DE2031829A1 - N dialkoxyalkyl substituted phenyl ethylammine derivatives - Google Patents

Description

H-dialkoxyalkyl-substituted phenylethylamine derivatives

-Substituted phenylethylamines are available as effective appetite suppressant useful.

Obesity affects a significant part of the population become a problem «Often the cause is simply the fact that the body does not lose that much calories is how the calorie intake would take. The problem can be solved by reducing or reducing the caloric intake Calorie output is increased. For many people, such as the frail or the elderly, however, is an increase in Calorie consumption impossible or at least not recommended. Hence, a way must be found to reduce caloric intake belittling, and preferably should do so in some way and done in a way that is tolerable for the patient.

The nature of the obesity problem requires that a prescribed treatment have characteristics such that it can be continued for a longer period of time «

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Drugs which reduce appetite are known; however, their use often has undesirable side effects accompanied. Appetite suppressant compounds should help curb cravings for food in the evening when the Most overeating takes place, be ingested * However, a product like amphetamine gets one stimulating effect shows that it can be difficult or impossible for the patient to sleep without sedative measures to find. It would therefore be very desirable that an appetite suppressant be made available that does decreases the need for food, but not at the same time Time causes the patient to show symptoms such as restlessness, irritability, insomnia and the like « It will of course be understood that a low level of stimulation may be desirable because patients who are prescribed a Following a lifestyle that requires low calorie intake, often symptoms of depression demonstrate.

It is an object of the present invention to provide a connection provide that is effective as an appetite suppressant and only allows the patient to show a minimum of side effects.

Another object of the present invention is to provide a compound that does not undesirably excite the patient when administered in a dose sufficient to induce appetite suppression.

These and other objects of the invention are achieved by providing an N-dialkoxyalkyl-substituted-phenylethylamine derivative that achieves the structural formula

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has in the mean?

R, R ^ and R _{2 are} hydrogen, chlorine, fluorine, lower alkyl or perfluorine lower alkyl, where the lower alkyl groups have 1 to 4 carbon atoms, cycloalkyl or cycloalkenyl, where the cyclic groups have J to 7 carbon atoms; and R ,, E ^ and Rc lower alkyl groups of 1 to 4 carbon atoms. The compound can be administered as a base, which has low solubility in water, or as a pharmaceutically acceptable salt such as the hydrochloride, fumarate, suecinate or oxalate. Such salts provide increased water solubility.

The compound can be administered orally in the form of a tablet, capsule, Pill, suspension, dispersible powder, elixir and the like administered or in the form of a solution or Suspension in saline solution can be injected. A unit dose composition contains a smaller proportion of the compound and a larger proportion of one pharmaceutically acceptable carrier.

In general, the compounds are prepared by reacting a phenylacetone of the formula

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with an amine of the formula

H ₀ IT-CH ₀ C '

with formation of the ketimine of the formula E ^. / \ τ *

If R, means hydrogen, an aldehyde reactant is used in the analogous reaction so that results in an imine intermediate which subsequently reduces will.

The preparation is illustrated more specifically by the following examples. ·

example 1 Production of ^ -Chlor-N-dimethoacyäthyl-amphetamin

A mixture of 23 g (0.148 mol) of 4-chlorophenylacetone, 16.8 g (0.160 mol) of 1-iadno-2,2-dimethoxy-thane and 300 ecm of dry benzene is heated to reflux temperature under a Dean-Stark trap until no water separates. This takes about 1 hour. At the end of this time, the benzene is removed under vacuum and the remaining yellow oil, a crude etimine, is taken up in 300 ml of methanol. The alcoholic solution is cooled in an ice bath and treated with 10.9 g (0.288 mol) of Na-

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Triiuaborhydrid added in small .Anteile with stirring. When the addition is complete, the reaction mixture becomes. Boiled under reflux for 3 hours. The solution is then concentrated, and the semi-solid residue is treated with 300 ml of water and made strongly alkaline by adding 25 ml of 45% aqueous potassium hydroxide and 20 g of potassium hydroxide pellets Ether solution washed once with water and dried over magnesium sulfate · After extraction, the oil is distilled. 26.55 g (71 %) of an oil are obtained which "boils at 1 mm at 131 to 132 ° C. (njp-1.5043).

Other representative examples of compounds according to the invention which are obtained according to the procedures of Example 1 are listed in Table I.

The hydrochloride salt of the abovementioned Mmethoxyäthylphenyläthylamins can be made according to the following example.

Example 1A .

A sample of the amine from example Λ is taken up in ether and treated with ethereal HCl. Recrystallization from methanol gives a hydrochloride which melts at 105-5 to 106.degree. Salts of the other compounds of the invention are prepared according to a similar procedure. .

The compounds according to the invention show good biological properties Effectiveness, especially as an appetite-depressing gown. It has been found that a dose that has a lower Proportion of the compounds according to the invention in a larger one Portion of a carrier contains, when oral or subcutaneous

"- 5 ■ - / ■
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Administration to rats caused a marked reduction in the food intake of the test rats compared to the control rats. Water-soluble compounds are usually administered subcutaneously in a saline solution containing 0.01 to 0.05 mmol per ml; water-insoluble compounds are suspended in fljraganthgutimi (0.5% gum in water) and the effective dose is administered orally in aqueous suspension at a ratio of 2 ml / kß.

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Table I. Representative appetite suppressing compounds Example E.

2 H H H 3 H H 4th H 3-CF ₅ H 5 H 3-Cl 4-01 6th H H 4-F 7th H 3-01 H 8th 2-01 H H 9 H 3-F 4-F " 10 H H 11 H H 12th H H' H- 13th H H 4-01 14th H H 4-CF 15th H H 4-F. 16 2-O ₅ F ₇ H H 17th H 4-CH, H

CH

OH ₅ CH

CH

CH ₃ CH ₃ CH ₇ CH, GH ₃ CH ₃ CH ₃

CH
CH

CH ₅
CH ₅
CH ₅

CH

CH ₅ CH ₅ CH ₅ CH ₅ CH ₅ CH ₅

CH

CH ₅

C ₂ H ₅ C ₂ H ₅

CH ₂

CH

The test method that is used to illustrate this biological effectiveness is a proportional one simple test. There will be two groups of four batten each fed on a 5 hour driving schedule, d. H. the whole Feeding period is for a period of 24 hours

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for each group 5 hours at the same time of day, namely 7 (Cage a week. About 1/2 hour before the feeding period is to begin, the control group is given saline and administering a dosage of the solid compound to the xest group. Water soluble forms of the compound, e.g. B. the hydrochloride salt, are used in different test groups administered at two different dose levels of 0.011 and 0.044 mnMt / kg body weight; the dose is for the insoluble compounds 0.0022 and 0.088 mH / kg. A measured amount of food is given to both groups (the same amount to each group), and at the end of the 5 hour period Feeding period, the remaining feed is measured to determine the intake. The test animals are with compared the control animals according to the following point system:

Assessment The amount of feed

which is absorbed less than in the control animals in %

0 5 or less

t 6-19

1+ 20-39

2+ 40-59

3+ 60-89

4+ 90 and above

Table II below shows the effectiveness of representative ones Classes of compounds according to the invention, based on the points system mentioned above.

The side effects of the compounds were also observed, and reactions such as increased irritability, ataxia, salivation, Convulsions, agitation of the fur and the like,

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The noted · The intensity of the effect will be according to the reviews "no symptoms, light, massive and strong" classified. ■

a belle II

Appetizing effectiveness shape activity
Low high
Dose dose 3+ Side effects
gene link
example soluble 2+ + easy 1 insoluble + 3+ easy 2 insoluble O 4+ no symptoms 3 insoluble 3+ 4+ moderate 4th soluble 3+ 3+ moderate 5 insoluble 1+ 1+ easy 6th insoluble. 1+ 2+ no symptoms 7th soluble ± 2+ no symptoms 8th insoluble + 3+ easy 12th insoluble 1+ 3+ easy 13th insoluble 3+ 3+ moderate 14th insoluble 1+ 1+ moderate 15th soluble t raw! the 12th no symptoms 17th end up! It. That so « 3sual as From the front egg

also the insoluble forms of the compound reduce the feed intake of the plague animals and that the side effects were within the tolerable range.

Ea is believed that the skilled person on the basis of the above description \ is enabled without explanation use this invention asu in its whole extent.

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Claims (1)

June 26, 1970 Claims Compounds of the formula P in which mean: B, & j and Bg hydrogen, chlorine, fluorine, halide alkyl or perfluoro-lower alkyl with 1 to 4 carbon atoms, cycloalkyl or cycloalkenyl with J to 7 carbon atoms and B * 5 B ^ and Bc lower alkyl with Λ to 4 carbon atoms; as well as the pharmaceutically acceptable salts of these compounds 2. Compounds according to claim 1, characterized in that that the salts are selected from the group of hydrochloride, fumarate, succinate and ozalate. ^ 3 * Connections according to claim 1, characterized in that « that B 4-chlorine, Bg and B ~ each hydrogen and B ~, B ^ and Be each represent methyl. 4. Compounds according to claim 1, characterized in that that B is hydrogen, B ^ 5-chlorine, Bg 4-chlorine and R ,, R ^ and Bc each represent alkyl of 1 to 4 carbon atoms. . 5. Compounds of the formula according to claim 1, characterized in that B and Ky each denote hydrogen, Bg 3-xrifluoromethyl and Βχ, B ^ and Bc each denote methyl. - 10 - 009882/2 256 6. Compounds of the formula according to claim 1, characterized in that R and R ^ are each hydrogen, R2 is 4-irifluoromethyl, R, methyl and R ^ and R _{c are} each Ni edrigalkyl with 1 to 4 carbon atoms. 7. Compounds according to claim 6, characterized in that that the alkyl groups are ethyl groups. 8. Compounds according to claim 6, characterized in that that the alkyl groups are ethyl groups. 9. Sen appetite suppressant in unity dosage form, containing a smaller proportion of a A compound according to the formula of claim 1 and a major proportion of a pharmaceutically acceptable one Srägers. 10. A method for reducing the feed intake of a warm-blooded animal, characterized in that one such Warm-blooded animals administered a compound according to the formula of claim 1 in an amount that reduces their appetite . 11. The method according to claim 10, characterized in that the compound is administered in a daily dose of less than 0.088 mmol per kg of body weight. 12. A compound according to claim 4, characterized in that that Rj, R ^ and R ^ each represent methyl. 13. Compound according to claim 4, characterized in that Rj is methyl and R ^ and R _{c are} each ethyl - 11 - 009882/2256 2629 . Compound according to claim 1, characterized in that: and R ₁ each represent Vasserstoi c each methyl. R and R ^ are each hydrogen, H ₂ 4-fluoro and IU, E ^ and 009882/2 2