U.S. patent application number 15/488140 was filed with the patent office on 2017-08-03 for ingenol-3-acylates iii and ingenol-3-carbamates.
This patent application is currently assigned to LEO LABORATORIES LIMITED. The applicant listed for this patent is LEO LABORATORIES LIMITED. Invention is credited to Gunnar GRUE-SORENSEN, Thomas HOGBERG, Xifu LIANG, Kristoffer M NSSON, Per VEDSO, Thomas VIFIAN.
Application Number | 20170217910 15/488140 |
Document ID | / |
Family ID | 45491187 |
Filed Date | 2017-08-03 |
United States Patent
Application |
20170217910 |
Kind Code |
A1 |
GRUE-SORENSEN; Gunnar ; et
al. |
August 3, 2017 |
INGENOL-3-ACYLATES III AND INGENOL-3-CARBAMATES
Abstract
The invention relates to compounds of general formula I
##STR00001## wherein R is heteroaryl optionally substituted by R7;
or R is heterocycloalkyl or heterocycloalkenyl, optionally
substituted by R8; or R is X wherein X is --NR11R12; and
pharmaceutically acceptable salts, hydrates, or solvates thereof,
for use--alone or in combination with one or more other
pharmaceutically active compounds--in therapy, for preventing,
treating or ameliorating diseases or conditions responsive to
stimulation of neutrophil oxidative burst, responsive to
stimulation of keratinocyte IL-8 release or responsive to induction
of necrosis.
Inventors: |
GRUE-SORENSEN; Gunnar;
(Ballerup, DK) ; LIANG; Xifu; (Ballerup, DK)
; HOGBERG; Thomas; (Ballerup, DK) ; M NSSON;
Kristoffer; (Ballerup, DK) ; VEDSO; Per;
(Ballerup, DK) ; VIFIAN; Thomas; (Ballerup,
DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LEO LABORATORIES LIMITED |
DUBLIN 2 |
|
IE |
|
|
Assignee: |
LEO LABORATORIES LIMITED
DUBLIN 2
IE
|
Family ID: |
45491187 |
Appl. No.: |
15/488140 |
Filed: |
April 14, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14748925 |
Jun 24, 2015 |
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15488140 |
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13996989 |
Aug 21, 2013 |
9102687 |
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PCT/DK2011/000154 |
Dec 22, 2011 |
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14748925 |
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61426378 |
Dec 22, 2010 |
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61448350 |
Mar 2, 2011 |
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61534055 |
Sep 13, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 239/28 20130101;
C07D 307/00 20130101; C07D 333/40 20130101; C07C 271/34 20130101;
C07D 493/08 20130101; C07D 405/06 20130101; A61K 31/502 20130101;
A61P 15/00 20180101; A61P 17/08 20180101; C07D 277/56 20130101;
C07D 233/90 20130101; A61K 31/4192 20130101; C07D 261/20 20130101;
C07D 231/14 20130101; C07D 277/32 20130101; C07D 295/205 20130101;
C07D 295/21 20130101; C07D 295/182 20130101; C07D 265/36 20130101;
C07D 333/38 20130101; C07D 249/06 20130101; C07D 261/18 20130101;
C07D 401/04 20130101; C07D 513/04 20130101; A61K 31/381 20130101;
A61P 17/02 20180101; C07C 271/36 20130101; C07C 271/38 20130101;
A61K 31/365 20130101; C07D 237/28 20130101; C07D 271/08 20130101;
A61P 35/02 20180101; A61K 31/416 20130101; C07D 307/94 20130101;
A61K 31/415 20130101; A61P 35/00 20180101; A61K 31/5375 20130101;
C07D 209/08 20130101; A61K 31/404 20130101; C07D 217/26 20130101;
C07D 495/04 20130101; C07D 213/79 20130101; A61P 17/00 20180101;
A61K 31/538 20130101; A61K 31/472 20130101; C07D 249/04 20130101;
C07D 215/50 20130101; A61P 17/12 20180101; C07D 231/56 20130101;
C07D 209/42 20130101; C07D 263/34 20130101; C07D 307/68 20130101;
C07D 309/08 20130101; C07D 277/587 20130101; A61P 43/00 20180101;
C07D 471/04 20130101; A61K 31/42 20130101; C07C 2603/86
20170501 |
International
Class: |
C07D 261/18 20060101
C07D261/18; C07D 249/06 20060101 C07D249/06; C07D 231/14 20060101
C07D231/14; C07D 231/56 20060101 C07D231/56; C07D 209/42 20060101
C07D209/42; C07D 333/40 20060101 C07D333/40; C07D 217/26 20060101
C07D217/26; C07D 215/50 20060101 C07D215/50; C07D 237/28 20060101
C07D237/28; C07D 233/90 20060101 C07D233/90; C07D 263/34 20060101
C07D263/34; C07D 261/20 20060101 C07D261/20; C07D 239/28 20060101
C07D239/28; C07D 213/79 20060101 C07D213/79; C07D 277/56 20060101
C07D277/56; C07D 307/68 20060101 C07D307/68; C07D 209/08 20060101
C07D209/08; C07D 513/04 20060101 C07D513/04; C07D 471/04 20060101
C07D471/04; C07D 307/94 20060101 C07D307/94; C07D 405/06 20060101
C07D405/06; C07D 271/08 20060101 C07D271/08; C07D 295/182 20060101
C07D295/182; C07C 271/38 20060101 C07C271/38; C07C 271/34 20060101
C07C271/34; C07D 493/08 20060101 C07D493/08 |
Claims
1. A compound of the general formula I ##STR00307## wherein R is
heteroaryl which may optionally be substituted by one or more
substituents independently selected from R7; or R is
heterocycloalkyl or heterocycloalkenyl, wherein said
heterocycloalkyl or heterocycloalkenyl are optionally substituted
by one or more substituents independently selected from R8; or R is
X; R7 represents halogen, cyano or hydroxyl; or R7 represents
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)-alkenyl,
(C.sub.3-C.sub.7)-cycloalkyl, heterocycloalkyl, aryl, heteroaryl
arylalkyl, heterocycloalkylalkyl or
(C.sub.3-C.sub.7)-cycloalkylalkyl, wherein said
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)-alkenyl,
(C.sub.3-C.sub.7)-cycloalkyl, heterocycloalkyl, aryl, heteroaryl
arylalkyl, heterocycloalkylalkyl or
(C.sub.3-C.sub.7)-cycloalkylalkyl are optionally substituted by one
or more substituents independently selected from R9; or R7
represents --NRaCORb, --CONRaRb, --COORc, --OCORa, --ORa,
--OCONRaRb, --NRaCOORb, --NRaCONRaRb, --NRaSO2NRaRb, --NRaSO2Rb,
--SO2NRaRb, --SO2Ra, --S(O)Ra, --SRa or --NRaRb; R9 represents
halogen, cyano, hydroxy, (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl, --NRaCORb, --COORc, --OCORa, --CONRaRb,
--OCONRaRb, --NRaCOORb, --NRaCONRaRb, --NRaSO2NRaRb, --NRaSO2Rb,
--SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa, --SRa or .dbd.O; R8
represents halogen, cyano or hydroxyl; or R8 represents
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, aryl, heteroaryl,
(C.sub.3-C.sub.7)-cycloalkyl or heterocycloalkyl, wherein said
C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, aryl, heteroaryl,
(C.sub.3-C.sub.7)-cycloalkyl or heterocycloalkyl are optionally
substituted by one or more substituents independently selected from
R10; or R8 represents --NRaCORb, --COORc, --OCORa, --CONRaRb,
--OCONRaRb, --NRaCOORb, --NRaCONRaRb, --NRaSO2NRaRb, --NRaSO2Rb,
--SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa, --SRa, .dbd.O, .dbd.N--ORa,
--O--N.dbd.CRaRb, NRaRb or --C(O)N(Ra)O--Rb; R10 represents
halogen, cyano, hydroxy, (C.sub.1-C.sub.4)-alkyl,
(C.sub.1-C.sub.4)alkoxy, halo(C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkoxy, hydroxy(C.sub.1-C.sub.4)alkyl,
cyano(C.sub.1-C.sub.4)alkyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, --NRaCORb, --COORc, --OCORa, --CONRaRb,
--OCONRaRb, --NRaCOORb, --NRaCONRaRb, --NRaSO2NRaRb, --NRaSO2Rb,
--SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa, --SRa or .dbd.O; Ra and Rb
represents hydrogen, (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl; Rc represents hydrogen,
(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.x)alkyl, cyano(C.sub.1-C.sub.x)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl; X represents --NR11R12;
wherein R11 and R12 independently represent hydrogen, or wherein
R11 and R12 independently represents (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocycloalkyl,
heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl,
heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl,
alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl or
alkylheterocycloalkyl, wherein said (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocycloalkyl,
heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl,
heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl,
alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl or
alkylheterocycloalkyl are optionally substituted by one or more
substituents independently selected from R13; R13 represents
halogen, cyano or hydroxyl, or R13 represents
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, aryl,
(C.sub.3-C.sub.7)cycloalkyl, heteroaryl or heterocycloalkyl,
wherein said (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
aryl, (C.sub.3-C.sub.7)cycloalkyl, heteroaryl or heterocycloalkyl
are optionally substituted by one or more substituents selected
from R14, or R13 represents --NRdCORe, --COORf, --OCORd, --CONRdRe,
--OCONRdRe, --NRdCOORe, --NRdCONRdRe, --NRdSO2Re, --NRdSO2NRdRe,
--SO2NRdRe, --SO2Rd, --S(O)Rd, --ORd, --SRd, .dbd.O, .dbd.N--ORd,
--O--N.dbd.CRdRe, --NRdRe or --C(O)N(Rd)-ORe wherein Rd and Re
independently represents hydrogen, (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl; Rf represents hydrogen,
(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxyl(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl; R14 represents halogen,
hydroxyl, cyano, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
halo(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkoxy,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, --NRdCORe, --COORf,
--OCORd, --CONRdRe, --OCONRdRe, --NRdCOORe, --NRdCONRdRe,
--NRdSO2Re, --NRdSO2NRdRe, --SO2NRdRe, --SO2Rd, --S(O)Rd, --ORd,
--SRd or .dbd.O; and pharmaceutically acceptable salts, prodrugs,
hydrates and solvates thereof.
2. A compound according to claim 1, wherein R is heteroaryl which
may optionally be substituted by one or more substituents
independently selected from R7, or R is heterocycloalkyl or
heterocycloalkenyl, each of which may optionally be substituted by
one or more substituents independently selected from R8; R7
represents halogen, cyano, hydroxyl; or R7 represents
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)-alkenyl,
(C.sub.3-C.sub.7)-cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
each of which is optionally substituted by one or more substituents
independently selected from R9; or R7 represents --NRaCORb,
--CONRaRb, --COORc, --OCORa, --ORa, --OCONRaRb, --NRaCOORb,
--NRaCONRaRb, --NRaSO2NRaRb, --NRaSO2Rb, --SO2NRaRb, --SO2Ra,
--S(O)Ra, --SRa; R9 represents halogen, cyano, hydroxy,
(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl, --NRaCORb,
--COORc, --OCORa, --CONRaRb, --OCONRaRb, --NRaCOORb, --NRaCONRaRb,
--NRaSO2NRaRb, --NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa,
--SRa, .dbd.O; R8 represents halogen, cyano, hydroxyl; or R8
represents (C.sub.1-C.sub.4)-alkyl, (C.sub.2-C.sub.4)alkenyl, aryl,
heteroaryl, (C.sub.3-C.sub.7)-cycloalkyl, heterocycloalkyl, each of
which is optionally substituted by one or more substituents
independently selected from R10, or R8 represents --NRaCORb,
--COORc, --OCORa, --CONRaRb, --OCONRaRb, --NRaCOORb, --NRaCONRaRb,
--NRaSO2NRaRb, --NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa,
--SRa, .dbd.O; R10 represents halogen, cyano, hydroxy,
(C.sub.1-C.sub.4)-alkyl, halo(C.sub.1-C.sub.4)alkyl, --NRaCORb,
--COORc, --OCORa, --CONRaRb, --OCONRaRb, --NRaCOORb, --NRaCONRaRb,
--NRaSO2NRaRb, --NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa,
--SRa, .dbd.O; Ra and Rb represents hydrogen,
(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl; Rc
represents (C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl.
3. A compound according to claim 1, wherein R is heteroaryl.
4. A compound according to claim 1, wherein heteroaryl is
isoxazolyl, pyridyl, quinolyl, isoquinolyl, indolyl, furyl,
thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thienyl, pyrimidinyl,
1,2,3-triazolyl, indazolyl, cinnolyl, 1,2-benzoxazolyl,
imidazothiazolyl, imidazopyridinyl, pyrrolyl, isothiazolyl,
tetrahydroindazolyl or oxadiazolyl.
5. A compound according to claim 1, wherein R7 is independently
selected one or more times from the group of
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, aryl, arylalkyl,
heterocycloalkylalkyl, (C.sub.3-C.sub.7)-cycloalkylalkyl,
(C.sub.3-C.sub.7)-cycloalkyl --COORc, --ORa or halogen.
6. A compound according to claim 5, wherein R7 is selected from
phenyl, methyl, ethyl, isopropyl, t-butyl, piperidyl,
tert-butyloxycarbonyl, benzyl, tetrahydropyranylmethyl,
--OCH.sub.3, cyclopropyl, allyl, cyclopropylmethyl, Cl, Br or
I.
7. A compound according to claim 1, wherein R9 is halogen, --ORa,
(C.sub.1-C.sub.4)alkyl or --SO2Ra.
8. A compound according to claim 7, wherein R9 is Cl, F,
--OCH.sub.3, methyl or methylsulfonyl.
9. A compound according to claim 1, wherein R is heterocycloalkyl
or heterocycloalkenyl.
10. A compound according to claim 1, wherein heterocycloalkyl or
heterocycloalkenyl is pyrrolidinyl, piperidinyl, morpholinyl,
5-oxabicyclo[2.2.2]octanyl, oxaspiro[4.5]dec-1-enyl, oxo-thiazolyl,
dihydrothiazolyl, oxo-pyranyl, azepanyl, azabicyclo[3.2.2]nonanyl,
benzoxazinyl, quinoxalinyl, isoindolinyl, dihydroquinolinyl,
indolinyl or dihydroquinoxalinyl.
11. A compound according to claim 1, wherein R8 is
(C.sub.1-C.sub.4)alkyl, aryl or .dbd.O.
12. A compound according to claim 11, wherein R8 is methyl, phenyl
or .dbd.O.
13. A compound according to claim 1, wherein R10 represents
halogen.
14. A compound according to claim 1, wherein R is --NR11R12.
15. A compound according to claim 1, wherein R11 and R12
independently represents hydrogen, (C.sub.1-C.sub.6)alkyl, aryl,
cycloalkyl, arylalkyl, heteroaryl, cycloalkylalkyl,
heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl.
16. A compound according to claim 1, wherein R11 and R12
independently represents hydrogen, methyl, ethyl, isopropyl,
phenyl, benzyl, cyclohexyl, indanyl, tetralinyl, phenylethyl,
cyclopropylmethyl, pyrazolyl, isoxazolylmethyl, cyclopentyl,
cyclopropyl, pyridyl, piperidyl, tetrahydropyranylmethyl,
tetrahydropyranyl, cyclobutyl, allyl, propynyl or thiazolyl.
17. A compound according to claim 1, wherein R13 represents
(C.sub.1-C.sub.4)alkyl, cyano, halogen, .dbd.O, --ORa or
--COORf.
18. A compound according to claim 17, wherein R13 represents
methyl, cyano, F, .dbd.O, --OCH.sub.3 or
--COOC(CH.sub.3).sub.3.
19. A compound according to claim 1, wherein R11 or R12
independently represent hydrogen.
20. A compound according to claim 1 said compound being selected
from the group consisting of: Ingenol
3-(5-methyl-3-phenyl-isoxazole-4-carboxylate), Ingenol
3-(5-methyl-3-(2-chloro-6-fluoro-phenyl)-isoxazole-4-carboxylate),
Ingenol 3-(1S-camphanate), Ingenol
3-(3-phenyltriazole-4-carboxylate, Ingenol
3-(2-phenylpyrazole-3-carboxylate, Ingenol
3-(1-methylindazole-3-carboxylate), Ingenol
3-(3-ethyl-5-methyl-isoxazole-4-carboxylate), Ingenol
3-(3-methyl-5-methyl-isoxazole-4-carboxylate), Ingenol
3-(1-methylindole-3-carboxylate), Ingenol
3-(3-phenylthiophene-2-carboxylate), Ingenol
3-(5-phenylisoxazole-3-carboxylate), Ingenol 3-(N-ethyl-carbamate),
Ingenol 3-(N,N-dimethyl-carbamate), Ingenol
3-(morpholine-4-carboxylate), Ingenol
3-(pyrrolidine-1-carboxylate), Ingenol
3-(N-methyl-N-phenyl-carbamate), Ingenol 3-(N,N-diethyl-carbamate),
Ingenol 3-(piperidine-1-carboxylate), Ingenol
3-(N-benzyl-N-methyl-carbamate), Ingenol
3-(N-cyclohexyl-N-methyl-carbamate), Ingenol
3-(N-cyclohexyl-carbamate), Ingenol 3-(N-phenyl-carbamate), Ingenol
3-(N-(indan-1-yl)-carbamate), Ingenol
3-(3,3-dimethyl-piperidine-1-carboxylate), Ingenol
3-(N-Methyl-N-tetralin-1-yl-carbamate), Ingenol
3-(N-(2-cyano-1-methyl-ethyl)-N-methyl-carbamate), Ingenol
3-(N-methyl-N-((S)-1-phenethyl)-carbamate), Ingenol
3-(N-methyl-N-(cyclopropylmethyl)-carbamate, Ingenol
3-(isoquinoline-1-carboxylate), Ingenol
3-(quinoline-4-carboxylate), Ingenol 3-(cinnoline-4-carboxylate),
Ingenol 3-(3-phenylimidazole-4-carboxylate), Ingenol
3-(5-phenyloxazole-4-carboxylate), Ingenol
3-(1,2-benzoxazole-3-carboxylate), Ingenol
3-(3-isopropyl-5-methyl-isoxazole-4-carboxylate), Ingenol
3-(3-(2-methoxyphenyl)-5-methyl-isoxazole-4-carboxylate), Ingenol
3-(4-bromo-2-methyl-pyrazole-3-carboxylate), Ingenol
3-(4-bromo-2-ethyl-pyrazole-3-carboxylate), Ingenol
3-(4-chloro-2-methyl-pyrazole-3-carboxylate), Ingenol
3-(5-bromopyrimidine-4-carboxylate), Ingenol
3-(3-bromopyridine-2-carboxylate), Ingenol
3-(5-methylthiazole-4-carboxylate), Ingenol
3-(4-chloro-1-methyl-pyrazole-3-carboxylate), Ingenol
3-(2,4-dimethylthiazole-5-carboxylate), Ingenol
3-(2,5-dimethyloxazole-4-carboxylate), Ingenol
3-(2,4-dimethylfuran-3-carboxylate), Ingenol
3-(3,5-diethylisoxazole-4-carboxylate), Ingenol
3-(N-(3-fluoro-phenyl)-N-methyl-carbamate), Ingenol
3-(N-(2,5-dimethylpyrazol-3-yl)-N-methyl-carbamate), Ingenol
3-(1H-indole-7-carboxylate), Ingenol
3-(2-tert-butyl-5-methyl-pyrazole-3-carboxylate), Ingenol
3-(5-tert-butyl-2-methyl-pyrazole-3-carboxylate), Ingenol
3-(6-methylimidazo[2,1-b]thiazole-5-carboxylate), Ingenol
3-(2-methylimidazo[1,2-a]pyridine-3-carboxylate), Ingenol
3-(2,4,5-trimethylfuran-3-carboxylate), Ingenol
3-(3-methylthiophene-2-carboxylate), Ingenol
3-(2-methyl-4-(1-piperidyl)pyrazole-3-carboxylate), Ingenol
3-(2-chloro-5-isopropyl-thiazole-4-carboxylate), Ingenol
3-(4-chloro-2,5-dimethyl-pyrazole-3-carboxylate), Ingenol
3-(1,2,4-trimethylpyrrole-3-carboxylate), Ingenol
3-(1,3,5-trimethylpyrrole-2-carboxylate), Ingenol
3-(1-ethyl-3,5-dimethylpyrrole-2-carboxylate), Ingenol
3-(1-tert-butyloxycarbonyl-3,3-dimethylpyrrolidine-2-carboxylate),
Ingenol 3-((2S)-1-phenylpyrrolidine-2-carboxylate), Ingenol
3-(1-isopropyl-3,5-dimethyl-pyrazole-4-carboxylate), Ingenol
3-(5-ethyl-3-isopropyl-isoxazole-4-carboxylate), Ingenol
3-(2-methylindazole-3-carboxylate), Ingenol
3-(5-methyl-3-tert-butyl-isoxazole-4-carboxylate), Ingenol
3-(2-methyl-3-oxo-4-oxaspiro[4.5]dec-1-ene-1-carboxylate), Ingenol
3-(1-tert-butyl-3,5-dimethyl-pyrazole-4-carboxylate), Ingenol
3-(3,5-dimethylisothiazole-4-carboxylate), Ingenol
3-(5-iodo-3-methylsothiazole-4-carboxylate), Ingenol
3-(4-(4-methoxyphenyl)-2-methyl-pyrazole-3-carboxylate), Ingenol
3-(4-(2-methylphenyl)-2-methyl-pyrazole-3-carboxylate), Ingenol
3-(2-methyl-4-(4-methylsulfonylphenyl)pyrazole-3-carboxylate),
Ingenol 3-(2-methyl-4-phenyl-pyrazole-3-carboxylate), Ingenol
3-(3,5-dimethyl-1-phenyl-pyrazole-4-carboxylate), Ingenol
3-(1,5-dimethyl-3-phenyl-pyrazole-4-carboxylate), Ingenol
3-(1-benzyl-3,5-dimethyl-pyrazole-4-carboxylate), Ingenol
3-(3,5-dimethyl-1-(tetrahydropyran-4-ylmethyl)pyrazole-4-carboxylate),
Ingenol 3-(4-methyl-2-oxo-3H-thiazole-5-carboxylate), Ingenol
3-(2-methyl-4,5,6,7-tetrahydroindazole-3-carboxylate), Ingenol
3-(1,2-dimethylindole-3-carboxylate), Ingenol
3-(5-methoxy-1,2-dimethyl-indole-3-carboxylate), Ingenol
3-(1,3,5-trimethylpyrazole-4-carboxylate), Ingenol
3-(4-methyl-1,2,5-oxadiazole-3-carboxylate), Ingenol
3-(2-methoxy-4-methyl-thiazole-5-carboxylate), Ingenol
3-(4,5-dimethylisoxazole-3-carboxylate), Ingenol
3-(4-bromo-1-methyl-pyrazole-3-carboxylate), Ingenol
3-(1,3-dimethylindole-2-carboxylate), Ingenol
3-(5-methoxy-1,3-dimethyl-indole-2-carboxylate), Ingenol
3-(2,4-dimethyl-6-oxo-pyran-3-carboxylate), Ingenol
3-(1-methyl-3-phenyl-indole-2-carboxylate), Ingenol
3-(3-methyl-5-(trifluoromethyl)isoxazole-4-carboxylate), Ingenol
3-(1,3-dimethylpyrrole-2-carboxylate), Ingenol
3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate),
Ingenol 3-(1-cyclopropyl-2,5-dimethyl-pyrrole-3-carboxylate),
Ingenol 3-(1,2,5-trimethylpyrrole-3-carboxylate), Ingenol
3-(2,4-dimethyl-1H-pyrrole-3-carboxylate), Ingenol
3-(1-methylpyrrole-2-carboxylate), Ingenol
3-(4-methyl-1H-pyrrole-2-carboxylate), Ingenol
3-(1,5-dimethylpyrrole-2-carboxylate), Ingenol
3-(3-methyl-1H-pyrrole-2-carboxylate), Ingenol
3-(1-cyclopropylpyrrole-2-carboxylate), Ingenol
3-(1-ethyl-2,4-dimethyl-pyrrole-3-carboxylate), Ingenol
3-(1-allyl-2,4-dimethyl-pyrrole-3-carboxylate), Ingenol
3-(1-(cyclopropylmethyl)-2,4-dimethyl-pyrrole-3-carboxylate),
Ingenol 3-(1-(2-methoxyethyl)-2,4-dimethyl-pyrrole-3-carboxylate),
Ingenol 3-(N-(3,5-dimethylisoxazol-4-yl)-N-methyl-carbamate),
Ingenol 3-(N-(1,5-dimethylpyrazol-3-yl)-N-methyl-carbamate),
Ingenol 3-(N-cyclopentyl-N-methyl-carbamate), Ingenol
3-(N-cyclopropyl-N-methyl-carbamate), Ingenol
3-(N-methyl-N-(2-pyridyl)-carbamate), Ingenol
3-(4-oxo-2,3-dihydroquinoline-1-carboxylate), Ingenol
3-(3,4-dihydro-2H-quinoline-1-carboxylate), Ingenol
3-(indoline-1-carboxylate), Ingenol 3-(azepane-1-carboxylate),
Ingenol 3-(N-(4-chloro-phenyl)-N-methyl-carbamate), Ingenol
3-(N-(4-fluoro-phenyl)-N-methyl-carbamate), Ingenol
3-(N-methyl-N-(2-methoxy-phenyl)-carbamate), Ingenol
3-(N-methyl-N-(2-methyl-phenyl)-carbamate), Ingenol
3-(3-oxo-2,4-dihydroquinoxaline-1-carboxylate), Ingenol
3-(N-ethyl-N-phenyl-carbamate), Ingenol
3-(2-trifluoromethyl-pyrrolidine-1-carboxylate), Ingenol
3-(3-azabicyclo[3.2.2]nonane-3-carboxylate), Ingenol
3-(2,3-dihydro-1,4-benzoxazine-4-carboxylate), Ingenol
3-(N-(2-fluoro-phenyl)-N-methyl-carbamate), Ingenol
3-(3-methyl-2,3-dihydro-1,4-benzoxazine-4-carboxylate), Ingenol
3-(2-trifluoromethyl-pyrrolidine-1-carboxylate) (ISOMER A), Ingenol
3-(2-trifluoromethyl-pyrrolidine-1-carboxylate) (ISOMER B), Ingenol
3-(N-methyl-N-(N-(tert-butyloxycarbonyl)-4-piperidyl)-carbamate),
Ingenol 3-(N-methyl-N-(3-methyl-phenyl)-carbamate), Ingenol
3-(3,4-dihydro-2H-quinoxaline-1-carboxylate), Ingenol
3-(isoindoline-2-carboxylate), Ingenol
3-(N-methyl-N-(tetrahydropyran-4-ylmethyl)-carbamate), Ingenol
3-(N-methyl-N-(tetrahydropyran-4-yl)-carbamate), Ingenol
3-(N-methyl-N-(3-methoxy-phenyl)-carbamate), Ingenol
3-(N-cyclobutyl-N-methyl-carbamate), Ingenol
3-(N-allyl-N-methyl-carbamate), Ingenol
3-(N-methyl-N-prop-2-ynyl-carbamate), Ingenol
3-(N-methyl-N-(4-methylthiazol-2-yl)-carbamate) or Ingenol
3-(N-(4-cyano-phenyl)-N-methyl-carbamate).
21. A method of preventing, treating, amelioration or prophylaxis
of physiological disorders or diseases associated with hyperplasia
or neoplasia by administration to a subject in need thereof a
compound according to claim 1.
22. The method according to claim 21, wherein the disorder or
disease is selected from cutaneous warts, genital warts, actinic
keratosis, squamous cell carcinoma (SCC), basal cell carcinoma
(BCC), lentigo maligna, cervical intraepithelial neoplasia, anal
intraepithelial neoplasia or vulva intraepithelial neoplasia.
23. A method of treatment or amelioration of cosmetic indications
by administration to a subject in need thereof a compound according
to claim 1.
24. The method according to claim 23, wherein the cosmetic
indication is selected from photodamaged skin or seborrheic
keratosis.
25. A method of preventing, treating, amelioration or prophylaxis
of physiological disorders or diseases responsive to stimulation of
neutrophil oxidative burst by administration to a subject in need
thereof a compound according to claim 1.
26. A method of preventing, treating, amelioration or prophylaxis
of physiological disorders or diseases responsive to stimulation of
keratinocyte IL-8 release by administration to a subject in need
thereof a compound according to claim 1.
27. A method of preventing, treating, amelioration or prophylaxis
of physiological disorders or diseases responsive to responsive to
induction of necrosis by administration to a subject in need
thereof a compound according to claim 1.
28. A pharmaceutical composition comprising a compound according to
claim 1 or a pharmaceutically acceptable stereoisomer, salt or in
vivo hydrolysable ester thereof together with a pharmaceutically
acceptable vehicle or excipient.
29. A pharmaceutical composition according to claim 28, wherein the
composition is suitable for topical administration.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a 37 C.F.R. .sctn.1.53(b)
divisional of, and claims priority to, U.S. application Ser. No.
14/748,925 filed on Jun. 24, 2015, which is a divisional of U.S.
application Ser. No. 13/996,989 filed on Aug. 21, 2013 (now U.S.
Pat. No. 9,102,687 issued on Aug. 11, 2015). Application Ser. No.
13/996,989 is the national phase under 35 U.S.C. .sctn.371 of
International Application No. PCT/DK2011/000154 filed on Dec. 22,
2011, which claims priority under 35 U.S.C. 119(e) to U.S.
Provisional Application No. 61/426,378 filed on Dec. 22, 2010, U.S.
Provisional Application No. 61/448,350 filed on Mar. 2, 2011 and
U.S. Provisional Application No. 61/534,055 filed on Sep. 13, 2011,
all of which are hereby expressly incorporated by reference into
the present application.
FIELD OF THE INVENTION
[0002] This invention relates to novel derivatives of
3-O-acyl-ingenol and 3-O-carbamoyl-ingenol and derivatives thereof
and their use as a medicament and in therapy. The invention also
provides pharmaceutical compositions comprising said compounds and
methods of treating diseases with said compounds.
BACKGROUND OF THE INVENTION
[0003] Ingenol-3-angelate (PEP005, ingenol mebutate) is a
diterpene-ester of the ingenol family which is isolated from
various Euphorbia species, particularly from Euphorbia peplus. The
compound is presently subject for clinical development for the
treatment of actinic keratosis and for non-melanoma skin
cancer.
[0004] WO99/08994 describes isolation of compounds from Euphorbia
plant and their use in cancer and other neoplastic diseases
hereunder actinic keratosis or solar keratosis.
[0005] Ingenol-3-acylates, mainly of long-chain saturated and
unsaturated aliphatic fatty acids, have been isolated from various
Euphorbia species [H. Gotta, Z. Naturforschung, (1984), 39b,
683-94; K. Abo, Fitoterapia, (1988), 244-46, S. Zayed, J. Cancer
Res. Clin. Oncol. (2001), 127, 40-47]. Furthermore, a small number
ingenol-3-acylates have been prepared by semi-synthesis (B. Sorg
et. al., Z. Naturforsch., (1982), 37b, 748-56). Some of these
ingenol derivatives have been described and tested to be strong
irritants and strong tumor-promoting agents. [B. Sorg et. al., Z.
Naturforsch., (1982), 37b, 748-56; B. Sorg et. al., Carcinogenesis,
(1987), 8, 1-4].
[0006] Besides the aliphatic ingenol esters, aromatic esters of
ingenol are known. Milliamine C, an ingenol-3-anthraniloate
derivative has been described (Marston, A. Planta Medica, (1983),
47, 141-47). Also ingenol-3-benzoate has been described (Sorg, B.;
Z Naturforschung, (1982), 37b, 748-56).
[0007] Heteroaromatic or heterocyclic 3-O-acyl ingenol derivatives
have not previously been disclosed.
[0008] Ingenol-3-carbamates have not previously been disclosed.
Differently substituted ingenol carbamates have been mentioned in
U.S. Pat. No. 5,955,501, U.S. Pat. No. 5,891,906, U.S. Pat. No.
5,891,870 and WO9202484.
[0009] Angelic acid and angelic acid esters, as present in
ingenol-3-angelate, are prone to isomerisation of the double bond
to form the tiglate ester, particularly at basic pH [Beeby, P.,
Tetrahedron Lett. (1977), 38, 3379-3382, Hoskins, W. M., J. Chem.
Soc. Perkin Trans. 1, (1977), 538-544, Bohlmann, F. et. al., Chem.
Ber. (1970), 103, 561-563].
[0010] Furthermore, ingenol-3-acylates are known to be unstable as
they rearrange to afford the ingenol-5-acylates and
ingenol-20-acylates [Sorg, B. et. al, Z. Naturforsch., (1982), 37B,
748-756].
[0011] Ingenol-3-angelate is believed to have a dual mode of
action: 1) Induction of cell death by direct cytoxicity or
induction of apoptosis and 2) an immunostimulatory effect dominated
by neutrophil recruitment and activation (Rosen, R. H., et al., J
Am Acad Derm (2011), e-published November 2011; Ersvaer, E., et
al., Toxins, (2010), 2, 174-194). Nanomolar concentrations of the
agent cause activation and modulation of protein kinase C (PKC)
classical and novel isoforms, with particular importance of
PKCdelta. Through activation of PKCdelta the agent induces
apoptosis in susceptible cells (Hampson, P., et al., Blood, (2005),
106, 1362-1368; Cozzi, S. J., et al., Cancer Res, (2006), 66,
10083-10091). Rapid cytotoxicity on cancer cells is observed at
high micromolar concentrations (Ogbourne, S. M., et al., Cancer Res
(2004), 64, 2833-2839). Through activation of various PKC isoforms
the agent also induces pro-inflammatory effects, including release
of pro-inflammatory mediators (Challacombe, J. M., et al., J
Immunol (2006), 177, 8123-8132, activation of vascular endothelium
(Hampson, P., et al., Cancer Immunol Immunother, (2008), 57,
1241-1251); chemoattraction of neutrophils through induction of
interleukin 8 in keratinocytes and development of specific
anti-cancer immune responses by CD8+ cells through adjuvant
properties in animal models (Le, T. T., et al., Vaccine, (2009),
27, 3053-3062).
[0012] Compounds exerting dual mode of action by induction of cell
death by direct cytoxicity or induction of apoptosis, and by an
immunostimulatory effect involving neutrophil recruitment and
activation, may be useful for treatment of conditions associated
with hyperplasia or neoplasia. Compounds inducing cell death by
primary and/or secondary necrosis and compounds exhibiting a
pro-apoptotic effect may reduce unwanted cell growth and remove
unwanted cells, and furthermore, stimulation of the innate immune
response and adjuvant effects may augment the biological response
against aberrant or transformed cells.
[0013] Compounds inducing cell death by primary and/or secondary
necrosis may be useful for treatment of cosmetic conditions, as
these compounds may kill or remove unwanted tissue or cells.
[0014] There is a need to find new ingenol derivatives which induce
cell death by cytotoxicity or apoptosis and/or induce an
immunostimulatory effect.
[0015] The present invention provides heterocyclic 3-O-acyl ingenol
derivatives and 3-O-carbamoyl ingenol derivatives useful for
treatment of conditions associated with the use of
ingenol-3-angelate or useful for conditions which are affected by
induction of cell death by cytoxicity or induction of apoptosis
and/or by an immunostimulatory effect.
[0016] Compounds of the present invention stimulate neutrophil
oxidative burst, which is part of the innate immune response.
[0017] Compounds of the present invention stimulate keratinocyte
IL-8 release, thus inducing an immunostimulatory effect.
[0018] Some compounds of the present invention induce rapid
necrosis.
[0019] Some compounds of the present invention exhibit activity in
the B16 mouse melanoma model indicating that the compounds possess
anti-tumor activity and are able to kill neoplastic and transformed
cells.
[0020] Some compounds of the present invention exhibit favorable
stability properties.
SUMMARY OF THE INVENTION
[0021] In an embodiment the invention provides a compound of the
general formula I
##STR00002##
[0022] wherein R is heteroaryl which may optionally be substituted
by one or more substituents independently selected from R7;
[0023] or R is heterocycloalkyl or heterocycloalkenyl, wherein said
heterocycloalkyl or heterocycloalkenyl are optionally substituted
by one or more substituents independently selected from R8;
[0024] or R is X;
[0025] R7 represents halogen, cyano or hydroxyl;
[0026] or R7 represents (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)-alkenyl, (C.sub.3-C.sub.7)-cycloalkyl,
heterocycloalkyl, aryl, heteroaryl arylalkyl, heterocycloalkylalkyl
or (C.sub.3-C.sub.7)-cycloalkylalkyl, wherein said
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)-alkenyl,
(C.sub.3-C.sub.7)-cycloalkyl, heterocycloalkyl, aryl, heteroaryl
arylalkyl, heterocycloalkylalkyl or
(C.sub.3-C.sub.7)-cycloalkylalkyl are optionally substituted by one
or more substituents independently selected from R9;
[0027] or R7 represents --NRaCORb, --CONRaRb, --COORc, --OCORa,
--ORa, --OCONRaRb, --NRaCOORb, --NRaCONRaRb, --NRaSO2NRaRb,
--NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --SRa or --NRaRb;
[0028] R9 represents halogen, cyano, hydroxy,
(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl, --NRaCORb,
--COORc, --OCORa, --CONRaRb, --OCONRaRb, --NRaCOORb, --NRaCONRaRb,
--NRaSO2NRaRb, --NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa,
--SRa or .dbd.O;
[0029] R8 represents halogen, cyano or hydroxyl;
[0030] or R8 represents (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, aryl, heteroaryl,
(C.sub.3-C.sub.7)-cycloalkyl or heterocycloalkyl, wherein said
C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, aryl, heteroaryl,
(C.sub.3-C.sub.7)-cycloalkyl or heterocycloalkyl are optionally
substituted by one or more substituents independently selected from
R10,
[0031] or R8 represents --NRaCORb, --COORc, --OCORa, --CONRaRb,
--OCONRaRb, --NRaCOORb, --NRaCONRaRb, --NRaSO2NRaRb, --NRaSO2Rb,
--SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa, --SRa, .dbd.O, .dbd.N--ORa,
--O--N.dbd.CRaRb, NRaRb or --C(O)N(Ra)O--Rb;
[0032] R10 represents halogen, cyano, hydroxy,
(C.sub.1-C.sub.4)-alkyl, (C.sub.1-C.sub.4)alkoxy,
halo(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkoxy,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, --NRaCORb, --COORc,
--OCORa, --CONRaRb, --OCONRaRb, --NRaCOORb, --NRaCONRaRb,
--NRaSO2NRaRb, --NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa,
--SRa or .dbd.O;
[0033] Ra and Rb represents hydrogen, (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl;
[0034] Rc represents hydrogen, (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.x)alkyl, cyano(C.sub.1-C.sub.x)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl;
[0035] X represents --NR11R12
[0036] wherein R11 and R12 independently represent hydrogen,
[0037] or
[0038] wherein R11 and R12 independently represents
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl or
(C.sub.2-C.sub.6)alkynyl, cycloalkyl, cycloalkenyl, aryl,
heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkylalkyl,
cycloalkenylalkyl, arylalkyl, heteroarylalkyl,
heterocycloalkylalkyl, heterocycloalkenylalkyl, alkylcycloalkyl,
alkylcycloalkenyl, alkylaryl, alkylheteroaryl or
alkylheterocycloalkyl, wherein said (C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.6)alkenyl or (C.sub.2-C.sub.6)alkynyl, cycloalkyl,
cycloalkenyl, aryl, heteroaryl, heterocycloalkyl,
heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl,
heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl,
alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl or
alkylheterocycloalkyl are optionally substituted by one or more
substituents independently selected from R13;
[0039] R13 represents halogen, cyano or hydroxyl,
[0040] or R13 represents (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, aryl, (C.sub.3-C.sub.7)cycloalkyl,
heteroaryl or heterocycloalkyl, wherein said
(C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl, aryl,
(C.sub.3-C.sub.7)cycloalkyl, heteroaryl or heterocycloalkyl are
optionally substituted by one or more substituents selected from
R14
[0041] or R13 represents --NRdCORe, --COORf, --OCORd, --CONRdRe,
--OCONRdRe, --NRdCOORe, --NRdCONRdRe, --NRdSO2Re, --NRdSO2NRdRe,
--SO2NRdRe, --SO2Rd, --S(O)Rd, --ORd, --SRd, .dbd.O, .dbd.N--ORd,
--O--N.dbd.CRdRe, --NRdRe or --C(O)N(Rd)-ORe
[0042] wherein Rd and Re independently represents hydrogen,
(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl;
[0043] Rf represents hydrogen, (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxyl(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl;
[0044] R14 represents halogen, hydroxyl, cyano,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
halo(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkoxy,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, --NRdCORe, --COORf,
--OCORd, --CONRdRe, --OCONRdRe, --NRdCOORe, --NRdCONRdRe,
--NRdSO2Re, --NRdSO2NRdRe, --SO2NRdRe, --SO2Rd, --S(O)Rd, --ORd,
--SRd or .dbd.O;
[0045] and pharmaceutically acceptable salts, prodrugs, hydrates
and solvates thereof.
[0046] In an embodiment the invention provides a compound of
formula I, for use as a medicament in therapy.
[0047] In an embodiment the invention provides a use of a compound
according to formula I, for the manufacture of a pharmaceutical
compound.
[0048] In an embodiment the invention provides a pharmaceutical
composition comprising a compound of formula I or a
pharmaceutically acceptable stereoisomer, salt or in vivo
hydrolysable ester thereof together with a pharmaceutically
acceptable vehicle or excipient.
[0049] In an embodiment the invention provides a pharmaceutical
composition suitable for topical administration comprising a
compound of formula I or a pharmaceutically acceptable
stereoisomer, salt or in vivo hydrolysable ester thereof together
with a pharmaceutically acceptable vehicle or excipient.
[0050] In an embodiment the invention provides a compound of
formula I for use in the treatment, prevention, amelioration or
prophylaxis of physiological disorders or diseases associated with
hyperplasia or neoplasia.
[0051] In an embodiment the invention provides use of a compound of
formula I for the manufacture of a medicament for the treatment,
amelioration or prophylaxis of physiological disorders or diseases
associated with hyperplasia or neoplasia.
[0052] In an embodiment the invention provides a method of
preventing, treating, amelioration or prophylaxis of physiological
disorders or diseases associated with hyperplasia or neoplasia by
administration to a subject in need thereof a compound of formula I
above.
[0053] In an embodiment the invention provides a compound of
formula I for use in the treatment or amelioration of cosmetic
indications.
[0054] In an embodiment the invention provides use of compound
according to formula I for the manufacture of a medicament for the
treatment or amelioration of cosmetic indications.
[0055] In an embodiment the invention provides a method of
treatment or amelioration of cosmetic indications by administration
to a subject in need thereof a compound of formula I above.
[0056] In an embodiment the invention provides a pharmaceutical
composition comprising a compound of formula I or a
pharmaceutically acceptable stereoisomer, salt or in vivo
hydrolysable ester thereof in combination with one or more other
therapeutically active agents.
DETAILED DESCRIPTION OF THE INVENTION
[0057] An embodiment the invention provides a compound of the
general formula I
##STR00003##
[0058] wherein R is heteroaryl which may optionally be substituted
by one or more substituents independently selected from R7;
[0059] or R is heterocycloalkyl or heterocycloalkenyl, each of
which may optionally be substituted by one or more substituents
independently selected from R8;
[0060] or R is X;
[0061] R7 represents halogen, cyano or hydroxyl;
[0062] or R7 represents (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, (C.sub.3-C.sub.7)cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, each of which is optionally
substituted by one or more substituents independently selected from
R9;
[0063] or R7 represents --NRaCORb, --CONRaRb, --COORc, --OCORa,
--ORa, --OCONRaRb, --NRaCOORb, --NRaCONRaRb, --NRaSO2NRaRb,
--NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --Sra or --NRaRb;
[0064] R9 represents halogen, cyano, hydroxy,
(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl, --NRaCORb,
--COORc, --OCORa, --CONRaRb, --OCONRaRb, --NRaCOORb, --NRaCONRaRb,
--NRaSO2NRaRb, --NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa,
--SRa or .dbd.O;
[0065] R8 represents halogen, cyano, hydroxyl;
[0066] or R8 represents (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, aryl, heteroaryl,
(C.sub.3-C.sub.7)cycloalkyl or heterocycloalkyl, each of which is
optionally substituted by one or more substituents independently
selected from R10,
[0067] or R8 represents --NRaCORb, --COORc, --OCORa, --CONRaRb,
--OCONRaRb, --NRaCOORb, --NRaCONRaRb, --NRaSO2NRaRb, --NRaSO2Rb,
--SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa, --SRa, .dbd.O, .dbd.N--ORa,
--O--N.dbd.CRaRb, NRaRb or --C(O)N(Ra)O--Rb;
[0068] R10 represents halogen, cyano, hydroxy,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
halo(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkoxy,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, --NRaCORb, --COORc,
--OCORa, --CONRaRb, --OCONRaRb, --NRaCOORb, --NRaCONRaRb,
--NRaSO2NRaRb, --NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa,
--SRa or .dbd.O;
[0069] Ra and Rb represents hydrogen, (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl;
[0070] Rc represents hydrogen, (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.x)alkyl, cyano(C.sub.1-C.sub.x)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl;
[0071] X represents --NR11R12
[0072] wherein R11 and R12 independently represent hydrogen,
[0073] or
[0074] wherein R11 and R12 independently represents
(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl or
(C.sub.2-C.sub.6)alkynyl, cycloalkyl, cycloalkenyl, aryl,
heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkylalkyl,
cycloalkenylalkyl, arylalkyl, heteroarylalkyl,
heterocycloalkylalkyl, heterocycloalkenylalkyl, alkylcycloalkyl,
alkylcycloalkenyl, alkylaryl, alkylheteroaryl or
alkylheterocycloalkyl, which may optionally be substituted by one
or more substituents independently selected from R13;
[0075] R13 represents halogen, cyano, hydroxyl,
[0076] or R13 represents (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)alkenyl, aryl, (C.sub.3-C.sub.7)cycloalkyl,
heteroaryl or heterocycloalkyl, each of which may be substituted by
one or more substituents selected from R14,
[0077] or R13 represents --NRdCORe, --COORf, --OCORd, --CONRdRe,
--OCONRdRe, --NRdCOORe, --NRdCONRdRe, --NRdSO2Re, --NRdSO2NRdRe,
--SO2NRdRe, --SO2Rd, --S(O)Rd, --ORd, --SRd, .dbd.O, .dbd.N--ORd,
--O--N.dbd.CRdRe, --NRdRe or --C(O)N(Rd)-ORe
[0078] wherein Rd and Re independently represents hydrogen,
(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl;
[0079] Rf represents hydrogen, (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxyl(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl or heterocycloalkyl;
[0080] R14 represents halogen, hydroxyl, cyano,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
halo(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkoxy,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl, --NRdCORe, --COORf,
--OCORd, --CONRdRe, --OCONRdRe, --NRdCOORe, --NRdCONRdRe,
--NRdSO2Re, --NRdSO2NRdRe, --SO2NRdRe, --SO2Rd, --S(O)Rd, --ORd,
--SRd or .dbd.O;
[0081] and pharmaceutically acceptable salts, prodrugs, hydrates
and solvates thereof.
[0082] Another embodiment the invention provides a compound of the
general formula I above wherein R is heteroaryl which may
optionally be substituted by one or more substituents independently
selected from R7,
[0083] or R is heterocycloalkyl or heterocycloalkenyl, each of
which may optionally be substituted by one or more substituents
independently selected from R8,
[0084] R7 represents halogen, cyano, hydroxyl;
[0085] or R7 represents (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.4)-alkenyl, (C.sub.3-C.sub.7)-cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, each of which may optionally be
substituted by one or more substituents independently selected from
R9;
[0086] or R7 represents --NRaCORb, --CONRaRb, --COORc, --OCORa,
--ORa, --OCONRaRb, --NRaCOORb, --NRaCONRaRb, --NRaSO2NRaRb,
--NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --SRa;
[0087] R9 represents halogen, cyano, hydroxy,
(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl, --NRaCORb,
--COORc, --OCORa, --CONRaRb, --OCONRaRb, --NRaCOORb, --NRaCONRaRb,
--NRaSO2NRaRb, --NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa,
--SRa, .dbd.O;
[0088] R8 represents halogen, cyano, hydroxyl;
[0089] or R8 represents (C.sub.1-C.sub.4)-alkyl,
(C.sub.2-C.sub.4)alkenyl, aryl, heteroaryl,
(C.sub.3-C.sub.7)-cycloalkyl, heterocycloalkyl, each of which is
optionally substituted by one or more substituents independently
selected from R10,
[0090] or R8 represents --NRaCORb, --COORc, --OCORa, --CONRaRb,
--OCONRaRb, --NRaCOORb, --NRaCONRaRb, --NRaSO2NRaRb, --NRaSO2Rb,
--SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa, --SRa, .dbd.O;
[0091] R10 represents halogen, cyano, hydroxy,
(C.sub.1-C.sub.4)-alkyl, halo(C.sub.1-C.sub.4)alkyl, --NRaCORb,
--COORc, --OCORa, --CONRaRb, --OCONRaRb, --NRaCOORb, --NRaCONRaRb,
--NRaSO2NRaRb, --NRaSO2Rb, --SO2NRaRb, --SO2Ra, --S(O)Ra, --ORa,
--SRa, .dbd.O;
[0092] Ra and Rb represents hydrogen, (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl;
[0093] Rc represents (C.sub.1-C.sub.4)alkyl,
halo(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, cyano(C.sub.1-C.sub.4)alkyl;
[0094] and pharmaceutically acceptable salts, prodrugs, hydrates
and solvates thereof.
[0095] An embodiment of the invention provides a compound of
formula I wherein R is heteroaryl.
[0096] An embodiment of the invention provides a compound of
formula I, wherein heteroaryl is isoxazolyl, pyridyl, quinolyl,
isoquinolyl, indolyl, furyl, thiazolyl, imidazolyl, pyrazolyl,
oxazolyl, thienyl, pyrimidinyl, 1,2,3-triazolyl, indazolyl,
cinnolyl or 1,2-benzoxazolyl.
[0097] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl and wherein said heteroaryl is
isoxazolyl, pyridyl, quinolyl, isoquinolyl, indolyl, furyl,
thiazolyl, imidazolyl, pyrazolyl, oxazolyl, thienyl, pyrimidinyl,
1,2,3-triazolyl, indazolyl, cinnolyl, 1,2-benzoxazolyl,
imidazothiazolyl, imidazopyridinyl, pyrrolyl, isothiazolyl,
tetrahydroindazolyl or oxadiazolyl.
[0098] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl and wherein said heteroaryl is
isoxazolyl, furyl, pyrazolyl, thienyl or pyrrolyl.
[0099] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl and wherein said heteroaryl is
isoxazolyl.
[0100] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl and wherein said heteroaryl is
furyl.
[0101] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl and wherein said heteroaryl is
isoxazolyl, furyl, pyrazolyl, thienyl or pyrrolyl, and wherein R7
represents (C.sub.1-C.sub.4)alkyl.
[0102] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl and wherein said heteroaryl is
isoxazolyl, furyl, pyrazolyl, thienyl or pyrrolyl, and wherein R7
represents (C.sub.1-C.sub.2)alkyl.
[0103] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl, and wherein heteroaryl is
isoxazolyl or furyl and wherein R7 represents
(C.sub.1-C.sub.2)alkyl.
[0104] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl and wherein said heteroaryl is
isoxazolyl, furyl, pyrazolyl, thienyl or pyrrolyl, and wherein R7
represents phenyl.
[0105] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl and wherein said heteroaryl is
isoxazolyl, furyl, pyrazolyl, thienyl or pyrrolyl, and wherein R7
represents phenyl or (C.sub.1-C.sub.4)alkyl and wherein R9
represents (C.sub.1-C.sub.4)alkyl, halogen or --ORa.
[0106] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl and wherein said heteroaryl is
indolyl, indazolyl or tetrahydroindazolyl.
[0107] An embodiment of the invention provides a compound of
formula I, wherein R is heteroaryl and wherein said heteroaryl is
indolyl, indazolyl or tetrahydroindazolyl, and wherein R7
represents (C.sub.1-C.sub.4)alkyl or --ORa.
[0108] An embodiment of the invention provides a compound of
formula I, wherein R7 is independently selected one or more times
from the group of (C.sub.1-C.sub.4)alkyl, aryl or halogen.
[0109] An embodiment of the invention provides a compound of
formula I, wherein R7 is independently selected one or more times
from the group of (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.4)alkenyl,
aryl, arylalkyl, heterocycloalkylalkyl,
(C.sub.3-C.sub.7)-cycloalkylalkyl, (C.sub.3-C.sub.7)-cycloalkyl
--COORc, --ORa or halogen.
[0110] An embodiment of the invention provides a compound of
formula I wherein R7 is selected from phenyl, methyl, ethyl,
isopropyl, Cl or Br.
[0111] An embodiment of the invention provides a compound of
formula wherein R7 is selected from phenyl, methyl, ethyl,
isopropyl, t-butyl, piperidyl, tert-butyloxycarbonyl, benzyl,
tetrahydropyranylmethyl, --OCH.sub.3, cyclopropyl, allyl,
cyclopropylmethyl, Cl, Br or I.
[0112] An embodiment of the invention provides a compound of
formula I above, wherein R9 is halogen or --ORa.
[0113] An embodiment of the invention provides a compound of
formula I above, wherein R9 is halogen, --ORa,
(C.sub.1-C.sub.4)alkyl or --SO2Ra.
[0114] An embodiment of the invention provides a compound of
formula I, wherein R9 is Cl, F or --OCH.sub.3.
[0115] An embodiment of the invention provides a compound of
formula I above, wherein R9 is Cl, F, --OCH.sub.3, methyl or
methylsulfonyl.
[0116] An embodiment of the invention provides a compound of
formula I, wherein R is heterocycloalkyl.
[0117] An embodiment of the invention provides a compound of
formula I above, wherein R is heterocycloalkyl or
heterocycloalkenyl.
[0118] An embodiment of the invention provides a compound of
formula I, wherein heterocycloalkyl is pyrrolidinyl, piperidinyl,
morpholinyl or 5-oxabicyclo[2.2.2]octane.
[0119] An embodiment of the invention provides a compound of
formula I, wherein R8 is (C.sub.1-C.sub.4)alkyl.
[0120] An embodiment of the invention provides a compound of
formula I above, wherein R is heterocycloalkyl or
heterocycloalkenyl and wherein said heterocycloalkyl or
heterocycloalkenyl is pyrrolidinyl, piperidinyl, morpholinyl,
5-oxabicyclo[2.2.2]octanyl, oxaspiro[4.5]dec-1-enyl, oxo-thiazolyl,
dihydrothiazolyl, oxo-pyranyl, azepanyl, azabicyclo[3.2.2]nonanyl,
benzoxazinyl, quinoxalinyl, isoindolinyl, dihydroquinolinyl,
indolinyl or dihydroquinoxalinyl.
[0121] An embodiment of the invention provides a compound of
formula I above, wherein R is heterocycloalkyl and wherein said
heterocycloalkyl is indolinyl, benzoxazinyl or
dihydroquinolinyl.
[0122] An embodiment of the invention provides a compound of
formula I, wherein R8 is methyl.
[0123] An embodiment of the invention provides a compound of
formula I, wherein R8 is (C.sub.1-C.sub.4)alkyl, aryl or
.dbd.O.
[0124] An embodiment of the invention provides a compound of
formula I, wherein R is --NR11R12.
[0125] An embodiment of the invention provides a compound of
formula I, wherein R11 and R12 independently represents hydrogen,
(C.sub.1-C.sub.6)alkyl, aryl, cycloalkyl, arylalkyl, heteroaryl or
cycloalkylalkyl.
[0126] An embodiment of the invention provides a compound of
formula I above, wherein R11 and R12 independently represents
hydrogen, (C.sub.1-C.sub.6)alkyl, aryl, cycloalkyl, arylalkyl,
heteroaryl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, (C.sub.2-C.sub.6)alkenyl or
(C.sub.2-C.sub.6)alkynyl.
[0127] An embodiment of the invention provides a compound of
formula I above, wherein R11 and R12 independently represents
hydrogen, (C.sub.1-C.sub.6)alkyl, aryl or arylalkyl.
[0128] An embodiment of the invention provides a compound of
formula I above, wherein R11 and R12 independently represents
hydrogen, (C.sub.1-C.sub.4)alkyl, cycloalkyl, phenyl or benzyl.
[0129] An embodiment of the invention provides a compound of
formula I above, wherein R11 and R12 independently represents
hydrogen, (C.sub.1-C.sub.4)alkyl, phenyl or benzyl, wherein said
(C.sub.1-C.sub.4)alkyl, phenyl or benzyl is optionally substituted
by one or more substituents selected from R13, wherein R13
represents halogen, (C.sub.1-C.sub.4)alkyl or --ORa.
[0130] An embodiment of the invention provides a compound of
formula I, wherein R11 and R12 independently represents hydrogen,
methyl, ethyl, isopropyl, phenyl, benzyl, cyclohexyl, indanyl,
tetralinyl, phenylethyl, cyclopropylmethyl or pyrazolyl.
[0131] An embodiment of the invention provides a compound of
formula I above, wherein R11 and R12 independently represents
hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, cyclohexyl,
indanyl, tetralinyl, phenylethyl, cyclopropylmethyl, pyrazolyl,
isoxazolylmethyl, cyclopentyl, cyclopropyl, pyridyl, piperidyl,
tetrahydropyranylmethyl, tetrahydropyranyl, cyclobutyl, allyl,
propynyl or thiazolyl.
[0132] An embodiment of the invention provides a compound of
formula I, wherein R13 represents (C.sub.1-C.sub.4)alkyl, cyano or
F.
[0133] An embodiment of the invention provides a compound of
formula I above, wherein R13 represents (C.sub.1-C.sub.4)alkyl,
cyano, halogen, .dbd.O, --ORa or --COORf.
[0134] An embodiment of the invention provides a compound of
formula I above, wherein R13 represents methyl, cyano, F, .dbd.O,
--OCH.sub.3 or --COOC(CH.sub.3).sub.3.
[0135] An embodiment of the invention provides a compound of
formula I, wherein R11 or R12 independently represent hydrogen.
[0136] An embodiment of the invention provides a compound of
formula I, said compound being:
[0137] Ingenol 3-(5-methyl-3-phenyl-isoxazole-4-carboxylate) or
[0138] Ingenol
3-(5-methyl-3-(2-chloro-6-fluoro-phenyl)-isoxazole-4-carboxylate)
or
[0139] Ingenol 3-(1S-camphanate) or
[0140] Ingenol 3-(3-phenyltriazole-4-carboxylate or
[0141] Ingenol 3-(2-phenylpyrazole-3-carboxylate or
[0142] Ingenol 3-(1-methylindazole-3-carboxylate) or
[0143] Ingenol 3-(3-ethyl-5-methyl-isoxazole-4-carboxylate) or
[0144] Ingenol 3-(3-methyl-5-methyl-isoxazole-4-carboxylate) or
[0145] Ingenol 3-(1-methylindole-3-carboxylate) or
[0146] Ingenol 3-(3-phenylthiophene-2-carboxylate) or
[0147] Ingenol 3-(5-phenylisoxazole-3-carboxylate) or
[0148] Ingenol 3-(N-ethyl-carbamate) or
[0149] Ingenol 3-(N,N-dimethyl-carbamate) or
[0150] Ingenol 3-(morpholine-4-carboxylate) or
[0151] Ingenol 3-(pyrrolidine-1-carboxylate) or
[0152] Ingenol 3-(N-methyl-N-phenyl-carbamate) or
[0153] Ingenol 3-(N,N-diethyl-carbamate) or
[0154] Ingenol 3-(piperidine-1-carboxylate) or
[0155] Ingenol 3-(N-benzyl-N-methyl-carbamate) or
[0156] Ingenol 3-(N-cyclohexyl-N-methyl-carbamate) or
[0157] Ingenol 3-(N-cyclohexyl-carbamate) or
[0158] Ingenol 3-(N-phenyl-carbamate) or
[0159] Ingenol 3-(N-(indan-1-yl)-carbamate) or
[0160] Ingenol 3-(3,3-dimethyl-piperidine-1-carboxylate) or
[0161] Ingenol 3-(N-Methyl-N-tetralin-1-yl-carbamate) or
[0162] Ingenol 3-(N-(2-cyano-1-methyl-ethyl)-N-methyl-carbamate)
or
[0163] Ingenol 3-(N-methyl-N-((S)-1-phenethyl)-carbamate) or
[0164] Ingenol 3-(N-methyl-N-(cyclopropylmethyl)-carbamate) or
[0165] Ingenol 3-(isoquinoline-1-carboxylate) or
[0166] Ingenol 3-(quinoline-4-carboxylate) or
[0167] Ingenol 3-(cinnoline-4-carboxylate) or
[0168] Ingenol 3-(3-phenylimidazole-4-carboxylate) or
[0169] Ingenol 3-(5-phenyloxazole-4-carboxylate) or
[0170] Ingenol 3-(1,2-benzoxazole-3-carboxylate) or
[0171] Ingenol 3-(3-isopropyl-5-methyl-isoxazole-4-carboxylate)
or
[0172] Ingenol
3-(3-(2-methoxyphenyl)-5-methyl-isoxazole-4-carboxylate) or
[0173] Ingenol 3-(4-bromo-2-methyl-pyrazole-3-carboxylate) or
[0174] Ingenol 3-(4-bromo-2-ethyl-pyrazole-3-carboxylate) or
[0175] Ingenol 3-(4-chloro-2-methyl-pyrazole-3-carboxylate) or
[0176] Ingenol 3-(5-bromopyrimidine-4-carboxylate) or
[0177] Ingenol 3-(3-bromopyridine-2-carboxylate) or
[0178] Ingenol 3-(5-methylthiazole-4-carboxylate) or
[0179] Ingenol 3-(4-chloro-1-methyl-pyrazole-3-carboxylate) or
[0180] Ingenol 3-(2,4-dimethylthiazole-5-carboxylate) or
[0181] Ingenol 3-(2,5-dimethyloxazole-4-carboxylate) or
[0182] Ingenol 3-(2,4-dimethylfuran-3-carboxylate) or
[0183] Ingenol 3-(3,5-diethylisoxazole-4-carboxylate) or
[0184] Ingenol 3-(N-(3-fluoro-phenyl)-N-methyl-carbamate) or
[0185] Ingenol 3-(N-(2,5-dimethylpyrazol-3-yl)-N-methyl-carbamate)
or
[0186] Ingenol 3-(1H-indole-7-carboxylate) or
[0187] Ingenol 3-(2-tert-butyl-5-methyl-pyrazole-3-carboxylate)
or
[0188] Ingenol 3-(5-tert-butyl-2-methyl-pyrazole-3-carboxylate)
or
[0189] Ingenol 3-(6-methylimidazo[2,1-b]thiazole-5-carboxylate)
or
[0190] Ingenol 3-(2-methylimidazo[1,2-a]pyridine-3-carboxylate)
or
[0191] Ingenol 3-(2,4,5-trimethylfuran-3-carboxylate) or
[0192] Ingenol 3-(3-methylthiophene-2-carboxylate) or
[0193] Ingenol 3-(2-methyl-4-(1-piperidyl)pyrazole-3-carboxylate)
or
[0194] Ingenol 3-(2-chloro-5-isopropyl-thiazole-4-carboxylate)
or
[0195] Ingenol 3-(4-chloro-2,5-dimethyl-pyrazole-3-carboxylate)
or
[0196] Ingenol 3-(1,2,4-trimethylpyrrole-3-carboxylate) or
[0197] Ingenol 3-(1,3,5-trimethylpyrrole-2-carboxylate) or
[0198] Ingenol 3-(1-ethyl-3,5-dimethylpyrrole-2-carboxylate) or
[0199] Ingenol
3-(1-tert-butyloxycarbonyl-3,3-dimethylpyrrolidine-2-carboxylate)
or
[0200] Ingenol 3-((2S)-1-phenylpyrrolidine-2-carboxylate) or
[0201] Ingenol 3-(1-isopropyl-3,5-dimethyl-pyrazole-4-carboxylate)
or
[0202] Ingenol 3-(5-ethyl-3-isopropyl-isoxazole-4-carboxylate)
or
[0203] Ingenol 3-(2-methylindazole-3-carboxylate) or
[0204] Ingenol 3-(5-methyl-3-tert-butyl-isoxazole-4-carboxylate)
or
[0205] Ingenol
3-(2-methyl-3-oxo-4-oxaspiro[4.5]dec-1-ene-1-carboxylate) or
[0206] Ingenol 3-(1-tert-butyl-3,5-dimethyl-pyrazole-4-carboxylate)
or
[0207] Ingenol 3-(3,5-dimethylisothiazole-4-carboxylate) or
[0208] Ingenol 3-(5-iodo-3-methyl-isothiazole-4-carboxylate) or
[0209] Ingenol
3-(4-(4-methoxyphenyl)-2-methyl-pyrazole-3-carboxylate) or
[0210] Ingenol
3-(4-(2-methylphenyl)-2-methyl-pyrazole-3-carboxylate) or
[0211] Ingenol
3-(2-methyl-4-(4-methylsulfonylphenyl)pyrazole-3-carboxylate)
or
[0212] Ingenol 3-(2-methyl-4-phenyl-pyrazole-3-carboxylate) or
[0213] Ingenol 3-(3,5-dimethyl-1-phenyl-pyrazole-4-carboxylate)
or
[0214] Ingenol 3-(1,5-dimethyl-3-phenyl-pyrazole-4-carboxylate)
or
[0215] Ingenol 3-(1-benzyl-3,5-dimethyl-pyrazole-4-carboxylate)
or
[0216] Ingenol
3-(3,5-dimethyl-1-(tetrahydropyran-4-ylmethyl)pyrazole-4-carboxylate)
or
[0217] Ingenol 3-(4-methyl-2-oxo-3H-thiazole-5-carboxylate) or
[0218] Ingenol
3-(2-methyl-4,5,6,7-tetrahydroindazole-3-carboxylate) or
[0219] Ingenol 3-(1,2-dimethylindole-3-carboxylate) or
[0220] Ingenol 3-(5-methoxy-1,2-dimethyl-indole-3-carboxylate)
or
[0221] Ingenol 3-(1,3,5-trimethylpyrazole-4-carboxylate) or
[0222] Ingenol 3-(4-methyl-1,2,5-oxadiazole-3-carboxylate) or
[0223] Ingenol 3-(2-methoxy-4-methyl-thiazole-5-carboxylate) or
[0224] Ingenol 3-(4,5-dimethylisoxazole-3-carboxylate) or
[0225] Ingenol 3-(4-bromo-1-methyl-pyrazole-3-carboxylate) or
[0226] Ingenol 3-(1,3-dimethylindole-2-carboxylate) or
[0227] Ingenol 3-(5-methoxy-1,3-dimethyl-indole-2-carboxylate)
or
[0228] Ingenol 3-(2,4-dimethyl-6-oxo-pyran-3-carboxylate) or
[0229] Ingenol 3-(1-methyl-3-phenyl-indole-2-carboxylate) or
[0230] Ingenol
3-(3-methyl-5-(trifluoromethyl)isoxazole-4-carboxylate) or
[0231] Ingenol 3-(1,3-dimethylpyrrole-2-carboxylate) or
[0232] Ingenol
3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate)
or
[0233] Ingenol 3-(1-cyclopropyl-2,5-dimethyl-pyrrole-3-carboxylate)
or
[0234] Ingenol 3-(1,2,5-trimethylpyrrole-3-carboxylate) or
[0235] Ingenol 3-(2,4-dimethyl-1H-pyrrole-3-carboxylate) or
[0236] Ingenol 3-(1-methylpyrrole-2-carboxylate) or
[0237] Ingenol 3-(4-methyl-1H-pyrrole-2-carboxylate) or
[0238] Ingenol 3-(1,5-dimethylpyrrole-2-carboxylate) or
[0239] Ingenol 3-(3-methyl-1H-pyrrole-2-carboxylate) or
[0240] Ingenol 3-(1-cyclopropylpyrrole-2-carboxylate) or
[0241] Ingenol 3-(1-ethyl-2,4-dimethyl-pyrrole-3-carboxylate)
or
[0242] Ingenol 3-(1-allyl-2,4-dimethyl-pyrrole-3-carboxylate)
or
[0243] Ingenol
3-(1-(cyclopropylmethyl)-2,4-dimethyl-pyrrole-3-carboxylate) or
[0244] Ingenol
3-(1-(2-methoxyethyl)-2,4-dimethyl-pyrrole-3-carboxylate) or
[0245] Ingenol 3-(N-(3,5-dimethylisoxazol-4-yl)-N-methyl-carbamate)
or
[0246] Ingenol 3-(N-(1,5-dimethylpyrazol-3-yl)-N-methyl-carbamate)
or
[0247] Ingenol 3-(N-cyclopentyl-N-methyl-carbamate) or
[0248] Ingenol 3-(N-cyclopropyl-N-methyl-carbamate) or
[0249] Ingenol 3-(N-methyl-N-(2-pyridyl)-carbamate) or
[0250] Ingenol 3-(4-oxo-2,3-dihydroquinoline-1-carboxylate) or
[0251] Ingenol 3-(3,4-dihydro-2H-quinoline-1-carboxylate) or
[0252] Ingenol 3-(indoline-1-carboxylate) or
[0253] Ingenol 3-(azepane-1-carboxylate) or
[0254] Ingenol 3-(N-(4-chloro-phenyl)-N-methyl-carbamate) or
[0255] Ingenol 3-(N-(4-fluoro-phenyl)-N-methyl-carbamate) or
[0256] Ingenol 3-(N-methyl-N-(2-methoxy-phenyl)-carbamate) or
[0257] Ingenol 3-(N-methyl-N-(2-methyl-phenyl)-carbamate) or
[0258] Ingenol 3-(3-oxo-2,4-dihydroquinoxaline-1-carboxylate)
or
[0259] Ingenol 3-(N-ethyl-N-phenyl-carbamate) or
[0260] Ingenol 3-(2-trifluoromethyl-pyrrolidine-1-carboxylate)
or
[0261] Ingenol 3-(3-azabicyclo[3.2.2]nonane-3-carboxylate) or
[0262] Ingenol 3-(2,3-dihydro-1,4-benzoxazine-4-carboxylate) or
[0263] Ingenol 3-(N-(2-fluoro-phenyl)-N-methyl-carbamate) or
[0264] Ingenol
3-(3-methyl-2,3-dihydro-1,4-benzoxazine-4-carboxylate) or
[0265] Ingenol 3-(2-trifluoromethyl-pyrrolidine-1-carboxylate)
(ISOMER A) or
[0266] Ingenol 3-(2-trifluoromethyl-pyrrolidine-1-carboxylate)
(ISOMER B) or
[0267] Ingenol
3-(N-methyl-N-(N-(tert-butyloxycarbonyl)-4-piperidyl)-carbamate)
or
[0268] Ingenol 3-(N-methyl-N-(3-methyl-phenyl)-carbamate) or
[0269] Ingenol 3-(3,4-dihydro-2H-quinoxaline-1-carboxylate) or
[0270] Ingenol 3-(isoindoline-2-carboxylate) or
[0271] Ingenol
3-(N-methyl-N-(tetrahydropyran-4-ylmethyl)-carbamate) or
[0272] Ingenol 3-(N-methyl-N-(tetrahydropyran-4-yl)-carbamate)
or
[0273] Ingenol 3-(N-methyl-N-(3-methoxy-phenyl)-carbamate) or
[0274] Ingenol 3-(N-cyclobutyl-N-methyl-carbamate) or
[0275] Ingenol 3-(N-allyl-N-methyl-carbamate) or
[0276] Ingenol 3-(N-methyl-N-prop-2-ynyl-carbamate) or
[0277] Ingenol 3-(N-methyl-N-(4-methylthiazol-2-yl)-carbamate)
or
[0278] Ingenol 3-(N-(4-cyano-phenyl)-N-methyl-carbamate).
[0279] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(N-methyl-N-phenyl-carbamate).
[0280] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(N-(3-fluoro-phenyl)-N-methyl-carbamate).
[0281] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(3-ethyl-5-methyl-isoxazole-4-carboxylate)
[0282] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(2,4-dimethylfuran-3-carboxylate).
[0283] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(3,5-diethylisoxazole-4-carboxylate).
[0284] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(2,4,5-trimethylfuran-3-carboxylate).
[0285] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(2-methyl-4-phenyl-pyrazole-3-carboxylate).
[0286] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(3-methylthiophene-2-carboxylate).
[0287] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(indoline-1-carboxylate).
[0288] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(5-methyl-3-phenyl-isoxazole-4-carboxylate).
[0289] An embodiment of the invention provides a compound of
formula I, said compound being Ingenol
3-(pyrrolidine-1-carboxylate).
DEFINITIONS
[0290] In the present context, the term "(C.sub.a-C.sub.b)alkyl"
wherein a and b are integers refers to a straight or branched chain
alkyl radical having from a to b carbon atoms, e.g. 1-7 or 1-6,
such as 1-4 or 1-3 carbon atoms. Thus when a is 1 and b is 7, for
example, the term includes methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl,
isohexyl and heptyl.
[0291] The term "carbocyclic" refers to a mono-, bi- or tricyclic
radical having up to 13 ring atoms, e.g. 3-13 or 3-10 ring atoms,
all of which are carbon, and includes aryl, cycloalkyl and
cycloalkenyl.
[0292] The term "cycloalkyl" refers to a mono-, bi- or tricyclic
saturated cycloalkane radical, comprising 3-13 carbon atoms, such
as 3-10, such as 3-8, such as 3-5 carbon atoms, and includes, for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptanyl and adamantyl.
[0293] The term "(C.sub.a-C.sub.b)alkenyl" wherein a and b are
integers refers to a mono-, di- or triunsaturated straight or
branched chain alkenyl radical having from a to b carbon atoms,
e.g. 2-7 or 2-6 or 2-4 or 2-3 carbon atoms. Thus when a is 1 and b
is 7, for example, the term includes ethenyl, allyl, propenyl; 1-,
2- or 3-butenyl; 1-, 2-, 3- or 4-pentenyl; 1-, 2-, 3-, 4- or
5-hexenyl.
[0294] The term "cycloalkenyl" refers to mono-, di- or
triunsaturated non-aromatic cyclic hydrocarbons radicals, including
polycyclic radicals, comprising 3-13 carbon atoms, such as 3-10,
such as 3-8, such as 3-5 carbon atoms, and includes, for example,
cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
[0295] The term "(C.sub.a-C.sub.b)alkynyl" wherein a and b are
integers refers to a straight or branched chain hydrocarbon radical
having from a to b carbon atoms, e.g. 2-7 or 2-6 or 2-4 or 2-3
carbon atoms, comprising 1-2 C--C triple bonds. Thus when a is 1
and b is 7, for example, the term includes ethynyl, propynyl,
butynyl, pentynyl or hexynyl.
[0296] The term "heterocyclic" refers to a carbocyclic radical as
defined above, comprising 1-4 heteroatoms, selected from O, N, or
S, and includes heteroaryl, heterocycloalkyl and
heterocycloalkenyl.
[0297] The term "heterocycloalkyl" refers to a cycloalkyl radical,
including polycyclic radicals, optionally fused with carbocyclic
rings, comprising 1-4 heteroatoms, selected from O, N, or S.
[0298] The term "heterocycloalkyl" furthermore refers to a
cycloalkyl radical, including polycyclic radicals, optionally fused
with carbocyclic rings, including aryl provided that the point of
attachment is through the non-aromatic ring, the cycloalkyl radical
comprising 1-4 heteroatoms, selected from O, N, or S. E.g.
piperazinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,
morpholinyl, imidazolidinyl, piperidinyl,
5-oxabicyclo[2.2.2]octane, dihydroquinolinyl, indolinyl,
dihydroquinoxalinyl, oxo-thiazolyl, oxo-pyranyl, azepanyl,
azabicyclo[3.2.2]nonanyl, benzoxazinyl, quinoxalinyl, isoindolinyl,
indolinyl or tetrahydropyranyl, in particular tetrahydrofuranyl,
pyrrolidinyl, dioxolanyl, morpholinyl, imidazolidinyl, piperidinyl
or 5-oxabicyclo[2.2.2]octane.
[0299] The term "heterocycloalkenyl" refers to a cycloalkenyl
radical as defined above, including polycyclic radicals, optionally
fused with carbocyclic rings, comprising 1-4 heteroatoms, selected
from O, N, or S, e.g. dihydropyranyl, dihydrothiazolyl.
[0300] The term "aryl" refers to a radical of aromatic carbocyclic
rings comprising 6-10 carbon atoms, in particular phenyl, and
optionally fused carbocyclic rings with at least one aromatic ring,
in particular 5- or 6-membered rings. Thus the term includes for
example 1,2,3,4-tetrahydro-naphthalenyl, phenyl, naphthyl, indenyl
or indanyl, in particular phenyl, naphthyl, indenyl or indanyl.
[0301] The term "heteroaryl" refers to radicals of heterocyclic
aromatic rings, optionally fused with carbocyclic rings or
heterocyclic rings, comprising 1-4 heteroatoms, selected from O, S
and N, and 1-12 carbon atoms, such as 1-4 heteroatoms and 1-6
carbon atoms, in particular 5- or 6-membered rings with 1-4
heteroatoms, or optionally fused bicyclic rings with 1-4
heteroatoms, and wherein at least one ring is aromatic. Thus the
term includes, for example, pyridyl, quinolyl, isoquinolyl,
indolyl, tetrazolyl, furyl, thiazolyl, imidazolyl,
imidazo[1,2-a]pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl,
isoxazolyl, oxadiazolyl, 1,2,4-triazolyl, thienyl, pyrazinyl,
pyrimidinyl, 1,2,3-triazolyl, isothiazolyl,
imidazo[2,1-b]thiazolyl, benzimidazolyl, benzofuranyl,
benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxazolyl,
indazolyl, cinnolyl, 1,2-benzoxazolyl, imidazothiazolyl,
imidazopyridinyl, pyrrolyl, isothiazolyl, tetrahydroindazolyl,
oxadiazolyl in particular pyridyl, quinolyl, isoquinolyl, indolyl,
tetrazolyl, furyl, thiazolyl, imidazolyl,
imidazo[1,2-a]pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl,
isoxazolyl, oxadiazolyl, 1,2,4-triazolyl, thienyl, pyrazinyl,
pyrimidinyl, 1,2,3-triazolyl, isothiazolyl,
imidazo[2,1-b]thiazolyl, benzimidazolyl, benzofuranyl,
benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxazolyl,
indazolyl, or in particular pyridyl, quinolyl, isoquinolyl,
indolyl, tetrazolyl, furyl, thiazolyl, imidazolyl,
imidazo[1,2-a]pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl,
isoxazolyl, oxadiazolyl, 1,2,4-triazolyl, thienyl, pyrazinyl,
pyrimidinyl, 1,2,3-triazolyl, isothiazolyl,
imidazo[2,1-b]thiazolyl, benzimidazolyl, benzofuranyl,
benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxazolyl,
indazolyl, cinnolyl, 1,2-benzoxazolyl.
[0302] The term "halogen" is intended to indicate a substituent
from the 7th main group of the periodic table, preferably fluoro,
chloro and bromo.
[0303] The term "alkoxy" is intended to indicate a radical of the
formula --OR, wherein R is alkyl as indicated above, e.g. methoxy,
ethoxy, n-propoxy, isopropoxy, butoxy, etc.
[0304] The term "haloalkoxy" is intended to indicate a radical of
the formula --O--R--X.sub.(1-3), wherein R is alkyl as indicated
above, and X is halogen as indicated above e.g.
trifluoromethoxy.
[0305] The term hydroxyalkyl is intended to indicate a primary,
secondary or tertiary radical of the formula --R--OH, wherein R is
alkyl as indicated above, e.g. hydroxymethyl or hydroxyethyl.
[0306] The term cyanoalkyl is intended to indicate a primary,
secondary or tertiary radical of the formula --R--CN, wherein R is
alkyl as indicated above, e.g. cyanomethyl or cyanoethyl.
[0307] The term haloalkyl is intended to indicate a primary,
secondary or tertiary radical of the formula --R--X.sub.(1-3),
wherein R is alkyl as indicated above, and X is halogen as
indicated above, e.g. trifluoromethyl, 2,2,2-trifluoroethyl or
difluoromethyl.
[0308] When two or more of the above defined terms are used in
combination, such as arylalkyl, heteroarylalkyl, cycloalkylalkyl
and the like, it is to be understood that the first mentioned
radical is a substituent on the latter mentioned radical, where the
point of attachment to another part of the molecule, is on the
latter radical.
[0309] The term "alkoxyalkyl" is intended to indicate an alkyl
radical as defined above, which is substituted with an alkoxy
radical as defined above, i.e. --R--O--R, wherein each R is alkyl,
same or different, as indicated above, e.g. methoxymethyl,
ethoxymethyl.
[0310] The term "cycloalkylalkyl" is intended to indicate a radical
of the formula --R'-cycloalkyl, wherein R' is alkyl as defined
above such as;
##STR00004##
[0311] The term "cycloalkenylalkyl" is intended to indicate a
radical of the formula --R'-cycloalkenyl, wherein R' is alkyl as
defined above such as;
##STR00005##
[0312] The term "arylalkyl" is intended to indicate a radical of
the formula --R'--Ar, wherein R' is alkyl as defined above and Ar
is aryl as defined above such as;
##STR00006##
[0313] The term "heteroarylalkyl" is intended to indicate a radical
of the formula --R'-Het, wherein R' is alkyl as defined above and
Het is heteroaryl as defined above such as;
##STR00007##
[0314] The term "heterocycloalkylalkyl" is intended to indicate a
radical of the formula --R'-heterocycloalkyl, wherein R' is alkyl
as defined above such as;
##STR00008##
[0315] The term "heterocycloalkenylalkyl" is intended to indicate a
radical of the formula --R'-heterocycloalkenyl, wherein R' is alkyl
as defined above such as;
##STR00009##
[0316] The term alkylcycloalkyl is intended to indicate a radical
of the formula -cycloalkyl-R' wherein R' is alkyl as defined above
such as;
##STR00010##
[0317] The term "alkylcycloalkenyl" is intended to indicate a
radical of the formula -cycloalkenyl-R', wherein R' is alkyl as
defined above such as;
##STR00011##
[0318] The term "alkylaryl" is intended to indicate a radical of
the formula --Ar--R', wherein R' is alkyl as defined above and Ar
is aryl as defined above such as;
##STR00012##
[0319] The term "alkylheteroaryl" is intended to indicate a radical
of the formula -Het-R', wherein R' is alkyl as defined above and
Het is heteroaryl as defined above such as;
##STR00013##
[0320] The term "alkylheterocycloalkyl" is intended to indicate a
radical of the formula -heterocycloalkyl-R', wherein R' is alkyl as
defined above such as;
##STR00014##
[0321] The term `substituted` as applied to any moiety herein is
intended to indicate substitution with compatible substituents.
[0322] The term "pharmaceutically acceptable salt" is intended to
indicate salts prepared by reacting a compound of formula I
comprising a basic moiety with a suitable inorganic or organic
acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric,
nitric, phosphoric, formic, acetic, 2,2-dichloroacetic, choline,
adipic, ascorbic, L-aspartic, L-glutamic, galactaric, lactic,
maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric,
gluconic, D-glucuronic, methanesulfonic, salicylic, succinic,
malonic, tartaric, benzenesulfonic, ethane-1,2-disulfonic,
2-hydroxy ethanesulfonic acid, toluenesulfonic, sulfamic or fumaric
acid. Pharmaceutically acceptable salts of compounds of formula I
comprising an acidic moiety may also be prepared by reaction with a
suitable base such as sodium hydroxide, potassium hydroxide,
magnesium hydroxide, calcium hydroxide, ammonia, or suitable
non-toxic amines, such as lower alkylamines, for example
triethylamine, hydroxy-lower alkylamines, for example
2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine, cycloalkylamines,
for example dicyclohexylamine, or benzylamines, for example
N,N'-dibenzylethylenediamine, and dibenzylamine, or L-arginine or
L-lysine.
[0323] The present invention further includes prodrugs of compounds
of general formula I, such as esters, acetals, ketals, or other
derivatives which undergo a biotransformation in vivo before
exhibiting their pharmacological effects.
[0324] The term "solvate" is intended to indicate a species formed
by interaction between a compound, e.g. a compound of formula I,
and a solvent, e.g. alcohol, glycerol or water, wherein said
species are in a solid form. When water is the solvent, said
species is referred to as a hydrate.
[0325] The compounds of formula I may be obtained in crystalline
form either directly by concentration from an organic solvent or by
crystallisation or recrystallisation from an organic solvent or
mixture of said solvent and a cosolvent that may be organic or
inorganic, such as water. The crystals may be isolated in
essentially solvent-free form or as a solvate, such as a hydrate.
The invention covers all crystalline modifications and forms and
also mixtures thereof.
[0326] The term "cancer" in the context of the present invention is
intended to cover skin cancer such as non-melanoma skin cancer,
malignant melanoma, Merkel cell carcinoma, squamous cell carcinoma,
basal cell carcinoma. Basal cell carcinomas covers as well
superficial basal cell carcinomas as nodular basal cell carcinoma.
Squamous cell carcinoma covers squamous cell carcinoma in situ
(Bowen's disease), invasive squamous cell carcinoma, cutaneous
squamous cell carcinoma, mucosal squamous cell carcinoma, head and
neck squamous cell carcinoma. Other cancer types includes
haematological cancer such as myeloid cancers in particular such as
acute myeloid leukemia and chronic myeloid leukemia; Cancer of the
prostate and bladder including benign prostatic hyperplasia,
prostatis intraepithelial carcinoma, carcinoma of the bladder,
adenocarcinoma of the prostate and renal cell carcinoma. Other
cancer include AIDS related cancer, acoustic neoma, adenocystic
carcinoma, adrenocortical cancer, agnogenic myeloid metaplasia,
alopecia, alveolar soft-part sarcoma, anal cancer, angiosarcoma,
aplastic anaemia, astrocytoma, ataxia-telangiectasia, basal cell
carcinoma (bcc), bladder cancer, bone cancers, bowel cancer, brain
stem glioma, brain and CNS cancers, breast cancer, CNS cancers,
carcinoid cancers, cervical cancer, childhood brain cancers,
childhood cancer, childhood soft tissue sarcoma, chondrosarcoma,
choriocarcinoma, colorectal cancers, cutaneous T-Cell lymphoma,
dermatof[iota]brosarcoma-protuberans, desmoplastic small round cell
cancer, ductal carcinoma, endocrine cancers, endometrial cancer,
ependymoma, esophageal cancer, Ewing's sarcoma, extra hepatic bile
duct cancer, eye cancer, eye: melanoma, retinoblastoma, fallopian
tube cancer, fanconi anaemia, fibrosarcoma, gall bladder cancer,
gastric cancer, gastrointestinal cancers, gastrointestinal
carcinoid cancer, genitourinary cancers, germ cell cancers,
gestational trophoblastic disease, glioma, gynecological cancers,
hematological malignancies including acute myeloid leukemia, head
and neck cancer, hepatocellular cancer, hereditary breast cancer,
histiocytosis, Hodgkin's disease, human papillomavirus,
hydatidiform mole, hypercalcemia, hypopharynx cancer, intra-ocular
melanoma, isle T-cell cancer, Kaposi's sarcoma, kidney cancer,
Langerhan's cell histiocytosis, laryngeal cancer, leiomyosarcoma,
li-fraumeni syndrome, lip cancer, liposarcoma, liver cancer, lung
cancer, lymphedema, lymphoma, Hodgkin's lymphoma, non-Hodgkin's
lymphoma, male breast cancer, malignant rhabdoid cancer of kidney,
medulloblastoma, mesothelioma, metastatic cancer, mouth cancer,
multiple endocrine neoplasia, mycosis fungoides, myelodysplastic
syndromes, myeloma, myeloproliferative disorders, nasal cancer,
nasopharyngeal cancer, nephroblastoma, neuroblastoma,
neurofibromatosis, nijmegen breakage syndrome, non-small cell lung
cancer (nsclc), ocular cancers, oesophageal cancer, oral cavity
cancer, oropharynx cancer, osteosarcoma, ostomy ovarian cancer,
pancreas cancer, paranasal cancer, parathyroid cancer, parotid
gland cancer, penile cancer, peripheral neuroectodermal cancers,
pituitary cancer, polycythemia vera, prostate cancer, rare cancers
and associated disorders, retinoblastoma, rhabdomyosarcoma,
rothmund Thomson syndrome, salivary gland cancer, sarcoma,
schwannoma, sezary syndrome, small cell lung cancer (sclc), small
intestine cancer, soft tissue sarcoma, spinal cord cancers, stomach
cancer, synovial sarcoma, testicular cancer, thymus cancer, thyroid
cancer, transitional cell cancer (bladder), transitional cell
cancer (renal-pelvis-/-ureter), trophoblastic cancer, urethral
cancer, urinary system cancer, uroplakins, uterine sarcoma, uterus
cancer, vaginal Cancer, vulva cancer, Waldenstrom's
macroglobulinemia and Wilms' Cancer. The solid cancer which is
treated using the methods of the present invention may be a primary
lesion or may be the result of metastasis of a primary cancer.
Furthermore, if the solid cancer is a metastasis of a primary
cancer, the primary cancer may be either a primary solid cancer as
described above or may be a dispersed primary cancer.
[0327] In an embodiment of the invention "cancer" is skin
cancer.
[0328] In embodiments of the invention, skin cancer is non-melanoma
skin cancer, malignant melanoma, Merkel cell carcinoma, squamous
cell carcinoma, squamous cell carcinoma, basal cell carcinoma such
as superficial basal cell carcinomas or nodular basal cell
carcinoma.
[0329] The phrase "physiological disorders or diseases associated
with hyperplasia or neoplasia" in the context of the present
invention is intended to cover disorders or diseases such as
cutaneous warts, including common warts (Verruca vulgaris), plantar
warts (Verruca plantaris) and flat warts (verruca plana); Genital
warts (condyloma acuminatum), Pyogenic granuloma, Haemangioma,
Scleroderma; Cancers and precancerous lesions such as Actinic
keratosis, Squamous cell carcinoma including squamous cell
carcinoma in situ (Bowen's disease), invasive squamous cell
carcinoma, cutaneous squamous cell carcinoma, mucosal squamous cell
carcinoma, head and neck squamous cell carcinoma; Basal cell
carcinoma including Superficial basal cell carcinoma and Nodular
basal cell carcinoma; Bladder cancer, Lentigo maligna, Cervical
dysplasia, Vulva dysplasia and anal dysplasia, Primary melanoma in
situ, Head and neck cancer, Cutaneous metastases of any cancer,
Kaposi's sarcoma, Keratoacanthoma, Merkel cell tumor, Prostate
cancer, Mycosis fungoides, Intraepithelial neoplasias including
anal, cervical, ductal, oral, perianal, prostatic, penile, vaginal
and vulvar intraepithelial neoplasia.
[0330] The term "cosmetic indications" in the context of the
present invention is intended to cover indications such as:
Photodamaged skin, Seborrheic keratosis, Scars, Keloids, Melasma,
Poikiloderma of Civatte, Tattoo removal, Naevi and Skin tags.
[0331] The term "photodamaged skin" in the context of the present
invention is intended to cover fine lines, wrinkles and UV-ageing.
UV ageing is often manifested by an increase in the epidermal
thickness or epidermal atrophy and most notably by solar elastosis,
the accumulation of elastin containing material just below the
dermal-epidermal junction. Collagen and elastic fibres become
fragmented and disorganised. At a cosmetic level this can be
observed as a reddening and/or thickening of the skin resulting a a
lethery appearance, skin fragility and irregular pigmentation, loss
of tone and elasticity, as well as wrinkling, dryness, sunspots and
deep furrow formation.
[0332] The term "viral infections" in the context of the present
invention is intended to cover HPV infections leading to formation
of warts on the body, such as the skin, genitals and mouth. HPV
refers to human papilloma virus. Other viruses are selected from
adeno-, papova-, herpes- (such as simplex) varicella-zoster,
Epstein-Barr-, CMV-, Pox- (such as small pox-) vaccinia-, hepatitis
A-, hepatitis B-, hepatitis C-, Rhino-, polio-, rubella-, arbo-,
rabies-, influenza-A and B, measles-, mumps-viruses, and HIV, HTLV
I and II. In an embodiment of the invention HPV infection refers to
common warts or genital warts.
[0333] The term "bacterial infections" in the context of the
present invention is intended to cover prokaryotic and eukaryotic
bacterial infections and Gram positive and Gram negative and Gram
variable bacteria and intracellular bacteria. Examples of bacteries
includes Treponema, Borrelia, Neisseria, Legionella, Bordetella,
Escherichia, Salmonella, Shigella, Klebsiella, Yersinia, Vibrio,
Hemophilus, Rickettsia, Chlamydia, Mycoplasma, Staphylococcus,
Streptococcus, Bacillus, Clostridium, Corynebacterium,
Proprionibacterium, Mycobacterium, Ureaplasma and Listeria. In
particular the species: Treponema pallidum, Borrelia Burgdorferi,
Neisseria gonorrhoea, Legionella pneumophila, Bordetella pertussis,
Escherichia coli, Salmonella typhi, salmonella typhimurium,
Shigella dysenteriae, Klebsiella pneumoniae, Yersinia pestis,
Vibrio cholerae, Hemophilus influenza, Rickettsia rickettsii,
Chlamydia trachomatis, Mycoplasma pneumonia, Staphylococcus aureus,
Streptococcus pneumoniae, Streptococcus pyogenes, Bacillus
anthracis, Clostridium botulinum, Clostridium tetani, clostridium
perfringens, Corynebacterium diphteriae, Proprionibacterium acne,
Mycobacterium tuberculosis, Mycobacterium leprae and Listeriare
monocytogenes. Lower eukaryotic organism includes yeast and fungus
such as Pneumocystis nerinii, Candida albicans, Aspergillus,
Histoplasma capsulatum, Blastomyces dermatitidis, Cryptococcus
neoformans, Trichophyton and Microsporum. Complex eukaryotic
organism includes worms, insects, aracnids, nematodes, aemobe,
Entamoeba histolytica, Giardia lamblia, Trichonomonas vaginalis,
Trypanosoma brucei gembiense, Trypanosoma cruzi, Blantidium coli,
Toxoplasma gondii, Cryptosporidium or Leishmania.
[0334] In the context of the present invention the term "wound
healing" means: reducing or minimizing scar tissue or improving
cosmesis or functional outcome in a wound and scar reduction,
wherein the wound is cutaneous, chronic or for example diabetes
associated, and includes cuts and lacerations, surgical incisions,
punctures, graces, scratches, compression wounds, abrasions,
friction wounds, chronic wounds, ulcers, thermal effect wounds,
chemical wounds, wounds resulting from pathogenic infections, skin
graft/transplant donor and recipient sites, immune response
conditions, oral wounds, stomach or intestinal wounds, damaged
cartilage or bone, amputation sides and corneal lesions.
[0335] The compounds of the present invention are contemplated in
the treatment of cancer, actinic keratosis, seborrheic keratosis,
viral infections, bacterial infections, wound healing, and
treatment of photodamaged skin.
[0336] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of superficial
basal cell carcinoma (BCC), nodular BCC, squamous cell carcinoma or
squamous cell carcinoma in situ (SCCIS).
[0337] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of actinic
keratosis.
[0338] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of Seborrheic
keratosis.
[0339] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of photodamaged
skin.
[0340] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of or lesions
caused by HPV infection.
[0341] In an embodiment of the invention the lesions are common
warts or genital warts.
[0342] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of squamous
cell carcinoma in situ or invasive squamous cell carcinoma.
[0343] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of cutaneous
squamous cell carcinoma, mucosal squamous cell carcinoma or head
and neck squamous cell carcinoma.
[0344] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of superficial
basal cell carcinoma or nodular basal cell carcinoma.
[0345] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of cutaneous
warts or genital warts
[0346] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of common
warts, plantar warts and flat warts.
[0347] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of lentigo
maligna.
[0348] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of cervical
intraepithelial neoplasia, anal intraepithelial neoplasia or vulva
intraepithelial neoplasia.
[0349] In an embodiment of the invention the compounds of the
invention are contemplated for use in the treatment of acute
myeloid leukemia.
[0350] In an embodiment the invention provides a method of
treatment of cancer, actinic keratosis, seborrheic keratosis, viral
infections, bacterial infections, wound healing, and treatment of
photodamaged skin by administration to a subject in need thereof a
compound of formula I.
[0351] In an embodiment the invention provides a method of
treatment actinic keratosis by administration to a subject in need
thereof a compound of formula I above.
[0352] In an embodiment the invention provides a method of
treatment Seborrheic keratosis by administration to a subject in
need thereof a compound of formula I above.
[0353] In an embodiment the invention provides a method of
treatment photodamaged skin by administration to a subject in need
thereof a compound of formula I above.
[0354] In an embodiment the invention provides a method of
treatment of lesions caused by HPV infection by administration to a
subject in need thereof a compound of formula I above.
[0355] In an embodiment the invention provides a method of
treatment of common warts or genital warts by administration to a
subject in need thereof a compound of formula I above.
[0356] In an embodiment the invention provides a method of
treatment of cutaneous squamous cell carcinoma, mucosal squamous
cell carcinoma or head and neck squamous cell carcinoma by
administration to a subject in need thereof a compound of formula I
above.
[0357] In an embodiment the invention provides a method of
treatment of common warts, plantar warts and flat warts by
administration to a subject in need thereof a compound of formula I
above.
[0358] In an embodiment the invention provides a method of
treatment of lentigo maligna by administration to a subject in need
thereof a compound of formula I above.
[0359] In an embodiment the invention provides a method of
treatment of cervical intraepithelial neoplasia, anal
intraepithelial neoplasia or vulva intraepithelial neoplasia by
administration to a subject in need thereof a compound of formula I
above.
[0360] In an embodiment the invention provides use a compound
according to formula I above in the manufacture of a pharmaceutical
composition for the treatment or amelioration of a disease,
disorder or condition responsive to stimulation of neutrophil
oxidative burst.
[0361] In an embodiment the invention provides use of a compound
according to formula I above in the manufacture of a pharmaceutical
composition for the treatment or amelioration of a disease,
disorder or condition responsive to stimulation of keratinocyte
IL-8 release.
[0362] In an embodiment the invention provides use of a compound
according to formula I above in the manufacture of a pharmaceutical
composition for the treatment or amelioration of a disease,
disorder or condition responsive to induction of necrosis.
[0363] In an embodiment the invention provides a method of
preventing, treating, amelioration or prophylaxis of physiological
disorders or diseases responsive to stimulation of neutrophil
oxidative burst by administration to a subject in need thereof a
compound according to formula I above.
[0364] In an embodiment the invention provides a method of
preventing, treating, amelioration or prophylaxis of physiological
disorders or diseases responsive to stimulation of keratinocyte
IL-8 release by administration to a subject in need thereof a
compound according to formula I above.
[0365] In an embodiment the invention provides a method of
preventing, treating, amelioration or prophylaxis of physiological
disorders or diseases responsive to responsive to induction of
necrosis by administration to a subject in need thereof a compound
according to formula I above.
[0366] In an embodiment the invention provides a compound according
to formula I above for use in the treatment or amelioration of a
disease, disorder or condition responsive to stimulation of
neutrophil oxidative burst.
[0367] In an embodiment the invention provides a compound according
to formula I above for use in the treatment or amelioration of a
disease, disorder or condition responsive to stimulation of
keratinocyte IL-8 release.
[0368] In an embodiment the invention provides a compound according
to formula I above for use in the treatment or amelioration of a
disease, disorder or condition responsive to induction of
necrosis.
[0369] In an embodiment the invention provides a method of
treatment of acute myeloid leukemia by administration to a subject
in need thereof a compound of formula I above.
[0370] In an embodiment the invention provides a compound of
formula I, for use in the treatment, prevention, amelioration or
prophylaxis of physiological disorders or diseases associated with
actinic keratosis, seborrheic keratosis, cancer, photodamaged skin
or lesions caused by HPV infection.
[0371] In an embodiment the invention provides the use of a
compound of formula I, for the manufacture of a medicament for the
treatment, amelioration or prophylaxis of physiological disorders
or diseases associated with actinic keratosis, Seborrheic
keratosis, cancer, photodamaged skin or lesions caused by HPV
infection.
[0372] In an embodiment the invention provides a method of
preventing, treating, amelioration or prophylaxis of physiological
disorders or diseases associated with actinic keratosis, Seborrheic
keratosis, cancer, photodamaged skin or lesions caused by HPV
infection by administration to a subject in need thereof a compound
of formula I.
[0373] Pharmaceutical Compositions
[0374] For use in therapy, compounds of the present invention are
typically in the form of a pharmaceutical composition. The
invention therefore relates to a pharmaceutical composition
comprising a compound of formula I, together with a
pharmaceutically acceptable excipient or vehicle. The excipient
must be "acceptable" in the sense of being compatible with the
other ingredients of the composition and not deleterious to the
recipient thereof.
[0375] Pharmaceutical compositions of the invention may be in unit
dosage form such as tablets, pills, capsules, powders, granules,
elixirs, syrups, emulsions, ampoules, suppositories or parenteral
solutions or suspensions; for oral, parenteral, opthalmic,
transdermal, intra-articular, topical, pulmonal, nasal, buccal or
rectal administration or in any other manner appropriate for the
formulation of compounds of the invention and in accordance with
accepted practices such as those disclosed in Remington: The
Science and Practice of Pharmacy, 21.sup.st ed., 2000, Lippincott
Williams & Wilkins.
[0376] For oral administration in the form of a tablet or capsule,
a compound of formula I may suitably be combined with an oral,
non-toxic, pharmaceutically acceptable carrier such as ethanol,
glycerol, water or the like. Furthermore, suitable binders,
lubricants, disintegrating agents, flavouring agents and colourants
may be added to the mixture, as appropriate. Suitable binders
include, e.g., lactose, glucose, starch, gelatin, acacia gum,
tragacanth gum, sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes or the like. Lubricants include, e.g.,
sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride or the like.
Disintegrating agents include, e.g., starch, methyl cellulose,
agar, bentonite, xanthan gum or the like. Additional excipients for
capsules include macrogols or lipids.
[0377] For the preparation of solid compositions such as tablets,
the active compound of formula I is mixed with one or more
excipients, such as the ones described above, and other
pharmaceutical diluents such as water to make a solid
preformulation composition containing a homogenous mixture of a
compound of formula I. The term "homogenous" is understood to mean
that the compound of formula I is dispersed evenly throughout the
composition so that the composition may readily be subdivided into
equally effective unit dosage forms such as tablets or
capsules.
[0378] In the form of a dosage unit, the compound may be
administered one or more times a day at appropriate intervals,
always depending, however, on the condition of the patient, and in
accordance with the prescription made by the medical practitioner.
Conveniently, a dosage unit of a formulation contain between 0.01
mg and 200 mg, preferably between 0.01 mg and 20 mg, such as 0.01-5
mg of a compound of formula I.
[0379] A suitable dosage of the compound of the invention will
depend, inter alia, on the age and condition of the patient, the
severity of the disease to be treated and other factors well known
to the practising physician. The compound may be administered
either orally, parenterally or topically according to different
dosing schedules, e.g. daily or with weekly intervals. In general a
single dose will be in the range from 0.01 to 200 mg/kg body
weight. The compound may be administered as a bolus (i.e. the
entire daily doses is administered at once) or in divided doses two
or more times a day.
[0380] If the treatment involves administration of another
therapeutically active compound it is recommended to consult
Goodman & Gilman's The Pharmacological Basis of Therapeutics,
9.sup.th Ed., J. G. Hardman and L. E. Limbird (Eds.), McGraw-Hill
1995, for useful dosages of said compounds. The administration of a
compound of the present invention with one or more other active
compounds may be either concomitantly or sequentially.
[0381] Liquid formulations for either oral or parenteral
administration of the compound of the invention include, e.g.,
aqueous solutions, syrups, aqueous or oil suspensions and emulsion
with edible oils such as cottonseed oil, sesame oil, coconut oil or
peanut oil.
[0382] Suitable dispersing or suspending agents for aqueous
suspensions include synthetic or natural gums such as tragacanth,
alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin,
methylcellulose or polyvinylpyrolidone.
[0383] For parenteral administration, e.g. intramuscular,
intraperitoneal, subcutaneous or intravenous injection or infusion,
the pharmaceutical composition preferably comprises a compound of
formula I dissolved or solubilised in an appropriate,
pharmaceutically acceptable solvent. For parenteral administration,
the composition of the invention may include a sterile aqueous or
non-aqueous solvent, in particular water, isotonic saline, isotonic
glucose solution, buffer solution or other solvent conventionally
used for parenteral administration of therapeutically active
substances. The composition may be sterilised by, for instance,
filtration through a bacteria-retaining filter, addition of a
sterilising agent to the composition, irradiation of the
composition, or heating the composition. Alternatively, the
compound of the invention may be provided as a sterile, solid
preparation, e.g. a freeze-dried powder, which is dissolved in
sterile solvent immediately prior to use. The composition intended
for parenteral administration may additionally comprise
conventional additives such as stabilisers, buffers or
preservatives, e.g. antioxidants such as methyl hydroxybenzoate or
the like.
[0384] Compositions for rectal administration may be in the form of
a suppository incorporating the active ingredient and a carrier
such as cocoa butter, or in the form of an enema.
[0385] Compositions suitable for intra-articular administration may
be in the form of a sterile aqueous preparation of the active
ingredient which may be in microcrystalline form, for example, in
the form of an aqueous microcrystalline suspension. Liposomal
formulations or biodegradable polymer systems may also be used to
present the active ingredient for both intra-articular and
ophthalmic administration.
[0386] Compositions suitable for topical administration, including
ophthalmic treatment, include liquid or semi-liquid preparations
such as liniments, lotions, gels, applicants, oil-in-water or
water-in-oil emulsions such as creams, ointments or pastes; or
solutions or suspensions such as drops. Compositions for ophthalmic
treatment may preferably additionally contain a cyclodextrin.
Compositions suitable for administration to the nasal or buccal
cavity or for inhalation include powder, self-propelling and spray
formulations, such as aerosols and atomizers.
[0387] Human skin, in particular the outer layer, the stratum
corneum, provides an effective barrier against penetration of
microbial pathogens and toxic chemicals. While this property of
skin is generally beneficial, it complicates the dermal
administration of pharmaceuticals in that a large quantity, if not
most, of the active ingredient applied on the skin of a patient
suffering from a dermal disease may not penetrate into the viable
layers of the skin where it exerts its activity.
[0388] Penetration of the skin is facilitated by addition of
penetration enhancers which include isopropyl alcohol, sulphoxides,
azones, pyrrolidines, alkanols, and glycols. In embodiments of the
invention the penetrations enhancers includes DMSO, laurocapram,
2-pyrrolidone, decanol and propylene glycol. In an embodiment of
the invention the penetration enhancer is isopropyl alcohol.
[0389] In embodiments of the invention the therapeutically active
compound is dissolved in a suitable solvent. Suitable solvents are
glycols, ketone, acetates and ethers. Ingenol compounds have been
shown to have good stability in alcohols such as benzyl alcohol and
isopropyl alcohol. In general, ingenol compounds have previously
shown to have good stability at low pH. In embodiments of the
present invention pH the pharmaceutical formulation is below 7. In
embodiments of the present invention the pH of the pharmaceutical
formulation is below 6. In embodiments of the present invention the
pH of the pharmaceutical formulation is below 4.5. In embodiments
of the present invention the pH of the pharmaceutical formulation
is below 4.0. In embodiments of the present invention the pH of the
pharmaceutical formulation is below 4.5 and no less than 2.5. In
embodiments of the present invention the pH of the pharmaceutical
formulation is below 4.0 and no less than 2.5. The preferred pH
range can be obtained by including an appropriate buffer. In an
embodiment of the invention the buffer is an acetate buffer. In
embodiments of the invention a citrate buffer is used. In
embodiments of the invention a mixed citrate-phosphate buffer is
used.
[0390] In one embodiment, the composition is an ointment. According
to the current FDA classification, an ointment is a semisolid
dosage from which may contain water and volatile substances in an
amount of up to 20% by weight and which contains more than 50% by
weight of hydrocarbons, waxes or polyols in the vehicle. Thus,
according to the invention, the ointment may be a water-in-oil
composition in which case the nanosuspension may be added as such
to the lipophilic components of the composition, such that the
composition contains up to 10% by weight or, preferably, up to 5%
by weight of the aqueous phase. Alternatively, the composition may
be a non-aqueous ointment which contains less than about 2%,
preferably less than 1%, of free water by weight of the
composition.
[0391] The ointment carrier may suitably contain a paraffin
selected from paraffins consisting of hydrocarbons with chain
lengths from C.sub.5-60 and mixtures thereof. A frequently used
ointment carrier is petrolatum, or white soft paraffin, which is
composed of hydrocarbons of different chain lengths, peaking at
about C.sub.40-44, or a mixture of petrolatum and liquid paraffin
(consisting of hydrocarbons of different chain lengths peaking at
C.sub.28-40). While petrolatum provides occlusion of the treated
skin surface, reducing transdermal loss of water and potentiating
the therapeutic effect of the active ingredient in the composition,
it tends to have a greasy and/or tacky feel which persists for
quite some time after application, and it is not easily spreadable.
It may therefore be preferred to employ paraffins consisting of
hydrocarbons of a somewhat lower chain length, such as paraffins
consisting of hydrocarbons with chain lengths peaking at
C.sub.14-16, C.sub.18-22, C.sub.20-22, C.sub.20-26 or mixtures
thereof. It has been found that such paraffins are more
cosmetically acceptable in that they are less tacky and/or greasy
on application and more easily spreadable. They are therefore
expected to result in improved patient compliance. Suitable
paraffins of this type are manufactured by Sonneborn and marketed
under the trade name Sonnecone, e.g. Sonnecone CM, Sonnecone DM1,
Sonnecone DM2 and Sonnecone HV. These paraffins are further
disclosed and characterized in WO08/141078 which is incorporated
herein by reference. (The hydrocarbon composition of the paraffins
has been determined by gas chromatography.)
[0392] To impart a desired viscosity to the composition, it may
suitably include a lipophilic viscosity-increasing ingredient such
as a wax. The wax may be a mineral wax composed of a mixture of
high molecular weight hydrocarbons, e.g. saturated C.sub.35-70
alkanes, such as microcrystalline wax. Alternatively, the wax may
be a vegetable or animal wax, e.g. esters of C.sub.14-32 fatty
acids and C.sub.14-32 fatty alcohols, such as beeswax. The amount
of viscosity-increasing ingredient may vary according to the
viscosifying power of the ingredient, but may typically be in the
range of about 1-20% by weight of the composition. When the
viscosity-increasing ingredient is microcrystalline wax it is
typically present in an amount in the range of about 5-15% by
weight, e.g. about 10% by weight, of the composition.
[0393] To maintain good physical stability of the composition, in
particular to avoid separation of the aqueous and lipid phases
therein, it may be advantageous to include a water-in-oil
emulsifier with an HLB value of 3-8. Examples of such emulsifiers
are polyoxyethylene C.sub.8-22 alkyl ethers, e.g. polyoxyethylene
stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl
ether or polyoxyethylene lauryl ether. The amount of emulsifier is
typically in the range of 2-10% w/w of the composition. In another
embodiment, the composition is a cream which may comprise similar
components to the ointment, but which is typically an
oil-in-water-emulsion containing a substantial amount of water.
[0394] The composition may also comprise other components commonly
used in dermal formulations, e.g. antioxidants (e.g.
alpha-tocopherol), preservatives such as benzyl alcohol, sodium
edetate, pigments, skin soothing agents, skin healing agents and
skin conditioning agents such as urea, allantoin or bisabolol, cf.
CTFA Cosmetic Ingredients Handbook, 2.sup.nd Ed., 1992. In an
embodiment of the invention the preservative is benzyl alcohol.
[0395] In an embodiment the composition is a gel. Suitable gelling
agents include, water soluble cellulose derived polymers, such as
hydroxyalkyl cellulose polymers. In embodiments of the invention
the polymers are hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose and hydroxypropylmethylcellulose. Other
gelling agents are celluloses such as carboxymethyl cellulose,
methylhydroxyethyl cellulose and methyl cellulose, carbomer such as
carbopol and carrageenans. In embodiments of the invention the
gelling agent is cellulose derived. In embodiments of the invention
the cellulose is a hydroxyalkylcellulose, such as
hydroxyethylcellulose.
[0396] In an embodiment of the invention the composition comprises
active compound, penetration enhancer, preservative, gelling agent
and buffer at a pH of below 4 and not less than 2.5. For topical
administration, the compound of formula I may typically be present
in an amount of from 0.001 to 20% by weight of the composition,
such as 0.01% to about 10%. In embodiments of the present invention
the active compound is present in 0.05-1%. In an embodiment of the
present invention the active compound is present in 0.01-0.5%. In
an embodiment of the present invention the active compound is
present in a concentration of around 0.1%. In an embodiment of the
invention the composition comprises 0.005-0.1% active compound,
20-40% isopropyl alcohol, 0.5-10% benzyl alcohol, 0.5-5% hydroxyl
ethyl cellulose and citrate buffer to 100%.
[0397] Formulation of ingenol derivatives in a gel for topical
application has been described in WO07/068963, which is
incorporated by reference.
METHODS OF PREPARATION
[0398] The compounds of formula I may for example be prepared using
the reactions and techniques outlined below together with methods
known in the art of synthetic organic chemistry, or variations
thereof as appreciated by those skilled in the art. Preferred
methods include, but are not limited to, those described below. The
reactions are carried out in solvents appropriate to the reagents
and materials employed and suitable for the transformations being
effected. Also, in the synthetic methods described below, it is to
be understood that all proposed reaction conditions, including
choice of solvent, reaction atmosphere, reaction temperature,
duration of experiment and work-up procedures, are chosen to be
conditions of standard for that reaction, which should be readily
recognized by one skilled in the art. Not all compounds falling
into a given class may be compatible with some of the reaction
conditions required in some of the methods described. Such
restrictions to the substituents which are compatible with the
reaction conditions will be readily apparent to one skilled in the
art and alternative methods can be used. The compounds of the
present invention or any intermediate may be purified if required
using standard methods well known to a synthetic organist chemist,
e.g. methods described in W. Armarego "Purification of Laboratory
Chemicals", Butterworth-Heinemann, 6.sup.th ed. 2009. Starting
materials are either known compounds, commercially available, or
they may be prepared by routine synthetic methods well known to a
person skilled in the art.
[0399] The compounds of the invention may for example be prepared
according to the following non-limiting general methods and
examples
##STR00015##
##STR00016##
##STR00017##
##STR00018##
[0400] The compounds of the general formula I can for example be
synthesised according to Scheme 1, 2, 3 or 4 by reacting ingenol
with a hydroxyl protecting agent or a dihydroxyl protecting agent
to afford the protected ingenol derivatives a or c according to
methods described in, but not limited to "Protective Groups in
Organic Synthesis", 4th ed. P. G. M. Wuts; T. W. Greene, John
Wiley, 2007 or in P. J. Kocienski, "Protecting Groups", 3rd ed. G.
Thieme, 2003 and references cited therein.
[0401] For example compound a, wherein the protective group (Pg) is
triphenylmethyl, can be synthesised by reacting ingenol with a
triphenylmethyl reagent such as triphenylmethylpyridinium
fluoroborate or triphenylmethyl chloride in a suitable solvent such
as pyridine, N,N-dimethylformamide or dichloromethane in the
presence or in the absence of base (e.g. Opferkuch et. al., Z.
Naturforschung, (1981), 36B, 878).
[0402] Compound a, wherein the protective group (Pg) is silyl, can
for example be synthesised by reacting ingenol with a silyl
chloride such as tert-butyldimethylsilyl chloride,
tert-butyldiphenylsilyl chloride or triisopropylsilyl chloride in a
suitable solvent such as N,N-dimethylformamide, pyridine,
dichloromethane, tetrahydrofuran or acetonitrile in the presence of
a suitable base such as imidazole, triethylamine,
N,N-diisopropylethylamine or 4-(N,N-dimethylamino)pyridine (e.g.
Sorg, B. et. al, Z. Naturforsch., (1982), 37B, 1640-47), or by
reacting compound (II) with a silyl triflate such as
tert-butyldimethylsilyl trifluoromethanesulfonate in a suitable
solvent such as dichloromethane in the presence of a suitable base
such as triethylamine.
[0403] Compound a wherein Pg is 2-tetrahydropyranyl, can for
example be synthesised by reacting ingenol with dihydropyran in a
suitable solvent such as dichloromethane or acetonitrile in the
presence of a suitable acid such as p-toluenesulfonic acid.
[0404] Compound c wherein the protective group (Pg) represents an
acetal such as benzylidene acetal can for example be prepared by
reacting ingenol with benzaldehyde or benzaldehyde dimethyl acetal
in a suitable solvent such as dichloromethane or
N,N-dimethylformamide in the presence of a suitable acid such as
p-toluenesulfonic acid.
[0405] Compound c wherein the protective group (Pg) represents a
ketal such as isopropylidene ketal can for example be synthesised
by reacting ingenol with a ketone such as acetone or a dimethoxy
ketal such as 2,2-dimethoxy propane in a suitable solvent such as
dichloromethane or N,N-dimethylformamide in the presence of a
suitable acid such as p-toluenesulfonic acid (e.g B. Sorg, Z.
Naturforsch. (1982), 37b, 748-756). Acetone and 2,2-dimethoxy
propane can also act as solvents.
[0406] As depicted in scheme 1 and 2 the protected ingenol
derivatives a or c may be esterified to give compounds of the
general formula b or d according to methods for esterification of
hydroxyl groups described in, but not limited to "Esterification"
by J. Otera, Wiley-VCH, 2003 and references cited therein. Compound
b or d can for example be synthesised by reacting compound a or c
with an activated acid derivative such as an acid halide such as
acid chloride. The esterification by reaction with acid chloride
can take place in a suitable solvent such as dichloromethane or
toluene without an activator, or it can take place in the presence
of a base such as pyridine, triethylamine or
4-(N,N-dimethylamino)pyridine (e.g. B. Sorg, Z. Naturforsch.
(1982), 37b, 748-756).
[0407] Compound b or d can for example be synthesised by reacting
compound a or c with activated acid derivative such as an acid
anhydride. The esterification by reaction with an acid anhydride
can take place without a catalyst (e.g. Opferkuch et. al., Z.
Naturforschung, (1981), 36B, 878), or in the presence of an acidic
catalyst using an acid such as perchloric acid or a Lewis acid such
as scandium (III) triflate or bismuth (III) triflate, or in the
presence of a base such as sodium hydrogencarbonate or
triethylamine.
[0408] Compound b or d can for example be synthesised by reacting
compound a or c with an activated acid derivative such as a mixed
anhydride of an acid such as trichlorobenzoic acid. The
esterification by reaction with a mixed anhydride can take place in
a suitable solvent without a catalyst, or in the presence of an
acidic catalyst using an acid such as perchloric acid or a Lewis
acid such as scandium (III) triflate or bismuth (III) triflate, or
in the presence of a base such as sodium hydrogencarbonate or
triethylamine.
[0409] Compound b or d can for example be synthesised by reacting
compound a or c with an acid in the presence a coupling reagent
such as a carbodiimide such as dicyclohexylcarbodiimide or
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide with or without the
presence of a base such as 4-(N,N-dimethylamino)pyridine and with
or without catalysts such as 4-(N,N-dimethylamino)pyridine in a
suitable solvent such as dichloromethane (e.g Appendino et. al.,
Eur. J. Org. Chem. (1999), 3413). Solid-supported coupling reagents
can also be used in the esterification step [Nam, N.-H., Journal of
Combinatorial Chemistry, (2003), 5, 479-545, or "Esterification" by
J. Otera, Wiley-VCH, 2003].
[0410] Compounds of formula b, d or I of scheme 1 or 2 above, can
for example be synthesised enzymatic esterification by reacting
compound a, c or ingenol with an acyl donor such as an acid
anhydride, an ester such as vinyl ester or a thioester in the
presence of an enzyme such as a lipase or an esterase.
[0411] As depicted in scheme 3 and 4 the protected ingenol
derivatives a or c may be carbamoylated to give compounds of the
general formula b or d according to methods for carbamoylation of
hydroxyl groups described in, but not limited to "Functions
Containing a Carbonyl Group and at Least One Chalcogen (but not
Halogen)" by H. Eckert in "Comprehensive Organic Functional Group
Transformations II" Eds. A. R. Katritzky and R. J. K. Taylor, Vol
6, p. 440-444, Elsevier, 2005 and references cited therein.
Compound b or d can for example be synthesised by reacting compound
a or c with an activated carbamic acid derivative such as a
carbamoyl halide such as a carbamoyl chloride. The carbamoylation
by reaction with a carbamoyl chloride can take place in a suitable
solvent such as acetonitrile, dichloromethane or toluene without an
activator, or it can take place in the presence of a base such as
pyridine, triethylamine, potassium carbonate or
4-(N,N-dimethylamino)pyridine.
[0412] Compound b or d can for example be synthesised by reacting
compound a or c with an isocyanate to give N-mono-substituted
carbamates. The carbamate formation by reaction with an isocyanate
can take place in a suitable solvent such as dichloromethane or
acetonitrile without a catalyst, or it can take place in the
presence of a base such as triethylamine.
[0413] The compounds of formula I may be prepared by selective
removal of the protective groups Pg from the compounds of the
general structure b or d according to methods for deprotection of
hydroxyl or dihydroxyl protective groups described, in but not
limited to "Protective Groups in Organic Synthesis", 4th ed. P. G.
M. Wuts; T. W. Greene, John Wiley, 2007 or in P. J. Kocienski,
"Protecting Groups", 3rd ed. G. Thieme, 2003 and references cited
therein.
[0414] Compounds of general formula I can for example be prepared
from compounds of general formula d wherein Pg represents an acetal
such as benzylidene acetal or a ketal such as an isopropyliden
ketal by cleavage of the protecting group in the presence of a
suitable acid such as aqueous hydrogen chloride, acetic acid,
trifluoroacetic acid or p-toluenesulfonic acid in a suitable
solvent such as methanol or aqueous tetrahydrofuran.
[0415] Compounds of general formula I can for example be prepared
from compounds of general formula b wherein Pg represents an
alkoxyalkyl such as 2-tetrahydropyranyl by cleaving the acetal
moiety, for example by acid catalysed cleavage in the presence of a
suitable acid such as p-toluenesulfonic acid in a suitable solvent
such as methanol.
[0416] Compounds of general formula I can for example be prepared
from compounds of general formula b wherein Pg represents silyl
such as tert-butyldimethylsilyl by reacting compound b with a
suitable acid such as hydrogen chloride in a suitable solvent such
as methanol or by reacting with a fluoride source such as tetra
n-butylammonium fluoride or tetrafluorosilane in a suitable solvent
such as tetrahydrofuran or acetonitrile.
[0417] Compounds of general formula I can for example be prepared
from compounds of general formula b wherein Pg represents
triphenylmethyl by reacting compound b with a suitable acid such as
formic acid or trifluoroacetic acid in a suitable solvent such as
ether, methanol or dichloromethane.
EXAMPLES
General
[0418] All the starting materials used are commercially available,
unless otherwise described. For 1H nuclear magnetic resonance (NMR)
spectra, chemical shift values (.delta.) (in ppm) are quoted;
tetramethylsilane (.delta.=0.00) is as standard. The value of a
defined singlet (s), doublet (d), triplet (t), quartet (q)) or a
range (m) is given. Carbamates may show duplicate signals, due to
the existence of syn/anti rotamers. All organic solvents used were
anhydrous, unless otherwise specified. Flash chromatography was
performed on silica gel. Appropriate mixtures of ethyl acetate and
heptane were used as eluents unless otherwise noted. Compounds were
detected on TLC plates by development with aqueous potassium
permanganate solution.
##STR00019##
Ingenol-5,20-acetonide
[0419] Ingenol (1.00 g, 2.30 mmol) was dissolved in a solution of
p-toluenesulphonic acid monohydrate in acetone (0.47 mg/mL, 22.5
mL). The solution was stirred at room temperature for 25 min. To
this solution was added a saturated aqueous solution of NaHCO.sub.3
(0.2 mL). The obtained mixture was concentrated in vacuo. The
residue was taken up in brine and extracted with ethyl acetate. The
combined organic phases were dried over sodium sulfate and
concentrated in vacuo. The residue was purified by flash
chromatography (heptane/ethyl acetate 19:1.fwdarw.heptane/ethyl
acetate 0:1), giving the title compound as a white solid (616 mg,
69%). (See also: Opferkuch, H. J. et. al., Z. Naturforsch., (1981),
86b, 878-887.)
[0420] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 5.91 (q, J=1.5 Hz,
1H), 5.79 (m, 1H), 4.25 (d, J=4.5 Hz, 1H), 4.20-4.07 (m, 3H), 3.93
(s, 1H), 3.51 (s, 1H), 2.57-2.41 (m, 2H), 2.25 (ddd, J=15.7, 8.4,
2.9 Hz, 1H), 1.85 (d, J=1.5 Hz, 3H), 1.77 (dt, J=15.8, 5.9 Hz, 1H),
1.41 (s, 3H), 1.35 (s, 3H), 1.13 (s, 3H), 1.05 (s, 3H), 1.00-0.87
(m, 4H), 0.70 (td, J=8.4, 6.4 Hz, 1H).
General Procedures for the Preparation of Compounds of General
Formula II
##STR00020##
[0421] Procedure a
[0422] A mixture of carboxylic acid (0.100 mmol),
dicyclohexylcarbodiimide (0.100 mmol),
4-(N,N-dimethylamino)-pyridine (0.0025 mmol) and
ingenol-5,20-acetonide (0.050 mmol) were stirred at room
temperature in dichloromethane for 20-24 h. The mixture was mixed
with ethyl acetate, filtered and washed with saturated aqueous
sodium chloride. The organic phase was dried with sodium sulphate,
concentrated in vacuo and purified by flash chromatography
(heptane.fwdarw.heptane/ethyl acetate 7:3), giving the title
compound as a white solid.
Procedure b
[0423] A mixture of acyl chloride (0.0625 mmol),
diisopropylethylamine (0.075 mmol), 4-(N,N-dimethylamino)-pyridine
(0.070 mmol) and ingenol-5,20-acetonide (0.050 mmol) were stirred
at 55.degree. C. in tetrahydrofuran for 6-20 h. The mixture was
mixed with ethyl acetate, filtered and washed with saturated
aqueous sodium chloride. The organic phase was dried with sodium
sulphate, concentrated in vacuo and purified by flash
chromatography (heptane.fwdarw.heptane/ethyl acetate 7:3), giving
the title compound as a white solid.
Procedure c
[0424] A mixture of carboxylic acid (0.100 mmol),
dicyclohexylcarbodiimide (0.100 mmol),
4-(N,N-dimethylamino)-pyridine (0.025 mmol) and
ingenol-5,20-acetonide (0.050 mmol) were stirred in a microwave
oven at 150.degree. C. in acetonitrile for 5 min. The mixture was
mixed with ethyl acetate, filtered and washed with saturated
aqueous sodium chloride. The organic phase was dried with sodium
sulphate, concentrated in vacuo and purified by flash
chromatography (heptane.fwdarw.heptane/ethyl acetate 7:3), giving
the title compound as a white solid.
Procedure d
[0425] A mixture of acyl chloride (0.125 mmol),
diisopropylethylamine (0.250 mmol), 4-(N,N-dimethylamino)-pyridine
(0.025 mmol) and ingenol-5,20-acetonide (0.050 mmol) were stirred
in a microwave oven at 150.degree. C. in acetonitrile for 10-30
min. The mixture was mixed with ethyl acetate, filtered and washed
with saturated aqueous sodium chloride. The organic phase was dried
with sodium sulphate, concentrated in vacuo and purified by flash
chromatography (heptane.fwdarw.heptane/ethyl acetate 7:3), giving
the title compound as a white solid.
General Procedure for the Preparation of Compounds of General
Formula I
##STR00021##
[0426] Procedure e
[0427] Ingenol-5,20-acetonide-3-acylate or
ingenol-5,20-acetonide-3-carbamate (0.10 mmol) was dissolved in
tetrahydrofuran (0.47 mL) under argon. An aqueous solution of HCl
(4 M, 4.7 .mu.L) was added. The solution was stirred at room
temperature for 20-27 h. Tetrahydrofuran may be replaced with
methanol and the reaction time at room temperature shortened to 0.5
h. The solution was concentrated in vacuo. The residue was purified
by flash chromatography (heptane/ethyl acetate
5:1.fwdarw.heptane/ethyl acetate 3:7), giving the title compound.
For more polar compounds a dichloromethane/methanol
98:2.fwdarw.dichloromethane/methanol 95:5 gradient was used.
General Procedure for the Preparation of Carbamoyl Chlorides
##STR00022##
[0428] Procedure f
[0429] To a solution of a secondary amine (1.2 mmol) in
dichloromethane (2 ml) at 0.degree. C. was added potassium hydrogen
carbonate (3.0 mmol) or a tertiary amine, such as triethylamine or
pyridine, followed by triphosgene (1.0 mmol). The mixture was
stirred at 0.degree. C. for 2 h, filtered and washed with
dichloromethane. The combined filtrates were concentrated in vacuo
giving the title compound.
General Procedures for the Preparation of
Ingenol-5,20-acetonide-3-carbamate Compounds of General Formula
III
##STR00023##
[0430] Procedure g
[0431] A mixture of a carbamoyl chloride (0.390 mmol), potassium
carbonate (0.616 mmol), and ingenol-5,20-acetonide (0.077 mmol) was
stirred at 80.degree. C. in acetonitrile for 16-24 h. The mixture
was filtered and washed with dichloromethane. The combined
filtrates were concentrated in vacuo and purified by flash
chromatography (heptane.fwdarw.heptane/ethyl acetate 7:3), giving
the title compound.
Procedure h
[0432] A mixture of a carbamoyl chloride (0.390 mmol), potassium
carbonate (0.616 mmol), and ingenol-5,20-acetonide (0.077 mmol) was
stirred in a microwave oven at 160.degree. C. in acetonitrile for
10 min. The mixture was filtered and washed with dichloromethane.
The combined filtrates were concentrated in vacuo and purified by
flash chromatography (heptane.fwdarw.heptane/ethyl acetate 7:3),
giving the title compound.
Procedure i
[0433] A mixture of an isocyanate (0.231 mmol), potassium carbonate
(0.385 mmol), and ingenol-5,20-acetonide (0.077 mmol) was stirred
at 80.degree. C. in acetonitrile for 16-24 h. The mixture was
filtered and washed with dichloromethane. The combined filtrates
were concentrated in vacuo and purified by flash chromatography
(heptane.fwdarw.heptane/ethyl acetate 7:3), giving the title
compound.
Procedure j
[0434] To a solution of ingenol-5,20-acetonide (0.10 mmol) in
tetrahydrofuran at 0.degree. C. under argon atmosphere was dropwise
added 1 M lithiumbis(trimethylsilyl)amide in THF (0.10 mmol). After
stirring for 10 min a carbamoyl chloride (0.20 mmol), dissolved in
0.2 ml THF, was dropwise added and the reaction mixture was slowly
returned to room temperature overnight. The mixture was added 2
drops of water followed by dichloromethane (1 ml), filtrated and
concentrated in vacuo. The crude product was purified by flash
chromatography (heptane.fwdarw.heptane/ethyl acetate 7:3), giving
the title compound.
General Procedure for Preparation of 4-aryl Substituted
1-methylpyrazole-5-carboxylic Acids
Procedure k
##STR00024##
[0436] The method described by G. C. Fu et al Angew. Chem. 2006,
118, 1304-1306 was employed.
[0437] A heterogeneous mixture of
1-methyl-4-bromopyrazole-5-carboxylic acid (1 mmol),
Tris(dibenzylideneacetone)dipalladium(0) (0.1 mmol), tricyclohexyl
phosphine (0.2 mmol), potassium phosphate (3 mmol) and the
appropriate phenylboronic acid (1.5 mmol), water (2 mL) and dioxane
(4 mL) were stirred in an argon atmosphere in a microwave oven at
180.degree. C. for 20 min. The mixture was cooled to room
temperature and partly evaporated, added 5N aq NaOH (1 mL), washed
3 times with diethyl ether. The aqueous solution was acidified with
4N HCl, the precipitate was isolated by filtration and dried to
provide the crude 4-aryl substituted 1-methylpyrazole-5-carboxylic
acid which was used without further purification.
##STR00025##
Preparation 601
Ingenol-5,20-acetonide-3-(5-methyl-3-(2-chloro-6-fluoro-phenyl)-isoxazole--
4-carboxylate (Compound 601)
[0438] Compound 601 was prepared according to Procedure d.
[0439] Starting material:
5-Methyl-3-(2-chloro-6-fluoro-phenyl)-isoxazole-4-carbonyl
chloride.
[0440] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.41-7.33 (m, 1H),
7.27-7.24 (m, 1H), 7.08-7.02 (m, 1H), 5.85-5.84 (d, 1H), 5.76-5.74
(m, 1H), 5.57 (s, 1H), 4.23-4.06 (m, 3H), 3.94 (s, 1H), 3.18 (s,
1H), 2.82 (s, 3H), 2.21-2.12 (m, 1H), 1.96-1.90 (m, 1H), 1.69-1.62
(m, 1H), 1.61 (d, 3H), 1.47 (s, 3H), 1.39 (s, 3H), 1.03 (s, 3H),
1.03 (s, 3H), 0.90-0.78 (m, 1H), 0.73 (d, 3H), 0.66-0.58 (m,
1H).
##STR00026##
Preparation 602
Ingenol-5,20-acetonide-3-(5-methyl-3-phenyl-isoxazole-4-carboxylate)
(Compound 602)
[0441] Compound 602 was prepared according to Procedure d.
[0442] Starting material: 5-Methyl-3-phenyl-isoxazole-4-carbonyl
chloride.
[0443] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.57-7.53 (m, 2H),
7.47-7.37 (m, 3H), 5.95 (d, 1H), 5.76 (m, 1H), 5.68 (s, 1H),
4.23-4.04 (m, 3H), 3.97 (s, 1H), 3.12 (s, 1H), 2.77 (s, 3H),
2.11-2.01 (m, 1H), 1.95-1.87 (m, 1H), 1.72 (d, 3H), 1.59-1.49 (m,
1H), 1.45 (s, 3H), 1.40 (s, 3H), 1.04 (s, 3H), 1.03 (s, 3H),
0.90-0.80 (m, 1H), 0.71 (d, 3H), 0.65-0.57 (m, 1H).
##STR00027##
Preparation 603
Ingenol-5,20-acetonide-3-(1S-camphanate) (Compound 603)
[0444] Compound 603 was prepared according to Procedure d.
[0445] Starting material: (1S)-Camphanic chloride.
[0446] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.10-6.09 (m, 1H),
5.80-5.79 (m, 1H), 5.66 (s, 1H), 4.25-4.11 (m, 3H), 4.02 (s, 1H),
3.17 (s, 1H), 2.61-2.56 (m, 1H), 2.48-2.39 (m, 1H), 2.29-2.20 (m,
1H), 2.09-2.02 (m, 1H), 1.94-1.88 (m, 1H), 1.79-1.65 (m, 5H), 1.45
(s, 3H), 1.42 (s, 3H), 1.12 (s, 3H), 1.10 (s, 3H), 1.09 (s, 3H),
1.05 (s, 3H), 0.99-0.86 (m, 7H), 0.73-0.65 (m, 1H).
##STR00028##
Preparation 604
Ingenol-5,20-acetonide-3-(3-phenyltriazole-4-carboxylate) (Compound
604)
[0447] Compound 604 was prepared according to Procedure c.
[0448] Starting material: 3-phenyltriazole-4-carboxylic acid.
##STR00029##
Preparation 605
Ingenol-5,20-acetonide-3-(2-phenylpyrazole-3-carboxylate) (Compound
605)
[0449] Compound 605 was prepared according to Procedure h, where
"carbamoyl chloride" was replaced with 2-phenylpyrazole-3-carbonyl
chloride.
##STR00030##
Preparation 606
Ingenol-5,20-acetonide-3-(1-methylindazole-3-carboxylate) (Compound
606)
[0450] Compound 606 was prepared according to Procedure h, where
"carbamoyl chloride" was replaced with 1-methylindazole-3-carbonyl
chloride.
##STR00031##
Preparation 607
Ingenol-5,20-acetonide-3-(3-ethyl-5-methyl-isoxazole-4-carboxylate)
(Compound 607)
[0451] Compound 607 was prepared according to Procedure c.
[0452] Starting material: 3-Ethyl-5-methyl-isoxazole-4-carboxylic
acid.
[0453] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.12 (m, 1H), 5.82-5.80
(m, 1H), 5.72 (s, 1H), 4.28-4.11 (m, 3H), 4.05 (s, 1H), 3.26 (s,
1H), 2.89 (q, 2H), 2.65 (s, 3H), 2.63-2.59 (m, 1H), 2.30-2.24 (m,
1H), 1.81 (d, 3H), 1.79-1.71 (m, 1H), 1.48 (s, 3H), 1.45 (s, 3H),
1.28 (t, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.01 (d, 3H), 0.94-0.86
(m, 1H), 0.74-0.66 (m, 1H).
##STR00032##
Preparation 608
Ingenol-5,20-acetonide-3-(3,5-dimethyl-isoxazole-4-carboxylate)
(Compound 608)
[0454] Compound 608 was prepared according to Procedure c.
[0455] Starting material: 3,5-Dimethyl-isoxazole-4-carboxylic
acid.
[0456] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.12 (s, 1H), 5.81-5.80
(m, 1H), 5.70 (s, 1H), 4.27-4.11 (m, 3H), 4.05 (s, 1H), 3.27 (s,
1H), 2.65 (s, 3H), 2.63-2.59 (m, 1H), 2.43 (s, 3H), 2.33-2.23 (m,
1H), 1.82-1.70 (m, 4H), 1.49 (s, 3H), 1.45 (s, 3H), 1.09 (s, 3H),
1.05 (s, 3H), 1.01 (d, 3H), 0.94-0.87 (m, 1H), 0.74-0.65 (m,
1H).
##STR00033##
Preparation 609
Ingenol-5,20-acetonide-3-(1-methylindole-3-carboxylate) (Compound
609)
[0457] Compound 609 was prepared according to Procedure c.
[0458] Starting material: 1-methylindole-3-carboxylic acid.
##STR00034##
Preparation 610
Ingenol-5,20-acetonide-3-(3-phenylthiophene-2-carboxylate)
(Compound 610)
[0459] Compound 610 was prepared according to Procedure c.
[0460] Starting material: 3-Phenylthiophene-2-carboxylic acid.
##STR00035##
Preparation 611
Ingenol-5,20-acetonide-3-(5-phenylisoxazole-3-carboxylate)
(Compound 611)
[0461] Compound 611 was prepared according to Procedure d.
[0462] Starting material: 5-Phenylisoxazole-3-carbonyl
chloride.
[0463] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.83-7.78 (m, 2H),
7.52-7.47 (m, 3H), 6.90 (s, 1H), 6-16-6.15 (m, 1H), 5.81 (m, 2H),
4.28-4.08 (m, 4H), 3.29 (s, 1H), 2.73-2.68 (m, 1H), 2.30-2.21 (m,
1H), 1.85 (d, 3H), 1.82-1.75 (m, 1H), 1.50 (s, 3H), 1.47 (s, 3H),
1.08 (s, 3H), 1.05 (d, 3H), 1.04 (s, 3H), 0.95-0.88 (m, 1H),
0.74-0.67 (m, 1H).
##STR00036##
Preparation 612
Ingenol-5,20-acetonide-3-(isoquinoline-1-carboxylate) (Compound
612)
[0464] Compound 612 was prepared according to Procedure c.
[0465] Starting material: Isoquinoline-1-carboxylic acid.
[0466] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.76-8.73 (m, 1H),
8.58 (d, 1H), 7.90 (d, 1H), 7.81 (d, 1H), 7.77-7.72 (m, 1H),
7.70-7.64 (m, 1H), 6.15 (m, 1H), 6.00 (s, 1H), 5.82-5.80 (m, 1H),
4.47 (s, 1H), 4.29-4.22 (m, 3H), 4.10 (s, 1H), 2.74-2.69 (m, 1H),
2.45-2.35 (m, 1H), 1.90 (d, 3H), 1.87-1.80 (m, 1H), 1.49 (s, 3H),
1.47 (s, 3H), 1.15 (s, 3H), 1.07 (s, 3H), 0.98-0.88 (m, 4H),
0.77-0.69 (m, 1H).
##STR00037##
Preparation 613
Ingenol-5,20-acetonide-3-(quinoline-4-carboxylate) (Compound
613)
[0467] Compound 613 was prepared according to Procedure c.
[0468] Starting material: Quinoline-4-carboxylic acid.
##STR00038##
Preparation 614
Ingenol-5,20-acetonide-3-(cinnoline-4-carboxylate) (Compound
614)
[0469] Compound 614 was prepared according to Procedure c.
[0470] Starting material: Cinnoline-4-carboxylic acid.
[0471] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.71 (s, 1H),
8.94-8.91 (m, 1H), 8.67-8.64 (m, 1H), 7.96-7.86 (m, 2H), 6.21-6.20
(m, 1H), 5.93 (s, 1H), 5.85-5.84 (m, 1H), 4.32-4.13 (m, 4H), 3.36
(s, 1H), 2.74-2.69 (m, 1H), 2.38-2.28 (m, 1H), 1.87 (d, 3H),
1.86-1.79 (m, 1H), 1.53 (s, 3H), 1.52 (s, 3H), 1.09 (s, 3H), 1.05
(s, 3H), 1.04 (d, 3H), 0.96-0.89 (m, 1H), 0.77-0.69 (m, 1H).
##STR00039##
Preparation 615
Ingenol-5,20-acetonide-3-(3-phenylimidazole-4-carboxylate)
(Compound 615)
[0472] Compound 615 was prepared according to Procedure c.
[0473] Starting material: 3-Phenylimidazole-4-carboxylic acid.
[0474] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.89 (d, 1H), 7.67
(d, 1H), 7.48-7.45 (m, 3H), 7.35-7.32 (m, 2H), 6.00-5.99 (m, 1H),
5.77-5.76 (m, 1H), 5.62 (s, 1H), 4.22-4.07 (m, 3H), 3.97 (bs, 1H),
3.17 (s, 1H), 2.34-2.29 (m, 1H), 2.25-2.16 (m, 1H), 1.76-1.67 (m,
4H), 1.40 (s, 3H), 1.37 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H),
0.92-0.84 (m, 4H), 0.71-0.63 (m, 1H).
##STR00040##
Preparation 616
Ingenol-5,20-acetonide-3-(5-phenyloxazole-4-carboxylate) (Compound
616)
[0475] Compound 616 was prepared according to Procedure c.
[0476] Starting material: 5-Phenyloxazole-4-carboxylic acid.
[0477] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.95-7.91 (m, 3H),
7.48-7.42 (m, 3H), 6.07-6.06 (m, 1H), 5.78-5.75 (m, 2H), 4.24-4.08
(m, 3H), 4.03-4.02 (m, 1H), 3.39 (s, 1H), 2.37-2.29 (m, 1H),
2.20-2.11 (m, 1H), 1.83 (d, 3H), 1.68-1.58 (m, 1H), 1.47 (s, 3H),
1.43 (s, 3H), 1.05 (s, 3H), 1.03 (s, 3H), 0.91-0.84 (m, 1H) 0.84
(d, 3H), 0.68-0.60 (m, 1H).
##STR00041##
Preparation 617
Ingenol-5,20-acetonide-3-(1,2-benzoxazole-3-carboxylate) (Compound
617)
[0478] Compound 617 was prepared according to Procedure c.
[0479] Starting material: 1,2-Benzoxazole-3-carboxylic acid.
[0480] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.14-8.11 (m, 1H),
7.70-7.60 (m, 2H), 7.46-7.39 (m, 1H), 6.21-6.19 (m, 1H), 5.89 (s,
1H), 5.83-5.81 (m, 1H), 4.30-4.11 (m, 4H), 3.34 (s, 1H), 2.77-2.72
(m, 1H), 2.30-2.21 (m, 1H), 1.89 (d, 3H), 1.81-1.72 (m, 1H), 1.52
(s, 3H), 1.49 (s, 3H), 1.07 (s, 3H), 1.05 (d, 3H), 1.04 (s, 3H),
0.95-0.88 (m, 1H), 0.74-0.66 (m, 1H).
##STR00042##
Preparation 618
Ingenol-5,20-acetonide-3-(3-isopropyl-5-methyl-isoxazole-4-carboxylate)
(Compound 618)
[0481] Compound 618 was prepared according to Procedure c.
[0482] Starting material:
3-Isopropyl-5-methyl-isoxazole-4-carboxylic acid.
[0483] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.12-6.11 (m, 1H),
5.82-5.79 (m, 1H), 5.73 (s, 1H), 4.28-4.10 (m, 3H), 4.06-4.05 (m,
1H), 3.46 (septet, 1H), 3.26 (s, 1H), 2.65 (s, 3H), 2.63-2.57 (m,
1H), 2.33-2.24 (m, 1H), 1.81 (d, 3H), 1.79-1.70 (m, 1H), 1.48 (s,
3H), 1.46 (s, 3H), 1.33 (d, 3H), 1.31 (d, 3H), 1.08 (s, 3H), 1.05
(s, 3H), 1.00 (d, 3H), 0.94-0.87 (m, 1H), 0.74-0.66 (m, 1H).
##STR00043##
Preparation 619
Ingenol-5,20-acetonide-3-(3-(2-methoxyphenyl)-5-methyl-isoxazole-4-carboxy-
late) (Compound 619)
[0484] Compound 619 was prepared according to Procedure c.
[0485] Starting material:
3-(2-Methoxyphenyl)-5-methyl-isoxazole-4-carboxylic acid.
[0486] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.44-7.35 (m, 2H),
7.04-6.99 (m, 1H), 6.96-6.92 (d, 1H), 5.93-5.91 (m, 1H), 5.75-5.72
(m, 1H), 5.67 (s, 1H), 4.20-4.13 (m, 2H), 4.06-4.00 (m, 1H), 3.92
(s, 1H), 3.76 (s, 3H), 2.98 (s, 1H), 2.74 (s, 3H), 2.03-1.95 (m,
1H), 1.87-1.78 (m, 1H), 1.69 (d, 3H), 1.58-1.50 (m, 1H), 1.42 (s,
3H), 1.38 (s, 3H), 1.04 (s, 3H), 1.03 (s, 3H), 0.88-0.80 (m, 1H),
0.76 (d, 3H), 0.66-0.58 (m, 1H).
##STR00044##
Preparation 620
Ingenol-5,20-acetonide-3-(4-bromo-2-methyl-pyrazole-3-carboxylate)
(Compound 620)
[0487] Compound 620 was prepared according to Procedure c.
[0488] Starting material: 4-Bromo-2-methyl-pyrazole-3-carboxylic
acid.
##STR00045##
Preparation 621
Ingenol-5,20-acetonide-3-(4-bromo-2-ethyl-pyrazole-3-carboxylate)
(Compound 621)
[0489] Compound 621 was prepared according to Procedure c.
[0490] Starting material: 4-Bromo-2-ethyl-pyrazole-3-carboxylic
acid.
##STR00046##
Preparation 622
Ingenol-5,20-acetonide-3-(4-chloro-2-methyl-pyrazole-3-carboxylate)
(Compound 622)
[0491] Compound 622 was prepared according to Procedure c.
[0492] Starting material: 4-Chloro-2-methyl-pyrazole-3-carboxylic
acid.
##STR00047##
Preparation 623
Ingenol-5,20-acetonide-3-(5-bromopyrimidine-4-carboxylate)
(Compound 623)
[0493] Compound 623 was prepared according to Procedure d, but
extending the reaction time to 40 min.
[0494] Starting material: 5-Bromopyrimidine-4-carbonyl chloride,
prepared from 5-bromopyrimidine-4-carboxylic acid by reaction with
1.25 eq. oxalyl chloride in dichloromethane and a drop of
dimethylformamide at room temperature for 30 min followed by
evaporation of volatiles in vacuum.
[0495] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.20 (s, 1H), 9.00
(s, 1H), 6.16-6.14 (m, 1H), 5.85 (s, 1H), 5.83-5.80 (m, 1H),
4.27-4.14 (m, 3H), 4.07-4.06 (m, 1H), 3.44 (s, 1H), 2.66-2.59 (m,
1H), 2.31-2.22 (m, 1H), 1.88 (d, 3H), 1.79-1.70 (m, 1H), 1.49 (s,
3H), 1.46 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.96 (d, 3H),
0.95-0.88 (m, 1H), 0.73-0.65 (m, 1H).
##STR00048##
Preparation 624
Ingenol-5,20-acetonide-3-(3-bromopyridine-2-carboxylate) (Compound
624)
[0496] Compound 624 was prepared according to Procedure d, but
extending the reaction time to 40 min.
[0497] Starting material: 3-Bromopyridine-2-carbonyl chloride,
prepared from 3-bromopyridine-2-carboxylic acid by reaction with
1.25 eq. oxalyl chloride in dichloromethane and a drop of
dimethylformamide at room temperature for 30 min followed by
evaporation of volatiles in vacuum.
[0498] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.60 (dd, 1H),
7.99 (dd, 1H), 7.30 (dd, 1H), 6.13-6.12 (m, 1H), 5.89 (s, 1H),
5.80-5.77 (m, 1H), 4.20-4.15 (m, 3H), 4.05 (s, 1H), 3.85 (s, 1H),
2.70-2.60 (m, 1H), 2.32-2.23 (m, 1H), 1.89 (d, 3H), 1.80-1.71 (m,
1H), 1.47 (s, 3H), 1.44 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 0.96
(d, 3H), 0.95-0.89 (m, 1H), 0.73-0.85 (m, 1H).
##STR00049##
Preparation 625
Ingenol-5,20-acetonide-3-(5-methylthiazole-4-carboxylate) (Compound
625)
[0499] Compound 625 was prepared according to Procedure c.
[0500] Starting material: 5-Methylthiazole-4-carboxylic acid.
[0501] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.85 (s, 1H),
6.13-6.11 (m, 1H), 5.79-5.77 (m, 2H), 4.25-4.13 (m, 3H), 4.06-4.05
(m, 1H), 3.50 (s, 1H), 2.78 (s, 3H), 2.72-2.67 (m, 1H), 2.31-2.22
(m, 1H), 1.85 (d, 3H), 1.81-1.72 (m, 1H), 1.48 (s, 3H), 1.45 (s,
3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.02 (d, 3H), 0.95-0.88 (m, 1H),
0.74-0.66 (m, 1H).
##STR00050##
Preparation 626
Ingenol-5,20-acetonide-3-(4-chloro-1-methyl-pyrazole-3-carboxylate)
(Compound 626)
[0502] Compound 626 was prepared according to Procedure c.
[0503] Starting material: 4-Chloro-1-methyl-pyrazole-3-carboxylic
acid.
##STR00051##
Preparation 627
Ingenol-5,20-acetonide-3-(2,4-dimethylthiazole-5-carboxylate)
(Compound 627)
[0504] Compound 627 was prepared according to Procedure c.
[0505] Starting material: 2,4-Dimethylthiazole-5-carboxylic
acid.
[0506] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.10-6.09 (m, 1H),
5.80-5.79 (m, 1H), 5.68 (s, 1H), 4.26-4.12 (m, 3H), 4.04-4.03 (m,
1H), 3.22 (s, 1H), 2.70 (s, 3H), 2.68 (s, 3H), 2.68-2.63 (m, 1H),
2.32-2.22 (m, 1H), 1.82-1.73 (m, 4H), 1.48 (s, 3H), 1.44 (s, 3H),
1.08 (s, 3H), 1.05 (s, 3H), 1.02 (d, 3H), 0.94-0.88 (m, 1H),
0.74-0.66 (m, 1H).
##STR00052##
Preparation 628
Ingenol-5,20-acetonide-3-(2,5-dimethyloxazole-4-carboxylate)
(Compound 628)
[0507] Compound 628 was prepared according to Procedure c.
[0508] Starting material: 2,5-Dimethyloxazole-4-carboxylic
acid.
[0509] .sup.1H NMR (300 MHz, CDCl.sub.3) 6 6.10-6.09 (m, 1H),
5.80-5.78 (m, 1H), 5.73 (s, 1H), 4.27-4.12 (m, 3H), 4.04 (bs, 1H),
3.37 (s, 1H), 2.67-2.62 (m, 1H), 2.55 (s, 3H), 2.43 (s, 3H),
2.31-2.22 (m, 1H), 1.82 (d, 3H), 1.79-1.71 (m, 1H), 1.47 (s, 3H),
1.41 (s, 3H), 1.08 (s, 3H), 1.04 (s, 3H), 1.01 (d, 3H), 0.94-0.87
(m, 1H), 0.73-0.65 (m, 1H).
##STR00053##
Preparation 629
Ingenol-5,20-acetonide-3-(2,4-dimethylfuran-3-carboxylate)
(Compound 629)
[0510] Compound 629 was prepared according to Procedure d.
[0511] Starting material: 2,4-Dimethylfuran-3-carbonyl
chloride.
[0512] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.05 (q, 1H),
6.09-6.08 (m, 1H), 6.80-6.78 (m, 1H), 5.73 (s, 1H), 4.26-4.12 (m,
3H), 4.05 (s, 1H), 3.34 (s, 1H), 2.69-2.62 (m, 1H), 2.54 (s, 3H),
2.33-2.24 (m, 1H), 2.13 (d, 3H), 1.81 (d, 3H), 1.78-1.69 (m, 1H),
1.48 (s, 3H), 1.44 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.00 (d,
3H), 0.91-0.86 (m, 1H), 0.74-0.65 (m, 1H).
##STR00054##
Preparation 630
Ingenol-5,20-acetonide-3-(3,5-diethylisoxazole-4-carboxylate)
(Compound 630)
[0513] Compound 630 was prepared according to Procedure d.
[0514] Starting material: 3,5-Diethylisoxazole-4-carbonyl chloride,
prepared from 3,5-diethylisoxazole-4-carboxylic acid by reaction
with 1.25 eq. oxalyl chloride in dichloromethane and a drop of
dimethylformamide at room temperature for 30 min followed by
evaporation of volatiles in vacuum.
[0515] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.13-6.11 (m, 1H),
5.82-5.80 (m, 1H), 5.73 (s, 1H), 4.28-4.11 (m, 3H), 4.05 (m, 1H),
3.26 (s, 1H), 3.09 (q, 2H), 2.89 (q, 2H), 2.62-2.57 (m, 1H),
2.34-2.24 (m, 1H), 1.81 (d, 3H), 1.79-1.70 (m, 1H), 1.48 (s, 3H),
1.45 (s, 3H), 1.30 (t, 3H), 1.29 (t, 3H), 1.08 (s, 3H), 1.05 (s,
3H), 1.01 (d, 3H), 0.93-0.87 (m, 1H), 0.74-0.66 (m, 1H).
##STR00055##
Preparation 631
Ingenol-5,20-acetonide-3-(1H-indole-7-carboxylate) (Compound
631)
[0516] Compound 631 was prepared according to Procedure c.
[0517] Starting material: 1H-Indole-7-carboxylic acid.
##STR00056##
Preparation 632
Ingenol-5,20-acetonide-3-(2-tert-butyl-5-methyl-pyrazole-3-carboxylate)
(Compound 632)
[0518] Compound 632 was prepared according to Procedure c, but
replacing acetonitrile with N,N-dimethylformamide.
[0519] Starting material:
2-tert-Butyl-5-methyl-pyrazole-3-carboxylic acid.
[0520] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.61 (s, 1H),
6.08-6.06 (m, 1H), 5.82-5.79 (m, 1H), 5.70 (s, 1H), 4.28-4.10 (m,
3H), 4.05-4.04 (m, 1H), 3.19 (s, 1H), 2.67-2.61 (m, 1H), 2.31-2.22
(m, 4H), 1.83-1.74 (m, 4H), 1.70 (s, 9H), 1.47 (s, 3H), 1.46 (s,
3H), 1.10 (s, 3H), 1.05 (s, 3H), 1.01 (d, 3H), 0.95-0.90 (m, 1H),
0.74-0.67 (m, 1H).
##STR00057##
Preparation 633
Ingenol-5,20-acetonide-3-(5-tert-butyl-2-methyl-pyrazole-3-carboxylate)
(Compound 633)
[0521] Compound 633 was prepared according to Procedure c, but
replacing acetonitrile with N,N-dimethylformamide.
[0522] Starting material:
5-tert-Butyl-2-methyl-pyrazole-3-carboxylic acid.
##STR00058##
Preparation 634
Ingenol-5,20-acetonide-3-(6-methylimidazo[2,1-b]thiazole-5-carboxylate)
(Compound 634)
[0523] Compound 634 was prepared according to Procedure c, but
replacing acetonitrile with N,N-dimethylformamide.
[0524] Starting material:
6-Methylimidazo[2,1-b]thiazole-5-carboxylic acid.
##STR00059##
Preparation 635
Ingenol-5,20-acetonide-3-(2-methylimidazo[1,2-a]pyridine-3-carboxylate)
(Compound 635)
[0525] Compound 635 was prepared according to Procedure c, but
replacing acetonitrile with N,N-dimethylformamide.
[0526] Starting material:
2-Methylimidazo[1,2-a]pyridine-3-carboxylic acid.
##STR00060##
Preparation 636
Ingenol-5,20-acetonide-3-(2,4,5-trimethylfuran-3-carboxylate)
(Compound 636)
[0527] Compound 636 was prepared according to Procedure c.
[0528] Starting material: 2,4,5-Trimethylfuran-3-carboxylic
acid.
##STR00061##
Preparation 637
Ingenol-5,20-acetonide-3-(3-methylthiophene-2-carboxylate)
(Compound 637)
[0529] Compound 637 was prepared according to Procedure c.
[0530] Starting material: 3-Methylthiophene-2-carboxylic acid.
##STR00062##
Preparation 638
Ingenol-5,20-acetonide-3-(2-methyl-4-(1-piperidyl)pyrazole-3-carboxylate)
(Compound 638)
[0531] Compound 638 was prepared according to Procedure d.
[0532] Starting material:
2-Methyl-4-(1-piperidyl)pyrazole-3-carbonyl chloride, prepared from
2-methyl-4-(1-piperidyl)pyrazole-3-carboxylic acid by reaction with
1.25 eq. oxalyl chloride in dichloromethane and a drop of
dimethylformamide at room temperature for 30 min followed by
evaporation of volatiles in vacuum.
[0533] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.27 (s, 1H),
6.15-6.13 (m, 1H), 5.80-5.76 (m, 2H), 4.26-4.4.10 (m, 6H),
4.05-4.04 (m, 1H), 3.58 (s, 1H), 2.99-2.83 (m, 4H), 2.77-2.72 (m,
1H), 2.31-2.21 (m, 1H), 1.84 (d, 3H), 1.76-1.51 (m, 7H), 1.49 (s,
3H), 1.44 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H), 1.01 (d, 3H),
0.93-0.86 (m, 1H), 0.72-0.64 (m, 1H).
##STR00063##
Preparation 639
Ingenol-5,20-acetonide-3-(2-chloro-5-isopropyl-thiazole-4-carboxylate)
(Compound 639)
[0534] Compound 639 was prepared according to Procedure c.
[0535] Starting material:
2-chloro-5-isopropyl-thiazole-4-carboxylic acid.
[0536] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.13-6.12 (m, 1H),
5.80-5.77 (m, 2H), 4.25-4.03 (m, 5H), 3.46 (s, 1H), 2.70-2.65 (m,
1H), 2.33-2.23 (m, 1H), 1.83 (d, 3H), 1.81-1.74 (m, 1H), 1.47 (s,
3H), 1.43 (s, 3H), 1.32 (d, 6H), 1.09 (s, 3H), 1.05 (s, 3H), 1.02
(d, 3H), 0.95-0.88 (m, 1H), 0.74-0.66 (m, 1H).
##STR00064##
Preparation 640
Ingenol-5,20-acetonide-3-(4-chloro-2,5-dimethyl-pyrazole-3-carboxylate)
(Compound 640)
[0537] Compound 640 was prepared according to Procedure c.
[0538] Starting material:
4-Chloro-2,5-dimethyl-pyrazole-3-carboxylic acid.
##STR00065##
Preparation 641
Ingenol-5,20-acetonide-3-(1,2,4-trimethylpyrrole-3-carboxylate)
(Compound 641)
[0539] Compound 641 was prepared according to Procedure c.
[0540] Starting material: 1,2,4-Trimethylpyrrole-3-carboxylic
acid.
[0541] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.28 (m, 1H),
6.06-6.04 (m, 1H), 5.78-5.75 (m, 2H), 4.21-4.15 (m, 3H), 4.05-4.04
(m, 1H), 3.52 (s, 1H), 3.46 (s, 3H), 2.73-2.68 (m, 1H), 2.48 (s,
3H), 2.33-2.23 (m, 1H), 2.20 (s, 3H), 1.81 (d, 3H), 1.78-1.68 (m,
1H), 1.48 (s, 3H), 1.43 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H), 0.99
(d, 3H), 0.93-0.86 (m, 1H), 0.72-0.64 (m, 1H).
##STR00066##
Preparation 642
Ingenol-5,20-acetonide-3-(1,3,5-trimethylpyrrole-2-carboxylate)
(Compound 642)
[0542] Compound 642 was prepared according to Procedure c.
[0543] Starting material: 1,3,5-Trimethylpyrrole-2-carboxylic
acid.
##STR00067##
Preparation 643
Ingenol-5,20-acetonide-3-(1-ethyl-3,5-dimethylpyrrole-2-carboxylate)
(Compound 643)
[0544] Compound 643 was prepared according to Procedure c.
[0545] Starting material: 1-Ethyl-3,5-dimethylpyrrole-2-carboxylic
acid.
##STR00068##
Preparation 644
Ingenol-5,20-acetonide-3-(1-tert-butyloxycarbonyl-3,3-dimethylpyrrolidine--
2-carboxylate) (Compound 644)
[0546] Compound 644 was prepared according to Procedure c.
[0547] Starting material:
1-tert-Butyloxycarbonyl-3,3-dimethylpyrrolidine-2-carboxylic
acid.
##STR00069##
Preparation 645
Ingenol-5,20-acetonide-3-((2S)-1-phenylpyrrolidine-2-carboxylate)
(Compound 645)
[0548] Compound 645 was prepared according to Procedure a, but
replacing dichloromethane with acetonitrile and reacting at
90.degree. C. for 18 h.
[0549] Starting material: (2S)-1-phenylpyrrolidine-2-carboxylic
acid.
##STR00070##
Preparation 646
Ingenol-5,20-acetonide-3-(1-isopropyl-3,5-dimethyl-pyrazole-4-carboxylate)
(Compound 646)
[0550] Compound 646 was prepared according to Procedure d, but with
reaction temperature 160.degree. C.
[0551] Starting material:
1-Isopropyl-3,5-dimethyl-pyrazole-4-carbonyl chloride, prepared
from 1-isopropyl-3,5-dimethyl-pyrazole-4-carboxylic acid by
reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
[0552] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.09-6.06 (m, 1H),
5.80-5.77 (m, 1H), 5.73 (s, 1H), 4.42 (septet, 1H), 4.25-4.12 (m,
3H), 4.05 (s, 1H), 3.39 (s, 1H), 2.70-2.65 (m, 1H), 2.52 (s, 3H),
2.41 (s, 3H), 2.33-2.24 (m, 1H), 1.82 (d, 3H), 1.78-1.69 (m, 1H),
1.48-1.44 (m, 12H), 1.07 (s, 3H), 1.05 (s, 3H), 1.00 (d, 3H),
0.93-0.86 (m, 1H), 0.73-0.65 (m, 1H).
##STR00071##
Preparation 647
Ingenol-5,20-acetonide-3-(5-ethyl-3-isopropyl-isoxazole-4-carboxylate)
(Compound 647)
[0553] Compound 647 was prepared according to Procedure a, but
replacing dichloromethane with acetonitrile and reacting at
90.degree. C. for 18 h.
[0554] Starting material:
5-Ethyl-3-isopropyl-isoxazole-4-carboxylic acid.
##STR00072##
Preparation 648
Ingenol-5,20-acetonide-3-(2-methylindazole-3-carboxylate) (Compound
648)
[0555] Compound 648 was prepared according to Procedure a, but
replacing dichloromethane with acetonitrile and reacting at
90.degree. C. for 18 h.
[0556] Starting material: 2-methylindazole-3-carboxylic acid.
##STR00073##
Preparation 649
Ingenol-5,20-acetonide-3-(5-methyl-3-tert-butyl-isoxazole-4-carboxylate)
(Compound 648)
[0557] Compound 649 was prepared according to Procedure c.
[0558] Starting material:
5-Methyl-3-tert-butyl-isoxazole-4-carboxylic acid.
##STR00074##
Preparation 650
Ingenol-5,20-acetonide-3-(2-methyl-3-oxo-4-oxaspiro[4.5]dec-1-ene-1-carbox-
ylate) (Compound 650)
[0559] Compound 650 was prepared according to Procedure c, but
keeping the reaction temperature at 140.degree. C. for 1 h.
[0560] Starting material:
2-Methyl-3-oxo-4-oxaspiro[4.5]dec-1-ene-1-carboxylic acid.
##STR00075##
Preparation 651
Ingenol-5,20-acetonide-3-(1-tert-butyl-3,5-dimethyl-pyrazole-4-carboxylate-
) (Compound 651)
[0561] Compound 651 was prepared according to Procedure c.
[0562] Starting material:
1-tert-Butyl-3,5-dimethyl-pyrazole-4-carboxylic acid.
##STR00076##
Preparation 652
Ingenol-5,20-acetonide-3-(3,5-dimethylisothiazole-4-carboxylate)
(Compound 652)
[0563] Compound 652 was prepared according to Procedure c.
[0564] Starting material: 3,5-Dimethylisothiazole-4-carboxylic
acid.
##STR00077##
Preparation 653
Ingenol-5,20-acetonide-3-(5-iodo-3-methyl-isothiazole-4-carboxylate)
(Compound 653)
[0565] Compound 653 was prepared according to Procedure c.
[0566] Starting material: 5-Iodo-3-methyl-isothiazole-4-carboxylic
acid.
##STR00078##
Preparation 654
Ingenol-5,20-acetonide-3-(4-(4-methoxyphenyl)-2-methyl-pyrazole-3-carboxyl-
ate) (Compound 654)
[0567] Compound 654 was prepared according to Procedure d.
[0568] Starting material:
4-(4-Methoxyphenyl)-2-methyl-pyrazole-3-carbonyl chloride, prepared
from 4-(4-methoxyphenyl)-2-methyl-pyrazole-3-carboxylic acid by
reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
4-(4-Methoxyphenyl)-2-methyl-pyrazole-3-carboxylic acid was
prepared according to Procedure k with (4-methoxyphenyl)boronic
acid as starting material.
[0569] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.43 (s, 1H),
7.28-7.23 (m, 2H), 6.88-6.82 (m, 2H), 5.95-5.94 (m, 1H), 5.76-5.71
(m, 1H), 5.71 (s, 1H), 4.22 (s, 3H), 4.20-4.00 (m, 3H), 3.96 (t,
1H), 3.81 (s, 3H), 3.07 (s, 1H), 2.04-1.94 (m, 1H), 1.75-1.70 (m,
4H), 1.52-1.45 (m, 4H), 1.41 (s, 3H), 1.02 (s, 6H), 0.90-0.78 (m,
1H), 0.68 (d, 3H), 0.63-0.55 (m, 1H).
##STR00079##
Preparation 655
Ingenol-5,20-acetonide-3-(4-(2-methylphenyl)-2-methyl-pyrazole-3-carboxyla-
te) (Compound 655)
[0570] Compound 655 was prepared according to Procedure d, but with
reaction temperature 100.degree. C.
[0571] Starting material:
4-(2-Methylphenyl)-2-methyl-pyrazole-3-carbonyl chloride, prepared
from 4-(2-methylphenyl)-2-methyl-pyrazole-3-carboxylic acid by
reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
4-(2-Methylphenyl)-2-methyl-pyrazole-3-carboxylic acid was prepared
according to Procedure k with (2-methylphenyl)boronic acid as
starting material.
[0572] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.37 (s, 1H),
7.22-7.09 (m, 4H), 5.83-5.82 (m, 1H), 5.74-5.72 (m, 1H), 5.60 (s,
1H), 4.25 (s, 3H), 4.21-3.99 (m, 3H), 3.91 (s, 1H), 2.99 (s, 1H),
2.14 (s, 3H), 2.04-1.95 (m, 1H), 1.72-1.67 (m, 1H), 1.58-1.53 (d,
4H), 1.47 (s, 3H), 1.39 (s, 3H), 1.03 (s, 6H), 0.84-0.77 (m, 1H),
0.69 (d, 3H), 0.64-0.56 (m, 1H).
##STR00080##
Preparation 656
Ingenol-5,20-acetonide-3-(2-methyl-4-(4-methylsulfonylphenyl)pyrazole-3-ca-
rboxylate) (Compound 656)
[0573] Compound 656 was prepared according to Procedure d, but with
reaction temperature 100.degree. C.
[0574] Starting material:
4-(4-methylsulfonylphenyl)-2-methyl-pyrazole-3-carbonyl chloride,
prepared from
4-(4-methylsulfonylphenyl)-2-methyl-pyrazole-3-carboxylic acid by
reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
4-(4-Methylsulfonylphenyl)-2-methyl-pyrazole-3-carboxylic acid was
prepared according to Procedure k with
(4-methylsulfonylphenyl)boronic acid as starting material.
[0575] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.97-7.89 (m, 2H),
7.63-7.54 (m, 2H), 7.51 (s, 1H), 5.98-5.96 (m, 1H), 5.78-5.75 (m,
1H), 5.68 (s, 1H), 4.25 (s, 3H), 4.20-3.98 (m, 4H), 3.18 (s, 1H),
3.06 (s, 3H), 2.12-2.03 (m, 1H), 1.92-1.87 (m, 1H), 1.69 (d, 3H),
1.59-1.50 (m, 1H), 1.48 (s, 3H), 1.43 (s, 3H), 1.03 (s, 3H), 1.02
(s, 3H), 0.86-0.79 (m, 1H), 0.68 (d, 3H), 0.65-0.57 (m, 1H).
##STR00081##
Preparation 657
Ingenol-5,20-acetonide-3-(2-methyl-4-phenyl-pyrazole-3-carboxylate)
(Compound 657)
[0576] Compound 657 was prepared according to Procedure d, but with
reaction temperature 100.degree. C.
[0577] Starting material: 2-methyl-4-phenyl-pyrazole-3-carbonyl
chloride, prepared from 2-methyl-4-phenyl-pyrazole-3-carboxylic
acid by reaction with 1.25 eq. oxalyl chloride in dichloromethane
and a drop of dimethylformamide at room temperature for 30 min
followed by evaporation of volatiles in vacuum.
2-Methyl-4-phenyl-pyrazole-3-carboxylic acid was prepared according
to Procedure k with phenylboronic acid as starting material.
[0578] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.46 (s, 1H),
7.34-7.28 (m, 5H), 5.91 (m, 1H), 5.75-5.73 (m, 1H), 5.69 (s, 1H),
4.23-3.94 (m, 7H), 3.08 (s, 1H), 2.03-1.93 (m, 1H), 1.80-1.73 (m,
1H), 1.67 (d, 3H), 1.52-1.44 (m, 4H), 1.41 (s, 3H), 1.02 (s, 3H),
1.02 (s, 3H), 0.84-0.78 (m, 1H), 0.65 (d, 3H), 0.62-0.54 (m,
1H).
##STR00082##
Preparation 658
Ingenol-5,20-acetonide-3-(3,5-dimethyl-1-phenyl-pyrazole-4-carboxylate)
(Compound 658)
[0579] Compound 658 was prepared according to Procedure d, but with
reaction temperature 140.degree. C.
[0580] Starting material:
3,5-Dimethyl-1-phenyl-pyrazole-4-carboxylic acid.
[0581] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.52-7.37 (m, 5H),
6.11-6.10 (m, 1H), 5.81-5.78 (m, 2H), 4.27-4.12 (m, 3H), 4.07 (s,
1H), 3.41 (s, 1H), 2.73-2.68 (m, 1H), 2.53 (s, 3H), 2.50 (s, 3H),
2.36-2.26 (m, 1H), 1.84 (d, 3H), 1.80-1.71 (m, 1H), 1.50 (s, 3H),
1.46 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.01 (d, 3H), 0.94-0.87
(m, 1H), 0.74-0.68 (m, 1H).
##STR00083##
Preparation 659
Ingenol-5,20-acetonide-3-(1,5-dimethyl-3-phenyl-pyrazole-4-carboxylate)
(Compound 659)
[0582] Compound 659 was prepared according to Procedure d.
[0583] Starting material:
1,5-Dimethyl-3-phenyl-pyrazole-4-carboxylic acid.
[0584] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.51-7.46 (m, 2H),
7.38-7.31 (m, 3H), 5.90-5.89 (m, 1H), 5.74-5.71 (m, 2H), 4.16-3.94
(m, 4H), 3.84 (s, 3H), 3.12 (s, 1H), 2.60 (s, 3H), 2.03-1.93 (m,
1H), 1.85-1.80 (m, 1H), 1.71 (d, 3H), 1.52-1.46 (m, 4H), 1.39 (s,
3H), 1.02 (s, 3H), 1.02 (s, 3H), 0.85-0.79 (m, 1H), 0.67 (d, 3H),
0.63-0.55 (m, 1H).
##STR00084##
Preparation 660
Ingenol-5,20-acetonide-3-(1-benzyl-3,5-dimethyl-pyrazole-4-carboxylate)
(Compound 660)
[0585] Compound 660 was prepared according to Procedure d.
[0586] Starting material:
1-Benzyl-3,5-dimethyl-pyrazole-4-carboxylic acid.
[0587] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.36-7.25 (m, 3H),
7.14-7.11 (m, 2H), 6.09-6.07 (m, 1H), 5.80-5.77 (m, 1H), 5.73 (s,
1H), 5.24 (s, 2H), 4.26-4.11 (m, 3H), 4.05 (s, 1H), 3.38 (s, 1H),
2.69-2.64 (m, 1H), 2.47 (s, 3H), 2.44 (s, 3H), 2.33-2.23 (m, 1H),
1.81 (d, 3H), 1.78-1.70 (m, 1H), 1.47 (s, 3H), 1.43 (s, 3H), 1.07
(s, 3H), 1.05 (s, 3H), 0.99 (d, 3H), 0.94-0.86 (m, 1H), 0.73-0.65
(m, 1H).
##STR00085##
Preparation 661
Ingenol-5,20-acetonide-3-(3,5-dimethyl-1-(tetrahydropyran-4-ylmethyl)pyraz-
ole-4-carboxylate) (Compound 661)
[0588] Compound 661 was prepared by heating a mixture of
ingenol-5,20-acetonide-3-(3,5-dimethyl-1H-pyrazole-4-carboxylate)
(15 mg), 4-iodomethyl-tetrahydro-2H-pyran (80 mg) and potassium
carbonate (40 mg) in N,N-dimethylformamide (0.5 ml) at 120.degree.
C. in a microwave oven for 20 min. Addition of water and extraction
with dichloromethane, followed by evaporation of solvent, gave a
crude product which was purified by chromatography as described in
Procedure c to give the title compound.
Ingenol-5,20-acetonide-3-(3,5-dimethyl-1H-pyrazole-4-carboxylat- e)
was prepared by Procedure c with
3,5-dimethyl-1H-pyrazole-4-carboxylic acid as starting
material.
##STR00086##
Preparation 662
Ingenol-5,20-acetonide-3-(4-methyl-2-oxo-3H-thiazole-5-carboxylate)
(Compound 662)
[0589] Compound 662 was prepared according to Procedure d.
[0590] Starting material: 4-Methyl-2-oxo-3H-thiazole-5-carbonyl
chloride, prepared from 4-methyl-2-oxo-3H-thiazole-5-carboxylic
acid by reaction with 1.25 eq. oxalyl chloride in dichloromethane
and a drop of dimethylformamide at room temperature for 30 min
followed by evaporation of volatiles in vacuum.
##STR00087##
Preparation 663
Ingenol-5,20-acetonide-3-(2-methyl-4,5,6,7-tetrahydroindazole-3-carboxylat-
e) (Compound 663)
[0591] Compound 663 was prepared according to Procedure d.
[0592] Starting material:
2-Methyl-4,5,6,7-tetrahydroindazole-3-carbonyl chloride, prepared
from 2-methyl-4,5,6,7-tetrahydroindazole-3-carboxylic acid by
reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
[0593] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.12-6.11 (m, 1H),
5.81-5.79 (m, 1H), 5.72 (s, 1H), 4.28-4.06 (m, 7H), 3.30 (s, 1H),
2.72-2.61 (m, 5H), 2.32-2.23 (m, 1H), 1.82-1.66 (m, 8H), 1.49 (s,
3H), 1.45 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.01 (d, 3H),
0.93-0.87 (m, 1H), 0.73-0.65 (m, 1H).
##STR00088##
Preparation 664
Ingenol-5,20-acetonide-3-(1,2-dimethylindole-3-carboxylate)
(Compound 664)
[0594] Compound 664 was prepared according to Procedure d.
[0595] Starting material: 1,2-dimethylindole-3-carbonyl chloride,
prepared from 1,2-dimethylindole-3-carboxylic acid by reaction with
1.25 eq. oxalyl chloride in dichloromethane and a drop of
dimethylformamide at room temperature for 30 min followed by
evaporation of volatiles in vacuum.
[0596] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.12-8.09 (m, 1H),
7.32-7.18 (m, 3H), 6.14 (m, 1H), 5.84 (s, 1H), 5.79-5.77 (m, 1H),
4.26-4.10 (m, 4H), 3.70 (s, 3H), 3.55 (s, 1H), 2.84-2.77 (m, 4H),
2.33-2.24 (m, 1H), 1.88 (d, 3H), 1.74-1.63 (m, 1H), 1.51 (s, 3H),
1.46 (s, 3H), 1.06-1.03 (m, 9H), 0.93-87 (m, 1H), 0.72-0.64 (m,
1H).
##STR00089##
Preparation 665
Ingenol-5,20-acetonide-3-(5-methoxy-1,2-dimethyl-indole-3-carboxylate)
(Compound 665)
[0597] Compound 665 was prepared according to Procedure d, but
extending reaction time to 75 min.
[0598] Starting material: 5-Methoxy-1,2-dimethyl-indole-3-carbonyl
chloride, prepared from 5-methoxy-1,2-dimethyl-indole-3-carboxylic
acid by reaction with 1.25 eq. oxalyl chloride in dichloromethane
and a drop of dimethylformamide at room temperature for 30 min
followed by evaporation of volatiles in vacuum.
[0599] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.64 (d, 1H), 7.18
(d, 1H), 6.87 (dd, 1H), 6.14-6.12 (m, 1H), 5.84 (s, 1H), 5.80-5.77
(m, 1H), 4.26-4.07 (m, 4H), 3.84 (s, 3H), 3.67 (s, 3H), 3.63 (s,
1H), 2.81-2.75 (m, 4H), 2.32-2.22 (m, 1H), 1.89 (d, 3H), 1.74-1.65
(m, 1H), 1.51 (s, 3H), 1.46 (s, 3H), 1.06 (s, 3H), 1.03 (s, 3H),
1.02 (d, 3H), 0.97-0.87 (m, 1H), 0.71-0.63 (m, 1H).
##STR00090##
Preparation 666
Ingenol-5,20-acetonide-3-(1,3,5-trimethylpyrazole-4-carboxylate)
(Compound 666)
[0600] Compound 666 was prepared according to Procedure d.
[0601] Starting material: 1,3,5-Trimethylpyrazole-4-carbonyl
chloride, prepared from 1,3,5-trimethylpyrazole-4-carboxylic acid
by reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
[0602] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.09-6.08 (m, 1H),
5.80-5.77 (m, 1H), 5.73 (s, 1H), 4.26-4.05 (m, 4H), 3.73 (s, 3H),
3.39 (s, 1H), 2.69-2.64 (m, 1H), 2.49 (s, 3H), 2.39 (s, 3H),
2.33-2.23 (m, 1H), 1.82 (d, 3H), 1.77-1.68 (m, 1H), 1.48 (s, 3H),
1.44 (s, 3H), 1.07 (s, 3H), 1.05 (s, 3H), 1.00 (d, 3H), 0.93-0.86
(m, 1H), 0.73-0.65 (m, 1H).
##STR00091##
Preparation 667
Ingenol-5,20-acetonide-3-(4-methyl-1,2,5-oxadiazole-3-carboxylate)
(Compound 667)
[0603] Compound 667 was prepared according to Procedure d.
[0604] Starting material: 4-Methyl-1,2,5-oxadiazole-3-carbonyl
chloride, prepared from 4-methyl-1,2,5-oxadiazole-3-carboxylic acid
by reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
##STR00092##
Preparation 668
Ingenol-5,20-acetonide-3-(2-methoxy-4-methyl-thiazole-5-carboxylate)
(Compound 668)
[0605] Compound 668 was prepared according to Procedure d.
[0606] Starting material: 2-Methoxy-4-methyl-thiazole-5-carbonyl
chloride, prepared from 2-methoxy-4-methyl-thiazole-5-carboxylic
acid by reaction with 1.25 eq. oxalyl chloride in dichloromethane
and a drop of dimethylformamide at room temperature for 30 min
followed by evaporation of volatiles in vacuum.
##STR00093##
Preparation 669
Ingenol-5,20-acetonide-3-(4,5-dimethylisoxazole-3-carboxylate)
(Compound 669)
[0607] Compound 669 was prepared according to Procedure d.
[0608] Starting material: 4,5-Dimethylisoxazole-3-carbonyl
chloride, prepared from 2-methoxy-4-methyl-thiazole-5-carboxylic
acid by reaction with 1.25 eq. oxalyl chloride in dichloromethane
and a drop of dimethylformamide at room temperature for 30 min
followed by evaporation of volatiles in vacuum.
##STR00094##
Preparation 670
Ingenol-5,20-acetonide-3-(4-bromo-1-methyl-pyrazole-3-carboxylate)
(Compound 670)
[0609] Compound 670 was prepared according to Procedure d.
[0610] Starting material: 4-Bromo-1-methyl-pyrazole-3-carbonyl
chloride, prepared from 4-bromo-1-methyl-pyrazole-3-carboxylic acid
by reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
##STR00095##
Preparation 671
Ingenol-5,20-acetonide-3-(1,3-dimethylindole-2-carboxylate)
(Compound 671)
[0611] Compound 671 was prepared according to Procedure d.
[0612] Starting material: 1,3-Dimethylindole-2-carbonyl chloride,
prepared from 1,3-dimethylindole-2-carboxylic acid by reaction with
1.25 eq. oxalyl chloride in dichloromethane and a drop of
dimethylformamide at room temperature for 30 min followed by
evaporation of volatiles in vacuum.
##STR00096##
Preparation 672
Ingenol-5,20-acetonide-3-(5-methoxy-1,3-dimethyl-indole-2-carboxylate)
(Compound 672)
[0613] Compound 672 was prepared according to Procedure d.
[0614] Starting material: 5-Methoxy-1,3-dimethyl-indole-2-carbonyl
chloride, prepared from 5-methoxy-1,3-dimethyl-indole-2-carboxylic
acid by reaction with 1.25 eq. oxalyl chloride in dichloromethane
and a drop of dimethylformamide at room temperature for 30 min
followed by evaporation of volatiles in vacuum.
##STR00097##
Preparation 673
Ingenol-5,20-acetonide-3-(2,4-dimethyl-6-oxo-pyran-3-carboxylate)
(Compound 673)
[0615] Compound 673 was prepared according to Procedure c.
[0616] Starting material: 2,4-Dimethyl-6-oxo-pyran-3-carboxylic
acid.
##STR00098##
Preparation 674
Ingenol-5,20-acetonide-3-(1-methyl-3-phenyl-indole-2-carboxylate)
(Compound 674)
[0617] Compound 674 was prepared according to Procedure d.
[0618] Starting material: 1-Methyl-3-phenyl-indole-2-carbonyl
chloride, prepared from 1-methyl-3-phenyl-indole-2-carboxylic acid
by reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
##STR00099##
Preparation 675
Ingenol-5,20-acetonide-3-(3-methyl-5-(trifluoromethyl)isoxazole-4-carboxyl-
ate) (Compound 675)
[0619] Compound 675 was prepared according to Procedure c.
[0620] Starting material:
3-Methyl-5-(trifluoromethyl)isoxazole-4-carboxylic acid.
##STR00100##
Preparation 676
Ingenol-5,20-acetonide-3-(1,3-dimethylpyrrole-2-carboxylate)
(Compound 676)
[0621] Compound 676 was prepared according to Procedure c, but
changing the reaction conditions to 60 min at 140.degree. C.
[0622] Starting material: 1,3-Dimethylpyrrole-2-carboxylic
acid.
##STR00101##
Preparation 677
Ingenol-5,20-acetonide-3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4--
carboxylate) (Compound 677)
[0623] Compound 677 was prepared according to Procedure d.
[0624] Starting material:
3,5-Dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonyl chloride,
prepared from 2,2,2-trifluoroethyl)pyrazole-4-carboxylic acid by
reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
[0625] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.11-6.09 (m, 1H),
5.80-5.79 (m, 1H), 5.73 (s, 1H), 4.61 (q, 2H), 4.27-4.05 (m, 4H),
3.35 (s, 1H), 2.68-2.61 (m, 1H), 2.56 (s, 3H), 2.41 (s, 3H),
2.35-2.24 (m, 1H), 1.82 (d, 3H), 1.79-1.70 (m, 1H), 1.48 (s, 3H),
1.45 (s, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.01 (d, 3H), 0.93-0.86
(m, 1H), 0.73-0.65 (m, 1H).
##STR00102##
Preparation 678
Ingenol-5,20-acetonide-3-(1-cyclopropyl-2,5-dimethyl-pyrrole-3-carboxylate-
) (Compound 678)
[0626] Compound 678 was prepared according to Procedure d, but
extending the reaction time to 60 min.
[0627] Starting material:
1-Cyclopropyl-2,5-dimethyl-pyrrole-3-carbonyl chloride, prepared
from 1-cyclopropyl-2,5-dimethyl-pyrrole-3-carboxylic acid by
reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
[0628] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.16 (m, 1H),
6.04-6.02 (m, 1H), 5.77-5.74 (m, 1H), 5.73 (s, 1H), 4.18-4.13 (m,
3H), 4.03 (s, 1H), 3.36 (s, 1H), 2.94-2.86 (m, 1H), 2.71-2.66 (m,
1H), 2.59 (s, 3H), 2.32-2.23 (m, 4H), 1.80-1.71 (m, 4H), 1.46 (s,
3H), 1.42 (s, 3H), 1.13-1.07 (m, 5H), 1.04 (s, 3H), 1.02 (d, 3H),
0.94-0.88 (m, 3H), 0.73-0.65 (m, 1H).
##STR00103##
Preparation 679
Ingenol-5,20-acetonide-3-(1,2,5-trimethylpyrrole-3-carboxylate)
(Compound 679)
[0629] Compound 679 was prepared according to Procedure d, but
extending the reaction time to 100 min.
[0630] Starting material: 1,2,5-Trimethylpyrrole-3-carbonyl
chloride, prepared from 1,2,5-trimethylpyrrole-3-carboxylic acid by
reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
[0631] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.22-6.21 (m, 1H),
6.04-6.02 (m, 1H), 5.77-5.73 (m, 2H), 4.19-4.14 (m, 3H), 4.03 (s,
1H), 3.40 (s, 3H), 3.38 (s, 1H), 2.72-2.66 (m, 1H), 2.51 (s, 3H),
2.32-2.23 (m, 1H), 2.19 (d, 3H), 1.80 (d, 3H), 1.78-1.71 (m, 1H),
1.47 (s, 3H), 1.42 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H), 1.02 (d,
3H), 0.94-0.88 (m, 1H), 0.73-0.65 (m, 1H).
##STR00104##
Preparation 680
Ingenol-5,20-acetonide-3-(2,4-dimethyl-1H-pyrrole-3-carboxylate)
(Compound 680)
[0632] Compound 680 was prepared according to Procedure d.
[0633] Starting material: 2,4-Dimethyl-1H-pyrrole-3-carbonyl
chloride, prepared from 2,4-dimethyl-1H-pyrrole-3-carboxylic acid
by reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
[0634] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.40 bs, 1H),
6.11-6.10 (m, 1H), 5.96-5.95 (m, 1H), 5.86-5.83 (m, 1H), 5.75 (s,
1H), 4.30-4.10 (m, 4H), 3.72 (bs, 1H), 2.66-2.61 (m, 1H), 2.41 (s,
3H), 2.33-2.23 (m, 4H), 1.87-1.76 (m, 4H), 1.47 (s, 3H), 1.46 (s,
3H), 1.12 (s, 3H), 1.07 (s, 3H), 0.97 (d, 3H), 0.95-0.89 (m, 1H),
0.77-0.69 (m, 1H).
##STR00105##
Preparation 681
Ingenol-5,20-acetonide-3-(1-methylpyrrole-2-carboxylate) (Compound
681)
[0635] Compound 681 was prepared according to Procedure d.
[0636] Starting material: 1-Methylpyrrole-2-carbonyl chloride,
prepared from 1-methylpyrrole-2-carboxylic acid by reaction with
1.25 eq. oxalyl chloride in dichloromethane and a drop of
dimethylformamide at room temperature for 30 min followed by
evaporation of volatiles in vacuum.
##STR00106##
Preparation 682
Ingenol-5,20-acetonide-3-(4-methyl-1H-pyrrole-2-carboxylate)
(Compound 682)
[0637] Compound 682 was prepared according to Procedure d, but
extending the reaction time to 75 min.
[0638] Starting material: 4-Methyl-1H-pyrrole-2-carbonyl chloride,
prepared from 4-methyl-1H-pyrrole-2-carboxylic acid by reaction
with 1.25 eq. oxalyl chloride in dichloromethane and a drop of
dimethylformamide at room temperature for 30 min followed by
evaporation of volatiles in vacuum.
[0639] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.97 (bs, 1H),
6.76-6.72 (m, 2H), 6.08-6.07 (m, 1H), 5.79-5.76 (m, 1H), 5.70 (s,
1H), 4.25-4.12 (m, 3H), 4.04-4.03 (m, 1H), 3.29 (s, 1H), 2.67-2.62
(m, 1H), 2.31-2.21 (m, 1H), 2.12 (s, 3H), 1.82-1.73 (m, 4H), 1.47
(s, 3H), 1.43 (s, 3H), 1.08 (s, 3H), 1.04 (s, 3H), 1.03 (d, 3H),
0.95-0.88 (m, 1H), 0.74-0.66 (m, 1H).
##STR00107##
Preparation 683
Ingenol-5,20-acetonide-3-(1,5-dimethylpyrrole-2-carboxylate)
(Compound 683)
[0640] Compound 683 was prepared according to Procedure c, but
extending the reaction time to 40 min.
[0641] Starting material: 1,5-Dimethylpyrrole-2-carboxylic
acid.
##STR00108##
Preparation 684
Ingenol-5,20-acetonide-3-(3-methyl-1H-pyrrole-2-carboxylate)
(Compound 684)
[0642] Compound 684 was prepared according to Procedure c, but
extending the reaction time to 40 min.
[0643] Starting material: 3-Methyl-1H-pyrrole-2-carboxylic
acid.
[0644] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.93 (bs, 1H),
6.86 (t, 1H), 6.12-6.08 (m, 2H), 5.80-5.77 (m, 1H), 5.71 (s, 1H),
4.26-4.13 (m, 3H), 4.05-4.04 (m, 1H), 3.38 (s, 1H), 2.69-2.64 (m,
1H), 2.35-2.23 (m, 4H), 1.82 (d, 3H), 1.79-1.70 (m, 1H), 1.48 (s,
3H), 1.44 (s, 3H), 1.07 (s, 3H), 1.04 (s, 3H), 1.02 (d, 3H),
0.94-0.88 (m, 1H), 0.73-0.65 (m, 1H).
##STR00109##
Preparation 685
Ingenol-5,20-acetonide-3-(1-cyclopropylpyrrole-2-carboxylate)
(Compound 685)
[0645] Compound 685 was prepared according to Procedure d.
[0646] Starting material: 1-Cyclopropylpyrrole-2-carbonyl chloride,
prepared from 1-cyclopropylpyrrole-2-carboxylic acid by reaction
with 1.25 eq. oxalyl chloride in dichloromethane and a drop of
dimethylformamide at room temperature for 30 min followed by
evaporation of volatiles in vacuum.
[0647] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.92 (dd, 1H),
6.88 (t, 1H), 6.09-6.06 (m, 2H), 5.79-5.75 (m, 2H), 4.24-4.13 (m,
3H), 4.05-4.04 (m, 1H), 3.79-3.71 (m, 1H), 3.32 (s, 1H), 2.70-2.65
(m, 1H), 2.32-2.23 (m, 1H), 1.84-1.73 (m, 4H), 1.47 (s, 3H), 1.44
(s, 3H), 1.09 (s, 3H), 1.05-0.88 (m, 11H), 0.74-0.66 (m, 1H).
##STR00110##
Preparation 686
Ingenol-5,20-acetonide-3-(1-ethyl-2,4-dimethyl-pyrrole-3-carboxylate)
(Compound 686)
[0648] Compound 686 was prepared according to Procedure d.
[0649] Starting material: 1-Ethyl-2,4-dimethyl-pyrrole-3-carbonyl
chloride, prepared from 1-ethyl-2,4-dimethyl-pyrrole-3-carboxylic
acid by reaction with 1.25 eq. oxalyl chloride in dichloromethane
and a drop of dimethylformamide at room temperature for 30 min
followed by evaporation of volatiles in vacuum.
[0650] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.33-6.32 (m, 1H),
6.06-6.04 (m, 1H), 5.77-5.75 (m, 2H), 4.21-4.17 (m, 3H), 4.04 (s,
1H), 3.81 (t, 2H), 3.54 (s, 1H), 2.74-2.69 (m, 1H), 2.50 (s, 3H),
2.34-2.24 (m, 1H), 2.21 (s, 3H), 1.82 (d, 3H), 1.76-1.67 (m, 1H),
1.47 (s, 3H), 1.42 (s, 3H), 1.33 (t, 3H), 1.07 (s, 3H), 1.04 (s,
3H), 0.99 (d, 3H), 0.93-0.86 (m, 1H), 0.72-0.64 (m, 1H).
##STR00111##
Preparation 687
Ingenol-5,20-acetonide-3-(1-allyl-2,4-dimethyl-pyrrole-3-carboxylate)
(Compound 687)
[0651] Compound 687 was prepared according to Procedure d.
[0652] Starting material: 1-Allyl-2,4-dimethyl-pyrrole-3-carbonyl
chloride, prepared from 1-allyl-2,4-dimethyl-pyrrole-3-carboxylic
acid by reaction with 1.25 eq. oxalyl chloride in dichloromethane
and a drop of dimethylformamide at room temperature for 30 min
followed by evaporation of volatiles in vacuum.
##STR00112##
Preparation 688
Ingenol-5,20-acetonide-3-(1-(cyclopropylmethyl)-2,4-dimethyl-pyrrole-3-car-
boxylate) (Compound 688)
[0653] Compound 688 was prepared according to Procedure d.
[0654] Starting material:
1-(Cyclopropylmethyl)-2,4-dimethyl-pyrrole-3-carbonyl chloride,
prepared from
1-(cyclopropylmethyl)-2,4-dimethyl-pyrrole-3-carboxylic acid by
reaction with 1.25 eq. oxalyl chloride in dichloromethane and a
drop of dimethylformamide at room temperature for 30 min followed
by evaporation of volatiles in vacuum.
##STR00113##
Preparation 689
Ingenol-5,20-acetonide-3-(1-(2-methoxyethyl)-2,4-dimethyl-pyrrole-3-carbox-
ylate) (Compound 689)
[0655] Compound 689 was prepared according to Procedure d.
[0656] Starting material:
1-(2-Methoxyethyl)-2,4-dimethyl-pyrrole-3-carbonyl chloride,
prepared from 1-(2-methoxyethyl)-2,4-dimethyl-pyrrole-3-carboxylic
acid by reaction with 1.25 eq. oxalyl chloride in dichloromethane
and a drop of dimethylformamide at room temperature for 30 min
followed by evaporation of volatiles in vacuum.
[0657] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.36 (m, 1H),
6.06-6.04 (m, 1H), 5.77-5.75 (m, 2H), 4.21-4.14 (m, 3H), 4.04 (s,
1H), 3.94 (t, 2H), 3.58 (t, 2H), 3.53 (s, 1H), 3.33 (s, 3H),
2.73-2.68 (m, 1H), 2.51 (s, 3H), 2.33-2.23 (m, 1H), 2.20 (d, 3H),
1.81 (d, 3H), 1.76-1.67 (m, 1H), 1.47 (s, 3H), 1.42 (s, 3H), 1.07
(s, 3H), 1.04 (s, 3H), 0.99 (d, 3H), 0.93-0.86 (m, 1H), 0.72-0.64
(m, 1H).
##STR00114##
Preparation 801
Ingenol-5,20-acetonide-3-(N-ethyl-carbamate) (Compound 801)
[0658] Compound 801 was prepared according to Procedure i.
[0659] Starting material: Ethyl isocyanate.
##STR00115##
Preparation 802
Ingenol-5,20-acetonide-3-(N,N-dimethyl-carbamate) (Compound
802)
[0660] Compound 802 was prepared according to Procedure g.
[0661] Starting material: N,N-Dimethylcarbamoyl chloride.
##STR00116##
Preparation 803
Ingenol-5,20-acetonide-3-(morpholine-4-carboxylate) (Compound
803)
[0662] Compound 803 was prepared according to Procedure g.
[0663] Starting material: Morpholine-4-carbonyl chloride.
[0664] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.04-6.03 (m, 1H),
5.77-5.76 (m, 1H), 5.45 (s, 1H), 4.23-4.12 (m, 3H), 3.97 (s, 1H),
3.70-3.63 (m, 4H), 3.50-3.47 (m, 5H), 2.52-2.47 (m, 1H), 2.34-2.25
(m, 1H), 1.78 (d, 3H), 1.77-1.70 (m, 1H), 1.46 (s, 3H), 1.39 (s,
3H), 1.10 (s, 3H), 1.05 (s, 3H), 0.97 (d, 3H), 0.94-0.85 (m, 1H),
0.73-0.65 (m, 1H).
##STR00117##
Preparation 804
Ingenol-5,20-acetonide-3-(pyrrolidine-1-carboxylate) (Compound
804)
[0665] Compound 804 was prepared according to Procedure g.
[0666] Starting material: Pyrrolidine-1-carbonyl chloride.
[0667] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.01 (m, 1H),
5.76-5.74 (m, 1H), 5.44 (s, 1H), 4.16-4.11 (m, 3H), 3.96 (s, 1H),
3.65 (s, 1H), 3.44-3.33 (m, 4H), 2.61-2.55 (m, 1H), 2.33-2.44 (m,
1H), 1.90-1.85 (m, 4H), 1.79 (d, 3H), 1.78-1.70 (m, 1H), 1.45 (s,
3H), 1.38 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 0.98 (d, 3H),
0.94-0.85 (m, 1H), 0.72-0.65 (m, 1H).
##STR00118##
Preparation 805
Ingenol-5,20-acetonide-3-(N-methyl-N-phenyl-carbamate) (Compound
805)
[0668] Compound 805 was prepared according to Procedure g.
[0669] Starting material: N-Methyl-N-phenyl-carbamoyl chloride.
##STR00119##
Preparation 806
Ingenol-5,20-acetonide-3-(N,N-diethyl-carbamate) (Compound 806)
[0670] Compound 806 was prepared according to Procedure g.
[0671] Starting material: N,N-Diethyl-carbamoyl chloride.
##STR00120##
Preparation 807
Ingenol-5,20-acetonide-3-(piperidine-1-carboxylate) (Compound
807)
[0672] Compound 807 was prepared according to Procedure g.
[0673] Starting material: Piperidine-1-carbonyl chloride.
##STR00121##
Preparation 808
Ingenol-5,20-acetonide-3-(N-benzyl-N-methyl-carbamate) (Compound
808)
[0674] Compound 808 was prepared according to Procedure g.
[0675] Starting material: N-Benzyl-N-methyl-carbamoyl chloride,
prepared from N-benzyl-N-methyl-amine according to Procedure f.
##STR00122##
Preparation 809
Ingenol-5,20-acetonide-3-(N-cyclohexyl-N-methyl-carbamate)
(Compound 809)
[0676] Compound 809 was prepared according to Procedure g.
[0677] Starting material: N-Cyclohexyl-N-methyl-carbamoyl chloride,
prepared from N-cyclohexyl-N-methyl-amine according to Procedure
f.
##STR00123##
Preparation 810
Ingenol-5,20-acetonide-3-(N-cyclohexyl-carbamate) (Compound
810)
[0678] Compound 810 was prepared according to Procedure i.
[0679] Starting material: Cyclohexyl isocyanate.
##STR00124##
Preparation 811
Ingenol-5,20-acetonide-3-(N-phenyl-carbamate) (Compound 811)
[0680] Compound 811 was prepared according to Procedure i.
[0681] Starting material: Phenyl isocyanate.
##STR00125##
Preparation 812
Ingenol-5,20-acetonide-3-(N-(indan-1-yl)-carbamate) (Compound
812)
[0682] Compound 812 was prepared according to Procedure i.
[0683] Starting material: Isocyanato-1-indane.
##STR00126##
Preparation 813
Ingenol-5,20-acetonide-3-(3,3-dimethyl-piperidine-1-carboxylate)
(Compound 813)
[0684] Compound 813 was prepared according to Procedure i.
[0685] Starting material: 3,3-Dimethyl-piperidine-1-carbonyl
chloride, prepared from 3,3-dimethyl-piperidine according to
Procedure f.
##STR00127##
Preparation 814
Ingenol-5,20-acetonide-3-(N-Methyl-N-tetralin-1-yl-carbamate)
(Compound 814)
[0686] Compound 814 was prepared according to Procedure i.
[0687] Starting material: N-Methyl-N-tetralin-1-yl-carbamoyl
chloride, prepared from N-methyl-N-(tetralin-1-yl)-amine according
to Procedure f.
##STR00128##
Preparation 815
Ingenol-5,20-acetonide-3-(N-(2-cyano-1-methyl-ethyl)-N-methyl-carbamate)
(Compound 815)
[0688] Compound 815 was prepared according to Procedure h.
[0689] Starting material:
N-(2-cyano-1-methyl-ethyl)-N-methyl-carbamoyl chloride, prepared
from N-(2-cyano-1-methyl-ethyl)-N-methyl-amine according to
Procedure f.
##STR00129##
Preparation 816
Ingenol-5,20-acetonide-3-(N-methyl-N-((S)-1-phenethyl)-carbamate)
(Compound 816)
[0690] Compound 816 was prepared according to Procedure h.
[0691] Starting material: N-Methyl-N-((S)-1-phenethyl)-carbamoyl
chloride, prepared from N-methyl-N-((S)-1-phenylethyl)-amine
according to Procedure f.
##STR00130##
Preparation 817
Ingenol-5,20-acetonide-3-(N-methyl-N-(cyclopropylmethyl)-carbamate)
(Compound 817)
[0692] Compound 817 was prepared according to Procedure h.
[0693] Starting material: N-(Cyclopropylmethyl)-N-methyl-carbamoyl
chloride, prepared from N-(cyclopropylmethyl)-N-methyl-amine
according to Procedure f.
[0694] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.03-6.02 (m, 1H),
5,76-5.74 (m, 1H), 5.45 (s, 1H), 4.17-4.12 (m, 3H), 3.97 (s, 1H),
3.59 (m, 1H), 3.30-3.13 (m, 2H), 2.99 (s, 3H), 2.56 (bs, 1H),
2.34-2.25 (m, 1H), 1.79-1.70 (m, 4H), 1.45 (s, 3H), 1.39 (s, 3H),
1.29 (m, 1H), 1.10 (s, 3H), 1.05 (s, 3H), 0.98 (d, 3H), 0.94-0.86
(m, 1H), 0.72-0.65 (m, 1H), 0.53-0.48 (m, 2H), 0.24-0.16 (m,
2H).
##STR00131##
Preparation 818
Ingenol-5,20-acetonide-3-(N-(3-fluoro-phenyl)-N-methyl-carbamate)
(Compound 818)
[0695] Compound 818 was prepared according to Procedure j.
[0696] Starting material: N-(3-Fluorophenyl)-N-methyl-carbamoyl
chloride, prepared from 3-fluoro-N-methyl-aniline according to
Procedure f with pyridine as the tertiary amine.
##STR00132##
Preparation 819
Ingenol-5,20-acetonide-3-(N-(2,5-dimethylpyrazol-3-yl)-N-methyl-carbamate)
(Compound 819)
[0697] Compound 819 was prepared according to Procedure h.
[0698] Starting material:
N-(2,5-Dimethylpyrazol-3-yl)-N-methyl-carbamoyl chloride, prepared
from N,1,3-trimethyl-1H-pyrazol-5-amine according to Procedure
f.
[0699] .sup.1H NMR (300 MHz, CDCl3) .delta. 5.96 (bs, 1H), 5.86 (s,
1H), 5.76-5.74 (m, 1H), 4.21-4.05 (m, 3H), 3.95 (s, 1H), 3.61 (s,
3H), 3.20 (s, 3H), 3.11 (bs, 1H), 2.21 (s, 3H), 1.84-1.74 (m, 4H),
1.57 (s, 3H), 1.45 (s, 3H), 1.38 (s, 3H), 1.07 (s, 3H), 1.04 (s,
3H), 0.90-0.83 (m, 1H), 0.75 (bd, 3H), 0.68-0.60 (m, 1H).
##STR00133##
Preparation 820
Ingenol-5,20-acetonide-3-(N-(3,5-dimethylisoxazol-4-yl)-N-methyl-carbamate-
) (Compound 820)
[0700] Compound 820 was prepared according to Procedure h.
[0701] Starting material:
N-[(3,5-Dimethylisoxazol-4-yl)methyl]-N-methyl-carbamoyl chloride,
prepared from 1-(3,5-dimethylisoxazol-4-yl)-N-methyl-methanamine
according to Procedure f.
[0702] .sup.1H NMR (300 MHz, CDCl3) .delta. 6.05 (s, 1H), 5.78-5.76
(m, 1H), 5.46 (s, 1H), 4.46 (bs, 1H), 4.24-4.11 (m, 4H), 3.98 (s,
1H), 3.52 (s, 1H), 2.78 (s, 3H), 2.50 (bs, 1H), 2.37 (s, 3H),
2.30-2.21 (m, 4H), 1.78 (d, 3H), 1.77-1.68 (m, 1H), 1.46 (s, 3H),
1.41 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.96 (d, 3H), 0.94-0.89
(m, 1H), 0.72-0.64 (m, 1H).
##STR00134##
Preparation 821
Ingenol-5,20-acetonide-3-(N-(1,5-dimethylpyrazol-3-yl)-N-methyl-carbamate)
(Compound 821)
[0703] Compound 821 was prepared according to Procedure h.
[0704] Starting material:
N-(1,5-Dimethylpyrazol-3-yl)-N-methyl-carbamoyl chloride, prepared
from N,1,5-trimethylpyrazol-3-amine according to Procedure f.
[0705] .sup.1H NMR (300 MHz, CDCl3) .delta. 5.96 (bs, 1H), 5.86 (s,
1H), 5.76-5.74 (m, 1H), 5.42 (s, 1H), 4.21-4.05 (m, 3H), 3.95 (s,
1H), 3.61 (s, 3H), 3.20 (s, 3H), 3.11 (bs, 1H), 2.21 (s, 3H),
2.12-2.02 (m, 1H), 1.82-1.64 (m, 5H), 1.45 (s, 3H), 1.38 (s, 3H),
1.07 (s, 3H), 1.04 (s, 3H), 0.90-0.85 (m, 1H), 0.75 (bs, 3H),
0.68-0.60 (m, 1H).
##STR00135##
Preparation 822
Ingenol-5,20-acetonide-3-(N-cyclopentyl-N-methyl-carbamate)
(Compound 822)
[0706] Compound 822 was prepared according to Procedure h.
[0707] Starting material: N-Cyclopentyl-N-methyl-carbamoyl
chloride, prepared from N-methylcyclopentanamine according to
Procedure f.
##STR00136##
Preparation 823
Ingenol-5,20-acetonide-3-(N-cyclopropyl-N-methyl-carbamate)
(Compound 823)
[0708] Compound 823 was prepared according to Procedure h.
[0709] Starting material: N-Cyclopropyl-N-methyl-carbamoyl
chloride, prepared from N-methylcyclopropanamine according to
Procedure f.
[0710] .sup.1H NMR (300 MHz, CDCl3) .delta. 6.04-6.01 (m, 1H),
5.77-5.74 (m, 1H), 5.47 (s, 1H), 4.17-4.12 (m, 3H), 3.98 (s, 1H),
3.52 (s, 1H), 3.27 (bs, 1H), 2.91 (s, 3H), 2.65-2.57 (m, 2H),
2.34-2.25 (m, 1H), 1.80-1.70 (m, 4H), 1.45 (s, 3H), 1.39 (s, 1H),
1.16-1.08 (m, 5H), 1.05 (s, 3H), 0.98 (d, 3H), 0.94-0.87 (m, 1H),
0.74-0.65 (m, 4H).
##STR00137##
Preparation 824
Ingenol-5,20-acetonide-3-(N-methyl-N-(2-pyridyl)-carbamate)
(Compound 824)
[0711] Compound 824 was prepared according to Procedure j.
[0712] Starting material: N-Methyl-N-(2-pyridyl)carbamoyl chloride,
prepared from N-methylpyridin-2-amine according to Procedure f.
[0713] .sup.1H NMR (300 MHz, CDCl3) .delta.8.38-8.36 (m, 1H),
7.73-7.67 (m, 1H), 7.43 (d, 1H), 7.09-7.05 (m, 1H), 6.00-5.98 (m,
1H), 5.76-5.74 (m, 1H), 5.71 (s, 1H), 5.04 (bs, 1H), 4.27-4.11 (m,
3H), 3.95 (s, 1H), 3.44 (s, 3H), 2.30-2.20 (m, 2H), 1.81 (d, 3H),
1.70-1.60 (m, 1H), 1.46 (s, 3H), 1.39 (s, 3H), 1.15 (s, 3H), 1.06
(s, 3H), 0.96-0.88 (m, 1H), 0.79 (d, 3H), 0.69-0.63 (m, 1H).
##STR00138##
Preparation 825
Ingenol-5,20-acetonide-3-(4-oxo-2,3-dihydroquinoline-1-carboxylate)
(Compound 825)
[0714] Compound 825 was prepared according to Procedure j.
[0715] Starting material: 4-Oxo-2,3-dihydroquinoline-1-carbonyl
chloride, prepared from 2,3-dihydro-1H-quinolin-4-one according to
Procedure f.
##STR00139##
Preparation 826
Ingenol-5,20-acetonide-3-(3,4-dihydro-2H-quinoline-1-carboxylate)
(Compound 826)
[0716] Compound 826 was prepared according to Procedure j.
[0717] Starting material: 3,4-Dihydro-2H-quinoline-1-carbonyl
chloride, prepared from 1,2,3,4-tetrahydroquinoline according to
Procedure f.
[0718] .sup.1H NMR (300 MHz, CDCl3) .delta. 7.68 (d, 1H), 7.16-6.98
(m, 3H), 6.03 (d, 1H), 5.77-5.75 (m, 1H), 5.58 (s, 1H), 4.23-4.11
(m, 3H), 4.00 (s, 1H), 3.82-3.72 (m, 2H), 3.39 (s, 1H), 2.79 (t,
2H), 2.46-2.41 (m, 1H), 2.29-2.20 (m, 1H), 2.01-1.92 (m, 2H), 1.81
(d, 3H), 1.71-1.63 (m, 1H), 1.46 (s, 3H), 1.41 (s, 3H), 1.08 (s,
3H), 1.04 (s, 3H), 0.92-0.83 (m, 4H), 0.71-0.63 (m, 1H).
##STR00140##
Preparation 827
Ingenol-5,20-acetonide-3-(indoline-1-carboxylate) (Compound
827)
[0719] Compound 827 was prepared according to Procedure j.
[0720] Starting material: Indoline-1-carbonyl chloride, prepared
from indoline according to Procedure f.
[0721] .sup.1H NMR (300 MHz, CDCl3) .delta. 7.87 (bs, 1H),
7.22-7.09 (m, 2H), 6.99-6.92 (m, 1H), 6.09 (bs, 1H), 5.79-5.77 (m,
1H), 5.57 (s, 1H), 4.25-4.12 (m, 3H), 4.08-4.02 (m, 3H), 3.50 (bs,
1H), 3.18-3.10 (m, 2H), 2.64 bs, 1H), 2.34-2.24 (m, 1H), 1.84 (s,
3H), 1.79-1.70 (m, 1H), 1.49 (s, 3H), 1.43 (s, 3H), 1.08 (s, 3H),
1.05 (s, 3H), 1.01 (d, 3H), 0.94-0.86 (m, 1H), 0.73-0.65 (m,
1H).
##STR00141##
Preparation 828
Ingenol-5,20-acetonide-3-(azepane-1-carboxylate) (Compound 828)
[0722] Compound 828 was prepared according to Procedure j.
[0723] Starting material: Azepane-1-carbonyl chloride, prepared
from azepane according to Procedure f.
[0724] .sup.1H NMR (300 MHz, CDCl3) .delta. 6.03-6.01 (m, 1H),
5.76-5.74 (m, 1H), 5.47 (s, 1H), 4.17-4.12 (m, 3H), 3.97 (s, 1H),
3.62 (s, 1H), 3.49-3.27 (m, 4H), 2.60-2.55 (m, 1H), 2.35-2.26 (m,
1H), 1.79-1.55 (m, 12H), 1.46 (s, 3H), 1.39 (s, 3H), 1.10 (s, 3H),
1.05 (s, 3H), 0.98 (d, 3H), 0.94-0.88 (m, 1H), 0.72-0.64 (m,
1H).
##STR00142##
Preparation 829
Ingenol-5,20-acetonide-3-(N-(4-chloro-phenyl)-N-methyl-carbamate)
(Compound 829)
[0725] Compound 829 was prepared according to Procedure j.
[0726] Starting material: N-(4-Chlorophenyl)-N-methyl-carbamoyl
chloride, prepared from 4-chloro-N-methyl-aniline according to
Procedure f.
[0727] .sup.1H NMR (300 MHz, CDCl3) .delta. 7.31 (d, 2H), 7.20 (d,
2H), 5.94 (s, 1H), 5.76-5.73 (m, 1H), 5.45 (s, 1H), 4.21-4.07 (m,
3H), 3.95 (s, 1H), 3.29 (s, 3H), 3.22 (s, 1H), 3.14 (d, 1H),
2.17-2.07 (m, 1H), 1.75 (d, 3H), 1.63-1.57 (m, 1H), 1.45 (s, 3H),
1.39 (s, 3H), 1.08 (s, 3H), 1.04 (s, 3H), 0.90-0.83 (m, 1H), 0.76
(d, 3H), 0.69-0.61 (m, 1H).
##STR00143##
Preparation 830
Ingenol-5,20-acetonide-3-(N-(4-fluoro-phenyl)-N-methyl-carbamate)
(Compound 830)
[0728] Compound 830 was prepared according to Procedure j.
[0729] Starting material: N-(4-Fluorophenyl)-N-methyl-carbamoyl
chloride, prepared from 4-fluoro-N-methyl-aniline according to
Procedure f.
[0730] .sup.1H NMR (300 MHz, CDCl3) .delta. 7.24-7.19 (m, 2H),
7.06-6.98 (m, 2H), 5.92 (bs, 1H), 5.76-5.73 (m, 1H), 5.45 (s, 1H),
4.17-4.06 (m, 3H), 3.95 (s, 1H), 3.28 (s, 3H), 3.23 (bs, 1H), 3.13
(d, 1H), 2.12-2.08 (m, 1H), 1.74 (d, 3H), 1.63-1.57 (m, 1H), 1.45
(s, 3H), 1.38 (s, 3H), 1.08 (s, 3H), 1.04 (s, 3H), 0.92-0.83 (m,
1H), 0.73 (d, 3H), 0.69-0.61 (m, 1H).
##STR00144##
Preparation 831
Ingenol-5,20-acetonide-3-(N-methyl-N-(2-methoxy-phenyl)-carbamate)
(Compound 831)
[0731] Compound 831 was prepared according to Procedure j.
[0732] Starting material: N-(2-Methoxyphenyl)-N-methyl-carbamoyl
chloride, prepared from 2-methoxy-N-methyl-aniline according to
Procedure f.
##STR00145##
Preparation 832
Ingenol-5,20-acetonide-3-(N-methyl-N-(2-methyl-phenyl)-carbamate)
(Compound 832)
[0733] Compound 832 was prepared according to Procedure j.
[0734] Starting material: N-(2-Methylphenyl)-N-methyl-carbamoyl
chloride, prepared from 2-methyl-N-methyl-aniline according to
Procedure f.
##STR00146##
Preparation 833
Ingenol-5,20-acetonide-3-(3-oxo-2,4-dihydroquinoxaline-1-carboxylate)
(Compound 833)
[0735] Compound 833 was prepared according to Procedure j.
[0736] Starting material: 3-Oxo-2,4-dihydroquinoxaline-1-carbonyl
chloride, prepared from 3,4-dihydro-1H-quinoxalin-2-one according
to Procedure f.
[0737] .sup.1H NMR (300 MHz, CDCl3) .delta. 8.82 (s, 1H), 7.72 (d,
1H), 7.15-7.01 (m, 2H), 6.90 (dd, 1H), 6.07-6.06 (m, 1H), 5.80-5.78
(m, 1H), 5.58 (s, 1H), 4.47 (d, 1H), 4.44 (d, 1H), 4.25-4.09 (m,
3H), 4.00 (s, 1H), 3.39 (s, 1H), 2.39 (bs, 1H), 2.29-2.20 (m, 1H),
1.81 (d, 3H), 1.72-1.63 (m, 1H), 1.45 (s, 3H), 1.42 (s, 3H), 1.08
(s, 3H), 1.04 (s, 3H), 0.92-0.84 (m, 4H), 0.71-0.63 (m, 1H).
##STR00147##
Preparation 834
Ingenol-5,20-acetonide-3-(N-ethyl-N-phenyl-carbamate) (Compound
834)
[0738] Compound 834 was prepared according to Procedure j.
[0739] Starting material: N-Ethyl-N-phenyl-carbamoyl chloride,
prepared from N-ethyl-aniline according to Procedure f.
[0740] .sup.1H NMR (300 MHz, CDCl3) .delta. 7.38-7.32 (m, 2H),
7.28-7.18 (m, 3H), 5.89 (s, 1H), 5.73-5.70 (m, 1H), 5.46 (s, 1H),
4.17-4.14 (m, 2H), 4.04 (bd, 1H), 3.94-3.93 (m, 1H), 3.79-3.64 (m,
2H), 3.16 (bs, 1H), 2.04-1.78 (m, 2H), 1.75 (d, 3H), 1.54-1.49 (m,
1H), 1.45 (s, 3H), 1.37 (s, 3H), 1.17 (t, 3H), 1.06 (s, 3H), 1.03
(s, 3H), 0.90-0.81 (m, 1H), 0.70-0.56 (m, 4H).
##STR00148##
Preparation 835
Ingenol-5,20-acetonide-3-(2-trifluoromethyl-pyrrolidine-1-carboxylate)
(Compound 835)
[0741] Compound 835 was prepared according to Procedure j.
[0742] Starting material: 2-(Trifluoromethyl)pyrrolidine-1-carbonyl
chloride, prepared from 2-(trifluoromethyl)pyrrolidine according to
Procedure f.
##STR00149##
Preparation 836
Ingenol-5,20-acetonide-3-(3-azabicyclo[3.2.2]nonane-3-carboxylate)
(Compound 836)
[0743] Compound 836 was prepared according to Procedure j.
[0744] Starting material: 3-Azabicyclo[3.2.2]nonane-3-carbonyl
chloride, prepared from 3-azabicyclo[3.2.2]nonane according to
Procedure f.
##STR00150##
Preparation 837
Ingenol-5,20-acetonide-3-(2,3-dihydro-1,4-benzoxazine-4-carboxylate)
(Compound 837)
[0745] Compound 837 was prepared according to Procedure j.
[0746] Starting material: 2,3-Dihydro-1,4-benzoxazine-4-carbonyl
chloride, prepared from 2,3-dihydro-1,4-benzoxazine according to
Procedure f.
##STR00151##
Preparation 838
Ingenol-5,20-acetonide-3-(N-(2-fluoro-phenyl)-N-methyl-carbamate)
(Compound 838)
[0747] Compound 838 was prepared according to Procedure j.
[0748] Starting material: N-(2-Fluoro-phenyl)-N-methyl-carbamoyl
chloride, prepared from 2-fluoro-N-methyl-aniline according to
Procedure f.
[0749] .sup.1H NMR (300 MHz, CDCl3) .delta. 7.29-7.21 (m, 2H),
7.14-7.06 (m, 2H), 5.87 (bs, 1H), 5.73-5.72 (m, 1H), 5.46 (s, 1H),
4.16-4.14 (m, 2H), 4.09-4.02 (m, 1H), 3.93 (s, 1H), 3.27 (s, 3H),
3.21 (s, 1H), 2.09-2.00 (m, 1H), 1.73 (bs, 4H), 1.52-1.45 (m, 4H),
1.38 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H), 0.88-0.82 (m, 1H),
0.65-0.55 (m, 4H).
##STR00152##
Preparation 839
Ingenol-5,20-acetonide-3-(3-methyl-2,3-dihydro-1,4-benzoxazine-4-carboxyla-
te) (Compound 839)
[0750] Compound 839 (a mixture of diastereomers) was prepared
according to Procedure j.
[0751] Starting material:
3-Methyl-2,3-dihydro-1,4-benzoxazine-4-carbonyl chloride, prepared
from 3-methyl-3,4-dihydro-2H-1,4-benzoxazine according to Procedure
f.
##STR00153##
Preparation 842
Ingenol-5,20-acetonide-3-(N-methyl-N-(N-(tert-butyloxycarbonyl)-4-piperidy-
l)-carbamate) (Compound 842)
[0752] Compound 842 was prepared according to Procedure j.
[0753] Starting material: tert-Butyl
4-(chlorocarbonyl(methyl)amino)piperidine-1-carboxylate, prepared
from tert-butyl 4-methylaminopiperidine-1-carboxylate according to
Procedure f.
[0754] .sup.1H NMR (300 MHz, CDCl3) .delta. 6.03-6.01 (m, 1H),
5.77-5.74 (m, 1H), 5.47 (s, 1H), 4.27-4.10 (m, 5H), 3.98 (s, 1H),
3.49-3.38 (m, 2H), 3.28 (bs, 1H), 2.78 (bs, 4H), 2.58-2.52 (m, 1H),
2.32-2.24 (m, 1H), 1.79-1.55 (m, 8H), 1.46 (s, 9H), 1.45 (s, 3H),
1.39 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.98 (d, 3H), 0.94-0.87
(m, 1H), 0.73-0.65 (m, 1H).
##STR00154##
Preparation 843
Ingenol-5,20-acetonide-3-(N-methyl-N-(3-methyl-phenyl)-carbamate)
(Compound 843)
[0755] Compound 843 was prepared according to Procedure j.
[0756] Starting material: N-Methyl-N-(3-methyl-phenyl)-carbamoyl
chloride, prepared from N,3-dimethylaniline according to Procedure
f.
##STR00155##
Preparation 844
Ingenol-5,20-acetonide-3-(3,4-dihydro-2H-quinoxaline-1-carboxylate)
(Compound 844)
[0757] Compound 844 was prepared according to Procedure j.
[0758] Starting material: 3,4-Dihydro-2H-quinoxaline-1-carbonyl
chloride, prepared from 1,2,3,4-tetrahydroquinoxaline according to
Procedure f.
[0759] .sup.1H NMR (300 MHz, CDCl3) .delta. 7.86 (bd, 1H), 7.67
(bs, 1H), 7.22-7.10 (m, 2H), 6.07-6.06 (m, 1H), 5.81-5.79 (m, 1H),
5.57 (s, 1H), 4.27-3.94 (m, 9H), 3.34 (s, 1H), 2.39 (bs, 1H),
2.30-2.21 (m, 1H), 1.82 (d, 3H), 1.73-1.64 (m, 1H), 1.47 (s, 3H),
1.43 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.92-0.84 (m, 4H),
0.71-0.63 (m, 1H).
##STR00156##
Preparation 845
Ingenol-5,20-acetonide-3-(isoindoline-2-carboxylate) (Compound
845)
[0760] Compound 845 was prepared according to Procedure j.
[0761] Starting material: Isoindoline-2-carbonyl chloride, prepared
from isoindoline according to Procedure f.
[0762] .sup.1H NMR (300 MHz, CDCl3) .delta. 7.32-7.25 (m, 4H),
6.07-6.06 (m, 1H), 5.78-5.76 (m, 1H), 5.51 (s, 1H), 4.79-4.72 (m,
4H), 4.20-4.13 (m, 3H), 4.00 (s, 1H), 3.59 (s, 1H), 2.66-2.61 (m,
1H), 2.35-2.25 (m, 1H), 1.82 (d, 3H), 1.81-1.72 (m, 1H), 1.48 (s,
3H), 1.41 (s, 3H), 1.09 (s, 3H), 1.04 (s, 3H), 1.01 (d. 3H),
0.94-0.86 (m, 1H), 0.73-0.65 (m, 1H).
##STR00157##
Preparation 846
Ingenol-5,20-acetonide-3-(N-methyl-N-(tetrahydropyran-4-ylmethyl)-carbamat-
e) (Compound 846)
[0763] Compound 846 was prepared according to Procedure j.
[0764] Starting material:
N-Methyl-N-(tetrahydropyran-4-ylmethyl)-carbamoyl chloride,
prepared from N-methyl-1-tetrahydropyran-4-yl-methanamine according
to Procedure f.
##STR00158##
Preparation 847
Ingenol-5,20-acetonide-3-(N-methyl-N-(tetrahydropyran-4-yl)-carbamate)
(Compound 847)
[0765] Compound 847 was prepared according to Procedure j.
[0766] Starting material:
N-Methyl-N-(tetrahydropyran-4-yl)-carbamoyl chloride, prepared from
N-methyltetrahydropyran-4-amine according to Procedure f.
[0767] .sup.1H NMR (300 MHz, CDCl3) .delta. 6.04-6.03 (m, 1H),
5.77-5.75 (m, 1H), 5.48 (s, 1H), 4.22-3.98 (m, 7H), 3.45 (bs, 3H),
2.82 (s, 3H), 2.58-2.52 (m, 1H), 2.33-2.24 (m, 1H), 1.85-1.58 (m,
8H), 1.45 (s, 3H), 1.39 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H), 0.99
(d, 3H), 0.94-0.86 (m, 1H), 0.73-0.65 (m, 1H).
##STR00159##
Preparation 848
Ingenol-5,20-acetonide-3-(N-methyl-N-(3-methoxy-phenyl)-carbamate)
(Compound 848)
[0768] Compound 848 was prepared according to Procedure j.
[0769] Starting material: N-Methyl-N-(3-methoxy-phenyl)-carbamoyl
chloride, prepared from N-methyl-3-methoxy-aniline according to
Procedure f.
##STR00160##
Preparation 849
Ingenol-5,20-acetonide-3-(N-cyclobutyl-N-methyl-carbamate)
(Compound 849)
[0770] Compound 849 was prepared according to Procedure h.
[0771] Starting material: N-Cyclobutyl-N-methyl-carbamoyl chloride,
prepared from N-methylcyclobutanamine according to Procedure f.
##STR00161##
Preparation 850
Ingenol-5,20-acetonide-3-(N-allyl-N-methyl-carbamate) (Compound
850)
[0772] Compound 850 was prepared according to Procedure h.
[0773] Starting material: N-Allyl-N-methyl-carbamoyl chloride,
prepared from N-methylprop-2-en-1-amine according to Procedure
f.
##STR00162##
Preparation 851
Ingenol-5,20-acetonide-3-(N-methyl-N-prop-2-ynyl-carbamate)
(Compound 851)
[0774] Compound 851 was prepared according to Procedure h.
[0775] Starting material: N-Methyl-N-prop-2-ynyl-carbamoyl
chloride, prepared from N-methylprop-2-yn-1-amine according to
Procedure f.
##STR00163##
Preparation 852
Ingenol-5,20-acetonide-3-(N-methyl-N-(4-methylthiazol-2-yl)-carbamate)
(Compound 852)
[0776] Compound 852 was prepared according to Procedure j.
[0777] Starting material:
N-Methyl-N-(4-methylthiazol-2-yl)carbamoyl chloride, prepared from
N,4-dimethylthiazol-2-amine according to Procedure f.
##STR00164##
Preparation 853
Ingenol-5,20-acetonide-3-(N-(4-cyano-phenyl)-N-methyl-carbamate)
(Compound 853)
[0778] Compound 853 was prepared according to Procedure j.
[0779] Starting material: N-(4-Cyano-phenyl)-N-methyl-carbamoyl
chloride, prepared from N-methyl-4-cyano-aniline according to
Procedure f.
##STR00165##
Example 501
Ingenol
3-(5-methyl-3-(2-chloro-6-fluoro-phenyl)-isoxazole-4-carboxylate)
(Compound 501)
[0780] Compound 501 was prepared according to Procedure e.
[0781] Starting material: Compound 601.
[0782] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.42-7.34 (m, 1H),
7.28-7.25 (m, 1H), 7.09-7.03 (m, 1H), 6.02 (d, 1H), 5.85-5.84 (m,
1H), 5.56 (s, 1H), 4.46 (d, 1H), 4.18-4.07 (m, 3H), 3.99-3.97 (m,
1H), 3.51 (s, 1H), 2.83 (s, 3H), 2.21-2.13 (m, 1H), 1.88-1.82 (m,
1H), 1.69-1.60 (m, 1H), 1.64 (d, 3H), 1.59 (s, 1H), 1.03 (s, 3H),
1.03 (s, 3H), 0.90-0.82 (m, 1H), 0.73 (d, 3H), 0.67-0.59 (m,
1H).
##STR00166##
Example 502
Ingenol 3-(5-methyl-3-phenyl-isoxazole-4-carboxylate) (Compound
502)
[0783] Compound 502 was prepared according to Procedure e.
[0784] Starting material: Compound 602.
[0785] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.56-7.53 (m, 2H),
7.48-7.38 (m, 3H), 6.00 (d, 1H), 5.94-5.93 (m, 1H), 5.66 (s, 1H),
4.31 (d, 1H), 4.16-4.01 (m, 3H), 3.98 (d, 1H), 3.36 (s, 1H), 2.77
(s, 3H), 2.29-2.25 (m, 1H), 2.05-1.96 (m, 1H), 1.80-1.74 (m, 1H),
1.74 (d, 3H), 1.27 (s, 1H), 1.03 (s, 3H), 1.02 (s, 3H), 0.90-0.82
(m, 1H), 0.71 (d, 3H), 0.65-0.57 (m, 1H).
##STR00167##
Example 503
Ingenol 3-(1S-camphanate) (Compound 503)
[0786] Compound 503 was prepared according to Procedure e.
[0787] Starting material: Compound 603.
[0788] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.09-6-05 (m, 2H),
5.69 (s, 1H), 4.28 (d, 1H), 4.21-4.12 (m, 3H), 4.03 (d, 1H), 3.62
(s, 1H), 2.55-2.42 (m, 2H), 2.31-2.21 (m, 2H), 2.12-2.03 (m, 1H),
1.99-1.89 (m, 1H), 1.80 (d, 3H), 1.77-1.65 (m, 2H), 1.13 (s, 3H),
1.09 (s, 6H), 1.05 (s, 3H), 0.98-0.86 (m, 7H), 0.74-0.66 (m,
1H).
##STR00168##
Example 504
Ingenol 3-(3-phenyltriazole-4-carboxylate) (Compound 504)
[0789] Compound 504 was prepared according to Procedure e.
[0790] Starting material: Compound 604.
[0791] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.28 (s, 1H), 7.55-7.49
(m, 5H), 6.05 (m, 1H), 6.02-6.01 (m, 1H), 5.70 (s, 1H), 4.69 (d,
1H), 4.15-4.10 (m, 3H), 4.01 (m, 1H), 3.55 (s, 1H), 2.40-2.37 (m,
1H), 2.24-2.15 (m, 2H), 1.75 (d, 3H), 1.74-1.64 (m, 1H), 1.04 (s,
3H), 1.04 (s, 3H), 0.92-0.85 (m, 4H), 0.71-0.63 (m, 1H).
##STR00169##
Example 505
Ingenol 3-(2-phenylpyrazole-3-carboxylate) (Compound 505)
[0792] Compound 505 was prepared according to Procedure e.
[0793] Starting material: Compound 605.
[0794] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 7.82 (d, 1H), 7.49-7.45
(m, 5H), 7.03 (d, 1H), 5.86-5.83 (m, 2H), 5.81 (s, 1H), 5.35 (d,
1H), 5.14 (s, 1H), 4.62 (t, 1H), 4.14-4.10 (m, 1H), 3.91-3.86 (m,
2H), 3.58 (d, 1H), 2.28-2.10 (m, 2H), 1.70 (d, 3H), 1.69-1.58 (m,
1H), 1.02 (s, 3H), 1.01 (s, 3H), 0.80-0.70 (m, 4H), 0.62-0.54 (m,
1H).
##STR00170##
Example 506
Ingenol 3-(1-methylindazole-3-carboxylate) (Compound 506)
[0795] Compound 506 was prepared according to Procedure e.
[0796] Starting material: Compound 606.
[0797] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.15-8.12 (m, 1H),
7.80-7.77 (m, 1H), 7.52-7.45 (m, 1H), 7.34-7.29 (m, 1H), 6,00 (m,
1H), 5.99 (s, 1H), 5.90-5.89 (m, 1H), 5.51 (d, 1H), 5.26 (s, 1H),
4.68 (t, 1H), 4.22-4.27 (m, 1H), 4.17 (s, 3H), 3.99-3.89 (m, 2H),
3.72 (d, 1H), 2.77-2.70 (m, 1H), 2.39-2.30 (m, 1H), 1.79 (d, 3H),
1.72-1.64 (m, 1H), 1.04 (s, 6H), 0.95 (d, 3H), 0.85-0.77 (m, 1H),
0.67-0.59 (m, 1H).
##STR00171##
Example 507
Ingenol 3-(3-ethyl-5-methyl-isoxazole-4-carboxylate) (Compound
507)
[0798] Compound 507 was prepared according to Procedure e. Compound
507 was obtained as an amorphous compound.
[0799] Starting material: Compound 607.
[0800] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.13-6.12 (m, 1H),
6.09-6.07 (m, 1H), 5.69 (s, 1H), 4.65 (bs, 1H), 4.24-4.15 (m, 3H),
4.11 (s, 1H), 3.68 (s, 1H), 2.88 (q, 2H), 2.66 (s, 3H), 2.59-2.54
(m, 1H), 2.34-2.15 (m, 2H), 1.83 (d, 3H), 1.79-1.71 (m, 1H), 1.29
(t, 3H), 1.07 (s, 3H), 1.05 (s, 3H), 1.01 (d, 3H), 0.96-0.90 (m,
1H), 0.74-0.66 (m, 1H).
##STR00172##
Example 508
Ingenol 3-(3-methyl-5-methyl-isoxazole-4-carboxylate) (Compound
508)
[0801] Compound 508 was prepared according to Procedure e.
[0802] Starting material: Compound 608.
[0803] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.12 (m, 1H), 6.08-6.07
(m, 1H), 5.69 (s, 1H), 4.74 (m, 1H), 4.23-4.16 (m, 3H), 4.11 (s,
1H), 3.71 (s, 1H), 2.66 (s, 3H), 2.59-2.54 (m, 1H), 2.43 (s, 3H),
2.36-2.26 (m, 2H), 1.84-1.71 (m, 4H), 1.07 (s, 3H), 1.06 (s, 3H),
1.01 (d, 3H), 0.95-0.89 (m, 1H), 0.74-0.66 (m, 1H).
##STR00173##
Example 509
Ingenol 3-(1-methylindole-3-carboxylate) (Compound 509)
[0804] Compound 509 was prepared according to Procedure e.
[0805] Starting material: Compound 609.
[0806] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.13-8.10 (m, 1H), 7.81
(s, 1H), 7.39-7.28 (m, 3H), 6.10 (m, 1H), 6.06 (d, 1H), 5.69 (s,
1H), 4.43 (bs, 1H), 4.17-4.12 (m, 4H), 3.86 (s, 3H), 3.69 (s, 1H),
2.68-2.63 (m, 1H), 2.41 (bs, 1H), 2.29-2.20 (m, 1H), 1.87 (d, 3H),
1.80-1.71 (m, 1H), 1.05-1.03 (m, 9H), 0.99-0.93 (m, 1H), 0.73-0.65
(m, 1H).
##STR00174##
Example 510
Ingenol 3-(3-phenylthiophene-2-carboxylate) (Compound 510)
[0807] Compound 510 was prepared according to Procedure e.
[0808] Starting material: Compound 610.
[0809] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.57 (d, 1H), 7.45-7.35
(m, 5H), 7.09 (d, 1H), 5.96-5.97 (m, 1H), 5.91 (d, 1H), 5.64 (s,
1H), 4.30 (d, 1H), 4.04-3.94 (m, 4H), 3.31 (s, 1H), 2.59 (bs, 1H),
2.10-2.04 (m, 2H), 1.77 (d, 3H), 1.64-1.55 (m, 1H), 1.01 (s, 3H),
0.97 (s, 3H), 0.90-0.82 (m, 4H), 0.66-0.58 (m, 1H).
##STR00175##
Example 511
Ingenol 3-(5-phenylisoxazole-3-carboxylate) (Compound 511)
[0810] Compound 511 was prepared according to Procedure e.
[0811] Starting material: Compound 611.
[0812] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.82-7.77 (m, 2H),
7.51-7.47 (m, 3H), 6.92 (s, 1H), 6.15-6.14 (m, 1H), 6.07 (d, 1H),
5.89 (s, 1H), 4.47 (d, 1H), 4.20-4.09 (m, 4H), 3.86 (s, 1H),
2.68-2.60 (m, 2H), 2.29-2.23 (m, 1H), 1.87-1.76 (m, 4H), 1.06 (s,
3H), 1.05-1.02 (m, 6H), 1.00-0.89 (m, 1H), 0.74-0.67 (m, 1H).
##STR00176##
Example 512
Ingenol 3-(isoquinoline-1-carboxylate) (Compound 512)
[0813] Compound 512 was prepared according to Procedure e. The
title compound was purified by flash chromatography
(dichloromethane/methanol 98:2.fwdarw.dichloromethane/methanol
95:5).
[0814] Starting material: Compound 612.
[0815] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.73 (d, 1H), 8.55
(d, 1H), 7.93-7.85 (m, 2H), 7.81-7.71 (m, 2H), 6.16-6.15 (m, 1H),
6.09-6.07 (m, 1H), 6.04 (s, 1H), 5.67 (s, 1H), 5.30 (s, 1H),
4.29-4.18 (m, 3H), 3.60 (d, 1H), 2.68-2.63 (m, 1H), 2.45-2.36 (m,
2H), 1.94 (d, 3H), 1.90-1.82 (m, 1H), 1.17 (s, 3H), 1.09 (s, 3H),
1.02-0.95 (m, 4H), 0.78-0.70 (m, 1H).
##STR00177##
Example 513
Ingenol 3-(quinoline-4-carboxylate) (Compound 513)
[0816] Compound 513 was prepared according to Procedure e. The
title compound was purified by flash chromatography
(dichloromethane/methanol 98:2.fwdarw.dichloromethane/methanol
95:5).
[0817] Starting material: Compound 613.
[0818] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.04 (d, 1H),
8.84-8.80 (m, 1H), 8.20-8.17 (m, 1H), 7.88 (d, 1H), 7.79-7.75 (m,
1H), 7.68-7.62 (m, 1H), 6.17 (m, 1H), 6.10 (d, 1H), 5.94 (s, 1H),
4.76 (d, 1H), 4.29-4.19 (m, 4H), 3.84 (s, 1H), 2.67-2.61 (m, 1H),
2.40-2.31 (m, 2H), 1.88 (d, 3H), 1.85-1.76 (m, 1H), 1.08 (s, 3H),
1.06 (s, 3H), 1.01 (d, 3H), 0.98-0.92 (m, 1H), 0.76-0.68 (m,
1H).
##STR00178##
Example 514
Ingenol 3-(cinnoline-4-carboxylate) (Compound 514)
[0819] Compound 514 was prepared according to Procedure e. The
title compound was purified by flash chromatography
(dichloromethane/methanol 98:2.fwdarw.dichloromethane/methanol
95:5).
[0820] Starting material: Compound 614.
[0821] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.65 (s, 1H),
8.89-8.86 (m, 1H), 8.65-8.61 (m, 1H), 8.10-8.00 (m, 2H), 6.14 (s,
1H), 6.04 (d, 1H), 5.93-5.92 (m, 1H), 5.78 (s, 1H), 5.59 (d, 1H),
4.69 (t, 1H), 4.28-4.23 (m, 1H), 4.04-3.92 (m, 2H), 3.73 (d, 1H),
2.64-2.57 (m, 1H), 2.45-2.37 (m, 1H), 1.83 (d, 3H), 1.80-1.71 (m,
1H), 1.08 (s, 3H), 1.05 (s, 3H), 0.93 (d, 3H), 0.85-0.79 (m, 1H),
0.69-0.61 (m, 1H).
##STR00179##
Example 515
Ingenol 3-(3-phenylimidazole-4-carboxylate) (Compound 515)
[0822] Compound 515 was prepared according to Procedure e. The
title compound was purified by flash chromatography
(dichloromethane/methanol 98:2.fwdarw.dichloromethane/methanol
95:5).
[0823] Starting material: Compound 615.
[0824] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.89 (d, 1H), 7.68
(d, 1H), 7.49-7.44 (m, 3H), 7.37-7.32 (m, 2H), 6.00-5.98 (m, 2H),
5.61 (s, 1H), 5.30 (s, 1H), 4.53 (d, 1H), 4.14-4.10 (m, 3H), 3.98
(bs, 1H), 3.53 (s, 1H), 2.65 (bs, 1H), 2.30-2.15 (m, 2H), 1.73-1.65
(m, 4H), 1.04 (s, 6H), 0.93-0.85 (m, 4H), 0.71-0.63 (m, 1H).
##STR00180##
Example 516
Ingenol 3-(5-phenyloxazole-4-carboxylate) (Compound 516)
[0825] Compound 516 was prepared according to Procedure e.
[0826] Starting material: Compound 616.
[0827] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.56 (s, 1H),
7.92-7.88 (m, 2H), 7.53-7.48 (m, .sup.3H), 5.92 (s, 1H), 5.90 (d,
1H), 5.86-5.85 (m, 1H), 5.42 (d, 1H), 5.00 (s, 1H), 4.63 (t, 1H),
4.14-4.08 (m, 1H), 3.98-3.85 (m, 2H), 3.64 (d, 1H), 2.25-2.10 (m,
2H), 1.75 (d, 3H), 1.51-1.44 (m, 1H), 1.01 (s, 3H), 0.99 (s, 3H),
0.77-0.70 (m, 4H), 0.58-0.50 (m, 1H).
##STR00181##
Example 517
Ingenol 3-(1,2-benzoxazole-3-carboxylate) (Compound 517)
[0828] Compound 517 was prepared according to Procedure e.
[0829] Starting material: Compound 617.
[0830] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.17-8.14 (m, 1H),
7.70-7.61 (m, 2H), 7.47-7.42 (m, 1H), 6.19-6.18 (m, 1H), 6.09-6.08
(m, 1H), 5.97 (s, 1H), 4.47 (d, 1H), 4.26-4.16 (m, 3H), 4.12 (bs,
1H), 3.80 (s, 1H), 2.73-2.65 (m, 1H), 2.32-2.23 (m, 2H), 1.90 (d,
3H), 1.86-1.74 (m, 1H), 1.06-1.03 (m, 9H), 0.97-0.90 (m, 1H),
0.75-0.67 (m, 1H).
##STR00182##
Example 518
Ingenol 3-(3-isopropyl-5-methyl-isoxazole-4-carboxylate) (Compound
518)
[0831] Compound 518 was prepared according to Procedure e.
[0832] Starting material: Compound 618.
[0833] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.13-6.12 (m, 1H),
6.08-6.07 (d, 1H), 5.69 (s, 1H), 4.67 (d, 1H), 4.23-4.18 (m, 3H),
4.11 (bs, 1H), 3.69 (s, 1H), 3.44 (septet, 1H), 2.65 (s, 3H),
2.60-2.51 (m, 1H), 2.35-2.22 (m, 2H), 1.83 (d, 3H), 1.79-1.70 (m,
1H), 1.33 (d, 3H), 1.32 (d, 3H), 1.07 (s, 3H), 1.06 (s, 3H), 1.00
(d, 3H), 0.96-0.86 (m, 1H), 0.74-0.66 (m, 1H).
##STR00183##
Example 519
Ingenol 3-(3-(2-methoxyphenyl)-5-methyl-isoxazole-4-carboxylate)
(Compound 519)
[0834] Compound 519 was prepared according to Procedure e.
[0835] Starting material: Compound 619.
[0836] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.46-7.36 (m, 2H), 7.04
(dt, 1H), 6.95 (d, 1H), 6.01 (d, 1H), 5.91-5.90 (m, 1H), 5.69 (s,
1H), 4.14-4.06 (m, 2H), 3.98 (dd, 1H), 3.91 (d, 1H), 3.82 (d, 1H),
3.77 (s, 3H), 3.26 (s, 1H), 2.75 (s, 3H), 2.26-2.21 (m, 1H),
1.99-1.89 (m, 1H), 1.72 (d, 3H), 1.65-1.61 (m, 1H), 1.55-1.46 (m,
1H), 1.04 (s, 3H), 1.04 (s, 3H), 0.90-0.83 (m, 1H), 0.74 (d, 3H),
0.65-0.57 (m, 1H).
##STR00184##
Example 520
Ingenol 3-(4-bromo-2-methyl-pyrazole-3-carboxylate) (Compound
520)
[0837] Compound 520 was prepared according to Procedure e.
[0838] Starting material: Compound 620.
[0839] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.52 (s, 1H), 6.15-6.14
(m, 1H), 6.08 (d, 1H), 5.84 (s, 1H), 5.30 (s, 1H), 4.21-4.05 (m,
7H), 3.85 (s, 1H), 2.77-2.73 (m, 1H), 2.30-2.17 (m, 2H), 1.87 (d,
3H), 1.80-1.72 (m, 1H), 1.08 (s, 3H), 1.06 (s, 3H), 1.00 (d, 3H),
0.97-0.90 (m, 1H), 0.75-0.67 (m, 1H).
##STR00185##
Example 521
Ingenol 3-(4-bromo-2-ethyl-pyrazole-3-carboxylate) (Compound
521)
[0840] Compound 521 was prepared according to Procedure e.
[0841] Starting material: Compound 621.
[0842] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.54 (s, 1H), 6.15-6.13
(m, 1H), 6.09-6.07 (m, 1H), 5.86 (s, 1H), 4.68-4.55 (m, 2H),
4.24-4.13 (m, 4H), 4.07 (d, 1H), 3.87 (s, 1H), 2.77-2.70 (m, 1H),
2.32-2.20 (m, 2H), 1.87 (d, 3H), 1.80-1.71 (m, 1H), 1.44 (t, 3H),
1.09 (s, 3H), 1.06 (s, 3H), 0.98 (d, 3H), 0.97-0.90 (m, 1H),
0.75-0.67 (m, 1H).
##STR00186##
Example 522
Ingenol 3-(4-chloro-2-methyl-pyrazole-3-carboxylate) (Compound
522)
[0843] Compound 522 was prepared according to Procedure e.
[0844] Starting material: Compound 622.
[0845] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.48 (s, 1H), 6.14-6.13
(m, 1H), 6.09-6.06 (m, 1H), 5.84 (s, 1H), 4.23-4.11 (m, 7H),
4.07-4.05 (d, 1H), 3.83 (s, 1H), 2.73-2.64 (m, 1H), 2.31-2.20 (m,
2H), 1.87 (d, 3H), 1.81-1.72 (m,1H), 1.08 (s, 3H), 1.06 (s, 3H),
1.00 (d, 3H), 0.97-0.87 (m, 1H), 0.75-0.67 (m, 1H).
##STR00187##
Example 523
Ingenol 3-(5-bromopyrimidine-4-carboxylate) (Compound 523)
[0846] Compound 523 was prepared according to Procedure e.
[0847] Starting material: Compound 623.
[0848] .sup.1H NMR (300 MHz, CDCl.sub.3) 9.21 (s, 1H), 9.02 (s,
1H), 6.16-6.14 (m, 1H), 6.09-6.07 (m, 1H), 5.96 (s, 1H), 4.22-4.12
(m, 4H), 4.06-4.04 (m, 2H), 2.57-2.52 (m, 1H), 2.33-2.24 (m, 2H),
1.90 (d, 3H), 1.88-1.79 (m, 1H), 1.10 (s, 3H), 1.06 (s, 3H),
0.98-0.90 (m, 4H), 0.75-0.67 (m, 1H).
##STR00188##
Example 524
Ingenol 3-(3-bromopyridine-2-carboxylate) (Compound 524)
[0849] Compound 524 was prepared according to Procedure e.
[0850] Starting material: Compound 624.
[0851] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.58 (dd, 1H), 8.03 (dd,
1H), 7.34 (dd, 1H), 6.11-6.13 (m, 1H), 6.07-6.05 (m, 1H), 5.98 (s,
1H), 4.74 (d, 1H), 4.21-4.15 (m, 3H), 4.00 (d, 1H), 3.69 (d, 1H),
2.56-2.48 (m, 2H), 2.34-2.24 (m, 1H), 1.91 (d, 3H), 1.83-1.74 (m,
1H), 1.12 (s, 3H), 1.05 (s, 3H), 0.98-0.92 (m, 4H), 0.75-0.67 (m,
1H).
##STR00189##
Example 525
Ingenol 3-(5-methylthiazole-4-carboxylate) (Compound 525)
[0852] Compound 525 was prepared according to Procedure e.
[0853] Starting material: Compound 625.
[0854] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.59 (s, 1H), 6.10-6.05
(m, 2H), 5.70 (s, 1H), 4.21-4.14 (m, 4H), 4.04 (s, 2H), 2.81 (s,
3H), 2.66-2.59 (m, 2H), 2.32-2.23 (m, 1H), 1.86 (d, 3H), 1.83-1.74
(m, 1H), 1.09 (s, 3H), 1.06 (s, 3H), 1.00 (d, 3H), 0.98-0.91 (m,
1H), 0.75-0.67 (m, 1H).
##STR00190##
Example 526
Ingenol 3-(4-chloro-1-methyl-pyrazole-3-carboxylate) (Compound
526)
[0855] Compound 526 was prepared according to Procedure e.
[0856] Starting material: Compound 626.
[0857] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.47 (s, 1H), 6.10-6.05
(m, 2H), 5.82 (s, 1H), 4.18-4.12 (m, 3H), 4.04 (d, 1H), 3.96 (s,
3H), 3.87 (s, 1H), 3.79 (d, 1H), 2.70-2.63 (m, 1H), 2.34-2.21 (m,
2H), 1.87 (d, 3H), 1.82-1.73 (m, 1H), 1.09 (s, 3H), 1.05 (s, 3H),
1.00 (d, 3H), 0.98-0.92 (m, 1H), 0.74-0.67 (m, 1H).
##STR00191##
Example 527
Ingenol 3-(2,4-dimethylthiazole-5-carboxylate) (Compound 527)
[0858] Compound 527 was prepared according to Procedure e.
[0859] Starting material: Compound 627.
[0860] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.10-6-08 (m, 1H),
6.07-6.05 (m, 1H), 5.69 (s, 1H), 4.61 (d, 1H), 4.21-4.15 (m, 3H),
4.08 (s, 1H), 3.62 (d, 1H), 2.70 (s, 3H), 2.69 (s, 3H), 2.62-2.54
(m, 2H), 2.32-2.25 (m, 1H), 1.82 (d, 3H), 1.80-1.73 (m, 1H), 1.07
(s, 3H), 1.05 (s, 3H), 1.01 (d, 3H), 0.97-0.90 (m, 1H), 0.74-0.66
(m, 1H).
##STR00192##
Example 528
Ingenol 3-(2,5-dimethyloxazole-4-carboxylate) (Compound 528)
[0861] Compound 528 was prepared according to Procedure e.
[0862] Starting material: Compound 628.
[0863] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.03-6.00 (m, 2H), 5.74
(s, 1H), 4.51-4.47 (m, 2H), 4.25-4.10 (m, 3H), 4.02 (bs, 1H), 3.55
(s, 1H), 2.59 (s, 3H), 2.57-2.54 (m, 1H), 2.44 (s, 3H), 2.31-2.22
(m, 1H), 1.81 (d, 3H), 1.79-1.71 (m, 1H), 1.07 (s, 3H), 1.05 (s,
3H), 0.98 (d, 3H), 0,95-0.88 (m, 1H), 0.73-0.65 (m, 1H).
##STR00193##
Example 529
Ingenol 3-(2,4-dimethylfuran-3-carboxylate) (Compound 529)
[0864] Compound 529 was prepared according to Procedure e. Compound
529 was obtained as an amorphous compound.
[0865] Starting material: Compound 629.
[0866] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.06 (q, 1H), 6.09-6.06
(m, 2H), 5.62 (m, 1H), 4.50 (d, 1H), 4.19-4.13 (m, 3H), 4.12-4.09
(m, 1H), 3.66 (s, 1H), 2.61-2.55 (m, 1H), 2.54 (s, 3H), 2.39 (t,
1H), 2.32-2.23 (m, 1H), 2.12 (d, 3H), 1.83 (d, 3H), 1.79-1.70 (m,
1H), 1.07 (s, 3H), 1.05 (s, 3H), 0.99 (d, 3H), 0.98-0.90 (m, 1H),
0.73-0.65 (m, 1H).
##STR00194##
Example 530
Ingenol 3-(3,5-diethylisoxazole-4-carboxylate) (Compound 530)
[0867] Compound 530 was prepared according to Procedure e.
[0868] Starting material: Compound 630.
[0869] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.14-6.12 (m, 1H),
6.08-6.07 (m, 1H), 5.70 (s, 1H), 4.68 (d, 1H), 4.23-4.18 (m, 3H),
4.12-4.11 (m, 1H), 3.69 (s, 1H), 3.09 (dq, 2H), 2.89 (dq, 2H),
2.59-2.52 (m, 1H), 2.35-2.25 (m, 2H), 1.83 (d, 3H), 1.79-1.70 (m,
1H), 1.31 (t, 3H), 1.29 (t, 3H), 1.07 (s, 3H), 1.05 (s, 3H), 1.01
(d, 3H), 0.96-0.89 (m, 1H), 0.74-0.65 (m, 1H); 0.5 mol of ethyl
acetate is observed: 4.12 (q, 0.5.times.2H), 2.04 (s,
0.5.times.3H), 1.26 (t, 0.5.times.3H).
##STR00195##
Example 531
Ingenol 3-(1H-indole-7-carboxylate) (Compound 531)
[0870] Compound 531 was prepared according to Procedure e.
[0871] Starting material: Compound 631.
[0872] .sup.1H NMR (300 MHz, CDCl.sub.3) 10.13 (bs, 1H), 7.90-7.85
(m, 2H), 7.31-7.29 (m, 1H), 7.18 (t, 1H), 6.62-6.60 (m, 1H),
6.13-6.12 (m, 1H), 6.08 (d, 1H), 5.84 (s, 1H), 4.69 (d, 1H),
4.27-4.16 (m, 4H), 3.85 (s, 1H), 2.71-2.66 (m, 1H), 2.43 (bs, 1H),
2.37-2.28 (m, 1H), 1.88 (d, 3H), 1.85-1.76 (m, 1H), 1.08 (s, 3H),
1.06 (s, 3H), 1.04 (d, 3H), 0.98-0.92 (m, 1H), 0.76-0.68 (m,
1H).
##STR00196##
Example 532
Ingenol 3-(2-tert-butyl-5-methyl-pyrazole-3-carboxylate) (Compound
532)
[0873] Compound 532 was prepared according to Procedure e.
[0874] Starting material: Compound 632.
[0875] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.65 (s, 1H), 6.09-6.06
(m, 2H), 5.69 (s, 1H), 4.40 (d, 1H), 4.20-4.13 (m, 3H), 4.08 (d,
1H), 3.54 (s, 1H), 2.60-2.55 (m, 1H), 2.33-2.24 (m, 5H), 1.82 (d,
3H), 1.80-1.75 (m, 1H), 1.70 (s, 9H), 1.08 (s, 3H), 1.06 (s, 3H),
1.01 (d, 3H), 0.98-0.91 (m, 1H), 0.75-0.67 (m, 1H).
##STR00197##
Example 533
Ingenol 3-(5-tert-butyl-2-methyl-pyrazole-3-carboxylate) (Compound
533)
[0876] Compound 533 was prepared according to Procedure e.
[0877] Starting material: Compound 633.
[0878] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.63 (s, 1H), 6.12-6.10
(m, 1H), 6.08-6.06 (d, 1H), 5.71 (s, 1H), 4.57 (d, 1H), 4.20-4.15
(m, 3H), 4.13 (s, 3H), 4.10 (d, 1H), 3.62 (s, 1H), 2.61-2.55 (m,
1H), 2.40 (t, 1H), 2.32-2.23 (m, 1H), 1.83 (d, 3H), 1.82-1.73 (m,
1H), 1.31 (s, 9H), 1.07 (s, 3H), 1.05 (s, 3H), 1.03 (d, 3H),
0.97-0.91 (m, 1H), 0.75-0.67 (m, 1H).
##STR00198##
Example 534
Ingenol 3-(6-methylimidazo[2,1-b]thiazole-5-carboxylate) (Compound
534)
[0879] Compound 534 was prepared according to Procedure e.
[0880] Starting material: Compound 634.
[0881] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.09 (d, 1H), 6.93 (d,
1H), 6.15-6.13 (m, 1H), 6.08 (d, 1H), 5.73 (s, 1H), 4.24-4.17 (m,
4H), 4.14-4.13 (m, 1H), 3.80 (bs, 1H), 2.63-2.59 (m, 5H), 2.33-2.25
(m, 1H), 1.86 (d, 3H), 1.80-1.71 (m, 1H), 1.06 (s, 3H), 1.05 (s,
3H), 1.02 (d, 3H), 0.97-0.90 (m, 1H), 0.74-0.66 (m, 1H).
##STR00199##
Example 535
Ingenol 3-(2-methylimidazo[1,2-a]pyridine-3-carboxylate) (Compound
535)
[0882] Compound 535 was prepared according to Procedure e.
[0883] Starting material: Compound 635.
[0884] .sup.1H NMR (300 MHz, CDCl.sub.3) 9.37 (d, 1H), 8.09 (s,
1H), 7.74 (d, 1H), 7.49-7.43 (m, 1H), 7.06-7.01 (m, 1H), 6.19-6.08
(m, 2H), 5.80 (s, 1H), 4.33-4.17 (m, 4H), 3.43 (bs, 2H), 2.72-2.63
(m, 4H), 2.33-2.24 (m, 1H), 1.88 (d, 3H), 1.80-1.71 (m, 1H), 1.06
(s, 3H), 1.05 (s, 3H), 1.03 (d, 3H), 0.97-0.85 (m, 1H), 0.75-0.67
(m, 1H).
##STR00200##
Example 536
Ingenol 3-(2,4,5-trimethylfuran-3-carboxylate) (Compound 536)
[0885] Compound 536 was prepared according to Procedure e.
[0886] Starting material: Compound 636.
[0887] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.07-6.04 (m, 2H), 5.63
(s, 1H), 4.65 (d, 1H), 4.20-4.14 (m, 3H), 4.09 (d, 1H), 3.71 (s,
1H), 2.80 (t, 1H), 2.62-2.56 (m, 1H), 2.50 (s, 3H), 2.32-2.23 (m,
1H), 2.17 (s, 3H), 2.04 (s, 3H), 1.82 (d, 3H), 1.78-1.69 (m, 1H),
1.06 (s, 3H), 1.05 (s, 3H), 0.98 (d, 3H), 0.94-0.90 (m, 1H),
0.72-0.65 (m, 1H).
##STR00201##
Example 537
Ingenol 3-(3-methylthiophene-2-carboxylate) (Compound 537)
[0888] Compound 537 was prepared according to Procedure e.
[0889] Starting material: Compound 637.
[0890] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.42 (d, 1H), 6.94 (d,
1H), 6.09-6.07 (m, 1H), 6.06-6.04 (m, 1H), 5.71 (s, 1H), 4.49 (bs,
1H), 4.22-4.12 (m, 3H), 4.09-4.08 (m, 1H), 3.63 (s, 1H), 2.70-2.60
(m, 2H), 2.57 (s, 3H), 2.32-2.22 (m, 1H), 1.84 (d, 3H), 1.81-1.72
(m, 1H), 1.05 (s, 3H), 1.04 (s, 3H), 1.02 (d, 3H), 0.96-0.90 (m,
1H), 0.73-0.66 (m, 1H).
##STR00202##
Example 538
Ingenol 3-(2-methyl-4-(1-piperidyl)pyrazole-3-carboxylate)
(Compound 538)
[0891] Compound 538 was prepared according to Procedure e.
[0892] Starting material: Compound 638.
[0893] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.36 (s, 1H), 6.10-6.07
(m, 2H), 5.69 (s, 1H), 4.23-4.13 (m, 3H), 4.10 (s, 3H), 4.01 (s,
1H), 2.97-2.82 (m, 4H), 2.68-2.62 (m, 1H), 2.31-2.22 (m, 1H), 1.87
(d, 3H), 1.84-1.59 (m, 8H), 1.55-1.49 (m, 2H), 1.10 (s, 3H), 1.05
(s, 3H), 0.99 (d, 3H), 0.98-0.94 (m, 1H), 0.74-0.66 (m, 1H).
##STR00203##
Example 539
Ingenol 3-(2-chloro-5-isopropyl-thiazole-4-carboxylate) (Compound
539)
[0894] Compound 539 was prepared according to Procedure e.
[0895] Starting material: Compound 639.
[0896] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.09-6.05 (m, 2H), 5.77
(s, 1H), 4.19-4.08 (m, 5H), 4.04-3.98 (m, 2H), 2.64-2.55 (m, 2H),
2.33-2.24 (m, 1H), 1.85 (d, 3H), 1.83-1.71 (m, 1H), 1.34 (d, 3H),
1.32 (d, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 1.01 (d, 3H), 0.97-0.91
(m, 1H), 0.75-0.67 (m, 1H).
##STR00204##
Example 540
Ingenol 3-(4-chloro-2,5-dimethyl-pyrazole-3-carboxylate) (Compound
540)
[0897] Compound 540 was prepared according to Procedure e.
[0898] Starting material: Compound 640.
[0899] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.14-6.12 (m, 1H),
6.08-6.06 (m, 1H), 5.83 (s, 1H), 4.21-4.04 (m, 8H), 3.85 (s, 1H),
2.73-2.68 (m, 1H), 2.42 (bs, 1H), 2.30-2.21 (m, 4H), 1.86 (d, 3H),
1.81-1.72 (m, 1H), 1.08 (s, 3H), 1.06 (s, 3H), 1.00 (d, 3H),
0.97-0.90 (m, 1H), 0.75-0.67 (m, 1H).
##STR00205##
Example 541
Ingenol 3-(1,2,4-trimethylpyrrole-3-carboxylate) (Compound 541)
[0900] Compound 541 was prepared according to Procedure e.
[0901] Starting material: Compound 641.
[0902] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.29 (m, 1H), 6.06-6.03
(m, 2H), 5.55 (s, 1H), 4.51 (d, 1H), 4.16-4.08 (m, 4H), 3.68 (s,
1H), 3.47 (s, 3H), 2.63-2.52 (m, 2H), 2.47 (s, 3H), 2.29-2.20 (m,
1H), 2.18 (s, 3H), 1.83 (d, 3H), 1.77-1.68 (m, 1H), 1.07 (s, 3H),
1.04 (s, 3H), 0.98 (d, 3H), 0.99-0.93 (m, 1H), 0.72-0.64 (m,
1H).
##STR00206##
Example 542
Ingenol 3-(1,3,5-trimethylpyrrole-2-carboxylate) (Compound 542)
[0903] Compound 542 was prepared according to Procedure e.
[0904] Starting material: Compound 642.
[0905] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.06-6.05 (m, 2H), 5.81
(s, 1H), 5.59 (s, 1H), 4.44 (d, 1H), 4.17-4.08 (m, 4H), 3.77 (s,
3H), 3.70 (s, 1H), 2.63-2.57 (m, 1H), 2.44 (t, 1H), 2.29-2.24 (m,
4H), 2.21 (s, 3H), 1.83 (d, 3H), 1.78-1.69 (m, 1H), 1.07 (s, 3H),
1.05 (s, 3H), 0.98 (d, 3H), 0.95-0.90 (m, 1H), 0.72-0.65 (m,
1H).
##STR00207##
Example 543
Ingenol 3-(1-ethyl-3,5-dimethylpyrrole-2-carboxylate) (Compound
543)
[0906] Compound 543 was prepared according to Procedure e.
[0907] Starting material: Compound 643.
[0908] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.07-6.05 (m, 2H), 5.81
(s, 1H), 5.58 (s, 1H), 4.43 (d, 1H), 4.32-4.24 (m, 2H), 4.17-4.09
(m, 4H), 3.67 (s, 1H), 2.62-2.57 (m, 1H), 2.36-2.34 (m, 1H),
2.30-2.20 (m, 7H), 1.84 (d, 3H), 1.78-1.69 (m, 1H), 1.27 (t, 3H),
1.07 (s, 3H), 1.05 (s, 3H), 0.98 (d, 3H), 0.95-0.90 (m, 1H),
0.72-0.65 (m, 1H).
##STR00208##
Example 544
Ingenol
3-(1-tert-butyloxycarbonyl-3,3-dimethylpyrrolidine-2-carboxylate)
(Compound 544)
[0909] Compound 544 was prepared according to Procedure e.
[0910] Starting material: Compound 644.
[0911] .sup.1H NMR (300 MHz, CDCl.sub.3) showed a mixture of
compounds.
##STR00209##
Example 545
Ingenol 3-((2S)-1-phenylpyrrolidine-2-carboxylate) (Compound
545)
[0912] Compound 545 was prepared according to Procedure e with the
following changes: Tetrahydrofuran was replaced with methanol and
the reaction time at room temperature was 0.5 h.
[0913] Starting material: Compound 645.
[0914] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.27-7.21 (m, 2H), 6.72
(t, 1H), 6.54 (d, 2H), 6.01-5.99 (m, 1H), 5.96 (d, 1H), 5.68 (s,
1H), 4.43 (dd, 1H), 4.13-4.03 (m, 2H), 3.88-3.83 (m, 2H), 3.49-3.37
(m, 3H), 2.70 (s, 1H), 2.46-2.39 (m, 1H), 2.28-2.20 (m, 2H),
2.13-1.96 (m, 3H), 1.75 (d, 3H), 1.68-1.57 (m, 1H), 1.49-1.40 (m,
1H), 1.03 (s, 3H), 0.96 (s, 3H), 0.89-0.81 (m, 4H), 0.62-0.54 (m,
1H).
##STR00210##
Example 546
Ingenol 3-(1-isopropyl-3,5-dimethyl-pyrazole-4-carboxylate)
(Compound 546)
[0915] Compound 546 was prepared according to Procedure e.
[0916] Starting material: Compound 646.
[0917] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.07-6.04 (m, 2H), 5.61
(s, 1H), 4.63 (d, 1H), 4.43 (septet, 1H), 4.19-4.10 (m, 4H), 3.70
(s, 1H), 2.70 (t, 1H), 2.62-2.58 (m, 1H), 2.52 (s, 3H), 2.40 (s,
3H), 2.31-2.22 (m, 1H), 1.83 (d, 3H), 1.79-1.70 (m, 1H), 1.46 (d,
6H), 1.07 (s, 3H), 1.04 (s, 3H), 0.99 (d, 3H), 0.97-0.90 (d, 1H),
0.73-0.65 (m, 1H).
##STR00211##
Example 547
Ingenol 3-(5-ethyl-3-isopropyl-isoxazole-4-carboxylate) (Compound
547)
[0918] Compound 547 was prepared according to Procedure e with the
following changes: Tetrahydrofuran was replaced with methanol and
the reaction time at room temperature was 0.5 h.
[0919] Starting material: Compound 647.
[0920] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.13-6.12 (m, 1H),
6.08-6.06 (d, 1H), 5.71 (s, 1H), 4.75 (d, 1H), 4.23-4.17 (m, 3H),
4.13-4.10 (m, 1H), 3.70 (s, 1H), 3.45 (septet, 1H), 3.12-3.04 (m,
2H), 2.58-2.46 (m, 2H), 2.35-2.26 (m, 1H), 1.83 (d, 3H), 1.79-1.70
(m, 1H), 1.33 (d, 3H), 1.32 (d, 3H), 1.30 (t, 3H), 1.07 (s, 3H),
1.06 (s, 3H), 1.00 (d, 3H), 0.96-0.89 (m, 1H), 0.74-0.66 (m,
1H).
##STR00212##
Example 548
Ingenol 3-(2-methylindazole-3-carboxylate) (Compound 548)
[0921] Compound 548 was prepared according to Procedure e with the
following changes: Tetrahydrofuran was replaced with methanol and
the reaction time at room temperature was 0.5 h.
[0922] Starting material: Compound 648.
[0923] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.97-7.94 (m, 1H),
7.81-7.78 (m, 1H), 7.39-7.34 (m, 1H), 7.31-7.26 (m, 1H), 6.22-6.21
(m, 1H), 6.10-6.08 (m, 1H), 5.86 (s, 1H), 4.75 (d, 1H), 4.54 (s,
3H), 4.26-4.18 (m, 4H), 3.80 (s, 1H), 2.74-2.69 (m, 1H), 2.32-2.22
(m, 2H), 1.91 (d, 3H), 1.75-1.67 (m, 1H), 1.07 (d, 3H), 1.05 (s,
3H), 1.04 (s, 3H), 0.97-0.90 (m, 1H), 0.73-0.65 (m, 1H).
##STR00213##
Example 549
Ingenol 3-(5-methyl-3-tert-butyl-isoxazole-4-carboxylate) (Compound
549)
[0924] Compound 549 was prepared according to Procedure e.
[0925] Starting material: Compound 649.
[0926] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.13-6.11 (m, 1H),
6.09-6.07 (m, 1H), 5.68 (s, 1H), 4.66 (bs, 1H), 4.22-4.15 (m, 3H),
4.12 (s, 1H), 3.67 (s, 1H), 2.62 (s, 3H), 2.60-2.53 (m, 1H),
2.33-2.23 (m, 2H), 1.83 (d, 3H), 1.78-1.69 (m, 1H), 1.44 (s, 9H),
1.07 (s, 3H), 1.06 (s, 3H), 0.98 (d, 3H), 0.96-0.89 (m, 1H),
0.74-0.66 (m, 1H).
##STR00214##
Example 550
Ingenol 3-(2-methyl-3-oxo-4-oxaspiro[4.5]dec-1-ene-1-carboxylate)
(Compound 550)
[0927] Compound 550 was prepared according to Procedure e with the
following changes: Tetrahydrofuran was replaced with methanol and
the reaction time at room temperature was 0.5 h.
[0928] Starting material: Compound 650.
[0929] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.15-6.13 (m, 1H),
6.09-6.07 (m, 1H), 5.76 (s, 1H), 5.00 (d, 1H), 4.26-4.11 (m, 4H),
3.72 (s, 1H), 2.60-2.55 (m, 1H), 2.45-2.42 (m, 1H), 2.31-2.13 (m,
5H), 1.95-1.90 (m, 1H), 1.82 (d, 3H), 1.78-1.67 (m, 7H), 1.58-1.50
(m, 2H), 1.08 (s, 3H), 1.06 (s, 3H), 1.01 (d, 3H), 0.95-0.89 (m,
1H), 0.75-0.67 (m, 1H).
##STR00215##
Example 551
Ingenol 3-(1-tert-butyl-3,5-dimethyl-pyrazole-4-carboxylate)
(Compound 551)
[0930] Compound 551 was prepared according to Procedure e.
[0931] Starting material: Compound 651.
[0932] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.08-6.05 (m, 2H), 5.58
(s, 1H), 4.47 (bs, 1H), 4.17-4.10 (m, 4H), 3.65 (s, 1H), 2.71 (s,
3H), 2.62-2.57 (m, 1H), 2.36-2.21 (m, 5H), 1.83 (d, 3H), 1.79-1.70
(m, 1H), 1.65 (s, 9H), 1.07 (s, 3H), 1.05 (s, 3H), 0.99 (d, 3H),
0.96-0.91 (m, 1H), 0.73-0.65 (m, 1H).
##STR00216##
Example 552
Ingenol 3-(3,5-dimethylisothiazole-4-carboxylate) (Compound
552)
[0933] Compound 552 was prepared according to Procedure e.
[0934] Starting material: Compound 652.
##STR00217##
Example 553
Ingenol 3-(5-iodo-3-methyl-isothiazole-4-carboxylate) (Compound
553)
[0935] Compound 553 was prepared according to Procedure e.
[0936] Starting material: Compound 653.
[0937] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.16-6.14 (m, 1H), 6.08
(d, 1H), 5.81 (s, 1H), 4.57 (d, 1H), 4.25-4.12 (m, 4H), 3.75 (s,
1H), 2.74 (s, 3H), 2.73-2.68 (m, 1H), 2.32-2.23 (m, 2H), 1.90 (d,
3H), 1.78-1.69 (m, 1H), 1.07 (s, 3H), 1.06 (s, 3H), 1.00 (d, 3H),
0.96-0.90 (m, 1H), 0.74-0.66 (m, 1H).
##STR00218##
Example 554
Ingenol 3-(4-(4-methoxyphenyl)-2-methyl-pyrazole-3-carboxylate)
(Compound 554)
[0938] Compound 554 was prepared according to Procedure e.
[0939] Starting material: Compound 654.
[0940] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.43 (s, 1H), 7.28-7.23
(m, 2H), 6.90-6.83 (m, 2H), 6.02-6.00 (m, 1H), 5.95-5.93 (m, 1H),
5.73 (s, 1H), 4.22 (s, 3H), 4.16-4.08 (m, 4H), 4.02-3.95 (m, 2H),
3.81 (s, 3H), 3.23 (s, 1H), 1.96-1.87 (m, 1H), 1.75 (d, 3H),
1.58-1.55 (m, 1H), 1.50-1.41 (m, 1H), 1.02 (s, 3H), 1.01 (s, 3H),
0.90-0.83 (m, 1H), 0.69 (d, 3H), 0.63-0.55 (m, 1H).
##STR00219##
Example 555
Ingenol 3-(4-(2-methylphenyl)-2-methyl-pyrazole-3-carboxylate)
(Compound 555)
[0941] Compound 555 was prepared according to Procedure e.
[0942] Starting material: Compound 655.
[0943] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.37 (s, 1H), 7.24-7.11
(m, 4H), 6.00-5.98 (m, 1H), 5.87-5.85 (m, 1H), 5.62 (s, 1H), 4.25
(s, 3H), 4.16-4.06 (m, 2H), 3.97-3.88 (m, 3H), 3.00 (s, 1H), 2.36
(bs, 1H), 2.15 (s, 3H), 1.94-1.84 (m, 1H), 1.66 (d, 3H), 1.61-1.48
(m, 2H), 1.04 (s, 3H), 1.02 (s, 3H), 0.90-0.83 (m, 1H), 0.72 (d,
3H), 0.65-0.57 (m, 1H).
##STR00220##
Example 556
Ingenol
3-(2-methyl-4-(4-methylsulfonylphenyl)pyrazole-3-carboxylate)
(Compound 556)
[0944] Compound 556 was prepared according to Procedure e.
[0945] Starting material: Compound 656.
[0946] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.91 (d, 2H), 7.58 (d,
2H), 7.51 (s, 1H), 6.02-6.01 (d, 1H), 5.96-5.95 (m, 1H), 5.72 (s,
1H), 4.25 (s, 3H), 4.16-4.03 (m, 5H), 3.62 (bs, 1H), 3.07 (s, 3H),
2.14-2.05 (m, 1H), 1.85-1.80 (m, 1H), 1.71 (d, 3H), 1.58-1.49 (m,
1H), 1.33-1.29 (m, 1H), 1.02 (s, 3H), 1.01 (s, 3H), 0.90-0.80 (m,
1H), 0.68 (d, 3H), 0.65-0.57 (m, 1H).
##STR00221##
Example 557
Ingenol 3-(2-methyl-4-phenyl-pyrazole-3-carboxylate) (Compound
557)
[0947] Compound 557 was prepared according to Procedure e.
[0948] Starting material: Compound 657.
[0949] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.47 (s, 1H), 7.37-7.31
(m, 5H), 6.01 (d, 1H), 5.92-5.91 (m, 1H), 5.71 (s, 1H), 4.24 (s,
3H), 4.16-4.11 (m, 2H), 4.01-3.95 (m, 3H), 3.17 (s, 1H), 2.09-2.03
(m, 1H), 1.93-1.84 (m, 1H), 1.72 (d, 3H), 1.64-1.59 (m, 1H),
1.49-1.41 (m, 1H), 1.03 (s, 3H), 1.02 (s, 3H), 0.88-0.81 (m, 1H),
0.67 (d, 3H), 0.63-0.55 (m, 1H).
##STR00222##
Example 558
Ingenol 3-(3,5-dimethyl-1-phenyl-pyrazole-4-carboxylate) (Compound
558)
[0950] Compound 558 was prepared according to Procedure e.
[0951] Starting material: Compound 658.
[0952] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.53-7.37 (m, 5H),
6.10-6.09 (m, 1H), 6.07-6.05 (m, 1H), 5.67 (s, 1H), 4.70 (d, 1H),
4.22-4.11 (m, 4H), 3.75 (s, 1H), 2.72-2.61 (m, 2H), 2.52 (s, 3H),
2.49 (s, 3H), 2.35-2.25 (m, 1H), 1.86 (d, 3H), 1.80-1.71 (m, 1H),
1.08 (s, 3H), 1.05 (s, 3H), 1.00 (d, 3H), 0.98-0.90 (m,1H),
0.74-0.66 (m, 1H).
##STR00223##
Example 559
Ingenol 3-(1,5-dimethyl-3-phenyl-pyrazole-4-carboxylate) (Compound
559)
[0953] Compound 559 was prepared according to Procedure e.
[0954] Starting material: Compound 659.
[0955] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.49-7.45 (m, 2H),
7.38-7.33 (m, 3H), 5.98 (d, 1H), 5.89-5.87 (m, 1H), 5.64 (s, 1H),
4.11-4.08 (m, 2H), 3.99-3.94 (m, 3H), 3.85 (s, 3H), 3.21 (s, 1H),
2.60 (s, 3H), 2.46 (bs, 1H), 1.95-1.85 (m, 1H), 1.73 (d, 3H),
1.71-1.64 (m, 1H), 1.50-1.42 (m, 1H), 1.02 (s, 3H), 1.01 (s, 3H),
0.90-0.84 (m, 1H), 0.68 (d, 3H), 0.63-0.55 (m, 1H).
##STR00224##
Example 560
Ingenol 3-(1-benzyl-3,5-dimethyl-pyrazole-4-carboxylate) (Compound
560)
[0956] Compound 560 was prepared according to Procedure e.
[0957] Starting material: Compound 660.
[0958] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.37-7.28 (m, 3H),
7.16-7.13 (m, 2H), 6.08-6.05 (m, 2H), 5.61 (s, 1H), 5.25 (s, 2H),
4.52 (bs, 1H), 4.18-4.10 (m, 4H), 3.67 (s, 1H), 2.61-2.56 (m, 1H),
2.45 (s, 3H), 2.44-2.41 (s, 4H), 2.31-2.22 (m, 1H), 1.82 (d, 3H),
1.79-1.70 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 0.98 (d, 3H),
0.94-0.86 (m, 1H), 0.73-0.65 (m, 1H).
##STR00225##
Example 561
Ingenol
3-(3,5-dimethyl-1-(tetrahydropyran-4-ylmethyl)pyrazole-4-carboxyla-
te) (Compound 561)
[0959] Compound 561 was prepared according to Procedure e.
[0960] Starting material: Compound 661.
[0961] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.08-6.05 (m, 2H), 5.60
(s, 1H), 4.53 (bs, 1H), 4.17-4-11 (m, 4H), 4.00-3.95 (m, 2H), 3.87
(d, 2H), 3.67 (s, 1H), 3.40-3.32 (m, 2H), 2.62-2.57 (m, 1H), 2.51
(s, 3H), 2.39 (s, 3H), 2.32-2.13 (m, 2H), 1.84 (d, 3H), 1.79-1.70
(m, 1H), 1.55-1.35 (m, 5H), 1.07 (s, 3H), 1.05 (s, 3H), 0.99 (d,
3H), 0.95-0.85 (m, 1H), 0.73-0.66 (m, 1H).
##STR00226##
Example 562
Ingenol 3-(4-methyl-2-oxo-3H-thiazole-5-carboxylate) (Compound
562)
[0962] Compound 562 was prepared according to Procedure e.
[0963] Starting material: Compound 662.
[0964] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 11.91 (bs, 1H), 5.93 (m,
1H), 5.88-5.86 (m, 1H), 5.73 (s, 1H), 5.41 (d, 1H), 5.12 (s, 1H),
4.64 (t, 1H), 4.18 (m, 1H), 3.98-3.85 (m, 2H), 3.63-3.58 (m, 1H),
2.56-2.51 (m, 1H), 2.38 (s, 3H), 2.33-2.26 (m, 1H), 1.78-1.64 (m,
4H), 1.03 (s, 6H), 0.89 (d, 3H), 0.81-0.74 (m, 1H), 0.65-0.57 (m,
1H).
##STR00227##
Example 563
Ingenol 3-(2-methyl-4,5,6,7-tetrahydroindazole-3-carboxylate)
(Compound 563)
[0965] Compound 563 was prepared according to Procedure e.
[0966] Starting material: Compound 663.
[0967] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.12-6.10 (m, 1H),
6.08-6.06 (m, 1H), 5.72 (s, 1H), 4.71 (s, 1H), 4.23-4.11 (m, 7H),
3.71 (s, 1H), 2.71-2.57 (m, 6H), 2.34-2.24 (m, 1H), 1.84 (d, 3H),
1.81-1.70 (m, 5H), 1.07 (s, 3H), 1.05 (s, 3H), 1.00 (d, 3H),
0.96-0.88 (m, 1H), 0.74-0.66 (m, 1H).
##STR00228##
Example 564
Ingenol 3-(1,2-dimethylindole-3-carboxylate) (Compound 564)
[0968] Compound 564 was prepared according to Procedure e.
[0969] Starting material: Compound 664.
[0970] .sup.1H NMR (300 MHz, CDCl.sub.3) 8.04-8.01 (m, 1H),
7.33-7-19 (m, 3H), 6.13-6.11 (m, 1H), 6.07-6.05 (m, 1H), 5.72 (s,
1H), 4.62 (d, 1H), 4.19-4.13 (m, 4H), 3.81 (s, 1H), 3.68 (s, 3H),
2.76-2.65 (m, 5H), 2.29-2.20 (m, 1H), 1.89 (d, 3H), 1.76-1.67 (m,
1H), 1.05-1.03 (m, 9H), 0.99-0.91 (m, 1H), 0.72-0.64 (m, 1H).
##STR00229##
Example 565
Ingenol 3-(5-methoxy-1,2-dimethyl-indole-3-carboxylate) (Compound
565)
[0971] Compound 565 was prepared according to Procedure e.
[0972] Starting material: Compound 665.
[0973] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.56 (d, 1H), 7.19 (d,
1H), 6.88 (dd, 1H), 6.13-6.11 (m, 1H), 6.07-6.06 (m, 1H), 5.69 (s,
1H), 4.66 (d, 1H), 4.18-4.13 (m, 4H), 3.83 (s, 1H), 3.82 (s, 3H),
3.65 (s, 3H), 2.73 (s, 3H), 2.72-2.62 (m, 2H), 2.29-2.20 (m, 1H),
1.90 (d, 3H), 1.76-1.69 (m, 1H), 1.05 (s, 3H), 1.03 (s, 3H), 1.02
(d, 3H), 0.99-0.92 (m, 1H), 0.72-0.64 (m, 1H).
##STR00230##
Example 566
Ingenol 3-(1,3,5-trimethylpyrazole-4-carboxylate) (Compound
566)
[0974] Compound 566 was prepared according to Procedure e.
[0975] Starting material: Compound 630.
[0976] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.08-6.05 (m, 2H), 5.62
(s, 1H), 6.07 (d, 1H), 4.19-4.10 (m, 4H), 3.73 (s, 3H), 3.71 (s,
1H), 3.73 (t, 1H), 2.62-2.57 (m, 1H), 2.50 (s, 3H), 2.38 (s, 3H),
2.32-2.22 (m, 1H), 1.83 (d, 3H), 1.78-1.69 (m, 1H), 1.06 (s, 3H),
1.05 (s, 3H), 0.99 (d, 3H), 0.97-0.90 (m, 1H), 0.73-0.65 (m,
1H).
##STR00231##
Example 567
Ingenol 3-(4-methyl-1,2,5-oxadiazole-3-carboxylate) (Compound
567)
[0977] Compound 567 was prepared according to Procedure e.
[0978] Starting material: Compound 667.
[0979] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.18-6.17 (m, 1H),
6.09-6.07 (m, 1H), 5.88 (s, 1H), 4.67 (d, 1H), 4.23-4.10 (m, 4H),
3.71 (s, 1H), 2.66-2.60 (m, 4H), 2.31-2.21 (m, 2H), 1.86 (d, 3H),
1.84-1.74 (m, 1H), 1.07 (s, 3H), 1.04 (s, 3H), 1.02 (d, 3H),
0.96-0.89 (m, 1H), 0.75-0.67 (m, 1H).
##STR00232##
Example 568
Ingenol 3-(2-methoxy-4-methyl-thiazole-5-carboxylate) (Compound
568)
[0980] Compound 568 was prepared according to Procedure e.
[0981] Starting material: Compound 668.
[0982] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.08-6.05 (m, 2H), 5.65
(s, 1H), 4.53 (bs, 1H), 4.22-4.13 (m, 3H), 4.06 (s, 1H), 3.58 (s,
1H), 3.33 (s, 3H), 2.60 (s, 3H), 2.59-2.52 (m, 1H), 2.41 (bs, 1H),
2.31-2.22 (m, 1H), 1.81 (d, 3H), 1.78-1.73 (m, 1H), 1.07 (s, 3H),
1.05 (s, 3H), 0.99 (d, 3H), 0.96-0.89 (m, 1H), 0.74-0.67 (m,
1H).
##STR00233##
Example 569
Ingenol 3-(4,5-dimethylisoxazole-3-carboxylate) (Compound 569)
[0983] Compound 569 was prepared according to Procedure e.
[0984] Starting material: Compound 669.
[0985] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.11-6.10 (m, 1H),
6.06-6.04 (m, 1H), 5.84 (s, 1H), 4.34 (d, 1H), 4.23-4.13 (m, 3H),
4.05 (d, 1H), 3.89 (s, 1H), 2.65-2.59 (m, 2H), 2.39 (s, 3H),
2.30-2.21 (m, 1H), 2.14 (s, 3H), 1.85 (d, 3H), 1.82-1.73 (m, 1H),
1.07 (s, 3H), 1.05 (s, 3H), 1.00 (d, 3H), 0.96-0.88 (m, 1H),
0.74-0.66 (m, 1H).
##STR00234##
Example 570
Ingenol 3-(4-bromo-1-methyl-pyrazole-3-carboxylate) (Compound
570)
[0986] Compound 570 was prepared according to Procedure e.
[0987] Starting material: Compound 670.
[0988] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.50 (s, 1H), 6.11-6.09
(m,1H), 6.08-6.06 (m, 1H), 5.81 (s, 1H), 4.18-4.11 (m, 3H), 4.04
(d, 1H), 3.98 (s, 3H), 3.88 (s, 1H), 3.75 (d, 1H), 2.73-2.68 (m,
1H), 2.30-2.21 (m, 2H), 1.88 (d, 3H), 1.82-1.73 (m, 1H), 1.09 (s,
3H), 1.06 (s, 3H), 1.01 (d, 3H), 0.99-0.92 (m, 1H), 0.75-0.67 (m,
1H).
##STR00235##
Example 571
Ingenol 3-(1,3-dimethylindole-2-carboxylate) (Compound 571).
[0989] Compound 571 was prepared according to Procedure e.
[0990] Starting material: Compound 671.
[0991] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.68-7.65 (m,1H),
7.40-7.32 (m, 2H), 7.17-7.12 (m, 1H), 6.14-6.13 (m, 1H), 6.08-6.06
(m, 1H), 5.79 (s, 1H), 4.60 (bs, 1H), 4.23-4.13 (m, 4H), 4.01 (s,
3H), 3.76 (s, 1H), 2.69-2.64 (m, 1H), 2.59 (s, 3H), 2.54-2.49 (m,
1H), 2.32-2.23 (m, 1H), 1.88 (d, 3H), 1.78-1.67 (m, 1H), 1.06 (s,
3H), 1.05 (s, 3H), 1.02 (d, 3H), 0.97-0.88 (m, 1H), 0.73-0.65 (m,
1H).
##STR00236##
Example 572
Ingenol 3-(5-methoxy-1,3-dimethyl-indole-2-carboxylate) (Compound
572)
[0992] Compound 572 was prepared according to Procedure e.
[0993] Starting material: Compound 672.
[0994] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.26-7.23 (m, 1H),
7.06-7.00 (m, 2H), 6.14-6.12 (m, 1H), 6.08-6.06 (m, 1H), 5.78 (s,
1H), 4.58 (bs, 1H), 4.22-4.14 (m, 4H), 3.99 (s, 3H), 3.87 (s, 3H),
3.75 (s, 1H), 2.68-2.62 (m, 1H), 2.55 (s, 3H), 2.49 (bs, 1H),
2.33-2.23 (m, 1H), 1.88 (d, 3H), 1.78-1.69 (m, 1H), 1.06 (s, 3H),
1.05 (s, 3H), 1.02 (d, 3H), 0.97-0.88 (m, 1H), 0.73-0.65 (m,
1H).
##STR00237##
Example 573
Ingenol 3-(2,4-dimethyl-6-oxo-pyran-3-carboxylate) (Compound
573)
[0995] Compound 573 was prepared according to Procedure e.
[0996] Starting material: Compound 673.
[0997] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.14-6.13 (m, 1H),
6.10-6.08 (m, 1H), 6.04 (s, 1H), 5.75 (s, 1H), 4.76 (bs, 1H),
4.22-4.18 (m, 3H), 4.12 (s, 1H), 3.76 (s, 1H), 2.51-2.46 (m, 1H),
2.44 (s, 3H), 2.33-2.26 (m, 1H), 2.23 (d, 3H), 2.11 (bs, 1H), 1.82
(d, 3H), 1.79-1.70 (m, 1H), 1.08 (s, 3H), 1.06 (s, 3H), 0.98 (d,
3H), 0.96-0.88 (m, 1H), 0.75-0.67 (m, 1H).
##STR00238##
Example 574
Ingenol 3-(1-methyl-3-phenyl-indole-2-carboxylate) (Compound
574)
[0998] Compound 574 was prepared according to Procedure e.
[0999] Starting material: Compound 674.
[1000] .sup.1H NMR (300 MHz, CDCl.sub.3) 7.46-7.34 (m, 8H),
7.15-7.10 (m, 1H), 6.01-5.99 (m, 1H), 5.89-5.87 (m, 1H), 5.73 (s,
1H), 4.12-4.11 (m, 5H), 3.98-3.91 (m, 2H), 3.81-3.79 (d, 1H), 3.02
(s, 1H), 2.35 (bs, 1H), 1.92-1.83 (m, 1H), 1.70-1.66 (d, 4H),
1.54-1.45 (m, 1H), 1.03 (s, 3H), 1.03 (s, 3H), 0.89-0.82 (m, 1H),
0.74 (d, 3H), 0.64-0.56 (m, 1H).
##STR00239##
Example 575
Ingenol 3-(3-methyl-5-(trifluoromethyl)isoxazole-4-carboxylate)
(Compound 575)
[1001] Compound 575 was prepared according to Procedure e.
[1002] Starting material: Compound 675.
[1003] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.16-6.14 (m, 1H),
6.09-6.06 (m, 1H), 5.77 (s, 1H), 4.25-4.14 (m, 3H), 4.10 (s, 1H),
3.08 (bs, 3H), 2.57-2.48 (m, 4H), 2.31-2.22 (m, 1H), 1.81 (d, 3H),
1.78-1.69 (m, 1H), 1.06 (s, 6H), 0.99 (d, 3H), 0.94-0.87 (m, 1H),
0.74-0.66 (m, 1H).
##STR00240##
Example 576
Ingenol 3-(1,3-dimethylpyrrole-2-carboxylate) (Compound 576)
[1004] Compound 576 was prepared according to Procedure e with the
following changes: Tetrahydrofuran was replaced with methanol and
the reaction time at room temperature was 0.5 h.
[1005] Starting material: Compound 676.
[1006] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.71 (d, 1H), 6.08-6.04
(m, 2H), 5.98 (d, 1H), 5.63 (s, 1H), 4.50 (d, 1H), 4.19-4.09 (m,
4H), 3.87 (s, 3H), 3.72 (s, 1H), 2.64-2.53 (m, 2H), 2.31 (s, 3H),
2.30-2.22 (m, 1H), 1.84 (d, 3H), 1.78-1.71 (m, 1H), 1.07 (s, 3H),
1.05 (s, 3H), 0.99 (d, 3H), 0.95-0.86 (m, 1H), 0.73-0.65 (m,
1H).
##STR00241##
Example 577
Ingenol
3-(3,5-dimethyl-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxylate)
(Compound 577)
[1007] Compound 577 was prepared according to Procedure e.
[1008] Starting material: Compound 677.
[1009] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.09-6.08 (m, 1H),
6.06-6.04 (m, 1H), 5.68 (s, 1H), 4.82 (d, 1H), 4.62 (q, 2H),
4.22-4.12 (m, 4H), 3.77 (s, 1H), 2.97 (bs, 1H), 2.63-2.58 (m, 1H),
2.55 (s, 3H), 2.41 (s, 3H), 2.34-2.24 (m, 1H), 1.83 (d, 3H),
1.79-1.70 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 0.99 (d, 3H),
0.96-0.88 (m, 1H), 0.73-0.65 (m, 1H).
##STR00242##
Example 578
Ingenol 3-(1-cyclopropyl-2,5-dimethyl-pyrrole-3-carboxylate)
(Compound 578)
[1010] Compound 578 was prepared according to Procedure e.
[1011] Starting material: Compound 678.
[1012] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.18-6.17 (m, 1H),
6.04-6.00 (m, 2H), 5.58 (s, 1H), 4.42 (d, 1H), 4.16-4.05 (m, 4H),
3.60 (s, 1H), 2.93-2.87 (m, 1H), 2.76 (bs, 1H), 2.61-2.56 (m, 4H),
2.28-2.19 (m, 4H), 1.80 (d, 3H), 1.78-1.71 (m, 1H), 1.15-1.08 (m,
2H), 1.06 (s, 3H), 1.03 (s, 3H), 0.99 (d, 3H), 0.95-0.88 (m, 3H),
0.72-0.65 (m, 1H).
##STR00243##
Example 579
Ingenol 3-(1,2,5-trimethylpyrrole-3-carboxylate) (Compound
579).
[1013] Compound 579 was prepared according to Procedure e.
[1014] Starting material: Compound 679.
[1015] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.23-6.22 (m, 1H),
6.05-6.00 (m, 2H), 5.57 (s, 1H), 4.31 (d, 1H), 4.16-4.06 (m, 4H),
3.57 (s, 1H), 3.41 (s, 3H), 2.60-2.54 (m, 2H), 2.51 (s, 3H),
2.28-2.19 (m, 4H), 1.81 (d, 3H), 1.79-1.72 (m, 1H), 1.07 (s, 3H),
1.04 (s, 3H), 1.00 (d, 3H), 0.98-0.92 (m, 1H), 0.73-0.65 (m,
1H).
##STR00244##
Example 580
Ingenol 3-(2,4-dimethyl-1H-pyrrole-3-carboxylate) (Compound
580)
[1016] Compound 580 was prepared according to Procedure e.
[1017] Starting material: Compound 680.
[1018] .sup.1H NMR (300 MHz, CDCl.sub.3) 10.51 (bs, 1H), 6.09-6.05
(m, 2H), 5.95 (d, 1H), 5.83 (s, 1H), 4.89 (bs, 1H), 4.54 (s, 1H),
4.23-4.07 (m, 4H), 3.11 (bs, 1H), 2.59-2.54 (m, 1H), 2.38 (s, 3H),
2.35-2.25 (m, 4H), 1.82 (d, 3H), 1.79-1.74 (m, 1H), 1.09 (s, 3H),
1.06 (s, 3H), 0.98-0.88 (m, 4H), 0.75-0.67 (m, 1H).
##STR00245##
Example 581
Ingenol 3-(1-methylpyrrole-2-carboxylate) (Compound 581)
[1019] Compound 581 was prepared according to Procedure e.
[1020] Starting material: Compound 681.
[1021] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.96 (dd, 1H), 6.84 (t,
1H), 6.14 (dd, 1H), 6.06-6.03 (m, 2H), 5.69 (s, 1H), 4.43 (d, 1H),
4.18-4.06 (m, 4H), 3.93 (s, 3H), 3.64 (s, 1H), 2.77 (bs, 1H),
2.62-2.57 (m, 1H), 2.31-2.21 (m, 1H), 1.82 (d, 3H), 1.80-1.73 (m,
1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.01 (d, 3H), 0.97-0.91 (m, 1H),
0.74-0.66 (m, 1H).
##STR00246##
Example 582
Ingenol 3-(4-methyl-1H-pyrrole-2-carboxylate) (Compound 582)
[1022] Compound 582 was prepared according to Procedure e.
[1023] Starting material: Compound 682.
[1024] .sup.1H NMR (300 MHz, CDCl.sub.3) 9.54 (s, 1H), 6.77-6.72
(m, 2H), 6.06-6.02 (m, 2H), 5.69 (s, 1H), 4.80 (d, 1H), 4.26-4.07
(m, 4H), 3.80 (s, 1H), 2.79 (t, 1H), 2.62-2.56 (m, 1H), 2.32-2.23
(m, 1H), 2.11 (s, 3H), 1.82-1.73 (m, 4H), 1.05 (s, 3H), 1.04 (s,
3H), 1.01 (d, 3H), 0.96-0.88 (m, 1H), 0.73-0.66 (m, 1H).
##STR00247##
Example 583
Ingenol 3-(1,5-dimethylpyrrole-2-carboxylate) (Compound 583)
[1025] Compound 583 was prepared according to Procedure e.
[1026] Starting material: Compound 683.
[1027] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.91 (d, 1H), 6.04-6.02
(m, 2H), 5.94 (d, 1H), 5.67 (s, 1H), 4.39 (d, 1H), 4.17-4.05 (m,
4H), 3.83 (s, 3H), 3.64 (s, 1H), 2.80 (t, 1H), 2.61-2.56 (m, 1H),
2.30-2.21 (m, 4H), 1.81 (d, 3H), 1.79-1.72 (m, 1H), 1.07 (s, 3H),
1.04 (s, 3H), 1.01 (d, 3H), 0.97-0.91 (m, 1H), 0.73-0.65 (m,
1H).
##STR00248##
Example 584
Ingenol 3-(3-methyl-1H-pyrrole-2-carboxylate) (Compound 584)
[1028] Compound 584 was prepared according to Procedure e.
[1029] Starting material: Compound 684.
[1030] .sup.1H NMR (300 MHz, CDCl.sub.3) 9.33 (s, 1H), 6.87 (t,
1H), 6.11 (t, 1H), 6.08-6.04 (m, 2H), 5.66 (s, 1H), 4.76 (d, 1H),
4.23-4.10 (m, 4H), 3.81 (s, 1H), 2.62-2.57 (m, 2H), 2.34-2.23 (m,
4H), 1.81 (d, 3H), 1.79-1.70 (m, 1H), 1.05 (s, 3H), 1.04 (s, 3H),
1.00 (d, 3H), 0.96-0.88 (m, 1H), 0.73-0.65 (m, 1H).
##STR00249##
Example 585
Ingenol 3-(1-cyclopropylpyrrole-2-carboxylate) (Compound 585)
[1031] Compound 585 was prepared according to Procedure e.
[1032] Starting material: Compound 685.
[1033] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.95 (dd, 1H), 6.91 (t,
1H), 6.09 (dd, 1H), 6.05-6.03 (m, 2H), 5.70 (s, 1H), 4.40 (d, 1H),
4.18-4.07 (m, 4H), 3.73 (m, 1H), 3.64 (s, 1H), 2.74 (t, 1H),
2.62-2.57 (m, 1H), 2.31-2.21 (m, 1H), 1.83 (d, 3H), 1.81-1.72 (m,
1H), 1.07 (s, 3H), 1.05 (s, 3H), 1.03-0.91 (m, 8H), 0.73-0.66 (m,
1H).
##STR00250##
Example 586
Ingenol 3-(1-ethyl-2,4-dimethyl-pyrrole-3-carboxylate) (Compound
586)
[1034] Compound 586 was prepared according to Procedure e.
[1035] Starting material: Compound 686.
[1036] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.34-6.33 (m, 1H),
6.05-6.02 (m, 2H), 5.58 (s, 1H), 4.60 (d, 1H), 4.17-4.08 (m, 4H),
3.81 (q, 2H), 3.73 (s, 1H), 2.77 (bs, 1H), 2.64-2.59 (m, 1H), 2.48
(s, 3H), 2.30-2.21 (m, 1H), 2.19 (d, 3H), 1.83 (d, 3H), 1.77-1.68
(m, 1H), 1.33 (t, 3H), 1.06 (s, 3H), 1.04 (s, 3H), 0.98 (d, 3H),
0.97-0.91 (m, 1H), 0.72-0.64 (m, 1H).
##STR00251##
Example 587
Ingenol 3-(1-allyl-2,4-dimethyl-pyrrole-3-carboxylate) (Compound
587)
[1037] Compound 587 was prepared according to Procedure e.
[1038] Starting material: Compound 687.
[1039] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.32 (q, 1H), 6.05-6.03
(m, 2H), 5.94-5.81 (m, 1H), 5.60 (s, 1H), 5.23-5.18 (m, 1H),
5.03-4.96 (m, 1H), 4.62 (d, 1H), 4.39-4.36 (m, 2H), 4.17-4.08 (m,
4H), 3.74 (s, 1H), 2.81 (bs, 1H), 2.64-2.59 (m, 1H), 2.45 (s, 3H),
2.31-2.22 (m, 1H), 2.19 (d, 3H), 1.83 (d, 3H), 1.77-1.68 (m, 1H),
1.07 (s, 3H), 1.04 (s, 3H), 0.98 (d, 3H), 0.97-0.90 (m, 1H),
0.72-0.64 (m, 1H).
##STR00252##
Example 588
Ingenol
3-(1-(cyclopropylmethyl)-2,4-dimethyl-pyrrole-3-carboxylate)
(Compound 588)
[1040] Compound 588 was prepared according to Procedure e.
[1041] Starting material: Compound 688.
[1042] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.42 (q, 1H), 6.05-6.03
(m, 2H), 5.58 (s, 1H), 4.58 (d, 1H), 4.17-4.08 (m, 4H), 3.73 (s,
1H), 3.63 (d, 2H), 2.74 (s, 1H), 2.64-2.59 (m, 1H), 2.50 (s, 3H),
2.30-2.24 (m, 1H), 2.20 (d, 3H), 1.83 (d, 3H), 1.77-1.68 (m, 1H),
1.13-1.08 (m, 1H), 1.07 (s, 3H), 1.04 (s, 3H), 0.98 (d, 3H),
0.97-0.91 (m, 1H), 0.72-0.59 (m, 3H), 0.34-0.29 (m, 2H).
##STR00253##
Example 589
Ingenol 3-(1-(2-methoxyethyl)-2,4-dimethyl-pyrrole-3-carboxylate)
(Compound 589)
[1043] Compound 589 was prepared according to Procedure e.
[1044] Starting material: Compound 689.
[1045] .sup.1H NMR (300 MHz, CDCl.sub.3) 6.37 (s, 1H), 6.05-6.03
(m, 2H), 5.57 (s, 1H), 4.54 (d, 1H), 4.16-4.08 (m, 4H), 3.94 (t,
2H), 3.71 (s, 1H), 3.58 (t, 2H), 3.33 (s, 3H), 2.70-2.58 (m, 2H),
2.49 (s, 3H), 2.30-2.21 (m, 1H), 2.19 (s, 3H), 1.83 (d, 3H),
1.77-1.68 (m, 1H), 1.07 (s, 3H), 1.04 (s, 3H), 0.98 (d, 3H),
0.97-0.91 (m, 1H), 0.72-0.64 (m, 1H).
##STR00254##
Example 701
Ingenol 3-(N-ethyl-carbamate) (Compound 701)
[1046] Compound 701 was prepared according to Procedure e.
[1047] Starting material: Compound 801.
[1048] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.98 (t, 1H),
5.86-5.83 (m, 2H), 5.37 (s, 1H), 5.20 (bs, 1H), 4.85 (s, 1H),
4.19-4.15 (m, 1H), 3.95-3.84 (m, 2H), 3.57-3.5 (m, 2H) (coincided
with water absorption), 3.05-3.00 (m, 2H), 2.5 (m, 1H) (coincided
with solvent absorption), 2.31-2.23 (m, 1H), 1.71 (d, 3H),
1.68-1.63 (m, 1H), 1.05 (s, 3H), 1.03 (t, 3H), 1.03 (s, 3H), 0.87
(d, 3H), 0.84-0.74 (m, 1H), 0.65-0.57 (m, 1H).
##STR00255##
Example 702
Ingenol 3-(N,N-dimethyl-carbamate) (Compound 702)
[1049] Compound 702 was prepared according to Procedure e.
[1050] Starting material: Compound 802.
[1051] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.86-5.84 (m,
2H), 5.45 (s, 1H), 5.28 (d, 1H), 4.94 (s, 1H), 4.65 (t, 1H),
4.20-4.15 (m, 1H), 3.97-3.84 (m, 2H), 3.57-3.55 (m, 1H), 2.84 (s,
6H), 2.5 (m, 1H) (coincided with solvent absorption), 2.33-2.24 (m,
1H), 1.70 (d, 3H), 1.68-1.63 (m, 1H), 1.05 (s, 3H), 1.03 (s, 3H),
0.88 (d, 3H), 0.81-0.74 (m, 1H), 0.64-0.57 (m, 1H).
##STR00256##
Example 703
Ingenol 3-(morpholine-4-carboxylate) (Compound 703)
[1052] Compound 703 was prepared according to Procedure e.
[1053] Starting material: Compound 803.
[1054] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.86-5.85 (m,
2H), 5.51 (s, 1H), 5.29 (d, 1H), 5.05 (s, 1H), 4.62 (t, 1H), 4.17
(m, 1H), 3.97-3.83 (m, 2H), 3.60-3.53 (m, 5H), 3.40-3.32 (m, 4H),
2.45-2.40 (m, 1H), 2.32-2.23 (m, 1H), 1.70 (d, 3H), 1.68-1.63 (m,
1H), 1.05 (s, 3H), 1.03 (s, 3H), 0.87 (d, 3H), 0.81-0.74 (m, 1H),
0.64-0.56 (m, 1H).
##STR00257##
Example 704
Ingenol 3-(pyrrolidine-1-carboxylate) (Compound 704)
[1055] Compound 704 was prepared according to Procedure e.
[1056] Starting material: Compound 804.
[1057] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.86-5.83 (m,
2H), 5.45 (s, 1H), 5.24 (d, 1H), 4.95 (s, 1H), 4.60 (t, 1H),
4.19-4.15 (m, 1H), 3.99-3.84 (m, 2H), 3.56 (d, 1H), 3.43-3.39 (m,
1H), 3.30-3.18 (m, 3H), 2.5 (m, 1H) (coincided with solvent
absorption), 2.32-2.24 (m, 1H), 1.84-1.76 (m, 4H), 1.72-1.65 (m,
4H), 1.05 (s, 3H), 1.03 (s, 3H), 0.87 (d, 3H), 0.83-0.74 (m, 1H),
0.64-0.56 (m, 1H).
##STR00258##
Example 705
Ingenol 3-(N-methyl-N-phenyl-carbamate) (Compound 705)
[1058] Compound 705 was prepared according to Procedure e. Compound
705 was obtained as an amorphous compound.
[1059] Starting material: Compound 805.
[1060] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.37-7.30 (m,
4H), 7.22-7.16 (m, 1H), 5.85-5.84 (m, 1H), 5.77 (s, 1H), 5.54 (s,
1H), 5.34 (d, 1H), 4.97 (s, 1H), 4.61 (t, 1H), 4.16-4.11 (m, 1H),
3.97-3.82 (m, 2H), 3.57 (d, 1H), 3.24 (s, 3H), 2.24-2.16 (m, 1H),
2.09-1.95 (m, 1H), 1.68 (d, 3H), 1.53-1.45 (m, 1H), 1.03 (s, 3H),
1.02 (s, 3H), 0.76-0.70 (m, 1H), 0.65 (d, 3H), 0.58-0.50 (m,
1H).
##STR00259##
Example 706
Ingenol 3-(N,N-diethyl-carbamate) (Compound 706)
[1061] Compound 706 was prepared according to Procedure e.
[1062] Starting material: Compound 806.
[1063] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.87-5.84 (m,
2H), 5.49 (s, 1H), 5.27 (d, 1H), 4.94 (s, 1H), 4.60 (t, 1H),
4.21-4.16 (m, 1H), 3.97-3.83 (m, 2H), 3.58 (d, 1H), 3.38-3.10 (m,
4H), 2.5 (m, 1H) (coincided with solvent absorption), 2.34-2.25 (m,
1H), 1.70 (d, 3H), 1.69-1.62 (m, 1H), 1.05 (t, 6H), 1.05 (s, 3H),
1.03 (s, 3H), 0.88 (d, 3H), 0.88-0.74 (m, 1H), 0.64-0.56 (m,
1H).
##STR00260##
Example 707
Ingenol 3-(piperidine-1-carboxylate) (Compound 707)
[1064] Compound 707 was prepared according to Procedure e.
[1065] Starting material: Compound 807.
[1066] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.86-5.84 (m,
2H), 5.47 (s, 1H), 5.29 (d, 1H), 4.90 (s, 1H), 4.61 (t, 1H),
4.20-4.15 (m, 1H), 3.96-3.83 (m, 2H), 3.57 (d, 1H), 3.38-3.27 (m,
4H), 2.48-2.42 (m, 1H), 2.33-2.24 (m, 1H), 1.70 (d, 3H), 1.68-1.62
(m, 1H), 1.58-1.40 (m, 6H), 1.05 (s, 3H), 1.03 (s, 3H), 0.88 (d,
3H), 0.84-0.75 (m, 1H), 0.64-0.56 (m, 1H).
##STR00261##
Example 708
Ingenol 3-(N-benzyl-N-methyl-carbamate) (Compound 708)
[1067] Compound 708 was prepared according to Procedure e.
[1068] Starting material: Compound 808.
[1069] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.31-7.24 (m,
5H), 5.86-5.82 (m, 2H), 5.53 (s, 1H), 5.34-5.28 (m, 1H), 5.03 (s,
0.4H), 4.91 (s, 0.6H), 4.61 (t, 1H), 4.54-4.32 (m, 2H), 4.24-4.12
(m, 1H), 3.99-3.83 (m, 2H), 3.58 (d, 1H), 2.84 (s, 3H), 2.37-2.18
(m, 2H), 1.73-1.47 (m, 4H), 1.05 (s, 3H), 1.02 (s, 3H), 0.90-0.70
(m, 4H), 0.61-0.53 (m, 1H).
##STR00262##
Example 709
Ingenol 3-(N-cyclohexyl-N-methyl-carbamate) (Compound 709)
[1070] Compound 709 was prepared according to Procedure e.
[1071] Starting material: Compound 809.
[1072] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 5.86-5.85 (m,
2H), 5.50 (s, 1H), 5.27-5.25 (m, 1H), 4.96-4.92 (m, 1H), 4.61 (t,
1H), 4.21-4.16 (m, 1H), 3.97-3.75 (m, 3H), 3.58 (d, 1H), 2.72 (s,
3H), 2.5 (m, 1H) (coincided with solvent absorption), 2.36-2.26 (m,
1H), 1.78-1.09 (m, 14H), 1.04 (s, 3H), 1.03 (s, 3H), 0.88 (d, 3H),
0.84-0.74 (m, 1H), 0.65-0.57 (m, 1H).
##STR00263##
Example 710
Ingenol 3-(N-cyclohexyl-carbamate) (Compound 710)
[1073] Compound 710 was prepared according to Procedure e.
[1074] Starting material: Compound 810.
[1075] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 6.90 (d, 1H),
5.85-5.81 (m, 2H), 5.35 (s, 1H), 5.16 (d, 1H), 4.84 (m, 1H), 4.58
(t, 1H), 4.20-4.15 (m, 1H), 3.97-3.81 (m, 2H), 3.50 (d, 1H),
3.25-3.20 (m, 1H), 2.5 (m, 1H) (coincided with solvent absorption),
2.32-2.23 (m, 1H), 1.80-1.52 (m, 10H), 1.30-1.09 (m, 4H), 1.06 (s,
3H), 1.04 (s, 3H), 0.87 (d, 3H), 0.81-0.74 (m, 1H), 0.65-0.57 (m,
1H).
##STR00264##
Example 711
Ingenol 3-(N-phenyl-carbamate) (Compound 711)
[1076] Compound 711 was prepared according to Procedure e.
[1077] Starting material: Compound 811.
[1078] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 9.44 (s, 1H),
7.50 (d, 2H), 7.29 (t, 2H), 6.99 (t, .sup.1H), 5.91-5.87 (m, 2H),
5.55 (s, 1H), 5.31 (d, 1H), 4.99 (s, 1H), 4.62 (t, 1H), 4.23-4.18
(m, 1H), 3.99-3.84 (m, 2H), 3.60 (d, 1H), 2.60-2.57 (m, 1H),
2.36-2.27 (m, 1H), 1.76 (d, 3H), 1.74-1.66 (m, 1H), 1.05 (s, 3H),
1.04 (s, 3H), 0.91 (d, 3H), 0.82-0.75 (m, 1H), 0.67-0.59 (m,
1H).
##STR00265##
Example 712
Ingenol 3-(N-(indan-1-yl)-carbamate) (Compound 712)
[1079] Compound 712 was prepared according to Procedure e.
[1080] Starting material: Compound 812.
[1081] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.43 (d, 1H),
7.26-7.18 (m, 4H), 5.86-5.84 (m, .sup.2H), 5.46 (s, 1H), 5.20 (d,
1H), 5.01 (q, 1H), 4.87 (s, 1H), 4.59 (t, 1H), 4.21-4.15 (m, 1H),
3.99-3.83 (m, 2H), 3.54 (d, 1H), 2.98-2.89 (m, 1H), 2.84-2.73 (m,
1H), 2.47-2.35 (m, 2H), 2.31-2.22 (m, 1H), 1.91-1.79 (m, 1H),
1.78-1.62 (m, 4H), 1.05 (s, 3H), 1.03 (s, 3H), 0.86 (d, 3H),
0.81-0.74 (m, 1H), 0.64-0.57 (m, 1H).
##STR00266##
Example 713
Ingenol 3-(3,3-dimethyl-piperidine-1-carboxylate) (Compound
713)
[1082] Compound 713 was prepared according to Procedure e.
[1083] Starting material: Compound 813.
[1084] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.04-6.02 (m, 1H),
5.99 (s, 1H), 5.19-5.17 (m, 1H), 4.78-4.69 (m, 1H), 4.16-4.07 (m,
3H), 4.01 (bs, 1H), 3.85-3.77 (m, 1H), 3.49-3.05 (m, 4H), 2.66 (bs,
1H), 2.51 (m, 1H), 2.29-2.22 (m, 1H), 1.78 (m, 3H), 1.70-1.55 (m,
3H), 1.42-1.31 (m, 2H), 1.10 (s, 3H), 1.04 (s, 3H), 0.99-0.82 (m,
10H), 0.72-0.65 (m, 1H).
##STR00267##
Example 714
Ingenol 3-(N-Methyl-N-tetralin-1-yl-carbamate) (Compound 714)
[1085] Compound 714 was prepared according to Procedure e.
[1086] Starting material: Compound 814.
[1087] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.19-7.10 (m, 4H),
6.06-5.95 (m, 2H), 5.50-5.20 (m, 2H), 4.74-4.50 (2 bs, 1H),
4.18-3.55 (m, 5H), 2.77-1.59 (m, 16H), 1.16-1.05 (m, 6H), 0.97-0.82
(m, 4H), 0.72-0.63 (m, 1H).
##STR00268##
Example 715
Ingenol 3-(N-(2-cyano-1-methyl-ethyl)-N-methyl-carbamate) (Compound
715)
[1088] Compound 715 was prepared according to Procedure e.
[1089] Starting material: Compound 815.
[1090] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.05-6.01 (m, 2H),
5.26 (s, 1H), 4.84-4.38 (m, 2H), 4.15-4.09 (m, 3H), 4.03 (m, 1H),
3.89-3.70 (m, 1H), 2.91-2.83 (m, 3H), 2.64-2.42 (m, 3H), 2.31-2.23
(m, 1H), 1.85-1.71 (m, 4H), 1.60 (m, 2H), 1.40-1.35 (m, 2H),
1.11-1.10 (m, 3H), 1.05 (s, 3H), 0.98-0.98 (m, 4H), 0.73-0.65 (m,
1H).
##STR00269##
Example 716
Ingenol 3-(N-methyl-N-((S)-1-phenethyl)-carbamate) (Compound
716)
[1091] Compound 716 was prepared according to Procedure e.
[1092] Starting material: Compound 816.
[1093] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.35-7.27 (m, 5H),
6.05-6.04 (m, 1H), 6.00 (s, 1H), 5.57-5.40 (m, 1H), 5.29 (s, 1H),
4.73-4.45 (2 bs, 1H), 4.13-4.08 (m, 3H), 4.03 (s, 1H), 3.76-3.69 (2
bs, 1H), 2.73-2.17 (m, 6H), 1.81 (d, 3H), 1.80-1.54 (m, 4H), 1.11
(s, 3H), 1.05 (s, 3H), 0.95-0.84 (m, 4H), 0.70-0.62 (m, 1H).
##STR00270##
Example 717
Ingenol 3-(N-methyl-N-(cyclopropylmethyl)-carbamate) (Compound
717)
[1094] Compound 717 was prepared according to Procedure e.
[1095] Starting material: Compound 817.
[1096] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.04-6.03 (d, 1H),
5.99 (s, 1H), 5.20-5.17 (m, 1H), 4.73 (bs, 1H), 4.16-4.06 (m, 3H),
4.02 (m, 1H), 3.83-3.77 (m, 1H), 3.29-3.10 (m, 2H), 3.00 (s, 3H),
2.63 (bs, 1H), 2.54-2.50 (m, 1H), 2.30-2.21 (m, 1H), 1.80-1.70 (m,
4H), 1.10 (s, 3H), 1.05 (s, 3H), 0.99-0.88 (m, 5H), 0.73-0.65 (m,
1H), 0.56-0.50 (m, 2H), 0.26-0.19 (m, 2H).
##STR00271##
Example 718
Ingenol 3-(N-(3-fluoro-phenyl)-N-methyl-carbamate) (Compound
718)
[1097] Compound 718 was prepared according to Procedure e. Compound
718 was obtained as an amorphous compound.
[1098] Starting material: Compound 818.
[1099] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.36-7.28 (m, 1H),
7.09-7.02 (m, 2H), 6.99-6.93 (m, 1H), 6.00 (d, 1H), 5.94 (s, 1H),
5.35 (s, 1H), 4.38 (bs, 1H), 4.13-4.05 (m, 3H), 3.99 (d, 1H), 3.59
(s, 1H), 3.32 (s, 3H), 2.45 (t, 1H), 2.19-2.12 (m, 2H), 1.76 (d,
3H), 1.70-1.62 (m, 1H), 1.09 (s, 3H), 1.05 (s, 3H), 0.94-0.88 (m,
1H), 0.79 (d, 3H), 0.70-0.62 (m, 1H).
##STR00272##
Example 719
Ingenol 3-(N-(2,5-dimethylpyrazol-3-yl)-N-methyl-carbamate)
(Compound 719)
[1100] Compound 719 was prepared according to Procedure e.
[1101] Starting material: Compound 819.
[1102] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.02 (bd, 1H),
5.95 (bs, 1H), 5.88 (s, 1H), 5.40 (s, 1H), 4.20-4.04 (m, 4H), 3.96
(m, 1H), 3.62 (s, 3H), 3.41 (bs, 1H), 3.21 (s, 3H), 2.51 (bs, 1H),
2.22 (s, 3H), 2.09-2.00 (m, 1H), 1.80-1.60 (m, 5H), 1.07 (s, 3H),
1.05 (s, 3H), 0.92-0.86 (m, 1H), 0.77 (bd, 3H), 0.69-0.64 (m,
1H).
##STR00273##
Example 720
Ingenol 3-(N-(3,5-dimethylisoxazol-4-yl)-N-methyl-carbamate)
(Compound 720)
[1103] Compound 720 was prepared according to Procedure e.
[1104] Starting material: Compound 820.
[1105] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.05-6.02 (m, 2H),
5.28 (s, 1H), 4.79 (bs, 1H), 4.37-4.24 (m, 2H), 4.14-4.10 (m, 3H),
4.04 (bs, 1H), 3.83 (bs, 1H), 2.80 (s, 4H), 2.49 (bs, 1H), 2.38 (s,
3H), 2.31-2.22 (m, 4H), 1.83-1.69 (m, 4H), 1.09 (s, 3H), 1.05 (s,
3H), 0.97-0.90 (m, 4H), 0.72-0.65 (m, 1H).
##STR00274##
Example 721
Ingenol 3-(N-(1,5-dimethylpyrazol-3-yl)-N-methyl-carbamate)
(Compound 721)
[1106] Compound 721 was prepared according to Procedure e.
[1107] Starting material: Compound 821.
[1108] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.20-5.87 (m, 4H),
5.53 (s, 1H), 4.17-4.11 (m, 3H), 3.89 (d, 1H), 3.69 (s, 3H), 3.50
(bs, 1H), 3.28 (s, 3H), 2.51 (bs, 1H), 2.30-2.21 (m, 5H), 1.85 (d,
3H), 1.72-1.63 (m, 1H), 1.13 (s, 3H), 1.06 (s, 3H), 1.00-0.93 (m,
1H), 0.85 (d, 3H), 0.72-0.65 (m, 1H).
##STR00275##
Example 722
Ingenol 3-(N-cyclopentyl-N-methyl-carbamate) (Compound 722)
[1109] Compound 722 was prepared according to Procedure e.
[1110] Starting material: Compound 822.
[1111] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.05-6.03 (m, 1H),
5.99-5.98 (bs, 1H), 5.16 (2xs, 1H), 4.70 (bs, 1H), 4.17-4.02 (m,
4H), 3.77 (s, 1H), 3.32-3.27 (m, 1H), 2.81 (s, 3H), 2.53-2.50 (m,
2H), 2.29-2.19 (m, 1H), 1.85-1.70 (m, 8H), 1.33-1.13 (m, 4H), 1.11
(s, 3H), 1.05 (s, 3H), 0.97-0.88 (m, 4H), 0.73-0.65 (m, 1H).
##STR00276##
Example 723
Ingenol 3-(N-cyclopropyl-N-methyl-carbamate) (Compound 723)
[1112] Compound 723 was prepared according to Procedure e.
[1113] Starting material: Compound 823.
[1114] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.05-6.03 (m, 1H),
6.00-5.98 (m, 1H), 5.15 (s, 1H), 4.46 (bs, 1H), 4.16-4.02 (m, 4H),
3.72 (s, 1H), 3.36-3.28 (m, 3H), 2.92 (s, 1H), 2.60-2.50 (m, 2H),
2.29-2.20 (m, 1H), 1.81 (d, 3H), 1.80-1.71 (m, 1H), 1.11 (s, 3H),
1.05 (s, 3H), 0.97-0.90 (m, 4H), 0.77-0.65 (m, 5H).
##STR00277##
Example 724
Ingenol 3-(N-methyl-N-(2-pyridyl)-carbamate) (Compound 724)
[1115] Compound 724 was prepared according to Procedure e.
[1116] Starting material: Compound 824.
[1117] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.36-8.34 (m, 1H),
7.81-7.75 (m, 1H), 7.29 (d, 1H), 7.15-7.11 (m, 1H), 6.34 (bs, 1H),
6.04-6.02 (m, 1H), 5.98-5.96 (m, 1H), 5.77 (s, 1H), 4.19-4.13 (m,
3H), 3.90 (d, 1H), 3.61 (d, 1H), 3.44 (s, 3H), 2.49 (t, 1H),
2.34-2.25 (m, 1H), 2.09-2.04 (m, 1H), 1.81 (d, 3H), 1.72-1.64 (m,
1H), 1.18 (s, 3H), 1.08 (s, 3H), 0.99-0.93 (m, 1H), 0.78 (d, 3H),
0.72-0.64 (m, 1H).
##STR00278##
Example 725
Ingenol 3-(4-oxo-2,3-dihydroquinoline-1-carboxylate) (Compound
725)
[1118] Compound 725 was prepared according to Procedure e.
[1119] Starting material: Compound 825.
[1120] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.02-7.99 (m, 1H),
7.81 (d, 1H), 7.53-7.48 (m, 1H), 7.24-7.19 (m, 1H), 6.06 (d, 1H),
6.00 (d, 1H), 5.53 (s, 1H), 4.89 (d, 1H), 4.36-4.27 (m, 1H),
4.18-4.05 (m, 5H), 3.83 (s, 1H), 2.85-2.75 (m, 3H), 2.40-2.35 (m,
1H), 2.30-2.20 (m, 1H), 1.84 (d, 3H), 1.72-1.63 (m, 1H), 1.06 (s,
3H), 1.04 (s, 3H), 0.93-0.86 (m, 4H), 0.71-0.63 (m, 1H).
##STR00279##
Example 726
Ingenol 3-(3,4-dihydro-2H-quinoline-1-carboxylate) (Compound
726)
[1121] Compound 726 was prepared according to Procedure e.
[1122] Starting material: Compound 826.
[1123] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.68 (bd, 1H),
7.17-7.00 (m, 3H), 6.03-6.01 (m, 1H), 5.98 (d, 1H), 5.43 (s, 1H),
4.64 (bs, 1H), 4.14-4.09 (m, 3H), 4.03 (d, 1H), 3.84-3.72 (m, 3H),
2.80 (t, 2H), 2.67 (bs, 1H), 2.43 (bs, 1H), 2.25-2.19 (m, 1H),
2.02-1.93 (m, 2H), 1.83 (d, 3H), 1.74-1.65 (m, 1H), 1.08 (s, 3H),
1.04 (s, 3H), 0.93-0.86 (m, 4H), 0.71-0.63 (m, 1H).
##STR00280##
Example 727
Ingenol 3-(indoline-1-carboxylate) (Compound 727)
[1124] Compound 727 was prepared according to Procedure e.
[1125] Starting material: Compound 827.
[1126] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.87 (bd, 1H),
7.18 (d, 2H), 6.99 (t, 1H), 6.06-6-05 (m, 2H), 5.41 (s, 1H), 4.62
(s, 1H), 4.17-4.02 (m, 6H), 3.80 (s, 1H), 3.17 (t, 2H), 2.57 (bs,
1H), 2.43 (bs, 1H), 2.31-2.23 (m, 1H), 1.85 (s, 3H), 1.78-1.73 (m,
1H), 1.08 (s, 3H), 1.04 (s, 3H), 0.99 (d, 3H), 0.95-0.90 (m, 1H),
0.73-0.65 (m, 1H).
##STR00281##
Example 728
Ingenol 3-(azepane-1-carboxylate) (Compound 728)
[1127] Compound 728 was prepared according to Procedure e.
[1128] Starting material: Compound 828.
[1129] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.04-6.02 (m, 1H),
5.98 (m, 1H), 5.20-5.19 (m, 1H), 5.87-5.85 (m, 1H), 4.13-4.08 (m,
3H), 4.03-4.01 (m, 1H), 3.84-3.81 (m, 1H), 3.47-3.26 (m, 4H),
2.80-2.76 (m, 1H), 2.55-2.50 (m, 1H), 2.30-2.22 (m, 1H), 1.80 (d,
3H), 1.75-1.56 (m, 9H), 1.11 (s, 3H), 1.04 (s, 3H), 0.94 (d, 3H),
0.91-0.86 (m, 1H), 0.72-0.65 (m, 1H).
##STR00282##
Example 729
Ingenol 3-(N-(4-chloro-phenyl)-N-methyl-carbamate) (Compound
729)
[1130] Compound 729 was prepared according to Procedure e.
[1131] Starting material: Compound 829.
[1132] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.35-7.30 (m, 2H),
7.23-7.20 (m, 2H), 6.00 (d, 1H), 5.93 (bs, 1H), 5.34 (s, 1H), 4.48
(bs, 1H), 4.13-4.05 (m, 3H), 3.98 (s, 1H), 3.60 (s, 1H), 3.30 (s,
3H), 2.62 (bs, 1H), 2.15-2.10 (m, 1H), 1.75 (s, 3H), 1.70-1.64 (m,
2H), 1.09 (s, 3H), 1.05 (s, 3H), 0.94-0.86 (m, 4H), 0.70-0.62 (m,
1H).
##STR00283##
Example 730
Ingenol 3-(N-(4-fluoro-phenyl)-N-methyl-carbamate) (Compound
730)
[1133] Compound 730 was prepared according to Procedure e.
[1134] Starting material: Compound 830.
[1135] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.28-7.01 (m, 4H),
6.00-5.98 (m, 1H), 5.91 (bs, 1H), 5.34 (s, 1H), 4.48 (bs, 1H),
4.11-4.04 (m, 3H), 3.97 (d, 1H), 3.59 (bs, 1H), 3.29 (s, 3H), 2.71
(bs, 1H), 2.12 (bs, 1H), 1.74 (s, 3H), 1.60 (bs, 2H), 1.09 (s, 3H),
1.05 (s, 3H), 0.94-0.87 (m, 1H), 0.73 (bs, 3H), 0.69-061 (m,
1H).
##STR00284##
Example 731
Ingenol 3-(N-methyl-N-(2-methoxy-phenyl)-carbamate) (Compound
731)
[1136] Compound 731 was prepared according to Procedure e.
[1137] Starting material: Compound 831.
[1138] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.32-7.28 (m, 1H),
7.19 (d, 1H), 7.02-6.98 (m, 2H), 5.99 (d, 1H), 5.82 (d, 1H), 5.68
(bs, 1H), 4.24 (s, 1H), 4.12 (s, 2H), 3.98 (d, 1H), 3.88-3.80 (m,
4H), 3.30-3.24 (m, 4H), 2.40 (bs, 1H), 1.95-1.91 (m, 1H), 1.72 (d,
3H), 1.55-1.48 (m, 2H), 1.10 (s, 3H), 1.04 (s, 3H), 0.95-0.87 (m,
1H), 0.64-0.55 (m, 4H).
##STR00285##
Example 732
Ingenol 3-(N-methyl-N-(2-methyl-phenyl)-carbamate) (Compound
732)
[1139] Compound 732 was prepared according to Procedure e.
[1140] Starting material: Compound 832.
[1141] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.23-7.16 (m, 4H),
6.04-5.80 (m, 2H), 5.41 (s, 1H), 4.11-3.90 (m, 4H), 3.24-3.16 (m,
4H), 2.29-2.19 (m, 4H), 1.77 (s, 3H), 1.72-1.45 (m, 4H), 1.06-1.02
(m, 6H), 0.92-0.83 (m, 1H), 0.64-0.56 (m, 4H).
##STR00286##
Example 733
Ingenol 3-(3-oxo-2,4-dihydroquinoxaline-1-carboxylate) (Compound
733)
[1142] Compound 733 was prepared according to Procedure e.
[1143] Starting material: Compound 833.
[1144] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.72 (bs, 1H),
7.68 (bd, 1H), 7.16-7.10 (m, 1H), 7.06-7.03 (m, 1H), 6.90 (dd, 1H),
6.04-6.02 (m, 2H), 5.57 (s, 1H), 4.72 (d, 1H), 4.49 (d, 1H), 4.39
(d, 1H), 4.20-4.11 (m, 3H), 4.02-4.00 (m, 2H), 2.77 (bs, 1H),
2.31-2.17 (m, 2H), 1.82 (d, 3H), 1.68-1.60 (m, 1H), 1.06 (s, 3H),
1.04 (s, 3H), 0.93-0.84 (m, 4H), 0.70-0.62 (m, 1H).
##STR00287##
Example 734
Ingenol 3-(N-ethyl-N-phenyl-carbamate) (Compound 734)
[1145] Compound 734 was prepared according to Procedure e.
[1146] Starting material: Compound 834.
[1147] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.40-7.20 (m, 5H),
5.99-5.97 (d, 1H), 5.88 (bs, 1H), 5.34 (s, 1H), 4.09-3.93 (m, 5H),
3.76-3.66 (dq, 2H), 3.44 (bs, 1H), 2.64 (bs, 1H), 2.01 (bs, 1H),
1.80-1.53 (m, 5H), 1.18 (t, 3H), 1.08 (s, 3H), 1.04 (s, 3H),
0.95-0.89 (m, 1H), 0.72-0.58 (m, 4H).
##STR00288##
Example 735
Ingenol 3-(2-trifluoromethyl-pyrrolidine-1-carboxylate) (Compound
735)
[1148] Compound 735 was prepared according to Procedure e.
[1149] Starting material: Compound 835.
[1150] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.04-6.00 (m, 2H),
5.31 (s, 1H), 4.84 (bs, 1H), 4.49-4.40 (bd, 1H), 4.16-4.02 (m, 4H),
3.83-3.47 (m, 3H), 2.90 (bs, 1H), 2.49 (bs, 1H), 2.31-2.22 (m, 1H),
2.13-1.91 (m, 4H), 1.80-1.70 (m, 4H), 1.10-1.09 (2xs, 3H), 1.05 (s,
3H), 0.97-0.89 (m, 4H), 0.73-0.65 (m, 1H).
##STR00289##
Example 736
Ingenol 3-(3-azabicyclo[3.2.2]nonane-3-carboxylate) (Compound
736)
[1151] Compound 736 was prepared according to Procedure e.
[1152] Starting material: Compound 836.
[1153] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.04-6.03 (m, 1H),
5.99-5.98 (m, 1H), 5.18 (s, 1H), 4.77 (bs, 1H), 4.12-4.07 (m, 3H),
4.03 (s, 1H), 3.84 (s, 1H), 3.74-3.65 (m, 2H), 3.59-3.50 (m, 2H),
2.60 (bs, 1H), 2.55-2.50 (m, 1H), 2.29-2.21 (m, 1H), 2.06-2.01 (bd,
2H), 1.80 (d, 3H), 1.78-1.62 (m, 9H), 1.11 (s, 3H), 1.04 (s, 3H),
0.99-0.90 (m, 4H), 0.72-0.65 (m, 1H).
##STR00290##
Example 737
Ingenol 3-(2,3-dihydro-1,4-benzoxazine-4-carboxylate) (Compound
737)
[1154] Compound 737 was prepared according to Procedure e.
[1155] Starting material: Compound 837.
[1156] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.81 (bs, 1H),
7.05-6.99 (m, 1H), 6.91-6.84 (m, 2H), 6.06-6.05 (m, 1H), 5.98-5.96
(m, 1H), 5.49 (s, 1H), 4.77 (s, 1H), 4.29 (t, 2H), 4.17-4.11 (m,
3H), 4.05-3.86 (m, 3H), 3.75 (s, 1H), 2.71 (s, 1H), 2.45-2.40 (m,
1H), 2.29-2.20 (m, 1H), 1.83 (d, 3H), 1.73-1.64 (m, 1H), 1.06 (s,
3H), 1.05 (s, 3H), 0.94-0.86 (m, 4H), 0.71-0.63 (m, 1H).
##STR00291##
Example 738
Ingenol 3-(N-(2-fluoro-phenyl)-N-methyl-carbamate) (Compound
738)
[1157] Compound 738 was prepared according to Procedure e.
[1158] Starting material: Compound 838. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.31-7.24 (m, 2H), 7.17-7.08 (m, 2H), 6.00-5.98
(m, 1H), 5.85 (s, 1H), 5.44 (s, 1H), 4.18-3.92 (m, 6H), 3.53 (s,
1H), 3.28 (s, 3H), 2.68 (s, 1H), 2.08-2.00 (m, 1H), 1.80 (d, 3H),
1.8-1.7 (m, 1H), 1.08 (s, 3H), 1.04 (s, 3H), 0.93-0.89 (m, 1H),
0.68-0.60 (m, 4H).
##STR00292##
Example 739
Ingenol 3-(3-methyl-2,3-dihydro-1,4-benzoxazine-4-carboxylate)
(Compound 739)
[1159] Compound 739 was prepared according to Procedure e.
[1160] Starting material: Compound 839.
[1161] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.98-7.95 (d, 1H),
7.05-6.98 (m, 1H), 6.91-6.85 (m, 2H), 6.08-5.96 (m, 2H), 5.48 (s,
1H), 4.88 (s, 1H), 4.73-4.68 (m, 1H), 4.20-4.04 (m, 6H), 3.83 (s,
1H), 2.75 (s, 1H), 2.54-2.48 (m, 1H), 2.38-2.29 (m, 1H), 1.81 (d,
3H), 1.79-1.72 (m, 1H), 1.25 (d, 3H), 1.09 (s, 3H), 1.06 (s, 3H),
0.97 (d, 3H), 0.91-0.86 (m, 1H), 0.74-0.64 (m, 1H).
##STR00293##
Example 740
Ingenol 3-(2-trifluoromethyl-pyrrolidine-1-carboxylate) (ISOMER A)
(Compound 740)
[1162] Compound 740 was prepared according to Procedure e. Compound
740 was the first isomer to be collected from the chromatographic
purification.
[1163] Starting material: Compound 835.
[1164] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.06-6.02 (m, 2H),
5.26 (s, 1H), 4.51 (s, 1H), 4.39 (s, 1H), 4.14-3.97 (m, 4H),
3.86-3.51 (m, 3H), 2.50-2.02 (m, 7H), 1.81 (s, 3H), 1.80-1.71 (m,
1H), 1.10 (s, 3H), 1.05 (s, 3H), 0.96 (d, 3H), 0.95-0.90 (m, 1H),
0.73-0.66 (m, 1H).
##STR00294##
Example 741
Ingenol 3-(2-trifluoromethyl-pyrrolidine-1-carboxylate) (ISOMER B)
(Compound 741)
[1165] Compound 741 was prepared according to Procedure e. Compound
741 was the second isomer to be collected from the chromatographic
purification.
[1166] Starting material: Compound 835.
[1167] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.06-6.00 (m, 2H),
5.25 (s, 1H), 4.59-4.43 (m, 2H), 4.14-4.03 (m, 4H), 3.72-3.52 (m,
3H), 2.50-2.02 (m, 7H), 1.81-1.72 (m, 4H), 1.11 (s, 3H), 1.05 (s,
3H), 0.99-0.93 (m, 4H), 0.71-0.66 (m, 1H).
##STR00295##
Example 742
Ingenol
3-(N-methyl-N-(N-(tert-butyloxycarbonyl)-4-piperidyl)-carbamate)
(Compound 742)
[1168] Compound 742 was prepared according to Procedure e.
[1169] Starting material: Compound 842.
[1170] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.05-6.03 (m, 1H),
6.00 (bs, 1H), 5.26-5.22 (m, 1H), 4.75-4.68 (m, 1H), 4.20-4.02 (m,
7H), 3.74 (s, 1H), 2.80-2.51 (m, 7H), 2.29-2.20 (m, 1H), 1.80 (d,
3H), 1.78-1.62 (m, 5H), 1.47 (s, 9H), 1.10 (s, 3H), 1.05 (s, 3H),
0.99-0.93 (m, 4H), 0.73-0.65 (m, 1H).
##STR00296##
Example 743
Ingenol 3-(N-methyl-N-(3-methyl-phenyl)-carbamate) (Compound
743)
[1171] Compound 743 was prepared according to Procedure e.
[1172] Starting material: Compound 843.
[1173] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.27-7.22 (m, 1H),
7.09-7.04 (m, 3H), 5.98-5.97 (m, 1H), 5.91 (bs, 1H), 5.33 (s, 1H),
4.11-3.94 (m, 5H), 3.48 (bs, 1H), 3.30 (s, 3H), 2.54 (bs, 1H), 2.35
(s, 3H), 2.03 (bs, 1H), 1.77 (s, 3H), 1.65-1.56 (m, 2H), 1.08 (s,
3H), 1.04 (s, 3H), 0.93-0.75 (m, 4H), 0.67-0.59 (m, 1H).
##STR00297##
Example 744
Ingenol 3-(3,4-dihydro-2H-quinoxaline-1-carboxylate) (Compound
744)
[1174] Compound 744 was prepared according to Procedure e.
[1175] Starting material: Compound 844.
[1176] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.87 (bd, 1H),
7.67 (bd, 1H), 7.23-7.11 (m, 2H), 6.07-6.05 (m, 2H), 5.50 (s, 1H),
4.64 (d, 1H), 4.19-3.96 (m, 9H), 3.78 (s, 1H), 2.39-2.22 (m, 3H),
1.84 (d, 3H), 1.75-1.67 (m, 1H), 1.09 (s, 3H), 1.05 (s, 3H),
0.96-0.85 (m, 4H), 0.72-0.64 (m, 1H).
##STR00298##
Example 745
Ingenol 3-(isoindoline-2-carboxylate) (Compound 745)
[1177] Compound 745 was prepared according to Procedure e.
[1178] Starting material: Compound 845.
[1179] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.31-7.25 (m, 4H),
6.05-6.03 (m, 2H), 5.36 (s, 1H), 4.89 (bs, 1H), 4.75 (s, 4H),
4.17-4.04 (m, 5H), 3.94 (s, 1H), 2.61-2.56 (m, 1H), 2.33-2.24 (m,
1H), 1.83 (d, 3H), 1.81-1.71 (m, 1H), 1.08 (s, 3H), 1.02 (s, 3H),
1.00 (d, 3H), 0.98-0.90 (m, 1H), 0.73-0.65 (m, 1H).
##STR00299##
Example 746
Ingenol 3-(N-methyl-N-(tetrahydropyran-4-ylmethyl)-carbamate)
(Compound 746)
[1180] Compound 746 was prepared according to Procedure e.
[1181] Starting material: Compound 846.
[1182] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.05-6.01 (m, 2H),
5.20 (d, 1H), 4.74 (s, 1H), 4.11-3.95 (m, 6H), 3.78 (d, 1H),
3.41-3.31 (m, 2H), 3.23-3.11 (m, 2H), 2.96 (s, 3H), 2.67 (bs, 1H),
2.53-2.51 (m, 1H), 2.29-2.19 (m, 1H), 1.94-1.86 (m, 1H), 1.80-1.70
(m, 4H), 1.59-1.54 (m, 2H), 1.40-1.27 (m, 2H), 1.09 (s, 3H), 1.05
(s, 3H), 0.98-0.88 (m, 4H), 0.73-0.65 (m, 1H).
##STR00300##
Example 747
Ingenol 3-(N-methyl-N-(tetrahydropyran-4-yl)-carbamate) (Compound
747)
[1183] Compound 747 was prepared according to Procedure e.
[1184] Starting material: Compound 847.
[1185] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.05-6.03 (m, 1H),
6.00 (bs, 1H), 5.23 (bs, 1H), 4.73 (bs, 1H), 4.25 (bs, 1H),
4.13-4.01 (m, 6H), 3.75 (s, 1H), 3.50-3.39 (m, 2H), 2.83 (s, 3H),
2.68 (bs, 1H), 2.52 (bs, 1H), 2.29-2.20 (m, 1H), 1.82-1.65 (m, 8H),
1.10 (s, 3H), 1.05 (s, 3H), 0.99-0.92 (m, 4H), 0.73-0.65 (m,
1H).
##STR00301##
Example 748
Ingenol 3-(N-methyl-N-(3-methoxy-phenyl)-carbamate) (Compound
748)
[1186] Compound 748 was prepared according to Procedure e.
[1187] Starting material: Compound 848.
[1188] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.29-7.24 (m, 1H),
6.86-6.80 (m, 3H), 5.98-5.96 (m, 1H), 5.92 (bs, 1H), 5.36 (s, 1H),
4.16-3.93 (m, 5H), 3.80 (s, 3H), 3.52 (bs, 1H), 3.31 (s, 3H), 2.63
(bs, 1H), 2.05 (bs, 2H), 1.80-1.57 (m, 4H), 1.08 (s, 3H), 1.04 (s,
3H), 0.95-0.89 (m, 1H), 0.75 (bs, 3H), 0.67-0.59 (m, 1H).
##STR00302##
Example 749
Ingenol 3-(N-cyclobutyl-N-methyl-carbamate) (Compound 749)
[1189] Compound 749 was prepared according to Procedure e.
[1190] Starting material: Compound 849.
[1191] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.04-6.03 (d, 1H),
5.99-5.98 (m, 1H), 5.18 (s, 1H), 4.81-4.73 (m, 1H), 4.60-4.35 (bs,
1H), 4.12-4.00 (m, 4H), 3.79 (s, 1H), 2.89 (s, 3H), 2.68 (bs, 1H),
2.55-2.50 (m, 1H), 2.30-2.22 (m, 1H), 2.19-2.09 (m, 4H), 1.79 (d,
3H), 1.78-1.62 (m, 3H), 1.10 (s, 3H), 1.04 (s, 3H), 0.99-0.92 (m,
4H), 0.72-0.65 (m, 1H).
##STR00303##
Example 750
Ingenol 3-(N-allyl-N-methyl-carbamate) (Compound 750)
[1192] Compound 750 was prepared according to Procedure e.
[1193] Starting material: Compound 850.
[1194] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.05-6.03 (m, 1H),
6.00-5.98 (m, 1H), 5.83-5.73 (m, 1H), 5.25-5.14 (m, 3H), 4.46 (bs,
1H), 4.12-3.76 (m, 7H), 2.94 (s, 3H), 2.56-2.50 (m, 2H), 2.28-2.21
(m, 1H), 1.80 (d, 3H), 1.78-1.70 (m, 1H), 1.10 (s, 3H), 1.05 (s,
3H), 0.97-0.88 (m, 4H), 0.73-0.65 (m, 1H).
##STR00304##
Example 751
Ingenol 3-(N-methyl-N-prop-2-ynyl-carbamate) (Compound 751)
[1195] Compound 751 was prepared according to Procedure e.
[1196] Starting material: Compound 851.
[1197] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.05-6.02 (m, 2H),
5.38 (bs, 1H), 4.21-4.01 (m, 7H), 3.80 (bs, 1H), 3.02 (s, 3H), 2.51
(bs, 2H), 2.30-2.21 (m, 2H), 1.81 (d, 3H), 1.78-1.71 (m, 1H), 1.10
(s, 3H), 1.05 (s, 3H), 0.99-0.90 (m, 4H), 0.73-0.65 (m, 1H).
##STR00305##
Example 752
Ingenol 3-(N-methyl-N-(4-methylthiazol-2-yl)-carbamate) (Compound
752)
[1198] Compound 752 was prepared according to Procedure e.
[1199] Starting material: Compound 852.
[1200] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 6.53-6.52 (m, 1H),
6.11-6.10 (m, 1H), 6.07-6.05 (m, 1H), 5.52 (s, 1H), 4.41 (bs, 1H),
4.19-4.05 (m, 5H), 3.61 (s, 3H), 2.56-2.51 (m, 1H), 2.35 (d, 3H),
2.34-2.25 (m, 2H), 1.85 (d, 3H), 1.83-1.71 (m, 1H), 1.08 (s, 3H),
1.05 (s, 3H), 0.98 (d, 3H), 0.96-0.90 (m, 1H), 0.74-0.66 (m,
1H).
##STR00306##
Example 753
Ingenol 3-(N-(4-cyano-phenyl)-N-methyl-carbamate) (Compound
753)
[1201] Compound 753 was prepared according to Procedure e.
[1202] Starting material: Compound 853.
[1203] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.66-7.62 (m, 2H),
7.49-7.44 (m, 2H), 6.02-6.00 (m, 1H), 5.99-5.97 (m, 1H), 5.41 (s,
1H), 4.76 (d, 1H), 4.15-4.09 (m, 3H), 4.03-4.01 (m, 1H), 3.75 (s,
1H), 3.37 (s, 3H), 2.73 (t, 1H), 2.28-2.19 (m, 2H), 1.77 (d, 3H),
1.71-1.62 (m, 1H), 1.09 (s, 3H), 1.06 (s, 3H), 0.95-0.82 (m, 4H),
0.72-0.64 (m, 1H).
Example 1
Neutrophil Oxidative Burst
[1204] PMN's (polymorphonuclear leukocytes) were isolated and
purified from fresh buffy coats by sequential sedimentation,
density centrifugation and lysis of contaminating erythrocytes.
Buffy coats were incubated with 2% methocel for 30-45 min to
differentially sediment red blood cells. The leukocyte-rich
supernatant was transferred to lymphoprep tubes to remove
mononuclear cells by density centrifugation (400.times.g, 30 min).
The pellet was resuspended and any remaining erythrocytes lysed
using 0.2% NaCl for 30 sec before restoring isotonicity by the
addition of 1.2% NaCl. This step was repeated until the cell pellet
appears relatively free of red blood cells. Cells were resuspended
in DPBS (Dulbecco's Phosphate Buffered Saline) (w.o. Ca.sup.2+,
Mg.sup.2+) and the concentration adjusted to 1.4.times.10.sup.6
cells/ml in HBSS (Hanks Balanced Salt solution) (w Ca.sup.2+,
Mg.sup.2+) containing 0.1% BSA (Bovine Serum Albumin) and 5 mM
glucose just prior to assay initiation. Titrated reference and test
compounds were pre-mixed with HE (Hydroethidine) (10 .mu.M final
assay concentration) before addition to 96-well plates containing
2.5.times.10.sup.5 cells. Following 40 min incubation at RT,
changes in the respiratory burst was estimated by measuring
fluorescence at 579 nm (excitation: 485 nm) using an Envision plate
reader.
[1205] Test compound titration curves were fitted to a
four-parameter sigmoidal curve after normalizing the effect of the
test compound to the effect of the positive control
(5.times.10.sup.-7 M PEP0005). Rel EC.sub.50 denotes the
concentration of test compound producing an effect that is midway
between the fitted top and bottom. Abs EC.sub.50 is the
concentration of test compound that provokes a response
corresponding to 50% of the maximal effect associated with the
positive control (5.times.10.sup.-7 M PEP0005).
Example 2
HeKa Cytokine Release (IL-8)
[1206] Primary human epidermal keratinocytes, HeKa, were seeded
(10,000 cells/well) in 96-well plates the day before the assay.
Test compounds were diluted in DMSO (dimethyl sulfoxide) and
further diluted in assay medium and pipetted into wells of 96
well-plates containing HeKa cells. The plates were incubated for 6
h at 37.degree. C. in humidified air with 5% CO.sub.2. Plates were
centrifuged briefly to spin down cells at 4.degree. C., the
supernatant was removed and analysed by Meso Scale Discovery (MSD)
4-spot cytokine assay (Pro-inflammatory II Ultra Sensitive kit,
MSD, MD, USA). The MSD assay employs a sandwich immunoassay format
where capture antibodies are coated in a patterned array on the
bottom of the wells of a 4-Spot-Multi-MSD plate. Standard samples
were incubated in the MULTI-SPOT plates as well, and the cytokine
(IL-8) binds to its corresponding capture antibody spot. The
cytokine level was quantitated on a SECTOR.TM. Imager using a
cytokine-specific Detection Antibody labelled with MSD
SULFO-TAG.TM. reagent.
[1207] Test compound titration curves were fitted to a
four-parameter sigmoidal curve after normalizing the effect of the
test compound to the effect of the positive control
(1.5.times.10.sup.-7 M PEP0005). Rel EC.sub.50 denotes the
concentration of test compound producing an effect that is midway
between the fitted top and bottom. Abs EC.sub.50 is the
concentration of test compound that provokes a response
corresponding to 50% of the maximal effect associated with the
positive control (1.5.times.10.sup.-7 M PEP0005).
Example 3
Necrosis Assay
[1208] HeLa cells (ATCC CCL-002) were grown in minimal essential
medium (Invitrogen catalog no. 42360) containing 10% fetal bovine
serum, 100 IU/ml penicillin and 100 .mu.g/ml streptomycin.
4,000-6,000 cells were seeded into 96-well black ViewPlates-plates,
clear bottom, (Perkin Elmer) in 100 .mu.l medium and incubated
overnight. Compounds were dissolved and pre-diluted in DMSO in
96-well polypropylene plates (Greiner) in a concentration range of
15 .mu.M to 600 .mu.M. At the time of the experiment cell plates
were placed on heating blocks at 37.degree. C., medium was removed
and 40 .mu.l fresh, pre-warmed medium was added per well. Cells
were incubated for 15 min before addition of compounds. In
parallel, 3 .mu.l of compounds were diluted with 197 .mu.l growth
medium on a Tecan freedom-EVO pipetting station using 250 .mu.l/s
pipetting speed, in order to ensure effective mixing of the highly
concentrated compound solutions with the aqueous phase. These
pre-dilution plates were then equilibrated on heating blocks at
37.degree. C. for 10 min. 80 .mu.l pre-diluted compound were
transferred manually to the corresponding wells containing HeLa
cells yielding compound concentrations of 10 .mu.M to 400 .mu.M.
Control conditions were 1% DMSO in growth medium (100% viability)
and 400 .mu.M ingenol mebutate in growth medium (0% viability).
Plates were incubated on the heating blocks at 37.degree. C. for 30
min. At the end of the incubation 10 .mu.l PrestoBlue reagent
(Invitrogen) were added to each well, plates were sealed with black
seal, followed by incubation at 37.degree. C. for 10 min with
gentle shaking (150 rpm). Subsequently, plates were placed at room
temperature for 20-30 min. Plates were read immediately after on an
Envision Fluorescence reader (Perkin Elmer) with excitation at 535
nm and emission at 630 nm. Test compound titration curves were
fitted to a four-parameter sigmoidal curve after normalizing the
effect of the test compound to the effect of the positive control
(4 10.sup.-4 M PEP0005/ingenol mebutate). Abs EC.sub.50 denotes the
concentration of test compound producing 50% effect.
[1209] Compounds of the present invention were tested in the
neutrophil oxidative burst assay according to the description in
example 1, in the HeKa cytokine release assay according to the
description in example 2 and in the necrosis assay according to the
description in example 3.
[1210] Compounds of the present invention display Rel EC.sub.50
values below 10000 nM in the neutrophil oxidative burst assay and
Rel EC.sub.50 values below 10000 nM in the HeKa cytokine release
assay.
[1211] Neutrophil oxidative burst Rel EC.sub.50 ranges
[1212] * indicates that Rel EC.sub.50 values are .gtoreq.100 nM
[1213] ** indicates that Rel EC.sub.50 values are .gtoreq.20 nM and
<100 nM
[1214] *** indicates that Rel EC.sub.50 values are <20 nM
[1215] HeKa cytokine release (IL-8) Rel EC.sub.50 ranges
[1216] * indicates that Rel EC.sub.50 values are .gtoreq.100 nM
[1217] ** indicates that Rel EC.sub.50 values are .gtoreq.20 nM and
<100 nM
[1218] *** indicates that Rel EC.sub.50 values are <20 nM
[1219] HeLa Necrosis EC.sub.50 ranges
[1220] * indicates that EC.sub.50 values are .gtoreq.350 .mu.M
[1221] ** indicates that EC.sub.50 values are .gtoreq.150 .mu.M and
<350 .mu.M
[1222] *** indicates that EC.sub.50 values are <150 .mu.M
[1223] Results are shown in the table below.
TABLE-US-00001 Neutrophil HeKa cytokine HeLa oxidative burst
release (IL-8) necrosis Compound name and number Rel EC.sub.50
range Rel EC.sub.50 range EC.sub.50 range Ingenol
3-(5-methyl-3-(2-chloro-6- ** *** *** fluoro-phenyl)-isoxazole-4-
carboxylate) (Compound 501) Ingenol 3-(5-methyl-3-phenyl- *** ***
*** isoxazole-4-carboxylate) (Compound 502) Ingenol
3-(1S-camphanate) ** -- -- (Compound 503) Ingenol
3-(3-phenyltriazole-4- ** ** -- carboxylate) (Compound 504) Ingenol
3-(2-phenylpyrazole-3- *** *** *** carboxylate) (Compound 505)
Ingenol 3-(1-methylindazole-3- *** *** *** carboxylate) (Compound
506) Ingenol 3-(3-ethyl-5-methyl-isoxazole- *** *** **
4-carboxylate) (Compound 507) Ingenol 3-(3-methyl-5-methyl- *** ***
** isoxazole-4-carboxylate) (Compound 508) Ingenol
3-(1-methylindole-3- *** *** -- carboxylate) (Compound 509) Ingenol
3-(3-phenylthiophene-2- ** *** *** carboxylate) (Compound 510)
Ingenol 3-(5-phenylisoxazole-3- ** -- *** carboxylate) (Compound
511) Ingenol 3-(isoquinoline-1-carboxylate) ** -- *** (Compound
512) Ingenol 3-(quinoline-4-carboxylate) *** -- *** (Compound 513)
Ingenol 3-(cinnoline-4-carboxylate) * * *** (Compound 514) Ingenol
3-(3-phenylimidazole-4- *** -- *** carboxylate) (Compound 515)
Ingenol 3-(5-phenyloxazole-4- *** ** *** carboxylate) (Compound
516) Ingenol 3-(1,2-benzoxazole-3- ** * *** carboxylate) (Compound
517) Ingenol 3-(3-isopropyl-5-methyl- *** *** ***
isoxazole-4-carboxylate) (Compound 518) Ingenol
3-(3-(2-methoxyphenyl)-5- *** *** ***
methyl-isoxazole-4-carboxylate) (Compound 519) Ingenol
3-(4-bromo-2-methyl- *** -- -- pyrazole-3-carboxylate) (Compound
520) Ingenol 3-(4-bromo-2-ethyl-pyrazole- *** *** ***
3-carboxylate) (Compound 521) Ingenol
3-(4-chloro-2-methyl-pyrazole- *** *** ** 3-carboxylate) (Compound
522) Ingenol 3-(5-bromopyrimidine-4- ** * * carboxylate) (Compound
523) Ingenol 3-(3-bromopyridine-2- ** -- ** carboxylate) (Compound
524) Ingenol 3-(5-methylthiazole-4- ** * * carboxylate) (Compound
525) Ingenol 3-(4-chloro-1-methyl-pyrazole- ** * * 3-carboxylate)
(Compound 526) Ingenol 3-(2,4-dimethylthiazole-5- *** ** **
carboxylate) (Compound 527) Ingenol 3-(2,5-dimethyloxazole-4- ** *
* carboxylate) (Compound 528) Ingenol 3-(2,4-dimethylfuran-3- ***
*** *** carboxylate) (Compound 529) Ingenol
3-(3,5-diethylisoxazole-4- *** *** *** carboxylate) (Compound 530)
Ingenol 3-(1H-indole-7-carboxylate) ** *** *** (Compound 531)
Ingenol 3-(2-tert-butyl-5-methyl- ** *** ***
pyrazole-3-carboxylate) (Compound 532) Ingenol
3-(5-tert-butyl-2-methyl- *** *** *** pyrazole-3-carboxylate)
(Compound 533) Ingenol 3-(6-methylimidazo[2,1- *** *** **
b]thiazole-5-carboxylate) (Compound 534) Ingenol
3-(2-methylimidazo[1,2- *** -- ** a]pyridine-3-carboxylate)
(Compound 535) Ingenol 3-(2,4,5-trimethylfuran-3- *** *** **
carboxylate) (Compound 536) Ingenol 3-(3-methylthiophene-2- *** ***
** carboxylate) (Compound 537) Ingenol 3-(2-methyl-4-(1- *** ** **
piperidyl)pyrazole-3-carboxylate) (Compound 538) Ingenol
3-(2-chloro-5-isopropyl- ** *** *** thiazole-4-carboxylate)
(Compound 539) Ingenol 3-(4-chloro-2,5-dimethyl- *** *** ***
pyrazole-3-carboxylate) (Compound 540) Ingenol
3-(1,2,4-trimethylpyrrole-3- *** *** ** carboxylate) (Compound 541)
Ingenol 3-(1,3,5-trimethylpyrrole-2- *** *** *** carboxylate)
(Compound 542) Ingenol 3-(1-ethyl-3,5- *** -- ***
dimethylpyrrole-2-carboxylate) (Compound 543) Ingenol
3-(1-tert-butyloxycarbonyl- * * **
3,3-dimethylpyrrolidine-2-carboxylate) (Compound 544) Ingenol
3-((2S)-1-phenylpyrrolidine-2- ** -- ** carboxylate) (Compound 545)
Ingenol 3-(1-isopropyl-3,5-dimethyl- *** *** **
pyrazole-4-carboxylate) (Compound 546) Ingenol
3-(5-ethyl-3-isopropyl- ** *** *** isoxazole-4-carboxylate)
(Compound 547) Ingenol 3-(2-methylindazole-3- ** *** **
carboxylate) (Compound 548) Ingenol 3-(5-methyl-3-tert-butyl- ***
*** -- isoxazole-4-carboxylate) (Compound 549) Ingenol
3-(2-methyl-3-oxo-4- *** *** ***
oxaspiro[4.5]dec-1-ene-1-carboxylate) (Compound 550) Ingenol
3-(1-tert-butyl-3,5-dimethyl- *** *** -- pyrazole-4-carboxylate)
(Compound 551) Ingenol 3-(3,5-dimethylisothiazole-4- ** ** **
carboxylate) (Compound 552) Ingenol 3-(5-iodo-3-methyl- *** *** **
isothiazole-4-carboxylate) (Compound 553) Ingenol
3-(4-(4-methoxyphenyl)-2- *** *** ***
methyl-pyrazole-3-carboxylate) (Compound 554) Ingenol
3-(4-(2-methylphenyl)-2- *** *** *** methyl-pyrazole-3-carboxylate)
(Compound 555) Ingenol 3-(2-methyl-4-(4- ** ** **
methylsulfonylphenyl)pyrazole-3- carboxylate) (Compound 556)
Ingenol 3-(2-methyl-4-phenyl- *** *** *** pyrazole-3-carboxylate)
(Compound 557) Ingenol 3-(3,5-dimethyl-1-phenyl- *** *** ***
pyrazole-4-carboxylate) (Compound 558) Ingenol
3-(1,5-dimethyl-3-phenyl- *** *** ** pyrazole-4-carboxylate)
(Compound 559) Ingenol 3-(1-benzyl-3,5-dimethyl- *** *** ***
pyrazole-4-carboxylate) (Compound 560) Ingenol 3-(3,5-dimethyl-1-
** -- ** (tetrahydropyran-4-ylmethyl)pyrazole- 4-carboxylate)
(Compound 561) Ingenol 3-(4-methyl-2-oxo-3H- ** -- *
thiazole-5-carboxylate) (Compound 562) Ingenol 3-(2-methyl-4,5,6,7-
*** *** *** tetrahydroindazole-3-carboxylate) (Compound 563)
Ingenol 3-(1,2-dimethylindole-3- *** *** *** carboxylate) (Compound
564) Ingenol 3-(5-methoxy-1,2-dimethyl- *** *** ***
indole-3-carboxylate) (Compound 565) Ingenol
3-(1,3,5-trimethylpyrazole-4- ** ** * carboxylate) (Compound 566)
Ingenol 3-(4-methyl-1,2,5-oxadiazole- ** * * 3-carboxylate)
(Compound 567) Ingenol 3-(2-methoxy-4-methyl- ** ** **
thiazole-5-carboxylate) (Compound 568) Ingenol
3-(4,5-dimethylisoxazole-3- ** -- ** carboxylate) (Compound 569)
Ingenol 3-(4-bromo-1-methyl- ** * ** pyrazole-3-carboxylate)
(Compound 570) Ingenol 3-(1,3-dimethylindole-2- *** *** ***
carboxylate) (Compound 571) Ingenol 3-(5-methoxy-1,3-dimethyl- ***
*** *** indole-2-carboxylate) (Compound 572) Ingenol
3-(2,4-dimethyl-6-oxo-pyran- ** ** -- 3-carboxylate) (Compound 573)
Ingenol 3-(1-methyl-3-phenyl-indole- *** *** *** 2-carboxylate)
(Compound 574) Ingenol 3-(3-methyl-5- *** *** ***
(trifluoromethyl)isoxazole-4- carboxylate) (Compound 575) Ingenol
3-(1,3-dimethylpyrrole-2- *** *** *** carboxylate) (Compound 576)
Ingenol 3-(3,5-dimethyl-1-(2,2,2- ** *** **
trifluoroethyl)pyrazole-4-carboxylate) (Compound 577) Ingenol
3-(1-cyclopropyl-2,5-dimethyl- *** *** *** pyrrole-3-carboxylate)
(Compound 578) Ingenol 3-(1,2,5-trimethylpyrrole-3- *** *** **
carboxylate) (Compound 579) Ingenol 3-(2,4-dimethyl-1H-pyrrole-3- *
* ** carboxylate) (Compound 580) Ingenol 3-(1-methylpyrrole-2- ***
*** ** carboxylate) (Compound 581) Ingenol
3-(4-methyl-1H-pyrrole-2- *** *** ** carboxylate) (Compound 582)
Ingenol 3-(1,5-dimethylpyrrole-2- *** *** ** carboxylate) (Compound
583) Ingenol 3-(3-methyl-1H-pyrrole-2- *** *** ** carboxylate)
(Compound 584) Ingenol 3-(1-cyclopropylpyrrole-2- *** *** ***
carboxylate) (Compound 585) Ingenol 3-(1-ethyl-2,4-dimethyl- ***
*** *** pyrrole-3-carboxylate) (Compound 586) Ingenol
3-(1-allyl-2,4-dimethyl- *** *** *** pyrrole-3-carboxylate)
(Compound 587) Ingenol 3-(1-(cyclopropylmethyl)-2,4- *** *** ***
dimethyl-pyrrole-3-carboxylate) (Compound 588) Ingenol
3-(1-(2-methoxyethyl)-2,4- ** *** ***
dimethyl-pyrrole-3-carboxylate) (Compound 589) Ingenol
3-(N-ethyl-carbamate) ** -- -- (Compound 701) Ingenol
3-(N,N-dimethyl-carbamate) ** * -- (Compound 702) Ingenol
3-(morpholine-4-carboxylate) ** * -- (Compound 703) Ingenol
3-(pyrrolidine-1-carboxylate) ** * -- (Compound 704) Ingenol
3-(N-methtyl-N-phenyl- *** *** ** carbamate) (Compound 705) Ingenol
3-(N,N-diethyl-carbamate) *** ** * (Compound 706) Ingenol
3-(piperidine-1-carboxylate) *** ** -- (Compound 707) Ingenol
3-(N-benzyl-N-methyl- ** *** -- carbamate) (Compound 708) Ingenol
3-(N-cyclohexyl-N-methyl- *** *** ** carbamate) (Compound 709)
Ingenol 3-(N-cyclohexyl-carbamate) *** ** -- (Compound 710) Ingenol
3-(N-phenyl-carbamate) ** *** -- (Compound 711) Ingenol
3-(N-(indan-1-yl)-carbamate) ** ** -- (Compound 712) Ingenol
3-(3,3-dimethyl-piperidine-1- ** *** ** carboxylate) (Compound
713)
Ingenol 3-(N-Methyl-N-tetralin-1-yl- * *** *** carbamate) (Compound
714) Ingenol 3-(N-(2-cyano-1-methyl- * -- *
ethyl)-N-methyl-carbamate) (Compound 715) Ingenol
3-(N-methyl-N-((S)-1- ** *** *** phenethyl)-carbamate) (Compound
716) Ingenol 3-(N-methyl-N- *** *** *
(cyclopropylmethyl)-carbamate) (Compound 717) Ingenol
3-(N-(3-fluoro-phenyl)-N- *** *** ** methyl-carbamate) (Compound
718) Ingenol 3-(N-(2,5-dimethylpyrazol-3- * -- *
yl)-N-methyl-carbamate) (Compound 719) Ingenol
3-(N-(3,5-dimethylisoxazol-4- ** -- * yl)-N-methyl-carbamate)
(Compound 720) Ingenol 3-(N-(1,5-dimethylpyrazol-3- ** ** *
yl)-N-methyl-carbamate) (Compound 721) Ingenol
3-(N-cyclopentyl-N-methyl- *** ** * carbamate) (Compound 722)
Ingenol 3-(N-cyclopropyl-N-methyl- *** ** * carbamate) (Compound
723) Ingenol 3-(N-methyl-N-(2-pyridyl)- -- ** * carbamate)
(Compound 724) Ingenol 3-(4-oxo-2,3-dihydroquinoline- *** -- **
1-carboxylate) (Compound 725) Ingenol
3-(3,4-dihydro-2H-quinoline-1- ** *** *** carboxylate) (Compound
726) Ingenol 3-(indoline-1-carboxylate) *** *** *** (Compound 727)
Ingenol 3-(azepane-1-carboxylate) ** ** -- (Compound 728) Ingenol
3-(N-(4-chloro-phenyl)-N- *** *** ** methyl-carbamate) (Compound
729) Ingenol 3-(N-(4-fluoro-phenyl)-N- -- -- ** methyl-carbamate)
(Compound 730) Ingenol 3-(N-methyl-N-(2-methoxy- ** -- **
phenyl)-carbamate) (Compound 731) Ingenol 3-(N-methyl-N-(2-methyl-
*** *** ** phenyl)-carbamate) (Compound 732) Ingenol 3-(3-oxo-2,4-
* -- ** dyhidroquinoxaline-1-carboxylate) (Compound 733) Ingenol
3-(N-ethyl-N-phenyl- ** *** ** carbamate) (Compound 734) Ingenol
3-(2-trifluoromethyl- *** -- ** pyrrolidine-1-carboxylate)
(Compound 735) Ingenol 3-(3-azabicyclo[3.2.2]nonane- *** *** **
3-carboxylate) (Compound 736) Ingenol 3-(2,3-dihydro-1,4- *** ***
*** benzoxazine-4-carboxylate) (Compound 737) Ingenol
3-(N-(2-fluoro-phenyl)-N- *** ** ** methyl-carbamate) (Compound
738) Ingenol 3-(3-methyl-2,3-dihydro-1,4- *** *** ***
benzoxazine-4-carboxylate) (Compound 739) Ingenol
3-(2-trifiuoromethyl- *** ** -- pyrrolidine-1-carboxylate) (ISOMER
A) (Compound 740) Ingenol 3-(2-trifluoromethyl- ** ** *
pyrrolidine-1-carboxylate) (ISOMER B) (Compound 741) Ingenol
3-(N-methyl-N-(N-(tert- ** -- ** butyloxycarbonyl)-4-piperidyl)-
carbamate) (Compound 742) Ingenol 3-(N-methyl-N-(3-methyl- *** ***
** phenyl)-carbamate) (Compound 743) Ingenol 3-(3,4-dihydro-2H- **
** ** quinoxaline-1-carboxylate) (Compound 744) Ingenol
3-(isoindoline-2-carboxylate) *** *** ** (Compound 745) Ingenol
3-(N-methyl-N- ** * * (tetrahydropyran-4-ylmethyl)- carbamate)
(Compound 746) Ingenol 3-(N-methyl-N- ** * *
(tetrahydropyran-4-yl)-carbamate) (Compound 747) Ingenol
3-(N-methyl-N-(3-methoxy- *** ** ** phenyl)-carbamate) (Compound
748) Ingenol 3-(N-cyclobutyl-N-methyl- *** -- * carbamate)
(Compound 749) Ingenol 3-(N-allyl-N-methyl- *** -- * carbamate)
(Compound 750) Ingenol 3-(N-methyl-N-prop-2-ynyl- ** -- *
carbamate) (Compound 751) Ingenol 3-(N-methyl-N-(4- *** *** **
methylthiazol-2-yl)-carbamate) (Compound 752) Ingenol
3-(N-(4-cyano-phenyl)-N- ** ** ** methyl-carbamate) (Compound 753)
Ingenol mebutate, ingenol-3-angelate *** *** **
Example 4
B16-F0 Mouse Melanoma Model for Evaluation of Anti-Tumor
Efficacy
[1224] B16-F0 mouse melanoma cells (ATCC.RTM. number CRL-6322.TM.)
were cultured in RPMI-1640 glutaMAX (Invitrogen, catalogue number
61870-010) supplemented with 10% fetal bovine serum and 1%
pencillin-Streptomysin (Invitrogen, catalogue number 15140-122) at
37.degree. C. in humidified air with 5% CO.sub.2. At day 0 of the
experiment, B16-F0 cells (70-90% confluent) were harvested by
trypsinization with TrypLE (Invitrogen, catalogue number
12605-010), washed, resuspended in RPMI-1640 glutaMAX and kept on
ice. Within 30 minutes, a volume of 50 .mu.l containing
0.5.times.10.sup.6 viable B16-F0 cells were injected intradermally
into shaved flanks of 10-week-old female C57BL/6JBomTac mice, one
injection per mouse. At experimental day 4, tumors were measured
with a digital caliper (Mahr 16 Ex H100207), and the tumor volumes
were estimated using the formula: Tumor volume=1/2*(longest
diameter)*(orthogonale diameter) 2. Mice with tumors ranging from 9
to 60 mm.sup.3 were included in the study and stratified into
treatment groups according to tumor size. The tumors were treated
topically with 20 .mu.l solution containing 0.1% test compound once
daily for 2 consecutive days. Vehicle was included in each
experiment as negative control. Tumors were measured daily, and
mice were euthanized when tumors exceed an estimated volume of 250
mm.sup.3. Mice with ulcerating tumors or compromised well-being
were euthanized regardless of tumor size and were included in the
data analysis as censored objects. The experiment was terminated at
experimental day 90, and mice with tumors below 250 mm.sup.3 at
this day were included in the data analysis as censored objects as
well. Kaplan Meier survival curves with tumor >250 mm.sup.3 as
surrogate death event were generated, and comparison of survival
curves were performed by Log-rank test. Specifically, tumor growth
in each treatment group was compared to tumor growth in the vehicle
group, to evaluate the efficacy of each compound to cure tumors or
delay tumor growth. P-values below 0.05 were considered
significant.
[1225] Some compounds of the present invention were testet in the
B16-F0 mouse melanoma model. Compounds possessing an effect which
was significantly better than vehicle are listed in the table
below.
TABLE-US-00002 Compounds with an effect significantly better than
vehicle in the B16-F0 mouse melanoma model Ingenol
3-(3,5-diethylisoxazole-4-carboxylate) (Compound 530) Ingenol
3-(2,4-dimethylfuran-3-carboxylate) (Compound 529) Ingenol
3-(3-ethyl-5-methyl-isoxazole-4-carboxylate) (Compound 507) Ingenol
3-(N-methyl-N-phenyl-carbamate) (Compound 705) Ingenol
3-(indoline-1-carboxylate) (Compound 727) Ingenol
3-(2,4,5-trimethylfuran-3-carboxylate) (Compound 536) Ingenol
3-(5-methyl-3-phenyl-isoxazole-4-carboxylate) (Compound 502)
Ingenol 3-(pyrrolidine-1-carboxylate) (Compound 704) Ingenol
3-(N-(3-fluoro-phenyl)-N-methyl-carbamate) (Compound 718)
* * * * *