Farnesyltransferase inhibitors

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new inhibitors of farnesyltransferase of the formula (I):

wherein R1 means hydrogen atom (H), group of the formula R5C(O)- wherein R5 means phenyl, pyridyl or N-methylpiperidine; R2 means hydrogen atom (H), isopropyl, cyclopentyl or N-methyltetrahydropyridyl; R3 means hydrogen atom (H), halogen atom; R4 means hydrogen atom (H), halogen atom; L means -CH2-Z- wherein Z means NH; Y means sulfur atom (S), S(O) or S(O)2; or its salt. Compounds of the formula (I) inhibit activity of enzyme, farnesyl(protein)transferase, that allows their using in pharmaceutical composition in cancer treatment.

EFFECT: valuable medicinal properties of inhibitors.

18 cl, 3 tbl, 3 sch, 6 ex

 

This invention relates to compounds that inhibit farnesiana gene products via inhibition of the enzyme, farnesyltransferase (FPT-Aza, APTase). In addition, the invention relates to methods of making the compounds, pharmaceutical compositions and to methods for treating diseases, particularly cancer, which is mediated through farnesiana.

Cancer, as it entails a change in expression or function of genes that regulate the growth and differentiation of cells. Not wanting to delve into theoretical discussion, the following text sets out fundamental scientific information related to ras in cancer. Genes ras often mutate in tumors. Genes encode proteins ras that binds the GTP-independent (GTP, GTP), which is reputed to be involved in signal transduction, proliferation and malignant transformation. Genes N-, and N-ras were identified as mutant forms of ras (Barbacid M, Ann. Rev. Biochem. 1987, 56:779-827). For biological activity required posttranslational modification of ras protein. Farnesiana ras catalyzed FPT-Azoy, as it represents a significant stage in the processing of ras. It occurs by transferring farnesenes group farnesylpyrophosphate (FPP, FPP) to the cysteine at the C-terminal of tetrapeptide ras in structural motif called the follower of the awn (block) SAAH. After additional post-translational modifications, including proteolytic cleavage at residue cysteine sequence SHAH and methylation of carboxyl cysteine, ras is able to attach to the cell membrane for signaling growth in the inner part of the cell. In normal cells, to stimulate the growth of cells, activated ras, deemed to be acting in combination with growth factors. In the case of tumor cells suggest that mutations in ras make it to stimulate cell division even in the absence of growth factors (Travis J, Science 1993, 260: 1877-1878), possibly due to the fact that ras is constantly in the activated GTP-th form, and not back in GDF (GDP)-inactivated form. Inhibition of farnesiana mutant gene products ras may block or reduce activation.

One class of known inhibitors farnesyltransferase is based on analogues of farnesylpyrophosphate; see, for example, European patent application EP 534546 from Merck. There are reports of inhibitors farnesyltransferase based on simulation sequence SHAH. Reiss (1990) in Cell 62, 81-8 reveals tetrapeptide, such as CVIM (Cys-Val-Ile-Met). James (1993) in Science 260, 1937-1942 reveals coworkers peptide-based connection benzodiazepine. Lerner (1995) in J. Biol. Chem. 270, 26802, and Eisai in international patent application WO 95/25086 RA is opening additional coworkers peptide compounds containing Cys as the first residue. European patent EP 696593 and PCT/GB96/01810 reveal additional inhibitors farnesyltransferase, including derivatives pyrrolidine. In addition, a number of inhibitors farnesiana ras disclosed and claimed in PCT/GB99/00369.

We have discovered that a particular substitution pyrrolidine provides special advantages in terms of inhibition farnesyltransferase.

In accordance with one aspect of the present invention features a compound of formula (I)

where R1and R2independently selected from H or a fragment prodrugs;

R3represents hydrogen or halogen;

R4represents hydrogen or halogen;

L represents-CH=CH - or-CH2-Z-, where Z is NH or O;

Y is S, S(O) or S(O)2;

or its salt.

Used herein, the term "alkyl" refers to groups with straight or branched chain, which may, unless otherwise agreed, to have from 1 to 20 and preferably from 1 to 6 carbon atoms. The term "aryl" includes phenyl. The term "halogen" includes fluorine, chlorine, bromine or iodine.

The term "heterocyclyl" or "heterocyclic" include groups having from 4 to 10 atoms in the ring, up to 5, of which are selected from oxygen, sulfur and nitrogen. Rings can be mono - or bicyclic and each number is CH may be aromatic or non-aromatic type.

If the valency of the ring, the nitrogen atoms can be substituted by either hydrogen or the group-Vice, such as alkyl. The sulfur atoms in the heterocyclic ring can be oxidized to S(O) or S(O)2group.

Examples of aromatic 5 - or 6-membered heterocyclic ring systems include imidazole, triazole, pyrazin, pyrimidine, pyridazine, pyridine, isoxazol, oxazol, isothiazol, thiazole and thiophene. 9 - or 10-membered bicyclic heteroaryl ring system is aromatic bicyclic ring system containing 6-membered ring condensed with either a 5-membered ring or another 6-membered ring. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, benzothiophen, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, predominate, pyrimidinemethanol, quinoline, isoquinoline, cinoxacin, hinzelin, phthalazine, cinnoline and naphthiridine.

Preferably monocyclic heteroaryl ring containing up to 3 heteroatoms, and bicyclic heteroaryl ring containing up to 5 heteroatoms. Preferred heteroatoms are N and S, especially n Usually attach heterocyclic ring with the other groups through carbon atoms. Suitable heterocyclic groups containing only N as hetaerae the atom, are pyrrole, pyridine, indole, quinoline, isoquinoline, imidazole, pyrazin, pyrimidine, purine and pteridine.

Hydrogenated or other substituted forms of the above-mentioned aromatic rings (which are non-aromatic), such as pyrolidine, piperidine or morpholine rings are examples of non-aromatic heterocyclic groups.

In this area there are various forms of prodrugs. As examples of such prodrug derivatives, see

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen;

c) N. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991);

d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988) and

(f) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

Suitable examples of the groups R1are hydrogen or a group of prodrugs of formula R5C(O)-, where R5represents optionally substituted aryl or heterocyclyl group. In particular, R5represents optionally substituted phenyl, optionally substituted pyridyl, optionally substituted furyl, optionally substituted isoxazol, optionally substituted tetrahydropyranyl or optionally substituted tetrahydrofuryl.

Suitable substituents for R5include alkylen the e group, such as methyl, haloalkyl groups such as trifluoromethyl, hydroxy, alkoxy, such as methoxy, or cyano.

Preferably R5represents phenyl, pyridyl or N-methylpiperidin.

Examples of groups of prodrugs for R2represent the in vivo degradable ester groups pharmaceutically acceptable complex ester which is cleaved in the human or animal with the receipt of the original acid. Accordingly, R2together with carboxypropyl to which it is linked, forms a pharmaceutically acceptable esters, such as C1-6alkalemia esters or C1-6cycloalkyl esters, for example methyl, ethyl, propyl, isopropyl, n-butyl or cyclopentyloxy; C1-6alkoxymethyl esters, for example methoxymethyl; C1-6alkanoyloxy esters, for example pivaloyloxymethyl; palidrome esters; C3-8cycloalkylcarbonyl1-6alkalemia esters, for example 1-cyclohexyloxycarbonyloxy; 1,3-dioxolane-2-ylmethylene esters, for example 5-methyl-1,3-dioxolane-2-ymetray; C1-6alkoxycarbonylmethyl esters, for example 1-methoxycarbonylmethylene; aminocarbonylmethyl esters and mono - or di-N-(Csub> 1-6alkyl) varieties, such as N,N-dimethylaminocarbonylmethyl esters and N-arylaminovinylketones esters, and pharmaceutically acceptable esters of optionally substituted heterocyclic groups.

Thus, in particular, R2selected from hydrogen, C1-4alkyl groups such as isopropyl, or cyclopentyl, or optionally substituted heterocyclic group, such as N-methyltetrahydrofolate.

R3represents respectively a halogen atom, in particular fluorine.

R4is preferably hydrogen or fluorine, in particular represents hydrogen.

The linking group L is preferably a group of the formula CH2-Z-, where Z is NH or O.

The group Y is preferably a group of S, S(O) or S(O)2. It should be understood that because some of the compounds videopreteen formula I may exist in optically active or racemic forms due to the presence of one or more asymmetric carbon atoms, the invention includes in its scope by definition any such optically active or racemic form which possesses the ability to inhibit FPT-ABC. Synthesis of optically active forms can be carried out by usual methods of organic chemistry well known in the art, n the example by synthesis from optically active starting compounds or by separation of the racemic form. Similar inhibitory ability against PPT-the basics can be estimated using standard laboratory methods mentioned below.

Chiral carbon atoms in the 2 and 4 positions pyrolidine ring in the formula I preferred in the (S) configuration.

Chiral carbon atom at the 2-position between the carbonyl and amine in the formula I preferred in the (S) configuration.

The compounds of formula I can form salts, which are included in the scope of the invention. Pharmaceutically acceptable salts are preferred, although can be used and other salts, for example, for the isolation or purification of compounds.

In the case where the compound contains a basic fragment, it can form pharmaceutically acceptable salts with a number of inorganic or organic acids, for example hydrochloric, Hydrobromic, sulfuric, phosphoric, triperoxonane, citric or maleic acid. In the case where the compound contains an acid fragment suitable pharmaceutically acceptable salt of the invention is a salt of an alkali metal such as sodium salt or potassium salt, alkaline earth metal, for example a salt of calcium or magnesium, ammonium salt or a salt with an organic base, which provides a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, Piperi the other, morpholine or Tris-(2-hydroxyethyl)amine. Specific salts of the compounds of the invention are the acetates, alkyl sulphonates, such as methyl - or ethylsulfonyl, fumarate, formate, succinate and gluconate.

A solvate such as a hydrate, also included in the scope of the invention and can be obtained well-known methods.

Specific examples of compounds of formula (I) shown in table 1.

Table 1
Conn.No.R1R2R3LY
1NNF-CH2NH-S
2N-CH(CH3)2F-CH2NH-S
3F-CH2About-S
4-CH(CH3)2F-CH2NH-S
5F -CH2NH-S
6-CH(CH3)2F-CH2NH-S
7-CH(CH3)2F-CH2About-SO2
8-CH(CH3)2F-CH2NH-S
9-CH(CH3)2F-CH=CH-S

In accordance with another aspect of the invention features a compound of formula (I) for use as a medicine.

In addition, in accordance with the invention is provided a compound of formula (I) for use in the manufacture of drugs for the treatment of diseases mediated through farnesiana ras, in particular cancer.

The connection is appropriately included in the pharmaceutical compositions for use in this way.

Thus, in accordance with another aspect of the invention features a pharmaceutical composition containing the above compound of formula (I) VM is the sty with a pharmaceutically acceptable diluent or carrier.

In accordance with another aspect of the invention features a method of treating diseases mediated through ras, especially cancer, by introducing an effective amount of the compounds of formula (I) to a mammal in need of such treatment.

In accordance with another feature of the invention features a compound of formula (I) or its pharmaceutically acceptable salt for use in the method of treatment of a human or animal therapeutic way.

In addition, the invention provides the use of compounds of formula (I) for the medicinal product for use in the treatment of diseases or conditions mediated through farnesiana, such as cancer.

Specific varieties of cancer which can be treated by a compound or composition of the present invention include

- carcinoma, including carcinoma of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin;

hematopoietic tumors of lymphoid origin, including acute lymphocytic leukemia, lymphoma b-cell and Burkitt's lymphoma;

hematopoietic tumors of myeloid origin, including acute and chronic myelogenous leukemias and promyelocytic leukemia;

- tumors of mesenchymal origin, including fibrosarcoma is and rhabdomyosarcoma, and

- other tumors, including melanoma, seminoma, teratocarcinoma, neuroblastoma and glioma.

The compounds of formula I are particularly useful for treatment of tumors having a high level ras mutations, such as tumors of the colon, lung and pancreas. With the introduction of the composition containing one of the compounds or combination of compounds) of the present invention, the growth of tumors in a host mammal is reduced.

The compounds of formula (I) can also be used to treat diseases other than cancer that may be associated with signal transduction pathways operating through ras, such as neurofibromatosis.

In addition, the compounds of formula (I) may be useful for treatment of diseases associated with SAH-containing proteins other than ras (for example, nuclear lamina and transducin), which also excision of modified enzyme, farnesyltransferase.

Compositions of the invention can be in a form suitable for oral use (for example, in the form of tablets, pellets, hard and soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example, in view of the finely ground powder or a liquid aerosol), for administration by insufflation (for example, in the form of finely ground powder) or for parenteral administration (for example, in the form of a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing or as a suppository for rectal dosing).

Compositions of the invention can be obtained by standard methods, using standard pharmaceutical excipients, well known in this field. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweetening agents, flavoring agents and/or preservatives.

Suitable pharmaceutically acceptable excipients for the compositions of the tablets include, for example, inert diluents, such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and dezintegriruetsja tools, such as corn starch or alginic acid; binding agents such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl - or propyl-p-hydroxybenzoate, and antioxidants, such as ascorbic acid. Composition for tablets can be coated or uncoated (shell) or to modify their raspadaemost and the subsequent absorption of the active component is and inside the gastrointestinal tract, or in order to improve their stability and/or appearance, in any case, the use of common tools for coatings and coating methods known in this field.

Compositions for oral administration can be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions generally contain the active ingredient in finely ground powdered form together with one or more suspendresume means, such as nutricosmetics, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabic gum; dispersing or moistening means, such as lecithin or condensation products of accelerated with fatty acids (for example, polyoxyethylenated), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit, such as polyox etilendiaminmonoatsetat, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of exit, such as polyethylenterephthalat. Aqueous suspensions may also contain one or more preservatives (such as ethyl - or propyl-p-hydroxybenzoate), antioxidants (such as ascorbic acid), coloring, flavoring and/or sweetening tools (such as sucrose, saccharin or aspartame).

Oil suspensions can be prepared by suspension of the active ingredient in a vegetable oil (such as peanut butter, olive oil, sesame oil or coconut oil) or mineral oil such as liquid paraffin). Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. To obtain a palatable oral preparation can be added sweetening tools, such as tools, listed above, and flavoring agents. Such compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for obtaining aqueous slurry by adding water, usually contain the active ingredient together with a dispersing or wetting agent, suspendium means and one or more canned nami. Examples of suitable dispersing or moisturizers and suspendida funds can serve as the above-mentioned respective means. In addition, there may be additional excipients, such as sweeteners, flavorings and colorings.

The pharmaceutical compositions of the invention can be in the form of emulsions of oil-in-water. The oil phase may represent vegetable oil, such as olive oil or peanut oil, or mineral oil, such as, for example, liquid paraffin, or a mixture of any of the aforementioned oils. Suitable emulsifying means can be, for example, resins of natural origin, such as the Arabian gum or tragacanth gum, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and anhydrides of exit (for example, servicemanual) and condensation products of the above partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening means, flavorings and preservatives.

Syrups and elixirs may be formulated with sweetening agents like glycerin, propylene glycol, sorbitol, aspartame or sucrose, and, in addition, may contain a means to mitigate, the preservative, romatizator and/or dye.

The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspensions, which can be obtained by known methods, using one or more of the appropriate dispersing or moisturizers and suspendida funds that have been mentioned above. In addition, the sterile injectable preparation may be in the form of an injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol.

The suppository formulations can be obtained by mixing the active ingredient with a suitable non-irritating excipient which is solid at normal temperature but becomes liquid at rectal temperature and therefore will melt in the rectum, while relieving drug. To suitable excipients include, for example, cocoa butter and polyethylene glycols.

Compositions for topical application such as creams, ointments, gels, and aqueous or oil solutions or suspensions can be obtained by combining in the composition of the active component with a normal, acceptable for local use, filler or diluent, using a conventional method well known in this field.

Compositions for administration by insufflation may be in the Orme finely ground powder, containing particles having an average diameter of, for example, 30 μm or much less, the powder itself includes or only the active component, either it is a powder of the active ingredient diluted with one or more physiologically acceptable carriers such as lactose. In this case, the powder for insufflation convenient to store in a capsule containing, for example, from 1 to 50 mg of the active ingredient, for use with turbomaster of this type, as used for insufflation of a known drug, sodium cromoglycate.

Compositions for administration by inhalation may be in the form of an aerosol under pressure adapted to the spraying of the active component or in the form of an aerosol containing finely ground solid or in the form of liquid drops. You can use a regular aerosol propellant, such as volatile fluorinated hydrocarbon or hydrocarbons, or aerosol device, respectively, are designed to spray a controlled amount of the active component.

Additional information on the structure can be found in Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

The number of the active component, which is combined with one or more excipients to obtain a one-time dose is stimulated form inevitably will vary depending on the host to be treated and the particular route of administration. For example, a composition intended for oral administration to humans, usually contains, for example, from 0.5 mg to 2 g of active funds, compounded with an appropriate and suitable amount of excipients which may vary from about 5 to about 98 wt.% of the total weight of the composition. Single dosage form typically contains from about 1 to about 500 mg of the active component. For more information on routes of administration and schemes of reception of medicines can be found in Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

According to well known principles of medicine the dose of the compounds of formula I in the case of its application for therapeutic or prophylactic purposes will naturally vary according to the nature and severity of the condition, age and sex of the animal or patient and the route of administration. As mentioned above, the compounds of formula I are useful for treating diseases or medical conditions that are caused solely or partly by the impact of farnesiana ras.

When using the compounds of formula I for therapeutic or prophylactic purposes it is usually injected to obtain the daily dose in the range, e.g. the measures from 0.5 to 75 mg per 1 kg of body weight, which take in a day, if required, in divided doses. In General, you can use lower doses in the case when using a parenteral route of administration. For example, for intravenous administration usually use a dose in the range, for example, from 0.5 to 30 mg per 1 kg of body weight. Similarly, in the case of administration by inhalation usually use a dose in the range, for example, from 0.5 to 25 mg per 1 kg of body weight. However, oral administration is preferable.

The compounds of formula (I)defined above may be used as the sole therapy or may involve, in addition to the compounds of the invention, one or more other substances and/or treatments. This combined treatment can be achieved through the simultaneous, sequential or separate introduction of individual components of the treatment. In the field of cancer medicine, to treat each patient with cancer, in practice, use a combination of different forms of treatment. In cancer medicine, in addition to the previously defined here treatment that inhibits the cell cycle, other(them) component(s) of such a combined treatment may be surgery, radiotherapy or chemotherapy. Such chemotherapy may cover three main categories of therapeutic is the means

(i) other means of inhibiting the cell cycle that operate by the same mechanism or mechanisms that differ from those described here previously;

(ii) cytostatic agents such as antioestrogens (e.g., fulvestrant, tamoxifen, toremifene, raloxifene, droloxifene, idoxifene), POCs (for example, megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, varsol, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bikalutamid, cyproterone acetate), agonists and antagonists LHVG (LHRH) (for example, goserelin acetate, leuprolide), inhibitors of testosterone-5α-dihydroorotase (for example, finasteride), antiinvasive means (for example, inhibitors of metalloproteinases, such marimastat, and inhibitors of receptor function plasminogen activator urokinase) and inhibitors of the function of a growth factor (such growth factors include for example platelet-derived growth factor and growth factor hepatocyte; such inhibitors include antibodies, growth factor, antibody growth factor receptor, tyrosine kinase inhibitors and inhibitors of the serine/threonine kinase) and

(iii) antiproliferative/antineoplastic means and their combinations used in cancer medicine, such as antimetabolites (for example antifolates like methotrexate, ftorpirimidinu like 5-torural is, analogues of purine and adenosine, cytosine arabinoside); antitumour antibiotics (for example anthracyclines like doxorubicin, daunomycin, epirubicin and idarubitsin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating means (for example, nitrogen mustard, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosamine, thiotepa); antimitoticescoy means (for example, vinylchloride, such vincristine, and taxoid, like Taxol, Taxotere); topoisomerase inhibitors (for example, epipodophyllotoxins like etoposide and teniposide, amsacrine, the topotecan). In accordance with this aspect of the invention provides a pharmaceutical product for the combined treatment of cancer, comprising a compound of formula (I)as defined above, and additional antitumor substance, as defined here previously.

Although the compounds of formula (I) are of value mainly as a therapeutic agent for use in relation to warm-blooded animals (including man), they also find application whenever you want to inhibit farnesiana. Therefore, they are useful as pharmacological standards for the development of new biological tests and trials of new pharmacological means is.

In accordance with another aspect of the present invention offers individual compounds, representing final products and their salts obtained in the following examples.

The compound of the invention or its salt can be obtained by any known method, which is used for obtaining such compounds or structurally related compounds. Such methods are illustrated by the following representative schemes, in which, unless stated otherwise, variables group have any of the values defined for formula I. Functional groups can be protected and subsequently may be removed protection standard ways. Examples of protective groups, such as aminosidine groups and groups that protect carboxypropyl (and how the implementation of protection and possible under appropriate conditions, methods of removing protection), see T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley & Sons, New York, 1991. Note that abbreviations are listed immediately before the following examples.

The protective group may be removed by any convenient method, described in the literature or known to the skilled specialist-chemist, which is designed to uninstall the protective group, such methods chosen to implement the UDA is giving protective group with minimal impact on the group, anywhere elsewhere in the molecule.

Specific examples of the protective groups is presented below for convenience, in which the term "lower" means that the group for which it is used, preferably has 1-4 carbon atoms. It should be understood that these examples are not exhaustive. And those specific examples of methods for removing protective groups, which are described below, similarly, are not exhaustive. The use of protective groups and methods of removing protection, not mentioned specifically, is, of course, within the scope of this invention.

Carboxyamide group may represent the residue of an aliphatic or analiticheskogo alcohol forming the ester, or the rest of silanol forming ester (specified alcohol or silanol combined with caffeine preferably contains 1-20 carbon atoms).

Examples carboxyamide groups include (1-12C)alkyl group with straight or branched chain (for example, isopropyl, t-butyl); lower alkoxy lower alkyl groups (for example, methoxymethyl, ethoxymethyl, isobutoxide); lower aliphatic, acyloxy lower alkyl groups (for example, acetoxymethyl, propionylacetate, butyraldoxime, pivaloyloxymethyl); lower alkoxycarbonyl lower alkyl groups (for example, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl); aryl bottom is their alkyl groups (for example, p-methoxybenzyl,about-nitrobenzyl,p-nitrobenzyl, benzhydryl and phthalidyl); three(lower alkyl)silyl groups (for example trimethylsilyl andt-butyldimethylsilyl); three (lower alkyl)silyl lower alkyl groups (for example, trimethylsilylmethyl) and (2-6C)alkeneamine group (for example, allyl and vinylaryl).

How, in particular, designed to remove groups that protect carboxyl include hydrolysis catalyzed by acid, a metal or an enzyme.

Examples hydroxyamine groups include lower alkeneamine group (e.g. allyl); lower alcoholnye groups (for example acetyl); lower alkoxycarbonyl group (for example,t-butoxycarbonyl); lower altneratively group (for example, allyloxycarbonyl); aryl lower alkoxycarbonyl group (for example, benzyloxycarbonyl,p-methoxybenzeneboronic,about-nitrobenzisoxazole,p-nitrobenzenesulfonyl); three lower alkyl/Arielle group (for example, trimethylsilyl,t-butyldimethylsilyl,t-butyldiphenylsilyl); aryl lower alkyl groups (e.g. benzyl) and Triaryl lower alkyl groups (for example, triphenylmethyl).

Examples aminosidine groups include formyl, kalkilya groups (e.g. benzyl and substituted benzyl, such asp-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl and triphenyl ethyl); di-p-untilmately and furylmethyl group; a lower alkoxycarbonyl (for example,t-butoxycarbonyl); lower alkenylbenzenes (for example, allyloxycarbonyl); aryl lower alkoxycarbonyl group (for example, benzyloxycarbonyl, p-methoxybenzenesulfonyl,about-nitrobenzisoxazole,p-nitrobenzenesulfonyl); trialkylsilyl (for example, trimethylsilyl andt-butyldimethylsilyl); alkylidene (for example, methylidene); benzylidene and substituted benzylidene.

Techniques for removal of hydroxy - and aminosidine groups include, for example, hydrolysis catalyzed by acid, base, metal or enzyme, or protolytic groups, such asabout-nitrobenzisoxazole, or fluoride ions for silyl groups.

Examples of protective groups for amide groups include Alcoceber (for example, benzyloxyethyl and substituted benzyloxyethyl); alkoxymethyl (for example, methoxymethyl and trimethylsilylethynyl); trialkyl/allcell (for example, trimethylsilyl,t-butyldimethylsilyl,t-butyldiphenylsilyl); tri alkyl/allsimilar-simetal (for example,t-butyldimethylsilyloxy,t-butyldiphenylchlorosilane); 4-alkoxyphenyl (e.g., a 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (e.g., 2,4-dimethoxyphenyl); 4-alkoxybenzyl (for example, 4-methoxybutyl); 2,4-di(alkoxy)b is nil (for example, 2,4-di(methoxy)benzyl, and ALK-1-enyl (for example, allyl, but-1-enyl and substituted vinyl, for example 2-phenylphenyl).

Arelaxation group can be introduced into the amide group by reacting the latter with an appropriate oralmaxillofacial and can be removed by catalytic hydrogenation. Alkoxymethyl, trialkyl/Arielle and trialkyl/similarieties groups can be introduced by the interaction of the amide with the corresponding chloride and removed by acid or in the case siliconebased groups fluoride ions. Alkoxyphenyl and alkoxybenzyl group respectively injected by arilirovaniya or alkylation with an appropriate halide and remove oxidation by suryamaninagar. Finally, ALK-1-aniline group can be entered by the interaction of the amide with the appropriate aldehyde and remove the acid.

In addition, the invention provides a method of obtaining compounds of videopreteen formula (I), and this method involves reacting the compounds of formula (II)

where L, R3and R4such as defined in relation to formula (I), R1'is R1defined in relation to formula (I), or its predecessor, and R5represents a protective group, such as the SIDE (VOS),

with the compound of the formula (III)

the de Y such as defined in relation to formula (I), and R2'represents a group R2defined in relation to formula (I), or its predecessor;

and then, if desired or if necessary, the implementation of one or more of the following stages:

a) removing the protective groups R5;

b) the conversion of any of the groups R1'and R2'predecessors in group R1R2and

c) transforming the above groups in various R1, R2group.

The reaction between the compounds of formula (II) and (III), respectively, is carried out in an organic solvent, such as dichloromethane, in the presence of a base, such as DMAP and EDC, and optionally in the presence of a nucleophilic catalyst, such as 1-hydroxybenzotriazole. Use moderate temperatures, for example from 0 to 50°S, it is convenient to use the ambient temperature.

Group R1'and R2'the precursors may include protective groups such as ester, which are not pharmaceutically acceptable. They can be converted to hydrogen or other groups prodrugs, using conventional methods, as shown below.

Removing the protective groups R5can be performed using conventional methods, such as interaction with TFU (TFA) and/or triethylsilanol.

The compounds of formula (II) respectively receive put the m removal of the protective groups from the compound of formula (IV)

where R1', R3, R4, R5and L such as is defined in relation to formula (II), and R6represents a protective group, in particular an alkyl group such as methyl. Unprotect respectively carried out using a strong base, such as alkali metal hydroxide, in particular sodium hydroxide. The reaction is respectively carried out in a solvent such as aqueous alcohol, in particular an aqueous methanol, at elevated temperatures, conveniently carried out at the boiling temperature of the solvent.

The compounds of formula (IV), where L is-CH2NH-, can be obtained by the combination of the compounds of formula (V)

where R3, R4and R6such as defined above,

with an aldehyde of formula (VI)

where R1'and R5such as defined above.

Suitable conditions combinations include using a reducing agent (for example, branfireun with acetic acid, NaCNBH3, NR3hydrogen plus catalyst, LiHBEt3diisobutylaluminium, sociallyengaged, borohydride) in the presence of a suitable solvent, for example methanol or ethanol and acetic acid.

The aldehydes of the formula (VI) can be obtained by recovery of the compounds of the formula (VII)

where R1'and R5such as defined above, R6represents alkyl, such as methyl, and R7is alkoxy, such as methoxy.

Use suitable strong reducing agents, such as sociallyengaged or DIBAL (DIBAL). The reaction is carried out in a solvent such as tetrahydrofuran, at low temperatures, for example from -50 to 0°With, in particular at about -40°C.

The compounds of formula (VII), respectively, obtained by interaction of the compounds of formula (VIII)

where R8represents a removable group, such as methanesulfonamido,

with the compound of the formula (IX)

where R1'such as defined above, and, in particular, is triphenylmethyl or trityloxy group. Reaction conditions must be obvious to the expert in this area, but, as a rule, the reaction is carried out in an organic solvent, such as ethanol, at moderate temperatures, for example from 0 to 60°and preferably at about 40°C.

The compounds of formula (VIII) can be obtained by the interaction of the compounds of formula (X)

where R5and R6and R7such as defined above,

with the compound of the formula (XI)

where Rsup> 8such as defined above, and Z represents a removable group, such as halogen, in particular chlorine. The reaction is accordingly carried out in an organic solvent, such as dichloromethane, in the presence of a weak base, such as triethylamine. Use moderate temperatures, for example from 0 to 30°C.

The compounds of formula (X), respectively, obtained by interaction of the compounds of formula (XII)

where R5such as defined above, with a compound of formula (XIII)

where R6and R7such as defined above.

A specific example of the compounds of formula (XIII) is an N,O-dimethylhydroxylamine. The reaction is accordingly carried out in the presence of a base (such as N-methylmorpholine with EDCI) and in an organic solvent such as dichloromethane.

The compounds of formula (XII) can be obtained N-protection of the corresponding hydroxy Proline, using known methods.

The compounds of formula (V), respectively, obtained by hydrogenation of compounds of formula (XIV)

where R3, R4and R6such as defined above.

Hydrogenation respectively carried out in the presence of a catalyst such as palladium-based catalyst.

The compounds of formula (XIV), respectively, receive mutual is the action of the compounds of formula (XV)

where R6such as defined above, and Z represents a removable group, such as halogen, such as bromine or chlorine, preferably chlorine,

with the compound of the formula (XVI)

where R3and R4such as defined above.

The reaction is accordingly carried out in the presence of a base, such as tributylamine, preferably sodium carbonate, tetrabutylammonium, and a catalyst such as a palladium catalyst, such as chloride bis(triphenylphosphine)palladium(II), in a suitable solvent, preferably dimethylformamide.

The compounds of formula (IV), where Z is-CH2O-, can be obtained by the coupling of compounds of formula (XVII)

where R3, R4and R6such as defined above,

with the compound of the formula (XVIII)

where R1'and R5such as defined above.

The reaction is accordingly carried out in conditions similar to the conditions described above for the reaction between compounds of formulae (V) and (VI).

The compounds of formula (XVIII), respectively, obtained by reduction of compound of formula (VI), for example, using a reducing agent such as sociallyengaged. The restoration carried out under ordinary conditions of rest retele, such as tetrahydrofuran.

The compounds of formula (XVII) can be obtained by protecting the corresponding carboxylic acid, for example, by the esterification of acid, using alcohol, in particular alkilany alcohol, such as methanol. The reaction is accordingly carried out in the presence of sulfurylchloride or the like, at elevated temperatures, conveniently at the boiling temperature of the solvent.

The acid itself can be obtained by removing the protection of the compounds of formula (XIX)

where R3and R4such as defined above, R10and R11represent a protective group, such as alkyl, in particular methyl groups.

Suitable reaction conditions unprotect include heating the compounds with a suitable reagent, such as pyridine hydrochloride, to high temperatures, such as, for example, from 200 to 250°S, and preferably at about 220°C.

The compounds of formula (XIX) is obtained by hydrogenation of compounds of formula (XX)

where R3, R4, R10and R11such as described above.

Suitable hydrogenation conditions include conditions described above for the hydrogenation of compounds of formula (XIV).

The compounds of formula (XX) can be obtained by the coupling of compounds of formula (XXI)

where 10and R11such as defined above, and Z represents a removable group, such as halogen, in particular bromine,

with the compound of the formula (XVI)as defined above, using conditions analogous to the conditions set forth above for the reaction between compounds of formula (XV) and (XVI).

The compounds of formula (IV), where L represents-CH=CH-, respectively, is produced by interaction of the compounds of formula (VI)defined above, with a compound of formula (XXII)

where R3, R4and R6such as defined above, R12is ion phosphate, such as diethylphosphate, or triphenylphosphine group.

The reaction is the reaction of Witting and respectively carried out in normal conditions. Suitable reaction conditions include the use of a base (e.g. potassium carbonate, metal hydride, metal alkoxide in the presence of an organic solvent (for example THF (THF), toluene, DMSO (DMSO)), optionally in the presence of an aqueous solvent (2-phase) and optionally in the presence of means forming a complex with the catalyst, which solubilities alkali metal ions in non-polar solvents, such as 1,4,7,10,13-pentachlorobenzene (also known as 15-crown-5) or 1,4,7,10,13,16-hexaoxacyclooctadecane (also known as 18-crown-6).

The compounds of formula (XXII) with the responsibility receive paths, such as described in PCT/GB98/000230 and in the specific example 19 the application. The details of the receipt also summarized below in scheme 3 below.

If necessary or desirable, the group R1and R2can be replaced by various other such groups after any of the above methods of obtaining, using conventional chemistry, and examples of this are discussed here below.

Biological activity experience in the following way. Farnesyltransferase (figs, FPT) partially purified from human placenta by fractionation of a solution of ammonium sulfate, and then (pay) anion exchange chromatography on Q-Sepharose® (Pharmacia, Inc.), essentially as described by Ray and Lopes-Belmonte (Ray To R. and Lopes-Belmonte J (1992) Biochemical Society Transations 20 494-497). The substrate for FPT represented Kras(CVIM C-terminal sequence). cDNA (cDNA) for oncogenic vall2 option c-Ki-ras-2 4B person was obtained from the plasmid pSWll-1 (ATSS). Then it was subcloned into polylinker appropriate expression vector, for example, RS. Kras received after the expression strain E. coli BL21. About expression and purification of c-KI-ras-2 and 4B vall2 variants in E. coli was also reported by Lowe et al. (P.N. Lowe et al., J. Biol. Chem. (1991) 266, 1672-1678).

Incubation of the sample with the enzyme containing 300 nm of tritium-labeled farnesylpyrophosphate (DuPont/New England Nuclear), 120 nm ras-CVIM, 50 mm Tris HCl, pH 8.0, 5 mm MgCl2, 10 μm ZnCl2, 5 mm deciteful and compounds added is at the respective concentrations in DMSO (DMSO) (3% final concentration in the test sample and the control-filler). Incubation was carried out for 20 minutes at 37°and interrupted acidic ethanol, as described Pompliano et al. (L. Pompliano et al., (1992) 31, 3800-3807). Then landed protein was collected in the films (In) filter glass fibre using the harvester cells Tomtec®and calculated tritium-labeled tag in a scintillation counter Wallac® 1204 Betaplate.

Although, as expected, the pharmacological properties of the compounds of the formula I vary with structural changes, in General, in the above test the compounds of formula I had IR50(IC50) in the range of, for example, from 0.01 to 200 microns.

For the tested compounds of the present invention in effective dose was not observed manifestations physiologically unacceptable toxicity.

Further, the invention is illustrated in the following non-limiting it to the examples in which, unless otherwise specified

(i) the evaporation is carried out with the help of rotary vacuum evaporation and handling procedures carried out after removal of residual solids by filtration;

(ii) the operation is carried out at room temperature, i.e. in the range of 18-25°and in the atmosphere of inert gas, such as argon;

(iii) column chromatography (according to the flash method) and liquid chromatography medium pressure (SJH, MPLC) carried out on silica Merck Kieselgel (Art. 9385) or to reverse the phase Merck Lichroprep RP-18, supplied Emags, Darmstardt, Germany;

(iv) outputs are provided for illustration only and they do not reach the maximum value;

(v) final products of formula I have satisfactory microanalysis data and their structure confirmed by methods of nuclear magnetic resonance (NMR) and mass spectrometry; chemical shifts were measured on the Delta scale; there were used the following abbreviations: (s) - singlet; d - doublet; t (t or tr) - triplet; m (m) - multiplet; W (br) - wide;

(vi) intermediate compounds, as a rule, characterized fully, and the purity was assessed by thin layer chromatography, infrared spectroscopy (IR, IR) or NMR spectrometry;

(vii) melting points are not corrected and were determined using an automatic device for determining the melting point type Mettler SP62 or equipment with an oil bath (inertial-oil equipment); melting points for the end products of the formula I were determined after crystallization from a suitable organic solvent, such as ethanol, methanol, acetone, simple ether or hexane, one or mixtures thereof, and

(viii) throughout the description of the application were used the following abbreviations:

SIDE (VOS)tert-butoxycarbonyl

DCC (DCCI) 1,3-dicyclohexylcarbodiimide

DMA (DMA)N,N-dimethylacetamide

DMAP (DMAP) 4-dimethylaminopyridine

DMF (DMF)N,N-dimethylformamide

DMSO (DMSO) dimethyl sulfoxide

EDC(EDC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

EACH (EEDQ) 2 ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline

HOBT (NOVT) 1-hydroxybenzotriazole

NMM (NMM)N-methylmorpholin

NMM-O (NMM-O) 4-methylmorpholin-Noxide

TFU (TFA) triperoxonane acid

THF (THF) tetrahydrofuran

(TMSI) trimethylsilylmethyl

TPAP (TRAP) tetrapropylammonium

Example 1

Getting connection No. 6 table 1

The applied method of obtaining generally disclosed in scheme 1 below. In particular, the mixture of compounds (xv), where R was N-methylpiperidin (4.8 g), triethylsilane (10 ml) and TFU (200 ml) was stirred at ambient temperature for 1 hour in nitrogen atmosphere. TFU is evaporated and the residue is dissolved in ethyl acetate (50 ml). Add HCl in simple ether (1M, 100 ml), and then a simple ether (100 ml). The obtained white solid substance produce by centrifugation, then washed with simple ether and centrifuged again (only 4 times). The solid is dried in a high vacuum, obtaining the compound 6 in table 1 in the form of cleaners containing hydrochloride salt (4.5 g).

Connection 6

Data1H-NMR (DMSO d6) δ: 1,14 (6N, m), and 1.7 (1H, m), 1,8-2,11 (7H, m), 2,02 (3H, s), 2,29-3,0 (10H, m)to 2.66 (3H, d), and 3.16 (1H, m), 3,2-to 3.52 (3H, m), 3,62 (1H, m), of 3.78 (1H, m), 4,0 (1H, m), 4,46 (1H, HF), 4,9 (1H, m)6,60 (N, m), 6,9-7,10 (3H, m), 7,19 (2H, m), 8,59 (1H, d).

MS (ES+) (elektrorazpredelenie) m/z 673,7 (M+N)+.

Starting material, compound (xv) in scheme 1, where R was N-methylpiperidin, obtained as follows.

The compound (xii) is a known compound and it is obtained as described in example 6 application PCT/GB99/00369. The mixture of compounds (xii) (50 g), hydrochloride isopropyl ether complex of L-methionine (19,0 g), DMAP (DMAP) (42.6 g) and EDC (20,0 g) in dichloromethane (500 ml) was stirred at ambient temperature for 18 hours. The solution was washed with aqueous citric acid (1 M), saturated salt solution and dried. Then diluted with the same amount of isohexane and applied directly to a flash column silica, elute with a mixture of ethyl acetate/isohexane(20:80, 20:70), receiving the compound (xiii) in scheme 1 (58,6 g) as a solid white foam.

The compound (xiii)

Data1H-NMR (CDCl3) δ: 1,26 (6N, m), 1,38 (N, C)of 1.41 (1H, m), 1,58 (1H, m), 2,02 (1H, m), is 2.05 (3H, s), 2,15-2,4 (2H, m), 2,47-2,7 (2H, m), 2,7-2,98 (6N, m), 3,06-to 3.34 (2H, m)of 3.9 (1H, m), 4,79 (2H, m)5,08 (1H, m), 6,34 (1H, d), 6,38 (2H, m)6,91 (3H, m), to 7.09 (2H, m), 7.18 in-7,35 (N, m), 7,43 (6N, m).

MS (ES+) (elektrorazpredelenie) m/z 890,5 (M+N)+.

TFU (80 ml) is added to a rapidly stirred solution of compound (xiii) (58,6 g) and triethylsilane (80 ml) in dichloromethane (4 l) under nitrogen atmosphere. Then the solution was stirred at ambient temperature for 4.5 hours is in, alkalinized with a saturated solution of sodium bicarbonate and dichloromethane layer is separated. After drying and evaporation to a smaller volume (500 ml), the contents are applied directly to a flash column with silica and elute with a mixture of ethyl acetate/hexane(30:70, 50:50), receiving the compound (xiv) in scheme 1 (35.5 g) as a white solid.

The compound (xiv)

Data1H-NMR (CDCl3) δ: 1,25 (6N, m), 1,46 (N,) and 1.5 (1H, m), by 1.68 (1H, m)1,70 (1H, d), from 2.00 (1H, m), of 2.08 (3H, s), of 2.21 (1H, m), of 2.56 (2H, m), 2,75-of 2.97 (4H, m), 3,05 (1H, m), 3,26 (2H, m), 3,4 (1H, m), 3,85 is 4.3 (2H, m), and 4.8 (2H, q), of 5.05 (1H, m), 6.35mm (1H, d), and 6.6 (2H, m), 6,92 (3H, m)and 7.1 (2H, m).

MC (ES+) (elektrorazpredelenie) m/z 648,7 (M+N)+.

A mixture of compound (xiv) (4.5 g), N-methylpiperidin-4-carboxylic acid (1.5 g), N-methylpiperidine (3.5 g), EDC (1.6 g) and HOBT (NOVT) (0,94 g) in dichloromethane (100 ml) is stirred under nitrogen atmosphere for 18 hours. Then applied directly to a flash column with silica and elute with a mixture of ethyl acetate/isohexane (1:1), ethyl acetate, a mixture of methanol/acacetin(10:90, 20:80), receiving compound xv in scheme 1, where R is N-methylpiperidin, (4.8 g) as a white foam.

Data1H-NMR (DMSO d6) δ: 1,15 (6N, m), 1,4 (N, C)was 1.69 (1H, m), 1,7-2,0 (7H, m), a 2.01 (3H, s), 2,11 (3H, s), 2,4-2,6 (4H, m), 2,63-2,82 (6N, m), 3.04 from (2H, m), or 3.28 (1H, m), 3,42 (1H, m), 3,7-4,0 (3H, m), of 4.44 (1H, m), 4,9 (1H, m), of 5.82 (1H, t), and 6.6 (2H, m), 6,9 (1H, m), 7,03 (2H, t), 7,38 (2H, m), 8,55 (1H, d).

MC (ES+) (with elektrorazpredelenie is) m/z 773,6 (M+N) +.

Example 2

Get connections 4 and 8 of table 1, using a method similar to the method described in example 1, from compound (xiv) in scheme 1, using the corresponding intermediate compounds.

The compound (xv) in scheme 1, where R represents phenyl

Data1H-NMR (CDCl3) δ: 1,28 (6N, m)1,50 (N, C)a 1.50 (1H, m), 1,90 (1H, m), is 2.05 (1H, m)2,07 (3H, s), of 2.23 (1H, m), 2.57 m (2H, m), 2,69 (1H, m), 2,82 (2H, m), 2,90 (2H, m), with 3.27 (2H, m), of 3.46 (1H, m), 4,1 (1H, m)to 4.23 (1H, m), 4,80 (2H, m), 5,07 (1H, m), 6,40 (1H, d), of 6.68 (2H, m), 6,93 (3H, m)and 7.1 (2H, m), 7,46 (2H, m), to 7.59 (1H, m), 7,94 (2H, d).

MS (EU+) (elektrorazpredelenie) m/z 752,71 (M+H)+.

Compound 4 in table 1

Data1H-NMR (DMSO d6) δ: 1,16 (7H, m), equal to 1.82 (1H, m)to 1.98 (2H, m), a 2.01 (3H, s), 3,4-3,9 (6N, m), up 3.22 (1H, m), 3,42 (2H, m), 3,80 (2H, m), 4,20 (1H, m), 4,47 (1H, HF), the 4.90 (1H, m), 6,62 (2H,m), 6,93-7,10 (3H, m), 7,19 (2H, m), EUR 7.57 (2H, t), of 7.70 (1H, t), 7,89 (2H, d), at 8.60 (1H, d).

MC (ES+) (elektrorazpredelenie) m/z 652 (M+N)+.

The compound (xv) in scheme 1, where R is 3-pyridyl

Data1H-NMR (CDCl3) δ: 1,27 (6N, m, 1,49 (N, C)a 1.50 (1H, m), with 1.92 (1H, m), 2,04 (1H, m), 2,10 (3H, s), of 2.23 (1H, m), of 2.56 (2H, m), 2,70 (1H, m), and 2.83 (2H, m), of 2.92 (2H, m), or 3.28 (2H, m), of 3.45 (1H, m), 4,14 (1H, m), 4,25 (1H, m), 4,80 (2H, m)5,08 (1H, m), 6,40 (1H, d), of 6.65 (2H, m), 6,93 (3H, m), 7,10 (2H, m), 7,42 (1H, m), 8,18 (1H, m), 8,80 (1H, m), 9,13 (1H, m).

MC (ES+) (elektrorazpredelenie) m/z 753,71 (M+H)+.

Compound 8 in table 1

Data1H-NMR (DMSO d6) δ: 1,15 (6N, m)of 1.20 (1H, m)to 1.86 (1H, m)of 1.97 (2H, m), 2,02 3H, C)2,40 of 2.92 (5H, m), 3,29 (1H, m), 3,37-of 3.60 (2H, m), 3,68-of 3.94 (2H, m), 4,28 (1H, m), 4,48 (1H, m), 4,89 (1H, m), to 6.67 (2H, m)to 7.00 (4H, m), 7,19 (2H, t), to 7.68 (1H, m), with 8.33 (1H, m), 8,61 (1H, d), 8,88 (1H, m), 9,06 (1H, m).

MC (ES+) (elektrorazpredelenie) m/z 653,56 (M+N)+.

Example 3

Obtain compound 7 of table 1

Compound 7 of table 1 are synthesized from compound (xxviii) in scheme 2, using a method similar to the method described in example 1 for the conversion of compound (xv) in figure 1 in connection 6.

Compound 7 of table 1

Data1H-NMR (DMSO d6+CD3COOD) δ: 1,1-1,25 (6N, m), 1,8-2,05 (1H, m), of 2.05 to 2.35 (2H, m), 2,6-3,05 (5H, m), 2,95 (3H, s), 3,05 and 3.4 (3H, m), 3,82 (1H, DD), 4,0-4,2 (1H, m), 4,2-4,4 (3H, m), 4,4-4,6 (1H, m), 4,85-5,0 (1H, m,), 6,9-7,1 (4H, m), 7,1-7,3 (3H, m), the 7.65 (1H, DD), and 8.3 (1H, DD), 8,87 (1H, DD), 9,07 (1H, d).

MC (ES+) (elektrorazpredelenie) m/z 686,5 (M+N)+.

Analysis

Calculated for C34H40N3S2O7F·2HCl·2H2O:

With 51.4; H 5,8; N 5.3; 8,0; Cl 8,9;

found: 51,2; N. Of 5.39; N 5,2; S 7,84; Cl 9,2.

Starting material, compound (xxviii), synthesized from the compound (xxv) in scheme 2 in a manner analogous to the method described in example 1 to obtain the compound (xv) in scheme 1, using the corresponding intermediate compounds. The compound (xxv) are obtained using the method described in example 12 application PCT/GB99/00369 and presented in General form in figure 2.

The compound (xxvi) in scheme 2

Data1H-NMR (CDCl3) δ: 1,2-1,35 6N, m), 1,35 (N, C), 1,8-2,05 (1H, m), 2,15-2,4 (1H, m), 2,45-3,3 (10H, m), 2,85 (3H, s), 3,7-4,3 (4H, m), 4,7-is 4.85 (1H, m), 5,0-5,2 (1H, m), and 6.5 (1H, d), 6,8-7,0 (4H, m), 7,0-to 7.15 (3H, m), 7,15-7,4 (N, m), 7,4-7,6 (6N, m).

MS (EU+) (elektrorazpredelenie) m/z 945,1 (M+Na)+.

The compound (xxvii) in scheme 2

Data1H-NMR (CDCl3) δ: 1,2-1,35 (6N, m), 1,45 (N, m)1,75 (1H, d), 1,9-2,1 (1H, m), 2,2-2,4 (1H, m), 2,45-2,7 (2H, m), 2.8 to a 3.4 (8H, m), 2,85 (3H, s), and 3.8 to 4.4 (4H, m), 4,7-is 4.85 (1H, m), 5,0-5,2 (1H, m), 6,55 (1H, d), 6,8-7,2 (7H, m).

MS(EU+) (elektrorazpredelenie) m/z 681,2 (M+N)+.

MS(EU) (elektrorazpredelenie) m/z of 679.2 (M-N)-.

The compound (xxviii) in scheme 2

Data1H-NMR (CDCl3) δ: 1,2-1,35 (6N, m), 1,45 (N, C)of 2.1-2.4 (2H, m), 2,45-to 2.65 (1H, m), 2,65-2,8 (1H, m), the 2.8 is-3.45 (8H, m), 2,85 (3H, s), of 4.0-4.4 (4H, m), 4,7-is 4.85 (1H, m), 5,0-5,2 (1H, m), 6,55 (1H, d), 6,8 to 7.2 (7H, m), 7,42 (1H, DD), 8,18 (1H, d), and 8.8 (1H, d), to 9.15 (1H, s).

MC (EC+) (elektrorazpredelenie) m/z 786,7 (M+N)+.

MS (EU) (elektrorazpredelenie) m/z 784,6 (M-N)-.

Example 4

Obtaining the compound (9) table 1

Compound 9 of table 1 are synthesized from compound (xxxxi), using a method similar to the method described in example 1 for the conversion of compound (xv) in scheme 1 compound 6 in table 1.

Compound 9 of table 1

Data1H-NMR (DMSO d6) δ: 1,13-1,22 (6N, m), with 1.92-2.06 to (6N, m), 2,39 is 2.46 (1H, m), 2,54-2,62 (2H, m), 2,66-and 2.83 (3H, m), 2,92-of 3.00 (2H, m), and 3.31 (1H, m), 3,81 (1H, m), 4,30 4,39 (1H, m), 4,47-of 4.57 (1H, m), the 4.90 (1H, m), 6,37 (1H, DD), for 6.81 (1H, d),? 7.04 baby mortality (2H, t), 7,15-of 7.25 (3H, m), 7,39-7,46 (2H, m), to 7.61 (1H, DD), of 8.27 (1H, is), 8,79 (1H, d), 8,87 (1H, DD), 9,05 (1H, d).

MS (EU+) (elektrorazpredelenie) m/z 650,1 (M+N)+.

Starting material (compound xxxx) in scheme 3) was synthesized from compound (xxxv), as shown in scheme 3, using the following procedure. The connection itself xxxv receive, as described in example 21 application PCT/GB98/00230, and summarized in figure 3.

Compound (xxxv) in figure 3 (20 g) dissolved in triethylphosphite (100 ml) and heated at 160°C in an atmosphere of nitrogen for 18 hours. The solution is evaporated to dryness and the residue is dissolved in dichloromethane and applied directly to a flash column with silica and elute with a mixture of ethyl acetate/isohexane(50:50, 100:0), receiving the compound (xxxvi) in the form of a colorless crystalline solid (19,4 g).

Compound (xxxvi) in scheme 3

Data1H-NMR (DMSO d6) δ: 1,15 (6N, t), and 2.79 (2H, t), is 3.10 (2H, t), 3,24 (2H, d), 3,81 (3H, s), 3,88-3,98 (4H, m), 7,02-7,10 (2H, m), 7,16-7,27 (3H, m), 7,35-7,40 (1H, m), 7,72 (1H, s).

MS (EU+) (elektrorazpredelenie) m/z 409,3 (M+N)+.

Compound (xxxvi) in figure 3 (17.5 g) was dissolved in tetrahydrofuran (500 ml) and cooled to -50°C in nitrogen atmosphere. Slowly at -40°add n-utility (1.6 M) (26,9 ml), and then the compound (x) (18.5 g) in the form of a solution in tetrahydrofuran (100 ml). The mixture is allowed the opportunity to warm up to 0°C. Then add aqueous saturated solution of ammonium chloride (300 ml) and the organic layer separated is dried over magnesium sulfate. The solution is evaporated to dryness and the residue is dissolved in dichloromethane and purified flash chromatography on a column elwira a mixture of ethyl acetate/isohexane(20:80, 30:70), receiving the compound (xxxvii) in figure 3 as a colorless solid foam. (10.4 g).

Compound (xxxvii) in scheme 3

Data1H-NMR (DMSO d6) δ: 1,16-of 1.30 (10H, m), 1,52-of 1.65 (1H, m), 2,68 is 2.80 (5H, m), 3.04 from-3,14 (2H, m), of 3.80 (3H, s), Android 4.04 (1H, m), 6,12 (1H, DD), 6,34 (1H, d), 7,06 (2H, t), 7,15-7,40 (N, m)of 7.48 (1H, DD), 7,74 (1H, d).

MS (EU+) (elektrorazpredelenie) m/z 728,8 (M+N)+.

Compound (xxxvii) in figure 3 is converted into a compound (xxxxi) in scheme 3, using a method similar to the method described in example 1 to obtain the compound (xv) in scheme 1, using the corresponding intermediate compounds.

Compound (xxxviii) in scheme 3

Data1H-NMR (DMSO d6) δ: 1,14-of 1.35 (10H, m), 1,53-of 1.66 (1H, m), 2,68-of 2.81 (5H, m), 3,10 (2H, t), Android 4.04 (1H, m), 6,10 (1H, DD), 6,34 (1H, d), 7,05 (2H, t), 7,14-7,39 (N, m), the 7.43 (1H, d), 7,76 (1H, s), 12,90 (1H, ush. C).

MS (EU) (elektrorazpredelenie) m/z 712,6 (M-N)-.

The compound (xxxx) in scheme 3

MS (EU+) (elektrorazpredelenie) m/z 645,6 (M+H)+.

The compound (xxxxi)

MS (EU+) (elektrorazpredelenie) m/z 750,6 (M+N)+.

Example 5

The pharmaceutical composition

The following are typical pharmaceutical dosage forms of the invention defined here (this active component is denoted by the term "compound X"), d is I therapeutic or prophylactic use for people:

a) Tablet Img tablet
Compound X100
Lactose Ph.Eur182,75
Nitrocresolsto 12.0
Pasta rice starch
(5 wt.%/about. paste)2,25
Magnesium stearate3,0
b) Tablet IImg tablet
Compound X50
Lactose Ph.Eur223,75
Nitrocresols6,0
Rice starch15,0
Polyvinylpyrrolidone
(5 wt.%/about. paste)2,25
Magnesium stearate3,0
(c) Tablet IIImg tablet
Compound X1,0
Lactose Ph.Eur93,25
Nitrocresols4,0
Pasta rice starch
(5 wt.%/about. paste)0,75
Magnesium stearate1,0
d) Capsulemg/capsule
Compound X10
LACT is for Ph.Eur 488,5
Magnesium1,5
e) Injection I50 mg/ml
Compound X5.0 wt.%/about.
1M sodium hydroxide solution15,0%vol/vol.
0.1 M hydrochloric
acid (to bring the pH
to 7, 6)
The polyethylene glycol 4004.5 wt.%/about.
Water for injection to 100%
f) Inertia II10 mg/ml
Connection X1.0 wt.%/about.
Sodium phosphate BP3.6 wt.%/about.
0.1 M hydroxide solution
sodium15,0%vol/vol.
Water for injection to 100%
g) Inertia III1 mg/ml, buffered
to pH 6
Compound X0.1 wt.%/about.
Sodium phosphate BP2.26 wt.%/about.
Citric acidof 0.38 wt.%/about.
The polyethylene glycol400 3.5 wt.%/about.
Water for injection to 100%
h) Aerosol Img/m the
Compound X10,0
Trioleate sorbitol13,5
Trichlorofluoromethane910,0
DICHLORODIFLUOROMETHANE490,0
i) Aerosol IImg/ml
Compound X0,2
Trioleate sorbitol0,27
Trichlorofluoromethane70,0
DICHLORODIFLUOROMETHANE280,0
Dichlorotetrafluoroethane1094,0
j) Aerosol IIImg/ml
Connection X2,5
Trioleate sorbitol3,38
Trichlorofluoromethane67,5
DICHLORODIFLUOROMETHANE1086,0
Dichlorotetrafluoroethaneto 191.6
k) Aerosol IVmg/ml
Compound X2,5
Soy lecithin2,7
Trichlorofluoromethane67,5
DICHLORODIFLUOROMETHANE1086,0
Dichlorotetrafluoroethaneto 191.6
l) Ointmentml
Compound X40 mg
Ethanol300 ál
Water300 ál/td>
1-Dodecylsulfate-2-he50 µl
Propylene glycolto 1 ml

Note

The above compositions can be obtained by conventional means, well known in the pharmaceutical field. The tablets (a)-(C) can be covered intersolubility shell by conventional means, for example, by obtaining coverage from acetamidoacrylate. Aerosol composition (h)-(k) can be used in combination with standard dosing aerosol dispersant, and suspendresume tools, trioleate sorbitol and soya lecithin may be replaced by alternative suspendium means, such as monooleate sorbitol, sesquioleate sorbitol, Polysorbate 89, polyricinoleate or oleic acid.

Example 6

Getting connection No. 1 table 1

(2S)-2-({2-(4-Florfenicol)-5-[({(2S,4S)-4-(mercapto)tetrahydro-1H-pyrrol-2-yl}methyl)amino]benzoyl}amino)-4-(methylsulfinyl)butane acid

(1) preparation of intermediate compound 1

Hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (8.0 g) is added to a stirred mixture of 4-(dimethylamino)pyridine(17,04 g), hydrochloride tert-butyl ester L-methionine (6,87 g) and intermediate (xii) (20 g) [known compound and it is obtained as described in the application PCT/GB99/00369] in dichloromethane (230 ml). The reaction mixture was then stirred for 24 hours at ambient temperature under nitrogen atmosphere. The reaction mixture is evaporated in vacuo to about 100 ml and diluted with isohexane (100 ml). This solution is then applied to a flash column silica, elute with a mixture of ethyl acetate/isohexane 20:80, 30:70. Fraction of the product are combined and evaporated in vacuum, obtaining an intermediate compound 1 as a colorless crisp foam (20 g).

Data1H-NMR (DMSO d6) δ: 1,31 (N, C), 1,40 (N, C), 1,64 of 1.8 (1H, m), 1,9-2,02 (2H, m), 2,02 (ZN, C), 2,3-2,6 (5H, m), 2,6-2,87 (5H, m), 2,9 totaling 3.04 (1H, m), 3,22 and 3.4 (1H, m), 3,63 to 3.8 (1H, m), 4,32-to 4.46 (1H, m), 5,65 to 5.8 (1H, m), 6.5 to 6,62 (2H, m), 6,84-to 6.95 (1H, d), 6,98-to 7.09 (2H, t), 7,15-7,4 (17H, m), 8,4-charged 8.52 (1H, sird).

(2) obtaining the compound No. 1

Intermediate compound 1 (1 g) dissolved in dichloromethane (5 ml) and the solution added dropwise to a solution of triethylsilane (3.5 ml) and 1,3-dimethoxybenzene (2,9 ml) TFU (100 ml). The reaction mixture was then stirred at ambient temperature for 4 hours in nitrogen atmosphere. The solvent is removed in vacuum and the obtained colorless oil was dissolved in ethyl acetate (20 ml), add 1.0 M solution of HCl in simple ether (20 ml) with sediment. Solid allocate by centrifugation, then washed with ether and re-centrifuged (only 4 times). After decanting the ether product of the tub to obtain 0.45 g of the hydrochloride M in the form of a white solid, which is optionally purified preparative HPLC with a reversed phase column (10μ Kromasil C8 reversed-phase (50 mm × 250 mm, elution with a mixture of 40% SN3CN/N2O/1,0% TFU). The product distinguish by lyophilization to obtain the connection specified by name, in the form of triptoreline salt.

Data1H-NMR (DMSO d6) δ: 1,54-1,7 (1H, m), 1.93 and is 2.1 (2H, m), 2,0 (3H, s), 2,49-2,6 (3H, m), 2,65-of 2.86 (4H, m), 2,9-3,1 (1H, 2D), 3,18 to 3.6 (4H, m), 3,63 to 3.8 (1H, m), 4,42-of 4.54 (1H, m), and 6.6 (1H, d), 6,62 (1H, s), 6,92-was 7.08 (3H, m), 7,13-of 7.25 (2H, m), 8,48 (1H, d), 8,88 (1H, Sirs), a 9.25 (1H, Sirs).

MS (ES+) (elektrorazpredelenie) m/z 506,3 (M+H)+.

Getting connection No. 2 table 1

Isopropyl-(2S)-2-({2-(4-florfenicol)-5-[({(2S,4S)-4-(mercapto) tetrahydro-1H-pyrrol-2-yl}methyl)amino]benzoyl}amino)-4-(methylsulfanyl)butanoate

The intermediate compound (xiii) (5g) [obtained as described in example 1, S. 41) dissolved in dichloromethane (20 ml) and the solution added dropwise to a solution of triethylsilane (17,95 ml) TFU (500 ml). The reaction mixture was then stirred at ambient temperature for 4 hours in nitrogen atmosphere. The solvent is removed in vacuum and the obtained colorless oil was dissolved in ethyl acetate (50 ml) and added dropwise 1.0 M solution of HCl in simple ether (50 ml) to precipitate the product as HCl salt. Solid allocate by centrifugation, then washed with simple ether and re-centrifuged (only 4 times). After decanting the ether, the product is dried in vacuum to obtain 3.04 from g white solid.

Data1H-NMR (DMSO d6+ CD3COOD) δ: 1,12-1,2 (6N, 2D), of 1.55 to 1.7 (1H, m), 1,94-2,03 (2H, m), a 2.01 (3H, s), 2,5-2,6 (3H, m), 2,68-2,87 (4H, m), 3,0-to 3.09 (1H, m), 3,21-3,6 (4H, m), 3,63 to 3.8 (1H, m), 4,48 (1H, t), 4,84-of 4.95 (1H, m,), 6,57-6,63 (2H, m), 6,94-7,05 (3H, m), 7,11-7,22 (2H, m).

MS (ES+) (elektrorazpredelenie) m/z 548,2 (M+N)+.

Protocol analysis of cells Hras5

The following Protocol is used the following abbreviations:

DMEM = modified, Dulbecco Wednesday Needle

FCS = fetal calf serum

HBSS = buffer saline Hepes

Step 1. The seeding of the cells to the desired density in 12-hole tablets

Environment used for sowing: DMEM + 5% devoid of impurities FCS and 2 mm glutamine.

Remove medium from the flask (162 cm2with almost fused cells Hras5. Add 2 ml of IX trypsin/HBSS and incubate the flask at 37°C for 5 min before until the shaking flask does not cause the release of cells. Neutralize the trypsin by adding 3 ml of DMEM + 10% FSC + glutamine. Transfer 5 ml sterile universal syringe and gently 2 or 3 times trying and pushed from the syringe using a needle 18G for the destruction of aggregates of cells.

Remove 0.2 ml of the suspension in the vessel Coulter, containing 15 ml of isotonic solution, and calculate the sample volume of 0.5 ml on the Coulter counter (counter, the mood is hydrated to detect particles of 8 μm or more).

Calculation:

Add calculated amount of uterine cell suspension to the desired volume of DMEM + 5% devoid of impurities whey + glutamine. Gently mix the diluted suspension and seeded 1 ml aliquots in 12-well plates (Costar).

Incubated tablets at 37°C/10% CO2throughout the night.

Size-density seeding of cells Hras5 = 20000 cells/well.

Step 2. Input connections.

Get the suspension in 30 mm uterine suspension in DMSO.

Prepare a solution of GSH (reduced glutathione): 0,307 g in 10 ml of deionized water = 100 mm. Sterilized by filtration through a syringe filter a small amount of 0.2 μm.

In 96-hole tablet spend cultivation each connection:

1:10=10 μl compound + 90 ál of GSH

1:3=20 μl compound +40 ál of GSH

Get the following breeding (30 mm stock solution):

1:10=3 mm

1:3=1 mm = 10 μm final

1:10=300 mcm ≡ 3 μm

1:10=100 μm ≡ 1 μm

1:10=30 mcm ≡ 0.3 microns

1:10=10 µm ≡ 0.1 ám

1:10=3 mcm ≡ 0.03 µm

Plan tablets

1 2 3 4 5 6 7 8 9 10 11 12

1 connection 1 2 3 4 etc.

2 breeding with decreasing concentration down tablet

3

4

5

6

7

8

Add 10 ál of the appropriate diluent to volume of 1 ml in 12-hole plate = the spy who s 1:100 and mix by gentle stirring to ensure the dispersion of DMSO.

Wells, control: dose with 10 μl of a solution of GSH.

Plan 12-hole tablets:

Replace the plates in the incubator on day 6.

The degree of reversion of the transformed phenotype analyzed on day 6.

Step 3. The analysis of cells

Evaluate the effects of reduced growth using a microscope.

Dropwise remove the medium from the tablet and add 1 ml of sterile concentrated solution of trypsin /HBSS (20 ml of 10 × trypsin + 80 ml of HBSS. The final concentration of trypsin = 2) to each well and leave for 20 min to allow the cells to detach and be separated into individual cells.

Several times trying to enter and push the contents of the wells pipette, capacity 5 ml, and then transfer the entire 1 ml of each sample in the vessel Coulter, containing 15 ml of isotonic. Calculate sample volume of 0.5 ml on the Coulter counter (a counter configured to detect particles of 8 μm or more).

The entire 1 ml 15 ml isotonic = dilution of 1:15 (approx).

Calculate 0.5 ml dilution ×2 ×15.

For example, it is estimated 12,000 in 0.5 ml of cultivation × 30 = total number of cells in 1 ml of sample wells = 360000 cells.

Calculate the growth inhibition at each concentration as a percentage of controls (controls = 100%) and, if necessary, build distorting the e dependence of dose-response.

IC50proliferation is defined as the concentration of compound that gives 50% of total reference number of cells (μm).

The results of the tests are presented in tables a and B.

Comparison of the compounds of the present invention and compounds of WO 97/06138 (D1)

Table a
LinkExample/ connection # StructureCellular IC50< / br>
(μm) (cells Hras5)
This applicationConnection 1, PL. 10,3
D133f (scheme 38, s)10
D134h (scheme 39, s)30
Table B
LinkExample/ connection # StructureCellular

IC50< / br>
(μm) (cells Hras5)
This applicationCompound 2, PL. 10,01-0,03
LinkExample/ connection # StructureCellular

IC50< / br>
(μm) (cells Hras5)
Connection 3, PL. 10,03-0,1
This applicationCompound 4, table. 10,03-0,1
This applicationCompound 5, table. 10,03-0,1
This applicationCompound 6, table. 10,03
This applicationCompound 7, table. 10,01-0,03
This applicationCompound 8, table. 10,03-0,1

LinkExample/ connection # StructureCellular IC50< / br>
(μm) (cells HrasS)
(The connection is included in the amount specified in paragraph 1 of this proposal)0,01-0,03
(The connection is included in the amount specified in paragraph 1 of this proposal)0,03/td>
(The connection is included in the amount specified in paragraph 1 of this proposal)0,03-0,1
D133 (scheme 38, S. 155)10
D134 (scheme 39, S. 157)0,3
D136(scheme 41, S. 161)1

1. The compound of formula (I)

where R1represents hydrogen or a group of the formula R5(C(O) -, where R5represents phenyl, pyridyl or N-methylpiperidin;

R2represents hydrogen, isopropyl, cyclopentyl or N-methyltetrahydrofolate;

R3represents hydrogen or halogen;

R4represents hydrogen or halogen;

L is-CH2-Z-, where Z represents NH;

Y is S, S(O) or S(O)2,

or its salt.

2. The compound of formula (I) according to claim 1, where R3represents halogen.

3. The compound of formula (I) according to claim 2, where R3is fluorine.

4. The compound of formula (I) according to Liu the WMD one of claims 1 to 3, where R4represents hydrogen or fluorine.

5. The compound of formula (I) according to any one of claims 1 to 3, where Y is S or S(O)2.

6. The compound of formula (I) according to any one of the preceding paragraphs, where the chiral carbon atom in the 2-nd position between the carbonyl and amine in formula I is (S)-configuration.

7. The compound of formula (I) according to any one of the preceding paragraphs, where the chiral carbon atom in the 2-m and 4-m provisions of the pyrolidine ring in the formula I is (S)-configuration.

8. Isopropyl-(2S)-2-({2-(4-florfenicol)-5-[({(2S,4S)-4-[(3-pyridylcarbonyl)sulfonyl]tetrahydro-1H-pyrrol-2-yl}methyl)amino] benzoyl}amino)-4-(methylsulfanyl)butanoate or its salt.

9. (2S)-2-({2-(4-Florfenicol)-5-[({(2S,4S)-4-(mercapto)-tetrahydro-1H-pyrrol-2-yl}methyl)amino]benzoyl}amino)-4-(methylsulfinyl)butane acid or its salt.

10. Isopropyl-(2S)-2-({2-(4-florfenicol)-5-[({(2S,4S)-4-(mercapto) tetrahydro-1H-pyrrol-2-yl}methyl)amino]benzoyl}amino)-4-(methylsulfanyl)butanoate or its salt.

11. The compound of formula (I)

where R1is benzoyl, R2is N-methylpiperidin-4-yl; R3is fluoro; L is-CH2-O-; Y represents S.

12. The compound of formula (I)

where R1represents pyridyl-3-ylcarbonyl, R2is isopr the saws; R3is fluoro; L is-CH2-O-; Y is SO2.

13. The compound of formula (I)

where R1is benzoyl, R2is N-methylpiperidin-4-yl; R3is fluoro; L is-CH2-NH-; Y is S.

14. The connection of claim 8, representing hydrochloride isopropyl-(2S)-2-({2-(4-florfenicol)-5-[({(2S,4S)-4-[(3-pyridylcarbonyl)sulfonyl]tetrahydro-1H-pyrrol-2-yl}methyl)amino] benzoyl}amino)-4-(methylsulfanyl)butanoate.

15. The compound according to any one of claims 1 to 14 for use as a drug for the treatment of cancer, mediated through farnesiana ras.

16. Pharmaceutical composition for treating a cancer mediated through farnesiana ras containing the compound according to any one of claims 1 to 14, together with a pharmaceutically acceptable diluent or carrier.

17. The compound according to any one of claims 1 to 14, designed to produce medicines used in the treatment of cancer, mediated through farnesiana ras.

18. The method of obtaining the compounds of formula (I)as defined in claim 1, including the interaction of the compounds of formula (II)

where L, R3and R4have the meanings indicated in claim 1, R1' represents a group R1as is specified in claim 1, or her predecessor and R5represents a protective group,

with the compound of the formula (III)

where Y has the meanings indicated in claim 1; and R2' represents a group R2as defined in claim 1, or its predecessor,

and then, if desired or if necessary, the implementation of one or more of the following stages:

a) removing the protective groups R5;

b) the conversion of any group precursor R1' and R2' in group R1and R2and

C) transforming the above groups in various R1, R2group.



 

Same patents:

FIELD: organic chemistry.

SUBSTANCE: invention relates to methods for stabilizing compounds based on benzimidazole or its physiologically acceptable salt. One variant of a method involves incorporation of crospovidone having small diameter of particles and at least one compound taken among sodium hydroxide and potassium hydroxide into benzimidazole-base compound represented by the formula (1):

wherein Het1 means:

Het2 means:

R1 and R2 are similar or different and taken among hydrogen atom, methoxy- and difluoromethoxy-group; R3 is taken among hydrogen and sodium atom; R4, R5 and R6 are similar or different and taken among group comprising hydrogen atom, methyl, methoxy-, methoxypropoxy- and trifluoroethoxy-group, or its physiologically acceptable salt. Other variants involve applying at least one compounds taken among sodium hydroxide and potassium hydroxide on core formed by incorporation of crospovidone into benzimidazole-base compound represented by the formula (1) or its physiologically acceptable salt, enteric soluble coating, or intermediate coating and the following applying additional enteric soluble coating on it. Also, invention relates to a method for prevention of the benzimidazole-base compound color change or its physiologically acceptable salts and this method involves incorporation of crospovidone and at least one compound taken among sodium hydroxide and potassium hydroxide into benzimidazole-base compound by cl. 1, or its physiologically acceptable salt.

EFFECT: improved stabilizing method.

7 cl, 2 tbl, 8 ex

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to arypyprazole anhydrous crystals B showing characteristic peaks in powdered roentgen rays diffraction at 2θ = 11.0°, 16.6°, 19.3°, 20.3° and 22.1°, specific infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-1 in IR-spectrum, endothermic peak at 141.5° in thermogravimetric/differential thermic analysis and endothermic peak at 140.7° C in differential scanning calorimetry, arypyprazole A hydrate, to methods for their preparing, pharmaceutical compositions comprising arypyprazole crystals B and methods for their preparing. Invention provides reduced hygroscopicity of arypyprazole crystals B.

EFFECT: improved preparing method.

57 cl, 14 tbl, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

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EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, insecticides, chemical technology.

SUBSTANCE: invention describes derivative of 1-aryl-3-cyano-5-heteroarylalkylaminopyrazole of the general formula (1): wherein A means: (A-1) , (A-2) , (A-3) and (A-4) and wherein X represents C-halogen; R1 represents (C1-C4)-alkyl group or halogen-(C1-C4)-alkyl group; A represents any group among (A-1) - (A-4) wherein R4 represents hydrogen atom or (C1-C4)-alkyl group; n = 0, 1 or 2 under condition that R1 represents halogen-(C1-C4)-alkyl group with exception for perhalogenalkyl group when A represents (A-1) and n = 0, and that n doesn't equal 0 when A represents (A-4). Also, invention describes derivative of pyrazole of the formula (2): wherein A means: (A-1) and Y means: (Y-1) , (Y-2) and (Y-3) wherein X, R2, R3 and R4 have values given above; R5 represents hydrogen atom; A represents (A-1); Y means any group among (Y-1) - (Y-3); Z represents halogen atom that are intermediate compounds used for synthesis of the compound (1). Invention describes methods for preparing compounds of the formula (1) and (2) and insecticide comprising compound of the formula (1) as an active component. Insecticide shows high systemic activity, high safety and reduced harmful effect on environment in vicinity areas of its applying.

EFFECT: improved methods for preparing, valuable insecticide properties of compound.

11 cl, 9 tbl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new heterocyclic compounds corresponding to general formulas: (I) , (II) , (Ia) and (Ib) wherein substitutes have values given in the description. Such compounds are reversible inhibitors of cathepsins S, K, F, L and B. Also, invention relates to a method for preparing these compounds, pharmaceutical composition eliciting inhibitory activity with respect to cysteine proteases and to a method for modulation of autoimmune diseases, treatment of Alzheimer's disease and osteoporosis.

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

42 cl, 106 ex

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein n = 1 or 2; R1 represents chlorine, fluorine, bromine atom, methyl or methoxy-group; R2 is taken among of one the following groups: (i) halogen atom, nitro-, hydroxy- amino- or cyano-group; (ii) -X1-R5 wherein X1 represents -O-, -S-, -SO-, -SO2-, NR6-, -CO-, -CONR6-, -NR6CO- wherein R6 represents hydrogen atom and R5 is taken among (C1-C6)-alkyl optionally substituted with one or some A, and so on; (iii) 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom and so on; R3 represents (C1-C6)-alkyl optionally substituted with one or some A and so on; A is taken among hydroxy-, amino-group, halogen atom, carboxy-, N-(C1-C4-alkyl)-amino-, N,N-di-(C1-C4-alkyl)-amino-group, carbamoyl and (C1-C6)-alkoxy-group; D is taken among: (i) -Xa-Rc wherein Xa represents -SO2, -CO-, -NRdCO-, -NRd- or -CONRd-; (iv) cyano-group or halogen atom; (v) -XcRf wherein Xc represents -C(O)- and Rf represents 4-8-membered heterocyclic group joined by nitrogen atom that represents saturated monocyclic ring comprising 4-8 carbon atoms among that at least one is nitrogen atom with optionally additional heteroatom taken independently among oxygen atom (O), optionally substituted at ring carbon atom by the hydroxy-group, halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or cyano-group; G represents (C1-C6)-alkanoyl; R4 represents hydrogen or fluorine atom; or to its pharmaceutically acceptable salt or its ester hydrolyzed in vivo. Also, invention proposes a method for preparing compound of the formula (I). Also, invention proposes pharmaceutical composition enhancing activity of pyruvate dehydrogenase comprising substituted derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I) or its pharmaceutically acceptable salt or ester hydrolyzed in vivo in combination with pharmaceutically acceptable vehicle or carrier. Invention provides preparing derivatives of N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide enhancing activity of pyruvate dehydrogenase.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 1 tbl, 85 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

The invention relates to stereochemical controlled way to obtain usacycling compounds of formula (Ia,), where R1R2CH-group in the 5-position of cyclic fragment and the hydroxy-group at the 3-position of cyclic element are in TRANS-position is obtained with respect to each other and where the substituent R44-polozheniii and the hydroxy-group at the 3-position of cyclic fragment are zespolony relative to each other and where n is 0 or 1, R1-R3is hydrogen, R4is hydrogen or lower alkyl, or R3andR4together mean WITH2-C6-alkylenes chain, R5-R7is hydrogen,R8is hydrogen, lower alkyl, (lower alkoxy)lower alkyl, phenyl or phenyl-lower alkyl, R6andR7together can also form a bond, and R5andR8together with the carbon atoms to which they are linked, can form an aromatic6ring system, R9is hydrogen or a protective amino group, or R8and R9together can form WITH3-C4-alkylenes chain or their salts

The invention relates to a new group of individual chemical compounds - cyclic amino compounds represented by the following formula:

< / BR>
where R1represents a phenyl group which may be optionally substituted by at least one Deputy, which represents a halogen atom; R2represents a C1-C8aliphatic acyl group or (C1-C4alkoxy) carbonyl group; and R3represents a saturated cyclic amino group which has from 2 to 8 carbon atoms in one or more cycles, with the highest nitrogen cycle has from 3 to 7 atoms in the cycle, and the specified saturated cyclic amino group substituted by a group having the formula-S-S-R4where R4and X have the meanings as defined below, and the said saturated cyclic amino group attached via its cyclic nitrogen atom adjacent to the carbon atom that is attached to the substituents R2and R1; R4represents a phenyl group which may be optionally substituted by at least one Deputy, selected IGP and nitro groups; WITH1-C6alkyl group which may be optionally substituted by at least one Deputy, selected from the group consisting of amino groups, carboxyl groups, (C1-C4alkoxy)carbonyl groups, substituents having the formula-NH-A1(where a1represents an-amino acid residue), and substituents having the formula-CO-AND2(where a2represents an-amino acid residue); or (C3-C8cycloalkyl group, and X represents a sulfur atom, sulfinol group or sulfonyloxy group, and the above-mentioned cyclic aminecontaining group may be optionally additionally substituted by a group having the formula = CR5R6where R5and R6are the same or different, and each independently represents a hydrogen atom, a carboxyl group, (C1-C4alkoxy)carbonyl group, karbamoilnuyu group, (C1-C4alkyl) karbamoilnuyu group or di-(C1-C4alkyl)karbamoilnuyu group; or their pharmacologically acceptable salts, pharmaceutical composition having inhibitory action in Rel is the prevention of disease, selected from the group consisting of embolism and thrombosis in a warm-blooded animal

The invention relates to new derivatives of azetidine and pyrrolidine General formula

< / BR>
where a represents an optionally unsaturated 5 - or 6-membered ring which may contain heteroatom selected from N and S, and which may be substituted by oxo or (1-6C) alkyl; R1, R2and R3independently of one another represent H, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, and halogen atom; X is an atom of O or S and n = 1 or 2, or its pharmaceutically acceptable salt, except 3-(naphthas-1-yl-oxy)-pyrrolidine and 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)-pyrrolidin

The invention relates to a method for obtaining compounds of formula III or its salt

< / BR>
(where R1is tertbutoxycarbonyl, benzyl; R3represents C1-C6alkyl interaction of the compounds of formula I

< / BR>
(where R1shall have the meaning given above and R2is methanesulfonyl group or p-toluensulfonyl group) with a compound of formula II

< / BR>
in the presence of a base

The invention relates to derivatives of 4-mercaptopyridine formulae of the following classes of i), ii) and iii), represented by the following formula:

< / BR>
where X1means N; C1-6alkoxyl1-6alkyl; C1-6alkoxyl1-6alkylsulphonyl; And means phenyl, naphthyl; X2means H, phenyl, phenyl WITH1-6alkyl; X3means N; C1-6alkyl; X4means1-6alkylsulfanyl, carbarnoyl;

< / BR>
where X5means-C(O)-C1-4alkyl-Phenyl; -C(O)-C1-6alkyl; -C(O)-C1-4alkylpyridine, and Ph and pyridyl optionally substituted C1-4the alkyl, C1-4alkoxy, C1-4alkalosis1-4by alkyl; a represents naphthyl; R3selected from the group comprising H; HE; NO2; -(CH2)nCOOR8where n is 0 to 3 and R8represents H, C1-4alkyl, C2-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, -CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl; a group of formula II: -CONR13-CHR14-COOR17where R13made the>alkyl; p is 0 to 3, and R3may be the same or different;

< / BR>
where X6has any value defined above for X5in ii); X7is Ph, optionally substituted by substituent (substituents), selected from the group comprising FROM1-4alkoxy; a represents Ph or naphthyl; R3and R such as defined above, or its N-oxide, MES, ester, pharmaceutically acceptable salt
The invention relates to N-methyl-N-/(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidine-1-yl)-ethyl/-2,2-diphenylacetamide, which can be used in the treatment of inflammatory bowel disease

The invention relates to new cyclic amine derivatives of General formula I, where R1represents a phenyl group substituted by halogen atom,2represents C1- C8aliphatic acyl group or (C1- C4alkoxy)carbonyl group, R3represents a 3 - to 7-membered saturated cyclic amino group which may form a condensed ring, where the specified cyclic amino group substituted by the Deputy selected from the group comprising: mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, C1- C4alkyl group, substituted mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, and the number of protective groups for the specified mercaptopropyl includes C1- C20alcoholnye group, C3- C20alkenone group and benzoline group, and the said cyclic amino group, furthermore preferably a substituted group of the formula =CR4R5where R4represents a hydrogen atom, and R5represents a hydrogen atom, a C1- C4alkyl group, carboxypropyl, (C1- C4-alkoxy)carbonyl GRU

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

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