DE3930950A1 - New derivatives of sorangicin A - are antibiotics active against resistant strains of myxo:bacterium - Google Patents

Abstract

New derivatives of sorangicin A of formula (I) and their salts with acids and bases are claimed. R1 = 1-4C alkoxy, 2-5C alkenoxy, benzyloxy, substd. heterocyclyl-(1-4C)alkyleneoxy, -O-(CH2)n-CONR5R6 or NR7R8; R2 and R3 = H, formyl or trialkylsilyl, or together form a -CO-, -CS-, -C(CH3)2- or -Si(alkyl)2- gp. R4 = H, CHO, 1-3C alkyl, SO2R13, C(S)-phenyl, (1-3C alkyl)-carbonyl or -CONHR11. R5 and R6 = H, 1-3C alkyl or substd. phenyl; n = 1-3. R7 = H, 1-4C alkyl or cyclohexyl. R8 = H, 1-6C alkyl, 1-3C alkylenesulphonic acid, a substd. carbocycle or heterocycle, NR9R10 (where R9 and R10 = H, 1-3C alkyl or substd. piperazine), 1-3C alkoxy, benzyl, hydroxy-(1-4C)alkylene, -C(=NH)NH2, -C(=NH)-NH-NH2 or cyclohexylaminocarbonyl. R7 and R8 may also form - (CH2)n- gp. where n = 4 or 5. R11 = H or COCCl3. R13 = halogen-substd. 1-4C alkyl or tolyl. R1 cannot be CH3, C2H5 or NR7R8 when R7 = H and R8 = H, CH3 or isopropyl or R7 and R8 are both CH3 or form a -(CH2)5- gp. and when R2, R3 and R4 are H. USE/ADVANTAGE - Like sorangicin A, (I) is an antibiotic active against myxobacterium. It can be used to treat infections that are resistant to sorangicin A itself.

Description

The present invention relates to synthetic Derivatives of sorangicin A. In particular, it refers to Derivatives on the C-1 ester group, on the vicinal OH groups bearing C-21 and C-22 atoms and on the C-25 atom are substituted, furthermore on oxidation and Reduction products, on shifted isomers Double bond in the trient part and on stereoisomers of these Links.

That isolated from Sorangium (Polyangium) cellulosum So ce12 Sorangicin A (R. Jansen, V. Wray, H. Irschik, H. Reichenbach, G. Höfle, Tetrahedron Lett. 26 (1985), 6031) is that in vivo most active antibacterial antibiotic to date  Myxobacteria (H. Irschik, R. Jansen, K. Gerth, G. Höfle, H. Reichenbach, J. Antibiot. 40, (1987) 7). Its isolation and that of other sorangicin variants from the culture broth of Sorangium cellulosum So ce12 is in DE patent application 39 09 298 described.

Antibacterial drugs are used today Medicine in a wide variety and variability is needed to effectively combat emerging resistance phenomena can. It is therefore the task of the inventors made from Sorangicin A, which has been fermentative on a microbiological basis Is manufactured a large number of ways to provide synthetic sorangicin variants. Accordingly, you have also set yourself the task To provide methods of making these connections.

Accordingly, compounds of the formula (I)

made available,
wherein R¹ is C₁-C₄ alkoxy, C₂-C₅ alkenoxy, benzyloxy, optionally substituted heterocyclyl- (C₁-C₄) alkyleneoxy, -O- (CH₂) _n CONR⁵R⁶, where R⁵ and R⁶ are the same or different and H, C₁- C₃-alkyl or optionally substituted phenyl and n is 1 to 3, or
wherein R¹ is NR⁷R⁸, where R⁷ can be H, C₁-C₄-alkyl or cyclohexyl and R⁸ H, C₁-C₆-alkyl, C₁-C₃-alkylene sulfonic acid, an optionally substituted carbocycle or heterocycle, where R⁹ and R¹⁰ can be the same or different and H, C₁-C₃-alkyl or optionally substituted piperazine, (and R⁸ also) C₁-C₃-alkoxy, benzyl, hydroxy-C₁-C₄-alkylene, C (= NH) NH₂, C (= NH) -NH- Is NH₂ or cyclohexylaminocarbonyl or R⁷ and R⁸ together can represent a (CH₂) _n group, in which n = 4 or 5;
R² and R³ are the same or different and can mean H, formyl or a trialkylsilyl group or R² and R³ together form a group selected from <C = O, <C = S, <C (CH₃) ₂ and Si (alkyl) ₂ is and
R⁴ is H, CHO, C₁-C₃-alkyl, SO₂R¹³, C (S) -phenyl, (C₁-C₃-alkyl) -carbonyl or CONHR¹¹, where R¹¹ is H or COCCl₃ and
R¹³ means optionally halogen-substituted C₁-C₄-alkyl or tolyl,
and their salts with acids and bases,
with the exception of those compounds in which R¹ is CH₃, C₂H₅ or NR⁷ R⁸ with R⁷ is hydrogen and R⁸ is hydrogen, methyl or isopropyl or with R⁷ is R⁸ is methyl or with R⁷ and R⁸ together is (CH₂) ₅ and R², R³ and R⁴ are each hydrogen. These compounds are already known from patent application P 39 09 298.

The term "optionally substituted" includes as it used in the section above, common substituents, for example F, Cl, Br, I, C₁-C₄-alkyl, C₁-C₄-alkoxy, Trifluoromethyl, NO₂, NH₂ carboxy and other substituents, which are accessible with the usual aromatic chemistry.

The substituents R¹, R², R³ and R⁴ are from each other independently.

Preferred compounds are those in which R¹ is as defined in claim 1 has the meaning given and R², R³ and R⁴ are hydrogen mean. Among these, those are very particularly preferred Compounds in which R¹ CH₂-CH = CH₂, CH₂-CH = CH (CH₃) ₂, CH₂-phenyl, -CH₂-CONH₂, CH₂-CON (CH₃) ₂, CH₂-CON (CON (C₂H₅) ₂, CH₂-CONH- (o, o-dimethylphenyl), CH₂- (N-methylpiperidin-3-yl) or NR⁷R⁸ is, where R⁷ is preferably hydrogen and R⁸ preferably iso-butyl, n-hexyl, CH₂CH₂CH₂-OH, CH (CH₃) CH₂-OH, CH₂CH₂-SO₃M with M equal to metal or hydrogen, 2'-aminophenyl, (4-pyridyl) methyl, NH₂, N (CH₃) ₂, N-amino-N'-methylpiperazine, OCH₃, C (= NH) NH₂, C (= NH) NH-NH₂ or CH₂-phenyl  is. Those are also very particularly preferred Compounds in which R¹NR⁷R⁸ is and R⁷ is methyl or Represents cyclohexyl and R⁸ OCH₃ or cyclohexylaminocarbonyl means.

Also preferred are compounds in which R¹ in Claim 1 has the meaning given, R² and R³ Are hydrogen and R⁴ that specified in claim 1 Has meaning. Are particularly preferred here Compounds in which R¹ is OH, methoxy, t-butoxy, O-CH₂-CH = CH₂, O-CH₂-CH = CH (CH₃) ₂ or a substituted or not represents substituted amino group and R⁴ is methyl, formyl, an ester group such as acetyl, propionyl or 1-methylpropionyl, CONH₂, CHNHCOCCl₃, SO₂CH₃, C (S) phenyl. All Compounds in which R 1 Hydrogen, NHCH₂CH₂CH₂OH, NHCH (CH₃) CH₂OH, NHC (= NH) NH₂ or NHC (= NH) means NH-NH₂ and R⁴ represents a formyl group, as well as compounds in which R¹ is hydrogen and R⁴ Methyl, an ester group such as acetyl, propionyl or 2-methylpropionyl, Is CONH₂ or SO₂CH₃.

Also preferred are compounds in which R¹ in Claim 1 has the meaning given, R² and R³ <CO, <CS, <C (CH₃) ₂ or <Si (tBu) ₂ or R² is Si (CH₃) ₂tBu and R³ is hydrogen and R⁴ has the meanings given in Claim 1 owns. Among them are particularly preferred Compounds in which R¹ is OH, methoxy, t-butoxy, O-CH₂-CH = CH₂ or O-CH₂-CH = CH (CH₃) ₂. Very particularly preferred  among the latter compounds are those in which R⁴ is hydrogen, methyl, formyl, acetyl, CONH₂, CONHC (O) CCl₃, C (S) is phenyl or SO₂CH₃.

Furthermore, compounds with the formula (II)

made available,
wherein R¹ has the meaning defined in claim 1 and X and Y each represent either oxygen, an acyl group and a hydrogen atom, two hydrogen atoms or a hydrogen atom and additionally a hydroxyl group or together with the carbon atoms to which they are attached, an oxirane group or a 1 , 3-dioxolane ring form and wherein
Z is either a hydrogen atom and OR⁴ with the meaning given for R⁴ in claim 1 or = O, F₂, NOH or NO- (C₁-C₃-alkyl),
and their salts with bases and acids.

The groups R1, X, Y and Z are independent of one another. Preferred are those compounds in which R 1 is hydroxy or represents an oxyalkyl or oxyalkylene group, namely in particular an O-methyl, O-t-butyl, O-CH₂-CH = CH₂, or O- CH₂-CH = CH (CH₃) ₂ group.

Compounds in which X and Y has the meanings given in claim 2 and Z is a Represents hydrogen atom and a hydroxy group. In doing so, when X and / or Y is a hydrogen atom and a hydroxy group is / are, this hydrogen atom both in the α-position as well as in the β position (the non-native position) be. Such compounds are also particularly preferred, in which X and Y each represent a hydrogen and a hydroxy group or mean an acyl group or together with the carbon atoms, to which they are attached, a 1,3-dioxolane ring represent and Z = O, F₂, NOH or NO (C₁-C₃) alkyl, for example NOMe means. Very particularly preferred in these Compounds R¹ the meaning hydroxy, and, if X = O or F₂ means also O-CH₂-CH = CH₂. The C-46 methyl group can in all the connections mentioned in this paragraph instead of in the native β configuration also exist in the α configuration.

Furthermore, compounds with the formula (III)  

provides wherein R¹, R² and R³ are the same as in the previous Have defined meanings, as well their salts with bases and acids.

Preferred are those compounds in which R 1 is hydroxy or an alkyloxy or alkyleneoxy group, in particular an O-methyl, O-t-butyl, O-CH₂-CH = CH₂ or O-CH₂-CH = CH (CH₃) ₂ group, or a substituted or unsubstituted Amine is. R² and R³ are preferably hydrogen or form together a <C (CH₃) ₂ group. Are very particularly preferred those compounds among them in which R² and R³ are hydrogen and R¹ is hydroxy or O-CH₂-CH = CH₂, and the one wherein R¹ is O-CH₂-CH = CH₂ and R² and R³ together form a <C (CH₃) ₂ group represent.  

Furthermore, the invention also includes such compounds, in which the trient part is not in the naturally occurring Conformation

but one of the following conformations:

Finally, the invention also provides connections Available through oxidation or reduction or through Shift the double bonds in the trient part from the above Connections are formed. These connections have the general formulas (IVa), (IVb), (V), (VI), (VIIa) or (VIIb):  

In formulas (IVa) and (IVb), R¹² is a Oxygen atom or a hydrogen atom and one  Hydroxy group, and in all of these formulas R¹, R², R³ and R⁴ has the meanings given in Claim 1.

Those compounds with the formulas (IV) are preferred to (VII), wherein R¹ is hydroxy or an alkoxy or alkyleneoxy group and in particular a methoxy, t-butyloxy, O-CH₂-CH = CH₂- or O-CH₂-CH = CH (CH₃) ₂ group or a substituted or is unsubstituted amine and R², R³ and R⁴ are each Mean hydrogen. Are very particularly preferred those compounds in which R1 is hydroxy.

The invention also provides methods of making the above mentioned compounds as well as those previously found in nature Sorangicin derivatives are available.

The procedures for making the synthetic sorangicin variants generally consist of individual stages. With each of these stages leaves or one or more Derivatize group (s); for the production of some of the compounds according to the invention is a combination of several of these stages required. If a selected one Implementation procedures undesirable reactions to other Substituents should be avoided, the organic engineer known protecting group techniques are used; the one there Intermediates that occur are also generally according to the invention.  

A first group of process stages effects the implementation from compounds in which R1 is hydroxy to compounds in which R¹ has the other meanings mentioned in claim 1 owns. The acid function on the C-1 atom of the Sorangicins converted into an ester or an amide. in the general free hydroxyl functions on the sorangicin scaffold not changed in such implementations; basically is this type of reaction therefore with all of the invention Compounds feasible in which R¹ is hydroxy.

The following scheme A explains the possibilities according to the invention for the production of the esters and amides mentioned.

A first process for making sorangicin esters, wherein R¹ is C₁-C₄ alkoxy (or wherein R¹ is methoxy) characterized in that a sorangicin derivative, in which R¹ is hydroxy, with a C₁-C₄ diazoalkane (or Diazomethane).

Although in principle any sorangicin derivatives for this implementation can be used, it is preferred to use them with Perform sorangicin A, d. H. with that connection with the formula (I), wherein R², R³ and R Wasserstoff are each hydrogen.  

Scheme A

Diazomethane is preferably used as the reagent, wherein you get a methyl ester.

A second process for making sorangicin esters, wherein R¹ is C₁-C₄ alkoxy is characterized in that that a sorangicin derivative in which R¹ is hydroxy, reacted under acidic conditions with a C₁-C₄ alkanol.

Although in principle any sorangicin derivatives for this implementation can be used, it is preferred to use them with Perform sorangicin A, d. H. with that connection with the formula (I), wherein R², R³ and R⁴ are each hydrogen are. An alcoholic, dry hydrogen chloride used, and very particularly the alcohol used is preferably methanol or ethanol, whereby a methyl or ethyl ester is obtained.

A third process for the production of sorangicin esters, in which R¹ is C₂-C₅-alkenoxy or benzyloxy, is characterized in that a sorangicin derivative in which R¹ is hydroxy is reacted with a compound of the formula R¹ X in the presence of a base , wherein R¹ ' ^C _n H _2n-1 with n = 2 to 5 or PhCH₂ and X is halogen and preferably chlorine or bromine.

Although in principle any sorangicin derivatives for this implementation can be used, it is preferred to use them with  Perform sorangicin A, d. H. with that connection with the formula (I), wherein R², R³ and R⁴ are each hydrogen are. The compound having the formula R 1 X is preferred Allyl chloride or bromide, 1-bromo or 1-chloro-4-methyl-2-butene or benzyl chloride or bromide. The base is arbitrary Lewis base, for example an amine, and is preferably N- Ethyl diisopropylamine.

A fourth process for the preparation of sorangicin esters, in which R¹ is -O- (CH₂) _n -C (O) NR⁵R⁶, where R⁵, R⁶ and n have the meanings given in Claim 1, is characterized in that a sorangicin Derivative in which R¹ is hydroxy, converted into the sodium salt with sodium carbonate in the presence of a solvent such as ethanol and then reacted with a compound of the formula X- (CH₂) _n -C (O) NR⁵R⁶, wherein X is halogen, preferably chlorine or bromine .

Although in principle any sorangicin derivative can be used for this reaction, it is preferred to carry it out with sorangicin A, ie with the compound of the formula (I) in which R², R³ and R⁴ are each hydrogen. As a compound with the formula X- (CH₂) _n -C (O) NR⁵R⁶ is preferably a chloro or bromoacetic acid amide such as chloro or bromoacetamide, 2-chloro-N, N-dimethylacetamide, N- (2-chloroacetyl) diethylamine and N- (2-chloroacetyl) -2,6-dimethylaniline is used, whereby a compound is obtained in which R¹ represents an optionally substituted carboxamidomethyl ester.

A fifth process causes the production of sorangicin esters, wherein the acid function with a heterocyclyl (C₁-C₄) alkanol is esterified, characterized in that 1,1'-carbonyldiimidazole mixed with iodomethane and the formed A product with a sorangicin derivative, wherein R¹ is a hydroxy group represents, and with the heterocyclyl (C₁-C₄) alkanol is implemented.

Although in principle any sorangicin derivatives for this implementation can be used, it is preferred to use them with Perform sorangicin A, d. H. with that connection with the formula (I), wherein R², R³ and R⁴ are each hydrogen are. The preferred hydroxy group-bearing heterocycle is (N-methylpiperidin-3-yl) methanol.

A first process for the production of sorangicin amides, thus those compounds in which R¹ NR⁷R⁸ with the in Claim 1 meanings for R⁷ and R⁸ is characterized in that a sorangicin derivative, wherein R¹ represents a hydroxy group in the presence of N, N'- Carbonyldiimidazole with an amine with the formula NHR⁷R⁸ implements.  

The amide formation using carbonyldiimidazole is a common method in organic chemistry and the Familiar to experts; according to this procedure, any produce the compounds of the invention in which R⁷ and R⁸ have the meanings given in Claim 1 including the meanings excluded there. For this purpose, the reaction product of carbonyldiimidazole is preferred first and sorangicin formed before the amine was added becomes. If the amine to be used NHR⁷R⁸ is a gaseous amine is conveniently left with a solution of the bead activated sorangicins in methylene chloride.

A desiccant is particularly preferred in this reaction, e.g. B. a molecular sieve or anhydrous calcium sulfate, added.

Although in principle any sorangicin derivatives for this implementation can be used, it is in one embodiment preferred to do it with sorangicin A, d. H. with that compound of formula (I) wherein R², R³ and R⁴ are each hydrogen. Preferred amines are preferred Ammonia, mono- or di (C₁-C₄) alkylamines, hydrazine or Hydrazine derivatives, carbocyclic and heterocyclic amines used. Ammonia is very particularly preferred, Methylamine, hydrazine and N-amino-N'-methylpiperazine.  

Another preferred group of amines following this Procedures with sorangicins can be implemented to Forming sorangicin amides are those that have more wear reactive groups. In this second embodiment the reaction is preferably carried out with hydroxy groups Sorangicines. Suitable examples of protected Sorangicins are Tris-O-formyl sorangicins. Preferred amines bearing reactive groups are (C₁-C₄) alkanolamines, Amino (C₁-C₄) alkyl sulfonic acids and sulfonates, guanidine and Guanidine derivatives. Particularly preferred amines are propan-3-olamine, Propan-2-olamine, aminoethylsulfuric acid sodium salt, Guanidine (particularly preferred in Form of hydrochloride) and aminoguanidine (especially preferably as aminoguanidinium nitrate). On request, the protected groups following the amidation of the Acid function can be unblocked at the OH functions, for example with the help of ammonia in the case of Tris-O-formylsorangicine. Also the free reactive groups optionally implemented on the amine introduced; to the For example, salts can be formed with acids or bases.

The production of N- Sorangicinyl-aminoethyl-2-sulfonic acids or their salts. For this, aminoethyl sulfuric acid can be reacted with sodium hydride and the product formed following the above procedure followed by reaction with a tris-O-formylsorangicin to be brought. In the resulting sodium sulfonate groups can  the sodium ion against another Cation, for example an alkyl-substituted ammonium ion, be replaced. The product can also be used afterwards be deblocked, for example with the help of aqueous NH₃.

A second process for making sorangicin amides, thus those compounds in which R¹ NR⁷R⁸ with the in Claim 1 meanings for R⁷ and R⁸ is characterized in that a sorangicin derivative, wherein R¹ represents a hydroxy group, an acid chloride or a mixed anhydride transferred, for example with Oxalic acid dichloride or pivalyl chloride, and in situ (i.e. in One-pot process) or after isolation of the activated Acid derivative with the corresponding amine with the formula HNR⁷R⁸ implements.

The amide formation with activation of the acid function is a common procedure in organic chemistry and the experts familiar; according to this procedure, any produce the compounds of the invention in which R⁷ and R⁸ have the meanings given in claim 1. Prefers the reaction mixture becomes an acylation catalyst or a sterically hindered base, e.g. B. Dimethylaminopyridine (DMAP) or N-methylmorpholine, added to trap the acid released. DMAP is particularly preferred here.  

It is preferred to implement this with a protected Perform sorangicin, especially with a sorangicin, wherein R², R³ and R⁴ each represent formyl groups, that is a tris-o-formylsorangicin. Preferred amines are preferred Ammonia, mono- or di- (C₁-C₄) alkylamines, optionally substituted Phenylamines, optionally substituted pyridinyls, Hydrazine or hydrazine derivatives, amino (C₁-C₄-) alkyl sulfonic acids and their salts, carbocyclic and heterocyclic Amines used. Particularly preferred amines are methylamine, Dimethylamine, propylamine, in particular isopropylamine, butylamine, in particular 2-methylpropylamine, hexylamine, in particular n-hexylamine, aminoethylsulfuric acid sodium salt, a phenylenediamine, in particular 1,2-phenylenediamine, a picolylamine, especially 4-picolylamine, Piperidine, benzylamine, dimethylhydrazine, in particular 1,1-dimethylhydrazine, O-methylhydroxylamine, especially as hydrochloride, and N, O-dimethylhydroxylamine.

A special procedure for sorangicin derivatives, wherein R¹ is NR⁷R⁸ and R⁷ and R⁸ cyclohexyl or cyclohexylaminocarbonyl mean is characterized in that the corresponding Sorangicin derivative, wherein R¹ is OH, in Presence of 4-dimethylaminopyridine with dicyclohexylcarbodiimide is implemented.  

If desired, the protected groups can join the Amidation of the acid function on the OH functions deblocked are, for example with the help of aqueous NH₃ in the case of Tris-O-formylsorangicine. Even the free reactive Groups on the introduced amine optionally further implemented will; for example, salts with acids or bases be formed.

Some esters can be split off selectively, e.g. B. the Allyl esters (R¹ = O-CH₂-CH = CH₂) with palladium or rhodium complexes and morpholine, making them excellent as Protection group suitable for the acid function.  

A second group of process stages effects the implementation of sorangicins in which R², R³ and / or R⁴ are hydrogen are to sorangicins, wherein R², R³ and / or R⁴ are the others have meanings mentioned in claim 1, and the corresponding Back reactions. This type of reaction also includes the protection group techniques with which for some implementations the OH groups on the C-21, C-22 and / or on the C-25 atom must be blocked.

The process steps mentioned are generally with all Derivatives possible, in which R¹ is that specified in claim 1 Has meanings; in general, however, they will preferably carried out with those sorangicins in which the C-1 group is present as a free acid or as an ester. Especially preferably R¹ is hydroxy, C₁-C₄-alkoxy or C₁-C₅- Alkenoxy, where hydroxy, methoxy, t-butyloxy, CH₂ = CH-CH₂-O- and (CH₃) ₂C = CH-CH₂-O- are very particularly preferred.

The process for producing tri-O-formylsorangicins, thus those compounds in which R², R³ and R⁴ each represent a formyl group, is characterized in that a sorangicin, wherein R², R³ and R⁴ are each hydrogen mean in the presence of an amine, e.g. B. of triethylamine,  and of acetic anhydride and optionally catalytic Amounts of an acylation catalyst, e.g. B. from DMAP with Formic acid is implemented.

This implementation is preferably used for the production of protected Intermediate products. Unblocking can be done with the help reach from aqueous NH₃, whereby one compound receives, wherein R² and R³ are hydrogen, while the Formyl group on C-25 atom is retained.

The following reactions are typical of vicinal OH groups; if R⁴ is hydrogen, this group remains unchanged. The following scheme B provides an overview.

1. The implementation of sorangicin derivatives in which R² and R³ Mean hydrogen, with tetramethyl orthocarbonate leads to Derivatives in which R² and R³ together form the group C = O. The reaction is preferably carried out in the presence of anhydrous calcium sulfate (e.g. drierite, available from Aldrich) and trichloroacetic acid.

2. The implementation of sorangicin derivatives in which R² and R³ Mean hydrogen, leads with a dialkyldihalosilane to sorangicins, wherein R² and R³ together represent a dialkylsilyl group form.  

Scheme B

The reaction is carried out with exclusion of water and preferably in the presence of triethylamine and 1-hydroxybenzotriazole. The Sorangicin to be used should not be in the free acid form are present (R¹ not = OH). Preferred as dialkyldihalosilane Di-t-butyldichlorosilane used.

3. The implementation of sorangicin derivatives in which R² and R³ Hydrogen means with acetone in the presence of trifluoroacetic acid or toluenesulfonic acid leads to derivatives in which R² and R³ together form the group C (CH₃) ₂. It is done preferably in the presence of a water scavenger like drierite (anhydrous calcium sulfate).

These 21,22-O-isopropylidene derivatives preferably serve as Intermediates with protected vicinal OH groups. The The isopropylidene groups are preferably cleaved with aqueous trifluoroacetic acid.

4. The implementation of sorangicin derivatives in which R² and R³ Hydrogen means with thiophosgene in the presence of a Acylation catalyst such as DMAP leads to derivatives in which R² and R³ together form the group C = S. As a sorangicine derivatives are preferably used in which R¹ is not Oh, and particularly preferably -O-CH₂-CH = CH₂ means. In connection This group can carry out the implementation on request Reaction with morpholine in the presence of a catalyst such as Tetrakis (triphenylphosphine) -Pd (O) can be split off again.  

5. The implementation of sorangicin derivatives in which R² and R³ Are hydrogen, with a trialkylsilyl chloride leads to Compounds in which R² represents a trialkylsilyl group. This reaction takes place in the absence of water and preferably in the presence of trimethylamine and 4-dimethylaminopyridine. To be favoured as silyl chloride t-butyldimethylsilyl chloride and as Sorangicin derivative is a sorangicine ester (R¹ = C₁-C₄-alkyl or C₂-C₅ alkenyl) used.

Sorangicins, in which R⁴ has the meanings given in Claim 1 owns can look like this Sorangicin derivatives in which R⁴ is hydrogen, getting produced. Compare the following scheme C:

• a) reaction with first a C₁-C₃ alkyl iodide and then with an alkali or alkaline earth hydride leads to sorangicins, in which R⁴ is C₁-C₃ alkyl. Iodomethane is preferably used, to obtain C-25 methoxy derivative.
• b) Reaction with the product of N, N-dimethylbenzamide and phosgene and then - in the presence of pyridine - with hydrogen sulfide leads to sorangicines in which R⁴ C (S) is phenyl. Scheme C
• c) reaction with a compound having the formula R¹³SO₂Cl, wherein R¹³ has the meaning defined in claim 1, in Presence of a base like triethylamine leads to sorangicins, in which R⁴ has the meaning SO₂R¹³. Is preferred as Sulfonyl chloride methanesulfonyl chloride, trifluoromethanesulfonic acid chloride or toluenesulfonic acid chloride used. Methanesulfonyl chloride is particularly preferred.
• d) reaction with trichloroacetyl isocyanate leads to Sorangicins, in which R⁴ means CONHCOCCl₃. These products can be treated by treating with an alcohol such as methanol Presence of alumina to sorangicines in which R⁴ CONH₂ means to be alcoholized.
• e) reaction with a compound of the formula [(C₁-C₃-alkyl) CO] ₂O leads to sorangicins, in which R⁴ has the meaning C (O) - (C₁-C₄) alkyl. The reaction takes place in the presence of pyridine and preferably dimethylaminopyridine. Preferred Anhydrides with the formula [(C₁-C₃-alkyl) CO] ₂O are acetic anhydride, Propionic anhydride or isobutyric anhydride.

The above-mentioned implementations a) to e), such as the Expert will of course be clear, including reactions on the groups R² and R³, provided that these represent hydrogen. It is therefore preferred to use these groups over the above Protect implementation levels. The implementation is preferred with acetone / trifluoroacetic acid to the 21,22-O-isopropylidene sorangicin derivatives  or with methyl orthoformate to the 21,22-O-cyclocarbonates. Around To produce compounds in which R² and R³ each Are hydrogen, these protective groups can be split off again will. In these cases it is preferred to use 21,22-O-isopropylidene sorangicine to use as starting compounds and following one of the implementations a) to e) Product with a strong acid, for example trifluoroacetic acid in dioxane / water.

To the acid group on the C-1 atom from undesired reactions To protect, it is sometimes beneficial to protect the Sorangicine use in the form of their esters. Is particularly preferred in such cases the use of a compound with R1 is equal to O-CH₂-CH = CH₂, optionally after one of the reactions according to a) to e) and if desired after the hydrolysis the isopropylidene group can be split off catalytically (e.g. Pd (O) complex and morpholine).

A third group of process steps effects on sorangicin derivatives, in which R² and R³ are each hydrogen, Oxidations, reductions or dehydrations on the C-21, C-22 atoms and C-25 atoms. With the help of this Different configuration isomers can also be implemented in a targeted manner produce.

The following scheme D explains the individual process steps.  

1. Put a sorangicin derivative in which R² and R³ each Mean hydrogen, in the absence of water with sulfuran, for example with Martins's Sulfuran dehydrating agent, um, you get product mixtures of two compounds, in which each have a molecule of water eliminated, namely for one is a compound of formula (II) wherein X is two Represents hydrogen atoms and Y means oxygen, and for others a compound of formula (II) wherein X and Y together with the C-21 and the C-22 atom to which they are attached form an oxirane group. In the latter connection are the hydrogen atoms of the C-21 and C-22 atoms in the α-position arranged. The two products can be ordered on request separate chromatographically.

2. The implementation of sorangicin derivatives with an oxidizing agent such as nickel peroxide, preferably under Heating, leads to compounds with the formula (II), in where X is oxygen and Y is a hydrogen atom and one Hydroxy group means.  

Scheme D

Although for the reactions 1. and 2. any sorangicin derivatives with the formula (I) can be used in where R² and R³ are hydrogen, it is preferred To use compounds in which R⁴ represents hydrogen and the C-1 group is present as a free acid or as an ester. R¹ is particularly preferably hydroxyl, C₁-C₄-alkoxy or C₁-C₅-alkenoxy, with hydroxy, methoxy and CH₂ = CH-CH₂-O- whole are particularly preferred.

3. The products from 2. can be mixed with a reducing agent like sodium cyanoborohydride back to compounds with the Reduce formula (I) wherein R² and R³ are each hydrogen mean. This gives (21R) derivatives (21-epi derivatives with α-H and β-OH group on the C-21 atom), depending on Starting compound in pure form or in a mixture with (21S) derivatives. Product mixtures can be created on request separate chromatographically.

4. The implementation of sorangicin derivatives with the formula (I), in which R² and R³ together represent C (CH₃) ₂ and R⁴ Hydrogen means with an oxidizing agent like Pyridinium chlorochromate or chromium trioxide leads to the corresponding compounds of formula (II), wherein Z Means oxygen.

Although in principle all sorangicins are for this are suitable in which R¹ has the meanings given in claim 1  own, the compounds with R¹ are OH or O-CH₂-CH = CH₂ prefers.

Leave the 21,22, -O-isopropylidene-25-oxosorangicin derivatives with a strong acid, for example trifluoroacetic acid Dioxane / water, in the corresponding 25-oxosorangicine (X and Y each transfer H + OH). One can Mixture of the (26R) and (26S) isomers (methyl group on the C-26 atom in the native β position (R isomer) or in the α position (S-Isomeres)), which can be chromatographed on request can be separated into the individual connections.

If the allyl ester is used (R¹ = -O-CH₂-CH = CH₂), can be implemented in a next step with Morpholine in the presence of a palladium (O) catalyst, the free acid are formed.

5. The reaction of compounds of formula (II), wherein Z represents oxygen and X and Y together represent a 1,3-dioxolane ring form with a fluorinating agent such as diethylamino-sulfur trifluoride (DAST) leads to the corresponding compounds of the formula (II), in which Z is two Represents fluorine atoms.

Although in principle all sorangicins are for this are suitable in which R¹ has the meanings given in claim 1  have, the compounds with R¹ are OH or -O-CH₂-CH = CH₂ prefers.

The 21,22-O-isopropylidene-25,25-difluorosorangicine derivatives can with a strong acid, for example with Hydrochloric acid, into the corresponding 25,25-difluorosorangicine (R² and transfer R³ to H). When the allyl ester is used is (R¹ = -O-CH₂CH = CH₂), can in a next step by reacting with morpholine in the presence of a palladium (O) catalyst, the free acid formed will.

6. The reduction of compounds with the formula (II), wherein Z means oxygen with an agent such as sodium cyanoborohydride leads to compounds in which Z is an α-hydroxy group and represents a β hydrogen atom (25R isomers). Through the Choice of the configuration of the starting materials can be targeted represent desired diastereomers, for example (25R, 26S) derivatives from compounds of the formula (II), in which the am C-26 atom-bound methyl group bound in the α-position is present.

Although in principle all Sorangicine are suitable in which R¹ has the meanings given in claim 1 have, the compounds with R¹ are OH or -O-CH₂-CH = CH₂ prefers. X and Y preferably each have the Meaning of hydrogen + hydroxy group.  

7. The 25-oxosorangicins (Z equals 0) can be with hydroxylamine or convert C₁-C₃ alkoxyamines into compounds, wherein Z = NOH or = NO (C₁-C₃) alkyl. Is methoxyamine the preferred alkoxyamine. A connection with is preferred R1 is OH and X and Y are each hydrogen + Hydroxy group used.

By choosing the configuration of the educts can also here again represent the desired diastereomers. For example, compounds of the formula (II) wherein the methyl group bonded to the C-26 atom is in the β-position is bound with a hydroxylamine hydrochloride Mixture of the 25E and 25Z-N-hydroxyimino isomers formed, which can be separated chromatographically.

A fourth group of process steps involves reactions and with 24,25-dehydrosorangicins.

The basic implementation is shown in the following scheme E.

If one leaves a sorangicin derivative with the formula (I), wherein R² and R³ represent protective groups and R⁴ represents hydrogen, with an elimination reagent, for example a sulfuran

Scheme E

how Martin's Sulfuran react, is obtained Compounds with the formula (III). It is preferred that R² and R³ together form a (CH₃) ₂ group. R¹ can at this reaction any of those specified in claim 1 Have meanings; however, it is preferred that the C-1 group is present as a free acid or as an ester. Especially preferably R¹ is hydroxy, C₁-C₄-alkoxy or C₁-C₅-alkenoxy, where hydroxy, methoxy, t-butyloxy, -O-CH₂-CH = CH₂ and (CH₃) ₂C = CH-CH₂-O- are very particularly preferred.

Following this step, the protecting groups are removed, for example by trifluoroacetic acid in dioxane / water, to convert R² and R³ to hydrogen.

Alternatively or additionally, R 1 can be according to a known or above-mentioned processes are converted into hydrogen.

The previously described sorangicins with the formulas (I), (II) and (III) can not only the previously in the trient part specified conformation but also have others Accept conformations, for example

These conformations arise under the influence of heat or Irradiation with visible or UV light. Depending on the derivative they are more or less stable.

A fifth group of process steps causes modifications in the trient section of the Sorangicine.

1. The oxidation of sorangicins with a quinone to Example with 2,3-dichloro-5,6-dicyanobenzoquinone, leads to a mixture of compounds (IVa) and (IVb), wherein R12 is a Represents oxygen atom. Leave the products (IVa) and (IVb) separate chromatographically. Those are preferred Compounds used, wherein R¹ as specified in claim 1 Has meanings and R², R³ and R⁴ are each hydrogen represent. Among these, those are very particularly preferred Compounds in which R¹ is hydroxy, C₁-C₄ alkoxy or C₁-C₅ alkenoxy is, wherein hydroxy, methoxy, t-butyloxy, CH₂ = CH-CH₂-O- and (CH₃) ₂C = CH-CH₂-O- are most preferred.

The above 33-O, 26-seco-36-oxo (37E, 39Z or 39E, 41Z) sorangicins can be with a reducing agent like  Sodium cyanoborohydride to compounds with the formulas (IVa) and (IVb), wherein R¹² is a hydrogen atom and a Represents hydroxy group.

All compounds of formula (IV) in which R¹ is none Hydroxy group is, of course then according to known or mentioned above Transfer processes to compounds in which R¹ die Hydroxy group means.

2. The reduction of sorangicins with a reducing agent like sodium amalgam, preferably in one with Ammonia / ammonium chloride buffered solution, leads to a Mixture of compounds (V) and (VI). The products (V) and (VI) can be separated chromatographically. To be favoured such compounds are used, wherein R¹ the in claim 1 has the meanings given and R², R³ and R⁴ each Represent hydrogen. Are very particularly preferred including those compounds in which R¹ is hydroxy, C₁-C₄ alkoxy or C₁-C₅-alkenoxy, where hydroxy, methoxy, t-butyloxy, CH₂ = CH-CH₂-O- and (CH₃) ₂C = CH-CH₂-O- most are preferred.

With the help of a special base such as Tetrabutylammonium fluoride can be shifted Achieve double bonds in the trient section. You get connections with the formulas (VIIa) and (VIIb), which can be determined with  of preparative column chromatography, for example let it separate chromatographically. For the preferred connections this applies under points 1 and 2 above. Said.

All described sorangicins can follow the described reactions continue with acids or bases in Salts are transferred.

Unless the sorangicin derivatives are for medical use the acids or bases mentioned should be provided pharmaceutically acceptable and the salts produced be tolerable.

The following examples illustrate the invention.

Protection group technology

General working procedure for the separation of the allyl ester protection group

18 mg (20 µmol) sorangicinallyl ester 14, 3.5 mg tetrakis (triphenyl- phosphine) palladium (0) (0.15 eq) and 2.6 mg triphenylphosphine (0.5 eq) are dissolved in 0.5 ml dry dichloromethane. The solution comes with 27 mg (0.2 mmol) morpholine were added and the mixture was stirred at RT for 5 h. After DC the spin-off quantitative.

The solution is washed three times with 1M hydrochloric acid and concentrated. The catalyst is separated off and purified using PSC or column chromatography. (Si 60, 0.5 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.2-0.3).
Yield: 9.7 mg = 57% sorangicin A

General working procedure to split off the Isopropylidene protecting group

30 mg (37 µmol) 21,22-O-isopropylidensorangicin 19 are dissolved in 1 ml THF and 0.2 ml water and 0.1 ml trifluoroacetic acid are added. The solution is flushed with nitrogen and heated with stirring in a closed vessel at 85 ° C. for 3 h. The cleavage takes place quantitatively after DC. The THF is distilled off in vacuo, the residue is diluted with water and the aqueous phase is extracted twice with dichloromethane. The solution is concentrated and the product is purified using PSC (silica gel Si 60, 0.5 mm; mobile solvent dichloromethane / methanol, 9: 1, v / v; RF 0.2-0.3).
Yield: 20 mg = 70% sorangicin A

Example 1

Type of derivative: ester
Substance name: Sorangicin A methyl ester

Manufacturing

1 .: Reaction of sorangicin A in ether with an excess of diazomethane.

2 .: Esterification of sorangicin A with 1N methanolic HCl. After TLC control (methylene chloride / methanol 15: 1), the reaction is carried out by adding aqueous sodium bicarbonate solution. completed. After removing the methanol i. Vac. the product is extracted from the aqueous phase with methylene chloride, dried with MgSO₄ and concentrated. It is cleaned chromatographically for analysis. (HD-Sil 18-30-60, methanol / water 70:30, detection UV at 313 nm).
Yield: 87%.
= + 66.9 (c = 0.5 in methanol).
UV (methanol): λ _max (1g ε): 300 nm (4.39).
1 H-NMR ([D₄] methanol): δ = 3.69 (3H, s, -OCH₃), 2.33 (2H, t, 6.9, 2-H₂).
13 C-NMR ([D₄] methanol): δ = 176.1 (C-1), 35.0 (C-2), 52.0 (-OCH₃).
Mass spectroscopy: (-) FAB (glycerol): m / z = 819 [MH] ^- , 911 [M-H + Mat] ^- .

High resolution: [C₄₈H₆₇O₁₆-H]
Calculated: 819.4684
Found: k819.4684

Example 2

Type of derivative: ester
Substance name: Sorangicin A ethyl ester

Manufacturing

Analogous to example 1, with anhydrous 1 N ethanolic HCl at room temperature. in 15 min. Purification by preparative TLC on silica gel, eluent toluene / ethanol 9: 1).
Yield: 50%.
1 H-NMR ([D₄] methanol): δ = 4.15 (2H, q, 7.1 -OCH₂), 1.28 (3H, t, 7.1, CH₃).
13 C-NMR ([D₄] methanol): δ = 175.7 (C-1), 61.4 (-OCH₂), 14.6 (-CH₃).

Example 3 Sorangicinallylester (14)

500 mg (0.625 mmol) sorangicin A are dissolved in 15 ml dry dichloromethane dissolved and with 0.75 ml (15 eq.) allyl bromide and 1.2 ml (10 eq.) N- Ethyldiisopropylamine added. The solution is flushed with nitrogen and sealed for 24 h at RT. A DC (eluent dichloromethane / Methanol, 9: 1, v / v; Educt Rf 0.25, product Rf 0.5) shows complete Sales.

Solvents and reagents are distilled off in a water jet vacuum at 40 ° C. The product is dissolved in 50 ml of ethyl acetate, washed twice with 1 M ammonia solution, twice with 1 M hydrochloric acid and once with water. The solvent of the organic phase is distilled off in vacuo, stripped off twice with a little toluene and then dried under a fine vacuum.
Yield 505 mg = 96%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.34 (d, J = 7.5 Hz, 2H, H-2); 4.56 (m 2H, OC H ₂-CH = CH₂); 5.93 (m, 1H, -C H = CH₂); 5.19, 5.31 (m, 2H, -CH = C H₂ ).
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 173.55 s (C-1); 65.17 t, 133.94 d, 117.78 t (allyl).
IR (film): ν = 3485, 3448, 3442, 2960, 2929, 2883, 1729, 1702, 1612, 1448, 1378, 1276, 1177, 1073, 975, 879, 738 cm ^-1 .
MS (20 eV): m / e (%) = 846 (4, M⁺), 828 (6), 810 (4), 413 (10), 289 (100), 209 (20), 95 (25) .

High resolution: C₅₀H₇₀O₁₁
Calculated: 846.4918
Found: 846.4941 (M⁺)

Example 4 Sorangicin (3'-methyl-2'-butenyl) ester (15)

50 mg (62 µmol) sorangicin A, 90 mg N-ethyldiisopropylamine (10 eq.) And 100 mg of 1-bromo-4-methyl-2-butene are dissolved in 2 ml of dry dichloromethane dissolved and stirred at RT for 3 h. A DC (eluent Dichloromethane / methanol, 9/1, v / v; Educt Rf 0.25, product Rf 0.55) shows full sales.

The solution is concentrated, dried in a water jet vacuum at 30 ° C. and taken up again in dichloromethane. The solution is washed once with water, once with dilute ammonia solution, twice with 1M hydrochloric acid and once more with water. The solvent is distilled off in vacuo, and dried in a fine vacuum for 2 h.
Yield: 54 mg = 99%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.26 (t, J = 7.5 Hz, 2H, H-2); 4.53, 5.32, 1.69, 1.74, (methylbutenyl).
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 173.78 s (C-1); 61.24 t, 120.03 d, 145.80 s, 17.90 q, 25.68 q (methylbutenyl).
IR (film): ν = 3454, 2962, 2927, 1700, 1613, 1448, 1380, 1264, 1176, 1069, 972, 872, 821, 747 cm ^-1 .
MS (FAB): m / e (%) = 872 [100 (MH) ^- ], 804 (27).

High resolution: C₅₂H₇₄O₁₁
Calculated: 873.5153
Found: 873.5150 (MH) ^-

Example 5 Sorangicin Benzyl Ester (13)

9 mg (11 µmol) sorangicin A, 4 mg N-ethyldiisopropylamine (3 eq.) And 10 mg Benzyl bromide are dissolved in 0.5 ml dichloromethane and 24 h at RT touched. A TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.25, product Rf 0.55) indicates complete conversion.

The reaction solution is washed twice with water, the organic phase is concentrated and the product is purified using PSC (silica gel Si 60, 0.25 mm, mobile phase dichloromethane / methanol, 9: 1, v / v; Rf 0.5).
Yield: 8 mg = 81%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.35 (d, J = 7.5 Hz, 2H, H-2); 5.11 (m, 2H, benzyl); 7.38 (m, 5H, benzyl).
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 173.84 s (C-1); 137.67 s, 128.73 d, 129.24 d, 66.26 t (benzyl)
IR (film): ν = 3425, 3037, 2960, 2927, 1708, 1612, 1453, 1382, 1277, 1179, 1071, 975, 738 cm ^-1 .
MS (70 eV): m / e (%) = 896 (0.6, M⁺), 872 (2), 860 (0.5), 549 (1.6), 463 (2), 339 (54 ), 91 (100).

High resolution: C₅₄H₇₂O₁₁
Calculated: 896.5074
Found: 896.5050 (M⁺)

Example 6

Type of derivative: ester
Substance name: Sorangicin A-carboxamidomethyl ester

Manufacturing

100 mg (0.112 mmol) sorangicin A were mixed with 12 mg (0.113 mmol) Na₂CO₃ in water in ethanol / water, in high vacuum. concentrated and by repeated addition of toluene and concentration in a high vacuum. dried. The residue was abs. In 0.5 ml. DMF with 21 mg (0.225 mmol) chloroacetamide at 50 ° C stirred for 15 hours. Then it was diluted with methylene chloride and against saturated sodium bicarbonate solution. shaken. The residue of the methylene chloride phase was prepared by prep. TLC (methylene chloride / methanol 9: 1) cleaned.
Yield: 64 mg (66%).
= + 61.1 (c = 0.9 in methanol).
UV (methanol): λ _max (1 g ε): 301 nm (4.40).
1 H-NMR ([D₄] methanol): δ = 4.57 (2H, s, -OCH₂-), 2.47 (2H, t, 2-H₂), otherwise like sorangicin A.
13 C-NMR ([D₄] methanol): δ = 174.5 (C-1), 172.7 (-CONH₂), 62.9 (-OCH₂-), otherwise like Sorangicon A.
Mass spectroscopy: (-) FAB (3NBA): m / z = 862 [MH] ^- , 1016 [M-H + Mat] ^- .

High resolution: [C₄₉H₆₈NO₁₂-H]
Calculated: 862.4741
Found: 862.4753

Example 7

Type of derivative: ester
Substance name: Sorangicin AN, N-dimethylcarboxamido methyl ester

Manufacturing

Analogous to Example 6 with 27.2 mg (23 µl, 0.224 mmol) of 2-chloro-N, N-dimethylacetamide, reaction time 6 h.
Yield: 76 mg (76%).
= + 58.9 (c = 0.8 in methanol).
UV (methanol): λ _max (1 g ε): 300 nm (4.49).
1 H-NMR ([D₄] methanol): δ = 4.84 (-OCH₂-), 3.05 + 2.98 (each 3H, s, -NCH₃), 2.45 (2H, t, 2-H₂) , otherwise like Sorangicin A.
13 C-NMR ([D₄] methanol): as example 8, but instead of 2 NC₂H₅ δ = 36.2 + 35.8 (each CH₃).

Example 8

Type of derivative: ester
Substance name: Sorangicin AN, N-diethylcarboxamidomethylter

Manufacturing

Analogous to Example 6, with 33.5 mg (30.4 µl, 0.224 mmol) of N- (2-chloroacetyl) diethylamine, reaction time 3 h. Then constrict i. Hochvak .. cleaning by prep. DC analog Ex. 6.
Yield: 60 mg (58%).
= + 56.9 (c = 1.0 in methanol).
UV (methanol): λ _max (1 g ε): 301 nm (4.41).
1 H-NMR ([D₄] methanol): δ = 4.83 (-OCH₂-), 3.37 (4H, m, 2 NCH₃), 2.45 (2H, t, 2-H₂), 1.27+ 1.16 (each 3H, t, -CH₃), otherwise like Sorangicin A.
13 C-NMR ([D₄] methanol): δ = 175.0 (C-1), 168.3 (-CON <), 62.1 (-OCH₂-), 42.2 +41.6 (-NCH₂) , 14.1 + 13.0 (-CH₃), otherwise like Sorangicin A.
Mass spectroscopy: (-) FAB (3NBA): m / z = 918 [MH] ^- , 1072 [M-H + Mat] ^- .

High resolution: [C₅₃H₇₇NO₁₂-H]
Calculated: 918.5367
Found: 918.5346

Example 9

Type of derivative: ester
Substance name: Sorangicin AN- (2 ′, 6′-dimethylphenyl) carboxamido methyl ester

Manufacturing

Analogous to Example 6, with 44 mg (0.224 mmol) of N- (2-chloroacetyl) -2,6-dimethylaniline, reaction time 3.5 h. Cleaning prep. TLC (2 mm) (methylene chloride / methanol 12: 1).
Yield: 60 mg (55%).
= + 52.9 (c = 1.0 in methanol).
UV (methanol): λ _max (1 g ε): 302 nm (4.38).
1 H-NMR ([D₄] methanol): δ = 7.12 (3H, m, aromat. -H), 4.79 (2H, s, -OCH₂), 2.51 (2H, t, 2-H₂) , 2.24 (6H, s, 2 -CH₃), otherwise like Sorangicin A.
13 C-NMR ([D₄] methanol): δ = 136.9, 129.0 (2 ×) +128.5 (aromat. -C), 18.3 (2 ×) (-CH₃), otherwise as in Ex. 8th.
Mass spectroscopy: (-) FAB (3NBA): m / z = 966 [MH] ^- , 1120 [M-H + Mat] ^- .

High resolution: [C₅₇H₇₇NO₁₂-H]
Calculated: 966.5367
Found: 966.5351

Example 10 Sorangicin (1'-methyl-3'-piperidinyl) methyl ester (87)

8 mg (50 µmol) 1,1'-carbonyldiimidazole are dry in 0.2 ml Chloroform dissolved, mixed with 14 mg (0.1 mmol) iodomethane and on for 1 h Heated to 65 ° C. A yellow solid precipitates out. This is now a Solution of 40 mg (50 µmol) sorangicin A and 100 mg (1-methyl-3-piperidine yl) -methanol injected in 1 ml of chloroform. After stirring for 3 h at 65 ° C shows a TLC of an acidified sample (solvent dichloromethane / Methanol, 9: 1, v / v) in addition to starting material with Rf 0.3, a polar product with Rf 0.15.

The chloroform is distilled off in vacuo, the residue in 2 h Fine vacuum dried, taken up in dichloromethane and with a 2M HCl solution in methanol / water 5: 1, acidified (pH 2-3).

The product is cleaned using PSC (silica gel Si 60,
Eluent dichloromethane / methanol, 85:15, v / v; Rf 0.2).
Yield: 15.6 mg = 34%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.29 (m, 1H, H-1); 1.56-1.72, 2.05, 2.27, 2.78, 2.89, 3.87, 3.97 (1-methyl-3-piperidinyl).
13 C NMR (acetone-d₆): 75.5 MHz, δ = 173.80 s (C-1); 24.80 t, 26.89, 36.13 d, 46.33 q, 56.29 t, 59.14 t, 67.03 d (1-methyl-3-piperidinyl).
IR (film): ν = 3429, 3045, 2931, 1729, 1698, 1612, 1378, 1272, 1208, 1180, 1069, 975, 825, 738 cm ^-1 .
MS (FAB): m / e (%) = 916 [8 (MH) ^- ], 805 (100), 579 (10), 402 (10).

High resolution: C₅₄H₇₉NO₁₁
Calculated: 916.5575
Found: 916.5524 (MH) ^-

Example 11

Type of derivative: amide
Substance name: Sorangicin A-amide

Manufacturing

50 mg (56 μmol) sorangicin A were stirred in 0.3 ml methylene chloride in the presence of 100 mg molecular sieve 4 A with 13 mg (1.4 equiv.) N, N-carbonyldiimidazole. When only traces of sorangicin A were still present after DC control, NH 3 gas was introduced with cooling. Then was diluted with methylene chloride and against aqueous ammonia solution. shaken out. The evaporation residue of the methylene chloride phase was by prep. TLC (methylene chloride / methanol 9: 1) cleaned.
Yield: 25 mg (55%).
= + 60.9 (c = 0.6 in methanol).
UV (methanol): λ _max (1 g ε): 301 nm (4.31).
1 H-NMR ([D₄] methanol): δ = 2.22 (2H, t, 7.6, 2-H₂).
13 C-NMR ([D₄] methanol): δ = 179.3 (C-1), 36.7 (C-2).
Mass spectroscopy: (-) FAB (3NBA): m / z = 805 [MH] ^- , 959 [M-H + Mat] ^- .

High resolution: [C₄₇H₆₇NO₁₀-H]
Calculated: 804.4687
Found: 804.4660

Example 12

Type of derivative: amide
Substance name: Sorangicin A-methylamide
Preparation: 1.) analogously to Example 21 over acid chloride, 2.) analogously to Example 11, with methylamine (gas).
Yield: 23 mg (50%).
= + 64.7 (c = 0.2 in methanol) .-
UV (methanol): λ _max (1 g ε): 300 nm (4.34).
1 H-NMR ([D₄] methanol): δ = 7.68 (1H, m, NH), 2.74 (3H, s, NCH₃), 2.19 (2H, t, 7.6, 2-H₂) .
13 C-NMR ([D₄] methanol): δ = 176.9 (C-1), 37.12 (C-2), 27.1 (C-3), 26.3 (NCH₃).
Mass spectroscopy: (-) FAB (3NBA): m / z = 819 [MH] ^- , 973 [M-H + 3NBA] ^- .

Example 13

Type of derivative: amide
Substance name: Sorangicin A-isopropylamide

Manufacturing

Acid chloride as in Example 21. The acid chloride from 50 mg formyl sorangicin A was stirred with 19 mg (29 µl, 320 µmol) 2-propylamine for 5 min at 0 ° C and 15 min at room temperature and then concentrated. After unblocking with methanolic ammonia, the product was prepared by prep. RP-HPLC purified (Nucleosil C18, 16 × 250 mm, methanol / water 75:25, 24 ml / min).
Yield: 21 mg (44%).
= + 66.2 (c = 0.4 in methanol).
UV (methanol): λ _max (1 g ε): 301 nm (4.42).
1 H-NMR ([D₄] methanol): δ = 3.98 (1H, dq, 6.6, -NCH =), 1.16 (, d, 6.6, 2 CH₃).
13 C-NMR ([D₄] methanol): δ = 175.5 (C-1), 42.5 (-NCH =), 22.9 (2 CH₃).
Mass spectroscopy: EI (270 ° C): m / z = 847 [M] ⁺.

High resolution: C₅₀H₇₃NO₁₀
Calculated: 847.5234
Found: 847.5226 (EI-MS)

Example 14

Type of derivative: amide
Substance name: Sorangicin A-isobutylamide

Manufacturing

As example 13, with 25 mg (34 µl, 340 µmol) isobutylamine (2-methylpropylamine). Cleaning by RP-HPLC (LiChrosorb RP-18, 16 × 250 mm, methanol / water 70:30 with 0.1% TEA and formic acid adjusted to pH 8.5.
Yield: 18 mg (37%).
= + 71.5 (c = 0.4 in methanol).
UV (methanol): λ _max (1 g ε): 301 nm (4.45).
1 H-NMR ([D₄] methanol): δ = 3.02 (2H, d, 6.9, -NCH₂-), 1.80 (1H, tq, <CH-), 0.94 (6H, d, 6.7, 2 CH₃).
13 C-NMR ([D₄] methanol): δ = 176.6 (C-1), 48.1 (-NCH₂-), 29.8 (<CH-), 20.7 (2 CH₃).
Mass spectroscopy: EI (250 ° C): m / z = 861 [M] ⁺.

High resolution: C₅₁H₇₅NO₁₀
Calculated: 861.5390
Found: 861.5412 (EI-MS)

Example 15

Type of derivative: amide
Substance name: Sorangicin-An-hexylamide

Manufacturing and cleaning

As example 13, with 34 mg (45 µl, 340 µmol)
Hexylamine for acid chloride from 50 mg formyl sorangicin A.
Yield: 13 mg (26%). [Α] = +61.6 (c = 0.25 in methanol).
UV (methanol): λ _max (lg ε): 300 nm (4.44).
1 H-NMR ([D₄] methanol): δ = 3.18 (2H, t, 7.0, -NCH₂), 1.7-1.1 (m, 4 CH₂), 0.95 (3H, t, 7.0, -CH₃).
13 C-NMR ([D₄] methanol): δ = 176.4 (C-1), 40.6 (-NCH₂), 37.5, 30.6, 27.9+ 23.9 (each CH₂), 14.6 (CH₃).
Mass spectroscopy: EI (250 ° C): m / z = 889 [M] ⁺.

High resolution: C₅₃H₇₉NO₁₀
Ber. 889.5703
Found 889.5687 (EI-MS)

Example 16

Derivative type: amide, 25-R
Substance name: 25-O-formyl-sorangicin AN- (3'-hydroxypropyl) amide

Manufacturing

50 mg (56 µmol) formyl sorangicin A were in 0.5 ml abs. Methylene chloride in the presence of about 100 mg of Drierite with 16.5 mg (100 µmol) carbonyldiimidazole stirred for 1 h. Then 21 mg (22 μl, 280 μmol) 3-amino-1-propanol were added and the mixture was stirred for a further 2 hours. The desiccant was filtered off. The filtrate was washed with acidic water and concentrated. After standing for 1 hour with dioxane / ammonia, the mixture was concentrated again. The residue was washed in ethyl acetate, concentrated with water and purified by RP-HPLC (Nucleosil C18, 10 μ, 16 × 250 nm, methanol / water 75:25, 16 ml / min).
Yield: 27 mg (56%). [Α] = +81.1 (c = 0.6 in methanol).
UV (methanol): λ _max (lg ε): 302 nm (4.35).
1 H-NMR ([D₄] methanol): δ = 8.18 (1H, s, -CHO), 3.61 (2H, t, 6.4, -NCH₂-), 3.29 (2H, t, 6.9, -OCH₂-), 1.74 ( 2H, German, 6.4, 6.9, -CH₂-), otherwise as example 33.
13 C-NMR ([D₄] methanol): δ = 176.2 (C-1), 162.0 (-CHO), 60.3 (-CH₂O-), 37.2 +37.1 (-CH₂-CH₂N <), otherwise as in Example 33.
Mass spectroscopy: (-) FAB (3NBA): m / z = 890 [MH] ⁻, 862 [M-CO-H] ⁻.

High resolution:
[C₅₁H₇₂NO₁₂]
Ber. 890.5041
Found 890.5018

[C₅₀H₇₂NO₁₁]
Ber. 862.5106
Found 862.5121

Example 17

Derivative type: amide, 25-R
Substance name: 25-O-formyl-sorangicin-AN- (2'-hydroxy-1'-methylethyl) amide

Manufacturing

Like Ex. 16, with 2-aminopropanol
Yield: 27 mg (54%). [Α] = +81.7 (c = 0.3 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.37).
1 H-NMR ([D₄] methanol): δ = 3.95 (1H, m, -NCH <), 3.49 (2H, m, -CH₂O-), 1.16 (3H, d, 6.7, -CH₃), otherwise as in Ex. 33.
13 C-NMR ([D₄] methanol): δ = 66.4 (-OCH₂-), 17.2 (-CH₃), otherwise as in Example 33.
Mass spectroscopy: (-) FAB (2NBA): m / z = 890 [MH] ⁻.

High resolution: C₅₁H₇₂NO₁₂
Ber. 890.5054
Found 890.5091

Example 18

Type of derivative: amide
Substance name: N-Sorangicinyl-aminoethyl-2-sulfonic acid Na⁺ or NHEt₃⁺

Manufacturing

80 mg aminoethylsulfuric acid were abs in 1.5 ml. DMF was stirred with 12 mg of sodium hydride at 0 ° C. for one hour and a solution of 50 mg (56 μmol) of triformylsorangicin, which was stirred for one hour with 22 mg of N, N-carbonyldiimidazole in methylene chloride, was added and the mixture was stirred at room temperature for one hour . It was then concentrated in an oil pump vacuum, shaken out in ethyl acetate with water at pH 4 (formic acid), concentrated and concentrated with methanol / conc. Unblocked ammonia 9: 1 for 3 hours. Purification by HPLC (Nucleosil C18 10 µ, 16 mm × 250 mm, methanol / aqueous buffer 65:35 (buffer triethylammonium formate pH 7). The main fraction was concentrated and extracted with ethyl acetate from the remaining buffer. Yield: 18 mg (as triethylammonium salt) (32%).
Alternatively: stir over formylsorangicinic acid chloride with 5 equivalents of DMAP or triethylamine and 5 equivalents of aminoethylsulfuric acid at -15 ° C for 10 min, 15 min at 0 ° C and 1 h at room temperature. Unblocking and cleaning analog. [Α] = +60.0 (c = 0.7 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.30).
1 H-NMR ([D₄] methanol): δ = 8.04 (1H, t, 5.3, NH), 4.07 (2H, t, 5.4, -OCH₂-), 3.50 (3H, m, 22-H), -NCH₂- ), 3.25 + 1.35 (TEA).
13 C-NMR ([D₄] methanol): δ = 176.4 (C-1), 66.4 (-OCH₂-), 40.1, 39.7 + 38.5 (-NCH₂-, C-2, C-34), 47.8 + 9.1 (TEA ).
Mass spectroscopy: (-) FAB (3NBA): m / z = 928 [MH] ⁻.

High resolution: [C₄₉H₇₁NO₁₄³²S-H]
Ber. 928.4517
Found 928.4501

Example 19

Type of derivative: amide
Substance name: Sorangicin-A- (2′-aminophenyl) amide

Manufacturing and cleaning

As example 13, with 30 mg (280 µmol) o-phenylenediamine for acid chloride from 50 mg formyl sorangicin A.
Yield: 10 mg (20%). [Α] = +59.6 (c = 0.4 in methanol).
UV (methanol): λ _max (lg ε): 240 (sh), 300 nm (4.42).
1 H-NMR ([D₄] methanol): δ = 7.24-6.81 (5H, m, 40-, 41- + 38-H, 2 aromatic.-H). 6.82 (1H, dd, 8.0, 1.2, aromat.-H), 6.70 (1H, ddd, 7.7, 7.7, 1.3, aromat.-H), 2.38 (2-H₂).
13 C-NMR ([D₄] methanol): δ = 175.1 (C-1), 37.0 (C-2), 27.1 (C-3).
Mass spectroscopy: (-) FAB (3NBA): m / z = 895 [MH] ⁻, 1049 [M-H + Mat] ⁻.

High resolution: [C₅₃H₇₂N₂O₁₀-H]
Ber. 895.5109
Found 895.5116

Example 20

Type of derivative: amide
Substance name: Sorangicin-A- (4′-pyridyl) methylamide

Manufacturing and cleaning

As example 13, with 91 mg (427 µmol) 4-picolylamine [4- (aminomethyl) pyridine] from acid chloride from 150 mg formylsorangicin.
Yield: 55 mg (36%). [Α] = +62.7 (c = 0.5 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.36).
1 H-NMR ([D₄] methanol): δ = 8.50 + 7.38 (each 2H, m, aromat.-H), 4.45 (4H, m, 36- + 13-H, -NCH₂-).
Mass spectroscopy: EI (250 ° C): m / z = 896 [M] ⁺.

High resolution: C₅₃H₇₂N₂O₁₀
Ber. 896.5186
Found 896.5177 (EI-MS)

Example 21

Type of derivative: amide
Substance name: Sorangicin A hydrazide

Manufacturing and cleaning

As example 25, with 200 ul hydrazinium hydroxide solution with ice cooling.
Yield: 25 mg (54%). [Α] = +72.2 (c = 0.2 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.38).
1 H-NMR ([D₄] methanol): δ = 2.17 (2-H₂), otherwise like sorangicin A.
13 C-NMR ([D₄] methanol): δ = 175.4 (C-1), otherwise like Sorangicin A.
Mass spectroscopy: (-) FAB (glycerol): m / z = 819 [MH] ⁻: (-) FAB (TEA): m / z = 819 [MH] ⁻.

Example 22

Type of derivative: amide
Substance name: Sorangicin A-dimethylhydrazide

Manufacturing

As Example 13, with 20 mg (26 µl, 340 µmol) dimethylhydrazine, cleaning MPLC (HD-Sil 18-20-60, 18.5 × 200 mm, methanol / water 70:30, 16 ml / min).
Yield: 22 mg (47%). [Α] = +68.0 (c = 0.6 in methanol).
UV (methanol): λ _max (lg ε): 302 nm (4.38).
1 H-NMR ([D₄] methanol): δ = 2.55 (6H, s, 2 NCH₃), 2.15 (2-H₂).
13 C-NMR ([D₄] methanol): δ = 173.6 (C-1), 47.3 (2 NCH₃).
Mass spectroscopy: (-) FAB (3NBA): m / z = 847 [MH] ⁻, 1001 [M-H + Mat] ⁻.

High resolution: [C₄₉H₇₂N₂O₁₀-H]
Ber. 847.5109
Found 847.5126

Example 23 N- (4-methylpiperazin-l-yl) sorangicinamide (86)

40 mg (50 µmol) sorangicin A are dissolved in 1 ml dry dichloromethane and cooled to -70 ° C. A solution of 10 mg (60 µmol) of 1,1'-carbonyldiimidazole is injected and stirred for 10 min at RT. TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.3) shows the active sorangicinimidazolide as the main lipophilic product with Rf 0.7. A solution of 40 mg of 1-amino-4-methylpiperazine hydrochloride (4 eq.) And 100 μl of N-ethyldiisopropylamine in 0.5 ml of acetonitrile is then added to the reaction mixture, and the whole is stirred at RT for 24 h. A DC (see above) shows a polar main product with Rf 0.1. The solution is concentrated, taken up in ethyl acetate and washed twice with 1 M ammonia solution. The product is separated and purified using PSC (silica gel Si 60, 1 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.1).
Yield: 7 mg = 16%
1 H-NMR (CD₃OD): 400 MHz, δ = 2.14 (t, J = 7.5 Hz, 2H, H-2); 2.85 (m, 8H, methylpiperazinyl), 2.54 (s, 3H, methylpiperazinyl).
13 C-NMR (CD₃OD): 75.5 MHz, δ = 173.05 s (C-1);
54.90 t, 54.54 t, 44.99 q (methylpiperazinyl).
IR (film): ν = 3394, 3297, 2956, 2929, 1696, 1665, 1612, 1457, 1380, 1278, 1206, 1176, 1145, 1069, 1039, 1017, 975, 736 cm ^-1 .
MS (FAB): m / e (%) = 902 [53 (MH) ⁻], 574 (16), 458 (100).

High resolution: C₅₂H₇₇N₃O₁₀
Calc .: 902.5531
Found: 902.5642 (MH) ⁻

Example 24

Type of derivative: amide
Substance name: Sorangicin A-methoxyamide

Manufacturing

Analogous to Example 13, with 7 mg (84 µmol) O-methylhydroxylamine.HCl in the presence of 10 mg (84 µmol) DMAP. Cleaning as in example 22.
Yield: 10 mg (21%). [Α] = +66.3 (c = 0.3 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.37).
1 H-NMR ([D₄] methanol): δ = 3.71 (3H, s, OCH₃), 2.09 (2-H₂).
Mass spectroscopy: (-) FAB (3NBA): m / z = 834 [MH] ⁻, 988 [M-H + Mat] ⁻.

High resolution: [C₄₈H₆₉NO₁₁-H]
Ber. 834.4792
Found 834.4799

Example 25

Derivative type: amide, 25-R
Substance name: 25-O-formyl-sorangicinyl-guanidine

Manufacturing

50 mg (56 µmol) formyl sorangicin A with 16.5 mg (100 µmol) carbonyldiimiazole in abs. Methylene chloride stirred at room temperature for 1 h, concentrated and in abs. DMF dissolved to 54 mg (560 µmol) guanidinium chloride and 100 mg Drierite in 1 ml abs. Given DMF and stirred for 20 h. After removing the desiccant i. Oil pump vacuum evaporated, washed with ethyl acetate in ethyl acetate and treated with dioxane / ammonia for 1 h after concentration. Purification by RP-HPLC (Nucleosil C18, 10 µ, 16 × 250 mm, methanol / water 65:35 + 0.1% formic acid.
Yield: 13 mg (26%). [Α] = +77.9 (c = 0.4 in methanol).
UV (methanol): λ _max (lg ε): 231 nm (3.96), 302 (4.30).
1 H-NMR ([D₄] methanol): δ = 8.46 (1H, s (br), NH), 8.18 (1H, s, -CHO), 5.07 (1H, d (br), 1.5, 25-H), 3.58 (2H, m, 22- + 23-H), 2.49 (2H, 2-H₂).
13 C-NMR ([D₄] methanol): δ = 177.1 (C-1), 157.1 (guanide-C), 75.5, 75.3 + 75.3 (C-13, -23 + -27), 74.4, 74.2 + 74.0 (C -21, -9 + -25), 37.9 + 36.7 (C-28 + -2).
Mass spectroscopy: (-) FAB (2NBA): m / z = 874 [M] ⁻.

High resolution: C₄₉H₆₈N₃O₁₁
Ber. 874.4855
Found 874.4854

Example 26

Derivative type: amide, 25-R
Substance name: 25-O-formyl-sorangicinyl-aminoguanidine

Manufacturing

As Example 25, with 77 mg (560 µmol) aminoguanidinium nitrate, purified as Example 25, with methanol / water 70:30 with 0.1% formic acid.
Yield: 11 mg (22%). [Α] = +83.9 (c = 0.8 in methanol).
UV (methanol): λ _max (lg ε): 302 nm (4.34).
1 H-NMR ([D₄] methanol): as example 25, but δ = 2.31 (2H, t, 2-H₂).
13 C-NMR ([D₄] methanol): as example 25, but δ = 188.1 (aminoguanide-C), 176.1 (C-1), 162.9 (-CHO), 39.9 (C-2).
Mass spectroscopy: (-) FAB (3NBA): m / z = 890 [M] ⁻.

High resolution: C₄₉H₇₀N₄O₁₁
Ber. 890.5041
Found 890.5000

Example 27

Type of derivative: amide
Substance name: Sorangicin A-dimethylamide

Manufacturing

Analogously to example 13, by introducing dimethylamine (gas) into a solution of the acid chloride from 50 mg of formyl sorangicin A.
Yield: 18 mg (38%). [Α] = +72.9 (c = 0.4 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.45).
1 H-NMR ([D₄] methanol): δ = 3.09 + 2.95 (each 3H, s, -NCH₃).
13 C-NMR ([D₄] methanol): δ = 175.9 (C-1), 38.0 + 35.8 (each NCH₃), 34.4 (C-2), 26.5 (C-3).
Mass spectroscopy: (-) FAB (3NBA): m / z = 833 [MH] ⁻, 987 [M-H + Mat] ⁻.

High resolution: [C₄₉H₇₁NO₁₀-H]
Ber. 832.4999
Found 832.5015

Example 28

Type of derivative: amide
Substance name: Sorangicin A-piperidid

Manufacturing and cleaning

As example 13, with 29 mg (33 µl), 340 µmol) piperidine for acid chloride from 50 mg formylsorangicin A.
Yield: 24 mg (49%). [Α] = +73.3 (c = 0.5 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.39).
1 H-NMR ([D₄] methanol): δ = 3.51 (5H, m, 22-H, 2 81148 00070 552 001000280000000200012000285918103700040 0002003930950 00004 81029 ′ - + 6′-H₂), 1.77-1.50 (14H, m, 45-H₃ , 26-H, 3-, 24-, 3'-, 4 '- + 5'-H₂).
13 C-NMR ([D₄] methanol): δ = 174.2 (C-1), 48.3, 44.1, 27.9, 27.0, 25.7 (C- 2 'to C-6').
Mass spectroscopy: EI (255): m / z = 873 [M] ⁺.

High resolution: C₅₂H₇₅O₁₀
Ber. 873.5390
Found 873.5413 (EI-MS)

Example 29 Sorangicin-N- (N-cyclohexylcarbamoyl) cyclohexylamide (16)

40 mg (50 µmol) sorangicin A, 20 mg dicyclohexylcarbodiimide (2 eq.) And 0.6 mg 4-dimethylaminopyridine (0.1 eq.) Are dissolved in 10 ml dichloromethane and mixed with 0.5 ml tert-butanol. The solution is stirred at RT for 16 h. TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.25, product Rf 0.4) shows that the reaction is complete. The solution is filtered, concentrated and the product is purified using PSC (silica gel Si 60, 1 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.5).
Yield: 46 mg = 91%
1 H-NMR (CD₃OD): 400 MHz, δ = 1.88 (t, J = 7 Hz, 2H, H-2);
Substituent: 3.62 (m, 1H); 3.52 (m, 1H); 1.90 (m, 4H); 1.39 (m, 16H).
13 C-NMR (CD₃OD): 100.6 MHz, δ = 173.43 s (C-1); 159.89 s, 51.80 d, 33.29 t, 27.04 t, 26.60 t (substituent).
IR (film): ν = 3444, 3404, 3082, 2933, 2858, 1700, 1648, 1550, 1449, 1382, 1272, 1073, 973, 738 cm ^-1 .
MS (FAB): m / e (%) = 1011 [8 (MH) ⁻], 886 (100), 805 (16).

High resolution: C₆₀H₈₈N₂O₁₁
Calculated: 886.5469
Found: 886.5507
(MH-CONHC₆H₁₁) ⁻

Example 30

Type of derivative: amide
Substance name: Sorangicin A-methoxymethylamide

Manufacturing

Analogous to Example 13, with 8.2 mg (84 µmol) N, O-dimethylhydroxylamine HCl in the presence of 10 mg (84 µmol) DMAP. Cleaning as in example 22.
Yield: 32 mg (68%). [Α] = +59.8 (c = 0.4 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.35).
1 H-NMR ([D₄] methanol): δ = 3.75 (3H, s, OCH₃), 3.21 (3H, s, NCH₃).
Mass spectroscopy: (-) FAB (3NBA): m / z = 848 [MH] ⁻, 1002 [M-H + Mat] ⁻.

High resolution: [C₄₉H₇₁NO₁₁-H]
Ber. 848.4987
Found 848.4966

Example 31

Type of derivative: amide
Substance name: Sorangicin-benzylamide

Manufacturing

1. Analogously to Example 12 or Example 11 with benzylamine.
2. over the formyl sorangicin acid chloride with benzylamine in pyridine: 50 mg (56 µmol) tri-O-formyl sorangicin A were at 0 ° C in toluene in the presence of a trace of pyridine with 35 mg (50 µl, 280 µmol) Oxallyl chloride added and concentrated after a few minutes. The residue was abs at -15 ° C. Methylene chloride mixed with 30 mg (30 µl, 280 µmol) benzylamine and 8 mg (67 µmol) DMAP and stirred at 0 ° C for 3 h. The mixture was then concentrated in vacuo. After adding methanolic ammonia, the mixture was stirred for 1 h and concentrated again. The residue was purified by RP chromatography (HD-Sil 18-20-60, 18.5 x 200 mm, methanol / water 70:30, 15 ml / min).
Yield: 26 mg (52%).
[α] = +61.4 (c = 0.6 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.36).
1 H-NMR ([D₄] methanol): δ = 8.4 (1H, t (br), NH), 7.32 (5H, m, aromat.-H), 4.39 (2H, m, -CH₂-), 2.28 (2 -H₂).
13 C-NMR ([D₄] methanol): δ = 176.2 (C-1), 37.3 (C-2), 27.1 (C-3), 140.2,
129.5, 128.6 + 128.2 (aromat.-C), 44.1 (-CH₂-).
Mass spectroscopy: (-) FAB (3NBA): m / z = 894 [MH] ⁻, 1048 [M-H + 3NBA] ⁻.

Example 32 25-O-methylsorangicinallyl ester (44)

31 mg (35 µmol) of 43 (Example 46) are reacted after the AAV to split off the isopropylidene protecting group. TLC (eluent toluene / methanol, 9: 1, v / v; educt RF 0.65) gives a main product with Rf 0.3 and a by-product with Rf 0.15 (25-methyl-O-sorangicin 45, see below). The products are cleaned using PSC (silica gel Si 60, 1 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.5).
Yield: 8.7 mg = 30%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.32 (t, J = 7.5 Hz, 2H, H-2); 3.35 (m, 1H, H-25); 3.29 (s, 3H, 25-O-methyl); 4.56, 5.18, 5.30, 5.35 (allyl).
IR (film): ν = 3448, 2960, 2929, 2877, 1733, 1700, 1613, 1448, 1378, 1272, 1175, 1096, 1071, 975, 885, 823, 745 cm ^-1 .
MS (FAB): m / e (%) = 859 [100 (MH) ⁻], 819 (2).

High resolution: C₅₁H₇₂O₁₁
Calculated: 859.4997
Found: 859.4995 (MH) ⁻

25-O-methylsorangicin (45) Method A

When the isopropylidene protecting group is split off from 43 (Example 46), the product is obtained as a secondary component (see above, Rf 0.15).
Yield (at 31 mg educt): 3.7 mg = 13%

Method B

8.7 mg (10 µmol) 44 are reacted according to the AAV to split off the allyl ester protective group. After TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.65), a product with Rf 0.3 is obtained. The cleaning is carried out with the help of PSC (silica gel Si 60, 0.25 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.3).
Yield: 5.6 mg = 68%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.29 (t, J = 7 Hz, 2H, H-2); 3.35 (1H, H-25); 3.29 (3H, 25-O-methyl).
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 174.43 s (C-1); 56.02 q (25-O-methyl).
IR (film): ν = 3446, 2962, 2929, 1700, 1612, 1380, 1270, 1206, 1177, 1149, 1096, 1069, 975, 821, 738 cm ^-1 .
MS (FAB): m / e (%) = 819 [100 (MH) ⁻], 744 (10).

High resolution: C₄₈H₆₈O₁₁
Calculated: 819.4684
Found: 819.4656 (MH) ⁻

Example 33

Derivative type: 25-R
Substance name: 25-O-Formyl-sorangicin A

Preparation: From 60 mg (67 µmol) of Tri-O-formyl-sorangicin A by treatment with chloroform / methanol / conc. Ammonia 3: 3: 1 (20 min) or with other ammoniacal solutions. Work up by evaporation i. Vac., Shaking against dil. Aqueous formic acid, drying with sodium sulfate, evaporation i. Vac.
Yield: 45 mg (80%). [Α] = +79.2 (c = 0.5 in methanol).
UV (methanol): λ _max (lg ε): 302 nm (4.43).
1 H-NMR ([D₄] methanol): δ = 8.17 (1H, s, formyl-H), 5.44 (2H, m, 29- + 30- H), 5.07 (1H, d (br), 2.5, 25-H), 3.85 (1H, dd, 9.6, 7.7, 31-H), 3.75 (1H, dd, 8.4, 6.1, 2.3, 27-H), 3.62 (1H, ddd, 10.7, 7.1, 2.8, 23 -H), 3.57 (1H, dd, 7.1, 4.0, 22-H), 1.92-1.27 (2H, m, 24-H₂), 1.0 (3H, d, 7.2, 46-H₃), 0.91 (3H, d , 6.6, 44-H₃), 0.81 (3H, d, 6.7, 47-H₃).
13 C-NMR ([D₄] methanol): δ = 162.0 (-CHO), 75.3 + 75.4 (C-27 + -23), 74.1, 74.3 + 74.3 (C-25, -21, -9), 35.9 (C -26), 28.2 + 28.4 (C-2 + -24) mass spectroscopy: (-) FAB (glycerol): m / z = 833 [MH] ⁻, 925 [M-H + Mat] ⁻.

High resolution: [C₄₈H₆₆O₁₂-H]
Ber. 833.4476
Found 833.4486

Example 34

Derivative type: 25-R
Substance name: 25-O-propionyl-sorangicin A

Manufacturing

100 mg (118 µmol) of isopropylidene sorangicin A were abs. Pyridine with 200 mg (200 ul, 1.5 mmol) propionic anhydride in the presence of about 3 mg DMAP stirred for 16 hours at room temperature. The mixture was then concentrated in an oil pump vacuum, taken up in dioxane / trifluoroacetic acid / water 10: 9: 1 and stirred at room temperature until the intermediate product was blocked according to TLC control (silica gel, methylene chloride / methanol 9: 1). Cleaning with MPlC (HD-Sil 18-20-60, 18.5 × 200, solvent gradient: A = methanol / water 60:40 with 0.2% HCOOH, B = methanol with 0.2% HCOOH, 5 min 100% A, in 45 min to 75% A (25% B), flow rate 12 ml / min, detection UV at 313 nm).
Yield: 34 mg (33%). [Α] = +70.1 (c = 0.5 in methanol).
UV (methanol): λ _max (lg ε): 300 nm (4.38).
1 H-NMR ([D₄] methanol): Sorangicin signals such as 33, δ = 2.37 (2H, q, 7.7, propionyl-CH₂), 1.14 (3H, t, 7.7, propionyl-CH₃).
13 C-NMR ([D₄] methanol): δ = 175.2, 28.2, 9.62 (-CO-CH₂-CH₃).
Mass spectroscopy: (-) FAB (glycerol): m / z = 861 [MH] ⁻, 953 [M-H + Mat] ⁻.

Example 35

Derivative type: 25-R
Substance name: 25-O-acetylsorangicin A

Manufacturing

50 mg (59 μmol) of 21,22-O-isopropylidene sorangicin A were treated with pyridine / acetic anhydride 1: 1 for 16 h. It was then evaporated in an oil pump vacuum, evaporated again after the addition of toluene and in ethyl acetate with water and sat. Sodium chloride solution washed and evaporated. The residue was dissolved in 1 ml of dioxane and after the addition of 1 ml of 20 percent. aq. Trifluoroacetic acid stirred at 60 ° C for 30 min. After constriction i. Oil pump vacuum. an ethyl acetate / water distribution was carried out and evaporated again. For analyt. For this purpose, a sample was purified by RP-HPLC (16 × 250 mm, HD-Sil 18-10-60, methanol / water 80:20, 18 ml / min).
Yield: 46 mg (92%).
Alternatively: 100 mg (112 µmol) sorangicin A, 150 mg Drierite and 1 mg trichloroacetic acid were dissolved in 0.5 ml abs. Dichloromethane mixed with 36 mg of methyl orthoformate, stirred for one hour, again with 36 mg of orthoester and stirred for a further hour. A trace of pyridine was then added, filtered and evaporated to dryness in an oil pump vacuum. The residue was treated with pyridine / acetic anhydride for 16 hours, concentrated in an oil pump vacuum and freed by further concentration with toluene with pyridine. The residue was then 1.5 hours with dioxane / 50% formic acid and 45 minutes with methylene chloride / methanol / conc. Treated ammonia 3: 3: 1. The salts were removed by methylene chloride / water (pH 4, formic acid) distribution. The residue was purified by MPLC (HD-Sil 18-30-60, methanol / water 70:30, 16.5 ml / min). Yield 42 mg (51%). [Α] = +61.4 (c = 0.5 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.41).
1 H-NMR ([D₄] methanol): δ = 4.9 (25-H + OH), 4.18 (1H, dd, 7.2, 4.4, 21-H), 3.74 (1H, ddd, 7.5, 7.0, 2, 27-H), 3.63 (1H, ddd, 10.6, 6.9, 3.6, 23-H), 356 (1H, dd, 6.8, 4.4, 22-H), 2.08 (3H, s, -COCH₃). 13 C-NMR ([D₄] methanol): δ = 177.6, (C-1), 75.6 (C-13 + -25), 35.9 (C-26), 28.3 + 28.2 (C-4 + -24), 171.9 +21.4 (-CO-CH₃).
Mass spectroscopy: (-) FAB (glycerin): m / z = 847 [MH] ⁻, 939 [M-H + Mat] ⁻.

Example 36

Derivative type: 25-R
Substance name: 25-O-isobutyryl-sorangicin A

Manufacturing and cleaning

Analogous to Example 34 with 200 µl isobutyric anhydride.
Yield: 26 mg (25%). [Α] = +61.5 (c = 0.3 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.16).
1 H-NMR ([D₄] methanol): Sorangicin signals such as 33, δ = 2.58 (1H, dq, isobutyryl-H), 1.18 (6H, m, isobutyryl-CH₃).
Mass spectroscopy: (-) FAB (glycerol): m / z = 875 [MH] ⁻, 967 [M-H + Mat] ⁻.

Example 37 25-O-carbamoyl orangicinallyl ester (52)

59 mg (64 µmol) 51 (Example 50) are reacted after the AAV to split off the isopropylidene protecting group. After TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt RF 0.75), a main product with Rf 0.5 and a by-product with Rf 0.2 (25-O-carbamoylsorangicin 53, see Example 38) are obtained. The products are cleaned using PSC (silica gel Si 60, 1 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.4).
Yield: 32 mg = 57%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.32 (t, J = 7 Hz, 2H, H-2); 4.70 (m, 1H, H-25); 5.79 (s, 2H, NH₂); 5.92, 5.31, 5.20, 4.56 (allyl).
IR (film): ν = 3375, 3324, 3276, 3167, 2986, 2929, 1698, 1612, 1384, 1268, 1150, 1110, 1060, 832, 740 cm ^-1 .
MS (FAB): m / e (%) = 888 [100 (MH) ⁻], 844 (14).

High resolution: C₅₁H₇₁NO₁₂
Calculated: 888.4898
Found: 888.4909 (MH) ⁻

Example 38 25-O-carbamoylsorangicin (53)

42 mg (47 µmol) 54 (Example 51) become after the AAV to split off the isopropylidene protective group implemented. After TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; Educt Rf 0.5) gives a product with Rf 0.2.

The product is cleaned using PSC (silica gel Si 60, 1 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.2).
Yield: 15 mg = 37%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.28 (t, J = 7 Hz, 2H, H-2); 4.70 (m, 1H, H-25); 5.79 (s, 2H, NH₂);
13 C-NMR (acetone-d-): 100.6 MHz, δ = 157.02 s, (- C ONH₂)
IR (film): ν = 3417, 3043, 2962, 2931, 2875, 1700, 1612, 1440, 1392, 1334, 1280, 1149, 1058, 975, 821, 738 cm ^-1 .
MS (FAB): m / e (%) = 848 [100 (MH) ^- , 805 (62), 765 (5).

High resolution: C₄₈H₆₇NO₁₂
Calculated: 848.4585
Found: 848.4529 (MH) ^-

Example 39 25-O-mesylsorangicinallyl ester (48)

55 mg (57 µmol) 47 (Example 49) after the AAV to split off the isopropylidene protective group implemented. After TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; Educt Rf 0.9) receives a main product with Rf 0.75 and a by-product with Rf 0.3 (25-mesylsorangicin, see below).

The products are cleaned using PSC (silica gel Si 60, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.6).
Yield: 25 mg = 47%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.32 (t, J = 7 Hz, 2H, H-2); 4.85 (m, 1H, H-25); 3.10 (s, 3H, -SO₂C H ₃); 5.94, 5.32, 5.20, 4.56 (allyl).
IR (film): ν = 3487, 2929, 2858, 1733, 1702, 1613, 1451, 1357, 1274 1176, 1071, 1039, 975, 904, 738 cm ^-1 .
MS (FAB): m / e (%) = 923 [4 (MH) ^- ], 795 (4), 619 (100), 482 (15).

High resolution: C₅₁H₇₂O₁₃S
Calculated: 923.4616
Found: 923.4631 (MH) ^-

Example 40 25-O-mesylsorangicin (49) Method A

When the isopropylidene protecting group of 47 (Sbs. 49) is split off, the product is obtained as a secondary component (see above, Rf 0.3).
Yield: 8.4 mg = 17%

Method B

According to the AAV, 25 mg (27 µmol) 48 (Example 39) are used to split off the allyl ester protective group implemented. After TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; Educt Rf 0.7) gives a product with Rf 0.4).

The products are cleaned using PSC (silica gel Si 60, 1 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; educt Rf 0.3).
Yield: 18 mg = 75%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.28 (t, J = 7 Hz, 2H, H-2); 4.85 (m, 1H, H-25); 3.10 (s, 3H, -SO₂C H ₃);
13 C-NMR (acetone-d₆): 100.6 MHz, δ = 36.78 q (-SO₂ C H₃).
IR (film): ν = 3407, 3027, 2883, 1708, 1613, 1448, 1353, 1270, 1178, 1071, 973, 908, 738 cm ^-1 .
MS (FAB): m / e (%) = 883 [100 (MH) ^- ], 805 (4).

High resolution: C₄₈H₆₈O₁₃S
Calc .: 883.4302
Found: 883.4371 (MH) ^-

Example 41

Derivative type: RRR
Substance name: Tri-O-formyl-sorangicin A

Preparation: 500 mg (560 µmol) sorangicin A, 1.14 g (1.58 ml, 11 mmol) triethylamine and 70 mg (570 mmol) DMAP and 171 mg (140 µl, 3.7 mmol) formic acid were added in 10 ml Cooled methylene chloride to -15 ° C, slowly added 1.2 g (1.11 ml, 11.7 mmol) of acetic anhydride and then stirred at 0 ° C for 30 min. Then was in the oil pump vacuum. constricted. The residue was taken up in pyridine, ice water was added and the mixture was evaporated again after 30 min. The residue was purified by methylene chloride / water distribution, evaporated to a solid foam and dried in an oil pump vacuum.
Yield: 480 mg (96%). [Α] = +98.0 (c = 0.5 in methanol).
UV (methanol): λ _max (1g ε): 302 nm (4.37).
1 H-NMR ([D₄] methynol): δ = 8.22, 8.19 + 8.08 (each 1H, s, -CHO), 5.75-5.30 (9H, m, with 21- or 22-H), 5.20 (1H , dd, 7.9, 3.2, 21- or 22-H), 5.06 (1H, d (br), 2.0, 25-H).
13 C-NMR ([D₄] methanol): δ = 162.2, 161.9 × 161.5 (-CHO), 76.1, 73.6 + 73.1 (C-21, -22, -25)
Mass spectroscopy: (-) FAB (glycerol): m / z = 889 [MH] ^- , 981 [M-H + Mat] ^- .

Example 42

Type of derivative: cyclocarbonate
Substance name: 21,22-O-carbonyl-sorangicin A

Preparation: 110 mg (123 µmol) Sorangicin A were abs. Methylene chloride in the presence of Drierite and 1 mg trichloroacetic acid with 50 mg (333 µmol) tetramethyl orthocarbonate stirred for 1 h at room temperature, with abs. Pyridine added, filtered and concentrated in a high vacuum. The residue was taken up in dioxane with 50% formic acid. added, stirred at room temperature for 16 hours and concentrated again. Purification by preparative TLC (silica gel, eluent toluene / ethanol 9: 1).
Yield: 57 mg (56%).
Alternatively: Heat sorangicin A in tetramethyl orthocarbonate. [Α] = +92.5 (c = 0.8 in methanol).
UV (methanol): λ _max (1g ε): 302 nm (4.45).
1 H-NMR ([D₄] methynol): δ = 5.72, (1H, dd, 15.5, 6.6, 20-H), 5.29 (1H, t, 7.7, 21-H), 4.60 (1H, t, 7.7 , 22-H), 4.01 (1H, ddd, 11.0, 7.8, 2.5, 23-H).
13 C-NMR ([D₄] methanol): δ = 156.4 (<C = O), 137.0 (C-19), 123.6 (C-20), 81.2 (C-22), 82.1 (C-22), 70.2 ( C-23).
Mass spectroscopy: (-) FAB (glycerin): m / z = 831 [MH] ^- , 923 [M-H + Mat] ^- .

High resolution: [C₄₈H₆₄O₁₂-H]
Ber. 831.4320
Found 831.4308

Example 43

Type of derivative: intermediate
Substance name: 21,22-O-thiocarbonyl sorangicin A allyl ester

Preparation: 50 mg (59 μmol) sorangicin A-allyl ester and 24 mg (196 μmol) DMAP were prepared under argon in abs. 1,2-dichloroethane was slowly mixed with 15 μl (23 mg, 200 μmol) thiophosgene and stirred for 30 min. The reaction mixture was then stirred into aqueous NaHCO₃ solution, extracted with methylene chloride, extracted with 0.1N hydrochloric acid, dried and evaporated. The residue was prepared by prep. HPLC cleaned (HD-Sil 18-10? -60, 16 × 250 mm, methanol / water 80: 20 ml / min).
Yield: 16 mg (30%).
1 H-NMR ([D₆] acetone): δ = 7.13 (2H, m, 40-H, 41-H), 6.98 (1H, dddd, 15, 11.2, 2, 1, 38-H), 6.43 (1H, dd, 11.2, 10.5, 39-H), 6.30 (1H, dd, 15.2, 4.2, 37-H), 6.13 (1H, dd, 10.0, 3.0, 12-H), 6.02 (1H, ddd, 10.0, 5.8 , 2.1, 11-H), 5.94 (2H, m, 19-H and allyl. = CH-), 5.75 (1H, dd, 15.3, 6.9, 20-H), 5.63- 5.54 (4H, m, 42 -, 21-, 15- and 16-H), 5.37-5.28 (5H, m, 30-, 29-, 7-, 10- and allyl. H), 5.18 (1H, m, allyl.H) , 4.81 (1H, dd, 7.9, 7.9, 22-H), 4.55 (3H, m, 36-H, allyl.-OCH₂-), 4.35 (2H, m, 13-H, 35-H), 4.23 ( 1H, d, 6.7, 33-H), 4.22 (1H, s, 9-H), 4.06 (2H, m, 23-H, 25-OH), 3.93 (2H, m, 25-H, 27-H) ), 3.80 (1H, m, 31-H), 2.43-2.05 (m, 6-H, 14-, 28-, 17- and 18-H₂), 2.33 (2H, t, 7.2, 2-H₂) , 1.98 (1H, ddd, 11.3, 6.4, 2.7, 34 _a -H), 1.83 (1H, dd, 11.3, 1.5, 34 _b -H), 1.76 (1H, ddd, 13.2, 11.5, 2.5, 24 _a - H), 1.68-1.52 (m, 24 _b - and 26-H, 3-H₂), 1.58 (3H, d, 1.2, 45-H₃), 1.42-1.1 (m, 32-H, 4- u. 5- H₂), 0.87 (3H, d, 7.1, 46-H₃), 0.86 (3H, d, 6.6, 44-H₃), 0.78 (3H, d, 6.8, 47-H₃).
13 C-NMR ([D₆] acetone): δ = 192.1 <C = S; 65.1, 133.8 u. 117.7 allyl. C.
Mass spectroscopy: (-) FAB (3NBA): m / z = 888 [MH] ^- .

High resolution: [C₅₁H₆₈O₁₁³²S-H]
Ber. 887.4404
Found 887.4388

Example 44

Type of derivative: Ketal
Substance name: 21,22-O-Ixopropyliden-sorangichin A

Preparation: 500 mg (560 µmol) Sorangicin A were abs in 15 ml. Dissolved acetone, concentrated to 5 ml and stirred with 1 g of Drierite and 5 mg of p-toluenesulfonic acid at room temperature for 2.5 hours. After filtering off the Drierite, the mixture was diluted with methyl chloride and poured out several times against water. The methylene chloride phase was washed with anhydrous. Dried sodium sulfate and concentrated.
Yield: 453 mg (96%). [Α] = +92 (c = 0.7 in methanol).
UV (methanol): λ _max (1g ε): 302 nm (4.48).
1 H-NMR ([D₄] methanol): δ = 4.63 (2H, m, 21- + 36-H), 4.25 (1H, s, 9-H), 3.97 (1H, dd, 6.3, 8.5, 22-H ), 3.8-3.9 (4H, m, 23-, 25-, 27- + 31-H), 1.44+ 1.35 (each 3H, s, -CH₃).
13 C-NMR ([D₄] methanol): δ = 109.7 (<C <), 28.1 × 25.6 (each CH₃), 81.1, 80.1,
73.9 + 72.7 (C-22, -23, -27+ -21).
Mass spectroscopy: (-) FAB (glycerol): m / z = 845 [MH] ^- , 937 [M-H + G1] ^- .

Example 45 21,22-O-isopropylidensorangicinallyl ester (20)

1.48 g (1.75 mmol) Sorangicinallylester 14 (Ex. 3) in 30 ml dry Dissolved acetone. 1.5 ml of trifluoroacetic acid are added dropwise and the mixture is stirred for 2 hours RT stirred. A TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.5, product Pf 0.8) indicates complete conversion.

The solution is concentrated, diluted with 100 ml of ether and poured into 150 ml of sodium hydrogen carbonate solution. The mixture is stirred vigorously for 5 minutes. The pH should now be 7-8. The organic phase is separated off, washed once with saturated sodium bicarbonate solution, twice with water, dried with sodium sulfate and the solvent is distilled off in vacuo. The product is dried under a fine vacuum for 2 hours.
Yield: 1.44 g = 93%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.32 (t, J = 7 Hz, 2H, H-2); 4.56 (m, 1H, H-21); 3.91 (m, 1H, H-22); 5.94, 5.32, 5.20, 4.56 (allyl);
1.38 (s, 3H, isopropylidene), 1.29 (s, 3H, isopropylidene);
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 133.79 d, 117.65 t, 65.04 t (allyl) 108.68 s, 28.10, 25.57 (isopropylidene)
IR (film): ν = 3479, 2960, 2931, 1735, 1700, 1612, 1451, 1378, 1237, 1208, 1069, 975, 823, 743 cm ^-1 .
MS (70 eV): m / e (%) = 886 (28, M⁺), 828 (20), 810 (15), 620 (14), 522 (12), 312 (11), 289 (100) .

High resolution: C₅₃H₇₄O₁₁
Calc .: 886.5231
Found: 886.5198 (M) ⁺

Example 46 21,22-O-isopropylidene-25-O-methylsorangicinallyl ester (43)

50 mg (56 µmol) 20 (Ex. 45) are dissolved in 0.5 mol dry DMF and 0.1 ml Iodomethane added. The mixture is added to 15 mg of sodium hydride and Stirred at RT for 2 h. TLC (eluent toluene / methanol, 9: 1, v / v; educt Rf 0.5, product Rf 0.65) indicates complete reaction.

0.1 ml of methanol is added dropwise to the reaction solution and the mixture is stirred for 10 min. Now all solvents are distilled off in vacuo, the residue is taken up in dichloromethane, washed five times with water, the organic phase is dried with sodium sulfate and the dichloromethane is distilled off in vacuo. The crude product of 45 mg contains a methylated and a lactonized derivative as secondary components. The main product is purified using column chromatography (silica gel HD-SIL 15-60, eluent petroleum ether / dichloromethane / methanol, 50: 49: 1, v / v / v).
Yield: 31.2 mg = 61%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.32 (t, J = 7 Hz, 2H, H-2); 4.56 (m, 1H, H-21); 3.91 (m, 1H, H-22); 3.36 (m, 1H, H-25); 3.29 (s, 3H, 25-0-methyl); 5.94, 5.32, 5.20, 4.56 (allyl);
1.38 (s, 3H, isopropylidene), 1.29 (s, 3H, isopropylidene);
IR (film): ν = 2958, 2931, 2873, 1735, 1702, 1612, 1453, 1376, 1259, 1210, 1096, 1071, 1017, 975, 877, 745 cm ^-1 .
MS (70 eV): m / e (%) = 900 (14, M⁺), 856 (19), 842 (15), 828 (6), 636 (5), 512 (5), 289 (100) .

High resolution: C₅₄H₇₆O₁₁
Calculated: 900.5388
Found: 900.5420 (M⁺)

Example 47

Derivative type: 21,22-acetal, 25-R
Substance name: 25-O-acetyl-21,21-0-isopropylidene sorangicin

Preparation: Treat isopropylidene sorangicin A with pyridine / acetic anhydride 1: 1 for 16 hours. Concentrate in an oil pump vacuum, concentrate again after adding toluene.
Yield: 99%
Mass spectroscopy: (-) FAB (TEA): m / z = 887 [MH] ^- .

Example 48

Type of derivative: intermediate
Substance name: 25-O-thiobenzoyl-21,22-O-isopropylidene sorangicin allyl ester

Preparation: 55 mg of N, N-dimethylbenzamide were extracted with abs. Evaporated toluene in an oil pump vacuum and treated with 0.35 ml phosgene in toluene for 16 hours. It was then evaporated in an oil pump vacuum after adding abs. Toluene evaporated a further two times and in 0.1 ml abs. Methylene chloride added. After adding 170 mg of isopropylidene sorangicinallyl ester, the mixture was stirred for 2 hours before pyridine was added and hydrogen sulfide was introduced. Then was shaken in methylene chloride with dil. Hydrochloric acid and then with NaHCO₃ solution and evaporated. Cleaning by prep. HPLC (HD-Sil 18-10? -60, 16 mm × 250 mm, methanol / water 83:17, 20 ml / min).
Yield: 82 mg (42%). [Α] = +92.6 (c = 0.4 in methylene chloride).
UV (methanol): λ _max (lg ε): 296 (4.52), 250 (sh).
1 H-NMR (CDCl₃): δ = 8.12 (2H, d), 7.54 (1H, dd) +738 (2H, dd, aromat.-H), 5.9, 5.25 + 4.5 (allyl.-H), 1.42 + 1.34 (each 3H, s, isopropyl-CH₃), 5.72 (1H, m, 25-H), 4.64 (21-H), 4.06 (22-H).
13 C-NMR (CDCl₃): δ = 173.3 (<C = S), 128.7 + 128.2 (aromat.-C), 118.0 + 64.9 (allyl.-C), 108.4, 27.1 + 25.2 (isoprop.-C).
Mass spectroscopy: (-) FAB (3NBA): m / z = 1005 [MH] ^- .

High resolution: [C₅₀H₇₈O₁₁³²S-H]
Calc .: 1005.5187
Found: 1005.5130

Example 49 21,22-O-isopropylidene-25-O-mesylsorangicinallyl ester (47)

54 mg (60 µmol) 20 (Ex. 45) are dissolved in 1 ml dry dichloromethane and mixed with 12 mg of triethylamine (2 eq.) And 11 mg of mesyl chloride (1.5 eq.) Were added. After stirring at RT for 30 min, TLC shows (mobile phase toluene / methanol, 9: 1, v / v; Educt Rf 0.5) a complete conversion to a slightly more lipophilic Product with Rf 0.55.

The solution is washed with 1 M hydrochloric acid and with water and the product in the organic phase is purified using PSC (silica gel Si 60, 1 mm, eluent toluene / methanol, 9: 1, v / v; Rf 0.5).
Yield: 46 mg = 81%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.32 (t, J = 7 Hz, 2H, H-2); 4.56 (m, 1H, H-21); 3.91 (m, 1H, H-22); 4.85 (m, 1H, H-25); 3.10 (s, 3H, -SO₂C H ₃); 5.94, 5.32, 5.20, 4.56 (allyl);
1.38 (s, 3H, isopropylidene), 1.29 (s, 3H, isopropylidene);
IR (film): ν = 2908, 2935, 1735, 1702, 1613, 1435, 1363, 1212, 1176, 1073, 975, 902, 803, 738 cm ^-1 .
MS (FAB): m / e (%) = 963 [100 (MH) ^- ], 923 (7).

High resolution: C₅₄H₇₆O₁₃S
Calculated: 963.4928
Found: 963.5021 (MH) ^-

Example 50 25-O-carbamoyl-21,22-O-isopropylidensorangicinallylester (51)

100 mg (0.11 mmol) 21,22-O-isopropylidensorangicinallylester 20 (Ex. 45) are dissolved in 2 ml dichloromethane, with 24 mg trichloroacetyl isocyanate (1.2 eq.) And stirred for 5 min. A DC (eluent dichloromethane / Acetone, 9: 1, v / v; Educt Rf 0.3, product Rf 0.45) shows complete Conversion to the intermediate (25-O- (N-trichloroacetyl) carbamoyl-21,22-O- isopropylidensorangicinallylester 50th.

The reaction solution is poured onto 20 g of aluminum oxide (Woelm Pharma, N-Super 1) in a column and eluted first with 20 ml of dichloromethane and then with 50 ml of methanol. TLC (eluent dichloromethane / acetone, 9: 1, v / v; Rf 0.25) indicates complete elimination.
Yield: 69 mg = 66%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.32 (t, J = 7 Hz, 2H, H-2); 4.56 (m, 1H, H-21); 3.91 (m, 1H, H-22); 4.69 (m, 1H, H-25); 5.77 (s, 2H, -N H ₂); 5.94, 5.32, 5.20, 4.56 (allyl);
1.38 (s, 3H, isopropylidene), 1.29 (s, 3H, isopropylidene);
IR (film): ν = 3375, 3324, 3251, 3191, 2958, 2933, 1695, 1612, 1453, 1382, 1272, 1208, 1108, 1069, 1039, 975, 929, 832, 740 cm ^-1 .
MS (20 eV): m / e (%) = 930 [0.6 (M + H) ⁺], 887 (1.6), 872 (1.8), 869 (1.6), 811 (3.6), 551 (4), 367 (4), 289 (73), 43 (100).

High resolution: C₅₄H₇₆NO₁₂
Calc .: 930.5367
Found: 930.5341 (M + H) ⁺

Example 51 25-O-carbamoyl-21,22-O-isopropylidensorangicin (54)

50 mg (60 µmol) acetal 44 are dissolved in 0.5 ml dry dichloromethane dissolved, mixed with 30 mg trichloroacetyl isocyanate (3 eq.) and 5 min touched. A TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.6, product Rf 0.65) shows complete conversion to the intermediate product (25- O- (N-trichloroacetyl) carbamoyl) -21,22-O-isopropylidensorangicin).

The dichloromethane is distilled off in vacuo and the residue is dissolved in 1 ml of a mixture of 0.9 ml of methanol, 0.1 ml of water and 0.04 ml of triethylamine. The solution is stirred in a closed vessel under a nitrogen atmosphere at 85 ° C. for 1 h. A DC shows the complete splitting off (Rf 0.5). The solution is concentrated, taken up in dichloromethane, washed twice with 0.2 M hydrochloric acid, the organic phase dried with sodium sulfate and the solvent distilled off in vacuo.
Yield: 52 mg = 99%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.29 (t, J = 7 Hz, 2H, H-2); 4.60 (m, 1H, H-21); 3.94 (m, 1H, H-22); 4.68 (m, 1H, H-25); 5.82 (s, 2H, -N H ₂);
1.38 (s, 3H, isopropylidene), 1.28 (s, 3H, isopropylidene);
IR (film): ν = 3454, 3205, 2963, 2933, 2877, 1702, 1610, 1444, 1382, 1332, 1266, 1203, 1149, 1069, 975, 877, 823, 738 cm ^-1 .
MS = (FAB): m / e (%) = 888 [100 (MH) ^- ], 843 (47), 803 (5).

High resolution: C₅₁H₇₁NO₁₂
Calculated: 888.4898
Found: 888.4889 (MH) ^-

Example 52 21,22-O-di-t-butylsilyl sensorangicinallyl ester (18)

42 mg (50 µmol) sorangicinallyl ester 14 (Ex. 3), 2 mg (15 µmol) hydroxybenzotriazole (freshly dehydrated hydrate) and 20 mg triethylamine (4 eq.) are dissolved in 1 ml of dry acetonitrile and with a few balls Mol sieve 3Å and 50 mg of di-t-butyldichlorosilane (4 eq.) Added. The solution is added under a nitrogen atmosphere in a closed vessel for 24 h 95 ° C stirred. TLC (mobile phase dichloromethane / methanol, 9: 1, v / v) shows in addition to some educt with Rf 0.5 a main product with Rf 0.8.

The solution is concentrated, taken up in dichloromethane and washed twice with water. The product is cleaned using PSC (silica gel Si 60, 1 mm, eluent toluene / methanol, 9: 1, v / v; Rf 0.5).
Yield: 12 mg = 24%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.32 (t, J = 7 Hz, 2H, H-2); 3.98 (m, 1H, H-21); 3.80 (m, 1H, H-22); 1.06 (s, 18H, t-butyl); 5.94, 5.32, 5.20, 4.56 (allyl);
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 133.50 d, 117.65 t, 65.00 t (allyl); 27.87 q, 27.46 q, 22.29 s, 20.34 s (di-t-butylsilylene).
IR (film): ν = 3485, 2964, 2937, 2900, 2861, 1735, 1700, 1613, 1473, 1380, 1272, 1147, 1096, 1015, 975, 826, 740 cm ^-1 .
MS (FAB): m / e (%) = 1003 [100 (M + H₂O-H) ^- ], 985 [48 (MH) ^- ], 927 (8).

High resolution: C₅₈H₈₆O₁₁Si
Calc .: 985.5861
Found: 985.5835 (MH) ^-

Example 53 21-O-tert-butyldimethylsilylsorangicin methyl ester (17)

25 mg (30 µmol) sorangicin methyl ester 1, 15 mg tert-butyldimethylsilyl chloride (3 eq.), 10 mg trimethylamine (3 eq.) And 3.6 mg 4-dimethylaminopyridine are dissolved in 5 ml of dry dichloromethane. The solution is stirred under nitrogen atmosphere at 40 ° C for 72 h. A DC (eluent Dichloromethane / methanol, 9: 1, v / v; Educt Rf 0.5, product Rf 0.8) shows an almost complete implementation.

The cleaning is carried out with the help of PSC (silica gel Si 60, 0.5 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.7).
Yield: 18 mg = 64%
1 H-NMR (acetone-d₆): 400 MHz, δ = 4.35 (m, 1H, H-21); 3.62 (s, 3H, 1-O-methyl); 0.91 (s, 9H, Si-t-butyl); 0.09 (s, 6H, Si-methyl).
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 51.47 q (1-O-methyl; 26.46 q, 1.45 s, -3.62 q, -4.36 q (dimethyl-t-butylsilyl).
IR (film): ν = 3425, 3043, 2931, 2908, 2860, 1735, 1735, 1718, 1613, 1442, 1378, 1259, 1177, 1083, 975, 838, 780, 738 cm ^-1 .
MS (20 eV): m / e (%) = 934 (0.5, M⁺), 878 (0.7), 802 (1), 513 (1), 473 (1.5), 387 (3), 263 (52) , 75 (100).

High resolution: C₅₄H₈₂O₁₁Si
Calculated: 934.5626
Found: 934.5624 (M⁺)

Example 54 22-oxosorangicin methyl ester (27)

82 mg (0.1 mmol) of sorangicin methyl ester 11 are dissolved in 10 ml of dry dichloromethane and 2 g of nickel peroxide are added. The mixture is heated in a closed vessel to 50 ° C. for 24 hours with vigorous stirring. TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.5, aldehyde Rf 0.6, ketone Rf 0.75) indicates complete reaction. The reaction mixture is filtered off, the residue is washed with dichloromethane and the filtrate is concentrated. The products are separated and purified using column chromatography (silica gel HD-SIL 15-60, eluent petroleum ether / dichloromethane / methanol, 50: 48: 2, v / v / v).
Yield: 27: 14 mg = 17%
1 H-NMR (acetone-d₆): 400 MHz, δ = 6.68 (d, J = 16 Hz, 1H, H-20); 4.22 (d, H = 3.5, 1H, H-22); 3.77 (s, 3H, 1-O-methyl).
13 C-NMR (acetone-d₆): 100.6 MHz, δ = 199.73 s (C-21); 51.40 q (1-O-methyl)
IR (film): ν = 3458, 2958, 2929, 2877, 1735, 1700, 1619, 1442, 1376, 1244, 1177, 1069, 977, 738 cm ^-1 .
MS (FAB): m / e (%) = 817 [100 (MH) ^- ], 528 (6).

High resolution: C₄₈H₆₆O₁₁
Calculated: 817.4527
Found: 817.4564 (MH) ^-

22-oxosorangicinallyl ester 28

83 mg (0.1 mmol) Sorangicinallyleslester 14 (Ex. 3) are oxidized like the methyl ester (see above) with nickel peroxide, detected and cleaned.
Yield: 28 (Rf 0.7): 9 mg = 11%
1 H-NMR (acetone-d₆): 300 MHz, δ = 6.68 (d, J = 16 Hz, 1H, H-20); 4.22 (d, J = 3.5, 1H, H-22); 5.93, 5.31, 5.19, 4.54 (allyl).
IR (film): ν = 3471, 3049, 2960, 1706, 1612, 1345, 1270, 1204, 1145, 1071, 1023, 975, 736, 703 cm ^-1 .
MS (FAB): m / e (%) = 843 [100 (MH) ^- ], 803 (9).

High resolution: C₅₀H₆₈O₁₁
Calculated: 843.4684
Found: 843.4642 (MH) ^-

22-oxosorangicin (26)

6 mg (7 µmol) of Allylester 28 are after the AAV to split off the Allylesterschutzgruppe implemented. After DC (eluent dichloromethane / Methanol, 9: 1, v / v; Educt Rf 0.7) gives a product with Rf 0.35.

The cleaning is carried out with the help of PSC (silica gel Si 60, 0.25 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.3).
Yield: 4.6 mg = 80%
1 H-NMR (acetone-d₆): 300 MHz, δ = 6.78 (d, J = 16 Hz, 1H, H-20); 4.25 (d, J = 3.5, 1H, H-22).
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 199.57 s (C-21).
IR (film): ν = 3450, 2980, 2931, 2875, 1696, 1617, 1444, 1378, 1270, 1177, 1149, 1093, 1056, 977, 819 cm ^-1 .
MS (FAB): m / e (%) = 803 [100 (MH) ^- ], 765 (8), 577 (15), 505 (12).

High resolution: C₄₇H₆₄O₁₁
Calculated: 803.4371
Found: 803.4356 (MH) ^-

Examples 55 and 56 21-deoxy-22-oxosorangicin methyl ester (29) 21,22-deoxy-21,22-epoxysorangicin methyl ester (31)

30 mg (37 µmol) sorangicin methyl ester 1 and 70 mg Martin's Sulfuran- Dehydrating agents (3 eq.) Are in 1.5 mol dry dichloromethane dissolved and stirred at RT for 30 min. A TLC (eluent toluene / methanol 9: 1, v / v; Educt Rf 0.3, product Rf 0.4) indicates complete conversion. The Product mixture is with the help of PSC (silica gel Si 60, 1 mm, eluent Toluene / methanol, 9: 1, v / v; Rf 0.3, gives 9 mg mixture) pre-cleaned.

The products are separated using preparative HPLC (Nucleosil 100, 7 µm, 250 × 20.5 mm, eluent petroleum ether / dichloromethane / methanol, 50: 48: 1.3, v / v / v).
Yield:
29: 2 mg = 7%
31: 2 mg = 7%

21-Deoxy-22-oxosorangicin methyl ester (29):
1 H-NMR (acetone-d₆): 400 MHz, δ = 3.29 (dd, J = 18 and 5 Hz, 1H, H-21b); 3.39 (dd, J = 18 and 6 Hz, 1H, H-21a); 4.24 (dd, J = 6 and 5 Hz, 1H, H-23); 3.62 (s, 3H, 1-O-methyl).
IR (film): ν = 3486, 2940, 2929, 2858, 1738, 1716, 1613, 1444, 1376, 1274, 1214, 1174, 1071, 975, 880, 826, 746 cm ^-1 .
MS (FAB): m / e (%) = 801 (MH) ^- , 243, 192, 175.

High resolution: C₄₈H₆₅O₁₀
Calculated: 801.4572
Found: 801.4583 (MH) ^-

21,22-deoxy-21,22-epoxysorangicin methyl ester (31):
1 H-NMR (acetone-d₆): 400 MHz, δ = 5.18 (m, 1H, H-20); 3.28 (dd, J = 8.5 and 2.2 Hz, 1H, H-21); 2.85 (dd, J = 3.5 and 2.2 Hz, 1H, H-22); 3.90 (m, 1H, H-23); 3.62 (s, 3H, 1-O-methyl).
IR (film): ν = 2958, 2927, 2858, 1737, 1710, 1613, 1459, 1448, 1378, 1272, 1216, 1174, 1071, 973, 880, 740 cm ^-1 .
MS (FAB): m / e (%) = 801 (MH) ^- , 243, 192, 175.

High resolution: C₄₈H₆₅O₁₀
Calculated: 801.4577
Found: 801.4583 (MH) ^-

21-deoxy-22-oxosorganicinallylester (30) 21,22-deoxy-21,22-epoxysorangicinallyl ester (32)

63 mg (75 µmol) Sorangicinallylester 14 (Ex. 3) in 1.5 ml dry Dissolved dichloromethane and cooled to -70 ° C. This is slowly becoming one Solution of 80 mg Martin's sulfuran dehydrating agent (2 eq.) In 0.5 ml of dichloromethane are injected. After stirring at RT for 30 min, TLC shows (Mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.5, product Rf 0.7) a full implementation. The product mix is made with the help the PSC (silica gel Si 60, 1 mm, eluent toluene / methanol, 9: 1, v / v; Rf 0.3, gives 30 mg mixture) pre-cleaned.

The products are separated using preparative HPLC (Nucleosil 100, 7 µm, 250 × 20.5 mm, eluent petroleum ether / dichloromethane / methanol, 50: 48: 1.3, v / v / v).
Yield:
30: 8 mg = 14%
32: 15 mg = 26%

21-deoxy-22-oxosorangicinallyl ester (30):
1 H-NMR (acetone-d₆): 400 MHz, δ = 3.29 (dd, J = 18 and 5 Hz, 1H, H-21b); 3.39 (dd, J = 18 and 6 Hz, 1H, H-21a); 4.24 (dd, J = 6 and 5 Hz, 1H, H-23); 5.93, 5.31, 5.19, 4.56 (allyl).
13 C-NMR (acetone-d₆): 100.6 MHz, δ = 42.05 t (C-21); 209.37 s (C-22); 65.15 t, 117.78 t, 133.76 d (allyl).
IR (film): ν = 3494, 2958, 2929, 2875, 2716, 1613, 1444, 1378, 1274, 1216, 1174, 1089, 1037, 977, 880, 740 cm ^-1 .
MS (20 eV): m / e (%) = 828 (12, M⁺), 810 (3), 590 (3), 499 (20), 312 (9), 289 (100).

High resolution: C₅₀H₆₈O₁₀
Calculated: 828.4812
Found: 828.4814 (M) ⁺

21,22-Deoxy-21,22-epoxyorangicinallylester (32):
1 H-NMR (acetone-d₆): 400 MHz, δ = 5.18 (m, 1H, H-20); 3.28 (dd, J = 8.5 and 2.2 Hz, 1H, H-21); 2.85 (dd, J = 3.5 and 2.2 Hz, 1H, H-22); 3.90 (m, 1H, H-23); 5.94, 5.31, 5.19, 4.56 (allyl).
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 55.93 d (C-21); 62.25 d (C-22); 65.15 t, 117.78 t, 133.76 d (allyl).
IR (film): ν 3489, 2980, 2929, 2860, 1735, 1710, 1613, 1457, 1376, 1276, 1216, 1176, 1071, 975, 880, 738 cm ^-1 :
MS (70 eV): m / e (%) = 828 (3.3, M⁺), 810 (1.8), 553 (10), 312 (6), 289 (83), 41 (100).
High resolution: C₅₀H₆₈O₁₀
Calculated: 828.4812
Found: 828.4815 (M⁺)

21-deoxy-22-oxosorangicin (33)

18 mg (22 µmol) of allyl ester 30 are split off after the AAV Allylesterschutzgruppe implemented. After DC (eluent dichloromethane / Methanol, 9: 1, v / v; Educt Rf 0.7) you get a product with Rf 0.4.

The cleaning is carried out with the help of PSC (silica gel Si 60, 0.5 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.4).
Yield: 12.6 mg: 74%
1 H-NMR (acetone-d): 400 MHz, δ = 3.29 (dd, J = 18) and. 5 Hz, 1H, H-21b); 3.40 (dd, J = 18 and 6 Hz, 1H, H-21a); 4.24 (dd, J = 6 and 5 Hz, 1H, H-23);
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 41.94 t (C-21); 109,310 s (C-22).
IR (film): ν = 3440, 3047, 2962, 2931, 1712, 1613, 1442, 1382, 1272, 1216, 1178, 1071, 977, 738 cm ^-1 .
MS (FAB): m / e (%) = 787 (MH) ^- .

High resolution: C₄₇H₆₄O₁₀
Calculated: 787.4421
Found: 787.4450 (MH) ^-

Example 57 (21RS) -sorangicin methyl ester (35)

7 mg (9 µmol) of ketone 27 (Example 54) are made according to the same procedure as for the preparation reduced from 64 (e.g. 68). A TLC (educt Rf 0.7) shows a product with Rf 0.5.

The cleaning is carried out using PSC (silica gel Si 60, 0.25 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.45). An analytical HPLC of the product (Nucleosil 100, 7 µm, eluent petroleum ether / dichloromethane / methanol, 50: 46: 4, v / v / v) shows an isomer ratio of sorangicin methyl ester to 21-epi-sorangicin methyl ester of 4: 6.
Yield: 5 mg mixture of isomers = 78%
1 H-NMR (CD₃OD): 400 MHz shows splitting into the mixture: 2 epimeric protons at C21, intensity ratio approx. 1: 1 δ = 4.20 and 4.07

(21R) Sorangicin (36)

9 mg (11 µmol) of ketone 26 (Ex. 54) are reduced according to the same procedure as for the preparation of 64 (Ex. 68). A DC (educt Rf 0.35) shows two products with RF 0.25 (Sorangicin A) and Rf 0.27. The products are separated and cleaned using PSC (silica gel Si 60, 0.5 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v). Yield: Rf 0.2 (Sorangicin A) 1.1 mg = 12%
Rf 0.25 1.8 mg = 20%
1 H-NMR (acetone-d₆): 400 MHz, δ = 4.03 (m, 1H, H-21); 3.39 (m, 1H, H-22)
IR (film): = 3471, 3049, 2960, 1706, 1612, 1345, 1270, 1204, 1145, 1071, 1023, 975, 736, 703 cm ^-1 .
MS (FAB): m / e (%) = 805 [100 (MH) ^- ], 367 (5), 199 (8), 122 (23).

High resolution: C₄₇H₆₆O₁₁
Calculator: 805.4527
Found: 805.4513 (MH) ^-

Example 58 21,22-O-isopropylidene-25-oxosorangicinallyl ester (58)

30 mg (34 µmol) 21,22-O-isopropylidensorangicinallylester 20 (Ex. 45) are in 1 ml Dichloromethane dissolved and with 20 mg pyridinium chlorochromate (3 eq.) transferred. After stirring at RT for 1 h, TLC (eluent toluene / methanol, 9/1, v / v; Educt Rf 0.5) a more lipophilic main product with Rf 0.6, that with vanilin / sulfuric acid spray reagent red-brown instead of green-brown stains.

The solution is filtered, concentrated and the product is purified using PSC (silica gel Si 60, 0.5 mm, eluent toluene / methanol, 9: 1, v / v; Rf 0.5).
Yield: 19 mg = 63%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.32 (t, J = 7 Hz, 2H, H-2); 4.68 (m, 1H, H-21); 4.16 (m, 1H, H-22); 2.63 (m, 1H, H-24a); 2.24 (m, 1H, H-24b); 2.19 (m, 1H, H-26); 5.94, 5.32, 5.20, 4.56 (allyl); 1.38 (s, 3H, isopropylidene), 1.29 (s, 3H, isopropylidene);
13 C-NMR (acetone-d₆): 100.6 MHz, δ = 209.48 s (C-25), 48.59 d (C-26); 41.78 t (C-24); 133.79 d, 117.65 t, 65.04 t (allyl) 108.68 s, 28.10 q, 25.57 q, (isopropylidene).
IR (film): = 3371, 3045, 2951, 2933, 2877, 1712, 1613, 1453, 1378, 1286, 1176, 1071, 977, 877, 738 cm ^-1 .
MS (70 eV): m / e (%) = 884 (0.1, M⁺), 826 (0.1), 588 (1), 289 (25), 43 (100).

High resolution: C₅₃H₇₂O₁₁
Calculated: 884.5074
Found: 884.5069 (M⁺)

Example 59 21,22-O-isopropylidene-25-oxosorangicin (59)

200 mg (0.24 mmol) acetal 44 are dissolved in 5 ml dichloromethane and with a 4 M solution of chromium trioxide in water. The mixture is stirred so strongly at RT for 5 h that the two phases form an emulsion form. A TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt 0.5, Product Rf 0.6, red-brown staining with vanilin / sulfuric acid) shows one full implementation.

The mixture is centrifuged, the organic phase is separated off with Diluted dichloromethane, washed once with sodium chloride solution and opened concentrated about 2 ml. (When evaporating to dryness, there is complete Decomposition of the product!)

The product is pre-cleaned on an open column with coarse silica gel (Si 60, 0.03-0.2 mm, mobile solvent dichloromethane / methanol, 95: 15, 9: 1, v / v) and with the aid of medium pressure column chromatography (silica gel HD-SIL 15-60 , Eluent petroleum ether / dichloromethane / methanol, 50: 49: 0.5-degree-1, v / v / v, 0.1% formic acid).
Yield: 92 mg = 46%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.26 (t, J = 7 Hz, 2H, H-2); 4.68 (m, 1H, H-21); 4.15 (m, 1H, H-22); 2.62 (m, 1H, H-24a); 2.20 (m, 1H, H-24b); 2.19 (m, 1H, H-26); 1.38 (s, 3H, isopropylidene), 1.29 (s, 3H, isopropylidene);
IR (film): = 3193, 3031, 2931, 2877, 1712, 1612, 1455, 1378, 1288, 1104, 1079, 975, 738 cm ^-1 .
MS (20 eV): m / e (%) = 844 (6, M⁺), 786 (4), 588 (4), 383 (4), 249 (100).

High resolution: C₅₀H₆₈O₁₁
Calculated: 844.4761
Found: 844.4746 (M⁺)

Examples 60 and 61 (26R) -25-oxosorangicin (60) (26S) -25-oxosorangicin (61)

90 mg (0.11 mmol) 59 (Ex. 59) are used after the AAV to split off the isopropylidene protecting group implemented. After DC (mobile phase dichloromethane / Methanol, 9: 1, v / v; Educt Rf 0.6) two products with Rf 0.3 and 0.4.

The products are separated and cleaned using PSC (silica gel Si 60, 1 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v). Yield: Rf 0.4 60: 41 mg = 48%
Rf 0.3 61: 19 mg = 22%

(26R) -25-oxosorangicin 60:
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.62 (m, 1 H; H-24a); 2.33 (m, 1H, H-24b); 2.31 (d, J = 10 Hz 1H, H-26);
13 C-NMR (acetone-d₆): 100.6 MHz, δ = 208.82 s (C-25); 49.27 d (C-26); 42.18 t (C-24).
IR (film): = 3432, 3392, 3052, 2960, 2931, 1712, 1612, 1453, 1378, 1340, 1278, 1073, 975, 877, 738 cm ^-1 .
MS (FAB): m / e (%) = 803 [42 (MH) ^- ], 459 (10), 306 (53), 199 (37), 153 (100).

High resolution: C₄₇H₆₄O₁₁
Calculated: 803.4371
Found: 803.4450 (MH) ^-

(26S) -25-oxosorangicin 61:
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.68 (m, 1H, H-24a); 2.30 (m, 1H, H-24b); 2.00 (d, J = 7 Hz 1H, H-26);
13 C-NMR (acetone-d₆): 100.6 MHz, s. Tab. 28
IR (film): = 3438, 2956, 2931, 1712, 1613, 1451, 1378, 1272, 1179, 1095, 1073, 975, 738 cm ^-1 .
MS (FAB): m / e (%) = 803 [16 (MH) ^- ], 459 (12), 306 (56), 199 (40), 153 (100).

High resolution: C₄₇H₆₄O₁₁
Calculated: 803.4371
Found: 803.4450 (MH) ^-

Example 62 (26R) -25-oxosorangicinallyl ester (62)

20 mg (24 µmol) 58 (Ex. 58) are used to split off the isopropylidene protecting group after the AAV implemented. The mixture is stirred at 85 ° C. for 5 h until TLC (Eluent toluene / methanol, 9: 1, v / v; Rf 0.2) shows that the more stable Diastereomers emerged as the main product.

The product is cleaned using PSC (silica gel Si 60, 0.5 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.4).
Yield: 5 mg = 26%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.63 (m, 1H, H-24a); 2.35 (m, 1H, H-24b); 2.31 (d, J = 10 Hz 1H, H-26);
IR (film): = 3401, 2958, 2931, 2875, 1735, 1700, 1612, 1455, 1378, 1274, 1204, 1152, 1071, 977, 821 cm ^-1 .
MS (20 eV): m / e (%) = 844 (1, M⁺), 826 (1), 515 (4), (413) (5), 383 (4), 289 (100).

High resolution: C₅₀H₆₈O₁₁
Calculated: 844.4761
Found: 844.4758 (M⁺)

Example 63 25,25-difluoro-25-deoxy-21,22-O-isopropylidensorangicinallyl ester (70)

40 mg (45 µmol) ketone 58 (Example 58) are dissolved in 1 ml dry dichloromethane, mixed with 50 ul diethylaminosulfur trifluoride, and 18 h at RT touched. TLC (eluent toluene / methanol, 9: 1, v / v; educt Rf 0.6) shows a complete conversion to a somewhat more lipophilic product the Rf 0.65 that with vanilin / sulfuric acid spray reagent green-brown instead stains red-brown.

The solution is washed twice with water and the product is purified using PSC (silica gel Si 60, 1 mm, eluent toluene / methanol, 9: 1, v / v; Rf 0.5).
Yield: 21.6 mg = 53%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.31 (t, J = 7 Hz, 2H, H-2); 4.64 (m, 1H, H-21); 4.05 (m, 1H, H-22); 2.00 (m, 1H, H-24a); 1.88 (m, 1H, H-24b); 1.91 (m, 1H, H-26); 5.94, 5.30, 5.19, 4.56 (allyl); 1.41 (s, 3H, isopropylidene), 1.30 (s, 3H, isopropylidene);
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 129.63 (t, J = 274 Hz, C-25); 54.82 t (C-24); 39.80 d (C-26).
¹⁹F-NMR (acetone-d₆): 377 MHz δ = -96.73 (d, J = 238 Hz)
-99.41 (d, J = 238 Hz)
IR (film): = 3041, 2950, 2931, 2875, 1737, 1702, 1613, 1455, 1372, 1320, 1255, 1204, 1174, 1112, 1071, 975, 977, 824, 738 cm ^-1 .
MS (FAB): m / e (%) = 905 [100 (MH) ^- ], 864 (35).

High resolution: C₅₃H₇₂F₂O₁₀
Calculated: 905.5016
Found: 905.4997 (MH) ^-

Example 64 25,25-difluoro-25-deoxy-21,22-O-isopropylidensorangicin (71)

15 mg (18 µmol) ketone 59 (Example 59) are dissolved in 1 ml dry dichloromethane, mixed with 20 ul diethylaminosulfur trifluoride and 20 h at RT touched. A TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.6) shows the conversion to a main product with Rf 0.85 and one By-product with Rf 0.6, both with vanilin / sulfuric acid spray reagent Color green brown instead of red brown.

The solution is washed twice with water and the by-product is separated off and purified using PSC (silica gel Si 60, 0.5 mm, mobile phase dichloromethane / methanol, 9: 1, v / v; Rf 0.5).
Yield: 3.0 mg = 20%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.27 (t, J = 7 Hz, 2H, H-2); 4.64 (m, 1H, H-21); 4.05 (m, 1H, H-22); 2.00 (m, 1H, H-24a); 1.88 (m, 1H, H-24b); 1.91 (m, 1H, H-26); 1.41 (s, 3 H, isopropylidene), 1.30 (s, 3 H, isopropylidene);
¹⁹F-NMR (acetone-d₆): 377 MHz, δ = -96.75 (d, J = 238 Hz)
-99.46 (d, J = 238 Hz)
IR (film): = 3440, 2987, 2873, 1704, 1613, 1455, 1378, 1347, 1216, 1147, 1112, 1073, 1917, 977, 875, 819, 738 cm ^-1 .
MS (FAB): m / e (%) = 865 [27 (MH) ^- ], 795 (6), 619 (100).

High resolution: C₅₀H₆₈F₂O₁₀
Calc .: 865.4703
Found: 865.4763 (MH) ^-

Example 65 25,25-difluoro-25-deoxy-sorangicinallyl ester (72)

27 mg (30 µmol) difluoride 70 (Example 63) are dissolved in 1.2 ml THF and with 0.6 ml 1 M hydrochloric acid added. The mixture is flushed with nitrogen and 48 h stirred at 30 ° C. TLC (eluent dichloromethane / methanol, 9: 1, v / v; Educt Rf 0.8) shows two by-products and many decomposition products Products with the Rf 0.7 and 0.35. The solution is concentrated, with water diluted and extracted twice with dichloromethane.

The products are separated and purified using PSC (silica gel Si 60, 1 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.5).
Yield: 5.0 mg = 19%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.31 (t, J = 7 Hz, 2H, H-2); 2.00 (m, 1H, H-24a); 1.88 (m, 1H, H-24b); 1.91 (m, 1H, H-26); 5.94, 5.30, 5.19, 4.56 (allyl).
¹⁹F-NMR (acetone-d₆): 377 MHz, δ = -96.39 (d, J = 236 Hz) -99.20 (d, J = 236 Hz)
IR (film): = 3419, 2959, 2931, 2877, 1696, 1615, 1440, 1382, 1270, 1263, 1149, 1091, 1054, 1015, 977, 871, 819 cm ^-1 .
MS (FAB): m / e (%) = 865 [100 (MH) ^- ], 844 (11), 806 (7).

High resolution: C₅₀H₆₈F₂O₁₀
Calc .: 865.4703
Found: 865.4769 (MH) ^-

Example 66 25,25-difluoro-25-deoxy-sorangicin (73) Method A

When the isopropylidene protecting group is split off from 70 (Example 63), the product is obtained as a secondary component (see above, Rf 0.35).
Yield (at 27 mg educt): 2.7 mg = 11%

Method B

5 mg (6 µmol) of allyl ester 72 (example 65) are reacted after the AAV to split off the allyl ester protecting group. After TLC (mobile phase dichloromethane / - methanol, 9: 1, v / v; educt Rf 0.7), a product with the Rf 0.35 is obtained. The product is cleaned using PSC (silica gel Si 60, 0.5 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v, Rf 0.3).
Yield: 2.2 mg = 46%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.26 (t, J = 7 Hz, 2H, H-2); 2.00 (m, 1H, H-24a); 1.88 (m, 1H, H-24b); 1.92 (m, 1H, H-26).
¹⁹F-NMR (acetone-d₆): 377 MHz, δ = -96.39 (d, J = 235 Hz)
-99.13 (d, J = 235 Hz)
IR (film): = 3432, 3051, 2960, 2929, 1706, 1613, 1446, 1347, 1268, 1179, 1077, 1042, 977, 877, 826, 742 cm ^-1 .
MS (FAB): m / e (%) = 825 [100 (MH) ^- ], 805 (6).

High resolution: C₄₇H₆₄F₂O₁₀
Calculated: 825.4390
Found: 825.4258 (MH) ^-

Example 67 (25R, 26S) Sorangicin (63)

11 mg (14 µmol) 60 (Example 61) are reduced and purified using the same procedure as for the preparation of 64 (Example 68) (educt Rf 0.45, product Rf 0.2).
Yield: 6.5 mg = 59%.
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.07 (m, 1H, H-24a); 1.40 (m, 1H, H-24b); 3.25 (m, 1H, H-25); 1.24 (dd, J = 10.5 and 9.5, 1H, H-26); 3.07 (m, 1H, H-27)
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 43.89 d (C-26).
IR (film): = 3440, 3047, 2960, 2927, 1700, 1610, 1453, 1378, 1272, 1204, 1149, 1073, 1037, 975, 738 cm ^-1 .
MS (FAB): m / e (%) = 805 [100 (MH) ^- ], 766 (18), 613 (70), 506 (20), 475 (14).

High resolution: C₄₇H₆₆O₁₁
Calculator: 805.4527
Found: 805.4470 (MH) ^-

Example 68 (25R) Sorangicin (64)

14 mg (17 µmol) 61 (Ex. 60) are dissolved in 2 ml of methanol, with 2 drops. a methanolic methyl orange solution and mixed with a solution of 6 mg sodium cyanoborohydride in methanol. The pH is kept below 3 with stirring by dropwise addition of 2 M methanolic hydrochloric acid (methanol / water, 5: 1) (indicator change). To complete the reaction, 2 mg of sodium cyanoborohydride are added twice in methanol. TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.4, product Rf 0.2) indicates a complete reduction after 1 h. The solution is concentrated, taken up in dichloromethane, and the product is purified using PSC (silica gel Si 60, 0.5 mm, mobile phase dichloromethane / methanol, 9: 1, v / v; Rf 0.2).
Yield: 6.5 mg = 46%
1 H-NMR (acetone-d₆): 400 MHz, δ = 1.87 (m, 1H, H-24a); 1.42 (m, 1H, H-24b); 3.81 (m, 1H, H-25); 1.77 (m, 1H, H-26); 3.29 (m, 1H, H-27).
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 38.44 d (C-26).
IR (film): = 3432, 3041, 2954, 2929, 2869, 1700, 1612, 1448, 1378, 1272, 1204, 1179, 1102, 1071, 1037, 975, 738 cm ^-1 .
MS (FAB): m / e (%) = 805 [100 (MH) ^- ], 764 (13).

High resolution: C₄₇H₆₆O₁₁
Calculator: 805.4527
Found: 805.4601 (MH) ^-

Example 69 (26S) -25- (N-hydroxyimino) -sorangicin (65)

5.5 mg (7 µmol) of ketone 60 (Example 61) are dissolved in 0.5 ml of ethanol and made into a Solution of 2 mg of hydroxylamine hydrochloride in 0.2 ml of water. The Mixture is slowly heated to 80 ° C. After 20 min a TLC shows (Mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.35, product Rf 0.25) full sales.

The solution is concentrated, diluted with water, with a little 1 M hydrochloric acid acidified and extracted twice with dichloromethane.

The organic phase is concentrated and the product is purified using PSC (silica gel Si 60, 0.5 mm, mobile phase dichloromethane / methanol, 9: 1, v / v; Rf 0.2).
Yield: 3.7 mg = 67%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.15 (m, 1H, H-26); 3.17 (m, 1H, H-27)
13 C-NMR (acetone-d₆): 75.5 MHz, δ = 157.85 s (C-25); 40.99 d (C-26).
IR (film): = 3446, 3043, 2927, 2875, 1696, 1612, 1451, 1380, 1351, 1278, 1204, 1073, 975, 821, 738 cm ^-1 .
MS (FAB): m / e (%) = 818 [100 (MH) ^- ], 765 (2).

High resolution: C₄₇H₆₅NO₁₁
Calculated: 818.4479
Found: 818.4382 (MH) ^-

Example 70 (26R, 25E) - (N-Hydroxyimino) Sorangicin (67) (26R, 25Z) - (N-Hydroxyimino) Sorangicin (68)

11.5 mg (14 µmol) of ketone 61 are dissolved in 1 ml of ethanol and washed with a Solution of 5 mg hydroxylaminohydrochloride in 0.5 ml water. The The mixture is heated to 80 ° C. with stirring. A DC (eluent dichloromethane / Methanol, 9: 1, v / v; Educt Rf 0.35) shows a after 15 min complete conversion to 2 products with Rf 0.2 and 0.15. The solution is concentrated, diluted with water, acidified with 1 M hydrochloric acid and extracted twice with dichloromethane.

The products are separated and cleaned using the PSC (mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.2 and 0.15).
Yield: Rf 0.2 67: 3.9 mg = 34%
Rf 0.15 68: 3.3 mg = 29%

A) (26R, 25E) - (N-Hydroxyimino) -sorangicin (67)
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.29 (m, 1H, H-26); 3.42 (m, 1H, H-27)
IR (film): = 3473, 2929, 2858, 1700, 1612, 1451, 1378, 1274, 1204, 1073, 1021, 975, 738, 703 cm ^-1 .
MS (FAB): m / e (%) = 818 (MH) ^-

High resolution: C₄₇H₆₅NO₁₁
Calculated: 818.4478
Found: 818.4384 (MH) ^-

B) (26R, 25Z) - (N-Hydroxyimino) -sorangicin (68)
1 H-NMR (acetone-d₆): 300 MHz, δ = 3.37 (m, 1H, H-26); 3.34 (m, 1H, H-27)
IR (film): = 3371, 3049, 2958, 2951, 1704, 1612, 1440, 1378, 1275, 1204, 1096, 1071, 1029, 975, 738, 703 cm ^-1 .
MS (FAB): m / e (%) = 818 (MH) ^-

High resolution: C₄₇H₆₅NO₁₁
Calculated: 818.4478
Found: 818.4384 (MH) ^-

Example 71 (26S) -25- (N-methoxyimino) sorangicin (69)

10 mg (12 µmol) ketone 60 (Example 61) are dissolved in 0.5 ml ethanol and made into a Solution of 4 mg methoxyamine hydrochloride in 0.2 ml water. The Mixture is slowly heated to 80 ° C with stirring. A DC (eluent Dichloromethane / methanol, 9: 1, v / v; Educt Rf 0.4, product RF 0.45) shows after 30 min a complete conversion to a slightly more lipophilic Product.

The solution is concentrated, diluted with water, acidified with a little 1 M hydrochloric acid and extracted twice with dichloromethane. The organic phase is concentrated and the product is purified using PSC (silica gel Si 60, 0.5 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.4).
Yield: 6.7 mg = 65%
1 H-NMR (acetone-d₆): 300 MHz, δ = 2.15 (m, 1H, H-26); 3.18 (m, 1H, H-27), 3.78 (s, 3H, NOC H ₃).
IR (film): = 3440, 3043, 2935, 1700, 1610, 1453, 1378, 1276, 1204, 1149, 1048, 975, 896, 823, 738 cm ^-1 .
MS (FAB): m / e (%) = 832 [100 (MH) ^- ], 802 (2)

High resolution: C₄₈H₆₇NO₁₁
Calc .: 832.4636
Found: 832.4500 (MH) ^-

Example 72 24,25-dehydro-25-deoxysorangicin (57) Method A

When the isopropylidene protecting group is split off from 55 (Example 74), the product is obtained as a secondary component (see above, Rf 0.15).
Yield (at 72 mg educt): 12 mg - 18%

Method B

34 mg (41 µmol) 56 (Example 73) become after the AAV to split off the allyl ester protecting group implemented. After TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; Educt Rf 0.7) gives a product with Rf 0.35.

The product is purified using column chromatography (silica gel HD-SIL Rp 18-40-60, eluent methanol / water, 85:15, v / v, 0.1% formic acid).
Yield: 13 mg = 40%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.26 (t, J = 7 Hz, 2H, H-2); 4.09 (m, 1H, H-23); 5.88 (m, 1H, H-24); 5.93 (dd, J = 11 and 6 Hz, 1H, H-25); 1.97 (m, 1H, H-26);
IR (film): = 3438, 3019, 2962, 2921, 2852, 1704, 1613, 1453, 1376, 1270, 1181, 1070, 1021, 975, 738 cm⁻¹.
MS (FAB): m / e (%) = 787 [20 (MH) ⁻], 446 (100, TEA).

High resolution: C₄₇H₆₄O₁₀
Calculated: 787.4421
Found: 787.4430 (MH) _-

Example 73 24,25-dehydro-25-deoxysorangicinallyl ester (56)

72 mg (83 µmol) 55 (Example 74) after the AAV to split off the isopropylidene protective group implemented. After TLC (eluent toluene / methanol, 9/1, v / v; Educt Rf 0.7) a main product with Rf 0.3 and a by-product with Rf 0.15 (25-deoxysorangicin-24-en 57, see below).

The products are purified using column chromatography (silica gel HD-SIL Rp 18-30-60, eluent methanol / water, 8: 1 degree 9: 1, v / v, 0.1% formic acid).
Yield: 34.8 mg = 51%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.30 (t, J = 7 Hz, 2H, H-2); 4.02 (m, 1H, H-23); 5.74 (m, 1H, H-24); 5.90 (dd, J = 11 and 6 Hz, 1H, H-25); 1.97 (m, 1H, H-26); 5.96, 5.32, 5.20, 4.53 (allyl);
IR (film): = 3459, 3039, 2960, 2931, 2877, 1735, 1700, 1613, 1449, 1376, 1272, 1177, 1073, 975, 885, 828, 738 cm⁻¹.
MS (70 eV): m / e (%) = 828 (1, M⁺), 810 (2), 521 (3), 413 (13), 289 (87), 95 (100).

High resolution: C₅₀H₆₈O₁₀
Calculated: 828.4812
Found: 828.4815 (M⁺)

Example 74 24,25-dehydro-25-deoxy-21,22-O-isopropylidensorangicinallyl ester (55)

100 mg (0.11 µmol) 20 (Ex. 45) are dissolved in 2 ml dry dichloromethane and flushed the solution with nitrogen. A solution of 190 mg Martins Sulfuran dehydrating agent (2.5 eq.) In 0.5 ml dichloromethane injected at RT under a nitrogen atmosphere and the mixture at 1 h 60 ° C stirred in a closed vessel. A TLC (eluent toluene / methanol, 9/1, v / v; Educt Rf 0.6, product Rf 0.7) shows complete Implementation.

After cooling to RT, the solution is mixed with 10 ul methanol and stirred for 10 min. The product is purified using column chromatography (silica gel HD-SIL 15-60, eluent petroleum ether / dichloromethane / methanol, 50: 49: 0.5-degree-0.8, v / v / v).
Yield: 73 mg = 75%
1 H-NMR (acetone-d₆): 400 MHz, δ = 2.31 (t, J = 7 Hz, 2H, H-2); 4.65 (m, 1H, H-21); 3.92 (m, 1H, H-22); 4.07 (m, 1H, H-23); 5.78 (m, 1H, H-24); 5.90 (dd, J = 11 and 6 Hz, 1H, H-25); 1.96 (m, 1H, H-26); 5.94, 5.32, 5.20, 4.56 (allyl); 1.38 (s, 3H, isopropylidene), 1.29 (s, 3H, isopropylidene).
IR (film): = 3361, 3041, 2960, 2933, 2879, 1735, 1702, 1613, 1451, 1378, 1288, 1216, 1174, 1071, 975, 875, 736 cm⁻¹.
MS (20 eV): m / e (%) = 868 (0.4, M⁺), 826 (0.3), 579 (1), 413 (3), 289 (70), 95 (100).

High resolution: C₅₃H₇₂O₁₀
Calculated: 868.5125
Found: 868.5113 (M⁺)

Examples 75 and 76 33-O, 36-seco-36-oxo- (37E, 39Z, 41Z) -sorangicin (76) 33-O, 36-seco-36-oxo- (37E, 39E, 41Z) -sorangicin (77)

40 mg (50 µmol) sorangicin A and 30 mg 2,3-dichloro-5,6-dicyanobenzoquinone are dissolved in 10 ml dichloromethane and stirred at RT for 2 h. A DC (Mobile phase dichloromethane / methanol, 9: 1, v / v; educt Rf 0.25) shows the complete conversion to a product with Rf 0.2.

The solution is filtered and concentrated. A first cleaning takes place with Using the PSC (silica gel Si 60, 1 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.2) and gives a crude mixture of 30 mg. An analytical HPLC (silica gel Nucleosil Rp 18, 7 µm; mobile solvent methanol / water, 75:25, v / v, 0.1% formic acid; UV detection 310 nm) shows that the product is made two isomers in a ratio of 3: 1.

The isomers are separated using column chromatography (silica gel HD-SIL 60-15, eluent petroleum ether / isopropanol / formic acid, 88: 12: 0.3, v / v / v).
Yield:
76: 24 mg = 60%
77: 7 mg = 18%

A) Z isomer (76):
1 H-NMR (acetone-d): 400 MHz, s. Tab.
IR (film): = 3396, 3047, 2964, 2871, 1704, 1594, 1557, 1438, 1384, 1345, 1264, 1208, 1147, 1081, 1017, 973, 803, 738 cm⁻¹.
UV (methanol): l _max (lg ε) = 317 nm (4.65)
MS (FAB): m / e (%) = 821 [100 (MH) ⁻], 805 (1).

High resolution: C₄₇H₆₆O₁₂
Calculated: 821.4476
Found: 821.4495 (MH) ⁻

B) E isomer (77):
1 H-NMR (acetone-d): 400 MHz, s. Tab. 18
IR (film): = 3402, 3052, 2966, 2935, 1714, 1648, 1617, 1598, 1457, 1426, 1382, 1347, 1266, 1208, 1095, 1083, 1019, 975, 736 cm⁻¹.
UV (methanol): l _max (lg ε) = 316 nm (4.52)
MS (FAB): m / e (%) = 821 [100 (MH) ⁻], 805 (2).

High resolution: C₄₇H₆₆O₁₁
Calculated: 821.4476
Found: 821.4495 (MH) ⁻

Example 77 33-O, 36-seco-36-hydroxy- (37E, 39Z, 41Z) -sorangicin methyl ester (78)

7 mg (8 µmol) of ketone 76 are made by the same procedure as for the preparation reduced from 64 (e.g. 68). A TLC (mobile phase dichloromethane / methanol, 9: 1, v / v; Educt Rf 0.4) shows a product with Rf 0.3.

The product is cleaned using PSC (silica gel Si 60, 0.25 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; Rf 0.3).
Yield: 5 mg = 71%
1 H-NMR (CD₃OD): 400 MHz, s. Tab.
IR (film): = 3452, 3033, 2954, 2925, 1733, 1698, 1613, 1442, 1380, 1276, 1179, 1068, 1014, 975, 738 cm⁻¹.
UV (methanol): l _max (lg ε) = 302 nm (4.41)
MS (FAB): m / e (%) = 837 (MH) ⁻

High resolution: C₄₈H₇₀O₁₂
Calc .: 837.4789
Found: 837.4841 (MH) ⁻

Example 78 33-O, 36-seco-36-hydroxy- (37E, 39E, 41Z) -sorangicin methyl ester (79)

9 mg (10 µmol) ketone 77 are reduced and purified by the same method as the 39Z isomer 78 (see above); Educt Rf 0.45, product Rf 0.3.
Yield: 6 mg = 63%
1 H-NMR (CD₃OD): 400 MHz, s. Tab.
IR (film): = 3431, 3035, 2925, 1733, 1700, 1612, 1440, 1345, 1266, 1183, 1075, 1010, 975, 738 cm⁻¹.
UV (methanol): l _max (lg ε) = 301 nm (4.44)
MS (): m / e (%) = 837 (MH) ⁻

High resolution: C₄₈H₇₀O₁₂
Calc .: 837.4789
Found: 837.4866 (MH) ⁻

Example 79 and 80 33-O, 36-seco-sorangicin (80) 37,42-dihydro- (38E, 40E) -sorangicin (81)

95 mg (0.12 mmol) sorangicin A are dissolved in 4 ml of methanol and with 4 ml Buffer ammonia / ammonium chloride, 0.5 M / 5 M (pH 8), added. To Solution is given about 1 g of coarse-grained sodium amalgan (2% Na) and 2 h stirred at RT until gas evolution has ceased.

A UV spectrum (methanol) of the reaction solution shows that the absorption maximum disappeared at 301 nm, and instead 4 bands at 213, 261, 270 and 281 nm can be seen. A DC (eluent dichloromethane / Methanol, 9: 1, v / v; Educt Rf 0.25) shows two products with the Rf 0.25 and 0.2.

The separation of the two products (which in turn represent product mixtures) is carried out with the aid of column chromatography (silica gel HD-SIL Rp 18- 40-60, eluent methanol / water, 75:25, v / v, 0.1% formic acid; UV Detection 254 nm).

1) The polar fraction consists of 20 mg and shows in the UV spectrum three bands at 261, 270 and 281 nm. An analytical HPLC (silica gel Nucleosil 100, 7 µm; Mobile phase petroleum ether / dichloromethane / methanol, 50: 44: 6, v / v / v, 0.1% formic acid; UV detection 270 nm) shows that the Substance consists of 3 isomers in a ratio of 1: 12: 3.

The main product is isolated using preparative HPLC (silica gel HD-SIL 100, 10 µm; eluent petroleum ether / dichloromethane / methanol, 50: 48: 2, v / v / v, 0.1% formic acid; UV detection 270 nm).
Yield: 80 11 mg = 12%

2) The lipophilic fraction consists of 24 mg and shows in the UV spectrum an absorption maximum at 230 nm. An analytical HPLC (silica gel and Eluent s. O.; UV detection 240 nm) shows that the substance from 3 Isomers in a ratio of 7: 2: 7.

The main product is isolated using preparative HPLC (silica gel HD-SIL 100, 10 µm; eluent petroleum ether / dichloromethane / methanol, 50: 48: 1.3, v / v / v, 0.1% formic acid; UV detection 242 nm).
Yield: 81 5 mg = 5%

A) 33-O, 36-seco-sorangicin (80):
1 H-NMR (acetone-d): 400 MHz, s. Tab.
13 C-NMR (acetone-d:): 75.5 MHz, s. Tab.
IR (film): = 3425, 2958, 2927, 2871, 1712, 1623, 1459, 1384, 1264, 1150, 1083, 1008, 975, 738, 697 cm⁻¹.
UV (methanol): l _max (lg ε) = 281 nm (4.06)
MS (FAB): m / e (%) = 807 [100 (MH) ⁻]

High resolution: C₄₇H₆₈O₁₁
Calculated: 807.4684
Found: 807.4700 (MH) ⁻

B) 37,42-Dihydro- (38E, 40E) -sorangicin (81):
1 H-NMR (acetone-d): 400 MHz, s. Tab.
13 C NMR (acetone-d): 75.5 MHz, s. Tab.
IR (film): = 3448, 3023, 2962, 2927, 1727, 14553, 1384, 1257, 1145, 1069, 975, 865, 819, 745, 699 cm⁻¹.
UV (methanol): l _max (lg ε) = 230 nm (4.33)
MS (FAB): m / e (%) = 807 [100 (MH) ⁻], 765 (3).

High resolution: C₄₇H₆₈O₁₁
Calculated: 807.4684
Found: 807.4700 (MH) ⁻

Example 81 and 82 (38Z, 40E) -isosorangicin (84) (38Z, 40Z) -isosorangicin (85)

60 mg (75 µmol) Sorangicin A is dissolved in 1 ml dry acetone, with 0.3 ml a 1 M solution of tetrabutylammonium fluoride in THF and stirred under nitrogen atmosphere at 65 ° C for 1 h. A DC (eluent Dichloromethane / methanol, 9: 1, v / v; Educt Rf 0.25) shows the complete Conversion to a somewhat more lipophilic product with Rf 0.3. A analytical HPLC (Nucleosil RP 18, 7 µm, mobile solvent methanol / water, 75:25, v / v, 0.1% formic acid; UV detection 291 nm) from the reaction mixture shows 98.5% product and 1.5% educt.

The solution is concentrated, taken up in dichloromethane, twice with 1 M Hydrochloric acid and washed twice with water. The product mixture is with Using preparative column chromatography (HD-SIL RP18-30-60, Eluent methanol / water, 7: 3, v / v, 0.1% formic acid; UV detection 313 nm) separated from the educt and cleaned. Yield crude product: 37 mg. An analytical HPLC (Nucleosil Si 100, 7 µm; eluent petroleum ether / dichloromethane / Methanol, 50: 44: 6, v / v / v, 0.1% formic acid; UV detection 291 nm) shows two isomers in a ratio of 63:37.

The two isomers are separated using PSC (silica gel Si 60, 2 × 0.5 mm, mobile solvent dichloromethane / methanol, 9: 1, v / v; RF 0.3) and give 4.8 mg of pure Z isomer and 5.1 mg of mixture. A second separation of the mixture gives 2.5 mg Z isomer and 2.1 mg E isomer.
Overall yield:
84 7.3 mg = 12%
85 2.1 mg = 4%

A) (38Z, 40E) -isosorangicin (84):
1 H-NMR (CD₃OD): 300 MHz, s. Tab.
13 C-NMR (DC₃OD): 75.5 MHz, s. Tab.
IR (film): = 3440, 3356, 3043, 2942, 1727, 1440, 1347, 1264, 1172, 1086, 1006, 975, 738 cm⁻¹.
UV (methanol): l _max (lg ε) = 290 nm (4.24)
MS (FAB): m / e (%) = 805 (MH) ⁻

High resolution: C₄₇H₆₆O₁₁
Calculator: 805.4527
Found: 805.4440 (MH) ⁻

B) (38Z, 40Z) -isosorangicin (85):
1 H-NMR (CD₃OD): 300 MHz, s. Tab.
13 C-NMR (CD₃OD): 75.5 MHz, s. Tab.
IR (film): = 3454, 3450, 2962, 2925, 1727, 1440, 1347, 1266, 1220, 1172, 1083, 1062, 1008, 975, 738 cm⁻¹.
UV (methanol): l _max (lg ε) = 292 nm (4.36)
MS (FAB): m / e (%) = 805 (MH) ⁻

High resolution: C₄₇H₆₆O₁₁
Calculator: 805.4527
Found: 805.4440 (MH) ⁻

1 H-NMR signals of Examples 75-82 in acetone-d₆

13 C-NMR signals of Examples 75, 76 and 79 to 82 in acetone-d₆

Example 83

Type of derivative: amide
Substance name: Sorangicin AN- (3-hydroxypropyl) amide

Production and cleaning: analogous to example 16. Unblocking with dioxane / conc. NH₃ 4 hours cleaning by prep. RP-HPLC (Nucleosil C18, 10 μ, 16 × 250 mm, methanol / water 75:25, 22 ml / min.
Yield: 24 mg (50%). [Α] = + 64.8 (c = 0.9 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.44).
1 H-NMR ([D₄] methanol): δ = 3.61 (2H, t, 6.3 Hz, -CH₂-N <), 3.29 (2H, t, 7.0 Hz, -CH₂-O-), 1.74 (2H, m, -CH₂-), 2.20 (2H, t, 2-H₂).
13 C-NMR ([D₄] methanol): δ = 176.4 (C-1), 60.3 (-CH₂-O), 37.2 (-CH₂-N <), 33.2 (-CH₂-).
Mass spectroscopy: (-) FAB (matrix 3NBA): m / e = 862 [MH] ⁻; 1016 [M-H + 3NBA] ⁻.

High resolution: C₅₀H₇₃NO₁₁-H
Calc .: 862.5105
Found: 862.5960

Example 84

Derivative type: amide, 25-O-formyl
Substance name: 25-O-formylsorangicin AN- (1-hydroxy-3-methyl-2-butyl) amide

Preparation and cleaning: analogous to Ex. 16, with 2-amino-3-methyl-1-butanol
Yield: 17 mg (33%). [Α] = + 78.9 (c = 0.7 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.42).
1 H-NMR ([D₄] methanol): like 25-O-formyl-sorangicin A but δ = 3.74 (1H, m, <CHN <), 3.60 (2H, m, -CH₂-O-), 1.91 ( 1H, m, <CH-), 1.2-0.9 (6H, m, 2 -CH₃).
13 C-NMR ([D₄] methanol): δ = 176.2 (C-1), 63.1 (-CH₂-O-), 57.1 (<CHN <), 29.8 (-CH <), 19.0 + 18.8 (each -CH₃) .
Mass spectroscopy: (-) FAB (matrix 3NBA): m / e = 918 [MH] ⁻; 1072 [M-H + 3NBA] ⁻.

High resolution: C₅₃H₇₆NO₁₂-H
Calculated: 918.5367
Found: 918.5305

Example 85

Type of derivative: amide
Substance name: Sorangicin AN- (1-hydroxy-3-methyl-2-butyl) -amide

Preparation and cleaning: analogous to Ex. 16, with 2-amino-3-methyl-1-butanol. Deblocking with dioxane / conc. NH₃ 6 hours at 60 ° C.
Yield: 16 mg (32%). [Α] = + 62.6 (c = 0.6 in methanol).
UV (methanol): λ _max (lg ε): 301 nm (4.44).
1 H-NMR ([D₄] methanol): δ = 3.73 (2H, m, 23-H + <CHN <), 3.60 (2H, m, -CH₂O-), 1.91 (1H, m, <CH-), 1.1-0.84 (15H, m, 44-, 46- and 47-H₃ + 2 -CH₃).
13 C-NMR ([D₄] methanol): δ = 176.4 (C-1), 63.1 (-CH₂O-), 57.7 (<CHN <), 29.8 (<CH-), 19.9 + 18.8 (each -CH₃).
Mass spectroscopy: (-) FAB (matrix 3NBA): m / e = 890 [MH] ⁻; 1044 [M-H + 3NBA] ⁻.

High resolution: C₅₂H₇₇NO₁₁-H
Calc .: 890.5418
Found: 890.5437

Example 86

Type of derivative: amide
Substance name: Sorangicin AN- (2-hydroxy-1-methyl-ethyl) -amide

Production and cleaning: analogous to Example 16, with 2-amino-1-propanol (alaninol). Deblocking with dioxane / conc. NH₃ 6 hours at 60 ° C.
Yield: 15 mg (31%). [Α] = + 68.7 (c = 0.8 in methanol).
UV (methanol): λ _max (lg ε): nm.
1 H-NMR ([D₄] methanol): δ = 3.96 (1H, m, <CHN <), 3.48 (3H, m, 22-H + -CH₂O-), 1.16 (3H, d, 6.8 Hz, -CH₃ -).
13 C-NMR ([D₄] methanol): δ = 176.1 (C-1), 66.3 (-CH₂O-), 48.1 (<CHN <), 17.2 (-CH₃).
Mass spectroscopy: (-) FAB (matrix 3NBA): m / e = 862 [MH] ⁻; 1016 [M-H + 3NBA] ⁻.

High resolution: C₅₀H₇₃NO₁₁-H
Calc .: 862.5105
Found: 862.5060

Example 87

Derivative type: 22-OR
Substance name: 22-O-acetylsorangicin A

Preparation: 50 mg sorangicin were in the presence of 1 mg DMAP in 0.9 ml abs. Slowly pyridine with ice cooling with 5.71 mg acetic anhydride in 100 µl abs. Pyridine was added and the mixture was stirred for 1 hour. After that i. Vac. constricted. After methylene chloride / water distribution, the residue was purified by RP-HPLC (LiChrosorb RP-18, 7 μ, methanol / water 75:25 with 0.1% HCOOH).
Yield: 9 mg (19%).
HPLC (column = Nucleosil C₁₈, 7 µ, 250 × 4.0 mm; mobile solvent methanol / water 75/25 with 0.1% formic acid, flow 2 ml / min., Detection of UV absorption at 300 nm) R _t = 8.98 min (sorangicin R _t = 7.23 min). [Α] = + 70.0 (c = 0.7 in methanol).
1 H-NMR ([D₄] methanol): δ = 4.98 (1H, m, 22-H), 4.37-4.31 (2H, m, 33- + 21- H), 3.93-3.82 (4H, m, 23-, 25-, 27- + 31-H), 2.10 (3h, S, acetyl-H₃).
13 C-NMR ([D₄] methanol): δ = 172.4 (<C = O), 21.0 (-CH₃).
Mass spectroscopy: (-) FAB (matrix 3NBA): m / e = 847 [MH] ⁻.

Example 88

Type of derivative: acid chloride
Substance name: Tri-O-formyl sorangicin Al chloride

Preparation: 50 mg of tri-O-formyl sorangicin A in 1 ml of abs. Toluene dissolved, with 1 drop of abs. Pyridine was added and about 100 μl oxallyl chloride was added while cooling with ice. It is then concentrated in an oil pump vacuum, after adding abs. Toluene is concentrated again and i. Vac. dried. IR (film on Irtran): like Tri-O-formyl sorangicin A, additional band at 1801 cm ^-1 .

1 H-NMR ([D₂] methylene chloride, + residues pyridinium chloride and toluene): δ = 8.11, 8.09, 7.99 (each 1H, formyl-H), 7.13-7.05 (1H, m, 41-H), 7.08 (1H, m , 40-H), 6.97 (1H, ddd, 15.3, 11.7, 1.5, 38-H), 6.41 (1H, dd, 11.2, 10.4, 39-H), 6.20 (1H, dd, 15.2, 4.2, 37-H), 6.08 (2H, m, 11- + 12-H), 5.91 (1H, German, 15.4, 6.0, 19-H), 5.67-5.47 (5H, m, 21-, 42-, 15- , 16- + 20-H), 5.39-5.24 (4H, m, 29-, 30-, 7- + 10-H), 5.17 (1H, dd, 7.5, 3.3, 22-H), 5.03 (1H, d (br.), 2.4, 25-H), 4.51 (1H, m, 36-H), 4.39-4.34 (2H, m, 13- + 35-H), 4.25 (1H, d, 6.3, 33- H), 4.15 (1H, s (br.), 9-H), 3.80 (1H, dd, 9.5, 7.7, 31-H), 3.75-3.67 (2H, m, 23- + 27-H), 2.89 (2H, t, 7.4) 2-H₂), 2.42-2.25 (3H, m, 6-H, 14- + 28-H _a ), 2.24-2.06 (6H, m, 14- + 28-H _b , 17th - + 18-H₂), 1.99 (1H, ddd, 11.4, 6.4, 2.6, 34-H _a ), 1.87 (1H, dd, 11.4, 1.2, 34-H _b ), 1.79-1.57 (5H, m, 24 - + 3-H₂, 26-H), 1.62 (3H, d, 0.8, 45-H₃), 1.40-1.15 (5H, m, 32-H, 4- + 5-H₂), 0.93 (3H, d, 7.2, 36-H₃), 0.87 (3H, m, 44-H₃), 0.77 (3H, d, 6.8, 47-H₃). 13 C-NMR ([D₂] methylene chloride, + residues pyridinium chloride and toluene): like tri-O-formylsorgangicin A, but δ = 174.12 (C-1), 47.51 (C-2), 26.78 + 25.56 (C-3 + -4).

Example 89

Derivative type: 21,22-OR
Substance name: 21,22-Di-O-acetyl-sorangicin A

Preparation: as example 87, with 11.4 mg acetic anhydride in 200 ul abs. Pyridine.
Yield: 9 mg (18%) (next to 8 mg So 1233).
HPLC (conditions as So 1233) R _t = 15.44 min. [Α] = +78.4 (c = 0.5 in methanol).
1 H-NMR ([D₄] methanol): δ = 5.67-5.51 (5H, m, 42-, 20-, 21-, 15- + 16-H), 5.04 (1H, dd, 7.4, 3.0, 22-H ), 2.10 + 2.00 (each 3H, s, acetyl-H₃).
13 C-NMR ([D₄] methanol): δ = 172.2 + 171.7 (≦ λτC = O), 22.03 +21.30 + 20.98 (C-44 + 2 acetyl-CH₃).
Mass spectroscopy: (-) FAB (matrix 3NBA): m / e = 889 [MH] ^- .

Claims (71)

1. Compounds with the formula (I) wherein R¹ is C₁-C₄ alkoxy, C₂-C₅ alkenoxy, benzyloxy, optionally substituted heterocyclyl- (C₁-C₄) alkyleneoxy, -O- (CH₂) _n - CONR⁵R⁶, where R wobei and R⁶ are identical or different and H, C₁- C₃-alkyl or optionally substituted phenyl and n is 1 to 3, or
wherein R¹ is NR⁷R⁸, where R⁷ can mean H, C₁-C₄-alkyl or cyclohexyl and R⁸ H, C₁-C₆-alkyl, C₁-C₃-alkylene sulfonic acid, an optionally substituted carbocycle or heterocycle, NR⁹R¹⁰, where R⁹ and R¹⁰ are the same or different and can be H, C₁-C₃-alkyl or optionally substituted piperazine, (and R⁸ furthermore) C₁-C₃- alkoxy, benzyl, hydroxy-C₁-C₄-alkylene, C (= NH) NH₂, C (= NH) - Is NH-NH₂ or cyclohexylaminocarbonyl or R⁷ and R⁸ together can represent a (CH₂) _n group, in which n = 4 or 5;
R² and R³ are the same or different and can mean H, formyl or a trialkylsilyl group or R² and R³ together form a group which unter λτC = O, ≦ λτC = S, ≦ λτC (CH₃) ₂ and ≦ λτSi (alkyl) ₂ is selected and
R⁴ is H, CHO, C₁-C₃-alkyl, SO₂R¹³, C (S) -phenyl, (C₁-C₃-alkyl) - carbonyl or CONHR¹¹, where R¹¹ is H or COCCl₃ and R¹³ is optionally substituted with halogen C₁-C₄-alkyl or tolyl, and their salts with bases and acids, with the exception of the compounds in which R¹ is CH₃, C₂H₅ or NR⁷R⁸ with R⁷ is hydrogen and R⁸ is hydrogen, methyl or isopropyl or with R⁷ is R⁸ is methyl or together with R⁷ and R⁸ is equal to (CH₂) ₅ and R², R³ and R⁴ are each hydrogen. 2. Compounds with the formula (II) wherein
R¹ has the meaning defined in claim 1 and
X and Y either each represent oxygen, an acyl group and a hydrogen atom, two hydrogen atoms or a hydrogen atom and additionally a hydroxyl group or together with the carbon atoms to which they are attached form an oxirane group or a 1,3-dioxolane ring and in which Z is either a Is hydrogen atom and OR⁴ with the meaning given in claim 1 for R⁴ or = O, F₂, NOH or NO- (C₁-C₃-alkyl),
and their salts with bases and acids. 3. Compounds according to claim 2, wherein Z is in the β-position arranged hydrogen atom and one in the α-position Hydroxy group means (25R isomer). 4. Compounds according to claim 2, wherein the in the C-21 position located hydrogen atoms are α-bonded. 5. Compounds according to claim 2, wherein the C-46 methyl group bound in the β position (the natural configuration). 6. Compounds according to claim 2, wherein the C-46 methyl group is bound in the α-position. 7. Compounds with the formula (III) wherein
R¹, R² and R³ have the meanings defined in the preceding claims, and their salts with bases and acids. 8. Compounds according to any one of the preceding claims, wherein the trient portion (C-36 to C-41) is in the following stereo conformations: 9. Compounds with the formulas (IVa) or (IVb) wherein
R¹² is an oxygen atom or a hydrogen atom and a hydroxy group and
R¹, R², R³ and R⁴ have the meaning defined in the preceding claims, with the exception of those compounds in which R¹ is hydrogen, R¹² is oxygen or a hydrogen and a hydroxyl group and R², R³ and R⁴ are hydrogen, and their salts with Bases and acids. 10. Compounds with the formula (V) wherein
R¹, R², R³ and R⁴ have the meaning defined in the preceding claims, and their salts with bases and acids. 11. Compounds with the formula (VI) wherein
R¹, R², R³ and R⁴ have the meaning defined in the preceding claims, and their salts with bases and acids. 12. Compounds with the formulas (VIIa) or (VIIb) wherein
R¹, R², R³ and R⁴ have the meaning defined in the preceding claims, and their salts with bases or acids. 13. Salts of compounds according to one of the preceding Claims, characterized in that the salts with pharmazeu table acceptable bases and acids are formed. 14. A method of establishing a connection according to one of the The preceding claims, wherein R¹ is C₁-C₄ alkoxy, and indeed including those excluded in claim 1 Connections, characterized in that the corresponding A compound according to any one of the preceding claims, wherein R¹ is OH means reacted with a C₁-C₄ diazoalkane. 15. A method of establishing a connection according to one of the Claims 1 to 13, wherein R¹ is C₁-C₄ alkoxy, thereby characterized in that the corresponding connection according to one of the  Claims 1 to 13, wherein R¹ is OH, under acid Conditions is implemented with a C₁-C₄ alkanol. 16. A method for producing a compound according to any one of claims 1 to 13, wherein R¹ is C₁-C₅-alkoxy, C₂-C₅-alkenoxy or Ben zyloxy, characterized in that the corresponding compound according to one of claims 1 to 13, wherein R¹ means OH, in the presence of a base is reacted with a compound of the formula R ^{1 ′} X, where R ^{1 ′ is} C _n H _2n , C _n H _2n-1 or PhCH₂ with n = 1 to 5 and X is halogen, preferably Chlorine or bromine. 17. A method for producing a compound according to any one of claims 1 to 13, wherein R¹ is -O- (CH₂) _n -C (O) NR⁵R⁶, wherein R⁵, R⁶ and n have the meanings defined in claim 1, characterized in that the corresponding compound according to any one of claims 1 to 13, wherein R¹ is OH, with a base, sodium carbonate and then with a compound having the formula X- (CH₂) _n C (O) NR⁵R⁶, wherein X is halogen, preferably chlorine or Bromine, is. 18. A method of establishing a connection according to one of the Claims 1 to 13, wherein R¹ is optionally substituted -O- (C₁-C₄-alkylene) (heterocyclyl), characterized in that that 1,1'-carbonylimidazole with Iodomethane added and the product formed with the corresponding connection according to one of claims 1 to 13,  wherein R¹ is hydroxy, and with an optionally substituted (Heterocyclyl) -C₁-C₄-alkenol is implemented. 19. A method of establishing a connection according to one of the Claims 1 to 13, wherein R¹ is NR⁷R⁸ and R⁷ and R⁸ cyclohexyl or cyclohexylaminocarbonyl, characterized in that that the corresponding connection according to one of claims 1 to 13, wherein R¹ is OH, in the presence of 4- Dimethylaminopyridine reacted with dicyclohexylcarbodiimide becomes. 20. A method of establishing a connection according to one of the Claims 1 to 13, wherein R¹ is NR⁷R⁸ and R⁷ and R⁸ are in Claim 1 defined meanings including those there have excluded meanings, characterized, that the corresponding connection according to one of claims 1 to 13, wherein R¹ is OH, in the presence of N, N'- Carbonyldiimidazole with a compound of the formula NHR⁷R⁸ is implemented. 21. The method according to claim 20, characterized in that R⁷ Is H and R⁸ H, C₁-C₆-alkyl, an optionally substituted Carbocycle or heterocycle or NR⁹R¹⁰, wherein R⁹ and R¹⁰ can be the same or different and hydrogen, C₁-C₃-alkyl or optionally substituted piperazine.   22. The method according to claim 20, characterized in that in the compound to be used R², R³ and R⁴ each one Represent formyl group and optionally the product, wherein R², R³ and R⁴ each represent a formyl group, with aqueous Ammonia is reacted to produce a compound wherein R² and R³ are each hydrogen and R⁴ formyl or hydrogen means. 23. The method according to claim 22, characterized in that R⁷ Is hydrogen and R⁸ is hydroxy (C₁-C₄) alkylene, a C₁-C₃ alkylene sulfonic acid, C (= NH) NH₂ or C (= NH) -NH-NH₂. 24. A method of establishing a connection according to one of the Claims 1 to 13, wherein R¹ is NR⁷R⁸ and R⁷ and R⁸ are in Claim 1 meanings defined including in Claim 1 have excluded meanings, thereby characterized in that the corresponding connection according to one of the Claims 1 to 13, wherein R¹ is OH, in an acid chloride or mixed anhydride, which is then converted into Presence of a nitrogen base such as pyridine with a compound is implemented with the formula NHR⁷R⁸. 25. The method according to claim 24, characterized in that the conversion to the acid chloride or the mixed anhydride with the help of an acid chloride such as oxalic acid dichloride or Pivalyl chloride is made.   26. The method according to claim 24 or 25, characterized characterized in that R², R³ and R⁴ in the to be used Compound each represent a formyl group and that the formed product, in which R², R³ and R⁴ each Represent formyl groups, optionally reacted with ammonia to form a compound wherein R² and R³ are each Are hydrogen and R⁴ means formyl or hydrogen. 27. A method of establishing a connection according to one of the Claims 1 to 13, wherein R¹ is hydrogen, thereby characterized in that the corresponding connection according to a of claims 1 to 13, wherein R¹ is C₁-C₄ alkoxy or C₂-C₅ alkyleneoxy represents acidic in a manner known per se or alkaline saponified. 28. A method of establishing a connection according to one of the Claims 1 to 13, wherein R¹ is hydrogen, characterized records that the corresponding connection according to one of the Claims 1 to 13, wherein R¹ is O-CH₂CH = CH₂ using a palladium (O) catalyst treated with morpholine. 29. A method of establishing a connection according to one of the Claims 1, 3 to 6 and 8 to 13, wherein R², R³ and R⁴ are each Formyl mean, characterized in that the corresponding Connection according to one of Claims 1, 3 to 6 and 8 to 13, wherein R², R³ and R⁴ each represent hydrogen, in the presence an amine, such as triethylamine, and acetic anhydride and  optional catalytic amounts of an acylation catalyst such as B. dimethylaminopyridine is reacted with formic acid. 30. A method of establishing a connection according to one of the Claims 1 and 3 to 13, wherein R² and R³ together form the group ≦ λτC = O, characterized in that the corresponding A compound according to any one of claims 1 to 13, wherein R² and R³ Are hydrogen, with tetramethyl orthocarbonate and a kataly table amount of an acid is implemented. 31. A method of establishing a connection according to one of the Claims 1 and 3 to 13, wherein R² and R³ together are one Represent dialkylsilylene group, characterized in that the corresponding connection according to one of claims 1 to 13, wherein R² and R³ are each hydrogen, with a Dialkyldihalosilan be implemented. 32. The method according to claim 31, characterized in that di-t-butyldichlorosilane is used as the dialkyldihalosilane and that in the connection according to one of claims 1 and 3 to 13, which is used as the starting compound, R¹ not water is fabric. 33. A method of establishing a connection according to one of the Claims 1 and 3 to 13, wherein R² and R³ together form a ≦ λτC (CH₃) ₂- Represent group, characterized in that the corresponding connection according to one of claims 1 and 3 to  13, wherein R² and R³ are each hydrogen, in the presence of a Acid, such as trifluoroacetic acid, is reacted with acetone. 34. Method for establishing a connection according to one of the Claims 1 and 3 to 13, wherein R² and R³ together form the group ≦ λτC = S, characterized in that the corresponding A compound according to any one of claims 1 and 3 to 13, wherein R² and R³ are each hydrogen in the presence of an acylation catalyst, such as dimethylaminopyridine with thiophosgene is implemented. 35. The method according to claim 34, characterized in that as a starting compound a compound of formula (I) is used, wherein R¹ is O-CH₂-CH = CH₂. 36. Method of establishing a connection according to one of the Claims 1 and 3 to 13, wherein R² is a trialkylsilyl group is characterized in that a connection according to one of the Claims 1 and 3 to 13, wherein R² is hydrogen, in Presence of an acid acceptor with a trialkylsilyl halide is implemented. 37. The method according to claim 36, characterized in that the Trialkylsilyl halide is t-butyldimethylsilyl chloride.   38. A method of establishing a connection according to one of the Claims 1 to 6 and 8 to 13, wherein R⁴ is C₁-C₃-alkyl, characterized in that the corresponding connection after one of claims 1 to 6 and 8 to 13, wherein R⁴ is hydrogen means with a C₁-C₃ alkyl iodide or bromide and one Alkali or alkaline earth hydride is implemented. 39. Method of establishing a connection according to one of the Claims 1 to 6 and 8 to 13, wherein R⁴ is C (S) phenyl, characterized in that the corresponding connection after one of claims 1 to 6 and 8 to 13, wherein R¹ is C₁-C₄ alkyl means, first with the product of N, N-dimethylbenzamide and Phosgene and then in the presence of pyridine Hydrogen sulfide is implemented. 40. Method of establishing a connection according to one of the Claims 1 to 6 and 8 to 13, wherein R⁴ is SO₂R¹³, wherein R¹³ has the meanings given in claim 1, thereby characterized in that the corresponding connection according to one of the Claims 1 to 6 and 8 to 13, wherein R⁴ is hydrogen, in the presence of a base such as triethylamine with a compound is implemented with the formula R¹³SO₂Cl. 41. The method according to claim 40, characterized in that R¹³ means methyl.   42. A method of establishing a connection according to one of the Claims 1 to 6 and 8 to 13, wherein R⁴ is C (O) -NH-C (O) -CCl₃, characterized in that the corresponding connection after one of claims 1 to 6 and 8 to 13, wherein R⁴ is hydrogen means is reacted with trichloroacetyl isocyanate. 43. A method of establishing a connection according to one of the Claims 1 to 6 and 8 to 13, wherein R⁴ is C (O) NH₂, thereby characterized in that the corresponding connection according to one of the Claims 1 to 6 and 8 to 13, wherein R⁴ is C (O) -NH-C (O) -CCl₃, in the presence of alumina with an alkanol such as methanol is treated. 44. A method of establishing a connection according to one of the Claims 1 to 6 and 8 to 13, wherein R⁴ is C (O) -C₁-C₄ alkyl means, characterized in that a connection after one of claims 1 to 6 and 8 to 13, wherein R⁴ is hydrogen means with in the presence of pyridine and / or DMAP / (C₁-C₃-alkyl) CO / ₂O is added. 45. The method according to claim 44, characterized in that the Compound having the formula [(C₁-C₃-alkyl) CO] ₂O Acetic anhydride, propionic anhydride or isobutyric acid is anhydride. 46. The method according to any one of claims 38 to 45, characterized characterized in that, provided that R² and R³ in the to be used  Compound with formula (I) together the group ≦ λτC (CH₃) ₂ represent this group if necessary in another Step with an acid, such as trifluoroacetic acid, in dioxane / Water is hydrolyzed to form a compound in which R² and R³ are each hydrogen. 47. Method of establishing a connection according to one of the Claims 1, 3 to 6 and 8 to 13, wherein R² and R³ are each Is hydrogen and R⁴ is CHO, characterized in that that the corresponding connection according to one of claims 1, 2, 4 to 6 and 8 to 13, wherein R², R³ and R⁴ are each CHO, with aqueous ammonia is treated. 48. Method of connecting after A compound of formula (II) according to claim 2, wherein X Is oxygen and Y is a hydrogen atom and a hydroxy group represents, characterized in that a connection after any one of claims 1 to 13, wherein R² and R³ are each Are hydrogen, is oxidized with nickel peroxide (NiO₂). 49. Method of making compounds of the formula (II) according to claim 2, wherein on the one hand X two hydrogen atoms represents and Y is oxygen or on the other hand X and Y together with the C-21 and C-22 atoms to which they are attached form an oxirane group (the hydrogen Substituents at C-21 and C-22 are arranged in the α-position), characterized in that a connection according to one of the  Claims 1 and 3 to 13, wherein R² and R³ are each hydrogen mean reacted with a sulfuran and the products obtained if necessary, separates chromatographically. 50. Process for the preparation of a (21R) isomer after a of claims 1 and 3 to 13, wherein R² and R³ each Mean hydrogen, characterized in that one A compound of formula (II) according to claim 2, wherein X Is oxygen and Y is a hydrogen atom and a hydroxy group represents, with a reducing agent such as sodium cyanoborohydride implemented and optionally the isomeric (21S) by-products separated chromatographically. 51. A process for the preparation of compounds of the formula (II) according to claim 2, in which Z is oxygen, characterized in that a compound of the formula (I) in which R⁴ is hydrogen and R² and R³ together are C (CH₃) ₂ mean, oxidized with an oxidizing agent such as CrO₃ or pyridinium chlorochromate and, if desired, the product then in any order

• a) treated with a strong acid such as trifluoroacetic acid in dioxane in order to convert X and Y into a hydroxyl group and a hydrogen atom,
• b) if diastereomers are formed in the reaction (a), these are separated chromatographically and / or
• c) when R¹ is CH₂ = CH-CH₂-O-, reacted with a Pd (O) catalyst and morpholine, the product obtained being a compound in which R¹ is OH.

52. Process for producing a compound having the formula (II) according to claim 2, wherein Z represents two fluorine atoms, thereby characterized in that a compound with the formula (II) where Z is oxygen with a fluorinating agent such as Reacting diethylammonium sulfur trifluoride and, if appropriate, if R² and R³ together ≦ λτC (CH₃) ₂ mean with a strong Reacts acid as hydrochloric acid to obtain a compound wherein X and Y are each a hydrogen atom and a hydroxy are group, and optionally if R¹ CH₂ = CH-CH₂-O- bedeu tet, with a Pd (O) catalyst and morpholine to Ver to obtain bonds wherein R¹ is hydrogen. 53. Process for producing (25R) isomers of the compound gene with the formula (I), wherein R⁴ represents hydrogen, thereby characterized in that a compound of formula (II), wherein Z is oxygen, with a reducing agent such as sodium cyano borohydride is reduced. 54. Process for producing a compound having the formula (II) according to claim 2, wherein Z = NOH, characterized in that that a compound of formula (II) wherein Z is oxygen is implemented with H₂NOH.   55. A process for producing a compound of formula (II) according to Claim 2, wherein Z = NO (C₁-C₃) alkyl, characterized in that that a compound of formula (II) wherein Z is oxygen is reacted with a (C₁-C₃) alkoxyamine hydrochloride. 56. The method according to any one of claims 53 to 55, characterized characterized in that a (26R) compound (= at the C-26 atom bound methyl group in the β position, the natural confi guration) is used. 57. The method according to any one of claims 53 to 55, characterized characterized in that a (26S) compound (= at the C-26 atom bound methyl group in the α-position, the non-natural Configuration) is used. 58. A process for the preparation of a compound of the formula (III) according to claim 7, characterized in that a compound of the formula (I) in which R² and R³ are protective groups is reacted with an elimination reagent and is optional

• a) the protective groups R² and R³ removed to obtain a compound in which R² and R³ each represent hydrogen, and / or
• b) if R¹ is not hydrogen, the ester group on the C-1 atom is split off to obtain a compound in which R¹ is hydrogen,

taking steps (a) and (b) in any order can perform.   59. The method of claim 49, wherein R² and R³ together are the Group C (CH₃) ₂ represent and the elimination of the protective group according to (a) with an acid such as trifluoroacetic acid in Dioxane / water can be done. 60. The method of claim 49, wherein the eliminating reagent is a sulfuran like Martin's sulfuran. 61. The method of claim 49, wherein R¹ is -O-CH₂-CH = CH₂ and the reaction according to (b) with a Pd (O) catalyst and Morpholine takes place. 62. A process for the preparation of a compound having the formula (I), (II) or (III), the trient part of which is in one of the conformations shown in claim 7, characterized in that a compound having the formula (I), (II ) or (III) either

• - irradiated with UV or visible rays or
• - warmed and
• - Subsequently, the possibly formed isomer mixture is separated, for example by chromatography.

63. Method of making connections with the formulas (IVa) or (IVb) according to claim 9, wherein R¹² be an oxygen atom means and R¹, R², R³ and R⁴ have the meaning of claim 1,  characterized in that a compound of the formula (I), in which R¹, R², R³ and R⁴ have the meaning given, reacted with a quinone and the mixture of cis-trans isomeric products (IVa) and (IVb) if appropriate separates chromatographically. 64. The method according to claim 54, characterized in that as Quinone 2,3-dichloro-5,6-dicyanobenzoquinone is used. 65. Process for producing a compound having the formula (IVa) or (IVb) according to claim 9, including the compounds excluded in claim 9, wherein R¹² is water atom and one Hydroxy group, characterized in that a A compound of formula (IVa) or (IVb) wherein R¹² Is oxygen and R1 is not hydrogen, with one Reductant is implemented and then optionally R1 is hydrolyzed to hydrogen. 66. The method according to claim 56, characterized in that the Reduction with sodium cyanoborohydride is carried out. 67. Process for the preparation of compounds having the formula (V) or (VI) according to claims 10 and 11, characterized in that that a compound of formula (I) wherein R¹, R², R³ and R⁴ have the meanings given in Claim 1, reduced with sodium amalgam and optionally the mixture of the products with the formulas (V) and (VI) chromatographically inclines and separates.   68. Process for the preparation of compounds of the formulas (VIIa) and (VIIb) according to claim 12, characterized in that one A compound of formula (I) wherein R¹, R², R³ and R⁴ are as in Formula (I) are defined with a sterically hindered Fluoride and optionally the mixture the products are cleaned and separated chromatographically. 69. The method according to claim 68, characterized in that as Fluoride tetra-n-butylammonium fluoride is used. 70. The method according to any one of claims 14 to 69, characterized characterized in that the product is subsequently mixed with an acid or base is converted into an acidic or basic salt.