FR2507180A1 - NOVEL PHENYLALKYLAMINES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINES - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS PHENYLALKYLAMINES OF THE FORMULA (CF DRAWING IN BOPI) IN WHICH R REPRESENTS HYDROGEN, A HALOGEN OR A RADICAL ALKYL OR ALCOXY, R REPRESENTS HYDROGEN, A HALOGEN, A RADICAL ALKYL OR A RESTEXY PHENYL, PHENOXY, PHENYLTHIO OR BENZOYL, R REPRESENTS HYDROGEN OR A RADICAL ALKYL, N MEANS 0, 1 OR 2, R REPRESENTS A RADICAL ALKYL, R REPRESENTS A RADICAL ALKYL OR A PHYSIOLOGICALLY DEGRADABLE ETHYL GROUP OR A AND R REPRESENT HYDROGEN, A RADICAL ALKYL, A PHENYLALKYL GROUP, OR A PHYSIOLOGICALLY DEGRADABLE GROUP TO A HYDROGEN ATOM, THE REMAINS CONTAINING NITROGEN BEING META OR PARA IN RELATION TO EACH OTHER. THESE COMPOUNDS MAY BE USED AS ANTI-HYPERGLYCEMA MEDICINES.

Description

The present invention relates to novel -phenylalkylamines, their

preparation and their application

  in therapeutics, as active ingredients of medicinal

  ments. In particular, the invention relates to the therapeutic use, as active ingredients of medicaments, of phenylalkylamines having the formula I R

  53 R ()

CH (CH 2) N 6 (

  in which R 1 represents a hydrogen or halogen atom or a C 1 -C 4 alkyl or alkoxy radical, R 2 represents a hydrogen or halogen atom, a C 1 -C 4 alkyl or alkoxy radical or a remainder of the formula o A means an oxygen or sulfur atom, a carbonyl group or a direct bond, and R 8 and R 9 each signify, independently of one another, a hydrogen atom or a halogen or a C 1 -C 4 alkyl or alkoxy radical, R 3 represents hydrogen or a C 1 -C 4 alkyl radical, n represents 0, 1 or 2, R 4 represents a C 4 -C 24 alkyl radical; , R 5 represents a hydrogen atom, a C 1 -C 24 alkyl radical or a physiologically degradable group to a hydrogen atom, and R 6 and R 7 represent, independently of one another, an atom of hydrogen, a C 1 -C 2 alkyl radical, a radical of formula 12. ## STR5 ## wherein R 1 represents a C 1 -C 6 alkylene radical and R 10 and R 11 each independently represent one of another, a a hydrogen or halogen atom or a C 1 -C 4 alkyl or alkoxy radical, or a group that is physiologically degradable to a hydrogen atom, the amino group and the aminoalkyl residue being located in meta or para relative to each other, in the form of a free base or an acid addition salt

pharmaceutically acceptable.

  Halogen means fluorine, chlorine or bromine; the alkyl residues present in the molecule

can be branched or not.

  The compounds of formula I are indicated by

  interesting pharmacodynamic properties; in part-

  In particular, they are able to inhibit hyperglycaemia, including postprandial hyperglycemia, as

  tests carried out in animals which have been administered

  beforehand starch by mouth.

  In these trials, male Wistar rats weighing about 200 g from Royal-Hart Breeders, New York are allowed to fast overnight (16 hours) prior to testing one hour after administration. vehicle 0.5% carboxymethylcellulose (CMC) or water or the vehicle containing the test substance (12.5 to 200 mg / kg), the rats are given oral starch ( 2.5 g / kg wheat starch cooked in 5% water) 30 minutes after starch absorption, the rats are anesthetized by intraperitoneal injection of hexobarbital sodium (120 mg / kg). by cardiac puncture and collected in a test tube containing 0.1 ml of heparin (1000 units / ml). Heparinized blood is used to determine

  the blood sugar level by means of an auto-analyzer.

  The change in% glucose in the blood is calculated by comparing the mean change in glucose in the blood after administration of the test substance (4 to 8 rats /

  treatment) with that obtained in the control animals.

  Owing to this property, the compounds of formula I can be used therapeutically as anti-hyperglycemic agents, in particular for inhibiting post-hyperglycemia.

  prandial, especially for diabetics.

  The appropriate daily dose indicated for the

  treatment of hyperglycaemia, especially hyperglycemia.

  postprandial plasma, is between about 200 and 3000 mg, advantageously administered in divided doses of 50 to 1500 mg 2 to 4 times per day, or in delayed form; in the case of postprandial hyperglycaemia, the daily dose will be administered in divided doses 3 times

per day at mealtimes.

  The invention also relates to a medicament containing, as active principle, a compound of formula

  I in the free base state or in the form of a pharmaceutically

just acceptable.

  The compounds of formula I can be administered

  in the form of a free base or in the form of pharmaceutically acceptable acid addition salts, for example the hydrochloride; these salts have the same order

  activity than the corresponding free bases.

  As already indicated, the compounds of formula I may also contain groups physiologically degradable to hydrogen atoms. Such groups may be any groups capable of being removed, for example by hydrolysis, so as to convert a tertiary amino group into a group. secondary amino under the

  conditions encountered in the gastrointestinal tract.

  The cleavage of such groups is caused, especially in the stomach, by hydrolytic enzymes, such as esterases and amidases. Representative of such groups are carboxymethyl, C 2 -C 6 alkanoyl, as per acetyl, succinyl, (sodium sulpho) lower alkyl, 1- (sodium sulpho) polyhydroxyalkyl and 1,3-bis (sodium sulpho) aralkyl,

  aryl means, for example, a phenyl or naphthyl group.

  Such groups can be introduced successively or simultaneously into the intermediate or final products according to the known methods, the protection of the groups

  which may be necessary for an introduction

selective

  As medicaments, the compounds of formula I and their pharmaceutically acid addition salts

  may be administered in the form of

  Pharmaceutical substances containing the active substance in combination with a pharmaceutically acceptable diluent or vehicle

  acceptable and possibly with other excipients.

  Such compositions are also part of the invention.

  The pharmaceutical compositions can be in the form of tablets, elixirs, capsules or suspensions for administration orally or in the form of solutions or injectable suspensions.

  intended for parenteral administration.

  The preferred pharmaceutical compositions of

  point of view of the ease of preparation and administration

  solid compositions, in particular tablets and capsules containing either a solid or

liquid.

  4- (N-methylhexadecylamino) -benzylamidine is described in British Patent No. 1,004,281; however, no pharmacological activity has been described up to

present for this compound.

  The invention also includes novel phenylalkylamines having the formula Ip R? e 3 R '(IP)

<CH (CH) R 6 (

R 4 R 2 R 2

  in which R 1 represents a hydrogen or halogen atom or a C 1 -C 4 alkyl or alkoxy radical, R 2 represents a hydrogen or halogen atom, a C 1 -C alkyl or alkoxy radical; 4, or a remainder of formula

_ R 9

  o A means an oxygen or sulfur atom, a carbonyl group or a direct bond, and R 8 and R 9 each signify, independently of one another, a hydrogen or halogen atom or a radical C 1 -C 4 alkyl or alkoxy, R represents a hydrogen atom or an alkyl radical

C 1 -C 4,

  n represents 0, 1 or 2, R represents a C 4 -C 24 alkyl radical, R represents a hydrogen atom, a C 1 -C 24 alkyl radical or a group that is physiologically degradable to a hydrogen atom, and R 6 and R; each independently of one another represents a hydrogen atom, a C 1 -C 24 alkyl radical, a radical of formula

-B_ 10

  B is C 1 -C 6 alkylene and R 10 and R 11 each independently of one another are hydrogen, halogen or C 1 -C 4 alkyl or alkoxy, or a group physiologically degradable to a hydrogen atom, the amino group and the aminoalkyl residue being located in meta or para to each other, and at least one of the symbols Ri, R, R, R 6 and R having a meaning other than hydrogen when R is hexadecyl, R is methyl and n = 0,

and their acid addition salts.

  The invention also relates to a process for the preparation of the compounds of formula Ip, according to which an amine of formula II is reacted

R 6 '(II)

  In which R 6 and R have the meanings given above, with a compound of formula III

R 3 '(III)

C H (CH 2) X

4 R 1 'R 2

R

  wherein R 1 to R 5 and N have the meanings given above, and X denotes a group capable of being removed. The reaction is carried out under known conditions for such reactions. Examples of groups which may be removed are halogens, for example chlorine, bromine or iodine, or alkyl or arylsulfonyl groups, for example

the tosyl group.

  According to another process of the invention, to prepare the compounds of formula Ip in which R 3, R 6 and R 7 represent hydrogen and N represents 0, a compound of formula IV is reduced

NC (IV)

  R 2 # in which R R 2, R 4 and R 5 have the meanings

previously.

  The reduction of the compound of formula IV to the corresponding compound of formula Ip can be carried out

  according to known methods for reducing an aromatic nitrile

  corresponding primary amine, for example by

  treatment with a metal hydride or by hydrogenation

  catalytic reaction; care should be taken not to affect other substituents located on

the core.

  A suitable method for preparing a compound of formula Ip is to treat the corresponding compound of formula IV with a reducing metal hydride such as a derivative of an aluminum hydride and an alkali metal, such as, for example, hydride of aluminum and lithium, under anhydrous conditions, at a moderate temperature, for example between about 100 and 700, preferably between about 20 and 30, in an inert organic medium,

  example in a cyclic ether, such as tetrahydro-

  furan. 4- (N-methylhexadecylamino) benzylamine can

  be prepared according to the methods described above.

  The compounds of formulas II and III are known

  or can be prepared in a known manner.

  The compounds of formula IV are described in the literature, for example in Belgian Patent No. 870 687; those which are not known can be prepared as described in the literature for the preparation of known compounds. For example, the compounds of formula IV can be prepared by alkylation, for example by substituting one or, successively, two atoms of hydrogen of the amino group of a 4-aminobenzonitrile, according to conventional methods. It should be noted that compounds containing primary amino groups can be converted, according to known methods, for example by reductive amination optionally followed by the introduction of another alkyl group, into corresponding secondary or tertiary amine compounds. The compounds of formula I or Ip thus obtained

  can then be isolated and purified in a known manner.

  They can be obtained as free base or in the form of acid addition salts. If necessary, the free bases of formula I can be converted into their acid addition salts; from the salts, we can release the

bases according to known methods.

  Examples of preferred substituents in the compounds of formula I are the following: R 1 = a) CH 3 b) H

R 2 = H

  R 3 = a) CH 3 b) H n = a) O b) 1 R 4 = a) C 4 -C 24 alkyl b) C 8 -C 20 alkyl c) C 12 -C 18 alkyl R 5 = a) H b) C 1 -C 4 alkyl c) C 4-24 alkyl d) C 8 -C 20 alkyl e) C 12 -C 18 alkyl R 6 = a) H b) C -C alkyl 8-C 20 R 7 = a) H b) C 8 -C 20 alkyl

  The alkyl groups are preferably unbranched.

  As the preferred physiologically degradable group, it is possible to

  C1-C4 alkanoyl groups, such as, for example, the acetyl group. When R 6 and / or R 7 represent a physiologically degradable group, preferably only one of the two substituents means a

alkanoyl group.

  The two residues containing nitrogen, that is to say the amino group and the aminoalkyl residue, are preferably located

  in para to each other.

  The combinations of these preferred groups are particularly

interesting.

  A particular group of compounds includes compounds of formula Ip wherein R a, R 6 and R; represent hydrogen, N means O R 1 represents an alkyl group containing from 4 to 24 carbon atoms, R denotes a hydrogen atom or a group physiologically

  degradable into a hydrogen atom.

  Among this group of compounds, the preferred compounds are those in which R 1 is a hydrogen atom and / or R 1 is straight chain and contains from 8 to 20 carbon atoms and / or

R 5 is hydrogen.

  The preferred groups mentioned above relate to the compounds of formula I and, in the case of

  compounds of formula Ip.

  As individual compounds particularly

  4-hexadecylamino-benzylamine

  and 4- (N-methylhexadecylamino) benzylamine.

  The following examples illustrate the present

  without limiting its scope.

  eratures are all given in degrees Celsius.

Example 1

  4-hexadecylaminobenzylamine (Compound No. 1) a) 4-hexadecylaminobenzyl bromide

  To a solution of 3.47 g of 4-EN-n-hexadecyl alcohol

  aminol-benzyl in 50 ml of tetrahydrofuran

  5.26 g of triphenylphosphine and 6.66 g of tetrabromomethane are added to (O). The reaction mixture is stirred at room temperature for 2 to 3 hours, water is added and the mixture obtained is extracted 5 times. The methylene chloride extracts are combined, the combined solution is washed twice with water, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The residue obtained is subjected to a flahchromatography with chloride

  of methylene to give 4-hexadecyl bromide

  aminobenzyl. b) 4-hexadecylaminobenzylamine To a solution of 100 ml of methanol saturated with ammonia (containing about 3.4 g of ammonia), a solution of 4.10 g of hexadecylaminobenzyl bromide was added dropwise and stirred. The reaction mixture is stirred at room temperature for 18 to 24 hours. The solvent is evaporated under reduced pressure to give a crude product.

  product thus obtained by rapid filtration of a solution

  methylene chloride on silica gel

(F = 67-70).

  Example 2 4-hexadecylaminobenzylamine (Compound No. 1) a) 4-hexadecylaminobenzonitrile

  In a 4-necked 2-liter flask equipped with a

  mechanical reactor, a dropping funnel and a nitrogen inlet tube, 21.0 g (0.43 mol)

  of 50% sodium hydride in 600 ml dimethylacetate

  tamide (DMA) then a solution of 50 g

  (0.42 moles) 4-amino-benzonitrile in 200 ml of DMA.

  After stirring the reaction mixture at room temperature,

  After stirring for half an hour, 129.2 g (0.42 mol) of 1-bromohexadecane in 300 ml of DMA are added dropwise and the reaction mixture is stirred at room temperature for a further 16 hours. The precipitate is filtered off with water and dried in air. The air-dried solid product is taken up in methylene chloride and dried over anhydrous sodium sulphate.

  filter and the solvent is removed under reduced pressure.

  A waxy solid product of tan color is obtained which, after recrystallization in hexane, gives pure 4-hexadecylaminobenzonitrile melting at

-61.5.

  b) 4-hexadecylamino-benzyl amine In a 4-necked 2-liter flask equipped with a dropping funnel, a reflux condenser and a mechanical stirrer, 12.0 g (0.31 mol ) of lithium aluminum hydride and a liter of tetrahydrofuran is then added dropwise

  a solution of 55 g (0.16 mole) of p-hexadecylamino-

  benzonitrile in 500 ml of tetrahydrofuran with continuous stirring The reaction mixture is then refluxed for 5 hours and stirred

  at room temperature for another 16 hours.

  The reaction mixture was decomposed by the addition of 400 ml of saturated aqueous sodium sulfate solution and extracted several times with ether. The combined ether extracts were washed with water and saturated chloride solution. of sodium, dried over anhydrous sodium sulfate, filtered and the solvent is removed under reduced pressure to give the crude 4-hexadecylamino-benzylamine which is recrystallized from acetonitrile The pure product

bottom at 67-70.

  By proceeding as described in Example 1 or 2 or as previously described and using suitable starting materials, the following compounds of formula I can be prepared:

T A B L E A U I

  (The residues containing nitrogen are located in the para position relative to each other, (R 4 R 5) N being in position 4) (Table I see next page)

  C0, - lpt ,, R1R2R3NR4R5R6R7F-

  ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## 16 H 33 HH 8? -CH 30 HHO nC 16 H 33 HHH 9 HHHO nC 16 H 33 CH 3 HH 35-36 "MHHHO nC 16 H 33 CH 3 -C-CH 3 H 71, 5-73 H -HHO nC 16 H 33 rk-C 16 H 33H H 36-38 * 12 HHH r-C 16 H 33 P-Cl 6 H 33 -C-CH 3 H 59.6-6 l

-2507180

T A B'I E A U

Claims (7)

  1. New phenylalkylamines, characterized in that they correspond to the formula Ip RIR (Ip) R 5 CH (CH 2) / 6 (Ip) R R 2 '7   in which R represents a hydrogen or halogen atom or a C 1 -C 4 alkyl or alkoxy radical, R 2 represents a hydrogen or halogen atom, a C 1 -C 4 alkyl or alkoxy radical; , or a residue of formula o A means an oxygen or sulfur atom, a carbonyl group or a direct bond and R 8 and R 9 each signify, independently of one another, a hydrogen or a halogen or a C 1 -C 4 alkyl or alkoxy radical, R a represents a hydrogen atom or an alkyl radical C 1 -41 N denotes 0, 1 or 2, R 1 represents a C 4 -C alkyl radical 24, R represents a hydrogen atom, a C 1 -C 24 alkyl radical or a physiologically degradable group to a hydrogen atom, and R 6 and R represent, independently of one another, an atom of hydrogen, a C 1 -C 24 alkyl radical, a radical of formula -B_ 1   R 1 -B is a C 1 -C 6 alkylene radical, and R 10 and R 11 each independently of one another is a hydrogen or halogen atom or an alkyl or alkoxy radical; C 1 -C 4, or a group physiologically degradable to a hydrogen atom, the amino group and the aminoalkyl residue being located in meta or para to each other, and at least one of the symbols R 1, R, R 5, R 6 and R having a meaning other than hydrogen when R 1 is a hexadecyl radical, R is a methyl radical and n = OO 2; phenylalkylamines according to claim 1, characterized in that R, R, R 6 and R 2 represent hydrogen, N represents 0, R 'represents a radical   alkyl containing from 4 to 24 carbon atoms and R representing   feels hydrogen or a physiologically degradable group in a hydrogen atom.   3. Phenylalkylamines according to claim 2, characterized in that R (represents hydrogen, R 4 represents a linear alkyl radical containing from 8 to 20   carbon atoms and R represents hydrogen. 4. 4-hexadecylaminobenzylamine.   5. The phenylalkylamines specified in one   any of claims 1 to 4, characterized in that   whether they are in the form of a free base or a acid addition salt.   6. A process for the preparation of phenylalkyl   amines specified in claim 1, and their salts, characterized in that an amine of formula II is reacted R HN / R 6 '(I   -R 7 wherein R 'and R; have the meanings given in claim 1, with a compound of formula III (formula III see next page) Re, R 5 'R 3' N, 4 3 R II CH (CH 2) X III) 4 R 1 R 2 '   wherein R 1 to R 5 and N have the meanings given in claim 1, and X represents a group capable of being eliminated, or when R R and R; are hydrogen and N is O, a compound of formula IV N is reduced R 4 '' 'N 1 5 RI 'R 2'.   in which R 1 to R 'have the meanings given in claim 1, and the compounds thus obtained are recovered in the form of   free base or in the form of acid addition salts.   The therapeutic application, as active ingredients of medicaments, of phenylalkylamines corresponding to the formula ## STR1 ## R 3 N R 7 CH (CH) 7   in which R 1 represents a hydrogen or halogen atom or a C 1 -C 4 alkyl or alkoxy radical, R 2 represents a hydrogen or halogen atom, a C 1 -C 4 alkyl or alkoxy radical; or a rest of formula 9   o A means an oxygen or sulfur atom, a carbonyl group or a direct bond, and R 8 and R 9 each signify, independently of one another, a hydrogen or halogen atom or a radical C 1 -C 4 alkyl or alkoxy, R 3 represents hydrogen or a C 1 -C 4 alkyl radical, n represents O, 1 or 2, R 4 represents a C 4 -C 24 alkyl radical, R 5 represents a hydrogen atom, a C1-C24 alkyl radical or a physiologically degradable group to a hydrogen atom, and R 6 and R 7 each represent, independently of one another, a hydrogen atom, a C 1 -C 24 alkyl radical, a radical of formula B 1 -2 <10   B represents a C 1 -C 6 alkylene radical and R 10 and R 11 each independently of one another means a hydrogen or halogen atom or a C 1 -C 4 alkyl or alkoxy radical; , or a group physiologically decomposable to a hydrogen atom, the amino group and the aminoalkyl residue being located in meta or para to each other, in the form of a free base or an addition salt of acids pharmaceutically acceptable.   8 A medicament, characterized in that it   as an active ingredient, a phenylalkylamine as specified in claim 7 in the form of   free base or a pharmaceutically acceptable acid addition salt acceptable.   9 A medicament, characterized in that it   as an active ingredient, 4-hexadecylamino- 25071 '80   benzylasine, as a free base or as an additive salt   of pharmaceutically acceptable acids.   10. A medicament, characterized in that it contains, as active principle, 4- (N-methylhexadecylamino) benzylamine, in the form of a free base or a salt   addition of pharmaceutically acceptable acids.   11. A pharmaceutical composition characterized in that it contains the active ingredient specified at one   any of claims 8 to 10, in association with   Pharmaceutically acceptable excipients and carriers.