1,2,5-thiadiazole derived intolerance-pyrimidinyl - piperazines and pharmaceutical composition based on them

 

(57) Abstract:

Describes the new 1,2,5-thiadiazole derived intolerance-pyrimidinyl-piperazines of General formula I, in which R1selected from hydrogen, R2, R3and R5independently selected from hydrogen, R4represents lower alkoxy; R6represents amino, lower alkylamino, di-lower alkylamino or lower alkoxy; X is selected from S, SO and SO2; Y and Z represent nitrogen, m is chosen from zero and integers from 1 to 3 and n is selected from integers of 1-5. The compounds may find application for use in the relief of vascular headaches. Also describes pharmaceutical compositions based on them. 2 C. and 7 C.p. f-crystals.

This invention in General relates to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention relates to 1,4-disubstituted piperazinone derivatives in which one Deputy is 1,2,5-thiadiazole; 1,2,5-thiadiazole-1-oxide, or 1,2,5-thiadiazole-1,1 - dioxide-substituted indole-3-illilnois group, and the other fragment is pyridinoline or pyrimidinyl ring. These compounds possess unique Setai headache, such as migraine or cluster headache type.

The authors Dowie and others described in the published patent application GB 2124210 a number of derivatives of 3-alkylamino-indole as potentially useful in the treatment of migraine. One representative of this series of compounds was specifically claimed in the later patent application Oxford GB 2162522, published on 5 February 1986. This particular connection is known in the literature as sumatriptan (I).

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A number of new derivatives of indoline was described by the authors, Manouri and others, in European patent application EPA 354094. These compounds are described as useful for the treatment of various CNS disorders, including depression, anxiety, or fear and migraine. These known compounds are the compounds of formula (II)

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in which R4represents aryl, pyridine or quinoline fragment.

Authors Smith and others, in U.S. patent 954502 described a series of 1,4-disubstituted piperazinone derivatives of the formula (III), which are useful as antidepressant agents.

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Indolenine the substituents R3and R4represented hydrogen, alkyl, alkoxyalkyl, halogen, carboxamide and trifluoromethyl.

Another series antidepressa authors Smith and others in U.S. patent 5077293.

A more immediate source of prior art is U.S. patent 5300506 concerning the early descriptions ANTIMIGRAINE alkoxyimino derivatives of the formula (IV)

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in which the substituents of the 5-indole (R1) include amino, alkoxy, amido, alkylsulfonyl and group

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It is believed that the closest source of prior art is an earlier patent application of the present applicants - application U.S. 08/122266, which informs ANTIMIGRAINE the compounds of formula (V):

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None of these known compounds is not suggested considering new 5-thiadiazoline (and its oxide)-substituted-indole-3-Illkirch derivatives pyridinyl or pyrimidinyl-piperazine derivatives for the treatment of migraine and cluster headaches type.

Migraine is one of a broad class of headaches, which also includes headaches cluster type, and other headaches that are considered to have the involvement of the vessels in its etiology, i.e., the etiology of which involved vessels. These headaches are often classified as vascular headaches. As overview information about headaches and their treatment, see, e.g whom, W. B. Saunders Co., Philadelphia, PA.

Frequently occurring irregular cases of headaches affect many people and are usually acute in nature and of short duration. Relief from headaches of this type is usually achieved mild analgesics, such as aspirin or acetaminophen. Such headaches are quite common, and although they are very painful and possibly annoying, they rarely make a person unable to work and Deplete his health. Chronic recurring headaches vascular category, however, often cause the patient to seek medical advice due to the severity of pain, which often leads to disability.

Although there is no universally accepted classification system for headache, vascular headache for the purposes of the present invention applies mainly to migraine and cluster headaches. Migraine is a common or classic type, as well as variants of migraine, which is familiar to specialists in this field. To the category associated with vascular headaches and subjected to treatment with the present invention may also include the others who Rania, as well as some of the headaches associated with the contraction of the heart muscle, and joint or mixed vascular and muscular headaches. Specialists in this field it is clear that no single treatment is not effective for all patients diagnosed with headache of the same subtype, and this raises further uncertainty to the classification of headaches.

Medications, as happened historically, the most commonly used to treat headaches, refer to the following group:

ergot alkaloids,

beta blokiruyuschij agents,

agents that block the calcium channels,

antidepressants and

mixtures thereof.

Support for recurring vascular headache is aggravated by the lack of a single method of treatment, which is effective for all patients with the same type of headache. Made available recently ANTIMIGRAINE drug (agent) Sumatriptan, has achieved some success in the treatment of migraine patients, but still has drawbacks. A further complication involves the use of anti migraine drugs that can cause dependence with long opolskie ANTIMIGRAINE agents, currently used, such as argote and methysergide, give with long-term use of strong limiting their use side effects.

Thus, there is a need for safe and effective medication for the treatment of migraine and associated disorders, which can be used or to remove the threat of a headache, or to facilitate an already existing pain.

The objects of the present invention relate to the use of new 5-(3,4-diamino-1,2,5-thiadiazole-1-oxide)-substituted indole-3-Illkirch pyridinyl derivatives and pyrimidinyl-piperazines for the treatment of vascular headaches, especially migraine and pain of cluster type; to processes for their preparation and to pharmaceutical compositions and medical uses.

The method of the present invention is designed to facilitate vascular or related vascular headaches, of which the most well known examples are migraine and cluster. The method comprises essentially the purpose for receiving a person in need of such treatment, 5-thiadiazole (or S-oxide)-substituted indole-3-Illkirch derivatives pyridinyl or pyrimidinyl-piperazine or their headlights transnasal assignment methods, pharmaceutical compositions, contains the subject of discussion ANTIMIGRAINE agents.

In a broad aspect, the present invention relates to indole-3-Illkirch derivatives pyridinyl or pyrimidinyl-piperazines, with useful protivomigrenoznami serotonergichesky properties and characterized by the formula I

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In the formula I R1is Deputy selected from hydrogen, halogen, lower alkyl and lower alkoxy.

R2, R3and R5independently selected from hydrogen and lower alkyl.

In preferred compounds, R2and R3are not both lower alkyl.

R4is lower alkoxy.

R6selected from amino, lower alkylamino, di-lower alkylamino and lower alkoxy.

The symbol "m" can be represented by an integer from 1 to 3 or zero, while n can be an integer from 1 to 5. In preferred compounds, m is zero and n=3.

X is selected from S, SO and SO2. The preferred compounds are those in which X represents SO.

Y and Z are independently selected from N and CN, provided that Y and Z cannot both be CH.

In addition to the above seastead the invention also includes stereoisomers, as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds of this series. The separation of the individual isomers is accomplished by application of various methods which are well known to specialists in this field.

The term "lower alkyl" refers to carbon radicals, such as straight and branched chain, containing from 1 to 4 carbon atoms, inclusive. Examples of these radicals are carbon chain, which can be methyl, ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl.

Lower alkoxy refers to (1-4)C alkyl groups bound to the oxygen atom. Thiadiazolyl fragment also covers sulfoxide (SO) and sulfonic (SO2) derivatives.

With the appropriate selection of the symbol Y and Z is denoted by or pyridine, or pyrimidine ring.

Pharmaceutically acceptable acid additive salts according to the invention are salts in which the counter-ion does not contribute significantly to the toxicity or does not violate the pharmacological activity of the salt, and how that is a rule preferred. In some cases, they have physical properties that make them more desirable for the preparation of finished pharmaceutical forms, such as solubility, lack of hygroscopicity, compressible, with regard to the education of tablets, and compatibility with other ingredients with which the substance can be used for pharmaceutical purposes. Salts are usually obtained by mixing the basic formula I with the selected acid, preferably by contact in solution using an excess of commonly used inert solvents such as water, ether, benzene, methanol, ethanol, ethyl acetate and acetonitrile. They can also be manufactured using metathesis or exchange reaction or processing ion exchange resin under conditions in which one anion salts of the compounds of formula I is replaced by another anion, allowing separation of the desired species in conditions, such as precipitation from solution or extraction into a solvent, or elution from ion exchange resins, or retention on ion-exchange resin. Pharmaceutically acceptable acids for the purposes of education salts of compounds of formula I include sulfuric, phosphoric, hydrochloric, Hydrobromic, idiscovered, lemon, is th, heptane and more.

The compounds of formula I can be obtained using the processes of synthesis and compounds shown in Schemes A and B.

Some compounds and methods of their synthesis will be presented in more detail in the specific embodiments below. On schemes of synthesis characters from R1to R6X, Y, Z, m and n have the meanings given above. The symbol Q represents a synthetic organic outgoing or deleted fragment or group, such as tosyl, mesyl, halide, sulfate, phosphate, etc.

The diagram presents A synthesis of compounds of formula I in which X represents SO or SO2. Scheme B illustrates the formation of compounds in which X represents S. Processes occur via the 5-amino-substituted intermediate compound of formula (6), in which the heterocyclic-substituted, pieperazinove fragment already included in the molecular structure. Modification of ways of synthesis can be performed to determine not only the desired R6-Deputy in thiadiazoline fragment (e.g., R4or NR2R3as shown), but also the desired identity of R5Deputy, or H or alkyl. For synthesis of the product in which R5

The synthesis process illustrated in scheme A, essentially include the building indolylmaleimideantibiotics fragment with a terminal amino group attached at the 5-position of the indole ring, such as compounds (6). This intermediate compound is subjected to reaction or with 1-oxide or 1,1-dioxide form 3,4-dialkoxyureas (3), giving the product of formula I in which R6represents alkoxy (R4). This product after displacement alkoxides fragment thiadiazole-amine yields a product of formula I in which R6represents the amino group, for example, the compound (1-2). As described above, the intermediate compound (6) can N-alkylaromatic 5-indolyl-amino late, giving the intermediate and the products in which R5represents an alkyl group.

The processes of scheme B include the synthesis of products with thiadiazoline ring (X is just S). This process, described previously in U.S. patent 4440933 and 4600778 for a number of antagonists of the histamine H2receptors, is applicable in this case. These U.S. patents are listed here for information. Essentially diagram illustrates the reaction of the intermediate compound (6) with 1,2-dialkoxy-substituted atendiendo with receiving easily similar product (1-3). As in scheme A, thiadiazolyl alkoxy Deputy (R6=R4) of the compound (1-3) can be replaced by the amine, giving the product of formula (1-4) in which R6represents amino function.

In scheme C are given path synthesis intermediates for use in the processes of schemes A and B; it represented, for example, some typical methods of synthesis, which give the original intermediate compounds for these schemes.

The reaction used in the diagrams A, B and C, and their use is familiar to specialists in the field of organic synthesis, and they will easily be understood by modification of the conditions and reagents. A skilled synthetic chemist knows how to adapt these processes for specific compounds of formula I, including other compounds covered by this invention but not specifically disclosed in the application. For professionals in this field also obvious variations of the methods of obtaining the same compounds slightly different way. To provide much detail in the description given below are typical examples of the synthesis section of concrete embodiments.

Serotonin has been linked with the pathophysiology of migraine by accumulating evidence, including increased excretion of migraine. This latter effect appears to be specific for migraine and is not the result of pain or stress (Anthony and others, "Plasma serotonin in migraine and stress". Arch. Neurol. 1967, 16:544-552). More importantly, intramuscular injection of reserpine lowers serotonin in the plasma and causes headache type regular migraines in people who suffer migraine. This induced headache can be relieved by slow intravenous injection serotoninnorepinephrine (Kimball and others, "Effect of serotonin in migraine patients". Neurology N. Y., 1960, 10:107-111).

Although it is shown that serotonin is effective in the treatment of migraine attacks, its use in the case of migraine eliminated its side effects, such as anxiety, nausea, loss of consciousness, hypersthene, a rush of blood to the face and parasthesia (Lance and others, "The control of cranial arteries by humoral mechanisms and its relation to the migraine syndrome". Headache. 1967, 7:93-102). For this reason, more specific serotonin agents that would be treated migraine without all other actions are potentially useful ANTIMIGRAINE medicines. Accumulating findings led to the realization that compounds with selectivity for 5-HT1Dsubtype of serotonin receptors would be clinically effective in the treatment of migraine. In this the formula I, of interest, have a activity, characterized by the fact that the IC50the values of these compounds is less than 100 malarnia. Preferred compounds are the values of the IC50below 10-malarney.

Determining properties of binding to 5-HT1Dwas performed with the use of this technique, as described by the authors Heuring and Peroutka, J. Neurosci. 7(3), 1987, 894-903; with only minor modifications. The values of the IC50(nm) in the experiment in vitro was determined for the compounds of this invention using titiraupenga serotonin.

In addition to these tests on the binding of 5-HT1Dthe ability of compounds of this invention cause a reduction on the model of saphenous vein dogs additionally demonstrates their usefulness in the treatment of vascular headaches. Preferred compounds demonstrate activity equal to or greater than that of the serotonin. In addition, these compounds showed much greater stability in vitro after incubation in liver homogenate of rats than the known number of indolyl-svartnik compounds described in the application U.S. 08/122266. All these above pharmacological tests indicate useful ANTIMIGRAINE action coenia migraine sufferers, which system provides the appointment of patients therapeutically effective amounts of compounds of formula I or its pharmaceutically acceptable salt. It is expected that the compounds of formula I may be administered to relieve migraine attack in its early stages, and are appointed for treatment of already established vascular headache.

We can assume that the purpose and the dosage of the compounds of formula I can be basically the same as in the case of known compounds sumatriptan, see Oxford, GB 2162522 A. Although these compounds may be administered intra-nasal or oral dose and dosage regimen must in each case be selected carefully with professional experience and taking into account the age, weight and condition of the recipient, method of appointment and the nature and severity of the disease. The daily dose is from about 0.05 to 10 mg/kg, preferably 0.1 to 2 mg/kg, when the tool is assigned parenteral, and about 1 to 50 mg/kg, preferably about 5 to 20 mg/kg, oral appointment. In some cases, sufficient therapeutic effect can be achieved at lower doses, while others may require higher doses. System purpose otnosytsy subcutaneous). It is found that when the compound of the present invention is prescribed orally, usually requires a greater amount of active agent to achieve the same effect as a smaller quantity given intra-nasal or parenteral. According to skilled clinical practice it is preferable to assign a data connection to a concentration level that will produce effective action caused, is not causing any harmful or unwanted side effects.

Compounds of the present invention can be administered to ANTIMIGRAINE purposes or as individual therapeutic agents or as mixtures with other therapeutic agents. In therapy they are usually given in the form of pharmaceutical compositions comprising caused a number of the compounds of formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. Pharmaceutical compositions which provide from about 1 to 500 mg of the active ingredient in dosage unit, are preferred, and they are usually prepared in the form of tablets, pellets, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions.

Compounds that are the subject of this invention, their methods of preparation and their biological activity will be more complete with the following examples which are given merely for purposes of illustration, and should not be construed as limiting the invention in its area or volume. In the following examples are used to illustrate the above-described synthesis process, temperature is expressed in degrees Celsius and the melting points are uncorrected. Spectral characteristics of nuclear magnetic resonance (NMR) refer to chemical shifts () are expressed in ppm (M. D. ) against tetramethylsilane (TMS) as reference standard. The relative area, are given for various shifts in the1the of deeds, with regard to multiplicity, is given as broad singlet (Shir.C.), the singlet (C.), multiplet (m), septet (hept.), Quartet (square), triplet (t ) or doublet (doctor ). Abbreviations used denote DMSO-d6(dateregistered), CDCl3(deuterochloroform) and are in other respects and instances regular. Infrared (IR) spectral descriptions include the magnitude of the absorption wavelength (cm-1) having an identification value of a functional group. Definition IR applied or pure, or using potassium bromide (KBr) as the diluent. Elemental analyses are given in percent by weight.

The following examples describe in detail the formation of compounds of formula I, as well as synthesis intermediates in each process. Specialists in this field, it is obvious that modifications as materials and techniques will allow you to obtain other compounds described in the application. On the basis of the preceding description and the following examples specialists in this field will be able to use the invention to the fullest extent. In addition, examples of the synthesis of certain intermediates and 1,2,5-thiadiazole compounds having amino substituents in the 3 - Ÿ information to give the opportunity to get some of these intermediates and products.

A. the production of intermediate compounds

Below are some typical procedures for obtaining synthetic intermediate compounds involved in the processes shown in the diagrams. Most of the original substances and some intermediate or industrial products are available, or procedures for their synthesis are freely available from the chemical literature, which allows specialists in the field of organic chemistry synthesis of fully to use them.

Example 1

5-[(5-Nitro-1H-indol-3-yl)methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione

Used the procedure described Flaugh1. Thus, a solution of 5-nitroindole (50.0 g, of 0.32 mol), acid Meldrum's (46,0 g of 0.32 mol), 37% aqueous formaldehyde (26,0 ml of 0.32 mol) and Proline (1.8 g, to 0.016 mole) in 200 ml of acetonitrile were mixed at room temperature for 18 hours. The resulting thick yellow suspension was filtered, and the filter cake was rinsed with acetonitrile, then with acetone and finally with ether. This substance was dried in vacuum, yielding the target compound (80.0 g, 81%) as a bright yellow solid, so pl. 182oC (decomp.). Uterine fluid the concentration of the AK above, giving another collection of product (7.0 g) as a dark yellow solid. Total yield = 87 g (89%); IR (KBr) 3330, 1767, 1732 cm-1;

1H NMR (DMSO-d6, 200 MHz) at 11.64 (S., 1H), 8.63 (D., J = 2.2 Hz, 1H), 7.96 (DD. , J = 9.0, 2.2 Hz, 1H), 7.49 (D., J = 9.0 Hz, 1H), 7.33 (D., J = 2.2 Hz, 1H), 4.84 (t, J = 4.6 Hz, 1H), 3.45 (D., J = 4.5 Hz, 2H), 1.78 (C., 3H), 1.55 (C., 3H).

Analysis:

Calculated for C15H14N2O6: C 56.60 H 4.43, N 8.80.

Found: C, 56.62 H 4.41, N 8.91.

1D. S. Farlow, M. E. Flaugh, S. D. Horvath, E. R. Lavignino, P. Pranc, Org. Prep. Proc. Int. 1981, 13, 39.

Example 2

Ethyl 5-nitro-3-(1H-ended)propionate

To a solution of [5-(5-nitroindole-3-yl)-methyl]-2,2-dimethyl - 1,3-dioxane-4,6-dione (10.0 g, 0.031 mol) in a mixture of pyridine (80 ml) and absolute ethanol (20 ml) was added 0.1 g of copper powder, and the mixture was heated to reflux distilled in an atmosphere of argon for 2 hours. The cooled mixture was filtered, and the filtrate was evaporated. The resulting residue was pulverized with a mixture of ether-dichloromethane, giving the target compound (7.3 g, 89%) as a solid substance, so pl. 118-121oC; IR (KBr) 3330, 1730 cm-1;

1H NMR (DMSO-d6, 200 MHz) 11.59 (Shir.S., 1H), 8.53 (D., J = 2.2 Hz, 1H), 7.97 (DD., J = 9.0, 2.3 Hz, 1H), 7.49 (D., J = 9.0 Hz, 1H), 7.40 (D., J = 2.1 Hz, 1H), 4.03 (sq, J = 7.1 Hz, 2H), 3.02 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 1.13 (T. reed (2.20 g, 0.058 mol) in 60 ml dry THF was added a solution of ethyl 5-nitro-3-indolepropionic (7.30 g, 0.028 mol) in 100 ml of dry THF, at 0oC in argon atmosphere. After stirring for 20 min the mixture was extinguished by careful addition of 3 ml of water. The resulting suspension was mixed for 10 minutes, and then it was filtered, and the filter cake was rinsed with additional THF. The filtrate was evaporated, and the residue was taken into ether, dried (sodium sulfate) and was evaporated, and the resulting solid substance was pulverized with hexane, giving the target compound (4.30 g, 70%) as a yellow solid, so pl. 107-110oC, IR (KBr) 3480, 3180, 1625 cm-1;

1H NMR (CDCl3, 200 MHz) 8.60 (D., J = 2.1 Hz, 1H), 8.35 (Shir.S., 1H), 8.11 (DD. , J = 9.0, 2.2 Hz, 1H), 7.38 (D., J = 8.9 Hz, 1H), 7.16 (m, 1H), 3.75 (t , J = 6.2 Hz, 2H), 2.91 (t, J = 7.2 Hz, 2H), 2.07-1.93 (m, 2H), 1.37 (Shir.S., 1H).

Example 4a

3-(3-Bromopropyl)-5-nitro-1H-indole

To a solution of triphenylphosphine (6.70 g, 0.025 mole) in 80 ml of acetonitrile was added a solution of 3-(3-hydroxypropyl)-5-nitro - 1H-indole (example 3) (4.30 g, 0.020 mole) in 75 ml of acetonitrile followed by the addition of a solution chetyrehpostovye carbon (8.00 g, 0.027 mol) in 25 ml of acetonitrile, at 0oC in argon atmosphere. The mixture was mixed at room Zitat-hexane, 1:9 then 1:4), giving the target compound (4.60 g, 84%) as a solid substance, so pl. 92-95oC; IR (pure) 3420, 1330 cm-1;

1H NMR (CDCl3, 200 MHz) 8.59 (D., J = 2.1 Hz, 1H), 8.40 (Shir.S., 1H), 8.13 (DD. , J = 9.0, 2.2 Hz, 1H), 7.40 (D., J = 9.1 Hz, 1H), 7.21 (D., J = 2.2 Hz, 1H), 3.45 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.26 (m, 2H).

Example 4b

3-(3-Improper)-5-nitro-1H-indole

A solution of 3-(3-hydroxypropyl)-5-nitro-1H-indole (1.13 g, 5.06 mmole) in 20 ml of acetonitrile was cooled to 0oC and was treated sequentially with triethylamine (1.05 g, 7.59 mmole) and methanesulfonamide (0.43 ml, 5.6 mmole) and the mixture stirred for 30 minutes, the Reaction mixture was extinguished 30 ml of water, and the organic material was extracted into ethyl acetate. The organic extracts were dried (magnesium sulfate) and concentrated in vacuo. The crude residue was dissolved in 20 ml of acetonitrile containing KI (1.7 g, 10.1 mmole) and heated to reflux distilled for 3 hours. The reaction mixture was cooled and the solvent was removed in vacuum. The residue was dissolved in 100 ml ethyl acetate and washed with water. An ethyl acetate layer was dried (magnesium sulfate) and concentrated, and the residue was purified using flash chromatography on a column (20% ethyl acetate in hexano), giving the target compound (1.37 g, 4.20 mmole, 83.97 (DD., J = 2.3, 9.0 Hz, 1H), 7.51 (D., J = 9.0 Hz, 1H), 7.43 (S., 1H), 3.30 (t, J = 6.7 Hz, 2H), 2.84 (t, J = 7.7 Hz, 2H), 2.11 (m, 2H);

IR (KBr) 1330, 1510, 810 cm-1;

MC (m/e 330 (M+).

Analysis:

Calculated for C11H11IN2O2: C 40.02 H 3.36, N 8.48.

Found: C, 40.26 H 3.27, N 8.51.

Example 5a

3-[3-[4-(5-Methoxy-4-pyrimidyl)-1-piperazinil]propyl]-5 - nitro-1H-indole

A mixture of 5-nitro-3-(3-bromopropyl)indole (0.57 g, 2.0 mmole), 1-(5-methoxy-4-pyrimidyl)piperazine (0.47 g, 2.4 mmole), KI (0.40 g, 2.4 mmole) and diisopropylethylamine (1.75 ml, 10.0 mmol) in 20 ml of acetonitrile was heated to boiling in an argon atmosphere for 6 hours. The cooled reaction mixture was diluted with ethyl acetate and was washed (water, brine). The aqueous phase was subjected to back extraction with dichloromethane, and the combined organic phase was washed (water, brine), dried (sodium sulfate) and was evaporated. The resulting residue was chromatographically (silicon dioxide/methylene chloride-methanol, 95: 5) to give a solid, which was pulverized with a mixture of dichloromethane-hexane, giving the target compound (0.55 g, 70%) as a yellow solid, so pl. 163-166oC; IR (KBr) 3440, 3175, 1578, 1320 cm-1;

1H NMR (CDCl3, 200 MHz) 8.60 (D., J = 22.86 (that is, J = 7.4 Hz, 2H), 2.59 (t, J = 4.9 Hz, 4H), 2.50 (t, J = 7.5 Hz, 2H), 2.05-1.90 (m, 2H).

Analysis:

Calculated for C20H24N6O3H2OCH2Cl2:

C 57.08 H 6.24, N 19.87.

Found: C, 57.37 H 5.85 N 19.53.

Example 5b

3-[3-[4-(3-Methoxy-4-pyridinyl)-1-piperazinil] propyl]-5-nitro-1H-indole

A mixture of 3-[3-improper]-5-nitro-1H-indole (1.4 g, 4.2 mmole), 1-(3-methoxy-4-pyridinyl)-piperazine (0.98 g, 5.09 mmole) and potassium carbonate (1.4 g, 10.2 mmole) in 30 ml of acetonitrile was heated to boiling for 4 hours. The reaction mixture was cooled and stirred for 12 hours. The solvent was removed, and the residue was dissolved in ethyl acetate and water, the aqueous layer was separated and was extracted with ethyl acetate. The organic extracts were dried (magnesium sulfate) and concentrated, and the resinous residue was purified using flash chromatography on silica gel (5% methanol in dichloromethane as eluent), giving 3-[3-[4-(3-methoxy-4-pyridinyl)-1 - piperazinil]propyl] -5-nitro-1H-indole (0.6 g, 36%) as a yellow solid; IR (KBr) 3600, 2400, 1600, 1520, 1330, 1250, 815 cm-1;

1H NMR (DMSO-d6, 300 MHz) 8.52 (D., J = 2.2 Hz, 1H), 8.10 (S., 1H), 8.02 (D. , J = 5.3 Hz, 1H), 7.96 (DD., J = 2.3, 9.0 Hz, 1H), 7.48 (D., J = 9.0 Hz, 1H), 7.42 (S., 1H), 6.81 (D., J = 5.4 Hz, 1H), 3.84 (C., 3H), 3.21 (Shir. C., 4H), 3.07 (d-(2-Pyridinyl)-1-piperazinil]propyl]-5-nitro-1-indole

A mixture of 3-[3-bromopropyl]-5-nitro-1H-indole (1.4 g, 4.2 mmole), 1-(2-pyridinyl)-piperazine (0.98 g, 5.09 mmole) and the Qadi carbonate (1.4 g, 10.2 mmole) in 30 ml of acetonitrile was heated to boiling for 4 hours. The reaction mixture was cooled, the solvent was removed, and the residue was dissolved in ethyl acetate and water. The aqueous layer was separated and was extracted with ethyl acetate. The organic extracts were dried (over magnesium sulfate) and concentrated, and the resinous residue was purified using flash chromatography on silica gel (5% methanol in dichloromethane), giving 3-[3-[4-(2-pyridinyl)-1 - piperazinil]propyl] -5-nitro-1H-indole (0.6 g, 36%) as a yellow solid; IR (KBr) 3182, 1520, 1330 cm-1;

1H NMR (DMSO-d6, 300 MHz) 8.52 (D., J = 2.24 Hz, 1H), 8.80 (DD., J = 1.8, 4.8 Hz, 1H), 7.95 (DD., J = 2.25, 9.0 Hz, 1H), 7.52-7.49 (m, 2H), 7.41 (S., 1H), 6.79 (D., J= 8.6 Hz, 1H), 6.60 (t, J = 6.6 Hz, 1H), 3.46 (t, J = 4.7 Hz, 4H), 2.78 (t, J = 7.4 Hz, 2H), 2.42 (t, J = 5.0 Hz, 4H), 2.34 (t, J = 6.9 Hz, 4H), 1.82 (dt., J = 7.4, 6.9 Hz, 2H);

MC (m/e 365 (M+).

Analysis:

Calculated for C20H23N5O2: C, 65.73 H 6.34 N 19.16.

Found: C, 65.35 H 6.26, N 18.87.

Example 5d

3-[3-[(3-Methoxy-2-pyridinyl)-1-piperazinil]propyl]-5-nitro-1H-indole

A mixture of 3-(3-bromopropyl)-5-nitro-1H-indole (0.88 g, 3.11 mmole), potassium carbonate (0.43 g, 3. was heated to boiling for 5 hours. The mixture was cooled, filtered and concentrated. The residue was purified using flash chromatography on a column using 5% methanol in dichloromethane as eluent, yielding the target compound (1.2 g, 99%) as a yellow foam; IR (KBr) 3300, 1520, 1330, 1240 cm-1;

1H NMR (DMSO-d6, 300 MHz) 8.54 (D., J = 2.2 Hz, 1H), 7.97 (DD., J = 2.2, 9.0 Hz, 1H), 7.77 (m, 1H), 7.50 (D., J = 9.0 Hz, 1H), 7.44 (S., 1H), 7.24 (D., J = 7.75 Hz, 1H), 6.90 (m, 1H), 3.78 (C., 3H), 3.33 (Shir.S., 2H), 2.80 (t, J = 7.3 Hz, 2H), 1.93 (m, 2H);

MC (m/f) 395 (M+).

Example 6

3-[3-[4-(5-Methoxy-4-pyrimidyl)-1-piperazinil]propyl]-5 - amino-1H-indole

To a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinil] propyl]-5-nitroindole (0.550 g, 1.39 mmole) in a mixture of ethanol (120 ml) and THF (40 ml) was added 10% palladium on activated carbon (0.30 g) and the mixture was gerasoulis in a Parr shaker at 40 lb./square inch (2.812 kg/cm2) for 18 hours. The mixture was then filtered through celite, and the catalyst was filtered by an additional amount of the mixture of ethanol-THF. Evaporation of the filtrate gave essentially pure target compound (0.557 g, 100%) as a brown foam. A sample of this material (0.143 g) was treated with excess methanolic HCl, and the resulting solution was diluted with acetone, giving a precipitate. Sediment hoteltravel); IR (KBr) 3410, 3200, 1630, 1540 cm-1;

1H NMR (DMSO-d6, 200 MHz) 11.22 (Shir.S., 1H), 10.20 (Shir.S., 1H), 8.60 (m , 1H), 8.20 (S., 1H), 7.55 (D., J = 1.6 Hz, 1H), 7.45 (D., J = 8.6 Hz, 1H), 7.35 (D., J = 2.1 Hz, 1H), 7.07 (DD., J = 8.6, 1.9 Hz, 1H), 4.89-4.82 (m, 2H), 3.91 (C., 3H), 3.8-3.0 (Shir.m., 8H), 2.76 (m, 2H).

Analysis:

Calculated for C20H26N6O4HClH2O:

C 45.29 H 6.08 N 15.85.

Found: C, 45.32 H 5.97 N 15.59.

Example 7

4-Methyl-5-amino-3-(3-hydroxypropyl)indole

A. 4-Methylindol

A mixture of 3-nitro-o-xylene (13.4 ml, 0.1 mol), dimethylformamide-dimethylacetal (40 ml, 0.3 mol) and pyrrolidine (10 ml, 0.12 mol) in 200 ml of dry DMF was heated at 120-130oC (oil bath temperature) in an argon atmosphere for 21 hours. The cooled mixture was poured into cold water (400 ml) and was extracted with ether (4x200 ml). The ether solution was washed (water, 4x100 ml), dried (sodium sulfate) and evaporated, giving a dark red viscous oil. This oil was taken in 150 ml of ethyl acetate, was added 1.5 g of 10% palladium on charcoal and the mixture was gerasoulis at 50 pounds/square inch (3.515 kg/cm2) in a Parr shaker for 1 hour. The reaction mixture was then filtered, the catalyst was rinsed with additional ethyl acetate; and the filtrate was evaporated, giving a dark party 4-methylindol (8.85 g, 68%) as a light yellow-brown oil;

1H NMR (DMSO-d6, 200 MHz) 11.04 (Shir.S., 1H), 7.29 (t, J = 2.7 Hz, 1H), 7.21 (D. , J = 7.7 Hz, 1H), 6.96 (t, J = 7.2 Hz, 1H), 6.75 (dt., J = 6.9, 0.8 Hz, 1H), 6.43 (m, 1H), 2.46 (C., 3H).

B. 1-Acetyl-4-methylindolin

To a solution of 4-methylindole (7.433 g, 0.0567 mol) in 100 ml of glacial acetic acid was added NaCNBH3(7.25 g, 0.12 mol) in portions over 1.5 hours. The reaction mixture was then concentrated in vacuo, water was added, and the solution was podslushivaet 10 N. NaOH. The resulting mixture was extracted with ethyl acetate (x3), and the organic extract was washed (brine), dried (sodium sulfate) and evaporated, giving an oil. Flash chromatography (silica/ethyl acetate-hexane, 1:4) this oil gave pure 4-methylindolin (6.962 g, 92%) as an oil:

1H NMR (DMSO-d6, 200 MHz), 6.78 (t, J = 7.6 Hz, 1H), 6.33 (D., J = 7.4 Hz, 1H), 6.30 (D., J = 7.6 Hz, 1H), 5.36 (Shir.S., 1H), 3.38 (t, J = 8.5 Hz, 2H), 2.81 (t, J = 8.5 Hz, 2H), 2.11 (C., 3H).

The resulting oil (6.945 g, 0.0522 mole) was taken in 10 ml of acetic anhydride. Was exothermic reaction, and after 15 min, the mixture was hardened. Volatiles were subsequently removed in vacuo, giving a solid.

The friction of this material with ether gave 6.317 g 1 Atalanta and rubbing the resulting residue with hexane gave additional 2.191 g of pure product. Total yield = 8.508 g (93%); IR (pure) 1649 cm-1;

1H NMR (DMSO-d6, 200 MHz) 7.86 (D., J = 7.9 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 6.80 (l., J = 7.5 Hz, 1H), 4.08 (t, J = 8.5 Hz, 2H), 3.03 (t, J = 8.5 Hz, 2H), 2.18 (C., 3H), 2.13 (C., 3H).

Analysis:

Calculated for C11H13NO: C AT 75.39 H 7.48 8.00 N.

Found: C, 75.41 H 7.53, N 7.95.

C. 4-Methyl-5-nitroindoline

A solution of 1-acetyl-4-methylindoline (8.260 g, 0.0372 mol) in 50 ml of concentrated sulfuric acid was cooled at 5oC, and then was added dropwise nitric acid so that the internal temperature was maintained at 5-10oC. After the addition was completed, the mixture was kept at the same temperature for 15 min, and then poured into 500 ml of crushed ice and the resulting suspension stirred until the ice melted. The slurry is then filtered, the filter cake was rinsed with water, and the residue was taken in dichloromethane. The organic phase was separated, and the aqueous phase was re-extracted with dichloromethane (x3). The combined organic phase was dried (sodium sulfate) and evaporated, giving a dark yellow solid. Chromatography (9x10 cm silica/dichloromethane, then dichloromethane-acetonitrile, 95: 5) of this solid gave an inseparable is about 9:1:

1H NMR (DMSO-d6, 200 MHz) 7.98 (D., J = 8.9 Hz), 0.88 (H), 7.89 (D., J = 8.9 Hz), 0.88 (H), 7.54 (D., J = 8.3 Hz, 0.12 H), 7.03 (D., J = 8.3 Hz, 0.12 H), 4.18 (t, J = 8.7 Hz, 2H), 3.14 (t, J =8.7 Hz, 2H), 2.37 (C., 3H), 2.19 (C. , 3H).

To a suspension of 1-acetyl-4-methyl-5(7)-nitroindoline (8.049 g, 0.0366 mol) in 75 ml of methanol was added 25 ml of alkali Clausena (see Fieser and Fieser, Reagents for Organic synthesis, volume 1, page 153), and the resulting mixture was heated on the steam bath until then, until it became homogeneous. The cooled reaction mixture was concentrated, and then it was diluted with water and the resulting suspension was filtered, giving an orange-brown solid. The filtrate was extracted with dichloromethane (x3), and the organic extract was dried (sodium sulfate) and evaporated, giving a solid. The combined solids were chromatographically (silica/ether-hexane, 1:1, and chloroform), yielding two fractions. Fraction 1 was taken in ether and the solution was treated decolorizing charcoal, filtered (celite) and evaporated, yielding 4-methyl-7-nitroindoline (0.575 g, 9%) as a dark orange solid, so pl. 125-127oC; IR (KBr) 3395, 1623, 1596 cm-1;

1H NMR (DMSO-d6, 200 MHz) 7.83 (Shir.S., 1H), 7.55 (D., J = 8.8 Hz, 1H), 6.36 (D., J = 8.8 Hz, 1H), 3.75 (t, J = 8.6 Hz, 1H), 2.99 (t, J ="ptx2">

Found: C At 60.99 H 5.71, N 15.48.

Fraction 2 was re-chromatographically (chloroform), giving a solid, which was pulverized with ether, giving 4-methyl-5-nitroindole (4.813 g, 74%) as an orange crystalline solid, so pl. 160-170oC; IR (KBr) 3330, 1598 cm-1;

1H NMR (DMSO-d6, 200 MHz) 7.85 (D., J = 8.8 Hz, 1H), 7.04 (Shir.S., 1H), 6.33 (D., J = 8.8 Hz, 1H), 3.63 (t, J = 8.8 Hz, 1H), 2.98 (t, J = 8.8 Hz, 2H), 2.38 (C., 3H).

Analysis:

Calculated for C9H10N2O2: C AT 60.66 H 5.66, N 15.72.

Found: C At 60.66 H 5.47, N 15.74.

D. 4-Methyl-5-nitroindole

To a suspension of 4-methyl-5-nitroindoline (4.767 g, 0.0268 mol) in 100 ml of methanol was added 2,3-dichloro-5,6-dicyano - 1,4-benzoquinone (6.697 g, 0.0295 mol) all at once, and the resulting mixture stirred at room temperature for 1 hour. The reaction mixture was then evaporated, and the residue was taken in dichloromethane. This solution was then washed with saturated aqueous sodium bicarbonate (4×), dried (sodium sulfate) and evaporated, giving a solid. Crystallization of the substance from a mixture of ethyl acetate-hexane (-20oC) gave 4.161 g of target compound in the form of a greenish-Golden needles, so pl. 179-180oC. Chromatography of the mother liquor (silicon dioxide/this is SUP>;

1H NMR (DMSO-d6, 200 MHz) 11.02 (Shir.S., 1H), 7.81 (D., J =9.0 Hz, 1H), 7.56 (t , J = 2.8 Hz, 1H), 7.39 (D., J = 8.9 Hz, 1H), 6.79 (m, 1H), 2.75 (c. 3H).

Analysis:

Calculated for C9H8N2O2: C 61.35 H 4.58 N 15.90.

Found: C, 61.32 H 4.40, N 15.96.

E. 5-(4-Methyl-5-nitroindole-3-ylmethyl)-2,2-dimethyl-1,3 - dioxane-4,6-dione

Procedure was performed Flaugh. Thus, a solution of 4-methyl-5-nitroindole (0.880 g, 5.00 mmol), Meldrum acid (0.864 g, 6.00 mmol), 37% aqueous formaldehyde (0.5 ml, 6.0 mmol) and D,L-Proline (0.029 g, 0.25 mmole) in 25 ml of acetonitrile were mixed at room temperature for 72 hours. The resulting yellow suspension was stored at -20oC, and then cool the mixture was filtered. The filter cake was washed with cold acetonitrile and ether and then was dried in vacuum, yielding the target compound (1.055 g, 64%) as a Canary yellow solid substance, so pl. 196-198oC (decomp.); IR (KBr) 3338, 1782, 1742 cm-1;

1H NMR (DMSO-d6, 200 MHz) 11.46 (Shir.S., 1H), 7.61 (D., J = 8.9 Hz, 1H), 7.32 (D., J = 8.9 Hz, 1H), 7.25 (D., J = 2.4 Hz, 1H), 4.74 (t, J = 5.0 Hz, 1H), 3.64 (D., J = 4.9 Hz, 1H), 2.80 (C., 3H), 1.84 (C., 3H), 1.69 (C., 3H).

Analysis:

Calculated for C16H16N2O6: C 57.83 H 4.85, N 8.43.

Found: C, 57.42, H 4.68, N 8.52.

6-dione (1.009 g, 3.04 mmole) in a mixture of pyridine (18 ml) and absolute ethanol (2 ml) was added 0.05 g of copper powder, and the mixture was heated to boiling in an argon atmosphere for 2 hours. The cooled mixture was filtered, and the filtrate was evaporated in vacuo, giving a viscous brown oil. This substance is taken into ethyl acetate, and the solution was filtered (1 N. HCl, saturated aqueous ammonium chloride, brine), dried (sodium sulfate) and evaporated giving a yellow solid. Rubbing with ether to give 423 mg of the target compound in the form of a reddish brown solid. Additional 166 mg of the product could be isolated by evaporation of the supernatant and re trituration with ether. Total yield = 671 mg (80%). An analytical sample was crystallized from a mixture of ethyl acetate-hexane, giving a reddish-brown crystals, so pl. 105-106oC; IR (KBr) 3340, 1717, 1517, 1335 cm-1;

1H NMR (DMSO-d6, 200 MHz) 11.47 (Shir.with. 1H), 7.63 (D., J = 9.0 Hz, 1H), 7.30 (D., J = 8.6 Hz, 1H), 7.28 (S., 1H), 4.06 (sq, J = 7.1 Hz, 2H), 3.18 (t , J = 7.1 Hz, 2H), 2.77 (SD, 3H), 2.68 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H).

Analysis:

Calculated for C14H16N2O4: C 60.86 H 5.84, N 10.14.

Found: C, 60.76, H 5.74, N 10.00.

G. 4-Methyl-5-nitro-3-(3-hydroxypropyl)indole

To Aspromonte (0.650 g, 2.36 mmole) in 2 ml dry THF, at 0oC in argon atmosphere. After 5 min, the cooling bath was removed and stirring continued at room temperature for 30 minutes the Reaction mixture was then extinguished by the sequential addition of 0.4 ml of water, 0.4 ml of 15% aqueous NaOH and finally, 1.2 ml of water. The resulting suspension was diluted with ethyl acetate, and then filtered, and the filter cake was rinsed with additional ethyl acetate. The filtrate was evaporated, and the residue was chromatographically (silica/dichloromethane-ethyl acetate, 2: 1), giving the target compound (0.458 g, 83%) as a solid. An analytical sample was crystallized from ethyl acetate, yielding acetate-hexane, giving a yellow-orange needles, so pl. 129 - 130oC; IR (KBr) 3543, 3210, 1616, 1520, 1330 cm-1;

1H NMR (DMSO-d6, 200 MHz) 11.43 (Shir. S., 1H), 7.63 (D., J = 8.9 Hz, 1H), 7.30 (D. , J = 8.7 Hz, 1H), 7.29 (S., 1H), 4.51 (t, J = 5.2 Hz, 1H), 5.20 (dt. , J = 6.2, 5.4 Hz, 2H), 2.91 (t, J = 7.7 Hz, 2H), 2.78 (C., 3H), 1.78 (m, 2H).

Analysis:

Calculated for C12H14N2O3: C 61.52 H 6.02 N 11.96.

Found: C, 61.23 H 5.85 N 11.90.

H. 4-Methyl-5-amino-3-(3-hydroxypropyl)indole

To a solution of 4-methyl-5-nitro-3-(3-hydroxypropyl)indole (0.365 g, 1.56 mmole) in 20 ml of absolute ateno) for 0.5 hours. The mixture was then filtered through a layer of celite, the catalyst was filtered by addition of ethanol, and the filtrate was evaporated, yielding the target compound (0.280 g, 88%) as a solid. An analytical sample was crystallized from ethyl acetate, giving painted in cream color of the needle, so pl. 141-142oC; IR (KBr) 3388, 3180, 1618 cm-1;

1H NMR (DMSO-d6, 200 MHz) 10.20 (Shir.S., 1H), 6.87 (D., J = 8.8 Hz, 1H), 6.83 (S. , 1H), 6.50 (D., J = 8.3 Hz, 1H), 4.43 (t, J = 5.2 Hz, 1H), 4.12 (SD , 2H), 3.47 (dt., J = 6.4, 5.3 Hz, 2H), 2.79 (t, J = 7.7 Hz, 2H), 2.31 (C., 3H), 1.73 (m, 2H).

Analysis:

Calculated for C12H16N2O: 70.55, H 7.90, N 13.72.

Found: C, 70.41 H 7.89, N 13.55.

Example 8

3,4-Dimethoxy-1,2,5-thiadiazole-1,1-dioxide

A solution of 3,4-dimethoxy-1,2,5-thiadiazole (1.48 g, 10.1 mmol) [obtained according to the procedure described in J. Org. Chm., 40, 2749 (1975)] in 20 ml of chloroform was added over a period of 1 min to a stirred solution of m-chlormadinone acid (4.11 g, 20.3 mmol, 85% assay) in 60 ml of chloroform. After stirring at ambient temperature for 1 hour, the mixture was heated to the temperature of reflux distilled for 8 hours and then stirred at ambient temperature for 1 hour. The reaction mixture was extraditables and evaporated under reduced pressure. The residue was treated with methanol and filtered, yielding 1.03 g of the product. Recrystallization from methanol gave the target compound, so pl. 200-202oC.

Analysis:

Calculated for C4H6N2O4S:

WITH 26.97 H 3.39, N 15.72 S 18.00.

Found: 26.82 H 3.18 N 16.09 S 18.00.

Example 9

3.4-Dimethoxy-1,2,5-thiadiazole-1-oxide

The solution dimethylacrylamide(4.0 g, 34.5 mmole) and pyridine (5.71 ml, 5.58 g, 70.6 mmol) in 8 ml of methylene chloride was added dropwise to a cold solution of thionyl chloride (2.61 ml, 4.25 g, 34.7 mmol) in 18 ml of methylene chloride under a stream of nitrogen with such speed that the reaction temperature was maintained between 0oC and 15oC. After stirring at ambient temperature for 20 min, the reaction mixture was filtered by two 11 ml portions of water 0.055 N. HCl. The aqueous phase was extracted with two 20 ml portions of methylene chloride, and the combined organic phase was dried and evaporated to dryness under reduced pressure. The solid residue was precrystallization from isopropyl alcohol, giving 3.0 g of the target compound, so pl. 137-139oC.

B. Products of the formula I

1. The product of formula I-1 (X = SO, SO2)

Example 10

3-[3-[4-(5-Methoxy-4-pyrimidyl)-1-piperazinil]inyl] propyl]-5-aminoindole (0.366 g, 1.0 mmol) and 3,4-dimethoxy-1,2,5 - thiadiazole-1-oxide (3) (0.162 g, 1.0 mmol) (see U.S. patent 4374248) in 20 ml of methanol is stirred at room temperature for 30 min, and then it was heated to boiling for 4 hours. The cooled mixture was evaporated, and the residue was pulverized with dichloromethane, giving 0.323 g of solid substance. This material was chromatographically (silicon dioxide/methylene chloride-methanol, 95:5, then methylene chloride-methanol-ammonium hydroxide, 95: 4.5: 0.5) to give the target compound (0.150 g, 30%) as a yellow solid, so pl. 164oC (decomp.); IR (KBr) 3330 (W), 1605, 1580, 1130 cm-1;

1H NMR (DMSO-d6, 400 MHz) 10.85 (S., 1H), 10.38 (SD, 1H), 8.23 (S., 1H), 8.18 (S., 1H), 8.02 (S., 1H), 7.57 (D., J = 8.7 Hz, 1H), 7.34 (D., J = 8.7 Hz, 1H), 7.17 (S., 1H), 4.17 (C., 3H), 3.83 (C., 3H), 3.68 (Shir.S., 4H), 2.69 (t, J = 7.4 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 1.84 (m, 2H).

Analysis:

Calculated for C23H28N8O3S H2O:

C 53.68 H 5.88 N 21.78.

Found: C, 53.87 H 5.88 N 21.63.

2. The product of formula I-2

Example 11

< / BR>
Anhydrous dimethylamine was barotiwala in 50 ml of absolute ethanol at -10oC for about 30 minutes To this cold solution was added a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinil]propyl]-5- (1-oxo-4-methoxy-1,2,5-tiavi temperature for 1 hour. The reaction mixture was then evaporated, giving not quite white solid, which was chromatographically (silicon dioxide/methylene chloride-methanol, 95: 5, then methylene chloride-methanol-ammonium hydroxide 95:4.5:0.5 to 90:9:1), giving the target compound (0.130 g, 62%) as not quite white solid substance, so pl. 150oC (decomp.); IR (KBr) 3310 (W), 1628, 1608, 1575 cm-1;

1H NMR (DMSO-d6, 200 MHz) 10.88 (Shir.S., 0.5 H), 9.88 (Shir.S., 0.5 H), 8.51 (Shir. S. , 1H), 8.23 (S.,1H), 8.11 (S., 1H), 8.02 (S., 1H), 7.38 (S., 2H), 7.18 (S. , 1H), 3.83 (C., 3H), 3,70 (Shir.S., 4H), 3.00 (C., 3H), 2.71 (m, 2H), 2.50 (m, 9H), 1.86 (m, 2H).

Analysis:

Calculated for C24H31N9O2S1,9H2O 0.04 CH2Cl2:

C 52.76 H 6.42, N 23.04.

Found: C, 52.37 H 6.02 N 23.50.

Example 12

3-[3-[4-(5-Methoxy-4-pyrimidyl)-1-piperazinil] propyl] -5- (1-oxo-4-methylamino-1,2,5-thiadiazole-3-yl)aminoindole

< / BR>
Anhydrous methylamine was barotiwala in 50 ml of absolute ethanol at -10oC for about 30 minutes To this cold solution was added 3-[3-[4-(5-methoxy-4-pyrimidyl)-1 - piperazinil] propyl] -5-(1-oxo-4-methoxy-1,2,5-thiadiazole-3 - yl)aminoindole (example 8) (0.200 g, 0.40 mmole) and the resulting solution stirred at room temperature for 3 hours. The reaction mixture as a pale yellow solid. This substance was precrystallization from aqueous DMSO, giving the target compound (0.100 g, 47%) as a pale yellow solid, so pl. 150-158oC; IR (KBr) 3310 (W), 1626, 1608, 1575 cm-1;

1H NMR (DMSO-d6, 200 MHz) 10.86 (Shir.S., 1H), 9.84 (Shir.S., 1H), 8.47 (Shir. S. , 1H), 8.22 (S., 1H), 8.09 (S., 1H), 8.01 (S., 1H), 7.37 (S., 2H), 7.17 (S., 1H), 3.82 (C., 3H), 3.67 (Shir.S., 4H), 3.00 (Shir.S., 3H), 2.70 (m , 2H), 2.54-2.33 (m, 6H), 1.83 (m, 2H).

Analysis:

Calculated for C23H29N9O2S1.3H2O 0.15 C2H6OS:

C 52.72 H 6.17, N 23.76.

Found: C, 52.90 H 6.21 N At 23.39.

Example 13

3-[3-[4-(5-Methoxy-4-pyrimidyl)-1-piperazinil] propyl] -5-(1-oxo-4-amino-1,2,5-thiadiazole-3-yl)aminoindole

Anhydrous ammonia was barotiwala in 40 ml of absolute ethanol at -10oC for about 15 minutes To this solution was added a solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1 - piperazinil] propyl] -5-(1-oxo-4-methoxy-1,2,5-thiadiazole-3 - yl)aminoindole (example 8) (0.175 g, 0.35 mmole) in 10 ml of absolute ethanol and the resulting solution stirred at room temperature for 1 hour. The reaction mixture was then evaporated giving a yellow resin. This substance was chromatographically (silicon dioxide/methylene chloride-methanol - ammonium hydroxide, 90:9:1), dawasa, and the residue was pulverized with acetone, yielding the hydrochloride of target compound (0.160 g, 76%) as a yellow solid, so pl. 158oC (decomp.); IR (KBr) 3380 (W), 3200 (W), 1628, 1574, 1543 cm-1;

1H NMR (DMSO-d6, 200 MHz) 10.0-11.3 (m, 2H), 8.64 (Shir. S., 1H), 8.29 (Shir. S., 1H), 8.20 (Shir. S., 1H), 7.60 (m,1H), 7.35 (D., J = 8.7 Hz, 1H), 6.96-7.22 (m , 1H), 4.89 (m, 2H), 3.90 (C., 3H), 3.62 (m, 4H), 3.16 (m, 4H), 2.77 (m, 2H), 2.14 (m, 2H).

Analysis:

Calculated for C22H27N9O2S2HCl2,2H2O 0,2 CH4O:

C 44.40 H 5.74, N 21.00.

Found: C, 44.44 H 6.14 N 21.25.

C. Procedures for biological studies

Example 14

Research agonists on lateral subcutaneous Vienna dogs

The lateral saphenous vein were obtained from the shot of the dog and cleaned of adhering material. The vessel is then cut into ring segments 2-3 mm in size and placed between the wires of stainless steel in tissue baths containing 20 ml of modified Krebs buffer that continuously aerialist 5% CO2/95% O2and maintained at 37oC. Tension (tone) in the period of peace ever manually to 1 g and was maintained until, until it reaches a stable baseline during the period balance 1 hour. Rest is serine, atropine and pyrilamine at a concentration of 1 μm for blocking 5-HT2, holinergicescoe and vitaminnogo effects. After 15 min with antagonists in a cumulative way is the response curve for the concentration of serotonin. In conclusion, bath washed several times, the voltage is again brought up to 1 g, and fabrics give the opportunity to return to equilibrium over a period of 45-60 minutes In the bath again added antagonists, and after 15 min for the selected test compounds are obtained response curves of concentration. Individual segments of the vessel are exposed to only one test connection.

The activity of the test compounds is expressed as relative activity and efficiency compared with 5-HT (which is arbitrarily taken as 1,0) in the same preparation vessels.

1. 1,2,5-Thiadiazole derived intolerance-pyrimidinyl-piperazines of the formula I

< / BR>
in which R1represents hydrogen;

R2, R3and R5represent hydrogen;

R4represents lower alkoxy;

R6represents amino, lower alkylamino, di-lower alkylamino or lower alkoxy;

X is selected from S, SO and SO2;

YR> or their pharmaceutically acceptable acid additive salt and/or solvate.

2. Connection on p. 1, in which X represents SO.

3. Connection on p. 2, in which R1, R2, R3and R5represent hydrogen.

4. Connection on p. 2, in which m = 0 and n = 3.

5. Connection on p. 2, in which R4represents methoxy.

6. Connection on p. 2, in which R1, R2, R3and R5represent hydrogen, R4is methoxy, Y and Z represent nitrogen, m = 0 and n = 3.

7. Connection under item 6, selected from the group consisting of compounds in which R6represents amino, methylamino, dimethylamino and methoxy.

8. Pharmaceutical composition having affinity to 5-HT1Dserotonin receptor, characterized in that it comprises a pharmaceutical carrier and from about 1 to 500 mg of active connections on p. 1 in dosage unit.

9. The pharmaceutical composition according to p. 8, having affinity to 5-HT1Dserotonin receptor, characterized in that it comprises a pharmaceutical carrier and from about 1 to 500 mg of active connections on p. 2 per dosage unit.

 

Same patents:

The invention relates to new derivatives pyridonecarboxylic acid, antitumor means containing them as effective ingredients, and to methods of producing new derivatives pyridonecarboxylic acid and t

The invention relates to a new derived tetrazole having effect in reducing blood sugar and lipid in the blood, and it contains the tool for use in the treatment of diabetes and hyperlipemia

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert
The invention relates to a method for anticancer drug prospidina, which is used in oncological practice, as well as in the treatment of rheumatoid arthritis

The invention relates to new substituted pyrrole General formula I

< / BR>
where R is hydrogen, hydroxyl;

R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;

R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,

R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;

R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;

R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);

Z - group-CH - or N-atom;

m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

< / BR>
where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

The invention relates to new derivatives of 5-arylindole formula I, where R1matter referred to in the description, A, B, C, and D each represent a carbon or one of them represents a nitrogen; R2, R3, R4, R5each independently represents hydrogen, C1- C6-alkyl, phenyl, halogen, cyano,- (CH2)mNR14R15, -(CH2)mOR9, -(CH2)mNR14COR9, -(CH2)mNR14CONHR9, -CO2R9; R6represents hydrogen, -OR10; R7, R8, R14, R15each independently represents hydrogen, C1- C6-alkyl, (CH2)xOR11; R9represents hydrogen, C1- C6-alkyl, phenyl; R10is1- C10-alkyl; R11is1- C6-alkyl; n = 0,1 or 2; m = 0, 1, 2 or 3; x = 2 or 3; the dotted line indicates the optional single bond or their pharmaceutically acceptable salts
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