Derivative of glutamic acid (options), pharmaceutical composition, method of inhibiting the growth and proliferation of cells derived thiophencarboxylic acid (options)

 

(57) Abstract:

Describes new derivatives of glutamic acid of the formula I, where A denotes sulfur; X is CH2; Y represents sulfur; B is hydrogen; C denotes hydrogen; R1and R2each independently represents hydrogen or lower alkyl, which inhibit the enzyme glycinamide ribonucleotide the formyl transferase (GARFT). Describes intermediate compounds for preparing compounds of formula I, pharmaceutical compositions containing the compounds of formula I, their use for the inhibition of GARFT and their use for inhibiting the growth and proliferation of cells of higher organisms or microorganisms, such as bacteria, yeast and fungi. The above compounds have antitumor, anti-inflammatory, antipsoriasis and/or immunosuppressive activity. The invention also relates to the production of compounds of formula I. 11 s and 21 C.p. f-crystals, 5 PL.

The invention relates to compounds of the following formula 1, which inhibit the enzyme glycinamide ribonucleotide the formyl transferase (GARFT). This invention also relates to intermediate compounds for obtaining these compounds, to pharmaceutical compositions that contain the tion of the cells of higher organisms or microorganisms, such as bacteria, yeast and fungi. These compounds have antitumor, anti-inflammatory, antipsoriasis and/or immunosuppressive activity. This invention also relates to the production of such compounds.

A large class of antiproliferative agents include compounds-antimetabolites. A concrete subclass of antimetabolites, known as antifolates or Antipolis, are antagonists of the vitamin folic acid. In a typical case, antifolates are strongly reminiscent of the structure of folic acid and include typical P-benzoyl glutamate part of folic acid. Glutamate part folic acid carries a double negative charge at physiological pH. Therefore, this compound and its analogs have an active energy-dependent transport system for passage through the cell membrane and have a metabolic effect.

GARFT is palatability enzyme in the metabolic pathway of purine biosynthesis de novo. This pathway is crucial for cell division and proliferation. It is known that blocking this pathway has an antiproliferative effect, in particular anticancer. Thus, it was synthesized thesis, " New Drugs, concepts and Results in Cancer Chemotherapy, Kluwer Academic Publishers, Boston (1992) , 65-87] that which was the prototype of specific forming a strong bond GARFT inhibitor, 5,10-daliasalabarria acid, exhibits antitumor activity.

Described [PCT/US 94/00418 filed 18.01.94] condensed heterocyclic derivative of glutamic acid, used as antiproliferative agents or GARFT inhibitors. The present invention continues this work by further development of useful antiproliferative agents and GARFT inhibitors.

Summary

The present invention relates to compounds defined below formula 1. These compounds are effective for inhibiting glycinamide ribonucleotide formyl transferase (GARFT) and inhibiting the growth and proliferation of cells of higher organisms or microorganisms, such as bacteria, yeast and fungi. This invention further relates to pharmaceutical compositions containing these compounds, and the use of these compounds as inhibitors of the enzyme GARFT.

As indicated above, the compounds according to the invention possess anti-proliferative activity, that is, a property that can itself be expressed in the form protivoopujolevy, in vivo turning into active connection. Preferred compounds according to the invention are particularly active in the inhibition of the enzyme GARFT. Particularly preferred compounds are active in the inhibition of growth of the cell line L1210, leukemia line of mouse cells that can be grown in tissue culture. Compounds according to the invention can also be active in inhibiting the growth of bacteria, such as gram-negative bacterium Escherichia coli, which can be grown in culture.

Compounds according to the invention and their pharmaceutically acceptable salts may be made in the traditional dose forms, such as capsules, tablets and injectables. Can also be used in solid or liquid pharmaceutically acceptable carriers, diluents or excipients.

Solid carriers include starch, lactose, dihydrate calcium sulphate, gypsum, sucrose, talc, gelatin, agar, pectin, gum Arabic, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline solution and water.

The carrier or diluent may include any material for the prolonged visualaid what about the media, the drug can be in the form of a syrup, the elixir, emulsion, soft gelatin capsule, sterile water for injection (for example, a solution or non-aqueous or aqueous liquid suspension.

Pharmaceutical drugs are prepared, following the traditional technology of pharmaceutical chemistry, including such steps as mixing, granulating and compressing (if necessary) in tablet forms, or mixing, filling and dissolving the ingredients in a suitable way to obtain the desired products for oral, parenteral, local, intravaginal, intranasal, intrabronchial, intraocular, ear or rectal.

The composition of the invention can also include one or more pharmaceutically active compounds. For example, the composition can contain one of the following antineoplastic agents: mitotic inhibitors, for example vinblastine); alkylating agents; inhibitors of dihydrofolate reductase or TS inhibitors; antimetabolites (for example 5-fluorouracil, citizenries); intercalating antibiotics, for example adriamycin, bleomycin), enzymes (for example asparaginase), topoisomerase inhibitors (e.g. etoposide; biological response modifiers the administrative agent, in particular, is known from WO 94/13295 (published 23.06.94) or WO 92/05153 (published 02.04.92). The composition of the invention can also contain one or more antibacterial, antigenic, antiparasitic, antiviral, antipsoriatics or anticoccidial agents. Examples of antibacterial agents are sulfonamides such as sulfamethoxazole, sulfadiazine, sulfamates and sulfadoxine; inhibitors digidrofolieva reductase, such as trimethoprim, bromazepam and trimetrexate; penicillins; cephalosporins; and hinolan carboxylic acid and condensed with isothiazol counterparts.

Another aspect of the invention relates to therapeutic methods of inhibiting the growth or proliferation of cells of higher organisms or microorganisms, in which the host (recipient) influence the effective amount of the compounds according to the invention. Compounds according to the invention, particularly useful in the treatment of mammalian hosts (recipients), such as man, in the treatment of birds. Particularly preferred therapeutic method includes the impact on the recipient effective for inhibition of GARFT number of compounds according to the invention.

Many described here antipope according to the invention. These compounds can be applied in the form of a pharmaceutically acceptable composition containing a diluent or carrier, as described above.

The dose of the composition contains at least an effective amount of the active compound and preferably consists of one or more pharmaceutical dose units. "Effective amount" denotes an amount sufficient for inhibition of metabolic pathways of folate, and leads to the next from this favorable effect in the application, for example, one or more pharmaceutical dose units.

Estimated daily dose for vertebrates contains up to 1 g of active compound per 1 kg of body weight of the recipient, preferably 0.5 g, more preferably 100 mg and most preferably about 50 mg and below. The selected dose can affect warm-blooded animal or a mammal, such as man, in need of treatment through inhibition of metabolic pathways of folate, using any suitable application method such doses, including local, for example in the form of ointment or cream; orally; rectally, for example in the form of a suppository; parenterally by injection; or by continuous II andstc is possible according to the invention give any one or more effects selected from among the following: antiproliferative effect, antibacterial effect, antiparasitic effects, antiviral effects, antipsoriatic effect, Antiprotozoal effect, anticoccidial effect, anti-inflammatory, immunosuppressive effect and this makes it the effect. These compounds are particularly useful when receiving antitumor effect in vertebrates having a tumor.

A detailed description of the invention

This invention relates, particularly, to antiproliferative derivative of glutamic acid of the formula I

< / BR>
where A represents sulfur;

X denotes CH2;

Y represents sulfur;

B represents hydrogen;

C denotes hydrogen;

R1and R2each independently represents hydrogen or lower alkyl.

Preferably the compound in which R1and R2each independently selected from hydrogen and ethyl.

More preferably a compound in which R1and R2each is hydrogen.

The most preferred compounds are

diethyl ether (4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H - pyrimido[5,4-b] [1,4]-thiazin-6-yl)-ethyl]-2,5-cyanoalanine-L-glutamic acid); and

4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b][1,4]- thiazin-6-yl)-anoma glutamic acid of the formula:

< / BR>
This compound has the properties of an inhibitor of the growth and proliferation of cells.

Preferred compounds having the following structure:

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and

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This invention relates also to pharmaceutical compositions having the property of inhibiting the growth and proliferatio cells comprising the active principle and a pharmaceutically acceptable carrier, diluent or excipient containing as active principle an effective amount of the above compounds.

Also, a method of inhibiting the growth or proliferation of cells of microorganisms or higher organisms, where the recipient mammal or bird, effect an effective amount of the above compounds.

According to this invention proposed the following intermediate compounds to obtain the above compound.

The compound of formula VI:

< / BR>
where Y represents sulfur;

B represents hydrogen;

C denotes hydrogen;

R6refers to a group which forms together with CO2easily hydrolyzable group; and

R4and R5denotes hydrogen or an easily removable astonishing group.

is hydrogen or tert-butoxycarbonyl.

The preferred 4-N-(tert-butoxycarbonyl)-3-hydroxy - 1-(2-carbomethoxy-5-thiophene)-Butin.

Compound of formula VII

< / BR>
where X' denotes CH2;

Y represents sulfur;

B represents hydrogen;

C denotes hydrogen;

R6refers to a group which forms together with CO2easily hydrolyzable group; and

R4and R5denotes hydrogen or an easily removable astonishing group.

Preferably, when R6is lower alkyl; and R4and R5independently represent hydrogen or tert-butoxycarbonyl.

The most preferred methyl-5-[(4-N-(tert-butoxycarbonyl)- amino-3-hydroxy)-butyl]-thienyl-carboxylate.

The compound of formula VIII

< / BR>
where X' denotes CH2;

A represents sulfur;

Y represents sulfur;

B represents hydrogen;

C denotes hydrogen;

R6refers to a group which forms together with CO2easily hydrolyzable group;

R4and R5denote hydrogen or an easily removable astonishing group; and

Ac represents a lower acyl.

Preferably, when R6is lower alkyl; and R4and R5independent oxycarbonyl)- amino-3-acetylthio)-butyl]-2-thiophene-carboxylate.

The compound of formula IX:

< / BR>
where A represents sulfur;

X' denotes CH2;

Y represents sulfur;

B represents hydrogen;

C denotes hydrogen;

R6refers to a group which forms together with CO2easily hydrolyzable influenza; and

R4and R5denote hydrogen or an easily removable nitrogen-protective influenza.

Preferably, when R6is lower alkyl; and R4and R5independently represent hydrogen or tert-butoxycarbonyl.

The most preferred methyl-5-[(4-N-(tert-butoxycarbonyl)- amino-Z-(dimethylallyl)thio)-butyl]-2-thiophene-carboxylate.

The compound of formula X":

< / BR>
where A represents sulfur;

X' denotes CH2;

Y represents sulfur;

B represents hydrogen;

C denotes hydrogen; and

R6refers to a group which forms together with CO2easily hydrolyzable group.

Preferably, when R6is lower alkyl.

The most preferred 6-[(5-carbomethoxy-2-yl)-ethyl]-2 - carbomethoxy-3-oxo-3,4,5,6-tetrahydro-[1,4]-thiazin.

The compound of formula XI"

< / BR>
where A represents sulfur;

X' denotes CH2;

the which forms together with CO2easily hydrolyzable group.

Preferably, when R6is lower alkyl.

The most preferred methyl-[2-(2-amino-4-oxo-4,6,7,8 - tetrahydro-3H-pyrimido [5,4-b][1,4]thiazin-6-yl)-ethyl]-2,5-tanout.

The compound of formula XII

< / BR>
where A represents sulfur;

X' denotes CH2;

Y represents sulfur;

B represents hydrogen;

C denotes hydrogen.

Preferred [2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H - pyrimido[5,4-b][1,4]thiazin-6-yl)-ethyl]-2,5-Tenova acid.

Although the compounds of formula 1 and shown in 4-oxforde and it's what is meant in this description, oxoprop still exists in tautomeric equilibrium with the corresponding 4-hydroxy-group. Therefore, it should be clear that "the compounds of formula I include as depicted in figures 4-oxo, and tautomeric 4-hydroxypoly. Thus, the invention also relates to pharmaceutically acceptable salts 4-hydroxycoumarin compounds represented by formula I.

The compounds of formula I are applicable as GARFT inhibitors. The compounds of formula I in which R1and R2each denotes hydrogen, are particularly active antitumor and antiprolifera easily hydrolyzable ester group with an attached CO2preferably ethyl group, are useful as intermediate compounds for the formation forms the connection with the free glutamic acid can be hydrolyzed in vivo and serve, therefore, as prodrugs.

Compounds according to the invention can be obtained, as described below. To obtain the compounds of formula I where X is CH2as an initial matter suitable compound of formula II:

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where B, C and Y are such as defined in formula I;

D denotes Cl, Br or I;

R6denotes hydrogen or a group which forms, together with the attached CO2easily hydrolyzable ester group. In the preferred case, D is bromine or iodine. R6in the preferred case denotes hydrogen, C1-C6alkyl, hydroxyalkyl, alkylaryl or arylalkyl, most preferably hydrogen or C1-C2alkyl.

The compound of formula II is subjected to interaction with the compound of the formula III:

< / BR>
where R3is substituted or unsubstituted C1-C6alkyl group or tizamidine silyl group. Preferably, when R3is CH2OH or trimethylsilyl.


< / BR>
where B, C and Y are such as defined in formula I;

R6is as defined in formula II;

R3is as defined in formula III.

When R3is tizamidine silyl group, the silyl group is preferably removed by means of nucleophilic base, such as methanol or ethanol, potassium carbonate or fluoride salts, such as potassium fluoride, cesium fluoride or tetrabutylammonium fluoride, in a solvent in which at least one of the reactants is at least partially soluble (for example, methanol, dimethylformamide, ethanol, dimethylacetamide, dimethyl sulfoxide or isopropanol) to give the compounds of formula V:

< / BR>
where B, C and Y are such as defined above for formula I, and

R6is as defined in formula II.

The compound of formula V is subjected to interaction with the electrophile, preferably N-protected glycinate, more predpochtitelnye dinucleophiles Foundation, preferably bis-trimethylsilylmethyl lithium bis-trimethylsilane potassium bis-trimethylsilane sodium or diisopropylamide lithium at low temperature, preferably from -90oC to 25oC, in a suitable solvent, in which one of the reactants is at least partially soluble, preferably tetrahydrofuran, diethyl ether or dioxane, to obtain the compounds of formula VI:

< / BR>
where B, C and Y are such as defined above for formula I;

R6such as defined above for formula II;

R4and R5each independently selected from hydrogen or an easily removable astonishing group.

In the preferred case, R4and R5represent hydrogen, tert-butoxycarbonyl, benzyloxycarbonyl or benzyl.

Then the compound of formula VI restore, preferably with gaseous hydrogen in the presence of a suitable metal catalyst, to obtain the compounds of formula VII:

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where B, C and Y are such as defined above for formula I;

R6such as defined above for formula II;

R4and R5such as defined above for formula VI.

Compound of formula VII is subjected to interaction of orida, in the presence of dinucleophiles base, preferably triethylamine or diisopropylethylamine, in a suitable solvent, in which at least one of the reactants is at least partially soluble, to obtain the activated hydroxy-group. This activated hydroxy-group is substituted with a suitable nucleophile, preferably teoksessa salt, more preferably thioacetate potassium, obtaining the compounds of formula VIII:

< / BR>
where A, B, C and Y are such as defined above for formula I;

R6such as defined above for formula II;

R4and R5such as defined above for formula VI;

Ac represents an acyl group, preferably acetyl.

Alternatively the compound of formula VII into a compound of formula VIII in one of the chemical stage, using triphenylphosphine, diethyl or dimethyl ether azodicarbonamide acid, and acidic nucleophile, preferably teoksessa acid, in a suitable solvent.

The compound of formula VIII is treated with a nucleophilic base, preferably potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide, in an alcohol solvent, preferably methanol, the ester hormonology acid, obtaining the compounds of formula IX:

< / BR>
where A, B, C and Y are such as defined above for formula I;

R6such as defined above for formula II;

R4and R5such as defined above for formula VI.

The compound of formula IX is treated under conditions suitable for removal of one or both of the protective groups R4and R5with obtaining the compounds of formula X:

< / BR>
where A, B, C and Y are such as defined above for formula I;

R6such as defined above for formula II.

If the protective group is tert-butoxy-carbonyl (t-BOC), the conditions for removal of this group is processing triperoxonane acid, followed by neutralization with obtaining the compounds of formula X.

The compound of formula X is subjected to interaction with an alkylating agent, preferably trimethyl or triethyl hydronium tetrafluoroborate, in a suitable solvent, preferably dichloromethane, with the formation of intermediate lachinova ether. Intermediate laktamny ether is subjected to interaction with guanidine in an alcoholic solvent, preferably methanol, ethanol or isopropanol, to obtain the compounds of formula XI:

< / BR>
where A, B, C and Y so the alternative case, the compound of formula X is converted into a compound of formula XI by reaction of compounds of formula X with Teollisuuden agent, preferably P2S5or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide, with the formation of tilantongo intermediate compounds. Then this connection can be alkilirovanii with an alkylating agent, preferably under the conditions or trimethyl or triethyl hydronium tetrafluoroborate, and then guanidine in an alcoholic solvent, preferably methanol, ethanol or isopropanol, to obtain the compounds of formula XI. The compound of formula XI hydrolyzing in basic conditions to obtain compounds of formula XII:

< / BR>
where A, B, C and Y are such as defined above for formula I.

If R6in the formula XI is hydrogen, hydrolysis reaction is not necessary, and the compound of formula XI combine peptide bond as described below.

The compound of formula XVII (or the compound of formula XI, where R6is hydrogen) in the form of free carboxylic acids may be linked by peptide bond (using known from the prior art funds) hydrochloride diapir glutamic acid getting diapir formula XIII:

< / BR>
where A, B, C and Y are such as defined above for formula I;

R1and R2each independently is gruppirovki the>alkyl, hydroxyalkyl, alkylaryl or arylalkyl.

And finally, if desired, the compound of formula XIII hydrolyzing to form form free glutamic acid compounds of formula I (R1and R2each is hydrogen).

Compounds according to the invention contain one or more chiral centers. This invention encompasses the racemic mixtures and mixtures of diastereoisomers, as well as optically active compounds, such as compounds essentially free from other optical isomers, these optically active compounds can be obtained is known from the prior art means.

Detailed examples of the preparation of preferred compounds of formula I are given below.

Example 1

4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b] [1,4] thiazin - 6-yl)ethyl]-2,5-cyanoalanine-L-glutamic acid (compound 1)

< / BR>
Obtaining methyl-5-bromo-2-thiophenecarboxylate 2:

< / BR>
Compound 2 (CAS register. room [62224-19-5]) get known [S. Gronowitz, Ark. Kemi 8, 1955, 87 and S. O. Lawesson, Ark.Kemi 11, 1957, 337] way.

Getting 5-ethinyl-2-carbomethoxy of thiophene 3:

< / BR>
To a stirred solution of 5 g (22.7 mmol) of bromide 3, 160 mg (0.23 mmol) of Tris-triphenylphosphine chloride picheny the solution stirred at 25oC. After 18 h the solvent is removed under reduced pressure and the raw residue is dissolved in 300 ml of diethyl ether (Et2O and extracted with 100 ml of 1N HCl and 100 ml of saturated solution of bicarbonate. The organic layer is dried (Na2SO4) and the solvent is removed under reduced pressure. The raw residue is subjected to flash chromatography on silica gel with a mixture of 5% Et2O/hexane to obtain 4.4 g (81% yield) silylamines product as a yellow solid. This material is directly used in the next stage.

To a solution of 4.4 g (18.5 mmol) of the above-mentioned silylamines acetylene in 50 ml of dimethylformamide (DMF) are added to 3.3 g (of 35.2 mmol) monohydrate potassium fluoride. After 15 min of incubation at 25oC the mixture was poured into 500 ml of Et2O and extracted 4 times with 100 ml of water (4 x 100 ml H2O). The organic solution is dried (Na2SO4) and remove the solvent under reduced pressure. The raw residue is subjected to flash chromatography on silica gel with a mixture of 10% Et2O/hexane to obtain 2.65 g (86% yield) of the desired product 3 as a solid orange substance.

NMR (CDCl3) : 3,45 (s, 1H), 3,88 (s, 3H), 7,22 (d, 1H, J = 3.5 Hz), the 7.65 (d, 1H, J = 3.5 Hz).

Ana is to be used an alternative method of removal of the silyl group. To a stirred suspension of 3.7 g (0.02 mol) of anhydrous K2CO3in 700 ml of methanol add 59,7 g cooked earlier silyl-acetylene in the form of solids. The suspension is stirred for 2 h at 35oC, and then methanol is evaporated. The remainder is added to 50 ml of water and the mixture extracted with 3 x 150 ml Et2O, and the combined organic fractions dried (Na2SO4) and evaporated. The raw residue is subjected to flash chromatography on silica gel using a mixture of 7% Et2O/hexane to give the desired product 3 with 98% yield (38,72 g).

Obtaining N-(tert-butoxycarbonyl)-glycines 4:

< / BR>
To a stirred solution of 2 g (12.4 mmol) of N-(tert-butoxycarbonyl)- 2-hydroxy-ethylamine (obtained from Sigma Chemicals) in 80 ml of CH2Cl2at -78oC add 1.3 ml (to 18.6 mmol) of dimethyl sulfoxide (DMSO) and 1.2 ml (13.7 mmol) of oxalyl chloride. After 5 min add to 5.4 ml (38.4 mmol) of triethylamine and allow the solution to warm to 25oC. the Mixture is then poured into 200 ml of Et2O and extracted with 100 ml of water, 100 ml of 0.5 N HCl and 100 ml of saturated solution of bicarbonate. The organic fraction is dried (Na2SO4) and remove the solvent under reduced pressure. The raw aldehyde dissolved in 100 ml of b is unstable, immediately used in the next stage.

Getting 4-N-(tert-butoxycarbonyl)-3-hydroxy-1-(2-carbomethoxy - 5-thiophene)-butyne 5:

< / BR>
To a solution of 1.7 g (10.2 mmol) of acetylene 3 in 10 ml dry tetrahydrofuran (THF) at -78oC add to 14.3 ml (14.0 mmol) of 1M solution of bis-trimethylsilyl lithium in THF. After 10 minutes of untreated previously prepared aldehyde 4 added dropwise in 5 ml of dry THF. The solution was stirred at -78oC for 10 min and allow to warm to 0oC for 20 minutes Add 5 ml of a saturated aqueous solution of ammonium chloride. The mixture is then poured into 200 ml of Et2O and washed with 100 ml of H2O and then 50 ml of a saturated solution of NaCl. The organic layer is dried (Na2SO4) and remove the solvent under reduced pressure. The raw residue is subjected to flash chromatography on silica gel with a mixture of 10-40% EtOAc/hexane to obtain 0.96 g (29% yield) of the desired alcohol 5 as a slightly yellow oil.

NMR (CDCl3) : of 1.46 (s, 9H), 3,38, and to 3.58 (AB, 2H, J = 3, 7 Hz), 3,88 (s, 3H), 4,71 (dt, 1H, J = 2,9, 5,2 Hz), of 5.05 (brs, 1H), 7,15 (d, 1H, J = 3,9 Hz), to 7.64 (d, 1H, J = 3,9 Hz).

IR (net): 2978,3, 1729,5, 1685, 1523, 1452, 1368, 1286, 1167, 1098, 959, 822, 750,4 cm-1.

Mass spectrometry high resolution:

Calc. for C15H19
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To a stirred solution of 940 mg (2.89 mmol) obtained acetylene 5 in 50 ml of ethyl acetate (EtOAc) was added 320 mg of 5% Pd/C. the Mixture was placed in a 40 psi of hydrogen gas and stirred at 25oC for 17 h the Mixture was filtered through Celite (datirovannaja earth) and the solvent was removed under reduced pressure. The raw residue was subjected to flash chromatography on silica gel with a mixture of 20% EtOAc/CH2Cl2to obtain 800 mg (84% yield) of the desired alcohol as a yellow oil.

NMR (CDCl3) : the 1.44 (s, 9H), is 1.81 (m, 2H), 2,28 (brs, 1H), 2,99 (m, 2H), 3,10 and 3,29 (AB, 2H, J = 3, 6,9 Hz), 3,74 (m, 1H), 3,86 (s, 3H), 4,89 (brs, 1H), PC 6.82 (d, 1H, J = 3,7 Hz), 7,63 (d, 1H, J = 3,7 Hz).

Anal. Calc. for C15H23NO5S: C, 54,69: H,? 7.04 BABY MORTALITY; N, 4,25; S 9,73.

Found: C, 54,79; H, 7,02; N, 4,29; S, 9,63.

The alternative method of obtaining alcohol 6 using bis-tert-butoxycarbonyl allylamine 14. Obtaining bis-tert-butoxycarbonyl allylamine 14.

< / BR>
To a solution of 57,10 g (1.0 mol) of allylamine and 1.2 g (0.01 mol) of dimethylaminopyridine (DMAP) in 500 ml of acetonitrile, add a solution of 220 g (1 mol) (t-BOC)2O in 100 ml of acetonitrile and the resulting mixture is stirred for 6 hours, the Reaction mixture was diluted with toluene (100 ml) and evaporated restorelayout additional 1.2 g (0.01 mol) of DMAP, to this mixture is added slowly a solution of 220 g (1 mol) (t-BOC)2O in 100 ml of acetonitrile. The reaction mixture was stirred for 12 h at 60oC, the solvent is evaporated under reduced pressure at 60oC and add NaHCO3(100 ml). This mixture is extracted with 3 x 150 ml of CH2Cl2combined organic layers washed with brine, dried (Na2SO4) and evaporated. The raw residue is purified chromatography on flash silica gel, elwira gradient of 5-20% EtOAc/hexane to obtain 156,9 g (63% yield) of the desired product 14 as a transparent crystalline solid (so pl. 43-44oC).

1NMR (CDCl3) : (ppm): to 1.5 (s, 18H), 4,18 (dd, 2H, J = 15 Hz, J = 1 Hz, 5,14 (ddd, 2H, J = 15 Hz, J = 10 Hz, J = 1 Hz), to 5.85 (ddt, 2H, J = 10 Hz, J = 5 Hz, J = 1 Hz).

IR (KBR): 2978, 2935, 2860, 1724, 1689, 1342, 1130 cm-1.

Anal. Calc. for C13H23NO4: C, 60,68; H, 9,01; N, 5,44;

Found: C, 60,78; H, 9,04; N, 5,50.

Obtaining 1-(bis-tert-butoxycarbonylamino)-2-ethanal 15:

< / BR>
A solution of 0.60 g (2.34 mmol) of bis-tert-butoxycarbonyl allylamine 14 in 20 ml of CH2Cl2was ozonirovanie (40 volts, 500 amperes, 1.0 l/min O2@ 3 psi) at -78oC until a blue color persists, add dimethyl sulfide and the mixture is stirred is sosialt organic fraction (Na2SO4) and evaporated. Chromatography using flash silica gel gives 603 mg (99% yield) of the desired product 15 in the form of a transparent crystalline solid (so pl. 37-39oC).

1NMR (CDCl3) : (ppm): 1.50 in (s, 18H), to 4.38 (s, 2H), of 9.55 (s, 1H).

IR (KBr): 2984, 2935, 2724, 1792, 1734, 1699, 1362, 1153 cm-1.

Anal. Calc. for C12H21NO5: C, 55,58; H, 8,16; N, 5.40 TO.

Found: C, 55,20; H, 8,19; N, 5,19.

Obtaining methyl-5-[(4-N-(tert-butoxycarbonyl)-amino-3-hydroxy)- butyl] -thienyl-2-carboxylate 6:

To a solution for 9.64 g (59 mmol) of 5-ethinyl-2-carbomethoxy of thiophene 3 in THF (250 ml) at -78oC added 65,6 ml (60 mmol, 0.9 M) HEXAMETHYL disilicide lithium (LiHMDS) and the mixture was stirred for 2 h at -78oC. a Solution of 15.6 g (60 mmol) of 1-(bis-tert-butoxycarbonylamino)-2-ethanal 15 in THF (40 ml) was added via cannula to the reaction mixture and the mixture was stirred for 8 h at -78oC. a Solution of 3.4 ml (60 mmol) of acetic acid in methanol (10 ml) was added to stop the reaction, the mixture was stirred for 10 min, heating to 0oC, was added water (60 ml). This mixture was extracted with EtOAc (3 x 100 ml) and the organic extracts washed with NaHCO3and dried (Na2SO4). The solvent was removed when ponie, aderrasi 7,38 g (30 wt.% acetylene starting material) 5% Pd on coal and was first made at 55 psi H2within 24 hours the Raw product of hydrogenation was filtered through Celite and the precipitate from the filter was washed with methanol (100 ml) and EtOAc (100 ml). The solvent is evaporated under reduced pressure, the raw residue was filtered through silica, elwira 50% EtOAc in hexane, and the solvent evaporated. The residue was salvational in 20 ml of methanol (MeOH), azeotroping with benzene (50 ml), and re-dissolved in dry MeOH (20 ml). This mixture was added to a freshly prepared solution of 60 ml (2M) of sodium methoxide in methanol. The reaction mixture was stirred for 45 min, was added HCl (0.1 M, 5 ml) and was extracted with the mixture EtOAc (3 x 75 ml). Combined organic fraction was washed with buffer pH 7 (1M), dried (Na2SO4) and evaporated. The raw residue was subjected to chromatography on flash silica gel, elwira 40% EtOAc/hexane to obtain to 9.32 g (48% yield) of the desired product 6.

Obtaining methyl-5-[(4-N-(tert-butoxycarbonyl)-amino-Z-acetylthio)- butyl]-2-thiophenecarboxylate 7:

< / BR>
To mix the solution 9,26 g (28.1 mmol) of the alcohol 6 in 100 ml of THF at 0oC was added to 5.9 ml (42 mmol) of triethylamine (TEA) and 2.4 ml (31 mmol) is solely to warm to 25oC. After 3 days the mixture was poured into 500 ml of water and was extracted with 800 ml of Et2O. the Organic layer was washed with 200 ml of water, 200 ml of 1N HCL, 200 ml of a saturated solution of bicarbonate and 100 ml saturated NaCl solution. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. The raw residue was subjected to flash chromatography on silica gel with a mixture of 25% EtOAc/hexane to obtain 10.3 g (95% yield) of the desired thioacetate 7 in the form of a yellow oil.

NMR (CDCl3) : the 1.44 (s, 9H), 1.91 a and 2,04 (ABm, 2H), is 2.37 (s, 3H), 2,96 (m, 2H), 3,36 (m, 2H), 3,61 (m, 1H), 3,86 (s, 3H), 4,74 (brs, 1H), 6,79 (d, 1H, J = 3.6 Hz), a 7.62 (d, 1H, J = 3.6 Hz).

IR (net): 3366, 2976,4, 1713, 1520, 1462,1, 1366, 1290,5, 1267,3, 1169, 1098, 752, 631 cm-1.

Mass spectrometry high resolution: Calc. for C17H25NO5S2: M+Cs+, 520,0229. Found: 520,0240.

Obtaining methyl-5-[(4-N-(tert-butoxycarbonyl)-amino-3- (dimethylallyl)thio)-butyl]-2-thiophenecarboxylate 8:

< / BR>
To a stirred solution of 10.2 g (26 mmol) of thioacetate 7 in 200 ml of dry methanol at 0oC added 7.2 g (52 mmol) of K2CO3and 3.7 ml (29 mmol) of dimethyl chloromelanite. After 3 h the mixture was poured into 500 ml of water and was extracted with Et2O (3 x 500 ml). The combined organic layers were washed with 500 ml of the Institute and the raw residue was taken flash chromatography on silica gel with a mixture of 30% EtOAc/hexane to obtain 11,46 g (93% yield) of the desired tiefer 8 in the form of a slightly yellow oil.

NMR (CDCl3) : the 1.44 (s, 9H), of 1.85 and 2.00 (ABm, 2H), 3,03 (s, 3H), 3,30 (m, 2H), 3,80 (s, 6H), 3,86 (s, 3H), 5,10 (brs, 1H), PC 6.82 (d, 1H, J = 3.8 Hz), 7,63 (d, 1H, J = 3.8 Hz).

IR (net): 3442, 2974, 2955, 1734, 1713, 1512, 1460, 1435, 1366, 1291, 1267, 1167, 1098, 1022, 752 cm-1.

Mass spectrometry high resolution:

Calc. for C20H29NO8S2: M+Cs+, 608,0389. Found: 608,0370.

Obtain 6-[(5-carbomethoxy-2-yl)-ethyl] -2-carbomethoxy-3 - oxo-3,4,5,6-tetrahydro-[1,4]-thiazine 9:

< / BR>
To a stirred solution of 470 mg (0,99 mmol) tiefer 8 in 12 ml of CH2Cl2at 0oC was added 4 ml triperoxonane acid (TFA). After 1.5 h the mixture was poured into 50 ml of a saturated solution of bicarbonate and was extracted with CH2Cl2(4 x 100 ml). The solvent was removed under reduced pressure and the raw residue was dissolved in 10 ml of methanol. After stirring at 25oC for 1.5 h the solvent was removed under reduced pressure and the raw residue was subjected to flash chromatography on silica gel with a mixture of 40% EtOAc/CH2Cl2to obtain 298 mg (88% yield) of the desired lactam 9 in the form of a colorless oil.

NMR (CDCl3) : of 1.94 (m, 2H), 3,01 (m, 2H), 3,4-3,7 (m, 4H), 3,80 3,82 and (s, 3H), a 3.87 (s, 3H), and 6.25 (brs, 1H), 6,83 (d, 1H, J = 3,7 Hz), to 7.64 (d, 1H, J = 3,7 Hz).

IR (pure): 2951,, 8,96; H, 4,99; N, 4,08, S, 18,62.

Found: C, 49,06; H, Is 4.93; N, 4.09 To, S, 18,60.

Obtaining methyl-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H - pyrimido[5,4-b][1,4]thiazin-6-yl)-ethyl]-2,5-tiecoat 10:

< / BR>
To a stirred solution of 1.9 g (5.5 mmol) of lactam 9 in 150 ml of dry CH2Cl2one portion was added 1.06 g (7.2 mmol) of tetrafluoroborate trimethylhexane. The solution was stirred for 6 h at 25oC. the resulting mixture was poured into 50 ml of 10% aqueous K2CO3and was extracted with CH2Cl2(3 x 200 ml). The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure. The resulting material was directly used in the next stage.

In a separate flask was placed 1,58 g (of 16.6 mmol) of dry guanidine hydrochloride. Added 600 ml of dry methanol. Dry argon was passed through this solution for 10 min, then added 926 mg (17,1 mmol) of dry sodium methoxide. To the mixture via cannula added raw laktamny ether, obtained previously, in 20 ml of MeOH. The solution was boiled under reflux in an argon atmosphere for 20 hours Summed pH to 4 with 1N HCl and the solvent was removed under reduced pressure. The raw residue was dissolved in 500 ml of CHCl32Cl2obtaining 413 mg whitish solid. This material is then dissolved in 25 ml of hot MeOH and slowly cooled to 4oC for 18 hours, the Solid was collected by filtration to obtain 180 mg (9% yield) of the desired pyrimidinone 10 in the form of a slightly yellow solid.

NMR (d6-DMSO) : 1,72 (m, 1H), of 1.88 (m, 1H), 2,8-up 3.22 (m, 4H), 3,50 (dt, 1H, J = 2, 8 Hz), of 5.99 (brs, 2H), only 6.64 (brs, 1H), 6,98 (d, 1H, J = 3.8 Hz), a 7.62 (d, 1H, J = 3.8 Hz), 10,02 (brs, 1H).

Mass spectrometry high resolution:

Calc. for C14H16N4O3S2: M+Na+, 375,0562. Found: 375,0550.

Can also be used following an alternative way of obtaining pyrimidinone 10. To a stirred solution of 500 mg (of 1.46 mmol) of lactam 9 in 20 ml of dry THF was added 648 mg (1,60 mmol) of the reagent Lawesson (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate - 2,4-disulfide). After this mixture was stirred at 25oC for 20 h, it was poured into 50 ml of a saturated solution of bicarbonate and extracted with 2 x 200 ml EtOAc. The combined organic layers washed with 50 ml saturated NaCl solution and dried (MgSO4) and remove the solvent under reduced D. the doctrine of 525 mg of the corresponding thiolactam 11:

< / BR>
This material is used immediately in the next stage.

To 525 mg thiolactam 11 in a mixture of 10 ml of dry THF and 10 ml of dry methanol is added 1.6 ml of 1N NaOH. To this mixture is added 0.1 ml (1.6 mmol) of methyl iodide to obtain methylated thiolactone, which is used as indicated below without purification. In a separate flask 1.39 g (14.6 mmol) of dry guanidine hydrochloride. To it add 300 ml of dry methanol. Dry argon is bubbled through this solution for 10 minutes, then add 796 mg (14.7 mmol) of dry sodium methoxide.

To the mixture via cannula add raw methylated thiolactam obtained previously. This solution is refluxed in an argon atmosphere for 48 hours Bring the pH to 4 with 1N HCl and under reduced pressure to remove the solvent. The raw residue is dissolved in 500 ml of CHCl3and washed with 2 x 100 ml of water. The organic layer is dried (MgSO4) and remove the solvent under reduced pressure. The raw residue is subjected to flash chromatography on silica gel with 5-10% MeOH/CH2Cl2. This material is then dissolved in 20 ml of hot MeOH and slowly cooled to 4oC for 18 hours, the Solid is collected by the filter is on-3H - pyrimido[5,4-b][1,4] thiazin-6-yl)-ethyl]-2,5-Teenboy acid 12:

< / BR>
To 180 mg (0.51 mmol) of pyrimidinone 10 add 5 ml of 1N NaOH in water. The resulting solution was stirred at 25oC for 20 h After cooling to 0oC bring the pH to 2 with 1N HCl. Solid brown substance is filtered off and washed with water and dried under vacuum to obtain 111 mg (64% yield) of the desired acid 12 in the form of a slightly brown solid.

NMR (d6-DMSO) : 1,72 (m, 1H), 1,92 (m, 1H), 2,78-3,68 (m), 6,07 (brs, 2H), of 6.68 (brs, 1H), 6,92 (d, 1H, J = 3,7 Hz), 7,52 (d, 1H, J = 3,7 Hz), 10,02 (brs, 1H), 12,89 (brs, 1H).

Mass spectrometry high resolution:

Calc. for C13H14N4O3S2: M+, 338,0507. Found: 338,0517.

Getting diethyl ester 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro - 3H-pyrimido[5,4-b] [1,4] thiazin-6-yl)-ethyl] -2,5-cyanoalanine-L-glutamic acid 13

< / BR>
To a stirred solution of 110 mg (0.33 mmol) previously obtained acid 12 in 5 ml of dry DMF is added 48 mg (0.36 mmol) hydrate (1-hydroxy-penetrate, 62 μl (0.36 mmol) of diisopropylethylamine, 86 mg (0.36 mmol) of the hydrochloride of diethyl ether glutamic acid and 106 mg (0.36 mmol) of methiodide 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide. The resulting solution is stirred in an argon atmosphere at 25oC for 20 h and then W water and then with 10 ml saturated NaCl solution and dried (MgSO4). The solvent is removed under reduced pressure and the raw residue is subjected to flash chromatography on silica gel with 0-10% MeOH/CH2Cl2to obtain 120 mg (71% yield) of the desired amide 13 in the form of a slightly yellow amorphous solid.

NMR (d6-acetone) : 1,20 (m, 6H), 2,2 (m, 1H), 2,46 (t, 1H, J = 7,6 Hz), 2,78 (s, 1H), 2,82 (s, 1H), 2,92-3,1 (m, 2H), 3,41 (m, 1H), and 3.72 (dt, 1H, J = 3,0, a 12.7 Hz), was 4.02-4,2 (m, 4H), 4,58 (m, 1H), 5,90 (brs, 1H), equal to 6.05 (brs, 1H), 6.90 to (d, 1H, J = 3.8 Hz), 7,58 (d, 1H, J = 3.8 Hz), 7,78 (d, 1H, J = 8 Hz).

Mass spectrometry high resolution:

Calc. for C22H29N5O6S2: M+H+, 524,1638. Found: 524,1650.

Getting 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H - pyrimido[5,4-b] [1,4]thiazin-6-yl)-ethyl]-2,5-cyanoalanine-L-glutamic acid 1:

To 115 mg (0.22 mmol) of diethyl ether 13 was added 3 ml of 1N NaOH solution in water. The resulting mixture was stirred at 25oC for 14 h, After cooling to 0oC brought the pH to 3.5 with aqueous HCl. The solid was filtered, washed with water and dried under vacuum to obtain 82 mg (80% yield) of the desired acid in the form of a whitish solid.

NMR (d6-DMSO) : 1,62-2,02 (m, 4H), and 2.27 (m, 2H), 2,78-3,00 (m, 3H), 4,27 (dd, 1H, J = 6, 6,8 Hz), 6,00 (brs, 2H), 6,63 (brs, 1H), to 6.88 (d, 1H, J = 3,7 Hz), 7,63 (d, 1H, J = 3,7 who Atria high resolution:

Calc. for C18H21N5O6S2: M+H+, 468,1012. Found: 468,1025.

Anal. Calc. for C18H21N5O6S2< / BR>
with ethyl ether 2-bromothiophene-5-carboxylic acid and 3-methylpropionyl subsequent reduction and acid hydrolysis to obtain the diol intermediate (35).

< / BR>
For C-6(R) compounds the nitrogen atom in the 8-position was introduced by monocotyledonae primary alcohol, followed by substitution with sodium azide. For C-6(S) compounds of the hydroxy-group was inverted by protection of the primary alcohol in the form of a silyl ether, metilirovaniya secondary alcohol, removal of the protective group and education inverted epoxide with sodium hydride. This epoxide is selectively opened in the least inhibited primary position sodium azide. Aspidosperma was restored in the presence of BOC (tert-butoxycarbonyl) anhydride with obtaining alcohols (36).

< / BR>
The sulfur atom in the 5 position was introduced by substitution of the appropriate nelfinavir connection KSAc. Acetylamine group was removed in the basic conditions in the presence of dimethylcarbonate, and as soon as BOC-Susitna group was removed, the free amine spontaneously qi is laktamny ether was treated with 3 equivalents of guanidine in the form of the free base in delegateuser ethanol to obtain 2-amino-4(3H)-oxopyrimidine[5,4-b] [1,4] -thiazines. Hydrolysis of ethyl esters, peptide combination and the hydrolysis was completed the synthesis of glutamic acid (16-17).

< / BR>
2(S)-[[[5-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b] [1,4] -thiazin-6-(R)-yl)ethyl]thiophene-2-yl]carbonyl]amino]entandikwa acid (16).

Obtained in the form of a whitish solid.

So pl. 191-194oC, foams;

[]589+61,9 (c=0,65, 1N NaOH);

IR (KBr) 3389, 3235, 3086, 2924, 1701, 1624, 1545, 1340 cm-1;

1H NMR (DMSO-d6) 1,70-2,04 (m, 4H), to 2.29 (t, 2H, J = 7,3 Hz), 2,90 (m, 2H), 3,13-of 3.53 (m, 3H, partially offset by H2O), the 4.29 (m, 1H), 6.30-in (s, 2H), 6,77 (s, 1H), 6.89 in (d, 1H, J = 3,7 Hz), 7,66 (d, 1H, J = 3,7 Hz) and 8.50 (d, 1H, J = 8.1 Hz), 10,30 (brs, 1H).

Anal. (C18H21N5O6S2]589-57,1 (c=0,61, 1N NaOH);

IR (KBr) 3353, 3094, 2926, 1711, 1641, 1605, 1559, 1454, 1400, 1333, 1279 cm-1;

1H NMR (DMSO-d6) 1,70-2,05 (m, 4H), to 2.29 (t, 2H, J = 7.4 Hz), 2,87 (m, 2H), 3,15-of 3.48 (m, 3H, partially offset by H2O), the 4.29 (m, 1H), 6,03 (s, 2H), 6,66 (s, 1H), 6.89 in (d, 1H, J = 3,7 Hz), the 7.65 (d, 1H, J = 3,7 Hz) and 8.50 (d, 1H, J = 7,7 Hz), of 10.05 (s, 1H), 12,50 (brs, 2H).

Anal. (C18H21N5O6S2< / BR>
where a represents sulfur;

X denotes CH2;

Y represents sulfur;

In denotes hydrogen;

With denotes hydrogen;

R1and R2each independently represents hydrogen or neither and ethyl.

3. Connection on p. 1, in which R1and R2each is hydrogen.

4. Connection on p. 1, selected from diethyl ether (4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido [5,4-b] [1,4]-thiazin-6-yl)-ethyl]-2,5-cyanoalanine-L-glutamic acid) and 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b] [1,4] -thiazin-6-yl)-ethyl]-2.5 cyanoalanine-L-glutamic acid.

5. Pharmaceutical composition having the property of inhibiting the growth and proliferation of cells, comprising the active principle and a pharmaceutically acceptable carrier, diluent or excipient, characterized in that the active agent contains an effective amount of the compounds of formula I

< / BR>
where a represents sulfur;

X denotes CH2;

Y represents sulfur;

In denotes hydrogen;

With denotes hydrogen;

R1and R2each independently represents hydrogen or lower alkyl.

6. The pharmaceutical composition under item 5, wherein R1and R2each is hydrogen.

7. Method of inhibiting the growth or proliferation of cells of microorganisms or higher organisms, characterized in that the recipient mammal or bird, effect efficient which means sulfur;

In denotes hydrogen;

With denotes hydrogen;

R1and R2each independently represents hydrogen or lower alkyl.

8. The method according to p. 7, wherein R1and R2each is hydrogen.

9. Derived thiophenecarboxylate formula VI

< / BR>
where Y represents sulfur;

In denotes hydrogen;

With denotes hydrogen;

R6refers to a group which forms together with CO2easily hydrolyzable group;

R4and R5independently represent hydrogen or an easily removable astonishing group.

10. Connection on p. 9, in which R6is lower alkyl and R4and R5independently represent hydrogen or tert-butoxycarbonyl.

11. Connection on p. 9, a 4-N-(tert-butoxycarbonyl)-3-hydroxy-1-(2-carbomethoxy-5-thiophene)-Butin.

12. Derived thiophenecarboxylate formula VII

< / BR>
where X' denotes CH2;

Y represents sulfur;

In denotes hydrogen;

With denotes hydrogen;

R6refers to a group which forms together with CO2easily hydrolyzable group;

R4and R5independently represent a hydrogen is an alkyl and R4and R5independently represent hydrogen or tert-butoxycarbonyl.

14. Connection on p. 12, which represents a methyl-5-[(4-N-(tert-butoxycarbonyl)-amino-3-hydroxy)-butyl]-thienyl-2-carboxylate.

15. Derived thiophenecarboxylate formula VIII

< / BR>
where X' denotes CH2;

And indicates sulfur;

Y represents sulfur;

In denotes hydrogen;

With denotes hydrogen;

R6refers to a group which forms together with CO2easily hydrolyzable group;

R4and R5independently represent hydrogen or an easily removable astonishing group;

AC represents a lower acyl.

16. Connection on p. 15, in which R6is lower alkyl and R4and R5independently represent hydrogen or tert-butoxycarbonyl.

17. Connection on p. 15, representing methyl-5-[(4-N-(tert-butoxycarbonyl)-amino-3-acetylthio)-butyl]-2-thiophene-carboxylate.

18. Derived thiophenecarboxylate formula IX

< / BR>
where a represents sulfur;

X' denotes CH2;

Y represents sulfur;

In denotes hydrogen;

With denotes hydrogen;

R6refers to a group which forms in the or easily removable astonishing group.

19. Connection on p. 18, in which R6is lower alkyl and R4and R5independently represent hydrogen or tert-butoxycarbonyl.

20. Connection on p. 18, which represents a methyl-5-[(4-N-(tert-butoxycarbonyl)-amino-3-(dimethylallyl)thio)-butyl]-2-thiophenecarboxylate.

21. Derived thiophenecarboxylate formula X

< / BR>
where a represents sulfur;

X' denotes CH2;

Y represents sulfur;

In denotes hydrogen;

With denotes hydrogen;

R6refers to a group which forms together with CO2easily hydrolyzable group.

22. Connection on p. 21, in which R6is lower alkyl.

23. Connection on p. 21, which represents 6-[(5-carbomethoxy-2-yl)-ethyl]-2-carbomethoxy-3-oxo-3,4,5,6-tetrahydro-[1,4]-thiazin.

24. Derived thiophenecarboxylate formula XI"

< / BR>
where a represents sulfur;

X' denotes CH2;

Y represents sulfur;

In denotes hydrogen;

With denotes hydrogen;

R6refers to a group which forms together with CO2easily hydrolyzable group.

25. Connection on p. 24, in which R6is lower alkyl.

26. Soedinenie.

27. Derived thiencarbazone acid of formula XII

< / BR>
where a represents sulfur;

X' denotes CH2;

Y represents sulfur;

In denotes hydrogen;

With denotes hydrogen.

28. Connection on p. 27, which represents [2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[5,4-b] [1,4] thiazin-6-yl)-ethyl] -2,5-tenovuo acid.

29. A derivative of glutamic acid formula

< / BR>
30. Connection on p. 29, having the properties of an inhibitor of the growth and proliferation of cells.

31. Connection on p. 30, having the following structure:

< / BR>
32. Connection on p. 30, having the following structure:



 

Same patents:

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< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

The invention relates to the field of chemical technology, specifically to a method for producing a thiophene-2,5-dicarboxylic acid, which is used as starting product for the production of high-performance optical brighteners for polymeric materials and can be used to obtain a polyester (modified) and polyamide fibres and plastics
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