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
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
• • 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
• • 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
  • 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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• This invention relates to peptides and derivatives thereof; to the preparation of such compounds; to formulations containing such compounds and the preparation of such formulations; and to the use of the compounds in human and veterinary medicine.
• a morphine agonist is a compound the biological activity of which mimics that of the natural alkaloid.
• the present invention provides the novel peptides of formula (I);
• X 1 and X 2 are the same or different and each is the radical of a basic amino acid (D or L);
• X 3 is a D or L radical having the formula: ##STR1## wherein R 2 is phenyl or 1,4-cyclohexadien-1-yl, a is 0, 1 or 2, b is 0 or 1, one of W and W 1 is a group --NR 3 -- and the other is hydrogen, provided that W is always --NR 3 -- when b is 0 and that when R 2 is 1,4-cyclohexadien-1-yl a is always 1 and b is always 0, where R 3 is hydrogen or a group selected from alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl and carboxyalkynyl, and where R 2 is optionally substituted by one or more groups each selected from hydroxy, alkoxy, alkanoyloxy, alkyl, nitro, trifluoromethyl, amino, N-alkylamino, halogen, N,N-dialkylamino and benzyloxy wherein the phenyl ring is
• X 4 and X 5 are the same or different and each is glycyl or a D or L radical selected from C-propargylglycyl, alanyl, ⁇ -alkyl alanyl, ⁇ -alanyl, valyl, norvalyl, leucyl, isoleucyl, norleucyl, prolyl, hydroxyprolyl, tryptophyl, asparaginyl and glutaminyl, where each of said radicals is optionally N 2 -substituted with an alkyl group;
• X 6 is selected from glycyl, a D or L radical selected from methionyl, leucyl, isoleucyl, norleucyl, valyl, norvalyl, prolyl, hydroxyprolyl, alanyl and histidyl, and the values recited hereinabove for X 3 ;
• X 7 is a D or L radical selected from seryl, homoseryl, O-alkyl seryl, O-alkyl homoseryl, threonyl, O-alkyl threonyl, methionyl sulphoxide, methionyl sulphone, ⁇ -homovalyl, homoleucyl, ⁇ -homoleucyl, S-methyl-homocysteinyl, homomethionyl, ⁇ -homomethionyl and the values recited hereinabove for X 6 ;
• X 8 is selected from the radical of a basic amino acid (D or L) and a D or L radical selected from seryl, threonyl, phenylalanyl and tyrosyl;
• X 9 is selected from glycyl, the radical of a basic amino acid (D or L), and a D or L radical selected from seryl and threonyl;
• R is selected from hydrogen, aralkyl, alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl and carboxyalkynyl;
• R 1 represents the hydroxyl of the 1-carboxyl group of the C-terminal amino acid residue or a group, replacing said 1-carboxyl group, selected from --CH 2 OR 4 , where R 4 is hydrogen or alkanoyl, and 5-tetrazolyl optionally substituted in the 1- or 2-position with a group selected from alkyl and benzyl; and
• n, p and q are each selected from 0 and 1
• X 7 is selected from L-leucyl and L-methionyl and either X 3 is selected from L-tyroSyl and L-3,5-diiodotyrosyl and X 6 is L-phenylalanyl, or X 3 is L-tyrosyl and X 6 is L-4-chlorophenylalanyl.
• amino acids and their radicals are those conventional in the art and may be found in, for example, Biochemistry, 11, 1726 (1972). In the above and throughout the following all references are to the L-amino acids and their radicals except in the case of glycine and unless otherwise stated.
• basic amino acid an amino acid having two basic functions and one carboxyl group
• radicals X 1 , X 2 , X 8 and X 9 may be mentioned lysyl (D and L), homoarginyl (D and L), ornithyl (D and L), histidyl (D and L), ⁇ , ⁇ -diaminobutyryl(D and L) and arginyl (D and L).
• the optional alkyl substituents of the radicals X 4 and X 5 , the alkyl moiety of the ⁇ -alkyl alanyl identity for X 4 and X 5 and the alkyl moiety of the O-alkyl seryl, O-alkyl homoseryl and O-alkyl threonyl identities for X 7 desirably have 1 to 4 and preferably 1 or 2 carbon atoms.
• the optional halogen substituents may be selected from fluorine, chlorine, bromine and iodine and the optional alkyl and alkoxy substituents together with the alkyl moieties of the optional alkanoyloxy, N-alkylamino and N,N-dialkylamino substituents desirably have 1 to 4 and preferably 1 or 2 carbon atoms.
• the phenyl or cyclohexadien-1-yl ring of the radical X 3 has 1 or 2 substituent groups thereon said groups are desirably located at the 3- and/or 4-position(s) of the said ring.
• the alkyl identity for R and for the group R 3 of the radical X 3 together with said moiety in the carboxyalkyl identity therefor may in particular have 1 to 4 carbon atoms, for example 1 or 2, but such groups having for example 1 to 10 or 1 to 20 carbon atoms are to be understood as also included.
• the alkenyl and alkynyl identities for R and R 3 together with said moieties in respectively the carboxyalkenyl and carboxyalkynyl identities therefor may in particular have 2 to 4 carbon atoms but such groups having for example 2 to 10 or 2 to 20 carbon atoms are to be understood as within the scope of formula (I).
• As particular values for said alkenyl and alkynyl groups respectively may be mentioned allyl ( ⁇ , ⁇ or ⁇ ) and propargyl.
• R is aralkyl this may be for example benzyl optionally substituted in the phenyl ring by one or more groups each selected from those recited hereinbefore in respect of the optional benzyloxy substituent of the group R 2 in the radical X 3 .
• R 1 is a group --CH 2 OR 4 wherein R 4 is alkanoyl the alkyl moiety of said alkanoyl group desirably has 1 to 4 and preferably 1 or 2 carbon atoms.
• R 1 is 5-tetrazolyl the optional alkyl substituent thereon desirably has 1 to 5 carbon atoms and the optional benzyl substituent thereon is itself optionally substituted in the phenyl ring by one or more groups each selected from those recited hereinbefore in respect of the optional benzyloxy substituent of the group R 2 in the radical X 3 .
• esters of the peptides of formula (I) may be mentioned the alkyl esters and the aryl esters.
• the alkyl esters include in particular those wherein the alkyl group has 1 to 4 carbon atoms, for example the methyl, ethyl and t-butyl esters, but esters wherein the alkyl group has for example 1 to 10 or 1 to 20 carbon atoms are to be understood as also included.
• the aryl esters include phenyl esters, for example halophenyl esters where the halo is for example chloro as in p-chlorophenyl.
• the alkyl groups may in particular have 1 to 5 carbon atoms but alkyl groups having for example 1 to 10 or 1 to 20 carbon atoms are to be understood as also included and in the N,N-dialkylamides the alkyl groups may be the same or different.
• the amides of the peptides should be understood to include those notionally derived not only from ammonia but also from heterocyclic bases such as pyrrolidine, piperidine and morpholine, that is to say, the pyrrolidineamides, piperidineamides and morpholineamides respectively.
• amides, N-alkylamides and N,N-dialkylamides of the peptides of formula (I) may be represented by the formula: ##STR2## wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , m, n, p, q and R have the meanings as hereinabove recited in formula (I) and R 5 , R 6 and the nitrogen atom to which they are attached together comprise a group selected from amino, pyrrolidino, piperidino, morpholino, N-alkylamino and N,N-dialkylamino where the "alkyl" in each instance has 1 to 20 carbon atoms.
• the activity resides in the base and the acid is of less importance although for therapeutic purposes it is preferably pharmacologically and pharmaceutically acceptable to the recipient.
• suitable acids include (a) mineral acids: hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids; (b) organic acids: tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycollic, gluconic, gulonic, succinic and arylsulphonic, for example p-toluenesulphonic, acids.
• the pharmaceutically and pharmacologically acceptable acid addition salts together with those salts which are not so acceptable have utility in isolation and purification of the bases, and of course the unacceptable salts are also valuable in the preparation of the acceptable salts by techniques well known in the art.
• those peptides and their derivatives containing a plurality of free amino groups may be obtained in the form of mono- or poly-acid addition salts, or as mixed salts of a plurality of acids.
• the identity of the cation is of less importance although for therapeutic purposes it is preferably pharmacologically and pharmaceutically acceptable to the recipient.
• suitable cations include sodium and potassium.
• X 1 and X 2 are the same or different and each is the radical of a basic amino acid (D or L);
• X 3 is selected from phenylalanyl (D or L) and C-phenylglycyl (D or L), where each of said groups is optionally N 2 -substituted with an alkyl group and is optionally substituted in the 3- and/or 4- position of the phenyl ring by a group(s) each selected from hydroxy, alkoxy, acyloxy and benzyloxy;
• X 4 is selected from glycyl, alanyl (D or L), valyl (D or L), norvalyl (D or L), leucyl (D or L), isoleucyl (D or L), norleucyl (D or L), prolyl (D or L) and hydroxyprolyl (D or L), where each of said groups is optionally N 2 -substituted with an alkyl group;
• X 5 is selected from asparaginyl (D or L), glutaminyl (D or L), where each of said groups is optionally N 2 -substituted with an alkyl group, and the values recited hereinabove for X 4 ;
• X 6 is selected from methionyl (D or L): leucyl (D or L), isoleucyl (D or L), norleucyl (D or L), valyl (D or L), norvalyl (D or L), prolyl (D or L), hydroxyprolyl (D or L), glycyl, alanyl (D or L) and the values recited hereinabove for X 3 ;
• X 7 is selected from methionyl (D or L), seryl (D or L), threonyl (D or L), leucyl (D or L), isoleucyl (D or L), norleucyl (D or L), valyl (D or L), norvalyl (D or L), prolyl (D or L), hydroxyprolyl (D or L), glycyl, alanyl (D or L) and the values recited hereinabove for X 3 ;
• X 8 and X 9 are the same or different and each is selected from seryl (D or L) and threonyl (D or L); and
• n, p and q are each selected from 0 and 1
• X 7 is other than methionyl or leucyl.
• X 1 and X 2 are the same or different and each is the radical of a basic amino acid
• X 3 and X 6 are the same or different and each is selected from phenylalanyl and C-phenylglycyl, where each of said groups is optionally N-substituted by an alkyl group and is optionally substituted in the 3- and/or 4-position of the phenyl ring by a group(s) each selected from hydroxy, alkoxy, acyloxy and benzyloxy;
• X 4 and X 5 are the same or different and each is selected from glycyl, alanyl (D or L), valyl (D or L), norvalyl (D or L), leucyl (D or L), isoleucyl (D or L), norleucyl (D or L), prolyl (D or L) and hydroxyprolyl (D or L), where each of said groups is optionally N-substituted by an alkyl group;
• X 7 is selected from methionyl, leucyl, isoleucyl, norleucyl, valyl, norvalyl, prolyl, hydroxyprolyl, glycyl, alanyl and the values recited hereinabove for X 3 and X 6 ;
• X 8 and X 9 are the same or different and each is selected from seryl and threonyl
• n, p and q are each selected from 0 and 1
• X 7 is other than methionyl or leucyl.
• morphine agonist properties of the peptides of formula (I) and their derivatives as hereinbefore defined include the following, which are given solely by way of illustration and should be understood to be non-limiting.
• the compounds exhibit analgesic activity, for example they are effective in reducing phenylbenzoquinone-induced writhing in mice when tested by a modification of the method of Hendershot et al. (J. Pharm. exp. Therap., 125 (1959) 237) (the compounds being administered by intracerebroventricular injection) and this reduction is abolished by naloxone.
• the compounds exhibit antitussive activity, for example when tested in guinea-pigs according to the method of Boura et al. Brit. J. Pharmacol, 39 (1970) 225.
• the compounds exhibit antidiarrhoeal activity, for example they are effective in reducing castor oil-induced diarrhoea in rats.
• X 4 is the radical of a D-amino acid, preferably D-alanine
• X 6 is L-phenylalanyl
• X 7 is the radical of a D-amino acid, preferably D-leucine or D-methionine.
• R, R 1 , p and q are as defined in formula (I);
• X 3 is L-tyrosyl, O 4' -acetyl-L-tyrosyl or N-methyl-L-tyrosyl;
• X 4 is glycyl, L-alanyl, ⁇ -methyl-alanyl or D-alanyl;
• X 5 is glycyl, sarcosyl or L-asparaginyl
• X 6 is L-phenylalanyl, L-tyrosyl or L-4-chlorophenylalanyl
• X 7 is L-leucyl, D-leucyl, L-methionyl, D-methionyl, L-norleucyl, L-threonyl or D- ⁇ -homoleucyl;
• X 8 is L-threonyl, D-threonyl, L-phenylalanyl, L-tyrosyl or L-lysyl;
• X 9 is glycyl or L-lysyl.
• X 3 is L-tyrosyl or N-methyl-L-tyrosyl
• X 7 is D-leucyl or D-methionyl.
• peptides of formula (I) and their derivatives as hereinabove recited may be prepared by any of the methods known in the art for the preparation of compounds of analogous structure. Thus they may be formed by the sequential coupling of appropriate amino acids using either classical methods of peptide synthesis or solid phase procedures, or by the initial preparation and subsequent coupling of peptide subunits.
• Such reactions may be effected by, for example, activating the carboxylic acid group of the ingoing amino acid and protecting the non-reacting amino and carboxylic acid groups.
• activating and protecting (masking) groups and of suitable reaction conditions giving the minimum of racemisation may be found in the following literature, all of which is incorporated herein by reference hereto, which is given purely by way of exemplification and which is intended to be neither exhaustive nor limiting.
• the peptides of formula (I) and their derivatives are obtained in the form of the free base or as an acid addition salt thereof of (in the case of the peptides themselves) as a salt thereof.
• the acid addition salts may be converted into the free bases or salts of other acids, and the bases may be converted into acid addition salts thereof, by techniques well known in the art.
• the peptides may be converted to salts thereof, and the salts converted to the peptides or to other salts, by well established techniques.
• peptides of formula (I) and their derivatives as hereinabove recited and acid addition salts thereof may thus be prepared by condensing a reagent (II)
• Y 1 is selected from the radical (X 1 ) m as defined in formula (I) and a partial radical sequence having the radical (X 1 ) m its N-terminal end and from thereon corresponding to formula (I), with a reagent (III)
• Y 2 corresponds to the balance of the above defined product, the reagents (II) and (III) being optionally protected and/or activated where and as appropriate; followed if necessary and as appropriate by one or both of the steps of deprotection of the product and conversion of the product into the base or a salt or an acid addition salt thereof.
• the reagent (II) identified above desirably corresponds to the N-terminal fragment thereof having either (i) the methionyl radical X 7 in the C-terminal position, the reagent (III) then having the radical (X 8 ) p in the N-terminal position, or (ii) the radical X 6 the C-terminal position, the reagent (III) then having the methionyl radical X 7 in the N-terminal position, and for general convenience the former possibility is preferred.
• arginyl (D or L) and homoarginyl (Har) (D or L) radicals may not only be incorporated into the peptide chain in the fashion described above but may also be formed in situ in the assembled chain, or in a subunit thereof, by guanidation of an ornithyl (D or L) or lysyl (D or L) radical respectively, using a reagent such as 1-guanyl-3,5-dimethylpyrazole.
• the amides, N-alkylamides and N,N-dialkylamides may be prepared by for example reaction of a peptide alkyl ester such as the methyl ester with ammonia, a heterocyclic base or a mono- or dialkylamine, as appropriate.
• the peptide esters may be prepared from the peptides by standard esterification procedures and the esters may be converted to the peptides by saponification.
• Substituent hydroxy group(s) in the group R 2 of the radical X 3 may be converted to alkoxy or benzyloxy groups by the use of the appropriate diazoalkane, for example diazomethane to provide methoxy groups.
• Substituent benzyloxy and alkanoyloxy group(s) in the group R 2 of the radical X 3 may be removed to leave hydroxy groups by hydrogenolysis in methanol using 10% palladium on charcoal catalyst and by alkaline hydrolysis respectively, and the hydroxy group(s) may be converted to alkanoyloxy groups by standard alkanoylation procedures. All these are conventional techniques in the peplide are and reference may be made to the literature referred to hereinabove for details of reaction conditions and of appropriate protection/deprotection procedures.
• the relief of pain for example pain arising from spasm of smooth muscle as in renal or biliary colic, pain due to terminal illness such as cancer, pain in the post-operative period, and obstetrical pain.
• Sedation for example in pre-anaesthetic medication; tranquillization; the induction of sleep, especially where sleeplessness is due to pain or cough., and the relief of anxiety in general.
• dyspnoea for example that of acute left ventricular failure or pulmonary oedema.
• the amount required of the peptide or derivative thereof or acid addition salt thereof (hereafter referred to as the active ingredient) will vary with the route of administration and with the severity of the condition to be treated, and will ultimately be at the discretion of the physician or veterinarian. In general however for each of utilities the dosage will be in the range 0.0025 ⁇ g. to 40 mg. per kilogram body-weight of mammal, preferably 0.025 ⁇ g. to 4.0 mg./kg.,and optionally 0.25 to 400 ⁇ g/kg. (all dosages calculated with reference to the peptide base).
• the active ingredients may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (buccal), vaginal and parenteral (including subcutaneous, intramuscular and intravenous). It will be appreciated that the preferred route will vary with the condition to be treated and thus for example in the relief of obstetrical pain administration directly into the spinal cord may be advantageous.
• the active ingredients While it is possible for the active ingredients to be administered as the raw chemical it is preferable to present them as a pharmaceutical formulation preparation.
• the formulations, both veterinary and for human use, of the present invention comprise an active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.
• the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Desirably the formulations should not include oxidising agents and other substances with which peptides are known to be incompatible.
• the formulations include those suitable for oral, rectal, nasal, topical (buccal), vaginal or parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend upon for example the active ingredient and the condition to be treated.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
• Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; or as a solution or a suspension in an aqueous liquid or a nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
• Moulded tablet may be made by moulding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
• Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, while a suitable formulation for nasal administration is nasal drops comprising the active ingredient in aqueous or oily solution.
• Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
• Formulations suitable for vaginal administration may be presented as pessaries, creams, pastes or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• Formulations suitable for parenteral administration conveniently comprise sterile aqueous solutions of the active ingredient, which solutions are preferably isotonic with the blood of the recipient.
• Such formulations may be conveniently prepared by dissolving solid active ingredient in water to produce an aqueous solution, and rendering said solution sterile and isotonic with the blood of the recipient.
• the formulations may be predicted in unit - or in multipurpose containers, for example sealed ampoules or vials.
• Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a article size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
• the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
• each unit thereof conveniently contains the active ingredient (as above defined) in an amount in the range 0.125 ⁇ g. to 2g., preferably 1.25 ⁇ g. to 200 mg. and optionally 12.5 ⁇ g. to 20 mg. (all weights calculated with reference to the peptide base).
• compositions comprising a peptide of formula (I), a pharmacologically and pharmaceutically acceptable salt, ester, amide, N-alkylamide or N,N-dialkylamide thereof or a pharmacologically and pharmaceutically acceptable acid addition salt thereof together with an acceptable carrier therefor.
• a method for the treatment of a mammal for a condition wherein an agent with a morphine-like effect is indicated comprising the administration to the mammal of a treatment effective non-toxic amount of a peptide of formula (I), a pharmacologically and pharmaceutically acceptable salt, ester, amide, N-alkylamide or N,N-dialkylamide thereof or a pharmacologically and pharmaceutically acceptable acid addition salt thereof.
• amino acid compositions of peptide hydrolysates (6N.HCl at 110° for 24 hours in evacuated sealed tubes) were determined with a Beckman-Spinco Model 120C amino acid analyser or with a Rank Chromostak amino acid analyser.
• OBu protecting groups on the alcoholic functions of threonine and serine were removed with trifluoroacetic acid containing 10% water, cleavage being allowed to proceed for 90 minutes.
• the peptide methyl esters (1), (5) were saponified in solution in methanol-water (3:1 v/v) by addition of 2N aqueous sodium hydroxide at pH 11.5 (pH stat).
• the protecting group Z was cleaved from the protected tripeptide (3) by hydrogenolysis in methanol in the presence of 10% palladium on charcoal catlyst.
• Characterising data for the intermediates (9) and (10) are as given in Table 3, wherein Rf refers to thin layer chromatography using Merck silica gel and the solvent systems indicated.
• Peptides of this formula were prepared by condensing the protected tetrapeptide BOC.Tyr.Gly.Gly.Phe-OH (Reference Preparations 1 and 2) with a suitably carboxy-protected amino acid derivative H-X 7 -OR ##STR5##
• --OR could be conveniently chosen from such residues as --OMe; --OEt; OBu t ; --OBzl; OBzl(p-NO 2 )etc. depending on the ultimate choice of the manner of deprotection.
• --OMe and --OEt the carboxyl group could be liberated by alkaline saponification; with --OBU t by mild acidolysis e.g. with trifluoroacetic acid or N-hydrogen chloride in acetic acid; with --OBzl or --OBzl(p--NO 2 ) by hydrogenolysis.
• the protected pentapepetide BOC.Tyr.Gly.Gly.Phe.X.OMe was dissolved in methanol (6ml.), water (3ml.) was added and the pH maintained at 11.5 to 12.0 with N.NaOH until the theoretical amount of alkali had been added.
• the solution was concentrated in vacuo to remove methanol, diluted with water. Traces of insoluble material were filtered, the solution extracted with ethyl acetate to remove any residual ester and the aqueous phase brought to pH3 with 0.7M citric acid solution. The precipitated peptide was extracted into ethyl acetate. The extract was washed with water, dried with MgSO 4 and concentrated in vacuo.
• Example 10 BOC.Tyr.Gly.Gly.Tyr.Leu.OBu was dissolved in methanol/methylene dichloride containing a few drops of borontrifluoride etherate. An excess of an ethereal solution of diazomethane was added and the solution allowed to stand at ambient temperature until its reaction with Pauly's reagent was negative. The solution was evaporated and the BOC and Bu protecting groups removed from the residual solid by means of N-hydrogen chloride in acetic acid in the presence of anisole in the normal manner. The peptide hydrochloride was isolated as a colourless amorphous powder after lyophilisation from aqueous solution.
• Example 21 the product peptide was purified by chromatography on a column of silica gel (Merck) by elution with n-butanol: acetic acid: water (3:1:1). The Pauly-positive fractions with Rf: 0.44 2 were combined, evaporated in vacuo and the residue lypophilised from aqueous solution.
• the peptide base of Example 105 was prepared by reduction of the compound H.Tyr.Gly.Gly.Phe.Leu.OMe: the reducing agent was lithium aluminium hydride but other equivalent agents, common in the art, could also be used.
• the peptide bases of Examples 111 and 112 were prepared by (a) preparing Z-leucineamide from the protected amino acid; (b) converting the amide to the nitrile (phosphorus oxychloride); (c) preparing the protected leucine tetrazole by reacting the nitrile with hydrazoic acid; (d) deprotecting the leucyl amino function by hydrogenolysis (10% palladium on charcoal); (e) assembling the pentapeptide in the customary manner.
• Massa Esterinum C is a commercially available suppository base consisting of a mixture of mono, di, and triglycerides of saturated vegetable fatty acids. It is marketed by Henkel International, Dusseldorf.
• Dissolve the compound of formula (I) in the Water for Injections Sterilise the solution by passage through a membrane filter, 0.2 ⁇ m pore size, filtrate in a sterile receiver. Fill into sterile glass vials, 2 ml/vial under aseptic conditions and freeze-dry. Close the vials with sterile rubber closures secured with an aluminium seal.
• the injection is reconstituted prior to administration by the addition of a convenient volume of Water for Injections or sterile saline solution.
• the weight of the compound of formula (I) is in each instance calculated with reference to the peptide base.
• the compounds were examined for their ability to inhibit neurally evoked contractions of the isolated mouse vas deferens preparation (method of Hughes et al, Brain Research, 88 (1975) 296, using pulses at 0.1 Hz).
• the concentration of the test compound in the organ bath was successively increased at intervals of ten contractions until either the contractions had decreased to less than 30% of the resting contraction height or the final bath concentration of the test compound had reached a minimum of 10 -4 M.
• the heights of the five contractions that immediately preceded the addition of the first "dose” of test compound were measured and their mean calculated.
• the resultant mean contraction associated with a particular bath concentration of test compound was calculated from the heights of the 6th, 7th, 8th, 9th and 10th contractions after the addition of the appropriate "dose” of test compound, i.e. the five contractions that immediately preceded the subsequent "dose” or washout.
• D5O was calculated, defined as the dose giving the response that is halfway between the maximum response and the minimum contraction of the tissue.

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• 1976
  • 1976-01-26 GB GB2900/76A patent/GB1577114A/en not_active Expired
• 1977
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  • 1977-01-26 AU AU21641/77A patent/AU515399B2/en not_active Expired
• 1988
  • 1988-02-01 US US07/148,159 patent/USH810H/en not_active Abandoned

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