LT3533B - O-heyteroaryl, o-alkylheteroaryl, o-alkenylheteroaryl and o-alkynylheteroaryl macrolides - Google Patents

Abstract

O- heteroaryl-, O alkylheteroaryl-. O-alkenylheteroaryl- and O-alkynylheteroarylmacrolides, in joint formula:<IMAGE>that are synthesized from respective original agents through alkylation and/or arylation cyclohexyl ring C-3'' and/or C-4'' atoms. These macrolide immunosuppressive is useful in mammal treatment in case of autoimmune diseases, infections and in the prevention of transplanted organ rejection and/or in the treatment of similar disorders, diseases and illnesses.

Description

The present invention describes Ο-heteroaryl-, O-alkylheteroaryl-, O-alkenylheteroaryl- and O-alkynylheteroaryl macrolides which are useful in the treatment of mammals for autoimmune diseases (such as juvenile diabetes mellitus, multiple sclerosis and rheumatoid arthritis), immunosuppression, infectious diseases and/or to prevent rejection of transplanted foreign organs (for example, in bone marrow transplantation, heart and xenografts), as well as useful in the treatment of locally inflammatory and hyperproliferative skin diseases and immune system-related diseases of the skin (such as psoriasis, atopic dermatitis, contact dermatitis, and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigus, epidermolysis bullosa, urticaria, angioedema, angiitis, erythema, cutaneous eosinophilia, alopecia areata, male pattern baldness alopecia, senile alopecia, reversible obstructive airway disease, especially asthma, alopecia, lymphovascular inflammation, cytomegalovirus infection, multidrug resistance, idiopathic thrombocytopenic purpura, Behcet's syndrome, conjunctivitis, Crohn's disease, Mooren's ulcer, uveitis, severe inflammation of the inner eye and/or liver damage associated with ischemic disease. In addition, some of the compounds of the present invention may have antagonistic properties and therefore may be useful to eliminate the activity of other immunosuppressive agents and/or reduce their toxicity.

More specifically, the present invention describes compounds having the general formula I:

I II IYU

wherein R _1F R ₂ , R ₃ , R ₄ , R ₅ , R ₁₀ , W and n are defined below.

This invention also describes a pharmaceutical composition comprising the compounds and a method for using these compounds and other agents for the treatment and prevention of certain disorders, ailments, diseases and conditions.

Fijisawa United States, European and Japanese patents and applications (U.S. Pat. No. 4,894,366, 1990, EPO 0,184,162 and PBJ No. 63-17884) and publications (J. Am.

Chem. Soc., 1987, 109, 5031 and J Antibiotics 1987, £0

1249) describes 17-allyl-1,14-dihydroxy-12-[2'-(4''hydroxy-3''-methoxy-cyclohexyl)-1'-methylvinyl]-23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4azatricyclo-[ 22. 3. 1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16tetraone (FR-900506) , (FK-506), (L-679, 934) 17-ethyl-l,

14-dihydroxy-12-[2'-(4''-hydroxy-3''-methoxycyclohexyl)-1 '-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27tetramethyl-11, 28-dioxa-4-azatricyclo-[22 . 3. 1.-0 ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone (FR-900520) 'and related compounds, which are starting materials for the synthesis of the described compounds. The synthesis of the said starting material (FR-900506) has been recently described (J. Am. Chem. Soc., 1989, iii, 1157). The Sandoz company's European patent application (EPO No. 0 356 399) describes the stereoisomers of FR-900506 and its derivatives at the 17th position. Fisons

I

firms in applications 3 European and WIPG for patents (EPO No. 0 323,042) and WO 89/05304) described various FR- 900506 FR-900520 and similar compounds. Sandoz applied for-

The European Patent Application (EPO No. 0 437 680) describes the chloro, bromo, iodo and azide derivatives of FR900506, FR-900520 and similar compounds. The Merck European Patent Application (EPO No. 0 428 365) describes various amino derivatives of FR-900506, FR900520 and similar compounds. The Fujisawa patent application (GB No. 2 245 891-A) describes various derivatives of FR-900506 containing a heterocyclic group.

Fijisawa's US patents (US Pat. No. 4,929,611, 1990; US Pat. No. 4,956,352, 1990; and US Pat. No. 45,110,811, 1992) describe the use of FK-506-type compounds in overcoming the body's resistance in organ transplantation. Sandoz's European patent application (EPO No. 0 315 978) describes the use of FR-900506 and similar compounds for the topical treatment of inflammatory and hyperproliferative skin diseases and skin-related immune diseases. Fisons' WIPO patent application (WO 91/04025) describes the use of various FR-900506 derivatives in the treatment of immunodepression. Fison's WIPO patent application (WO 90/14826) describes The use of FR-900506 and related compounds in the treatment of immunodepression and reversible obstructive airway diseases, especially asthma. The use of FK-506 and related compounds in the treatment of alopecia is described in the European patent application by Fujisawa (EPO No. 0 423 714). Various studies have shown the efficacy of FK-506 in the treatment of a number of diseases, such as rheumatoid arthritis, (C. Arita, et. ai., Clinical Exp. Immunol., 1990, 82, 456-461; N. Inamura, et ai., Clin. Immunol. Immunopathol, 1988, 46 82-90) early diabetes (N. Murase, et ai., Diabetes, 1990, 39 1584-86; N. Murase, et ai., Lancet, 1990, 336 373-74), posterior uveitis, (H. Kawashima, Invest. Ophtalmoi. Vis. Sci., 1988, 29, 1265-71), liver damage associated with ischemic disease (M. Sakr, et ai., Life Sci., 1990, 47, 687-91), allergic

I encephalomyelitis (K. Deguchi, et ai., Brain Nerve, 1990, 42, 391-97), glomerulonephritis (J. McCauley, et ai., Lancet, 1990, 335 674), systemic lupus erythematosus (K. Takabayashi, et ai., Clin. Immunol. Immunopathol. 1989, 51 110-117), 110-117), multidrug resistance (M. Naito, et ai., Cancer Chemother. Pharmacol., 1992, 29 195-200), lymphangiitis (WO 91/17754), cytomegalovirus infection (GB No. 2 247 620A) and idiopathic thrombocytopenic purpura and Graves' disease (WO 91/19495).

Dysregulation of immune regulation has been shown to occur in a variety of autoimmune diseases and chronic inflammations, including systemic lupus erythematosus, chronic rheumatoid arthritis, type I and type II diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, and other conditions such as Crohn's disease, ulcerative colitis, bullous pemphigus, sarcoidosis, psoriasis, ichthyosis, and Graves' ophthalmopathy. Although the pathogenesis of each of these diseases may be different, they share the common feature of the production of numerous autoantibodies and self-reactive lymphocytes. Such autoreactivity may, in part, result in a loss of homeostatic control that allows for normal immune function.

Similarly, after bone marrow or organ transplantation, host lymphocytes recognize antigens of the foreign tissue and begin to produce antibodies, which causes a rejection reaction.

One of the end results of the autoimmune or rejection process is tissue destruction caused by the inflammatory cells and the substances that the cells release. The mechanism of action of anti-inflammatory agents such as NSAIDs (nonsteroidal anti-inflammatory drugs) and corticosteroids is based on the inhibition of these substances.

II activity or secretion, but have no effect on the immune nature of the disease. On the other hand, cytotoxic agents such as cyclophosphamide act so nonspecifically that both normal and autoimmune responses are blocked. Indeed, it is likely that patients treated with such nonspecific immunosuppressants may die from both the infection and the autoimmune disease they are suffering from.

Cyclosporine A, approved by the US Food and Drug Administration (FDA) in 1983, is currently the main drug used to prevent rejection of transplanted organs. The drug works by suppressing the body's immune system, preventing it from mobilizing its vast arsenal of natural defenses to reject the foreign protein in the transplanted organ. Although cyclosporine A is effective in combating transplant rejection, it is toxic to the kidneys and causes some undesirable side effects, such as impaired kidney function, abnormal liver function, and gastrointestinal discomfort.

In this field, there is a constant search for newer, safer drugs with fewer side effects.

Tricyclic, 23-membered macrolide immunosuppressant - tacrolimus, FR-90D506, FK-506,

Ii ii I ii ll 1.1. I

(17-allyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''methoxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone) and similar compounds isolated and characterized by Tanaka, Kuroda and co-workers at Fujisawa Pharmaceutical Co (Japan), see J, Am. Chem. Soc., 1987, 109, 5031 and

U.S. Pat. No. 4,894,366, 1990) , have been shown to have particularly high immunosuppressive activity. Fujisawa in U.S. patents (U.S. Pat. No. 4,929,611, 1990, U.S. Pat.

No. 4,956,352, 1990 and U.S. Pat. No. 45,110,811, 1992) describe the use of FK-506-type compounds to overcome host resistance in organ transplantation. Of particular note is the compound FR-900506, which is reported to be 100 times more effective than cephalosporin in suppressing the immune system in vitro (J. Antibiotics 1987, '40,' 1256). Furthermore, these compounds are known to have local activity in the treatment of inflammatory and hyperproliferative skin diseases and immune diseases affecting the skin (EPO No. 0 315 978).

The compound FK-506 and similar compounds may be useful in the treatment of obstructive airway diseases, especially asthma (WO 90/14826), male pattern or senile alopecia (EPO No. 0 423 714), rheumatoid arthritis (C. Arita, et, ai., Clinical Exp. Immunol. , 1990, 82,

II II II k k

456-461; N. Inamura, 'et ai., Clin. Immunol. Immunopathol. 1988, 46 82-90) incipient diabetes (N. Murase, et ai., Diabetes, 1990, 39 1584-86; N. Murase, et ai., Lancet, posterior uveitis, (H. Kawashima, Vis. Sci., 1988,

1990, 336 373-74),

Invest. Ophthalmol.

29, liver damage associated with ischemic disease et ai., Life Sci., 1990, 47, 687-91),

1265-71), (M. Sakr, allergic encephalomyelitis (K. Deguchi, et al., Brain Nerve, 1990, 42, 391-97), glomerulonephritis (J. McCauley, et al.,

Lancet, 1990, 335 674), systemic lupus (K. Tabaa 1., Clin. Immunol. Immunopathol. 198 9, 51

110-117), multidrug resistance kayashi, et 110-117), (M. Naito, et ai., Cancer Chemother. Pharmacol., 1992, lymphadenopathy and vasculitis cytomegalovirus infection (GB No. 2 (WO

195-200), 91/17754) ,

247 620A) and for the treatment of idiopathic thrombocytopenic rosacea and Graves' disease (WO 91/19495).

A. Purpose of the invention

The novel compound of the present invention (or a pharmaceutically acceptable salt thereof) has the structural formula I:

-i 2

ch ₃ o och ₃ in which

^R1 is:

(1) heteroaryl;

(2) substituted heteroaryl containing substituents X, Y and Z;

(3) heteroaryl-C _{1-10 -alkyl} ;

(4) substituted heteroaryl-C 1-4 -alkyl, wherein the heteroaryl group is substituted with X, Y, and Z and the alkyl moiety may be substituted with one or more substituents selected from:

(a) hydroxyl, (b) oxo, (c) γ-alkoxy, (d) arylC ₁ _ ₃ -alkoxy, (e) substituted arylC ₁ _ ₃ -alkoxy, in which the aryl group is substituted by X, Y and Z, (f) unsubstituted or substituted aryloxy, in which the aryl group is substituted by X, Y and Z, (g) -OCO-C 1 _ 8 -alkyl, (h) -NR R , where R and R independently of each other are optionally (i) hydrogen, (ii) substituted or unsubstituted C 1 _{_ 10} , having one or more substituents, optionally including:

(a') aryl, unsubstituted or substituted by X, Y, Z, (b') heteroaryl, unsubstituted or substituted by X,

Y, Z, (C)-OH,

II I ί,ί ι (d') Vg-alkoxy, (e') -CO ₂ H, (f') -CO ₂ -C ₁ _ ₆ -alkyl, (g') -C ₃ _ ₇ -cycloalkyl and (h') -OR ¹¹ , (iii) C ₃ _ ₁₀ -alkenyl, unsubstituted or substituted by one or more substituents, optionally including:

(a') aryl, unsubstituted or substituted by X, Y, Z, (b') heteroaryl, unsubstituted or substituted by X,

Y, Z, (C) -OH, (d') Ci-g-Alkoxy group, (e') -CO ₂ H, (f') -CO ₂ -C ₁ _ ₆ -alkyl, (g') -C ₃ _ ₇ -cycloalkyl and (h') -OR ¹¹ ,

7 (iv) or when R , R and the N atom to which they are attached form an unsubstituted or substituted 3-7 membered heterocyclic ring which may contain one or two additional heteroatoms independently selected from the group consisting of O, S(O) _p , NR ¹⁴ , where R ¹⁴ is hydrogen or C-._ ₆ -alkyl, unsubstituted or substituted by phenyl, p equal to 0, 1 or 2, for example morpholine, thiomorpholine, piperidine or piperazine, (i) -NR ⁶ -CO ₁ _ ₆ -alkyl-R ⁷ , where R ⁶ and R ⁷ are as defined above, (j) -NR ⁶ CO ₂ -C ₁ _ ₆ -alkyl-R ⁷ , (k) -NR ⁶ -CO-NR ⁶ R ⁷ , (l) -OCONRYR ⁷ , (m) -COOR ⁶ ,

I u (n) (o) (p) (q) (r) (5)

-CHO, aryl, substituted heteroaryl containing substituents X, Y and Z,

-OR ¹¹ , and

-S(O) _p - _{C1-6 -} alkyl;

heteroaryl-C ₁ _ ₁₀ -alkyl, where one or more carbon atoms are replaced by a group selected from: NR ⁶ -, -o-, -S (O) _p -, -CO ₂ , -O ₂ C-, -CONR ⁶ -, -NR ⁶ CO~, nr ⁶ conr ⁷ -,· (6) substituted heteroaryl-C ₁ _ ₁₀ -alkyl, where one or more alkyl carbon atoms are replaced by a group selected from: -NR-,-Ο-, -S(O) _p -, -CO ₂ , heteroaryl

-CONR ⁶ -, -NR ⁶ CO-,

-nr ⁶ conr ⁷ group

-O ₂ C-, the group is substituted with X, Y and Z, and the alkyl group may be optionally substituted with one or more substituents, including:

(a) (b) (c) (d) (e) (f) (g) (h) (i) hydroxyl, oxo,

C ₁ _ ₆ -alkoxy group, arylC ₁ _ ₃ -alkoxy group, substituted arylC ₁ . ₃ -alkoxy group, in which the aryl group is substituted by X, Y and Z, unsubstituted or substituted aryloxy group, in which the aryl group is substituted by X, Y and Z,

-OCO-C _1-6 -alkyl,

-NR ⁶ R ⁷ , where R ⁶ and R ⁷ have the meanings defined above,

-NR ⁶ CO-C ₁ _ ₆ -alkyl-R ⁷ , when the values of R ⁶ and R ⁷ are defined above, t I . I ii 1.1 ,ι J u

(j) -NR ⁶ CO ₂ -C ₁ _ ₆ -alkyl-R ⁷ , (k) -nr ⁶ co-nr ⁶ r ⁷ , (D -oconr ⁶ r ⁷ , (m) -COOR ⁶ , (n) -CHO, (o) aril, (P) replaced aryl, in which there are substitutions X, Y and Z, (q) -OR ¹¹ , and (r) -S (O) p-C^g-alkyl; (7) heteroaryl-C ₃ _ ₁₀ -alkenyl, one to four double some alkenyl bonds; have since (8) heteroaryl-C ₃ _ ₁₀ -alkenyl, when alkenyl have since

one to four double bonds and when one or more alkyl carbon atoms are replaced by a group selected from: -NR ⁶ -, -0-, -S(O) _p ~, -CO ₂ , -O ₂ C-,

-CONR ⁶ -, -NR ⁶ CO-, -NR ⁶ CONR ⁷ -;

(9) substituted heteroaryl-C ₃ _ ₁₀ -alkenyls, where the alkenyl has from one to four double bonds and where one or more alkyl carbon atoms are replaced by a group selected from: -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 with X, Y and Z, and the alkyl group may be optionally substituted with one or more substituents, including:

(a) hydroxyl, (b) oxo, (c) C1-6-alkoxy, (d) aryl- _{C1-3 -} alkoxy, (e) substituted _{arylC1-3 -} alkoxy, in which the aryl group is substituted by X, Y and Z,

I.Uil 1 m III

I I illll'll·!

(f) unsubstituted or substituted aryloxy, in which the aryl group is substituted by X, Y and Z, (g) -OCO-Cf.g-alkyl, (h) -NR R , where R and R are as defined above (i) -NR ⁶ CO-C ₁ _ ₆ -alkyl, in which R ⁶ is as defined above, (j) -NR ⁶ CO ₂ -C ₁ _ ₆ -alkyl, (k) -NR ⁶ CO-NR ⁶ R ⁷ , (l) -OCONR ⁶ R ⁷ , (m) -COOR ⁶ , (n) -CHO, (o) aryl, (p) substituted aryl, in which X, Y and Z are substituted, (q) -OR ^U , and (r) -S (O) p-Cj.g-alkyl;

R can be optionally:

(1) R ¹ values;

(2) hydrogen;

(3) phenyl;

(4) substituted phenyl having substituents X, Y, Z;

(5) 1- or 2-naphthyl;

(6) substituted 1- or 2-naphthyl having substituents X, Y, Z;

(7) biphenyl;

(8) substituted biphenyl having substituents X, Y, Z;

(9) _{C1-10 alkyl} ;

(10) substituted C _{1_10 -alkyl} , optionally having one or more substituents, including:

I

(a) hydroxyl, (b) oxo group, (c) C _x _ ₆ -s what group is it, (d) or i lC ₁ _ ₃ -alco xy group, 5 (e) substituted arylC ₁ _ ₃ -alkoxy group, in which the aryl group is substituted by X, Y and Z, (f) unsubstituted or substituted aryloxy group, in which the aryl group contains substituents X, Y and Z, (g) -OCO-CYg-alkyl, 10 (h) 6 7 6 7 -NR R , where R and R have the meanings defined above, (i) -NR ⁶ CO-C ₁ _ ₆ -alkyl-R', in which R ⁶ and R ⁷ are as defined above, (j) -COOR , with R values as defined above, 15 (k) -CHO, (D phenyl, (m) substituted phenyl having substituents X, Y and Z, (n) 1- or 2-naphthyl, (o) substituted 1- or 2-naphthyl, having substituents X, 20 Y, z, (P) biphenyl, (q) substituted biphenyl having substituents X, Y, Z, (r) OR ¹¹ , and (s) -S(0)p-C1-6-alkyl; 25 - (11) C ₃ . ₁₀ -alkenyl; (12) substituted C ₃ _ ₁₀ -alkenyl optionally having one or more substituents, including: (a) hydroxyl, 30 (b) oxo group, (c) . C ,_ ₆ -s carboxy group,

(d) phenyl-C1-3-alkoxy, (e) substituted phenyl- _{C1-3 -} alkoxy, wherein the phenyl group is substituted by X, Y and Z, (f) -OCO-C1-3-alkyl,

7 6 7 (g) -NR R , where R and R have the meanings defined above, (h) -NR ⁶ CO-C ₁ _ ₆ -alkyl, where R ⁶ has the meanings defined above, (i) -COOR , where R has the meanings defined above, (j) -CHO, (k) phenyl, (l) substituted phenyl having substituents X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl having substituents X, Y and Z, (o) biphenyl, (p) substituted biphenyl having substituents X, Y and Z, (q) -OR ¹¹ , and (r) -S (O)p-C 1.8 -alkyl;

(13) C ₃ _ ₁₀ -alkynyl;

(14) substituted C ₃ _ ₁₀ -alkynyl optionally having one or more substituents, including:

(a) hydroxyl, (b) oxo, (c) C1-6-alkoxy, (d) phenyl- _C1-3 - _alkoxy , (e) substituted phenyl- _{C1-3 -} alkoxy, in which the phenyl group is substituted by X, Y and Z, (f) -OCO-C1-6-alkyl,

Litas

R ⁷ has the values defined above when R is defined (g) -NR ⁶ R ⁷ , where R ⁶ and the values, (h) -NR ⁶ CO-C ₁ _ ₆ -alkyl, above, (i) -COOR ⁶ , where R ⁶ has the values defined above, (j) -CHO, (k) phenyl, (l) substituted phenyl having substituents X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl having substituents X, Y and Z, (o) biphenyl, (p) substituted biphenyl having substituents X, Y and Z, (q) -OR ¹¹ , and (r) -S (O) _p -C ₁ _ ₆ -alkyl;

(15) -R ¹¹ ;

11

R is hydrogen, hydroxy, OR or C1-6-alkoxy;

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

R ⁵ is methyl, ethyl, propyl or allyl;

R ¹⁰ is hydrogen, hydroxy, OR ¹¹ or fluorine;

R ¹¹ can optionally be:

(a) -PO(OH)OM ⁺ , where M ⁺ is a positively charged inorganic or organic ion,

-so ₃ , ”M ⁺ , (b) (C) (d) (i) (ii) (iii) (iv) (v) (vi) (vii) (viii) (ix)

-CO (CH ₂ ) _q CO ₂ ^_ M ⁺ , where q is 1-3, and

-CO-C ₁ _ ₆ -alkyl-NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ have the meanings defined above and the alkyl group may be optionally substituted with one or more substituents, including:

hydroxyl,

CX ₆ -alkoxy group,

-NR ^lu R ¹⁷ , where R ¹⁶ and R ¹⁷ independently of each other can optionally be:

(a') hydrogen, and (b') C1-6-alkyl,

-COOR ⁵ , where R ⁶ is as defined above, phenyl, substituted phenyl having substituents X, Y and Z, heteroaryl,

-SH, and

-SC _{1_6 -} alkyl;

W is O or (H, OH);

X, Y and Z are independently of each other optionally:

(a) hydrogen, (b) C _{1_10 -alkyl} , unsubstituted or substituted by one or more substituents, optionally including:

(i) aryl, (ii) substituted aryl having substituents X', Y' and

Z' , (iii) heteroaryl, (iv) substituted heteroaryl having substituents X', Y' and Z ', (v) unsubstituted or substituted aryloxy radical having substituents X', Y' and Z' in the aryl group, (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 . ₆ -alkyl-R ⁷ , (xiii) -NR ⁶ CO ₂ -C ₁ _ ₆ -alkyl-R ⁷ , (xiv) -NR ⁶ CONR ⁶ R ⁷ , (xv) -OCONR ^e R ⁷ , (xvi) -CONR ⁶ R ⁷ , (c) C,_ ₁₀ -alkyl, where one or more alkyl carbon atoms are replaced by a group selected from: -NR ⁶ -, -O-, -S (O) _p -, -CO ₂ , -O ₂ C-, -CONR ⁶ -, -NR ⁶ CO-,

-NR ⁶ CONR ⁷ -, -CO-, -CH(OH)-, alkenyl or alkynyl and alkyl may be unsubstituted or substituted with one or more substituents optionally including:

(i) aryl, (ii) substituted aryl having substituents X', Y' and Z', (iii) heteroaryl,

I III I 31 III ll I i ui «ι mum t

(iv) substituted heteroaryl having substituents X', Y' and Z' , (v) unsubstituted or substituted aryloxy radical, having substituents X', Y' and Z' in the aryl group, (vi) -OR ⁶ , (vii) -OR ¹¹ , (viii) -OCOR ⁶ , (ix) -oco ₂ r ⁶ , (X) -no. ⁶ and ⁷ , (xi) -CHO, (xii) -AcO-C18-alkyl- ^R7 , (xiii) -NR ⁶ CO ₂ -C ₁ _ ₆ -alkyl-R ⁷ , (xiv) -nr ⁶ conr ⁶ r ⁷ , (xv) -oconr ⁶ r ⁷ , (xvi) -conr ⁶ r ⁷ , (d) halogen, (e) -no. ⁶ and ⁷ , (f) -CN, (g) -CHO, (h) - cf ₃ , (i) 8 8 -SR , where R is hydrogen, C1-8 alkyl, trifluoromethyl or phenyl, (j) -SOR ⁸ , (k) -so ₂ r ⁸ , (D -conr ⁶ r ⁷ , (m) R ⁹ O(CH2)m-, where R ⁹ is hydrogen, C/g-alkyl, hydroxy-C2-3-alkyl, -CF ₃ , phenyl, R ¹¹ or naphthyl and m is 0, 1, 2 or 3, (n) -CH (OR ¹² ) (OR ¹³ ) , where R ¹² and R ¹³ are C ₁ . ₃ -alkyl or together form an ethylenic or propylenic bridge,,

II 11

Oh

(o) R ⁹ CO(CH ₂ ) _m -, where R ⁹ and m meanings defined (P) above, 0 9 f ROC(CH ₂ ) _m -, where R ⁹ and m meanings defined (q) or above, and -R ¹¹ ; any two of X, Yes, Z can to be connected in order to

to form a saturated ring containing 5, 6 or 7 atoms, between the atoms of this ring there are 1 or 2 oxygen atoms, the remaining atoms are carbon, for example, dioxolanil or dioxanil;

X', Y' and Z' are independently of each other optionally:

(a) hydrogen, (b) C ₁ _ ₇ -alkyl, (c) C ₂ _ ₆ -alkenyl, (d) halogen, (e) (CH ₂ ) _m -NR R , where R , R and m are as defined above, (f) -CN, (g) -cho, (h) -CF ₃ , (i) -SR ⁸ , where R ³ is hydrogen, C ₁ _ ₆ -alkyl, trifluoromethyl or phenyl, (j) -SOR , where R is as defined above, (k) -SO ₂ R , where R is as defined above, (l) -CONR ⁶ R ⁷ , where ^R and ^R are as defined above, (m) R ⁹ O(CH ₂ ) _m -, where ^R and m are as defined above, m ui; mum (n) -CH(OR ¹² ) (OR ¹³ ) , where R ¹² and R ¹³ are as defined above,

Oh

II (o) R ⁹ CO (CH ₂ ) _m -, where R ⁹ and m are as defined above,

Oh

II (p) R ⁹ OC (CH ₂ ) _m -, where R ⁹ and m are as defined above, and (q) -R ¹¹ ;

n is 1 or 2.

The compounds of this invention have asymmetric centers and all optical isomers and mixtures thereof are included within the scope of this invention.

Furthermore, compounds containing carbon-carbon double bonds may exist in Z and E forms, and thus all isomeric forms of these compounds are included within the scope of the present invention.

In the event that any variable (e.g., alkyl, aryl, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^u , X, Y, Z, and 1.1.) occurs more than once in any of the variables or in Formula 1, its value at each occurrence is independent of its value at any other occurrence.

The term alkyl, as used herein, includes such alkyl groups having a specified number of carbon atoms, which are straight, branched or cyclic in configuration. Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, secondary and tertiary butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. Alkyl is an alkyl group consisting of the specified number of carbon atoms attached through an oxygen bridge, for example, methoxy, ethoxy, propoxy, butoxy and pentoxy. The term alkenyl includes a hydrocarbon chain consisting of the indicated number of carbon atoms, straight or branched, and containing at least one unsaturated bond, which may be present anywhere in the chain, for example, ethenyl, propenyl, butenyl, pentenyl, dimethylpentenyl, etc., and includes the E and Z forms when present; the term heteroarylalkyl includes heteroaryl groups as defined herein and linked through a straight or branched alkyl chain consisting of 1 to 10 carbon atoms. The term Halogen, as used herein, means fluorine, chlorine, bromine or iodine.

It will be understood by those skilled in the art that pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate, or organic acid salts such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, or palmoate, salicylate, or stearate. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (especially ammonium salts with amines of the formula HNR ^S R ⁷ ).

A heteroaryl group includes, as understood in this invention, acridine, carbazole, cinnoline, dibenzofuran, dibenzothiophene, quinoxaline, pyrazole, indole, benzotriazole, furan, benzofuran, quinoline, isoquinoline, pyrazine, pyridazine, pyridine, pyrimidine, pyrrole, which may or may not be substituted.

I III I II OI I i UI IK I1.UU1

In compounds of Formula 1, any carbon atom or nitrogen atom (if any) in the heteroaryl group may be replaced by X, Y and Z, but compounds in which the nitrogen atom is replaced by some of X, Y and Z may be relatively unstable and are not preferred over others.

The term heteroaryl includes, as understood in this invention, the following heteroaromatic groups which may have X, Y and Z substituents at the indicated positions, when Q is -N(X)-, -O-, -S-, -SO- or _-SO2- :

x.

X.

Y v

X (Pyridazine) (Pyridin)

Y z \nJ (Pyrimidine) (Pyrazine)

X (Cinnoline)

I IBI ί .11 III ; I t III Ιϊ'Iii f III,t

Aryl or aromatic groups may include phenyl or naphthyl, unsubstituted or substituted with 1-3 radicals independently selected from the group consisting of alkyl, alkenyl, halogen, carboxyl, CHO, amino-, mono-alkylamino radical, dialkylaminoalkyl, alkylthio-, alkylsulfinyl, alkylsulfonyl, trifluoromethyl, amide, monoalkylamide, dialkylamide, hydroxy-, hydroxyalkyl, R ¹¹ O-alkyl, alkoxy-, alkoxyalkyl, formamide, formamidoalkyl, alkyl-CO ₂ -, alkyl-CO ₂ -alkyl, carboxyl, acyl-CO ₂ H, alkyl-O ₂ C, alkyl-O ₂ C-alkyl and OR ^U .

For compounds of formula I, heteroaryls selected from the group consisting of:

X

X

and

L i l JI m i i m n: ii m where the values of X are defined above.

In a compound of formula 1, the following values are more suitable:

^R2 is:

(1) hydrogen, (2) methyl, (3) ethyl, (4) propyl, (5) aul, (6) R ¹¹ , (7) _{C2_3 -} alkyl-OH, (8) _{C2-3 -} alkyl- ^R11 ; _ 2 R is: (D hydrogen, (2) hydroxy, (3) -OR ¹¹ ,

R ³ and R ⁴ together form a double bond;

R ¹⁰ is hydrogen, hydroxy, fluorine or -OR ^U ;

W is O; and n is equal to 2.

In one embodiment of the present invention, the heteroaryl is indole, as shown by the following formulas:

I ίΙ

defined above when X, Y, and Z have values.

More suitable examples of this invention are as follows:

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(2-furanyl)methoxy-3''-methoxy-cyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2 , 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(2-furanyl)methoxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-(2-furanyl)-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1 raone;

O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tet17-Ethyl-l, 14-dihydroxy-12-[ 2 ' - (4 ''-(2-thiophene)-methoxy-3''-methoxycyclohexyl)-1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-aza~ tricyclo-[ 22.3.1.0 raone;

4.9.

octacos-18-ene-2,3,10,16-tet17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(2-thiophene)-methoxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2 , 3, 10, 16-tetraone;

I ui ί ji ιι j i f ui .k i»i«

17-Eti1-1,14-dihydroxy-12-[2'(4''-(3-thiophene)-methoxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-L 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-hydroxy-3''-(2thiophene)-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-(3-thiophene)-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

17-Ethyl-1, 14-dihydroxy-12-[ 2'—(4''-(2-thiophene)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(2-benzothienyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-en2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(5-indolyl)oxy3''-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(5-indolyl)oxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14, 20-trihydroxy-12-[ 2'-(4''-(5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl] -23, 25I Ll Ll Ii I! L II III .. Lili dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(5-indolyl)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4''-(5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl)-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4''-(5-indolyl)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-en-2 , 3, 10, 16-tetraone;

17-Allyl-1, 14-dihydroxy-12-[ 2'(4''-(5-indolyl)oxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1, 14, 20-trihydroxy-12-[ 2'-(4(5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1,20-dihydroxy-12-[2'-(4''(5-indolyl)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

I am

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(5-indoII)oxy3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4''-(5-indolyl)oxy3''-ethoxycyclohexyl)-1'-methylvinyl]-23, . 25-dimethoxy13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1-hydroxy-12-[ 2'-(4''-(5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'(4''-(1N-methyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16-tetraone ;

17-Ethyl-1, 14, 20-trihydroxy-12-[ 2'-(4''-(1N-methyl-5indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2 , 3, 10, 16-tetraone;

17-Ethyl-1, 14, 20-trihydroxy-12-[ 2'-(4''-(lN-methyl-5indolyl)oxy-3''-hydroxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-diLT 3533 B oxa-4-azatricyclo[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Ethyl-1, 20-dihydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Eti1-1,20-dihydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

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

17-Allyl-1,20-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1-hydroxy-i2-[ 2'-(4''-(1N-methyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azaLT 3533 B tricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''(1N-ethyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22. 3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16tetraone;

17-Allyl-1-hydroxy-12-[ 2'-(4''-(1N-ethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-l-hydroxy-12-[ 2 ' -(4''-(l-N-methyl-5-indolyl)oxy-3''-allyloxycyclohexyl)-1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4ι ι ι i II 2 1 1 Μ Ι.Ι1Η I.

LT 3533 Β azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Eti1-1, 14-dihydroxy-12-[2'-(4''-(1-N-methyl-5-indolyl)-oxy-3''-propyloxycyclohexyl)-1'-methylvinyl]-23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1-hydroxy-12-[ 2 ¹ -(4 ¹ '-(1N-methyl-5-indolyl)oxy-3''-propyloxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-i-propyloxycyclohexyl)-1'-methylvinyl]23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1.0 ^4.9 ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Ethyl-1, 14-dihydroxy-12-[ 2'(4''-(1N-ethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14, 20-trihydroxy-12-[ 2'-(4''-(lN-ethyl-5indolyl)-oxy-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-en-2, 3, 10,

16- tetraon;

17- Ethyl-l, 20-dihydroxy-12-[ 2'-(4''-(lN-ethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4ΙΙΙ,Ι II UI .1 I II III K mini azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-ethyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1, 14-dihydroxy-12-[ 2'(4'' - (1N-ethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-28-ene-2, 3, 10, 16-tetraone;

17-Allyl-1, .14, 20-trihydroxy-12-[ 2'-(4''-(1N-ethyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28dioxa-4-azatricyclo-[ 22.3 . 1. O ^4,9 ] octacos-18-en-2, 3,

10,16-tetraone;

17-Allyl-1,20-dihydroxy-12-[2'-(4''-(1N-ethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'(4''-(1N-ethyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-l-hydroxy-12-[ 2 ' - (4 ''-(lN-ethyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4I Π ii Iii ii : i ii . utn i azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1-hydroxy-12-[ 2'-(4''-(1N-ethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-t 22.3.1.O ⁴ ' ⁹ ] octacos-18-en-2, 3, 10, 16-tetraone;

17-Allyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-ethyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methyvinyl]-23, 25dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''(1N-propyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14, 20-trihydroxy-12-[ 2'-(4''-(1-N-propyl5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(1N-propyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[ 2'(4''-(1N-propyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl[ -23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone;

m i m

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

17-Ethyl-1, 20-dihydroxy-12-[ 2'-(4''-(1N-propyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16tetraone;

17-Allyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-propyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1, 14, 20-trihydroxy-12-[ 2'-(4''-(1-N-propyl5-indolyl-oxy-3''-methoxycyclohexyl)-1'methylvinyl]23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-f 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16-tetraone;

17-Allyl-1,20-dihydroxy-12-[2'-(4''(1N-propyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O 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''-hydroxycyclohexyl)-1'-methylvinyl]-23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, tetraone;

10, 16LT 3533 B

17-Ethyl-1-hydroxy-12-[2'-(4''-(1N-propyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo© 22.3.1.O ^4,9 ] octocose-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1-hydroxy-12-[ 2'-(4''-(1N-propyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-propyl-5-indolyl)-oxy-3''-texycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^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''-ethoxycyclohexyl)-1'-methylvinyl]-23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-f 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ⁴ ' ⁹ ] octacos-18-en-2 , 3, 10, 16-tetraone;

17-Ethyl-1, 14, 20-trihydroxy-12-[ 2'(4''-(1N-allyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-en-2, 3, 10,

16-tetraone;

17-Ethyl-1, 20-dihydroxy-12-[ 2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16-tet5 raone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-410 azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14, 20-trihydroxy-12-[ 2'-(4 -(1N-allyl-5indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl] 15 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Ethyl-1,20-dihydroxy-12-[2'-(4''-(1-N-allyl-5-indo20 III)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1_. O ^4,9 ] o«ctacose-18-en-2, 3, 10, 16-tetraone ;

17-Allyl-1,14-dihydroxy-12-[2-'(4''-(1N-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1, 14, 20-trihydroxy-12-[ 2'-(4''-(1N-allyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1 ¹ -methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-en-2, 3, 10,

16-tetraone;

I EI

17-Allyl-1,20-dihydroxy-12-[2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1, 14-dihydroxy-12-[ 2'-(4''- (1N-allyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] cktakoz-18-en-2, 3, 10, 16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1-hydroxy-12-[ 2'-(4''-(1N-allyl-5-indolyl)-oxy-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;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23, 25dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1, 14-dihydroxy-12-[ 2'(4' ¹ -(1N-allyl-5-indolyl)-oxy!3''-ethoxycyclohexyl)-1'-methylvinyl]-23, 25dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16-tetraone ;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1-N-2-hydroxyethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2, 3,

10,16-tetraone;

17-Ethyl-1,14,20-trihydroxy-12-[2'-( ^4'1- (1N-2-hydroxyethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] octacos-18-en2, 3, 10, 16-tetraone;

17-Ethyl-l, 20-dihydroxy-12-[ 2'-(4''-(1-N-2-hydroxyethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll,

28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3,

10,16-tetraone;

17-Ethyl-l,. 14-dihydroxy-12-[ 2'-(4''-(1-N-2-hydroxyethyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3,

10,16-tetraone;

17-Ethyl-1, 14, 20-trihydroxy-12-[ 2'-(4''-(lN-2-hydroxyethyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl11, 28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-en2, 3, 10, 16-tetraone;

17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(1-N-2-hydroxyethyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,

28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3,

10,16-tetraone;

17-Allyl-l, 14-dihydroxy-12-[ 2'-(4''-(l-N-2-hydroxyethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll,

28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2, 3,

10,16-tetraone;

17-Allyl-1, 14-dihydroxy-12-[ 2'-(4''-(1-N-hydroxyethyl5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

26-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-benzyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 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-benzyl5-indolyl)-oxy-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-en-2, 3, 10,

16- tetraon;

17- Ethyl-1,20-dihydroxy-12-[2'-(4''-(1-N-benzyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'(4''-(1N-benzyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-l, 14, 20-trihydroxy-12-[ 2 ' - (4''-(1-N-benzyl5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28LT 3533 B dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Ethyl-1, 20-dihydroxy-12-[ 2'-(4''-(1N-benzyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16-tetraone ;

17-Allyl-1, 14-dihydroxy-12-[ 2'-(4''-(lN-benzyl-5-indole)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1.0 ⁴ ' ⁹ ] octacos-18-en-2, 3, 10, 16-tetraone ;

17-Allyl-1, 14, 20-trihydroxy-12-[ 2 ' - (4''-(1-N-benzyl5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Allyl-1, 20-dihydroxy-12-[ 2'-(4''-(1N-benzyl-5-ynidolyl)-oxy-3''-methoxycyclohexyl)-1'methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16-tetraone ;

17-Allyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-benzyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1 ¹ -methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1-hydroxy-12-[ 2'-(4''-(1N-benzyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azaLT 3533 B tricyclo-[ 22.3.1. θ'*' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Allyl-1-hydroxy-12-[2'(4''-(1N-benzyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatric_chloro-[22.3.1. O ^4,9 ] octacos-18-en-2 , 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-benzyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ]-octacose-18-ene-2,3,10,16-tetraone;

17-Allyl-1, 14-dihydroxy-12-[ 2'-(4''-(lN-benzyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1, O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[2'—(4''-(1-N-cyclopropyl5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2 , 3, 10,

16- tetraon;

17- Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1-N-cyclopropyl5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Allyl-l, 14-dihydroxy-12-[ 2' — (4' '-(1-N-cyclopropyl5-indolyl)-oxy-3' '-methoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-diΙ.ΚΙ I . J. UI .1 I I III .Hl «..

oxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-en-2, 3, 10,

16-tetraone;

17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1-N-cyclopropyl5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo-[22.3.1. O ⁴ ' ⁹ ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Ethyl-1, 14-dihydroxy-12-[2'-(4''-(1N-cyclopropylS-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Allyl-1, 14-dihydroxy-12-[ 2'-(4''-(1N-cyclopropylS-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2 , 3, 10,

16- tetraon;

17- Ethyl-1-hydroxy-12-[ 2'-(4''-(1N-cyclopropyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16-tetraone ;

17-Allyl-1-hydroxy-12-[ 2'-(4''-(1N-cyclopropyl-S-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-en-2, 3, 10, 16-tetraone ;

17-Ethyl-1-hydroxy-12-[2'-(4''-(1-N-tryptophanyl-carbonyl-methoxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4I Ii ll iii ,; ι ii u uiihi azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1-hydroxy-12-[2'-14''-(3-indolyl)ethylamino-carbonyl-methoxy-3''-methoxycyclohexyl)-1'-methylvinyl]23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[2'—(4 ¹ '-(3-hydroxypropyl)-indol-5-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll,

28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3,

10,16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(3''-hydroxy-4''-(1-hydroxyethylindol-5-yl)-oxycyclohexyl)-1'-methylvinyl]23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Ethyl-1, 14-dihydroxy-12-[ 2'—(4''-(1-hydroxyethylindol-6-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 1,9, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Ethyl-1,' 14-dihydroxy-12-[ 2' - (4'' - (1-methylindol-6yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo© 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16-tetraone ;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1-dibenzylphosphonoxy-ethylindol-5-yl)oxy-3''-methoxycyclohexyl)-1' methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethylLT 3533 B

11, 28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-en2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1-phosphonoxy-ethylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16- tetraone monopotassium salt;

17- Ethyl-1, 14-dihydroxy-12-[ 2 ' - (4 '' - (1-(N, N-dimethylglycyl-oxy)ethylindol-5-yl)oxy-3''-methoxycyclohexyl )-1'-methylvinyl]-23> 25-dimethoxy-13, 19, 21, 27tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'(4''-(1-succinyloxytylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,

28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3,

10,16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'(4''-(1-methyl-3-phenylindol-5-yl)oxy-3''--methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-137 19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16- tetraon;

17- Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(l-methyl-3-(2-hydroxyethyl)-indol-5-yl)oxy-3''-methoxycyclohexyl)-1' methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl11, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-en2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'(4''-(1,3-dimethylindol5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,

25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4I II azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-en-2, 3, 10, 16-tetraone ;

17-Ethyl-1, 14-dihydroxy-12-[ 2'—(4''-(9'-methylcarbazol3'-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-l, 14-dihydroxy-12-[ 2' - (4 ” - ((2 - (3 '-diethylaminopropionyloxy)ethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1 '-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-((2''''-(3''''-dimethylaminopropionyloxy)ethyl)indol-5'''-yl)oxy-3''-methoxycyclohexyl )-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 17-tetramethyl-ll, 28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2' - (4''-((2'''' - (3'''''aminopropionyloxy)ethyl)indole-5'''-ii)-oxy-3''-methoxycyclohexyl)-1' -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;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-((2''' - (3'''''benzyloxycarbonyl-2'''''-benzyloxycarbonylamino-propionyloxy)ethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1 ' -methylvinyl]-23,25-dimethoxy-13,19, 21, 27tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-((2' ' ' ' - (aspartyloxy)ethyl)indol-5'''-yl)oxy-3''-methoxycyclohexyl)1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetraIII I II III

II Methyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos18-en-2, 3, 10, 16-tetraone:

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-((2'''-( ¹¹ '''-imidazolylcarbonyloxy)ethyl)indol-5'''-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2 ' - (4 ” - ((2 - (1 '''-piperazinecarbonyloxy)ethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo[22.3.1.O ^4,9 ]octacose-18-ene-2,3,10,16-tetraone;

17-Ethyl-l, . 14-dihydroxy-12-[ 2'-(4''- (1'''-(2''''(2'''''-hydroxy)ethylaminocarbonyloxy)ethyl)indol-5'''yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16-tetraone ;

17-Ethyl-1, 14-dihydroxy-12-[ 2' — (4''-(1'''-(2''''-(isopropylaminocarbonyloxy)ethyl)indol-5'''-yl)oxy-3''-methoxycyclohexyl)-1' -methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4-(l'-(2(1'''''-piperidinecarbonyloxy)ethyl)indole-5'''-ii)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[2'-(4''-(1'-(2(1'' ' ' '-morpholinecarbonyloxy)ethyl)indole-5'''-ii)oxy

3''-Methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[2'-(4''-(1'''-(2''''-(diphenylaminocarbonyloxy)ethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-l, 14-dihydroxy-l2-[ 2'-(4''-(l' ^, '-(2''''-(diethylaminocarbonyloxy)ethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1' -methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(l'-(2''' ' - (methanesulfonyloxyethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1 ' -methylvinyl] -23, 25-dimethoxy-13, 19, 21,

27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-l, 14-dihydroxy-12-[ 2'-(4''-(l'''-(2''''-(azidoethyl)indol-5'''-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-en2, 3, 10, 16-tetraone;

17-Ethyl-l, 14-dihydroxy-12-[ 2'-(4''-(l'''-(2''''-(aminoethyl)indole-5'''-ii)oxy-3''methoxycyclohexyl)-1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1.0 ^4,9 ] octacos-18-en2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(l'''-t-butyldimethyl-silyloxyethoxyethyl)indol-5'''-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19,

IIII E .1 III - I II IIIIIILIUl

21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1'''-hydroxyethoxy-ethyl)indol-5'''-yl)oxy-3''-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone;

17-Ethyl-1, 14-dihydroxy-12-[2'-(3''-methoxy-4''-(1'''(1''''-oxoprop-3''''-ii)indol-5'''-ii)oxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27tetramethyl-ll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone; and

17-Ethyl-l,. 14-dihydroxy-12-[ 2'-(3''-methoxy-4'(1''''-carboxyet-2''''-ii)indole-5'''-ii)oxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4.9 ] octacos-18-ene-2, 3, 10, 16-tetraone.

Among the compounds of this invention are compounds of formula X, XI, XII and XIII:

II,

i n n m ių t

XII

OCH ₃ ch ₃ o

ί. Ii

II III i m m,

XIII when ^R is H and R' values are selected from the following groups of substituents:

R ⁶ R ^{7 R2} R ^{3 R5} phenyl phenyl ch ₃ OH ethyl phenyl H ch ₃ OH ethyl benzyl H. ch ₃ OH ethyl 4-HO ₂ C-benzyl H ch ₃ OH ethyl 4-H;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 ₃ OH ethyl 4-( _CH3 ) _2N -benzyl H ch ₃ OH ethyl 3-HO _? C-benzyl H ch ₃ OH ethyl 3-H,NCO-benzyl H ch ₃ OH ethyl 3-CH ₃ O-benzyl H ch ₃ OH ethyl 3-l!O-benzyl H ch ₃ OH ethyl

I UI

UI

3-Cl-benzyl H ch ₃ OH ethyl 3-( _CH3 ) _2N -benzyl H ch ₃ OH ethyl 4-pyridyl H ch ₃ OH ethyl 3-pyridyl H ch ₃ OH ethyl 2-pyridyl H ch ₃ OH ethyl 4-pyridylmethyl H ch ₃ OH ethyl 3-pyridylmethyl H ch ₃ OH ethyl 2-pyridylmethyl H ch ₃ OH ethyl phenyl phenyl ch ₃ H ethyl phenyl H ch ₃ H ethyl benzyl H ch ₃ H ethyl 4-HO ₂ C-benzyl H ch ₃ H ethyl 4-H ₂ NCO-benzyl H ch ₃ 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-( _CH3 ) _2N -benzyl H ch ₃ H ethyl 3-HO ₂ C-benzyl H ch ₃ H ethyl 3-H ₂ NCO-benz ii H ch ₃ H ethyl 3-CH ₃ O-benzyl H ch ₃ H ethyl 3-HO-benzyl H ch ₃ H ethyl 3-Cl-benzyl H ch ₃ H ethyl 3-( _CH3 ) _2N -benzyl H ch ₃ H ethyl 4-pyridyl H ch ₃ H ethyl 3-pyridyl H ch ₃ H ethyl 2-pyridyl H ch ₃ H ethyl 4-pyridylmethyl H ch ₃ H ethyl 3-pyridylmethyl H ch ₃ H ethyl

i—πιτ

- TT—ΤΓΓ

2-pyridylmethyl H ch ₃ H phenyl phenyl ch ₃ OH phenyl H ch ₃ OH benzyl H ch ₃ OH 4-HO ₂ C-benzyl H ch ₃ OH 4-H ₂ NCO-benzyl H ch ₃ OH 4-CH ₃ O-benzyl H ch ₃ OH 4-HO-benzyl H ch ₃ OH 4-Cl-benzyl H ch ₃ OH 4-( _CH3 ) _2N -benzyl H ch ₃ OH 3-HO ₂ C-benzyl H ch ₃ OH 3-H ₂ NCO-benzyl H ch ₃ OH 3-CH ₃ O-benzyl H ch ₃ OH 3-HO-benzyl H ch ₃ OH 3-Cl-benzyl H ch ₃ OH 3-( _CH3 ) _2N -benzyl H ch ₃ OH 4-pyridyl H ch ₃ OH 3-pyridyl H' ch ₃ OH 2-pyridyl H ch ₃ OH 4-pyridylmethyl H ch ₃ OH 3-pyridylmethyl H ch ₃ OH 2-pyridylmethyl H ch ₃ OH CH ₃ H ch ₃ OH ch ₃ ch ₂ H ch ₃ OH ch ₃ ch ₂ ch ₂ H ch ₃ OH ( _CH3 ) _2CH H ch ₃ OH ch ₂ ch ₂ ch ₂ H ch ₃ OH h ₂ ncoch ₂ ch ₂ H ch ₃ OH

ethyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl allyl ethyl ethyl ethyl ethyl ethyl ethyl

HOCH ₂ CH ₂ H ch ₃ OH ethyl high ₂ ch ₂ ch ₂ H ch ₃ OH ethyl ch ₃ ch ₃ ch ₃ OH ethyl ch ₃ ch ₂ ch ₃ ch ₂ ch ₃ OH ethyl ch ₃ ch ₂ ch ₂ ch ₃ ch ₂ ch ₂ ch ₃ OH ethyl high ₂ ch ₂ high ₂ ch ₂ ch ₃ OH ethyl high ₂ ch ₂ ch ₂ high ₂ ch ₂ ch ₂ ch ₃ OH ethyl ch ₃ H ch ₃ H ethyl ch ₃ ch ₂ H ch ₃ H ethyl ch ₃ ch ₂ ch ₂ H ch ₃ H ethyl (CH ₃ ) ₂ ch H ch ₃ H ethyl ho ₂ ch ₂ ch ₂ H ch ₃ H ethyl h ₂ ncoch ₂ ch ₂ H ch ₃ H ethyl high ₂ ch ₂ H ch ₃ H ethyl high ₂ ch ₂ ch ₂ H ch ₃ H ethyl ch ₃ ch ₃ ch ₃ H ethyl ch ₃ ch ₂ ch ₃ ch ₂ ch ₃ H ethyl ch ₃ ch ₂ ch ₂ ch ₃ ch ₂ ch ₂ ch ₃ H eeil high ₂ high ₂ high ₂ high ₂ ch ₃ H ethyl high ₂ ch ₂ ch ₂ high ₂ ch ₂ ch ₂ ch ₃ H ethyl ch ₃ H H OH ethyl ch ₃ ch ₂ H H OH ethyl ch ₃ ch ₂ ch ₂ H H OH ethyl (CH ₃ ) ₂ ch H H OH ethyl ch ₂ ch ₂ ch ₂ H H OH ethyl h ₂ ncoch ₂ ch ₂ H H OH ethyl high ₂ high ₂ H H OH ethyl high ₂ ch ₂ ch ₂ H H OH ethyl

m : ii you ! I. I 11. ί t

ch ₃ ch ₃ H OH ethyl ch ₃ ch ₂ ch ₃ ch ₂ H OH ethyl ch ₃ ch ₂ ch ₂ ch ₃ ch ₂ ch ₂ H OH ethyl high ₂ high ₂ high ₂ high ₂ H OH ethyl high ₂ ch ₂ ch 2 HOCH ₂ CH ₂ CH ₂ H OH ethyl -ch ₂ ch ₂ oh 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 oh ₂ ch ₂ - ch ₃ OH ethyl -ch ₂ ch ₂ ch ₂ ch ₂ ch ₂ - H OH ethyl -ch ₂ ch ₂ oh ₂ ch ₂ - H OH ethyl -ch ₂ ch ₂ ch ₂ ch ₂ ch ₂ - H OH ethyl -ch ₂ ch ₂ oh ₂ ch ₂ - ch ₃ H alyl -ch ₂ ch ₂ ch ₂ ch ₂ ch ₂ - ch ₃ H alyl -ch ₂ ch ₂ oh ₂ ch ₂ - ch ₃ OH alyl -ch ₂ ch ₂ ch ₂ ch ₂ ch ₂ - H OH alyl -ch ₂ ch ₂ oh ₂ ch ₂ - H OH alyl -ch ₂ ch ₂ ch ₂ ch ₂ ch ₂ - H OH alyl

Among the compounds embodying the invention are compounds of formula XIV, XV, XVI and XVII:

I illll III III i ui. ,ι.·ι

XIV ^{11111 1 iu} 1 1' [ ,Κ ! I.

T Tm ^- t τητ | illll III 11 (j I ι .1·· J·· ¹

ch ₃ o

I IIINIHE

ch ₃ o och ₃

I 1131 III II ,1 I I I1L L· L

when R ^6a is H or selected from such CH ₃ , and the substitutions R ² , R ³ , groups: R ⁵ and R ⁶ meanings R ⁶ R ² R ^{3 R5} H CH ₃ OH ethyl ch ₃ ch ₃ OH ethyl ch ₃ ch ₂ ch ₃ OH ethyl ch ₂ =chch ₂ ch ₃ OH ethyl ch ₃ ch ₂ ch ₂ ch ₃ OH ethyl ( _CH3 ) _2CH ch ₃ OH ethyl ch ₂ ch ₂ ch ₂ ch ₃ OH ethyl h ₂ ncoch ₂ ch ₂ ch ₃ OH ethyl high ₂ high ₂ ch ₃ OH ethyl high ₂ ch ₂ ch ₂ ch ₃ OH ethyl _{( CH3} ) _2CH2 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 ₃ OH ethyl 3-pyridylmethyl ch ₃ OH ethyl 2-pyridylmethyl ch ₃ OH ethyl benzyl ch ₃ OH ethyl 4-HO ₂ C-benzyl ch ₃ OH ethyl 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-Cl-benzyl ch ₃ OH ethyl 4-( _CH3 ) _2N -benzyl ch ₃ OH ethyl

is

3-HO ₂ C-benzyl ch ₃ OH ethyl 3-H ₂ NCO-benzyl ch ₃ OH ethyl 3-CH ₃ O-benzyl ch ₃ OH ethyl 3-HO-benzyl ch ₃ OH ethyl 3-Cl-benzyl ch ₃ OH ethyl 3-( _CH3 ) _2N -benzyl ch ₃ OH ethyl 2-HO-benzyl ch ₃ OH ethyl 2-Cl-benzyl ch ₃ OH ethyl 2-( _CH3 ) _2N -benzyl ch ₃ OH ethyl CH ₃ ch ₃ H ethyl cyh ₃ ch ₂ ch ₃ H ethyl ch ₂ =chch ₂ ch ₃ H ethyl ch ₃ ch ₂ ch ₂ ch ₃ H ethyl (CH ₃ ) ₂ ch ch ₃ H ethyl ch ₂ ch ₂ ch ₂ ch ₃ H ethyl h ₂ ncoch ₂ ch ₂ ch ₃ H ethyl high ₂ high ₂ ch ₃ H ethyl high ₂ ch ₂ ch ₂ ch ₃ H ethyl _{( CH3} ) _2CH2 ch ₃ H ethyl phenyl ch ₃ H ethyl 4-pyridyl · ch ₃ H ethyl 3-pyridyl ch ₃ 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 ₃ H ethyl 4-HO ₂ C-benzyl ch ₃ H ethyl

I III! III III! I I I 1. K·I

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-( _CH3 ) _2N -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 ₃ O-benzyl ' ch ₃ H ethyl 3-HO-benzyl ch ₃ H ethyl 3-Cl-benzyl ch ₃ H ethyl 3-( _CH3 ) _2N -benzyl ch ₃ H ethyl 2-HO ₂ C-benzyl ch ₃ H ethyl 2-H ₂ NCO-benzyl ch ₃ H ethyl 2-CH ₃ O-benzyl ch ₃ H ethyl 2-HO-benzyl ch ₃ H ethyl 2-Cl-benzyl ch ₃ H ethyl 2-( _CH3 ) _2N -benzyl ch ₃ H ethyl 2-HO ₂ C-benzyl ch ₃ H ethyl 2-H ₂ NCO-benzyl ch ₃ H ethyl 2-CH ₃ O-benzyl ch ₃ H ethyl 2-HO-benzyl ch ₃ H ethyl 2-Cl-benzyl ch ₃ H ethyl 2-( _CH3 ) _2N -benzyl ch ₃ H ethyl ch ₃ ch ₃ OH alyl _CH3CH ;, ch ₃ OH alyl ch ₂ =chch ₂ ch ₃ OH alyl ch ₃ ch ₂ ch ₂ ch ₃ OH alyl (CH ₃ ) ₂ ch ch ₃ OH alyl

ι ι,ηι. ι .nu iii

I 1 ΗΙΠϋί

ch ₂ ch ₂ ch ₂ ch ₃ OH alyl h ₂ ncoch ₂ ch ₂ ch ₃ OH alyl high ₂ high ₂ ch ₃ OH alyl high ₂ ch ₂ ch ₂ ch ₃ OH alyl _{( CH3} ) _2CH2 ch ₃ OH allyl phenyl ch ₃ OH alyl 4-pyridyl ch ₃ OH alyl 3-pyridyl ch ₃ OH alyl 2-pyridyl ch ₃ OH allyl 4-pyridylmethyl ch ₃ OH allyl 3-pyridylmethyl ch ₃ OH allyl 2-pyridylmethyl ch ₃ OH alyl benzyl ch ₃ OH alyl 4-HO ₂ C-benzyl ch ₃ OH alyl 4-H ₂ NCO-benzyl ch ₃ OH alyl 4-CH ₃ O-benzyl ch ₃ OH alyl 4-HO-benzyl ch ₃ OH alyl 4-Cl-benzyl ch ₃ OH alyl 4-( _CH3 ) _2N -benzyl ch ₃ OH alyl 3-HO ₂ C-benzyl ch ₃ OH alyl 3-H ₂ NCO-benzyl ch ₃ OH alyl 3-CH ₃ O-benzyl ch ₃ OH alyl 3-HO-benzyl ch ₃ OH alyl 3-Cl-benzyl ch ₃ OH alyl 3-( _CH3 ) _2N -benzyl ch ₃ OH alyl ' 2-HO ₂ C-benzyl ch ₃ OH alyl 2-H ₂ NCO-benzyl ch ₃ OH alyl 2-CH ₃ O-benzyl ch ₃ OH alyl

I fili III .11 ;l f I i a. j.Bii

2-HO-benzyl ch ₃ OH alyl 2-Cl-benzyl ch ₃ OH alyl 2-( _CH3 ) _2N -benzyl ch ₃ OH alyl

Among the compounds embodying this invention are compounds of formula XVIII, XIX, XX and XXI:

^{1 ΙΊΙ11} ' ¹ “ll 11 II, III: Hll;

R ^a

XVIII ch ₃ o

III III III

I I ,111,1,11

OH

OCH,

_CH3O

IUI I 1111 OI

E NUIMI Ii

I'm sorry :ι i i

ch ₃ o och ₃

I .01 I 1111 III

when R ^oa is H or selected from such CH ₃ , and the substitutions 71 R, R ² , R ³ groups: and R ⁵ meanings R ^a R ² R ^{3 R5} ch ₃ CH ₃ OH ethyl ch ₃ ch ₂ ch ₃ OH ethyl ch ₂ =chch ₂ ch ₃ OH ethyl ch ₃ ch ₂ ch ₂ ch ₃ OH ethyl ( _CH3 ) _2CH ch ₃ OH ethyl ch ₂ ch ₂ ch ₂ ch ₃ OH ethyl h ₂ ncoch ₂ ch ₂ ch ₃ OH ethyl high ₂ high ₂ ch ₃ OH ethyl high ₂ ch ₂ ch ₂ ch ₃ OH ethyl (CH ₃ ) 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 ₃ OH ethyl 3-pyridylmethyl ch ₃ OH ethyl 2-pyridylmethyl ch ₃ OH ethyl benzyl ch ₃ OH ethyl 4-HO ₂ C0benzyl ch ₃ OH ethyl 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-Cl-benzyl ch ₃ OH ethyl 4-( _CH3 ) _2N -benzyl ch ₃ OH ethyl 3-HO ₂ C-benzyl ch ₃ OH ethyl

I III III 11

Π i I H,ii. L·!:

3-H ₂ NCO-benzyl ch ₃ oh ethyl 3-CH ₃ O-benzyl ch ₃ OH ethyl 3-HO-benzyl ch ₃ OH ethyl 3-Cl-benzyl ch ₃ OH ethyl 3-( _CH3 ) _2N -benzyl ch ₃ OH ethyl 2-HO ₂ C-benzyl ch ₃ OH ethyl 2-H ₂ NCO-benzyl ch ₃ OH ethyl 2-CH ₃ O-benzyl ch ₃ OH ethyl 2-HO-benzyl ch ₃ OH ethyl 2-Cl-benzyl ch ₃ OH ethyl 2-( _CH3 ) _2N -benzyl ch ₃ OH ethyl ch ₃ ch ₃ H ethyl ch ₃ ch ₂ ch ₃ H ethyl ch,=chch ₂ ch ₃ H ethyl ch ₃ ch ₂ ch ₂ ch ₃ H ethyl ( _CH3 ) _2CH ch ₃ H ethyl ch ₂ ch ₂ ch ₂ ch ₃ H ethyl h ₂ ncoch ₂ ch ₂ ch ₃ H ethyl high ₂ ch ₂ ch ₃ H ethyl high ₂ ch ₂ ch ₂ ch ₃ H ethyl (CH ₃ ) ₂ ch ₂ ch ₃ H ethyl phenyl ch ₃ H ethyl 4-pyridyl ch ₃ H ethyl 3-pyridyl ch ₃ H ethyl 2-pyridyl ch ₃ H ethyl 4-pyridylmethyl ch ₃ H ethyl 3-pyridylmethyl ch ₃ H ethyl 2-pyridinium methyl ch ₃ H ethyl

), UI. I 1111 III

I 1 HlM'.ll.t

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-( _CH3 ) _2N -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 ₃ O-benzyl ch ₃ H ethyl 3-HO-benzyl ch ₃ H ethyl 3-Cl-benzyl ch ₃ H ethyl 3-( _CH3 ) _2N -benzyl ch ₃ H ethyl 2-HO ₂ C-benzyl ch ₃ H ethyl 2-H ₂ NCO-benzyl ch ₃ H ethyl 2-CH ₃ O-benzyl ch ₃ H ethyl 2-HO-benzyl ch ₃ H ethyl 2-Cl-benzyl ch ₃ H ethyl 2-( _CH3 ) _2N -benzyl ch ₃ H ethyl ch ₃ ch ₃ OH alyl ch ₃ ch ₂ ch ₃ OH alyl ch ₂ =chch ₂ ch ₃ OH alyl ch ₃ ch ₂ ch ₂ ch ₃ OH alyl (CH ₃ ) ₂ ch ch ₃ OH alyl ch ₂ ch ₂ ch ₂ ch ₃ OH alyl h ₂ ncoch ₂ ch ₂ ch ₃ OH alyl high ₂ high ₂ ch ₃ OH alyl high ₂ ch ₂ ch ₂ ch ₃ OH alyl

I 1119 III 11 l I ^! , lll.l·.·!',

(CH ₃ )' ₂ CH ₂ CH ₃ OH alyl phenyl ch ₃ OH alyl 4-pyridyl ch ₃ OH alyl 3-pyridyl ch ₃ OH alyl 2-pyridyl ch ₃ OH alyl 4-pyridylmethyl ch ₃ OH alyl 3-pyridylmethyl ch ₃ OH alyl 2-pyridylmethyl ch ₃ OH alyl benzyl ch ₃ OH alyl 4-HO ₂ C-benzyl ch ₃ OH alyl 4-H ₂ NCO-benzyl ch ₃ OH alyl 4-CH ₃ O-benzyl ch ₃ OH alyl 4-HO-benzyl ch ₃ OH alyl 4-Cl-benzyl ch ₃ OH alyl 4-( _CH3 ) _2N -benzyl ch ₃ OH alyl 3-HO ₂ C-benzyl ch ₃ OH alyl 3-H ₂ NCO-benzyl ch ₃ OH allyl 3-CH ₃ O-benzyl ch ₃ OH allyl 3-HO-benzyl ch ₃ OH alyl 3-Cl-benzyl ch ₃ OH alyl 3-( _CH3 ) _2N -benzyl ch ₃ OH alyl 2-HO ₂ C-benzyl ch ₃ OH alyl 2-H ₂ NCO-benzyl ch ₃ OH alyl 2-CH ₃ O-benzyl ch ₃ OH alyl 2-HO-benzyl ch ₃ OH alyl 2-Cl-benzyl ch ₃ OH alyl 2-( _CH3 ) _2N -benzyl ch ₃ OH alyl

1111 «I ι ιιιι ι,ι·ε

Among the compounds of this invention are compounds having the formula XVIII:

t îi r i ii n Trr ιι· m iii :ι ι ι Η* 1.1111

LT 3533 B

when X, R , R and R are substituent groups: values are selected from such X ^R2 R ^{3 R5} 1-imidazolylmethyl ch ₃ OH ethyl 2-imidazolylmethyl ch ₃ OH ethyl 3-thiazolylmethyl ch ₃ OH ethyl 2-thiazolylmethyl ch ₃ OH ethyl 2-oxazolylmethyl ch ₃ OH ethyl 5-Tetrazolylmethyl ch ₃ OH ethyl 4-pyridylmethyl ch ₃ OH ethyl 3-pyridylmethyl ch ₃ OH ethyl 2-pyridylmethyl ch ₃ OH ethyl benzyl ch ₃ OH ethyl 4-HO ₂ C-benzyl ch ₃ OH ethyl 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-R ¹¹ 0-benzyl ch ₃ OH ethyl 4-Cl-benzyl ch ₃ OH ethyl 4-( _CH3 ) _2N -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 O-benzyl ch ₃ OH ethyl 3-HO-benzyl ch ₃ OH ethyl 3-R ⁿ 0-benzyl ch ₃ OH ethyl 3-Cl-benzyl ch ₃ OH ethyl 3-( _CH3 ) _2N -benzyl ch ₃ OH ethyl 2-HO ₂ C-benzyl ch ₃ OH ethyl

and—

LUJI

1111 III

II 111111111

2-H ₂ NCO-benzyl ch ₃ OH ethyl 2-CH ₃ O-benzyl ch ₃ OH ethyl 2-HO-benzyl ch ₃ OH ethyl 2-R ⁿ 0-benzyl ch ₃ OH ethyl 2-Cl-benzyl ch ₃ OH ethyl 2-( _CH3 ) _2N -benzyl ch ₃ OH ethyl 3-(4-pyridyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(3-pyridyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(2-pyridyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-phenylimidazol-2-ylmethyl ch ₃ OH ethyl 3-(4-HO ₂ C-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(4-H ₂ NCO-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(4-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(4-HO-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(4-R ^xl O-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(4-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(4-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(3-HO ₂ C-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(3-H ₂ NCO-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(3-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(3-HO-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(3-R ⁿ 0 -phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl 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-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl

3-(2-HO-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(2-R ^{1 :L} 0 -phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(2-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 3-(2-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl ch ₃ OH ethyl 1-imidazolylmethyl ch ₃ H ethyl 2-imidazolylmethyl ch ₃ H ethyl 3-thiazolylmethyl ch ₃ H ethyl 2-thiazolylmethyl ch ₃ H ethyl 2-oxazolylmethyl ch ₃ H ethyl 5-Tetrazolylmethyl ch ₃ H ethyl 4-pyridylmethyl ch ₃ H ethyl 3-pyridylmethyl ch ₃ H ethyl 2-pyridylmethyl ch ₃ H ethyl 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-R ^U 0-benzyl ch ₃ H ethyl 4-Cl-benzyl ch ₃ H ethyl 4-( _CH3 ) _2N -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 ₃ O-benzyl ch ₃ H ethyl 3-HO-benzyl ch ₃ H ethyl 3-R ⁿ 0-benzyl ch ₃ H ethyl 3-Cl-benzyl ch ₃ H ethyl 3-( _CH3 ) _2N -benzyl ch ₃ H ethyl

, H4

III III

I t llllli U HE

2-HO ₂ C-benzyl 2-H ₂ NCO-benzyl ch ₃ ch ₃ H H ethyl ethyl 2-CH ₃ O-benzyl ch ₃ H ethyl 2-HO-benzyl ch ₃ H ethyl 2-R ⁿ 0-benzyl ch ₃ H ethyl 2-Cl-benzyl ch ₃ H ethyl 2-( _CH3 ) _2N -benzyl ch ₃ H ethyl 3-(4-pyridyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(3-pyridyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(2-pyridyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-phenylimidazol-2-ylmethyl ch ₃ H ethyl 3-(4-H0 ₂ C-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(4-H ₂ NC0-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(4-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(4-HO-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(4-R ^u 0-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(4-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(4-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(3-HO ₂ C-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 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-ylmethyl ch ₃ H ethyl 3-(3-R ¹¹⁰ -phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ 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-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl

I III .11! .(I ;i f I canines;

3-(2-HO-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(2-R ⁿ O-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(2-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 3-(2-CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl ch ₃ H ethyl 1-imidazolylmethyl h H ethyl 2-imidazolylmethyl H H ethyl 3-thiazolylmethyl H H ethyl 2-thiazolylmethyl H H ethyl 2-oxazolylmethyl H H ethyl 5-Tetrazolylmethyl 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 4-Cl-benzyl H H ethyl 4-( _CH3 ) _2N -benzyl H H ethyl 3-HO ₂ C-benzyl H H ethyl 3-H ₂ NCO-benzyl H H ethyl 3-CH ₃ O-benzyl H H ethyl 3-HO-benzyl H H ethyl 3-R ^1:L O-benzyl H H ethyl 3-Cl-benzyl H H ethyl 3-( _CH3 ) _2N -benzyl H H ethyl

·1

1111 «I

11ί. !.ί ·1

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 ⁿ 0-benzyl H H ethyl 2-Cl-benzyl H H ethyl 2-( _CH3 ) _2N -benzyl H H ethyl 3-(4-pyridyl)-imidazol-2-ylmethyl H H ethyl 3-(3-pyridyl)-imidazol-2-ylmethyl H H ethyl 3-(2-pyridyl)-imidazol-2-ylmethyl H H ethyl 3-phenylimidazol-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-ylmethyl H H ethyl 3-(4-R ¹¹⁰ -phenyl)-ylmidazol-2-ylmethyl H H ethyl 3-(4-Cl-phenyl)-imidazol-2-ylmethyl 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-ylmethyl H H ethyl 3-(3-R ^xl O-phenyl)-imidazol-2-ylmethyl H H ethyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl H H ethyl 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-CH ₃ O-phenyl)-imidazol-2-ylmethyl H H ethyl

i II·. lll II .iii ’,Ι 1..1.11.

3-(2-HO-phenyl)-imidazol-2-ylmethyl H H ethyl 3-(2-R ⁿ 0 -phenyl)-imidazol-2-ylmethyl H H ethyl 3-(2-Cl-phenyl)-imidazol-2-ylmethyl H H ethyl 3-(2-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl H H ethyl 1-imidazolylmethyl ch ₃ OH alyl 2-imidazolylmethyl ch ₃ OH alyl 3-thiazolylmethyl ch ₃ OH alyl 2-thiazolylmethyl ch ₃ OH alyl 2-oxazolylmethyl ch ₃ OH alyl 5-Tetrazolylmethyl ch ₃ OH alyl 4-pyridylmethyl ch ₃ OH alyl 3-pyridylmethyl ch ₃ OH alyl 2-pyridylmethyl ch ₃ OH alyl benzyl ch ₃ OH alyl 4-HO ₂ C-benzyl ch ₃ OH alyl 4-H ₂ NCO-benzyl ch ₃ OH alyl 4-CH ₃ O-benzyl ch ₃ OH alyl 4-HO-benzyl ch ₃ OH alyl 4-R ^u 0-benzyl ch ₃ OH alyl 4-Cl-benzyl ch ₃ OH alyl 4-( _CH3 ) _2N -benzyl ch ₃ OH alyl 3-HO ₂ C-benzyl ch ₃ OH alyl 3-H ₂ NCO-benzyl ch ₃ OH alyl 3-CH ₃ O-benzyl ch ₃ OH alyl 3-HO-benzyl ch ₃ OH alyl 3-RX-benzyl ch ₃ OH alyl 3-Cl-benzyl ch ₃ OH alyl 3-( _CH3 ) _2N -benzyl ch ₃ OH alyl

2-HO ₂ C-benzyl ch ₃ OH alyl 2-H ₂ NCO-benzyl ch ₃ OH alyl 2-CH ₃ O-benzyl ch ₃ OH alyl 2-HO-benzyl ch ₃ OH alyl 2-R ^u 0-benzyl ch ₃ OH alyl 2-Cl-benzyl ch ₃ OH alyl 2-( _CH3 ) _2N -benzyl ch ₃ OH alyl 3-(4-pyridyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(3-pyridyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(2-pyridyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-phenylimidazol-2-ylmethyl ch ₃ . OH alyl 3-(4-H0 ₂ C-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(4-H ₂ NCO-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(4-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(4-HO-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(4-R ^u 0-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(4-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(4-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(3-HO ₂ C-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(3-H ₂ NCO-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(3-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(3-HO-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(3-R ^xl O-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(3-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(2-HO ₂ O-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(2-H _; NC0-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(2-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl

i IMI III II ' I l II', Lili

3-(2-HO-phenyl)-imidazol-2-ylmethyl CH ₃ OH alyl 3-(2-R ⁿ 0 -phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(2-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 3-(2-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl ch ₃ OH alyl 1-imidazolylmethyl ch ₃ H alyl 2-imidazolylmethyl ch ₃ H alyl 3-thiazolylmethyl ch ₃ H alyl 2-thiazolylmethyl ch ₃ H alyl 2-oxazolylmethyl ch ₃ H alyl 5-te t razolilmet.il ch ₃ H alyl 4-pyridylmethyl ch ₃ H alyl 3-pyridylmethyl ch ₃ H alyl 2-pyridylmethyl ch ₃ H alyl benzyl ch ₃ H alyl 4-HO ₂ C-benzyl ch ₃ H alyl 4-H ₂ NCO-benzyl ch ₃ H alyl 4-CH ₃ O-benzyl ch ₃ H alyl 4-HO-benzyl ch ₃ H alyl· 4-R ¹¹ 0-benzyl ch ₃ H alyl 4-Cl-benzyl ch ₃ H alyl 4-( _CH3 ) _2N -benzyl ch ₃ H alyl 3-HO ₂ C-benzyl ch ₃ H alyl 3-H ₂ NCO-benzyl ch ₃ H alyl 3-CH ₃ O-benzyl ch ₃ H alyl 3-HO-benzyl ch ₃ H alyl 3-R ⁿ 0-benzyl ch ₃ H alyl 3-Cl-benzyl ch ₃ H alyl 3-( _CH3 ) _2N -benzyl ch ₃ H alyl·

I liW

III HI l ϊ Hliu.i·!.

2-HO ₂ C-benzyl CH ₃ H alyl 2-H ₂ NCO-benzyl ch ₃ H alyl 2-CH ₃ O-benzyl ch ₃ H alyl 2-HO-benzyl ch ₃ H alyl 2-R ^u 0-benzyl. ch ₃ H alyl 2-Cl-benzyl ch ₃ H alyl 2-( _CH3 ) _2N -benzyl ch ₃ H alyl 3-(4-pyridyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(3-pyridyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(2-pyridyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-phenylimidazol-2-ylmethyl ch ₃ . H alyl 3-(4-HO ₂ C-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(4-H ₂ NCO-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(4-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(4-HO-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(4-R ^u 0-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(4-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(4-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(3-HO ₂ C-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(3-H ₂ NCO-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(3-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(3-HO-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(3-R ⁿ 0 -phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(3-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(2-H0 ₂ C-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(2-H ₂ NC0-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(2-CH ₃ O-phenyl)-imidazol-2-ylmethyl ch ₃ H ' alyl

i ,aa u ,ιιι ., 1 I. .11. J. 11

3-(2-HO-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(2-R ⁿ 0 -phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(2-Cl-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 3-(2-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl ch ₃ H alyl 1-imidazolylmethyl H OH alyl 2-imidazolylmethyl H OH alyl 3-thiazolylmethyl H OH alyl 2-thiazolylmethyl H OH alyl 2-oxazolylmethyl H OH alyl 5-Tetrazolylmethyl H OH alyl 4-pyridylmethyl H OH alyl 3-pyridylmethyl H OH alyl 2-pyridylmethyl H OH alyl benzyl H OH alyl 4-HO ₂ C-benzyl H OH alyl 4-H ₂ NCO-benzyl H OH alyl 4-CH ₃ O-benzyl H OH alyl 4-HO-benzyl H OH alyl 4-R ¹¹ 0-benzyl H OH alyl 4-Cl-benzyl H OH alyl 4-( _CH3 ) _2N -benzyl H OH alyl 3-H0 ₂ C-benzyl H OH alyl 3-H ₂ NCO-benzyl H OH alyl 3-CH ₃ O-benzyl H OH alyl 3-HO-benzyl H OH alyl 3-R ^i:i O-benzyl H OH alyl 3-Cl-benzyl H OH alyl 3-( _CH3 ) _2N -benzyl H OH alyl

i e·, m 91 ii t t ΊΚ M III

2-HO ₂ C-benzyl H OH alyl 2-H ₂ NCO-benzyl H OH alyl 2-CH ₃ O-benzyl H OH alyl 2-HO-benzyl H OH alyl 2-Yo-benzyl H OH alyl 2-Cl-benzyl· H OH alyl 2-(CH ₃ ) ₂ N-benzyl H OH alyl 3-(4-pyridyl)-imida'ZOl-2-ylmethyl H OH allyl 3-(3-pyridyl)-imidazol-2-ylmethyl H OH alyl 3-(2-pyridyl)-imidazol-2-ylmethyl H OH allyl 3-phenylimidazol-2-ylmethyl H OH alyl 3-(4-HO ₂ C-phenyl)-imidazol-2-ylmethyl H OH alyl 3-(4-H ₂ NCO-phenyl)-imidazol-2-ylmethyl H OH alyl 3-(4-CH ₃ O-phenyl)-imidazol-2-ylmethyl H OH alyl 3-(4-HO-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(4-R ⁿ 0 -phenyl)-imidazol-2-ylmethyl H OH alyl 3-(4-Cl-phenyl)-imidazol-2-ylmethyl H OH alyl 3-(4-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl H OH alyl 3-(3-HO ₂ C-phenyl)-imidazol-2-ylmethyl H OH alyl 3-(3-H ₂ NCO-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(3-CH ₃ O-phenyl)-imidazol-2-ylmethyl H OH alyl 3-(3-HO-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(3-R ⁿ 0 -phenyl)-imidazol-2-ylmethyl H OH alyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl H OH alyl 3-(3-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl H OH alyl 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-CH ₃ O-phenyl)-imidazol-2-ylmethyl H OH alyl

ii m ii l 1 III!, i; !.

3-(2-HO-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(2-R ^u 0-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(2-Cl-phenyl)-imidazol-2-ylmethyl H OH allyl 3-(2-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl H OH alyl 1-imidazolylmethyl H H allyl 2-imidazolylmethyl H H alyl 3-thiazolylmethyl H H alyl 2-thiazolylmethyl H H alyl 2-oxazolylmethyl H H alyl 5-Tetrazolylmethyl H H alyl 4-pyridylmethyl H H alyl 3-pyridylmethyl H H alyl 2-pyridylmethyl H H alyl benzyl H H alyl 4-H0 ₂ C-benzyl H H alyl 4-H ₂ NCO-benzyl H H alyl 4-CH ₃ O-benzyl H H alyl 4-HO-benzyl H H alyl 4-R ^U 0-benzyl H H alyl 4-Cl-benzyl H H alyl 4-( _CH3 ) _2N -benzyl H H allyl 3-H0 ₂ C-benzyl H H alyl 3-H ₂ NC0-benzyl H H alyl 3-CH ₃ 0-benzyl H H alyl 3-H0-benzyl H H alyl 3-R ¹¹ 0-benzyl H H alyl 3-Cl-benzyl H H alyl 3-( _CH3 ) _2N -benzyl H H allyl

I III III II I I H 1111111.1

2-HO ₂ C-benzyl H H alyl 2-H ₂ NCO-benzyl H H alyl 2-CH ₃ O-benzyl H H allyl 2-HO-benzyl H H allyl 2-R ^u 0-benzyl H H alyl 2-Cl-benzyl H H alyl 2-( _CH3 ) _2N -benzyl H H allyl 3-(4-pyridyl)-imidazol-2-ylmethyl H H allyl 3-(3-pyridyl)-imidazol-2-ylmethyl H H allyl 3-(2-pyridyl)-imidazol-2-ylmethyl H H allyl 3-phenylimidazol-2-ylmethyl· H. H alyl 3-(4-HO ₂ C-phenyl)-imidazol-2-ylmethyl H H alyl 3-(4-H ₂ NCO-phenyl)-imidazol-2-ylmethyl H H allyl 3-(4-CH ₃ O-phenyl)-imidazol-2-ylmethyl H H alyl 3-(4-HO-phenyl)-imidazol-2-ylmethyl H H alyl 3-(4-R ⁿ O-phenyl)-imidazol-2-ylmethyl H H alyl 3-(4-Cl-phenyl)-imidazol-2-ylmethyl H H alyl 3-(4-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl H H alyl 3-(3-HO ₂ C-phenyl)-imidazol-2-ylmethyl H H alyl 3-(3-H ₂ NCO-phenyl)-imidazol-2-ylmethyl H H allyl 3-(3-CH ₃ O-phenyl)-imidazol-2-ylmethyl H H alyl 3-(3-HO-phenyl)-imidazol-2-ylmethyl H H alyl 3-(3-R ⁿ O-phenyl)-imidazol-2-ylmethyl H H alyl 3-(3-Cl-phenyl)-imidazol-2-ylmethyl H H alyl 3-(3-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl H H alyl 3-(2-HO ₂ C-phenyl)-imidazol-2-ylmethyl H H alyl 3-(2-H ₂ NCO-phenyl)-imidazol-2-ylmethyl H H allyl 3-(2-CH,O-phenyl)-imidazol-2-ylmethyl H H alyl

·Ι BU II I I Iii. Lili

3-(2-HO-phenyl)-imidazol-2-ylmethyl

3-(2-R ^xl O-phenyl)-imidazol-2-ylmethyl 3-(2-Cl-phenyl)-imidazol-2-ylmethyl 3-(2-(CH ₃ ) ₂ N-phenyl)-imidazol-2-ylmethyl

H H allyl

H H allyl

H H allyl

H H allyl

B. SYNTHESIS OF COMPOUNDS

The starting materials for the synthesis of the compounds of this invention are described 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} radical; R ⁴ is hydrogen, or R ³ and R ⁴ together form a double bond;

R ⁵ is methyl, ethyl, propyl or butyl; and n is equal to 1 or 2.

The preparation and characterization of compounds of formula II are described in the literature (see U.S. Pat. No. 4,894,366, 1990 0116; U.S. Pat. No. 4,929,611, publ. May 29, 1990; U.S.

I Iii lll III 'Ii Iii: H·.L same. No. 3,244,592, ; EPO no. 0 323 042, ; EPO no. 0 356 399,; PBJ 63-17884; J. Am. Chem. Soc., 1987, 109, 5031;

J. Antibiotics, 1987, 40, 1249; J. Antibiotics, 1988,

41(11), 1592; and J. Antibiotics, 1992, 4 5 (1), 118).

Both bioenzymatic and synthetic methods are described. The synthetic route for the preparation of compounds of formula II may involve modifications of the route described in J.Am. Chem. Soc., 1989, lll, 1157.

Biological fermentation and subsequent synthetic modification is currently the most suitable method for the production of compounds of formula II. Organisms belonging to the genus Streptomyces, such as Streptomyces tsukubaensis, No. 9993 and Streptomyces hygroscopicus, var. ascomycetis, No. 14891, placed in an aqueous nutrient medium, produce the desired compounds in quantities that can be isolated. The nutrient medium contains assimilable carbon and nitrogen sources, and aerobic conditions are preferred.

During fermentation, four compounds with formula II are produced:

(A) ,4 when is methyl, hydroxyl, R ⁴ is hydrogen, R ⁵ is allyl and

1 equals 2; hydroxyl equals 2; hydroxyl equals 1.

is O, R is n is 2

(B) when E is methyl, W is 0, R ³ is hi- , R ⁴ is hydrogen, R ⁵ is ethyl and n is 2 (C) when E is methyl, W is 0, R ³ is hi- , R ⁴ is hydrogen, R ⁵ is methyl and n is 2 and (D) when E is methyl, W is 0, — 3 R is

5 is hydroxyl, R is hydrogen, R is allyl and n is

A lyophilized sample of isolated Streptomyces tsukubaensis, No. 9993, was deposited at the Fermentation Research Institute, Agency of Industrial Science and Technology (No. 1-3, Higashi 1-chcme, Yatabemachi Tsukuba-gun, Ibaraki Prefecture, Japan), under deposit No. FERM P-7886 (deposit date: 1984.10.5.), and subsequently, in accordance with the Budapest Agreement, deposited there on 19.10.1985 with a new deposit No. FERM BP-927.

Using the four compounds prepared by the above fermentation method, it is easy to prepare the remaining compounds of formula II. The Aul group in the R ⁵ radical can be easily reduced to propyl by known methods, as described, for example, in U.S. Pat. No. 4,894,366. The hydroxy group in the R ³ radical can be protected by well-known methods, for example, as described in EPO No. 0,323,042. The hydroxy group in the C-4 radical can be protected in an analogous manner. In addition, the hydroxy group in the R ³ radical can be reduced to hydrogen or eliminated, thereby forming a double bond with R ⁴ (these methods are described in U.S. Pat. No. 4,894,366, EPO No. 0,323,042, EPO No. 0,413,532). The carbonyl group in the W radical can be reduced to an alcohol using methods described in EPO No. 0 323 042 or EPO

No. 0 445 975.

The resulting methyl at the E radical can be replaced by hydrogen or demethylated and then suitably protected, if necessary. Such demethylation of compounds in which E is methyl can be carried out by a demethylation reaction using compounds of formula II as the supporting medium. For example, compound A, described above according to formula II, can be demethylated at E using the microorganism Actinomycetales ATCC No. 53771 (described in U.S. Pat. No. 4,981,792) or using the microorganism Streptomyces tsukubaensis, No. 9993 (described in EPO No. 0,353,678). Analogously, compound B, described above according to formula II, can be demethylated at E using the microorganism Actinoplanacete sp., ATCC No. 53771 (described in EPO No. 0,349,061). Furthermore, the compound of formula II, where E is H, W is O, R ³ is 4 5 hydroxy, R is hydrogen, R is ethyl and n | II III || I iu ii. UBUI is equal to 2, can be synthesized directly by fermentation using a mutant microorganism Streptomyces hygroscopicus sup. ascomyceticus, No. 53855 (this microorganism is a blocked mutant of Streptomyces hygroscopicus sup. ascomyceticus, No. 14891

EPO No. 0 388 152). Analogously, (described compound of formula II, where E is H, W is O, R is hydroxy, R ⁴ is hydrogen, R ⁵ is methyl and n is 2, can be synthesized directly by fermentation using a mutant, microorganism Streptomyces hygroscopicus (this microorganism is sup. ascomyceticus, (described EPO No. 0 388 sup. ascomyceticus, No. 53855 Streptomyces hygroscopicus No. 14891 blocked mutant)

153). The hydroxy group at C-3 can be protected using similar methods to those used for protecting hydroxyl groups at ^R3 and/or C-4, as described, for example, in U.S. Pat. No. 4,894,366.

Suitable groups for protecting hydroxyl are well known, for example methylthiomethyl, ethylthiomethyl; trisubstituted groups, for example trimethylsilyl, triethylsilyl, tri-butylsilyl, tri-i-propylsilyl, t-butyldimethylsilyl, tri-t-butylsilyl, methyldiphenylsilyl, ethyldiphenylsilyl, t-butyldiphenylsilyl, etc.; acids, for example acetyl, pivaloylbenzoyl,

4-methoxybenzoyl, 4-nitrobenzoyl and an aliphatic acid substituted with an aromatic group which is a derivative of a carboxylic acid.

Compounds A, B, C and D of formula II, the organisms producing them, fermentation conditions, isolation methods and chemical modification of the products are fully described in U.S. Pat. No. 4,894,366, 1990; U.S. Pat. No. 4,894,366, 1990.

929,611, 1990; U.S. Pat. No. 5,110,811, 1992.

New processes for the production of new compounds according to this invention

12356789 are illustrated below, where R, R, R, R, R, R R,

II 11 .1 I I 1 II.

R ¹⁰ , R ¹¹ , E, W, and n are as defined above unless otherwise indicated. It will be apparent to those skilled in the art, upon consideration of the synthetic route provided below, that other compounds of formula I can be synthesized by substituting the appropriate reagents and agents in the synthetic scheme provided.

I m m :ι ι i u··.

REACTION scheme a

I.

III III

I I III I. II

REACTION SCHEME B

4c 4b

E IL H

REACTION SCHEME B (CONTINUED)

( R ² ) ₃ Bi(OAc) ₂ Cu(OAc) ₂ CH ₂ C1 ₂

4a

5a

4b

5b

IIBIl· IJJLlill

I NIKIU, 10 J

REACTION SCHEME C

I am a HUN.

REACTION SCHEME D

2b

IIIIJIH !J

100 reaction scheme e

4c

4b

1I0UI 1111

I I ί AL I, I

101

REACTION SCHEME E (CONTINUED)

a'

4a'

4b‘ b*

REACTION SCHEME F

III· m I: : I ! I JU !,

102

Θ

REACTION SCHEME G

Ulll UUI

Hey! IU ί i, Kl

103

ch ₃ o och.

,i Oh oh, weaves

EtjO

ch ₃ o och ₃

1111 3111111 III E 11

I 11. »11 i U I

104

REACTIONS

DIAGRAM G (CONTINUED)

REACTION SCHEME H iubiili mm ι

E I L1IJ I , Kl

105

CH ₃ O och ₃

K(Ph) ₃ BH

THF

5

illllll 11.1 L I; . 1 LlJlI bH

106

REACTION SCHEME I

ch ₃ o och, ,10

,10

Illll I1U1II1IH

II! i, ft i.

107

REACTION SCHEME J

8'

8

I ·ΙΙΙΙ iJIEIIIJ.L · , I n.u ;; i

108

REACTION SCHEME J (CONTINUED)

9

UI 11.11 n.

REACTION SCHEME J

109 (CONTINUED)

_CH3O

ΗΙ.Ι IHIUllIilE ί; , Louis I

110

REACTION SCHEME J (CONTINUED)

HF-pyridine

THF

TO MII lllll :ll 1 ΙΙ,ΗΙΙ.I,; KJ

111

Reaction Scheme A:

As shown in Reaction Scheme A, a solution of 4''-hydroxy-3''methoxymacrolide in an inert organic solvent such as methylene chloride, benzene, toluene, chloroform or the like or a mixture thereof is treated with triheteroaryl bismuth diacetate (wherein R ¹ is heteroaryl) (synthesized immediately before use by adding acetic acid to triheteroaryl bismuth carbonate in an inert organic solvent such as methylene chloride, chloroform or the like or a mixture thereof) in the presence of a catalytic amount of copper (II) acetate and a temperature of 20-50°C, preferably room temperature, for a period of from one hour to seven days, more preferably one day, to provide 4''-O-heteroaryl-3''-methoxymacrolide 2. Alternatively, the triheteroaryl bismuth(V) reagent can be synthesized by treating the triheteroaryl bismuthine with a suitable oxidizing agent such as peracetic acid, benzoyl peroxide, iodobenzenediacetate, bis(trifluoroacetoxy)iodobenzoic acid, and the like, in an inert solvent such as methylene chloride, chloroform, benzene, toluene, or the like, or a mixture thereof. The triheteroaryl bismuth(V) reagent may be used without purification or may be purified by chromatography on silica gel. Triheteroaryl bismuthines may be prepared by reacting the appropriate heteroaryl Grignard reagent or heteroaryl lithium derivative with bismuth trichloride in an inert organic solvent such as tetrahydrofuran, diethyl ether, toluene, or 1,4-dioxane, or a mixture thereof, for a period of time from 1 hour to 48 hours at or near room temperature. General procedures for the synthesis and use of triaryl bismuth reagents are provided in Barton, D.H.E., et al., J. Chem. Soc. Chem. Commun., 1986, 65 and in the works cited herein.

112

I : 1.01! · a

Reaction Scheme B:

As shown in Reaction Scheme B, 3'',4''-dihydroxy macrolide 3 is treated with triheteroaryl bismuth diacetate as described in Reaction Scheme A. This gives a mixture consisting of 3''-hydroxy-4''-O-heteroaryl macrolide 4a, 3''-O-heteroaryl-4''-hydroxymacrolide 4b and 3'',4''-di-O-heteroaryl macrolide 4c. At this stage, a solution of 3''-hydroxy-4''-O-heteroaryl macrolide 4a or 3''-O-heteroaryl-4''-hydroxymacrolide 4b can be treated with triarylbismuth diacetate (prepared immediately before use according to the procedures outlined above) to yield 3''-O-aryl-4''-O-heteroaryl macrolide 5a, or 3''-O-heteroaryl-4''-O-aryl macrolide 5a, respectively.

Reaction Scheme C:

As shown in Reaction Scheme C, the 14-hydroxy group in macrolide 5a or 5b (wherein R ¹ , R ² , R ⁵ , R ¹⁰ , W, and n are as defined above) can be eliminated by treatment with p-toluenesulfonic acid, benzenesulfonic acid, or methanesulfonic acid in an inert organic solvent, such as benzene or toluene, at a temperature of from 40°C to 60°C for about 0.5 to 6 hours or for a time sufficient to eliminate the 14-hydroxy group. After neutralization with an aqueous solution of a weak base, such as an aqueous saturated solution of sodium bicarbonate, the 14,15-dehydromacrolide 6a or 6b is obtained. Alternatively, the 14-hydroxy group can be eliminated by activation and subsequent elimination with a base, as described in U.S. Pat. No. 4,894,366.

By changing the sequence of synthesis steps, all substitution variations can be obtained.

l· Iii ,. s

113

Reaction Scheme D:

As shown in the reaction scheme D, 4''-hydroxy-3'' methoxymacrolide in solution in an inert organic solvent such as methylene chloride, chloroform, pentane, hexane, cyclohexane, heptane or a mixture thereof, is treated with a heteroarylalkyl, heteroarylalkenyl or heteroarylalkynyl trichloroacetimidate reagent (prepared by reacting the appropriate sodium alkoxide with trichloroacetonitrile as described in Wessel, H.P., Iversen, T., Bundle, D.R., J. Chem.Soc., Perkin Trans. I, 1985, 2247), in the presence of a mild acid catalyst such as trifluoromethanesulfonic acid, p-trifluoromethanesulfonic acid, methanesulfonic acid or mixtures thereof, at a temperature of 20°-50°C for a period of time from 1 hour to seven days, to give 4''-O-heteroarylalkyl-, 4''-O-heteroarylalkenyl- or 4''-O-heteroarylalkynyl-3''-methoxymacrolide 2a.

Reaction scheme E:

Analogously to Reaction Scheme E, 34''-dihydroxymacrolide _3_ in an inert organic solvent such as methylene chloride, chloroform, pentane, hexane, cyclohexane, heptane or a mixture thereof is treated with a heteroarylalkyl, 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 time from 1 hour to seven days, preferably 6 hours, to give a mixture consisting of 4''-O-heteroarylalkyl-, 4''-O-heteroarylalkenyl- or 4''-O-heteroarylalkynyl3''-hydroxymacrolide 4a ¹ , 3''-O-heteroarylalkyl-, 3''O-heteroarylalkenyl- or 3''- O-heteroarylquinyl-4-hydroxymacrolide 4b' and 3'',4''-di-O-heteroarylalkyl-,

IMU IIUI JI II! SI .1 II

114

3'',4''-di-O-heteroarylalkenyl- and 3'',4''-di-O-heteroarylalkynyl macrolide 4c'. Subsequently, a solution of 4''-O-heteroaryl-, 4''-O-heteroarylalkyl-, 4''-O-heteroarylalkenyl- or 4 ''-O-heteroarylalkynyl-3''-hydroxymacrolide 4a from Reaction Scheme B or 4a', or a solution of 3''-O-heteroaryl-, 3 ¹ '-O-heteroarylalkyl-, 3''-O-heteroarylalkynyl- or 3''-O-heteroarylalkynyl-4''-hydroxymacrolide 4a from Reaction Scheme B or 4b', can be treated with an arylalkyl-, alkenyl-, or alkynyltrichloroacetimidate according to the procedures described above) to yield macrolide 5a ¹ or 5b ¹ .

The procedures described in Reaction Schemes C and D can be, if necessary, carried out according to the procedures described in Reaction Scheme E or F. Alternatively, the procedures described in Reaction Scheme F can be carried out.

The macrolide in each of the above reaction schemes (wherein R and/or R contains alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and where R ³ is hydroxy or C 1-6 alkoxy, R ⁴ is hydrogen, or R ³ and R ⁴ together form a double bond) can be reduced to the reduced macrolide by treatment with tri-n-butyltin hydride in the presence of a tetrakis(triphenylphosphine)palladium(O) catalyst and acetic acid in an organic solvent such as toluene or tetrahydrofuran at near room temperature for a period of 2 to 10 hours.

The procedures described in Reaction Scheme F can be performed on monosubstituted products of Reaction Scheme B (and vice versa) to synthesize mixed disubstituted products. Indeed, in Reaction Schemes B and F, treatment of monosubstituted products with different reagents can yield mixed disubstituted products.

115

Reaction scheme F:

The hydroxyl groups at C-3'', C-4'' and/or C-14 can be protected by known methods applied to compounds of formula II, for example, by treatment with 2,6-lutidine and triisopropylsilyl trifluoromethanesulfonate in methylene chloride solution; 2,6-lutidine and t-butyldimethylsilyl-trifluoromethanesulfonate in methylene chloride solution; pyridine and acetic anhydride in methylene chloride solution; pyridine and p-nitrobenzoyl chloride in dichloromethane solution; imidazole and t-butyldiphenylsilyl chloride in methylene chloride solution; and the like. For example, as shown in Reaction Scheme F, the C-4'', 14-dihydroxy-C-3 ' ' -methoxy macrolide Ί_ can be protected at the C-14 position as a t-butyldimethylsilyl ether by treatment with t-butyldimethylsilyltrifluoromethanesulfonate in methylene chloride solution to give the C-4'', 14-diO-TBDMS macrolide. Treatment with toluenesulfonic acid in methanol selectively removes the C-4'' ether to give the C-14-O-TBDMS macrolide 8.

Reaction scheme G:

As shown in Reaction Scheme G, 4''-hydroxy-3''R ² 0-macrolide J3 or 3 ''-hydroxy-4''-R ² 0-macrolide (not shown in the scheme) (where R ³ is a protected hydroxyl or hydrogen) can be reacted with alkenyl trichloroacetimidate (where alkenyl is C ₃ _ ₁₀ alkenyl) under the conditions shown in Reaction Scheme E to afford O-alkenyl macrolide 10 . Treatment with a stoichiometric amount of osmium tetroxide in an inert organic solvent such as diethyl ether or tetrahydrofuran, with an amino base such as pyridine at room temperature or near room temperature affords the corresponding glycol 11 (where A is C _x _ ₈ alkyl). Treatment of glycol, 11 with sodium metaper iodate in a tetrahydrofuran/'water mixture yields aldehyde 12. Alternatively, alkenylιαηιι JUU.JIIt ii ii ..mmi,

116 Macrolide 10 can be treated with sodium metaperiodate in the presence of catalytic amounts of osmium tetroxide in an organic solvent to give the aldehyde directly. Aldehyde 12 can be further oxidized to the carboxylic acid 13 by any known method.

Reaction scheme H:

As shown in Reaction Scheme H, a wide range of compounds can be synthesized from aldehyde 12. Reaction of aldehyde 12 with primary or secondary amines, HNR R (wherein ^R and/or ^R are as defined above and contain a heteroaryl group) in an organic solvent such as tetrahydrofuran affords an imine which is reduced in situ with a hydride reducing agent such as sodium cyanoborohydride to afford macrolide 14 containing an aminoalkoxy group at the C-4'' position. Aldehyde 12 can be reduced to the corresponding alcohol 15 by treatment with a hydride reducing agent such as potassium triphenylborohydride or sodium cyanoborohydride in an organic solvent such as tetrahydrofuran. Alcohol 15 can then be modified using the methods shown in Reaction Scheme B (where R ¹ has the values defined above) or in Reaction Scheme E to give macrolide 116. The procedures described in Reaction Scheme H can be readily adapted to the synthesis of compounds containing analogous groups at the C-3'' position.

Reaction scheme I:

Amide derivatives can be synthesized from carboxylic acid 13 according to reaction scheme I. Carboxylic acid 13 can be coupled to a primary 6 7 6 7 or secondary amine, HNR R (where R and/or R are as defined above and contain a heteroaryl group) by any commonly used peptide coupling method, such as BOP reagent or DCC/HOBT.

I Ι·ΙΙ!Ι HUi 1.

J Ji UI! . i B ;

Reaction scheme J:

117

Hydroxyl or fluorine can be introduced at the C-20 position using the procedures outlined in Reaction Scheme I. As shown in Reaction Scheme R, the 4'14-dihydroxymacrolide (or 14-deoxymacrolide) is protected as a di(t-butyldimethylsilyl ether) by treatment with t-butyldimethylsilyl triphosphate 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 disubstituted macrolide is oxidized at the C-20 position by treatment with selenium dioxide in an alcoholic solvent such as ethanol in the presence of pyridine at the boiling point of the solvent to give the 20-hydroxymacrolide (18). The 20-hydroxymacrolide is then derivatized at the C-20 position by alkylation, acylation or phosphorylation and, using methods known to those skilled in the art, to give ether, ester or phosphate derivatives. It is further shown that treatment of 20-hydroxy-4'',14-di-OTBS-macrolide with diethylaminesulfonyltrifluoride in an inert organic solvent such as methylene chloride, chloroform or the like at a temperature of about 0°C to -90°C, preferably -78°C, affords 20-fluoro-4, 14-di-OTBS macrolide (19). Removal of the silyl ether protecting groups by treatment with hydrogen fluoride-pyridine complex in tetrahydrofuran affords 20-fluoro-4, 14-dihydroxymacrolide, which can then be derivatized by any of the methods previously described. The procedures outlined in Reaction Scheme J can also be performed on 3'',4'',14-trihydroxymacrolide to afford 20-fluoro-3'',4'',14-trihydroxymacrolide. The procedures set forth in Reaction Scheme J may be carried out before, in conjunction with, or after the procedures set forth in Reaction Schemes A-I.

The target compounds of formula I obtained by the reactions explained above can be isolated and

I· FOR HILL I 'i I I J, 101· ί

118 purified by known methods, such as extraction, precipitation, fractional crystallization, recrystallization, chromatography, etc.

In compounds of formula I, OR ¹ may be substituted at the C-4'' or C-3'', or C-4'' and C-3'' positions (where R ² is independently selected from the values of R ¹ ), but preferably -OR ¹ is substituted at the C-4'' position.

It should be emphasized that during the above-mentioned reactions and during the processes occurring in the reaction mixture after the reaction, the stereoisomers of the starting materials and final products, due to the presence of asymmetric carbon atoms or double bonds in the final products having formula I, may sometimes transform into other stereoisomers, and such cases are also included in the scope of this invention.

In the present invention, compounds having asymmetric centers may be in the form of racemates, mixtures of diastereomers and individual isomers, and all isomeric forms are included in the present invention. They may be synthesized using methods which are, for example, indicated in publications describing the synthesis routes of macrolide FR-900506 fragments and the total synthesis of macrolide FR-900506 itself (J. Am. Chem. Soc. , 1989, 111, 1157; J. Am. Chem. Soc. 1990, 112, 2998; J. Org. Chem. 1990, 55, 27 86; J. Am. Chem. Soc. 1990, 112, 5583; Tetrahedron

Lett. 1988, 29, 277; Tetrahedron Lett. 1988, 29, 3895; 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. 1988,

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.

ιι·ιιιι To Linus,ι

119 1989, 30, 6963; Synlett 1990, 38; J. Org. Chem. 1990, 55, 2284; J. Org . Chem. 1990, 55, 2771; J. Org. Chem. 1990, 55, 2776; Tetrahedron Lett. 1990, 31, 1439; Tetrahedron Lett . 1990, 31, 3007; Tetrahedron Lett. 1990, 31, 3283, 3287) . The compounds of this invention may form salts with children-

various inorganic and organic acids and bases and such salts are also included in the compounds of the present invention. Examples of salts of such acids (which are negative counterions and are designated herein as M') may include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, methanesulfonate, lactate, maleate, 2-naphthalenesulfonate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate and undecanoate. Basic salts (which are positive counterions and are designated herein as M ⁺ ) may include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups may be quaternized with the following agents: lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates including dimethyl, diethyl, dibutyl, and diamyl sulfates; long-chain halides including decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides such as benzyl bromide, etc. Non-toxic physiologically acceptable salts are preferred, although other salts are also useful, for example in isolating or purifying the product.

Ι ·ιυι UIUilHI 'i I II JII JII·

120

Salts can be prepared by standard methods, for example by reacting the product as a free base with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by lyophilization, or by exchanging the anion of the existing salt for another anion on a suitable ion exchange resin.

C. Use of the compounds according to the present invention.

The compounds of formula I can be used as immunosuppressants or antimicrobial compounds according to methods and in dosages known and indicated for compounds of formula I. These compounds exhibit pharmacological activities, such as antimicrobial activity, and the like, and are therefore useful in the treatment and prevention of transplant resistance or rejection of transplanted organs or tissues (e.g., heart, kidney, liver, lung, bone marrow, cornea, pancreas, small intestine, limbs, muscle, nerve, bone marrow, skin, pancreatic islet cells, etc., including xenotransplantation), in the treatment of graft-versus-host disease by bone marrow transplantation, in the treatment of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, nephrotic lupus syndrome, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes mellitus, type II adult-onset diabetes, uveitis, steroid-dependent nephrotic syndrome, and steroid-dependent resistant nephrosis, palmar and sole purulent rash, allergic encephalomyelitis, glomerulonephritis, and 1.1., and infectious diseases caused by pathogenic microorganisms.

Compounds of formula I are also useful in the treatment of inflammatory, proliferative and hyperproliferative skin diseases and manifestations of immune disorders.

j ji ui 111

121 on the skin, for example psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigus, bullous epidermolysis, urticaria, angioedema vasculitis, erythema, cutaneous eosinophilia, acne, alopecia areata, eosinophilic fasciitis and atherosclerosis. The compounds of formula I are particularly useful for hair regeneration, for example in the treatment of male or female pattern alopecia or senile alopecia, for the prevention of epilation, for the maturation of hair and/or for the promotion of hair formation and growth.

Compounds of formula I are also useful in the treatment of respiratory diseases, such as sarcoidosis, pneumosclerosis, idiopathic interstitial pneumonia and reversible obstructive airway diseases, including asthma, including bronchial asthma, allergic asthma, hereditary asthma, acquired asthma, dust asthma, especially chronic intractable asthma (for example, late-onset asthma and airway hypersensitivity), bronchitis, etc. Compounds of formula I may also be useful in the treatment of liver damage associated with ischemic disease.

The compounds of this invention are also suitable for use in certain eye diseases, such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, keratoconus, corneal epithelial dystrophy, corneal leucoma, eye cyst, Moreno's ulcer, scleritis, Graves' ophthalmopathy, severe intraocular inflammation, etc.

Compounds of formula I are also useful in the treatment of multiple drug resistance of cancer cells (i.e., increasing the activity and/or sensitivity of chemotherapeutic agents), inflammation of the mucosa or blood vessels or its proI ·Ι1ΙΙ iBLIlII; i! I I . .11B J EI« ί

122 phylacteries (e.g., leukotriene B _4- mediated diseases, gastric ulcers, vascular damage due to ischemic disease and thrombosis, ischemic bowel disease (e.g., Crohn's disease and ulcerative colitis, necrotizing enterocolitis, or intestinal damage associated with thermal burns, cytomegalovirus infection, especially HCMV infection.

Furthermore, the compounds of formula I are useful in the treatment and prevention of kidney diseases, including interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome and diabetic nephropathy; nervous diseases, including multiple myositis, Guillain-Barre syndrome, Meniere's disease and radiculopathy; endocrine diseases, including hyperthyroidism and Graves' disease; blood diseases, including pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia; bone diseases, including osteoporosis; respiratory diseases, including sarcoidosis, pneumofibrosis and idiopathic interstitial pneumonia; skin diseases, including dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T-cell lymphoma; circulatory diseases, including arteriosclerosis, aortitis, multiple arteritis nodosa and myocarditis; collagenous scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease; nephrotic syndrome; haemolytic uraemic syndrome and muscular dystrophy.

Furthermore, the compounds of the present invention are useful in the treatment of diseases such as gastrointestinal inflammation and allergies, such as Celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food-related allergic diseases,

I IBIUI uui«jjjj i.

1.1: Hll):: a

123 with symptomatic manifestations outside the digestive tract, such as migraine, rhinitis and eczema.

The compounds of the present invention also exhibit liver regenerative activity and/or exhibit activity in stimulating hepatocyte hypertrophy and hyperplasia. Therefore, they are useful in the treatment and prevention of liver diseases, such as immunogenic diseases (including chronic autoimmune liver diseases such as autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (such as toxin-induced necrosis, viral hepatitis, shock or anoxia), hepatitis B, non-A and non-B hepatitis and cirrhosis.

The compounds of this invention are useful as antimicrobial agents, and therefore can be used in the treatment of diseases caused by pathogenic microorganisms and other similar cases.

Compounds of formula I may act as antagonists of macrocyclic immunosuppressants, including 12(2'-cyclohexyl-1 ¹ -methylvinyl)-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos18-ene derivatives, and thus be useful in the treatment of immunodepression (for example, AIDS, cancer, senile dementia, trauma (including wound healing, surgery and shock), chronic bacterial infection and some central nervous system disorders), immunosuppressant overdose or toxicity, and as an adjuvant in vaccination.

The pharmaceutical compositions of the present invention may be used in the form of pharmaceutical preparations, such as solid, semi-solid or liquid forms, containing one or more compounds of the present invention as active ingredients in admixture with organic or inorganic carriers or

I fllll: llfil.111 li .11 i .11 . I lli l·

124 excipients suitable for topical, enteral or parenteral use. The active ingredient may be combined with, for example, conventional non-toxic, pharmaceutically acceptable carriers for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. Carriers used include water, glucose, gelatin, mannitol, starch paste, magnesium trisilicate, talc, keratin, colloidal silicon, potato starch, urea and other carriers suitable for use in the manufacture of preparations which may be solid, semi-solid or liquid; in addition, adjuvants, stabilizing, thickening and coloring agents and flavorings may be used. For example, compounds of formula I may be used with hydroxypropyl methylcellulose as described in U.S. Pat. No. 4,916,138, 1990, or with a surfactant as described in EPO No. 0,428,169. Oral dosage forms may be prepared as described in T. Hondo, et al., Transplantation Proceedings, 1987, XIX, Supp. 6, 17-22. Dosage forms for topical use may be prepared as described in EPO No. 0,423,714. The pharmaceutical composition comprises an amount of the active target compound sufficient to achieve the desired effect, depending on the process or disease state.

Compounds of formula I used in the treatment of disorders and diseases caused by disorders of the immune system can be administered orally, topically, parenterally, by inhalation, by nebulization, or rectally. Their dosage units contain conventional non-toxic, pharmaceutically acceptable carriers, adjuvants, and excipients. The term parenteral as used herein refers to subcutaneous injections, intravenous, intramuscular, intrasternal injections, or infusion procedures.

lllll flIUIILIE i with. > i a i

125

In the treatment of reversible obstructive airway disease, it is more suitable to use a compound of formula I for inhalation into the lungs, particularly in powder form.

In order to modify the activity and/or toxicity of FK-506-type immunosuppressants, a compound of formula I may be administered before, together with, or after administration of the FK-506-type compound.

Compounds of formula I can be used in combination therapy with an antiproliferative agent selected from the group consisting of: azathioprine brequinar sodium, deoxysperguaine, misaribine, mycophenolic acid morpholino ester, cyclosporine, and rapamycin.

The dosages of the compounds of the present invention are from about 0.005 mg to about 50 mg per kilogram of body weight per day, more preferably from about 0.1 mg to about 10 mg per kilogram of body weight per day. Such dosages are useful for the above indications (from about 0.7 to about 3.5 mg per patient per day, assuming a patient weight of 70 kg). Furthermore, the compounds of the present invention can be administered on an intermittent basis; i.e. daily, semi-weekly, weekly, semi-monthly or monthly.

The amount of active ingredient that may be combined with the carrier to produce a single dosage form will vary depending on the subject being treated and the route of administration. For example, a formulation for oral administration to humans may contain from 0.5 mg to 5 g of active compound in admixture with an appropriate and conventional amount of carrier ranging from about 5 to 95% of the total composition. A dosage unit will generally contain from about 0.01 mg to about 500 mg, more preferably from about 0.5 mg to about 100 mg of active compound.

126 threads. In a preparation intended for topical use, the amount of the compound of formula I in the formulation may be

from 0.0001% until 60% by weight, more suitable quantity from 0.001 to 10 % by weight, most suitable quantity 5 from 0.005 to 0.8 % by weight.

It is understood that the specific dosage for each patient depends on a variety of factors, including the activity of the compounds being administered, the individual's age, body weight, general health, gender, diet, time and route of administration, rate of excretion, drug combinations, and the severity of the condition being treated.

The following examples are merely illustrative of the present invention and should not be construed as limiting the scope or spirit of the present invention.

127

SYNTHESIS OF STARTING MATERIALS AND INTERMEDIATES

17-Ethyl-1-hydroxy-12-[2'-(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl·]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azartricyclo[ 22.3.1. O ⁴ ' ⁹ ] -octacose-18-ene-2, 3, 10, 16-tetraone

Solution containing 500 mg of 17-Ethyl-1,14-dihydroxy12-[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 7 ml of benzene were treated with 10 mg of p-toluoylsulfuric acid and heated at 60°C for two hours. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was chromatographed over silica gel (66% ethyl acetate: 33% hexane: 1% methanol) to give 350 mg of product. This material was dissolved in 10 ml of ethyl acetate and reduced in the presence of 15 mg of 5% Rh/C. Hydrogen was bubbled through the reaction mixture and stirred until the reaction was complete. The mixture was filtered through diatomaceous _earth , concentrated and the residue chromatographed (75% _CH2Cl2 :5% MeOH:20% hexane) to give 294 mg of product.

17-Ethyl-1-hydroxy-12-[2'-(4'',3''-dihydroxy-oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,

27- tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone

Solution containing 210 mg of 17-ethyl-1,14-dihydroxy-12[2'-(4''-hydroxy-3''-hydroxycyclohexy)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,

28- dioxa-4-azatricyclo-[ 2.2.3 .1. O ^4.9 ] octacos-18-en-2,.

3, 10, 16-tetraone, 40 ml of benzene and catalytic amount imi liauni’ ii ι i ui ui

128 p-toluenesulfonic acid, boiled for 4 hours under nitrogen. The solvent was removed under reduced pressure, the dark residue was chromatographed (silica gel, 7% i-propanol/CH ₂ Cl ₂ ) and 180 mg of a white solid was obtained - 17-ethyl-1-hydroxy-12-[2'-(4''-hydroxy3''-isopropyloxycyclohexyl)-1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[22.3.1. O ⁴ ' ⁹ ] octacos-14, 18-diene-2,3,10,16tetraone. This material was dissolved in ethanol (20 ml) and treated with 5% Rh/C (40 mg). Hydrogen was bubbled through the flask for 30 minutes, then the mixture was filtered through celite. Chromatography (silica gel) gave 172 mg of the title compound. Mass spectra,

H, C NMR spectra are consistent with the structure of the named compound.

17-Ethyl-1-hydroxy-12-[2'-(4''-triisopropylsilyloxy3''-methoxycyclohexyl)-1'-methylvinyl]-14-triisopropylsilyloxy-23, 25-dimethoxy-13, 19, 21, 27-tetramethylll, 28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ] octacos-18-ene2, 3, 10, 16-tetraone

To a cooled (0°C) solution of 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo-[2.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone (120 mg) and dry methylene chloride (15 ml) were added 2,6-lutidine (64.3 mg) and triisopropylsilyl-trifluoromethanesulfonate (184 mg). The reaction temperature was raised to room temperature and stirred overnight under nitrogen. To stop the reaction, 10 ml of water was added and extracted with ethyl acetate. The organic layer washed (water, saturated NaHCO ₃ , saturated NaCl) and dried (anhydrous MgSO 4 ). After removal of the solvent, chromatographed on silica gel (70% hexane/ethyl acetate) to give 150 mg of product. Mass spectrum: (FAB 1110 (M ⁺ + Li).

imi mm ι:

129

17-Ethyl-1-hydroxy-12-[2'-(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16- tetraon

The title compound from the above procedure (680 mg) was dissolved in methylene chloride (45 ml) and 10% p-toluenesulfonic acid in methanol (45 ml) was added with stirring. The mixture was stirred at room temperature and the reaction was monitored by thin layer chromatography (TLC). After 4 hours, the reaction was quenched by adding saturated sodium bicarbonate solution and extracted three times with ethyl acetate. After working up by known methods and removing the solvent, the residue was chromatographed on a silica gel column (80% ethyl acetate/hexane) to give 560 mg of product (2a) as a white solid. Mass spectrum: (FAB) 954 (M ⁺ + Li).

17- Ethyl-1-hydroxy-12-[2' — (4''-t-butyldimethylsilyloxy3''-methoxycyclohexyl)-1'-methylvinyl] -14- t-butyldimethylsilyloxy-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[22.3.1.O ⁴ ' ⁹ ] octacos18- ene-2, 3, 10, 16-tetraone to a cooled (0°C) solution containing 17-ethyl-1,14dihydroxy-12-[2'-(4''-hydroxy-3''-methoxycyclohexyl)-1 ' -methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27tetramethyl-11, 28-dioxa-4-azatricyclo-[22.3.1.0 ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone (395 mg) and dry methylene chloride (15 ml) were added to 2,6-lutidine (160 mg) and t-butyldimethylsilyl-trifluoromethanesulfonate (250 mg). The reaction temperature was raised to room temperature and stirred overnight under nitrogen. To stop the reaction, 10 ml of water was added and extracted with ethyl acetate. The organic layer was washed (water, saturated NaHCO ₃ , saturated NaCl) and dried (without

130 aqueous MgSO ₄ ). Removal of the solvent gave 500 mg of crude product. Mass spectrum: (FAB) 1023 (M ⁺ + Li).

17-Ethyl-1-hydroxy-12-[2'-(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethyl-silyloxy-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3, 10,

16- tetraon

The product from the previous example (500 mg) was dissolved in acetonitrile (20 ml) and 100 ml of hydrogen fluoride (48%) was added. The reaction mixture was stirred for 20 min at room temperature, quenched by addition of saturated sodium bicarbonate solution, and then extracted with ethyl acetate. After removal of the solvent in vacuo, the residue was chromatographed on silica gel (80% ethyl acetate/hexane) to give 300 mg of product. Mass spectra, ⁴ H ¹³ C NMR spectra were consistent with the structure of the title compound.

17- Ethyl-1-hydroxy-12-[ 2'-(4''-t-butyldimethylsilyloxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-[2'-(3'',4''-dihydroxycyclohexyl)-1'-methylvinyl]-2 3,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ⁴ ' ⁹ ]octacos-18-ene-2,3,10,16-tetraone (3.01 mg) and dry methylene chloride (70 ml) was added excess imidazole (809 mg) and t-butyldimethylsilyl chloride (716 mg). Stirring for 3 days at room temperature, the mixture is diluted with ethyl acetate, then the ethyl acetate layer is washed with IN HCl, saturated NaHCO ₃ solution, saturated NaCl solution and purified by flash chromatography (ethyl acetate: hexane (1:3)). 941 mg of the title compound is obtained.

11, η.: ι ί

LT 3533 B

131 of the compound. ^{The Χ} Η NMR spectra are consistent with the structure of the desired compound.

17-Ethyl-1-hydroxy-12-[2'-(4''-t-butyldimethylsilyloxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2 , 3, 10, 16-tetraone

To a solution containing 17-ethyl-1-hydroxy-12-[2'-(4''hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[2.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone (200 mg) and dry methylene chloride (3 ml) was added excess 2,6-lutidine (45 μΐ) and stirred at room temperature. After 10 minutes, trifluoromethanesulfonate (64 μΐ) was injected via syringe. After 15 minutes, the reaction mixture was diluted with ethyl acetate, extracted with saturated bicarbonate, washed with saturated NaCl solution, and dried over magnesium sulfate. After removal of the solvent in vacuo, the product was purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2) + 1% methanol). 235 mg of the title compound was obtained. . ^X H NMR spectra were consistent with the structure of the desired compound.

17-Ethyl-1,20-dihydroxy-12-[2'-(4''-t-butyldimethylsilyloxy-3''-methoxycyclohexyl-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.0 ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone

To a solution containing 17-ethyl-1-hydroxy-12-[2'-(4''t-butyldimethylsilyloxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethylll, 28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ] octacos-18-ene2, 3, 10, 16-tetraone (235 mg) and 95% ethanol (2.2 ml) was added 53 μΐ of pyridine with stirring and then

132 selenium dioxide (58 mg). The flask was connected to a water condenser and heated to 70°C with a heating grid. After 20 h, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was poured into saturated sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated NaCl solution, and dried over magnesium sulfate. The solution was concentrated, and the product was purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2) + 1% methanol). 89 mg of the title compound was obtained.

The U NMR spectra are consistent with the structure of the desired compound.

17-Ethyl-20-fluoro-1-hydroxy-12-[2'-(4''-t-butyldimethylsilyloxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 2-1, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone

A solution of 17-ethyl-20-dihydroxy-12-[2'(4''-t-butyldimethylsilyloxy-3''-methoxycyclohexyl)1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27tetramethyl-11, 28-dioxa-'4-azatricyclo-[22.3.1.O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone (30.5 mg) and methylene chloride (0.5 ml) was cooled to -78°C in a dry ice/isopropanol bath. Sulfur diethylamine trifluoride (4.5 μΐ) was added to the stirred solution. After 3 min. saturated sodium bicarbonate (500 μΐ) was added, followed by ethyl acetate (2 ml) and the mixture was warmed to room temperature. Extraction with ethyl acetate, drying over magnesium sulfate. The product is purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2) + 1% methanol). 22 mg of the title compound are obtained.

I Ii 11... i B

133

17-Ethyl-1,20-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. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone

To a solution containing 17-ethyl-1,20-dihydroxy-12-[2 '(4''-t-butyldimethylsilyloxy-3''-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ⁴ ' ⁹ ] octacos-1 8-ene-2,3,10,16-tetraone (7 mg) and acetonitrile (0.3 ml), a 2% solution of hydrogen fluoride in aqueous acetonitrile (100 μΐ) was added and the mixture was stirred at room temperature. After 28 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate and the organic phase was dried by passing through a column filled with magnesium sulfate. The concentrate is purified by flash chromatography on silica gel (ethyl acetate:hexane (2:1) + 1% methanol) to give the title compound.

17-Ethyl-20-fluoro-1-hydroxy-12-[2'-(4''-hydroxy-3''methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone

To a solution containing 17-ethyl-20-fluoro-1-hydroxy-12[2'-(4''-t-butyldimethylsilyloxy-3''-methoxycyclohexyl)-1 '-methylvinyl]-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone (7 mg) and acetonitrile (0.3 ml) was added a 2% solution of hydrogen fluoride in aqueous acetonitrile (100 μΐ) and the mixture was stirred at room temperature. After 2 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate and the organic phase was dried by passing through a column filled with magnesium sulfate. The concentrate is purified by flash chromatography on . J. liti ! III L uaiui ΒΐΜΐιΐί ri .1

134 silica gel (ethyl acetate:hexane (1:1) + 1% methanol) to give the title compound.

Mass spectrum: (FAB) 816 (M ⁺ + Na).

Partial ¹³ C NMR spectrum, chemical shifts: 211.5 (C-16); 196.1 (2) 169.3 (10); 165.0 (3); 138.1 (C-19);

135.8 (C-1'); 121.0 (C-18' major); 84.1 (C-3'');

43.1 (C-15); 26.0 (C-21).

17-Ethyl-1,14,20-trihydroxy-12-[ 2'-(4''-hydroxy-3'methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone

ALTERNATIVE SYNTHESIS ROUTE

To a solution containing 17-ethyl-1,14-dihydroxy-12-[2 '(4 ''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,

16-tetraone (5.15 g, 0.065 mol) and glacial acetic acid (500 ml) were added at room temperature to a solution of selenium dioxide (9.27 g, 0.083 mol) in water (90 ml). The reaction mixture was stirred at room temperature for 41 h, then poured into a stirred mixture of water (3 L) and celite. After stirring for 15 min, the mixture was filtered through a pad of celite and extracted with diethyl ether (1 x 2L, 2 x 1L). The organic fractions were washed with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate, filtered and evaporated in vacuo. The product was purified by chromatography on silica gel (acetone:hexane 2:5) to give the title compound, whose mass and NMR spectra were consistent with the structure.

ιιβιιιιι oniui.ii U

I JI UJU. 11J

135

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(2-furanyl) _m ethoxy3''-methoxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatric 1 o -[ 22.3.1. O ^4,9 ] octacos-18en-2, 3, 10, 16-tetraone

To a solution containing 17-ethyl-1,14-dihydroxy-12-[2'(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16tetraone (63 mg, dissolved in 1.0 ml of methylene chloride), furfuryl trichloroacetimidate (39 μΐ, neat) was added and the reagents were stirred for 5 minutes. Camphorsulfonic acid (3.7 mg) was added and the mixture was stirred at room temperature.

After 4.5 hours, the reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (3x5 ml). The combined organic layers were washed with brine and dried over magnesium sulfate. The concentrate was purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2) + 1% methanol) to give the title compound (20 mg). Mass spectrum: (FAB) 878 (M+Li). Partial ¹ H NMR, chemical shifts: 7.38 pis, 1H); 6.30 (m, 3H); 5.32 M, 5.19 pld J = 3Hz); 4.83m, 4.21M pis, 1H); 4.62 (dd J = 15Hz, 2H); 4.41 (see J=14Hz, 1H).

AND EXAMPLE 3

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-furanyl)methoxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] ocucacos-18-ene-2, 3, 10, 16-tetraone and 17-Ethyl-l,14-dihydroxy-12-[ 2'-(4''-hydroxy-3''—(2- furanyl)methoxycyclohexyl)-1'-methylvinyl] -23, 25-dimeIMII.ll 11911. IIII! .1 I .11 ..IH l.ll

136 toxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3. 1.0 ⁴ ' ⁹ ] octacos-18-en-2,_3,_10,_16tetraone

To a solution containing 17-ethyl-1,14-dihydroxy-12-[2'(3'',4''-dihydroxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16tetraone (52 mg, dissolved in 0.9 ml of methylene chloride), furfuryl trichloroacetamide (20 μΐ, neat) was added and the reagents were stirred for 5 minutes. Camphorsulfonic acid (2 mg) was added and the mixture was stirred at room temperature. After 3.5 hours, the reaction was quenched by adding saturated sodium bicarbonate solution and extracted with ethyl acetate (3x5 ml). The combined layers were washed with brine and dried over magnesium sulfate. The concentrate was purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1) + 1% methanol) to give the title compounds (16 mg of the 4''ether; 13 mg of the 3'' ether).

4'' ether: Mass spectrum: (FAB) 864 (M+Li). Partial ⁴ H NMR, chemical shifts: 7.38 pis, 1H) ; 6.30 (m,

3H); 5.32 M, 5.19m pld J = 3Hz, 1H); 4.83m, 4.21M pis,

1H); 4.62 (dd J= 15Hz, 2H); 4.41 pld J = 14Hz, 1H).

3'' ether: Mass spectrum: (FAB) 864 (M+Li). Partial

NMR, chemical shifts: 7.44 (pis, 1H); 6.37 (m,

2H); 5.32M, 5.19m (pld J = 3Hz, 1H); 4.88m, 4.27M pis,

1H); 4.41 pld J = 14Hz, 1H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'—(4''-(2-thiophene)-methoxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azaLT 3533 B

137 tricyclo-[2.3.1. O ^4,9 ] octacos-18-en-2, 3, 10, 16-tetraone imi unm .

I Ui III: J i a :

The title compound was synthesized as described in Figure 1 using 2-thiophenylmethyltrichloroacetimidate as the alkylating agent.

Partial ^X H NMR, chemical shifts: 7.27 (m, 1H) :

6.96 (m, 2H); 5.31M, 5.18m pld J = 3Hz, 1H) ; 4.81m, 4.22M (pis, 1H); 4.41 (pld J = 14 Hz, 1H); 3.07 (dJ = 4Hz, 1H).

AND EXAMPLE 6

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(2-thiophene)-methoxy3''-hydroxycyclohexyl)'-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3, 10, 16-tetraone and 17-ethyl-1,14-dihydroxy-12-[ 2'-(4''-methoxy-3''—(2-thiophene)-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11, 28-dioxa-4azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2,3,10, 16-tetraone

The title compounds were synthesized as described in Figures 2 and 3 using 2-thiophenylmethyltrichloroacetamidate as the alkylating agent.

4 ' ' ether: Masses spectrum: (FAB) 896 (M+Na). Partial U NMR, chemical displacements : 7.29 (m, 1H); 6.97 (m, 2H) ; 5.31M, 5.19m (e.g. J = 3Hz, 1H); 4.41 (e.g. J = 14Hz, 1H); 3.04 (d J = 4Hz, 1H); 2.63M, 2.61 m (s, 1H). 3 ' ' ether; Mass spectrum: (FAB) 880 (M+Na). Partial 1 ’H NMR, chemical displacements : 7.28 (m, 1H); 6.97 (m, 2H) ; 5.19m, 5.19m (e.g. J = 3Hz , 1H) ; 4.41 (pl. J = 14 Hz, 1H) ; 3.08 (dJ = 3Hz, 1H); 2. 69 (s, 1H) .

I MIDI II13I11H I. I! I.11. Lily II

138

AND EXAMPLE 8

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(3-thiophene)-methoxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16tetraone and 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-(3-thiophene)-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-11,28dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10, 16-tetraone

The title compounds were synthesized as described in Figures 2 and 3 using 3-thiophenylmethyltrichloroacetimidate as the alkylating agent.

4 ' ' ether: Masses spectrum: (FAB) 880 (M+Li) . Partial Y NMR, chemical shifts: 7.30 (m, 1H) ; 7.04 (m, 2H) ; 5.31 M, 5.19m (e.g., J = 3Hz, 1H); 4.89 m, 4.19 M (s, 1H); 4.41 (pld J = 14Hz, 1H); 3. 04 (dJ = 4Hz, 1H). 3' ' ether: Masses spectrum: (FAB) 880 (M+Li) . Partial Y NMR, chemical displacements: 7.28 (m, 2H) ; 7.05 (dd, J = = 5.2 Hz, 1H); 5 .31M, 5.19m (pld, J = 3Hz, 1H); 4.83 m, 4.25 M (pis, H) ; 4.41 9pld, J = 14Hz, H); 3.06 (d, J = 3Hz, 2.69 (s, H) .

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(2-benzothienyl)oxy-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

To a stirred solution of tri(benzothien-2-yl)bismuthine (100 mg, 0.164 mmol) in methylene chloride (2 ml) was added peracetic acid;

11: ιιΐ;:! u ;

139 acid (0.05 ml, 0.224 mmol, 32% solution in acetic acid) and then 17-ethyl1,14-dihydroxy-12-[2 ' - (4 ''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27tetramethyl-11, 28-dioxa-4-azatricyclo-[22.3.1. 0 ^4,9 ]octacos-18-ene-2, 3, 10, 16-tetraone (100 mg, 0.126 mmol) and Cu(OAc) ₂ (15 mg, 0.083 mmol) were added over 10 minutes.

The reaction mixture was stirred for 16 hours at room temperature. The reaction was quenched by the addition of saturated sodium bicarbonate solution, then extracted 3 times with methylene chloride. The extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was isolated and purified by preparative TLC 3X on silica gel (3:1, hexane/acetone) to give 23 mg of 17-Ethyl-1,14-dihydroxy~12-[2'(4''-(2-benzothienyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]octacos-18-ene-2,3,

10,16-tetraone.

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(thien-2-yl)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13, 19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.0 ⁴ ' ⁹ ] and others z-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(thien-2-yl)bismuthine (80 mg, 0.175 mmol) in methylene chloride (2 mL) was added peracetic acid (0.06 mL, 0.253 mmol, 32% solution in acetic acid) and then 17-ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-methoxycyclohexyl)'1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene2,3,10,16-tetraone (100 mg, 0.126 mmol) and Cu(OAc) ₂ (10 mg, 0.055 mmol) were added over 15 minutes.

ι·ι .imu ιιιι.. . i hin«

140

The reaction mixture was stirred for 3 days at room temperature. The reaction was quenched by the addition of saturated sodium bicarbonate solution, followed by extraction with methylene chloride. The extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was isolated and purified by preparative TLC twice on silica gel (2:1, hexane/acetone) to give 36 mg of 17-Ethyl-1,14-dihydroxy-12-[2'-(4(thien-2-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1.O ^4,9 ]octacos-18-ene-2,3,10,16-tetraone.

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[ 2' — (4''-5-indolylaminocarbonylmethoxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23.25- domethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.0 ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone

STAGE 11A

17-Ethyl-1-hydroxy-14-t-butyldimethylsilyloxy-12-[ 2'(4''-t-butyldimethylsilyloxy-3''-methoxycyclohexyl)1'-methylvinyl] --23,25-dimethoxy-13,19,21,27-tetramethylll,28-dioxa-4-azatricyclo- [ 22.3.1.O ^4,9 ] -octacose-18-en2,3,10,16-tetraone

To a solution containing 17-ethyl-1,14-dihydroxy-12-[2'(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone (2g) and dry methylene chloride (25ml) was added excess 2,6-lutidine (1.2ml) and the mixture was stirred at room temperature. After 10 minutes, t-butyldimethylsilyl trifluoromethanesulfonate was injected via syringe.

141 (1.8 ml). After 1 hour the reaction mixture was diluted with ethyl acetate, washed with 1N HCl, water, saturated sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate. The solvent was removed in vacuo and flash chromatography on silica gel (ethyl acetate:hexane (1:60 + 1% methanol) gave the title compound (2.37 g). ¹ H NMR spectrum was consistent with the desired structure.

STAGE 11B

17-Ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)—12—[ 2'(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl] 2 3,2 5-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3, 10, i 6-tetraone

To a solution containing 17-Ethyl-1-hydroxy-14-t-butyldimethylsilyloxy-12-[2'-(4''-t-butyldimethylsilyloxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricicyclohexyl)-22.3.1. O ^4,9 ] -octacos-18-ene-2,3, 10, 16-tetraone (2.37 g) (STEP 11A) and dry methylene chloride (25 ml) was added a 10% solution of p-toluenesulfonic acid in methanol (10 ml) and the mixture was stirred at room temperature. After 10 minutes, the mixture was cooled to 0°C and the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate, flash-chromatographed using acetate:hexane (1:2) + 1%

The concentrate was purified on silica gel (ethyl methanol) to give the title compound (2.1 g).

The H NMR spectrum is consistent with the desired structure.

Ι·ΙΙΙΙΙ J1BMI.III.III »1 I 11 ll'UP B

142

STAGE 11C

17-Ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)-12-[2' (4''-allyloxy-3' '-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1,0 one

4.9.

To a solution of octacos-18-ene-2,3,10,16-tetraone containing 17-Ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)-12-[2'-(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone (2.1 g) (STEP 11B) and 24 ml of a 33% methylene chloride solution in cyclohexane, allyl trichloroacetimidate (938 mg, neat) was added and the reaction mixture was stirred for 5 minutes. Trifluoromethanesulfonic acid (41 μΐ, neat) was slowly added via syringe and the mixture was stirred at room temperature. After 24 hours of reaction, the mixture was diluted with ethyl acetate, saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate. The concentrate was purified by flash chromatography on silica gel (ethyl acetate : hexane (1:5) + 1% methanol) to give the title compound (1.03 g) of the desired structure.

H NMR spectrum

STAGE 11D

17-Ethyl-l-hydroxy-14-t-butyldimethylsilyloxy)-12-[ 2 '(4''-2,3-dioxy-l-propoxy)-3''-methoxycyclohexyl)-1'methylvinyl]-2 3,25-dimethoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene2,3,10,16-tetraone

To a solution containing 17-ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)-12-[2'-(4''-allyloxy-3''-methoxycycloLT 3533 B

143 hexyl)-1 ¹ -methylvinyl] -2 3,25-dimethoxy-13,19,21,27tetramethyl-11 , 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone (1.03 g) (STEP 11C) and 22 ml tetrahydrofuran, N-methylmorpholine N-oxide (883 mg) was added, followed by a 0.25 M solution of osmium tetroxide in THF (871 μΐ) and the mixture was stirred at room temperature. After 3 hours, the reaction was quenched by adding 20% sodium bisulfite (20 ml), the precipitate was filtered through celite and washed with ethyl acetate. The combined filtrates were washed with 20% sodium bisulfite (2 times), saturated sodium bicarbonate and brine and dried over magnesium sulfate. The concentrate was purified by flash chromatography on silica gel (ethyl acetate : hexane (2:1) + 1% methanol) to give the title compound (705 mg). ^X H NMR spectrum was consistent with the desired structure.

HE STAGE

17-Ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)—12—[ 2'(4''-ethanaloxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo[ 22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone

To a solution of 17-Ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)—12—[2'-(4''-(2,3-dioxy-1-propoxy)3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone (1.56 g) (STEP 11D) and 20% tetrahydrofuran solution (20 mL), sodium metaperiodate (510 mg) was added and the mixture was stirred vigorously for 30 minutes. An additional 170 mg of sodium metaperiodate was added. After 30 minutes, the mixture was diluted with ethyl acetate, filtered through celite, and rinsed with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine,

I take UlIilUIII. IU .1 i II!·.: I fl I

4 was dried over magnesium sulfate and purified by flash chromatography on silica gel (ethyl acetate : hexane (1:2) + 1% methanol) to give the title compound (1.45 g). ¹ H NMR spectrum was consistent with the desired structure.

STAGE 11F

17-Ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)—12—[ 2' (4''-carboxymethoxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3,

10, 16-tetraone

To a solution containing 17-ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)-12-[2'-(4' '-ethanaloxy-3' '-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21,

27-tetramethyl-11, takoz-18-en-2, 3,

28-dioxa-4-azatricyclo-[22.3.1.0 ^4,9 ]oc16-tetraone (311 mg) (STEP 11E) and t-butanol (6.6 mL) and 2-methyl-2-butene (1.65 mL) were slowly added, sodium chlorite (273 mg) and sodium dihydrogen phosphate (272 mg) in water (2.7 mL). After 2 h, the solvent was removed in vacuo, the residue was dissolved in water and acidified to pH 3 with 1N HCl. The aqueous layer was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were washed with brine. They were then dried over magnesium sulfate and purified by flash chromatography on silica gel (2% methanol in methylene chloride, then 2% methanol in methylene chloride + 0.5% acetic acid) to give the title compound (1.45 g). ^{The X} H NMR spectrum is consistent with the desired structure.

STAGE 11G

17-Ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)-12-t 2'(4''-5-indolylamino-carbonylmethoxy-3''-methoxy-cycloI HILU IttVIfllUII. III 11 I ll 1. 11

145 hexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21,

27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone

To a solution containing 17-ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)-12-[2 ' - (4 ''-carboxymethoxy-3''-methoxycyclohexyl)-1 ¹ -methylvinyl] -23, 25-dimethoxy-13, 19,

21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone (311 mg) (STEP 11F) and dry methylene chloride (1.6 mL) were added, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (103 mg) was added, followed by triethylamine (43 μΐ). After 10 minutes, 5-aminoindole (43 mg) was added to the reaction mixture and stirred for 1 hour. The mixture was diluted with ethyl acetate and washed with 1N HCl, water, saturated sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:2) + 1% methanol) to give the title compound (138 mg). ^{The 1} H NMR spectrum was consistent with the desired structure.

STAGE 11H

17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-5-indolylaminocarbonylmethoxy-3''-methoxy-cyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -oktakoz-18-en-2,_3,

10, 16-tetraone

To a solution containing 17-ethyl-1-hydroxy-14-t-butyldimethylsilyloxy)-12-[2 ' - (4''-5-indolylamino-carbonylmethoxy-3''-methoxy-cyclohexyl)-1'-methylvinyl] -23, 25dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[22.3.1. O ⁴ ' ⁹ ] -octacos-18-ene-2 , 3, 10, 16tetraone (138 mg per ml tetrahydrofuran polyΙ·ΙΙΙΙΙ! HWJII.UI UI I i! »

146 in a propylene tube), 200 μΐ of hydrogen fluoride-pyridine complex (40% solution in tetrahydrofuran-pyridine (2:1)) was added and the mixture was stirred at room temperature. After 2 days, the reaction was quenched by careful addition of sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel (ethyl acetamethanol) to give the compound. Mass spectrum (FAB) 971 (M+Li); partial ^X H NMR spectrum, chemical shifts: 9.52 (pis, 1H) ; 8.15 (pis, 1H) ; 7.91 (s, 1H) ; 7.30 (s,

2H); 7.16 (dd, J = 3.3Hz, 1H) ; 6.49 (dd, J = 3Hz, 1H) ; 4.41 (pld, J = 14 Hz, 1H).

hexane (1:1) + 1% of the name indicated

EXAMPLE

17-Ethyl-1-hydroxy-12-[ 2'-(4''-(methyl-N-tryptophanylcarbonylmethoxy-3''-methoxy-cyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1.0 ^4,9 ] -oktakoz-18-en-2,_3,

10, 16-tetraone

STAGE 12A

17-Ethyl-1-hydroxy-12-[ 2' — (4''-(allyloxy-3' '-methoxycyclohexyl)-1'-methylvinyl] -2 3, 25-dimethoxy-13, 19,

21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ]-octacose-18-ene-2,3,10,16-tetraone

To a solution containing 17-ethyl-1-hydroxy-12-[2'-(4''hydroxy-3''-methoxy-cyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] -octacos-18-ene-2, 3, 10, 16tetraone (510 mg) and 6.6 ml of 33% methylene chloride in cyclohexane, was added a solution of trichoracetimidate ai .ii nm ;

147 (266 mg, neat) and the reaction was stirred for 5 minutes. Trifluoromethanesulfonic acid (12 μΐ, neat) was slowly added via syringe and the mixture was stirred at room temperature. After 24 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:9) + 1% methanol) to give the title compound (434 mg). ^X H NMR spectrum was consistent with the desired structure.

STAGE 12B

17-Ethyl-l-hydroxy-12-[ 2'—(4''-(2,3-dioxy-1-propoxy)-3''-methoxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4azatricyclo-(22.3.1, O ^4,9 ] octacos-18-ene-2, 3, 10, 16tetraone

To a solution containing 17-ethyl-1-hydroxy-12-[2'-(4''allyloxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16tetraone (434 mg) (STEP 12A) and 15 mL of tetrahydrofuran, N-methylmorpholine N-oxide (431 mg) was added, followed by 0.25 M osmium tetroxide solution in THF (425 μΐ) and the mixture was stirred at room temperature. After

After 4.5 hours, the reaction was quenched by adding 20% sodium bisulfite (20 ml), the precipitate was filtered through celite and washed with ethyl acetate. The combined filtrates were washed with 20% sodium bisulfite (2 times), saturated sodium bicarbonate and brine and dried over magnesium sulfate. The concentrate was purified by flash chromatography on silica gel (ethyl acetate:hexane (3:1) + 1% methanol) to give the title compound.

Title compound 148 (177 mg). Y NMR spectrum consistent with the desired structure.

STAGE 12C

17-Ethyl-1-hydroxy-12-[2'-(4''-ethanaloxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,

27-Tetramethyl-ll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-[2'-(4''(2,3-dioxy-1-propoxy)-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene2,3,10,16-tetraone (177 mg) (STEP 12B) in 20% aqueous tetrahydrofuran (2 ml), sodium metaperiodate (67 mg) was added and the mixture was stirred vigorously for 30 minutes. A further 20 mg of sodium metaperiodate was then added. After 30 minutes, the mixture was diluted with ethyl acetate, filtered through celite, and rinsed with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and purified by flash chromatography on silica gel (ethyl acetate:hexane (2:3) + 1% methanol) to give the title compound (157 mg). ¹ H NMR spectrum was consistent with the desired structure.

STAGE 12D

17-Ethyl-1-hydroxy-12-[ 2'-(4''-carboxymethoxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, -21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] -octacose-18-ene-2, 3, 10, 16-tetraone

To a solution containing 17-ethyl-1-hydroxy-12-[2'-(4''ethanaloxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,

I ·ΙΙΙΙ 1IUII11.111,1 II. 11.1.1 II. IIIH.I1.WI

149

25-Dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4azatricyclo-[22.3.1. O ⁴ ' ⁹ ] -octacos-18-ene-2 , 3, 10, 16tetraone (157 mg) (STEP 12C), t-butanol (4 mL) and 2-methyl-2-butene (1 mL) were added, sodium chlorite (159 mg) and sodium dihydrogen phosphate (159 mg) in water (1.6 mL). After 1 hour, the solvent was removed in vacuo, the residue was dissolved in water and acidified to pH 3 by adding 1N HCl. The aqueous layer was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were washed with brine. They were then dried over magnesium sulfate and purified by flash chromatography on silica gel (2% methanol in methylene chloride, then 2% methanol in methylene chloride in Ο. 5% acetic acid) to give the title compound (114 mg). ¹ H NMR spectrum was consistent with the desired structure.

STAGE 12E

17-Ethyl-1-hydroxy-12-[ 2'-(4''-methoxy-N-tryptophanylcarbonylmethoxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, -21, 27-tetramethyl-11, 28-dioxa-4-azatricio-[ 22.3.1.O ^4,9 ] -oktakoz-18-en-2, 3,

10, 16-tetraone

To a solution containing 17-ethyl-1-hydroxy-±2-[2 ' (4 ''carboxymethoxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28dioxa-4-azatricyclo-[22.3.1.O ^4,9 ] -octacos-18-en-2, 3,

10, 16-tetraone (39 mg.) (STEP 12D) in methylene chloride (0.5 ml), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (31 mg) was added followed by triethylamine (14 μΐ). After 10 minutes, tryptophan methyl ester hydrochloride (24 mg) was added to the reaction mixture and stirred for 1 hour. The mixture was diluted with ethyl acetate and washed with 1N HCl, water, saturated sodium bicarbonate and brine, respectively.

150 solution. The organic layer was dried over magnesium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1) + 1% methanol) to give the title compound (28 mg). Mass spectrum (FAB) 1041 (M + Li); partial ^X H NMR spectrum, chemical shifts: 8.21 (pis, 1H); 8.04 (pld, J = 8Hz, 1H); 7.56 (d, J = 8Hz, 1H); 7.33 (d,

J=8Hz, 1H) ; 7.11 (m, 3H); 4.41 (pld, J=14Hz, 1H); 3.64 (s, 3H).

EXAMPLE

17-Ethyl-1-hydroxy-12-[ 2'-(4''-3-indolylethylaminocarbonylmethoxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23, 25-dimethoxy-13,19,-21,27-teramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ]-octacose-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1-hydroxy-12-[2'-( ^4' -carboxymethoxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone (13 mg) (STEP 12D) in methylene chloride (150 μΐ) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (10.3 mg) followed by triethylamine (4.3 μΐ). After 10 minutes, tryptamine (5 mg) was added to the reaction mixture and stirred for 1 hour. The mixture was diluted with ethyl acetate and washed with 1N HCl, water, saturated sodium bicarbonate and brine respectively. The organic layer was dried over magnesium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1) + 1% methanol) to give the title compound (7.5 mg). Mass spectrum (FAB) 983 (M + Li) ; partial ^X H NMR spectrum, chemical shifts: 8.32 (pis, 1H) ; 7.89 (m, 1H) ; 7.58 (d, J=8Hz, 1H) ; 7.31 (m,

I ·ΙΙΙΙ 1IH1IIIJII.I II. III. I I и

151

1H); 7.10 (m, 3H); 4.51 (pld, J=3Hz, 1H) ; 4.41 (pld,

J=14Hz, 1H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

STAGE 14A l-Methyl-5-bromindol

A mixture of sodium hydroxide (0.4 g, 10 mmol) and DMSO (20 ml) was heated to 80-85°C for 6 hours until most of the solids dissolved and then cooled to room temperature. To the stirred mixture was added 5-bromoindole (2.0 g, 10 mmol), followed by methyl iodide (0.62 ml, 10 mmol) after 1 hour. Stirring was continued for 3 hours until the reaction was complete by TLC. The reaction mixture was diluted with water and extracted with ether. The extracts were washed twice with water, dried over Na ₂ SO ₄ , and concentrated in vacuo to give 2.08 g of 1-methyl-5-bromoindole as a yellow oil, which was observed to crystallize.

STAGE 14B

Tri(l-Methyl-indol-5-yl)bismuthine

To a solution of l-methyl-5-bromoindole (5.0 g, 23.8 mmol) in ether (100 ml) at -78°C was added a 1.7 M solution of t-butyllithium in pentane (28 ml, 47.6 mmol). The mixture was stirred at -78°C for 1 hour. Then, a solution of bismuth trichloride (2.36 g, 7.5 mmol) in THF was added to the reaction mixture via syringe.

152 (25 ml). The reaction mixture was kept in a cooling bath for two hours, then allowed to warm to room temperature overnight. In the morning, ice water was added to the mixture and the product was extracted twice with toluene.

The extracts were combined, washed with water, dried over Na ₂ SO ₄ , and concentrated in vacuo to a volume of approximately 30 ml. After keeping the solution in the refrigerator for several hours, the solid product was filtered off, washed with cold toluene, and dried in vacuo to give tri(1-methyl10 indol-5-yl)bismuthine (1.7 g) as a mustard-colored solid.

STAGE 14C

17-Ethyl-1,14-dihydroxy-12-[2'-)4''-(1N-methyl-5-indolyl)oxy-3'.'-methoxycyclohexyl)-1'-methylvinyl]-2 3,25dimethoxy-13,19,-21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ]-octacose-18-ene-2,3,10,16-tetraone

To a stirred solution containing tri(1-methyl-indol-5-yl) bismuthine (450 mg, 0.75 mmol) (STEP 14 B) and methylene chloride. (10 ml), peracetic acid (0.158 ml, 0.75 mmol, 32% solution in acetic acid) was added, after 15 minutes 17-ethyl-1,14-dihydroxy-12-[2'25 (4''-hydroxy-3''-methoxy-cyclohexyl)-1'-methylvinyl] 23,2 5-dimethoxy-13,19,21,27-tetramethyl-11,2 8-dioxa-4aza-tricyclo-[22.3.1.O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (350 mg, 0.442 mmol) and Cu(OAc) ₂ were added. The mixture was stirred at room temperature for 2 days. The reaction was quenched by adding saturated aqueous NaHCO ₃ solution and the product was extracted 3 times with methylene chloride. The extracts were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated and purified twice by preparative TLC to give 203 mg of the title compound as a colorless solid. Mass spectrum (FAB) 927 (M+Li); partial Z NMR spectrum, (CDC1 ₃ , 200 MHz) ι·ιιιι mum, m ,ι i

153 chemical shifts: 7.19 (pis, 1H) ; 7.17 (d, J=10Hz, 1H) ; 6.98 (d, J=4Hz, 1H) ; 6.91 (dd, J= 3Hz and 10Hz, 1H); 6.34 (d, J=4Hz, 1H); 3.72 (s, 3H); 3.51 (s, 3H).

EXAMPLE

17-Ethyl-1,14,20-trihydroxy-12-[ 2' — (4'(1-N-methylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo- [ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri-(1-methyl-indol-5yl)bismuthine (350 mg, 0.584 mmol) and methylene chloride (6 mL) was added peracetic acid (0.15 mL, 0.74 mmol, 32% solution in acetic acid), and after 15 minutes, 17-ethyl-1,14,20-trihydroxy-12-[2'(4''-hydroxy-3''-methoxy-cyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4aza-tricyclo-[22.3.1.O ^4,9 ] -octacos-18-ene-2,3,10,16tetraone (250 mg, 0.32 mmol) and Cu(OAc)2 (35 mg, 0.138 mmol). The mixture was stirred at room temperature for 2 days. The reaction was quenched by adding saturated aqueous NaHCO3 solution and the product was extracted twice with methylene chloride. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was isolated and purified by flash co-ion chromatography on silica gel (3:1 hexane/acetone) and preparative TLC (3% methanol in methylene chloride) to give 111 mg of the title compound. Mass spectrum (FAB) 943 (M + Li) ; partial ⁷ H NMR spectrum, (CDCl3, 200 MHz) chemical shifts: 7.21 (pis, 1H) ; 7.18 (d, J=7.5 Hz, 1H) ;

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

6.37 (d, J=3Hz, 1H); 3.75 (s, 3H); 3.59 (s, 3H).

154

EXAMPLE

17-Ethyl-1-hydroxy-12-[2'-(4''-(1N-methyl-indol-5yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.0 ⁴ ' ⁹ ] -octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-methyl-indol-5yl)bismuthine (35 mg, 0.058 mmol) and methylene chloride (0.7 ml) was added peracetic acid (0.015 ml, 0.074 mmol, 32% solution in acetic acid), and after 15 minutes, 17-ethyl-1-hydroxy-12-[2'-(4''-hydroxy-3''-methoxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo-[22.3.1.O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (25 mg, 0.032 mmol) and Cu(OAc) ₂ (5 mg, 0.03 mmol) . The mixture was stirred at room temperature for 3 days. The reaction was quenched by adding saturated aqueous NaHCO ₃ solution and the product was extracted twice with methylene chloride. The extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC on silica gel (2:1 hexane/acetone, then 5% methanol in methylene chloride) to give 10.2 mg of the title compound. Partial 0 NMR spectrum, (CDCl ₃ , 200 MHz) chemical shifts: 7.18 (pis, 1H) ; 7.16 (d, J=7Hz,

1H); 6.98 (d, J=3Hz, 1H) ; 6.92 (dd, J=2.5Hz and 7.5Hz,

1H); 6.33 (d, J=3Hz, 1H); 3.64 (s, 3H); 3.51 (s, 3H).

AND EXAMPLE 18

17-Eti1-1,14-dihydroxy-12-[ 2'—{3''-hydroxy-4'-(1-Ντε tyl-indol-5-ii)oxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ⁴ ' ⁹ ] -octacos-18-ene-2,3,10,16-tetraone and 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-hydroxy-3''-(1-Nmethyl-indol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25II . IM 11 II

155 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ]-octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-methyl-indol-5yl)bismuthine (150 mg, 0.25 mmol) and methylene chloride (2 mL) was added peracetic acid (0.05 mL, 0.23 mmol, 32% solution in acetic acid), followed 15 minutes later by the addition of 17-ethyl-1,14-dihydroxy-12-[2'-(3'',4''-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1. O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.129 mmol) and Cu(OAc)2 (20 mg, 0.11 mmol). The mixture was stirred at room temperature for 2 days. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution and the product was extracted twice with methylene chloride. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC on silica gel (2:1 hexane/acetone, then 5% methanol in methylene chloride) to give 19 mg of 17-Ethyl-1,14-dihydroxy-12[2'-(3''-hydroxy-4''-(1N-methyl-indol-5-yl)oxycyclohexyl)-1'-methylvinyl]-2 3,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0 ⁴ ' ³ ]-octacos-18-ene-2,3,10,16-tetraone. Partial ^X H NMR spectrum, (CDCl3, 200 MHz) chemical shifts: 7.19 (d, J=10Hz, 1H); 7.17 (d, J=2.5 Hz, 1H) ; 7.00 (d, J-3Hz, 1H) ; 6.88 (dd, J=2.5Hz and 10Hz, 1H) ; 6.35 (d, J=3Hz, 1H) ; 3.73 (s, 3H) , and 33 mg of 17-ethyl-1,14-dihydroxy-12-[ 2'-(4''hydroxy-3''-(1-N-methyl-indol-5-ii)oxycyclohexyl)-1' methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll , 28-dioxa-4-azatricyclo-[ 22.3.1.0 ^4,9 ]-octacose-18-ene2,3,10,16-tetraone. Partial ^X H NMR spectrum, (CDC1 ₃ , 200 MHz) chemical shifts: 7.18 (d, J=8Hz 1H); 7.16 (d, J=2.5 Hz, 1H); 6.98 (d, J=3Hz, 1H); 6.88 (dd,

J=2.5Hz, and 8Hz, 1H); 6.33 (d, J=3Hz, 1H); 3.73 (s, 3H).

IMI! 1! UBU E I! .1 I l.ll IJ1

156

EXAMPLE

Tri(indol-5-yl)bismuthine

To a solution of 5-bromoindole (5.0 g, 25.5 mmol) in ether (50 ml) at 0°C was added a suspension of KH (2.8 g, 25 mmol, 35% suspension in oil, washed three times with hexane) in ether (40 ml). The reaction mixture was stirred for 20 minutes, then cooled to -78°C. A pre-cooled solution of t-butyllithium (29.7 ml,

50.5 mmol, 1.7 M solution in pentane), after 40 minutes, a solution of bismuth trichloride (1.89 g, 6.0 mmol) in THF (25 ml) was added. The reaction mixture was kept in a cooling bath for two hours, then allowed to warm to room temperature overnight. The reaction was quenched by the addition of ice water and the product was extracted 3 times with toluene. The extracts were combined, washed with water, dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was diluted with 75 ml of toluene and kept overnight at 4°C. The solid product was filtered off and air-dried. Tri(indol-5yl)bismuthine (1.53 g) was obtained.

Stage 19B

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(indol-5-yl)oxy3'-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(indol-5-yl)bismuthine (1.3 g, 2.33 mmol), synthesized according to the procedures outlined in STEP 14B, and methylene chloride (30 mL), was added peracetic acid (0.5 mL, 2.31 mmol, 32% solution in acetic acid), followed by the addition of 17-ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxyLT 3533 B] over 10 minutes.

157

3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13.19.21.27- tetramethyl-11,28-dioxa-4-aza-tricyclo[ 22.3.1. O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (1.0 g, 1.26 mmol) and Cu(OAc)2 (100 mg, 0.55 mmol). The mixture was stirred at room temperature for 3 days. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution and the product was extracted twice with methylene chloride. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC (2 times) on silica gel (2:1 hexane/acetone and once hexane/ethyl acetate 2:1) to give 208 mg of the title compound. Mass spectrum (FAB) M + 906. Partial ⁴ H NMR spectrum, (CDCl3, 200 MHz) chemical shifts: 8.12 (pis, 1H) ; 7.26 (d, J=10Hz, 1H) ; 7.22 (d, J=2.5Hz, 1H) ; 7.18 “(m, 1H) ; 6.9 (dd, J=2.5 Hz and 10Hz, 1H); 6.44 (m, 3H); 3.53 (s, 3H).

EXAMPLE

17-Allyl-1,14-dihydro-oxy-12-[2'-(4''-(indol-5-yl)oxy3''-methoxycyclohexylT-1'-methylvinyl]-23,25-dimethoxy13.19.21.27-tetramethyl-11,28-dioxa-4-azatricycloI 2.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(indol-5-yl)bismuthine (150 mg, 0.27 mmol) and methylene chloride (3 mL) was added peracetic acid (0.05 mL, 0.23 mmol, 32% solution in acetic acid), and after 15 minutes 17-allyl-1,14-dihydroxy-12-[2'-(4''-hydroxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1. O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.124 mmol) and Cu(OAc) ₂ (20 mg, 0.11 mmol). The mixture was stirred at room temperature for 2 days. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ solution and the product was extracted with methylene chloride. Extracts

158 were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was separated and purified by preparative TLC (2 times) 2:1 hexane/acetone, then 5% methanol in methylene chloride) to give 11 mg of the title compound. Mass spectrum (FAB) M+Li 925. Partial ⁴ H NMR spectrum, (CDCl ₃ 200 MHz) chemical shifts: 8.12 (pis, 1H) ; 7.24 (d, J=10Hz, 1H) ; 7.22 (d, J=2.5Hz, 1H) ; 7.17 (t, J=3Hz, 1H) ; 6.9 (dd, J=3Hz and 10Hz, 1H) ; 6.44 (pis, 3H); 5.70 (m, 1H); 3.53 (s, 3H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(l-ethylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] -octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-ethylindol-5yl)bismuthine (150 mg, 0.23 mmol), synthesized according to the procedures outlined in STEP 14A and B, and methylene chloride (3 mL), peracetic acid (0.063 mL, 0.03 mmol, 32% solution in acetic acid) was added, followed 15 minutes later by the addition of 17-ethyl-1,14-dihydroxy-12-[2'-(4''hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19-21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol) and Cu(OAc) ₂ (20 mg, 0.11 mmol). The mixture was stirred at room temperature for 3 days. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ solution and the product was extracted twice with methylene chloride. The extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a brown oil. The product was isolated and purified by preparative TLC (twice) on silica gel (first 2:1 hexane/acetone and then 3% methanol in methylene chloride) to give 60 mg of the title compound.

IBI |J, ».1111! I; .1 I h, UI 1.11

159

Mass spectrum (FAB) M+Na 957. Partial ^Χ Η NMR spectrum, (CDC1 ₃ , 200 MHz) chemical shifts: 7.19 (d, J=10Hz, 1H); 7.18 (d, J=3Hz, 1H); 7.05 (d, J=4Hz, 1H); 6.90 (J=3Hz, 10H); 6.35 (d, J=4Hz, 1H); 4.09 (kv, J=6.7Hz,

2H); 3.5 (s, 3H); 1.4 (t, J=6.7 Hz, 3H) .

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-ethylindol-5yl)oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,2 8-dioxa-4-azatricyclo-[ 22.3.1.0 ^4,9 ] -octacose-18-ene-2,3,1.0,16-tetraone

To a solution containing tri(l-ethylindol-5-yl)bismuthine (0.2 g), synthesized according to the procedures specified in

In STEP 14A AND B, and methylene chloride (2 mL), peracetic acid (37 μL, 0.2 mmol) was added. After stirring for 15 minutes at room temperature, 17-ethyl1,14-dihydroxy-12[2'-(4'',3''-dihydroxy-cyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-aza-tricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene2,3,10,16-tetraone (0.2 g, 0.25 mmol) was added followed by Cu(OAc) ₂ (20 mg) and the reaction mixture was stirred for 2 days. Saturated aqueous NaHCO ₃ solution was then added and the product was extracted twice with methylene chloride. The extracts are combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. A mixture consisting of 17-ethyl-1,14-dihydroxy-12-[2'-(4''-(1-ethylindol-5-yl)oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone and 17-ethyl-1,14-dihydroxy-12-[2'-(4 ''-hydroxy-3''-(1-ethylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O 4,9]-octacos-18-ene-2,3,10,16-tetraone ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone was separated by chromatography (silica gel, 3:1,

II 1.11

160 hexane:ethyl acetate to give the title compound (0.035 g).

TLC (silica gel, 3:1, hexane:ethyl acetate) R _f =0.55. Partial ¹ H NMR spectrum, (CDCl ₃ , 200 MHz) chemical shifts: 7.21 (d, J=10 Hz, 1H); 7.14 (d, J=3 Hz, 1H); 7.08 (d, J=4Hz, 1H); 6.85 (dd, J=3 Hz and 10 Hz, 1H); 6.36 (d, J=4Hz, 1H); 4.10 (qv, J=6.7 Hz, 2H); 1.42 (t, J=6.7 Hz, 3H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(l-propylindol-5yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.O ^4,9 ] -ocfacoz-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(l-propylindol-5yl)bismuthine (200 mg, ^- ' 0.29 mmol), synthesized according to the procedures outlined in STEP 14A and B, and methylene chloride (3 mL), was added peracetic acid (0.075 mL, 0.36 mmol, 32% solution in acetic acid), and after 10 minutes, 17-ethyl-l,14-dihydroxy-12-[2'-(4''hydroxy-3 '' -methoxycyclohexyl) -1' -methylvinyl] -23,25dimethoxy-l 3 ,19,21,27-tetramethyl-l 1,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.19 mmol) and Cu(OAc) ₂ (30 mg, 0.17 mmol. The mixture was stirred at room temperature for 20 h. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ solution and the product was extracted with methylene chloride. The extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC (3 times) on silica gel (2:1 hexane/acetone; 3% methanol in methylene chloride; 2:1 hexane/acetone) to give 70 mg of the title compound. Mass spectrum (FAB) M+Na 971. Partial X NMR spectrum, (CDC1 ₃ , 200 MHz) che161

mass displacements: 7.17 (d, J=10 Hz, 1H) ; 7.02 (d, J=4 Hz, 1H) ; 6.88 (dd,. J= = 3Hz and J=10Hz, 1H) ; 6.32 (d, J=4Hz, 1H); 3.97 (t, J=7) Hz, 2H); 3.50 (s, 3H); 1.8 (m, 2H) .

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-propylindol-5yl)oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19-21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(l-propylindol-5yl)bismuthine (200 mg, 0.29 mmol), synthesized according to the procedures outlined in STEP 14D and B, and methylene chloride (3 mL), peracetic acid (0.075 mL, 0.36 mmol, 32% solution in acetic acid) was added, followed 10 minutes later by the addition of 17-ethyl-l,14-dihydroxy-12-[2'(3'',4''-dihydroxy-3''-cyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-l,28-dioxa-4aza-tricyclo-[22.3.1.O ⁴ ' ⁹ ]-octacos-18-ene-2,3, 10, 16-tetraone (150 mg, 0.19 mmol) and Cu(OAc) ₂ (30 mg, 0.17 mmol). The mixture was stirred at room temperature for 20 h. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ solution and the product was extracted with methylene chloride. The extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated and purified from the C-3'' ether by preparative TLC to give the title compound.

EXAMPLE

17-Ethyl-1, 14-dihydroxy'-12-[ 2'-(4'' - (1-hydroxyethylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

162

STAGE 25A

1-(2-Hydroxyethyl)-5-bromoindole

A mixture of NaOH (4.4 g, 0.011 mol) and DMSO (175 ml) was stirred at 100°C for 5 h, then cooled to 20°C. To this mixture was added 5-bromoindole (20 g, 0.102 mol) and the reaction mixture was stirred at room temperature for 8 h. A solution of ethylene oxide (5.1 g, 0.125 mol) in DMSO (20 ml) was prepared by bubbling gas into DMSO. This solution was slowly added to the reaction mixture with bromoindole and stirred for a further 2.5 h. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo until crystallization began. The crude product was recrystallized from diethyl ether:hexane (3:2) to give the title compound (6.25 g).

STAGE 25B

1-(2-t-Butyldimethylsilyloxyethyl)-5-bromoindole

A solution of 1-(2-hydroxyethyl)-5-bromoindole (6 g, 0.025 mol), t-butyldimethylsilyl chloride (4.5 g, 0.03 mol) and triethylamine (4.2 ml, 0.03 mol) in methylene chloride (60 ml) was stirred for 12 hours at room temperature. The reaction mixture was then washed twice with water, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (yellow oil). The Z NMR spectrum was consistent with the desired structure.

I AM INVOLVED X «Lili II

II X III IJ

163

STAGE 25C

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

To a solution of 1-(2-t-butyldimethylsilyloxyethyl)-5-bromoindole (1.4 g, 0.004 mol) in diethyl ether (14 ml) was added t-butyllithium (4.7 ml of a 1.7 M solution in pentane, 0.008 mol) at -78°C. Stirring was continued for 1.5 hours, then a solution of bismuth trichloride (0.4 g, 0.013 mol) in THF (4 ml) was added. The reaction mixture was stirred at -78°C for 2 hours, then allowed to slowly warm to room temperature and stirred for a further 8 hours. The reaction mixture was then poured into water and extracted with toluene. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. Purification by chromatography (silica gel, 4:1, hexane:ethyl acetate) afforded the title compound (semi-solid). ¹ H NMR spectrum consistent with the desired structure.

STAGE 25D

17-Ethyl-1,14-dihydroxy-12~L 2'-4''-(1-t-butyldimethylsilyloxytylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] -octacose-18-en2,3,10,16-tetraone

To a solution of tri[1-(2-t-butyldimethylsilyloxyethyl)-indol-5-yl]bismuthine (1.03 g, 0.001 mol) in methylene chloride (10 ml) at room temperature was added peracetic acid (150 μΐ). Stirring was continued for 15 minutes, then 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-aza-tricyclo-[22.3.1.O ^4,9 ]oct:acos-18-ene-2, 3, 10, 16-tetraone (1 g) and, Cu(OAc) ₂

III

164 (0.04 g). The mixture was stirred at room temperature for 20 h. The reaction was quenched by the addition of saturated aqueous NaHCO ₃ solution and the product was extracted with methylene chloride. The extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, 3:1, hexane:ethyl acetate) to give the title compound (0.38 g). ¹ H NMR spectrum was consistent with the desired structure.

STAGE 25E

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-hydroxyethylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1.0 ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone into a solution containing 17-ethyl-1,14-dihydroxy-12-[2'(4''-(1-butyldimethylsilyloxyethylindol-5-yl)oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1.0 4,9 ]-octacos-18-ene-2,3,10,16-tetraone

19,21,27-Tetramethyl-11,28-dioxa-4-azatricyclo 22.3.1. O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (0.38 g) in methylene chloride (10 ml) was added at room temperature to para-toluenesulfonic acid (0.05 g) in methanol (10 ml). The reaction mixture was stirred for 3 hours until TLC analysis indicated that the reaction was complete. The reaction mixture was poured into saturated NaHCO ₃ solution and extracted twice with methylene chloride. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, 2:1, hexane:ethyl acetate) to give the title compound (0.245 g). Mass spectrum (FAB) M+Li 957. Partial ^X H

NMR spectrum, (CDC1 ₃ , 200 MHz) chemical shifts: 7.18 (d, J=10 Hz, IH); 7.16 (pis, IH); 7.06 (d, J=4Hz,

IH) ; 6.86 (dd, J=3Hz, and 10Hz, 1H) ; 6.33 (d, J=4 Hz,

I ·η <3 HALUI II J II i II ui

165

1H); 4.13 (t, J=6.7 Hz, 2H); 3.83 (t, J=6.7Hz, 2H); 3.43 (s, 3H) .

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1'-allylindol-5'ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

STAGE 26A

1-Ali1-5-bromoindole »

To a stirred mixture of NaOH (204 mg, 5.1 mmol, 1 eq.) in dimethylsulfoxide (10 mL) was added 5-bromoindole (1.0 g, 5.1.. mmol, 1 eq.). The mixture was stirred for 3 h until the NaOH was completely dissolved (approximately 1 h). Allyl iodide (0.466 mL, 5.1 mmol, 1 eq.) was added to this solution via syringe. After 2 h, the mixture was diluted with water and extracted twice with diethyl ether. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by flash chromatography on silica gel (4:1 hexane/acetone) to give 730 mg of the title compound (7.5 mg) as l-allyl-5-bromoindole.

STAGE 26B

Tri-(1-allylindol-5-yl)bismuthine

To a solution of l-allyl-5-bromoindole (730 mg, 3.09 mmol, 1 eq) in diethyl ether (15 mL) at -78°C under nitrogen was added a 1.7 M solution of t-butyllithium in pentane (1.8 mL, 3.09 mmol, 1 eq) with stirring. The mixture was stirred at -78°C under nitrogen. 1.1 l.ll I

166 atmosphere for 1 hour. Then, a solution of bismuth trichloride (292 mg, 0.93 mmol, 0.3 equiv) in dry THF (3 mL) was added dropwise to the reaction mixture via syringe. The ice bath was filled with dry ice and the flask was capped. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was then diluted with toluene and washed with brine. The layers were separated and the aqueous layer was extracted three times with toluene. The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was dissolved in ether and filtered through a 0.4 micron PTFE membrane. The product crystallized spontaneously. The solution was cooled in a refrigerator. The crystals were collected to give 200 mg of tris (l-al-i-lindol-5-yl) bismuthine.

STAGE 26C

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-allylindol-5'ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.0 ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(l-allylindol-5ii)bismuthine (186 mg, 0.275 mmol, 1.2 equiv) and methylene chloride (3 ml) was added peracetic acid (0.064 ml, 0.303 mmol, 32% solution in dilute acetic acid, 1.32 equiv). To this solution was added THF (1 mL) and, after 10 minutes, 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-aza-tricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone (181 mg, 0.229 mmol, 1 eq) and copper (II) acetate (10 mg, 0.055 mmol, 0.24 eq). The mixture was sealed and stirred overnight. The reaction mixture was diluted with saturated aqueous NaHCO ₃ and the product was extracted 4 times with methylene chloride. The organic extracts are combined, dried over beI BIIIJI .11111.1111. !. I II .11111 n

167 aqueous Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was separated and purified by flash chromatography on silica gel (2:1 hexane/acetone) and preparative TLC (3.5% methanol/methylene chloride) to give 56 mg of pure title compound. Mass spectrum (FAB) M+Li 953. Partial ^Z H NMR spectrum, (CDC1 ₃ , 200 MHz) chemical shifts: 7.17 (bs, 1H) ; 7.15 (d, J=10 Hz, 1H) ; 7.02 (d, J=3Hz, 1H) ; 6.88 (dd, J=2Hz and 10Hz, 1H); 6.36 (d, J=3Hz, 1H); 5.95 (m, 1H); 4.63 (pld, J=14Hz, 1H); 3.50 (s, 3H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'—(4*'-(1'-allylindole-5'ii)oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ]-octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(1-allylindol-5yl)bismuthine (1.0 g, 1.48 mmol, 1.2 eq), methylene chloride (9 mL), and THF (3 mL) was added peracetic acid (0.315 mL, 1.62 mmol, 1.32 eq, 32% solution in dilute acetic acid). To this solution was added 17ethyl-1,14-dihydroxy-12-[2'-4 (4'',3''-dihydroxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo-[22.3.1.O ^4,9 ]-octa (0.1 eq), Reaction mixture

1.23 mmol, 0.123 mmol), 4 days. aqueous cos-18-ene-2,3,10,16-tetraone (956 mg, eq.) and copper(II) acetate (22 mg,

The mixture was sealed and stirred, diluted with saturated aqueous sodium chloride, and extracted twice with methylene chloride. The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The product was isolated and purified by flash chromatography on silica gel (3:1 hexane/acetone) and preparative TLC (3.5% methanol/methylene chloride) to give 163 mg of pure 17-ethyl-1,14-diNaHCO.

111 u

168 hydroxy-12-[2'-(4''-(1'-allylindol-5'-yl)oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1. O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone. Mass spectrum (FAB) M+Li. 953. Partial ^X H NMR spectrum, (CDCl ₃ , 200 MHz) chemical shifts: 7.17 (d, J=10 Hz, 1H) ;

7.15 (pis, 1H) ; 7.05 (d, J=3Hz, 1H) ; 6.86 (dd, J=10Hz and J=2.5Hz, 1H) ; 6.39 (d, J=3Hz, 1H) ; 6.05-5.85 (m,

1H); 4.66 (pld, J=5Hz, 2H); 4.57 (pld, J=5Hz, 1H); 4.38 (pld, J=13Hz, 1H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(9'-methylcarbazol3'-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.0 ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

STAGE 28A

Tri(9-methylcarbazol-3-yl)bismuthine

To a stirred solution of 3-bromo-9-methylcarbazole (646 mg, 2.48 mmol, 1 eq) in diethyl ether (12 mL) at -78°C (carbazole not completely dissolved) under nitrogen was added a 1.7 M solution of t-butyllithium in pentane (3.0 mL, 4.96 mmol, 2 eq). The mixture was rapidly warmed to room temperature and then rapidly cooled to -78°C and stirred under nitrogen for 40 min. A solution of bismuth trichloride (235 mg, 0.744 mmol, 0.3 eq) in dry THF (2.5 mL) was then added dropwise via syringe to the reaction mixture. The ice bath was filled with dry ice and the flask was capped. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was then poured into a separatory funnel containing salt

IJHII1I „UILiliII UI I U .11 IH I.

169 solution and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with ether and a mixture of ether and methanol. The solid was collected to give 200 mg and filtered through a 0.4 micron PTFE membrane. The product crystallized spontaneously. The solution was cooled in a refrigerator. The crystals were collected to give 200 mg of tri(9-methylcarbazol-3-yl)bismuthine. The supernatant was kept until further purification.

STAGE 28B

17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(9'-methylcarbazol3'-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13, 19,21,2 7-tetramethyl-11,28-dioxa-4azatricyclo-L 22.3.1.0 ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri-(9-methylcarbazol-3yl)bismuthine (200 mg, 0.267 mmol, 1.2 eq), methylene chloride (3 mL) and THF (1 mL) was added peracetic acid (0.062 mL, 0.295 mmol, 1.32 eq; 32% solution in dilute acetic acid). To this solution was added 17-ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy3''-methoxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1. O ^4,9 ] -octacos-18-ene-2,3, 10, 16-tetraone (175 mg, 0.222 mmol, 1 eq) and copper (II) acetate (10 mg, 0.055 mmol, 0.24 eq). The mixture was sealed and stirred for 48 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ solution and extracted 4 times with methylene chloride. The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated and purified by flash chromatography on silica gel (3:1 hexane/acetone) and preparative TLC (3.5% meLT 3533 B

170 ethanol/methylene chloride), giving 100 mg of pure title compound. Mass spectrum (FAB) M+Li 977. Partial ^X H NMR spectrum, (CDC1 ₃ , 200 MHz) chemical shifts: 7.68 (d, J=2 Hz, 1H) ; 7.48-7.10 (m, 6H) ;

4.58 (pld, J=4.8Hz, 1H) ; 4.39 (pld, J=14Hz, 1H) ; 3.80 (s, 3H); 3.53 (s, 2H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1'-benzylindol-5yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo[22.3.1įQ ⁴ ' ⁹ ] -octacose-18-ene-2,3,10,16-tetraone

STAGE 29A l-Benzyl-5-bromindole

To a mixture of NaOH (204 mg, 5.1 mmol, 1 eq) and DMSO (10 ml) was added 5-bromoindole (1.0 g,

5.1 mmol, 1 eq) . The reaction mixture was stirred at room temperature for 20 h after the NaOH had completely dissolved (approximately 1 h). To this solution was added benzyl bromide (0.606 ml, 5.1 mmol, 1 eq) via syringe. After 7 h. the reaction mixture was diluted with water and extracted four times with diethyl ether. The combined ether extracts were dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo. The product was recrystallized from a mixture of diethyl ether and hexane to give 888 mg of l-benzyl-5-bromoindole.

ι ·υι i iai m i; i .ι ι : i. iii

171

STAGE 29B

Tri(l-benzylindol-5-yl)bismuthine

To a stirred solution of l-benzyl-5-bromoindole (888 mg, 3.105 mmol, 1 eq) in diethyl ether (15 mL) at -78°C (indole not completely dissolved) under nitrogen was added a 1.7 M solution of t-butyllithium in pentane (3.65 mL, 6 _t 21 mmol, 2 eq). The mixture was stirred at -78°C under nitrogen for 1 h. A solution of bismuth trichloride (294 mg, 0.932 mmol, 0.3 eq) in dry THF (3.0 mL) was then added dropwise via syringe to the reaction mixture. The ice bath was filled with dry ice and the flask was capped. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was then poured into a separatory funnel containing brine and extracted four times with methylene chloride. The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with ether. The solid was collected to give 200 mg and filtered through a 0.4 micron PTFE membrane. The product crystallized spontaneously. The solution was cooled in a refrigerator. The crystals were collected to give 200 mg of tri(l-benziindol-5-yl)bismuthine. The supernatant was stored until further purification.

STAGE 29C

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1'-benzylindol-5yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-1 3,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.0 ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a stirred solution of tri(l-benzylindol-5yl)bismuthine (200 mg, 0.242 mmol, 1.2 equiv), methylene chloride (3 mL), and THF (1 mL) was added peracetic acid (0.060 mL, 0.285 mmol, 1.4 equiv; 32% triI !, III ; IIJIIHI Ii ,1! .1 II I 1,11 III

172 parts in dilute acetic acid). To this solution was added 17-ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone (159 mg, (10 mg, eq.) and copper (II) acetate 0.24 eq.). The mixture was sealed and stirred. The reaction mixture was diluted with saturated aqueous sodium hydroxide solution and extracted twice.

0.202 mmo1,

0.055 mmol, overnight.

aqueous NaHCO ₃ solution and 4 methylene chloride. The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated and purified by flash chromatography on silica gel (3:1 hexane/acetone) and preparative TLC (3.5% methanol/methylene chloride) to give 100 mg of pure title compound. Mass spectrum (FAB) M+Li

1003

Partial H NMR spectrum, :cdci

3'

200 MHz) chemical shifts: 7.3-7.0 (m, 8H); 6.84 (dd, J=9Hz, 1H) ; 6.40 (d, J=3Hz, 1H) ; 5.23 (pis, 2H) ; 4.6 (pld, J=6Hz, 1H); 4.38 (pld, J=14Hz, 2H); 3.50 (s, 3H).

EXAMPLE

17-Ethyl-1-hydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)oxy-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -octacose-18-ene-2, 3, 10, 16-tetraone

STAGE 31A

17-Ethyl-l-hydroxy-12-[ 2 ' - (4''-(t-butyldimethylsiloxy)3''-allyloxycyclohexyl)-1'.-methylvinyl]-23,25-dimethoxy-13, 19,21,27-tetramethyl-11,2 8-dioxa-4-azatricyclo[ 22.3.1.0 ⁴ ' ⁹ ] -octacose-18-ene-2,3,10,16-tetraone

To a solution containing 17-ethyl-1-hydroxy-12-[2'-(4''t-butyldimethylsiloxy)-3''-hydroxycyclohexyl)-1'-methyl-3533 B

173 tylvynyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-aza-tricyclo-[ 22.3.1. O ⁴ ' ⁹ ] -octacos-18-ene2,3,10,16-tetraone (300 mg) and 9 ml of 33% methylene chloride in cyclohexane, aul trichloroacetamidate (138 mg, neat) was added and the reaction was stirred for 5 minutes. Trifluoromethanesulfonic acid (18 μΐ, neat) was slowly added via syringe and the mixture was stirred at room temperature. After 3 days the reaction mixture was diluted with ethyl acetate and the reaction was quenched by adding saturated sodium bicarbonate solution. The layers were separated, the organic layer was washed with brine, and flash-chromatographed on silica gel (ethyl acetate:hexane (1:4) + 1% methanol) to give the title compound (230 mg, trichloroacetamide present). ^{The 1} H NMR spectrum was consistent with the desired structure.

STAGE 31B

17-Ethyl-1-hydroxy-12-[2'-(4''-hydroxy-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,2j3-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone

To a solution containing 17-ethyl-1-hydroxy-12-[2'-(4''t-butyldimethyloxy)-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl]-11,28-dioxa-4-aza-tricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene2,3,10,16-tetraone (115 mg) (STEP 31A) and acetonitrile (2.5 mL) was added a 2% HF solution in aqueous acetonitrile (40 μΐ) and the reaction was stirred at room temperature. After 5 hours, the reaction mixture was diluted with ethyl acetate and the reaction was quenched by the addition of saturated sodium bicarbonate solution. The layers are separated, the organic layer is washed with brine and dried over magnesium sulfate. The concentrate is purified by flash chromatography on silica.

174 gel (ethyl acetate:hexane (1:2)) to give the title compound (42 mg). ¹ H NMR spectrum is consistent with the desired structure.

STAGE 31C

17-Ethyl-1-hydroxy-12-[2'(4''-(1N-methyl-5-indolyl)oxy-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ]-octacose-18-ene-2,3,10,16-tetraone

To a solution containing tri(methylindol-5-yl)bismuthine (53 mg) and methylene chloride (700 μΐ). peracetic acid (17 μΐ) was added and the mixture was stirred at room temperature for 15 minutes. 17-Ethyl-1-hydroxy-12-[2'(4''-hydroxy-3''-allyloxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1.O ⁴ - ⁹ ] -octacos-18-ene-2,3,10,16-tetraone (42 mg) was dissolved in methylene chloride (270 μΐ) and added to the reaction mixture. After 18 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, brine and dried over magnesium sulfate. The concentrate was purified by flash chromatography on silica gel (ethyl acetate:hexane (1:3) + 1% methanol) to give the title compound (25 mg). Mass spectrum (FAB) 938 (M+Li); Partial ¹ NMR spectrum, chemical shifts: 7.19 (s, 1H) ; 7.18 (d,J=9Hz, 1H) ; 6.98 (d, J=3Hz, 1H) ; 6.92 (dd, J=9.3Hz, 1H) ; 6.34 (d, J=3Hz,

1H); 5.89 (m, 1H); 4.56 (brd, J=4Hz, 1H); 3.72 (s, 3H).

EXAMPLE

17-Ethyl-1-hydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)oxy-3''-n-propyloxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,29-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] -octacose-18-en-2, 3, 10, 16-tetraone ll ΧΚΙ.ΙΙΙΙ N Ί II II lU III

175

To a solution of 17-ethyl-1-hydroxy-12-[2'-(4''(1N-methyl-5-indolyl)-oxy-3''-allyloxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone (20 mg) (Example 31) in ethyl acetate (500 μΐ) was added rhodium on carbon (5 mg). The flask was charged with hydrogen and the mixture was stirred at room temperature. After 1.5 hours, the mixture was filtered through celite, then the solvent was evaporated in vacuo to give the title compound (20 mg). Mass spectrum (FAB) (M+Li); Partial ^! NMR spectrum, chemical shifts: 7.18 (s, 1H) ; 7.16 (d, J=9 Hz, 1H) ; 6.96 (d, J=3Hz, 1H) ; 6.92 (dd, J=9.3Hz, 1H) ; 6.34 (D, J=3Hz, 1H); 4.55 (pld, J=4Hz, 1H); 3.72 (s, 3H).

EXAMPLE

17-Ethyl-1, 14-dihydr.oxy-12-[ 2 ' - (4 '' - (1N-methyl-5-indolyl)-oxy-3''-i-propyloxycyclohexyl)-1'-methylvinyl] 23,2 5-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

STAGE 33A

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-i-propyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a solution containing 17-ethyl-1,14-dihydroxy-12-[2'(3'',4''-dihydroxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-1 3,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone (300 mg) and 4.5 ml of 33% methylene chloride in cyclohexane, isopropyl trichloroacetamidate (142 mg, neat) was added and the reaction was stirred for 5 minutes.

176

Trifluoromethanesulfonic acid (13.4 μΐ, neat) was slowly added via syringe and the mixture was stirred at room temperature. After 5 days, the reaction mixture was diluted with ethyl acetate and quenched with saturated sodium bicarbonate solution. The layers were separated, the organic layer was washed with brine and dried over magnesium sulfate. The concentrate was purified by preparative TLC on silica gel (ethyl acetate : hexane (1:1) t 1% methanol) to give the title compound (42 mg). ¹ H NMR spectrum was consistent with the desired structure.

STAGE 33B

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-i-propyloxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.10 ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a solution of tri(1-methylindol-5-yl)bismuthine (52 mg) in methylene chloride (700 μΐ) was added peracetic acid (17 μΐ) and the mixture was stirred at room temperature for 15 minutes. 17-Ethyl-1,14-dihydroxy-12[ 2'-(4''-hydroxy-3''-i-propyloxycyclohexyl) -1'-methylvinyl] -23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[ 2.3.1. O ^4,9 ] -octacos-18-ene-2, 3,10,16-tetraone (42 mg) was dissolved in methylene chloride (450 μΐ) and added to the reaction mixture. After 18 hours of reaction, the mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate. The concentrate was purified by preparative TLC on silica gel (ethyl acetate:hexane (1:1) + 1% methanol) to give the title compound (9 mg). Mass spectrum (FAB) 956 (M+Li); Partial ^X NMR spectrum, chemical shifts: 7.19 (s, 1H); 7.16 (d,,

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

177

1H); 6.34 (d, J=3Hz, 1H) ; 4.41 (pld, J=14Hz, 1H); 2.72 (s, 3H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-yloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

STAGE 34A

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-t-butyldimethylsiloxy)-3' ¹ -hydroxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo -[ 22.3.1. O ^4,9 ] -octacos-18-ene-2, 3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(3'',4''-dihydroxycyclohexyl)-1'-methylvinyl]-23,2 5di-methoxy-13,19,21,27-t.tetramethyl-1 1,28-dioxa-4-azatricyclo-[22.3.1. O ⁴ ' ⁹ ] -octacos-18-ene-2, 3,10, 16-tetraone (1.0 g) in dry methylene chloride (14 ml) was added 2,6-lutidine (240 μΐ) and the mixture was stirred at room temperature. After 10 minutes, t-butyldimethylsilyltrifluoromethanesulfonate (295 μΐ) was added via syringe. After 15 minutes, the reaction mixture was diluted with ethyl acetate, washed with 1N HCl, water, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate. The solvent was evaporated in vacuo and purified by flash chromatography on silica gel (ethyl acetate/hexane (1:3) + 15 methanol) to give the title compound (293 mg). ^: Η NMR spectrum consistent with the desired structure.

178

STAGE 34B

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-t-butyldimethylsiloxy)-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ]-octacose-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''-t-butyldimethylsiloxy)-3''-hydroxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-aza-tricyclo-[22.3.1.O ^4,9 ] -octacos-18-ene2,3,10,16-tetraone (290 mg) and 3.9 ml of 33% methylene chloride in cyclohexane, allyl trichloroacetimidate (131 mg, neat) was added and the reaction mixture was stirred for 5 minutes. Trifluoromethanesulfonic acid ¹ (6 μl, neat) was slowly added via syringe and the mixture was stirred at room temperature. After 5 days, the reaction mixture was diluted with ethyl acetate and quenched with saturated sodium bicarbonate solution. The layers were separated, the organic layer was washed with brine and dried over magnesium sulfate. The concentrate was purified by preparative TLC on silica gel (ethyl acetate:hexane (1:5) + 1% methanol) to give the title compound (150 mg). ^{The 1} H NMR spectrum was consistent with the desired structure.

STAGE 34C

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a solution containing 17-ethyl-1-hydroxy-12-[2'-(4''t-butyldimethylsiloxy)-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-aza-tricyclo-[22.3.1.0 ^4,9 ] -octacos-18-ene-2,3, ι: III BLIUII li .1 ll (I .I,III III.·

179

10,16-tetraone (150 mg) and acetonitrile (3 ml) were added, 2% HF solution in aqueous acetonitrile (80 μΐ) was added and the reaction was stirred at room temperature. After 2 hours, the reaction mixture was diluted with ethyl acetate and quenched with saturated sodium bicarbonate solution. The layers were separated, the organic layer was washed with brine and dried over magnesium sulfate. The concentrate was purified by flash chromatography on silica gel (ethyl acetate-hexane (1:1) + 1% methanol) to give the title compound (63 mg). ^{The 1} H NMR spectrum was consistent with the desired structure.

STAGE 34D

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-N-methyl-5-indole)-oxy-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-1,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ]-octacose-18-ene-2,2,10, 16-tetraone

To a solution containing tri(l-methylindol-5-yl)bismuthine (60 mg) and methylene chloride (1 mL), peracetic acid (23 μΐ) was added and the mixture was stirred at room temperature for 15 minutes.

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-allyloxy-cyclohexyl-1'-methylvinyl]-23,25-dimethoxy-13,19,

21,27-Tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1. O ^4,9 ] -octacos-18-ene-2,3, 10, 16-tetraone (60 mg) was dissolved in methylene chloride (500 μΐ) and added to the reaction mixture. After 20 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, brine and dried.

The concentrate was purified by silica gel chromatography (ethyl acetate:hexane (1:2) + 1% methanol) to give the title compound (26 mg). Partial ^X-ray NMR spectrum, chemical shifts; 7.18 (s, 1H); 7.16 (d, over magnesium sulfate, by rative TLC method

180

J=9 Hz, 1H) ; 6.97 (d, J=3Hz, 1H) ; 6.91 (dd, J=9.3Hz,

1H); 6.34 (d, J=3Hz, 1H) ; 5.89 (m, 1H); 4.57 (pld, J=4Hz, 1H) ; 4.41 (pld, J=4Hz, 1H) ; 3.70 (s, 3H).

EXAMPLE

17- Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-n-propyloxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo[2.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''-(1N-methyl-5-indolyl)-oxy-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos18-ene-2,3,10,16-tetraone (14 mg) in ethyl acetate (400 μΐ) was added rhodium on carbon (4 mg). The flask was filled with hydrogen and the mixture was stirred at room temperature. After 1.5 hours, the mixture was filtered through celite, then the solvent was evaporated in vacuo. Purification was carried out by flash chromatography to give the title compound (10 mg). Partial NMR spectrum of ¹ , chemical shifts: 7.17 (s, 1H) ; 7.15 (d, J=9 Hz, 1H) ; 6.97 (d,

J=3Hz, 1H) ; 6.92 (dd, J=9.3Hz, 1H) ; 6.34 (d, J=3Hz,

1H); 4.56 (pld, J=4Hz, 1H) ; 4.40 (pid, J=14Hz, 1H) ;

3.71 (s, 3H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1'-3-t-butyldimethylsilyloxypropylindol-5-yl)-oxy-3''-allyloxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ]-octacose-18-ene-2,3,10,15-tetraone

181

To a solution of tri-(3-t-butyldimethylsilyloxypropyl)indol-5-yl)bismuthine (0.43 g, 0.4 mmol) and methylene chloride (4' ml) at room temperature was added peracetic acid (0.075 ml, 32% solution in acetic acid and after 15 minutes 17-ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-methoxycyclohexyl1'-methylvinyl]-23,15-dimethoxy-13,19,21,27-tetramethyl

11,28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ]-octacose-2,3,10,

16-tetraone (350 mg, 0.44 mmol) and Cu(OAc) ₂ (30 mg). The reaction mixture was stirred for 2 days. The reaction was quenched by the addition of saturated sodium bicarbonate solution and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC on silica gel (3:1, hexane/acetone) to give the title compound (144 mg).

EXAMPLE

17- Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-(3-hydroxypropyl)indol-5-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19-21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''-(1-(3-t-butyldimethylsilyloxypropylindol-5-yl)-oxy-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 (144 mg) in methylene chloride (4 ml) at room temperature was added p-toluenesulfonic acid (20 mg) in methanol (4 ml). The reaction mixture was stirred for 3 hours. The reaction was quenched by adding saturated sodium bicarbonate solution and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, you

182 were filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC on silica gel (2:1, hexane/acetone) to give the title compound (81 mg). Partial ^X NMR spectrum, (CDCl ₃ , 200MHz) d:7.22 (d, J=9Hz, 1H); 7.18 (d, J=3 Hz, 1H); 7.07 (d, J=3Hz, 1H); 6.89 (dd, J=3Hz, and

J=9Hz, 1H) ; 6.34 (d, 3Hz, 1H); 4.20 (t, J=6.5Hz, 2H) ; 2.00 (m, 2H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(3''-hydroxy-4''-(1-tbutyldimethylsilyloxyethyl-5-yl)-oxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo-[- 22.3.1.O ^4,9 ] -octacose-18-en2,3,10,16-tetraone

To a solution of tri[1-(2-t-butyldimethylsilyloxyethyl)indol-5-yl] bismuthine (250 mg, 0.24 mmol) and methylene chloride (2 ml) at room temperature, peracetic acid (0.05 ml, 32% solution in acetic acid) was added and after 1.5 minutes, 17-ethyl-1,14dihydroxy-12-[2'-(3'',4''-dihydroxycyclohexyl)-1'methylvinyl]-2 3,2 5-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (200 mg, 0.25 mmol) and Cu(OAc) ₂ (20 mg). The reaction mixture was stirred for 2 days. The reaction was quenched by the addition of saturated sodium bicarbonate solution and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was isolated and purified by preparative TLC on silica gel (3:1, hexane/acetone) to give the title compound (74 mg).

183

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[ 2'-(3''-hydroxy-4''-(l-tbutyldimethylsilyloxyethyl-5-yl)-oxycyclonexyl)-1'-methylvinyl]-23,2 5-dimethoxy-13, 19,21,27-tetramethyl-11,2 8dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -oktakoz-18-en-2,3,10,

16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(3''-hydroxy-4''-(1-t-butyldimethylsilyloxyethylindol-5-yl)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1. O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (74 mg) in methylene chloride (2 ml) was added at room temperature p-toluenesulfonic acid (10 mg) in methanol (2 ml). The reaction mixture was stirred for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate solution and the mixture was extracted with methylene chloride. The extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give the title compound.

(44 . 8mg) Partial ^X NMR spectrum, (CDC1 _3,200 MHz) d: 7.24 (d, J=9Hz, IH) ; 7.15 (d, J= = 3 Hz, IH) ; 7.12 (d, J=3, 5Hz, IH); 6.86 (dd, J=3Hz and J=9Hz, IH) ; 6.39 (d, J=3, 5Hz, IH); 4.20 ( t, J=5Hz, 2H).

EXAMPLE

Tri-[1-2(t-butyldimethylsilyloxyethyl)-indol-6-yl]-bismuthine

Stage A: 6-Bromoindole

To a solution of 4-bromo-2-nitrotoluene (4.3 g, 20 mmol) in DMF (40 ml) was added DMF dimethylacetal (7.15 g, 60 mmol) and pyrrolidine (1.4 g, 20 mmol). The solution was heated to

184

110°C for four hours, then cooled to room temperature and diluted with ethyl ether. The mixture was washed three times with water, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The residue was dissolved in 80% acetic acid (125 ml) and heated to 75°C. Zinc dust (9.75 g, 150 mmol) was added portionwise over 20 minutes. The reaction mixture was heated at 85°C for 2 hours, cooled to about 35°C and filtered to remove unreacted zinc. The filtrate was diluted with ethyl ether, washed 3 times with water and saturated NaHCO ₃ solution. The solution was dried over sodium sulfate, filtered and concentrated in vacuo to about 30 ml, then diluted with hexane and filtered. The filtrate was concentrated until a solid off-white material was formed, which was dissolved in hexane, filtered, concentrated and 1.65 g of the title compound was obtained as a light green material.

Stage B:

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

To a suspension of NaH (192 mg, 4.8 mmol, 60% dispersion in oil) in DMF (4 ml) was added dropwise a solution of 6-bromoindole (0.85 g, 4.34 mol) in DMF (4 ml). Stirred for 10 min at room temperature, then 2-t-butyldimethylsilyloxyethyl bromide (1.15 g, 4.8 mmol, neat) was added and the mixture was stirred for 1.5 h, then poured into a mixture of ice water and hexane. The organics were washed twice with water, dried over sodium sulfate, filtered and concentrated in vacuo to give a dark oil. The product was isolated by flash chromatography (silica gel, 4:1, hexane/acetone) to give 1.04 g of the title compound (oil).

Hillll! U ii I .!.1.11 Ii·

185

Stage C:

Tri[1-2-(t-butyldimethylsilyloxyethyl)-indol-6-yl]-bismuthine

To a solution of 1-2(t-butyldimethylsilyloxyethyl)-6-bromoindole (1.0 g, 2.81 mmol) in ethyl ether (10 ml) at -78°C was added t-butyllithium (3.4 ml, 5.8 mmol, 1.7 M solution in pentane). Stir for 10 min, then add a solution of bismuth trichloride (285 mg, 0.9 mmol) in THF (3 ml). The reaction mixture was stirred at -78°C for an additional 10 min, then allowed to slowly warm to room temperature overnight. The reaction mixture was then poured into a mixture of ice water and methylene chloride. The organic layer was washed with water, dried over Na ₂ SO ₄ and concentrated in vacuo to give a dark oil. Purification by flash chromatography (silica gel, 4:1, hexane:acetone) gave the title compound (630 mg, dark oil), which was used crude (Example 41, next step).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-t-butyldimethylsilyloxyethylindol-6-yl)-oxy-3''-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] -octacos-18-ene2,3,10,16-tetraone to a solution containing tri[ 1-2(t-butyldimethylsilyloxyethyl)-indol-6-yl] -bismuthine (0.6 g, 0.58 mmol) and methylene chloride (5 ml), at room temperature, peracetic acid (0.080 ml, 32% solution in acetic acid) is added and after 15 minutes 17-ethyl-1,14dihydroxy-12-[ 2'- (4''-hydroxy-3''-methoxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -octacosLT 3533 B

186

18-ene-2, 3,10,16-tetraone (350 mg, 0.44 mmol) and Cu(OAc) ₂ (30 mg). The reaction mixture was stirred for 20 h. The reaction was quenched by the addition of saturated sodium bicarbonate solution and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The product was isolated and purified by preparative TLC on silica gel (3:1, hexane/acetone) to give the title compound (150 mg).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-(3-hydroxyethyl)indol-6-yl)-oxy-3'''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -octacose-18-ene-2,3,10,16tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''-(lt-butyldimethylsilyloxyethylindol-6-yl)-oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1. O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (150 mg) in methylene chloride (4 ml) at room temperature was added p-toluenesulfonic acid (20 mg) in methanol (4 ml). The reaction mixture was stirred for 2 hours. The reaction was quenched by the addition of saturated sodium bicarbonate solution and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give the title compound (55 mg). Partial ⁴ NMR spectrum, (CDCl ₃ , 200 MHz) d: 7.47 (d, J=6Hz, 1H);'..7.O3 (d, J=3 Hz, 1H); 6.94 (pis, 1H); 6.82 (dd, J=1.5 HZ and J=6Hz, 1H); 6.41 (d,

I·Ι1 .1! «Ι.1ΙΙΙ! li I JI JUIII 1!·

187

J=3Hz, 1H) ; 6.41 (t, J=3Hz, 1H) ; 4.20 (t, J=5Hz, 2H) ;

3.93 (t, J=5Hz, 2H); 3.50 (s, 3H).

EXAMPLE

Tri(l-methylindol-6-yl)bismuthine

To a solution of l-methyl-6-bromoindole (760 mg, 3.6 mmol) in ethyl ether (15 ml) at -78°C was added t-butyllithium (4.4 ml, 7.5 mmol, 1.7 M solution in pentane). Stir for 10 minutes, then add bismuth trichloride (375 mg,

1.2 mmol) in THF (4 mL) and the cooling was stopped. The reaction mixture was stirred for 4 h, then poured into ice water and extracted with methylene chloride. The extracts were combined, washed with water, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to a dark oil. The product was crystallized from methanol to give the title compound (290 mg, tan solid).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-methylindol-6yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.0 ^4,9 ] -octacose-18-ene-2,3,10,16-tetraone

To a solution of tri[l-methylindol-6-yl]bismuthine (200 mg, 0.33 mmol) and methylene chloride (2 ml) at room temperature was added peracetic acid (0.070 ml, 32% solution in acetic acid) and after 15 minutes 17-ethyl-l,14-dihydroxy-12-[2'-(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21, 27-tetramethyl-l,28-dioxa-4-azatricyclo-[22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.19 mmol) and Cu(OAc) ₂ (30 mg) were added. The reaction mixture is stirred for 4 days.

188 nas. The reaction was quenched by the addition of saturated sodium bicarbonate solution and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was isolated and purified by preparative TLC on silica gel (2:1, hexane/acetone) to give the title compound (76 mg).

Partial ^X NMR spectrum, (CDCl, 400 MHz) δ: 7.44 (d, J=7Hz, 1H); 6.91 (d, J=3 Hz, 1H); .6.88 (d, J=2Hz, 1H); 6.81 (m, 1H); 6.37 (d, J=3Hz, 1H); 3.68 (s,,3H), 3.51 (s, 3H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(1-dibenzylphosphonooxyethylindol-5-yl)-oxy-3''-methoxycyclohexyl)1'-methylvinyl]-23,25-dimePoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -octacose-18-ene2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''-(1-hydroxyethylindol-5-yl)-oxy-3''-methoxycyclohexyl)-1 '-methylvinyl]-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone (202 mg, azeotrope with toluene) in dry THF was added dibenzyl phosphate (88.6 mg) followed by triphenylphosphine (83.5 mg). The reaction mixture was cooled to 0°C and diethyl azodicarboxylate (50 ml) was added. The reaction mixture was stirred for 5 minutes, the ice bath was removed and stirred at room temperature for 2 hours. The reaction mixture was directly applied to a silica gel column and purified (ethyl acetate:hexane (2:3) + 1% methanol) to give the title compound (197 mg).

Partial NMR spectrum of ⁴ , (CDC1 ₃ ) d: 7.29 (m, 6H); 7.18 (m,

5H); 7.12 (d, J=9Hz, 1H) ; 7.0 (d, J=4Hz, 1H) ; 6.89 (dd,

I B UBUI. . I II I III III

189

J=9.2Hz, 1H); 6.36 (t, J=4Hz, 1H) ; 4.82 (m, 4H); 4.40 (pld, J=14Hz, 1H) ; 4.20 (m, 4H).

EXAMPLE

17-Ethyl-1,14-hydroxy-12-[2'-(4''-(1-phosphonooxyethylindol-5-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] -oktakoz-18-en-2,3,10,

16-tetraone monopotassium salt

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''-(1-dibenzylphosphatethylindol-5-yl)-oxy-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 (197 mg) in methanol (3.2 ml) was added potassium bicarbonate (16.3 mg) dissolved in water (200 ml). Palladium hydroxide on carbon was added and hydrogen was bubbled through the reaction mixture. When the reaction was complete (10 min by TLC), it was filtered through celite, washed with methanol and a small amount of water. The solvent was removed in vacuo and the crude material was purified on a HP-20 column to give the title compound (69 mg). Partial ^X NMR spectrum, (CD ₃ OD) d: 7.34 (d, J=9Hz, 1H) ;

7.27 (d, J=4Hz, 1H) ; 7.12 (d, J=2Hz, 1H) ; 6.85 (dd, J=9.2 Hz, 1H) ; 6.31 (d, J=4Hz, 1H) ; 5.23 (m, 2H); 4.35 (m, 2H); 4.13 (m, 2H); 4.13 (m, 2H).

EXAMPLE

17- Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(1-N,N-dimethyl)glycyloxy)ethylindol-5-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-2 3,2 5-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] -octacose18-ene-2,3,10,16-tetraone

190

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''-(1-hydroxyethylindol-5-yl)-oxy-3''-methoxycyclohexyl)-1 '-methylvinyl]-2 3,2 5-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone (26.6 mg) in dry methylene chloride (0.3 ml) was added at room temperature N,N-dimethylglycine hydrochloride (5.8 mg), DMAP (3.4 mg) and EDC (8 mg), respectively. The reaction mixture was stirred for 4 hours, diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, the solvent was removed in vacuo, and the crude material was purified by flash chromatography (1:2, acetone/hexane) to give 23 mg of the title compound.

Partial ^X NMR spectrum, (CDC1 ₃ ) d: 7.21 (m, 2H); 7.04 (d, J=4Hz, 1H); 6.91 (dd, J=9, 2Hz, 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

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-succinyloxytylindol-5-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ]-octacose-18-ene-2,3,10,16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''-(1-hydroxyethylindol-5-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] -octacos-18-ene-2,3,10,16-tetraone (109 mg) in dry methylene chloride was added succinic anhydride (11.5 mg) and triethylamine (19 ml). DMAP (7 mg) was then added and the reaction was monitored by TLC. After 1.5 hours, the reaction mixture was diluted with ethyl acetate and the pH was adjusted

IBIUI II .1 1 .11.111 III

191 to 4 with 1N HCl. The reaction mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried over magnesium sulfate. The crude material was purified by flash chromatography (3% methanol/CH ₂ Cl ₂ ) to give 66 mg of the title compound.

Partial NMR spectrum of ¹ , (CDC1 ₃ ) d: 7.19 (m, 2H); 7.04 (d, J=4Hz, 1H) ; 6.91 (dd, J=9, 2Hz, 1H) ; 6.39 (d, J=4 Hz, 1H); 4.32 (m, 4H); 2.49 (pis, 4H) .

EXAMPLE

17-Ethyl,14-dihydroxy-12-[2'-(4''-(l-methyl-3phenylindol-5-yl)-oxy-3''-methoxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll,28-dioxa-4 -azatricyclo[ 22.3.1.O ^4,9 ] -octacose-18-en2,3,10,16-tetraone

Stage A: 5-bromo-3-phenylisatin

To a stirred solution containing 5-bromisatin (5 g,

22.1 mmol, 1 eq) in dry THF (150 ml) was added phenylmagnesium bromide (14.7 ml, 44.2 mmol, 2 eq, 3M solution in diethyl ether). (The Grignard reagent was added at -78°C. The reaction mixture became too viscous to stir after the addition of approximately 5 ml of Grignard reagent. The cooling bath was removed and the remaining Grignard reagent was rapidly added dropwise.) The reaction mixture was stirred overnight. TLC analysis showed that a small amount of starting material remained unreacted. An additional 1.5 ml of Grignard reagent was added and the reaction mixture was stirred for an additional 6 hours. The reaction mixture was poured into a separatory funnel containing saturated aqueous ammonium chloride and extracted 4 times with diethyl ether. OrI U 11

The 192 ganol extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The product was used without further purification.

Stage B: 5-Bromo-3-phenylindole

To a stirred solution of 5-bromo-3-phenylisatin (6.39 g, 21 mmol, 1 equiv) in dry THF (50 mL) at 0°C was added lithium aluminum hydride (2.0 g, 52.5 mmol, 2.5 equiv) portionwise over 1.5 h. The cooling bath was removed and stirred overnight. The mixture was cooled to 0°C and 1N aqueous HCl was carefully added to quench the reaction. The mixture was filtered through celite and the celite was washed with THF. The filtrate was concentrated in vacuo, dissolved in ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.

Stage C: 5-Bromo-l-methyl-3-phenylindole

To a stirred solution of 5-bromo-3-phenylindole (2.4 g, 8.78 mmol, 1 eq) in dimethylformamide (20 mL) was added NaH (422 mg, 60% dispersion in oil, 10.54 mmol,

1.2 eq) . The mixture was stirred for 15 minutes. Methyl iodide (0.6 ml, 9.66 mmol, 1.1. eq) was added via syringe and the reaction mixture was stirred for 3 hours. The reaction was quenched by adding water and extracted 4 times with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography (2:1 hexane/acetone) to give 1.63 g of 5-bromo-1-methyl-3-phenylindole.

Stage D: Tri(l-methyl-3-phenylindol-5-yl)bismuthine

To a stirred solution of 5-bromo-1-methyl-3-phenylindole (1.63 g, 5.7 mmol) in ethyl ether (35 ml) under nitrogen atmosphere, at

I ·ΙΙ UBUI II .1 .1 11.IK 11

193

At -78°C, t-butyllithium (6.7 ml, 11.4 mmol, 1.7 M solution in hexane, 2 equiv) was added dropwise via syringe. Stir for 10 minutes at -78°C. Then a solution of bismuth trichloride (540 mg, 1.71 mmol, 0.3 equiv) in THF (7 ml) was added dropwise rapidly. The reaction mixture was stirred at -78°C for another 10 minutes, then the cooling bath was removed and the mixture was allowed to slowly warm to room temperature. After 3 hours of reaction, the mixture was poured into a separatory funnel with water and extracted 4 times with methylene chloride. The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with ether, the solid was collected, washed with ether, and 710 mg of tri(1-methyl-3-phenylindol-5-yl)bismuthine was obtained.

Stage E:

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-methyl-3-phenylindol-5-yl)-oxy-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-2,3,10,16tetraone To a stirred solution of tri(1-methyl-3-phenylindol-5-yl)bismuthine (645 mg, 0.78 mmol, 1.2 equiv) in methylene chloride (10 mL) and THF (3 mL) was added peracetic acid (0.514 mL, 32% solution in dilute acetic acid, 0.858 mmol, 1.3 equiv). The mixture was stirred for 15 minutes and then 17-ethyl-1,14-dihydroxy-12-[2'-(4''hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0 ⁴ ' ⁹ ]-octacos-18-ene-2,3,10,16-tetraone (514 mg, 0.65 mmol, 1 eq) and Cu(OAc) ₂ (12 mg, 0.065 mmol, 0.1 eq) were added. The flask was sealed and the mixture was stirred for 48 hours. The reaction was quenched by adding saturated sodium bicarbonate solution and the mixture was extracted 4 times with methylene chloride. The organic extracts were combined and evaporated. .u .ι ii .aaui

194 dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (2:1, hexane/acetone and 3.5% methanol/methylene chloride) to give 17ethyl-1,14-dihydroxy-12-[2'-(4''-(1-methyl-3-phenyl-indol-5yl)-oxy-3''-methoxycyclohexyl)-1'-methyl-vinyl]-23,25dimethoxy-1 3,19,21,27-tetramethyl-11,2 8-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone (74 mg).

Mass spectrum (FAB) 1003 (M ⁺ + Li); 996 (M ⁺ ) . Partial ¹ NMR spectrum, (CDC1 ₃ , 400 MHz) d: 7.59 (s, J=7Hz, 2H); 7.50 (m, 1H) ; 7.41 (t, J=7Hz, 2H) ; 7.25-7.15 (m, 3H); 6.99 (dd, J=9Hz, J=2Hz, 1H) ; 4.57 (d, J=6Hz, 1H); 4.39 (pld, J=13Hz, 1H); 3.78 (s, 3H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(l-methyl-3-(2-hydroxyethyl)indol-5-yl)oxy-3''-methoxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] -octacose-18-en2,3,10,16-tetraone

Stage A: 5-Bromo-3-hydroxyethylindole

To a stirred solution of 5-bromoindole-3-acetic acid (1.9 g, 7.48 mmol, 1 eq) in dry THF (17 mL) at 0°C was added lithium aluminum hydride (570 mg, 14.96 mmol, 2 eq) in portions over 30 minutes. The reaction mixture coagulated. THF (20 mL) was added and the cooling bath was removed. The mixture was stirred vigorously. The mixture was stirred overnight. The reaction was carefully quenched by the addition of 1N aqueous HCl and then acidified by the addition of 2N HCl. The mixture was filtered through celite and the celite was washed with THF. The filtrate was concentrated in vacuo, dissolved in ethyl acetate and washed with water. The organic

The 195 layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Analysis of the residue by TLC revealed unreacted starting material. The residue was dissolved in diethyl ether and extracted with 0.25N aqueous NaOH. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 1.16 g of 5-bromo-3-hydroxyethylindole.

Step B: 5-Bromo-3-(2-t-butyldimethylsilyloxy)ethylindole

To a stirred solution of 5-bromo-3-hydroxyethylindole (1.16 g, 4.83 mmol, 1 eq) in methylene chloride (12 mL) was added triethylamine (1.0 mL, 7.25 mmol,

1.5 eq), followed by t-butyldimethylchlorosilane (875 mg,

1.2 mmol, 1.2 eq) and dimethylaminopyridine (catalytic amount). The mixture was stirred overnight, poured into a separatory funnel with water and extracted 4 times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated. 1.66 g of 5-bromo-3(2-t-butyldimethylsilyloxy)ethylindole was obtained.

Stage C:

5-Bromo-1-methyl-3-2-t-butyldimethylsilyloxy)ethylindole

To a stirred solution of 5-bromo-3-(2-t-butyldimethylsilyloxy)ethylindole (1.66 g, 4.66 mmol, 1 eq) and DMF (15 mL) was added NaH (225 mg, 60% dispersion in oil, 5.6 mmol, 1.2 eq). After 15 min, iodomethane (0.320 mL, 5.13 mmol, 1.1 eq) was added. The mixture was stirred for 4 h, poured into a separatory funnel with water, and extracted twice with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 1.49 g of 5-bromo-1-methyl-3-(2-t-butyldimethylsilyloxy)ethylindole.

i a u imu. she .ι

H J 3.1,1

196

Stage D:

Tri-(1-methyl-3-(2-t-butyldimethylsilyloxy)ethylindol-5yl)bismuthine

To a stirred solution of 5-bromo-1-methyl-3-(2-t-butyldimethylsilyloxy)ethylindole (1.49 mg, 4.03 mmol, 1 equiv) in diethyl ether (15 mL) at -78°C under nitrogen was added t-butyllithium (4.8 mL, 8.06 mmol, 2 equiv, 1.7 M solution in pentane) via syringe. Stir for 10 min at -78°C, then a solution of bismuth trichloride (381 mg, 1.21 mmol, 0.3 equiv) in THF (5 mL) was rapidly added via syringe. Stir for 7 min at -78°C under nitrogen. The cooling bath was removed and the mixture was allowed to warm to room temperature. After 1 h, the mixture was poured into a separatory funnel with water and extracted 4 times with methylene chloride. The organic extracts were combined, washed with water, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. 554 mg of crude product was obtained. According to ^{the 1} H NMR spectrum, the residue contained a 2:1 mixture of the desired bismuthine and reduced indole. This crude mixture was used in the subsequent reaction.

Stage E:

17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(1-methyl-3-(2-tbutyldimethylsilyloxyethyl)indole-5-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-2 3,2 5-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.Q ^4,9 ] octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of tri-(l-methyl-3-(2-t-butyldimethylsilyloxyethyl)indol-5-yl)bismuthine (554 mg, crude) in methylene chloride (10 mL) and THF (3 mL) was added peracetic acid (0.120 mL, 32% solution in dilute acetic acid, 0.571 mmol). The mixture was stirred i w mm i :ι ii n,n iii

197 minutes and then 17-ethyl-1,14-dihydroxy12-[2'-(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ⁴ ' ⁹ ]-octacos-18-ene-2,3,10,

16-tetraone (347 mg, 0.439 mmol) and Cu(OAc) ₂ (24 mg, 0.13 mmol). The mixture was stirred overnight. It was then poured into a separatory funnel with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by flash chromatography on silica gel (2:1, hexane/acetone) to give 17-ethyl-1,14-dihydroxy-12-[2'-(4''-(1-methyl-3-(2-t-butyldimethylsilyloxyethyl)indol-5-yl)-oxy-3''-methoxycyclohexyl)1'-methyl-vinyl]-2 3,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-azatric3cyclo-[22.3.1.O ^4,9 ]-octacos-18-ene2,3,10,16-tetraone (200 mg, brown oil).

Stage F:

17- Ethyl-1,14-dihydroxy-12-[ 2'-(4''-1-methyl-3-(2-hydroxyethyl)-indol-5-yl)-oxy-3''-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] -octacose-18-ene2,3,10,16-tetraone

T, a stirred solution containing 17-ethyl-1,14-dihydroxy12-[2'-(4''-(1-methyl-3-(2-t-butyldimethylsilyloxyethyl)indol-5-yl)-oxy-3''-methoxycyclohexyl)-1'-methyl-vinyl]-23,2 5-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16tetraone (200 mg) and methylene chloride (6 ml) and methanol (6 ml), was added p-toluenesulfonic acid monohydrate (30 mg). The reaction mixture was stirred for 3 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and the mixture was extracted 4 times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate,

Illll .Iii uaill II ,1 I III U I.. L

198 filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (1:1, hexane/acetone and 7% methanol/methylene chloride) to give 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-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone (75 mg).

Mass spectrum (FAB) 972 (M ⁺ + Li). Partial NMR spectrum of ¹ , (CDCl ₃ , 400 MHz) d: 7.17-7.13 (m, 2H); 6.94 (dd,

J=9Hz, J=2Hz, 1H) ; 6.88 (s, 1H); 4.58 (d, J=6Hz, 1H) ; 4.39 (pld, J=13Hz, 1H) ; 3.84 (t, J=6Hz, 2H) ; 3.70 (s, 3H); 2.94 (t, J=7Hz, 2H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1,3-dimethylindol5-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ]-octacose-18-ene-2,3,10,16-tetraone

Stage A: 5-Bromo-3-methylindole

To a stirred solution containing 5-bromisatin (5 g,

22.1 mmol, 1 equiv) in dry THF (150 ml) was added via syringe to methylmagnesium bromide (32 ml, 1.4 M solution in toluene, 44.2 mmol, 2 equiv). After 45 min, TLC analysis showed that a small amount of starting material remained unreacted. 3.2 ml of methylmagnesium bromide was added and stirred for an additional 1 h. The reaction mixture was cooled to 0°C. Lithium aluminum hydride (1.26 g, 33.15 mmol, 1.5 equiv) was added portionwise. Stirred for 30 min. The cooling bath was removed and stirred overnight. The mixture was cooled to 0°C and the reaction was quenched by the careful addition of 1N HCl.

Acidified with 2N lysine, stirred with aqueous HCl. Cooling bath for 3 hours. Filtered through celite.

liLUIII Ii ii II .1.1.111 lill

199

The celite was washed with THF. The filtrate was concentrated in vacuo. The residue was diluted with water and extracted 4 times with methylene chloride. The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was applied to a glass filter filled with silica gel and eluted with hexane/acetone (4:1). The fractions containing the desired product were collected and concentrated in vacuo to give 2.85 g of 5-bromo-3-methylindole.

Stage B:

5-Bromo-1,3-dimethylindole

To a stirred solution of 5-bromo-3-methylindole (2.85 g, 13.6 mmol, 1 eq) and DMF (35 mL) was added NaH (651 mg, 60% dispersion in oil, 16.28 mmol,

1.2 eq) . Stir for 15 minutes, then add iodomethane (0.930 ml, 14.93 mmol, 1.1 eq). The mixture is stirred for 2 hours. The DMF is evaporated in vacuo. The residue is diluted with water and extracted 4 times with diethyl ether. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. 3.04 g of 5-bromo-1,3-dimethylindole is obtained (brown oil).

Stage C: Tri(1,3-dimethylindol-5-yl)bismuthine

To a stirred solution of 5-bromo-1,3-dimethylindole (3.04 g, 13.57 mmol, 1 eq) in ethyl ether (50 ml) under nitrogen at -78°C was added dropwise t-butyllithium (16 ml,

27.2 mmol, 1.7 M solution in hexane, 2 equiv) . Stir for 10 minutes at -78°C. Then a solution of bismuth trichloride (1.28 g, 4.07 mmol, 0.3 equiv) in THF (17 ml) was quickly added dropwise via syringe. The reaction mixture was stirred at -78°C for another 5 minutes, then the cooling bath was removed and the mixture was allowed to slowly warm to room temperature.LT 3533 B

200 ratures. The reaction mixture is poured into a separatory funnel with ice water and extracted 4 times with methylene chloride. The organic extracts are combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue is triturated with ether, the solid is filtered off.- . The filtrate is concentrated in vacuo, 1.28 g of a brown oil is obtained. According to ^{the X} H NMR spectrum, the residue contains a mixture of the desired tri(1,3-dimethylindol-5-yl)bismuthine and dimethylindole in a ratio of 1:2. This crude mixture is used in the following Step D.

Stage D:

17-Ethyl-1,14-dihydroxy-12-[2'-(4'-(1,3-dimethylindol-5yl)-oxy-3''-methoxycyclohexyl)-1'-ethylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] -octakaz-18-ene-2,3,10,16-tetraone

To a stirred solution containing tri(1,3-dimethylindol-5yl)-indol-5-yl)bismuthine (approximately 420 mg [1.28 g of material containing one-third of bismuthine, 0.7 mmol, was added

1.2 eq] and methylene chloride (12 ml) and THF (4 ml) was added peracetic acid - (0.193 ml, 32% solution in acetic acid, 0.916 mmol, 1.3 eq). To this mixture was added 17-ethyl-1,14-dihydroxy-12-[2' — (4’’-hydroxy-3’’-methoxy-cyclohexyl)-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 (464 mg, 0.59 mmol, 1 eq) and Cu(OAc) ₂ (3.0 mg, 0.176 mmol. 0.3 eq). The reaction mixture was stirred for 4 days. The reaction was quenched by the addition of saturated sodium bicarbonate solution and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was isolated and purified by flash chromatography on silica gel (2:1, hexane/acetone and again 3.5% methanol/methylene chloride) and preparative TLC.

L min i! ,ι ji .0..11 ui.

Method 201 (eluted 6 times with 4:1 hexane/acetone) gave 117 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4''-(1,3dimethylindol-5-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,

16- tetraon.

Mass spectrum (FAB) 934 (M ⁺ ). Partial ^X NMR spectrum, (CDCl3, 400 MHz) d: 7.14-7.10 (m, 2H); 6.91 (dd, J=9Hz, J=2Hz, 1H); 6.76 (s, 1H).; 4.57 (s, J=9Hz, 1H); 4.39 (pld, J=13Hz, 1H); 3.66 (s, 3H); 2.24 (s, 3H).

EXAMPLE

17- Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-benzylindol-5-yl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,2 5dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0 ^4,9 ]-octa-cos-18-ene-2,3,10,16-tetraone r· to a stirred solution containing tri (1-benzylindol-5-yl)indol-5-yl)bismuthine ^ (approximately 1.28 g, 1.54 mmol,

1.2 eq) and methylene chloride (9 mL) and THF (3 mL) were added peracetic acid (0.357 mL, 32% solution in dilute acetic acid, 1.60 mmol, 1.3 eq). To this mixture were added 17-ethyl-1,14-dihydroxy-12-[2'(3 '' , 4''-dihydroxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.0 ⁴ ']-octacos-18-ene-2,3,10,16-tetraone (1 g, 1.28 mmol, 1 eq) and Cu(OAc) ₂ (23 mg). The reaction mixture was stirred for 2 days. The reaction was quenched by the addition of saturated sodium bicarbonate solution and the mixture was extracted 4 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 (2:1, hexane/acetone, 3.5% methanol/' methylene chloride) and again (2:1 hexaUflllt .1! .1 II ! 1IIIU11.

202 nas/acetone) , 25-3 mg of 17-ethyl-1,14-dihydroxy12-[2'-(4''-(1-benzylindol-5-yl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone are obtained.

Mass spectrum (FAB) 934 (M ⁺ + Li). Partial NMR spectrum of ¹ , (CDC1 ₃ , 400 MHz) d: :7.30-7.05 (m, 8H) ; 6.82 (dd, J=8Hz, J=2Hz, 1H) ; 6.43 (d, J=3Hz, 1H) ; 5.27 (s, 2H) ; 4.58 (d, J=6Hz, 1H); 4.40 (pld, J=13Hz, 1H).

EXAMPLE

17-Ethyl-1,14-dihydroxy-12-[ 2 ' - (4''-(1-(3-hydroxypropyl)indol-5-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] -2 3,25-dimethoxy-13/19, 21,2 7-tetramethyl-11,28dioxa-4-azatricyclo-[ 22.3.1.0 ^4,9 ] -octacose-18-en-2,3,

10,16-tetraone

Step A: 2-t-Butyldimethylsilyloxy)ethyl bromide

To a solution of 2-bromoethanol (50 g, 0.40 mol) in methylene chloride (50 ml) was added t-butyldimethylchlorosilane (63.4 g, 0.42 m), triethylamine (45.4 g, 0.45 mol) and dimethylaminopyridine (0.5 g). The mixture was stirred overnight, washed 3 times with water. The organic fraction was dried over sodium sulfate, filtered and concentrated in vacuo to give 85 g of the title compound (light yellow oil).

⁴ NMR spectrum, (CDC1 ₃ ) , chemical shifts: 3.85 (t,

2H); 3.36 (t, 2H); 0.86 (s, 9H); 0.05 (s, 6H).

Step B: 1-2(t-Butyldimethylsilyloxyethyl)-5-bromoindole

To a suspension of NaH (12 g, 0.3 mol, 60% dispersion in oil) in DMF (200 ml) was added dropwise 5-bromoindole (50 g, ι nu mini χι ι π..ιιι ιιι.ι

203

0.255 mol) solution in DMF (300 ml). Stir for 15 minutes at room temperature, then add 2-t-butyldimethylsilyloxyethyl bromide (60 g, 0.255 mol, neat) and stir for 1 hour, then pour into a mixture of ice water and hexane. The organics are washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The product is purified by column chromatography (silica gel, 3:1, hexane/acetone) to give 68.6 g of the title compound (light yellow oil).

^X NMR spectrum, (CDC1 ₃ ) , chemical shifts: 7.72 (s,

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).

STAGE C:

17- Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-(3-t-butyldimethylsilyloxypropyl)indol-6-yl)-oxy-3''-methoxycyclohexyl)-1 '-methylvinyl]-23,2 5-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone tri[1-(3-t-butyldimethylsilyloxypropyl)indol-6-yl] )bismuthine (0.917 g, crude) was added to a solution of peracetic acid (7 mol) in methylene chloride at room temperature and 17-ethyl-1,14dihydroxy-12-[2 ' - (4''-hydroxy-3''-methoxycyclohexyl)-1' -methylvinyl] -2 3,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ] -octacos18- ene-2-, 3, 10, 16-tetraone (500 mg. 0.63 mmol) and Cu(OAc) ₂ (50 mg). The mixture was stirred for 2 days. The reaction was then quenched by addition of saturated sodium bicarbonate solution, and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was isolated and purified by preparative TLC.1111 HIL

204 method on silica gel (3:1, hexane/acetone) to give the title compound (318 mg).

STAGE D:

17-Ethyl-1, 14-dihydroxy-12-[ 2'(4'' - (1-(3-hydroxypropyl)-indol-6-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,

28-dioxa-4-azatricyclo-[ 22.3.1.0 ^4,9 ]-octacose-18-en-2,

3, 10, 16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''-(1-(3-t-butyldimethylsilyloxypropyl)indol-6-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-di15 methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1. O ^4,9 ]-octacos-18-ene-2,3,10,16tetraone (318 mg) in methylene chloride (5 ml) was added p-toluenesulfonic acid (25 mg) in methanol (5 ml) at room temperature. The reaction mixture was stirred for 3 hours. The reaction was quenched by adding saturated sodium bicarbonate solution and the mixture was extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1, hexane/acetone) to give the title compound (190 mg).

Partial NMR spectrum ^{of 4} , (CDC1 ₃ , 200 MHz), chemical shifts: 7.43 (d, J=9Hz, 1H); 7.02 (d, J=2 Hz, 1H);

6.98 (d, J=3Hz, 1H) ; 6.78 (dd, J=2Hz and J=9Hz, 1H) ;

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

2H) .

EXAMPLE

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-((2'''-(3''''diethylaminopropionyloxy)ethyl)indole-5''-ii)-oxy-3''LT 3533 B

205 methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] -octacose-18-ene-2, 3, 10, 16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-±2-[2'-(4''-(1'''-(2''''-hydroxyethyl)indol-5''''ii)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-L 22.3.1. O ^4,9 ]-octacos-18-ene-2,3,10,16tetraone (200 mg, 0.210 mmol, 1 eq) in methylene chloride (2 mL) under nitrogen was added 3-N,N-diethylaminopropionic acid hydrochloride (57 mg, 0.315 mmol,

1.5 eq), dimethylaminopyridine (26 mg, 0.210 mmol, 1 eq) and EDC (60 mg, 0.315 mmol, 1.5 eq). The reaction mixture was stirred for 1 h. It was then diluted with ethyl acetate, washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography (3:2 hexane/acetone) to give 194 mg of 17-ethyl-1,14-dihydroxy-12-[2'- (4'.' - ((2''''-(3'''''-diethylaminopropionyloxy)ethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,cos-15-ene-2,1079 (M ⁺ +1)

28-dioxa-4-azatricyclo-[22.3.1.O ⁴ ' ⁹ ] -octa3, 10, 16-tetraone. Mass spectrum (BAB)

EXAMPLE

17-Ethyl-l, 14-dihydroxy-12-[ 2'-(4”-((2''-(3'dimethylaminopropionyloxy)ethyl)indol-5'''-ii)-oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo[ 22.3 .1. O ^4,9 ]-octacose-18-ene-2, 3, 10, 16-tetraone in iii

ΙΙΒΙΙΙ. b I .1 JUinB.l

206

The title compound is prepared as described in Example 54 using 3-N,N-dimethylaminopropionic acid.

EXAMPLE

17-Ethyl-l, 14-dihydroxy-12-[ 2'-(4''-((2 ^, '' ^, -(3' ^,,, 'aminopropionyloxy)ethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] -octacose-18-ene-2, 3, 10, 16-tetraone

The title compound is prepared as described in Example 54 using appropriately protected 3-aminopropionic acid and subsequent removal of the amino protecting group.

EXAMPLE

17-Ethyl-l, 14-dihydroxy-12-[ 2' - (4''-((2''''-(3''''benzyloxycarbonyl-2'''''-benzyloxycarbonylamino-propionyloxy)ethyl)indole-5'''-ii)-oxy-3''-methoxycyclohexyl)-1' -methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27tetramethyl-ll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3, , 10, 16-tetraone

To a stirred solution containing 17-ethyl-1,14-dihydroxy-12-[2'—(4''-(1'''-(2''''-hydroxyethyl)indol5'''-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-en-2,3,

To 10,16-tetraone (500 mg, 0.526 mmol, 1 eq) in methylene chloride (5 ml) under nitrogen atmosphere was added N-Cbz-

aspartic acid beta-benzyl ester (225 mg, 0.631 mmol, 1.2 eq) , dimethylaminopyridine (64 mg, 0.526 mmol, 1 eq) and EDC (120 mg, 0.631 mmol, 1.2 eq) . The reaction mixture is stirred 2 hours. TLC

well, okay.

UBU t 1 .1 I .1 I ii Π ·

Analysis of 207 indicated that the reaction was complete. The mixture was diluted with ethyl acetate, washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by flash chromatography (70:30 hexane/acetone) to give 687 mg of 17ethyl-1,14-dihydroxy-12-[2'- (4'- ((2'-'-'-'- (3'-'-'-benzyloxycarbonyl-2'''''-benzyloxycarbonylamino-propionyloxy)ethyl)indol-5'-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone.

EXAMPLE

17-Eti1-1, 14-dihydroxy-12-[ 2'-(4''-((2' ¹¹ '-(aspartyloxy)ethyl)indol-5'''-ii)-oxy-3''-methoxycyclohexyl)1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-i8-ene-2, 3, 10, 16-tetraone

To a stirred solution containing 17-ethyl-1,14-dihydroxy-12-[2'-(4''-((2'''-(3'''''-benzyloxycarbonyl-2'''''-benzyloxycarbonylamino-propionyloxy)ethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,

28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ]-octacose-18-en-2,

3, 10, 16-tetraone (125 mg, 0.093 mmol, 1 eq) in methanol (2 mL) was added palladium hydroxide on carbon (25 mg). The flask was filled with hydrogen and stirred for 30 min. The reaction mixture was filtered through a 0.45 micron PTFE membrane and concentrated in vacuo. The product was purified by flash chromatography (100:10:5:0.5/CHCl3:MeOH: formic acid:water) to give 95 mg of 17-ethyl-1, 14-dihydroxy-12-[2'-(4((2' ' ' ' -(aspartyloxy)ethyl)indol-5'''-ii)-oxy-3''-meI III 11 imu, i i ii ιιιιι u *

208 toxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo[22.3.1. O ^4,9 ] -octacos-18-ene-2, 3, 10, 16-tetraone. Mass spectrum (FAB) 1067 (M ^T ) .

EXAMPLE

17-Eti1-1, 14-dihydroxy-12-[ 2'-(4''-((2''''-(l'''''imidazolylcarbonyloxy)ethyl)indole-5'''-ii)-oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo[ 22.3.1. O ⁴ ' ⁹ ] -octacose-18-ene-2, 3, 10, , 16-tetraone

To a stirred solution containing 17-ethyl-1,14-dihydroxy'12-[2' - (4'' - (1''' - (2''''' -hydroxyethyl) indol5'''-ii)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] -octacos-18-ene-2,3,10,

16-tetraone (1.5 g, 1.58 mmol, 1 eq) in methylene chloride (15 mL) under nitrogen was added carbonyldiimidazole (256 mg, 1.58 mmol, 1 eq). After 45 min, the reaction mixture was diluted with ethyl acetate, washed with 1N HCl and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was used without further purification.

EXAMPLE

17- Ethyl-l, 14-dihydroxy-12-[ 2'-(4''-((2''''-(l'''''piperazinecarbonyloxy)ethyl)indole-5'''-ii)-oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-azatricyclo-' [ 22.3.1 . O ^4,9 ]-octacose-18-ene-2,3,10,16-tetraone

To a stirred solution containing 17-ethyl-1,14-dihydroxy-12-[2 ' - (4' '-( (2' ' ' '-(1' ' ' ''-imidazolylcarboLT 3533 B

209 nyloxy)ethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl ) -1 '-methylvinyl] -23 , 25-dimethoxy-13, 19, 21, 27tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone (100 mg, 0.096 mmol, 1 eq) and THF Ί ml) at room temperature under a nitrogen atmosphere was added piperazine (82 mg, 0-.956 mmol, 10 eq). The mixture was stirred for 2 hours at room temperature, kept overnight in the refrigerator and stirred for another 6 hours at room temperature. The mixture was diluted with ethyl acetate, washed with 1 N HCl, saturated sodium bicarbonate solution and brine. The product was purified by flash chromatography on silica gel (5% methanol/methylene chloride + 1% ammonium hydroxide) to give 74 mg. Mass spectrum (FAB) 1064 (M ⁺ +1).

EXAMPLE 61

17- Ethyl-l, 14-dihydroxy-12-[ 2'-(4' ^, -(l'''-(2''''(2''''' - (2'''' -hydroxy)ethylaminocarbonyloxy)ethyl)indole-5 ''' -ii) -oxy-3 -methoxycyclohexyl) -1' -methylvinyl] -23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11,28-dioxa-4-azatriocyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'—(4''-(1-''''-(2''''-(1'''''-imidazolyloxy)ethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos18-ene-2,3,10,16-tetraone (100 mg, 0.096 mmol, eq) and THF (i mL) at room temperature under nitrogen was added ethanolamine (29 μΐ, 0.478 mmol, 5 eq). The reaction mixture was stirred overnight. The mixture was diluted with ethyl acetate, washed with 1N HCl, saturated sodium bicarbonate solution, and brine. The product was purified by flash chromatography on

Illlll ii IBIU. 11 I II .1111111JK.I.

210 silica gel (45/65 acetone hexane) and 50 mg of 17-ethyl-1,14-dihydroxy-12-[2'- (4'' - ((2'''' - (2''''''hydroxy)ethyleneaminocarbonyloxy)ethyl)indol-5'''-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone are obtained.

Mass spectrum (FAB) 1061 (M ⁺ +Na); 1038 (M ⁺ +l).

EXAMPLE 62,

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(l'''-(2''''(2''''-(isopropylaminocarbonyloxy)ethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-di15-methoxy-13, 19, 21, 27-tetramethyl-1, 28-dioxa-4-azatricyclo-[ 22.3.1 ]-octacose- ¹⁸ -ene-2,3, 10,16-tetraone.

To a stirred solution containing 17-ethyl-1,14-dihydroxy-12-[2'-(4''-(1'''-(2''''-(1''''-imidazolyl-carbonyloxy)ethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-aza-tricyclo-[22.3.1. O ^4,9 ] -octacos-18-ene-2, 3, 10, 16-tetraone (116 mg, 0.111 mmol, 1 equiv) and THF (1 ml) , ..at room temperature under nitrogen atmosphere, isopropylamine (48 μΐ, 0.555 mmol, 5 equiv.) was added. The reaction mixture was stirred overnight. The mixture was diluted with ethyl acetate, washed with 1N HCl and brine. The product was purified by flash chromatography on silica gel (2:3 acetone hexane) to give 50 mg of 17-ethyl-1,14-dihydroxy-12[2'- (4'- (1'''-(2''''-(2''''-(isopropylaminocarbonyloxy)ethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-aza-tricyclo-[22.3.1.O ^4,9 ]-octacos-1835 en-2,3,10,16-tetraone. Mass spectrum (FAB) 1043 (M ⁺ +Li).

211

17-Ethyl-1, 14-dihydroxy-12-f (1''''-piperidinecarbonyloxy)ethyl)indole-5'''-ii)-oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-aza-tricyclo- 22.3.1.O ^4,9 ]-octacose-18-en-2, 3, 10, 16-tetraone

EXAMPLE

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2 ^, -(4 ^, '-(1' ^,, -(2' ^, ''-(1' ^,, ' ^,- imidazolylcarbonyloxy)ethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27tetramethyl-11,2S-dioxa-4-aza-tricyclo-[22.3.1.0 tacos-18-ene-2,3,10,16-tetraone (150 mg, 0.143 mmol, 1 equiv) and THF (1 ml) at room temperature under nitrogen was added piperidine (42 μΐ, 0.717 mmol, 5 equiv). The reaction mixture was stirred 1 hour. The mixture was diluted with ethyl acetate, washed with 1N HCl and brine. The product was purified by flash chromatography on silica gel (4:1 hexane/acetone) to give 115 mg of 17-ethyl-1,14-dihydroxy-12-[2'- (4'- (1'- (2''''-(1''''-piperidinecarbonyloxy)ethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-aza-tricyclo-[22.3.iO ⁴ ' ⁹ ]-octacos-18-ene-2,3,

10, 16-tetraone.

-okMass spectrum (FAB) 1062 (M)

Example

17-Ethyl-1, 14-dihydroxy-12-[2'-(4''-(2''''(1'''''-morpholinecarbonyloxy)ethyl)indole-5'''-ii)-oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] -octacose-18-ene-2, 3, 10, 16tetraone

111911 I.LUU. JI .1 11 J1BI1B.L

212

To a stirred solution containing 17-ethyl-1,14-dihydroxy-12-[2' — (4' '-(1' ' '-(2' ' ' '-(1' ' ' ' ' -imidazolylcarbonyloxy)-ethyl)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. O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone (100 mg, 0.096 mmol, equiv) and THF (1 mL), morpholine (42 μΐ, 0.478 mmol, equiv) was added at room temperature under nitrogen. The reaction mixture was stirred for 4 h. The mixture was diluted with ethyl acetate, washed with IN HCl, saturated sodium bicarbonate solution, and brine. The product was purified by preparative TLC on silica gel (4% methanol/methylene chloride) to give 85 mg of the product. The compound was further purified by preparative TLC on silica gel (4% methanol/methylene chloride) to give 67 mg of 17-ethyl-1, 14dihydroxy-12-[ 2 ' - (4 '' - (1''' - (2 '''' - (1''''''-morpholinecarbonyloxy)ethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27tetramethyl-11, 28-dioxa-4-aza-tricyclo-[ 22.3.1.O ^4,9 ] octacos-18-en-2, 3, 10, of 16-tetraone.

Mass spectrum (FAB) 1064 (M ⁺ ).

EXAMPLE

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(l'''-(2''''-(diphenylaminocarbonyloxy)ethyl)indole-5'''-ii)-oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-aza-tricyclo[ 22.3 .1.0 ^4,9 ]-octacose-18-ene-2, 3, 10, 16-tetraone

To a stirred solution containing 17-ethyl-1,14-di-. hydroxy-12-[2'— (4''-(1'''-(2''''-hydroxyethyl)indol5'''-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-en-2,3,

UIII JI .1 11 1LII III.!.

213

10,16-tetraone (100 mg, 0.105 mmol, 1 eq) in methylene chloride (1 mL) under nitrogen was added diphenylcarbamyl chloride (29 mg, 0.13 mmol, 1.2 eq), triethylamine (22 μΐ, 0.16 mmol, 1.5 eq) and dimethylaminopyridine (3 mg, 0.021 mmol, 0.2 eq). The reaction mixture was stirred overnight. Additional diphenylcarbamyl chloride (15 mg) and triethylamine (11 μΐ) were added. After 3 h, the mixture was diluted with ethyl acetate, washed with 1N aqueous HCl, water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by preparative TLC (3% MeOH/methylene chloride) to give 50 mg of 17-ethyl-1,14-dihydroxy-12-[2*-(4' ^T —(1' ^,T — (2 '''' —(diphenylaminocarbonyloxy) -ethyl) indol-5 '''-.yl)-oxy-3''-methoxycyclohexyl·)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-aza-tricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone.

Mass spectrum (FAB) 1046 (M ⁺ ).

EXAMPLE

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1'''-(2''''-(diethylaminocarbonyloxy)ethyl)indole-5'''-ii)-oxy-3''-methoxycyclohexyl )-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-aza-tricyclo[ 22.3.1.0 ^4,9 ]-octacose-18-ene-2, 3, 10, 16-tetraone

To a stirred solution containing 17-ethyl-1,14-dihydroxy-12-[2'- (4'- (1'- (2'-)-hydroxyethyl)indol-5'-)-oxy-3'-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,-28dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-en-2,3,

10,16-tetraone (100 mg, 0.105 mmol, 1 eq) in methylene chloride (1 mL) under nitrogen was added diethylcarbamyl chloride (16 μΐ, 0.13 mmol, 1.2 eq), triethylamine (22 μΐ, 1.5 eq), and dimethylaminopyridine (3 mg, 1.0 eq). The reaction mixture was stirred overnight. The mixture was heated at reflux for 4 days. The mixture was then cooled, diluted with ethyl acetate, washed with 1N aqueous HCl, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by preparative TLC (3% MeOH/methylene chloride) to give 16 mg of 17-ethyl-1,14-dihydroxy-12-[2'- (4''-(1''' - (2'''''-(diethylaminocarbonyloxyethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13> 19,21,27tetramethyl-11,28-dioxa-4-aza-tricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone. Mass spectrum (FAB) 1057 (M ⁺ +Li).

EXAMPLE

17-Ethyl-1, 14-dihydroxy-12-[ 2 '-(4' ¹ -(1'''- <2'''-methanesulfonyloxyethyl)indole-5'''-ii)-oxy-3''-methoxycyclohexyl)-1' -methylvinyl]-23, 25-dimethoxy-13, 19, 21,

27-tetramethyl-ll, . 28-dioxa-4-aza-tricyclo-[ 22.3.1.0 ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone

To a stirred solution containing 17-ethyl-1,14-dihydroxy-12-[2'-(4''-(1'''-(2''''-hydroxyethyl)indol5''' - ii)-oxy-3 '' -methoxycyclohexyl)-1 ' «-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo-[22.3.1.O ^4,9 ]-octacos-18-en-2,3,

10, 16-tetraone (500 mg, 0.526 mmol, 1 eq) in methylene chloride (20 mL) under nitrogen at 0°C was added triethylamine (147 μΐ, 1.053 mmol, 2 eq) followed by methanesulfonyl chloride (54 μΐ, 0.579 mmol, 1.1 eq). The reaction mixture was stirred for 10 minutes and the cooling bath was removed. The reaction mixture was stirred at room temperature for 3 hours. The mixture was stored in the refrigerator for

I IIUI

215 overnight. The solvent was removed in vacuo. The product was used further without purification.

EXAMPLE

17-Ethyl-l, 14-dihydroxy-12-[ 2'-(4''-(l' ^,, -(2''''-azido-ethyl)indole-5'''-ii)-oxy-3''-methoxycyclohexyl)-1'methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl, 28-dioxa-4-aza-tricyclo-[ 22.3.1.O ^4,9 ]-octacose-18en-2, 3, 10, 16-tetraone

To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4''-(1'''-(2''' ^1- methanesulfonyloxyethyl)-indol-5'''-yl)-oxy-3''-methoxycyclohexyl)-1 ¹ methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl11,28-dioxa-4-aza-tricyclo-[22.3.1.O ^4,9 ]-octacos-18ene-2,3,10,16-tetraone (0.526 mmol, 1 eq) and DMF 10 mL) under nitrogen atmosphere was added sodium azide (171 mg, 2.63 mmol, 5 eq). The reaction mixture was heated at 60°C for 2 hours. The solvent was removed in vacuo. The residue was diluted with ethyl acetate and washed with brine. The aqueous layer was extracted 3 times with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (2:1 hexane/acetone) to give 310 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4''-(1'''—(2'' ^T '-azidoethyl)indol-5'''-ii)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1. O ^4,9 ]-octacose-18-ene-2, 3, 10, 16-tetraone.

Mass spectrum (FAB) 975 (M ⁺ ).

IU III UUIIE JI .1 I J u. nu

216

EXAMPLE*

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1'''-(2''''-amino-ethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl)-1' methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl, 28-dioxa-4-aza-tricyclo-[ 22.3.1. O ^4,9 ]-octacoz-18-en2,3,10,16 tetraone

To a stirred solution containing 17-ethyl-1,14-dihydroxy-12-[2'-(4''-(1'-(2''''-azido-ethyl)indol5'''-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-aza-tricyclo-[22.3.1.O ⁴ ' ⁹ ]-octacos-18-en-2,3,

10,16-tetraone (260 mg, 0.27 mmol, 1 eq) and THF (6 mL), water (7 drops) was added followed by triphenylphosphine (87 mg, 0.33 mmol, 1.25 eq). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo. The product was purified by flash chromatography on silica gel (10% MeOH/methylene chloride) to give 227 mg of 17-ethyl-1,14-dihydroxy12-[2'-(4'\-(1'''-(2''''-amino-ethyl)indol-5'''-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13, -19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-j 22.3.1.0 ^4,9 ]-octacos-18-ene-2 , 3, 10, 16-tetraone. Mass spectrum (FAB) 956 (M ⁺ + Li).

example

17-Ethyl-l, . 14-Dihydroxy-12-[ 2' — (4''-(1'''-t-butyldimethylsilyloxyethoxyethyl)indole-5'''-ii)-oxy-3''-methoxy-cyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27+tetramethyl-ll, 28-dioxa-4-aza-tricyclo[ 22.3.1.0 ⁴ '· ⁹ ]-octacos-18-en-2, 3, 10, 16-tetraone

To a stirred solution of tri[1-(2-t-butyldi-methylsilyloxyethoxyethyl)indol-5-yl)-indol-5-yl] bismuthine (360 mg, 0.31 mmol) and methylene chloride (3 ml) at room temperature was added peracetic acid (0.05 ml, % solution in acetic acid) and after 10 minutes 17-ethyl-1,14-dihydroxy-12-[2'-(3'',

4''- dihydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] -octacos-18-ene-2, 3, 10, 16-tetLT 3533 B and Cu(OAc) ₂ (20 mg) . hours. Reaction suraon (200 mg, 0.25 mmol)

The reaction mixture was stirred for 18 h, quenched with saturated sodium bicarbonate solution, and extracted with methylene chloride. The organic extracts were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was isolated and purified by preparative chromatography (3:1, hexane/acetone),

TLC gave 120 mg of the title compound (dark oil)

EXAMPLE

17-Ethyl-1, 14-dihydroxy-12-[ 2'-(4''-(1'''-hydroxyethoxyethylindole-5'''-ii)-oxy-3''-methoxycyclohexyl)1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-ll, 28-dioxa-4-aza-tricyclo ^- l 22.3.1. O ^4,9 ] -octacose-18-ene-2, 3, 10, 16-tetraone

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''-(lt-butyldimethylsilyloxyethoxyethylindol-5'''ii)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1.0 ⁴ ' ⁹ ]-octacos-18-ene-2,3,10,16tetraone (120 mg) in methylene chloride (3 ml) was added p-toluenesulfonic acid (20 mg) in methanol (3 ml) at room temperature. The reaction mixture was stirred for 3 hours. The reaction was quenched by adding saturated sodium bicarbonate solution and the mixture was extracted with methylene chloride. The extracts are combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The product is purified by preparative TLC on a silica LT 3533 B.

218 kageli (2:1, hexane/acetone) and the title compound (51 mg) was obtained. Partial NMR spectrum of ¹ , (CDCl ₃ , 200 MHz), chemical shifts: 7.19 (d, J=9Hz, 1H); 7.17 (d, J=2 Hz, 1H); 7.08 (d, J=3.5 Hz, 1H); 6.89 (dd, J=2Hz and J=9Hz, 1H); 6.34 (d, J=3.5 Hz, 1H); 4.22 (t, J=5Hz, 2H); 3.73 (t., J=5Hz, 2H); 3.57 (t, J=5Hz,

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

EXAMPLE

17-Ethyl-l, 14-dihydroxy-12-[ 2'-(3''-methoxy-4''-(1'''(1''''-oxoprop-3''''-ii)indole-5'''-ii)oxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-l3, 19, 21, 27tetramethyl-ll, 28-dioxa-4-aza-tricyclo-[ 22.3.1.O ^4,9 ] octacos-18-e n-2, 3, 10, 16-tetron

To a solution of 17-ethyl-1,14-dihydroxy-12-[2'(4''—(1''' — (3''''-hydroxypropyl)-indol-5 '''-yl)-oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ]-octacos-18-ene-2,3,10,16-tetraone (700 mg, 0.726 mmol) and methylene chloride (25 mL), DMSO (2 mL) and diisopropylethylamine (3.7 mL) were added followed by pyridine-sulfur trioxide complex (650 mg, 4.1 mmol). The mixture was stirred for 20 minutes, then poured into saturated sodium bicarbonate solution and extracted with methylene chloride, the extract was dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel (4:1, hexane/acetone) to give the title compound (457 mg).

Partial ^X NMR spectrum, (CDC1 ₃ , 200 MHz), chemical shifts: 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=2Hz and

J=9Hz, 1H) ; 6.33 (d, J=3.5 Hz, 1H) ; 4.39 (t, J=5Hz,

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

111110.1

Ι,ΒΙΙΙί .!! .1 II :1.111111 UIS

219

EXAMPLE

17-Ethyl-1, 14-dihydroxy-12-[2'-(3''-methoxy-4''-(1'''(1''''-carboxyet-2''''-ii)indole-5'''-ii)oxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-l3, 19, 21, 27tetramethyl-ll, 28-dioxa-4-aza-tricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone

To a stirred solution containing 17-ethyl-1,14-dihydroxy-12-[2' — (3 *'-methoxy-4''-(1 ''' — (1''''-oxoprop3''''-ii)-indol-5'''-ii)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-aza-tricyclo-[22.3.1.O ^4,9 ] -octacos-18-en-2 ,3,

10,16-tetraone (100 mg), 5-bromoindole (300 mg) and 2methyl-2-butene (0.80 ml) in t-butanol (4 ml) were added. A solution of sodium chlorite (15 mg) and a solution of sodium dihydrogen phosphate (15 mg) in water (0.15 ml) were added. The reaction mixture was stirred for 0.5 h, then concentrated in vacuo. The residue was poured into 10 ml of water containing two drops of 2N HCl and diethyl ether.

The organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by preparative TLC (2 times): initially 2:1 hexane/acetone, then 7% methanol in methylene chloride, and flash chromatography on a C ₁₈ column with 60% acetonitrile in water. 11 mg of the title compound was obtained. Mass spectrum (FAB) 1001 (M ⁺ +Na) .

Using the general procedures described in Examples 1-73, the following compounds of formula I (wherein R ⁴ is hydrogen, R ⁵ is methyl, ethyl, propyl or acetyl; R ¹⁰ is hydrogen and n=2) were prepared from appropriately substituted starting materials and reagents.

220

EXAMPLE No. R ¹

R'

^R5

OH

OH

OH

CHjCHj

_{CH3CH2 ​}

CKjCHj

OH

OH

OH

OH

6h ₃

C H,

OH

CH,

CHjCfí

CKjCHj

CH ₃ CH ₂ ch ₃ ch ₂

CH ₃ CHj

CHjCHj

I IBIltl Ι.Ι·11ί H .1 II 9111:1 U.I,

221

EXAMPLE

T-Cell Proliferation Test

1. Sample preparation

The test compounds are dissolved in absolute alcohol at a concentration of 1 mg/ml.

2. Test

C57B1/6 mouse spleens are sterilely dissected and carefully dissociated in chilled to 0°C RPMI 1640 culture medium (GIBC, Grand Island, N.Y.) containing 10% heat-treated fetal calf serum (GIBO). The cells are pelleted by centrifugation at 1500 rpm for 8 minutes. Contaminated erythrocytes are removed by treating the pellet with ammonium chloride lysis buffer (GIBO) for 2 minutes at 4°C. Chilled medium is added and the cells are centrifuged again at 1500 rpm for 8 minutes. T-lymphocytes are isolated by passing the cell suspension through a nylon fiber column as follows: Prepare a nylon fiber column by filling washed and dried nylon fiber into 20 ml plastic syringes. The columns are sterilized by autoclaving for 30 minutes at 25°F. Nylon fiber columns are moistened with warm (37 °C) culture medium and washed with the same medium. The washed spleen cells are resuspended in warmed medium and slowly loaded onto the column. The columns are then incubated for 1 hour at 37 °C in an upright position. Unadsorbed T-lymphocytes are eluted from the columns by exposure to warmed culture medium and the cell suspension is centrifuged as described above.

Purified T-lymphocytes are resuspended (2.5 χ 10 ⁵ cells/ml) in complete culture medium consisting of RPMI 1640 medium with 10% heat-inactivated

UII grow up ii ι i ...uju ji. j.

222 fetal calf serum, 100 mM glutamine, 1 mM sodium pyruvate, 2 x 10 ⁵ M 2-mercaptoethanol and 50 µg/ml gentamicin. Ionomycin (250 ng/ml) and PMA 10 ng/ml are added. The cell suspension is immediately dispensed into 96-well flat-bottomed microtiter plates (Kostar), 200 μΐ per well. The test compounds are dispensed at various dilutions at 20 μΐ per well with three replicates. 17-allyl-1, 14dihydroxy-12-[2'-(4''-hydroxy-3''-methoxy-cyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27tetramethyl-11, 28-dioxa-4-aza-tricyclo-[22.3.1.O ^4,9 ] octacos-18-ene-2, 3, 10, 16-tetraone was used as the standard. The plates with the cultures were incubated for 44 hours at 37 °C in a humidified atmosphere consisting of 5

CO and air. T-lymphocyte proliferation was assessed by measuring the uptake of tritiated thymidine. After 44 hours, cells were pulse-labeled with 2 microcuries per well of tritiated thymidine (NEN, Cambridge, MA). After an additional 4 hours of incubation, cultures were harvested onto glass fiber filters using a sample multi-collector. The radioactivity of the filter discs corresponding to individual wells was measured by standard liquid scintillation counting methods (beta-counter). The average number of scintillations per minute per replicate well was calculated and the results were expressed as the concentration of compound required to inhibit 50% of the uptake of tritiated thymidine by T-cells.

A series of compounds were tested according to the presented methodology. T-cell proliferation was inhibited according to the above test by the compounds presented in the following sections.

see those pav Ldin in the pictures: 1, n, 12, 13, 14, 15, 16, 17 31, 32, 33, 34, 35, 37, 39 51, 52, 53, 54, 57, 58, 60 71, 72 and 73

3, 4, 5, 6, 7, 8, 9, 10 18, 19, 20, 21, 23, 26, 28 42, 44, 46, 47, 48, 49, 50 61, 62, 63, 64, 65, 66, 69

Hey!

223

The results of this test reliably demonstrate the immunosuppressive activity inherent in the compounds of this invention.

In order to determine antagonistic activity, the above procedure is modified as follows: dilutions of the compounds are incubated with 17-allyl-1, 14-dihydroxy-12[2'-(4''-hydroxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13, 19, 21, 27-tetramethyl-11, 28dioxa-4-aza-tricyclo-[22.3.1.O ^4,9 ]-octacos-16-ene-2, 3, 10, 16-tetraone (standard) at a concentration of

1.2 nM, ie the concentration that inhibits T-cell proliferation by 100%. The concentration of compound that reduces the inhibition caused by the standard itself by 50% is measured and the ED ₅₀ value is determined.

While the above description provides the principles of the present invention with examples provided for illustrative purposes, it is understood that the practice of the invention encompasses all possible variations, adaptations, modifications, deletions or additions to the methodologies or protocols described herein that fall within the scope of the claims and their equivalents.

Claims (10)

DEFINITION OF THE INVENTION 1 »1 44 UBO I r I1U, IIIU 253 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[ 2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-2 3,2 5dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'—(4''-(1N-2-hydroxyethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-en-2,3,10, 16- tetraon; 17- Ethyl-1,14,20-trihydroxy-12-[ 2' — (4''-(1N-2-hydroxyethyl-5-indolyl)-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-ene-2,3,10, 16- tetraon; 17- Ethyl-1,20-dihydroxy-12-[ 2'—(4''-(1N-2-hydroxyethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-en-2,3,10, 16- tetraon; 17- Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(1N-2-hydroxyethyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo-[ 22.3.1.0 ⁴ ' ⁹ ] octacos-18-en-2,3,10, 16- tetraon; 17- Eti1-1,14,20-trihydroxy-12-[ 2' -(4' '-(1-N-2-hydroxyethyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,2 5-dimethoxy-13,19,21,27-tetramethyl-11,28IIIIL , 11111«! She ;IL I J.JIBJ; 254 dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2,3,10, 16- tetraon; 17- Ethyl-l,20-dihydroxy-12-[2'-(4''-(1-N-2-hydroxyethyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1-N-2-hydroxyethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1-N-hydroxyethyl5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16tetraone; 17-Eti1-1,14-dihydroxy-12-[ 2'-(4''-(1N-benzyl-5-indoiii)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-2 3,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Eti1-1,14,20-trihydroxy-12-[2'-(4''-(1N-benzyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(1-N-benzyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-2 3, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] ok.takoz-18-en-2,3, 10, 16-tetraone; I 1IU ELI IUHD Ϊ: !l 1 .1!« 1,113 255 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-benzyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4''-(1N-benzyl-5indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(1N-benzyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-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; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1N-benzyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12-[2'-(4''-(1N-benzyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,20-dihydroxy-12-[2'-(4''-(1-N-benzi1-5-indo iii)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-2 3,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^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''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3,10,16-tetraone; 1111 256 17-Ethyl-1-hydroxy-12-[ 2' — (4''-{1N-benzyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12-[ 2 ¹ -(4''-(1N-benzyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-benzyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-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-benzyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25dime tox i-13, 19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10, Ιβ-t-etraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-cyclopropyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3,10,16-tetraone ; 17-Ethyl-1,14-dihydroxy-12-[ 2' — (4'' - (1N-cyclopropyl-5indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-en-2, 3,10,16-tetraone ; 17-Ali1-1,14-dihydroxy-12-[2'—(4''-(1N-cyclopropyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-en-2, 3,10,16-tetraone ; 257 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1N-cyclopropyl-5indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-cyclopropyl-5indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2,3,10, 16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1N-cyclopropyl-5indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12-[ 2'-(4''-(1N-cyclopropyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12-[ 2'-(4''-(1N-cyclopropyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12-[2'-(4''-methoxy-N-tryptophanylcarbonyl-methoxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3, 10, 16tetraone ; 17-Ethyl-1-hydroxy-12-[ 2'-(4''-(3-indolyl)ethylaminocarbonyl-methoxy-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-2,3,10,16tetraone; lllil. IIHIIII! JI Jll III ILIIIIIIJ. IU I 258 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-1-(3-hydroxypropyl)-indolyl-5-yl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-en-2,3,10, 16- tetraon; 17- Ethyl-1,14-dihydroxy-12-[ 2'-(3''-hydroxy-4''-(1hydroxyethylindol-5-yl)-oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-en-2, 3,10,16tetraone ; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(1-hydroxyethylindol-6-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-methylindol-6yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-1 3 , 19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'—(4''-(1-dibenzylphosphonoxy-ethylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'methylvinyl]-2 3,25-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-phosphonoxy-ethylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-2 3,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatrici<lo-[22.3.1.O ^4,9 ] octacos-18-ene-2, 3,10,16tetraone menopotassium salt; 17-Ethyl-1,14-dihydroxy-12-[ 2 ¹ —(4''-(1-(N,N-dimethylglycyloxy)ethylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'' Ui ELI 259 methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1-succinyloxytylindol-5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-en-2,3,10, 16- tetraon; 17- Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(1-methyl-3-phenylindolyl-5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(l-methyl-3-(2-hydroxyethyl)-indol-5-yl)oxy-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; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1,3-dimethylindol5-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(9'-methylcarbazol3'-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''- ((2'''-(diethylaminopropionyloxy)ethyl)indole-5''-ii)oxy-3''methoxycyclohexyl)-1'-methylvinyl] -23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; ιιιιι ΙΙΙίΙΙΙΙί Ii .III III I llllll, ,1,1,1 J 260 17-Ethyl-1,14-dihydroxy-12-[ 2 '-(4''-((2''''-(3''''-dimethylaminopropionyloxy)ethyl)indol-5'''-yl)oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13.19.21.27- tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-((2'''-(3''''aminopropionyloxy)ethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-l3,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4 ^,, -((2''''-(3' ^,,, 'benzyloxycarbonyl-2'''''-benzyloxycarbonylaminopropionyloxy)ethyl)indol-5'''-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-2 3,25-dimethoxy-13,19,21,27tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-((2''''-(aspartyloxy)ethyl)indol-5'''-yl)oxy-3''-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-((2''''-(1'''''imidazolylcarbonyloxy)ethyl)indole-5'''-ii)oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13.19.21.27- tetramethyl-ll, 28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-((2''''-(1''''piperazinecarbonyloxy)ethyl)indole-5'''-ii)oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13.19.21.27- tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 261 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4 ^IT -(1'''-(2''''(2'''''-hydroxy)ethylaminocarbonyloxy)ethyl)indole-5'''ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl] -23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''- (1'''- (2'''-(isopropylaminocarbonyloxy)ethyl)indol-5'''-yl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13.19.21.27- tetramethyl-11,28-dioxa-4-azhtricyclo[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l, 14-dihydroxy-12-[ 2^(4^-(1^-(2-^(1'''''-piperidinecarbonyloxy)ethyl)indole-5'''-ii)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy13.19.21.27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.0 ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l, 14-dihydroxy-12-[ 2^(4^-(1^^(2^^(11 i * ι i-morpholinecarbonyloxy)ethyl)indole-5'''-ii)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-l, 14-dihydroxy-12-[ 2'-(4''-(l'''-(2''''(diphenylaminocarbonyloxy)ethyl)indole-5'''-ii)oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10, 16-tetraone; 17-Ethyl-l, 14-dihydroxy-12-[ 2--(4^-(1^^(2^^(diethylaminocarbonyloxy)ethyl)indole-5'''-ii)oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3, 10,16-tetraone; lllll· llhlllll .11 .III II J.II1BI, I 11 262 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4 ^TT -(l'''-(2'' ^,T (methanesulfonyloxyethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1'''-(2'''''azidoethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1'''-(2'''-aminoethyl)indole-5'''-ii)oxy-3''-methoxycyclohexyl)-1'methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene2,3,10,16-tetraone; 17-Ethyl-l, 14-dihydroxy-12-[ 2'-(4-(l '-t-butyldimethylsilyloxyethylindole-5'''-ii)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-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-tetramethylll, 28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene2,3,10,16-tetraone; 17- Ethyl-1,14-dihydroxy-12-[2'-(3''-methoxy-4''-(1'''(1''''-oxoprop-3''''-yl)indol-5'''-yl)oxycyclohexyl)-1'-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; and i from ii.i 1UIUI1 Ji ii lt Lili L! .11,1 263 17-Ethyl-1,14-dihydroxy-12-[2'-(3''-methoxy-4''-(1'''(1''''-carboxyet-2''''-ii)indole-5'''-ii)oxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll, 28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos5 18-ene-2,3,10,16-tetraone; or a pharmaceutically acceptable salt thereof. 1 Illi »J 245 17-Eti1-1,14-dihydroxy-12-[2'-(4''-(1N-methyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo[22.3.1.O ^4,9 ] octacos-18-ene-2, 3,10, 16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14,20-trihydroxy-12-[ 2'-(4'lN-methyl-5indoII)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone ; 17-Eti1-1,14,20-trihydroxy-12-[ 2'-(4''-(lN-methyl-5indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa~4azatriclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-methoxycyclohexyl·)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22''. 3.1. O ^4,9 ] octacos-18-ene-2,3,10, 16-tetraone; 17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1-N-methyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25ιιιι ΙΙΙΙΙΜΙΙ! I! ,ΙΙί ,11 I„H I IJ J 246 dimethoxy-13,19,21,27-tetramethyl-11,2 8-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12-[2'-(4''-(1N-methyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28- ^dioxa -4azatricyclo[ ^22.3.1.O4'9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ali1-1,20-dihydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10, 16-tetraone; 17-Ethyl-1-hydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-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-Eti1-1,14-dihydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,.27-tetramethyl-1,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ali1-1,14-dihydroxy-12-[2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(1N-ethyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl] -23,2 5dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12-[2'-(4''-(1-N-ethyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-2 3,2 5-dime1 Ml JI J UHIKI JI .1 1 I III Ll·· J! 247 toxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-en-2, 3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)-oxy-3''-allyloxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3, 10, 16-tetraone; 17-Ethyl-1-hydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)oxy-3''-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^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''-n-propyloxycyclohexyl)-1'-methylvinyl] 23.25- dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1-hydroxy-12-[ 2'-(4''-(1N-methyl-5-indolyl)oxy-3''-n-propyloxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^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''-i-propyloxycyclohexyl)-1'-methylvinyl] 23.25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.0 ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(1N-ethyl-5-indo111-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4''-(1-N-ethyl-5indoII)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] ιιιι IUIUK L! ,11 11 J JIUIj , I 248 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10, 16-tetraone; 17-Ethyl-1,20-dihydroxy-12-[2'—(4''-(1N-ethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^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''-hydroxycyclohexyl)-1'-methylvinyl]-2 3, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2, 3,10, 16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1N-ethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12-[ 2'-(4''-(1N-ethyl-5-indolyl)-oxy-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; 17-Allyl-1,20-dihydroxy-12-[2'-(4''-(1N-ethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ali1-1,14-dihydroxy-12-[ 2'-(4''-(1N-ethyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12-[2'-(4''-(1-N-ethyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dime1 IIU 3) AUGUST ·!; Ί 1 DU D'I. 249 toxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3, 10, 16-tetraone; 17-Allyl-1-hydroxy-12-[ 2'-(4'(1-N-ethyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-2 3,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] 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'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2,3,10, 16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-propyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[2'-(4''-(1N-propyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(1N-propyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1. O ^4,9 ] octacos-18-ene-2, 3, 10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(1N-propyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14,20-trihydroxy--12-[2'-(4''-(1-N-propyl-5indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4I 1)11 IUIMI IS iii J UB.IIIJ 250 azatricyclo-[ 22.3.1.O ^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''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,18-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[ 2'-(4''-(1N-propyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-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-1,14,20-trihydroxy-12-[ 2'-(4''-(1N-propyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 2 3,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo-[ 22.3.1.O ^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'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1N-propyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12-[2'-(4''-(1N-propyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ali1-1-hydroxy-12-[2'-(4''-(1-N-propyl-5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dii iu i UUD i; ii 1 .1 .IMI. U* 251 methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3, 10, 16-tetraone; 17-Ethy 1-1,14-dihydroxy-12-[ 2'-(4''-(1N-propyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-2 3,2 5dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'—(4''-(1N-propyl-5-indolyl)-oxy-3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Eti1-1,14-dihydroxy-12-[2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3,10, 16-tetraone; 17-Ethyl-1,14,20-trihydroxy-12-[ 2'-(4''-(1N-allyl-5indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^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'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-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'-methylvinyl]-23, I III I imiaiš n iii. i UBU. 1 l ll 252 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12-[2'-(4''-(1-N-allyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(LN-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-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'-methylvinyl]-23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,20-dihydroxy-12-[2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-2 3,2 5-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ⁴ ' ⁹ ] octacos-18-ene-2, 3,10,16-tetraone; 17-Ethyl-1-hydroxy-12-[ 2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12-[2'-(4''-(1N-allyl-5-indolyl)-oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2, 3,10,16-tetraone; 1 111 ιΝ Ιλ·Ι· '1 Ί II. .11111.111 243 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-(3-thiophene)-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricio-[ 22.3.1. O ^4,9 ] octacos-1S-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4'(2-thiophene)oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13.19.21.27-tetramethyl-1,28-dioxa-4-azatricyclo [ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(2-benzothienyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(5-indolyl)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13.19.21.27- tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(5-indolyl)oxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-en-2, 3,10,16-tetraone; 17-Eti1-1,14,20-trihydroxy-12-[ 2'-(4''-(5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,20-dihydroxy-12-[ 2' — (4''-(5-indolyl)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1-hydroxy-12-[2'-(4''-(5-indolyl)oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxyI III I Ullllllll .11 III II Lllll!. I 1..I.I 244 13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ⁴ ' ⁹ ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'—(4''-(5-indolyl)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(5-indolyl)oxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,14,20-trihydroxy-12-[2'-(4''-(5-indolyl)oxy-3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-1 3,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1,20-dihydroxy-12-[ 2'-(4''-(5-indolyl)oxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3, 10, 16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(5-indolyl)oxy3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.O ^4,9 ] octacos-18-en-2, 3,10,16-tetraone; 17-Allyl-1,14-dihydroxy-12-[2'-(4''-(5-indolyl)oxy3''-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13.19.21.27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Allyl-1-hydroxy-12-[2'-(4''-(5-indolyl)oxy-3''methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13.19.21.27-tetramethyl-11,2S-dioxa-4-azatricyclo[22.3.1.O ^4,9 ] octacos-18-ene-2,3,10, 16-tetraone; (1) hydrogen, (2) hydroxy, (3) OR ¹¹ , or R ³ and R ⁴ together form a double bond; R ¹⁰ is hydrogen, hydroxy, fluorine or OR ¹¹ ; W is 0; and n is 2. lol 11111! JI Iii II IJIIUII .1 11,1 242 (1) hydrogen, (2) methyl, (3) ethyl, (4) propyl, (5) allyl, (6) R ¹¹ , (7) -C ₂ - ₃ alkyl-OH; and (8) C ₂ - ₃ alkyl--OR ¹¹ ; R ³ is optionally: (1) R ¹ values; (2) hydrogen; (3) phenyl; (4) substituted phenyl having substituents X, Y, Z; (5) 1- or 2-naphthyl; (6) substituted 1- or 2-naphthyl having substituents X, Y, Z; (7) biphenyl; (8) substituted biphenyl having substituents X, Y, Z; (9) _C1-10 alkyl; (10) substituted (©^-alkyl, wherein one or more substituents are optionally: (a) hydroxyl, (b) oxo group, (c) C ₁ _ ₆ -alkoxy group, (d) ari lC ₁ _ ₃ -alcohol i group, (e) substituted arylC ₁ _ ₃ -alkoxy group, in which the aryl group is substituted by X, Y and Z, (f) unsubstituted or substituted aryloxy group, in which the aryl group contains substituents X, Y and Z, (g) -OCO-Cj.g-alkyl, (h) 6 7 6 7 NR R , where R and R have the meanings defined above, (i) -NR ⁶ CO-C ₁ _ ₆ -alkyl-R ⁷ , in which R ⁶ and R ⁷ are as defined above, (j) COOR ⁵ , where R ⁶ has the values defined above, iui.ii iiuui ii ι i jnui 230 (k) -CHO, (i) phenyl, (m) substituted phenyl having substituents X, Y and Z, (n) 1- or 2-naphthyl, (c) substituted 1- or 2-naphthyl having substituents X, Y, Z, (p) biphenyl, (q) substituted biphenyl having substituents X, Y, Z, (r) -OR ¹¹ , and (s) S (O) p-C 1-8 -alkyl; (11) C ₃ _ ₁₀ -alkenyl; (12) substituted C ₃ _ ₁₀ -alkenyl optionally having one or more substituents, including: (a) hydroxyl, (b) oxo, (c) C^g-alkoxy, (d) phenyl-C ₁ _ ₃ -alkoxy, (e) substituted phenyl-C _: . ₃ -alkoxy, in which the phenyl group is substituted by X, Y and Z, (f) -OCO-C^g-alkyl, (g) -NR ⁶ R', in which R ⁶ and R ⁷ have the meanings defined above, (h) -NR ⁶ CO-C ₁ _ ₆ -alkyl, in which R ⁶ has the meanings defined above, (i) -COOR ⁶ , in which R ⁶ has the meanings defined above, (j) -CHO, (k) phenyl, (l) substituted phenyl, in which X, Y and Z, (m) 1- or 2-naphthyl, I III t ! LKBIIK Ii I II acute 231 (n) substituted 1- or 2-naphthyl having substituents X, Y and Z, (o) biphenyl, (P) substituted biphenyl having substituents X, Y and Z, (q) -0R ¹¹ , and (r) -S (0) p-C^g-alkyl ; (13) C ₃ _ ₁₀ -alkylation; (12) substituted C ₃ _ ₁₀ -alkynyl optionally having one or more substituents, including: (a) hydroxyl, (b) oxo group, (c) C ₁ _ ₆ -alkoxy group, (d) phenyl-C ₁ _ ₃ -alkoxy group, (e) substituted phenyl-C ₁ _ ₃ -alkoxy group, in which the phenyl group is substituted by X, Y and Z, (f) -OCO-C.-g-alkyl, (g) -NR ⁶ R', in which R ⁶ and R ⁷ have the meanings defined above, (h) -NR ⁶ CO-C ₁ _ ₆ -alkyl, in which R ⁶ has the values defined above, (i) -COOR ⁶ , where R ⁶ has the values defined above, (j) -CHO, (k) phenyl, (D substituted phenyl having substituents X, Y and Z, (m) 1- or 2-naphthyl, (n) substituted 1- or 2-naphthyl having substituents X, Y and Z, (o) biphenyl, (P) substituted biphenyl having substituents X, Y and Z, I.«11 m .ii .i i .imu !. 232 (q) -OR ¹¹ , and (r) -S (0) pC 1 -6 -alkyl; (15) -R ¹¹ ; R ³ is hydrogen, hydroxyl, OR ¹¹ or C 1-6 -alkoxy; R ⁴ is hydrogen or R ³ and R ⁴ together form a double bond; R ⁵ is methyl, ethyl, propyl or allyl; R ¹⁰ is hydrogen, hydroxy, OR ¹¹ or fluorine; R ¹ can optionally be: (a) -PO(OH)OM ⁺ , where M ⁺ is a positively charged inorganic or organic ion, (b) -SO ₃ 'M ⁺ , (c) -CO(CH ₂ )qCO ₂ M ⁺ , where q is 1-3, and (d) -CO-C ₁ _ ₆ -alkyl-NR ⁶ R ⁷ , where R ⁶ and R ⁷ have the meanings defined above and the alkyl group is unsubstituted or optionally substituted with one or more substituents, including: (i) hydroxyl, (ii) C ₁ -C ₆ -alkoxy, (iii) -NR ¹⁶ R ¹⁷ , wherein R ¹⁶ and R ¹⁷ independently of each other may optionally be: (a') hydrogen, and (b') C ₃ _ ₆ -alkyl, (iv) -COOR ⁶ , wherein R ⁶ is as defined above, (v) phenyl, (vi) substituted phenyl having substituents X, Y and Z, ιιιιιικ Ji ii .iLig ui 233 (vii) heteroaryl, (viii) -SH, and (ix) -S-Ci-g-alkyl; W is O or (H, OH); X, Y and Z are independently of each other optionally: (a) hydrogen, (b) C1-4-alkyl, unsubstituted or substituted with one or more substituents, optionally including: (i) aryl, (ii) substituted aryl having substituents X', Y' and Z', (iii) heteroaryl, (iv) substituted heteroaryl having substituents X', Y' and Z ' , (v) unsubstituted or substituted aryloxy radical having substituents X', Y' and Z' in the aryl group, (vi) -OR ⁶ , (vii) -OR ¹¹ , (viii) -OCOR ^S , (ix) -OCO ₂ R ⁶ , (x) -NR ^S R ⁷ , (xi) -CHO, (xii) -NR ⁶ CO-C _: _ ₆ -alkyl-R ⁷ , (xiii) -NR ⁶ CO ₂ -C ,_ ₆ -alkyl-R ⁷ , (xiv) -NR ⁶ CONR ⁶ R ^? , (XV) -oconr ⁵ r\ (xvi) -CONR ⁶ R ⁷ , ιιιυι 234 (c) y.^-alkyl, where one or more alkyl carbon atoms are replaced by a group selected from: -NR ⁶ -, -O-, -S(O) _p -, -CO ₂ , -O ₂ C-, -CONR ⁶ -, -NR ⁶ CO-, -NR ⁶ CONR ⁷ -, -CO-, -CH(OH)-, alkenyl or alkynyl and alkyl may be unsubstituted or substituted with one or more substituents optionally including: (i) aril, (ii) substituted aryl having substituents X', Y' and Z' (iii) heteroaryl, (iv) substituted heteroaryl having substituents X', and Z ' , (v) unsubstituted or substituted aryloxyradical having substituents X', Y' and Z ' in the aryl group, (vi) -OR ⁶ , (vii) -OR ¹¹ , (viii ) -OCOR ⁶ , (ix) -OCO ₂ R ⁶ , (x) -no. ⁶ and ⁷ , (xi) -CHO, (xii) -NR ⁶ CO-C ₁ _ ₆ -alkyl-R ⁷ , (xiii ) -NR ⁶ CO ₂ -C ₁ . _6- alkyl-R ⁷ , (xiv) -nr ⁶ conr ⁶ r ⁷ , (xv) -oconr ⁶ r ⁷ , (xvi) -conr ⁶ r ⁷ , (d) halogen, (e) -no. ⁶ and ⁷ , (f) -CN, (g) -CHO, (h) -CF ₃ , I.UIIK !; .1 II Jhll UI· 235 (i) -SR ⁸ , when R ⁸ is hydrogen, C^g-alkyl, trifluoromethyl or phenyl, (j) -SOR ⁸ , (k) -SO ₂ R ⁸ , (l) -conr ⁶ r ⁷ , (m) R ⁹ O(CH ₂ ) _m -, when R ⁹ is hydrogen, C^g-alkyl, hydroxy-C ₂ _ ₃ -alkyl, -CF ₃ , phenyl, R ¹¹ or naphthyl and m is 0, 1, 2 or 3, (n) -CH (OR ¹² ) (OR ¹³ ) , when R ¹² and R ¹³ are C ₁ _ ₃ -alkyl or together form an ethyl or propyl bridge, (o) R ⁹ COO (CH ₂ ) _m ~, where R ⁹ and m are as defined above, (p) R ⁹ OCO (CH ₂ ) n,-, in which R ⁹ and m are as defined above, and (q) -R ¹¹ ; or any two of X, Y, Z may be joined to form a saturated ring containing 5, 6 or 7 atoms, the atoms of this ring containing 1 or 2 oxygen atoms, the remaining atoms being carbon, X', Y' and Z' are independently of each other optionally: (a) hydrogen, (b) C^-alkyl, (c) C ₂ _ ₆ -alkenyl, (d) halogen, (1) heteroaryl; 1. A compound having the formula I: or a pharmaceutically acceptable salt thereof, wherein ^R1 is: 2. A compound according to claim 1, wherein the absolute configuration in Formula I is as defined in Formula III: III ιι·!ΐ,ιι, .. I 1 ΙίΙΙΙΙ.';,;! LT 3533 B 237 (2) substituted heteroaryl containing substituents X, Y and Z; 3. A compound according to claim 1, wherein the heteroaryl is selected from the group consisting of: (Pyrimidine) (Pyrazine) lllll 238 X (Isoquinoline) X (Quinoxaline) where Q is -N(X)-, -O or -S-. (3) heteroaryl-C _{1-10 -alkyl} ; 4. The compound according to claim 3, wherein the heteroaryl is selected from the group consisting of: I «1,1 U-l ιιι» m ·; Ί 1 .11 EC [,! . 239 MISS lllllllli I! .III lt for I litas, :i 1.1 i 240 where the values of X are defined in point 1 i ui ai 241 (4) substituted heteroaryl-C ₁ _ ₁₀ -alkyl, wherein the heteroaryl group contains substituents X, Y and Z and the alkyl moiety may be substituted with one or more substituents selected from: (a) hydroxyl, (b) oxo-, (c) C1-6-alkoxy, Hey! IBIU: I! .1 II 11:11 1.1Λ .I. 225 (d) aryl-C ₁ _ ₃ -alkoxy groups, (e) substituted arylC ₁ _ ₃ -alkoxy groups, in which the aryl group is substituted by X, Y and Z, (f) unsubstituted or substituted aryloxy group, in which the aryl group is substituted by X, Y and Z, (g) -OCO-C^g-alkyl, (h) -NR R , where R and R' independently of each other are optionally (i) hydrogen, (ii) substituted or unsubstituted C ₁ . ₁₀ -alkyl having one or more substituents, among which optionally: (a ¹ ) aryl, unsubstituted or substituted by X, Y, Z, (b ¹ ) heteroaryl, unsubstituted or substituted by X, Y, Z, (C) -OH, (d') C^g-alkoxy, (e') -CO ₂ H, (f') -CO ₂ -C ₁ _ ₆ -alkyl, (g') -C ₃ .. ₇ -cycloalkyl and (h') -OR ¹¹ , (iii) C ₃ _ ₁₀ -alkenyl, unsubstituted or substituted by one or more substituents, optionally including: (a') aryl, unsubstituted or substituted by X, Y, Z, (b') heteroaryl, unsubstituted or substituted by X, Y, Z, (c') -OH, (d') C 6 -C 6 -Alkoxy group, UBUI. J.I 226 (e') -CO ₂ H, (f) -CO ₂ -C ₁ _ ₆ -alkyl, (g') -C ₃ _ ₇ -cycloalkyl and (h') -OR ¹¹ , 5. The compound of claim 1, wherein the heteroaryl is: R ² is optionally: (5) heteroaryl-C ₁ _ ₁₀ -alkyl, in which one or more carbon atoms are replaced by a group selected from: -NR ⁶ -, -O-, -S(O) _p -, -CO ₂ , -O ₂ C-, -CONR ⁶ -, -NR ⁶ CO-, -NR ⁶ CONR ⁷ -; 6. A compound selected from the group consisting of: 17-Eti1-1,14-dihydroxy-12-[2'-(4''-(2-furanyl)methoxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(2-furanyl)methoxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-(2furanyl)-methoxycyclohexyl)-1'-methylvinyl]-23,25dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[ 22.3.1. O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone ; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(2-thiophene)-methoxy3''-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[ 2'-(4''-(2-thiophene)-methoxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-(3-thiophene)-methoxy3''-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 17-Ethyl-1,14-dihydroxy-12-[2'-(4''-hydroxy-3''-(2thiophene)-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa~4-azatricyclo-[ 22.3.1.O ^4,9 ] octacos-18-ene-2,3,10,16-tetraone; 6 7 6 7 (e) (CH ₂ ) _m -NRR , where R , R and m are as defined above, (f) -CN, (g) -cho, imu . ii i.mi.ui 236 (h) -cf ₃ , (i) 8 8 -SR , where R is hydrogen, C ₁ _ ₆ -alkyl, trifluoro- thyl or phenyl, (j) -SOR , where R values defined above, (k) 8 8 -SO ₂ R , where the values of R defined above, (D -CONR ⁶ R ⁷ , in which R ⁶ and 7 R' values defined above, (m) R ⁹ O(CH ₂ ) _m -, where R ⁹ and m values are defined above, (n) -CH (OR ¹² ) (OR ¹³ ) , in which R 12 . „13 . , ~ . and R values are described- drawn above, J ¹ (o) R CO(CH ₂ ) _m -, where R and m are as defined above, II (6) substituted heteroaryl-C ₁ _ ₁₀ -alkyl, in which one or more alkyl carbon atoms are replaced by a group selected from: -NR ⁶ -, -O-, -S(O) _p -, -CO ₂ , -0 ₂ C-, -CONR ⁶ -, -NR ^b CO, -NR ⁶ CONR ⁷ -, heteroaryl group ι ικιι ιιι.ιι ι ι ι ι χι ω n ι 227 is substituted with X, Y and Z, and alkyl is substituted with one or more selected from the group consisting of: group can be alternately (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) (k) (D (m) (n) (o) (P) (g) (r) 6 7 (iv) or when R , R and the N atom to which they are attached form an unsubstituted or substituted 3-7 membered heterocyclic ring which may contain one or two additional heteroatoms independently selected from the group consisting of O, S(O) _p , NR ¹⁴ , where R ¹⁴ is hydrogen or C ₁ _ ₆ -alkyl, unsubstituted or substituted by phenyl, p equals 0, 1 or 2, (i) -NR ⁶ CO-C ₁ _ ₆ -alkyl-R ⁷ , in which R ⁶ and R ⁷ are as defined above, (j) -NR ⁶ CO ₂ -C ₁ _ ₆ -alkyl-R ⁷ , (k) -NR ⁶ CO-NR ⁶ R ⁷ , (l) -oconr ⁶ r ⁷ , (m) -COOR ⁶ , (n) -CHO, (o) aryl, (p) substituted aryl substituted with X, Y and Z, (q) -OR ¹¹ , and (r) -S(O) _p -C ₁ _ ₆ -alkyl; 7. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound according to claim 1. (7) 8. Use of a compound according to claim 1 for the manufacture of medicaments for the treatment of immunoregulatory disorders. (8) hydroxyl, oxo group, C ₁ _ ₆ -alkoxy group, aryl-C ₁ _ ₃ -alkoxy group, substituted arylC ₁ _ ₃ -alkoxy group, in which the aryl group is substituted by X, Y and Z, unsubstituted or substituted aryloxy group, in which the aryl group is substituted by X, Y and Z, -OCO-C1-6-alkyl, -NR ⁶ R ⁷ , where R ⁶ and R ⁷ have the meanings defined above, -NR ⁶ CO-C ₁ _ ₆ -alkyl-R ⁷ , -NR ⁶ CO ₂ -C ₁ _ ₆ -alkyl-R ⁷ , -nr ⁶ co-nr ^s r ⁷ , -oconr ⁶ r ⁷ , -COOR ⁶ , -CHO, aryl, substituted aryl containing substituents X, Y and Z, -OR ¹¹ , and -S(O)p-C1-6-alkyl; heteroaryl-C ₃ -C ₁₀ -alkenyl, wherein the alkenyl has one to four double bonds; heteroaryl-C ₃ _ ₁₀ -alkenyl, in which the alkenyl has from one to four double bonds and where one or more alkyl carbon atoms are replaced I U:! I Group 228 optionally selected from: -NR ⁰ -, -0-, -S(O) _p -, -CO ₂ , -O ₂ C-, -CONR ⁶ -, -NR ^S CO-, -NR ⁶ CONR ⁷ -; 9. Use of a compound according to claim 1 for the manufacture of medicaments for the treatment of transplant resistance. 9 9 (p) R CO(CH ₂ ) _m -, in which R and m are as defined above, and (g) -R ¹¹ ; n is 1 or 2. (9) substituted heteroaryl-C ₃ _ ₁₀ -alkenyl, wherein the alkenyl has from one to four double bonds and where one or more alkyl carbon atoms may be replaced by a group selected from: -NR ⁶ -, -O-, -S (O) _p -, -CO ₂ , -O ₂ C-, -CONR ⁶ -, -NR ⁶ CO-, -NR°CONR ⁷ -, the heteroaryl group is substituted with X, Y and Z, and the alkyl group may be optionally substituted with one or more substituents, including: (a) hydroxide, (b) oxo, (c) C1-6-alkoxy, (d) aryl- _C1-3 -alkoxy, (e) substituted _{arylC1-3 - alkoxy} , in which the aryl group is substituted by X, Y and Z, (f) unsubstituted or substituted aryloxy, in which the aryl group is substituted by X, Y and Z, (g) -OCO-C1-6-alkyl, (h) -NR ^S R ⁷ , in which R ⁶ and R ⁷ are as defined above, (i) -NR°CO- _C1-6 -alkyl, in which R ⁶ is as defined above, (j) -NR ⁶ CO _{2 -C1-6 -} alkyl, (k) -nr ⁶ co-nr ⁶ r ⁷ , (l) -OCONR ⁶ R ⁷ , (m) -COOR ⁶ , (n) -CHO, (o) aryl, (p) substituted aryl containing substituents X, Y and Z, (q) -OR ¹¹ , and I III II I uiu .i! ι .ι ..ι;· υι.ι 229 (r) -S (O) p-C 1-6 -alkyl; R ² can be optionally: 10. Use of a compound according to claim 1 for the manufacture of medicaments for the treatment of inflammatory and hyperproliferative skin diseases or for the treatment of immune-related diseases affecting the skin.