HU211897A9 - D-heteroaryl, o-alkylheteroaryl, o-alkenylheteroaryl and o-alkynylheteroarylmacrolides having immunosuppressive activity - Google Patents

Description

Summary of the Invention

The application is in part a continuation of filing application 07/756,946, filed September 9, 1991, which is hereby terminated.

The present invention relates to O-heteroaryl, β-alkyl-heteroaryl, O-alkenyl-heteroaryl and O-alkenyl-heteroaryl macrolides which are useful in treating mammalian recipients such as autoimmune diseases (e.g., juvenile acute diabetes mellitus, multiple sclerosis and rheumatoid arthritis), immunodepression, infectious diseases, may also be used to prevent the rejection of foreign organ transplants (e.g. also eczema dermatitis, seborrheic dermatitis, Lichen Planes, Pemphigus, bladder Pemphigoid, Epidermolysis bullosa., urticaria, vasculitis, vasculitides, erythema, eosinophilia of the skin, Lupus erythematosus, Alopecia a reata) as well as characteristic male baldness, old age baldness, reversible airway obstruction, especially asthma, baldness. inflammation of the mucous membranes and blood vessels; infection with cytomagalus virus; multidrug resistance; purpura with primary decreased platelet count. Behcet's disease. conjunctivitis. Crohn's disease. Mooren's ulcer. uveitis. severe intraocular inflammation and / or hepatic injury with ischemia. In addition, some of the compounds of the invention may have antagonistic properties and thus be used to reverse the immunosuppressive effect and / or reduce the toxicity of other immunosuppressive agents.

More particularly, the present invention relates to compounds of formula (I). where R ¹ , R ² , R ^? , R ⁴ , R ⁵ . R ¹⁰ . The meanings of W and n are given below.

The present invention also relates to pharmaceutical compositions containing the compounds, and to the use of the compounds and other agents for the treatment and prevention of certain diseases and conditions.

Brief Description of the Related Art

U.S. Patent No. 4,894,366, issued January 16, 1990, European Patent Publication No. 0 184 162, and U.S. Patent Nos. 63-17884. 17-allyl, 14-dihydroxyl-12- [2 '- (U.S. Patent No. 6,198, and J. Am. Chem. Soc. 1987, 09, 5031, and J. Antiobiotics 1987, 40, 1249). 4 '-hydroxy-3-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-telramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos18-ene-2,3,10,16-tetraone (FR-900506), (FK-506), (L679 934). 17-ethyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11 , 28-dioxa-4-azatricyclo [22.3.1,0 ^4-9] octacos-18-ene-2.3,10,16-tetraone (FR900520), and several other related compounds which are starting materials for the described compounds. Synthetic preparation of said starting compound (FR-900506) has recently been described (see J. Am. Chem. Soc., 1989, 111, 1157). EP 0 356 399 discloses stereoisomers and position 17 derivatives of FR 900506. European Patent Application 0 323 042 and WO 89/05304. International Patent Application Publication Nos. 5,631,900 and 5,195,195, discloses various derivatives and related compounds of FR 900506 and FR 900520. European Patent Publication No. 0 437 680 discloses chloro, bromo, azido derivatives and related compounds of FR 900506 and FR 900520. European Patent Publication No. 0 428 365 describes various amino derivatives of FR 900506, FR 900520 and related compounds. A GB 2,245,891-A. United Kingdom Patent No. 5,950,600 discloses compounds FR 900506 containing a heterocyclic group.

U.S. Patent Nos. 4,929,611, 4,926,352, and 5,110,811 disclose the use of FK-506-type compounds in the treatment of transplant resistance. EP 0 315 978 describes the use of compound FR 900506 and related compounds for the topical treatment of skin manifestations of inflammatory and hyperproliferative skin diseases and diseases of immunological origin. WO 91/04025. International Patent Application Publication No. 3,600,195 discloses the use of various derivatives of FR 900506 for the treatment of immunodepression. WO 90/14826. International Patent Application Publication No. 3,600,900 discloses the use of compound FR 900506 and related compounds for the treatment of reversible respiratory diseases, particularly asthma. European Patent Application EP 0 423 714 describes the use of FK-506 and its derivatives as a hair revitalizing agent.

Numerous studies have suggested the efficacy of FK506 in a variety of diseases including, but not limited to, rheumatoid arthritis (C. Arita et al., Clinical Exp. Immunol., 1990, 82, 456-461; N. Imanura et al., Clin. Immunol. Immunopathol., 1988, 46, 82-90), sudden onset diabetes (N. Murase et al., Diabetes 1990, 39, 1584-86; N. Murase et al., 1990, 336, 373-74). ), posterior uveitis (H. Kawashima, Invest. Ophthalmol. Vis. Sci. 1988, 29, 1265-71), hepatic injury with ischemia (M. Sakr et al., Life Sci. 1990, 47, 687-91). , allergic brain inflammation (K. Deguchi et al., Brain Nerve, 1990, 42, 391-97), glomerulonephritis (J. McCauley et al., 1990, 335, 674). and systemic lupus erythematosus (K. Takabayashi et al., Clin. Immunol. Immunopathol. 1989, 5, 110-117), multidrug resistance (M. Naito et al., Cancer Chemother. Pharmacol., 29, 195-200, 1992). ), mucosal and vascular inflammation (International Patent Application Publication No. WO 91/17754), cytomegalovirus infection (GB)

HU 211 897 A9

British Patent Application Publication No. 247,620A) and primary purpura and Basedow's disease with reduced platelet count (International Patent Application Publication No. WO 91/19495).

BACKGROUND OF THE INVENTION

Immune-regulatory abnormalities are found in a number of "autoimmune" and chronic inflammatory diseases, such as systemic lupus erythematosis, chronic rheumatoid arthritis, type I and type II diabetes mellitus, inflammatory bone diseases, epecirrhosis, uveitis, multiple sclerosis , ulcerative colitis, bladder pemphigoid, sarcoidosis, psoriasis, scaling and Graves' eye disease. Although the pathogenesis behind these conditions may be quite different, the appearance of various autoantibodies and self-reactive lymphocytes is common. Such self-reactivity may be partly due to the loss of homeostatic control during which the normal immune system functions.

Similarly, after bone marrow or organ transplantation, the recipient's lymphocytes recognize foreign tissue antigens and begin to form antibodies, leading to rejection of the transplanted tissue.

One end result of an autoimmune or rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents such as NSAIDs and corticosteroids mainly act by blocking the action or secretion of these mediators, but do nothing to alter the immunological basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamides, act in a non-specific manner to deactivate both normal and autoimmune reactions. Indeed, patients treated with such non-specific immunosuppressive agents are equally likely to die of infections and autoimmune diseases.

Currently, the most commonly used active ingredient in the prevention of transplant rejection is cyclosporine A, which was authorized in 1983 by the US FDA. It works by preventing the body's immune system from mobilizing its various defenses to reject foreign proteins from the transplanted organ. Although cyclosporin A is effective in preventing transplant rejection, it is nephrotoxic and is known to have a number of undesirable side effects such as renal failure, abnormal liver function and gastrointestinal disorders.

Thus, new, safer, less active side effects with similar effects are in constant research.

The 23-membered tricyclo-macrolide is an immunosuppressant tacrolimus, FR 900506, FK-506 (17-allyl-1,14-dihydroxyl-12- [2 '- (4 "-hydroxy-3" -methoxy-cyclohexyl) -1']. -methyl 1-vinyl] -23,25-dimethoxy-13,19,2], 27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,

16-tetraone) and related compounds isolated and characterized by Tanaka, Kuroda et al., Japan, Fujisawa Pharmaceutical Co. (J. Am. Chem. Soc. 1987, 109, 5031, and 4,894,366). , U.S. Patent No. 4,198,161,1990, which was shown to be exceptional immunosuppressive. U.S. Patent Nos. 4,929,611, 4,956,352 and 5,110,811 to Fujisawa disclose the use of FK-506 compounds for the treatment of transplant resistance. More specifically, FR 900506 has been reported to be one hundred times more potent than cyclosporine in suppressing in vitro immune systems (see J. Antiobiotics, 1987, 40, 1256). In addition, the compounds are known to have local activity for the treatment of inflammatory and hyperproliferative skin diseases and skin phenomena associated with immunologically-mediated diseases (see European Patent Application Publication No. 0 315 978).

In addition, FK-506 and related compounds have been found to be effective in treating airway obstruction, particularly asthma (see International Patent Application Publication No. WO 90/14826), in the treatment of characteristic male baldness or in elderly baldness (see 0 423 714). European Patent Application Publication Publication No. 4,198,198, for the treatment of rheumatoid arthritis (see C. Arita et al., Clinical Exp. Immunol. 1990, 82, 456-461; N. Inamura et al., Clin. Immunol. ), for the treatment of sudden onset diabetes (see N. Murase et al., 1990, 39, 1584-86; et al., Chain, 1990, 336, 373-74), posterior uveitis (H. Kawashima, Invest. Ophthalmol. Vis. Sci., 1988, 29, 1265-71), liver injury with ischemia (M. Sakr et al., Life Sci. 1990, 47, 687-91), allergic brain inflammation (K. Deguchi et al., Brain Nerve). , 1990, 42, 391-97), glum erulonephritis (J. McCauley et al., Chain, 335, 674, 1990); and systemic lupus erythematosus (K. Takabayashi et al., Clin. Immunol. Immunpathol., 1989, 51, 110-117), multidrug resistance (M. Naito et al., Cancer Chemother. Pharmacol. 29, 195-200, 1992), mucosal and vascular inflammation (WO 91/17754). ), cytomegalovirus infection (British Patent Publication No. GB 2247620A), and primary treatment of purpura and Basedow's disease with decreased platelet count (International Patent Application Publication No. WO 91/19495).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel compounds of formula I and their pharmaceutically acceptable salts. In the general formula (I)

R ¹ is (1) heteroaryl, (2) substituted heteroalyl wherein the substituent is X, Y or Z, (3) heteroalyl (C 1 -C 10) alkyl,

A9 (4) substituted heteroalyl (C1-C10) alkyl wherein the heteroalyl is substituted with X, Y and Z and the alkyl moiety may be substituted with one or more of the following:

(a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) aryl (C 1-3) alkoxy, (e) substituted aryl (C 1-3) alkoxy, wherein the substituents on the aryl group are X, Y and Z, (f) the unsubstituted or substituted aryloxy group wherein the aryl substituents are X, Y and Z, (g) -OCO- (C 1 -C 6) alkyl, (h) -NR ⁶ is a group of the formula R ⁷ wherein R ⁶ and R ⁷ are each independently;

(i) hydrogen, (ii) C 1-10 alkyl, optionally substituted with one or more of the following:

(a ') aryl optionally X,

Y and Z may be substituted, (b ') heteroaryl optionally substituted with X, Y and Z, (c') hydroxy, (d ') C 1-6 alkoxy, (e') -CC b H , (f) -CO- (C 1-6 alkyl).

(g ') -C 3-7 cycloalkyl, and (h') -OR ¹¹ group of formula (iii) C3-10 alkenyl. optionally substituted with one or more of the following substituents:

(a ') an aryl group which is optionally X,

Y and Z may be substituted, (b ') heteroaryl optionally substituted with X, Y and Z, (c') hydroxyl, (C 1 -C 6 alkoxy), (e ') -CO ₂ H (f) -CO ₂ - (C 1 -C 6) alkyl, (g ') C 3 -C 7 cycloalkyl, and (h') -OR ¹¹ , (iv) or R ⁶ and R ⁷ together with the nitrogen atom to which it is attached, form an unsubstituted or substituted 3- to 7-membered heterocyclic ring containing one or more further heteroatoms selected from the group consisting of S (O) _p and O ¹⁴ where R ¹⁴ is hydrogen or optionally substituted with phenyl. C 1-6 alkyl, and p is 0, 1 or 2, such as morpholine, thiomorpholine, piperidine or piperazine;

(i) -NR ⁶ CO- (C 1 -C 6 alkyl) -R ⁷ wherein R ⁶ and R ⁷ are as defined above, (j) -NR ⁶ CO ₂ - (C 1 -C 6 alkyl) -R ⁷ , (k) -NR ⁶ CONR ⁶ R ⁷ , (1) -OCONR ⁶ R ⁷ , (m) -COOR ⁶ , (n) -CHO, o) aryl, (p) substituted aryl, wherein the substituent is X, Y and Z, (q) -OR ¹¹ , and (r) -S (O) _p - (C 1 -C 6) alkyl;

(5) heteroaryl-C 1 -C 4 alkyl, where one or more of the carbon atoms in the alkyl moiety is substituted, may be -NR ⁶ , oxygen, -S (O) _p , -CO ₂ -. -O ₂ C, -CONR ⁶ -, -NR ⁶ CO-, -NR ⁶ CONR ⁷ ;

(6) a substituted heteroaryl (1 K) -alkyl-alkyl-group in which one or more of the carbon atoms in the alkyl group is substituted may be: -NR ⁶ , -O, -S (O) _p -, CO ₂ , -O ₂ C, CONR ⁶ , -NR ⁶ CO- NR ⁶ CONR ⁷ ; the heteroaryl group is substituted by X, Y and Z and the alkyl group may be substituted by one or more of the following groups:

(a) hydroxy, (b) oxo, (c) (C 1 -C 6) alkoxy, (d) aryl (C 1 -C 3) alkoxy, (e) substituted aryl (C 1 -C 3) alkoxy, wherein the substituents on the aryl group are X, Y and Z, (f) optionally unsubstituted or substituted aryloxy, wherein the aryl substituents are X, Y and Z, (g) -OCO- (C 1 -C 6) alkyl, (h) -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above, (i) -NR ⁶ CO- (C 1 -C 6 alkyl) -R ⁷ , (j) -NR ⁶ CO ₂ - (C 1 -C 6 alkyl) -R ⁷ , (k) -NR ⁶ CONR ⁶ R ⁷ , (1) -OCONR ⁶ R ⁷ , (m) -COOR ⁶ , (n) -CHO, (o) aryl, (p) substituted aryl, wherein the substituents are X, Y and Z, (q) -OR, and

A9 (r) -S (O) _p - (C1-C6) alkyl;

(7) heteroaryl (C 3 -C 10) alkenyl wherein the alkenyl contains 1-4 double bonds;

(8) heteroaryl (C 3 -C 10) alkenyl wherein the alkenyl contains 1 to 4 double bonds and one or more of the alkyl carbon atoms is substituted, the substituent may be -NR ⁶ , oxygen, -S ( O) a group of the formula _p , -CO ₂ -, -O ₂ C, -CONR ⁶ -, -NR ⁶ CO-, -NR'CONR ⁷ ;

(9) a substituted heteroaryl (C 3 -C 10) alkenyl wherein the alkenyl contains 1 to 4 double bonds and one or more of the alkyl carbon atoms is substituted, the substituent may be: -NR ⁶ -; group, oxygen, -S (O) _p -. -CO ₂ -, -O ₂ C -, -CONR ⁶ -, -NR ⁶ CO -, -NR ⁶ CONR ⁷ - and the heteroaryl group is substituted with X, Y and Z, the alkyl group being and may be replaced by one or more of the following substituents:

(a) hydroxy, (b) oxo, (c) C 1-6 -alkoxy, (d) aryl-C 1-3 -alkoxy, (e) substituted aryl (C 1-3) -alkoxy, wherein the substituents on the aryl group are X, Y and Z, (f) optionally substituted aryloxy wherein the aryl substituents are X, Y and Z, (g) -OCO- (C 1 -C 6) alkyl, (h) -NR ^6; R ⁷ wherein R ⁶ and R ⁷ are as defined above, (i) -NR ⁶ CO- (C 1 -C 6 alkyl) -R ⁷ , (j) -NR ⁶ CO ₂ - (1-) C 6 alkyl-R ⁷ , (k) -NR ⁶ CONR ⁶ R ⁷ , (1) -OCONR ⁶ R ⁷ , (m) -COOR ⁶ , (n) - CHO, (o) aryl, (p) substituted aryl wherein X, Y and Z, (q) -OR ¹¹ are substituted, and (r) -S (O) _p - (C 1 -C 6) alkilj group;

R ² has the same meaning as R ¹ ;

(2) hydrogen;

(3) phenyl;

(4) substituted phenyl, wherein the substituent is

X, Y and Z;

(5) 1- or 2-naphthyl;

(6) a substituted 1- or 2-naphthyl group, wherein the substituent is X, Y and Z;

(7) biphenyl;

(8) substituted biphenyl wherein X, Y and Z are substituted;

(9) C 1-10 alkyl;

(10) substituted C 1 -C 10 alkyl, wherein the substituent is one or more of the following:

(a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) aryl (C 1-3) alkoxy, (e) substituted aryl (C 1-3) alkoxy, wherein the substituents on the aryl group are X, Y and Z, (f) optionally substituted aryloxy, wherein the aryl substituents are X, Y and Z, (g) -OCO- (C 1 -C 6) alkyl, (h) -NR ^6; R ⁷ wherein R ⁶ and R ⁷ are as defined above, (i) -NR ⁶ CO- (C 1 -C 6 alkyl) -R ⁷ wherein R ⁶ and R ⁷ are as defined above, (R ) -COOR ⁶ wherein R ⁶ is as defined above, (k) -CHO, (l) phenyl, (m) substituted phenyl, wherein the substituents are X, Y and Z, (η) 1- or 2 naphthyl, (o) substituted 1- or 2-naphthyl, where X, Y and Z are substituted, (p) biphenyl, (q) substituted biphenyl, wherein X, Y and Z are substituted, (r) -OR ¹¹ , and (s) - S (O) _p - (C 1 -C 6) alkyl;

(11) C 3-10 alkenyl;

(12) substituted C 3 -C 10 alkenyl, wherein the substituent is one or more of the following:

(a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) phenyl (C 1-3) alkoxy, (e) substituted phenyl (C 1-3) alkoxy, wherein the substituents on the phenyl group are X, Y and Z, (f) -OCO- (C 1 -C 6 alkyl), (g) -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above, (h) -NR ^{6 is} CO- (C 1 -C 6 alkyl) wherein R ⁶ is as defined above, (i) -COOR ⁶ wherein R ⁶ is as above, (j) -CHO-, (k) phenyl. , (l) substituted phenyl wherein X, Y and Z, (m) 1- or 2-naphthyl, are substituted,

A9 (n) substituted 1- or 2-naphthyl, wherein the substituent is X. Y and Z, (o) biphenyl, (p) substituted biphenyl, wherein the substituent is X, Y and Z, (q) - OR ¹¹ and (r) -S (O) _p - (C 1 -C 6) alkyl;

(13) C 3-10 alkynyl, (14) substituted C 3-10 alkynyl, wherein the substituent is one or more of the following:

(a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) phenyl (C 1-3) / alkoxy, (e) substituted phenyl (C 1-3) alkoxy, wherein the substituents on the phenyl group are X, Y and (R 1 -OCO- (C 1 -C 6) alkyl), (g) -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above, (h) -NR ^{6 is} CO- (C 1-6 alkyl) wherein R ⁶ is as defined above, (i) -COOR ⁶ wherein R ⁶ is as above, (j) -CHO-, (k) phenyl. , (l) substituted phenyl wherein X, Y and Z are substituted, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl wherein X and Y are Z, (o) biphenyl, (p) substituted biphenyl wherein the substituent is X. Y and Z, (q) -OR ¹¹ , and (15) -R;

R ³ is hydrogen, hydroxy. -OR ¹¹ . C 1-6 alkoxy;

R ⁴ is hydrogen or R ³ and R ⁴ together form a double bond;

^R5 is methyl, ethyl, propyl or allyl;

R ¹⁰ is hydrogen, hydroxy, -OR ¹¹ , or fluoro;

R ¹¹ is (a) -PO (OH) O'M ⁺ , wherein M ⁺ is a positively charged inorganic or organic anion, (b) -SO <M ⁺ , (c) -CO (CH ₂ ) q CO _{1 '} M ^+. wherein q is 13 and (d) -CO- (C 1 -C 6 alkyl) -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above and the alkyl moiety is optionally substituted with one or more of the following substituents: :

(i) hydroxy, (ii) C 1-6 alkoxy, (iii) -NR ¹⁶ R ¹⁷ , wherein R ¹⁶ and R ¹⁷ are each independently (a ') hydrogen, and (b) C 1-6 alkyl. , (iv) -COOR ⁶ wherein R ⁶ is as defined above, (v) phenyl, (vi) substituted phenyl wherein X, Y and Z are substituted, (vii) heteroaryl, (viii) -SH. and (ix) -S- (C 1 -C 6) alkyl;

W is oxo or (hydrogen and hydroxy);

X, Y and Z are each independently (a) hydrogen, (b) C 1-10 alkyl, which may be optionally substituted with one or more of the following:

(i) aryl, (ii) substituted aryl wherein X ', Y' and Z 'are substituted, (iii) heteroaryl, substituted heteroaryl wherein X', Y 'and Ζ', (v) optionally substituted aryl -oxy, in which the substituents on the aryl moiety are X ', Y'and Z', (vi) -OR ⁶ , (vii) -OR ⁶ , (viii) -OCOR ⁶ , (ix) -OCO ₂ R ⁶ , (x) -NR ⁶ R ⁷ , (xi) -CHO, (xii) -NR ⁶ CO- (C 1-6 alkyl) - R ⁷ , (xiii) -NR ⁶ CO ₂ - (C 1 -C 6 alkyl) -R ⁷ , (xiv) -NR ⁶ CONR ⁶ R ⁷ , (xv) -OCONR ⁶ R ⁷ , (xvi) -CONR ⁶ R ⁷ , (c) C 1 -C 10 alkyl, wherein one or more alkyl carbon atoms may be replaced by -NR ⁶ - t, oxygen, -S (O) _p -, -CO ₂ , -O ₂ C,

-CONR ⁶ -, -NR ⁶ CO -, -NR ⁶ CONR ⁷ -, -CO-, -CH (OH) -, alkenyl or alkenyl, and the alkyl is optionally substituted with one or more of the following:

(i) aryl, (ii) substituted aryl wherein X ', Y' and Z 'are substituted, (iii) heteroaryl, (iv) substituted heteroaryl wherein X', Y 'and Z' are substituted, (v) substituted aryloxy. wherein the substituents on the aryl moiety are X ^- . Y'.ésZ '

A9 (vi) -OR ⁶ , (vii) -OR ¹¹ , (viii) -OCOR ⁶ , (ix) -OCO ₂ R ⁶ , (x) - NR ⁶ R ⁷ , (xi) -CHO, (xii) -NR ⁶ CO- (C 1 -C 6 alkyl) -R ⁷ , (xiii) -NR ⁶ CO ₂ - (1- (C 6 -alkyl) -R ⁷ , (xiv) -NR ⁶ CONR ⁶ R ⁷ , (xv) -OCONR ⁶ R ⁷ , (xvi) -CONR ⁶ R ⁷ , ( d) halogen, (e) -NR ⁶ R ⁷ , (f) -CN, (g) -CHO, (h) -CH ₃ , (i) -SR ^8. wherein R ⁸ is hydrogen, C 1-6 alkyl, trifluoromethyl or phenyl, (j) -SOR ⁸ , (k) -SO ₂ R ⁸ , (1) -CONR ⁶ R ⁷ , (m) R ⁹ O (CH 2) m, a wherein R ⁹ is hydrogen, (C 1 -C 6) -alkyl, hydroxy (C 2 -C 3) -alkyl, -CF 3, phenyl, R ¹¹ or naphthyl, and m is 0,

1,2 or 3.

(n) -CH (OR ¹² ) (OR ¹³ ) wherein R ¹² and R ¹³ are C 1-3 alkyl or together form an ethyl or propyl bridge, (ο) O II

OR ⁹ CO (CH ₂ ) _m - wherein R ⁹ and m are as defined above, (p) O II

OR ^{9 is} CO (CH ₂ ) _m - wherein R ⁹ and m are as defined above and (q) -R ¹¹ ;

or any two of X, Y and Z may be taken together to form a saturated 5-, 6- or 7-membered ring, the ring atoms being one or two oxygen atoms and the other being a carbon atom such as dioxolanyl or dioxanyl;

X 'Y' and Z 'are independently selected from (a) hydrogen, (b) C 1-7 alkyl, (c) C 2-6 alkenyl, (d) halogen, (e) - (CH ₂ ) _m -NR ⁶ R ⁷ wherein R ⁶ , R ⁷ and m are as defined above, (f) -CN, (g) -CHO, (h) -CF ₃ , (i) -SR ⁸ ; wherein R ⁸ is hydrogen, C 1-6 alkyl, trifluoromethyl or phenyl; (j) -SOR ⁸ wherein R ⁸ is as defined above, (k) -SO ₂ R ⁸ a group wherein R ⁸ is as defined above, (1) -CONR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above, (m) R ⁹ O (CH ₂ ) _m wherein R ⁹ is the group (n) -CH (OR ¹² ) (OR ¹³ ) above wherein R ¹² and R ¹³ are as defined above, (ο) O II

R ^{9 is} CO (CH ₂ ) _m -, wherein R ⁹ and m are as defined above, (P) 0

II

R ^{9 is} CO (CH ₂ ) _m - wherein R ⁹ and m are as defined above and (q) -R ¹¹ ; n is 1 or 2.

The compounds of the present invention have asymmetric centers, and all optical isomers and mixtures thereof are encompassed by the present invention.

In addition, carbon-carbon double bond compounds can exist in Z- and E-forms, and this invention relates to all isomers of the compounds.

If a variable (e.g., alkyl, aryl, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁰ , X, Y, Z and the like) occurs more than once within any variable or in formula (I), its definition for each occurrence is independent of its definition at other occurrences.

As used herein, the term "alkyl" refers to alkyl groups having the specified number of carbon atoms, which may be straight, branched, or cyclic. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, chair and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. , cycloheptyl, norbomyl and the like. The term "alkoxy" refers to a C 1-6 alkyl group bonded through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy. The term "alkenyl" as used herein means a hydrocarbon chain having a predetermined number of carbon atoms and having at least one unsaturation at any point on the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethylpentyl and the like. They can be E or Z, where possible. By "heteroarylalkyl" is meant heteroaryl which is bonded through a straight or branched alkyl group having from 1 to 10 carbon atoms. By "halogen" is meant fluorine, chlorine, bromine or iodine.

One of ordinary skill in the art will recognize that pharmaceutically acceptable salts include, but are not limited to, salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide or nitrate, and salts with organic acids such as malate, maleate, fumarate, tartrate, citrate, acetate, lactate, methane sulfonate, paratolu7

A9 is understood to mean olsulfonate or palmoate, salicylate or stearate. Similarly, among the cations are pharmaceutically acceptable include, but are not limited to include the sodium, potassium, calcium, aluminum, lítiumés ammonium salt (including, in particular, HNR ⁶ R ⁷ of Formula ammonium salts formed with amines).

Exemplary heteroaryl groups include acridine, carbazole, cinnoline, dibenzofuran, dibenzothiophene, quinoxaline, pyrazole, indole, benzotriazole, furan, benzofuran, quinoline, isoquinoline, pyrazine, pyridazine, pyridine, pyrimidine. they are optionally substituted.

In the compounds of formula I, the heteroaryl group may be optionally substituted on X, Y and Z at any suitable carbon or nitrogen atom (if present), but certain X, Y and Z substituents directly on the heteroaryl ring nitrogen may be relatively unstable; are not beneficial.

As used herein, the term "heteroaryl" refers to the following heteroaromatic groups, which may have X, Y and Z substituents, as noted, and wherein Q is -N (X) -, -O-, -S-, -SO- or an -SO ₂ group: (a), (b), (c), (d), (e), (O, (g), (h), (i), (j), (k), (1), (m), (n), (o), (p), (q).

The aryl or aromatic group may be phenyl or naphthyl. which may be optionally substituted with 1 to 3 substituents independently selected from alkyl, alkenyl. halo. carboxyl, CHO-. amino. monoalkylamino, dialkylamino. aminoalkyl. monoalkyl amino alkyl. dialkyl aminoalkyl. alkylthio, alkylsulfinyl, alkylsulfonyl. trifluoromethyl, amido. mono-amido. dialkylamido. hydroxy, hydroxyalkyl, RO-alkyl, alkoxy. alkoxyalkyl, formamido, alkyl CO ₂ -. formamidoalkyl, alkyl-CO ₂ -alkyl, carboboxy, alkyl-CO ₂ H, alkyl-O ₂ C-, alkyl-O ₂ C-alkyl, or -OR.

In formula (I), heteroaryl is preferably selected from the group consisting of (20), (21), (22), (23), (24), (25). (26), (27), (28), (29), (30), (31), (32), (33), (34), (35) or (36) or the general formula: wherein X is as defined above.

The following substituent meanings in formula (I) are also preferred:

R ² is (1) hydrogen, (2) methyl, (3) ethyl, (4) propyl, (5) allyl, (6) R ¹¹ , (7) C 2 -C 3 alkyl-OH, and (8) C2-3 ^alkyl-OR11 group of the formula

R ³ is (1) hydrogen, (2) hydroxy, (3) -OR, or R ³ and R ^{4 taken} together form a double bond,

R ¹⁰ is hydrogen, hydroxy, fluoro, or -OR ¹¹ ,

W is oxygen and n is 2.

The present invention relates to compounds wherein the heteroaryl is a swept indole group represented by formula (37) or (38), wherein X, Y and Z are as defined above.

Preferred compounds of the present invention are:

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (2-furanyl) -3 '-methoxycyclohexyl) - r -methyl-vinyl] -23,25-dimethoxy-13.19.21.27 - tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4 "- (2-furanyl) -metoxi3" -hydroxy-cyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13.19.21. 27-tetramethyl-1,2,8-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' -hydroxy) -3 '- (2-furanyl) methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4- azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4 "- (2-thiophene) -metoxi3" -methoxy-cyclohexyl) -T-methylvinyl] -23,25-dimetoxi13.19.21.27 - tetramethyl-l l, 28-dioxa-4-azatricyclo [22.3.1.0 ^{4 9]} octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (2-thiophene) methoxy-3'-hydroxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13.19.21.27 - tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4 "- (3-thiophene) -metoxi3" -hydroxy-cyclohexyl) -r-methylvinyl] -23,25-dimetoxi13,19,21 , 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl 1-1,14-dihydroxy-12- (2 '- (4' -hydroxy-3 '- (2-thiophene) methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' -hydroxy-3 '' - (3-thiophene) methoxycyclohexyl) - r -methyl-vinyl] -23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,11,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (2-thiophene) -oxy-3 'methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19 , 21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4 "- (2-benzothienyl) -oxi3" -methoxy-cyclohexyl) -r-methylvinyl] -23,25-dimetoxi13,19,21 , 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3 'methoxycyclohexyl) -? - methylvinyl] -23,25-dimethoxy-13,19, 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3 'hydroxy-cyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13,19 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 &lt; ⁴ &gt;]ycatacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (5-indolyl) oxy] 3-methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy

HU 211 897 A9

13.19.21.27-Tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy13.19.21 .27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12- (2 '- (4' - (5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21. 27-Tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;octaquacos-18-ene-2,3,10,16-tetraone;

17-allyl-1,14-dihydroxy-12- (2 '- (4' - (5-indolyl) oxy-3 "methoxycyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13,19 , 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (5-Indolyl) oxy-3 'hydroxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-azatricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19 , 21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 9]} octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,20-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3''metoxi-cyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13, 19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo | 22.3.1.0 ^4-9] octacos-18-ene-2,3,10.16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy13.19.21 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁹ &gt;]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- (2 '- (4' - (5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy13.19.21 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] octacos-18-ene-2,3,11,16-tetraone;

17-Allyl-1-hydroxy-12- (2 '- (4' - (5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21. 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [2 2.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3-methoxycyclohexyl) -methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone;

17-Elyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-methyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] - 23,25dimeloxi-13,19,21,27-tetramethyl-l 1, 28-dioxa-4-azatricyclo [03.22.10 ^4-9] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-trichloro [22.3.1.0 ^4.9 ] octacos-18-ene-2,3,10,16- tetraone; 17-Ethyl-l, 20-dihydroxy-12- [2 '- (4 "- (lN-methyl-5-indolyl) oxy-3' -meloxi-cyclohexyl) -l'-methylvinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1-methyl-5-indolyl) oxy-3-hydroxycyclohexyl) -methyl-vinyl] -23,2510 dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]lokactos-18-ene-2,3,10,16-tetraone;

17-Allyl 1,1,14-Dihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;Joktakoz-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl- vinyl] -23,25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone;

17-Allyl-1,20-dihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatric azabicyclo [22.3.1 .0 ^49] octacos-18-ene-2,3,10,16-tetraone 17-Ethyl-1-hydroxy-12- (2 '- (4' - (1-methyl-5-indolyl) oxy 3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Allyl-l, 14-dihydroxy-12- (2 '- (4 "- (lN-methyl-5-indolyl) oxy-3' -ethoxy-cyclohexyl) -l'-methylvinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 2,10 &gt;]octoclocos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1N-methyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-methyl-5-indolyl) oxy-3 'allyloxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-dihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'allyloxycyclohexyl) -methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 '-n-propyloxy-cyclohexyl) -1'-methyl -vinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16- tetraone;

17-Ethyl-1-hydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy 3 '-n-propyloxy-cyclohexyl) -1'-methyl-vinyl ] -23,25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;] joktakoz-18-ene-2,3,10,16- tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 '-propyloxy-cyclohexyl) -methyl- methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatriciklo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23 25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.10 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

HU 211 897 A9

17-Ethyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0] -cyclo-lactos-18-ene-2,3,10,16-tetraone; 17-ethyl-l, 20-dihydroxy-12- [2 '- (4 "- (lN-ethyl-5-indolyl) oxy-3" -methoxy-cyclohexyl) -l'-methylvinyl] -23,25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-ethyl-5-indole 1) oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 2,10-octacos-18-ene-2,3,10,16-tetraone;

17-allyl-1,14-dihydroxy-12- [2 '- (4 "- (lN-ethyl-5-indolyl) oxy-3" -methoxy-cyclohexyl) -l'-methylvinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 2,10-octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1' methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11.28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone ;

17-Allyl-l, 20-dihydroxy-12- [2 '- (4 "- (lN-ethyl-5-indolyl) oxy-3" -methoxy-cyclohexyl) -l'-methylvinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 2,10 &gt;]octoclocos-18-ene-2,3,10,16-tetraone;

17-Al 11-14-Dihydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclof 22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3-methoxy-cyclohexyl) -1'-methyl-vinyl] -23.25-dimethoxy-13.19.21.27 - tetramethyl-11,28-dioxa-4-aza-tricyclo [2.2.3.1.0 &lt; ⁴ &gt;] ⁹ -octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy .19.21.27- tetramethyl-11,28-dioxa-4-azatricyclo 122.3.1.0 ^{4 9]} oklakoz-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3-ethoxycyclohexyl) -1'-methyl vinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 '' methoxycyclohexyl) -1-methylvinyl) -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'methoxycyclohexyl) -methyl-vinyl] -23 25-dimethoxy-13,19,21,27-tetramethyl-1,28,8-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [2 2.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'hydroxycyclohexyl) -1'-methyl vinyl] - 23,25dimetoxi- 13,19,21,27-tetramethyl-11,28-dioxa-4-o azatrici out octacos-l 8-ene-2,3,10,16-tetraone [22.3.1.0 ^{4 '9];} 17-Ethyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 '' hydroxycyclohexyl]) - 1'-methyl vinyl] - 23,25dimetoxi- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10.16-tetraone;

17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-13,19,2 1,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'methoxycyclohexyl) -r-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 2,10 &gt;]octocacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1, 20-dihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,1,2,2,2,2-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy - 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;]octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] -23 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl 1-1,14-dihydroxy-12- (2 '- <4' - (1N-allyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;]octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl 1-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-allyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1' - methyl vinyl] -23,25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone 17-Ethyl-1,20-dihydroxy-12- (2 '- (4' - (1N-allyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-1, 3,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 1,14-Dihydroxy-12-1,2 '- (4' - (1N-allyl-5-indolyl) oxy-3-hydroxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-N-allyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl ] -23.25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1N-allyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] -23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

HU 211 897 A9

17-Allyl-l, 14-dihydroxy-12- [2 '- (4 "- (lN-allyl-5-indolyl) oxy-3" -methoxy-cyclohexyl) -l'-methylvinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 (1H-Joktakoz-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12- [2 ^; - (4 "- (1-N-Allyl-5-indolyl) -oxy-3" -methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11 28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ -octaco-18-2,3,10,16-tetraone;

17-Allyl-1,20-dihydroxy-12- [2 '- (4' - (1N-allyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- (2 '- (4' - (1N-allyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -methyl-vinyl] -23,25-dimethoxy - 13,19,21,27-tetramethyl-l 1, 28-dioxa-4-azatricyclo [22.3.1,0 ^4-9] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12- (2 '- (4' - (1-N-allyl-5-indolyl) oxy3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25- dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12- (2 '- (4 "- (lN-allyl-5-indolyl) -oxi3'-methoxycyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13. 19.21.27-Tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4 "- (lN-allyl-5-indolyl) oxy-3' -ethoxy-cyclohexyl) -l'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ -octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1N-allyl-5-indolyl) oxy-3-ethoxycyclohexyl) -1'-methyl vinyl] -23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-Ν-2-hydroxyethyl-5-indolyl) oxy-3 ”methoxycyclohexyl) -1′-methyl vinyl ] 23.25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatriciklo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-β-2-hydroxyethyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16tetraon ;

17-Ethyl-1,20-dihydroxy-12- (2 '- (4' - (1-β-2-hydroxyethyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl ] 23.25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-β-2-hydroxyethyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl vinyl ] 23.25-dimethoxy-13,19,21,27-tetramethyl-1,2,8-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (1N-2-hydroxyethyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1,0 ^4-9] octacos-18-ene-2,3,10,16tetraon ;

17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1-Ν-2-hydroxyethyl-5-indolyl) oxy-3 ′ -hydroxycyclohexyl) -1'-methyl-vinyl ] 23.25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-2-hydroxyethyl)

5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl vinyl] 23.25-dimethoxy-13,19,21,27-tetramethyl-1, 28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-hydroxyethyl-5-indolyl) -oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] 23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 &lt; 4 &gt;]joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-benzyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23, 25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl- vinyl] -23,25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl I-1,14-dihydroxy-12- (2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl- vinyl] -23,25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l, 20-dihydroxy-12- [2 '- (4 "- (lN-benzyl-5-indolyl) oxy-3" -hydroxy-cyclohexyl) -l'-methylvinyl] -23, 25dimetoxi- 13,19,21,27-tetramethyl-1,28-dioxa-4-azatric azabicyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] - 23.25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1' -methyl -vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt; -] lactocta-18-ene-2,3,10,16 tetrone;

17-Allyl-1,20-dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;Joktakoz-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl] - 23.25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12- (2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1-hydroxy-12- (2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

HU 211 897 A9

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -methyl-vinyl] -23 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-benzyl-5-indolyl) oxy-3 '-ethoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-azatriciklof22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -methyl-vinyl] 23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl vinyl] 23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] 23.25-dimethoxy -13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) -oxy-3 '' -hydroxycyclohexyl) -1'-methyl-vinyl] 23.25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3 '-ethoxycyclohexyl) -1'-methyl vinyl] -23.25-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 &lt; ⁴ &gt;] octacos-18-ene-2,3,10,16-tetraone;

17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) -oxy-3 '-ethoxy-cyclohexyl) -1'-methyl-vinyl] -23, 25dimetoxi 13.19.21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-l-hydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3-methoxy-cyclohexyl) -r-methylvinyl] -23,25- dimethoxy-13.19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2.3.10.16-tetraone;

17-Allyl-1-hydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1-hydroxy-12- [2 '- (4' -methoxy-N-tryptophanylcarbonylmethoxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] 23.25-dimethoxy-13,19 , 21,27-tetramethyl-11,28-dioxa-4azatriciklo [22.3.1,04,9] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1.14-dihydroxy-12- [2 '- (4' - (3-indolyl) ethyl-amino-carbonyl-methoxy-3 "-methoxy-cyclohexyl) -r-methylvinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1- (3-hydroxypropyl) indol-5-yl) oxy-3 'methoxycyclohexyl) -r-methyl vinyl ] 23.25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (3' -hydroxy-4 '- (1-hydroxyethylindol-5-yl) oxycyclohexyl) -1'-methyl vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-cyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone ;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-hydroxyethylindol6-yl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-l, 14-dihydroxy-12- [2 '- (4 "- (l-methyl-indol-6-yl) oxy-3" -methoxy-cyclohexyl) -l'-methylvinyl] -23 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-dibenzylphosphonyoxyethylindol-5-yl) oxy-3 'methoxycyclohexyl) -1'-methyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo [22.3.1,04,9] octacos-18-én2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-phosphonyloxyethylindol-5-yl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl ] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,11,16-tetraone monopotassium salt;

17-Ethyl-1,14-dihydroxy-12- (2 '- (4 "- (1- (N, N-dimethylglycyloxy) ethylindol-5-yl) oxy-3") -methoxycyclohexyl) -1'-methyl-1-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1,04,9] octacos-18 -en2.3.10.16- tetraon;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-succinyloxyethylindol-5-yl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl ] -23,25-dimethoxy-13.19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16tetraon;

17-Ethyl-l, 14-dihydroxy-12- [2 '- (4 "- (l-methyl-3-phenyl-indol-5-yl) oxy-3" -methoxy-cyclohexyl) -l'-methyl -vinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16 tetrone;

17-Ethyl 1 -1,14-dihydroxy-12- [2 '- (4' - (1-methyl-3- (2-hydroxyethyl) indol-5-yl) oxy-3 'methoxy) cyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene 2,3.10.16-tetraone ;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1,3-dimethylindol-5-yl) oxy-3 '-methoxy-cyclohexyl) -methyl-vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl 1-1,14-dihydroxy-12- [2 '- (4' - (- 9'-methylcarbazol-3'-yl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl ] -23,25dimetoxi-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (3 '''-diethylamino-propionyloxy) -ethyl) -indol-5'')) ) -oxy-3 '-methoxy-cyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18- I-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (3 '''- dimethylaminopropionyloxy) ethyl) indole-5'') yl) oxy-3 '-methoxy-cyclohexyl) -1'-methylvinyl] -23,25-dimetoxi13.19.21.27- tetramethyl-1,28-dioxa-4-azatricyclo ^[4 22.3.1Ό ⁹ ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4 "- ((2" "- (3" ") -amine)

A9 nopropionyloxy) ethyl) indol-5 "'-yl) oxy-3" methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl- 1, 1,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (3 '' ') benzyloxycarbonyl-2' '') - benzyloxycarbonylamino) -propionyloxy-ethyl) -indol-5 '' -yl) -oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27- tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '- (aspartyloxy) ethyl) indol-5' '-yl) oxy-3' methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 2,10 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (1 '''-imidazolylcarbonyloxy) ethyl) indol-5''-yl) oxy-3 "-methoxy-cyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1 0 ^{4 9]} octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (1 '''- piperazinecarbonyloxy) ethyl) indol-5''-yl) -oxy-3 '-methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; + &gt;I-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((1 '' -2 '' - (2-hydroxy) ethylaminocarbonyloxy) ethyl) ) -indol-5''-yl) oxy-3-methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11.28-dioxa-4-aza-tricyclo [2 2.3.1.0 + 'joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '''- isopropylaminocarbonyloxy) ethyl) indol-5''-yl ) oxy-3 "-methoxy-cyclohexyl) -r-methylvinyl] -23,25-dimetoxi13.19.21.27- tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] oktakoz- 18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '- (2''-(1'') piperidinecarbonyloxy) ethyl) indol-5' yl) oxy -3 "methoxycyclohexyl) -! '-methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos-18-ene-2,3,10,16-tetraone ;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '''-(1''') morpholinocarbonyloxy) ethyl) -indole-5 ''-yl)oxy-3' -methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '' - (diphenylaminocarbonyloxy) ethyl) indol-5 '''-yl) -oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; + &gt;I-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '- (diethylaminocarbonyloxy) ethyl) indol-5''yl) oxy -3 '-metoxiciklohexil) -l'-methylvinyl] -23,25-dimetoxi13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1,04,9] octacos-18 -en-2,3,11,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '' - methanesulfonyloxy) ethyl) indol-5 '' -yl) oxy-3 '-Methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos18-ene- 2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '-azidoethyl) indol-5''-yl)oxy-3' methoxycyclohexyl) -l 'methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo [22.3.1.0 ^{4' 9]} octacos-18-én2,3,10,16- tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '-aminoethyl) -indol-5''-yl)oxy-3' methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' t-butyldimethylsilyloxyethoxyethylindol-5 '' -yl) oxy-3 ' -methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos18-ene -2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' -hydroxyethoxyethylindol-5 '' -yl) oxy-3-methoxycyclohexyl) -1'- methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo [22.3.1Ό ^{4 9]} octacos-18-én2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12- [2 '- (3 "-methoxy-4" - (1 "'(1""-oxoprop-1""-yl)-indol-5") -yl) oxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene2 , 3,10,16-tetraone; and

17-Ethyl-1,14-dihydroxy-12- [2 '- (3' '-methoxy-4' '- (1' '- (1' ') -carboxyeth-2' '-yl) -indol-5') 1'-yl) -oxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.04,9] octacos- 18 én2,3,10,16-tetraone;

Representative compounds of the present invention are compounds of formulas (X), (XI), (XII) and (ΧΠΙ), wherein R ^6a is hydrogen or methyl and R ² , R ³ , R ⁵ , R ⁶ and R ⁷ are from the following table.

R ⁶ R ⁷ R ² R ³ R ⁵ phenyl phenyl ch ₃ OH ethyl phenyl H ch ₃ OH ethyl benzyl H ch ₃ OH ethyl 4-benzyl-HO22C H ch, OH ethyl 4-H ₂ NCO-benzyl H ch ₃ OH ethyl 4-CH ₃ O-benzyl H ch ₃ OH ethyl 4-HO-benzyl H ch ₃ OH ethyl 4-C1-benzyl H ch ₃ OH ethyl 4- (CH ₃ ) ₂ N-benzyl H CH OH ethyl 3-HO ₂ C-benzyl H CH OH ethyl 3-H ₂ NCO-benzyl H ch ₃ OH ethyl _3-CH3 O-benzyl H ch ₃ OH ethyl 3-HO-benzyl H ch ₃ OH ethyl 3-Cl-benzyl H CH OH ethyl 3- (CH ₂ ) ₂ N-benzyl H CH OH ethyl 4-pyridyl H CH OH ethyl 3-pyridyl H CH OH ethyl

HU 211 897 A9

R ⁶ R ⁷ R ² R ³ R ⁵ 2-pyridyl H ch ₃ OH ethyl 4-pyridylmethyl H ch, OH ethyl 3-pyridylmethyl H ch, OH ethyl 2-pyridylmethyl H ch ₃ OH ethyl phenyl phenyl ch, H ethyl phenyl H ch, H ethyl benzyl H ch ₃ H ethyl 4-HO ₂ 2C-benzyl H ch, H ethyl 4-H ₂ NCO-benzyl H ch, H ethyl 4-CH ₃ O-benzyl H ch ₃ H ethyl 4-HO-benzyl H ch ₃ H ethyl 4-Cl-benzyl H ch ₃ H ethyl 4- (CH ₂ ) ₂ N-benzyl H ch, H ethyl 3-HO ₂ C-benzyl H ch, H ethyl 3-H _; NCO-benzyl H ch, H ethyl 3-CH, O-benil H ch, H ethyl 3-HO-benzyl H ch, H ethyl 3-Cl-benzyl H CH H ethyl 3- (CH ₂ ) ₂ N-benzyl H CH H ethyl 4-pyridyl H CH H ethyl 3-pyridyl H CH H ethyl 2-pyridyl H CH H ethyl 4-pyridyl-methyl H CH H ethyl 3-pyridyl-methyl H CH H ethyl 2-pyridylmethyl H CH H ethyl phenyl phenyl CH OH allyl phenyl H CH OH allyl benzyl H CH OH allyl 4-HO ₂ C-benzyl H CH OH allyl 4-H ₂ NCO-benzyl H CH OH allyl 4-CH, O-benzyl H CH OH allyl 4-HO-benzyl H CH OH allyl 4-Cl-benzyl H CH OH allyl 4- (CH ₂ ) ₂ N-benzyl H CH OH allyl 3-HO ₂ C-benzyl H CH OH allyl 3-H ₂ NCO-benzyl H CH OH allyl 3-CH, O-benzyl H CH OH allyl 3-HO-benzyl H CH OH allyl 3-Cl-benzyl H CH OH allyl 3- (CH ₂ ) ₂ N-benzyl H CH OH allyl 4-pyridyl H CH OH allyl 3-pyridyl H CH OH allyl 2-pyridyl H CH OH allyl 4-pyridylmethyl H CH OH allyl

R ⁶ R ⁷ R ² R ³ R ⁵ 3-pyridylmethyl H CH OH allyl 2-pyridylmethyl Η ch ₃ OH allyl CH ₃ H ch ₃ OH ethyl ch ₃ ch ₂ Η ch ₃ OH ethyl ch ₃ ch ₂ ch ₂ H ch ₃ OH ethyl (CH ₃ ) ₂ CH H ch ₃ OH ethyl ho ₂ cch ₂ ch ₂ H ch ₃ OH ethyl h ₂ ncoch ₂ ch ₂ H CH OH ethyl hoch ₂ ch ₂ H CH ₃ OH ethyl hoch ₂ ch ₂ ch ₂ H ch ₃ OH ethyl ch ₃ CH ch ₃ OH ethyl ch ₃ ch ₂ CH, CH ₂ ch ₃ OH ethyl ch ₃ ch ₂ ch ₂ CH ₃ CH ₂ CH ₂ CH OH ethyl hoch ₂ ch ₂ hoch ₂ ch ₂ ch, OH ethyl hoch ₂ ch ₂ ch ₂ hoch ₂ ch ₂ ch ₂ ch ₃ OH ethyl CH Η CH H ethyl ch ₃ ch ₂ H CH H ethyl ch, ch ₂ ch ₂ H CH H ethyl (CH ₂ ) ₂ CH H CH H ethyl ho ₂ cch ₂ ch ₂ H CH H ethyl h ₂ ncoch ₂ ch ₂ H CH ₃ H ethyl HOCH ₂ CHt H CH H ethyl hoch ₂ ch ₂ ch ₂ H CH H ethyl CH CH CH H ethyl ch, ch ₂ ch, ch ₂ CH H ethyl ch, ch ₂ ch ₂ ch, ch ₂ ch ₂ CH H ethyl hoch ₂ ch ₂ hoch ₂ ch ₂ CH H ethyl hoch ₂ ch ₂ ch ₂ hoch ₂ - ch ₂ ch ₂ CH H ethyl CH Η H OH ethyl ch ₃ ch ₂ Η H OH ethyl ch, ch ₂ ch ₂ Η H OH ethyl (CH ₂ ) ₂ CH Η H OH ethyl ho, cch ₂ ch ₂ Η H OH ethyl h ₂ ncoch ₂ ch ₂ Η H OH ethyl hoch ₂ ch ₂ Η H OH ethyl hoch ₂ ch ₂ ch ₂ Η H OH ethyl CH CH H OH ethyl ch, ch ₂ CH ₃ CH ₂ H OH ethyl ch, ch ₂ ch ₂ ch ₃ ch ₂ ch ₂ H OH ethyl hoch ₂ ch ₂ hoch ₂ ch ₂ H OH ethyl hoch ₂ ch ₂ ch ₂ hoch ₂ - ch ₂ ch ₂ H OH ethyl

HU 211 897 A9

R ⁶ R ⁷ R ² R ³ R ⁵ -CH ₂ CH ₂ - och ₂ ch ₂ - ch ₃ H ethyl -CH ₂ CH ₂ -CH ₂ CH ₂ CH ₂ ch ₃ H ethyl -ch ₂ ch ₂ - och ₂ ch ₂ - ch ₃ OH ethyl -ch ₂ ch ₂ - ch ₂ ch ₂ ch ₂ H OH ethyl -ch ₂ ch ₂ - och ₂ ch ₂ - H OH ethyl -ch ₂ ch ₂ - ch ₂ ch ₂ ch ₂ H OH ethyl -ch ₂ ch ₂ - och ₂ ch ₂ - ch, H allyl -ch ₂ ch ₂ - ch ₂ ch ₂ ch ₂ ch ₃ H allyl -ch ₂ ch ₂ - och ₂ ch ₂ - ch, OH allyl -ch ₂ ch ₂ - CH ₂ CH ₂ CH ₂ H OH allyl Γ -ch ₂ ch ₂ - och ₂ ch ₂ - H OH allyl -ch ₂ ch ₂ - ch ₂ ch ₂ ch ₂ H OH allyl

Also representative of the compounds of the present invention are the formulas XIV, XV, XVI and XVII, wherein R ^6a is hydrogen or methyl and R ² , R ³ , R ⁵ and R ⁶ are as defined in the following table. selected:

R ⁶ R ² R ³ R ⁵ H CH OH ethyl CH CH OH ethyl CH ₃ CH ₂ CH OH ethyl ch ₂ = chch-, CH OH ethyl ch, ch ₂ ch ₂ CH OH ethyl (CH ₃ ) ₂ CH ch ₃ OH ethyl ho ₂ cch ₂ ch ₂ ch ₃ OH ethyl h ₂ ncoch ₂ ch ₂ ch ₃ OH ethyl hoch ₂ ch ₂ ch ₃ OH ethyl hoch ₂ ch ₂ ch ₂ ch ₃ OH ethyl (CH ₂ ) ₂ CH ₂ ch, OH ethyl phenyl ch ₃ OH ethyl 4-pyridyl ch ₃ OH ethyl 3-pyridyl ch ₃ OH ethyl 2-pyridyl ch, OH ethyl 4-pyridylmethyl ch ₃ OH ethyl 3-pyridylmethyl ch, OH ethyl 2-pyridylmethyl ch ₃ OH ethyl benzyl CH OH ethyl 4-HO ₂ C-benzyl CH OH ethyl

R ⁶ R ² R ³ R ⁵ 4-H ₂ NCO-benzyl ch ₃ OH ethyl 4-CH ₃ O-benzyl ch ₃ OH ethyl 4-HO-benzyl ch ₃ OH ethyl 4-C1-benzyl ch ₃ OH ethyl 4- (CH ₃ ) ₂ N-benzyl ch ₃ OH ethyl 3-HO ₂ C-benzyl ch ₃ OH ethyl 3-H ₂ NCO-benzyl ch ₃ OH ethyl 3-CH ₃ benzyl ch ₃ OH ethyl 3-HO-benzyl ch ₃ OH ethyl 3-Cl-benzyl ch ₃ OH ethyl 3- (CH ₃ ) ₂ N-benzyl ch ₃ OH ethyl 2-HO ₂ C-benzyl CH OH ethyl 2-H ₂ NCO-benzyl-benzyl ch ₃ OH ethyl 2- (CH ₃ ) O-benzyl CH OH ethyl CH ch ₃ H ethyl CH ₃ CH ₂ ch ₃ H ethyl ch ₂ = chch ₂ ch ₃ H ethyl ch ₃ ch ₂ ch ₂ ch, H ethyl (CH ₃ ) ₂ CH ch, H ethyl ho ₂ cch ₂ ch ₂ ch ₃ H ethyl h ₂ ncoch ₂ ch ₂ ch ₃ H ethyl hoch ₂ ch ₂ CH H ethyl hoch ₂ ch ₂ ch ₂ ch ₃ H ethyl (CH ₂ ) ₂ CH ₂ CH H ethyl phenyl CH H ethyl 4-pyridyl CH H ethyl 3-pyridyl CH ₃ H ethyl 2-pyridyl CH H ethyl 4-pyridylmethyl CH H ethyl 3-pyridylmethyl CH H ethyl 2-pyridylmethyl ch ₃ H ethyl benzyl CH H ethyl 4-HO ₂ C-benzyl ch ₃ H ethyl 4-H ₂ NCO-benzyl CH H ethyl 4-CH, O-benzyl CH H ethyl 4-HO-benzyl ch ₃ H ethyl 4-Cl-benzyl ch ₃ H ethyl 4- (CH ₃ ) ₂ N-benzyl ch ₃ H ethyl 3-HO ₂ C-benzyl ch ₃ H ethyl 3-H ₂ NCO-benzyl CH H ethyl 3-CH ₃ benzyl CH H ethyl 3-HO-benzyl ch ₃ H ethyl 3-Cl-benzyl ch ₃ H ethyl 3- (CH ₂ ) ₂ N-benzyl ch, H ethyl 2-HO-benzyl ch, H ethyl 2-Cl-benzyl ch ₃ H ethyl 2- (CH ₂ ) ₂ N-benzyl CH H ethyl 2-HO-benzyl CH H ethyl

HU 211 897 A9

R ⁶ R ² R ³ R ⁵ 2-Cl-benzyl ch ₃ H ethyl 2- (CH ₃ ) ₂ N-benzyl ch ₃ H ethyl ch, ch, OH allyl ch ₃ ch ₂ ch, OH allyl ch ₂ = chch ₂ ch ₃ OH allyl ch ₃ ch ₂ ch ₂ ch ₃ OH allyl (CH ₃ ) ₂ CH ch ₃ OH allyl ho ₂ cch ₂ ch ₂ ch, OH allyl h ₂ ncoch ₂ ch ₂ ch, OH allyl hoch ₂ ch ₂ ch ₃ OH allyl hoch ₂ ch ₂ ch ₂ ch ₃ OH allyl (CH ₃ ) ₂ CH ₂ ch, OH allyl phenyl ch, OH allyl 4-pyridyl ch, OH allyl 3-pyridyl ch, OH allyl 2-pyridyl ch, OH allyl 4-pyridylmethyl CH OH allyl 3-pyridylmethyl CH OH allyl 2-pyridylmethyl CH OH allyl benzyl CH OH allyl 4-HO ₂ C-benzyl CH OH allyl 4-H ₂ NCO-benzyl CH OH allyl 4-CH, O-benzyl CH OH allyl 4-HO-benzyl CH OH allyl 4-Cl-benzyl CH OH allyl 4- (CH ₂ ) ₂ N-benzyl CH OH allyl 3-HO ₂ C-benzyl CH OH allyl 3-H ₂ NCO-benzyl CH OH allyl 3-CH, -benzyl CH OH allyl 3-HO-benzyl CH OH allyl 3-Cl-benzyl CH OH allyl 3- (CH,) iN-benzyl CH OH allyl 2-HO _; benzyl CH OH allyl 2-H ₂ NCO-benzine] CH OH allyl 2-CH, O-benzyl CH OH allyl 2-HO-benzyl CH OH allyl 2-Cl-benzyl CH OH allyl 2- (CH ₂ ) ₂ N-benzyl CH OH allyl

Other representative compounds of the present invention are compounds of formulas XVIII, XIX, XX and XXI wherein R ^6a is hydrogen or methyl and R a, R ² , R ³ and R ⁵ are selected from the following table.

Ra R ² R ³ R ⁵ CH CH OH ethyl ch, ch ₂ CH OH ethyl ch ₂ = chch ₂ CH ₃ OH ethyl ch ₃ ch ₂ ch. CH OH ethyl

(CH ₃ ) ₂ CH CH OH ethyl ho ₂ cch ₂ ch ₂ CH OH ethyl h ₂ ncoch ₂ ch ₂ CH OH ethyl hoch ₂ ch ₂ CH OH ethyl hoch ₂ ch ₂ ch ₂ CH OH ethyl (CH ₂ ) ₂ CH ₂ ch ₃ OH ethyl phenyl ch ₃ OH ethyl 4-pyridyl ch ₃ OH ethyl 3-pyridyl ch ₃ OH ethyl 2-pyridyl ch ₃ OH ethyl 4-pyridylmethyl CH OH ethyl 3-pyridylmethyl ch ₃ OH ethyl 2-pyridylmethyl ch ₃ OH ethyl benzyl ch, OH ethyl 4-HO ₂ C-benzyl CH OH ethyl 4-H ₂ NCO-benzyl CH OH ethyl 4-CH, O-benzyl ch ₃ OH ethyl 4-HO-benzyl CH OH ethyl 4-Cl-benzyl CH OH ethyl 4- (CH ₂ ) ₂ N-benzyl CH OH ethyl 3-HO ₂ C-benzyl CH OH ethyl 3-H ₂ NCO-benzyl CH OH ethyl 3-CH, O-benzyl CH OH ethyl 3-HO-benzyl CH OH ethyl 3-Cl-benzyl CH OH ethyl 3- (CH ₂ ) ₂ N-benzyl CH OH ethyl 2-HO ₂ C-benzyl CH OH ethyl 2-H ₂ NCO-benzyl CH OH ethyl 2-CH, O-benzyl CH OH ethyl 2-HO-benzyl ch ₃ OH ethyl 2-Cl-benzyl CH OH ethyl 2- (CH ₃ ) _2. '- benzyl CH OH ethyl CH CH H ethyl CH ₃ CH ₂ CH H ethyl ch ₂ = chch ₂ CH H ethyl ch, ch ₂ ch ₂ ch ₃ H ethyl (CH ₃ ) ₂ CH CH H ethyl ho ₂ cch ₂ ch ₂ CH H ethyl h ₂ ncoch ₂ ch ₂ CH H ethyl hoch ₂ ch ₂ CH H ethyl hoch ₂ ch ₂ ch ₂ CH H ethyl (CH ₂ ) ₂ CH ₂ CH H ethyl phenyl CH H ethyl 4-pyridyl CH H ethyl

HU 211 897 A9

3-pyridyl ch, H ethyl 2-pyridyl ch ₃ H ethyl 4-pyridylmethyl ch ₃ H ethyl 3-pyridylmethyl ch ₃ H ethyl 2-pyridylmethyl ch ₃ H ethyl benzyl ch, H ethyl 4-HO ₂ C-benzyl ch ₃ H ethyl 4-H ₂ NCO-benzyl ch ₃ H ethyl 4-CH, O-benzyl ch ₃ H ethyl 4-HO-benzyl ch. H ethyl 4-Cl-benzyl ch ₃ H ethyl 4- (CH ₃ ) ₂ N-benzyl CH H ethyl 3-HO ₂ C-benzyl CH H ethyl 3-H ₂ NCO-benzyl ch ₃ H ethyl 3-CH, O-benzyl ch ₃ H ethyl 3-HO-benzyl i ch, H ethyl 3-Cl-benzyl ch, H ethyl 3- (CH ₂ ) ₂ N-benzyl ch. H ethyl 2-HO ₂ C-benzyl CH H ethyl 2-H ₂ NCO-benzyl CH H ethyl 2-CH, O-benzyl ch, H ethyl 2-HO-benzyl CH H ethyl 2-Cl-benzyl CH H ethyl 2- (CH ₂ ) ₂ N-benzyl CH H ethyl CH CH OH allyl CH, CH _; CH OH allyl ch ₂ = chch ₂ CH OH allyl ch, ch ₂ ch ₂ CH OH allyl (CH ₂ ) ₂ CH CH OH allyl ho ₂ cch ₂ ch ₂ CH OH allyl h ₂ ncoch ₂ ch ₂ CH OH allyl hoch ₂ ch ₂ CH OH allyl hoch ₂ ch ₂ ch ₂ CH ₃ OH allyl (CH ₂ ) ₂ CH ₂ CH OH allyl phenyl ch ₃ OH allyl 4-pyridyl CH OH allyl 3-pyridyl CH OH allyl 2-pyridyl CH OH allyl 4-pyridylmethyl CH ₃ OH allyl 3-pyridylmethyl ch ₃ OH allyl 2-pyridylmethyl CH OH allyl benzyl CH OH allyl 4-HO ₂ C-benzyl CH OH allyl 4-H ₂ NCO-benzyl CH OH allyl 4-CH ₃ O-benzyl CH OH allyl

4-HO-benzyl ch ₃ OH allyl 4-Cl-benzyl ch ₃ OH allyl 4- (CH ₃ ) ₂ N-benzyl ch ₃ OH allyl 3-HO ₂ C-benzyl ch ₃ OH allyl 3-H ₂ NCO-benzyl ch ₃ OH allyl _3-CH3 O-benzyl ch ₃ OH allyl 3-HO-benzyl ch ₃ OH allyl 3-Cl-benzyl ch ₃ OH allyl 3- (CH ₃ ) ₂ N-benzyl ch ₃ OH allyl 2-HO ₂ C-benzyl ch, OH allyl 2-H ₂ NCO-benzyl ch ₃ OH allyl 2-CH, O-benzyl ch ₃ OH allyl 2-HO-benzyl ch ₃ OH allyl 2-Cl-benzyl CH OH allyl 2- (CH ₃ ) ₂ N-benzyl CH OH allyl

Other representative compounds of the present invention are represented by formula (XIII) wherein R ^{a is} -CO (CH ₂ ) 1-4, wherein X is, and X, R ² , R ³ and R ⁵ are selected from the following table:

X R ² R ³ R ⁵ 1-imidazolyl-methyl CH OH ethyl 2-imidazolyl-methyl ch ₃ OH ethyl 3-thiazolylmethyl CH OH ethyl 2-thiazolylmethyl CH OH ethyl 2-oxazolylmethyl CH OH ethyl 2-pyridylmethyl ch, OH ethyl benzyl ch ₃ OH ethyl 4-HO ₂ C-benzyl CH OH ethyl 4-H ₂ NCO-benzyl CH OH ethyl 4-CH, O-benzyl CH OH ethyl 4-HO-benzyl CH OH ethyl 4-R ^H O-Benzyl CH OH ethyl 4-Cl-benzyl CH OH ethyl 4- (CH ₃ ) ₂ N-benzyl CH ₃ OH ethyl 3-HO ₂ C-benzyl CH OH ethyl 3-H ₂ NCO-benzyl CH OH ethyl 3-CH, O-benzyl CH OH ethyl 3-HO-benzyl CH OH ethyl 3-benzyl-RO CH OH ethyl 3-Cl-benzyl CH OH ethyl 3- (CH ₃ ) ₂ N-benzyl CH ₃ OH ethyl 2-HO ₂ C-benzyl CH OH ethyl 2-H ₂ NCO-benzyl CH OH ethyl 2-CH, O-benzyl CH OH ethyl

HU 211 897 A9

X d2 R ^x R ³ R ⁵ 2-HO-benzyl CH OH ethyl 2-R ⁿ O-benzyl CH OH ethyl 2-Cl-benzyl CH OH ethyl 2- (CH ₂ ) ₂ N-benzyl CH OH ethyl 3- (4-pyridyl) -imidazol-2-yl methyl ch ₃ OH ethyl 3- (3-pyridyl) imidazol-2-yl methyl ch ₃ OH ethyl 3- (2-pyridyl) -imidazol-2-yl methyl ch, OH ethyl 3-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ OH ethyl 3- (4-CH ₇ O-phenyl) -imidazol-2-ylmethyl ch ₃ OH ethyl 3- (4- (CH,) _2- N-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (3-H0 ₂ C-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3-13-CH (O-phenyl) -imidazole- CH OH ethyl 2-ylmethyl _ 3- (3-HO-phenyl) -imidazol-2-yl methyl CH OH ethyl

3- (3- (CH,) _2- N-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (2-H ₂ NCO-phenyl) -imidazole CH OH ethyl zol-2-ylmethyl 3-t 2-CH, O-phenyl) -imidazol-2-ylmethyl 1 CH OH ethyl 3- (2-HO-phenyl) -imidazol-2-yl methyl CH OH ethyl 3- (2-R ¹¹ O-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (2-Cl-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (2- (CH ₂ ) ₂ N -phenyl) imidazol-2-ylmethyl CH OH ethyl 1-imidazolyl-methyl CH H ethyl 2-imidazolyl-methyl CH H ethyl 3-thiazolylmethyl CH H ethyl 2-thiazolylmethyl CH H ethyl 2-oxazolylmethyl CH H ethyl 5-tetrazolyl-methyl CH H ethyl 4-pyridylmethyl CH H ethyl

X R ² R ³ R ⁵ 3-pyridylmethyl CH H ethyl 2-pyridylmethyl CH H ethyl benzyl CH H ethyl 4-HO ₂ C-benzyl CH H ethyl 4-H ₂ NCO-benzyl CH H ethyl 4-CH ₃ O-benzyl CH H ethyl 4-HO-benzyl CH H ethyl 4-R ⁿ -O-benzyl CH H ethyl 4-Cl-benzyl CH H ethyl 4- (CH ₂ ) ₂ N-benzyl CH H ethyl 3-HO ₂ C-benzyl CH H ethyl 3-H ₂ NCO-benzyl CH H ethyl 3-CH, O-benzyl CH H ethyl 3-HO-benzyl CH H ethyl 3-R ⁿ -O-benzyl CH H ethyl 3-Cl-benzyl CH H ethyl 3- (CH ₂ ) ₂ N-benzyl CH H ethyl 2-HO ₂ C-benzyl CH H ethyl 2-H ₂ NCO-benzyl CH H ethyl 2-CH, O-benzyl CH H ethyl 2-HO-benzyl CH H ethyl 2-benzyl-R''O CH H ethyl 2-0-benzyl CH H ethyl 2- (CH ₂ ) ₂ N-benzyl CH H ethyl 3- (4-Pyridyl) -imidazol-2-ylmethyl CH H ethyl 3- (3-Pyridyl) -imidazol-2-ylmethyl CH H ethyl 3- (2-Pyridyl) -imidazol-2-ylmethyl CH H ethyl 3-phenyl-imidazol-2-ylmethyl CH H ethyl 3- (4-HO ₂ C-phenyl 1-imidazol-2-ylmethyl) CH H ethyl 3- (4-phenyl-H7NCO) -imida- zol-2-ylmethyl CH H ethyl 3- (4-CH, O-phenyl) -imidazol- 2-ylmethyl CH H ethyl 3- (4-HO-phenyl) -imidazol-2-yl methyl CH H ethyl 3- (4-R ¹⁰ O-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (4-Cl-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (4- (CH,) _2- N-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl CH H ethyl

HU 211 897 A9

X R ² R ³ R ⁵ 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ H ethyl 3- (3-CH ₃ O-phenyl) -imidazol-2-ylmethyl ch ₃ H ethyl 3- (3-HO-phenyl) -imidazol-2-yl methyl ch ₃ H ethyl 3- (3-R ¹¹ 0-phenyl) -imidazol-2-ylmethyl ch ₃ H ethyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl ch ₃ H ethyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl CH H ethyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ H ethyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (2-CH, O-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (2-HO-phenyl) -imidazol-2-ylmethyl ch ₃ H ethyl 3- (2-R ¹¹ 0-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (2-Cl-phenyl) -imidazol-2-yl methyl CH H ethyl 3- (2- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl CH H ethyl 1-imidazolyl-methyl H OH ethyl 2-imidazolyl-methyl H OH ethyl 3-thiazolylmethyl H OH ethyl 2-thiazolylmethyl H OH ethyl 2-oxazolylmethyl H OH ethyl 5-tetrazolyl-methyl H OH ethyl 4-pyridylmethyl H OH ethyl 3-pyridylmethyl H OH ethyl 2-pyridylmethyl H OH ethyl benzyl H OH ethyl 4-HO ₂ C-benzyl H OH ethyl 4-H ₂ NCO-benzyl H OH ethyl 4-CH ₃ O-benzyl H OH ethyl 4-HO-benzyl H OH ethyl 4-R ^1] O-Benzyl H OH ethyl 4-Cl-benzyl H OH ethyl 4- (CH ₃ ) ₂ N-benzyl H OH ethyl 3-HO ₂ C-benzyl H OH ethyl 3-H ₂ NCO-benzyl H OH ethyl 3-CH, O-benzyl H OH ethyl 3-HO-benzyl H OH ethyl

X R ² R ³ R ⁵ 3-R ⁿ -O-benzyl H OH ethyl 3-Cl-benzyl H OH ethyl 3- (CH ₃ ) ₂ N-benzyl H OH ethyl 2-HO ₂ C-benzyl H OH ethyl 2-H ₂ NCO-benzyl H OH ethyl 2-CH ₃ O-benzyl H OH ethyl 2-HO-benzyl H OH ethyl 2-R ⁿ O-benzyl H OH ethyl 2-Cl-benzyl H OH ethyl 2- (CH ₃ ) ₂ N-benzyl H OH ethyl 3- (4-pyridyl) -imidazol-2-yl methyl H OH ethyl 3- (3-pyridyl) imidazol-2-yl methyl H OH ethyl 3- (2-pyridyl) -imidazol-2-yl methyl H OH ethyl 3-phenyl-imidazol-2-ylmethyl H OH ethyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (4-CH ₃ O-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (4-HO-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (4-R ¹¹ O-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (4-Cl-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (4- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH ethyl 3- (3-H0 ₂ C-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (3-CH ₃ O-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (3-HO-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (3-R ⁾ -O-Phenyl / imidazol-2-ylmethyl H OH ethyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH ethyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl H OH ethyl

HU 211 897 A9

X R ² R ³ R ⁵ 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- _(2-CH3 O-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (2-HO-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (2-R ¹¹ O-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (2-Cl-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (2- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH ethyl 1-imidazolyl-methyl H H ethyl 2-imidazolyl-methyl H H ethyl 3-thiazolylmethyl H H ethyl 2-thiazolylmethyl H H ethyl 2-yl-methyl] H H ethyl 5-tetrazolyl-methyl H H ethyl 4-pyridylmethyl H H ethyl 3-pyridylmethyl H H ethyl 2-pyridyl-methyl H H ethyl benzyl H H ethyl 4-HO ₂ C-benzyl H H ethyl 4-H ₂ NCO-benzyl H H ethyl 4-CH ₃ O-benzyl H H ethyl 4-HO-benzyl H H ethyl 4-nitro-benzyl H H ethyl 4-Cl-benzyl H H ethyl 4- (CH, bN-Benzyl H H ethyl 3-HO ₂ C-benzyl H H ethyl 3-H ₂ NCO-benzyl H H ethyl 3-CH ^ O-benzyl H H ethyl 3-HO-benzyl H H ethyl 3-benzyl-RO H H ethyl 3-Cl-benzyl H H ethyl 3- (CH ₃ ) ₂ N-benzyl H H ethyl 2-HO ₂ C-benzyl H H ethyl 2-H ₂ NCO-benzyl H H ethyl 2-CH ₃ O-benzyl H H ethyl 2-HO-benzyl H H ethyl 2-R ^II O-benzyl H H ethyl 2-Cl-benzyl H H ethyl 2- (CH ₃ ) ₂ N-benzyl H H ethyl 3- (4-pyridyl) -imidazol-2-yl methyl H H ethyl

X R ² R ³ R ⁵ 3- (3-pyridyl) imidazol-2-yl methyl H H ethyl 3- (2-pyridyl) -imidazol-2-yl methyl H H ethyl 3-phenyl-imidazol-2-ylmethyl H H ethyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (4-CH ₃ O-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (4-HO-phenyl) -imidazol-2-yl methyl H H ethyl 3- (4-R ^1, 0-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (4-Cl-phenyl) -imidazol-2-yl methyl H H ethyl 3- (4- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H ethyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (3-CH ₃ O-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (3-HO-phenyl) -imidazol-2-yl methyl H H ethyl 3- (3-R ¹¹ O-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl H H ethyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H ethyl 3- (2-HO ₂ C-phenyl 1-imidazol-2-ylmethyl) H H ethyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (2-CH ₃ O-phenyl i-imidazol-2-ylmethyl H H ethyl 3- (2-HO-phenyl) -imidazol-2-yl methyl H H ethyl 3- (2-R ¹¹ O-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (2-Cl-phenyl) -imidazol-2-yl methyl H H ethyl 3- (2- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H ethyl 1-imidazolyl-methyl ch ₃ OH allyl 2-imidazolyl-methyl ch ₃ OH allyl 3-thiazolylmethyl ch ₃ OH allyl 2-thiazolylmethyl ch ₃ OH allyl

HU 211 897 A9

X R ² R ³ R ⁵ 2-oxazolylmethyl ch ₃ OH allyl 5-tetrazolyl-methyl ch ₃ OH allyl 4-pyridylmethyl ch ₃ OH allyl 3-pyridylmethyl ch ₃ OH allyl 2-pyridylmethyl ch, OH allyl benzyl ch ₃ OH allyl 4-HO ₂ C-benzyl ch ₃ OH allyl 4-H ₂ NCO-benzyl ch ₃ OH allyl 4-CH ₃ O-benzyl ch ₃ OH allyl 4-HO-benzyl ch ₃ OH allyl 4-nitro-benzyl ch ₃ OH allyl 4-Cl-benzyl ch, OH allyl 4- (CH ₂ ) ₂ N-benzyl ch, OH allyl 3-HO ₂ C-benzyl CH OH allyl 3-H ₂ NCO-benzyl ch ₃ OH allyl 3-CH, O-benzyl ch ₃ OH allyl 3-HO-benzyl ch ₃ OH allyl R ^ S-O-Benzyl ch ₃ OH allyl 3-Cl-benzyl ch, OH allyl 3- (CH ₂ ) ₂ N-benzyl ch, OH allyl 2-HO ₂ C-benzyl ch, OH allyl 2-H ₂ NCO-benzyl ch, OH allyl 2-CH, O-benzyl ch, OH allyl 2-HO-benzyl ch, OH allyl 2-benzyl-RO ch, OH allyl 2-Cl-benzyl ch, OH allyl 2- (CH ₂ ) ₂ N-benzyl ch, OH allyl 3- (4-pyridyl) -imidazol-2-yl methyl CH OH allyl 3- (3-pyridyl) imidazol-2-yl methyl CH OH allyl 3- (2-pyridyl) -imidazol-2-yl methyl CH OH allyl 3-phenyl] -imidazol-2-ylmethyl CH OH allyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch, OH allyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (4-CH, O-phenyl) -imidazol- 2-ylmethyl ch ₃ OH allyl 3- (4-HO-phenyl) -imidazol-2-yl methyl CH OH allyl 3- (4-R ¹¹ O-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (4-Cl-phenyl) -imidazol-2-yl methyl CH OH allyl

X R ² R ³ R ⁵ 3- (4- (CH,) _2- N-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (3-CH, O-phenyl) -imidazol- 2-ylmethyl ch ₃ OH allyl 3- (3-HO-phenyl) -imidazol-2-yl methyl ch ₃ OH allyl 3- (3-R ¹ '0-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl ch ₃ OH allyl 3- (3- (CH,) _2- N-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch, OH allyl 3- (2-CH, O-phenyl) -imidazol- 2-ylmethyl ch, OH allyl 3- (2-HO-phenyl) -imidazol-2-yl methyl CH OH allyl 3- (2-R ¹¹ O-phenyl) -imidazol-2-ylmethyl CH OH allyl 3- (2-Cl-phenyl) -imidazol-2-yl methyl CH OH allyl 3- (2- (CH ₂ ) ₂ N -phenyl) imidazol-2-ylmethyl CH OH allyl 1-imidazolyl-methyl CH H allyl 2-imidazolyl-methyl CH H allyl 3-thiazolylmethyl CH H allyl 2-thiazolyl-methyl CH H allyl 2-oxazolylmethyl CH H allyl 5-tetrazolyl-methyl CH H allyl 4-pyridylmethyl CH H allyl 3-pyridylmethyl CH H allyl 2-pyridylmethyl CH H allyl benzyl CH H allyl 4-HO ₂ C-benzyl CH H allyl 4-H ₂ NCO-benzyl CH H allyl 4-CH, O-benzyl CH H allyl 4-HO-benzyl CH H allyl 4-R ^l! O-benzyl CH H allyl 4-C1-benzyl CH H allyl 4- (CH ₂ ) ₂ N-benzyl CH H allyl 3-HO ₂ C-benzyl CH H allyl

HU 211 897 A9

X R ² R ³ R ⁵ 3-H ₂ NCO-benzyl ch ₃ H allyl _3-CH3 O-benzyl ch ₃ H allyl 3-HO-benzyl ch ₃ H allyl 3-benzyl-RO ch ₃ H allyl 3-Cl-benzyl ch ₃ H allyl 3- (CH ₃ ) ₂ N-benzyl ch ₃ H allyl 2-HO ₂ C-benzyl ch ₃ H allyl 2-H ₂ NCO-benzyl ch ₃ H allyl 2-CH ₃ O-benzyl ch ₃ H allyl 2-HO-benzyl ch ₃ H allyl 2-benzyl-RO ch ₃ H allyl 2-Cl-benzyl ch ₃ H allyl 2- (CH ₃ ) ₂ N-benzyl ch ₃ H allyl 3- (4-pyridyl) -imidazol-2-yl methyl ch ₃ H allyl 3- (3-pyridyl) imidazol-2-yl methyl ch ₃ H allyl 3- <2-pyridyl) imidazole-2-i1- methyl ch ₃ H allyl 3-phenyl] -imidazol-2-ylmethyl] ch ₃ H allyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (4-CH ₃ O-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (4-HO-phenyl) -imidazol-2-yl methyl ch ₃ H allyl 3- (4-R ¹¹ O-Phenyl) imidazol-2-yl methyl ch ₃ H allyl 3- (4-Cl-phenyl) -imidazol-2-yl methyl ch ₃ H allyl 3- (4- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl ch ₃ H allyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (3-CH ₃ O-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (3-HO-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (3-R ¹¹ O-Phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl ch ₃ H allyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl ch ₃ H allyl

X R ² R ³ R ⁵ 3- (2-H0 ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- _(2-CH3 O-phenyl) -imidazole-2-ylmethyl ch ₃ H allyl 3- (2-HO-phenyl) -imidazol-2-yl methyl ch ₃ H allyl 3-1,2-R ¹ * O-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (2-Cl-phenyl) -imidazol-2-yl methyl ch ₃ H allyl 3- (2- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl ch ₃ H allyl 1-imidazolyl-methyl Η OH allyl 2-imidazolyl-methyl H OH allyl 3-thiazolylmethyl H OH allyl 2-thiazolylmethyl H OH allyl 2-oxazolylmethyl H OH allyl 5-tetrazolyl-methyl H OH allyl 4-pyridyl-methyl] H OH allyl 3-pyridylmethyl H OH allyl 2-pyridylmethyl H OH allyl benzyl H OH allyl 4-HO ₂ C-bcnzil H OH allyl 4-H ₂ NCO-benzyl H OH allyl 4-CH ₃ O-benzyl H OH allyl 4-HO-benzyl H OH allyl 4-nitro-benzyl H OH allyl 4-C1-benzyl H OH allyl 4- (CH ₃ ) ₂ N-benzyl H OH allyl 3-HO ₂ C-bcnzil H OH allyl 3-H ₂ NCO-benzyl H OH allyl _3-CH3 O-benzyl H OH allyl 3-HO-benzyl H OH allyl 3-benzyl-RO H OH allyl 3-Cl-benzyl H OH allyl 3- (CH ₃ ) ₂ N-benzyl H OH allyl 2-HO ₂ C-benzyl H OH allyl 2-H ₂ NCO-benzyl H OH allyl 2-CH ₃ O-benzyl H OH allyl 2-HO-benzyl H OH allyl 2-R ^, 10-O-benzyl H OH allyl 2-Cl-benzyl H OH allyl 2- (CH ₃ ) ₂ N-benzyl H OH allyl

HU 211 897 A9

X R ² R ³ R ⁵ 3- (4-pyridyl) -imidazol-2-yl methyl H OH allyl 3- (3-pyridyl) imidazol-2-yl methyl H OH allyl 3- (2-pyridyl) -imidazol-2-yl methyl H OH allyl 3-phenyl-imidazol-2-ylmethyl H OH allyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (4-phenyl-HjNCO) -imida- zol-2-ylmethyl H OH allyl 3- (4-CH ₃ O-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (4-HO-phenyl) -imidazol-2-yl methyl H OH allyl 3- (4-R ¹¹ O-Phenyl) -imidazol-2-ylmethyl H OH allyl 3- (4-Cl-phenyl) -imidazol-2-yl methyl H OH allyl 3- (4- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH allyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl- H OH allyl 3 -13-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (3-CH ₃ O-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (3-HO-phenyl) -imidazol-2-yl methyl H OH allyl 3-t 3-R ¹¹ O-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl H OH allyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH allyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H OH allyl 3- _(2-CH3 O-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (2-HO-phenyl) -imidazol-2-yl methyl H OH allyl 3- (2-R ¹¹ O-Phenyl) imidazol-2-ylmethyl H OH allyl 3- (2-Cl-phenyl) -imidazol-2-yl methyl H OH allyl 3- (2- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH allyl l-imidazolylmethyl H H allyl 2-imidazolyl-methyl H H allyl

X R ² R ³ R ⁵ 3-methyl-thiazolyl H H allyl 2-thiazolylmethyl H H allyl 2-oxazolylmethyl H H allyl 5-tetrazolyl-methyl H H allyl 4-pyridylmethyl H H allyl 3-pyridylmethyl H H allyl 2-pyridylmethyl H H allyl benzyl H H allyl 4-HO ₂ C-benzyl H H allyl 4-H ₂ NCO-benzyl H H allyl 4-CH ₃ O-benzyl H H allyl 4-HO-benzyl H H allyl 4-R ⁿ -O-benzyl H H allyl 4-C1-benzyl H H allyl 4- (CH ₃ ) ₂ N-benzyl H H allyl 3-HO ₂ C-benzyl H H allyl 3-H ₂ NCO-benzyl H H allyl _3-CH3 O-benzyl H H allyl 3-HO-benzyl H H allyl 3-R ⁿ -O-benzyl H H alli, 3-Cl-benzyl H H allyl 3- (CH ₃ ) ₂ N-benzyl H H allyl 2-HO ₂ C-benzyl H H allyl 2-H ₂ NCO-benzyl H H allyl 2-CH ₃ O-benzyl H H allyl 2-HO-benzyl H H allyl 2-benzyl-R''O H H allyl 2-Cl-benzyl H H allyl 2- (CH ₃ ) ₂ N-benzyl H H allyl 3- {4-pyridyl) -imidazol-2-yl methyl H H allyl 3- (3-pyridyl) imidazol-2-yl methyl H H allyl 3- (2-pyridyl) -imidazol-2-yl methyl H H allyl 3-Phenylimidazol-2-ylmethyl 1 H H allyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl H H allyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H allyl 3- (4-CH ₃ O-phenyl) -imidazole-2-ylmethyl H H allyl 3- (4-HO-phenyl) -imidazol-2-yl methyl H H allyl 3- (4-R ¹⁰ O-phenyl) -imidazol-2-ylmethyl H H allyl

HU 211 897 A9

X R ² R ³ R ⁵ 3- (4-Cl-phenyl) -imidazol-2-yl methyl H H allyl 3- (4- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H allyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl H H allyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H allyl 3- (3-CH ₃ O-phenyl) -imidazol-2-ylmethyl H H allyl 3- (3-HO-phenyl) -imidazol-2-yl methyl H H allyl 3- (3-R ^{, 10} -phenyl) -imidazol-2-ylmethyl H H allyl 3- (3-Cl-phenyl) -imidazol-2-n- methyl H H allyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H allyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl H H allyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-yl-methyl! H H allyl 3- _(2-CH3 O-phenyl) -imidazol-2-ylmethyl H H allyl 3- (2-HO-phenyl) -imidazol-2-yl methyl H H allyl 3- (2-R ¹¹ O-Phenyl) imidazol-2-ylmethyl H H allyl 3- (2-Cl-phenyl) -imidazol-2-yl- H H allyl methyl 3-12- (CH ₃ ) ₂ N -phenyl] -imidazol-2-ylmethyl H H allyl _

B. Preparation of Compounds of the Invention

The starting compounds required for the preparation of the compounds of the present invention are represented by formula (II), wherein

E is hydrogen or methyl;

W is O or (H, OH);

R ³ is hydrogen, hydroxy or C 1-6 alkoxy,

R ⁴ is hydrogen or R ³ and R ⁴ together form a double bond,

^R5 is methyl, ethyl, propyl or allyl, and n is 1 or the second

The preparation and characterization of compounds of formula (II) is well known in the art. See, e.g., U.S. Patent No. 4,894,366, U.S. Patent 4,929,611, U.S. Patent No. 3,244,592, Nos. 0,333,042 and 0,356,399. European Patent Application Publication No. PBJ 63-17884. J. Am. Chem. Soc., 1987, 09, 5031; Antibiotics 1987,

40, 1249, J. Antibiotics 1988, 41 (11), 1592; and J.

Anübiotics 1992, 45 (1), 118],

Both biological fermentation and synthetic processes are known. The compounds of formula (II) may be synthetically prepared, for example, by modification of the procedure described in J. Am. Chem. Soc., 1989, 111, 1157.

The biological fermentation process followed by synthetic modification is currently preferred in the literature for the preparation of compounds of formula (Π). Organisms of the genus Streptomyces, such as Streptomyces tsukubaensis, No. 9993, Streptomyces hygroscopicus, var. ascomycetis, No. 14891, is prepared in an aqueous medium in isolated amounts to produce the desired compounds. The medium contains assimilable sources of carbon and nitrogen, preferably under aerobic conditions. The fermentation process produces four compounds of formula II: (A) wherein E is methyl, W is oxygen, R ³ is hydroxy, R ⁴ is hydrogen, R ⁵ is allyl, and n is 2; (B) wherein E is methyl, W is oxygen, R ³ is hydroxy, R ⁴ is hydrogen, R ⁵ is ethyl, and n is 2; (C) wherein E is methyl, W is oxygen, R ³ is hydroxy, R ⁴ is hydrogen, R ⁵ is methyl and n is 2, and (D) wherein E is methyl, W is oxygen, R ³ is hydroxy. . R ⁴ is hydrogen, R ⁵ is allyl and n is 1.

A lyophilized sample of isolated Streptomyces tsukubaensis, No. 9993, was deposited at the Fermentation Research Institute, No. 1-3, Higashi 1-Chome, Yatabemachi Tsikuba-gun, Ibaraki Prefecture, Japan. : FERM P-7886, deposited on October 5, 1984, then re-converted under the Budapest Convention on October 19, 1985 and renamed FERM BP-927.

Of the four compounds obtained by fermentation as described above, the other compounds of formula II are readily prepared. Suitable reduction of the allyl group at R ^{5 to a} propyl group is well known in the art, for example, in U.S. Patent No. 4,894,366. The hydroxy group at R ³ can be protected by known methods, for example, as disclosed in European Patent Application No. 0 323 042. Similarly, the hydroxyl group at the C-4 'site can be protected. In addition, the hydroxy group at the R ³ position can be reduced or removed to form a hydrogen bond to form a double bond with R ⁴ (see, for example, U.S. Pat. No. 4,894,366 and U.S. Patent Nos. 0,323,042 or 0,413,532). In place of W, the carbonyl group can be reduced to an alcohol according to the procedure described in European Patent Application Nos. 0 323 042 or 0 445 975.

HU 211 897 A9

At this site, the methyl group may be replaced by hydrogen or demethylated and optionally protected if necessary. This demethylation of compounds containing E is methyl can be accomplished by a fermentation reaction using the compounds of formula II as nutrients. For example, the compound of formula (II), referred to above as (A), may be demethylated at E at the microorganism Actinomycetales ATCC No. 53771 (known from U.S. Patent No. 4,981,792) or Streptomyces tsukubaensis, No. 9993, which is known from European Patent Publication No. 0 353 678. Similarly, the compound of formula (II), referred to above as (B), may be demethylated at its E site by the action of Actinoplanacete sp. ATCC No. 53771, which is known from European Patent Application Publication No. 0 349 061. In addition, a compound of formula II wherein E is hydrogen, W is oxygen, R ³ is hydroxy, R ⁴ is hydrogen, R ⁵ is ethyl, and n is 2 may be prepared directly by fermentation using Streptomyces hygroscopicus, sup. ascomycetiscus, a mutant microorganism of No. 53855 (which is a blocked mutant of Streptomyces hygroscopicus, sup. ascomyceticus No. 14891 and is known from European Patent Application Publication No. 0 388 152). Similarly, a compound (II) wherein E is hydrogen, W is O, ^R3 is hydroxyl, ^R4 is hydrogen, ^R5 is methyl and n is 2, directly obtainable by fermentation of Streptomyces hygroscopicus. sup. ascomyceticus, a mutant microorganism of No. 53855 (which is a blocked mutant of Streptomyces hygroscopicus, sup. ascomyceticus No. 14891 and is known from European Patent Application Publication No. 0 388 153). The C-3 "hydroxy group may be protected by a similar procedure as that used to protect the R ³ site and / or C-4" hydroxy group, as described, for example, in U.S. Patent No. 4,894,366.

Suitable protecting groups for the hydroxyl group are well known in the art, such as methylthiomethyl, ethylthiomethyl, trisubstituted silyl, such as trimethylsilyl, triethylsilyl, tributylsilyl, triisopropylsilyl. -, t-butyldimethylsilyl, tri-t-butylsilyl, methyldiphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl and the like; acyl groups such as acetyl, pivaloyl, benzoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, and aromatic substituted aliphatic acyl groups which are derivatives of carboxylic acids and the like.

Compounds (A), (B), (C) and (D) of the formula (II), organisms suitable for the preparation of these compounds, fermentation conditions, methods of separation and chemical modification of the products are well known. U.S. Pat. No. 4,894,366; U.S. Pat

929 611; and U.S. Patent 5,110,811.

The following describes new processes for preparing the novel compounds of the invention. In the formulas, R ¹ , R ² , R ³ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , E, W and n, unless otherwise stated, have the meanings given above. . It will be apparent to one skilled in the art from the following synthetic routes that the other compounds of formula (I) may be prepared if the reagents used in the process are replaced by appropriate other reagents.

Scheme (A):

In Scheme A, a 4 '-hydreoxy-3' -methoxymacrolide of formula (1) is dissolved in an inert solvent such as methylene chloride, benzene, toluene, chloroform or the like, or a mixture thereof, and trietheroaryl bismuth diacetate reagent (R ¹ is heteroaryl), prepared immediately before use by adding acetic acid to a suspension of triheteroaryl bismuth diacetate in an inert organic solvent such as methylene chloride, chloroform or the like, or in the presence of a catalytic amount of copper (II) acetate at 20-50 ° C, preferably at room temperature, the reaction is carried out for 1 hour to 7 days, preferably one day, so that the 4 '-O-heteroaryl of formula (2) -3 "-methoxy-macrolide is obtained. The triheteroaryl bismuth (V) reagent may also be prepared by treating triheteroaryl bismuth with a suitable oxidizing agent such as peracetic acid, benzoyl peroxide, hydrogen peroxide, iodobenzene diacetate, bis (trifluoroacetoxy) iodobenzene, or the like. in a solvent such as methylene chloride, chloroform, benzene, toluene or the like. The triheteroaryl bismuth (V) reagent may be used without purification or may be purified by chromatography on silica gel. Triheteroaryl bismuthines can be prepared by reacting the appropriate heteroaryl-Grignard reagent or lithium heteroaryl compound with bismuth trichloride in an inert solvent such as tetrahydrofuran, diethyl ether, toluene,

In 1,4-dioxane or a mixture thereof at room temperature or near for 1-48 hours. General procedures for the preparation of triaryl bismuth reagents can be found in Barton, D.H.E. et al., J. Chem. Soc. Chem. Commun., 1986, 65, and references therein.

Scheme B:

Scheme B illustrates the reaction of 3 ", 4" -dihydroxymacrolide 3 with a triheteroaryl bismuth diacetate reagent as described in Scheme A

A mixture of 3 'hydroxy-4' -O-heteroaryl macrolide (4a), 3 '-Oheteroaryl-4' hydroxy macrolide (4b) and 3 'of formula 4c is obtained. ", 4" -di-O-heteroaryl macrolide. In this step, a solution of 3 "-hydroxy-4" O-heteroaryl macrolide of formula 4a or a solution of 3 "-O-heteroaryl-4" hydroxy macrolide of formula 4b can be reacted with a triaryl bismuth diacetate reagent (prepared immediately before use by the procedure described above) to give 3 "-O-aryl-4" -O-heteroaryl macrolide of formula 5a or 3 "-O-heteroaryl-4" of formula 5a - O-arylacrolide is prepared.

Scheme C:

Scheme (C) illustrates that a 14-hydroxyl group can be removed from a macrolide of formula (5a) or (5b) (wherein R ¹ , R ² , R ⁵ , R ¹⁰ , W and n are as defined above) if reacting the compound with paratoluenesulfonic acid, benzenesulfonic acid or methanesulfonic acid in an inert organic solvent such as benzene or toluene at 40-60 ° C for 0.5-6 hours or for a time sufficient to remove the 14-hydroxyl group. After neutralization with a weak aqueous base such as saturated aqueous sodium bicarbonate, the 14,15-dihydro-macrolides of formula (6a) or (6b) are obtained. The hydroxyl group at position 14 may also be removed by activating the compound and then carrying out an alkaline elimination process known in U.S. Patent No. 4,894,366.

By changing the sequence of the synthetic steps, any possible substituent variation can be obtained.

Scheme (iD):

Scheme (D) illustrates that a solution of 4 "-hydroxy-3" -methoxymacrolide (1) in an inert organic solvent such as methylene chloride, chloroform, pentane, hexane, cyclohexane, heptane, or a mixture thereof is a heteroaryl. alkyl, heteroarylalkenyl or heteroarylalkynyl trichloroacetimidate reagent (prepared by reaction of the appropriate sodium alkoxide with trichloroacetonitrile according to Wessel, P.P. Inversen, T., Bundle, DR, J.). Chem. Soc., Perkin Trans. I, 1985, 2247) in the presence of a weak acid catalyst such as trifluoromethanesulfonic acid, paratoluenesulfonic acid, methanesulfonic acid or a mixture thereof at a temperature of 20-50 ° C for one hour to seven days. and thus preparing 4 "-O-heteroarylalkenyl, 4" -O-heteroarylalkenyl or 4 "-O-heteroarylalkenyl-3" -methoxymacrolide of formula 2a.

Scheme (E)

Scheme (E) shows a similar reaction of a solution of the 3 ', 4' -dihydroxymacrolide (3) in an inert organic solvent such as methylene chloride, chloroform, pentane, hexane, cyclohexane, heptane or a mixture thereof to a heteroaryl. alkyl, heteroarylalkenyl or heteroarylalkynyl trichloroacetimidate reagent (prepared as described in Reaction Scheme D) at a temperature of 20-50 ° C, preferably 40 ° C for a period of 1 hour to 7 days, preferably for 6 hours to form a mixture of 4 "-O-heteroarylalkenyl, 4" -O-heteroarylalkenyl or 4 "-O-heteroarylalkynyl-3 of formula 4a ' hydroxy macrolide, 3 "-O-heteroarylalkenyl, 3" -O-heteroarylalkenyl or 3 "-O-heteroarylalkynyl-4" -hydroxymacrolide of formula 4b ', and (4c'). 3 ", 4" -di-O-heteroaryl-alkyl, -heteroaryl-alkenyl or -heteroaryl-alkynyl macrolide. Subsequently, 4 "-Oheteroaryl, 4" -O-heteroarylalkyl, 4 "-O-heteroarylalkenyl or 4" -O-heteroaryl of formula 4a or 4a 'shown in Scheme B -alkynyl-3-hydroxy macrolide, or 3 "-O-heteroaryl, 3" Ο-heteroarylalkyl, 3 "-O-heteroaryl represented by the following general scheme: (4b) or (4b '). alkenyl or 3 "O-heteroaryl-alkynyl-4" -hydroxymacrolide can be reacted with an arylalkyl, alkenyl or alkynyl trichloroacetimidate as described above to give (5a ') or (5b') macrolides live.

The procedures outlined in Scheme (C) and (D) may optionally be carried out according to Scheme (E) or (F). Alternatively, the procedure outlined in Reaction Scheme (F) may be carried out.

A macrolide prepared according to any one of the above schemes (wherein R ¹ and / or R ^{2 is} alkenyl, substituted alkenyl, alkynyl or substituted alkynyl and R ³ is hydroxy or C 1-6 alkoxy, R ⁴ is hydrogen or R ³ and R ⁴ double bond), can be reduced with trin-n-butyltin hydride in the presence of letrakis (triphenylphosphine) palladium (O) catalyst and acetic acid in an organic solvent such as toluene or tetrahydrofuran at room temperature for 2 to 10 hours, and thus producing the reduced macrolide.

The procedures described in Scheme (F) may also be applied to the monosubstituted products of Scheme (B) (and vice versa) to prepare the mixed disubstituted compounds. In fact, in the reaction scheme, the reaction of the monosubstituted product with different reagents results in the mixed disubstituted compounds.

Scheme F:

Scheme (F) illustrates that the C-3 ", C-4" and / or C-14 hydroxyl groups may be protected by methods previously employed for compounds of formula II, such as 2,6-glutidine and triisopropylsilyl -trifluoromethanesulfonate in methylene chloride solution; With 2,6-lutidine and t-butyldimethylsilyl trifluoromethanesulfonate

A9 in brine solution; pyridine and acetic anhydride in methylene chloride solution; pyridine and benzoyl chloride in dichloromethane solution; pyridine and pnitrobenzoyl chloride in dichloromethane solution; imidazole and p-butyldiphenylsilyl chloride in methylene chloride solution and the like. For example, as shown in Scheme F, the C-4 ", 14-dihydroxy-C-3" methoxymacrolide of formula (7) can be protected at the 14-position in the form of t-butyldimethylsilyl ether by reacting the compound with t-butyldimethylsilyl trifluoromethanesulfonate in methylene chloride to give C-4 ', 14-di-OTBDMS macrolide. The toluenesulfonic acid reaction is then used to selectively remove the C-4 silyl ether in methanol to give the C-14O-TBDMS macrolide (8).

Scheme (G):

Scheme (G) illustrates that the 4 '-hydroxy-3' -R ² O-macrolide of formula (9) or the 3 '-hydroxy-4' -R ² O-macrolide (not shown in the scheme) ) - where R ³ is a protected hydroxy group or hydrogen - can be reacted with alkenyl trichloroacetimidate - where alkenyl is a C 3 -C 10 alkenyl group under the reaction conditions described in Scheme (E) to give the O-alkenyl macrolide of formula (10) live. This compound is reacted with a stoichiometric amount of osmium tetroxide in an inert organic solvent such as diethyl ether or tetrahydrofuran in the presence of an amine base such as pyridine at room temperature or at ambient temperature to give glycol of formula (11) wherein A is C 1-8 alkyl. . The glycol (11) is reacted with sodium metaperiodate dissolved in a mixture of tetrahydrofuran and water to give the aldehyde (12). Alternatively, the alkenyl acrolide of formula (10) is reacted with sodium metaperiodate in the presence of a catalytic amount of osmium tetroxide in an organic solvent to provide the aldehyde directly. The aldehyde 12 can be further oxidized to the carboxylic acid 13 by any known method.

Scheme (H):

As shown in Scheme (H), various compounds can be prepared from the aldehyde (12). Reaction of the aldehyde 12 with a primary or secondary amine with a compound of the formula HNR ⁶ R ⁷ wherein R ⁶ and / or R ⁷ is as defined above and contains a heteroaryl group in an organic solvent such as tetrahydrofuran yields an imine which is in situ. reduction with a hydride reducing agent, such as sodium cyanoborohydride, the macrolide (14) containing an aminoalkoxy group at the C-4 'position is obtained. The aldehyde (12) may also be reduced to the corresponding alcohol (15) by reaction with a hydride reducing agent such as potassium triphenylborohydride or sodium cyanoborohydride in an organic solvent such as tetrahydrofuran. The alcohol of formula (15) may be further modified by the procedures outlined in Scheme B (where R ¹ is as defined above) or Scheme E to give the macrolide of formula (16). The procedures shown in Scheme (H) are also readily applicable to the preparation of compounds having similar groups at the C-3 'position.

Scheme (I):

Reaction Scheme (I) illustrates that the carboxylic acids (13) can also be converted into amide derivatives. The carboxylic acid of formula (13) is reacted with a primary or secondary amine of formula HNR ⁶ R ⁷ , wherein R ⁶ and / or R ⁷ are as defined above and contains a heteroaryl group, by any conventional coupling procedure for peptide preparation, such as BOP or DCC / HOBT. -with.

Scheme (J):

Scheme (J) illustrates how to introduce a hydroxyl or fluorine group at the C-20 position. As shown in Scheme (R), 4 ', 14-dihydroxymacrolide (or 14-deoxymacrolide) is protected in the form of di (t-butyldimethylsilyl ether) such that the compound is t- butyl dimethyl triflate in an inert organic solvent such as methylene chloride, chloroform or the like in the presence of a non-nucleophilic base such as 2,6-lutidine. The doubly protected macrolide is oxidized at the C-20 position as shown in Scheme J by oxidation with selenium dioxide in an alcoholic solvent such as ethanol in the presence of pyridine at the boiling point of the solvent and thus 20-Hydroxy macrolide is obtained. This 20-hydroxymacrolide can be further converted, for example, by alkylation, acylation or phosphorylation at the C-20 position to form an ether, ester, or phosphate derivative, well known to those skilled in the art. It is also disclosed that the 20-hydroxy-4 ", 14-di-OTBS-macrolide is reacted with diethylamino sulfur trifluoride in an inert organic solvent such as methylene chloride, chloroform or the like at a temperature of 0 ° C to -90 ° C, preferably - At a temperature of about 78 ° C, 20-fluoro-4'-14-di-OTBS macrolide (19) is prepared. Removal of the silyl ether protecting group with tetrahydrofuran by the hydrogen fluoride-pyridine complex provides the 20-fluoro-4 ', 14-dihydroxymacrolide which can be further converted by any of the methods described above. The procedure outlined in Scheme (J) may also be carried out with 3 ", 4", 14-trihydroxymacrolide to give 20-fluoro-3 ", 4", 14-trihydroxymacrolide. The procedures outlined in Scheme (J) may also be carried out before, during, or after the Schemes (A) to (I).

HU 211 897 A9

The compounds of formula (I) of the present invention prepared by the reactions described above may be isolated and purified by conventional techniques such as extraction, precipitation, fractional crystallization, recrystallization, chromatography, or the like.

In the compounds of formula (I), the OR ¹ group may be substituted at the C-4 'or C-3' position or both at the C-4 'and C-3' positions (where R ² is independently R ¹ ). however, it is preferred that the OR 'group is substituted at the C-4' position.

It will be appreciated that in the aforementioned reactions and reaction mixtures, stereoisomers or as stereoisomers of the compounds of the invention of formula (I) due to asymmetric carbon atoms or double bonds may be converted to the other stereoisomer. These cases are also within the scope of the present invention.

In the present invention, compounds having asymmetric centers may exist in the form of racemates, diastereomeric mixtures or individual diastereomeric forms, and all isomeric forms of the compounds are within the scope of the present invention. They can be prepared by the methods described in the synthesis of the FR 900506 macrolide fragments or FR 900966 macrolide itself. These publications are as follows: J. Am. Chem. Soc., 1989, 777, 1157; J. Am. Chem. Soc., 7/2, 1990, J. Org. Chem. 1990, 55, 2786; J. Am. Chem. Soc., 772, 5583 (1990); Tetrahedron Lett., 29, 277 (1988); Tetrahedron Lett.,

1988, 29, 281; Tetrahedron Lett., 29, 3895 (1988); J. Org. Chem., 1988, 53, 4643; Tetrahedron Lett., 1988, 29, 4245; Tetrahedron Lett., 1988, 29, 4481; J. Org. Chem. 1989, 54, 9; J. Org. Chem., 1989, 54, 12; J. Org. Chem., 1989, 54, 15; J. Org. Chem., 1989, 54, 17; Tetrahedron Lett. 1989, 30, 919; Tetrahedron Lett.,

1989, 30, 1037; J. Org. Chem., 1989, 54, 2785; J. Org. Chem. 1989, 54, 4267; Tetrahedron Lett. 1989, 30, 5235; Tetrahedron Lett. 1989, 30, 6611; Tetrahedron Lett., 1989, 30. 6963; Synlett, 1990, 38; J. Org. Chem.,

1990, 55, 2771; J. Org. Chem. 55, 2776 (1990); Tetrahedron Lett. 1990, 37, 1439; Tetrahedron Lett. 1990, 37, 1443: Tetrahedron Lett., 1990, 37, 3007; Tetrahedron Lett., 1990,37,3287

The compounds of the present invention form salts with various organic and inorganic acids and bases, which are also within the scope of the present invention. Examples of such acid addition salts (which are negative counterions and defined herein as M) include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, ethanesulfonate, fumarate, h , hydrobromide, hydroiodide, methanesulfonate, lactal, maleate, methanesulfonate, 2-naphthalenesulfonate, oxalate, pamoate. persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate and undecanoate. Examples of basic salts (which are positive counterins and are defined herein as M ⁺ ) include: ammonium salts, alkali metal salts such as sodium, lithium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts with organic bases, e.g. , N-methyl-D-glucamine salts or salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups may also be quatemized with reagents such as lower alkyl halides such as methyl, ethyl, propyl, butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, diamyl sulfates, long-chain halides, such as decyl, lauryl, myristyl or stearyl chlorides, bromides or iodides; aralkyl halides such as benzyl bromide and the like. Non-toxic, physiologically acceptable salts are preferred, but other salts are useful, for example, in isolation or purification of the product.

Salts may be prepared by conventional means, for example, by reacting the free base with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in water, which is removed in vacuo, or by lyophilization. anions are exchanged for another anion on a suitable ion exchange resin.

C: Applicability of Compounds of the Invention

The compounds of formula (I) may be used as immunosuppressants or antimicrobial compounds by methods and routes of administration previously known for compounds of formula (II). These compounds have pharmacological activity, such as immunosuppressive, antimicrobial activity and the like, and are therefore useful in the treatment and prevention of transplantation or resistance to transplant rejection of organs or tissues. (Examples of transplanted organs or tissues include the heart, kidney, liver, lung, bone marrow, cornea, pancreas, intestinal tenue, extremities, muscles, nerves, duodenum, including xenograft.) they can also be used in graft versus host diseases for bone marrow transplantation and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosis, nephrotic syndrome lupus, Hashimoto's thyroid gland, multiple sclerosis, multiple sclerosis, mellitus, type II adult sudden diabetes, uveitis, nephrotic syndrome, steroid dependent and steroid resistant nephrosis, palm-planter pustulosis, allergic encephalitis, glomerulonephritis and the like, as well as pathogenic microorganisms.

The compounds of formula (I) may also be used to treat skin manifestations of inflammatory, proliferative and hyperbuilding disorders, as well as immunologically directed diseases. Such diseases include: psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis, and other eczema dermatitis, seborrheic dermatitis, Lichen pla28

A9 nus, Pemphigus, bladder Pemphigoid, Epidermolysis bullosa, urticaria, vasculitis, vasculitides, erythema, cutaneous eosinophilia, acne, Alopecia areata, eosinophilic fasciitis and atherosclerosis. In particular, the compounds of formula I can be used for hair revitalization, for example, for the treatment of typical male or female baldness or old age baldness, as they prevent epilation, promote germination of hair and / or promote hair formation and growth.

The compounds of formula I are also useful in the treatment of respiratory disorders such as sarcoidosis, ftbroid lung, primary interstitial pneumonia, and reversible airway obstruction such as asthma, including bronchial asthma, allergic asthma, asthma, extrinsic asthma and pulmonary asthma, particularly chronic or chronic asthma, such as late asthma and respiratory hyperresponsiveness, bronchitis and the like. The compounds of formula (I) may also be used for the treatment of ischemia-associated liver growth.

The compounds of the invention may also be used in certain eye disorders such as keratoconjunctivitis, spring conjunctivitis, uveitis with Behcet's disease, keratitis, herpes keratitis, chronic cornea, dystorphia epithelialis comae, corneal leukemia, ulcers, scleritis, Graves's eye disease, severe intraocular inflammation and the like.

The compounds of formula (I) are useful tumor multidrug in the treatment of resistance (i.e., increase the action and / or sensitivity of chemotherapeutic agents), as well as treatment and prevention of mucosal or vascular inflammation by (e.g., triggered B ₄ by leukotriene diseases, gastric ulcers. Ischemic diseases and thrombosis vascular injury, ischemic bowel disease, inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) and enteric ulcerative burns, cytomegalovirus infection, especially HCMV infection.

The compounds of formula (I) are also useful in the treatment or prevention of kidney disease, such as interstitial kidney inflammation, Goodpasture syndrome, hemolytic uremic syndrome and diabetic kidney disease; and for the treatment of neurological disorders such as multiple myositis, Guillain-Barre syndrome, Meniere's disease and nerve root disease; treating endocrine disorders such as thyroid hyperfunction and Basedow's disease; for the treatment and prevention of blood disorders such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, primary platelet purpura, autoimmune hemolytic anemia, white blood cell deficiency and erythrocyte depletion; bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, fibroid lung, primary interstitial pneumonia; skin diseases such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergenic sensitization and cutaneous T-cell lymphoma; circulatory diseases such as arteriosclerosis, aortic syndrome, polyarteritis nodosa and myocardosis; collagen-containing scleroderma, Wegener's granuloma, and Sjogren's syndrome; adiposis; eosinophilic fasciitis, periodontal disease; nephrotic syndrome; for the treatment of hemolytic uremic syndrome and muscle wasting.

The compounds of the present invention are also useful in the treatment of inflammatory bowel allergy disorders such as, for example, gonadal celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis, and in the treatment of nutritional allergic disorders, which migraine, rhinitis or eczema.

The compounds of the present invention also have liver regenerating effects and / or hypertrophy, hyperplasia or hepatocyte stimulating activity. Therefore, the compounds are useful in the treatment and prevention of various liver diseases such as immunogenic diseases (e.g., chronic autoimmune liver disease including autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver reflexes, acute hepatic necrosis (e.g. viral hepatitis, shock or anoxia), hepatitis B virus, non-A / non-B hepatitis, and cirrhosis.

The compounds of the invention are also useful as antimicrobial agents and are therefore useful in the treatment of diseases caused by pathogenic microorganisms.

The compound of formula (I) may also be used as macrocyclic immunosuppressive compounds such as 12- (2'-cyclohexyl-1'-methyl-vinyl) -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3 .

1Ό4 ⁹ ] as antagonists of octacos-18-ene derivatives and are therefore useful in the treatment of immunodepression (e.g., AIDS, cancer, anxiety disorder, trauma, including wounding, surgery or shock), and chronic bacterial infections and certain central nervous system disorders. as an adjuvant in the case of overdose or toxicity of compounds, and in the case of antigen administration during vaccination.

The pharmaceutical compositions of the present invention may be solid, semi-solid or liquid, containing as active ingredient one or more compounds of the invention which, when admixed with an organic or inorganic carrier or vehicle, make the active ingredient suitable for external, internal or parenteral administration. For example, the active ingredient may be admixed with conventional, non-toxic, pharmaceutically acceptable carriers to form tablets, capsules, suppositories, solutions, emulsions, suspensions, and other suitable dosage forms. Suitable excipients include water, glucose, lactose, acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, or other excipients which are solid or semi-solid or liquid.

EN 211 897 For the manufacture of A9. The formulations may also contain excipients, stabilizers, thickeners, coloring agents or perfumes. The compounds of formula (I) may be used, for example, with hydroxypropylmethylcellulose (see U.S. Patent No. 4,916,138) or with a surfactant (see European Patent Application Publication No. 0428169). Oral formulations may be prepared according to T. Hondo et al., Transplantation Proceedings, 1987, XIX, Supp. 6, 17-22. Formulations suitable for external administration may be prepared as described in European Patent Application Publication No. 0 423 714. The active ingredient of the invention is incorporated into the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease.

For the treatment of diseases and conditions caused by immune disorders, the compound of formula (I) may be administered orally, topically, parenterally, by inhalation or rectally in the form of conventional non-toxic pharmaceutically acceptable carriers, excipients and carriers. The term "parenteral" refers to subcutaneous injections. intravenous, intramuscular, intrasternal injection or infusion.

For the treatment of reversible airway obstruction, the compound of formula (I) is preferably administered by inhalation into the lungs, particularly in powder form.

To modify the activity and / or toxicity of FK-506 type immunosuppressants, the compound of formula (I) may be administered before, during or after administration of the FK-506 type compound.

The compounds of formula (I) may optionally be used in combination with active proliferative agents to supplement its therapeutic effect. Particularly preferred antiproliferative agents for such adjunctive therapy include azathioprine, brequinar sodium, deoxyspergualin, mizaribine, morpholino ester of mycophenolic acid, cyclosporine and rapamycin.

The dosage of the compounds of the invention is generally about 0.005 mg to about 50 mg per day per kg body weight, preferably about 0.1 mg to about 10 mg / kg body weight per day. for treating the conditions detailed above, a patient of about 70 kg / day is usually assumed to have a 0.7-3.5 mg are added. In addition, the compounds of the invention may be administered periodically; that is, daily, semi-weekly, weekly, semi-monthly or monthly.

The amount of active ingredient to be mixed with the vehicle to produce the dosage unit will depend upon the patient being treated and the route of administration. For example, in a formulation for oral administration to humans, the formulation will contain from 0.5 to 5 mg of active ingredient in admixture with an appropriate amount of a carrier. The latter amount is about 5-95% by weight of the total composition. Dosage unit dosage forms are generally 0.01 -

They contain from 500 mg, preferably from 0.5 to 100 mg of active ingredient. For external administration, the compounds of the formula I according to the invention are formulated, for example, in an amount of 0.0001-60% by weight, preferably 0.001-10% by weight, especially 0.005-0.8% by weight.

However, it will be appreciated that the appropriate dosage for a particular disease will depend on a number of factors including the efficacy of the compound employed, the age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, active ingredient combination, and the severity of the disease being treated.

The present invention is illustrated by the following examples, but is not intended to be limited thereto.

THE INITIAL INTERMEDIATE COMPOUNDS

PRODUCTION

17-Ethyl-1-hydroxy-12- [2 '- (4' -hydroxy-3-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28 dioxa-4-azatricyclo [22.3. LO ⁴ · ^9] octacos-yl 8-ene-2,3,10,16-tetraone 500 mg of 17-ethyl-l-hydroxy-12- [2 '- (4 "-hydroxy-3" methoxycyclohexyl) - T-methylvinyl] -23,25-dimethoxy-13,

19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo [22.3.1.0 ⁴ • ^9] octacos-18-ene-2,3,10,16-tetraone To a solution of 7 ml of benzene was added 10 mg of paratoluenesulfonic acid and heating the solution at 60 ° C for 2 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel. Elution was carried out with a mixture of 66% ethyl acetate, 33% hexane and 1% methanol. 350 mg of product are obtained. This product was dissolved in 10 mL of ethyl acetate and 15 mg of palladium on charcoal 5% was added. A hydrogen flask was placed over the reaction mixture and the mixture was stirred until the reaction was complete. The reaction mixture was filtered through diatomaceous earth, concentrated and the residue was purified by chromatography. Elution was carried out with a mixture of 75% by volume methylene chloride, 5% by volume of methanol and 20% by volume of hexane. 294 mg of compound are obtained.

7-Ethyl-1-hydroxy-12- [2 '- (4', 3 '-dihydroxycyclohexyl) -N'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl -11,28-dioxa-4-azatricyclo [22.3. l. (A ^s] octacos-18-ene-2.3,10,16-tetraone

210 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3 '-hydroxycyclohexyl) -1-methyl-vinyl] -23,25-dimethoxy-13,19,21,27 tetramethyl-11,28-dioxa-4-azatricyclo [22.3. 1.0 ⁴⁹ ] A solution of octacos-18-ene-2,3,10,16-tetraone and a catalytic amount of paratoluenesulfonic acid in 40 ml of benzene was heated under reflux for 4 hours under nitrogen. The solvent was evaporated in vacuo and the dark residue was purified by chromatography on silica gel. Eluent 7

Methylene chloride containing 9% by volume of isopropanol was used. 180 mg 17-ethyl-1-hydroxy-12- [2 '- (4' -hydroxy-3 '-isopropyloxycyclohexyl) -methyl-vinyl] -23.2

5-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; Joktakoz-18-ene-2,3,10,16-tetraone is obtained in the form of a white solid. form. The resulting compound was dissolved in ethanol (20 mL) and palladium on charcoal (40 mg, 5%) was added. Hydrogen was then passed through the reaction flask for 30 minutes, and the mixture was filtered through a cellite filter. The solvent was removed and the residue was purified by chromatography on silica gel. 172 mg of the title compound are obtained. The molecular weight of the Ή and ³ C NMR conform to the structure of the title compound.

17-Ethyl-1-hydroxy-12- [2 '- (4' -triisopmpylsilyloxy-3-methoxy-cyclohexyl)] - methyl-vinyl] -23,25-dimethoxy-13,19,21,27 -tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] octacos-18-2,3,10,16-tetraone 120 mg 17-ethyl-1,14-dihydroxy-12- [ 2 '- (4' -Hydroxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3 . 1.0 ⁴ - ⁹ ] To a solution of octacos-18-ene-2,3,10,16-tetraone in 15 ml of anhydrous methylene chloride at 0 ° C was added 64.3 mg of 2,6-lutidine followed by 184 mg of triisopropylsilyl trifluoromethanesulfonate. The reaction mixture was allowed to warm to room temperature and stirred overnight under a nitrogen atmosphere. The reaction mixture was mixed with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed and the residue was purified by chromatography on silica gel. The eluent was ethyl acetate containing 70% (v / v) hexane. 150 mg of the desired compound are obtained. M = (FAB) I110 (M ⁺ Li).

17-Ethyl-1-hydroxy-12- [2 '- (4' -hydroxy-3-methoxycyclohexyl)} '-methyl-vinyl] -14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21 , 27-tetramethyl 11,28-dioxa-4-aza-tricyclo [22.3.1 (fi · ⁹ Joktakoz-18-ene] 2,3,3,10,16-tetraone

680 mg of the compound prepared according to the preceding preparation are dissolved in 45 ml of methylene chloride and 45 ml of 10% methanolic sulfonic acid in methanol are added with stirring. The mixture was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography. After 4 hours, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The reaction mixture was worked up in the usual manner, the solvent was distilled off and the residue was purified by chromatography on silica gel. Elution was carried out with 80 volumes of hexane containing ethyl acetate. 560 mg of 2a is obtained in the form of a white solid. M = (FAB) 945 (M ⁺ + Li).

] 7-Ethyl-1-hydroxy-12- [2 '- (4-t-butyldimethylsilyloxy-3' -methoxycyclohexyl) -] - methyl-vinyl} -14-t-butyldimethylsiloxide 23,25-Dimethoxy-13,19,21,27-tetramethyl-1], 28-dioxa-4-azatricyclo [22.3.1 dfi ⁹ ] octacos-18-ene-2,3,10,16-tetraone

395 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3 '' -methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21 , 27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3. 1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone (Compound Ia) in 15 ml of anhydrous methylene chloride at 0 ° C was added 160 mg of 2.6 lutidine followed by 250 mg of t- -butyl-dimethylsilyl trifluoromethanesulfonate. The reaction mixture was allowed to warm to room temperature and then stirred under nitrogen. After 6 hours, the reaction was quenched with water (10 mL) and extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to give 500 mg of crude product. M = (FAB) 1023 (M ⁺ + Li).

17-Ethyl-1-hydroxy-12- [2 '- (4-hydroxy-3-methoxycyclohexyl) -! 1-methyl-vinyl] - 4-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. (fi · ⁹ Joktakoz-18-en 2,3,3,10,16-tetraon

500 mg of the compound prepared in the preceding example are dissolved in 20 ml of acetonitrile and 100 ml of 48% hydrogen fluoride are added. After stirring for 20 minutes at room temperature, saturated aqueous sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel. Elution was carried out with hexane containing 80% by volume ethyl acetate. 300 mg of a compound having a molecular weight Ή and a ¹³ C NMR spectrum corresponding to the title compound are obtained.

17-Ethyl-1-hydroxy-12- [2 '- (4-tert-butyldimethylsilyloxy) -3-methoxycyclohexyl) -] - methyl vinyl] -23,25-dimethoxy-13,19 , 21,27-Tetramethyl-11,28-dioxa-4-aza-bicyclo [22.3.1 (fi] ⁹ ] octacos-18-ene-2,3,10,16-tetraone

3.01 g of 17-ethyl-1-hydroxy-12- [2 '- (3', 4 '-dihydroxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21, 27-tetramethyl-1,1,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; Joktakoz-1

To a solution of 8-ene-2,3,11,16-tetraone in 70 ml of anhydrous methylene chloride was added an excess of imidazole (809 mg), followed by addition of 716 mg of tert-butyldimethylsilyl chloride. After stirring for 3 days at room temperature, the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and purified by flash chromatography. Elution was carried out with ethyl acetate / hexane (1: 3 v / v). 941 mg of the title compound are obtained. The @ 1 H-NMR spectrum of the compound is consistent with the proposed structure.

17-Ethyl-1-hydroxy-12- [2 '- (4-tert-butyldimethylsilyloxy-3-methoxycyclohexyl) -1'-methyl-vinyl] -23,2531

HU 211 897 A9 Dimethoxy-13,19,21,2 7-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone

200 mg of 17-ethyl-1-hydroxy-12- [2 '- (4 "-hydroxy-3" methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,

19,21,27-tetramethyl-l l, 28-dioxa-4-azatricyclo [22.3.1.0 ⁴ • ^9] added octacos-18-ene-2,3, l 0,16-tetraone in 3 ml of dry methylene chloride an excess of 2,6-lutidine (45 μΐ) was added and the mixture was stirred at room temperature. 10 minutes later, 64 μΐ tert-butyldimethylsilyl trifluoromethanesulfonate was added via syringe. After 15 minutes, the mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate was added, the layers were separated, and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution was carried out with a 1: 2 by volume mixture of ethyl acetate / hexane and 1% by volume methanol. 235 mg of the title compound are obtained. The 1 H-NMR spectrum was consistent with the desired structure.

17-Etd-1,20-dihydroxy-12- [2 '- (4-tert-butyldimethylsilyloxy) -3 &apos; -methoxy-cyclohexyl) -4'-methyl-vinyl] -23.25 -dimethoxy-13.19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. (d ⁹ Loktakoz-18 on 2.3.10.16-tetraon

235 mg of 17-ethyl-1-hydroxy-12- [2 '- (4 "-tert-butylsilyloxy) -3" -methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3. 1.0 ⁴⁹ ] To a solution of octacos-18-ene-2,3,10,16-tetraone in 2.2 ml of 95% ethanol was added 53 μΐ of pyridine followed by 58 mg of selenium dioxide. The flask is fitted with a water heater and heated to 70 ° C with the help of a heating jacket. After 20 hours, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth and the filtrate was poured into a saturated aqueous solution of sodium bicarbonate. This solution was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solution was evaporated. The residue was purified by flash chromatography on silica gel. Elution was carried out with a 1: 2 by volume mixture of ethyl acetate / hexane and 1% by volume methanol. 89 mg of the title compound are obtained. The 1 H-NMR spectrum was consistent with the desired structure.

17-Ethyl-20-fluoro-hydroxy-1,2-1,2 '- (4-tert-butyldimethylsilyloxy) -3 &apos; -methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1. Cd ⁹ ] octactin -18.2.3.10.16-tetraon

30.5 mg 17-ethyl-20-dihydroxy-12- [2 '- (4 "-tert-butyldimethylsilyloxy) -3" -methoxycyclohexyl) -1'-methyl-vinyl] -23.25 a solution of -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone in 0.5 ml of methylene chloride Cool to -78 ° C in a dry ice / isopropanol bath. While stirring, 4.5 μΐ of diethylamino sulfur trifluoride was added. After 3 minutes, 500 μΐ of saturated sodium bicarbonate followed by 2 ml of ethyl acetate were added and the mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and purified by flash chromatography on silica gel. Elution was carried out with a 1: 2 by volume mixture of ethyl acetate / hexane and 1% by volume methanol. 22 mg of the title compound are obtained. The 1 H-NMR spectrum was consistent with the desired structure.

] 7-Ethyl-1,20-dihydroxy-12- [2 '- (4- (hydroxy-3''-methoxy-cyclohexyl)]-' -methyl-vinyl] -23,25-dimethoxy-13.19.21.27- tetramethyl-l], 28-dioxa-4-azatriciklol22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16-tetraone mg of 17-ethyl-l, 20-dihydroxy-12- [2 '- (4 "-tert-butyldimethylsilyloxy) -3" -methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28 dioxa-4 -azatriciklo [22.3.1,0 ^4-9] octacos-18-ene-2,3,10,16-tetraone to a solution of 0.3 mL of acetonitrile 100 μΐ prepared with 2% aqueous acetonitrile H fluoride solution and the mixture was stirred at room temperature. After 28 hours, the reaction mixture was diluted with ethyl acetate, extracted with a saturated aqueous solution of sodium bicarbonate, and dried over a column of magnesium sulfate. The concentrate was purified by flash chromatography on silica gel. Elution was carried out with a 2: 1 by volume mixture of ethyl acetate / hexane and 1% by volume of methanol. The title compound is obtained.

17-Ethyl-2-fluoro -] - hydroxy] 2- [2 '- (4- (hydroxymethoxycyclohexyl)] -' - methylvinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl- l 1,28-dioxa-4-azatricyclo 22.3.1 .Cd {· ^9] octacos-l 8-ene-2,3,10,16-tetraone mg of 17-ethyl-20-fluoro-l-hydroxy-12- [2 '- (4 "- (t-butyldimethylsilyl) -3" -methoxy-cyclohexyl) -r-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28 To a solution of di-oxa-4-azatricyclo [22.3.1.0 &lt; ⁴ &gt; ^-9 ] octacos-18-ene-2,3,10,16-tetraone in 0.3 ml of acetonitrile is added 100 μΐ of a 2% aqueous solution of acetonitrile in hydrogen fluoride After 2 hours, the reaction mixture was diluted with ethyl acetate, extracted with saturated aqueous sodium bicarbonate, and the organic layer was dried over a column of magnesium sulfate. The concentrate was purified by flash chromatography on silica gel with ethyl acetate. hexane in 1: 1 v / v methanol M - (FAB) 816 (M + Na).

Partial ¹³ C NMR δ: 211.5 (C-16); 196.1 (2); 169.3 (1); 165.0 (3); 138.1 (C-19); 135.8 (C-1 '); 121.0 (C-18 'major); 84.1 (C-3 '); 43.1 (Cl 5); 26.0 (C21).

17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4-hydroxy-3-methoxycyclohexyl) -! '-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 d ⁹ ] octacos-18-ene-2,3,10, 16-Tetraone (Alternative Process Version)

HU 211 897 A9

5.15 g (0.065 mol) of 17-ethyl-1,14-dihydroxy-12- [2 '(4' -hydroxy-3 '-methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-aza tricyclo a solution of p octacos-18-ene-2,3,10,16-tetraone in 500 ml of glacial acetic acid [22.3.1 .0 ^49] a solution of 9.27 g (0.083 mol) of selenium dioxide in 90 ml of water is added at room temperature. After stirring at room temperature for 41 hours, the reaction mixture was poured into 3 L of water and celite with stirring. After stirring for 15 minutes, the mixture is filtered through a pad of celite and extracted with diethyl ether (1 x 2 L). The organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The product is purified by chromatography on silica gel. Elution was carried out with a 2: 5 by volume mixture of acetone and hexane. The title compound has mass and 1 H NMR spectra consistent with structure.

Example 1

17-Ethyl], 14-dihydroxy-12- (2 '- (4- (2-phytanyl) methoxy-3-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13, 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt; ^-9 ] octacos-18-ene-2,3,10,16-tetraone 63 mg 17-ethyl-1,14- dihydroxy-12- [2 '- (4' -hydroxy-3-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo To a solution of [22.3. 1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone in 1.0 ml of methylene chloride was added 39 μΐ of furfuryl trichloroacetimidate and the reagents were allowed to stir for 5 minutes. After stirring at room temperature for 4.5 hours, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate and extracted three times with 5 ml of ethyl acetate each time, and the organic phases were combined with a saturated aqueous solution of sodium chloride. wash and dry over anhydrous magnesium sulfate. Purification was carried out on silica gel eluting with ethyl acetate / hexane (1: 2 v / v) and 1% methanol in solvent. 20 mg of compound are obtained. M = (FAB) 878 (M + Li).

Partial ¹³ C NMR δ: 7.38 (brs, 1H); 6.30 (m, 3H);

5.32 M, 5.19 m (brd J = 3 Hz, 1H); 4.83 m, 4.21 (brs, 1H); 4.62 (dd, J = 15 Hz, 2H); 4.41 (brd,

J = 14 Hz, 1H).

Examples 2 and 3

17-Ethyl-1,14-dihydroxy] -2- [2 '- (4- (2-furanyl) methoxy-3-hydroxycyclohexyl) -! '-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &gt;, ⁹ ] octacos-18-ene-2,3 , 10,16-tetraon and

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' -hydroxy-3 '- (2-furanyl) methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy -13,19,21,27-tetramethyl-1,1,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone;

mg 17-ethyl-1,14-dihydroxy-12- [2 '- (3', 4 '-dihydroxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27 added octacos-18-ene-2,3,10,16-tetraone in 0.9 mL methylene chloride-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ^9] added 20 μΐ furfuryl trichloro -acetimidate and reagents were allowed to mix for 5 minutes. Thereafter, 2 mg of camphorsulfonic acid were added and the mixture was stirred at room temperature for 3.5 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The concentrate was purified by flash chromatography on silica gel. The eluent was ethyl acetate / hexane (1: 1 v / v methanol). 16 mg of 4 "ether and 13 mg of 3" ether are obtained.

The characteristics of the 4 "ether are: M = (FAB) 864 (M + Li). Partial ¹³ C NMR δ: 7.41 (brs, 1H); 6.30 (m, 2H);

5.32M, 5.19m (brd, J = 3Hz, 1H); 4.87m, 4.19m (brs, 1H); 4.41 (brd, J = 14 Hz, 1H);

Characteristics of 3 "ether: M = (FAB) 864 (M + Li). Partial ¹³ C NMR δ: 7.44 (brs, 1H); 6.37 (m, 2H);

5.32M, 5.19m (brd, J = 3Hz, 1H); 4.88m, 4.27M (brs, 1H); 4.41 (brd, J = 14 Hz, 1H).

Example 4

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (2-thiophene) methoxy-3-methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13 , 19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo [22.3.1.O ⁴ · ⁹ Joktakoz-18-ene-2,3,10,16-tetraone;

The compound was prepared according to the procedure of Example 1 except that 2-methylphenylmethyl trichloroacetimidate was used as the alkylating agent. Partial Ή NMR δ: 7.27 (m, 1H); 6.96 (m, 2H);

5.31M, 18m (brd, J = 3Hz 1H); 4.8 µm, 4.22M (brs, 1H); 4.41 (brd, J = 14 Hz, 1H); 3.07 (d, J = 4

Hz, 1H).

Examples 5 and 6

17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (2-thiophene) methoxy-3-hydroxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;} octacos-18-ene-2,3,10,16-tetraone, and

17-Ethyl 1-1,14-dihydroxy-12- (2 '- (4' -hydroxy-3 '- (2-thiophene) methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-1,1,8-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone

The title compounds were prepared essentially as described in Examples 2 and 3 except that 3-thiophenylmethyl trichloroacetimidate was used as the alkylating agent.

4 ”ether: M = (FAB) 896 (M + Na). Partial Ή NMR δ: 7.29 (m, 1H); 6.97 (m, 2H);

5.3M, 5.19m (brd, J = 3Hz, 1H); 4.41 (brd, J = 14

HU 211 897 A9

Hz, 1H); 3.04 (d, J = 4Hz, 1H); 2.63M, 2.16m (s, 1H);

3 ”ether characteristics: M = (FAB) 880 (M + Li).

Partial Ή NMR δ: 6.97 (m, 2H); 5.31M, 5.19m (brd,

J = 3 Hz (1H); 4.41 (brd, J = 14 Hz, 1H); 3.08 (d, J = 3 Hz, 1H); 2.69 (s, 1H).

Examples 7 and 8

17-Ethyl-1,14-dihydroxy-12- (2 '- (4- (3-thiophene) methoxy-3' -hydroxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ joktakoz-18-ene-2,3,10,16-tetraone, and

17-Ethyl-1,14-dihydroxy-12- [2 '- (4 "-hydroxy-3" - (3-thiophene) methoxy-cyclopropyl] cyclohexylamino) -l'-methylvinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16-tetraone

The title compounds are prepared essentially as described in Examples 2 and 3 as alkylating agents

3-Thiophenylmethyl trichloroacetimidate was used.

The characteristics of the 4 "ether are: M = (FAB) 880 (M + Li). Partial Ή NMR δ: 7.04 (m, 2H); 5.31M, 5.19m (brd,

J = 3 Hz, 1H); 4.89m, 4.19M (s, 1H); 4.41 (brd,

J = 14 Hz, 1H) ;, 3.04 (d, J = 4 Hz, 1H).

The 3 '' ether has the characteristics: M = (FAB) 880 (M + Li). Partial Ή NMR δ: 7.28 (m, 2H); 7.05 (dd, J = 5.2

Hz (1H); 5.31. 5.19m (brd. J = 3Hz, 1H); 4.83;

4.25M (brs. 1H); 4.41 (brd. J = 14 Hz. 1H); 3.06 (d,

J = 3Hz. IH); 2.69 (s. 1H).

Example 9

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (benzothien-2-yl) oxy-3-methoxycyclohexyl) -! '-methyl-vinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene 2,3,3,10,16- tetraone

To a solution of tri (benzothien-2-yl) bismuthine (100 mg, 0.164 mmol) in methylene chloride (2 mL) was added peracetic acid (0.05 mL, 0.224 mmol) (in 32% acetic acid), followed by 100 min. 17-ethyl-1,14-dihydroxy-12 [2 '- (4' -hydroxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -17,25-dimethoxy-13,19 mg (0.126 mmol) , 21,27-tetramethyl-11,28-dioxa- ⁴ -azatricyclo [22.3.1.0 &lt; ⁴ &gt; ^-9 ] octacos-18-ene-2,3,10,16-tetraone and 15 mg (0.083 mmol) of Cu (OAc) ₂ -. t. After stirring at room temperature for 16 hours, the reaction mixture was quenched with saturated aqueous NaHCO ₃ and extracted three times with methylene chloride. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative thin layer chromatography three times on silica gel. The eluent was eluted with hexane / acetane (3: 1). 23 mg 17-ethyl-1,14-dihydroxy-12- [2 '- (4' (benzothien-2-yl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23.25-dimethoxy 13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] octacos-18-ene-2,3,10,16-tetraone is obtained.

Example 10

17-Ethyl-1,14-dihydroxy-12- (2 '- (4''- (thien-2-yl) oxy-3-methoxy-cyclohexyl) -1'-methyl-vinyl) -23,25-dimethoxy- 13,19,21,2 7-tetramethyl-l- 11,28-dioxa-4-azatricyclo (22.3.1.0 ⁴ · ⁹ joktakoz-18-ene-2,3,10,16-tetraone (80 mg, 0.175 mmol), tri- To a solution of (thien-2-yl) -bismuthine in 2 ml of methylene chloride was added 0.060 ml (0.253 mmol) of peracetic acid (32% in acetic acid) with stirring, and after 15 minutes 100 mg (0.126 mmol) of 17-ethyl 1,14-Dihydroxy-12- [2 '- (4' -hydroxy-3 '-methoxy-cyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa -4-azatricyclo [22.3. 1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone and 10 mg (0.055 mmol) of Cu (OAc) ₂ . After stirring at room temperature for 3 days, the reaction was quenched by the addition of saturated aqueous NaHCO ₃ and extracted with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified twice by preparative thin layer chromatography on silica gel. The eluent was eluted with 2: 1 hexane: acetone. 36 mg 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (thien-2-yl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23, 25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ -octacos-18-ene-2,3,10,16-tetraone is obtained.

Example 11

17-Ethyl-1,14-dihydroxy-12- [2 '- (4-5-indolylaminocarbonyl-3-ethoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,2], 27-tetramethyl-ll, 28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-l 8-tetraone én2,3,10,16

The step

17-Ethyl-1-dihydroxy-14- (tert-butyldimethylsilyloxy) -12- [2 '- (4-tert-butyldimethylsilyloxy) -3'-methoxycyclohexyl)]' methyl] -23,25-dimetoxi13,19,21,27-letrametil-ll, 28-dioxa-4-azatricikIOÍ22.3.1.0 ⁴ · ⁹ [octacos-18-ene-2,3,10,16 tetraone 2.0 g 17-ethyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3 'methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13 .

19.21.27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.

1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone To a solution of 25 ml of dry methylene chloride and 1.2 ml of 2,6-lutidine was added excess and the mixture was stirred at room temperature. After 10 minutes, tert-butyldimethylsilyl trifluoromethanesulfonate (1.8 mL) was added to the reaction mixture via syringe. After 1 hour, the reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and then saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by silica gel flash chromatography. Elution was carried out with a 1: 6 v / v mixture of ethyl acetate / hexane and 1% methanol. 2.37 g of the title compound are obtained. The Ή NMR spectrum corresponds to the desired structure.

HU 211 897 A9

11B. step

17-ethyl -] - hydroxy-14- (tert-butyl-dimethylsilyl) ·

12- [2 '- (4-hydroxy-3' '- methoxycyclohexyl)}' - methylvinyl] -23,25-dimethoxy-13,19,21,2 7-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3. ^ LO Joktakoz-2,3,10,16-tetraone-lSén

2.37 g of 17-ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) -12- [2 '- (4 "-tert-butyldimethylsilyloxy) -3" -methoxy, prepared in Step 11A -cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2 To a solution of 3,10,16tetraone in 25 ml of anhydrous methylene chloride is added 25 ml of a 10% solution of paratoluenesulfonic acid in methanol and the mixture is stirred at room temperature for 10 minutes. The reaction mixture was then cooled to 0 ° C and quenched by addition of saturated aqueous sodium bicarbonate solution. The mixture was diluted with ethyl acetate and the phases were separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The concentrate was purified by flash chromatography on silica gel. Elution was carried out with a 1: 2 by volume mixture of ethyl acetate / hexane and 1% by volume of methanol. 2.1 g of the title compound are obtained with 1 H NMR spectra consistent with the expected structure.

Step 11C

17-Ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) 12- [2 '- (4''-allyloxy-3-methoxycyclohexyl) -1'-methylvinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3] .0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone

2.1 g of 11B. 17-ethyl-1-hydroxy-14-tert-butyldimethylsilyloxy-12- [2 '- (4' -hydroxy-3''-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,

19,21,27-tetramethyl-1,2,8-dioxa-4-aza-tricyclo [22.3.1. O ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone in 24 ml of 33% cyclohexane in methylene chloride is added 938 mg of pure allyl trichloroacetimidate and the mixture is allowed to stir for 5 minutes. Then 41 μΐ trifluoromethanesulfonic acid was added slowly via syringe and the mixture was stirred at room temperature. After 24 hours, the reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, water, and then with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The concentrate was purified by flash chromatography on silica gel. Elution was carried out with a 1: 5 by volume mixture of ethyl acetate / hexane and 1% by volume of methanol. 1.03 g of the title compound is obtained, which Ή NMR spectrum is consistent with the expected structure.

11D. step

17-Ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) 1,2-1,2 '- (4- (2,3-dioxy-1-propoxy) -3''- methoxycyclohexyl) - ] &apos; -methyl-vinyl] -23,25-dimethoxy-l3,19,21,27tetrametil-Il, 28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-I8-ene-2,3,10 16-tetraone

I, 03 g 1 IC. 17-Ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) -12- [2 '- (4 "allyloxy] 3-methoxycyclohexyl) -1'-methyl vinyl ] -23,25-dimetoxi13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.

1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone To a solution of 22 ml of tetrahydrofuran was added 883 mg of N-methylmorpholine N-oxide followed by 871 μΐ of 0.25 molar osmium tetraoxide in tetrahydrofuran. After stirring at room temperature for 3 hours, the reaction mixture was quenched by the addition of 20% sodium bisulfite (20 mL), and the resulting precipitate was washed with a cellite filter and ethyl acetate. The filtrates were combined, washed twice with 20% sodium bisulfite, then with saturated aqueous sodium bicarbonate, and finally with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel flash chromatography. Elution was carried out with a 2: 1 by volume mixture of ethyl acetate / hexane and 1% by volume methanol. 705 mg of the title compound are obtained with 1 H NMR spectra consistent with the expected structure.

HE. step

17-Ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) 12- [2 '- (4' - (ethanalyloxy-3 '' -methoxycyclohexyl) -1 'methyl-vinyl] -23,25-dimethoxy-1 3,19,21,27-tetramethyl-II, 28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ Joktakoz-18-ene-2,3,10,16-tetraone

1.56 g of 11D. 17-Ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) -12- [2 '- (4' - (2,3-dioxy-1-propoxy) -3 '-methoxycyclohexyl) ) -1'-Methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azaricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10 To a solution of 16-tetraone in 20 ml of 20% aqueous tetrahydrofuran is added 510 mg of sodium metaperiodate and the mixture is vigorously stirred for 30 minutes. An additional 170 mg of sodium metaperiodate was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate, filtered through a pad of cellite, and rinsed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel flash chromatography. Elution was carried out with a 1: 2 by volume mixture of ethyl acetate / hexane and 1% by volume methanol. 1.45 g of the title compound are obtained with 1 H NMR spectra consistent with the expected structure.

11F. step

17-Ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) 12- [2 '- (4' -carboxymethoxy-3 '-methoxy-cyclohexyl) 1'-methyl-vinyl] - 23,25-dimethoxy-3,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-I8-ene-2,3, l 0,16-tetraone

311 mg of 11E. 17-ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) -12- [2 '- (4' - (ethan

HU 211,897 A9 aloxy-3 ' -methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [ 22.3.1.0 ⁴ - ⁹ ] To a solution of octacos-18-ene-2,3,10,16-tetraone in 6.6 ml of tert-butanol and 1.65 ml of 2-methyl-2-butene is added 273 mg of sodium chlorite and 272 mg of sodium dihydrogen phosphate dissolved in 2.7 ml of water. The addition is slow. After 2 hours, the solvent was distilled off in vacuo, the residue was dissolved in water and acidified to pH 3 with 1N hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 x 10 mL), and the organic layers were combined and washed with saturated aqueous sodium chloride. It was dried over anhydrous magnesium sulfate and purified by flash chromatography on silica gel. Elution is carried out first with a mixture of 2% by volume of methanol in methylene chloride and then with a mixture of 2% by volume of methanol in methylene chloride and 0.5% by volume of acetic acid. 255 mg of the title compound are obtained with 1 H NMR spectra consistent with the expected structure.

] 1G. step

17-Ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) 12- [2 '- (4-5-indolylaminocarbonylmethoxy-3-methoxycyclohexyl) -! '-methyl-vinyl] -23,25-dimetoxi13,19,2], 27-tetramethyl-ll, 28-dioxa-4-azatricyclo [22.3.1.0 ^4-9} octacos-18-ene-2,3,10 , 16-tetraone 150 mg 11F. 17-Ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) -12- [2 '- (4 "-carboxymethoxy-3" -methoxy-cyclohexyl) -1'-methyl -vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.

3.1.0 ⁴⁹ ] To a solution of octacos-18-ene-2,3,10,16-tetraone in 1.6 ml of methylene chloride is added 103 mg of benzotnazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate. followed by 43 μΐ triethylamine. After 10 minutes, 5 mg of 5-aminoindole was added to the reaction mixture, which was stirred for 1 hour, diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. . The organic layer was dried over anhydrous magnesium sulfate and purified by flash chromatography on silica gel. Elution with ethyl acetate / hexane (1: 2 v / v). methanol-containing solvent mixture. 138 mg of the title compound are obtained with Ή NMR spectra consistent with the expected structure.

l ^l Step H.

17-Ethyl], 14-dihydroxy-1 2- [2 '- (4''-5-indolylaminocarbonylmethoxy-3' -methoxycyclohexyl) -1'-methyl-vinyl] -23,25- dimethoxy-13,19,21,27-telrametil-yl, 4-28dioxa azatriciklol22.3.1.0 ⁴ · ⁹ Jokíakoz én2,3,10,16-18-tetraone

138 mg of 17-ethyl-1-hydroxy-14- (tert-butyldimethylsilyloxy) -12- [2 '- (4 "-5-indolylaminocarbonylmethoxy-3" methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,

To a solution of 19,21,27-tetramethyl-1,28,8-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] octacos-18-ene-2,3,10,16-tetraone in 1 ml of tetrahydrofuran is added 200 μl of polypropylene Hydrofluoride-pyridine complex (as a solution in 40% tetrahydrofuran: pyridine 2: 1 by volume) and stirred at room temperature. After 2 days, the reaction was quenched by careful addition of saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phases are combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel. Elution was carried out with a 1: 1 by volume mixture of ethyl acetate / hexane and 1% by volume of methanol. The title compound was obtained.

M = (FAB) 971 (M + Li).

Partial * C NMR δ: 9.52 (brs, 1H); 8.15 (brs, 1H);

7.91 (s, 1H); 7.30 (s, 2H); 7.16 (dd, J = 3.3 Hz, 1H);

6.49 (dd, J = 3 Hz, 1H); 4.41 (brd, J / 14 Hz, 1H).

Example 12

17-Ethyl] -hydroxy-12- [2 '- (4-methyl-N-tryptophanylcarbonylmethoxy-3-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19 , 21,27-tetramethyl-11,28dioxa-4-azatricyclo [22.3.1.0 ⁴ · 18 ⁹ Jokíakoz- én2,3,10,16-tetraone

12A. step

17-Ethyl-1-hydroxy-12- [2 '- (4' -allyloxy-3-methoxycyclohexyl) -! -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ Joktakoz-18-ene-2,3,10,16-tetraone 510 mg 17-ethyl-1-hydroxy-12- [2 '- (4' -hydroxy-3 'methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl- 1,1,28-dioxa-4-azatricyclo [22. 3.1.0 ⁴⁹ ] To a solution of octacos-18-ene-2,3,10,16-tetraone in 6.6 ml of 33% by volume methylene chloride in cyclohexane was added 266 mg of pure allyl trichloroacetimidate and the mixture was stirred for 5 minutes. Then 12 μ 12 trifluoromethanesulfonic acid was added slowly via syringe and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then diluted with ethyl acetate, washed with saturated aqueous sodium carbonate, water, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate. The concentrate was purified by flash chromatography on silica gel. Elution was carried out with a mixture of ethyl acetate: hexane (1: 9 by volume) and methanol (1% by volume). 434 mg of the title compound are obtained with 1 H NMR spectra consistent with the expected structure.

12B. step

17-Ethyl-1-hydroxy-12- [2 '- (4' - (2,3-dioxy-1-propoxy) 3-methoxycyclohexyl) -] - methyl vinyl] -23,25-dimethoxy- / 3,19,21,27-tetramethyl - //, 28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ⁹ jokíakoz-18-ene-2,3,10,16-tetraone 434 mg of 12A. 17-Ethyl-1-hydroxy-12- [2 '- (4'-allyloxy-3' -methoxy-cyclohexyl) -1'-methyl-vinyl] -7,25-dimethoxy-13,19,21 27-tetrametil36

HU 211 897 A9

To a solution of 11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone in 15 ml of tetrahydrofuran was added 431 mg of N-methylmorpholine N-oxide, followed by μΐ 0.25 M solution of osmium tetroxide in tetrahydrofuran and the mixture was stirred at room temperature. After 4.5 hours, the reaction was quenched by the addition of 20% sodium bisulfite, and the resulting precipitate was washed with a cellite filter and ethyl acetate. The filtrates were combined, washed twice with 20% sodium bisulfite, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The concentrate was purified by flash chromatography on silica gel. The eluent was a 3: 1 by volume mixture of ethyl acetate / hexane and 1% methanol in solvent. 177 mg of the title compound are obtained with a Ή NMR spectrum consistent with the expected structure.

12C. step

17-Ethyl-1-hydroxy-12- [2 '- (4' -ethanoloxy) -3-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy] 3, J9.21, 27-tetramethyl]], 28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone 25

177 mg of 12B. 17-ethyl-1-hydroxy-12- [2 '- (4' - (2,3-dioxy-1-propoxy) -3 '-methoxycyclohexyl) -T-methyl-vinyl] prepared in Step 23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} oktakoz18-ene-2,3,10,16-tetraone 2 ml of 20% To a solution of aqueous tetrahydrofuran in water was added 67 mg of sodium metaperiodate and the mixture was vigorously stirred for 30 minutes. An additional 20 mg of sodium metaperiodate was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate, filtered through a cell filter, and the residue was washed with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then purified by flash chromatography on silica gel. The eluent was eluted with a 2: 3 by volume mixture of ethyl acetate / hexane and 1% methanol. 157 mg of the title compound are obtained having a Ή NMR spectrum consistent with the desired structure.

12D. step

17-Ethyl-1-hydroxy-12- [2 '- (4-carboxymethoxy) -3'-methoxycyclohexyl)]' -methyl-vinyl] -23,25-dimethoxy-13,] 9,21,27- tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ -octacos-8-ene-2,3,10,16-tetraone 50

157 mg of 12C. 17-Ethyl-1-hydroxy-12- [2 '- (4' -ethanoloxy-1-propoxy) -3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; To a solution of 2-methyl-2-butene is added 150 mg of sodium chlorite and 159 mg of sodium dihydrogen phosphate in 1.6 ml of water slowly. One hour later, the solvent was distilled off in vacuo, the residue was dissolved in water and acidified to pH 3 with 1N hydrochloric acid. The aqueous phase was washed with ethyl acetate (3 x 10 mL), and the organic layers were combined and washed with saturated aqueous sodium chloride. It is then dried over anhydrous magnesium sulfate and purified by flash chromatography on silica gel. Elution was carried out with a mixture of 2% methanol in methylene chloride and then 2% methanol in methylene chloride and 0.5% acetic acid. 114 mg of the title compound are obtained with 1 H NMR spectra consistent with the desired structure.

12E. step

17-Ethyl-1-hydroxy-12-12 '- (4-methoxy-N-tryptophanylcarbonylmethoxy-3' -methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19, 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-2,3,3,10,16-tetraone mg 12D. 17-ethyl-1-hydroxy-12- [2 '- (4' -carboxymethoxy) -3 '' -methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19; To a solution of 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; Joktakoz-18-ene-2,3,10,16-tetraone in 0.5 ml of methylene chloride is added 31 mg of benzo -triazol-1-yloxy-tris (-dimethylamino) phosphonium hexafluorophosphate and 14 μΐ triethylamine. After 10 minutes, 24 mg of tryptophan methyl ester hydrochloride was added and the mixture was stirred for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and finally saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and purified by flash chromatography on silica gel. Elution was carried out with ethyl acetate / hexane (1: 1 v / v methanol). 28 mg of the title compound are obtained.

M = (FAB) 1041 (M + Li).

Partial Ή NMR δ: 8.21 (brs, 1H); 8.04 (brd, J = 8 Hz)

IH); 7.56 (d, J = 8 Hz, 1H); 7.33 (d, J = 8 Hz, 1H);

7.11 (m, 3H); 4.41 (brd, J = 14 Hz, 1H); 3.64 (s,

3H).

Example 13

17-Ethyl-1-hydroxy-12- [2 '- (4''-3-indolyl-ethylaminocarbonylmethoxy-3' -methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy -13,19,21,27-tetramethyl-ll, 28dioxa-4-azatricyclo [22.3.1.0 ⁴ · ⁹ Joktakoz-18-tetraone én2,3,10,16 mg Example 12 prepared in step D. 17-ethyl- 1-Hydroxy-12- [2 '- (4' -carboxymethoxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1

1,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,

To a solution of 10,16-tetraone in 150 μΐ methylene chloride was added 103 mg benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate and 4.3 μΐ triethylamine. After 10 minutes, 5 mg tryptamine was added and the mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and then

Purify by flash chromatography on silica gel. Elution was carried out with ethyl acetate / hexane (1: 1 v / v methanol). 7.5 mg of the title compound are obtained.

M = (FAB) 983 (M + Li).

Partial Ή NMR δ: 8.32 (brs, 1H); 7.89 (m, 1H); 7.58 (d, J = 8 Hz, 1H); 7.31 (m, 1H); 7.10 (m, 3H); 4.51 (brd, J = 3 Hz, 1H); 4.41 (brd, J = 14 Hz, 1H).

Example 14

17-Ethyl-1,14-dihydroxy-12-1,2 '- (4- (1N-methyl-5-indolyl) oxy-3''-methoxycyclohexyl)-1'-methyl-vinyl] 23.25-dimethoxy- 13,19,21,27-tetramethyl-1 1,28-dioxa-4-aza-tricyclo [22.3.1. (f ⁹ ) octaco-18-2,3,3,10,16-tetraone

14A. example

Methyl-5-bromoindole

A mixture of sodium hydroxide (0.4 g, 10 mmol) in DMSO (20 mL) was heated to 80-85 ° C for 6 h, during which time the solid was largely dissolved and cooled to room temperature. 2.0 g (10 mmol) of 5-bromoindole are added with stirring, followed by one hour later 0.62 ml (10 mmol) of methyl iodide. The reaction mixture was stirred for a further 3 hours, at which time TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with water and extracted with diethyl ether. The organic phases were washed twice with water, dried over anhydrous sodium sulfate and concentrated in vacuo. 2.08 g of l-methyl-5-bromoindole is obtained as a yellow oil. crystallizes on standing.

14B. step

Tri (1-methyl-indol-5-yl) -bismuth

To a solution of l-methyl-5-bromoindole (5.0 g, 23.8 g mmol) in diethyl ether (100 mL) at -78 ° C was added 1.7 mL of t- in pentane (28 mL, 47.6 mmol). butyl lithium solution. After stirring at -78 ° C for 1 hour, a solution of bismuth trichloride (2.36 g, 7.5 mmol) in tetrahydrofuran (25 mL) was added via syringe. The cooling bath was maintained for another 2 hours, then the mixture was allowed to warm to room temperature and allowed to stand overnight. In the morning, the reaction mixture was poured into ice water and the product was extracted twice with toluene. The organic phases are combined, washed with water, dried over anhydrous sodium sulfate and dried under vacuum for ca. Concentrate to a volume of 30 ml. The residue was stored in a refrigerator for several hours, the solid formed was filtered off, washed with cold toluene and dried in vacuo. 1.7 g of tri (1-methylindol-5-yl) bismuth are obtained. which is a mustard solid.

14C. step

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (IN-methyl-5-indolyl) oxy-3-methoxycyclohexyl) -1'-methyl vinyl} 23.25-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ Joktakoz-18-ene 2,3,3,10,16-tetraone

450 mg (0.75 mmol) 14B. To a solution of the tri (1-methylindol-5-yl) bismuthine prepared in Step A (10 mL) in methylene chloride was added 0.158 mL (0.75 mmol) of peracetic acid (as a 32% acetic acid solution) and after 15 min. 350 mg (0.442 mol) of 17-eul-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy- 13,19,

21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone and Cu (OAc) 2t. After stirring for 2 days at room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The organic solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product is isolated and purified twice by preparative thin layer chromatography. 203 mg of the title compound are obtained as a colorless solid.

M = (FAB) 927 (M + Li).

Ή partial NMR (200 MHz, CDC1 ₃₎ 8: 7.19 (bs, IH);

7.17 (d, J = 10 Hz, 1H); 6.98 (d, J = 4 Hz, 1H); 6.91 (dd, J = 3 Hz and 10 Hz, 1H); 6.34 (d, J = 4 Hz, 1H);

3.72 (s, 3H); 3.51 (s, 3H).

Example 15

17-Ethyl-l. 14.20-trihydroxy-12- (2 '- (4' - (1-N-melyl-5-indolyl) oxy-3-methoxycyclohexyl) -} 'methyl vinyl] 23,25-dimethoxy-13,19, 21,27-tetramethyl] l, 28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ⁹ Joktakoz én2,3,10,16-18-tetraone

To a solution of 350 mg (0.584 mmol) of tri (1-methylindyl-5-yl) bismuthine in 6 ml of methylene chloride was added 0.15 ml (0.74 mmol) of peracetic acid (32% acetic acid), then, after 15 minutes, 25 mg (0.32 mmol) of 17-ethyl-1,14,20-trihydroxy-12- [2 '- (4' hydroxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl]. -23,25dimetoxi- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraont 35 mg (0.138 mmol) Cu (OAc) ₂ . After stirring for 2 days at room temperature, the reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The organic solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The products were isolated by flash chromatography on silica gel. The eluent was eluted with hexane / acetone (3: 1) and purified by preparative thin layer chromatography. Methylene chloride containing 3% by volume of methanol was used as eluent. 111 mg of the title compound are obtained.

M = (FAB) 943 (M + Li).

Partial Ή NMR (200 MHz, CDCl ₃ ) δ: 7.21 (bs, 1H);

7.18 (d, J = 7.5 Hz, 1H); 6.98 (d, J = 3 Hz, 1H);

6.94 (dd, J = 2.5 Hz and 7.5 Hz, 1H); 6.37 (d, J = 3

Hz, 1H); 3.75 (s, 3H); 3.59 (s, 3H).

Example 16

17-Ethyl-1-hydroxy-12- (2 '- (4- (1-methyl-5-indolyl) oxy-3-methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13 , 19,21,27-tetramethyl-1,2,8-dioxa-4-aza38

HU 211 897 A9 Tricycle [22.3.1. 06 ⁹ ] To a solution of octacos-18-ene-2,3,10,16-tetraone mg (0.058 mmol) tri (1-methylindol-5-yl) bismuthine in 0.7 mL methylene chloride was added 0.015 mL ( 0.074 mmol) of peracetic acid (as a 32% acetic acid solution), and after 15 minutes 25 mg (0.032 mmol) of 17-ethyl-1-hydroxy-12- [2 '- (4 "-hydroxy-3" -methoxycyclohexyl) - 1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.

I. 0 ⁴ - ⁹ ] octacos-18-ene-2,3,10,16-tetraone and 5 mg (0.03 mmol) of Cu (OAc) ₂ . After stirring for 3 days at room temperature, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted twice with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative thin layer chromatography. The mixture was eluted with hexane / acetone 2: 1 (v / v) followed by 5% methanol in methylene chloride. 10.2 mg of the title compound are obtained.

Partial Ή NMR (200 MHz, CDCl ₃ ) δ: 7.18 (bs, 1H);

7.16 (d, J = 7.5 Hz, 1H); 6.98 (d, J = 3 Hz, 1H);

6.92 (dd, J = 2.5 Hz and 7.5 Hz, 1H); 6.33 (d, J = 3

Hz, 1H); 3.64 (s, 3H); 3.51 (s, 3H).

Examples 17 and 18

17-Ethyl-1,14-dihydroxy-12- [2 '- (3' -hydroxy-4- (1-N-methyl-indol-5-yl) -oxycyclohexyl) -1'-methyl-vinyl] 23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ³⁹ Joktakoz-18-ene] 2,3,10,16-tetraone and

17-Ethyl-l, 14-dihydroxy-12- [2 '- (4 "-hydroxy-3" - (l-methyl-indol-5-yloxy) cyclohexyl) -l'-methylvinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-1,2,8-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone

To a solution of tri-1-methylindol-5-yl) bismuthine (150 mg, 0.25 mmol) in methylene chloride (2 mL) was added peracetic acid (0.05 mg, 0.23 mmol) (as a 32% acetic acid solution). and 10 minutes later, 100 mg (0.129 mmol) of 17-ethyl-1,14-dihydroxy-12- [2 '- (3', 4 '-hydroxycyclohexyl) -1'-methyl-vinyl] -23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;] joktakoz-18-ene-2,3,10,16-tetraone 20 mg (0.11 mol) ) Cu (OAc) ₂ -t. After stirring for 2 days at room temperature, the reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate and extracted twice with methylene chloride. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The products were isolated and purified by duplicate preparative thin layer chromatography. The eluent was eluted with a 2: 1 by volume mixture of hexane / acetone followed by methylene chloride containing 5% by volume of methanol. 19 mg 17-ethyl-1,14-dihydroxy-12- [2 '- (3' -hydroxy- (1-methylindol-5-yl) oxycyclohexyl) 1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-II, 28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,

10.16-tetraone,

Partial Ή NMR (200 MHz, CDCl ₃ ) δ: 7.19 (d, J = 10

Hz 1H); 7.17 (d, J = 2.5 Hz, 1H); 7.00 (d, J = 3 Hz,

IH); 6.88 (dd, J = 2.5 Hz and 10 Hz, 1H); 6.35 (d,

J = 3 Hz, 1H); 3.73 (s, 3H) and mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3 '- (1-methylindol-5-yl) oxycyclohexyl) - 1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10 We get a 16-tetraon,

Partial 1 H NMR (200 MHz, CDCl ₃ ) δ: 7.18 (d, J = 8)

Hz 1H); 7.18 (d, J = 8 Hz, 1H); 7.16 (d, J = 2.5 Hz,

IH); 6.98 (d, J = 3 Hz, 1H); 6.88 (dd, J = 2.5 Hz)

Hz, 1H); 6.33 (d, J = 3Hz, 1H); 3.73 (s, 3H).

Example 19

Tri (indol-5-yl) bismuth

A solution of 5-bromoindole (5.0 g, 25.5 mmol) in diethyl ether (50 mL) was added slowly at 0 ° C to 2.8 g (25 mmol) of KH (35% in oil, washed three times with hexane). ) To a suspension of 40 ml of diethyl ether. To the reaction mixture was added dropwise a syringe-cooled solution of 29.7 mL (50.5 mmol) of 1.7 M pentane in t-butyllithium, and after 40 min, a solution of 1.89 (6.0 mmol) BiCl _{3 in} 25 mL of tetrahydrofuran. The cooling bath was kept there for a further 2 hours, and then the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with ice water and extracted three times with toluene. The toluene solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with 75 mL of toluene and stored overnight at 4 ° C. The solid was filtered and air-dried. 1.53 g of tri (indol-5-yl) bismuth are obtained.

19B. step

17-Ethyl-l. 14-Dihydroxy-12-1,2 '- (4' - (indol-5-yl) oxy-3-methoxycyclohexyl) -1'-methylvinyl J-23,25-dimethoxy-13,19,21,27 -tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone

To a solution of tri (indol-5-yl) bismuthine (1.3 g, 2.33 mmol) in Example 14 Step B (30 mL of methylene chloride) was added 0.50 mL (2.31 mmol) of peracetic acid (32%). acetic acid solution), and after 10 minutes, 1.0 g (1.26 mmol) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "-hydroxy-3" -methoxycyclohexyl) -1 'methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11, 28-dioxa-4-azatricyclo [22.3.1.0 ^{4' 9]} octacos-18-ene-2,3,

10,16-tetraone and 100 mg (0.55 mmol) of Cu (OAc) ₂ . After stirring at room temperature for 3 days, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted twice with methylene chloride. The methylene chloride solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative thin layer chromatography (2: 1 hexane: acetone, 2: 1 hexane: ethyl acetate). 208 mg of the title compound are obtained.

M = (FAB) 906 (M).

Ή partial NMR (200 MHz, CDC1 ₃₎ δ: 8.12 (bs, IH);

7.26 (d, J = 10 Hz, 1H); 7.22 (d, J = 2.5 Hz, 1H);

HU 211 897 A9

7.18 (m, 1H); 6.9 (dd, J = 2.5 Hz and 10 Hz, 1H);

6.44 (m, 1H); 3.53 (s, 3H).

Example 20

17-Allyl-1,4-dihydroxy-12- (2 '- (4' - (indol-5-yl) oxy-3-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13 , 19,21,27-tetramethyl] l, 28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ⁹ Joktakoz-18-ene-2,3,10,16-tetraone (150 mg, 0.27 mmol), tri- To a solution of (indol-5-yl) -bismuthine in 3 mL of methylene chloride was added 0.05 mL (0.23 mmol) of peracetic acid (as a 32% acetic acid solution), followed by 100 mg (0.124 mmol) after 15 minutes. 17-allyl-1,14-dihydroxy-12- [2 '- (4' hydroxy-3 '-methoxy-cyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl- 11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone and Cu (OAc) 20 mg (0.11 mmol) ₂ -t. The After stirring at room temperature for 2 days, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The extraction solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative thin layer chromatography (eluent: hexane / acetone = 2: 1) followed by methylene chloride (5% v / v). 11 mg of the title compound are obtained.

M = (FAB), M + Li 925.

Partial Ή NMR (200 MHz, CDCl3) δ: 8.12 (bs, 1H);

7.24 (d, J = 10 Hz, 1H); 7.22 (d, J = 2.5 Hz, 1H);

7.17 (t. J = 3 Hz. 1H); 6.9 (dd. J = 3 Hz and 10 Hz,

1H): 6.44 (bs, 1H); 5.70 (m, 1H); 3.53 (s. 3H).

Example 21

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1-ethylindol-5-yl) oxy-3''methoxycyclohexyl) -! '-methyl-vinyl] -23.25dimetoxi-13,19,21,27-tetramethyl-11,28-dioxa-4azatriciklo [22.3.1.0 ⁴ · ⁹ Joktakoz-18-ene-2,3,10,16-tetraone

To a solution of 150 mg (0.23 mmol) of tri- (1-ethylindol-5-yl) bismuthine prepared in steps 14A and B in 3mmL of methylene chloride is added 0.063 mL (0, 3 mmol) of peracetic acid (as a 32% acetic acid solution), and after 15 minutes 100 mg (0.126 mmol) of 17-ethyl-1,14-dihydroxy-12 [2 '- (4 "-hydroxy-3" -methoxy) -cyclohexyl) -1'-methyl-vinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10, 16-tetraone and 20 g (0.11 mmol) of Cu (OAc) ₂ . The reaction mixture was stirred at room temperature for 3 days, then quenched with saturated aqueous sodium bicarbonate and extracted twice with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. A brown oil is obtained and the desired product is isolated and purified by preparative thin layer chromatography on silica gel. The eluent was first mixed with hexane / acetone 2: 1 (v / v) followed by methylene chloride (3% v / v). 60 mg of the title compound are obtained.

M = (FAB), M + Na 957.

Partial 1 H NMR (200 MHz, CDCl ₃ ) δ: 7.19 (d, J = 10)

Hz, 1H); 7.18 (d, J = 3 Hz, 1H); 7.05 (d, J = 4Hz,

IH); (dd, J = 3 Hz, 10 Hz, 1H); 6.35 (d, J = 4 Hz,

IH); 4.09 (q, J = 6.7 Hz, 2H); 3.5 (s, 3H); 1.4 (t,

J = 6.7 Hz, 3H).

Example 22

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-ethyl-indyl-5-yl) -oxy-3-methoxy-cyclohexyl) -! '-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1 H, 28-dioxa-4-azatricyclo {22.3.1.0 ⁴⁹ Joktakoz-18-ene-2,3,10,16-tetraone

To a solution of 0.2 g of tri (1-ethylindol-5-yl) bismuthine prepared in Steps A and B of Example 14 in 2 mL of methylene chloride was added 37 μΐ (0.2 mmol) of acetic acid at room temperature. The mixture was stirred for 15 minutes at room temperature and then 0.2 g (0.25 mmol) of 17-ethyl-1,14-dihydroxy-12- [2 '(4', 3 '-dihydroxycyclohexyl) -1'- methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16 tetraone and mg (0.11 mmol) of Cu (OAc) ₂ and the reaction mixture was stirred for 2 days. The reaction mixture is then treated with ca. Saturated aqueous sodium bicarbonate solution (20 ml) was added and the mixture was extracted twice with methylene chloride. The organic solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "- (l-methyl-indol-5-yl) oxy-3''- methoxycyclohexyl) -l'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone and 17-ethyl-1,14-dihydroxy-1 2- [2 '- (4' -hydroxy-3 '- (1-ethylindol-5-yl) oxycyclohexyl) -1'-methyl vinyl] - A mixture of 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone by chromatography on silica gel we separate it. The eluent was eluted with hexane / ethyl acetate (3: 1). 0.035 g of the title compound is obtained. TLC (silica gel, hexane: ethyl acetate = 3/1), Rf = 0.55. Partial Ή NMR (200 MHz, CDCl ₃ ) δ: 7.21 (d, J = 10

Hz, 1H); 7.14 (d, J = 3 Hz, 1H); 7.08 (d, J = 4Hz,

IH); 6.85 (dd, J = 3 Hz and 10 Hz, 1H); 6.36 (d, J = 4

Hz, 1H); 4.10 (q, J = 6.7 Hz, 2H); 1.42 (t, J = 6.7

Hz, 3H).

Example 23

17-Ethyl-1,14-dihydroxy-12- (2 '- (4- (J-propyl-5-indolyl) oxy-3' methoxycyclohexyl) -1'-methyl vinyl] -23,25dimethoxy -13,19,21,27-tetramethyl-1,28-dioxa-4azatriciklo [22.3.1.0 ⁴ · ⁹ Joktakoz-18-ene-2,3,10,16-tetraone

To a solution of tri (1-propylindol-5-yl) bismuthine (200 mg, 0.29 mmol) analogous to that described in Example 14 Steps A and B in 3 mL of methylene chloride was added 0.075 mL ( Peracetic acid (as a 32% acetic acid solution), and after 10 minutes 150 mg (0.19 mmol) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "-hydroxy-3"). methoxy-ciklo40

EN 211,897 A9 hexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos18- ene-2,3,10,16-tetraone and 30 mg (0.17 mmol) of Cu (OAc) et al. After stirring at room temperature for 20 hours, the reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The extraction solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative thin layer chromatography on silica gel. Elution was carried out with hexane / acetone 2: 1 (v / v), then methylene chloride (3% v / v) and finally with hexane / acetone (2: 1 v / v). 70 mg of the title compound are obtained.

M = (FAB), M + Na 971.

Ή partial NMR (200 MHz, CDC1 ₃₎ δ: 7.17 (d, J = 10 Hz, IH); 7.02 (d, J = 4Hz, 1H); 6.88 (dd, J = 3 Hz and 10 Hz, 1H); 6.32 (d, J = 4Hz, 1H); 3.97 (t, J = 7Hz, 2H); 3.50 (s, 3H); 1.80 (m, 2H).

Example 24

17-Ethyl-1,14-dihydroxy-12- (2 '- (4- (1-propyl-5-yl) oxy-3' -hydroxycyclohexyl) -1'-methyl-vinyl] -23,25- dimethoxy-13,19,2,2,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 3 &gt; Joktakoz-IS-ene, 3,10,16-tetraone 200 mg (0.29 mmol)] Example 3 To a solution of tri (1-propyl-indyl-5-yl) -bismuthine prepared in analogy to Steps A and B in 3 ml of methylene chloride was added 0.075 ml (0.36 mmol) of peracetic acid (32%). acetic acid solution), and after 10 minutes 150 mg (0.19 mmol) of 17-ethyl-1, 14-dihydroxy-12- [2 '- (3', 4 '-dihydroxy-3' -cyclohexyl) 1 '-methyl] -vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-II, 28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;

3,10,16-tetraone and 30 mg (0.17 mmol) of Cu (OAc) ₂ . After stirring at room temperature for 20 hours, the reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate and extracted with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product is separated from the C-3 'ether by preparative thin layer chromatography on silica gel.

Example 25

17-Ethyl-N, 4-dihydroxy-1,2- (2 '- (4- (1-hydroxyethylindol-5-yl) oxy-3''methoxycyclohexyl)-N'-methyl vinyl] -23,25-dimethoxy-13] 9,2l, 27-tetramethyl-ll, 28dioxa-4-azatricyclo [22.3.1.0 ^4'9} octacos-18-tetraone én2,3,10,16

25A. Step 1- (2-Hydroxy-ethyl) -5-bromo-indole

A mixture of MDSO with 175 ml of 4.4 g (0.011 mol) NaOH was heated to 100 ° C for 5 hours with stirring and then cooled to 20 ° C ^c. 5-Bromoindole (20 g, 0.102 mol) was added and the reaction mixture was stirred at room temperature for 8 hours. A solution of 5.1 g (0.0125 mole) of ethylene oxide and 20 ml of dimethyl sulfoxide in ethylene oxide was bubbled through DMSO. This ethylene oxide solution is then added slowly to the bromoindole reaction mixture and stirring is continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The ethereal solutions were combined and concentrated in vacuo to crystallize the product. The crude product was recrystallized from diethyl ether / hexane (3: 2) to give 6.25 g of the title compound.

25B. step

- (2-t-Butyldimethylsilyloxyethyl) -5-bromoindole g (0.025 mol) 1- (2-hydroxyethyl) -5-bromoindole 4.5 g (0.03 mol) A solution of t-butyldimethylsilyl chloride and 4.2 ml (0.03 mol) of triethylamine in 60 ml of methylene chloride was stirred for 12 hours at room temperature. The reaction mixture was then washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The title compound is obtained in the form of a yellow oil, with Ή NMR consistent with the expected structure.

25C. step

Tri [1- (2-t-butyldimethylsilyloxyethyl) indol-5-yl] bismuthine

To a solution of 1.4 g (0.004 mol) of 1- (2-t-butyl demethylsilyloxyethyl) -5-bromoindole in 14 ml of diethyl ether was added 4.7 ml (0.008 mol) at -78 ° C. ) A solution of t-butyllithium in 1.7 M pentane. After stirring for 1.5 hours, bismuth trichloride (0.4 g, 0.013 mol) dissolved in tetrahydrofuran (4 ml) was added. The reaction mixture was stirred at -78 ° C for 2 hours, then allowed to warm slowly to room temperature and stirred for a further 8 hours. The reaction mixture was then poured into water and extracted with toluene. The organic extraction solutions were combined. dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue was purified by chromatography on silica gel. The eluent was eluted with hexane / ethyl acetate (4: 1). 1.03 g of the title compound is obtained, which is a semi-solid. The 1 H NMR spectrum was consistent with the expected structure.

25D. step

17-Ethyl-1,14-dihydroxy-12- (2 '- (4''- (t-butyldimethylsilyloxyethylindol-5-yl) oxy-3''-methoxycyclohexyl) ) -1'-methyl-vinyl-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2, 3,10,16-tetraone

To a solution of 1.03 g (0.001 mol) of tri [1- (2-t-butyldimethylsilyloxyethyl) indol-5-yl] -bromutin in 10 ml of methylene chloride is added 150 μl of peracetic acid at room temperature. After stirring for 15 minutes, 1 g of 17-ethyl-1,14-dihydroxy-12- [2 '(4' -hydroxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25 g was added. dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-az

GB 211 897 A9 atriciklo [22.3.1,0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone and 0.04 g of Cu (OAc) ₂ -t and the reaction 20 hours at room temperature agitated. A saturated aqueous sodium bicarbonate solution was then added and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue was purified by chromatography on silica gel. The eluent was twice twice with 3: 1 hexane: acetate. 0.38 g of the title compound is obtained with 1 H NMR consistent with the expected structure.

Step 25E

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-hydroxyethylindol-5-yl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ joktakoz-18-ene, 2/3/10/16-tetraone

0.38 g 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (t-butyldimethylsilyloxyethylindol-5-yl) oxymethoxycyclohexyl) 1 ' -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; To a solution of tetraone in 10 ml of methylene chloride is added at room temperature a solution of 0.05 g of paratoluenesulfonic acid in 10 ml of methanol. After stirring for 3 hours, the reaction was complete by TLC on silica gel (hexane: acetate = 2: 1). The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted twice with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by chromatography on silica gel. The eluent was eluted with a 2: 1 by volume mixture of hexane and ethyl acetate. 0.245 g of the title compound are obtained.

M = (FAB), M + Li 957.

Partial Ή NMR (200 MHz, CDCl3) δ: 7.18 (d, J = 10

Hz, 1H); 7.16 (bs, 1H); 7.06 (d, j = 4 Hz, 1H); 6.86 (dd, J = 3Hz, 10Hz, 1H); 6.33 (d, J = 4Hz, 1H);

4.13 (t, J = 6.7 Hz, 2H); 3.83 (t, J = 6.7 Hz, 2H);

3.43 (s, 3H).

Example 26

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1'-allylindol5'-yl) oxy-3-methoxycyclohexyl) -1'-methylvinyl] 23.25 dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ⁹ Joktakoz-18-tetraone én2.3.10.16-

26A. step

Allyl-5-bromoindole

To a mixture of 204 mg (5.1 mmol, 1 equivalent) of NaOH in DMSO was added 1.0 g (5.1 mmol, 1 equivalent) of 5-bromoindole. The solution was stirred for a further 3 hours after complete dissolution of NaOH (about 1 hour). Allyl iodide (0.466 mL, 5.1 mmol, 1 equivalent) was then added via syringe. After 2 hours, the reaction mixture was diluted with water and extracted twice with diethyl ether. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel. The eluent was eluted with 4: 1 hexane: acetone. 730 mg of 1-allyl-5-bromoindole are obtained.

26B. step

Tri (1-allyl-indol-5-yl) -bismuth

To a solution of 1-allyl-5-bromoindole (730 mg, 3.09 mmol, 1 equivalent) in diethyl ether (15 mL) at -78 ° C under nitrogen was added stirring (1.8 mL, 3.09 mmol, 1 equivalent), A solution of t-butyllithium in 7M pentane. The mixture was stirred at -78 ° C under a stream of nitrogen for 1 hour and then a solution of bismuth trichloride (292 mg, 0.93 mmol, 0.3 equiv.) In dry tetrahydrofuran (3 mL) was added dropwise via syringe. Dry ice is added to the ice bath and the flask is covered. The mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was then diluted with toluene and washed with a saturated aqueous sodium chloride solution. The phases are separated and the aqueous phase is extracted three times with toluene. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in diethyl ether and filtered through a 0.4 µm pTFE membrane. The product begins to crystallize and the solution is stored in a refrigerator and the crystals are collected to give 200 mg of tri (1-allylindol-5-yl) -bismuth.

26C. step

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1'-allylindol5'-yl) oxy-3 'methoxycyclohexyl) -! '-methyl-vinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene 2,3,3,10,16-tetraone

To a solution of 186 mg (0.275 mol, 1.2 equivalents) of tri (1-allylindol-5-yl) -bismuthine in 3 ml of methylene chloride was added 0.064 ml (0.303 mmol, 1.32 equivalents) of peracetic acid (32%). dilute acetic acid solution). To the solution was added 1 mL of THF, 181 mg (0.0229 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "-hydroxy-3" -methoxycyclohexyl) - 1'-methyl-vinyl] -2,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3 .

10,16-tetraone and 10 mg (0.05 mmol, 0.24 equivalent) of copper (II) acetate. The mixture was sealed and stirred overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel. The eluent was eluted with hexane / acetone (2: 1 v / v) and then purified by preparative thin layer chromatography (eluent: 3.5% methanol / methylene chloride) to give 56 mg of the pure title compound.

HU 211 897 A9

Μ = (FAB), M + Li 953.

Partial 1 H-NMR (200 MHz, CDCl ₃ ) δ: 7.17 (bs, 1H);

7.15 (d, J = 10 Hz, 1H); 7.02 (d, J = 3 Hz, 1H); 6.88 (dd, J = 2 Hz and 10 Hz, 1H); 6.36 (d, J = 3 Hz, 1H);

5.95 (m, 1H); 4.63 (bd, J = 14 Hz, 1H); 3.50 (s, 3H);

Example 27

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1'-allylindol5'-yl) oxy-3' -hydroxycyclohexyl) -1'-methyl-vinyl] 23.25- dimethoxy-13,19,2,2,27-tetramethyl] 1,28-dioxa-4-aza-tricyclo [22.3.1.0] octacos-18-ene 2,3.10.16-tetraone

To a solution of 1.0 g (1.48 mmol, 1.2 equivalents) of tri (1-allyl-indol-5-yl) -bismuthine in 9 mL of methylene chloride and 3 mL of tetrahydrofuran was added 0.315 mL (1.62 mmol, 1.32 mmol) equivalent) peracetic acid (in 32% dilute acetic acid). To the solution was added 956 mg (1.23 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12 [2 '- (4', 3 '-dihydroxycyclohexyl) -1'-methyl-vinyl] -23. 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone and 22 mg (0.123 mmol) 0.1 equivalents) of copper (II) acetate. The mixture was sealed and stirred for 4 days. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel. The eluent was eluted with hexane / acetone 3: 1 (v / v) followed by preparative TLC (3.5% methanol in methylene chloride) to give 163 mg of pure 17-ethyl-1,14-dihydroxy-12- [2 '- (4'). -r-allyl-indol-5'-yl) -oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11.28-dioxa -4-Azatricyclo [22.3.1.0 ⁴⁹ ] octacos18-ene-2,3,10,16-tetraone is obtained.

M = (FAB), M + Li 953.

Partial Ή NMR (200 MHz, CDCl3) δ: 7.17 (d, J = 10 Hz, 1H); 7.15 (brs, 1H); 7.05 (d, j = 3 Hz, 1H); 6.86 (dd, J = 10 Hz and 2.5 Hz, 1H); 6.39 (d, J = 3 Hz, 1H); 6.05-5.85 (m, 1H); 4.66 (brd, J = 8.5 Hz, 2H);

4.75 (brd, J = 5 Hz, 1H); 4.38 (brd, J = 13 Hz, 1H).

Example 28

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (9'-methylcarbazol-3'-yl) oxy-3 '-methoxycyclohexyl) -] - methyl vinyl ] 23.25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ^9] oktakoz-] 8-tetraone én2.3.10.16-

28A. step

Tri (9-methylcarbazol-3-yl) -bizmutin

To a mixture of 646 mg (2.48 mmol, 1 equivalent) of 3-bromo-9-methylcarbazole in 12 mL of diethyl ether was added 3.0 mL ( ⁴⁹ 6 mmol, equivalent) of a solution of t-butyllithium in 1.7 M pentane. The mixture was quickly warmed to room temperature, then cooled rapidly to -78 ° C and stirred under a stream of nitrogen for 40 minutes. To this reaction mixture was added dropwise, via syringe, a solution of bismuth trichloride (235 mg, 0.747 mmol, 0.3 equiv.) In dry tetrahydrofuran (2.5 mL). Add ice to the ice bath and seal the flask. The reaction mixture was allowed to slowly warm to room temperature overnight. The mixture was then poured into a separatory funnel containing saturated aqueous sodium chloride solution and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The solid residue was triturated with diethyl ether followed by diethyl ether / methanol. The resulting solid was filtered to give tri-9-methylcarbazol-3-yl-bismuthine (200 mg). The supernatant is retained for further purification.

28B. step

17-Ethyl-1,14-dihydroxy-12- (2 '- (4- (9'-methylcarbazol-3'-yl) oxy-3' -methoxycyclohexyl) -1'-methyl vinyl]. 25-dimethoxy-13,19,21,2 7-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 Joktakoz-18-ene 2,3,10,16-tetraone

To a solution of tri-9-methylcarbazol-3-yl-bismuthine (200 mg, 0.267 mmol, 1.2 equivalents) in methylene chloride (3 mL) and tetrahydrofuran (1 mL) was added 0.062 mL (0.295 mmol, 1.32 equivalent) with stirring. peracetic acid (in 32% dilute acetic acid). The solution was then treated with 175 mg (0.222 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl]. -23,25-dimethoxy-13,19,21,7-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; + &gt;] joktakoz-18-ene-2,3,10,16-tetraone and 10 mg Copper (II) acetate (0.055 mmol, 0.24 equivalents) was added and the mixture was sealed and stirred for 48 hours. The product was isolated and purified by flash chromatography on silica gel using hexane / acetone (3: 1 v / v) as the eluent by preparative thin layer chromatography (3.5% MeOH / CHoridCl 3,5). mg of the title compound is obtained.

M = (FAB), M + Li 977.

Partial Ή NMR (200 MHz, CDCl ₃ ) δ: 7.68 (d, J = 2)

Hz, 1H); 7.48-7.10 (m, 6H); 4.58 (bd, J = 4.8 Hz,

IH); 4.39 (bd, J = 14 Hz, 1H); 3.80 (s, 3H); 3.53 (s,

2 H).

Example 29

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1'-benzylindol5-yl) oxy-3' '-methoxycyclohexyl)] -' - methyl vinyl] 23.25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 jokacotaz-18-ene] 2,3,10,16-tetraone

Step 29.A

Benzyl-5-bromoindole

204 mg (5.1 mmol, 1 equivalent) of NaOH in 10 mL

HU 211 897 A9

To the mixture in DMSO was added 1.0 g (5.1 mmol, 1 equivalent) of 5 bromoindole. The solution was stirred for 20 hours after complete dissolution of NaOH (about 1 hour). Benzyl bromide (0.606 mmol, 5.1 mmol, 1 equivalent) was then added via syringe. After seven hours, the reaction mixture was diluted with water and extracted four times with diethyl ether. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by crystallization from ether / hexane. 888 mg of 1-benzyl-5-bromoindole are obtained.

29B. step

Tri (1-benzylindol-5-yl) bismuth

To a mixture of 888 mg (3.105 mmol, 1 equivalent) of 1-benzyl-5-bromoindole in 15 mL of diethyl ether at -78 ° C (not all indole is in solution) is added 3.65 mL (6.21 mmol) of nitrogen, 2 equivalents) of a 1.7 molar solution of t-butyllithium in pentane. The mixture was stirred at -78 ° C for 1 hour under a stream of nitrogen and a solution of bismuth trichloride (294 mg, 0.392 mmol, 0.3 eq) in 3 mL of anhydrous tetrahydrofuran was added dropwise via syringe. To the nervous bath, add dry ice and cover the flask. The mixture was allowed to warm slowly to room temperature overnight. The reaction mixture was then poured into a separatory funnel containing saturated aqueous sodium chloride solution and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The solid residue was triturated with diethyl ether. The solid was recovered to give 200 mg of tri (1-benzylindol-5-yl) bismuth. The supernatant is also retained for further purification.

29C. step

17-Ethyl-1,14-dihydroxy-12-12 '- [4- (1'-benzylindol5-yl) oxy-3-methoxycyclohexyl) -1'-methylvinyl] 23,25-dimethoxy-13 , 19,21,2 7-Tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;

To a mixture of 200 mg (0.242 mmol, 1.2 equivalents) of tri (1-benzylindol-5-yl) bismuthine in 3 mL of methylene chloride and 1 mL of tetrahydrofuran was added 0.060 mL (0.285 mmol, 1.4 equivalents) of peracetic acid ( 32% in dilute acetic acid). To the solution was then added 159 mg (0.202 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "-hydroxy-3" -methoxy-cyclohexyl) -1'-methyl-vinyl]. -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3, l 0,16-tetraone and 10 mg (0.055 mmol, 0.24 equivalents) of copper (II) acetate. The mixture was sealed and stirred overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by flash chromatography on silica gel.

Hexane / acetone (3.1: v / v) was used as eluent. Subsequently, 100 mg of the title compound were obtained by preparative thin layer chromatography using 3.5 volumes of methanol in methylene chloride as eluent.

M = (FAB), M + Li 1003.

Partial Ή NMR (200 MHz, CDCl ₃ ) δ: 7.3-7.0 (m,

8H); 6.84 (dd, J = 9 Hz, 1H); 6.40 (d, 3H); 5.23 (bs,

2 H); 4.6 (bd, J = 6 Hz, 1H); 4.38 (bd, J = 14 Hz,

IH); 3.50 (s, 3H).

Example 31

17-Ethyl-1-hydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'allyloxy-cyclohexyl) -1'-methyl-vinyl] -23 , ^{25dimetoxi-13,19,21,27-tetramethyl-1,28-dioxa-4} 4azatriciklol22.3.1.0 · ^9] octacos-l 8-ene-2,3,10,16-tetraone

Step A] 7-Ethyl-1-hydroxy-12- (2 '- (4''- (tert-butyldimethylsilyloxy) -3'-allyloxycyclohexite) -1'-methyl- vinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1 (fi ⁹ joktakoz-18-ene] 2,3,10,16-tetraone

300 mg of 17-ethyl-1-hydroxy-12- [2 '- (4' (tert-butyldimethylsilyloxy) -3 '-hydroxycyclohexyl) -1'-methyl-vinyl] 23,25- 9 ml of cyclohexane containing 33% by volume of methylene chloride octacos-18-ene-tetraone 2,3.10,16-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatriciklo [22.3.1.0 ⁴ · ^9] To this solution was added 138 mg of allyl trichloroacetimidate and the mixture was allowed to stir for 5 minutes. Thereafter, 18 µl of trifluoromethanesulfonic acid was added via syringe and allowed to stand at room temperature. Three days later, the mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate was added. The phases are separated, the organic phase is washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The concentrate was purified by flash chromatography on silica gel. Elution was carried out with a 1: 4 by volume mixture of ethyl acetate / hexane and 1 volume of methanol. 230 mg of the title compound are obtained, trichloroacetamide is also present. The Ή NMR spectrum is consistent with the expected structure.

31B. step

17-Ethyl-1-hydroxy-12- [2 '- (4''-hydroxy-3''-allyloxycyclohexyl) -! '-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.19 ⁹ ] octacos-18-ene-2,3,10, 16-Tetraone 115 mg of 17-ethyl-1-hydroxy-12- [2 '- (4 "- (tert-butyldimethylsilyloxy) -3" allyloxycyclohexyl) -1'-methyl prepared in Step 31A. -vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,2,8-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10 To a solution of 16-tetraone in 2.5 ml of acetonitrile was added 40 µl of 2% aqueous acetonitrile HF and the mixture was stirred at room temperature. After 4 hours, the solution was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate solution.

EN 211 897 A9. The phases are separated, the organic phase is washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The concentrate was purified by flash chromatography on silica gel. Elution was carried out with a 1: 2 by volume mixture of ethyl acetate and hexane. 42 mg of the title compound are obtained having the 1 H NMR spectrum consistent with the expected structure.

3ic. step

7-Ethyl-1-hydroxy-12- [2 '- (4''- (1N-methyl-5-indolyl) oxy-3' allyloxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy -13,19,21,27-tetramethyl-1,28-dioxa-4azatriciklo [22.3.1.O ⁴ · tri ^(9-methyl Joktakoz-18-ene-2,3,10,16-te Traon g To a solution of -indol-5-yl) -bismuthine in 700 μΐ methylene chloride was added 17 μΐ peracetic acid and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was then treated with 42 pg

17-Ethyl-1-hydroxy-12- [2 '- (4' - (hydroxy-3 '-allyloxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21 A solution of 27-tramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1O ^4,9 ] octacos18-ene-2,3,10,16-tetraone in 270 μΐ of methylene chloride. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. containing 25 mg of the title compound.

M = (FAB), M + Li 938.

Partial 1 H-NMR (200 MHz, CDCl 3) δ: 7.19 (s, 1H);

7.18 (d, J = 9 Hz, 1H); 6.98 (d, J = 3 Hz, 1H); 6.92 (dd, J = 9.3 Hz 1H); 6.34 (d, J = 3 Hz, 1H); 5.89 (m,

1H); 4.56 (brd, J = 4Hz, 1H); 3.72 (s, 3H).

Example 32

17-Etd-1-hydroxy-12-12 '- (4'N-methyl-5-indolyl) oxy-3''η-porpolyloxycyclohexyl)-]' - methyl vinyl] 23,25-dimethoxy- 13,19.21,27-tetramethyl-ll, 28-dioxa-4-azatriciklol22.3. 10 ⁴ · ⁹ Joktakoz-18-ene 2,3,3,10,16-tetraone mg 17-Ethyl-1-hydroxy-12- [2 '- (4' - (1N-methyl-5-indolyl) oxy) prepared according to Example 31. -3 "-allyloxy-cyclohexyl) -1'-methyl-vinyl) -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos- To a solution of 18-ene-2,3,10,16-tetraone in 500 μΐ of ethyl acetate was added 5 mg of radium on charcoal. The flask was filled with hydrogen and the mixture was stirred at room temperature. After 1.5 hours, the reaction mixture was filtered through a pad of celite, and the solvent was evaporated in vacuo to give 20 mg of the title compound.

M = (FAB). M + Li 940.

Ή partial NMR (200 MHz, CDC1 ₃₎ δ: 7.18 (s, 1H);

7.16 (d, J = 9 Hz, 1H); 6.96 (d, J = 3Hz, 1H); 6.92 (dd, J = 9.3 Hz, 1H); 6.43 (d, J = 3 Hz, 1H); 4.55 (brd, J = 4Hz, 1H); 3.72 (s, 3H).

Example 33

17-Ethyl-1,14-dihydroxy-12- [2 '- (4''- (1-N-methyl-5-indolyl) oxy-3-isoporproxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-3,19,21,27-tetramethyl-4-l1,28dioxa azatri cyclo [22.3.1.0 ⁴ · 18 ⁹ Joktakoz- én2,3,10,16-tetraone

33A. step

17-Ethyl-1,14-dihydroxy-1 2- [2 '- (4' -hydroxy-3 '' -isopropyloxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13, 19,21,27-tetramethyl-1,2,8-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ -octozo-18-ene-2,3,10,16-tetraone 300 mg of 17-ethyl- 1,14-dihydroxy-12- [2 '- (3', 4 '-dihydroxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,

Containing 4.5 ml of 33% by volume of methylene chloride, 21,27-tetramethyl-1,28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ^9] octacos-18-ene-2,3,10,16-tetraone isopropyl trichloroacetimidate (142 mg) was added to the solution of cyclohexane and the reagents were allowed to stir for 5 minutes. Then 13.4 μΐ trifluoromethanesulfonic acid was added slowly via syringe and the reaction mixture was stirred at room temperature. After 5 days, the reaction mixture was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The phases are separated, the organic phase is washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The concentrate was purified by preparative thin layer chromatography on silica gel. Elution was carried out with a 1: 1 by volume mixture of ethyl acetate / hexane and 1% by volume of methanol. 42 mg of the title compound are obtained having the 1 H NMR spectrum consistent with the expected structure.

33B. step

17-Ethyl-l, 14-dihydroxy-12- [2 '- (4- (lN-methyl-5-indolyl) oxy-3''- isopropyl-cyclohexyl) -l'-methylvinyl] - 23,25-Dimethoxy-13.19,21,27-tetramethyl-1 1,28-dioxa-4-aza-tricyclone 22.3.1.0 ⁴ · ⁹ Joktakoz-18-ene 2,3,3,10,16-tetraone mg tri (1-methylindole) To a solution of -5-yl) -bizmutine in 700 μΐ methylene chloride was added 17 μΐ peracetic acid and the mixture was stirred at room temperature for 15 minutes. 42 mg 17-ethyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3 '-isopropyloxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19, 21,27-tetramethyl-l l, 28-dioxa-4-azatric azabicyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16-tetraont 450 μΐ was dissolved in methylene chloride and the solution of to the previous reaction mixture. After 18 hours, the reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The concentrate was purified by preparative thin layer chromatography on silica gel. Elution was carried out with a 1: 1 by volume mixture of ethyl acetate / hexane and 1% by volume of methanol. 9 mg of the title compound are obtained.

M = (FAB), M + Li 956.

Ή partial NMR (200 MHz, CDC1 ₃₎ δ: 7.19 (s, 1H);

7.16 (d, J = 9 Hz, 1H); 6.97 (d, J = 3Hz, 1H); 6.92 (dd, 9.3 Hz, 1H); 6.34 (d, J = 3Hz, 1H); 4.41 (brd,

J = 14 Hz, 1H); 2.72 (s, 3H).

HU 211 897 A9

Example 34

17-Ethyl-1,14-dihydroxy-12- (2 '- (4- (1N-methyl-5-indolyl) oxy-3' allyloxycyclohexyl) -1'-methyl vinyl] -23.25- dimethyl dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1. O ⁹ · 18 ⁹ Joktakoz- én2,3,10,16-tetraone

34. The Step

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (tert-butyldimethylsilyloxy) -3-hydroxycyclohexyl) -! '-methyl-vinyl] 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclool 22.3.1.0 ⁴ · ⁹ Joktakoz-18-ene 2,3.10.16-tetraone

1.0 g of 17-ethyl-1,14-dihydroxy-12- [2 '- (3', 4 '-dihydroxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19, Of a solution of 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone in 14 ml of anhydrous methylene chloride lutidine was added and the mixture was stirred at room temperature. After 10 minutes, 295 μΐ of tert-butyldimethylsilyl trifluoromethanesulfonate was added via syringe. After 15 minutes, the reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off in vacuo. The residue was purified by silica gel flash chromatography. Elution was carried out with a 1: 3 by volume mixture of ethyl acetate / hexane and 1% by volume of methanol. 293 mg of the title compound are obtained with 1 H NMR consistent with the expected structure.

34B. step

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (tert-butyldimethylsilyloxy) -3-allyloxycyclohexyl) -1'-methyl-vinyl] -23, 25-Dimethoxy-1 3,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. CA · ⁹ Joktakoz-18-ene 2,3.10.16-tetraone

290 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (tert-butyldimethylsilyloxy) -3 '-hydroxycyclohexyl) -1'-methyl 1-vinyl] -23, 25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone with 3.9 ml of 33% by volume methylene chloride in cyclohexane To this solution was added 131 mg of allyl trichloroacetimidate and the reagents were allowed to stir for 5 minutes. Then, 6 μΐ trifluoromethanesulfonic acid was added slowly via syringe and stirred at room temperature. After 5 days, the reaction mixture was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The phases are separated, the organic phase is washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The concentrate was purified by preparative thin layer chromatography on silica gel. Elution was carried out with a mixture of ethyl acetate / hexane (1: 5 by volume) and 1 volume of methanol. 150 mg of the title compound are obtained with Ή NMR spectra consistent with the expected structure.

34C. step

17-Ethyl-1,14-dihydroxy-12-β2 '- (4-hydroxy-3-allyloxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11 , 28-dioxa-4-azatricyclo [22.3.1.O ⁴ · ⁹ Joktakoz-18-ene-2,3,10,16-tetraone 150 mg of 17-ethyl-l, 14-dihydroxy-12- [2'- (4 "- (tert-butyldimethylsilyloxy) -3" allyloxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,28- To a solution of dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone in 3 ml of acetonitrile was added 80 μ 80 of 2% aqueous acetonitrile in HF and the mixture was stirred at room temperature. After 2 hours, the solution was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The phases are separated, the organic phase is washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The concentrate was purified by flash chromatography on silica gel. Elution was carried out with ethyl acetate / hexane (1: 1 v / v methanol). 63 mg of the title compound are obtained with 1 H NMR spectra.

34D. Step] 7-Ethyl-1,14-dihydroxy-12- [2 '- (4''- (1-methyl-5-indolyl) oxy-3-allyloxy-cyclohexyl) -1'-methyl-vinyl ] 23,25-dimethoxy-3,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.O ⁴ · 18 ⁹ Joktakoz- én2,3,10,16-tetraone mg To a solution of tri (1-methylindol-5-yl) -bismuthine in 1.0 ml of methylene chloride was added 23 μΐ of peracetic acid and the mixture was stirred at room temperature for 15 minutes. 60 mg

17-ethyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy) -3 '-allyloxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19, 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] octacos18-ene-2,3,10,16-tetraone was treated with 500 μΐ of methylene chloride and added to the previous reaction mixture. After 20 hours, the reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and then with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The concentrate was purified by preparative thin layer chromatography on silica gel. Elution was carried out with a 1: 2 by volume mixture of ethyl acetate / hexane and 1% by volume of methanol. 26 mg of the title compound are obtained.

Partial Ή NMR (200 MHz, CDCl ₃ ) δ: 7.18 (s, 1H);

7.16 (d, J = 9 Hz, 1H); 6.97 (d, J = 3 Hz, 1H); 6.91 (dd, J = 9.3 Hz, 1H); 6.34 (d, J = 3 Hz, 1H); 5.89 (m, 1H); 4.57 (brd, J = 4 Hz, 1H); 4.41 (brd, J = 14

Hz, 1H); 3.70 (s, 3H).

Example 35

17-Ethyl-1,14-dihydroxy-12- (2 '- (4- (1-methyl-5-indolyl) oxy-3-n-propyloxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-I3,19,21,27-tetramethyl-ll, 28dioxa-4-azatricyclo [22.3.1.0 ⁴ · ⁹ Joktakoz-18-tetraone én2,3,10,16 mg of 17-ethyl-l, 14-dihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'allyloxy-cyclohexyl) -1'-methyl-vinyl] -23,

HU 211 897 A9

25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;] joktakoz-18-ene-2,3,10,16-tetraone 400 μΐ ethyl- To a solution of acetate in ethyl acetate was added 4 mg of rhodium on charcoal. The flask was filled with hydrogen and the mixture was stirred at room temperature. After 1.5 hours, the reaction mixture was filtered through a pad of celite and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution was carried out with a 1: 1 by volume mixture of ethyl acetate / hexane and 1% by volume methanol. 10 mg of the title compound are obtained.

Partial Ή NMR (200 MHz, CDCl ₃ ) δ: 7.17 (s, 1H);

7.15 (d, J = 9 Hz, 1H); 6.97 (d, J = 3Hz, 1H); 6.92 (dd, J = 9.3 Hz, 1H); 6.34 (d, J = 3Hz, 1H); 4.56 (brd, J = 4Hz, 1H); 4.40 (brd, J = 14 Hz, 1H); 3.71 (s, 3H).

Example 36

17-Ethyl-1,14-dihydroxy-12- [2 '- (4 - (1- (3-t-butyldimethylsilyloxypropylindol-5-yl) oxy-3-methoxycyclohexyl) -} '-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 * ⁹ ] octacos-18-ene-2,3 10,16-Tetraone To a solution of 0.43 g (0.4 mmol) of tri [1- (3-t-butyldimethylsilyloxypropyl) -indol-5-yl] -bromutin in 4 ml of methylene chloride Peracetic acid (0.075 mL, 32% dilute in acetic acid) was added at room temperature, and after 15 minutes 35 mg (0.44 mmol) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4') -hydroxy-3 was added. '-Methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18- en-2,3,10,16-tetraone and 30 mg of Cu (OAc) ₂ t. The reaction mixture was stirred for 2 days, then saturated aqueous sodium bicarbonate was added and the mixture was extracted with methylene chloride. dried over sulfate, filtered and concentrated in vacuo k) The product is isolated and purified by preparative thin layer chromatography on silica gel. The eluent was a 3: 1 by volume mixture of hexane and acetone. 144 mg of the title compound are obtained.

Example 37

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (3-hydroxypropyl) -indol-5-yl) -oxy-3-methoxy-cyclohexyl) -1'-methyl-vinyl] -23 , 25-dimethoxy-3,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3]. l.O ^ joktakoz-2,3,10,16-tetraone-lSén

144 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "- (1- (3-t-butyldimethylsilyloxypropylindol-5-yl) oxy-3") methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,

21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ^9] octacos-18-ene-2,3, l0,16-tetraone 4 ml of methylene chloride at room temperature was added 20 mg of paratoluenesulfonic 4 ml of methanol solution. The reaction mixture was stirred for 3 hours, quenched with saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The extraction solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by preparative thin layer chromatography on silica gel. The eluent was 2: 1 hexane: acetone. 81 mg of the title compound are obtained.

Partial Ή NMR (200 MHz, CDCl ₃ ) δ: 7.22 (d, J = 9)

Hz, 1H); 7.18 (d, J = 3Hz, 1H); 7.07 (d, J = 3Hz,

1H); 6.89 (dd, J = 3 Hz and J = 9 Hz, 1H); 6.34 (d,

J = 3 Hz, 1H); 4.20 (t, J = 6.5 Hz, 2H); 2.00 (m,

2 H).

Example 38

17-Ethyl-1,14-dihydroxy-12- [2 '- (3-hydroxy-4- (1-t-butyldimethylsilyloxyethylindol-5-yl) oxy-cyclohexyl) -1' -methyl-vinyl} -23,25-dimethoxy-J 3,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 (f ⁹ ) octacos-18-ene-2,3, 10.16-tetraone

To a solution of 250 mg (0.24 mmol) of tri [1- (3-t-butyldimethylsilyloxypropyl) indol-5-yl] bismuthine in 2 ml of methylene chloride was added 0.05 ml of peracetic acid (32 ml) at room temperature. % acetic acid) and after 15 minutes 200 mg (0.25 mmol) of 17-ethyl-1,14-dihydroxy-12- [2 '- (3', 4 '-dihydroxycyclohexyl) -1' -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 (K'-octocos-18-ene-2,3,10, 16-Tetraone and 20 mg of Cu (OAc) ₂ t are added. The reaction mixture is stirred for 2 days, then saturated aqueous sodium bicarbonate solution is added and the mixture is extracted with methylene chloride and the organic extracts are combined, dried over sodium sulfate and filtered The product was isolated and purified by preparative thin layer chromatography on silica gel (hexane: acetone = 3: 1) to give 74 mg of the title compound.

Example 39

17-Ethyl-1,14-dihydroxy-12- {2 '- (3-hydroxy-4- (1-hydroxyethylindol-5-yl) oxy-cyclohexyl) -1'-methyl-vinyl] -23, 25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 (fi] ⁹ Joclazoz-18-ene-2,3,10,16-tetraone mg 17-ethyl-1,14- dihydroxy-12- [2 '- (3' -hydroxy-4 '- (t-butyldimethylsilyloxyethylindol-5-yl) oxycyclohexyl) -1'-methyl vinyl] -23, 25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; octaquacos-18-ene-2,3,11,16-tetraone prepared with 2 ml of methylene chloride A solution of 10 mg of paratoluenesulfonic acid in 2 ml of methanol was added to the solution at room temperature, the reaction mixture was stirred for 3 hours, quenched with saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The product is dried over anhydrous, filtered and concentrated in vacuo to give the product by preparative thin layer chromatography on silica gel. He was eluted with 2: 1 hexane: acetone. 44.8 mg of the title compound are obtained. Partial 1 H NMR (200 MHz, CDCl ₃ ) δ: 7.24 (d, J = 9)

Hz, 1H); 7.15 (d, J = 3Hz, 1H); 7.12 (d, J = 3.5 Hz,

1H); 6.86 (dd, J = 3 and J = 9 Hz, 1H); 6.39 (d,

J = 3.5 (1H); 4.20 (t, J = 5, 2H).

HU 211 897 A9

Example 40

Tri [l-2 (t-butyldimethyl-silyloxy-ethyl) -indol-6-yl] bismuthine

Step A. 6-Bromoindole

To a solution of 4-bromo-2-nitrotoluene (4.3 g, 20 mmol) in dimethylformamide (40 mL) was added dimethylformamide dimethylacetal (7.15 g, 60 mmol) and pyrrolidine (1.4 g, 20 mmol). The solution was heated to 110 ° C for 4 hours, then cooled to room temperature and diluted with diethyl ether. The reaction mixture was washed three times with water. dried over anhydrous sodium sulfate, filtered and the solvent was distilled off. The residue was dissolved in 125 ml of 80% aqueous acetic acid and heated to 75 ° C. Zinc powder (9.75 g, 150 mmol) was added gradually over 20 minutes. The reaction mixture was heated at 85 'C for 2 hours, then cooled to about 35 ° C and the unreacted zinc removed by filtration. The filtrate was diluted with diethyl ether, washed three times with water and then with saturated aqueous sodium bicarbonate. The solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to ca. The reaction mixture was concentrated to 30 ml, diluted with hexane and filtered. The filtrate was evaporated to give an off-white solid which was dissolved in hexane, filtered and evaporated. 1.65 g of the title compound are obtained as a light green solid.

Step B 1- (2-t-Butyldimethylsilyloxyethyl) -6-bromoindole

A solution of 6-bromoindole (0.85 g, 4.34 mmol) in dimethylformamide (4 mL) was added dropwise to a suspension of NaH (60% dispersion) (192 mg, 4.8%) in dimethylformamide (4 mL). After stirring for 10 minutes at room temperature, 1.15 g (4.8 mmol) of 2-t-butyldimethylsilyloxyethyl bromide are added and the mixture is stirred for 1.5 hours. Ice water and hexane were added to the reaction mixture, the layers were separated, the organic layer was washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. A dark oil is obtained from which the title compound is isolated by flash chromatography on silica gel. The eluent was eluted with 4: 1 hexane: acetone. 1.04 g of the expected compound is obtained in the form of an oil.

Step C: Tri [1- (2-t-Butyl-Dimethylsilyloxy-ethyl) -indol-6-yl] -Bummutine

To a solution of 1.0 g (2.81 mmol) of 1- (2-t-butyldimethylsilyloxyethyl) 6-bromoindole in 10 ml of diethyl ether at -78 ° C is added 3.4 ml (5.8 mmol) of t-butyllithium (as a 1.7 M solution in pentane). After stirring for 10 minutes, a solution of 285 mg (0.9 mmol) of BiCl _{3 in} 3 mL of tetrahydrofuran was added. The reaction mixture was stirred for an additional 10 minutes at -78 ° C and then allowed to warm to room temperature overnight. Ice water and methylene chloride are added to the reaction mixture, and the phases are separated. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. A dark oil was obtained, which was purified by flash chromatography on silica gel (hexane: acetone = 4: 1) to give 630 mg of the title compound as a dark oil (about 60% purity), which was used in Example 41 without further purification.

Example 41

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1-t-butyldimethylsilyloxyethylindol-6-yl) oxy-3-methoxycyclohexyl) - 1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3 10,16-tetraone

To a solution of 0.60 g (0.58 mmol) of tri [1- (2-t-butyldimethylsilyloxyethyl) indol-6-yl] -bromutin in 5 ml of methylene chloride is added 0.080 ml of peracetic acid (32 ml) at room temperature. % acetic acid solution) and after 15 minutes 350 mg (0.44 mmol) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "-hydroxy-3" -methoxycyclohexyl) -1' -methyl-vinyl] -23,25-dimethoxy-13,19,21, 27-tetramethyl-l 1, 28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ^9] octacos-18-ene-2,3, 10,16-tetraone and 30 mg Cu (OAc) ₂ t. After stirring for 20 hours, a saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative thin layer chromatography on silica gel eluting with hexane / acetone (3: 1). 150 mg of the title compound are obtained.

example

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1-hydroxyethylindol-6-yl) oxy-3' -methoxy-cyclohexyl) -1'-methyl-vinyl] 23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ joktakoz-18-ene] 2,3,10,16-tetraone

150 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (t-butyldimethylsilyloxyethylindol-6-yl) oxy-3 'methoxycyclohexyl) - 1'-methylvinyl] -23,25-dimethoxy-13,19,21, 27-tetramethyl-l 1, 28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ^9] octacos-18-ene-2, To a solution of 3.1 l of 0.16-tetraone in 4 mL of methylene chloride is added a solution of 20 mg of paratoluenesulfonic acid in 4 mL of methanol at room temperature. The reaction mixture was stirred for 2 hours, quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by preparative thin layer chromatography on silica gel eluting with hexane / acetone 2: 1 (v / v). 55 mg of the title compound are obtained.

Partial Ή NMR (200 MHz, CDCl ₃ ) δ: 7.47 (d, J = 6

Hz, 1H); 7.03 (d, J = 3Hz, 1H); 6.94 (bs, 1H); 6.82 (dd, J = 1.5 Hz and J = 6 Hz, 1H); 6.41 (d, J = 3 Hz,

1H); 4.20 (t, J = 5 Hz, 2H); 3.93 (t, J = 5 Hz, 2H);

3.50 (s, 3H).

HU 211 897 A9

Example 43

Tri (l-methyl-indol-6-yl) -bizmutin

To a solution of 1-methyl-6-bromoindole (760 mg, 3.6 mmol) in diethyl ether (15 mL) was added at -78 ° C

4.4 ml (2.5 mmol) of a 1.7 molar solution of t-butyllithium in pentane. After 10 minutes added to the reaction mixture was removed Biol added and the cooling bath 4 in ₃ ml of tetrahydrofuran, 375 mg (1.2 mmol). The reaction mixture was stirred for 4 hours, then poured into ice water and extracted with methylene chloride. The extraction solutions were combined, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. A dark oil was obtained which crystallized from menthanol to give 290 mg of the title compound as a yellow-red solid.

Example 44 7-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-methylindol-6-yl) oxy-3 '' methoxycyclohexyl) -] 'methyl vinyl] -23,25dimetoxi-13,19.21,27-tetramethyl-11,28-dioxa-4azatric azabicyclo [22.3 ./. ⁴ 0 · ⁹ joktakoz-18-ene-2,3,10,16-tetraone

To a solution of tri (1-methylindol-6-yl) bismuthine (200 mg, 0.33 mmol) in methylene chloride (2 mL) was added peracetic acid (0.70 mL, 32% acetic acid) at room temperature and after 15 min. 150 mg (0.19 mmol)

17-ethyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3 '-methoxy-cyclohexyl) -]' -methyl-vinyl] -23,25-dimethoxy-13,19,

21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone and 30 mg Cu (OAc) ₂ t. After stirring for 4 days, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by preparative thin layer chromatography on silica gel eluting with hexane / acetone 2: 1 (v / v). 76 mg of the title compound are obtained.

Partial 1 H-NMR (200 MHz, CDCl 3) δ: 7.44 (d, J = 7)

Hz, 1H); 6.91 (d, J = 3 Hz, 1H); 6.88 (d, J = 2 Hz,

IH); 6.81 (m, 1H); 6.37 (d, J = 3 Hz, 1H); 3.68 (s,

3H); 3.51 (s, 3H).

Example 45

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-dibenzylphosphonyloxyethylindol-5-yl) oxy-3-methoxycyclohexyl) 1'-methyl -vinyl] -23,25-dimethoxy- [3,3] 9,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 (fi ⁹ joktakoz-18-ene-2,3,10] , 16 6-tetraon

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-hydroxyethylindol5-yl) -oxy-3 '-methoxy-cyclohexyl) -1' purified by azeotropic distillation with toluene (202 mg) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10 To a solution of 16-tetraone in anhydrous tetrafuran was added 88.6 mg dibenzylphosphate, followed by 83.5 mg triphenylphosphine. The mixture was cooled to 0 ° C and diethyl azodicarboxylate (50 mL) was added. The mixture was stirred at 0 ° C for 5 minutes, then removed in an ice bath and stirred at room temperature for 2 hours. The crude reaction mixture was directly passed through a silica gel column and eluted with a 2: 3 v / v mixture of ethyl acetate / hexane and 1% methanol. 197 mg of the title compound are obtained.

Partial 1 H-NMR (CDCl ₃ ) δ: 7.29 (m, 6H); 7.18 (m,

5H); 7.12 (d, J = 9 Hz, 1H); 7.0 (d, J = 4Hz, 1H);

6.89 (dd, J = 9.2 Hz, 1H); 6.36 (d, J = 4Hz, 1H);

4.82 (m, 4H); 4.40 (brd, J = 14 Hz, 1H); 4.20 (m,

4H).

Example 46

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-phosphonooxyethylindol-5-yl) oxy-3 '' -methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,2 7-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. (fi · ⁹ joktakoz 18én-2,3,10,16-tetraone monopotassium salt 197 mg-17-ethyl-l, 14-dihydroxy-12- [2 '- (4 "- (l-dibenzylphosphate-ethylindol -5-yl) -oxy-3 '' -methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3. 1.0 ⁴ - ⁹ ] octacos-18-2,

Solution of 3,10,16-tetraone in 3.2 ml of methanol

Potassium bicarbonate (16.3 mg) was dissolved in water (200 ml). Palladium hydroxide on charcoal is added to the reaction mixture and hydrogen is added to the reaction mixture by means of a balloon filled with hydrogen. After the reaction was complete (which was observed after about 10 minutes by TLC), the mixture was filtered through a cellite filter, rinsed with methanol and a little water. The solvent was evaporated in vacuo to give a crude product which was purified on an HP-20 column to give 69 mg of the title compound.

Partial 1 H-NMR (CD ₃ OD) δ: 7.34 (d, J = 9 Hz, 1H);

7.27 (d, J = 4Hz, 1H); 7.12 (d, J = 2 Hz, 1H); 6.85 (dd, J = 2 Hz, 1H); 6.31 (d, J = 4 Hz, 1H); 5.23 (m,

2 H); 4.35 (m, 2H); 4.13 (m, 2H).

Example 47

17-Ethyl-1,14-dihydroxy-12- (2 '- (4''- (1- (N, N-dimethylglycyloxy) ethylindol-5-yl) oxy-3-methoxycyclohexyl) ) -] &apos; -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3 l ^(fi-18-en-9 loktakoz.. 2,3,10,16-tetraone

26.6 mg 17-ethyl-1,14-dihydroxy-12- [2 '- (1-hydroxyethylindol-5-yl) oxy-3' -methoxy-cyclohexyl) -1'-methyl-vinyl] -J- 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-0,3 ml 2,3,10,16tetraon to a solution of anhydrous methylene chloride, 5.8 mg of N, N-dimethylglycine hydrochloride salt,

3.4 mg DMAP and 8 mg EDC were added at room temperature. The reaction mixture was stirred for 4 hours and then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. The crude product obtained was subjected to flash chromatography

Purified by Method A9. Elution was carried out with a 1: 2 by volume mixture of acetone and hexane. 23 mg of the title compound are obtained.

Partial 1 H-NMR (200 MHz, CDCl ₃ ) δ: 7.21 (m, 2H);

7.04 (d, J = 4Hz, 1H); 6.91 (dd, J = 9, 2 Hz, 1H);

6.49 (d, J = 4 Hz, 1H); 4.41 (m, 2H); 4.32 (m, 2H);

3.07 (s, 3H); 2.26 (s, 3H).

Example 48] 7-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1-succinyloxyethylindol-5-yl) oxy-3' methoxycyclohexyl) -1 '- methylvinyl] -23,25-dimethoxy-13,19,21,27-tetrametil11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ⁹ Joktakoz-2,3,10,16-tetraone-18én

109 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-hydroxyethylindol-5-yl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,1

To a solution of 6-tetraone in anhydrous methylene chloride was added 11.5 mg of succinic anhydride and 19 mg of triethylamine. To the reaction mixture was then added 7 mg of DMAP and the progress of the reaction was monitored by TLC. After 1.5 hours, the reaction mixture was diluted with ethyl acetate and adjusted to pH 4 with 1N hydrochloric acid. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase is extracted with ethyl acetate, the organic phases are combined and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The crude product obtained is purified by flash chromatography. The eluent was methylene chloride containing 3 volumes of methanol. 66 mg of the title compound are obtained.

Partial 1 H-NMR (CDCl 3) δ: 7.19 (m, 2H); 7.04 (d.

J = 4 Hz, 1H): 6.91 (dd, J = 9.2 Hz, 1H); 6.39 (d,

J = 4 Hz, 1H): 4.32 (m, 4H); 2.49 (brs, 4H).

Example 49] 7-Ethyl-1,14-dihydroxy-12-1,2 '- (4' '- (1-methyl-3-phenylindol-5-yl) oxy-3' -methoxycyclohexyl) -] - methyl -vinyl] -23,25-dimethoxy-J 3.19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 (fi-octacos-18-ene] 2,3,10,16-tetraone

Step A 5-Bromo-3-phenylisatin To a mixture of 5 g (22.1 mmol, 1 equivalent) of 5-bromo-isatin in 150 mL of anhydrous tetrahydrofuran was added 14.7 mL (44.2 mmol, 2 equivalents) with stirring. phenylmagnesium bromide (as a 3M solution in diethyl ether). The addition of Grignard reagent is started at -78 ° C. The reaction mixture was stirred for ca. After adding 5 ml of Grignard reagent it becomes so viscous that it is immiscible. The cooling bath was removed and the remaining Grignard reagent added to the reaction mixture by rapid dropwise addition. The reaction mixture was stirred overnight and then stopped by thin layer chromatography to detect little unreacted starting material. Therefore, an additional 1.5 ml of Grignard reagent was added and the reaction mixture was stirred for an additional 6 hours. The mixture was then transferred to a separatory funnel containing saturated aqueous ammonium chloride and extracted four times with diethyl ether. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The product is used without further purification.

Step B: 5-Bromo-3-phenylindole

To a solution of 5.39 g (21 mmol, 1 equivalent) of 5-bromo-3-phenylisatin in 50 ml of anhydrous tetrahydrofuran was added in portions 2.0 g (52.5 mmol, 2.5 g) with stirring at 0 ° C for 1.5 hours. equivalent) lithium aluminum hydride. The cooling bath was removed and the reaction mixture was stirred overnight. The mixture was then cooled to 0 'C and 1N aqueous hydrochloric acid was carefully added. The mixture was then filtered through a cellite filter and the cellite washed with tetrahydrofuran. The filtrate was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.

Step C: 5-Bromo-1-methyl-3-phenylindole

To a solution of 2.4 g (8.78 mmol, 1 equivalent) of 5-bromo-3-phenylindole in 20 mL of dimethylformamide was added 422 mg of a 60% solution of sodium hydride in oil (10.54 mmol, 1.2 mL). equivalent). After stirring for 15 minutes, methyl iodide (0.6 mL, 9.66 mmol, 1.1 eq.) Was added via syringe and the reaction stirred for 3 hours. The mixture was then diluted with water and extracted four times with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography. The eluent was eluted with 2: 1 hexane: acetone. 1.63 g of 5-bromo-1-methyl-3-phenylindole are obtained.

Step D: Tri (1-Methyl-S-phenylindole-5-bis-bismuthine)

To a solution of 1.63 g (5.7 mmol, 1 equivalent) of 5-bromo-1-methyl-3-phenylindole in 35 ml of diethyl ether at -78 ° C under nitrogen is added dropwise via syringe 6.7. ml (11.4 mmol, 2 equivalents) of a solution of t-butyllithium in 1.7 M hexane. The reaction mixture was stirred for 10 min at -78 ° C and then 540 mg (1.71 mmol, 0.3 eq) of BiCl ₃ was added dropwise, dropwise. The reaction mixture was stirred for 10 minutes at -78 ° C, then the cooling bath was removed and the mixture was allowed to warm to room temperature. Three hours later, the reaction mixture was poured into a separatory funnel containing water and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether, the solid filtered, and washed with diethyl ether. 710 mg of tri (1-methyl-3-phenylindol-5-yl) bismuth are obtained.

HU 211 897 A9

Step E: 17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1-methyl-3-phenylindol-5-yl) oxy-3''methoxycyclohexyl) - l'methyl] -23,25-dimethoxy-13,19,21,27-tetrametilll, 28-dioxa-4-azatricyclo [22.3.]. 0 ^{4 '9]} octacos-18én-2,3,10, 16-tetraone

To a solution of 645 mg (0.78 mmol, 1.2 equivalents) of tri (1-methyl-3-phenylindol-5-yl) bismuthine in 10 mL of methylene chloride and 3 mL of tetrahydrofuran was added 0.514 mL (0.858 mmol, , 3 equivalents) of peracetic acid (in the form of a 32% acetic acid solution). After stirring for 5 minutes, 174-ethyl-1,14-dihydroxy-12- [2 '- (4''-hydroxy-3' -methoxycyclohexyl) -1'-methyl (514 mg, 0.65 mmol, 1 equivalent) was added. vinyl] -23,25-dimethoxy-13,19,21,27tetrametil-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraont and 12 mg (0.065 mmol, 0.1 equivalent) of Cu (OAc) ₂ t. The flask was sealed and the mixture was stirred. After 48 hours, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel. The eluent was eluted with hexane / acetone 2: 1 (v / v) followed by methylene chloride containing 3.5% (v / v) methanol to give 78 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-methyl)). -3-phenylindol-5-yl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa -4-Azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone is obtained.

M = (FAB) 1003 (M + Li); 996 (M +).

Partial 1 H-NMR (400 MHz, CDCl 3) δ: 7.59 (d, J = 7)

Hz (2H); 7.50 (m, 1H); 7.41 (tj = 7 Hz, 2H);

7.25-7.15 (m, 3H); 6.99 (dd, J = 9 Hz, J = 2 Hz,

IH); 4.57 (d, J = 6 Hz, 1H); 4.39 (bd. J = 13 Hz,

IH); 3.78 (s, 3H).

Example 50

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1-methyl-3- (2-hydroxyethyl) indol-5-yl) oxy-3-methoxycyclohexyl) 1' - methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 * ⁹ ] octacos-18-ene-2,3,10, l6-tetraon

Step A: 5-Bromo-3-hydroxyethylindole

To a solution of 1.9 g (7.48 mmol, 1 equivalent) of 5-bromoindole-3-acetic acid in 17 ml of anhydrous tetrahydrofuran is added 570 mg (1.6 mmol, 2 equivalents) of lithium aluminum in portions over 30 minutes. hydride. The reaction mixture coagulates. Thereafter, 20 ml of tetrahydrofuran were added and the cooling bath was removed. Stir vigorously overnight. The reaction mixture was then carefully added with 1N aqueous hydrochloric acid and then acidified with 2N aqueous hydrochloric acid. The mixture was filtered through a cellite filter and the cellite washed with tetrahydrofuran. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. TLC analysis of the residue indicated that it also contained unreacted starting material. The residue was dissolved in diethyl ether and extracted with 0.25 N aqueous sodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. 1.16 g of 5-bromo-3-hydroxyethylindole are obtained.

Step B 5-Bromo-3- (2-t-butyldimethylsilyloxy) indole

To a solution of 5-bromo-3-hydroxyethylindole (1.16 g, 4.83 mmol, 1 equivalent) in methylene chloride (12 mL) was added triethyl (1.0 mL, 7.25 mmol, 1.3 equiv.). amine followed by 875 mg (1.2 mmol, 1.2 equivalents) of t-butyldimethylchlorosilane and a catalytic amount of dimethylaminopyridine. The reaction mixture was stirred overnight, then poured into a separatory funnel containing water and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 1.66 g of 5-bromo-3- (2-t-butyldimethylsilyloxy) ethyl indole are obtained.

Step C: 5-Bromo-1-methyl-3- (2-t-butyldimethylsilyloxy) ethylindole

To a solution of 1.66 g (4.66 mmol, 1 equivalent) of 5-bromo-3- (2-t-butyldimethylsilyloxy) ethylindole in 15 mL of dimethylformamide was added 225 mg (5 mL) of (6 mmol, 1.2 equivalents) of NaH (as a 60% oil dispersion). After 15 minutes, 0.320 ml (5.13 mmol, 1.1 equivalents) of iodomethane were added to the reaction mixture. The reaction mixture was stirred for 4 hours, then poured into a separatory funnel containing water and extracted twice with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. 1.49 g of 5-bromo-1-methyl-3- (2-t-butyldimethylsilyloxy) ethyl indole are obtained.

Step D: Tri (1-Methyl-3- (2-t-butyldimethylsilyloxy) ethylindol-5-yl) -bismuthine

A solution of 1.49 g (4.03 mmol, 1 equivalent) of 5-bromo-1-methyl-3- (2-t-butyldimethylsilyloxy) ethyl indole in 15 ml of diethyl ether was added at -78 ° C. 4.8 ml (8.06 mmol, 2 equivalents) of t-butyllithium in a 1.7 molar solution of pentane are added dropwise via a syringe under nitrogen. After stirring for 10 min at -78 ° C, a solution of 381 mg (1.21 mmol, 0.3 eq) of BiCl 3 in 5 mL of tetrahydrofuran was added dropwise via syringe. The mixture was stirred at -78 ° C for 7 minutes under a stream of nitrogen, then the cooling bath was removed and the reaction was allowed to warm to room temperature. One hour later, the mixture was poured into a separatory funnel containing water and extracted four times with methylene chloride. The organic extra51

The A9 mesh solutions were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 554 mg of crude product are obtained. The @ 1 H NMR spectrum of the residue indicates that the ratio of the desired bismuthine to the reduced indole is ca. 2: the first This crude mixture was used for the next step without purification.

Step E: 17-Ethyl-1,14-dihydroxy-12- [2 '- (4 - (] - methyl3- (2-t-butyldimethylsilyloxyethyl) indol-5-yl) oxy-3 &apos; -methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-3,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3. 1. (f- ⁹ ) Octacos-18-ene-2,3,10,16-tetraone 554 mg tri (1-methyl-3- (2-t-butyldimethylsilyloxy) ethyl indole-5 To a solution of the crude product of the preceding step containing the allyl-bismuthine in 10 ml of methylene chloride and 3 ml of tetrahydrofuran was added 0.120 ml (0.571 mmol) of peracetic acid (32% in dilute acetic acid), followed by 347 mg (0.439 mmol). 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "hydroxy-3" -methoxy-cyclohexyl) -l'-methylvinyl] -23,25dimetoxi-13,19,21,27-tetramethyl l l, 28-dioxa-4-azatricyclo [22.3.1,0 ^{4 9]} octacos-18-ene-2,3,10,16-tetraont, then (24 mg, 0:13 mmol) Cu (OAc) ₂ -t After stirring overnight, the reaction mixture was poured into a separatory funnel containing saturated aqueous sodium bicarbonate and extracted four times with methylene chloride. The residue was purified by silica gel column chromatography (eluent: hexane / acetone = 2: 1). 200 mg of 17-ethyl. 14-Dihydroxy-12- [2 '- (4' - (1-methyl-3- (2-t-butyldimethylsilyloxyethyl) indol-5-yl) oxy-3 'methoxy -cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl II. 28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,

3,10,16-tetraone was obtained as a brown oil.

Step F: 17-Ethyl-1,4] dihydroxy-12-12 '- (4' - (1) methyl-3- (2-hydroxyethyl) indol-5-yl) oxy-3 methoxycyclohexyl) -! '-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16- tetraone 200 mg 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-methyl-3- (2-t-butyldimethylsilyloxyethyl) indol-5-yl) ) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. To a solution of O-octacos-18-ene-2,3,10,16-tetraone in 6 mL of methylene chloride and 6 mL of methanol is added 30 mg of paratoluenesulfonic acid monohydrate with stirring. After stirring for 3 hours, a saturated aqueous sodium bicarbonate solution was added and the mixture was extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by preparative thin layer chromatography on silica gel. The eluent was first eluted with a 1: 1 by volume mixture of hexane / acetone and then with methylene chloride containing 7% by volume of methyl alcohol. 75 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-methyl-3- (2-hydroxyethyl) -indol-5-yl) -oxy-3 '-methoxy-cyclohexyl) ) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 &lt; 4 &gt;] Joktakoz-18-ene-2,3, 10,16-Tetraone is obtained.

M = (FAB) 872 (M + Li).

Partial 1 H-NMR (400 MHz, CDCl ₃ ) δ: 7.17-7.13 (m, 2H); 6.94 (dd, J = 9 Hz, J = 2 Hz, 1H); 6.88 (s,

IH); 4.58 (d, J = 6Hz, 1H); 4.39 (bd, J = 13 Hz,

IH); 3.84 (t, J = 6Hz, 2H); 3.70 (s, 3H); 2.94 (t,

J = 7 Hz, 2H).

Example 51

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1,3-dimethylindol-5-yl) oxy-3-methoxycyclohexyl) -! '-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · 18 ⁹ Joktakoz- én2,3,10,16- tetraone

Step A: To a solution of 5-bromo-3-methylindole g (22.1 mmol, 1 equivalent) in 5 mL of anhydrous tetrahydrofuran was added dropwise via syringe 32 mL (44.2 mmol, eq.) of methyl magnesium bromide in a 1.4 molar solution of toluene. 45 minutes later, thin layer chromatography indicated that a small amount of unreacted bromo-isatin was still present. Methyl magnesium bromide (3.7 mL) was added to the reaction mixture and stirred for one hour. The reaction mixture was then cooled to 0 ° C, and 1.26 g (33.15 mmol, 1.5 equivalents) of lithium aluminum hydride was added portionwise, and the mixture was stirred at 0 ° C for 30 minutes. At this time, the cooling bath was removed and the reaction mixture was stirred overnight. The mixture was then cooled again to 0 ° C and 1N aqueous hydrochloric acid was carefully added and then acidified with 2N aqueous hydrochloric acid. The cooling bath was removed, the mixture was stirred for 3 hours, then filtered through a pad of celite and washed with tetrahydrofuran on a pad of celite. The filtrate was concentrated in vacuo, the residue diluted with water and extracted four times with methylene chloride. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was applied to a bed of silica gel on a sintered glass filter and eluted with hexane / acetone (4: 1). The fractions containing the desired product were collected and concentrated in vacuo. 2.85 g of 5-bromo-3-methylindole are obtained.

Step B: 5-Bromo-1,3-dimethylindole

To a solution of 2.85 g (13.6 mmol, 1 equivalent) of 5-bromo-3-methylindole in 35 mL of dimethylformamide was added 651 mg (16.28 mmol, 1.2 equivalents) of NaH in a 60% oil dispersion. form. The mixture was stirred for 15 minutes then added 0.930 mL (l ⁴ '3mmól ^9, 1.1 eq) of iodomethane. After stirring for 2 hours, the dimethylformamide was evaporated in vacuo. The residue was diluted with water and extracted four times with diethyl ether. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.

Evaporate. 3.04 g of 5-bromo-1,3-dimethylindole are obtained, which is a reddish liquid.

Step C: Tri (1, 3-Dimethyl-indol-5-yl) -Butmutine 3.04 g (13.57 mmol, 1 equivalent) of 5-bromo-1,3-dimethyl-indole in 50 mL of diethyl ether To a solution of this solution at -78 ° C was added dropwise a syringe 16 mL (27.2 mmol, 2 equivalents) of t-butyllithium (1.7 M in hexane) under a stream of nitrogen. After stirring for 10 min at -78 ° C, a solution of 1.28 g (4.07 mmol, 0.3 eq) of BiCl _{3 in} 17 mL of tetrahydrofuran was added dropwise via syringe. After stirring for 5 minutes at -78 ° C, the cooling bath was removed and the reaction was allowed to warm to room temperature. The reaction mixture was then transferred to a separatory funnel containing ice water and extracted four times with methylene chloride. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and the resulting solid filtered. The filtrate was concentrated in vacuo to give 1.28 g of a brown oil. The residual Ή NMR spectrum showed a yield of ca. Containing the desired tri (1,3-dimethylindol5-yl) bismuthine and dimethyl indole in a ratio of 1: 2. This mixture was used without purification for the next Step D.

Step D: 17-Ethyl-J, 14-dihydroxy-12- [2 '- (4- (1,3-dimethylindol-5-yl) oxy-3' methoxycyclohexyl) -1 '- methylvinyl] -23,25-dimethoxy-! 3,19,21,27-tetrametilll. 28-dioxa-4-azatricyclo [22.3.1. (A ⁹ ) octacos-18-ene-2,3,10,16-tetraone

420 mg (0.7 mmol, 1.7 equivalents) of tn (1,3-dimethylindol-5-yl) -bismuthine (since 1.28 g of the material prepared in Step C contains about one third of bismuth). To a solution of methylene chloride (4 mL) and tetrahydrofuran (4 mL) was added 0.193 mL (0.916 mmol,

1.3 equivalents) of peracetic acid (as a 32% acetic acid solution). To the reaction mixture was added 464 mg (0.59 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' hydroxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl]. -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone followed by mg (0.176 mmol, 0.3 equivalents) of Cu (OAc) ₂ . After stirring for 4 days, the reaction was quenched by addition of saturated aqueous sodium bicarbonate solution and extracted four times with methylene chloride. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel. The eluent was first mixed with hexane / acetone 2: 1 (v / v) followed by methylene chloride containing 3.5% (v / v) methanol. The product is then purified by preparative thin layer chromatography. Elute 6 times with 4: 1 hexane: acetone. 117 mg of desired 17-ethyl-1,14-dihydroxy-12- [2 '(4' - (1,3-dimethylindol-5-yl) oxy-3 'methoxycyclohexyl) r -methyl-vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;] joktakoz-18-ene-2,3,

10,16-Tetraone is obtained.

M = (FAB) 934 (M ⁺ ).

Partial 1 H-NMR (400 MHz, CDCl ₃ ) δ: 7.14-7.10 (m, 2H); 6.91 (dd, J = 9 Hz, J = 2 Hz, 1H); 6.76 (s, 1H); 4.57 (d, J = 6Hz, 1H); 4.39 (bd, J = 13 Hz, 1H); 3.66 (s, 3H); 2.24 (s, 3H).

Example 52

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1-benzylindol5-yl) oxy-3-hydroxycyclohexyl) -! '- methylvinyl] 23,25-dimethoxy] 3,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;} octacos-18-ene 2,3,3,10,16- tetraone

To a solution of 1.28 (1.54 mmol, 1.2 equivalents) of tri (1-methylindol-5-yl) bismuthine in 9 mL of methylene chloride and 3 mL of tetrahydrofuran was added 0.357 mL (1.69 mmol, 1 mL) with stirring. 3 equivalents) of peracetic acid (in the form of a 32% acetic acid solution). To the reaction mixture was then added 1 g (1.28 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (3', 4 '-dihydroxycyclohexyl) -1'-methyl-vinyl]. , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone followed by mg Cu (OAc) ₂ -t. The reaction mixture was stirred for 2 days, then saturated aqueous sodium bicarbonate was added and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel. The eluent was first mixed with hexane / acetone 2: 1 (v / v) followed by methylene chloride containing 3.5% (v / v) methanol. 253 mg 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-benzylindol-5-yl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl ] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraont we get.

M = (FAB) 990 (M ⁺ + Li).

Partial 1 H-NMR (400 MHz, CDCl 3 δ: 7.30-7.05 (m, 8H): 6.82 (dd, J = 2 Hz, J = 8 Hz, 1H); 6.43 (d,

J = 3 Hz, 1H); 5.27 (s, 2H); 4.58 (d, J = 6Hz, 1H),

4.40 (bd, J = 13 Hz, 1H).

Example 53

17-Ethyl-1,14-dihydroxy-1 2- [2 '- (4' - (1- (3-hydroxypropyl) indol-6-yl) oxy-3-methoxycyclohexyl) -1 'methyl- vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1, 28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone

Step A: To a solution of 2-t-Butyldimethylsilyloxyethyl bromide in 50 g (0.40 mol) of 2-bromoethanol in 50 ml of methylene chloride was added 63.4 g (0.42 mol). t-butyldimethylchlorosilane, 45.4 g (0.45 mole) of triethylamine and 0.5 g of dimethylaminopyridine. The reaction mixture was stirred overnight and washed three times with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 85 g of the title compound are obtained in the form of a pale yellow oil.

HU 211,897 ¹H-NMR (CDClj) δ: 3.85 (t, 2H); 3.36 (t, 2H); 0.86 (s,

9H); 0.05 (s, 6H).

Step B: To a suspension of 1- (2-Butyldimethylsilyloxyethyl) -5-bromoindole in g (0.3 mol) of sodium hydride (as a 60% oily dispersion) in 200 ml of dimethylformamide a solution of 50 g (0.255 mol) of 5-bromoindole in 300 ml of dimethylformamide is added. After stirring for 15 minutes, pure 2-t-butyldimethylsilyloxyethyl bromidol (60 g, 0.255 mol) was added dropwise and the mixture was stirred for an additional hour. Ice water and diethyl ether were added to the reaction mixture and the phases were separated. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography over silica gel. The eluent was eluted with 3: 1 hexane: acetone. 68.6 g of the title compound are obtained in the form of a pale yellow oil.

1 H-NMR (CDCl ₃ ) δ: 7.72 (2, 1H); 7.1-7.3 (m. 3H);

6.4 (d, 1H); 4.18 (t, 2H); 3.86 (t, 2H); 0.8 (s, 9H);

-0.18 (s. 6H).

Step C: 17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1- (3-t-butyldimethylsilyloxypropyl) indol-6-yl) oxy-3 methoxy) -cyclohexyl) -1'-methyl-vinyl] -23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁹ &gt; Joktakoz-18-ene-2,3,10.16 Tetraone To a solution of 0.917 g of crude tri [1- (3-t-butyldimethylsilyloxyethyl) indol-6-yl] -bromutine in 7 ml of methylene chloride is added 0.10 ml of peracetic acid (32%) at room temperature. dilute acetic acid) and then 15 minutes later 500 mg (0.63 mmol) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3 'methoxycyclohexyl) -1 '-methyl-vinyl] -23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone and 50 mL of Cu (OAc) ₂ . After stirring for 2 days, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative thin layer chromatography on silica gel. The eluent was eluted with 3: 1 hexane: acetone. 318 mg of the title compound are obtained.

Step D: 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1- (3-hydroxypropyl) indol-6-yl) oxy-3 '' methoxycyclohexyl) -] - N -ethyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-U, 28-dioxa-4-aza-tricyclo [22.3.1. Cd ⁹ ] octacos-18-ene-2,3,10,16-tetraone

318 mg 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1- (3-t-butyldimethylsilyloxypropyl) indol-6-yl) oxy-3 ' methoxy-cyclohexyl) -r-methylvinyl] -23,25-dimethoxy-13,19,

21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ^9] added octacos-18-ene-2,3,10,16-tetraone in 5 ml of methylene chloride at room temperature was added 25 mg of paratoluenesulfonic Of a solution of 5 ml of methyl alcohol. After stirring for 3 hours, a saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by preparative thin layer chromatography on silica gel. The eluent was eluted with 2: 1 hexane: acetone. 190 mg of the title compound are obtained.

Partial 1 H-NMR (200 MHz, CDCl ₃ ) δ: 7.43 (d, J = 9 Hz, 1H); 7.02 (d, J = 2 Hz, 1H); 6.98 (d, J = 3 Hz, 1H); 6.78 (dd, J = 8 Hz and J = 9 Hz, 1H); 6.38 (d, J = 3 Hz, 1H); 4.20 (t, J = 6.5 Hz, 2H); 2.00 (m, 2H).

Example 54

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (2 '' - (3 '''- diethylaminopropionyloxy) ethyl) indol-5'-yl) oxy-3-methoxy-cyclohexyl) -! '-Methyl-vinyl] -23,25-tetramethyl-dimetoxi13,19,21,27 -]], 28-dioxa-4-azatricyclo [22.3.1. Cd- ⁹ joktakoz-18-ene-2,3,10,16-tetraone 200 mg (0.210 mmol, 1 equivalent) 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "- (1""-(2""-Hydroxy) -ethyl) -indol-5" -yl) -oxy-3 "-methoxy-cyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27 To a solution of methyl tetraethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt; ^-9 ] octacos-18-ene-2,3,10,16-tetraone in 2 mL of methylene chloride was added 57 mg (0.315) under nitrogen with stirring. mmol (1.5 equivalents) of 3-N, N-diethylaminopropionic acid hydrochloride. 26 mg (0.210 mmol, 1 equivalent) of dimethylaminopyridine and 60 mg (0.315 mmol, 1.5 equivalent) of EDP. After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid, saturated aqueous sodium carbonate solution and then saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography over silica gel. The eluent was eluted with hexane / acetone (3: 2). 194 mg 17-Ethyl-1,14-dihydroxy-12- [2 '- (4 "- (2""(3""' - diethylaminopropionyloxy) ethyl) indole-5"'- yl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone is obtained. M = (FAB) 1079 (M ⁺ + 1).

Example 55

17-Ethyl-1,14-dihydroxy-12- [2 '- (4 "- (2"' - (3 '' '- dimethyl-propionyl-amino) ethyl) indole-5' '- yl ) oxy-3 "methoxycyclohexyl) -r-methylvinyl] -23,25-dimethoxy-13,

19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1. 0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone

The title compound was prepared as in Example 54 except that 3-N, N-dimethylaminopropionic acid was used.

HU 211 897 A9

Example 56] 7-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (2 '''-(3''''' - aminopropionyloxy) ethyl) indole] 5 '' -yl) oxy-3-methoxycyclohexyl) -! '-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10, 16-Tetraone The title compound was prepared as described in Example 54, except using appropriately protected 3-aminopropionic acid, and deprotecting the amino group.

and stir for 30 minutes. The reaction mixture was filtered through a 0.45 µm PTFE membrane and concentrated in vacuo. The product was purified by flash chromatography. The eluent is a mixture of trichloromethane / methanol / formic acid / water (100: 10: 5: 0.5). 95 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (2 '' - (aspartyloxy) ethyl) indole-5 '' - (I) oxy-3 'methoxy) -cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; 3,10,16-tetraone is obtained.

Example 57

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (2''-(3'') - benzoxycarbonyl-2''' - benzyloxycarbonylaminopropionyloxy) -ethylindol-5 '''-yl)oxy-3' -methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-3,7,9,2J, 27-tetramethyl-U, 28 -dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone 500 mg (0.526 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [ 2 '- (4' - (1 '' - (2 '' - hydroxyethyl) indol-5 '' yl) oxy-3 '-methoxycyclohexyl) -1'-methyl vinyl] -23, 25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone prepared with 5 ml of methylene chloride of N-Cbz-aspartic acid P-benzyl ester, 64 mg (0.526 mmol, 1 equivalent) of dimethylaminopyridine and 120 mg (0.631 mmol, , 2 equivalents) EDP. The reaction mixture was stirred for 2 hours, during which time TLC analysis indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and then saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography. The eluent was eluted with 70:30 hexane / acetone. 687 mg of 17-ethyl-1,14-dihydroxy-12 [2 '- (4' - (2 '' - (3 ''') - benzyloxycarbonyl-2''' - benzyloxycarbonylaminopropionyl) oxy) ethyl) indole-5 '' - yl) oxy-3 "-methoxy-cyclohexyl) -l'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11 28-dioxa-4-azatricyclo [22.3.1.0 &lt; ⁴ &gt; ^-9 ] octacos-18-ene-2,3,10,16-tetraone is obtained.

Example 58) 7-Ethyl], 4-dihydroxy-2- [2 '- (4- (2- (aspartyloxy) ethyl) indol-5'-yl) oxy-3-methoxy] cyclohexyl) 1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ joktakoz-18-ene-2, 3.10,11,6-tetraone

125 mg (0.093 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "- (2""-(3'") - benzyloxycarbonyl-2 '") -benzyloxycarbonylamino-propionyloxy) -ethyl) -indol-5 '' -yl) -oxy-3 '-methoxy-cyclohexyl) -methyl-vinyl] -23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22nd 3.1.0 ⁴⁹ ] To a solution of octacos-18-ene-2,3,10,16-tetraone in 2 ml of methanol is added 25 mg of palladium hydroxide on charcoal. Fill the flask with hydrogen59. example

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (2 "" - (''''' imidazolylcarbonyloxy} ethyl) indol-5 '' -yl) -oxy-3-methoxy-cyclohexyl) -! '-methyl-vinyl] -23,25-dimetoxi13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo [22.3.1.0 ^{4' 9]} octacos-18-ene-2,3,10 16-tetraone

1.5 g (1.58 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '') - hydroxyethyl) indole) 5 '' - yl) oxy-3 "-methoxy-cyclohexyl) -l'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [ ⁴ 22.3.1.0 ^'9] octacos-18-ene-2,3,10,16-tetraone to a solution of 15 ml of methylene chloride under nitrogen was added carbonyldiimidazole (256 mg, 1.58 mmol, 1 eq) with stirring. After 45 minutes, the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid and then with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was used without further purification.

Example 60

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (2''''- piperazinecarbonyloxy) ethyl) indol-5''-yl) oxy-3-methoxy -cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1] CA- ⁹ ] octacos-18-ene. -2,3,10,16-tetraone 100 mg (0.096 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "- (2""-(1"'') imidazolyl) carbonyloxy) ethyl-indole-5 '' - yl) oxy-3 "-methoxy-cyclohexyl) -l'metil] -23,25-dimethoxy-13,19,21,27-dioxa-tetrametil11,28 -4-azatricyclo [22.3.1,0 ^4-9] was added octacos-18-ene -2,3,10,16-tetra-prepared 1 mL of THF at room temperature under nitrogen was added 82 mg (0.956 mmol, 10 eq) of piperazine. The reaction mixture was stirred at room temperature for 2 hours, stored in the refrigerator overnight, and stirred for another 6 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The product was purified by flash chromatography on silica gel. The eluent was first a solvent mixture containing 5% methanol in methylene chloride, followed by 5% methanol in methylene chloride and 1% by volume ammonium hydroxide. 74 mg of the title compound are obtained.

M = (FAB) 1064 (M ⁺ l).

HU 211 897 A9

Example 61

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (7 '-2 - (2-hydroxy) ethylaminocarbonyloxy) ethyl) indole-5''- yl) -oxi3 "-methoxy-cyclohexyl) -! '-methyl-vinyl] -23,25-dimetoxi13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10, 16-Tetraone 100 mg (0.096 mmol, 1 equivalent) 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (2 '' - (Γ '''' - imidazolylcarbonyloxy)) ethyl-indole-5 '' - yl) oxy-3 "-methoxy-cyclohexyl) -Γ-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa To a solution of -4-azatricyclo [22.3.1.0 &lt; 4 &gt;] joktakoz-18-ene-2,3,10,16-tetraone in 1 ml of tetrahydrofuran was added 29 μl (0.478 mmol, 5 equivalents) of nitrogen in nitrogen at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The product was purified by flash chromatography on silica gel. Elution was carried out with a 45:65 by volume mixture of acetone / hexane. 50 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1'-2 '' - (2 '''hydroxy) ethylaminocarbonyloxy) ethyl) - indole-5 '' - yl) -oxi3-methoxycyclohexyl) -l'-methylvinyl] -23.25-dimetoxi13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.

I. 0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone is obtained.

M = (FAB) 1061 (M ⁺ + Na); 1038 (M ⁺ + 1).

Example 62

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '-isopropylaminocarbonyloxy) ethyl) indol-5''' yl) oxy3'-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos- 18-I-tetraone 2,3.10.16

116 mg (0.111 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '''' -imidazolylcarbonyloxy)) ethyl indol-5 '' - yl) -oxy-3 '' - methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-II, 28-dioxa-4-aza-tricyclo To a solution of [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,3,10,16-tetraone in 1 ml of tetrahydrofuran is added 48 μl (0.555 mmol, 5 equivalents) of nitrogen at room temperature with stirring. After stirring overnight, the reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and brine. The product was purified by flash chromatography on silica gel. Elution was carried out with a 2: 3 by volume mixture of acetone and hexane. 50 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' (1 '' - (2 '' - isopropylaminocarbonyloxy) ethyl) indol-5 '' -yl) - oxy-3 '' - methoxy-cyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18- i-2,3,10,16-tetraone is obtained. M = (FAB) 1043 (M ⁺ + Li).

Example 63

17-Ethyl-1,14-dihydroxy-12- [2 '- (4''- (1 L piperidinecarbonyloxy) ethyl) indol-5 "' -yl) oxy-3" methoxycyclohexyl ) -l 'vinilJ-methyl-23,25-dimetoxi13,19,2J, 27-tetramethyl-] J, 28-dioxa-4-azatricyclo [22.3.1 .θ' ^49] octacos-18-ene-2, 3,10,16-Tetraone 150 mg (0.113 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (Γ '' - (2 ''') - ""'-Imidazolylcarbonyloxy)-ethylindol-5''-yl)oxy-3' -methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19, To a solution of 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; Joktakoz-18-ene-2,3,10,16-tetraone in 1 ml of tetrahydrofuran at room temperature was added 42 μΐ of nitrogen with stirring. Piperadine (0.717 mmol, 5 equivalents) was stirred for 1 hour, diluted with ethyl acetate, washed with 1 N hydrochloric acid and brine, and the product was purified by flash chromatography on silica gel (eluent: hexane: acetone = 4: 1). 115 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '' - (1 ''') piperidinecarbonyloxy) ethyl) indole) -5 "'- yl) oxy-3" -methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,

27-Tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone is obtained.

M = (FAB) 1062 (M ⁺ ).

Example 64

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2-morpholinocarbonyloxy) ethyl) indol-5 '' yl) oxy-3 "methoxycyclohexyl) ^{-1-methylvinyl]} -23,25-dimetoxi13.19.21.27- tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^49] octacos-l 8-ene-2, 3,10,16-Tetraone 100 mg (0.096 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "- (1""-(2"") - "" imidazolyl-carbonyloxy) ethyl-indole-5 '' - yl) oxy-3 "-methoxy-cyclohexyl) -l'metil] -23,25-dimethoxy-13,19,21, 27-tetramethyl-11,

To a solution of 28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; . The reaction mixture was stirred for 4 hours, then diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated aqueous sodium chloride. The product was purified by preparative thin layer chromatography on silica gel. The eluent was methylene chloride containing 4 volumes of methyl alcohol. 85 mg of product are obtained. The compound was further purified by preparative thin layer chromatography on silica gel eluting with 4% methanol in methylene chloride to give 67 mg of 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' (1 '' -). (2 '' - (N '''- morpholino-yloxy) ethyl) indole-5''yl) oxy-3 "-methoxy-cyclohexyl) -l'-methylvinyl] -23,25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0] -of-octacos-18-ene-2,3,10,16-tetraone is obtained. M = (FAB) 1064 (M ⁺ ).

Example 65

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '' - (diphenylaminocarbonyloxy) ethyl) indol-5 '')) ) -oxy-3'-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18 ene-2,3,10,16-tetraone

100 mg (0.105 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '' - hydroxy) ethyl) -indole-5 '' yl) oxy-3 '-methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone 1 ml me56

To a solution of A9 in ethylene chloride was added 29 mg (0.13 mmol, 1.2 equivalents) of diphenylcarbamyl chloride, 22 μ] (0.6 mmol, 1.5 equivalents) triethylamine and 3 mg (0.021) in a stream of nitrogen. mmol (0.2 equiv.) of dimethylaminopyridine. After stirring overnight, an additional 15 mg of diphenylcarbamyl chloride and 11 μΐ of triethylamine were added. After 3 hours, the reaction mixture was diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid, water and then with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by preparative thin layer chromatography. The eluent was methylene chloride containing 3% by volume of methanol. 50 mg 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '') (diphenylaminocarbonyloxy) ethyl) indol-5 '') ) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1. O + 'joktakoz-18-ene-2,3,10,16-tetraone is obtained.

M = (FAB) 1046 (M ⁺ ).

Example 66

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1''-(2''''- (diethylaminocarbonyloxy) ethyl) indol-5''-yl) oxy-3-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0] octacos-1 8-ene-2,3,10,16-tetraone 100 mg (0.105 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "- (1"' - (2 ")) "-Hydroxyethyl) -indole-5 '" (1D-oxy-3 "-methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28 To a solution of -dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone in 1 ml of methylene chloride was added 16 μΐ (0.13 mmol, 1.2 equivalents) of diethyl carbamyl chloride in a stream of nitrogen. 22 μΐ (1.5 equivalents) of triethylamine and 13 mg (1.0 equivalents) of dimethylaminopyridine were stirred overnight and then heated under reflux for 4 days. diluted with ethyl acetate, 1N aqueous hydrochloric acid, and saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by preparative thin layer chromatography. The eluent was methylene chloride containing 3% by volume of methanol. 16 mg of 17-ethyl, 14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '' - (diethylaminocarbonyloxy) ethyl) indole-5 '') yl) oxy-3 '' -methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-II, 28-dioxa-4-aza-tricyclo [22.3.1.0 + ^ octacos-18-ene is 2,3,3,10,16-tetraone.

M = (FAB) 1057 (M ⁺ + Li).

Example 67

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1' - (2-methanesulfonyloxy) ethyl) indol-5 '' yl) oxy-3-methoxycyclohexyl ) -] '- methyl vinyl] -23,25-dimethoxy-13,19,21,2-7-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0] octacos-18-ene-2,3,10 16-Tetraone 500 mg (0.526 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '') - hydroxyethyl) indole) 5 '' - yl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [ 22nd 3.1.0 ⁴ ' ⁹ ] To a solution of octacos-18-ene-2,3,10,16-tetraone in 20 ml of methylene chloride was added 147 μΐ (1.053 mmol, 2 equivalents) of triethylamine under nitrogen with stirring at 0 ° C. 54 μΐ (0.579 mmol, 1.1 equivalents) of methanesulfonyl chloride. The reaction mixture was stirred for 10 minutes and then the cooling plug was removed. The reaction mixture was stirred at room temperature for 3 hours and then stored overnight in a refrigerator. The solvent was then evaporated in vacuo. The product was used without further purification.

Example 68

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' '- (!' '- (2' '' 'azidoethyl) indol-5' '-yl) oxy-3' - methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1, 28-dioxa-4-aza-tricyclo [22.3.1.0] Joktakoz-18ene-2,3,10, 16-tetraone

0.526 mmol (1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '') - methanesulfonyloxyethyl) indol5 '' - yl) - oxy-3 "-methoxy-cyclohexyl) -l'-methylvinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4'9 To a solution of octacos-18-ene-2,3,10,16-tetraone in 10 ml of dimethylformamide was added 171 mg (2.63 mmol, 5 equivalents) of sodium azide under a stream of nitrogen. The reaction mixture was heated at 60 ° C for 2 hours and the solvent was evaporated in vacuo. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The aqueous phase was extracted three times with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel. The eluent was eluted with 2: 1 hexane: acetone. 310 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4 "(1"'. (2 "" - azidoethyl) indol-5 "" -yl) oxy-3 "- methoxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene- 2,3,10,16-tetraone is obtained.

M = (FAB) 975 (M ⁺ ).

Example 69

17-Ethyl-1,14-dihydroxy-12- [2 '- (4 - (]' - (2 '-aminoethyl) -indol-5'-yl) oxy-3-methoxycyclohexyl) -] 'methyl-vinyl-23,25-dimethoxy-13,19,21,27-tetramethyl], 28-dioxa-4-aza-tricyclo [22.3.1.0] octacos-18-ene-2,3,10,16-tetraone

260 mg (0.27 mmol, 1 equivalent) of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '') - azidoethyl) -indole-5 ') "-yl) oxy-3" -methoxy-cyclohexyl) -l'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3. To a solution of 1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone in 6 ml of tetrafuran was added 7 drops of water followed by triphenylphosphine (87 mg, 0.33 mmol, 1.25 equivalents). After stirring at room temperature for 16 hours, the solvent was evaporated in vacuo. The product was purified by flash chromatography on silica gel. The eluent was methylene chloride containing 10% by volume methanol. 227 mg

HU 211 897 A9

17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '' - aminoethyl) indol-5 '' -yl) oxy-3 'methoxy -cyclohexyl) -r-methyl-vinyl] -23,25-dimethoxy-1 3,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2 , 3,10,16tetraone is obtained.

M (FAB) 956 (M ⁺ + Li).

Example 70

17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '-butyl-dimethylsilyloxy-ethoxy-ethyl-indol-5'-yl) -oxy-3- methoxycyclohexyl) -l'-methylvinyl] -23,25-dimethoxy] 3], 9,21,27-tetramethyl -]}, 28-dioxa-4-azatricyclo [22.3. 1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone 360 mg (0.31 mmol) tri [1- (2-t-butyldimethylsilyloxyethoxy) ethyl] -indole-5 To a solution of -yl] -bizmutine in 3 ml of methylene chloride was added 0.05 ml of peracetic acid (as a 32% acetic acid solution) at room temperature, and after 10 minutes, 200 mg (0.25 mmol) of 17-ethyl-1,14-dihydroxy-12 - [2 '- (3', 4 '' - Dihydroxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4- azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone and 20 mg Cu (OAc) ₂ . After stirring for 18 hours, a saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative thin layer chromatography. The eluent was eluted with 3: 1 hexane: acetone. 120 mg of the title compound are obtained in the form of a dark oil.

Example 71

17-Ethyl-1,14-dihydroxy-12- [2 '- (4- (1 "' -hydroxyethoxy-ethylindol-5 '' -yl) -oxy-3 '' - methoxy-cyclohexyl) - l 'vinilj-methyl-23,25-dimethoxy-l-3,19,21.27 tetrametil11,28-dioxa-4-azatricyclo [22.3.1.O ⁴ · ⁹ joktakoz-2,3,10,16-tetraone-18én

120 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - t-butyldimethylsilyloxyethoxy) indol-5 '' -yl) oxy -methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13.19.21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.2]. 3.1.0 ⁴⁹ ] To a solution of octacos-18-ene-2,3,10,16-tetraone in 3 ml of methylene chloride is added a solution of 20 mg of paratoluenesulfonic acid in 3 ml of methanol at room temperature. The reaction mixture was stirred for 3 hours, quenched with saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative thin layer chromatography. The eluent was eluted with 2: 1 hexane: acetone. 51 mg of the title compound are obtained.

Partial 1 H-NMR (200 MHz, CDCl ₃ ) δ: 7.19 (d, J = 9

Hz 1H); 7.17 (d, J = 2 Hz, 1H); 7.08 (d, J = 3.5 Hz,

1H); 6.89 (dd, J = 2 and J = 9 Hz, 1H); 6.34 (d, J = 3.5

Hz, 1H); 4.22 (t, J = 5 Hz, 2H); 3.73 (t, J = 5 Hz, 2H);

3.57 (t, J = 5 Hz, 2H); 3.39 (t, J = 5Hz, 2H).

Example 72

17-Ethyl-1,14-dihydroxy-12- [2 '- (3' -methoxy-4 '' - (1 (1-oxopropyl-3-yl) indol-5'-yl) oxy) cyclohexyl) 1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ joktakoz-18-ene-2, 3,10,16-tetraone

700 mg (0.726 mmol) of 17-ethyl-1,14-dihydroxy-12 [2 '- (4 "- (r" - (3 "" - hydroxypropyl) -indol-5' "- yl) oxy] methoxy-cyclohexyl) -r-methylvinyl] -23,25-dimetoxi13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.

To a solution of I.O. ^4,9 ] octacos-18-ene-2,3,10,16-tetraone in 25 ml of methylene chloride was added 2 ml of dimethylsulfoxide and 3.7 ml of diisopropylethylamine, and 650 mg (4 ml) was added. (1 mmol) of pyridine-sulfur trioxide. The reaction mixture was stirred for 20 minutes and then poured into saturated aqueous sodium bicarbonate. The product was extracted with methylene chloride, the organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel. The eluent was eluted with 4: 1 hexane: acetone. 457 mg of the title compound are obtained.

Partial 1 H-NMR (200 MHz, CDCl ₃ ) δ: 9.77 (s, 1H); 7.19 (d, J = 2 Hz, 1H); 7.15 (d, J = 9 Hz, 1H); 7.04 (d, J = 3.5

Hz, 1H); 6.89 (dd, J = 2 and 9 Hz, 1H); 6.33 (d, J = 3.5

Hz, 1H); 4.39 (t, J = 5 Hz, 2H); 2.94 (t, J = 5Hz, 2H).

Example 73

17-Ethyl-1,14-dihydroxy-12- [2 '- (3''-methoxy-4-(r' (1 "'-carboxyeth-2''-yl))-indole-5''- yloxy) cyclohexyl) -l 'vinilj-methyl-23,25-dimethoxy-l3,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 joktakoz ⁴ · ^9-one 8-I-tetraone 2.3,10,16

100 mg of 17-ethyl-1,14-dihydroxy-12- [2 '- (3 "-methoxy-4" (1 "". (1 "" - oxoprop-1 "" -yl)) -indole- 5 '' - yl) -oxycyclo] -ohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-1 3,19,21,27-tetramethyl-II, 28-dioxa-4-aza-tricyclo [22.3]. 1 .0 ^ octacoz-18-en-2,3,

To a solution of 10,16-tetraone, 300 mg of 5-bromoindole and 0.80 ml of 2-methyl-2-butene in 4 ml of t-butanol are added 15 mg of sodium chloride and 15 mg of sodium dihydrogen phosphate 0.15 ml of water. The reaction mixture was stirred for half an hour and then concentrated in vacuo. The residue was taken up in 10 ml of water containing 2N hydrochloric acid and taken up in diethyl ether, and the phases were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by preparative thin layer chromatography. The eluent was first eluted with hexane / acetone 2: 1 (v / v) and then with methylene chloride (7% v / v methanol). The product was then purified by flash chromatography on a C-18 column packed with 60% CH ₃ CN in water. 11 mg of the title compound are obtained. M = (FAB) 1001 (M + Na).

1-73. Using the general procedure described in Example 1A, the following compounds of formula (I) (wherein R ⁴ is hydrogen, R ⁵ is methyl, ethyl, propyl or allyl, R 10 is hydrogen and n is 2) are prepared from the correspondingly substituted starting compounds. and reagents.

HU 211 897 A9

Example- song R * R ² R ^{3 *} R ⁵ 74th CH s- ° H OH CH ₃ CH ₂ 75th MONTH CH OH ch ₃ ch ₂ 76th HO CH, ch ₃ OH ch ₃ ch ₂ 77th C3 ch ₃ OH ch ₃ ch ₂ 78th CH.CH, C & f ^CH> ch ₃ OH ch ₃ ch ₂ 79th MONTH MONTH ch ₃ OH ch ₃ ch ₂ 80th HOjC-V COkj CH. ch ₃ OH ch ₃ ch ₂ 81st ΟζΗ CH, fcH, ch ₃ OH ch ₃ ch ₂ 82nd ^ch > CH. ch ₃ OH ch ₃ ch ₂

Example 83

Investigation of T-cell proliferation

1. Preparation of the sample

Test compounds are dissolved in absolute ethanol at a concentration of 1 mg / ml.

2. The test

Spleens of C57B1 / 6 mice were removed under sterile conditions and weakly dissociated in ice-cold RPMI

1640 culture medium (GIBC, Grand Island, N. Y.), to which 10% heat inactivated fetal serum (GIBO) was added. Cells were pelleted by centrifugation at 1500 rpm for 8 minutes. The contaminating erythrocytes were removed by reacting the pellet with ammonium chloride lysis buffer (GIBO) for 2 minutes at 4 ° C. Cold medium was then added and the cells were centrifuged again at 1500 rpm for 8 minutes. The T-lymphocytes are then isolated by separating them from the cell suspension on a nylon wool column as follows: a nylon wool column is prepared by ca. Place 4 g of washed and dried nylon wool in 20 ml plastic syringes. The columns were sterilized by autoclaving at 25 F for 30 minutes. The columns filled with nylon wool were moistened with warm culture medium (37 ° C) and rinsed with the same medium. The washed spleen cells are resuspended in warm medium and slowly transferred to nylon wool. The columns were then incubated in an upright position for one hour at 37 ° C. Non-adherent T lymphocytes are eluted from the column with warm culture medium and the cell suspension is centrifuged as above.

Purified T-lymphocytes were resuspended in 2.5x10 ⁵ cells / ml in complete culture medium containing heat-inactivated fetal calf serum from RPMI 1640, 100 mM glutamine, 1 mM sodium pyruvate, 2x10 ⁵ mol 2-mercaptoethanol / ml gentamicin. An additional 250 ng / ml ionomycin and 10 ng / ml PMA were added. The cell suspension was immediately dispensed into 96-well, Lapus-bottomed microculture plates (Costar) at a concentration of 200 μΙ / well. Different dilutions of test compound are added at a concentration of 20 μΙ / well for every 3 wells. 17-Allyl-1,14-dihydroxy-12- [2 '- (4' -hydroxy-3 '-methoxycyclohexyl) -T-methyl-vinyl] -23,25-dimethoxy-13,19,21,27- used octacos-18-ene-2, 3,10,16-tetraone compound - tetrametil11,28-dioxa-4-azatricyclo ^[9 22.3.1,0 ^4]. The culture plates were then incubated at 37 ° C in a humidified atmosphere consisting of 5% v / v carbon dioxide and 95% v / v air for 44 hours. T-lymphocyte proliferation is measured by incorporation of tritiated thymidine. After 44 hours in culture, cells are labeled with two pCi / well tritiated thymidine (NEN, Cambridge, MA). After an additional 4 hours incubation, cultures were harvested on a glass fiber filter using a multiple sample collector. The radioactivity on each filter well plate is measured by a standard liquid scintillation counting method (Betacounter). The average counts per minute for duplicate wells are calculated and the results are expressed as the concentration of compound required to inhibit T cell uptake of tritiated thymidine by 50%.

Several compounds were tested according to the above mentioned methods. In the above assay, the following compounds are effective in inhibiting T cell proliferation: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17 , 18, 19, 20, 21, 23, 26, 28, 31.32, 33, 34, 35, 37, 39.42, 44.46, 47.48, 49, 50, 51.52, 53, 54 , 57, 58, 60, 61.62, 63, 64.65.66, 69, 71, 72 and 73.

The result of this assay is representative of the immunosuppressive activity of the compounds of the invention.

In order to determine the antagonistic effect, the above procedure was modified in that the various diluted compounds were standard as 17-allyl-1,14-dihydroxy-12- (2 '- (4' -hydroxy-3 '-methoxycyclohexyl) -T-methyl- vinyl 1] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-2,3,10,

Co-cultured with 16-tetraone, the latter compound

HU 211 897 A9

At a concentration of 1.2 nM, which is 100% inhibition of T cell proliferation, the concentration of compound required to reverse the inhibition obtained by the standard alone was determined to determine the ED. _5o values.

The foregoing description is intended to illustrate the invention and to illustrate the examples herein. It is to be understood that the practice of the invention includes any modification, adaptation, modification, deletion and addition of said methods and examples, and the following claims apply thereto and their equivalents.

Claims (17)

1,2 or 3, (n) -CH (OR ¹² ) (OR ¹³ ) wherein R ¹² and R ¹³ are C 1 -C 3 alkyl or together form an ethyl or propyl bridge, (ο) O II R ^{9 is} CO (CH ₂ ) m -, wherein R ⁹ and m are as defined above, (P) o II R ^{9 is} CO (CH ₂ ) _m - wherein R ⁹ and m are as defined above and (q) -R ¹¹ ; or any two of X, Y and Z may be taken together to form a 5-, 6- or 7-membered saturated ring, one or two of which is oxygen and the other is carbon, X 'Y' and Z 'are independently selected from (a) hydrogen, (b) (C 1 -C 7) alkyl, (c) (C 2 -C 6) alkenyl, (d) halo, (e) - (CH ₂ ) m -NR ⁶ R ⁷ wherein R ⁶ , R ⁷ and m are as defined above, (f) -CN, (g) -CHO, GB 211 897 A 9 (h) -CHj group, (i) -SR ⁸ group wherein R ⁸ is hydrogen, C 1-6 alkyl, trifluoromethyl or phenyl group, ⁸ of formula (j) -SOR a group wherein R ⁸ is as defined above, (k) -SO ² R ⁸ wherein R ⁸ is as defined above, (1) -CONR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above, (m) ) R ^{9 is} O (CH ₂ ) m wherein R ⁹ and m are as defined above, (n) -CH (OR ¹² ) (OR ¹³ ) wherein R ¹² and R ¹³ are as defined above, ( ο) O II R ^{9 is} CO (CH ₂ ) m -, wherein R ⁹ and m are as defined above, (p) O II R ^{9 is} CO (CH ₂ ) m - wherein R ⁹ and m are as defined above and <q) is -R ¹¹ ; n is 1 or 2. Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R ¹ is (1) heteroaryl which may be (a), (b), (c), (d), (e), (f), (g). ), (h), (i), (j), (k), (1), (m), (n), (o), (p), (q), wherein Q is -N (X) -, -O-, or -S-, (2) substituted heteroallyl, wherein the heteroalyl is a group as defined above and the substituent is X. Y or Z. Compounds according to claim 1, the absolute configuration of which is represented by the general formula (III). (2) hydrogen; (3) ethyl, (4) propyl, (5) allyl. Compounds according to claim I, wherein the heteroaryl group is selected from the group consisting of; (20), (21). (22), (23). (24). (25), (26). (27), (28). (29), (30), (31), (32), (33), (34), (35) or (36). or a group of the general formula wherein X is according to claim 1. (3) phenyl; (3) heteroalyl (C 1 -C 10) alkyl wherein the heteroaryl is a group as defined above, (4) substituted heteroalyl (C 1 -C 10) alkyl wherein the heteroalyl group is as defined above and X, Y and It is substituted with Z and the alkyl moiety may be substituted with one or more of the following substituents: (a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) aryl (C 1-3) alkoxy, wherein the aryl may be phenyl or naphthyl, (e) substituted aryl-; C 1-3 -alkoxy, wherein the aryl group is as defined above and X, Y and Z are substituents; (f) unsubstituted or substituted aryloxy wherein X, Y and Z are aryl. (g) -OCO- (C 1 -C 6) alkyl, (h) -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are each independently (i) hydrogen, (ii) C 1 -C 10 alkyl, optionally substituted with one or more of the following substituents: (a ') an aryl group which may be substituted with an aryl group as defined above and optionally substituted with X, Y and Z, (b') a heteroaryl group which may be a heterolaryl group as defined above and optionally substituted with X, Y and Z, (c ') ) hydroxy, (d ') C1-6 alkoxy, (e') C 0 ₂ H group, (f) -CO ₂ - (l-O-alkyl group, (g ') -C 3-7 cycloalkyl, and (h ') -OR' ¹ , (iii) C 3 -C 10 alkenyl, which may be optionally substituted with one or more of the following: (a ') an aryl group which may be substituted with an aryl group as defined above and optionally substituted with X, Y and Z, (b') a heteroaryl group which may be a heteroaryl group as defined above and optionally substituted with X, Y and Z, (c) hydroxy, (d ') C 1-6 alkoxy, (e) -CO ₂ H, (f') -CO ₂ - (C 1-6 alkyl), (g ') C 3-7 cycloalkyl, and (h ') -OR (iv) or R ⁶ and R ⁷ together with the nitrogen to which they are attached form a heterocyclic ring which may be morpholine, thiomorpholine, piperidine or piperazine, (i) -NR ⁶ CO- (C 1-6 alkyl) -R ⁷ wherein R ⁶ and R ⁷ are as defined above, (j) -NR ⁶ CO ₂ - (C 1 -C 6 alkyl) -R ⁷ , (k) -NR ⁶ CONR ⁶ R ⁷ a group of formula (I) -OCONR ⁶ R ⁷ , (m) -COOR ⁶ , (n) -CHO, (o) aryl which may be an aryl group as defined above, a (p) substituted aryl group which may be an aryl group as defined above and wherein the substituent is X, Y and Z, (q) -OR ¹¹ , and (r) -S (O) _p - (1) C 6 -C 6 alkyl; The compound of claim 1, wherein the heteroaryl is a group of Formula 37; R ² is (1) hydrogen, (2) methyl. (4) substituted phenyl, wherein the substituent is X, Y and Z; 5. Compounds of formula X, XI, XII and XIII, or a pharmacologically acceptable salt thereof, wherein R ⁶ a is hydrogen or methyl and R ^{2 is} . The values of R ³ , R 1 - R ⁶ and R ⁷ are selected from the following table. R ⁶ R ⁷ R ² R ³ R ⁵ phenyl phenyl ch ₃ OH ethyl phenyl H ch ₃ OH ethyl benzyl H ch ₃ OH ethyl 4-HO ₂ 2C-benzyl H ch ₃ OH ethyl 4-H ₂ NCO-benzyl H ch ₃ OH ethyl 4-CH ₃ O-benzyl H ch ₃ OH ethyl 4-HO-benzyl H ch ₃ OH ethyl 4-Cl-benzyl H ch, OH ethyl 4- (CH ₃ ) ₂ N-benzyl H ch ₃ OH ethyl 3-HO ₂ C-benzyl H ch ₃ OH ethyl 3-H ₂ NCO-benzyl H ch ₃ OH ethyl _3-CH3 O-benzyl H ch ₃ OH ethyl 3-HO-benzyl H ch ₃ OH ethyl 3-Cl-benzyl H ch ₃ OH ethyl 3- (CH ₃ ) ₂ N-benzyl H ch, OH ethyl 4-pyridyl H ch, OH ethyl 3-pyridyl H ch, OH ethyl 2-Pyridine I H ch, OH ethyl 4-pyridylmethyl H ch ₃ OH ethyl 3-pyridylmethyl H ch ₃ OH ethyl 2-pyridylmethyl H CH OH ethyl phenyl phenyl CH H ethyl phenyl H CH H ethyl - benzyl H CH ₃ H ethyl 4-HO ₂₂ C-benzyl H CH H ethyl 4-H ₂ NCO-benzyl H CH H ethyl 4-CH, O-benzyl H CH H ethyl 4-HO-benzyl H CH H ethyl 4-Cl-benzyl H ch ₃ H ethyl 4- (CH ₃ ) ₂ N-benzyl H CH H ethyl 3-HO ₂ C-benzyl H CH H ethyl 3-H ₂ NCO-benzyl H ch, H ethyl _3-CH3 O-benil H CH H ethyl 3-HO-benzyl H CH H ethyl 3-Cl-benzyl H CH H ethyl 3- (CH ₃ ) ₂ N-benzyl H ch ₃ H ethyl 4-pyridyl H ch ₃ H ethyl 3-pyridyl H ch ₃ H ethyl 2-pyridine l H CH H ethyl 4-pyridylmethyl H CH H ethyl 3-pyridylmethyl H CH H ethyl 2-pyridylmethyl H ch ₃ H ethyl phenyl phenyl ch ₃ OH allyl phenyl H CH OH allyl HU 211 897 A9 R ⁶ R ⁷ R ² R ³ R ⁵ benzyl H ch ₃ OH allyl 4-HO ₂₂ C-benzyl H ch ₃ OH allyl 4-H ₂ NCO-benzyl H ch ₃ OH allyl 4-CH ₃ O-benzyl H ch ₃ OH allyl 4-HO-benzyl H ch ₃ OH allyl 4-Cl-benzyl H ch ₃ OH allyl 4- (CH2) ₂ N-benzyl H ch ₃ OH allyl 3-HO ₂ C-benzyl H ch ₃ OH allyl 3-H ₂ NCO-benzyl H ch ₃ OH allyl _3-CH3 O-benil H ch ₃ OH allyl 3-HO-benzyl H ch ₃ OH allyl 3-Cl-benzyl H ch ₃ OH allyl 3- (CH ₃ ) ₂ N-benzyl H ch ₃ OH allyl 4-pyridyl H CH OH allyl 3-pyridyl H ch ₃ OH allyl 2-pyridyl H ch ₃ OH allyl 4-pyridylmethyl H ch ₃ OH allyl 3-pyridylmethyl H ch ₃ OH allyl 2-pyridylmethyl H ch ₃ OH allyl CH H ch ₃ OH allyl ch, ch ₂ H ch ₃ OH allyl ch, ch ₂ ch ₂ H CH OH allyl (CH ₂ ) ₂ CH H ch ₃ OH allyl ho ₂ cch ₂ ch ₂ H ch ₃ OH allyl , H ₂ NCOCH ₂ CH ₂ H ch ₃ OH allyl hoch ₂ ch ₂ H ch ₃ OH allil j hoch ₂ ch ₂ ch ₂ H ch ₃ OH allil i CH CH ch ₃ OH CH ^ CHt i ~ r ch, ch ₂ ch ₃ OH I ~~ ethyl ι ch, ch ₂ ch ₂ ch, ch ₂ ch ₂ ch ₃ OH ethyl hoch ₂ ch ₂ hoch ₂ ch ₂ ch ₃ OH ethyl hoch ₂ ch ₂ ch ₂ hoch ₂ ch ₂ c h ₂ ch ₃ OH ethyl CH Η CH H ethyl ch ₃ ch ₂ H ch ₃ H ethyl ch ₃ ch ₂ ch ₂ H CH H ethyl (CH ₂ ) ₂ CH H CH ₃ H ethyl ho ₂ cch ₂ ch ₂ H ch ₃ H ethyl h ₂ ncoch ₂ ch ₂ H ch ₃ H ethyl hoch ₂ ch ₂ H ch ₃ H ethyl hoch ₂ ch ₂ ch ₂ H ch ₃ H ethyl CH CH ch ₃ H ethyl CH, CH ₂ CH ₃ CH ₂ ch ₃ H ethyl R ⁶ R ⁷ R ² R ³ R ⁵ CH ₃ CH ₂ CH ₂ CH ₃ CH ₂ CH ₂ ch ₃ Η ethyl hoch ₂ ch ₂ HOCH ₂ CH ₂ ch ₃ Η ethyl hoch ₂ ch ₂ ch ₂ HOCH ₂ CH ₂ C h ₂ ch ₃ Η ethyl ch ₃ H H ΟΗ ethyl ch ₃ ch ₂ H Η ΟΗ ethyl ch ₃ ch ₂ ch ₂ H Η ΟΗ ethyl (ch ₃ ) ₂ ch H Η ΟΗ ethyl ho ₂ cch ₂ ch ₂ H Η ΟΗ ethyl h ₂ ncoch ₂ ch ₂ H Η ΟΗ ethyl hoch ₂ ch ₂ H Η ΟΗ ethyl hoch ₂ ch ₂ ch ₂ H Η ΟΗ ethyl CH3 CH3 Η ΟΗ ethyl CH 3 CH ₂ CH 3 CH ₂ Η ΟΗ ethyl hch ₂ ch ₂ hch ₂ ch ₂ Η ΟΗ ethyl hoch ₂ ch ₂ hoch ₂ ch ₂ Η ΟΗ ethyl hoch ₂ ch ₂ ch ₂ hoch ₂ ch ₂ c h ₂ Η ΟΗ ethyl -ch ₂ ch ₂ and ₂ ch ₂ - CH Η ethyl -ch ₂ ch ₂ ch ₂ ch ₂ ch ₂ CH Η ethyl -CH2CH2OCH2CH2- ch ₃ ΟΗ ethyl -CH2CH2CH2CH2CH2- Η ΟΗ ethyl -CH2CH2OCH2CH2- Η ΟΗ ethyl -CH2CH2CH2CH2CH2- Η ΟΗ ethyl -CH2CH2OCH2CH2- ch ₃ Η allyl -CH2CH2CH2CH2CH2- ch ₃ Η allyl -CH2CH2OCH2CH2- CH ΟΗ allyl -CH2CH2CH2CH2CH2- Η ΟΗ allyl -CH2CH2OCH2CH2- Η ΟΗ allyl -CH2CH2CH2CH2CH2- Η ΟΗ allyl (5) 1- or 2-naphthyl; (5) heteroaryl-C 1 -C 4 alkyl, where one or more of the carbon atoms in the alkyl moiety are as defined above, and the substituent may be -NR ⁶ , oxygen, -S (O) _p - a group of the formula: -CO ₂ -, -O ₂ C -, -CONR ⁶ -, -NR ⁶ CO -, -NR ⁶ CONR ⁷ -; 6. Compounds of formulas (XIV), (XV), (XVI) and (XVII), or pharmaceutically acceptable salts thereof, wherein R ⁶ a is hydrogen or methyl; R ² , R ³ , R ⁵ and R ⁶ are as defined in the following table: selected: R ⁶ R ² R ³ R ⁵ H CH OH ethyl CH CH OH ethyl CH ₃ CH ₂ CH OH ethyl ch ₂ = chch ₂ ch ₃ OH ethyl ch ₃ ch ₂ ch ₂ CH OH ethyl (CH ₃ ) ₂ CH ch ₃ OH ethyl ho ₂ cch ₂ ch ₂ ch ₃ OH ethyl h ₂ ncoch ₂ ch ₂ ch, OH ethyl HU 211 897 A9 R ⁶ R ² R ³ R ⁵ HOCH ₂ CH ₂ ch ₃ OH ethyl hoch ₂ ch ₂ ch ₂ CH? OH ethyl (CH ₃ ) ₂ CH ₂ ch, OH ethyl phenyl ch ₃ OH ethyl 4-pyridyl ch ₃ OH ethyl 3-pyridyl ch, OH ethyl 2-pyridyl ch, OH ethyl 4-pyridylmethyl CH OH ethyl 3-pyridylmethyl CH OH ethyl 2-pyridylmethyl CH OH ethyl benzyl CH OH ethyl 4-HO ₂ C-benzyl CH OH ethyl 4-H ₂ NCO-benzyl CH OH ethyl 4-CH, O-benzyl ch ₃ OH ethyl 4-HO-benzyl CH OH ethyl 4-Cl-benzyl CH OH ethyl 4- (CH ₂ ) ₂ N-benzyl CH OH ethyl 3-HO ₂ C-benzyl CH OH ethyl 3-H, benzyl isocyanate CH OH ethyl 3-CH, -benzyl CH OH ethyl 3-HO-benzyl CH OH ethyl 3-Cl-benzyl CH OH ethyl 3- (CH ₂ ) ₂ N-benzyl CH OH ethyl 2-HO-benzyl CH OH ethyl 2-Cl-benzyl CH OH ethyl 2- (CH ₃ ) ₂ N-benzyl CH OH ethyl CH CH H ethyl ch, ch ₂ CH H ethyl ch ₂ = chch ₂ CH H ethyl ch, ch ₂ ch ₂ CH H ethyl (CH ₂ ) ₂ CH CH H ethyl ho ₂ cch ₂ ch ₂ CH ₃ H ethyl h ₂ ncoch ₂ ch ₂ CH H ethyl hoch ₂ ch ₂ CH H ethyl hoch ₂ ch ₂ ch ₂ CH H ethyl (CH ₃ ) ₂ CH ₂ CH H ethyl phenyl CH ₃ H ethyl 4-pyridyl CH H ethyl 3-pyridyl CH H ethyl 2-pyridyl CH H ethyl 4-pyridylmethyl CH H ethyl 3-pyridylmethyl CH H ethyl 2-pyridylmethyl CH H ethyl R ⁶ R ² R ³ R ⁵ benzyl CH ₃ H ethyl 4-HO ₂ C-benzyl ch ₃ H ethyl 4-H ₂ NCO-benzyl ch ₃ H ethyl 4-CH ₃ O-benzyl ch ₃ H ethyl 4-HO-benzyl ch ₃ H ethyl 4-Cl-benzyl ch ₃ H ethyl 4- (CH ₂ ) ₂ N-benzyl ch ₃ H ethyl 3-HO ₂ C-benzyl ch ₃ H ethyl 3-H ₂ NCO-benzyl ch ₃ H ethyl 3-CH, -benzyl ch ₃ H ethyl 3-HO-benzyl CH H ethyl 3-Cl-benzyl CH H ethyl 3- (CH ₂ ) ₂ N-benzyl CH H ethyl 2-HO ₂ C-benzyl CH H ethyl 2-H ₂ NCO-benzyl CH H ethyl 2-CH, O-benzyl CH ₃ H ethyl 2-HO-benzyl CH H ethyl 2-Cl-benzyl CH H ethyl 2- (CH ₂ ) ₂ N-benzyl CH H ethyl CH CH OH allyl CH, CH ₂ CH OH allyl CH ₂ = CHCH ₂ CH OH allyl ch ₃ ch ₂ ch ₂ CH OH allyl (CH ₃ ) ₂ CH CH OH allyl HO ₂ CCH ₂ CH ₂ ch ₃ OH allyl h ₂ ncoch ₂ ch ₂ ch ₃ OH allyl hoch ₂ ch ₂ CH OH allyl hoch ₂ ch ₂ ch ₂ CH OH allyl (CH ₂ ) ₂ CH ₂ CH OH allyl phenyl CH OH allyl 4-pyridyl CH OH allyl 3-pyridyl CH OH allyl 2-pyridyl CH OH allyl 4-pyridylmethyl CH OH allyl 3-pyridylmethyl CH OH allyl 2-pyridylmethyl CH OH allyl benzyl CH OH allyl 4-H ₂ C-benzyl CH OH allyl 4-H ₂ NCO-benzyl CH OH allyl 4-CH, O-benzyl CH OH allyl 4-HO-benzyl CH OH allyl 4-Cl-benzyl CH OH allyl 4- (CH ₂ ) ₂ N-benzyl CH OH allyl 3-HO ₂ C-benzyl ch ₃ OH allyl HU 211 897 A9 R ⁶ R ² R ³ R ⁵ 3-H ₂ NCO-benzyl ch ₃ OH allyl 3-CH, -benzyl ch ₃ OH allyl 3-HO-benzyl ch ₃ OH allyl 3-Cl-benzyl ch ₃ OH allyl 3- (CH ₃ ) ₂ N-benzyl ch ₃ OH allyl 2-HO ₂ C-benzyl ch ₃ H allyl 2-H ₂ NCO-benzyl ch ₃ H allyl 2-CH ₃ O-benzyl ch ₃ H allyl 2-HO-benzyl ch, OH allyl 2-Cl-benzyl ch ₃ OH allyl 2- (CH ₃ ) ₂ N-benzyl ch ₃ OH allyl Ί. Compounds of formula (XVIII), (XIX), (XX) and (XXI), or pharmaceutically acceptable salts thereof, wherein R ^6a is hydrogen or methyl and R a, R 1, R ³ and R ⁵ are selected from the following table. Ra R ² R ³ R ⁵ CH CH OH ethyl CH, CH ₂ ch, OH ethyl ch ₂ = chch ₂ ch, OH ethyl ch, ch ₂ ch ₂ CH OH ethyl (CH ₃ ) ₂ CH ch ₃ OH ethyl ho ₂ cch ₂ ch ₂ ch, OH ethyl H.NCOCHtCHt l Z CH OH ethyl HOCH ₂ CH ₂ CH OH ethyl hoch ₂ ch ₂ ch ₂ ch ₃ OH ethyl (CH ₂ ) ₂ CH ₂ CH OH ethyl phenyl CH OH ethyl 4-pyridyl CH OH ethyl 3-pyridyl ch ₃ OH ethyl 2-pyridyl ch ₃ OH ethyl 4-pyridylmethyl CH OH ethyl 3-pyridylmethyl CH OH ethyl 2-pyridylmethyl ch, OH ethyl benzyl ch, OH ethyl 4-HO ₂ C-benzyl ch ₃ OH ethyl 4-H ₂ NCO-benzyl ch ₃ OH ethyl 4-CH, O-benzyl ch ₃ OH ethyl 4-HO-benzyl ch ₃ OH ethyl 4-Cl-benzyl ch ₃ OH ethyl 4- (CH ₂ ) ₂ N-benzyl ch, OH ethyl 3-HO ₂ C-benzyl ch ₃ OH ethyl 3-H ₂ NCO-benzyl CH OH ethyl Ra R ² R ³ R ⁵ 3-CH, O-benzyl CH OH ethyl 3-HO-benzyl CH ₃ OH ethyl 3-Cl-benzyl ch ₃ OH ethyl 3- (CH ₂ ) ₂ N-benzyl ch, OH ethyl 2-HO ₂ C-benzyl ch, OH ethyl 2-H ₂ NCO-benzyl ch ₃ OH ethyl 2-CH, O-benzyl ch ₃ OH ethyl 2-HO-benzyl ch ₃ OH ethyl 2-Cl-benzyl ch ₃ OH ethyl 2- (CH ₂ ) ₂ N-benzyl ch ₃ OH ethyl ch ₃ ch, H ethyl ch ₃ ch ₂ ch ₃ H ethyl ch ₂ = chch ₂ ch, H ethyl ch ₃ ch ₂ ch ₂ CH H ethyl (CH ₃ ) ₂ CH ch ₃ H ethyl ho ₂ cch ₂ ch ₂ CH H ethyl h ₂ ncoch ₂ ch ₂ CH ₃ H ethyl hoch ₂ ch ₂ CH H ethyl hoch ₂ ch ₂ ch ₂ CH H ethyl (CH ₃ ) ₂ CH ₂ ch ₃ H ethyl phenyl ch ₃ H ethyl 4-pyridyl CH H ethyl 3-pyridyl CH H ethyl 2-pyridyl CH H ethyl 4-pyridylmethyl CH H ethyl 3-pyridylmethyl CH H ethyl 2-pyridylmethyl CH H ethyl benzyl CH H ethyl 4-HO ₂ C-benzyl CH H ethyl 4-H ₂ NCO-benzyl CH H ethyl 4-CH, O-benzyl CH H ethyl 4-HO-benzyl CH H ethyl 4-Cl-benzyl CH H ethyl 4- (CH ₂ ) ₂ N-benzyl CH H ethyl 3-HO ₂ C-benzyl CH H ethyl 3-H ₂ NCO-benzyl CH H ethyl _3-CH3 O-benzyl CH H ethyl 3-HO-benzyl CH H ethyl 3-Cl-benzyl CH H ethyl 3- (CH ₃ ) ₂ N-benzyl CH H ethyl 2-HO ₂ C-benzyl CH H ethyl 2-H ₂ NCO-benzyl CH H ethyl HU 211 897 A9 Ra R ² R ³ R ⁵ 2-CH, O-benzyl ch ₃ H ethyl 2-HO-benzyl ch ₃ H ethyl 2-Cl-benzyl ch ₃ H ethyl 2- (CH ₃ ) ₂ N-benzyl ch ₃ H ethyl ch ₃ ch ₃ OH allyl ch, ch ₂ ch ₃ OH allyl ch ₂ = chch ₂ ch ₃ OH allyl ch ₃ ch ₂ ch ₂ ch ₃ OH allyl (CH ₃ ) ₂ CH ch ₃ OH allyl ho ₂ cch ₂ ch ₂ ch, OH allyl h ₂ ncoch ₂ ch ₂ ch, OH allyl hoch ₂ ch ₂ ch ₃ OH allyl hoch ₂ ch ₂ ch ₂ ch, OH allyl (CH ₃ ) ₂ CH ₂ ch ₃ OH allyl phenyl CH OH allyl 4-pyridyl CH OH allyl 3-pyridyl CH OH allyl 2-pyridyl CH OH allyl 4-pyridylethyl CH OH allyl 3-pyridyl-ethyl CH OH allyl 2-pyridyl-ethyl CH OH allyl benzyl CH OH allyl 4-HO ₂ C-benzyl CH OH allyl 4-H ₂ NCO-benzyl CH OH allyl 4-CH ₃ O-benzyl CH OH allyl 4-HO-benzyl CH OH allyl 4-Cl-benzyl CH OH allyl 4- (CH ₂ ) ₂ N-benzyl CH OH allyl 3-HO ₂ C-benzyl CH OH allyl 3-H ₂ NCO-benzyl CH OH allyl 3-CH, O-benzyl CH OH allyl 3-HO-benzyl CH OH allyl 3-Cl-benzyl CH OH allyl 3- (CH ₂ ) ₂ N-benzyl ch ₃ OH allyl 2-HO ₂ C-benzyl ch ₃ OH allyl 2-H ₂ NCO-benzyl CH OH allyl 2-CH ₃ O-benzyl CH OH allyl 2-HO-benzyl CH OH allyl 2-Cl-benzyl CH OH allyl 2- (CH ₂ ) ₂ N-benzyl CH OH allyl (6) R ¹¹ , (7) C 2 -C 3 alkyl-OH, and (8) C 2 -C 3 alkyl-OR ¹¹ , R ³ is (1) hydrogen, (2) hydroxy, (3) -OR ¹¹ , or R ³ and R ^{4 taken} together form a double bond, R ¹⁰ is hydrogen, hydroxy, fluoro or -OR ', W is oxygen and n is 2. (6) a substituted 1- or 2-naphthyl group, wherein the substituent is X, Y and Z; (6) substituted heteroaryl (C 1 -C 10) alkyl wherein the heteroaryl is A9 is a group as defined above; one or more of the carbon atoms in the alkyl group are substituted, the substituent may be: -NR ⁶ , oxygen, -S (O) _p -, -CO 3 -, -O ₂ C, -CONR ⁶ -. , -NR ⁶ CO- -NR ⁶ CONR ⁷ -; the heteroaryl group is substituted by X, Y and Z and the alkyl group may be substituted by one or more of the following groups: (a) hydroxy, (b) oxo, (c) C 1-6 -alkoxy, (d) aryl (C 1-3) -alkoxy, wherein aryl is a group as defined above, (e) substituted aryl (I). - (C3-C3) -alkoxy, wherein the aryl group is as defined above, and X, Y and Z are substituents, (f) optionally substituted aryloxy, wherein the aryl group is as defined above, and X, Y and Z are (g) ) -OCO- (C 1-6 alkyl), (h) -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above, (i) -NR ⁶ CO- (C 1-6 alkyl) R ^{7 is} (j) -NR ⁶ CO ₂ - (C 1 -C 6 alkyl) -R ⁷ . (k) -NR ⁶ CONR ⁶ R ⁷ , (1) -OCONR ⁶ R ⁷ , (m) -COOR ⁶ , (n) -CHO, (o) aryl, an aryl group as defined above, a (p) substituted aryl group, an aryl group as defined above, and the substituents X, Y and Z, (q) -OR ¹¹ , and (r) -S (O) _p - (C 1 -C 6) alkilj group; (7) biphenyl; (7) heteroaryl-C3-C10 alkenyl, wherein the heteroaryl is defined above and the alkenyl group contains 1-4 double bonds; ⁵ is 8 (XVIII) with a compound of formula or pharmaceutically acceptable salts thereof, where Ra CO-site _(CH2) l-4 Part X is and X, R ^2, R ^3, and R is selected from the following table: X R ² R ³ R ⁵ 1-imidazolyl-methyl ch ₃ OH ethyl 2-imidazolyl-methyl ch ₃ OH ethyl 3-Thiazole 1-methyl CH OH ethyl 2-thiazolylmethyl ch ₃ OH ethyl 2-oxazolylmethyl ch ₃ OH ethyl 2-pyridylmethyl ch, OH ethyl benzyl ch ₃ OH ethyl 4-HO ₂ C-benzyl ch ₃ OH ethyl 4-H ₂ NCO-benzyl ch. OH ethyl 4-CH ₃ O-benzyl ch ₃ OH ethyl 4-HO-benzyl ch ₃ OH ethyl 4-R ⁿ -O-benzyl ch ₃ OH ethyl 4-C1-benzyl ch ₃ OH ethyl 4- (CH ₃ ) ₂ N-benzyl CH OH ethyl 3-HO ₂ C-benzyl ch ₃ OH ethyl 3-H ₂ NCO-benzyl CH OH ethyl 3-CH, O-benzyl CH OH ethyl 3-HO-benzyl ch ₃ OH ethyl 3-benzyl-R''O ch ₃ OH ethyl 3-Cl-benzyl CH OH ethyl 3- (CH ₂ ) ₂ N-benzyl CH OH ethyl 2-HO ₂ C-benzyl CH OH ethyl 2-H ₂ NCO-benzyl CH OH ethyl 2-CH, O-benzyl CH OH ethyl 2-HO-benzyl CH OH ethyl 2-benzyl-RO CH OH ethyl 2-Cl-benzyl CH OH ethyl 2- (CH ₃ ), N-benzyl CH OH ethyl 3- (4-pyridyl) -imidazol-2-yl methyl CH OH ethyl 3- (3-pyridyl) imidazol-2-yl methyl CH OH ethyl 3- (2-pyridyl) -imidazol-2-yl methyl CH OH ethyl 3-phenyl-imidazol-2-ylmethyl CH OH ethyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (4-CH ₃ O-phenyl) -imidazol-2-yl-methyl CH OH ethyl 3- (4- (CH,) _2- N-phenyl) -imidazol-2-ylmethyl CH OH ethyl 3- (3-HO ₂ C-phenyl) -imidazol-2-yl-melyl ch ₃ OH ethyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl CH OH ethyl HU 211 897 A9 X R ² R ³ R ⁵ 3- (3-CH ₃ O-phenyl) -imidazol-2-ylmethyl ch ₃ OH ethyl 3- (3-HO-phenyl) -imidazol-2-yl methyl ch, OH ethyl 3- (3-R ¹¹ 0-phenyl) -imidazol-2-ylmethyl ch ₃ OH ethyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl ch ₃ OH ethyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl ch ₃ OH ethyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ OH ethyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ OH ethyl 3- _(2-CH3 O-phenyl) -imidazol-2-ylmethyl ch ₃ OH ethyl 3- (2-HO-phenyl) -imidazol-2-yl methyl ch, OH ethyl 3- (2-R ¹¹ O-phenyl) -imidazol-2-ylmethyl ch ₃ OH ethyl 3- (2-Cl-phenyl) -imidazol-2-yl methyl ch ₃ OH ethyl 3- (2- (CH ₂ ) ₂ N -phenyl) imidazol-2-ylmethyl ch ₃ OH ethyl 1-imidazolyl-methyl ch ₃ H ethyl 2-imidazolyl-methyl ch ₃ H ethyl 3-thiazolylmethyl ch ₃ H ethyl 2-thiazolylmethyl CH H ethyl 2-oxazolylmethyl ch, H ethyl 5-tetrazolyl-methyl ch ₃ H ethyl 4-pyridyl-methyl ch, H ethyl 3-pyridylmethyl ch, H ethyl 2-pyridylmethyl ch, H ethyl benzyl CH H ethyl 4-HO ₂ C-benzyl CH H ethyl 4-H ₂ NCO-benzyl ch ₃ H ethyl 4-CH ₃ O-benzyl ch ₃ H ethyl 4-HO-benzyl CH H ethyl 4-nitro-benzyl ch ₃ H ethyl 4-Cl-benzyl ch ₃ H ethyl 4- (CH ₃ ) ₂ N-benzyl ch ₃ H ethyl 3-HO ₂ C-benzyl CH H ethyl 3-H ₂ NCO-benzyl ch ₃ H ethyl _3-CH3 O-benzyl CH H ethyl 3-HO-benzyl ch ₃ H ethyl 3-benzyl-RO ch ₃ H ethyl 3-Cl-benzyl ch ₃ H ethyl 3- (CH ₃ ) ₂ N-benzyl ch ₃ H ethyl 2-HO ₂ C-benzyl ch ₃ H ethyl X R ² R ³ R ⁵ 2-H ₂ NCO-benzyl ch ₃ Η ethyl 2-CH ₃ O-benzyl ch ₃ H ethyl 2-HO-benzyl ch ₃ H ethyl 2-R ⁿ O-benzyl ch ₃ H ethyl 2-Cl-benzyl ch ₃ H ethyl 2- (CH ₃ ) ₂ N-benzyl ch ₃ H ethyl 3- (4-pyridyl) -imidazol-2-yl methyl ch ₃ H ethyl 3- (3-pyridyl) imidazol-2-yl methyl ch ₃ H ethyl 3- (2-pyridyl) -imidazol-2-yl methyl ch ₃ H ethyl 3-phenyl-imidazol-2-ylmethyl ch ₃ H ethyl 3- (4-H0 ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ H ethyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-yl-melyl ch ₃ H ethyl 3- (4-CH ₃ O-phenyl) -imidazole-2-ylmethyl ch ₃ H ethyl 3- (4-HO-phenyl) -imidazol-2-yl methyl ch ₃ H ethyl 3- (4-R ¹¹ O-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (4-C 1 -Phenyl) imidazol-2-ylmethyl CH H ethyl 3- (4- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl CH H ethyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (3-CH ₃ O-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (3-HO-phenyl) -imidazol-2-yl methyl CH H ethyl 3- (3-R '' O-phenyl) -imidazol-2-ylmethyl CH H ethyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl CH H ethyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl ch ₃ H ethyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ H ethyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ H ethyl 3- _(2-CH3 O-phenyl) -imidazol-2-ylmethyl ch ₃ H ethyl 3- (2-HO-phenyl) -imidazol-2-yl methyl ch ₃ H ethyl ^3-f2-R1 '0-phenyl) -imidazol-2-ylmethyl ch ₃ H ethyl HU 211 897 A9 X R ² R ³ R ⁵ 3- (2-Cl-phenyl) -imidazol-2-yl methyl CH ₃ H ethyl 3- (2- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl ch ₃ H ethyl 1-imidazolyl-methyl H OH ethyl 2-imidazolyl-methyl H OH ethyl 3-thiazolylmethyl H OH ethyl 2-thiazolylmethyl H OH ethyl 2-oxazolylmethyl H OH ethyl 5-tetrazolyl-methyl H OH ethyl 4-pyridylmethyl H OH ethyl 3-pyridylmethyl H OH ethyl 2-pyridylmethyl H OH ethyl benzyl H OH ethyl 4-HO ₂ C-benzyl H OH ethyl 4-H ₂ NCO-benzyl H OH ethyl 4-CH ₃ O-benzyl H OH ethyl 4-HO-benzyl H OH ethyl 4-R ¹¹ O-Benzyl H OH ethyl 4-Cl-benzyl H OH ethyl 4- (CH ₃ ) ₂ N-benzyl H OH ethyl 3-HO ₂ C-benzyl H OH ethyl 3-H ₂ NCO-benzyl H OH ethyl _3-CH3 O-benzyl H OH ethyl 3-HO-benzyl H OH ethyl 3-benzyl-RO H OH ethyl 3-Cl-benzyl H OH ethyl 3- (CH ₃ ) ₂ N-benzyl H OH ethyl 2-HO ₂ C-benzyl H OH ethyl 2-H ₂ NCO-benzyl H OH ethyl 2-CH ₃ O-benzyl H OH ethyl 2-HO-benzyl H OH ethyl 2-benzyl-RO H OH ethyl 2-Cl-benzyl H OH ethyl 2- (CH ₃ ) ₂ N-benzyl H OH ethyl 3- (4-pyridyl) -imidazol-2-yl methyl H OH ethyl 3- (3-pyridyl) imidazol-2-yl methyl H OH ethyl 3- (2-pyridyl) -imidazol-2-yl methyl H OH ethyl 3-phenyl-imidazol-2-ylmethyl H OH ethyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (4-CH ₃ O-phenyl) -imidazol-2-ylmethyl H OH ethyl X R ² R ³ R ⁵ 3- (4-HO-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (4-R ¹ 'O-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (4-Cl-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (4- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH ethyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (3-CH ₃ O-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (3-HO-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (3-R ^, O-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH ethyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (2-H ₂ NCO-phenyl) -imidazo) -2-ylmethyl H OH ethyl 3- (2-CH ₃ O-phenyl l-imidazol-2-ylmethyl H OH ethyl 3- (2-HO-phenyl) -imidazol-2-yl methyl H OH ethyl 3- (2-R ¹ 'O-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (2-Cl-phenyl) -imidazol-2-ylmethyl H OH ethyl 3- (2- (CH ₇ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH ethyl 1-imidazolyl-methyl H H ethyl 2-imidazolyl-methyl H H ethyl 3-thiazolylmethyl H H ethyl 2-thiazolylmethyl H H ethyl 2-oxazolylmethyl H H ethyl 5-tetrazolyl-methyl H H ethyl 4-pyridylmethyl H H ethyl 3-pyridylmethyl H H ethyl 2-pyridylmethyl H H ethyl benzyl H H ethyl 4-HO ₂ C-benzyl H H ethyl 4-H ₂ NCO-benzyl H H ethyl 4-CH ₃ O-benzyl H H ethyl 4-HO-benzyl H H ethyl 4-R ¹¹ O-Benzyl H H ethyl HU 211 897 A9 X R ² R ³ R ⁵ 4-Cl-benzyl H H ethyl 4- (CH ₃ ) ₂ N-benzyl H H ethyl 3-HO ₂ C-benzyl H H ethyl 3-H ₂ NCO-benzyl H H ethyl _3-CH3 O-benzyl H H ethyl 3-HO-benzyl H H ethyl R ^ S-O-Benzyl H H ethyl 3-Cl-benzyl H H ethyl 3- (CH ₃ ) ₂ N-benzyl H H ethyl 2-HO ₂ C-benzyl H H ethyl 2-H ₂ NCO-benzyl H H ethyl 2-CH, O-benzyl H H ethyl 2-HO-benzyl H H ethyl 2-R ⁿ O-benzyl H H ethyl 2-Cl-benzyl H H ethyl 2- (CH ₂ ) ₂ N-benzyl H H ethyl 3- (4-pindyl) -imidazol-2-ylmethyl H H ethyl 3- (3-pyridyl) imidazol-2-yl methyl H H ethyl 3- (2-pyridyl]) - imidazol-2-yl) - methyl H H ethyl 3-phenyl-imidazol-2-ylmethyl H H ethyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl 1- - H H ethyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H ethyl 3-t4-CH, O-t'enil) imidazole 2-ylmethyl H H ethyl 3- (4-HO-phenyl) -imidazol-2-yl methyl H H ethyl 3- (4-R ¹¹ O-Phenyl) imidazol-2-ylmethyl H H ethyl 3- (4-Cl-phenyl) -imidazol-2-yl methyl H H ethyl 3- (4- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H ethyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (3-CH, O-phenyl) -imidazol- 2-ylmethyl H H ethyl 3- (3-HO-phenyl) -imidazol-2-yl methyl H H ethyl 3-β-R ¹¹ O-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl H H ethyl X R ² R ³ R ⁵ 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H ethyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H ethyl 3- _(2-CH3 O-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (2-HO-Phenyl) -imidazole-2-ylmethyl H H ethyl 3- (2-R ¹¹ O-phenyl) -imidazol-2-ylmethyl H H ethyl 3- (2-Cl-phenyl) -imidazol-2-yl methyl H H ethyl 3- (2- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H ethyl 1-imidazolyl-methyl ch ₃ OH allyl 2-imidazolyl-methyl ch ₃ OH allyl 3-thiazolylmethyl ch ₃ OH allyl 2-thiazolylmethyl ch ₃ OH allyl 2-oxazolylmethyl ch ₃ OH allyl 5-tetrazolyl-methyl ch ₃ OH allyl 4-pyridylmethyl ch, OH allyl 3-pyridylmethyl ch ₃ OH allyl 2-pyridylmethyl ch, OH allyl benzyl ch ₃ OH allyl 4-HO ₂ C-benzyl ch ₃ OH allyl 4-H ₂ NCO-benzyl ch ₃ OH allyl 4-CH, O-benzyl ch. OH allyl 4-HO-benzyl ch ₃ OH allyl 4-R ⁿ -O-benzyl ch ₃ OH allyl 4-Cl-benzyl ch, OH allyl 4- (CH ₂ ) ₂ N-benzyl ch ₃ OH allyl 3-HO ₂ C-benzyl ch ₃ OH allyl 3-H ₂ NCO-benzyl ch, OH allyl _3-CH3 O-benzyl ch ₃ OH allyl 3-HO-benzyl ch, OH allyl 3-R ⁿ -O-benzyl ch, OH allyl 3-Cl-benzyl CH OH allyl 3- (CH ₂ ) ₂ N-benzyl CH ₃ OH allyl 2-HO ₂ C-benzyl ch ₃ OH allyl 2-H ₂ NCO-benzyl ch ₃ OH allyl 2-CH ₃ O-benzyl ch ₃ OH allyl 2-HO-benzyl ch ₃ OH allyl 2-R ⁿ O-benzyl CH OH allyl 2-C1-benzyl CH OH allyl 2- (CH ₂ ) ₂ N-benzyl CH OH allyl 3- (4-pyridyl) -imidazol-2-yl methyl CH OH allyl HU 211 897 A9 X R ² R ³ R ⁵ 3- (3-pyridyl) imidazol-2-yl methyl ch, OH allyl 3- (2-pyridyl) -imidazol-2-yl methyl CH OH allyl 3-phenyl-imidazol-2-ylmethyl ch, OH allyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (4-CH, O-phenyl) -imidazol- 2-ylmethyl ch, OH allyl 3- (4-HO-phenyl) -imidazol-2-yl methyl ch, OH allyl 3- (4-R ¹¹ O-Phenyl) imidazol-2-ylmethyl ch, OH allyl 3- (4-Cl-phenyl) -imidazol-2-yl methyl ch, OH allyl 3- (4- (CH,) _2- N-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch, OH allyl 3- (3-H ₂ NCO-Phenyl) -imidazol-2-ylmethyl! ch, OH allyl 3- (3-CH, 0-phenyl) -tmidazol- 2-ylmethyl ch ₃ OH allyl 3- (3-HO-phenyl) -imidazol-2-yl methyl ch, OH allyl 3- (3- (CH,) _2- N-phenyl) -imidazol-2-ylmethyl CH OH allyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl CH OH allyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch, OH allyl 3- (2-CH, O-phenyl) -imidazol-2-ylmethyl ch, OH allyl 3- (2-HO-í'enil) imidazol-2-yl methyl ch, OH allyl 3- (2-R ¹¹ O-phenyl) -imidazol-2-ylmethyl ch ₃ OH allyl 3- (2-Cl-phenyl) -imidazol-2-yl methyl ch, OH allyl 3- (2- (CH ₂ ) ₂ N -phenyl) imidazol-2-yl methyl ch, OH allyl 1-imidazolyl-methyl ch ₃ H allyl 2-imidazolyl-methyl ch, H allyl 3-thiazolylmethyl ch, H allyl 2-thiazolylmethyl CH H allyl 2-oxazolylmethyl CH H allyl 5-tetrazolyl-methyl CH H allyl 4-piridil-met.il CH H allyl 3-pyridylmethyl CH H allyl 2-pyridylmethyl CH H allyl X R ² R ³ R ⁵ benzyl CH H allyl 4-HO ₂ C-benzyl CH H allyl 4-H ₂ NCO-benzyl CH H allyl 4-CH, O-benzyl CH H allyl 4-HO-benzyl CH H allyl 4-R ⁿ -O-benzyl CH H allyl 4-Cl-benzyl CH H allyl 4- (CH ₂ ) ₂ N-benzyl CH H allyl 3-HO ₂ C-benzyl CH H allyl 3-H ₂ NCO-benzyl CH H allyl 3-CH, O-benzyl CH H allyl 3-HO-benzyl CH H allyl 3-R ⁿ -O-benzyl CH H allyl 3-Cl-benzyl CH H allyl 3- (CH ₂ ) ₂ N-benzyl CH H allyl 2-HO ₂ C-benzyl CH H allyl 2-H ₂ NCO-benzene CH H allyl 2-CH, O-benzyl CH H allyl 2-HO-benzyl CH H allyl 2-R ^u O-benzyl CH H allyl 2-Cl-benzyl CH H allyl 2- (CH ₂ ) ₂ N-benzyl CH H allyl 3- (4-pyridyl) -imidazol-2-yl methyl CH H allyl 3- (3-pyridyl) imidazol-2-yl methyl CH H allyl 3- (2-pyridyl) -tmidazol-2-yl methyl CH H allyl 3-phenyl-imidazol-2-ylmethyl CH H allyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl CH H allyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl CH H allyl 3- (4-CH, O-phenyl) -imidazol- 2-ylmethyl CH H allyl 3- (4-HO-phenyl) -imidazol-2-yl methyl CH H allyl 3- (4-R ^H O -phenyl) -timidazol-2-ylmethyl CH H allyl 3- (4-Cl-phenyl) -imidazol-2-ylmethyl CH H allyl 3- (4- (CH,) _2- N-phenyl) -imidazol-2-ylmethyl CH H allyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl CH H allyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl CH H allyl 3- (3-CH, O-Phenyl) -imidazol-2-ylmethyl CH H allyl HU 211 897 A9 X R ² R ³ R ⁵ 3- (3-HO-phenyl) -imidazol-2-yl methyl ch ₃ H allyl 3- (3-R ¹¹ O-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl ch ₃ H allyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl ch ₃ H allyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- _(2-CH3 O-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl 3- (2-HO-phenyl) -imidazol-2-yl methyl ch ₃ H allyl 3- (2-R ¹¹ O-phenyl) -imidazol-2-ylmethyl ch ₃ H allyl ! 3- (2-Cl-phenyl) -imidazol-2-yl J is methyl ch ₃ H allyl 3- (2- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl ch ₃ H allyl 1-imidazolyl-methyl H OH allyl 2-imidazolyl-methyl H OH allyl 3-thiazolylmethyl H OH allyl 2-thiazolylmethyl H OH allyl 2-oxazolylmethyl H OH allyl 5-tetrazolyl-methyl H OH allyl 4-pyridylmethyl H 1 OH allyl 3-pyridylmethyl H OH allyl 2-pyridylmethyl H OH allyl benzyl ——. H OH allyl 4-HO ₂ C-benzyl H OH allyl 4-H ₂ NCO-benzyl H OH allyl 4-CH ₃ O-benzyl H OH allyl 4-HO-benzyl H OH allyl 4-R ⁿ -O-benzyl H OH allyl 4-Cl-benzyl H OH allyl 4- (CH ₃ ) ₂ N-benzyl H OH allyl 3-HO ₂ C-benzyl H OH allyl 3-H ₂ NCO-benzyl H OH allyl _3-CH3 O-benzyl H OH allyl 3-HO-benzyl H OH allyl 3-R ¹⁰ O-benzyl H OH allyl 3-Cl-benzyl H OH allyl 3- (CH ₃ ) ₂ N-benzyl H OH allyl 2-HO ₂ C-benzyl H OH allyl 2-H ₂ NCO-benzyl H OH allyl X R ² R ³ R ⁵ 2-CH ₃ O-benzyl H OH allyl 2-HO-benzyl H OH allyl 2-R ⁿ O-benzyl H OH allyl 2-Cl-benzyl H OH allyl 2- (CH ₃ ) ₂ N-benzyl H OH allyl 3- (4-pyridyl) -imidazol-2-yl methyl H OH allyl 3- (3-pyridyl) imidazol-2-yl methyl H OH allyl 3- (2-pyridyl) -imidazol-2-yl methyl H OH allyl 3-phenyl-imidazol-2-ylmethyl H OH allyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (4-CH ₃ O-phenyl) -imidazole-2-ylmethyl H OH allyl 3- (4-HO-phenyl) -imidazol-2-yl methyl H OH allyl 3- ^(4-R] 'O-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (4-Cl-phenyl) -imidazol-2-yl methyl H OH allyl 3- (4- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH allyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (3-CH ₃ O-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (3-HO-phenyl) -imidazol-2-yl methyl H OH allyl 3- (3-R ¹¹ O-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (3-C) phenyl) -imidazol-2-yl methyl H OH allyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH allyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H OH allyl 3- _(2-CH3 O-phenyl) -imidazol-2-ylmethyl H OH allyl 3- (2-HO-phenyl) -imidazol-2-yl methyl H OH allyl 3- (2-R''O-phenyl) -imidazol-2- ylmethyl H OH allyl HU 211 897 A9 X R ² R ³ R ⁵ 3- (2-Cl-phenyl) -imidazol-2-yl methyl H OH allyl 3- (2- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H OH allyl 1-imidazolyl-methyl H H allyl 2-imidazolyl-methyl) H H allyl 3-thiazolylmethyl H H allyl 2-thiazolylmethyl H H allyl 2-oxazolylmethyl H H allyl 5-tetrazolyl-methyl H H allyl 4-pyridylmethyl H H allyl 3-pyridylmethyl H H allyl 2-pyridylmethyl H H allyl benzyl H H allyl 4-HO ₂ C-benzyl H H allyl 4-H ₂ NCO-benzyl H H allyl 4-CH ₃ O-benzyl H H allyl 4-HO-benzyl H H allyl 4-R ⁿ -O-benzyl H H allyl 4-Cl-benzyl H H allyl 4- (CH ₃ ) ₂ N-benzyl H H allyl 3-HO ₂ C-benzyl H H allyl 3-H ₂ NCO-benzyl H H allyl _3-CH3 O-benzyl H H allyl 3-HO-benzyl H H allyl R ^ S-O-Benzyl H H allyl 3-Cl-benzyl H H allyl 3- (CH ₃ ) ₂ N-benzyl H H allyl HO-2> C-benzyl H H allyl 2-H ₂ NCO-benzyl H H allyl 2-CH ₃ O-benzyl - H H allyl 2-HO-benzyl H H allyl 2-benzyl-RO H H allyl 2-Cl-benzyl H H allyl 2- (CH ₃ ) ₂ N-benzyl H H allyl 3- (4-pyridyl) -imidazol-2-yl methyl H H allyl 3- (3-pyridyl) imidazol-2-yl methyl H H allyl 3- (2-pyridyl) -imidazol-2-yl methyl H H allyl 3-phenyl-imidazol-2-ylmethyl H H allyl 3- (4-HO ₂ C-phenyl) -imidazol-2-ylmethyl H H allyl 3- (4-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H allyl 3- (4-CH ₃ O-phenyl) -imidazol-2-ylmethyl _ H H allyl X R ² R ³ R ⁵ 3- (4-HO-phenyl) -imidazol-2-yl methyl H H allyl 3- (4-R * * O-phenyl) -imidazol-2-ylmethyl H H allyl 3- (4-Cl-phenyl) -imidazol-2-yl methyl H H allyl 3- (4- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H allyl 3- (3-HO ₂ C-phenyl) -imidazol-2-ylmethyl H H allyl 3- (3-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H allyl 3- (3-CH ₃ O-phenyl, imidazole-2-ylmethyl H H allyl 3- (3-HO-phenyl) -imidazol-2-yl methyl H H allyl 3- (3-R ¹¹ O-Phenyl) imidazol-2-ylmethyl H H allyl 3- (3-Cl-phenyl) -imidazol-2-yl methyl H H allyl 3- (3- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H allyl 3- (2-HO ₂ C-phenyl) -imidazol-2-ylmethyl H H allyl 3- (2-H ₂ NCO-phenyl) -imidazol-2-ylmethyl H H allyl 3- _(2-CH3 O-phenyl) -imidazole-2-ylmethyl H H allyl 3- (2-HO-phenyl) -imidazol-2-yl methyl H H allyl 3-12-R ¹ '(θ-phenyl) -imidazol-2-ylmethyl H H allyl 3- (2-Cl-phenyl) -imidazol-2-ylmethyl H H allyl 3- (2- (CH ₃ ) ₂ N -phenyl) imidazol-2-ylmethyl H H allyl (8) substituted biphenyl wherein the substituents are X, Y and Z; (8) heteroaryl (C3-10 alkenilj group wherein the heteroaryl group is a group as defined above, an alkenyl group containing 1-4 double bonds and one of the alkyl carbon atoms is substituted with one or more, the substituent is ^-NR6 - of formula a group selected from oxygen, -S (O) _p -, -CO ₂ -, -O ₂ C -, -CONR ⁶ -, -NR ⁶ CO-, -NR ⁶ CONR ⁷ -; 9. A compound selected from: 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (2-furanyl) methoxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21. 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ -octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4 "- (2-furanyl) -metoxi3" -hydroxy-cyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13.19.21. 27-tetramethyl-1,2,8-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' -hydroxy) -3 '- (2-furanyl) methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy .19.21.27- tetramethyl-1,28-dioxa-4-azatricyclo [22.3.1Ό ^{4 9]} octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (2-thiophene) methoxy-3 '-methoxy-cyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13.19.21.27 - tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] oclazo-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (2-thiophene) methoxy-3 '-hydroxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-74 HU 211 897 A9 (9) C 1-10 alkyl; (9) substituted heteroaryl-C3-C10 alkenyl wherein the heteroaryl is defined above, alkenyl contains 1-4 double bonds and one or more of the alkyl carbon atoms is substituted with: -NR ^{6 is} -O, -S (O) _p- , -CO ₂ , -O ₂ C, -CONR ⁶ -, -NR ⁶ CO -, -NR ⁶ CONR ⁷ -, the heteroalyl group being substituted with X, Y and Z, and the alkyl group being substituted with one or more of the following: (a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) aryl (C 1-3) alkoxy, wherein aryl is a group as defined above, (e) substituted aryl (I), C3-C3-alkoxy in which the aryl group is as defined above and its substituents X, Y and Z, (f) optionally substituted aryloxy group in which the aryl group is as defined above and its substituents are X, Y and Z, (g) - OCO- (C 1-6 -alkyl), (h) -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above, (i) -NR ⁶ CO- (C 1-6 -alkyl) wherein R ⁶ is as defined above, (j) -NR ⁶ CO ₂ - (C 1 -C 6 alkyl) wherein R ⁶ is as defined above, (k) -NR ⁶ CONR ⁶ R ⁷ , (l) -OCONR ⁶ R ⁷ , (m) -COOR ⁶ , (n) -CHO, (o) aryl, which is an aryl group as defined above ort, (p) substituted aryl which is as defined above and the substituents are X, Y and Z, (q) -OR, and (r) -S (O) _p - (C 1-6) alkyl; ; R ² has the same meaning as R ¹ ; A compound of formula (Ia) or a pharmacologically acceptable salt thereof, wherein R ¹ and R ² are a combination of the substituents given in the following table: HU 211 897 A9 R ¹ R ² (the) ckj io CH ₃ (B) CH? CO Η (C) ch ₃ (D) οα ch ₃ (E) οα ch ₃ (F) 03 Η (G) ς Η (H) 1 ς Η (υ οα CH 1 Ο, Η R ¹ R ² (K) CQ ch ₃ (1) οα Η (M) α, Oo. ch ₃ (Η) CO Η (Ο) ΜΟ S ΟΟ, ch ₃ (Ρ) ΜΟ S οα Η (10) substituted C 1 -C 10 alkyl, wherein the substituent is one or more of the following: (a) hydroxy, (b) oxo, (c) C 1-6 -alkoxy, (d) aryl (C 1-3) -alkoxy, wherein aryl is a group as defined above, (e) substituted aryl (I). A C3-C3 alkoxy group in which the aryl group is one A9 and the substituents X, Y and Z, (f) optionally substituted aryloxy, wherein the aryl substituents are X, Y and Z, (g) -OCO- (C 1 -C 6 alkyl) -. a group of the formula (h) -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above, (i) -NR ⁶ CO- (C 1 -C 6 alkyl) -R ⁷ wherein R ⁶ and R ⁷ is as defined above, (j) -COOR ⁶ , wherein R ⁶ is as defined above, (k) -CHO, (1) phenyl, (m) substituted phenyl, wherein X, Y and Z are substituted. , (η) a 1- or 2-naphthyl group, (o) a substituted 1- or 2-naphthyl group where X is Y and Z, (p) biphenyl group, (q) substituted biphenyl group where X is substituted. , Y and Z, a group of formula ^I, and (s) -S (O) _p (r) -OR - (C1-C6) ^alkyl; A compound according to claim 10, which is represented by formula (1). (11) C 3-10 alkenyl; A compound according to claim 10, which is represented by formula (2). (12) substituted C 3 -C 10 alkenyl, wherein the substituent is one or more of the following: (a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) phenyl (C 1-3) alkoxy, (e) substituted phenyl (C 1-3) alkoxy, wherein the substituents on the phenyl are X, Y and Z, (f) -OCO- (C 1 -C 6) alkyl, (g) -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above. (h) -NR ⁶ CO- (C 1 -C 6 alkyl) wherein R ⁶ is as defined above, (i) -COOR ⁶ wherein R ⁶ is as defined above, (j) -CHO-. , (k) phenyl, (1) substituted phenyl wherein X, Y and Z are substituted, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl wherein X is , Y and Z, (o) biphenyl, (p) substituted biphenyl wherein the substituent is X, Y and Z, (q) -OR ¹¹ , and (r) -S (O) _p - (1-6). (C 1 -C 4) alkyl; A compound according to claim 10, which is represented by formula (3). 13.19.21.27- tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (3-thiophene) methoxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21. 27- tetramethyl-11,28-dioxa-4-azatricik _r lo [22.3.1.0 ^4,9] octacos-18-ene - 2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' -hydroxy-3 '- (2-thiophene) methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' -hydroxy-3 '- (3-thiophene) -methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (2-thiophene) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy13.19.21 .27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (2-benzothienyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21. 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 2,10 &gt;]loca-cos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3 "methoxycyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13.19.21 .27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3 'hydroxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy13.19.21 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (5-indolyl) oxy3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13. 19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; Joktakoz-] 8-ene-2,3,10,16-tetraone; 17-Ethyl-l, 20-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3 "methoxycyclohexyl) -T-methylvinyl] -23,25-dimetoxi13,19, 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l-hydroxy-12- (2 '- (4' - (5-indolyl) oxy-3 "-methoxy-cyclohexyl) -r-methylvinyl] -23,25-dimetoxi13,19,21 , 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] octacos-18-ene-2,3,10,16-tetraone; 17-allyl-1,14-dihydroxy-12- (2 '- (4' - (5-indolyl) oxy-3 "methoxycyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13,19 , 21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3 'hydroxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l, 14,20-trihydroxy-12- [2 '- (4' - (5-indolyl) -oxi3 "-methoxy-cyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13, 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-allyl-1,20-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3 "methoxycyclohexyl) -l'-methylvinyl] -23,25-dimetoxi13,19 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (5-indolyl) oxy-3 'ethoxycyclohexyl) -1-methylvinyl] -23,25-dimethoxy-13,19, 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- (2 '- (4' - (5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy13,19 21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12- (2 '- (4' - (5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21 27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl ] -23.25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl ] -23.25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl 1-1,20-dihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,2,8-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1-methyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-1,1,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] - 23,25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl- vinyl] -23,25 dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt; Joktakoz-18-ene-2,3,10,16-tetraone 17-Allyl-1, 20-dihydroxy-12- (2 '- (4' - (1-methyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;Joktakoz-18-ene-2,3,10,16-tetraone; Ethyl 1-hydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy 3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy .19.21.27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt; ^-9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [2.2.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] - 23,25-Dimethoxy-13,1 9,21,27-tetramethyl-1,28-dioxa-4-azatriocyclo [22.3.1. Cryo-octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-methyl-5-indolyl) oxy-3 '-ethoxycyclohexyl) -1'-methyl vinyl] -23, 25 di75 A9 methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-l-hydroxy-12- [2 '- (4 "- (lN-methyl-5-indolyl) oxy-3" -methoxy-cyclohexyl) -l'-methylvinyl] -23,25-dimethoxy -13,19,21,27-tetramethyl-1,2,8-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 'allyloxycyclohexyl) -1'-methyl vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; -l-dihydroxy-12- (2 '- (4 "- (lN-methyl-5-indolyl) oxy-3" -allyloxy-cyclohexyl) -l'-methylvinyl] -23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl -1,14-dihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 '-n-propyloxycyclohexyl) -1'-methyl -vinyl? 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' - (1N-methyl-5-indolyl) oxy3 '-n-propyloxy-cyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 9]} octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-methyl-5-indolyl) oxy-3 '-propyloxy-cyclohexyl) -1'-methyl-vinyl ] 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-ethyl-5-indole 1) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 '' methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt; C] - Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23 , 25-dimethoxy-13,19,21,27-tetramethyl-1,2,8-dioxa-4-aza-tricyclo [22.3. 1-O-Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] -23 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [2.2.3.1.0] joktakoz-18-ene-2,3,11,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,20-dihydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3-hydroxycyclohexyl) -1'-methyl-vinyl] -23 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21 .27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12- [2 '- (4' - (1-N-ethyl-5-indolyl) oxy] 3-methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13 19.21.27-Tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-ethyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [10.1] octaclocale-ene, 3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl- vinyl] -23,25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] - 23,25-Dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^49] Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl- vinyl] -23,25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.1] Clioctocos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-l 1, 28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ⁹ Joktakoz-18-ene-2,3,10,16-tetraone ; 17-Allyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] 23 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa- ⁴ -azatricyclo [22.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,20-dihydroxy-12- (2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^49] Joktakoz-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl] -23,25dimetoxi- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴ · ⁹ Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12- [2 '- (4' - (1-N-propyl-5-indoyl) oxy-3-methoxycyclohexyl) -1'-methyl-vinyl] -23,25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; HU 211 897 A9 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 2,10 &gt;]lokactos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-propyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-allyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo [2 2.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16 tetrone; 17-Ethyl -1,14,20-trihydroxy-12- (2 '- (4' - (1N-allyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; ethyl-l, 20-dihydroxy-12- (2 '- (4 "- (lN-allyl-5-indolyl) oxy-3" -methoxy-cyclopropyl] cyclohexylamino) -l'-methylvinyl] -23,25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1N-allyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] -23.25 -dimethoxy-13,1,2,2,2,2-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-N-allyl-5-indolyl) oxy-3-hydroxycyclohexyl) -1'-methyl vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1-N-allyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -methyl-vinyl] -23, 25-dimethoxy-13.19.21,27-tetramethyl-1,1,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-allyl-5-indolyl) oxy-3-methoxycyclohexyl) -1'-methyl-vinyl] -23 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.1] -cyclooctacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-N-allyl-5-indolyl) oxy-3-methoxycyclohexyl) -1'-methyl vinyl] -23 25-dimethoxy-13.19.21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴ &gt;] ⁹ -octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1, 20-dihydroxy-12- [2 '- (4' - (1H-allyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;]octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-allyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -methyl-vinyl] -23 , 25dimetoxi- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [03.22.10 ^4-9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl 1-hydroxy-12- (2 '- (4' - (1N-allyl-5-indolyl) oxy3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13,19,21, 27-Tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]joktakoz-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12- (2 '- (4' - (1-N-allyl-5-indolyl) oxy3 '-methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13 , 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-allyl-5-indolyl) oxy-3 '-ethoxy-cyclohexyl) -1'-methyl-vinyl] -23,25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-allyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-2-hydroxyethyl-5-indolyl) -oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 2,10-octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-β-2-hydroxyethyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl -vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 2, &gt;.; 17-Ethyl-1,20-dihydroxy-12- (2 '- (4' - (1-N-2-hydroxyethyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -methyl-vinyl] -23,25dimetoxi- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricik lo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-2-hydroxyethyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -r-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-β-2-hydroxyethyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16tetraon ; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1N-2-hydroxyethyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatriciklo [22.3.1,0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-2-hydroxyethyl-5 indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl- vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 2,10-octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-hydroxyethyl-5-indolyl) -oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] - 23,25dimetoxi-1 3,19,21,27-telrametil-11,28-dioxa-4-one azatricik o [22.3.1.0 ^{4 9]} octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-Dimethoxy-13,19,21,27-tetramethyl-1,2,8-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl -1,14,20-trihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1' -methyl- vinyl] -23,25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1-benzyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23, 25-dimethoxy-13,19,21,27-tetramethyl-l 1, 28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-1,3,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;octaquacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12- (2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl- vinyl] -23,25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl] - 23.2577 GB 211 897 A9 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 '' - methoxycyclohexyl) -1'-methyl-vinyl] 23.25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Allyl-1,20-dihydroxy-12- [2 '- (4''- (1-N-benzyl-5-indolyl) oxy-3' -methoxy-cyclohexyl) -1'-methyl-vinyl] 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1N-benzyl-5-indolyl) oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] 23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;octaquacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12- (2 '- (4' - (1-benzyl-5-indolyl) oxy-3-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy- 13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]joktakoz-18-ene-2,3,10,16-letraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 '' - ethoxy-cyclohexyl) -1 ' -methyl 1-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 (j'joktakos-18-ene-2,3 10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-benzyl-5-indolyl) oxy-3 'ethoxycyclohexyl) -1'-methyl vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] 23.25-dimethoxy -13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 &gt;.beta.-lloctacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) -oxy-3 '-hydroxycyclohexyl) -1'-methyl-vinyl] 23.25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3 'methoxycyclohexyl) -methyl-vinyl] -23 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]Joktakoz-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3 'hydroxy-cyclohexyl) -1'-methyl-vinyl] - 23,25-dimethoxy-13,19,21,27-tetramethyl-1,1,28-dioxa-4-aza-tricyclo [22.3.1 (d] Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) -oxy-3 '-ethoxycyclohexyl) -6-methyl-vinyl] -23,25-dimethoxy - 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12- [2 '- (4' - (1N-cyclopropyl-5-indolyl) oxy-3 '-ethoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy- 13,19,21,27-tetramethyl-1,2,8-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;Joktakoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23, 25-Dimethoxy-13,19,21,27-tetramethyl-1, 28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12- [2 '- (4' - (1-N-cyclopropyl-5-indolyl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23 25-di-methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; 4 &gt;]joktaxoz-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12- [2 '- (4' -methoxy-N-tryptophanylcarbonylmethoxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13, 19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-hydroxy-12- [2 '- (4' - (3-indolyl) ethyl-aminocarbonyl, methoxy-3 "-methoxy-cyclohexyl) -l'-methylvinyl] 23,25 -dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 2,10-octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1- (3-hydroxypropyl) indol-5-yl) oxy-3 'methoxycyclohexyl) -1'-methyl- vinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;octaquacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (3' -hydroxy-4 '- (1-hydroxy-ethyl-indol-5-yl) -oxycyclohexyl) -1'-methyl- methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatriciklo [22.3.1.0 ^4-9] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-hydroxyethylindol6-yl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl] -23, 25dimetoxi- 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 9]} octacos-18-ene-2,3, l 0,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-methylindol-6-yl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-dibenzylphosphonyoxyethyl-indol-5-yl) -oxy-3 '-methoxy-cyclohexyl) -6-methyl-vinyl ] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-phosphonyloxyethylindol-5-yl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl ] Monopotassium salt of 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- (2 '- (4' - (1- (Ν, Ν-dimethylglycyloxy) ethylindol-5-yl) oxy-3 'methoxy) cyclohexyl) -l'metil] -23,25-dimethoxy-13,19,21,27-tetrametil11,28-dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-én2,3, 10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-succinyloxyethylindol-5-yl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl- vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1-methyl-3-phenylindol-5-yl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl -vinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; HU 211 897 A9 17-Ethyl-1,14-dihydroxy-12- [2 '- (4 "- (1-methyl-3- (2-hydroxyethyl) indol-5-yl) oxy-3" methoxycyclobexyl) ) -] '- methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo [22.3.1.0 ^{4' 9]} octacos-18-tetraone én2.3.10.16- ; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1,3-dimethylindol-5-yl) oxy-3 'methoxycyclohexyl) -1'-methyl vinyl ] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (- 9'-methylcarbazol-3'-yl) oxy-3 '-methoxycyclohexyl) -1'-methyl- vinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (3 '''- diethylaminopropionyloxy) ethyl) indol-5''-yl) oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octaco -18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (3 '''- dimethylaminopropionyloxy) ethyl) indol-5''-yl) -oxy-3 '-methoxy-cyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18 ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (3 '''- aminopropionyloxy) ethyl) indol-5''-yl)oxy-3' -methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos18-ene-2,3 10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (3 ''') - benzyloxycarbonyl-2''' - benzyloxycarbonylaminopropionyl) -oxy) -ethyl) -indole-5 "-iii) -oxy-3" -methoxycyclohexyl) -! '-methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [2 2.3.1.0 ^{4 9} ] octacos-18-ene-2,3,10,16 tetrone; 17-Ethyl-l. 14-dihydroxy-12- [2 '- (4' - ((2 '' - (aspartyloxy) ethyl) indol-5 '' -yl) oxy-3 'methoxycyclohexyl) -1 · methyl- vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1 (K'-octocos-18-ene-2,3.10.16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (1 '''- imidazolylcarbonyloxy) ethyl) indol-5''-yl) -oxy-3 '-methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^{4 9} ] octacos-18 ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((2 '' - (1 '' '- piperazinecarbonyloxy) ethyl) indol-5' '-yl) oxy-3 '-methoxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; / RTI &gt;I-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((1 '' -2 '' (2 '''-hydroxy) ethylaminocarbonyloxy) ethyl) - indole-5 '' - yl) oxy-3 "-methoxy-cyclohexyl) -l'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo [22.3.1.0 ⁴⁹ ] octacos-18-en-2.10.10.16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - ((1 '' - (2 '' - isopropylaminocarbonyloxy) ethyl) indol-5 '') ) -oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '' - (1-piperidinecarbonyloxy) ethyl) indol-5 '')) ) -oxy-3 '-methoxy-cyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '' morpholinocarbonyloxy) ethyl) indol-5 '' yl) oxy 3 &apos; -methoxycyclohexyl) -1'-methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-1,28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴⁹ ] octacos-18-ene- 2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4 "- (1- (2""- (di-phenylaminocarbonyloxy) ethyl) indol-5'" -yl) - oxy-3 '-metoxiciklohexil) -r-methylvinyl] -23,25-dimetoxi13.19.21.27- tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1,0 ^4-9] octacos-18- I-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '''- (diethylaminocarbonyloxy) ethyl) indol-5''-yl) oxy-3 '-methoxycyclohexyl) -r-methyl-vinyl] -23,25-dimethoxy-13.19.21.27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18 ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '' - methanesulfonyloxy) ethyl) indol-5 '' -yl) oxy-3 '-Methoxycyclohexyl) -1'-methyl-1-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1, 28-dioxa-4-aza-tricyclo [22.3.1.0 ⁴ - ⁹ ] octacos18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4''-(1''-(2''- azidoethyl) indol-5''-yl)oxy-3' methoxycyclohexyl ) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 ^4,9 ] octacos-18-ene 2,3,3,10,16 tetrone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - (2 '') aminoethyl) indol-5 '' -yl) oxy-3 'methoxycyclohexyl ) -1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo [22.3.1.0 &lt; ⁴⁹ &gt;tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 't-butyldimethylsilyloxyethoxyethylindol-5''-yl)oxy-3' - methoxycyclohexyl) -1'-methyl vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-l 1, 28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} I oktakoz18- -2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (4' - (1 '' - hydroxyethoxyethylindol-5 '' -yl) oxy-3 'methoxycyclohexyl) -1' methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo [22.3.1.0 ^4-9] octacos-18-én2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12- [2 '- (3 "-methoxy-4" - (("(1""-oxo-prop-1""-yl)-indol-5") - yloxy) cyclohexyl) l'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetrametil11,28-dioxa-4-azatricyclo [22.3.1.0 ^{4 '9]} octacos-18- én2,3,10,16-tetraone; and 17-Ethyl-1,14-dihydroxy-12- [2 '- (3 "-methoxy-4" - (1'"-(1" carboxyeth-2 "" -yl)) indole-5 "'- yl) -oxycyclohexyl) -methyl-vinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-1,2,8-dioxa-4-azatricyclo [22.3.1.0 ^4,9 ] octacos-18 ene-2,3,10,16-tetraone; (13) C 3-10 alkynyl, (14) substituted C 3-10 alkynyl. wherein the substituent is one or more of the following groups: (a) hydroxy, (b) oxo, (c) C 1-6 alkoxy, (d) phenyl (C 1-3) alkoxy, (e) substituted phenyl (C 1-3) alkoxy, wherein the substituents on the phenyl group are X, Y and Z, (f) -OCO- (C 1 -C 6 alkyl), (g) -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above, (h) ) -NR ⁶ CO- (C 1 -C 6 alkyl) wherein R ⁶ is as defined above, (i) -COOR ⁶ wherein R ⁶ is as defined above, (j) -CHO-, k) phenyl, (l) substituted phenyl wherein X, Y and Z are substituted, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl wherein X, Y is substituted. and Z, (o) biphenyl, (p) substituted biphenyl, wherein the substituent is X, Y and Z, (q) -OR, and (15) -R; R ³ is hydrogen, hydroxy, -OR ¹¹ , C 1-6 alkoxy; R ⁴ is hydrogen or R ³ and R ⁴ together form a double bond; ^R5 is methyl, ethyl, propyl or allyl; R ¹⁰ is hydrogen, hydroxy, -OR ¹¹ , or fluoro; R ¹¹ is (a) -PO (OH) OM ⁺ , in which is a positively charged inorganic or organic anion selected from ammonium, sodium, lithium, potassium, calcium, magnesium, dicyclohexylamine, N-methyl-D-glucamine, arginine or lysine, (b) -SO ₃ -M ⁺ , (c) -CO (CH ₂ ) _q CO ₂ -M ⁺ in which q is 1-3, and (d) -CO- (C 1 -C ⁶ alkyl) -NR ^{6 R7} wherein ^R6 and ^R7 are as defined above and alkyl is optionally substituted with one or more substituents selected from (i) hydroxy, (ii) C1-6 alkoxy, (iii) -NR ^{I6 R17} group wherein ^R16 and ^R17 are independently selected from (a ') hydrogen, and (b') C1-6 alkyl, (iv) -COOR ⁶ wherein R ⁶ is as defined above, (v) phenyl, (vi) substituted phenyl wherein X, Y and Z are substituted, A9 (vii) heteroaryl, which is a heteroaryl group as defined above, (viii) -SH, and (ix) -S-O-C6-alkyl); W is oxo or (hydrogen and hydroxy); X, Y and Z are each independently (a) hydrogen, (b) C 1-10 alkyl, which may be optionally substituted with one or more of the following: (i) an aryl group which is an aryl group as defined above, (ii) a substituted aryl group which is an aryl group as defined above, and the substituents X ', Y' and Z ', (iii) a heteroaryl group which is a heteroaryl group heteroaryl, which is a heteroaryl group as defined above, and the substituents X ', Y', and Z ', (v) an optionally substituted aryloxy group, wherein the aryl group is as defined above, and the substituents on the aryl moiety are X', Y ', and Z ', (vi) -OR ⁶ , (vii) -OR ¹¹ , (viii) -OCOR ⁶ , (ix) -OCO ₂ R ⁶ , (x) - NR ⁶ R ⁷ , (xi) -CHO, (xii) -NR ⁶ CO- (C 1 -C 6 alkyl) -R ⁷ , (xiii) -NR ⁶ CO ₂ - (1- (C 6 -alkyl) -R ⁷ , (xiv) -NR ⁶ CONR ⁶ R ⁷ , (xv) -OCONR ⁶ R ⁷ , (xvi) -CONR ⁶ R ⁷ , (c) C 1 -C 10 alkyl, in which one or more alkyl carbon atoms may be replaced by NR ⁶ -, oxygen, -S (O) p-, -CO ₂ , -O ₂ C, -CONR ⁶ -, -NR ⁶ CO -, -NR ^ CONR ⁷ -, -CO-, -CH (OH), alkenyl or alkenyl, and alkyl is optionally substituted with one or more of the following: (i) an aryl group which is an aryl group as defined above, (ii) a substituted aryl group which is an aryl group as defined above and the substituents X ', Y'and Z', (iii) a heteroaryl group which is a heteroaryl group as defined above which is a heteroaryl group as defined above and the substituents X ', Y' and Z ', (v) an optionally substituted aryloxy group, wherein the aryl group is a group as defined above and the substituents on the aryl moiety X', Y ', and Z ', (vi) -OR ⁶ , (vii) -OR', (viii) -OCOR ⁶ , (ix) -OCO ₂ R ⁶ , (x) -NR ⁶ R ⁷ , (xi) -CHO, (xii) -NR ⁶ CO- (C 1 -C 6 alkyl) -R ⁷ , (xiii) -NR ⁶ CO ₂ - (C 1 -C 6) alkyl) -R ⁷ , (xiv) -NR ⁶ CONR ⁶ R ⁷ , (xv) -OCONR ⁶ R ⁷ (xvi) -CONR ⁶ R ⁷ , (d) halogen, (e) -NR ⁶ R ⁷ , (f) -CN, (g) -CHO, ( h) -CF ₃ , (i) -SR ⁸ wherein R ⁸ is hydrogen, C 1-6 alkyl, trifluoromethyl or phenyl; (j) -SOR ⁸ , (k) ) -SO ² R ⁸ , (1) -CONR ⁶ R ⁷ , (m) R ⁹ O (CH 2) m, in which R ⁹ is hydrogen, (C 1 -C 6) -alkyl, hydroxy (2) C 3 -C 3 alkyl, -CF 3, phenyl, R 'or naphthyl, and m is 0, A compound according to claim 10, which is represented by formula (4). A compound according to claim 10, which is represented by formula (5). A compound according to claim 10, which is represented by formula (6). A compound according to claim 10, which is represented by formula (7).