may have a Deputy,

5) 5-14-membered heteroaryl group which may have a Deputy,

6)₇-C₁₀aracelio group which may have a Deputy,

7)₃-C₈cycloalkyl group which may have a Deputy,

8)_{4 -C9cycloalkylcarbonyl group which may have a Deputy,}

9) 5-14-membered heteroaryl group which may have a Deputy, or

10) 5-14-membered non-aromatic heterocyclic group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

13. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^E5CO-O-, where R^E5represents a group of formula (VII):

where n₄represents 1 or 2,

R^N25represents a

1) a hydrogen atom, or

2)₁-C₆alkyl group which may have a Deputy, and

R^N26represents a

1) a hydrogen atom, or

2)₁-C₆alkyl group which may have a Deputy of its pharmacologically acceptable salt or hydrate;

14. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^E6CO-O-, where R^E6represents a group of formula (VIII):

where n₂and n₃identical or different, independently represent an integer from 0 to 4,

X₃represents a

1) -CHR^N29-,

2) -NR^N30-,

3) -O-,

4) -S-,

5) -SO - or

6) -SO₂-,

R^N27before the hat is

1) a hydrogen atom, or

2)₁-C₆alkyl group which may have a Deputy,

R^N28represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3)₆-C₁₄aryl group which may have a Deputy, or

4)₇-C₁₀aracelio group which may have a Deputy,

R^N29represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3) unsaturated With₂-C₁₀alkyl group which may have a Deputy,

4)₁-C₆alkoxygroup, which may have a Deputy,

5)₆-C₁₄aryl group which may have a Deputy,

6) 5-14-membered heteroaryl group which may have a Deputy,

7)₇-C₁₀aracelio group which may have a Deputy,

8)₃-C₈cycloalkyl group which may have a Deputy,

9)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

10) 5-14-membered heteroaryl group which may have a Deputy,

11) -NR^N31R^N32where R^N31and R^N32identical or different, independently represent a hydrogen atom or a C₁-C₆alkalinuria, which may have a Deputy, or form a 5 to 14-membered non-aromatic heterocyclic group together with the nitrogen atom to which R^N31and R^N32attached, or

12) 5-14-membered non-aromatic heterocyclic group which may have a Deputy, and

R^N30represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3) unsaturated With₂-C₁₀alkyl group which may have a Deputy,

4)₆-C₁₄aryl group which may have a Deputy,

5) 5-14-membered heteroaryl group which may have a Deputy,

6)₇-C₁₀aracelio group which may have a Deputy,

7)₃-C₈cycloalkyl group which may have a Deputy,

8)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

9) 5-14-membered heteroaryl group which may have a Deputy, or

10) 5-14-membered non-aromatic heterocyclic group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

15. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^E7CO-O-, where R^E7represents a group of formula (IX):

where n₅is an integer from 1 to 3, and

R^N33represents a

1) amino group,

2) an amino group which may have a Deputy,

3) pyrrolidin-1-ilen group which may have a Deputy,

4) piperidine-1-ilen group which may have a Deputy, or

5) morpholine-4-ilen group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

16. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^E8CO-O-, where R^E8represents a group of formula (X):

where n₅is an integer from 1 to 3,

R^N34represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3)₆-C₁₄aryl group which may have a Deputy, or

4)₇-C₁₀aracelio group which may have a Deputy,

R^N35represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3)₃-C₈cycloalkyl group which may have a Deputy,

4) 3-8-membered non-aromatic heterocyclic group which may have a Deputy,

5)₆-C₁₄aryl group which may have a Deputy,

6) 5-14-membered heteroaryl group which may have a Deputy,

7)₇-C₁₀aracelio group which may have a Deputy,

8) 5-14-membered heteroaryl group which may have a Deputy, or

9)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

17. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^eCO-O-, where R^erepresents a group of formula (XI):

where n₅is an integer from 1 to 3, and

R^N36represents a

1) a hydrogen atom,

2)₁-C₈alkyl group which may have a Deputy,

3)₃-C₆cycloalkyl group which may have a Deputy,

4)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

5)₇-C₁₀aracelio group which may have a Deputy,

6) pyridyloxy group which may have a Deputy, or

7) tetrahydropyranyloxy group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

18. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^E10CO-O-, where the R ^E10represents a group of formula (XII):

where m₁, m₂, m₃and m₄identical or different, independently represent 0 or 1,

n₅is an integer from 1 to 3 and

R^dN37represents a

1) a hydrogen atom,

2)₁-C₆alkyl group which may have a Deputy,

3) unsaturated With₂-C₁₀alkyl group which may have a Deputy,

4)₆-C₁₄aryl group which may have a Deputy,

5) 5-14-membered heteroaryl group which may have a Deputy,

6)₇-C₁₀aracelio group which may have a Deputy,

7)₃-C₈cycloalkyl group which may have a Deputy,

8)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

9) 5-14-membered heteroaryl group which may have a Deputy, or

10) 5-14-membered non-aromatic heterocyclic group which may have a Deputy,

its pharmacologically acceptable salt or hydrate;

19. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^E11CO-O-, where R^E11represents a group of the formula (XIII):

where m₅PR is dstanley an integer from 1 to 3, and n₅represents 2 or 3,

its pharmacologically acceptable salt or hydrate;

20. Connection in accordance with 7, where R^7Eand/or R^Eindependently represent R^E12CO-O-, where R^E12represents a group selected from the group consisting of:

or a group selected from the group consisting of:

moreover, in both groups in the ring may be Deputy,

its pharmacologically acceptable salt or hydrate;

21. The compound according to 1, where R¹⁶represents a hydroxyl group;

its pharmacologically acceptable salt or hydrate;

22. The compound according to 1, where

[1] W represents

R³and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21'represent a hydrogen atom,

[2] W represents

R³and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21'represent a hydrogen atom,

[3] W represents

R³, R¹⁶and R²¹provide the amount of hydroxyl group, R⁷is acetoxy, and R¹⁷, R²⁰and R^21'represent a hydrogen atom,

[4] W represents

R²¹and R^21'form oxoprop together with the carbon atom to which R²¹and R^21'attached, R³, R¹⁶and R²⁰represent a hydroxyl group, R⁷is acetoxy, and R¹⁷represents a hydrogen atom,

[5] W represents

R³, R¹⁶, R²⁰and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁷and R^21'represent a hydrogen atom,

[6] W represents

R³, R⁷, R¹⁶and R²¹represent a hydroxyl group, and R¹⁷, R²⁰and R^21'represent a hydrogen atom,

[7] W represents

R³, R¹⁷, R¹⁶and R²¹represent a hydroxyl group, R⁷is acetoxy, and R²⁰and R^21'represent a hydrogen atom, or

[8] W represents

R²¹and R^21'form oxoprop together with the carbon atom to which Oromo R ²¹and R^21'attached, R³and R¹⁶represent a hydroxyl group, R⁷is acetoxy, and R¹⁷and R²⁰represents a hydrogen atom,

its pharmacologically acceptable salt or hydrate;

23. The compound according to 1, which represents:

(8E,12E,14)-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 18),

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

(8E,12E,14)-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 21),

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

(8E,12E,14)-7-(N-(3-(N',N'-dimethylamino)propyl)-N-methylcarbamoyl)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 27),

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 28),

(8E,12E,14)-3,16,21-trihydroxy-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 29),

(8E,12E,14)-316,21-trihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 39),

(8E,12E,14)-3,16,21-trihydroxy-7-((4-(4-hydroxypiperidine-1-yl)piperidine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 40),

(8E,12E,14)-3,16,21-trihydroxy-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 42),

(8E,12E,14)-7-((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 43),

(8E,12E,14)-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-OLED (compound 44),

(8E,12E,14)-3,16,21-trihydroxy-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 49),

(8E,12E,14)-7-(N-(2-(N',N'-dimethylamino)ethyl)-N-methylcarbamoyl)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 50),

(8E,12E,14)-7-(N-(2-(N',N'-dimethylamino)ethyl)carbanilate)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 51) or

(8E,12E,14)-3,16,21-trihydroxy-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 55);

24. Connection in accordance with claim 1, which is:

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-meth is l-N-(1-methylpiperidin-4-yl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 29),

(8E,12E,14)-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-OLED (compound 39),

(8E,12E,14)-7-((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 43),

(8E,12E,14)-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-OLED (compound 44), or

(8E,12E,14)-3,16,21-trihydroxy-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 55);

25. Drug containing the compound in accordance with any of 1-24, its pharmacologically acceptable salt or hydrate as an active ingredient;

26. A pharmaceutical composition comprising a compound according to any of 1-24, its pharmacologically acceptable salt or hydrate as an active ingredient;

27. Medicinal product in accordance with 25 as an agent for the prophylaxis or treatment of a disease against which effective regulation of gene expression;

28. Medicinal product in accordance with 25 as an agent for the prophylaxis or treatment of a disease against which effective inhibition of VEGF production;

29. Medicinal product in accordance with 25 in Kacha is TBE agent for prevention or treatment of disease, against which effective antiangiogenic effect;

30. Medicinal product in accordance with 25 as an inhibitor of angiogenesis;

31. Medicinal product in accordance with 25 as an antitumor agent;

32. Medicinal product in accordance with 25 as a therapeutic agent for the treatment of hemangioma;

33. Medicinal product in accordance with 25 as an inhibitor of cancer metastasis;

34. Medicinal product in accordance with 25 as a therapeutic agent for the treatment of retinal revascularization or diabetic retinopathy;

35. Medicinal product in accordance with 25 as a therapeutic agent for the treatment of inflammatory diseases;

36. Medicinal product in accordance with 25 as a therapeutic agent for treating inflammatory diseases, comprising deforming arthritis, rheumatoid arthritis, psoriasis and delayed-type hypersensitivity;

37. Medicinal product in accordance with 25 as a therapeutic agent for treatment of atherosclerosis;

38. Medicinal product in accordance with 25 as a therapeutic agent for treatment of solid malignant tumors;

39. Medicinal product in accordance with 38, where a solid malignant tumor is lung cancer, the tumor is a brain, breast cancer, prostate cancer, ovarian cancer, cancer of the colon or melanoma;

40. Medicinal product in accordance with 25 as a therapeutic agent for the treatment of leukemia;

41. Medicinal product in accordance with 25 as an antitumor agent based on the regulation of gene expression;

42. Medicinal product in accordance with 25 as an antitumor agent based on the inhibition of VEGF production;

43. Medicinal product in accordance with 25 as an antitumor agent based on the effect of inhibition of angiogenesis;

44. A method of preventing or treating a disease against which effective regulation of gene expression, including an introduction to the patient a pharmacologically effective dose of a medicinal product in accordance with 25;

45. A method of preventing or treating a disease against which effective inhibition of VEGF production comprising administration to a patient a pharmacologically effective dose of a medicinal product in accordance with 25;

46. A method of preventing or treating a disease against which effectively inhibiting angiogenesis comprising the administration to a patient a pharmacologically effective dose of a medicinal product in accordance with 25;

47. The use of compounds in accordance with any of 1-24, E. what about the pharmacologically acceptable salt or hydrate for the manufacture of an agent for prevention or treatment of disease, against which effective regulation of gene expression;

48. The use of compounds in accordance with any of 1-24, its pharmacologically acceptable salt or hydrate for the manufacture of an agent for prevention or treatment of diseases against which effective inhibition of VEGF production;

49. The use of compounds in accordance with any of 1-24, its pharmacologically acceptable salt or hydrate for the manufacture of an agent for prevention or treatment of diseases against which effective inhibition of angiogenesis;

50. The use of compounds in accordance with any of 1-24, its pharmacologically acceptable salt or hydrate for the manufacture of an agent for the prophylaxis or treatment of solid malignant tumors;

51. The method of obtaining compounds of 6-deoxy 11107, characterized in that includes culturing a microorganism belonging to the genus Streptomyces which is capable to produce the compound of formula (I):

where [1] W represents

R³and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21'represent a hydrogen atom, or

[2] W represents

R³and R²¹provide the amount of hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21'represent a hydrogen atom, and

collecting from the culture of the connection defined in [1] or [2] (hereinafter referred to as "compound 6-deoxy 11107");

52. The strain Streptomyces sp. A-1543 (FERM BP-8442), which is able to produce compound 6-deoxy 11107 in accordance with 51;

53. The way to obtain 6-dezoxidanti biological transformation of compounds of formula (I):

where [1] W represents

R³and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21'represent a hydrogen atom,

(hereinafter referred to as "6-deoxy V") in the compound of formula (I), where

[3] W represents

R³, R¹⁶and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁷, R²⁰and R^21'represent a hydrogen atom,

[4] W represents

R²¹and R^21'form oxoprop together with the carbon atom to which R²¹and R^21'attached, R³, R¹⁶and R²⁰represent a hydroxyl group, R⁷PR is dstanley acetochlor, and R¹⁷represents a hydrogen atom,

[5] W represents

R³, R¹⁶, R²⁰and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁷and R^21'represent a hydrogen atom,

[6] W represents

R³, R⁷, R¹⁶and R²¹represent a hydroxyl group, and R¹⁷, R²⁰and R^21'represent a hydrogen atom,

[7] W represents

R³, R¹⁷, R¹⁶and R²¹represent a hydroxyl group, R⁷is acetoxy, and R²⁰and R^21'represent a hydrogen atom, or

[8] W represents

R²¹and R^21'form oxoprop together with the carbon atom to which R²¹and R^21'attached, R³and R¹⁶represent a hydroxyl group, R⁷is acetoxy, and R¹⁷and R²⁰represents a hydrogen atom (these connections are referred to hereinafter as "6-dezoxidanti"), containing

1) the stage at which it is possible to conduct biological transformation stage incubation 6-deoxy V in the presence of culture is inogo solution strains, selected from microorganisms belonging to the bacteria, or the product obtained from the culture of cells of strain, and

2) collection 6-dezoxidanti of the incubated solution;

54. The method according to 53, where the organism related to bacteria is strain a-1544 (FERM BP-8446) or strain a-1545 (FERM BP-8447); and

55. Strain a-1544 (FERM BP-8446) or strain a-1545 (FERM BP-8447), which is able to convert 6-deoxy V 6-detoxication.

The best way of carrying out the invention

The following describes the various terms, symbols and the like used in this specification.

In this description chemical formula of the compound of the present invention is shown for convenience in the form of planimetric formula. However, the present invention may include specified isomers derived from this chemical formula. The present invention may include all isomers and their mixtures, such as geometric isomers, generated by the connection configuration, optical isomers based on asymmetric carbon atom, rotamer, stereoisomers and tautomers and mixtures of these isomers. 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 in the molecule ASI the metric carbon atom and exists in the form of an optically active substance or racemate, the invention covers both optically active substance, and the racemate. Although there may be crystalline polymorphs connection, the connection is not limited to a single crystalline form and can exist in a single crystal form or in the form of a mixture of multiple crystal forms. The compound of formula (I) in accordance with the present invention or its salt can be anhydrate or hydrate. As anhydrate and hydrate 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 its salt is also included in the present invention.

The term "halogen atom"used in the description to this application, refers to fluorine atom, chlorine atom, bromine atom and iodine atom. Among them, preferred are, for example, fluorine atom, chlorine atom and bromine atom. Are generally preferred are a fluorine atom and a chlorine atom.

"C₁-C₂₂alkyl group" when used in the description to this application refers to an unbranched or branched alkyl group containing 1-22 carbon atoms. Examples include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, from the waste group, second-boutelou group, tert-boutelou group, n-pentelow group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropylene group, 1-ethylpropyl group, n-hexoloy group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-popypropylene group, 1-methylbutyl 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-naniloa group and n-decile group. Preferably, "C₁-C₂₂alkyl group" refers to an unbranched or branched alkyl group containing 1-6 carbon atoms. Examples include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group and n-pentelow group. Of them, preferred are, for example, methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group.

"Unsaturated With₂-C₂₂alkyl group" when used in the description to this application regarding the priority for unbranched or branched alkenylphenol group, containing 2-22 carbon atoms, or an unbranched or branched alkenylphenol group containing 2-22 carbon atoms. Examples include vinyl group, allyl group, 1-propenyloxy group, Isopropenyl group, 2-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-pentanediol group, 1-hexenyl group, 1,3-hexadienyl group, 1,5-hexadienyl group, etinilnoy group, 1-propenyloxy group, 2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-ethinyl-2-propenyloxy group, 2-methyl-3-butenyloxy group, 1-pantanillo group, 1-hexylamino group, 1,3-hexadienyl group and 1.5-hexadienyl group. Preferably, unsaturated With₂-C₂₂alkyl group" refers to an unbranched or branched alkenylphenol group containing 2-10 carbon atoms, or an unbranched or branched alkenylphenol group containing 2-10 carbon atoms. Preferred examples include vinyl group, allyl group, 1-propenyloxy group, Isopropenyl group, 3-methyl-2-butenyloxy group, 3,7-dimethyl-2,6-octadienal group, etinilnoy group, 1-propenyloxy group, 2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group I3-methyl-1-propenyloxy group.

"C₆-C₁₄aryl group" when used in the description to this application refers to an aromatic cyclic hydrocarbon group containing 6-14 carbon atoms, and includes monocyclic group and a condensed ring, such as the bicyclic or tricyclic group group. Examples are phenyl group, angenlina group, 1-naftalina group, 2-naftalina group, atulananda group, heptylaniline group, Indianola group, acenaphthylene group, fluoroaniline group, phenylaniline group, phenanthroline group and antarctilyne group. Preferred are, for example, phenyl group, 1-naftalina group and 2-naftalina group.

"5-14-Membered heteroaryl group" in the description to this application refers to 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 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, imidazole the other 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 group, pteridinyl group, imidazolidinyl group, pirazinamida group, accidenily group, phenanthridinone group, carbazolyl group, carbazolyl group, pyrimidinyl group, phenanthroline group, pensinula group, imidazopyridine group, imidazolidinyl group, pyrazolopyrimidine group and pyrazolopyrimidine group; sulfur-containing aromatic heterocyclic group such as thienyl group and benzothiazoline group; oxygen-containing aromatic heterocyclic group, such as furilla group, Pernilla group, cyclopentadienyl group, benzoperylene group and isobenzofuranone group; and aromatic heterocyclic groups containing two or more different heteroatoms, such as thiazolidine group, isothiazolinone group, benzothiazolyl group, benzothiadiazole group, phenothiazinyl group, isoxazolyl group, furazolidine group, phenoxazin the ilen group, oxazolidine group, isoxazolyl group, benzoxazolyl group, oxadiazolyl group, pyrazoloquinoline group, imidazothiazole group, thienopyridine group, properally group and pyridoxamine group. Preferred are, for example, thienyl group, furilla group, pyridinoline group, pyridazinyl group, pyrimidinyl group and piratininga group.

"3-14-Membered non-aromatic heterocyclic group" when used in the description to this application refers to 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 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-disabi is yclo[4.3.0]Danilina group, hinkleyville group, tetrahydrofuranyl group and tetrahydrobiopterine group. The aforementioned non-aromatic heterocyclic group include a group derived from Spiridonovka rings and non-aromatic condensed ring (for example, a group derived from phthalimide rings, operations of the rings or the like).

"C₇-C₂₂kalkilya group" when used in the description to this application refers to a group corresponding to a certain higher "C₂-C₂₂alkyl group, the substituted part of which is defined above, substituted "₆-C₁₄aryl group". Specific examples include a benzyl group, penicilina group, 3-phenylpropionate group, 4-phenylbutyrate group, 1-naphthylmethyl group and 2-naphthylmethyl group. It is preferable kalkilya group containing 7-10 carbon atoms, for example, benzyl group or penicilina group.

"5-14-Membered heteroalkyl group" when used in the description to this application refers to a group corresponding to a certain higher "C₁-C₂₂alkyl group containing defined above "5 to 14-membered heteroaryl group" as a substituent. Specific examples are thienylmethyl group, purimetla group, pyridinylmethyl group, p is reasimilacija group, pyrimidinylidene group and personalitly group. Preferred are, for example, thienylmethyl group, purimetla group and pyridinylmethyl group.

"C₃-C₁₄cycloalkyl group" when used in the description to this application means cycloalkyl group containing 3-14 carbon atoms. Suitable examples are cyclopropyl group, cyclobutyl group, cyclopentenone group, tsiklogeksilnogo group, cycloheptyl group and cyclooctyl group. Preferred are, for example, cyclopentene group, tsiklogeksilnogo group, cycloheptyl group and cyclooctyl group.

"C₄-C₉cycloalkylation group" when used in the description to this application means a group corresponding to defined above, With₁-C₂₂alkyl group"defined above containing "C₃-C₁₄cycloalkyl group" as a substituent. Specific examples are cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group and cyclooctylmethyl group. Preferred are, for example, cyclopropylmethyl group, cyclobutylmethyl group and cyclopentylmethyl group.

"C₁-C₂₂alkoxy is the UPP" when used in the description to this application, means a group obtained by the addition of oxygen atom to the end defined above, With₁-C₂₂alkyl groups. Examples of suitable groups include methoxy group, ethoxypropan, n-propoxylate, isopropoxide,

n-butoxypropyl, isobutoxy, second-butoxypropan,

tert-butoxypropan, n-pentyloxy, isopentylamine,

second-pentyloxy, n-hexyloxy, isohexadecane,

1,1-DIMETHYLPROPANE, 1,2-dimethylpropyleneurea,

2,2-dimethylpropylene, 1-ethyl-2-methylpropoxy,

1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,

1,1-dimethylbutyramide, 1,2-dimethylbutyramide,

2,2-dimethylbutyramide, 2,3-dimethylbutylamino,

1,3-dimethylbutyramide, 2-itivuttaka,

2-methylphenoxy, 3-methylphenoxy and hexyloxy.

Preferred are a methoxy group, ethoxypropan, n-propoxylate, isopropoxide, isobutoxide and 2,2-dimethylpropyleneurea.

"Unsaturated With₂-C₂₂alkoxygroup" when used in the description to this application means a group obtained by the addition of oxygen atom to the end of a defined above unsaturated With₂-C₂₂alkyl groups. Examples of suitable groups are vinyloxy, alliancegroup,

1-propene is oxygraph, isopropenylacetate,

2-methyl-1-propionyloksypo, 2-methyl-2-propionyloksypo,

1-butenyloxy, 2-butenyloxy, 3-butenyloxy,

1-pentyloxy, 1-hexaniacinate,

1,3-hexanediamine, 1,5-hexanediamine,

propargyloxy and 2-butenyloxy. Preferred are, for example, alliancegroup, propargyloxy and 2-butenyloxy.

"C₆-C₁₄alloctype" when used in the description to this application means a group obtained by attaching atom cicloral to the end defined above, With₆-C₁₄aryl group". Specific examples are fenoxaprop, ingenjorsfirma, 1-naphthyloxy, 2-naphthyloxy, aspleniaceae, heptylaniline, indatadialogruta, acenaphthylene, fluorenylacetamide, phenyleneoxy, fenantrenkhinona and anthranilamide. Preferred are, for example, fenoxaprop, 1-naphthyloxy and 2-naphthyloxy.

"C₇-C₂₂arancelaria" when used in the description to this application means a group obtained by the addition of oxygen atom to the end defined above, With₇-C₂₂aranceles group". Specific examples are benzyloxy,

penetratiegraad, 3-phenylpropyl the group,

4-phenylbutyraldehyde, 1-naphthalenyloxy and

2-naphthalenyloxy. It is preferable, for example, benzyloxy.

"5-14-Membered heteroarylboronic" when used in the description to this application means a group obtained by the addition of oxygen atom to the end of a defined above "5 to 14-membered heteroalkyl group". Specific examples are titelmelodie, feniletilamina,

pyridylmethylamine, pyridinylmethyl,

pyrimidinediamine and personalitytasha.

The preferred compounds are, for example, titelmelodie, feniletilamina and pyridylmethylamine.

"5-14-Membered heteroanalogues" when used in the description to this application, means a group obtained by the addition of oxygen atom to the end of a defined above 5-14-membered heteroaryl group". Specific examples are paralelograma, peridiniaceae, peridiniaceae,

pyrimidinamine, personalantispy, trisalicylate,

tetraallyloxyethane, benzothiazolylthio,

pyrazolylborate, imidazolylalkyl,

benzimidazolylthio, indoleacetate,

isoindolines, indolizinium, purinacare,

indazole is a sigroup, hinolincarbonova,

izohinolinove, kinoliteratura,

palatinolinotype, naphthyridinone,

hinoksalinovym, ginasolinspu,

sinolingua, peridiniaceae,

imidazotriazine, pirazinoizohinolina,

criminologica, phenanthridinone,

carbazochrome, carbetopendecinia,

pyrimidinylidene, fenantroliniya,

panathiniakos, imidazopyridines,

imidazopyrimidines, pyrazolopyrimidinones,

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.

Preferred are, for example, tailorship is, peridiniaceae, pyrimidinylidene or personalantispy.

"Aliphatic C₂-C₂₂acyl group" when used in the description to this application means a group obtained by joining the carbonyl group by the end defined above, With₁-C₂₂alkyl groups or unsaturated With₂-C₂₂alkyl groups. Examples are acetyl group, propylaniline group, Butyrina group, isobutylene group, valerina group, isovaleryl group, pivellina group, Carolina group, dekheila group, Laurila group, Mirandolina group, palmifolia group, caarolina group, Archidona group, calolina group, Propylamine group, crotonoideae group, isotretinoina group, olaola group and linoleoyl group. Preferred are aliphatic acyl group containing 2-6 carbon atoms, such as acetyl group, propylaniline group, Butyrina group, isobutylene group and calolina group.

"Aromatic With₇-C₁₅acyl group" when used in the description to this application means a group obtained by joining the carbonyl group by the end defined above, With₆-C₁₄aryl group or 5 to 14-membered heteroaryl group". Examples is the tsya benzoline group, 1-napolina group, 2-napolina group, pokoleniya group, nicotinoyl group, isonicotinoyl group, frolina group and thiophenecarboxylate group. Preferred are, for example, benzoline group, pokoleniya group, nicotinoyl group and isonicotinoyl group.

"C₁-C₂₂alkylsulfonyl group" when used in the description to this application means sulfonyloxy group, which is attached with defined above With₁-C₂₂alkyl group". Specific examples are methanesulfonyl group, acanaloniidae group, n-propanesulfonyl group and isopropylaniline group. It is preferable, for example, methanesulfonyl group.

"C₆-C₁₄arylsulfonyl group" when used in the description to this application means sulfonyloxy group, which is attached with defined above With₆-C₁₄aryl group". Specific examples are benzolsulfonat group, 1-naphthalenesulfonyl group and 2-naphthalenesulfonyl group. It is preferable, for example, benzolsulfonat group.

"Aliphatic C₂-C₂₂alloctype" when used in the description to this application means a group obtained by the addition of oxygen atom to the end of a defined in the above "aliphatic C ₂-C₂₂acyl group". Examples are acetoxygroup, propionyloxy and akilattirattu. Preferred are, for example, acetoxygroup and propionyloxy.

"C₂-C₂₂alkoxycarbonyl group" when used in the description to this application means a group obtained by joining the carbonyl group by the end defined above, With₁-C₂₂alkoxygroup". Examples are methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, solutionline group, sec-butoxycarbonyl group and tert-butoxycarbonyl group. Preferred are, for example, ethoxycarbonyl group, isopropoxycarbonyl group and tert-butoxycarbonyl group.

"Unsaturated With₃-C₂₂alkoxycarbonyl group" when used in the description to this application means a group obtained by joining the carbonyl group to the end of a defined above unsaturated With₂-C₂₂alkoxygroup". Examples are vinyloxycarbonyl group, allyloxycarbonyl group, 1-propanecarboxylate group, isopropoxycarbonyl group, propylenecarbonate group and 2-butyloxycarbonyl group. Preferred is compulsory is, for example, allyloxycarbonyl group.

"C₁-C₂₂allylthiourea" when used in the description to this application means a group obtained by attaching a sulfur atom to the end defined above, With₁-C₂₂alkyl groups. Examples are methylthiourea, ethylthiourea, n-PropertyGroup and isopropylthio. Preferred are, for example, methylthiourea and ethylthiourea.

"C₁-C₂₂alkylsulfonyl group" when used in the description to this application means a group obtained by joining sulfanilic group by the end defined above, With₁-C₂₂alkyl groups. Examples are methanesulfonyl group, econsultancy group, n-propanesulfonyl group and isopropylaniline group. Preferred are, for example, methanesulfonyl group or econsultancy group.

"C₁-C₂₂alkylsulfonates" when used in this specification means a group obtained by the addition of oxygen atom to the end defined above, With₁-C₂₂alkylsulfonyl group". Examples are methysulfonylmethane, econsultancy, n-propanesulfonate and isopropylphenoxy. It is preferable, for example, methysulfonylmethane.

The quality is TBE substituent group, "which may have a substitute, when used in the description of this application is one or more groups selected from:

(1) halogen atom,

(2) a hydroxyl group,

(3) Tilney group,

(4) nitro group,

(5) nitrosopropane,

(6) ceanography,

(7) a carboxyl group,

(8) sulfonyloxy,

(9) amino group,

(10)₁-C₂₂alkyl group (e.g. methyl group, ethyl group, n-sawn group, isopropyl group, n-butilkoi group, isobutylene group, sec-butilkoi group or tert-butilkoi group)

(11) unsaturated With₂-C₂₂alkyl groups (for example, vinyl group, allyl group, 1-propenyloxy group, Isopropenyl group, etinilnoy group, 1-propanolol group, 2-propanolol group, 1-botinelli group, 2-botinelli group or 3-botinelli group)

(12)₆-C₁₄aryl group (e.g. phenyl group, 1-naftilos group or 2-naftilos group)

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

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

(15)₃-C₁₄cycloalkyl group (for example, cyclopropene group, cyclobutyl group, cyclopentyloxy group, tsiklogeksilnogo group, cycloheptyl group or cyclooctyl group)

(16)₁-C₂₂alkoxygroup (for example, metoxygroup, ethoxypropan, n-propoxylate, isopropoxy,

Deut-propoxylate, n-butoxypropyl, isobutoxy,

Deut-butoxypropyl or tert-butoxypropyl),

(17) unsaturated With₂-C₂₂alkoxygroup (for example, vinyloxy, alliancegroup, 1-propenyloxy,

isopropenylacetate, acidilactici, 1-propenyloxy,

2-propenyloxy, 1-butenyloxy or

2-butenyloxy),

(18)₆-C₁₄alloctype (for example, phenyloxy, 1-naphthyloxy or 2-naphthyloxy),

(19)₇-C₂₂aralkylated (for example, benzyloxy,

penetrometry, 3-phenylpropylamine,

4-phenylbutyraldehyde, 1-naphthalenyloxy or

2-naphthalenyloxy the s)

(20) 5-14-membered heteroarylboronic (for example, canimmediately, fullmetalchemy,

pyridylmethylamine, pyridinylmethyl,

pyrimidinediamine or personalantispy),

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

(22) aliphatic C₂-C₂₂acyl 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, acryloyloxy group, propylamino group, crotonoyl group, isotretinoinsee group, OleOle group or linoleoyl group)

(23) aromatic C₇-C₁₅acyl group (for example, bentilee group, 1-naphthalenol group or 2-naftolin group)

(24) aliphatic C₂-C₂₂alloctype (for example, acetochlor, propionyloxy or akilattirattu),

(25)₂-C₂₂alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxide bonalnoy group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxyethene group, sec-butoxycarbonyl group or tert-butoxycarbonyl group)

(26) unsaturated With₃-C₂₂alkoxycarbonyl group (for example, vinyloxycarbonyl group,

allyloxycarbonyl group, 1-propanecarboxylate group,

isopropoxycarbonyl group,

propylenecarbonate group or

2-butyloxycarbonyl group)

(27)₁-C₂₂allylthiourea (for example, methylthiourea, ethylthiourea, n-PropertyGroup or isopropylthio),

(28)₁-C₂₂alkylsulfonyl group (for example, methanesulfonyl group, ethanolamines group, n-propanesulfonyl group or isopropanolamine group)

(29)₁-C₂₂alkylsulfonyl group (for example, methanesulfonyl group, acanaloniidae group, n-propanesulfonyl group or isopropanolamine group)

(30)₆-C₁₄arylsulfonyl group (for example, benzolsulfonate group, 1-naphthalenesulfonyl group or 2-naphthalenesulfonyl group)

(31)₁-C₂₂alkylsulfonates (for example, methanesulfonamido, econsultancy,

n-propanesulfonate or isopropylphenoxy the s)

(32) carbamoyl group,

(33) formyl group, and the like. Preferred are, for example, amino group, With₁-C₂₂alkyl group, unsaturated With₂-C₂₂alkyl group, a C₆-C₁₄aryl group, a 5-14-membered heteroaryl group, a 3-14 membered non-aromatic heterocyclic group and C₃-C₁₄cycloalkyl group. In particular, the Deputy preferably represents one or two substituent, such as, for example, amino group, With₁-C₂₂alkyl group, 3-14-membered non-aromatic heterocyclic group and C₃-C₁₄cycloalkyl group. In addition, the above amino group (9) and carnemolla group (31), data as Deputy in the above-described group which may have a substitute, each can be optionally substituted with one or two₁-C₂₂alkyl groups, unsaturated With₂-C₂₂alkyl groups or With₆-C₁₄aryl groups.

The following is an explanation of the compounds of formula (I) according to the present invention.

The compound of formula (I) inhibits the production of VEGF in hypoxic conditions, has inhibitory activity against cell proliferation in solid tumorsin vivoand activein vivodose not causing creatures who spent reducing body mass. Among these compounds, preferred is a compound of the formula (I-a), more preferred compound of formula (I-b), and particularly preferred compound of formula (I-C). In addition, the compound of formula (I), where R¹⁶represents a hydroxyl group, is a compound exhibiting a very high stability in aqueous solution.

Since the compound of the formula (I) is obtained using known reactions chemical transformations for functional groups (e.g. hydroxyl group), located at position 3, position 7, position 16 and the position 21, and in position 3, position 7, position 16 and the position 21 can be entered the same substituents. As a structural feature is the side chain in position 7 and/or a side chain at position 21, a group of more preferred compounds can be defined as compounds of formula (I-d). In addition, the compounds of formula (I)in which R²¹forms exoframe together with the carbon atom that is attached to R²¹as the compounds of formula (I-d), belong to the group of compounds with good activity. As examples of specific options is more preferable compounds among the compounds of formula (I-d), you can specify the connection described above as options "7"-"20" of the present invention.

Preferred is reamers compounds of formula (I) described below. A representative group of preferred compounds, including compounds described in the examples below, is, for example:

(8E,12E,14)-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 18),

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

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

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

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(3-(N',N'-dimethylamino)propyl)-N-methylcarbamoyl)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 27),

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 28),

(8E,12E,14)-3,16,21-trihydroxy-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 29),

(8E,12E,14)-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-OLED (compound 39),

(8E,12E,14)-3,16,21-trihydroxy-7-((4-(4-hydroxypiperidine-1-yl)Pieper is DIN-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 40),

(8E,12E,14)-3,16,21-trihydroxy-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 42),

(8E,12E,14)-7-((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 43),

(8E,12E,14)-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-OLED (compound 44),

(8E,12E,14)-3,16,21-trihydroxy-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 49),

(8E,12E,14)-7-(N-(2-(N',N'-dimethylamino)ethyl)-N-methylcarbamoyl)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 50),

(8E,12E,14)-7-(N-(2-(N',N'-dimethylamino)ethyl)carbanilate)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 51) or

(8E,12E,14)-3,16,21-trihydroxy-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 55). Of those, more preferred are, for example, compound 29, compound 39, compound 43, compound 44 and the connection 55.

The following describes the method of obtaining the compounds of formula (I) according to the present invention.

The compound of formula (I) can be obtained by chemical modification of powaga connection such as the connection of the 6-deoxy 11107 or 6-detoxication using the conventional method as follows. The connection of the 6-deoxy 11107 obtained by culturing under aerobic conditions strain belonging to the genus Streptomyces, which is able to produce compound 6-deoxy 11107 as a physiologically active substance of the formula (I), where [1] W represents

R³and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21'represent a hydrogen atom (6-deoxy V),

[3] W represents

R³, R¹⁶and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁷, R²⁰and R^21'represent a hydrogen atom (6-deoxy 11107D),

[7] W represents

R³, R¹⁷, R¹⁶and R²¹represent a hydroxyl group, R⁷is acetoxy, and R²⁰and R^21'represent a hydrogen atom, and collecting the compound from the cells and the culture solution; and 6-detoxication receive biological transformation of compounds of formula (I), where

[1] W represents

R³and R^{21/sup> represent a hydroxyl group, R7is acetoxy, and R16, R17, R20and R21'represent a hydrogen atom (hereinafter referred to as "6-deoxy V"), in the compound of formula (I), where}

[2] W represents

R³and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21'represent a hydrogen atom,

[4] W represents

R²¹and R^21'form oxoprop together with the carbon atom to which R²¹and R^21'attached, R³, R¹⁶and R²⁰represent a hydroxyl group, R⁷is acetoxy, and R¹⁷represents a hydrogen atom,

[5] W represents

R³, R¹⁶, R²⁰and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁷and R^21'represent a hydrogen atom,

[6] W represents

R³, R⁷, R¹⁶and R²¹represent a hydroxyl group, and R¹⁷, R²⁰and R^21'represent a hydrogen atom, or

[8] W submitted is a

R²¹and R^21'form oxoprop together with the carbon atom to which R²¹and R^21'attached, R³and R¹⁶represent a hydroxyl group, R⁷is acetoxy, and R¹⁷and R²⁰represents a hydrogen atom, and chemical modification of standard connections using appropriate traditional method.

The present invention is described in detail below in relation to the obtaining compounds of 6-deoxy 11107 fermentation, obtaining 6-dezoxidanti using reaction Bioperine and modification of the active substance by the method of organic synthesis.

First described method of obtaining compounds of 6-deoxy 11107.

The connection of the 6-deoxy 11107 (in particular, 6-deoxy V), which can be converted into the compound 6-deoxy 11107D (biologically active substance) of the present invention can be obtained by microbial fermentation.

As a microorganism to obtain compound 6-deoxy 11107 you can use any microorganism, if only it was a strain capable of producing the compound 6-deoxy 11107. For example, the strain for the production of 6-deoxy L can be obtained from the strain isolated from soil, or well-known strain, capable of producing similar V,a typical mutation processing using for example, ultraviolet radiation or mutagenic agent such as N-methyl-N'-nitro-N-nitrosoguanidine (NTG) as a mutagen, or by such method as gene splitting with homologous recombination.

As an example of the microorganism for producing the compound 6-deoxy 11107 you can call the following Deposit of the microorganism. The specified strain was put on the international deposited in International Patent Organism Depositary (IPOD), National Institute of Advanced Industrial Science and Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan. In particular, Streptomyces sp. Mer-11107 was deposited on December 19, 2000, as FERM P-18144 in the National Institute of Bioscience and Human-Technology Agency of Industrial Science and Technology in 1-1-3 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan and was transferred to the International Patent Organism Depositary (IPOD), National Institute of Advanced Industrial Science and Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan under the international Deposit number FERM BP-7812 November 27, 2001

There are no particular restrictions on the strains for the production of compound 6-deoxy 11107, including mutants of these strains, if they belonged to the genus Streptomyces and had the ability to produce compound 6-deoxy 11107. In addition to the above-described strain may be cited as an example of the strain Streptomyces sp. A-1543. The specified strain was deposited at the International Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan, as FERM P-18942 July 23, 2002, and was transferred to the International Patent Organism Deositary (IPOD), National Institute of Advanced Industrial Science and Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan under the international Deposit number FERM BP-8442 July 28, 2003

Below is a detailed description of obtaining compounds of 6-deoxy 11107 1. characteristics of the selected producer strain 2. method of cultivation of the producer strain and 3. method of purification of the active substance.

1. Characteristics of the isolated strain-producer

It is assumed that as the strain for use in the present invention can be used with any strain belonging to the genus Streptomyces and capable of producing the compound 6-deoxy 11107. As typical strains of the authors of the present invention offer the strain number Mer-11107 and a mutant of this strain And 1543. Microbiological characteristics of these strains are given below.

(1). Morphology

In the specified strain from vegetative hyphae depart spiral aerial hyphae. At the end of the Mature aerial hyphae formed a chain of argument, consisting of about 10-20 bar dispute. Each dispute has a size of about 0.7 microns×1,0 μm and has a smooth surface. Atypical bodies, such as the sporangium, the sclerotia and the flagellum is not observed.

(2). Growth conditions in different cultural environments

Below shows the cultural characteristics of the strain after cultivation at 28°for TLD is weeks in different cultural environments. Hue is described in accordance with the color disks of Tresner and marked with the name of the color and the symbol shown in parentheses.

1) Agar medium with yeast and malt extracts

The strain grows well. Aerial hyphae cultivated strain on the surface of the split, divide, and form a light-gray spores (light grey; d). The opposite side has a light yellow melon. (EA). Soluble pigment is observed.

2) Agar medium with oatmeal

The strain grows moderately. Aerial hyphae cultivated strain on the surface is slightly forked, divided and form a gray spores (grey; g). The opposite side has a bodily reddish-brown color, (DS) or color putty (1¹/₂the EU). Soluble pigment is observed.

3) Agar medium with inorganic salts and starch

The strain grows well. Aerial hyphae cultivated strain on the surface of the split, divide and form a gray spores (grey; f). The opposite side has a color yellowish brown (4ig) or grey (g). The production of soluble pigment is observed.

4) Agar medium with glycerol and asparagine

The strain grows well. Aerial hyphae cultivated strain on the surface of the split, divide, and form a white spores (white; a). The opposite side has a CEE is pearl pink (sa). Soluble pigment is observed.

5) Agar medium with peptone, yeast extract and iron

The strain grows poorly. Aerial hyphae cultivated strain on the surface is not forked. The opposite side has a light yellow melon (EA). Soluble pigment is observed.

6) the tyrosine agar medium

The strain grows well. Aerial hyphae cultivated strain on the surface of the split, divide, and form a white spores (white;). The opposite side has a color mother-of-pearl pink (sa). Soluble pigment is observed.

(3). The use of different carbon sources

The following shows the state of growth of the strain after culturing in medium at 28°within two weeks with the addition of various carbon sources in the agar culture medium of Pridham-Gottlieb.

1) L-arabinose ±

2) D-xylose ±

3) D-glucose +

4) D-fructose +

5) Sucrose +

6) Inositol +

7) L-rhamnose -

8) D-mannitol +

9) Raffinose +

(The symbol "+" means "positive", the symbol "±" means "weakly positive" and the symbol "-" means "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, olivinovye within two weeks): 12° S-37°

(b) the Interval of the optimal cultivation temperature (agar medium with yeast and malt extracts, cultivation within two weeks): 21°-33°

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

(h) the Formation of hydrogen sulphide (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 NaCl (agar medium with yeast and malt extracts, cultivation within two weeks): grows at NaCl concentration of 4% or below

(5). Cellular component

Was discovered LL-diaminopimelic acid from cell membranes of strain.

2. Method of cultivation of the strain-producer

The connection of the 6-deoxy 11107 according to the present invention can be obtained by inoculation of the above-described strain on itutuloy environment and aerobic cultivation of strain. As the strain for the production of compound 6-deoxy 11107 in the present invention is not limited to the above-described strain, you can use any strain belonging to the genus Streptomyces and capable of producing the compound 6-deoxy 11107.

The method of culturing the above microorganism, in principle, corresponds to the usual method of cultivation of the microorganism, but usually, it is preferable to carry it out under aerobic conditions such as a liquid cultivation in the flask with shaking cultivation in the tank or the like. For cultivation can be used in any cultural environment, only that it contained a power source that can be used by the microorganism belonging to the genus Streptomyces. Can be used any of various cultural environments, synthetic, semi-synthetic or natural. As sources of carbon in the composition of the medium can be used, for example, glucose, sucrose, fructose, glycerol, dextrin, starch, molasses and soybean oil, alone or in combination of two or more sources. As nitrogen sources can be used organic sources of nitrogen, such as a pharmaceutical environment, peptone, meat extract, soybean powder, casein, amino acid, yeast extract and urea, and neorg the organic sources of nitrogen, such as sodium nitrate and ammonium sulphate, alone or in combination of two or more sources. In addition, for example, can be added salts such as sodium chloride, potassium chloride, calcium carbonate, magnesium sulfate, sodium phosphate, potassium phosphate and cobalt chloride, salts of heavy metals and vitamins, such as vitamin b and Biotin, if their use is necessary. When during cultivation foaming culture medium, the medium can be added appropriately different defoamers. When adding antifoam concentration you bring to this, which will not have a harmful effect on the production of target substances. Preferably, the use concentration of, for example, 0.05% or below.

The cultivation conditions can be selected so that the above-described strain grew well and were able to produce above the substance, respectively. Preferably, for example, to bring the pH to about 5-9 and usually close to neutral. The cultivation temperature is usually maintained within the range of 20°S-40°preferably 23°-35°C. the Time of cultivation is approximately two to eight days, usually about three to five days. These culturing conditions can be changed in accordance with the type and properties used which has been created microorganism, external conditions and the like, and can be designed for optimal conditions. The connection of the 6-deoxy 11107 according to the present invention, accumulated in the culture solution can be collected by conventional methods of separation using its characteristics, for example, by the method of solvent extraction or absorption method resins.

3. Method of purification of the active substance

To collect the 6-deoxy 11107 from the culture solution after cultivation can be generally used methods of separation and purification used for the selection of microbial metabolite from the culture solution. For example, it fits into all the appropriate methods, such as extraction with an organic solvent using methanol, ethanol, butanol, ethyl acetate, chloroform or the like, various kinds of ion-exchange chromatography, gel-filtration chromatography using Sephadex LH-20 or the like, activated carbon, treatment by the method of adsorption/desorption using absorption chromatography or thin layer chromatography using silica gel or the like and high-performance liquid chromatography using a column with reversed phase applicable for this method. Cleaning methods are not particularly limited to the methods described in this description.

Connect the imposition of the 6-deoxy 11107 can be isolated and purified, using these methods individually or in combination of two or more methods in an arbitrary order or repeatedly.

The following describes the second method of obtaining compounds of 6-deoxy 11107.

1. A microorganism that produces 6-detoxication biopreparation

6-Detoxication of the present invention can be obtained by hydroxylation of the hydrogen atom in position 16 connection of the 6-deoxy 11107, obtained as described above (in particular, 6-deoxy V), using Bioperine.

As a microorganism to obtain compound 6-deoxy 11107 you can use any microorganism, if only it was a strain capable of hydroxypyruvate the hydrogen atom in position 16 connection of the 6-deoxy 11107 (in particular, 6-deoxy V), the transformation of the connection in the connection 6-deoxy 11107D of the present invention. As representative examples of such a microorganism can be called the strain A-1544 and strain a-1545 extracted from soil by the authors of the present invention. These strains were deposited at the international deposited in International Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan on July 23, 2002, as FERM P-18943 and FERM P-18944, respectively, and were transferred to the International Patent Organism Depositary (IPOD), National Institute of Advanced Industrial Science and Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan30 July 2003 under international Depositary numbers FERM BP-8446 and FERM BP-8447, respectively.

2. Getting 6-dezoxidanti using reaction Bioperine

6-Detoxication receive, making the connection of the 6-deoxy 11107 (in particular, 6-deoxy V) to come into contact with cells or cell preparation described above strain or its mutant. Usually 6-detoxication is produced by adding the compound 6-deoxy 11107 (in particular, 6-deoxy V) as a predecessor in the culture solution obtained by inequilibrium described above strain in a culture medium containing a source of power, and aerobic cultivation of a strain, or a suspension of washed cells of the above-described strain in a suitable buffer solution. When the connection get into the culture solution, the connection of the 6-deoxy 11107 (in particular, 6-deoxy V) can be added into the culture solution at any time prior to cultivation or for a specified period of time after the start of cultivation. Although it is possible to cultivate the specified strain for the preparation of culture solution or washed cells or the indicated strain with the previous connection was a common method of cultivation of the microorganism is usually preferred to carry out the cultivation in aerobic conditions, such as liquid cultivation in the flask with in what tracyanum, cultivation in a tank or the like.

For cultivation can be used in any cultural environment, only that it contained a power source that can be used by the microorganism. Can be used any of various cultural environments, synthetic, semi-synthetic or natural.

As sources of carbon in the composition of the medium can be used, for example, glucose, galactose, sucrose, maltose, fructose, glycerin, dextrin, starch, molasses and soybean oil, alone or in combination of two or more sources. As nitrogen sources can be used organic sources of nitrogen, such as a pharmaceutical environment, peptone, meat extract, soybean meal, fish meal, flour from gluten, casein, yeast, amino acid, yeast extract and urea, and inorganic nitrogen sources such as sodium nitrate and ammonium sulfate, alone or in combination of two or more sources. In addition, for example, may optionally be added salts such as sodium chloride, potassium chloride, calcium carbonate, magnesium sulfate, sodium phosphate, potassium phosphate, copper sulfate, ferrous sulfate, manganese chloride and cobalt chloride, salts of heavy metals, vitamins, such as vitamin b and Biotin, and klatratoobrazovanie tool such as qi is latextrem. When during cultivation foaming culture medium, the medium can be added appropriately different defoamers. When adding antifoam concentration you bring to this, which will not have a harmful effect on the production of a target substance.

The cultivation conditions can be selected so that the above strain is well developed, providing the possibility of transforming the compound 6-deoxy 11107 (in particular, 6-deoxy V) 6-detoxication, respectively. Preferably, for example, to bring the pH to about 5-9 and usually close to neutral. The temperature of the cultivation support is usually in the range of 20-40°preferably 24-30°C. the Time of cultivation is from about one to eight days, usually two to five days.

The above various culturing conditions can be changed in accordance with the type and properties of the used microorganism, external conditions and the like, and can be designed for optimal conditions. 6-Detoxication accumulated in the culture solution can be recovered by conventional methods of separation using its characteristics, for example, by the method of solvent extraction or absorption method resins.

3. The cleanup method 6-des is xiaodian

To collect 6-dezoxidanti from the culture solution after cultivation can be generally used methods of separation and purification used for the selection of microbial metabolite from the culture solution, the appropriate method of cleaning compound 6-deoxy 11107 (in particular, 6-deoxy V)described above. 6-Detoxication can be isolated and purified using these methods individually or in combination of two or more methods in an arbitrary order or repeatedly.

The following describes the method of obtaining the compounds of formula (I), other than the connection of the 6-deoxy 11107 and 6-dezoxidanti.

Various compounds of formula (I) can be synthesized by converting a hydroxyl group and/or acetochlor in isolated and purified compound 6-deoxy 11107 or 6-detoxication as starting substances according to the General methods of organic synthesis. Typical examples of the synthesis methods are: a method of deriving urethane, Century way of deriving thiourethane, S. a method of deriving a simple ether, D. a method of obtaining a derived complex ester, that is, the method of obtaining the derived complex ester of phosphoric acid or a derivative of ester aminophosphonic acids, F. a method of obtaining a derived complex ester of sulfuric acid or sophistication of the CSOs ether amigorena acid, G. a method of obtaining a halogenated derivative, N. the method of obtaining the derived complex ester sulfonic acid, I. the method of deriving Amin and J. a method of obtaining oxopropanal oxidation of the hydroxyl group. Introduction and removal of the protective group for hydroxyl group can be performed as described in the literature method (see T.W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons Inc., 3rd Edition) or similar method depending on the type of the protective group and the stability of connections used for a particular obtain. The compound of formula (I) can be obtained by using reactions introduction and removal of the protective group for hydroxyl group and the above-described receiving in a suitable combination. In particular, the compound of formula (I), where R³, R⁷, R¹⁶, R¹⁷, R²⁰and R²¹represents the substituents mentioned in the above class 10), can be obtained according to the methods of obtaining derived urethane, derived thiourethane derived complex ester amigorena acid and amine derivative or the like; a compound of formula (I), where R³, R⁷, R¹⁶, R¹⁷, R²⁰and R²¹represents the substituents mentioned in the above classes 3)to (6)can be obtained according to the method of deriving simple EPE is a; the compound of formula (I), where R³, R⁷, R¹⁶, R¹⁷, R²⁰and R²¹represents the substituents mentioned in the above class 7), can be obtained according to the method of obtaining the derived complex ester; compound of formula (I), where R³, R⁷, R¹⁶, R¹⁷, R²⁰and R²¹represents the substituents mentioned in the above grade 12) or (13)may be obtained according to the method of obtaining the derived complex ester of phosphoric acid or a derivative of ester aminophosphonic acid; the compound of formula (I), where R³, R⁷, R¹⁶, R¹⁷, R²⁰and R²¹represents the substituents mentioned in the above class 11), can be obtained according to the method of obtaining the derived complex ester of sulfuric acid or a derivative of ester sulfonic acid; the compound of formula (I), where R³, R⁷, R¹⁶, R¹⁷, R²⁰and R²¹represents the substituents mentioned in the above-described class 9), can be obtained by the method for producing a halogenated derivative; a compound of formula (I), where R³, R⁷, R¹⁶, R¹⁷, R²⁰and R²¹represents the substituents mentioned in the above class 8), can be obtained using the reaction injection and removal of the protective groups for hydroxyl groups is; and oxoproline the compounds of formula (I), where R³, R⁷, R¹⁶, R¹⁷, R²⁰and R²¹represents the substituents mentioned in the above class 1)can be obtained according to the method of obtaining oxopropanal oxidation of the hydroxyl group.

The following describes the synthesis methods used to obtain the compounds of formula (I).

A. Method of deriving urethane

In the formulas, R³, R^16xand R^21xindependently represent a hydrogen atom or a protective group, provided that R³, R^16xand R^21xdo not represent simultaneously a hydrogen atom; R^3y, R^16yand R^21yindependently represent a hydrogen atom, a protective group or a group represented by the formula, R^fO-CO-, where R^frepresents a C₆-C₁₄aryl group which may have (a) substituent(s), provided that R^3y, R^16yand R^21ydo not represent simultaneously a hydrogen atom; and R^3s, R^16Cand R^Sindependently represent a hydrogen atom, a protective group or a group represented by the formula, R^N1R^N2N-CO-, where R^N1and R^N2are as defined above, provided that R^3s, R^16Cand R^Sdo not represent simultaneously atom bodoro the A.

Stage A1 is the stage of obtaining the compounds of formula (IA). This phase of the conduct, protecting a hydroxyl group(s) of compound 6-deoxy 11107D (described above the connection, as defined in [3]).

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

Examples of protective groups are 1-ethoxyethyl,

tetrahydropyranyl, 1-methyl-l-methoxyethyl, 1-(2-chloroethoxy)ethyl,

1-methoxycyclohexyl, 4-methoxycarbonylpropionyl,

4-methoxycarbonylaminophenyl, S,S-dioxide

4-methoxycarbonylaminophenyl, methoxymethyl, methylthiomethyl,

methoxyethoxymethyl, trichloroacetyl, trimethylsilylmethyl,

trimethylsilyloxy, tert-butyldimethylsilyl, triethylsilyl,

diethylenediamine, trimethylsilyl, triisopropylsilyl,

methyl-di-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, each derivative in which the hydroxyl group is protected 1-amoxicilan, tetrahydropyranyl, 1-methoxycyclohexyl, 4-methoxycarbonylpropionyl, 4-methoxycarbonylaminophenyl or S,S-deok is the home of 4-methoxycarbonylaminophenyl, can be synthesized by treating compound 6-deoxy 11107D corresponding simple vinyl ether, such as ethylenically ether or dihydropyran, in the presence of acid. As the acid used organic acids such as p-toluensulfonate pyridinium (PPTS), p-toluensulfonate acid, camphorsulfonic acid, acetic acid, triperoxonane acid or methansulfonate acid, and the usual inorganic acids such as hydrogen chloride, nitric acid, hydrochloric acid and sulfuric acid. Preferably use, for example, p-toluensulfonate pyridinium (PPTS), p-toluensulfonate acid and camphorsulfonic acid. The solvent used in the reaction is not particularly restricted, but is desirable inert solvent which does not easily interact with the original substance. 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, HEXAMETHYL is formed, and sulfoxidov, such as dimethylsulfoxide. Preferably use, for example, dichloromethane, chloroform and tetrahydrofuran. The reaction time is from 10 minutes to five days, preferably one-two days. 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 connection 6-deoxy 11107D 1-200 equivalents and 0.05 to 2 equivalents, respectively, and, preferably, 30-50 equivalents and 0.1 to 0.3 equivalent, respectively.

Examples of other protective groups include methoxymethyl, methylthiomethyl, methoxyethoxymethyl, trichloroacetyl, trimethylsilylmethyl, trimethylsilyloxy, tert-butyldimethylsilyl, triethylsilyl, trimethylsilyl, diethylenediamine, triisopropylsilyl, tert-butyldimethylsilyl, diphenylmethylsilane, benzyl, p-methoxybenzyl, p-methylbenzyl, p-nitrobenzyl, p-Chlorobenzyl and triphenylmethyl. A derivative in which a hydroxyl group protected these protective groups can be synthesized by reacting the parent substance with chloride, bromide or triftoratsetata appropriate protective group in the presence of a base. As the Foundation of the use of conventional organic base is s or inorganic base. Examples of organic bases are aromatic bases such as imidazole, 4-(N,N-dimethylamino)pyridine (which is synonymous with 4-dimethylaminopyridine, N,N-dimethylaminopyridine and dimethylaminopyridine), pyridine, 2,6-lutidine and kallidin; tertiary amines, such as N-methylpiperidine, N-methylpyrrolidine, triethylamine, trimethylamine, diisopropylethylamine, cyclohexyldimethylamine, N-methylmorpholine and 1,8-bis(dimethylamino)naphthalene; secondary amines, such as diisobutylamine and dicyclohexylamine; acility, such as motility and utility; and alkoxides of metals, such as sodium methoxide and ethoxide sodium. Examples of inorganic bases are the hydrides of alkali metals, such as sodium hydride and potassium hydride; alkaline earth metal hydrides such as calcium hydride; hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate and cesium carbonate and bicarbonates of alkali metals such as sodium bicarbonate. Examples of preferred bases for the protection of hydroxyl groups, silyl protecting group is an aromatic base such as imidazole and 4-dimethylaminopyridine, and tertiary amines, such as triethylamine. The solvent used in the reaction is not particularly restricted, but gelatin the n solvent, which cannot easily communicate with the source material. Examples of such solvents are the above-described inert solvents, of which preferred examples are tetrahydrofuran, dichloromethane and N,N-dimethylformamide. The reaction time is from 10 minutes to three days, preferably one-two days. 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 connection 6-deoxy 11107D 1-20 equivalents and 0.5 to 30 equivalents, preferably 1 to 15 equivalents and 0.5 to 20 equivalents, respectively.

Hydroxyl(s) group(s) of compound 6-deoxy 11107D may(may) be selectively protected(s) by selecting the reagent and its equivalence used to protect the hydroxyl(s) of the group or 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 in position is AI 3 can be selectively protected by the restriction of the equivalence of chlorotriethylsilane or tert-butylcholinesterase. In addition, after defending two or three of the four hydroxyl groups of the silyl group of the remaining two or one hydroxyl group can be protected above ethoxyethylene groups 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 are inorganic bases, including hydrides of alkali metals, such as sodium hydride and potassium hydride; alkaline earth metal hydrides such as calcium hydride; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; carbonates of alkali metals such as lithium carbonate, sodium carbonate and potassium carbonate; bicarbonates of alkali metals such as sodium hydrogen carbonate, and alkoxides of metals such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium, and such grounds as guanidine and 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 inert solvents, alcohol solvents such as methanol, ethanol, isopropanol and tert-butanol, and water. Oksanaeroshina can be used in mixture of two or more solvents. A preferred example of the solvent is an alcoholic solvent or mixture of alcohol and halogenated solvent. The reaction time is from 10 minutes to five days, preferably from 30 minutes to one 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 to 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 carbonyl diimidazol 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. Preferably use, for example, diisopropylethylamine, 4-dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate with the source material. Examples is aka solvents are the above-described inert solvents, of which, preferably, is used, for example, tetrahydrofuran, dichloromethane and 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 to 20 equivalents, respectively, preferably 1-5 equivalents and 1 to 10 equivalents, respectively. The reaction time is from 10 minutes to 30 hours, preferably one to four 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 OR^3A, OR^6A, OR^16Aand OR^21Awere not protected at stage A1, the hydroxyl group can be converted into a carbonate group on stage A3. In particular, the hydroxyl group of compound (IA), other than a hydroxyl group in position 7 of compound (IA)can be converted into a carbonate group as well as in the case of hydroxyl group in position 7, the process of joining the base and derived chloroformiate in equivalents, corresponding to the number of hydroxyl groups into carbonate.

Stage A4 stage is obtaining the compounds of formula (IVA). This stage is realized by the processing of the carbonate compound of formula (IIIA) with the amine(R ^N1R^N2H), 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,

the 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'-dimethylethylenediamine,

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, pyrrolidino,

piperidine, piperazine, homopiperazine, 4-hydroxypiperidine,

4-methoxypiperidine 1-methylpiperazin, 1-ethylpiperazin,

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)pyrrolidin,

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-amino-ethyl)-4-methylpiperazin,

1-(3-aminopropyl)-4-methylpiperazin,

1-(3-(N-methylamino)propyl)-4-methylpiperazin,

1-amino-4-methylpiperidine, 1-methylamino-4-methylpiperidin,

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-naphthyl is in,

benzylamine, N-methylbenzylamine, phenethylamine, N-methylphenethylamine,

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, is used, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate with the source material. Examples of such solvents are the above-described inert solvents, of which, preferably, is used, for example, tetrahydrofuran, dichloromethane and N,N-dimethylformamide. The amount of amine and base used in the reaction, relative to the compound of formula (IIIA) is 1-10 equivalents and 2 to 20 equivalents, respectively, preferably 1.5 to 5 equivalents and 2 to 10 equivalents, respectively. The reaction time is from 10 minutes to 30 hours, preferably one to two hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux, and preferably is, -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 may represent, for example, utilitzant, methyl isocyanate or phenylisocyanate. Examples of the base are the aforementioned organic bases and inorganic bases, of which, preferably, is used, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate with the source material. Examples of such solvents are the above-described inert solvents, of which, preferably, is used, for example, tetrahydrofuran, dichloromethane and N,N-dimethylformamide. The number of bases and isocyanate used in the reaction, relative to the compound of formula (IIIA) is 3 to 100 equivalents and 1 to 20 equivalents, respectively, preferably 5-20 3-10 equivalents and equivalents, respectively. In the case of chloride of copper(1) its amount is 1 to 10 equivalents, preferably 2 to 6 equivalents. The reaction time is from 10 minutes to 30 hours, preferably one or two the Asa. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

Further, the compound with a hydroxyl group, in which one or two of the groups OR³, OR^16xand OR^21xwere not protected at stage A1, can be converted into a derivative containing multiple urethane structures, the conversion of hydroxyl groups in the carbonate group at the stage A3 and then the conversion of the carbonate groups in 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) processing for removing protection in an inert solvent as described below. The reaction of removing the protective group of hydroxyl group, which change depending on the type of protective group, carried out by a method well known in the chemistry of organic synthesis.

The reaction of removing the protection for the respective hydroxyl groups, protected, for example, 1-amoxicilan, tetrahydropyranyl, 1-methoxycyclohexyl, 4-methoxycarbonylpropionyl, 4-methoxycarbonylaminophenyl or S,S-dioxide 4-methoxycarbonylaminophenyl, can be easily carried out by treatment with an acid in an inert solvent. As the acid used above organic and N. the organic acids and the like. Preferred examples are p-toluensulfonate pyridinium, n-toluensulfonate acid and camphorsulfonic acid. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate with the predecessor. Preferred are, for example, alcohol solvents such as methanol, ethanol, isopropanol and tert-butanol. These solvents may be used in mixture with the above-described inert solvents. The amount of acid used in the reaction, relative to the compound of formula (IVA) is 0.5 to 5 equivalents and preferably 1-3 equivalents. The reaction time is from 10 minutes up to ten days, preferably one to four days. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

Further, in the case where a hydroxyl group protected by other protective group, for example, tert-butyldimethylsilyl, triethylsilyl, diethylethanolamine, trimethylsilyl, triisopropylsilyl, di-tert-butylmethylether or diphenylmethylsilane, the protective group may be removed, for example, treatment with a fluoride-anion or acid. As the fluoride anion is used, for example, tetrabutylammonium, hydrogen fluoride, the fluoride to the lia and hydrogen chloride-pyridine. As the acid used above organic and inorganic acids and the like. Preferred examples are acetic acid, formic acid, triperoxonane acid, p-toluensulfonate pyridinium and camphorsulfonic acid. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate with the source material. Examples are the abovementioned inert solvents, of which, preferably, is used, for example, tetrahydrofuran, diethyl ether and water. The amount of the 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, respectively, preferably 1 to 4 equivalents and 0.5 to 3 equivalent, respectively. The reaction time is from 10 minutes to 30 hours, preferably one to two 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 the first stage, and the different ways of protecting described in the fifth stage, each of the hydroxyl groups in position 3 and position 21 can be selectively subjected to the reaction of formation derived from the receipt of the product the aqueous urethane.

In addition, the method of selective modification of the hydroxyl group in position 3 or position 21, carried out using different combinations of methods to protect and unprotect, can also be applied to other methods of modification are described below.

Century Way of deriving thiourethane

In the formulas, R³, R^16xand R^21xare as defined above; R^3s, R^16Cand R^Sindependently represent a hydrogen atom, a protective group or a group represented by the formula, R^N1R^N2N-CS-, where R^N1and R^N2are as defined above, provided that R^3s, R^16Cand R^Sdo not represent simultaneously a hydrogen atom; and R^3d, R^16dand R^21dindependently represent a hydrogen atom or a group represented by the formula, R^N1R^N2N-CS-, where R^N1and R^N2are as defined above.

Stage B1 is the stage of synthesis of the compounds of formula (IB) using isothiocyanate 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 oxide bis(anti). Isothiocyanate used in this reaction, the CCA is about the limit, and he may represent, 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-yl)ethylisothiocyanate. Thiocarbamoylation used in this reaction is not particularly restricted, and it may represent, 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, is used, for example, diisopropylethylamine, 4-dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate with the source material. Examples of the solvent are described above inert solvents, of which, preferably, is used, for example, tetrahydrofuran, dichloromethane, N,N-dimethylformamide and toluene. Quantity the quantity of a base or oxide bis(anti) and isothiocyanate or thiocarbanilide in relation to the compound of formula (IIA) is 1-5 equivalents and 1-10 equivalents, accordingly, 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.

In addition, the transformation of the hydroxyl group in the compound of formula (IIA), where one or two OR³, OR^16xand OR^21xwere not protected in thiocarbamoylation on stage B1 can also be synthesized from a compound of formula (IB)containing several thiocarbamoyl groups.

Then removal of the release(s) of the group or groups of the hydroxyl group in accordance with the stage A5 can be synthesized derived thiourethane formula (IIB).

C. Method of deriving a simple ether

In the formulas, R^3E, R^Eand R^Eindependently represent a hydrogen atom or a protective group, provided that R^3E, R^Eand R^Edo not represent simultaneously a hydrogen atom and at least one of R^3E, R^Eand R^Erepresents a hydrogen atom; R^3f, R^16fand R^21findependently represent a protective group or₁-C₂₂alkyl group which may have a Deputy; R^3g, R^16g and R^21gindependently represent a hydrogen atom, alkyl group or karbamoilnuyu group; and R^7grepresents an acetyl group or karbamoilnuyu group.

Stage C1 is the stage of synthesis of the compounds of formula (IC). This stage is carried out in the same manner as the reaction stage A1 method A. However, the number of protected hydroxyl groups is one or two.

Alternatively, a compound in which one of the substituents in position 3 and position 21 represents a hydroxyl group, and the other is a protected hydroxyl group, can be synthesized by the combination of different ways of protecting the hydroxyl group of the corresponding stage A1 method and different methods to unprotect a protected hydroxyl group, the corresponding stage A5.

Stage C2 is the stage of synthesis of the compounds of formula (IIC). This stage is carried out by alkylation of the unprotected hydroxyl group or groups in the compound (IC).

The alkylation can be carried out by treatment with alkylating agent of formula R^m-X in the presence of a base. Deputy R^mrepresents a C₁-C₂₂alkyl group which may have a substituent and includes, for example, methyl group, ethyl group and benzyl group. X represents a leaving group. Examples of the leaving gr is PPI are chlorine, 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 communicate with the source material. Examples are the above-described inert solvents, of which, preferably, is used, for example, diethyl ether, tetrahydrofuran, dimethoxyethane and toluene. The amount of alkylating agent and base used in the reaction, relative to the compound of formula (IC) is 3-20 5-30 equivalents and equivalents, respectively, preferably 3-5 equivalents and 5-10 equivalents, respectively. The reaction time is from 10 minutes to 48 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.

Stage C3 is the stage of synthesis of the compounds of formula (IIIC). At this stage, the implementation stage A2 stage A3 stage A4 stage A5, when required, can be obtained connection, Modific is automatic as carbamoyl group, and alkyl group. In addition, the implementation stage only A5 can be obtained compound, subjected only to the alkylation. Stage C3 can be carried out using the conditions of the reaction stage A2 stage A3 stage A4 stage A5.

In the formulas, R³, R^16xand R^21xare the same as previously defined, and R^3f', R^7f', R^16f'and R^21f'independently represent 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 subjecting the compound of formula (IIA) reaction stage C2 and then the reaction stage A5 manner similar to that described above.

In addition, in this case derived in which thiocarbamoyl the group entered into a hydroxyl group in position 7 and the alkyl group introduced into one or two hydroxyl groups at position 3 and position 21 can be obtained by subjecting the compound of formula (IIIC) reaction stage B1 and then the reaction stage A5.

Further, the use of unsaturated alkylating agent, kalkiliya agent or heteroarylboronic agent capable of giving the desired compound of formula (I), instead of the alkylating agent as described above can be obtained corresponding derived Ave the buffer of net broadcasts.

D. Method of obtaining derived complex ester

In the formulas, R^3E, R^Eand R^Eindependently represent a hydrogen atom or a protective group, provided that R^3E, R^Eand R^Edo not represent simultaneously a hydrogen atom and at least one of R^3E, R^Eand R^Erepresents a hydrogen atom; and R^3h, R^16hand R^21hindependently represent a hydrogen atom or a group represented by the formula, R^COCO-, where R^COrepresents a hydrogen atom, a C₁-C₂₂alkyl group which may have a Deputy, unsaturated With₂-C₂₂alkyl group which may have a Deputy, With₆-C₁₄aryl group which may have a Deputy, 5-14-membered heteroaryl group which may have a Deputy, With₇-C₂₂aracelio group which may have a Deputy, or a 5-14-membered heteroaryl group which may have a Deputy, provided that R^3h, R^16hand R^21hdo not represent simultaneously a hydrogen atom.

Stage D1 is the stage of transformation of the hydroxyl group, which was not protected in ester group using the compounds of formula (IC), synthesized at the stage S1, as the original is about substance.

The etherification is carried out, for example, using an acid anhydride in combination with a base, galogenangidridy acid in combination with a base, a carboxylic acid, in combination with a condensing agent, or reaction of Mitsunobu. As the acid anhydride used various anhydrides of carboxylic acids. Examples include mixed anhydride containing, for example, acetic acid, propionic acid, butyric acid, valeric acid or benzoic acid; symmetric anhydride; cyclic anhydride such as succinic anhydride, glutaric anhydride or adipic anhydride. Preferred are acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride and the like. As gelegenheid use, for example, various acid chlorides and bromohydrin, of which a preferred example is acetylchloride, propionitrile, benzoyl chloride and benzylbromide. Examples of the base are above organic and inorganic bases, of which preferred examples are imidazole, 4-dimethylaminopyridine, pyridine and sodium hydride. As the carboxylic acid using various carboxylic acids, which are preferred, for example, acetic acid and propionic acid. As the condensing agent is predpochtitelnye are for example, dicyclohexylcarbodiimide, triperoxonane anhydride, carbonyldiimidazole, N,N-diisopropylcarbodiimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. In the reaction of Mitsunobu hydroxyl group may be substituted by various carboxylic acids 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 communicate with the source material. Examples are the above-described inert solvents, of which, preferably, is used, for example, dichloromethane, chloroform and tetrahydrofuran. The amount used in the reaction of the anhydride of the acid with a base, gelegenheid together with the base and the carboxylic acid together with a condensing agent relative to the compound of formula (IC) is 1-10 equivalents of 3 to 20 equivalents, 1-10 equivalents with 3-20 equivalents and 1 to 20 equivalents with 1-20 equivalents, respectively, 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. In addition, the reaction can be, when necessary, accelerated by adding 0.2 to 2 equivalents of 4-dimethylaminopyridine. The reaction time is from 10 minutes to 30 hours, preferred is entrusted, one to two hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux and preferably from -10°C to 50°C.

Then removing the protective group for hydroxyl group synthesized thus ester derivative according to the method similar to that described for stage A5 can be obtained compound of the formula (ID).

In addition, by conducting the esterification reaction similar to the reaction in stage D1, using the compound 6-deoxy 11107D as starting substances can also be atrificial one to three hydroxyl groups.

In the formulas, R³, R^16xand R^21xare as defined above, and R^3h', R^7h', R^16h'and R^21h'independently represent a hydrogen atom or a group represented by the formula, R^COCO-, where R^COrepresents the same group as defined above.

Derivative represented by the formula (ID'), where the hydroxyl group in position 7 etherification, can be obtained by subjecting the compound of formula (IIA) stage D1 according to the method described above, and then subjecting the product stage A5.

That is, the Method of obtaining the derived complex ester of phosphoric acid or a derivative of ester aminophosphonic acid

In f is mulah R ³, R^16xand R^21xare as defined above, and R³ⁱ, R⁷ⁱ, R¹⁶ⁱand R²¹ⁱindependently represent a hydrogen atom, a group represented by the formula (R^N3O)₂PO-, (R^N1R^N2N)₂PO - or (R^N1R^N2N)(R^N3O)PO-, where R^N1, R^N2and R^N3have the same meanings as defined above.

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

The formation of ester of phosphoric acid is carried out, for example, using phosphorylcholine and base. As phosphorylchloride in the present invention can use various types, examples of which are dialkoxybenzene, diphenylacetonitrile, 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 and sodium carbonate. The solvent, use is th in each of the reactions, not particularly limited, but preferable solvent, which cannot easily communicate with the source material. Examples are the above-described inert solvents, of which, preferably, is used, for example, dichloromethane, chloroform, tetrahydrofuran and 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, respectively, preferably 1 to 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.

Then removing the protective group for hydroxyl group synthesized thus derived complex ester of phosphoric acid according to a similar method, performed on stage A5 can be obtained compound of the formula (IE).

In addition, by formation of ester of phosphoric acid method, like stage E1, using compound 6-deoxy 11107D as starting substances can also be converted into esters of phosphoric acid for one to four hydroxyl groups.

F. a method of obtaining a derived complex ester of sulfuric acid is you or derived complex ester of sulfamic acid

In the formulas, R³, R^16xand R^21xare as defined above, and R^3j, R^7j, R^16jand R^21jindependently represent a hydrogen atom or a group represented by the formula, R^N1R^N2N-SO₂or R^N4Oh-SO₂-where R^N1, R^N2and R^N4independently represent 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 educt in the ester of sulphuric acid.

The formation of ester of sulfuric acid is carried out, using gelegenheid sulfuric acid and a base or the like. As gelegenheid sulfuric acid can be used various types. Examples include alkoxycarbonyl and N,N-disubstituted sulfhemoglobin. As a basis you can use the above organic and inorganic bases, and the like. Preferred are, for example, pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiethanolamine, sodium hydride, n-utility, potassium carbonate and sodium carbonate. The solvent used in each of the reactions is not particularly limited, but preferable solvent, which cannot easily communicate with the predecessor. Can be used describe the data above inert solvents. Preferably use, for example, dichloromethane, chloroform, tetrahydrofuran and N,N-dimethylformamide. The number of gelegenheid sulphuric acid and base used in the reaction, relative to the compound of formula (IIA) is 1-10 equivalents and 2 to 20 equivalents, respectively, preferably 1 to 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.

Then removing the protective group for hydroxyl group synthesized thus derived complex ester of sulfuric acid according to a similar methodology stage A5, can be synthesized from a compound of formula (IF).

In addition, by formation of ester sulfuric acid method, like stage F1, using the compound 6-deoxy 11107D as starting substances can also be converted into esters of sulfuric acid for one to four hydroxyl groups.

G. a method of obtaining a halogenated derivative

In the formulas, R³, R^16xand R^21xare as defined above, and R^3k, R^16kand R^21kindependently represent hydroxyl the Yu group or halogen atom.

Stage G1 is the phase transformation of the hydroxyl group in the halogen with the use of the compounds of formula (IA) as the starting material.

This halogenation reaction can be carried out, processing diethylaminoacetate (DAST) or triphenylphosphine, for example, tetrabromide carbon, bromine, tribromide phosphorus, iodine or carbon tetrachloride in the presence of a base. As the base can be used organic and inorganic bases, such as diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate with the predecessor. Examples are tetrahydrofuran, dichloromethane and N,N-dimethylformamide. In particular, preferred is the reaction of fluorination using diethylaminoacetate. The number of diethylaminoacetate (DAST)used in the reaction, relative to the compound of formula (IA) is 1 to 5 equivalents and preferably 1 to 3 equivalents. The reaction time is from 10 minutes to 10 hours. The reaction temperature ranges from -78°C to room temperature.

Then removing the protective group for hydroxyl group in the groups synthesized so is m follows halogenated derivative according to the method stage A5, can be synthesized from a compound of formula (IG).

N. The method of obtaining the derived complex ester sulfonic acid

In the formulas, R³, R^16xand R^21xare as defined above, and R^3l, R^7l, R^16land R^21lindependently represent a hydrogen atom or a group represented by the formula, R^N5SO₂-where R^N5represents the same group as defined above.

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

Sulfonylamine can be carried out by treatment with sulphonylchloride, such as p-toluensulfonate, methanesulfonate and benzosulphochloride, in the presence of a base. As a basis you can use the usual organic and inorganic bases, such as diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate with the source material. Examples are tetrahydrofuran, dichloromethane and N,N-dimethylformamide. The number of sulphonylchloride and base used in the reaction, with respect to the connection fo the formula (IIA) is from 1 to 5 equivalents and 2 to 10 equivalents, accordingly, 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.

Then removing the protective group for hydroxyl group in the synthesized so halogenated derivative according to the method stage A5, can be synthesized derivative represented by the formula (IH)in which a hydroxyl group sulfonylureas in position 7.

In addition, carrying out the etherification way, like stage N1, using the compound 6-deoxy 11107D as starting substances can also be sulfonylureas one to four hydroxyl groups.

I. Method of deriving Amin

In the formulas, R³, R^16xand R^21xare as defined above, and R^3m, R^7m, R^16mand R^21mindependently represent a hydroxyl group or a group of the formula R^N1R^N2N-, where R^N1and R^N2independently represent the same group as defined above.

Stage I1 stage is the conversion of a hydroxyl group directly in the amine or the stage of transformation of the hydroxyl group in a comfortable leaving the group, and then turning the leaving group and the ID and the subsequent transformation of the azide to the amine recovery, using the compound of the formula (IIA) as the starting material.

When the hydroxyl group is transformed into azide, can be used, for example, 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 or 5) sodium azide in the presence of a base. As a basis you can use the above organic and inorganic bases. Preferably use, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. In addition, the hydroxyl group can also be converted into azide by treatment with sodium azide in the presence of palladium catalyst. Example palladium catalyst is Pd(PPh₃)₄. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate 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, nab is emer, triphenylphosphine or sociallyengaged. In addition, recovery to the amine can be carried out 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 communicate 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.

A hydroxyl group can be converted into a suitable leaving group by the procedure similar to that described for G1 phase (halogenoalkane) or for stage N1 (sulfonylurea). Examples of suitable leaving groups are chlorine, bromine, iodine, methansulfonate group and p-toluensulfonyl group.

Then the processing of the specified compounds in which the hydroxyl group is converted into a leaving group, with an amine in an inert solvent in the presence of a base it is possible to synthesize a compound in which a hydroxyl group is converted into the amino group or the amino group with the Deputy.

Examples of the amine used are methylamine, ethylamine, dimethylamine and diethylamine. As a basis you can use indicated the data above organic and inorganic bases, and the like. Preferably use, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate with the source material. Can be used above inert solvents. Preferably use, for example, tetrahydrofuran, dichloromethane and N,N-dimethylformamide. The reaction time is from 10 minutes to 30 hours, preferably one to two hours. The reaction temperature ranges from -78°C to the boiling temperature under reflux, preferably from -10°C to 50°C.

Then removing the protective group for hydroxyl group in the synthesized thus derived amine according to the same methodology stage A5 can be obtained compound of the formula (II). In addition, carrying out the amination of a similar methodology stage I1 using 6-deoxy 11107D as starting substances can also be minirovat one or two hydroxyl groups.

In addition, alkylation, acylation, carbamoylethyl or sulfonylamine amino group, respectively, the compounds of formula (II) by a method well known in the chemistry of organic synthesis, or the methods described above can be obtained connection form is s (I).

J. a Method of producing catasetinae (oxidation of hydroxyl group)

In the formula of any one of R^3Jaand R^3Jbrepresents a hydroxyl group and the other represents a hydrogen atom, or R^3Jaand R^3Jbtogether with the carbon atom to which R^3Jaand R^3Jbattached, represent oxoprop; and one of R^21Jaand R^21Jbrepresents a hydroxyl group and the other represents a hydrogen atom, or R^21Jaand R^21Jbtogether with the carbon atom to which R^21Jaand R^21Jbattached, represent oxoprop.

Stage J1 is the stage of synthesis of exocoetidae represented by the formula (IIJ), oxidation of the hydroxyl group of compound 6-deoxy 11107D as the original substance.

The oxidizing agent used at this stage is, for example, manganese dioxide, chlorproma pyridinium, pyridinium dichromate, reagent dessa-Martin or reagents used in the oxidation will Roll. The solvent used in the reaction are not particularly limited, but preferable solvent, which cannot easily communicate with the source material. Examples are tetrahydrofuran, dichloromethane, chloroform, and toluene. The reaction temperature ranges from -78°C to the boiling temperature to the reflux condenser is m 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. Particularly preferred is the reaction using a reagent dessa-Martin. As a solvent for oxidation using reagent dessa-Martin particularly preferred are dichloromethane and chloroform. The amount of oxidizing agent used in the reaction, relative to the specified connection (6-deoxy 11107D) corresponds 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 one to eight hours.

Next, at stage j-1, using the compound obtained in the preliminary education derived by the method described above for the urethane derivative, tourmanova derivative, ester derivative, alkyl derivatives or the like, instead of 6-deoxy 11107D, can be synthesized compound in which a hydroxyl group in position 3 or position 21 of these derivatives are converted into exoframe. In addition, oxidation of the hydroxyl group in position 7 of the compound represented by formula IIA), can also be obtained 7-exocoetidae.

And yet, combining in different ways methods to protect and unprotect the aforesaid stages A1 and A5 with stage J1, hydroxyl group in position 3, position 7 and/or position 21 can selectively be turned into exoframe. In addition, by conducting the reaction of education, respectively, urethane derivative, tourmanova derivative, ester derivative or alkyl derivatives of compounds, hydroxyl group which was previously turned into exoframe, in accordance with the method described above, it is possible to synthesize the compound, modified as appropriate modification and education oxopropanal, respectively.

A suitable combination reactions A-J and methods to protect and unprotect a hydroxyl group, described above, can be synthesized from a compound represented by the formula (I).

Upon completion of the reaction, the target product of each reaction is recovered from the reaction mixture by conventional methods. For example, the target compound can be obtained by removing insoluble substances by filtration and removal of solvent by evaporation of the appropriate way, if insoluble substance is present, or by diluting the reaction mixture with an organic solvent such as ethyl acetate, washing of the mixture water is, drying the organic layer over anhydrous magnesium sulfate and then by evaporating the solvent. The target product may optionally be purified by the conventional method, such as column chromatography, thin-layer chromatography or high performance liquid chromatography.

The compound of formula (I) can be synthesized from the isolated and purified 6-deoxy 11107D and connection 6-deoxy 11107D using conventional methods of organic synthesis. Representative A. derivatives of urethane, B. derivatives thiourethane, C. derivatives of simple ether, D. derivatives of ester, that is, derivatives of ester of phosphoric acid or derivatives of ester monolitdomstrojj acids, F. derivatives of ester of sulfuric acid, and derivatives of ester sulfamic acid, G. halogenated derivatives, N. derivatives of ester sulfonic acid, I. amine derivatives and J. catasetinae can be obtained in the ways described by modifying the conditions of stage 1A of the protection of the hydroxyl group.

Next, to prove the usefulness of the present invention was determined inhibitory effect on the transcription of VEGF, inhibiting effect on the proliferation of cells WiDr colon cancer human inhibitory effect on the proliferation of solid malignant swollen the Lee, the weight loss (acute toxicity) and stability in aqueous solution of the compounds, as typical representatives of compounds of formula (I) according to the present invention.

Example 1 test

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 placental alkaline phosphatase (PLAR) to construct reporter vector.

To obtain the promoter region of the human VEGF cloned VEGF gene from a library of phages. On the basis of the VEGF cDNA (GenBank accession number: H) were determined by PCR-primer in the sequence described as SEQ ID NO:1 or SEQ ID NO:2, for PCR to obtain a fragment of about 340 BP genomic Library of phages man (human genomic library, Clontech) was skanirovali using this fragment as a probe to obtain pUC18-VEGFA containing VEGF 5'-flanking region of approximately a 5.4 KBP Using Kpn I/Nhe I digested pUC18-VEGFA obtaining VEGF promoter region of approximately a 2.3 KBP and put it in multiclone site Kpn I/Nhe I reporter vector placental alkaline phosphatase (PLAP) (Goto et al, Mol. Pharmacol., 49, 860-873, 1996)to construct a vector VEGF-PLAP.

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

As was confirmed in the message Minchenko et al. (Cell. Mol. Biol. Res. 40, 35-39, 1994), U251 cells/1-8 are reporter system, which secretes PLAP into the culture medium in hypoxic conditions (incubator with 2% O₂and which is reflected transcription from the VEGF promoter. Using the obtained clone was carried out by screening compounds inhibiting the production of VEGF caused by hypoxic stimulation.

Example 2 test

Inhibitory activity against VEGF transcription derivative of 6-deoxy 11107D

To exclude the influence of alkaline phosphatase in serum, cells U251/1-8 washed two times sufficient amount of PBS (phosphate buffered saline) and treated at 65°C for 20 min to inactivate the alkaline phosphatase in the serum. Cells were diluted in culture medium DMEM containing 10% indicated serum, and were sown in 96-well tablets 4×10⁴cells/180 μl per well.

Cell cultivation in CO₂incubator (5% CO₂) at 37°during the night and was added 20 ml of the above culture is astora, containing the test compound with 3-fold serial dilutions. Then the cells were cultured in hypoxic (2% CO₂) incubator for 18 hours. To measure the PLAP activity in the culture supernatant to 50 ál 0,28M Na₂CO₃-NaHCO₃buffer solution (pH of 10.0, 8.0 mm MgSO₄) were added 10 μl of culture supernatant and then 50 μl of alkaline phosphatase substrate (Lumistain, Genome Science Laboratories Co., Ltd.). After the interactions within one hour, was determined by chemical luminescence using microtransmitter (Perkin Elmer) for measuring the PLAP activity in the form of activity of alkaline fosfatazy. PLAP activity in terms 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. Determine the values of the IC₅₀derivatives of 6-deoxy 11107D shown in examples (n=2-3). The values of the IC₅₀representative compounds are shown in table 1.

The compound of formula (I) showed high inhibitory activity against VEGF transcription.

Example 3 test

Inhibitory activity against proliferation of human cells WiDr colon cancer

Human cells WiDr colon cancer, cultured in the modified Dulbecco environment Needle containing 10% serum fetal cow, penicillin (100 units/ml) and streptomycin (100 μg/ml) (DMEM, manufacturer Sigma Co.), were sown in 96-well tablets 2×30³cells/well. Cells were cultured overnight in CO₂the incubator was added 20 ml of the above culture solution containing the test compound with 3-fold serial dilutions, for culturing cells. Three days were added 50 μl of a solution of 3.3 mg/ml MTT, and then cells were cultured for one hour. ZAT is m formazan, educated recovery with the help of living cells, was extracted with 100 ál of DMSO to determine the optical density (A/A), which was used as a measure of the number of living cells.

Determined concentration of the compounds of formula (I) for 50% inhibition of cell proliferation WiDr colon cancer human (n=2-3). The values of the IC₅₀for representative compounds are shown in table 2.

The compounds of formula (I) showed high inhibitory activity against cell proliferation WiDr colon cancer che is owaka.

Example 4 tests

Inhibitory activity against the growth of solid tumor

To investigate the inhibitory activity against the growth of solid tumors, compounds of formula (I)in vivosubcutaneously implanted human cells WiDr colon cancer in the body of each naked mouse. When tumor volume of each mouse was reached about 100 mm³mice were divided into groups so that both groups had the same average volume of tumors. The control group consisted of ten mice, and the group entered the derivatives of the 6-deoxy 11107D from five mice. The derivative was administered to each mouse in the group, intended for the introduction of the derivative, intravenous injection in the amount of 0.625 mg/kg/day, 1.25 mg/kg/day, 2.5 mg/kg/day, 5 mg/kg/day or 10 mg/kg/day, and each mouse of the control group were injected media.

Measured volumes of the tumors on day 15, to determine the relative ratio of tumor volume (T/C%)choose tumor volume of the control group as 100%. Each T/C% for representative compounds of formula (I) shown in table 3. Measured body weight on the day of the beginning of the introduction, day 5, day 8, day 12 and day 15 (or 16)to test the relative changes in body weight in the case of the introduction of representative compounds, taking the body weight on the day of the beginning of the introduction of 100%. Minimum relative the cylinder the coefficients of body weight, which are the relative ratios of body weight on the day of body weight were lowest, are shown in table 3.

The compound of formula (I) showed inhibitory activity against the growth of WiDr tumors of the colon of a person evenin vivodose not causing a significant reduction of body weight.

Example 5 testing

Stability in aqueous solution

The compound of formula (I) was dissolved in DMSO at a concentration 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. The resulting solution was used as a solution of sample and incubated at 25°With within 24 hours.

Solution the sample before and after incubation were analyzed by high-performance liquid chromatography chromatograms. Interest sod is neigh connection remaining in the solution sample after incubation was determined from the peak area of the chromatogram. Results for representative compounds are shown in table 4.

Although the content FD895 decreased to 83% after 24 hours, the remaining percentage of connections 18, 19, 20, 22, 39, 43, 44 and 45 as representative compounds of formula (I) was 95-96%. These results show that the derivative of 6-deoxy 11107D as the compound of formula (I) stable in aqueous solutions.

As can be seen from the above examples, pharmacological test, the compound of formula (I) according to the present invention modifies the expression of genes and therefore, in particular, inhibits the production of VEGF. Traces of the tion, as expected, the connection can be used as anti-cancer drugs, in particular drugs for the treatment of solid malignant tumors, inhibiting metastasis of a cancer, a treatment for diabetic retinopathy, a treatment for rheumatoid arthritis and means to ensure echonomy. In addition, as can be seen from example 4 toxicity tests, since an inhibitory effect on tumor growth WiDr colon of a man seen at the dose not causing a significant reduction of body weight of the test mice, the compound of formula (I) is a highly secure connection. Therefore, the compound is effective for prevention or treatment of diseases against which effective regulation of gene expression, diseases against which effective inhibitory activity against the production of VEGF, and the diseases against which effective inhibiting angiogenesis activity. "Prevention or treatment" means the prevention, treatment or both. In particular, the compound of formula (I) according to the present invention effectively as antitumor agents or inhibitors of tumor metastasis, acting against a solid malignant tumors. Examples of solid malignant tumors include pancreatic cancer, cancer of the same is of RCU, 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, villous carcinoma, osteosarcoma, soft tissue sarcoma and ovarian cancer. Especially preferable to use the compound against cancer, such as cancer of the colon, breast cancer, prostate cancer, lung cancer, head and neck cancer or ovarian cancer. In addition, the connection effectively as antitumor agents for the treatment of leukemia. In addition, the connection is effectively also as a means for the treatment of hemangiomas. And moreover, the connection effectively as a tool for the treatment of diabetic retinopathy, a treatment for rheumatoid arthritis or treatment for hemangioma, based on the inhibitory effect on the production of VEGF. In accordance with another variation, a compound effective for the treatment of inflammatory diseases, including osteoarthritis, psoriasis, allergic reaction of the delayed type, and atherosclerosis.

When the above-described connection must be made in the form of an injection solution, active component add, when necessary, a pH regulator, a buffer, with habilitator, the solubilizer, or the like to obtain injection solution for subcutaneous, intramuscular, intra-articular or intravenous injection.

When the above-described connection must be entered as a tool for the treatment or prevention of various diseases, it can be administered orally in the form of tablets, powder, granules, capsules, syrup or the like or parenterally in the form of an aerosol, suppository, injection solution, means for external use or drops. The dose varies depending on the severity of the symptom, age, type of liver disease and the like, and is for an adult is usually from about 1 mg to 100 mg per day as single dose or in separate doses, administered over several times.

The drug is manufactured using conventional components and conventional methods. In particular, when made of solid dosage form for oral administration, the active component of the type carrier and, if necessary, binder, baking powder, grease, dye, corrective substance, substance, masking the smell, or the like and then the resulting mixture is made of tablets, coated tablets, granules, powder, capsules or the like. Of course, tablets or granules may be appropriate about what Asom covered sugar gelatin or other coverings.

In accordance with this invention the compound of formula (I) according to the present invention inhibits, in particular, production of VEGF and angiogenesis by changes in the expression of genes shows high anti-tumor effect on the model ofin vivosolid tumors and has also stability in aqueous solution. Therefore, the present invention can provide, for example, for the treatment of cancer, in particular, for the treatment of a solid cancer, the inhibitor of cancer metastasis, the treatment for diabetic retinopathy, treatment for rheumatoid arthritis or treatment for echonomy.

Examples

The present invention is described hereinafter in more detail by way of examples, concerning ways to get 6-deoxy V (examples 1-4), reactions bioperene of 6-deoxy L 6-deoxy 11107D (examples 5-11), analogues of 6-deoxy 11107D (examples 12-17) and derivatives of 6-deoxy 11107D (examples 18-60), and reference examples. But we should not assume that these examples limit the present invention.

Below shows the meaning of the abbreviations used in the chemical formulas in the examples:

DEIPS: diethylethanolamine group

HER: 1-amoxicilina group

TES: triethylsilyl group.

Example 1

Obtaining mutant Mer-11107

In the present invention Streptomyces sp. Mer-1107 (Deposit number: FERM BP-7812) were forced to mutate using N-methyl-N'-nitroso-N-nitrosoguanidine in Tris-maleate buffer solution (pH 6.0) (100 µg/ml 28°C, one hour) and distributed strain in agar culture medium with yeast and malt extract for spore formation. The obtained spores were collected, part of the dispute were bred and distributed by the agar culture medium with yeast and malt extracts for the formation of colonies. Each cell is taken as a sample from the colonies, was made in a test tube with a volume of 15 ml containing 2 ml of culture medium for sowing (glucose: 2%, 2% soybean meal (Esusan-meat, manufacturer Ajinomoto Co., Inc.): 1%, yeast extract (manufacturer Oriental Yeast Co., Ltd.): 0.5%, sodium chloride: 0.25% and calcium carbonate: 0,32%, pH 6.8), and cultured on a shaker at 25°C for two days. Then 0.5 ml of the seed culture solution was introduced into a test tube with a volume of 15 ml containing 2 ml of producing culture medium (soluble starch: 7%, flour from gluten: 0,8%, pharmaceutical environment: 0.8% calcium carbonate: 0,1%; pH 7.5), and the cells were cultured on a shaker at 25°C for four days. The culture solution was extracted with ethyl acetate and analyzed by TLC (Merck 5715, acetone:toluene=1:1, painted phosphomolybdenum acid)to take the strain A-1543, a strain in which the spot other than V (Rf: 0.5). The resulting strain was deposited at the International Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japa as FERM P-18942 July 23, 2002 and was transferred to the International Patent Organism Depositary (IPOD), National Institute of Advanced Industrial Science and Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan under the international Deposit number FERM BP-8442 July 28, 2003

Example 2

Cultivation And-1543

Frozen seed culture And 1543 were first thawed. 0.2 ml of thawed culture was made in a conical flask of 250 ml containing 20 ml of culture medium for sowing (glucose: 2%, 2% soybean meal (Esusan-meat, manufacturer Ajinomoto Co., Inc.): 1%, yeast extract (manufacturer Oriental Yeast Co., Ltd.): 0.5%, sodium chloride: 0.25% and calcium carbonate: 0,32%, pH 6.8), and the cells were cultured on a shaker at 25°C for three days. Then 0.6 ml of the seed culture solution was made in 60 ml of producing culture medium (soluble starch: 5%, flour from gluten: 1%, pharmaceutical environment: 2% and the calcium carbonate is 0.1%; pH 7.5), and sowing, and the mixture was cultured on a shaker at 25°within five days.

Example 3

Purification of 6-deoxy L and 6-deoxy 11107BI

The culture solution obtained by the method of example 2 (1.2 l), was divided into a filtrate and cells using a centrifuge. The supernatant was extracted with ethyl acetate (1.2 l). Cells were extracted with acetone (500 ml) and the extract was filtered to obtain the acetone extract. The acetone from the acetone extract was removed by distillation under reduced pressure and the eat distilled product was extracted with ethyl acetate (1 liter). Accordingly an ethyl acetate layer was washed with water and then dried, when dehydrating with anhydrous sodium sulfate. Furthermore, these layers were concentrated together under reduced pressure to obtain 531 mg of the crude active fraction. The crude active fraction was subjected to column chromatography on silica gel (Russ. name gel 60, 25 g), washed with toluene (50 ml) and was suirable mixed solution of toluene with ethyl acetate (3:1;./about.) (300 ml) to give 161 mg of the crude active fraction containing 6-deoxy V, and 34 mg of the crude active fraction containing 6-deoxy 11107BI. The crude active fraction containing 6-deoxy V, was subjected to preparative high performance liquid chromatography (HPLC), preparative conditions (A1), described below, receiving elyuirovaniya fractions 6-deoxy W. Then removed by distillation of the solvent with the receipt of 118.8 mg 6-deoxy W. Similarly was fractionally crude active fraction containing 6-deoxy V, using HPLC to preparative conditions (A2)described below, and then removed by distillation of the solvent to obtain 11.0 mg 6-deoxy L.

Conditions (A1) preparative HPLC:

Column: CAPCELL PACK C18 UG120, diameter: 30 mm, length: 250 mm (manufacturer Shiseido Co., Ltd.)

Volume flow: 20 ml/min

Detection: 240 nm

The eluate: acetone is home to the thrill/water (60:40, about./vol.), isocratic

Conditions (A2) preparative HPLC:

Column: CAPCELL PACK C18 UG120, diameter: 30 mm, length: 250 mm (manufacturer Shiseido Co., Ltd.)

Volume flow: 20 ml/min

Detection: 240 nm

The eluate: acetonitrile/water (65:35, vol/vol.), isocratic

The retention time of the above-described compounds in the following conditions HPLC analysis shown below. Conditions (a) HPLC analysis:

Column: CAPCELL PACK C18 SG120, diameter: 4.6 mm, length: 250 mm (manufacturer Shiseido Co., Ltd.)

Temperature: 40°

Volumetric flow rate: 1 ml/min

Detection: 240 nm

The eluate: acetonitrile/water (60:40, vol/vol.), isocratic

Retention time:

6-deoxy W: 12.0 minutes.

6-deoxy V: 26,4 minutes

Example 4

Physico-chemical properties of 6-deoxy L

Physico-chemical properties of 6-deoxy V shown below. Determined the structure of 6-deoxy L, which is represented by the formula (XVI").

1. Characteristics: colorless powder

2. Molecular weight: 520, ESI-MS 543 (M+Na)⁺, ESI-MS 519 (M-H)^-

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

4. Color reaction: positive for iodine, sulfuric acid and phosphomolybdenum acid

5. Ultraviolet absorption spectrum (methanol, the maximum value) nm: 240 (ε 33500)

6. The infrared spectrum is absorbed in the I (KBr)cm ^-1: 3449, 2965, 1734, 1714, 1456, 1372, 1242, 1170

7.¹H-NMR (CD₃OD, 400 MHz): δ ppm (integral intensity, multipletness, the binding constant J (Hz)): of 0.87 (3H, d, J=7,0 Hz)of 0.90 (3H, d, J=7,0 Hz)to 0.94 (3H, d, J=7,3 Hz)to 0.97 (3H, d, J=7,0 Hz), a 1.08 (3H, d, J=7,0 Hz), 1,17-to 1.21 (1H, m), 1,24-of 1.36 (2H, m), 1,42-of 1.52 (3H, m), 1,61-of 1.66 (3H, m), of 1.74 (3H, d, J=1.1 Hz), 1,89 is 1.96 (1H, m), from 2.00 (3H, s), 2,41-2,47 (1H, m), 2,43 (1H, DD, J=5,5, to 13.9 Hz), of 2.51-of 2.58 (1H, m), of 2.56 (1H, DD, J=3,7, a 13.9 Hz), 2,65 (1H, DD, J=2,2, 8.1 Hz), of 2.72 (1H, dt, J=2,2, 5,9 Hz), 3,51 (1H, dt, J=a 4.4, and 8.4 Hz), 3.75 to of 3.80 (1H, m), 4,91 (1H, DD, J=8,8, to 10.6 Hz), 5,00 (1H, d, J=a 10.6 Hz), 5,42 (1H, DD, J=9,2, 15,0 Hz), 5,49 (1H, DD, J=9,2, of 15.0 Hz), the 5.65 (1H, DD, J=8,4, 15,0 Hz), between 6.08 (1H, d, J=a 10.6 Hz), 6,32 (1H, DD, J=10,6, 15,0 Hz).

Example 5

Physico-chemical properties of 6-deoxy L

Physico-chemical properties of 6-deoxy V shown below. Determined the structure of 6-deoxy L, which is represented by the following formula.

1. Molecular weight: 504, ESI-MC 527 (M+Na)⁺, ESI-MS 503 (M-H)^-

2.¹H-NMR (CD₃OD, 400 MHz): δ ppm (integral intensity, multipletness, the binding constant J (Hz)): 0,86 (3H, d, J=6,6 Hz)to 0.92 (3H, t, J=7,3 Hz)to 0.97 (3H, d, J=6.6 Hz), and 0.98 (3H, d, J=6.6 Hz), a 1.01 (3H, d, J=7,0 Hz), 1,25-1,35 (3H, m), 1,53-to 1.61 (3H, m)1,72 (3H, d, J=0.7 Hz), 1,89-of 1.95 (1H, m), from 2.00 (3H, s), 2,02-of 2.05 (2H, m), 2,10 (1H, DD, J=7,0, and 14.3 Hz), 2,27-2,31 (1H, m), 2,43 (1H, DD, J=5,1, to 13.9 Hz), 2,50-of 2.56 (1H, m), of 2.56 (1H, DD, J=3.3V), a 13.9 Hz), 3,18 (1H, dt, J=3.3, which is 8.8 Hz), 3.75 to of 3.80 (1H, m), 4,91 (1H, overlapped, H₂A)to 5.00 (1H, d, J=a 10.6 Hz), 5,32 (1H, DD, J=7,3, to 15.4 Hz), 5,38 (1H, DD, J=6,2, to 15.4 Hz), 5,41 (1H, DD, J=9,2, 15,0 Hz), 5,49 (1H, DD, J=9,2, to 15.4 Hz), 5,64 (1H, DD, J=7,7, 15,0 Hz), the 6.06 (1H, d, J=11,0 Hz), 6,21 (1H, DD, J=9,9, 15,0 Hz).

Example 6

Obtaining strain for the conversion of 6-deoxy L 6-deoxy 11107D

The beveled portion of culture medium (agar culture medium with yeast and malt extracts) strain isolated from soil, was made in a conical flask of 250 ml containing 20 ml of seed culture medium [soluble starch: 2,4%, glucose: 0,1%, soybean meal (Esusan meat, manufacturer Ajinomoto Co., Inc.): of 0.5%, beef extract (manufacturer Difco Co.): of 0.3%, yeast extract (manufacturer Difco Co.): 0.5%, tripton-peptone (manufacturer Difco Co.): 0.5% calcium carbonate: 0,4%], and the cells were cultured on a shaker at 28°C for three days to obtain a seed culture solution. Then 0.6 ml of the seed culture solution was introduced into the conical flask 500 ml, containing 60 ml of a production culture medium [potato starch: 2%, glucose: 2%, soybean meal (Esusan meat, manufacturer Ajinomoto Co., Inc.): 2%, yeast extract: 0.5%, sodium chloride: 0,25%, calcium carbonate: 0,32, copper sulfate: 0,0005%, manganese chloride: 0,0005% and zinc sulfate: 0,0005%; pH 7.4], and the cells were cultured on a shaker at 28°C for four days. Each 2 ml of the obtained culture Rast is ora was made in a test tube with a volume of 15 ml and centrifuged at 3000 rpm for 5 minutes, to collect cells. Cells suspended in 2 ml of 50 mm phosphate buffer solution (pH 6.0). Then prepared as the substrate 6-deoxy V in the form of 5 mg/ml in dimethyl sulfoxide and added 0.04 ml of suspension. After the addition the mixture was shaken at 28°C for 23 hours to implement hydroxylation reactions. Upon termination of the reaction were analyzed by HPLC, taking two strains, which appeared in the peak 6-deoxy 11107D: strain a-1544 and strain a-1545. These strains have been deposited in International Patent Organism Depositary, National Institute of Advanced Industrial Science and Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan on July 23, 2002, as FERM P-18943 and FERM P-18944, respectively, and were transferred to the International Patent Organism Depositary (IPOD), National Institute of Advanced Industrial Science and Technology in Central 6, 1-1-1 Higashi, Tsukuba-shi, Ibaraki 305-8566, Japan, July 30, 2003 under international Depositary numbers FERM BP-8446 and FERM BP-8447, respectively.

The retention time of the above-described compounds in the following conditions of the analysis by HPLC is shown below.

Conditions (b) analysis by HPLC:

Column: CAPCELL PACK C18 SG120 diameter: 4.6 mm, length: 250 mm (manufacturer Shiseido Co., Ltd.)

Temperature: 40°

Volumetric flow rate: 1 ml/min

Detection: 240 nm

The eluate: acetonitrile/water (50:50, vol/vol.), isocratic

Retention time:

6-deoxy V: 27,2 min

6-deoxy 11107D: 8,2 minutes

Example

The cultivation of the A-1544

The beveled portion of culture medium (agar culture medium with yeast and malt extracts) strain A-1544 was made in a conical flask of 250 ml containing 25 ml of seed culture medium (potato starch: 2%, glucose: 2%, soybean meal (Esusan meat, manufacturer Ajinomoto Co., Inc.): 2%, yeast extract: 0.5%, sodium chloride: 0,25%, calcium carbonate: 0,32, copper sulfate: 0,0005%, manganese chloride: 0,0005% and zinc sulfate: 0,0005%; pH 7.4)and the cells were cultured on a shaker at 28°C for three days to obtain a seed culture solution. Then every 0.75 ml of the obtained seed culture solution was made in a test tube with a volume of 2 ml serum (manufacturer Sumitomo Bakelite Co., Ltd.) and added an equal amount of 40% aqueous solution of glycerol. The mixture was stirred and was then frozen at -70°obtaining a frozen seed culture. Received frozen seed culture was thawed. 0.25 ml of the culture were made in a conical flask of 250 ml containing 25 ml of medium for sowing (potato starch: 2%, glucose: 2%, soybean meal (Esusan meat, manufacturer Ajinomoto Co., Inc.): 2%, yeast extract: 0.5%, sodium chloride: 0,25%, calcium carbonate: 0,32, copper sulfate: 0,0005%, manganese chloride: 0,0005% and zinc sulfate: 0,0005%; pH 7.4)and cultured on a shaker at 28°C for two days with p is the receiving of the seed culture solution. Then 0.25 ml of the seed culture solution was made in a conical flask of 250 ml containing 25 ml of production culture medium (potato starch: 2%, glucose: 2%, soy flour (S-San meat, manufacturer Ajinomoto Co., Inc.): 2%, yeast extract: 0.5%, sodium chloride: 0,25%, calcium carbonate: 0,32, copper sulfate: 0,0005%, manganese chloride: 0,0005% and zinc sulfate: 0,0005%; pH 7.4) and the cells were cultured on a shaker at 25°C for four days.

Example 8

Getting 6-deoxy 11107D reaction Bioperine

Each of the culture solutions of strain A-1544, obtained by the method of example 7 (30 conical flasks of 25 ml/250 ml each)were subjected to centrifugation at 3000 rpm for 10 minutes to collect cells. Cells suspended in 25 ml of 50 mm phosphate buffer solution (pH 6.0). Then prepared as the substrate 6-deoxy V in the form of 50 mg/ml in dimethyl sulfoxide and added to 0.25 ml of the solution to the suspension. After the addition the mixture was shaken at 28°C for 22 hours to implement hydroxylation reactions. Upon completion of the reaction the reaction product was centrifuged at 5000 rpm for 20 minutes to separate the product in the filtrate and cells. The supernatant was extracted with ethyl acetate (750 ml). Cells were extracted with acetone (500 ml) and the extract was filtered to obtain acetone e is stricta. The acetone from the acetone extract was removed by distillation under reduced pressure and then distilled product was extracted with ethyl acetate (750 ml). Accordingly an ethyl acetate layer was washed with water and then dried, when dehydrating over anhydrous sodium sulfate. Furthermore, these layers were concentrated together under reduced pressure to obtain 365 mg of the crude active fraction. The crude active fraction was subjected to column chromatography on silica gel (Russ. name gel 60, 35 g), washed with toluene (70 ml) and was suirable mixed solution of toluene with ethyl acetate (4:1; about./about.) (500 ml) and a mixed solution of toluene with acetone (2:1; vol/about.) (300 ml) to give 139 mg of the crude active fraction containing 6-deoxy 11107D and 6-deoxy VR, 78 mg of the crude active fraction containing 6-deoxy 11107AV, and 78 mg of the crude active fraction containing 6-deoxy 11107D 20-HE and 6-deoxy 11107F. The crude active fraction containing 6-deoxy 11107D and 6-deoxy VR, was subjected to preparative high performance liquid chromatography (HPLC), preparative conditions (B1), described below, receiving buervenich fractions 6-deoxy 11107D and fractions of 6-deoxy VR. Then removed by distillation of the solvent to obtain 6-deoxy 11107D (67,0 mg) and 6-deoxy VR (8.1 mg). Similarly, fractionally crude active fraction, which won 6-deoxy 11107AV and the crude active fraction, containing 6-deoxy 11107D 20-HE and 6-deoxy 11107F, using HPLC to preparative conditions (A1)described above, and the preparative conditions (B2)described below, respectively. Then removed by distillation solvents with obtaining 6-deoxy 11107AV, (9,3 mg), 6-deoxy 11107D 20-HE (19.9 mg) and 6-deoxy 11107F (22,1 mg).

Example 9

Cultivation And-1545

The beveled portion of culture medium (agar culture medium with yeast and malt extracts) strain A-1545 was made in a conical flask of 250 ml containing 25 ml of seed culture medium (potato starch: 2%, glucose: 2%, soybean meal (Esusan meat, manufacturer Ajinomoto Co., Inc.): 2%, yeast extract: 0.5%, sodium chloride: 0,25%, calcium carbonate: 0,32, copper sulfate: 0,0005%, manganese chloride: 0,0005% and zinc sulfate: 0,0005%; pH 7.4)and the cells were cultured on a shaker at 28°C for three days to obtain a seed culture solution. Then every 0.75 ml of the obtained seed culture solution was introduced into a test tube with a volume of 2 ml serum (manufacturer Sumitomo Bakelite Co., Ltd.) and added an equal amount of 40% aqueous solution of glycerol. The mixture was stirred and was then frozen at -70°obtaining a frozen seed culture. Received frozen seed culture was thawed. 0.25 ml of the culture were made in a conical flask of 250 ml containing the th 25 ml of culture medium for sowing (potato starch: 2%, glucose: 2%, soybean meal (Esusan meat, manufacturer Ajinomoto Co., Inc.): 2%, yeast extract: 0.5%, sodium chloride: 0,25%, calcium carbonate: 0,32, copper sulfate: 0,0005%, manganese chloride: 0,0005% and zinc sulfate: 0,0005%; pH 7.4)and the cells were cultured on a shaker at 28°C for two days to obtain a seed culture solution. Then 0.25 ml of the seed culture solution was made in a conical flask of 250 ml containing 25 ml of production culture medium (potato starch: 2%, glucose: 2%, soybean meal (Esusan meat, manufacturer Ajinomoto Co., Inc.): 2%, yeast extract: 0.5%, sodium chloride: 0,25%, calcium carbonate: 0,32, copper sulfate: 0,0005%, manganese chloride: 0,0005% and zinc sulfate: 0,0005%; pH 7.4)and the cells were cultured on a shaker at 25°C for four days.

Example 10

Getting 6-deoxy 11107D reaction Bioperine

Each of the culture solutions of strain A-1545, obtained by the method of example 9 (40 conical flasks of 25 ml/250 ml each)were subjected to centrifugation at 3000 rpm for 10 minutes to collect cells. Cells suspended in 25 ml of 50 mm phosphate buffer solution (pH 6.0). Then prepared as the substrate 6-deoxy V in the form of 50 mg/ml in dimethyl sulfoxide and added to 0.25 ml of the solution to the suspension. After the addition the mixture was shaken at 28°C for 22 hours to DL the implementation of hydroxylation reactions. Upon completion of the reaction the reaction product was centrifuged at 5000 rpm for 20 minutes to separate the product in the filtrate and cells. The supernatant was extracted with ethyl acetate (1 liter). Cells were extracted with acetone (500 ml) and the extract was filtered to obtain the acetone extract. The acetone from the acetone extract was removed by distillation under reduced pressure and then distilled product was extracted with ethyl acetate (1 liter). Accordingly an ethyl acetate layer was washed with water and then dried, when dehydrating over anhydrous sodium sulfate. Furthermore, these layers were concentrated together under reduced pressure to obtain 537 mg of the crude active fraction. The crude active fraction was subjected to column chromatography on silica gel (Russ. name gel 60, 50 g), washed with toluene (100 ml) and was suirable mixed solution of toluene with ethyl acetate (4:1; about./about.) (600 ml) and a mixed solution of toluene with acetone (2:1; vol/about.) (600 ml) to give 112 mg of the crude active fraction containing 6-deoxy 11107D, and 47 mg of the crude active fraction containing 6-deoxy 11107D 20-HE, 6-deoxy 11107D 17-one and 6-deoxy 11107D 17-OH (epimere position 17). The crude active fraction containing 6-deoxy 11107D, was subjected to preparative high performance liquid chromatography (HPLC), preparative conditions (B1)described below, with receipt is m elyuirovaniya fractions 6-deoxy 11107D. Then removed by distillation of the solvent to obtain 6-deoxy 11107D (67.2 per mg). Similarly, fractionally crude active fraction containing 6-deoxy 11107AV, and the crude active fraction containing 6-deoxy 11107D 20-HE, 6-deoxy 11107D 17-one and 6-deoxy 11107D 17-OH (epimere position 17), using HPLC to preparative conditions (A1)described above, and the preparative conditions (B2)described below, respectively. Then removed by distillation solvents with obtaining 6-deoxy 11107AV (5.7 mg), 6-deoxy 11107D 20-HE (9.0 mg), 6-deoxy 11107D 17-one (5.9 mg) and 6-deoxy 11107D 17-OH (epimere position 17) (6.4 mg).

Conditions (B1) preparative HPLC:

Column: CAPCELL PACK C18 UG120, diameter: 30 mm, length: 250 mm (manufacturer Shiseido Co., Ltd.)

Volume flow: 20 ml/min

Detection: 240 nm

The eluate: acetonitrile/water (40:60, about./vol.), isocratic

Condition (B2) preparative HPLC:

Column: CAPCELL PACK C18 UG120, diameter: 30 mm, length: 250 mm (manufacturer Shiseido Co., Ltd.)

Volume flow: 20 ml/min

Detection: 240 nm

The eluate: acetonitrile/water (35:65, about./vol.), isocratic

The retention time of the above-described compounds in the following conditions of the analysis by HPLC is shown below.

Conditions (C) analysis by HPLC:

Column: CAPCELL PACK C18 SG120 diameter: 4.6 mm, length: 250 mm (manufacturer Shiseido Co., Ltd.)

Temperature: 40°

Surround R is retired: 1 ml/min

Detection: 240 nm

The eluate: acetonitrile/water (45:55, about./vol.), isocratic

Retention time:

6-deoxy 11107D: 12.5 minutes

Analogue 1 (6-deoxy VR): 11.4 minutes

Analogue 2 (6-deoxy 11107D 20-HE): 7.3 minutes

Analogue 3 (6-deoxy 11107F): 4.6 minutes

Similar to the 4 (6-deoxy 11107D 17-HE): 7,8 minutes

Analogue 5 (6-deoxy 11107D 17-HE): 8.3 minutes

Analogue 6 (6-deoxy 11107AV): 17.8 minutes.

Example 11

Physico-chemical properties of 6-deoxy 11107D

Physico-chemical properties of 6-deoxy 11107D shown below. As defined, 6-deoxy 11107D has a structure represented by formula (XVII').

1. Molecular weight: 536, ESI-MC 559 (M+Na)⁺, ESI-MS 535 (M-H)^-

2.¹H-NMR (CD₃OD, 400 MHz): δ ppm (integral intensity, multipletness, the binding constant J (Hz)): of 0.87 (3H, d, J=7,0 Hz)of 0.90 (3H, d, J=7,0 Hz)to 0.94 (3H, t, J=7,3 Hz)to 0.97 (3H, d, J=6.6 Hz), 1,21-of 1.26 (1H, m)of 1.29 to 1.37 (3H, m)of 1.34 (3H, s), 1,44-of 1.52 (2H, m), 1.60-to of 1.64 (1H, m), of 1.65 (1H, DD, J=6,2, to 13.9 Hz), or 1.77 (3H, d, J=1.1 Hz), to 1.86 (1H, DD, J=5,4, a 13.9 Hz), 1,89-of 1.94 (1H, m), from 2.00 (3H, s), 2,43 (1H, DD, J=5,5, to 13.9 Hz), 2,50-2,60 (1H, m), of 2.56 (1H, DD, J=3.3, which is 13.9 Hz), to 2.66 (1H, DD, J=2,2, 7,7 Hz), 2,89 (1H, dt, J=2,2, 6.2 Hz), 3,52 (1H, dt, J=4,8, and 8.4 Hz), 3.75 to of 3.80 (1H, m), the 4.90 (1H, overlapped, H₂About), free 5.01 (1H, d, J=a 10.6 Hz), 5,42 (1H, DD, J=9,2, 15,0 Hz), of 5.50 (1H, DD, J=9,2, 15,0 Hz), 5,86 (1H, d, J=15,0 Hz), 6,13 (1H, d, J=a 10.6 Hz), of 6.52 (1H, DD, J=11,0, 15,0 Hz).

Example 12

Physico-chemical properties of the analogue 1 (6-deoxy WR)

Physico-chemical properties of the analogue 1 shown below. As defined, alternative 1 has a structure represented by the following formula.

1. Molecular weight: 550, ESI-MC 573 (M+Na)⁺, ESI-MS 549 (M-H)^-

2.¹H-NMR (CD₃OD, 400 MHz): δ ppm (integral intensity, multipletness, the binding constant J (Hz)): 0,86 (3H, d, J=7,0 Hz)to 0.97 (3H, d, J=6.6 Hz), a 1.01 (3H, t, J=7.0 Hz), 1,25 (3H, s)of 1.29 and 1.35 (2H, m)of 1.34 (3H, s), 1,58-of 1.65 (2H, m), 1,68 (1H, DD, J=6,2, 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), 1,88-of 1.93 (1H, m), from 2.00 (3H, s), 2,42 (1H, DD, J=5,1, and 14.3 Hz), 2,52-of 2.58 (1H, m), of 2.56 (1H, DD, J=3.3V, and 14.3 Hz), 2,61 was 2.76 (2H, m)of 3.00 (1H, d, J=2.2 Hz), 3,17 (1H, dt, J=2,2, 5,9 Hz), 3.75 to of 3.80 (1H, m), 4,91 (1H, DD, J=9,2, 10,3 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,42 (1H, DD, J=9,2, 15,0 Hz), of 5.50 (1H, DD, J=9,2, 15,0 Hz), by 5.87 (1H, d, J=15,4 Hz), 6,14 (1H, d, J=11,0 Hz), 6,53 (1H, DD, J=of 11.0 to 15.4 Hz).

Example 13

Physico-chemical properties of the analogue 2 (6-deoxy 11107D 20-HE)

Physico-chemical properties similar 2 shown below. As it was determined that alternative 2 has a structure represented by the following formula.

1. Molecular weight: 552, ESI-MC 575 (M+Na)⁺, ESI-MS 551 (M-H)^-

2.¹H-NMR (CD₃OD, 400 MHz): δ ppm (integral intensity, multipletness, the binding constant J (Hz)): of 0.87 (3H, d, J=7,0 Hz)to 0.97 (3H, d, J=7,0 Hz), a 1.01 (3H, t, J=7,3 Hz), was 1.04 (3H, s), 1,25-1,35 (3H, m)of 1.35 (3H, s), 1,55-1,65 (2H, m), 1.69 in (1H, DD, J=5,9, a 13.9 Hz), 1,72-to 1.77 (1H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,9, a 13.9 Hz), 1,88-of 1.95 (1H, m), 2,0 (3H, C)2,43 (DD, J=5,4, a 13.9 Hz), 2,50-2,60 (1H, m), of 2.56 (1H, DD, J=3.3, which is 13.9 Hz), 2,90 (1H, d, J=2.2 Hz), 3,10 (1H, dt, J=2,2, 5,9 Hz), 3,30 (1H, DD, J=2,0 and 10.7 Hz), 3.75 to-3,81 (1H, m), 4,71 (1H, DD, J=9,2, 10,3 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,42 (1H, DD, J=8,8, 15,0 Hz), of 5.50 (1H, DD, J=8,9, or 15.0 Hz), by 5.87 (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).

Example 14

Physico-chemical properties of analogue 3 (6-deoxy 11107F)

Physico-chemical properties similar 3 shown below. As defined, similar 3 has a structure represented by the following formula.

1. Molecular weight: 494, ESI-MC 517 (M+Na)⁺, ESI-MS 493 (M-H)^-

2.¹H-NMR (CD₃OD, 400 MHz): δ ppm (integral intensity, multipletness, the binding constant J (Hz)): of 0.90 (6H, d, J=7,0 Hz)to 0.94 (3H, t, J=7,3 Hz)of 1.07 (3H, d, J=6.6 Hz), 1,21-of 1.26 (2H, m), 1,27-of 1.30 (1H, m)of 1.34 (3H, s), 1,43-and 1.54 (2H, m), 1,57 by 1.68 (3H, m)of 1.78 (3H, s)to 1.87 (1H, DD, J=5,1, to 13.9 Hz), 2,42 (1H, DD, J=5,5, and 14.3 Hz), 2,52-of 2.58 (1H, m), 2.57 m (1H, DD, J=3.3V, and 14.3 Hz), to 2.67 (1H, DD, J=2,2, 8.1 Hz), 2,89 (1H, dt, J=2,2, 5,9 Hz), 3,52 (1H, dt, J=4,8, 9,2 Hz), 3,57 (1H, DD, J=a 9.5, 9.9 Hz), to 3.73-with 3.79 (1H, m), 5,02 (1H, d, J=a 10.6 Hz), 5,31 (1H, DD, J=9,5, 15,0 Hz), vs. 5.47 (1H, DD, J=9,2, 15,0 Hz), 5,86 (1H, d, J=15,0 Hz), 6,12 (1H, d, J=11,0 Hz), 6,53 (1H, DD, J=11,0, 15,0 Hz).

Example 15

Physico-chemical properties similar to the 4 (6-deoxy 11107D 17-IT)

Physico-chemical properties similar to the 4 shown below. As defined, similar to the 4 has a structure represented by the following formula.

1. M is molecular weight: 552, ESI-MC 575 (M+Na)⁺, ESI-MS 551 (M-H)^-

2.¹H-NMR (CD₃OD, 400 MHz): δ ppm (integral intensity, multipletness, the binding constant J (Hz)): of 0.87 (3H, d, J=6.2 Hz), to 0.88 (3H, d, J=7,0 Hz)to 0.94 (3H, t, J=7,3 Hz)to 0.97 (3H, d, J=7.0 Hz), 1.25 and 1,25 (3H, m), 1,32 (3H, s), 1,44-of 1.55 (2H, m), 1,57-to 1.67 (2H, m), 1.77 in (3H, s), 1,88-of 1.95 (1H, m), from 2.00 (3H, s), 2,43 (1H, DD, J=5,5, to 13.9 Hz), to 2.57 (1H, DD, J=3.3, which is 13.9 Hz), of 2.51-2,61 (1H, m), 2,84 (1H, DD, J=2,2, 7,7 Hz), of 2.92 (1H, DD, J=2,2, 6,6 Hz), 3,12 (1H, d, J=6.6 Hz), of 3.54 (1H, dt, J=4,8, 7,7 Hz), 3,74-3,81 (1H, m), 4,91 (1H, DD, J=9,1, 10,3 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,42 (1H, DD, J=9,1, of 14.7 Hz), of 5.50 (1H, DD, J=8,8, of 14.7 Hz), of 5.92 (1H, d, J=15,0 Hz), 6,14 (1H, d, J=11,0 Hz), to 6.58 (1H, DD, J=11,0, 15,0 Hz).

Example 16

Physico-chemical properties of analogue 5 (6-deoxy 11107D 17-IT)

Physico-chemical properties similar 5 shown below. As defined, similar 5 has a structure represented by the following formula. This compound is a stereoisomer of the hydroxyl group in position 17 similar to the 4.

1. Molecular weight: 552, ESI-MC 575 (M+Na)⁺, ESI-MS 551 (M-H)^-

2.¹H-NMR (CD₃OD, 400 MHz): δ ppm (integral intensity, multipletness, the binding constant J (Hz)): of 0.87 (3H, d, J=6,6 Hz)to 0.89 (3H, d, J=7,0 Hz)to 0.94 (3H, t, J=7,3 Hz)to 0.97 (3H, d, J=7,0 Hz), 1,20-1,40 (3H, m)of 1.34 (3H, s), 1,43-to 1.67 (4H, m), 1.77 in (3H, s), 1,87 is 1.96 (1H, m), from 2.00 (3H, s), 2,43 (1H, DD, J=5,1, to 13.9 Hz), to 2.57 (1H, DD, J=3.3, which is 13.9 Hz), 2,54 is 2.55 (1H, m), 2,93-2,96 (2H, m), 3,44 (1H, d, J=3.3 Hz), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), 3,74-3,81 (1H, m,), 4,91 (1H, peracre the th H ₂O), free 5.01 (1H, d, J=a 10.6 Hz), 5,42 (1H, DD, J=8,8, 15,0 Hz), of 5.50 (1H, DD, J=9,2, 15,0 Hz), to 5.93 (1H, d, J=15,4 Hz), 6,13 (1H, d, J=11,0 Hz), 6,59 (1H, DD, J=11,0, or 15.9 Hz).

Example 17

Physico-chemical properties of analogue 6 (6-deoxy 11107AV)

Physico-chemical properties similar 6 shown below. As defined, similar 6 has a structure represented by the following formula.

1. Molecular weight: 534, ESI-MC 557 (M+Na)⁺, ESI-MS 533 (M-H)^-

2.¹H-NMR (CD₃OD, 400 MHz): δ ppm (integral intensity, multipletness, the binding constant J (Hz)): of 0.87 (3H, d, J=6.6 Hz), of 0.97 (3H, d, J=7,7 Hz), and 0.98 (3H, t, J=7,3 Hz)of 1.07 (3H, d, J=7,0 Hz), 1,28-1,32 (2H, m)of 1.33 (3H, s), 1,58-of 1.64 (2H, m), and 1.63 (1H, DD, J=6,6, and 14.3 Hz), or 1.77 (3H, d, J=1.1 Hz), 1,88-of 1.94 (1H, m), 1,89 (1H, DD, J=5,1, and 14.3 Hz), of 2.28 to 2.35 (1H, m), 2,42 (1H, DD, J=5,5, and 14.3 Hz), 2,52-2,63 (4H, m)of 2.75 (1H, DD, J=2,2, 8,4 Hz), only 2.91 (1H, dt, J=2,2, 6,6 Hz), 3.75 to of 3.80 (1H, m), 4,91 (1H, DD, J=8,8, 10,3 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,42 (1H, DD, J=8,8, 15,0 Hz), of 5.50 (1H, DD, J=9,2, 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).

Example 18

(8E,12E,14)-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 18)

Example 18-1 stage

(1) (8E,12E,14)-7-acetoxy-3,16,21-Tris(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old

(8E,12E,14)-7-Acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old (6-deoxy 11107D) (129 mg, 240 μmol) was dissolved in methylene chloride (2 ml). Ethylenically ether (1.4 ml, 14.4 mmol) and p-toluensulfonate pyridinium (19.9 mg, 79.2 mmol) was added to the reaction mixture at room temperature and the reaction mixture was stirred at the same temperature for 4.5 hours. This reaction mixture was diluted with ethyl acetate (30 ml) and the organic layer was washed with purified water (10 ml) and saturated salt solution (10 ml). The obtained organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain specified in the connection header in the form of the crude product (188 mg).

ESI-MS m/z 775 (M+Na)⁺.

Example 18-2 stage

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

(8E,12E,14)-7-Acetoxy-3,6,16,21-Tris(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (186 mg) as a crude product was dissolved in methanol (2 ml). To the reaction mixture were added potassium carbonate (75,0 mg, 543 μmol) and the reaction mixture was stirred at room temperature for three hours. The resulting reaction solution was diluted with ethyl acetate (50 ml) and org the organic layer was washed with saturated salt solution (10 ml) twice. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained concentrate was purified column chromatography on silica gel (Merck Silica gel 60, 63-200 μm; hexane:ethyl acetate=3:1→2:1) to obtain the specified title compound (131 mg, 185 μmol, 78,6%, stage 2) in the form of a colorless oil.

ESI-MS m/z 733 (M+Na)⁺.

Example 18-3 stage

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

(8E,12E,14)-3,16,21-Tris(1-Ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (129 mg, 182 μmol) was dissolved in methylene chloride (1 ml). To the reaction mixture were added triethylamine (127 μl, 911 mmol) and 4-dimethylaminopyridine (67,0 mg, 548 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. To the obtained reaction mixture was added dropwise a solution of 4-nitrophenylphosphate (112 mg, 556 mmol) in methylene chloride (1 ml) and the reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate (10 ml) and purified water (10 ml) twice and a saturated salt solution (10 ml). The obtained organic layer was dried over betwedn the m sodium sulfate, was filtered and concentrated. The obtained concentrate was purified column chromatography on silica gel (Merck Silica gel 60, 63-200 μm; hexane:ethyl acetate=5:1→4:1) to obtain the specified title compound (137 mg, 156 μmol, 85,8%) as a colourless oil.

ESI-MS m/z 898 (M+Na)⁺.

Example 18-4 stage

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

(8E,12E,14)-3,16,21-Tris(1-Ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxydecane-8,12,14-trien-11-OLED (26.6 mg, 30.4 mmol) was dissolved in tetrahydrofuran (0.5 ml). To the reaction mixture was added a solution of 1-methylpiperazine (4,4 μl, 49 mmol) in tetrahydrofuran (0.5 ml) and the reaction mixture was stirred at room temperature for 2.5 hours. The resulting reaction solution was concentrated and the concentrate was purified column chromatography on silica gel (Fuji Silysia NH Silica gel, 100 μm; hexane:ethyl acetate=1:1) to obtain the specified title compound (25.1 mg, 30.0 μmol, 98,7%) as a colourless oil.

ESI-MS m/z 837 (M+H)⁺.

Example sheet 18-5 stage

(5) (8E,12E,14)-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 18)

(8E,12E,14)-,16,21-Tris(1-Ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (25.1 mg, 30.0 mmol) was dissolved in a mixed solution (1:1) of tetrahydrofuran and 2-methyl-1-propanol (1 ml). To the reaction mixture at room temperature was added p-toluensulfonate pyridinium (23,7 mg, 94,3 Microm). The reaction mixture was stirred at the same temperature in a period of 24.5 hours and then added p-toluensulfonate pyridinium (8,7 mg, 34.6 mmol). The reaction mixture was stirred for 4.5 hours. The reaction mixture was diluted with ethyl acetate (30 ml) and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate (6 ml) and purified water (6 ml) twice and a saturated salt solution (6 ml). The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained concentrate was purified by thin-layer chromatography (Fuji Silysia NH Silica gel plate, chloroform:methanol=40:1) to obtain specified in the connection header (12,2 mg and 19.6 mmol, 65,3%) as a colourless oil.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=6.6 Hz), of 0.93 (3H, t, J=7,3 Hz), 0,99 (3H, d, J=6.6 Hz), 1,19-of 1.37 (3H, m)of 1.33 (3H, s), 1,40-of 1.65 (4H, m), of 1.65 (1H, DD, J=5,5, and 14.3 Hz), to 1.77 (3H, d, J=0.7 Hz), to 1.86 (1H, DD, J=5,5, and 14.3 Hz), 1,89-of 1.97 (1H, m)to 2.29 (3H, s), 2,35 at 2.45 (5H, m), 2,53-2,60 (1H, m), of 2.56 (1H, DD, J=3,7, a 13.9 Hz), to 2.66 (1H, DD, J=2,2, 8.1 Hz), is 2.88 (1H, dt, J=2,2, 5,5 Hz), 3,42-of 3.54 (5H, m), 3,74-3,81 (1H, m), 4,79 (1H, DD, J=9,2, 9,2 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,44 (1H, DD, J=8,8, 15,0 Hz), of 5.50 (1H, DD, J=9,2, 15,0 Hz), 5,86 (1H, d, J=15,0 Hz), 6,12 (1H, d, J=11,0 Hz), 6,52 (1H, DD, J=11,0, 15,0 Hz). ESI-MS m/z 621 (M+H)⁺.

Example 19

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazine-1-yl)carbonyl)oxy-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 18.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), 0,98-of 1.03 (3H, m), 1,20 by 1.68 (8H, m)of 1.33 (3H, s), 1.77 in (3H, s), 1,83-to 1.98 (4H, m), of 2.34 (3H, s), 2,42 (1H, DD, J=5,5, to 13.9 Hz), 2,50-of 2.66 (6H, m)to 2.66 (1H, DD, J=2,2, 7,7 Hz), 2,89 (1H, DD, J=2,2, 6.2 Hz), 3,44-3,59 (5H, m), 3,74-of 3.80 (1H, m), 4,80 (1H, DD, J=9,2, 9,2 Hz), 5,02 (1H, d, J=a 10.6 Hz), 5,44 (1H, DD, J=9,2, 15,0 Hz), of 5.50 (1H, DD, J=9,2, 15,0 Hz), 5,86 (1H, d, J=15,0 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=11,0, 15,0 Hz). ESI-MS m/z 635 (M+H)⁺.

Example 20

(8E,12E,14)-7-(N-(2-(N',N'-diethylamino)ethyl-N-methyl)carbanilate)-3,16,21-trihydroxy-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 by a method similar to that described in example 18.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=8,1 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), 0,98-1,11 (9H, m), 1,19 by 1.68 (8H, m)of 1.33 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,5, and 14.3 Hz), 1,88-to 1.98 (1H, m), 2,42 (1H, DD, J=5,5, and 14.3 Hz), of 2.51 2.63 in (8H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,87-2,95 (4H, m), 3,30-3,39 (2H, m), 3,52 (1H, dt, J=4,4, 8,8 Hz), 3,74-3,82 (1H, m), 4,80 (1H, DD, J=9,2, 9,2 Hz), 5,01 1H, d, J=a 10.6 Hz), 5,44 (1H, DD, J=9,2, 15,0 Hz), of 5.50 (1H, DD, J=9,2, 15,0 Hz), 5,86 (1H, d, J=15,4 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 651 (M+H)⁺.

Example 21

(8E,12E,14)-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 21)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 18.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7,3 Hz)of 0.93 (3H, t, J=7,3 Hz), 0,99 (3H, d, J=6.6 Hz), 1,19-1,67 (16H, m)of 1.33 (3H, s), 1.77 in (3H, s), 1,82-of 1.97 (4H, m), 2,42 (1H, DD, J=5,5, and 14.3 Hz), 2,42-2,61 (7H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,69-of 2.86 (2H, m), is 2.88 (1H, dt, J=2,2, 5,9 Hz), 3,52 (1H, dt, J=4,8, and 8.4 Hz), to 3.73-3,81 (1H, m), 4,12-4,22 (2H, m), of 4.77 (1H, DD, J=9,2, 9,2 Hz), 5,01 (1H, d, J=a 10.6 Hz), 5,43 (1H, DD, J=9,2, 15,0 Hz), 5,49 (1H, DD, J=9,2, 15,0 Hz), 5,86 (1H, d, J=15,0 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 689 (M+H)⁺.

Example 22

(8E,12E,14)-7-(N-(2-(N',N'-diethylamino)ethyl)carbanilate)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 22)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 18.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,3 Hz)to 0.89 (3H, d, J=7,3 Hz)of 0.93 (3H, t, J=7,3 Hz), 0,99 (3H, d, J=7,0 Hz)of 1.05 (6H, t, J=7.0 Hz), 1,19-of 1.65 (7H, m)of 1.33 (3H, s), of 1.65 (1H, DD, J=5,5, 13,9 Hz)of 1.76 (3H, what), 1,80-1,90 (1H, m)to 1.86 (1H, DD, J=5,5, to 13.9 Hz), 2,42 (1H, DD, J=5,1, to 13.9 Hz), of 2.51 at 2.59 (4H, m), 2,58 (4H, q, J=7.0 Hz), to 2.66 (1H, DD, J=2,2, 7,7 Hz), 2,89 (1H, dt, J=2,2, 5,5 Hz), 3,15-3,20 (2H, m), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), 3.72 points-of 3.80 (1H, m), 4,74 (1H, DD, J=a 9.5, 9.5 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,41 (1H, DD, J=9,2, 15,0 Hz), of 5.48 (1H, DD, J=9,5, 15,0 Hz), 5,86 (1H, d, J=15,4 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 637 (M+H)⁺.

Example 23

(8E,12E,14)-7-((4-(2,2-dimethylpropyl)piperazine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 23)

Example 23-1 stage

(1) (8E,12E,14)-7-acetoxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-old

A solution of (8E,12E,14)-7-acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (54 mg, 0.1 mmol), 4-dimethylaminopyridine (124 mg, 1 mmol) and triethylamine (102 mg, 1 mmol) in methylene chloride (2.5 ml) was cooled to 5°C. To the reaction mixture was added dropwise a solution of triethylsilane (152 mg, 1 mmol) in methylene chloride (0.5 ml) and then the reaction mixture was stirred at room temperature during the night. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with water. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Receiving the hydrated residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-50 μm; ethyl acetate:hexane=1:19→1:14) to obtain specified in the connection header (77,1 mg, 88%) as a colourless oil.

ESI-MS m/z 901 (M+Na)⁺.

Example 23-2 stage

(2) (8E,12E,14)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-old

(8E,12E,14)-7-Acetoxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-old (77 mg, 0,0875 mmol) was dissolved in methanol (2 ml). To the resulting methanol solution was added potassium carbonate (36,5 mg, 0,262 mmol) and methanol (1 ml) and the reaction mixture was stirred at room temperature for four hours. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate:hexane=1:9→1:6→1:4→1:3) to obtain specified in the connection header (38,6 mg, 50%) as a colourless oil.

ESI-MS m/z 859 (M+Na)⁺.

Example 23-3 stage

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

A solution of (8E,12E,14 the)-7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (38,6 mg, 0.046 mmol), 4-dimethylaminopyridine (26 mg, 0,207 mmol) and triethylamine (28 mg, 0.276 mmol) in methylene chloride (2 ml) was cooled to 5°C. To the reaction mixture was added a solution of 4-nitrophenylphosphate (29 mg, was 0.138 mmol) in methylene chloride (1 ml) and the reaction mixture was stirred at 5°C for one hour. The reaction mixture was diluted with ethyl acetate and then the organic layer was 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, dried over anhydrous magnesium sulfate and filtered. Then the filtrate was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate:hexane=1:14) to obtain specified in the connection header (46,1 mg, 100%) as a pale yellow oil.

ESI-MS m/z 1024 (M+Na)⁺.

Example 23-4 stage

(4) (8E,12E,14)-7-((4-(2,2-dimethylpropyl)piperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-old

A solution of 1-(2,2-dimethylpropyl)piperidineacetate (12 mg, 20 μmol) and triethylamine (10 mg, 0.1 mmol) in tetrahydrofuran (0.7 ml) was added dropwise to a solution of (8E,12E,14)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,16,tis(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (10 mg, 10 mmol) in tetrahydrofuran (0.5 ml) and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with an aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography (Merck, Art 1,05628; ethyl acetate-hexane, 1:6) to obtain the specified title compound (9.7 mg, 95%) as a colourless oil.

ESI-MS m/z 1019 (M+N)⁺.

Example 23-5 stage

(5) (8E,12E,14)-7-((4-(2,2-dimethylpropyl)piperazine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 23)

A solution of (8E,12E,14)-7-((4-(2,2-dimethylpropyl)piperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (9.7 mg, 9.5 μmol) in tetrahydrofuran (1 ml) was cooled to 5°C. To the reaction mixture was added dropwise tetrabutylammonium (1.0m solution in tetrahydrofuran, 31 μl, 31 mmol) and the reaction mixture was stirred at room temperature within two hours. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with an aqueous solution of sodium bicarbonate. Organic is Loy was dried over anhydrous magnesium sulfate, was filtered and concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel plate, methanol-methylene chloride, 1:49) to obtain the specified title compound (6.3 mg, 98%) as a colourless oil.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.85 to 0.92 (15H, m)to 0.94 (3H, t, J=7,6 Hz), 0,99 (3H, d, J=6.8 Hz), 1,19-1,69 (11H, m), 1.77 in (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 1,87-of 1.97 (1H, m), is 2.09 (2H, s), 2,38-2,61 (7H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,34-to 3.52 (4H, m), 3,52 (1H, TD, J=4,4, 7,6 Hz), 3,74-3,81 (1H, m), 4.75 V-4,82 (1H, m), free 5.01 (1H, d, J=10,8 Hz), 5,43 (1H, DD, J=8,8, 14,8 Hz), of 5.50 (1H, DD, J=9,2, 14,8 Hz), 5,86 (1H, d, J=15.2 Hz), 6,12 (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 24

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

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 23.

¹H-NMR (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), and 1.00 (3H, d, J=6.8 Hz), is 1.11 (3H, t, J=7.2 Hz), 1,19-1,70 (11H, m), 1.77 in (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 1,88 of 1.99 (1H, m), of 2.38-2.49 USD (7H, m), of 2.51-2,61 (2H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,40 is 3.57 (5H, m), 3,74-3,82 (1H, m), 4,76 of 4.83 (1H, m), free 5.01 (1H, d, J=10,8 Hz), 5,44 (1H, DD, J=8,8, 15.2 Hz), the 5.51 (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), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 635 (M+H) .

Example 25

(8E,12E,14)-7-((4-(N,N-dimethylamino)piperidine-1-yl)carbonyl)oxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-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 23.

¹H-NMR (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), and 1.00 (3H, d, J=6.8 Hz), 1,19-1,70 (13H, m), 1.77 in (3H, d, J=0.8 Hz), 1,82 of 1.99 (4H, m), of 2.28 (6H, s), 2,32-the 2.46 (2H, m), 2,50-2,62 (2H, m)to 2.67 (1H, DD, J=2,4, a 7.6 Hz), 2,68-is 2.88 (2H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,52 (1H, TD, J=4,4, 8.0 Hz), 3,74-3,82 (1H, m), 4,11-is 4.21 (2H, m), 4.75 V-4,82 (1H, m), 5,02 (1H, d, J=10,8 Hz), 5,44 (1H, DD, J=8,8, 15.2 Hz), of 5.50 (1H, DD, J=9,2, 14,8 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 649 (M+H)⁺.

Example 26

(8E,12E,14)-7-(N-(3-(N',N'-dimethylamino)propyl)carbanilate)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 26)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 18.

¹H-NMR (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=7.4 Hz), and 1.00 (3H, d, J=6.4 Hz), 1,19-1,71 (10H, m)of 1.34 (3H, s), 1.77 in (3H, s), 1,82-1,90 (2H, m), 2,24 (6H, s), of 2.34 (2H, t, J=7,6 Hz), 2,42 (1H, DD, J=5,4, of 14.2 Hz), 2,50-2,60 (2H, m)to 2.66 (1H, DD, J=2,2, 7,8 Hz), 2,89 (1H, dt, J=2,2, 5.6 Hz), 3,10 (2H, t, J=6.8 Hz), 3,48-3,55 (1H, m), 3.72 points-is 3.82 (1H, m), 4,74 (1H, DD, J=94, 9.4 Hz), 5,02 (1H, d, J=10,8 Hz), lower than the 5.37-of 5.53 (2H, m), 5,86 (1H, d, J=15.2 Hz), 6,12 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 623 (M+H)⁺.

Example 27

(8E,12E,14)-7-(N-(3-(N',N'-dimethylamino)propyl)-N-methylcarbamoyl)-3,16,21-trihydroxy-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 18.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=7,2 Hz)to 0.89 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.4 Hz), a 1.01 (3H, d, J=6.4 Hz), 1,19-1,79 (10H, m)of 1.34 (3H, s), 1.77 in (3H, s), 1,82-to 1.98 (2H, m), and 2.26 (6H, s), 2,28-is 2.37 (2H, m), 2,42 (1H, DD, J=5,2, of 14.0 Hz), of 2.51 at 2.59 (2H, m)to 2.66 (1H, DD, J=2,2, 7,8 Hz), 2,83-to 2.94 (4H, m), 3,22-3,37 (2H, overlapped CD₃OD), 3,48-3,55 (1H, m), 3,74-3,82 (1H, m), 4,70-4,96 (1H, overlapped, H₂O)5,02 (1H, d, J=10,8 Hz), 5.40 to-of 5.55 (2H, m), 5,86 (1H, d, J=15.6 Hz), 6,12 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 637 (M+H)⁺.

Example 28

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(piperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 28)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 18.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=6.6 Hz), of 0.93 (3H, t, J=7,3 Hz), 0,99 (3H, d, J=7,2 Hz), 1,19-of 1.37 (3H, m)of 1.33 (3H, s), 1,40-and 1.54 (2H, m), 1,54 by 1.68 (3H, m)of 1.75 (3H, ), 1,82-to 1.98 (2H, m), 2,35 is 2.46 (1H, m), 2,48-260 (2H, m), 2,62 of 2.68 (1H, m), 2,68 is 2.80 (4H, m), 2,82 of 2.92 (1H, m), 3,34-of 3.54 (5H, m), 3.72 points-is 3.82 (1H, m), 4,74 to 4.92 (1H, overlapped, H₂About), free 5.01 (1H, d, J=10.4 Hz), 5,34 is 5.54 (2H, m), 5,86 (1H, d, J=15,0 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 607 (M+H)⁺.

Example 29

(8E,12E,14)-3,16,21-trihydroxy-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 29)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 18.

¹H-NMR (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=7,6 Hz), 0,99 (3H, d, J=6.8 Hz), 1.00 m of-1.04 (1H, m), 1,19-1,68 (11H, m)of 1.33 (3H, s), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, (14,0 Hz), 1,90-to 1.98 (1H, m), 2,04-of 2.16 (2H, m), of 2.28 (3H, s), 2,42-2,60 (3H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), and 2.79 (3H, s), 2,84 are 2.98 (3H, m), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), 3.72 points-of 3.80 (1H, m), 3,82-3,98 (1H, m), 4,76 to 4.92 (1H, overlapped, H₂About), free 5.01 (1H, d, J=10.4 Hz), 5,44 (1H, DD, J=9,2, 15.2 Hz), of 5.50 (1H, DD, J=9,2, 15.2 Hz), 5,86 (1H, d, J=15.2 Hz), 6,12 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 649 (M+H)⁺.

Example 30

(8E,12E,14)-3,16,21-trihydroxy-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 30)

Example 30-1 stage

(1) (8E,12E,14)-7-acetoxy-3,21-bis(diethylazodicarboxylate)-16-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old

A solution of (8E,12E,14)-7-acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (177 mg, 0.33 mmol) and imidazole (450 mg, of 6.61 mmol) in methylene chloride (6 ml) was cooled to 5°C. To the reaction mixture was added dropwise a solution of diethylazodicarboxylate (272 mg, of 1.65 mmol) in methylene chloride (1.5 ml) and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with water. The obtained organic layer was washed with saturated salt solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=1:19→1:9→1:6→1:4) to obtain specified in the connection header (242,9 mg, 93%) as a colourless oil.

ESI-MS m/z 815(M+Na)⁺.

Example 30-2 stage

(2) (8E,12E,14)-3,21-bis(diethylazodicarboxylate)-7,16-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old

0,2M Solution of guanidine/guanidine nitrate (mixture of methanol-methylene chloride, 9:1) (3,9 ml, 0.78 mmol) was added to (8E,12E,14)-7-acetoxy-3,21-bis(diethylazodicarboxylate)-16-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (307 mg, 0,3868 mmol) and reactio the ing the mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with an aqueous solution of ammonium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:4) to obtain specified in the connection header (to 271.5 mg, 93%) as a colourless oil.

ESI-MS m/z 773 (M+Na)⁺.

Example 30-3 stage

(3) (8E,12E,14)-3,21-bis(diethylazodicarboxylate)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-18,19-epoxydecane-8,12,14-trien-11-old

A solution of (8E,12E,14)-3,21-bis(diethylazodicarboxylate)-7,16-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (271 mg, 0,3605 mmol), 4-dimethylaminopyridine (22 mg, 0.18 mmol) and triethylamine (369 mg, 3.61 mmol) in methylene chloride (5 ml) was cooled to 5°C. To the solution was added dropwise a solution of 4-nitrophenylphosphate (374 mg, 1.8 mmol) in methylene chloride (3 ml) and the reaction mixture was stirred when 5-10°C for one hour. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with an aqueous solution of sodium bicarbonate. The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and which has centriole under reduced pressure. 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→1:6) to obtain specified in the connection header (319,6 mg, 97%) as a pale yellow oil.

ESI-MS m/z 938 (M+Na)⁺.

Example 30-4 stage

(4) (8E,12E,14)-3,21-bis(diethylazodicarboxylate)-16-hydroxy-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-old

A solution of 1-(4-methylpiperidin-1-yl)piperazine (11.7 mg, 63.3 mmol) in tetrahydrofuran (1 ml) and triethylamine (13 mg, to 0.127 mmol) was added dropwise to a solution of (8E,12E,14)-3,21-bis(diethylazodicarboxylate)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-18,19-epoxydecane-8,12,14-trien-11-olide (29 mg, of 31.6 mmol) in tetrahydrofuran (2 ml) and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with an aqueous solution of sodium bicarbonate. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel plate; ethyl acetate-hexane, 9:1) to obtain the specified title compound (18.5 mg, 61%) as a colourless oil.

When the EP 30-5 stage

(5) (8E,12E,14)-3,16,21-trihydroxy-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 30)

A solution of (8E,12E,14)-3,21-bis(diethylazodicarboxylate)-16-hydroxy-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-olide (18.5 mg, 19.2 μmol) in tetrahydrofuran (2 ml) was cooled to 5°C. To the solution was added dropwise tetrabutylammonium (1.0m solution in tetrahydrofuran, of 42.3 μl, of 42.3 μmol) and the reaction mixture was stirred at room temperature for four hours. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with an aqueous solution of sodium bicarbonate. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography (Fuji Silysia NH Silica gel plate; methanol-dichloromethane, 1:24) to obtain specified in the connection header (7,6 mg, 56%) as a colourless oil.

¹H-NMR (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), and 1.00 (3H, d, J=6.8 Hz), 1,19-1,69 (13H, m), 1.77 in (3H, s), 1,82-of 1.97 (4H, m), 1,98 e 2.06 (2H, m), of 2.25 (3H, ), 2,24 of-2.32 (1H, m), 2,42 (1H, DD, J=5,2, of 14.0 Hz), 2,48-2,60 (6H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,87-2,95 (3H, m), 3,38-3,55 (5H, m), 3,74-3,81 (1H, m), 4.75 V-4,82 (1H, m), 501 (1H, d, J=10.4 Hz), 5,44 (1H, DD, J=8,8, 14,8 Hz), of 5.50 (1H, DD, J=9,2, 14,8 Hz), 5,86 (1H, d, J=15.2 Hz), 6,12 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 704 (M+H)⁺.

Example 31

(8E,12E,14)-7-((4-(2-cyanoethyl)piperazine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-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 18.

¹H-NMR (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), and 1.00 (3H, d, J=6.8 Hz), 1,19-1,69 (11H, m), 1.77 in (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 1,88-1,98 (1H, m), 2,38 is 2.51 (5H, m), 2,52-2,60 (2H, m), 2,61-2,70 (5H, m), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,40 of 3.56 (5H, m), 3,74-3,81 (1H, m), 4,76-4,82 (1H, m), free 5.01 (1H, d, J=10.4 Hz), J=5,44 (1H, DD, J=8,8, 14,8 Hz), of 5.50 (1H, DD, J=9,2, 14,8 Hz), 5,86 (1H, d, J=15.2 Hz), 6,12 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 660 (M+H)⁺, 682 (M+Na)⁺.

Example 32

(8E,12E,14)-3,16,21-trihydroxy-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 32)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 30.

¹H-NMR (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), 0,97-of 1.07 (3H, m), 1,19-2,03 (25H, m), 2,38-2,69 (10H, m), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,30 is 3.40 (1H, blocked by D ₃OD), 3,52 (1H, TD, J=a 4.4, and 8.4 Hz), to 3.73-3,81 (1H, m), 3,89-to 3.99 (1H, m), 4,74-a 4.86 (1H, overlapped, H₂O)5,02 (1H, d, J=10,8 Hz), 5.40 to-of 5.55 (2H, m), 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 33

(8E,12E,14)-7-((4-(2-(N,N-dimethylamino)ethyl)piperazine-1-yl)carbonyl)oxy)-3,16,21-trihydroxy-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 30.

¹H-NMR (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), and 1.00 (3H, d, J=6.8 Hz), 1,19-1,69 (11H, m), 1.77 in (3H, d, J=0.8 Hz), to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 1,88-1,98 (1H, m), of 2.28 (6H, s), 2,39-2,49 (5H, m), 2,49-2,61 (6H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,89 (1H, dt, J=2.0 a, 6,0 Hz), 3,40 of 3.56 (5H, m), 3.75 to-3,81 (1H, m), 4,75 of 4.83 (1H, m), 5,02 (1H, d, J=10,8 Hz), 5,44 (1H, DD, J=8,8, 14,8 Hz), of 5.50 (1H, DD, J=9,2, 14,8 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 678 (M+H)⁺.

Example 34

(8E,12E,14)-7-((4-benzylpiperazine-1-yl)carbonyl)oxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 34)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 18.

¹H-NMR (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=7.2 Hz), 0,99 (3H, d, J=7,2 Hz), 1,14-of 1.32 (3H, m), 34 (3H, C), 1,36 is 1.70 (5H, m), 1.77 in (3H, d, J=1.2 Hz), 1,78 is 1.96 (2H, m), a 2.36-2,48 (5H, m), 2,52-2,60 (2H, m)to 2.67 (1H, DD, J=2,4, 10.4 Hz), 2,89 (1H, dt, J=1,6, 5,2 Hz), 3,41-to 3.58 (7H, m), 3,74-3,82 (1H, m), 4,78 (1H, DD, J=9,0, 9.0 Hz), free 5.01 (1H, d, J=10.4 Hz), 5,44 is 5.54 (2H, m), by 5.87 (1H, d, J=15.2 Hz), 6,12 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz), 7,22-7,38 (5H, m); ESI-MS m/z 697 (M+H)⁺.

Example 35

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(1-methylpiperidin-4-yl)carbanilate)-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 18.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=7,2 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), 0,99 (3H, d, J=6.8 Hz), 1,20-of 1.32 (3H, m)of 1.34 (3H, s), 1,36-1,72 (5H, m), 1.77 in (3H, d, J=1.2 Hz), 1,80-1,90 (6H, m), 2,04-to 2.18 (2H, m), and 2.26 (3H, s), 2,42 (1H, DD, J=5,6, or 14.8 Hz), of 2.51 at 2.59 (2H, m)to 2.67 (1H, DD, J=2,4, 8.0 Hz), 2,78-of 2.86 (2H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,35 is 3.40 (1H, m), 3,48-of 3.54 (1H, m), 3,74-of 3.80 (1H, m), 4,70-rate 4.79 (1H, m), free 5.01 (1H, d, J=10,8 Hz), 5,38-5,42 (2H, m), 5,86 (1H, d, J=15.6 Hz), 6,12 (1H, d, J=11.2 Hz), of 6.52 (1H, DD, J=11,2, 15.2 Hz); ESI-MS m/z 635 (M+H)⁺.

Example 36

(8E,12E,14)-3,16,21-trihydroxy-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 36)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 18.

¹H-NMR (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), a 1.01 (3H, d, J=6.8 Hz), 1,20-of 1.32 (3H, m)of 1.34 (3H, s), 1,35 is 1.70 (5H, m), 1.77 in (3H, s), 1,82 is 2.01 (2H, m), 2,43 (1H, DD, J=5,2, of 14.0 Hz), of 2.51-2,62 (2H, m)to 2.66 (1H, DD, J=2,0, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,38-of 3.48 (4H, m), 3,49-3,55 (1H, m), 3,56-3,66 (4H, m), 3,74-3,82 (1H, m), 4.80 to to 4.92 (1H, overlapped, H₂O)5,02 (1H, J=10,8 Hz), 5.40 to-to 5.56 (2H, m), by 5.87 (1H, d, J=14,8 Hz), 6,13 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz), 6,86 (2H, d, J=6,4 Hz)to 8.12 (2H, d, J=6.4 Hz); ESI-MS m/z 684 (M+H)⁺.

Example 37

(8E,12E,14)-7-((4-cyclohexylpiperazine-1-yl)carbonyl)oxy)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-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 18.

¹H-NMR (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=7.4 Hz), and 1.00 (3H, d, J=6.4 Hz), 1,08-of 1.41 (8H, m)of 1.34 (3H, s), 1.41 to to 1.70 (6H, m), 1.70 to to 1.98 (6H, m), 1.77 in (3H, in ), 2.25 to 2.35 (1H, m), 2,42 (1H, DD, J=5,4, of 14.2 Hz), 2,50-2,63 (6H, m)to 2.66 (1H, DD, J=2,2, 7,8 Hz), 2,89 (1H, dt, J=2,2, 5.6 Hz), 3,37-3,55 (5H, m), 3,74-3,82 (1H, m), 4.75 V-4,82 (1H, m), 5,02 (1H, d, J=10,8 Hz), 5,40 is 5.54 (2H, m), 5,86 (1H, d, J=15.2 Hz), 6,12 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 689 (M+H)⁺.

Example 38

(8E,12E,14)-3,16,21-trihydroxy-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 38)

Specified in the title compound (colorless m is slo) was synthesized by the method similar to that described in example 18.

¹H-NMR (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=7.4 Hz), and 1.00 (3H, d, J=6.4 Hz), 1,20-1,98 (14H, m)of 1.34 (3H, s), 1.77 in (3H, s), 2,38-2,62 (8H, m)to 2.66 (1H, DD, J=2,2, 7,8 Hz), 2,89 (1H, dt, J=2,2, 5.6 Hz), 3,37-3,56 (7H, m), 3,74-3,82 (1H, m), 3,94-was 4.02 (2H, m), 4,76-4,82 (1H, m), 5,02 (1H, d, J=10.4 Hz), 5.40 to is 5.54 (2H, m), 5,86 (1H, d, J=15.2 Hz), 6,12 (1H, d, J=10.0 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 691 (M+H)⁺.

Example 39

(8E,12E,14)-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-OLED (compound 39)

(8E,12E,14)-3,21-bis(diethylazodicarboxylate)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-18,19-epoxydecane-8,12,14-trien-11-old (31 mg, 0,034 mmol)obtained in example 30-3 stage, was dissolved in tetrahydrofuran (2 ml). Then to the mixture was added 1-isopropylpiperazine (9.7 mg, 0,068 mmol) and triethylamine (10.3 mg, 0.10 mmol) and the reaction mixture was stirred in nitrogen atmosphere at room temperature for two hours. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with an aqueous solution of sodium bicarbonate and a saturated solution of salt. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified column chromatography on Sealy is agile (Fuji Silysia NH Silica gel; the ethyl acetate-hexane, 20:80 →25:75) to obtain (8E,12E,14)-3,21-bis(diethylazodicarboxylate)-16-hydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (26 mg, 0,028 mmol). ESI-MS m/z 919(M+N)⁺.

The resulting product (25 mg, or 0.027 mmol) was dissolved in tetrahydrofuran (1 ml) and to the mixture was added dropwise tetrabutylammonium (1.0m solution in tetrahydrofuran, of 0.081 ml, of 0.081 mmol). The reaction mixture was stirred in nitrogen atmosphere at room temperature for two hours. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with an aqueous solution of sodium bicarbonate and a saturated solution of salt. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Fuji Silysia NH Silica gel; methylene chloride-methanol, 100:0.5 to→100:2) to obtain the specified title compound (14.6 mg) as a colourless oil.

¹H-NMR (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=7.4 Hz), 0,99-of 1.05 (9H, m), 1,16-a 2.00 (12H, m)of 1.34 (3H, s), 1.77 in (3H, s), 2,42 (1H, DD, J=5,2, of 14.0 Hz), 2,48 was 2.76 (7H, m), 2,84 are 2.98 (2H, m), 3,38-to 3.58 (5H, m), 3,74-3,82 (1H, m), 4,76-4,91 (1H, m), 5,02 (1H, d, J=10,8 Hz), 5.40 to-to 5.56 (2H, m), 5,86 (1H, d, J=15.2 Hz), 6,12 (1H, d, J=10.0 Hz), of 6.52 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 663 (M+H)⁺.

Example 40

(8E,12E,14)-3,16,21-trihydroxy-7-(1-(4-(4-hydroxypiperidine-1-yl)piperidine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 40)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 30.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=6,8 Hz)to 0.89 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.4 Hz), 0,99 (3H, d, J=6.4 Hz), 1,20-1,70 (12H, m)of 1.34 (3H, s), 1.77 in (3H, s), 1,82-to 1.98 (6H, m), 2,29-of 2.38 (2H, m,), 2,38-2,60 (4H, m)to 2.66 (1H, DD, J=7,6, 2.0 Hz), 2,70-only 2.91 (5H, m), 3,49-3,55 (1H, m), 3,55-of 3.64 (1H, m), 3,74-3,81 (1H, m), 4,11-4,20 (2H, m), 4.75 V-to 4.81 (1H, m), 5,02 (1H, d, J=10,8 Hz), 5.40 to is 5.54 (2H, m), 5,86 (1H, d, J=15.2 Hz), 6,12 (1H, d, J=10,8 Hz), of 6.52 (1H, DD, J=11,2, the 15.6 Hz); ESI-MS m/z 705 (M+H)⁺.

Example 41

(8E,12E,14)-3,16,21-trihydroxy-7-((4-(2-hydroxyethyl)piperazine-1-yl)carbonyl)oxy-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 18.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=6.0 Hz), to 0.89 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,3 Hz), 0,99 (3H, d, J=6.8 Hz), 1.18 to 1.69 in (11H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,6, of 14.0 Hz), 1,88-to 1.98 (1H, m), 2,35-2,61 (9H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,82 of 2.92 (1H, m), 3,38-3,55 (5H, m), 3,60-of 3.80 (3H, m), 4,70-a 4.86 (1H, overlapped, H₂About), free 5.01 (1H, d, J=10,8 Hz), 5,34 is 5.54 (2H, m), 5,86 (1H, d, J=15.2 Hz), 6,12 (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 42

(8E,12E,14)-3,16,21-trihydroxy-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 42)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 18.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,2 Hz)to 0.89 (3H, d, J=6.8 Hz), were 0.94 (3H, t, J=7,6 Hz), 0,99 (3H, d, J=7,2 Hz), 1,20-1,69 (13H, m), 1.77 in (3H, s), 1,82-to 1.98 (4H, m), 2,33 is 2.46 (3H, m), 2,50-2,60 (4H, m)to 2.66 (1H, DD, J=2,0, 8.0 Hz), 2,72-of 2.86 (1H, m), 2,89 (1H, dt, J=2,0, 6.4 Hz), 3,52 (1H, dt, J=4,0, 8.0 Hz), 3,68 (4H, DD, J=4,8, 4,8 Hz), to 3.73-3,82 (1H, m), 4.09 to is 4.21 (4H, m), 4,70-is 4.85 (1H, m), free 5.01 (1H, d, J=10,8 Hz), 5.40 to-of 5.55 (2H, m), 5,86 (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 691 (M+H)⁺.

Example 43

(8E,12E,14)-7-((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 43)

(8E,12E,14)-3,21-bis(diethylazodicarboxylate)-16-hydroxy-6,10,12,16,20-pentamethyl-7-((4-nitrophenoxy)carboxy)-18,19-epoxydecane-8,12,14-trien-11-old (40 mg, 0,044 mmol)obtained in example 30-3 stage, was dissolved in tetrahydrofuran (2 ml). Then to the mixture was added 1-acylhomoserine (11 mg, 0,088 mmol) and triethylamine (0,061 mg, 0.44 mmol) and the reaction mixture was stirred in nitrogen atmosphere at room temperature overnight. The reaction mixture once alali with ethyl acetate and then the organic layer was washed with water and saturated salt solution. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Kanto Silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:1 →methylene chloride-methanol, 1:9) to obtain (8E,12E,14)-3,21-bis(diethylazodicarboxylate)-7-((4-acylhomoserine-1-yl)carbonyl)oxy-16-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-olide (34 mg, of 0.038 mmol) as colourless oil.

The resulting product (34 mg, of 0.038 mmol) was dissolved in tetrahydrofuran (1 ml) and to the mixture was added dropwise tetrabutylammonium (1.0m solution in tetrahydrofuran, 0,187 ml, 0,187 mmol). The reaction mixture was stirred in nitrogen atmosphere at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate and then the organic layer was washed with an aqueous solution of sodium bicarbonate and a saturated solution of salt. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (Kanto silica gel 60N, 40 to 50 μm; methylene chloride-methanol, 100:1,5→methylene chloride-methanol-28% aqueous solution of ammonium hydroxide, 100:5:1) to obtain specified in the connection header (23,3 mg) as a colourless oil.

¹H-NMR (CD_{3 OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=7,2 Hz)to 0.89 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.2 Hz), a 1.01 (3H, d, J=6,8 Hz)of 1.09 (3H, t, J=7.2 Hz), 1,20-1,69 (11H, m), 1.77 in (3H, s), 1,82-1,90 (3H, m), 1,90-to 1.98 (1H, m), 2,42 (1H, DD, J=5,2, of 14.0 Hz), 2,52-2,72 (9H, m), 2,89 (1H, dt, J=2,4, 6.4 Hz), 3,42-of 3.60 (5H, m), 3.75 to 3,82 (1H, m), 4,70-of 4.90 (1H, overlapped, H2O)5,02 (1H, d, J=10,8 Hz), 5.40 to-of 5.55 (2H, m), 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 649 (M+H)⁺.}

Example 44

(8E,12E,14)-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-OLED (compound 44)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 30.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,88 (3H, d, J=6,4 Hz)to 0.89 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,6 Hz), and 1.00 (3H, d, J=6,8 Hz)of 1.07 (6H, d, J=6.4 Hz), 1,20-1,69 (11H, m), 1.77 in (3H, Sirs), to 1.86 (1H, DD, J=5,2, 14,0 Hz), 1,89-to 1.98 (1H, m), 2,42 (1H, DD, J=5,2, of 14.0 Hz), 2,48-2,60 (6H, m)to 2.66 (1H, DD, J=2,4, 8.0 Hz), 2,67-2,78 (1H, m), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,40 is 3.57 (5H, m), 3,74-3,82 (1H, m), 4,77-4,91 (1H, overlapped, H₂About), free 5.01 (1H, d, J=10.4 Hz), 5.40 to-of 5.55 (2H, m), 5,86 (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 649 (M+H)⁺.

Example 45

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

Specified in the title compound (colorless oil) which was intesively way similar to that described in example 30.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,32-0,54 (4H, m)of 0.87 (3H, d, J=8.0 Hz), of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,2 Hz), and 1.00 (3H, d, J=6.0 Hz), 1,14-2,00 (19H, m), 2,42 (1H, DD, J=5,6, of 14.0 Hz), 2,42-2,62 (2H, m,), to 2.66 (1H, DD, J=2,0, 8.0 Hz), 2.70 height of 2.92 (5H, m), 3,37-to 3.58 (5H, m), 3,68-3,82 (1H, m), 4,77-4,91 (1H, overlapped, H₂O)5,0 (1H, d, J=10,8 Hz), 5,44-of 5.55 (2H, m), 5,86 (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 46

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

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 30.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,40-0,52 (4H, m)of 0.87 (3H, d, J=5.6 Hz), to 0.89 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7,2 Hz), and 0.98 (3H, d, J=6.0 Hz), 1,20-1,70 (12H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 1,89-to 1.98 (1H, m), 2,42 (1H, DD, J=5,6, of 14.0 Hz), 2,50-2,63 (6H, m)to 2.66 (1H, DD, J=2,0, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6,0 Hz), 3,36-to 3.49 (4H, m), 3,52 (1H, dt, J=4,8 and 7.6 Hz), 3,74-3,82 (1H, m), 4,77-of 4.90 (1H, overlapped, H₂About), free 5.01 (1H, d, J=10.4 Hz), 5,44-of 5.55 (2H, m), 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 647 (M+H)⁺, 670 (M+Na)⁺.

Example 47

(8E,12E,14)-3,16,21-trihydroxy-7-((N-(4-hydroxy-1-methylpiperidin-4-yl)methyl-N-methyl)carbanilate)-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 47)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 30.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,86 (3H, d, J=6,8 Hz)of 0.90 (3H, d, J=7,2 Hz), were 0.94 (3H, t, J=7.2 Hz), a 1.01 (3H, d, J=6.8 Hz), 1,20-1,70 (15H, m), 1.77 in (3H, s)to 1.86 (1H, DD, J=5,2, of 14.0 Hz), 1,89-to 1.98 (1H, m), 2,27 (1,5H, s), 2,28 (1,5H, s), 2,34 is 2.46 (3H, m), 2,50-of 2.64 (6H, m)to 2.66 (1H, DD, J=2,0, 8.0 Hz), 2,89 (1H, dt, J=2,4, 6.4 Hz), 3,0 (1,5H, C)3,02 (1,5H, s), 3,52 (1H, 10 dt, J=4,8, 8.0 Hz), 3,74-3,82 (1H, m), 4,74 to 4.92 (1H, overlapped, H₂About), free 5.01 (1H, d, J=10.4 Hz), 5.40 to-of 5.55 (2H, m), 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 679 (M+H)⁺.

Example 48

(8E,12E,14)-7-(((1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)carbonyl)oxy-3,16,21-trihydroxy-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 example 30.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): to 0.92 (3H, d, J=6.8 Hz), were 0.94 (3H, d, J=7,2 Hz), and 0.98 (3H, t, J=7.2 Hz), 1,03 (1,5H, d, J=6.8 Hz), 1.06 a (1,5H, d, J=6.8 Hz), 1,10-1,22 (3H, m), 1,22-of 1.75 (8H, m)to 1.38 (3H, ), 1,76-2,03 (4H, m), equal to 1.82 (3H, s), 2,47 (1H, DD, J=5,6, 14.4 Hz), 2,54-2,77 (6H, m), 2,83-to 2.99 (2H, m), 3,22-to 3.33 (1H, m), 3,53-3,63 (2H, m), the 3.65 (1H, Sirs), 3,79-3,88 (1H, m), 4,36 (0,5H, s), 4,39 (0,5H, ), 4,77-4,91 (1H, m), is 5.06 (1H, d, J=10.4 Hz), the 5.45 5,63 (2H, m), 5,91 (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 647 (M+H)⁺.

Example 49

(8E,12E,14)-3,16,21-trihydroxy-7-(((1S,4S)-5-isopropyl-2,5-is estabillo[2.2.1]heptane-2-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-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 example 30.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): to 0.92 (3H, d, J=7,6 Hz)to 0.94 (3H, d, J=7,2 Hz), and 0.98 (3H, t, J=7,6 Hz)1,03 (1,5H, d, J=7,2 Hz), 1,09-1,16 (6N, m), 1,21-of 1.75 (8H, m)to 1.38 (3H, s), 1.77 in-2,03 (4H, m), equal to 1.82 (3H with), 2,47 (1H, DD, J=5,6, 14.4 Hz), 2,52 is 2.75 (5H, m)to 2.94 (1H, dt, J=2.0 a, 6,0 Hz), 3,05-and 3.16 (1H, m), 3,21-to 3.34 (1H, m), 3,51-the 3.65 (2H, m), of 3.77-to 3.89 (2H, Sirs), 4,35 (0,5H, C)to 4.38 (0,5H, s), 4,79-4,91 (1H, m), is 5.06 (1H, d, J=10,8 Hz), the 5.45 5,61 (2H, m), 5,91 (1H, d, J=15.6 Hz), 6,17 (1H, d, J=10,8 Hz), to 6.57 (1H, DD, J=10,8, 15.2 Hz); ESI-MS m/z 661 (M+H)⁺.

Example 50

(8E,12E,14)-7-(N-(2-(N',N'-dimethylamino)ethyl)-N-methylcarbamoyl)-3,16,21-trihydroxy-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 example 23.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7,3 Hz)of 0.93 (3H, t, J=7,3 Hz), 1,01 (3H, sird, J=6.2 Hz), 1,19-1,68 (7H, m)of 1.33 (3H, s), of 1.65 (1H, DD, J=6,2, to 13.9 Hz), or 1.77 (3H, d, J=1,1 Hz), to 1.86 (1H, DD, J=6,2, to 13.9 Hz), 1,89-to 1.98 (1H, m), and 2.27 (6H, s), 2,42 (1H, DD, J=5,5, to 13.9 Hz), 2,45-2,60 (4H, m)to 2.66 (1H, DD, J=2,2, 7,7 Hz), 2,87 of 2.92 (4H, m), 3,37-of 3.42 (2H, m), 3,52 (1H, dt, J=4,8, 8,4 Hz), 3,74-3,81 (1H, m), 4,74-4,82 (1H, m), free 5.01 (1H, d, J=a 10.6 Hz), 5.40 to-of 5.53 (2H, m), 5,86 (1H, d, J=15,4 Hz), 6,12 (1H, DD, J=1,1, and 11.0 Hz), of 6.52 (1H, d, J=of 11.0 to 15.4 Hz); ESI-MS m/z 623 (M+H)⁺.

Example 51

(8E,12E,14)-7-(N-(2-(N',N'-what metilamino)ethyl)carbanilate)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-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 23.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,3 Hz)to 0.89 (3H, d, J=7,3 Hz)of 0.93 (3H, t, J=7,3 Hz), 0,99 (3H, d, J=6.6 Hz), 1,20-1,68 (7H, m)of 1.33 (3H, s), of 1.65 (1H, DD, J=6,2, to 13.9 Hz), 1.77 in (3H, s)and 1.83-at 1.91 (1H, m)to 1.86 (1H, DD, J=6,2, to 13.9 Hz in), 2.25 (6H, s), 2,39 is 2.46 (1H, m), 2,43 (2H, t, J=7.0 Hz), 2,52-2,60 (2H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,89 (1H, dt, J=2,2, 6.2 Hz), 3,21 (2H, t, J=7.0 Hz), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), to 3.73-3,81 (1H, m), 4,74 (1H, DD, J=a 9.5, 9.5 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,38-5,52 (2H, m), 5,86 (1H, d, J=15,0 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, d, J=of 11.0 to 15.0 Hz); ESI-MS m/z 609 (M+H)⁺.

Example 52

(8E,12E,14)-3,16,21-trihydroxy-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 52)

(1) (8E,12E,14)-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(morpholine-4-yl)ethyl)carbanilate)-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 52-1)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 23.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.625 (6H, q, J=8.1 Hz), 0,634 (6H, q, J=8,1 Hz)of 0.65 (6H, q, J=8.1 Hz), or 0.83 (3H, t, J=7,3 Hz)to 0.85 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7,0 Hz), 0,93-1,01 (N, m), 1,15-1,32 (2H, m), 1,39-to 1.63 (6H, m)of 1.42 (3H, s)of 1.75 (3H, s), 1,83-of 1.92 (1H, m)of 1.93 (1H, DD, J=4,8, a 13.9 Hz), 2,33 (1H, DD, J=6,2, 1,6 Hz), 2,44-2,60 (8H, m), 2,61 (1H, DD, J=2,2, 8.1 Hz), 2,85-2,90 (1H, t), of 2.92 (3H, s), 3,38-to 3.49 (2H, t), 3,61-and 3.72 (4H, m), 3,74 (1H, dt, J=3,7, 6,6 H), 3,90-3,98 (1H, t), 4,72-to 4.81 (1H, t), is 4.93 (1H, d, J=10,6 Hz), 5,41-5,52 (2H, m), of 5.82 (1H, d, J=15,0 Hz), 6,12 (1H, d, J=11,0 Hz), 6,50 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 1008 (M+H)⁺.

(2) (8E,12E,14)-3,16,21-trihydroxy-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 52)

Remove the protective groups for hydroxyl groups in the compound 52-1 manner similar to that described in example 23, to obtain the specified title compound (colorless oil).

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), a 1.01 (3H, d, J=7,0 Hz), 1,19-of 1.65 (7H, m)of 1.33 (3H, s), of 1.65 (1H, DD, J=5,5, and 14.3 Hz), or 1.77 (3H, d, J=1,1 Hz), to 1.86 (1H, DD, J=5,5, and 14.3 Hz), 1,89-to 1.98 (1H, m), 2,42 (1H, DD, J=5,5, to 13.9 Hz), 2,42-2,61 (8H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,86-to 2.94 (1H, m), 2.91 in (3H, s), 3,34-of 3.48 (2H, m), 3,52 (1H, dt, J=4,8, 8,4 Hz), 3,63-3,71 (4H, m), 3,74-3,81 (1H, m), 4,74 of 4.83 (1H, m), free 5.01 (1H, d, J=a 10.6 Hz), 5,41 is 5.54 (2H, m), 5,86 (1H, d, J=15,0 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 665 (M+H)⁺.

Example 53

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(piperidine-1-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 53)

(1) (8E,12E,14)-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(piperidine-1-yl)ethyl)carbanilate)-3,16,21-Tris(triethylsilane)-18,19-apocriticus the -8,12,14-trien-11-OLED (connection 53-1)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 23.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,59-0,68 (18H, m)of 0.82 (3H, t, J=7,3 Hz)to 0.85 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7.0 Hz), 0.95 to-1,02 (N, m), 1,15-1,63 (14H, m)of 1.42 (3H, s)of 1.75 (3H, s), 1,83-of 1.92 (1H, m), 1.93 and (1H, DD, J=4,8, a 13.9 Hz), 2,32 (1H, DD, J=6,2, to 13.6 Hz), 2,41-2,59 (8H, m), 2,61 (1H, DD, J=2,2, 8.1 Hz), 2,85 of 2.92 (4H, m), 3,38-3,44 (2H, m), 3,74 (1H, dt, J=3.3, then a 7.0 Hz), 3,91-3,98 (1H, m), 4,71-4,80 (1H, m), is 4.93 (1H, d, J=a 10.6 Hz), 5.40 to-5,52 (2H, m), of 5.82 (1H, d, J=15,4 Hz), 6,11 (1H, d, J=11,0 Hz), 6,50 (1H, DD, J=of 11.0 to 15.4 Hz). ESI-MS m/z 1006 (M+H)⁺.

(2) (8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(piperidine-1-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 53)

Remove the protective groups for hydroxyl groups in the compound 53-1 manner similar to that described in example 23, to obtain the specified title compound (colorless oil).

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,7 Hz)to 0.89 (3H, d, J=7,3 Hz)of 0.93 (3H, t, J=7,3 Hz), 1,01 (3H, sird, J=6.2 Hz), 1,19-1,68 (14H, m)of 1.33 (3H, s), 1.77 in (3H, d, J=1.1 Hz), to 1.86 (1H, DD, J=5,5, 14,3 Hz), 1,89-of 1.97 (1H, m), 2,39-2,60 (9H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,86-of 2.93 (1H, m), 2,90 (3H, s), 3,36-of 3.46 (2H, m), 3,52 (1H, dt, J=4,8, and 8.4 Hz), 3,74-3,81 (1H, m), 4,74-4,82 (1H, m), free 5.01 (1H, d, J=a 10.6 Hz), 5,41-of 5.53 (2H, m), 5,86 (1H, d, J=15,4 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 663 (M+H)⁺.

Example 54

(8E,12E,14)-3,16,21-trihydroxy,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 54)

(1) (8E,12E,14)-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(pyrrolidin-1-yl)ethyl)carbanilate)-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 54-1)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 23.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,59-0,68 (18H, m)of 0.82 (3H, t, J=7,3 Hz)to 0.85 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7.0 Hz), 0.95 to-1,02 (N, m)of 1.15 to 1.31 (2H, m)of 1.42 (3H, s), 1,39-1,63 (6N, m)of 1.75 (3H, d, J=0,7 Hz), 1,75-of 1.93 (5H, m)of 1.93 (1H, DD, J=4,8, a 13.9 Hz), 2,32 (1H, DD, J=6,2, to 13.6 Hz), 2,50-2,69 (9H, m), 2,85-of 2.93 (4H, m), 3,39-of 3.46 (2H, m), 3,74 (1H, dt, J=3,3, 6,6 Hz), 3,90-3,98 (1H, m), 4,71-4,80 (1H, m), is 4.93 (1H, d, J=a 10.6 Hz), 5.40 to-5,52 (2H, m), of 5.82 (1H, d, J=15,0 Hz), 6,12 (1H, d, J=11,0 Hz), 6,50 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 992 (M+H)⁺.

(2) (8E,12E,14)-3,16,21-trihydroxy-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 54)

Remove the protective groups for hydroxyl groups in the compound 54-1 manner similar to that described in example 23, to obtain the specified title compound (colorless oil).

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7,3 Hz)of 0.93 (3H, t, J=7,3 Hz), 1,01 (3H, sird, J=6.6 Hz), 1,19-of 1.65 (7H, m)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), 1,77-of 1.84 (4H, m)to 1.86 (1H, DD, J=5,5, to 13.9 Hz), 1,89-to 1.98 (1H, m), 2,42 (1H, DD, J=5,1, and 14.3 Hz), 2,50-2,67 8H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,86-of 2.93 (1H, m), 2,90 (3H, s), 3,39 is-3.45 (2H, m), 3,52 (1H, dt, J=4,8, 8.1 Hz), 3,74-3,82 (1H, m), 4,74 of 4.83 (1H, m), free 5.01 (1H, d, J=a 10.6 Hz), 5,41-of 5.53 (2H, m), 5,86 (1H, d, J=15,4 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 649 (M+N)⁺.

Example 55

(8E,12E,14)-3,16,21-trihydroxy-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 55)

(1) (8E,12E,14)-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)carbonyl)oxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 55-1)

A solution of (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (0,3M solution in a mixture of N,N-dimethylformamide-chloroform (1:9), 80 ál, 24 mmol) in tetrahydrofuran (0.5 ml) was added dropwise to a solution of (8E,12E,14)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-3,6,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-olide (12.7mm mg, 12.7 mmol), obtained in example 23-3 stage in tetrahydrofuran (0.5 ml) at room temperature. The reaction mixture was stirred at room temperature for five hours and then solvent was removed by evaporation. The obtained residue was purified column chromatography on silica gel (Fuji Silysia NH Silica gel; ethyl acetate:hexane=1:2) to obtain specified in the connection header (12,2 mg) as a colourless oil is.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,59-0,68 (18H, m)of 0.82 (3H, t, J=7,7 Hz)to 0.85 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7.0 Hz), 0.95 to-1,02 (30H, m), of 1.18 and 1.33 (2H, m), 1,39-to 1.63 (6H, m)of 1.42 (3H, s), 1,72-to 1.98 (4H, m), a 1.75 (3H, d, J=1.1 Hz), 2,32 (1H, DD, J=6,2, to 13.6 Hz), 2,38 (1,5H, s), 2.40 a (1,5H, s), 2,52-2,90 (6H, t), 3,19 of 3.28 (1H, t), 13,44-to 3.52 (2H, t), 3,74 (1H, dt, J=3,3, 6,6 Hz), 3,90-of 3.97 (1H, m), or 4.31 (0,5H with), 4,35 (0,5H, s), 4,71-rate 4.79 (1H, m), is 4.93 (1H, d, J=a 10.6 Hz), 5,41-5,52 (2H, m), of 5.82 (1H, d, J=15,4 Hz), 6,11 (1H, d, J=11,0 Hz), 6,50 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 976 (M+H)⁺.

(2) (8E,12E,14)-3,16,21-trihydroxy-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 55)

(8E,12E,14)-6,10,12,16,20-pentamethyl-7-(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)carbonyl)oxy-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-old obtained in example 55-1 stage (12,2 mg, 12.5 μmol) was dissolved in tetrahydrofuran (0.5 ml). To the mixture was added dropwise with stirring at room temperature tetrabutylammonium (1.0m solution in tetrahydrofuran, 0,050 ml 0,050 mmol). The reaction mixture was stirred at room temperature for two hours and then the reaction mixture is added dropwise tetrabutylammonium (1.0m solution in tetrahydrofuran, a 0.012 ml, 0.012 mmol). The reaction mixture was additionally stirred for another 30 minutes and then was added methanol (50 ml). The resulting reaction mixture was purified in the thin-layer chromatography (Fuji Silysia NH Silica gel plate; chloroform-methanol 40:1) to obtain specified in the connection header (7,3 mg) as a colourless oil.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=6,6 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), and 0.98 (1,5H, d, J=7,0 Hz), 1,01 (1,5H, d, J=7,0 Hz), 1,19-of 1.80 (9H, m)of 1.33 (3H, s), 1.77 in (3H, d, J=1.1 Hz), 1,83-of 1.97 (3H, m), 2,38-to 2.40 (1H, m), 2,38 (1,5H, s), 2.40 a (1,5H, s), 2,50-2,61 (1H, m), of 2.56 (1H, DD, J=3,7, and 14.3 Hz), 2,62-a 2.71 (1H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,75 (0,5H, DD, J=1,8, 10,3 Hz), 2,81 (0,5H, DD, J=1,8, 10,3 Hz), 2,89 (1H, dt, J=2,2, 5,9 Hz), 3,20 (0,5H, DD, J=1,8, 10,3 Hz), 3,25 (0,5H, DD, J=1,8, 10,3 Hz), 3,44-3,55 (3H, m), 3,74-3,81 (1H, m), or 4.31 (0,5H, s), 4,34 (0,5H, s), 4,74-4,82 (1H, m), free 5.01 (1H, d, J=a 10.6 Hz), 5,42-of 5.53 (2H, m), 5,86 (1H, d, J=15,4 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz). ESI-MS m/z 633 (M+H)⁺.

Example 56

(8E,12E,14)-7-(N-(1-azabicyclo[2.2.2]Octan-3-yl)carbanilate)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 56)

(1) (8E,12E,14)-7-(N-(1-azabicyclo[2.2.2]Octan-3-yl)carbanilate)-6,10,12,16,20-pentamethyl-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 56-1)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 23.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,59 (18H, m)of 0.82 (3H, t, J=7,3 Hz)to 0.85(3H, d, J=7,0 Hz)to 0.88 (3H, d, J=7,0 Hz), 0,95-1,01 (30H, m), 1.18 to 1,89 (14H, m)of 1.42 (3H, s), of 1.74 (3H, s)of 1.93 (1H, DD, J=4,8, a 13.9 Hz), 2,32 (1H, DD, J=6,2, 13,2 Hz), 2,50-2,61 (3H, m), 2,61 (1H, DD, J=2,2, ,4 Hz), 2,72-only 2.91 (5H, m), 3,19 of 3.28 (1H, m), 3,66-of 3.78 (2H, m), 3,90-of 3.97 (1H, m), 4,68-of 4.75 (1H, m), is 4.93 (1H, d, J=a 10.6 Hz), 5,38-of 5.50 (2H, m), of 5.82 (1H, d, J=15,4 Hz), 6,11 (1H, d, J=11.0 in Hz)of 6.49 (1H, DD, J=11,0, to 15.4 Hz); ESI-MS m/z 990 (M+H)⁺.

(2) (8E,12E,14)-7-(N-(1-azabicyclo[2.2.2]Octan-3-yl)carbanilate)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 56)

Remove the protective groups for hydroxyl groups in the compound 56-1 manner similar to that described in example 23, to obtain the specified title compound (colorless oil).

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7,3 Hz)of 0.93 (3H, t, J=7,3 Hz), a 1.01 (3H, d, J=6.6 Hz), 1.18 to 1,94 (15H, m)of 1.33 (3H, s)of 1.76 (3H, d, J=0.7 Hz), 2,42 (1H, DD, J=5,5, 14,3 Hz), 2,49-2,60 (3H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,69 of 2.92 (5H, m), 3,17-of 3.25 (1H, m), 3,52 (1H, dt, J=a 4.4, and 8.4 Hz), 3,64-3,70 (1H, m), of 3.73-3,81 (1H, m), 4,70-rate 4.79 (1H, m), free 5.01 (1H, d, J=a 10.6 Hz), 5,39-5,51 (2H, m), 5,86 (1H, d, J=15,4 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 647 (M+H)⁺.

Example 57

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(N'-methylamino)cyclohexyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 57)

(1) (8E,12E,14)-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(N'-methylamino)cyclohexyl)carbamoylated-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 57-1)

Specified in the header connect the out (colorless oil) was synthesized by the method similar to that described in example 23.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,59-0,69 (18H, m)of 0.82 (3H, t, J=7,3 Hz)to 0.85 (3H, d, J=7,0 Hz), 0,85-of 0.91 (3H, m), 0,95-1,03 (30H, m), 1,07 by 1.68 (13H, m)of 1.42 (3H, s), 1,71-to 1.82 (2H, m)of 1.75 (3H, s), 1,83-1,94 (1H, m), of 1.94 (1H, DD, J=4,8, a 13.9 Hz), 2,08-of 2.16 (1H, m), 2,29-of 2.36 (1H, m), of 2.33 (3H, s), 2,47-2,61 (3H, m), 2,61 (1H, DD, J=2,2, 8.1 Hz), 2,78 (3H, s), 2,85-2,90 (1H, m), 3.72 points-3,86 (2H, m), 3,91-of 3.97 (1H, m), 4,78 (1H, DD, J=9,2, 9,2 Hz), is 4.93 (1H, d, J=a 10.6 Hz), 5,41-5,52 (2H, m), of 5.82 (1H, d, J=15,0 Hz), 6,11 (1H, d, J=11,0 Hz), 6,50 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 1006 (M+H)⁺.

(2) (8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(2-(N'-methylamino)cyclohexyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 57)

Remove the protective groups for hydroxyl groups in the compound 57-1 manner similar to that described in example 23, to obtain the specified title compound (colorless oil).

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,86 (3H, sird, J=5,9 Hz)to 0.89 (3H, d, J=7,3 Hz)of 0.93 (3H, t, J=7,3 Hz), 0,97-1,68 (16H, m)of 1.33 (3H, s), 1,71-to 1.82 (2H, m)of 1.76 (3H, d, J=0.7 Hz), to 1.86 (1H, DD, J=5,5, to 13.9 Hz), 1,90 of 1.99 (1H, m), 2,07-of 2.16 (1H, m), 2,32 (3H, s), 2,42 (1H, DD, J=5,5, to 13.9 Hz), 2,47-2,63 (3H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,78 (3H, s), is 2.88 (1H, dt, J=2,2, 6.2 Hz), 3,52 (1H, dt, J=4,8, 8.1 Hz), 3,74-3,82 (2H, m), to 4.81 (1H, DD, J=a 9.9, 9.9 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,42-of 5.53 (2H, m), 5,86 (1H, d, J=15,4 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 663 (M+H)⁺.

Example 58

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(morpholine-4-yl)ethyl)carbamoyl and)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 58)

(1) (8E,12E,14)-6,10,12,16,20-pentamethyl-7-(N-(2-(morpholine-4-yl)ethyl)carbanilate)-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 58-1)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 23.

¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 0,59-0,68 (18H, m) of 0.82 (3H, t, J=7,7 Hz)to 0.85 (3H, d, J=6,6 Hz)to 0.89 (3H, d, J=7.0 Hz), 0.95 to-1,02 (N, m), 1,16-1,32 (2H, m), 1,39-of 1.62 (6H, m)of 1.42 (3H, s)of 1.75 (3H, s), a 1.75-of 1.87 (1H, 5 m)of 1.93 (1H, DD, J=4,8, a 13.9 Hz), 2,32 (1H, DD, J=6,2, to 13.6 Hz), 2,42-2,61 (8H, m), 2,61 (1H, DD, J=2,2, 8,4 Hz), 2,85-2,90 (1H, m), of 3.32 (2H, t, J=6.6 Hz), to 3.67 (4H, t, J=4,8 Hz), 3,74 (1H, dt, J=3,3, 6,6 Hz), 3,90-3,98 (1H, m), 4,71 (1H, DD, J=8,8, 8,8 Hz), is 4.93 (1H, d, J=a 10.6 Hz), lower than the 5.37-of 5.50 (2H, m), of 5.82 (1H, d, J=15,0 Hz), 6,11 (1H, d, J=11.0 in Hz)of 6.49 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 994 (M+H)⁺.

(2) (8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(morpholine-4-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 58)

Remove the protective groups for hydroxyl groups in the compound 58-1 manner similar to that described in example 23, to obtain the specified title compound (colorless oil).

¹H NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=7,0 Hz)of 0.93 (3H, t, J=7,3 Hz), and 1.00 (3H, d, J=7,0 Hz), 1,19-1,64 (7H, m)of 1.33 (3H, s), of 1.65 (1H, DD, J=5,5, to 13.9 Hz), of 1.76 (3H, d, J=0,7 Hz), 1,83-1,90 (1H, m)to 1.86 (1H, DD, J=5,5, to 13.9 Hz), 2,38-2,60 (9H, m)to 2.66 (1H, DD, J2,2, 8.1 Hz), is 2.88 (1H, dt, J=2,2, 5,5 Hz), 3,23 (2H, dt, J=1,1, 7,0 Hz), 3,52 (1H, dt, J=4,8, 8,1 Hz)to 3.67 (4H, t, J=4,8 Hz), to 3.73-of 3.80 (1H, m), 4,74 (1H, DD, J=a 9.9, 9.9 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,38-the 5.51 (2H, m,), 5,86 (1H, d, J=15,0 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.0 Hz); ESI-MS m/z 651 (M+H)⁺.

Example 59

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(piperidine-1-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 59)

(1) (8E,12E,14)-6,10,12,16,20-pentamethyl-7-(N-(2-(piperidine-1-yl)ethyl)carbanilate)-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 59-1)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 23.

¹H NMR (CD₃OD, 400 MHz) δ (ppm): 0,59-0,68 (18H, m)of 0.82 (3H, t, J=7,7 Hz)to 0.85 (3H, d, J=7,3 Hz)to 0.89 (3H, d, J=6.6 Hz), 0,95-1,02 (N, m), 1,16-1,32 (2H, m), 1,39-1,62 (12H, m)of 1.42 (3H, s), of 1.74 (3H, s), 1,76-of 1.85 (1H, m)of 1.93 (1H, DD, J=4,8, a 13.9 Hz), 2,32 (1H, DD, J=6,6, to 13.6 Hz), 2,41-2,61 (8H, m), 2,61 (1H, DD, J=2,2, 8,4 Hz), 2,84-2,90 (1H, m), 3,23 (2H, t, J=7.0 Hz), 3,74(1H, dt, J=3,7, 7,0 Hz), 3,90-of 3.97 (1H, m), 4,70 (1H, DD, J=9,2, 9,2 Hz), is 4.93 (1H, d, J=a 10.6 Hz), lower than the 5.37-of 5.50 (2H, m), of 5.82 (1H, d, J=15,4 Hz), 6,11 (1H, d, J=11.0 in Hz)of 6.49 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 992 (M+H)⁺.

(2) (8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(piperidine-1-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 59)

Remove the protective group for the guy who rossilini groups in connection 59-1 way similar to that described in example 23, to obtain the specified title compound (colorless oil).

¹H NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,3 Hz)to 0.89 (3H, d, J=7,3 Hz)of 0.93 (3H, t, J=7,3 Hz), 0,99 (3H, d, J=7,0 Hz), 1,19-1,68 (14H, m)of 1.33 (3H, s)of 1.76 (3H, d, J=1.1 Hz), 1,83-1,90 (1H, m), 1,86 (1H, DD, J=5,5, to 13.9 Hz), 2,38-2,60 (9H, m)to 2.66 (1H, DD, J=2,6, 8.1 Hz), 2,89 (1H, dt, J=2,6, 5,5 Hz), 3,23 (2H, DD, J=6,2, 7,7 Hz), 3,52 (1H, dt, J=4,8, and 8.4 Hz), to 3.73-of 3.80 (1H, m), 4,74 (1H, DD, J=a 9.9, 9.9 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,38-the 5.51 (2H, m), 5,86 (1H, d, J=15,4 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 649 (M+H)⁺.

Example 60

(8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(pyrrolidin-1-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 60)

(1) (8E,12E,14)-6,10,12,16,20-pentamethyl-7-(N-(2-(pyrrolidin-1-yl)ethyl)carbanilate)-3,16,21-Tris(triethylsilane)-18,19-epoxydecane-8,12,14-trien-11-OLED (connection 60-1)

Specified in the title compound (colorless oil) was synthesized by a method similar to that described in example 23.

¹H NMR (CD₃OD, 400 MHz) δ (ppm): 0,59-0,68 (18H, m)of 0.82 (3H, t, J=7,7 Hz)to 0.85 (3H, d, J=7,0 Hz)to 0.89 (3H, d, J=6.6 Hz), 0,95-1,02 (N, m), 1,15-1,30 (2H, m), 1,39-to 1.61 (6H, m)of 1.42 (3H, s)of 1.75 (3H, d, J=0,7 Hz), 1,75-of 1.85 (5H, m)of 1.93 (1H, DD, J=4,8, a 13.9 Hz), 2,32 (1H, DD, J=6,6, to 13.6 Hz), 2,50-2,62 (9H, m), 2,85-2,90 (1H, m), 3,24 (2H, t, J=7.0 Hz), 3,74 (1H, dt, J=3.3, then a 7.0 Hz), 3,90-of 3.97 (1H, m), 4,71 (1H, DD, J=a 9.5, 9.5 Hz), is 4.93 (1H, d, J=a 10.6 Hz), lower than the 5.37-of 5.50 (2H, m), of 5.82 (1H, d, J=15,4 Hz), 11 (1H, d, J=11.0 in Hz)of 6.49 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 978 (M+H)⁺.

(2) (8E,12E,14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-(2-(pyrrolidin-1-yl)ethyl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-OLED (compound 60)

Remove the protective groups for hydroxyl groups in the compound 60-1 manner similar to that described in example 23, to obtain the specified title compound (colorless oil).

¹H NMR (CD₃OD, 400 MHz) δ (ppm): of 0.87 (3H, d, J=7,7 Hz)to 0.89 (3H, d, J=7,3 Hz)of 0.93 (3H, t, J=7,3 Hz), and 1.00 (3H, d, J=6.6 Hz), 1,20-of 1.65 (7H, m)of 1.33 (3H, s), of 1.65 (1H, DD, J=5,5, to 13.9 Hz), of 1.76 (3H, d, J=1,1 Hz), 1,76-1,90 (5H, m)to 1.86 (1H, DD, J=5,5, to 13.9 Hz), 2,42 (1H, DD, J=5,1, to 13.9 Hz), 2.49 USD 2.63 in (8H, m)to 2.66 (1H, DD, J=2,2, 8.1 Hz), 2,89 (1H, dt, J=2,2, 5,5 Hz), 3,24 (2H, t, J=7,3 Hz), 3,52 (1H, dt, J=4,8, 8,1 Hz), 3,74-3,81 (1H, m), 4,74 (1H, DD, J=a 9.9, 9.9 Hz), free 5.01 (1H, d, J=a 10.6 Hz), 5,38-the 5.51 (2H, m), 5,86 (1H, d, J=15,4 Hz), 6,12 (1H, d, J=11.0 in Hz)of 6.52 (1H, DD, J=of 11.0 to 15.4 Hz); ESI-MS m/z 635 (M+H)⁺.

1. The compound represented by formula (I):

where W represents

and R³, R⁷, R¹⁶, R¹⁷, R²⁰, R²¹and R^21′identical or different, independently represent

1) a hydrogen atom,

2) a hydroxyl group, or oxoprop, provided that oxoprop limited oxopropoxy formed R³what if R ⁷together with the carbon atom that is attached to the group R³or R⁷and exography formed by groups of R²¹and R^21′together with the carbon atom that is attached to R²¹and R^21′,

3)₁-C₂₂alkoxygroup, which may have a Deputy,

4) unsaturated With_2-22alkoxygroup, which may have a Deputy,

5)₇-C₂₂aralkylated, which may have a Deputy,

6) RC(=Y)-O-, where Y represents an oxygen atom, and R represents a

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C) a 5-14-membered heteroaryl group which may have a Deputy,

d)₆-C₁₄alloctype, which may have a Deputy,

7) R^s1R^s2R^s3SiO-, where R^s1, R^s2and R^s3identical or different, independently represent

a) C₁-C₆alkyl group, or

(b) (C₆-C₁₄aryl group,

8) R^N1R^N2N-R^M-where R^Mrepresents a

a) a single bond,

b) -CO-O-,

R^N1and R^N2identical or different, independently represent

(a) a hydrogen atom,

(b) (C_{1 -C22alkyl group which may have a Deputy,}

C) a 5-14-membered heteroaryl group which may have a Deputy,

d) 3-14-membered non-aromatic heterocyclic group formed R^N1and R^N2together with the nitrogen atom that is attached to R^N1and R^N2moreover , 3-14-membered non-aromatic heterocyclic group may have a Deputy,

e)₃-C₁₄cycloalkyl group which may have a Deputy, or

f) 3-14 membered non-aromatic heterocyclic group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

2. The compound according to claim 1, represented by formula (I-a):

where W, such as defined above, and R^3a, R^7a, R^16a, R^17a, R^20a, R^21aand R^21a'identical or different, independently represent

1) a hydrogen atom,

2) a hydroxyl group, or oxoprop, provided that oxoprop limited oxopropoxy formed R^3aor R^7atogether with the carbon atom that is attached to the group R^3aor R^7aand exography formed by groups of R^21aand R^21a′together with the carbon atom that is attached to R^21aand R^21a′,

3) 1-C₂₂alkoxygroup, which may have a Deputy,

4) R^aC(=Y^a)-O-, where Y^arepresents an oxygen atom, and R^arepresents a

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C) a 5-14-membered heteroaryl group which may have a Deputy,

d)₆-C₁₄alloctype, which may have a Deputy,

5) R^aS1R^aS2R^aS3SiO-, where R^aS1, R^aS2and R^aS3identical or different, independently represent

a) C₁-C₆alkyl group, or

(b) (C₆-C₁₄aryl group, or

6) R^aN1R^aN2N-R^aM-where R^aMrepresents-CO-O - and R^aN1and R^aN2identical or different, independently represent

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C) a 5-14-membered heteroaryl group which may have a Deputy,

d) 3-14-membered non-aromatic heterocyclic group formed R^aN2and R^aN2together with the nitrogen atom that is attached to R^aN1and R^aN2moreover , 3-14-membered non-aromatic heterocyclic group may have a Deputy,

e)₃ -C₁₄cycloalkyl group which may have a Deputy, or

f) 3-14 membered non-aromatic heterocyclic group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

3. The compound according to claim 1, represented by formula (I-b):

where W, such as defined above, and R^3b, R^7b, R^16b, R^17b, R^20b, R^21band R^21′bthe same or different, independently represent

1) a hydrogen atom,

2) a hydroxyl group, or oxoprop, provided that oxoprop limited oxopropoxy formed R^3bor R^7btogether with the carbon atom that is attached to the group R^3bor R^7band exography formed by groups of R^21band R^21b′together with the carbon atom that is attached to R^21aand R^21b′,

3)₁-C₂₂alkoxygroup, which may have a Deputy,

4) R^bC(=O)-O-, where R^brepresents a

a)₁-C₂₂alkyl group which may have a Deputy,

b) a 5-14-membered heteroaryl group which may have a Deputy,

C)₆-C₁₄alloctype, which may have a Deputy,

5) R^bS1R^bS2R^bS3SiO-, the de R ^bS1, R^bS2and R^bS3identical or different, independently represent

a) C₁-C₆alkyl group, or

(b) (C₆-C₁₄aryl group, or

6) R^bN1R^bN2N-R^bM-where R^bMrepresents-CO-O - and R^bN1and R^bN2identical or different, independently represent

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C) 3-14-membered non-aromatic heterocyclic group formed R^bN1and R^bN2together with the nitrogen atom that is attached to R^bN1and R^bN2moreover , 3-14-membered non-aromatic heterocyclic group may have a Deputy,

a)₃-C₁₄cycloalkyl group which may have a Deputy, or

f) 3-14 membered non-aromatic heterocyclic group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

4. The compound according to claim 1, represented by formula (I-c):

where W, such as defined above, and R^3c, R^7c, R^16c, R^17c, R^20c, R^21cand R^21′cidentical or different, independently represent

1) a hydrogen atom,

2) a hydroxyl group or oxoprop is, provided that oxoprop limited oxopropoxy formed R^3cor R^7ctogether with the carbon atom that is attached to the group R^3cor R^7cand exography formed by groups of R^21cand R^21c′together with the carbon atom that is attached to R^21cand R^21c′,

3) R^cC(=O)-O-, where R^crepresents a C₁-C₂₂alkyl group which may have a Deputy,

4) R^cS1R^cS2R^cS3SiO-, where R^cS1, R^cS2and R^cS3identical or different, independently represent

a) C₁-C₆alkyl group, or

(b) (C₆-C₁₄aryl group, or

5) R^cN1R^cN2N-R^cM-where R^cMrepresents-CO-O-, and R^cN1and R^cN2identical or different, independently represent

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C) 3-14-membered non-aromatic heterocyclic group formed R^cN1and R^cN2together with the nitrogen atom that is attached to R^cN1and R^cN2moreover , 3-14-membered non-aromatic heterocyclic group may have a Deputy,

a)₃-C₁₄cycloalkyl group which may have a Deputy, or

e) -14-membered non-aromatic heterocyclic group, which may have a Deputy, its pharmacologically acceptable salt or hydrate.

5. The compound according to claim 1, represented by formula (I-d):

where R^3dand R^16dindependently represent

1) hydroxyl group,

2)₁-C₂₂alkoxygroup, which may have a Deputy,

3) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

4)₇-C₂₂aralkylated, which may have a Deputy,

5) R^dC(=O)-O-, where R^drepresents a

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C) a 5-14-membered heteroaryl group which may have a Deputy,

d)₆-C₁₄alloctype, which may have a Deputy,

6) R^dN1R^dN2N-CO-O-, where R^dN1and R^dN2identical or different, independently represent

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C) a 5-14-membered heteroaryl group which may have a Deputy,

d) 3-14-membered non-aromatic heterocyclic group which may have a Deputy, or

e) 3-14-membered neuroma the practical heterocyclic group, formed R^dN1and R^dN2together with the nitrogen atom that is attached to R^dN1and R^dN2moreover , 3-14-membered non-aromatic heterocyclic group may have a Deputy, and R^7dand R^21didentical or different, independently represent

1) hydroxyl group,

2)₁-C₂₂alkoxygroup, which may have a Deputy,

3) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

4)₇-C₂₂aralkylated, which may have a Deputy,

5) R^dC(=O)-O-, where R^dsuch as defined above,

6) R^dN1R^dN2N-CO-O-, where R^dN1and^RdN2such as defined above, its pharmaceutically acceptable salt or hydrate.

6. The compound according to claim 1, where R⁷and/or R⁶independently represent RC(=Y)-O-, where Y and R such as defined above, or R^N1R^N2N-R^M′-where R^M′represents-CO-O - and R^N1and R^N2such as defined above, its pharmaceutically acceptable salt or hydrate.

7. The compound according to claim 5, represented by formula (I-e):

where R^3e, R^16eand R^21eidentical or different, independently represent

1) hydroxyl group,

2)₁-C₂₂alkoxygroup, which may have a Deputy,

3) unsaturated With₂-C₂₂alkoxygroup, which may have a Deputy,

4)₇-C₂₂aralkylated, which may have a Deputy, or

5) R^eN1R^eN2N-CO-O-, where R^eN1and R^eN2independently represent

(a) a hydrogen atom, or

b) C₁-C₆alkyl group which may have a Deputy, and R^7eis an R^eC(=Y^e)-O-, where Y^erepresents an oxygen atom and R^erepresents a

(a) a hydrogen atom,

(b) (C₁-C₂₂alkyl group which may have a Deputy,

C) a 5-14-membered heteroaryl group which may have a Deputy,

d) a group of the formula (III):

where (A) n is an integer from 0 to 4,

X_erepresents a

(i)- (CHR^eN4-,

ii)-NR^eN5-,

iii) -O-,

R^eN1represents a

(i) a hydrogen atom, or

ii) C₁-C₆alkyl group which may have a Deputy,

R^eN2represents a

(i) a hydrogen atom, or

ii) C₁-C₆alkyl group which may have substituent R ^eN3and R^eN4identical or different, independently represent

(i) a hydrogen atom,

ii) C₁-C₆alkyl group which may have a Deputy,

iii) a 5-14-membered heteroaryl group which may have a Deputy,

iv)₃-C₈cycloalkyl group which may have a Deputy,

v)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

vi) a 5 to 14-membered non-aromatic heterocyclic group which may have a Deputy,

vii) -NR^eN6R^eN7where R^eN6and R^eN7identical or different, independently represent a hydrogen atom or a C₁-C₆alkyl group which may have a Deputy, or viii) 5-14-membered non-aromatic heterocyclic group formed R^eN3and R^eN4together with the nitrogen atom that is attached to R^eN3and R^eN4and 5-14 membered non-aromatic heterocyclic group may have a Deputy, and

R^eN5represents a

(i) a hydrogen atom,

ii) C₁-C₆alkyl group which may have a Deputy,

iii) a 5-14-membered heteroaryl group which may have a Deputy,

iv)₃-C₈cycloalkyl group which may have a Deputy shall stitely,

v)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

vi) a 5 to 14-membered non-aromatic heterocyclic group which may have a Deputy, or

vii) a 5 to 14-membered non-aromatic heterocyclic group formed R^eN3and R^eN5together with the nitrogen atom that is attached to R^eN3and R^eN5and 5-14 membered non-aromatic heterocyclic group may have a Deputy,

In) X_e, n, R^eN3, R^eN4and R^eN5independently represent a group as defined above, and R^eN1and R^eN2independently represent a 5 to 14-membered non-aromatic heterocyclic group formed together groups of R^eN1and R^eN2and 5-14 membered non-aromatic heterocyclic group may have a Deputy,

(C) X_e, n, R^eN2, R^eN4and R^eN5independently represent a group as defined above, and R^eN1and R^eN3independently represent a 5 to 14-membered non-aromatic heterocyclic group formed together groups of R^eN1and R^eN3and 5-14 membered non-aromatic heterocyclic group may have a Deputy, or

D) X_e, n, R^eN1, R^eN4and R^eN5independently represent a group as defined above, and R^eN2and R^eN independently represent a 5 to 14-membered non-aromatic heterocyclic group formed together groups of R^eN2and R^eN3and 5-14 membered non-aromatic heterocyclic group may have a Deputy, or

i) a group of the formula (IV):

where R^eN8and R^eN9identical or different, independently represent

(i) a hydrogen atom,

ii) C₁-C₆alkyl group which may have a Deputy,

iii) a 5-14-membered heteroaryl group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

8. The compound according to claim 5, where R^7dand/or R^21dindependently represent R^e1C(=Y^e1)-O-,

where Y^e1represents an oxygen atom and R^e1represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy,

3) 5-14-membered heteroaryl group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

9. The compound according to claim 5, where R^7dand/or R^21dare R^e2C(=Y^e2)-O-, where Y^e2represents an oxygen atom and R^e2represents a group of formula (III^′):

where (A) n is an integer from 0 to 4,

X₁represents a

l) -CHR^eN13-,

2) -NR^eN14-,

3) -O-,

R^eN10and R^eN11identical or different, independently represent

1) a hydrogen atom, or

2) C₁-C₆alkyl group which may have a Deputy, R^eN12and R^eN13identical or different, independently represent

1) a hydrogen atom,

2) C₆-C₆alkyl group which may have a Deputy,

3) 5-14-membered heteroaryl group which may have a Deputy,

4)₃-C₈cycloalkyl group which may have a Deputy,

5)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

6) 5-14-membered non-aromatic heterocyclic group which may have a Deputy,

7) -NR^eN15R^eN16where R^eN15_andR^eN16identical or different, independently represent a hydrogen atom or a C₁-C₆alkyl group which may have a Deputy, or

8) 5-14-membered non-aromatic heterocyclic group formed together groups of R^eN12and R^eN13and 5-14 membered non-aromatic heterocyclic gr is the PAP may have a Deputy, and R^eN14represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy,

3) 5-14-membered heteroaryl group which may have a Deputy,

4)₃-C₈cycloalkyl group which may have a Deputy,

5)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

6) 5-14-membered non-aromatic heterocyclic group which may have a Deputy,

7) 5-14-membered non-aromatic heterocyclic group formed together with the nitrogen atom that is attached to the group R^eN14and one Deputy selected from the group consisting of R^eN10, R^eN11and R^eN12and 5-14 membered non-aromatic heterocyclic group may have a Deputy, or

8) 5-14-membered non-aromatic heterocyclic group formed together with the nitrogen atom that is attached to the group R^eN14and the two substituents selected from the group consisting of R^eN10, R^eN11and R^eN12and 5-14 membered non-aromatic heterocyclic group may have a Deputy, or

In) n, X₁R^eN11, R^eN13and R^eN14are the same as defined above, and R^eN10and R^eN12together to form a 5-14-membered neuroma the practical heterocyclic group, and 5-14 membered non-aromatic heterocyclic group may have a Deputy, its pharmacologically acceptable salt or hydrate.

10. The connection according to claim 9, where X₁represents-NR^dN14-where NR^dN14such as defined above, its pharmaceutically acceptable salt or hydrate.

11. The compound according to claim 5, where R^7dand/or R^21dindependently represent R^e3C(=Y^e3)-O-, where Y^e3represents an oxygen atom and R^e3represents a group of formula (V):

where n₁is an integer from 0 to 6,

R^eN17represents a

1) a hydrogen atom, or

2) C₁-C₆alkyl group which may have a Deputy, and R^eN18represents a

1) a hydrogen atom,

2) an amino group which may have a Deputy,

3) pyridyloxy group which may have a Deputy,

4) pyrrolidin-1-ilen group which may have a Deputy,

5) piperidine-1-ilen group which may have a Deputy,

6) morpholine-4-ilen group which may have a Deputy, or

7) piperazine-1-ilen group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

12. The compound according to claim 5, g is e R ^7dand/or R^21dindependently represent R^e4CO-O-, where R^e4represents a group of formula (VI):

where n₂and n₃identical or different, independently represent an integer from 0 to 4,

X₂represents a

l)-CHR^eN21-,

2) -NR^eN22-,

3) -O-,

R^eN19represents a

1) a hydrogen atom, or

2) C₁-C₆alkyl group which may have a Deputy, R^eN20represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy, R^eN21represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy,

3) 5-14-membered heteroaryl group which may have a Deputy,

4)₃-C₈cycloalkyl group which may have a Deputy,

5)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

6) -NR^eN23R^eN24where R^eN23and R^eN24identical or different, independently represent a hydrogen atom or a C₁-C₆alkyl group which may have a Deputy, or

7) 5-14-membered non-aromatic GE is eroticlick group, which may have a Deputy, and R^eN22represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy,

3) 5-14-membered heteroaryl group which may have a Deputy,

4)₃-C₈cycloalkyl group which may have a Deputy,

5)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

6) 5-14-membered non-aromatic heterocyclic group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

13. The compound according to claim 5, where R^7dand/or R^21dindependently represent R^e5CO-O-, where R^e5represents a group of formula (VII):

where n₄represents 1 or 2,

R^eN25represents a

1) a hydrogen atom, or

2) C₁-C₆alkyl group which may have a Deputy, and R^eN26represents a

1) a hydrogen atom, or

2) C₁-C₆alkyl group which may have a Deputy of its pharmacologically acceptable salt or hydrate.

14. The compound according to claim 5, where R^7dand/or R^21dindependently represent R^e6CO-O-, where R^e6is a group of four who uly (VIII):

where n₂and n₃identical or different, independently represent an integer from 0 to 4,

X₃represents a

l) -CHR^eN29-,

2) -NR^eN30-,

3) -O-,

R^eN27represents a

1) a hydrogen atom, or

2) C₁-C₆alkyl group which may have a Deputy,

R^eN28represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy,

R^eN29represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy,

3) 5-14-membered heteroaryl group which may have a Deputy,

4)₃-C₈cycloalkyl group which may have a Deputy,

5)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

6) -NR^eN31R^eN32where R^eN31and R^eN32identical or different, independently represent a hydrogen atom or a C₁-C₆alkyl group which may have a Deputy, or form a 5 to 14-membered non-aromatic heterocyclic group together with the nitrogen atom to which R^eN31and R^eN32attached, or

R^eN30represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy,

3) 5-14-membered heteroaryl group which may have a Deputy,

4)₇-C₁₀aracelio group which may have a Deputy,

5)₃-C₈cycloalkyl group which may have a Deputy,

6)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

7) 5-14-membered non-aromatic heterocyclic group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

15. The compound according to claim 5, where R^7dand/or R^21dindependently represent R^e7CO-O-, where R^e7represents a group of formula (IX):

where n₅is an integer from 1 to 3, and

R^eN33represents a

1) amino group,

2) an amino group which may have a Deputy,

3) pyrrolidin-1-ilen group which may have a Deputy,

4) piperidine-1-ilen group which may have a Deputy, or

5) morpholine-4-strong group, which can be the t to have a Deputy, its pharmacologically acceptable salt or hydrate.

16. The compound according to claim 5, where R^7dand/or R^21dindependently represent R^e8CO-O-, where R^e8represents a group of formula (X):

where n₅is an integer from 1 to 3,

R^{enabled through the en34 pin}represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy,

R^eN35represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy,

3)₃-C₈cycloalkyl group which may have a Deputy,

4) 3-8-membered non-aromatic heterocyclic group which may have a Deputy,

5) 5-14-membered heteroaryl group which may have a Deputy,

6)₇-C₁₀aracelio group which may have a Deputy,

7)₄-C₉cycloalkylcarbonyl group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

17. The compound according to claim 5, where R^7dand/or R^21dindependently represent R^edCO-O-, where

R^e9represents a group of formula (XI):

where n 5is an integer from 1 to 3, and

R^eN36represents a

1) a hydrogen atom,

2)₁-C₈alkyl group which may have a Deputy,

3)₃-C₆cycloalkyl group which may have a Deputy,

4)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

5)₇-C₁₀aracelio group which may have a Deputy,

6) pyridyloxy group which may have a Deputy, or

7) tetrahydropyranyloxy group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

18. The compound according to claim 5, where R^7dand/or R^21dindependently represent R^e10CO-O-, where R^e10represents a group of formula (XII):

where m₁, m₂, m₃and m₄identical or different, independently represent 0 or 1,

n₅is an integer from 1 to 3 and

R^eN37represents a

1) a hydrogen atom,

2) C₁-C₆alkyl group which may have a Deputy,

3) 5-14-membered heteroaryl group which may have a Deputy,

4)₃-C₈cycloalkyl group, to ora may have a Deputy,

5)₄-C₉cycloalkylcarbonyl group which may have a Deputy,

6) 5-14-membered non-aromatic heterocyclic group which may have a Deputy, its pharmacologically acceptable salt or hydrate.

19. The compound according to claim 5, where R^7dand/or R^21dindependently represent R^e11CO-O-, where R^e11represents a group of the formula (XIII):

where m₅is an integer from 1 to 3 and n₅represents 2 or 3, its pharmacologically acceptable salt or hydrate.

20. The compound according to claim 5, where R^7dand/or R^21dindependently represent R^e12CO-O-, where R^e12represents a group selected from the group consisting of:

or a group selected from the group consisting of:

moreover, in both groups in the ring may be Deputy, its pharmacologically acceptable salt or hydrate.

21. The compound according to claim 1, where R¹⁶represents a hydroxyl group, its pharmacologically acceptable salt or hydrate.

22. The compound according to claim 1, where

[1] W represents

,

R³The R ²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21′represent a hydrogen atom,

[2] W represents

R³and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21′represent a hydrogen atom,

[3] W represents

,

R³, R¹⁶and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁷, R²⁰and R^21′represent a hydrogen atom,

[4] W represents

,

R²¹, R^21′form oxoprop together with the carbon atom to which R²¹and R^21′attached, R³, R¹⁶and R²⁰represent a hydroxyl group, R⁷is acetoxy, and R¹⁷represents a hydrogen atom,

[5] W represents

,

R³, R¹⁶R²⁰and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁷and ^21′represent a hydrogen atom,

[6] W represents

,

R³, R¹⁷, R¹⁶and R²¹represent a hydroxyl group, and R¹⁷, R²⁰and R^21′represent a hydrogen atom,

[7] W represents

,

R³, R¹⁷, R¹⁶and R²¹represent a hydroxyl group, R⁷is acetoxy, and R²⁰and R^21′represent a hydrogen atom, or

[8] W represents

R²¹and R^21′form oxoprop together with the carbon atom to which R²¹and R^21′attached, R³and R¹⁶represent a hydroxyl group, R⁷is acetoxy, and R¹⁷and R²⁰represents a hydrogen atom, its pharmaceutically acceptable salt or hydrate.

23. The compound according to claim 1, which is:

(8E, 12E, 14)-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-old,

(8E, 12E, 14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazine-1-yl)carbonyl)oxy-18,19-epoxydecane-8,12,14-trien-11-old,

(8E, 1E, 14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-((4-(piperidine-1-yl)piperidine-1-yl)carbonyl)oxy-18,19-epoxygenase-8,12,14-trien-11-old,

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

(8E, 12E, 14E)-7-(N-(3-(N',N'-dimethylamino)propyl)-N-methylcarbamoyl)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old,

(8E, 12E, 14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(piperazine-1-yl)carbonyl)oxy-18,19-hepatitisa-8,12,14-trien-11-old,

(8E, 12E, 14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(-methylpiperidin-4-yl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-old,

(8E, 12E, 14)-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-old,

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

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

(8E, 12E, 14)-7-((4-acylhomoserine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old,

(8E, 12E, 14)-3,16,21-trihydroxy-7-((4-isopropylpiperazine-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-EP is citricos-8,12,14-trien-11-old,

(8E, 12E, 14)-3,16,21-trihydroxy-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-old,

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

(8E, 12E, 14E)-7-(N-(2-(N',N'-dimethylamino)ethyl)carbanilate)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-Olid or

(8E, 12E, 14)-3,16,21-trihydroxy-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-old.

24. The compound according to claim 1, which is:

(8E, 12E, 14)-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7-(N-methyl-N-(1-methylpiperidin-4-yl)carbanilate)-18,19-epoxydecane-8,12,14-trien-11-old,

(8E, 12E, 14)-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-old,

(8E, 12E, 14)-7-((4-acylhomoserine-1-yl)carbonyl)oxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxydecane-8,12,14-trien-11-old,

(8E, 12E, 14)-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-Olid or

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

25. Drug, possess cytotoxic activity containing a compound according to any one of claims 1 to 24, its pharmacologically acceptable salt or hydrate as the active component.

26. Pharmaceutical composition having cytotoxic activity containing a compound according to any one of claims 1 to 24, its pharmacologically acceptable salt or hydrate as the active component.

27. Drug on A.25 as an agent for the prophylaxis or treatment of a disease against which effective regulation of gene expression.

28. Drug on A.25 as an agent for the prophylaxis or treatment of a disease against which effective inhibition of VEGF production.

29. Drug on A.25 as an agent for the prophylaxis or treatment of a disease against which an effective antiangiogenic effect.

30. Drug on A.25 as an inhibitor of angiogenesis.

31. Drug on A.25 as an antitumor agent.

32. Drug on A.25 as a therapeutic agent for the treatment of hemangiomas.

33. Drug on A.25 as an inhibitor of metastasis of cancer.

34. Drug on A.25 as a therapeutic agent for the treatment of retinal revascularization or diabetic retin is patii.

35. Drug on A.25 as a therapeutic agent for treatment of atherosclerosis.

36. Drug on A.25 as a therapeutic agent for treatment of solid malignant tumors.

37. Drug for p, where a solid malignant tumor is lung cancer, brain tumor, breast cancer, prostate cancer, ovarian cancer, cancer of the colon or melanoma.

38. Drug on A.25 as a therapeutic agent for the treatment of leukemia.

39. Drug on A.25 as an antitumor agent based on the regulation of gene expression.

40. Drug on A.25 as an antitumor agent based on the inhibition of VEGF production.

41. Drug on A.25 as an antitumor agent based on the effect of inhibition of angiogenesis.

42. A method of preventing or treating a disease against which effective regulation of gene expression, including an introduction to the patient a pharmacologically effective dose of the drug on A.25.

43. A method of preventing or treating a disease against which effective inhibition of VEGF production comprising administration to a patient a pharmacologically effective dose of the drug on A.25.

44. JV is a method for prevention or treatment of disease, against which effectively inhibiting angiogenesis comprising the administration to a patient a pharmacologically effective dose of the drug on A.25.

45. The use of compounds according to any one of claims 1 to 24, its pharmacologically acceptable salt or hydrate for the manufacture of an agent for prevention or treatment of diseases against which effective regulation of gene expression.

46. The use of compounds according to any one of claims 1 to 24, its pharmacologically acceptable salt or hydrate for the manufacture of an agent for prevention or treatment of diseases against which effective inhibition of VEGF production.

47. The use of compounds according to any one of claims 1 to 24, its pharmacologically acceptable salt or hydrate for the manufacture of an agent for prevention or treatment of diseases against which effective inhibition of angiogenesis.

48. The use of compounds according to any one of claims 1 to 24, its pharmacologically acceptable salt or hydrate for the manufacture of an agent for the prophylaxis or treatment of solid malignant tumors.

49. The method of obtaining compounds of 6-deoxy 11107, characterized in that includes culturing a microorganism belonging to the genus Streptomyces which is capable to produce the compound of formula (I):

where [1] W represents

R³and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21′represent a hydrogen atom, or

[2] W represents

R³and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21′represent a hydrogen atom, and collecting from the culture of the connection defined in [1] or [2] (hereinafter referred to as "compound 6-deoxy 11107").

50. The strain Streptomyces sp.-1543 (FERM BP-8442), which is able to produce compound 6-deoxy 11107 according to § 49.

51. The way to obtain 6-dezoxidanti biological transformation of compounds of formula (I):

where [1] W represents

,

R³and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁶, R¹⁷, R²⁰and R^21′represent a hydrogen atom,

(hereinafter referred to as "6-deoxy 11107") in the compound of formula (I), where

[3] W represents

,

R³, R¹⁷, R¹⁶and R²¹represents the t of a hydroxyl group, R⁷is acetoxy, and R¹⁷, R²⁰and R^21′represent a hydrogen atom,

[4] W represents

,

R²¹and R^21′form oxoprop together with the carbon atom to which R²¹and R^21′attached, R³, R¹⁶and R²⁰represent a hydroxyl group, R⁷is acetoxy, and R¹⁷represents a hydrogen atom,

[5] W represents

,

R³, R¹⁶, R²⁰and R²¹represent a hydroxyl group, R⁷is acetoxy, and R¹⁷and R^21′represent a hydrogen atom,

[6] W represents

,

R³, R⁷, R¹⁶and R²¹represent a hydroxyl group, and R¹⁷, R²⁰and R^21′represent a hydrogen atom,

[7] W represents

,

R³, R¹⁷, R¹⁶and R^21′represent a hydroxyl group, R⁷is acetoxy, and R²⁰and R²¹represent a hydrogen atom, or

[8] W represents

,

R²¹and R^21′form oxoprop together with the carbon atom to which R²¹and R^21′attached, R³and R¹⁶represent a hydroxyl group, R⁷is acetoxy, and R¹⁷and R²⁰represents a hydrogen atom (these connections are referred to hereinafter as "6-dezoxidanti"), containing

1) the stage at which it is possible to conduct biological transformation, the stage of incubation of the 6-deoxy 11107 In the presence of a culture solution of a strain selected from microorganisms belonging to the genus Streptomyces, or product obtained from the culture of cells of strain, and

2) collection 6-dezoxidanti of the incubated solution.

52. The method according to § 51, where the organism related to bacteria is strain a-1544 (FERM BP-8446) or strain a-1545 (FERM BP-8447).

53. Strain a-1544 (FERM BP-8446) or strain a-1545 (FERM BP-8447), which is able to turn the 6-deoxy 11107 In 6-detoxication.