FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION (See section 10 and rule 13)
NOVEL HYDRAZIDE CONTAINING TAXANE CONJUGATES
SUN PHARMA ADVANCED RESEARCH COMPANY LTD.
A company incorporated under the laws of India having their office at 17/B, MAHAL INDUSTRIAL ESTATE, MAHAKALI CAVES ROAD, ANDHERI (E), MUMBAI-400093, MAHARASHTRA. INDIA.
The following specification describes the nature of this invention

NOVEL HYDRAZIDE CONTAINING TAXANE CONJUGATES
The present invention relates to novel hydrazide containing carboxylate derivatives of taxanes and salts thereof for use as chemotherapeutic agents for prevention and treatment of cancer.
BACKGROUND OF THE INVENTION
The term "Taxane" is generally referred to the diterpenes produced from plants of the genus Tuxus. The term denotes a compound containing the core structure as in the formula below:

The basic taxane core structure may further be substituted or may contain unsaturatiuons in the ring to yield a number of compounds, generically known as taxanes. The taxane group of drugs include paclitaxel and docetaxel. Paclitaxel (Taxol®. Bristol Meyers Squibb) is a naturally occurring complex diterpenoid. which was originally isolated from the needles and bark of the Pacific yew tree (Tax us Brevifolia) which is a rare slow-growing tree with limited geographic distribution. The drug was discovered as part of a National Cancer Institute program in which extracts of thousands of plants and natural products were screened foranti-neoplastic activity. Later research led to semi-synthetic preparation of the drug from precursor chemicals called baccatins. which were derived from the needles and twigs of the Kuropean or Himalayan yew tree (Taxus hacaila). The drug was approved in United States in December 1992. for treatment of patients with metastatic carcinoma of the ovary after failure of first-line or subsequent chemotherapy. It is currently marketed for the treatment of patients with cancer of lung, breast cancer and advanced forms of Kaposi's sarcoma.


Docetaxel (Taxotere®. Sanofi Aventis). which is reportedly the more potent congener of paclitaxel, is the first "taxoid." i.e.. taxol-like compound. The main use of docetaxel is in the treatment of a variety of cancers after the failure of initial chemotherapy. It is marketed towards the treatment of breast cancer, prostate cancer, non-small cell cancer, gastric adenocarcinoma, and squamous cell carcinoma of head and neck. Clinical data has shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal and gastric cancer and melanoma cells (Lyseng-Williamson K.A., Drugs 2005;65(17):2513-31). Docetaxel has been shown to improve survival as an adjuvant therapy with doxorubicin and cyclophosphamide for the treatment of node-positive breast cancer, and so docetaxel has the benefit of aiding other treatments. Formula A below represents structure of Paclitaxel and Docetaxel with the conventional numbering system for this class of drugs, which is also followed throughout this application.
R'

Paclitaxel (R=Ph; R> acetyl)
Docetaxel (R= /e/7-butyloxy; R'= hydrogen)
Formula A
The first-generation taxanes, paclitaxel and docetaxel, are currently considered to be two of the most exciting drugs in cancer chemotherapy. Both of these exhibit significant and broad spectrum anticancer activity against various cancers which have not been effectively treated by other chemotherapeutic drugs. The anticancer activity of these drugs is through a unique mechanism of action which involves binding reversibiy to microtubules with high affinity, causing stabilization of the microtubules and preventing

their depolymerization from calcium ions, decreased temperature and dilution, preferentially at the plus end of the microtubule, thereby inhibiting cell proliferations. Thus unlike other microtunbule poisons such as vinca alkaloids, cochicine and cryptophyscines which inhibit tubulin polymerization, taxanes stabilize microtubules.
Although both paclitaxel and docetaxel have demonstrated to be unique antitumor agents, there are several limitations to their effectiveness, including poor selectivity for killing of cancer cells vs. normal cells, development of multidrug resistance (MDR), and poor solubility in aqueous media which are generally employed for administered drugs. The low aquesous solubility necessitates the preparation of these drugs in non-aqueous medium, for example, a mixture of Cremophor EL" (a polyethoxylated castor oil) and ethanol as co-solvent is used in the dosage forms to solubilize paclitaxel. Unfortunately, the high amount of Cremophor EL" required to deliver the indicated dose of paclitaxel, excacerbates the side effects of taxol in patients. Weiss et al ( J. Clin. Oncol.. 1990, 8, 1263-1268) and several others have reported various hypersensitive reactions, which include severe skin rashes, hives, flushing, dyspnea, tachycardia, and others in patients treated with such formulation. These effects are attributed partly due to Cremophor EL", which is responsible for histamine release (Rowinsky. E. K. et al. J. Natl Cancer Inst. 1990; 82, 1247-59). Like paclitaxel, docetaxel (<0.05mg/mL) is also poorly soluble in water. The currently used, and the most preferred solvent used to dissolve docetaxel is polysorbate 80 (Tween" 80). Like Cremophor EL®, the polysorbate also, often causes hypersensitivity reactions in patients. Further, the polysorbate cannot be used with PVC delivery apparatus because of its tendency to leach toxic diethylhexvl phthalate. Thus special provisions are required for the preparation and administration of paclitaxel solutions to ensure safe drug delivery to patients, which inevitably leads to higher costs for the preparation..
Several groups have investigated the synthesis of prodrug form of taxanes. with a view of improving the aqueous solubility of taxanes and to develop safer clinical formulations. The studies have been directed to synthesizing taxane analogs wherein 2"- and/or 7 or 10-


position is derivatized with suitable groups. These efforts yielded taxane conjugates or protaxanes that were reported to have higher water solubilty than the parent taxane. Some of the prior art compounds can be exemplified by the following references,
U.S. Patent No. 4,942,184 (Haugwitz R.D. el al.) discloses water soluble taxols having various substituted acyl groups at 2'-(J-position;
U.S. Patent No. 4.960.790 (Stella V..I. el al.) discloses water soluble taxols. the 2' and/or 7-hydroxy of which is derivatized with a selected amino acid or an amino acid mimetic compound;
U.S. Patent No. 5,352,805 (1994) and 5,411.984 (1995) (Kingston David el al.) discloses sulfonated 2'-acryloyl, sulfonated 2'-(7-acyl acid taxol and substituted 2'-benzoyl and 2',7-dibenzoyl taxol which have improved water solubility;
U.S. Patent No. 5.817.840 (1998) (Nicolaou K C el al.) discloses alkaline sensitive water soluble protaxols. protaxol composition include 2"-and/or 7-(7-ester and 2'-and/or l-O-carbonate derivatives of taxol, which have enhanced water solubility besides increased in vitro cytotoxic activity compared to paclitaxel;
U.S. Patent No. 5.977.163 (1999) (Chun Li el al.) discloses water soluble taxane derivatives formed by conjugation with polymers such as polyethylene glycol, poly(L-glutamic acid). poly(L-aspartic acid);
PCT application published as W09414787 (Poss M. A. et al ) discloses water soluble prodrug form of taxanes possessing a phosphonoxy group at the C-7. C-10 and/or at the 2'- position of the side chain of a taxane.
Numerous other studies have also been reported in the literature with regard to conjugates of taxanes for improvement of aqueous solubility. These include:


Salts of 2'-succinylpaclitaxel and 2"-glutarylpaclitaxel, Deutsch et al. (./. Med. Chem. 1989.32.788-792);
Sulfonate derivatives -Zhao. Z. et al. (./. Nat. Prod. 1991, 54, 1607-1611);
2' and 7- Amino acid derivatives of paclitaxel and their salts - Mathew et al. (,/. Med. Chem. 1992,35. 145-151);
7-Phosphate paclitaxel analogues- Vyas et al. (Bioorg. Med. Chem. Lett. 1993. 3. 1357-1360);
T- and 7- Phosphonoxyphenyl-propionate paclitaxel-Ueda. Y. et al. (Bioorg. Med. Chem. Lett. 1993.3. 1761-1366);
2' and 7-Polyethylene glycol esters of paclitaxel-Greenwald et al. (./. org. Chem. 1995, 60, 331 -336 and ./. Med. Chem. 1996. 39. 424-431);
2'- and 7-Methylpyridinium acetate analogues of paclitaxel-Nicholaou K. C. et al. (Angew Chemie 1994. 106, 1672-1675) and Paloma I. G. et al. (Chem. Biol. 1994, 1, 107-112);
Prodrug of paclitaxel with malic acid at the 2'postion- Damen, E. W. P. et al (Bioorg. Med. Chem. Lett. 2000, 8, 427-432).
DESCRIPTION OF THE INVENTION
The present invention provides novel hydrazide group containing carboxylate derivatives of taxanes, compounds of formula I. and salts thereof that have enhanced aqueous solubility.
The novel taxane conjugates of the present invention can, in general, be described as 2'-. 7- and/or 10- position ester of taxane. represented by the general formula I or salts thereof

Formula-I
wherein
R1 represents hydrogen or R4;
R2 represents hydrogen, acetyl or R4;
R3 represents alkyl. O-alkyl. -NH- alkyl. aryl or heterocyclyl;
R4 represents moiety selected from a group consisting of (A):

O O Rs
X N ^R6
H
(A)
wherein
X represents a single bond, alkylene, alkenylene, alkynylene. arylene or a
heterocyclylene moiety;
R5 and R6, are same or different and are independently selected from hydrogen, alkyl, aryl
or heterocyclyl;
or R5 and R6 may form together with the nitrogen atom to which they are attached a
heterocyclyl ring system;


In one of the embodiments, the present invention relates to compounds of formula I wherein R1 is hydrogen
In another embodiment, the present invention relates to compounds of formula I wherein R1 is hydrogen. R2 is selected from hydrogen or acetyl and R3 is selected from phenyl or tert-butyloxy.
In yet another embodiment of the present invention, the compounds of formula I are selected from the compounds wherein R4 represents moiety (A).
The novel taxane conjugates of the present invention are more water soluble than taxanes of formula A and are relatively easier to formulate and administer using aqueous infusion fluids such as sodium chloride solution, dextrose solution or a combination of these, or dextrose in ringers solution. The novel taxane conjugates are hydrolysed in aqueous fluids including intravenous aqueous fluids and plasma to give an active taxane compound of formula-IA. which otherwise would have been difficult to formulate because of its insoluble nature. The compound of formula-IA may be represented by the structure below.


O-H

Formula-IA
wherein. R7 represents hydrogen or acetyl. R3 represents alkyl O-alkyl. -NH- alkyl. aryl or heterocyclyl.


The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
The general terms used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings, unless otherwise indicated.
As used herein "alky!" can be straight-chain, branched, or cyclic aliphatic group containing 1 to 20 carbon atoms, and can optionally contain one or more unsaturations and/or can have one or more hetero atom incorporated therein and optionally, in each case have one or more hydrogen atoms replaced by halogen, -OH, alkyl, -O-alkyl, -OCO-(C1-C3)-alkyl. (C1-C13)-cycloalkyl, aryl or heterocyclic radical. As used herein 'alkyl including one or more unsaturations' is to be understood as meaning 'alkenyl" and/or 'alkynyl". Exemplary alkyl groups include methyl, ethyl, ^-propyl, /'-propyl, n-butyl, /-butyl. t-pentyl, 3-pentyl. 2-octyl and the like. Exemplary alkenyl groups include ethenyl, propenyl, 1-butenyl. (Z)-2-butenyl. (£)-3-methylbut-2-enyl. (E)-2,4-pentadienyl, (Z)-3-heptenyl and the like. Rxemplary alkynyl groups include ethynyl. propynyl, 1-butynyl, 2-butynyl, 4-methyi-2-pentynyl, 2,4-hexadiynyl and the like.
The term 'alkylene' refers to a divalent alkyl group containing 1 to 10 carbon atoms, optionally having one or more hetero atoms, arylene or heterocyclylene incorporated therein, and optionally in each case have one or more hydrogen atoms replaced by halogen, hydroxyl. alkyl, O-alkyl, aryl or heterocyclyl groups. Exemplary alkylene group include -CH2-, -CM(C6H5)CH2-. -CH2CH2CH2-. -CH2(C6H4)CH2-, -CH2CH(CH3)2CH2-and the like.
The term "alkenylene" refers to alkylene having 2 to 10 carbon atoms and having at least one double bond, the double bonds being in either E or Z configuration Exemplary


alkenylene group include -CFI=CH-, -CH2-CH=CH-CH2-. -CH=C(CH3)-CH2- and the like..
The term 'alkynylcne" refers to a divalent alkynyl group containing 2 to 10 carbon atoms, having at least one triple bond. Exemplary alkynylene group include -C=C-. –CH2-C=C-. CH(CH3)-C=C-. -CH2-C=C-CH2- and the like.
As used herein 'cycloalkyl" is to be understood as meaning monocyclic, bicyclic, tricyclic and polycyclic ring systems such as cyclopropyl, cyclopentyl. cyclohexyl, cycloheptyl. norbornyl, adamantyl and the like. The term "cycloalkyl" as used herein can optionally contain one or more unsaturations and/or substitutions for e.g. halogen. -OH. -O- alkyl, -OC(O)- alkyl, (C3-C13)-cycloalkyl, aryl or heterocyclic radical.
As used herein 'halogen" or 'halo group" refers to -F, -CI, -Br, or-I.
As used herein 'aryl" is to be understood as meaning aromatic ring systems, optionally having one or more hydrogen atoms replaced by halogen, alkyl. O-alkyl. aryl. or heterocyclyl groups. Example of aryl group includes phenyl, naphthyl. anthraccnyl. phenanthryl.etc.
The term 'arylene’ refers to a aryl-diyl group, optionally having one or more hydrogen atoms replaced by halogen, alkyl. O-alkyl. aryl or heterocyclyl groups. For example, 1.2-phenylenyl, 1,4-naphthalenyl etc.
As used herein 'heterocyclyl' or 'heterocyclic ring" is to be understood as meaning ring systems which, in addition to carbon, also contain one or more hetero atoms, such as, for example, nitrogen, oxygen or sulfur which may be unsaturated or wholly or partly saturated. This definition furthermore includes ring systems in which the heterocyclyl


rings are aromatic, i.e. "hctcroaryl". or heterocyclic radical that is fused with benzene rings.
Hetcrocyclyl is especially a five, six or seven-membered ring system with one or two heteroatoms for e.g. 2-piperazinyl. 2- or 3-pyrrolidinyl. 2-oxo-5-pyrrolidinyl, piperidinyl, N-benzyl-4-piperidinyl. A'-alkyl-4-piperidinyl. N-alkyl-piperazinyl. morpholinyl. e.g. 2-or 3-morpholinyi. 2-oxo-lH-azepin-3-yl. 2-tetrahydrofuranyl, or 2-methyl-l,3-dioxolan-
2-yl.
Examples of heteroaryl rings are benzimidazolyl, l-[(C1-C6)-alkyl]benzimidazolyl. imidazolyl, 2- or 3-thienyl. 2- or 3-furyl, benzoxazolyl, benzothiazolyl. 2-, 3- or 4-pyridyl. pyrimidinyl. 4-. 5- or 6-pyridazin-2H-yl-3-one, 4-. 5- or 6-pyridazin-2-( C1-C6)-alkyl-2/Y-yl-3-one. 2-benzyl-4-. -5- or -6-pyridazin-2H-yl-3-one, 3- or 4-pyridazinyl, 2-, 3-. 4- or 8-quinolinyl, 1-. 3- or 4-isoquinolinyl. 1-phthalazinyl. 3- or 4-cinnolinyl. 2- or 4-quinazolinyl. 2-pyra/inyl. 2-quinoxalinyl. 2-. 4- or 5-oxazolyl. 3-. 4- or 5-isoxazolyl. 2-. 4- or 5-thiazolyl. 3-. 4- or 5-isothiazolyl, l-(C1-C6)-alkyl]-2-. -4- or -5-imidazolyl. 3-. 4-or 5-pyrazolyl. l-[( C1-C6)-alkyl]-3-. -4- or -5-pyrazolyl. 1- or 4-[1.2.4J-triazolyl. 4- or 5-[l,2,3]-triazolyl. l-[( C1-C6)-alkyl]-4- or -5-[l,2.3]triazolyl, 3-, 4- or 7-indolyl, N-[( C1-C6)-alkyl]-3-, -4- or -7-indolyl, 2-[( C1-C6)-alkyl]-3(2H)-indazolyi, l-[( C1-C6)-alkyl]-3(lH)-indazolyl. 5-tetrazolyl. 1-[( C1-C6)-alkyl]-lH-tetrazolyl, 2-[( C1-C6)-alkyl]-2H-tetrazolyl.
The term "heterocyclylene" refers to a heterocyclyl-diyl group, optionally having one or more hydrogen atoms replaced by halogen, alkyl, O-alkyl. aryl or heterocyclyl groups. For example pyridin-3,5-diyl. imidazol-2,4-diyl, thiazol-2,5-diyl, benzimidazol-l,6-diyl, pyrimidin-2.4-diyl etc.
Any asymmetric carbon atoms may be present in the (R)-, (,S')- or (A1.^-configuration. The compounds may thus be present as mixtures of isomers or as pure isomers.


The invention relates also to possible tautomers of the compounds of formula I.
Where the plural form is used for compounds, salts and the like, this is taken to mean also a single compound, salt, or the like.
Salts are especially the pharmaceutically acceptable salts of compounds of formula I. Such salts are formed, e.g. as acid addition salts, preferably with organic or inorganic acids or from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts. Suitable inorganic acids are. e.g. halogen acids, such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids are, e.g. carboxylic, phosphonic. sulfonic or sulfamic acids, e.g. acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartartic acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid. methylmaleic acid. cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethanesulfonic acid. 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid. 1.5-naphthalene-disulfonic acid, 2-. 3- or 4-methylbenzenesulfonic acid, mcthylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid. A'-cyclohexylsulfamic acid. A'-methyl-. A'-ethyl- or A'-propylsulfamic acid, or other organic protonic acids, such as ascorbic acid.
In the presence of negatively charged radicals, such as carboxy or sulfo, salts may also be formed with bases, e.g. metal or ammonium salts, such as alkali metal or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, e.g. triethylamine or


tris(2-hydroxyethyl)amine. or heterocyclic bases, e.g. N-ethylpiperidine or N.N'-dimethylpiperazine.
When an acid group are present in the same molecule, a compound of formula I may also form internal salts.
For isolation or purification purposes it is also possible to use pharmaceutically unacceptable salts, e.g. picrales or perchlorates. For therapeutic use. only pharmaceutically acceptable salts or free compounds are employed and these are therefore preferred.
In view of the close relationship between the novel compounds in free form and those in the form of their salts, including those salts that can be used as intermediates, e.g. in the purification or identification of the novel compounds, any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
The compounds of the present invention can be exemplified by the following non-limiting examples:

Compound Chemical Name
1.01 2'-[(/V-Piperidin-l-yl)succinamidoyl]taxol
1.02 10-Deacetyl-A^debenzoyl-A'-(/ert-butyloxycarbonyl)- 2*-[(/V-morpholin-4-yl)succinamidoyl]taxol
1.03 10-Deacetyl-A'-debenzoyl-/V-(/wt-butyloxycarbonyl)- 2'.7-bis[(A?-piperidin-l-yl)succinamidoyl |taxol
1.04 10-Deacetyl-/V-debenzoyl-iV-(/cTt-butyloxycarbonyl)- 2*-J(A'-piperidin-1 -\i)suecinamido\T|taxol


1.05 lO-Deacetyl-A'-debenzoyl-iV^/f/l-butyloxycarbonyl)- 2*-|T5-methyl-3-(piperidin-1 -ylcarbamoyl)methyl| hexanoyl|taxol
1.06 10-Deacetyl-A'-debenzoyl-/V-(/cTt-butyloxycarbonyl)- 2*-| 4-(piperidin-l-y 1 carbamoyl )butyryl]taxol
1.07 10-Deacetyl-A/'-debenzoyl-A'-(/tj/-t-butyloxycarbonyl)- 2*-[ 3.3-dimethyl-4-(piperidin-1-ylcarbamoyl)butyryl]taxol
1.08 2*-[3-(yV-(piperidin-l-yl)-carbamoyl)benzoyl]taxol
1.09 2'-[(Z)-3-(Piperidin-l-ylcarbamoyl)acroyl] taxol
PROCESS FOR PREPARATION OF COMPOUNDS OF THE PRESENT INVENTION
The present invention provides process for preparation of the compounds of the formula I. comprising, reacting the compound of formula II with a compound of formula III. (Scheme-I)

O—R,
O /R2R/^NH O \ 3- P- u )—c\/ 0—Ri O O R5H M Formula-Ill OxR3 I^IH O Ph^^Vl)'
HO o^V\ o _/-- ,6 R4

Scheme-I
In the compounds of formula-II and -III, R1, R2. R3, R4. R5. R6 and X are as defined above for formula I; Y is a leaving group and is in activated form, preferably in the presence of an inert base and/or a suitable catalyst in an inert solvent. The compound of formula III can alternatively be generated in situ from the corresponding acid (Y=OH)


and then condensed with the compound of formula II to generate the compound of formula I. Compounds of formula III, wherein Y=OH may be prepared by a process known in the art, for example, by condensation of the corresponding dicarboxylic acid of the general formula X-(COOH)2:, or its mono ester, or a cyclic anhydride of the general formula X-(CO)2O with a suitable hydrazine derivative. H2N-NR5R6.
A derivative of the formula-Ill in activated form is especially a halide. reactive ester, a reactive anhydride or a reactive cyclic amide. The method of preparation of such activated derivatives form the corresponding acid is, in general, known in the art. For example, activated form of formula-Ill wherein Y is a halide can be obtained for example by treatment of the corresponding acid with a halogenating agent such as thionyl chloride, phosphorus pentaehloride or oxalyl chloride.
The reactive esters of the acid of formula-Ill may be for example,
• esters unsaturated at the linking carbon atom of the esterifying radical, for example esters of the vinyl ester type, such as actual vinyl esters, which may be obtained, for example, by transesterification of a corresponding ester with vinyl acetate; or carbamoylvinyl esters, which may be obtained, for example, by treatment of the corresponding acid with an isoxazolium reagent like 1.2-oxazolium or Woodward method; or 1- alkoxyvinyl esters, which may be prepared, for example, by treatment of the corresponding acid with a alkoxyacetylene;
• esters of the amidino type, such as N,N-disubstituted amidino esters, which may be obtained for example, by treatment of the corresponding acid with a suitable N,N-disubstituted carbodiimide, for example. N,N-dicyclohexylcarbodiimide or by treatment of the corresponding acid with N,N-disubstituted cyanamide;
• suitable aryl esters, especially phenyl esters suitably substituted by electron withdrawing substituents. which may be obtained, for example, by treatment of the corresponding acid with a suitably substituted phenol, for example. 4-


nitrophenol, 4-methylsulfonylphenol. in presence of a condensation agent, such as N,N-dicyclohexylcarbodiimide;
• cyanomethyl esters, which may be prepared, for example, by treatment of the
corresponding acid with chloroacetonitrile in the presence of a base;
• thio esters, for example, nitro-substituted. phenylthio esters which may be
obtained, for example, by treatment of the corresponding acid with nitro-
substituted. thiophenols. or inter alia by the anhydride or carbodiimide method;
• amino or amido esters which may be obtained, for example, by treatment of the corresponding acid with an A-hydroxyamino or N,N-hydroxyamido compound, for example. ALhydroxysuccinimide, A-hydroxypiperidine, N,N-hydroxyphthalimide or 1-hydroxybenzotriazole. for example by the anhydride or carbodiimide method;
• silyl esters, which may be synthesised. for example, by treatment of the corresponding acid with a silylating agent, for example, hexamethyldisilazane.
Anhydrides of the acid of formula-Ill may be symmetric or preferably mixed anhydrides of that acid, for example, anhydrides with inorganic acids, such as
• acid halides. especially acid chlorides obtainable as mentioned vide supra.
• azides. which may be obtained, for example, from a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid
• anhydrides with carbonic acid semiderivatives. for example carbonic acid alkyl semiesters. which may be obtained, for example, by treatment of the corresponding acid with haloformic. such as chloroformic, acid, alkyl esters or with a l-alkoxycarbonyl-2-alkoxy-l,2-dihydroquinoline. for example 1-alkoxycarbonyl-2-cthoxy-1.2-dihydroquinoline or
• anhydrides with dihalogenated phosphoric acid which may be obtained, for example, by treatment of the corresponding acid with phosphorus oxychloride.
Alternatively, the activated compound of formula-Ill may be an anhydride with organic acids, such as mixed anhydrides with organic carboxylic acids, which may be obtained.


for example, by treatment of the corresponding acid with an unsubstituted or substituted alkane- or phenylalkane-carboxyiic acid halide. for example phenylacetic acid chloride, pivalic acid chloride or trifluoroacetic acid chloride or the mixed anhydride can be obtained with organic sulfonic acids, which may be prepared, for example, by treatment of a salt, such as an alkali metal salt, of the corresponding acid, with a suitable organic sulfonic acid halide. such as alkane-or aryl-. for example methane- or /j-toluenesulfonic acid chloride or activated compound of formula III may form mixed anhydride of organic phosphonic acids, which may be obtained, for example, by treatment of the corresponding acid with a suitable organic phosphonic anhydride or phosphonic cyanide; mixed phosphonic acid anhydrides method. The symmetric anhydrides may be obtained, for example, by condensation of the corresponding acid in the presence of a carbodiimide or of 1 -diethylaminopropyne.
Suitable cyclic amides may be amides with five-membered aromatic compounds with two nitrogen atoms, such as amides with imidazoles, obtainable, for example, by treatment of the corresponding acid with MA'-carbonyldiimidazole; or pyrazoles. for example 3.5-dimethylpyrazole (obtainable, for example, by way of the acid hydrazide by treatment with acetylacetone).
Derivatives of the acid of formula-Ill in activated form are preferably formed in situ. For example. A',A'"-disubstituted amidino esters can be formed in situ by reacting a mixture of the acid of formula-Ill and the compound of formula-II in the presence of a suitable yV,Ar-disubstituted carbodiimide, for example MyV'-dicyclohexylcarbodiimide. Reactive mixed anhydrides of the acid of formula-II with an organic phosphonic acid may be formed in situ by reaction with e.g. propylphosphonic anhydride or diethylcyanophosphonate in the presence of suitable base, preferably a tertiary amine, e.g. triethylamine or dimethylaminopyridine.


The reaction can be carried out in a manner known per se, the reaction conditions being dependent especially on whether, and if so how. the acid group of formula-Ill has been activated, usually in the presence of a suitable solvent or diluent or of a mixture thereof and. if necessary, in the presence of a condensation agent. Customary condensation agents are. for example, carbodiimides. for example. N,N'-diethyl-. N,N--diisopropyl. N,N-dieyclohexyl- or N-ethyl-N-(3-diethylaminopropyl)-carbodiimide. suitable carbonyl compounds, for example carbonyldiimidazole, or 1,2-oxazolium compounds, for example 2-ethy 1-5-phenyI-1,2-oxazolium 3"-sulfonate and 2-tert-butyl-5-methyl-isoxazolium perchlorate. or a suitable acylamino compound, for example. 2-ethoxy-l-ethoxycarbonyl-1.2-dihydroquinoline. Customary acid-binding condensation agents, for example, alkali metal carbonates or hydrogen carbonates, for example sodium or potassium carbonate or hydrogen carbonate (customarily together with a sulfate), or organic bases, such as. customarily, pyridine or triethyamine, or sterically hindered tri-alkylamines. for example N,N--diisopropyl-A'-ethylamine.
Alternatively, the compounds of formula I can be synthesized using a compound of formula IV, wherein Y is a leaving group and is in activated form for the reaction, the substituents R1. R2. R. R4. R5, R6 . X are as defined above. The compound of formula-IV can be generated in situ from the corresponding acid. i.e. Y=OH which in turn can be prepared from the compound of formula-II by methods known to those skilled in the art. Activated compounds of formula-IV can be prepared using acid of formula-IV. wherein Y=OH, in a manner similar to compounds of formula-Ill, as described above in detail. The activated compound thus obtained may be subsequently condensed with the hydrazine compound of formula V to obtain the required hydrazide compound of formula I (Scheme II). Compounds of formula-V may be prepared from the corresponding amines using process generally known in the art for the preparation of hydrazines. For example. the desired hydrazine of formula-V may be prepared from the corresponding amine by nitrosation/ diazotization and subsequent reduction using reducing agents like zinc-acid, sodium bisulfite, by catalytic hydrogenation etc.



O—R,
R NH O
O—R,
Y' "O

Kormula-IV

/R6
H2N—N
Re
Formula-V

Formula-I

Scheme-II
The compound of formula-l may be isolated in crude form by methods known to those skilled in the art. Final purification can be carried over by preparative chromatography or by other methods known to those skilled in the art such as acid-base purification, leaching etc.
The compounds of formula I wherein 7- and /or 10-position are also substituted, besides 2"-position, with -OR4 may be prepared from the corresponding compounds of formula-I possessing -011 group at these positions.
The compounds of formula-II. used as a starting material for the reaction, are either known in the art and commercially available or can be prepared by following known methods, for example. Wani, M. C; Wall. M. E.. .J. Chem. Soc. 93. 2325 (1971); Kingston, D. G. I.. .J. Org. Chem. 62. 3775-78 (1997). European Patent No. 253, 738. United States Patent No. 4.814.470. which is incorporated herein by reference.
The compounds of formula-I. including their salts, are also obtainable in the form of hydrates.
The prodrugs of formula I release the taxane under physiological conditions, which binds to the microtubules, reversibly. with high affinity. The binding of the taxane to the


microtubule stabilizes microtubules and prevents depolymerization induced by microtubule disrupting agents like CaCl2. thereby inhibiting cell proliferations. Thus, the taxanes exhibit a unique mechanism of action in that . they promote the assembly of microtubules but inhibits their disassembly, therreby interfereing with the G2 and M phases of cell division. Accordingly, the taxane conjugates of the present invention may be utilised in the treatment of a disease which responds to an inhibition of microtubule depolymerisation. more preferably in the treatment of cancer. More preferably, the compounds of formula-1 of the present invention are useful in the prophylactic or especially therapeutic management of cancer. Furthermore, the compounds of formula-I are useful for the treatment of other warm-blooded animals. Such a compound may also be used as a reference standard in the test systems, to permit a comparison with other compounds.
For use in therapy, a compound of formula-I or a salt thereof, may be administered in a therapeutically effective amount to a patient in need thereof. The term "therapeutically effective amount" refers to a sufficient amount of compound of formula-I or salt thereof, which is effective for prophylactic and/or therapeutic treatment of a condition caused due to inhibition of microtubule depolymerisation. especially, for treatment of cancer, in a mammal in need thereof, at a reasonable benefit/risk ratio applicable to any medical treatment. The specific thereapeutic effective dose level for any particular patient will depend upon a variety of factors including the type of cancer being treated, the stage or the severity of the disease, the activity of the compound employed, the specific pharmaceutical preparation employed, the individual pharmacokinetic data and the mode of administration of the active ingredient.
Furthermore, the compounds of formula-I may be administered for tumour therapy, either separately or in addition to chemotherapy, radiotherapy, immunotherapy, surgical intervention or a combination of these. The compounds may be administered as a part of long-term therapy or as adjuvant therapy in the context of other treatment strategies, as


described above. Other possible treatments may be therapy to maintain the patient's status after remission or tumor regression, or even chemopreventive therapy, e.g. in patients at risk.
The compounds of the present invention may be administered in the form of a suitable pharmaceutical preparation, for example, as parenteral preparations, to a warm-blooded animal in need thereof. The pharmaceutical preparation may comprise the active ingredient alone, or preferably, together with a pharmaceutical^ acceptable carrier. The pharmaceutical preparation may comprise from approximately 1% to approximately 95% active ingredient for a single-dose administration. Suitable pharmaceutical preparations may be solutions of the active ingredient, especially isotonic aqueous solutions, dispersions or suspensions which, for example in the case of lyophilized compositions comprising the active ingredient alone or together with a carrier can be made up before use. The pharmaceutical preparation may comprise pharmaceutically acceptable carriers such as stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers etc. Further, the preparations may be prepared in a manner known per se, for example by means of conventional dissolving and lyophilizing processes. The said solutions or suspensions may optionally contain viscosity-increasing agents or solubilizers. For sterile preparations, they may be subjected to end-stage sterilization and/or may contain excipients to prevent microbial contamination, for example preservatives.


The following examples serve to illustrate the invention without limiting the invention in
its scope.
Example 1
2'-|(N-Piperidin-l-yl)succinamidoyl|taxol (Compound 1.01)

A mixture of paclitaxel (0.60g. 0.70mmol), N-piperidin-l-yl-succinamie acid (0.56g. 2.81mmol) 1.3-dicyclohexylcarbodimide(0.434g. 2.10mmol) and 4-dimethyl-aminopyridine (0.257g, 2.10mmol) in anhydrous methylene chloride (50ml) was stirred under a blanket of nitrogen at 25-30°C for 4.0 hrs. The reaction mixture was cooled to 5°C and filtered to remove precipitated dicyclohexylurca. Filtrate was washed with water, dried, and concentrated in vacuo. The residue was purified by column chromatography (40% acetone in hexane) to yield the title compound as a white solid, m.p. 165-I69°C.
Compounds 1.08 & 1.09 were synthesized in a manner analogous to compound 1.01.
Example 2
10-Deacetyl-N-dcbcnzoyl-N-(tert-butyloxycarbonyl)-2,-[(N-morpholin-4-yl)succinamidoyl| taxol (Compound 1.02)



i °

A mixture of docetaxel (0.500g. 0.61 mmol), N-morpholin-4-yl-succinamic acid (0.250g, 1.23mmol). l-ethyl-3-[3-dimethylaminopropyl]- carbodiimide hydrochloride (0.296g. 1.54mmol) and 4-dimethylaminopyridine (0.070g. 0.61 mmol) in anhydrous methylene chloride (20ml) was stirred under a blanket of nitrogen at 25-30°C for 6.0hrs. The reaction mixture was quenched with water; the organic layer was separated, washed with water, dried and concentrated in vacuo. The residue was purified by column chromatography (40% acetone in hexane) to yield the title compound as a white solid, m.p. 155-157°C.
Compounds 1.04. 1.05, 1.06 & 1.07 were synthesized in an analogous manner.
Example 3
10-Deacetyl-N-debenzoyl-/V-(te/-t-butyloxycarbonyl)- 2',7-bis[(N-piperidin-l-
yl)succinamidoyl]taxol (Compound 1.03)

A mixture of docetaxel (2.0g. 2.47mmol). A'-piperidin-l-yl-succinamic acid (1.98g. 9.9mmol) 1.3-dicyclohexylcarbodimide( 1.53g. 7.4mmol), 4-dimethylaminopyridine (032g, 2.4mmol) in anhydrous methylene chloride (50ml) was stirred under a blanket of nitrogen at 25-30°C for 3.5hrs. The reaction mixture was cooled to 5°C and filtered to remove the precipitated dicyclohexylurea. The filtrate was washed with water, dried, concentrated in vacuo and the residue was purified by preparative HPLC (acetonitrile-


water gradient. ODS Shimpaek column) to yield the title compound as a white solid, m.p 136-138°C.
The compound 1.04 was prepared and purified in a manner similar to that of compound 1.03. however docetaxel. A'-piperidin-l-yl-succinamic acid, 1,3-dicyclohexylcarbodimide, 4-dimethylaminopyridine taken were in the mole ratios of 1.0:1.1:2.0:0.5.
Tables 1 and 2 illustrate the chemical structures and the mass spectrometry data of the
representative examples.
Table 1- Representative compounds of formula-I


P~"Ri

Formula-I

Comp No. R, «2 l<3 I<4 Chemical Name
I.OI II COCII, Phenyl / A Xjfl '-' K 0 2'-[(,V-Piperidin-l-yl)succinaniidoylJtaxol
1.02 H II /-Butyloxy II ""' NII H 0 IO-Deacetyl-,V-debenzoyl-/V-(/c'/-t-butyloxycarbonyl)- 2"-[(/V-morpholin-4-yl)succinamidoyl]taxol
I.03 II H0 II /-Bntyloxy 0 I0-Deacetyl-/V-debenzoyl-/V-(/wt-butyloxycarbonyl)- 2\7-bis[(/V-piperidin-l-yl)succinamidoyl]taxol


1.04 H 11 /-Butyloxy ° Ai (T ti ^0 10-Deacetyl-A'-debenzoyl-A/-(/wt-butyloxycarbonyl)- 2'-[(A'-piperidin-l-yl)succinamidoyl]taxol
1.05 H II /-Butyloxy \/ \/ N \/ 10-Deacetyl-A'-debenzoyl-A'-(/wt-butyloxycarbonyl)- 2'-[[5-methyl-3-(piperidin-l-ylcarbainoyl)methyl]hexanoyl|taxol
1.06 H 11 /-Butyloxy o o c' NI ^ X I JH 10-Deacetyl-A'-deben/,oyl-A'-(/c/'t-butyloxycarbonyl)- 2'-[ 4-(piperidin-l-ylcarbamoyl)butyryl]taxol
1.07 H II /-Butyloxy o o A A1 A X A JH 10-Deacetyl-A'-debenzoyl-A'-(/wt-butyloxycarbonyl)- 2'-[3,3-dimethyl-4-(pipendin-1-ylcarbamoyl)butyryl]taxol
1.08 11 COCIh Phenyl XJ H 2'-[3-(A'-(piperidin-l-yl)-carbamoyl)benzoyl]taxol
1.09 11 COCII;, Phenyl A-A X)H 2'-[(Z)-3-(Piperidin-l-ylcarbamoyl)acroyl] taxol
Tablc-2: Spectral data for the synthesized compounds

Comp. No 'H-NIMR (6 ppm), MASS (ES+, ni/z.)
1.01 I.l3(s, 311). 1.22(s. 311). I.60-I.67(m. 1214). 1.83-1.92(m. 611). 2.04-2.38(m, 311). 2.23(s. 311). 2.42(s. 311). 2.49-2.94(m. 811). 3.79(d. .7=6.841 Iz, 1 H). 4.19(d. ./=8.30l Iz. Ill), 4.3 l(d, ,7=8.32llz, IH), 4.4l-4.43(m. 1II). 4.97(d. ,7=8.75Hz. 1 H). 5.43(d. .7=3.61 Hz. IH), 5.67(d. ,/=6.86llz. II1), 5.89-5.94(111, 214), 6.20(m, IH), 6.28(s, III), 7.30-7.34(m. 2H), 7.40-7.43(m. 611), 7.49-7.64(111. 414). 7.83(d. .7-7.41 Hz. 2H). 8.l3(d. .7-7.42H/. 2H). MASS : 1036.56
1.02 I.l2(s. 311). I.22(s. 311). I.33(s, 911). 1.63-1.70(m, IH), l.74(s, 311). 1.8 l-l .87(m. 211). 1.93(s. 3H). 2.l4-2.37(m. 3H), 2.4l(s, 3H), 2.54-2.84(m. 8H). 3.48-3.80(m. 411), 3.9l(d. .7=6.18llz. IH), 4.17-4.26(111, 411). 4.32(d. ,7=8.37Hz, IH), 4.94(s. 111). 4.97-5.50(m. 3H). 5.68(d. ,/=6.72Hz. 111). 6.20(s. IH). 7.29-7.38(m. 5H). 7.5l(t. ,7=7.44Hz, 211). 7.6l(t. ,7=7.l8llz. IH), 8.1 l(d. .7-=7.42Hz, 2H). MASS : 992.12
1.03 I.l2(s,3ll). 1.20(s, 3H). l.34(s.9H), 1.63(m, 1211), 1.81(s,3H), 1.96(s. 311). 2.27-2.37(m. 6H), 2.42(s, 3H), 2.50-2.55(m, 3H), 2.62-2.82(m, 8H), 3.04(m, 3H), 3.98-3.99(br-s, 1 H), 4.19(d, ,7=8.25Hz, IH), 4.32(d, ,7=8.26Hz. IH), 4.4l(s, IH), 4.95(d. .7=8.56Hz, 1H).


5.28(s, III). 5.32(s. 111). 5.40-5.56(m, 411). 5.67(d, ./-6.45Hz, 111). 6.10-6.16(m. 2H). 7.30-7.38(m. 5H). 7.5l(t. ./=7.33Hz, 2H). 7.6l(t. ./-7.01Hz, IH). 8.1 l(d. .7=7.41 Hz. 2H). MASS: 1 172.69
1.04 1.10(s. 3H). 1.16(s. 311), l.25(s, 3H), 1.28-1.42(m, 2H), l.38(s, 911). 1.66-1.7l(m, 6H), 1.71(s. 311), 1.82-l.89(ni. 411). 2.36(s, 311), 2,l9-2.47(m, 3H), 2.7l-2.74(m. 4H). 3.29(s, IH), 3.82(t, ./-6.39Hz, 1 H), 4. l7-4.29(m, 1 H). 4.1 8(d, .7=8.17Hz. 1 H), 4.25(d. ./=8.38Hz, IH), 4.31-4.32(m. IH), 4.69(d, .7=7.1 Hz, 111), 4.94(d, ./-8.84Hz, 111), 5.20-5.25(m, 3H), 5.6l(d, ,/=5.39Hz, 111). 6.05-6.15(m, IH). 6.3 l-6.33(d, ,7=9.22Hz, IH), 7.24-7.40(m. 5H), 7.5l-7.55(m, 3H). 8.09(d. ,/=7.59Hz, 2H). MASS : 990.3
1.05 0.82-0.91(m. 611), 1.11-1.29(111, 8H). I.33(s. 9H), 1.60-1,75(m. 1411). 1.85-2.05(s, 6H), 2.3l-2.44(ni. I0H), 2.56-3.01(111. 4H), 3.93-3.94(s, IH), 4.19-4.34(m. 4H), 4.97(d, ./=7.24Hz. IH), 5.21(c). ./-7.96Hz, IH). 5.27-5.78(m. 3H), 6.08-6.26(m, 2H), 6.65(s. IH). 7.29-7.41(111, 511). 7.51-7.61(111,311), 8.1 1-8.13(m, 211). MASS: 1060.67
1.06 I.12(s. 311), l.22(s. 311). I.33(s. 911). 1.64-1.72(m, IH), l.75(s. 3H). 1.82-1.91(m, 4H). I.96(s, 3H), 2.18-2.63(111, 8H), 2.44(s. 3H), 2.74-2.99(m, 2H). 3.93(c). .7=6.351 Iz, IH). 4.19(d, ./-7.33Hz, III). 4.26-4.31(m, 1II), 4.32(d. ,/=8.38Hz, lH),4.96(s. Ill).5.2l(s. III). 5.32-5.70(m. 4H). 6.08-6.50(m. 311). 7.29-7.3 l(m. 3H), 7.38(1. .7=6.821 Iz. 211), 7.5 l(t. .7=7.541 Iz. 2H). 7.61 (1. .77.3 11 Iz, 1II). 8.1 1 (d. ./-7.47Hz, 2H). MASS: 1004.1 8
1.07 0.97(s, 3H), 1.1 l(s, 311). I.l3(s. 3H). 1.24(s, 311). I.33(s, 9H). l.40-1.49(m, 2H), 1.66-l.70(m, 511), l.76(s, 311), 1.82-2.05(m, 211). I.98(s, 3H), 2.16-2.84(m, 1011), 2.46(s, 3H), 3.00(m. IH). 3.95(c), ./-6.55Hz, IH), 4.20-4.35(m, 411). 4.98(d, ./-7.94Hz, IH), 5.21-5.74(s. 5H), 6.25-6.27(m. IH), 6.88(br-s, IH), 7.30-7.33(m, 3H). 7.35-7.4 1 (m. 2H). 7.5 l(t, ,7=7.59Hz. 211), 7.6l(t,./ 7.31Hz. IH), 8.12(d. ,/=7.28Hz, 2H). MASS: 1032.52
1.08 I.13(s. 3H). I.22(s. 3H). 1.60-1.67(m. 1211). I.83-I.92(m, 6H), 2.04-2.38(m. 311), 2.23(s, 3H). 2.42(s, 311). 2.49-2.94(in, 8H). 3.79(d, ./-6.84Hz. IH), 4.19(d, .7=8.301 Iz. IH), 4.3 l(d, ,7=8.32Hz, IH), 4.41-4.43(111, 111), 4.97(d, ,7=8.75Hz. 1 H), 5.43(d, .7=3.61 Hz, IH), 5.67(d, ,/=6.86Hz, IH). 5.89-5.94(111, 2H), 6.20(m, IH). 6.28(s, IH). 7.30-7.34(m. 211), 7.40-7.43(m, 611). 7.49-7.64(111, 4H), 7.83(d, .7-7.41 Hz, 2H), 8.13(d, ./=7.42llz, 2H). MASS: 1084.5
1.09 1.14(s, 311), 1.24(s, 3H). 1.60-l.68(m, 6H). I.68(s, 3H), l.80-2.04(m, 3H), 2.23(s, 3H). 2.l5-2.77(m, 7H), 2.48(s, 311), 3.82(d, ,7=6.85Hz, IH), 4.20(d, ,7-8.l8Hz, IH), 4.33(d. .7=8.52Hz, IH), 4.45(m. 1 H), 4.98(d, .7=9.15Hz, 1 H), 5.53-5.55 (m, 1 H), 5.69(d, .7=7.09Hz, III), 6.00(dd, ,7;=9.101 Iz, .7:=2.79Hz, IH). 6.23-6.5l(m, 2H), 6.73-7.16(m, 2H), 7.34-7.66 (m.lOll). 7.70(s. 111). 7.75(dd, .7,-8.41-lz. ./;=!.61 Hz, 214). 8.12-8.16(m, 211). MASS: 1034.61
Conversion of compounds of the present invention to an active taxane compound in human plasma :
The conversion of the test compound 1.04 of the present invention to the active taxane compound was determined in the human plasma sample. 2000 ng per ml concentration of the test compound was added in human plasma at ambient temperature and the test sample was kept in an incubator maintained at 37°C. Aliquots of the sample were taken at definite time intervals and subjected to analysis. The samples were analysed for the amount of unconverted test compound and for the amount of docetaxel formed in the test


solution using LC-MS/MS. operating in selected reaction monitoring (SRM) mode, as
follows :
Column : Hypurity Aquastar C-18. 50x2.1 mm. 3 micron
Mobile Phase : 10 mmol ammonium acetate-acetonitrile, 40:60
Flow Rate: 250ml/ min
Oven Temperature: 45°C
Retention time of compound 1.04: 13.9min
Retention time of Docetaxel: 0.79min
The parent ion > product ions monitored were the following:
m/z 990.6 > 345.980 and m/z 990.6 > 182.366 (compound 1.04) and m/z 830 > 247.866
and m/z 830 > 303.974 ( for docetaxel)
The percentage ofuncoverted test compound 1.04 as measured at different time intervals
is given in Table 3 below. The mass peak area was also measured for the test compound
1.04 and docetaxel and are as given in Table 4. The time vs area plot for test compound
and docetaxel is shown in figure 1 and 2.
Table 3

Time ( hrs) % Unconverted Compound 1.04
0.0 100
0.5 59.1
1.0 40.3
2.0 4.7
4.0 0.1
Table 4

COMPOUND 1.04 DOCETAXEL
TIM E( hrs) AREA TIME(hrs) AREA
0 24696932.5 0 10447.0
0.5 19303514.4 0.5 70713.8
1 16791382.3 1 125083.0
2 1 1789443.5 2 243846.6


3 6259891.0 3 331 134.0
4 3007853.1 4 464924.3
6 904115.8 6 546298.2
As observed from the data in Table 3 and 4 and in figures 1 and 2. the taxane conjugates
of the present invention are converted to the active taxane compound in physiological
conditions. The compounds of the present invention thus are useful in the treatment of
cancer.
In summary, the present invention provides novel hydrazide containing taxane conjugates
of formula-I or salts thereof.


O—R1

Formula-I
wherein.
R1 represents hydrogen or R4;
R2 represents hydrogen, acetyl or R4;
R3 represents alkyl. O-alkyl.-NH- alkyl. aryl or heterocyclyl;
R4 represents moiety selected from a group consisting of (A)


O

O

Rc
.N.

-FL

(A)
wherein. X represents a single bond, alkylene, alkenylene. alkynylene. arylene or a heterocyclylene moiety;


R5, R6
are the same or different and are independently selected from hydrogen, alkyl,
aryl or heterocyclyl;
or R5 and R6 may form together with the nitrogen atom to which they are attached a
heterocyclyl ring system.