• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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    • 专利摘要:

    公开号:SU923367A3
    申请号:SU802872253
    申请日:1980-01-18
    公开日:1982-04-23
    发明作者:Марксер Адриан
    申请人:Циба-Гейги Аг (Инофирма)；
    IPC主号:
    专利说明:

    39 with a diethylene or dipropylene triamine derivative of the general formula 11 HgH-CHgtCHglp-HN-AlK-NH-CY-Rjl X where p, x, y, A1Ki and R5 have the above-mentioned values, with the release of the target product or If Rj has the value of a lower alkoxycarbonyl group, the resulting compound is saponified, the desired product is isolated in free form, as a racemate or as its antipodes, or as a salt. For the preparation of salts, especially such acids are used which are suitable for the formation of therapeutically suitable salts. As such acids, for example, could life hydrohalic acids, sulfuric Lot ki, phosphoric acid, nitric kis lot, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids such -kaK formic, acetic, propionora, succinic glycolic, lactic, malic , vinna, citric, ascorbic acid, maleic, hydroxymaleic or benzvicogradnaya acid, phenylacetic, benzoic, p-aminobenzoic, anthraniline, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, emboxy acid, me ansulfo-, hydroxyethanesulfonic, ethylene sulfonic acid; halogen sulfo, toluenesulfo, naphthalenesulphonic acid or sulfamic acid; methionine, tryptophan, lysine or arginine. These or other salts of the new compounds, such as picrates, can also serve to purify the resulting free bases by converting the free bases into salts, the latter are isolated and the bases are again released from the salts. Based on the number of asymmetric Satoms and the choice of starting materials and working methods, new compounds can be in the form of racemic mixtures, as racemates or as optical antipodes. The racemic mixtures based on the physicochemical differences of the constituent parts by a known method can be divided into pure racemates, for example, with the aid of chromotography and / or fractionated crystallization. Pure racemates by known methods, for example by recrystallization 7. FROM an optically active solvent, using microorganisms, or by converting with optically active acids that form salts with the racemic compound, and separating the resulting salts based on their different solubilities, can be decomposed into diastereomers, from which the antipodes can be released using a suitable agent . Particularly useful optically active acids are, for example, the O- and L-forms of tartaric acid, di-o-toluene acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid. Preferably, the more effective of both antipodes is isolated. You can also get the final products in the form of pure racemates of the corresponding optical antipodes. One or more asymmetric C-atoms of the starting materials obtained are used in the form of pure racemates of the corresponding optical antipodes. The novel active substances or pharmaceutically acceptable salts can be administered orally or rectally, as well as parenterally. According to the invention, the pharmaceutical compositions contain at least one compound of the general formula (I) as an active substance together with conventional pharmaceutical carriers. The type of media depends on the application. For oral treatment of tumors, especially solid unit dosage forms, such as tablets, dragees and capsules, are taken into account. Daily doses contain between 8 and 100 mg / kg of warm-blooded. Suitable single unit dosage forms, such as dragees or tablets, contain predominantly 10-200 mg of the active principle according to the invention, the content of the active substance being 10-90% by weight. To obtain tablets and pills of the compound of general formula (I). combined with solid powdered carriers, such as lactose, sucrose, sorbitol, corn starch, potato starch or amylopectin, arbitrary cellulose or gelatin, preferably with the addition of substances that impart lubricity like magnesium or calcium stearate or polyethylene glycol of suitable molecular weight. Dragee cores are then coated, for example, with concentrated sugar solutions, which may still contain Arabic rubber, talc and / or titanium dioxide, or lacon, dissolved in a mixture of easily volatile organic solvents. Dyestuffs can be added to these coatings to designate various doses of the active substance. Soft gelatin capsules and other closed capsules consist of a mixture of gelatin and glycerin and may contain mixtures of a compound of formula (1) with a polyethylene glycol. The separable capsule contains granules of the active substance with solid powdered carriers, such as lactose, sucrose, sorbitol, magnet, starches like potato starch, maize or amylopectin, cellulose derivatives and gelatins, as well as magnesium stearate or stearic acid. Obtaining typical forms of application in examples 1-6. Example 1. 250.0 g of the active ingredient is mixed with 550.0 g of lactose and 292.0 g of potato starch and the mixture is moistened with an alcohol solution of 8 g of gelatin and granulated through a sieve. After drying, 60.0 g of potato starch, 60.0 g of talc, 10.0 g of magnesium stearate and 20.0 g of colloidal silicon dioxide are mixed in and the mixture is compressed into 10,000 tablets weighing 125 mg and 25 mg of active ingredient, which Desires can be provided with partial notches for finer dosage adjustments. Example 2. From 100.0 g of the active substance, 379.0 g of lactose and an alcohol solution, 6.0 g of gelatin is obtained in granulation, which, after drying, is mixed with 10.0 g of colloidal two and silicon, 0 g of talc, 60.0 grams of potato starch and grams of magnesium stearate, and pressed into 10,000 pieces of dragees. The latter are then coated with a concentrated syrup of 533.5 grams of crystalline sucrose, 20.0 grams of gellac, 75.0 grams of Arabic rubber, 250.0 grams of talc, 20.0 grams of colloidal silicon dioxide, and 1.5 grams of dye and tapering. Each dragee obtained weighs 150 mg and each contains 10 mg of active substance. Example 3. To prepare a syrup with 0.25 VHbiM active substance content, 3 l of distilled water was dissolved with 1.5 l of glycerol, A2 g of p-hydroxybenzoic acid methyl ester, 18 g of p-hydroxybenzoic acid methyl ester and with slight heating to 25 , 0 g of the active substance are added j l of 70% rastB6f3a sorbitol, 1000 g of crystalline sucrose, 350 g of glucose and an aromatic substance, for example 250 g or 5 g of natural lemon flavor, filter the resulting solution and add the filtrate with distilled water to 10 liters . PRI meer k. To obtain 1000 capsules with the content of active substance in each 100 mg, mix 100 g of the active substance with 173.1 g of lactose, uniformly moisten the mixture with an aqueous solution of 2.0 g of gelatin and granulate it through a suitable sieve (for example, sieve Ø). The granulate is mixed with 10.0 g of dried corn starch and 15.0 g of talc and is evenly filled into 1000 capsules of hard gelatin with a size of 1. Example 5. As rectally used pharmaceutical preparations, for example, suppositories are used. consist of a combination of a compound of general formula (I) as an active substance with a basic suppository. As the bulk of suppositories, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanopes are suitable. Gelatin rectal capsules can also be used, which consist of a combination of the active substance with a base mass; liquid triglycerides, polyethylene glycols or paraffin hydrocarbons are taken into account as the basis. Example 6. For parenteral administration, solutions for the injection of the above described salts are suitable for injection | i3. Injectable, hydrochloride solutions are prepared as follows. 20.0 g of the active substance hydrochloride are dissolved in 1500 ml of boiled pyrogen-free water and the solution is diluted with the same water to 2000 ml. The solution is filtered, filled into 1000 "1 ml of 2 ml and sterilized. One ampoule (2 ml) contains 20 mg of 1.0% active substance. Receiving, new compounds of General formula (I) and intermediate products for, examples. 9 Example 7. 22 Or 2-chloro-benzimide ethyl ester hydrochloride, prepared from 2-chloro-6-nitrile and one equivalent of ethyl alcohol in chloroform and saturating the resulting solution with hydrogen chloride gas, and 23.6 g of 1- (1- (1- aminoethyl- (2) -amino) -ethyl (2) -3 (p-tolyl) -urea, obtained by slowly dropping 1 mole of p-tolyl isocyanate into a solution of 3 moles of diethylenetriamine in toluene, is heated in 150 ml of ethyl alcohol. formation of ammonia with reflux before boiling. The alcohol solution is evaporated in vacuo to a small volume and por ionically mixed with acetone: ethyl acetate (1: 1) and triturated, and crystalline 1- (2) -2 - {2-chlorophenyl) -2-imidazolin-1-yl (ethyl) is precipitated in Example 2 ) 3 (p tolyl) -urea in the form of hydrochloride, so pl. 108 C, The base released by potassium carbonate is melted at 166-1-8 ° C. Example 8. Analogously to Example 1, the following compounds are obtained. 1.1- (2-) 2- (2,6-Dichloropanilomethyl) -2-imidoazolin-1-yl (-ethyl) -3 - (p-tolyl) -urea, m.p. 9 97 ° C; 2.1- (2 -) - (2-chlorophenyl) -2-imzdazolin-1-yl (-3) (p-tolyl) -urea, m.p. 1b6-1b7 ° C; 3.1 - (2-) 2- (Anilinomethyl) -2-imidazolin-1-yl (-ethyl) -3 (p-tolyl) -urea, m.p. 159-1b1 ° C. 1- (2-) 2- (2,6-Dichloropanilomethyl) 2-imidoazolin-1-yl- (ethyl-) - (nyl) urea, m.p. 1b3-1b5 C 5.1- (2) 2- (2 -Chloroanilinomethyl) -2-imidazolin-1-yl (-ethyl) -3 (3 trifluoromethylphenyl) -urea, so pl. l8l183 c. 6.1- (2-) 2- (4-Chlorophenylmethyl) -2-imidazolidin-1-yl (-ethyl) -3 (-three fluoromethylphenyl) -urea, mp. 1731 ° C; 7.1- (2-) 2- (2-Chloranilinomethyl) -2-imidazolin-1-yl (-ethyl) -3 (p-tolyl urea, mp 8. 1 (2-) C2-anilinomethyl) -2 and iDozo
    LIN-1-yl (-ethyl) -3- (3-chlorophenyl) -mocheium, m.p. 1 0-1 / + 3 ° C.
    9.1- (2-) 2- (Ani-oinomethyl) -2-imidazolin-1-yl (-ethyl) -3 (3-trifluoromethylphenyl) -urea, mp. 128-130-С
    10.1- (2-) 2- (2-Chlorophenylmethyl) -2-imidoazolin-1-yl (-ethyl) -3 (-chlorophenyl) -urea, mp. WITH
    alcohol. The residue consists of sodium chloride; the solution, after complete concentration, gives crystalline 1-12-) 2- (2-chlorophenyl} -2-imidazolin-1-yl (, -ethyl) -3 (-carboxyphenyl)-urea-1-yl hydrochloride, which is recrystallized from methanol-isopropanol and melts at 2 0-; 242 ° С with decomposition 7 11.1- (2-) 2 - (- Chloranilinomethyl) -2-imidazolin-1-yl (-ethyl) -3- (4-tolyl) -urea, mp; 17b -179 ° C 12.1- (2-) 2-Benzyl-imidazolin 1-yl (-ethyl) -3- (4-tolyl) -urea, mp. IlS-ISI C 13.1- (2-) 2- ( 2-hydroxyphenyl) -2-imidazolinyl (-ethyl) -3 (4-tolyl) -urea.y, mp 115 ° C- (with decomposition). N. 1- {2-) 2- (| - Methoxyphenyl) -2-imidazolinyl (-ethyl) -3 {4-toliol) -urea, so pl. 66-70 ° C. 15. 1- (2-) 2- (4-Pyridyl) -2-imidazolinyl (-ethyl) -3 - (- Tolyl) -urea, mp. 109-111 ° C. 16. 1- (2-) 2- (2-Pyridyl) -2-imidazolinyl (-ethyl) -3 - (- tolyl) -urea, mp. 1b5-1b7 ° C. 17. 1- (2-) 2- (2-Chlorof) 2-imidazolin-1-yl {-ethyl) -3, - (-4-ethoxy-carbonyl-phenyl) -urea hydrochloride. m.p. YO ° C (with decomposition). 18.7- (2-) 2- (2-Pyridyl) -3-imidazolin-1-yl (-ethyl) -3 - (- ethoxycarbonyl-phenyl) -urea, mp. 152-15 ° C. 19.1- (2-) 2 - ("- Pyridyl) -2-imidazolin-1-yl (-ethyl) -3 (-ethoxycarbonylfeNIL) -urea, mp. 120 C. 20. Oxalate 1- (2-) 2- (2-chlorophenyl) -2-imidazolin-1-yl (-ethyl) -3- (phenylthiourea), so pl. I42c. 21.1- (2-) 2- (3-Pyridylmethyl) -2-imidazolin-1-yl (-ethyl) -3- (4-ethoxycarbonyl-phenyl) -urea, mp 168; 22. 1- (2-) 2 - (., 6-dimethyl-4-pyrimidinylamino) -2-imidazolin-1-yl-3 (α-ethoxycarbonyl-phenyl) urea hydrochloride, mp. 218-220C. Example 9-22.6g of 1- (2-) 2 (2-chlorophenyl) -2-imidazolin-1-yl (-ethyl) -3 (α-ethoxycarbonylphenyl) -urea hydrochloride obtained in Example 2 is dissolved in 900 ml of alcohol and mixed with 50 ml of 1N sodium alkali. After adding 200 ml of 2N. the sodium alkali is stirred overnight, neutralized with 200 ml of 2 n. hydrochloric acid and slightly acidified with 51 ml of 1N. hydrochloric acid. During the rotation evaporated to a dry residue and the residue is evaporated twice with 100 ml
    权利要求:
    Claims (1)
    [1]
    SUMMARY OF THE INVENTION A method for producing imide-azoline derivatives of the general formula
    N— 45
    AIK-NH-C-Y-TC ’
    II 3 where K ^ and Rj are unsubstituted or substituted with halogen, lower alkyl, lower alkoxy. hydroxy, carboxy group. or lower alkoxycarbonyl phenyl, pyridyl or pyrimidinyl;
    η is 0. or 1; _ m- 0 or 1;
    P is 1;
    Rry is hydrogen or lower alkyl;
    AEK - ethylene;
    X is oxygen or sulfur; Y is an imino group or a direct bond, or salts thereof, characterized in that the compound of the general formula W
    On where R, R q, η and m have the indicated signs. are subjected to interaction with diethylene or dipropylene triamine derivative of General formula III
    I - cn 2 (CH 2 ) p - Ж - A1K ~ МН - с - γ-R З X where p, x, y, A1K and Я ^ have the indicated meanings, with the isolation of the target product or if the substituent Rj has the value of the lower alkoxycarbonyl group, the obtained compound is saponified, the target product is isolated in free form, as a racemate or as its antipodes, or as a salt.
    I
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