DE2739440A1 - PENTAPEPTIDE AND MEDICINAL PRODUCTS CONTAINING IT - Google Patents

Description

PATENT LAWYERS R. SPLANEMANN dr. B. REITZNER J. RICHTER F. WERDERMANN

DIPL.-ING. OIPL.-CHEM. OIPL.-ING. DIPL.-ING.

MONKS

David Howard Coy 4319 Perrier Street New Orleans / USA

and

Abba Jeremiah Kastin 4400 Morales Street Metairie / USA

HAMBURG

βοοο munchen 2 September 1, 1977 ^{T 113}

τι «« »jom)» «w / a« »

Tekg.ammc _: Invents Munchen

un «.. Aktc: 1544 -I- 10.077

Your sign:

Pentapeptides and pharmaceuticals containing them

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description

The invention relates to new pentapeptides of the general formula

H-Tyr-X-Gly-Phe-Met-Y I

wherein X is a D-amino acid which is selected from the group D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-threonine, D-methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-asparagine, D-lysine and D-arginine and Y mean NHg or OH, as well as their salts, in particular their pharmaceutically acceptable salts, the new intermediate products for production of the new pentapeptides and pharmaceutical agents containing them and their use for relief of pain in mammals and the elimination of depressive states.

While there are already a number of analgesic agents currently used to provide relief from the weak to the strong Pain are used, but one is constantly looking for even better analgesics because of the numerous Problems That Occur With The Agents Currently Available · Aspirin and related salicylates are considered non-narcotic analgesic agents are considered useful are useful for the relief of mild to moderate pain in addition to their anti-inflammatory properties and antipyretic agents · The intake of salicylic acid or related salicylates, however, can lead to epigastric pain, nausea, and vomiting. These in large The widely used class of non-narcotic analgesics can also cause gastric ulceration and even hemorrhage cause in laboratory animals as well as in humans.

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An exacerbation of digestive tract ulcer symptoms and erosive gastritis has been noted in high dose patients, i.e., arthritis patients. «Aspirin is also one of the most common Causes of drug poisoning in children and has potential severe toxicity if not is used properly.

Acetaminophen is also considered a non-narcotic analgesic agent that is useful in the treatment of mild pain associated with simple headache, ordinary muscle pain and the like Acetaminophen especially suitable for patients who cannot take aspirin, i.e. for ulcer patients, his However, use is contraindicated in patients who are sensitive to it, except for their drawbacks the mild non-narcotic analgesic agents are not sufficiently potent in terms of their potential side effects Effect to relieve the severe pain that occurs during surgery, cancer and the like.

Unfortunately, the potent analgesic agents that can relieve such severe pain are also narcotic agents and their use involves the danger of Development of a physical and sometimes also psychological dependency with eich · To date there is none Effective remedies for severe pain that are completely safe. Therefore, there is an urgent need for improved analgesic agents for the treatment of both low pain as well as severe pain · The present invention satisfies this need.

In addition to the need to develop improved analgesic agents, there is also a need for improved psychotropic agents that will replace the

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offer current therapy or an alternative to it. The compounds according to the invention have in addition to their analgesic activity (effectiveness) also has an antidepressant activity (effectiveness). Your usefulness as an analgesic agent is improved because many patients suffering from pain also vary Have states of anxiety and depression

A recently identified pentapeptide, methionine encephalin, has the following structure: H-Tyr-Gly-Gly-Phe-Met-OH (see Hughes et al, "Nature", 2 £ 8, 577 (1975)). This Peptide is found in many areas of the brain where it is obviously used as a neurotransmitter or neuromodulator acts in a central pain suppression system. The natural peptide binds stereospecifically partially purified brain opiate receptor centers (see e.g. Bradbury et al, "Nature", 260, 793 (1976)), it is very active in bioassays for opiate activity, however it exhibits little analgesic effect of a short time Duration when injected directly into the brain of a rat (see e.g. Beluzzi et al, "Nature", 260, 625 (1976)).

It has now surprisingly been found that when the methionine encephalin is in the 2-position by a D-amino acid is substituted, strong analgesic agents are obtained. Besides their analgesic activity (effectiveness) the new compounds obtained thereby also have excellent antidepressant activity (effectiveness).

The invention relates to new pentapeptides, in particular new methionine caphalin derivatives, which can be used as analgesic and antidepressant agents, intermediates suitable for the production of the new pentapeptides, and pharmaceutical agents (preparations) and their use for the relief of pain and for the elimination of depressive states. The new pentapeptides act

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it is in particular methionine encephalin, which is substituted in the 2-position by a D-amino acid, and the corresponding amides _o

The new compounds according to the invention can by general formula are shown

H-Tyr-X-Gly-Fhe-Met-Y I

wherein X is a D-amino acid which is selected from the group D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-threonine, D -Methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-asparagine, D-lysine and D-arginine, and Y VEL ^ or OH, and the salts, in particular the pharmaceutically acceptable salts thereof.

Unless otherwise indicated, all of the chiral amino acid residues mentioned here are in the natural or L-configuration before.

The term "pharmaceutically acceptable salts" used here includes the non-toxic alkali metal, alkaline earth metal and ammonium salts commonly used in the pharmaceutical industry, e.g. the sodium, potassium, lithium, calcium, magnesium, barium and ammonium salts, which are prepared according to methods known per se getting produced. This term also includes non-toxic acid addition salts, which in general are prepared by reacting the compounds according to the invention with a suitable organic or inorganic one Acid. Representative examples of these salts include the hydrochlorides, hydrobromides, sulfates, bisulfates, Acetates, oxalates, valerates, oleates, laurates, borates, benzoates, lactates, phosphates, tosylates, citrates, maleates, fumarates,

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Succinates, tartrates, napsylates and the like.

The invention also relates to intermediates general formula

R ³ -Tyr (R ² ) - X - GIy - Phe - Met - E ¹ II

wherein fi is selected from the group NB ^ t OH and one derivatized insoluble polystyrene resin carrier of the formula

ι pru Ajr t »irjr AWL-

III

Polystyrene or 0 - CHp resin support IV

B is a protecting group for the phenolic hydroxyl group of tyrosine, which is selected from tetrahydropyranyl, tert-butyl, trityl, benzoyl, 2,4-dichlorobenzyl, benzyloxycarbonyl and 2-bromobenzylo: cycarbonyl (2-Br-Z), where the latter is preferred, means .; R can also be a hydrogen atom, which means that there is no protecting group on the phenolic hydroxyl interface, and R * stands for a protective group which would also be used in the solid phase synthesis of the peptides of the formula (I), which is selected from the group of protective groups of the acyl type, the protective groups of the aromatic urethane type, the cycloalkyl urethane protecting groups, the thiourethane type protecting groups, the alkyl type protecting groups, the Trialkylsilane or aliphatic urethane protecting groups, and wherein X is a D-amino acid, as in formula (I) defined, means. If X is a Ώ-amino acid with a represents functional side chain, the following protective groups are suitable

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D-tyrosine; as noted above for R · D-serine, D-threonine; a protective 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 are preferably Benzyl or tert-butyl is. D-lysine; a protecting group for the amino function, which is preferably either benzyloxycarbonyl or 2-chlorobenzyloxycarbonyl acts. D-arginine; a protecting group for the guanidino function, which is preferably either tosyl or is about nitro.

The term "acyl-type protecting groups" as used herein refers to groups _{illustrated by, but not limited to, pormyl, trifluoroacetyl f} tosyl, hitrososulfenyl and the like. The term "aromatic urethane-type protecting groups" as used herein ⁿ refers to groups such as benzyloxycarbonyl, p-ethoxybenzyloxycarbonyl, p-biphenylisopropyloxycarbonyl, 2,5-dimethoxyphenylisopropyloxycarbonyl groups and the like. Cyclohexylcarbonyl, isoboronyloxycarbonyl groups, and the like. The term ^w urethane-type protecting groups "as used herein refers to, but is by no means limited to, groups such as phenylthiocarbonyl. The term" alkyl-type protecting groups "used herein includes such as them commonly used in this field, e.g. trityl. As used herein, the term "trialkylsilane" includes compounds such as trimethylsilane, triethylsilane, tributylsilane, and the like · Among the preferred protecting groups, the "aliphatic ürethan-Schut" groups ¹¹ include tert-butyloxycarbonyl, Diisopropyloxycarbonyl, Ieopropyloxycarbonyl, allyloxycarbonyl and the like ·

The polystyrene resin support is preferably

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-> r- 2739AAÜ

a copolymer of styrene with about 1 to 2 % divinylbenzene as a crosslinking agent which causes the polystyrene polymer to become completely insoluble in most organic solvents. In formula III / 0 stands for phenyl.

When choosing a specific side chain protecting group to be used in the synthesis of the peptides of Formula I. is to be, various conditions must be met »

(a) The protecting group must be opposite the reagent and below that required for removal of the α-amino protecting group in each The conditions chosen for the synthesis stage,

(b) the protecting group must retain its protective properties and must not be chemically modified and

(c) the side chain protective group must be removable at the end of the solid phase synthesis under reaction conditions, which do not change the peptide chain

The pentapeptides of formulas (I) and (II) are prepared using standard solid phase methods. The synthesis begins at the terminal C-end of the peptide using an α-amino-protected resin -Amino-protected methionine on a chloromethylated resin, a hydroxymethyl resin or a Benshydrylaminhars · Such a chloromethylated resin is sold under the trade name Bio-beads SX-1 by the company Bio Rad Laboratories, Richmond, California / USA and is the manufacture of the hydroxymethyl resin by Bodonesky et al. in "Ohem. Ini. (London) ¹¹ , ^ 8, 1597 (1% 6). The benzhydrylamine hair is described by Pietta and Marshall in" Chem. Commun. ", 650 (1970) and it is commercially available from Beckman Instruments, Palo Alto,

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In preparing the compounds of the invention, the α-amino-protected methionine is coupled to the chloromethylated resin using, for example, a cesium bicarbonate catalyst according to the method described by Gisin in "HeIv. Chim. Acta.", 6, 14-76 (1973) . After the initial coupling, the α -amino protecting group is removed by selecting suitable reagents, such as trifluoroacetic acid or hydrochloric acid solutions in organic solvents at room temperature.After removal of the α-amino protecting group, the remaining protected amino acids are gradually in the desired order coupled to produce the compound of formula II. Each protected amino acid is generally reacted in a 3-fold excess using a suitable carboxyl group activator, such as dicyclohexylcarbodiimide, dissolved, for example, in 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 can cleave not only the peptide from the resin but also any residual side chain protecting groups Resin is used, the hydrogen fluoride treatment leads to the formation of the free peptide acids of the formula I (Y »OH). If the benzhydrylamine resin is used, the hydrogen fluoride treatment leads directly to the free peptide amides of the formula I (Y« NH ₂ ) When the chloromethylated resin is used is, the side chain protected peptide can alternatively be cleaved by treating the peptide harses with ammonia to form the desired side chain protected amide. The side chain protection is then removed in the usual way by treatment with hydrogen fluoride, the amides of the formula I being obtained.

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273944Q

The solid phase process discussed above is on
is known and it is essentially described by JM Stewart in "Solid Phase Peptide Synthesis", Freeman and Co., San Francisco, 1969 ".

The compounds of formula I are useful as analgesic and antidepressant agents when taken in daily doses
from 0.001 to 10 mg / kg body weight, preferably in
divided doses, administered to mammals. The compounds are preferably administered parenterally,
ie, administered intravenously, intraperitoneally, intramuscularly, or subcutaneously. The compounds can also be administered in various other ways, for example orally or sublingually or vaginally, rectally or nasally. Pharmaceutical agents (preparations) which are suitable for these types of administration therefore represent a further aspect of the present invention.

The analytical activity of the compounds of the formula I was determined in the rat tail pinch test, as described by D'Amour and Smith in "J. Pharmac. Exp.! ¹¹ , £ 2, 74 (19AI),
is described. The presently preferred analgesic agent of the present invention is D-AIa methionine kephalin (X = D-alanine, Y = OH), which is considerably more potent than methionine kephalin and morphine.

The antidepressant activity (effectiveness) was in the
DOPA potentiation test as described by Everett in "Proc.
1st Int. Symp. Antidepressant Drugs, Excerp. Med. Int.
Cong. Ser. ", No. 122, 164 (1966).

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

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example 1

Preparation of O ^ -Bromobenz ^ loxycarbonyl-L-tyrosyl-D-alanyl-glycyl-L-phenylalanyl-L-methionyl-O-C ^ resin

1.08 g (0.50 milliliter) tert-butyloxycarbonyl-methionine-O-CHo-resin, prepared according to the method of Gisin, ⁿ Helv. Chim. Acta. ", £ 6, 1476 (1973)" were introduced into the reaction vessel of an automatic beptide synthesizer from Beckman, Model 990, which was programmed to carry out the washing and reaction cycles indicated below: a) methylene chloride, (b) 33% trifluoroacetic acid in methylene chloride (2 times 2.5 minutes or 25 minutes), (c) methylene chloride, (d) ethanol, (e) chloroform, (f) 10% triethylamine in chloroform (2 times 5 minutes each), (g) chloroform and (h) methylene chloride.

The deprotected resin was then treated with 400 mg (1.5 mmol) of tert-butyloxycarbonyl (t-Boc) -phenylalanine in Methylene chloride was stirred and 1.5 »moles of dicyclohexylcarbodiimide were added. The mixture was stirred for 2 hours stirred at room temperature and the peptide resin was then successively with methylene chloride (3 times), ethanol (3 times) and methylene chloride (3 times) · The bound amino acid was · with 33% trifluoroacetic acid in methylene chloride (2 times for 2.5 and 25 minutes, respectively) from the Deprotected and then the above-mentioned steps (c) to (h) were carried out.

The amino acids given below (1.5 mol) were then coupled in succession using the same cycle of work t t-Boc-Gly; t-Boc-D-AIa; t -Boc-Tyr (2-Br-Z). That Completed pentapeptide resin was washed 3 times with methanol and dried under reduced pressure, whereby 1.04 g of material was obtained.

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Example 2

Production of L-tyrosyl-D-alanyl-L-glycyl-L-phenylalanyl- L-methionine

The deprotection and cleavage of the pentapeptide from the resin obtained by following the procedure of Example 1 were carried out by treating 1.04 g of the peptide resin with 20 ml of hydrogen fluoride and 2 ml of anisole for 45 minutes at ⁰ ° C. The hydrogen fluoride was removed under reduced pressure and the anisole was removed by washing with ethyl acetate.

The crude peptide was purified by gel filtration on a Sephadex G-15 column (2.5 cm 95 cm) by eluting with 0.2 molar Acetic acid purified and the fractions obtained, which had a main maximum in UV absorption at 280 nm, were collected and evaporated to dryness.

The remaining oil was on a Sephadex G-25 column (2.5 cm χ 95 cm), which was previously with the lower phase and then with the upper phase of n-butanol / acetic acid / water (4/1/5) - Solvent system had been equilibrated. By eluting with the upper phase, a material with a symmetrical main maximum was obtained and this was evaporated to dryness and lyophilized with a dilute acetic acid solution, whereupon 119 ag of a white flaky powder was obtained, [cdp ⁶ - +40 , 40 ° (C - 0.69, 0.1 M HOAc).

The product was homogeneous in the thin layer chromatography in four separate solvent systems on silica gel, when 20 µg of the product was given up and visualized by adding Hinhydrin-Beagene and subsequent addition of Ohlor / Starch-Potassium Iodide-Beagene. It became the

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Rf values given below are obtained:

A) 1-butanol / acetic acid / water (V1 / 5 »upper phase) ■ 0.52;

B) ethyl acetate / pyridine / acetic acid / water (5/5/1/3) - 0.81;

C) 2-propanol / IM acetic acid (2/1) »0.69,

D) I-butanol / acetic acid / water / ethyl acetate (1/1/1/1) = 0.66.

Example 3

Preparation of the 0-2-bromobenzyloxycarbonyl-L-tyrosyl-D-leucyl-Ir-glycyl-Ii-phenylalanyl-Ij-methionyl-O-C 1-4 resin

Under the conditions given in Example 1, the t-Boc derivatives of Phe, GIy, D-Leu and Tyr (2-Br-Z) were successively with 0.63 g (0.50 millimoles) of a Met-O-C ^ resin coupled. The completed, dried pentapeptide resin weighed 1.07 g.

Example 4-

Production of L-tyrosyl-D-leucyl-L-glycyl-L-phenylalanyl- L-methionine

The above compound was prepared by removing the protective group and cleavage of the desired peptide from the resin support of Example 3 under the conditions given in Example 2. The crude peptide was purified by gel filtration on a Sephadex G-15 column (2.5 cm χ 95 cm) by eluting with 2.0-aolar acetic acid and subsequent partition chromatography, as indicated in Example 2, purified "138 μg of pentapeptide were obtained in the form of a white, flaky powder, Ca] ^ ⁶ " + 39.96 ° (C = 1.05, 50 % HOAc). The product was homogeneous in thin layer chromatography using the spray reagents and solvent systems as indicated in Example 2: (A) 0.71; (B) = 0.79; (C) = 0.70; (D) = 0.75. The amino acid analysis gave: Tyr 0.99, Leu 0.99, GIy 1, OC, Phe 1.00 and Met 0.9Λ. 809809/1106

Example 5

Preparation of the O-2-bromobenzyloxycarbonyl-L-tyrosyl-D-phenylalanyl-Ir-phenylalanyl-Ir-methionyl-0-CH2 resin

Under the conditions given in Example 1, the t-BOc derivatives of Phe, GIy, D-Phe and Tyr (2-Br-Z) were successively mixed with 0.63 g (0.50 mmol) of Met-O-CH ₂ - Resin coupled to give the desired peptide-resin which, when dried, weighed 1.08 g.

Example 6

Production of L-Tyrosyl-D-phenylalanyl-L-glycyl-Ir-phenyl- alanyl-L-methionine

The pentapeptide was deprotected and removed from the resin support of Example 5 below that in Example 2 split off specified conditions. The crude peptide was purified by gel filtration on a Sephadex G-15 column (2.5 cm χ 95 cm) by eluting with 50% acetic acid and subsequent Partition chromatography purified as in Example 2. This gave 230 mg of pentapeptide in the form of a white

-O

flaky powder, [cup = -8.6 ° (C = 1.04, 50% HOAc). The product was on thin layer chromatography in use of the spray reagents and solvent systems as given in Example 2, homogeneous: (A) = 0.65; (B) »0.80; (G) = 0.66; (D) = 0.78. The amino acid analysis found: Tyr 0.99, Phe 1.99, GIy 1.01, Met 1.00.

Example 7

Preparation of the 0-2-bromobenzyloxycarbonyl-L-tyrosyl-D-alanyl- If-phenylalanyl-II-methionylbenghydrylamine resin

Under the conditions given in Example 1, the t-Boc derivatives of Met, Phe, GIy, D-AIa and Tyr (2-Br-Z) were with

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0.63 g (0.5 nmol) of a benzhydrylamine resin coupled, sold by Bookman Instruments, FaIo Alto, California / USA. Sa’s completed, dried pentapeptide resin weighed 1.14 g.

Example 8

Production of L-Tyrosyl-D-alanyl-L-glycyl-L-phenylalanyl- «·» d

The pentapeptide amide was freed from the protective group under the conditions given in Example 2 and cleaved from the resin support of Example 7. The crude material was purified by gel filtration and partition chromatography as in Example 2, 17 mg of a fluffy white powder, COU5 ⁶ - ♦ 37.04 ° (C-0.27, 0.1 M HOAc). The product was homogeneous in thin layer chromatography using the spray reagents and solvent systems as indicated in Example 2: (A) - 0.56, (B) - 0.82, (C) 0.56, (D) - 0.62. The amino acid analysis gave: Tyr 0.99, ^ Ia 1.04, GIy 1.00, Phe 1.00, Met 0.95, »Hj 0.95.

The present application also relates to pharmaceutical agents or preparations which are used as active ingredients (Active ingredient) at least one of the compounds of the formula I given above, optionally in combination with a pharmaceutical carrier or diluent contain the compounds according to the invention can be administered orally, parenteral ”, nasal, vaginal, rectal or subligual Way · can be administered and they can be in dosage forms be prepared that are suitable for any type of administration

Fixed dosage forms for oral administration include

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Capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound (the Active ingredient) with at least one inert diluent, such as sucrose, lactose or starch, mixed. As is customary in practice, these dosage forms can also except inert diluents contain other additional substances, such as lubricants such as magnesium stearate. In the case of the capsules, tablets and pills, the dosage forms can also contain buffers. Combined with enteric coatings can also be made into tablets and pills.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, Suspensions, syrups and elixirs containing inert diluents as commonly used in the art such as water.As well as inert diluents, such preparations can also contain adjuvants, such as wetting agents, emulsifying agents and suspending agents, and sweeteners, flavoring agents and perfuming agents.

For preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or carriers are propylene glycol, Polyethylene glycol, vegetable oils such as olive oil, and injectables organic esters, such as ethyl oleate »These dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. You can, for example, by filtering through a bacteria retention filter, by incorporating Sterilizing agents in the preparations, by means of scalding of the preparations or by heating the preparations. They can also be in the form of sterile solid preparations or preparations are manufactured,

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Ζ «

those in sterile water or any other sterile injectable medium immediately prior to their use can be solved

The preparations (preparations) for rectal or vaginal administration are preferably Suppositories that, in addition to the active substance (the active ingredient), also have excipients, such as cocoa butter or a Suppository wax, may contain

The preparations (preparations) for nasal or sublingual administration are also involved in this field known standard auxiliary materials.

The dosage of the active ingredient in the preparations according to the invention can be varied; the amount of however, the active ingredient (drug) should be large enough to provide a suitable dosage form chosen dosage depends on the desired therapeutic effect, on the mode of administration and on the duration of the treatment. In general, doses between 0.001 and 10 mg / kg body weight daily in mammals are used given for effective pain or depression relief.

The invention is explained in more detail below with the aid of a few specific examples of pharmaceutical preparations, but without being limited to it.

Example 9

Tablets with a weight of 200 mg and the composition given below were produced

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Component mg

L-tyrosyl-D-alanyl-L-glycyl-L-phenylalanyl-L-methionine 50

Strength 120

colloidal silicon dioxide 27

Magnesium stearate 3

Example 10

Sterile 10 ml ampoules were produced containing 10 mg of L-tyrosyl-D-alanyl-L-glycyl-L-phenylalanyl-L-methionine amide, 0.1% sodium bisulfate, 0.7 % sodium chloride and 0.5% per ml % Contained chlorobutanol as a preservative.

Example 11

Pure administration in the form of nasal drops or one Nasal sprays, topical aqueous preparations containing 1 mg L-tyrosyl-D-leucyl-L-glycyl-L-phenylalanyl-L-methionine, 3 ~ 8 mg glycerol, 40 mg sorbitol, 0.02 mg benzalkanium chloride and purified water ad 1 ml contained «

Further examples of compounds of the formula I which are obtained by the methods of Examples 1 are given below until 8 were made:

Ir-lyrosyl-D-isoleucyl-L-glycyl-L-phenylalanyl-II-methionine L-tyrosyl-D-tyrosyl-L-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-tryptophyl-L-glycyl-L-phenylalanyl-II-methionine L-tyrosyl-D-serinyl-L-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-threonyl-L-glycyl-L-phenylalanyl-L-methionine L-tyrosyl-D-methionyl-L-glycyl-L-phenylalanyl-II-methionine L-tyrosyl-D-glutamyl-L-glycyl-L-phenylalanyl-L-methionine L-Tyrosyl-D-aspartyl-L-glycyl-L-phenylalanyl-iiaethionine L-tyrosyl-D-asparaginyl-L-glycyl-Ir-phenylalanyl-L-methionine L-Tyrosyl-D-lysyl-L-glycyl-Ir-phenylalanyl-L-methionine II-Tyrosyl-D-arginyl-L-glycyl-L-phenylalanyl-L-methionine

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L-Tyrosyl-D-glutaminyl-Ir-glycyl-Ir-phenylalanyl-L-methionine Ir ^ I ^ osyl-D-i8ole ^ lcyl-Iι- · glycyl · -Iι-phenylalazlyl-Ir-Inβthionina ^ ιid L-Tyrosy l-D-tyroeyl-L-glycyl-L-phenylalanyl-Ir-methionine aniide Ir-Tyrosyl-D-txryptophyl-L-glycyl-Ir-phenylalanyl-L-methionine amide L- ^ I ^ osyl-D-seriiiyl-I ^ -glycyl-Ii-phenylalai ^ l-L-methioiiinaiaid L-Tyrosyl-D-threonyl-L-glycyl-L-phenylalanyl-L-methioninaaiid L-Tyrosyl-D-methionyl-L-glycyl-L-phenylalanyl-L-methioninaaiid L-tyrosyl-D-glutamyl-L-glycyl-L-phenylalanyl-Ir-methionine amide L-T ^ osyl-D-aepartyl-L-glycyl-L-phenylalanyl-L-methionine amide L-Tyrosyl-D-aeparginyl-L-glycyl-Ir-pheiiylalanyl-L-methioninaaid Ir-Tyrosyl-D-lysyl-L-glycyl-L-phenylalanyl-L-methionine amide Ir-Tyrosyl-D-arginyl-L-glycyl-Ir-phenylalanyl-L-iaethioninamide L-Tryosyl-D-glutaminyl-L-glycyl-L-phenylalanyl-L-methionine amide.

Using the usual feptide nomenclature, the The following abbreviations are used for the chiral amino acid residues:

Try - L-tyrosine GIy - L-glycine Phe - L-fhenylalanine Mead - L-methionine D-AIa- D-alanine D-Leu- D-leucine D-Phe- D-fhenylalanine

Unless it is expressly stated whether the chiral amino acid set is in the natural (I ^ configuration or in the D configuration, the residues have the configuration as indicated in the amino acid analyzes in Examples 2, 4, 6 and 8.

809809/1106

Claims (1)

3 3 üU U Claims 1. Pentapeptide, characterized by the general formula ίί-Tyr-vi-Gly-Phe-Met-Y (I) wherein X is a D-amino acid which is selected from the group D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tyrosine, D-tryptophene, D-serine, D-threonine, D -Methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-asparagine, ΰ-lysine and D-arginine _rj and Ύ NH ₂ or OH, or a salt, in particular a pharmaceutically acceptable S ^ Iz ₁₁ thereof. 2. Compound according to claim 1, characterized in that that in the general formula Y is OH. 3. A compound according to claim 1, characterized in that Y is NH ₂ in the general formula. 4-. Connection according to Claims 1 to 5, characterized in that that in the general formula X is D-alanine. 5. Compound according to claims 1 to 3, characterized in that that in the general formula X denotes D-leucine. 6. A compound according to claims 1 to 3, characterized in that that in the general formula X denotes D-phenylalanine. 7β compound according to claim 3, characterized in that B t! V! B U y / 1 1 (J 6 ORIGINAL INSPECTED - 2 - 27 yrs that X is D-phenylalanine. 8. A compound according to claim 3, characterized in that X is D-alanine. 9 · Compound according to claim 3 »characterized in that X denotes D-leucine. 10. L-Tyrosyl-D-alanyl-L-glycyl-L-phenylalanyl-L-methionine. 11. L-Tyrosyl-D-leucyl-L-glycyl-L-phenylalanyl-L-methionine. 12. L-Tyrosyl-D-phenylalanyl-L-glycyl-L-phenylalanyl-L-methionine. 13. L-Tyrosyl-D-alanyl-L-glycyl-L-phenylalanyl-L-methionine arid. 14-e pharmaceutical agent for oral, parenteral, nasal, rectal, vaginal or sublingual administration, characterized in that there is at least one compound the general formula H-Tyr-X-Gly-Phe-Met-Y (I) wherein X is a D-amino acid which is selected from the group D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-threonine, D Methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-asparagine, D-lysine and D-arginine ₁ and Y denote NHo or OH, or at least one pharmaceutically acceptable salt thereof as active ingredient in a therapeutically effective amount, optionally in combination with at least one pharmaceutically acceptable carrier or diluent «contains. 809809/1106 ORIGINAL INSPECTED 2739UÜ 15 · Pharmaceutical agent according to claim 14, characterized characterized in that it is in the form of a preparation suitable for parenteral administration. 16. Pharmaceutical agent according to claim 14, characterized characterized in that it is in the form of a preparation suitable for nasal administration, 17. Pharmaceutical agent according to claim 14, characterized characterized in that it is in the form of a for the sublingual Administration of a suitable preparation. 18 · Pharmaceutical agent according to claim 14, characterized in that it is in the form of a for the rectal or vaginal administration suitable preparation is available. 19. Pharmaceutical agent according to claim 14, characterized characterized in that it is in the form of a preparation suitable for oral administration. 20. Pharmaceutical agent according to claims 14 to 19t, characterized in that it is used as the active component (Active ingredient) L-Tyrosyl-D-alanyl-L-glycyl-L-phenylalanyl-L-methionine contains. 21. Pharmaceutical agent according to claims 14 to 19, characterized in that it is the active component (active ingredient) L-tyrosyl-D-leucyl-L-glycyl-L-phenylalanyl-L-methionine contains. 22. Pharmaceutical agent according to claims 14 to 19 »characterized in that it is used as the active component (Active ingredient) Ir-Tyrosyl-D-phenylalanyl-L-glycyl-L-phenylalanyl-L-methionine contains. 23. Pharmaceutical agent according to claims 14 to 809809/1106 ORIGINAL INSPECTEP 2739A4Ü 19 »characterized in that it contains L-tyrosyl-D-phenylalanyl-L-glycyl-L-phenylalanyl-L-aethioninamide as the active component. 24. Use of the pharmaceutical agent according to claims 14 to 23 for pain relief in mammals and / or for the elimination of states of depression. 25 «connection, characterized by the general formula R ³ -Tyr- (R ² ) -X-Gly-Phe-Met-R ¹ (II) in which: R OH, NH ₂ or an insoluble polystyrene carrier of the formula which has been converted into a derivative or -0-CH ₀ - (polystyrene- R is a protecting group selected from t-butyl, Tetrahydropyranyl, trityl, benzoyl, 2,4-dichlorobenzyl, Benzyloxycarbonyl and 2-bromobenzyloxycarbonyl, R * hydrogen or an α-amino acid protecting group and X is a D-amino acid, which is selected from the group D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-threonine, D-methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-asparagine, D-lysine and D-arginine. 809809/1106