DE2752341A1 - BIOLOGICALLY ACTIVE AMIDES, THE PROCESS FOR THEIR MANUFACTURING AND THE PHARMACEUTICAL FORMULATIONS CONTAINING THEM - Google Patents

Description

DR. BEPG DIPL-INC. STAPF DIPL-ING. SCHWABE DR. DR. SANDMAIR 27 PATENT LAWYERS P.O. Box 860245, 8000 Munich 86

• 9 ·

Attorney File 28 64-1 November 23, 1977

Be / Sch

The Wellcome Foundation Limited London N.W. 1 / Great Britain

"Biologically active amides, processes for their preparation and pharmaceutical formulations containing them"

This invention relates to peptides and their derivatives, the manufacture these compounds, formulations which contain these compounds and the preparation of these formulations, and the use of the compounds in human and veterinary medicine.

A 522

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(089) 988272 Muierkircherslc 45 - 8000 Munich 80 Banks: 988273 Telegrams: Bayerische Vereinsbank Munich 453100 988274 BERCSTAPF PATENT Some Hypo-Bank Munich 3890002624 983310 TELEX: 05245 * 0 MOUNTAIN d Post check Munich 65343-808

In particular, the present invention relates to peptides and their derivatives that exhibit morphine agonist activity. As generally accepted and as the term is used here, u: '^ r a morphine agonist is to be understood as a compound, whose biological effectiveness mimics that of the natural alkaloid.

The pharmacological properties and therapeutic uses of morphine are described in the literature, see, for example, "The Phamacological Basis of Therapeutics", Goodman, L.S. and Gilman, A.eds by The MacMillan Company, New York, Third Edition (1965) in particular Chapter 15, pages 247-266, and "Martindale: The Extra Phamacopoeia ", Blacow, N.W. ed., Published by The Pharmaceutical Press, London, 26th Edition (1972), especially pages 1100-1106, all of which are incorporated herein by reference will. It is also known (see Goodman, L.S. et al., Supra, Chapter 16) that repeated administration of Morphine causes the recipient to become dependent on the drug and only to get used to it and causes withdrawal symptoms to occur if the administration is interrupted. Accordingly, studies have been carried out for many years with the aim of finding a compound that has the spectrum of activity of morphine, which, however, lacks its disadvantages.

The present invention provides novel peptides of the general Formula (I)

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/ 11

R- (X ¹ ) _m - (X ² ) _n -X ³ -X * -X ⁵ -X ⁶ -R ^{> t} (I)

together with their salts, esters, amides, N-alkylamides and N.N-dialkylamides and their acid addition salts, these Compounds exhibit morphine agonist activity in both in vitro and in vivo studies; where in the general formula (I):

the radicals X and Xr are the same or different and each the residue of a basic amino acid (D or L), X * a D or L residue of the general formula

W ¹ W R <- (CH ₂ ) _a . (CH) ₁₅ -CH-CO-

where R is phenyl or 1,4-cyelohexadien-i-yl, a = O, 1 or 2, b »O or 1, one of the radicals W and W ^ a -NR * - Group and the other is hydrogen, with the proviso that W is always an -NR * group when b is - O, and that when R is a 1,4-cyclohexadien-i-yl group, a is always 1 and b is im-. mer O, where R * is hydrogen or an alkyl, alkenyl, Alkynyl, carboxyalkyl, carboxyalkenyl and / or carboxy

is alkynyl, and wherein R is optionally substituted is by one or more groups, namely hydroxy, alkoxy, alkanoyloxy, alkyl, nitro, trifluoromethyl, amino, N-alkylamino, halogen, NN-dialkylamino and / or benzyloxy groups, in which the phenyl ring optionally is substituted by one or more groups, namely hydroxy, alkoxy, alkanoyloxy, halogen, alkyl, nitro, trifluoromethyl,

809821/1037

2 7 b 2 3 4 1

Amino, N-alkylamino and / or NN-dialkylamino groups, X ^ is a D radical, namely a C-propargylglycyl, alanyl, alpha-alkylalanyl, valyl, norvalyl, leucyl, isoleucyl, norleucyl -, prolyl, hydroxyprolyl, tryptophyl, asparaginyl and / or glutaminyl radical, in which each of the radicals is given-

if it is N-substituted by an alkyl group ,

X ^ a glycyl group or a D or L radical, namely a C-propargylglycyl, alanyl, alpha-alkylalanyl, ß-alanyl,

Valyl, norvalyl, leucyl, isoleucyl, norleucyl, prolyl,

Hydroxyprolyl, tryptophyl, asparaginyl and / or glutaminyl radical and each of these radicals is optionally N -substituted

is with an alkyl group,

X is a glycyl group, a D or L radical, namely methionyl,

Is leucyl, isoleucyl, norleucyl, valyl, norvalyl, prolyl, hydroxyprolyl, alanyl and / or histidyl radical, as well as the Values as given above for X ^,

R hydrogen, aralkyl, alkyl, alkenyl, alkynyl, carboxyalkyl,

Is carboxyalkenyl and / or carboxyalkynyl,

R is the hydroxyl group of the 1-carboxyl group of the C-terminal

Amino acid residues or a group that includes these 1-carboxyl

Il η

group, namely the group -CHoOR, in which R is hydrogen or alkanoyl and the 5-tetrazolyl group is optionally substituted in the 1- or 2-position with an alkyl and / or benzyl group and
each m and n, independently of one another, is O and 1,

except for the amides, N-alkylamides and N.N-dialkylamides and their Acid addition salts, in which X is a D or L radical of the general formula

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U Λ CHo.CHJ

* 2 NR ⁵

where R * is hydrogen or alkyl.

The abbreviations that are used here for the amino acids and their residues are those that are customary in this field and they are, for example, in Biochemistry, 11,
1726 (1972). In the preceding and following description, all references to the L-amino acids and their residues refer, except in the case of Glycii / ind, unless otherwise stated.

Under the term "basic amino acid" here is one

Amino acid with two basic functions and a carboxyl

1 group and as examples of the radicals X and X can be mentioned lysyl- (D- and L}, homoarginyl- (D- and L-), ornithyl- (D- and L-), histidyl- (D- and L-), «, If -diaminobutyryl- (D- and L-) and arginyl (D- and L-) residues.

In the general formula (I), the alkyl substituents which may be present in the radicals X and X ^ and the alkyl part of the rt-alkylalanyl unit for X and X? desirably 1 to 4, and preferably 1 or 2 carbon atoms. In the phenyl or 1,4-cyclohexadien-i-yl ring R ^{2 of} the radical J / and in any benzyloxy substituents present here, the halogen sub-

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7 b 2 3 4

stable fluorine, chlorine, bromine and / or iodine atoms and the
optionally present alkyl and / or alkoxy substituents together with the alkyl portions of the optionally present alkanoyloxy, N-alkylamino and NN-dialkylamino substituents desirably 1 to 4 and preferably 1 or
Have 2 carbon atoms.

If the phenyl or cyclohexadien-1-yl ring of the radical X ^

Has 1 or 2 substituent groups, these are groups
desirably located in the 3 and / or 4 positions of the ring.

The Alk.yieinneit for R and for the group R ^ of the radical X *
can together with said part in the carboxyalkyl unit in particular 1 to 4, for example 1 or 2 carbon atoms
have, but it should be noted that groups with, for example, 1 to 10 or 1 to 20 carbon atoms are also provided. The alkenyl and alkynyl units for R
and R ^ can together with said parts in the corresponding carboxyalkenyl and carboxyalkynyl units in particular

Have 2 to 4 carbon atoms, but it should be pointed out that groups with, for example, 2 to 10 or 2 to 20 carbon atoms also fall within the range of the general
Formula (I) fall. As special values for the alkenyl resp.
Alkynyl groups include allyl («, β or Y) and propargyl groups.

If R is an aralkyl group, this can be, for example, an ßenzyl group which is optionally present in the phenyl ring

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one or more groups is substituted, namely those as already mentioned above with regard to the optionally available

2

lying benzyloxy substituents of the group R in the radical X ^

were specified.

When R ^ is a -CHgO «group, where R is an alkanoyl radical, the alkyl portion of the alkanoyl group may desirably have 1 to 4, and preferably 1 or 2, carbon atoms. When R ^ is 5-tetrazolyl, the alkyl substituent optionally present there can desirably be 1 to 5 carbon atoms and the optionally present benzyl substituent as such optionally in the phenyl ring by one or more groups, namely those as they are with regard to the optionally before -

p benzyloxy substituents of the group R in the remainder

X * have been described.

The alkyl esters and the aryl esters are to be mentioned as esters of the peptides of the general formula (I). To the alkyl esters particularly include those in which the alkyl group has 1 to 4 carbon atoms has, for example the methyl, ethyl, and t-butyl esters, but esters in which the alkyl group for example has 1 to 10 or 1 to 20 carbon atoms, also included. The aryl esters include phenyl esters, for example halophenyl esters in which the halogen atom for example chlorine as in p-chlorophenyl.

In the N-alkyl- and N.N-dialkylamides of the peptides of the general Formula (I) can contain the alkyl groups in particular 1 to

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Have 5 carbon atoms, but should be noted is that alkyl groups having, for example, 1 to 10 or 1 to 20 carbon atoms are also included and in the N.N-dialkylamides can have the same or different alkyl groups be. It should be noted that the amides of the peptides include those that conceptually do not derived only from ammonia, but also from heterocyclic bases, such as pyrrolidine, piperidine and morpholine, i.e. the Pyrrolidinamides or piperidinamides and morpholinamides.

It can therefore be a subclass of the amides, the N-alkylamides and N.N-dialkylamides of the peptides of the general formula (i) are represented by the general formula

wherein X ¹ , X ² , X ⁵ , X ⁴ , X ⁵ , X ⁶ , m, η and R have the same meanings as in the general formula (I) and the radicals R ^ and R and the nitrogen atom with which they are connected, together form a group, namely an amino, pyrrolidino, piperidino, morpholino, N-alkylamino and / or NN-dialkylamino group, wherein the "alkyl" part in each case has 1 to 20 carbon atoms.

In the acid addition salts of the peptides of general formula (I) and their derivatives, as discussed previously, the activity though ^f ^ ^ ife ffWftifQ ^he purposes is based on the base and the acid has less meaning, preferably

2 7 b 2 y

pharmacologically and pharmaceutically acceptable for the recipient is. Examples of suitable acids include

(a) Mineral acids: hydrochloric acid, hydrobromic acid, phosphoric acid, Metaphosphoric acid, nitric acid and sulfuric acids,

(b) organic acids: tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, Gluconic acid, gulonic acid, succinic acid and arylsulfonic acid, for example p-toluenesulfonic acid. The pharmaceutical and pharmacologically acceptable acid addition salts are together with the salts, which are not tolerated, (for example the salts of hydrofluoric and perchloric acids) for Isolation and purification of the bases suitable and of course the unsuitable salts are equally valuable for the production of suitable salts, as is known to the person skilled in the art. Peptides and their derivatives that contain a large number of free amino groups have, can in the form of mono- or polyacid addition salts or as mixed salts of a variety of acids.

In the same way, in the salts of the peptides (which have the peptide as a carboxylate anion together with a cation) the identity of the cation is of lesser importance, although for therapeutic purposes it is preferred that it be pharmacological and is pharmaceutically acceptable for the recipient. Examples of suitable cations include sodium and potassium.

The morphine agonist properties of the peptides of the general Formula (I) and its derivatives as explained above.

809821/1037

./ ,. / 75234

it

have the following properties, which are presented here for explanatory purposes only can be specified without restriction.

(A) in vitro ;

(1) Inhibition of neural contractions of the isolated vas deferens of mice by means of studies according to the method of Hughes et al. (Brain Research, 88 (1975) 296) (using vibrations at 0.1 Hz), the Inhibition is abolished by means of the well-known narcotic antagonist naloxone (i-N-allyl ^ .e-dihydro-i ^. -Hydroxynormorphinone).

(2) Reduction of the electrically induced contractions of the isolated IleuqKron guinea pigs prepared for stimulation according to the method of Paton (Brit. J. Pharmacol., 12 (1957) 119-127). (Each intestinal segment was exposed to the anode skewered and hung up with 2 to 3 g load. Stimulus parameters: Frequency: 0.1 Hz; Duration: 0.4 minutes; tension (supramaximal) 30-40 V; the contractions became isotonic transfer).

(B) In vivo :

(1) The compounds have analgesic activity and they are effective in, for example, mice in the "standard hot plate method, provided that the investigation is carried out by the method of Eddy, N.B. et al. (J. Pharm. Exp. Therap. 107, 385 (1953)), where the compounds were administered by intracerebral ventricular injection, and these Activity is canceled by naloxone.

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49

(2) The compounds have cough-relieving activity when they are used, for example, in guinea pigs by the method von Boura et al. Brit. J. Pharmacol., 39 (1970) 225 will.

(3) The compounds have anti-diarrhea activity, and they are effective in reducing, for example Diarrhea induced by castor oil in rats.

As subclasses of the peptides of the general formula (T) and of their derivatives, there can be mentioned such compounds, wherein

(1) m and η are both 0,

(2) R hydrogen,

(3) X ⁵ L-tyrosyl,

(4) X ⁴ J-alanyl,

(5) X ⁵ glycyl,

(6) X ^ L-phenylalanyl, L-4-chlorophenylalanyl or L-4-nitrophenylalanyl, preferably L-4-chlorophenylalanyl and L-4-nitrophenylalanyl and especially L-4-nitrophenylalanyl and

(7) R is the hydroxy portion of the 1-carboxyl group of the C-terminal Is amino acid residue.

A further subclass of the peptides of the general formula (I) and their derivatives can be compounds of the general formula

H.Tyr.D-Ala.Gly.X ⁶ .R ¹

be mentioned in which

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X ⁶ L-phenylalanyl, L-4-chlorophenylalanyl or L-4-nitrophenylalanyl and

r ' ^{1 is} the hydroxyl portion of the 1-carboxyl group of the C-terminal amino acid residue.

Preferred esters of this subclass are alkyl esters in which the alkyl group is 1 to 10, preferably 1 to 4 and in particular 1 or 2 carbon atoms and the preferred The alkyl group has N-alkylamides and N.N-dialkylamides or groups 1 to 5, in particular 1 or 2 carbon atoms.

The peptides of the general formula (I) and their derivatives, as explained above, can be prepared by any method which is suitable for the production of compounds of analogous structure. So they can be formed through one another then coupling appropriate amino acids using either classical methods of peptide preparation or by solid phase methods or by the initial preparation and subsequent coupling of the peptide subunits.

Such reactions can be brought about, for example, by that the carboxylic acid group of the supplied amino acid is activated and the amino and not subject to the reaction Protects carboxylic acid groups. Such methods are in the peptide field known. Details regarding suitable activation and protection (masking) groups and suitable ones Reaction conditions (both for the coupling reactions and for the removal of the protective groups) with the formation of mini-

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si

painter racemization can be found in the following literature, to which reference is made as a whole, this serving solely for the purpose of explanation. It should be noted that they is neither complete nor limiting of the scope of the invention.

(a) Published British Patent Application 1,042,487,
1 048 086 and 1 281 383.

(b) Schröder and Lüebke, "The Peptides" (Academic Press)

(1965)

(c) Bellean and Malek, J. Am. Chem. Soc, 90, 165 (1968).

(d) Tilak, Tetrahedron Letters, 849 (1970).

(e) Beyerman, HeIv. Chim. Acta., 56, 1729 (1973).

(f) Stewart and Young, "Solid Phase Peptide Synthesis" (W.H. Freeman and Co ^) (1969)

Depending on the reaction conditions, peptides of the general formula (I) and their derivatives are obtained in the form of the free base or as their acid addition salts or (in the case of the peptides as such) as their salt. The acid addition salts can be converted into the free bases or salts of other acids and the bases can be converted into the acid addition salts by known methods
being transformed. In the same way, the peptides in
their salts and the salts are converted into the peptides or other salts by known methods.

The peptides of the general formula (I) and their derivatives, as explained above, and acid addition salts can therefore
be prepared in such a way that a reactant (II)

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aa

R - Y ¹ - OH (II),

wherein Y ^{1 is} the radical (X ^) _1n , as explained in formula (I), or

is a partial residue sequence with the residue (X ^) _n at its N-terminal end and from here in accordance with the general formula (I), with a reactant (III)

HY ² (III),

wherein Y ² corresponds to the remainder of the product defined above, condensed and the reactants (II) and (III) optionally protected and / or activated, if and to the extent necessary, and then, if and insofar as necessary, one or both steps to remove the Protecting groups of the product and converting the product to the base or a salt or an acid addition salt thereof.

It should be noted that, as would be apparent to those skilled in the peptide art known, the arginyl (D or L) and homoarginyl (Har) (D- or L-) residues can not only be incorporated into the peptide chain in the manner described above, but that they also in situ in the entire chain or in a subunit thereof by guanidation of an ornithyl (D- or L-) or a lysyl (D or L -) residue using a Reaction partner, such as 1-guanyl-3,5-dimethylpyrazole, formed can be.

It should also be noted that other in situ conversions of the peptides of the general formula (I) and their

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Derivatives are possible. The amides, N-alkylamides and NN-dialkylamides can therefore be prepared, for example, by reacting a peptide alkyl ester such as the methyl ester with ammonia, a heterocyclic base or a mono- or dialkylamine, depending on suitability. The peptide esters can be prepared from the peptides using standard esterification processes produced and the esters can be converted into the peptides by means of saponification. The substituting hydroxy group (s) in the group R of the radical Ί / can be converted into the alkoxy or benzyloxy groups using: the appropriate diazoalkane, for example diazomethane, with the formation of methoxy groups. The substituting benzyloxy and alkanoyloxy group (s) in the group R of the radical Ί? can be removed with formation of hydroxyl groups by hydrogenolysis in methanol, for which a 10 # palladium-on-charcoal catalyst or alkaline hydrolysis is used and the hydroxyl group or groups can be converted into alkanoyloxy groups using standard alkanoylation processes. All of these methods are conventional in the peptide art and reference is made to the literature cited above for details of reaction conditions and suitable methods of adding and removing protecting groups.

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Because of their already explained morphine agonist effectiveness, which the peptides of the general formula (I) together with their pharmacological and pharmaceutically acceptable salts, Esters, amides, N-alkylamides and N.N-dialkylamides and their pharmacologically and pharmaceutically acceptable acid addition salts they can be used in the treatment of mammals in both human and veterinary medicine be used for all conditions in which an agent with a morphine-like effect is indicated. For specific uses, that should be mentioned here include, for example:

(1) Relief of pain (analgesia), for example pain caused by smooth muscle spasms Kidney and biliary colic are caused, pain in the End-stage disease such as cancer, pain in the postoperative Period and pain during delivery.

(2) For reassurance, for example in the pre-aesthetic Medication, to calm down, to induce sleep, especially in the case of insomnia as a result of pain or Cough, and to relieve anxiety in general.

(3) To suppress cough.

(4) To relieve shortness of breath, for example in the case of acute left-sided ventricular defect or pulmonary edema.

(5) For inducing constipation, for example after ileostomy or colostomy, and for treating diarrhea and dysentery.

(6) The induction of euphoria and the treatment of depression, for example, if it is accompanied with the loading

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27523 *

as

Relief from pain in the end-stage disease such as cancer.

Each of these uses will vary the amount of peptide or its derivative or acid addition salt required (hereinafter referred to as active ingredient) with the type of administration and the severity of the treatment the intended condition and will ultimately be subject to the care of the doctor or veterinarian. Generally will however, for each of these uses dosages in the range of 0.0025 / Ug to 40 mg per kg of body weight of the mammal, preferably 0.025 / Ug to 4.0 mg / kg and in particular 0.25 to 400 / UgAg (all dosages are calculated in relation to the peptide base).

The active ingredients can be administered by any route, appropriate for the conditions envisaged for treatment, with appropriate modes of administration oral, rectal, nasal, local (buccal), vaginal and parenteral (including subcutaneous, intramuscular and intravenous) treatment. It is clear that the preferred treatment will change with the treatment conditions and that, for example, to relieve pain in delivery, administration directly into the spinal cord can be beneficial.

Although it is possible to use the active ingredients as boh chemicals too administered, it is preferred to present them as a pharmaceutical formulation.

The formulations of the present invention, both for the

0 0 9 o21 / 10 3 7

SG

Human as well as veterinary medicine comprise an active ingredient, as defined above, with one or more suitable for this purpose Carriers and, optionally, other therapeutic ingredients. The carrier or carriers must in the sense of "suitable" be that they are compatible with the other ingredients of the formulation and not harmful to the recipient. Desirable Formulations should not contain oxidizing agents and other substances known to be are incompatible with the peptides.

The formulations are for oral, rectal, nasal, topical (buccal), vaginal or parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route of administration in each given case will depend, for example, on the active substance and on the conditions intended for treatment. the Formulations can expediently be presented in the form of dosage units and they can all on the Process suitable for the field of pharmacy. All procedures include the step of bringing the The active ingredient with the carrier which contains one or more additional ingredients. In general, the formulations prepared by uniformly combining the active ingredient with liquid carriers or finely divided solid carriers or both and brought into intimate contact and that, if necessary, the product is then brought into the desired formulation form.

The formulations of the present invention suitable for oral administration can be used as separate units

SQ9821 / 1037

such as capsules, cachettes or tablets are presented by each of which contains a predetermined amount of the active ingredient; they can also be presented as powder or granules or as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, latwerge or paste.

A tablet can be produced by compression or deformation, optionally with one or more additional ingredients will. Compressed tablets can be prepared by adding the active ingredient in a suitable device in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, Inert diluents or extenders, surface-active agents or dispersants. Molded tablets can do this be prepared by placing in a suitable device a mixture of the powdered compound, moistened with an inert liquid diluent.

Formulations for rectal administration can be presented as suppositories with conventional carriers such as cocoa butter while a suitable formulation for nasal administration are nasal drops that contain the active ingredient in aqueous or contain oily solution »

Formulations suitable for topical administration in the mouth belong to lozenges that contain the active ingredient in a

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a?

flavor base], usually sucrose and acacia or tragacanth, and lozenges that contain the active ingredient in an inert base material, such as gelatin and glycerin or sucrose and acacia gum included.

Formulations which are suitable for vaginal administration can be in the form of pessaries, creams, pastes or Spriihl'orm-i; ie -; i \ '.:. : arrobo-en vercen, which also contain the active ingredient carriers which are known to the person skilled in the art with regard to their suitability.

Formulations for parenteral administration conveniently include sterile aqueous solutions of the active ingredient, which solutions are preferably isotonic with the blood of the recipient are. Such formulations can expediently be prepared by adding the solid active ingredient to water Formation of an aqueous solution dissolves and renders this solution sterile and isotonic with the recipient's blood. The formulations can be presented in unitary or multi-dose containers, for example in sealed ampoules or tubes will.

Formulations suitable for nasal administration wherein the carrier is a solid, including a coarse powder having a particle size in the range of 20 to 500 µm, are ingested in the same manner as snuff, that is, by rapid inhalation through the nasal passage from one Container that is held close to the nose .

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BATH ORIGINAL

-21-

275234

It should be noted that in addition to those previously mentioned If the formulations of this invention contain one or more additional ingredients such as diluents, Extenders, buffers, flavorings, binders, surface-active agents Agents, thickeners, lubricants, preservatives (including antioxidants) and the like may contain.

If the formulation for human or veterinary use is presented in the form of dosage units, for example in such forms of dosage units as specifically indicated above, each unit expediently contains the active ingredient (as defined above) in an amount in the range from 0.16 μg to 2 g, preferably 1.25 / Ug to 200 mg and optionally 12.5 / Ug to 20 mg (with all weights calculated in relation to the peptide base).

After this, it should be noted that the objects of this invention, as described here, are primarily and not exclusively for example:

(a) The peptides of the general formula (I), as defined above, and their salts, esters, amides, N-alkylamides and N.N-dialkylamides and their acid addition salts.

(b) Process as described above for the preparation of the peptides of the general formula (I) and their derivatives, as described under (a) described above, and their acid addition salts.

(c) Pharmaceutical formulations containing a peptide of the general Formula (I), a pharmacologically and pharmaceutically

809821710 37

wearable salt, ester, amide, N-alkylamide or N.N-dialkylamide the same or a pharmacologically and pharmaceutically acceptable acid addition salt thereof, together with include a suitable carrier.

(d) Process for the preparation of the pharmaceutical formulations, as defined under (c) above.

(e) Method of treating a mammal for conditions in which an agent having a morphine-like effect is indicated is, for which the mammal is given a treatment-effective, non-toxic amount of a peptide of the general formula (I) pharmacologically and pharmaceutically acceptable salt, ester, amide, N-alkylamide or N.N-dialkylamide of the same or a phar macologically and pharmaceutically acceptable acid addition salt of the same administered.

(f) procedures corresponding to (e) for the treatment of conditions, as specifically given above under (1), (2), (3), (4), (5) or (6).

The following examples serve exclusively to illustrate the present invention without restricting the scope of the invention. All temperatures are in ⁰ C.

Experimental section

The following abbreviations are used below

HOBT 1-Hydroxybenzotriazole DGCI dicyclohexylcarbodiimide DMF dimethylformamide

80982 1/1 037

tertiary - 35 - Benzyl 34 BOC But y1oxycarbony1 BzI

The peptides were recorded by means of thin layer chromatography Merck silica gel plates using the following solvent systems checked:

1 methyl ethyl ketone

2 n-butanol: acetic acid: water (3: 1: 1)

3 chloroform: methanol: 32 # acetic acid (120: 90: 40)

4 chloroform: methanol: 32 # ammonia (120: 90: 40)

5 n-butanol, acetic acid: ethyl acetate: water (1: 1: 1: 1)

6 chloroform: methanol (8: 1)

7 chloroform: methanol: 32 # acetic acid (120: 90: 5)

8 chloroform: methanol: 32 # ammonia (120: 90: 5)

The optical rotations were determined on a Bendix NPL automatic polarimeter.

The amino acid compositions of the peptide hydrolysates (6N.HC1 at 110 ° for 24 hours in evacuated closed tubes) were determined using a Beckman-Spinco Model 12OC amino acid analyzer or determined with a Rank Chromostak amino acid analyzer.

The following general methods of manufacture were used of the peptides used.

a) The couplings were carried out in DMP and averaged out using DCCI.

b) The amino acid esters.hydrochlorides were converted into the free Ester by adding a tertiary base, either triethylamine or converted to N-methylmorpholine.

c) HOBT was added at the coupling step when the fragment condensation was a peptide with an optically active Carboxy-terminated amino acid concerned.

d) The couplings were allowed to take place ^{in a cold room at + 40 G for 24 hours.}

e) After coupling, cleaning was effected by washing with acid and base to remove the unconverted reactants.

f) The alkaline saponifications were carried out in aqueous methanol with an autotitrator at _pH 11.5 to 12.0 with N.NaOH.

g) Benzyloxycarbonyl protective groups were removed by hydrogenolysis in methanol / acetic acid with 10 $ palladium on charcoal.

h) The acetate salts obtained from the previous hydrogenolysis were converted into the corresponding hydrochlorides by adding methanolic hydrogen chloride.

i) The benzyl protecting groups were removed by hydrogenolysis in methanol with 10 # palladium on charcoal.

Ö) Tertiary butyl and tertiary butyloxycarbonyl protective groups were converted into Go ^ en-

809821/1037

v-v'C unlearned from Anise 1, who acts as an iianswer. The split allowed to run for 60 to 90 minutes.

Lie end peptides were isolated as hydrochlorides and lyophilized from the aqueous solution.

example 1

H. Tyr. D-AIa. GIy. Phe. OH

This compound was prepared according to the scheme given in Table I. The product, as a hydrochloride addition salt, had the following characterization values after lyophilization from the aqueous solution:

Rf: 0.41 ^2; 0.66 ⁴ ; O, 23 ⁸

Z ~ cx_7jp ' ^{+ 64} » ⁶ ° (C = 0.5 in methanol).

Example 2

H. Tyr. D-AIa. GIy. Phe. OMe

This compound was prepared from the product of Example 1 by reaction with methanolic hydrogen chloride. The ester, like the hydrochloride addition salt, had the following characterizing values after lyophilization from the aqueous solution:

Rf: 0.57 ² ; O.88 ³ ; O, 63 ⁵

<fcX__7jp: + 57.2 ° (C «0.5 in methanol)

The same product, with similar characterization values, was obtained from treating the product of stage 5 in the table I in the following way:

809821/1037

31 »

BzI
I.
BOC. Tyr. D-AIa. GIy. Phe. OMe

I 10 # Pd / CH ₂
BOC. Tyr. D-AIa. GIy. Phe. OMe

I N-HC1 / H0ÄC
H. Tyr. D-AIa. GIy. Phe. OMe

80982 1/1037

COPY

Table I.

H.Tyr

D.Ala .GIy-

-Phe.OH

BOC. D-Al a.OH

BOC-D-Al a

BzI BOC-Ty r. OH

Bzl BOC-Tyr.

H.Gly.OMe

HOBT / DCCI coupling GIy.OMe

BzI BOC-Tyr-

BzI BOC.Tyr.

fzl

BOC.Tyr- BOC.Tyr-H.Tyr

φ Ν.HCl / HOAc. D-AIa - GIy.OMe

HOBT / DCCI coupling

.D-AIa

JY.NaOH / MeOH D-AIa

D-AIa

D-AIa

D-AIa

D-AIa

GIy.OMe

.GIy.OH H.Phe.OMe

GIy-

GIy.

GIy-

HOBT / DCCI \ coupling

Phe.OMe

© I ^ .NaOH / HeOH

> I.

. Phe.OH 1ΟΪ Pd / C Phe.OH

<g>! JJ. HCl / HOAc GIy Phe.OH

809821/1037 COPY

The following peptides were determined according to standard methods with the characterizing values given below produced in peptide chemistry analogously to the preceding examples. G-terminal derivatives are according to convention specified, i.e .:

-OMe: methyl ester -Oheptyl (n): n-heptyl ester -NHEt: ethylamide

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Example compound Rf C ⁰ Od ⁵ < ⁱⁿ methanol)

3 H. Tyr. J) -AIa. ^G1 y £ - ^p he. OH

4 H. Tyr. D-AIa. GIy. Phe (4Cl). OH 0.4l '+ 55.9 ° (c «0.3)

5 H. Tyr. .D-AIa. JO-AIa * Phe.OH HCl

6 H. Tyr. D-AIa. GIy. Phe. Oheptyl (n) HCl 0.65 * + 46.1 ° (c = 0.2) oo

O.6O ⁵ ; O .44 ⁷ 0.41 ⁷ Ο.72 ³ ; O .67 ⁵ Ο.65 ²

7 H. Tyr. D-AIa. GIy. PheUNOg) .0Me HCL Ο.6θ ⁷ ; O.5 * ⁸ + 59Λ ° (c = 0. "3)

8 H. Tyr. D-AIa. GIy. PheUNOg). NHEt HCl Ο.53 ² ? Ο.68 ⁷ ; O.6l ⁸ + 36.9 ° (c = 0.5) ^

9 H. Tyr. D-AIa. GIy. PheUN0 ₂ ) .0H HCl Ο.43 ² ; Ο.49 ⁷ ϊ Ο.55 ⁸ + 66.3 ° (c = 0.5)

cn κ; co

Example: pharmacological effectiveness

The peptides of the preceding examples were tested according to standard pharmacological methods for the following activities examined.

(A) Analgesia in mice on hot plate examination (hot plate test) (Modification of the method of Eddy, N.B. et al., J. Pharm. Exp. Therap. (1953) 107, 385, the peptide administered by intracerebral ventricular injection).

(B) Efficacy against diarrhea in rats. In this experiment the rats were starved for 24 hours, then the peptide administered subcutaneously and 15 minutes later 1 ml of castor oil administered orally per rat.

The corresponding ED, -Q values were derived from the values obtained calculated (i.e. the dose required to produce the appropriate effect in 50% of the animals) expressed as Weight of peptide base per mouse / rat.

Peptide from
example Analgesia
(Mice: hot plates)
ED ₁ -Q iev
Cug / mouse) Antidiarrhea
(Rats)
ED ₅₀ sc
(mg / kg) 1 0.7 5.0 2 0.2 0.7 4- 5.0 1.0 6th 3.0 3.0 7th 0.5 0.3 8th 0.07 0.3 9 1.0
80982 1/1037 0.5

Pharmaceutical formulations

A) tablet formulation (20 ms / tablet)

Compound of formula (I) 20 mg

Lactose? 6mg

Corn starch 10 mg

Gelatin 2 mg

Magnesium stearate 2 mg

The compound of the general formula (I), lactose and corn starch are mixed, the mixture is granulated with a solution of the Gelatin dissolved in water. The granules are dried, the magnesium stearate is added and pressed to form Tablets; 110 mg per tablet.

B) suppositories (5 mg / product)

Compound of general formula (I) 250 mg

Suppository base

(Massa Esterinum C) to 100 g

The suppository base material is melted at 40 ° C gradually adding the compound of the general formula (I) in the form of a fine powder and mixing until homogeneous. Man then pour into suitable molds (2 g per mold) and allow to settle.

Massa Esterinum C is a commercially available suppository base material and consists of a mixture of mono-, di- and triglycerides of saturated vegetable fatty acids. It is from Henkel International, Düsseldorf, launched.

809821/1037

ko

C) pessary (5 mg / product)

Connection of general

Formula (I) 5 mg

Lactose 400 mg

Povidone 5 mg

Magnesium stearate 5 mg

The compound of formula (I) and lactose are mixed, the mixture is granulated with a solution of povidone in 50 # aqueous Ethanol, dries the granules and adds magnesium stearate. It is pressed using a suitably shaped punch 415 mg per pessary.

D) Freeze-dried injection 100 mg / ampoule

Connection of general

Formula (I) 100 mg

Water for injections to 2.0 ml

The compound of general formula (I) is dissolved in water for injections, the solution is sterilized, for which purpose it is through a membrane filter, 0.2 µm pore size, passes, collects the filtrate in a sterile container and fill into sterile glass ampoules, 2 ml / ampoule, under aseptic conditions and performs freeze-drying. The ampoules are closed with sterile rubber closures and those with an aluminum closure secured.

The injection material is before administration by adding a suitable volume of injection water or by adding restored by sterile saline.

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In the previous examples is the weight of the compound of the general formula (I) calculated in each case in relation to the peptide base.

-Patent claims- 809821/1037

Claims (1)

Patent claims: or a salt, ester, amide, N-alkylamide or N.N-dialkylamide the same or an acid addition salt thereof, wherein 1 p the radicals X and X, identical or different, and each of the Residue of a basic amino acid (D or L), X * a D or L residue of the general formula W ¹ W P * R ^ - (CH ₀ ). (CH) ,. CH.GO-, ^ a D where R is phenyl or 1,4-cyclohexadien-i-yl, a = 0, 1 or 2, b = 0 or 1, one of the radicals W and W is a -NR ^ group and the other is hydrogen, with the proviso that W is always -NR * - when b = 0 and that when R is 1,4-cyclohexadien-1-yl is, a is always 1 and b is always 0, R * is hydrogen or alkyl, Alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl and / or car- boxyalkynyl and R optionally by one or more hydroxy, Alkoxy, alkanoyloxy, alkyl, nitro, tirifluoromethyl, Amino, N-alkylamino, halogen, N.N-Djalkylamino and / or Benzyloxy groups is substituted, the phenyl ring optionally by one or more hydroxy, alkoxy, alkanoyloxy, halogen, alkyl, nitro, trifluoromethyl, amino, N-alkylamino and / or N, N-bialkylamino groups is substituted, X is a D radical from the group C-propargylglycyl, alanyl, ORIGINAL INSPECTED 809821 / 103t , 2f 7 b 2 J 4 "Ä oC-alkylalanyl, valyl, norvalyl, leucyl, isoleucyl, norleucyl, Prolyl, hydroxyprolyl, tryptophyl, asparaginyl and glutaminyl, wherein, each of the radicals optionally with an alkyl group N is substituted, X ^ 'glycyl or a D or L radical from the group C-propargylglycyl, alanyl, * -alkylalanyl, ß-alanyl, valyl, norvalyl, leucyl, isoleucyl, norleucyl, prolyl, hydroxyprolyl, tryptophyl, asparaginyl and glutaminyl, in which each of the radicals is optionally substituted with an alkyl group N, X is from the group glycyl, a D or L radical from the group methionyl, leucyl, isoleucyl, norleucyl, valyl, norvalyl, prolyl, hydroxyprolyl, alanyl and histidyl and the above have specified values for iP , R hydrogen, aralkyl, alkyl, alkenyl, alkynyl, carboxyalkyl, Carboxyalkenyl and carboxyalkynyl, R is the hydroxyl group of the 1-carboxyl group of the C-terminal amino acid residue or a group which replaces this 1-carboxyl group, namely a -CHoOR group, in which R is hydrogen or alkanoyl and a 5-tetrazolyl group, which is optionally in 1- or 2- Position is substituted with an alkyl and / or benzyl group and
each m and n, independently of one another, is O and 1, except for the amides, N-alkylamides and N.N-dialkylamides and their Acid addition salts, in which X ^ is a D or L radical of the general Formula is 809821/10. CH ^ .CH.CO-, where R 1 is hydrogen or alkyl. 2. peptide or derivative thereof according to claim 1, or a
Acid addition salt thereof, characterized in that m and η are both 0. 3. Peptide or derivative thereof according to any of the preceding the claims, or an acid addition salt thereof, characterized in that R is hydrogen is. 4. Peptide or derivative thereof according to the preceding claims, or an acid addition salt thereof, characterized in that X ^ L-Tyrcsy "* 5. Peptic, or L'erivat thereof according to one of the preceding claims, or an acid addition salt thereof, characterized in that X is D-alanyl
is. 6. peptide or derivative thereof according to one of the preceding claims, or an acid addition salt thereof, characterized in that X ^ is glycyl 809821/1011 ORIGINAL INSPECTED 2 7 b ^ 3 A Ί 7. peptide or derivative thereof according to one of the preceding claims, or an acid addition salt thereof, characterized in that X ^ from the
Group is L-phenylalanyl, L-4-chlorophenylalanyl and L-4-nitrophenylalanyl. 8. Peptide or derivative thereof according to one of the preceding claims, or the acid addition salt thereof, characterized gekennzeichn et that R is the hydroxyl group of 1-carboxyl group of the C-terminal amino acid residue is. 9. peptide or derivative thereof according to claim 1, or a
Acid addition salt thereof, characterized in that it has the general formula H.Tyr.D-AIa.GIy.X ⁶ .R ¹ wherein X is selected from the group L-phenylalanyl, L-4- chlorophenylalanyl and L-4 - nitrophenylalanyl and R is the hydroxyl group is the 1-carboxyl group of the C-terminal amino acid residue. 10. A compound according to claim 1 of the formula H.Tyr.D-Ala.Gly.Phe.OH
or an acid addition salt thereof. 11. A compound according to claim 1 of the formula H.Tyr.D-AIa.GIy.Phe.OMe 809821/1037 or an acid addition salt thereof. 12. A compound according to claim 1 of the formula H.Tyr.D-Ala.Gly.Phe (4Cl) .0H or an acid addition salt thereof. 13. A compound according to claim 1 of the formula H.Tyr.D-Ala.Gly.Phe.Oheptyl (n) or an acid addition salt thereof. 14. A compound according to claim 1 of the formula H.Tyr.D-Ala.GIy.Phe (4NO ₂ ) .OMe or an acid addition salt thereof. 15. A compound according to claim 1 of the formula H.Tyr.D-Ala.GIy.Phe (4NO ₂ ) .NHEt or an acid addition salt thereof. 16. A compound according to claim 1 of the formula H.Tyr.D-Ala.Gly.Phe (4N0 ₂ ) .0H or an acid addition salary of the same. 17. Pharmacologically and pharmaceutically acceptable salt or Acid addition salt of a peptide or its derivative according to 809821/1037 2/5234 any one of claims 1 to 16. 13. Process for the preparation of a peptide or derivative thereof According to one of claims 1 to 16, or an acid addition salt the same, characterized in that a reaction partner (II) RY ¹ -OH (II), wherein R has the meaning defined in formula (I) and Y the radical (X), as explained in the formula (I), or a partial radical sequence with the radical (X) at its N end and from here according to the general formula (I), with a reactant (III) HY ² (III), where Y corresponds to the remainder of the product defined above, is implemented and the reactants (II) and (III) are optionally protected and / or activated, if and to the extent necessary, and thereafter, if and as necessary, one or both steps to remove the protecting groups from the product and converting the product into the base or a salt or an acid addition salt thereof. 19 · peptide or derivative thereof according to one of claims 1 to 16, or an acid addition salt thereof, thereby characterized in that they are produced by a method according to claim 18. 809821/1057 - JK) - 20. Pharmaceutical formulation, characterized in that it is a non-toxic, treatment-effective Amount of a peptide according to any one of claims 1 to 16 or a pharmacologically and pharmaceutically acceptable one Salt, ester, amide, N-alkylamide or N.N-dialkylamide the same or a pharmacologically and pharmaceutically acceptable acid addition salt thereof together with one suitable carrier. 21. Formulation according to claim 20, characterized in that it is used for oral, rectal, nasal, buccal, vaginal and parenteral administration is suitable. 22. Formulation according to claim 20, characterized in that it is used for oral, rectal, vagi nal and parenteral administration is suitable. 23 · Formulation according to claim 20, characterized that they contain the peptide or a derivative thereof or an acid addition salt thereof in solution in an aqueous medium. 24. Formulation according to one of claims 20 to 23, characterized in that it is in the form of dosage units is available. 25. Formulation according to claim 24, characterized in that - 809821/1037 -ν indicates that each dosage unit the
Contains peptide or its derivative or its acid addition salt in an amount of 0.125 / Ug to 2 g, calculated on the peptide base. 26. Formulation according to claim 20, characterized that it is in the form of a tablet suitable for oral administration. 27 · Process for the preparation of a formulation according to a of claims 20 to 26, characterized in that the ingredients of the formulation are mixed and, if necessary, brings the product into the desired shape. 809821/1037