U.S. patent application number 11/141060 was filed with the patent office on 2005-10-13 for verification of translation.
Invention is credited to Fahnrich, Marianne, Haberey, Martin, Kirsch, Gerald, Langer, Gernot, Neef, Gunter, Schwarz, Katica, Steinmeyer, Andreas, Wiesinger, Herbert.
Application Number | 20050227951 11/141060 |
Document ID | / |
Family ID | 7844754 |
Filed Date | 2005-10-13 |
United States Patent
Application |
20050227951 |
Kind Code |
A1 |
Steinmeyer, Andreas ; et
al. |
October 13, 2005 |
Verification of translation
Abstract
The invention relates to new vitamin D derivatives of general
formula (I), process for their production, intermediate products of
the process as well as the use for production of pharmaceutical
agents.
Inventors: |
Steinmeyer, Andreas;
(Berlin, DE) ; Neef, Gunter; (Berlin, DE) ;
Kirsch, Gerald; (Berlin, DE) ; Schwarz, Katica;
(Berlin, DE) ; Wiesinger, Herbert; (Berlin,
DE) ; Haberey, Martin; (Berlin, DE) ;
Fahnrich, Marianne; (Berlin, DE) ; Langer,
Gernot; (Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
7844754 |
Appl. No.: |
11/141060 |
Filed: |
June 1, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11141060 |
Jun 1, 2005 |
|
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09509934 |
May 3, 2000 |
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09509934 |
May 3, 2000 |
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PCT/EP98/06159 |
Sep 29, 1998 |
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Current U.S.
Class: |
514/167 ;
552/653 |
Current CPC
Class: |
A61P 17/06 20180101;
A61K 31/59 20130101; A61P 11/06 20180101; A61P 3/14 20180101; A61K
31/59 20130101; A61P 9/10 20180101; A61P 17/08 20180101; A61P 19/08
20180101; A61P 35/00 20180101; A61K 39/395 20130101; A61P 17/04
20180101; A61K 39/395 20130101; A61P 3/10 20180101; A61P 17/14
20180101; A61P 29/00 20180101; A61K 39/395 20130101; A61P 17/00
20180101; A61P 3/02 20180101; A61K 31/59 20130101; A61P 5/50
20180101; A61P 19/02 20180101; A61P 37/02 20180101; A61K 38/13
20130101; A61P 15/16 20180101; A61P 19/00 20180101; A61P 37/00
20180101; A61P 37/04 20180101; A61P 37/06 20180101; A61K 38/13
20130101; A61P 15/18 20180101; C07C 401/00 20130101; A61P 25/28
20180101; A61K 38/13 20130101; A61P 19/10 20180101; A61K 31/59
20130101; A61K 2300/00 20130101; A61K 31/435 20130101; A61K 2300/00
20130101; A61K 31/59 20130101; A61K 31/445 20130101; A61K 2300/00
20130101; A61K 31/59 20130101 |
Class at
Publication: |
514/167 ;
552/653 |
International
Class: |
A61K 031/59; C07C
401/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 1, 1997 |
DE |
197 44 127.0 |
Claims
1. Vitamin D derivatives of general formula I, 30in which Y.sub.1
means a hydrogen atom, a hydroxyl group, a fluorine, chlorine or
bromine atom or a group --OCOR.sub.8, in which R.sub.8 is an
aliphatic or aromatic radical with 1 to 12 C atoms, Y.sub.2 means a
hydrogen atom or a group --(CO)R.sub.9, in which R.sub.9 is an
aliphatic or aromatic radical with 1 to 12 C atoms, R.sub.1 and
R.sub.2 each mean a hydrogen atom or together an exocyclic
methylene group, R.sub.3 and R.sub.4, independently of one another,
mean a hydrogen atom, a chlorine or fluorine atom, an alkyl group
with 1 to 4 carbon atoms, together a methylene group or together
with quaternary carbon atom 20 a 3- to 7-membered, saturated or
unsaturated carbocyclic ring, V and W together mean an E-double
bond or V means a hydroxyl group and W means a hydrogen atom, Q
means a straight-chain or branched carbon unit with up to 10 carbon
atoms, which at any positions can have .alpha.- or .beta.-hydroxyl
groups, which in turn can be etherified or esterified, keto groups,
amino groups or halogen atoms, Z means a straight-chain or
branched-chain, saturated or unsaturated hydrocarbon radical with
up to 12 carbon atoms, which at any positions can have keto groups,
.alpha.- or .beta.-hydroxyl groups, which in turn can be etherified
or esterified, amino groups, fluorine, chlorine, or bromine
atoms.
2. Vitamin D derivatives of general formula I according to claim 1,
in which Q means an unsubstituted, unbranched alkylene unit with 1
or 2 carbon atoms, and Z means a straight-chain 1-oxoalkyl
radical.
3. Vitamin D derivatives of general formula I according to claim 1,
in which Q means a --CH(OH)--CH.sub.2--CH.sub.2 radical, and Z
means a straight-chain 1-oxoalkyl radical.
4. Vitamin D derivatives of general formula I according to claim 1,
in which Q means a hydroxymethyl group and Z means a
straight-chain, saturated or unsaturated alkyl group.
5. Vitamin D derivatives of general formula I according to claim 1,
namely
(5Z,7E,22E)-(1S,3R)-25-Acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-
-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxopropyl)-26,27-cyclo-9,10--
secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-ox-
obutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10-
(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxohexyl)-26,27-cyclo-
-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10-
(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxooctyl)-26,27-cyclo-
-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(-
19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxodecyl)-26,27-cyclo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E)-(1S,3R,22S)-25--
acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-tr-
iene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxopropyl)-26,27-cyclo-9,10-s-
ecocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxop-
ropyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(-
19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxobutyl)-26,27-cyclo-9-
,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-
-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10-
(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxohexyl)-26,27-cyclo--
9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(-
1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10-
(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxoheptyl)-26,27-cyclo-
-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25--
(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(-
19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxononyl)-26,27-cyclo-9-
,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-
-oxononyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxodecyl)-26,27-cyclo-9,10-secocholesta-5,7,10(-
19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxodecyl)-26,27-cyclo-9-
,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E,22E)-(1S,3R)-25-ac-
etyl-26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-dio-
l,
(5Z,7E,22E)-(1S,3R)-25-(1-oxopropyl)-26,27-cyclo-24a-homo-9,10-secochol-
esta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxobutyl)--
26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxopentyl)-26,27-cyclo-24a-homo-9,10-secocholes-
ta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxohexyl)-26-
,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxoheptyl)-26,27-cyclo-24a-homo-9,10-secocholes-
ta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxooctyl)-26-
,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxononyl)-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R)-25-(1-oxodecyl)-26,-
27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E)-(1S,3R,22S)-25-acetyl-26,27-cyclo-24a-homo-9,10-secocholesta-5,7,-
10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-acetyl-26,27-cyclo-24a--
homo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxopropyl)-26,27-cyclo-24a-homo-9,10-secocholes-
ta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxopropyl)-26-
,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxobutyl)-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxobutyl)-26,2-
7-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxopentyl)-26,27-cyclo-24a-homo-9,10-secocholes-
ta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxopentyl)-26-
,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxohexyl)-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxohexyl)-26,2-
7-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxoheptyl)-26,27-cyclo-24a-homo-9,10-secocholes-
ta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxoheptyl)-26-
,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxooctyl)-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxooctyl)-26,2-
7-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxononyl)-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxononyl)-26,2-
7-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22S)-25-(1-oxodecyl)-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E)-(1S,3R,22R)-25-(1-oxodecyl)-26,2-
7-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-triene-1,3,22-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-26,27-cyclo-24a,24b-dihomo-9,10-secocho-
lesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-acet-
yl-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-
,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxopropyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopropyl)-26,27-cyclo-24a,24b-dihomo-9,10--
secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)--
25-(1-oxobutyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-
-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxobutyl)-26,27-cycl-
o-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxopentyl)-26,27-cyclo-24a,24b-dihomo-9,10--
secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)--
25-(1-oxopentyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),2-
2-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxohexyl)-26,27-cyc-
lo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxohexyl)-26,27-cyclo-24a,24b-dihomo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(S,3R,24R)-25-
-(1-oxoheptyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22--
tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxoheptyl)-26,27-cycl-
o-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxooctyl)-26,27-cyclo-24a,24b-dihomo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-2-
5-(1-oxooctyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22--
tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxononyl)-26,27-cyclo-
-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxononyl)-26,27-cyclo-24a,24b-dihomo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-2-
5-(1-oxodecyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22--
tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxodecyl)-26,27-cyclo-
-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-24-methoxy-26,27-cyclo-24a,24b-dihomo-9-
,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24S)--
25-acetyl-24-methoxy-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(1-
9),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxopropy-
l)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-
-diol,
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxopropyl)-26,27-cyclo-24a-
,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxobutyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxobutyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxopentyl)-26,27-cyclo-24a,24b-d-
ihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxopentyl)-26,27-cyclo-24a,24b-d-
ihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxohexyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxohexyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxoheptyl)-26,27-cyclo-24a,24b-d-
ihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxoheptyl)-26,27-cyclo-24a,24b-d-
ihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxooctyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxooctyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxononyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxononyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxodecyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxodecyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
(5Z,7E,22E)-(1S,3R,24S)-25-methyl-26,27-cyclo-9,10-secocholesta-5,7,10(19-
),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-methyl-26,27-cyclo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-ethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-
,22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-ethyl-26,27-cyclo-9,-
10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-propyl-26,27-cyclo-9,10-secocholesta-5,7,10(19-
),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-propyl-26,27-cyclo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-butyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-
,22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-butyl-26,27-cyclo-9,-
10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-pentyl-26,27-cyclo-9,10-secocholesta-5,7,10(19-
),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-pentyl-26,27-cyclo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-hexyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-
,22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-hexyl-26,27-cyclo-9,-
10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-heptyl-26,27-cyclo-9,10-secocholesta-5,7,10(19-
),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-heptyl-26,27-cyclo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-octyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-
,22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-octyl-26,27-cyclo-9,-
10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-nonyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-
,22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-nonyl-26,27-cyclo-9,-
10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-decyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-
,22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-decyl-26,27-cyclo-9,-
10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24S)-25-ethylene-26,27-cyclo-9,10-secocholesta-5,7,10(-
19),22-tetraene-1,3,24-triol,
(5Z,7E,22E)-(1S,3R,24R)-25-ethylene-26,27-cy-
clo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-propenyl)-26,27-cyclo-9,10-secocholes-
ta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(-
1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-tr-
iol,
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-butenyl)-26,27-cyclo-9,10-secocho-
lesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24R)-2-
5-(1-butenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24--
triol,
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-pentenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24R-
)-25-(1-pentenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-
,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-hexenyl)-26,27-cyclo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,-
24R)-25-(1-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1-
,3,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-heptenyl)-26,27-cyclo-9,1-
0-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-heptenyl)-26,27-cyclo-9,10-secocholes-
ta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(-
1-octenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-tri-
ol,
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-octenyl)-26,27-cyclo-9,10-secochol-
esta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-
-(1-nonenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-t-
riol,
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-nonenyl)-26,27-cyclo-9,10-secoch-
olesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24S)--
25-(1-decenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-
-triol,
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-decenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24S-
)-25-(1-propenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-
,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-propenyl)-26,27-cyclo-9,10--
secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R-
,24S)-25-(1-butenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene--
1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-butenyl)-26,27-cyclo-9,1-
0-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-pentenyl)-26,27-cyclo-9,10-secocholes-
ta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(-
1-pentenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-tr-
iol,
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-hexenyl)-26,27-cyclo-9,10-secocho-
lesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-2-
5-(1-hexenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24--
triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-heptenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24R-
)-25-(1-heptenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-
,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-octenyl)-26,27-cyclo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,-
24R)-25-(1-octenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1-
,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-nonenyl)-26,27-cyclo-9,10-
-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3-
R,24R)-25-(1-nonenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-
-1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-decenyl)-26,27-cyclo-9,-
10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-decenyl)-26,27-cyclo-9,10-secocholest-
a-5,7,10(19),22-tetraene-1,3,24-triol.
6. Process for the production of vitamin D derivatives of general
formula I, whereby a compound of general formula II 31in which
Y'.sub.1 means a hydrogen atom, a halogen atom, or a protected
hydroxyl group and Y'.sub.2 means a hydroxy protective group, is
converted into the compound of general formula I by simultaneous or
successive cleavage of the hydroxy and keto protective groups and
optionally by partial or complete esterification of free hydroxyl
groups.
7. Use or the vitamin D derivatives of general formula I for the
production of pharmaceutical agents.
8. Use of the vitamin D derivatives of general formula I according
to claim 7 for the production of pharmaceutical agents for the
therapy of hyperproliferative diseases of the skin, pruritus, tumor
diseases, precancerous stages, disorders of the immune system,
inflammatory diseases, rheumatoid arthritis, asthma, auto-immune
diseases, multiple sclerosis, diabetes mellitus, AIDS as well as
rejection reactions in the case of autologous, allogeneic or
xenogeneic transplants.
9. Use according to claim 8, wherein the pharmaceutical agent also
is combined with other substances that have an immunosuppressive
action, such as cyclosporin A, FK 506, rapamycin and anti-CD 4
antibodies.
10. Use of the vitamin D derivatives of general formula I according
to claim 7 for the production of pharmaceutical agents for the
therapy of atrophic skin or wound healing, the therapy of secondary
hyperparathyroidism, renal osteodystrophia, as well as senile and
postmenopausal osteoporosis, diabetes mellitus type II and the
therapy of degenerative diseases of the peripheral and central
nervous system as well as the regulation of hair growth.
11. Use of vitamin D derivatives of general formula I according to
claim 7, which antagonize the action of calcitriol in HL 60 cells,
for the therapy of hypercalcemias or granulomatous diseases, of
paraneoplastic hypercalcemias, of hypercalcemia in the case of
hyperparathyroidism, for male and female birth control or as
immunostimulants, as well as in hirsutism, for the therapy and
prophylaxis of arteriosclerosis, and for the therapy of
inflammatory diseases.
12. Intermediate products or general formula XII within the
production of vitamin D derivatives of general formula I according
to claim 1: 32in which R.sub.6 means a straight-chain or branched
alkyl group with up to 11 carbon atoms or a hydrogen atom, and K
means a keto protective group.
13. Intermediate product according to claim 10, wherein K stands
for 1,3-dioxolan, 1,3-dioxane, 5,5-methyl-1,3-dioxane or a
dialkoxyketal.
Description
[0001] The invention relates to new vitamin D derivatives of
general formula I 1
[0002] process for their production, intermediate products of the
process as well as the use for the production of pharmaceutical
agents.
PRIOR ART
[0003] Natural vitamins D.sub.2 and D.sub.3 are inherently
biologically inactive and are converted into biologically active
metabolites [1.alpha.,25-dihydroxy vitamin D.sub.3 (calcitriol) or
-D.sub.2] only after hydroxylation at C-atom 25 in the liver and at
C-atom 1 in the kidney. The action of the active metabolites
involves the regulation of the calcium and phosphate concentration
in the serum; they counteract a dropping of the calcium
concentration in the serum by increasing the calcium absorption in
the intestine and under certain circumstances promoting calcium
mobilization from the bones. FIG. 1 shows known vitamin D
derivatives together with the commonly used numbering diagram.
[0004] In addition to their pronounced effect on the calcium and
phosphate metabolism, the active metabolites of vitamins D.sub.2
and D.sub.3 and their synthetic derivatives have a
proliferation-inhibiting and differentiation-stimulating action on
tumor cells and normal cells, such as, for example, skin cells. In
addition, a pronounced effect on cells of the immune system
(inhibiting of proliferation and interleukin 2-synthesis of
lymphocytes, increase of cytotoxicity and phagocytosis in vitro of
monocytes) has been found, which manifests itself in an
immunomodulatory action, and finally, because of a stimulating
action on bone-forming cells, an increased formation of bone in
normal and osteoporotic rats is found [R. Bouillon et al. "Short
Term Course of 1,25(OH).sub.2D.sub.3 Stimulates Osteoblasts But Not
Osteoclasts," Calc. Tissue Int. 49, 168 (1991)].
[0005] All actions are mediated by bonding to the vitamin D
receptor. Because of the bonding, the activity of specific genes is
regulated.
[0006] When using biologically active metabolites of vitamins
D.sub.2 and D.sub.3, a toxic effect on the calcium metabolism is
produced (hypercalcemia).
[0007] By structural manipulations of the side chain,
therapeutically usable effectiveness can be separated from
undesirable hypercalcemic activity. A suitable structural variant
is the introduction of 24-hydroxy derivatives.
[0008] 1.alpha.-Cholecalciferols that are hydroxylated in
24-position are already described in DE 25 26 981. They have a
lower toxicity than the corresponding non-hydroxylated
1.alpha.-cholecalciferol. Further, 24-hydroxy derivatives are
described in the following patent applications: DE 39 33 034, DE 40
03 854, DE 40 34 730, EP 0 421 561, EP 0 441 467, WO 87/00834, and
WO 91/12238.
[0009] Finally, 25-carboxylic acid derivatives of calcitriol that
are hydroxylated at C-24 are described in WO 94/07853, and said
derivatives exhibit a more advantageous spectrum of action than
calcitriol. The equivalent is also true for new vitamin D
derivatives with substituents at C-25 (WO 97/00242). While the
ability to trigger a hypercalcemia is considerably weakened,
proliferation-inhibiting and differentiation-stimulating actions
are maintained. Generally, however, the introduction of the
24-hydroxyl group results in metabolic destabilization of the
derivatives, especially if a cyclopropyl ring is in the neigboring
position. For this reason, these compounds are only conditionally
suitable for systemic administration.
[0010] There is therefore a need for new vitamin D derivatives that
have as advantageous a spectrum of action as the compounds that are
described in the prior art (especially WO 94/07853 and WO
97/00242), but that are better suited for systemic administration
owing to their higher metabolic stability.
[0011] The object of this patent application is to make available
such vitamin D derivatives. This object is achieved by the
compounds that are disclosed in the claims.
[0012] This invention therefore relates to vitamin D derivatives of
general formula I, 2
[0013] in which
[0014] Y.sub.1 means a hydrogen atom, a hydroxyl group, a fluorine,
chlorine or bromine atom or a group --O(CO)R.sub.8, in which
[0015] R.sub.8 is an aliphatic or aromatic radical with 1 to 12 C
atoms,
[0016] Y.sub.2 means a hydrogen atom or a group --(CO)R.sub.9, in
which
[0017] R.sub.9 is an aliphatic or aromatic radical with 1 to 12 C
atoms,
[0018] R.sub.1 and R.sub.2 each mean a hydrogen atom or together an
exocyclic methylene group,
[0019] R.sub.3 and R.sub.41 independently of one another, mean a
hydrogen atom, a chlorine or fluorine atom, an alkyl group with 1
to 4 carbon atoms, together a methylene group or together with
quaternary carbon atom 20 a 3- to 7-membered, saturated or
unsaturated carbocyclic ring,
[0020] V and W together mean an E-double bond or V means a hydroxyl
group and W means a hydrogen atom,
[0021] Q means a straight-chain or branched carbon unit with up to
10 carbon atoms, which at any positions can have .alpha.- or
.beta.-hydroxyl groups, which in turn can be etherified or
esterified, keto groups, amino groups or halogen atoms,
[0022] Z means a straight-chain or branched-chain, saturated or
unsaturated hydrocarbon radical with up to 12 carbon atoms, which
at any positions can have keto groups, .alpha.- or .beta.-hydroxyl
groups, which in turn can be etherified or esterified, amino
groups, fluorine, chlorine, or bromine atoms.
[0023] The invention also relates to a process for the production
of the compounds according to the invention, intermediate products
in the production process as well as use of the compounds according
to the invention for the production of pharmaceutical agents.
[0024] Especially advantageous embodiments of the invention are the
subject of the subclaims.
[0025] Radicals R.sub.1 and R.sub.2 preferably stand for hydrogen
atoms.
[0026] For R.sub.3 and R.sub.41 the following preferred
combinations apply: R.sub.3=H, R.sub.4=methyl or R.sub.3=methyl,
R.sub.4=H; R.sub.3=F, R.sub.4=methyl or R.sub.3=methyl, R.sub.4=F;
R.sub.3, R.sub.4=methyl; R.sub.3 and R.sub.4 together form a
methylene group or together with tertiary carbon atom 20 form a
cyclopropyl ring.
[0027] Optional radicals R.sub.8 and R.sub.9 are organic groups
with 1 to 12 C atoms. These radicals can be saturated or
unsaturated, branched or unbranched, acyclic, carbocyclic or
heterocyclic. Examples of radicals R.sub.8 and R.sub.9 are methyl,
ethyl, propyl, i-propyl, butyl or phenyl groups. The radicals of
naturally occurring amino acids, such as, e.g.,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH.sub.2-Ph, --CH.sub.2OH,
--CH(OH)--CH.sub.3, --CH.sub.2SH, --CH.sub.2--SCH.sub.3,
--CH.sub.2CO.sub.2H, --CH.sub.2CH.sub.2--CO.sub.2H,
--(CH.sub.2).sub.4--NH.sub.2, --(CH.sub.2).sub.3--C(NH)NH.sub.2,
but also the radicals of the amino acids tryptophan, tyrosine or
histamine are also possible, however.
[0028] The preferred radicals are derived from C.sub.1 to C.sub.9,
especially C.sub.2 to C.sub.5 alkanecarboxylic acids, such as, for
example, acetic acid, propionic acid, butyric acid or pivaloyl
acid. Among the aromatic groups, the phenyl group and substituted
phenyl groups are preferred.
[0029] Q is a straight-chain or branched carbon unit with up to 10
carbon atoms, e.g., --CH.sub.2--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, --(CH.sub.2).sub.7--,
--CH.sub.2--C(CH.sub.3).sub.2- --CH.sub.2--,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3)--CH.sub.2--- . The
carbon atoms that are contained in Q can have hydroxyl groups at
any positions, e.g., --CH(OH)--, --CH.sub.2--CH(OH)--,
--CH.sub.2--CH.sub.2--CH(OH)--, --CH(OH)--CH.sub.2--,
--CH(OH)--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH(OH)--CH.sub.2--CH(OH)--CH.- sub.2--,
--CH.sub.2--CH(OH)--CH.sub.2--, --CH.sub.2--CH(OH)--CH.sub.2--CH(-
OH)--CH.sub.2--. The hydroxyl groups can in turn be esterified or
etherified, e.g., --CH(OCH.sub.3)--,
--CH.sub.2--CH(OC.sub.2H.sub.5)--,
--CH.sub.2--CH(OCOCH.sub.3)--CH.sub.2--CH(OCOCH.sub.3)--CH.sub.2--,
--CH.sub.2--CH(OCOC.sub.4H.sub.9)--CH.sub.2--. Group Q can also
exhibit keto-groups, amino groups or halogen atoms, e.g., --CO--,
--CO--CH.sub.2, --CO--CH.sub.2--CH.sub.2--, --CH.sub.2COCH.sub.2--,
--CH(Cl)--, --CH(Cl)--CH.sub.2--, --CH.sub.2--CH(Cl)--,
--CH(NH.sub.2)--, --CH(NH.sub.2)--CH.sub.2--,
--CH(N(CH.sub.3).sub.2)--CH(N(CH.sub.3).sub.2- )--CH.sub.2--,
--CH.sub.2--CH(N(CH.sub.3).sub.2)--CH.sub.2--CH(N(CH.sub.3)-
.sub.2)--CH.sub.2--, --CH(F)--, --CH(F)--CH.sub.2--,
--CH.sub.2--CH(F)--CH.sub.2.
[0030] The following groups Q are preferred:
[0031] Q is an unsubstituted, unbranched alkylene unit with 1, 2 or
3 carbon atoms or
[0032] Q is a hydroxymethylene group (hydroxyl group in .alpha.- or
.beta.-position) or
[0033] Q=--CH(OH)--CH.sub.2-- or --CH(OH)--CH.sub.2--CH.sub.2--
(hydroxyl groups in .alpha.- or .beta.-position).
[0034] Radical Y1 preferably stands for a hydrogen atom, a fluorine
atom or a hydroxyl group.
[0035] Z is a straight-chain or branched-chain, saturated or
unsaturated hydrocarbon radical with up to 12 carbon atoms, e.g.,
--CH.sub.3--CH 2--CH.sub.3, --(CH.sub.2).sub.2--CH.sub.3,
--(CH.sub.2).sub.3--CH.sub.3, --(CH.sub.2).sub.4--CH.sub.3,
--(CH.sub.2).sub.5--CH.sub.3--(CH.sub.2).su- b.6--CH.sub.3,
--(CH.sub.2).sub.7--CH.sub.3'--CH.sub.2--C(CH.sub.3).sub.2--
-CH.sub.2--CH.sub.3,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3)--CH.-
sub.2--CH.sub.3. The carbon atoms that are contained in Z can
exhibit hydroxyl groups at any positions, e.g., --CH(OH)--CH.sub.3,
--CH.sub.2--CH(OH)--CH.sub.3'--CH.sub.2--CH(OH)--CH.sub.2--CH(OH)--CH.sub-
.2--CH.sub.3, --CH.sub.2--CH(OH)--CH.sub.2--CH.sub.3,
--CH.sub.2--CH(OH)--CH.sub.2--CH(OH)--CH.sub.2--CH.sub.3. In turn,
the hydroxyl groups can be esterified or etherified, e.g.,
--CH(OCH.sub.3)--CH.sub.3,
--CH.sub.2--CH(OC.sub.2H.sub.5)--CH.sub.3,
--CH.sub.2--CH(OCOCH.sub.3)--CH.sub.2--CH(OCOCH.sub.3)--CH.sub.2--CH.sub.-
3, --CH.sub.2--CH(OCOC.sub.4H.sub.9)--CH.sub.2--CH.sub.3. Group Z
can also exhibit keto groups, amino groups or halogen atoms, e.g.,
--CH.sub.2COCH.sub.2--CH.sub.3, --CH.sub.2--CH(Cl)--CH.sub.3,
--CH.sub.2--CH(N(CH.sub.3).sub.2)--CH.sub.2--CH(N(CH.sub.3).sub.2)--CH.su-
b.2--CH.sub.3, --CH.sub.2--CH(F)--CH.sub.2--CH.sub.3.
[0036] The following groups Z are preferred:
[0037] Z is a 1-oxoalkyl group with 1-12 carbon atoms,
[0038] Z is an alkyl group with 1-12 carbon atoms,
[0039] Z is an alkenyl group with 1-12 carbon atoms, in which the
double bond can have E- or Z-geometry and can be present at any
positions of the side chain.
[0040] The groups V and W either together form an E-double bond or
V is a hydroxyl group and W is a hydrogen atom. The two
possibilities for the structural element in question are pictured
below: 3
[0041] Of the compounds of general formula I according to the
invention, the following compounds are quite especially
preferred:
[0042]
(5Z,7E,22E)-(1S,3R)-25-Acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(-
19),22-tetraene-1,3-diol,
[0043]
(5Z,7E,22E)-(1S,3R)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19),22-tetraene-1,3-diol,
[0044]
(5Z,7E,22E)-(1S,3R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19),22-tetraene-1,3-diol,
[0045]
(5Z,7E,22E)-(1S,3R)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19),22-tetraene-1,3-diol,
[0046]
(5Z,7E,22E)-(1S,3R)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19),22-tetraene-1,3-diol,
[0047]
(5Z,7E,22E)-(1S,3R)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19),22-tetraene-1,3-diol,
[0048]
(5Z,7E,22E)-(1S,3R)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19),22-tetraene-1,3-diol,
[0049]
(5Z,7E,22E)-(1S,3R)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19),22-tetraene-1,3-diol,
[0050]
(5Z,7E,22E)-(1S,3R)-25-(1-oxodecyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19),22-tetraene-1,3-diol,
[0051]
(5Z,7E)-(1S,3R,22S)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(-
19)-triene-1,3,22-triol,
[0052]
(5Z,7E)-(1S,3R,22R)-25-acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(-
19)-triene-1,3,22-triol,
[0053]
(5Z,7E)-(1S,3R,22S)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19)-triene-1,3,22-triol,
[0054]
(5Z,7E)-(1S,3R,22R)-25-(1-oxopropyl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19)-triene-1,3,22-triol,
[0055]
(5Z,7E)-(1S,3R,22S)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19)-triene-1,3,22-triol,
[0056]
(5Z,7E)-(1S,3R,22R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19)-triene-1,3,22-triol,
[0057]
(5Z,7E)-(1S,3R,22S)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19)-triene-1,3,22-triol,
[0058]
(5Z,7E)-(1S,3R,22R)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19)-triene-1,3,22-triol,
[0059]
(5Z,7E)-(1S,3R,22S)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19)-triene-1,3,22-triol,
[0060]
(5Z,7E)-(1S,3R,22R)-25-(1-oxohexyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19)-triene-1,3,22-triol,
[0061]
(5Z,7E)-(1S,3R,22S)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19)-triene-1,3,22-triol,
[0062]
(5Z,7E)-(1S,3R,22R)-25-(1-oxoheptyl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19)-triene-1,3,22-triol,
[0063]
(5Z,7E)-(1S,3R,22S)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19)-triene-1,3,22-triol,
[0064]
(5Z,7E)-(1S,3R,22R)-25-(1-oxooctyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19)-triene-1,3,22-triol,
[0065]
(5Z,7E)-(1S,3R,22S)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19)-triene-1,3,22-triol,
[0066]
(5Z,7E)-(1S,3R,22R)-25-(1-oxononyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19)-triene-1,3,22-triol,
[0067]
(5Z,7E)-(1S,3R,22S)-25-(1-oxodecyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19)-triene-1,3,22-triol,
[0068]
(5Z,7E)-(1S,3R,22R)-25-(1-oxodecyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19)-triene-1,3,22-triol,
[0069]
(5Z,7E,22E)-(1S,3R)-25-acetyl-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19),22-tetraene-1,3-diol,
[0070]
(5Z,7E,22E)-(1S,3R)-25-(1-oxopropyl)-26,27-cyclo-24a-homo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3-diol,
[0071]
(5Z,7E,22E)-(1S,3R)-25-(1-oxobutyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3-diol,
[0072]
(5Z,7E,22E)-(1S,3R)-25-(1-oxopentyl)-26,27-cyclo-24a-homo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3-diol,
[0073]
(5Z,7E,22E)-(1S,3R)-25-(1-oxohexyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3-diol,
[0074]
(5Z,7E,22E)-(1S,3R)-25-(1-oxoheptyl)-26,27-cyclo-24a-homo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3-diol,
[0075]
(5Z,7E,22E)-(1S,3R)-25-(1-oxooctyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3-diol,
[0076]
(5Z,7E,22E)-(1S,3R)-25-(1-oxononyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3-diol,
[0077]
(5Z,7E,22E)-(1S,3R)-25-(1-oxodecyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3-diol,
[0078]
(5Z,7E)-(1S,3R,22S)-25-acetyl-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19)-triene-1,3,22-triol,
[0079]
(5Z,7E)-(1S,3R,22R)-25-acetyl-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19)-triene-1,3,22-triol,
[0080]
(5Z,7E)-(1S,3R,22S)-25-(1-oxopropyl)-26,27-cyclo-24a-homo-9,10-seco-
cholesta-5,7,10(19)-triene-1,3,22-triol,
[0081]
(5Z,7E)-(1S,3R,22R)-25-(1-oxopropyl)-26,27-cyclo-24a-homo-9,10-seco-
cholesta-5,7,10(19)-triene-1,3,22-triol,
[0082]
(5Z,7E)-(1S,3R,22S)-25-(1-oxobutyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19)-triene-1,3,22-triol,
[0083]
(5Z,7E)-(1S,3R,22R)-25-(1-oxobutyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19)-triene-1,3,22-triol,
[0084]
(5Z,7E)-(1S,3R,22S)-25-(1-oxopentyl)-26,27-cyclo-24a-homo-9,10-seco-
cholesta-5,7,10(19)-triene-1,3,22-triol,
[0085]
(5Z,7E)-(1S,3R,22R)-25-(1-oxopentyl)-26,27-cyclo-24a-homo-9,10-seco-
cholesta-5,7,10(19)-triene-1,3,22-triol,
[0086]
(5Z,7E)-(1S,3R,22S)-25-(1-oxohexyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19)-triene-1,3,22-triol,
[0087]
(5Z,7E)-(1S,3R,22R)-25-(1-oxohexyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19)-triene-1,3,22-triol,
[0088]
(5Z,7E)-(1S,3R,22S)-25-(1-oxoheptyl)-26,27-cyclo-24a-homo-9,10-seco-
cholesta-5,7,10(19)-triene-1,3,22-triol,
[0089]
(5Z,7E)-(1S,3R,22R)-25-(1-oxoheptyl)-26,27-cyclo-24a-homo-9,10-seco-
cholesta-5,7,10(19)-triene-1,3,22-triol,
[0090]
(5Z,7E)-(1S,3R,22S)-25-(1-oxooctyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19)-triene-1,3,22-triol,
[0091]
(5Z,7E)-(1S,3R,22R)-25-(1-oxooctyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19)-triene-1,3,22-triol,
[0092]
(5Z,7E)-(1S,3R,22S)-25-(1-oxononyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19)-triene-1,3,22-triol,
[0093]
(5Z,7E)-(1S,3R,22R)-25-(1-oxononyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19)-triene-1,3,22-triol,
[0094]
(5Z,7E)-(1S,3R,22S)-25-(1-oxodecyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19)-triene-1,3,22-triol,
[0095]
(5Z,7E)-(1S,3R,22R)-25-(1-oxodecyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19)-triene-1,3,22-triol,
[0096]
(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-26,27-cyclo-24a,24b-dihomo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0097]
(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-26,27-cyclo-24a,24b-dihomo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0098]
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxopropyl)-26,27-cyclo-24a,24b-dihomo-
-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0099]
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopropyl)-26,27-cyclo-24a,24b-dihomo-
-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0100]
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxobutyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0101]
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxobutyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0102]
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxopentyl)-26,27-cyclo-24a,24b-dihomo-
-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0103]
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopentyl)-26,27-cyclo-24a,24b-dihomo-
-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0104]
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxohexyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0105]
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxohexyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0106]
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxoheptyl)-26,27-cyclo-24a,24b-dihomo-
-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0107]
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxoheptyl)-26,27-cyclo-24a,24b-dihomo-
-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0108]
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxooctyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0109]
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxooctyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0110]
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxononyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0111]
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxononyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0112]
(5Z,7E,22E)-(1S,3R,24R)-25-(1-oxodecyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0113]
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxodecyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0114]
(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-24-methoxy-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0115]
(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-24-methoxy-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0116]
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxopropyl)-26,27-cyclo-24a-
,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0117]
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxopropyl)-26,27-cyclo-24a-
,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0118]
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxobutyl)-26,27-cyclo-24a,-
24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0119]
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxobutyl)-26,27-cyclo-24a,-
24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0120]
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxopentyl)-26,27-cyclo-24a-
,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0121]
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxopentyl)-26,27-cyclo-24a-
,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0122]
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxohexyl)-26,27-cyclo-24a,-
24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0123]
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxohexyl)-26,27-cyclo-24a,-
24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0124]
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxoheptyl)-26,27-cyclo-24a-
,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0125]
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxoheptyl)-26,27-cyclo-24a-
,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0126]
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxooctyl)-26,27-cyclo-24a,-
24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0127]
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxooctyl)-26,27-cyclo-24a,-
24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0128]
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxononyl)-26,27-cyclo-24a,-
24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0129]
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxononyl)-26,27-cyclo-24a,-
24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0130]
(5Z,7E,22E)-(1S,3R,24R)-24-methoxy-25-(1-oxodecyl)-26,27-cyclo-24a,-
24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0131]
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxodecyl)-26,27-cyclo-24a,-
24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol,
[0132]
(5Z,7E,22E)-(1S,3R,24S)-25-methyl-26,27-cyclo-9,10-secocholesta-5,7-
,10(19),22-tetraene-1,3,24-triol,
[0133]
(5Z,7E,22E)-(1S,3R,24R)-25-methyl-26,27-cyclo-9,10-secocholesta-5,7-
,10-(19),22-tetraene-1,3,24-triol,
[0134]
(5Z,7E,22E)-(1S,3R,24S)-25-ethyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0135]
(5Z,7E,22E)-(1S,3R,24R)-25-ethyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0136]
(5Z,7E,22E)-(1S,3R,24S)-25-propyl-26,27-cyclo-9,10-secocholesta-5,7-
,10(19),22-tetraene-1,3,24-triol,
[0137]
(5Z,7E,22E)-(1S,3R,24R)-25-propyl-26,27-cyclo-9,10-secocholesta-5,7-
,10(19),22-tetraene-1,3,24-triol,
[0138]
(5Z,7E,22E)-(1S,3R,24S)-25-butyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0139]
(5Z,7E,22E)-(1S,3R,24R)-25-butyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0140]
(5Z,7E,22E)-(1S,3R,24S)-25-pentyl-26,27-cyclo-9,10-secocholesta-5,7-
,10(19),22-tetraene-1,3,24-triol,
[0141]
(5Z,7E,22E)-(1S,3R,24R)-25-pentyl-26,27-cyclo-9,10-secocholesta-5,7-
,10(19),22-tetraene-1,3,24-triol,
[0142]
(5Z,7E,22E)-(1S,3R,24S)-25-hexyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0143]
(5Z,7E,22E)-(1S,3R,24R)-25-hexyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0144]
(5Z,7E,22E)-(1S,3R,24S)-25-heptyl-26,27-cyclo-9,10-secocholesta-5,7-
,10(19),22-tetraene-1,3,24-triol,
[0145]
(5Z,7E,22E)-(1S,3R,24R)-25-heptyl-26,27-cyclo-9,10-secocholesta-5,7-
,10(19),22-tetraene-1,3,24-triol,
[0146]
(5Z,7E,22E)-(1S,3R,24S)-25-octyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0147]
(5Z,7E,22E)-(1S,3R,24R)-25-octyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0148]
(5Z,7E,22E)-(1S,3R,24S)-25-nonyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0149]
(5Z,7E,22E)-(1S,3R,24R)-25-nonyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0150]
(5Z,7E,22E)-(1S,3R,24S)-25-decyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0151]
(5Z,7E,22E)-(1S,3R,24R)-25-decyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol,
[0152]
(5Z,7E,22E)-(1S,3R,24S)-25-ethylene-26,27-cyclo-9,10-secocholesta-5-
,7,10(19),22-tetraene-1,3,24-triol,
[0153]
(5Z,7E,22E)-(1S,3R,24R)-25-ethylene-26,27-cyclo-9,10-secocholesta-5-
,7,10(19),22-tetraene-1,3,24-triol,
[0154]
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-propenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0155]
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-propenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0156]
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-butenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0157]
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-butenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0158]
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-pentenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0159]
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-pentenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0160]
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-hexenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0161]
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-hexenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0162]
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-heptenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0163]
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-heptenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0164]
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-octenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0165]
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-octenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0166]
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-nonenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0167]
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-nonenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0168]
[5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-decenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0169]
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-decenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0170]
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-propenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0171]
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-propenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0172]
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-butenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0173]
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-butenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0174]
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-pentenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0175]
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-pentenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0176]
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-hexenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0177]
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-hexenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0178]
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-heptenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0179]
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-heptenyl)-26,27-cyclo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0180]
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-octenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0181]
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-octenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0182]
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-nonenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0183]
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-nonenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0184]
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-decenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol,
[0185]
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-25-(1-decenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol.
[0186] The substances according to the invention have a
considerably higher metabolic stability than the structurally
related compounds of the prior art and are therefore suitable in a
special way for systemic administrations.
[0187] Relative to the structurally related compounds of the prior
art, some of the substances according to the invention are also
characterized in that they show a stronger action on cell
differentiation, whereby the action on the calcium balance does not
increase. Others of the substances according to the invention,
however, exhibit an antagonistic or partial agonistic profile of
action, which makes possible new uses.
[0188] Determination of Biological Activity
[0189] The vitamin D activity of the substances according to the
invention is determined with the aid of the calcitriol-receptor
test. It is carried out using a protein extract from the intestines
of juvenile pigs.
[0190] Receptor-containing protein extract is incubated in a test
tube with .sup.3H-calcitriol (5.times.10.sup.-10 mol/l) in a
reaction volume of 0.270 ml in the absence and in the presence of
test substances for two hours at 4.degree. C. To separate free and
receptor-bound calcitriol, a charcoal-dextran absorption is carried
out. 250 .mu.l of a charcoal-dextran suspension is fed to each test
tube and incubated at 4.degree. C. for 20 minutes. Then, the
samples are centrifuged at 10,000 g for 5 minutes at 4.degree. C.
The supernatant is decanted and measured in a .beta.-counter after
1 hour of equilibration in Picofluor 15.TM..
[0191] The competition curves that are obtained at various
concentrations of test substance as well as of reference substance
(unlabeled calcitriol) at constant concentration of the reference
substance (.sup.3H-calcitriol) are placed in relation to one
another, and a competition factor (KF) is determined.
[0192] It is defined as a quotient of the concentrations of the
respective test substance and the reference substance, which are
necessary for 50% competition: 1 KF = Concentration of test
substance at 50 % competition Concentration of reference substance
at 50 % competition
[0193] It is common to the compounds according to the invention
that they all have a considerable affinity to the calcitriol
receptor.
[0194] To determine the acute hypercalcemic action of various
calcitriol derivatives, the test that is described below is carried
out:
[0195] The action of control (solution base), reference substance
(1,25-dihydroxy vitamin D.sub.3=calcitriol) and test substance is
tested in each case after one-time subcutaneous administration in
groups of 10 healthy male rats (140-170 g). During the testing
time, the rats are kept in special cages to determine the excretion
of water and mineral substances. Urine is collected in 2 fractions
(0-16 hours and 16-22 hours). An oral dose of calcium (0.1 mmol of
calcium in 6.5% alpha-hydroxypropyl-cellulose, 5 ml/animal)
replaces at 1600 hours the calcium intake that is lacking by food
deprivation. At the end of the test, the animals are killed by
decapitation and exsanguinated to determine the serum-calcium
values. For the primary screen test in vivo, an individual standard
dose (200 .mu.g/kg) is tested. For selected substances, the result
is supported by establishing a dose-effect relation.
[0196] A hypercalcemic action is shown in serum-calcium level
values that are higher than in the control.
[0197] The significance of differences between substance groups and
controls and between test substance and reference substance are
supported with suitable statistical processes. The result is
indicated as dose ratio DR (DR=factor of test substance
dose/reference substance dose for comparable actions).
[0198] The differentiation-stimulating action of calcitriol
analogues is also detected quantitatively.
[0199] It is known in the literature [Mangelsdorf, D. J. et al., J.
Cell. Biol. 98: 391 (1984)] that the treatment of human leukemia
cells (promyelocyte cell line HL 60) in vitro with calcitriol
induces the differentiation of cells to macrophages.
[0200] HL 60 cells are cultivated in tissue culture medium (RPMI
10% fetal calf serum) at 37.degree. C. in an atmosphere of 5%
CO.sub.2 in air.
[0201] For substance testing, the cells are centrifuged off, and
2.0.times.10.sup.5 cells/ml in phenol red-free tissue culture
medium is taken up. The test substances are dissolved in ethanol
and diluted with tissue culture medium without phenol red to the
desired concentration. The dilution stages are mixed with the cell
suspension at a ratio of 1:10, and 100 .mu.l each of this cell
suspension that is mixed with substance is pipetted into an
indentation of a 96-hole plate. For control, a cell suspension is
mixed analogously with the solvent.
[0202] After incubation for 96 hours at 37.degree. C. in 5%
CO.sub.2 in air, 100 .mu.l of an NBT-TPA solution (nitro blue
tetrazolium (NBT), final concentration in the batch of 1 mg/ml,
tetradecanoyl phorbolmyristate-13-acetate (TPA), final
concentration in the batch of 2.times.10.sup.-7 mol/l) is pipetted
into each indentation of the 96-hole plate in the cell
suspension.
[0203] By incubation for 2 hours at 37.degree. C. and 5% CO.sub.2
in air, NBT is reduced to insoluble formazan because of the
intracellular oxygen radical release, stimulated by TPA, in the
cells that are differentiated to macrophages.
[0204] To complete the reaction, the indentations of the 96-hole
plate are suctioned off, and the cells are affixed to the bottom of
the plate by adding methanol and dried after affixing. To dissolve
the intracellular formazan crystals that are formed, 100 .mu.l of
potassium hydroxide (2 mol/l) and 100 .mu.l of dimethyl sulfoxide
are pipetted into each indentation and ultrasonically treated for 1
minute. The concentration of formazan is measured by
spectrophotometry at 650 nm.
[0205] As a yardstick for the differentiation induction of HL 60
cells to macrophages, the concentration of formed formazan applies.
The result is indicated as a dose ratio (DR=factor of test
substance dose/reference substance dose for comparable semi-maximum
actions).
[0206] To determine the metabolic stability, the test substance is
incubated with tissue homogenate (from the rat liver) in the
presence of buffer systems. The drop in starting concentration is
tracked as a function of time. After a certain time, the incubation
is stopped, and the unaltered test substance is extracted from the
homogenate (diethyl ether), concentrated by evaporation under
nitrogen, isolated via HPLC (mobile solvent: acetonitrile/water)
and detected using UV-absorption.
[0207] The results of the calcitriol-receptor test and the
determination of the dose ratio of the differentiation induction of
HL 60 cells and the dose ratio for hypercalcemia as well as the
half-life in the liver homogenate are summarized below: Examples of
test compounds:
[0208]
(5Z,7E,22E)-(1S,3R)-25-Acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(-
19),22-tetraene-1,3-diol 66
[0209]
(5Z,7E,22E)-(1S,3R)-25-(1-oxobutyl)-26,27-cyclo-9,10-secocholesta-5-
,7,10(19),22-tetraene-1,3-diol 71
[0210]
(5Z,7E,22E)-(1S,3R)-25-(1-oxopentyl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19),22-tetraene-1,3-diol 76
[0211]
(5Z,7E,22E)-(1S,3R)-25-acetyl-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19),22-tetraene-1,3-diol 126
[0212]
(5Z,7E)-(1S,3R,22S)-25-acetyl-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19)-triene-1,3,22-triol 127
[0213]
(5Z,7E,22E)-(1S,3R)-25-(1-oxobutyl)-26,27-cyclo-24a-homo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3-diol 131
[0214]
(5Z,7E,22E)-(1S,3R)-25-(1-oxopentyl)-26,27-cyclo-24a-homo-9,10-seco-
cholesta-5,7,10(19),22-tetraene-1,3-diol 136
[0215]
(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-26,27-cyclo-24a,24b-dihomo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol 168b
[0216]
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxobutyl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 175b
[0217]
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopentyl)-26,27-cyclo-24a,24b-dihomo-
-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 182b
[0218]
(5Z,7E,22E)-(1S,3R,24S)-25-ethyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol 214a
[0219]
(5Z,7E,22E)-(1S,3R,24R)-25-ethyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol 214b
[5Z,7E,22E,25(E)]-(1S,3R,24R)-25-(1-b-
utenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
221b
[0220]
(5Z,7E,22E)-(1S,3R,24S)-25-butyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24,-triol 226a
[0221]
(5Z,7E,22E)-(1S,3R,24R)-25-butyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol 226b
[0222]
(5Z,7E,22E)-(1S,3R,24R)-25-hexyl-26,27-cyclo-9,10-secocholesta-5,7,-
10(19),22-tetraene-1,3,24-triol 231b
[0223]
(5Z,7E,22E)-(1S,3R,24R)-25-heptyl-26,27-cyclo-9,10-secocholesta-5,7-
,10(19),22-tetraene-1,3,24-triol 236b
[0224]
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-octenyl)-26,27-cyclo-9,10-secoc-
holesta-5,7,10(19),22-tetraene-1,3,24-triol 246b
[0225] Comparison Compounds:
[0226] Calcitriol
(5Z,7E,22E)-(1S,3R,24S)-26,27-Cyclo-9,10-secocholesta-5,7,10(19),22-tetrae-
ne-1,3,24-triol (calcipotriol)
[0227]
1 Compound KF DR HL 60 DR Ca T1/2 (min) 66 10 0.5 30 110 71 9 1.7
100 120 76 7 19 >100 >120 81 40 9 >>300 >120 126 5
0.5 20 120 127 30 4 >100 120 131 10 0.2 30 120 132 20 2 >100
100 136 10 17 >100 >120 168b 3 7 >100 120 175b 1 3 >100
90 182b 2 18 >100 100 214a 3 1.5 >>1 80 214b 1 0.1 >1
100 221b 2 0.1 10 90 226a 4 2 >>1 80 226b 3 0.4 >5 100
231b 9 2 >100 75 236b 20 4 >>30 100 246b 10 2 >>10
100 calcitriol 1 1 1 120 calcipotriol 1 1 50 40
[0228] In addition to an affinity to the vitamin D receptor, which
is comparable to that of calcitriol, the compounds listed partially
show a likewise comparable or better cell-differentiating
activity.
[0229] The induction of a hypercalcemia is carried out, however,
only at very much higher doses than in the case of calcitriol.
[0230] The metabolic stability of the compounds equals that of
calcitriol and is considerably higher than that of the structurally
related calcipotriol.
USE OF THE COMPOUNDS ACCORDING TO THE INVENTION
[0231] By the reduced property of triggering a hypercalcemia as
well as the high metabolic stability, the substances according to
the invention are suitable in a special way for the production of
pharmaceutical agents for the treatment of diseases that are
characterized by hyperproliferation and deficient cell
differentiation. Included in these are, for example,
hyperproliferative diseases of the skin (psoriasis, pityriasis
subia pilasis, acne, ichthyosis) and pruritus, as well as tumor
diseases and precancerous stages (for example, tumors of the
intestines, carcinomas of the breast, lung tumors, prostate
carcinomas, leukemias, T-cell lymphomas, melanomas, Batazell
Larzin, squamous carcinoma, actinic keratoses, cervix dysplasias,
and metastasizing tumors of any type).
[0232] Also, for the treatment and prophylaxis of diseases that are
characterized by a disequilibrium of the immune system, the
substances according to the invention are suitable. These include
eczemas and diseases of the atopic Formon series and inflammatory
diseases (rheumatoid arthritis, asthma), as well as auto-immune
diseases, such as, for example, multiple sclerosis, diabetes
mellitus type I, myasthenia gravis, lupus erythematosus,
scleroderma, bullous skin diseases (pemphigus, pemphigoid), further
rejection reactions in the case of autologous, allogeneic or
xenogeneic transplants, as well as AIDS. In all these diseases, the
new compounds of general formula I can be combined advantageously
with other substances that have an immunosuppressive action, such
as cyclosporin A, FK 506, rapamycin and anti-CD 4-antibodies.
[0233] The substances are also suitable for therapy of secondary
hyperparathyroidism and renal osteodystrophia because of the
property of calcitriols to drop the parathormone synthesis.
[0234] Owing to the presence of the vitamin D receptor in the
insulin-producing cells of the pancreas, the substances are
suitable by increasing the insulin secretion for the therapy of
diabetes mellitus type II.
[0235] Further, it has been found, surprisingly enough, that by
topical application of the compounds according to the invention on
the skin of mice, rats and guinea pigs, an increased reddening of
the skin and increase of the thickness of the epidermis can be
induced. The increase in the reddening of the skin is determined
based on the increase in the red value of the skin surface that can
be quantified with a calorimeter. The red value is typically
increased 1.5-fold after the substance (dose 0.003%) is
administered three times at intervals of 24 hours. The increase in
the thickness of the epidermis is quantified in the histological
preparation. It is typically increased 2.5-fold. The number of
proliferating epidermal cells (cells in the S-phase of the cell
cycle) is determined by flow cytometry and is typically increased
by a factor of 6.
[0236] These properties of the derivatives in the vitamin D series
according to the invention can appear suitable for therapeutic use
in the case of atrophic skin, as it occurs in natural skin aging
because of increased light exposure or medicinally-induced skin
atrophy by treatment with glucocorticoids.
[0237] Further, it can be assumed that wound healing can be
accelerated by topical application with the new compounds.
[0238] In cell populations of the hair follicle, which contribute
decisively to hair growth or to hair cycle regulation, it was
possible to detect vitamin D.sub.3 receptor proteins [Stumpf, W. E.
et al., Cell Tissue Res. 238, 489 (1984); Milde, P. et al., J.
Invest. Dermatol. 97, 230 (1991)]. In addition, in vitro findings
on isolated hair follicle keratinocytes show a
proliferation-inhibiting and differentiation-stimula- ting
influence of 1,25-(OH).sub.2-D.sub.3.
[0239] From clinical observations, it is known that the vitamin
D.sub.3-resistant rickets often accompanies alopecia, which
develops in early infancy. Experimental findings show that the
vitamin D.sub.3 bonding site of the VDR in this disease mutates,
i.e., is defective [Kristjansson, K. et al., J. Clin. Invest. 92,
12 (1993)]. Keratinocytes, which were isolated from the hair
follicles of these patients, do not react in vitro to the addition
of 1,25-(OH).sub.2-D.sub.3 [Arase, S. et al., J. Dermatol. Science
2, 353 (1991)].
[0240] These findings indicate a decisive role for
1,25-(OH).sub.2-D.sub.3 in the regulation of hair growth.
[0241] These analogues are therefore especially suitable for the
production of pharmaceutical agents for the treatment of diseases
which accompany disrupted hair growth (androgenetic alopecia,
alopecia areata/totalis, chemotherapy-induced alopecia) or for
supporting physiological hair growth without causing the
side-effects of calcitriol (especially hypercalcemia).
[0242] Senile and postmenopausal osteoporosis is characterized by
an increased bone turnover with an overall negative balance. Owing
to the bone shrinkage especially of trabecular bones, fractures
result to an increased extent. Owing to the stimulating action of
calcitriol, both in the number and the conduct of synthesis of
cells forming new bones (osteoblasts), the substances according to
the invention are suitable for therapy and prophylaxis of senile
and postmenopausal osteoporosis (EP 0 634 173 A1), of
steroid-induced osteoporosis as well as for accelerated healing of
arthroplasties without causing the side-effects of calcitriol
(especially hypercalcemia). For the therapy of various forms of
osteoporosis, they can be combined advantageously with estradiol or
other derivatives of estrogen.
[0243] Finally, it was possible to show that calcitriol increases
the synthesis of a growth substance for nerve cells (nerve growth
factor) [M. S. Saporito et al. Brain Res. 633, 189 (1994)]. The
compounds according to the invention are therefore also suitable
for treating degenerative diseases of the peripheral and central
nervous system, such as Alzheimer's disease and amyotrophic lateral
sclerosis.
[0244] In addition, it has been found that certain compounds of
general formula I in HL 60 cells antagonize, surprisingly enough,
the action of calcitriol (see also WO 94/07853, WO 97/00242).
[0245] Such compounds can be used for the therapy of
hypercalcemias, such as, for example, in hypervitaminosis D or
intoxication with calcitriol and calcitriol-like active substances,
or in the case of increased extrarenal calcitriol synthesis in
granulomatous diseases (sarcoidosis, tuberculosis). Also,
paraneoplastic hypercalcemias (for example, in osteolytic
metastases and tumors with increased synthesis of
parathormone-related peptides) as well as in hypercalcemias in the
case of hyperparathyroidism.
[0246] In addition, calcitriol antagonists can be used for birth
control. In the reproductive tracts of female and male animals, the
vitamin D receptor is expressed. It is known that the female and
male fertility of vitamin-D-deficient animals is reduced. By
short-term substitution of calcitriol, the reproductive output can
be increased. Calcitriol antagonists are therefore able to
influence female and male fertility.
[0247] Since calcitriol, under certain conditions, shows an
immunosuppressive action, calcitriol receptor antagonists can also
be used as immunostimulants, e.g., in the case of weak defenses
against infections.
[0248] Calcitriol is known to be able to modulate hair growth.
Calcitriol antagonists can therefore be used therapeutically in the
case of undesirable hair growth, e.g., in hirsutism.
[0249] Vitamin D has long been known to play a stimulating role in
the formation of arteriosclerotic plaque. In such vascular lesions,
a calcitriol-regulated protein, osteopontin, is found to be
increased, to which a role in vascular sclerosis is attributed [R.
Eisenstein et al. Arch. Path. 77, 27 (1964), L. A. Fitzpatrick et
al., J. Clin. Invest. 94, 1597 (1994)]. Calcitriol antagonists are
therefore suitable for therapy and prophylaxis of all types of
arteriosclerosis.
[0250] Finally, calcitriol antagonists are suitable because of the
property of calcitriol to increase unspecific immune reactions of
monocytic cells, for therapy of inflammatory diseases, especially
of a chronic nature, such as rheumatoid arthritis, Crohn's disease,
ulcerative colitis, and granulomatous diseases such as sarcoidosis
and other foreign-body reactions.
[0251] For all listed therapeutic applications, it is true that the
compounds according to the invention are able to achieve a
therapeutic action in the above-mentioned clinical pictures without
causing the side-effects of calcitriol (especially
hypercalcemia).
[0252] This invention thus relates to pharmaceutical preparations
that contain at least one compound according to general formula I
together with a pharmaceutically compatible vehicle.
[0253] The compounds can be formulated as solutions in
pharmaceutically compatible solvents or as emulsions, suspensions
or dispersions in suitable pharmaceutical solvents or vehicles or
as pills, tablets or capsules, which contain solid vehicles in a
way known in the art. For topical use, the compounds are
advantageously formulated as creams or ointments or in a similar
form of pharmaceutical agent that is suitable for topical use. Each
such formulation can also contain other pharmaceutically compatible
and nontoxic adjuvants, such as, e.g., stabilizers, antioxidants,
binders, dyes, emulsifiers or flavoring additives. The compounds
are advantageously administered by injection, intravenous infusion
of suitable sterile solutions, as an aerosol via bronchial tubes
and lungs, or as oral dosage via the alimentary tract or topically
in the form of creams, ointments, lotions or suitable transdermal
patches, as is described in EP-A 0 387 077.
[0254] The daily dose is approximately 0.1 .mu.g/patient/day-1000
.mu.g/patient/day,
[0255] preferably 1.0 .mu.g/patient/day-500 .mu.g/patient/day.
[0256] Process for the Production of the Compounds According to the
Invention
[0257] The production of the vitamin D derivatives of general
formula I is carried out according to the invention from a compound
of general formula II, 4
[0258] in which Y'.sub.1 means a hydrogen atom, a halogen atom or a
protected hydroxyl group and Y'.sub.2 means a hydroxy protective
group.
[0259] Z' is distinguished from Z in that optionally present
hydroxyl groups or keto groups can be present in protected
form.
[0260] The protective groups are preferably alkyl-, aryl- or mixed
alkylaryl-substituted silyl groups, e.g., the trimethylsilyl (TMS),
triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS),
tert-butyldiphenylsilyl (TBDPS) or triisopropylsilyl (TIPS) groups
or another standard hydroxy protective group (methoxymethyl,
methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl and
tetrahydropyranyl groups); for the keto groups, these are
preferably ketals (1,3-dioxolans, 1,3-dioxanes, dialkoxyketals)
(see T. W. Greene, P. G. M. Wuts "Protective Groups in Organic
Synthesis," 2.sup.nd Edition, John Wiley & Sons, 1991).
[0261] By simultaneous or successive cleavage of the hydroxy and
keto protective groups and optionally by partial, successive or
complete esterification of the free hydroxyl groups, II is
converted into a compound of general formula I.
[0262] In the case of the silyl protective groups or the
trimethylsilylethoxymethyl group, tetrabutylammonium fluoride,
hydrofluoric acid or hydrofluoric acid/pyridine or acidic ion
exchanger is used for their cleavage; in the case of the ether
groups (methoxymethyl, methoxyethoxymethyl, ethoxyethyl,
tetrahydropyranyl ether) and ketals, the latter are cleaved off
under catalytic action of acid, for example, p-toluenesulfonic
acid, pyridinium-p-toluenesulfonate, acetic acid, hydrochloric
acid, phosphoric acid or an acidic ion exchanger.
[0263] The esterification of the free hydroxy groups can be carried
out according to standard processes with the corresponding
carboxylic acid chlorides, -bromides or -anhydrides.
[0264] The production of the starting compounds for general formula
II starts from various starting compounds depending on the
ultimately desired substitution pattern in 10- and 20-position.
[0265] For the production of compounds of general formula II, in
which R.sub.1 and R.sub.2 together mean an exocyclic methylene
group and Y'.sub.1 means a hydrogen atom or a protected hydroxyl
group and Y'.sub.2 means a hydroxy protective group, a start is
made from known aldehyde III [M. Calverley Tetrahedron 43, 4609
(1987), WO 87/00834]. 5
[0266] For Y'.sub.1 and Y'.sub.2, protective groups other than
those mentioned in the bibliographic references can be obtained by
analogous procedure using correspondingly modified silyl chlorides
(e.g., tert-butyldiphenylsilyl chloride instead of
tert-butyldimethylsilyl chloride). By foregoing the corresponding
stages for 1.alpha.-hydroxylation, derivatives of Y'.sub.1.dbd.H
type can be obtained.
[0267] The compounds of general formula III are now converted,
analogously to known processes, into aldehydes of general formula
IV [EP 647 219, WO 94/07853, M. J. Calverley, L. Binderup Bioorg.
Med. Chem. Lett. 3, 1845-1848 (1993)]. 6
[0268] For R.sub.3 and R.sub.4, the definitions that are already
mentioned above apply.
[0269] To establish the natural vitamin D-triene system, a
photochemical isomerization of the compounds of general formula IV
is performed. Irradiation with ultraviolet light is carried out in
the presence of a so-called triplet sensitizer. Within the scope of
this invention, anthracene is used in this respect. By cleavage of
the .pi.-bond of the 5,6-double bond, rotation of the A ring by
180.degree. around the 5,6-single bond and reestablishing the
5,6-double bond, the stereoisomerism on the 5,6-double bond is
reversed, whereby compounds of general formula V accumulate, 7
[0270] In principle, this isomerization reaction is also possible
in a later stage. By way of example, the reactions of aldehyde VI
with natural configuration at C-20 are described below. 8
[0271] In principle, however, the following reactions are also
possible with the above-mentioned substitution models at C-20.
[0272] First, the synthesis of compounds, which represent a special
case of general formula II, is described. R.sub.1 and R.sub.2 thus
form together a methylene group, R.sub.3 is a hydrogen atom and
R.sub.4 is a methyl group, Q is a methylene group and Z' means a
straight-chain 1-oxoalkyl group with 1-12 carbon atoms, in which
the keto group is protected (e.g., ketal: dialkoxyketal,
1,3-dioxolan, 1,3-dioxane, 5,5-dimethyl-1,3-dioxane).
[0273] Starting material for the side-chain fragments is an
acetoacetic acid ester of general formula VII. 9
[0274] R.sub.5 can be a straight-chain or branched alkyl group with
up to 6 carbon atoms (preferably methyl or ethyl group). To create
longer chains, compound VII is double-deprotonated with two
equivalents of one or two different bases (e.g., lithium
diisopropylamide, n-butyllithium, sodium hydride, potassium
hydride) and then alkylated with an equivalent of an alkyl halide
(bromide or iodide) at the reactive position, whereby the compound
of general formula VIII accumulates [L. Weiler et al. J. Am. Chem.
Soc. 96, 1082-1087 (1974), N. Haddad et al. J. Org. Chem. 60,
6883-6887 (1995), D. F. Taber et al. J. Org. Chem. 60, 2283-2285
(1995)]. R.sub.6 means a straight-chain or branched alkyl group
with up to 11 carbon atoms.
[0275] Compounds VII or VIII are now reacted with a base (e.g.,
potassium carbonate, sodium carbonate, potassium alcoholate) and
1,2-dibromoethane, whereby compounds of general formula IX are
produced. R.sub.6 has the meaning already mentioned or is a
hydrogen atom [D. F. Taber et al. J. Org. Chem. 57, 436-441
(1992)].
[0276] The keto group of compound IX is now converted into a ketal
under standard conditions, whereby compound X is produced, in which
K means a keto protective group. As keto protective groups, all in
"Protective Groups in Organic Synthesis," 2nd Edition, John Wiley
& Sons, 1991 (T. W. Greene, P. G. M. Wuts) are suitable (e.g.,
1,3-dioxolan, 1,3-dioxane, 5,5-dimethyl-1,3-dioxane,
dialkoxyketals). By way of example, 1,3-dioxolan derivative X
(K=--O--CH.sub.2--CH.sub.2--O--) is described below. The use of
other ketal groups is, however, possible in principle. 10
[0277] Reduction of the ester unit to alcohol XI can be carried out
with a standard reducing agent (e.g., lithium aluminum hydride,
diisobutylaluminum hydride). Subsequent oxidation under the usual
conditions (manganese dioxide, pyridinium chlorochromate,
pyridinium dichromate, Swern conditions) yields aldehyde XII as an
important intermediate product (depicted in the drawing as a
1,3-dioxolan derivative, not limited to this protective group, but
rather also can be produced with other keto protective groups, see
above). In a Wittig reaction with the ylide of
methyltriphenylphosphonium iodide or bromide (deprotonation with,
e.g., n-butyllithium), olefin XIII is generated. 11
[0278] The double bond can now be hydroborated under standard
conditions and converted into alcohol XIV after oxidative
working-up [Pelter, Smith, Brown, Borane Reagents; Academic Press:
New York, 1988; H. C. Browm et al. Heterocycles 25, 641-567
(1987).] The alcohol function is now tosylated (XV, X.dbd.OTos) and
reacted with the thiophenolate anion to thioether XV (X.dbd.SPh).
Oxidation (e.g., with hydrogen peroxide, metachloroperbenzoic acid,
tert-butylhydroperoxide, sodium periodate) then yields sulfone XV
(X.dbd.SO.sub.2Ph) [P. C. Bulman Page et al. Synth. Comm. 23,
1507-1514 (1993)].
[0279] Sulfone XV is now deprotonated with a base (e.g.,
n-butyllithium, lithium diisopropylamide, sodium hydride, potassium
hydride) and reacted at low temperature (between -100.degree. C.
and -20.degree. C.) with aldehyde VI, whereby hydroxysulfones of
general formula. XVI (X.dbd.SO.sub.2Ph) accumulate. 12
[0280] Conversion of the hydroxysulfones into compounds that carry
a double bond in the side chain is possible in the case of vitamin
D derivatives, preferably by reaction with a sodium amalgam [H. F.
DeLuca et al. Bioorg. Chem. 15, 152-166 (1987), H. F. DeLuca et al.
Biochemistry 29, 190-196 (1990)]. 13
[0281] In addition to the olefins of general formula XVII, the
alcohols of general formula XVIII, which are separated by
chromatography, also accumulate.
[0282] The compounds of general formulas XVII and XVIII can be
regarded as special cases of general formula II and can be
converted into the title compounds of general formula I as
described above.
[0283] Below, the synthesis of compounds that represent another
special case of general formula II is described. R.sub.1 and
R.sub.2 together thus form a methylene group, R.sub.3 is a hydrogen
atom, and R.sub.4 is a methyl group, Q is an ethylene group and Z'
has the definition already mentioned above.
[0284] To create the side-chain fragments, aldehydes of general
formula XII are reacted in the Horner-Wadsworth-Emmons reactions
with deprotonated phosphonoacetic acid esters (base: e.g., lithium
diisopropylamide, n-butyllithium, sodium hydride, potassium
hydride), whereby esters of general formula XIX accumulate. 14
[0285] Reduction under Birch conditions (lithium, sodium or calcium
in liquid ammonia or amines) yields the alcohols of general formula
XX (X.dbd.OH).
[0286] The alcohol group is now tosylated (XX, X.dbd.OTos) and
reacted with the thiophenolate anion to thioether XX (X.dbd.SPh).
Oxidation (e.g., with hydrogen peroxide, metachloroperbenzoic acid,
tert-butylhydroperoxide, sodium periodate) then yields sulfone XX
(X.dbd.SO.sub.2Ph) [P. C. Bulman Page et al. Synth. Comm. 23,
1057-1514 (1993)].
[0287] Sulfone. XX is now deprotonated with a base (e.g.,
n-butyllithium, lithium diisopropylamide, sodium hydride, potassium
hydride) and reacted at low temperature (between -100.degree. C.
and -20.degree. C.) with aldehyde VI, whereby hydroxysulfones of
general formula XXI (X.dbd.SO.sub.2Ph) accumulate. 15
[0288] Conversion of the hydroxysulfones into compounds that carry
a double bond in the side chain is possible in the case of vitamin
D derivatives, preferably by reaction with a sodium amalgam [H. F.
DeLuca et al. Bioorg. Chem. 15, 152-166 (1987), H. F. DeLuca et al.
Biochemistry 29, 190-196 (1990)]. 16
[0289] In addition to the olefins of general formula XXII, the
alcohols of general formula XXIII, which are separated by
chromatography, also accumulate.
[0290] The compounds of general formulas XXII and XXIII can be
regarded as special cases of general formula II and can be
converted into the title compounds of general formula I as
described above.
[0291] Below, the synthesis of compounds that represent another
special case of general formula II is described. R.sub.1 and
R.sub.2 together thus form a methylene group, R.sub.3 is a hydrogen
atom and R.sub.4 is a methyl group, Q means
--CH(OH)--CH.sub.2--CH.sub.2--, and Z' has the meaning already
mentioned above.
[0292] In this case, the aldehyde of general formula XII is
converted with oxopropylphosphonic acid dialkyl ester in the
presence of a base (triethylamine, ethyldiisopropylamine,
triisopropylamine, diazabicyclononane, diazabicycloundecane, sodium
hydride) with the optional addition of lithium chloride into ketone
XXIV [S. Masamune et al. Tetrahedron Lett. 25, 2183-2186 (1984), B.
Resul et al. J. Med. Chem. 36, 243-248 (1993)]. 17
[0293] Reaction to form saturated ketones of general formula XXV
can be carried out by Birch reduction (described above) optionally
followed by reoxidation (e.g., with pyridinium dichromate,
pyridinium chlorochromate, Swern conditions) or by hydrogenation of
the double bond. To avoid hydrogenolytic cleavage of the
cyclopropyl ring, platinum(VI) oxide or a soluble rhodium catalyst
(e.g., Wilkinson's catalyst) should be used as a catalyst.
[0294] Ketones XXV are regioselectively deprotonated with a base
(e.g., lithium diisopropylamide, lithium or sodium hexamethyl
disilazide) and reacted at low temperature with the aldehyde of
general formula VI, whereby compounds of general formula XXVI
(X.dbd.OH) accumulate. 18
[0295] The hydroxyl group is then converted into a leaving group
under standard conditions, whereby compounds of general formula
XXVI (X=e.g. acetate, trifluoroacetate, tosylate, mesylate or
triflate) are produced.
[0296] Elimination with the aid of bases (e.g., diazabicyclononane,
diazabicycloundecane, triethylamine, diisopropylamine,
ethyldiisopropylamine) at optionally increased reaction
temperatures yields the ketones of general formula XXVII. 19
[0297] The carbonyl groups in XXVII can now be reduced to
diastereomeric alcohols XXVIII (reducing agent: e.g., sodium
borohydride/cerium trichloride, lithium aluminum hydride,
diisobutylaluminum hydride, lithium borohydride) and are separated
by chromatography. 20
[0298] The cleavage of the protective groups at the compound of
general formula XXVIII, which is to be viewed as a special case of
general formula II, should be carried out in a successive manner.
The ketal is cleaved off by mild acid reaction conditions (e.g.,
pyridinium-p-toluenesulfonate, oxalic acid/silica gel), whereby
compounds of general formula XXIX accumulate. As described,
compounds of general formula I are then obtained.
[0299] Below, the synthesis of compounds that represent another
special case of general formula II is described. R.sub.1 and
R.sub.2 together thus form a methylene group, R.sub.3 is a hydrogen
atom and R.sub.4 is a methyl group, Q means --CH(OH)--, and Z'
means an alkyl or alkenyl group with 1-12 carbon atoms.
[0300] The aldehyde of general formula XII, if R.sub.6 is a
hydrogen atom, is reacted with alkyltriphenylphosphonium salts in
the presence of bases (e.g., n-butyllithium, sodium hydride,
potassium hydride) in Wittig reactions, whereby compounds of
general formula XXX accumulate. R.sub.7 means a straight-chain or
branched alkyl or alkenyl group with 1-10 carbon atoms. Double-bond
E,Z-mixtures usually occur. Chromatographic separation of isomers
is carried out only at a later stage. 21
[0301] The cleavage of the ketal unit is carried out under acidic
reaction conditions (e.g., hydrochloric acid, acetone;
p-toluenesulfonic acid, methanol; oxalic acid, silica gel), whereby
compounds of general formula XXXI are obtained.
[0302] Ketones XXXI are deprotonated with a base (e.g., lithium
diisopropylamide, lithium or sodium hexamethyldisilazide) and
reacted at low temperature with the aldehyde of general formula VI,
whereby compounds of general formula XXXII (X.dbd.OH) accumulate.
22
[0303] The hydroxyl group is then converted under standard
conditions into a leaving group, whereby compounds of general
formula XXXII (X=e.g., acetate, trifluoroacetate, tosylate,
mesylate or triflate) are produced.
[0304] Elimination with the aid of bases (e.g., diazabicyclononane,
diazabicycloundecane, triethylamine, diisopropylamine,
ethyldiisopropylamine) at optionally higher reaction temperatures
yields the ketones of general formula XXXIII.
[0305] The carbonyl groups in XXXIII can now be reduced to the
diastereomeric alcohols XXXIV (reducing agent: e.g., sodium
borohydride/cerium trichloride, lithium aluminum hydride,
diisobutylaluminum hydride, lithium borohydride) and are separated
by chromatography. 23
[0306] The compound of general formula XXXIV can be regarded as a
special case of general formula II and is converted, as described,
into the compound of general formula I.
[0307] In addition, the double bond of the compound of general
formula XXX can be hydrogenated, whereby a compound of general
formula XXXV accumulates. As catalysts, soluble rhodium catalysts
(Wilkinson's catalyst) or platinum(VI) oxide are to be preferred
here. 24
[0308] The cleavage of the ketal to form ketone XXXVI and the
linkage to the vitamin D skeleton are carried out as described
above, so that finally a compound of general formula XXXVII that is
to be regarded as a special case of general formula II is produced.
25
[0309] The conversion into a compound of general formula I is
carried out as described.
[0310] For synthesis of compounds of general formula II for which
R.sub.1 and R.sub.2 are hydrogen atoms, a convergent synthesis
method must be employed, in which CD- and A-ring fragments are
synthesized separately. For synthesis of the CD-fragments, aldehyde
XXXVIII that is known in the literature [H. H. Inhoffen et al.
Chem. Ber. 92, 7.81-791 (1958); H. H. Inhoffen et al. Chem. Ber.
92, 1772-1788 (1959); W. G. Dauben et al., Tetrahedron Lett. 30,
677-680 (1989)] is used, 26
[0311] in which P means an acyl-, alkyl- or aryl-substituted silyl
group, or a tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl or
ethoxyethyl group, an acyl group (e.g., acetyl or benzoyl group) or
another hydroxy protective group (see T. W. Greene, P. G. M. Wuts
Protective Groups in organic Synthesis, 2.sup.nd Edition, John
Wiley and Sons, Inc. 1991).
[0312] According to the known processes, the already described
modifications at C-20 can be introduced here (WO 94/07853), whereby
a compound of general formula XXXIX accumulates. 27
[0313] The introduction of the side chains is carried out here
analogously to the case of vitamin D-aldehyde XII, whereby
compounds of general formula XL are obtained. 28
[0314] V' means a protected hydroxyl group or together with W an
E-double bond. The other variables were already defined
previously.
[0315] In the selection of suitable protective groups (e.g.,
P=triethylsilyl, V'=tetrahydropyranoxy), P is selectively cleaved
off (e.g., with tetrabutylammonium fluoride), whereby the compound
of general formula XLI accumulates. 29
[0316] Oxidation according to known methods (e.g., pyridinium
chlorochromate, pyridinium dichromate, Swern conditions) produces a
compound of general formula XLII, which by reaction with the anion,
produced by a base (e.g., lithium diisopropylamide,
n-butyllithium), of the phosphine oxide of general formula XLIII
known in the literature [H. F. DeLuca et al. Tetrahedron Lett. 32,
7663-7666 (1991)], in which Y'.sub.2 has the already described
meaning, is converted into corresponding compounds of general
formula II for which the following is true: Y'.sub.1.dbd.OY'.sub.2.
Further reaction to form the compound of general formula I is
carried out as already described.
[0317] The following examples are used for a more detailed
explanation of the invention.
Synthesis of the Starting Compounds in the 24-Methylene Series
1.
(5Z,7E)-(1S,3R)-1,3-Bis[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-9,10-se-
copregna-5,7,10(19)-triene-20-carbaldehyde 2
[0318] 7.5 g of
(5E,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]-
oxy]-9,10-secopregna-5,7,10(19)-triene-20-carbaldehyde 1 [M. J.
Calverley Tetrahedron 43, 4609-4619 (1987)] is dissolved in 200 ml
of toluene, 2 g of anthracene and 0.5 ml of triethylamine are added
and irradiated while nitrogen is passing through it in a Pyrex
apparatus with a high-pressure mercury-vapor lamp for 30 minutes.
Then, it is filtered, concentrated by evaporation, and the residue
is chromatographed on silica gel with ethyl acetate/hexane, whereby
7.1 g of title compound 2 is obtained as a colorless foam.
[0319] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.05 ppm (s,
12H); 0.55 (s, 3H); 0.88 (s, 18H); 1.11 (d, 3H); 2.37 (m, 1H); 4.18
(m, 1H); 4.37 (m, 1H); 4.84 (brs, 1H); 5.17 (brs, 1H); 6.00 (d,
1H); 6.22 (d, 1H); 9.58 (d, 1H)
2. 1-Acetylcyclopropanecarboxylic acid methyl ester 4
[0320] 56 g of acetoacetic acid methyl ester 3 is dissolved in 500
ml of acetone, and 276.2 g of potassium carbonate as well as 86 ml
of dibromoethane are added while being cooled with ice. It is
heated under nitrogen to 50.degree. C. and stirred for 72 hours at
this temperature. After cooling, the mixture is diluted with ethyl
acetate, washed with water and saturated sodium chloride solution,
dried on sodium sulfate and concentrated by evaporation. The
residue is distilled in a vacuum, whereby 66 g of the title
compound is obtained as a colorless oil.
[0321] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.48 ppm (s, 4H);
2.47 (s, 3H); 3.74 (s, 3H)
3. 1-(2-Methyl-1,3-dioxolan-2-yl)cyclopropanecarboxylic acid methyl
ester 5
[0322] 18.7 g of 4 is dissolved in 500 ml of benzene, 30 ml of
ethylene glycol and 1 g of p-toluenesulfonic acid are added and
heated under nitrogen in a water separator for 12 hours. After
cooling, sodium bicarbonate solution is added, extracted with ethyl
acetate, dried on sodium sulfate and concentrated by evaporation,
whereby 23 g of title compound 5 accumulates as a colorless
oil.
[0323] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.02 ppm (m, 2H);
1.16 (m, 2H); 1.61 (s, 3H); 3.69 (s, 3H); 3.92 (m, 4H)
4. 1-(2-Methyl-1,3-dioxolan-2-yl)cyclopropane methanol 6
[0324] 11.2 g of 5 is dissolved in 150 ml of toluene and cooled
under nitrogen to 0.degree. C. 125 ml of DIBAH solution (1.2 M in
toluene) is now slowly added in drops and stirred for 2 more hours.
Then, 1.25 ml of isopropanol and 25 ml of water are added in drops
and stirred overnight. The precipitate is filtered off, the
filtrate is concentrated by evaporation and chromatographed on
silica gel with ethyl acetate/hexane, whereby 9.1 of title compound
6 accumulates as a colorless oil.
[0325] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.47 ppm (m, 2H);
0.72 (m, 2H); 1.41 (s, 3H); 2.92 (t, OH); 3.53 (d, 2H); 3.97 (m,
4H)
5. 1-(2-Methyl-1,3-dioxolan-2-yl)cyclopropanecarbaldehyde 7
[0326] 10 g of 6 is dissolved in 500 ml of dichloromethane, and 3.7
g of sodium acetate and 19.3 g of pyridinium chlorochromate are
added at room temperature under nitrogen. After 3 hours at room
temperature, it is filtered on silica gel, concentrated by
evaporation, diluted with diethyl ether, filtered again, and the
solvent is removed, whereby 7.8 g of title compound 7 is obtained
as a colorless oil.
[0327] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=1.16 ppm (m, 4H);
1.57 (s, 3H); 3.97 (m, 3H); 9.49 (s, 1H)
6. 2-(1-Ethenylcyclopropyl)-2-methyl-1,3-dioxolan 8
[0328] 44.6 g of methyltriphenylphosphonium bromide in 700 ml of
diethyl ether is introduced, and 50 ml of n-butyllithium solution
(2.5 M in hexane) is added in drops at 0.degree. C. under nitrogen.
It is stirred for 1 more hour at room temperature and then 9.5 g of
7 in 10 ml of diethyl ether is added. After 1 hour, the reaction
solution is quenched with sodium chloride solution, extracted with
ethyl acetate, washed with sodium chloride solution, dried on
sodium sulfate, and the solvent is removed. The residue is
chromatographed on silica gel with ethyl acetate/hexane, whereby
5.4 g of title compound 8 is obtained as a colorless oil.
[0329] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.59 ppm (m, 2H);
0.86 (m, 2H); 1.41 (s, 3H); 3.95 (m, 4H); 4.98 (d, 1H); 4.99 (d,
1H); 6.21 (dd, 1H)
7. 1-(2-Methyl-1,3-dioxolan-2-yl)cyclopropanethanol 9
[0330] 5.4 g of 8 is dissolved in 200 ml of tetrahydrofuran (THF),
and 14 ml of borane-THF solution (1.0 M in THF) is added in drops
at 0.degree. C. under nitrogen. The reaction mixture is then
allowed to reach room temperature, and it is stirred for 2 more
hours. After cooling was again performed at 0.degree. C., 17 ml of
water, 17 ml of aqueous sodium hydroxide solution (25%) and 2 ml of
hydrogen peroxide (30%) are added in succession and stirred for 1
more hour. Then, sodium thiosulfate solution is added, extracted
with ethyl acetate, washed with sodium chloride solution, dried on
sodium sulfate and concentrated by evaporation. The residue is
chromatographed on silica gel with ethyl acetate/hexane, whereby
3.9 g of title compound 9 is obtained as a colorless oil.
[0331] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.=0.29 ppm (m, 2H);
0.73 (m, 2H); 1.43 (s, 3H); 1.63 (t, 2H); 3.52 (t, OH); 3.79 (q,
2H); 3.93 (m, 4H)
8. 4-Methylbenzenesulfonic acid
2-[1-(2-methyl-1,3-dioxolan-2-yl)cycloprop- yl]ethyl ester 10
[0332] 470 mg of 9 is dissolved in 10 ml of pyridine, and
p-toluenesulfonyl chloride is added at 0.degree. C. under nitrogen.
It is stirred for 1 hour at 0.degree. C., and then sodium
bicarbonate solution is added. It is extracted with ethyl acetate,
washed with dilute hydrochloric acid and then with sodium
bicarbonate solution, dried on sodium sulfate and concentrated by
evaporation. After the residue is chromatographed on silica gel
with ethyl acetate/hexane, 670 mg of the title compound remains as
a colorless oil.
[0333] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.27 ppm (m, 2H);
0.61 (m, 2H); 1.29 (s, 3H); 1.78 (t, 2H); 2.46 (s, 3H); 3.80 (m,
4H); 4.23 (t, 2H); 7.35 (d, 2H); 7.81 (d, 2H)
9. 2-Methyl-2-[1-[2-(phenylsulfanyl)ethyl]cyclopropyl]-1,3-dioxolan
11
[0334] 590 mg of 10 is dissolved in 2 ml of dimethylformamide (DMF)
and added under nitrogen to a mixture of 300 mg of
potassium-t-butylate and 0.27 ml of thiophenol in 5 ml of DMF. It
is stirred for 1 hour at room temperature and then quenched with
sodium chloride solution. It is extracted with ethyl acetate,
washed with sodium bicarbonate solution and sodium chloride
solution, dried on sodium sulfate, concentrated by evaporation, and
the residue is chromatographed on silica gel with ethyl
acetate/hexane, whereby 630 mg of title compound 11 accumulates as
a yellowish oil.
[0335] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.29 ppm (m, 2H);
0.68 (m, 2H); 1.38 (s, 3H); 1.75 (t, 2H); 3.10 (m, 2H); 3.92 (m,
4H); 7.28 (d, 5H)
10.
2-Methyl-2-[1-[2-(phenylsulfonyl)ethyl]cyclopropyl]-1,3-dioxolan
12
[0336] 480 mg of 11 is dissolved in 18 ml of methanol, and 180 mg
of potassium carbonate, 221 mg of acetonitrile and 612 mg of
hydrogen peroxide are added under nitrogen and stirred for 6 hours
at room temperature. Sodium thiosulfate solution is now added,
extracted with ethyl acetate, washed with sodium chloride solution,
dried on sodium sulfate, concentrated by evaporation, and the
residue is chromatographed on silica gel with ethyl acetate/hexane,
whereby 380 mg of title compound 12 is obtained as a colorless
oil.
[0337] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.25 ppm (m, 2H);
0.68 (m, 2H); 1.23 (s, 3H); 1.78 (m, 2H); 3.39 (m, 2H); 3.82 (m,
4H); 7.57 (t, 2H); 7.66 (t, 1H); 7.90 (d, 2H)
11. 3-Oxohexanoic acid methyl ester 13
[0338] 44.4 g of sodium hydride suspension (60% in paraffin oil) is
introduced into 1500 ml of THF, and 107.5 ml of acetoacetic acid
methyl ester 3 is added under nitrogen at 0.degree. C. After 10
minutes, 440 ml of n-butyllithium solution (2.5 M in hexane) is
then added in drops, and it is stirred for another 30 minutes at
0.degree. C. Now, 88.9 ml of iodoethane is added, and it is stirred
overnight at room temperature. For working-up, it is again cooled
to 0.degree. C. and neutralized with 4N hydrochloric acid. The
organic phase is diluted with ethyl acetate, washed with
thiosulfate solution and sodium chloride solution, dried on sodium
sulfate and concentrated by evaporation. The residue is then
chromatographed on silica gel with ethyl acetate/hexane, whereby
95.13 g of title compound 13 is obtained as a colorless oil.
[0339] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.93 ppm (t, 3H);
1.64 (quint, 2H); 2.52 (t, 2H); 3.46 (s, 2H); 3.75 (s, 3H)
12. 1-Oxobutylcyclopropanecarboxylic acid methyl ester 14
[0340] 95 g of 13 is reacted analogously to 2., and 110 g of title
compound 14 is obtained as a colorless oil.
[0341] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.91 ppm (t, 3H);
1.43 (s, 4H); 1.61 (quint, 2H); 2.81 (t, 2H); 3.75 (s, 3H)
13. 1-(2-Propyl-1,3-dioxolan-2-yl)cyclopropanecarboxylic acid
methyl ester 15
[0342] 113 g of 14 is reacted analogously to 3., and 78 g of title
compound 15 is obtained as a colorless oil.
[0343] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.91 ppm (t, 3H);
1.00 (m, 2H); 1.04 (m, 2H); 1.40 (m, 2H); 2.04 (m, 2H); 3.68 (s,
3H); 3.93-3.98 (m, 4H)
14. 1-(2-Propyl-1,3-dioxolan-2-yl)cyclopropanemethanol 16
[0344] 52 g of 15 is reacted analogously to 4., and 41.50 g of
title compound 16 is obtained as a colorless oil.
[0345] .sup.1H-NMR (306 MHz, CDCl.sub.3): .delta.=0.40 ppm (m, 2H);
0.68 (m, 2H); 0.93 (t, 3H); 1.40 (m, 2H); 1.84 (m, 2H); 2.98 (t,
OH); 3.50 (d, 2H); 3.98 (m, 4H)
15. 1-(2-Propyl-1,3-dioxolan-2-yl)cyclopropanecarbaldehyde 17
[0346] 25.65 g of 16 is reacted analogously to 5., and 19.62 g of
title compound 17 is obtained as a colorless oil.
[0347] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.92 ppm (t, 3H);
1.10 (s, 4H); 1.42 (m, 2H); 1.90 (m, 2H); 3.98 (m, 4H); 9.58 (s,
1H)
16. 2-(1-Ethenylcyclopropyl)-2-propyl-1,3-dioxolan 18
[0348] 4.2 g of 17 is reacted analogously to 6., and 4.15 g of
title compound 18 is obtained as a colorless oil.
[0349] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.54 ppm (m, 2H);
0.80 (m, 2H); 0.90 (t, 3H); 1.40 (m, 2H); 1.75 (m, 2H); 3.96 (m,
4H); 4.94 (d, 1H); 4.95 (d, 1H); 6.23 (dd, 1H)
17. 1-(2-Propyl-1,3-dioxolan-2-yl)cyclopropanethanol 19
[0350] 4.15 g of 18 is reacted analogously to 7., and 2.71 g of
title compound 19 is obtained as a colorless oil.
[0351] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.22 ppm (m, 2H);
0.69 (m, 2H); 0.94 (t, 3H); 3.65 (t, OH); 3.70 (m, 2H); 3.94 (m,
4H)
18. 4-Methylbenzenesulfonic acid
2-[1-(2-propyl-1,3-dioxolan-2-yl)cyclopro- pyl]ethyl ester 20
[0352] 1.85 g of 19 is reacted analogously to 8., and 1.41 g of
title compound 20 is obtained as a colorless oil.
[0353] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.20 ppm (m, 2H);
0.59 (m, 2H); 0.87 (t, 3H); 1.70 (t, 2H); 2.45 (s, 3H); 3.80 (m,
4H); 4.26 (t, 2H); 7.35 (d, 2H); 7.80 (d, 2H)
19.
2-[1-[2-(Phenylsulfanyl)ethyl]cyclopropyl]-2-propyl-1,3-dioxolan
21
[0354] 1.41 g of 20 is reacted analogously to 9., and 980 mg of
title compound 21 is obtained as a colorless oil.
[0355] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.23 ppm (m, 2H);
0.65 (m, 2H); 0.92 (t, 3H); 1.75 (t, 2H); 3.12 (t, 2H); 3.94 (m,
4H); 7.30 (m, 5H)
20.
2-[1-[2-(Phenylsulfonyl)ethyl]cyclopropyl]-2-propyl-1,3-dioxolan
22
[0356] 910 mg of 21 is reacted analogously to 10., and 722 mg of
title compound 22 is obtained as a colorless oil.
[0357] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.18 ppm (m, 2H);
0.62 (m, 2H); 0.86 (t, 3H); 1.32 (m, 2H); 1.58 (m, 2H); 1.72 (m,
2H); 3.40 (m, 2H); 3.81 (m, 4H); 7.57 (t, 2H); 7.65 (t, 1H); 7.90
(d, 2H)
3-Oxoheptanoic acid methyl ester 23
[0358] 118 ml of acetoacetic acid methyl ester 3 is reacted with
n-ne iodopropane analogously to 11., and 135 g of title compound 23
is obtained as a colorless oil.
[0359] 1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.91 ppm (t, 3H); 1.32
(hex, 2H); 1.59 (quint, 2H); 2.53 (t, 2H); 3.47 (s, 2H); 3.75 (s,
3H)
22. 1-Oxopentylcyclopropanecarboxylic acid methyl ester 24
[0360] 135 g of 23 is reacted analogously to 2., and 123 g of title
compound 24 is obtained as a colorless oil.
[0361] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.90 ppm (t, 3H);
1.30 (hex, 2H); 1.42 (s, 4H); 1.58 (quint, 2H); 2.83 (t, 2H); 3.72
(s, 3H).
23. 1-(2-Butyl-1,3-dioxolan-2-yl)cyclopropanecarboxylic acid methyl
ester 25
[0362] 59 g of 24 is reacted analogously to 3., and 45 g of title
compound 25 is obtained as a colorless oil.
[0363] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.89 ppm (t, 3H);
1.00 (m, 2H); 1.12 (m, 2H); 1.30 (m, 4H); 2.05 (m, 2H); 3.68 (s,
3H); 3.96 (m, 4H)
24. 1-(2-Butyl-1,3-dioxolan-2-yl)cyclopropanemethanol 26
[0364] 25 g of 25 is reacted analogously to 4., and 16.8 g of title
compound 26 is obtained as a colorless oil.
[0365] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.40 ppm (m, 2H);
0.69 (m, 2H); 0.89 (t, 3H); 1.32 (m, 4H); 1.84 (m, 2H); 3.02 (brs,
OH); 3.50 (brs, 2H); 3.97 (m, 4H)
25. 1-(2-Butyl-1,3-dioxolan-2-yl)cyclopropanecarbaldehyde 27
[0366] 16.3 g of 26 is reacted analogously to 5., and 16.0 g of
title compound 27 is obtained as a colorless oil.
[0367] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.90 ppm (t, 3H);
1.10 (s, 4H); 1.33 (m, 4H); 1.90 (m, 2H); 3.98 (m, 4H); 9.58 (s,
1H)
26. 2-Butyl-2-(1-ethenylcyclopropyl)-1,3-dioxolan 28
[0368] 5.0 g of 27 is reacted analogously to 6., and 3.89 g of
title compound 28 is obtained as a colorless oil.
[0369] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.54 ppm (m, 2H);
0.80 (m, 2H); 0.90 (t, 3H); 1.30 (m, 4H); 1.79 (m, 2H); 3.94 (m,
4H); 4.94 (d, 1H); 4.95 (d, 1H); 6.22 (dd, 1H)
27. 1-(2-Butyl-1,3-dioxolan-2-yl)cyclopropanethanol 29
[0370] 1.51 g of 28 is reacted analogously to 7., and 1.10 g of
title compound 29 is obtained as a colorless oil.
[0371] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.22 ppm (m, 2H);
0.69 (m, 2H); 0.90 (t, 3H); 1.31 (m, 4H); 1.60 (t, 2H); 1.83 (m,
2H); 3.63 (brs, OH); 3.70 (m, 2H); 3.94 (m, 4H)
28. 4-Methylbenzenesulfonic acid
2-[1-(2-butyl-1,3-dioxolan-2-yl)cycloproy- l]ethyl ester 30
[0372] 1.10 g of 29 is reacted analogously to 8., and 1.05 g of
title compound 30 is obtained as a colorless oil.
[0373] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.20 ppm (m, 2H);
0.60 (m, 2H); 0.89 (t, 3H); 1.70 (t, 2H); 2.47 (s, 3H); 3.80 (m,
4H); 4.24 (t, 2H); 7.33 (d, 2H); 7.79 (d, 2H)
29. 2-Butyl-2-[1-[2-(phenylsulfanyl)ethyl]cyclopropyl]-1,3-dioxolan
31
[0374] 1.05 g of 30 is reacted analogously to 9., and 675 mg of
title compound 31 is obtained as a colorless oil.
[0375] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.23 ppm (m, 2H);
0.64 (m, 2H); 0.90 (t, 3H); 1.30 (m, 4H); 1.72 (m, 4H); 3.11 (m,
2H); 3.91 (m, 4H); 7.28 (m, 5H)
30. 2-Butyl-2-[1-[2-(phenylsulfonyl)ethyl]cyclopropyl]-1,3-dioxolan
32
[0376] 1.15 g of 31 is reacted analogously to 10., and 913 mg of
title compound 32 is obtained as a colorless oil.
[0377] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.19 ppm (m, 2H);
0.64 (m, 2H); 0.87 (t, 3H); 1.28 (m, 6H); 1.72 (m, 2H); 3.40 (m,
2H); 3.82 (m, 4H); 7.58 (t, 2H); 7.68 (t, 1H); 7.92 (d, 2H)
31. 3-Oxooctanoic acid methyl ester 33
[0378] 23 g of acetoacetic acid methyl ester 3 is reacted with
n-iodobutane analogously to 11., and 29.4 g of title compound 33 is
obtained as a colorless oil.
[0379] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.9.0 ppm (t,
3H); 1.29 (m, 4H); 1.60 (m, 2H); 2.52 (t, 2H); 3.46 (s, 2H); 3.73
(s, 3H)
32. 1-Oxohexylcyclopropanecarboxylic acid methyl ester 34
[0380] 18.3 g of 33 is reacted analogously to 2., and 15.2 g of
title compound 34 is obtained as a colorless oil.
[0381] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.89 ppm (t, 3H);
1.30 (m, 4H); 1.45 (s, 4H); 1.60 (m, 2H); 2.81 (t, 2H); 3.75 (s,
0.3H)
33. 1-(2-Pentyl-1,3-dioxolan-2-yl)cyclopropanecarboxylic acid
methyl ester 35
[0382] 15.1 g of 34 is reacted analogously to 3., and 13.2 g of
title compound 35 is obtained as a colorless oil.
[0383] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.89 ppm (t, 3H);
1.00 (m, 2H); 1.14 (m, 2H); 1.30 (m, 6H); 2.05 (m, 2H); 3.69 (s,
3H); 3.92 (m, 4H)
34. 1-(2-Pentyl-1,3-dioxolan-2-yl)cyclopropanemethanol 36
[0384] 10.0 g of 35 is reacted analogously to 4., and 7.3 g of
title compound 36 is obtained as a colorless oil.
[0385] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.40 ppm (m, 2H);
0.69 (m, 2H); 0.90 (t, 3H); 1.33 (m, 6H); 1.85 (m, 2H); 3.01 (t,
OH); 3.50 (d, 2H); 3.97 (m, 4H)
35. 1-(2-Pentyl-1,3-dioxolan-2-yl)cyclopropanecarbaldehyde 37
[0386] 7.3 g of 36 is reacted analogously to 5., and 5.9 g of title
compound 37 is obtained as a colorless oil.
[0387] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.89 ppm (t, 3H);
1.10 (s, 4H); 1.24-1.47 (m, 6H); 1.90 (m, 2H); 3.98 (m, 4H); 9.58
(s, 1H)
36. 2-(1-Ethenylcyclopropyl)-2-pentyl-1,3-dioxolan 38
[0388] 5.3 g of 37 is reacted analogously to 6., and 1.98 g of
title compound 38 is obtained as a colorless oil.
[0389] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.53 ppm (m, 2H);
0.80 (m, 2H); 0.89 (t, 3H); 1.20-1.45 (m, 6H); 1.77 (m, 2H); 3.96
(m, 4H); 4.96 (d, 1H); 4.97 (d, 1H); 6.23 (dd, 1H)
37. 1-(2-Pentyl-1,3-dioxolan-2-yl)cyclopropanethanol 39
[0390] 1.70 g of 38 is reacted analogously to 7., and 1.20 g of
title compound 39 is obtained as a colorless oil.
[0391] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.23 ppm (m, 2H);
0.70 (m, 2H); 0.90 (t, 3H); 1.22-1.43 (m, 6H); 1.62 (m, 2H); 1.85
(m, 2H); 3.57 (brs, OH); 3.70 (m, 2H); 3.94 (m, 4H)
38. 4-Methylbenzenesulfonic acid
2-[1-(2-pentyl-1,3-dioxolan-2-yl)cyclopro- pyl]ethyl ester 40
[0392] 456 mg of 39 is reacted analogously to 8., and 620 mg of
title compound 40 is obtained as a colorless oil.
[0393] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.20 ppm (m, 2H);
0.60 (m, 2H); 0.90 (t, 3H); 1.29 (m, 6H); 1.63 (m, 2H); 1.72 (t,
2H); 2.47 (s, 3H); 3.80 (m, 4H); 4.25 (t, 2H); 7.35 (d, 2H); 7.80
(d, 2H)
39.
2-Pentyl-2-[1-[2-(phenylsulfanyl)ethyl]cyclopropyl]-1,3-dioxolan
41
[0394] 610 mg of 40 is reacted analogously to 9., and 499 mg of
title compound 41 is obtained as a colorless oil.
[0395] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.21 ppm (m, 2H);
0.63 (m, 2H); 0.89 (t, 3H); 1.19-1.42 (m, 6H); 1.72 (m, 4H); 3.10
(m, 2H); 3.90 (m, 4H); 7.30 (m, 5H)
40.
2-Pentyl-2-[1-[2-(phenylsulfonyl)ethyl]cyclopropyl]-1,3-dioxolan
42
[0396] 318 mg of 41 is reacted analogously to 10., and 287 mg of
title compound 42 is obtained as a colorless oil.
[0397] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.17 ppm (m, 2H);
0.62 (m, 2H); 0.88 (t, 3H); 1.23 (m, 6H); 1.58 (m, 2H); 1.70 (m,
2H); 3.39 (m, 2H); 3.83 (m, 4H); 7.59 (t, 2H); 7.67 (t, 1H); 7.92
(d, 2H)
41. 3-Oxononanoic acid methyl ester 43
[0398] 53.5 ml of acetoacetic acid methyl ester 3 is reacted with
n-iodopentane analogously to 11., and 87.9 g of title compound 43
is obtained as a colorless oil.
[0399] .sup.1H-NMR (300 MHz, CDCl.sub.3): =0.88 ppm (t, 3H); 1.29
(m, 6H); 1.60 (m, 2H); 2.53 (t, 2H); 3.45 (s, 2H); 3.74 (s, 3H)
42. 1-Oxoheptylcyclopropanecarboxylic acid methyl ester 44
[0400] 87.9 g of 43 is reacted analogously to 2., and 99.6 g of
title compound 44 is obtained as a colorless oil.
[0401] .sup.1H-NMR (300 MHz, CDCl.sub.3): .epsilon.=0.88 ppm (t,
3H); 1.29 (m, 6H); 1.45 (s, 4H); 1.58 (m, 2H); 2.82 (t, 2H); 3.72
(s, 3H)
43. 1-(2-Hexyl-1,3-dioxolan-2-yl)cyclopropanecarboxylic acid methyl
ester 45
[0402] 102.4 g of 44 is reacted analogously to 3., and 85.86 g of
title compound 45 is obtained as a colorless oil.
[0403] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.89 ppm (t, 3H);
1.00 (m, 2H); 1.15 (m, 2H); 1.30 (m, 0.8H); 2.05 (m, 2H); 3.67 (s,
3H); 3.94 (m, 41H)
44. 1-(2-Hexyl-1,3-dioxolan-2-yl)cyclopropanemethanol 46
[0404] 63.45 g of 45 is reacted analogously to 4., and 51.92 g of
title compound 46 is obtained as a colorless oil.
[0405] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.40 ppm (m, 2H);
0.70 (m, 2H); 0.90 (t, 3H); 1.32 (m, 8H); 1.87 (m, 2H); 3.01 (brs,
OH); 3.51 (d, 2H); 3.97 (m, 4H)
45. 1-(2-Hexyl-1,3-dioxolan-2-yl)cyclopropanecarbaldehyde 47
[0406] 10 g of 46 is reacted analogously to 5., and 7.9 g of title
compound 47 is reacted as a colorless oil.
[0407] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.89 ppm (t, 3H);
1.10 (s, 4H); 1.29 (m, 8H); 1.90 (m, 2H); 3.97 (m, 4H); 9.60 (s,
1H)
46. 2-(1-Ethenylcyclopropyl)-2-hexyl-1,3-dioxolan 48
[0408] 5.65 g of 47 is reacted analogously to 6., and 4.9 g of
title compound 48 is obtained as a colorless oil.
[0409] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.57 ppm (m, 2H);
0.80 (m, 2H); 0.89 (t, 3H); 1.32 (m, 8H); 1.78 (m, 2H); 3.95 (m,
4H); 4.98 (d, 1H); 4.99 (d, 1H); 6.23 (dd, 1H)
47. 1-(2-Hexyl-1,3-dioxolan-2-yl)cyclopropanethanol 49
[0410] 3.6 g of 48 is reacted analogously to 7., and 2.9 g of title
compound 49 is obtained as a colorless oil.
[0411] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.22 ppm (m, 2H);
0.69 (m, 2H); 0.89 (t, 3H); 1.30 (m, 8H); 1.60 (t, 2H); 1.85 (m,
2H); 3.57 (brs, OH); 3.69 (m, 2H); 3.95 (m, 4H)
48. 4-Methylbenzenesulfonic acid
2-[1-(2-hexyl-1,3-dioxolan-2-yl)cycloprop- yl]ethyl ester 50
[0412] 2.1 g of 49 is reacted analogously to 8., and 2.3 g of title
compound 50 is obtained as a colorless oil.
[0413] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.22 ppm (m, 2H);
0.60 (m, 2H); 0.90 (t, 3H); 1.29 (m, 8H); 1.68 (m, 2H); 1.73 (t,
2H); 2.48 (s, 3H); 3.84 (m, 4H); 4.29 (t, 2H); 7.38 (d, 2H); 7.82
(d, 2H)
49. 2-Hexyl-2-[1-[2-(phenylsulfanyl)ethyl]cyclopropyl]-1,3-dioxolan
51
[0414] 2.3 g of 50 is reacted analogously to 9., and 1.98 g of
title compound 51 is obtained as a colorless oil.
[0415] .sup.1H-NMR (300 MHz, CDCl.sub.3): .epsilon.=0.20 ppm (m,
2H); 0.61 (m, 2H); 0.89 (t, 3H); 1.19-1.42 (m, 8H); 1.73 (m, 4H);
3.10 (m, 2H); 3.91 (m, 4H); 7.30 (m, 5H)
50.
2-Hexyl-2-[1-[(2-(phenylsulfonyl)ethyl]cyclopropyl]-1,3-dioxolan
52
[0416] 1.98 g of 51 is reacted analogously to 10., and 1.50 g of
title compound 52 is obtained as a colorless oil.
[0417] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.18 ppm (m, 2H);
0.63 (m, 2H); 0.89 (t, 3H); 1.28 (m, 8H); 1.58 (m, 2H); 1.72 (m,
2H); 3.40 (m, 2H); 3.82 (m, 4H); 7.58 (t, 2H); 7.67 (t, 1H); 7.92
(d, 2H)
51. 3-Oxodecanoic acid methyl ester 53
[0418] 30 ml of acetoacetic acid methyl ester 3 is reacted with
n-iodohexane analogously to 11., and 57.8 g of title compound 53 is
obtained as a colorless oil.
[0419] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.=0.88 ppm (t, 3H);
1.29 (m, 6H); 1.60 (m, 2H); 2.53 (t, 2H); 3.45 (s, 2H); 3.74 (s,
3H)
52. 1-Oxooctylcyclopropanecarboxylic acid methyl ester 54
[0420] 57.8 g of 53 is reacted analogously to 2., and 62.6 g of
title compound 54 is obtained as a colorless oil.
[0421] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.88 ppm (t, 3H);
1.30 (m, 10H); 1.40 (s, 4H); 2.82 (t, 2H); 3.68 (s, 3H)
53. 1-(2-Heptyl-1,3-dioxolan-2-yl)cyclopropanecarboxylic acid
methyl ester 55
[0422] 16.2 g of 54 is reacted analogously to 3., and 13.9 g of
title compound 55 is obtained as a colorless oil.
[0423] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.89 ppm (t, 3H);
1.00 (m, 2H); 1.12 (m, 2H); 1.30 (m, 10H); 2.05 (m, 2H); 3.68 (s,
3H); 3.93 (m, 4H)
54. 1-(2-Heptyl-1,3-dioxolan-2-yl)cyclopropanemethanol 56
[0424] 9.6 g of 55 is reacted analogously to 4., and 7.9 g of title
compound 56 is obtained as a colorless oil.
[0425] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.40 ppm (m, 2H);
0.70 (m, 2H); 0.90 (t, 3H); 1.30 (m, 10H); 1.87 (m, 2H); 3.00 (d,
OH); 3.51 (d, 2H); 3.98 (m, 4H)
55. 1-(2-Heptyl-1,3-dioxolan-2-yl)cyclopropanecarbaldehyde 57
[0426] 11.4 g of 56 is reacted analogously to 5., and 7.6 g of
title compound 57 is obtained as a colorless oil.
[0427] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.89 ppm (t, 3H);
1.10 (s, 4H); 1.30 (m, 10H); 1.90 (m, 2H); 3.98 (m, 4H); 9.58 (s,
1H)
56. 2-(1-Ethenylcyclopropyl)-2-heptyl-13-dioxolan 58
[0428] 3.2 g of 57 is reacted analogously to 6., and 2.4 g of title
compound 58 is obtained as a colorless oil.
[0429] .sup.1H-NMR (300 MHz, CDCl.sub.3): .epsilon.=0.54 ppm (m,
2H); 0.80 (m, 2H); 0.90 (t, 3H); 1.30 (m, 10H); 1.78 (m, 2H); 3.95
(m, 4H); 4.95 (d, 1H); 4.96 (d, 1H); 6.23 (dd, 1H)
57. 1-(2-Heptyl-1,3-dioxolan-2-yl)cyclopropanethanol 59
[0430] 2.4 g of 58 is reacted analogously to 7., and 1.8 g of title
compound 59 is obtained as a colorless oil.
[0431] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.=0.23 ppm (m, 2H);
0.70 (m, 2H); 0.90 (t, 3H); 1.30 (m, 10H); 1.61 (t, 2H); 1.84 (m,
2H); 3.57 (brs, OH); 3.70 (m, 2H); 3.95 (m, 4H)
58. 4-Methylbenzensulfonic acid
2-[1-(2-heptyl-1,3-dioxolan-2-yl)cycloprop- yl]ethyl ester 60
[0432] 1.6 g of 59 is reacted analogously to 8., and 1.34 g of
title compound 60 is obtained as a colorless oil.
[0433] .sup.1H-NMR (300 MHz, CDCl.sub.3): .epsilon.=0.23 ppm (m,
2H); 0-0.59 (m, 2H); 0.89 (t, 3H); 1.30 (m, 10H); 1.68 (m, 2H);
1.75 (t, 2H); 2.47 (s, 3H); 3.86 (m, 4H); 4.30 (t, 3H); 7.37 (d,
2H); 7.79 (d, 2H)
59.
2-Heptyl-2-[1-[2-(phenylsulfanyl)ethyl]cyclopropyl]-1,3-dioxolan
61
[0434] 920 mg of 60 is reacted analogously to 9., and 743 mg of
title compound 61 is obtained as a colorless oil.
[0435] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.20 ppm (m, 2H);
0.58 (m, 2H); 0.89 (t, 3H); 1.30 (m, 10H); 1.72 (m, 4H); 3.08 (m,
2H); 3.91 (m, 4H); 7.30 (m, 5H)
60.
2-Heptyl-2-[1-[2-(phenylsulfonyl)ethyl]cyclopropyl]-1,3-dioxolan
62
[0436] 450 mg of 61 is reacted analogously to 10., and 356 mg of
title compound 62 is obtained as a colorless oil.
[0437] 1H-NMR (300 MHz, CDCl.sub.3) .delta.=0.18 ppm (m, 2H); 0.63
(m, 2H); 0.90 (t, 3H); 1.27 (m, 10H); 1.58 (m, 2H); 1.71 (m, 2H);
3.39 (m, 2H); 3.82 (m, 4H); 7.60 (t, 2H); 7.68 (t, 1H); 7.92 (d,
2H)
EXAMPLE 1
(5Z,7E,22E)-(1S,3R)-25-Acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22--
tetraene-1,3-diol 66
[0438] 61. Lithium diisopropylamide is prepared in 20 ml of THF at
-78.degree. C. under nitrogen from 0.18 ml of diisopropylamine and
0.57 ml of n-butyllithium solution (2.5 M in hexane). 380 mg of
sulfone 12 is added in drops to 1 ml of THF, and it is stirred for
30 more minutes at -78.degree. C. Then, 200 mg of aldehyde 2 in 0.5
ml of THF is added, and it is stirred for another 30 minutes. It is
quenched with sodium chloride solution, extracted with diethyl
ether, washed with sodium chloride solution, dried on sodium
sulfate and concentrated by evaporation. The residue is
chromatographed on silica gel with ethyl acetate/hexane, whereby
189 mg of (5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)sil-
yl]oxy]-25-(2-methyl-1,3-dioxolan-2-yl)-23-phenylsulfonyl-26,27-cyclo-9,10-
-secocholesta-5,7,10(19)-trien-22-ol 63 accumulates as a colorless
foam.
[0439] 62. 150 mg of 63 is introduced into 5 ml of methanol under
nitrogen, and 10 ml of saturated, methanolic disodium hydrogen
phosphate solution is added, and it is stirred for 15 minutes at
room temperature. Then, 650 mg of a sodium amalgam (5%) is added,
and it is stirred for 1 more hour. The mercury produced is
decanted, and the reaction mixture is extracted with
dichloromethane. After the organic phase is washed with sodium
chloride solution, it is dried on sodium sulfate, the solvent is
removed, and the residue is chromatographed on silica gel with
ethyl acetate/hexane, whereby 65 mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,-
1-dimethylethyl)silyl]oxy]-25-(2-methyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,1-
0-secocholesta-5,7,10(19),22-tetraene 64 and 70 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
methyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-2-
2-ol 65 accumulate in succession as colorless foams.
[0440] .sup.1H-NMR (300 MHz, CDCl.sub.3) 64: .delta.=0.03 ppm (s,
12H); 0.25 (m, 2H); 0.48 (m, 2H); 0.52 (s, 3H); 0.85 (s, 18H); 0.98
(d, 3H); 1.32 (s, 3H); 3.80 (m, 4H); 4.16 (m, 1H); 4.36 (m, 1H);
4.82 (s, 1H); 5.15 (s, 1H); 5.20 (m, 2H); 6.00 (d, 1H); 6.23 (d,
1H)
[0441] 65: .delta.=0.04 ppm (s, 12H); 0.23 (m, 2H); 0.52 (s, 3H);
0.58 (m, 2H); 0.85 (d, 3H); 0.85 (s, 18H); 1.32 (s, 3H); 3.55 (m,
1H); 3.82 (m, 4H); 4.16 (m, 1H); 4.36 (m, 1H); 4.83 (s, 1H); 5.16
(s, 1H); 6.01 (d, 1H); 6.23 (d, 1H)
[0442] 63. 35 mg of 64 is dissolved in 10 ml of
dichloromethane/methanol (1:9), and it is stirred under nitrogen at
room temperature with 350 mg of Dowex ion exchanger (activated) for
48 hours. Then, it is filtered, the filtrate is washed with sodium
bicarbonate solution and sodium chloride solution, dried on sodium
sulfate, concentrated by evaporation, and the residue is
chromatographed on silica gel with ethyl acetate/hexane, whereby 13
mg of title compound 66 accumulates as a colorless foam.
[0443] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.53 ppm
(s, 3H); 0.78 (m, 2H); 1.01 (d, 3H); 1.20 (m, 2H); 2.10 (s, 3H);
4.19 (m, 1H); 4.39 (m, 1H); 4.98 (s, 1H); 5.30 (s, 1H); 5.32 (m,
2H); 6.01 (d, 1H); 6.38 (d, 1H)
EXAMPLE 2
64.
(5Z,7E)-(1S,3R,22S)-25-Acetyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-
-triene-1,3,22-triol 67
[0444] 11 mg of 65 is reacted analogously to 63., and 4.4 mg of the
title compound is obtained as a colorless foam.
[0445] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.55 ppm
(s, 3H); 0.88 (d, 3H); 0.89 (t, 3H); 0.90 (m, 4H); 2.08 (s, 3H);
3.57 (m, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.97 (s, 1H); 5.30 (s,
1H); 6.01 (d, 1H); 6.38 (d, 1H)
EXAMPLE 3
(5Z,7E,22E)-(1S,3R)-25-(1-Oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,10(1-
9),22-tetraene-1,3-diol 71
[0446] 65. 573 mg of aldehyde 2 is reacted with 700 mg of sulfone
22 analogously to 61., and 687 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-23-phenylsulfonyl-25-(2-propyl-1,3-dioxolan-2-yl)--
26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-22-ol 68 is obtained
as a colorless foam.
[0447] 66. 500 mg of 68 is reacted analogously to 62., whereby 189
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
propyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetr-
aene 69 and 156 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2-p-
ropyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-22-
-ol 70 accumulate in succession as colorless foams.
[0448] .sup.1H-NMR (300 MHz, CDCl.sub.3): 69: .delta.=0.03 ppm (s,
12H); 0.23 (m, 2H); 0.48 (m, 2H); 0.51 (s, 3H); 0.86 (s, 18H); 0.89
(t, 3H); 0.99 (d, 3H); 3.89 (m, 4H); 4.17 (m, 1H); 4.37 (m, 1H);
4.83 (s, 1H); 5.15 (s, 1H); 5.20 (m, 2H); 5.99 (d, 1H); 6.22 (d,
1H)
[0449] 70: .delta.=0.04 ppm (s, 12H); 0.23 (m, 2H); 0.54 (s, 3H);
0.60 (m, 2H); 0.83 (t, 3H); 0.89 (d, 3H); 0.90 (s, 18H); 3.61 (m,
1H); 3.88 (m, 4H); 4.18 (m, 1H); 4.38 (m, 1H); 4.85 (s, 1H); 5.18
(s, 1H); 6.01 (d, 1H); 6.23 (d, 1H)
[0450] 67. 180 mg of 69 is treated analogously to 63., and 85 mg of
title compound 71 is obtained as a colorless foam.
[0451] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.52 ppm
(s, 3H); 0.72 (m, 2H); 0.87 (t, 3H); 1.00 (d, 3H); 1.15 (m, 2H);
1.51 (hex, 2H); 2.37 (t, 2H); 4.18 (m, 1H); 4.38 (m, 1H); 4.95 (s,
1H); 5.29 (s, 1H); 5.30 (m, 2H); 6.00 (d, 1H); 6.35 (d, 1H)
EXAMPLE 4
68.
(5Z,7E)-(1S,3R,22S)-25-(1-Oxobutyl)-26,27-cyclo-9,10-secocholesta-5,7,-
10(19)-triene-1,3,22-triol 72
[0452] 140 mg of 70 is reacted analogously to 63., and 39 mg of the
title compound is obtained as a colorless foam.
[0453] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.53 ppm
(s, 3H); 0.88 (d, 3H); 0.89 (t, 3H); 0.90 (m, 4H); 2.38 (t, 2H);
3.56 (m, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.96 (s, 1H); 5.28 (s,
1H); 6.01 (d, 1H); 6.38 (d, 1H)
EXAMPLE 5
(5Z,7E,22E)-(1S,3R)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7,10(-
19),22-tetraene-1,3-diol 76
[0454] 69. 573 mg of aldehyde 2 is reacted with 300 mg of sulfone
32 analogously to 61., and 420 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-23-phenylsulfonyl-25-(2-butyl-1,3-dioxolan-2-yl)-2-
6,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-22-ol 73 is obtained
as a colorless foam.
[0455] 70. 250 mg of 73 is reacted analogously to 62., whereby 98
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
butyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetra-
ene 74 and 82 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1-dimethylethy-
l)silyl]oxy]-25-(2-butyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19)-trien-22-ol 75 accumulate in succession as colorless
foams.
[0456] .sup.1H-NMR (300 MHz, CDCl.sub.3): 74: .delta.=0.03 ppm (s,
12H); 0.21 (m, 2H); 0.47 (m, 2H); 0.51 (s, 3H); 0.86 (s, 18H); 0.88
(t, 3H); 0.98 (d, 3H); 3.86 (m, 4H); 4.17 (m, 1H); 4.37 (m, 1H);
4.82 (s, 1H); 5.15 (s, 1H); 5.18 (m, 2H); 5.99 (d, 1H); 6.22 (d,
1H)
[0457] 75: .delta.=0.03 ppm (s, 12H); 0.21 (m, 2H); 0.54 (s, 3H);
0.58 (m, 2H); 0.88 (t, 3H); 0.89 (d, 3H); 0.89 (s, 18H); 3.57 (m,
1H); 3.86 (m, 4H); 4.17 (m, 1H); 4.37 (m, 1H); 4.82 (s, 1H); 5.17
(s, 1H); 6.00 (d, 1H); 6.22 (d, 1H)
[0458] 71. 65 mg of 74 is treated analogously to 63., and 28 mg of
title compound 76 is obtained as a colorless foam.
[0459] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .epsilon.=0.53 ppm
(s, 3H); 0.71 (m, 2H); 0.89 (t, 3H); 1.00 (d, 3H); 1.10 (m, 2H);
2.38 (t, 2H); 4.17 (m, 1H); 4.38 (m, 1H); 4.95 (s, 1H); 5.29 (s,
1H); 5.29 (m, 2H); 6.0 (d, 1H); 6.37 (d, 1H)
EXAMPLE 6
72.
(5Z,7E)-(1S,3R,22S)-25-(1-Oxopentyl)-26,27-cyclo-9,10-secocholesta-5,7-
,10(19)-triene-1,3,22-triol 77
[0460] 82 mg of 75 is reacted analogously to 63., and 34 mg of the
title compound is obtained as a colorless foam.
[0461] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .epsilon.=0.54 ppm
(s, 3H); 0.89 (d, 3H); 0.89 (t, 3H); 0.90 (m, 4H); 2.36 (t, 2H);
3.55 (m, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.96 (s, 1H); 5.28 (s,
1H); 6.01 (d, 1H); 6.37 (d, 1H)
EXAMPLE 7
(5Z,7E,22E)-(1S,3R)-25-(1-Oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,10(1-
9),22-tetraene-1,3-diol 81
[0462] 73. 171 mg of aldehyde 2 is reacted with 210 mg of sulfone
42 analogously to 61., and 194 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-25-(2-pentyl-1,3-dioxolan-2-yl)-23-phenylsulfonyl--
26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-22-ol 78 is obtained
as a colorless foam.
[0463] 74. 175 mg of 78 is reacted analogously to 62., whereby 65
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
pentyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetr-
aene 79 and 40 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1-dimethyleth-
yl)silyl]oxy]-25-(2-pentyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholest-
a-5,7,10(19)-trien-22-ol 80 accumulate in succession as colorless
foams.
[0464] .sup.1H-NMR (300 MHz, CDCl.sub.3): 79: .delta.=0.03 ppm (s,
12H); 0.22 (m, 0.2H); 0.45 (m, 2H); 0.52 (s, 3H); 0.85 (s, 18H);
0.85 (t, 3H); 0.98 (d, 3H); 3.85 (m, 4H); 4.17 (m, 1H); 4.37 (m,
1H); 4.83 (s, 1H); 5.16 (s, 1H); 5.18 (m, 2H); 6.00 (d, 1H); 6.23
(d, 1H)
[0465] 80: .delta.=0.03 ppm (s, 12H); 0.22 (m, 2H); 0.53 (s, 3H);
0.58 (m, 2H); 0.88 (t, 3H); 0.89 (d, 3H); 0.89 (s, 18H); 3.56 (m,
1H); 3.86 (m, 4H); 4.16 (m, 1H); 4.36 (m, 1H); 4.82 (s, 1H); 5.17
(s, 1H); 6.00 (d, 1H); 6.22 (d, 1H)
[0466] 75. 64 mg of 79 is treated analogously to 63., and 26 mg of
title compound 81 is obtained as a colorless foam.
[0467] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.53 ppm
(s, 3H); 0.70 (m, 2H); 0.89 (t, 3H); 0.99 (d, 3H); 1.10 (m, 2H);
2.37 (t, 2H); 4.17 (m, 1H); 4.38 (m, 1H); 4.96 (s, 1H); 5.30 (s,
1H); 5.31 (m, 2H); 6.00 (d, 1H); 6.36 (d, 1H)
EXAMPLE 8
76.
(5Z,7E)-(1S,3R,22S)-25-(1-Oxohexyl)-26,27-cyclo-9,10-secocholesta-5,7,-
10(19)-triene-1,3,22-triol 82
[0468] 35 mg of 80 is reacted analogously to 63., and 174 mg of the
title compound is obtained as a colorless foam.
[0469] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.55 ppm
(s, 3H); 0.89 (d, 3H); 0.90 (t, 3H); 0.91 (m, 4H); 2.37 (t, 2H);
3.56 (m, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.96 (s, 1H); 5.28 (s,
1H); 6.01 (d, 1H); 6.38 (d, 1H)
EXAMPLE 9
(5Z,7E,22E)-(1S,3R)-25-(1-Oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7,10(-
19),22-tetraene-1,3-diol 86
[0470] 77. 573 mg of aldehyde 2 is reacted with 1.07 g of sulfone
52 analogously to 61., and 432 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-25-(2-hexyl-1,3-dioxolan-2-yl)-23-phenylsulfonyl-2-
6,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-22-ol 83 is obtained
as a colorless foam.
[0471] 78. 432 mg of 83 is reacted analogously to 62., whereby 93
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
hexyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetra-
ene 84 and 48 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1-dimethylethy-
l)silyl]oxy]-25-(2-hexyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholesta--
5,7,10(19)-trien-22-ol 85 accumulate in succession as colorless
foams.
[0472] .sup.1H-NMR (300 MHz, CDCl.sub.3): 84: .delta.=0.03 ppm (s,
12H); 0.20 (m, 2H); 0.46 (m, 2H); 0.52 (s, 3H); 0.85 (s, 18H); 0.88
(t, 3H); 0.99 (d, 3H); 3.85 (m, 4H); 4.17 (m, 1H); 4.37 (m, 1H);
4.82 (s, 1H); 5.15 (s, 1H); 5.20 (m, 2H); 6.00 (d, 1H); 6.22 (d,
1H)
[0473] 85: .delta.=0.03 ppm (s, 12H); 0.20 (m, 2H); 0.53 (s, 3H);
0.55 (m, 2H); 0.87 (t, 3H); 0.88 (d, 3H); 0.89 (s, 18H); 3.55 (m,
1H); 3.84 (m, 4H); 4.16 (m, 1H); 4.36 (m, 1H); 4.82 (s, 1H); 5.16
(s, 1H); 6.01 (d, 1H); 6.23 (d, 1H)
[0474] 79. 93 mg of 84 is treated analogously to 63., and 31 mg of
title compound 86 is obtained as a colorless foam.
[0475] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.53 ppm
(s, 3H); 0.69 (m, 2H); 0.87 (t, 3H); 1.00 (d, 3H); 1.08 (m, 2H);
2.36 (t, 2H); 4.16 (m, 1H); 4.36 (m, 1H); 4.94 (s, 1H); 5.27 (s,
1H); 5.27 (m, 2H); 5.99 (d, 1H); 6.34 (d, 1H)
EXAMPLE 10
80.
(5Z,7E)-(1S,3R,22S)-25-(1-Oxoheptyl)-26,27-cyclo-9,10-secocholesta-5,7-
,10(19)-triene-1,3,22-triol 87
[0476] 48 mg of 85 is reacted analogously to 63., and 16 mg of the
title compound is obtained as a colorless foam.
[0477] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.53 ppm
(s, 3H); 0.86 (d, 3H); 0.88 (t, 3H); 0.90 (m, 4H); 2.35 (t, 2H);
3.55 (m, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.95 (s, 1H); 5.28 (s,
1H); 6.00 (d, 1H); 6.35 (d, 1H)
EXAMPLE 11
(5Z,7E,22E)-(1S,3R)-25-(1-Oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,10(1-
9),22-tetraene-1,3-diol 91
[0478] 81. 460 mg of aldehyde 2 is reacted with 600 mg of sulfone
62 analogously to 61., and 532 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-25-(2-heptyl-1,3-dioxolan-2-yl)-23-phenylsulfonyl--
26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-22-ol 88 is obtained
as a colorless foam.
[0479] 82. 500 mg of 88 is reacted analogously to 62., whereby 145
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
heptyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetr-
aene 89 and 158 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1-dimethylet-
hyl)silyl]oxy]-25-(2-heptyl-1,3-dioxolan-2-yl)-26,27-cyclo-9,10-secocholes-
ta-5,7,10(19)-trien-22-ol 90 accumulate in succession as colorless
foams.
[0480] .sup.1H-NMR (300 MHz, CDCl.sub.3): 89: .delta..+-.0.04 ppm
(s, 12H); 0.21 (m, 2H); 0.45 (m, 2H); 0.52 (s, 3H); 0.87 (s, 18H);
0.87 (t, 3H); 0.99 (d, 3H); 3.85 (m, 4H); 4.17 (m, 1H); 4.36 (m,
1H); 4.82 (s, 1H); 5.15 (s, 1H); 5.20 (m, 2H); 6.00 (d, 1H); 6.22
(d, 1H)
[0481] 90: .delta.=0.03 ppm (s, 12H); 0.21 (m, 2H); 0.53 (s, 3H);
0.54 (m, 2H); 0.88 (t, 3H); 0.88 (d, 3H); 0.89 (s, 18H); 3.54 (m,
1H); 3.84 (m, 4H); 4.17 (m, 1H); 4.36 (m, 1H); 4.83 (s, 1H); 5.18
(s, 1H); 6.00 (d, 1H); 6.23 (d, 1H)
[0482] 83. 121 mg of 89 is treated analogously to 63., and 52 mg of
title compound 91 is obtained as a colorless foam.
[0483] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.52 ppm
(s, 3H); 0.70 (m, 2H); 0.88 (t, 3H); 0.99 (d, 3H); 1.10 (m, 2H);
2.36 (t, 2H); 4.17 (m, 1H); 4.37 (m, 1H); 4.94 (s, 1H); 5.28 (s,
1H); 5.30 (m, 2H); 5.99 (d, 1H); 6.35 (d, 1H)
EXAMPLE 12
84.
(5Z,7E)-(1S,3R,22S)-25-(1-Oxooctyl)-26,27-cyclo-9,10-secocholesta-5,7,-
10(19)-triene-1,3,22-triol 92
[0484] 130 mg of 90 is reacted analogously to 63., and 41 mg of
title compound 92 is obtained as a colorless foam.
[0485] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.55 ppm
(s, 3H); 0.86 (d, 3H); 0.87 (t, 3H); 0.90 (m, 4H); 2.36 (t, 2H);
3.55 (m, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95 (s, 1H); 5.27 (s,
1H); 6.00 (d, 1H); 6.36 (d, 1H)
Synthesis of the Starting Compounds in the 24-Methylene-24-homo
Series
85. (E)-3-[1-(2-Methyl-1,3-dioxolan-2-yl)cyclopropyl]propenoic acid
methyl ester 93
[0486] 3.2 g of sodium hydride suspension (60% in paraffin oil) is
introduced into 750 ml of THF, cooled under nitrogen to 0.degree.
C., and 10.9 g of dimethylphosphonoacetic acid methyl ester is
added. Then, 7.5 g of aldehyde 7 is added in drops to 15 ml of THF,
and it is stirred at room temperature for 2 hours. It is now
quenched carefully with sodium chloride solution, extracted with
ethyl acetate, washed with sodium chloride solution, dried on
sodium sulfate, and the solvent is removed. The residue is
chromatographed on silica gel with ethyl acetate/hexane, whereby
9.5 g of title compound 93 accumulates as a colorless oil.
[0487] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.73 ppm (m, 2H);
1.09 (m, 2H); 1.45 (s, 3H); 3.72 (s, 3H); 3.95 (m, 4H); 5.79 (d,
1H); 7.18 (d, 1H)
86. 3-[1-(2-Methyl-1,3-dioxolan-2-yl)cyclopropane]-1-propanol
94
[0488] 100 ml of liquid ammonia is introduced, and 2 g of lithium
is added in portions. Then, 3.1 g of 93 is added in drops to 20 ml
of THF, and it is stirred overnight at room temperature, whereby
the ammonia is evaporated. The residue is taken up in ethyl
acetate, washed with sodium chloride solution, dried on sodium
sulfate, concentrated by evaporation, and chromatographed on silica
gel with ethyl acetate/hexane, whereby 1.5 g of title compound 94
is obtained as a colorless oil.
[0489] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.29 ppm (m, 2H);
0.62 (m, 2H); 1.40 (s, 3H); 1.51-1.70 (m, 4H); 3.62 (t, 2H); 3.90
(m, 4H)
87. 4-Methylbenzenesulfonic acid
3-[1-(2-methyl-1,3-dioxolan-2-yl)-cyclopr- opyl]propyl ester 95
[0490] 350 mg of 94 is reacted analogously to 8., whereby 405 mg of
title compound 95 accumulates as a colorless oil.
[0491] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.19 ppm (m, 2H);
0.60 (m, 2H); 1.32 (s, 3H); 1.44 (m, 2H); 1.79 (m, 2H); 2.46 (s,
3H); 3.85 (m, 4H); 4.02 (t, 2H); 7.35 (d, 2H); 7.79 (d, 2H)
88.
2-Methyl-2-[1-[3-(phenylsulfanyl)ethyl]cyclopropyl]-1,3-dioxolan
96
[0492] 400 mg of 95 is reacted analogously to 9., whereby 380 mg of
title compound 96 accumulates as a colorless oil.
[0493] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.27 ppm (m, 2H);
0.60 (m, 2H); 1.38 (s, 3H); 1.61 (m, 2H); 1.76 (m, 2H); 2.92 (t,
2H); 3.89 (m, 4H); 7.28 (m, 5H)
89.
2-Methyl-2-[1-[3-(phenylsulfonyl)ethyl]cyclopropyl]-1,3-dioxolan
97
[0494] 375 mg of 96 is reacted analogously to 10., whereby 268 mg
of title compound 97 is obtained as a colorless oil.
[0495] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.20 ppm (m, 2H);
0.62 (m, 2H); 1.31 (s, 3H); 1.52 (m, 2H); 1.87 (m, 2H); 3.12 (t,
2H); 3.83 (m, 4H); 7.58 (t, 2H); 7.66 (t, 1H); 7.91 (d, 2H)
90. (E)-3-[1-(2-Propyl-1,3-dioxolan-2-yl)cyclopropyl]propenoic acid
methyl ester 98
[0496] 6.0 g of aldehyde 17 is reacted analogously to 85., and 6.7
g of title compound 98 is obtained as a colorless oil.
[0497] 0.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.70 ppm (m, 2H);
0.90 (t, 3H); 0.90 (m, 2H); 1.03 (m, 2H); 1.73 (m, 2H); 3.72 (s,
3H); 3.95 (m, 4H); 5.70 (d, 1H); 7.25 (d, 1H)
91. 3-[1-(2-Propyl-1,3-dioxolan-2-yl)cyclopropane]-1-propanol
[0498] 6.7 g of 98 is reacted analogously to 86., whereby 5.3 g of
title compound 99 is obtained as a colorless oil.
[0499] .sup.1H-NMR (300 MHz, CDCl.sub.3) 0.23 ppm (m, 2H); 0.60 (m,
2H); 0.92 (t, 3H); 3.62 (t, 2H); 3.90 (m, 4H)
92. 4-Methylbenzenesulfonic acid
3-[1-(2-propyl-1,3-dioxolan-2-yl)cyclopro- pyl]propyl ester 100
[0500] 1.3 g of 99 is reacted analogously to 8., whereby 1.52 g of
title compound 100 accumulates as a colorless oil;
[0501] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.12 ppm (m, 2H);
0.57 (m, 2H); 0.90 (t, 3H); 2.47 (s, 3H); 3.83 (m, 4H); 4.02 (t,
2H); 7.35 (d, 2H); 7.79 (d, 2H)
93.
2-[1-[3-(Phenylsulfanyl)ethyl]cyclopropyl]-2-propyl-1,3-dioxolan
101
[0502] 1.5 g of 100 is reacted analogously to 9., whereby 1.11 g of
title compound 96 accumulates as a colorless oil.
[0503] .sup.1H-NMR (300 MHz, CDCl.sub.3): .epsilon.=0.20 ppm (m,
2H); 0.58 (m, 2H); 0.91 (t, 3H); 2.91 (t, 2H); 3.88 (m, 4H); 7.28
(m, 5H)
94.
2-[1-[3-(Phenylsulfonyl)ethyl]cyclopropyl]-2-propyl-1,3-dioxolan
102
[0504] 1.1 g of 101 is reacted analogously to 10., whereby 785 mg
of title compound 102 is obtained as a colorless oil.
[0505] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.17 ppm (m, 2H);
0.59 (m, 2H); 0.90 (t, 3H); 3.10 (t, 2H); 3.85 (m, 4H); 7.58 (t,
2H); 7.67 (t, 1H); 7.90 (d, 2H)
95. (E)-3-[1-(2-Butyl-1,3-dioxolan-2-yl)cyclopropyl]propenoic acid
methyl ester 103
[0506] 5.0 g of aldehyde 27 is reacted analogously to 85., and 4.6
g of title compound 103 is obtained as a colorless oil.
[0507] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.70 ppm (m, 2H);
0.89 (t, 3H); 1.04 (m, 2H); 1.30 (m, 4H); 1.79 (m, 2H); 3.72 (s,
3H); 3.96 (m, 4H); 5.71 (d, 1H); 7.25 (d, 1H)
96. 3-[1-(2-Butyl-1,3-dioxolan-2-yl)cyclopropane]-1-propanol
[0508] 1.5 g of 103 is reacted analogously to 86., whereby-1.09 g
of title compound 104 is obtained as a colorless oil.
[0509] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.23 ppm (m, 2H);
0.60 (m, 2H); 0.92 (t, 3H); 3.61 (t, 2H); 3.92 (m, 4H)
97. 4-Methylbenzenesulfonic acid
3-[1-(2-butyl-1,3-dioxolan-2-yl)cycloprop- yl]propylester 105
[0510] 1.09 g of 104 is reacted analogously to 8., whereby 1.36 g
of title compound 105 accumulates as a colorless oil.
[0511] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.12 ppm (m, 2H);
0.58 (m, 2H); 0.89 (t, 3H); 2.47 (s, 3H); 3.85 (m, 4H); 4.02 (t,
2H); 7.35 (d, 2H); 7.80 (d, 2H)
98. 2-Butyl-2-[1-[3-(phenylsulfanyl)ethyl]cyclopropyl]-1,3-dioxolan
106
[0512] 800 mg of 105 is reacted analogously to 9., whereby 967 mg
of title compound 106 accumulates as a colorless oil.
[0513] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.20 ppm (m, 2H);
0.59 (m, 2H); 0.90 (t, 3H); 2.89 (t, 2H); 3.85 (m, 4H); 7.27 (m,
5H)
99. 2-Butyl-2-[1-[3-(phenylsulfonyl)ethyl]cyclopropyl]-1,3-dioxolan
107
[0514] 950 g of 106 is reacted analogously to 10., whereby 634 mg
of title compound 107 is obtained as a colorless oil.
[0515] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.15 ppm (m, 2H);
0.60 (m, 2H); 0.90 (t, 3H); 3.09 (t, 2H); 3.83 (m, 4H); 7.58 (t,
2H); 7.68 (t, 1H); 7.91 (d, 2H)
100. (E)-3-[1-(2-Pentyl-1,3-dioxolan-2-yl)cyclopropyl]propenoic
acid methyl ester 108
[0516] 1.8 g of aldehyde 37 is reacted analogously to 85., and 1.1
g of title compound 108 is obtained as a colorless oil.
[0517] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.70 ppm (m, 2H);
0.88 (t, 3H); 1.03 (m, 2H); 1.30 (m, 6H); 372 (s, 3H); 3.95 (m,
4H); 5.71 (d, 1H); 7.24 (d, 1H)
101. 3-[1-(2-Pentyl-1,3-dioxolan-2-yl)cyclopropane)-1-propanol
[0518] 2.68 g of 108 is reacted analogously to 86., whereby 1.57 g
of title compound 109 is obtained as a colorless oil.
[0519] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.23 ppm (m, 2H);
0.60 (m, 2H); 0.90 (t, 3H); 3.61 (t, 2H); 3.91 (m, 4H)
102. 4-Methylbenzenesulfonic acid
3-(1-(2-pentyl-1,3-dioxolan-2-yl)cyclopr- opyl]propylester 110
[0520] 590 mg of 109 is reacted analogously to 8., whereby 456 g of
title compound 110 accumulates as a colorless oil.
[0521] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.18 ppm (m, 2H);
0.60 (m, 2H); 0.90 (t, 3H); 2.48 (s, 3H); 3.85 (m, 4H); 4.02 (t,
2H); 7.35 (d, 2H); 7.81 (d, 2H)
103.
2-Pentyl-2-[1-[3-(phenylsulfanyl)ethyl]cyclopropyl]-1,3-dioxolan
111
[0522] 350 mg of 110 is reacted analogously to 9., whereby 272 mg
of title compound 111 accumulates as a colorless oil.
[0523] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.19 ppm (m, 2H);
0.59 (m, 2H); 0.89 (t, 3H); 2.87 (t, 2H); 3.85 (m, 4H); 7.28 (m,
5H)
104.
2-Pentyl-2-[1-[3-(phenylsulfonyl)ethyl]cyclopropyl]-1,3-dioxolan
112
[0524] 245 mg of 111 is reacted analogously to 10., whereby 191 mg
of title compound 112 is obtained as a colorless oil.
[0525] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.14 ppm (m, 2H);
0.57 (m, 2H); 0.88 (t, 3H); 3.09 (t, 2H); 3.82 (m, 4H); 7.58 (t,
2H); 7.67 (t, 1H); 7.89 (d, 2H)
105. (E)-3-[1-(2-Hexyl-1,3-dioxolan-2-yl)cyclopropyl]propenoic acid
methyl ester 113
[0526] 5.65 g of aldehyde 47 is reacted analogously to 85., and
4.81 g of title compound 113 is obtained as a colorless oil.
[0527] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.70 ppm (m, 2H);
0.89 (t, 3H); 1.04 (m, 2H); 1.29 (m, 8H); 3.72 (s, 3H); 3.96 (m,
4H); 5.71 (d, 1H); 7.25 (d, 1H)
106. 3-[1-(2-Hexyl-1,3-dioxolan-2-yl)cyclopropane]-1-propanol
117
[0528] 2.0 g of 113 is reacted analogously to 86., whereby 1.7 g of
title compound 114 is obtained as a colorless oil.
[0529] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.22 ppm (m, 2H);
0.60 (m, 2H); 0.89 (t, 3H); 3.62 (t, 2H); 3.90 (m, 4H)
107. 4-Methylbenzenesulfonic acid
3-[1-(2-hexyl-1,3-dioxolan-2-yl)cyclopro- pyl]propyl ester 115
[0530] 1.7 mg of 114 is reacted analogously to 8., whereby 1.6 g of
title compound 115 accumulates as a colorless oil.
[0531] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 0.20 ppm (m, 2H);
0.60 (m, 2H); 0.91 (t, 3H); 2.49 (s, 3H); 3.85 (m, 4H); 4.03 (t,
2H); 7.36 (d, 2H); 7.81 (d, 2H)-108.
2-Hexyl-2-[1-[3-(phenylsulfanyl)ethyl]cyclopropyl]- -1,3-dioxolan
116.
[0532] 1.5 mg of 115 is reacted analogously to 9., whereby 1.37 g
of title compound 116 accumulates as a colorless oil.
[0533] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.19 ppm (m, 2H);
0.60 (m, 2H); 0.90 (t, 3H); 2.87 (t, 2H); 3.85 (m, 4H); 7.30 (m,
5H)
109.
2-Hexyl-2-[1-[3-(phenylsulfonyl)ethyl)cyclopropyl]-1,3-dioxolan
117
[0534] 654 mg of 116 is reacted analogously to 10., whereby 630 mg
of title compound 117 is obtained as a colorless oil.
[0535] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.14 ppm (m, 2H);
0.58 (m, 2H); 0.86 (t, 3H); 3.09 (t, 2H); 3.82 (m, 4H); 7.57 (t,
2H); 7.65 (t, 1H); 7.89 (d, 2H)
110. (E)-3-[1-(2-Heptyl-1,3-dioxolan-2-yl)cyclopropyl]propenoic
acid methyl ester 118
[0536] 2.2 g of aldehyde 57 is reacted analogously to 85., and 1.7
g of title compound 118 is obtained as a colorless oil.
[0537] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.70 ppm (m, 2H);
0.89 (t, 3H); 1.04 (m, 2H); 1.29 (m, 10H); 3.72 (s, 3H); 3.95 (m,
4H); 5.71 (d, 1H); 7.25 (d, 1H)
111. 3-[1-(2-Heptyl-1,3-dioxolan-2-yl)cyclopropane]-1-propanol
[0538] 1.6 g of 118 is reacted analogously to 86., whereby 987 mg
of title compound 119 is obtained as a colorless oil.
[0539] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.23 ppm (m, 2H);
0.60 (m, 2H); 0.89 (t, 3H); 3.62 (t, 2H); 3.90 (m, 4H)
112. 4-Methylbenzenesulfonic acid
3-(1-(2-heptyl-1,3-dioxolan-2-yl)cyclopr- opyl]propylester 120
[0540] 900 mg of 119 is reacted analogously to 8., whereby 1.3 g of
title compound 120 accumulates as a colorless-oil.
[0541] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.22 ppm (m, 2H);
0.60 (m, 2H); 0.90 (t, 3H); 2.48 (s, 3H); 3.85 (m, 4H); 4.03 (t,
2H); 7.37 (d, 2H); 7.81 (d, 2H)
113.
2-Heptyl-2-[1-[3-(phenylsulfanyl)ethyl]cyclopropyl]-1,3-dioxolan
121
[0542] 1.3 mg of 120 is reacted analogously to 9., whereby 921 mg
of title compound 121 accumulates as a colorless oil.
[0543] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.22 ppm (m, 2H);
0.62 (m, 2H); 0.90 (t, 3H); 2.90 (t, 2H); 3.85 (m, 0.4H); 7.30 (m,
5H)
114.
2-Heptyl-2-[1-[3-(phenylsulfonyl)ethyl]cyclopropyl]-1,3-dioxolan
122
[0544] 456 mg of 121 is reacted analogously to 10., whereby 376 mg
of title compound 122 is obtained as a colorless oil.
[0545] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.17 ppm (m, 2H);
0.59 (m, 2H); 0.89 (t, 3H); 3.10 (t, 2H); 3.82 (m, 4H); 7.58 (t,
2H); 7.67 (t, 1H); 7.90 (d, 2H)
EXAMPLE 13
(5Z,7E,22E)-(1S,3R)-25-Acetyl-26,27-cyclo-24a-homo-9,10-secocholesta-5,7,1-
0(19),22-tetraene-1,3-diol 126
[0546] 115. 343 mg of aldehyde 2 is reacted with 260 mg of sulfone
97 analogously to 61., and 402 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-25-(2-methyl-1'-3-dioxolan-2-yl)-23-phenylsulfonyl-
-26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-trien-22-ol 123
is obtained as a colorless foam.
[0547] 116. 400 mg of 123 is reacted analogously to 62., whereby
123 mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-25-(2-
-methyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(1-
9),22-tetraene 124 and 70 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1--
dimethylethyl)silyl]oxy]-25-(2-methyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-h-
omo-9,10-secocholesta-5,7,10(19)-trien-22-ol 125 accumulate in
succession as colorless foams.
[0548] .sup.1H-NMR (300 MHz, CDCl.sub.3): 124: .delta.=0.03 ppm (s,
12H); 0.23 (m, 2H); 0.52 (s, 3H); 0.55 (d, 2H); 0.86 (s, 18H); 0.86
(d, 3H); 1.32 (s, 3H)--; 3.83 (m, 4H); 4.16 (m, 1H); 4.36 (m, 1H);
4.82 (s, 1H); 5.15 (s, 1H); 5.22 (m, 2H); 6.00 (d, 1H); 6.23 (d,
1H)
[0549] 125: .delta.=0.04 ppm (s, 12H); 0.23 (m, 2H); 0.52 (s, 3H);
0.55 (m, 2H); 0.85 (d, 3H); 0.86 (s, 18H); 1.32 (s, 3H); 3.61 (m,
1H); 3.82 (m, 4H); 4.16 (m, 1H); 4.36 (m, 1H); 4.82 (s, 1H); 5.15
(s, 1H); 6.01 (d, 1H); 6.23 (d, 1H)
[0550] 117. 98 mg of 124 is reacted analogously to 63., whereby 43
mg of title compound 126 is obtained as a colorless foam.
[0551] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.53 ppm
(s, 3H); 0.78 (m, 2H); 1.00 (d, 3H); 1.20 (m, 2H); 2.00 (s, 3H);
4.19 (m, 1H); 4.38 (m, 1H); 4.99 (s, 1H); 5.28 (m, 2H); 5.30 (s,
1H); 6.01 (d, 1H); 6.38 (d, 1H)
EXAMPLE 14
118.
(5Z,7E)-(1S,3R,22S)-25-Acetyl-26,27-cyclo-24a-homo-9,10-secocholesta--
5,7,10(19)-triene-1,3,22-triol 127
[0552] 61 mg of 125 is reacted analogously to 63., and 24 mg of the
title compound is obtained as a colorless foam.
[0553] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.56 ppm
(s, 3H); 0.80 (m, 2H); 0.86 (d, 3H); 0.89 (t, 3H); 1.18 (m, 2H);
2.03 (s, 3H); 3.67 (m, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.99 (s,
1H); 5.32 (s, 1H); 6.01 (d, 1H); 6.38 (d, 1H)
EXAMPLE 15
(5Z,7E,22E)-(1S,3R)-25-(1-Oxobutyl)-26,27-cyclo-24a-homo-9,10-secocholesta-
-5,7,10(19),22-tetraene-1,3-diol 131
[0554] 119. 570 mg of aldehyde 2 is reacted with 780 mg of sulfone
102 analogously to 61., and 606 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-23-phenylsulfonyl-25-(2-propyl-1,3-dioxolan-2-yl)--
26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-trien-22-ol 128
is obtained as a colorless foam.
[0555] 120. 600 mg of 128 is reacted analogously to 62., whereby
230 mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
propyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19-
),22-tetraene 129 and 186 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1--
dimethylethyl)silyl]oxy]-25-(2-propyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-h-
omo-9,10-secocholesta-5,7,10(19)-trien-22-ol 130 accumulate in
succession as colorless foams.
[0556] .sup.1H-NMR (300 MHz, CDCl.sub.3): 129: .delta.=0.03 ppm (s,
12H); 0.18 (m, 2H); 0.50 (m, 2H); 0.51 (s, 3H); 0.84 (s, 18H); 0.85
(t, 3H); 0.96 (d, 3H); 3.85 (m, 4H); 4.17 (m, 1H); 4.36 (m, 1H);
4.82 (s, 1H); 5.15 (s, 1H); 5.25 (m, 2H); 6.00 (d, 1H); 6.23 (d,
1H)
[0557] 130: .delta.=0.03 ppm (s, 12H); 0.19 (m, 2H); 0.50 (s, 3H);
0.56 (m, 2H); 0.87 (t, 3H); 0.88 (d, 3H); 0.89 (s, 18H); 3.57 (m,
1H); 3.86 (m, 4H); 4.17 (m, 1H); 4.37 (m, 1H); 4.81 (s, 1H); 5.17
(s, 1H); 6.00 (d, 4H); 6.23 (d, 1H)
[0558] 121. 220 mg of 129 is treated analogously to 63, and 73 mg
of title compound 131 is obtained as a colorless foam.
[0559] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.56 ppm
(s, 3H); 0.73 (m, 2H); 0.87 (t, 3H); 1.00 (d, 3H); 1.11 (m, 2H);
2.26 (t, 2H); 4.17 (m, 1H); 4.37 (m, 1H); 4.96 (s, 1H); 5.29 (s,
1H); 5.35 (m, 2H); 6.00 (d, 1H); 6.36 (d, 1H)
EXAMPLE 16
122.
(5Z,7E)-(1S,3R,22S)-25-(1-oxobutyl)-26,27-cyclo-24a-homo-9,10-secocho-
lesta-5,7,10(19)-triene-1,3,22-triol 132
[0560] 180 mg of 130 is reacted analogously to 63., and 38 mg of
the title compound is obtained as a colorless foam.
[0561] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): =0.53 ppm (s, 3H);
0.70 (m, 2H); 0.88 (d, 3H); 0.89 (t, 3H); 1.12 (m, 2H); 2.19 (t,
2H); 3.62 (m, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.96 (s, 1H); 5.29
(s, 1H); 6.00 (d, 1H); 6.36 (d, 1H)
EXAMPLE 17
(5Z,7E,22E)-(1S,3R)-25-(1-Oxopentyl)-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19),22-tetraene-1,3-diol 136
[0562] 123. 286 mg of aldehyde 2 is reacted with 390 mg of sulfone
107 analogously to 61., and 325 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-23-phenylsulfonyl-25-(2-butyl-1,3-dioxolan-2-yl)-2-
6,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-trien-22-ol 133 is
obtained as a colorless foam.
[0563] 124. 200 mg of 133 is reacted analogously to 62., whereby 85
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
butyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-
,22-tetraene 134 and 70 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1-di-
methylethyl)silyl]oxy]-25-(2-butyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-homo-
-9,10-secocholesta-5,7,10(19)-trien-22-ol 135 accumulate in
succession as colorless foams.
[0564] .sup.1H-NMR (300 MHz, CDCl.sub.3): 134: .delta.=0.03 ppm (s,
12H); 0.18 (m, 2H); 0.51 (m, 2H); 0.52 (s, 3H); 0.86 (s, 18H); 0.87
(t, 3H); 0.99 (d, 3H); 3.85 (m, 4H); 4.17 (m, 1H); 4.36 (m, 1H);
4.82 (s, 1H); 5.15 (s, 1H); 5.18 (m, 2H); 6.00 (d, 1H); 6.22 (d,
1H)
[0565] 135: .delta.=0.04 ppm (s, 12H); 0.22 (m, 2H); 0.55 (s, 3H);
0.58 (m, 2H); 0.89 (t, 3H); 0.89 (d, 3H); 0.89 (s, 18H); 3.68 (m,
1H); 3.90 (m, 4H); 4.18 (m, 1H); 4.38 (m, 1H); 4.85 (s, 1H); 5.18
(s, 1H); 6.01 (d, 1H); 6.23 (d, 1H)
[0566] 125. 43 mg of 134 is treated analogously to 63., and 23 mg
of title compound 136 is obtained as a colorless foam.
[0567] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .epsilon.=0.54 ppm
(s, 3H); 0.70 (m, 2H); 0.88 (t, 3H); 0.98 (d, 3H); 1.10 (m, 2H);
2.27 (t, 2H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95 (s, 1H); 5.28 (s,
1H); 5.28 (m, 2H); 5.99 (d, 1H); 6.36 (d, 1H)
EXAMPLE 18
126.
(5Z,7E)-(1S,3R,22S)-25-(1-Oxopentyl)-26,27-cyclo-24a-homo-9,10-secoch-
olesta-5,7,10(19)-triene-1,3,22-triol 137
[0568] 48 mg of 135 is reacted analogously to 63., and 23 mg of the
title compound is obtained as a colorless foam.
[0569] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2) .delta.=0.55 ppm (s,
3H); 0.71 (m, 2H); 0.87 (d, 3H); 0.89 (t, 3H); 1.12 (m, 4H); 2.23
(t, 2H); 3.64 (m, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.94 (s, 1H);
5.28 (s, 1H); 6.00 (d, 1H); 6.35 (d, 1H)
EXAMPLE 19
(5Z,7E,22E)-(1S,3R)-25-(1-Oxohexyl)-26,27-cyclo-24a-homo-9,10-secocholesta-
-5,7,10(19),22-tetraene-1,3-diol 141
[0570] 127. 286 mg of aldehyde 2 is reacted with 185 mg of sulfone
112 analogously to 61., and 187 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-25-(2-pentyl-1,3-dioxolan-2-yl)-23-phenylsulfonyl--
26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-trien-22-ol 138
is obtained as a colorless foam.
[0571] 128. 125 mg of 138 is reacted analogously to 62., whereby 35
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
pentyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19-
),22-tetraene 139 and 27 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-25-(2-pentyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-ho-
mo-9,10-secocholesta-5,7,10(19)-trien-22-ol 140 accumulate in
succession as colorless foams.
[0572] .sup.1H-NMR (300 MHz, CDCl.sub.3): 139: .delta.=0.04 ppm (s,
12H); 0.17 (m, 2H); 0.52 (m, 2H); 0.53 (s, 3H); 0.86 (s, 18H); 0.87
(t, 3H); 0.98 (d, 3H); 3.84 (m, 4H); 4.17 (m, 1H); 4.36 (m, 1H);
4.82 (s, 1H); 5.16 (s, 1H); 5.24 (m, 2H); 6.00 (d, 1H); 6.23 (d,
1H)
[0573] 140: .delta.=0.04 ppm (s, 12H); 0.18 (m, 2H); 0.54 (s, 3H);
0.55 (m, 2H); 0.87 (t, 3H); 0.89 (d, 3H); 0.89 (s, 18H); 3.62 (m,
1H); 3.84 (m, 4H); 4.17 (m, 1H); 4.37 (m, 1H); 4.83 (s, 1H); 5.16
(s, 1H); 6.00 (d, 1H); 6.23 (d, 1H)
[0574] 129. 35 mg of 139 is treated analogously to 63., and 16 mg
of title compound 141 is obtained as a colorless foam.
[0575] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.56 ppm
(s, 3H); 0.70 (m, 2H); 0.88 (t, 3H); 0.98 (d, 3H); 1.09 (m, 2H);
2.23 (t, 2H); 4.17 (m, 1H); 4.36 (m, 1H); 4.97 (s, 1H); 5.28 (s,
1H); 5.29 (m, 2H); 5.99 (d, 1H); 6.34 (d, 1H)
EXAMPLE 20
130.
(5Z,7E)-(1S,3R,22S)-25-(1-Oxohexyl)-26,27-cyclo-24a-homo-9,10-secocho-
lesta-5,7,10(19)-triene-1,3,22-triol 142
[0576] 25 mg of 140 is reacted analogously to 63., and 11 mg of the
title compound is obtained as a colorless foam.
[0577] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.55 ppm
(s, 3H); 0.71 (m, 2H); 0.87 (d, 3H); 0.87 (t, 3H); 1.14 (m, 2H);
2.23 (t, 2H); 3.65 (m, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.95 (s,
1H); 5.28 (s, 1H); 6.00 (d, 1H); 6.36 (d, 1H)
EXAMPLE 21
(5Z,7E,22E)-(1S,3R)-25-(1-Oxoheptyl)-26,27-cyclo-24a-homo-9,10-secocholest-
a-5,7,10(19),22-tetraene-1,3-diol 146
[0578] 131. 573 mg of aldehyde 2 is reacted with 630 mg of sulfone
117 analogously to 61., and 599 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-25-(2-hexyl-1,3-dioxolan-2-yl)-23-phenylsulfonyl-2-
6,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-trien-22-ol 143 is
obtained as a colorless foam.
[0579] 132. 500 mg of 143 is reacted analogously to 62., whereby
156 mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
hexyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-
,22-tetraene 144 and 98 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1-di-
methylethyl)silyl]oxy]-25-(2-hexyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-homo-
-9,10-secocholesta-5,7,10(19)-trien-22-ol 145 accumulate in
succession as colorless foams.
[0580] .sup.1H-NMR (300 MHz, CDCl.sub.3): 144: .delta.=0.03 ppm (s,
12H); 0.19 (m, 2H); 0.48 (m, 2H); 0.53 (s, 3H); 0.85 (s, 18H); 0.90
(t, 3H); 0.98 (d, 3H); 3.86 (m, 4H); 4.16 (m, 1H); 4.36 (m, 1H);
4.83 (s, 1H); 5.16 (s, 1H); 5.25 (m, 2H); 6.00 (d, 1H); 6.24 (d,
1H)
[0581] 145: .delta.=0.04 ppm (s, 12H); 0.19 (m, 2H); 0.55 (s, 3H);
0.56 (m, 2H); 0.87 (t, 3H); 0.89 (d, 3H); 0.90 (s, 18H); 3.63 (m,
1H); 3.84 (m, 4H); 4.17 (m, 1H); 4.37 (m, 1H); 4.83 (s, 1H); 5.16
(s, 1H); 6.01 (d, 1H); 6.23 (d, 1H)
[0582] 133. 95 mg of 144 is treated analogously to 63., and 27 mg
of title compound 146 is obtained as a colorless foam.
[0583] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .epsilon.=0.54 ppm
(s, 3H); 0.71 (m, 2H); 0.86 (t, 3H); 1.00 (d, 3H); 1.12 (m, 2H);
2.22 (t, 2H); 4.16 (m, 1H); 4.36 (m, 1H); 4.94 (s, 1H); 5.25 (s,
1H); 5.25 (m, 2H); 5.99 (d, 1H); 6.34 (d, 1H)
EXAMPLE 22
134.
(5Z,7E)-(1S,3R,22S)-25-(1-Oxoheptyl)-26,27-cyclo-24a-homo-9,10-secoch-
olesta-5,7,10(19)-triene-1,3,22-triol 147
[0584] 43 mg of 145 is reacted analogously to 63., and 14 mg of the
title compound is obtained as a colorless foam.
[0585] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.55 ppm
(s, 3H); 0.73 (m, 2H); 0.85 (d, 3H); 0.86 (t, 3H); 1.13 (m, 2H);
2.21 (t, 2H); 3.64 (m, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.94 (s,
1H); 5.28 (s, 1H); 6.00 (d, 1H); 6.35 (d, 1H)
EXAMPLE 23
(5Z,7E,22E)-(1S,3R)-25-(1-Oxooctyl)-26,27-cyclo-24a-homo-9,10-secocholesta-
-5,7,10(19),22-tetraene-1,3-diol 151
[0586] 135. 200 mg of aldehyde 2 is reacted with 200 mg of sulfone
122 analogously to 61., and 272 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-d-
imethylethyl)silyl]oxy]-25-(2-heptyl-1,3-dioxolan-2-yl)-23-phenylsulfonyl--
26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19)-trien-22-ol 148
is obtained as a colorless foam.
[0587] 136. 272 mg of 148 is reacted analogously to 62., whereby 78
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
heptyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-homo-9,10-secocholesta-5,7,10(19-
),22-tetraene 149 and 110 mg of
(5Z,7E)-(1S,3R,22S)-1,3-bis[[dimethyl(1,1--
dimethylethyl)silyl)oxy)-25-(2-heptyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a-h-
omo-9,10-secocholesta-5,7,10(19)trien-22-ol 150 accumulate in
succession as colorless foams.
[0588] .sup.1H-NMR (300 MHz, CDCl.sub.3): 149: .delta.=0.05 ppm (s,
12H); 0.20 (m, 2H); 0.50 (m, 2H); 0.53 (s, 3H); 0.89 (s, 18H); 0.89
(t, 3H); 0.99 (d, 3H); 3.86 (m, 4H); 4.17 (m, 1H); 4.37 (m, 1H);
4.84 (s, 1H); 5.17 (s, 1H); 5.25 (m, 2H); 6.00 (d, 1H); 6.24 (d,
1H)
[0589] 150: .delta.=0.03 ppm (s, 12H); 0.18 (m, 2H); 0.52 (s, 3H);
0.52 (m, 2H); 0.88 (t, 3H); 0.88 (d, 3H); 0.89 (s, 18H); 3.60 (m,
1H); 3.83 (m, 4H); 4.17 (m, 1H); 4.37 (m, 1H); 4.82 (s, 1H); 5.17
(s, 1H); 6.00 (d, 1H); 6.24 (d, 1H)
[0590] 137. 70 mg of 149 is treated analogously to 63., and 27 mg
of title compound 151 is obtained as a colorless foam.
[0591] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.54 ppm
(s, 3H); 0.70 (m, 2H); 0.88 (t, 3H); 0.99 (d, 3H); 1.10 (m, 2H);
2.22 (t, 2H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95 (s, 1H); 5.29 (s,
1H); 5.30 (m, 2H); 5.99 (d, 1H); 6.35 (d, 1H)
EXAMPLE 24
138.
(5Z,7E)-(1S,3R,22S)-25-(1-Oxooctyl)-26,27-cyclo-24a-homo-9,10-secocho-
lesta-5,7,10(19)-triene-1,3,22-triol 152
[0592] 110 mg of 150 is reacted analogously to 63., and 38 mg of
the title compound is obtained as a colorless foam.
[0593] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.54 ppm
(s, 3H); 0.72 (m, 2H); 0.89 (d, 3H); 0.89 (t, 3H); 1.12 (m, 2H);
2.22 (t, 2H); 3.63 (m, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.96 (s,
1H); 5.29 (s, 1H); 6.01 (d, 1H); 6.37 (d, 1H)
Starting Materials in the 24-Hydroxymethylene-24a,24b-dihomo
Series
[0594] 139.
(E)-4-[1-(2-Methyl-1,3-dioxolan-2-yl)cyclopropyl]-3-buten-2-on- e
153
[0595] 13.8 g of lithium chloride (anhydrous) is introduced into
120 ml of acetonitrile under nitrogen, and 49.8 ml of
oxopropylphosphonic acid dimethyl ester, 51.3 ml of
diisopropylethylamine and 5.4 g of aldehyde 7 are added in
succession. It is stirred for 18 hours at room temperature, and
then sodium chloride solution is added. It is extracted with ethyl
acetate, washed with sodium chloride solution and dried on sodium
sulfate. The residue is chromatographed on silica gel with ethyl
acetate/hexane, whereby 5.3 g of the title compound accumulates as
a colorless oil.
[0596] .sup.1H-NMR (300 MHz, CDCl): .delta.=0.75 ppm (m, 2H); 1.10
(m, 2H); 1.42 (s, 3H); 2.25 (s, 3H); 3.96 (m, 4H); 6.00 (d, 1H);
7.10 (d, 1H)
140. 4-[1-(2-Methyl-1,3-dioxolan-2-yl)cyclopropyl]butan-2-one
154
[0597] 1.23 g of 153 is dissolved in THF, and 200 mg of
platinum(IV) oxide is added in an argon stream. Using a
hydrogenating apparatus, it is hydrogenated until no more hydrogen
is consumed, flushed with nitrogen, filtered and concentrated by
evaporation. The residue is chromatographed on silica gel with
ethyl acetate/hexane, whereby 1.19 g of title compound 154
accumulates as a colorless oil.
[0598] .sup.1H-NMR (300 MHz, CDCl.sub.3): .epsilon.=0.23 ppm (m,
2H); 0.64 (m, 2H); 1.38 (s, 3H); 1.70 (dd, 2H); 2.15 (s, 3H); 2.64
(dd, 2H); 3.89 (m, 4H)
141.
(E)-4-[1-(2-Propyl-1,3-dioxolan-2-yl)cyclopropyl]-3-buten-2-one
155
[0599] 2.0 g of aldehyde 17 is reacted analogously to 139., and 2.1
g of title compound 155 is obtained as a colorless oil.
[0600] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.70 ppm (m, 2H);
0.90 (t, 3H); 1.09 (m, 2H); 1.40 (m, 2H); 2.27 (s, 3H); 3.97 (m,
4H); 5.92 (d, 1H); 7.18 (d, 1H)
142. 4-[1-(2-Propyl-1,3-dioxolan-2-yl)cyclopropyl]butan-2-one
156
[0601] 740 mg of 155 is reacted analogously to 140., and 709 mg of
title compound 156 is obtained as a colorless oil.
[0602] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.19 ppm (m, 2H);
0.60 (m, 2H); 0.91 (t, 3H); 2.13 (s, 3H); 2.65 (t, 2H); 3.90 (m,
4H)
143. (E)-4-(1-(2-Butyl-1,3-dioxolan-2-yl)cyclopropyl]-3-buten-2-one
157
[0603] 3.0 g of aldehyde 27 is reacted analogously to 139., and 2.7
g of title compound 157 is obtained as a colorless oil.
[0604] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.72 ppm (m, 2H);
0.90 (t, 3H); 1.08 (m, 2H); 1.31 (m, 4H); 1.78 (m, 2H); 2.26 (s,
3H); 3.97 (m, 4H); 5.91 (d, 1H); 7.17 (d, 1H)
144. 4-[1-(2-Butyl-1,3-dioxolan-2-yl)cyclopropyl]butan-2-one
158
[0605] 1.6 g of 157 is reacted analogously to 140., and 1.42 g of
title compound 158 is obtained as a colorless oil.
[0606] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.19 ppm (m, 2H);
0.61 (m, 2H); 0.90 (t, 3H); 1.32 (m, 4H); 1.67 (m, 2H); 1.76 (m,
2H); 2.15 (s, 3H); 2.68 (t, 2H); 3.90 (m, 4H)
145.
(E)-4-[1-(2-Pentyl-1,3-dioxolan-2-yl)cyclopropyl]-3-buten-2-one
159
[0607] 2.5 g of aldehyde 37 is reacted analogously to 139., and 2.9
g of title compound 159 is obtained as a colorless oil.
[0608] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.71 ppm (m, 2H);
0.90 (t, 3H); 1.08 (m, 2H); 1.30 (m, 6H); 1.77 (m, 2H); 2.27 (s,
3H); 3.97 (m, 4H); 5.92 (d, 1H); 7.18 (d, 1H)
146. 4-[1-(2-Pentyl-1,3-dioxolan-2-yl)cyclopropyl]butan-2-one
160
[0609] 1.7 g of 159 is reacted analogously to 140., and 1.51 g of
title compound 160 is obtained as a colorless oil.
[0610] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.19 ppm (m, 2H);
0.61 (m, 2H); 0.90 (t, 3H); 1.32 (m, 6H); 1.75 (m, 2H); 2.17 (s,
3H); 2.64 (m, 2H); 3.89 (m, 4H)
147.
(E)-4-[(1-(2-Hexyl-1,3-dioxolan-2-yl)cyclopropyl]-3-buten-2-one
161
[0611] 3.44 g of aldehyde 47 is reacted analogously to 139., and
2.3 g of title compound 161 is obtained as a colorless oil.
[0612] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.72 ppm (m, 2H);
0.89 (t, 3H); 1.08 (m, 2H); 1.29 (m, 8H); 1.77 (m, 2H); 2.27 (s,
3H); 3.96 (m, 4H); 5.92 (d, 1H); 7.18 (d, 1H)
148. 4-(1-(2-Hexyl-1,3-dioxolan-2-yl)cyclopropyl]butan-2-one
162
[0613] 800 mg of 161 is reacted analogously to 140., and 710 g of
title compound 162 is obtained as a colorless oil.
[0614] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.18 ppm (m, 2H);
0.59 (m, 2H); 0.89 (t, 3H); 1.29 (m, 8H); 1.63 (m, 2H); 1.74 (m,
2H); 2.13 (s, 3H); 2.65 (m, 2H); 3.90 (m, 4H)
EXAMPLE 25
(5Z,7E,22E)-(1S,3R,24R)-25-Acetyl-26,27-cyclo-24a,24b-dihomo-9,10-secochol-
esta-5,7,10(19),22-tetraene-1,3,24-triol 168a and
(5Z,7E,22E)-(1S,3R,24S)--
25-acetyl-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetra-
ene-1,3,24-triol 168b
[0615] 149. A solution of 1 mmol of lithium diisopropylamide in 5
ml of THF is produced, cooled to -78.degree. C., and 202 mg of
ketone 154 is added in drops to 1 ml of THF. It is stirred for 30
minutes at -78.degree. C., and then 229 mg of aldehyde 2 is added
in drops to 1 ml of THF. It is stirred for another 30 minutes at
this temperature, then quenched with sodium chloride solution,
extracted with ethyl acetate, the organic phase is washed with
sodium chloride solution, dried on sodium sulfate and concentrated
by evaporation. Chromatography of the residue on silica gel with
ethyl acetate/hexane yields 189 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-22-hydroxy-
-25-(2-methyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,10-secochole-
sta-5,7,10(19)-trien-24-one 163 as a colorless foam, which is
immediately further reacted.
[0616] 150. A solution of 60 mg of 163, 0.2 ml of acetic anhydride,
0.11 ml of triethylamine and a spatula-tip full of
4-dimethylaminopyridine (DMAP) is stirred for 2 hours under
nitrogen at room temperature. Sodium bicarbonate solution is now
added, extracted with ethyl acetate, washed with sodium chloride
solution, dried on sodium sulfate and concentrated by evaporation,
whereby 172 mg of (5Z,7E)-(1S,3R)-22-acetoxy-1,3-bis[[dim-
ethyl(1,1-dimethylethyl)silyl]oxy]-25-(2-methyl-1,3-dioxolan-2-yl)-26,27-c-
yclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19)-trien-24-one 164
is obtained as a colorless foam, which is immediately further
reacted.
[0617] 151. 172 mg of 164 is dissolved in 10 ml of toluene, 1 ml of
diazabicycloundecane (DBU) is added under nitrogen, and it is
heated for 30 minutes to 40.degree. C. Then, it is concentrated by
evaporation, and the residue is chromatographed on silica gel with
ethyl acetate/hexane, whereby 129 mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl-
)silyl]oxy]-25-(2-methyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,1-
0-secocholesta-5,7,10(19),22-tetraen-24-one 165 accumulates as a
colorless foam.
[0618] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.04 ppm
(s, 12H); 0.21 (m, 2H); 0.54 (s, 3H); 0.60 (m, 2H); 0.86 (s, 18H);
1.09 (d, 3H); 1.33 (s, 3H); 3.83 (m, 4H); 4.17 (m, 1H); 4.35 (m,
1H); 4.82 (s, 1H); 5.16 (s, 1H); 5.94 (d, 1H); 6.01 (d, 1H); 6.23
(d, 1H); 663 (dd, 1H)
[0619] 152. 130 mg of 165 is dissolved in 1 ml of THF, and 5 ml of
methanol, 75 mg of cerium trichloride (heptahydrate), and, after 10
minutes, 8 mg of sodium borohydride are added at 0.degree. C. under
nitrogen. It is stirred for 30 minutes at 0.degree. C., and then
quenched with saturated ammonium chloride solution. It is extracted
with ethyl acetate, dried on sodium sulfate and concentrated by
evaporation. The residue is chromatographed on silica gel with
ethyl acetate/hexane, whereby 60 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylet-
hyl)silyl]oxy]-25-(2-methyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo--
9,10-secocholesta-5,7,10(19),22-tetraen-24-ol 166a and 32 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(2-methyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-
-5,7,10(19),22-tetraen-24-ol 166b are obtained in succession as
colorless foams.
[0620] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 166a: .delta.=0.04
ppm (s, 12H); 0.22 (m, 2H); 0.53 (s, 3H); 0.56 (m, 2H); 0.86 (s,
18H); 1.01 (d, 3H); 1.32 (s, 3H); 3.83 (m, 4H); 3.91 (m, 1H); 4.17
(m, 1H); 4.36 (m, 1H); 4.82 (s, 1H); 5.16 (s, 1H); 5.33 (dd, 1H);
5.45 (dd, 1H); 6.00 (d, 1H); 6.23 (d, 1H)
[0621] 166b: .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.03
ppm (s, 12H); 0.22 (m, 2H); 0.53 (s, 3H); 0.56 (m, 2H); 0.86 (s,
18H); 1.01 (d, 3H); 1.32 (s, 3H); 3.82 (m, 4H); 3.85 (m, 1H); 4.17
(m, 1H); 4.36 (m, 1H); 4.82 (s, 1H); 5.16 (s, 1H); 5.30 (dd, 1H);
5.41 (dd, 1H); 6.00 (d, 1H); 6.23 (d, 1H)
[0622] 153. 300 mg of silica gel is introduced into 10 ml of
dichloromethane, and 0.3 ml of aqueous oxalic acid solution (10%)
is added under nitrogen. It is stirred for 5 minutes at room
temperature, and then 40 mg of 166a is added in drops to 2 ml of
dichloromethane. It is stirred for one hour at room temperature,
sodium bicarbonate is added, it is filtered off and concentrated by
evaporation, whereby 39 mg of
(5Z,7E,22E)-(1S,3R,24R)-25-acetyl-1,3-bis[[dimethyl(1,1-dimethylethyl)sil-
yl]oxy]-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraen-
-24-ol 167a accumulates as a colorless foam, which is immediately
further reacted.
[0623] 154. 38 mg of 167a is dissolved in 5 ml of THF, 150 mg of
tetrabutylammonium fluoride (hydrate) is added, and it is stirred
under nitrogen for 12 more hours at room temperature. Then, sodium
chloride solution is added, extracted with ethyl acetate, washed
with sodium chloride solution, dried on sodium sulfate and
concentrated by evaporation. The residue is chromatographed on
silica gel with ethyl acetate/hexane, whereby 9 mg of title
compound 168a accumulates as a colorless foam.
[0624] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.55 ppm
(s, 3H); 0.78 (m, 2H); 1.02 (d, 3H); 1.18 (m, 2H); 1.93 (s, 3H);
3.92 (m, 1H); 4.16 (m, 1H); 4.37 (m, 1H); 4.95 (s, 1H); 5.28 (s,
1H); 5.36 (dd, 1H); 5.58 (dd, 1H); 5.99 (d, 1H); 6.31 (d, 1H)
[0625] 155. 32 mg of 166b is reacted analogously to 153., whereby
24 mg of
(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-1,3-bis[[dimethyl(1,1-dimethylethyl)sil-
yl]oxy]-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraen-
-24-ol 167b is obtained as a colorless foam, which is immediately
further reacted.
[0626] 156. 24 mg of 167b is reacted analogously to 154., whereby 6
mg of title compound 168b accumulates as a colorless foam.
[0627] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.55 ppm
(s, 3H); 0.77 (m, 2H); 1.03 (d, 3H); 1.20 (m, 2H); 1.93 (s, 3H);
3.91 (m, 1H); 4.16 (m, 1H); 4.37 (m, 1H); 4.95 (s, 1H); 5.28 (s,
1H); 5.32 (dd, 1H); 5.45 (dd, 1H); 5.99 (d, 1H); 6.31 (d, 1H)
EXAMPLE 26
157.
(5Z,7E,22E)-(1S,3R,24R)-25-Acetyl-24-methoxy-26,27-cyclo-24a,24b-diho-
mo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol 169a and
(5Z,7E,22E)-(1S,3R,24S)-25-acetyl-24-methoxy-26,27-cyclo-24a,24b-dihomo-9-
,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol 169b
[0628] 58 mg of 166a is dissolved in 5 ml of
dichloromethane/methanol (1:1), 380 mg of Dowex ion exchanger is
added, and it is stirred for 12 hours under nitrogen at room
temperature. It is then filtered off, the filtrate is washed with
sodium bicarbonate solution, dried on sodium sulfate and
concentrated by evaporation. The residue is chromatographed on
silica gel with ethyl acetate/hexane, whereby 32 mg of a
diastereomer mixture accumulates. By HPLC separation, 11 mg of
title compound 169b and 13 mg of title compound 169a are then
obtained in succession as colorless foams.
[0629] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 169a: .delta.=0.56
ppm (s, 3H); 0.72 (m, 2H); 1.07 (d, 3H); 1.15 (m, 2H); 1.97 (s,
3H); 3.19 (s, 3H); 3.39 (m, 1H); 4.18 (m, 1H); 4.38 (m, 1H); 4.96
(s, 1H); 5.12 (dd, 1H); 5.29 (s, 1H); 5.55 (dd, 1H); 6.00 (d, 1H);
6.35 (d, 1H)
[0630] 169b: .delta.=0.56 ppm (s, 3H); 0.72 (m, 2H); 1.07 (d, 3H);
1.15 (m, 2H); 1.96 (s, 3H); 3.18 (s, 3H); 3.39 (m, 1H); 4.17 (m,
1H); 4.37 (m, 1H); 4.96 (s, 1H); 5.13 (dd, 1H); 5.29 (s, 1H); 5.55
(dd, 1H); 6.00 (d, 1H); 6.36 (d, 1H)
EXAMPLE 27
(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxobutyl)-26,27-cyclo-24a,24b-dihomo-9,10-se-
cocholesta-5,7,10(19),22-tetraene-1,3,24-triol 175a and
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxobutyl)-26,27-cyclo-24a,24b-dihomo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol 175b
[0631] 158. 700 mg of ketone 156 is reacted with 350 mg of aldehyde
2 analogously to 149., and 490 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1--
dimethylethyl)silyl]oxy]-22-hydroxy-25-(2-propyl-1,3-dioxolan-2-yl)-26,27--
cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19)-trien-24-one 170
is obtained as a colorless foam, which is immediately further
reacted.
[0632] 159. A solution of 490 mg of 170 is reacted analogously to
150., whereby 505 mg of
(5Z,7E)-(1S,3R)-22-acetoxy-1,3-bis[[dimethyl(1,1-dimeth-
ylethyl)silyl]oxy]-25-(2-propyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dih-
omo-9,10-secocholesta-5,7,10(19)-trien-24-one 171 is obtained as a
colorless foam, which is immediately further reacted.
[0633] 160. 505 mg of 171 is reacted analogously to 151., whereby
290 mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25--
(2-propyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta--
5,7,10(19),22-tetraen-24-one 172 accumulates as a colorless
foam.
[0634] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.06 ppm
(s, 12H); 0.19 (m, 2H); 0.54 (s, 3H); 0.58 (m, 2H); 0.86 (s, 18H);
0.92 (t, 3H); 1.08 (d, 3H); 3.84 (m, 4H); 4.17 (m, 1H); 4.36 (m,
1H); 4.83 (s, 1H); 5.16 (s, 1H); 5.96 (d, 1H); 6.02 (d, 1H); 6.24
(d, 1H); 6.64 (dd, 1H)
[0635] 161. 350 mg of 172 is reacted analogously to 152., and after
chromatography on silica gel with ethyl acetate/hexane, 160 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(2-propyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-
-5,7,10(19),22-tetraen-24-ol 173a and 109 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,-
3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2-propyl-1,3-dioxolan-2-y-
l)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraen-24-o-
l 173b are obtained in succession as colorless foams.
[0636] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 173a: .delta.=0.03
ppm (s, 12H); 0.18 (m, 2H); 0.53 (s, 3H); 0.55 (m, 2H); 0.87 (s,
18H); 0.90 (t, 3H); 1.02 (d, 3H); 3.83 (m, 4H); 3.90 (m, 1H); 4.16
(m, 1H); 4.35 (m, 1H); 4.83 (s, 1H); 5.15 (s, 1H); 5.31 (dd, 1H);
5.43 (dd, 1H); 6.00 (d, 1H); 6.23 (d, 1H)
[0637] 173b: .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.03
ppm (s, 12H); 0.17 (m, 2H); 0.54 (s, 3H); 0.55 (m, 2H); 0.87 (s,
18H); 0.90 (t, 3H); 1.02 (d, 3H); 3.84 (m, 4H); 3.85 (m, 1H); 4.16
(m, 1H); 436 (m, 1H); 4.83 (s, 1H); 5.15 (s, 1H); 5.30 (dd, 1H);
5.41 (dd, 1H); 6.00 (d, 1H); 6.23 (d, 1H)
[0638] 162. 85 mg of 173a is reacted analogously to 153., whereby
59 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(1-oxobutyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-t-
etraen-24-ol 174a accumulates as a colorless foam, which is
immediately further reacted.
[0639] 163. 59 mg of 174a is reacted analogously to 154., whereby
19 mg of title compound 175a accumulates as a colorless foam.
[0640] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.55 ppm
(s, 3H); 0.72 (m, 2H); 0.89 (t, 3H); 1.02 (d, 3H); 1.16 (m, 2H);
2.18 (t, 2H); 3.92 (m, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95 (s,
1H); 5.29 (s, 1H); 5.35 (dd, 1H); 5.51 (dd, 1H); 5.99 (d, 1H); 6.34
(d, 1H)
[0641] 164. 61 mg of 173b is reacted analogously to 153., whereby
45 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(1-oxobutyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-t-
etraen-24-ol 174b is obtained as a colorless foam, which is
immediately further reacted.
[0642] 165. 45 mg of 174b is reacted analogously to 154., whereby
21 mg of title compound 175b accumulates as a colorless foam.
[0643] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.56 ppm
(s, 3H); 0.72 (m, 2H); 0.88 (t, 3H); 1.02 (d, 3H); 1.15 (m, 2H);
2.20 (t, 2H); 3.92 (m, 1H); 4.18 (m, 1H); 4.38 (m, 1H); 4.95 (s,
1H); 5.28 (s, 1H); 5.33 (dd, 1H); 5.46 (dd, 1H); 6.00 (d, 1H); 6.34
(d, 1H)
EXAMPLE 28
166.
(5Z,7E,22E)-(1S,3R,24R)-24-Methoxy-25-(1-oxobutyl)-26,27-cyclo-24a,24-
b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol 176a and
(5Z,7E,22E)-(1S,3R,24S)-24-methoxy-25-(1-oxobutyl)-26,27-cyclo-24a,24b-di-
homo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol 176b
[0644] 71 mg of 173a is reacted analogously to 157., and 21 mg of
title compound 176b and 18 mg of title compound 176a are obtained
as colorless foams.
[0645] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 173a: .delta.=0.54
ppm (s, 3H); 0.70 (m, 2H); 0.86 (t, 3H); 1.06 (d, 3H); 1.13 (m,
2H); 3.15 (s, 3H); 3.38 (m, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.96
(s, 1H); 5.14 (dd, 1H); 5.28 (s, 1H); 5.53 (dd, 1H); 5.99 (d, 1H);
6.35 (d, 1H)
[0646] 173b: .delta.=0.55 ppm (s, 3H); 0.70 (m, 2H); 0.87 (t, 3H);
1.06 (d, 3H); 1.14 (m, 2H); 3.16 (s, 3H); 3.39 (m, 1H); 4.17 (m,
1H); 4.37 (m, 1H); 4.96 (s, 1H); 5.14 (dd, 1H); 5.29 (s, 1H); 5.52
(dd, 1H); 6.00 (d, 1H); 6.35 (d, 1H)
EXAMPLE 29
(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxopentyl)-26,27-cyclo-24a,24b-dihomo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol 182a and
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxopentyl)-26,27-cyclo-24a,24b-dihomo-9,10--
secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 182b
[0647] 167. 100 mg of ketone 158 is reacted with 200 mg of aldehyde
2 analogously to 149., and 120 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1--
dimethylethyl)silyl]oxy]-25-(2-butyl-1,3-dioxolan-2-yl)-22-hydroxy-26,27-c-
yclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19)-trien-24-one 177
is obtained as a colorless foam, which is immediately further
reacted.
[0648] 168. A solution of 120 mg of 177 is reacted analogously to
150., whereby 134 mg of
(5Z,7E)-(1S,3R)-22-acetoxy-1,3-bis[[dimethyl(1,1-dimeth-
ylethyl)silyl]oxy]-25-(2-butyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-diho-
mo-9,10-secocholesta-5,7,10(19)-trien-24-one 178 is obtained as a
colorless foam, which is immediately further reacted.
[0649] 169. 134 mg of 178 is reacted analogously to 151., whereby
72 mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2--
butyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,-
10(19),22-tetraen-24-one 179 accumulates as a colorless foam.
[0650] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.03 ppm
(s, 12H); 0.18 (m, 2H); 0.56 (s, 3H); 0.57 (m, 2H); 0.89 (s, 18H);
0.90 (t, 3H); 1.09 (d, 3H); 3.85 (m, 4H); 4.17 (m, 1H); 4.36 (m,
1H); 4.85 (s, 1H); 5.16 (s, 1H); 5.96 (d, 1H); 5.98 (d, 1H); 6.24
(d, 1H); 6.65 (dd, 1H)
[0651] 170. 70 mg of 179 is reacted analogously to 152., and after
chromatography on silica gel with ethyl acetate/hexane, 28 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(2-butyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta--
5,7,10(19),22-tetraen-24-ol 180a and 29 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3--
bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2-butyl-1,3-dioxolan-2-yl)--
26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
180b are obtained in succession as colorless foams.
[0652] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 180a: .delta.=0.05
ppm (s, 12H); 0.17 (m, 2H); 0.54 (s, 3H); 0.55 (m, 2H); 0.89 (s,
18H); 0.90 (t, 3H); 1.02 (d, 3H); 3.85 (m, 4H); 3.92 (m, 1H); 4.17
(m, 1H); 4.37 (m, 1H); 4.84 (s, 1H); 5.17 (s, 1H); 5.32 (dd, 1H);
5.46 (dd, 1H); 6.01 (d, 1H); 6.25 (d, 1H)
[0653] 180b: .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.05
ppm (s, 12H); 0.18 (m, 2H); 0.54 (s, 3H); 0.55 (m, 2H); 0.89 (s,
18H); 0.90 (t, 3H); 1.02 (d, 3H); 3.84 (m, 4H); 3.90 (m, 1H); 4.17
(m, 1H); 4.37 (m, 1H); 4.84 (s, 1H); 5.16 (s, 1H); 5.32 (dd, 1H);
5.42 (dd, 1H); 6.01 (d, 1H); 6.25 (d, 1H)
[0654] 171. 25 mg of 180a is reacted analogously to 153., whereby
19 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(1-oxopentyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22--
tetraen-24-ol 181a accumulates as a colorless foam, which is
immediately further reacted.
[0655] 172. 19 mg of 181a is reacted analogously to 154., whereby 5
mg of title compound 182a accumulates as a colorless foam.
[0656] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.54 ppm
(s, 3H); 0.73 (m, 2H); 0.86 (t, 3H); 1.01 (d, 3H); 1.14 (m, 2H);
2.19 (t, 2H); 3.93 (m, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.94 (s,
1H); 5.28 (s, 1H); 5.34 (dd, 1H); 5.48 (dd, 1H); 6.00 (d, 1H); 6.34
(d, 1H)
[0657] 173. 23 mg of 180b is reacted analogously to 1534., whereby
20 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-
-25-(1-oxopentyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),-
22-tetraen-24-ol 181b is obtained as a colorless foam, which is
immediately further reacted.
[0658] 174. 20 mg of 181b is reacted analogously to 1545., whereby
4.5 mg of title compound 182b accumulates as a colorless foam.
[0659] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.54 ppm
(s, 3H); 0.72 (m, 2H); 0.88 (t, 3H); 1.01 (d, 3H); 1.13 (m, 2H);
2.19 (t, 2H); 3.90 (m, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95 (s,
1H); 5.28 (s, 1H); 5.31 (dd, 1H); 5.45 (dd, 1H); 6.00 (d, 1H); 6.34
(d, 1H)
EXAMPLE 30
(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxohexyl)-26,27-cyclo-24a,24b-dihomo-9,10-se-
cocholesta-5,7,10(19),22-tetraene-1,3,24-triol 188a and
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxohexyl)-26,27-cyclo-24a,24b-dihomo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol 188b
[0660] 175. 180 mg of ketone 160 is reacted with 406 mg of aldehyde
2 analogously to 149., and 195 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1--
dimethylethyl)silyl]oxy]-22-hydroxy-25-(2-pentyl-1,3-dioxolan-2-yl)-26,27--
cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19)-trien-24-one 183
is obtained as a colorless foam, which is immediately further
reacted.
[0661] 176. A solution of 195 mg of 183 is reacted analogously to
150., whereby 210 mg of
(5Z,7E)-(1S,3R)-22-acetoxy-1,3-bis[[dimethyl(1,1-dimeth-
ylethyl)silyl]oxy]-25-(2-pentyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dih-
omo-9,10-secocholesta-5,7,10(19)-trien-24-one 184 is obtained as a
colorless foam, which is immediately further reacted.
[0662] 177. 210 mg of 184 is reacted analogously to 151., whereby
165 mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25--
(2-pentyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta--
5,7,10(19),22-tetraen-24-one 185 accumulates as a colorless
foam.
[0663] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.05 ppm
(s, 12H); 0.17 (m, 2H); 0.56 (s, 3H); 0.57 (m, 2H); 0.88 (s, 18H);
0.89 (t, 3H); 1.08 (d, 3H); 3.83 (m, 4H); 4.16 (m, 1H); 4.36 (m,
1H); 4.83 (s, 1H); 5.15 (s, 1H); 5.94 (d, 1H); 6.00 (d, 1H); 6.24
(d, 1H); 6.64 (dd, 1H)
[0664] 178. 165 mg of 185 is reacted analogously to 152., and after
chromatography on silica gel with ethyl acetate/hexane, 46 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl)oxy)-25-
-(2-pentyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-
-5,7,10(19),22-tetraen-24-ol 186a and 35 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3-
-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2-pentyl-1,3-dioxolan-2-yl-
)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
186b are obtained in succession as colorless foams.
[0665] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 186a:
.epsilon.=0.05 ppm (s, 12H); 0.17 (m, 2H); 0.54 (s, 3H); 0.55 (m,
2H); 0.88 (s, 18H); 0.89 (t, 3H); 1.03 (d, 3H); 3.85 (m, 4H); 3.91
(m, 1H); 4.17 (m, 1H); 4.36 (m, 1H); 4.84 (s, 1H); 5.17 (s, 1H);
5.33 (dd, 1H); 5.47 (dd, 1H); 6.01 (d, 1H); 6.25 (d, 1H)
[0666] 186b: .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.05
ppm (s, 12H); 0.17 (m, 2H); 0.54 (s, 3H); 0.55 (m, 2H); 0.88 (s,
18H); 0.89 (t, 3H); 1.02 (d, 3H); 3.85 (m, 4H); 3.88 (m, 1H); 4.16
(m, 1H); 4.36 (m, 1H); 4.84 (s, 1H); 5.16 (s, 1H); 5.30 (dd, 1H);
5.42 (dd, 1H); 6.01 (d, 1H); 6.24 (d, 1H)
[0667] 179. 46 mg of 186a is reacted analogously to 153., whereby
39 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(1-oxohexyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-t-
etraene-24-ol 187a accumulates as a colorless foam, which is
immediately further reacted.
[0668] 180. 39 mg of 187a is reacted analogously to 154., whereby
11 mg of title compound 188a accumulates as a colorless foam.
[0669] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.54 ppm
(s, 3H); 0.71 (m, 2H); 0.86 (t, 3H); 1.00 (d, 3H); 1.12 (m, 2H);
2.18 (t, 2H); 3.93 (m, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.94 (s,
1H); 5.28 (s, 1H); 5.34 (dd, 1H); 5.48 (dd, 1H); 5.99 (d, 1H); 6.33
(d, 1H)
[0670] 181. 35 mg of 186b is reacted analogously to 153., whereby
27 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(1-oxohexyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-t-
etraen-24-ol 187b is obtained as a colorless foam, which is
immediately further reacted.
[0671] 182. 27 mg of 187b is reacted analogously to 154., whereby
8.5 mg of title compound 188b accumulates as a colorless foam.
[0672] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.55 ppm
(s, 3H); 0.72 (m, 2H); 0.88 (t, 3H); 1.01 (d, 3H); 1.15 (m, 2H);
2.19 (t, 2H); 3.92 (m, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95 (s,
1H); 5.27 (s, 1H); 5.33 (dd, 1H); 5.46 (dd, 1H); 6.00 (d, 1H); 6.34
(d, 1H)
EXAMPLE 31
(5Z,7E,22E)-(1S,3R,24R)-25-(1-Oxoheptyl)-26,27-cyclo-24a,24b-dihomo-9,10-s-
ecocholesta-5,7,10(19),22-tetraene-1,3,24-triol 194a and
(5Z,7E,22E)-(1S,3R,24S)-25-(1-oxoheptyl)-26,27-cyclo-24a,24b-dihomo-9,10--
secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 194b
[0673] 183. 710 mg of ketone 162 is reacted with 573 mg of aldehyde
2 analogously to 149., and 580 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1--
dimethylethyl)silyl]oxy]-25-(2-hexyl-1,3-dioxolan-2-yl)-22-hydroxy-26,27-c-
yclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19)-trien-24-one 189
is obtained as a colorless foam, which is immediately further
reacted.
[0674] 184. A solution of 580 mg of 189 is reacted analogously to
150., whereby 603 mg of
(5Z,7E)-(1S,3R)-22-acetoxy-1,3-bis[[dimethyl(1,1-dimeth-
ylethyl)silyl]oxy]-25-(2-hexyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-diho-
mo-9,10-secocholesta-5,7,10(19)-trien-24-one 190 is obtained as a
colorless foam, which is immediately further reacted.
[0675] 185. 603 mg of 190 is reacted analogously to 151., whereby
304 mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25--
(2-hexyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5-
,7,10(19),22-tetraen-24-one 191 accumulates as a colorless
foam.
[0676] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.05 ppm
(s, 12H); 0.19 (m, 2H); 0.57 (s, 3H); 0.59 (m, 2H); 0.89 (s, 18H);
0.90 (t, 3H); 1.09 (d, 3H); 3.85 (m, 4H); 4.17 (m, 1H); 4.37 (m,
1H); 4.85 (s, 1H); 5.16 (s, 1H); 5.96 (d, 1H); 6.01 (d, 1H); 6.24
(d, 1H); 6.66 (dd, 1H)
[0677] 186. 295 mg of 191 is reacted analogously to 152., and after
chromatography on silica gel with ethyl acetate/hexane, 130 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(2-hexyl-1,3-dioxolan-2-yl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta--
5,7,10(19),22-tetraen-24-ol 192a and 80 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3--
bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(2-hexyl-1,3-dioxolan-2-yl)--
26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
192b are obtained as colorless foams.
[0678] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 192a: .delta.=0.03
ppm (s, 12H); 0.18 (m, 2H); 0.56 (s, 3H); 0.56 (m, 2H); 0.89 (s,
18H); 0.90 (t, 3H); 1.04 (d, 3H); 3.86 (m, 4H); 3.93 (m, 1H); 4.18
(m, 1H); 4.38 (m, 1H); 4.86 (s, 1H); 5.19 (s, 1H); 5.35 (dd, 1H);
5.48 (dd, 1H); 6.01 (d, 1H); 6.26 (d, 1H)
[0679] 192b: .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.03
ppm (s, 12H); 0.18 (m, 2H); 0.55 (s, 3H); 0.55 (m, 2H); 0.88 (s,
18H); 0.89 (t, 3H); 1.03 (d, 3H); 3.84 (m, 4H); 3.89 (m, 1H); 4.16
(m, 1H); 4.36 (m, 1H); 4.85 (s, 1H); 5.17 (s, 1H); 5.31 (dd, 1H);
5.43 (dd, 1H); 6.01 (d, 1H); 6.24 (d, 1H)
[0680] 187. 80 mg of 192a is reacted analogously to 153., whereby
64 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(1-oxoheptyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22--
tetraen-24-ol 193a accumulates as a colorless foam, which is
immediately further reacted.
[0681] 188. 64 mg of 193a is reacted analogously to 154., whereby
21 mg of title compound 194a accumulates as a colorless foam.
[0682] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.56 ppm
(s, 3H); 0.71 (m, 2H); 0.87 (t, 3H); 1.01 (d, 3H); 1.14 (m, 2H);
2.20 (t, 2H); 3.93 (m, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.95 (s,
1H); 5.27 (s, 1H); 5.35 (dd, 1H); 5.48 (dd, 1H); 5.99 (d, 1H); 6.34
(d, 1H)
[0683] 189. 76 mg of 192b is reacted analogously to 153., whereby
57 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-(1-oxoheptyl)-26,27-cyclo-24a,24b-dihomo-9,10-secocholesta-5,7,10(19),22--
tetraen-24-ol 193b is obtained as a colorless foam, which is
immediately further reacted.
[0684] 190. 57 mg of 193b is reacted analogously to 154., whereby
17 mg of title compound 194b accumulates as a colorless foam.
[0685] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.56 ppm
(s, 3H); 0.73 (m, 2H); 0.88 (t, 3H); 1.01 (d, 3H); 1.15 (m, 2H);
2.19 (t, 2H); 3.91 (m, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95 (s,
1H); 5.28 (s, 1H); 5.32 (dd, 1H); 5.47 (dd, 1H); 6.00 (d, 1H); 6.35
(d, 1H)
Synthesis of the Starting Materials in the 25-Alkyl Series
191. 2-(1-Ethylcyclopropyl)-2-methyl-1,3-dioxolan 195
[0686] 500 mg of olefin 8 is dissolved in 15 ml of ethyl acetate,
150 mg of platinum(IV) oxide is added and hydrogenated in a
hydrogenating apparatus until no more hydrogen is taken up. After
filtration, it is concentrated by evaporation, whereby 398 mg of
title compound 195 is obtained as a colorless oil, which is
immediately further reacted.
192. 1-(1-Ethylcyclopropyl)-1-ethanone 196
[0687] 370 mg of 195 is dissolved in 15 ml of acetone, and 1 ml of
4N hydrochloric acid is added at room temperature under nitrogen.
It is stirred for 1 hour, and then diluted with sodium bicarbonate
solution. After extraction with ether, drying on sodium sulfate,
removal of the solvent and chromatography on silica gel with ethyl
acetate/hexane, 178 mg of title compound 196 accumulates as a
colorless oil.
[0688] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.77 ppm (m, 2H);
0.90 (t, 3H); 1.18 (m, 2H); 1.64 (q, 2H); 2.03 (s, 3H)
193. 2-[1-(1-Butenyl)cyclopropyl]-2-methyl-1,3-dioxolan 197
[0689] 7.2 g of propyltriphenylphosphonium bromide is dissolved in
100 ml of diethyl ether, and 7.5 ml of n-butyllithium solution (2.5
M in hexane) is added in drops under nitrogen at room temperature.
It is stirred for 1 hour, and then 2.34 g of aldehyde 7 is added to
10 ml of diethyl ether. It is stirred for 1 more hour, quenched
with sodium chloride solution, extracted with ethyl acetate, washed
with sodium chloride solution, dried on sodium sulfate and
concentrated by evaporation. The residue is chromatographed on
silica gel with ethyl acetate/hexane, whereby 1.8 g of title
substance 197 is obtained as a colorless oil (1:3 E,Z-mixture that
cannot be separated).
[0690] .sup.1H-NMR (300 MHz, CDCl.sub.3): E-Isomer: .delta.=0.50
ppm (m, 2H); 0.78 (m, 2H); 0.97 (t, 3H); 1.38 (s, 3H); 2.02 (q,
2H); 3.89 (m, 4H); 5.48 (dt, 1H); 5.80 (d, 1H)
[0691] Z-Isomer: .delta.=0.47 ppm (m, 2H); 0.81 (m, 2H); 0.97 (t,
3H); 1.38 (s, 3H); 2.22 (q, 2H); 390 (m, 4H); 5.46 (dt, 1H); 5.60
(d, 1H)
194. 1-[1-(1-Butenyl)cyclopropyl)-1-ethanone 198
[0692] 1.1 g of 197 is reacted analogously to 192., and 740 mg of
title compound 198 is obtained as a colorless oil (1:3 E,Z-mixture
that cannot be separated).
[0693] .sup.1H-NMR (300 MHz, CDCl.sub.3): E-Isomer: .epsilon.=0.98
ppm (t, 3H); 1.01 (m, 2H); 1.33 (m, 2H); 2.11 (q, 2H); 2.20 (s,
3H); 5.54 (dt, 1H); 6.01 (d, 1H)
[0694] Z-Isomer: .epsilon.=0.88 ppm (m, 2H); 0.99 (t, 3H); 1.42 (m,
2H); 2.15 (q, 2H); 2.21 (s, 3H); 5.62 (dt, 1H); 5.71 (d, 1H)
195. 1-(1-Butylcyclopropyl)-1-ethanone 199
[0695] 250 mg of 198 is reacted analogously to 191, and 195 mg of
title compound 199 is obtained as a colorless oil.
[0696] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.75 ppm (m, 2H);
0.90 (t, 3H); 1.18 (m, 2H); 1.32 (m, 2H); 1.59 (m, 2H); 2.02 (s,
3H)
196. 2-(1-(1-Hexenyl)cyclopropyl]-2-methyl-1,3-dioxolan 200
[0697] 2.07 g of pentyltriphenylphosphonium bromide and 600 mg of
aldehyde 7 are reacted analogously to 193., and 567 g of title
substance 200 is obtained as a colorless oil (8:1 E,Z-mixture that
cannot be separated).
[0698] .sup.1H-NMR (300 MHz, CDCl.sub.3): E-Isomer (Main
diastereomer): .delta.=0.52 ppm (m, 2H); 0.78 (m, 2H); 0.90 (t,
3H); 1.40 (s, 3H); 2.00 (q, 2H); 3.90 (m, 4H); 5.42 (dt, 1H); 5.82
(d, 1H)
197. 1-(1-Hexylcyclopropyl)-2-methyl-1,3-dioxolan 201
[0699] 250 mg of 200 is reacted analogously to 191., and 243 mg of
title compound 201 is obtained as a colorless oil.
[0700] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.25 ppm (m, 2H);
0.58 (m, 2H); 0.87 (t, 3H); 1.28 (m, 8H); 1.39 (s, 3H); 1.48 (m,
2H); 3.88 (m, 4H)
198. 1-(1-Hexylcyclopropyl)-1-ethanone 202
[0701] 330 mg of 201 is reacted analogously to 192., and 181 mg of
title compound 202 is obtained as a colorless oil.
[0702] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.75 ppm (m, 2H);
0.89 (t, 3H); 1.18 (m, 2H); 1.28 (m, 8H); 1.58 (m, 2H); 2.02 (s,
3H)
199. 2-(1-(1-Heptenyl)cyclopropyl]-2-methyl-1,3-dioxolan 203
[0703] 1.93 g of hexyltriphenylphosphonium bromide and 900 mg of
aldehyde 7 are reacted analogously to 193., and 879 mg of title
substance 203 is obtained as a colorless oil (1:3 E,Z mixture that
cannot be separated).
[0704] .sup.1H-NMR (300 MHz, CDCl.sub.3): E-Isomer: .delta.=0.52
ppm (m, 2H); 0.78 (m, 2H); 0.90 (t, 3H); 1.40 (6H); 1.41 (s, 3H);
2.02 (q, 2H); 3.90 (m, 4H); 5.43 (dt, 1H); 5.80 (d, 1H)
[0705] Z-Isomer: .delta.=0.47 ppm (m, 2H); 0.82 (m, 2H); 0.90 (t,
3H); 1.40 (m, 6H); 2.20 (q, 2H); 3.91 (m, 4H); 5.47 (dt, 1H); 5.61
(d, 1H)
200. 1-(1-Heptylcyclopropyl)-2-methyl-1,3-dioxolan 204
[0706] 550 mg of 203 is reacted analogously to 191., and 450 mg of
title compound 204 is obtained as a colorless oil.
[0707] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.28 ppm (m, 2H);
0.59 (m, 2H); 0.89 (t, 3H); 1.28 (m, 10H); 1.40 (s, 3H); 1.48 (m,
2H); 3.90 (m, 4H)
201. 1-(1-Heptylcyclopropyl)-1-ethanone 205
[0708] 445 mg of 204 is reacted analogously to 192., and 307 mg of
title compound 205 is obtained as a colorless oil.
[0709] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.75 ppm (m, 2H);
0.89 (t, 3H); 1.18 (m, 2H); 1.28 (m, 10H); 1.58 (m, 2H); 2.02 (s,
3H)
202. (Z)-2-Methyl-2-[(1-(1-octenyl)cyclopropyl]-1,3-dioxolan
206
[0710] 4.87 g of heptyltriphenylphosphonium bromide and 1.25 g of
aldehyde 7 are reacted analogously to 193., and 978 mg of title
substance 206 is obtained as a colorless oil (only Z-isomer).
[0711] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.48 ppm (m, 2H);
0.81 (m, 2H); 0.89 (t, 3H); 1.29 (8H); 1.40 (s, 3H); 2.02 (m, 2H);
3.92 (m, 4H); 5.48 (dt, 1H); 5.62 (d, 1H)
203. 2-Methyl-1-(1-octylcyclopropyl)-1,3-dioxolan 207
[0712] 400 mg of 206 is reacted analogously to 191., and 390 mg of
title compound 207 is obtained as a colorless oil.
[0713] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.28 ppm (m, 2H);
0.59 (m, 2H); 0.90 (t, 3H); 1.28 (m, 12H); 1.39 (s, 3H); 1.48 (m,
2H); 3.90 (m, 4H)
204. 1-(1-Octylcyclopropyl)-1-ethanone 208
[0714] 390 mg of 207 is reacted analogously to 192., and 250 mg of
title compound 208 is obtained as a colorless oil.
[0715] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.77 ppm (m, 2H);
0.90 (t, 3H); 1.18 (m, 2H); 1.28 (m, 12H); 1.58 (m, 2H); 2.02 (s,
3H)
205. 1-[1-(1-Octenyl)cyclopropyl]-1-ethanone 209
[0716] 330 mg of 206 is reacted analogously to 192., and 270 mg of
title compound 209 is obtained as a colorless oil.
[0717] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.=0.90 ppm (m, 2H);
0.90 (t, 3H); 1.18 (m, 2H); 1.30 (m, 8H); 1.44 (m, 2H); 2.10 (q,
2H); 2.22 (s, 3H); 5.64 (dt, 1H); 5.74 (d, 1H)
EXAMPLE 32
(5Z,7E,22E)-(1S,3R,24S)-25-Ethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),-
22-tetraene-1,3,24-triol 214a and
(5Z,7E,22E)-(1S,3R,24R)-25-ethyl-26,27-c-
yclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 214b
[0718] 206. 129 mg of 196 is reacted with 286 mg of aldehyde 2
analogously to 149., and 187 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethy-
l)silyl)oxy)-25-ethyl-22-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19)--
trien-24-one 210 is obtained as a colorless foam, which is
immediately further reacted.
[0719] 207. 170 mg of 210 is reacted analogously to 150., and 151
mg of
(5Z,7E)-(1S,3R)-22-acetoxy-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-
-25-ethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-24-one 211
is obtained as a colorless foam, which is immediately further
reacted.
[0720] 208. 151 mg of 211 is reacted analogously to 151., and 110
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-eth-
yl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one 212
is obtained as a colorless foam.
[0721] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.04 ppm
(s, 12H); 0.54 (s, 3H); 0.73 (m, 2H); 0.87 (s, 18H); 0.92 (m, 2H);
0.93 (t, 3H); 1.05 (d, 3H); 4.17 (m, 1H); 4.37 (m, 1H); 4.83 (s,
1H); 5.17 (s, 1H); 6.01 (d, 1H); 6.11 (d, 1H); 6.23 (d, 1H); 6.70
(dd, 1H)
[0722] 209. 110 mg of 212 is reacted analogously to 152., and after
chromatography on silica gel with ethyl acetate/hexane, 42 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-ethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
213a and 25 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)sily-
l]oxy]-25-ethyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
213b are obtained in succession as colorless foams.
[0723] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 213a: .delta.=0.03
ppm (s, 12H); 0.25 (m, 2H); 0.42 (m, 2H); 0.53 (s, 3H); 0.85 (t,
3H); 0.86 (s, 18H); 1.02 (d, 3H); 3.80 (m, 1H); 4.16 (m, 1H); 4.36
(m, 1H); 4.83 (s, 1H); 5.16 (s, 1H); 5.33 (dd, 1H); 5.50 (dd, 1H);
6.01 (d, 1H); 6.23 (d, 1H)
[0724] 213b: .delta.=0.03 ppm (s, 12H); 0.25 (m, 2H); 0.43 (m, 2H);
0.53 (s, 3H 0.85 (t, 3H); 0.85 (s, 18H); 1.03 (d, 3H); 3.78 (m,
1H); 4.17 (m, 1H); 4.36 (m, 1H); 4.83 (s, 1H); 5.16 (s, 1H); 5.33
(dd, 1H); 5.45 (dd, 1H); 6.01 (d, 1H); 6.23 (d, 1H)
[0725] 210. 42 mg of 213a is reacted analogously to 154., and 18 mg
of title compound 214a is obtained as a colorless foam.
[0726] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.29 ppm
(m, 2H); 0.42 (m, 2H); 0.57 (s, 3H); 0.88 (t, 3H); 1.03 (d, 3H);
3.81 (d, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.95 (s, 1H); 5.29 (s,
1H); 5.35 (dd, 1H); 5.51 (dd, 1H); 6.00 (d, 1H); 6.35 (d, 1H)
[0727] 211. 25 mg of 213b is reacted analogously to 154., and 9.5
mg of title compound 214b is obtained as a colorless foam.
[0728] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.27 ppm
(m, 2H); 0.44 (m, 2H); 0.57 (s, 3H); 0.89 (t, 3H); 1.02 (d, 3H);
3.79 (d, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.96 (s, 1H); 5.29 (s,
1H); 5.34 (dd, 1H); 5.48 (dd, 1H); 6.00 (d, 1H); 6.36 (d, 1H)
EXAMPLE 33
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-Butenyl)-26,27-cyclo-9,10-secocholesta-
-5,7,10(19),22-tetraene-1,3,24-triol 220b,
(5Z,7E,22E,25(E)]-(1S,3R,24S)-25-(1-butenyl)-26,27-cyclo-9,10-secocholesta-
-5,7,10(19),22-tetraene-1,3,24-triol 221a and
[5Z,7E,22E,25(E)]-(1S,3R,24R-
)-25-(1-butenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,-
24-triol 221b
[0729] 212. 460 mg of 198 is reacted with 573 mg of aldehyde 2
analogously to 149., and 546 mg of (5Z,
7E)-(1S3R)-1,3-bis[dimethyl(1,1-dimethylethyl-
)silyl]oxy]-25-(1-butenyl)-22-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10-
(19)-trien-24-one 215 is obtained as a colorless foam, which is
immediately further reacted.
[0730] 213. 275 mg of 215 is reacted analogously to 150., and 265
mg of
(5Z,7E)-(1S,3R)-22-acetoxy-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-
-25-(1-butenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-24-one
216 is obtained as a colorless foam, which is immediately further
reacted.
[0731] 214. 265 mg of 216 is reacted analogously to 151., and 214
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1--
butenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one
217 is obtained as a colorless foam (1:3 E:Z-mixture).
[0732] 215. 214 mg of 217 is reacted analogously to 152., and after
chromatography on silica gel with ethyl acetate/hexane, 31 mg of
[5Z,7E,22E,25(Z)]-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]o-
xy]-25-(1-butenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24--
ol 218b, 27 mg of
[5Z,7E,22E,25(E)]-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dime-
thylethyl)silyl]oxy]-25-(1-butenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(1-
9),22-tetraen-24-ol 219a and 22 mg of
(5Z,7E,22E,25(E)]-(1S,3R,24R)-1,3-bi-
s[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-(1-butenyl)-26,27-cyclo-9,10-s-
ecocholesta-5,7,10(19),22-tetraen-24-ol 219b are obtained in
succession as colorless foams.
[0733] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 218b: .delta.=0.03
ppm (s, 12H); 0.53 (s, 3H); 0.86 (s, 18H); 0.93 (t, 3H); 1.01 (d,
3H); 3.49 (d, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.84 (s, 1H); 5.17
(s, 1H); 5.42 (m, 2H); 5.49 (m, 2H); 6.01 (d, 1H); 6.23 (d, 1H)
[0734] 219a: .delta.=0.03 ppm (s, 12H); 0.53 (s, 3H); 0.87 (s,
18H); 0.94 (t, 3H); 1.03 (d, 3H); 3.60 (d, 1H); 4.17 (m, 1H); 4.37
(m, 1H); 4.83 (s, 1H); 5.17 (s, 1H); 5.40 (dt, 1H); 5.46 (m, 2H);
5.59 (d, 1H); 6.01 (d, 1H); 6.23 (d, 1H)
[0735] 219b: .delta.=0.04 ppm (s, 12H); 0.53 (s, 3H); 0.87 (s,
18H); 0.95 (t, 3H); 1.01 (d, 3H); 3.48 (d, 1H); 4.17 (m, 1H); 4.37
(m, 1H); 4.84 (s, 1H); 5.18 (s, 1H); 5.41 (m, 2H); 5.50 (m, 2H);
6.01 (d, 1H); 6.24 (d, 1H)
[0736] 216. 17 mg of 218b is reacted analogously to 154., and 7 mg
of title compound 220b is obtained as a colorless foam.
[0737] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .epsilon.=0.42 ppm
(m, 2H); 0.53 (s, 3H); 0.56 (m, 2H); 0.94 (t, 3H); 1.02 (d, 3H);
3.49 (m, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.93 (s, 1H); 5.29 (s,
1H); 5.41 (m, 2H); 5.45 (m, 1H); 6.00 (d, 1H); 6.33 (d, 1H)
[0738] 217. 27 mg of 219a is reacted analogously to 154., and 11 mg
of title compound 221a is obtained as a colorless foam.
[0739] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.44 ppm
(m, 2H); 0.54 (s, 3H); 0.57 (m, 2H); 0.97 (t, 3H); 1.03 (d, 3H);
3.59 (d, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.95 (s, 1H); 5.29 (s,
1H); 5.45 (m, 3H); 5.58 (d, 1H); 6.00 (d, 1H); 6.36 (d, 1H)
[0740] 218. 22 mg of 219b is reacted analogously to 154., and 8 mg
of title compound 221b is obtained as a colorless foam.
[0741] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.45 ppm
(m, 2H); 0.55 (s, 3H); 0.58 (m, 2H); 0.97 (t, 3H); 1.02 (d, 3H);
3.49 (d, 1H); 4.18 (m, 1H); 4.38 (m, 1H); 4.96 (s, 1H); 5.29 (s,
1H); 5.42 (m, 2H); 5.50 (m, 2H); 6.01 (d, 1H); 6.36 (d, 1H)
EXAMPLE 34
(5Z,7E,22E)-(1S,3R,24S)-25-Butyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),-
22-tetraene-1,3,24-triol 226a and
(5Z,7E,22E)-(1S,3R,24R)-25-butyl-26,27-c-
yclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 226b
[0742] 219. 195 mg of 199 is reacted with 400 mg of aldehyde 2
analogously to 149., and 275 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethy-
l)silyl]oxy]-25-butyl-22-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19)--
trien-24-one 222 is obtained as a colorless foam, which is
immediately further reacted.
[0743] 220. 275 mg of 222 is reacted analogously to 150., and 245
mg of
(5Z,7E)-(1S,3R)-22-acetoxy-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-
-25-butyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-24-one 223
is obtained as a colorless foam, which is immediately further
reacted.
[0744] 221. 245 mg of 233 is reacted analogously to 151., and 214
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-but-
yl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one 224
is obtained as a colorless foam.
[0745] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .epsilon.=0.04 ppm
(s, 12H); 0.54 (s, 3H); 0.74 (m, 2H); 0.87 (s, 18H); 0.88 (t, 3H);
0.92 (m, 2H); 1.06 (d, 3H); 4.17 (m, 1H); 4.36 (m, 1H); 4.83 (s,
1H); 5.15 (s, 1H); 6.01 (d, 1H); 6.14 (d, 1H); 6.23 (d, 1H); 6.66
(dd, 1H)
[0746] 222. 214 mg of 224 is reacted analogously to 152., and after
chromatography on silica gel with ethyl acetate/hexane, 80 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-butyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
225a and 41 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)sily-
l]oxy]-25-butyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
225b are obtained in succession as colorless foams.
[0747] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 225a: .delta.=0.03
ppm (s, 12H); 0.25 (m, 2H); 0.43 (m, 2H); 0.53 (s, 3H); 0.86 (t,
3H); 0.86 (s, 18H); 1.03 (d, 3H); 3.79 (m, 1H); 4.17 (m, 1H); 4.36
(m, 1H); 4.83 (s, 1H); 5.16 (s, 1H); 5.35 (dd, 1H); 5.50 (dd, 1H);
6.01 (d, 1H); 6.23 (d, 1H)
[0748] 225b: .delta. 0.03 ppm (s, 12H); 0.24 (m, 2H); 0.43 (m, 2H);
0.53 (s, 3H); 0.86 (t, 3H); 0.87 (s, 18H); 1.03 (d, 3H); 3.77 (m,
1H); 4.17 (m, 1H); 4.36 (m, 1H); 4.83 (s, 1H); 5.16 (s, 1H); 5.33
(dd, 1H); 5.45 (dd, 1H); 6.01 (d, 1H); 6.23 (d, 1H)
[0749] 223. 80 mg of 225a is reacted analogously to 154., and 37 mg
of title compound 226a is obtained as a colorless foam.
[0750] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.28 ppm
(m, 2H); 0.44 (m, 2H); 0.58 (s, 3H); 0.89 (t, 3H); 1.03 (d, 3H);
3.79 (d, 1H); 4.18 (m, 1H); 4.38 (m, 1H); 4.96 (s, 1H); 5.29 (s,
1H); 5.37 (dd, 1H); 5.51 (dd, 1H); 6.00 (d, 1H); 6.36 (d, 1H)
[0751] 224. 41 mg of 225b is reacted analogously to 154., and 17 mg
of title compound 226b is obtained as a colorless foam.
[0752] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.26 ppm
(m, 2H); 0.44 (m, 2H); 0.58 (s, 3H); 0.88 (t, 3H); 1.02 (d, 3H);
3.78 (d, 1H); 4.18 (m, 1H); 4.38 (m, 1H); 4.97 (s, 1H); 5.29 (s,
1H); 5.34 (dd, 1H); 5.48 (dd, 1H); 6.00 (d, 1H); 6.36 (d, 1H)
EXAMPLE 35
(5Z,7E,22E)-(1S,3R,24S)-25-Hexyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),-
22-tetraene-1,3,24-triol 231a and
(5Z,7E,22E)-(1S,3R,24R)-25-hexyl-26,27-c-
yclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 231b
[0753] 225. 120 mg of 202 is reacted with 287 mg of aldehyde 2
analogously to 149., and 256 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethy-
l)silyl]oxy]-25-hexyl-22-hydroxy-26,27-cyclo-9,10-sechocholesta-5,7,10(19)-
-trien-24-one 227 is obtained as a colorless foam, which is
immediately further reacted.
[0754] 226. 256 mg of 227 is reacted analogously to 150., and 234
mg of
(5Z,7E)-(1S,3R)-22-acetoxy-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-
-25-hexyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-24-one 228
is obtained as a colorless foam, which is immediately further
reacted.
[0755] 227. 234 mg of 228 is reacted analogously to 151., and 104
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)-silyl]oxy]-25-he-
xyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one 229
is obtained as a colorless foam.
[0756] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta. 0.05 ppm
(s, 12H); 0.56 (s, 3H); 0.74 (m, 2H); 0.88 (s, 18H); 0.89 (t, 3H);
0.93 (m, 2H) 1.08 (d, 3H); 4.18 (m, 1H); 4.38 (m, 1H); 4.85 (s,
1H); 5.17 (s, 1H); 6.01 (d, 1H); 6.15 (d, 1H); 6.23 (d, 1H); 6.73
(dd, 1H)
[0757] 228. 104 mg of 229 is reacted analogously to 1523., and
after chromatography on silica gel with ethyl acetate/hexane, 37 mg
of
(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-hexyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
230a and 35 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)sily-
l]oxy]-25-hexyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
230b are obtained in succession as colorless foams.
[0758] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 230a: .delta.=0.04
ppm (s, 12H); 0.24 (m, 2H); 0.43 (m, 2H); 0.54 (s, 3H); 0.87 (t,
3H); 0.87 (s, 18H); 1.02 (d, 3H); 3.77 (m, 1H); 4.17 (m, 1H); 4.36
(m, 1H); 4.84 (s, 1H); 5.16 (s, 1H); 5.34 (dd, 1H); 5.50 (dd, 1H);
6.01 (d, 1H); 6.24 (d, 1H)
[0759] 230b: .delta.=0.04 ppm (s, 12H); 0.23 (m, 2H); 0.43 (m, 2H);
0.54 (s, 3H); 0.87 (t, 3H); 0.87 (s, 18H); 1.03 (d, 3H); 3.75 (d,
1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.84 (s, 1H); 5.16 (s, 1H); 5.33
(dd, 1H); 5.46 (dd, 1H); 6.01 (d, 1H); 6.24 (d, 1H)
[0760] 229. 37 mg of 230a is reacted analogously to 154., and 17 m
g of title compound 231a is obtained as a colorless foam.
[0761] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.28 ppm
(m, 2H); 0.43 (m, 2H); 0.58 (s, 3H); 0.90 (t, 3H); 1.04 (d, 3H);
3.80 (d, 1H); 4.18 (m, 1H); 4.38 (m, 1H); 4.96 (s, 1H); 5.28 (s,
1H); 5.35 (dd, 1H); 5.51 (dd, 1H); 6.01 (d, 1H); 6.36 (d, 1H)
[0762] 230. 31 mg of 230b is reacted analogously to 154., and 10 mg
of title compound 231b is obtained as a colorless foam.
[0763] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.28 ppm
(m, 2H); 0.46 (m, 2H); 0.59 (s, 3H); 0.89 (t, 3H); 1.04 (d, 3H);
3.79 (d, 1H); 4.18 (m, 1H); 4.38 (m, 1H); 4.97 (s, 1H); 5.29 (s,
1H); 5.35 (dd, 1H); 5.48 (dd, 1H); 6.00 (d, 1H); 6.37 (d, 1H)
EXAMPLE 36
(5Z,7E,22E)-(1S,3R,24S)-25-Heptyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-
,22-tetraene-1,3,24-triol 236a and
(5Z,7E,22E)-(1S,3R,24R)-25-heptyl-26,27-
-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol
236b
[0764] 231. 300 mg of 205 is reacted with 573 mg of aldehyde 2
analogously to 149., and 556 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethy-
l)silyl]oxy]-25-heptyl-22-hydroxy-26,27-cyclo-9,10-secocholesta-5,7,10(19)-
-trien-24-one 232 is obtained as a colorless foam, which is
immediately further reacted.
[0765] 232. 305 mg of 232 is reacted analogously to 150., and 278
mg of
(5Z,7E)-(1S,3R)-22-acetoxy-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-
-25-heptyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-24-one
233 is obtained as a colorless foam, which is immediately further
reacted.
[0766] 233. 278 mg of 233 is reacted analogously to 151., and 203
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-hep-
tyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one 234
is obtained as a colorless foam.
[0767] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.05 ppm
(s, 12H); 0.57 (s, 3H); 0.74 (m, 2H); 0.89 (s, 18H); 0.89 (t, 3H);
0.94 (m, 2H); 1.09 (d, 3H); 4.18 (m, 1H); 4.38 (m, 1H); 4.87 (s,
1H); 5.18 (s, 1H); 6.01 (d, 1H); 6.14 (d, 1H); 6.22 (d, 1H); 6.75
(dd, 1H)
[0768] 234. 200 mg of 234 is reacted analogously to 152., and after
chromatography on silica gel with ethyl acetate/hexane, 80 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-heptyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
235a and 38 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)sily-
l]oxy]-25-heptyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
235b are obtained in succession as colorless foams.
[0769] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 235a: .delta.=0.04
ppm (s, 12H); 0.24 (m, 2H); 0.43 (m, 2H); 0.53 (s, 3H); 0.86 (t,
3H); 0.86 (s, 18H); 1.02 (d, 3H); 3.75 (m, 1H); 4.17 (m, 1H); 4.36
(m, 1H); 4.84 (s, 1H); 5.16 (s, 1H); 5.33 (dd, 1H); 5.50 (dd, 1H);
6.00 (d, 1H); 6.23 (d, 1H)
[0770] 235b: .delta.=0.04 ppm (s, 12H); 0.24 (m, 2H); 0.43 (m, 2H);
0.53 (s, 3H); 0.87 (t, 3H); 0.87 (s, 181H); 1.03 (d, 3H); 3.76 (d,
1H); 4.17 (m, 1H); 4.36 (m, 1H); 4.83 (s, 1H); 5.15 (s, 1H); 5.33
(dd, 1H); 5.45 (dd, 1H); 6.00 (d, 1H); 6.23 (d, 1H)
[0771] 235. 75 mg of 235a is reacted analogously to 154., and 51 mg
of title compound 236a is obtained as a colorless foam.
[0772] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.26 ppm
(m, 2H); 0.43 (m, 2H); 0.56 (s, 3H); 0.88 (t, 3H); 1.02 (d, 3H);
3.78 (d, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.95 (s, 1H); 5.28 (s,
1H); 5.34 (dd, 1H); 5.50 (dd, 1H); 6.00 (d, 1H); 6.35 (d, 1H)
[0773] 236. 33 mg of 235b is reacted analogously to 154., and 17 mg
of title compound 236b is obtained as a colorless foam.
[0774] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.26 ppm
(m, 2H); 0.44 (m, 2H): 0.56 (s, 3H); 0.87 (t, 3H); 1.03 (d, 3H);
3.76 (d, 1H); 4.16 (m, 1H); 4.36 (m, 1H); 4.95 (s, 1H); 5.28 (s,
1H); 5.33 (dd, 1H); 5.45 (dd, 1H); 6.00 (d, 1H); 6.35 (d, 1H)
EXAMPLE 37
(5Z,7E,22E)-(1S,3R,24S)-25-Octyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),-
22-tetraene-1,3,24-triol 241a and
(5Z,7E,22E)-(1S,3R,24R)-25-octyl-26,27-c-
yclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,24-triol 241b
[0775] 237. 250 mg of 208 is reacted with 500 mg of aldehyde 2
analogously to 149., and 432 mg of
(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethy-
l)silyl]oxy]-22-hydroxy-25-octyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)--
trien-24-one 237 is obtained as a colorless foam, which is
immediately further reacted.
[0776] 238. 380 mg of 237 is reacted analogously to 150., and 356
mg of
(5Z,7E)-(1S,3R)-22-acetoxy-1,1-bis[[dimethyl(1,1-dimethylethyl)-silyl]oxy-
]-25-octyl-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-24-one
238 is obtained as a colorless foam, which is immediately further
reacted.
[0777] 239. 356 mg of 238 is reacted-analogously to 151., and 310
mg of
(5Z,7E,22E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-oct-
yl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one 239
is obtained as a colorless foam.
[0778] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.04 ppm
(s, 12H); 0.57 (s, 3H); 0.74 (m, 2H); 0.88 (s, 18H); 0.89 (t, 3H);
0.93 (m, 2H); 1.09 (d, 3H); 4.18 (m, 1H); 4.38 (m, 1H); 4.87 (s,
1H); 5.18 (s, 1H); 6.01 (d, 1H); 6.14 (d, 1H); 6.23 (d, 1H); 6.76
(dd, 1H)
[0779] 240. 310 mg of 239 is reacted analogously to 152., and after
chromatography on silica gel with ethyl acetate/hexane, 130 mg of
(5Z,7E,22E)-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-25-
-octyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
240a and 53 mg of
(5Z,7E,22E)-(1S,3R,24R)-1,3-bis[[dimethyl(1,1-dimethylethyl)sily-
l]oxy]-25-octyl-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-ol
240b are obtained in succession as colorless foams.
[0780] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 240a: .delta.=0.04
ppm (s, 12H); 0.24 (m, 2H); 0.43 (m, 2H); 0.55 (s, 3H); 0.88 (t,
3H); 0.88 (s, 18H); 1.04 (d, 3H); 3.79 (m, 1H); 4.18 (m, 1H): 4.38
(m, 1H); 4.86 (s, 1H); 5.18 (s, 1H); 5.36 (dd, 1H); 5.51 (dd, 1H);
6.01 (d, 1H); 6.25 (d, 1H)
[0781] 240b: .delta.=0.04 ppm (s, 12H); 0.24 (m, 2H); 0.43 (m, 2H);
0.56 (s, 3H); 0.88 (t, 3H); 0.89 (s, 18H); 1.05 (d, 3H); 3.78 (d,
1H); 4.18 (m, 1H); 4.38 (m, 1H); 4.84 (s, 1H); 5.18 (s, 1H); 5.35
(dd, 1H); 5.48 (dd, 1H); 6.01 (d, 1H); 6.25 (d, 1H)
[0782] 241. 130 mg of 240a is reacted analogously to 154., and 67
mg of title compound 241a is obtained as a colorless foam.
[0783] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.28 ppm
(m, 2H); 0.45 (m, 2H); 0.57 (s, 3H); 0.89 (t, 3H); 1.04 (d, 3H);
3.79 (d, 1H); 4.18 (m, 1-H); 4.38 (m, 1H); 4.97 (s, 1H); 5.29 (s,
1H); 5.36 (dd, 1H); 5.51 (dd, 1H); 6.01 (d, 1H); 6.36 (d, 1H)
[0784] 242. 53 mg of 240b is reacted analogously to 154., and 16 mg
of title compound 241b is obtained as a colorless foam.
[0785] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .epsilon.=0.28 ppm
(m, 2H); 0.47 (m, 2H); 0.57 (s, 3H); 0.89 (t, 3H); 1.05 (d, 3H);
3.79 (d, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.96 (s, 1H); 5.29 (s,
1H); 5.35 (dd, 1H); 6.01 (d, 1H); 6.37 (d, 1H)
EXAMPLE 38
[5Z,7E,22E,25(Z)]-(1S,3R,24S)-25-(1-Octenyl)-26,27-cyclo-9,10-secocholesta-
-5,7,10(19),22-tetraene-1,3,24-triol 246a and
[5Z,7E,22E,25(Z)]-(1S,3R,24S-
)-25-(1-octenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3,-
24-triol 246b
[0786] 243. 250 mg of 209 is reacted with 573 mg of aldehyde 2
analogously to 149., and 550 mg of
[5Z,7E,25(Z)]-(1S,3R)-1,3-bis[[dimethyl(1,1-dimeth-
ylethyl)silyl]oxy]-22-hydroxy-25-(1-octenyl)-26,27-cyclo-9,10-secocholesta-
-5,7,10(19)-trien-24-one 242 is obtained as a colorless foam, which
is immediately further reacted.
[0787] 244. 540 mg of 242 is reacted analogously to 150., and 476
mg of
[5Z,7E,25(Z)]-(1S,3R)-22-acetoxy-1,3-bis[[dimethyl(1,1-dimethylethyl)sily-
l]oxy]-25-(1-octenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19)-trien-24-on-
e 243 is obtained as a colorless foam, which is immediately further
reacted.
[0788] 245. 476 mg of 243 is reacted analogously to 151., and 323
mg of
[5Z,7E,22E,25(Z)]-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]--
25-(1-octenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraen-24-one
244 is obtained as a colorless foam.
[0789] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.06 ppm
(s, 12H); 0.57 (s, 3H); 0.74 (m, 2H); 0.89 (s, 18H); 0.89 (t, 3H);
0.93 (m, 2H); 1.09 (d, 3H); 4.18 (m, 1H); 4.38 (m, 1H); 4.88 (s,
1H); 5.19 (s, 1H); 6.01 (d, 1H); 6.23 (d, 1H); 6.54 (d, 1H); 6.72
(dd, 1H)
[0790] 246. 320 mg of 244 is reacted analogously to 152., and after
chromatography on silica gel with ethyl acetate/hexane, 128 mg of
245a and 68 mg of
[5Z,7E,22E,25(E)]-(1S,3R,24S)-1,3-bis[[dimethyl(1,1-dimethyl-
ethyl)silyl]oxy]-25-(1-octenyl)-26,27-cyclo-9,10-secocholesta-5,7,10(19),2-
2-tetraen-24-ol 245b are obtained in succession as colorless
foams.
[0791] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 245a: .delta.=0.03
ppm (s, 12H); 0.24 (m, 2H); 0.43 (m, 2H); 0.54 (s, 3H); 0.86 (t,
3H); 0.87 (s, 18H); 1.02 (d, 3H); 3.50 (m, 1H); 4.18 (m, 1H); 4.37
(m, 1H); 4.85 (s, 1H); 5.16 (s, 1H); 5.42 (m, 2H); 5.50 (m, 2H);
6.00 (d, 1H); 6.23 (d, 1H)
[0792] 245b: .epsilon.=0.03 ppm (s, 12H); 0.24 (m, 2H); 0.43 (m,
2H); 0.54 (s, 3H); 0.87 (t, 3H); 0.87 (s, 18H); 1.03 (d, 3H); 3.48
(d, 1H); 4.17 (m, 1H); 4.37 (m, 1H); 4.83 (s, 1H); 5.17 (s, 1H);
5.39 (m, 2H); 5.51 (m, 2H); 6.01 (d, 1H); 6.24 (d, 1H)
[0793] 247. 48 mg of 245a is reacted analogously to 154., and 26 mg
of title compound 246a is obtained as a colorless foam.
[0794] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): .delta.=0.55 ppm
(m, 2H); 0.58 (s, 3H); 0.69 (m, 2H); 0.90 (t, 3H); 1.04 (d, 3H);
3.53 (d, 1H); 4.18 (m, 1H); 4.38 (m, 1H); 4.98 (s, 1H); 5.29 (s,
1H); 5.47 (m, 2H); 5.52 (m, 2H); 6.01 (d, 1H); 6.37 (d, 1H)
[0795] 248. 40 mg of 245b is reacted analogously to 154., and 16 mg
of title compound 246b is obtained as a colorless foam.
[0796] .sup.1H-NMR (300 MHz, CD.sub.2Cl.sub.2): 0.6=0.54 ppm (m,
2H); 0.59 (s, 3H); 0.68 (s, 3H); 0.89 (t, 3H); 1.04 (d, 3H); 3.50
(d, 1H); 4.17 (m, 1H); 4.38 (m, 1H); 4.97 (s, 1H); 5.29 (s, 1H);
5.40 (m, 2H); 5.51 (m, 2H); 6.01 (d, 1H); 6.38 (d, 1H)
* * * * *