Ways of getting thiosemicarbazones pyridine-2 - carboxaldehyde and intermediate pyridine-2 - carboxaldehyde

 

(57) Abstract:

The invention relates to an improved process for the preparation of compounds of formula (I), where R4represents N or CH3that includes the interaction of the compounds of formula 2 in which R1represents a group of NO2with thiosemicarbazide with getting thiosemicarbazone formula S1, and subsequent reduction of the obtained compound. A way to get thiosemicarbazone formula TS2, including the interaction of compounds 2, in which R1represents a group NHP with thiosemicarbazide. The proposed methods obtain the intermediate compounds 2, where R1is NO2, NH2, NHP, NPP', N3or CO2R2P and P' represent a protective group, R2represents C1-C3alkyl, R4represents N or CH3and the compounds of formula (4). The proposed means of receipt of thiosemicarbazones pyridine-2-carboxaldehyde allow to increase the yield of target products up to 30% from readily available starting materials. 4 N. and 17 C.p. f-crystals, 3 ill., 1 PL.

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The scope of the invention

The present invention relates to new chemical synthesis of the two is one of the major causes of death, and effective treatment of many solid tumors is still unattainable. It is assumed that new anticancer drugs having a strong inhibitory effect on ribonucleotides, representing an essential enzyme for the replication of cells, would be a useful addition to the medicinal treatment of cancer existing in the present time.

It is well known that the reductive conversion of ribonucleotides to the corresponding deoxyribonucleotides is a key step in DNA biosynthesis. As deoxyribonucleotide present in mammalian cells at extremely low levels, the researchers suggested that the inhibitor ribonucleotides may be more effective than the inhibitor of DNA polymerase, by blocking DNA synthesis. Cm. Cory and Chiba "Combination Chemotherapy Directed at the Components of Nucleoside Diphosphate Reductase", Ingibitors of Ribonucleoside diphosphate reductase Activity, ("Combination chemotherapy aimed at components nucleosidephosphorylases", activity Inhibitors ribonucleopeptide) North, J. G. and Cory A. M., Eds.: Pergamon Press; Oxford, 1989, pp. 245-264. Accordingly, in this work it is assumed that the development of strong inhibitors ribonucleotides could have ecalo study of new thiosemicarbazones -(N)-heterocyclic carboxaldehyde (PCT), the class of the most potent inhibitors ribonucleopeptide. It was reported about a number of the PCT, such as thiosemicarbazone 5-hydroxypyridine-2-carboxaldehyde (NR), thiosemicarbazone 4-methyl-5-amino-1-formilitary (MAIQ-1), thiosemicarbazone 5-(acetylamino)pyridine-2-carboxaldehyde (5-AAR), thiosemicarbazone 3 - and 5-aminopyridine-2-carboxaldehyde (3-AR and 5-AR) and their 4-methylanisole derivatives (3 AMR and 5-AMR), thiosemicarbazone 3 - and 5-hydroxy-4-methylpyridin-2-carboxaldehyde (3-NMR and 5-NMR). Cm. DeConti et al., Cancer Res., 1972, 32, 1455-1462; Agrawa1 et al., J. Med. Chem., 1976, 19, 970-972; French et al., J. Med. Chem. , 1974, 17, 172-181; Lui et al., J. Med. Chem., 1992, 35, 3672-3677; Wang et al., J. Med. Chem., 1992, 35, 3667-3671.

Study the relationship between structure and activity of a number of NTS showed that 3-AP and 3-AMR are much better therapeutic effect against L1210 leukemia, M-109 lung carcinoma and A carcinoma of the ovary of a person, other than NTS, known to the present time. Liu et al., J. Med. Chem., 1992, 35, 3672-3677; Agrawal et al., "The Chemistry and Biological. Activity of the -(N)-Heterocyclic Carboxaldehyde Thiosemicarbazones". Progress in Medicinal Chemistry; Ellis, G. P.; West, G. B., Eds.; Elsevier/North-Holland Biomedical Press: New York, 1978; Vol. 15, pp. 321-356. In addition, 3-AP and 3-AMR are potent agents with significant antitumor activity compared with hydroxyurea (HU) approved the study of these compounds requires large-scale receiving these agents.

As highlighted in Fig.1, the first synthesis of 3-AP and 3-AMR was carried out in the laboratories of the other Alan, Sartorelli (Dr. Alan Sartorelli) at Yale University. Although the previous synthesis was as the advantages of low cost materials used in the production method, the scheme of synthesis proved to be difficult due to the long sequence of reactions, low yields and difficulties. For this reason, the authors of the present invention investigated the synthesis and developed new methods for the preparation of 3-AP and 3-AMR.

Objectives of the invention

The objective of the invention is the development of efficient chemical synthesis of thiosemicarbazone 3-aminopyridine-2-carboxaldehyde (3-AP) and thiosemicarbazone 3-amino-4-methylpyridin-2-carboxaldehyde (3-AMR).

Brief description of the invention

The present invention relates to an improved efficient chemical synthesis of thiosemicarbazone 3-aminopyridine-2-carboxaldehyde (3-AP) and thiosemicarbazone 3-amino-4-methylpyridin-2-carboxaldehyde (3-AMR).

In the present invention developed an efficient synthesis of 3-AP and 3-AMR. According to the method of the present invention the target chemotherapeutic agents derived from readily available source wishesto prior art, the total output is less than 10%.

The present invention relates to a new synthesis of 3-AP and 3-AMR, special key step is the reaction of vanilinovoi on the still (Stille) or HEC (Heck), which flows in the C-2 position of the pyridine fragment, resulting in high yields to 2-vinylpyridinium intermediate connection (often up to 70%), which can easily be converted to the number of synthetic steps, flowing with high outputs, 3-AR 3-AMR, respectively. In this way the pyridine fragment of P, below, is converted into 2-vinyl derivative of 2-VP using reaction vanilinovoi by HEC or Steele, as shown in scheme 2.

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where R represents Cl, Br, I, OMs, OTf or OTs;

R1is NO2, NH2, NHP, NPP', N3or CO2R2;

P and P' represent a protective group;

R2represents Me, Et, Pr or i-Pr;

R3represents H, C1-C20alkyl, aryl, substituted aryl, or CO2R2;

R4represents N or CH3.

Protective groups which can be used as R and R' include ester groups, such as C(O)OR5where R5represents an alkyl group such as methyl, ethyl, impregnated. They may also use other aminosidine groups, which are well known in this field.

The reaction of 2-vanilinovoi preferably occurs when using a reagent selected from the following: VI3Sn=NDS3, (OH)2-B-CH=CHR3, ClZnCH= CHR3and XMgCH=CHR3(Grignard reagent, where X represents a halogen such as I, Br, Cl, among others). The reaction vanilinovoi proceeds in the presence of triphenylphosphine (h3and/or tetrakis(triphenylphosphine)palladium [Pd(h3)4), usually in a solvent such as toluene, xylene or other organic solvent under heating. With the introduction of the vinyl group at C-2 position of the pyridine such a group can be subsequently converted into the aldehyde (by ozonolysis or equivalent method), which can then be transformed into thiosemicarbazone of carboxaldehyde in obtaining 3-AR 3-AMR. In an alternative reaction vanilinovoi using styrene, 3-methylpropanoate or similar inilirely reagents in combination with palladium acetate [Pd(OAc)2] and triphenylphosphine (h3will introduce a vinyl group at C-2 position of the pyridine fragment, which can easily be converted into 2-carboxaldehydes of the invention include improved synthesis of the preceding level. Prior art transformation derived 2-chloropyrimidine 2-methylpyrimidine derivative represented two-stage process, with a total yield of only 60%. According to the present invention, this conversion is carried out in one stage with the release of approximately 90%. When carrying out such motivation in terms Suzuki (Suzuki) the present invention in addition to reducing the number required for the synthesis stages and increasing the overall output also simplifies the process and, therefore, simplifies large-scale commercial production. High yield in this reaction is an unexpected result.

In addition, while the prior art requires the difficult transformation of 2-carboxaldehyde in acetal and restoration of the nitro group in 3-position before engagement with thiosemicarbazide in the 2-position, the authors of the present invention discovered a shorter and more efficient way, in which 2-carboxaldehyde directly interacts with thiosemicarbazide and then simply restore the nitro group.

In preferred aspects of the present invention these methods have the advantage that allow the generation of large number of outputs. Methods according to this invention receive anticancer compounds of high purity with outputs suitable for large-scale and commercial reception. These methods are addressed to a relatively low outputs of ways in the prior art and make the organization of serial production of 3-AP and 3-AMR economically viable.

Brief description of figures

In Fig.1, scheme 1 shows the synthesis of 3-AP and 3-AMR on the prior art, each synthesis proceeds via the pyridine 2-carboxaldehyde intermediate compound (4 and 11). In the case of 3-AR synthesis proceeds, culminating in a total yield of approximately 9.3 percent. In case 3, AMR synthesis ends with a total output of approximately 2.3%.

In Fig. 2, scheme 2, shows two new synthesis of 3-AR of 2-chloro-3-nitropyridine 1 and a new synthesis of 2-chloro-3-aminopyridine 19. These syntheses lead to the end result with the total outputs in the range from 31.5% and 68.4%. Indeed, the chemical process described for the synthesis, was used to obtain 3-AR in excess of 20 grams in one stage.

In Fig. 3, scheme 3, the two new synthesis of 3-AMR via the intermediate 2-carboxaldehyde 11. These syntheses lead to the end repolished in this description to refer to the pathological process, which leads to the formation and growth of cancerous or malignant tumors, i.e., an abnormal tissue that grows as a result of rapid multiplication (proliferation) of cells, often more rapidly than normal tissue, and continues to grow after exposure, which triggers the termination of the new growth. Malignant tumors have a partial or complete deficiency of the structural organization and functional coordination with normal tissue and for the most part penetrate into the surrounding tissue, forming metastases in several places, and will probably reappear after attempted removal and to cause death of the patient, if you do not take adequate treatment. As used herein, the term "neoplasia" is used to describe all of the cancer sickness and covers or includes the pathological process associated with malignant blood, ascitic and solid tumors.

The term "protected" is used to denote a phosphate group or a hydroxyl group in any one or more of the intermediate compounds, which are protected from undesirable interactions, but the protection which can easily be removed under certain conditions. The protective group, the cat is ilililil, tert-butyldimethylsilyl, tert-butyl, triphenylsilanol and tert-butyldiphenylsilyl, along with many others, including ester groups such as methyl, ethyl, sawn, ISO-propyl, bucilina and tert-bucilina ester groups, along with others. Protective groups can be selected in a wide range of class silyl protective group, the protective groups, ethers and the protective groups of esters, each protective group is selected for its ability to protect a fragment of spam flowing interaction and ease of their removal and chemical compatibility. As discussed earlier, the amine groups in the intermediate compounds of the present invention can also be protected.

Improved synthesis of 3-AP and 3-AMR of the present invention, have higher yields and more safely and easily implemented, highlighted in schemes 2 and 3, respectively. As proven in Fig.2, for the synthesis of 3-AR were developed three synthetic way. Favorably reduced the number of stages in the method known from the prior art (see Fig. 1, scheme 1), by excluding stages of introduction acetaldol protect and unprotect the synthesis predshestvuyuschee make hydrazone 15 and subsequent functional recovery of nitro group to amino group is carried out with the use or tin dichloride (see Atwal K. S., et al., J. Med. Chem., 1996, 39, 305-313, to describe reactions of this type), or sodium sulfide (recovery Zinin, see Porter, H. K., Org. React., 1973, 20, 455-483). Along the path From N-Boc-protected 2-carboxaldehyde 22 directly injected into the reaction thiosemicarbazide and simultaneously removing the protective group with 3 AR. These General approaches lead to 3-AR with good outputs.

Three different approaches are shown in scheme 2 for the synthesis of 2-carboxaldehyde pyridine intermediates (compounds 4 and 22). In the first of these three approaches is shown as path A, methylation of 2-chloropyridine connection 1 with subsequent oxidation of the 2-methyl group with selenium dioxide leads to 2-carboxaldehyde connection 4, which is easily converted into 3-AR in two stages with high yields. In an alternative approach, shown as a branch from the path And 2-methyl-3-nitropyridine 3 interacts with dimethylformamide-dimethylacetal (DMFDMA, although this reaction can be used any such acetylene analogues DMFDMA) to obtain the intermediate compounds 3A, the subsequent oxidation periodates sodium (NaI4) leads to aldehyde 4 with a total yield of 84%, a significant improvement compared with the oxidation method 2 may be implemented with a total yield of 55%.

In an alternative method, shown as the upper branch of the path, the introduction of the 2-vinyl group using a palladium-mediated reaction vanilinovoi the Steele as a key stage (see Attwood M. R., et al., Tetrahedron Lett. , 1996, 37, 2731; Skoda-Foldes R., et al., Tetrahedron Lett. , 1996, 37, 2085; and Sabramanyam S., et al., Tetrahedron Lett., 1996, 37, 459), followed by ozonolysis leads to 2-carboxaldehyde connection 4 with a very high yield. In the third method, shown as path and the lower branch of the path, used palladium-mediated reaction vanilinovoi Hake (see Sit, S. Y., et al., Bioorg. Med. Chem. Lett., 1996, 6, 499; and I. Ojima, et al., Chem. Rev., 1996, 96, 635-662, for descriptions of the reactions of this type), followed by ozonolysis to obtain carboxaldehyde compounds 4 or 22 (where R represents a protective group for 3-aminopropane, including t-Boc group, ester group or similar protective group, which is well known in this area and consistent with the chemistry used in this reaction sequence), which can easily turn into a 3-AR using thiosemicarbazide then using conditions (e.g., acid) to remove a group protecting the amino group, or directly using thiosemicarbazide in Hcl. in accordance with the prior art, unexpectedly favorable results. This represents a great advantage for the industrial scale preparation of 3-AR for clinical purposes and the final therapeutic applications.

In Fig.3 presents two efficient ways of synthesis of 3-AMR. As is illustrated in Fig.3, synthesis, starting with dimethylpyridine 8, reduces the number of stages of the initial synthesis and increases total output. The nitrosation of dimethylpyridine 8 with subsequent oxidation of the 2-methyl group leads to a 2-carboxaldehyde 11, which is directly subjected to interaction with thiosemicarbazide, receiving 2-thiosemicarbazone 27 high yield. Finally, 2-thiosemicarbazone 27 turn 3 AMR or in terms of recovery Zinio, or using tin dichloride, causing the yield of the reaction is greater than about three times the yield in the synthesis of 3-AR in the prior art. Synthesis, starting with a substituted analogue of pyridine 24, provides a more efficient synthesis of 2-carboxaldehyde 11 through the use of reaction vanilinovoi the still flowing with high yields, after transformation of the 2-hydroxyl group equivalent of pyridine 24 2-OTf group. Ozonolysis of 2-vinyl group leads to 2-carboxylic what hodom of thiosemicarbazone 27, which restores 3 AMR to complete the synthesis of the use or restoration conditions on Zinio, or tin dichloride. The path of synthesis, including ventiliruemye the Steele with getting the key intermediate compound 11, eliminates difficult of nitration and oxidation of 2-methyl group and unexpectedly highly improves the overall yield in excess of 15 times the output of the 3-AMR in the method of obtaining the prior art.

Although the preferred synthetic chemical methods have been described above, an ordinary person skilled in the art it will be obvious that to get similar results, you can use the replacement stages or equivalent stage. For example, the technician can easily replace some reagents and virtually all of the solvents used to obtain the intermediate compounds, as indicated in the various schemes. Education 2-vinylpyridine intermediate compounds, for example, can easily be performed with any suitable vinyl-forming reagents or combination of reagents (including triphenylphosphine or tetranitroaniline palladium as appropriate) and any suitable solvent. Oxidizing agents for converting vinyl gr is on and the ozone but can also be used with other suitable oxidizing agents. In the case of hydrogenolysis (for example, 3-nitro, 3-amino) suitable application of SnCl2or Na2S. an Ordinary person skilled in the art can easily replace the use of one of the protective group to another protective group, consistent with the overall chemistry used in the synthesis.

In particular, the key to effective synthesis of 3-AP or 3 AMR is flowing with high yield introduction of a methyl or vinyl groups, preferably vinyl groups, preferably vinyl, 2-position of the pyridine fragment using the reactions of vanilinovoi Hake or Steele or reactions of methylation in the conditions of the Suzuki. These reactions take place in the 2-position of the pyridine fragment with high yield (typically greater than 50% and, in most cases, greater than 70%). The advantage of the reaction of vanilinovoi is that the 2-vinyl group can be easily converted using flowing with a high yield of ozonolysis reaction carried out in a polar solvent such as methanol, 2-carboxaldehyde group for further transformations in 2-thiosemicarbazone. Preferred reaction vanilinovoi representatives of the following: Bu3SnCH= CHR3, (OH)2-B-SnCH=CHR3, ClZnCH=CHR3and XMgCH=CHR. The reaction vanilinovoi proceeds in the presence of triphenylphosphine (h3and/or tetrakis(triphenylphosphine)palladium [Pd(PPh3)4] usually in a solvent such as toluene, by heating. The advantage of the reaction of methylation in the Suzuki conditions compared to the two-step methylation of the prior art is to significantly increase the yield, reduce the number of stages and, therefore, the required processing and ease of scale synthesis for commercial production. Alternatively, for the introduction of the vinyl group in the 2-position 3-nitropyridine can best way to implement the interaction of 2-methyl-3-nitropyridine with dimethylformamide-dimethylacetal (DMFDMA) to give 2-dimethylamino-vinyl-3-risperidone connection 3A, the subsequent oxidation which periodates sodium (NaIO4results carboxaldehyde 4 with unexpectedly high 84% yield.

With the introduction of a methyl or vinyl group at C-2 position of the pyridine this group can be converted into aldehyde, which is finally transformed into thiosemicarbazone of carboxaldehyde. Whereas in prior art the d interaction with thiosemicarbazide 2-position, this method is shorter and more efficient way, in which 2-carboxaldehyde directly interacts with thiosemicarbazide and then simply restore the nitro group. Recovery of 3-nitro in this way of synthesis is easily accomplished using standard conditions recovery (SnC12or PA2S, along with other means of recovery). Synthesis of 3-AP or 3 AMR in accordance with the present invention ends with an unexpectedly high yield of at least 30%, based on readily available starting materials. In some embodiments the output may reach 55% or more.

The present invention is further described, for illustrative purposes only, in the following examples. The person skilled in the art should understand that these examples are not restrictive and that changes in details may be made without departing from the essence and within the scope of the present invention.

Examples

This section provides detailed conditions of the reactions and the characteristics of each connection in the following methods. All NMR spectra were recorded at 300 MHz for1H and 75 MHz for13With the NMR spectrometer QE Plus 300 MHz. Mass spectra of registriere. All solvents were distilled before use.

Synthesis of compound 3 (2-metal-3-nitropyridine) (3)

Method 1. Into the flask containing diethylmalonate (20 g, 0.125 mol), add sodium (2.0 g, 0,087 mol). The reaction mixture is stirred for 1 hour at room temperature, and then heated to 120oC (oil bath temperature) for 50 minutes. To this yellow suspension solids add toluene (120 ml) followed by addition of a solution of 2-chloro-3-nitropyridine 1 (12.8 g, 0.08 mol) in 40 ml of toluene. The reaction mixture is heated at the boiling point under reflux for 8 hours and then stirred overnight at room temperature. The solvent is removed under reduced pressure and the residue is dissolved in 30% N2SO4(60 ml). This reaction mixture is heated at 125oC (oil bath) for 7 hours, cooled and poured on ice (200 g). The reaction mixture was neutralized with a saturated solution Panso3, filtered through celite, extracted several times with diethyl ether. The combined extracts dried over anhydrous Na2SO4. The solvent is evaporated and the residue is distilled under reduced pressure, obtaining of 6.65 g (60%) of the desired product 3.

(578 mg, 0.5 mmol) and K2CO3(2,073 g, 15.0 mmol) in dioxane (25 ml) is heated at the boil under reflux for 2 days. The mixture is then cooled to room temperature and filtered. The solvent is removed and the residue is subjected to flash chromatography (50% ethyl acetate in hexano), getting 623 mg (90%) of 2-methyl-3-nitropyridine 3.

1H-NMR (Dl3) is 2.88 (s, 3H), of 7.36 (DD, 1H, J=4,8 and 8.4 Hz), of 8.28 (DD, 1H, J=1.2 and 8.1 Hz, 8,73 (DD, 1H, J=1.2 and 4.8 Hz).

The synthesis of compounds 2-carboxaldehyde (4)

To a solution of 2-methyl-3-nitropyridine 3 (2,07 g, 0.015 mol) in 35 ml of dioxane is added selenium dioxide (1.88 g, is 0.017 mol). The reaction mixture is heated at the boil under reflux for 16 hours, then cooled to room temperature and filtered. The solvent is removed under reduced pressure and the residue purified flash chromatography on silica gel (hexane-tO=1:1) to give 1.60 g (70%) of the target aldehyde 4.

1H-NMR (CDCl3) 7,71 (d, 1H, J=4.8 and 8.2 Hz), 8,29 (DD, 1H, J=1.1 and 8.0 Hz), 9,01 (d, 1H, J=1.1 and 4.5 Hz), 10,31 (s, 1H).

An alternative synthesis of compounds 2-carboxaldehyde (4)

A solution of 2-methyl-3-nitropyridine (3) (276 mg, 2 mmol) and dimethylformamide-dimethylacetal (DMFDMA) (477 mg, 4 mmol) in dimethylformamide (DMF) (1 ml) and negreau night. The solvent is removed under reduced pressure and the residue dried in vacuum. The reaction mixture was absolutely clean and contained a single product, compound 3A - 2-dimethylaminovinyl-3-nitropyridine, which is used in the next stage of oxidation without further purification. A solution of 3A, obtained above, and the NaI4(1,283 g, 6 mmol) in 50% aqueous THF (20 ml), stirred at room temperature for 2 hours, filtered and extracted several times CH2CL2. The combined extracts washed with saturated saline and dried over anhydrous Na2SO4. Emit flash chromatography on silica gel (hexane - EtOAc=1:1) to give 256 mg (84%) of 2-carboxaldehyde 4.

Synthesis gerasinomova connection 15 from 2-carboxaldehyde (4)

A mixture of carboxaldehyde 4 (750 mg, is 4.93 mmol) and thiosemicarbazide (540 mg, of 5.92 mmol) in 70% ethanol (25 ml) was stirred at room temperature for 6 hours, filtered and washed with N2OH, C2H5OH, diethyl ether and dried in vacuum, obtaining 893 mg (80%) of the target hydrazone 15.

1H-NMR (DMSO-d6) 7,09 (ush., 1H), to 7.67 (DD, 1H, J=4.9 and 8.2 Hz), of 8.27 (s, 1H), scored 8.38 (d, 1H, J=7,7 Hz), 8,60 (ush., 1H), cent to 8.85 (d, 1H, J=4.4 Hz), of $ 11.97 (s, 1H).

13C-NMR (DMSO-d6) 125,226.

Synthesis of 2-vinylpyridine connection 16

A solution of 2-chloro-3-nitropyridine 1 (417 mg, 2,63 mmol), Pd(PPh3)4(32 mg, was 0.026 mmol), triphenylphosphine (20 mg, 0,078 mmol) and vinyltrimethylsilane (1,00 g, and 3.16 mmol) in toluene (15 ml) is heated at the boil under reflux for 2 hours. The reaction mixture is cooled to room temperature and then quenched with water (10 ml). The resulting mixture was extracted with EtOAc (330 ml). The combined organic layers are dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue purified by chromatography on silica gel (20-30% EtOAc/hexane), getting 339 mg (86%) of the desired product 16 in the form of a pale yellow oil.

1H-NMR (Dl3) is 8.75 (DD, 1H, J=1.3 and 4.5 Hz), 8,16 (DD, 1H, J=1.3, 8.1 Hz), 7.23 percent and 7.36 (m, 2H), 6,59 (DD, 1H, J=1,6 and 16.7 Hz), 5,70 (DD, 1H, J= 1,6 and 10.4 Hz);

LRMS m/e 151 (MN+).

Synthesis of 2-polyacetylene and 2-carboxaldehyde compounds (17 and 4) from 2-vinylpyridine connection (16)

A methanol solution (20 ml) of 2-vinylpyridine) - derivatives 16 (800 mg, 5.33 mmol) is subjected to ozonolysis at -78oC for 15 minutes. The reaction is quenched (at -78o(C) Me2S (2.2 ml) and the resulting reaction mixture is stirred over night at room temperature. The solvent is evaporated and the residue evaluation of the P> Range 1H-NMR corresponds to previously published literature data (Santorelli et al., J. Med. Chem., 1992, 35, 3672-3677).

1NMR Polyacetal 17 (CDCl3): 8,78 (m, 1H), 8.34 per (m, 1H), EUR 7.57 (m, 1H), 6,10 (d, 1H, J=8,7 Hz), of 5.53 (m, 1H), 3,47 (s, 3H).

Synthesis of 2-vinyl-ester compounds 18

A mixture of 2-chloro-3-nitropyridine 1 (1.20 g, 7.6 mmol), methyl acrylate (1.31 g, of 15.2 mmol), triethylamine (0,92 g, 9.1 mmol), triphenylphosphine (0,60 g, 2.28 mmol), Pd(OAc)2(0.17 g, from 0.76 mmol) and 15 ml of DMF in a sealed ampoule is heated at 120oWith in 24 hours. The reaction mixture is cooled to room temperature and then quench the reaction with water (10 ml). The resulting mixture was extracted with tO (330 ml). The combined organic layers washed with saturated saline, dried over Na2SO4and filtered. The filtrates are concentrated and the residue purified by chromatography on silica gel (hexane: tO=4: 1), receiving 0,80 g (51%) of the desired product 18 as a yellow solid.

1H-NMR (Dl3) cent to 8.85 (DD, 1H, J=1.5 and 4.5 Hz), 8,16 (DD, 1H, J=1.5 and 8.1 Hz), 7,49 (DD, 1H, J=4,8 and 8.4 Hz), 7,22 (d, 1H, J=15.3 Hz), 3,85 (c, 3H).

LRMS m/e 201 (MN+).

HRMS calculated for C9H8N2ABOUT4208,0484 found 208,0484.

Synthesis of 2-polyacetylene and 2-carbonl-methyl chloride (12:1; 130 ml) is subjected to ozonolysis at -78oWith control over the course of the reaction is carried out by TLC. After completion of the reaction the excess of O3remove, barbotine through the reaction mixture O2at -78oC for 5 minutes. Then the reaction quenched (at -78oC) using the Me2S (5 ml) and the resulting reaction mixture was stirred at room temperature overnight. The solvent is evaporated and the residue purified by chromatography on silica gel (hexane:tOAc=4:1 to hexane:tO=1: 1), receiving 0,286 g (83%) of a mixture of products and 17 4 (17/4=1:2).

Synthesis gerasinomova connection 15 from a mixture of Polyacetal and carboxaldehyde (17 and 4)

To an aqueous-ethanol solution (10 ml ethanol and 5 ml of water) aldehyde 4 and polyacetale 17 (850 mg, is 4.85 mmol) is added at room temperature conc. HCl (1 ml), and then thiosemicarbazide (483 mg, of 5.34 mmol). The reaction mixture was stirred at room temperature for 6 hours. At this point, the yellow solid is collected by filtration. The thus obtained solid substance was washed successively with water and ethanol three times and dried in high vacuum for 1 hour, obtaining 1.0 g of the desired product 15 with the release of 92%.

Synthesis of compound 7 (3-AR) of the hydrazone (15)

Preactional the mixture is heated at boiling under reflux overnight in an atmosphere of N2and filtered. The solid crude product is dissolved in 30 ml of hot water and filtered. The filtrate is then adjusted to pH 7.5 with saturated solution of NaHCO3and stirred at room temperature for 30 minutes, filtered, washed with H2O, C2H5OH and diethyl ether. The obtained yellow solid product additionally repeatedly extracted with THF. The combined THF extracts evaporated and the residue is dried in vacuum, obtaining 316 mg (81%) 3-AR.

Method 2. The mixture of nitro compounds 15 (450 mg, 2.0 mg) and Na2S (468 mg, 6 mmol) in a mixture of H2O/S2H5OH (1:1, 20 ml) was stirred at room temperature for 18 hours, concentrated. The residue was adjusted to pH 7.5 1N Hcl solution, filtered, washed with N2OH, C2H5OH, CH2CL2and dried in vacuum, obtaining 355 mg (91%) of 3-AR 7.

1H-NMR (DMSO-d6) to 6.43 (ush., 2H), 7,07 (m, 2H), 7,80 (DD, 1H, J=1,2 and 4.2 Hz), 7,95 (ush., 1H), 8,15 (ush., 1H), 8,31 (s, 1H), of 11.29 (s, 1H).

13C-NMR (DMSO-d6) 122,2, 124,4, 132,8, 137,1, 144,0, 149,2, 177,0.

LRMS (FAB) m/e 196 (MN+).

HRM3 calculated for C7H9N5S 196,0657 found 196,0657.

Synthesis of 2-aminopyridine derived 20

Method 1. The reaction is carried out in a sealed ampoule
l), triphenylphosphine (1.31 g, 5.0 mmol) and Pd(OAc)2(0.12 g, 0.50 mmol) in DMF (20 ml) is heated at 130oC for 24 hours in a sealed ampoule. After that the reaction mixture is cooled to room temperature and quench the reaction with saturated solution of Panso3(10 ml) and water (10 ml). The reaction mixture was extracted with EtOAc (g ml). The combined organic layers washed with saturated saline solution, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo, the residue chromatographic (25% ethyl acetate in hexano) to give 1.47 g (75%) of the desired product 20.

Method 2. The reaction carried out at 1 atmosphere

A suspension of 2-chloro-3-aminopyridine 19 (20 g, 155,6 mmol), styrene (89 ml, 778 mmol), sodium bicarbonate (26 g, 311 mmol), triphenylphosphine (2J g, 78 mmol) and Pd(OAc)2(1,74 g, 7.8 mmol) is heated at 135oWith in 48 hours. After that the reaction mixture is cooled to room temperature and then was added 100 ml of ethyl acetate. This mixture is filtered through celite and the filtrate concentrated in vacuo. The remainder chromatographic (25% ethyl acetate in hexano), receiving an increase of 22.7 g (74%) of the desired product 20 as a yellow solid.

Synthesis of aldehyde 22 derived from 2-aminopyridine 20

Derived billaut (t-Boc)2O (of 6.68 g, 30,61 mmol). After stirring this solution at room temperature for several hours to add a further quantity (t-Boc)2O (2,78 g of 12.76 mmol). The reaction mixture is additionally stirred for 15 hours at room temperature. Then from molochnotovarnuyu suspension evaporated solvent. After removal of solvent, the obtained residue is placed in 100 ml of a mixture of EtOAc/Et2O (1:1). The resulting solution was washed with saturated saline solution. The organic layer is separated and stored. The aqueous layer was again extracted with the same mixture of solvents (g ml). The combined organic layers are dried and concentrated in vacuo to give 10 g of crude product 21 as a light brown solid product.

The crude N-Boc protected derivative of pyridine 21 (~25.5 mmol) is dissolved in Meon (120 ml) and dichloromethane (30 ml). The resulting solution was cooled to -78oWith and subjected to ozonolysis for -45 minutes. Reaction stop Me2S (8 ml) and stirred at room temperature overnight. The solvents are removed in vacuo, the residue is purified by chromatography on silica gel (10-15% ethyl acetate in hexano), receiving 5,23 g (92% for two steps) of the target aldehyde 22 in the form of a white t and thiosemicarbazide (622 mg, 7,27 mmol) in a mixture of EtOH/H2(22.5 ml, ethanol content 67%) add 3 ml conc. HCl. The resulting solution was heated at the boil under reflux for 3 hours. The reaction mixture is cooled to room temperature and filtered. The crude yellowish salt of 3-AR-Hcl transferred into the flask. In this flask, add 40 ml of hot water and 8 ml of 10% NAHCO3. The mixture is stirred at room temperature for 1 hour (at pH~7.5V). The solid is filtered off and then washed with water (10 ml), EtOH (3 ml) and Et2O (10 ml). The obtained solid is dried in high vacuum for several hours, getting 1,195 g (93%) target 3-AR 7.

Synthesis of compound 10

Fuming sulfuric acid (500 g, 5.1 mol) is slowly added to 2,4-lutidine 8 (55 ml, 0.48 mol) and cooled in an ice bath with stirring. Then slowly add potassium nitrate (87,5 g, 0.86 mol). The reaction mixture was stirred at room temperature for 1 hour and then heated at 110oC for an additional 7 hours, cooled to room temperature and stirred over night. The reaction mixture was poured on ice (1.0 kg) and neutralized to pH 9 solid NaOH, extracted with ether. The combined extracts dried over anhydrous PA2SO4

1H-NMR (CDC13) to 2.35 (s, 3H), 2.57 m (s, 3H), 7,13 (d, 1H, J=4,8 Hz), 8,46 (d, 1H, J=5.0 Hz).

Synthesis of compound (11)

A mixture of 3-nitropyridine 10 (760 mg, 5 mmol) and selenium dioxide (555 mg, 5 mmol) in 15 ml of dioxane is boiled for 14 hours in an atmosphere of N2add additional SO2(555 mg, 5 mmol). The reaction mixture is refluxed for another 8 hours, filtered through celite. The solvent is removed under reduced pressure and allocate the remainder of the flash chromatographia on silicagel (hexane:tO=2:1) to give 357 mg (43%) of aldehyde 11.

1H-NMR (CDC13) to 2.42 (s, 3H), 7,54 (d, 1H, J=4.9 Hz), 8,76 (d, 1H, J= 4.9 Hz), 10,02 (s, 1H).

Synthesis of hydrazone 27 from 2-carboxaldehyde (11)

A mixture of aldehyde 11 (3,110 g, 18,73 mmol) and thiosemicarbazide (2.65 g, 29,08 mmol) in 70% ethanol is stirred at room temperature for 8 hours, filtered, washed with N2O, C2H5OH, diethyl ether and dried in vacuum, obtaining 4.12 g (92%) of hydrazone 27.

1H-NMR (DMSO-d6) of 2.30 (s, 3H), 6,68 (ush., 1H), 7,58 (d, 1H, J=5,1 Hz), of 8.04 (s, 1H), 8,65 (d, 1H, J=4,8 Hz), 8,72 (ush., 1H), 12,01 (s, 1H).

13C-NMR (DMSO-d6) 615,7, 126,5, 137,7, 139,6, 142,3, 144,9, 150,5, 178�about 240,0557.

Synthesis of 2-O-Tf compounds 25

To 2-hydroxy-3-nitro-4-methylpyridine 24 (is 3.08 g, 20 mmol) and 4-dimethylaminopyridine (2,44 g, 20 mmol), dissolved in 5 ml of CH2Cl2slowly add the anhydride of triftoratsetata (5.7 g, 21 mmol) at 0oC. the Reaction mixture was stirred at 0oWith overnight, then diluted with 200 ml of CH2Cl2followed by washing with water and saturated saline solution, dried over gSO4. The crude compound after removal of the solvent chromatographic on a column of silica gel using 50% ethyl acetate in hexane, receiving of 4.95 g of target compound 25 (87%).

1H-NMR (DMSO-d6) scored 8.38 (d, 1H, J=5,1 Hz), 7,39 (d, 1H, J=5,1 Hz), 2,53 (s, 3H).

Synthesis of 2-vinylpyridine connection 26

A mixture of triflate (salt triftoratsetata) 2-hydroxy-3-nitro-4-methylpyridine 25 (7,74 g, 27,06 mmol), tributyltinhydride (10.3 g, 32,47 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.56 g, 1.35 mmol) in 100 ml of anhydrous toluene is heated at the boil under reflux for 3 hours, then cooled to room temperature and quenched the reaction by adding 20 ml of saturated salt solution. The mixture is then extracted with ethyl acetate (CH ml) and the combined organic layers is agile (hexane: ethyl acetate= 5:3), getting 2,82 g of target compound 26 (yield 70%).

1H-NMR (DMSO-d6) 8,51 (d, 1H, J=5,1 Hz), 7,13 (d, 1H, J=5,1 Hz), of 6.66 (DD, 1H, J=10.5 and 12.3 Hz), 6,55 (d, 1H, J=1.8 Hz), 5,63 (DD, 1H, J=10.5 and 1.8 Hz), 2,32 (s, 3H).

HRMS calculated for C8H8N2O2164,0586 found 164,0586.

Synthesis of 2-carboxaldehyde 11 from 2-vinylpyridine connection 26

A solution of olefin 26 (a 4.03 g, 24,54 mmol) in 100 ml of methanol is subjected to ozonolysis at -78oC and the reaction monitored by TLC. After completion of the reaction the excess of O3remove, barbotine through the reaction mixture ABOUT2at -78oC for 5 minutes. The reaction is quenched (at -78o(C) Me2S (10 ml) and the resulting reaction mixture was stirred at room temperature overnight. The solvent is evaporated and the residue purified by chromatography on silica gel (hexane: tO=4:1 to hexane: tO=2:1) to give 3.51 g (96%) of aldehyde 11.

Synthesis of compound 14 (3 AMR) from gerasinomova connection 27

Method 1. To a solution of SnC122H2O (2,256 g, 10 mmol) in 6 ml ethanol add nitrosoaniline 27 (478 mg, 2 mmol). The reaction mixture is heated at boiling under reflux in an atmosphere2during the night, cooled and filtered. The solid product solution is live at room temperature for 30 minutes, filtered and washed with N2O2H5HE and diethyl ether. The obtained yellow solid product is then repeatedly extracted with THF. The combined extracts evaporated to dryness, getting 227 mg 3 AMR 14. The first ethanol, the filtrate evaporated and the residue was adjusted to pH 8 with a saturated solution Panso3, extracted with THF twice. The combined THF extracts evaporated and the solid residue washed with H2O, C2H5OH and diethyl ether. For additional purification of the solid product several times extracted with THF. The combined THF extracts evaporated, receiving an additional portion of 3-AMR (45 mg). Total yield: 65% (272 mg).

Method 2. A solution of nitro compounds 27 (120 mg, 0.5 mmol) and Na2S (117 mg, 1.5 mmol) in 6 ml of a mixture 1:1 H2O/C2H5OH is heated at the boil under reflux for 3 hours in an atmosphere of N2. The solvent is concentrated and then brought to pH 7 1N Hcl solution, filtered and washed with N2OH, C2H5OH, CH2Cl2and dried in vacuum, obtaining 65 mg (62%) 3 AMR 14.

1H-NMR (DMSO-d6) of 2.16 (s, 3H), 6,16 (ush., 2H), 6,99 (d, 1H, J=4.4 Hz), 7,76 (d, 1H, J=4.4 Hz), 7,93 (ush., 1H), 8,17 (ush., 1H), a 8.34 (s, 1H), 11,33 (s, 1H).

FABMS calculated for C8H11N5

Values used abbreviations are presented in the table.

1. The method of obtaining pyridine-2-carboxaldehyde compounds of the formula

< / BR>
where R1is NO2, NH2, NHP, NPP', N3or CO2R2;

R and R' represent a protective group;

R2represents methyl, ethyl, propyl or isopropyl;

R4represents N or CH3,

comprising the reaction of vanilinovoi the compounds of formula

< / BR>
where R represents Cl, Br, I, -O-S(O2)-CH3, -O-S(O2)-CF3or-O-S(O2)-C6H4-CH3-a pair of;

R1, R2, R4, R and R' are defined above, to obtain compounds of the formula

< / BR>
where R1, R2, R4P and P' are defined above;

R3represents H, C1-C20alkyl, aryl, substituted aryl, or CO2R2;

subsequent ozonolysis of the obtained compound 2-VP obtaining compound 2-N -

p. 1, in which R3is N.

4. The method according to p. 1, in which R3represents a phenyl group.

5. The method according to p. 1, in which R4is N.

6. The method according to p. 1, in which R4is CH3.

7. The method according to p. 1, in which R1is NO2.

8. The method according to p. 1, in which R1represents NH2.

9. The method according to p. 1, in which R represents-O-S(O2)-CH3, -O-S(O2)-C6H4-CH3-steam or-O-S(O2)-CF3.

10. The method of producing thiosemicarbazones pyridine-2-carboxaldehyde formula

< / BR>
where R4represents N or CH3,

including the interaction of the compounds of formula

< / BR>
with thiosemicarbazide with getting thiosemicarbazone formula TS1

< / BR>
subsequent reduction of the obtained compound TS1 for recovery of nitro group to amino group.

11. The method according to p. 10, in which R4is N.

12. The method according to p. 10, in which R4is CH3.

13. The method according to p. 10, in which the specified stage of recovery is carried out in the presence of tin dichloride.

14. The method according to p. 10, in which is yosemitenational formula

< / BR>
where R4represents N or CH3;

P represents a protective group,

including the interaction of the compounds of formula

< / BR>
with thiosemicarbazide with obtaining the above thiosemicarbazone.

16. The method according to p. 15, in which R4is N.

17. The method according to p. 15, in which R4is CH3.

18. The method according to p. 15, in which the specified protective group R represents-C(=O)O-(CH3)3.

19. The method of obtaining the compounds of formula 4

< / BR>
including the interaction of the compounds of formula 3:

< / BR>
with dimethylformamide-dialkylated with the formation of the compounds of formula 3A

< / BR>
followed by the interaction of compounds 3A with an oxidizing agent with the formation of compounds 4, wherein the specified connection 4 allocate at least 75% yield based on the specified connection 3.

20. The method according to p. 19, wherein said dimethylformamide-dealkylation represents dimethylformamide, dimethylacetal,

21. The method according to p. 19, wherein said oxidizing agent is periodate sodium.

 

Same patents:

The invention relates to a method for producing compounds of formula (I) by the coupling of compounds of formula (II) with the compound of the formula (III) and a base in the presence of a solvent at elevated temperature

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to a continuous method of hydrolysis of cyanopyridines in adiabatic conditions, which is a continuous Association of two or more of the supplied flow with formation of a reaction mixture containing cyano, water and a base, heating it to a temperature sufficient to initiate the hydrolysis of the cyano

The invention relates to a continuous method of hydrolysis of cyanopyridines in adiabatic conditions, which is a continuous Association of two or more of the supplied flow with formation of a reaction mixture containing cyano, water and a base, heating it to a temperature sufficient to initiate the hydrolysis of the cyano

The invention relates to new triaromatic compounds of General formula I, characterized in p

The invention relates to new N1-[2,2-dimethyl-1S-(pyridin-2-ylcarbonyl)propyl] -N4-hydroxy-2R-isobutyl-3S-methoxybenzamido or its pharmaceutically acceptable salt, hydrate or solvate

The invention relates to new cyanoguanidine F.-ly (I)

< / BR>
where connection to the pyridine ring is in the 3rd or 4th position, R1indicates one or more substituents selected from the group consisting of hydrogen, C1-C4the alkyl or alkoxy, Q denotes a4-C20linear saturated divalent hydrocarbon radical, X denotes a carbonyl, carbylamine, aminocarbonyl, oxycarbonyl, oxycarbonyl, carbonyloxy, aminocarbonyl, iminodicarboxylate, oxycarbonyl or occationally, Y denotes a phenylene, R2denotes hydrogen, halogen

The invention relates to new cyanoguanidine F.-ly (I)

< / BR>
or their tautomeric forms, where accession to the pyridine ring is in the 3rd or 4th position; R1represents one or more substituents, which may be the same or different and selected from the group consisting of hydrogen, halogen, or C1-C4-alkoxygroup; X is a linear or branched, saturated or unsaturated C9-C20is a hydrocarbon radical or a group-Q-Ar-R, where Ar is phenyl, Q is a linear or branched, saturated or nienasycenie5-C20is a divalent hydrocarbon radical, R is hydrogen or halogen

The invention relates to new guanidinum formula (I)

< / BR>
in which adherence to the pyridine ring is in the 3rd or 4th position, R represents one or more substituents, which may be the same or different and selected from the group consisting of hydrogen, halogen, or alkoxygroup, X represents a simple bond, substituted C3-C7cycloalkyl, Allen, one or two sulfur atom, Q1and Q2denote WITH1-C10divalent linear or branched hydrocarbon radical

The invention relates to new cyanoguanidine F.-ly (I)

< / BR>
where connection to the pyridine ring is in the 3rd or 4th position; R is one or more substituents selected from the group consisting of hydrogen, C1-C4the alkyl or alkoxy; Q5-C14linear saturated divalent hydrocarbon radical; X is carboxy, amino, tetrahydropyranyloxy,1-C4is saturated or unsaturated, alkoxycarbonyl, alkoxycarbonyl or di(alkoxy)fosfinovoi

The invention relates to a method for producing 2-phenyl-3-aminopyridine or substituted phenyl derivatives, which is that the connection f-crystals (VIII) is subjected to interaction with connection f-crystals (IV) in which the substituents have the following meanings: X is Cl, Br or J; Z is H, (C1-C4)alkyl, methoxy, triptoreline, F or CL; Ar is (C6-C10)aryl; R3and R4selected from H4(C1-C6)alkyl

The invention relates to new derivatives of carbamino acid of General formula 1, where R1and R2independently of one another denote alkyl, aryl, aralkyl, heteroaryl, cycloalkyl or heterocyclyl, R3and R4independently of one another denote hydrogen, alkyl, halogen, hydroxyl or aryl, R5means-COOR6, R6denotes hydrogen or alkyl, And indicates alkylen or albaniles, denotes-O(CH2)m- or -(CH2)n-, m denotes an integer from 1 to 8, inclusive, n represents an integer from 0 to 8, inclusive, or their racemates, or individual isomers, or their new pharmaceutically acceptable salt, or solvate

The invention relates to new derivatives of aryl - and heteroarylboronic General formula I, where R1denotes a substituted phenyl or pyridyl, R2denotes a substituted phenyl, R3denotes hydrogen, (lower)alkyl, cyano, carboxy, esterified carboxylate, phenyl, 1H-tetrazolyl or the group,- CONR5R6, R5denotes hydrogen or the radical R7, R6represents -(CH2)mR7or R5and R6together with the nitrogen atom to which they are attached, denote morpholino, 2,6-dimethylmorpholine, piperidino, 4-(lower)alkylpiperazine, 4-(lower)alkoxyimino, 4-(lower)alkoxycarbonylmethyl or 4 formylpiperazine,7denotes phenyl, substituted phenyl, pyridyl, 1H-tetrazolyl, (lower)alkyl, cyano(lower)alkyl, hydroxy(lower)alkyl, di(lower)alkylamino(lower)alkyl, carboxy(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl, (lower)alkoxycarbonyl(lower)alkyl or phenyl(lower)alkoxycarbonyl, Radenotes hydrogen or hydroxy, Rbrepresents hydrogen, Z represents hydroxy or the group-OR8or-OC(O)NR8, R8denotes pyridyl or pyrimidinyl, X represents nitrogen or CH, m is 0, 1 or 2, n is 0, 1 or 2, and

The invention relates to a series of compounds, their pharmaceutically acceptable salts and their N-oxides, a process for the production of the above-mentioned compounds, salts or N-oxides, to pharmaceutical preparations containing the said compounds, dosage units of drugs and to methods of treating patients using the mentioned preparations and dosage units

The invention relates to a method for producing 2-phenyl-3-aminopyridine or substituted phenyl derivatives, which is that the connection f-crystals (VIII) is subjected to interaction with connection f-crystals (IV) in which the substituents have the following meanings: X is Cl, Br or J; Z is H, (C1-C4)alkyl, methoxy, triptoreline, F or CL; Ar is (C6-C10)aryl; R3and R4selected from H4(C1-C6)alkyl
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