Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to synthetic analogues of the ecteinascidins, particularly of ecteinascidin 736 (ET-736), pharmaceutical compositions containing them, methods for their manufacture and their use as antitumoral agents.
• E-736 ecteinascidin 736
• the ecteinascidins are exceedingly potent antitumor agents isolated from the marine tunicate Ecteinascidia turbinata.
• Ecteinascidin 736 (ET-736) was first discovered by Rinehart and features a tetrahydro- ⁇ -carboline unit in place of the tetrahydroisoquinoline unit more usually found in the ecteinascidin compounds isolated from natural sources; See for example Sakai et al., Proc. Natl. Acad. Sci. USA 1992, vol. 89, 11456-11460.
• ET-736 U.S. Patent No. 5,149,804 describes Ecteinascidin 736 (ET-736), isolated from the Caribbean tunicate Ecteinascidia turbinata, and it structure. ET-736 protects mice in vivo at very low concentrations against P388 lymphoma, B16 melanoma, and Lewis lung carcinoma.
• WO03014127 describes several synthetic analogues of ET-736 and their cytotoxic activity against tumoral cells.
• WO03014127 describes compounds A to D together with their cytotoxic activity against a panel of cancer cell lines.
• PM01183 Another compound described in this patent application, PM01183, is currently in clinical trials for the treatment of cancer.
• PM01183 has the following chemical structure:
• PM01183 has demonstrated a highly potent in vitro activity against solid and non-solid tumour cell lines as well as a significant in vivo activity in several xenografted human tumor cell lines in mice, such as those for breast, kidney and ovarian cancer. PM01183 exerts its anticancer effects through the covalent modification of guanines in the DNA minor groove that eventually give rise to DNA double-strand break, S-phase arrest and apoptosis in cancer cells.
• X is -NH- or -0-
• 3 ⁇ 4 is -OH or -CN
• R 3 is hydrogen or a -OR b group
• R a is selected from hydrogen, substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• Prot 1 TM is a protecting group for amino, with the proviso that when R4 is hydrogen then X is -0-.
• X is -NH-
• R 3 is hydrogen or a -OR b group
• R a is selected from hydrogen, substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C Ci 2 alkyl, substituted or unsubstituted
• Prot* 111 is a protecting group for amino.
• X is -0-
• Ri is -OH or -CN
• R 3 is hydrogen or a -OR b group
• R is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C Ci 2 alkyl, substituted or unsubstituted
• ProtTM is a protecting group for amino.
• R 3 is hydrogen or a -OR b group
• R4 is selected from -CH 2 NH 2 and -CH-NHProlTM;
• R is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl and substituted or unsubstituted C 2 -Ci 2 alkynyl; and Prot ⁇ 1 is a protecting group for amino.
• X is -NH- or -0-
• R 3 is hydrogen
• R is selected from hydrogen, substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted
• Prot ⁇ 1 is a protecting group for amino
• X is - H- or -0-
• Ri is -OH or -CN
• R 3 is a -OR b group
• R is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C Ci 2 alkyl, substituted or unsubstituted
• ProtTM is a protecting group for amino
• R 3 is hydrogen or a -OR b group
• R is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alk nyl;
• R b is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• Prot ⁇ 1 is a protecting group for amino
• X is -NH- or -0-
• Ri is -OH or -CN
• R 2 is acetyl
• R 3 is hydrogen or a -OR b group
• R b is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• Prot " 1 is a protecting group for amino
• a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable carrier.
• a dosage form comprising a pharmaceutical composition according to the present invention.
• a compound, pharmaceutical composition or dosage form according to the present invention for use as a medicament.
• a compound, pharmaceutical composition or dosage form according to the present invention for use in the treatment of cancer.
• a compound, pharmaceutical composition or dosage form according to the present invention for the manufacture of a medicament for the treatment of cancer.
• a method for the prevention or treatment of cancer comprising administering an effective amount of a compound according to the present invention, administering an effective amount of a pharmaceutical composition according to the present invention, or administering an effective amount of a dosage form according to the present invention to a patient in need thereof, notably a human.
• a compound according to the present invention for the treatment of cancer, or in the preparation of a medicament preferably for the treatment of cancer.
• kits comprising a therapeutically effective amount of a compound according to the present invention and a pharmaceutically acceptable carrier.
• the kit is for use in the treatment of cancer.
• X is -NH- or -0-
• R 3 is hydrogen or a -OR b group
• R a is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted C Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted
• Prot 111 is a protecting group for amino
• the process may include the further step of replacing the cyano group in the compound of formula IV with a hydroxy group to give a compound of formula I, IA, IB, IC, ID, IE, IF, or IG where Ri is OH.
• FIG. 1 Tumor total diameter evaluation of HT1080 tumors in mice treated with placebo, compound C, 4-S, and 12-S.
• FIG. 1 Tumor volume evaluation of MDA-MB-231 tumors in mice treated with placebo, compound C, 4-S, and 12-S.
• Figure 3. Tumor volume evaluation of H460 tumors in mice treated with placebo, compound C, 4-S, and 12-S.
• FIG. 1 Tumor volume evaluation of H526 tumors in mice treated with placebo, compound C, 4-S, and 12-S.
• FIG. 1 Tumor volume evaluation of HGC-27 tumors in mice treated with placebo, compound C, 4-S, and 12-S.
• FIG. 10 Tumor volume evaluation of MDA-MB-231 tumors in mice treated with placebo, PM01183 and 4-R.
• FIG. 14 Tumor volume evaluation of A2780 tumors in mice treated with placebo, PM01183 and 4-R.
• FIG. 1 Tumor total diameter evaluation of HT1080 tumors in mice treated with placebo, compound D and 12-R.
• FIG. 19 Tumor volume evaluation of MDA-MB-231 tumors in mice treated with placebo, compound D and 12-R.
• Figure 20 Tumor volume evaluation of H460 tumors in mice treated with placebo, compound D and 12-R.
• FIG. 21 Tumor volume evaluation of H526 tumors in mice treated with placebo, compound D and 12-R.
• FIG. 22 Tumor volume evaluation of H82 tumors in mice treated with placebo, compound D and 12-R.
• FIG. 23 Tumor volume evaluation of A2780 tumors in mice treated with placebo, compound D and 12-R.
• FIG. 24 Tumor volume evaluation of HGC-27 tumors in mice treated with placebo, compound D and 12-R.
• FIG. 25 Tumor total diameter evaluation of HT1080 tumors in mice treated with placebo, PM01183 and 19-S.
• FIG. 26 Tumor volume evaluation of MDA-MB-231 tumors in mice treated with placebo, PM01183 and 19-S.
• FIG. 27 Tumor volume evaluation of H460 tumors in mice trated with placebo, PM01183 and 19-S.
• FIG. 28 Tumor volume evaluation of A2780 tumors in mice treated with placebo, PM01183 and 19-S.
• FIG. 29 Tumor volume evaluation of HGC27 tumors in mice treated with placebo, PM01183 and 19-S.
• Figure 30 Tumor total diameter evaluation of HT1080 tumors in mice treated with placebo, PM01183 and 19-R.
• FIG. 31 Tumor volume evaluation of MDA-MB-231 tumors in mice treated with placebo, PM01183 and 19-R.
• FIG. 32 Tumor volume evaluation of H460 tumors in mice treated with placebo, PM01183 and 19-R.
• FIG. 33 Tumor volume evaluation of A2780 tumors in mice treated with placebo, PM01183 and 19-R.
• FIG. 34 Tumor volume evaluation of HGC-27 tumors in mice treated with placebo, PM01183 and 19-R.
• FIG. 35 Tumor total diameter evaluation of HT1080 tumors in mice treated with placebo, compound C and 39-S.
• FIG 36 Tumor volume evaluation of MDA-MB-231 tumors in mice treated with placebo, compound C and 39-S.
• Figure 37 Tumor volume evaluation of H460 tumors in mice treated with placebo, compound C and 39-S.
• FIG. 38 Tumor volume evaluation of H526 tumors in mice treated with placebo, compound C and 39-S.
• FIG. 39 Tumor volume evaluation of H82 tumors in mice treated with placebo, compound C and 39-S.
• Figure 40 Tumor volume evaluation of A2780 tumors in mice treated with placebo, compound C and 39-S.
• FIG. 41 Tumor volume evaluation of HGC27 tumors in mice treated with placebo, compound C and 39-S.
• Figure 42 Tumor total diameter evaluation of HT1080 tumors in mice treated with placebo, compound D and 47-R.
• FIG 43 Tumor volume evaluation of MDA-MB-231 tumors in mice treated with placebo, compound D and 47-R.
• FIG. 44 Tumor volume evaluation of H460 tumors in mice treated with placebo, compound D and 47-R.
• FIG. 45 Tumor volume evaluation of H526 tumors in mice treated with placebo, compound D and 47-R.
• FIG. 46 Tumor volume evaluation of H82 tumors in mice treated with placebo, compound D and 47-R.
• FIG. 47 Tumor volume evaluation of A2780 tumors in mice treated with placebo, compound D and 47-R.
• FIG. 48 Tumor volume evaluation of HGC27 tumors in mice treated with placebo, compound D and 47-R.
• FIG. 49 Tumor total diameter evaluation of HT1080 tumors in mice treated with placebo, ET-736 and 32.
• FIG. 50 Tumor volume evaluation of MDA-MB-231 tumors in mice treated with placebo, ET-736 and 32.
• FIG. 51 Tumor volume evaluation of H460 tumors in mice treated with placebo, ET-736 and 32.
• FIG 52 Tumor volume evaluation of H526 tumors in mice treated with placebo, ET-736 and 32.
• FIG 53 Tumor volume evaluation of H82 tumors in mice treated with placebo, ET-736 and 32.
• Figure 54 Tumor volume evaluation of A2780 tumors in mice treated with placebo, ET-736 and 32.
• FIG. 55 Tumor volume evaluation of HGC27 tumors in mice treated with placebo, ET-736 and 32.
• Figure 56 Tumor total diameter evaluation of HT1080 tumors in mice treated with placebo, PM01183 and 35.
• FIG. 57 Tumor volume evaluation of MDA-MB-231 tumors in mice treated with placebo, PM01183 and 35.
• FIG. 58 Tumor volume evaluation of H460 tumors in mice treated with placebo, PM01183 and 35.
• FIG. 59 Tumor volume evaluation of A2780 tumors in mice treated with placebo, PM01183 and 35.
• FIG. 60 Tumor volume evaluation of HGC27 tumors in mice treated with placebo, PM01183 and 35.
• FIG. 61 Tumor volume evaluation of PC-3 tumors in mice treated with placebo, 12-S and 12- R.
• Figure 62 Tumor volume evaluation of PC-3 tumors in mice treated with placebo and 4-S.
• Figure 63 Tumor volume evaluation of DU-145 tumors in mice treated with placebo and 4-S.
• Figure 64 Tumor volume evaluation of 22Rvl tumors in mice treated with placebo and 4-S.
• Figure 65 Tumor volume evaluation of PC-3 tumors in mice treated with placebo and 39-S.
• Figure 66 Tumor volume evaluation of DU-145 tumors in mice treated with placebo and 39-S.
• Figure 67 Tumor volume evaluation of 22Rvl tumors in mice treated with placebo and 39-S.
• the alkyl groups may be branched or unbranched, and preferably have from 1 to about 12 carbon atoms.
• One more preferred class of alkyl groups has from 1 to about 6 carbon atoms.
• Even more preferred are alkyl groups having 1, 2, 3 or 4 carbon atoms.
• Methyl, ethyl, n-propyl, isopropyl and butyl, including ⁇ -butyl, isobutyl, sec-butyl and ieri-butyl are particularly preferred alkyl groups in the compounds of the present invention.
• the alkenyl groups may be branched or unbranched, have one or more double bonds and from 2 to about 12 carbon atoms.
• One more preferred class of alkenyl groups has from 2 to about 6 carbon atoms. Even more preferred are alkenyl groups having 2, 3 or 4 carbon atoms.
• Ethenyl, 1-propenyl, 2-propenyl, 1- methylethenyl, 1-butenyl, 2-butenyl, and 3-butenyl are particularly preferred alkenyl groups in the compounds of the present invention.
• the alkynyl groups may be branched or unbranched, have one or more triple bonds and from 2 to about 12 carbon atoms.
• One more preferred class of alkynyl groups has from 2 to about 6 carbon atoms. Even more preferred are alkynyl groups having 2, 3 or 4 carbon atoms.
• Suitable aryl groups in the compounds of the present invention include single and multiple ring compounds, including multiple ring compounds that contain separate and/or fused aryl groups.
• Typical aryl groups contain from 1 to 3 separated and/or fused rings and from 6 to about 18 carbon ring atoms.
• Preferably aryl groups contain from 6 to about 10 carbon ring atoms.
• Specially preferred aryl groups included substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted phenanthryl and substituted or unsubstituted anthryl.
• Suitable heterocyclic groups include heteroaromatic and heteroalicyclic groups containing from 1 to 3 separated and/or fused rings and from 5 to about 18 ring atoms.
• Preferably heteroaromatic and heteroalicyclic groups contain from 5 to about 10 ring atoms, most preferably 5, 6, or 7 ring atoms.
• Suitable heteroaromatic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., coumarinyl including 8-coumarinyl, quinolyl including 8-quinolyl, isoquinolyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimi
• Suitable heteroalicyclic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S and include, e.g., pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pirrolinyl, 3-pyrrolinyl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazol
• the halogen substituents include F, CI, Br, and I.
• pharmaceutically acceptable salt and “ester” refers to any pharmaceutically acceptable salt or ester which, upon administration to the patient is capable of providing (directly or indirectly) a compound as described herein.
• non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
• the preparation of salts can be carried out by methods known in the art.
• salts of the compounds provided herein are synthesized from the parent compounds, which contain a basic or acidic moiety, by conventional chemical methods.
• such salts are, for example, prepared by reacting the free acid or base of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.
• nonaqueous media like ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred.
• acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and -toluenesulfonate.
• mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate
• organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and -toluenesulfonate.
• alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, NN- dialkylenethanolamine, triethanolamine and basic aminoacids salts.
• the compounds of the invention may be in crystalline or amorphous form either as free compounds or as solvates (e.g. hydrates) and it is intended that all forms are within the scope of the present invention.
• Methods of solvation are generally known within the art. Stereoisomerism about the asymmetric carbons with unspecified stereochemistry is possible, therefore in such cases the asymmetric carbons can have (R) or (5) configuration. All diastereomers generated by a specific configuration of such asymmetric carbons in conjunction with the other asymmetric carbons present in the molecule, and mixtures thereof, are considered within the scope of the present invention.
• Stereoisomerism about the double bond is also possible, therefore in some cases the molecule could exist as (£)-isomer or (Z)-isomer. If the molecule contains several double bonds, each double bond will have its own stereoisomerism, that could be the same or different than the stereoisomerism of the other double bonds of the molecule. Furthermore, compounds referred to herein may exist as atropoisomers. The single stereoisomers including diastereoisomers, geometric isomers and atropoisomers of the compounds referred to herein, and mixtures thereof fall within the scope of the present invention.
• compounds referred to herein may exist in isotopically-labelled forms. All pharmaceutically acceptable salts, esters and isotopically labelled forms of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention.
• Suitable protecting groups are well known for the skilled person in the art.
• a general review of protecting groups in organic chemistry is provided by Wuts, PGM and Greene TW in Protecting Groups in Organic Synthesis, 4 th Ed. Wiley-Interscience, and by Kocienski PJ in Protecting Groups, 3 rd Ed. Georg Thieme Verlag.
• These references provide sections on protecting groups for OH, amino and SH groups. All these references are incorporated by reference in their entirety.
• an OH protecting group is defined to be the
• protected OH groups include ethers, silyl ethers, esters, sulfonates, sulfenates and sulfinates, carbonates, and carbamates.
• the protecting group for the OH can be selected from methyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, »-methoxybenzyloxymethyl, [(3,4- dimethoxybenzyl)oxy]methyl, »-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, [(R)-l-(2- nitrophenyl)ethoxy]methyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, [ ⁇ p- phenylphenyl)oxy]methyl, i-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2- methoxyethoxymethyl, 2-cyanoethoxymethyl, bis(2-chloroethoxy)methyl, 2,2,2- trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, menthoxymethyl, 0-bis(2-acetoxy- ethoxy)methyl, t
• the protecting group for the OH can be selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, 2- norbornyldimethylsilyl, i-butyldimethylsilyl, i-butyldiphenylsilyl, tribenz lsilyl, tri-/?-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-i-butylmethylsilyl, bis(i-butyl)-l-pyrenylmethoxysilyl, tris(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, t- butylmethoxyphenylsilyl,
• esters the protecting group for the OH together with the oxygen atom of the unprotected OH to which it is attached form an ester that can be selected from formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trichloroacetamidate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, -chlorophenoxyacetate, phenylacetate, diphenylacetate, 3-phenylpropionate, bisfluorous chain type propanoyl, 4-pentenoate, 4- oxopentanoate, 4,4-(ethylenedithio)pentanoate, 5[3-bis(4-methoxyphenyl)hydro- xymethylphenoxy]levulinate, pivaloate, 1-adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzo
• sulfonates, sulfenates and sulfinates the protecting group for the OH together with the oxygen atom of the unprotected OH to which it is attached form a sulfonate, sulfenate or sulfinates that can be selected from sulfate, allylsulfonate, methanesulfonate, benzylsulfonate, tosylate, 2-[(4-nitrophenyl)ethyl]sulfonate, 2-trifluoromethylbenzenesulfonate, 4- monomethoxytritylsulfenate, alkyl 2,4-dinitrophenylsulfenate, 2,2,5,5-teframethylpyrrolidin-3- one-l-sulfinate, and dimethylphosphinothioyl.
• the protecting group for the OH together with the oxygen atom of the unprotected OH to which it is attached form a carbonate that can be selected from methyl carbonate, methoxymethyl carbonate, 9- fluorenylmethyl carbonate, ethyl carbonate, bromoethyl carbonate, 2-(methylthiomethoxy)ethyl carbonate, 2,2,2-trichloroethyl carbonate, l,l-dimethyl-2,2,2-trichloroethyl carbonate, 2- (trimethylsilyl)ethyl carbonate, 2-[dimethyl(2-naphthylmethyl)silyl]ethyl carbonate, 2- (phenylsulfonyl)ethyl carbonate, 2-(triphenylphosphonio)ethyl carbonate, cis-[4- [[(methoxytri1yl)sulfenyl]oxy]tetrahydrofuran-3-yl]oxy carbon
• the protecting group for OH together with the oxygen atom of the unprotected OH to which it is attached forms a carbamate that can be selected from dimethyl thiocarbamate, N-phenyl carbamate, and N-methyl-N-(o-nitrophenyl) carbamate.
• an amino protecting group is defined to be the N-bonded moiety resulting from the protection of the amino group through the formation of a suitable protected amino group.
• protected amino groups include carbamates, ureas, amides, heterocyclic systems, N-alkyl amines, N-alkenyl amines, N-alkynyl amines, N-aryl amines, imines, enamines, N-metal derivatives, N-N derivatives, N-P derivatives, N-Si derivatives, and N-S derivatives.
• the protecting group for the amino group together with the amino group to which it is attached form a carbamate that can be selected from methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate, 2,6-di-i-butyl- 9-fluorenylmethyl carbamate, 2,7-bis(trimethylsilyl)fluorenylmethyl carbamate, 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 17- tetrabenzo[a,c,g,z]fluorenylmethyl carbamate, 2-chloro-3-indenylmethyl carbamate, benz[ ]inden-3-ylmethyl carbamate, l,l-dioxobenzo[ ?]-thiophene-2-ylmethyl carbamate, 2- methylsulfonyl-3 -phenyl- l
• the protecting groups for the amino group can be selected from phenothiazinyl-(10)-carbonyl, N'-jp-toluenesulfonylaminocarbonyl, N- phenylaminothiocarbonyl, 4-hydroxyphenylaminocarbonyl, 3-hydroxytryptaminocarbonyl, and N'-phenylaminothiocarbonyl.
• the protecting group for the amino together with the amino group to which it is attached form an amide that can be selected from formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, pent-4-enamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl amide, benzamide, ⁇ -phenylbenzamide, o-nitrophenylacetamide, 2,2- dimethyl-2-(o-nitrophenyl)acetamide, o-nitrophenoxyacetamide, 3 -(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, o- nitrobenzamide, 3 -(4-i-butyl-2,6-dinitrophenyl)-2,2-dimethylpropanamide, o
• the protecting group for the amino group together with the amino group to which it is attached form a heterocyclic system that can be selected from 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N- dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiglycoloyl, N- dithiasuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsiloxy)pyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct, N- 1 , 1 ,3,3-tetramethyl-l ,3-disilaisoindoline, N-diphenylsilyldiethylene, N-5-substituted- 1 ,3
• the protecting group for the amino group can be selected from N- methyl, N-i-butyl, N-allyl, N-prenyl, N-cinnamyl, N-phenylallyl, N-propargyl, N- methoxymethyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-cyanomethyl, N-2- azanorbornenes, N-benzyl, N-4-methoxybenzyl, N-2,4-dimethoxybenzyl, N-2-hydroxybenzyl, N-ferrocenylmethyl, N-2,4-dinitrophenyl, o-methoxyphenyl, -methoxyphenyl, N-9- phenylfluorenyl, N-fluorenyl, N-2-picolylamine N'-oxide, N
• the protecting group for the amino group can be selected from N-l,l-dimethylthiomethylene, N- benzylidene, N-/?-methoxybenzylidene, N-diphenylmethylene, N-[2-pyridyl)mesityl]methylene, N-(N ⁇ V-dimethylaminomethylene), N-(N,N-dibenzylaminomethylene), N-(N-i-butylaminome- thylene), NN-isopropylidene, Np-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N- (5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene, and N-i-butylidene.
• the protecting group for the amino group can be selected from N-(5,5- dimethyl-3-oxo-l -cyclohexenyl), N-2,7-dichloro-9-fluorenylmethylene, N-l -(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl, N-(l,3-dimemyl-2,4,6-(l /,3i/,5 /)-trioxopyrirnidine-5-ylidene)- methyl, N-4,4,4-trifluoro-3-oxo-l-butenyl, and N-(l-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl).
• the protecting group for the amino group can be selected from N-borane, N-diphenylborinic ester, N-diethylborinic ester, N-9-borabicyclononane, N- difluoroborinic ester, and 3,5-bis(trifluoromethyl)phenylboronic acid; and also including N- phenyl(pentacarbonylchromium)carbenyl, N-phenyl(pentacarbonyl-tungsten)carbenyl, N- methyl(pentacarbonylchromium)carbenyl, N-methyl(pentacarbonyltungsten)carbenyl, N-copper chelate, N-zinc chelate, and a 18-crown-6-derivative.
• ⁇ - ⁇ derivatives the protecting group for the amino group together with the amino group to which it is attached form a ⁇ - ⁇ derivative that can be selected from N-nitroamino, N-nitrosoamino, amine N-oxide, azide, triazene derivative, and N-trimethylsilylmethyl-N-benzylhydrazine.
• the protected group for the amino group together with the amino group to which it is attached form a ⁇ - ⁇ derivative that can be selected from diphenylphosphinamide, dimethylthiophosphinamide, diphenylthiophosphinamide, dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, and iminotriphenylphosphorane.
• the protecting group for the NH 2 can be selected from i-butyldiphenylsilyl and triphenylsilyl.
• the protected amino group can be selected from N- sulfenyl or N-sulfonyl derivatives.
• the N-sulfenyl derivatives can be selected from benzenesulfenamide, 2-nitrobenzenesulfenamide, 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfe- namide, l-(2,2,2-trifluoro-l,l-diphenyl)ethylsulfenamide, and N-3-nitro-2-pyridinesulfenamide.
• the N-sulfonyl derivatives can be selected from methanesulfonamide, trifluoromethanesulfonamide, i-butylsulfonamide, benzylsulfonamide, 2-(trimethylsilyl) ethanesulfonamide, 7-toluenesulfonamide, benzenesulfonamide, o-anisylsulfonamide, 2- nitrobenzenesulfonamide, 4-nitrobenzenesulfonamide, 2,4-dinitrobenzenesulfonamide, 2- naphthalenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide, 2-(4- methylphenyl)-6-methoxy-4-methylsulfonamide, 9-anthracenesulfonamide, pyridines- sulfonamide, benzothiazole-2-sulfonamide,
• S-bonded moiety resulting from the protection of the SH group through the formation of a suitable a protected SH group examples include thioethers, disulfides, silyl thioethers, thioesters, thiocarbonates, and thiocarbamates.
• the protecting group for the SH can be selected from S-alkyl, S-benzyl, S-p- methoxybenzyl, S-o-hydroxybenzyl, S- ⁇ -hydroxybenzyl, S-o-acetoxybenzyl, S-p- acetoxybenzyl, S- ⁇ ?-nitrobenzyl, S-o-nitrobenzyl, S-2,4,6-trimethylbenzyl, S-2,4,6,- trimethoxybenzyl, S-4-picolyl, S-2-picolyl-N-oxide, S-2-quinolinylmethyl, S-9-anthrylmethyl, S-9-fluorenylmethyl, S-xanthenyl, S-ferrocenylmethyl, S-diphenylmethyl, S-bis(4- methoxyphenyl)methyl, S-5-dibenzosuberyl, S-triphenylmethyl, 4-methoxytrityl, S-diphenyl-4- pyr
• the protected SH group can be selected from S-ethyl disulfide, S-i-butyl disulfide, S-2-nitrophenyl disulfide, S-2,4-dinitrophenyl disulfide, S-2- phenylazophenyl disulfide, S-2-carboxyphenyl disulfide, and S-3-nitro-2-pyridyl disulfide.
• the protecting group for the SH can be selected from the list of groups that was listed above for the protection of OH with silyl ethers.
• the protecting group for the SH can be selected from S-acetyl, S-benzoyl, 5-2- methoxyisobutyryl, S-trifluoroacetyl, S-N-[[p-biphenylyl)-isopropyloxy]carbonyl]-N-methyl-y- aminothiobutyrate, and S-N-( ⁇ butoxycarbonyl)-N-memyl-y-aminothiobutyrate.
• thiocarbonate protecting group for the SH can be selected from S-2,2,2-trichloroethoxycarbonyl, S-i-butoxycarbonyl, S-benzyloxycarbonyl, S- »-methoxybenzyloxycarbonyl, and S- fluorenylmethylcarbonyl.
• the protected SH group can be selected from S-(N-ethylcarbamate) and S-(N-methoxymethylcarbamate) .
• the compound may be a compound of formula I or a pharmaceutically acceptable salt or ester thereof:
• X is - ⁇ - or -0-
• R. ! is -OH or -CN;
• R 3 is hydrogen or a -OR b group
• R a is selected from hydrogen, substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• Prot ⁇ 1 is a protecting group for amino
• the compound of formula I may be a compound of formula IC, or a pharmaceutically acceptable salt or ester thereof:
• X is - H-
• R 3 is hydrogen or a -OR b group
• R a is selected from hydrogen, substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted
• Prot NH is a protecting group for amino.
• the compound of formula I may be a compound of formula ID, or a pharmaceutically acceptable salt or ester thereof:
• X is -0-
• R 3 is hydrogen or a -OR b group
• R a is selected from hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C Ci 2 alkyl, substituted or unsubstituted
• Prot* 111 is a protecting group for amino.
• the compound of formula I may be a compound of formula
• X is -NH- or -0-
• Ri is -OH or -CN
• R 3 is hydrogen or a -OR b group
• R4 is selected from -CH 2 NH 2 and -CH 2 NHProt NH ;
• R is selected from hydrogen, substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl and substituted or unsubstituted C 2 -Ci 2 alkynyl; and Prot 11 is a protecting group for amino.
• the compound of formula I may be a compound of formula
• X is -NH- or -0-
• Ri is -OH or -CN;
• R 3 is hydrogen
• R a is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted
• Prot ⁇ 1 is a protecting group for amino
• the compound of formula I may be a compound of formula IB or a pharmaceutically acceptable salt or ester thereof:
• X is -NH- or -0-
• R 3 is a -0R b group
• R a is selected from hydrogen, substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted
• Prot* 11 is a protecting group for amino
• the compound of formula I may be a compound of formula IF or a pharmaceutically acceptable salt or ester thereof:
• X is -NH- or -0-
• R 3 is hydrogen or a -OR b group
• R a is selected from hydrogen, substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• Prot 1 TM is a protecting group for amino
• the compound of formula I may be a compound of formula IG or a pharmaceutically acceptable salt or ester thereof:
• X is -NH- or -0-
• Ri is -OH or -CN
• R 2 is acetyl
• R 3 is hydrogen or a -OR b group
• R b is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• Prot ⁇ 1 is a protecting group for amino
• Preferred compounds of the compounds of formula I, IA, IB, IC, ID, IE, IF, or IG are those having general formula a or b, or a pharmaceutically acceptable salt or ester thereof:
• R4 may not be hydrogen.
• Preferred compounds of the compounds of formula I, IA, IB, ID, IF, or IG may be those having formula c or a pharmaceutically acceptable salt or ester thereof:
• R 3 is hydrogen or a -OR group
• R is selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alk nyl;
• R b is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl.
• Preferred compounds include compounds of general formula I, IA, IB, IE, IF, IG, la, IAa, IBa, IEa, IFa, IGa, lb, IAb, IBb, IEb, IFb, and IGb, wherein:
• X is -NH-
• R 2 ; R 3 ; R,; R a ; R b ; R c ; and Prot ⁇ 1 are as defined as above.
• Preferred compounds include compounds of general formula I, IA, IB, IE, IF, IG, la, IAa, IBa, IEa, IFa, IGa, lb, IAb, IBb, IEb, IFb, and IGb, wherein:
• X is -0-
• R 2 ; R 3 ; R,; R a ; R b ; R c ; and ProtTM 1 are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, IC, ID, IE, IG, la, IAa, IBa, ICa, IDa, IEa, IGa, lb, IAb, IBb, ICb, IDb, IEb, and IGb, wherein: and X; R 2 ; R 3 ; R4; R a ; R b ; R c ; and Prot 1 TM are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, IC, ID, IE, DJ, la, IAa, D3a, ICa, IDa, IEa, IFa, lb, IAb, IBb, ICb, D3b, IEb, and IFb, wherein:
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted w-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec- butyl and substituted or unsubstituted tert-butyl.
• R 2 is acetyl;
• Ri; R 3 ; R4; R b ; R c ; and Prot 1 are as defined as above.
• Further preferred compounds include compounds of general formula I, IB, IC, ID, IE, IF, IG, la, IBa, ICa, D3a, IEa, IFa, IGa, lb, D3b, ICb, IDb, IEb, IFb, and IGb, wherein: R 3 is hydrogen or a -OR b group for compounds of formula I, IC, ID, IE, IF, IG, la, ICa, IDa, IEa, IFa, IGa, lb, ICb, IDb, IEb, IFb, or IGb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted w-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec- butyl and substituted or unsubstituted teri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-bvAy ⁇ .
• Most preferred R c is methyl. More preferred R4 is selected from -CH 2 OH and -CH 2 H 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• Ri; R 2 ; R 3 ; R a ; and R b are as defined as above.
• X is -NH-; and R 2 ; R 3 ; R4; R a ; R b ; R c ; and ProrTM 1 are as defined as above.
• R is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ierf-butyl.
• R 2 is acetyl;
• R 3 ; 3 ⁇ 4; R b ; R c ; and ProtTM 1 are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, IC, IE,
• X is -NH-;
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, IE, IF, IG, la, ICa, IEa, IFa, IGa, lb, ICb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R 2 ; R4; R a ; R°; and ProtTM are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, IC, IE, IF, IG, la, IAa, IBa, ICa, IEa, IFa, IGa, lb, IAb, IBb, ICb, IEb, IFb, and IGb, wherein: X is -NH-;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, or substituted or unsubstituted ierf-butyl.
• Most preferred R c is methyl.
• More preferred R4 is selected from CH 2 OH and CH 2 H 2 . More preferably, R, may be -CH 2 NH 2 .
• R is -CH 2 OH; and 3 ⁇ 4; R 2 ; R 3 ; R a ; and R b are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, IC, IE, IF, IG, la, IAa, IBa, ICa, IEa, IFa, IGa, lb, IAb, IBb, ICb, IEb, IFb, and IGb, wherein: X is -NH-;
• Ri is -OH
• R" is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl.
• R 2 is acetyl;
• R 3 ; R4; R b ; R c ; and ProtTM are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, IC, IE,
• X is -NH-;
• Ri is -OH
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, IE, IF, IG, la, ICa, IEa, IFa, IGa, lb, ICb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted w-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted iert-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R 2 ; 3 ⁇ 4; R a ; R c ; and Prot ⁇ 1 are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, IC, IE, IF, IG, la, IAa, IBa, ICa, IEa, IFa, IGa, lb, IAb, IBb, ICb, IEb, IFb, and IGb, wherein: X is -NH-;
• Ri is -OH
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl.
• Most preferred R c is methyl. More preferred t is selected from CH 2 OH and CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• R 2 ; R 3 ; R a ; and R b are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, IC, IE,
• X is -NH-;
• R" is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted feri-butyl.
• R 2 is acetyl;
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, IE, IF, IG, la, ICa, IEa, IFa, IGa, lb, ICb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• X is -NH-;
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted feri-butyl.
• R 2 is acetyl;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted ierf-butyl.
• Most preferred R c is methyl. More preferred R4 is selected from CH 2 OH and CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred 4 is -CH 2 OH;
• Further preferred compounds include compounds of general formula I, IA, IB, IC, IE, IF, IG, la, IAa, IBa, ICa, IEa, IFa, IGa, lb, IAb, IBb, ICb, IEb, IFb, and IGb, wherein: X is -NH-;
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, IE, IF, IG, la, ICa, IEa, IFa, IGa, lb, ICb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted ieri-butyl.
• Most preferred R c is methyl. More preferred R4 is selected from CH 2 OH and CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• R 2 ; and R a are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, IC, IE,
• X is -NH-;
• R" is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl.
• R 2 is acetyl;
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, IE, IF, IG, la, ICa, IEa, IFa, IGa, lb, ICb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R4; R c ; and Prot 1 TM are as defined as above.
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ferf-butyl.
• R 2 is acetyl;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-bvAy ⁇ .
• Most preferred R c is methyl. More preferred R4 is selected from CH 2 OH and CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• X is -NH-;
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted feri-butyl.
• R 2 is acetyl;
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, IE, IF, IG, la, ICa, IEa, IFa, IGa, lb, ICb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted w-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted iert-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl.
• Most preferred R c is methyl. More preferred R4 is selected from CH 2 OH and CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• X is -NH-;
• Ri is -OH
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ierf-butyl.
• R 2 is acetyl;
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, IE, IF, IG, la, ICa, IEa, IFa, IGa, lb, ICb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-b tyl.
• Most preferred R c is methyl. More preferred R4 is selected from CH 2 OH and CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE,
• IF, IG, la IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R. ! is -OH
• R 2 ; R 3 ; R4; R a ; R b ; R c ; and Prot 1 * 1 are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted «-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ierf-butyl.
• R 2 is acetyl;
• R 3 ; 4; R b ; R°; and ProtTM 1 are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R 3 is hydrogen or a -OR b group for compounds of formula I, ID, IE, IF, IG, la, IDa, IEa, IFa, IGa, lb, IDb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl.
• More preferred R 3 is hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R 2 ; R4; R ; R c ; and Prot 1 " 1 are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl.
• Most preferred R c is methyl. More preferred R4 is selected from -CH 2 OH and CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• Rij R 2 ; R 3 ; R a ; and R b are as defined as above.
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted feri-butyl.
• R 2 is acetyl;
• R 3 ; 3 ⁇ 4; R b ; R c ; and Prot 1 TM are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, D3a, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• Ri is -OH
• R 3 is hydrogen or a -OR b group for compounds of formula I, ID, IE, IF, IG, la, IDa, IEa, IFa, IGa, lb, IDb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted CVC 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R 2 ; R4; R a ; R c ; and ProtTM are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl.
• Most preferred R c is methyl. More preferred R4 is selected from -CH 2 OH and CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• R 2 ; R 3 ; R a ; and R b are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted feri-butyl.
• R 2 is acetyl;
• R 3 is hydrogen or a -OR b group for compounds of formula I, ID, IE, IF, IG, la, IDa, IEa, IFa, IGa, lb, IDb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula ⁇ 3, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted H-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted iert-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• Rij t ; R c ; and Prot 1 TM are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl.
• R 2 is acetyl;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted ieri-butyl.
• Most preferred R c is methyl. More preferred R4 is selected from -CH 2 OH and -CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R 3 is hydrogen or a -OR b group for compounds of formula I, ID, IE, IF, IG, la, IDa, IEa, IFa, IGa, lb, IDb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted H-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted iert-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted ierf-buryl.
• Most preferred R c is methyl. More preferred R4 is selected from - CH 2 OH and -CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• R 2 ; and R a are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R" is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted feri-butyl.
• R 2 is acetyl;
• R 3 is hydrogen or a -OR b group for compounds of formula I, ID, IE, IF, IG, la, IDa, IEa, IFa, IGa, lb, IDb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted CVC 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R 4 ; R c ; and Prat 1 TM are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE,
• IF, IG, la IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R" is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted tert-butyl.
• R 2 is acetyl;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl.
• Most preferred R c is methyl. More preferred R4 is selected from - CH 2 OH and -CH 2 NH 2 . More preferably, R 4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• R 3 ; and R b are as defined as above.
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ferf-butyl.
• R 2 is acetyl;
• R 3 is hydrogen or a -OR b group for compounds of formula I, ID, IE, IF, IG, la, IDa, IEa, IFa, IGa, lb, IDb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula IB, IBa or IBb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl.
• Most preferred R c is methyl. More preferred R4 is selected from -CH 2 OH and -CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH;
• Further preferred compounds include compounds of general formula I, IA, IB, ID, IE, IF, IG, la, IAa, IBa, IDa, IEa, IFa, IGa, lb, IAb, IBb, IDb, IEb, IFb, and IGb, wherein: X is -0-;
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted feri-butyl.
• R 2 is acetyl;
• R 3 is hydrogen or a -OR b group for compounds of formula I, ID, IE, IF, IG, la, IDa, IEa, IFa, IGa, lb, IDb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa, or IAb; and R 3 is a -OR b group for compounds of formula ⁇ 3, IBa or Kb; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted H-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted rc-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted iert-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted ierf-butyl.
• Most preferred R c is methyl. More preferred t is selected from -CH 2 OH and -CH 2 NH 2 . More preferably, R4 may be -CH 2 NH 2 . Most preferred R4 is -CH 2 OH.
• Further preferred compounds include compounds of general formula Ic, IAc, IBc, IDc, and IGc wherein: and R 2 ; R 3 ; R a and R b are as defined as above.
• Further preferred compounds include compounds of general formula Ic, IAc, IBc, IDc, IFc, and IGc, wherein:
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted H-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec- butyl and substituted or unsubstituted iert-butyl.
• R 2 is acetyl;
• R 3 ; R b are as defined as above.
• Further preferred compounds include compounds of general formula Ic, IAc, IBc, IDc, IFc, and IGc, wherein: R 3 is hydrogen or a -OR b group for compounds of formula Ic, IDc, IFc, or IGc; R 3 is hydrogen for compounds of formula IAc; and R 3 is a -OR b group for compounds of formula IBc; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted w-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R 2 ; and R a are as defined as above.
• Further preferred compounds include compounds of general formula Ic, IAc, IBc, IDc, IFc, and IGc, wherein:
• Ri is -OH
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted w-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec- butyl and substituted or unsubstituted iert-butyl.
• R 2 is acetyl;
• R 3 ; and R b are as defined as above.
• Further preferred compounds include compounds of general formula Ic, IAc, IBc, IDc, IFc, and IGc, wherein: R 3 is hydrogen or a -OR b group for compounds of formula Ic, IDc, IFc, or IGc; R 3 is hydrogen for compounds of formula IAc; and R 3 is a -OR b group for compounds of formula IBc; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted teri-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• R is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec- butyl and substituted or unsubstituted tert-butyl.
• R 2 is acetyl;
• R 3 is hydrogen or a -OR b group for compounds of formula Ic, IDc, IFc, or IGc; R 3 is hydrogen for compounds of formula IAc; and R 3 is a -OR b group for compounds of formula IBc; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted tert-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group;
• Further preferred compounds include compounds of general formula Ic, IAc, IBc, IDc, IFc, and IGc, wherein:
• Ri is -OH
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec- butyl and substituted or unsubstituted tert-butyl.
• R 2 is acetyl;
• R 3 is hydrogen or a -OR b group for compounds of formula Ic, IDc, IFc, or IGc; R 3 is hydrogen for compounds of formula IAc; and R 3 is a -OR b group for compounds of formula IBc; where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted tert-butyl. More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group.
• R a is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted feri-butyl.
• R 2 is acetyl.
• R 3 is hydrogen or a -OR" group where R b is a substituted or unsubstituted Ci-C 6 alkyl.
• Particularly preferred R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n- butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl and substituted or unsubstituted ieri-butyl.
• More preferred R 3 are hydrogen and methoxy, being hydrogen the most preferred R 3 group.
• R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted teri-butyl.
• Most preferred R c is methyl.
• More preferred R4 is selected from H, CH 2 OH and CH 2 NH 2 .
• Most preferred R4 is -CH 2 OH.
• R° is a substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl.
• Most preferred R c is methyl. More preferred R4 is selected from CH 2 OH and CH 2 NH 2 . Most preferred R 4 is -CH 2 OH.
• particularly preferred X is - H-.
• particularly preferred X is -0-.
• Preferred compounds according to the present invention include:
• R4 is selected from -CH 2 NH 2 and -CH 2 NHProt NH ;
• Prot 1 TM is a protecting group for amino.
• R 3 is hydrogen or a group for compounds of formula Ic, IDc, IFc, IGc; R 3 is hydrogen for compounds of formula IAc; or R 3 is a -OR b group for compounds of formula IBc; R a is selected from hydrogen, and substituted or unsubstituted C C 6 alkyl; and R b is substituted or unsubstituted Ci-C 6 alkyl.
• Particularly preferred compounds according to the present invention include:
• X is - H-
• R c is selected from substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl.
• X is -0-
• R c is selected from substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl.
• X is - H-
• R4 is selected from -CH 2 NH 2 and -CH 2 NHProt NH ;
• Prot 1 TM is a protecting group for amino.
• X is -0-
• R4 is selected from -CH 2 NH 2 and -CH 2 NHProt NH ;
• Prot 1 TM is a protecting group for amino.
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, ID, IF, IG, la, ICa,
• R 3 is hydrogen for compounds of formula
• R 3 is a -OR b group for compounds of formula IB, IBa or IBb;
• R a is selected from hydrogen, and substituted or unsubstituted Ci-C 6 alkyl
• R b is substituted or unsubstituted Ci-C 6 alkyl
• R c is substituted or unsubstituted Ci-C 6 alkyl.
• R 3 is hydrogen or a -0R b group for compounds of formula I, IC, ID, IE, IF, IG, la, ICa, IDa, IEa, IFa, IGa, lb, ICb, IDb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa or IAb; or R 3 is a -OR b group for compounds of formula IB, IBa or IBb; R4 is selected from -CH 2 NH 2 and -CHzNHProlTM;
• R a is selected from hydrogen, and substituted or unsubstituted Ci-C 6 alkyl
• R b is substituted or unsubstituted Ci-C 6 alkyl
• Prot 1 TM is a protecting group for amino.
• R 3 is hydrogen or a -OR b group for compounds of formula Ic, IDc, IFc, IGc; R 3 is hydrogen for compounds of formula IAc; or R 3 is a -OR b group for compounds of formula IBc;
• R a is substituted or unsubstituted Ci-C 6 alkyl
• R b is substituted or unsubstituted Ci-C 6 alkyl.
• More preferred compounds according to the present invention include
• X is - H-
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, IF, IG, la, ICa, IFa, IGa, lb, ICb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa or IAb; or R 3 is a -OR b group for compounds of formula IB, IBa or IBb;
• R a is selected from hydrogen and substituted or unsubstituted Ci-C 6 alkyl; and R b is substituted or unsubstituted Ci-C 6 alkyl.
• X is -0-
• R 3 is hydrogen or a -OR b group for compounds of formula I, ID, IF, IG, la, IDa, IFa, IGa, lb, IDb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa or IAb; or R 3 is a -OR b group for compounds of formula IB, IBa or IBb;
• R a is selected from hydrogen and substituted or unsubstituted Ci-C 6 alkyl; and R b is substituted or unsubstituted Ci-C 6 alkyl.
• X is - H-
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, IE, IF, IG, la, ICa,
• R 3 is hydrogen for compounds of formula
• R 3 is a -OR b group for compounds of formula IB, IBa or IBb;
• R4 is selected from -CH 2 NH 2 and -CHzNHProlTM
• R a is selected from hydrogen and substituted or unsubstituted Ci-C 6 alkyl
• R b is substituted or unsubstituted Ci-C 6 alkyl
• Prot 1 TM is a protecting group for amino.
• R 3 is hydrogen or a group for compounds of formula I, ID, IE, IF, IG, la, IDa,
• R 3 is hydrogen for compounds of formula
• R 3 is a -OR b group for compounds of formula IB, IBa or IBb;
• R4 is selected from -CH 2 NH 2 and -CHzNHProlTM
• R a is selected from hydrogen and substituted or unsubstituted Ci-C 6 alkyl
• R b is substituted or unsubstituted Ci-C 6 alkyl
• Prot 1 ⁇ 11 is a protecting group for amino.
• R 3 is hydrogen or a group for compounds of formula I, IC, ID, IF, IG, la, ICa, IDa, IFa, IGa, lb, ICb, IDb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa or IAb; or R 3 is a -OR b group for compounds of formula IB, IBa or IBb; R4 is -CH 2 OH;
• R a is substituted or unsubstituted Ci-C 6 alkyl
• R b is substituted or unsubstituted Ci-C 6 alkyl.
• R4 is selected from -CH 2 NH 2 and -CHzNHProlTM
• R a is substituted or unsubstituted Ci-C 6 alkyl
• R b is substituted or unsubstituted Ci-C 6 alkyl
• Prot 1 ⁇ 11 is a protecting group for amino.
• X is - H-
• R 3 is hydrogen or a -OR b group for compounds of formula I, IC, IF, IG, la, ICa, IFa, IGa, lb, ICb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa or IAb; or R 3 is a -OR b group for compounds of formula IB, IBa or IBb;
• R a is selected from hydrogen and substituted or unsubstituted Ci-C 6 alkyl
• R b is substituted or unsubstituted CpQ alkyl
• R c is a substituted or unsubstituted C]-C 6 alkyl.
• R 3 is hydrogen or methoxy for compounds of formula Ic, IDc, IFc, or IGc; R 3 is hydrogen for compounds of formula IAc; or R 3 is methoxy for compounds of formula IBc; and
• R a is substituted or unsubstituted Ci-C 6 alkyl.
• Particularly more preferred compounds according to the present invention include:
• X is -NH-
• R 2 is acetyl for compounds of formula IG, IGa or IGb;
• R 3 is hydrogen or methoxy for compounds of formula I, IC, IF, IG, la, ICa, IFa, IGa, lb, ICb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa or IAb; and R 3 is methoxy for compounds of formula IB, IBa or IBb;
• R a is substituted or unsubstituted CpQ alkyl.
• X is -0-
• R 3 is hydrogen or methoxy for compounds of formula I, ID, IF, IG, la, IDa, IFa, IGa, lb, IDb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa or IAb; or R 3 is methoxy for compounds of formula IB, IBa or IBb;
• R a is substituted or unsubstituted Ci-C 6 alkyl.
• X is - H-;
• R 2 is acetyl for compounds of formula IG, IGa or IGb;
• R 3 is hydrogen or methoxy for compounds of formula I, IC, IE, IF, IG, la, ICa, IEa, IFa, IGa, lb, ICb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa or IAb; or R 3 is methoxy for compounds of formula IB, IBa or IBb;
• Rt is selected from -CH 2 NH 2 and
• R a is substituted or unsubstituted Ci-C 6 alkyl
• Prot 1 TM is a protecting group for amino.
• X is -0-
• R 3 is hydrogen or methoxy for compounds of formula I, ID, IE, IF, IG, la, IDa, IEa, IFa, IGa, lb, IDb, IEb, IFb, or IGb; R 3 is hydrogen for compounds of formula IA, IAa or IAb; or R 3 is methoxy for compounds of formula IB, IBa or IBb;
• R4 is selected from -CH 2 NH 2 and -CH 2 NHProt NH ;
• R a is substituted or unsubstituted Ci-C 6 alkyl
• Prot 1 TM is a protecting group for amino.
• R a is selected from methyl, ethyl, -propyl, isopropyl and butyl, including w-butyl, sec-butyl, isobutyl and ieri-butyl.
• R 3 is hydrogen or a methoxy for compounds of formula I, IC, ID, IE, IF, IG, la, ICa, IDa, IEa, IFa, IGa, lb, ICb, IDb, IEb, IFb, and IGb; R 3 is hydrogen for compounds of formula IA, IAa or IAb; or R 3 is methoxy for compounds of formula IB, IBa or IBb; R4 is selected from -CH 2 NH 2 and -CUsNHProt 1 ;
• R a is selected from methyl, ethyl, -propyl, isopropyl and butyl, including n-butyl, sec-butyl, isobutyl and teri-butyl;
• Prot 1 ⁇ 11 is a protecting group for amino.
• R 3 is hydrogen
• R a is selected from methyl, ethyl, -propyl, isopropyl and butyl, including w-butyl, sec-butyl, isobutyl and ieri-butyl.
• R 3 is methoxy
• R a is selected from methyl, ethyl, n-propyl, isopropyl and butyl, including «-butyl, sec-butyl, isobutyl and tert-b tyl.
• X is -NH-
• R 2 is acetyl
• R 3 is hydrogen
• R is -CH 2 OH.
• X is -0-
• R 2 is acetyl
• R 3 is hydrogen
• R is -CH 2 OH.
• IAa is -CH 2 OH.
• X is - H-
• R 2 is acetyl
• R 3 is hydrogen
• R is -CH 2 H 2 .
• X is -0-
• R 2 is acetyl
• R 3 is hydrogen
• R 2 is acetyl
• R 3 is hydrogen
• R4 is -CH 2 OH.
• R 2 is acetyl
• R 3 is hydrogen
• R 2 is acetyl
• R 3 is hydrogen
• R 3 is hydrogen
• R 2 is acetyl
• R 3 is methoxy
• the preferences described above for the different substituents are combined.
• the present invention is also directed to such combinations of preferred substitutions (where allowed by possible substituent groups) in compounds of formula I, IA, IB, IC, ID, IE, IF, IG, la, IAa, D3a, ICa, IDa, IEa, IFa, IGa, lb, IAb, D3b, ICb, IDb, IEb, D7b, IGb, Ic, IAc, IBc, IDc, IFc or IGc according to the present invention.
• compositions comprising a compound of formula I, IA, IB, IC, ID, IE, IF, IG, la, IAa, IBa, ICa, IDa, IEa, IFa, IGa, lb, IAb, IBb, ICb, IDb, IEb, IFb, IGb, Ic, IAc, IBc, IDc, IFc or IGc of the invention and uses thereof
• a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable carrier.
• the administration form include without limitation oral, topical, parenteral, sublingual, rectal, vaginal, ocular and intranasal.
• Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
• the compositions are administered parenterally.
• Pharmaceutical compositions of the invention can be formulated so as to allow a compound according to the present invention to be bioavailable upon administration of the composition to an animal, preferably human.
• compositions can take the form of one or more dosage units, where for example, a tablet can be a single dosage unit, and a container of a compound according to the present invention may contain the compound in liquid or in aerosol form and may hold a single or a plurality of dosage units.
• the pharmaceutically acceptable carrier or vehicle can be particulate, so that the compositions are, for example, in tablet or powder form.
• the carrier(s) can be liquid, with the compositions being, for example, an oral syrup or injectable liquid.
• the carrier(s) can be gaseous, or liquid so as to provide an aerosol composition useful in, for example inhalatory administration. Powders may also be used for inhalation dosage forms.
• carrier refers to a diluent, adjuvant or excipient, with which the compound according to the present invention is administered.
• Such pharmaceutical carriers can be liquids, such as water and oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
• the carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, disaccharides, and the like.
• auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
• the compounds and compositions according to the present invention, and pharmaceutically acceptable carriers are sterile. Water is a preferred carrier when the compounds according to the present invention are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
• Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like.
• excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like.
• the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
• composition When intended for oral administration, the composition is preferably in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
• the composition can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
• a solid composition typically contains one or more inert diluents.
• binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, corn starch and the like; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agent such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
• a liquid carrier such as polyethylene glycol
• the composition can be in the form of a liquid, e.g. an elixir, syrup, solution, emulsion or suspension.
• the liquid can be useful for oral administration or for delivery by injection.
• a composition can comprise one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
• a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent can also be included.
• the preferred route of administration is parenteral administration including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intracerebral, intraventricular, intrathecal, intravaginal or transdermal.
• the preferred mode of administration is left to the discretion of the practitioner, and will depend in part upon the site of the medical condition (such as the site of cancer).
• the compounds according to the present invention are administered intravenously. Infusion times of up to 24 hours are preferred to be used, more preferably 1 to 12 hours, with 1 to 6 hours being most preferred. Short infusion times which allow treatment to be carried out without an overnight stay in a hospital are especially desirable. However, infusion may be 12 to 24 hours or even longer if required. Infusion may be carried out at suitable intervals of, for example, 1 to 4 weeks.
• the liquid compositions of the invention can also include one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides, polyethylene glycols, glycerin, or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
• sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides, polyethylene glycols, glycerin, or other solvents
• antibacterial agents such as benzyl alcohol or methyl paraben
• agents for the adjustment of tonicity such as sodium chloride or dextrose.
• a parenteral composition can be enclosed in an ampoule,
• the amount of the compound according to the present invention that is effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgement of the practitioner and each patient's circumstances.
• compositions comprise an effective amount of a compound of the present invention such that a suitable dosage will be obtained.
• the correct dosage of the compounds will vary according to the particular formulation, the mode of application, and its particular site, host and the disease being treated, e.g. cancer and, if so, what type of tumor. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease should be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
• the amount is at least about 0.01% of a compound of the present invention, and may comprise at least 80%, by weight of the composition. When intended for oral administration, this amount can be varied to range from about 0.1% to about 80% by weight of the composition.
• Preferred oral compositions can comprise from about 4% to about 50% of the compound of the present invention by weight of the composition.
• compositions of the present invention are prepared so that a parenteral dosage unit contains from about 0.01% to about 10 % by weight of the compound of the present invention. More preferred parenteral dosage unit contains about 0.5 % to about 5 % by weight of the compound of the present invention.
• the composition is suitable for doses from about 0.1 mg/kg to about 250 mg/kg of the animal's body weight, preferably from about 0.1 mg/kg and about 20 mg/kg of the animal's body weight, and more preferably from about 1 mg/kg to about 10 mg/kg of the animal's body weight.
• the compound of the present invention can be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings.
• it can be desirable to administer one or more compounds of the present invention, or compositions locally to the area in need of treatment.
• administration can be by direct injection at the site (or former site) of a cancer, tumor or neoplastic or pre-neoplastic tissue.
• Pulmonary administration can also be employed, e.g. by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
• the compound of the present invention can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
• compositions can take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
• suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin.
• compositions can be prepared using methodology well known in the pharmaceutical art.
• a composition intended to be adniinistered by injection can be prepared by combining a compound of the present invention with water, or other physiologically suitable diluent, such as phosphate buffered saline, so as to form a solution.
• a surfactant can be added to facilitate the formation of a homogeneous solution or suspension.
• compositions according to the present invention include:
• compositions comprising a compound of the present invention and a disaccharide.
• Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof.
• Lyophilised pharmaceutical compositions comprising a compound of the present invention and a disaccharide.
• Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellobiose, isosaccharose, isotrehalose, turanose, melibiose, gentiobiose, and mixtures thereof.
• the ratio of the active substance to the disaccharide in embodiments of the present invention is determined according to the solubility of the disaccharide and, when the formulation is freeze dried, also according to the freeze-dryability of the disaccharide. It is envisaged that this active substance:disaccharide ratio (w/w) can be about 1:10 in some embodiments, about 1:20 in other embodiments, about 1:50 in still other embodiments. It is envisaged that other embodiments have such ratios in the range from about 1:5 to about 1:500, and still further embodiments have such ratios in the range from about 1 : 10 to about 1 :500.
• composition comprising a compound of the present invention may be lyophilized.
• composition comprising a compound of the present invention is usually presented in a vial which contains a specified amount of such compound.
• the present invention provides a method of treating a patient in need thereof, notably a human, affected by cancer which comprises administering to the affected individual a therapeutically effective amount of a compound or composition according to the present invention.
• the present invention provides a compound or composition for use as medicament.
• the present invention provides a compound or composition for use in the treatment of cancer, and more preferably a cancer selected from lung cancer, including non- small cell lung cancer and small cell lung cancer, colon cancer, breast cancer, pancreas cancer, sarcoma, ovarian cancer, prostate cancer and gastric cancer.
• the compounds and compositions according to the present invention are useful for inhibiting the multiplication, or proliferation, of a tumor cell or cancer cell, or for treating cancer in an animal.
• the compounds and compositions according to the present invention show excellent activity in the treatment of cancers such as lung cancer including non-small cell lung cancer and small cell lung cancer, colon cancer, breast cancer, pancreas cancer, sarcoma, ovarian cancer, prostate cancerand gastric cancer.
• cancers such as lung cancer including non-small cell lung cancer and small cell lung cancer, breast cancer, pancreas cancer and colorectal cancer.
• cancer it is meant to include tumors, neoplasias and any other malignant disease having as cause malignant tissue or cells.
• treating means reversing, attenuating, alleviating or inhibiting the progress of the disease or condition to which such term applies, or one or more symptoms of such disorder or condition.
• treatment refers to the act of treating as “treating” is defined immediately above.
• the compounds and compositions according to the present invention can be administered to an animal that has also undergone surgery as treatment for the cancer.
• the additional method of treatment is radiation therapy.
• the compound or composition according to the present invention is administered concurrently with radiation therapy.
• the radiation therapy is administered prior or subsequent to administration of the compound or composition of the present invention, preferably at least an hour, three hours, five hours, 12 hours, a day, a week, a month, more preferably several months (e.g. up to three months) prior or subsequent to administration of a compound or composition of the present invention.
• any radiation therapy protocol can be used depending upon the type of cancer to be treated.
• x-ray radiation can be administered; in particular, high-energy megavoltage (radiation of greater than 1 MeV energy) can be used for deep tumors, and electron beam and orthovoltage x-ray radiation can be used for skin cancers.
• Gamma-ray emitting radioisotopes such as radioactive isotopes of radium, cobalt and other elements, can also be administered.
• kits comprising a therapeutically effective amount of a compound according to the present invention and a pharmaceutically acceptable carrier.
• the kit according to this embodiment is for use in the treatment of cancer, and more preferably a cancer selected from lung cancer, including non-small cell lung cancer and small cell lung cancer, colon cancer, breast cancer, pancreas cancer, sarcoma, ovarian cancer, prostate cancer and gastric cancer.
• a process for obtaining a compound of formula 1, 1A, IB, IC, ID, IE, IF, IG, la, IAa, IBa, ICa, IDa, IEa, IFa, IGa, lb, IAb, IBb, ICb, IDb, IEb, IFb, or IGb , or a pharmaceutically acceptable salt or ester thereof, comprising the step of reacting a compound of formula II with a compound of
• X is - H- or -0-
• R 3 is hydrogen or a -OR b group
• R a is selected from hydrogen, substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R b is selected from substituted or unsubstituted Ci-Ci 2 alkyl, substituted or unsubstituted C 2 -Ci 2 alkenyl, and substituted or unsubstituted C 2 -Ci 2 alkynyl;
• R c is selected from substituted or unsubstituted C Ci 2 alkyl, substituted or unsubstituted
• Prot* 111 is a protecting group for amino
• the process further comprises the step of deprotecting such amino group to provide a compound of formula I, IA, IB, IC, ID, IE, IG, la, IAa, IBa, ICa, IDa, IEa, IGa, lb, IAb, IBb, ICb, IDb, IEb, or IGb wherein R, is -CH 2 NH 2 and Rj is cyano.
• the process further comprises the step of replacing the cyano group in the compound of formula IV or in the compound of formula I, IA, IB, IC, ID, IE, IG, la, IAa, IBa, ICa, IDa, IEa, IGa, lb, IAb, IBb, ICb, IDb, IEb, or IGb
• R is - CH 2 NH 2 and R] is cyano with a hydroxy group to give a compound of formula I, IA, IB, IC, ID, IE, IF, IG, la, IAa, D3a, ICa, IDa, IEa, D7a, IGa, lb, IAb, ffib, ICb, IDb, IEb, IFb or IGb
• 3 ⁇ 4 is OH:
• Preferred processes according to the present invention include:
• R 2 is a -C(— 0)R a group where R a is substituted or unsubstituted C1-C12 alkyl.
• R a is a substituted or unsubstituted Ci-C 6 alkyl. More preferred R a is a substituted or unsubstituted alkyl group selected from methyl, ethyl, n-propyl, isopropyl, and butyl, including «-butyl, sec-butyl, isobutyl and iert-butyl, being methyl the most preferred R a group.
• ⁇ A process wherein the compound of formula III is selected from a compound of formula Ilia, Illb and Hie:
• X is selected from - H- and -0-;
• R 3 is selected from hydrogen and OR b where R b is substituted or unsubstituted C
• R b is a substituted or unsubstituted Ci-C 6 alkyl. More preferred R b is a substituted or unsubstituted alkyl group selected from methyl, ethyl, w-propyl, isopropyl, and butyl, including n-butyl, sec-butyl, isobutyl and tert- butyl. More preferred R 3 is hydrogen or methoxy. Most preferred R 3 is hydrogen; R 4 is selected from -CH 2 OH and -CH 2 NHProt NH where Prot 1 TM is a protecting group for amino. It is particularly preferred that the compound of formula III is a compound of formula Ilia or Illb.
• Compound 1 was prepared as described in Example 20 of WO 01/87895.
• Reference compounds A, B, C, D, E, F, ET-736, and PM01183 were prepared as described in WO 03/014127 (Compounds 19, 18, 44, 43, 2, 1, 26, and 27 respectively).
• R f 0.7 (CH 2 C1 2 :CH 3 0H, 9:1).
• Rf 0.5 (CH 2 C1 2 :CH 3 0H, 9:1).
• Rf 0.2 (CH 2 C1 2 :CH 3 0H, 9:1).
• Rf 0.5 (CH 2 C1 2 :CH 3 0H, 1:1).
• Rf 0.20 (CH 2 C1 2 :CH 3 0H, 10:1).
• Rf 0.2 (CH 2 Cl 2 :CH 3 OH, 4:1).

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• 2019
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  • 2019-08-09 HR HRP20191442 patent/HRP20191442T1/hr unknown
  • 2019-08-13 CY CY20191100872T patent/CY1121884T1/el unknown
  • 2019-08-13 CY CY20191100873T patent/CY1121885T1/el unknown
  • 2019-10-24 CL CL2019003057A patent/CL2019003057A1/es unknown
  • 2019-10-25 CO CONC2019/0011967A patent/CO2019011967A2/es unknown
  • 2019-10-25 PH PH12019550224A patent/PH12019550224A1/en unknown
  • 2019-10-25 MX MX2021016058A patent/MX2021016058A/es unknown
  • 2019-10-27 SA SA523440283A patent/SA523440283B1/ar unknown
  • 2019-10-28 ZA ZA2019/07119A patent/ZA201907119B/en unknown
  • 2019-11-26 EC ECSENADI201983967A patent/ECSP19083967A/es unknown
• 2021
  • 2021-04-02 US US17/221,445 patent/US11339180B2/en active Active
• 2022
  • 2022-01-14 AU AU2022200249A patent/AU2022200249C1/en active Active
  • 2022-01-14 AU AU2022200250A patent/AU2022200250C1/en active Active
  • 2022-03-09 AU AU2022201657A patent/AU2022201657A1/en not_active Abandoned
  • 2022-04-05 US US17/714,114 patent/US11713325B2/en active Active
  • 2022-07-04 JP JP2022107785A patent/JP7422812B2/ja active Active
• 2023
  • 2023-01-24 JP JP2023008821A patent/JP7490835B2/ja active Active
  • 2023-06-15 CY CY20231100283T patent/CY1126061T1/el unknown
  • 2023-06-22 US US18/213,082 patent/US12384800B2/en active Active

Patent Citations (4)

Non-Patent Citations (7)