EP0015274A1 - Derives ameliores d'encephaline - Google Patents

Derives ameliores d'encephaline

Info

Publication number
EP0015274A1
EP0015274A1 EP19790900664 EP79900664A EP0015274A1 EP 0015274 A1 EP0015274 A1 EP 0015274A1 EP 19790900664 EP19790900664 EP 19790900664 EP 79900664 A EP79900664 A EP 79900664A EP 0015274 A1 EP0015274 A1 EP 0015274A1
Authority
EP
European Patent Office
Prior art keywords
compound
methionine
amino
leucine
resin
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.)
Withdrawn
Application number
EP19790900664
Other languages
German (de)
English (en)
Inventor
Abba J. Kastin
David H. Coy
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.)
Individual
Original Assignee
Individual
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 US05/912,412 external-priority patent/US4213968A/en
Priority claimed from US05/915,981 external-priority patent/US4180501A/en
Application filed by Individual filed Critical Individual
Publication of EP0015274A1 publication Critical patent/EP0015274A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C07K14/70—Enkephalins
    • C07K14/702—Enkephalins with at least 1 amino acid in D-form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C07K14/67—Lipotropins, e.g. beta, gamma lipotropin
    • C07K14/672—Lipotropins, e.g. beta, gamma lipotropin with at least 1 amino acid in D-form
    • 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
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • potent analgesic agents capable of relieving such severe pain are also narcotic agents and their use entails the risk of producing physical and sometimes psychological dependence. There are as yet no agents effective against severe pain that are entirely free of this risk.
  • analgesic agents for treating mild as well as severe pain.
  • psychotropic agents for providing improved psychotropic agents or to provide an alternative to current therapy.
  • the compounds of this invention in addition to their analgesic activity, also exhibit anti-depressant activity and their usefulness as analgesic agents is enhanced since many patitents suffering from pain also exhibit varying states of depression.
  • Hughes et al identified a pentapeptide, methionine enkephalin.which has the following structure, H-Tyr-Gly-Gly-Phe-Met-OH[see Hughs et al, Nature, 258, 577 (1975) ].
  • the peptide is found in many areas of the brain where it appears to act as a neurotransmitter or neuro- modulator in. a central pain suppressive system.
  • the natura peptide binds stereospecifically to partially purified brain opiate receptor cites [see, for example, Bradbury et al., Nature, 260, 793 (1976)], is very active in Bioassays for opiate activity, but exhibits only weak analgesic activity of short duration when injected directly into the brain of the rat[See, for example, Belluzzi et al.,Nature,260, 625(1976)].
  • methionine enkephalin was substituted in the 2-position with a D-amino acid, potent analgesic agents are obtained.
  • the D-amino acid 2 analogs ajso exhibit other central nervous system and hormonal activites.
  • salts refers to the non-toxic alkali metal, alkaline earth metal and ammonium salts commonly used in the pharmaceutical industry including the sodium, potassium, lithium, calcium, magnesium, barium and ammonium salts,prepared by well known methods, as well as the non-toxic acid addition salts which are generally prepared by reacting a compound of this invention with a suitable organic or inorganic acid, or in situ.
  • Representative salts include the hydrochloride, hydrobromide sulfate,bisulfate,acetate, oxalate,valerate, oleate,laurate borate,benzoate, lactate,phosphate,tosylate,napsylate and the like.
  • loweralkyl refers to straight or branched chaim alkyl groups having from 1 to 6 carbon atoms such as methyl, ethyl, n-propoyl, iso-propyl,n-butyl, sec-butyl, tert-butyl, n-pentyl and the like.
  • R 1 is selected from a group consisting of NH 2 , 0H, represented
  • R 2 is a protecting group for the phenolic hydroxyl group of tyrosine selected from the group consisting of tetrahydropyranyl, tert-butyl, trityl, benzoyl, 2,4-dichlorobenzyl, benzyloxcarbonyl and 2-bromobenzyloxycarbonyl(2-BrZ);
  • R 3 is a protecting groups which would be used by one skilled in the art of solid-phase synthesis of the peptides selected from the group consisting of acyl type protecting groups, aromatic urethan-type protecting groups, cycloalkyl urethan protecting groups, thio urethan type protecting groups, trialkylsilance groups or aliphatic urethan protecting groups; and
  • X is a D-amino acid as defined in formula I or when X is D-tyrosine, D-threonine, D-serine, D-glutamic acid or D-lysine, a protected chiral amino acid residue as defined below.
  • the protected residue is X(R 2 ) wherein R 2 is a protecting group for the alcoholic hydroxy function and is as defined above.
  • the protected residue is X(RA) wherein R ⁇ is benzyl or tert-butyl.
  • R 5 is a protecting group for the epsilon amino function selected from the group consisting of benzyloxycarbonyl or 2-chlorobenzyloxycarbonyl.
  • the protected residue is X(R 6 ) wherein R 6 is a protecting group for the guanidino function such as tosyl or nitro.
  • acyl type protecting groups refers to groups illustrated but not restricted to fo ⁇ nyl, trifluoro-acetyl, tosyl, nitrosulfonyl , and the like.
  • aromatic urethan-type protecting groups is represented by groups such as benzyloxcarbonyl (Cbz), ⁇ _-methoxybenzyloxycarbonyl , p_-biphenyl, isopropyloxycarbonyl, 2,5-dimethoxycarbonyl, cyclohexylcarbonyl, isobornyloxy- carbonyl, etc.
  • “Urethan type protecting groups” include compounds such as trimethylsilane, triethylsilane, tributylsilane and the like.
  • the preferred protecting groups, the "aliphatic urethan protecting groups” include tert-butyloxycarbonyl, diisopropyloxycarbonyl, isopropyloxycarbonyl, allyloxycarbonyl and the like .
  • the polystyrene support resin is preferably a copoly of styrene with about 1-2% divinyl benzene as a cross-linking agent which causes the polystyrene polymer, to be completely insoluble in most organic solvents.
  • ⁇ is phenyl.
  • the protecting group In selecting a particular side-chain protecting group to be used in the synthesis of the peptides of formula I, several conditions must be met: (a) the protecting group must stable to the reagent and under reaction conditions selected for removing the alpha-amino protecting group at each step of the synthesis; (b) the protecting group must retain its protect ing properties and not be chemically modified; and (c) the si chaim protecting group must be removable at the end of the solid-phase synthesis under reaction conditions that will not alter the peptide chain.
  • the peptides of this invention are prepared using standard solid-phase techniques. The synthesis is commenced from the C-terminal end of the peptide using an alpha- amino protected resin.
  • a suitable starting material can be prepared, for instance, by attaching an alpha-amino protected methionine to a chloromethylated resin, a hydroxymethyl resin or a benzhydrylamine resin.
  • chloromethylated resin is sold under the tradename Bio-beads SX-1 by Bio Rad • Laboratories , Richmond, California and the preparation of the hydroxymenthyl resin is described by Bodanszky et al., Chem. Ind. (London) 38, 1957(1966).
  • the benzyhydryl resin has been described by Pietta and Marshall, Chem. Commun. , 650 (1970) and is commercially available from Beckman Instrument, Palo Alto , California.
  • an ⁇ -amino protected methionine or leucine or phenylalanine or pentafluorophenylalanine is coupled to the chloromethylated resin with the aid of, for example, cesium bicarbonate catalyst, according to the method described by Gisin, Helv. Chim Acta,56, 1476(1973).
  • the ⁇ -amino protecting group is removed by a choice of reagents including trifluoroacetic acid or hydrochloric acid solutions in organic solvents at room temperature.
  • the remaining protected amino acids are coupled stepwise in the desired order to obtain the compounds of formula II.
  • Each protected amino acid is generally reacted in a 3-fold excess using an appropriate carboxyl group activator such as dicyclohexylcarbodiimide in solution in, for example, methylene chloride-dimethylformamide mixtures.
  • the bis-t-Boc derivative of lysine is coupled to the chloromethylated resin with the aid of, for example, cesium bicarbonate catalyst according to the method of Gisin, supra. After the intial coupling, the amino protecting groups are removed as described above.
  • the desired peptide is removed from the resin support by treatment with a reagent such as hydrogen fluoride which not only cleaves the peptide from the resin, but also cleaves all remaining side-chain protecting groups.
  • a reagent such as hydrogen fluoride which not only cleaves the peptide from the resin, but also cleaves all remaining side-chain protecting groups.
  • the side-chain protected peptide can be cleaved by treatment of the peptide-resin with ammonia to give the desired side chain protected amide or with an alkylamine or dialkylamine to give a side-chain protected alkylamide or dialkylamide. Side-chain protection is then removed in the usual fashion by treatment with hydrogen fluoride to give the amides of this invention.
  • the solid phase procedure discussed above is well kno in the art and has been essentially described by J.M. Stewart "Solid Phase Peptide Synthesis",Freeman and Co., San Francisc 1969.
  • the compounds of this invention are useful as analge agents when administered to mammalian hosts at dosages of from 0.1 to 100 mg/kg of body weight daily, preferrably in divided dosages.
  • the compounds are administered by parenteral routes of administration, i.e. intravenous, intraperitoneal, intramuscluar or subcutaneous routes of administration, but can also be administerd by a variety of other routes including sublingual, nasal, vaginal, rectal, or, at higher dosages, oral. Accordingly, one aspect of the present inventi inlcudes pharmaceutical compositions suitable for such routes of administration.
  • the analgesic activity of the compounds of this invention was established in the rat tail flick test, D'Amour and Smith, J. Pharmac. Exp. Ther., 72, 74(1941).
  • the following examples further illustrate the present invention.
  • Examples 1-8 are drawn to the preparation of compounds wherein n is 1 and Y is methionine or leucine.
  • the remaining examples are drawn to the N,N-bis-penta and tetra peptides derivatives wherein n is 2 and Y is lysine.
  • the bis-peptides of this invention are represented by the formulae VI and VII:
  • the free amino resin was then stirred with tert-butyloxycarbonyl (t-Boc) methionine(347 mg, 1.5 mmoles) in methylene chloride and dicyclohexylcarbodiimide(1.5 mmoles) was added thereot.
  • the mixture was stirred at room temperature for 2 hours and the peptide resin was then washed successively with methylene chloride(3 times), ethanol (3 times) and methylene chloride(3 times).
  • the attached amino acid was deportected with 33 % trifluoroacetic acid in methylene chloride( 2 times for 2.5 and 25 minutes each) and then steps (c) through (h) as described in the above wash were performed.
  • EXAMPLE 4 Preparation of L-tyrosyl-D-leucyl-L-glycyl-L-pentafluoro- phenylalanyl-L-methionine enkephalin amide
  • the above-named compound is prepared by deprotecti and cleaving the desired peptide from the resin support of Example 3 under the conditions described in Example 2.
  • the crude peptide is purified by gel filtration on a column (2.5 x 95 cm) of Sephadex G-15 by elution with 2.0 molar acetic acid followed by partition chromatography as described in Example 2.
  • EXAMPLE 5 Preparation of 0-2-bromobenzyloxycarbonyl-L-tyrosyl-D-phenyl- alanyl-L-pentafluoroalanyl-L-methionyl-benhydrylamine resin Using the conditions described in Example 1, the t-Boc derivatives of pentafluorophenylalanine, glycine, D-phenylalanine and tyrosine[F 5 Phe,Gly, D-Phe and Tyr(2BrZ) are coupled successively to a methionine-benzhydryl resin(0.63 g, 0.50 mmole) to yield the desired peptide resin.
  • EXAMPLE 6 Preparation of 0-2-bromobenzyloxycarbonyl-L-tyrosyl-D-phenyl- alanyl-L-pentafluoroalanyl-L-methionyl-benhydrylamine resin Using the conditions described in Example 1,
  • Example 5 The pentapeptide of Example 5 is deprotected and cleaved from the resin support of Example 5 under the conditions described in Example 2.
  • the crude peptide is purified by gel filtration on a column (2.5 x 95 cm) of Sephadex G-15 gel by elution with 50% acetic acid followed by partition chromatography as described in Example 2.
  • EXAMPLE 8 Preparation of L-tyrosyl-D-alanyl-glycyl-L-pentafluorophenyl- alanyl-L-methionine enkephalin The above pentapeptide was deprotected and cleaved from the resin support of Example 7 under the conditions described in Example 2. The crude material was purified by gel filtration and partition chromatography as described in Example 2 to yield the desired product.
  • Benzhydrylamine resin (1.88 g, 1.0 mmole), purchased from Beckman instruments, Palo Alto, California, was placed in the reaction vessel of a Beckman MDdel 990 automatic pepticie synthesizer, programmed as described in Example 1.
  • the free amino acid resin was then stirred with N ⁇ ,N ⁇ -bis-tert-butyloxycarbonyl(t-boc)lysine(1.04 g, 3. Ommoles) in methylene chloride and dicyclohexylcarbodiimide(3. Ommoles) was added thereto.
  • the mixture was stirred at room temperature for 2 hours and the peptide resin was then washed successively with methylene chloride(3 times), ethanol(3 times) and methylene chloride(3 times).
  • the attached amino acid was deprtected with 33 % trifluoroacetic acid in methylene chloride( 2 times for 2.5 and 25 minutes each) and then steps (c) through (h), as described in Example 1, were performed.
  • the crude peptide was purufied by gel filtration on a column of Sephadex G-25(2.5 x 95 cm) gel by elution with 0.2 molar acetic acid followed by partition chromatography on Sephadex G-25 gel using 1-butanol:acetic acid:water(4:1:5) as the eluant.
  • the peptide was obtained as a fluffy white powder (290 mg).
  • the branched chaim peptide amide was deprotected and cleaved from the resin support of Example 3 under the conditions described in Example 10 and Example 2.
  • the crude material was purified by gel filtration and partition chromatography as described in Example 10 to yield a fluffy white powder (440 mg) .
  • the product was homogeneous by thin layer chromatography using the spray reacgents and solvent system described in Example 10: (A), 0.27; (B) 0.84; (C), 0.56; (D), 0.63.
  • Amino acid analysis gave: Gly, l.97;Ala, 2.04; Tyr, 2.00; Phe,2.04;Lys, 1.01.
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient at least one of the compounds of formula I in association with a pharmaceutical carrier or diluent.
  • the compounds of this invention can be administered by oral, parenteral,nasal, vaginal, rectal or sublingual routes of administration and can be formulated in dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one intert diluent such as sucrose, lactose, or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • additional substances other than inert diluents e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration included pharmaceutically acceptable emulsions, solutions, suspensio syrups and elixirs containing inert diluents commonly used in the art such as water.
  • such compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • Preparations according to this invention for paren eral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving wetting, emulsifying and dispersing agents. They may be sterilized by, for example, filtration through a bacteria- retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • Compostions for rectal or vaginal administration are preferably suppoitories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
  • compositions for nasal or sublingual administratio are also prepared with standard excipients well known in the art.
  • the dosage of active ingredient in the composition of this invention may be varied, however, it is necessary that the amount of the active ingredient shall be such that a suitable dosage form is obtained.
  • the selected dosages depend upon the desired therapeutic effect, on the route of administration and on the duration of treatment.
  • the compounds of this invention also exhibit psychotropic activity and may be useful in treating depres and the like states.
  • EXAMPLE 13 Tablets weighing 200 mg and having the following composition are formulated by standard methods: Ingredient Mg L-Tyrosyl-D-alanyl-glycyl- L-pentafluorophenylalanyl- L-methionine enkephalin amide 25
  • EXAMPLE 14 Sterile 10 ml ampoules are prepared containing 1 mg per ml of N ,N -bis (L-tyrosyl-D-alanyl-L-glycyl-L-phenylalanyl-L-methionine enkephaline)lysine amide, 0.1 percent sodium bisulfate, 0.7 percent sodium chloride, and 0.5 percent chlorbutanol as a preservative.
  • Topical aqueous formulations for administration by nose drops or nasal spray are formulated containing 1 mg of L-tyrosyl-D-leucyl-glycyl-L-pentafluorophenylalanyl-L-leucine enkephalin amide, 3.8 mg glycerine, 40 mg. sorbital, 0.02 mg benzalkonium chloride and purified water q.s. 1 ml.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Polypeptides representes par la formule (R1)5 (H-Tyr-X-Gly-Phe-(R)n)m-Y-Z ou X est la glycine ou un residu a pouvoir d'acide D-amino choisi parmi le groupe constitue D-alanine, D-leucine, D-isoleucine, D-valine, D-norvaline, D-phenylalanine, D-tyrosine, D-tryptophane, D-serine, D-threonine, D-methionine, D-glutamine, acide D-aspartique, D-asparagine, D-lysine, D-proline, D-histidine et D-arginine; R est la methionine lorsque m est leucine et n est 1; n est 0 ou 1; R1 est l'hydrogene ou fluoro; m est 1 ou 2 avec la restriction que lorsque m vaut 1, X ne peut etre la glycine; Y est la lysine lorsque m est 2 et la methionine ou la leucine lorsque m vaut 1 avec la restriction que lorsque m vaut 1, n vaut 0; et Z est choisi parmi le groupe hydroxy, amino, akylamino-inferieur, dialkylamino-inferieur et alkoxy inferieur et leurs sels pharmaceutiquement acceptables.
EP19790900664 1978-06-05 1980-01-10 Derives ameliores d'encephaline Withdrawn EP0015274A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US05/912,412 US4213968A (en) 1978-06-05 1978-06-05 Enkephalin derivatives
US912412 1978-06-05
US915981 1978-06-16
US05/915,981 US4180501A (en) 1978-06-16 1978-06-16 Bis (polypeptide) derivatives of enkephalin

Publications (1)

Publication Number Publication Date
EP0015274A1 true EP0015274A1 (fr) 1980-09-17

Family

ID=27129598

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19790900664 Withdrawn EP0015274A1 (fr) 1978-06-05 1980-01-10 Derives ameliores d'encephaline

Country Status (2)

Country Link
EP (1) EP0015274A1 (fr)
WO (1) WO1980000022A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2933947A1 (de) * 1979-08-22 1981-03-12 Hoechst Ag, 6000 Frankfurt Neue peptidamide und verfahren zu ihrer herstellung.

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4092304A (en) * 1976-08-09 1978-05-30 G. D. Searle & Co. 4-Substituted enkephalin derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8000022A1 *

Also Published As

Publication number Publication date
WO1980000022A1 (fr) 1980-01-10

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