Organic compounds

• US 4,291,022 A
• Filed: 05/23/1980
• Issued: 09/22/1981
• Est. Priority Date: 03/11/1975
• Status: Expired due to Term

• Current Assignee: Fidelity Union Trust Company Executive Trustee Under Sandoz Trust
• Original Assignee: Sandoz Inc. (Novartis Ag)
• Inventors: Bauer, Wilfried, Sandrin, Edmond
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US06/152,706
• Time in Patent Office: 487 Days
• Field of Search: 260/112.5 S, 424/177
• US Class Current: 514/11.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/6555 at least 1 amino acid in D-form
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/1005 and aliphatic
• CPC Class Codes: Y10S 930/16 Somatostatin; related peptides
• CPC Class Codes: Y10S 930/26 Containing cys-cys disulfide bridge between nonadjacent cysteine residues

Abstract

This invention provides new compounds of formula I, ##STR1## wherein R₁, X, Y and Z are amino acid residues and

each B is hyrogen or together are a bond,

useful as growth hormone secretion inhibitors.

Claims

1. A compound of formula I, ##STR53## wherein R₁ is (i) H,

(ii) NH₂,

(iii) H--Ala--NH--;

H--Tyr--NH--;

H--Cys--NH--;

H--Val--NH--;

H--Lys--NH--;

H--(α

-amino-isobutyryl)--NH--;

H--Phe--NH

(iv) NH₂ --NH--CO--NH--;

(v) C₆ H₅.NH--CO--Gly--NH--;

H--Ala--Gly--NH--;

H--Val--Gly--NH--;

H--α

--phenyl--Gly--NH--,

(vi) R₂ --A--CO--NH--,

wherein

R₂ is lower alkyl, phenyl, or phenyl substituted by halogen, hydroxy, amino lower alkyl or lower alkoxy,

A is a direct bond, alkylene containing up to 6 carbon atoms or --NH--,

(vii) R₂ --Ala--NH--;

R₂ --Ala--Gly--NH--;

wherein R₂ is as defined above,

(viii) C₆ H₅.A^I.CO--M--NH--,

wherein

A^I is an alkylene chain of up to 6 carbon atoms, and

--M-- is --(mono- or di-Hal)--Phe, --Gly-- or --Ala--,

(ix) T--(mono- or di-Hal)--Phe--NH, wherein T-- is H--, H--Val-- or benzoyl--,

(x) ##STR54## wherein A^I is as defined above, and

--L-- is --Val--(mono- or di-Hal)-- Phe--α

--phenyl--Gly--, and

n is an integer between 4 and 10,

each B is hydrogen or the two radicals B form a direct bond,

X is --Lys--, or --Nle--, and

Y is --Asn--, --Gln-- or --Thr--, and

Z signifies the radicals;

(i) --CO--asparaginol;

--CO--leucinol;

--CO--iso-leucinol;

--CO--valinol;

--CO--norleucinol;

--CO--glutaminol;

--CO--threoninol;

(ii) --CO--Leu;

--CO--Ser;

--CO--Iso--Leu;

--CO--Val, and their corresponding amides, wherein the amide portion signifies the radical --CO--NR₄ R₅ (wherein R₄ and R₅ independently are hydrogen or lower alkyl) or the radical ##STR55## (wherein n is as defined above);

(iii) --CO--ThrOR₃ or --CO--SerOR₃ (wherein R₃ is lower alkyl);

or

(iv) --CO--NH--(CH₂)_k --OH (wherein k is an integer between 2 and

     6), or ##STR56## (wherein 1₁ and 1₂ independently signify a whole number from 1 to

     6);

wherein in formula I the unit containing radicals R₁, X, Y and Z, as well as in the remaining units of the peptide sequence, at least one unit may be present in D form,

with the proviso that when R₁ is H--Cys--NH or H--(D)--Cys--NH, B--B is other than a direct bond,

or a pharmaceutically acceptable acid addition salt or complex thereof.

2. A compound of claim 1 wherein

Z signifies the radicals

(ii) --CO--Asparaginol;

--CO--leucinol;

--CO--iso-leucinol;

--CO--valinol;

--CO--norleucinol;

--CO--glutaminol;

--CO--threoninol;

or

(v) --CO--NH--(CH₂)_k --OH (wherein k is an integer between 2 and

     6), or ##STR57## wherein 1₁ and 1₂ independently signify a whole number from 1 to

     6).

3. A compound of claim 2 wherein Z represents ##STR58## (wherein 1₁ and 1₂ independently signify a whole number from 1 to 6).

4. A compound of formula I of claim 1 of the formula

6. A pharmaceutical composition useful in inhibiting growth hormone secretion comprising as active ingredient a pharmaceutically effective amount of a compound of formula I as defined in claim 1.

7. A method of inhibiting growth hormone secretion in a subject in need of such treatment, which method comprises administering an effective amount of a compound of formula I as defined in claim 1.

5. A compound of formula ##STR62##