EP0401253A1 - 2-aminoacetamid-derivate - Google Patents

2-aminoacetamid-derivate

Info

Publication number
EP0401253A1
EP0401253A1 EP89902415A EP89902415A EP0401253A1 EP 0401253 A1 EP0401253 A1 EP 0401253A1 EP 89902415 A EP89902415 A EP 89902415A EP 89902415 A EP89902415 A EP 89902415A EP 0401253 A1 EP0401253 A1 EP 0401253A1
Authority
EP
European Patent Office
Prior art keywords
methylethyl
diphenyl
general formula
compound
alkyl
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.)
Pending
Application number
EP89902415A
Other languages
English (en)
French (fr)
Inventor
Ronald Conrad Griffith
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.)
Fisons Corp
Original Assignee
Fisons Corp
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
Priority claimed from US07/145,866 external-priority patent/US4871872A/en
Application filed by Fisons Corp filed Critical Fisons Corp
Publication of EP0401253A1 publication Critical patent/EP0401253A1/de
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • This invention relates to novel chemical compounds, processes for their preparation, pharmaceutical compositions containing them, and methods of treatment involving their use.
  • Ar 1 and Ar 2 which may be the same or different, represent phenyl optionally substituted by fluorine,
  • R, R 1 and R 2 which may be the same or different, represent hydrogen or alkyl C 1-4
  • R 3 represents hydrogen, alkyl C 1-4 , phenylinethyl or 2-(aminocarbonyl)ethyl
  • R 4 represents hydrogen, alkyl C 1-6 , cy ⁇ lopropyl, or a group -COCH(R 5 )NH 2 in which R 5 represents hydrogen or methyl, provided that, when R 2 and R 3 both represent hydrogen, then R 4 is other than hydrogen, and pharmaceutically acceptable acid addition salts thereof .
  • This invention also relates to diastereoisomers and optical isomers (and mixtures thereof) of the compounds of general formula I.
  • the 2-amincacetamide derivatives of general formula I as described fully above are conveniently prepared by suitable amide bond forming reactions.
  • a process for the preparation of a compound of general formula I which process comprises a) producing a compound of general formula I in which R 4 represents hydrogen, alkyl C 1- 6 or cyclopropyl, by directly coupling an amine of general formula II,
  • R 4 represents hydrogen, alkyl C 1- 6 or cyclopropyl
  • X represents a urethane protecting group, followed by removal of the protecting group X
  • R 4b represents hydrogen, alkyl C 1- 6 or cyclopropyl, or c) producing a compound of general formula I in which R 4 represents a group -COCHR 5 NH 2 , by reacting an amine of general formula VI,
  • reaction of process a) is preferably carried out in an inert solvent in the presence of a coupling reagent such as dicyclohexylcarb ⁇ diimide with or without 1-hydroxybenzotriazole or other additives.
  • a coupling reagent such as dicyclohexylcarb ⁇ diimide with or without 1-hydroxybenzotriazole or other additives.
  • Urethane protecting groups which X may represent include benzyloxycarbonyl (CBZ) and t-butyloxy ⁇ arbonyl (SOC).
  • the group X may be removed by conventional methods, eg by catalytic hydrogenation in the case of CBZ groups or treatment with an acid such as trifluoroacetic or hydrochloric acid in the case of BOC groups.
  • Most of the amines of general formula II are known compounds and may be purchased commercially or conveniently prepared by suitable modifications of the reported procedures. Some of the amines II are not known, but are prepared by similar procedures. The preparation of some non-commercially available amines of general formula II is described below (see “Preparation of Intermediates").
  • the reaction of process b) is preferably carried out in a solvent such a lower alkanol, for example methanol or ethanol, or a chlorinated solvent, for example chloroform or methylene chloride or mixtures thereof.
  • Leaving groups which L. may represent include halide, especially chloride.
  • Compounds of formula IV may be prepared by reacting an amine of formula II with an activated two carbon acid derivative which contains a leaving group alpha to the carbonyl, ie a compound of general formula VIII,
  • reaction of process c) may be performed under conditions analogous to those suitable for process a).
  • the compounds of general formula I possess asymmetric centres, and therefore optical isomers and diastereomeric forms are possible. Such compounds are conveniently prepared from optically active starting materials by the methods described above.
  • the compounds of general formula I are basic compounds and may be used as such or in the form of their pharmaceutically acceptable acid addition salts.
  • Such salts may be prepared by treatment with various inorganic or organic acids, such as hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, succinic, furmaric, malic, maleic, tartaric, citric, benzoic, methanesulphonic or carbonic acids.
  • Ar 1 and Ar 2 are the same, especially compounds in which Ar 1 and Ar 2 represent phenyl.
  • Ar 1 or Ar 2 When either Ar 1 or Ar 2 is substituted by fluorine, it is preferably 4-fluorophenyl.
  • R, R 1 , R 2 and R 3 represent alkyl C 1- 4 , they preferably represent methyl.
  • R represents alkyl C 1- 4 .
  • R 2 is hydrogen.
  • the compounds of general formula I possess useful pharmaceutical properties. In particular they possess useful antiepileptic properties and useful sedative properties. These activities were assessed by standard methods. Antiepileptic activity was measured by assessing a compound's ability to prevent the hind limb tonic extension component of the seizure in groups of mice induced by maximal electroshock (MES) after oral or intraperitoneal admin is tration according to the procedures of the Epilepsy Branch, NINCDS as published by R J Porter et al, Cleve Clin Quarterly (1984) 51, 293, and compared to the standard agents dilantin and phenobarbital. Activites (ED 50 's) in the range of 10-400 m/k after oral administration in this assay system were obtained. Sedative activity was assessed by behavioural observation in groups of mice. Selected compounds exhibited activity in the range of 30-600 m/k in this assay.
  • MES maximal electroshock
  • a) a method of treatment of epilepsy which method comprises administration of a therapeutically effective quantity of a compound of general formula I to a human or animal patient suffering from that condition.
  • b) the use of a compound of general formula I in the manufacture of a medicament for the treatment of epilepsy c) a method of sedation of a human or animal patient, which method comprises administration of a therapeutically effective quantity of a compound of general formula I to that patient, and d) the use of a compound of general formula I in the manufacture of a medicament for use as a sedative.
  • the dosage administered will naturally depend on the particular compound employed, the mode of administration and the desired effect. However, in general satisfactory results are obtained when the compounds are administered at a dosage of from 0.05 ⁇ g to 3.5g, which may be administered in divided doses of, for example, 1 ⁇ g to 750mg.
  • the compounds of general formula I may be administered by a wide variety of routes and may act systemically or locally.
  • the compounds may be administered by oral or nasal inhalation to the lung, to the buccal cavity, oesophageally, rectally, topically to the skin or to other available surfaces of the body by injection, eg intravenously, intramuscularly, intraperitoneally, or by surgical implant.
  • a pharmaceutical composition comprising preferably less than 80%, and more preferably less than 50%, by weight of a compound of general formula I, or a pharmaceutically acceptable acid addition salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose , dextrose or mannitol, talc , stearic ac id , starch , sodium bicarbonate and/or gelatin; for suppositories - natural or hardened oil or waxes; and for inhalation compositions - coarse lactose.
  • 1,2-Diphenyl-2-propylamine hydrochloride Prepared by suitable modification of the procedure described by Christol (Bull Soc Chim Pr, 1963, 4, 877) and Ho and Smith (Tetrahedron, 1970, 26, 4277) as follows:
  • (+)-1,2-diphenyl-2-propylamine This oil (32.3g, 0.153 mol) was dissolved in 200 ml hot 95% ethanol and added to a stirred solution of (+)-dibenzoyl tartaric acid monohydrate (57.55g, 0.153 mol) in 600 ml of refluxing 95% ethanol. A white solid crystallised immediately, which was stirred at reflux for 5 minutes, then allowed to cool to ambient temperature.
  • (+) -1 , 2-diphenyl-2-pro ⁇ ylami ne as an oil.
  • Intermediate F N-Methyl-1,2-diphenyl-2-propylamine hydrochloride
  • N-formyl-1,2-diphenyl-2-propylamine (23.6g, 0.1 mol) was added to a stirred suspension of LiAlH 4 (15.0g, 0.395 mol) in 1 litre of dry tetrahydrofuran. After 2 hours the mixture was heated at 35°C for 22 hours, then refluxed for 2 hours, and allowed to cool to room temperature. Water was added to decompose the excess LiAlH 4 , and the mixture filtered to remove the solid salts. Evaporation of the solvent gave 23.0g of the crude product as a yellow oil. This was dissolved in 180 ml of ethyl acetate and 20 ml of isopropanol and acidified with HC1 gas. Upon standing a white solid crystallised which was collected by filtration and vacuum dried at 65°C to give 21.7g (84%) of N-methyl-1,2-diphenyl-2-propylamine hydrochloride, mp 200-201°C.
  • N-carboethoxy-1,2-diphenylethylamine 35.0g, 0.13 mmol
  • the mixture was heated to reflux for 8 hours.
  • the mixture was cooled in an ice-water bath and water (13 ml), 15% NaOH (13 ml) and water (39 ml) were carefully added to the mixture.
  • the mixture was warmed to ambient temperature and the precipitated salts were removed by filtration through celite. Removal of solvent gave N-methyl-1,2-diphenylethylamine (26.8g) as a colourless oil.
  • the residual oil was recrystallised from ethyl acetate (500 ml) and then methanol (500 ml) to give a white solid, 12.9g. This was dissolved in methanol (200 ml) and acidified with HCl gas to give a white solid, 12.5g. This was dissolved in 900 ml of methanol and 90 ml of 10% HCl, and hydrogenated at 40 psi in a Parr apparatus over 3.0g of 10% Pd/C catalyst for 4 hours. The catalyst was removed by filtration, and the solvent evaporated to a white solid (6.5g).
  • Example 3 2-(L-Alaninamido)-N-(1,2-diphenyl-methylethyl) acetamide
  • Example 4 (2S)-2-(L-alaninamido)-N-(1,2-diphenyl-1-methylethyl) propanamide
  • the residue was treated with ethylacetate (125 ml), filtered, an additional 250 ml of ethylacetate added, and the mixture washed with cold 1% HCl (150 ml), brine (200 ml), dried and the solvent evaporated.
  • the residue was dissolved in 400 ml of methanol and 35 ml of 10% HCl and hydrogenated at 40 psi in a Parr apparatus over 3.0g of 5% Pd/C catalyst for 3 hours. The catalyst was removed by filtration, solvent evaporated and the residue dissolved in water (300 ml) and chloroform (300 ml), basified to pH 11 with 50% NaOH, shaken and separated.
  • N-methy1-1,2-diphenyl-1-methylethylamine, 2-glycinamido-N-methyl-N-(1,2-di-phenylethyl)acetamide hydrochloride or 2-gylcinamido-N-methyl-N-(1,2-diphenyl-1-methylethyl) acetamide hydrochloride may be prepared.
  • the residue was treated with ethyl acetate (100 ml), filtered, an additional 300 ml of ethyl acetate added, and then washed with 1% cold HCl (100 ml), brine (2 ⁇ 100 ml), dried over MgSO 4 , and the solvent evaporated.
  • the residue was dissolved in 450 ml of methanol and 35 ml of 10% HCl and hydrogenated at 40 psi in a Parr apparatus over 3.0g of 5% Pd/C catalyst for 3 hours .
  • the catalyst was removed by filtration, the solvent evaporated and the residue dissolved in water (200 ml) and chloroform (300 ml), basified to pH 11 with 50% NaOH, shaken and separated.
  • Example 17 2-(Methylamino)-N-(1,2-diphenyl-1-methylethyl)-acetamide hydrochloride.
  • Example 22 2-(Butylamino)-N-(1,2-diphenyl-1-methylethyl)-acetamide hydrochloride Prepared by the method of Example 17 using n-butylamine; mp 192°C.
  • Example 23

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP89902415A 1988-01-20 1989-01-10 2-aminoacetamid-derivate Pending EP0401253A1 (de)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US14594388A 1988-01-20 1988-01-20
US14586588A 1988-01-20 1988-01-20
US145866 1988-01-20
US145943 1988-01-20
US07/145,866 US4871872A (en) 1988-01-20 1988-01-20 2-[(2-aminoacetyl)amino]acetamide derivatives
US145865 1988-01-20

Publications (1)

Publication Number Publication Date
EP0401253A1 true EP0401253A1 (de) 1990-12-12

Family

ID=27386328

Family Applications (2)

Application Number Title Priority Date Filing Date
EP89902415A Pending EP0401253A1 (de) 1988-01-20 1989-01-10 2-aminoacetamid-derivate
EP89300164A Expired - Lifetime EP0326240B1 (de) 1988-01-20 1989-01-10 2-Aminoacetamid Derivate

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP89300164A Expired - Lifetime EP0326240B1 (de) 1988-01-20 1989-01-10 2-Aminoacetamid Derivate

Country Status (9)

Country Link
EP (2) EP0401253A1 (de)
JP (1) JPH02503089A (de)
AT (1) ATE96144T1 (de)
CA (1) CA1315477C (de)
DE (1) DE68909961T2 (de)
DK (1) DK460789A (de)
IE (1) IE890161L (de)
PT (1) PT89483B (de)
WO (1) WO1989006646A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2083972T3 (es) * 1988-08-12 1996-05-01 Astra Ab Arilalquil-aminas y -amidas con propiedades anticonvulsivas y neuroprotectoras.

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2449638A (en) * 1946-05-10 1948-09-21 Wyeth Corp Substituted glycinamides
DE955508C (de) * 1954-07-28 1957-01-03 Cilag Ag Verfahren zur Herstellung von antikonvulsivisch wirkenden Carbonsaeureamiden
GB1420067A (en) * 1972-02-15 1976-01-07 Astra Laekemedel Ab Aryldiamides
SE408171B (sv) * 1975-09-04 1979-05-21 Astra Laekemedel Ab Analogiforfarande for framstellning av nya aralkylamider av 2-aminopropropionsyra, vilka amider har framakologiska egenskaper

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8906646A1 *

Also Published As

Publication number Publication date
WO1989006646A1 (en) 1989-07-27
PT89483B (pt) 1994-02-28
DE68909961T2 (de) 1994-02-10
EP0326240B1 (de) 1993-10-20
DK460789A (da) 1989-11-20
JPH02503089A (ja) 1990-09-27
EP0326240A1 (de) 1989-08-02
ATE96144T1 (de) 1993-11-15
DE68909961D1 (de) 1993-11-25
DK460789D0 (da) 1989-09-19
CA1315477C (en) 1993-03-30
PT89483A (pt) 1989-10-04
IE890161L (en) 1989-07-20

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