C-4 carbonate-bearing taxanes

 

(57) Abstract:

The invention relates to new S-4 carbonate-bearing similarly to taxanes of formula 1 and their pharmaceutical salts:

where R denotes phenyl, isopropyl or tert.butyl; R1denotes-C(O)RZin which RZmeans (CH3)3CO-, (CH3)3CLO2-, CH3(CH2)3Oh, cyclobutyl, cyclohexyloxy or 2-furyl and R2denotes CH3C(O)O-, and also to pharmaceutical compositions based on them and their use as protophobic agents to treat diseases of humans and animals. The technical result - obtaining new derivatives taxane valuable antitumor effect. 3 N. and 10 C.p., f-crystals, 3 tables.

The scope to which the invention relates.

This invention relates to antitumor compounds. More specifically, the invention provides a new, orally active derivatives of paclitaxel, pharmaceutical preparations based on them and their use as orally injected anticancer agents.

Prior art

Paclitaxel is a natural product, extracted sasano, he has an excellent antitumor activity in vivo animal models, recent studies have found a unique method of action which includes abnormal polymerization of tubulin and gap mitosis. It is used clinically to combat a number of cancer diseases in humans. It is important anticancer agent with therapeutic and commercial points of view. Continue numerous clinical trials to expand the applications of this agent in the treatment of proliferative diseases in humans. The results of clinical trials of TAXOL® is described by many authors. Recent review articles of various authors is provided in the meeting materials Seminars in Oncology, 1999, 26 (1, Suppl. 2). Other examples are: Rowinsky et al., in TAXOL®: A Novel Investigational Antimicrotubule Agent, J. Natl. Cancer Inst 82: pp 1247-1259, 1990; Rowinsky and Donehower in “The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics”, Pharmac. Ther., 52: 35-84, 1991; Spencer and Faulds in Paclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer”, Drugs, 48(5) 794-847, 1994; by K. C. Nicolaou et al. in “Chemistry and Biology of TAXOL®”, Angew. Chem., Int. Ed. Engl., 33: 15-44, 1994; by F. A. Holmes, A. P. Kudelka, J. J. Kavanaugh, M. H. Huber, J. A. Ajani, V. Valero in the book “Taxane Anticancer Agents, Basic Science and Current Status” edited by Gunda Georg T., Thomas T. Chen, Iwao Ojima and Dolotrai M. Vyas, 1995, American Chemical Society sources, cited in this description.

It was found that semi-synthetic analogue of paclitaxel, called docetaxel, also has good antitumor activity and is the active ingredient of commercially available anti-cancer agent TAXOTERE®. See Biologically Active Taxol Analogues with Deleted A-Ring Side Chain Substitutents and Variable C-2' Configurations, J. Med. Chem., 34, pp 1176-1184 (1991); Relationships between the Structure of Taxol, Analogues and Their Antimitotic Activity, J. Med. Chem., 34, pp 992-998 (1991). Review of clinical studies TAXOTERE® Jorge E. Curtes and Richard Pazdur appeared in the Journal of Clinical Oncology, 1995, 13(10), 2643-2655. The structures of paclitaxel and docetaxel are listed below together with the usual for this class of compounds, the numbering system of atoms; this system is also used in this application.

paclitaxel (TAXOL®): R = Ph; R' = acetyl;

docetaxel (TAXOTERE®) R = tert-butoxy; R' = hydrogen

Evidence that paclitaxel does not have activity when administered orally, can be found in the next paragraph of the application WO 98/53811, Samuel Broder, Kenneth L. Duchin and Sami Selim and cited in this paragraph references, which reads as follows: “Paclitaxel is very poorly absorbed when administered orally (less than 1%); see Eisemann et al., Second NCI Workshop on Taxol and Taxus (Sept. 1992); Suffness et al., Thaana 0%, a Suffiiess and others have reported that oral administration of paclitaxel is not possible, as when administered orally with a dose of 160 mg/kg/day found no antitumor activity. Moreover, it was not developed an effective method of oral administration of paclitaxel (namely, the method of increasing the bioavailability of paclitaxel when administered orally) or other taxan or analogues of paclitaxel, such as docetaxel, which exhibit antitumor activity. For this reason, still paclitaxel does not impose people orally and in the treatment of diseases that respond to paclitaxel”. Another message J. Terwogt et al., The Lancet, July 25 th, 1998, vol.352, p.285 also describes the low bioavailability of paclitaxel when administered orally. In our work we have introduced paclitaxel orally in doses up to 160 mg/kg in the model tumors in mice (sc M109) and observed no signs of activity, we did as Suffness, the conclusion, that the further introduction will not be effective, despite the fact that the toxic dose has not been reached. Moreover, our attempts to detect the activity of the input oral paclitaxel against xenografts of human tumors implanted in the body antimycotic mice Il is ethylcarbonate analogues taxane, which have unexpected activity when administered orally and therefore can be used against proliferative diseases. Some of the known sources of relevance to this invention, below.

Some derivatives taxane with a modification on the C-4 gidroksidnoi group known from the prior art.

In U.S. patent 5808102, Poss et al. and international application WO 94/14787 describes analogues taxane modified at position C-4.

Gunda Georg I, et al. describe the synthesis of C-4 analogue broadcasting in Tetrahedron Letters, 1994, 35(48), 8931-8934.

S. Chen et al. describe obtaining p-4 cyclopropylamino ether in the Journal of Organic Chemistry, 1994, 59(21), 6156-6158.

U.S. patent 5840929, Chen, Shu-Hui, describing-4 methoxyamine derivatives, was issued November 24, 1998. On the same subject published: Chen, Shu-Hui, the First syntheses of C-4 methyl ether paclitaxel analogs and unexpected reactivity of 4-deacetyl-4-methyl ether baccatin III, Tetrahedron Lett. 1996, 37(23), 3935-3938.

The following reference discusses a series C-4 ether or carbonate analogues: Chen, Shu-Hui, Wei, Jian-Mei; Long, Byron H.; Fairchild, Craig A.; Carboni, Joan; Mamber, Steven W.; Rose, William C.; Johnston, Kathey; Casazza, Anna M.; et al. Novel C-4 paclitaxel (Taxsol) analogs: potent antitumor agents. Bioorg. Med. Chem. Lett. 1995, 5(22), 2741-2746.

Getting C-4 aziridination analog is 263-2267.

The following sources describe reactions or transformations that can be used to obtain C-4 analogues.

A new method of modification in the C-4 position 10-deacetylbaccatin-III Uoto, Kouichi; Takenoshita, Haruhiro; Ishiyama, Takashi; Terasawa, Hirofumi; Soga, Tsunehiko. Chem. Pharm. Bull, 1997, 45(12), 2093-2095.

Samaranayke, Gamini; Neidigh, Kurt A.; Kingston, David G. I. Modified taxols, 8 Deacylation and reacylation of baccatin III. J. Nat. Prod. 1993, 56(6), 884-898.

Datta, Apurba; Jayasinghe, Lalith R.; Georg, Gunda I. 4-Deacetyltaxol and 10-Acetyl-4-deacetyltaxotere: Synthesis and Biological Evaluation. J. Med. Chem. 1994, 37(24), 4258-4260. Despite the above examples C-4 analogues and methods of obtaining them, there is no information about orally active C-4 analogs. And TAXOL® and TAXOTERE® do not show oral activity in models of humans or animals, as specified in the following sources about takanah and oral modulators. Thus, the prior art does not contain the assumption that C-4 taxanes are different from other taxan and, therefore, they should not be active when administered orally. As we know, in the prior art there are no C-4 analogues, which could be administered orally.

This invention describes the new C-4 analogues, which due to their unique substitution have activity at Perera xanav, active when administered orally.

There are methods of introducing taxan in the presence of modulators, which reportedly allows to increase the content of taxan in plasma by oral administration: Terwogt, Jetske M., Meerum; Beijnen, Jos H., Ten Bokkel Huinink, Wim W.; Rosing, Hilde; Schellens, Jan H. M. Coadministration of cyclosporin enables oral therapy with paclitaxel. Lancet(1998), 352(9124), 285.

Terwogt, Jetske M., Meerum; Malingre, Mirte M., Beijnen, Jos H., Huinink, Wim W. ten Bokkel; Rosing, Hilde; Koopman, Franciska J.; Van Tellingen, Olaf, Swart, Manha; Schellens, Jan H. M. Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin. Cancer Res. (1999), 5(11), 3379-3384.

Hansel, Steven C. A method of making taxanes orally bioavailable by coadministration with cinchonine. Application WO 9727855, published on August 7, 1997.

Broder, Samuel; Duchin, Kenneth L.; Sclim, Sami. Method and compositions for administering taxanes orally to human patients using cyclosporin a to enhance bioavailability. Application WO 9853811, published on 3 December 1998. In these messages, there is no evidence of antitumor activity, but the presence of taxan plasma extrapolated that indicates their potential usefulness in the treatment of cancer.

Published at least one report on the activity of prodrugs by oral administration using preclinical animal models: Scola, Paul M.; Kadow, John F.; Vyas, Dolatrai M. Preparation of paclitaxel prodrug derivatives. Application EP 747385, publican and there are no messages on further study of these compounds.

Recently appeared abstract, which describes similar taxane (IDN-5109) with oral activity against tumors in mice, he became known to American Association of Cancer Researchers in Philadelphia in 1999. The source of this message is:

Pratesi G, Polizzi D, Totoreto M, Riva A, Bombardelli E, Zunino F.: IDN5109 a new taxane active after oral administration. Proc. Am. Assoc. Cancer Res. 1999, 40, Abs 1905, Istituto Nazionale Tumori, 20133 Milan and Indena SpA, 20139, Milan, Italy. The structure of this compound is very different from the structure of the compounds according to the invention. In contrast to the compounds according to the present invention IDN-5109 obtained on the basis of 14-beta-hydroxyacetone III and contains an acetate group at the hydroxyl at position-4.

There are two sources about iv activity this connection:

Nicoletti ML, Rossi S, Monardo, Stura S, Morazzoni P, Bombardelli E, Valoti G., Giavazzi R.: Antirumor efficacy of a paclitaxel analogue, IDN5109, on human ovarian carcinoma xenografts with different sensitivity to paclitaxel. Proc. Am. Assoc. Cancer Res. 1999, 40 Abs 1910 [Evals+citations].

Polizzi Donatella; Pratesi, Graziella; Totoreto Monica; Supino, Rosanna; Riva, Antonella; Bombardelli, Ezio; Franco Zunino. A novel taxane with improved tolerability and therapeutic activity in a panel of human rumor xenografts. Cancer Res. 1999, 59(5), 1036-1040.

Paclitaxel is a drug, which is highly dependent on the regimen used and which usually benefits from a long-lasting effect on the tumor. This refers to mecanizatorii, that only occurs during a short period of cycle of the cancer cells. Currently used for intravenous infusion (1-3 hours) are effektivnye and eliminate the routine use of long (>24 hours) continuous schemes. However Texan, injected oral, to ensure such a long period of exposure may lead to increased treatment costs and complexity. Recently conducted clinical trials for repeated introduction once a week moderate (namely different from the maximally-tolerated) doses of TAXOL®, and Texan, administered orally, is ideal for such a scheme. Other clinical indications for use taxan (for example, rheumatoid arthritis, multiple sclerosis) benefit from the availability taxane, administered orally. Introduced orally effective Texan is as an attractive alternative to currently used in parenteral scheme introduction taxane and medication with potential therapeutic benefit, as will the study of many schemes introduction.

Thus, it is obvious that there is a need to taksang with good bioavailability and high effektivnosti

The present invention relates to novel antitumor compounds of the formula I or their pharmaceutically acceptable salts:

where R denotes phenyl, isopropyl or tert.butyl;

R1denotes-C(O)RZwhere RZis (CH3)3CO-, (CH3)3CLO2-, CH3(CH2)3Oh, cyclobutyl, cyclohexyloxy or 2-fullam;

R2denotes CH3C(O)O-.

Another aspect of this invention relates to a method of inhibiting the growth of tumors in the body of a mammal, which includes an introduction to the specified mammal is effective against tumors of the amount of the compounds of formula I or its pharmaceutically acceptable salts. It is preferable to use the oral method of administration.

Another aspect of this invention relates to a pharmaceutical composition that contains an effective against tumors of the amount of the compounds of formula I or its pharmaceutically acceptable salts in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants.

Detailed description of the invention

In neobatrachia, used once, retain the same value throughout the description, unless otherwise specified.

The numbers after the symbol “C” denotes the number of carbon atoms, which may contain specific group. For example, “C1-6alkyl” means a linear or branched carbon chain having from one to six atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl, Deut.pencil, isopentyl and n-hexyl. Depending on the context, “1-6alkyl” may also refer to1-6alkylene that connects two groups; examples include propane-1,3-diyl, butane-1,4-diyl, 2-methylbutane-1,4-diyl etc. “2-6alkenyl” means a linear or branched carbon chain having at least one carbon-carbon double bond and containing from 2 to 6 carbon atoms; examples include ethynyl, propenyl, Isopropenyl, butenyl, Isobutanol, pentanol and hexanol. Depending on the context, “2-6alkenyl” can also refer to C2-6alcindoro that connects two groups; examples include ethylene-1,2-diyl (vinile), 2-methyl-2-butene-1,4-diyl, 2-hexene-1,6-diyl etc. “2-6quinil” means a linear or branched plenary include: ethinyl, PROPYNYL, butynyl and hexenyl. Used herein, the terms tert.bucalossi and tert.butoxy are interchangeable.

“Aryl” means an aromatic hydrocarbon radical containing from 6 to 10 carbon atoms; examples include phenyl and naphthyl. “Substituted aryl” means aryl substituted by one to five (but preferably one to three) substituents selected from C1-6alkanoyloxy, hydroxy, halogen, C1-6of alkyl, trifloromethyl, C1-6alkoxy, aryl, C2-6alkenyl,1-6alkanoyl, nitro, amino, cyano, azido,1-6alkylamino, di-C1-6alkylamino and amido. “Halogen” means fluorine, chlorine, bromine and iodine.

“Heteroaryl” means a five - or six-membered aromatic ring containing at least one and up to 4 atoms different from carbon, selected from oxygen, sulfur and nitrogen. Examples of heteroaryl include: thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, tetrazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazini etc.

“Group protecting the hydroxyl” includes, without limitation, essential, such as IU ITIL, 1-methoxy-1-methoxyethyl, tetrahydropyranyl, tetrahydropyranyl, dialkylacrylamide, such as dimethylsilicone ether, and trialkylsilyl esters, for example trimethylsilyloxy ether, triethylsilyl ether and tert.butyldimethylsilyloxy ether, dialkylacrylamide esters, such as diisopropylperoxydicarbonate ester; ester groups such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di - and trihaloacetic, for example chloroacetyl, dichloroacetyl, trichloroacetyl, TRIFLUOROACETYL; and carbonates, such as methyl, ethyl, 2,2,2-trichloroethyl, allyl, benzyl and p-nitrophenyl. Additional examples of the groups protecting the hydroxyl can be found in well-known works, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd, 1999, John Wiley and Sons, New York.

“Ph” means phenyl; “ipr” means isopropyl.

The substituents in the substituted alkyl, alkenyl, quinil, aryl and heteroaryl and fragments described herein, may represent an alkyl, alkenyl, quinil, aryl, heteroaryl and/or may contain nitrogen, oxygen, sulfur, halogen, and includes, for example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen, such as chlorine or fluorine, nitro, amino or keto.

The preferred option is

Even more preferred are the compounds of formula I or their pharmaceutically acceptable salts, are presented in table II.

New compounds having the General formula I, possess significant inhibitory activity against abnormal cell proliferation and have therapeutic properties that allow the treatment of patients with pathological conditions associated with abnormal cell proliferation. In addition, these compounds are characterized by significant oral bioavailability and thus have a positive therapeutic effect after oral administration. Pathological conditions include abnormal proliferation of malignant and non-malignant cells in various tissues and/or organs, including, without limitation, muscles, bone and/or connective tissue, skin, brain, lungs and genital organs; lymphatic system and/or renal system; cells of the mammary gland and/or hematite; liver, digestive system and pancreas; thyroid and/or adrenal glands. These pathological conditions include psoriasis, solid tumors; ovarian cancer, breast, brain, prostate, colon, stomach, kidney and/or testjoin, melanoma, multiple myeloma, chronic lymphocytic leukemia, and acute or chronic granulocytic lymphoma.

The new compounds according to the invention is particularly suitable for the treatment of lymphoma, non-Hodgkin's lymphoma, multiple myeloma, melanoma and ovarian cancer, bladder, oesophageal, lung and breast cancer. Connections can be used for the prevention or delay of symptoms or recurrence of these symptoms, or for the treatment of these pathological conditions. The compounds can be used as inhibitors delay the development of blood vessels as in the case of cancer, and in case of abnormal wound healing or other hyperproliferative diseases-dependent formation of blood vessels.

In addition, the compounds of formula I are suitable for the treatment and/or prevention of policestate kidney (PKD) and rheumatoid arthritis. Compounds according to the invention can also be used for the treatment of Alzheimer's disease, or Parkinson's disease, or multiple sclerosis. Although some products of General formula I are of interest due to their advantages compared to commercial takanami when iv introduction, the main advantage is and what s normal methods of organic chemistry. Schemes 1-3, describing obtain the compounds of formula I, are given only for illustration and do not limit the methods of producing compounds only these methods.

The compound of the formula I can be obtained by methods shown in the following schemes 1-3. These methods can be easily modified to produce compounds of formula I described herein methods. Further variations of these methods of obtaining these compounds, several other schemes obvious to the expert. The numbering of the atoms in a derived baccatin III formula II is the same as shown above for the structure taxane.

One way of preparing compounds according to the invention is shown in Scheme 1. At the stage of (a) azetidine IV is reacted with a compound of formula II (derived baccatin III). Class azetidinone (-lactam) of formula IV are well known. The methods of obtaining the appropriately substituted-lactams can be found in U.S. patent 5175315, the application EP 0590267, other U.S. patents and in the literature referred to above or in the references listed in: Ojima et al. in Tetrahedron, 48, No. 34, pp 6985-7012 (1992); Journal of Organic Chemistry, 56, pp 1681-1683 (1991) and Tetrahedron Letters, 33, No. 39, pp 5737-5740 (1992); by Brieva et al. in J. Org. Chem., 58, pp 1068-1075; by Palomo et al., Tetrahedron Letters, 31, No. 44, pp 6429-6432 (1990) and Rey, Allan W.; Droghini, Robert; Douglas, the IKI listed as references. Methods that can be adapted for other azetidinone formula IV, which are not described in this application or in the above links, or other sources, obvious to the expert.

Derivatives baccatin III (formula II) can be attached to the side chain using methods already well known in the prior art. Many of these sources and Tetrahedron, 48, No. 34, PP 6985-7012 (1992) describe how, when the class azetidinone formula IV is reacted with (C)13-hydroxyl derivatives baccatin III or a metal alkoxide with obtaining analogues taxane with different (C) 13-the side chains. At stage (a) of scheme 1, it is preferable to convert the hydroxyl group in (C)13-position in the metal alkoxide before the combination. The formation of the alkoxide of the metal can be carried out by reaction of the compound of formula II with a strong metal base, such as diisopropylamide lithium1-6alkality, bis(trimethylsilyl)-amide lithium, sodium or potassium, finality, sodium hydride, potassium hydride, lithium hydride, etc., for Example, when the lithium alkoxide, a compound of the formula II can react with n-butyllithium in an inert solvent, such as tetrahydrofuran. For example, the accession substituted boccacino to fit the 3045, USA 5227400, USA 5336785 and U.S. patent 5254580, USA 5294637 or EP 0590267 A2. Some examples of application-lactams for other substituted derivatives taxane described in the application WO 94/14787. It also describes the alternative method of attachment of the chains substituted azaserine to replaced baccatin, which can be used for compounds according to the invention. This alternative method is described in the publication Kingston et al., Tetrahedron Letters(1994), 35(26), 4483-4484. Further information about alternative methods of attaching a side chain to baccatin contained in Thottathil et al., application EP 735036 published 10/2/96.

Scheme 1

Scheme 2

In this description R3and R4denote a group protecting the hydroxyl group. A group protecting the hydroxyl represent groups which can be used to block or protect a hydroxyl function, and they are well known to specialists in this field. Preferably, these groups were such that you can remove the methods that do not cause degradation of the remaining part of the molecule. Examples of such easily removable group which protects the hydroxyl include chloroacetyl, methoxymethyl, 1-methy ether, and trialkylsilyl esters, such as trimethylsilyloxy ether, triethylsilyl ether and tert.butyldimethylsilyloxy ether, dialkylacrylamide esters, such as diisopropylperoxydicarbonate esters; 2,2,2-trichloroacetyl, 2,2,2-Trichloroisocyanuric (or just Trichloroisocyanuric), benzyloxycarbonyl, etc., Other suitable groups for protection of hydroxyl groups, which can be used can be found in Chapter 2, “Protecting Groups in Organic Synthesis”, 3rdEd, by Theodora W. Greene and Peter G. M. Wuts (1999, John Wiley and Sons, New York). The protective group of the compounds of the formula IV, which is used often in well-known publications, is trialkylsilyl. The most preferred groups for R3include 1-methyl-1-methoxyethyl (IOE), trialkylsilyl ether or dialkylaminoalkyl ether, such as diisopropylperoxydicarbonate ether. The most preferred group for R4is dialkylaminoalkyl ether, such as diisopropylperoxydicarbonate ether, but preferred are also trialkylsilyl ether or carbonate, such as benzylcarbamoyl. At the stage (b), a protective group, R3or R4or perhaps both are removed. If R3or R4represent protective groups of the user and other fluoride sources. For example, the application can find tetrabutylammonium, peridiniidae, potassium fluoride or cesium fluoride. The potassium fluoride can be used in combination with a complexing agent such as 18-crown-6 or similar to facilitate desirelove. Under these conditions usually use a solvent, such as acetonitrile. To remove the silyl groups can be applied to other conditions, such as hydrochloric acid moderate concentration or triperoxonane acid and a co-solvent, such as acetonitrile or THF. The same acidic conditions suitable for the removal of 1-methyl-1-methoxyaniline (IOE) protective group.

Used in fact, the conditions depend on the protective groups R3and R4. For example, according to one preferred method, you can apply the MOR group as R3and diisopropylethylamine group as R4. In this case, at the stage (b) use a mild acidic conditions using hydrochloric acid and an organic solvent. Obtained 2'-deprotection connection is exposed to the source of fluoride, such as Triethylenetetramine, in THF at stage (C) obtaining the compound I after chromatographic or Chris is Lermontovo baccatin.

Another aspect of the present invention includes the synthesis of compounds I with new substituents R2in the C-10 position. These compounds can be obtained by attaching alternative ester groups, and not acetamidino group, which is shown in scheme 3.

An alternative method of preparing compounds I are presented in scheme 2. It involves the conversion of one compound V in which R' forms a nitrogen protecting group, for example tert.SIV(CO)-(tert.Vos) or h2OS(O)-(Z). These groups can be removed by acid hydrolysis or in the case of CBZ-hydrogenolysis. Getting amine intermediate VI is described in the examples and is well known methods. Intermediate amine VI is dissolved in an inert solvent, such as ethyl acetate, and add a base, such as sodium bicarbonate. To obtain compounds I add a stoichiometric or slightly higher number of carboxylic acids (i.e. R'-C(O)CL), chloroformate or anhydride of the acid.

Deriving baccatin formula II (as shown in scheme 1, where R2means ASO-) is shown in figure 3 and illustrated in preparative example 7. Specific examples below, can be adapted for connection, covered by this invention but not specifically described. Professionals in this field also it is obvious that you can change the methods of obtaining the same connection.

In the following examples, all temperatures are in degrees Celsius unless otherwise specified. The data of nuclear magnetic resonance (NMR) refer to the chemical shifts are expressed in ppm (ppm) when using as a benchmark tetramethylsilane (TMS). Relative values specified for the various shifts in the proton NMR correspond to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts described as broad singlet (bs or br s), broad doublet (bd or br d), broad triplet (bt or br t), wide quadruplet (bq or br q), singlet (s), multiplet (m), doublet (d), quadruplet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quadruplet (dq). As the solvent for NMR using deuterated acetone-d6, DMSO-d6 (perdeuteromethoxy), D-20 (deuterated water), Dl3(deuterated chloroform) and other conventional deuterated solvents. The data of IR include only wavelengths (cm-1) characterizing the functional group.

C is sleduyushij experiments used silica gel 60 with a particle size 230-400 mesh mesh, shipped EM Separations Technology.

Abbreviations used in this description, are common. Some of them: GIVING (deacetylbaccatin III); MS (mass spectroscopy); HRMS (mass spectroscopy high resolution); AC (acetyl); Ph (phenyl); v/v (volume/volume); FAB (bombardment by fast electrons); NOBA (m-nitrobenzyl alcohol); min (minute, -s); h or HR (h, s); DCC (1,3-dicyclohexylcarbodiimide); BOC (tert.butoxycarbonyl); CBZ or Cbz (benzyloxycarbonyl); Bn (benzyl); Bz (benzoyl), Thos (2,2,2-Trichloroisocyanuric); DMS(dimethylallyl); TBAF (tetrabutylammonium); DMAP (4-dimethylaminopyridine); TES (triethylsilyl); DMSO (dimethylsulfoxide); THF (tetrahydrofuran); HMDS (hexamethyldisilazane); MeOTf (metalcraft); NMO (morpholine-N-oxide); (DHQ)2PHAL (hydrogenin-1,4-phthalazinedione fluids); Tf = triflate = triftorbyenzola; LRMS (mass spectroscopy low-resolution); ESI (electrospray ionization); TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical); DBU (diazobicyclo); l (chlorodimethylsilyl ether); AC (acetyl); Ah (aryl); DCI (desorption chemical ionization); DMF (dimethylformamide); LiHMDS (hexamethyldisilazane lithium or bis(trimethylsilyl)amide and lithium); i-Rgon (isopropyl alcohol); rt (room temperature is); MSRV (meta-chloroperoxybenzoic acid); LDA (diisopropylamide lithium); TBS (tert.butyldimethylsilyl); 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane); DEAD (diethylazodicarboxylate); Red-Al® (Aldrich Catalogue) is a 65 wt.%-s ' solution of bis(2-methoxyethoxy)aluminiumhydride in toluene; DCM means dichloromethane; “sat” means saturated.

Preparative examples

Preparative example I

(+)-CIS-4-tert.butyl-1-tert.butyloxycarbonyl-3-triethylsilyl-azetidin-2-he

Trimethylacetaldehyde (20,3 ml, 1.25 EQ) was added to a stirred suspension of p-anisidine (18,4 g, 0,150 mol) and anhydrous Na2SO4(150 g) in anhydrous DCM (250 ml) at room temperature. After 2 hours the mixture was filtered and washed the solid residue of an additional amount of anhydrous DCM. Was removed from the filtrate the solvent and dissolve the crystalline residue in anhydrous DCM (750 ml) and placed in a nitrogen atmosphere. Was added triethylamine (48,0 ml, 2.3 equiv) and cooled the reaction mixture to -78°C. was Added dropwise benzyloxyacetophenone to 27.2 ml, 1.15 EQ) and then gave the reaction mixture to warm to room temperature. After 24 hours the mixture was washed with 0.5 M Hcl (twice), saturated aqueous NaHCOAlance silica gel (gradient elution with 20% DCM in hexane, containing 0-20% EtOAc) to give (+)-CIS-4-tert.butyl-3-benzyloxy-1-p-methoxybenzylidene in the form of a crystalline solid (46,9 g, 92%).1H NMR (CDCl3) of 1.09 (s, 9H), 3,81 (s, 3H), 4,15 (d, 1H, J=5.5 Hz), of 4.77 (d, 1H, J=11,9 Hz), to 4.81 (d, 1H, J=5.5 Hz), to 5.03 (d, 1H, J=11,9 Hz), 6.87 in-the 7.43 (m, 9H); LRMS (ESI) 340 ([M+H]+). The solution ammoniumnitrate cerium (60,4 g, 3.6 EQ) in 900 ml of water was added to a well stirred solution of azetidinone (10,38 g of 30.6 mmol) in acetonitrile (600 ml) on an ice bath for 1 h, the Reaction mixture then was extracted with EtOAc (twice) and the combined organic extracts were washed with saturated aqueous solution Panso3(twice), 20% aqueous solution NS3, a saturated solution Panso3and brine. After drying (Na2SO4) remove the solvents and the residue was subjected to chromatography on a column of silica gel (gradient elution portions of hexane containing 10-40% EtOAc) to give the 5,64 g of slightly contaminated (+)-CIS-3-benzyloxy-4-tert.utilisation. 1H NMR (CDCl3) was 1.04 (s, 9H), 3,51 (d, 1H, J=5,2 Hz), 4,71 (m, 2H), 4,96 (d, 1H, J=11,9 Hz), 6,10 (brs, 1H), 7,35 (m, 5H). A suspension of this product (5,54 g of 23.8 mmol) and 2.5 g of 10% Pd on coal in absolute EtOH (100 ml) was first made (34 f/inch2(234,4 kPa) H2the apparatus Parra) for 23 hours was Added 2 g of Pd-catalyst and was removed from the filtrate the solvent to obtain crude (+)-CIS-3-hydroxy-4-(tert.butyl)azetidin-2-it. 1H NMR (Dl3+ 1 drop of D2O) of 1.05 (s, 9H), 3,48 (d, 1H, J=5.0 Hz), to 4.98 (d, 1H, J=5.0 Hz). This product was dissolved in dry DMF (40 ml) was added imidazole (3,24 g, 2 EQ) and triethylsilane (4,0 ml, 1 EQ). After 10 minutes the reaction mixture was distributed between water and a mixture of EtOAc and hexane (1:1). The organic phase is washed with water (twice), brine and then dried (Na2SO4). The solvent was removed and the residue was subjected to chromatography on a column of silica gel (gradient elution with 20-25% EtOAc in hexane) to give (+)-CIS-4-tert.butyl-3-triethylenediamine-2-it (3,86 g): 1H NMR (CDCl3) 0,70 (m, 6H), and 0.98 (m, 18H), 3,39 (d, 1H, J=5.0 Hz), 4,88 (dd, 1H, J=2,1, 5.0 Hz), between 6.08 (br s, 1H). The solution of this azetidinone (2,04 g, a 7.92 mmol), diisopropylethylamine (of 1.66 ml, 1.2 EQ), di-tert.BUTYLCARBAMATE (1.90 g, 1.1 EQ) and p-dimethylaminopyridine (194 mg, 0.2 EQ) in dry DCM (24 ml) was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM, washed with brine and dried (Na2SO4). Removal of solvent followed by chromatography on silica gel (elution 0-20% EtOAc in hexane) resulted in a 2.71 g (96%) of the compound indicated in the heading in the form of oil:1H NMR (Dl3) 0,70 (m, 6N), and 1.00 (m, 9H), of 1.09 (s, 9H), of 1.53 (s, 9H), 3,90 (d, 1H, J=6.5 Hz), is 4.93 (d, 1H, J=6.5 Hz).

Pre the LASS="ptx2">

Isobutyraldehyde (4,62 ml, 1.25 EQ) was added to a stirred suspension of p-anisidine (5,00 g of 40.7 mmol) and anhydrous Na2SO4(25 g) in anhydrous DMC (80 ml) at room temperature. After 1 hour the reaction mixture was filtered and the solid washed with additional anhydrous DHM. From the filtrate solvent was removed and the residue was dissolved in anhydrous DHM (200 ml) and placed in a nitrogen atmosphere. Was added triethylamine (13.1 ml, 2.3 EQ) and the reaction mixture was cooled to -78°C. was added dropwise acetoxyacetyl (5,00 ml, 1.15 EQ) and left the mixture to warm to room temperature. After 20 h the mixture was washed with 0.5 M Hcl (twice), saturated aqueous NaHCO3, brine and dried (Na2SO4), the solvent was removed and the residue was subjected to chromatography on a column of silica gel (gradient elution with a mixture of 20-30% EtOAc hexane) to give (+)-CIS-3-acetoxy-4-isopropyl-1-p-methoxybenzylidene-2-it is in the form of a solid substance (7,15 g, 63%):1H NMR (Dl3) 0,99 (d, 3H, J=7.0 Hz), of 1.02 (d, 3H, J=7.0 Hz), measuring 2.20 (s, 3H), 3,82 (s, 3H), 4,24 (t, 1H, J=5.6 Hz), the 6.06 (d, 1H, J=5.3 Hz), 6,88-7,38 (m, 4H). The solution ammoniumnitrate cerium (51,3 g, 3.6 EQ) in 750 ml of water was added to a well stirred solution of azetidinone (7.2 g, 26.0 mmol) in ACE the nnye organic extracts washed with saturated aqueous NaHCO3(twice), 20% aqueous solution NS3, saturated aqueous Panso3and brine. After drying (Na2SO4) the solvent was removed to obtain 4.26 deaths ƒ technical (+)-CIS-3-acetoxy-4-isopropylpyridine-2-it: 1H NMR (Dl3) 0,86 (d, 3H, J=6.6 Hz), 0,99 (d, 3H, J=6.6 Hz), 1,89 (m, 1H), 2,17 (s, 3H), 3,52 (dd, 1H, J=4,8, and 9.0 Hz), 5,96 (dd, 1H, J=2.5 and 4.6 Hz), 6,38 (brs, 1H); LRMS (negative ESI) 170[(M-H)-]. A suspension of this product (4.26 deaths / g, 24,9 mmol) and K2CO3(102 mg, 0.03 EQ) in Meon (40 ml) was left at room temperature under stirring for 1.5 hours Then neutralization was added Amberlite IR-20. The mixture was filtered and solvent was removed from the filtrate to obtain technical (+)-CIS-3-hydroxy-4-isopropylpyridine-2-it. This product was dissolved in dry DMF (40 ml) was added imidazole (3,39 g, 2 EQ) and triethylsilane (4,19 ml, 1 EQ). After 10 minutes the reaction mixture was distributed between water and a mixture of EtOAc and hexane (1:1). The organic phase is washed with water (twice), brine and then dried (Na2SO4). The solvent was removed and the residue was subjected to chromatography on a column of silica gel (gradient elution, a mixture of 25-35% EtOAc hexane) to give (+)-CIS-4-isopropyl-3-triethylenediamine-2-he (4,63 g, 77%):1H NMR (D13) 0,65-of 1.03 (m, 21H), lamina (0,90 ml, 1.2 EQ), di-tert.BUTYLCARBAMATE (1.04 g, 1.1 EQ) and p-dimethylaminopyridine (106 mg, 0.2 EQ) in dry DCM (10 ml) was left under stirring at room temperature for 30 minutes. The mixture was diluted with DCM, washed with brine and dried (Na2SO4). Removal of solvent followed by chromatography on a column of silica gel (gradient elution of 10-20% EtOAc in hexane) allowed us to obtain 1.31 g (88%) of the compound indicated in the title, in the form of oil:1H NMR (CDCl3) 0,66-of 1.07 (m, 21H), of 1.53 (s, 9H), of 2.15 (m, 1H), a 3.87 (t, 1H, 1=6,4 Hz), 4,88 (d, 1H, J=6,1 Hz); LRMS (ESI) 344(M+H)+].

Preparative example 3

(+)-CIS-1-benzoyl-4-isopropyl-3-triethylenediamine-2-he

A solution of (+)-CIS-4-isopropyl-3-triethylenediamine-2-it (486 mg, 2.00 mmol), benzoyl chloride (0,255 ml, 1.1 EQ), diisopropylethylamine (0,346 ml, 1.2 EQ) and p-dimethylaminopyridine (244 mg, 1 EQ) in dry DCM (6 ml) was left under stirring for 6 hours at 0°C. bath was Removed and the reaction mixture was left under stirring overnight. Then it was diluted with DCM and washed with water, aqueous Hcl solution (0,1 N), saturated aqueous NaHCO3, brine and dried (Na2SO4). Removal of solvent followed by chromatography on a column is Mr (CDCl3) 0,47-0,94 (m, 21H), is 2.09 (m, 1H), 4,07 (m, 1H), and 4.75 (m, 1H), 7.24 to 7,76 (m, 5H).

Preparative example 4

(3R,4R)-1-neopentylene-4-phenyl-3-triethylenediamine-2-he

With the aforementioned method using neopentylglycol (3R,4R)-4-phenyl-3-triethylenediamine-2-he turned specified in the header connection:

1H NMR (Dl3) for 0,19 0,62 (m, 15 NM), to 0.88 (s, 3H), 2,43 (d, 1H, J=13,8 Hz), 2,62 (d, 1H, J=14.1 Hz), the 4.90 (d, 1H, J=5.7 Hz), of 4.95 (d, 1H, J=6.0 Hz), 7,05-7,17 (m, 5H).

Preparative example 5

(3R,4R)-1-cyclobutanecarbonyl-4-phenyl-3-triethylenediamine-2-he

With the aforementioned method using cyclobutanecarbonitrile transformed (3R,4R)-4-phenyl-3-triethylenediamine-2-it is in the connection specified in the header:1H NMR (CDCl3) 0,18-0,61 (m, 15 NM), 1,66-2,22 (m, 6N), 3,61 (m, 1H), 4,89 (d, 1H, J=5.7 Hz), 4,94 (d, 1H, J=5.7 Hz), 7.03 is-to 7.18 (m, 5H).

Preparative example 6

(3R,4R)-1-neopentylglycol-4-phenyl-3-triethylenediamine-2-he

With the aforementioned method using pointillistic, (3R, 4R)-4-phenyl-3-triethylenediamine-2-he turned in the connection specified in the header:1H NMR (Dl3) of 0.39 to 0.97 (m, 24N), to 3.73 (d, 1H, J=10,2 Hz), 3,90 (d, 1H,SS="ptx2">

To a solution of 10-deacetylbaccatin (47,4 g, 87 mmol) in anhydrous N,N-dimethylformamide (DMF) (500 ml) was added imidazole (47 g, 691 mmol) at room temperature. The solution was stirred for 10-15 minutes until a clear solution is formed. To the reaction mixture are added 58 ml, 332 mmol, diisopropylaniline. The reaction mixture was stirred at room temperature for 16 hours was Added to the solution for the additional number of diisopropylaniline (6 ml) and the reaction mixture was stirred for 60 min. Liquid chromatography high resolution shows completion of the reaction. To this mixture was added methanol (36 ml) and was stirred for 60 minutes the Reaction was stopped and the mixture was diluted with tert.butylmethylamine (TVMA) (500 ml) and water (200 ml). The layers were separated, washed the organic phase with brine (250 ml), dried (sodium sulfate) and evaporated, getting trisilalkane derived baccatin I (91 g, >100% yield) as a white amorphous product, which was used in the next stage without further purification.

ESELRMS M+calculated for C50H84O13Si3: 977 found 977.

2) Synthesis derived baccatin 2

To the solution derived baillargeon (35 ml, 320 mmol). Observed the precipitation of the compounds. The reaction mixture (suspension) was stirred for 0.5 hours at a temperature of 0°C. the Solid product was filtered and washed with cold DMF (3 × 150 ml). After drying by air solid product was again dissolved in TWO (700 ml) and the resulting solution washed with water (3 × 200 ml), brine (250 ml) and dried (sodium sulfate). The solution was filtered through silica filter. Removal of the solvent under vacuum was allowed to get 2 exit 77% (70 g).

ESELRMS M+calculated for C50H90O13Si4: 1035 found 1035.

3) Synthesis derived baccatin 3

To a stirred solution of 2 (to 66.3 g, 64 mmol) in toluene (680 ml) at a temperature of -34°C was added dropwise Red-Al (50 ml, 160 mmol, 65 wt.%-s ' solution of bis(2-methoxyethoxy)aluminiumhydride in toluene) for 10 minutes, the Reaction mixture was heated to -25°C and was stirred for 1.5 hours To the reaction mixture was added dropwise methanol (62 ml) at an internal temperature of -20 to -25°C. the Solution was diluted, TWO (500 ml) was added 1 N solution of sodium hydroxide (60 ml) and brine (60 ml). The solution was stirred for 30 minutes. To the mixture was added celite (12 g), was stirred for 10 minutes and filtered CETEM solution was passed through the gasket, made of silica, before removing the solvent. There was obtained white solid with a yield of 97% (62 g).

ESILRMS M+calculated for C50H88O12Si4: 993, found: 993.

4) Synthesis derived baccatin 4

In an argon atmosphere to a solution of 3 (62 g, 62 mmol) in anhydrous tetrahydrofuran (THF) (600 ml) at -60°With dropwise added LHMDS (bis(trimethylsilyl)amide lithium) (125 ml, 125 mmol, 1M solution in THF). The solution was stirred for 15 minutes followed by the addition of methylchloroform (9 ml, 116 mmol), the internal temperature of the solution was maintained equal to -60°C. the Reaction mixture was slowly heated to 0°C and was stirred for 3 hours. After completion of the reaction was added saturated ammonium chloride (300 ml). The reaction mixture was extracted with TWO (100 ml). The organic layer was washed with saturated ammonium chloride (200 ml), water (200 ml), brine (200 ml), dried (sodium sulfate) and evaporated to obtain 4 in the form of oil (67 g, > 100%). Technical product used in the next stage without additional purification.

ESILRMS M+calculated for C52H90O14Si4: 1051, found: 1051.

5) Synthesis derived baccatin 5

hydrofluoric acid (56 ml, 344 mmol) at room temperature. The reaction mixture was stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (350 ml) and washed with water (200 ml), brine (200 ml), dried (sodium sulfate) and evaporated to obtain 5 (43 g, yield >100% technical product). Re-suspension of technical compounds in a mixture of hot ethyl acetate (350 ml) and hexanol (50 ml) resulted in the receipt of net 5 with the release of 90%.

ESILRMS M+calculated for C29H36ABOUT11: 560, found: 560.

6) Synthesis derived baccatin 6

To mix the solution derived baccatin 5 (32 g, 57 mmol) and imidazole (11,7 g, 172 mmol) in DMF (220 ml) at -65°With the added diisopropylethylamine (26,8 ml) in an argon atmosphere. The temperature of the reaction mixture was maintained equal to -60°C and the mixture was stirred for 2 hours. After completion of the reaction (HPLC) solution was added imidazole in methanol (11,7 g of imidazole dissolved in 35 ml of methanol) and stirred solution at 0°C for 30 minutes the Mixture was extracted with TWO (500 ml). The organic phase is washed with water (4 × 150 ml), dried (sodium sulfate) and evaporated to obtain technical 6 (45 g). Technical product was then dissolved in acetonitrile (150 m is solid (34 g, yield 84%).

ESILRMS M+calculated for C96H57O12Si: 704, found: 704.

7) Synthesis derived baccatin 7

4-deazetil-7-[bisopropol(methoxy)]silyloxy-4-methoxycarbonyl]-baccatin

To the solution derived baccatin 6 (33,2 g, 47 mmol) in DMF (200 ml) was added dropwise LHMDS (61,2 ml of 61.2 mmol) at -43°C. the Reaction mixture was stirred for 15 minutes followed by the addition of acetic anhydride (5.8 ml, 63 mmol). The mixture was stirred for 30 minutes at -40°C. was Added acetic acid (3.6 ml) and removed the cooling bath. The reaction mixture was extracted with TWO (300 ml). The organic layer was separated and washed with water (3 × 150 ml), brine (150 ml), dried (sodium sulfate) and evaporated to obtain technical product. Purification of this compound was carried out by crystallization from a mixture TNR:heptane (1:6). Of 40 g was obtained 21 g of crystalline derivative baccatin 7 (yield 60%).

ESILRMS M+calculated for C38H54ABOUT13Si: 746 found: 746.

Example 1. Compound Ia

3'-t.butyl-3'-N-tert.butyloxycarbonyl-4-deazetil-3'-devinyl-3'-N-Dibenzoyl-4-O-methoxycarbonylethyl

Rast is sapropel(methoxy)]silyloxy-4-methoxycarbonylamino (1.13 g, of 1.52 mmol) in dry THF (100 ml) under nitrogen atmosphere was cooled to -50°C and the solution was added LiHMDSA (1.97 ml, 1.3 equiv, 1.0 M in THF). After 5 minutes, put the mixture in a bath which was kept at a temperature of from -35 to -30°C for 20 hours and then at -25°C for 24 hours. Then the reaction was interrupted saturated aqueous NH4Cl and extracted with a mixture of EtOAc and hexane (1:1). The organic extracts were washed with brine and dried (Na2SO4). The solvent was removed and the residue was subjected to chromatography (radial chromatography on a plate of silica gel with a thickness of 6 mm; gradient elution 5-20% EtOAc in hexane) to give 1.55 g 3'-t.butyl-3'-N-tert.butyloxycarbonyl-7-[bisopropol-(methoxy)]silyloxy-4-deazetil-3'-devinyl-3'-N-Dibenzoyl-4-O-methoxycarbonyl-2'-criticallyacclaimed in the form of a mixture 2',3'-diastereomers. This mixture was dissolved in dry THF (60 ml) was added Triethylenetetramine (0,92 ml, 4 EQ). After 22 hours at room temperature the reaction mixture was neutralized with a saturated aqueous solution Panso3and then was extracted with EtOAc. The organic extracts were washed with brine, dried (Na2SO4) and remove the solvents. The residue was subjected to chromatography (radial chromatography is investing) 210 mg(18%): 2'S 3'R-3'-t.butyl-3-N-tert.butyloxycarbonyl-4-deazetil-3'-devinyl-3'-M-Dibenzoyl-4-O-methoxycarbonylethyl {1H NMR (CDCl3) l-04(s,9H), l,13(s,3H), l,20(s,3H), of 1.37 (s, 9H), of 1.65 (s, 1H), of 1.66 (s, 3H), 1,84-of 1.93 (m, 2H), 2,17 (s, 3H), of 2.25 (s, 3H), by 2.55 (m, 3H), 3.00 and (d, 1H, J=6.5 Hz), 3,74 (d, 1H, J=10,8 Hz), with 3.79 (d, 1H, J=6,9 Hz) to 3.92 (s, 3H), 4,16 (d, 1H, J=8.5 Hz), 4,33 (d, 1H, J=8.5 Hz), 4,42 (m, 1H), 4,54 (d, 1H, J=6.5 Hz), to 4.87 (d, 1H, J=a 10.6 Hz), free 5.01 (d, 1H, J=7,7 Hz), of 5.68 (d, 1H, J=7,0 Hz), USD 5.76 (m, 1H), 6,32 (s, 1H), 7,44-with 8.05 (m, 5H); LRMS (ESI) 846 [(M+H)+]} and 668 mg (56%) of the compound indicated in the heading {1H NMR (CDCl3) of 1.07 (s, N), to 1.14 (s, 3H), 1,24 (s, 3H), of 1.33 (s, 9H), of 1.66 (s, 4H), of 2.23 (s, 3H), 2,38 at 2.59 (m, 4H), 3,11 (d, 1H, J=5.8 Hz), of 3.77 (d, 1H, J=11,1 Hz), 3,82 (d, 1H, J=7,0 Hz), of 3.96 (s, 3H), 4,20 (d, 1H, J=8.6 Hz), 4,33 (d, 1H, J=8.6 Hz), 4,39 (m, 1H), 4.53-in (d, 1H, J=5.4 Hz), 4,88 (d, 1H, J=a 10.6 Hz), to 4.98 (d, 1H, J=7.9 Hz), 5,69 (d, 1H, J=7,1 Hz), 6,03 (m, 1H), 6,28 (s, 1H), 7,40-8,11 (m, 5H); LRMS (ESI) 846 [(M+H)+]}.

Example 2. Compound Ib

3'-N'-t.butyloxycarbonyl-4-deazetil-3'-devinyl-3'-N-desbenzoyl-3'-isopropyl-4-O-methoxycarbonyl-paclitaxel

With the aforementioned method (+)-CIS-1-tert.butyloxycarbonyl-4-isopropyl-3-triethylsilyl-azetidin-2-he combined with 4-deazetil-7-[bisopropol-(methoxy)]silyloxy-4-O-methoxycarbonylamino.

After removing the protection and chromatographic selection received the connection specified in the header.

1H NMR (CDCl3+D2O) of 1.03 (d, 3H, J=6,7 Hz) of 1.09 (d, 3H, J=6,7 Hz), 1.14 in (s, 3H), 1,24 (s, 3H), of 1.31 (s, 9H), of 1.66 (m, 3H), 1,83-2,02 (m, 5H), 2,24 (s, 3HH), to 4.98 (d, 1H, J=7.8 Hz), 5,69 (d, 1H, J=7,0 Hz), 6,11 (m, 1H), 6,28 (s, 1H), 7,45-to 8.12 (m, 5H); LRMS (ESI) 832 [(M+N)+].

Example 3. Compound IC

3'-N-neopentylene-4-deazetil-3'-N-Dibenzoyl-4-O-methoxycarbonyl-paclitaxel

A solution of (3R,4R)-1-neopentylglycol-4-phenyl-3-methylselenocysteine-2-it (525 mg, 1.4 EQ) and 4-deazetil-7-[bisopropol(methoxy)]silyloxy-4-O-methoxycarbonylamino (523 mg, 0.7 mmol) in dry THF (15 ml) was cooled to a temperature of -50°C and under stirring solution was added LiHMDSA (from 0.84 ml, 1.2 equiv, 1.0 M in THF). After 40 min the reaction mixture was allowed to warm to 0°C. After 1.5 hours the reaction was interrupted saturated aqueous NH4CL, the reaction mixture was extracted with EtOAc. The organic extract was washed with a saturated aqueous solution of NH4Cl, water, brine and dried (Na2SO4). Removal of solvent followed by chromatography on a column of silica gel (elution with mixtures of from 0 to 20% EtOAc in hexane) was allowed to get 2,78 mg(54%) 3'-N-neopentylglycol-7-[bisopropol(methoxy)]-silyloxy-4-deazetil-3'-N-mebensole-4-O-methoxycarbonyl-2'-triethylchlorosilane. This substance was collected and processed by criticalintegrated (0,161 ml, 4 EQ) in dry THF (6 ml) and left to stand prnow the mixture was extracted with EtOAc. The organic extracts were washed with brine and dried (PA2SO4). Removal of solvent and chromatography on a column of silica gel (gradient elution, a mixture of 20-50% EtOAc in hexane) resulted in the receipt of 151 mg (71%) of the connection specified in the header;1H NMR (Dl3) 0,96-2,58 [N, including 0.96 (s, N), to 1.14 (s, 3H), 1,24 (s, 3H), of 1.66 (s, 3H), of 1.84 (s, 3H), of 2.23 (s, 3H)], to 3.58 (br s, 1H), of 3.77 (s, 3H), 3,80 (d, 1H, J=5.5 Hz), 4,19 (d, 1H, J=8,3 Hz) to 4.33 (d, 1H, J=8.7 Hz), 4,36 (m, 1H) and 4.65 (d, 1H, J=2.0 Hz), of 4.95 (d, 1H, J=8.5 Hz), to 5.58 (dd, 1H, J=2,3, 8,8 Hz), 5,69 (d, 1H, J=7,0 Hz), 6,11 (d, 1H, J=8,9 Hz), 6,16 (m, 1H), 6,27 (s, 1H), 7,29-to 8.12 (m, 10H); LRMS (ESI) 864 [(M+N)+].

Example 4. Connection Id

3'-N-cyclobutyl-4-deazetil-3'-N-Dibenzoyl-4-O-methoxycarbonylethyl

With the aforementioned method, using (3R,4R)-1-cyclobutyl-4-phenyl-3-triethylenediamine-2-it, 4-deazetil-7-[bisopropol(methoxy)]silyloxy-4-O-methoxycarbonylmethyl turned specified in the header of the product.1H NMR (CDCl3) 1,14-2,53 [m, 27H, including to 1.14 (s, 3H), 1,25 (s, 3H), 1,67 (s, 3H), of 1.84 (s, 3H), 2,24 (s, 3H)], 301 (m, 1H), of 3.56 (br s, 1H), 3,81 (s, 3H), 3,82 (m, 1H), 4,20 (d, 1H, J=8,4 Hz), 4,34 (d, 1H, J=8.5 Hz), 4,37 (m, 1H), and 4.68 (d, 1H, J=2.3 Hz), 4,96 (d, 1H, J=8.6 Hz), to 5.58 (dd, 1H, J=2,4, and 9.0 Hz), 5,70 (d, 1H, J=7,0 Hz), 6,16 (m, 2H), 6,27 (s, 1H), 7,29-to 8.14 (m, 10H); LRMS (ESI) 848 [(M+N)+].

Example 5. Connection S

3'-t.butyl-3'-N-cyclohe method for cyclohexyloxycarbonyl, 3'-t.butyl-3-N-tert.butyloxycarbonyl-4-deazetil-3'-dephenyl-3'-N-Dibenzoyl-4-O-methoxycarbonylethyl turned into a product that is listed in the title:1H NMR (CDCl3+D2O) 1,10-2,61 [N, including of 1.10 (s, 9H), of 1.16 (s, 3H), 1.26 in (s, 3H), 1.69 in (s, 3H), of 1.95 (s, 3H), and 2.26 (s, 3H)], a-3.84 (m, 2H), 3,99 (s, 3H), 4,23 (d, 1H, J=8.6 Hz), and 4.40 (m, 3H), of 4.57 (s, 1H), 5,02 (m, 2H), the 5.7 (d, 1H, J=7,08 Hz), the 6.06 (m, 1H), 6.30-in (s, 1H), 7,46-8,13 (m, 5H); LRMS (ESI) 872 [(M+N)+].

Example 6. Connection If

3'-t.butyl-4-deazetil-3'-dephenyl-3'-N-desbenzoyl-3'-N-neopentylene-4-O-methoxycarbonylethyl.

Using the above methodology and tert.butylcatechol, 3'-t.butyl-3-N-tert.butyloxycarbonyl-4-deazetil-3'-dephenyl-3'-N-Dibenzoyl-4-O-methoxycarbonylethyl turned in the connection specified in the header:1H NMR (CDCl3+D2O) 1,00-2,56 [N, including a 1.00 (s, 9H), is 1.11 (s, 9H), of 1.16 (s, 3H), 1.26 in (s, 3H), 1.69 in (s, 3H), 1.91 a (s, 3H), and 2.26 (s, 3H)], 3,83 (d, 1H, J=7,1 Hz), 3,98 (s, 3H), 4,17 (d, 1H, J=10.1 Hz), 4.26 deaths (d, 1H, J=8,8 Hz), 4,37 (m, 2H), 4,55 (s, 1H), 5,00 (d, 1H, J=7.5 Hz), 5,73 (m, 2H), 6,02 (m, 1H), 6,29 (s, 1H), 7,45-8,13 (m, 5H); LRMS (ESI) 844 [(M+N)+].

Example 7. Compound Ig

4-deazetil-3'-N-desbenzoyl-3'-N-tert.butoxycarbonyl-4-O-methoxycarbonyl-paclitaxel.

With the aforementioned method, using (3R,4R)-1-tert.butoxycarbonyl-4-Fe), 6,27 (s, 1H), to 6.19 (m, 1H), of 5.68 (d, J=6,9 Hz, 1H), 5,35-of 5.29 (m, 2H), equal to 4.97 (d, J=7.7 Hz, 1H), 4,63 (d, J=3,9 Hz, 1H), 4,27-4,37 (m, 1H), 4,25 (AB q, J=8,8 Hz, J=47,7 Hz, 2H,), 3,85-3,81 (m, 4H), 3,40 (d, J=5,1 Hz, 1H), 2,59-of 1.03 (m, M, including singlets at 2,24, 1,87, 1,71, 1,27, 1,14, 3H each, 1,32, N).

Example 8. Compound Ih

4-deazetil-3'-N-desbenzoyl-3'-N-n-butoxycarbonyl-4-O-methoxycarbonylethyl.

With the aforementioned method, using (3R,4R)-1-n-butoxycarbonyl-4-phenyl-3-triethylenediamine-2-he got the connection Ih:1H NMR (300 MHz, Dl3) 8,11 (d, J=7,4 Hz, 2H), 7,62-7,29 (m, 10H), 6,27 (s, 1H), 5,69 (d, J=7,0 Hz, 1H,), 5,41 (abq, J=47,4 Hz, 9.4 Hz, 2H), equal to 4.97 (d, J=7,0 Hz, 1H), of 4.66 (br s, 1H), to 4.38-4,32 (m, 1H), 4.26 deaths (abq, J=45,0 Hz, 8.6 Hz, 2H), a 3.83 (s, 3H), 3,42 (brd, J=4,1 Hz, 1H), 2,59 to 2.35 (m, 4H), 2,24 (m, 3H), of 1.86 (s, 3H), 1,67 (s, 3H), of 1.65 (d, J=33,0 Hz, 3H), 1,67 (s, 3H), 1,51 to 1.47 (m, 2H), 1,24 (s, 3H), 1.14 in (s, 3H), or 0.83 (m, 3H).

The data of elemental analysis: calculated for C45H55NO16: 62,42; N 6,40; N 1,62; found: 62,28; N. Of 6.45; N, 1,55.

Example 9. Connection Ij

3'-N-desbenzoyl-3'-N-cyclobutanecarbonyl-3'-dephenyl-3'-t.butyl-4-deazetil-4-methoxycarbonylmethylene.

A solution of 3'-N-desbenzoyl-3'-N-tert.butyl-3'-dephenyl-3'-t.butyl-4-deazetil-4-methoxycarbonylmethyl (2.30 g, of 2.72 mmol) in DCM (15.0 ml) was treated triperoxonane acid (15.0 ml) and premesis3in 150 ml of water. The phases were separated and concentrated the organic layer in vacuo. The product can be purified by chromatography on a column of silica gel with elution with a mixture of 4% methanol/DCM, but is usually used without purification. Technical 3'-N-desbenzoyl-3'-dephenyl-3'-t.butyl-4-deazetil-4-methoxycarbonylmethylene was dissolved in ethyl acetate (15.0 ml) and treated with saturated solution of NaHCO3(15.0 ml). Added cyclobutanecarbonitrile (460 μl, 4,08 mmol, 1.5 EQ) and stirred vigorously two-phase mixture at room temperature for 20 minutes. The mixture was diluted with ethyl acetate and separated phases. The organic phase was washed with saturated Panso3and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuum. Purification by preparative chromatography with reversed phase (elution with a mixture of 20% acetonitrile/water over 5 minutes, then with a mixture of 60% acetonitrile/water over 45 min, then isocratic conditions for 45 min at a speed of expiration of 250 ml/min) resulted in a compound that is specified in the header (1.47 g, yield 65% with a purity of 97% (IHVR)) in the form of a white amorphous material with the following physical properties:1H NMR (Dl313With NMR (CDCl3, 75 MHz) 203,70, 174,99, 174,93, 171,46, 166,89, 153,21, 142,54, 133,74, 133,20, 130,22, 129,81, 128,72, 84,13, 83,21, 78,92, 76,09, 75,68, 74,94, 73,39, 72,06, 70,17, 58,36, 57,73, 56,03, 51,07, 45,74, 43,34, 39,91, 35,94, 35,47, 27,37, 26,85, 25,60, 25,44, 22,12 20,95, 18,29, 14,95, 9,72; LRMS (ESI) 828,51 ((M+1)+, 100%); 886,57 ((M+NH4ACN)+, 15%); 826,48 ((M-1)-; 100%).

Example 10. Connection Ik

3'-N-desbenzoyl-3'-N-(2-furoyl)-3'-dephenyl-3'-t.butyl-4-deazetil-4-methoxycarbonylmethylene.

Get this connection, as described above. Get it (2,13 g, 73% yield with a purity of 98% (IHVR)) in the form of a white amorphous product with the following physical properties:1H NMR (Dl3, 300 MHz) 8,15-8,08 (m, 2H), of 7.64-7,56 (m, 1H), 7,52-7,25 (m, 3H), 7,03 (dd, J=0.6 Hz, J=3,4 Hz, 1H), 6,78 (d, J=10,2 Hz, 1H), 6.48 in (dd, J=1.8 Hz, J=3.5 Hz, 1H), and 6.25 (s, 1H), the 6.06 (dd, J=7,6 Hz, J=8,9 Hz, 1H), 5,70 (d, J=7,0 Hz, 1H), 5,00 (dd, J=1.9 Hz, J=9.4 Hz, 1H), 4,40-4,32 (m, 3H), 4,23 (d, J=8.6 Hz, 1H), of 4.05 (s, 3H), 3,48 (d, J=4.5 Hz, 1H), 2,60-of 2.50 (m, 2H), of 2.38 (dd, J=3.3 Hz, J=8,8 Hz, 1H), 2,23 (s, 3H), 2.05 is (s, 1H), 1,95-of 1.85 (m, 1H), is 1.81 (s, 3H), by 1.68 (s, 3H), 1,21 (s, 3H), 1.14 in(s, 12H);13With NMR (CDCl3, 75 MHz) 203,71, 174,23, 171,55, 167,06, 158,22, 153,06, 147,65, 144,30, 142,53, 133,93, 133,36, 130,32, 129,42, 128,88, 114,95, 112,51, 84,20, 83,48, 79,06, 77,�-1)-, 100%).

Biological properties

Another aspect of this invention relates to a method of inhibiting tumors in humans and/or other mammal by oral administration in the body containing the tumor, anticancer effective amount of the compounds of formula I.

The materials and techniques used for in vivo testing of oral input taxan, listed below.

Materials

Animals. Normal or atipicheskie (“Nude”) mice and naked rats, they were implanted subcutaneously (sc) chopped tumor or tumor fragments. Murine tumor was implanted in normal mice, human tumor - naked mice or rats. The tumor. Used tumours were included, most commonly, a murine lung carcinoma, M109, murine carcinoma of the breast, MOM 16/S, human carcinoma of the ovary, A, tumors of the rectum human HCT-116 and HCT-116/pk. Compound I showed antitumor activity after oral administration in one or more of the above-mentioned models of tumors.

Methods of obtaining the results shown in table III

Experiments were performed using animicheskih (“Nude”) mice. Usually treatment of disenografco tumors of the ovary of a person. Usually there were 8 animals in the control groups also had 8 mice. The compound was administered at the dose indicated in table III, namely, 1 times a day through day five times (i.e q2d×5).

Treatment takanami performed oral with a probe using a medium consisting of 10% ethanol + 10% Cremophor EL + 80% water. The amount of fluid was 0.01 ml per gram of body weight of the mouse. Typical years of experience in the mice includes evaluating each of the test compounds, administered in three different doses. Antitumor activity was assessed by determining the size of the tumors in all affected by the treatment and control mice over time. Each animal is identified, the growth of tumors implanted in each animal was measured once or twice a week with a caliper. Was determined by the difference in time required to reach a given size (for example, 500 or 1000 mg) tumors in the treated treatment (T) and control (C) groups, and assessment of absolute and relative antitumor effects (for example, between connections) was made on the basis of the time delay achievement of tumors of a given size. Animals with tumors weighing 35 mg or less at the end of the experiment was called “cured”. About during which tumor size was doubled (TVDT) for tumors in control animals in each experiment. Activity in the tested group was defined as the activity that caused the delay of tumor growth (mean time to reach the tumor of a given size) relative to the growth of control tumors (namely, T-S), 3.32-fold compared with TVDT. The activity was expressed in log killing cells, which was equal to (T-C)/(TVDT × 3,32). Toxicity was determined by measuring the average body weight of all animals during the experiment, before and soon after any administration of medication. In addition, it was believed that animals have died as a result of harm caused by the treatment, if they died before any death in animals of the control group with tumors that are smaller than the specified value. No outcomes, no Declaration about the activity were not taken into account for a particular group, if more than one animal in this group died as a result of treatment.

All compounds listed in table III, were characterized by oral administration of antitumor activity in models of tumor ScM109 implanted mice, which was considered equivalent antitumor activity of paclitaxel, administered intravenously, in accordance with the optimal scheme of administration and dosage.

In vivo activity of orally Akti is in Ia-Ik had considerable oral antitumor activity. Significant antitumor activity was defined as approximately one log cell death. This is the opposite of the results that would be observed for compounds that do not have oral activity, such as paclitaxel, which is the active ingredient in commercially available anticancer drugs TAXOL® is administered intravenously and is not introduced orally, because it is not active in this introduction.

In the treatment of various tumors compound of formula I according to the invention can be used a method similar to that used for paclitaxel, for example, see Physician's Desk Reference, 49thEdition, Medical Economics, p. 682, 1995. Dosage, method and scheme for the introduction of compounds according to the invention is not limited to; oncologist, a specialist in the treatment of tumors will be able without additional experiments to find the scheme of introduction of the compounds according to the invention. Thus, the compound of formula I may be introduced by any method, parenteral or oral. Parenteral administration includes intravenous, intraperitoneal, vnutrishkolnoe and subcutaneous administration.

The dose used to implement the methods according to the invention, are doses that allow preventive Leonenko connections and personal characteristics of the patient. In General use doses that are therapeutically effective for the treatment of disorders caused by abnormal cell proliferation. The products according to the invention can enter as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to a relatively high or low dose, and then they entered a small dose or even stops the introduction of the connection. When intravenous dose may, for example, be from about 20 to about 500 mg/m2for 1-100 hours When orally administered dose can be 5-1000 mg/kg/day. Your dose will vary depending on the specific composition, method of administration, the specific places of the body and the type of tumor. In determining the dose you should take into account many factors modifying drug action, including age, weight, sex, diet, and physical condition of the patient.

The invention also provides for pharmaceutical preparations (compositions) containing an antitumor effective amount of the compounds of formula I in combination with one or more pharmaceutically acceptable carriers, excipients, rabbae of paclitaxel or its derivatives can be found, for example, in U.S. patents 4960790 and 4814470, given the examples you can obtain compositions with the compounds according to the invention. Additional examples of compositions of paclitaxel can be found in the references cited above. For example, the compound of formula I may be in compositions in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premixes, and in other suitable forms. You can also prepare sterile solid compositions, for example, dried by freezing, and, if desired, in combination with other pharmaceutically acceptable excipients. Such solid compositions can be reconstituted by adding sterile water, saline solution or a mixture of water and an organic solvent, such as propylene glycol, ethanol, etc. or other sterile environment, input immediately before use by parenteral injection.

Typical pharmaceutically acceptable carriers are, for example, mannitol, urea, dextrans, lactose, potato and maize starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethylcellulose, polyvinylpyrrolidone, calcium carbonate, etiloleat, isopropylmalate may also contain non-toxic auxiliary substances, such as emulsifiers, stabilizers, wetting, etc., for example, sorbitanoleat, triethanolamine, polyoxyethylenated, glyceryltrinitrate, dioctylsulfosuccinate sodium, etc.

1. The compound of formula I or its pharmaceutically acceptable salt

where R denotes phenyl, isopropyl or tert-butyl;

R1denotes-C(O)RZin which RZmeans (CH3)3CO-, (CH3)3CLO2-, CH3(CH2)3Oh, cyclobutyl, cyclohexyloxy or 2-furyl;

R2denotes CH3C(O)O-.

2. Connection on p. 1, selected from the group consisting of

3. Compound Ia under item 2.

4. Connection on p. 2, selected from the group consisting of

5. Connection on p. 1, characterized in that R represents tert-butyl.

6. Antitumor pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of paragraphs.1-5 and a pharmaceutically acceptable carrier.

7. The composition according to p. 6, characterized in that the connection is any connection on p. 2 and the composition additionally contains cremophor, atanasie by p. H.

9. The composition according to p. 6, intended for oral administration to a mammal.

10. Method of inhibiting tumor growth in the body of a mammal, comprising an introduction to the specified mammal the compound according to any one of paragraphs.1-5.

11. The method according to p. 10, characterized in that the introduction is carried out orally.

12. The method according to p. 11, characterized in that the said connection is a connection on p. 2.

13. The method according to p. 12, characterized in that the said connection is a connection on p. 3.



 

Same patents:

The invention relates to a method for producing compounds of formula I:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid, R1means phenyl or a straight or branched alkyl or alkenyl and R2means hydrogen or acetyl, which comprises: (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III:

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or a straight or branched alkyl or alkenyl, obtaining the compounds of formula IV:

(C) removing trichloroethylene protective groups of the compounds of formula IV with connection inflectional acetylation of the hydroxyl group in position 10 of the compounds of formula V to obtain the compounds of formula VI:

e) acid hydrolysis oxazolidinone ring compounds of the formula VI to obtain the compounds of formula I

The invention relates to a new method of acylation of the hydroxyl group taxane, including processing taxane allermuir agent selected from the group consisting of anhydrides, dicarbonate, thiodicarb and isocyanate in the reaction mixture containing less than one equivalent of base for each equivalent taxane, preferably 1:1-1:100, with the formation of the C(10) acylated taxane

The invention relates to a new method of obtaining Taxol, its analogs and their intermediates, including the stage of protection of the hydroxy-group at C-7 position 9-dihydro-13-deacetylbaccatin III a suitable protecting group; oxidation of the hydroxy-group in position C-9; and attaching a suitable side chain at position C-13

The invention relates to a new method of obtaining paclitaxel - anticancer agent and intermediate products for its partial synthesis: the compound of formula (II)

< / BR>
where a represents a group

< / BR>
R1the protection group of the hydroxyl or hydrogen atom, and R2is a hydrogen atom,

and the compound of formula (III)

< / BR>
where each of the groups R4and R5- aryl, and each of the groups R6and R7- halogenated methyl

The invention relates to chemistry, in particular to pharmaceutical chemistry, and can be used for the production of anticancer drug

Derivatives taxane // 2188198

The invention relates to a derivative of 7- (alkoxycarbonyl-substituted) -10-hydroxy-taxan following formula 3b:

< / BR>
in which R1, R2, R4, R5, R6and R14defined above
The invention relates to medicine, Oncology
The invention relates to medicine, in particular to cancer, and can be used in the treatment of resectable, including locally common forms of lung cancer

The invention relates to compositions and methods for the treatment and prevention of such diseases and conditions as graft rejection, surgical adhesions, inflammatory bowel disease, nasal polyps, and includes delivery to the site of inflammation antimicrotubular agent is paclitaxel, or an analogue or derivative
The invention relates to medicine, in particular to cancer, and can be used in the treatment of locally common forms of lung cancer, including inoperable

The invention relates to compounds of formula (I) or (II)

or their pharmaceutically acceptable salts, where Y and Z each for each case independently represents a D - or L-natural or unnatural-amino acid; n in each case independently is 0 or 4, (I) provided that both n cannot simultaneously be 0; and 0 or 4 (II)

moreover, these amino acids (I) are chain: X1-X2-X3-X4where X1represents Tyr or Trp, which may be protected by a BOC group; X2represents D-Trp; X3represents Lys, which may be protected by a BOC group; X4is a Nal, Tyr or Thr; m is 0; a represents N or R1b means HE or OR1; (II) X1is a natural or non-natural D - or L-isomer of Phe, Trp or Tyr, where in the case when X1is Tyr, an aromatic ring in its side chain optionally substituted by R6; X2is a D - or L-isomer of Trp; X3represents Lys; X4represents Opticheskie ring, disposed in its side chain may be optionally substituted by R6or in the case when X4is either Ser or Thr, the oxygen atom located in its side chain, optionally may be substituted by one or more R1

The invention relates to the objects of the invention characterized in the claims, i.e

The invention relates to medicine, namely to compositions and methods for potentiating the therapeutic effects of interferon, and can be used for preparation of medicines interferon for use in medicine and veterinary medicine

The invention relates to medicine, in particular to Oncology, and for the treatment of various cancers
The invention relates to medicine, in particular to Oncology
The invention relates to a derivative of platinum tetrachloride, and method of production thereof

The invention relates to compositions and methods for the treatment and prevention of such diseases and conditions as graft rejection, surgical adhesions, inflammatory bowel disease, nasal polyps, and includes delivery to the site of inflammation antimicrotubular agent is paclitaxel, or an analogue or derivative
Up!