KR820001304B1 - Process for the preparation of phenethanol amines - Google Patents

Abstract

Title compds. (I; R1 = H, F; R2 = hydroxy, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetylamino, methanesulfonylamino), useful as antitumor agents, were prepd. by the reduction of carbonyl compd. (II). Thus, 450 ml diethyl ether soln. contg. 37.8 g 2-bromoacetophenone was added in a 1000 ml diethyl ether contg. 72.9 g 1,1-dimethyl-3-(4-methoxy phenyl)propylamine for 1 hr, and refluxed for 7 days to give 20 g N-(2-phenyl-2-oxoethyl)-1,1-dimethyl-3-(4-methoxyphenyl)propylamine(m.p. 180.7-181.5≰C).

Description

Method for preparing phenatanolamine

The present invention relates to a process for the preparation of novel phenethanolamines and pharmaceutically harmless salts thereof useful for increasing the antitumor activity of tumor cell decay drugs.

Wherein R ¹ is hydrogen or fluorine atom and R ² is hydroxy, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetylamino or methanesulfonyl amino.

Although its usefulness has been studied in the treatment of tumors, few compounds have proven to be sufficiently useful for the granular treatment of human tumors. An important drawback of using all known tumor cell disruption drugs is the degree of toxicity. For example, the use of certain anti-tumor agents at the dosages needed to granularly treat or eliminate tumors may delay the growth of other tumors. Mixed chemotherapy was used to eliminate the extreme toxic effects of continuous administration of various antitumor agents. By using more than one anti-tumor agent, the required dose reduction of each drug component and consequently the accumulated toxic effects attributable to each drug can be detected. So far, in all these combination chemotherapy, all drug components have been granularly effective anti-tumor agents and all have their own toxic effects.

The compounds of the present invention are the only substances which, by their predetermined doses, do not exhibit antitumor activity per se but can increase the beneficial effects of drugs known to be granularly useful antitumor agents.

Compounds similar to the compounds of the present invention are described in US Pat. No. 3,816,516 as β-agonists useful as chemotherapeutic agents for heart disease.

The compounds of the present invention are useful for increasing the antitumor activity of known tumor cell disrupting drugs. Such known drugs include anti-metabolites such as formulations 5-fluorouracil and 6-mercaptopurine and phytoalkaloids such as vindesine, vincristine and vinplastin. Efficacy is also enhanced by the compounds of the invention with methotrexate. The compounds of the present invention are preferably used to increase the tumor cell decay activity of agents such as cytoic acid, 5-fluorouracil, 6-mercaptopurine, methotrexate and vinca alkaloids. Tumor solid tumors that can be effectively treated with tumor cell decay drugs whose efficacy is enhanced by the compounds of the present invention, particularly neuroblastoma and solid tumors of the breast, ovary, lung, stool, stomach, colon and urinary tract, and the like We treat tumors such as adenocarcinoma retinoblastoma. The invention is carried out by administering to a patient receiving an antitumor agent known to be used in the particular disease to be treated in an amount that enhances efficacy. Since the effectiveness of such known tumor cell decay drugs is increased by the action of the compounds of the present invention, it is possible to know the desired clinical effect of tumor cell decay drugs.

The present invention furthermore comprises a method for administering a mammal, characterized by administering a granularly effective or suboptimal amount of a tumor cell decay drug that is known to be effective against the particular tumor to be treated, together with an amount of compound of the invention that enhances efficacy. To provide a method for treating a tumor. According to the invention this compound is used to elevate the antitumor activity of a compound selected from among cytoic acid, 5-fluorouracil, methotrexate, 6-mercaptopurine and carbinalkaloid tumor cell decay drugs. A further preferred aspect of the present invention is to treat solid tumors in the human body by administering a compound of the present invention and a drug known to be effective in treating such tumors.

The compounds according to the invention can be prepared by alkylating 1,1-dimethyl-3-arylpropylamine with haloacetophenones such as benzoylmethyl halide. In this alkylation reaction, the compound of the present invention is prepared by providing N-benzoylmethyl-1,1-dimethyl-3-arylpropylamine and then reducing the benzoyl carbonyl moiety.

In other words, the carbonyl compound of the following structural formula (II) is reduced.

The compound of formula (II) is a novel compound and serves as the only step to prepare the compound of formula (I) by reducing the compound of formula (II). The reduction reaction is preferably carried out in an inert organic solvent at 15 to 115 ° C.

In describing the preparation method described above, benzoylmethyl halides such as benzoylmethyl bromide and 0-fluorobenzoylmethyl iodide may be substituted with propylamine derivatives such as 1,1-dimethyl-3- (4-hydroxyphenyl) propylamine. React. It is preferable that the phenolic hydroxy group of arylpropylamine is protected during the condensation reaction so that unnecessary side reactions do not occur. Commonly used protecting groups include ether-forming groups such as methyl and benzyl and esters such as acetates. Benzoylmethylhalide and 1,1-dimethyl-3-arylpropylamine are generally used in approximately equimolar amounts. However, if necessary, an excess of amine can be used and later separated from the desired product in an appropriate manner. The alkylation reaction is best carried out in a suitable solvent such as diethyl ether, benzene, dichloromethane and the like, when it is carried out at a temperature of about 25 to 70 DEG C, it is usually finished within 2 to 10 hours. N-benzoylmethyl-1, -dimethyl-3-arylpropylamine is usually recovered by filtering the reaction mixture to remove unreacted starting materials and then removing the solvent from the filtrate by evaporation or the like. The product thus prepared can be further purified by conventional methods such as salt formation and crystallization, if necessary.

Next, the N-benzoylmethylpropylamine derivative is reduced to obtain a compound of the present invention. This reduction reaction is carried out by reducing the carbonyl group to the carbinol moiety in accordance with a catalytic hydrogenation reaction using a catalyst such as platinum or palladium, or a metal hydride reduction reaction using an agent such as sodium borohydride.

The S-optical isomers of the above formula have substantially no biological activity and most of the effective activity is present in the R-optical isomer. The R-optical isomer of the above structural formula is therefore an important compound of the present invention.

However, from the economic point of view, it is preferable to use a racemate dl mixture of isomers, since inactive S-isomers do not poison the biological system at the expected dose, thus isolating the isomers or protecting the optically active starting materials. You need to know that you don't have to.

As can be seen from the above structural formula, the compound of the present invention is a secondary amine, and since the nitrogen atom of the amine is basic, the compound easily forms acid addition salts with some inorganic and organic acids.

Thus, pharmaceutically harmless salts of amines having the above structural formula are provided by the present invention. The resulting salts should not have the unnecessary pharmaceutical properties possessed by the parent amine base, while not limiting the particular acid used to form pharmaceutically harmless salts. Many kinds of inorganic acids can be used to form toxic non-toxic pharmaceutically salts of the present invention. Commonly used acids include hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, nitric acid, and the like. Typical organic acids include acetic acid, butyric acid, maleic acid, succinic acid, lactic acid, oxalic acid, p-toluenesulfonic acid, and the like.

Like most amine acid addition salts, the nontoxic pharmaceutically toxic acid addition salts according to the invention are characterized by being highly crystalline solids and thus can be crystallized and purified in conventional solvents, of course these salts are sodium hydroxide. Or by reacting with a base such as potassium carbonate, it can be easily converted to an amine freebase. Since the salt of the present invention is highly crystalline and water soluble, it is preferable to use the salt when formulating a drug suitable for oral or parenteral administration.

Representative examples of the compounds according to the invention are as follows.

N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-dimethylaminocarbonylphenyl) propylamine; R-N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-aminocarbonylphenyl) propylamine; N- [2- (2-fluorophenyl) -2-hydroxyethyl] -1,1-dimethyl-3- (4-hydroxyphenyl) propylamine; N- [2- (2-fluorophenyl) -2-hydroxyethyl] -1,1-dimethyl-3- (4-methylaminocarbonylphenyl) -propylamine bromide; N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-hydroxyphenyl) propylaluminum acetate; R-N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-methylaminocarbonylphenyl) propylaluminum isobutyrate; R-N- [2- (2-fluorophenyl) -2-hydroxyethyl] -1,1-dimethyl-3- (4-hydroxyphenyl) propylaluminium chloride; R-N- [2- (2-fluorophenyl) -2-hydroxyethylmethyl] -1,1-dimethyl-3- (4-aminocarbonylphenyl) propylamine oxalate; R-N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-aminocarbonylphenyl) propylaluminum p-toluenesulfonate and the like.

As noted above, the compounds of the present invention are useful as potentiators of known antitumor agents that are commonly used. In other words, the compounds of the present invention increase the efficiency of the commonly used tumor cell disrupting agents unexpectedly. These surprising results allow for more effective treatments when clinically used antitumor agents are used in less than the allowed effective treatment or when tumor cell decay drugs are administered at normal clinical values. Since the compounds of the present invention do not have antitumor effects per se and are not toxic to healthy cells at predetermined doses, the total effect of the mixed chemotherapy according to the present invention is better than in the use of tumor cell decay drugs at the time of treatment of the tumor. It is more effective and shows less toxic side effects.

The potency synergy of the compounds of the present invention can be seen in many laboratory examples. Such tests determine, for example, mitosis inhibition. The compounds of the present invention can stop cells cultured in the mitotic phase (medium) of the cell cycle without clearly affecting the cell cycle of other stages.

This mitotic inhibitory effect indicates that the compound has a beneficial effect on the biological activity of the anti-tumor agent and is tested in ovary cells of Chinese hamsters. The compound of the present invention is administered in an amount of 20 meg / ml and counted the number of cells arrested on mitosis among 1000 cultured cells, and compared with the control group which stopped mitosis without drug administration. Table 1 shows the mitotic stop assay and makes two evaluations for each compound. Results are expressed as percentage of cells arrested in mitosis 5 hours after contact with a compound of the invention.

TABLE 1

Proportion of mitosis (mean control = percentage on mitosis)

Compounds according to the invention show significant increases in the efficacy of antitumor agents when orally administered to mice suffering from transplanted tumors. In a typical experiment, laboratory mice are infected with a subcutaneous implant of tumor tissue in the armpit using a trocar. The initial tumor size in each animal is generally about 2 mm 2 and the length and width are measured periodically in mm. Typical tumor systems implanted include Adenocarcinoma 755, Aly Fast Strain of tracheal carcinoma and Mecca lympharcoma. Tumor cell disintegrating agents used in tests for determining that the compounds according to the present invention enhance the effect include cytoic acid, 5-fluorouracil, binddesin, methotrexate and 6-mercaptopurine. Twenty or thirty infected animals are usually selected as controls and administered with placebo. Ten infected animals are selected to administer known tumor cell disruption agents. The other 10 infected animals are administered a known tumor cell disruptor in addition to the compound of the present invention.

Table 2 shows the results of mixed chemotherapy in the treatment of mice infected with adenocarcinoma tumors similar to human breast tumors (755 tumors). 6-mercaptopurine (when administered alone as indicated by 6MP in the table and 6MP and the compound N- (2-phenyl-2-hydroxyethyl) -1,1 of the present invention) The result of treatment with a mixture of -dimethyl-3- (4-hydroxyphenyl) propylaluminium bromide (indicated by A in the table) is shown. Oral administration of 1.5 mg / kg once a day for 28 days In a group of 10 other rats, 6 mg (1.5 mg / kg) and the compound (A) of the present invention were combined twice a day for 3.75 mg / kg for 28 days. Subcutaneously in the amount of kg.

The results of treatment are indicated by the average size of tumor growth in mm 2 and the number of surviving test animals among those treated in each test group. Tumor size is measured after the date of initial tumor implantation as indicated in the table. The mean tumor size of the test group on the day scheduled to be measured is shown in column I and column II of each day measured is the number of surviving animals in the particular test group.

TABLE 2

N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3 for antitumor activity of 5-fluorouracil (denoted as 5FU in Table 3) in the treatment of mechalymph sarcoma in rats A similar test is made to determine the synergistic effect of-(4-hydroxyphenyl) -propylaluminium bromide (Compound A). Five test animals are administered intraperitoneally with 5-fluorouracil once daily in an amount of 4 mg / kg. Five infected animals were intraperitoneally administered with 5FU administered once daily in an amount of 4 mg / kg and a potency-boosting agent (Compound A) injected subcutaneously in an amount of 18.75 mg / kg twice daily. do.

Twenty different groups of animals received placebo. Column I on each day of insertion shows tumor size in mm 2 and column II shows the number of surviving animals in each test group. As can be seen from the data in Table 3, the average size of the tumors after 14 days of treatment with the group to which the combination therapy according to the present invention was treated was about 1/2 of the average size of the tumors in the group treated with 5-FU alone. . Furthermore, after 18 days of treatment, three of the five animals in combination therapy were still alive while all controls and animals administered with 5-FU alone were lethal.

TABLE 3

Similarly, large rat lungs are infected with alifest tumor strains of tracheal support cancer. One infected group of animals is intraperitoneally administered cytoxane once daily in an amount of 10 mg / kg. Compounds N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-hydroxyphenyl) propylaluminium bromide (indicated by A in Table 4) together with cytoic acid Significant synergistic effects when administered. Animals subjected to mixed chemotherapy are intraperitoneally administered cytoxane once daily in an amount of 10 mg / kg and Compound A is subcutaneously injected twice daily in an amount of 10 mg / kg. The results are shown in Table 4. From this, the tumor in the animal group administered with a mixture of cytoic acid and N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-hydroxyphenyl) -propylaluminum bromide The average size was only 20 mm 2 on day 19 after treatment, whereas the mean size of tumors in the group of animals treated with cytosan was 1340 mm 2, which is almost the same as that of the control group receiving placebo.

TABLE 4

In a test showing the synergistic effect of the compound according to the present invention on the tumor cell disruption of vinca alkaloids, rats implanted with adenocarcinoma (CA 755 tumors) were treated with placebo, binddesin and vaccin, and the compound N- (2-phenyl of the present invention. A mixture of -2-hydroxyethyl) -1,1-dimethyl-2- (4-aminocarbonylphenyl) propylaluminum chloride (denoted as compound B in Table 4) is administered.

Bindesin is administered intraperitoneally in amounts of 0.6 mg / kg on days 1,5,9 and 13 of the test. Animals receiving mixed chemotherapy are given intraperitoneally with bindecine according to the above dosages and in an amount of N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl in an amount of 7.5 mg / kg twice daily for 15 days. 3- (4-amino carbonylphenyl) propylaluminium chloride is administered intraperitoneally. The test results are shown in Table 5. Column I on each day measured shows the average size of tumors in each test group in mm2, and column II shows the number of animals from which tumors were removed from each test group still alive on any particular day. As can be seen from the data in Table 5, on day 40 of the trial, three of the ten animals treated with the combination therapy according to the invention were still alive and two of these three had tumors removed. In contrast, the animals that received only control and bindesin were all killed up to 40 days and no tumors were removed after 13 days of testing.

TABLE 5

5-Fluorouracil is not effective against 755 adenocarcinoma in rats but becomes very effective when administered in combination with a compound of the invention. These results are shown in data in Table 6. Rats are transplanted with 755 adenocarcinoma and infected. 30 animals were injected with placebo and 10 were given 5-fluorouracil alone, again 10 with 5-fluorouracil and N- (2-phenyl-2-hydroxyethyl) -1,1- Dimethyl-3- (4-aminocarbonylphenyl) propylaninium chloride is mixed and administered. In all cases, counting starts on the fifth day after farming. 5-Fluorouracil is administered intraperitoneally to animals when 5-FU is administered alone or in combination therapy once at 5, 9 and 13 days. Animals treated with combination therapy receive N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-aminocarbonylphenyl) propyl annium chloride (Compound B) in addition to 5-FU. Subcutaneously inject in an amount of 7.5 mg / kg 6 two days per day between 5 and 14 days. The test results are shown in Table 6. Column I at each measurement day shows the average size of tumors in each test group in mm 2 and column II shows the number of animals free of tumors in the living. While mixed chemotherapy using the compound of the present invention in combination with 5-fluorouracil is effective for the treatment of 755 adenocarcinoma, the use of 5-fluorouracil alone is ineffective.

TABLE 6

From the results in Table 7, the total tumors can be observed to be relieved. Rats are transplanted with 755 adenocarcinoma and infected. Thirty rats were used as a control and only placebo was injected. Ten mice were intraperitoneally injected with 6-mercaptopurine (6MP) once daily in an amount of 4 mg / kg on days 5, 9 and 13 after transplantation. To the other 10 animals, after transplantation, N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl- in an amount of 3.75 mg / kg twice daily for 10 days, starting from day 5 3- (4-aminocarbonylphenyl) propylaluminium chloride is injected subcutaneously.

At the same dosage as above, it is administered in combination with 6MP. The mean size of tumors in each group of test animals on the day of measurement is shown in Table 7, and column II shows the number of animals from which tumors were removed from those still alive. Twenty-four of 30 animals who received placebo by the 23rd day were killed, and 10 total animals who received 6-mercaptopurin alone were killed by 29 days. Of the 10 animals administered with a mixture of 6MP and the compound according to the invention, only four were killed at 73 days after transplantation and all six remaining live tumors were removed.

TABLE 7

Dose-modified cytoic acid and combinations of cytoic acid with N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-aminocarbonylphenyl) propylaninium chloride Similar experiments are carried out. Ten animals infected with 755 adenocarcinoma were tested intraperitoneally once a day at a dose of 25 mg / kg on 5, 9 and 13 days. Another infected group of animals is injected at 12.5 mg / kg once daily with cytosan at day 5, 9 and 13. Intraperitoneal injection of cytoic acid in an amount of 12.5 mg / kg to the third other animal group on day 5, 9 and 13, followed by twice daily compound (compound B) of the present invention between 5 and 14 days. Subcutaneous injection in an amount of 7.5 mg / kg. The results are shown in Table 8. As indicated by the data, all control animals and animals treated with tumor cell disintegrator alone were all killed after 73 days. In contrast, 6 of 10 animals treated with mixed chemotherapy were alive until 73 days after testing and all living animals had tumors removed.

TABLE 8

As indicated in the above experimental results, the compounds according to the present invention are useful for enhancing the efficacy of antitumor agents. Thus, the compounds can be used in combination with known tumor decay drugs for the treatment of neoplastic diseases.

N- [2-phenyl (and 2-fluorophenyl) -2-hydroxyethyl] -1,1-dimethyl-3- (4-substituted phenyl) propyl amine of the present invention may be used for oral or parenteral administration. Formulated. The formulations generally contain 1 to 50% by weight of the compound according to the invention. This compound can be mixed with various suitable pharmaceutical carriers, excipients and diluents. Typical carriers and diluents include dextrose, sucrose, starch powder, cellulose fibers, sorbitol, mannitol, polyvinylpyrrolidone, methylsencellulose, ethyl lactate, methylhydroxybenzoate, silica, Liquid paraffins and related excipients and carriers. The formulations contain one or more compounds of the invention and, if necessary, contain antitumor agents, such as cytoic acid, 6-mercaptofuran, and the like, in combination with an effective drug and potentiator in a single-dose form, administering an effective amount to provide a mixed chemotherapy. To do this. It is, however, preferred that the compounds of the present invention be formulated separately from the antitumor agent and two or more agents administered separately.

For oral administration, the compounds of the present invention can be mixed with carriers such as starch and sucrose to be tableted or filled into gelatin capsen. Alternatively, the compounds may be formulated in the form of syrups or suspensions by dissolving in sterile water, brine. For parenteral administration, for example intramuscular, subcutaneous or intravenous injection, the compounds may be mixed with isotonic saline or glucose, or dissolved in a suitable solvent such as water, bottled and lyophilized into powder form.

Such powders are easy to reconstitute by addition of sterile water or saline for intramuscular injection. The compounds may also be formulated in the form of suppositories, buccal seals for convenient administration.

According to the treatment method of the present invention, the compound of the above formula is administered in combination with antitumor agents known to be useful for the treatment of such diseases to patients suffering from a neoplastic disease and feeling the need for treatment.

The predetermined dose of the compound according to the invention is an amount sufficient to increase the efficacy of known tumor cell disintegrating agents. These dosages vary with the antitumor agent, the severity of the disease, the route of administration, and the factors that are associated with which the particular tumor efficacy to be treated is elevated. However, the compounds according to the invention are generally administered in an amount of 0.5 to 50 mg per gram of body weight of the animal. The preferred dosage is 1-20 mg / kg and is administered 1-4 times a day.

As described above, it is preferable to formulate and administer the potentiator of the present invention separately from the antitumor agent. 10 mg / kg twice daily for a compound such as, for example, N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-dimethylaminocarbonylphenyl) propylaluminum acetate It may be appropriately formulated for administration in the amount of. Tumor cell disruption agents such as cytoxane, etc., are administered in a conventional manner in a clinical or suboptimal amount.

For example, agents such as cytoxane are generally administered orally in an amount of 1 to 5 mg / kg once a day for the treatment of solid tumors such as neuroblastoma, ovarian adenocarcinoma, retinoblastoma, and the like. Commonly known side effects by continued cytoxane therapy include secondary malignancy, leukopenia, nausea, anorexia, oral mucosa and jaundice.

According to the present invention, the compound of the above structural formula is administered in combination with cytoic acid in an amount of 1 to 5 mg / kg or less, thereby increasing the comprehensive effect of known tumor cell disintegrating agents on malignant tissue.

The following specific examples are provided to more fully illustrate the invention. This embodiment is by no means limiting of the invention and should not be so interpreted.

[Production Example 1]

1,1-dimethyl-3- (4-methoxyphenyl) propylamine

After stirring a cold solution of 56 g of sodium cyanide in 125 ml of acetic acid, 140 ml of concentrated sulfuric acid solution containing 125 ml of acetic acid was added and diluted. 170.8 g of 1,1-dimethyl-1-hydroxy-3- (4-methoxyphenyl) propane is added in small portions over 10 minutes to the stirred acid solution. After the addition of alcohol was completed, the reaction mixture was heated to 75 ° C. for 30 minutes, cooled to 25 ° C., and further stirred for 2 hours.

The reaction mixture is then poured into 400 ml of brine and neutralized by adding sodium carbonate. The aqueous solution is extracted several times with diethyl ether, the extracts on ether are combined, washed with water and dried. Evaporation under reduced pressure removes the solvent to afford 142.8 g of N-formyl-1,1 -dimethyl-3- (4-methoxyphenyl) propylamine.

The compound is dissolved in 1000 ml of 2.7 N hydrochloric acid, and the acid reaction mixture is heated at 100 ° C. for 12 hours. The acidic mixture was cooled and added to 500 ml of water and washed with ethyl acetate. Sodium hydroxide is added to the aqueous layer to make it alkaline and the alkaline reaction mixture is extracted with diethyl ether. The extracts on ether are combined, washed with water and dried. The solvent is evaporated and the product distilled to yield 72.9 g of 1,1-dimethyl-3- (4-methoxyphenyl) propylamine having a boiling point of 110 to 120 ° C. at 1.0 Torr.

[Production Example 2]

1,1-dimethyl-1-hydroxy-4- (4-hydroxycarbonylphenyl) propane was reacted with sodium cyanide according to the method of Preparation Example 1, followed by hydrolysis of the intermediate N-proylamine 1 , 1-dimethyl-3- (4-hydroxycarbonyl phenyl) propylamine is obtained. This amine is converted to hydrochloride and then reacted with thionyl chloride to give 1,1-dimethyl-3- (4-chlorocarbonylphenyl) propylamine.

The acid chloride thus produced is reacted with excess ammonia to obtain 1,1-dimethyl-3- (4-aminocarbonylphenyl) propylamine and similarly the acid chloride is reacted with a slight excess of methylamine and dimethylamine. To give 1,1-dimethyl-3- (4-methylaminocarbonylphenyl) propylamine and 1,1-dimethyl-3- (4-dimethylaminocarbonylphenyl) propylamine, respectively.

Example 1

N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl-3- (4-hydroxyphenyl) propylamine

72.9 g of 1,1-dimethyl-3- (4-methoxyphenyl) propylamine was dissolved in 1000 ml of diethyl ether, and 37.8 g of 2-bromoaceto was dissolved in 450 ml of diethyl ether over 1 hour. A solution of phenone is added dropwise. After the addition reaction is complete, the reaction mixture is heated to reflux and stirred for one week. The reaction mixture is then cooled to room temperature and filtered to give 53 g of unreacted amine as hydrobromide. The filtrate was washed with water, dried and evaporated to collect the solvent and crystallized from ethanol and ethyl acetate to give 20 g of N- (2-phenyl-2-oxoethyl) -1,1-dimethyl-3- (4-methoxyphenyl ) Propylamine is obtained. Melting point 180.7-181.5 ° C

The resulting amine is dissolved in 200 ml of aqueous hydrobromic acid, and the acidic reaction mixture is heated to reflux and stirred for 12 hours. After cooling the mixture to room temperature, the crude product precipitates as crystals. The crystalline material was collected by filtration and recrystallized twice from ethanol to give 13.0 g of N- (2-phenyl-2-oxoethyl) -1,1-dimethyl-3- (4-hydroxyphenyl) propylaluminum bromide (melting point). 212 ° C. (decomposition) is obtained.

To 235 ml of a 90% solution prepared by adding ethanol to 2 g of 5% palladium / carbon water, 13.0 g of N- (2-phenyl-2-oxoethyl) -1,1-dimethyl-3- (4- Hydroxyphenyl) propylaluminum bromide was dissolved to prepare a solution, followed by stirring for 2 hours and 15 minutes under hydrogen pressure of 60 psi. The reaction mixture was filtered, the solvent was evaporated, the filtrate was concentrated to give a solid residue, which was then crystallized in ethyl acetate to give N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl- having a melting point of 169 to 170 ° C. 5.5 g of 3- (4-hydroxyphenyl) propylamibromide are obtained.

Elemental Analysis for C ₁₉ H ₂₆ NO ₂ Br

Theoretic: C 60.00, H 6.89, N 3.68

Found: C 60.17, H 6.59, N 3.61

The amine hydrogen bromide is dissolved in 50 ml of methanol, and a small amount of a solution of excess hydrogen chloride is added to diethyl ether, followed by stirring at room temperature. The amine hydrochloride was precipitated in solution, collected by filtration, and the solid product was recrystallized three times in methanol and ethyl acetate to give N- (2-phenyl-2-hydroxyethyl) -1,1-dimethyl- with a melting point of 180 to 182 캜. 3- (4-hydroxyphenyl) propylaminium chloride is obtained.

Elemental Analysis for C ₁₉ H ₂₆ NO ₂

Theoretic: C 67.91, H 7.80, N 4.17

Found: C 68.13, H 7.59, N 4.22

Example 2

The following formulations are prepared according to the invention for use in the treatment of solid tumors.

The ingredients are mixed well and then slippered with 1% magnesium stearate for compression. This tablet is administered 1 to 2 tablets per day in combination with an oral dose of 2 mg / kg orally administered to a 60-kg-weight patient once a day to treat solid tumors such as neuroblastoma and ovarian adenocarcinoma. .

Example 3

Preparation of parenteral liquid

The solution is administered to a patient weighing 60 kg in combination with an agent such as 5-fluorouracil in sub-optimal amounts 1 to 3 times a day and continued until the cell count of cerebrospinal fluid returns to normal. This formulation is well suited for the treatment of solid tumors such as osteosarcoma and rhabdomyosarcoma.

Example 4

Intravenous Formulation

The solution is administered to a patient weighing 50 to 70 kg in combination with an agent such as 6-mercaptopurine within one to two doses per day.

Tumors treated with these agents include solid tumors such as breast, colon, stomach, colon, ovary and bladder.

Claims (1)

A process for preparing the following compound of formula (I), characterized in that the carbonyl compound of formula (II) is reduced and the product racemate is split into R-isomers.

Wherein R ¹ is hydrogen or fluorine and R ² is hydroxy, aminocarbonyl, methylamino carbonyl, dimethylaminocarbonyl, acetylamino or methane sulfonylamino.