US20050277596A1 - Novel use of peptide compounds for treating amyotrophic lateral sclerosis - Google Patents

Novel use of peptide compounds for treating amyotrophic lateral sclerosis Download PDF

Info

Publication number
US20050277596A1
US20050277596A1 US11/145,965 US14596505A US2005277596A1 US 20050277596 A1 US20050277596 A1 US 20050277596A1 US 14596505 A US14596505 A US 14596505A US 2005277596 A1 US2005277596 A1 US 2005277596A1
Authority
US
United States
Prior art keywords
lower alkyl
use according
unsubstituted
aryl
heterocyclic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/145,965
Other languages
English (en)
Inventor
Thomas Stohr
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UCB Pharma GmbH
Original Assignee
Schwarz Pharma AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schwarz Pharma AG filed Critical Schwarz Pharma AG
Priority to US11/145,965 priority Critical patent/US20050277596A1/en
Assigned to SCHWARZ PHARMA AG reassignment SCHWARZ PHARMA AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STOEHR, THOMAS
Publication of US20050277596A1 publication Critical patent/US20050277596A1/en
Priority to US12/212,864 priority patent/US7718161B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia

Definitions

  • the present invention is directed to the use of a class of peptide compounds for treating amyotrophic lateral sclerosis (ALS) and other forms of motoneuron diseases and peripheral neuropathies.
  • ALS amyotrophic lateral sclerosis
  • R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group or electron donating group;
  • R 1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with an electron donating group or an electron withdrawing
  • U.S. Pat. No. 5,773,475 also discloses additional compounds useful for treating CNS disorders. These compounds are N-benzyl-2-amino-3-methoxy-propionamide having the Formula (IIa): wherein Ar is aryl which is unsubstituted or substituted with halo; R 3 is lower alkoxy; and R 1 is methyl.
  • WO 02/074297 relates to the use of a compound according to Formula (IIa) wherein Ar is phenyl which may be substituted by at least one halo, R 3 is lower alkoxy containing 1-3 carbon atoms and R 1 is methyl for the preparation of pharmaceutical compositions useful for the treatment of allodynia related to peripheral neuropathic pain.
  • WO 02/074784 relates to the use of a compound having Formula (Ia) or/and Formula (IIa) showing antinociceptive properties for treating different types and symptoms of acute and chronic pain, especially non neuropathic inflammatory pain, e.g. rheumatoid arthritic pain or/and secondary inflammatory osteo-arthritic pain.
  • non neuropathic inflammatory pain e.g. rheumatoid arthritic pain or/and secondary inflammatory osteo-arthritic pain.
  • Amyotrophic lateral sclerosis is characterized by degeneration and loss of motoneurons in the anterior horn of the spinal cord and of the brainstem and, to a variable extent, by degeneration of the descending motor pathways within the cortico-spinal tract (Deng et al., 1993; Rothstein et al., 1995). This disorder leads to progressive muscular atrophy, weakness, paralysis and eventually death due to respiratory failure (Andersen et al., 1995). ALS occurs in both familial (FALS) and sporadic (SALS) forms. FALS accounts for 5-10% of cases, with an autosomal dominant pattern of inheritance (Gurney et al., 1994; Rosen et al., 1993).
  • SOD1 cytosolic Cu,Zn superoxide dismutase
  • mice In order to establish an animal model for familial ALS, several strains of transgenic mice that carry the human SOD1 gene have been produced. Mice overproducing wild-type human Cu,Zn SOD are clinically normal and in fact show increased resistance to oxidative stress (Yang et al., 1994). Mice producing mutant Cu,Zn SOD rapidly develop a progressive motoneuron disease that strongly resembles ALS (Gurney et al., 1994; Mohajeri et al., 1998). This phenotype occurs in mice expressing the G93A mutation as well as a glycine ⁇ arginine mutation (Gurney et al., 1994).
  • the present invention concerns the use of said compounds of Formulae (Ib) or/and (IIb) for the preparation of a pharmaceutical composition for the prevention, alleviation or/and treatment of motoneuron disorders such as ALS, progressive spinal muscular atrophies or progressive bulbar palsy, or/and peripheral neuropathies such as Guillain-Barré Syndrome or Charcot-Marie-Tooth Syndrome.
  • motoneuron disorders such as ALS, progressive spinal muscular atrophies or progressive bulbar palsy, or/and peripheral neuropathies such as Guillain-Barré Syndrome or Charcot-Marie-Tooth Syndrome.
  • a compound according to the invention has the general Formula (Ib) wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocyclic, heterocyclic lower alkyl, lower alkyl heterocyclic, lower cycloalkyl or lower cycloalkyl lower alkyl, and R is unsubstituted or is substituted with at least one electron withdrawing group, and/or at least one electron donating group; R 1 is hydrogen or lower alkyl, lower alkenyl, lower alkynyl, aryl lower alkyl, aryl, heterocyclic lower alkyl, lower alkyl heterocyclic, heterocyclic, lower cycloalkyl, lower cycloalkyl lower alkyl, each unsubstituted or substituted with at least one electron donating group and/or at least one electron withdrawing group; and R 2 and R 3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkynyl
  • the compound according has the general Formula (IIb) wherein Ar is aryl, especially phenyl, which is unsubstituted or substituted with at least one halo; R 3 is —CH 2 -Q, wherein Q is lower alkoxy; and R 1 is lower alkyl, especially methyl.
  • the present invention is also directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to Formula (Ib) or/and Formula (IIb) useful for the prevention, alleviation or/and treatment of motoneuron disorders or/and peripheral neuropathies.
  • lower alkyl groups when used alone or in combination with other groups, are lower alkyl containing from 1 to 6 carbon atoms, especially 1 to 3 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.
  • lower alkoxy groups are lower alkoxy containing from 1 to 6 carbon atoms, especially 1 to 3 carbon atoms, and may be straight chain or branched. These groups include methoxy, ethoxy, propoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • aryl lower alkyl groups include, for example, benzyl, phenylethyl, phenylpropyl, phenylisopropyl, phenylbutyl, diphenylmethyl, 1,1-diphenylethyl, 1,2-diphenylethyl, and the like.
  • aryl when used alone or in combination, refers to an aromatic group which contains from 6 up to 18 ring carbon atoms and up to a total of 25 carbon atoms and includes the polynuclear aromatics. These aryl groups may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings.
  • a polynuclear aromatic compound as used herein, is meant to encompass bicyclic and tricyclic fused aromatic ring systems containing from 10-18 ring carbon atoms and up to a total of 25 carbon atoms.
  • the aryl group includes phenyl, and the polynuclear aromatics e.g., naphthyl, anthracenyl, phenanthrenyl, azulenyl and the like.
  • the aryl group also includes groups like ferrocenyl.
  • Aryl groups may be unsubstituted or mono or polysubstituted with electron withdrawing or/and electron donating groups as described below.
  • “Lower alkenyl” is an alkenyl group containing from 2 to 6 carbon atoms and at least one double bond. These groups may be straight chained or branched and may be in the Z or E form. Such groups include vinyl, propenyl, 1-butenyl, isobutenyl, 2-butenyl, 1-pentenyl, (Z)-2-pentenyl, (E)-2-pentenyl, (Z)-4-methyl-2-pentenyl, (E)-4-methyl-2-pentenyl, pentadienyl, e.g., 1, 3 or 2,4-pentadienyl, and the like.
  • lower alkynyl is an alkynyl group containing 2 to 6 carbon atoms and may be straight chained as well as branched. It includes such groups as ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl and the like.
  • lower cycloalkyl when used alone or in combination is a cycloalkyl group containing from 3 to 18 ring carbon atoms and up to a total of 25 carbon atoms.
  • the cycloalkyl groups may be monocyclic, bicyclic, tricyclic, or polycyclic and the rings are fused.
  • the cycloalkyl may be completely saturated or partially saturated.
  • Cycloalkyl includes the cis or trans forms. Cycloalkyl groups may be unsubstituted or mono or polysubstituted with electron withdrawing or/and electron donating groups as described below. Furthermore, the substituents may either be in endo or exo positions in the bridged bicyclic systems.
  • electron-withdrawing and electron donating refer to the ability of a substituent to withdraw or donate electrons, respectively, relative to that of hydrogen if the hydrogen atom occupied the same position in the molecule. These terms are well understood by one skilled in the art and are discussed in Advanced Organic Chemistry, by J. March, John Wiley and Sons, New York, N.Y., pp. 16-18 (1985) and the discussion therein is incorporated herein by reference.
  • Electron withdrawing groups include halo, including bromo, fluoro, chloro, iodo and the like; nitro, carboxy, lower alkenyl, lower alkynyl, formyl, carboxyamido, aryl, quaternary ammonium, haloalkyl such as trifluoromethyl, aryl lower alkanoyl, carbalkoxy and the like.
  • Electron donating groups include such groups as hydroxy, lower alkoxy, including methoxy, ethoxy and the like; lower alkyl, such as methyl, ethyl, and the like; amino, lower alkylamino, di(loweralkyl) amino, aryloxy such as phenoxy, mercapto, lower alkylthio, lower alkylmercapto, disulfide (lower alkyldithio) and the like.
  • substituents may be considered to be electron donating or electron withdrawing under different chemical conditions.
  • the present invention contemplates any combination of substituents selected from the above-identified groups.
  • halo includes fluoro, chloro, bromo, iodo and the like.
  • acyl includes lower alkanoyl containing from 1 to 6 carbon atoms and may be straight chains or branched. These groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, tertiary butyryl, pentanoyl and hexanoyl.
  • a heterocyclic group contains at least one sulfur, nitrogen or oxygen ring atom, but also may include several of said atoms in the ring.
  • the heterocyclic groups contemplated by the present invention include heteroaromatics and saturated and partially saturated heterocyclic compounds. These heterocyclics may be monocyclic, bicyclic, tricyclic or polycyclic and are fused rings. They may preferably contain up to 18 ring atoms and up to a total of 17 ring carbon atoms and a total of up to 25 carbon atoms.
  • the heterocyclics are also intended to include the so-called benzoheterocyclics.
  • heterocyclics include furyl, thienyl, pyrazolyl, pyrrolyl, methylpyrrolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, piperidyl, pyrrolinyl, piperazinyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, benzofuryl, benzothienyl, morpholinyl, benzoxazolyl, tetrahydrofuryl, pyranyl, indazolyl, purinyl, indolinyl, pyrazolindinyl, imidazolinyl, imadazolindinyl, pyrrolidinyl, furazanyl, N-methylindolyl, methylfuryl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridyl
  • the preferred heterocyclics are thienyl, furyl, pyrrolyl, benzofuryl, benzothienyl, indolyl, methylpyrrolyl, morpholinyl, pyridiyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl.
  • the preferred heterocyclic is a 5 or 6-membered heterocyclic compound.
  • the especially preferred heterocyclic is furyl, pyridyl, pyrazinyl, imidazolyl, pyrimidinyl, or pyridazinyl.
  • the most preferred heterocyclics are furyl and pyridyl.
  • R is aryl lower alkyl, especially benzyl especially those wherein the phenyl ring thereof is unsubstituted or substituted with electron donating groups or/and electron withdrawing groups, such as halo (e.g., F).
  • halo e.g., F
  • the preferred R 1 is H or lower alkyl.
  • the most preferred R 1 group is methyl.
  • the preferred electron donating substituents or/and electron withdrawing substituents are halo, nitro, alkanoyl, formyl, arylalkanoyl, aryloyl, carboxyl, carbalkoxy, carboxamido, cyano, sulfonyl, sulfoxide, heterocyclic, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(loweralkyl) amino, amino lower alkyl, mercapto, mercaptoalkyl, alkylthio, and alkyldithio.
  • sulfide encompasses mercapto, mercapto alkyl and alkylthio, while the term disulfide encompasses alkyldithio.
  • Especially preferred electron donating or/and electron withdrawing groups are halo or lower alkoxy, most preferred are fluoro or methoxy. These preferred substituents may be present on any one of the groups in Formula (Ib) or/and (IIb), e.g. R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R′ 6 , R 7 , R 8 and/or R 50 as defined herein.
  • the ZY groups representative of R 2 and R 3 include hydroxy, alkoxy, such as methoxy, ethoxy, aryloxy, such as phenoxy; thioalkoxy, such as thiomethoxy, thioethoxy; thioaryloxy such as thiophenoxy; amino; alkylamino, such as methylamino, ethylamino; arylamino, such as anilino; lower dialkylamino, such as, dimethylamino; trialkyl ammonium salt, hydrazino; alkylhydrazino and arylhydrazino, such as N-methylhydrazino, N-phenylhydrazino, carbalkoxy hydrazino, aralkoxycarbonyl hydrazino, aryloxycarbonyl hydrazino, hydroxylamino, such as N-hydroxylamino (—NH—OH), lower alkoxy amino [(NHOR 18 ) wherein R 18 is
  • the preferred heterocyclic groups representative of R 2 and R 3 are monocyclic 5- or 6-membered heterocyclic moieties of the formula: or those corresponding partially or fully saturated form thereof wherein n is 0 or 1; and R 50 is H or an electron withdrawing group or electron donating group;
  • A, E, L, J and G are independently CH, or a heteroatom selected from the group consisting of N, O, S; but when n is 0, G is CH, or a heteroatom selected from the group consisting of NO, O and S with the proviso that at most two of A, E, L, J and G are heteroatoms.
  • heteroaromatic moiety When n is 0, the above heteroaromatic moiety is a five membered ring, while if n is 1, the heterocyclic moiety is a six membered monocyclic heterocyclic moiety.
  • the preferred heterocyclic moieties are those aforementioned heterocyclics which are monocyclic.
  • R 2 or R 3 When R 2 or R 3 is a heterocyclic of the above formula, it may be bonded to the main chain by a ring carbon atom. When n is 0, R 2 or R 3 may additionally be bonded to the main chain by a nitrogen ring atom.
  • R 2 and R 3 are hydrogen, aryl, e.g., phenyl, aryl alkyl, e.g., benzyl and alkyl.
  • R 2 and R 3 may be unsubstituted or mono or poly substituted with electron donating or/and electron withdrawing groups. It is preferred that R 2 and R 3 are independently hydrogen, lower alkyl, which is either unsubstituted or substituted with electron withdrawing groups or/and electron donating groups, such as lower alkoxy (e.g., methoxy, ethoxy, and the like), N-hydroxylamino, N-lower alkylhydroxyamino, N-loweralkyl-O-loweralkyl and alkylhydroxyamino.
  • lower alkoxy e.g., methoxy, ethoxy, and the like
  • R 2 and R 3 are hydrogen.
  • n is one.
  • Z is O, NR 4 or PR 4 ; Y is hydrogen or lower alkyl; ZY is NR 4 NR 5 R 7 , NR 4 OR 5 , ONR 4 R 7 ,
  • n 1
  • R 2 is hydrogen and R 3 is lower alkyl which may be substituted or unsubstituted with an electron donating or electron withdrawing group, NR 4 OR 5 , or ONR 4 R 7 .
  • n 1
  • R 2 is hydrogen and R 3 is lower alkyl which is unsubstituted or substituted with hydroxy or loweralkoxy
  • NR 4 OR 5 or ONR 4 R 7 wherein R 4 , R 5 and R 7 are independently hydrogen or lower alkyl, R is aryl lower alkyl, which aryl group may be unsubstituted or substituted with an electron withdrawing group and R 1 is lower alkyl.
  • aryl is phenyl, which is unsubstituted or substituted with halo.
  • R 2 is hydrogen and R 3 is hydrogen, an alkyl group which is unsubstituted or substituted by at least an electron donating or electron withdrawing group or ZY.
  • R 3 is hydrogen, an alkyl group such as methyl, which is unsubstituted or substituted by an electron donating group, or NR 4 O 5 or ONR 4 R 7 , wherein R 4 , R 5 and R 7 are independently hydrogen or lower alkyl.
  • the electron donating group is lower alkoxy, and especially methoxy or ethoxy.
  • R 2 and R 3 are independently hydrogen, lower alkyl, or ZY;
  • Z is O, NR 4 or PR 4 ;
  • ZY is NR 4 R 5 R 7 , NR 4 OR 5 , ONR 4 R 7 ,
  • R is aryl lower alkyl.
  • the most preferred aryl for R is phenyl.
  • the most preferred R group is benzyl.
  • the aryl group may be unsubstituted or substituted with an electron donating or electron withdrawing group. If the aryl ring in R is substituted, it is most preferred that it is substituted with an electron withdrawing group, especially on the aryl ring.
  • the most preferred electron withdrawing group for R is halo, especially fluoro.
  • the preferred R 1 is lower alkyl, especially methyl.
  • R is aryl lower alkyl and R 1 is lower alkyl.
  • R 3 is hydrogen, a lower alkyl group, especially methyl, which may be substituted by electron donating group, such as lower alkoxy, (e.g., methoxy, ethoxy and the like), NR 4 OR 5 or ONR 4 R 7 wherein these groups are defined hereinabove.
  • R 3 is as defined herein, but especially hydrogen, loweralkyl, which is unsubstituted or substituted by at least an electron donating group or electron withdrawing group or ZY. It is even more preferred that R 3 is, in this embodiment, hydrogen, an alkyl group which is unsubstituted or substituted by an electron donating group, NR 4 OR 5 or ONR 4 R 7 .
  • R 3 is CH 2 -Q, wherein Q is lower alkoxy, especially containing 1-3 carbon atoms; NR 4 OR 5 or ONR 4 R 7 wherein R 4 is hydrogen or alkyl containing 1-3 carbon atoms, R 5 is hydrogen or alkyl containing 1-3 carbon atoms, and R 7 is hydrogen or alkyl containing 1-3 carbon atoms.
  • the most preferred R 1 is CH 3 .
  • the most preferred R 3 is CH 2 -Q, wherein Q is methoxy.
  • the most preferred aryl is phenyl.
  • the most preferred halo is fluoro.
  • the most preferred compounds include:
  • R 1 may be one or more of the substituents listed hereinabove in combination with any and all of the substituents of R 2 , R 3 , and R with respect to each value of n.
  • the compounds utilized in the present invention may contain one or more asymmetric carbons and may exist in racemic and optically active forms.
  • the configuration around each asymmetric carbon can be either the D or L form. It is well known in the art that the configuration around a chiral carbon atoms can also be described as R or S in the Cahn-Prelog-Ingold nomenclature system. All of the various configurations around each asymmetric carbon, including the various enantiomers and diastereomers as well as racemic mixtures and mixtures of enantiomers, diastereomers or both are contemplated by the present invention.
  • the compounds of the present invention is of the formula wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R′ 6 , R 7 , R 8 , R 50 , Z and Y are as defined previously.
  • the term configuration shall refer to the configuration around the carbon atom to which R 2 and R 3 are attached, even though other chiral centers may be present in the molecule. Therefore, when referring to a particular configuration, such as D or L, it is to be understood to mean the D or L stereoisomer at the carbon atom to which R 2 and R 3 are attached. However, it also includes all possible enantiomers and diastereomers at other chiral centers, if any, present in the compound.
  • the compounds of the present invention are directed to all the optical isomers, i.e., the compounds of the present invention are either the L-stereoisomer or the D-stereoisomer (at the carbon atom to which R 2 and R 3 are attached). These stereoisomers may be found in mixtures of the L and D stereoisomer, e.g., racemic mixtures. The D stereoisomer is preferred.
  • R is benzyl which is unsubstituted or substituted with at least one halo group, wherein R 3 is CH 2 -Q, wherein Q is lower alkoxy containing 1-3 carbon atoms and wherein R 1 is methyl.
  • R is unsubstituted benzyl or benzyl substituted with at least one halo group which is a fluoro group.
  • 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 compounds utilized in the present invention are useful as such as depicted in the Formulae (Ib) or/and (IIb) or can be employed in the form of salts in view of its basic nature by the presence of the free amino group.
  • the compounds of Formulae (Ib) or/and (IIb) form salts with a wide variety of acids, inorganic and organic, including pharmaceutically acceptable acids.
  • the salts with therapeutically acceptable acids are of course useful in the preparation of formulation where enhanced water solubility is most advantageous.
  • These pharmaceutically acceptable salts have also therapeutic efficacy.
  • These salts include salts of inorganic acids such as hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric acid and sulfuric acids as well as salts of organic acids, such as tartaric, acetic, citric, malic, benzoic, perchloric, glycolic, gluconic, succinic, aryl sulfonic, (e.g., p-toluene sulfonic acids, benzenesulfonic), phosphoric, malonic, and the like.
  • inorganic acids such as hydrochloric, hydroiodic, hydrobromic, phosphoric, metaphosphoric, nitric acid and sulfuric acids
  • organic acids such as tartaric, acetic, citric, malic, benzoic, perchloric, glycolic, gluconic, succinic, aryl sulfonic, (e.g., p-to
  • the present invention is further directed to a method for the prevention, alleviation or/and treatment of a disease or condition as described above in a mammal, including a human being, comprising administering at least one compound of Formulae (Ib) or/and (IIb).
  • the compound utilized in the present invention is used in therapeutically effective amounts.
  • the physician will determine the dosage of the present therapeutic agents which will be most suitable and it will vary with the form of administration and the particular compound chosen, and furthermore, it will vary with the patient under treatment, the age of the patient, the type of malady being treated. He will generally wish to initiate treatment with small dosages substantially less than the optimum dose of the compound and increase the dosage by small increments until the optimum effect under the circumstances is reached. When the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally.
  • the compounds are useful in the same manner as comparable therapeutic agents and the dosage level is of the same order of magnitude as is generally employed with these other therapeutic agents.
  • the compounds of the present invention are administered in amounts ranging from about 1 mg to about 100 mg per kilogram of body weight per day, more preferred in amounts ranging from about 1 mg to about 10 mg per kilogram of body weight per day.
  • This dosage regimen may be adjusted by the physician to provide the optimum therapeutic response.
  • Patients in need thereof may be treated with doses of the compound of the present invention of at least 50 mg/day, preferably of at least 200 mg/day, more preferably of at least 300 mg/day and most preferably of at least 400 mg/day.
  • a patient in need thereof may be treated with doses at a maximum of 6 g/day, more preferably a maximum of 1 g/day and most preferably a maximum of 600 mg/day. In some cases, however, higher or lower doses may be needed.
  • the daily doses are increased until a predetermined daily dose is reached which is maintained during the further treatment.
  • several divided doses may be administered daily.
  • three doses per day may be administered, preferably two doses per day. It is more preferred to administer a single dose per day.
  • an amount of the compounds of the present invention may be administered which results in a plasma concentration of 0.1 to 15 ⁇ g/ml (trough) and 5 to 18.5 ⁇ g/ml (peak), calculated as an average over a plurality of treated subjects.
  • the compounds of Formulae (Ib) or/and (IIb) may be administered in a convenient manner, such as by oral, intravenous (where water soluble), intramuscular, intrathecal or subcutaneous routes. Oral or/and i.v. administration is preferred.
  • composition of the present invention may be prepared for the treatment regimen as described above, in particular for the treatment with doses as described above, to effect plasma concentrations as described above, for administration periods or/and administration routes as specified in the embodiments of the present invention as described above.
  • the method of the present invention as described above for the treatment of a mammal including a human being in need thereof comprises administering a compound of the present invention in combination with administering a further active agent for the prevention, alleviation or/and treatment of a motoneuron disorder or/and a peripheral neuropathy.
  • the compound of the present invention and the further active agent may be administered together, i.e. in a single dose form, or may be administered separately, i.e. in a separate dose form.
  • the pharmaceutical composition of the present invention may comprise a compound of the present invention as defined above and may further comprise a further active agent for the prevention, alleviation or/and treatment of a motoneuron disorder or/and a peripheral neuropathy.
  • the pharmaceutical composition may comprise a single dose form or may comprise a separate dose form comprising a first composition comprising a compound of the present invention as defined above and a second composition comprising the further active agent.
  • the further active agent for the prevention, alleviation or/and treatment of a motoneuron disorder or/and a peripheral neuropathy may be any suitable agent known to a person skilled in the art.
  • the compounds of the present invention may be used for the preparation of a pharmaceutical composition as described above.
  • the compounds of Formulae (Ib) or/and (IIb) 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 capsules, or it may be compressed into tablets, or it may be incorporated directly into the fool of the diet.
  • the active compound of Formulae (Ib) or/and (IIb) 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 compositions and preparations should contain at least 1% of active compound of Formulae (Ib) or/and (IIb).
  • 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 of Formulae (Ib) or/and (IIb) in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention contains between about 10 mg and 6 g active compound of Formulae (Ib) or/and (IIb).
  • 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.
  • 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
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint,
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations.
  • sustained release dosage forms are contemplated wherein the active ingredient is bound to an ion exchange resin which, optionally, can be coated with a diffusion barrier coating to modify the release properties of the resin.
  • 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.
  • 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 dispersions 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, thimerosal, and the like. In 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, aluminium 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.
  • 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.
  • the preferred methods of preparation are vacuum drying the freeze-drying technique plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agent, isotonic and absorption delaying agents for pharmaceutical active substances as 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 compositions.
  • Dosage unit form 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 specifics for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material an the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such as 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 described.
  • a unit dosage form can, for example, contain the principal active compound in amounts ranging from about 10 mg to about 6 g. Expressed in proportions, the active compound is generally present in from about 1 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.
  • patient refers to a warm blooded animal, and preferably mammals, such as, for example, cats, dogs, horses, cows, pigs, mice, rats and primates, including humans.
  • mammals such as, for example, cats, dogs, horses, cows, pigs, mice, rats and primates, including humans.
  • the preferred patient is a human.
  • treat refers to either relieving the pain associated with a disease or condition, to curing or alleviating the patient's disease or condition or to prolonging survival.
  • the compounds of the present invention are administered to a patient suffering from the aforementioned type of disorder in an effective amount. These amounts are equivalent to the therapeutically effective amounts described hereinabove.
  • SPM 927 which is the synonym for Harkoseride.
  • the standard chemical nomenclature is (R)-2-acetamide-N-benzyl-3-methoxypropionamide.
  • the international non-proprietary name of SPM 927 is lacosamide.
  • FIG. 1 shows that SPM 927 dose dependently prolongs life-span of SOD mutant mice.
  • FIG. 2 shows that SPM 927 (30 mg/kg) attenuates motor impairment (grid performance) of SOD mutant mice.
  • FIG. 3 shows that SPM 927 (10 mg/kg) attenuates motor impairment (latency of compound muscle action potential) of SOD mutant mice.
  • the present study investigates the effects of SPM 927 to protect or to reduce impairments observed in this ALS model.
  • behavioral measurements and EMGs are performed in SOD-G93A mice overexpressing mutant human Cu,Zn SOD.
  • the transgenic mouse strain used for this study is G1H (Gurney et al., 1994). The animals begin to show signs of posterior limb weakness at around 3 months of age and die at 4 months.
  • mice 40 mice are included in the study and divided into 4 groups of 10 mice.
  • mice were weighed every day. The general status of the mice was checked daily, especially for the presence of tremor, for skin aspect and for muscle wasting. EMG testing was performed once every week, starting on D70 of age until the death of the animals. The survival rate and the interval from symptom onset until death were recorded.
  • Electromyographic recordings were performed using a Neuromatic 2000M electromyography apparatus.
  • EMG the mice are anesthetized (60 mg kg-1, Imal confusing@).
  • the measured parameters are the amplitude and the latency of the compound muscle action potential (CMAP).
  • CMAP is measured in gastrocnemius muscle after stimulation of the sciatic nerve.
  • a reference electrode is inserted near the Achilles tendon and an active needle placed at the base of the tail.
  • a ground needle is inserted on the lower back of the mouse.
  • the sciatic nerve is stimulated with a single 0.2 ms pulse at supramaximal intensity (12.9 mA).
  • the amplitude (mV) and the latency of the response (ms) are measured.
  • the amplitude is indicative of the number of active motor units, while distal latency reflects motor nerve conduction velocity.
  • the animals were treated from day 60 (before the beginning of the clinical signs) until the animal's death.
  • the treatment was administered twice daily intraperitoneally.
  • a global analysis of the data was made using one factor or repeated measures analysis of variance (ANOVA).
  • the Fisher test or the Student-Newman-Keuls t test was used to allow multiple comparisons of individual test groups with a control group or between paired groups. Intra-group analysis was performed to evaluate the variation of performance within each group.
  • SPM 927 and related compounds are useful for the treatment of amyotrophic lateral sclerosis and for the treatment of other motoneuron diseases including, but not limited to, progressive spinal muscular atrophies and progressive bulbar palsy.
  • SPM 927 and related compounds are active for the treatment of peripheral neuropathies including, but not limited to, Guillain-Barré Syndrome or Charcot-Marie Tooth Syndrome.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US11/145,965 2004-06-09 2005-06-07 Novel use of peptide compounds for treating amyotrophic lateral sclerosis Abandoned US20050277596A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11/145,965 US20050277596A1 (en) 2004-06-09 2005-06-07 Novel use of peptide compounds for treating amyotrophic lateral sclerosis
US12/212,864 US7718161B2 (en) 2004-06-09 2008-09-18 Method for treating a motoneuron disorder

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US57806304P 2004-06-09 2004-06-09
EP04013636A EP1604656A1 (de) 2004-06-09 2004-06-09 Neue Verwendung von Peptidverbindungen zur Behandlung von amyotropher Lateralsklerose (ALS)
EP04013636.8 2004-06-09
US11/145,965 US20050277596A1 (en) 2004-06-09 2005-06-07 Novel use of peptide compounds for treating amyotrophic lateral sclerosis

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/212,864 Continuation US7718161B2 (en) 2004-06-09 2008-09-18 Method for treating a motoneuron disorder

Publications (1)

Publication Number Publication Date
US20050277596A1 true US20050277596A1 (en) 2005-12-15

Family

ID=34925316

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/145,965 Abandoned US20050277596A1 (en) 2004-06-09 2005-06-07 Novel use of peptide compounds for treating amyotrophic lateral sclerosis
US12/212,864 Expired - Fee Related US7718161B2 (en) 2004-06-09 2008-09-18 Method for treating a motoneuron disorder

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/212,864 Expired - Fee Related US7718161B2 (en) 2004-06-09 2008-09-18 Method for treating a motoneuron disorder

Country Status (14)

Country Link
US (2) US20050277596A1 (de)
EP (2) EP1604656A1 (de)
JP (1) JP2008501753A (de)
CN (1) CN1960720A (de)
AT (1) ATE544449T1 (de)
AU (1) AU2005251459A1 (de)
BR (1) BRPI0511875A (de)
CA (1) CA2565102A1 (de)
EA (1) EA200602220A1 (de)
MX (1) MXPA06014194A (de)
TW (1) TW200701984A (de)
UA (1) UA87843C2 (de)
WO (1) WO2005120476A2 (de)
ZA (1) ZA200608594B (de)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050288234A1 (en) * 2004-06-24 2005-12-29 Schwarz Pharma Ag Novel use of peptide compounds for treating essential tremor and other tremor syndromes
US20060046957A1 (en) * 2004-08-27 2006-03-02 Schwarz Pharma Ag Novel use of peptide compounds for treating bone cancer pain, chemotherapy-and nucleoside-induced pain
US20070043120A1 (en) * 2005-08-18 2007-02-22 Bettina Beyreuther Therapeutic combination for painful medical conditions
US20070048372A1 (en) * 2005-08-18 2007-03-01 Srz Properties, Inc. Method for treating non-inflammatory osteoarthritic pain
US20070054962A1 (en) * 2001-03-20 2007-03-08 Norma Selve Method for treating acute or chronic pain
US20070197657A1 (en) * 2005-08-18 2007-08-23 Srz Properties, Inc. Method for treating non-inflammatory musculoskeletal pain
US20090005433A1 (en) * 2006-12-14 2009-01-01 Guy A Higgins Fluorinated Compounds
US20100016403A1 (en) * 2006-12-14 2010-01-21 Guy Higgins Use of d-serine derivatives for the treatment of anxiety disorders
US20100099770A1 (en) * 2001-03-21 2010-04-22 Schwarz Pharma Ag Method for treating diabetic peripheral neuropathic pain
US7718161B2 (en) 2004-06-09 2010-05-18 Ucb Pharma Gmbh Method for treating a motoneuron disorder
US20100240576A1 (en) * 2006-06-15 2010-09-23 Thomas Stoehr Anticonvulsant combination therapy
US20100273714A1 (en) * 2006-06-15 2010-10-28 Schwarz Pharma Ag Peptide compounds for treating refractory status epilepticus
US20100324144A1 (en) * 2006-06-30 2010-12-23 Schwarz Pharma Ag Therapy for hyperexcitability disorders
US20110130350A1 (en) * 2004-10-02 2011-06-02 Ucb Pharma Gmbh Synthesis scheme for lacosamide
US8008351B2 (en) 2004-04-16 2011-08-30 Ucb Pharma Gmbh Methods for prophylaxis or treatment of conditions associated with cortical spreading depression
US10149818B2 (en) 2010-12-02 2018-12-11 Ucb Pharma Gmbh Daily formulation of lacosamide

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4664924B2 (ja) * 2003-12-02 2011-04-06 ウーツェーベー ファルマ ゲーエムベーハー 中枢神経因性疼痛の治療のためのペプチド化合物の新規使用
US20100256179A1 (en) * 2004-03-26 2010-10-07 Ucb Pharma Gmbh Combination therapy for pain in painful diabetic neuropathy
US20070042969A1 (en) * 2004-03-26 2007-02-22 Srz Properties, Inc. Combination therapy for pain in painful diabetic neuropathy
EP1579858A1 (de) * 2004-03-26 2005-09-28 Schwarz Pharma Ag Neue Verwendung von Peptidverbindungen zur Behandlung von diabetishen Neuropathie
EP1604655A1 (de) 2004-06-09 2005-12-14 Schwarz Pharma Ag Neue Verwendung von Peptidverbindungen zur Behandlung von Trigeminusneuralgie
US20060252749A1 (en) * 2005-01-28 2006-11-09 Srz Properties, Inc. Lacosamide for add-on therapy of psychosis
WO2009053070A1 (en) 2007-10-23 2009-04-30 Schwarz Pharma Ag Compounds for treating demyelination conditions
US8829033B2 (en) 2009-09-23 2014-09-09 The University Of North Carolina At Chapel Hill N-benzylamide substituted derivatives of 2-(acylamido)acetic acid and 2-(acylamido)propionic acids: potent neurological agents
WO2011101863A2 (en) 2010-02-19 2011-08-25 Cadila Healthcare Limited Extended release pharmaceutical compositions of lacosamide
AU2011335415B2 (en) 2010-12-02 2016-05-19 Ucb Pharma Gmbh Once daily formulation of lacosamide
MX2018008021A (es) 2015-12-30 2018-11-09 Adamas Pharmaceuticals Inc Metodos y composiciones para el tratamiento de trastornos relacionados con convulsiones.
US11278634B1 (en) 2021-02-12 2022-03-22 Extrovis Ag Stable parenteral composition of lacosamide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5773475A (en) * 1997-03-17 1998-06-30 Research Corporation Technologies, Inc. Anticonvulsant enantiomeric amino acid derivatives

Family Cites Families (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US227961A (en) * 1880-05-25 Envelope-fastener
US277596A (en) * 1883-05-15 Top-prop nut
US261204A (en) * 1882-07-18 Joel gadbuey
US101582A (en) * 1870-04-05 Improved refrigerator
DE2413125C2 (de) 1974-03-15 1983-06-30 Schering Ag, 1000 Berlin Und 4619 Bergkamen Indolylacetylaminosäurederivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneipräparate
DE2627069A1 (de) 1975-06-19 1977-01-20 Ajinomoto Kk Verfahren zur herstellung von substituierten schwefelhaltigen l-aminosaeuren
DE2735537A1 (de) 1977-08-06 1979-02-22 Troponwerke Gmbh & Co Kg Indolacetoxyacetylaminosaeurederivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
JPS557242A (en) 1978-06-30 1980-01-19 Tanabe Seiyaku Co Ltd Phenethylamine derivative
FR2480747A1 (fr) 1980-04-17 1981-10-23 Roques Bernard Derives d'acides amines et leur application therapeutique
FR2489319A1 (fr) 1980-08-27 1982-03-05 Clin Midy Derives de l'acide amino-4 butyrique et les medicaments, actifs notamment sur le systeme nerveux central, en contenant
DE3134933A1 (de) 1981-09-03 1983-03-31 Hoechst Ag, 6230 Frankfurt "harnstoffderivate, verfahren zu ihrer herstellung und diese enthaltende medikamente sowie deren verwendung"
US5378729A (en) 1985-02-15 1995-01-03 Research Corporation Technologies, Inc. Amino acid derivative anticonvulsant
ATE62222T1 (de) 1985-02-15 1991-04-15 Res Corp Technologies Inc Aminosaeure-derivate und ihre anwendung zur herstellung eines antikrampfmittels.
JPS61242589A (ja) 1985-04-22 1986-10-28 Mitsui Toatsu Chem Inc Ｌ−含硫アミノ酸の製造方法
PH24782A (en) 1985-10-24 1990-10-30 Sankyo Co Composition containing a penem or carbapenem antibiotic and the use of the same
NZ222045A (en) 1986-08-21 1989-10-27 Res Corp Technologies Inc From diamides up to tetrapeptides for use as anticanvulsants
CA2056911C (en) 1990-12-11 1998-09-22 Yuuichi Nagano Hiv protease inhibitors
KR950704280A (ko) 1992-12-11 1995-11-17 베르너 발데크 벤즈아제피논 유도체(Benzazepinone Derivatives)
DE19533023B4 (de) 1994-10-14 2007-05-16 Basf Ag Neue Carbonsäurederivate, ihre Herstellung und Verwendung
JP4313435B2 (ja) 1995-07-24 2009-08-12 トラスティーズ オブ ボストン ユニバーシティー プレグネノロンサルフェート誘導体によるｎｍｄａレセプター活性の抑制
DE19544687A1 (de) 1995-11-30 1997-06-05 Thomae Gmbh Dr K Aminosäurederivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung
GB9601724D0 (en) 1996-01-29 1996-03-27 Merck Sharp & Dohme Therapeutic agents
DE19614534A1 (de) 1996-04-12 1997-10-16 Basf Ag Neue Carbonsäurederivate, ihre Herstellung und Verwendung
DE19614533A1 (de) 1996-04-12 1997-10-16 Basf Ag Neue alpha-Hydroxysäurederivate, ihre Herstellung und Verwendung
US6277825B1 (en) 1996-07-22 2001-08-21 University Of Utah Research Foundation Use of conantokins for treating pain
US6126939A (en) 1996-09-03 2000-10-03 Yeda Research And Development Co. Ltd. Anti-inflammatory dipeptide and pharmaceutical composition thereof
DE19636046A1 (de) 1996-09-05 1998-03-12 Basf Ag Neue Carbonsäurederivate, ihre Herstellung und Verwendung als gemischte ET¶A¶/ET¶B¶-Rezeptorantagonisten
US6420429B1 (en) 1997-12-23 2002-07-16 Yissum Research Development Company Of The Hebrew University Of Jerusalem Brain targeted low molecular weight hydrophobic antioxidant compounds
US6048899A (en) * 1997-03-17 2000-04-11 Research Corporation Tech., Inc. Anticonvulsant enantiomeric amino acid derivatives
WO1999002146A1 (fr) 1997-07-08 1999-01-21 Ono Pharmaceutical Co., Ltd. Derives d'acide amine
DE19743142A1 (de) 1997-09-30 1999-04-01 Knoll Ag Pharmazeutische Kombinationspräparate
DE19743140A1 (de) 1997-09-30 1999-04-01 Knoll Ag Pharmazeutische Kombinationspräparate
DE19744799A1 (de) 1997-10-10 1999-04-15 Knoll Ag Pharmazeutische Kombinationspräparate
NZ504316A (en) 1997-10-31 2002-12-20 Basf Ag Pyrimidine substituted carboxylic acid derivatives which have amido side-chains useful as endothelin receptor antagonists
ES2164040T3 (es) 1998-04-14 2008-02-01 The General Hospital Corporation Uso de d-serina o de d-alanina para el tratamiento de la esquizofrenia.
GB9816228D0 (en) 1998-07-24 1998-09-23 Pfizer Ltd Isoquinolines
DE10029014A1 (de) 2000-06-15 2001-12-20 Univ Schiller Jena Urokinase-Hemmstoffe
DE10041478A1 (de) 2000-08-24 2002-03-14 Sanol Arznei Schwarz Gmbh Neue pharmazeutische Zusammensetzung
AU2002224847A1 (en) 2000-11-21 2002-06-03 U C B, S.A. N-alkylated gaba compounds, processes for their preparation and their use as medicaments
ES2262567T3 (es) * 2001-03-20 2006-12-01 Schwarz Pharma Ag Nuevo uso de una clase peptidica de compuesto para tratamiento del dolor inflamatorio no neuropatico.
ES2185606T3 (es) 2001-03-21 2003-05-01 Sanol Arznei Schwarz Gmbh Nuevo uso de una clase de compuestos peptidicos para tratamiento de la alodinia u otros tipos diferentes de dolor cronico o fantasma.
MXPA03009676A (es) 2001-04-26 2004-02-12 Bristol Myers Squibb Co CONTROL DE COMPACTIBILIDAD A TRAVeS DE CRISTALIZACION.
US7687080B2 (en) 2002-11-25 2010-03-30 Taraxos Inc. Treatment of neuropathy
DE10326303A1 (de) 2003-06-11 2004-12-30 Celares Gmbh Reagenzien zur Modifikation von Biopharmazeutika, deren Herstellung und Anwendung
US20050227961A1 (en) 2004-04-08 2005-10-13 Vela Pharmaceuticals, Inc. Compositions and methods for treatment of neuropathic pain, fibromyalgia and chronic fatigue syndrome
EP1604654A1 (de) 2004-05-18 2005-12-14 Schwarz Pharma Ag Neue Verwendung von Peptidverbindungen zur Behandlung von Dyskynesien
EP1604656A1 (de) 2004-06-09 2005-12-14 Schwarz Pharma Ag Neue Verwendung von Peptidverbindungen zur Behandlung von amyotropher Lateralsklerose (ALS)

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5773475A (en) * 1997-03-17 1998-06-30 Research Corporation Technologies, Inc. Anticonvulsant enantiomeric amino acid derivatives

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070054962A1 (en) * 2001-03-20 2007-03-08 Norma Selve Method for treating acute or chronic pain
US8053476B2 (en) 2001-03-20 2011-11-08 Ucb Pharma Gmbh Method for treating peripheral neuropathic pain
US20100099770A1 (en) * 2001-03-21 2010-04-22 Schwarz Pharma Ag Method for treating diabetic peripheral neuropathic pain
US20110082211A1 (en) * 2001-03-21 2011-04-07 Ucb Pharma Gmbh Method for treating tinnitus aureum
US8008351B2 (en) 2004-04-16 2011-08-30 Ucb Pharma Gmbh Methods for prophylaxis or treatment of conditions associated with cortical spreading depression
US7718161B2 (en) 2004-06-09 2010-05-18 Ucb Pharma Gmbh Method for treating a motoneuron disorder
US7427601B2 (en) 2004-06-24 2008-09-23 Schwarz Pharma Ag Method for treating tremor
US20050288234A1 (en) * 2004-06-24 2005-12-29 Schwarz Pharma Ag Novel use of peptide compounds for treating essential tremor and other tremor syndromes
US8536137B2 (en) 2004-08-27 2013-09-17 Ucb Pharma Gmbh Methods for treating nucleoside-induced pain
US20100029543A1 (en) * 2004-08-27 2010-02-04 Schwarz Pharma Ag Methods for treating nucleoside-induced pain
US7687553B2 (en) 2004-08-27 2010-03-30 Schwarz Pharma Ag Method for treating bone cancer pain or chemotherapy induced pain
US20060046957A1 (en) * 2004-08-27 2006-03-02 Schwarz Pharma Ag Novel use of peptide compounds for treating bone cancer pain, chemotherapy-and nucleoside-induced pain
US20110130350A1 (en) * 2004-10-02 2011-06-02 Ucb Pharma Gmbh Synthesis scheme for lacosamide
US8809585B2 (en) 2004-10-02 2014-08-19 Ucb Pharma Gmbh Synthesis scheme for lacosamide
US20080280835A1 (en) * 2005-08-18 2008-11-13 Bettina Beyreuther Novel Use of Peptide Compounds For Treating Muscle Pain
US20070197657A1 (en) * 2005-08-18 2007-08-23 Srz Properties, Inc. Method for treating non-inflammatory musculoskeletal pain
US20070043120A1 (en) * 2005-08-18 2007-02-22 Bettina Beyreuther Therapeutic combination for painful medical conditions
US20070048372A1 (en) * 2005-08-18 2007-03-01 Srz Properties, Inc. Method for treating non-inflammatory osteoarthritic pain
US9095557B2 (en) 2006-06-15 2015-08-04 Ucb Pharma Gmbh Anticonvulsant combination therapy
US20100240576A1 (en) * 2006-06-15 2010-09-23 Thomas Stoehr Anticonvulsant combination therapy
US8735356B2 (en) 2006-06-15 2014-05-27 Ucb Pharma Gmbh Anticonvulsant combination therapy
US8828943B2 (en) 2006-06-15 2014-09-09 Ucb Pharma Gmbh Anticonvulsant combination therapy
US20100273714A1 (en) * 2006-06-15 2010-10-28 Schwarz Pharma Ag Peptide compounds for treating refractory status epilepticus
US9446011B2 (en) 2006-06-15 2016-09-20 Ucb Pharma Gmbh Anticonvulsant combination therapy
US20100324144A1 (en) * 2006-06-30 2010-12-23 Schwarz Pharma Ag Therapy for hyperexcitability disorders
US9308183B2 (en) 2006-06-30 2016-04-12 Ucb Pharma Gmbh Therapy for hyperexcitability disorders
US20100016403A1 (en) * 2006-12-14 2010-01-21 Guy Higgins Use of d-serine derivatives for the treatment of anxiety disorders
US20090005433A1 (en) * 2006-12-14 2009-01-01 Guy A Higgins Fluorinated Compounds
US8450336B2 (en) 2006-12-14 2013-05-28 Nps Pharmaceuticals, Inc Use of D-serine derivatives for the treatment of anxiety disorders
US7902401B2 (en) 2006-12-14 2011-03-08 Nps Pharmaceuticals, Inc. Fluorinated compounds
US10149818B2 (en) 2010-12-02 2018-12-11 Ucb Pharma Gmbh Daily formulation of lacosamide

Also Published As

Publication number Publication date
US20090018198A1 (en) 2009-01-15
BRPI0511875A (pt) 2008-01-15
ATE544449T1 (de) 2012-02-15
EP1755577A2 (de) 2007-02-28
EP1755577B1 (de) 2012-02-08
US7718161B2 (en) 2010-05-18
MXPA06014194A (es) 2007-03-12
AU2005251459A1 (en) 2005-12-22
WO2005120476A2 (en) 2005-12-22
WO2005120476A3 (en) 2006-02-16
EA200602220A1 (ru) 2007-04-27
ZA200608594B (en) 2008-04-30
CA2565102A1 (en) 2005-12-22
EP1604656A1 (de) 2005-12-14
UA87843C2 (ru) 2009-08-25
CN1960720A (zh) 2007-05-09
JP2008501753A (ja) 2008-01-24
TW200701984A (en) 2007-01-16

Similar Documents

Publication Publication Date Title
US7718161B2 (en) Method for treating a motoneuron disorder
US7416864B2 (en) Method for treating dyskinesia
US8338641B2 (en) Method for treating atypical facial pain
US20060100157A1 (en) Novel use of peptide compounds for treating pain in painful diabetic neuropathy
US20140128377A1 (en) Methods of treating refractory repetitive seizures
US20090018197A1 (en) Methods for treating status epilepticus and related conditions
WO2006000397A1 (en) Novel use of peptide compounds for treating essential tremor and other tremor syndromes
EP1243262A1 (de) Neue Verwendung von Peptidverbindungen bei der Behandlung von nicht-neuropathischem Entzündungsschmerz
KR20070030781A (ko) 근위축성 측삭 경화증의 치료를 위한 펩티드 화합물의신규한 용도

Legal Events

Date Code Title Description
AS Assignment

Owner name: SCHWARZ PHARMA AG, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:STOEHR, THOMAS;REEL/FRAME:016671/0356

Effective date: 20050531

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION