Peptide compounds, in particular LHRH-antagonists

Details Peptide compounds, in particular LHRH-antagonists Peptide compounds, in particular LHRH-antagonists

1994-05-04

1996-06-18

Chan, Christina Y.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530328, 530313, A61K 3800, A61K 3802, C07K 500, C07K 700

Patent

active

055277772

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of international application PCT/DE92/00427 filed May 22, 1992.
The invention relates to peptide compounds, in particular LHRH antagonists, their production and use as medicines, further, amino acids with nitrogen in the side chain and their production. (LHRH=luteinizing hormone-releasing hormone)
The luteinizing hormone-releasing hormone is produced in mammals in the hypothalamus. In the pituitary gland, it stimulates the release of luteinizing hormones (LH) and follicle-stimulating hormones (FSH). The latter in turn control the production of androgens and estrogens in the reproductive organs.
By administration of single doses of LHRH or synthetic agonists, increased production of steroid hormones (e.g. testosterone) can be achieved. Long term administration leads, however, to a reduction of hormone production. This effect has been used for some time for treating hormone-dependent tumors (prostate cancer).
The accompanying effect of this treatment is the initial stimulation of the hormones to be suppressed. This effect, which leads to transient tumor growth (tumor flare-up) in hormone-dependent tumors, can be avoided by using LHRH antagonists. Karten et al. (Endocrine Rev. 7, 44, 1986) and Dutta (Drugs of the Future 13, 761, 1988) have described the development of LHRH antagonists.
But effective LHRH antagonists, which have basic amino acids in 6- and 8-position, release undesirably high amounts of histamine. Various efforts have been made to reduce the release of histamine. European publication EP-OS 097 031 describes arginine derivatives in 6-position. European publication EP-OS 0 277 829 represents basic amino acid derivatives in 6- and 8-position. European publication EP-OS 0 299 402 discloses the combination of citrulline in 6-position with arginine in 8-position, in which quite little histamine is released.
It has now been found, surprisingly, that by exchange of 6- and 8-position for lysine derivatives, which are substituted on omega-nitrogen, an increase in the effect of reducing the release of histamine can be achieved.
According to the invention, peptide compounds of formula I are claimed, ##STR1## in which
X stands for a naphthoyl, naphthylacetyl, naphthylpropionyl, benzoyl group or an acyl group with 1-7 carbon atoms,
X.sub.1 stands for D-(1)-Nal, D-(2)-Nal, D-Phe, D-(4-Y)-Phe, D-(3)-Qal or a direct bond,
X.sub.2 stands for D-Phe, D-(4-Y)-Phe or a direct bond,
X.sub.3 stands for D-Trp, D-Phe, D-(4-Y)-Phe, D-(3)-Pal, D-(2)-Nal or a direct bond,
in which Y has the meaning already mentioned for X.sub.1,
X.sub.6 stands for D-Cit, D-Hci, D-Orn, D-Lys or D-Neu,
X.sub.8 stands for L-Orn, L-Arg, L-Lys or L-Neu, and at least one of radicals X.sub.6 and X.sub.8 is an Neu, and
X.sub.10 stands for D-Ala-NH.sub.2, Gly-NH.sub.2, azaglycine, -NHEt or -NH(CO)NH.sub.2, and Neu represents a group of formula II, ##STR2## in which Z stands for a group
>CH.sub.2, >C.dbd.O, >CH(OH), >O, >S, >S.dbd.O, >SO.sub.2, >NR.sub.1 oder >N(CO)R.sub.2 group, --CH(OH)--, or --SO.sub.2 --, --NR.sub.1 -- or --N(CO)R.sub.2 --, ##STR3## in which n stands for 1 to 8, or Neu represents a group of formula IV, ##STR4## in which W represents one of radicals ##STR5##
and n stands for a number from 1 to 8.
The text comprises some abbreviations, whose meaning is explained below. There, the rules set by the IUPAC-IUB Commission for biochemical nomenclature are followed (Biochemistry 11: 1726 (1972 and Biochem. J. 219: 345 (1984)).


______________________________________ Ape 2-amino-pentanoic acid Ahx 2-amino-hexanoic acid Ahp 2-amino-heptanoic acid Aoc 2-amino-octanoic acid Ano 2-amino-nonanoic acid Mor morpholin-4-yl- Pip piperidin-l-yl- Pyr pyrrolidin-l-yl- Tht tetrahydro-1,4-thiazin-4-yl- Mpz 4-methyl-piperazin-l-yl- Pon 4-piperidon-l-yl- Hpi 4-hydroxy-piperidin-l-yl- Aps 4-aza-pentamethylenesulfon-4-yl- (1)-Nal 3-(naphth-l-yl)-alanine (2)-Nal 3-(naphth-2-yl)-alanine (3)-Pal 3-(3-pyridyl)-alanine (3)-Qal 3-(quinol-3-yl)-alanine Hci homocitrulline 1I

REFERENCES:
patent: 4667014 (1987-05-01), Nestor, Jr. et al.
Liu et al., Science in China (Series B), vol. 34, No. 2, pp. 201-208 (Feb. 1991).
Lane, "Sodium Cyanoborohydride--A Highly Selective Reducing Agent for Organic Functional Groups," Synthesis, No. 3, pp. 135-146 (Mar. 1975).
Barrass et al., "The Formation of Cyclic Lactams from Derivatives of Basic Amino-acids," J. Chem. Soc., Part IV, pp. 4830-4834 (1957).

Affiliated with

Also associated with

Rating

Peptide compounds, in particular LHRH-antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Peptide compounds, in particular LHRH-antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Peptide compounds, in particular LHRH-antagonists will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-222918