Organic Compounds

The present invention relates to organic compounds, e.g. mutilins, such as pleuromutilins, which are useful as antimicrobials, e.g. antibiotics.

We have now found salts of pleuromutilins which exhibit surprising activity.

In one aspect the present invention provides a pleuromutilin in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid.

"Pleuromutilin" as used herein are pleuromutilins which have the ability to form a salt with an acid, such as an acid addition salt, e.g. pleuromutilins which comprise functional chemical groups which have the ability to form an acid addition salt upon addition of an acid.

2-[(2,6-dichlorophenyl)amino]benzeneacetic acid is also known as diclofenac.

In another aspect the present invention provides a pleuromutilin, which has the ability to form an acid addition salt, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid.

Pleuromutilins in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid are herein also designated as "compound(s) of (according to) the present invention".

A pleuromutilin in a compound of the present invention may exist in the form of isomers and mixtures thereof, e.g. including diastereoisomers and mixtures thereof. Isomeric mixtures may be separated as appropriate, e.g. according to a method as conventional, to obtain pure isomers. The present invention includes a pleuromutilin in a compound of the present invention in any isomeric form and in any isomeric mixture, such as described in patent literature cited below, which patent literature is introduced herein by reference with respect to isomeric forms of pleuromutilins. Preferably the configuration in the mutilin ring is the same as in a naturally produced mutilin.

Pleuromutilin, e.g. a compound of formula

is a naturally occurring antibiotic, e.g. produced by the basidomycetes Pleurotus mutilus and P. passeckerianus, see e.g. The Merck Index, 12th edition, item 7694. A number of further pleuromutilins having the principle ring structure of pleuromutilin and having e.g. antibacterial activity are known.

A pleuromutilin in a compound for the present invention includes a pleuromutilin having the basic structural elements as set out in formula

The following numbering system is used in the present application:

The dotted line between positions 19 an 20 (and between positions 1 and 2) is a bond or is no bond. In a compound of formula A or of formula PLEU a hydrogen atom in positions 4, 7 and/or 8 of the ring system may be replaced by deuterium, and if the dotted line between positions 1 and 2 is no bond (single bond between positions 1 and 2) the ring system may be further substituted in positions 1 and/or 2, e.g. by halogen, deuterium or hydroxy. The group -O- in position 14 is further substituted, preferably by a substituted carbonyl group.

Examples of pleuromutilins in a compound of the present invention include e.g. a compound as disclosed, such as a compound as claimed, in

- GB1312148, GB1410505, DE3405632, US3987194, US4278674, US4130709, EP0013768, EP0153277 (e.g. including Valnemulin (Econor®)), US516526, WO9322288, WO9725309, WO9805659, WO9821855, WO9921855, WO0007974, WO0027790, WO0037074, WO0073287, WO0007974, WOOl 14310, WO0109095, WOOl 14310, WO0174788, WO0204414, WO0212199, WO0222580, WO0230929, WO0238528, WO0037074, WO2004011431.

Preferred pleuromutilins in a compound of the present invention include e.g. compounds as disclosed in WO0109095, e.g. a compound, of formula

wherein R is hydrogen or alkyl; R ₁ is hydrogen or a group of formula

X

— C-R

⁹ wherein X is S, O, or NR ₁₀ , wherein R ₁₀ is H or alkyl, or N ⁺ (R' ₁₀ ) ₂ wherein R' ₁₀ is alkyl in the presence of an appropriate anion; and R ₉ is amino, alkyl, aryl, heterocyclyl or mercapto; and, if X is oxygen, R ₉ is additionally hydrogen; R ₂ is arylene, e.g. phenylene; or heterocyclene; R ₄ is hydrogen or alkyl; R ₅ is hydrogen or alkyl; R ₃ , R ₃ ', R ₆ , R ₇ and R ₈ independently of each other are hydrogen or deuterium; or R and R ₂ together with the nitrogen atom to which they are attached form non-aromatic heterocyclene and R ₁ is a group of formula X

_ ll

^ wherein X and Rg are as defined above; e.g. a compound of formula

wherein R _{1 s} is hydrogen or a group of formula

wherein R _6s is hydrogen or deuterium; R _2s is hydrogen, methyl or tert-butyl;

R _7s is hydrogen or methyl; and R _3s , R ₄₃ and Rs _s are hydrogen or deuterium, such as a compound of formula

-WO0109095 or such as a compound of formula

e.g. including a compound of formula

Other preferred pleuromutilins in a compound of the present invention include e.g. compounds as disclosed in WO0204414, e.g. a compound selected from 14-O-[(cycloalkyl- sulfanyl)acetyl]mutilins; 14-O-[(cycloalkyl-alkyl-sulfanyl)acetyl]mutilins; 14-O- [(cycloalkoxy)acetyl]mutilins; or 14-0-[(cycloalkyl-alkoxy)acetyl]mutilins, such as of formula

wherein R is hydrogen; R ₁ is hydrogen or a group of formula X

^ wherein X is sulphur, oxygen or NR _1O , wherein R ₁₀ is hydrogen or alkyl; and R ₉ is amino, alkyl, aryl or heterocyclyl; and, if X is oxygen, R ₉ is additionally hydrogen; Y is sulphur or oxygen; R ₂ is hydrogen or one or more substituents, R ₄ is hydrogen or alkyl; R ₅ is hydrogen or alkyl; R ₃ and R ₃ ' are hydrogen, deuterium, or halogen; R ₆ , R ₇ and R ₈ are hydrogen or deuterium; m is a number selected from 0 to 4; n is a number selected from 0 to 10; and p is a number selected from 0 to 10; with the proviso that n plus p are at least 1; e.g. a compound of formula

l _p -WO0204414

wherein R _lp is hydrogen or the residue of an amino acid; e.g. a compound of formula

PP -WO0204414

e.g. including compounds of formula

PPP -WO0204414 -WO0204414

Other preferred pleuromutilins in a compound of the present invention include e.g. a compound as disclosed in WO0222580, of formula

wherein R and R ₂ together with the nitrogen atom to which they are attached form pyrrolidinyl or piperidinyl, R ₁ is a group of formula X

Il

^ , R ₃ and R' ₃ are hydrogen, deuterium or halogen, R ₄ is hydrogen or alkyl, R ₅ is hydrogen or alkyl, R ₆ , R ₇ and R ₈ are hydrogen or deuterium; R ₉ is amino, alkyl, aryl, heterocyclyl or mercapto; and, if X is oxygen, R ₉ is additionally hydrogen; Rio is hydrogen

or alkyl, R' _1O is alkyl, X is sulphur, oxygen, NR ₁ O, or N ⁺ (R^o) ₂ in the presence of an appropriate anion, Y is sulphur or oxygen, and m is 0, 1 or 2; with the proviso that, when R and R ₂ together with the nitrogen atom to which they are attached form piperidinyl, m is 0, Y is S and Y is attached in position 3 of said piperidine ring, that group of formula I which is attached to the piperidine ring via the residue Y is either in the (S)-configuration or in the (Reconfiguration, preferably in the (S)- configuration; preferably a compound of formula

wherein R _3p , R' _3p , R _6p , R _7p and Rs _p are, index-number correspondingly, as defined for a compound of formula I-WO0222580 for R ₃ , R' ₃ , R ₆ , R ₇ and R ₈ ; and Rs _p is hydrogen or one or more substituents, and if the group attached to the piperidine ring via the sulphur atom is in position 3 of said piperidine ring and R _5p is hydrogen, then the group attached to the sulphur atom is either in the (S)-configuration or in the (Reconfiguration, such as a compound of formula

e.g. including compounds of formula

'pp _in p-W " "O ^0"2--2--2 ^« -5 ^ϊ -"8-'0^ PPP _n P-WO0222580 e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S- configuration or in the R-confϊguration.

In a pleuromutilin in a compound of the present invention each single defined substituent may be a preferred substituent, e.g. independently of each other substituent defined.

In another aspect the present invention provides a compound of formula I _pp -WO0204414, such as a compound of formula I _ppp - WO0204414 and I _pppp - WO0204414, e.g. wherein the - group attached to the pleuromutilin via the sulphur atom is either in the S-configuration or in the R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2- [(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid.

In another aspect the present invention provides a compound of formula I _ss -WO0109095 in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid.

In another aspect the present invention provides a compound of formula I _sss -WO0109095, such as a compound of formula I _ssss - WOOl 09095, e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S-configuration or in the R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid.

In another aspect the present invention provides a compound of formula I _pp -WO0222580, such as a compound of formula I _PPP -WO0222580 or I _PPPP -WO0222580, e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S -configuration or in the R-configuration, in the form of a salt with, salicylic acid, azelaic acid, sebacic acid or 2- [(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid..

In another aspect the present invention provides the compound 14-O-[(N-((R)-Valyl)- piperidine-3(S)-yl)-sulfanylacetyl)-mutilin in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid.

A compound of the present invention maybe prepared as appropriate, e.g. according, e.g analogously, to a method as conventional; e.g. a pleuromutilin may be dissolved or suspended in appropriate solvent, preferably organic solvent, e.g. including halogenated hydrocarbons, such as CH ₂ Cl ₂ , an alcohol, such as methanol, ethanol, an ether, such as dimethylether, diisopropylether or tetrahydrofuran, a ketone, such as acetone, and the suspension or solution obtained may be treated with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, e.g. as such, e.g. or dissolved or suspended in a solvent, e.g. in an amount that is at least equivalent to the amount of the pleuromutilin used. From the mixture obtained a compound of the present invention may be isolated as appropriate, e.g.

- from the mixture obtained a solid may precipitate, e.g. in crystalline form, which may be ■ isolated by filtration, centrifugation,

- from the mixture obtained solvent may be evaporated off and the evaporation residue may, be collected,

- the mixture obtained may be subjected to lyophilisation.

A compound of the present invention obtained maybe purified as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. by extraction and/or by chromatography; e.g. before or after isolation

The compounds of the present invention exhibit pharmacological activity and are therefore useful as pharmaceuticals, such as antimcrobials or antibiotics, in the treatment of tuberculosis, in the treatment of Helicobacter infections. Such activity is e.g. described in correspondingly cited literature.

We have found that compounds of the present invention are particularly useful in the treatment of acne. E.g. in commercially available in vitro acne assays (the determination of the minimal inhibitory concentration (MIC) is performed according to the approved NCCLS guidelines ¹ -* by agar dilution technique on Wilkins-Chalgren Agar - 1) National committee for clinical laboratory standards. Methods for Antimicrobial susceptibility testing of anaerobic bacteria. 1993. (NCCLS document M11-A3 3 ^rd edition. Vol. 13, No. 26)

the compound 14-O-[(N-((R)-Valyl)-piperidine-3(S)-yl)-sulfanylacetyl)-mut ilin in the form of a salt with salicylic acid shows remarkably better activity than the compound 14-0-[(N- ((R)-Valyl)-piperidine-3(S)-yl)-sulfanylacetyl)-mutilin in the form of a hydrochloride.

In another aspect the present invention provides a compound of formula

- I _pp - WO0204414, such as a compound of formula I _ppp - WO0204414 or I _pPPp - WO0204414, e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S- configuration or in the R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid,

- I _ss -WO0109095 in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2- [(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid,

- I _sss -WO0109095, such as a compound of formula I _sss -WO0109095, e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S-configuration or in the R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2- [(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid, or

- I _P p-WO0222580, such as a compound of formula I _ppp -WO0222580 or I _pppp -WO0222580, e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S- configuration or in the R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid, such as the compound 14-O-[(N-((R)-Valyl)-piperidine-3(S)-yl)-sulfanylacetyl)-mut ilin in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid, for use in the preparation of a medicament for the treatment of acne.

In another aspect the present invention provides a method of treating acne comprising administering an effective amount of a compound of formula

- I _pp - WO0204414, such as a compound of formula I _ppp - WO0204414 or I _pppp - WO0204414, e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S- confϊguration or in the R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid,

- I _ss -WOO 109095 in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2- [(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid,

- WWOO 109095, such as a compound of formula I _SSS -WO0109095, e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S-configuration or in the

R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2- [(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid, or

- Ipp-WO0222580, such as a compound of formula I _ppp -WO0222580 or Ip _PP p-WO0222580, e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S- configuration or in the R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6-dichlorophenyl)ammo]benzeneacetic acid, preferably salicylic acid, such as the compound 14-O-[(N-((R)-Valyl)-piperidine-3(S)-yl)-sulfanylacetyl)-mut ilin in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid, to a subject in need of such treatment.

hi another aspect the present invention provides a pharmaceutical composition for the treatment of acne comprising a compound of formula

- I _pp - WO0204414, such as a compound of formula I _ppp - WO0204414 or I _pppp - WO0204414,- e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S- configuration or in the R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid,

- I _ss -WO0109095 in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2- [(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid,

- I _sss -WOO 109095, such as a compound of formula I _sss -WO0109095, e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S-configuration or in the R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2- [(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid, or

- I _Pp -WO0222580, such as a compound of formula I _ppp -WO0222580 or I _pppp -WO0222580, e.g. wherein the group attached to the pleuromutilin via the sulphur atom is either in the S- configuration or in the R-configuration, in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid, such as the compound 14-O-[(N-((R)-Valyl)-piperidine-3(S)-yl)-sulfanylacetyl)-mut ilin in the form of a salt with salicylic acid, azelaic acid, sebacic acid or 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid, preferably salicylic acid, in association with at least one pharmaceutical excipient, e.g. appropriate carrier and/or diluent, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers.

For pharmaceutical use a compound of the present invention includes one or more, preferably one, compounds of the present invention, e.g. a combination of two or more compounds of the present invention.

Treatment includes treatment and prophylaxis.

For such treatment, the appropriate dosage will, of course, vary depending upon, for example, the chemical nature and the pharmakokinetic data of a compound of the present invention employed, the individual host, the mode of administration and the nature and severity of the conditions being treated. However, in general, for satisfactory results in larger mammals, for example humans, an indicated daily dosage is in the range from about 0.01 g to about 1.0 g of a compound of the present invention; conveniently administered, for example, in divided doses up to four times a day.

A compound of the present invention maybe administered by any conventional route, for example enterally, e.g. including nasal, buccal, rectal, oral, administration; parenterally, e.g: including intravenous, intramuscular, subcutaneous administration; or topically; e.g. including epicutaneous, intranasal, intratracheal administration; e.g. in form of coated or uncoated tablets, capsules, (injectable) solutions, solid solutions, suspensions, dispersions, solid dispersions; e.g. in the form of ampoules, vials, in the form of creams, gels, pastes, inhaler powder, foams, tinctures, Hp sticks, drops, sprays, or in the form of suppositories.

A compound of the present invention may be used for pharmaceutical treatment according to the present invention alone, or in combination with one or more other pharmaceutically active agents. Such other pharmaceutically active agents include agents which are appropriate for the treatment of inflammation, e.g. including skin inflammation, including agents useful for the treatment of acne.

In another aspect the present invention provides a pharmaceutical composition according to the present invention further comprising another agent which is appropriate in the treatment of skin inflammation, e.g. acne.

Combinations include fixed combinations, in which two or more pharmaceutically active agents are in the same formulation; kits, in which two or more pharmaceutically active agents in separate formulations are sold in the same package, e.g. with instructions for coadministration; and free combinations in which the pharmaceutically active agents are packaged separately, but instructions for simultaneous or sequential administration are given.

Such compositions may be manufactured according, e.g. analogously to a method as conventional, e.g. by mixing, granulating, coating, dissolving or lyophilizing processes. Unit dosage forms may contain, for example, from about 0.5 mg to about 1000 mg, such as 1 mg to about 500 mg.

In the following Examples all temperatures are in degrees Celsius ( ⁰ C) and are uncorrected.

Example 1

14-O-[(N-((R)-Valyl)-piperidine-3(S)-yl)-sulfanylacetyl)- mutilin in the form of a salt with salicylic acid

1.38g (10 mmol) of salicylic acid are added to a stirred cooled (5°) solution of 5.16 g (10 mmol) of 14-O-[(N-((R)-Valyl)-piperidine-3(S)-yl)-sulfanyl-acetyl)-mu tilin in 30 ml of

CH ₂ Cl ₂ . The mixture obtained is stirred for 15 minutes at room temperature and from the mixture obtained solvent is evaporated to dryness under reduced pressure. Amorphous material obtained is dried for further 5 hours at reduced pressure.

14-O-[(N-((R)-Valyl)-piperidine-3(S)-yl)-sulfanylacetyl)- mutilin in the form of a salt with salicylic acid is obtained.

¹ HNMR (DMSOd ₆ , -1:1 mixture of stable rotamers):

7.7-8.3 (b, 3H, NH ₃ ⁺ ), 6.6, 7.1, 7.6 (3 x m, 4H, salicylate), 6.15 (2xdd,

IH, H19, J=17.6Hz, J=I 1.2Hz), 5.6 (2xd, IH, H14, J=8.2Hz), 5.05 (m, 2H, H20),

4.5 (b, IH, H-OH) ₅ 4.08 (dd, 0.5H, H2-Piperidin, J=13.7Hz, J=3.3Hz),

3.08 (dd, 0.5H, H2-Piperidin, J=I 3.7Hz, J=9.8Hz), 3.89 (dd, 0.5H, H2- Piperidin,

J=13.1Hz, J=3.2Hz), 3.41 (m, 0.5H, H2-Piperidin), AB-System: ^V _A =3.44, ^V _B =3.33 (2H,

SCH ₂ ,J=14.9Hz), 2.83, 2.96 (2xm, IH, CHS), 2.4 (b, IH, H4), 1.34 (s, 3H, CH ₃ -15),

1.05 (s, IH, CH ₃ -18), 0.9, 1.0 (2xm, 6H, (CH ₃ ) ₂ -Val), 0.81 (d, 3H, CH ₃ -17, J=6.9Hz), 0.63

(m, 3H, CH ₃ -16).

Example 2

14-O-[(N-((R)-Valyl)-piperidine-3(S)-yl)-sulfanylacetyl)m utilin in the form of a salt with sebacic acid

The salt is prepared analogously to Example 1.

¹ H-NMR (DMSOd ₆ , - 1:1 mixture of stable rotamers):

6.12 (2xdd, IH, H-19, J=17.1 Hz, J=ILl Hz), 5.55 (2xd, IH, H-14, J=8.6 Hz), 5.05 (m, 2H, H-

20), 4.5 (b, IH, 11-OH), 3.98 (m, 1.5H, H-2 piperidine), 3.49 (m,1.5H, H-2 piperidine, α-H

VaI), 3.42 (d, IH, H-I l, J=6Hz), 3.30 (m, 0.5H, H-2 piperidine), 3.27(m, 2H, H-22), 3.10 (2xm,

2xO.5H, H-2 piperidine), 2.86 (m, 1.5H, H-2 piperidine, CH-S), 2.4, (b,lH, H-4), 2.22 - 2.02 (m, 4H, H-2, 10, 13a), 2,14 (t, 4H, α-H sebacate), 1.92-1.98 (m, IH, H-4 piperidine), 1.58-1.72 (m, 4H, β-H VaI, Ia, 8a, H-3 piperidine), 1.42-1.52 (m, 8H, H-6, 7a, H-3 piperidine, H-4 piperidine, β -H sebacate), 1.34 (s, 3H, CH ₃ -15), 1.20-1.32 (m, HH, H-I, 7, 13, γ-H sebacate, δ-H sebacate), 1.05 (s, 3H, CH ₃ -18), 1.00 (m, IH, H-8), 0.87, 0.75 (2xm, 6H, (CH ₃ ) ₂ -Val), 0.80 (d, 3H, CH3-17, J = 6.8 Hz), 0.62 (m, 3H, CH ₃ -16).

Example 3

14-O-[(N-((R)-Valyl)-piperidine-3(S)-yI)-sulfanylacetyl)m «ti]in in the form of a salt with azelaic acid

The salt is prepared analogously to Example 1. ¹ H-NMR (DMSO-d ₆ , - 1:1 mixture of stable rotamers):

6.12 (2xdd, IH, H-19, J=17.1 Hz, J=I Ll Hz), 5.55 (2xd, IH, H-14, J=8.6 Hz), 5.05 (m, 2H, H- 20), 4.5 (b, IH, 11-OH), 3.98 (m, 1.5H, H-2 piperidine), 3.49 (m,1.5H, H-2 piperidine, α-H VaI), 3.42 (d, IH, H-I l, J=6Hz), 3.30 (m, 0.5H, H-2 piperidine), 3.27(m, 2H, H-22), 3.10 (2xm, 2x0.5H, H-2 piperidine), 2.86 (m, 1.5H, H-2 piperidine, CH-S), 2.4, (b,lH, H-4), 2.22 - 2.02 (m, 4H, H-2, 10, 13a), 2,14 (t, 4H, α-H azelate), 1.92-1.98 (m, IH, H-4 piperidine), 1.58-1.72 (m, 4H, β-H VaI, Ia, 8a, H-3 piperidine), 1.42-1.52 (m, 8H, H-6, 7a, H-3 piperidine, H-4 piperidine, β -H azelate), 1.34 (s, 3H, CH ₃ -15), 1.20-1.32 (m, 9H, H-I, 7, 13, γ-H azelate, δ-H azelate), 1.05 (s, 3H, CH ₃ -18), 1.00 (m, IH, H-8), 0.87, 0.75 (2xm, 6H, (CH ₃ ) ₂ -Val), 0.80 (d, 3H, CH ₃ -17, J = 6.8 Hz), 0.62 (m, 3H, CH ₃ -16).