GB1592385A - Methionine enkephalin derivatives - Google Patents

Methionine enkephalin derivatives Download PDF

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GB1592385A
GB1592385A GB3638777A GB3638777A GB1592385A GB 1592385 A GB1592385 A GB 1592385A GB 3638777 A GB3638777 A GB 3638777A GB 3638777 A GB3638777 A GB 3638777A GB 1592385 A GB1592385 A GB 1592385A
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phenylalanyl
tyrosyl
glycyl
methionine
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C07K14/70Enkephalins
    • C07K14/702Enkephalins with at least 1 amino acid in D-form
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

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Description

(54) NOVEL METHIONINE ENKEPHALIN DERIVATIVES (71) We, DAVID HOWARD COY, a citizen of Great Britain and ABBA JERE MIAH KASTIN, a citizen of the United States of America, residing, respectively, at 4319 Perrier Street, New Orleans, Louisiana 65515 and 4400 Morales Street, Metairie, Louisiana 7002, U.S.A., do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to methionine enkephain derivatives, to pharmaceutical compositions containing such compounds and to their preparation and use.
While there are a number of analgesic agents currently utilized to relieve mild to severe pain, the search for improved analgesics is a continuing one because of the numerous problems associated with the presently available reagents. Aspirin and related salicylates are considered to be non-narcotic analgesic agents useful for reheving mild to moderate pain in addition to their usefulness as anti-inflammatory and anti-pyretic agents. However, the ingestion of salicyclic acid or related salicyclics may result in epigastric distress, nausea and vomiting. This widely used class of non-narcotic analgesic agents may also cause gastric ulceration and even hemorrage both in experimental animals and man. Exacerbation of peptic ulcer symptoms and erosive gastritis have all been reported in patients on high dose therapy, e.g., arthritis patients. Aspirin is also one of the most common causes of drug poisoning in young children and has a potential of serious toxicity if used improperly.
Acetaminophen is also considered to be a non-narcotic analgesic agent useful in treating mild pain associated with simple headache and common muscular aches. While acetaminophen is particularly useful for patients who cannot take aspirin, e.g., ulcer patients, its use is contraindicated in individuals who have exhibited a sensitivity to it. In addition to their drawbacks in view of their potential side effects, the mild non-narcotic analgesic agents are not sufficiently potent to relieve the severe pain associated with surgery and cancer.
Unfortunately, the potent analgesic agents capable of relieving such severe plain 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.
Thus, there is an urgent need for improved analgesic agents for treating mild as well as severe pain. The present invention provides such agents.
In addition to the need for improved analgesic agents, there is also a need for improved psychotropic agents to replace or to provide an alternative to current therapy. The compounds of this invention, in addition to their analgesic activity, also exhibit anti-depressant activity. Thus their usefulness as analgesic agents is enhanced since many patients suffering from pain also exhibit varying states of anxiety and depression.
A recently identified pentapeptide, methionine enkephalin, has the following structure, H-Tyr-Gly-Gly-Phe-Met-OH [see Hughes et al., Nature, 258, 577 (1975)]. This peptide is found in many areas of the brain where it appears to act as a neurotransmitter or neuromodulator in a central pain suppressive system. The natural peptide binds stereospecifically to partially purified brain opiate receptor sites [for instance see Bradbury et al., Nature, 260,793(1976j, is very active in bioassays for opiate activity, but exhibits only weak analgesic agent of short duration when injected directly into the brain of the rat, [for instance, see Belluzzi et al., Nature, 260, 625 (1976)].
We have unexpectedly found that when methionine enkephalin is substituted in the 2-position with a D-amino acid, potent analgesic agents are obtained. In addition to their analgesic activity, the compounds exhibit excellent anti-depressant activity.
This invention relates to pentapeptides, and more specifically relates to methionine enkephalin derivatives which are useful as analgesic and anti-depressant agents, to intermediates useful in the preparation of the pentapeptides, and to pharmaceutical compositions and methods employing such pentapeptides.
Specifically, the novel pentapeptides are methionine enkephalin substituted in the 2-position with a D-amino acid and the corresponding amides.
The compounds of this invention are represented by formula I: H-Tyr-X-Gly-Phe-Met-Y (I) wherein X is a D-amino acid radical selected from D-alanyl, D-leucyl, D-isoleucyl, D-valyl, D-phenylalanyl, D-tyrosyl, D-tryptophanyl, D-seryl, D-threonyl, D-methionyl, Dglutamyl, D-glutaminyl, D-aspartyl, D-asparaginyl, D-lysyl, or D-arginyl; and Y is NH2 or OH, and the pharmaceutically acceptable salts thereof.
All chiral amino acid residues identified herein are in the natural or L-configuration unless otherwise specified.
The term "pharmaceutically acceptable salts", as used herein, 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 which are prepared by methods well known in the art. The term also includes non-toxic acid addition salts which are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid. Representative salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate and napsylate.
Also contemplated within the scope of the present invention are intermediates of formula II: R3-Tyr(R2) - X - Gly - Phe - Met - Rl (11) wherein Rl is selected from NH2, OH, or a derivatized insoluble polystyrene resin support represented by the formula III or IV as follows:
(III) If H II |polystyrene resin tesin suppor and - 0 - cH - polystyrene (IV) 2 resin support R2 is a protecting group for the phenolic hydroxyl group of tyrosine selected from tetrahydropyranyl, tert - butyl, trityl, benzoyl, 2,4-dichlorobenzyl, benzyloxycarbonyl, and 2-bromobenzyloxycarbonyl (2-Br Z). The latter is preferable. R2 may also be a hydrogen atom which means there is no protecting group on the phenolic hydroxyl function; R is hydrogen or an X-amino protecting group which would also be used in the solid-phase synthesis of the peptides (I) e.g. acyl type protecting groups, aromatic urethan-type protecting groups, cycloalkyl urethan protecting groups, thio urethan type protecting groups, alkyl type protecting groups, trialkylsilane groups or aliphatic urethan protecting groups; X is a D-amino acid radical as defined in formula (I).
When X is a D-amino acid radical with a functional side-chain, the following protective groups may be used: D-tyrosine; same as R2 described herein. D-serine, D-threonine; a protecting group for the alcoholic hydroxyl functions which is preferably a benzyl group. D-glutamic acid, D-aspartic acid; a protecting group for the carboxylic acid functions which is preferably benzyl or tert-butyl. D-lysine; a protecting group for the amino function which is preferably either benzyloxycarbonyl or 2-chlorobenzyloxycarbonyl. D-arginine; a protecting group for the guanidino function which is preferably either tosyl or nitro.
The term "acyl type protecting groups" refers to groups illustrated but not restricted to formyl, trifluoroacetyl, tosyl and nitrosulfenyl.
The term "aromatic urethan-type protecting groups" is represented by groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-biphenylisopropyloxycarbonyl and 2,5-dimethoxyphenylisopropyloxycarbonyl.
The term "cycloalkyl urethan protecting group", as used herein, refers to groups such as cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexylcarbonyl and isoboronyloxycarbonyl.
"Urethan type protecting groups" include but are not limited to groups such as phenylthiocarbonyl.
"Alkyl type protecting groups" are those commonly used in the art such as trityl.
"Trialkysilane groups" include compounds such as trimethylsilane, triethylsilane and tributylsilane.
The preferred protecting groups, the "aliphatic urethan protecting groups" include tert-butyloxycarbonyl, diisopropyloxycarbonyl, isopropyloxycarbonyl and allyloxycarbonyl.
The polystyrene resin support is preferably a copolymer of styrene with about 1 to 2% divinyl benzene as a cross-linking agent which causes the polystyrene polymer to be completely insoluble in most organic solvents. In formula III, Q) is phenyl.
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 be stable to the reagent and under reaction conditions selected for removing the a-amino protecting group at each step of the synthesis; (b) the protecting group must retain its protecting properties and not be chemically modified; and (c) the side-chain protecting group must be removable at the end of the solid-phase synthesis under reaction conditions that will not alter the peptide chain.
The pentapeptides of formulae (I) and (II) are prepared using standard solid-phase techniques. The synthesis is commenced from the C-terminal end of the peptide using an a-amino protected resin. A suitable starting material can be prepared, for instance, by attaching an a-amino protected methionine to a chloromethylated resin, a hydroxymethyl resin, or a benzhydrylamine resin. One such chloromethylated resin is sold under the tradename Bio-beads SX-1 by Bio Rad Laboratories, Richmond, California and the preparation of the hydroxymethyl resin is described by Bodonszky et al., Chem. Ind.
(London) 38, 1957 (1966). The benzhydrylamine resin has been described by Pietta and Marshall, Chem. Commun., 650 (1970) and is commercially available from Beckman Instrument, Palo Alto, California.
In the preparation of the compounds of this invention, a-amino protected-methionine 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).
After the initial coupling, the a-amino protecting group is removed by a choice of reagents including trifluoroacetic acid or hydrochloric acid solutions in organic solvents at room temperature. After removal of the a-amino protecting group, 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.
After the desired amino acid sequence has been completed, 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. When the chloromethylated resin is used, hydrogen fluoride treatment results in the formation of the free peptide acids of formula I (Y=OH). When the benzhydrylamine resin is used, hydrogen fluoride treatment results directly in the free peptide amides of formula I (Y=NH2). Alternatively, when the chloromethylated resin is employed, the side-chain protected peptide can be cleaved by treatment of the peptide-resin with ammonia to give the desired side-chain protected amide. Side-chain protection is then removed in the usual fashion by treatment with hydrogen fluoride to give the amides of formula I.
The solid-phase procedure discussed above is well known in the art and has been essentially described by J.M. Stewart, "Solid Phase Peptide Synthesis: (Freeman and Co., San Francisco, 1969).
The compounds of formula I are useful as analgesic and anti-depressant agents when administered to mammalian hosts at dosages of from 0.001 to 10 mg/kg of body weight daily, preferably in divided dosages. The compounds are preferably administered by parenteral routes, i.e., the intravenous, intraperitoneal, intramuscular or subcutaneous routes of administration. The compounds may also be administered by a variety of other routes including orally or sublingually or by vaginal, rectal or nasal routes of administration. Accordingly, one aspect of the present invention includes pharmaceutical compositions suitable for such routes of administration.
The analgesic activity of the compounds of formula I was established in the rat tail flick test as described by D'Amour and Smith, J. Pharmac. Exp. Ther., 72, 74 (1941). The presently preferred analgesic agent of this invention is D-Ala2-methionine enkephalin (X=D-alanine; Y=OH) which is considerably more potent than methionine enkephalin as well as morphine.
The anti-depressant activity was established in the DOPA potentiation test described by Everett, Proc. 1st Int. Symp. Anti-depressant Drugs, Excerp. Med. Int. Cong. Ser. no. 122, 164 (1966).
The following Examples further illustrate the present invention in which all ratios, parts and percentages are by weight.
EXAMPLE 1 Preparation of O-2-Bromobenzyloxycarbonyl-L-tyrosyl-D-alanyl-glycyl-L-phenylalanyl-L- methionyl- 0- CH2 resin Tert-butyloxycarbonyl-methionine-O-CH2-resin 1.08 g. 0.50 mmole), prepared by the method of Gisin, Helv. Chim. Acta., 56, 1476 (1973 , was placed in the reaction vessel of a Beckman Model 990 automatic peptide synthesizer, programmed to carry out the following cycle of washes and reactions: (a) methylene chloride; (b) 33% trifluoroacetic acid in methylene chloride (2 times for 2.5 and 25 minutes each); (c) methylene chloride; (d) ethanol; (e) chloroform; ((f) 10% triethylamine in chloroform (2 times for 5 minutes each); (g) chloroform; and (h) methylene chloride.
The deprotected resin was then stirred with tert-butyloxycarbonyl (t-Boc) phenylalanine (400 mg., 1.5 mmoles) in methylene chloride, and dicyclohexylcarbodiimide (1.5 mmoles) 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 deprotected 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.
The following amino acids (1.5 mmoles) were then coupled successively by the same cycle of events; t-Boc-Gly-OH; t-Boc-D-Ala-OH; t-Boc-Tyrt2-BrZ)-OH. The completed pentapeptide resin was washed with methanol (3 times) and dried under reduced pressure whereupon 1.04 g of material was obtained.
EXAMPLE 2 Preparation of L-tyrosyl-D-alanyl-glycyl-L-phenylalanyl-L-methionine Removal of the protecting group and cleavage of the pentapeptide from the resin obtained according to the method of Example 1 was carried out by treating 1.04 g of the peptide-resin with hydrogen fluoride (20 ml) and anisole (2 ml) at 0 C for 45 minutes. The hydrogen fluoride was removed at reduced pressure and the anisole removed by washing with ethyl acetate.
The crude peptide was purified by gel filtration on a column (2.5 x 95 cm) of Sephadex G-15 by elution with 0.2 molar acetic acid and fractions shown to contain a major peak by uv absorption at 280 nm were pooled and evaporated to dryness.
The residual oil was applied to a column (2.5 x 95 cm) of Sephadex G-25, previously equilibrated with the lower phase followed by the upper phase of n-butanol: acetic acid: water (4:1:5) solvent system. Elution with the upper phase yielded a major symmetrical peak and material from this was evaporated to dryness and lyophilized from dilute acetic acid solution to yield a white, fluffy powder (119 mg); [a]26 = +40.400 (C = 0.69, 0.1 M HOAc).
The product was homogeneous by thin layer chromatography in four separate solvent systems on silica gel when loads of 20 ug were applied and visualized by exposure to ninhydrin reagent followed by chlorine/starch-potassium iodide reagent. The following Rf values were obtained: (A) 1-butanol: acetic acid: water (4:1:5 upperphase), 0.52; (B) ethyl acetate: pyridine: acetic acid: water ((5:5:1:3) 0.81; (C) 2-propanol: 1M acetic acid (2:1), 0.69; (D) 1-butanol:acetic acid: water: ethyl acetate (1:1:1:1), 0.66.
EXAMPLE 3 Preparation of 0-2-Bromobenzyloxyearbonyl-L-tyrosyl-D-leucyl-glycyl-L-phenylalanyl-L- rnethionyl-O-CH2-resin Using the conditions described in Example 1, the t-Boc derivatives of H-Phe-OH, H-Gly-OH, D-Leu-OH, and H-Tyr(2-BrZ)-OH were coupled successively to a H-Met-O CH2-resin (0.63 g, 0.50 mmole). The completed, dried pentapeptide resin weighed 1.07 g.
EXAMPLE 4 Preparation of L-tyrosyl-D-leucyl-glycyl-L-phenylalanyl-L-methionine The above-named compound was prepared by deprotecting and cleaving the desired peptide from the resin support of Example 3 under the conditions described in Example 2.
The crude peptide was 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. The pentapeptide was obtained as a white, fluffy powder (138 mg); [a]26 = + 39.96 (C = 1.05, 50% HOAC).
The product is homogeneous by thin layer chromatography using the spray reagents and solvent systems described in Example 2: (A), 0.71; (B), 0.79; (C), 0.70; (D), 0.75. Amino acid analysis gave: Tyr, 0.99; Leu, 0.99; Gly, 1.00; Phe, 1.00; Met, 0.94.
EXAMPLE 5 Preparation of O-2-Bromobenzyloxycarbonyl-L-tyrosyl-D-phenylalanyl-glycyl-L phenylalanyl -L -methionyl - 0- CH2-resin Using the conditions described under Example 1, the t-Boc derivatives of H-Phe-OH, H-Gly-OH, H-D-Phe-OH, and H-Tyr(2-BrZ)-OH were coupled successively to a H-Met O-CH2-resin (0.63 g, 0.50 mmole) to yield the desired peptide resin which, when dried, weighed 1.08 g.
EXAMPLE 6 Preparation of L-tyrosyl-D-phenylalanyl-glycyl-L-phenylalanyl-L-methionine The pentapeptide was deprotected and cleaved from the resin support of Example 5 under the conditions described in Example 2. The crude peptide was purified by gel filtration on a column (2.5 x 95 cm) of Sephadex G-15 by elution with 50% acetic acid followed by partition chromatography as described in Example 2. The pentapeptide was obtained as a white fluffy powder (230 mg); [a]26 = -8.6" (C = 1.04, 50% HOAc).
The product is homogeneous by thin layer chromatography using the spray reagents and solvent systems described in Example 2: (A), 0.65; (B), 0.80, (C), 0.66; (D), 0.78. Amino acid analysis gave: Tyr, 0.99; Phe, 1.99; Gly, 1.01; Met, 1.00.
EXAMPLE 7 Preparation of O-2-bromobenzyloxycarbonyl-L-tyrosyl-D-analyl-glycyl-L-phenylalanyl-L methionyl-benzhydrylamine resin Using the conditions described under Example 1, the t-Boc derivatives of H-Met-OH, H-Phe-OH, H-Gly-OH, H-D-Ala-OH, and H-Tyr(2-BrZ)-OH were coupled to a benzhydrylamine resin (0.63 g, 0.5 mmole) which was purchased from Beckman Instruments, Palo Alto, California. The completed, dried pentapeptide resin weighed 1.14 g.
EXAMPLE 8 Preparation of L-tyrosyl-D-alanyl-glycycl-L-phenylalanyl-L-methionine amide The pentapeptide amide 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 a fluffy white powder (17 mg); [a]26 = +37.040 C = 0.27, 0.1 M HOAc).
The product is homogeneous by thin layer chromatography using the spray reagents and solvent systems described in Example 2.
(A), 0.56; (B), 0.82; (C), 0.56; (d), 0.62. Amino acid analysis gave: Tyr, 0.99; Ala, 1.04; Gly, 1.00; Phe, 1.00; Met, 0.95; NH3, 0.95.
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. In such solid dosage forms, the active compound is admixed with at least one inert 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. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Besides, inert diluents, 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 parenteral administration include sterile aqueous or non-aqueous solutions, suspendions, or emulsions. Examples of 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.
Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
The dosage of active ingredient in the compositions of this invention may be varied; however, it is necesesary that the amount of the active ingredient shall be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage levels of between 0.001 to 10 mg./kg. of body weight daily are administered to mammals to obtain effective relief from pain or to relieve depression.
The following examples further illustrate the pharmaceutical compositions which are a feature of this invention.
EXAMPLE 9 Tablets weighing 200 mg. and having the following compositions are formulated: Ingredient Mg L-Tyrosyl-D-alanyl-glycyl-L- phenylalanyl-L-methionine . . 50 Starch . . 120 Colloidal silica . 27 Magnesium stearate . 3 EXAMPLE 10 Sterile 10 ml. ampoules can be prepared containing 10 mg per ml of L-Tyrosyl-D-alanylglycyl-L-phenylalanyl-L-methionine amide, 0.1 percent sodium bisulfate, 0.7 percent sodium chloride, and 0.5 percent chlorobutanol as a preservative.
EXAMPLE 11 Topical aqueous formulations for administration by nose drops or nasal sprays are formulated containing 1 mg of L-tyrosyl-D-leucyl-glycyl-L-phenylalanyl-L-methionine, 3.8 mg. glycerine, 40 mg. sorbital, 0.02 mg. benzalkonium chloride and purified water q.s. 1 ml.
The following compounds are illustrative of additional compounds of formula I which are prepared according to the methods of examples 1-8: L-Tyrosyl-D-isoleucyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-tyrosyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-tryptophyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-serinyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-threonyl-glycyl-L-phenylalanyl-L. methionine L-Tyrosyl-D-methionyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-glutamyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-aspartyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-asparaginyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-lysyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-arginyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-glutaminyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-isoleucyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-tyrosyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-tryptophyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-serinyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-threonyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-methionyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-glutamyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-aspartyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-asparginyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-lysyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-arginyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-glutaminyl-glycyl-L-phenyylalanyl-L-methionine amide In keeping with standard peptide nomenclature, abbreviations for chiral amino acid residues have been used herein as follows: Try - L-tyrosine Gly - glycine Phe - L-phenylalanine Met - L-methionine D-Ala- D-alanine D-Leu - D-leucine D-Phe - D-phenylalanine The exception to specifying whether the chiral amino acid residue are in the natural (L) configuration or the D configuration is in the amino acid analyses reported in Examples 2, 4, 6 and 8.
The words "Beckman" and "Sephadex" are registered Trade Marks.
WHAT WE CLAIM IS: 1. A compound of the formula H-Tyr-X-Gly-Phe-Met-Y wherein X is a D-amino acid radical selected from D-alanyl, D-leucyl, D-isoleucyl, D-valyl, D-phenylalanyl, D-tyrosyl, D-tryptophanyl, D-seryl, D-threonyl, D-methionyl, Dglutamyl, D-glutaminyl, D-aspartyl, D-asparginyl, D-lysyl or D-arginyl, Y is NH2 or OH, or a pharmaceutically acceptable salt thereof.
2. A compound in accordance with claim 1 wherein Y is OH.
3. A compound in accordance with claim 1 wherein Y is NH2.
4. A compound in accordance with claim 2 wherein X is D-alanyl.
5. A compound in accordance with claim 2 wherein X is D-leucyl.
6. A compound in accordance with claim 2 wherein X is D-phenylalanyl.
7. A compound in accordance with claim 3 wherein X is D-phenylalanyl.
8. A compound in accordance with claim 3 wherein X is D-alanyl.
9. A compound in accordance with claim 3 wherein X is D-leucyl.
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (22)

**WARNING** start of CLMS field may overlap end of DESC **. EXAMPLE 11 Topical aqueous formulations for administration by nose drops or nasal sprays are formulated containing 1 mg of L-tyrosyl-D-leucyl-glycyl-L-phenylalanyl-L-methionine, 3.8 mg. glycerine, 40 mg. sorbital, 0.02 mg. benzalkonium chloride and purified water q.s. 1 ml. The following compounds are illustrative of additional compounds of formula I which are prepared according to the methods of examples 1-8: L-Tyrosyl-D-isoleucyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-tyrosyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-tryptophyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-serinyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-threonyl-glycyl-L-phenylalanyl-L. methionine L-Tyrosyl-D-methionyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-glutamyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-aspartyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-asparaginyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-lysyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-arginyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-glutaminyl-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-isoleucyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-tyrosyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-tryptophyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-serinyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-threonyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-methionyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-glutamyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-aspartyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-asparginyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-lysyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-arginyl-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-glutaminyl-glycyl-L-phenyylalanyl-L-methionine amide In keeping with standard peptide nomenclature, abbreviations for chiral amino acid residues have been used herein as follows: Try - L-tyrosine Gly - glycine Phe - L-phenylalanine Met - L-methionine D-Ala- D-alanine D-Leu - D-leucine D-Phe - D-phenylalanine The exception to specifying whether the chiral amino acid residue are in the natural (L) configuration or the D configuration is in the amino acid analyses reported in Examples 2, 4, 6 and 8. The words "Beckman" and "Sephadex" are registered Trade Marks. WHAT WE CLAIM IS:
1. A compound of the formula H-Tyr-X-Gly-Phe-Met-Y wherein X is a D-amino acid radical selected from D-alanyl, D-leucyl, D-isoleucyl, D-valyl, D-phenylalanyl, D-tyrosyl, D-tryptophanyl, D-seryl, D-threonyl, D-methionyl, Dglutamyl, D-glutaminyl, D-aspartyl, D-asparginyl, D-lysyl or D-arginyl, Y is NH2 or OH, or a pharmaceutically acceptable salt thereof.
2. A compound in accordance with claim 1 wherein Y is OH.
3. A compound in accordance with claim 1 wherein Y is NH2.
4. A compound in accordance with claim 2 wherein X is D-alanyl.
5. A compound in accordance with claim 2 wherein X is D-leucyl.
6. A compound in accordance with claim 2 wherein X is D-phenylalanyl.
7. A compound in accordance with claim 3 wherein X is D-phenylalanyl.
8. A compound in accordance with claim 3 wherein X is D-alanyl.
9. A compound in accordance with claim 3 wherein X is D-leucyl.
10. L-Tyrosyl-D-alanyl-glycyl-L-phenylalanyl-L-methionine.
11. L-Tyrosyl-D-leucyl-glycyl-L-phenylalanyl-L-methionine.
12. L-Tyrosyl-D-phenylalanyl-glycyl-L-phenylalanyl-L-methionine.
13. L-Tyrosyl-D-analyl-glycyl-L-phenylalanyl-L-methionine amide.
14. A pharmaceutical composition suitable for oral, parenteral, nasal, rectal, vaginal or sublingual administration comprising a compound as claimed in any preceding claim.
15. A pharmaceutical composition in accordance with claim 14 for parenteral administration.
16. A pharmaceutical composition in accordance with claim 14 for nasal administration.
17. A pharmaceutical composition in accordance with claim 14 for sublingual administration.
18. A pharmaceutical composition in accordance with claim 14 for rectal or vaginal administration.
19. A pharmaceutical composition in accordance with claim 14 for oral administration.
20. A compound of the formula: R3-Tyr(R2)-X-Gly-Phe-Met-R wherein: Rl is OH, NH2 or a derivatized, insoluble polystyrene support of the formula:
H H II - N - c - polystyrene resin suppor or - o - cH2 - polystyrene R2 is hydrogen or a protecting group selected from tert-butyl, tetrahydropyranyl, trityl, benzoyl, 2,4-dichlorobenzyl, benzyloxycarbonyl or 2-bromobenzyloxycarboxyl, R3 is hydrogen or an a-amino protecting group, X is as defined in Claim 1, and 8 represents phenyl, with the proviso that when R3 is OH or NH2 R1 or R2 is other than hydrogen.
21. A compound as defined in Claim 1 or Claim 20 substantially as herein described with reference to any one of Examples 1 to 8.
22. A pharmaceutical composition comprising a therapeutically effective amount of a methionine enkaphalin derivative substantially as herein described with reference to any one of Examples 9 to 11.
GB3638777A 1977-08-31 1977-08-31 Methionine enkephalin derivatives Expired GB1592385A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2129434A (en) * 1982-10-08 1984-05-16 Ciba Geigy Ag Production of azo compounds
US4459225A (en) * 1979-08-22 1984-07-10 Hoechst Aktiengesellschaft Peptide amides and process for their manufacture

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4459225A (en) * 1979-08-22 1984-07-10 Hoechst Aktiengesellschaft Peptide amides and process for their manufacture
GB2129434A (en) * 1982-10-08 1984-05-16 Ciba Geigy Ag Production of azo compounds

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