CA2487246A1 - Novel uses of cephaibols - Google Patents

Abstract

The invention relates to the use of compounds of general formula AcPhe-Aib-A ib- Aib-x-w-Leu-y-Aib-Hyp-Gln-z-Hyp-Aib-Pro-R, in which R represents Phe-ol or P he- al and w, x, y, and z have the following meaning: a) w represents Gly or Ala ; x represents Aib, and y and z represent Iva; b) w represents Gly; x, y, and z represent Iva; c) w represents Gly; x and z represent Aib, and y represents Iva; d) w represents Gly; x, y, and z represent Aib; or e) w represents Gly; x and y represent Aib, and z represents Iva; or of general formula AcPhe-Iva-G ln- Aib-Ile-Thr-Aib-Leu-Aib-x-Gln-Aib-Hyp-Aib-Pro-Phe-Ser, in which x represents Hyp or Pro, and the physiologically acceptable salts thereof for producing a medicament having a neurological and/or immunosuppressive effect.

Description

Novel uses of cephaibols The invention relates to the use of cephaibols for producing pharmaceuticals which have a neurological and immunosuppressant effect.
Peptides containing up to 20 amino acids, some of which are structurally unusual, are produced by bacteria and fungi by way of their secondary metabolism using nonribosomal peptide synthetases. Many of the secondary metabolites having a peptide structure which are thus far known possess interesting biological effects as antibiotics, enzyme inhibitors, cardiotonics, immunomodulators, insecticides, nematocides, etc. (see, for example, Grafe, U. Biochemie der Antibiotika [Biochemistry of the antibiotics], Spektrum Heidelberg, 1992).
Within the structural class of the peptide active compounds, what are termed the peptaibols are distinguished by the fact that they contain an unusually large number of amino acids (up to 20) including a high proportion of alpha-aminobutyric acid (Bruckner, H. , Konig, W.A., Greiner, M., Jung, G. Angew. Chem. Int. Ed. Engl.

(1979), 476 -477). Furthermore, peptaibols are frequently acetylated at the N
terminus and have a residue containing an alcohol group (e.g. phenylalaninol) or an aldehyde group at the C terminus.
The mode of action of the peptaibols is generally assumed to be the formation of pores in biological membranes (M. K. Das et al. Biochemistry, 25, 7110-7117, 1986).
As a result, ions can penetrate into the cell in an uncontrolled manner and interfere with the vital biochemical processes, something which could explain the antibiotic effect of many peptaibols. In addition to the antibiotic effect, various peptaibols have been observed to have other biological effects which are different.
Ampullosporins induce pigment formation in Phoma desfructiva and produce neuroleptic effects in the mouse (W099112598; DE199148644; M. Ritzau et al. J. Antibiotics 50, 722-728, 1997; Kronen et al., J. Antibiotics, 54, 175-178, 2001 ). While bergofungin components (A. Berg et al. J. Antibiotics 52, 666-669, 1999) inhibit prolylendopeptidase in submicromolar concentrations, they have no effects on Phoma -destructiva. Clonostachin (T. Chikanishi et al. J. Antibiotics, 50, 105-110, 1997) inhibits platelet aggregation. The antiviral peptaivirins A and B (B.-S.
Yun et al. Tetrahedron Letters, 41, 1429-1431, 2000) have recently been described. It is not possible to provide any uniform explanation for, and prediction of, the biological activities of the various peptaibols because of the differences in the structures of these compounds.
The cephaibols, which are composed linearly of 16 or 17 amino acids or amino acid derivatives, some of which are not encodable, constitute another group of the peptaibol antibiotics. The structure, preparation and biological activities of the cephaibols are described, for example, in WO 00168256 or M. Schiell et al., J.
Antibiotics, 54 (2001 ) 220-233. Cephaibols have inhibitory effects on endoparasites and/or ectoparasites which are pathogenic to humans andlor animals, such as trematodes, nematodes, arachnida and some insects. In addition to this, the cephaibols exhibit antibacterial activities.
It has now been found, surprisingly, that, in a variety of test models, cephaibols exhibit additional effects due to which they are suitable for therapeutic use as immunosuppressants or agents which possess a neurological, in particular neuroleptic, effect.
The invention consequently relates to the use of compounds of the formula I
AcPhe-Aib-Aib-Aib-x-w-Leu-y-Aib-Hyp-Gln-z-Hyp-Aib-Pro-R (I) in which R is Phe-of or Phe-al, and w, x, y and z have the following meaning:
a) w is Gly or Ala; x is Aib; and y and z are Iva;

b) w is Gly; x, y and z are Iva;

c) w is Gly; x and z are Aib and y is Iva;

d) w is Gly; x, y and z are Aib; or e) w is Gly; x and y are Aib and z is Iva;

or of comp ounds of the formula II

AcPhe-Iva-Gln-Aib-Ile-Thr-Aib-Leu-Aib-x-Gln-Aib-Hyp-Aib-Pro-Phe-Ser (II) in which x is Hyp or Pro; and to the physiologically tolerated salts thereof, for producing a pharmaceutical which has a neurological andlor immunosuppressant effect.
Compounds of the formula I or II are also termed peptide active compounds or cephaibols.
The invention furthermore relates to the use of the cephaibois A, A1, B, C, D, E, P
and Q.
Cephaibol A denotes a compound of the formula I in which R is Phe-ol, w is Gly, x is Aib, and y and z are Iva.
AcPhe-Aib-Aib-Aib-Aib-Gly-Leu-Iva-Aib-Hyp-Gln-Iva-Hyp-Aib-Pro-Phe-of (SEQ ID No.1) Cephaibol A Phe1 I Aib3 Aib5 Leu7 N~~~N~H~N G~H O
0 O 0 y HN
Aib2 Aib4 Iva8 O N H2 O~' Hypl3 Gtnl1 NH
Phe-ollfi P~oIS
Aib9 HO N N~N N N N N
H H
O O O HyplO
I / Aibl4 OH Ival2 OH
Cephaibol A1 denotes a compound of the formula I in which R is Phe-ol, w is Ala, x is Aib, and y and z are Iva.
AcPhe-Aib-Aib-Aib-Aib-Ala-Leu-Iva-Aib-Hyp-Gln-Iva-Hyp-Aib-Pro-Phe-of (SEQ ID No. 8) Cephaibol A1 Phe1 \ I Aib3 Leu7 O O AibS O
v ~N N N~ N N~ N N O
H /' \ H/ II i' \ H\ 11 H
O Aib2 O Aib4 0 Aia6 HN\/
~IvaB
HZ
ProlS GInl1 NH
Aibl4 O O
N N Hypl3 N O Aib O
HO N N N N
\ O O H ~ O H

Phe-o116 OH Ival2 OH
Cephaibol B denotes a compound of the formula I in which R is Phe-ol, w is Gly, and x, y and z are Iva.
AcPhe-Aib-Aib-Aib-Iva-Gly-Leu-Iva-Aib-Hyp-Gln-Iva-Hyp-Aib-Pro-Phe-of (SEQ ID No. 2) Phe1 ~. Iva5 Cephaibol (3 I Aib3 Leu7 ~N N~N~N~N N~N O
H O H O H O GIy6 H HN
AIb2 Aib4 lva6 O NHz O
Phe-0116 ProlS HYP13 GInl1 ~ Aib9 O
HO N~N H N N H N
O O O HyplD
Aib14 OH Ival2 OH
Cephaibol C denotes a compound of the formula I in which R is Phe-ol, w is Gly, x and z are Aib and y is Iva.
AcPhe-Aib-Aib-Aib-Aib-Gly-Leu-Iva-Aib-Hyp-Gln-Aib-Hyp-Aib-Pro-Phe-of (SEQ ID No. 3) Cephaibol C Phe1 I Aib3 AIDS leu7 N N~H~N~H~N~N O
GI
0 Aib2 0 Aib4 0 ~ HN IvaB
0 NH= O~"
ProlS Glnl~ NH
Hypl r3 n n n ~ Aib9 HO ~~~rv~N~N~rv, ~! III [~~/'J ' \H
i~
/ Phe-oH6 Aibl4 OH Aibl2 HyplO
Cephaibol D denotes a compound of the formula i in which R is Phe-ol, w is Gly, and x, y and z are Aib.

5 AcPhe-Aib-Aib-Aib-Aib-Gly-Leu-Aib-Aib-Hyp-Gln-Aib-Hyp-Aib-Pro-Phe-of (SEQ ID No. 4) Cephaibot f7 I Aib3 AibS
O ~ O O O
~H N~H~N~H~N~H O
GI
O Aib2 O Aib4 0 ~ HN AibB
0 NHi O
ProlS Glnt~ ~NH
Hypl ~(3 n n n Aib9 J O O ~ O
Phe-0176 Aib54 AIbl2 Hyp~O
Cephaibol E denotes a compound of the formula I in which R is Phe-ol, w is Gly, x and y are Aib and z is Iva.
AcPhe-Aib-Aib-Aib-Aib-Gly-Leu-Aib-Aib-Hyp-Gln-Iva-Hyp-Aib-Pro-Phe-of (SEQ ID No. 5) Phe1 Cephaibol E
~ ( Aib3 AibS ~ Leu7 ~ w n ~ ~ ~ n ~ G~y6 " HN
Aib2 Aib4 ~ AibB
ProlS Hypl3 ~ib9 HO N N~H
O I'O
I / Phe-0116 Aibl4 H IvalZ
HyplO
Cephaibol P denotes a compound of the formula II in which x is Hyp.
AcPhe-Iva-Gln-Aib-Ile-Thr-Aib-Leu-Aib-Hyp-Gln-Aib-Hyp-Aib-Pro-Phe-Ser (SEQ ID No. 6) O NHZ IleS
Cephaibol P phel /
I GIn3 Tht60 pib7 v ~H N H N/ \ H N H~O
O O O HN
pat Aib4 OH
LeuB
O NHS O
Serl7 HO ProlS Aibl4 NH
Ginl1 Aib9 ~ N N HYP13~ 'N O
HOOC"H H ~ N~H H N
O O / \ O
Aibl2 HyplO
Phel6 OH OH
Cephaibol Q denotes a compound of the formula II in which X is Pro.
AcPhe-Iva-Gln-Aib-Ile-Thr-Aib-Leu-Aib-Pro-Gln-Aib-Hyp-Aib-Pro-Phe-Ser (SEQ ID No. 7) Cephaibol0 / O~/ NHz tle5 Phe1 ~ GInJ ~ Thr6 n ~ n n n Aib7 Iva2 Aib4 i ~OH v ~.LeuB
Serl7 NH
HO' ~ P~$ Ai~ ~ ~ GInl1 7C Aib9 N a HYP~3 a 0 OH Aibl2 ?rol0 Pne~s AcPhe denotes N-acetylphenylalanine, Aib denotes a-aminoisobutyric acid, Ala denotes alanine, Iva denotes isovaline, Hyp denotes hydroxyproline, Phe-of denotes phenylalaninol, Phe-al denotes phenylalaninal, Phe denotes phenylalanine, Gly denotes glycine, Leu denotes leucine, Gln denotes glutamine, Pro denotes proline, Ile denotes isoleucine, Thr denotes threonine and Ser denotes serine.
The abovementioned compounds are known and can be prepared, for example, as described in WO 00168256 or Schieil et al, J. Antibiotics, 54 (2001 ), 220-233. The above-described cephaibols can be produced, for example, by the microorganism Acremonium tubakii FH 1685 DSM 12774, with the microorganism being fermented under suitable conditions until the cephaibols accrue in the fermentation medium and can then be isolated and purified (WO 00168256; Schiell et al, J.
Antibiotics, 54 (2001 ), 220-233). An isolate was deposited in the Deutsche Sammlung von Mikroorganismen and Zellkulturen [German collection of microorganisms and cell cultures] GmbH, Mascheroder Weg 1 B, D 38124 Brunswick, Germany, in accordance with the rules of the Budapest treaty, on 31 March 1999 under the following number: Acremonium tubakii FH 1685 DSM 12774.
The invention also relates to the use of the cephaibols of the formulae I and II in the form of their racemates, racemic mixtures and pure enantiomers and also their diastereomers and mixtures thereof. Provided the abovementioned compounds permit diastereoisomeric or enantiomeric forms, and accrue as their mixtures in the chosen synthesis, separation into the pure stereoisomers is achieved either by chromatography on an optionally chiral support material or, provided the abovementioned racemic compounds are capable of salt formation, by means of the fractional crystallization of the diastereomeric salts which are formed using an optically active base or acid as auxiliary agent.
The present invention also encompasses the use of obvious chemical equivalents of the compounds of the formula I or II. Examples of such equivalents are esters, ethers, addition salts, complexes or partial hydrolysis products.
Physiologically tolerated salts of compounds of the formula I or li are understood as being both their organic salts and their inorganic salts, as are described in Remington's Pharmaceutical Sciences (17t" edition, page 1418 (1985)). Because of the physical and chemical stability and the solubility, sodium salts, potassium salts, calcium salts and ammonium salts, inter alia, are preferred for acidic groups;
salts of hydrochloric acid, sulfuric acid or phosphoric acid or of carboxylic acids or sulfonic acids, such as acetic acid, citric acid, benzoic acid, malefic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid, inter alia, are preferred for basic groups.
The invention also relates to pharmaceutical preparations which comprise one or more of the cephaibols. Preference is given to using the cephaibols admixed with suitable auxiliary substances or carrier material. Any pharmacologically tolerated carrier materials andlor auxiliary substances can be used as carrier material.
Examples of frequently employed carrier substances or auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal or vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols.
In general, the pharmaceuticals are administered orally, locally or parenterally;
however, rectal use is also possible in principle. Examples of suitable solid or liquid galenic preparation forms are granules, powders, tablets, sugar-coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, aerosols, drops or injectable solutions in ampoule form, and preparations providing protracted release of the active compound, in the production of which carrier substances and additives and/or adjuvants, such as disintegrants, binders, coating agents, swelling agents, ligands, lubricants, flavorings, sweeteners or solubilizers, are customarily used.
Where appropriate, the dosage units for oral administration can be microencapsulated in order to delay release or extend it over a relatively tong period of time, for example by means of coating or embedding the active compound, in particle form, in suitable polymers, waxes or the like.
The pharmaceutical preparations are preferably produced and administered in dosage units, with each unit containing, as the active constituent, a defined dose of one or more compounds of the cephaibols according to the invention. This dose can be up to about 2000 mg, preferably, however, from about 1 to 1000 mg, per day, in the case of solid dosage units such as tablets, capsules and suppositories, and up to about 1000 mg, preferably, however, from about 10 to 300 mg, per day, in the case of solutions for injection in ampoule form.
The daily dose to be administered depends on the bodyweight, age, sex and condition of the mammal. However, higher or lower daily doses may possibly be appropriate. The daily dose can be administered either by means of a once-only administration, in the form of a single dosage unit, or else in two or more smaller dosage units, or by means of the multiple administration of subdivided doses at defined intervals.
The invention also relates to a process for producing a pharmaceutical, in which process the cephaibols are brought, together with customary carrier substances and, where appropriate, additives andlor auxiliary substances, into the or a suitable form for administration.
Disturbances of the nervous system, in particular of the central nervous system, are the cause of a diverse variety of diseases. These include diseases which are accompanied by psychopathological symptoms, such as hallucinations, delusion and psychomotor excitation, or by other symptoms. While examples which may be mentioned here are schizophrenia, epilepsy and Parkinson's disease, a large number of other diseases are known which either affect the control of body functions or are frequently of a psychotic nature. These diseases are usually progressive.
They are treated medicinally with psychotropic drugs, which include, for example, neuroleptic agents, antidepressants and tranquilizers. Their function is to eliminate or attenuate the psychopathological symptoms. Tranquilizers are compounds which 5 mainly have a calming effect on the psyche and which reduce anxiety.
Antidepressants are substances which improve a pathologically cast-down prevailing mood and are able to eliminate depressive delusions. Neuroleptic agents are suitable for calming psychomotor excitation, affective excitability and vigilance and reducing drive, spontaneous movements and expression motoricity, in connection 10 with which the intellectual faculties should be retained.
In in-vivo experiments carried out in mice, the abovementioned cephaibols exhibit neuroleptic effects, such as hypothermia or a reduction in spontaneous motility. On the basis of these observed pharmacological effects, it is assumed that the compounds of the formulae f and I I and, in particular, the cephaibols A, A1, B, C, D, E, P and Q can be used as agents which act on the central or peripheral nervous system and which are suitable for treating neurological diseases, for example for treating diseases or disease states in which psychotropic drugs such as neuroleptic agents, antidepressants or tranquilizers, in particular neuroleptic agents, are used.
This includes, for example, their use in association with hallucinations, delusions, psychomotor excitation, apprehensive agitation, schizophrenia, acute manic phases, acute psychotic syndromes, such as paranoid or paranoid-hallucinatory states, and states of anxiety and tension, and also their use in connection with anesthesia premedication, neuroleptanalgesia or neuroleptanasthesia, or their use in connection with vomiting.
In addition, the above-described cephaibols induce pigment formation in Phoma destructive in a similar way to the known cyclosporin A, which is an effective immunosuppressant. The compounds of the formulae I and il, and in particular the cephaibols A, A1, B, C, D, E, P and Q, are consequently also suitable for being used in connection with diseases and conditions in which immunosuppressants are employed, in particular in transplantation medicine or in association with autoimmune diseases. These uses include, for example, their use in chronic glomerulonephritis involving nephrotic syndrome, chronic inflammatory intestinal diseases, myasthenia gravis, autoimmune hepatitis, thrombocytopenic purpura, or inflammatory rheumatic diseases, such as dermatomyositis, lupus erythematodes, rheumatoid arthritis and scleroderma.
Treatment of diseases or disease states is also to be understood as including their prophylactic treatment for the purpose of preventing them or delaying their appearance.
The activity of the cephaibols was tested as follows:
Neuroleptic effect of the cephaibols in the mouse model a) Influence on spontaneous motility The influence of cephaibols A, B, C, D and E on motoricity in laboratory mice was observed over various periods of time (from 5 min up to 24 hours). Following the intraperitoneal administration of in each case 10 mg of cephaibol A, B, C, D
or Elkg, motoricity (climbing) was observed to be impaired, in comparison with the control mice, under the chosen experimental conditions and after differing periods of observation. The observed effects were particularly pronounced after administering cephaibols B and C.
The observed inhibition of motoricity points to the tested cephaibols possessing neuroleptic properties. Fright reactions (noises) were retained, thereby ruling out the possibility of the cephaibols having a narcotic effect in the experimental arrangement.
b) Hypothermia As compared with the control animals, and under the chosen experimental conditions, the intraperitoneal administration of in each case 10mg of cephaibol A, B, C or Elkg to laboratory mice produced a marked reduction in body temperature (particularly pronounced in the case of cephaibols B and C) which could be observed over a relatively long period of time and which likewise points to the tested cephaibols possessing neuroleptic properties.

Immunosuppressant effect in the Phoma destructive model The induction of pigment formation in the fungus Phoma destructive is a test model for, inter alia, identifying a potential immunosuppressant effect in test substances.
The implementation of the Phoma destructive test has been described by K.
Dornberger et al. in J. Antibiotics, 48, 977-989, 1995.
The organism Phoma destructive is a fungus which is known to be pathogenic to plants and which grows, in feebly colored colonies, on agar plates which have been inoculated with vegetative mycelium. Cell differentiation processes, which are accompanied by the formation of a pigment and therefore enable cell differentiation to be detected, are initiated under the influence of special inducers. The pigment, which is a melanin-like substance, can be recognized by its color and quantified photometrically or by measuring the zone size. The known immunosuppressant cyclosporin A gives rise to a morphological change and pigment formation in the test organism.
It has now been found that the cephaibols according to the invention bring about similar pigment formation in Phoma destructive to that illustrated by cyclosporin A.
Experimental arrangement:
The fungus Phoma destructive was cultured on sloping agar tubes containing culture medium A or B at from 20 to 25°C and then stored at from 4 to 6°C and reinoculated in a 2-year rhythm.
Culture medium A: Malt extract, 40 gIL, Yeast extract, 4 gIL, Agar, 15 gIL.
Culture medium B: Potato-glucose agar (E. Merck), 39 gIL.
Inoculation culture:
The fungus Phoma destructive was cultured at from 20 to 25°C for 11 days on medium B in 100 mm diameter petri dishes and, after that, washed off with 10 ml of a sterile 0.9% solution of NaCI. The wash-off can be used for 5 days when stored at 6°C.
Punched-hole plate agar diffusion test:
The agar diffusion test method was a modification of the standardized agar diffusion assay described in the European Pharmacopoeia [Deutscher Apothekerverlag Stuttgart, pages 113-118, 1997]: 40 mL of test agar medium were liquefied and brought to a constant temperature of 50°C; from 8 to 10 mL of the inoculation culture were added under sterile conditions and the mixture was then poured into 150 mm diameter test plates. After the plates had cooled, 12 punched holes of 9 mm in diameter were arranged on the plate using a punching implement [J, V. Benett et al.
Appl. Micr. 14, 170-177, 1966]. The test holes were loaded with 50 pL of the solution to be tested, with one test hole containing cyclosporin as the control substance (1 pg of cyclosporin A in 50 NL of methanol). The plates which had been prepared in this way were cultured at from 20 to 25°C for from 4 to 5 days.
Under the above-described test conditions, the cephaibols give rise to pigment formation which resembles the yellow pigmentation induced by cyclosporin A.
This effect was particularly pronounced in the case of cephaibols A, B and C.

SEQUENCE LISTING
<110> Aventis Pharma Deutschland GmbH
<120> Novel uses of cephaibols <130> DERV 2002/002?
<140>
<141>
<150> 10222792.6 <151> 2002-05-23 <160> 8 c170> Patentln Yer. 2.1 <210> 1 c211> 16 <212> PRT
<213> acremonium tubakii <220>
<221> PEPTIDE
<222> (1) <223> Xaa = AcPhe <220>
<221> PEPTIDE
c222> (2) . . (5) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (S) <223> Xaa = Iva <220>
<221> PEPTIDE
<222> (9) <223> Xaa = Aib c220>
<221> PEPTIDE
<222> (10) <223> Xaa = Hyp <220>
<221> PEPTIDE
<222> (12) <223> Xaa = Iva <220>
<221> PEPTIDE
<222> (13) <223> Xaa= Ayp <220>
<221> PEPTIDE
<222> (14) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (16) <223> Xaa = Phe-of <400> 1 Xaa Xaa Xaa Xaa Xaa Gly T~eu Xaa Xaa Xaa Gln Xaa Xaa Xaa Pro Xaa <210> 2 <211> 16 <212> PRT
<213> acremoni,um tubakii <220>
<221> PEPTIDE
<222> (1) <223> Xaa = AcPhe <220>
<221> PEPTIDE
<222> (2) . . (4) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (5) <223> Xaa = Iva <220>
<221> PEPTIDE

<222> (S) <223> Xaa = Iva <220>
<221> PEPTIDE
<222> (9) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (10) <223> Xaa = Hyp <220>
<221> PEPTIDE
<222> (12) <223> Xaa = Iva <220>
<221> PEPTIDE
<222> (I3) <223> Xaa = Hyp <220>
<221> PEPTIDE
<222> (14) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (16) <223> Xaa = Phe-of <400> 2 Xaa Xaa Xaa Xaa Xaa Gly veu Xaa Xaa Xaa Gln Xaa Xaa Xaa Pro Xaa <210> 3 <21I> 16 <212> PRT
<213> acremonium tuhakii <220>
<221> PEPTIDE
<222> (1) <223> Xaa = AcPhe <220>
<Z21> PEPTIDE
<222> (2) . . (5) <223 > Xaa = Aib <220>
<221> PEPTIDE
<222> (8) <223> Xaa = Iva <220>
<221> PEPTIDE
<222> (9) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (10) <223> Xaa = Hyp <220>
<221> PEPTIDE
<222> (12) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> {13) <223> Xaa = Hyp <220>
<221> PEPTIDE
<222> (14) <223> Xaa = A=b <220>
<22I> PEPTIDE
<222> {16) <223> Xaa = Phe-of <400> 3 Xaa Xaa Xaa Xaa Xaa Gly Leu Xaa Xaa Xaa Gln Xaa Xaa Xaa Pro Xaa <210> 4 <211> 16 <212> PRT
<213> acremonium tubakii <220>
<221> PEPTIDE
<222> (1) <223> Xaa = AcPhe <220>
<221> PEPTIDE
<222> (2) . . (5) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (8) . - (9) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (10) <223> Xaa = Hyp <220>
<221> PEPTIDE
<222> (12) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (13) <223> Xaa = Hyp <220>
<221> PEPTIDE
<222> (14) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (16) <223> Xaa = Phe-of <400> 4 Xaa Xaa Xaa Xaa Xaa Gly Leu Xaa Xaa Xaa Gln Xaa Xaa Xaa Pro Xaa <210> 5 <211> 16 <212> PRT
<213> acremonium tubakii <220>
<221> PEPTIDE
<222> (1) <223> Xaa = AcPhe c220>
<221> PEPTIDE
<222> (2) . . (5) <223> Xaa = A
<220>
<221> PEPTIDE
<222> (6) . . (9) <223> Xaa = Aib <220>
<221> PEPTIDE
c222> (10) <223> Xaa = AyP
<220>
<221> PEPTIDE
<222> (12) <223> Xaa = Iva <220>
<221> PEPTIDE
<222> (13) <223> Xaa = EYP
<220>
<221> PEPTIDE
<222> (14) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (16) <223> Xaa = Phe-of <400> 5 Xaa Xaa Xaa Xaa Xaa Gly heu Xaa Xaa Xaa Gln Xaa Xaa Xaa Pro Xaa <210> 6 <211> 17 <212> PRT
<213> acremonium tubakii c220>
<221> PEPTIDE
c222> {1) <223> Xaa = AcPhe <220>
<221> PEPTIDE
<222> {2) <223> Xaa = Iva c220>
<221> PEPTIDE
<222> (4) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (7) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (9) <223 > Xaa = A.ib <220>
<221> PEPTIDE
<222> (10) <223> Xaa = Iiyp <220>
<221> PEPTIDE
<222> (12) <223> Xaa = Aib <22D>
<221> PEPTIDE
<222> (13) <223> Xaa = Hyp <220>
<221> PEPTIDE
<222> (14) <223> Xaa = Aib c4D0> 6 Xaa Xaa Gln Xaa I3.e Thr Xaa heu Xaa Xaa Gln Xaa Xaa Xaa Pro Phe Ser <21D> 7 <211> 17 <212> PRT
<213> acremonium tubakii <220>
<221> PEPTIDE
c222> (1) c223> Xaa = AcPhe <220>
<221> PEPTT_DE
<222> (2) <223> Xaa = Iva <220>
<221> PEPTIDE
<222> (4) <223> Xaa = Aib c220>
<221> PEPTIDE
c222> (7) c223> Xaa = A~-b c220>
<221> PEPTIDE
c222> (9) c223> Xaa =
<220>
<221> PEPTIDE

c222> (12) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (13) <223> Xaa = Hyp <220>
<221> PEPTIDE
<222> (14) <223> Xaa = Aib c400> 7 Xaa Xaa Gln Xaa Ile Tbr Xaa Leu Xaa Pro Gln Xaa Xaa Xaa Pro Phe Z 5 ~ 10 15 Ser <2I0> 8 <211> lfi <212> PRT
<213> acremonium tubakii <220>
<22I> PEPTIDE
c222> (1) <223> Xaa = AcPhe <220>
<221> PEPTIDE
<222> (2) .. (5) <223> Xaa = Aib <220>
<221> PEPTIDE
<222> (8) <223> Xaa = Iva <220>
<221> PEPTIDE
<222> (9) <223> Xaa = Aib <220>

<221> PEPTIDE
<222> (10) <223> Xaa = Eyp <220>
<221> PEPTIDE
<222> (12) <223> Xaa = Iva <220>
<221> PEPTIDE
<222> (13) <223> Xaa = Hyp <220>
<221> PEPTIDE
<222> (14) c223> Xaa = Aib <220>
c221> PEPTIDE
<222> (16) <223> Xaa = Phe-of <400> 8 Xaa Xaa Xaa Xaa Xaa Ala Leu Xaa Xaa Xaa G3n Xaa Xaa Xaa Fro Xaa

Claims (7)

claims:

1. The use of compounds of the formula I
AcPhe-Aib-Aib-Aib-x-w-Leu-y-Aib-Hyp-Gln-z-Hyp-Aib-Pro-R (I) in which R is Phe-ol or Phe-al, and w, x, y and z have the following meaning:
a) w is Gly or Ala; x is Aib; and y and z are Iva;
b) w is Gly; x, y and z are Iva;
c) w is Gly; x and z are Aib and y is Iva;
d) w is Gly; x, y and z are Aib; or e) w is Gly; x and y are Aib and z is Iva;
or of compounds of the formula II
AcPhe-Iva-Gln-Aib-Ile-Thr-Aib-Leu-Aib-x-Gln-Aib-Hyp-Alb-Pro-Phe-Ser (II) in which x is Hyp or Pro, and the physiologically tolerated salts thereof, for producing a pharmaceutical having a neurological and/or immunosuppressant effect.

2. The use of the compounds of the formula I as set forth in claim 1 in which R is Phe-ol, and the physiologically tolerated salts thereof.

3. The use of the compounds of the formula I or II as set forth in claims 1 and 2, these compounds having the formulae AcPhe-Aib-Aib-Aib-Aib-Gly-Leu-Iva-Aib-Hyp-Gln-Iva-Hyp-Aib-Pro-Phe-ol;
AcPhe-Aib-Aib-Aib-Aib-Ala-Leu-Iva-Aib-Hyp-Gln-Iva-Hyp-Aib-Pro-Phe-ol;
AcPhe-Aib-Aib-Aib-Iva-Gly-Leu-Iva-Aib-Hyp-Gln-Iva-Hyp-Aib-Pro-Phe-ol;
AcPhe-Aib-Aib-Aib-Aib-Gly-Leu-Iva-Aib-Hyp-Gln-Aib-Hyp-Aib-Pro-Phe-ol;
AcPhe-Aib-Aib-Aib-Aib-Gly-Leu-Aib-Aib-Hyp-Gln-Aib-Hyp-Aib-Pro-Phe-ol;
AcPhe-Aib-Aib-Aib-Aib-Gly-Leu-Aib-Aib-Hyp-Gln-Iva-Hyp-Aib-Pro-Phe-ol;

AcPhe-Iva-Gln-Aib-Ile-Thr-Aib-Leu-Aib-Hyp-Gln-Aib-Hyp-Aib-Pro-Phe-Ser; or AcPhe-Iva-Gln-Aib-Ile-Thr-Aib-Leu-Aib-Pro-Gln-Aib-Hyp-Aib-Pro-Phe-Ser;
and the physiologically tolerated salts thereof.

4. The use of the compounds of the formula I or II as set forth in claims 1 to 3 for producing a medicament having a neuroleptic effect.

5. The use of the compounds of the formula I or II as set forth in claims 1 to 3 for producing a medicament having an immunosuppressant effect.

6. The use of the compounds of the formula I or II as set forth in claims 1 to 3 for producing a medicament for treating hallucinations, delusions, psychomotor excitation, apprehensive agitation, schizophrenia, acute manic phases, acute psychotic syndromes, and states of anxiety and tension.

7. The use of the compounds of the formula I or II as set forth in claims 1 to 3 for producing a medicament for treating chronic glomerulonephritis involving nephrotic syndrome, chronic inflammatory intestinal diseases, myasthenia gravis, autoimmune hepatitis, thrombocytopenic purpura or inflammatory rheumatic diseases, or for use in transplantation medicine.