Europfiisches Patentamt
`
`European Patent Office
`
`69 Publication number:
`
`Office européen des brevets
`
`0 263 506
`
`A2
`
`EUROPEAN PATENT APPLICATION
`
`9 6
`
`9
`
`@ Application number: 871146233
`
`@ Date of filing: 07.10.87 A
`
`@ lnt. cm; A61 K 31/16 , A61 K 37/02 ,
`A61K 31/38 , A61K 31/34 ,
`//C0701 03/50
`
`@ Priority: 07.10.86 us 915254
`31.07.87 us 80528
`
`@ Date of publication of application:
`13.04.88 Bulletin 88/15
`
`Designated Contracting States:
`ATBECH DEESFRGBGRITLI LU NLSE
`
`® Applicant: Research Corporation
`Technologies, Inc.
`suite 853 25 Broadway
`New York New York(US)
`
`Inventor: Kohn, Harold L
`3735 Latma Drive
`
`Houston Texas(US)
`inventor: Watson, Darrell
`801 N. Pearl
`
`Belton Texas(US)
`
`Representative: Brauns, Hans-Adolf, Dr. rer.
`nat. et al
`Hoffmann. Eitle 8: Partner, Patentanwalte
`Arabellastrasse 4
`
`D-8000 Munich 81 (DE)
`
`® Ahttconvuisant composition containing amino acid derivative and use of said amino acid
`derivative.
`
`@ The present invention relates to an anticonvulsant composition comprising a compound of the formula:
`
`R
`
`1
`
`C Ho
`
`n.
`
`R
`l2
`H
`R-N-[C-C-NH]
`ll
`0
`
`IR
`
`3
`
`EP0263506A2
`
`together with a
`where Fl, R1. R2 and R3 and n are as defined in claim 1 as effective ingredient.
`pharmaceutically acceptable carrier, said composition being useful in the treatment of epilepsy and other
`CNS disorders, and the use of the above effective ingredient
`in the preparation of an anticonvulsant
`medicament.
`
`Xerox Copy Centre
`
`EXHIBIT
`ACTAVIS. AMNEAL.
`AUROBINDO.
`BRECKENRIDGE.
`VENNOOT.
`SANDOZ. SUN
`IPR20l4-01126-1023 p. 1
`
`IPR2014-01126-1023 p. 1
`
`

`
`O 263 506
`
`ANTICONVULSANT COMPOSITION CONTAINING AMINO’ ACID DERIVATIVE AND USE OF SAID AMINO
`ACID DERIVATIVE
`
`The present invention relates to compounds having central nervous system (CNS) activity which are
`useful
`in the treatment of epilepsy and other CNS disorders. More specifically. the compounds of this
`invention can be characterized as protected amino acid derivatives having the following general formula:
`
`1.12
`R—1\lH C-CNH C—R
`r
`{ll
`}I‘»u
`CR3
`0
`
`1
`
`I
`
`I
`
`I
`
`wherein R and R1, independently. are hydrogen, lower alkyl, lower alkenyl, lower alkynyl. aryl lower alkyl.
`aryl, heterocyclic, lower alkyl heterocyclic, polynuclear aromatic, or lower alkyl polynuclear aromatic, each
`unsubstituted or substituted with at least one substituent;
`Hz and Fls, independently, are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl,
`heterocyclic,
`lower alkyl heterocyclic, polynuclear aromatic or lower alkyl polynuclear aromatic. each
`unsubstituted or substituted with at least one substituent, halogen or a heteroatom containing oxygen.
`nitrogen, sulfur or phosphorous substituted with hydrogen, lower alkyl or aryl, said lower alkyl or aryl groups
`being substituted or unsubstituted: and
`n is 1 to 4.
`
`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 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
`paramethadione, are used in the treatment of nonconvulsive seizures. Phenacemide. a phenyl-acetylurea, is
`one of the most well known anticonvulsants employed today, while 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 esterified diazepine derivatives useful in the treatment of epilepsy
`and other nervous disorders. US. 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. US. Patent No.
`4,209,516 to Heckendorn. et al. relates to triazole derivatives which exhibit anticonvulsant activity and are
`useful in the treatment of epilepsy and conditions of tension and agitation. US. 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 amine 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.
`The present invention relates to compounds of the following general formula:
`
`IPR2014-01126-1023 o. 2
`
`IPR2014-01126-1023 p. 2
`
`

`
`O 263 506
`
`C
`R NH CEEIH
`3-nll R1
`{ill
`(I )
`._.O
`CR3
`lower alkyl,
`lower alkenyl, lower alkynyl. aryl
`lower alkyl.
`wherein Fl and R1. independently. are hydrogen,
`aryl, heterocyclic.
`lower alkyl heterocyclic. polynuclear aromatic or lower alkyl polynuclear aromatic. each
`unsubstituted or substituted with at least one substituent;
`R2 and Fig. independently, are hydrogen. lower alkyl, lower alkenyl. lower alkynyl. aryl lower alkyl. aryl.
`heterocyclic.
`lower alkyl heterocyclic, polynuclear aromatic or
`lower alkyl polynuclear aromatic. each
`unsubstituted or substituted with at
`least one substituent. halogen or a heteroatom containing oxygen.
`nitrogen. sulfur or phosphorous substituted with hydrogen. lower alkyl or aryl, said lower alkyl or aryl groups
`being substituted or unsubstituted: and
`n is 1 to 4.
`
`in compositions of
`invention contemplates employing the compounds of. Formula I
`The present
`pharmaceutically 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 treatment of epilepsy. nervous anxiety. psychosis. insomnia
`and other related central nervous system disorders.
`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. hexyl, and the like.
`The aryl groups of R. R1, R2 and R3 are aromatic compounds containing from 6 to 10 ring carbon atoms;
`and include phenyl. a-and ,6-naphthyl. Moreover. the aryl groups also include organometallic compounds
`wherein a metal or metalloidal atom is sandwiched between two aromatic compounds, e.g.. cyclopendienyl
`compounds. Ferrocene is an example of this latter class of compounds.
`The ‘ aryl
`lower alkyl groups include.
`for example. benzyl. phenethyl, phenpropyl. phenisopropyl.
`phenbutyl and the like, diphenylmethyl. 1,1-diphenylethyl. 1,2-diphenylethyl, and the like.
`.
`The lower alkenyl and lower alkynyl groups contain from 2 to 6 carbon atoms and may be straight chain
`or branched.
`
`lower alkenyl and lower alkynyl are vinyl.
`i.e..
`the unsaturated alkyl substituents.
`Exemplary of
`acetylenic. allyl. propenyl, butenyl. pentenyl. hexenyl. propynyl. butynl. pentynyl, hexynyl. pentadienyl. and
`the like.
`i
`
`The heterocyclic substituents contemplated by the present invention are N, O or S containing rings
`which may be monocyclic or bicyclic or tricyclic and which may contain up to 4 heteroatoms in the rings
`and which may contain up to 13 ring carbon atoms and up to a total of 18 carbon atoms. These
`heterocyclic substituents include heteroaromatics and saturated and partially unsaturated heterocyclic
`compounds such as furyl.
`thienyl. pyranyl. pyrrolyl.
`imidazoyl. pyrazolyl, pyridyl. pyrazinyl. pyrimidyl.
`pyridazinyl.
`indolyl.
`thiazolyl. oxazolyl.
`isothiazolyl,
`isoxazolyl, piperidyl. pyrrolinyl. piperazinyl. quinolyl.
`trizaolyl. tetrazolyl, and the like.
`The polynuclear aromatic substituents contemplated herein are polyaromatic compounds containing up
`to 4 fused rings and containing up to 18 ring carbon atoms. for example. naphthyl, anthracenyl, phenanth-
`renyl, azulenyl and the like.
`The heteroafom containing substituents include. for example. methoxy. ethoxy. phenoxy. thiomethoxy.
`thioethoxy,
`thiophenoxy. methylamino, ethylamino. aniline‘, dimethylamino, trimethylamino. fluoro. chloro.
`bromo. iodo, and the like.
`The aryl groups such as phenyl. ferrocenyl. and the like, the alkyl groups, the aryl lower alkyl groups.
`the lower alkenyl group. the lower alkynyl groups and heterocyclic.
`lower alkyl heterocyclic. polynuclear
`aromatic, and lower alkyl polynuclear aromatic may carry one or more substituents which can be
`characterized as either electron withdrawing groups such as halo. including bromo. fluoro. chloro. iodo. and
`the like, nitro, acyl. carboxyl. carboalkoxy, carboxamide. cyano. sulfonyl, sulfoxide. heterocyclic, guanidine.
`quaternary ammonfiim, and the like: or as electron donating groups such as hydroxy. alkoxy including
`methoxy. ethoxy. and the like. alkyl, amino. substituted amino. phenoxy. substituted phenoxy. thiol, sulfide.
`disulfide. and the like. One skilled in the art will appreciate that the aforesaid substituents may have electron
`donating or electron withdrawing properties under different chemical conditions. Moreover,
`the present
`invention contemplates any combination of substituents selected from the above—detined groups.
`
`IPR2014-01126-1023 p.
`
`‘
`
`IPR2014-01126-1023 p. 3
`
`

`
`0 263 S06
`
`Preferred compounds of the present invention have the following general formula:
`
`R-
`it
`CH NHc—cNHc—R,
`2
`u
`l
`n
`4
`01-130
`
`wherein R: is H or lower alkyl, R2 and R3 are as defined above and A is one to three substituents selected
`from the above-defined groups.
`The alkyl groups of Hi can be unsubstituted or substituted with one or more substituents which can be
`characterized as either electron withdrawing groups or electron donating groups as defined above.
`The alkyl groups of R2 and R3, including the alkyl portion of the aryl alkyl, or the alkyl heterocyclic and
`alkyl polynuclear aromatic groups, or the alkyl or aryl groups of the heteroatom containing substituents. as
`well as the alkenyl, alkynyl. aryl. heterocyclic and polynuclear aromatic groups of R2 and Fig. may also be
`unsubstituted or substituted with one or more substituents which can be characterized as either electron
`withdrawing groups or electron donating groups as defined above.
`The preferred compounds of the present invention are those where n is 1 but di, tri-and tetra-peptides
`are acceptable.
`"
`The compounds of the present invention may contain one (1 )V 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
`including mixtures of the stereoisomeric forms.
`The following three schemes of preparation are generally exemplary of the process which can be
`employed for the preparation of the present complex:
`
`IPR2014-01126-1023 p. 4
`
`IPR2014-01126-1023 p. 4
`
`

`
`0263506
`
`excess
`
`on
`11:2
`R-NE—C—$—NH,
`R3
`
`0 R
`u
`:2
`RHK-C-E-NH-E-R
`R3
`0
`
`Scheme II
`
`R
`I2
`HOOC—?-NH
`R3
`
`'
`
`"
`
`_'
`
`O
`ll
`3
`-NH—CR1
`3
`
`‘R
`ClCOEt
`
`Et3N
`
`o
`o R
`n
`u
`I2
`RNH-C-—Cl1—-NHCR1
`3
`R
`
`/
`
`‘
`
`'
`
`0
`O O R
`[2
`n
`n
`n
`EtOCOC—C‘1-NH-CR1
`R
`3
`
`+
`
`C02 + EtOH
`
`IPR2014-01126-1023 p.'5 _
`
`IPR2014-01126-1023 p. 5
`
`

`
`or 263 506
`
`Scheme III
`
`CH0
`0
`00
`l
`I!
`II
`II H
`R1 REE-C-CC}-I
`R2CCOH
`as .
`
`0
`022,0
`ll
`-l
`-sn
`R, c1<H—c——c:<HR
`
`F
`
`_
`
`o ' OR.O
`ll __
`l
`--u
`R c-.\.-z—<l:——cop.4
`R2
`
`R1CNH-C-CNI-IR
`.l
`R2
`
`these compounds can be prepared by art-recognized procedures from known
`More specifically,
`compounds or readily preparable intermediates. For instance, compounds of Formula I can be prepared by
`reacting amines of Formula ll with an acylating derivative of a carboxylic acid of Formula Ill under amide
`forming conditions:
`
`a
`on
`12
`ll
`I25
`3
`R - Ni-c-c—N«]-—c-c-NH2
`
`+
`
`o
`u
`Rl—C-OH'——}
`
`I
`
`R3
`
`II»
`
`wherein R. R1. R2. Fla are as defined hereinabove.
`
`Alternatively, the compound of Formula I can be prepared by reacting an amine of Formula IV with an
`acylating derivative of a carboxylic acid of Formula V under amide forming conditions:
`
`RNH
`
`0.
`OR
`R
`ll
`H nlzfé
`:3
`2+HOOC-C - N-[C-C—N]— c —- R ————————)
`I
`I
`1
`.R n—l
`R2
`3
`
`‘ v
`
`Iv
`
`I
`
`55
`
`wherein R. R1. R2 and R3 are as defined hereinabove.
`Another useful method for preparing a compound of Formula l involves simple substitution reactions.
`An exemplary procedure is as follows:
`
`.a
`
`BAD ORIGINAL Q
`
`IPR2014-01126-1023 u
`
`.
`
`IPR2014-01126-1023 p. 6
`
`

`
`O 263 506
`
`H
`
`L'O
`O
`l
`H
`ll
`R1 - C—[N-C-C—]NHR + R3 — L——————+ I
`I
`n
`R
`
`VI
`
`2
`
`VII
`
`wherein R, R1, R2 R4 and n have the aforesaid meanings and R3 is defined heretofore except it is not aryl,
`heteroaromatic or polynuclear aromatic and L and L’ are independently a good leaving group. such as
`halide. tosylates, mesoylates. brosylaies, benzyloxy and the like. In this procedure the amine of Formula VI
`is reacted with a compound of Formula Vll under substitution conditions. The reaction may take place in the
`presence of an acid, such as inorganic acid. e.g., hydrochloric acid, sulfuric acid or Lewis acid, such as
`boron trifluoride and the like or in the presence of a base, such as triethylamine.
`In the procedure
`However. when R: is heteroaromatic. aryl or polynuclear aromatic, L is hydrogen.
`under these circumstances. the reaction should take place in the presence of an acid catalyst, such as an
`inorganic acid, e.g., hydrochloric acid or a Lewis acid, such as borontrifluoride.
`The amide forming conditions referred to herein involve the use of known derivatives of the described
`acids, such as the acylhalides, (e.g., R-% -X,
`0
`wherein X is Cl. Br, and the like). anhydrides
`
`O
`H
`
`O
`H
`
`(e~gof R
`
`1
`
`I
`
`mixed anhydrides. lower alkyl esters, carbodiimides. carbonyldiimidazoles. and the like. It is preferred that
`the acylating derivative used is the anhydride.
`
`o
`0
`M
`H
`l—c—o—c«Rl.
`
`R
`
`As in any organic reaction. solvents can be employed such as methanol. ethanol, propanol. acetone.
`tetrahydrofuran. dioxane. dimethylformamide, dichloromethane, chloroform, and the like. The reaction is
`normally effected at or near room temperature. although temperatures from 0°C up to the reflux tempera-
`ture 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.. triethylamine, pyridine. picolines and the like, particularly where hydrogen
`halide is formed by the amide forming reaction, e.g.. acyl halide and the amine of Formula ll. Of course, in
`those reactions where hydrogen halide is produced. any of the commonly used hydrogen halide acceptors
`can also be used.
`
`The exact mineral acid or Lewis acid employed in the reaction will vary depending on the given
`transformation. the temperature required for the conversion and the sensitivity of the reagent toward the
`acid in the reaction employed.
`The various ‘substituents on the present new compounds, e.g., as defined in Ft, R1. R2 and Fla can be
`present in the starting compounds, added to any one of the intennediates or added after 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. Alkanoyl
`groups can be substituted onto the aryl groups by Friedel-Crafts acylation. The acyl groups can be then
`transformed to the corresponding alkyl groups by various methods, including the Wolff-Kishner reduction
`and Clemmenson reduction. Amino groups can be alkylated to form mono. dialkylamino and trialkylamino
`groups; and mercapto and hydroxy groups can be alkylated to form corresponding thioethers or ethers,
`respectively. 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.
`
`'
`
`IPR2014-01126-1023 p. 7
`
`IPR2014-01126-1023 p. 7
`
`

`
`0 263 506
`
`In the above reactions, if the substituents themselves are reactive. than 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 & Sons, 1981.
`The present compounds obviously exist in stereoisomeric forms and the products obtained thus can be
`mixtures of the isomers, which can be resolved. Altemativeiy, by selection of specific isomers as starting
`compounds or synthetic intermediates, 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 about 10 mg to about
`100 mg per kilogram of body weight per day. A preferred dosage regimen for optimum results would be
`from about 20 mg to about 50 mg per kilogram of body weight per day, and such dosage units are
`employed that a total of from about 1.0 gram to about 3.0 grams of the active compound for a subject of
`about 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 one to three times a day in
`dosages of about 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), intramuscular, or subcutaneous routes.
`The active compound may be orally administered, for example, with an inert diluent or with an
`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, wafers. and the like. Such composi-
`tions 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 about 80% 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 about 5 and 1000 mg of active
`compound.
`The tablets, troches, pills, capsules and the like 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, alginic acid and the like; 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 carrier. 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
`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 pharmaceutically
`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 pharmaceutical 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 of 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, and the like), suitable mixtures thereof. and vegetable oils. The proper
`fluidity 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,
`
`IPR2014-01126-1023 p. 8
`
`

`
`O 263 506
`
`in many cases. it will be preferable to include
`chlorobutanol, phenol, sorbic acid. thimerosal. and the like.
`isotonic agents. for example. sugars or sodium chloride. Prolonged absorption of the injectable composi-
`tions 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 A
`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
`injectable 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 antitungal agents, isotonic and absorption delaying agents. and the like. 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
`compositions is contemplated. Supplementary active ingredients can also be incorporated into the composi-
`tions.
`
`is especially advantageous to formulate parenteral compositions in dosage unit form for ease of
`it
`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 about
`5 to about 1000 mg, with from about 250 to about 750 mg being preferred. Expressed in proportions, the
`active compound is generally present in from about 10 to about 750 mg/ml 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 1
`
`General Methods.
`
`Melting points were determined with a Thomas-Hoover melting point apparatus and are uncorrected.
`Infrared spectra (lFi) were run on a Beckman lFi-4250 and Perkin-Elmer 1330 spectrophotometer and
`calibrated against the 1601~cm" band of polystyrene. Absorption values are expressed in wave numbers
`(cm"). Proton nuclear magnetic resonance (‘H NMR) spectra were recorded on Varian Associates Models
`T-60 and FT-80A, and Nicolet NT-300 NMR spectrometers: Carbon nuclear magnetic resonance (“*0 NMR)
`spectra were run on a Varian Associates Models FT-80A and Nicolet NT-300 instrument. Chemical shifts
`are in parts per million (5 values) relative to Me4Si. 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 and a Bell-Howell 21-491 spectrometer. High-resolution (El mode) mass spectra were
`performed by Drs. James Hudson and John Chinn 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. In particular. acetonitrile and triethylamine were distilled from CaH2, while dichloromethane was
`distilled from P205. Acetic anhydride. benzaldehyde and ethyl chloroformate were fractionally distilled.
`
`IPR2014-01126-1023 p. 9
`
`IPR2014-01126-1023 p. 9
`
`

`
`D 263 506
`
`Preparation g N-Acetyl-D,L-alanine-N’-benzylamide.
`
`Acetic anhydride (2.20 g, 0.022 mol) was slowly added to a methylene chloridesolution (30 mL) of D,L-
`alanine-N-benzylamide (3.80 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 NaOHe(15 mL) and H20 (15 mL), dried (Na2SO.)
`and concentrated in vacuo. The residue was recrystallized from CH2Cl2. Yield: 2.50 g (54%).
`mp 139-141 "C.
`-
`‘H NMR (DMSO-ds): 5 122 (d,J = 7.1 Hz, 3H), 1.84 (s. 3H), 4.04»4.50 (m, 3H), 726 (s, 5H), 8.11 (br d,J =
`7.3 Hz, 1H), 8.42 (br t,J = 6 Hz, 1H).
`“C NMR (DMSO-ds): 18.2, 22.4, 41.9, 48.2, 126.5, 126.9, 128.1, 139.4, 168.9, 172.4 ppm.
`lR (CHClg) 3440, 3300, 3005, 1660, 1515 cm“.
`Mass spectrum (Cl mode), mle: 221 (P+1); mol wt 220.1208 (Calculated for C12H1aN-202, 220.1212).
`
`Preparation 91‘ N-Acetyl-D-and L-amino acid-N-benzylamides.
`
`General Procedure. The D-or L-amino acid amide (11 mmol) was dissolved in dichloromethane (15 mL)
`and then acetic anhydride (1.23 g, 1.40 mL, 12 mmol) was added dropwise. The solution was stirred at
`room temperature (18 h) and then concentrated to dryness. The residue was recrystallized from
`chloroform/hexane.
`
`N—Acetyl-D-alanine-N‘-bengylamide. Yield: 1.36 g (56%).
`mp 139-141 ‘C.
`[a] ,7,-3
`= +362 (c 2.5. MeOH).
`‘H NMR (30 MHz, DMSO-de):51.25(d,J = 7.1 Hz, 3H), 1.86 (s, 3H), 4.10450 (m, 1H), 4.30 (d,J = 8.0 Hz,
`2H), 7.26 (s. 5H), 3.09 (d,J = 7.3 Hz, 1H), 3.40 (t,J = 6.0 Hz, 11-1).
`we NMR (80 MHz, DMSO-da): 13.3, 22.5. 42.0, 43.4, 126.6, 127.0 (2C), 128.2 (ac), 139.4, 169.2, 172.5 ppm.
`IR (KBr): 3290, 1635 (br), 1540, 1455. 700, 695 cm".
`Mass spectrum, mle (relative intensity): 221 (30), 114 (20). 106 (40), 91 (80), 87 (100). T7 (5), 72 (20), 65 '
`(5).
`Elemental analysis
`Calculated for Ct2H1sN202 65.42% C; 7.34% H; 12.72% N.
`Found
`65.31% C; 7.28% H; 12.63% N.
`
`N-Acetyl-L-alanine~N’-benzylamide. Weld: 1.11 g (46%).
`mp 139-142°C.
`[:1] 33 = -35.3 (c 2.5, MeOH).
`‘H NMR (80 MHz, DMSO-ds): 5 1.23 (d,J = 7.2 Hz. 3H), 1.86 (s, 3H), 4.26-4.35 (m, 1H), 4.29 (d,J = 5.8 Hz,
`2H), 7.22-7.33 (s, 5H), 8.10 (d,J = 7.4 Hz, 1H), 8.42 (t,J = 5.8 Hz, 1H).
`13C NMR (80 MHz, DMSO—da): 18.3, 22.6, 42.0, 48.4, 126.7, 127.0 (2C), 128.3 (2C), 139.5, 169.2, 172.6
`ppm
`.
`IR (KBr): 3290, 1635 (br), 1545, 1450, 700, 695 cm“-.
`Mass spectrum, "mle (relative intensity): 221 (40), 114 (40), 106 (80), 106 (80), 91 (75), 87 (100), 77 (5). 72
`(15), 65 (5).
`'
`Elemental analysis
`Calculated for C12H1sN2O2 65.42% C; 7.34% H; 12.72% N.
`Found
`65.58% C; 7.32% H; 12.43% N.
`
`Preparation o_f N-Ace§yl~D.L-Ehenylglycine-N'—methylamide.
`
`Acetic anhydride (2.90 g, 28 mmol) was added dropwise to D,L—phenylgIycine-N-methylamide (3.4 g, 20
`mmol) and allowed to stir at room temperature (1.5 h). During this time, a copious white precipitate formed.
`This material was collected by filtration, dried in vacuo and recrystallized from absolute alcohol. Yield: 2.00
`g (49%).
`
`IPR2014-01126-102-3 p. 10
`
`IPR2014-01126-1023 p. 10
`
`

`
`0 263 506
`
`_
`mp 232-235°C (dec).
`‘H NMR (DMSO-da): 8 1.89 (s. 3H), 2.58 (d.J = 4.6 Hz. 3H), 5.42.(d..J = 8.1 Hz. 1H), 7.35 (s. 5H), 8.18 (br
`q.J = 4.2 Hz. 1H). 8.47 (d.J = 8.1 Hz. 1H).
`13C NMR (DMSO-da): 22.4. 25.5. 56.3, 127.1. 127.3, 128.1. 139.0. 168.9. 170.3 ppm.
`IR (KBr): 3310. 1645 cm".
`Mass spectrum (Cl mode). m/e: 207 (P+ 1).
`Elemental analysis
`Calculated for C11H1AN2O2 64.06% C; 6.86% H; 13.58% N.
`Found
`63.79% C; 6.66% H; 13.27% N.
`
`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 g (8 91.).
`mp 140-142°C.
`1H NMR (DMSO-ds): 5 1.88 (s. 3H). 3.74 (d.J = 5.3 Hz. 2H), 4.30.(d.J = 5.1 Hz. 2H), 7.27 (s. SH). 8.37 (br
`s. 1H). 8.75 (br s. 1H).
`13C NMR (DMSO-ds): 22.5. 42.0. 42.5. 126.6. 127.1 (2C). 128.1 (2C). 139.3. 169.0. 169.6 ppm.
`IR (KBr): 3060, 1655. 1640, 1560. 1545, 1450. 1300. 740, 710 cm".
`Mass spectrum. m/e (relative intensity): 206 (3), 147 (12). 106 (100), 91 (75). 73 (50).
`Elemental analysis
`Calculated for C-.1HuN202 64.05% C; 6.86% H: 13.58% N.
`Found
`64.03% C: 6.7 % H: 13.61% N.
`
`Preparation Q‘ N-Acegyl-D.L-valine-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:
`2.35 g (86%).
`mp 192-193"C.
`‘H NMR (DMSO-d6): 8 0.83 (d.