BE897566A - W-AMINO ACID DERIVATIVES, THEIR PREPARATION AND USE AS WELL AS THE COMPOSITIONS CONTAINING THESE DERIVATIVES. - Google Patents

Description

       

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 formed by
Midit Fiduciary company registered for: "Amino acid derivatives, their preparation and use as well as the compositions containing these derivatives".



  Inventors: CORDI Alexis.



   GILLET Claude.



   ROBA Joseph.



   NIEBES Paul.



   JANSSENS DE VAREBEKE Philippe.



   LAMBELIN Georges.

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  The present invention relates to amino acid derivatives as well as the salts of these derivatives, their methods of preparation as well as pharmaceutical compositions containing at least one of these derivatives and their method of use.



   The present invention includes derivatives of w-amino acids which correspond to the general formula 1
 EMI2.1
 as well as the salts of these compounds formed with pharmaceutically usable metals, acids or bases.



  In the general formula 1: R represents: - a linear or branched alkyl radical C, Cg, C <, Cr,
 EMI2.2
 C, Q,,
Cy, Cg, Cg, C- a linear or branched alkyl radical C2, C3, C4 substituted by a phenyl or phenoxy ring optionally substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two halogen atoms such as fluorine, chlorine or bromine;

     - a linear or branched acyl radical C2, C3, C4, C5,
C6 substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two atoms halogen such as fluorine, chlorine or bromine;

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 EMI3.1
 R represents: - hydrogen; - a linear or branched acyl radical C2, C3, C4, C5,
C6, C7, C8, C9, C10, C11;

     - a linear or branched acyl radical C?, Cg, C., Cr,
C6 substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4 or by one or two atoms of halogen such as fluorine, chlorine or bromine; R? represents: - a hydroxyl group; - An alkoxy group R30-, in which R3 is a linear or branched alkyl radical Cl'C2 or C3; - an amine group (-NH2); n has the values 3,4 or 5; According to a preferred form of the invention, the subject of the invention is compounds of formula I, in which:

   R represents: - a linear or branched alkyl radical C2, C3, C4, C5,
 EMI3.2
 Cg, Q,, Cy, Cg, Cg, C- a linear or branched alkyl radical C2, C3, C4 substituted by a phenyl or phenoxy ring optionally substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two halogen atoms such as fluorine, chlorine or bromine; - a linear or branched acyl radical C2, C3, C4, C5,
C6 substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C ,, Cp, C, C, or by one or two halogen atoms such as fluorine, chlorine or bromine;

   

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 RI represents: - hydrogen; - a linear or branched acyl radical Cp, C3, C4, C5,
C6, C7, C8, C9, C10, C11; - a linear or branched acyl radical C C3, C., Cr,
C6 substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4 or by one or two atoms of halogen such as fluorine, chlorine or bromine;

   R2 represents: - a hydroxyl group; - an alkoxy group R30-, in which R3 is a linear or branched C1, C2 or C3 alkyl radical; - an amine group (-NH2); n has the values 3,4 or 5; - when R represents a dodecyl radical and R, hydrogen, R2 does not represent a hydroxyl radical, - when n has the value 4 and when R? represents a hydroxyl group and R. hydrogen, R does not represent an n radical. butyl or n. octyl, - when n has the value 4 and when R2 represents an ethoxy group and Ri of hydrogen, R does not represent an ethyl radical or n. butyl, - when R represents an n radical.

   butyl, Ri of hydrogen and R2 a methoxy or hydroxyl radical, n does not have the value 3, - when R represents a radical i. propyl, Ry of hydrogen and R2 a hydroxyl radical, n does not have the value 5.

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  According to another preferred form of the invention, this relates to compounds of formula 1 in which: R represents: - a linear or branched alkyl radical C-Co '- a linear or branched alkyl radical C2-C4 substituted by a phenyl or phenoxy ring optionally substituted by a methyl or methoxy radical or by a chlorine atom; R. represents: - hydrogen a linear or branched acyl radical C2-C11 - a linear or branched acyl radical Cp-Cc substituted by a phenyl ring optionally substituted by a methyl or methoxy radical or by a chlorine atom;

   R2 represents: - a hydroxyl group - an alkoxy group R30, in which R3 is a linear or branched alkyl radical Cl-C3 - an amine group; n has the values 3,4 and 5 - when n has the value 4 and when R2 represents a hydroxyl group and Ri of hydrogen, R does not represent an n-butyl or n-octyl radical; - when n has the value 4 and when R2 represents an ethoxy group and R. of hydrogen, R does not represent an ethyl radical or n. butyl; - when R represents an n radical. butyl, R, hydrogen and R2 a methoxy or hydroxyl radical, n does not have the value 3; - when R represents a radical i. propyl, R, hydrogen and R2 a hydroxyl radical, n does not have the value 5.

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  According to another preferred form of the invention, the subject of the invention is derivatives of formula 1 in which: R represents: a linear or branched C2-C6 acyl radical substituted by a phenyl ring optionally substituted by a methyl or methoxy radical or a chlorine atom; Ri represents hydrogen;
 EMI6.1
 Rp: represents- a hydroxyl group; - An alkoxy group R30, in which R3-is a linear or branched C1-c3 alkyl radical; - an amine group; n has the values 3,4 and 5.



  A preferred class of products of formula I is that in which: R represents a linear or branched C2-C10 alkyl group;
 EMI6.2
 R, hydrogen; represents R2 represents: - a hydroxyl group; - An alkoxy group R30, in which R3 is a linear or branched C1-c3 alkyl radical; - an amine group; n has the values 3,4 and 5; - when n has the value 4 and when R2 represents a hydroxyl group and Ri of hydrogen, R does not represent a radical n. butyl or n. octyl; - when n has the value 4 and when R2 represents an ethoxy group and R. of hydrogen, R does not represent an ethyl radical or n. butyl;

   - when R represents an n radical. butyl, R, hydrogen and R2 a methoxy or hydroxyl radical, n does not have the value 3; - when R represents a radical i. propyl, R .. of hydrogen and R2 a hydroxyl radical, n does not have the value 5.

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  Another preferred class of products of formula I is that in which: R represents: a linear or branched Cp-C alkyl group; - a linear or branched C2-C6 acyl group substituted with a phenyl ring; R, represents hydrogen; Rp represents: - a hydroxyl group; - an alkoxy group R30, in which R3 is a linear or branched C1-C3 alkyl radical; n has the value 3; when R represents an n radical. butyl, R2 does not represent a methoxy or hydroxyl radical.



  A last preferred class of products of formula 1 is that in which: R represents: a linear or branched C2-C10 alkyl radical; - a linear or branched C2-C6 acyl radical substituted by a phenyl ring;
 EMI7.1
 Ri represents hydrogen; R2 represents an amine group (-NH2); and n is 3.



  Examples of compounds according to the invention are: 4-n. pentylaminobutanamide
 EMI7.2
 5-n. pentylaminopentanamide 6-n. pentylaminohexanamide 4-n acid. pentylaminobutanoic 5- (p.tolylacetylamino) pentanamide 6-n. decylaminohexanamide
 EMI7.3
 6- [4- [enylacetyl)

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 If the derivatives of formula I are in the form of addition salts with acids, they can be transformed, according to usual methods, into free bases or into addition salts with other acids.



  The most commonly used salts are non-toxic, pharmaceutically usable acid addition salts formed with suitable inorganic acids, for example hydrochloric acid, sulfuric acid or phosphoric acid or with suitable organic acids , such as aliphatic, cycloaliphatic, araliphatic or heterocyclic, carboxylic or sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic acids , aspartic, glutamic, benzoic, anthranilic, hydroxybenzoic, salicylic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, pantothenic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic,

      stearic, alginic, -hydroxybutyric, oxalic, malonic, galactaric, galacturonic.



  In the case where R2 represents a hydroxyl group, the derivatives of the invention can exist in the form, either of zwitterion, or of metal salts or of addition salts with bases, non-toxic and pharmaceutically usable.



   If derivatives of the invention in which R2 represents a hydroxyl group are obtained in the form of a salt, they can be converted into acid or into other salts according to conventional methods.

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  These salts can be derived from metals such as, for example sodium, potassium, lithium, calcium, magnesium, aluminum, iron, or can be addition salts with bases such as, for example, ammonia or amines such as ethylamine, isopropylamine, ethanol amine, diethylamine, diethanolamine triethylamine, or basic amino acids, natural or not, such as lysine, arginine, l 'ornithine.



  The compounds of formula 1 may have one or more asymmetric carbon atoms and are therefore capable of existing in the form of optical isomers, racemates or diastereoisomers; all these forms are part of the present invention.



  The derivatives of the invention can therefore be used either in the form of mixtures containing several diastereoisomers whatever their relative proportions or in the form of pairs of enantiomers in equal proportions (racemic mixture) or not, or also in the form of compounds optically pure.



  The products of the invention can be used in the treatment of neurological, psychic or cardiovascular disorders such as, for example, epilepsy, depression, dyskinesias such as Parkinson's disease, muscular spasticities of nervous origin, hypertension, hypotension, sleep disturbances, memory impairment, as well as anthelmintic and analgesic agents.



  The present invention also covers pharmaceutical compositions containing, as active ingredient, at least one compound of general formula 1 or a salt, with an additive and / or an excipient used in galenic pharmacy.

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  These compositions are prepared so that they can be administered orally, rectally or parenterally.



  They can be solids, liquids or gels and can be presented, depending on the route of administration, in the form of powders, tablets, dragees, coated tablets, capsules, granules, syrups, suspensions, emulsions, solutions, suppositories or of gels. These compositions can also comprise another therapeutic agent having a similar or different activity to the products of the invention.



  The compounds of the invention are prepared according to methods which form part of the present invention and defined below. In cases where the processes give rise to the production of new intermediate compounds, these new compounds, as well as the processes which serve for their preparation, also form part of the present invention.



  Method A.



  According to this procedure, product II is converted into the derivative of formula 1:
 EMI10.1
 R, R ,, Rp and n are as defined above and Z represents a group which, by the action of an appropriate reagent, can be converted into an amide, carboxylic acid or ester function.

   Examples of these functions are, among others, the amide function, the carboxylic acid function, the nitrile function, the ester function (-COOR ', in which R' represents either Rg, specified above, or an alkyl or phenyl radical substituted in such a way that it activates the ester against attack by a nucleophile), the function

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 EMI11.1
 NH. amidine (-C), acid halide function NH / (-C., X represents a halogen such as chlorine, v
 EMI11.2
 bromine iodine), anhydride function, imidate function
 EMI11.3
 0R) (-C 3 or N-carbonylimidazole group.



  NH
 EMI11.4
 Z can also represent a precursor group of carboxylic acid such as for example, the trihalomethyl group (-CX, in which X represents a chlorine, bromine or iodine atom), an oxazoline group, a hydroxymethylene group (-CH20H) , a formyl group (-CHO) which may or may not be present in a protected form such as, for example, a dithioacetal, cyclic or not, an a, ss-d-ihydroxyalkyl or aJkenyl group (-CHOH-CHOH-R4 or -CH = CH-R4 in which R4 represents a linear C1-C20 alkyl radical), an acetyl group (-CO-CH3), a 1-hydroxyethyl group (-CHOH-CHo), an acetonyl group (-CH? -CO -CH), a 2-hydroxypropyl-1 group (-CH2-CHOH-CH3) or a halogen atom, such as chlorine,

   bromine or iodine.
 EMI11.5
 



  The group-CH-Z can also represent the group
 EMI11.6
 8 - 'R 2
 EMI11.7
 different from each other and represent a function chosen from the following series: nitrile, carboxylic, carbamoyl or alkoxycarbonyl (-COOR3, R3 having the values given above).

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  The transition from product II to product I, that is to say the conversion of the group Z or -CH? -Z into a group (-COR2) can be carried out by conventional reactions very well documented in chemistry, such as for example :
 EMI12.1
 a) -conversion of carboxylic acid to amide.



  Several chemical formation.



   - For example, the carboxylic acid can be placed in the presence of ammonia, the pyrolysis of the salt thus formed leads to the amide, as does the action of a dehydrating agent such as P205.



   - Another way of proceeding consists in transforming the carboxylic acid into an acid halide and then into an amide by the action of ammonia.



   - Yet another way of proceeding consists in reacting a carboxylic acid and ammonia in the presence of a coupling reagent as used in peptide synthesis such as, for example, dicyclohexylcarbodiimide, N-ethyl-N '-3-dimethylamino-propylcarbodiimide, phosphines, phosphites, silicon or titanium tetrachloride. b) -Conversion of a nitrile into an amide or an acid. The nitriles can be hydrolyzed to an amide or an acid, either in an acid medium or in a basic medium.



   If the hydrolysis is carried out under acidic conditions, concentrated sulfuric acid, concentrated aqueous hydrochloric acid, aqueous hydrobromic acid, nitric acid, formic acid can be used in the absence of solvent. , acetic acid in the presence of boron trifluoride.



   - Another way to convert a nitrile into an amide, in an acid medium, consists in treating said nitrile

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 with hydrochloric acid in an alcohol such as ethanol. An intermediate iminoether is thus formed which thermally transforms into an amide.



   - If the hydrolysis is carried out under basic conditions, we will use, for example, potassium hydroxide in the t. butanol or an aqueous solution of an alkali or alkaline earth metal hydroxide. The presence of hydrogen peroxide facilitates hydrolysis.



   The nature of the group formed, an amide or a carboxyl group, essentially depends on the reaction conditions used. c) Transformation of a nitrile into an ester.



   This conversion is done by opposing the nitrile to an alcohol in an acid medium. As the solvent, alcohol or any other inert solvent can be used.



   An intermediate iminoether is thus formed which is converted into an ester by hydrolysis. d) Conversion of an ester into an amide.



   The aminolysis of an ester is conventionally carried out by opposing the ammonia to the ester, either in water or in an inert organic solvent. e) Conversion of an amidine to an amide.



   This reaction is mainly carried out by acid hydrolysis in an aqueous or alcoholic medium. The acid can be inorganic like hydrochloric acid or sulfuric acid or organic acid like acetic acid. f) Conversion of an acid halide, an anhydride or an N-carbonylimidazolyl group into a carboxylic or alkoxycarbonyl (-COOR3) group.

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   This transformation takes place easily by opposing product II to water to form the carboxyl group (hydrolysis reaction) or to an alcohol R30H,
R3 being a linear or branched C1-C3 'alkyl radical to form the aikoxycarbonyl-COORg group (alcoholysis reaction).



   These reactions are carried out in the presence of an excess of water or alcohol or with a stoichiometric amount of these reagents in the presence of an inert solvent. The alcoholysis is advantageously carried out in the presence of a catalyst such as an organic or inorganic acid or base. g) When the group Z of formula II represents a carboxylic acid precursor such as a trihalomethyl group or an oxazoline, the conversion to the carboxylic acid is carried out either in water or in an inert organic solvent in the presence of acid.



   As the acid, a mineral acid is generally used such as halogenated hydracids, sulfuric acid, concentrated or diluted, nitric acid, concentrated or diluted, phosphoric acid or an organic acid such as acetic acid.
 EMI14.1
 h) The conversion of the group group
 EMI14.2
 , / Bl - o, the values 2 -CH2-Z, representing the data given above, in a carboxymethyl group is made by hydrolysis in basic or acid medium under conditions identical to those described previously for the hydrolysis of a nitrile, followed by 'a period of heating in an acid medium in order to decarboxylate the intermediate α-diacid obtained.

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 i) The conversion of other precursor groups of the carboxylic acid group to a carboxylic group by oxidation.



   This conversion especially concerns intermediates II in which Z represents a group such as
 EMI15.1
 - OH -CHOH-CH - -CO-CH, -CH = CH-R in which
CHR4 has the values defined above. It is conventionally carried out by means of a large number of oxidizing agents and according to a wide variety of well-known methods.



   Oxidation takes place via several intermediate products which can be isolated in certain cases and, depending on the nature of the oxidizing agent, it takes place in water or in an inert organic solvent.



   It goes without saying that the choice of oxidizing agent and of the reaction conditions will depend on the nature of the group Z and so as to keep the other groups present in molecule II intact. j) The transformation of an acid into an ester and vice versa.



   Esterification of an acid is a very general reaction that can occur in many ways.



   - Conventionally, the acid and the alcohol are reacted in the presence of an acid catalyst. This reaction is advantageously carried out under anhydrous conditions and one of the reactants is used in large excess. The solvent can be either one of the reactants or an inert organic solvent.



   - Another way of proceeding consists in distilling the water as soon as it forms using an appropriate device. The reaction conditions are identical to those described above with the exception

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 that one of the reagents should not be used in large excess.



   The hydrolysis of the ester takes place under conditions of acidic or basic catalysis, but in this case, one of the reactants, in this case water, is used in very large excess. k) The conversion of the group Z representing an alkoxycarbonyl group (-COOR '), a carboxylic group, its salt or its anion into an alkoxycarbonyl group (-COORg).



   Depending on the nature of Z, this conversion can be done by esterification, as described in the preceding paragraph, by transesterification, by heating the derivative II containing the group —COOR ′ in the presence of an excess of alcohol R30H and of a cat. - acid or basic lyser, advantageously by continuously eliminating by distillation the alcohol R'OH formed, or by alkylation by means of the reagent Erg, in which
W represents an easily substitutable group such as a halogen such as chlorine, bromine or iodine, a group
O-mesyl, O-tosyle, a sulfate group (-O-SO2-OR3), an acyloxy group (R5-CO-0) or a hydroxyl group.



   R3 represents a linear or branched C1-C3 alkyl group and R5 represents an R3 or phenyl group.



   The alkylation of the carboxylic group, of its salt or of its anion is normally carried out in an inert organic solvent in the presence of a weak inorganic base or preferably of an organic base such as pyridine or triethylamine.



  1) The conversion of Z, representing a halogen atom to a carboxylic acid group.



   This conversion is conventionally done in trans-

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 forming the halogenated product into an organometallic derivative, the treatment of which with carbon dioxide, followed by the hydrolysis of the intermediate formed, provides the carboxylic group. The metal used can be lithium, magnesium, zinc or manganese.



  In order to avoid side reactions during this conversion, the functional group RRiN-present in molecule II, will be adequately protected.



  For a better understanding of the process, the main access routes to derivative II are described below 1. Derivative II can be obtained at the expense of product III or IV by alkylation or acylation according to the diagrams below.
 EMI17.1
 in which R, R ,, Z, W and n have the values defined above, but in the reagent R1W, the group RI does not represent hydrogen.
 EMI17.2
 



  RW and RiW can also represent a ketene of
 EMI17.3
 R formula 6, so that the group D 7 R 7 CH-CO-, obtained after the acylation of derivatives III or "7"

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 IV, corresponds, as the case may be, to a group R or Ri.



  This alkylation or acylation reaction can be carried out in an inert organic solvent such as a chlorine hydrocarbon, an alcohol or an aliphatic or aromatic hydrocarbon, chosen according to the nature of the reagent.



  The reaction takes place at a temperature between 0 C and the reflux temperature of the solvent.



  Advantageously, the reaction can be carried out in the presence of an organic base such as triethylamine, pyridine or N-dimethylaniline or an inorganic base such as hydroxides, carbonates and bicarbonates of alkali or alkaline earth metals or of finely pulverized lime .



  A variant of this process is illustrated below:
 EMI18.1
 R, R ,, M, Z and n have the values defined above.



  The above reaction is similar to the alkylation reaction of derivatives III or IV described above, and it goes without saying that the operating conditions for these three reactions are entirely comparable.



  According to another variant of the process, the derivative II can be synthesized by acylation of a primary amine with a carboxylic acid making use of phosgene as a coupling agent. Phosgene can be introduced

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 in a solution of the amine and the carboxylic acid or it can be opposed to one of the two reactants and the intermediate formed in this way is then opposed to the second reactant.



  This variant in which the phosgene is reacted with amine IV, followed by the transformation of the intermediate isocyanate, is illustrated by the following diagram:
 EMI19.1
 in which Ri represents hydrogen, Z and n have the values specified above and the group Rn-CO corresponds to the group R as defined above.



  According to another variant, the derivative II in which R represents an alkyl or substituted alkyl group as defined above, can be obtained by acylation of the derivatives III or IV, as described above, followed by a reduction of the amide obtained as an intermediary. Many methods are described for effecting tell reduction, but it is obvious that in the choice of reaction conditions, care must be taken to preserve the functionality of group Z.



  2. Another access route to derivative II is characterized by the formation of an intermediate minium salt VIII from an amine and a carbonyl compound VII.

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 EMI20.1
 The reduction of the iminium salt leads to derivative II.
 EMI20.2
 



  R O ..



  RN-1 Il Re C I.-I H NH + H-C- (CH.) ,, - Z ----- N = C R / RI v 11 v i i i VII reduction N- (CH2) R1 II
 EMI20.3
 The condensation between the amine and the carbonyl derivative VII is conventionally carried out in an inert organic solvent, preferably immiscible with water. Advantageously, the reaction is catalyzed by a mineral or organic acid.



  The reduction is carried out in a suitable solvent in a conventional manner by means of hydrogen in the presence of a hydrogenation catalyst, by means of an alkali metal hydride, by aluminum and lithium hydride or by means of another reducing agent, but it goes without saying that the reduction method of the salt of minium will be chosen so as to keep intact the functionality of group Z. By choosing the reagents differently, one can carry out a variant of this process which allows product II to be passed through intermediates carrying the same chemical functions as above.

  <Desc / Clms Page number 21>

 
 EMI21.1
 



  R C = 0. c-N- "10 10 R {R / 0 n 10 R10 C) x IX IV Reduction R 9, c H fl Pug, /, Rl0> - (CH2) 1 II
 EMI21.2
 P. ,, and n have the meanings given above while the groups Rg and RIO have
 EMI21.3
 R values such that the group CH is equivalent to R. o 10
 EMI21.4
 The condensation of the carbonyl derivative with the amine IV and the reduction of the minium salt X take place under the conditions described above.



  It should be noted that when R. represents hydrogen, the condensations described above lead to an imine of formula:
 EMI21.5
 / H R-N = C or C = N-) -Z) xi
 EMI21.6
 in which R, R9'RIO'Z n have the values defined above. Synthesis conditions

  <Desc / Clms Page number 22>

 and reduction of imines XI and XII are completely comparable to those of the synthesis and reduction of the minium salts VIII and X.



  3. Another access route to the derivatives of formula II consists in the transformation of a product of formula XI by means of the reagent XIV, according to the scheme below
 EMI22.1
 R, Ri, W and n have the meanings given previously, M represents hydrogen or a metal such as lithium, sodium, potassium or magnesium and Z has the values given previously compatible with the envisaged reaction such that: a nitrile group, a trihalomethyl group or a cyclic or non-cyclic dithioacetal group.



  The transformation of product XIII can be carried out according to different conventional methods, chosen according to the nature of W and Z. Some of these methods are summarized below, by way of example: a) when Z represents a nitrile group or trihalomethyl, the reaction can be carried out in various solvents such as for example water, a lower alcohol, dimethylformamide or in mixtures of solvents, miscible or not.



   In several cases, it is advantageous to work in the presence of an organic base or a phase transfer catalyst.

  <Desc / Clms Page number 23>

 b) when Z represents a cyclic dithioacetal group or not, the reaction takes place under anhydrous conditions at low temperature, in an inert solvent such as diethyl ether or tetrahydrofuran.



   Product II is then obtained by deprotection of the formyl group by well known methods such as hydrolysis in an acid medium or by the action of mercuric salts.
 EMI23.1
 



  4. Another route to derivatives of formula II
 EMI23.2
 in group-CH "'consists' 8
 EMI23.3
 in the alkylation of a derivative XV by means of reagent XVI according to the following scheme:
 EMI23.4
 R, R., B. ,, B?, M and n have the values given above, except for W which, in this case, does not represent a hydroxyl group.



  M represents an alkali metal such as sodium, potassium or lithium.



  This conventional reaction is generally carried out under an inert atmosphere and under anhydrous conditions using a solvent such as an alcohol or an aliphatic or aromatic hydrocarbon.



  Method B.



  This process consists in the opening of a lactam XVIII, under the action of a base or an acid. Said lactam

  <Desc / Clms Page number 24>

 XVIII is conventionally obtained from lactone XVII according to the scheme:
 EMI24.1
 R, R2'M and n have the values defined above.



  The conversion of lactone to lactam takes place in an inert organic solvent, advantageously at the reflux temperature of the reaction medium.



  The opening of the lactam can be done under the action of ammonia, an amide, an alcoholate or a hydroxide of an alkali metal, or under the action of a mineral acid such as l hydrochloric acid or sulfuric acid. It takes place in water or in an inert organic solvent such as an ether, an alcohol, an aliphatic, aromatic hydrocarbon or a chlorinated hydrocarbon.



  It is obvious that the methods described for the synthesis of compound II can also be applied to
 EMI24.2
 products in which group Z already has value
 EMI24.3
 o from group C as 2

  <Desc / Clms Page number 25>

 thus directly to the products of the invention corresponding to the general formula I.



  It goes without saying that for all the processes for the synthesis of the compounds of formulas 1 and II, as well as for those mentioned
 EMI25.1
 for the transformation of group Z and CH2-Z into a group
 EMI25.2
 - and the reaction conditions R2
 EMI25.3
 are chosen so as to keep intact the functional groups already present in the molecule and which are not involved in the envisaged reaction.



  Thus, in order to be able to carry out the synthesis of compounds 1 and II, it is sometimes necessary to use protective groups in order to preserve the functionality of the groups present in the starting molecule. The choice of experimental conditions will condition the choice of protecting groups which, as well as the processes for their introduction and the deprotection methods, are well described in the literature.

  <Desc / Clms Page number 26>

 



  Below are given detailed examples of the preparation of some derivatives of the invention.



  The main purpose of these examples is to further illustrate the particular characteristics of the methods according to the invention.



  Example 1.



  Synthesis of 4-n. pentylaminobutanamide.



  5 9 (0.041 m) of 4-chlorobutanamide are dissolved in 19 ml (0.165 m) of pentanamine and stirred for 48 hours at room temperature. By addition of ether (400 ml), a precipitate forms which is filtered and recrystallized twice from isopropanol.



  F (C): 187.
 EMI26.1
 
 <tb>
 <tb>



  Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 51.7 <SEP> 10.1 <SEP> 13.4
 <tb>% <SEP> found <SEP> 52.0 <SEP> 10.2 <SEP> 13.4
 <tb>
 Example 2.



  Synthesis of 5-n. pentylaminopentanamide. a) The mixture is refluxed for 48 hours, a mixture of 4.5 9 of 5-chloropentanenitrile (0.040 m), 3.8 9 (0.044 m) of pentanamine, 3.7 g of sodium bicarbonate in 60 ml of absolute ethanol. The sodium chloride formed is filtered and the filtrate is evaporated to dryness under vacuum to remove the excess pentanamine. The residual oil is dissolved in ether and added with ether / HCl. A white precipitate is formed which is filtered (5-n hydrochloride pentylaminopentanenitrile).



  F (C): 207-209.

  <Desc / Clms Page number 27>

 b) 2.78 g (0.013 m) of 5-n hydrochloride. pentylaminopentanenitrile are suspended in 3.4 ml of concentrated HCl and stirred at 50C for 6 days. The clear solution obtained is poured onto 20 ml of isopropanol, the solid which crystallizes is filtered and washed with isopropanol.



  F (C): 216-217
 EMI27.1
 
 <tb>
 <tb> Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 53.9 <SEP> 10.4 <SEP> 12.5
 <tb>% <SEP> found <SEP> 54.2 <SEP> 10.5 <SEP> 12.6
 <tb>
 Example 3.



  Synthesis of 6-decylaminohexanamide.



  4.5 g of 6-chlorohexanamide (0.030 m) are heated to reflux in 100 ml of ethanol containing 5.2 g of decanamine (0.033 m) and 2.52 g of NaHCO3 (0.033 m). After 2 days and 2 nights, the solution is cooled, filtered and evaporated; the solid is recrystallized twice from ethyl acetate. The solid obtained is dissolved in ethanol and added with ether / HCl; the new solid obtained is recrystallized twice from isopropanol.



  F (C): 206.
 EMI27.2
 
 <tb>
 <tb>



  Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 62.6 <SEP> 11.5 <SEP> 9.1
 <tb>% <SEP> found <SEP> 63.0 <SEP> 11.7 <SEP> 9.3
 <tb>
 Example 4.



  Synthesis of 5- (p. Tolylacetylamino) pentanamide.



  To a solution of 0.7 g (0.017 m) of NaOH and 2 g of 5-aminopentanamide (0.017 m) in 10 ml of cooled water

  <Desc / Clms Page number 28>

 at 0 ° C., 2.9 g (0.017 m) of p-tolylacetyl chloride and a solution of 0.7 g of NaOH in 4 ml of water are added simultaneously dropwise. The suspension which has formed is stirred for one hour at room temperature. The solid is filtered and recrystallized twice from isopropanol.



    F (OC): 206.
 EMI28.1
 
 <tb>
 <tb>



  Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 67.7 <SEP> 8. <SEP> 1 <SEP> 11.3
 <tb>% <SEP> found <SEP> 67. <SEP> 8 <SEP> 8. <SEP> 1 <SEP> 11.3
 <tb>
 Example 5.



  Synthesis of 4-pentylaminobutanoic acid.



  7.75 g of penta- are introduced into a bottle of Parr
 EMI28.2
 nal (0.090 m), 7.73 9 gamma aminobutanoic acid (0.075 m), 800 mg of 10% palladium on carbon, 5 g of 3 A molecular sieve and 200 ml of absolute ethanol. The bottle is shaken under a hydrogen atmosphere for 18 hours.



  The suspension is filtered and the filtrate is evaporated to dryness at 20 ° C. under reduced pressure. The solid is washed with ether, dissolved in a minimum of ethanol and added with ether.



  The crystals obtained are recrystallized again in the same manner.



  F (C): 161-162.
 EMI28.3
 
 <tb>
 <tb>



  Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 62.4 <SEP> 11.0 <SEP> 8. <SEP> 1
 <tb>% <SEP> found <SEP> 62.1 <SEP> 11.1 <SEP> 8. <SEP> 0
 <tb>
 Example 6.



  Synthesis of 6 - [3- (3,4-dimethoxyphenyl) propanoylamino] hexanamide.
 EMI28.4
 



  To a solution of 2.6 g (0.020 m) of 6-aminohexanamide and 0.8 g of NaOH in 15 ml of water, cooled to O'C, 4.69 (0.02) is added simultaneously m) of 3- 4- chloride

  <Desc / Clms Page number 29>

 (3, dimethoxyphenyl) propanoyl and 2.4 g of NaOH in 20 ml of water. The suspension is stirred for 2 hours at room temperature. Then, the solid is filtered and recrystallized from isopropanol.



  F (C): 137.
 EMI29.1
 
 <tb>
 <tb>



  Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 63.3 <SEP> 8, <SEP> 1 <SEP> 8, <SEP> 7
 <tb>% <SEP> found <SEP> 63.2 <SEP> 8, <SEP> 2 <SEP> 8, <SEP> 6
 <tb>
 Example 7.



  Synthesis of 6-n. pentylaminohexanamide.



  The mixture is refluxed for 4 days, a mixture of 5 g of 6-chlorohexanamide (0.033 m), 4.25 ml of pentanamine (0.037 m) and 2.8 g of sodium bicarbonate (0.034 m) in 100 ml of ethanol. Then, after cooling the solution, the salts are filtered and the solvents are evaporated to dryness. The product which solidifies is crystallized twice from ethyl acetate, dissolved in a minimum of methanol and added with etherHCl1. The solid that forms is filtered and dried.



  F (C): 190.5
 EMI29.2
 
 <tb>
 <tb> Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 55.8 <SEP> 10.6 <SEP> 11, <SEP> 8
 <tb>% <SEP> found <SEP> 55.8 <SEP> 10.6 <SEP> 11, <SEP> 8
 <tb>
 Example 8.



  Synthesis of 4-n. hexylaminobutanamide. a) The mixture is refluxed for 2 days, a mixture of
 EMI29.3
 18.5 ml of 4-chlorobutanenitrile 2 m), 29.1 ml of hexanamine (0.22 m) and 18.5 g of sodium bicarbonate (0.22 m) in 500 ml of ethanol. Then, the suspension is cooled, the salts are filtered and the filtrate is evaporated. The residue is partitioned between water and dichloromethane. The dichloromethane phase is washed with

  <Desc / Clms Page number 30>

 water, dried over K2C03 and evaporated at room temperature. The excess hexanamine is evaporated under high vacuum and the residual oil is dissolved in anhydrous ether and added with ether / HCl. The solid which appears is filtered, dissolved in a minimum of methanol and added with anhydrous ether.

   The product thus obtained is used as is in the next step. b) 4.2 g of 4-hexylaminobutanenitrile (0.02 m) are stirred for 4 days at 5 ° C. in 5 ml of concentrated HCl. Then, this solution is poured into 50 ml of ice-cold acetone.



  The white solid which forms is recrystallized from isopropanol.



  F (C): 194
 EMI30.1
 
 <tb>
 <tb> Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 53.9 <SEP> 10.4 <SEP> 12.6
 <tb>% <SEP> found <SEP> 54.1 <SEP> 10.4 <SEP> 12.6
 <tb>
 
 EMI30.2
 Example 9.



  Synthesis of 4- [amino] butanamide.



  650 mg of 4-hexylaminobutanamide hydrochloride (0.003m) are dissolved in 9.4 ml of 1 N KOH at 10 C. To this solution are added dropwise 0.65 ml of 4-chlorophenylacetic acid chloride . An oil immediately appears and solidifies. After 2 hours of reaction, the oil is extracted with ether, the ethereal phase is washed with water and 1N hydrochloric acid, dried over K2CO3 and evaporated. The residual solid is recrystallized from ethyl acetate.



  F (C): 105-106.
 EMI30.3
 
 <tb>
 <tb>



  Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 63, <SEP> 1 <SEP> 8, <SEP> 0 <SEP> 8, <SEP> 2
 <tb>% <SEP> found <SEP> 63.0 <SEP> 7.9 <SEP> 8, <SEP> 1 <SEP>
 <tb>
   # calculated for a content of 1.03% H2O.

  <Desc / Clms Page number 31>

 



  Example 10.



  Synthesis of 5-n. dodecylaminopentanamide. a) 7.4 g of dodecanamine (0.04 m), 4.23 g of 5-chloropentanenitrile (0.036 m) and 3.4 g of sodium bicarbonate (0.04 m) are heated at reflux for 2 days in 100 ml of ethanol. Then, the cooled solution is filtered and the filtrate evaporated. The residual oil is distilled under 0.25 mm Hg. The distilling fraction is collected at 170 C. It is dissolved in ethanol and added with ether / HCl. The precipitating solid is filtered and used without further purification in the next step. b) 2 g of 5-dodecylaminopentanenitrile hydrochloride (0.007 m) are dissolved in 50 ml of acetic acid. This solution is saturated with dry hydrochloric acid and stirred at room temperature for 2 days.



  The acetic acid is then evaporated, the solid taken up in ether is filtered and the solid recrystallized twice from isopropanol.



  F (C): 212.
 EMI31.1
 
 <tb>
 <tb>



  Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 63.6 <SEP> 11, <SEP> 6 <SEP> 8, <SEP> 7
 <tb>% <SEP> found <SEP> 63.9 <SEP> 11, <SEP> 6 <SEP> 8, <SEP> 8
 <tb>
 

  <Desc / Clms Page number 32>

 Example 11.



  Synthesis of 4-n. pentylaminobutanamide. a) A mixture of 18.5 ml of 4-chlorobutanenitrile (0.2 m), 19.1 g of pentanamine (0.22 m) and 18.5 g of sodium bicarbonate is heated at reflux for 2 days. (0.22 m) in 500 ml of ethanol. Then, the suspension is cooled, the salts are filtered and the filtrate is evaporated.



  The residue is partitioned between water and dichloromethane.



  The dichloromethane phase is washed with water, dried over K2CO3 and evaporated to room temperature. The excess pentanamine is evaporated under high vacuum and the residual oil is dissolved in anhydrous ether and added with ether / HCl.



  The solid which appears is filtered, dissolved in a minimum of methanol and added with anhydrous ether until an abundant precipitate is obtained which is filtered and used as is in the following step. b) 3.1 g of 4-pentylaminobutanenitrile (0.02 m) are dissolved in 30 ml of glacial acetic acid and saturated with HCl at room temperature.



  After 24 hours of stirring, the acetic acid is evaporated and the residual solid is recrystallized from isopropanol.



  F (C): 187.5
 EMI32.1
 
 <tb>
 <tb> Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 51.7 <SEP> 10.1 <SEP> 13.4
 <tb>% <SEP> found <SEP> 51, <SEP> 8 <SEP> 10.2 <SEP> 13.4
 <tb>
 Example 12 Synthesis of 4-n. pentylaminobutanamide.



  2.76 g of 4-aminobutanamide hydrochloride (0.02 m), 1.9% of pentanal (0.022 m), 100 mg of 10% Pd / C and 50 ml of ethanol.



  The bottle is shaken overnight under an atmosphere of hydrogen at room temperature. The catalyst is then filtered, the solvent is evaporated and the residue is solidified in ether. The solid obtained is recrystallized 3 times from isopropanol.

  <Desc / Clms Page number 33>

 F (C): 186.5
 EMI33.1
 
 <tb>
 <tb> Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 51, <SEP> 7 <SEP> 10.1 <SEP> 13.4
 <tb>% <SEP> found <SEP> 52.0 <SEP> 10.3 <SEP> 13.5
 <tb>
 Example 13 Synthesis of 4-n. pentylaminobutanamide.



  3.1 g of N-pentylpyrrolidone (0.02 m) are introduced into a 200 ml flask containing 3.9 g of sodium amide (0.1 m) suspended in 50 ml of toluene. The suspension is brought to reflux for 3 days, after which 10 ml of H 2 O and sufficient 1 N HCl are added to make the solution acidic (pH 2). The aqueous phase is decanted and lyophilized. The residue is extracted with boiling isopropanol, the solid which crystallizes is filtered and recrystallized 2 times from isopropanol.



  F (C): 186
 EMI33.2
 
 <tb>
 <tb> Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 51.7 <SEP> 10.1 <SEP> 13.4
 <tb>% <SEP> found <SEP> 51.4 <SEP> 10.0 <SEP> 13.7
 <tb>
 Example 14 Synthesis of 4- (2-phenylethylamino) butanoic acid. a) In a 1 liter flask cooled in an ice bath, 500 ml of toluene and 15.2 ml of pyrrolidone (0.2 m) are introduced under nitrogen. To this solution, 9.6 g of sodium hydride (0.4 m) are added three times. After one hour of stirring at 00C the suspension is allowed to return to room temperature. 37.15 ml of 2-phenyl-1-bromoethane (0.27 m) are then added and the whole is brought to reflux for 12 hours.



  After adding 100 ml of water, the toluene phase which is decanted and washed 3 times with water, dried over K2C03 and
 EMI33.3
 evaporated; The residual oil is distilled under 10 mmHg.



  We collect the colorless liquid which distils at 175 C which is identified as N-

  <Desc / Clms Page number 34>

 b) 17.9 g of N- (2-phenylethyl) pyrrolidone (0.095 m) are brought to reflux in 25 ml of concentrated HCl for 20 hours. The solution is then evaporated to dryness and the residual solid is crystallized from methyl ethyl ketone.



  F (C): 149-150.
 EMI34.1
 
 <tb>
 <tb>



  Analysis <SEP> elementary <SEP>: <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 59, <SEP> 1 <SEP> 7.4 <SEP> 5, <SEP> 8
 <tb>% <SEP> found <SEP> 59.2 <SEP> 7.5 <SEP> 5.7
 <tb>
 Example 15.



  Synthesis of the ethyl ester of 4- (2-phenylethylamino) butanoic acid.



  1 9 of 4- (2-phenylethylamino) butanofque acid hydrochloride (0.004 m) is brought to reflux for 1 hour in 10 ml of 5N ethanol / HCl. The solution is then evaporated to dryness and the solid obtained is recrystallized from methyl ethyl ketone.



  F (C) 206-207
 EMI34.2
 
 <tb>
 <tb> Analysis <SEP> elementary <SEP> C <SEP> H <SEP> N
 <tb>% <SEP> calculated <SEP> 61, <SEP> 9 <SEP> 8, <SEP> 2 <SEP> 5.1
 <tb>% <SEP> found <SEP> 61, <SEP> 9 <SEP> 8.2 <SEP> 5.2
 <tb>
 Table I given below groups together the derivatives of the above examples as well as other derivatives of the invention prepared according to the above methods. All the compounds listed in Table 1 give a correct C.H.N. elementary analysis.

  <Desc / Clms Page number 35>

 
 EMI35.1
 
 EMI35.2
 



  CP code No R Ri R2 n F (C) PEb solvent 2081 1 Isopropanol (1) 0 Il 2455 2 (0) 'CHoC-H 164-166 Isopropanol 2624 3 g (CH2) 2- 3 188-189 Isopropanol (1 ) 2631 4 nCBH17- 195-196 Isopropanol (1) 2632 5 nC5Hjl-H 216-217 Isopropanol (1) 2633 6 nC6H13- 3 193-194 Isopropanol (1) 2657 7 214-215 Et0H (1) 2659 8 nC5Hl1- 190 -191 MeOH-Ether

  <Desc / Clms Page number 36>

 
 EMI36.1
 
 EMI36.2
 Code CP NO R R, R2 n F (C) Solvent of PEb (C) / mb recrystallization. zo 2678 9 nCH -) - C - NH 3 76-78 Benzene-Pentane 2679 10 CI-o) -O) - 5 193 Isopropanol (1) 2681 11 CHg- <)) -,) -.

   H NH2 5 196 Isopropanol (1) 2685 12 (o) - (at 4- H NH2 3 179-180 Isopropanol 0 2711 13 nC6H13-Cl - CH-C-NH2 AcOEt 6 13-2-c-NH2 3 0 2684 14 Y (CH2) - - &commat; -CH-t 3 88-89 AcOEt 2728 15 (o) - (CH2) - 5 195 Et0H (1) 2818 16 nCH-H

  <Desc / Clms Page number 37>

 
 EMI37.1
 
 EMI37.2
 CodeCP n F (C) Solvent of PEb (OC) / mb recrystallization.



  2982 17 n. C4Hg- 5 184 EtOH (1) 2983 18 n. C9H19- 5 205 MeOH-Ether (1) 2984 19 O (CH2) 4- 5 169 Et0H (1) 3002 20 n. - 5 206 EtOH (1) 3003 21 n. H- 5 201 Isopropanol (1) 3027 22 -CH-CH-H 5 170/2. 10'3 1 2 CH3 3028 23 n. CHg-CH- H NH2 5 180/8. 10-4 1 2 C2HS 3045 24 212 Ac0H (1)

  <Desc / Clms Page number 38>

 
 EMI38.1
 
 EMI38.2
 Code R R, R2 n F (C) Solvent of recrystallization PEb.



  0 &commat; lll 3063 25 <5) -CH-C- 2, cli Cl 0 3064 26 Br- <\ -CH-C- 5 149 Isopropanol 3065 27 CH3-0- - H NH2 4 204 MeOH (1) 0 &commat; II 3073 28-CH-CH 5 109. 6 Isopropanol D 1 2 L OCH3 0 Il 3074 29 CH30 H NH2 5 137 Isopropanol 3075 30 n. C H NH2 4 212 Isopropanol

  <Desc / Clms Page number 39>

 
 EMI39.1
 
 EMI39.2
 1 CodeCP n F (C) Solvent of PEb (C) / mb recrystallization.



  0 Il 3076 31 C-C- -C- 206 Isopropanol 0 Il 250/3. 10-3 3077 32 n. C5HU- 1 C2HS 3078 33 CH3-CH2- 166 Isopropanol 0 3087 34 n. C5Hll- 0 Il 3088 35 rt. H- oCH-C-NH 4 75 AcOEt CH30 3089 36 CHO-CHCH-H 192 EtOH-Ether (1) 0 (1 240 / 10-3 3112 n. C5H-

  <Desc / Clms Page number 40>

 
 EMI40.1
 
 EMI40.2
 l CodeCP n F (C Solvent from C C3H7 Il 190110-3 3113 38 n. CH-C-NH2 ru C3H7 0 3114 39 n. CH- Hg-t-NH 4 240 / 10'3 CH 3115 40-CH-H 4 151 MeOH-Ether (1) CH 0 3 3116 41 n. C5H- 90 AcOEt-Pentane 0 3117 42 n. C5Hll- il Il NH2 4 3117 42 - CC-NH2 77 AcOEt 3124 43 CH .-- H Isopropanol 3125 44 not.

   C.-H ,, - 4 130 Methyl ethyl ketone (l) 3 il

  <Desc / Clms Page number 41>

 
 EMI41.1
 
 EMI41.2
 CodeCP PEb &verbar; 3128 -CH-b-H 4 118 AcOEt 3147 46 <-CH-CH- 3 149 Methyl ethyl ketone (1) 3148 47 CH 0- <-O (CH 3148 47 CH30 (CH2) - 3 151, 5 AcOEt-Isopropanol 3149 48 <-) -C- 9 AcOEt 0 3150 C)) - CH-C-H 3151 50 -CH-C-H H C2H5 c 2H5 3152 51 C2H5

  <Desc / Clms Page number 42>

 
 EMI42.1
 
 EMI42.2
 CodeCP n F (C) PEb solvent (oC) 0 3153 52 <Ô'-CH - H 3 109. 6 AcOEt C2H5.



  3154)) - - CH-C-H 3154 53 c H -'- H OH 3 85 AcOEt C2H5 3154 3155 54 -L- 5 122 Isopropanol 0-3 3156 55 n. CrH- 3 0.



  3157 56 &commat; - '3158 57 n. H- 5 94-95 Methyl ethyl ketone (1) 1 3159 58 zo (C) -L 3 63 MeOH-H.

  <Desc / Clms Page number 43>

 
 EMI43.1
 
 EMI43.2
 



  CodeCP n F (OC) PEb solvent --------------- p ------------------------- ---------------- 3160 59 &commat; (CH2) -C- H OCH3 3 180/2. 10-3 Q 3161 60 &commat; (CH2) H 3 128 AcOEt q 3162 61 CH3-0 H OH 3 81 AcOEt 3163 62 z (CHJ- H-, '\ C3H7 c 3H7 3164 63 &commat; (CH) - H OC2HS 5 156-158 Acetone-Ether ( 1) 3165 64 zo (CH) - 3 217-218 Me0H

  <Desc / Clms Page number 44>

 
 EMI44.1
 
 EMI44.2
 CodeCP n FOC) of PEb 3166 65 &commat; - (CH2) 2- H OC2HS 3 206-207 Methyl ethyl ketone (1) 3167 3167 66 0> - (CH2) 3- 3168 67 <-C- H OCZH5 3 170 / 10-1 19, 3169 68 0 (CH2) C- CH 3170 69 Cl - CH2-C-H 4 108 Toluene-Heptane p H 168/10 -1 3171 70 <3 3 l C2H5 0 CH-- 3173 71 - - CH, 3

  <Desc / Clms Page number 45>

 
 EMI45.1
 
 EMI45.2
 CodeCP n F (OC) PEb solvent (OC) / mb recrystallization.



  3174 72 &commat; - (CH) - H OCH3 5 169-170 Acetone-Ether (1) 3175 73 &commat; - 5 200/2. 10-3 q CH-C- / C3H7 (1) hydrochloride

  <Desc / Clms Page number 46>

 The products of the invention were subjected to a series of pharmacological tests, the methodology of which is described below.



  The Du 50 are calculated according to the method of Lichtfield and Wilcoxon (J. Pharmacol. Exp. Ther. 96, 99, 1949) and expressed in mg / kg. The products are administered orally to mice. In general, the products of the invention have been found to be not very toxic.



  The effect on behavior is studied using a method derived from that of S. Irwin (Gordon Res. Conf. On Medicinal Chem., 133,1959). The substances, suspen-
 EMI46.1
 due to 1% tragacanth gum mucilage, are administered orally using an intragastric probe to groups of 5 fasted male mice for 18 hours.



  The doses tested depending on the activity observed range from 3000 to 3 mg / kg.



  Behavior is studied 2,4, 6 and 24 hours after treatment. Observation is extended if symptoms persist at this time. Mortalities are recorded during the 14 days following treatment.



  None of the products tested induced abnormal behavior in mice.
 EMI46.2
 



  - - - - ------- --- The numbers refer to the numbers given to the products in column 2 of table I.



  In general, certain products of the invention are endowed with an anticonvulsant activity.



  The anticonvulsant effect is examined against tonic convulsions induced by bicuculline. The compounds of the invention are administered orally at a dose of 10 mg / kg, to twenty mice, three hours before the intravenous injection of bicuculline, at a dose of 0.7 mg / kg. The number of mice protected against tonic convulsions and death is noted.

  <Desc / Clms Page number 47>

 



  In this test, products # 1,5, 8, 10 and 13 were found to be particularly active and give a protection percentage equal to or greater than 55%.



  CP 2081 (Compound 1 in Table I) was further evaluated. In the bicucullin-induced seizure inhibition test, the
 EMI47.1
 ED50 is 3 mg / kg. At a dose of 300 mg / kg, the percentage of protection against convulsions induced by bicuculline is 75%.



  CP 2081 also has an antagonistic effect on convulsions induced by leptazole and by electroshock.



  Biochemical tests have demonstrated that certain products of the invention exhibit a GABA-mimetic effect.



  This effect was examined in vitro using a method derived from that of C. Braestrup and M. Nielsen (Brain Research Bulletin, Vol 5, Suppl. 2, p. 681-684 (1980)).



  A rat brain homogenate (without cerebellum), washed to remove GABA (acid-y-aminobutanofque) present, is used to measure the binding to the receptor

  <Desc / Clms Page number 48>

 
 EMI48.1
 - ("binding") by means of H-ftunitrazepam in the presence and in the absence of increasing concentrations of the products to be tested or of a reference product (in this case GABA).



  Non-specific binding is determined in the presence of Diazepam.



  Incubation takes place for 60 minutes at 0 ° C., on a homogenate diluted 200 times.



  After incubation, the samples are filtered and washed on Whatman GFB filters. After drying the filter at 60 for 20 minutes, the residual radioactivity is measured using a liquid scintillator in an appropriate medium.



  Under these conditions, the product CP 2818 (compound No. 16 of Table I) behaves like a GABA-mimetic,
 EMI48.2
 characterized by an ECrn ("Enhancernent of 4, 7. 10 compared to the ECg of 8, 2.10 of GABA and by an efficiency identical to that of GABA.



  CP 2818 was also evaluated in vitro in the test for binding of 3H-muscimol to synaptic membranes in rat brains. This test is specific for GABAergic receptors and makes it possible to demonstrate an agonist or antagonist effect at GABA receptors. These are directly linked to the benzodiazepine receptors.



  The preparation of synaptic membranes and the test
 EMI48.3
 3 of 3H-muscimol binding to synaptic membranes are identical to those published by Enna S. J. and Snyder S. H. in Brain Research 100, 81-97 (1978).



  The specific binding value of 3H-muscimol to membranes is obtained by making the difference between the binding of 3H-muscimol alone and of this binding in the presence of 10 M of GABA.



  Different concentrations of CP 2818 were used to determine the concentration of the product needed

  <Desc / Clms Page number 49>

 
 EMI49.1
 to inhibit the binding of jH-muscimol to membranes by 50% (ICrn). For the CP 2818 an IC50 of 2.5 x 10-5 M was obtained. The GABA ICS0 in this system is 2. 10 M.



  The antagonistic effect vis-à-vis the convulsions induced by bicuculline, leptazole and by electroshock as well as the GABA-mimetic effect indicate that the compounds of the invention have pharmaceutical properties which make them specially indicated for the treatment of various forms of epilepsy and dyskinesias such as Parkinson's disease.



  In addition, the activity of the products in the central nervous system makes these compounds potentially useful for the treatment of certain cardiovascular disorders such as hypertension and hypotension, for the treatment of mental disorders such as depression, memory and sleep disturbances, as well as analgesic agents.



   Certain products of the invention also exhibit anthelmintic activity.



   This activity is measured in rats, infested with
Nippostrongylus Brasiliensis (stage L3).



   The product to be tested is administered by esophageal tube, in the form of mucilage, 8 days after the infestation.



   Rats   ? were sacrificed on the 12th day and the parasites were counted in the intestine. The results obtained are ex-

  <Desc / Clms Page number 50>

 awarded as a percentage of effectiveness compared to a control group.



  In this test, the product CP 2081 (compound n 1 of table I) has a percentage of effectiveness of 91 at the dose of 50 mg / kg.



  In humans, the compounds of the invention will be administered orally, at doses ranging from 50 mg to 4000 mg; intravenously, the doses will be 5 mg to 1000 mg.



  The products of the invention can be used in various dosage forms. The examples which follow are not limiting and relate to the galenical formulations containing an active product designated by the letter A. This active product can be formed by one of the following compounds: 4-n. pentylaminobutanamide
 EMI50.1
 5-n. pentylaminopentanamide 6-n. pentylaminohexanamide 4-n acid. pentylaminobutanoic 5-pentanamide 6-n. decylaminohexanamide 6- [4- [

  <Desc / Clms Page number 51>

 (p. tolylacetylamino) Tablets.
 EMI51.1
 
 <tb>
 <tb>



  AT <SEP> 600 <SEP> mg
 <tb> starch <SEP> Sta-Rx <SEP> 1500 <SEP> 80 <SEP> mg
 <tb> hydroxypropylmethylcellulose <SEP> 20 <SEP> mg
 <tb> aerosol <SEP> 5 <SEP> mg
 <tb> stearate <SEP> from <SEP> magnesium <SEP> 15 <SEP> mg
 <tb> A <SEP> 100 <SEP> mg
 <tb> starch <SEP> from <SEP> but <SEP> 100 <SEP> mg
 <tb> lactose <SEP> 80 <SEP> mg
 <tb> aerosol <SEP> 5 <SEP> mg
 <tb> talc <SEP> 5 <SEP> mg
 <tb> stearate <SEP> from <SEP> magnesium <SEP> 10 <SEP> mg
 <tb> Capsules.
 <tb>



  AT <SEP> 50 <SEP> mg
 <tb> lactose <SEP> 110 <SEP> mg
 <tb> starch <SEP> from <SEP> but <SEP> 20 <SEP> mg
 <tb> gelatin <SEP> 8 <SEP> mg
 <tb> stearate <SEP> from <SEP> calcium <SEP> 12 <SEP> mg
 <tb> A <SEP> 200 <SEP> mg
 <tb> polyvinylpyrrolidone <SEP> 10 <SEP> mg
 <tb> starch <SEP> from <SEP> corn <SEP> 100 <SEP> mg
 <tb> Cutina <SEP> HR <SEP> 10 <SEP> mg
 <tb> Injectable <SEP> I. <SEP> M. <SEP> or <SEP> I. <SEP> V.
 <tb>



  AT <SEP> 20 <SEP> mg
 <tb> chloride <SEP> sodium <SEP> 40 <SEP> mg
 <tb> acetate <SEP> sodium <SEP> ad <SEP> pH <SEP> = <SEP> 7
 <tb> water <SEP> distilled <SEP> for <SEP> injectables <SEP> ad <SEP> 5 <SEP> ml
 <tb>
 

  <Desc / Clms Page number 52>

 Injectable I. M.
 EMI52.1
 
 <tb>
 <tb>



  AT <SEP> 200 <SEP> mg
 <tb> benzoate <SEP> from <SEP> benzyl <SEP> 1 <SEP> g
 <tb> oil <SEP> for <SEP> injection <SEP> ad <SEP> 5 <SEP> ml
 <tb> Syrup.
 <tb>



  AT <SEP> 5 <SEP> g <SEP>
 <tb> acid <SEP> tartaric <SEP> 0.5 <SEP> g
 <tb> nipasept <SEP> 0.1 <SEP> g
 <tb> sucrose <SEP> 70 <SEP> g
 <tb> aroma <SEP> 0.1 <SEP> g
 <tb> water <SEP> ad <SEP> 100 <SEP> ml
 <tb> Solution.
 <tb>



  AT <SEP> 2 <SEP> g <SEP>
 <tb> sorbitol <SEP> 50 <SEP> 9
 <tb> glycerin <SEP> 10 <SEP> g
 <tb> gasoline <SEP> from <SEP> mint <SEP> 0.1 <SEP> g
 <tb> propylene <SEP> glycol <SEP> 10 <SEP> g
 <tb> water Demineralized <SEP> <SEP> ad <SEP> 100 <SEP> ml
 <tb> Suppository.
 <tb>



  AT <SEP> 500 <SEP> mg
 <tb> butylhydroxyanisol <SEP> 10 <SEP> mg
 <tb> glycerides <SEP> semi-synthetic <SEP> ad <SEP> 3 <SEP> g
 <tb> Gel <SEP> rectal.
 <tb>



  AT <SEP> 100 <SEP> mg
 <tb> carbomer <SEP> 15 <SEP> mg
 <tb> triethanolamine <SEP> ad <SEP> pH <SEP> 5.4
 <tb> water Purified <SEP> <SEP> 5 <SEP> g
 <tb>



    

Claims (1)

 CLAIMS 1. Derivative of w-amino acids of general formula I  EMI53.1  as well as their racemic mixtures or not, their optically pure isomers and the salts of these compounds formed with pharmaceutically usable acids, bases and metals, in which: R represents - a linear or branched alkyl radical C2, C3, C4, C5 ,  EMI53.2  Cg, Q,, Cy, Cg, Cg, C- a linear or branched alkyl radical C2, C3, C4 substituted by a phenyl or phenoxy ring which may be substituted by one or two linear or branched alkyl radicals C- ,, Cp, C, C, by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two halogen atoms, such as fluorine, chlorine or bromine, - a linear acyl radical or branched C2, C3, C4, C5, C6 substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals Cl'C2, C 31 C4, by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two halogen atoms, such as fluorine, chlorine  EMI53.3  or bromine, Ri represents - - linear or branched acyl radical C,,  <Desc / Clms Page number 54>  C7, C8, C9, C10, C11, - a linear or branched acyl radical C2, C3, C4, C5, C6 substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear alkoxy radicals  EMI54.1  or,, or by one or two halogen atoms, such as fluorine, chlorine or bromine, R branched Ci, C- a hydroxyl group - an alkoxy group R30-,    in which R3 is a linear or branched alkyl radical CI'C2 or C3 '- an amine group n has the values 3,4 or 5; 2. Derivative according to claim 1, characterized in that in the formula I R represents - a linear or branched alkyl radical C2, C3, C4, C5,  EMI54.2  C, Q,, Cy, Cg, Cg, C- a linear or branched alkyl radical C2, C3, C4 substituted by a phenyl or phenoxy ring which may be substituted by one or two linear or branched alkyl radicals C., C , C, C, by one or two linear or branched alkoxy radicals C1, C2, C3, C4, or by one or two halogen atoms, such as fluorine, chlorine or bromine, - a linear or branched acyl radical C2, C3, C4, C5, C6 substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals C1, C2, C3, C4, by one or two linear or branched alkoxy radicals C ,, C2, C3, C4, or by a or two halogen atoms, such as fluorine, chlorine or bromine,  EMI54.3  Ri represents - hydrogen - a linear or branched acyl radical C2, C3, C4, C5, C6  <Desc / Clms Page number 55>   C7, C8, C9, C10, C11, - a linear or branched acyl radical C2, C3, C4, C5, C6 substituted by a phenyl ring optionally substituted by one or two linear or branched alkyl radicals C1'2'3'C4 ' by one or two linear or branched alkoxy radicals C1, C2, C3, C4 or by one or two halogen atoms, such as fluorine, chlorine or bromine,    R? represents - a hydroxyl group - an alkoxy group R30-, in which R3 is a linear or branched alkyl radical CI'C2 or C3 '- an amine group n has the values 3,4 or 5; - when R represents a dodecyl radical and R. of the hydrogen, R2 does not represent a hydroxyl radical, - when na has the value 4 and when R2 represents a hydroxyl group and Ri of hydrogen, R does not represent a radical not. butyl or n. octyl, - when n is 4 and when R2 represents an ethoxy group and R, hydrogen, R does not represent an ethyl radical or n. butyl, - when R represents an n radical.  butyle, R. from hy-  EMI55.1  drogen and R2 a methoxy or hydroxyl radical, n does not have the value 3, - when R represents an isopropyl radical, Ri of the hydrogen and R2 a hydroxyl radical, n does not have the value 5. 3. Derivative according to any one of claims 1 and 2, characterized in that in formula I, R represents  EMI55.2  a C2-CIO alkyl radical. 4. A derivative according to any one of claims 1 and 2, characterized in that, in formula I, R represents a C2-CS alkyl radical.  <Desc / Clms Page number 56>   5. Derivative according to any one of claims 1 and 2, characterized in that, in formula I, R represents a C6-C12 alkyl radical. 6. Derivative according to any one of claims 1 and 2, characterized in that, in formula I, R is a C5-C7 radical. 7. Derivative according to any one of claims 1 and 2, characterized in that, in formula I, R represents a C2-C4 alkyl radical substituted by a phenyl or phenoxy ring which themselves can be substituted by a methyl radical or methoxy or with a chlorine atom.  8. A derivative according to any one of claims 1 and 2, characterized in that, in formula I, R represents a CZ-C4 acyl radical substituted by a phenyl radical itself substituted by one or two methyl or methoxy radicals or by one or two chlorine or bromine atoms .  9. Derivative according to any one of the claims  EMI56.1  1 to 8, characterized in that, in formula I, RI represents an acyl radical C-Cc. 10. Derivative according to any one of claims 1 to 8, characterized in that, in formula I, Ri represents an acyl radical Ce-C,.,. 11. Derivative according to any one of claims 1 to 8, characterized in that, in formula I, Ri represents an acyl radical C2-C4 substituted by a phenyl radical itself substituted by one or two methyl radicals or methoxy or by one or two chlorine or bromine atoms.  <Desc / Clms Page number 57>   12. Derivative according to any one of claims 1 to 8, characterized in that, in formula I, R represents hydrogen and R2 represents an amino radical.  13. A derivative according to claim 1, characterized in that it is chosen from the group formed by the compounds: 4-n. pentylaminobutanamide  EMI57.1  5-n. pentylaminopentanamide 6-n. pentylaminohexanamide 4-n acid. pentylaminobutanoic 5- pentanamide 6-n. decylaminohexanamide 6- [4- [14.  Amine derivative, in particular for the preparation of the derivatives according to any one of the preceding claims, characterized in that it corresponds to formula II:  EMI57.2  in which R, R, and n have the meanings given above and Z is an amide function, a carboxylic acid function, a nitrile function, a function  EMI57.3  ester (COOR ', in which R're represents either R3' specified above, or an alkyl or phenyl radical substituted in such a way that it activates the ester  <Desc / Clms Page number 58>    EMI58.1  vis-à-vis the attack of a nucleophile), a function  EMI58.2  amid-ine / NH an acid halide function ze NH2 2 (C, where X represents a halogen such as chlorine, ",  EMI58.3  bromine or iodine), an anhydride function, a function  EMI58.4  0R)  imidate (-C / j or the N-carbonylimidazolyl group,  EMI58.5  Z can also represent a carboxylic acid precursor group such as the trihalomethyl group (-CX3 'in which X represents a chlorine, bromine or iodine atom), an oxazoline group, a hydroxymethylene group (-CH20H), a group formyl (-CHO) which may or may not be present in a protected form such as a cyclic dithioacetal or not, an a, p-dihydroxyalkyl or alkenyl group (-CHOH-CHOH-R or -CH = CH-R., in which R4 represents a linear alkyl radical (C-Co), acetyl group (-CO-CH), 1-hydroxyethyl group (-CHOH-CH3) 'an acetonyl group (-CH-CO-CH.), 2-hydroxypropyl group- l (-CH-CHOH-CH) or a halogen atom, such as chlorine, bromine or iodine,  or the grouping group  EMI58.6  B CH in and B2 can be equal or oB2  EMI58.7  different from each other and represent a function chosen from the following series: nitrile, carbamoyl or alkoxycarbonyl (-COORo, having the values given previously).  <Desc / Clms Page number 59>   15. Process for the synthesis of derivatives according to any one of claims 1 to 13, characterized in that it consists in converting a derivative of formula II  EMI59.1  into a corresponding compound of formula I, R, R, and n having the meanings given above, Z representing a group which, by the action of an appropriate reagent, can be converted into an amide, carboxylic or alkoxycarbonyl function ( -COORg), such as the amide function, the carboxylic acid function, the nitrile function, the ester function (-COOR ', in which R'represent either R, specified previously, or an alkyl or phenyl radical substituted in such a way  EMI59.2  that it activates the ester vis-à-vis the attack of a nu-  EMI59.3  cleophile), NH function ('2 acid halide (C)  X represents a halogen x  EMI59.4  such as chlorine, bromine or iodine), the an-  EMI59.5  0R hydride, the imidate function OR 3) or the NH group  EMI59.6  N-carbonylimidazole, Z can also represent a precursor group of carboxylic acid such as the trihalomethyl group (-CX, in which X represents a chlorine, bromine or iodine atom), an oxazoline group, a hydroxymethylene group (-CH20H ), a formyl group (-CHO) which may or may not be present in a protected form such as a cyclic dithioacetal or not, an a group, -dihydro-  <Desc / Clms Page number 60>    EMI60.1  xyalkyl or alkenyl (-CHOH-CHOH-R4 or -CH = CH-R., which R4 represents a linear alkyl radical C-Co), acetyl group (-CO-CH3), 1-hydroxyethyl group (-CHOH-CH) ,  acetonyl group (-CH-CO-CH), 2-hydroxypropyl-1 group (-CH-CHOH-CH) or a halogen atom such as chlorine, bromine or iodine, or the group group  EMI60.2  B CH in which B, and 82 can be equal or difzo  EMI60.3  between them and represent a function chosen from the following series: nitrile, carboxylic, carbamoyl or alkoxycarbonyl (-COORo, having the values given above). 16. Process for the synthesis of derivatives according to any one of claims 1 to 13, characterized in that it consists in subjecting a condensation reaction to an amine of formula RNH- (CH?) Or) nZ with an alkylating reagent or acylation such as  EMI60.4  R RW, R. M, COOH, C = 0, or an amine R7 "7. K of formula NH with a compound W- (CH2) or OHC-) -Z RI  EMI60.5  if necessary followed by a reduction in the amide, imine or iminium intermediate function obtained; in these formulas R, R. and n having the meanings given  EMI60.6  R6 above, the groups "" CH-CO, -CH-CH., R - RR Ro-CH H "10  EMI60.7  where appropriate, a reduction, representing the group R or R, the value of a chlorine, bromine or iodine atom, of a group such as O-tosyl, O-mesyl, sulfate, acyloxy or hydroxyl and Z having the meaning  <Desc / Clms Page number 61>    EMI61.1  0 of group C ", has the values R previously. 2  EMI61.2  17.  Process for the synthesis of derivatives according to any one of Claims 1 to 13, characterized in that a lactam of formula XVIII  EMI61.3  in which R and n have the meanings given above, is converted into a derivative of formula I, under the action of a mineral acid or under the action of ammonia, an amide, an alcoholate or an alkali metal hydroxide. 18. Pharmaceutical composition, characterized in that it comprises at least one of the derivatives of formula 1 or one of its salts, combined with one or more pharmaceutically suitable excipients or optionally with other therapeutic agents. 19. Composition according to Claim 18, characterized in that it is in the form of dragees, tablets, capsules, tablets, granules, capsules, solutions, syrups, emulsions, suspensions or gels containing conventional additives or excipients. galenic pharmacy.  <Desc / Clms Page number 62>  20. Composition according to Claim 18, characterized in that it comprises at least one of the derivatives of formula 1 in solution in particular in sterile water or in an oil such as peanut oil or ethyl oleate . 21. A method of using the derivatives of formula I, characterized in that they are administered at doses of 50 mg to 4000 mg orally and from 5 mg to 400 mg parenterally. 22. Method of using the derivatives according to formula 1 in the treatment of various forms of epilepsy, in the treatment of muscular spasticities of nervous origin, in the treatment of dyskinesias such as Parkinson's disease, in the treatment of disorders psychic agents such as depression, sleep disturbances and memory impairment, in the treatment of certain cardiovascular disorders such as hypertension and hypotension as well as as analgesic and anthelmintic agents.