LH-RH peptide analogues, their uses and pharmaceutical...

Details LH-RH peptide analogues, their uses and pharmaceutical... LH-RH peptide analogues, their uses and pharmaceutical...

1999-11-30

2003-07-01

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S013800, C514S016700, C530S323000

Reexamination Certificate

active

06586402

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to LH-RH peptide analogues, to their use and to pharmaceutical compositions in which they are present.
LH-RH, or luteinizing hormone-releasing hormone, is a neurohumoral hormone produced in the hypothalamus which stimulates the secretion of the gonadotrophins, LH (luteinizing hormone) and FSH (follicle-stimulating hormone), which in turn regulate the endocrine and exocrine functions of the ovary in the female, and of the testis in the male. It has the following structural formula (SEQ ID NO: 39):
 1   2   3   4   5   6   7   8   9   10
pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
Historically (Karten and Rivier, Endocr. Rev., 1986, 7(1), 44-66), synthetic improvement of LH-RH activity has been achieved first, by replacement of the C-terminal glycinamide by an ethylamide directly bound to Pro
9
, and then, by introduction of D-Ala in position 6. Both independent breakthroughs yielded analogs each about 5 times more active than LH-RH. All therapeutically useful agonists result from further major improvement in position 6 with the introduction of hydrophobic aliphatic or aromatic D-amino acids instead of D-Ala, with or without the combined Pro
9
-N-ethylamide modification. On this C-terminal end, only slight improvements have been obtained with fluorinated amides or with azaglycinamide. Replacement of Trp in position 3 by 1Nal has been reported (Karten and Rivier, 1986, cf above) to give an agonist twice as potent as LH-RH, without further synthetic or therapeutic developments.
The only other individual amino acid modification noticed to increase the biological activity of some agonists was found in position 7. Thus, N-methylation of Leu
7
in LH-RH itself did not increase its potency, but enhanced the activity of some already potent synthetic agonists with certain D-amino acids in position 6 such as D-Trp (Karten and Rivier, 1986, cf above); furthermore, charged and bulkier L-amino acids than leucine (Ser(OBu
t
), Asp(O-Bu
t
), Glu(O-Bu
t
), BocLys) somewhat improved the activity of [des-Gly
10
; Pro
9
-N-ethylamide]-LH-RH but reduced the potency of 6-modified agonists (Karten and Rivier, 1986, cf above).
As far as antagonists are concerned, numerous modifications in all positions but Pro
9
, and a wide variety of combinations among them, have been tried with unequal success to achieve inhibition of endogenous LH-RH activity (Dutta, Drugs of the Future, 1988, 13(8), 761-787; Karten and Rivier, Endoc. Rev., 1986, 7(1), 44-66). For example, antide, a standard potent LH-RH antagonist, results from amino acid changes in positions 1, 2, 3, 5, 6, 8 and 10. N-methylation of Leu
7
brought about a decrease in potency, and the only changes in this position reported to increase it (2-fold maximum) were the replacement of Leu
7
by Trp
7
or Phe
7
.
BRIEF SUMMARY OF THE INVENTION
It has now been found that the replacement of Leu
7
by highly hydrophobic amino acids, increases the activity of LH-RH itself or of known highly active analogues (agonists or antagonists) of LH-RH.
Especially, it has been found that the replacement of Leu
7
by adamantylalanine (Ada) or neopentylglycine (Npg) increases the activity of LH-RH itself and makes it possible to obtain analogs with a high affinity for the LH-RH receptors. More specifically, the [Npg
7
]-LH-RH analogues of this invention are potent LH-RH agonists/antagonists in vivo.
DETAILED DESCRIPTION OF THE INVENTION
Thus, according to one aspect of the present invention, LH-RH peptide analogues with high affinity for the LH-RH receptors are provided, in which a non-aromatic hydrophobic amino acid having from 7 to 20 carbon atoms, such as for example Ada
7
or, preferably, Npg
7
is substituted for Leu
7
. Preferably these peptide analogues are of the formula (SEQ ID NO: 1):
A1-A2-A3-A4-A5-A6-HAA-A7-Pro-Z  (I)
in which:
A1 is pGlu; D-pGlu; Sar; N-AcSar; Pro or a derivative thereof such as N-AcPro, ForPro, OH-Pro, Ac-OH-Pro, dehydro-Pro or Ac-dehydro-Pro; Ser; D-Ser; Ac-D-Ser; Thr; D-Thr; Ac-D-Thr; or an aromatic D-amino acid which may be acylated, such as D-Phe, D-HPhe, D-Tyr, D-Trp, D-Nal, D-1Nal, D-diphenyl-Ala, D-Bal, D-Pal, D-4Pal or D-Qal, where D-Phe and D-Trp may be substituted by one or more halogens, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, nitro or trifluoromethyl groups;
A2 is a direct bond; His; or an aromatic D-amino acid such as D-Phe, D-HPhe, D-Tyr, D-Trp, D-Nal, D-1Nal, D-diphenyl-Ala, D-Bal, D-Pal, D-4Pal or D-Qal, where D-Phe and D-Trp may be substituted by one or more halogens, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, nitro or trifluoromethyl groups;
A3 is an aromatic L- or D-amino acid such as Phe, HPhe, Tyr, Trp, Nal, 1Nal, diphenyl-Ala, Bal, Pal, 4Pal or Qal, where Phe and Trp may be substituted by one or more halogens, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, nitro or trifluoromethyl groups;
A4 is Ala, Ser, D-Ser, N-MeSer, Ser(OBu
t
), Ser(OBzl) or Thr;
A5 is an aromatic L-amino acid such as Phe, HPhe, Tyr, Trp, Nal, 1Nal, diphenyl-Ala, Bal, Pal, 4Pal or Qal, where Phe and Trp may be substituted by one or more halogens, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, nitro or trifluoromethyl groups; or a basic L- or D-amino acid such as Arg, HArg, Orn, Lys, HLys, Cit, HCit, APhe or ACha, where Arg and HArg may be N-substituted by a (C
1
-C
6
)alkyl or a (C
3
-C
6
)cycloalkyl group on one or both nitrogen atoms, and where Orn, Lys, HLys, APhe and ACha may be N-substituted by one or two (C
1
-C
6
)alkyl or (C
3
-C
6
)cycloalkyl groups, or by a nicotinoyl, isonicotinoyl, 6-methyl-nicotinoyl, glycyl-nicotinoyl, nicotinyl-azaglycyl, furyl, glycyl-furyl, furyl-azaglycyl, pyrazinyl, pyrazinyl-carbonyl, picolinoyl, 6-methyl-picolinoyl, shikimyl, shikimyl-glycyl, Fmoc or Boc group;
A6 is Gly; D-Pro; D-Ser; D-Thr; D-Cys; D-Met; D-Pen; D-(S-Me)Pen; D-(S-Et)Pen; D-Ser(OBu
t
); D-Asp(OBu
t
); D-Glu(OBu
t
); D-Thr(OBu
t
); D-Cys(OBu
t
); D-Ser(OR
1
) where R
1
is a sugar moiety; an aza-amino acid such as azaGly or azaAla; D-His which may be substituted on the imidazole ring by a (C
1
-C
6
)alkyl or by a (C
2
-C
7
)acyl group; an aliphatic D-amino acid with a (C
1
-C
8
)alkyl or a (C
3
-C
6
)cycloalkyl side chain such as D-Ala, D-Abu, D-Aib, D-3Aib, D-Val, D-Nva, D-Leu, D-Ile, D-Tle, D-Nle, D-Hol, D-Npg, D-CPa, D-Cpa, D-Cba or D-Cha; an aromatic D-amino acid such as D-Phe, D-HPhe, D-Tyr, D-Trp, D-Nal, D-1Nal, D-diphenyl-Ala, D-anthryl-Ala, D-phenanthryl-Ala, D-benzhydryl-Ala, D-fluorenyl-Ala, D-Bal, D-Pal, D-4Pal or D-Qal, where D-Phe and D-Trp may be substituted by one or more halogens, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, nitro or trifluoromethyl groups; D-cyclohexadienyl-Gly; D-perhydronaphthyl-Ala; D-perhydrodiphenyl-Ala; or a basic L- or D-amino acid such as Arg, HArg, Orn, Lys, HLys, Cit, HCit, APhe or ACha, where Arg and HArg may be N-substituted by a (C
1
-C
6
)aLkyl or a (C
3
-C
6
)cycloalkyl group on one or both nitrogen atoms, and where Orn, Lys, HLys, APhe and ACha may be N-substituted by one or two (C
1
-C
6
)alkyl or (C
3
-C
6
)cycloalkyl groups, or by a nicotinoyl, isonicotinoyl, 6-methyl-nicotinoyl, glycyl-nicotinoyl, nicotinyl-azaglycyl, furyl, glycyl-furyl, furyl-azaglycyl, pyrazinyl, pyrazinyl-carbonyl, picolinoyl, 6-methyl-picolinoyl, shikimyl, shikimyl-glycyl, Fmoc or Boc group;
HAA is a non-aromatic hydrophobic amino acid of from 7 to 20 carbon atoms;
A7 is a basic L- or D-amino acid such as Arg, HArg, Orn, Lys, HLys, Cit, HCit, APhe or ACha, where Arg or HArg may be N-substituted by a (C
1
-C
6
)alkyl or a (C
3
-C
6
)cycloalkyl group on one or both nitrogen atoms, and where Orn, Lys, HLys, APhe or ACha may be N-substituted by one or two (C
1
-C
6
)alkyl or (C
3
-C
6
)cycloalkyl groups, or by a nicotinoyl, isonicotinoyl, 6-methyl-nicotinoyl, glycyl-nicotinoyl, nicotinyl-azaglycyl, furyl, glycyl-furyl, furyl-azaglycyl, pyrazinyl, pyrazinyl-carbonyl, picolinoyl, 6-methyl-picolinoyl, shikimyl, shikimyl-glycyl, Fmoc or Boc grou

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