NL8202227A - 4-AMINO.BENZYLAMINE DERIVATIVES AND METHODS FOR THEIR PREPARATION AND USE AS PHARMACEUTICS. - Google Patents

Description

* 4-1-1-Amino-benzylamine derivatives and are preferred for their preparation and use as pharmaceuticals.

The invention relates to novel amino-benzylamine derivatives, their acid addition salts, for their preparation, pharmaceutical preparations containing them and their use as pharmaceuticals, in particular as anti-hyperglycemic agents.

The invention relates in particular to pharmaceutical preparations containing one or more compounds of the formula 1, containing a hydrogen or halogen atom, an alkyl group with 1 - H carbon atoms or an alkoxy - 10 group with 1 - b carbon atoms, Rg a hydrogen - or halogen atom, an alkyl group with 1 - U carbon atoms, an alkoxy group with 1 - ^ carbon atoms or a group of formula 1a, in which A contains an oxygen or sulfur atom or a carbonyl group or a direct bond and Rg and R ^ independently of one another, represent a hydrogen or halogen atom or an alkyl group with 1 - b carbon atoms or an alkoxy group with 1 - U carbon atoms, R ^ a hydrogen atom or an alkyl group with 1 - U carbon atoms, n 0, 1 or 2, R ^ an alkyl group with b - 2b carbon atoms, R ^ a hydrogen atom, an alkyl group with 1 - 20 2b carbon atoms or a group which can be broken down physiologically into a hydrogen atom and Rg and R ^, independently, a hydrogen atom, an alk yl group of 1 -2b carbon atoms or a group of formula 1b, in which an alkylene group of 1 - 6 carbon atoms and R 1 and R 2, independently of one another, contains a hydrogen or halogen atom or an alkyl group of 1 - 1 carbon atoms or represent an alkoxy group having 1 - b carbon atoms, or a group capable of being physiologically degradable to a hydrogen atom, wherein the / nitrogen-containing groups are placed meta or para relative to each other, and / or the pharmaceutically acceptable acid addition salts thereof. If desired, a pharmaceutically acceptable carrier and / or diluent are also present in the pharmaceutical preparations.

Halogen represents a fluorine, chlorine or bromine atom, while the alkyl groups may be branched or unbranched.

The compounds of the formula I according to the invention have a farraacological action. In particular, they are capable of inhibiting hyperglycemia, especially post-prandial hyperglycemia, as evidenced by tests involving oral starch nutrition.

These tests were performed on male Wistar rats (approximately 200g body weight)

Royal-Hart Breeders, New York). The animals were fasted overnight (16 hours) for the experiments. One hour after the oral administration of the vehicle (0.5¾ carboxymethylcellulose (CMC) or water) control or drug (12.5-200 mg / kg), the rats were orally fed starch (2.5g / kg) boiled wheat starch in 5% water). Thirty minutes after starch administration, the rats were anesthetized by intraperitoneal injection of sodium hexobarbital (120 mg / kg). Blood was then obtained by cardiac puncture and collected in a test tube containing 0.1 ml of heparin (1,000 units per ml). The heparinized blood was used to determine the blood sugar level using an auto-analyzer. The percent change in blood sugar was calculated by comparing the mean change in blood sugar after oral starch feeding (U-8 rats per treatment) to that of a control group.

So

The compounds are indicated for use as anti-hyperglycemic agents, in particular as anti-hyperglycemic agents, especially in diabetics.

8202227 -3- Λ

* * V

An indicated suitable daily dose for the treatment of hyperglycemia (especially the postprandial) is about 200-3000 mg, suitably in single doses of 50-1500 mg two to four times daily or in a slowly released form, in in particular, in the case of post-prandial hyperglycemia, administered three times a day with meals,

Thus, the invention also relates to a method of inhibiting hyperglycemia by administering one or more compounds of the invention of the formula 1 and / or their salts, and also to the use of these compounds and their salts as pharmaceuticals , for example, as / hyperglycemic agents, particularly as agents for inhibiting postprandial hyperglycemia or for use in the therapeutic treatment of the human or animal body.

The compounds of the formula I according to the invention can be administered both in free base form and in the form of pharmaceutically acceptable acid addition salts, such as the hydrochloride, the salts having a similar effect as the free forms.

As mentioned above, the compounds may also contain groups that can be broken down physiologically to hydrogen atoms. Such groups may be of the known type in which a tertiary amine moiety is cleaved (for example, by hydrolysis) to form a secondary amine moiety under conditions prevailing in a gastrointestinal tract to form pharmaceutically acceptable derivatives. The cleavage of such groups is caused in particular in the stomach by hydrolytic enzymes such as esterases and amidases. Examples of such groups are the carboxymethyl group, lower alkanoyl groups, for example the acetyl, succinyl, 1- (sodium sulfo) lower alkyl group, 1-35 (sodium sulfo) polyhydroxyalkyl group and the 1,3-bis (sodium 8202227 *% -u - sulpho) aralkyl group, wherein aryl represents, for example, a phenyl or naphthyl group and contains alkanyl 2 to 6 carbon atoms. Such groups may be introduced sequentially or simultaneously into the intermediate or final products in a conventional manner, which may require protection of reactive amino groups for the selective introduction.

The compounds of formula 1 of the invention, and / or their pharmaceutically acceptable acid addition salts, may optionally together with a pharmaceutically acceptable diluent and / or carrier and optionally other excipients, orally, in forms such as tablets, elixirs, capsules or suspensions. suspensions, or parenterally in forms such as injectable solutions or suspensions, are administered.

Recommended pharmaceutical preparations from the viewpoint of ease of preparation and administration are solid capsules filled with preparations, especially tablets and / or solid or liquid preparations.

The compound U- (N-methylhexadecylamino) -benzylamine is known from Hephep & Patent 1,002,281, but no useful pharmaceutical activity of this compound has been reported.

The invention thus further provides new compounds which fall within the scope of the above formula 1. Such compounds are those of formula 5 wherein 25 'is a hydrogen or halogen atom or an alkyl group of 1 - U carbon atoms or an alkoxy group of 1 - b carbon atoms, Rg * a hydrogen or halogen atom or an alkyl group of 1 - k carbon atoms an alkoxy group with 1 - t carbon atoms or a group of formula 1a, in which A is an oxygen or sulfur atom or a carbonyl group or a direct bond and Rq and R1 are, independently, a hydrogen or halogen atom or an alkyl group with 1 - k carbon atoms or an alkoxy group with 1 - ^ carbon atoms, R ^ 'a hydrogen atom or an alkyl group with 1 - b carbon atoms, 35 n 0, 1 or 2, Rj' an alkyl group with b - 2b carbon atoms, R ^ ' a hydrogen atom, an alkyl group of 1 - 2b carbon atoms or 8202227 *% -5- a group which can be broken down physiologically into a hydrogen atom and Rg * and R ^ independently, a hydrogen atom, an alkyl group with 1 - 2b carbon atoms or a group with formula l b, wherein B represents an alkylene group with 5 1-6 carbon atoms and R 1 and R 2, independently of one another, a hydrogen or halogen atom or an alkyl group with 1 to 1 carbon atoms or an alkoxy group with 1 to 1 carbon atoms, or a a group which can be decomposed iysiologically to a hydrogen atom, wherein the nitrogen-containing groups meta or para are placed relative to each other, provided that when R 'represents the hexadecyl group and R' represents the methyl group and n = 0, at least one of the substituents R 1, Rg ', R', Rg 'and R' 'has a meaning other than hydrogen, or an acid addition salt thereof.

The compounds of formula 5 can be prepared according to the invention by reacting an amine of formula 2 with a compound of formula 3, wherein R 1 - R 1 'and n have the meanings defined above and X is a cleavable group.

The reaction can be conducted under conditions customary for such reactions. Examples of cleavable groups are halogen atoms, for example a chlorine, bromine or iodine atom, or alkyl or arylsulfonyl groups, for example the tosyl group.

Compounds of formula 5 in which R ', Rg' and Rj 'represent a hydrogen atom and in which n = 0 can also be prepared according to the invention by reduction of a compound of formula 1 ».

The reduction of a compound of formula k to a corresponding compound of formula 5 may be by methods conventional for reducing a cyano group on an aromatic core to the corresponding primary amine, for example, by treatment with a metal hydride or by catalytic hydrogenation , taking care to avoid alteration of any other ring substituents that may be present.

A suitable method of preparing a compound of the invention of formula 5 is by treating a corresponding compound of formula 4 with a metal hydride reducing agent, such as an alkali metal aluminum hydride derivative, for example, LiAlHj., Under substantially anhydrous conditions, at moderate temperatures for example from about 10 to 70 ° C, preferably from about 20 to 30 ° C, in an inert organic environment, for example a cyclic ether, such as tetrahydrofuran 10 (THF).

The compounds of formulas 2 and 3 are known or can be obtained in a conventional manner.

The compounds of formula IV are either known from the literature, for example, Belgian Patent 870,687, Der-15 Went Abstract 23,959B, or, if not known, may be in a manner analogous to that described in the literature for preparing the known compounds are performed. For example, the compounds of formula IV can be prepared by alkylation, that is, by replacing by conventional methods one or two of the hydrogen atoms of the amino function of a 4-aminobenzonitrile.

It will also be appreciated that compounds containing primary amino groups can be converted, for example by reductive amination if desired followed by introduction of a further alkyl group, into the corresponding secondary and tertiary amino compounds in a conventional manner.

The known compounds of formula 1 can be prepared in an analogous manner.

The compounds of the formula I (or 5) according to the invention can be separated and purified by customary methods. They can be obtained in the free base form or in the form of an acid addition salt. The free base forms and acid addition salt forms can be prepared and converted into one another in the usual manner.

Examples of recommended substituents in the compounds of the invention of formula 1 are: 8202227 -7- H1 = a) CH3

b) H

R2 = H R3 = a) CH3

B) H

n = a) 0 b) 1 = a) alkyl b) C 8 -C 20 alkyl 10 c) C 12 -C 18 alkyl

R5 a a) H

b) C 1 -C 1 -alkyl c) C 1 -C 8 -alkyl d) C 8 -C 20 alkyl 15 e) C 12 -C 18 alkyl

Rg * a) H

b) C 2 -C 20 alkyl * a) H

t) C8 -C20 alkyl 20

The alkyl groups are preferably unbranched.

A recommended group that can be broken down physiologically is an alkanoyl group with 1 t / l carbon atoms, for example the acetyl group. If Rg and / or R8 represent a physiologically degradable group, then preferably only one of them at a time is an alkanoyl group.

The groups containing two nitrogen atoms are preferably placed para to each other.

Combinations of these recommended groups are of particular interest.

A special group of compounds includes those of formula 5 * wherein / ig ', Rg' and Rj 'represent a hydrogen atom, n = 0, R ^' an alkyl group with 1 * - 2b carbon atoms and R ^ 'a hydrogen atom or a group which can be broken down physiologically into a hydrogen-35 atom.

Within this group are recommended compounds which are 8202227 -8- where R 'represents a hydrogen atom and / or R' is unbranched and contains 8 to 20 carbon atoms and / or R 'represents a hydrogen atom.

The aforementioned recommended groups satisfy the 5 compounds of the invention of the formula 1 and are suitably those of the formula 5.

Two particularly important special compounds are U-hexadecylamino-benzylamine and H-Cn-methylhexadecylamino) -benzylamine.

10

Example I;

Preparation of 4-hexadecylaminobenzylamine (compound

No. 1).

i) U-Hexadecylaminobenzyl bromide.

5.26 g of triphenylphosphine and 6.66 g of tetrabromomethane were added to a solution of 3.5 g of N / n-hexadecyl amino-7-benzyl alcohol in 50 ml of dry tetrahydrofuran at 0 ° C. The reaction mixture was then stirred at room temperature for 2-3 hours. Water was then added to the mixture and the resulting mixture was extracted five times with methylene chloride. The methylene chloride extracts were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered and the filtrate evaporated. The resulting residue was then rapidly chromatographed on methylene chloride to give he-hexadecylaminobenzyl bromide.

ii) U-Hexadecylaminobenzylamine.

To a solution of 100 ml of methanol saturated with ammonia (containing about 3½ ammonia) (dropwise) a solution of 10 g of H-hexa-decylamino-benzyl bromide was added and the resulting reaction mixture was stirred at room temperature for 18-2 hours. The solvent was then removed by evaporation under reduced pressure to obtain a crude product. The product of this example was purified by rapid filtration of a methylene chloride solution over silica gel (mp: 67-70 ° C).

8202227 -9-

Example II:

Preparation of U-Hexadecylaminobenzylamine (Compound No. 1).

i) -Hexadecylaminobenzonitrile.

5 To a 2 liter four neck round bottom flask equipped with a mechanical stirrer, addition funnel and gas inlet tube, 21.0g (0.003 mol) of a 50 # solution of sodium hydride in 600ml dimethyl acetamide (DMA) was added and then a solution was dripped of 50 g (0.2 moles) of U-amino-10 benzonitrile in 200 ml of DMA. After the reaction mixture was stirred at room temperature for 30 minutes, a solution of 129.2 g (0.2 mole) of 1-bromhexadecane in 300 ml of DMA was added and the reaction mixture was allowed to stir at room temperature for an additional 16 hours. The reaction mixture was then poured into water, the precipitate was filtered off and air-dried. The air dried solid product was taken up in methylene chloride, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. There was thus obtained a tan-colored wax-like solid product, from which purified hexadecylaminobenzonitrile, m.p. 60 DEG-61.5 DEG C., was obtained by recrystallization from hexane.

i i) -1-Hexadecylamino-benzylamine.

Into a 2 liter four neck round bottom flask equipped with an addition funnel, reflux condenser and mechanical stirrer, 12.0 g (0.31 mole) of lithium aluminum hydride and 1 liter of tetrahydrofuran. A solution of 55g (0.16 mol) p-hexadecyl-30-aminobenzonitrile in 500 ml of tetrahydrofuran was then added dropwise with continuous stirring. The reaction mixture was then heated under reflux for 5 hours and stirred for an additional 16 hours at room temperature. The reaction mixture was then decomposed by adding 0.00 ml of a saturated aqueous sodium sulfate solution and extracted several times with ether. The combined ether extracts were washed with water and a saturated solution of 8202227 Τ -1-10 sodium chloride in water and dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to give a residue (the crude title). product), from which the purified title compound, m.p. 67-70 ° C, was obtained by crystallization with acetonitrile.

In an analogous manner as described in Examples I and II, or as described above, the following compounds of the formula 1 according to the invention were obtained using suitable starting materials.

Table A (nitrogen-containing groups in the para position relative to any other (R ^) (Rj-) N group in the 4 position).

Compound R ^ R2 R ^ n R6 R7 Melt “no. Point

2 Η Η H 0 n.C12H25 Η Η H

3 Η Η Η 0 η010Η21 Η Η H

b Η Η H 0 n.C ^ H ^ Η Η H

5 Η Η H 0 (CH3) 3CC10H21 Η Η H

6 3-C1 Η H 0 U, C16H33 Η Η H

7 2-CH3 Η H 0 n.Cl6H33 Η Η H

8 2-CH30 Η H 0 n.Cl6H33 Η Η H

9 Η Η H 0 n.Cl6H33 CH3 Η H 35-36 ° 0 II o 10 Η Η H 0 a.ClgH33 CH3 -C-CH3 H 71.5-73 11 Η Η H 0 n.Cl6H33 nC ^ H ^ Η H 36-38 ° 0 12 Η Η H 0 n.Cl6H33 nC ^ H ^ -C-CH3 H 59.6-61 ° 8202227

Claims (13)

1. Compounds of formula 3 »wherein R 1 'is a hydrogen or halogen atom, an alkyl group with 1 - carbon atoms or an alkoxy group with 1 - U carbon atoms, Rg * a hydrogen or halogen atom, an alkyl group with 1 - k carbon atoms, an alkoxy group with 1 - ^ carbon atoms or a group of formula 1a, in which A is an oxygen or sulfur atom, a carbonyl group or a direct bond and Rg and R ^, independently of each other, a hydrogen or halogen atom , an alkyl-10 group with 1 - k carbon atoms or an alkoxy group with 1 - U carbon atoms, R ^ 'a hydrogen atom or an alkyl group with 1 - carbon atoms, n 0, 1 or 2, R ^' an alkyl group with 4 - 2k carbon atoms, R ^ 'a hydrogen atom, an alkyl group with 1 - 2k carbon atoms or a group which can be broken down physiologically into a hydrogen atom and Rg' and R ^ ', independently of each other, a hydrogen atom, an alkyl group with 1 - 2k carbon atoms a group of formula 1b, wherein B is an alkylene group of 1 to 6 ko hydrogen atoms and R10 and R4, independently of one another, represent a hydrogen or halogen atom or an alkyl group with 1 - H carbon atoms or an alkoxy group with 1 - 4 carbon atoms, or a group which can be broken down physiologically into a hydrogen atom and the nitrogen-containing groups meta or para placed relative to each other under the condition that if R ^ * the hexadecyl group and R ^ 1 represent the methyl group and n * 0, at least one of the substituents R ^ ', Rg', Rg ', Rg * and Rj 'has a meaning other than hydrogen, or an acid addition salt thereof. Compounds according to claim 1, wherein R ^ ', Rg's r »30 and R ^' represent a hydrogen atom, n = 0, R ^ 'represents an alkyl group with U - 2k carbon atoms and R ^' represents a hydrogen atom or a group which is physiologically until a hydrogen atom can be broken down. 3. Compounds according to claim 2, wherein R 'represents a hydrogen atom and / or R' is unbranched and contains 8-20202227 -12 V V carbon atoms and / or R 'represents a hydrogen atom. 4_. 4-Hexadecylaminobenzylamine. A process for preparing an aromatic compound, characterized in that a compound as defined in claim 1 is prepared by reacting an amine of formula 2 with a compound of formula 3, wherein R 1 '- --γ' and n have the meanings defined above and X is a divisible group? or if R ', Rgf and R' 'represent a hydrogen atom and n = 0, to reduce a compound of formula 4 and to recover the compound thus obtained in free base form or in the form of an acid addition salt thereof. 6, Pharmaceutical preparations containing one or more compounds of formula 1, wherein R 1 is a hydrogen or halogen atom, an alkyl group with 1 to 4 carbon atoms or an alkoxy group with 1 to 4 carbon atoms, Rg is a hydrogen or halogen atom, an alkyl group with 1 - 4 carbon atoms, an alkoxy group with 1 - 1+ carbon atoms or a group of formula 1a, in which A is an oxygen or sulfur atom, a carbonyl group or a direct bond and Rg and Rp, independently, of a hydrogen or halogen atom, an alkyl group with 1 - 1 * carbon atoms or an alkoxy group with 1 - 4 carbon atoms, a hydrogen atom or an alkyl group with 1-4 carbon atoms, n 0,1 or 2, R ^ an alkyl group with 4-24 carbon atoms, R ^ a hydrogen atom, an alkyl group of 1 to 24 carbon atoms or a group which can be physiologically decomposed into a hydrogen atom and Rg and Rjy independently, a hydrogen atom, an alkyl group of 1 to 24 carbon atoms, a group of formula 1 b, wherein B represents an alkylene group of 1 to 6 carbon atoms and Rjq and Rj, independently of one another, a hydrogen or halogen atom or an alkyl group of 1 to 4 carbon atoms or an alkoxy group of 1 to 4 carbon atoms, or a group physiologically can be decomposed to a hydrogen atom, wherein the nitrogen-containing groups are placed meta or para relative to each other, and / or wish to have a physiologically acceptable acid addition salt thereof, if desired, together with a pharmaceutically acceptable carrier and / or diluent. 7. A method for inhibiting hyperglycemia in a patient suffering from it, characterized in that one or more compounds according to claims 1 to 3 or a preparation according to claim 6 are administered to this patient. Pharmaceutical preparation containing one or more compounds according to claims 1-3 and / or a salt thereof. Method for inhibiting hyperglycemia, in particular postprandial hyperglycemia, characterized in that a compound according to claims 1 - 3 and / or a salt thereof, or a preparation according to claim 6 is used. 10. Preparation according to claim 6, characterized in that 1 u-hexadecylaminobenzylamine and / or 1 - (n-methylhexadecyl-amino) -benzylamine and / or a salt thereof are used. Process according to claim 7, characterized in that 1-hexadecylaminobenzylamine and / or 1 - (1 + -methylhexa-decylamino) -benzylamine and / or a salt thereof are used. 12. Method as described in the description and / or examples. 13. A method for preparing a therapeutic composition, characterized in that one or more compounds according to any one of the preceding claims, and / or a salt thereof, are introduced into a dosage form suitable for such use. 1 ^. Shaped therapeutic preparations made by the method of claim 11. t 8202227