LHRH antagonists having improved solubility properties

Details LHRH antagonists having improved solubility properties LHRH antagonists having improved solubility properties

2000-03-14

2003-09-30

Brumback, Brenda (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S300000, C530S313000, C530S328000, C530S333000, C530S335000, C530S337000

Reexamination Certificate

active

06627609

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to LHRH antagonists having improved solubility properties, processes for the preparation of these compounds, medicaments in which these compounds are contained, and the use of the medicaments for the treatment of hormone-dependent tumours and hormone-influenced non-malignant disorders such as benign prostate hyperplasia (BPH) and endometriosis.
2. Background Information
The nomenclature used for the definition of the peptides agrees with that nomenclature explained by the IUPAC-IUB Commission on Biochemical Nomenclature (European J. Biochem. 1984, 138, 9-37), in which, in agreement with the conventional representation, the amino groups at the N terminus appear to the left and the carboxyl group at the C terminus appears to the right. The LH-RH antagonists such as the peptides according to the invention include naturally occurring and synthetic amino acids, the former including Ala, Val, Leu, Ile, Ser, Thr, Lys, Arg, Asp, Asn, Glu, Gln, Cys, Met, Phe, Tyr, Pro, Trp and His. The abbreviations for the individual amino acid residues are based on the trivial names of the amino acids and are Ala=alanine, Arg=arginine, Gly=glycine, Leu=leucine, Lys=lysine, Pal(3)=3-(3-pyridyl)alanine, Nal(2)=3-(2-naphthyl)-alanine, Phe=phenylalanine, Cpa=4-chlorophenylalanine, Pro=proline, Ser=serine, Thr=threonine, Trp=tryptophan, Try=tyrosine and Sar=sarcosine. All amino acids described here originate from the L series, if not mentioned otherwise. For example, D-Nal(2) is the abbreviation for 3-(2-naphthyl)-D-alanine and Ser is the abbreviation for L-serine. Substitutions on the &egr; amino group in the side chain of lysine are represented by a term placed in brackets behind Lys, if appropriate in the form of an abbreviation.
Other abbreviations used are:
Ac Acetyl
Atz 3-Amino-1,2,4-triazole-5-carbonyl
B 4-(4-Amidinophenyl)amino-1,4-dioxobutyl
Boc tert-Butyloxycarbonyl
Bop Benzotriazol-1-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate
DCC Dicyclohexylcarbodiimide
DCM Dichloromethane
Ddz Dimethoxyphenyl-dimethylmethylenoxy-carbonyl (Dimethoxy-dimethyl-Z)
DIC Diisopropylcarbodiimide
DIPEA N,N-Diisopropylethylamine
DMF Dimethylformamide
Fmoc Fluorenylmethyloxycarbonyl
HF Hydrofluoric acid
HOBt 1-Hydroxybenzotriazole
HPLC High-pressure liquid chromatography
Me Methyl
TFA Trifluoroacetic acid
Z Benzyloxycarbonyl
The peptides according to the invention are analogues of the luteinizing -hormone-releasing hormone (LH-RH), which has the following structure:
p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2, [LH-RH, gonadorelin] (SEQ ID NO:1).
For more than 20 years, researchers have sought selective potent antagonists of the LH-RH decapeptide [M. Karten and J. E. Rivier, Endocrine Reviews 7, 44-66 (1986)]. The high interest in such antagonists is based on their usefulness in the field of endocrinology, gynaecology, contraception and cancer. A large number of compounds have been prepared as potential LH-RH antagonists. The most interesting compounds which have been found to date are those compounds whose structures are a modification of the LH-RH structure.
The first series of potent antagonists was obtained by the introduction of aromatic amino acid residues into the positions 1, 2, 3 and 6 or 2, 3 and 6. The customary way of writing the compounds is as follows: the amino acids are first indicated which have taken the place of the amino acids originally present in the peptide chain of LH-RH, the positions in which the exchange took place being marked by superscripted figures. Furthermore, by the notation “LH-RH” placed afterwards it is expressed that these are LH-RH analogues in which the exchange has taken place.
Known antagonists are: [Ac-D-Cpa
1,2
, D-Trp
3,6
] LH-RH (D. H. Coy et al., In: Gross, E. and Meienhofer, J. (Eds) Peptides; Proceedings of the 6th American Peptide Symposium, pp. 775-779, Pierce Chem. Co., Rockville Ill. (1979): [Ac-Pro
1
, D-Cpa
2
, D-Nal(2)
3,6
] LH-RH (U.S. Pat. No. 4,419,347) and [Ac-Pro
1
, D-Cpa
2
, D-Trp
3,6
] LH-RH (J. L. Pineda, et al., J. Clin. Endocrinol. Metab. 56, 420, 1983).
In order to improve the action of antagonists, basic amino acids, for example D-Arg, were later introduced into the 6 position. For example [Ac-D-Cpa
1,2
, D-Trp
3
, D-Arg
6
, D-Ala
10
] LH-RH (ORG-30276) (D. H. Coy, et al., Endocrinology 100, 1445, 1982); and [Ac-D-Nal(2)1, D-Phe(4-F)
2
, D-Trp
3
, D-Arg
6
] LH-RH (ORF 18260) (J. E. Rivier et al., in: Vickery B. H. Nestor, Jr. J. J., Hafez, E.S.E (Eds). LHRH and its Analogs, pp. 11-22 MTP Press, Lancaster, UK 1984).
Further potent LH-RH antagonists are described in WO 92/19651, WO 94/19370, WO 92/17025, WO 94/14841, WO 94/13313, U.S. Pat. No. 5,300,492, U.S. Pat. No. 5,140,009, EP 0 413 209 A1 and DE 195 44 212 A1.
The latter discloses compounds having a modified ornithine or lysine unit in position 6 and which correspond to the following formula:
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-Tyr
5
-D-Xxx
6
-Leu
7
-Arg
8
-Pro
9
-D-Ala
10
-NH
2
,
in which D-Xxx is an amino acid group of the general formula (VI)
Further known LH-RH antagonists are antarelix, ganirelix and cetrorelix.
Antarelix:
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-Tyr
5
-D-Hci
6
-Leu
7
-Lys(iPr)
8
-Pro
9
-D-Ala
10
-NH
2
Ganirelix:
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-Tyr
5
-D-hArg(Et)
2
6
-Leu
7
-hArg(Et)
2
8
-Pro
9
-D-Ala
10
-NH
2
Cetrorelix:
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-Tyr
5
-D-Cit
6
-Leu
7
-Arg
8
-Pro
9
-D-Ala
10
-NH
2
.
SUMMARY OF THE INVENTION
The aim of the invention is to create novel LH-RH antagonists which have an increased enzymatic stability and significantly improved water solubility.
This object is achieved by compounds of the following general formula (I)
A-Xxx
1
-Xxx
2
-Xxx
3
-Xxx
4
-Xxx
5
-Xxx
6
-Xxx
7
-Xxx
8
-Xxx
9
-Xxx
10
-NH
2
  (I)
in which
A is an acetyl or a 3-(4-fluorophenyl)propionyl group,
Xxx
1
is D-Nal(1) or D-Nal(2),
Xxx
2
-Xxx
3
is D-Cpa-D-Pal(3) or a single bond,
Xxx
4
is Ser,
Xxx
5
is N-Me-Tyr,
Xxx
6
is D-Cit, D-Hci or a D-amino acid group of the general formula (II)
in which n is the number 3 or 4, where R
1
is a group having the general formula III
—(CH
2
)
p
—CO—NR
2
R
3
  (III)
where p is an integer from 1 to 4, R
2
is hydrogen or an alkyl group and R
3
is an unsubstituted or substituted aryl group or heteroaryl group, or R
1
is a 3-amino-1,2,4-triazole-5-carbonyl group or R
1
is a ring of the general formula (IV)
in which q is the number 1 or 2, R
4
is a hydrogen atom or an alkyl group, R
5
is a hydrogen atom or an alkyl group and X is an oxygen or sulphur atom,
Xxx
7
is Leu or Nle,
Xxx
8
is Arg or Lys(iPr),
Xxx
9
is Pro and
Xxx
10
is Ala, D-Ala or Sar,
and their salts with pharmaceutically acceptable acids, in particular the acetates, embonates and trifluoroacetates.
Among the compounds according to the invention, those are particularly preferred in which Xxx
6
is D-[&egr;-N′-(imidazolidin-2-on-4-yl)formyl]-Lys, D-(3-amino-1,2,4-triazole-3-carbonyl)-Lys, abbreviated D-Lys(Atz) or D-[&egr;-N′-4-(4-Amidinophenyl)-amino-1,4-dioxo-butyl]-Lys, abbreviated D-Lys(B).
Further particularly preferred compounds according to the invention are:
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-N-Me-Tyr
5
-D-Hci
6
-Nle
7
-Arg
8
-Pro
9
-D-Ala
10
-NH
2
,
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-N-Me-Tyr
5
-D-Lys(Atz)
6
-Leu
7
-Arg
8
-Pro
9
-D-Ala
10
-NH
2
,
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-N-Me-Tyr
5
-D-Lys(B)
6
-Leu
7
-Lys(iPr)
8
-Pro
9
-D-Ala
10
-NH
2
,
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-N-Me-Tyr
5
-D-Lys(B)
6
-Leu7 -Arg8-Pro9-D-Ala
10
-NH
2
,
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-N-Me-Tyr
5
-D-Hci
6
-Nle
7
-Lys(iPr)
8
-Pro
9
-D-Ala
10
-NH
2
,
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-N-Me-Tyr
5
-D-Hci
6
-Nle
7
-Lys(iPr)
8
-Pro
9
-Sar
10
-NH
2
,
Ac-D-Nal(2)
1
-D-Cpa
2
-D-Pal(3)
3
-Ser
4
-N-M

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