Européiisches Patentamt
`
`European Patent Ofilce
`
`Office européen des brevets
`
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`
`® Publication number:
`
`0194 464 B1
`
`EU ROPEAN PATENT SPECIFICATION
`
`a 6
`
`9
`
`Date of publication of patent specification: 03.04.91 ® Int. Cl.-5: CCl7C 237/12, C07C 323/52,
`A61 K 31/16, A61 K 37/02
`
`@ Application number: 861018653
`
`@ Date or filing: 14.02.86
`
`@ Amino acid derivatives and use thereof for the preparation of an anticonvulsant.
`
`@ Priority: 15.0235 us 702195
`
`Date of publication of application:
`17.09.86 Bulletin 85133
`
`@ Proprietor: Research Corporation Technol-
`ogies, Inc. (a Delaware corp.)
`6840 East Broadway Boulevard
`Tucson Arizona 85710-2815(US)
`
`Publication of the grant of the patent:
`03.04.91 Bulletin 9'll'l4
`
`Designated Contracting States:
`AT BE CH DE FR GB lT Ll LU NL SE
`
`References cited:
`EP-A- U 007 441
`EP-A- U 045 707
`GB-A-1 051 220
`US-A- 3 707 559
`
`EP-A- 0 038 758
`DE-A- 1 927 592
`US-A- 2 676 188
`
`TETRAHEDRON, vol. 33. no. 5, 1977, pages
`489-495. Pergamon Press, GB; M. IKEDA et
`al.: "Photochemical synthesis of
`1.2,3,4-tetrahydroisoquinolin-3-ones from N-
`chloroacetylbenzylamines"
`
`(79 Inventor: Kohn, Harold L
`3735 Latma Drive
`
`Houston, TX(US)
`inventor: Watson, Darrell
`801 North Pearl
`
`Belton, TX(US)
`
`Representative: Eitle, Werner, Dlpl.-lng. et al
`Hoffmann, Eitle & Partner Patentanwitlte Ar-
`abellastrasse 4
`W-B000 Miinchen 81(DE)
`
`\
`
`EP0194464B1
`
`Note: Vwthin nine months from the publication of the mention of the grant of the European patent. any person
`may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition
`shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee
`has been paid (Art. 99(1) European patent convention).
`
`Rank Xerox (UK) Business Sen.-Em
`
`EXHIBIT
`ACTAVIS. AMNEAL.
`AUROBINDO.
`BRECKENRIDGE.
`VENNOOT.
`SANDOZ. SUN
`
`IPR20l4-01126-1020 p. 1
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`IPR2014-01126- Exhibit 1020 p. 1
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`EP 0 194 464 B1
`
`TETRAHEDRON LE'I'l'ERS, vol. 25. no. 42,
`1984. pages 4841-4344, Pergamon Press Ltd.,
`GB; .1. GARCIA et al.: "New synthetic "tricks".
`Triphenylphosphine-mediated amide forma-
`tion from carboxylic acids and a2ides"
`
`JOURNAL OF THE AMERICAN CHEMICAL SO-
`C|I:‘l'Y, vol. 106, no. 2, 25th January ‘[984.
`pages 457-459, American Chemical Soclety,
`US; B.H. LIPSHUTZ et aI.: "Heterocycles in
`synthesis: Chiral amino acidsldipeptides via
`a novel photooxidative cleavage of trisub-
`stituted irnidazoles"
`
`JOURNAL OF THE AMERICAN CHEMICAL S0-
`CIETY, vol. 105. no. 26, 28th December 1983,
`pages 7703-7713, American Chemical Soci-
`ety, US; B.H. LIPSHUTZ et al.: "HeterocycIes
`as masked diarnideldipeptide equivalents.
`Formation and reactions of substituted
`
`5-(acylamino)oxazoles as intermediates en
`route to the cyclopeptide alkaloids"
`
`JOURNAL OF MEDICINAL CHEMISTRY, vol.
`28, no. 5, 1985, pages 661-606; S. CORTES at
`al.: "Effect of structural modification of the
`
`hydaution ring on anticonvulsant activity"
`
`'
`
`L/r‘‘'..
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`EP 0194 464 31
`
`Description
`
`The predominant application of anticonvulsant drugs is the control and prevention of seizures asso-
`ciated with epilepsy or related central nervous system disorders. Epilepsy refers to many types of recurrent
`seizures produced by paroxysmal excessive neuronal discharges in the brain; the two main generalized
`seizures are petit mal. which is associated with myoclonic jerks, akinetic seizures,
`transient
`loss of
`consciousness. but without convulsion; and grand mal which manifests itself in a continuous series of
`seizures and convulsions with loss of consciousness.
`
`The mainstay of treatment for such disorders has been the long-term and consistent administration of
`anticonvulsant drugs. Most drugs in use are weak acids that. presumably. exert their action on neurons, glial
`cells or both of the central nervous system. The majority of these compounds are characterized by the
`presence of at least one amide unit and one or more benzene rings that are present as a phenyl group or
`part of a cyclic system.
`Much attention has been focused upon the development of anticonvulsant drugs and today many such
`drugs are well known. For example,
`the hydantoins. such as phenytoin. are useful
`in the control of
`generalized seizures and all forms of partial seizures. The oxazolidinediones. such as trimethadione and
`paramethadlone, are used in the treatment of nonconvulsive seizures. Phenacemide. a phenylacetylurea. is
`one of the most well known anticonvulsants employed today. although much attention has recently been
`dedicated to the investigation of the diazepines and piperazines. For example. U.S. Patent Nos. 4.002.764
`and 4,178,378 to Allgeier, et al. disclose esterilied diazepine derivatives useful in the treatment of epilepsy
`and other nervous disorders. U.S. Patent No. 3.887.543 to Nakanishi. et al. describes a thieno [2.3-e]{1.4]
`diazepine compound also having anticonvulsant activity and other depressant activity. U.S. Patent No.
`4.209.516 to Heckendorn, at al. relates to triazole derivatives which exhibit anticonvulsant activity and are
`useful
`in the treatment of epilepsy and conditions of
`tension and agitation.
`l-‘lnally. U.S. Patent No.
`4,372,974 to Fish. et al. discloses a pharmaceutical
`formulation containing an aliphatic amino acid
`compound in which the carboxylic acid and primary amino are separated by three or
`four units.
`Administration of these compounds in an acid pH range are useful in the treatment of convulsion disorders
`and also possess anxiolytic and sedative properties.
`Unfortunately. despite the many available pharmacotherapeutic agents. a significant percentage of the
`population with epilepsy or related disorders are poorly managed. Moreover. none of the drugs presently
`available are capable of achieving total seizure control and most have disturbing side-effects. Clearly,
`current therapy has failed to "seize control" of these debilitating diseases.
`DE 1 927 692 discloses amino acid derivatives. the closest of which are N-phenylacetyI-D.l_—alanine-N-
`methylamide and N-phenylacetyl-D.L-phenylglycine-N-methylamide. Both of these prior art compounds
`demonstrated no anticonvulsant activity under standard testing procedures at dosage levels above 300 mg
`kg" while the closest compounds of the present application. N—acetyl-D.l_-alanine-N-benzylamide and N-
`acetyl~D.L-phenylglycine-N-benzylamide. exhibit activity at levels less than 100 mg kg".
`It is one object of the present invention to provide novel compounds exhibiting anticonvulsant activity.
`Another object of this invention is to provide pharmaceutical compositions useful in the treatment of
`epilepsy and other central nervous system disorders.
`The present invention is directed to a compound having the general formula (I):
`
`R
`13
`
` H NH —q—1~iH -3
`2
`#2
`E
`
`1
`
`I
`
`independently are hydrogen. C1-C5 alkyl or phenyl and the
`
`is C1-C5 alkyl. R2 and H3,
`wherein R1
`pharmaceuticaly acceptable salts thereof;
`wherein the benzyl moiety, Fir, H2 and H3 may be substituted by halo. nitro. carboxyl. carboalkoxyl,
`carboxamide, cyano or thiol. alkylthio, alkoxy. alkyl. amino or phenoxy;
`with the proviso that:
`when R1 is methyl. H2 is hydrogen. and Fla is hydrogen. methyl. isopropyl or isobutyl then the benzyl
`moiety cannot be unsubstituted benzyl: or
`_
`when R1 is methyl and Fla and R3 are hydrogen. then the benzyl moiety cannot be substituted with 3-
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`
`EP 0194 464 B1
`
`methoxy.
`The present invention contemplates employing the above compounds in compositions of pharmaceuti-
`cally acceptable dosage forms. Where the appropriate substituents are employed, the present invention
`also includes pharmaceutically acceptable addition salts. Moreover,
`the administration of an effective
`amount of the present compounds. in their pharmaceutically acceptable forms or the addition salts thereof.
`can provide an excellent regime for the treament of epilepsy. nervous anxiety, psychosis. insomnia and
`other related central nervous system disorders.
`In accordance with the present invention. anticonvulsant compounds are p_rovided having the general
`formula I. These compounds can be incorporated into pharmaceutical compositions and employed for the
`treatment of epilepsy and related central nervous system disorders such as anxiety. psychosis and
`insomnia.
`
`The alkyl groups exemplary of the substituents are lower alkyl containing from 1 to 6 carbon atoms and
`may be straight chain or branched. These groups include methyl. ethyl. propyl. isopropyl. butyl. isobutyl.
`tertiary butyl. amyl and hexyl.
`Preferred compounds of formula (I) are those wherein the benzyl moiety is substituted. F11
`is hydrogen and R3 is methyl.
`Especially preferred compounds are: N-acetylphenylglycine-N‘-benzylamide. N—trimethylacetyl—a|anine-
`N'—benzylamide. N-acetyl—alanine-N'—3~fIuoro-benzylamide. N-acetyl-alanine-N‘-3-methoxy-benzylamide.
`A further compound within the scope of the invention is N-acetyl-methionine-N’-benzylamide.
`The compounds of the present invention may contain one (1) or more asymmetric carbon atoms and
`may exist in racemic and optically active forms. Depending upon the substituents. the present compounds
`may form addition salts as well. All of these forms are contemplated to be within the scope of this invention.
`The compounds of the present invention can be prepared by art-recognized procedures from known
`compounds or readily preparable intermediates. For instance. compounds of Formula I can be prepared by
`reacting amines of Formula It with an acylating derivative of a carboxylic acid of Formula Ill under amide
`fonning conditions:
`
`is methyl. Fla
`
`3 '2
`@4a2-riH- -cL-NH2 +
`
`Ft
`
`33
`
`E
`
`-
`°-Or-I ———.5
`
`121-
`
`I
`
`:1
`
`III
`
`wherein R1. R2, R3 are as defined hereinabove.
`The amide forming conditions referred to herein involve the use of known derivatives of the described
`acids. such as the acylhalides. (e.g..
`
`wherein X is Cl. Br) anhydrides (e.g..
`
`R-§'X;
`
`111- E-O-E:-R1) ,
`
`I
`
`lower alkyl esters. carbodiimides and carbonyldimidazoles.
`mixed anhydrides.
`acylating derivative used is the anhydn'de.
`
`It
`
`is preferred that
`
`the
`
`R -£..-£i.
`
`1
`
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`
`EP 0 194 464 B1
`
`As in any organic reaction. solvents can be employed such as methanol. ethanol. propanol, acetone.
`tetrahydrofuran. dioxane. dimethylformamide. dichloromethane and chloroform. The reaction is normally
`effected at or near room temperature, although temparatures from 0° C up to the reflux temperature of the
`reaction mixture can be employed.
`As a further convenience. the amide forming reaction can be effected in the presence of a base. such
`as tertiary organic amine. e.g.. trimethylamine. pyridine and picolines. particularly where hydrogen halide is
`formed by the amide forming reaction. e.g.. aryl halide and the amine of Formula ll. Of course. in these
`reactions where hydrogen halide is produced. any of the commonly used hydrogen halide acceptors can
`also be used.
`
`The various substituents on the present new compounds. e.g.. as defined in R1, F12 and R3 can be
`present in the starting compounds. added to any one of the intermediates or added alter formation of the
`final products by the known methods of substitution or conversion reactions. For example. the nitro groups
`can be added to the aromatic ring by nitration and the nitro group converted to other groups. such as amino
`by reduction. and halo by diazotization of the amino group and replacement of the diazo group. All-ranoyl
`groups can be substituted onto the aryl groups by Friedel-Crafts acylaljon. The acyl groups can be then
`transformed to the corresponding alkyl groups by various methods. includeing the Wollt-lfishner reduction
`and Clemmenson reduction. Amino groups can be alkylated to form mono and dialkylamino groups: and
`mercapto and hydroxy groups can be alkylated to form corresponding ethers. Primary alcohols can be
`oxidized by oxidizing agents known in the art
`to form carboxylic acids or aldehydes. and secondary
`alcohols can be oxidized to form ketones. Thus. substitution or alteration reactions can be employed to
`provide a variety of substituents throughout the molecule of the starting material. intermediates. or the final
`product.
`In the above reactions. if the substituents themselves are reactive. then the substituents can themselves
`be protected according to the techniques known in the art. A variety of protecting groups known in the art
`may be employed. Examples of many of these possible groups may be found in "Protective Groups in
`Organic Synthesis." by T.W. Green. John Wiley 8: Sons, 1981.
`The present compounds obviously exist in stereoisomeric forms and the procucts obtained thus can be
`mixtures of the isomers, which can be resolved. Alternatively. by selection of specific isomers as starting
`compounds. the preferred stereoisomer can be produced.
`The active ingredients of the therapeutic compositions and the compounds of the present invention
`exhibit excellent anticonvulsant activity when administered in amounts ranging from 10 mg to 100 mg per
`kilogram of body weight per day. A preferred dosage regimen for optimum results would be from 20 mg to
`50 mg per kilogram of body weight per day. and such dosage units are employed that a total of from 1.0
`gram to 3.0 grams of the active compound for a subject of 70 kg of body weight are administered in a 24»
`hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response and is
`preferably administered three times a day in dosages of 600 mg per administration. For example. several
`divided doses may be administered daily or the dose may be proportionally reduced as indicated by the
`exigencies of the therapeutic situation. A decided practical advantage is that the active compound may be
`administered in an convenient manner such as by the oral.
`intraveneous (where water soluble).
`in-
`tramuscular or subcutaneous routes.
`
`for example. with an inert diluent or with an
`The active compound may be orally administered.
`assimilable edible carrier. or it may be enclosed in hard or soft shell gelatin capsule. or it may be
`compressed into tablets. or it may be incorporated directly with the food of the diet. For oral therapeutic
`administration. the active compound may be incorporated with excipients and used in the form of ingestible
`tablets. buccal
`tablets, troches. capsules. elixirs, suspensions. syrups and wafers. Such compositions and
`preparations should contain at least 1% of active compound. The percentage of the compositions and
`preparations may. of course. be varied and may conveniently be between about 5 to 80 9.4. of the weight of
`the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable
`dosage will be obtained. Preferred compositions or preparations according to the present invention are
`prepared so that an oral dosage unit form contains between 5 and 1000 mg of active compound.
`The tablets.
`troches. pills and capsules may also contain the following: A binder such as gum
`tragacanth, acacia. corn starch or gelatin: excipients such as dicalcium phosphate: a disintegrating agent
`such as corn starch. potato starch and alginic acid; a lubricant such as magnesium stearate: and a
`sweetening agent such as sucrose,
`lactose or Saccharin may be added or a flavoring agent such as
`peppermint, oil of wintergreen. or cherry flavoring. When the dosage unit form is a Capsule. it may contain.
`in addition to materials of the above type. a liquid can'ier. Various other materials may be present as
`coatings or to otherwise modify the physical form of the dosage unit. For instance. tablets. pills. or capsules
`may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound. sucrose as a
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`
`EP 0194 464 B1
`
`sweetening agent. methyl and propylparabens as preservatives. a dye and flavoring such as cherry or
`orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutlcally
`pure and substantially non-toxic in the amounts employed.
`in addition.
`the active compound may be
`incorporated into sustained-release preparations and formulations.
`The active compound may also be administered parenterally or intraperitoneally. Dispersions can also
`be prepared in glycerol.
`liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary
`conditions of storage and use.
`these preparations contain a preservative to prevent
`the growth of
`microorganisms.
`The phannaceutical forms suitable for injectable use include sterile aqueous solutions (where water
`soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions
`or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability
`exists.
`It must be stable under the conditions ol manufacture and storage and must be preserved against
`the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or
`dispersion medium containing. for example. water. ethanol. polyol (for example, glycerol, propylene glycol.
`and liquid polyethylene glycol). suitable mixtures thereof, and vegetable oils. The proper iluidity can be
`maintained. for example. by the use of a coating such as lecithin. by the maintenance of the required
`particle size in the case of dispersion and by the use of surfactants. The prevention of the action of
`microorganisms can be brought about by various antibacterial and antifungal agents, for example. parabens.
`chlorobutanol. phenol. sorbic acid and thimerosa|.ln many cases, it will be preferable to include isotonic
`agents. for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be
`brought about by the use in the compositions of agents delaying absorption. for example. aluminum
`monostearate and gelatin.
`Sterile injectable solutions are prepared by incorporating the active compound in the required amount in
`the appropriate solvent with various of the other ingredients enumerated above. as required. followed by
`filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active
`ingredient
`into a sterile vehicle which contains the basic dispersion medium and the required other
`ingredients from those enumerated above.
`In the case of sterile powders for the preparation of sterile
`iniectable solutions.
`the preferred methods of preparation are vacuum drying and the freeze-drying
`technique which yield a powder of the active ingredient plus any additional desired ingredient from
`previously sterile-filtered solution thereof.
`As used herein, "pharmaceutically acceptable carrier" includes any and all solvents. dispersion media,
`coatings. antibacterial and antifungal agents.
`isotonic and absorption delaying agents. The use of such
`media and agents for pharmaceutical active substances is well known in the art. Except insofar as any
`conventional media or agent is incompatible with the active ingredient. its use in the therapeutic composi-
`tions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
`It
`is especially advantageous to formulate parenteral compositions in dosage unit form for ease of
`administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units
`suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined
`quantity of active material calculated to produce the desired therapeutic effect
`in association with the
`required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are
`dictated by and directly dependent on (a) the unique characteristics of the active material and the particular
`therapeutic effect to be achieved. and (b) the limitations inherent in the art of compounding such an active
`material for the treatment of disease in living subjects having a diseased condition in which bodily health is
`impaired as herein disclosed in detail.
`The principal active ingredient is compounded for convenient and effective administration in effective
`amounts with a suitable pharmaceutically acceptable carrier in dosage unit form as hereinbefore disclosed.
`A unit dosage form can. for example. contain the principal active compound in amounts ranging from 5 to
`1000 mg. with from 250 to 750 mg being preferred. Expressed in proportions. the active compound is
`generally present in from 10 to 750 mglml of carrier. In the case of compositions containing supplementary
`active ingredients. the dosages are determined by reference to the usual dose and manner of administration
`of the said ingredients.
`For a better understanding of the present invention together with other and further objects. reference is
`made to the following description and example.
`
`EXAMPLE I_
`
`General Methods. Melting points were determined with a Thomas-Hoover melting point apparatus and
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`
`EP 0 194 464 B1
`
`infrared spectra (IR) were run on a Beckman IFt-4250 spectrophotometer and calibrated
`are uncorrected.
`against the l601-cm"‘ band of polystyrene. Absorption values are expressed in wave numbers (cm"').
`Protonhuclear magnetic resonance (‘H NMFt) spectra were recorded on Varian Associates Models T-60
`and I-‘l'—BOA NMFl spectrometers. Carbon nuclear magnetic resonance (“*0 NMR) spectra were run on a
`Varian associates Models Fl’-BOA instrument. Chemical shifts are in parts per million (5 values) relative to
`M6431. and coupling constants (J values) are in hertz. Mass spectral data were obtained at an ionizing
`voltage of 70 eV on a Hewlett-Packard 5930 gas chromatograph-mass spectrometer. High-resolution (El
`mode) mass spectra were performed by Dr. James Hudson at the Department of Chemistry. University of
`Texas at Austin, on a CEC21-110B double-focusing magnetic-sector spectrometer at 70 eV. Elemental
`analyses were obtained at Spang Microanalytical Laboratories. Eagle Harbor. Ml.
`The solvents and reactants were of the best commercial grade available and were used without further
`purification unless noted. All anhydrous reactions were run under nitrogen. and all glassware was dried
`before use.
`
`Preparation of N-Acetyl-D.L-alanine-N’-benzylamide.
`
`Acetic anhydride (2.20 g. 0.022 mol) was slowly added to a methylene chloride solution (30 mL) of D.L—
`alanine-N-benzylamide (3.60 g. 0.021 mol) and allowed to stir at room temperature (3 h). The mixture was
`then successively washed with H20 (15 mL). 1% aqueous NaOH (15 mL) and H20 (15 mL). dried (Na2SO.t)
`and concentrated in vacuo. The residue was recrystallized from CH2Cl2.
`Yield: 2.50 g (5434? """‘
`mp 139-241 ‘C.
`‘H NMR (DMSO-d.;): 5 1.22 (d.J = 7.1 Hz, 3H), 1.84 (s. 3H),
`4.04-4.50 (rn. 3H), 7.26 (s. SH). 8.11 (br d.J = 7.3 Hz.
`1H). 8.42 (br t..J = 6 Hz, 1H).
`"*0 NMR (DMSO-ds): 18.2. 22.4, 41.9. 48.2. 126.5. 126.9.
`123.1. 139.4. 168.9. 172.4 ppm.
`IFl (CHC13) 3440. 3300. 3005. 1660, 1515 cm“.
`Mass spectrum (Cl mode). me: 221 (P+ 1); mol wt 220.1208
`
`Preparation of N-Acetylglycine~N'—benzylamide.
`
`The D.L-amino acid amide (11 mmol) was dissolved in dichloromethane (15mL) and then acetic
`anhydride (1.23 g. 1.40 mL. 12 mmol) was added dropwise. The solution was stirred at room temperature
`(4-6 h) and then concentrated to dryness. The residue was recrystallized from chloroform! hexane.
`Yield: 1.84 9 (31%).
`mp 140-142” C.
`‘H NMF1‘ (DMSO-dsit .5 1.88 (s. 3H), 3.74 (d.J = 5.3 Hz. 2H),
`4.30 (d.J = 5.1 Hz. 2H) . 7.27 (s. 5H) . 8.37 (s. 1H),
`8.75 (8. 1H).
`‘3c NMH (DMSO-d5): 22.5. 42.0. 42.5, 126.6. 127.1 (2C),
`123.1 (2C) .139.3. 169.0. 169.6 ppm.
`IR (KBr): 3060. 1655, 1640. 1560. 1535. 1450. 1300. 740. 710
`cm".
`
`Mass spectrum. mle (relative intensity): 147 (12). 106
`(100). 91 (75). 73 (50).
`
`Elemental analysis
`Calculated for C11H14N2O2
`Found
`
`64.05% C?
`
`6.86% H}
`
`64.03% C:
`
`6.79% H;
`
`13-58% N‘
`13.61% N.
`
`IO
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`Preparation of N-AcetyI-D.L-valine-N‘-benzylamide.
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`
`EP 0194 464 B1
`
`The D.L-amino acid amide (11 mmol) was dissolved in dichloromethane (15mL) and then acetic
`
`anhydride (1.23 g, 1.40 mL, 12 mmol) was added dropwise, The solution was stirred at room temperature
`(46 h) and then concentrated to dryness. The residue was recrystallized from chloroform! hexane.
`Yield: 2.35 g (86%).
`mp 192-193' 0.
`‘H NMR (DMSO-d;): 6 0.83 (d.J = 6.7 Hz, SH). 1.87 (s. 3H),
`1.73~2.09(m, 1H), 4-11(d,J = 8.9 Hz, 1H),4.27 (d.J =
`5.9 Hz, 2H), 7.26 (s, 5H), 7.89 (d.J = 8.BHz, 1H), 8.84
`(t.J = 5.8 Hz, 1|-l).
`“*0 NMR (DMSO~ds) : 18.1, 19.2, 22.4. 30.2, 41.9. 57.8,
`126.6. 127.1 (20). 128.1 (20) 139.4. 169.2. 171.1 ppm.
`IR (KBr) : 1620, 1540, 1530. 1450, 1380. 1290. 745. 690 cm".
`Mass spectrum, mle (relative intensity): 142 (16). 114 (43).
`106 (29), 91 (W), 72 (100), 55 (29).
`
`Elemental analysis
`
`Calculated for C
`
`N O
`H
`14 20 2 2
`
`Found
`
`67.70% 0;
`67.58% C;
`
`8.13% H; 11.28% N.
`
`8.05% H; 11.10% N.
`
`Preparation o_f N—AcetyI—D. L-phenylgIycine—N'-benzylamide.
`
`The D.L-amino acid amide (11 mmol) was dissolved in dichloromethane (15mL) and then acetic
`anhydride (1.23 g. 1.40 mL. 12 mmol) was added dropwise. The solution was stirred at room temperature
`(4-6 h) and then concentrated to dryness. The residue was recrystallized from chloroform! hexane.
`Yield: 2.05 g (66%).
`hp 202-203-0.
`‘H NMR (DMSO-ds): 5 1.91 (s. 3H) , 4-.27 (d.J = 5.6 Hz, 2H).
`5.50 (d.J = 7.9 Hz, IH) , 7.21 (s. 5H) , 7.36 (s. 5H.)
`8.38-8.86 (m, 2H).
`'30 NMR (DMSO'Cis): 22.3. 42.0. 56.3, 126.6 (2C) , 127.0.
`127.1 (20) . 127.4 (20) . 1213.1 (20) . 1313.9, 139.0. 168.9.
`169.9 ppm.
`IR (KBr): 3020, 1655, 1580, 1530, 1450. 1265, 745, 690 cm".
`Mass spectrum, mle (relative intensity): 233 (20) , 264 (21),
`149 (100) , 131 (20) , 118(34) , 106 (92) , 91 (70) , 79
`(56). 77 (54). 65 (45), 51 (37).
`
`Elementa l ana ly si 5
`Calculated for C
`
`Found
`
`N O
`H
`17 18 2 2
`
`72'31% C’
`72.49% C:
`
`6.44% H;
`
`6.47% H;
`
`9.92% N.
`
`9.89% N.
`
`Preparation o_f N-AcetyI-D,L-alanine-N‘-(3-methoxy-)benzy[amide
`
`The D.L-amino acid amide (11 mmol) was dissolved in dichloromethane (15mL) and then acetic
`anhydride (1.23 g. 1.40 mL. 12 mmol) was added dropwise. The solution was stirred at room temperature
`(4-6 h) and then concentrated to dryness. The residue was recrystallized from chloroform! hexane.
`Yield: 0.47 g (17%).
`mp 112-115'0.
`‘H NMR(DMSO-ds):51.23 (d.J = 7. 1 Hz, 3H) , 1.35 (s. 3H.)
`3.73 (s. 3H) 3.99-4.43 (m. 1H), 4.25 (d.J = 6.1 Hz,
`2H) . s.5e7.35 (rn. 41-1) . 3.05 (d.J = 7.4 1-12, 1H) .1135
`
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`|PR2014-01126- Exhibit 1020 p. 8
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`EP 0194 464 B1
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`(1.3 = 6.0 Hz. 11-1).
`13., NMFl (DMSO-d5): 13.1, 22.5. 41.3, 413.3,s4.9, 112.2.
`112.3. 119.o.129.2, 141.0, 159.3. 139.o.172.4 ppm.
`111 (KBr): 3270. 3065. 1525. 1530. 1450, 1260. 1150. 1095.
`900. 775, 700. 390 cm".
`
`Elemental analysis
`
`Calculated for C
`
`Found
`
`13H
`
`19N2°3
`
`62.37% C;
`
`7.26% H;
`
`ll.19% N.
`
`62.29% C;
`
`7.l3%_H;
`
`11.08% N.
`
`Preparation g N-Trimelhylacetyl-D.L-alanine—N'-benzylamide.
`
`D.L-Alanine-N-benzylamide (2.45 g, 13.75 mmol) was dissolved in dichloromethane (20 mL) and
`isobulyric anhydride (2.17 g, 2.28 mL. 13.75 mmol) was added dropwise. The solution was stirred at room
`temperature (1 h) and then heated to reflux (18 h). After cooling to room temperature,
`the solution was
`concentrated to dryness and the solid residue was recrystallized from benzenefpetroleum ether (30—60' C).
`Yield: 1.37 g (40%).
`mp 123-124°C.
`‘H NMFl(DM3O-ds):15 1.12 (s. 9H) . 1.27 (d.J = 7.1 Hz. 3H).
`4.23-4.42 (m, 1H), 4.31 (d.J = 5.4 Hz. 2H). 7.23-7.30
`(m.5H),7.38(d.J = 7.4 Hz. 11-1). 8.26 (t.J = 5.5 Hz.
`11-1).
`“*0 NMR (DMSO-da): 18.1. 27.2 (3C) . 37.9. 42.0. 48.4, 126.6.
`127.0 (20) , 128.2 (20) . 139.4. 172.5. 177.1 ppm.
`IR (KBr) : 3300. 3035, 1645. 1530. 1455. 1250. 745. 695 cm“.
`
`Elemental analysis
`
`Calculated for C
`
`15H22N2°2
`
`Found
`
`68.66% C;
`
`8.47% H:"10-53% N-
`
`68.91% C.’
`
`8.l4% H; 10.61% N.
`
`Preparation of N-Acety|-D.L-methionine—N-benzylamide.
`
`N-Acetyl-D.L-methionine (4.78 g. 25 mmol) was combined with acetonitrile (75 mL) and the mixture was
`placed into an ice/salt water bath (-5' C). Triethylamine (2.53 g. 3.48 mL. 25 mmol) was added dropwise.
`followed by ethyl chloroformate (2.71 g. 2.39 mL. 25 mmol). All additions were done slowly so that the
`temperature of the mixture did not rise above 0' —C. The mixture was then stirred at -5'0 (20 min).
`Benzylamine (3.00 g. 3.06 mL. 28 mmol) in acetonitrile (5 mL) was added dropwise and the mixture was
`stirred at -5° C (1 h) and then room temperature (18 h).
`The mixture was filtered and a white precipitate was collected and dried in vacuo and idenlilied as the
`desired product (‘H NMH and ‘3C NMH analyses). The filtrate was concentrafiad in vacuo and the residue
`was combined with hot tetrahydrofuran (50 mL) and cooled in the freezer (3 h). resulting in the formation of
`a white precipitate. The mixture was filtered and the precipitate was collected, dried in vacuo, and identified
`as triethylammonium hydrochloride (lit. mp5 254' C).
`_
`The latter filtrate containing tetrahydroluran was concentrated in vacuo and the resulting residue was
`pun'fied by flash column chromatography (ethyl acetate). A white_solid (Ft.
`0.50. ethyl acetate) was
`isolated and was 1
`identified as the desired product
`(‘H NMF-l and “C NMR analyses). The two solids
`identified
`as N-acetyl-D.Lmethionlne-N-benzylamide were
`combined
`and
`recrystallized
`from
`benzene/petroleum ether (30-60°C). Yield: 2.98 g (43%).
`mp 134-135' C.
`‘H NMFI (OM30-Cl1;)I¢5' 1.69-1.94 (m, 21-1) , 1.3715. 31-1) , 2.02 (5.
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`3H) , 2.29-2.59 (m, 2H) , 4.10-4.53 (m, 11-1) , 4.29 (d,J =
`6.0 Hz, 2H) , 7.26 (s, 5H) , 3.12 (d,J = 3.5 Hz, 1H) , 6.47
`(1.3 = 6.0 Hz, 1H).
`"31: NMR omso-us): 14.6. 22.5, 29.7, 31.9, 42.0, 52.0,
`126.6, 127.0 (2c) , 129.2 (20) , 139.4, 169.5. 171.4 ppm.
`IR (KBr): 3290, 1630, 1545, 1395, 1290, 750, 700 cm—‘.
`
`Elemental analysis
`
`Calculated for C14H20t\12O2S
`Found
`
`59.96% C;
`
`7.20% H; 9.99% N.
`
`60.02% C;
`
`7.14% H; 9.91% N.
`
`Preparation of N-Acetyl-alanine-N‘-3-fluoro-benzylamide.
`
`N-Acetyl-alanine (3.28 9, 25 mmol) was combined with acetonitrile (100 mL) and the mixture was placed
`into an ice/salt bat;h at -5° C. Triethylamine (2.53 g, 3.5 mL, 25 mmol) was added dropwise followed by the
`addition of ethyl chloroformate (2.71 g, 2.40 mL, 25 mmol). All additions were done slowly so that the
`temperature of the mixture did not rise above 0° C. The mixture was then stirred at -5' C for 20 minutes. 3-
`Fluoro-benzylamine (3.58 g. 28 mmol, 5 mL) and acetonitrile was added dropwise and was stirred at -5' C
`for one hour and then at room temperature for 18 hours. The reaction became homogenous during this time
`interval.
`
`The solution was concentrated in vacuo and the residue was combined with hot tetrahydroluran (100
`mL) and cooled in the freezer for 3 hours resulting in the formation of a white precipitate. The mixture was
`fittered and the precipitate was collected, dried in vacuo and identified as ethylamnonium hydrochloride
`(3.51 g, mp 253-257'C). The filtrate was concfintrated in vacuo and the resulting yellow solid was
`recrystallized from chloroformldiethyl ether.
`Yield: 3.22 g (54%).
`mp 120-121 ° c.
`‘H NMR (DMSO-dg): 5 1.27 (d,J = 7.1 Hz, 3H), 1.90 (s. H).
`4.23-4.41 (m,1H),4.33(d,J = 6.1 Hz. 2H), 7.05-7.37
`(m, 4H), 8.19 (d,J = 7.1 Hz, 1H), 8.53 (t.J = 6.1 Hz.
`1H).
`'30 NMFl (DMSO-dc): 17.9. 22.4, 41.5, 43.5, 113.3 (d,J = 24.4
`Hz), 113.5 (d,J = 21.7 Hz). 122.8, 130.1 (d,J = 7.9 Hz).
`142.4 (d,J = 7.4 Hz), 182.3 (d,J = 243.6 Hz), 169.6,
`172.8.
`
`IR (KBr): 3280, 1645, 1545. 1450, 745. 680. Mass spectrum, mle (relative intensity) : 238 (18) . 151 (22).
`124 (49) , 114 (47) , 109 (100) , 87 (76) 72 (27).
`
`Elemental analysis
`Calculated
`
`Found
`
`68.40% C;
`
`5.30% H;
`
`11.76% N.
`
`60.55% C;
`
`6.32% H;
`
`11.71% N.
`
`50
`
`Pharmacology. The following compounds were tested for anticonvulsant activity using male Carworth
`Farms #1 mice:
`
`55
`
`N-Acetyl-D,L-alanine—N'-benzylamide
`N—Aoetyl-D,L-phenylglycine-N‘-methylamide
`N—Acety|glycine-N-benzylamide
`N-Acetyl-D.L-valine-N-benzylamide
`N-Acetyl-D,L-phenylglycine-N-benzylamide
`N~Acetyl-D,L-alanine-N—(3-methoxy)-benzylamide
`N-Trimeth