Acremonic Acid Derivatives

Abstract

A compound of formula

Description

EXAMPLE 1

6-O-(2′-fluoroisobutyryl)-24, 25-dihydro-acremonic acid (compound of formula I, wherein R is —COR₁, wherein R₁ is 2-fluoroisopropyl)

A. 3-O-Benzyloxymethyl-acremonic acid P1-benzyloxymethylester (compound of formula IV_P)

9.68 ml of BOM-Cl are added to a solution of 10 g of acremonic acid and 12.2 ml of Hünig's base in 40 ml of anhydrous CH₂Cl₂ at −10°. The reaction mixture obtained is stirred for 15 minutes and allowed to warm up to rt, stirring is continued under argon for 24 hours. H₂O is added to the mixture obtained, the two phases obtained are separated. The organic layer obtained is washed with H₂O, brine and saturated aqueous NaHCO₃-solution, dried and solvent is evaporated. 3-O-Benzyloxymethyl-acremonic acid benzyloxymethylester is obtained.

¹H-NMR (200 MHz, DMSO+D₂O): δ (ppm)=7.32-7.37 (m, 10H, arom.-H), 5.66 (d, J=8.5Hz, H-16), 5.32 (dd, J=6.2Hz, J=16.3Hz, 2H, BOM-CH₂), 5.08 (t, J=6.4Hz, 1H, 24-H), 4.57-4.83 (m, 7H, 6-H, 3×BOM-CH₂), 3.54 (s, 1H, 3-H), 3.34 (s, 1 H, 7-H), 2.00/1.84 (2s, 2×3H, H-34, H-36).

B. 3-O-Benzyloxymethyl-6-deacetyl-acremonic acid benzyloxymethylester (compound of formula V_P)

6.97 ml of 2N NaOH are added at 0° to a solution of 11.38 g of 3-O-benzyloxymethyl-acremonic acid benzyloxymethylester in 75 ml of a mixture of THF/MeOH/H₂O=5/4/1. To the reaction mixture obtained 20 ml of THF are added and the solution obtained is stirred at rt for 16 hours. 1.4 ml of 2N NaOH are added to the mixture obtained and solvent is evaporated. The residue obtained is distributed between H₂O and Et₂O, the mixture obtained is extracted, the organic layer obtained is washed with H₂O and brine, dried and solvent is evaporated. 3-O-Benzyloxymethyl-6-deacetyl-acremonic acid benzyloxymethylester is obtained.

¹H-NMR (200 MHz, DMSO): δ (ppm)=7.26-7.32 (m, 10H, arom.-H), 5.68 (d, J=8.2Hz, H-16), 5.32 (dd, J=6.2Hz, J=18.8Hz, 2H, BOM-CH₂), 5.08 (t, 1H, 24-H), 4.47-4.81 (m, 6H, 3×BOM-CH₂), 3.51 (s, 1H, 3-H), 3.49/3.34 (2s, 1H, 6-H, 7-H), 1.85 (1s, 3H, H-34).

¹³C-NMR (50 MHz, DMSO): δ (ppm)=169.56, 168.57, 149.13, 138.18, 137.10, 131.67, 129.09, 128.21, 128.15, 127.66, 127.50, 127.35, 127.27, 123.0, 92.97, 88.18, 82.84, 78.32, 75.84, 73.75, 71.12, 68.62, 49.05, 47.88, 43.55, 42.48, 36.23, 35.66, 30.02, 28.13, 27.89, 25.96, 25.59, 25.38, 22.86, 22.37, 20.75, 20.37, 18.71, 18.32, 17.43.

C. 3-O-Benzyloxymethyl-6-O-(2′-fluoro-butyryl)-acremonic acid, benzyloxymethylester (compound of formula VI_P, wherein R₁ is 2-fluoroisopropyl)

5.02 g of 2-fluoroisobutyric acid are added to a solution of 22.84 g 3-O-benzyloxymethyl-6-deacetyl-acremocic acid, benzyloxymethylester and 3.97 g of DMAP in anhydrous CH₂Cl₂ under argon at 0°. 9.06 g of EDCl are added and the mixture obtained is stirred at rt overnight. The mixture obtained is concentrated and the concentration residue obtained is distributed between EtOAc and H₂O and extracted. The organic layer obtained is washed with H₂O, brine and saturated, aqueous Na₂CO₃-solution, dried and solvent is evaporated. 3-O-Benzyloxymethyl-6-O-(2′-fluoroisobutyryl)-acremonic acid, benzyloxymethylester is obtained.

¹H-NMR (500 MHz, CDCl₃): δ (ppm)=7.35-7.28 (m, 10H, arom.-H), 5.84 (d, 1H, J=8.6Hz, H-16), 5.41/5.27 (2d, J1=J2=6.1Hz, 2H, BOM-CH₂), 5.10 (dt, J=7.2Hz, J=1.3Hz, 1H, 24-H), 4.85-4.83 (m, 1H, BOM-CH₂), 4.73-4.59 (m, 7H, 6-H, 3×BOM-CH₂), 3.62 (d, J=1.8Hz, 1H, 3-H), 3.44 (d, J=2.6Hz, 1H, 7-H), 1.93 (1s, 3H, 34-H), 1.61 (d, J=3.9Hz, 3a′-CH₃), 1.57 (d, J=3.7Hz, 3b′-CH₃).

¹³C-NMR (125 MHz, CDCl₃): δ (ppm)=172.82 (d, J=25Hz, 1′-C), 170.59, 169.22, 148.65, 138.11, 137.02, 132.52, 130.70, 128.44, 128.41, 127.92, 127.80, 127.73, 127.63, 123.12, 93.51, 92.50 (d, J=181Hz, 2′-C), 88.45, 83.53, 80.32, 78.01, 74.27, 71.96, 69.63, 49.71, 48.49, 43.13, 40.92, 39.94, 39.50, 36.62, 35.77, 31.40, 28.83, 28.32, 26.39, 25.99, 25.70, 24.80 (d, J=24Hz, 3a′-C), 24.68 (d, J=24Hz, 3b′-C), 23.71, 23.66, 21.63, 20.78, 18.16, 17.75, 17.21.

D. 6-O-(2′-fluoroisobutyryl)-24, 25-dihydro-acremonic acid (compound of formula I, wherein R is —COR₁, wherein R₁ is 2-fluoroisopropyl)

20.99 g of 3-O-benzyloxymethyl-6-O-(2′-fluoroisobutyryl)-acremonic acid, benzyloxymethylester are hydrogenated at 1 atm in the presence of Pd(OH)₂/C in 235 ml of a mixture of EtOAc/MeOH=10/1 overnight, the mixture obtained is filtered and solvent is evaporated.

6-O-(2′-fluoroisobutyryl)-24, 25-dihydro-acremonic acid is obtained.

The solid can be recrystallized from cyclohexane/EtOAc: mp=157-160° C.

EXAMPLE 2

3-O-Benzyloxymethyl-6-O-pivaloyl-acremonic acid benzyloxymethylester (compound of formula VI_P, wherein R₁ is t.butyl)

1.31 ml of pivaloyl chloride are added at rt to a solution of 5.504 g of 3-O-benzyloxymethyl-6-deacetyl-acremonic acid benzyloxymethylester and 1.13 g of DMAP in anhydrous pyridine under argon. The mixture obtained is stirred under argon at 500 for 20 hours, poured over ice and extracted with EtOAc. The organic layer obtained is washed with H₂O and brine, dried, and solvent is evaporated.

3-O-Benzyloxymethyl-6-O-pivaloyl-acremonic acid benzyloxymethylester is obtained. Splitting off the benzyloxymethyl protecting group and hydrogenation of the double bond is carried out analogously to Example 1, step D.

Analogously to the methods as described in examples 1 and 2, but using appropriate starting materials, compounds of formula I, wherein R is as defined in TABLE 1 below, are obtained. ¹H-NMR data (in DMSO, if not otherwise indicated) of the compounds are also set out in TABLE 1.

TABLE 1
EX	R	1H-NMR
1		5.82 (d, 1H, J=8.7 Hz, 16-H), 4.63 (d, 1H, J=10.6 Hz, 6-H, 3.71(s, 1H, 3-H), 3.43 (s, 1H, 7-H), 1.94 (1s, 3H, 34-H), 1.60 (d, J=4.7 Hz, 3a′-CH3), 1.55 (d, J=4.6 Hz, 3b′-CH3)
2		5.61 (d, J=8.1 Hz, 1H, 16-H), 4.60 (d, J=9.7 Hz, 1H, 6-H),3.47 (s, 1H, 3-H), 3.19 (s, 1H, 7-H), 1.88 (s, 3H, 34-CH3),1.13 (s, 9H, 3 × 3′-CH3)
3		5.62 (d, J=8.2 Hz, 1H, 16-H), 4.63 (dd, J=9.7 Hz, J=2.0 Hz,1H, 6-H), 3.47 (s, 1H, 3-H), 3.19 (d, J=2.0 Hz, 1H, 7-H),1.89 (s, 3H, 34-CH3), 1.21-2.44 (m, 2′-H, 3′-CH2, 4′-CH2)
4		5.64 (d, J=7.9 Hz, 1H, 16-H), 4.65 (d, J=10.2 Hz, J=2.0 Hz, 6-H), 3.48 (s, 1H, 3-H), 3.10 (s, 1H, 7-H), 1.92-2.56 (m,9H, cont. 2′-CH2), 1.89 (s, 3H, 34-CH3), 1.03 (d, J=7.0 Hz,3 H, 3′-CH3)
5		5.59 (d, J=8.3 Hz, 1H, 16-H), 4.60 (d, J=9.9 Hz, 1H, 6-H),3.47 (s, 1H, 3-H), 3.30 (s, 1H, 7-H), 1.92-2.56 (m, 9H,cont. 2′-CH2), 1.89 (s, 3H, 34-CH3), 0.77-1.80 (m, cont.3′-CH2, 4′-CH3)
6		5.57 (d, J=8.3 Hz, 1H, 16-H), 4.65 (dd, J=7.9 Hz, J=2.5 Hz,1H, 6-H), 3.93 (dd, J=17.1, J=28.5, 2H, 2′-CH2), 3.45 (s,1H, 3-H), 3.32 (d, J=2.5 Hz, 1H, 7-H)
7		5.60 (d, J=8.2 Hz, 1H, 16-H), 4.60 (d, J=10.0 Hz, 1H, 6-H), 3.48 (s, 1H, 3-H), 3.31 (s, 1H, 7-H), 1.92-2.56 (m,9H, cont. 2′-CH2), 1.89 (s, 3H, 34-CH3), 0.76-1.80 (m,cont. 3′-CH2, 4′-CH2, 5′-CH2, 6′-CH2, 7′-CH3)
8		5.62 (d, J=6.8 Hz, 1H, 16-H), 4.70 (d, J=9.9 Hz, 1H, 6-H),3.84-4.20 (m, 2H, 2′-CH2), 3.32-3.44 (m, 5H, 3-H, 7-H,—OCH3)
9		5.62 (d, 1H, 16-H), 4.62 (d, 1H, 6-H), 3.45 (s, 1H, 3-H),3.33 (s, 1H, 7-H), 1.92-2.56 (m, 9H, cont. 2′-CH2), 1.88(s, 3H, 34-CH3), 0.76-1.80 (m, cont. 3′-CH2, 4′-CH2, 5′-CH3)
10		5.61 (d, 1H, J=8.2 Hz, 16-H), 4.61 (d, J=9.3 Hz, 1H, 6-H),3.48 (s, 1H, 3-H), 3.31 (s, 1H, 7-H), 1.92-2.56 (m, 9H,cont. 2′-CH2), 1.87 (s, 3H, 34-CH3), 0.76-1.80 (m, cont.3′-CH2, 4′-CH2, 5′-CH2, 6′-CH3)
11		5.61 (d, J=8.3 Hz, 16-H), 4.63 (d, J=10.1 Hz, 1H, 6-H), 3.53-3.59 (m, 2H, 2′-CH2), 3.47 (s, 1H, 3-H), 3.32 (s,1H, 7-H), 3.22 (s, 3H, —OCH3)
12		8.21 (s, 1H, 1′-H), 5.62 (d, J=7.9 Hz, 1H, 16-H), 4.66 (dd,1H, 6-H), 3.48 (s, 1H, 3-H), 3.38 (d, J=2.8 Hz, 1H, 7-H),1.89 (s, 3H, 34-CH3)
13		8.28 (dd, J=5.8 Hz, 1H, NH), 5.60 (d, J=8.1 Hz, 1H, 16-H),4.64 (dd, J=8.3 Hz, J=2.4 Hz, 1H, 6-H), 3.60 (dd, J=5.8 Hz,2′-CH2), 3.47 (s, 1H, 3-H), 3.34 (d, J=2.4 Hz, 1H, 7-H),1.85/1.87 (2s, 2 × 3H, 34-CH3, 4′-CH3)
14		5.61 (d, J=7.7 Hz, 1H, 16-H), 4.60 (d, J=9.8 Hz, 1H, 6-H),3.47 (s, 1H, 3-H), 3.25 (s, 1H, 7-H), 2.48-2.84 (m, 2′-H),1.88 (s, 3H, 34-CH3), 1.00-2.45 (m, 3′-CH2, 4′-CH2, 5′-CH2, 6′-CH2)
15		5.61 (d, J=8.3 Hz, 1H, 16-H), 4.61 (d, J=10.0 Hz, 1H, 6-H),3.46 (s, 1H, 3-H), 3.27 (s, 1H, 7-H), 3.09 (quin, J=8.3 Hz,2′-H)
16		5.64 (d, J=8.33 Hz, 1H, 16-H), 4.63 (d, J=10.0 Hz, 1H, 6-H), 3.48 (s, 1H, 3-H), 3.35 (s, 1H, 7-H), 1.95-2.50 (m,cont. 2′-CH2, 3′-H), 1.90 (s, 3H, 34-CH3),0.96/0.95/0.93/0.92 (4s, 4 × 4′-CH3).
17		5.61 (d, J=8.3 Hz, 1H, 16-H), 4.67 (d, 1H, 6-H), 3.47 (s,1H, 3-H), 3.09-3.40 (m, 5H, 7-H, 2′-CH2, NH2)
18		5.60 (d, J=8.5 Hz, 1H, 16-H), 4.60 (d, J=10.0 Hz, 1H, 6-H), 3.49 (s, 1H, 3-H), 3.32 (s, 1H, 7-H), 1.87 (s, 3H, 34-CH3), 1.12/1.00 (2s, 2 × 3H, 4′-CH3)
19		5.61 (d, J=7.9 Hz, 1H, 16-H), 4.60 (d, J=10.3 Hz, 1H, 6-H), 3.49 (s, 1H, 3-H), 3.35 (s, 1H, 7-H), 1.89 (s, 3H, 34-CH3), 1.00 (s, 9H, 4′-CH3)
20		5.63 (d, J=8.3 Hz, 1H, 16-H), 4.59 (d, J=9.9 Hz, 1H, 6-H),3.47 (s, 1H, 3-H), 3.24 (s, 1H, 7-H), 0.99-2.35 (m, cont.2′-H, 3′-CH2, 4′-CH2, 5′-CH2, 6′-CH2, 7′-CH2)
21		5.64 (d, J=8.3 Hz, 1H, 16-H), 4.72 (d, J=8.8 Hz, 1H, 6-H),3.90-4.18 (m, 2H, 2′-CH2), 3.36-3.57 (m, 4H, 3-H, 7-H,4′-CH2)
22		5.61 (m, 1H, 16-H), 4.6-4.7 (m, 1H, 6-H), 4.19-4.35 (m,1H, H-2′), 3.80 (m, 2H, 4′-CH2), 3.34-3.45 (m, 2H, 3-H, 7-H)
23		5.62 (d, J=7.5 Hz, 1H, 16-H), 4.65 (d, J=9.5 Hz, 6-H),3.03-3.93 (m, 3′-CH2, 5′-CH2, 3-H, 7-H)
24		5.61 (d, J=8.3 Hz, 1H, 16-H), 4.60 (d, J=11.2 Hz, 6-H),3.47 (s, 1H, 3-H), 3.28 (s, 1H, 7-H), 1.04 (s, 3H, —CH3(3′-C))
25		5.64 (d, J=8.3 Hz, 1H, 16-H), 4.72 (d, J=8.9 Hz, 1H, 6-H),4.09 (dd, 2H, 2′-CH2), 3.60-3.64/3.46-3.50 (2m, 5H, 4′-CH2, 5′-CH2, 3-H), 3.37 (s, 1H, 7-H), 3.27 (s, 3H, —OCH3)
26		5.84 (d, J=8.7 Hz, 1H, 16-H), 4.77 (d, J=10.5 Hz, 6-H),4.10 (sept., 1H, 2′-H), 3.74 (s, 1H, 3-H), 3.50 (s, 1H, 7-H)
27		5.58 (d, J=8.3 Hz, 1H, 16-H), 4.57 (d, J=10.1 Hz, 6-H),3.57 (s, 3H, —OCH3), 3.45 (s, 1H, 3-H), 3.29 (s, 1H, 7-H).
28		5.61 (d, J=8.1 Hz, 1H, 16-H), 4.60 (d, J=9.8 Hz, 1H, 6-H),3.10-3.48 (m, 6H, 5′-H, OCH3, 3-H, 7-H)
29		5.61 (d, J=8.0 Hz, 1H, 16-H), 4.61 (d, J=10.0 Hz, 6-H), 3.49 (s, 1H, 3-H), 3.05-3.30 (m, 5H, 4′-H, OCH3, 7-H)
30		5.62 (d, J=8.2 Hz, 1H, 16-H), 4.59 (d, J=9.7 Hz, 1H, 6-H),3.45 (s, 1H, 3-H), 3.17 (d, 1H, 7-H), 1.40-2.45 (m, cont.adamantyl —CH and CH2)
31		5.63 (d, 1H, 16-H), 4.60 (d, J=10.1 Hz, 1H, 6-H), 3.46 (s,1H, 3-H), 3.26 (s, 1H, 7-H), 1.87 (s, 3H, 34-CH3), 1.00-1.24 (m, cont. 12H, 2 × CH3(C-2′), 4′-CH3)
32		5.63 (d, J=8.2 Hz, 1H, 16-H), 4.56 (d, J=10.2 Hz, 6-H),3.45 (s, 1H, 3-H), 3.29 (s, 1H, 7-H), 1.15 (s, 12H, 4 ×—CH3(3′-C))
33		5.63 (d, J=8.2 Hz, 1H, 16-H), 4.60 (d, J=10.0 Hz, 6-H),3.45 (s, 1H, 3-H), 3.24 (s, 1H, 7-H), 0.70-1.80 (m, 39H,cont. —CH3(2′-C), 3′-CH2, 4′-CH2)
34		5.62 (d, J=8.2 Hz, 1H, 16-H), 4.63 (d, J=9.8 Hz, 1H, 6-H),3.73 (dd, J=10.7 Hz, J=15.9 Hz, 2H, —CH2Cl), 3.47 (s, 1H,3-H), 3.35 (d, 1H, 7-H), 1.87 (s, 3H, 34-CH3), 1.20 (s, 6H,2 × CH3(C-2′)
35		5.63 (d, J=8.4 Hz, 1H, 16-H), 4.66 (d, J=10.0 Hz, 1H, 6-H), 3.46 (s, 1H, 3-H), 3.26 (d, 1H, 7-H), 3.16 (s, 3H,OCH3), 1.87 (s, 3H, 34-CH3), 1.31 (s, 6H, 2 × CH3(C-2′)
36		5.62 (d, J=8.1 Hz, 1H, 16-H), 4.65 (d, J=9.9 Hz, 1H, 6-H),3.17-3.55 (m, 4H, 3-H, 7-H, —OCH2), 1.87 (s, 3H, 34-CH3), 1.32 (s, 6H, 2 × CH3(C-2′)
37		7.28-7.38 (m, 3H, arom.H), 6.93 (d, 1H, arom.H), 5.76(d, J=8.6 Hz, 1H, 16-H), 4.79 (d, J=11.2 Hz, 1H, 6-H),3.70 (s, 1H, 3-H), 3.61 (d, 1H, 7-H), 2.98 (s, 6H,—N(CH3)2)
38		5.77 (d, J=8.4 Hz, 1H, 16-H), 4.51 (d, J=10.5 Hz, 1H, 6-H), 3.60-3.74 (m, 2H, 3-H, —OCH(CH3)2), 3.34 (s, 1H, 7-H), 1.88 (s, 3H, 34-CH3), 1.00-1.50 (m, cont., 2 × CH3(C-2′), —OCH(CH3)2)
39		7.82 (d, J=8.9 Hz, 2H, arom.H), 6.57 (d, J=8.9 Hz, 2H,arom.H), 5.71 (d, J=8.4 Hz, 1H, 16-H), 4.67 (d, J=10.5 Hz,1H, 6-H), 3.63 (s, 1H, 3-H), 3.52 (d, 1H, 7-H), 2.96 (s,6H, —N(CH3)2)
40		5.81 (d, H=8.3 Hz, 1H, 16-H), 4.62 (d, J=10.4 Hz, 1H, 6-H), 3.69 (s, 1H, 3-H), 3.25-3.45 (m, 5H, 7-H, —OCH3),1.92 (s, 3H, 34-CH3), 1.16 (s, 6H, 2 × CH3(C-2′)
41		5.86 (d, 1H, 16-H), 4.74 (d, J=9.1 Hz, 1H, 6-H), 3.32-3.79(m, 4H, 3-H, 7-H, 2′-CH2)
42		5.82 (d, J=8.4 Hz, 1H, 16-H), 4.58 (d, J=10.8 Hz, 1H, 6-H), 4.50/4.26 (ddd, J=8.8 Hz, H=13.2 Hz, J=47.1 Hz, 2H,—CH2F), 3.70 (s, 1H, 3-H), 3.38 (s, 1H, 7-H), 1.93 (s, 3H,34-CH3), 1.15-1.21 (m, cont.6H, 2 × CH3(C-2′)
43		5.82 (d, J=8.7 Hz, 1H, 16-H), 4.53 (d, J=10.6 Hz, 1H, 6-H), 3.71 (d, J=2.1 Hz, 1H, 3-H), 3.40 (s, 1H, 7-H), 2.49-2.56 (m, 3H, 13-H, 2′-H, 22a-H), 2.09-2.35 (m, 5H, 22b-H, 5-H, 8-H, 12a-H, 15a-H), 1.94 (s, 3H, 34-CH3), 1.82-1.89 (m, 3H, 4-H, 2a-H, 11a-H), 1.67-1.72 (m, 3H, 1a-H,12b-H, 2b-H), 1.35-1.53 (m, 6H, 25-H, 11b-H, 23-CH2,15b-H, 1b-H), 1.14-1.19 (m, 14H, 19-CH3, 2 × 3′-CH3, 30-CH3, 24-CH2), 1.03 (s, 3H, 18-CH3), 0.89 (d, J=6.9 Hz,3H, 28-CH3), 8.86 (d, J=6.9 Hz, 6H, 26-CH3, 27-CH3)
44		5.82 (d, J=8.6 Hz, 1H, 16-H), 4.70 (d, J=10.5 Hz, 1H, 6-H), 3.70 (s, 1H, 3-H), 3.48 (s, 1H, 7-H), 1.94 (s, 3H, 34-CH3), 1.57-1.28 (m, cont. 4H, 2 × CH2(cyclopropyl)).
45		5.83 (d, J=8.6 Hz, 1H, 16-H), 4.65-4.58 (m, 1H, 6-H),3.71 (s, 1H, 3-H), 3.56/3.49 (2s, 1H, 7-H), 2.62-2.27 (m,cont. CH(cyclopropyl)), 2.26-2.07/1.95-1.62 (2 m, cont.CH2(cyclopropyl)).
46		5.80 (d, J=8.7 Hz, 1H, 16-H), 4.63 (d, J=10.7 Hz, 1H, 6-H), 3.73 (s, 1H, 3-H), 3.51 (s, 1H, 7-H), 2.61-2.38 (m,cont. CH(cyclopropyl)), 2.38-2.22/2.00-1.63 (2 m, cont.CH2(cyclopropyl)).
47		5.83 (d, J=8.7 Hz, 1H, 16-H), 4.63 (d, J=10.9 Hz, 1H, 6-H), 3.71 (s, 1H, 3-H), 3.48 (s, 1H, 7-H), 2.51-2.38 (m,cont. 2′-H), 2.09-1.97 (m, 1 H, CHH(cyclopropyl)), 1.96-1.63 (m, cont. CHH(cyclopropyl)).
48		5.80 (d, J=8.7 Hz, 1H, 16-H), 4.63 (d, J=10.7 Hz, 1H, 6-H), 3.71 (s, 1H, 3-H), 3.50 (s, 1H, 7-H), 2.50-2.39 (m,cont. 2′-H), 2.20-2.00 (m, cont. CHH(cyclopropyl)), 1.86-1.75 (m, cont. CHH(cyclopropyl)).
49		5.85-5.82 (m, 1H, 16-H), 4.57-4.53 (m, 1H, 6-H), 3.71 (s,1H, 3-H), 3.46/3.41 (2 s, 2 × 1H, 7-H), 2.82 (m, cont.—OCOCH(CH3)CHHCF3), 2.49-2.05 (m, cont.—OCOCH(CH3)CHHCF3), 1.32-1.23 (m, cont.—OCOCH(CH3)CHHCF3).

The compounds of examples 2, 30, 31 and 34 in TABLE 1 are obtained analogously as described on Example 2, but using appropriate starting materials; all other compounds of TABLE 1 are obtained analogously as described in Example 1, but using appropriate starting materials. The compounds of examples 1, 2, 34, 42 and 43 are also obtained in the form of a sodium salt.

EXAMPLE 50

6-O-Methyl-24, 25-dihydro-acremonic acid (compound of formula I_P, wherein R is methyl)

A. 3-O-Benzyloxymethyl-6-O-methyl-24, 25-dihydro-acremonic acid diphenylmethylester

0.67 ml of LiHMDS (1M in THF) are added to a solution of 500 mg of 3-O-Benzyloxymethyl-6-deacetyl-acremonic acid diphenylmethylester (which may be obtained according to a method as described in reaction A in example 1 but using appropriate starting materials) in 5 ml of dry N,N-dimethylformamide at −10° and to the mixture obtained 0.06 ml of CH₃I are added after 10 minutes. The mixture obtained is stirred at rt for 2 hours and poured onto ice. The mixture obtained is extracted 3 times with EtOAc. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography. 3-O-Benzyloxymethyl-6-O-methyl-acremonic acid diphenylmethylester is obtained.

B. 6-O-Methyl-24, 25-dihydro-acremonic acid

241 mg of 3-O-benzyloxymethyl-6-O-methyl-acremonic acid diphenylmethylester are hydrogenated at 1 atm in the presence of Pd(OH)₂/C in 3 ml of EtOAc overnight, the mixture obtained is filtered, solvent is evaporated and the evaporation residue is subjected to chromatography. 6-O-methyl-24, 25-dihydro-acremonic acid is obtained.

Analogously as described in Example 50, but using appropriate starting materials, compounds of formula I, wherein R is as defined in TABLE 2 below, are obtained. ¹H-NMR data (in DMSO, if not otherwise indicated) of the compounds are also set out in TABLE 2.

TABLE 2
EX	R	1H-NMR
50		5.65 (d, J=8.3 Hz, 1H, 16-H), 3.34-3.53 (m, 2H, 3-H, 7-H),3.19 (s, 3H, —OCH3), 2.80 (d, 1H, J=9.6 Hz, 6-H)
51		5.66 (d, 1H, 16-H), 3.21-3.65 (m, 4H, —OCH2, 3-H, 7-H),2.91 (d, 1H, 6-H)
52		5.64 (d, J=8.3 Hz, 1H, 16-H), 3.14-3.53 (m, 4H, —OCH2, 3-H, 7-H), 2.88 (d, J=9.5 Hz, 1H, 6-H)
53		5.54 (d, J=8.4 Hz, 1H, 16-H), 3.08-3.40 (m, 4H, —OCH2, 3-H, 7-H), 2.76 (d, J=9.2 Hz, 1H, 6-H)

In TABLE 3 below there are listed mass spectroscopy data of intermediates of formula

wherein R₁ is as defined in TABLE 3, useful in the production of a compound of formula I_P. The numbers in column “EX”, marked with an apostroph (e.g. 1′), are intermediates used in the production of a the corresponding compound of formula I_P in TABLE 1. E.g. the intermediate “1′” in TABLE 3 is the intermediate used in the production of the compound of Example 1 in TABLE 1. Mass spectroscopy data (m/z (ESI)), also set out in TABLE 3, are determined by a Finnigan Navigator ThermoQuest LC/MS system.

TABLE 3
EX	Prot2	R1	Prot1	m/z (ESI)
1′	BOM		BOM	[M + Na]+ = 883.4
2′	BOM		BOM	[M + Na]+ = 879.5
3′	BOM		DPM	[M + Na]+ = 909.4
4′	H		DPM	[M + Na]+ = 777.3
5′	H		DPM	[M + Cl]− = 803.4
6′	BOM		DPM	[M]+ = 989.4
7′	BOM		DPM	[M + Na]+ = 953.5
8′	BOM		DPM	[M + Na]+ = 914.1
9′	BOM		DPM	[M + Na]+ = 925.0
10′	BOM		DPM	[M + Na]+ = 939.2
11′	BOM		DPM	[M + Na]+ = 926.9
12′	BOM	hydrogen	DPM	[M + Na]+ = 869.0
13′	BOM		DPM	[M + Cl]− = 951.9
14′	BOM		DPM	[M + Na]+ = 937.0
15′	BOM		DPM	[M + Na]+ = 923.0
16′	BOM		DPM	[M + Na]+ = 925.0
17′	BOM		DPM	[M + Na]+ = 1031.8
18′	BOM		DPM	[M + Na]+ = 938.8
19′	BOM		DPM	[M + Na]+ = 939.0
20′	BOM		DPM	[M + Na]+ = 951.0
21′	BOM		DPM	[M + Na]+ = 927.1
22′	BOM		DPM	[M + Na]+ = 939.3
23′	BOM		DPM	[M + Na]+ = 939.3
24′	BOM		DPM	[M + Na]+ = 923.2
25′	BOM		BOM	[M + Na]+ = 911.5
26′	BOM		BOM	[M]+ = 950.4
27′	BOM		BOM	[M + Na]+ = 909.2
28′	BOM		BOM	[M + Na]+ = 935.5
29′	BOM		BOM	[M + Na]+ = 935.5
30′	BOM		BOM	[M + Na]+ = 957.6
31′	BOM		BOM	[M + Na]+ = 894.0
32′	BOM		BOM	[M + Na]+ = 919.0
33′	BOM		BOM	[M + Na]+ = 877.4
34′	BOM		BOM	[M + Na]+ = 913.4
35′	BOM		BOM	[M + Na]+ = 895.4
36′	BOM		BOM	[M + Na]+ = 921.6
37′	BOM		BOM	[M + Na]+ = 942.5
38′	BOM		BOM	[M + Na]+ = 923.7
39′	BOM		BOM	[M + Na]+ = 942.5
40′	BOM		BOM	[M + Na]+ = 909.5
41′	BOM		BOM	[M + Na]+ = 972.2
42′	BOM		BOM	[M + Na]+ = 897.8
43′	BOM		BOM	[M + Na]+ = 865.5
44′	BOM		BOM	[M + Na]+ = 931.5
45′	BOM		BOM	[M + Na]+ = 915
46′	BOM		BOM	[M + Na]+ = 915
47′	BOM		BOM	[M + Na]+ = 899.5
48′	BOM		BOM	[M + Na]+ = 899.5
49′	BOM		BOM	[M + Na]+ = 933.4

In TABLE 4 below there are listed mass spectroscopy data of intermediates of formula

wherein R″ is as defined in TABLE 4, useful in the production of a compound of formula I_P. The numbers in column “EX”, marked with an apostroph (e.g. 50′), are intermediates used in the production of a the corresponding compound of formula I_P in TABLE 2. E.g. the intermediate “50′” in TABLE 4 is the intermediate used in the production of the compound of Example 50 in TABLE 2. Mass spectroscopy data (m/z (ESI)), also set out in TABLE 4, are determined by a Finnigan Navigator ThermoQuest LC/MS system.

	TABLE 4
	EX	Prot2	R″	Prot1	m/z (ESI)
	50′	BOM	methyl	DPM	[M + Na]+ = 855.1
	51′	BOM	ethyl	DPM	[M + Na]+ = 869.4
	52′	BOM	n-propyl	DPM	[M + Na]+ = 883.3
	53′	BOM	n-hexyl	DPM	[M + Na]+ = 925.5

Claims

1. 2-(16-Acetoxy-3,7-dihydroxy-4,8,10,14-tetramethyl-6-[hydroxy, (C1-22)alkoxy or carbonyloxy]-hexadecahydro-cyclopenta[a]phenanthren-17-ylidene)-6-methyl-heptanoic acids.

2. A The compound of the formula

3. A compound of claim 2, wherein R is hydrogen, (C1-6)alkyl, or CO—R1, and R1 is hydrogen, (C1-6)alkyl, (C3-6)cycloalkyl, (C1-3)alkoxy-(C1-3)alkyl, methoxy-(C1-2)alkoxy-(C1-2)alkyl, aminomethyl, halo(C1-4)alkyl comprising one or two halogen atoms, hydroxymethyl, hydroxycarbonylmethyl, methoxycarbonyl-(C1-2)alkyl, phenyl, tetrahydrofuranyl or adamantanyl.

4. A compound of claim 2, wherein R is a group of formula

5. The compound of claim 2 in the form of a salt.

6. (canceled)

7. (canceled)

8. A pharmaceutical composition comprising a compound of claim 2 in association with at least one pharmaceutical excipient.

9. The pharmaceutical composition according to claim 8, further comprising another pharmaceutically active agent.

10. A method of treating microbial diseases, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 2.

11. A compound of formula

12. A compound of formula

13. A compound of formula