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HK1206004B - Ingenol-3-acylates iii and ingenol-3-carbamates - Google Patents

Ingenol-3-acylates iii and ingenol-3-carbamates Download PDF

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Publication number
HK1206004B
HK1206004B HK15106654.7A HK15106654A HK1206004B HK 1206004 B HK1206004 B HK 1206004B HK 15106654 A HK15106654 A HK 15106654A HK 1206004 B HK1206004 B HK 1206004B
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Hong Kong
Prior art keywords
compound
ingenol
methyl
carbamate
procedure
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HK15106654.7A
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Chinese (zh)
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HK1206004A1 (en
Inventor
Gunnar GRUE-SØRENSEN
Xifu Liang
Thomas Högberg
Kristoffer MÅNSSON
Per VEDSØ
Thomas Vifian
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Leo Laboratories Limited
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Publication of HK1206004A1 publication Critical patent/HK1206004A1/en
Publication of HK1206004B publication Critical patent/HK1206004B/en

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Description

Ingenol-3-acylate III and ingenol-3-carbamate
The divisional application of the international application with the application numbers PCT/DK2011/000154 and invented as "ingenol-3-acylate III and ingenol-3-carbamate", filed on 12/22/2011, the international application entered the chinese country at 21/8/2013 with the application number 201180068162.3.
Technical Field
The present invention relates to novel derivatives of 3-O-acyl-ingenol and 3-O-carbamoyl-ingenol and derivatives thereof and their use as medicaments and in therapy. The invention also provides pharmaceutical compositions comprising the compounds and methods of treating diseases with the compounds.
Background
Ingenol-3-angelate (PEP005, ingenol mebutate) is a diterpene ester of the ingenol family isolated from various Euphorbia species, in particular Euphorbia milifolia (Euphorbia peplus). The compound is currently in clinical development for the treatment of actinic keratosis and non-melanoma skin cancers.
WO99/08994 describes the isolation of compounds from euphorbia and the use of these compounds in cancer and other neoplastic diseases and actinic or solar keratoses.
Ingenol-3-acylates, mainly long-chain saturated and unsaturated aliphatic fatty acids, have been isolated from various euphorbia species [ h.gotta, z.naturforschung, (1984),39b, 683-94; abo, Fitoterapia (1988),244-46, S.Zaied, J.cancer Res.Clin.Oncol. (2001),127,40-47 ]. In addition, a few 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 as potent stimulators and potent tumour promoters [ b.sorg et al, z.naturforsch., (1982),37b, 748-56; sorg et al, Carcinogenesis, (1987),8,1-4 ].
In addition to aliphatic ingenol esters, aromatic esters of ingenol are also known. Trifoline (Milliamine) C (ingenol-3-anthranilate derivative) has been described (Marston, A. planta medical, (1983),47,141-47). Ingenol-3-benzoate is also described (Sorg, B.; Znaturforschung, (1982),37b, 748-56).
Heteroaromatic or heterocyclic 3-O-acylingenol derivatives have not been previously disclosed.
Ingenol-3-carbamate has not been previously disclosed. Differently substituted ingenol carbamates are mentioned in US5955501, US5891906, US5891870 and WO 9202484.
Angelic acid and angelates (present in ingenol-3-angelate) are easily isomerized at the double bond to tiglic acid esters, especially at basic pH [ Beeby, P., Tetrahedron Lett. (1977),38, 3379-.
Furthermore, ingenol-3-acylates are known to be unstable because they rearrange to give ingenol-5-acylates and ingenol-20-acylates [ Sorg, B., et al, Z. Naturforsch., (1982),37B,748-756 ].
Ingenol-3-angelate is believed to have dual modes of action 1) induction of cell death by direct cytotoxicity or induction of apoptosis, and 2) immune stimulation dominated by recruitment and activation of neutrophils (Rosen, r.h., et al, J Am Acad Derm (2011), electronic publication Nov 2011; ersvaer, E., et al, Toxins, (2010),2, 174-. Nanomolar concentrations of the active agent cause activation and modulation of both classical and novel isoforms of Protein Kinase C (PKC), with PKC being particularly important. The agent induces apoptosis of susceptible cells by activating PKC (Hampson, P., et al, Blood, (2005),106, 1362-1008; Cozzi, S.J., et al, Cancer Res, (2006),66, 10083-10091). At high micromolar concentrations, a rapid cytotoxic effect on Cancer cells was observed (Ogbourne, s.m., et al, Cancer Res (2004),64, 2833-. The agent also induces proinflammatory effects, including release of proinflammatory mediators by activation of various PKC isoforms (Challacombe, J.M., et al, J Immunol (2006),177, 8123-; the neutrophil chemotaxis by inducing interleukin 8 in keratinocytes and the specific anti-cancer immune response of CD8+ cells in animal models by adjuvant properties (Le, t.t., et al, vaccine, (2009),27, 3053-.
Compounds that induce cell death by direct cytotoxicity or induction of apoptosis and that exert a dual mode of action by immunostimulation involving recruitment and activation of neutrophils are useful in treating conditions associated with hyperplasia or tumors. Compounds that induce cell death by primary and/or secondary necrosis and compounds that exhibit pro-apoptotic effects may reduce unwanted cell growth and remove unwanted cells, and in addition, stimulation of the innate immune response and adjuvant effects may increase the biological response to aberrant or transformed cells.
Compounds that induce cell death by primary and/or secondary necrosis may be useful in treating cosmetic conditions because these compounds may kill or remove unwanted tissues or cells.
There is a need to find new ingenol derivatives that can induce cell death by cytotoxicity or apoptosis and/or induce immune stimulatory effects.
The present invention provides heterocyclic 3-O-acylingenol derivatives and 3-O-carbamoyl ingenol derivatives which are useful in the treatment of conditions associated with the use of ingenol-3-angelate, or in the treatment of conditions affected by induction of cell death by cytotoxicity or induction of apoptosis and/or by immunostimulation.
The compounds of the invention stimulate the oxidative burst of neutrophils, which is part of the innate immune response.
The compounds of the invention stimulate the release of keratinocyte IL-8, thereby inducing an immunostimulatory effect.
Certain compounds of the invention induce rapid necrosis.
Certain compounds of the invention exhibit activity in the mouse melanoma model of B16, indicating that the compounds have anti-tumor activity and are capable of killing tumors and transformed cells.
Certain compounds of the present invention exhibit good stability.
Summary of The Invention
In one embodiment, the present invention provides compounds of formula I and pharmaceutically acceptable salts, prodrugs, hydrates, and solvates thereof:
wherein R is heteroaryl, which may be optionally substituted with one or more substituents independently selected from R7;
or R is heterocycloalkyl or heterocycloalkenyl, wherein said heterocycloalkyl or heterocycloalkenyl is optionally substituted with one or more substituents independently selected from R8;
or R is X;
r7 represents halogen, cyano or hydroxy;
or R7 represents (C)1-C4) Alkyl, (C)2-C4) -alkenyl, (C)3-C7) Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heterocycloalkyl alkyl or (C)3-C7) -cycloalkylalkyl, wherein (C) is1-C4) Alkyl, (C)2-C4) -alkenyl, (C)3-C7) -cycloalkyl, heterocycloalkyl, aryl, heteroaryl,Arylalkyl, heterocycloalkyl, or (C)3-C7) -cycloalkylalkyl is optionally substituted with 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)1-C4) Alkyl, halo (C)1-C4) Alkyl, -NRaCORb, -COORc, -OCORa, -CONRaRb, -OCONRaRb, -NRaCOORb, -NRaCONRaRb, -NRaSO2NRaRb、-NRaSO2Rb、-SO2NRaRb、-SO2Ra, -s (O) Ra, -ORa, -SRa, or ═ O;
r8 represents halogen, cyano or hydroxy;
or R8 represents (C)1-C4) Alkyl, (C)2-C4) Alkenyl, aryl, heteroaryl, (C)3-C7) -cycloalkyl or heterocycloalkyl, wherein said (C)1-C4) Alkyl, (C)2-C4) Alkenyl, aryl, heteroaryl, (C)3-C7) -cycloalkyl or heterocycloalkyl 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, -O, -N-ORa, -O-N-CRaRb, NRaRb, or-c (O) N (Ra) O-Rb;
r10 represents halogen, cyano, hydroxy, (C)1-C4) Alkyl radicals, (C)1-C4) Alkoxy, halo (C)1-C4) Alkyl, halo (C)1-C4) Alkoxy, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) Alkyl, aryl, heteroaryl, and the like,Cycloalkyl, heterocycloalkyl, -NRaCORb, -COORc, -OCORa, -CONRaRb, -OCONRaRb, -NRaCOORb, -NRaCONRaRb, -NRaSO2NRaRb、-NRaSO2Rb、-SO2NRaRb、-SO2Ra, -s (O) Ra, -ORa, -SRa, or ═ O;
ra and Rb represent hydrogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) Alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
rc represents hydrogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, hydroxy (C)1-Cx) Alkyl, cyano (C)1-Cx) Alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; x represents-NR 11R 12;
wherein R11 and R12 independently represent hydrogen,
or
Wherein R11 and R12 independently represent (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl or alkylheterocycloalkyl, wherein (C) is1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl or alkylheterocycloalkyl optionally substituted with one or moreSubstituted with one substituent independently selected from R13;
r13 represents halogen, cyano or hydroxy,
or R13 represents (C)1-C4) Alkyl, (C)2-C4) Alkenyl, aryl, (C)3-C7) Cycloalkyl, heteroaryl or heterocycloalkyl, wherein (C) is1-C4) Alkyl, (C)2-C4) Alkenyl, aryl, (C)3-C7) Cycloalkyl, heteroaryl or heterocycloalkyl optionally substituted with 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, ═ O, ═ N-ORd, -O-N ═ CRdRe, -NRdRe, or-c (O) N (Rd) -ORe,
wherein Rd and Re independently represent hydrogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) Alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
rf represents hydrogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) Alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; r14 represents halogen, hydroxy, cyano, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, halo (C)1-C4) Alkyl, halo (C)1-C4) Alkoxy, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) Alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRdCORe, -COORf, -OCORd, -CONRdRe, -OCONRdRe、-NRdCOORe、-NRdCONRdRe、-NRdSO2Re、-NRdSO2NRdRe、-SO2NRdRe、-SO2Rd, -s (O) Rd, -ORd, -SRd, or ═ O.
In one embodiment, the present invention provides a compound of formula I for use as a therapeutic agent.
In one embodiment, the present invention provides the use of a compound of formula I for the preparation of a pharmaceutical compound.
In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable stereoisomer, salt or in vivo hydrolysable ester thereof, and a pharmaceutically acceptable carrier or excipient.
In one embodiment, the present 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, and a pharmaceutically acceptable carrier or excipient.
In one embodiment, the present invention provides compounds of formula I for use in the treatment, prevention, amelioration or prevention of physiological conditions or diseases associated with hyperplasia or tumors.
In one embodiment, the present invention provides the use of a compound of formula I in the manufacture of a medicament for the treatment, amelioration or prevention of a physiological condition or disease associated with a hyperplasia or tumor.
In one embodiment, the present invention provides a method of preventing, treating, ameliorating, or preventing a physiological condition or disease associated with a hyperplasia or a tumor, the method comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the present invention provides a compound of formula I for use in treating or ameliorating a cosmetic indication.
In one embodiment, the present invention provides the use of a compound of formula I in the manufacture of a medicament for the treatment or amelioration of a cosmetic indication.
In one embodiment, the present invention provides a method of treating or ameliorating a cosmetic indication comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the present invention provides a pharmaceutical composition which comprises 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
One embodiment of the present invention provides compounds of formula I and pharmaceutically acceptable salts, prodrugs, hydrates, and solvates thereof:
wherein R is heteroaryl, which may be optionally substituted with one or more substituents independently selected from R7;
or R is heterocycloalkyl or heterocycloalkenyl, each of which is optionally substituted with one or more substituents independently selected from R8;
or R is X;
r7 represents halogen, cyano or hydroxy;
or R7 represents (C)1-C4) Alkyl, (C)2-C4) Alkenyl, (C)3-C7) Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, each of which is optionally substituted with 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)1-C4) Alkyl, halo (C)1-C4) Alkyl, -NRaCORb, -COORc, -OCORa, -CONRaRb, -OCONRaRb, -NRaCOORb, -NRaCONRaRb, -NRaSO2NRaRb、-NRaSO2Rb、-SO2NRaRb、-SO2Ra, -s (O) Ra, -ORa, -SRa, or ═ O;
r8 represents halogen, cyano, hydroxy;
or R8 represents (C)1-C4) Alkyl, (C)2-C4) Alkenyl, aryl, heteroaryl, (C)3-C7) Cycloalkyl or heterocycloalkyl, each of which is optionally substituted with 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, -O, -N-ORa, -O-N-CRaRb, NRaRb, or-c (O) N (Ra) O-Rb;
r10 represents halogen, cyano, hydroxy, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, halo (C)1-C4) Alkyl, halo (C)1-C4) Alkoxy, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) Alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRaCORb, -COORc, -OCORa, -CONRaRb, -OCONRaRb, -NRaCOORb, -NRaCONRaRb, -NRaSO2NRaRb、-NRaSO2Rb、-SO2NRaRb、-SO2Ra, -s (O) Ra, -ORa, -SRa, or ═ O;
ra and Rb represent hydrogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) Alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
rc represents hydrogen, (R) represents hydrogenC1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, hydroxy (C)1-Cx) Alkyl, cyano (C)1-Cx) Alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; x represents-NR 11R 12;
wherein R11 and R12 independently represent hydrogen,
or
Wherein R11 and R12 independently represent (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkylaryl, alkylheteroaryl, or alkylheterocycloalkyl, optionally substituted with one or more substituents independently selected from R13;
r13 represents halogen, cyano, hydroxy,
Or R13 represents (C)1-C4) Alkyl, (C)2-C4) Alkenyl, aryl, (C)3-C7) Cycloalkyl, heteroaryl or heterocycloalkyl, each of which is optionally substituted with 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, ═ O, ═ N-ORd, -O-N ═ CRdRe, -NRdRe, or-c (O) N (Rd) -ORe;
wherein Rd and Re independently represent hydrogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) Alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl;
rf represents hydrogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) Alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl; r14 represents halogen, hydroxy, cyano, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, halo (C)1-C4) Alkyl, halo (C)1-C4) Alkoxy, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) Alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -NRdCORe, -COORf, -OCORd, -CONRdRe, -OCONRdRe, -NRdCOORe, -NRdCONRdRe, -NRdSO2Re、-NRdSO2NRdRe、-SO2NRdRe、-SO2Rd, -s (O) Rd, -ORd, -SRd, or ═ O.
Another embodiment of the present invention provides compounds of formula I above and pharmaceutically acceptable salts, prodrugs, hydrates, and solvates thereof,
wherein R is heteroaryl, which may be optionally substituted with one or more substituents independently selected from R7,
or R is heterocycloalkyl or heterocycloalkenyl, each of which is optionally substituted with one or more substituents independently selected from R8,
r7 represents halogen, cyano, hydroxy;
or R7 represents (C)1-C4) Alkyl, (C)2-C4) -alkenyl, (C)3-C7) -cycloalkyl, heterocycloalkyl, aryl, heteroaryl, all optionally substituted with 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)1-C4) Alkyl, halo (C)1-C4) Alkyl, -NRaCORb, -COORc, -OCORa, -CONRaRb, -OCONRaRb, -NRaCOORb, -NRaCONRaRb, -NRaSO2NRaRb、-NRaSO2Rb、-SO2NRaRb、-SO2Ra、-S(O)Ra、-ORa、-SRa、＝O；
R8 represents halogen, cyano, hydroxy;
or R8 represents (C)1-C4) Alkyl radicals, (C)2-C4) Alkenyl, aryl, heteroaryl, (C)3-C7) -cycloalkyl, heterocycloalkyl, each of which is optionally substituted with 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、＝O；
R10 represents halogen, cyano, hydroxy, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, -NRaCORb, -COORc, -OCORa, -CONRaRb, -OCONRaRb, -NRaCOORb, -NRaCONRaRb, -NRaSO2NRaRb、-NRaSO2Rb、-SO2NRaRb、-SO2Ra、-S(O)Ra、-ORa、-SRa、＝O；
Ra and Rb represent hydrogen, (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, cyano (C)1-C4) An alkyl group;
rc represents (C)1-C4) Alkyl, halo (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, hydroxy(C1-C4) Alkyl, cyano (C)1-C4) An alkyl group.
An embodiment of the invention provides compounds of formula I wherein R is heteroaryl.
An embodiment of the invention provides compounds of formula I wherein heteroaryl is isoOxazolyl, pyridyl, quinolyl, isoquinolyl, indolyl, furyl, thiazolyl, imidazolyl, pyrazolyl,Azolyl, thienyl, pyrimidinyl, 1,2, 3-triazolyl, indazolyl, cinnolinyl or 1, 2-benzoAn azole group.
An embodiment of the invention provides compounds of formula I wherein R is heteroaryl and wherein said heteroaryl is isoheteroarylOxazolyl, pyridyl, quinolyl, isoquinolyl, indolyl, furyl, thiazolyl, imidazolyl, pyrazolyl,Azolyl, thienyl, pyrimidinyl, 1,2, 3-triazolyl, indazolyl, cinnolinyl, 1, 2-benzoOxazolyl, imidazothiazolyl, imidazopyridinyl, pyrrolyl, isothiazolyl, tetrahydroindazolyl orA diazolyl group.
An embodiment of the present invention provides compounds of formula I, wherein RIs heteroaryl and wherein said heteroaryl is isoAzolyl, furyl, pyrazolyl, thienyl or pyrrolyl.
An embodiment of the invention provides compounds of formula I wherein R is heteroaryl and wherein said heteroaryl is isoheteroarylAn azole group.
An embodiment of the invention is the provision of a compound of formula I where R is heteroaryl and where the heteroaryl is furanyl.
An embodiment of the invention provides compounds of formula I wherein R is heteroaryl and wherein said heteroaryl is isoheteroarylOxazolyl, furyl, pyrazolyl, thienyl or pyrrolyl, and wherein R7 represents (C)1-C4) An alkyl group.
An embodiment of the invention provides compounds of formula I wherein R is heteroaryl and wherein said heteroaryl is isoheteroarylOxazolyl, furyl, pyrazolyl, thienyl or pyrrolyl, and wherein R7 represents (C)1-C2) An alkyl group.
An embodiment of the invention provides compounds of formula I wherein R is heteroaryl, and wherein heteroaryl is isoheteroarylAzolyl or furanyl and in which R7 represents (C)1-C2) An alkyl group.
An embodiment of the invention provides compounds of formula I wherein R is heteroaryl and whichWherein said heteroaryl is isoOxazolyl, furyl, pyrazolyl, thienyl or pyrrolyl and wherein R7 represents phenyl.
An embodiment of the invention provides compounds of formula I wherein R is heteroaryl and wherein said heteroaryl is isoheteroarylOxazolyl, furyl, pyrazolyl, thienyl or pyrrolyl and wherein R7 represents phenyl or (C)1-C4) Alkyl and wherein R9 represents (C)1-C4) Alkyl, halogen or-ORa.
One embodiment of the present invention provides compounds of formula I wherein R is heteroaryl and wherein said heteroaryl is indolyl, indazolyl or tetrahydroindazolyl.
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)1-C4) Alkyl or-ORa.
An embodiment of the invention provides compounds of formula I wherein R7 is independently selected from (C)1-C4) Alkyl, aryl or halogen one or more times.
An embodiment of the invention provides compounds of formula I wherein R7 is independently selected from (C)1-C4) Alkyl, (C)2-C4) Alkenyl, aryl, arylalkyl, heterocycloalkyl, (C)3-C7) -cycloalkylalkyl, (C)3-C7) -cycloalkyl, -COORc, -ORa or halogen one or more times.
An embodiment of the present invention provides a compound of formula I wherein R7 is selected from phenyl, methyl, ethyl, isopropyl, Cl or Br.
Hair brushAn embodiment of the invention is the provision of a compound of formula I where R7 is selected from the group consisting of phenyl, methyl, ethyl, isopropyl, tert-butyl, piperidinyl, tert-butyloxycarbonyl, benzyl, tetrahydropyranylmethyl, -OCH3Cyclopropyl, allyl, cyclopropylmethyl, Cl, Br or I.
An embodiment of the invention provides a compound of formula I, above, wherein R9 is halogen or-ORa.
An embodiment of the invention provides compounds of formula I, above, wherein R9 is halogen, -ORa, (C)1-C4) Alkyl or-SO2Ra。
An embodiment of the invention provides a compound of formula I, wherein R9 is Cl, F, or-OCH3。
An embodiment of the invention provides compounds of formula I, above, wherein R9 is Cl, F, -OCH3Methyl or methylsulfonyl.
One embodiment of the present invention provides compounds of formula I wherein R is heterocycloalkyl.
An embodiment of the present invention provides a compound of formula I, above, wherein R is heterocycloalkyl or heterocycloalkenyl.
An embodiment of the invention provides compounds of formula I, wherein heterocycloalkyl is pyrrolidinyl, piperidinyl, morpholinyl, or 5-oxabicyclo [2.2.2] octane.
An embodiment of the invention provides compounds of formula I wherein R8 is (C)1-C4) An alkyl group.
An embodiment of the invention provides compounds 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]Octyl, oxaspiro [4.5]]Dec-1-enyl, oxo-thiazolyl, dihydrothiazolyl, oxo-pyranyl, azepanyl, azabicyclo [3.2.2]Nonyl, benzoAn oxazinyl, quinoxalinyl, dihydroisoindolyl, dihydroquinolinyl, indolinyl, or dihydroquinoxalinyl group.
An embodiment of the present invention provides compounds of formula I above wherein R is heterocycloalkyl and wherein said heterocycloalkyl is indolinyl, benzoAn oxazinyl group or a dihydroquinolinyl group.
An embodiment of the invention is the provision of a compound of formula I where R8 is methyl.
An embodiment of the invention provides compounds of formula I wherein R8 is (C)1-C4) Alkyl, aryl or ═ O.
An embodiment of the invention is the provision of a compound of formula I, where R is-NR 11R 12.
An embodiment of the invention provides compounds of formula I, wherein R11 and R12 independently represent hydrogen, (C)1-C6) Alkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, or cycloalkylalkyl.
An embodiment of the invention provides compounds of formula I, above, wherein R11 and R12 independently represent hydrogen, (C)1-C6) Alkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl.
An embodiment of the invention provides compounds of formula I, above, wherein R11 and R12 independently represent hydrogen, (C)1-C6) Alkyl, aryl or arylalkyl.
An embodiment of the invention provides compounds of formula I, above, wherein R11 and R12 independently represent hydrogen, (C)1-C4) Alkyl, cycloalkyl, phenyl or benzyl.
An embodiment of the invention provides compounds of formula I, above, wherein R11 and R12 independently represent hydrogen, (C)1-C4) Alkyl, phenyl or benzyl, wherein (C) is1-C4) Alkyl, phenyl or benzyl optionally substituted by one or more substituents selected from R13, wherein R13 represents halogen, (C)1-C4) Alkyl or-ORa.
An embodiment of the invention provides compounds of formula I wherein R11 and R12 independently represent hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, cyclohexyl, indanyl, tetralinyl, phenylethyl, cyclopropylmethyl or pyrazolyl.
An embodiment of the invention provides compounds of formula I, above, wherein R11 and R12 independently represent hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, cyclohexyl, indanyl, tetrahydronaphthyl, phenylethyl, cyclopropylmethyl, pyrazolyl, iso-naphthylAzolylmethyl, cyclopentyl, cyclopropyl, pyridyl, piperidyl, tetrahydropyranylmethyl, tetrahydropyranyl, cyclobutyl, allyl, propynyl, or thiazolyl.
An embodiment of the invention provides compounds of formula I, wherein R13 represents (C)1-C4) Alkyl, cyano or F.
An embodiment of the invention provides a compound of formula I, above, wherein R13 represents (C)1-C4) Alkyl, cyano, halogen, ═ O, -ORa, or-COORf.
An embodiment of the present invention provides a compound of formula I, above, wherein R13 represents methyl, cyano, F, ═ O, -OCH3or-COOC (CH)3)3。
An embodiment of the invention is the provision of a compound of formula I, where R11 or R12 independently represent hydrogen.
One embodiment of the present invention provides a compound of formula I, said compound being:
ingenol 3- (5-methyl-3-phenyl-isoOxazole-4-carboxylic acid ester) or
Ingenol 3- (5-methyl-3- (2-chloro-6-fluoro-phenyl) -isoOxazole-4-carboxylic acid ester) or
Ingenol 3- (1S-camphanoate) or
Ingenol 3- (3-phenyltriazole-4-carboxylate) or
Ingenol 3- (2-phenylpyrazole-3-carboxylate) or
Ingenol 3- (1-methylindazole-3-carboxylate) or
Ingenol 3- (3-ethyl-5-methyl-iso-euphorbia root)Oxazole-4-carboxylic acid ester) or
Ingenol 3- (3-methyl-5-methyl-isoOxazole-4-carboxylic acid ester) or
Ingenol 3- (1-methylindole-3-carboxylate) or
Ingenol 3- (3-phenylthiophene-2-carboxylate) or
Ingenol 3- (5-phenyliso)Oxazole-3-carboxylic acid ester) or
Ingenol 3- (N-ethyl-carbamate) or
Ingenol 3- (N, N-dimethyl-carbamate) or
Ingenol 3- (morpholine-4-carboxylate) or
Ingenol 3- (pyrrolidine-1-carboxylate) or
Ingenol 3- (N-methyl-N-phenyl-carbamate) or
Ingenol 3- (N, N-diethyl-carbamate) or
Ingenol 3- (piperidine-1-carboxylate) or
Ingenol 3- (N-benzyl-N-methyl-carbamate) or
Ingenol 3- (N-cyclohexyl-N-methyl-carbamate) or
Ingenol 3- (N-cyclohexyl-carbamate) or
Ingenol 3- (N-phenyl-carbamate) or
Ingenol 3- (N- (indan-1-yl) -carbamate) or
Ingenol 3- (3, 3-dimethyl-piperidine-1-carboxylate) or
Ingenol 3- (N-methyl-N-tetrahydronaphthalen-1-yl-carbamate) or
Ingenol 3- (N- (2-cyano-1-methyl-ethyl) -N-methyl-carbamate) or
Ingenol 3- (N-methyl-N- ((S) -1-phenylethyl) -carbamate) or
Ingenol 3- (N-methyl-N- (cyclopropylmethyl) -carbamate) or
Ingenol 3- (isoquinoline-1-carboxylate) or
Ingenol 3- (quinoline-4-carboxylate) or
Ingenol 3- (cinnoline-4-carboxylate) or
Ingenol 3- (3-phenylimidazole-4-carboxylate) or
Ingenol 3- (5-phenyl)Oxazole-4-carboxylic acid ester) or
Ingenol 3- (1, 2-benzo)Oxazole-3-carboxylic acid ester) or
Ingenol 3- (3-isopropyl-5-methyl-iso-propyl)Oxazole-4-carboxylic acid ester) or
Ingenol 3- (3- (2-methoxyphenyl) -5-methyl-isoOxazole-4-carboxylic acid ester) or
Ingenol 3- (4-bromo-2-methyl-pyrazole-3-carboxylate) or
Ingenol 3- (4-bromo-2-ethyl-pyrazole-3-carboxylate) or
Ingenol 3- (4-chloro-2-methyl-pyrazole-3-carboxylate) or
Ingenol 3- (5-bromopyrimidine-4-carboxylate) or
Ingenol 3- (3-bromopyridine-2-carboxylate) or
Ingenol 3- (5-methylthiazole-4-carboxylate) or
Ingenol 3- (4-chloro-1-methyl-pyrazole-3-carboxylate) or
Ingenol 3- (2, 4-dimethylthiazole-5-carboxylate) or
Ingenol 3- (2, 5-dimethyl)Oxazole-4-carboxylic acid ester) or
Ingenol 3- (2, 4-dimethylfuran-3-carboxylate) or
Ingenol 3- (3, 5-diethyliso)Oxazole-4-carboxylic acid ester) or
Ingenol 3- (N- (3-fluoro-phenyl) -N-methyl-carbamate) or
Ingenol 3- (N- (2, 5-dimethylpyrazol-3-yl) -N-methyl-carbamate) or
Ingenol 3- (1H-indole-7-carboxylate) or
Ingenol 3- (2-tert-butyl-5-methyl-pyrazole-3-carboxylate) or
Ingenol 3- (5-tert-butyl-2-methyl-pyrazole-3-carboxylate) or
Ingenol 3- (6-methylimidazo [2,1-b ] thiazole-5-carboxylate) or
Ingenol 3- (2-methylimidazo [1,2-a ] pyridine-3-carboxylate) or
Ingenol 3- (2,4, 5-trimethylfuran-3-carboxylate) or
Ingenol 3- (3-methylthiophene-2-carboxylate) or
Ingenol 3- (2-methyl-4- (1-piperidinyl) pyrazole-3-carboxylate) or
Ingenol 3- (2-chloro-5-isopropyl-thiazole-4-carboxylate) or
Ingenol 3- (4-chloro-2, 5-dimethyl-pyrazole-3-carboxylate) or
Ingenol 3- (1,2, 4-trimethylpyrrole-3-carboxylate) or
Ingenol 3- (1,3, 5-trimethylpyrrole-2-carboxylate) or
Ingenol 3- (1-ethyl-3, 5-dimethylpyrrole-2-carboxylate) or
Ingenol 3- (1-tert-butyloxycarbonyl-3, 3-dimethylpyrrolidine-2-carboxylate) or
Ingenol 3- ((2S) -1-phenylpyrrolidine-2-carboxylate) or
Ingenol 3- (1-isopropyl-3, 5-dimethyl-pyrazole-4-carboxylate) or
Ingenol 3- (5-ethyl-3-isopropyl-iso-propyl-iso-terpene)Oxazole-4-carboxylic acid ester) or
Ingenol 3- (2-methylindazole-3-carboxylate) or
Ingenol 3- (5-methyl-3-tert-butyl-iso-butyl)Oxazole-4-carboxylic acid ester) or
Ingenol 3- (2-methyl-3-oxo-4-oxaspiro [4.5] dec-1-ene-1-carboxylate) or
Ingenol 3- (1-tert-butyl-3, 5-dimethyl-pyrazole-4-carboxylate) or
Ingenol 3- (3, 5-dimethylisothiazol-4-carboxylate) or
Ingenol 3- (5-iodo-3-methyl-isothiazol-4-carboxylate) or
Ingenol 3- (4- (4-methoxyphenyl) -2-methyl-pyrazole-3-carboxylate) or
Ingenol 3- (4- (2-methylphenyl) -2-methyl-pyrazole-3-carboxylate) or
Ingenol 3- (2-methyl-4- (4-methylsulfonylphenyl) pyrazole-3-carboxylate) or
Ingenol 3- (2-methyl-4-phenyl-pyrazole-3-carboxylate) or
Ingenol 3- (3, 5-dimethyl-1-phenyl-pyrazole-4-carboxylate) or
Ingenol 3- (1, 5-dimethyl-3-phenyl-pyrazole-4-carboxylate) or
Ingenol 3- (1-benzyl-3, 5-dimethyl-pyrazole-4-carboxylate) or
Ingenol 3- (3, 5-dimethyl-1- (tetrahydropyran-4-ylmethyl) pyrazole-4-carboxylate) or
Ingenol 3- (4-methyl-2-oxo-3H-thiazole-5-carboxylate) or
Ingenol 3- (2-methyl-4, 5,6, 7-tetrahydroindazol-3-carboxylate) or
Ingenol 3- (1, 2-dimethylindole-3-carboxylate) or
Ingenol 3- (5-methoxy-1, 2-dimethyl-indole-3-carboxylate) or
Ingenol 3- (1,3, 5-trimethylpyrazole-4-carboxylate) or
Ingenol 3- (4-methyl-1, 2,5-Diazole-3-carboxylic acid ester) or
Ingenol 3- (2-methoxy-4-methyl-thiazole-5-carboxylate) or
Ingenol 3- (4, 5-dimethylisol)Oxazole-3-carboxylic acid ester) or
Ingenol 3- (4-bromo-1-methyl-pyrazole-3-carboxylate) or
Ingenol 3- (1, 3-dimethylindole-2-carboxylate) or
Ingenol 3- (5-methoxy-1, 3-dimethyl-indole-2-carboxylate) or
Ingenol 3- (2, 4-dimethyl-6-oxo-pyran-3-carboxylate) or
Ingenol 3- (1-methyl-3-phenyl-indole-2-carboxylate) or
Ingenol 3- (3-methyl-5- (trifluoromethyl) isoOxazole-4-carboxylic acid ester) or
Ingenol 3- (1, 3-dimethylpyrrole-2-carboxylate) or
Ingenol 3- (3, 5-dimethyl-1- (2,2, 2-trifluoroethyl) pyrazole-4-carboxylate) or
Ingenol 3- (1-cyclopropyl-2, 5-dimethyl-pyrrole-3-carboxylate) or
Ingenol 3- (1,2, 5-trimethylpyrrole-3-carboxylate) or
Ingenol 3- (2, 4-dimethyl-1H-pyrrole-3-carboxylate) or
Ingenol 3- (1-methylpyrrole-2-carboxylate) or
Ingenol 3- (4-methyl-1H-pyrrole-2-carboxylate) or
Ingenol 3- (1, 5-dimethylpyrrole-2-carboxylate) or
Ingenol 3- (3-methyl-1H-pyrrole-2-carboxylate) or
Ingenol 3- (1-cyclopropylpyrrole-2-carboxylate) or
Ingenol 3- (1-ethyl-2, 4-dimethyl-pyrrole-3-carboxylate) or
Ingenol 3- (1-allyl-2, 4-dimethyl-pyrrole-3-carboxylate) or
Ingenol 3- (1- (cyclopropylmethyl) -2, 4-dimethyl-pyrrole-3-carboxylate) or
Ingenol 3- (1- (2-methoxyethyl) -2, 4-dimethyl-pyrrole-3-carboxylate) or
Ingenol 3- (N- (3, 5-dimethylisoi) sOxazol-4-yl) -N-methyl-carbamate) or
Ingenol 3- (N- (1, 5-dimethylpyrazol-3-yl) -N-methyl-carbamate) or
Ingenol 3- (N-cyclopentyl-N-methyl-carbamate) or
Ingenol 3- (N-cyclopropyl-N-methyl-carbamate) or
Ingenol 3- (N-methyl-N- (2-pyridyl) -carbamate) or
Ingenol 3- (4-oxo-2, 3-dihydroquinoline-1-carboxylate) or
Ingenol 3- (3, 4-dihydro-2H-quinoline-1-carboxylate) or
Ingenol 3- (indoline-1-carboxylate) or
Ingenol 3- (azepane-1-carboxylate) or
Ingenol 3- (N- (4-chloro-phenyl) -N-methyl-carbamate) or
Ingenol 3- (N- (4-fluoro-phenyl) -N-methyl-carbamate) or
Ingenol 3- (N-methyl-N- (2-methoxy-phenyl) -carbamate) or
Ingenol 3- (N-methyl-N- (2-methyl-phenyl) -carbamate) or
Ingenol 3- (3-oxo-2, 4-dihydroquinoxaline-1-carboxylate) or
Ingenol 3- (N-ethyl-N-phenyl-carbamate) or
Ingenol 3- (2-trifluoromethyl-pyrrolidine-1-carboxylate) or
Ingenol 3- (3-azabicyclo [3.2.2] nonane-3-carboxylate) or
Ingenol 3- (2, 3-dihydro-1, 4-benzoOxazin-4-carboxylic acid esters) or
Ingenol 3- (N- (2-fluoro-phenyl) -N-methyl-carbamate) or
Ingenol 3- (3-methyl-2, 3-dihydro-1, 4-benzoOxazin-4-carboxylic acid esters) or
Ingenol 3- (2-trifluoromethyl-pyrrolidine-1-carboxylate) (isomer A) or
Ingenol 3- (2-trifluoromethyl-pyrrolidine-1-carboxylate) (isomer B) or
Ingenol 3- (N-methyl-N- (N- (tert-butyloxycarbonyl) -4-piperidinyl) -carbamate) or
Ingenol 3- (N-methyl-N- (3-methyl-phenyl) -carbamate) or
Ingenol 3- (3, 4-dihydro-2H-quinoxaline-1-carboxylate) or
Ingenol 3- (isoindoline-2-carboxylate) or
Ingenol 3- (N-methyl-N- (tetrahydropyran-4-ylmethyl) -carbamate) or
Ingenol 3- (N-methyl-N- (tetrahydropyran-4-yl) -carbamate) or
Ingenol 3- (N-methyl-N- (3-methoxy-phenyl) -carbamate) or
Ingenol 3- (N-cyclobutyl-N-methyl-carbamate) or
Ingenol 3- (N-allyl-N-methyl-carbamate) or
Ingenol 3- (N-methyl-N-prop-2-ynyl-carbamate) or
Ingenol 3- (N-methyl-N- (4-methylthiazol-2-yl) -carbamate) or
Ingenol 3- (N- (4-cyano-phenyl) -N-methyl-carbamate).
One embodiment of the present invention provides a compound of formula I, said compound being ingenol 3- (N-methyl-N-phenyl-carbamate).
One embodiment of the present invention provides a compound of formula I, said compound being ingenol 3- (N- (3-fluoro-phenyl) -N-methyl-carbamate).
One embodiment of the present invention provides a compound of formula I, said compound being ingenol 3- (3-ethyl-5-methyl-isoOxazole-4-carboxylic acid ester).
One embodiment of the present invention provides a compound of formula I, said compound being ingenol 3- (2, 4-dimethylfuran-3-carboxylate).
One embodiment of the inventionThe scheme provides a compound of formula I, which is ingenol 3- (3, 5-diethylisol)Oxazole-4-carboxylic acid ester).
One embodiment of the present invention provides a compound of formula I which is ingenol 3- (2,4, 5-trimethylfuran-3-carboxylate).
One embodiment of the present invention provides a compound of formula I, said compound being ingenol 3- (2-methyl-4-phenyl-pyrazole-3-carboxylate).
One embodiment of the present invention provides a compound of formula I, said compound being ingenol 3- (3-methylthiophene-2-carboxylate).
One embodiment of the present invention provides a compound of formula I, said compound being ingenol 3- (indoline-1-carboxylate).
One embodiment of the present invention provides a compound of formula I, said compound being ingenol 3- (5-methyl-3-phenyl-isoOxazole-4-carboxylic acid ester).
One embodiment of the present invention provides a compound of formula I which is ingenol 3- (pyrrolidine-1-carboxylate).
Definition of
In this context, the term "(C)a-Cb) Alkyl "(where a and b are integers) refers to straight or branched chain alkyl groups having a to b carbon atoms, for example 1-7 or 1-6, for example 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.
The term "carbocyclic" refers to a mono-, di-, or tricyclic group having up to 13 ring atoms, e.g., 3-13 or 3-10 ring atoms, all ring atoms being carbon, and includes aryl, cycloalkyl, and cycloalkenyl groups.
The term "cycloalkyl" refers to a mono-, di-or tricyclic saturated cycloalkane group containing 3 to 13 carbon atoms, such as 3 to 10, such as 3 to 8, such as 3 to 5 carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptanyl and adamantyl.
Term "(C)a-Cb) Alkenyl "(wherein a and b are integers) refers to mono-, di-or tri-unsaturated straight or branched chain alkenyl groups having a to b carbon atoms, for example 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 vinyl, allyl, propenyl; 1-, 2-or 3-butenyl; 1-, 2-, 3-or 4-pentenyl; 1-, 2-, 3-, 4-or 5-hexenyl.
The term "cycloalkenyl" refers to mono-, di-or tri-unsaturated non-aromatic cyclic hydrocarbon radicals comprising 3 to 13 carbon atoms, such as 3 to 10, such as 3 to 8, such as 3 to 5 carbon atoms, including polycyclic radicals, and including, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.
Term "(C)a-Cb) Alkynyl "(wherein a and b are integers) refers to a straight or branched chain hydrocarbon group containing 1-2C-C triple bonds having a to b carbon atoms, for example 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 ethynyl, propynyl, butynyl, pentynyl or hexynyl.
The term "heterocycle" refers to a carbocyclic group as defined above containing 1 to 4 heteroatoms selected from O, N or S, and includes heteroaryl, heterocycloalkyl, and heterocycloalkenyl.
The term "heterocycloalkyl" refers to a cycloalkyl group, including polycyclic groups, optionally fused to a carbocyclic ring, containing 1-4 heteroatoms selected from O, N or S.
The term "heterocycloalkyl" also refers to a cycloalkyl group, including polycyclic groups, optionally fused to a carbocyclic ring (including aryl), provided that the point of attachment is through a non-aromatic ring, the cycloalkyl group containing 1-4 heteroatoms selected from O, N or S. For example, 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]Nonyl, benzoOxazinyl, quinoxalinyl, dihydroisoindolyl, indolinyl or tetrahydropyranyl, in particular tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, morpholinyl, imidazolidinyl, piperidinyl or 5-oxabicyclo [2.2.2]Octane.
The term "heterocycloalkenyl" refers to a cycloalkenyl group as defined above containing 1-4 heteroatoms selected from O, N or S, including polycyclic groups, optionally fused to a carbocyclic ring, e.g., dihydropyranyl, dihydrothiazolyl.
The term "aryl" refers to aromatic carbocyclic groups comprising 6 to 10 carbon atoms, in particular phenyl, and optionally fused carbocyclic rings having at least 1 aromatic ring, in particular 5-or 6-membered rings. Thus, the term includes, for example, 1,2,3, 4-tetrahydro-naphthyl, phenyl, naphthyl, indenyl or indanyl, especially phenyl, naphthyl, indenyl or indanyl.
The term "heteroaryl" refers to a heterocyclic aromatic ring group, optionally fused to a carbocyclic or heterocyclic ring, comprising 1 to 4 heteroatoms selected from O, S and N and 1 to 12 carbon atoms, for example 1 to 4 heteroatoms and 1 to 6 carbon atoms, in particular a 5-or 6-membered ring having 1 to 4 heteroatoms, or an optionally fused bicyclic ring having 1 to 4 heteroatoms, and wherein at least 1 ring is aromatic. The term includes, for example, pyridyl, quinolyl, isoquinolyl, indolyl, tetrazolyl, furyl, thiazolyl, tetrazolyl, pyridyl, etc,Imidazolyl, imidazo [1,2-a ]]Pyrimidinyl, pyrrolyl, pyrazolyl,Azolyl radical, isoAzolyl group,Oxadiazolyl, 1,2, 4-triazolyl, thienyl, pyrazinyl, pyrimidinyl, 1,2, 3-triazolyl, isothiazolyl, imidazo [2,1-b ]]Thiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothienylAzolyl, indazolyl, cinnolinyl, 1, 2-benzoOxazolyl, imidazothiazolyl, imidazopyridinyl, pyrrolyl, isothiazolyl, tetrahydroindazolyl, indazolyl, oxazolyl, isothiazolyl, oxazolyl, oxazol,Oxadiazolyl, especially pyridyl, quinolyl, isoquinolyl, indolyl, tetrazolyl, furyl, thiazolyl, imidazolyl, imidazo [1,2-a ]]Pyrimidinyl, pyrrolyl, pyrazolyl,Azolyl radical, isoAzolyl group,Oxadiazolyl, 1,2, 4-triazolyl, thienyl, pyrazinyl, pyrimidinyl, 1,2, 3-triazolyl, isothiazolyl, imidazo [2,1-b ]]Thiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothienylOxazolyl, indazolyl, or, in particular, pyridyl, quinolyl, isoquinolyl, indolyl, tetrazolyl, furyl, thiazolyl, imidazolyl, imidazo [1,2-a ]]Pyrimidinyl, pyrrolyl, pyrazolyl,Azolyl radical, isoAzolyl group,Oxadiazolyl, 1,2, 4-triazolyl, thienyl, pyrazinyl, pyrimidinyl, 1,2, 3-triazolyl, isothiazolyl, imidazo [2,1-b ]]Thiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothienylAzolyl, indazolyl, cinnolinyl, 1, 2-benzoAn azole group.
The term "halogen" means a substituent from main group 7 of the periodic table of elements, preferably fluorine, chlorine and bromine.
The term "alkoxy" means a group of the formula-OR, wherein R is an alkyl group as shown above, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, and the like.
The term "haloalkoxy" means a compound of the formula-O-R-X(1-3)Wherein R is alkyl as shown above and X is halogen as shown above, e.g. trifluoromethoxy.
The term hydroxyalkyl means a primary, secondary or tertiary group of the formula-R-OH, wherein R is an alkyl group as shown above, such as hydroxymethyl or hydroxyethyl.
The term cyanoalkyl means a primary, secondary or tertiary group of the formula-R-CN, wherein R is an alkyl group as shown above, for example cyanomethyl or cyanoethyl.
The term haloalkyl means a compound of the formula-R-X(1-3)Wherein R is an alkyl group shown above and X is a halogen shown above, such as trifluoromethyl, 2,2, 2-trifluoroethyl, or difluoromethyl.
When two or more of the above-defined terms are used in combination, e.g., arylalkyl, heteroarylalkyl, cycloalkylalkyl, etc., it is understood that the first-mentioned group is a substituent on the latter-mentioned group, wherein the point of attachment to another part of the molecule is on the latter group.
The term "alkoxyalkyl" means an alkyl group as defined above substituted with an alkoxy group as defined above, i.e., -R-O-R, wherein each R is the same or different alkyl group shown above, e.g., methoxymethyl, ethoxymethyl.
The term "cycloalkylalkyl" means a radical of formula-R '-cycloalkyl, wherein R' is alkyl as defined above, e.g.
The term "cycloalkenylalkyl" means a group of formula-R '-cycloalkenyl wherein R' is alkyl as defined above, e.g.
The term "arylalkyl" means a group of the formula-R '-Ar, wherein R' is an alkyl group as defined above and Ar is an aryl group as defined above, e.g.
The term "heteroarylalkyl" means a group of the formula-R '-Het wherein R' is alkyl as defined above and Het is aryl as defined above, e.g.
The term "heterocycloalkylalkyl" means a group of the formula-R '-heterocycloalkyl wherein R' is alkyl as defined above, e.g.
The term "heterocycloalkenylalkyl" means a group of the formula-R '-heterocycloalkenyl, wherein R' is alkyl as defined above, e.g.
The term alkylcycloalkyl means a group of the formula-cycloalkyl-R ', wherein R' is alkyl as defined above, e.g.
The term "alkylcycloalkenyl" means a group of the formula-cycloalkenyl-R ', wherein R' is alkyl as defined above, e.g.
The term "alkylaryl" means a group of the formula-Ar-R ', wherein R' is an alkyl group as defined above and Ar is an aryl group as defined above, for example;
the term "alkylheteroaryl" means a group of formula-Het-R ', wherein R' is alkyl as defined above and Het is heteroaryl as defined above, for example;
the term "alkylheterocycloalkyl" means a group of formula-heterocycloalkyl-R ', wherein R' is alkyl as defined above, for example;
the term 'substituted' as used in any part herein means substituted with compatible substituents.
The term "pharmaceutically acceptable salt" means a salt prepared by reacting a compound of formula I containing a basic group with a suitable inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, 2-dichloroacetic acid, choline, adipic acid, ascorbic acid, L-aspartic acid, L-glutamic acid, galactaric acid, lactic acid, maleic acid, L-malic acid, phthalic acid, citric acid, propionic acid, benzoic acid, glutaric acid, gluconic acid, D-glucuronic acid, methanesulfonic acid, salicylic acid, succinic acid, malonic acid, tartaric acid, benzenesulfonic acid, ethane-1, 2-disulfonic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfamic acid or fumaric acid. Pharmaceutically acceptable salts of compounds of formula I containing an acidic group may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, ammonia or a suitable non-toxic amine, such as a lower alkylamine, e.g. triethylamine, hydroxy-lower alkylamine, e.g. 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine, a cycloalkylamine, e.g. dicyclohexylamine or benzylamine, e.g. N, N' -dibenzylethylenediamine and dibenzylamine or L-arginine or L-lysine.
The invention further includes prodrugs of compounds of formula I, such as esters, acetals, ketals or other derivatives, which undergo biotransformation in vivo and then exhibit their pharmacological effects.
The term "solvate" means a substance formed by the interaction between a compound, e.g. a compound of formula I, and a solvent, e.g. alcohol, glycerol or water, wherein said substance is in solid form. When water is the solvent, the substance is referred to as a hydrate.
The compounds of formula I can be obtained in crystalline form either directly by concentration from an organic solvent or by crystallization or recrystallization from an organic solvent or a mixture of said solvent and a co-solvent, which may be organic or inorganic, for example water. The crystals are isolated in a substantially solvent-free form or in the form of solvates, such as hydrates. The present invention covers all crystalline modifications and forms and mixtures thereof.
The term "cancer" in the context of the present invention is intended to cover skin cancers such as non-melanoma skin cancers, malignant melanoma, Merkel cell carcinoma, squamous cell carcinoma and basal cell carcinoma. Basal cell carcinomas include superficial basal cell carcinomas as well as nodular basal cell carcinomas. Squamous cell carcinoma includes squamous cell carcinoma in situ (bowen's disease), invasive squamous cell carcinoma, squamous cell carcinoma of the skin, squamous cell carcinoma of the mucosa, squamous cell carcinoma of the head and neck. Other types of cancer include haematological cancers such as bone marrow cancers, particularly such as acute and chronic myeloid leukemia; prostate and bladder cancer, including benign prostatic hyperplasia, carcinoma of the prostate epithelium, carcinoma of the bladder, prostate adenocarcinoma, and renal cell carcinoma. Other cancers include AIDS-related cancers, acoustic neuroma, adenoid cystic carcinoma, adrenocortical cancer, idiopathic myelination, alopecia, soft tissue alveolar sarcoma, anal cancer, angiosarcoma, aplastic anemia, astrocytoma, ataxia telangiectasia, basal cell carcinoma (bcc), bladder cancer, bone cancer, intestinal cancer, brain stem glioma, brain and CNS cancer, breast cancer, CNS cancer, carcinoid cancer, cervical cancer, juvenile brain cancer, juvenile stage soft tissue sarcoma, chondrosarcoma, choriocarcinoma, colorectal cancer, cutaneous T-cell lymphoma, dermatofibrosarcoma protruberans, desmoplastic small round cell carcinoma, ductal cancer, endocrine cancer, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, extrahepatic bile duct cancer, ocular melanoma, retinoblastoma, fallopian tube cancer, angioma, angiomatosis, neuroblastoma, carcinoma, neuroblastoma, telangiectasis, and neuroblastoma, Fanconi anemia, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid, genitourinary cancer, germ cell cancer, gestational trophoblastic disease, glioma, gynecological cancer, hematologic malignancy including acute myelogenous leukemia, head and neck cancer, hepatocellular carcinoma, hereditary breast cancer, histiocytosis, hodgkin's disease, human papillomavirus, hydatidiform mole, hypercalcemia, hypopharyngeal cancer, intraocular melanoma, islet cell cancer, kaposi's sarcoma, kidney cancer, langerhans's cytosis, laryngeal cancer, leiomyosarcoma, liflamming's syndrome, lip cancer, liposarcoma, liver cancer, lung cancer, lymphedema, lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, male breast cancer, renal malignant rhabdoid tumor, medulloblastoma, mesothelioma, metastatic cancer, oral cancer, multiple endocrine tumor disease, tumor, neuroblastoma, breast cancer, colon cancer, mycosis fungoides, myelodysplastic syndrome, myeloma, myeloproliferative disease, nasal cancer, nasopharyngeal cancer, wilms 'tumor, neuroblastoma, neurofibromatosis, Nijmegen fragmentation syndrome, non-small cell lung cancer (nsclc), eye cancer, esophageal cancer, oral cancer, oropharyngeal cancer, osteosarcoma, fistulization ovarian cancer (ostomoovarian carcinoma), pancreatic cancer, paranasal sinus cancer, parathyroid cancer, parotid gland cancer, penile cancer, peripheral neuroectodermal cancer, pituitary cancer, polycythemia vera, prostate cancer, rare cancers and related disorders, retinoblastoma, rhabdomyosarcoma, RostoThomus syndrome, salivary gland carcinoma, sarcoma, schwanoma, schwannoma, West Zery's syndrome, small cell lung cancer (sclc), small bowel cancer, soft tissue sarcoma, spinal cord cancer, gastric cancer, synovial sarcoma, testicular cancer, thyroid cancer, cervical, Transitional cell carcinoma (bladder), transitional cell carcinoma (renal-renal pelvis-/-ureter), trophoblast Cancer, Cancer of the urinary tract, Cancer of the urinary system, uroplakins, uterine sarcoma, uterine Cancer, vaginal Cancer, vulvar Cancer, waldenstrom's macroglobulinemia, and Wilms' Cancer. The solid cancer treated using the methods of the invention may be a primary lesion or may be a consequence of metastasis of the primary cancer. Furthermore, if the solid cancer is a metastasis of a primary cancer, the primary cancer may be a primary solid cancer as described above or may be a diffuse primary cancer.
In one embodiment of the invention, the "cancer" is a skin cancer.
In an embodiment of the invention, the skin cancer is a non-melanoma skin cancer, a malignant melanoma, a Merkel cell carcinoma, a squamous cell carcinoma, a basal cell carcinoma such as superficial basal cell carcinoma or nodular basal cell carcinoma.
In the context of the present invention, the phrase "physiological disorder or disease associated with hyperplasia or tumor" includes disorders or diseases such as cutaneous warts, including Verruca vulgaris (Verruca vulgaris), plantar warts (plantar warts) and flat warts (Verruca plana); genital warts (condyloma acuminatum), pyogenic granulomas, hemangiomas, scleroderma; cancers and precancerous conditions 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, malignant freckles, cervical dysplasia, vulvar and anal dysplasias, primary orthotopic melanoma, head and neck cancer, skin metastases of any cancer, kaposi's sarcoma, keratoacanthoma, Merkel cell tumors, prostate cancer, mycosis fungoides, intraepithelial neoplasias including anal, cervical, breast ductal, oral, perianal, prostate, penile, vaginal and vulvar intraepithelial neoplasias.
In the context of the present invention, the term "cosmetic indications" includes indications such as photodamaged skin, seborrheic keratosis, scars, keloids, chloasma, bevacet's skin heterosis, tattoo removal, hemorrhoids and skin tags.
In the context of the present invention, the term "photodamaged skin" is intended to cover fine lines, wrinkles and UV-ageing. UV aging is often manifested as an increase in epidermal thickness or atrophy, and most notably as solar elastosis, i.e., the accumulation of elastin-containing material immediately beneath the dermoepidermal junction. Collagen and elastic fibers break apart and collapse. At the cosmetic level, reddening and/or thickening of the skin can be observed, leading to a leathery appearance, skin fragility and irregular pigmentation, loss of complexion and elasticity, and the formation of wrinkles, dryness, freckles and deep marks.
In the context of the present invention, the term "viral infection" is intended to cover HPV infections that lead to the formation of warts on the body, such as the skin, genitalia and mouth. HPV refers to human papilloma virus. The other virus is selected from the group consisting of adenovirus, papovavirus, herpes virus (such as herpes simplex virus) varicella zoster virus, epstein barr virus, CMV virus, poxviruses (such as smallpox virus) vaccinia virus, hepatitis a virus, hepatitis b virus, hepatitis c virus, rhinovirus, poliovirus, rubella virus, arbovirus, rabies virus, influenza a and b virus, measles virus, mumps virus and HIV, HTLV I and II. In one embodiment of the invention, the HPV infection involves an ordinary or genital wart.
In the context of the present invention, the term "bacterial infection" is intended to cover both prokaryotic and eukaryotic bacterial infections as well as gram-positive and gram-negative bacteria and gram-stained indefinite and intracellular bacteria. Examples of bacteria include Treponema (Treponema), Borrelia (Borrelia), Neisseria (Neisseria), Legionella (Legionella), Bordetella (Bordetella), Escherichia (Escherichia), Salmonella (Salmonella), Shigella (Shigella), Klebsiella (Klebsiella), Yersinia (Yersinia), Vibrio (Vibrio), haemophilus (Hemophilus), Rickettsia (Rickettsia), Chlamydia (Chlamydia), Mycoplasma (Mycoplasma), Staphylococcus (Staphylococcus), Streptococcus (Streptococcus), Bacillus (Bacillus), Clostridium (Clostridium), Corynebacterium (Corynebacterium), propionibacterium (propionibacterium), Mycobacterium (Mycobacterium), Mycobacterium (urella) and urella (Ureaplasma). In particular of the species Treponema pallidum (Treponema pallidum), Borrelia Burgdorferi (Borrelia Burgdorferi), Neisseria gonorrhoeae (Neisseria gonorrhoea), Legionella pneumophila (Legionella pneumophila), Bordetella pertussis (Bordetella pertussis), Escherichia coli (Escherichia coli), Salmonella typhi (Salmonella typhi), Salmonella typhimurium (Salmonella typhimurium), Shigella dysenteriae (Shigella dysenteriae), Klebsiella pneumoniae (Klebsiella pneoniae), Bacillus pestis (Yersinia pestis), Vibrio cholerae (Vibrio urella), Haemophilus influenzae (Hemophilus fluuezae), Rickettsia rickettsii (Rittsiae), Clostridium chlamydomonas (Clostridium perfringens), Clostridium botulinum (Clostridium botulinum), Clostridium botulinum pneumonia (Clostridium botulinum), Clostridium botulinum toxin (Clostridium pneumoniae (Clostridium botulinum), Clostridium botulinum toxin (Clostridium botulinum), Clostridium botulinum toxin (Clostridium botulinum), Clostridium botulinum toxin (Clostridium botulinum) and Clostridium botulinum toxin (Clostridium botulinum) strain, Clostridium botulinum toxin (Clostridium botulinum) and Clostridium botulinum toxin (Clostridium botulinum) strain), Clostridium botulinum toxin (Clostridium botulinum toxin, Corynebacterium diphtheriae (Corynebacterium diphtheriae), Corynebacterium acnes (Propionibacterium acid), Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium leprae (Mycobacterium leprae) and Listeria monocytogenes (Listeria monocytogenes). Lower eukaryotes include yeasts and fungi such as Pneumocystis nerinii, Candida albicans (Candida albicans), Aspergillus (Aspergillus), Histoplasma capsulatum (Histoplasma capsulatum), Blastomyces dermatitidis (Blastomyces dermatitidis), Cryptococcus neoformans (Cryptococcus neoformans), Trichophyton (Trichophyton) and Microsporum (Microsporum). Complex eukaryotes include worms, insects, spiders, nematodes, aemobes, entomorphs of dysentery (Entamoeba histolytica), Giardia lamblia (Giardia lamblia), Trichomonas vaginalis (Trichomonas vagianas), Trypanosoma gambiae (Trypanosoma brucei), Trypanosoma cruzi (Trypanosoma cruzi), Pacific pouch Cologyne coli (Blanidium coli), Toxoplasma gondii (Toxoplasma), Cryptosporidium (Cryptosporidium) or Leishmania (Leishmania).
In the context of the present invention, the term "wound healing" means the reduction or minimization of scar tissue or the improvement of cosmetic or functional outcomes in wounds and scar reductions, wherein the wounds are cutaneous, chronic or, for example, diabetes-related wounds and include cuts and lacerations, surgical incisions, punctures, abrasions, scratches, crush wounds, abrasions, friction wounds, chronic wounds, ulcers, heat-affected wounds, chemical wounds, wounds resulting from pathogenic infections, skin grafts/graft donor and recipient sites, immune response situations, mouth wounds, stomach or intestinal wounds, damaged cartilage or bone, amputation sides and corneal lesions.
The compounds of the present invention are expected to be useful in the treatment of cancer, actinic keratosis, seborrheic keratosis, viral infections, bacterial infections, wound healing, and photodamaged skin.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of superficial Basal Cell Carcinoma (BCC), nodular BCC, squamous cell carcinoma or Squamous Cell Carcinoma In Situ (SCCIS).
In one embodiment of the invention, the compounds of the invention are intended for the treatment of actinic keratosis.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of seborrheic keratosis.
In one embodiment of the invention, the compounds of the present invention are intended for use in the treatment of photodamaged skin.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of pathologies resulting from HPV infections.
In one embodiment of the invention, the lesion is a common wart or a genital wart.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of squamous cell carcinoma in situ or of invasive squamous cell carcinoma.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of cutaneous, mucosal or head and neck squamous cell carcinoma.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of superficial basal cell carcinoma or nodular basal cell carcinoma.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of cutaneous or genital warts.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of common warts, plantar warts and flat warts.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of malignant freckles.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of cervical intraepithelial neoplasia, anal intraepithelial neoplasia or vulvar intraepithelial neoplasia.
In one embodiment of the invention, the compounds of the invention are intended for the treatment of acute myeloid leukemia.
In one embodiment, the present invention provides a method of treating cancer, actinic keratosis, seborrheic keratosis, viral infections, bacterial infections, wound healing, and treating photodamaged skin comprising administering to an individual in need thereof a compound of formula I.
In one embodiment, the present invention provides a method of treating actinic keratosis comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the present invention provides a method of treating seborrheic keratosis comprising administering to an individual in need thereof a compound of formula I above.
In one embodiment, the present invention provides a method of treating photodamaged skin comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the present invention provides a method of treating a lesion caused by HPV infection, the method comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the present invention provides a method of treating common or genital warts, the method comprising administering to a subject in need of treatment a compound of formula I above.
In one embodiment, the present invention provides a method of treating squamous cell carcinoma of the skin, squamous cell carcinoma of the mucosa, or squamous cell carcinoma of the head and neck, comprising administering to a subject in need thereof a compound of formula I as above.
In one embodiment, the present invention provides a method of treating verruca vulgaris, plantar warts, and flat warts comprising administering to a subject in need of treatment a compound of formula I above.
In one embodiment, the present invention provides a method of treating a malignant freckle, the method comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the present invention provides a method of treating cervical intraepithelial neoplasia, anal intraepithelial neoplasia or vulvar intraepithelial neoplasia, the method comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the present invention provides the use of a compound of formula I above in the manufacture of a pharmaceutical composition for the treatment or amelioration of diseases, disorders or conditions responsive to stimulation of a neutrophil oxidative burst.
In one embodiment, the invention provides the use of a compound of 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.
In one embodiment, the present invention provides the use of a compound of formula I above for the preparation of a pharmaceutical composition for the treatment or amelioration of a disease, disorder or condition that is responsive to the induction of necrosis.
In one embodiment, the present invention provides a method of preventing, treating, ameliorating or preventing a physiological condition or disease responsive to stimulation of a neutrophil oxidative burst, comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the invention provides a method of preventing, treating, ameliorating, or preventing a physiological condition or disease that is responsive to stimulation of keratinocyte IL-8 release, the method comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the present invention provides a method of preventing, treating, ameliorating, or preventing a physiological condition or disease that is responsive to the induction of necrosis, comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the present invention provides the above compounds of formula I for use in the treatment or amelioration of diseases, disorders, or conditions responsive to stimulation of the oxidative burst of neutrophils.
In one embodiment, the invention provides the above compounds of formula I for use in treating or ameliorating a disease, disorder or condition responsive to stimulation of keratinocyte IL-8 release.
In one embodiment, the present invention provides the above compounds of formula I for use in the treatment or amelioration of a disease, disorder or condition responsive to the induction of necrosis.
In one embodiment, the present invention provides a method of treating acute myeloid leukemia comprising administering to a subject in need thereof a compound of formula I above.
In one embodiment, the present invention provides a compound of formula I for use in the treatment, prevention, amelioration or prophylaxis of physiological conditions or diseases associated with actinic keratosis, seborrheic keratosis, cancer, photodamaged skin or lesions caused by HPV infection.
In one embodiment, the present invention provides the use of a compound of formula I for the preparation of a medicament for the treatment, amelioration or prevention of physiological disorders or diseases associated with actinic keratosis, seborrheic keratosis, cancer, photodamaged skin or lesions caused by HPV infection.
In one embodiment, the present invention provides a method of preventing, treating, ameliorating or preventing a physiological condition or disease associated with actinic keratosis, seborrheic keratosis, cancer, photodamaged skin, or a lesion caused by HPV infection, the method comprising administering to a subject in need thereof a compound of formula I.
Pharmaceutical composition
For use in therapy, the compounds of the invention are generally in the form of pharmaceutical compositions. The present invention therefore relates to pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable excipient or carrier. An excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
The pharmaceutical compositions of the present invention may be in unit dosage forms such as tablets, pills, capsules, powders, granules, elixirs, syrups, emulsions, ampoules, suppositories, or parenteral solutions or suspensions; for oral, parenteral, ocular, transdermal, intra-articular, topical, pulmonary, intranasal, buccal or rectal administration or in any other manner suitable for formulation of The compounds of The present invention and in accordance with accepted practices such as those disclosed in Remington: The Science and Practice of Pharmacy, 21 st edition, 2000, Lippincott Williams & Wilkins.
For oral administration in the form of tablets or capsules, the compounds of formula I may be suitably mixed with an oral, non-toxic pharmaceutically acceptable carrier, such as ethanol, glycerol, water and the like. In addition, suitable binders, lubricants, disintegrating agents, flavoring agents, and coloring agents may also be added to the mixture as appropriate. Suitable binders include, for example, lactose, glucose, starch, gelatin, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, for example, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Other excipients for use in capsules include polyethylene glycols or lipids.
For the preparation of solid compositions, such as tablets, the active compound of formula I is mixed with one or more excipients, such as those described above, and other pharmaceutical diluents, such as water, to produce a solid preformulation composition comprising a homogenous mixture of the compound of formula I. The term "homogeneous" is understood to mean that the compound of formula I is dispersed uniformly throughout the composition so that the composition can be readily subdivided into equivalent unit dosage forms such as tablets or capsules.
In dosage unit form, the compound may be administered one or more times per day at appropriate intervals, but this will generally depend on the condition of the patient and according to the prescription given by the physician. Conveniently, the dosage unit of the formulation comprises from 0.01mg to 200mg, preferably from 0.01mg to 20mg, for example from 0.01 to 5mg, of a compound of formula I.
The appropriate dosage of the compounds 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 known to the practitioner. The compounds are administered orally, parenterally or topically according to different dosing schedules, for example at daily or weekly intervals. Typically, a single dose is in the range of 0.01 to 200mg/kg body weight. The compounds may be administered daily in the form of a bolus (i.e., the entire daily dose is administered once) or in two or more divided doses.
If The treatment involves administration of another therapeutically active compound, for useful doses of said compound, reference is suggested to Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9 th edition, J.G.Hardman and L.E.Limbird (Eds.), McGraw-Hill 1995. Administration of a compound of the invention and one or more other active compounds may be simultaneous or sequential.
Liquid formulations for oral or parenteral administration of the compounds of the invention include, for example, aqueous solutions, syrups, aqueous or oil suspensions, and emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinylpyrrolidone.
For parenteral administration, e.g., intramuscular, intraperitoneal, subcutaneous or intravenous injection or drip, the pharmaceutical composition preferably comprises a compound of formula I dissolved or solubilized in a suitable pharmaceutically acceptable solvent. For parenteral administration, the compositions of the invention may comprise sterile aqueous or non-aqueous solvents, in particular water, isotonic saline, isotonic glucose solution, buffer solutions or other solvents commonly used for the parenteral administration of therapeutically active substances. The composition can be sterilized, for example, by filtration through a bacteria-retaining filter, by adding a sterilizing agent to the composition, by irradiating the composition, or by heating the composition. Alternatively, the compounds of the invention may also be provided in the form of a sterile solid preparation, for example a lyophilized powder, which is dissolved in a sterile solvent immediately prior to use. Compositions for parenteral administration may also contain conventional additives such as stabilizers, buffers or preservatives, for example antioxidants such as methyl hydroxybenzoate and the like.
Compositions for rectal administration may be in the form of suppositories or enemas incorporating the active ingredient and a carrier such as cocoa butter.
Compositions suitable for intra-articular administration may be in the form of sterile aqueous preparations of the active ingredient in microcrystalline form, for example in the form of aqueous microcrystalline suspensions. Liposomal formulations or biodegradable polymer systems can also be used to present active ingredients for intra-articular and ocular administration.
Compositions suitable for topical administration, including ophthalmic treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, dressings, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. The composition for ophthalmic treatment preferably further comprises a cyclodextrin. Compositions suitable for intranasal or buccal administration or for inhalation include powder, self-propelled and spray formulations, such as aerosols and nebulisers.
The human skin, particularly the outer, stratum corneum, provides an effective barrier to the penetration of microbial pathogens and toxic chemicals. While this property of the skin is generally beneficial, it complicates the dermal administration of drugs because a large, if not large, amount of the active ingredient applied to the skin of a patient suffering from a skin disorder may not penetrate to the effective skin layer in which it exerts its activity.
Penetration of the skin may be enhanced by the addition of penetration enhancers including isopropyl alcohol, sulfoxides, azones, pyrrolidines, alkanols, and glycols. In an embodiment of the invention, the penetration enhancer comprises DMSO, lauryl nitrogenKetones, 2-pyrrolidone, decanol and propylene glycol. In one embodiment of the invention, the penetration enhancer is isopropyl alcohol.
In an embodiment of the invention, the therapeutically active compound is dissolved in a suitable solvent. Suitable solvents are glycols, ketones, acetates and ethers. Ingenol compounds have been demonstrated to have good stability in alcohols such as benzyl alcohol and isopropanol. In general, ingenol compounds have previously been shown to have good stability at low pH. In an embodiment of the invention, the pH of the pharmaceutical formulation is below 7. In an embodiment of the invention, the pH of the pharmaceutical formulation is below 6. In an embodiment of the invention, the pH of the pharmaceutical formulation is below 4.5. In an embodiment of the invention, the pH of the pharmaceutical formulation is below 4.0. In an embodiment of the invention, the pH of the pharmaceutical formulation is below 4.5 and not below 2.5. In an embodiment of the invention, the pH of the pharmaceutical formulation is below 4.0 and not below 2.5. The preferred pH range may be obtained by including an appropriate buffer. In one embodiment of the invention, the buffer is an acetate buffer. In an embodiment of the invention, a citrate buffer is used. In an embodiment of the invention, a mixed citrate-phosphate buffer is used.
In one embodiment, the composition is an ointment. According to the current FDA classification, an ointment is a semisolid dosage form that may contain up to 20% by weight water and volatile materials and more than 50% by weight 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 to the lipophilic component of the composition such that the composition contains up to 10% by weight or preferably up to 5% by weight of an aqueous phase. In addition, the composition may also be a non-aqueous ointment comprising less than about 2%, preferably less than 1%, free water by weight of the composition.
The ointment carrier may suitably comprise a chain length selected from C5-60And paraffins and mixtures thereof. The ointment carrier usually used is vaseline or white soft paraffin composed of different chain lengths with a peak value at about C40-44Or vaseline and liquid paraffin (with peaks at C of different chain lengths)28-40Hydrocarbon composition) of the same. Although petrolatum may provide a barrier layer on the surface of the skin being treatedReduce the transdermal loss of water and enhance the therapeutic effect of the active ingredient in the composition, but it tends to have a greasy and/or sticky feel which persists for a considerable period of time after application and it is not easy to apply. Thus, it is preferred to use paraffins composed of hydrocarbons of lower chain length, for example with a chain length peak at C14-16、C18-22、C20-22、C20-26Paraffin wax or mixtures thereof. These waxes have been found to be more acceptable in cosmetics because they are not sticky and/or greasy when applied and are easier to apply. Thus, they are expected to result in improved patient compliance. Suitable paraffinic hydrocarbons of this type are produced by Sonneborn and sold under the trade names Sonnecone, such as Sonnecone CM, Sonnecone DM1, Sonnecone DM2 and Sonnecone HV. These paraffins are further disclosed and characterized in WO08/141078, which is hereby incorporated by reference. (the hydrocarbon composition of the paraffin wax was determined by gas chromatography.)
In order to impart the desired viscosity to the composition, it may suitably comprise a lipophilic viscosity building component such as a wax. The wax may be composed of a high molecular weight hydrocarbon such as saturated C35-70A mixture of alkanes, for example microcrystalline wax. In addition, the wax may also be a vegetable or animal wax, e.g. C14-32Fatty acids and C14-32Esters of fatty alcohols, for example beeswax. The amount of tackifying component can vary depending on the tackifying power of the component, but is typically in the range of about 1 to 20 weight percent of the weight of the composition. When the viscosity-building component is a microcrystalline wax, it is typically present in an amount of about 5 to 15% by weight, for example about 10% by weight, of the composition.
In order to maintain good physical stability of the composition, in particular to avoid separation of the aqueous and lipid phases therein, it preferably comprises a water-in-oil emulsifier having an HLB value of from 3 to 8. An example of such an emulsifier is polyoxyethylene C8-22Alkyl ethers, such as polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether or polyoxyethylene lauryl ether. The amount of emulsifier is typically 2-10% w/w by weight of the composition.
In another embodiment, the composition is a cream comprising ingredients similar to ointments, but which are typically oil-in-water emulsions containing a large amount of water.
The composition may also contain other Ingredients commonly used in skin formulations such as antioxidants (e.g. alpha-tocopherol), preservatives such as benzyl alcohol, sodium edetate, pigments, skin emollients, skin healing agents and skin conditioning agents such as urea, allantoin or bisabolol, see CTFA Cosmetic Ingredients Handbook, 2 nd edition, 1992. In one embodiment of the invention, the preservative is benzyl alcohol.
In one embodiment, the composition is a gel. Suitable gelling agents include water-soluble cellulose-derived polymers, such as hydroxyalkyl cellulose polymers. In an embodiment of the invention, the polymer is hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose. Other gelling agents are celluloses, such as carboxymethyl cellulose, methylhydroxyethyl cellulose and methyl cellulose, carbopols, such as carbomers and carrageenan. In an embodiment of the invention, the gelling agent is a cellulose derivative. In an embodiment of the invention, the cellulose is a hydroxyalkyl cellulose such as hydroxyethyl cellulose.
In one embodiment of the invention, the composition comprises an active compound, a penetration enhancer, a preservative, a gelling agent, and a buffer having a pH of less than 4 and not less than 2.5. For topical administration, the compounds of formula I are generally present in an amount of from 0.001 to 20%, for example from 0.01% to about 10% by weight of the composition. In an embodiment of the invention, the active compound is present in an amount of 0.05-1%. In one embodiment of the invention, the active compound is present in an amount of 0.01 to 0.5%. In one embodiment of the invention, the active compound is present at a concentration of about 0.1%. In one embodiment of the invention, the composition comprises 0.005-0.1% active compound, 20-40% isopropanol, 0.5-10% benzyl alcohol, 0.5-5% hydroxyethyl cellulose and citrate buffer to 100%.
Formulations of ingenol derivatives in gel form for topical administration have been described in WO07/068963, which is incorporated herein by reference.
Preparation method
The compounds of formula I can be prepared, for example, using the reactions and techniques outlined below, as well as methods known in the art of synthetic organic chemistry or variations of the methods understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reaction is carried out in a solvent suitable for the reagents and starting materials used and for the transformations carried out. Furthermore, it should be understood that in the synthetic methods described below, all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and choice of workup method, should be selected as the conditions standard for the reaction, which should be readily identifiable by the skilled person. Not all compounds falling within a given class are compatible with some of the reaction conditions required in some of the methods described. Limitations on substituents that are compatible with reaction conditions will be apparent to those skilled in the art, and alternative methods may be used. If desired, the compounds of the invention or any intermediates are purified using standard methods known to synthetic organic chemists, for example the method described in w. The starting materials are known compounds, are commercially available, or can be prepared by conventional synthetic methods known to those skilled in the art.
The compounds of the present invention may be prepared, for example, according to the following non-limiting general methods and examples.
Scheme I
Scheme 2
Scheme 3
Scheme 4
Compounds of general formula I can be synthesized, for example, according to scheme 1,2,3, or 4: according to, for example, "protecting groups in organic synthesis", 4 th edition, p.g.m.wuts; t.w. greene, John Wiley,2007 or p.j. kocienski, "protecting groups", 3 rd edition g.thieme,2003 and references cited therein, reacting ingenol with a hydroxy protecting agent or a dihydroxy protecting agent to give protected ingenol derivatives a or c.
For example, compound a, wherein the protecting group (Pg) is triphenylmethyl, may be synthesized by reacting ingenol with a triphenylmethyl reagent such as triphenylmethyl pyridine fluoroborate or triphenylmethyl chloride in a suitable solvent such as pyridine, N-dimethylformamide or dichloromethane, in the presence or absence of a base (e.g. Opferkuch et al, z. naturforschung, (1981),36B, 878).
Compound a, wherein the protecting group (Pg) is a silyl group, may be synthesized, for example, 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-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 triflate, in a suitable solvent, such as dichloromethane, in the presence of a suitable base, such as triethylamine.
Compound a (where Pg is 2-tetrahydropyranyl) may be synthesised for example by reacting ingenol with dihydropyran in a suitable solvent such as dichloromethane or acetonitrile in the presence of a suitable acid such as p-toluene sulphonic acid.
Compound c, wherein the protecting group (Pg) represents an acetal such as benzylidene acetal, may be prepared, for example, 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.
Compound c, wherein the protecting group (Pg) represents a ketal such as isopropylidene ketal, can be synthesized, for example, by reacting ingenol with a ketone such as acetone or a dimethoxy ketal such as 2, 2-dimethoxypropane 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-dimethoxypropane may also serve as solvents.
Protected ingenol derivatives a or c are esterified as described in schemes 1 and 2, according to the hydroxy esterification methods described in, for example, "esterification", j. Compound b or d can be synthesized, for example, by reacting compound a or c with an activated acid derivative, such as an acid halide, for example an acid chloride. Esterification by reaction with an acid chloride can be carried out in a suitable solvent such as dichloromethane or toluene without an activating agent, or can be carried out 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-.
Compound b or d can be synthesized, for example, by reacting compound a or c with an activated acid derivative such as an anhydride. Esterification by reaction with an anhydride can be carried out without a catalyst (e.g., Opferkuch et al, z. naturforschung, (1981),36B,878), or with an acid such as perchloric acid or a Lewis acid such as scandium (III) or bismuth (III) trifluoromethanesulfonate in the presence of an acidic catalyst, or in the presence of a base such as sodium bicarbonate or triethylamine.
Compounds b or d can be synthesized, for example, by reacting compounds a or c with activated acid derivatives, such as mixed anhydrides of acids, e.g., trichlorobenzoic acid. The esterification by reaction with the mixed anhydride can be carried out in a suitable solvent without a catalyst, or in the presence of an acidic catalyst with an acid such as perchloric acid or a Lewis acid such as scandium (III) trifluoromethanesulfonate or bismuth (III) trifluoromethanesulfonate, or in the presence of a base such as sodium hydrogencarbonate or triethylamine.
Compounds b or d can be synthesized, for example, by reacting compound a or c with an acid in the presence of a coupling agent such as a carbodiimide, e.g., dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide, in the presence or absence of a base such as 4- (N, N-dimethylamino) pyridine, with or without a catalyst such as 4- (N, N-dimethylamino) pyridine in a suitable solvent such as dichloromethane (e.g., appendix et al, eur.j.org.chem. (1999), 3413). Solid-supported coupling agents may also be used in the esterification step [ Nam, N. -H., Journal of combinatorial chemistry, (2003),5, 479-.
The compounds of formula b, d or I of schemes 1 or 2 above may be synthesized, for example, by enzymatic esterification by reacting compound a, c or ingenol with an acyl donor such as an anhydride, ester such as a vinyl ester or thioester in the presence of an enzyme such as a lipase or esterase.
As depicted in schemes 3 and 4, protected ingenol derivatives a or c can be carbamoylated to give compounds of formula b or d according to the hydroxy Group carbamoylation procedures as described in, for example, "Functional groups containing a carbonyl Group and at least one chalcogen (but not halogen)," H.Eckert, "Comprehensive Organic Functional Group Transformations II", A.R.Katritzky and R.J.K.Taylor, Vol 6, p.440-444, Elsevier, 2005 and references cited therein. Compound b or d can be synthesized, for example, by reacting compound a or c with an activated carbamic acid derivative, e.g., a carbamoyl halide, e.g., carbamoyl chloride. Carbamoylation by reaction with carbamoyl chloride may be carried out in a suitable solvent such as acetonitrile, dichloromethane or toluene without an activating agent, or may be carried out in the presence of a base such as pyridine, triethylamine, potassium carbonate or 4- (N, N-dimethylamino) pyridine.
Compounds b or d can be synthesized, for example, by reacting compounds a or c with isocyanates to give N-mono-substituted carbamates. The carbamate formation by reaction with the isocyanate may be carried out in a suitable solvent such as dichloromethane or acetonitrile without a catalyst, or may be carried out in the presence of a base such as triethylamine.
Compounds of formula I may be prepared by selective removal of the protecting group Pg from compounds of general structure b or d according to procedures such as, but not limited to, "protecting groups in organic synthesis", 4 th edition, p.g.m.wuts; t.w. greene, John Wiley,2007 or p.j. kocienski, "protecting groups", 3 rd edition, g.thieme,2003 and references cited therein.
Compounds of formula I may be prepared, for example, from compounds of formula d (wherein Pg represents an acetal such as a benzylidene acetal or ketal such as an isopropylidene ketal) by removing the protecting group in the presence of a suitable acid such as hydrochloric acid, acetic acid, trifluoroacetic acid or p-toluenesulfonic acid in a suitable solvent such as methanol or aqueous tetrahydrofuran.
The compounds of formula I may be prepared, for example, from compounds of formula b (wherein Pg represents alkoxyalkyl such as 2-tetrahydropyranyl) by removal of the acetal moiety, for example by acid catalysed cleavage, in the presence of a suitable acid such as p-toluene sulphonic acid in a suitable solvent such as methanol.
Compounds of formula I may be prepared, for example, from compounds of formula b (wherein Pg represents a silyl group such as tert-butyldimethylsilyl group) by reacting compound b with an appropriate acid such as hydrochloric acid in an appropriate solvent such as methanol or by reacting with a fluorine source such as tetra-n-butylammonium fluoride or tetrafluorosilane in an appropriate solvent such as tetrahydrofuran or acetonitrile.
Compounds of formula I can be prepared, for example, from compounds of formula b (wherein Pg represents triphenylmethyl) by reacting compound b with an appropriate acid, for example formic acid or trifluoroacetic acid, in an appropriate solvent, for example diethyl ether, methanol or dichloromethane.
Examples
SUMMARY
All materials used are commercially available unless otherwise described. For the 1H Nuclear Magnetic Resonance (NMR) spectrum, the chemical shift value () (ppm) is given; tetramethylsilane (═ 0.00) was used as a standard. The values of the defined singlet(s), doublet (d), triplet (t), quartet (q) or range (m) are given. Carbamates may show repetitive signals due to the presence of cis/trans rotamers. All organic solvents used are anhydrous unless otherwise indicated. Flash chromatography was performed on silica gel. An appropriate mixture of ethyl acetate and heptane was used as eluent unless otherwise stated. The compounds were detected on TLC plates by development with aqueous potassium permanganate solution.
Ingenol-5, 20-acetonide
Ingenol (1.00g,2.30mmol) was dissolved in a solution of p-toluenesulfonic acid monohydrate in acetone (0.47mg/mL,22.5 mL). The solution was stirred at room temperature for 25 min. To this solution was added saturated NaHCO3Aqueous solution (0.2 mL). Mixing the obtained mixtureThe mixture was concentrated in vacuo. Brine was added to the residue 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 → heptane/ethyl acetate 0:1) to give the title compound (616mg, 69%) as a white solid. (see also: Opferkuch, H.J. et al, Z.Naturforsch., (1981),86b,878-
1H NMR(300MHz,CDCl3)5.91(q,J＝1.5Hz,1H),5.79(m,1H),4.25(d,J＝4.5Hz,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＝15.7,8.4,2.9Hz,1H),1.85(d,J＝1.5Hz,3H),1.77(dt,J＝15.8,5.9Hz,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＝8.4,6.4Hz,1H)。
General Process for the preparation of Compounds of the formula II
Method a
A mixture of formic acid (0.100mmol), dicyclohexylcarbodiimide (0.100mmol), 4- (N, N-dimethylamino) -pyridine (0.0025mmol) and ingenol-5, 20-acetonide (0.050mmol) was 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 solution. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (heptane → heptane/ethyl acetate 7:3) to give the title compound as a white solid.
Method b
A mixture of acid chloride (0.0625mmol), diisopropylethylamine (0.075mmol), 4- (N, N-dimethylamino) -pyridine (0.070mmol) and ingenol-5, 20-acetonide (0.050mmol) was stirred in tetrahydrofuran at 55 ℃ for 6-20 h. The mixture was mixed with ethyl acetate, filtered and washed with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (heptane → heptane/ethyl acetate 7:3) to give the title compound as a white solid.
Method c
A mixture of formic acid (0.100mmol), dicyclohexylcarbodiimide (0.100mmol), 4- (N, N-dimethylamino) -pyridine (0.025mmol) and ingenol-5, 20-acetonide (0.050mmol) was stirred in acetonitrile for 5min at 150 ℃ in a microwave oven. The mixture was mixed with ethyl acetate, filtered and washed with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (heptane → heptane/ethyl acetate 7:3) to give the title compound as a white solid.
Method d
A mixture of acid chloride (0.125mmol), diisopropylethylamine (0.250mmol), 4- (N, N-dimethylamino) -pyridine (0.025mmol) and ingenol-5, 20-acetonide (0.050mmol) was stirred in acetonitrile for 10-30min at 150 ℃ in a microwave oven. The mixture was mixed with ethyl acetate, filtered and washed with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (heptane → heptane/ethyl acetate 7:3) to give the title compound as a white solid.
General Process for the preparation of Compounds of formula I
Method e
Ingenol-5, 20-acetonide-3-acylate or ingenol-5, 20-acetonide-3-carbamate (0.10mmol) was dissolved in tetrahydrofuran (0.47mL) under argon. Aqueous HCl (4M, 4.7. mu.L) was added. The solution was stirred at room temperature for 20-27 h. The tetrahydrofuran can be replaced by methanol and the reaction time at room temperature can be shortened to 0.5 h. The solution was concentrated in vacuo. The residue was purified by flash chromatography (heptane/ethyl acetate 5:1 → heptane/ethyl acetate 3:7) to afford the title compound. For more polar compounds, a dichloromethane/methanol 98:2 → dichloromethane/methanol 95:5 gradient may be utilized.
General Process for preparing carbamoyl chlorides
Method f
To a solution of the secondary amine (1.2mmol) in dichloromethane (2ml) at 0 deg.C was added potassium bicarbonate (3.0mmol) or a tertiary amine such as triethylamine or pyridine followed by triphosgene (1.0 mmol). The mixture was stirred at 0 ℃ for 2h, filtered and washed with dichloromethane. The combined filtrates were concentrated in vacuo to give the title compound.
General Process for the preparation of ingenol-5, 20-acetonide-3-carbamate compounds of general formula III
Method g
A mixture of carbamoyl chloride (0.390mmol), potassium carbonate (0.616mmol) and ingenol-5, 20-acetonide (0.077mmol) was stirred in acetonitrile at 80 ℃ 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 → heptane/ethyl acetate 7:3) to afford the title compound.
Method h
A mixture of carbamoyl chloride (0.390mmol), potassium carbonate (0.616mmol) and ingenol-5, 20-acetonide (0.077mmol) was stirred in acetonitrile for 10min at 160 ℃ in a microwave oven. The mixture was filtered and washed with dichloromethane. The combined filtrates were concentrated in vacuo and purified by flash chromatography (heptane → heptane/ethyl acetate 7:3) to afford the title compound.
Method i
A mixture of isocyanate (0.231mmol), potassium carbonate (0.385mmol) and ingenol-5, 20-acetonide (0.077mmol) was stirred in acetonitrile at 80 ℃ 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 → heptane/ethyl acetate 7:3) to afford the title compound.
Method j
To a solution of ingenol-5, 20-acetonide (0.10mmol) in tetrahydrofuran was added dropwise a 1M solution of lithium (trimethylsilyl) amide in THF (0.10mmol) at 0 ℃ under an argon atmosphere. After stirring for 10min carbamoyl chloride (0.20mmol) in 0.2ml THF was added dropwise and the reaction mixture was slowly returned to room temperature overnight. The mixture was added to 2 drops of water, then dichloromethane (1ml) was added, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (heptane → heptane/ethyl acetate 7:3) to afford the title compound.
General procedure for the preparation of 4-aryl-substituted 1-methylpyrazole-5-carboxylic acids
Method k
The method described in G.C.Fu et al Angew.chem.2006,118,1304-1306 was used.
A heterogeneous mixture of 1-methyl-4-bromopyrazole-5-carboxylic acid (1mmol), tris (dibenzylideneacetone) dipalladium (0) (0.1mmol), tricyclohexylphosphine (0.2mmol), potassium phosphate (3mmol) and the appropriate phenylboronic acid (1.5mmol), water (2mL) and dioxane (4mL) was stirred in a microwave oven at 180 ℃ for 20min under argon. The mixture was cooled to room temperature and partially evaporated, 5N aqueous NaOH (1mL) was added and washed 3 times with diethyl ether. The aqueous solution was acidified with 4N HCl and the precipitate was isolated by filtration and dried to give the crude 4-aryl-substituted 1-methylpyrazole-5-carboxylic acid, which was used without further purification.
Preparation example 601:
ingenol-5, 20-acetonide-3- (5-methyl-3- (2-chloro-6-fluoro-phenyl) -iso Azole-4-carboxylic acid Ester (Compound 601)
Compound 601 was prepared according to procedure d.
Starting from 5-methyl-3- (2-chloro-6-fluoro-phenyl) -isoOxazole-4-carbonyl chloride.
1H NMR(300MHz,CDCl3)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)。
Preparation 602:
ingenol-5, 20-acetonide-3- (5-methyl-3-phenyl-iso-propyl ester Azole-4-carboxylic acid ester) (compound 602)
Compound 602 was prepared according to procedure d.
Starting from 5-methyl-3-phenyl-isoOxazole-4-carbonyl chloride.
1H NMR(300MHz,CDCl3)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)。
Preparation example 603
Ingenol-5, 20-acetonide-3- (1S-camphane-oate) (Compound 603)
Compound 603 was prepared according to procedure d.
Starting material (1S) -benzoyl chloride.
1H NMR(300MHz,CDCl3)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)。
Preparation example 604:
ingenol-5, 20-acetonide-3- (3-phenyltriazole-4-carboxylate) (Compound 604)
Compound 604 was prepared according to procedure c.
The raw material is 3-phenyl triazole-4-formic acid.
Preparation example 605:
ingenol-5, 20-acetonide-3- (2-phenylpyrazole-3-carboxylate) (Compound 605)
Compound 605 was prepared according to method h, wherein "carbamoyl chloride" was replaced with 2-phenylpyrazole-3-carbonyl chloride.
Preparation 606:
ingenol-5, 20-acetonide-3- (1-methylindazole-3-carboxylate) (Compound 606)
Compound 606 was prepared according to method h, wherein "carbamoyl chloride" was replaced with 1-methylindazole-3-carbonyl chloride.
Preparation example 607:
ingenol-5, 20-acetonide-3- (3-ethyl-5-methyl-iso-propyl ester) Azole-4-carboxylic acid ester) (compound 607)
Compound 607 was prepared according to procedure c.
Starting material 3-ethyl-5-methyl-isoOxazole-4-carboxylic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation 608:
ingenol-5, 20-acetonide-3- (3, 5-dimethyl-iso-dimethyl) Azole-4-carboxylic acid ester) (Compound 608)
Compound 608 was prepared according to procedure c.
Raw material 3, 5-dimethyl-isoOxazole-4-carboxylic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation 609:
ingenol-5, 20-acetonide-3- (1-methyl) ketoneIsoindole-3-carboxylate) (Compound 609)
Compound 609 was prepared according to procedure c.
The raw material is 1-methylindole-3-formic acid.
Preparation 610:
ingenol-5, 20-acetonide-3- (3-phenylthiophene-2-carboxylate) (Compound 610)
Compound 610 was prepared according to procedure c.
The raw material is 3-phenyl thiophene-2-formic acid.
Preparation example 611:
ingenol-5, 20-acetonide-3- (5-phenyliso) Azole-3-carboxylic acid ester) (Compound 611)
Compound 611 was prepared according to procedure d.
Starting material 5-phenylisoOxazole-3-carbonyl chloride.
1H NMR(300MHz,CDCl3)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)。
Preparation 612:
ingenol-5, 20-acetonide-3- (isoquinoline-1-carboxylate) (Compound 612)
Compound 612 was prepared according to procedure c.
The raw material is isoquinoline-1-formic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 613:
ingenol-5, 20-acetonide-3- (quinoline-4-carboxylate) (Compound 613)
Compound 613 was prepared according to procedure c.
The raw material is quinoline-4-formic acid.
Preparation 614:
ingenol-5, 20-acetonide-3- (cinnoline-4-carboxylate) (Compound 614)
Compound 614 was prepared according to procedure c.
Cinnoline-4-formic acid as raw material.
1H NMR(300MHz,CDCl3)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)。
Preparation example 615:
ingenol-5, 20-acetonide-3- (3-phenylimidazole-4-carboxylate) (Compound 615)
Compound 615 was prepared according to procedure c.
The raw material is 3-phenylimidazole-4-formic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation 616:
ingenol-5, 20-acetonide-3- (5-phenyl) Azole-4-carboxylic acid ester) (Compound 616)
Compound 616 was prepared according to procedure c.
Starting material 5-phenylOxazole-4-carboxylic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 617:
ingenol-5, 20-acetonide-3- (1, 2-benzo) Oxazole-3-carboxylic acid ester) (compound 617)
Compound 617 was prepared according to procedure c.
Starting material 1, 2-benzoOxazole-3-carboxylic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation 618:
ingenol-5, 20-acetonide-3- (3-isopropyl-5-methyl-iso-propyl) Azole-4-carboxylic acid ester) (compound 618)
Compound 618 was prepared according to procedure c.
Raw material 3-isopropyl-5-methyl-isoOxazole-4-carboxylic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation 619:
ingenol-5, 20-acetonide-3- (3- (2-methoxyphenyl) -5-methyl-iso Azole-4-carboxylic acid ester (Compound 619)
Compound 619 was prepared according to procedure c.
Starting from 3- (2-methoxyphenyl) -5-methyl-isoOxazole-4-carboxylic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 620:
ingenol-5, 20-acetonide-3- (4-bromo-2-methyl-pyrazole-3-carboxylate) (Compound 620)
Compound 620 was prepared according to procedure c.
The raw material is 4-bromo-2-methyl-pyrazole-3-formic acid.
Preparation example 621:
ingenol-5, 20-acetonide-3- (4-bromo-2-ethyl-pyrazole-3-carboxylate) (Compound 621)
Compound 621 was prepared according to procedure c.
The raw material is 4-bromo-2-ethyl-pyrazole-3-formic acid.
Preparation 622:
ingenol-5, 20-acetonide-3- (4-chloro-2-methyl-pyrazole-3-carboxylate) (Compound 622)
Compound 622 was prepared according to procedure c.
The raw material is 4-chloro-2-methyl-pyrazole-3-formic acid.
Preparation example 623:
ingenol-5, 20-acetonide-3- (5-bromopyrimidine-4-carboxylate) (Compound 623)
Compound 623 was prepared according to procedure d, but the reaction time was extended to 40 min.
Starting material 5-bromopyrimidine-4-carbonyl chloride, prepared from 5-bromopyrimidine-4-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation example 624:
ingenol-5, 20-acetonide-3- (3-bromopyridine-2-carboxylate) (Compound 624)
Compound 624 was prepared according to procedure d, but with the reaction time extended to 40 min.
Starting material 3-bromopyridine-2-carbonyl chloride, prepared from 3-bromopyridine-2-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation example 625:
ingenol-5, 20-acetonide-3- (5-methylthiazole-4-carboxylate) (Compound 625)
Compound 625 was prepared according to procedure c.
The raw material is 5-methylthiazole-4-formic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 626:
ingenol-5, 20-acetonide-3- (4-chloro-1-methyl-pyrazole-3-carboxylate) (Compound 626)
Compound 626 was prepared according to procedure c.
The raw material is 4-chloro-1-methyl-pyrazole-3-formic acid.
Preparation example 627:
ingenol-5, 20-acetonide-3- (2, 4-dimethylthiazole-5-carboxylate) (Compound 627)
Compound 627 was prepared according to procedure c.
The raw material is 2, 4-dimethylthiazole-5-formic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 628:
ingenol-5, 20-acetonide-3- (2, 5-dimethyl) Oxazole-4-carboxylic acid ester) (compound 628)
Compound 628 is prepared according to procedure c.
Raw material 2, 5-dimethylOxazole-4-carboxylic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 629:
ingenol-5, 20-acetonide-3- (2, 4-dimethylfuran-3-carboxylate) (Compound 629)
Compound 629 was prepared according to procedure d.
The raw material is 2, 4-dimethyl furan-3-carbonyl chloride.
1H NMR(300MHz,CDCl3)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)。
Preparation example 630:
ingenol-5, 20-acetonide-3- (3, 5-diethylisoisovaleryl) ester Azole-4-carboxylic acid ester) (Compound 630)
Compound 630 was prepared according to procedure d.
Starting material 2, 4-diethylfuran-3-carbonyl chloride, prepared from 2, 4-diethylfuran-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation example 631:
ingenol-5, 20-acetonide-3- (1H-indole-7-carboxylate) (Compound 631)
Compound 631 was prepared according to procedure c.
The raw material is 1H-indole-7-formic acid.
Preparation example 632:
ingenol-5, 20-acetonide-3- (2-tert-butyl-5-methyl-pyrazole-3-carboxylate) (Compound 632)
Compound 632 was prepared according to procedure c, but using N, N-dimethylformamide instead of acetonitrile.
The raw material is 2-tert-butyl-5-methyl-pyrazole-3-formic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 633:
ingenol-5, 20-acetonide-3- (5-tert-butyl-2-methyl-pyrazole-3-carboxylate) (Compound 633)
Compound 633 was prepared according to procedure c, but using N, N-dimethylformamide instead of acetonitrile.
The raw material is 5-tert-butyl-2-methyl-pyrazole-3-formic acid.
Preparation example 634:
ingenol-5, 20-acetonide-3- (6-methylimidazo [2, 1-b)]Thiazole-5-carboxylic acid ester) (compound 634)
Compound 634 was prepared according to procedure c, but using N, N-dimethylformamide instead of acetonitrile.
The raw material is 6-methylimidazo [2,1-b ] thiazole-5-formic acid.
Preparation example 635:
ingenol-5, 20-acetonide-3- (2-methylimidazo [1, 2-a)]Pyridine-3-carboxylic acid ester) (compound635)
Compound 635 was prepared according to procedure c, but using N, N-dimethylformamide instead of acetonitrile.
The raw material is 2-methylimidazo [1,2-a ] pyridine-3-formic acid.
Preparation example 636:
ingenol-5, 20-acetonide-3- (2,4, 5-trimethylfuran-3-carboxylate) (Compound 636)
Compound 636 is prepared according to procedure c.
The raw material is 2,4, 5-trimethyl furan-3-formic acid.
Preparation 637:
ingenol-5, 20-acetonide-3- (3-methylthiophene-2-carboxylate) (Compound 637)
Compound 637 is prepared according to procedure c.
The raw material is 3-methylthiophene-2-formic acid.
Preparation example 638:
ingenol-5, 20-acetonide-3- (2-methyl-4- (1-piperidinyl) pyrazole-3-carboxylate) (compound 638)
Compound 638 was prepared according to procedure d.
Starting material 2-methyl-4- (1-piperidinyl) pyrazole-3-carbonyl chloride, prepared from 2-methyl-4- (1-piperidinyl) pyrazole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation 639:
ingenol-5, 20-acetonide-3- (2-chloro-5-isopropyl-thiazole-4-carboxylate) (Compound 639)
Compound 639 was prepared according to procedure c.
The raw material is 2-chloro-5-isopropyl-thiazole-4-formic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 640:
ingenol-5, 20-acetonide-3- (4-chloro-2, 5-dimethyl-pyrazole-3-carboxylate) (compound 640)
Compound 640 was prepared according to procedure c.
The raw material is 4-chloro-2, 5-dimethyl-pyrazole-3-formic acid.
Preparation 641:
ingenol-5, 20-acetonide-3- (1,2, 4-trimethylpyrrole-3-carboxylate) (Compound 641)
Compound 641 is prepared according to procedure c.
The raw material is 1,2, 4-trimethylpyrrole-3-formic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 642:
ingenol-5, 20-acetonide-3- (1,3, 5-trimethylpyrrole-2-carboxylate) (Compound 642)
Compound 642 was prepared according to procedure c.
The raw material is 1,3, 5-trimethylpyrrole-2-formic acid.
Preparation example 643:
ingenol-5, 20-acetonide-3- (1-ethyl-3, 5-dimethylpyrrole-2-carboxylate) (compound 643)
Compound 643 was prepared according to procedure c.
The raw material is 1-ethyl-3, 5-dimethylpyrrole-2-formic acid.
Preparation example 644:
ingenol-5, 20-acetonide-3- (1-tert-butyloxycarbonyl-3, 3-dimethylpyrrolidine-2-carboxylic acid Ester) (Compound 644)
Compound 644 was prepared according to procedure c.
The raw material is 1-tert-butyloxycarbonyl-3, 3-dimethylpyrrolidine-2-formic acid.
Preparation example 645:
ingenol-5, 20-acetonide-3- ((2S) -1-phenylpyrrolidine-2-carboxylate) (Compound 645)
Compound 645 was prepared according to procedure a, but replacing dichloromethane with acetonitrile and reacting at 90 ℃ for 18 h.
The raw material is (2S) -1-phenylpyrrolidine-2-formic acid.
Preparation example 646:
ingenol-5, 20-acetonide-3- (1-isopropyl-3, 5-dimethyl-pyrazole-4-carboxylate) (compound 646)
Compound 646 was prepared according to procedure d, but at a reaction temperature of 160 ℃.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation 647:
ingenol-5, 20-acetonide-3- (5-ethyl-3-isopropyl-iso-propyl) Azole-4-carboxylic acid ester) (compound 647)
Compound 647 was prepared according to procedure a, but replacing dichloromethane with acetonitrile and reacted at 90 ℃ for 18 h.
Raw material of 5-ethyl-3-isopropyl-isoOxazole-4-carboxylic acid.
Preparation 648:
ingenol-5, 20-acetonide-3- (2-methylindazole-3-carboxylate) (Compound 648)
Compound 648 was prepared according to procedure a, but replacing dichloromethane with acetonitrile and reacting at 90 ℃ for 18 h.
The starting material was 2-methylindazole-3-carboxylic acid.
Preparation example 649:
ingenol-5, 20-acetonide-3- (5-methyl-3-tert-butyl-iso-butyl) Azole-4-carboxylic acid ester) (compound 648)
Compound 649 was prepared according to procedure c.
Raw material of 5-methyl-3-tert-butyl-isoOxazole-4-carboxylic acid.
Preparation 650:
ingenol-5, 20-acetonide-3- (2-methyl-3-oxo-4-oxaspiro [4.5]]Dec-1-ene-1-carboxylic acid Ester) (Compound 650)
Compound 650 was prepared according to procedure c, but the reaction temperature was maintained at 140 ℃ for 1 h.
The raw material is 2-methyl-3-oxo-4-oxaspiro [4.5] dec-1-ene-1-formic acid.
Preparation 651:
ingenol-5, 20-acetonide-3- (1-tert-butyl-3, 5-dimethyl-pyrazole-4-carboxylate) (compound 651)
Compound 651 was prepared according to procedure c.
The raw material is 1-tert-butyl-3, 5-dimethyl-pyrazole-4-formic acid.
Preparation 652:
ingenol-5, 20-acetonide-3- (3, 5-dimethylisothiazole-4-carboxylate) (Compound 652)
Compound 652 was prepared according to procedure c.
The raw material is 3, 5-dimethyl isothiazole-4-formic acid.
Preparation example 653:
ingenol-5, 20-acetonide-3- (5-iodo-3-methyl-isothiazole-4-carboxylate) (compound 653)
Compound 653 was prepared according to procedure c.
The raw material is 5-iodine-3-methyl-isothiazole-4-formic acid.
Preparation example 654:
ingenol-5, 20-acetonide-3- (4- (4-methoxyphenyl) -2-methyl-pyrazole-3-carboxylate) (conversion to Compound 654)
Compound 654 is prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo. 4- (4-methoxyphenyl) -2-methyl-pyrazole-3-carboxylic acid was prepared according to method k starting from (4-methoxyphenyl) boronic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 655:
ingenol-5, 20-acetonide-3- (4- (2-methylphenyl) -2-methyl-pyrazole-3-carboxylate) (Compound Object 655)
Compound 655 was prepared according to method d, but the reaction temperature was 100 ℃.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo. 4- (2-methylphenyl) -2-methyl-pyrazole-3-carboxylic acid was prepared according to method k starting from (2-methylphenyl) boronic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation 656:
ingenol-5, 20-acetonide-3- (2-methyl-4- (4-methylsulfonylphenyl) pyrazole-3-carboxylate) (Compound 656)
Compound 656 was prepared according to procedure d, but at a reaction temperature of 100 ℃.
Starting material 4- (4-methylsulfonylphenyl) -2-methyl-pyrazole-3-carbonyl chloride, which was prepared from 4- (4-methylsulfonylphenyl) -2-methyl-pyrazole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo. 4- (4-Methylsulfonylphenyl) -2-methyl-pyrazole-3-carboxylic acid was prepared according to method k starting from (4-methylsulfonylphenyl) boronic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 657:
ingenol-5, 20-acetonide-3- (2-methyl-4-phenyl-pyrazole-3-carboxylate) (compound 657)
Compound 657 was prepared according to method d, but at a reaction temperature of 100 ℃.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo. 2-methyl-4-phenyl-pyrazole-3-carboxylic acid was prepared according to method k starting from phenylboronic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation 658:
ingenol-5, 20-acetonide-3- (3, 5-dimethyl-1-phenyl-pyrazole-4-carboxylate) (compound 658)
Compound 658 was prepared according to procedure d, but at a reaction temperature of 140 ℃.
The raw material is 3, 5-dimethyl-1-phenyl-pyrazole-4-formic acid.
1H NMR(300MHz,CDCl3)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).
Preparation example 659:
ingenol-5, 20-acetonide-3- (1, 5-dimethyl-3-phenyl-pyrazole-4-carboxylate) (compound 659)
Compound 659 was prepared according to method d.
The raw material is 1, 5-dimethyl-3-phenyl-pyrazole-4-formic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 660:
ingenol-5, 20-acetonide-3- (1-benzyl-3, 5-dimethyl-pyrazole-4-carboxylate) (compound 660)
Compound 660 was prepared according to procedure d.
The raw material is 1-benzyl-3, 5-dimethyl-pyrazole-4-formic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation example 661:
ingenol-5, 20-acetonide-3- (3, 5-dimethyl-1- (tetrahydropyran-4-ylmethyl) pyrazol-4-yl) methyl Acid ester) (Compound 661)
Compound 661 was prepared by heating a mixture of ingenol-5, 20-acetonide-3- (3, 5-dimethyl-1H-pyrazole-4-carboxylate) (15mg), 4-iodomethyl-tetrahydro-2H-pyran (80mg) and potassium carbonate (40mg) in N, N-dimethylformamide (0.5ml) in a microwave oven at 120 ℃ for 20 min. Water was added and extracted with dichloromethane, then the solvent was evaporated to give the crude product, which was purified by chromatography as described in method c to give the title compound. Ingenol-5, 20-acetonide-3- (3, 5-dimethyl-1H-pyrazole-4-carboxylate) was prepared by method c starting from 3, 5-dimethyl-1H-pyrazole-4-carboxylic acid.
Preparation 662:
ingenol-5, 20-acetonide-3- (4-methyl-2-oxo-3H-thiazole-5-carboxylate) (compound 662)
Compound 662 was prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation 663:
ingenol-5, 20-acetonide-3- (2-methyl-4, 5,6, 7-tetrahydroindazol-3-carboxylate) (Compound (I) 663)
Compound 663 is prepared according to procedure d.
Starting material 2-methyl-4, 5,6, 7-tetrahydroindazole-3-carbonyl chloride was prepared from 2-methyl-4, 5,6, 7-tetrahydroindazole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation example 664:
ingenol-5, 20-acetonide-3- (1, 2-dimethylindole-3-carboxylate) (Compound 664)
Compound 664 was prepared according to procedure d.
Starting material 1, 2-dimethylindole-3-carbonyl chloride, prepared from 1, 2-dimethylindole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation example 665:
ingenol-5, 20-acetonide-3- (5-methoxy-1, 2-dimethyl-indole-3-carboxylate) (compound 665)
Compound 665 was prepared according to procedure d, but with an extended reaction time to 75 min.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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).
Preparation example 666:
ingenol-5, 20-acetonide-3- (1,3, 5-trimethylpyrazole-4-carboxylate) (Compound 666)
Compound 666 was prepared according to procedure d.
Starting material 1,3, 5-trimethylpyrazole-4-carbonyl chloride, which was prepared from 1,3, 5-trimethylpyrazole-4-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation 667:
ingenol-5, 20-acetonide-3-, (4-methyl-1, 2,5- Oxadiazole-3-carboxylic acid ester) (Compound 667)
Compound 667 was prepared according to procedure d.
Raw material 4-methyl-1, 2,5-Oxadiazole-3-carbonyl chlorides from 4-methyl-1, 2,5-Oxadiazole-3-carboxylic acid was prepared by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation 668:
ingenol-5, 20-acetonide-3- (2-methoxy-4-methyl-thiazole-5-carboxylate) (compound 668)
Compound 668 is prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation 669:
ingenol-5, 20-acetonide-3- (4, 5-dimethylisovaleryl) compound Azole-3-carboxylic acid ester) (Compound 669)
Compound 669 was prepared according to procedure d.
Raw material 4, 5-dimethyl isoOxazole-3-carbonyl chloride, prepared from 2-methoxy-4-methyl-thiazole-5-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation example 670:
ingenol-5, 20-acetonide-3- (4-bromo-1-methyl-pyrazole-3-carboxylate) (Compound 670)
Compound 670 was prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation example 671:
ingenol-5, 20-acetonide-3- (1, 3-dimethylindole-2-carboxylate) (Compound 671)
Compound 671 is prepared according to procedure d.
Starting material 1, 3-dimethylindole-2-carbonyl chloride, prepared from 1, 3-dimethylindole-2-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation 672:
ingenol-5, 20-acetonide-3- (5-methoxy-1, 3-dimethyl-indole-2-carboxylate) (compound 672)
Compound 672 was prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation example 673:
ingenol-5, 20-acetonide-3- (2, 4-dimethyl-6-oxo-pyran-3-carboxylate) (compound 673)
Compound 673 was prepared according to procedure c.
The starting material was 2, 4-dimethyl-6-oxo-pyran-3-carboxylic acid.
Preparation example 674:
ingenol-5, 20-acetonide-3- (1-methyl-3-phenyl-indole-2-carboxylate) (Compound 674)
Compound 674 is prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation 675:
ingenol-5, 20-acetonide-3- (3-methyl-5- (trifluoromethyl) iso Oxazole-4-carboxylic acid ester) (compound (III) Thing 675)
Compound 675 was prepared according to procedure c.
Starting material 3-methyl-5- (trifluoromethyl) isoOxazole-4-carboxylic acid.
Preparation example 676:
ingenol-5, 20-acetonide-3- (1, 3-dimethylpyrrole-2-carboxylate) (Compound 676)
Compound 676 was prepared according to procedure c, except that the reaction conditions were changed to react at 140 ℃ for 60min.
The raw material is 1, 3-dimethyl pyrrole-2-formic acid.
Preparation example 677:
ingenol-5, 20-acetonide-3- (3, 5-dimethyl-1- (2,2, 2-trifluoroethyl) pyrazole-4-carboxylic acid Ester) (Compound 677)
Compound 677 was prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation 678:
ingenol-5, 20-acetonide-3- (1-cyclopropyl-2, 5-dimethyl-pyrrole-3-carboxylate) (compound 678)
Compound 678 was prepared according to procedure d, but with the reaction time extended to 60min.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation example 679:
ingenol-5, 20-acetonide-3- (1,2, 5-trimethylpyrrole-3-carboxylate) (Compound 679)
Compound 679 was prepared according to procedure d, but with the reaction time extended to 100 min.
Starting material 1,2, 5-trimethylpyrrole-3-carbonyl chloride, which was prepared from 1,2, 5-trimethylpyrrole-3-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation example 680:
ingenol-5, 20-acetonide-3- (2, 4-dimethyl-1H-pyrrole-3-carboxylate) (Compound 680)
Compound 680 was prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)10.40bs,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)。
Preparation example 681:
ingenol-5, 20-acetonide-3- (1-methylpyrrole-2-carboxylate) (Compound 681)
Compound 681 was prepared according to procedure d.
Starting material 1-methylpyrrole-2-carbonyl chloride, prepared from 1-methylpyrrole-2-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation example 682:
ingenol-5, 20-acetonide-3- (4-methyl-1H-pyrrole-2-carboxylate) (Compound 682)
Compound 682 was prepared according to procedure d, but the reaction time was extended to 75 min.
Starting material 4-methyl-1H-pyrrole-2-carbonyl chloride, prepared from 4-methyl-1H-pyrrole-2-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation example 683:
ingenol-5, 20-acetonide-3- (1, 5-dimethylpyrrole-2-carboxylate) (Compound 683)
Compound 683 was prepared according to procedure c, but with an extension of the reaction time to 40 min.
The raw material is 1, 5-dimethylpyrrole-2-formic acid.
Preparation 684:
ingenol-5, 20-acetonide-3- (3-methyl-1H-pyrrole-2-carboxylate) (Compound 684)
Compound 684 was prepared according to procedure c, but with the reaction time extended to 40 min.
The raw material is 3-methyl-1H-pyrrole-2-formic acid.
1H NMR(300MHz,CDCl3)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)。
Preparation 685:
ingenol-5, 20-acetonide-3- (1-cyclopropylpyrrole-2-carboxylate) (Compound 685)
Compound 685 was prepared according to procedure d.
Starting material 1-cyclopropylpyrrole-2-carbonyl chloride, prepared from 1-cyclopropylpyrrole-2-carboxylic acid by reaction with 1.25 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation 686:
ingenol-5, 20-acetonide-3- (1-ethyl-2, 4-dimethyl-pyrrole-3-carboxylate) (compound 686)
Compound 686 was prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation 687:
ingenol-5, 20-acetonide-3- (1-allyl-2, 4-dimethyl-pyrrole-3-carboxylate) (Compound 687)
Compound 687 was prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation example 688:
ingenol-5, 20-acetonide-3- (1- (cyclopropylmethyl) -2, 4-dimethyl-pyrrole-3-carboxylate) (Compound 688)
Compound 688 was prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
Preparation 689:
ingenol-5, 20-acetonide-3- (1- (2-methoxyethyl) -2, 4-dimethyl-pyrrole-3-carboxylic acid Ester) (Compound 689)
Compound 689 was prepared according to procedure d.
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 equivalents of oxalyl chloride in dichloromethane and 1 drop of dimethylformamide at room temperature for 30 minutes, followed by evaporation of the volatiles in vacuo.
1H NMR(300MHz,CDCl3)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)。
Preparation example 801:
ingenol-5, 20-acetonide-3- (N-ethyl-carbamate) (Compound 801)
Compound 801 was prepared according to procedure i.
The raw material is ethyl isocyanate.
Preparation example 802:
ingenol-5, 20-acetonide-3- (N, N-dimethyl-carbamate) (Compound 802)
Compound 802 was prepared according to procedure g.
The raw material is N, N-dimethyl carbamyl chloride.
Preparation example 803:
ingenol-5, 20-acetonide-3- (morpholine-4-carboxylate) (Compound 803)
Compound 803 was prepared according to procedure g.
The raw material is morpholine-4-carbonyl chloride.
1H NMR(300MHz,CDCl3)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)。
Preparation example 804:
ingenol-5, 20-acetonide-3- (pyrrolidine-1-carboxylate) (Compound 804)
Compound 804 was prepared according to procedure g.
Raw material pyrrolidine-1-carbonyl chloride.
1H NMR(300MHz,CDCl3)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)。
Preparation example 805:
ingenol-5, 20-acetonide-3- (N-methyl-N-phenyl-carbamate) (Compound 805)
Compound 805 was prepared according to procedure g.
The starting material was N-methyl-N-phenyl-carbamoyl chloride.
Preparation 806:
ingenol-5, 20-acetonide-3- (N, N-diethyl-carbamate) (Compound 806)
Compound 806 was prepared according to procedure g.
The raw material is N, N-diethyl-carbamyl chloride.
Preparation example 807:
ingenol-5, 20-acetonide-3- (piperidine-1-carboxylate) (Compound 807)
Compound 807 was prepared according to method g.
The raw material is piperidine-1-carbonyl chloride.
Preparation example 808:
ingenol-5, 20-acetonide-3- (N-benzyl-N-methyl-carbamate) (Compound 808)
Compound 808 was prepared according to procedure g.
Starting material N-benzyl-N-methyl-carbamoyl chloride, prepared from N-benzyl-N-methyl-amine according to method f.
Preparation example 809:
ingenol-5, 20-acetonide-3- (N-cyclohexyl-N-methyl-carbamate) (compound 809)
Compound 809 was prepared according to procedure g.
Starting material N-cyclohexyl-N-methyl-carbamoyl chloride, prepared from N-cyclohexyl-N-methyl-amine according to procedure f.
Preparation 810:
ingenol-5, 20-acetonide-3- (N-cyclohexyl-carbamate) (Compound 810)
Compound 810 was prepared according to procedure i.
The raw material is cyclohexyl isocyanate.
Preparation example 811:
ingenol-5, 20-acetonide-3- (N-phenyl-carbamate) (Compound 811)
Compound 811 was prepared according to procedure i.
Starting material phenyl isocyanate.
Preparation example 812:
ingenol-5, 20-acetonide-3- (N- (indan-1-yl) -carbamate) (Compound 812)
Compound 812 was prepared according to procedure i.
The raw material is isocyanate-1-indane.
Preparation example 813:
ingenol-5, 20-acetonide-3- (3, 3-dimethyl-piperidine-1-carboxylate) (Compound 813)
Compound 813 was prepared according to procedure i.
Starting material 3, 3-dimethyl-piperidine-1-carbonyl chloride, which was prepared from 3, 3-dimethyl-piperidine according to procedure f.
Preparation example 814:
ingenol-5, 20-acetonide-3- (N-methyl-N-tetrahydronaphthalen-1-yl-carbamate) (compound 814)
Compound 814 was prepared according to procedure i.
Starting material N-methyl-N-tetrahydronaphthalen-1-yl-carbamoyl chloride, prepared from N-methyl-N- (tetrahydronaphthalen-1-yl) -amine according to procedure f.
Preparation example 815:
ingenol-5, 20-acetonide-3- (N- (2-cyano-1-methyl-ethyl) -N-methyl-carbamate) (Compound 815)
Compound 815 was prepared according to procedure h.
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.
Preparation example 816:
ingenol-5, 20-acetonide-3- (N-methyl-N- ((S) -1-phenylethyl) -carbamate) (Compound (I) Thing 816)
Compound 816 was prepared according to procedure h.
Starting material N-methyl-N- ((S) -1-phenylethyl) -carbamoyl chloride, prepared from N-methyl-N- ((S) -1-phenylethyl) -amine according to procedure f.
Preparation example 817:
ingenol-5, 20-acetonide-3- (N-methyl-)N- (cyclopropylmethyl) -carbamic acid ester) (compound 817)
Compound 817 was prepared according to procedure h.
Starting material N- (cyclopropylmethyl) -N-methyl-carbamoyl chloride, prepared from N- (cyclopropylmethyl) -N-methyl-amine according to procedure f.
1H NMR(300MHz,CDCl3)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)。
Preparation 818:
ingenol-5, 20-acetonide-3- (N- (3-fluoro-phenyl) -N-methyl-carbamate) (compound 818)
Compound 818 was prepared according to procedure j.
Starting material N- (3-fluorophenyl) -N-methyl-carbamoyl chloride, prepared from 3-fluoro-N-methyl-aniline according to procedure f using pyridine as tertiary amine.
Preparation example 819:
ingenol-5, 20-acetonide-3- (N- (2, 5-dimethylpyrazol-3-yl) -N-methyl-carbamic acid Ester) (Compound 819)
Compound 819 was prepared according to procedure h.
Starting material N- (2, 5-dimethylpyrazol-3-yl) -N-methyl-carbamoyl chloride, which was prepared from N,1, 3-trimethyl-1H-pyrazol-5-amine according to procedure f.
1H NMR(300MHz,CDCl3)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)。
Preparation 820:
ingenol-5, 20-acetonide-3- (N- (3, 5-dimethylisovaleryl) ether Azol-4-yl) -N-methyl-carbamic acid ester Acid ester) (Compound 820)
Compound 820 was prepared according to procedure h.
Starting material N- [ (3, 5-dimethyliso)Oxazol-4-yl) methyl]-N-methyl-carbamoyl chloride, derived from 1- (3, 5-dimethylisoOxazol-4-yl) -N-methyl-methylamine was prepared according to method f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 821:
ingenol-5, 20-acetonide-3- (N- (1, 5-dimethylpyrazol-3-yl) -N-methyl-carbamic acid Ester) (Compound 821)
Compound 821 was prepared according to procedure h.
Starting material N- (1, 5-dimethylpyrazol-3-yl) -N-methyl-carbamoyl chloride, which was prepared from N,1, 5-trimethylpyrazol-3-amine according to method f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 822:
ingenol-5, 20-acetonide-3- (N-cyclopentyl-N-methyl-carbamate) (Compound 822)
Compound 822 was prepared according to procedure h.
Starting material N-cyclopentyl-N-methyl-carbamoyl chloride, prepared from N-methylcyclopentylamine according to procedure f.
Preparation example 823:
ingenol-5, 20-acetonide-3- (N-cyclopropyl-N-methyl-carbamate) (Compound 823)
Compound 823 was prepared according to procedure h.
Starting material N-cyclopropyl-N-methyl-carbamoyl chloride, prepared from N-methylcyclopropylamine following procedure f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 824:
ingenol-5, 20-acetonide-3- (N-methyl-N- (2-pyridyl) -carbamate) (compound 824)
Compound 824 was prepared according to procedure j.
Starting material N-methyl-N- (2-pyridyl) carbamoyl chloride, prepared from N-methylpyridin-2-amine according to procedure f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 825:
ingenol-5, 20-acetonide-3- (4-oxo-2, 3-dihydroquinoline-1-carboxylate) (Compound 825)
Compound 825 was prepared according to procedure j.
Starting material 4-oxo-2, 3-dihydroquinolin-1-carbonyl chloride, prepared from 2, 3-dihydro-1H-quinolin-4-one according to procedure f.
Preparation example 826:
ingenol-5, 20-acetonide-3- (3, 4-dihydro-2H-quinoline-1-carboxylate) (Compound 826)
Compound 826 was prepared according to procedure j.
Starting material 3, 4-dihydro-2H-quinoline-1-carbonyl chloride, which was prepared from 1,2,3, 4-tetrahydroquinoline according to procedure f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 827:
ingenol-5, 20-acetonide-3- (indoline-1-carboxylate) (Compound 827)
Compound 827 is prepared according to procedure j.
Starting material indoline-1-carbonyl chloride, which was prepared from indoline according to procedure f.
1H NMR(300MHz,CDCl3)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),2.64bs,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)。
Preparation example 828:
ingenol-5, 20-acetonide-3- (azepane-1-carboxylate) (Compound 828)
Compound 828 was prepared according to procedure j.
Starting material azepane-1-carbonyl chloride, which was prepared from azepane according to method f.
1H NMR(300MHz,CDCl3)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)。
Preparation 829:
ingenol-5, 20-acetonide-3- (N- (4-chloro-phenyl) -N-methyl-carbamate) (compound 829)
Compound 829 is prepared according to procedure j.
Starting material N- (4-chlorophenyl) -N-methyl-carbamoyl chloride, prepared from 4-chloro-N-methyl-aniline according to procedure f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 830:
ingenol-5, 20-acetonide-3- (N- (4-fluoro-phenyl) -N-methyl-carbamate) (compound 830)
Compound 830 was prepared according to procedure j.
Starting material N- (4-fluorophenyl) -N-methyl-carbamoyl chloride, prepared from 4-fluoro-N-methyl-aniline according to method f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 831:
ingenol-5, 20-acetonide-3- (N-methyl-N- (2-methoxy-phenyl) -carbamate) (Compound Article 831)
Compound 831 was prepared according to procedure j.
Starting material N- (2-methoxyphenyl) -N-methyl-carbamoyl chloride, prepared from 2-methoxy-N-methyl-aniline according to method f.
Preparation example 832:
ingenol-5, 20-acetonide-3- (N-methyl-N- (2-methyl-phenyl) -carbamate) (compound 832)
Compound 832 was prepared according to procedure j.
Starting material N- (2-methylphenyl) -N-methyl-carbamoyl chloride, prepared from 2-methyl-N-methyl-aniline according to procedure f.
Preparation example 833:
ingenol-5, 20-acetonide-3- (3-oxo-2, 4-dihydroquinoxaline-1-carboxylate) (Compound 833)
Compound 833 was prepared according to procedure j.
Starting material 3-oxo-2, 4-dihydroquinoxaline-1-carbonyl chloride, which is prepared from 3, 4-dihydro-1H-quinoxalin-2-one according to method f.
1H NMR(300MHz,CDCl3)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)。
Preparation 834:
ingenol-5, 20-propanilKetone-3- (N-ethyl-N-phenyl-carbamate) (Compound 834)
Compound 834 was prepared according to procedure j.
Starting material N-ethyl-N-phenyl-carbamoyl chloride, prepared from N-ethyl-aniline according to procedure f.
1H NMR(300MHz,CDCl3)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)。
Preparation 835:
ingenol-5, 20-acetonide-3- (2-trifluoromethyl-pyrrolidine-1-carboxylate) (Compound 835)
Compound 835 was prepared according to procedure j.
Starting material 2- (trifluoromethyl) pyrrolidine-1-carbonyl chloride, which was prepared from 2- (trifluoromethyl) pyrrolidine according to procedure f.
Preparation example 836:
ingenol-5, 20-acetonide-3- (3-azabicyclo [3.2.2] 2]Nonane-3-carboxylic acid ester) (compound 836)
Compound 836 was prepared according to procedure j.
Starting material 3-azabicyclo [3.2.2] nonane-3-carbonyl chloride, which was prepared from 3-azabicyclo [3.2.2] nonane according to procedure f.
Preparation 837:
ingenol-5, 20-acetonide-3- (2, 3-dihydro-1, 4-benzo Oxazine-4-carboxylic acid esters) (compounds 837)
Compound 837 was prepared according to procedure j.
Starting from 2, 3-dihydro-1, 4-benzoOxazine-4-carbonyl chloride from 2, 3-dihydro-1, 4-benzoThe oxazines are prepared according to procedure f.
Preparation example 838:
ingenol-5, 20-acetonide-3- (N- (2-fluoro-phenyl) -N-methyl-carbamate) (compound 838)
Compound 838 was prepared according to procedure j.
Starting material N- (2-fluoro-phenyl) -N-methyl-carbamoyl chloride, prepared from 2-fluoro-N-methyl-aniline according to procedure f.
1H NMR(300MHz,CDCl3)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)。
Preparation 839:
ingenol-5, 20-acetonide-3- (3-methyl-2, 3-dihydro-1, 4-benzo Oxazine-4-carboxylic acid esters (Compound 839)
Compound 839 (mixture of diastereomers) was prepared according to procedure j.
The raw material is 3-methyl-2, 3-dihydro-1, 4-benzoOxazine-4-carbonyl chloride from 3-methyl-3, 4-dihydro-2H-1, 4-benzoThe oxazines are prepared according to procedure f.
Preparation 842:
ingenol-5, 20-acetonide-3- (N-methyl-N- (N- (tert-butyloxycarbonyl) -4-piperidinyl) -amino Carbamate) (Compound 842)
Compound 842 was prepared according to procedure j.
Starting material tert-butyl 4- (chlorocarbonyl (methyl) amino) piperidine-1-carboxylate, which was prepared from tert-butyl 4-methylaminopiperidine-1-carboxylate according to method f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 843:
ingenol-5, 20-acetonide-3- (N-methyl-N- (3-methyl-phenyl) -carbamate) (compound 843)
Compound 843 was prepared according to procedure j.
Starting material N-methyl-N- (3-methyl-phenyl) -carbamoyl chloride, prepared from N, 3-dimethylaniline according to procedure f.
Preparation example 844:
ingenol-5, 20-acetonide-3- (3, 4-dihydro-2H-quinoxaline-1-carboxylate) (Compound 844)
Compound 844 was prepared according to procedure j.
Starting material 3, 4-dihydro-2H-quinoxaline-1-carbonyl chloride, which is prepared from 1,2,3, 4-tetrahydroquinoxaline according to method f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 845:
ingenol-5, 20-acetonide-3- (isoindoline-2-carboxylate) (Compound 845)
Compound 845 was prepared according to procedure j.
Starting material isoindoline-2-carbonyl chloride, which was prepared from isoindoline according to procedure f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 846:
ingenol-5, 20-acetonide-3- (N-methyl-N- (tetrahydropyran-4-ylmethyl) -carbamate) (Compound 846)
Compound 846 is prepared according to procedure j.
Starting material N-methyl-N- (tetrahydropyran-4-ylmethyl) -carbamoyl chloride, prepared from N-methyl-1-tetrahydropyran-4-yl-methylamine according to method f.
Preparation example 847:
ingenol-5, 20-acetonide-3- (N-methyl-N- (tetrahydropyran-4-yl) -carbamate) (Compound Substance 847)
Compound 847 was prepared according to procedure j.
Starting material N-methyl-N- (tetrahydropyran-4-yl) -carbamoyl chloride, prepared from N-methyltetrahydropyran-4-amine according to method f.
1H NMR(300MHz,CDCl3)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)。
Preparation example 848:
ingenol-5, 20-acetonide-3- (N-methyl-N- (3-methoxy-phenyl) -carbamate) (Compound Thing 848)
Compound 848 was prepared according to procedure j.
Starting material N-methyl-N- (3-methoxy-phenyl) -carbamoyl chloride, prepared from N-methyl-3-methoxy-aniline according to procedure f.
Preparation 849:
ingenol-5, 20-acetonide-3- (N-cyclobutyl-N-methyl-carbamate) (compound 849)
Compound 849 was prepared according to procedure h.
Starting material N-cyclobutyl-N-methyl-carbamoyl chloride, prepared from N-methylcyclobutylamine according to procedure f.
Preparation example 850:
ingenol-5, 20-acetonide-3- (N-allyl-N-methyl-carbamate) (Compound 850)
Compound 850 was prepared according to procedure h.
Starting material N-allyl-N-methyl-carbamoyl chloride, prepared from N-methylprop-2-en-1-amine according to procedure f.
Preparation example 851:
ingenol-5, 20-acetonide-3- (N-methyl-N-prop-2-ynyl-carbamate) (Compound 851)
Compound 851 was prepared according to procedure h.
Starting material N-methyl-N-prop-2-ynyl-carbamoyl chloride, which was prepared from N-methylprop-2-yn-1-amine according to method f.
Preparation 852:
ingenol-5, 20-acetonide-3- (N-methyl-N- (4-methylthiazol-2-yl) -carbamate) (conversion to ingenol Compound 852)
Compound 852 was prepared according to procedure j.
Starting material N-methyl-N- (4-methylthiazol-2-yl) carbamoyl chloride, prepared from N, 4-dimethylthiazol-2-amine according to procedure f.
Preparation example 853:
ingenol-5, 20-acetonide-3- (N- (4-cyano-phenyl) -N-methyl-carbamate) (compound 853)
Compound 853 was prepared according to procedure j.
Starting material N- (4-cyano-phenyl) -N-methyl-carbamoyl chloride, prepared from N-methyl-4-cyano-aniline according to procedure f.
Example 501:
ingenol 3- (5-methyl-3- (2-chloro-6-fluoro-phenyl) -iso Azole-4-carboxylic acid ester) (Compound 501)
Compound 501 was prepared according to procedure e.
The raw material is compound 601.
1H NMR(300MHz,CDCl3)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)。
Example 502:
ingenol 3- (5-methyl-3-phenyl-iso Azole-4-carboxylic acid ester) (Compound 502)
Compound 502 was prepared according to procedure e.
Starting material compound 602.
1H NMR(300MHz,CDCl3)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)。
Example 503
Ingenol 3- (1S-camphanoate) (Compound 503)
Compound 503 was prepared according to procedure e.
Starting material, compound 603.
1H NMR(300MHz,CDCl3)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)。
Example 504
Ingenol 3- (3-phenyltriazole-4-carboxylate) (Compound 504)
Compound 504 was prepared according to procedure e.
Starting material compound 604.
1H NMR(300MHz,CDCl3)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)。
Example 505
Ingenol 3- (2-phenylpyrazole-3-carboxylate) (Compound 505)
Compound 505 was prepared according to procedure e.
Starting material, compound 605.
1H NMR(300MHz,DMSO-d6)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)。
Example 506
Ingenol 3- (1-methylindazole-3-carboxylate) (Compound 506)
Compound 506 was prepared according to procedure e.
Starting material, compound 606.
1H NMR(300MHz,DMSO-d6)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)。
Example 507
Ingenol 3- (3-ethyl-5-methyl-iso-euphorbia root) Azole-4-carboxylic acid ester) (Compound 507)
Compound 507 was prepared according to procedure e. Compound 507 was obtained as an amorphous compound.
Starting material compound 607.
1H NMR(300MHz,CDCl3)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)。
Example 508
Ingenol 3- (3-methyl-5-methyl-iso Azole-4-carboxylic acid ester) (Compound 508)
Compound 508 was prepared according to procedure e.
Starting material compound 608.
1H NMR(300MHz,CDCl3)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)。
Example 509
Ingenol 3- (1-methylindole-3-carboxylate) (Compound 509)
Compound 509 was prepared according to procedure e.
Starting material compound 609.
1H NMR(300MHz,CDCl3)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)。
Example 510
Ingenol 3- (3-phenylthiophene-2-carboxylate) (Compound 510)
Compound 510 was prepared according to procedure e.
Starting material compound 610.
1H NMR(300MHz,CDCl3)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)。
Example 511
Ingenol 3- (5-phenyliso) Azole-3-carboxylic acid ester) (Compound 511)
Compound 511 was prepared according to procedure e.
Starting material compound 611.
1H NMR(300MHz,CDCl3)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).
Example 512
Ingenol 3- (isoquinoline-1-carboxylate) (Compound 512)
Compound 512 was prepared according to procedure e. The title compound was purified by flash chromatography (dichloromethane/methanol 98:2 → dichloromethane/methanol 95: 5).
Starting material, compound 612.
1H NMR(300MHz,CDCl3)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)。
Example 513
Ingenol 3- (quinoline-4-carboxylate) (Compound 513)
Compound 513 was prepared according to procedure e. The title compound was purified by flash chromatography (dichloromethane/methanol 98:2 → dichloromethane/methanol 95: 5).
Compound 613 as starting material.
1H NMR(300MHz,CDCl3)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).
Example 514
Ingenol 3- (cinnoline-4-carboxylate) (Compound 514)
Compound 514 was prepared according to procedure e. The title compound was purified by flash chromatography (dichloromethane/methanol 98:2 → dichloromethane/methanol 95: 5).
Starting material compound 614.
1H NMR(300MHz,DMSO-d6)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)。
Example 515
Ingenol 3- (3-phenylimidazole-4-carboxylate) (Compound 515)
Compound 515 was prepared according to procedure e. The title compound was purified by flash chromatography (dichloromethane/methanol 98:2 → dichloromethane/methanol 95: 5).
Starting material compound 615.
1H NMR(300MHz,CDCl3)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)。
Example 516
Ingenol 3- (5-phenyl) Azole-4-carboxylic acid ester) (Compound 516)
Compound 516 was prepared according to procedure e.
Compound 616 as the starting material.
1H NMR(300MHz,DMSO-d6)8.56(s,1H),7.92-7.88(m,2H),7.53-7.48(m,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)。
Example 517
Ingenol 3- (1, 2-benzo) Oxazole-3-carboxylic acid ester) (Compound 517)
Compound 517 was prepared according to procedure e.
Starting material, compound 617.
1H NMR(300MHz,CDCl3)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)。
Example 518
Ingenol 3- (3-isopropyl-5-methyl-iso-propyl) Azole-4-carboxylic acid ester) (Compound 518)
Compound 518 was prepared according to procedure e.
Starting material compound 618.
1H NMR(300MHz,CDCl3)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)。
Example 519
Ingenol 3- (3- (2-methoxyphenyl) -5-methyl-iso Oxazole-4-carboxylic acid ester (compound 519)
Compound 519 was prepared according to procedure e.
Starting material compound 619.
1H NMR(300MHz,CDCl3)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)。
Example 520
Ingenol 3- (4-bromo-2-methyl-pyrazole-3-carboxylate) (compound 520)
Compound 520 was prepared according to procedure e.
Starting material, compound 620.
1H NMR(300MHz,CDCl3)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)。
Example 521
Ingenol 3- (4-bromo-2-ethyl-pyrazole-3-carboxylate) (compound 521)
Compound 521 was prepared according to procedure e.
Starting material compound 621.
1H NMR(300MHz,CDCl3)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)。
Example 522
Ingenol 3- (4-chloro-2-methyl-pyrazole-3-carboxylate) (compound 522)
Compound 522 was prepared according to procedure e.
Starting material, compound 622.
1H NMR(300MHz,CDCl3)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)。
Example 523
Ingenol 3- (5-bromopyrimidine-4-carboxylate) (Compound 523)
Compound 523 is prepared according to procedure e.
Starting material, compound 623.
1H NMR(300MHz,CDCl3)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)。
Example 524
Ingenol 3- (3-bromopyridine-2-carboxylate) (Compound 524)
Compound 524 was prepared according to procedure e.
Starting material compound 624.
1H NMR(300MHz,CDCl3)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)。
Example 525
Ingenol 3- (5-methylthiazole-4-carboxylate) (Compound 525)
Compound 525 was prepared according to procedure e.
Compound 625 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 526
Ingenol 3- (4-chloro-1-methyl-pyrazole-3-carboxylate) (compound 526)
Compound 526 was prepared according to procedure e.
Compound 626 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 527
Ingenol 3- (2, 4-dimethylthiazole-5-carboxylate) (Compound 527)
Compound 527 was prepared according to procedure e.
Starting material, compound 627.
1H NMR(300MHz,CDCl3)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)。
Example 528
Ingenol 3- (2, 5-dimethyl) Azole-4-carboxylic acid ester) (Compound 528)
Compound 528 is prepared according to procedure e.
Starting material, compound 628.
1H NMR(300MHz,CDCl3)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)。
Example 529
Ingenol 3- (2, 4-dimethylfuran-3-carboxylate) (Compound 529)
Compound 529 was prepared according to procedure e. Compound 529 was obtained as an amorphous compound.
Starting material compound 629.
1H NMR(300MHz,CDCl3)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)。
Example 530
Ingenol 3- (3, 5-diethyliso) Azole-4-carboxylic acid ester) (Compound 530)
Compound 530 was prepared according to procedure e.
Starting material compound 630.
1H NMR(300MHz,CDCl3)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); 0.5mol of ethyl acetate 4.12(q,0.5X2H),2.04(s,0.5X3H),1.26(t,0.5X3H) were observed.
Example 531
Ingenol 3- (1H-indole-7-carboxylate) (Compound 531)
Compound 531 was prepared according to procedure e.
Compound 631 as starting material.
1H NMR(300MHz,CDCl3)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)。
Example 532
Ingenol 3- (2-tert-butyl-5-methyl-pyrazole-3-carboxylate) (Compound 532)
Compound 532 was prepared according to procedure e.
Starting material compound 632.
1H NMR(300MHz,CDCl3)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)。
Example 533
Ingenol 3- (5-tert-butyl-2-methyl-pyrazole-3-carboxylate) (Compound 533)
Compound 533 was prepared according to procedure e.
Compound 633 as raw material.
1H NMR(300MHz,CDCl3)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)。
Example 534
Ingenol 3- (6-methylimidazo [2,1-b ]]Thiazole-5-carboxylic acid ester) (compound 534)
Compound 534 was prepared according to procedure e.
Starting material compound 634.
1H NMR(300MHz,CDCl3)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)。
Example 535
Ingenol 3- (2-methyl)Imidazo [1,2-a ]]Pyridine-3-carboxylic acid ester) (Compound 535)
Compound 535 was prepared according to procedure e.
Compound 635 as starting material.
1H NMR(300MHz,CDCl3)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)。
Example 536
Ingenol 3- (2,4, 5-trimethylfuran-3-carboxylate) (Compound 536)
Compound 536 was prepared according to procedure e.
Starting material compound 636.
1H NMR(300MHz,CDCl3)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)。
Example 537
Ingenol 3- (3-methylthiophene-2-carboxylate) (Compound 537)
Compound 537 was prepared according to procedure e.
The raw material is a compound 637.
1H NMR(300MHz,CDCl3)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)。
Example 538
Ingenol 3- (2-methyl-4- (1-piperidinyl) pyrazole-3-carboxylate) (compound 538)
Compound 538 was prepared according to procedure e.
Starting material, compound 638.
1H NMR(300MHz,CDCl3)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)。
Example 539
Ingenol 3- (2-chloro-5-isopropyl-thiazole-4-carboxylate) (compound 539)
Compound 539 was prepared according to procedure e.
Starting material compound 639.
1H NMR(300MHz,CDCl3)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)。
Example 540
Ingenol 3- (4-chloro-2, 5-dimethyl-pyrazole-3-carboxylate) (compound 540)
Compound 540 was prepared according to procedure e.
Raw material, compound 640.
1H NMR(300MHz,CDCl3)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)。
Example 541
Ingenol 3- (1,2, 4-trimethylpyrrole-3-carboxylate) (Compound 541)
Compound 541 is prepared according to procedure e.
Starting material compound 641.
1H NMR(300MHz,CDCl3)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)。
Example 542
Ingenol 3- (1,3, 5-trimethylpyrrole-2-carboxylate) (compound 542)
Compound 542 was prepared according to procedure e.
Compound 642 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 543
Ingenol 3- (1-ethyl-3, 5-dimethylpyrrole-2-carboxylate) (Compound 543)
Compound 543 is prepared according to procedure e.
Starting material compound 643.
1H NMR(300MHz,CDCl3)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)。
Example 544
Ingenol 3- (1-tert-butyloxycarbonyl-3, 3-dimethylpyrrolidine-2-carboxylate) (compound 544)
Compound 544 was prepared according to procedure e.
Starting material compound 644.
1H NMR(300MHz,CDCl3) Mixtures of compounds are shown.
Example 545
Ingenol 3- ((2S) -1-phenylpyrrolidine-2-carboxylate) (Compound 545)
Compound 545 was prepared according to method e with the modification that tetrahydrofuran was replaced with methanol and the reaction time at room temperature was 0.5 h.
Starting material, compound 645.
1H NMR(300MHz,CDCl3)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)。
Example 546
Ingenol 3- (1-isopropyl-3, 5-dimethyl-pyrazole-4-carboxylate) (compound 546)
Compound 546 was prepared according to procedure e.
Starting material, compound 646.
1H NMR(300MHz,CDCl3)6.07-6.04(m,2H),5.61(s,1H),4.63(d,1H),4.43 (heptad, 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).
Example 547
Ingenol 3- (5-ethyl-3-isopropyl-iso-propyl-iso-terpene) Azole-4-carboxylic acid ester) (Compound 547)
Compound 547 was prepared according to procedure e with the modification that tetrahydrofuran was replaced with methanol and the reaction time at room temperature was 0.5 h.
Starting material, compound 647.
1H NMR(300MHz,CDCl3)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)。
Example 548
Ingenol 3- (2-methylindazole-3-carboxylate) (compound 548)
Compound 548 was prepared according to method e with the modification that tetrahydrofuran was replaced with methanol and the reaction time at room temperature was 0.5 h.
Compound 648 as starting material.
1H NMR(300MHz,CDCl3)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)。
Example 549
Ingenol 3- (5-methyl-3-tert-butyl-iso-butyl) Azole-4-carboxylate) (Compound 549)
Compound 549 is prepared according to procedure e.
Compound 649 as starting material.
1H NMR(300MHz,CDCl3)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)。
Example 550
Ingenol 3- (2-methyl-3-oxo-4-oxaspiro [4.5]]Dec-1-ene-1-carboxylic acid ester (compound) 550)
Compound 550 was prepared according to procedure e with the modification that tetrahydrofuran was replaced with methanol and the reaction time at room temperature was 0.5 h.
Starting material, compound 650.
1H NMR(300MHz,CDCl3)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)。
Example 551
Ingenol 3- (1-tert-butyl-3, 5-dimethyl-pyrazole-4-carboxylate) (Compound 551)
Compound 551 was prepared according to procedure e.
Compound 651 as starting material.
1H NMR(300MHz,CDCl3)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)。
Example 552
Ingenol 3- (3, 5-dimethylisothiazole-4-carboxylate) (Compound 552)
Compound 552 was prepared according to procedure e.
Starting material compound 652.
Example 553
Ingenol 3- (5-iodo-3-methyl-isothiazole-4-carboxylate) (compound 553)
Compound 553 was prepared according to procedure e.
Compound 653 as starting material.
1H NMR(300MHz,CDCl3)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)。
Example 554
Ingenol 3- (4- (4-methoxyphenyl) -2-methyl-pyrazole-3-carboxylate) (compound 554)
Compound 554 was prepared according to procedure e.
Starting material, compound 654.
1H NMR(300MHz,CDCl3)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)。
Example 555
Ingenol 3- (4- (2-methylphenyl) -2-methyl-pyrazole-3-carboxylate) (compound 555)
Compound 555 was prepared according to procedure e.
Starting material compound 655.
1H NMR(300MHz,CDCl3)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)。
Example 556
Ingenol 3- (2-methyl-4- (4-methylsulfonylphenyl) pyrazole-3-carboxylate) (compound 556)
Compound 556 was prepared according to procedure e.
Starting material compound 656.
1H NMR(300MHz,CDCl3)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)。
Example 557
Ingenol 3- (2-methyl-4-phenyl-pyrazole-3-carboxylate) (Compound 557)
Compound 557 was prepared according to procedure e.
Compound 657 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 558
Ingenol 3- (3, 5-dimethyl-1-phenyl-pyrazole-4-carboxylate) (compound 558)
Compound 558 was prepared according to procedure e.
Starting material, compound 658.
1H NMR(300MHz,CDCl3)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)。
Example 559
Ingenol 3- (1, 5-dimethyl-3-phenyl-pyrazole-4-carboxylate) (compound 559)
Compound 559 is prepared according to procedure e.
Compound 659 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 560
Ingenol 3- (1-benzyl-3, 5-dimethyl-pyrazole-4-carboxylate) (Compound 560)
Compound 560 was prepared according to procedure e.
Starting material, compound 660.
1H NMR(300MHz,CDCl3)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)。
Example 561
Ingenol 3- (3, 5-dimethyl-1- (tetrahydropyran-4-ylmethyl) pyrazole-4-carboxylate) (compound 561)
Compound 561 was prepared according to procedure e.
Starting material, compound 661.
1H NMR(300MHz,CDCl3)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)。
Example 562
Ingenol 3- (4-methyl-2-oxo-3H-thiazole-5-carboxylate) (Compound 562)
Compound 562 was prepared according to procedure e.
Starting material compound 662.
1H NMR(300MHz,DMSO-d6)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)。
Example 563
Ingenol 3- (2-methyl-4, 5,6, 7-tetrahydroindazole-3-carboxylate) (Compound 563)
Compound 563 is prepared according to procedure e.
Compound 663 as raw material.
1H NMR(300MHz,CDCl3)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)。
Example 564
Ingenol 3- (1, 2-dimethylindole-3-carboxylate) (Compound 564)
Compound 564 was prepared according to procedure e.
Starting material compound 664.
1H NMR(300MHz,CDCl3)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)。
Example 565
Ingenol 3- (5-methoxy-1, 2-dimethyl-indole-3-carboxylate) (compound 565)
Compound 565 was prepared according to procedure e.
Raw material, compound 665.
1H NMR(300MHz,CDCl3)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)。
Example 566
Ingenol 3- (1,3, 5-trimethylpyrazole-4-carboxylate) (Compound 566)
Compound 566 was prepared according to procedure e.
Starting material compound 630.
1H NMR(300MHz,CDCl3)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)。
Example 567
Ingenol 3- (4-methyl-1, 2,5- Diazole-3-carboxylic acid ester) (compound 567)
Compound 567 was prepared according to procedure e.
Starting material, compound 667.
1H NMR(300MHz,CDCl3)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)。
Example 568
Ingenol 3- (2-methoxy-4-methyl-thiazole-5-carboxylate) (compound 568)
Compound 568 was prepared according to procedure e.
Raw material 668 compound.
1H NMR(300MHz,CDCl3)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)。
Example 569
Ingenol 3- (4, 5-dimethylisol) Azole-3-carboxylic acid ester) (Compound 569)
Compound 569 was prepared according to procedure e.
Compound 669 as raw material.
1H NMR(300MHz,CDCl3)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)。
Example 570
Ingenol 3- (4-bromo-1-methyl-pyrazole-3-carboxylate) (compound 570)
Compound 570 was prepared according to procedure e.
Raw material: compound 670.
1H NMR(300MHz,CDCl3)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)。
Example 571
Ingenol 3- (1, 3-dimethylindole-2-carboxylate) (Compound 571)
Compound 571 was prepared according to procedure e.
Starting material, compound 671.
1H NMR(300MHz,CDCl3)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)。
Example 572
Ingenol 3- (5-methoxy-1, 3-dimethyl-indole-2-carboxylate) (Compound 572)
Compound 572 is prepared according to procedure e.
Starting material compound 672.
1H NMR(300MHz,CDCl3)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)。
Example 573
Ingenol 3- (2, 4-dimethyl-6-oxo-pyran-3-carboxylate) (Compound 573)
Compound 573 was prepared according to procedure e.
Compound 673 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 574
Ingenol 3- (1-methyl-3-phenyl-indole-2-carboxylate) (Compound 574)
Compound 574 was prepared according to procedure e.
Starting material compound 674.
1H NMR(300MHz,CDCl3)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)。
Example 575
Ingenol 3- (3-methyl-5- (trifluoromethyl) iso Azole-4-carboxylic acid ester) (Compound 575)
Compound 575 is prepared according to procedure e.
Compound 675 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 576
Ingenol 3- (1, 3-dimethylpyrrole-2-carboxylate) (Compound 576)
Compound 576 was prepared according to procedure e with the modification that tetrahydrofuran was replaced with methanol and the reaction time at room temperature was 0.5 h.
Starting material, compound 676.
1H NMR(300MHz,CDCl3)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)。
Example 577
Ingenol 3- (3, 5-dimethyl-1- (2,2, 2-trifluoroethyl) pyrazole-4-carboxylate) (Compound 577)
Compound 577 was prepared according to procedure e.
Compound 677 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 578
Ingenol 3- (1-cyclopropyl-2, 5-dimethyl-pyrrole-3-carboxylate) (compound 578)
Compound 578 was prepared according to procedure e.
Starting material, compound 678.
1H NMR(300MHz,CDCl3)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)。
Example 579
Ingenol 3- (1,2, 5-trimethylpyrrole-3-carboxylate) (Compound 579)
Compound 579 was prepared according to procedure e.
Compound 679 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 580
Ingenol 3- (2, 4-dimethyl-1H-pyrrole-3-carboxylate) (Compound 580)
Compound 580 was prepared according to procedure e.
Compound 680 as starting material.
1H NMR(300MHz,CDCl3)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)。
Example 581
Ingenol 3- (1-methylpyrrole-2-carboxylate) (Compound 581)
Compound 581 was prepared according to procedure e.
Starting material compound 681.
1H NMR(300MHz,CDCl3)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)。
Example 582
Ingenol 3- (4-methyl-1H-pyrrole-2-carboxylate) (Compound 582)
Compound 582 was prepared according to procedure e.
Raw material, compound 682.
1H NMR(300MHz,CDCl3)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)。
Example 583
Ingenol 3- (1, 5-dimethylpyrrole-2-carboxylate) (Compound 583)
Compound 583 was prepared according to procedure e.
Compound 683 as raw material.
1H NMR(300MHz,CDCl3)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)。
Example 584
Ingenol 3- (3-methyl-1H-pyrrole-2-carboxylate) (Compound 584)
Compound 584 is prepared according to procedure e.
Starting material compound 684.
1H NMR(300MHz,CDCl3)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)。
Example 585
Ingenol 3- (1-cyclopropylpyrrole-2-carboxylate) (Compound 585)
Compound 585 was prepared according to procedure e.
The raw material is compound 685.
1H NMR(300MHz,CDCl3)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)。
Example 586
Ingenol 3- (1-ethyl-2, 4-dimethyl-pyrrole-3-carboxylate) (compound 586)
Compound 586 is prepared according to procedure e.
Compound 686.
1H NMR(300MHz,CDCl3)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)。
Example 587
Ingenol 3- (1-allyl-2, 4-dimethyl-pyrrole-3-carboxylate) (Compound 587)
Compound 587 was prepared according to procedure e.
Starting material, compound 687.
1H NMR(300MHz,CDCl3)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)。
Example 588
Ingenol 3- (1- (cyclopropylmethyl) -2, 4-dimethyl-pyrrole-3-carboxylate) (Compound 588)
Compound 588 was prepared according to procedure e.
Compound 688 as starting material.
1H NMR(300MHz,CDCl3)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)。
Example 589
Ingenol 3- (1- (2-methoxyethyl) -2, 4-dimethyl-pyrrole-3-carboxylate) (Compound 589)
Compound 589 was prepared according to procedure e.
Starting material, compound 689.
1H NMR(300MHz,CDCl3)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)。
Example 701:
ingenol 3- (N-ethyl-carbamate) (compound 701)
Compound 701 was prepared according to procedure e.
Starting material, compound 801.
1H NMR(300MHz,DMSO-d6)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) (coincident with water absorption), 3.05-3.00(m,2H),2.5(m,1H) (coincident 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).
Example 702:
ingenol 3- (N, N-dimethyl-carbamate) (Compound 702)
Compound 702 was prepared according to procedure e.
Starting material compound 802.
1H NMR(300MHz,DMSO-d6)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) (coinciding 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).
Example 703:
ingenol 3- (morpholine-4-carboxylate) (compound 703)
Compound 703 was prepared according to procedure e.
Compound 803 as starting material.
1H NMR(300MHz,DMSO-d6)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)。
Example 704:
ingenol 3- (pyrrolidine-1-carboxylate) (Compound 704)
Compound 704 was prepared according to procedure e.
Compound 804.
1H NMR(300MHz,DMSO-d6)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) (coinciding 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).
Example 705:
ingenol 3- (N-methyl-N-phenyl-carbamate) (compound 705)
Compound 705 was prepared according to procedure e. Compound 705 was obtained as an amorphous compound.
Starting material, compound 805.
1H NMR(300MHz,DMSO-d6)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)。
Example 706:
ingenol 3- (N, N-diethyl-carbamate) (Compound 706)
Compound 706 was prepared according to procedure e.
Starting material compound 806.
1H NMR(300MHz,DMSO-d6)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) (coinciding 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).
Example 707:
ingenol 3- (piperidine-1-carboxylate) (compound 707)
Compound 707 was prepared according to procedure e.
Starting material, compound 807.
1H NMR(300MHz,DMSO-d6)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)。
Example 708:
ingenol 3- (N-benzyl-N-methyl-carbamate) (compound 708)
Compound 708 was prepared according to procedure e.
Raw material, compound 808.
1H NMR(300MHz,DMSO-d6)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)。
Example 709:
ingenol 3- (N-cyclohexyl-N-methyl-carbamate) (compound 709)
Compound 709 was prepared according to procedure e.
Starting material compound 809.
1H NMR(300MHz,DMSO-d6)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) (coinciding 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).
Example 710:
ingenol 3- (N-cyclohexyl-carbamate) (compound 710)
Compound 710 was prepared according to procedure e.
Starting material, compound 810.
1H NMR(300MHz,DMSO-d6)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) (coinciding 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).
Example 711:
ingenol 3- (N-phenyl-carbamate) (Compound 711)
Compound 711 was prepared according to procedure e.
Compound 811 as starting material.
1H NMR(300MHz,DMSO-d6)9.44(s,1H),7.50(d,2H),7.29(t,2H),6.99(t,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)。
Example 712:
ingenol 3- (N- (indan-1-yl) -carbamate) (Compound 712)
Compound 712 was prepared according to procedure e.
Starting material, compound 812.
1H NMR(300MHz,DMSO-d6)7.43(d,1H),7.26-7.18(m,4H),5.86-5.84(m,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)。
Example 713:
ingenol 3- (3, 3-dimethyl-piperidine-1-carboxylate) (Compound 713)
Compound 713 was prepared according to procedure e.
Starting material, compound 813.
1H NMR(300MHz,CDCl3)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)。
Example 714:
ingenol 3- (N-methyl-N-tetrahydronaphthalen-1-yl-carbamate) (compound 714)
Compound 714 is prepared according to procedure e.
Starting material compound 814.
1H NMR(300MHz,CDCl3)7.19-7.10(m,4H),6.06-5.95(m,2H),5.50-5.20(m,2H),4.74-4.50(2bs,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)。
Example 715:
ingenol 3- (N- (2-cyano-1-methyl-ethyl) -N-methyl-carbamate) (compound 715)
Compound 715 was prepared according to procedure e.
Starting material compound 815.
1H NMR(300MHz,CDCl3)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)。
Example 716:
ingenol 3- (N-methyl-N- ((S) -1-phenylethyl) -carbamate) (compound 716)
Compound 716 was prepared according to procedure e.
Starting material compound 816.
1H NMR(300MHz,CDCl3)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(2bs,1H),4.13-4.08(m,3H),4.03(s,1H),3.76-3.69(2bs,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)。
Example 717:
ingenol 3- (N-methyl-N- (cyclopropylmethyl) -carbamate) (compound 717)
Compound 717 was prepared according to procedure e.
Raw material 817.
1H NMR(300MHz,CDCl3)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)。
Example 718:
ingenol 3- (N- (3-fluoro-phenyl) -N-methyl-carbamate) (compound 718)
Compound 718 was prepared according to procedure e. Compound 718 was obtained as an amorphous compound.
Starting material, compound 818.
1H NMR(300MHz,CDCl3)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)。
Example 719:
ingenol 3- (N- (2, 5-dimethylpyrazol-3-yl) -N-methyl-carbamate) (compound 719)
Compound 719 is prepared according to procedure e.
Raw material of compound 819.
1H NMR(300MHz,CDCl3)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)。
Example 720:
ingenol 3- (N- (3, 5-dimethylisoi) s Oxazol-4-yl) -N-methyl-carbamic acid ester) (compound 720)
Compound 720 was prepared according to procedure e.
Starting material, compound 820.
1H NMR(300MHz,CDCl3)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)。
Example 721:
ingenol 3- (N- (1, 5-dimethylpyrazol-3-yl) -N-methyl-carbamate) (compound 721)
Compound 721 was prepared according to procedure e.
Starting material, compound 821.
1H NMR(300MHz,CDCl3)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)。
Example 722:
ingenol 3- (N-cyclopentyl-N-methyl-carbamate) (compound 722)
Compound 722 was prepared according to procedure e.
Starting material compound 822.
1H NMR(300MHz,CDCl3)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)。
Example 723:
ingenol 3- (N-cyclopropyl-N-methyl-carbamate) (compound 723)
Compound 723 was prepared according to procedure e.
Raw material compound 823.
1H NMR(300MHz,CDCl3)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)。
Example 724:
ingenol 3- (N-methyl-N- (2-pyridyl) -carbamate) (compound 724)
Compound 724 was prepared according to procedure e.
Starting material, compound 824.
1H NMR(300MHz,CDCl3)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)。
Example 725:
ingenol 3- (4-oxo-2, 3-dihydroquinoline-1-carboxylate) (Compound 725)
Compound 725 was prepared according to procedure e.
Starting material compound 825.
1H NMR(300MHz,CDCl3)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)。
Example 726:
ingenol 3- (3, 4-dihydro-2H-quinoline-1-carboxylate) (Compound 726)
Compound 726 was prepared according to procedure e.
Raw material, compound 826.
1H NMR(300MHz,CDCl3)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)。
Example 727:
ingenol 3- (indoline-1-carboxylate) (compound 727)
Compound 727 was prepared according to procedure e.
Starting material compound 827.
1H NMR(300MHz,CDCl3)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)。
Example 728:
ingenol 3- (azepane-1-carboxylate) (Compound 728)
Compound 728 was prepared according to procedure e.
Raw material, compound 828.
1H NMR(300MHz,CDCl3)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)。
Example 729:
ingenol 3- (N- (4-chloro-phenyl) -N-methyl-carbamate) (compound 729)
Compound 729 was prepared according to procedure e.
Starting material compound 829.
1H NMR(300MHz,CDCl3)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).
Example 730:
ingenol 3- (N- (4-fluoro-phenyl) -N-methyl-carbamate) (compound 730)
Compound 730 was prepared according to procedure e.
Raw material, compound 830.
1H NMR(300MHz,CDCl3)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)。
Example 731:
ingenol 3- (N-methyl-N- (2-methoxy-phenyl) -carbamate) (compound 731)
Compound 731 was prepared according to procedure e.
Compound 831 as raw material.
1H NMR(300MHz,CDCl3)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)。
Example 732:
ingenol 3- (N-methyl-N- (2-methyl-phenyl) -carbamate) (compound 732)
Compound 732 is prepared according to procedure e.
Starting material, compound 832.
1H NMR(300MHz,CDCl3)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)。
Example 733:
ingenol 3- (3-oxo-2, 4-dihydroquinoxaline-1-carboxylate) (Compound 733)
Compound 733 was prepared according to procedure e.
Compound 833 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 734:
ingenol 3- (N-ethyl-N-phenyl-carbamate) (compound 734)
Compound 734 is prepared according to procedure e.
Compound 834 as the starting material.
1H NMR(300MHz,CDCl3)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)。
Example 735:
ingenol 3- (2-trifluoromethyl-pyrrolidine-1-carboxylate) (compound 735)
Compound 735 is prepared according to procedure e.
Compound 835 is used as raw material.
1H NMR(300MHz,CDCl3)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)。
Example 736:
ingenol 3- (3-azabicyclo [3.2.2] 2]Nonane-3-carboxylic acid ester) (Compound 736)
Compound 736 was prepared according to procedure e.
Starting material compound 836.
1H NMR(300MHz,CDCl3)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)。
Example 737:
ingenol 3- (2, 3-dihydro-1, 4-benzo Oxazine-4-carboxylic acid ester) (Compound 737)
Compound 737 was prepared according to procedure e.
Starting material, compound 837.
1H NMR(300MHz,CDCl3)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)。
Example 738:
ingenol 3- (N- (2-fluoro-phenyl) -N-methyl-carbamate) (compound 738)
Compound 738 is prepared according to procedure e.
Starting material, compound 838.
1H NMR(300MHz,CDCl3)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)。
Example 739:
ingenol 3- (3-methyl-2, 3-dihydro-1, 4-benzo Oxazine-4-carboxylic acid esters) (compound 739)
Compound 739 was prepared according to procedure e.
Starting material, compound 839.
1H NMR(300MHz,CDCl3)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)。
Example 740:
ingenol 3- (2-trifluoromethyl-pyrrolidine-1-carboxylate) (isomer a) (compound 740)
Compound 740 was prepared according to procedure e. Compound 740 is the first isomer collected from chromatographic purification.
Compound 835 is used as raw material.
1H NMR(300MHz,CDCl3)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)。
Example 741:
ingenol 3- (2-trifluoromethyl-pyrrolidine-1-carboxylate) (isomer B) (compound 741)
Compound 741 was prepared according to procedure e. Compound 741 is the second isomer collected from chromatographic purification.
Compound 835 is used as raw material.
1H NMR(300MHz,CDCl3)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)。
Example 742:
ingenol 3- (N-methyl-N- (N- (tert-butyloxycarbonyl) -4-piperidinyl) -carbamate) (esterification Compound 742)
Compound 742 was prepared according to procedure e.
Starting material compound 842.
1H NMR(300MHz,CDCl3)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)。
Example 743:
ingenol 3- (N-methyl-N- (3-methyl-benzene)Yl) -carbamate) (compound 743)
Compound 743 is prepared according to procedure e.
Starting material, compound 843.
1H NMR(300MHz,CDCl3)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)。
Example 744:
ingenol 3- (3, 4-dihydro-2H-quinoxaline-1-carboxylate) (Compound 744)
Compound 744 was prepared according to procedure e.
Starting material, compound 844.
1H NMR(300MHz,CDCl3)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)。
Example 745:
ingenol 3- (isoindoline-2-carboxylate) (Compound 745)
Compound 745 is prepared according to method e.
Starting material, compound 845.
1H NMR(300MHz,CDCl3)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)。
Example 746:
ingenol 3- (N-methyl-N- (tetrahydropyran-4-ylmethyl) -carbamate) (compound 746)
Compound 746 was prepared according to procedure e.
Raw material compound 846.
1H NMR(300MHz,CDCl3)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)。
Example 747:
ingenol 3- (N-methyl-N- (tetrahydropyran-4-yl) -carbamate) (compound 747)
Compound 747 is prepared according to procedure e.
Starting material, compound 847.
1H NMR(300MHz,CDCl3)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)。
Example 748:
ingenol 3- (N-methyl-N- (3-methoxy-phenyl) -carbamate) (compound 748)
Compound 748 was prepared according to procedure e.
Starting material, compound 848.
1H NMR(300MHz,CDCl3)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)。
Example 749:
ingenol 3- (N-cyclobutyl-N-methyl-carbamate) (compound 749)
Compound 749 is prepared according to procedure e.
Starting material, compound 849.
1H NMR(300MHz,CDCl3)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)。
Example 750:
ingenol 3- (N-allyl-N-methyl-carbamate) (compound 750)
Compound 750 was prepared according to procedure e.
Compound 850 as starting material.
1H NMR(300MHz,CDCl3)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)。
Example 751:
ingenol 3- (N-methyl-N-prop-2-ynyl-carbamate) (compound 751)
Compound 751 was prepared according to procedure e.
Starting material compound 851.
1H NMR(300MHz,CDCl3)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)。
Example 752:
ingenol 3- (N-methyl-N- (4-methylthiazol-2-yl) -carbamate) (compound 752)
Compound 752 was prepared according to procedure e.
Raw material, compound 852.
1H NMR(300MHz,CDCl3)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)。
Example 753:
ingenol 3- (N- (4-cyano-phenyl) -N-methyl-carbamate) (compound 753)
Compound 753 was prepared according to procedure e.
Compound 853 as the starting material.
1H NMR(300MHz,CDCl3)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:
PMN's (polymorphonuclear leukocytes) were isolated and purified from fresh buffy coat by serial sedimentation, density centrifugation and lysis of contaminating red blood cells, the buffy coat was incubated with 2% methylcellulose for 30-45 minutes to differentially sediment red blood cells, the leukocyte-enriched supernatant was transferred to a lymphocyte separation tube to remove monocytes by density centrifugation (400 × g,30 min.) the cell pellet was resuspended and any remaining red blood cells were lysed with 0.2% NaCl for 30 seconds, then the blood cells were restored to isotonicity by addition of 1.2% NaCl, the procedure was repeated until the pellet appeared substantially free of red blood2+,Mg2+) And in HBSS (Hanks Balanced salt solution) (w Ca) containing 0.1% BSA (bovine serum albumin) and 5mM glucose2+,Mg2+) Adjusting the concentration to 1.4 × 106Cell/ml. titration reference and test compound were premixed with HE (hydroethidine) (final assay concentration of 10. mu.M) and added to a solution containing 2.5 × 105Individual cells in 96-well plates. After 40 minutes of incubation at room temperature, the change in respiratory burst was estimated using an Envision plate reader by measuring the fluorescence at 579nm (excitation: 485 nm).
The effect of the test compound was normalized to a positive control (5 × 10)-7M PEP0005), a titration curve of the test compound is fitted to a four parameter sigmoidal curve. Rel EC50The concentration of test compound that produces an effect that is centered between the top and bottom of the fit is indicated. Abs EC50Is caused to correspond to a positive control (5 × 10)-7M PEP0005) concentration of test compound in response to 50% of maximal effect.
Example 2
HeKa cytokine release (IL-8):
on the day before the assay, primary human epidermal keratinocytes HeKa were seeded (10.000 cells/well) into 96-well plates. The test compound was diluted in DMSO (dimethyl sulfoxide) and further diluted in the test medium, and then pipetted into the wells of a 96-well plate containing HeKa cells. The plates were incubated at 37 ℃ in a 5% CO atmosphere2The humidified air was kept warm for 6 hours. The plates were centrifuged at 4 ℃ for a short time to pellet the cells, the supernatant removed and analyzed by Meso Scale Discovery (MSD) 4-point cytokine assay (Pro-assay II Ultra Sensitive kit, MSD, MD, USA). The MSD assay employs a sandwich immunoassay format in which capture antibodies are coated in a patterned array on the bottom of the wells of a 4-Spot-Multi-MSD plate. The standard samples were also incubated in a MULTI-SPOT plate, and cytokine (IL-8) was bound to their corresponding capture antibody SPOTs. Cytokine levels at SECTORTMQuantitation was performed on Imager using cytokine-specific detection antibodies labeled with MSD SULFO-TAGTM reagent.
The effect of the test compound was normalized to the positive control (1.5 × 10)-7M PEP0005), a titration curve of the test compound is fitted to a four parameter sigmoidal curve. Rel EC50The concentration of test compound that produces an effect that is centered between the top and bottom of the fit is indicated. Abs EC50Is caused to correspond to a positive control (1.5 × 10)-7M PEP0005) concentration of test compound in response to 50% of maximal effect.
Example 3
Necrosis test
HeLa cells (ATCC CCL-002) were grown in minimal basal medium (Invitrogen Cat. No. 42360) containing 10% fetal bovine serum, 100IU/ml penicillin and 100. mu.g/ml streptomycin. 4,000-6,000 cells were seeded100 μ l of medium in 96-well black ViewPlates plates (Perkin Elmer) on a clear bottom and incubated overnight. Compounds were dissolved in DMSO and pre-diluted in 96-well polypropylene plates (Greiner) at concentrations ranging from 15 μ M to 600 μ M. For the experiments, the cell plates were placed on a 37 ℃ heat block, the medium was removed and 40 μ l of fresh pre-heated medium was added to each well. Cells were incubated for 15 minutes and then compound was added. At the same time, 3. mu.l of the compound was diluted with 197. mu.l of growth medium on a Tecan free-EVO pipetting station at a pipetting speed of 250. mu.l/s to ensure efficient mixing of the high concentration compound solution with the aqueous phase. These pre-diluted plates were then equilibrated at 37 ℃ for 10 minutes on a heating block. 80 μ l of the prediluted compound was manually transferred to the corresponding wells containing HeLa cells to give a compound concentration of 10 μ M to 400 μ M. Control conditions were 1% DMSO in growth medium (100% survival) and 400. mu.M ingenol mebutate in growth medium (0% survival). The plates were incubated on a heating block at 37 ℃ for 30 minutes. At the end of the incubation, 10 μ l prestoblue reagent (Invitrogen) was added to each well, the plate was sealed with a black seal, and then incubated at 37 ℃ for 10 minutes with gentle shaking (150 rpm). Subsequently, the plates were left at room temperature for 20-30 minutes. The plates were then immediately read on an EnvisionFluorescence reader (Perkin Elmer), excited at 535nm and emitting at 630 nm. The effect of the test compound is normalized to a positive control (410)-4M PEP 0005/ingenol mebutate), a titration curve of the compound to be tested is fitted to a four-parameter sigmoidal curve. Abs EC50The concentration of test compound that produced a 50% effect is indicated.
The compounds of the invention were tested in the neutrophil oxidative burst assay as described in example 1, in the HeKa cytokine release assay as described in example 2 and in the necrosis assay as described in example 3.
Rel EC in neutrophil oxidative burst assays50A value of less than 10000nM Rel EC in the HeKa cytokine release assay50Values less than 10000 nM.
Rel EC in neutrophil oxidative burst50Range of
Indicates Rel EC50The value is more than or equal to 100nM
Indicates Rel EC50The value is more than or equal to 20nM and<100nM
indicates Rel EC50Value of<20nM
HeKa cytokine Release (IL-8) Rel EC50Range of
Indicates Rel EC50The value is more than or equal to 100nM
Indicates Rel EC50The value is more than or equal to 20nM and<100nM
indicates Rel EC50Value of<20nM
EC of HeLa necrosis50Range of
Indicate EC50The value is more than or equal to 350 mu M
Indicate EC50The value is not less than 150 mu M and<350μM
indicates EC50Value of<150μM
The results are shown in the following table.
Example 4
B16-F for evaluation of antitumor efficacy0 mouse melanoma model
B16-F0 mouse melanoma cells (B)Number CRL-6322TM) In RPMI-1640glutaMAX (Invitrogen, catalog # 61870-010) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin (Invitrogen, catalog # 15140-122) at 37 ℃ in a medium containing 5% CO2The culture was carried out in humidified air. On day 0 of the experiment, B16-F0 cells (70-90% fusion) were harvested by trypsinization with TrypLE (Invitrogen, Cat. No. 12605-010-. In 30 minutes, the catalyst will contain 0.5X106A50 μ l volume of live B16-F0 cells was injected intradermally into the shaved waist of 10 week old female C57BL/6JbomTac mice, once per mouse. On day 4 of the experiment, tumors were measured with electronic calipers (Mahr 16 ExH100207) and tumor volumes were estimated using the following formula: tumor volume 1/2 (longest diameter) 2 (orthogonal diameter). The size of the tumor is 9 to 60mm3Mice within the range were included in the study and divided into treatment groups according to tumor size. Tumors were treated locally with 20 μ l of a solution containing 0.1% of the test compound 1 time a day for 2 consecutive days. Vehicle was included as a negative control in each experiment. Tumors were measured daily and when the estimated volume of the tumor exceeded 250mm3Rats were euthanized at time. Rats with ulcerated tumors or impaired health were euthanized and included in the data analysis as well as the subjects examined, regardless of tumor size. The experiment was ended on day 90, and tumors were less than 250mm on this day3The mouse of (3) was also included in the data analysis as an examination subject. Kaplan Meier survival curves were plotted and tumors were assigned>250mm3Designated as death events, comparison of survival curves was performed by the Log-rank test. Specifically, tumor growth in each treatment group was compared to that of the vehicle group to evaluate the efficacy of each compound to cure or delay tumor growth. P-values below 0.05 are considered to be effective.
Some of the compounds of the invention were tested in the B16-F0 mouse melanoma model. Compounds with significantly better efficacy than vehicle are listed in the table below.

Claims (17)

1. Compounds of formula I and pharmaceutically acceptable salts thereof
Wherein:
r is-NR 11R 12;
wherein R11 and R12 independently represent hydrogen,
or
Wherein R11 and R12 independently represent (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl, (C)3-C8) Cycloalkyl, aryl, heteroaryl, heterocycloalkyl, (C)3-C8) Cycloalkyl- (C)1-C4) Alkyl, aryl- (C)1-C4) Alkyl, heteroaryl- (C)1-C4) Alkyl or heterocycloalkyl- (C)1-C4) Alkyl, wherein aryl represents phenyl, indanyl or tetrahydronaphthyl, and heteroaryl represents isoOxazolyl, pyrazolyl, pyridyl or thiazolyl and heterocycloalkyl represents piperidinyl or tetrahydropyranyl, wherein (C)1-C6) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) Alkynyl, (C)3-C8) Cycloalkyl, aryl, heteroaryl, heterocycloalkyl, (C)3-C8) Cycloalkyl- (C)1-C4) Alkyl, aryl- (C)1-C4) Alkyl, heteroaryl- (C)1-C4) Alkyl or heterocycloalkyl- (C)1-C4) Alkyl is optionally substituted with one or more substituents independently selected from R13;
r13 represents halogen, cyano, (C)1-C4) Alkyl, -COORf or-ORd, ═ O,
wherein Rd represents (C)1-C4) An alkyl group;
rf represents (C)1-C4) An alkyl group.
2. The compound of claim 1, wherein R11 and R12 independently represent hydrogen, (C)1-C6) Alkyl, aryl, (C)3-C8) Cycloalkyl, aryl- (C)1-C4) Alkyl, heteroaryl, (C)3-C8) Cycloalkyl- (C)1-C4) Alkyl, heteroaryl- (C)1-C4) Alkyl, heterocycloalkyl- (C)1-C4) Alkyl, (C)2-C6) Alkenyl or (C)2-C6) An alkynyl group,wherein aryl represents phenyl, indanyl or tetralin, and heteroaryl represents isoOxazolyl, pyrazolyl, pyridyl or thiazolyl and heterocycloalkyl represents piperidinyl or tetrahydropyranyl.
3. A compound as claimed in claim 1 or 2 wherein R11 and R12 independently represent hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, cyclohexyl, indanyl, tetrahydronaphthyl, phenylethyl, cyclopropylmethyl, pyrazolyl, iso-propylAzolylmethyl, cyclopentyl, cyclopropyl, pyridyl, piperidyl, tetrahydropyranylmethyl, tetrahydropyranyl, cyclobutyl, allyl, propynyl, or thiazolyl.
4. A compound as claimed in claim 1 or claim 2, wherein R13 represents methyl, cyano, F, ═ O, -OCH3or-COOC (CH)3)3。
5. A compound as claimed in claim 1 or 2, wherein R11 or R12 independently represent hydrogen.
6. The compound of claim 1, selected from the group consisting of:
ingenol 3- (N-ethyl-carbamate),
Ingenol 3- (N, N-dimethyl-carbamate),
Ingenol 3- (N-methyl-N-phenyl-carbamate),
Ingenol 3- (N, N-diethyl-carbamate),
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- (N-methyl-N-tetrahydronaphthalen-1-yl-carbamate),
Ingenol 3- (N- (2-cyano-1-methyl-ethyl) -N-methyl-carbamate),
Ingenol 3- (N-methyl-N- ((S) -1-phenylethyl) -carbamate),
Ingenol 3- (N-methyl-N- (cyclopropylmethyl) -carbamate),
Ingenol 3- (N- (3-fluoro-phenyl) -N-methyl-carbamate),
Ingenol 3- (N- (2, 5-dimethylpyrazol-3-yl) -N-methyl-carbamate),
Ingenol 3- (N- (3, 5-dimethylisoi) sOxazol-4-yl) -N-methyl-carbamates) and their use,
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- (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- (N-ethyl-N-phenyl-carbamate),
Ingenol 3- (N- (2-fluoro-phenyl) -N-methyl-carbamate),
Ingenol 3- (N-methyl-N- (N- (tert-butyloxycarbonyl) -4-piperidinyl) -carbamate), ingenol 3- (N-methyl-N- (3-methyl-phenyl) -carbamate),
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).
7. Use of a compound according to claim 1 or 6 for the preparation of a medicament.
8. Use of a compound according to claim 7 for the preparation of a medicament for the treatment, amelioration or prevention of a physiological condition or disease associated with a hyperplasia or a tumor.
9. The use of claim 8, wherein the condition or disease is selected from cutaneous warts, genital warts, actinic keratosis, Squamous Cell Carcinoma (SCC), Basal Cell Carcinoma (BCC), malignant freckles, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, or vulvar intraepithelial neoplasia.
10. Use of a compound according to claim 7 for the manufacture of a medicament for the treatment or amelioration of a cosmetic indication.
11. Use according to claim 10, wherein the cosmetic indication is selected from photodamaged skin or seborrheic keratosis.
12. Use of a compound according to claim 7 for the preparation of a pharmaceutical composition for the treatment or amelioration of diseases, disorders or conditions responsive to stimulation of the oxidative burst of neutrophils.
13. Use of a compound according to claim 7 for the preparation of a pharmaceutical composition for the treatment or amelioration of a disease, disorder or condition responsive to stimulation of keratinocyte IL-8 release.
14. Use of a compound according to claim 7 for the preparation of a pharmaceutical composition for the treatment or amelioration of a disease, disorder or condition responsive to the induction of necrosis.
15. A pharmaceutical composition comprising a compound of claim 1 or 6, or a pharmaceutically acceptable stereoisomer or salt thereof, and a pharmaceutically acceptable carrier or excipient.
16. The pharmaceutical composition of claim 15, wherein the composition is suitable for topical administration.
17. A pharmaceutical composition comprising a compound according to claim 1 or 6, or a pharmaceutically acceptable stereoisomer or salt thereof, in combination with one or more other pharmaceutically active agents.
HK15106654.7A 2010-12-22 2015-07-13 Ingenol-3-acylates iii and ingenol-3-carbamates HK1206004B (en)

Applications Claiming Priority (6)

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US61/426,378 2010-12-22
US201161448350P 2011-03-02 2011-03-02
US61/448,350 2011-03-02
US201161534055P 2011-09-13 2011-09-13
US61/534,055 2011-09-13

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