Process for preparing 2-pyridylmethylsulphinylbenzimidazoles

(54) A method for producing 2-pyridylmethylsulfinylbenzimidazoles

The invention relates to a process for the production of novel compounds having valuable gastric acid secretion properties in mammals including humans. Effects on gastric acid secretion and pharmaceutical compositions containing these novel compounds are also discussed.

It is an object of the present invention to provide compounds which act on gastric acid secretion and which inhibit exogenously or endogenously stimulated gastric acid secretion. These compounds can be used in the treatment of gastric ulcer disease.

It is known that the compounds of formula (I)

<img file="CS261873B2_D0001.tif" />

<img file="CS261873B2_D0002.tif" />

where

R¹ and R² denotes a group selected from hydrogen, alkyl, halogen, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carbamoyl, carbamoyloxy, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl and acyl at any position,

R³ represents a group selected from hydrogen, alkyl, acyl, alkoxycarbonyl, carbamoyl, alkoxycarbonylmethyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, and alkylsulfonyl; and

R⁴ denotes a group selected from the group consisting of straight and branched alkylene groups having 1 to 4 carbon atoms,

281873 wherein at most one methylene group is present between the sulfur atom and the pyridyl group and wherein the pyridyl group is optionally further substituted by alkyl or halogen, they have an inhibitory effect on gastric acid secretion.

However, it has now surprisingly been found that the compounds described below have an even greater inhibitory effect than the compounds mentioned above.

The compounds of the invention have the general formula III

<img file="CS261873B2_D0003.tif" />

where

R¹ and R²which are identical or different are selected from hydrogen, halogen, alkyl of 1 to 7 carbon atoms, methoxycarbonyl, ethoxycarbonyl, alkoxy of 1 to 5 carbon atoms and alkanoyl of 1 to 4 carbon atoms in any position,

R^E represents a group selected from the group consisting of hydrogen, methyl and ethyl,

R³, R⁴ and R⁵which are identical or different are selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy and ethoxyethoxy, wherein R is³, R⁴ and R⁵ does not simultaneously represent a hydrogen atom and when it represents two of the substituents R³, R⁴and R⁵ a hydrogen atom, the third of these R substituents³, R⁴ and R⁵ is other than methyl.

Alkyl R¹ and R² in formula III, it is suitably an alkyl of up to 7 carbon atoms, preferably up to 4 carbon atoms. Such an alkyl R 1¹ or R² is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

Halogenem R¹ and R² is chlorine, bromine, fluorine or iodine.

Alkoxy R¹ and R² suitably form alkoxy groups with up to 5 carbon atoms, preferably up to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy or isopropoxy.

Alkanoyl R¹ and R² suitably have up to 4 carbon atoms and are, for example, formyl, acetyl or propionyl, preferably acetyl.

A preferred group of compounds of formula (III) are those wherein R @ 1¹ and R² are the same or different and are selected from the group consisting of hydrogen, alkyl, methoxycarbonyl, alkoxy and alkanoyl, wherein R is¹ and R² they do not simultaneously denote hydrogen,⁶ is hydrogen and R is³, R⁴ and R⁵ are the same or different and are selected from the group consisting of hydrogen, methyl, methoxy and ethoxy, wherein R is³, R⁴ and R⁵ they do not always denote a hydrogen atom and when they represent two substituents R³, R⁴ and R⁵ hydrogen, the third of these substituents R @ 1³, R⁴ and R⁵not methyl.

Another preferred group of compounds of formula (III) are those wherein R is¹ and R² are the same or different and each is selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy, and alkanoyil;^(B) is selected from the group consisting of hydrogen, methyl and ethyl;³ denotes methyl, R⁴ is methoxy and R is⁵ denotes methyl.

A third preferred group of compounds of formula (III) are those wherein R 1 is R 2¹ and R² are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy and ailkanoyl;^(B) is selected from the group consisting of hydrogen, methyl and ethyl;³R is hydrogen;⁴ is methoxy and R is⁵ is methyl or R 1³ denotes methyl, R⁴ denotes methoxy and R⁵ represents hydrogen.

A fourth preferred group of compounds of formula (III) are those wherein R is¹and R² are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy and alkanoyl;⁶ represents hydrogen, methyl or ethyl;³ and R⁵ represents a hydrogen atom and R⁴ represents a methoxy group.

A fifth preferred group of compounds of formula (III) are those wherein R 1¹ and R² are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy and alkanoyl;⁶ is selected from the group consisting of hydrogen, methyl and ethyl and R 1³ and R⁵ denotes methyl groups and R @ 1⁴ is hydrogen.

A sixth preferred group of compounds of formula (III) are those wherein R is¹and R² are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, ethoxycarbonyl, alkoxy and alkanoyl;^(B) is selected from the group consisting of hydrogen, methyl and ethyl;³and R⁵ represents a hydrogen atom and R⁴ represents ethoxy, methoxyethoxy or ethoxyethoxy.

A seventh preferred group of compounds of formula (III) are those wherein R 1¹and R² are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, methoxycarbonyl, alkoxy and alkanoyl;⁶ is selected from the group consisting of hydrogen, methyl and ethyl and R 1³, R⁴ and R⁵ is methyl.

According to the invention, the compounds of the formula III are prepared by the preparation of a compound of the formula VII

<img file="CS261873B2_D0004.tif" />

where

R¹ and R^of and is reacted with a compound of formula VIII

<img file="CS261873B2_D0005.tif" />

where

R⁶, R³, R⁴ and R⁵ have the above meanings and one of the symbols Z¹ and Z^of denotes a reactive esterified hydroxy group and a second SH group,

<img file="CS261873B2_D0006.tif" />

where

R¹, R², R⁶, R⁴, R³ and R⁵ are as defined above, which is then oxidized to a compound of formula III which, if present as a base, can be converted to an acid addition salt or, if present as a salt, can be converted to its base.

The above substituents Z¹ .a Z^of are reactive esterified hydroxy groups such as a hydroxy group esterified with a strong inorganic or organic acid, preferably hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or a strong organic sulfonic acid such as a strong aromatic acid such as benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid.

The oxidation of the sulfur atom in the above chains to sulfinyl (S-&gt; O) occurs in the presence of an oxidizing agent selected from the group consisting of nitric acid, hydrogen peroxide, peroxyacids, peresters, ozone, nitrogen dioxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, tertiary. -butyl hypochloride, diazobicyclo [2.2.2] octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cerium ammonium nitrate, bromine, chlorine and sulfuryl chloride. The oxidation usually takes place in a solvent in which the oxidizing agent is present in some excess relative to the product to be oxidized.

Depending on the process conditions and starting materials, the end product is obtained either as the free base or as an acid addition salt, which are included within the scope of the invention. Thus, basic, neutral or mixed salts, such as gaming, mono-, sesqui- or polyhydrates, can be obtained. The acid addition salts of the novel compounds can be converted into the free bases in a manner known per se using basic sieves such as alkalis or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. In the preparation of acid addition salts, preferably those acids which form therapeutically acceptable salts are used. These acids include hydrohalogenic acids, sulfuric, phosphoric, nitric and perchloric acids, aliphatic, alicyclic, aromatic, heterocyclic carboxylic acids or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic acids. , roalein, hydroxymalein, pyruvic, phenyillacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic, embonic acid, methansuilfonic acid_; ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthylsulfonic or sulfanilic acids, methionine, tryptophan, lysine or arginine.

These or other salts of the novel compounds, such as picrates, can serve as cleaning agents of the free bases obtained. Base salts can be formed, separated from solution, and then the free base can again be recovered from the pure salt solution of the new salt. Because of the relationship between the new free base compounds and their salts, it is to be understood that the corresponding salts are included within the scope of the invention.

Some of the novel compounds may be present as optical isomers or racemate depending on the choice of starting material and process, or, if they contain at least 2 asymmetric carbon atoms, may be present as a mixture of isomers (racemic mixture).

The obtained isomeric mixtures (racemic mixtures) can be separated into two stereoisomerically (diastereometrically) pure racemates by chromatography or fractional crystallization.

The racemates obtained can be resolved by known methods, for example, by recrystallization from an optically active solvent using microorganisms, by reaction with optically active acid-forming salts which can be separated by resolution based on the different solubility of the diastereomers. Suitable optically active acids are the L- and D-forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, quinic acid. Preferably, the more active portion is isolated from both antipodes.

The starting materials are known or, if new, can be obtained in a manner known per se.

In clinical use, the compounds of the invention are administered orally, rectally or by injection in the form of a pharmaceutical composition containing the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic acid addition salt such as hydrochloride, lactate, acetate, sulfamate, in combination with a pharmaceutically acceptable carrier. The carrier may be in solid form, semi-solid form, or in the form of a liquid solvent or as a capsule. The usual amount of active ingredient is 0.1 to 95% by weight. 0.5 to 20 wt. for injectables and 2 to 50 wt. in formulations for oral administration.

In preparing pharmaceutical compositions comprising a compound of the invention in the form of a dosage unit for oral administration, the selected compound may be admixed with a solid powder carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives or gelatin, as well as a friction reducing agent. such as magnesium stearate, calcium stearate and poilyethylene glycol waxes. The mixture is then compressed into tablets. In preparing the coated tablets, the core thus prepared is coated with a concentrated sugar solution, which may contain gum arabic, gelatin, talc, titanium dioxide or varnish dissolved in a volatile organic solvent or solvent mixture. Various colorants may be added to this coating to distinguish tablets with different active compounds or different amounts of active compound present.

Soft gelatin capsules can be prepared which contain a mixture of the active compound or compounds of the invention and a vegetable oil. The hard gelatin capsules may contain granules of the active compound in combination with a solid powdered carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

Dosage units for rectal administration may be presented in the form of suppositories containing the active ingredient in admixture with a neutral fat base or may be prepared in the form of gelatin rectal capsules containing the active ingredient in admixture with vegetable or paraffin oil.

Liquid compositions for oral administration may be prepared in the form of syrups or suspensions, for example as solutions containing 0.2 to 20% by weight of the composition. active ingredient, the remainder consisting of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid compositions may contain coloring agents, flavoring agents, saccharin, and carboxymethylcellulose as a thickening agent.

Solutions for parenteral administration by injection may be prepared as aqueous solutions of the pharmaceutically acceptable water-soluble salt of the active compound, preferably at a concentration of 0.5 to 10% by weight. These solutions may also contain stabilizing agents and / or buffers and may be prepared in ampoules with different dosage units.

Pharmaceutical tablets for oral use are prepared as follows:

The solids are ground or crosslinked to a certain particle size, and the binder is homogenized and suspended in a suitable solvent. The therapeutically active compounds and excipients are mixed with a binder solution. The resulting mixture is moistened to form a uniform slurry of wet snow consistency. Moistening causes the particles to clump a little and the resulting mass is passed through a stainless steel sieve with a mesh size of about 1 mm. The mixture layer is dried in carefully controlled drying chambers for approximately 10 hours to achieve the desired particle size and consistency. The granules of the dried mixture are sieved to remove any dust. Tablet disintegrating aids, reducing friction and preventing adhesion are added to this mixture. Finally, the mixture is compressed into tablets using a suitable punch and die machine to obtain a suitable tablet size. The pressure applied affects the size of the tablet, its strength and its water solubility. This pressure should be in the range of 49 to 490 MPa. Tablets are produced at a rate of 20,000 to 200,000 pieces per hour. Tablets, especially those that are coarse and bitter, may be coated with a layer of sugar or other palatable substance. The tablets are then packaged using machines with electronic counting equipment. The different types of packaging consist of glass or plastic cups, boxes, tubes and other containers for special dosing.

The usual daily dose of the active ingredient varies according to the individual need and the mode of administration. In general, oral dosages range from 100 to 400 mg per day of active ingredient and intravenous dosages range from 5 to 20 mg per day.

The following examples illustrate embodiments of the invention without departing from the invention

281873 limited. Temperatures are given in degrees Celsius.

In the following examples, starting materials are prepared by the following methods:

1)

A 1,2-diamino compound, such as o-phenylenediamine, is reacted with potassium ethylxanthate, according to Org. Synth., Vol. 30, p. 56 to give 2-mercaptobenzimidazoil.

2)

2-Chloromethylpyridine is prepared by reacting 2-hydroxymethylpyridine with thionyl chloride, according to Arch. Pharm., Vol. 26, pp. 448-451 (1956).

3)

2-Chloromethylbenzimidazole is prepared by condensing o-phenylenediamine with chloroacetic acid.

Example 1

28.9 g of 2- [2- (4,5-dimethyl] pyridylmethyl-thio] - (5-acetyl-6-methyl) -benzimidazoil are dissolved in 160 ml of chloroform and portion-wise to 5 ° C with stirring and cooling. After 24 minutes, the precipitated m-chlorobenzoic acid was filtered off, the filtrate was diluted with methylene chloride, washed with sodium carbonate solution, dried over sodium sulfate and evaporated under reduced pressure, and the residue crystallized upon dilution with acetonitrile. 2- (2- (4,5-dimethyl) pyridylmethylsulfinyl) - (5-acetyl-6-methylbenzimidazoil) was recrystallized from acetonitrile to yield 22.3 g, m.p. 158 ° C.

Example 1a

Dissolve 0.1 mol of 4,6-dimethyl-2-mercaptobenzimidazole in 20 ml of water and 200 ml of ethanol containing 0,2 mod sodium hydroxide. 0.1 Mod of 2-chloromethyl- (3,5-dimethylpyridine hydrochloride) is added and the mixture is refluxed for 2 hours, the sodium chloride is filtered off and the solution is evaporated under reduced pressure, the residue is dissolved in acetone and treated with activated carbon. Then an equivalent amount of concentrated hydrochloric acid is added and 2- [2- (3,5-dimethyl-pyridylmethylmethyl) - [4,6-dimethyl] benzimidazole monohydrochloride is isolated. The yield was 0.05 mole of product.

This compound is then oxidized as in Example 1 to give the corresponding sulfinyl compound, m.p. 50-55 ° C.

Example 1b

22.0 g of 2-mercapto- (5-acetyl-6-methyl) benzimidazole and 19.5 g of chloromethyl- (4,5-dimethylpyridine hydrochloride) are dissolved in 200 ml of 95% ethanol, followed by the addition of 8 g of sodium hydroxide in 20 ml of water. The solution is refluxed for 2 hours, the sodium chloride is filtered off and the solution is evaporated under reduced pressure, and the residue of 2- [2- (4,5-dimethylpyridylmethylthio) - (5-acetyl-6-methyl) benzimidazole is recrystallized 70^!% ethanol. Yield 10.6 g.

This compound is then oxidized as in Example 1 to give the corresponding sulfinyl derivative. Melting point: 158 degrees Celsius.

Examples 2 to 30

The process for the preparation of the other compounds of the general formula (III) is carried out as in the examples mentioned above. The prepared compounds are summarized in Table 1, where the substituents in those compounds are also indicated.

Table 1

<img file="CS261873B2_D0007.tif" />

R⁽ (III)

<td>Example</td><td>R¹</td><td>R^of</td><td>R⁶</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>Temperature thaw Deň: 32 ° C</td>

<td> 1</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>CH3</td><td>C'H3</td><td> 158</td>

<td> 2</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td> 163</td>

<td> 3</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td> 141</td>

<td> 4</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>H</td><td> 160</td>

<td> 5</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>ICH3</td><td>CH3</td><td>H</td><td> 163</td>

<td> 6</td><td>4-CH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>H</td><td>CHó</td><td> 50 — 55</td>

<td> 7</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>1CH3</td><td>H</td><td>CH3</td><td> 171</td>

<td> 8</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>CH3</td><td> 190</td>

<td> 9</td><td>5-COCHs</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 165</td>

<td> 10</td><td>4-CH3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>II</td><td> 122</td>

<td> 11</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>iCH3</td><td>OCH3</td><td>CD</td><td> 156</td>

<td> 12</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>H</td><td>Target</td><td> 144</td>

<td> 13</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH.3</td><td>iCHj</td><td>OX</td>

<td> 14</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 169</td>

<td> 15</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OC2H5</td><td>H</td><td> 148</td>

<td> 16</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>OCH3</td><td>H</td><td> 175</td>

<td> 17</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>OCH3</td><td>, CH3</td><td> 155</td>

<td> 18</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>CH3</td><td> 158</td>

<td> 19</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>, CH3</td><td>H</td><td>CH3</td><td> 141</td>

<td> 20</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 142</td>

<td> 21</td><td>5-COCH3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 162</td>

<td> 22</td><td>5-OCH3</td><td>H</td><td>H</td><td>H</td><td>OCH3</td><td>ICH3</td><td> 178</td>

<td> 23</td><td>5-OCH3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>ICH3</td><td> 156</td>

<td> 24</td><td>5-CH3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>ICH3</td><td> 181</td>

<td> 25</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td>OGH3</td><td>CH3</td><td> 165</td>

<td> 26</td><td>5-C1</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 185</td>

<td> 27</td><td>5-CH3</td><td>H</td><td>H</td><td>H</td><td>OC2H4OCH3</td><td>H</td><td> 119</td>

<td> 28</td><td>5-COOC2H5</td><td>H</td><td>H</td><td>1CH3</td><td>OCH3</td><td>, CH3</td><td> 150—155</td>

<td> 29</td><td>5-COOCH 3</td><td>H</td><td>CH3</td><td>C'H3</td><td>H</td><td>'CH3</td><td> 130</td>

<td> 30</td><td>5-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>H</td><td>'CH3</td><td> 152</td>

<td colspan="2">Biological effect</td><td></td><td></td><td colspan="2">use automatic</td><td>titrator</td><td>with pH-meter.</td>

The compounds of the invention have valuable therapeutic properties as inhibitors of gastric acid secretion, as shown in the following tests. To determine the ability to inhibit gastric acid secretion, conscious experiments on dogs were performed and gastric fistula of the usual type and duodenal fistula, which is used for direct intraduodenal administration of test compounds. After 18 hours of fasting without water, dogs were given a subcutaneous infusion of pentagastrin (1-4 nmol / kg.h) lasting 6-7 hours. Gastric juice was collected in samples at 30 minute intervals. An aliquot of each sample was titrated with 0.1N sodium hydroxide to pH 7.0 to determine the titratable acid concentration, z (Radiometer, Copenhagen, Denmark.) Acid production was calculated as mmol H⁺/60 minutes. The percent inhibition compared to the control was calculated for each compound and the highest inhibitory effect is shown in Table 2. Test compounds suspended in 0.5% methylcellulose (Methocel)^R) were administered intraduodenally at doses of 4 to 20 µmol / kg when the secretory response to pentagastrin reached a steady state level.

In the tests, the previously known compounds were compared with the compounds of the invention, as shown in Table 2.

The following gastric acid inhibition effect data were obtained for compounds tested by the method described.

Table 2

<img file="CS261873B2_D0008.tif" />

<td>Example</td><td>R¹</td><td>R²</td><td>R⁶</td><td>R³</td><td>R⁴</td><td>R⁵</td><td>Dose mole / kg</td><td>Effect % inhibition</td>

<td> 1</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td> 2</td><td> 90</td>

<td> 4</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>H</td><td> 1</td><td> 60</td>

<td> 7</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>H</td><td>CH3</td><td> 2</td><td> 100</td>

<td> 8</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>CH3</td><td> 4</td><td> 100</td>

<td> 9</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 2</td><td> 95</td>

<td> 11</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 70</td>

<td>X</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>CH3</td><td>H</td><td> 20</td><td> 30</td>

<td>X</td><td>5-COCH3</td><td>6-CH3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td> 8</td><td> 80</td>

<td> 2</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td> 2</td><td> 60</td>

<td> 5</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>H</td><td> 2</td><td> 90</td>

<td> 12</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>H</td><td>CH3</td><td> 2</td><td> 70</td>

<td> 13</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>CH3</td><td>CH3</td><td> 4</td><td> 80</td>

<td> 14</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 2</td><td> 100</td>

<td> 15</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OC2H5</td><td>H</td><td> 4</td><td> 75</td>

<td> 16</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>OCH3</td><td>H</td><td> 0,5</td><td> 65</td>

<td> 17</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 90</td>

<td> 18</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>CH3</td><td></td><td></td>

<td>X</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td> 4</td><td> 50</td>

<td>X</td><td>5-COOCH 3</td><td>6-CH3</td><td>H</td><td>Br</td><td>H</td><td>H</td><td> 4</td><td> 0</td>

<td> 6</td><td>4-iOH 3</td><td>6-CH3</td><td>H</td><td>CI-13</td><td>H</td><td>CH3</td><td> 4</td><td> 40</td>

<td> 10</td><td>4-ΠΗ3</td><td>6-CH3</td><td>H</td><td>H</td><td>OCH3</td><td>H</td><td> 2</td><td> 40</td>

<td>X</td><td>4-CH3</td><td>6-CH3</td><td>H</td><td>H</td><td>H</td><td>H</td><td> 4</td><td> 30</td>

<td>X</td><td>4-CH3</td><td>6-CH3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td> 12</td><td> 50</td>

<td> 3</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td>CH3</td><td> 4</td><td> 100</td>

<td> 19</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>CH3</td><td>H</td><td>CH3</td><td> 2</td><td> 60</td>

<td> 20</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 65</td>

<td>X</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td> 20</td><td> 90</td>

<td>X</td><td>5-COOCH 3</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td> 20</td><td> 50</td>

<td> 21</td><td>5-COCH3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 60</td>

<td>X</td><td>5-COCH3</td><td>H</td><td>H</td><td>H</td><td>H</td><td>OC2H5</td><td> 20</td><td> 40</td>

<td> 22</td><td>5-OCH3</td><td>H</td><td>H</td><td>H</td><td>OCHs</td><td>CH3</td><td></td><td></td>

<td> 23</td><td>5-OCH3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 65</td>

<td>X</td><td>5-OCH.3</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td>H</td><td> 20</td><td> 10</td>

<td> 24</td><td>5-CH3</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0 5</td><td> 50</td>

<td>X</td><td>5-GHs</td><td>H</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td> 4</td><td> 50</td>

<td> 25</td><td>H</td><td>H</td><td>H</td><td>CH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 60</td>

<td>X</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td> 4</td><td> 50</td>

<td> 28</td><td>5-COOC2H5</td><td>H</td><td>H</td><td>GH3</td><td>OCH3</td><td>CH3</td><td> 0,5</td><td> 50</td>

<td> 26</td><td>5-C1</td><td>H</td><td>H</td><td>CH3i</td><td>OCHs</td><td>CH3</td><td> 0,5</td><td> 25</td>

<td> 27</td><td>5-CH3</td><td>H</td><td>H</td><td>H</td><td>OC2H4</td><td>OCH3 14</td><td> 0,5</td><td> 30</td>

<td> 29</td><td>5-COOCH 3</td><td>H</td><td>CH3</td><td>CH3</td><td>H</td><td>CH3</td><td> 0,5</td><td> 40</td>

χ - designation for a previously known compound