DE19816903A1 - New dipeptide derivatives useful as neuropeptide Y agonists and/or antagonists for treating cardiovascular disorders, coronary, cerebral or renal vasospasms, obesity, bulimia and asthma - Google Patents

Abstract

N-(homo)piperazinylcarbonylacyl dipeptide derivatives (I) are new. Dipeptide derivatives of formula (I) and their salts are new: R<3> = a group of formula (i) or (ii): n = 2 or 3; Q, U = CH2, CO or NH, provided that Q and U can be the same only when they are CH2; A = (a) a 3- to 6-membered (un)saturated optionally bridged ring that may contain an O, S or N atom and is linked to the carbonyl groups through two adjacent C atoms; (b) a group of formula (iii) or (iv): or (c) CH2-W-CH2; W = a bond, O, S, NR<6>, CR<4>R<5> or 3-7C cycloalkylidene; R<6> = 1-6C alkyl or phenyl(1-3C)alkyl; R<4>, R<5> = H, 1-6C alkyl or phenyl; B = Arg, Lys, Ser, His, Pro, Ala, Val, Phe, Phe(p-CN), Phe(p-C(NH)NH2), Asn, Asp, Gly or Orn in L or D configuration, optionally with protected side chains; D = Tyr, Phe, Cha, His, Cys, Thr, Ser, Asp, Glu, Tyr(3,5-di-Br), Phe(p-F), Phe(p-Cl), Phe(p-NO2), phenylglycine, 2-thienylalanine, cyclohexylalanine, homophenylalanine or N-methyl-phenylalanine, in L or D configuration, optionally with protected side chains. An Independent claim is also included for carboxylic acids of formula (II):

Description

The invention relates to novel substituted dipeptides of general formula I.

and their pharmaceutically acceptable salts. The Compounds have NPY agonist and / or NPY antagonistic properties.

The abbreviations used in this description and the claims for the amino acids correspond to the usual three-letter code as z. In Europ. J. Biochem., 138, 9 (1984). The remaining abbreviations are explained below:

Bum = t-butyloxymethyl
Boc = t-butoxycarbonyl
Bzl = benzyl
Cha = L-cyclohexylalanine
DCCI = dicyclohexylcarbodiimide
DC = thin-layer chromatogram
DCH = dicyclohexylurea
DIC = diisopropylcarbodiimide
DMF = dimethylformamide
Fmoc = 9-fluorenylmethoxycarbonyl
HOBt = hydroxybenzotriazole
Hpa = L-homophenylalanine
HPLC = High Performance Liquid Chromatography
Me = methyl
Mtr = 4-methoxy-2,3,6-trimethylphenylsulfonyl
Orn = L-ornithine
Phg = L-phenylglycine
RT = room temperature
tBu = t-butyl
TFA = trifluoroacetic acid
THF = tetrahydrofuran
Thi = L-2- (2-thienyl) alanine
Z = benzyloxycarbonyl.

The term amino acid includes (if in the following text not expressly stated otherwise) natural and unnatural amino acids, both the D as well as the L-shape. Further, the term includes "α-amino acid" also α, α-disubstituted Amino acids.

If an amino acid without a prefix is specified (eg Orn) this statement stands for the L-form of the amino acid. The D-form is expressly stated.

The invention relates to novel substituted dipeptides of general formula I.

and their pharmaceutically acceptable salts, wherein R ^{3 is} a group of the general formula

means
n is 2 or 3,
Q and U are CH ₂ , C = O or NH, where
Q and U can only be the same if they mean CH ₂ ;
A

• (a) one consisting of 3 to 6 ring atoms saturated or unsaturated, bridged or unbridged ring, wherein all Ring atoms are carbon or a ring atom O, S or N is and the other ring atoms Carbon, with 2 adjacent each C atoms of the ring to those with the group A. bonded carbonyl groups;
• (b) the group
  or
  is;
• (c) the group is -CH ₂ -W-CH ₂ - wherein W is a bond, O, S, NR ⁶ (wherein R ^{6 is} (C ₁ -C ₆ ) alkyl or phenyl- (C ₁ -C ₃ ) alkyl), the group
  (wherein R ⁴ and R ^{5 are} independently hydrogen, (C ₁ -C ₆ ) alkyl or phenyl),
  or W for the group
  (wherein m is 2, 3, 4, 5 or 6);

B Arg, Lys, Ser, His, Pro, Ala, Val, Phe, Phe (p-CN), Phe (pC (NH) NH ₂

), Asn, Asp, Gly or Orn in the L or D configuration, optionally with protected side chains;
D Tyr, Phe, Cha, His, Cys, Thr, Ser, Asp, Glu, Tyr (3,5-di-Br), Phe (pF), Phe (p-Cl), Phe (p-NO ₂

) Phenylglycine, 2-thienylalanine, cyclohexylalanine, Homophenylalanine or N-methyl-phenylalanine, in the L or D configuration, if necessary with protected side chains.

The compounds can be amino acids (see definition the groups B and D) whose side chains are protected. As protective groups are those in the Synthesis usual groups suitable. Preferred are such protecting groups, the homoaromatic groups such as For example, benzyl.  

Possess compounds of general formula I. Acid groups, mainly carboxyl groups, or phenolic hydroxy groups, and / or basic groups such as B. guanidino or amino functions. links of the general formula I can therefore either as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, Phosphoric acid, sulfonic acid or organic acids (such as for example, maleic acid, fumaric acid, citric acid, Tartaric acid or acetic acid) or as salts with pharmaceutically usable bases such as alkali or Alkaline earth metal hydroxides or carbonates, zinc or Ammonium hydroxides or organic amines such. B. Diethylamine, triethylamine, triethanolamine u. a. available.

The chiral centers in the new peptides can each have R, S or R, S configuration.

Preference is given to peptide derivatives of the general formula I, wherein one of the groups Q and U is C = O and the other NH.

Also preferred are compounds of general formula I, wherein A is a phenyl linked in the 1- and 2-position, a furyl or thienyl linked in 3- and 4-position, a 5-norbornene ring linked in the 2- and 3-position or the group

wherein p is 1, 2, 3 or 4; or
wherein A is the group -CH ₂ -W-CH ₂ -, wherein W is a bond, O, S, NR ⁶ (wherein R ^{6 is} phenyl (C ₁ -C ₃ ) alkyl), the group

(wherein R ⁴ and R ^{5 are} independently hydrogen, (C ₁ -C ₃ ) alkyl or phenyl), or the group

(wherein m is 3, 4, 5 or 6); in particular those in which A is the group -CH ₂ -W-CH ₂ , where W is the group

where m is 4 or 5.

Another preferred aspect of the invention are compounds of general formula I wherein
B is Arg, Lys, Ser, His, Pro, Ala, Val, Phe, Phe (p-CN) Phe (pC (NH) NH _2), Asn, Asp, Gly or Orn; and
D Tyr, Phe, Cha, His, Tyr (3,5-di-Br), Phe (pF), Phe (p-Cl), Phe (p-NO ₂ ), phenylglycine, 2-thienylalanine, cyclohexylalanine, homophenylalanine, N-methyl-phenylalanine, Tyr (O-methyl), Tyr (O-benzyl), Tyr (O-2,6-dichlorobenzyl), Cys (benzyl), Thr (benzyl), Ser (benzyl), Asp (benzyl) or glu (benzyl);
in particular those in which B is Arg, Phe, Phe (p-CN) or Phe (pC (NH) NH ₂ ) and D is Tyr, Tyr (Bzl) or Phe.

The following compounds according to the invention 1:

2:

3:

4:

and
5:

and their pharmaceutically acceptable salts are to be emphasized.

Test results for compounds according to the invention:
Receptor affinity was measured on an NPY receptor preparation derived from rabbit kidney by displacement of ¹²⁵ I-labeled NPY. The thus obtained IC ₅₀ values for the above-mentioned compound:

connection IC ₅₀ [M] 1 3,6,10 ^-8 2 6.10 ^-6 3 6,9,10 ^-8 4 (as chloride) 1.10 ^-6 5 1.10 ^-5

The compounds of the invention can be used for therapy Cardiovascular disorders such as hypertension and Hypotension, coronary, cerebral and renal Used vasospasms as well as obesity and bulimia become. In addition, these compounds can be considered valuable tools for the production and cleaning (Affinity chromatography) of antibodies and in RIA or ELISA assays.

The invention therefore also relates to the use of Compounds of the invention as a remedy and pharmaceutical preparations containing these compounds contain. The application on humans is preferred. The Application of the compounds of the invention can intravenous, subcutaneous, intramuscular, intraperitoneal, intranasal, inhalative, transdermal, preferred by Promoted iontophoresis or literature-known enhancers, and taken orally.

For parenteral administration, the compounds of the formula I or their physiologically tolerable Salts, possibly with the usual substances such as Solubilizers, emulsifiers or other auxiliaries brought in solution, suspension or emulsion. When Solvents come z. B. in question: water, physiological saline solutions or alcohols, eg. B.  Ethanol, propanediol or glycerine, sugar solutions like Glucose or mannitol solutions or else a mixture from different solvents.

In addition, the compounds by implants, z. B. from polylactide, polyglycolide or Polyhydroxybutyric acid or intranasal preparations be applied.

The compounds of the invention can be prepared by methods known per se by sequentially condensing the respective amino acids or peptide derivative partial sequences and isolating the resulting compound in free form or in the form of the desired salt. It is preferred, the dicarboxylic acid derivative of the general formula

with the dipeptide component of the general formula HBD-NH ₂ (III) (wherein A, B, D, R ³ and n are as defined for general formula I). The said starting compounds contain protective groups if necessary.

However, it is also possible to carry out the steps of the manufacturing process in a different order. Thus, for example, it is also possible first to couple a reactive derivative of the dicarboxylic acid HOOC-A-COOH (IV) with the dipeptide component HBD-NH ₂ (III) and then with the amine component of the general formula

to implement the amide.

The sequence of the method steps can also be chosen as such be that the last step is the introduction of the Amino acid D or the construction of a side chain of a Amino acid takes place.

The individual steps of the procedure can after be carried out known methods.

The compounds of the invention can be prepared by well-known methods of peptide chemistry, such as. In "Houben-Weyl, Methods of Organic Chemistry, Vol. 15/2", or after the solid-phase peptide synthesis (for example BRC Sheppard, Int. J. Pept. Prot. Res., 21, 118 [1983]) or equivalent known methods. The respective amino acids or partial amino acid sequences are condensed stepwise and the resulting peptides are isolated in free form or in the form of the desired salts. The amino-protecting groups used are those described in "Houben-Weyl, Methoden der organischen Chemie, Vol. 15/1", the benzyloxycarbonyl group (Z) being preferred in conventional syntheses and the fluorenylmethoxycarbonyl group (Fmoc) in solid-phase syntheses. The side chain of arginine was protected by protonation in the case of conventional synthesis, in the case of solid phase synthesis the Mtr group was used. In the solid phase peptide synthesis, for. B. also used the following side chain protected amino acids:
Lys (Boc), His (Bum), Ser (tBu) and Asp (tBu). The specific conditions of synthesis are given in the following examples.

For the synthesis of the compounds of the general formula I according to the solid-phase synthesis are suitable as anchor groups all those which provide Peptidamide in the cleavage of the peptide from the polymeric carrier. The benzhydrylamino anchor group (PG Pietta et al., J. Org. Chem. 39, 44 (1974)) and the 4-methylbenzyhdrylamine anchor group (GR Matsueda et al., Peptides 2, 45 (1981)) are preferably used in combination with the BOC-amino protecting group , In combination with the Fmoc protecting group different anchor groups are applicable:
p-aminomethyl-phenoxymethyl group (P. Pietta et al., J. Org. Chem., 40, 2995 (1975).) Bis- and trialkoxybenzylamine linkers (F. Albericio, G. Barany, Int. J. Pept. Prot. Res 30, 206 (1987) Benzhydryl alcohol linker (G. Breipohl et al., Tetrah. Lett., 28, 5651 (1987)).

Especially the dimethoxyphenoxyvaleric acid anchor, the on alanine-loaded benzhydrylamine polystyrene over the carboxy group has been attached, has proven itself.

After cleavage of the amino protecting group of the resin coupled amino acid with a suitable reagent z. B. trifluoroacetic acid in dichloromethane in the case of BOC group or a 20-50% solution of piperidine in DMF in the case of the Fmoc group are suitable coupled with protected amino acids. This cycle will Run through one after another as often as you want the resin bound peptide has emerged.  

For coupling, those known in peptide chemistry Methods (see Houben-Weyl, Methods of Organic Chemie Bd 15/2 be applied. Preferably used carbodiimides, such as. Dicyclohexylcarbodiimide, Diisopropylcarbodiimide or ethyl (3-dimethylamino propyl) carbodiimide or O-benzotriazole tetramethyl uronium hexafluorophosphate or benzotriazol-1-yl-oxy tris- (dimethylamino) phosphonium hexafluorophosphate. By addition of 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine (HOObt) optionally suppresses the racemization or the Reaction rate can be increased. The Amino acids Asn and Gln are preferred in the form of their N-protected p-nitrophenyl ester coupled. The Clutches are usually equipped with a 2- to 5-fold excess of N-protected amino acid (or an equivalent amount thereof) and Coupling reagent in solvents such as dichloromethane, Dimethylformamide, N-methylpyrrolidone (NMP) or Mixtures of these are performed. The course of the Coupling reaction is confirmed by the Kaiser test (E. Kaiser u. a., anal. Biochem. 34, 595 (1970) or by the TNBS test tracked. If an incomplete Acylation is detected, the coupling is up to Completeness repeated. The solid phase synthesis can both manually and automatically with the help of a Peptidsynthesizers done.

Preferred are solid phase syntheses using of the dimethoxyvaleric acid linker, Fmoc-amino protection groups and the automatic synthesizer from ABI self-developed synthesis programs. It will Double clutches performed, the first with DCC / HOBt in DMF, the second with symmetrical anhydrides in N-methylpyrrolidone. After the first clutch is a  Washing step with N-ethylmorpholine in NMP interposed. After the second clutch takes place Capping with acetic anhydride and N-ethylmorpholine. The resin is washed with each coupling step DMF, NMP and isopropanol.

After construction of the peptides on the resin, the peptide with suitable reagents such as liquid hydrogen fluoride in Case of the built-up by the BOC strategy peptides or trifluoroacetic acid in the case of after Fmoc strategy constructed peptides from the polymeric carrier be split off. When using the above Anchor groups you get directly the corresponding Peptide amides. With these reagents are usually and when using the appropriate side chains Protective also functional, while the Synthesis-protected groups of the peptide released.

Usually, in the cleavage of the peptide of the resin as cation scavenger substances such as phenol, Cresol, anisole, thiocresol, thioanisole, indole, Di-ethyl sulfide or ethyl methyl sulfide or a Mixture of these substances to the hydrogen fluoride or added to the trifluoroacetic acid.  

The starting compounds of general formula II

are new connections. They can be prepared by known methods. Preferably, a reactive derivative (eg, anhydride) of the dicarboxylic acid HOOC-A-COOH (IV) with the amine component of the general formula

in a solvent (e.g., methylene chloride) to the amide (II). The amine component (V), wherein R ^{3 is} the group

is analogous to the description in J. Pharm. Pharmac. (1969) 21, 520-530 become.

The amine component (V), wherein R ^{3 is} the group

is analogous to the description in US Pat. 36 60 380 getting produced.

example 1

Preparation of cyclopentane-1- [acetic acid- (4- (5,6-) dihydro-6-oxomorphanthidin-11-yl) -piperazid)] - 1- acetic acid

11- (1-piperazino) -5,6-dihydro-6-oxomorphanthidine analogously to the description in J. Pharm. Pharmac., (1969) 21, 520-530. This gives a colorless Solid.

5.4 g of 3,3-tetramethylene glutaric anhydride (32 mmol) are suspended in 180 ml of methylene chloride and on Cooled to 0 ° C. While stirring and ice cooling, a Solution of 9.5 g of 11- (1-piperazino) -5,6-dihydro-6- oxomorphanthidine (32 mmol) in 50 ml of methylene chloride dropwise. It is allowed to stand at room temperature for 60 hours Stir, add 60 ml of water and filter. The organic phase of the filtrate is separated and still washed twice with 50 ml of water. It is dried over sodium sulfate, the solvent is in vacuo removed and the residue in ethyl acetate to Crystallization brought. The rainfall will  filtered off and with a little diisopropyl ether rewashed. This gives 5.2 g of cyclopentane-1 [Acetic acid, ethyl (4- (5,6-dihydro-6-oxomorphanthidin-11-yl) - piperazide)] - 1-acetic acid (yield 35%) as colorless Solid. Mp 154-157 ° C.

Preparation of H-Arg-Tyr-NH ₂

15 g of Z-Arg-OH.HCl (43.5 mmol), 7.83 g of H-Tyr-NH ₂ (43.5 mmol) and 6.66 g of HOBt (43.5 mmol) are dissolved in 160 ml of absolute DMF dissolved, the mixture was cooled to 3-5 ° and treated with stirring with 52.2 mmol DCI. It is left for 1 h at 3-5 °, and then stirred overnight at room temperature. Thin layer control shows complete conversion. The precipitated DCH is filtered off, the filtrate is concentrated under reduced pressure and finally in a high vacuum and the residue taken up in 600 ml of 0.1 N HCl. The insolubles are filtered off and the filtrate is neutralized with 60 ml of 1N NaOH. After addition of 150 ml of saturated NaHCO ₃ solution, the precipitated viscous oil is decanted off and filtered. The filtrate is concentrated to dryness, the residue taken up with 300 ml of a mixture of acetonitrile / water / methanol in the ratio 4: 1: 1 and filtered with suction from the insoluble. The filtrate is chromatographed directly on silica gel with acetonitrile / water / methanol (4: 1: 1) as eluant. The uniform fractions of the eluate in the TLC are combined and concentrated in vacuo to constant weight. This gives 18.9 g of Z-Arg-Tyr-NH ₂ .HCl (yield 86%) as a white solid, mp: 96-106 °.

18.9 g of Z-Arg-Tyr-NH ₂ .HCl (37 mmol) are dissolved in 500 ml of methanol, mixed with 2 g of pd-carbon (5%) and autoclaved at 20 ° for 3 h at a pressure of 5 Bar H ₂ subjected to hydrogenolysis. The reaction mixture is filtered and the filtrate concentrated to constant weight. This gives 13.5 g of H-Arg-Tyr-NH ₂ .HCl (yield 98%) as a white solid.
Mp .: 114-24 ° (Zers.).

Coupling of H-Arg-Tyr-NH ₂ .HCl with cyclopentane-1- [acetic acid (4- (5,6-dihydro-6-oxomorphanthidin-11-yl) -piperazide)] - 1-acetic acid hydrochloride

1 g of cyclopentane-1- [acetic acid- (4- (5,6-dihydro-6-oxo-morphanthidin-11-yl) -piperazide)] - 1-acetic acid hydrochloride (2 mmol) is treated with 0.36 g of CDI (2 , 2 mmol) for 1.5 hours at room temperature in 20 ml of DMF. Then, a solution of 0.75 g of H-Arg-Tyr-NH ₂ .HCl (2 mmol) in 20 ml of DMF is slowly added dropwise. The mixture is stirred overnight (about 16 hours) at room temperature, then the solvent is removed in vacuo. The crude product is stirred with 20 ml of methylene chloride and 20 ml of water and digested. The viscous residue is chromatographed on alumina using acetonitrile / methanol / water 4: 1: 1 as eluent. The uniform fractions of the eluate in the TLC are combined and freed from the solvent in vacuo. The residue is taken up in methanol, acidified with ethereal hydrochloric acid and concentrated to dryness in vacuo. 0.3 g of the compound of this example is obtained as a beige solid.
Yield 17.5%; FAB-MS: (M + H) ⁺ = 780.4.

Example 2

The preparation is carried out analogously to Example 1.
MS: (M + H) ⁺ = 771.

Example 3

The preparation is carried out analogously to Example 1.

p-Cyano-phenylalanine can be prepared as described below. The further reactions to

are carried out according to the methods customary in peptide synthesis.  

Preparation of p-cyano-phenylalanine

One from 8.5 g of sodium and 370 ml of anhydrous ethanol fresh prepared sodium methylate solution is at room temperature and within about 15 minutes to one out of 73.3 g Bromomethylbenzonitrile, 82 g of diethyl acetamidomalonate (97%), 18.3 g of potassium iodide and 1700 ml of dry dioxane was added dropwise. It is stirred for 30 minutes Room temperature and then boiled for 5 hours under reflux. One lets stand at room temperature for about 16 hours, then heated to 70 ° C. and filtered from the insoluble. The filtrate is brought to 15 ° C cooled and stirred into 3.2 l of ice water. The resulting Rainfall is collected in a nutsche, thoroughly with Washed water and dried at 80 ° C. 120 g are obtained α- (acetylamino) -α - [(4-cyanophenyl) methyl] malonate as colorless crystals. Mp 168-170 ° C.

123 g of α- (acetylamino) -α - [(4-cyanophenyl) methyl] Diethyl malonate are dissolved in 330 ml of glacial acetic acid and after Add 660 ml of 3 N aqueous hydrochloric acid for 6 hours Reflux cooked. It is cooled to 8 ° C and filtered, the Filtrate is evaporated in a water-jet vacuum. Last leftovers of water and acetic acid are made by azeotropic distillation removed with xylene.

The crude product is dissolved in the required amount of methanol and filtered hot. The filtrate is stirred thoroughly after cooling to room temperature with the same volume of diisopropyl ether. The precipitate is filtered off and dried at 80 ° C. 78 g of p-cyanophenylalanine are obtained as colorless crystals. IR (KBr): 2235 (C~N); 1740 (COOH) cm ^-1 .

Example 4

800 mg (1 mmol) of the compound of Example 3 are dissolved in 35 ml of methanol and treated with 20 ml of petroleum ether. The mixture is cooled with ice and saturated with hydrogen chloride. After 16 hours, it is evaporated in vacuo, the residue is taken up in methanol and cooled with ice with ice. Ammonia solution adjusted to a pH of about 10. After 24 hours, it is evaporated to dryness in vacuo at 40-45 ° C. It is mixed with methylene chloride and methanol (85:15), filtered and the residue is washed. The collected filtrates are freed from the solvent in vacuo. The residue is washed with diisopropyl ether (ultrasonic bath) and dried.
MS (thermospray): M⁺ = 812.

Example 5

The preparation is analogous to Example 3. MS: (M + H) ⁺ 840.

The piperazine derivative 2 required for the preparation is obtained by catalytic hydrogenation of the compound 1. Compound 1 is prepared by the method described in the literature, for. B. according to US Pat. 36 60 380

158 g are dissolved in 2.1 l of ethanol and treated with 36 g of palladium on charcoal, 10% strength. It is hydrogenated at 60 ° C under 50 bar for 5 h. The mixture is then filtered off from the catalyst and the solvent is removed in vacuo.
Yield: 98 g (79%). FP 253-254 ° C.

Pharmaceutical preparations injection

200.0 mg active substance *
1.2 mg monopotassium dihydrogen phosphate = KH ₂

PO ₄

(Buffer)
0.2 mg disodium hydrogen phosphate = (buffer) NaH ₂

PO ₄

.2 H ₂

O
94.0 mg sodium chloride (isotonan) or
520.0 mg glucose (isotonan)
4.0 mg albumin (protease protection)
qs sodium hydroxide, ad pH 6
qs hydrochloric acid, ad pH 6
ad 10 ml of water for injections

injection

200 mg active substance *
94 mg sodium chloride or
520 mg of glucose
4 mg albumin
qs sodium hydroxide, ad pH 9
qs hydrochloric acid, ad pH 9
ad 10 ml of water for injections

lyophilisate

200 mg active substance *
520 mg mannitol (Isotonans / scaffold builder)
4 mg albumin

Solvent 1 for lyophilisate

10 ml of water for injections

Solvent 2 for lyophilisate

20 mg Polysorbate®80 = Tween®80 (surfactant)
10 ml of water for injections

* Active ingredient: compounds of the invention, e.g. B. that of Examples 1 to 5.
Dose for humans of 67 kg

Claims (15)

1. dipeptide of general formula I.
or its pharmaceutically acceptable salt, wherein R ^{3 is} a group of the general formula
means;
n is 2 or 3, Q and U are CH ₂ , C = O or NH, where Q and U can only be the same if they are CH ₂ ;
A

• (a) is a saturated or unsaturated, bridged or unbridged ring consisting of 3 to 6 ring atoms, in which all the ring atoms are carbon or one ring atom is O, S or N and the other ring atoms are carbon, each with 2 adjacent carbon atoms of the ring the carbonyl groups linked to the group A are bonded;
• (b) the group
  or
  is;
• (c) the group is -CH ₂ -W-CH ₂ - wherein W is a bond, O, S, NR ⁶ (wherein R ^{6 is} (C ₁ -C ₆ ) alkyl or phenyl- (C ₁ -C ₃ ) alkyl), the group
  (wherein R ⁴ and R ^{5 are} independently hydrogen, (C ₁ -C ₆ ) alkyl or phenyl),
  or W for the group
  (wherein in 2, 3, 4, 5 or 6);

B Arg, Lys, Ser, His, Pro, Ala, Val, Phe, Phe (p-CN), Phe (pC (NH) NH ₂ ), Asn, Asp, Gly or Orn in the L or D configuration optionally with protected side chains;
D Tyr, Phe, Cha, His, Cys, Thr, Ser, Asp, Glu, Tyr (3,5-di-Br), Phe (pF), Phe (p-Cl), Phe (p-NO ₂ ) Phenylglycine, 2-thienylalanine, cyclohexylalanine, homophenylalanine or N-methyl-phenylalanine, in the L or D configuration, optionally with protected side chains. 2. A compound according to claim 1, wherein one of Groups Q and U C = O and the other NH. 3. A compound according to claim 1 or 2, wherein A is a linked in the 1- and 2-position phenyl, a linked in 3- and 4-position furyl or thienyl, a 2- and 3-position linked 5-norbornene ring or the group
wherein p is 1, 2, 3 or 4 means. A compound according to any one of claims 1 to 3, wherein A is the group -CH ₂ -W-CH ₂ -, wherein W is a bond O, S, NR ⁶ (wherein R ^{6 is} phenyl (C ₁ -C ₃ ) alkyl), the group
(wherein R ⁴ and R ^{5 are} independently hydrogen, (C ₁ -C ₃ ) alkyl or phenyl), or the group
(wherein in 3, 4, 5 or 6). A compound according to claim 4, wherein A is the group -CH ₂ -W-CH ₂ -, where W is the group
where m is 4 or 5. 6. A compound according to any one of claims 1 to 5, wherein
B is Arg, Lys, Ser, His, Pro, Ala, Val, Phe, Phe (p-CN) Phe (pC (NH) NH _2), Asn, Asp, Gly or Orn; and
D Tyr, Phe, Cha, His, Tyr (3,5-di-Br), Phe (pF), Phe (p-Cl), Phe (n-NO ₂ ), phenylglycine, 2-thienylalanine, cyclohexylalanine, homophenylalanine, N-methyl-phenylalanine, Tyr (O-methyl), Tyr (O-benzyl), Tyr (O-2,6-dichlorobenzyl), Cys (benzyl), Thr (benzyl), Ser (benzyl), Asp (benzyl) or glu (benzyl). A compound according to claim 5 wherein B is Arg, Phe, Phe (p-CN) or Phe (pC (NH) NH ₂ ) and D is Tyr, Tyr (Bzl) or Phe. 8. A compound according to claim 1
or a pharmaceutically acceptable salt thereof. 9. A process for preparing a compound according to one of claims 1 to 8 or its salts, characterized in that according to known Methods gradually the respective amino acids or peptide derivative subsequences condensed and the resulting compound in free form or isolated in the form of the desired salt. 10. Pharmaceutical preparation containing a A compound according to any one of claims 1 to 8.   11. Use of a compound according to one of Claims 1 to 8 for the treatment of coronary, cerebral or renal vasospasm or of Cardiovascular disorders such as hypertension and Hypotension. 12. Use of a compound according to one of Claims 1 to 8 for the treatment of obesity. 13. Use of a compound according to one of Claims 1 to 8 for the treatment of bulimia. 14. Compound of the general formula II,
wherein A, R ³ and n are as defined in any one of claims 1 to 8. 15. A process for the preparation of a compound according to claim 14, characterized in that a reactive derivative of the dicarboxylic HOOC-A-COOH (IV) with the amine component of the general formula
in a solvent to the amide (II) is reacted.