DE2608336A1 - NEW ORGANIC COMPOUNDS, THEIR PRODUCTION AND USE - Google Patents

Description

SAWDOZ-PATENT-GMBH 7850 Loerrach

Case 100-4314

New organic compounds, their production and uses

The present invention relates to new compounds of the formula I,

SB SB

CH CH.

χ i- , Z

R ₁ -CH-CO-XY-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-NH-CH-Z I 3

wherein R ₁ (i) H,

(ii) NH ₂ ,

(iii) H-AIa-NH-f

H-Tyr-NH-;

H-Cys-NH-;

H-VaI-NH-;

H-Lys-NH-?

H- (α-amino-isobutyryl) -NH-;

H-Phe-NH-f

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(Iv) NH ₂ -NH-CO-NH-; (ν) C ^ H _C .NH-CO-Gly-NH-;
DO H-Ala-Gly-NH-; H-VaI-GIy-NH-; Η-α-phenyl-Gly-NH-; (Vi) R-A-CO-NH-,

(vii)

(viii)

(ix)

(X)

where R _{2 represents} lower alkyl, phenyl or phenyl which is substituted by halogen, hydroxy, amino, lower alkyl or lower alkoxy, A represents a direct bond, an alkylene radical each having up to 6 carbon atoms or -NH-, R ₂ -AIa-NH-?

R ₂ -AIa-GIy-NH-; wherein R _{3 has the} above meaning,

CgH ₅ .A ¹ .CO-M-NH-,

where A ^{1 is} an alkylene radical with up to 6 carbon atoms and -M- - (mono- or di-Hal) -Phe-, -GIy- ° the -AIa- is, T- (mono- or di-Hal) - Phe-NH-, where T- is H-, H-Val- or benzoyl

stands,

Vn ^C where A has the above meaning and

-L- for -VaI-, -VaI- (mono- or di-Hal) -Phe-, -cc-Phenyl-Gly- and η stands for an integer between 4 and 10, ~ means,

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B stands for H or both B stands for a direct bond between the S atoms,

X for -Lys-, -Nie- or -Cys- and
Υ stand for -Asn-, -GIn- or -Thr- and Z stands for the radicals (i) H? (ii) COOH; (iii) COOR ₃ (where R _{3 represents} a lower alkyl group); (iv) -CO-NR ₄ R ₅ (where R ₄ and R 1, independently of one another, denote hydrogen or a lower alkyl group); (v) -CON ^ jCH ₂ ) _n , (where η has the above meaning); (vi) CH_OH; (vii) -CO-asparaginol; -CO-Leucinol; -CO-isoleucinol; -CO-Valinolf -CO-Norleucinol; -CO-glutaminol; -CO-threoninol; (viii) -CO-Leu? -CO-Ser; -CO-Iso-Leu; -CO-VaI and

their corresponding amides, in which the amide moiety is the remainder

-CO-NO. R _c or -CO-nTcH ,,), means (where n, R ₄ and 4 5 v _> / 2 η. 4

R _{5 has the} above meaning), or (ix) -CO-TlIrOR ₃ or -CO-SerOR ₃ , (where R _{3 has the} above meaning); (x) -CO-NH- (CH ₂ ) .- 0H (where k is an integer between 2 and 6), or -CO-NH-CH- [CH ₉ ] _Ί OH (where I ₁

I ^{Δ 1} I ^λ

^L [CH] OH 2

and I ₂ independently of one another are an integer between 1 and 6); (xi) -CO-N0; (xii) -CO-NH-R ₆ (in which R _{ß denotes} a 5 or 6-membered saturated heterocyclic ring which contains an oxygen atom as a ring member, or denotes a 5 or 6-membered lactone ring), where in formula I the Radicals R ^, X, Y and Z as well as the other units of the peptide sequence, at least one unit can be in the D-form,

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where when X is Lys and Y is Asn and all others Units of peptide sequence 3 to 14 are in the D or L form, and if so

(i) R ₁ H-Ala-Gly-NH- or

H- (D) -AIa-GIy-NH- mean, Z not for COOH, COOR ₃ , CH ₂ OH or

CONR ₄ R ₅ can be or, if (ii) R ₁ H, NH ₂ or H- (D) -AIa-GIy-NH-

means,
Z not for H, COOH, CONR ₄ R or

CON (CH ₀ ). , _ can stand ν— ^ 2. 4 or 5

or when
(iii) R ₁ H- (a-amino-isobutyryl) -NH- or

H- (D) -AIa-NH- means that Z cannot stand for H or COOH

or when
(iv) R _{1 means} H-Ala-Gly-NH-,

Z cannot stand for H or if

. (v) R H-AIa-NH-, or -

R ₂ '-CO-NH- (where R "* stands for lower alkyl or unsubstituted phenyl), Z cannot stand for COOH, and

where if R. H-Cys-NH or H- (D) -CyS-NH and / or X -Cys- or - (D) -Cys mean, B-B cannot stand for a direct bond.

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Halogen means bromine, fluorine and preferably chlorine. The meaning lower alkyl or lower alkoxy includes up to 6 carbon atoms, but preferably means 2 or 1 carbon atoms.

If R_ is substituted phenyl, this is preferred mono- or di-substituted, but especially mono-substituted. There is preferably one substituent in the para position.

In the case of A or when A is alkylene, these preferably contain up to 3 carbon atoms. With regard to the Meaning (viii) A is preferably trimethylene. With regard to the meaning (x), A preferably denotes Methylene.

Examples of - (mono- or di-Hal) -Phe parts are - (2Cl) Phe-; - (3Cl) Phe-; - (4Cl) P.he- or - (3,4-diCl) Phe-. η preferably denotes an integer 5 or 4. R, preferably denotes, for example, H- (mono or di-Hal) -PlIe-NH-, phenyl-CO-NH-, H-VaI- (mono- or di-Hal) - Phe-NH- _r phenylbutyryl-NH- or a radical containing - (D) -AIa, benzoyl- (mono- or di-Hal) -Phe-NH-, cyclohexylacetyl-α-phenyl-GIy-NH-, cyclohexylacetyl-Val -dnono- or di-Hal) -Phe-NH-, cyclohexylacetyl-Val-NH-, H-VaI-NH, H, H- (cc-amino-isobutyryl) -NH-? H- (mono- or di-Hal) -Phe-NH-; ~ X preferably denotes Lys and in particular Nie, Y preferably denotes GIn and in particular Asn. k preferably denotes 2 or 3.

If Z has the meaning (x) or (xii), this preferably comprises a -CO-NH-CH-CH ₂ -O- sequence, and means, for example, -CO · NH «CH (CH ₂ -OH) CH ₂ - CH ₂ -CH ₂ -OH; -CO-NH-CH (CH ₂ OH) -CH ₃ -CH ₂ OH; -CO-NH- CH-CH ₃ -CH ₂ ■ CO Ό

-CO-NH'CH CH-CO · 0 · CH.,; -CO-NH · CH-CH- -CH ₀ O'CH «; IZ ι Z j ZZ ι Z

-CO-NH-CH

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Z preferably does not denote H, CH ₂ OH ₁ COOH or COOR ₃ .

With the preferred meaning given above, the amino acids are both in the D and in the L — shape in front.

The present invention includes methods of manufacture of compounds of the above

Formula. You can use methods well known for the synthesis of compounds of this type or corresponding chemical equivalents.

For example, the compounds of the above formula can be prepared

a) by having at least one protecting group specified in a protected compound of formula I. Sequence is present, removed, or

b) by adding two peptide units, each of which has at least one amino acid in protected or contains unprotected form, linked together by an amide bond, the peptide bond in should take place in such a way that the amino acid sequence contained in the formula I is produced and then if appropriate, process stage a) is carried out, or

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c) by transferring a group Z into another group Z with the definition given above, whereby an unprotected or protected compound of the formula I is obtained "and in the latter case the Procedure step a) is carried out., Or.

d) by reacting a compound of formula I is _f woring B is hydrogen, is oxidized to give a compound of Formula I, wherein BB is a direct bond.

It is in peptide chemistry per se known methods; they can be carried out analogously to the processes described in the examples below will.

Insofar as the production of the starting products is not specifically described, these are compounds known or can be prepared and purified by methods known per se. Likewise, these can be prepared analogously to the processes described in the examples.

The compounds can zforrrr in SaI or in the form of their Complexes exist.

As acid addition salts are particularly salts of the Mention hydrochloric acid and acetic acid.

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Complexes are to be understood as meaning the complex-like compounds which have not yet been clarified in terms of their structure and which are formed when certain inorganic or organic substances are added to the compounds of the formula I. Such inorganic substances are compounds derived from metals such as calcium, magnesium, aluminum, cobalt and especially from zinc, especially sparingly soluble salts such as phosphates, pyrophosphates and polyphosphates and hydroxides of these metals, and also alkali metal polyphosphates. Organic substances are, for example, non-antigenic gelatine, e.g. oxypolygelatine, polyvinylpyrrolidone and carboxymethyl cellulose, also sulfonic or phosphoric acid esters of alginic acid, dextran, polyphenols and polyalcohols, especially polyphloretin phosphate and phytic acid, and polymers of amino acids, e.g. protamine, polyglutamic acid or polyasparagic acid.
The compounds are characterized by pharmaceutical

ecological activity. In particular, they inhibit GH secretion. They are therefore used in diabetes mellitus, in the treatment of acromegaly, angiopathy _f and in the use of these compounds for diagnostic purposes. The manufactured according to the invention

Connections can

administered in pharmaceutically acceptable salt form or in the form of their complexes. Such salt or Complex forms can be prepared from the free bases or vice versa by methods known per se. The present invention also encompasses pharmaceuticals

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Preparations containing a compound of the formula I in pharmaceutically acceptable salt or complex form and in admixture with a carrier or a solvent. Such pharmaceutical preparations can be used as Tablets or as solutions for injection or infusion. A pharmaceutical solution is preferred buffered at a pH between 5 and 8.

The present invention also encompasses pharmaceutical preparations which contain compounds of the formula I in which R _{1 is} H- (a-amino) -isobutyryl-NH- or H- (D) -AIa-NH, X Lys, Y Asn, Z -CONR ₄ R ₅ or -CO-N (CH ₃ J _{4 Qder 5.} Preferably each B is hydrogen.

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In the following examples, all temperatures are given in degrees Celsius and are uncorrected.

The following abbreviations are used:

Cbo = carbobenzyloxy

MBzI = p-methoxybenzyl

Iabu = H- (ct-amino-isobutyryl) -

(4Cl) Phe = p-chlorophenylalanyl

ACOH = acetic acid

OCP = trichlorophenyl ester

Trp = L-tryptophanyl

OSu = 0-succinimide

All end compounds are characterized in the hydrochloride salt form. Unless otherwise stated the amino acids are in the L-form.

20th

In the table below, [ ⁰ O _n refers to

ACOH 1% v / v (c = 1), unless otherwise stated.

(1) relates to ACOH 20% v / v (c = 1)

(2) relates to ACOH 1% v / v (c = 0.25)

(3) relates to ACOH 30% v / v (c = 1)

(4) relates to ACOH 40% v / v (c = 1)

(5) relates to ACOH 50% v / v (c = 1)

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Example I r H- (4Cl) Phe-Cys-liys-Asn-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH

Dissolve 480 mg of Cbo- (4Cl) Phe-Cys (MBzI) -Lys (BOC) -Asn-Phe-Phe-Trp-Lys (Cbo) -Thr-Phe-Thr-Ser-Cys (MBzI) -OBzI, 410 mg H-Try-OH, 320 mg H-Cys-OH · HCl and 1.2 ml thioanisole at 0 ° in 5 ml of trifluoroacetic acid and 10 ml of Bortris (trifluoroacetate) 2 molar in trifluoroacetic acid are added. The mixture is shaken for 1 hour at room temperature, cooled and mixed with 50 ml of tert-butyl alcohol, concentrated in vacuo and the residue is treated with a solution of 0.01 M 2-mercapto-ethanol in ether. Afterward is centrifuged. The solid residue is dissolved in a little 10% acetic acid and chromatographed on Sephadex G 25 purified in the system 0.01 M mercaptoethanol in 10% acetic acid. The residue can also be in 30% acetic acid or in a mixture of n-butanol / glacial acetic acid / water (e.g. 4: 2: 1) dissolved and by chromatography on Sephadex G 25 in the system 0.01 M mercaptoethanol in 30% acetic acid or as a mixture Butanol / glacial acetic acid / water. The fractions which contain the desired product are combined, dissolved in 0.1 η hydrochloric acid and lyophilized to give the title compound.

M.p. 195 ° (dec.); [α] £ ° = - 20.5 ° 'in AcOH (c = 1) The starting material is prepared as follows :

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Cbo-Lys_ (BOC) ^ - Asn-PJie-OMe

74.8 g of Cbo-Lys (BOC) -ONP are in a solution of 51 g of H-Asn-Phe-OMe · HCl and 21 ml of triethylamine are reacted in 300 ml of dimethylformamide. After work-up creates the title compound.

M.p. 175 ° f M r = -4.4 ° in dimethylformamide
(c = 1.0)

92 g of Cbo-Lys (BOC) -Asn-Phe-OMe are in a
Suspended solution of 2 l of dioxane and 400 ml of water. Palladium-carbon is added and the mixture is hydrogenated under normal pressure. The title compound is obtained after working up.

M.p. 122 °; [a] ^ ⁰ = - 8.3 ° in dimethylformamide
(c = 1.0)

20 g of H-CyS (MBzI) -OMeXH ₃ SO ₃ H and 7 ml of triethylamine are dissolved in 120 ml of dimethylformamide and mixed with
18.2 g of Cbo- (4Cl) Phe-ONP were added. One lets
Stand for 16 hours and concentrate at room temperature,

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where Cbo- (4Cl) Phe-Cys (MBzI) -OMe (m.p. 115 °) after Is obtained for a long time. The latter is dissolved in methanol and hydrazine hydrate is added stand at room temperature for a day. The title compound is obtained after work-up.

M.p. 158 °; [cc] ^ = - 9.9 ° in dimethylformamide (c = 1)

6 g of Cbo- (4Cl) Phe-Cys (MBzI) -NH-NH are in 80 ml Dissolved dimethylformamide, cooled to -20 °, with 6 ml of 5.3 N hydrochloric acid in dioxane, then with 1.3 ml tert-butyl nitrite was added and the mixture was stirred at -20 ° for 10 minutes. After adding 5.5 ml of triethylamine at -20 °, 8.4 g of H-Lys (BOC) -Asn-Phe-OMe are added, and the mixture is left at 0 ° overnight stand, concentrated, mixed with water at 0 ° to pH 2. The precipitate is filtered off and mixed with Water washed. The resulting Cbo- (4Cl) Phe-Cys (MBzI) -Lys (BOC) -Asn-Phe-OMe is made from methanol recrystallized, then dissolved in dimethylformamide and treated with 7 ml of hydrazine hydrate. Man left to stand for one day at room temperature, concentrated and the residue crystallized from methanol to give the title compound.

on

M.p. 260 ° i [cx] p = - 23 ° in dimethylformamide (c «1.0)

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§2 £ -i: Y £ i9 ^ ° il2hr-Phe-Thr-Ser ^ C ^ s (MBzI) -OB zl

In a manner analogous to paragraph d), 2.3 g of BOC-Lys (Cbo) -Thr-Phe-Thr-Ser-NH-NH are added to 1.86 g H-Cys (MBzl) -OBzl implemented; the title compound is obtained.

M.p. 169 °; [α] _β ^Ο = - 16 ° in dimethylformamide (c = 1).

2.3 g of BOC-Lys (Cbo) -Thr-Phe-Thr-Ser-Cys (MBzI) -OBzI are dissolved in a mixture of 10 ml of methylene chloride and 6 ml of trifluoroacetic acid and left to stand for 25 minutes at room temperature. Then H-Lys (Cbo) -Thr-Phe-Thr-Ser-Cys (MBzI) -OBzI · trifluoroacetate is precipitated with ether, filtered off and washed well with ether. The residue is dissolved in 7 ml of dimethylformamide, 1.5 g of BOC-Trp-OCP and 0.3 ml of triethylamine are added and the mixture is left to stand overnight at room temperature. The product is precipitated with ether / ethyl acetate (1: 1) and filtered. It is dried and the title compound is obtained.

M.p. 167 °; M ^ ° = - 1? Ί5 ° in dimethylformamide (c = 1)

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g) BOC ^ Phe ^ Trg-LYSJCbo ^ -Thr ^ Phe-Thr-Ser ^ CYSjtMBzl ^ -OBzl

36 g of BOC ~ Trp-Lys (Cbo) -Thr-Phe-Thr-Ser-Cys (MBzI) -OBzI are reacted with 20 g of BOC-Phe-ONP in a manner analogous to paragraph f); one gets the title connection.

M.p. 210 ° i [cx] p ° = 15 ° in dimethylformamide (c = 1.0).

1.5 g BOC-Phe-Trp-Lys (Cbo) -Thr-Phe-Thr-Ser-Cys (MBzI) -OBzI are dissolved in 30 ml of methylene chloride and 30 ml of trifluoroacetic acid. Leave for 25 minutes stand at room temperature, evaporate in vacuo and precipitate with ether. After filtering, washing with Ether and drying gives H-Phe-Trp-Lys (Cbo) -Thr-Phe-Thr-Ser-Cys (MBzI) -OBzI · trifluoroacetate.

0.9 g of Cbo- (4Cl) Phe-Cys (MBzI) -Lys (BOC) -Asn-Phe-NH-NH ₂ are dissolved in 20 ml of dimethylformamide, cooled to -20 ° and with 0.6 ml of 5.3 N hydrochloric acid in dioxane, then 0.1 ml of tert-butyl nitrite and stirred for 15 minutes at -20 °. 0.7 ml of triethylamine and 1.5 g of H-Phe-Trp-Lys (Cbo) -Thr-Phe-Thr-Ser-Cys- (MBzl) -OBzl · trifluoroacetate are added. It is left to stand overnight at 0 °, evaporated in vacuo, stirred with 100 ml of water, filtered, the residue is washed with water, then with methanol,

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warms in methanol, filtered and receives the title compound.

OCs
M.p. 270 ° in dimethylformamide

In an analogous manner, after the corresponding protected connections have been established, the following Compounds of the formula A obtained after splitting off the protective groups,

P-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Q A

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E.g. NO.

M.p. /

r ι ²⁰ [a]

NH-CO-Cys-Lys-Asn

NH-CO-Cys-Lys-Gln

H-Tyr-Cys-Lys-Asn NH,

-CO-Cys-Lys-Asn

_{e =} J- (CH ₂ ) ₃ -CO-Cys-Lys-Asn

-CO-Gly-Cys-Lys-Asn

• NH-CO-Gly-Cys-Lys-Asn

H-Cys-Cys-Lys-Asn H-Cys-Cys-Asn H-Lys-Cys-Lys-Asn H- (4Cl) Phe-Cys-Nle-Asn H- (4Cl) Phe-Cys-Lys-Asn H -Iabu-Cys-Lys-Asn H-Iabu-Cys-Lys-Thr Cys-OH
Cys-OH
Cys-OH
Cys-OH

Cys-OH
Cys-OH

Cys-OH

CyS-NH ₂

CyS-NH ₂

CyS-NH ₂

CyS-NH ₂

CyS-NH ₂

CyS-NH ₂

CyS-NH ₂

160 ° / -17.2 °

150 ° / -24.6 °

160 ° / -20.0 °

170 ° / -19.8 °

160 ° / -33.1 °

170 ° / -27.7 °

160 ° / -34.3 °

160 ° / -24.5 °

170 ° / -23.3 °

175 ° / -27.8 °

170 ° / -22.4 °

175 ° / -23.2 °

165 ° / -21.0 °

165 ° V -20.2 °

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E.g. NO Smp
[α]

-C0- (4Cl) Phe-Cys-Lys-Asn

V (CH) -CO-GIy-Cys-Nle-Gln ^ ~~ y (CH ₂ ) -CO-Cys-Lys-Asn f ~ \ NH-CO-Cys-Lys-Asn

NH-CO-Cys-Lys-Gln

• NH-CO-Cys-Nle-Asn NH-CO-Gly-Cys-Nle-Gln

NH ₂ -NH-CO-Cys-Lys-Asn

(CH ₂ J ₃ -CO- (D) AIa-CyS-LyS-ASn

Benzoyl-Cys-Nle-Asn Benzoyl-Cys-Lys-Asn (JrCO- (4Cl) Phe-Cys-Nle-Asn

H- (D) -Ala-Gly-Cys-Lys-Asn H-Ala-Gly-Cys-Lys-Asn Cys-NH,

Cy s-NH,

Cys-NH,

Cys-NH,

Cys-NH,

Cys-NH,

Cys-NH

CyS-NH ₂
CyS-NH ₂

CyS-NH ₂
Cys-NH

CyS-NH ₂
Cys-Val-NH,

160 ° / -18.7 °

155 ° / -18.7 °

145 ° / -19.5 °

160 ° / _m -25.3 ° ^U}

135 ° / -29.5 °

145 ° / -10.7 °

150 ° / -13.4 °

130 ° / -15.8 °

140 ^ö / -13.7 °

160 ° / -34.4 °

155 ° / -37.9 °

Cys

-O

220 ° / -47 ° (2)

210 ° / -45 ° (2)

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A29 A3O A31 A3 2 A33 A34 A35

H- (4Cl) Phe-Cys-Nle-Asn H-Iabu-Cys-Nle-Asn H-Iabu- * Cys-Lys-Asn H- (D) -Ala-Gly-Cys-Lys-Asn H- (D) -Ala-Gly-Cys-Nle-Asn H- (D) -Val-Cys-Lys-Asn H- (α-phenylglycyl) -Cys-Lys-Asn H- (D) -VaI- (4Cl) Phe-Cys-Lys-Asn H- (D) -Ala-Cys-Lys-Asn H-Cys-Lys-Asn

Cyclohexylacetyl- (D) -Val-Cys-Lys-Asn

Cyclohexylacetyl- (α-phenylglycyl) -Cys-Lys-Asn

Cyclohexylacetyl- (D) -VaI- (4Cl) Phe-Cys-Ly s-A s η

Benzoyl- (3,4-dichloro) Phe-Cys-Lys-Asn Benzoyl- (3,4-dichloro) Phe-Cys-Nle-Asn H- (D) -Ala-Gly-Cys-Nle-Asn Cys asparaginol

Cys asparaginol

Cys asparaginol

Cys asparaginol

Cys-Asparagi
nol

CyS-NH ₂
CyS-NH ₂

CyS-NH ₂
CyS-NH ₂

CyS-NH ₂
CyS-NH ₂
CyS-NH ₂
CyS-NH ₂

CyS-NH ₂

CyS-NH ₂

155 ° / -22.5 °

150 ° / -44.3 °

160 ° / -47.4 °

150 ° / -52.7 °

165 ° / -49.50 (1)

175 ° / -47.0 °

180 ° / -33.3 °

165 ° / -30.9 °

180 ° / -27.5 °

160 ° / -19.8 ^{o (3)}

¹⁶⁵ ° / -19.6 °

165 ° / _23.7 ° (3)

¹⁸⁰ ° { -22.5 °

^{1750 7} -23.5 ^{or similar}

160 ^p / -> 23.9 ° (4)

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P. 260 Q B336 E.g
No H- (D) -Phe-Cys-Nle-Asn Cys-NH A4 5 H-Phe-Cys-Nle-Asn CyS-NH ₂ 175 ° / A46 H- (3Cl) Phe-Cys-Nle-Asn Cys-asparagi-
nol 170 ° /
-30.8 ° (3) A47 H- (2Cl) Phe-Cys-Nle-Asn Cys-asparagi-
nol 165 ° /
-35.0 ° (3) A48 H- (3,4diCl) Phe-Cys-Nle-Asn Cys-asparagi-
nol 170 ° /
-29.8 ° (3] A4 9 CH ₂ -C = O 162 ° /
-25.5 ° (3] H- (4Cl) Phe-Cys-Nle-Asn Cys-NH-CH ' A50 H- (4Cl) Phe-Cys-Nle-Asn CyS-NH- [CH ₂ ] ₂ -OH 165 ° / A51 H- (4Cl) Phe-Cys-Nle-Asn Cy ₅ -NH-CCH ₂₁₃ -OH 135 ° /
-38.5 ° A52 H- (4Cl) Phe-Cys-Nle-Asn Cys-threoninol 132 ° /
-39.2 ° A53 H- (4Cl) Phe-Cys-Nle-Asn Cys-Thr-O-CH- 142 ° /
-41.5 ° A54 H- (4Cl) Phe-Cys-Nle-Asn Cys-Ser-0- 'CH 150 ° /
-4 3.6 ° A55 H- (4Cl) Phe-Cys-Nle-Asn Cys-Ser-NH ₂ 145 ° /
-41.0 ° A56 CH ₂ OH 153 ° /
-40.2 ° H- (4Cl) Phe-Cys-Nle-Asn Cys-NH-CH-CH OH A57 H- (4Cl) Phe-Cys-Nle-Asn Cys-glutaminol 138 ° /
-37.7 ° A58 153 ° /
-29.5 °

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E.g
No. P. Q Cys asparaginol
Cys asparaginol M.p. /
ri ²⁰
[a] _D A59
A6O
A61
A62
A63
A64 H- (4Cl) Phe-Cys-Nle-Asn
H- (4Cl) Phe-Cys-Nle-Asn
H- (4Cl) Phe-Cys-Nle-Asn
H- (D) -Phe-Cys-Nle-Asn CH-CH ₀ -OH
CyS-NH-CH-CH ₂ -OH
CH-CH ₀ -CH-OH
Cys -NH-CH-CH-OH
^ CH ₂ -CH
Cys-NH-CH C = O
^ CH ₂ -O ^
Cys asparaginol 142 ° /
-26.8 °
135 ° /
-27.8 °
153 ° /
-29.3 °
162 ° /
-25.5 °
165 ° /
-27.4 °
168 ° /
- 36 .2 H- (D) -VaI- (4Cl) Phe-Cys-Nle-Asn
H- (D) -Ala- (4Cl) Phe-Cys-Nle-Asn

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²² "Case 100-4314

Example 2;

H- (D) -Ala-Gly-Cys-Nle-Asn-Phe-Phe-Trp-Lys-Tlir-Phe-Thr-Ser-Cys-Asparaginol

0.4 g of the compound from Example A33 is dissolved in a mixture of methanol and 0.5% acetic acid and bring the pH by adding Ammonium hydroxide solution with stirring to pH 6. 0.1 M potassium ferricyanide solution is added slowly while stirring, until the yellow color persists. After stirring for a further 15 minutes, the pH is with Acetic acid adjusted to 4-5. Filter through a short column of Bio Rad AG 3 / x4 (Cr ^ form) [= weakly basic anion exchanger]. The filtrate is then left slowly at 0 ° through a column with Bio Rex 70 (-COOH form) [= weakly acidic cation exchanger]. The column is then with an acetic acid gradient with increasing acetic acid concentration or with a Acetic acid-pyridine gradient eluted. Factions that containing the desired product are combined and lyophilized. The lyophilisate is dissolved in a little n-butanol / Glacial acetic acid / water (2: 1: 1) or 30% acetic acid dissolved and chromatographed on Sephadex G 25 in the same mixture cleaned. The fractions which contain the desired product are combined, lyophilized and the title compound is obtained.

[a] tr = -36 ° (c = 1 in 95% acetic acid).

609840/1132

- 23 - 100-4314

In an analogous manner, the corresponding compounds with a free SH function (Examples 1 / Al-7, AlO-32, A34-64) the corresponding connections are established with an S-S bridge.

609840/1132

Claims (6)

Patent claims : where R, (i) H, (ii) NH ₂ , (iii) H-AIa-NH-; H-Tyr-NH-; H-Cys-NH-; H-VaI-NH-; H-Lys-NH-? H- (α-amino-isobutyryl) -NH-; H-Phe-NH-; (iv) NH ₂ -NH-CO-NH-; (ν) C II .NH-CO-GIy-NH-; H-AIa-GIy-NH-; H-VaI-GIy-NH-; II-cx-phenyl ~ Gly-NH-; (vi) R ₂ -A-CO-NH-, (vii) where R "represents lower alkyl, phenyl or phenyl which is substituted by halogen, hydroxy, amino, lower alkyl or lower alkoxy, A represents a direct bond, an alkylene radical each having up to 6 carbon atoms or -NH-,
R ₂ -AIa-NH-; 609840/1132 - 25 - 100-4314 R ₂ -AIa-GIy-NH-;
where R_ has the above meaning, (Viii) CH-.A ¹ .CO-M-NH-, wherein A is an alkylene radical having up to 6 carbon atoms and -M- - (mono- or di-Hal) -Phe-, -GIy- or -AIa- means, (ix) T- (mono- or di-Hal) -Phe-NH-, where T- is H-, H- Val- or benzoyl,
(x) (CH ₀ ) _n CiLA ¹ XO-L-NH, wherein A has the above meaning and • -L- stands for -VaI-, -VaI- (mono- or di-Hal) -Phe-, -ct-phenyl-Gly- and η stands for an integer between 4 and 10 ,
B stands for H or both B stands for a direct bond between the S atoms,
X for -Lys-, -Nie- or -Cys- and
Y stands for -Asn-, -GIn- or -Thr- and Z stands for the radicals (i) H; (ii) COOH; (iii) COOR ₃ (where R_ represents a lower alkyl group); (iv) -CO-NR ₄ R ₅ (where R. and R _{5 are} independently hydrogen or a lower alkyl group); (v) , (where η has the above meaning); (vi) H ₂ ) CH ₃ OH; (vii) -CO-asparaginol; -CO-Leucinol; -CO-isoleucinol; -CO-valinol; -CO-norleucinol; -CO-glutaminol; -CO-threoninol; (viii) -CO-Leu; -CO-Ser; -CO-Iso-Leu; -CO-VaI and their corresponding amides, in which the amide moiety is the radical -CO-NR.R _q or -CO-nTch.,), (where n, R. and 609840/1132. ' - 26 - 100-4314 R _{5 has the} above meaning), or (ix) -CO-ThrOR ₃ or -CO-SerOR-, (where R has the above meaning); (x) -CO-NH- (CH ₂ ), -OH (where k is an integer between 2 and 6), or -CO-NH-CH- [CH] ₁ OH (where I ₁ and '- [CHJ ₁ OH 1 _? independently of one another is an integer between 1 and 6); (xi) -CO-n] jD; (xii) -CO-NH-R ₆ (in which R _g denotes a 5 or 6-membered saturated heterocyclic ring which contains an oxygen atom as a ring member, or denotes a 5 or 6-membered lactone ring), where in formula I the Radicals R ₁ , X, Y and Z as well as in the case of the other units of the peptide sequence, at least one unit can be in the D form, where when X is Lys and Y Asn and all other units of the peptide sequence 3 to 14 are in the D or L-shape, and if (i) R ₁ H-Ala-GIy-NH- or H- (D) -AIa-GIy-NH- mean, Z not for COOH, COOR ₃ , CH ₂ OH or CONR.R, - or, if (ii) R ₁ H, NH ₂ or H- (D) -AIa-GIy-HH- means,
Z not for H, COOH, CONR.R _c or CON (CH ,.). ,,. can stand ^ - ^ 2 4 or 5 or, if (iii) R, H- (oc-amino-isobutyryl) -NH- or H- (D) -AIa-NH- means that Z cannot stand for H or COOH or, if (iv) R _{1 is} H-Ala-Gly-NH-, Z cannot stand for H or if 609840/1132 -27- 100-4314 26Ü8336 (ν) R, H-AIa-NH, or R 'denotes -CO-NH- (where R ₉ ' denotes lower alkyl or unsubstituted phenyl), Z cannot denote COOH, and where when R is H-Cys-NH or H- (D) -Cys-NH and / or X is -Cys- or - {D) -Cys, B-B is not a direct bond. 2. Process for the preparation of compounds of the formula I, SB SB CH CH R -CH-CO-X-Y-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-NH-CH-Z where R ,, B, X, Y and Z have the above meaning, as well as acid addition salts and complexes of these compounds, characterized in that the Compounds of the above formula r— .. Represents methods known from peptide chemistry and, if appropriate, subsequently to methods known per se Wise converted into their acid addition salts and complexes. 609840 / 1.132 - 28 - 100-4 314 3. Compounds of formula I according to claim 1, wherein when R. is H- (a-amino) -isobutyryl-NH- or H- (D) -AIa-NH, X is Lys, Y Asn, Z is not -CO- NR ₄ R ₅ or -CO-N ^ JCH ₂ ) _{4 or 5} can stand. 4. The method according to claim 2 for the preparation of the compounds of the formula I according to claim 3. 5. Helping means, characterized in that they contain compounds of the formula I according to Claim 1. 6. Remedies, characterized in that they fertilize compounds of the formula I, wherein R _{1 is} H- (a-amino) -isobutyryl-NH- or H- (D) -AIa-NH, X is Lys, Y is Asn and Z is -CO-NR ₄ R ₅ or -CO-N JCH ₃ J _{4 Q which may be 5} contain. SANDOZ-PATENT-GMBH 3700 / BA / ER / IL 609840/1 132