GnRH ANTAGONISTS

Abstract: Peptides are provided which have improved duration of GnRH antagonistic properties and/or which can be synthesized more economically. These antagonists may be used in the same manner as the compounds of which they are analogs to regulate fertility and to treat steroid-dependent tumors and for other short-term and long-term treatment indications. One particularly effective peptide, a decapeptide analog of the GnRH antagonist Acyline, has the formula: Ac-D-2Nal-D-4Cpa-D-Dpr(methylcarbamoyl)-Ser-4Aph(acetyl)-D-4Aph(acetyl)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2. It continues to exhibit very substantial suppression of LH secretion at 96 hours following injection. Other economically attractive and pharmacologically effective analogs have the formulas: Ac-D-2Nal-D-4Cpa-Xaa3-Ser-4Aph(acetyl)-D-4Aph(acetyl)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2; and Ac-D-2Nal-D-4Cpa-Xaa3-Ser-4Aph(L-hydroorotyl)-D-4Aph(acetyl)-Leu-Lys(isopropyl)-Pro-D-Ala-NH2, wherein Xaa3 is D-Gln or Gln.

Description: GnRH ANTAGONISTS This invention relates generally to peptides which are antagonists of human gonadotropin releasing hormone (GnRH) and have advantageous physical, chemical and biological properties. More particularly, the present invention relates to decapeptides which inhibit gonadal function and the release of the steroidal hormones progesterone and testosterone and which are less expensive to make than comparable GnRH peptide antagonists and to methods of administering pharmaceutical compositions containing such decapeptides for such purpose and particularly to manage conditions resulting from the hypersecretion of gonadal steroids. BACKGROUND OF THE INVENTION Follicle stimulating hormone (FSH) and luteinizing hormone (LH) , sometimes referred to as gonadotropins or gonadotropic hormones, are released by the pituitary gland which is attached by a stalk to the hypothalamus. Hormone release by the anterior lobe of the pituitary gland usually requires prior release of hormones produced by the hypothalamus, such as the decapeptide GnRH. The administration of GnRH analogs that are antagonistic to the normal function of GnRH has been used to suppress secretion of gonadotropins in mammals generally and to suppress or delay ovulation. The search for improved GnRH antagonists has resulted in the making of Antide, i.e. [Ac-D-2Nal 1 , D-4ClPhe 2 , D- 3Pal 3 , Lys(Nic) 5 , D-Lys(Nic) 6 , ILys 8 , D-Ala 0 ] -GnRH; and Cetrorelix, i.e. [Ac-D-2Nal 1 , D-4ClPhe 2 , D-3Pal 3 , D-Cit 6 , D- Ala 10 ]-GnRH. U.S. Patent No. 5,516,887 describes GnRH antagonists which are said to be more effective than Antide in suppressing plasma testosterone, e.g. [Ac-D-2Nal 1 , D- 4ClPhe 2 , D-3Pal 3 , D-N e -carbamoyl Lys 6 , Ilys 8 , D-Ala 10 ] -GnRH, which is referred to as Antarelix. U.S. Patent No. 5,296,468, issued March 22, 1994, discloses the design and synthesis of a number of GnRH antagonists wherein the side chains of selected residues are reacted to create cyanoguanidino moieties, some of which subsequently spontaneously convert to a desired heterocycle, e.g. a 3-amino-l, 2 , 4-triazole(atz) . Such cyanoguanidino moieties are built upon the omega-a ino group in an amino acid side chain, such as lysine, ornithine, 4-amino phenylalanine (4Aph) or an extended chain version thereof, such as 4-amino homophenylalanine (4Ahp) . GnRH antagonists having such significantly modified or unnatural amino acids in the 5- and 6-positions exhibit good biological potency, and those built upon 4Aph are generally considered to be preferred. One that is especially preferred is Azaline B, i.e. [Ac-D-2Nal 1 , D- 4ClPhe 2 , D-3Pal 3 , 4Aph(atz) 5 , D-4Aph(atz) 6 , ILys 8 , D-Ala 10 ]- GnRH. U.S. Patent No. 5,506,207 discloses biopotent GnRH antagonists wherein amino-substituted phenylalanine side chains of residues in the 5- and 6-positions are acylated; one particularly potent decapeptide is Acyline, i.e. [Ac-D- 2Nal 1 , D-4ClPhe 2 , D-3Pal 3 , 4Aph(Ac) 5 , D-4Aph(Ac) 6 , ILys 8 , D- Ala 10 ]-GnRH. Despite the attractive properties of these GnRH antagonists, the search has continued for still further improved GnRH antagonists, particularly those which exhibit long duration of biological action and which can be formulated less expensively. It can frequently be important that a peptide analog, for both short-term and long-term treatment indications, should exhibit a long duration of activity with respect to LH secretion, a property which may be enhanced by the peptide's resistance to proteolytic enzyme degradation in the body, and should provoke relatively little histamine release. In addition, to facilitate administration of these compounds to mammals, particularly humans, without significant gelling, it is considered extremely advantageous for such GnRH antagonistic decapeptides to have high solubility in water at normal physiologic pH, i.e. about pH 5 to about pH 7.4. Moreover, as these compounds are considered for clinical investigation, the cost of preparation becomes a factor, and it is noticed that all of the above peptides utilize D- 3Pal in the 3-position — requiring a protected amino acid which is particularly expensive to purchase or synthesize. Equally biopotent analogs that can be less expensively synthesized would be attractive, and the 3-position is one target for cost reduction. SUMMARY OF THE INVENTION It has now been found that, by the substitution of less expensive residues in the 3-position in this subclass of linear GnRH antagonists, which includes Cetrorelix, Antarelix, Acyline, Azaline B, Antide and others, the cost can be reduced without reducing biopotency Not only are these analogs less expensive to synthesize than peptides containing the heretofore preferred D-3Pal 3 , but also the particularly advantageous property of long duration of bioactivity is often unexpectedly obtained. Generally, linear GnRH antagonist decapeptides having the following formula, closely related analogs, and pharmaceutically acceptable salts thereof, are less expensive to synthesize than comparable prior art compounds and often have improved pharmacological properties, particularly long duration of bioactivity: X-D-2Nal- (A) D-Phe-Xaa 3 -Ser-Xaa 5 -Xaa 6 -Leu-Xaa 8 -Pro-Xaa 10 wherein: X is an acyl group of 7 carbon atoms or less or Q, 0 with Q being -c-NHR, with R being H or lower alkyl; A is 4C1, 4F, 4Br, 4N0 2 , 4CH 3 , 40CH 3 , 3,4C1 2 or C α Me4Cl; Xaa 3 is D-Gln, Gin, D-Asn, Asn or D-Dpr(Q) ; Xaa 5 is Tyr, Aph(Q-,) , Amf(Q 1 ) or Lys(Nic), with Q 1 being Q, For, Ac, 3-amino-l, 2 , 4-triazole, β-Ala (3-amino-l, 2 , 4- triazole) , Gab(3-amino-l, 2 , 4-triazole) , D-, L- or D/L-Hor, or D-, L- or D/L-Imz; Xaa 6 is D-Aph(Q 2 ) , D-Amf(Q 2 ) D-Lys(Nic), D-Cit, D-Hci or D-Pal, with Q 2 being Q, For, Ac, 3-amino-l, 2 , 4-triazole, β-Ala(3-amino-l,2 , 4-triazole) , or Gab(3-amino-l, 2 , 4- triazole) , D-, L- or D/L-Hor, or D-, L- or D/L-Imz; Xaa 8 is Lys(ipr), Arg, Har, Har(Et 2 ) , or Arg(Et 2 ) ; and Xaa 10 is D-Ala-NH 2 , NHCH 2 CH 3 , Gly-NH 2 , AzaGly-NH 2 , Ala- NH 2 , Agl-NH 2 , D-Agl-NH 2 , Agl(Me)-NH 2 or D-Agl (Me) -NH 2 , provided however that the o-amino group of Xaa 5 may be methylated. In another aspect, the invention provides a method for in vivo or in vitro diagnosis of a condition where GnRH is causing excess hormonal secretion or tumor growth, which method comprises administering a GnRH antagonist peptide of the type described above and monitoring for hormonal secretion or for tumor cell proliferation. These antagonists are particularly useful to suppress the secretion of gonadotropins and as fertility regulators in humans because they exhibit long duration of activity as a result of the residue that is present in the 3-position of the decapeptide, i.e. continuing to substantially suppress LH secretion for at least about 4 days. They have excellent solubility in aqueous buffers at physiologic pHs and acceptable side effects with respect to stimulation of histamine release, i.e. better than the GnRH superagonists which are now being clinically used; they also exhibit minimal gelling upon subcutaneous (sc) injection. These GnRH antagonists also perform well in an anaphylactoid assay causing a relatively small wheal. As a result, these peptides find particular use in administration to mammals, especially humans, as fertility regulators and for the treatment of pathological conditions such as precocious puberty, hormone-dependent neoplasia, dysmenorrhea, endometriosis, steroid-dependent tumors, and the other short-term and long-term indications mentioned hereinbefore. They are also useful diagnostically. Because these GnRH antagonists are readily soluble in the physiologic pH range of about 5 to about 7.4, they can be formulated and administered in concentrated form, particularly at a pH between about 5 and about 7. Because of their polar character, they are particularly suitable for use in slow-release preparations based upon known copolymers. Because of the 3-position substitutions, these analogs are less expensive to produce than comparable analogs containing D-3Pal 3 . Because many of these GnRH antagonists exhibit effective suppression of LH and FSH for long duration, they are particularly effective for the contraceptive treatment of male mammals (with the administration of testosterone) and for the treatment of steroid-dependent tumors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Over the last 10-12 years, the particular properties of each of the 10 residues in the sequence of GnRH, from the standpoint of creating effective antagonists, have been studied in depth, and as a result of these studies, it has been discovered that there are various equivalent residues that can be chosen and that substitutions of one of these equivalents for another does not significantly detract from the biological potency of decapeptide GnRH antagonists. Such equivalent substitutions may be made in the GnRH antagonists of the present invention. For example, it has become generally accepted that the inclusion of a para-substituted D-Phe or 2,4 dichloro- substituted D-Phe or D-C β methyl4ClPhe residue in the 2- position adds significantly to GnRH antagonist activity; however, the specific identity of the ring substituent is of only relatively minor importance when selected from among the following: chloro, fluoro, bro o, nitro, methyl and alkoxy. Therefore, such residues in the 2-position are considered to be the equivalent of D-4ClPhe which is commonly used therein. The N-terminus is preferably N- acylated, preferably by acetyl (Ac) , but also by other acyl groups having not more than 7 carbon atoms, e.g. formyl(For), acrylyl (Acr) , propionyl (Pn) , butyryl(By), valeryl(Vl), vinylacetyl (Vac) and benzoyl(Bz); alternatively, a substituted or unsubstituted carbamoyl group may be present. Other longer acyl groups are considered to be equivalents but are less preferred. The α-amino group on the 5-position residue may be optionally methylated, as disclosed in U.S. Patent No. 5,110,904, to increase solubility in water, but such modification may result in a shortening of duration of LH suppression and in greater potential for histamine release. The C-terminus is preferably D-Ala-NH 2 ; however, Gly-NH 2 , NHCH 2 CH 3 , AzaGly-NH 2 , Agl-NH 2 , D-Agl-NH 2 , Agl(Me)-NH 2 and D-Agl (Me) -NH 2 may instead be used as they are considered to be known equivalents. As hereinbefore disclosed, the present invention is considered to provide a genus of GnRH antagonists which are generally improvements of known GnRH antagonists that have a substitution in the 3-position and which are represented by the following formula: X-D-Nal- (A) D-Phe-Xaa 3 -Ser-Xaa 5 -Xaa 6 -Leu-Xaa 8 -Pro-Xaa 10 wherein: X is an acyl group of 7 carbon atoms or less or Q, 0 with Q being -c-NHR, with R being H or lower alkyl; A is 4C1, 4F, 4Br, 4N0 2 , 4CH 3 , 40CH 3 , 3,4C1 2 or C α Me4Cl; Xaa 3 is D-Gln, Gin, D-Asn, Asn or D-Dpr(Q) ; Xaa 5 is Tyr, AphfQ,), A-mf O.-,) or Lys(Nic), with Q-, being Q, For, Ac, 3-amino-l, 2 ,4-triazole, β-Ala(3-amino-l, 2 , 4- triazole) or Gab(3-amino-l, 2 , 4-triazole) ; Xaa 6 is D-Aph(Q 2 ), D-Amf(Q 2 ), D-Lys(Nic), D-Cit, D-Hci or D-Pal, with Q 2 being Q, For, Ac, 3-amino-l, 2 ,4-triazole, β-Ala(3-amino-l,2 ,4-triazole) or Gab(3-amino-l , 2 , 4- triazole) ; Xaa g is Lys(ipr), Arg, Har, Har(Et 2 ), or Arg(Et 2 ); and Xaa 10 is D-Ala-NH 2 , NHCH 2 CH 3 , Gly-NH 2 , AzaGly-NH 2 , Ala- NH 2 , Agl-NH 2 , D-Agl-NH 2 , Agl(Me)-NH 2 or D-Agl (Me) -NH 2 , provided however that the α-amino group of Xaa 5 may be methylated. By D-Nal is meant the D-isomer of alanine which is substituted by naphthyl on the β-carbon atom, i.e., also referred to as β-D-Nal or 3-D-Nal. Preferably D-2Nal is employed wherein the attachment to naphthalene is at the 2-position on the ring structure; however, D-lNal may also be used. D-Cpa represents chloro-D-Phe, and D-4ClPhe, i.e. D-4Cpa, is preferred. D-Pal represents the D-isomer of alanine which is substituted by pyridyl on the β-carbon atom; the linkage is preferably to the 3-position on the pyridine ring, i.e. β-3-pyridyl-D-Ala. D-2Pal is considered the equivalent. By 4Aph is meant 4NH 2 Phe wherein the amino substituent on the phenyl ring is at the 4- position; 3NH 2 -phenylalanine (3Aph) is considered its equivalent. By Amf is meant phenylalanine where an amino group is coupled to the phenyl ring through a methylene linkage. Coupling is preferably to the 4 position; however, 3Amf is considered equivalent. By Gab is meant gamma amino butyric acid. By atz is meant 3-amino-l, 2 , 4- triazole. 4Aph(atz) is also known by the more precise chemical name 4- (3 '-amino-lH-1' , 2 ' , 4 '-triazoyl-5'-yl) aminophenylalanine. By Lys(Nic) is meant N £ -nicotinoyl lysine, i.e. the e-amino group of Lys is acylated with 3- carboxypyridine. By Har is meant homoarginine. By D-Cit is meant the D-isomer of citrulline, and by D-Hci is meant the D-isomer of homocitrulline, which may also be called D- N e -carbamoyl lysine. By ILys or Lys(ipr) is meant N £ - isopropyl lysine, i.e. the e-amino group of Lys is alkylated. By AzaGly-NH 2 is meant NHNHCONH 2 . By Dbu is meant alpha, gamma-diamino butyric acid, and by Dpr is meant α,β-diamino propionic acid. By Agl is meant - aminoglycine, and in Agl (Me), the side chain amino group is methylated. By Cb is meant carbamoyl, and by MeCbm is meant methylcarbamoyl or -CONHCH 3 . By lower alkyl is meant C- j -C ς , preferably C, to C 3 and more preferably C, or C 2 , i.e. methyl (Me) or ethyl (Et). Although the preferred D-isomers for incorporation in the 6-position of these GnRH antagonists are specifically disclosed, it should be understood that as a result of the extensive research in the field over the past two decades, there are many known equivalent D-isomers. Such prior art D-isomer substitutions may be compatible and not detract from the biopotency of these improved compounds, particularly the extended duration afforded by the 3- position substitutions disclosed herein; thus, they may optionally be utilized. Likewise, it is known that Leu 7 may be substituted by Phe 7 to provide GnRH antagonists with equivalent properties. A preferred subgenus of GnRH antagonists has the formula: X-D-Nal-D-4ClPhe-Xaa 3 -Ser-Xaa 5 -Xaa 6 -Leu-Lys ( ipr) -Pro-D-Ala- NH 2 wherein: X is an acyl group of 7 carbon atoms or less or Q, 0 with Q being - C -NHR, with R being H or methyl or ethyl; Xaa 3 is D-Gln, Gin or D-Dpr(Q) ; Xaa 5 is Aph(Ac) , Aph(Q), Amf(Q), or Aph(atz); and Xaa 6 is D-Aph(Ac), D-Amf(Q), D-Aph(Q) or D-Aph(atz). An additional genus of GnRH antagonists embodying features of the present invention and including additional substitutions in the 5- and 6-positions has the formula: X-D-Nal- (A) D-Phe-Xaa 3 -Ser-Xaa 5 -Xaa 6 -Leu-Xaa 8 -Pro-Xaa 10 wherein: X is For, Ac, Acr, Pn, By, VI, Vac, Bz or Q, 0 II with Q being --Cc--NNHHRR, and with R being H or lower alkyl; A is 4C1, 4F, 4Br, 4N0 2 4CH 3 , 40CH 3 , 3,4Cl 2 or C α Me4Cl; Xaa 3 is D-Gln, Gin, D-Asn, Asn or D-Dpr(Q) ; Xaa 5 is Aph(Q.) or Amf(Q 1 ) with Q 1 being Ac, 3-amino- 1, 2 , 4-triazole, Q or (D- or L-Imz) Xaa 6 is D-Aph(Q 2 ) , D-Amf(Q 2 ) , D-Lys(Nic) , D-Cit, D-Hci or D-Pal, with Q 2 being For or Q ; Xaa 8 is Lys(ipr) , Arg, Har, Har(Et 2 ) or Arg(Et 2 ) ; and Xaa 10 is D-Ala-NH 2 , NHCH 2 CH 3 , Gly-NH 2 , AzaGly-NH 2 , Ala- NH 2 , Agl-NH 2 , D-Agl-NH 2 , Agl(Me)-NH 2 or D-Agl (Me) -NH 2 , provided however that the -amino group of Xaa 5 may be methylated. By Hor is meant the L-isomer of hydroorotic acid. By Imz is meant L-2-Imidazolidone-4-carboxylic acid. Both Hor and Imz can be used as the L- or D-isomers or as a D/L mixture . A preferred subgenus of such GnRH antagonists has the formula: Ac-D-2Nal-D-4Cpa-Xaa 3 -Ser-4Aph (Hor) -D-4Aph (Ac) -Leu-ILys-Pro- Xaa 10 , wherein Xaa 3 is D-Gln, Gin or D-Dpr(Q) , 0 with Q being _ C _ NHR and with R being H or methyl; and Xaa ιo i- s D-Ala-NH 2 or an equivalent. The compounds of the present invention can be synthesized by classical peptide solution synthesis, and such synthesis is preferred for large quantities of product. To obtain limited quantities, e.g. less than 1 kg, it may be preferable to synthesize them using a solid phase technique. A chloromethylated resin or a hydroxymethylated resin may be used; however, a methylbenzhydrylamine(MBHA) resin, a benzhydrylamine (BHA) resin or some other suitable resin known in the art which directly provides a C-terminal amide upon cleavage is preferably employed. Should equivalent peptides having a substituted amide at the C-terminus be desired, they are preferably synthesized using an N-alkylamino methyl resin as taught in United States Patent No. 4,569,967, issued February 11, 1986. Solid phase, chain elongation synthesis is usually conducted in a manner to stepwise add individual amino acids to the chain, e.g. in the manner set forth in detail in the U.S. Patent No. 5,296,468. Side-chain protecting groups, as are well known in the art, are preferably included as a part of any amino acid which has a particularly reactive or labile side chain when it is being coupled into the chain being built upon the resin. Such synthesis provides a fully protected intermediate peptidoresin. One example of a chemical intermediate which might be used to synthesize a GnRH antagonist having a desired carbamoyl-containing residue in the 3-position is represented by the formula: X 1 -D-Nal-D-4ClPhe-Xaa 3 (X 3 or X 5 )- Ser(X 2 )-Aph(X 3 )-D-Aph(X 3 )-Leu-ILys(X 4 )-Pro-X 6 wherein X 1 is an α-amino protecting group of the type known to be useful in the art in the stepwise synthesis of poly-peptides and when X in the desired peptide composition is a particular acyl group, that group may be used as the protecting group. Among the classes of α-amino protecting groups covered by X 1 are (1) acyl-type protecting groups, such as formyl(For), trifluoroacetyl, phthaloyl, p-toluenesulfonyl (Tos) , benzoyl(Bz), benzenesulfonyl, dithiasuccinoyl (Dts) o-nitrophenylsulfenyl(Nps) , tritylsulfenyl, o-nitrophenoxyacetyl, acrylyl (Acr) , chloroacetyl, acetyl (Ac) and γ-chlorobutyryl; (2) aromatic urethan-type protecting groups, e.g., benzyloxycarbonyl (Z) , fluorenylmethyloxycarbony1 (Fmoc) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxy-carbonyl (C1Z) , p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl and p-methoxybenzyloxycarbonyl; (3) aliphatic urethan protecting groups, such as tertbutyloxycarbonyl (Boc) , diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl and allyloxycarbonyl; (4) cycloalkyl urethan-type protecting groups, such as cyclopentyloxycarbonyl, adamantyloxycarbonyl and cyclohexyloxycarbony1; (5) thiourethan-type protecting groups, such as phenylthiocarbonyl; (6) alkyl-type protecting groups, such as allyl (Aly), triphenylmethyl(trityl) and benzyl(Bzl); (7) trialkylsilane groups, such as trimethylsilane. The preferred α-amino protecting group is Boc. X 2 is a protecting group for the hydroxyl side chain of Ser, e.g. Ac, Bz , trityl, 2 , 6-dichlorobenzyl or benzyl ether (Bzl) and is preferably Bzl. X 3 is a protecting group for a side chain amino group of Dpr or the like which is not removed when the α-amino protecting group or another amino-protecting group is removed. Illustrative examples include (1) base-labile groups, such as Fmoc, or some other weak-acid stable, aromatic urethane-type protecting group; (2) thiol-labile groups, such as dithiasuccinoyl (Dts) which may be removed or cleaved by thiolysis; (3) hydrazine-labile groups, such as phthaloyl(Pht) which is cleaved by hydrazinolysis; (4) nucleophile-labile groups, such as o-nitrophenyl- sulfenyl (Nps) and the like which are cleaved by thioaceta ide or by weak acids or their salts; (5) photo- labile groups which are cleaved by photolysis; and (6) groups selectively removable by reduction, such as Dts. Fmoc is preferred for a Boc SPPS strategy. X 4 is an acid-labile protecting group for a primary or secondary amino side chain group, such as Z or 2C1Z. X 5 is hydrogen or a protecting group from the amido group of Gin, such as xanthenyl (xan) . However, Gin or Asn is preferably coupled without side chain protection in the presence of hydroxybenzotriazole (HOBt) . X 6 may be D-Ala-, Gly-, Ala-, Agl-, D-Agl-, Agl (Me)- or D-Agl (Me) -NH- [resin support], or N(Et) -[resin support]; X 6 may also be an amide either of Gly or of D-Ala, or a lower alkyl substituted amide attached directly to Pro, or AzaGly-NH 2 . The criterion for selecting side chain protecting groups X 2 through X 5 is that the protecting group should generally be stable to the reagent under the reaction conditions selected for removing the α-amino protecting group (preferably Boc) at each step of the synthesis. These protecting groups generally should not be split off under coupling conditions but should be removable upon completion of the synthesis of the desired amino acid sequence under reaction conditions that will not alter the peptide chain. The protecting groups initially employed for the 3-position amino acids and also for the 5- and 6- position residues are preferably removed, and selective reactions are carried out prior to cleavage of the ultimate peptide from the resin, as explained hereinafter. When the X 6 group is D-Ala-NH- [resin support], an amide bond connects D-Ala to a BHA resin or to a MBHA resin; this is likewise the case when Agl or D-Agl is used at the C- terminus. When X 6 is N(Et)-[resin support], an amide bond connects Pro to an N-alkylaminomethyl resin (NAAM) . When the N-terminus is to be acetylated, for example, it is possible to employ acetyl as the X 1 protecting group for the α-amino group of β-D-Nal in the 1-position by adding it to the amino acid before it is coupled to the peptide chain; however, a reaction is preferably carried out with the peptide intermediate on the resin. After deblocking the α-amino group and while desired side chain groups remain protected, acetylation is preferably carried out by reacting with acetic anhydride, alternatively reaction can be carried out with acetic acid, in the presence of diisopropyl or dicyclohexyl carbodiimide (DIC or DCC) , or by some other suitable acylation reaction as known in the art. A similar procedure is carried out when a carbamoyl or substituted carbamoyl group is desired at the N-terminus. When the deprotected side chain amino groups are modified while the residue is part of the peptide chain, the reaction may be carried out using an appropriate isocyanate in the presence of an appropriate base, for example, N,N-diisopropylethylamine (DIEA) , although the use of such a base is optional. When an unsubstituted carbamoyl group is desired in the final product, the deprotected amino side chain may be reacted with benzyl isocyanate, trimethylsilyl isocyanate or tert- butyl isocyanate, with the latter being preferred. Using such a strategy, the t-butyl moiety is removed during deprotection, leaving the carbamoyl as a part of a urea group . The invention also provides a preferred method for making a GnRH antagonist having, for example, the formula: Ac-D-2Nal-D-4Cpa-D-Dpr (MeCbm) -Ser-4Aph (Ac) -D-4Aph (Ac) -Leu- ILys-Pro-D-Ala-NH 2 , which method comprises (a) forming an intermediate peptide having the formula: Boc-Ser(X 2 )- 4Aph(X 3 )-D-4Aph(X 3 )-Leu-ILys(X 4 )-Pro-X 6 wherein X 2 is hydrogen or a protecting group for a hydroxyl group of Ser; X 3 is a base-labile, hydrazine-labile or other appropriately labile protecting group for an amino group; X 4 is an acid- labile protecting group for an amino side chain; X 6 is D-Ala-NH-[resin support]; (b) removing X 3 from 4Aph and D- 4Aph and reacting the deprotected primary amino groups with acetic anhydride; (c) completing the chain elongation to create the intermediate X 1 -D-2Nal-D-4Cpa-D-Dpr (X 3 ) -Ser (X 2 ) - 4Aph(Ac)-D-4Aph(Ac)-Leu-ILys(X 4 )-Pro-X 6 , wherein X 1 is an α- amino protecting group; (d) removing X 3 from the 3-position residue to deprotect the side chain primary amino group of this amino acid residue of the intermediate peptide; (e) reacting this deprotected side chain primary amino group with methyl isocyanate; (f) acylating the N-terminus and (g) splitting off any remaining protecting groups and/or cleaving from resin support included in X 6 . Purification of the final peptide may be effected by ion exchange chromatography, partition chromatography or by using HPLC, as known in the art, see J. Rivier, et al. J. Chromatography . 288. 303-328 (1984) and C. Miller and J. Rivier, Biopolvmers (Peptide Science), 4), 265-317 (1996). The GnRH antagonists of the invention are considered to be effective at levels of less than 100 micrograms per kilogram of body weight, when administered subcutaneously at about noon on the day of proestrus, to prevent ovulation in female rats. For prolonged suppression of ovulation, it may be necessary to use dosage levels in the range of from about 0.1 to about 2.5 milligrams per kilogram of body weight. The antagonists are also effective to arrest spermatogenesis when administered to male mammals on a regular basis and can thus be used as contraceptives. Because these compounds will reduce testosterone levels and thus libido (an undesired consequence in the normal, sexually active male) , it may be desirable to administer replacement dosages of testosterone along with the GnRH antagonist in order to achieve azoospermia or hair growth while maintaining libido. These antagonists can also be used to regulate the production of gonadotropins and sex steroids and for other of the long-term and short-term indications as indicated hereinbefore, and they can be used in veterinary applications as contraceptives for pets. The peptides provided by the invention are particularly soluble at physiological pHs and can be prepared as relatively concentrated solutions for administration, particularly for subcutaneous injection. These peptides are well-tolerated in the body and do not tend to gel when administered subcutaneously at effective concentrations. Generally pharmaceutical compositions including such peptides and a suitable pharmaceutically acceptable excipient can be administered iv, ip, subcutaneously or the like at levels of between about 0.001 mg to about 2.5 mg per Kg of body weight per day, with 0.5 g/Kg/day usually being sufficient. The appropriately protected D- or L-hydroorotyl- containing, carbamoyl-containing and/or D- or L-Imidazolidone-carbonyl-containing amino acids may be synthesized and then employed in a chain elongation peptide synthesis. However, an equally valid synthesis is effected by initially incorporating an appropriately protected 4Aph, 4Amf or Dpr residue at the desired position in the peptide intermediate, and this may be the laboratory method of choice where only small quantities are initially desired. This strategy is accomplished by subsequently deprotecting the particular residue (either immediately or subsequently during the synthesis) and then reacting the deprotected side chain amino group with the desired reagent. The present invention is further described by the examples which follow. EXAMPLE 1 The peptide having the formula: Ac-D-2Nal-D- 4Cpa-D-3Pal-Ser-Lys(Nic)-D-Lys(Nic)-Leu-ILys-Pro-D-Ala-NH 2 (Antide) has been found to exhibit very good biological properties as a GnRH antagonist, as has the peptide which is now referred to as Acyline and which differs from Antide in only the 5- and 6-positions. It has now been found that if certain substitutions are made for the 3-position residue of these decapeptides, or other GnRH antagonists of known biopotency, a GnRH antagonist which is less expensive to make and/or which has improved duration of bioactivity in vivo can be obtained. The following decapeptide [D-Dpr (MeCbm) 3 ] -Acyline, or alternatively, [Ac-D-2Nal 1 , D-4Cpa 2 , D-Dpr (MeCbm) 3 , 4Aph(Ac) 5 , D-4Aph(Ac) 6 , ILys 8 , D-Ala 10 ] -GnRH (Peptide No. 1) is synthesized by solid-phase synthesis. This peptide has the following formula: Ac-D-2Nal-D-4Cpa-D-Dpr (methylcarbamoyl) -Ser-4Aph (acetyl) -D- 4Aph (acetyl) -Leu-Lys (isopropyl) -Pro-D-Ala-NH 2 . About 9.3 grams (0.54 mmol/g) of MBHA resin (Bachem) are initially used, and Boc-protected D-Ala is coupled to the resin over about an 8-hour period in dimethylformamide (DMF) or N-methylpyrrolidone(NMP) /CH 2 C1 2 using about 10 millimoles of Boc derivative and diisopropyl- carbodii ide(DIC) and anhydrous 1-hydroxybenzotriazole (HOBt) as activating/coupling reagents. The D-Ala residue attaches to the MBHA residue by an amide bond. Following the coupling of each amino acid residue, washing, deblocking and then coupling of the next amino acid residue are carried out in accordance with the following manual synthesis schedule for about 0.5 to 1 gram of starting resin: The above schedule is used for coupling of each of the amino acids of the peptide of the invention after the first amino acid has been attached. N α Boc protection is used for each of the amino acids coupled throughout the synthesis. N a Boc-β-D-2Nal is prepared by a method known in the art, e.g. as described in detail in U.S. Patent No. 4,234,571, issued November 18, 1980; it is also commercially available from SyntheTech, Oregon, U.S.A. The side chain primary amino groups of 4Aph in the 5-position and of D-4Aph in the 6-position are protected by Fmoc. Benzyl ether (Bzl) is preferably used as a side chain protecting group for the hydroxyl group of Ser; however, Ser may be coupled without side chain protection. N α Boc-Lys (ipr, Z) is used for the 8-position residue. After adding Ser for the 4-position residue as N α Boc-Ser (Bzl) , the following intermediate is present: Boc-Ser (Bzl) -4Aph (Fmoc) -D-4Aph(Fmoc) -Leu-Lys (ipr, Z) - Pro-D-Ala-NH-[MBHA resin support]. The Fmoc protecting groups are removed from both residues by successive treatments with 25 percent piperidine in DMF(10 ml) for about 15 minutes each. After preferably washing the peptidoresin with DMF, the newly freed amino groups are treated with a large excess of acetic anhydride in DMF at room temperature for 30 minutes, or until complete as checked using a ninhydrin test, to acetylate both side chains. The peptidoresin is then subjected to the standard wash with MeOH and DCM. Following completion of the acetylation of the 4Aph and D-4Aph residue side chains, N a Boc,N β Fmoc-protected D-Dpr is coupled to the chain for the residue in the 3-position. Once the residue has been coupled, the Boc protection is removed, and the final two residues are subsequently added to complete the chain. After deblocking the α-amino group at the N-terminus using trifluoroacetic acid (TFA) , acetylation is achieved using a large excess of acetic anhydride in dichloromethane (DCM) or DMF for about 30 minutes. By starting with an appropriately large amount of resin, portions of the peptidoresin intermediate may be removed at this time for use in 3 parallel syntheses described hereinafter. Following acetylation of the N-terminus, about 500 mgs of the peptidoresin are treated with 25% piperidine to selectively deprotect the D-Dpr side chain. The partially deprotected peptidoresin is then reacted with methyl isocyanate in the presence of 2.7 mmol of DIEA, an appropriate base, in 10 ml of DMF for 2 hours at room temperature to form the methylcarbamoyl-subεtituted residue. The peptidoresin is dried, and then cleavage of the peptide from the resin and deprotection of the Ser and the Lys side chains are carried out at about 0°C. with 15 ml of HF and anisole (0.5 ml) as a scavenger for about 1.5 hours. After the removal of HF under vacuum, the resin is washed twice with 100 ml of ethyl ether. The cleaved peptide is extracted with 0.2% TFA in 25% CH 3 CN/H 2 0, repeating the process and using 100 ml each time. The extracts are pooled and lyophilized, and they provide about 160 mg of a crude peptide powder. Purification of the peptide is then effected by preparative reverse-phase high performance liquid chromatography (RP-HPLC) , as known in the art and specifically set forth in J. Rivier, et al. J. Chromatography , 288, 303-328 (1984) . The first preparative RP-HPLC separation uses a gradient TEAP (triethylammonium phosphate) buffer system, and a final separation is carried out using a 0.1% TFA (trifluoroacetic acid) gradient, all as described in detail in the J. Chromatography article. The peptide (about 51 mg) is judged to be substantially homogeneous using capillary zone electrophoresis (CZE) , and the purity is estimated to be about 100%. Amino acid analysis of the purified peptide is consistent with the formula for the prepared structure. Molecular weight as determined by liquid secondary ion mass spectrometry (LSIMS) is measured as 1527.8 Da which is in agreement with the expected mass of 1527.8 Da for this peptide. Hydrophilicity is tested by measuring retention time using RP-HPLC with a gradient of 40% Buffer B to 70% Buffer B over 30 minutes, with Buffer A being TEAP pH 7.0 and Buffer B being 70% CH 3 CN and 30% Buffer A at pH 7.0. Peptide No. 1 is more hydrophilic than Acyline, eluting about 1.8 minutes ahead of Acyline. Its solubility in aqueous buffers at a pH of from about 5 to about 7 and its resistance to in vivo gelling, along with its long-acting biopotency to suppress circulating LH levels as described hereinafter, render it particularly suitable for administration by subcutaneous injection, compared to other compounds of generally comparable biological efficacy that are short-acting. The peptide is hereinafter referred to as Peptide No. 1 and is assayed . in vivo to determine its effectiveness to suppress secretion of LH in rats. Measurement of circulating LH levels in castrated male Sprague-Dawley rats treated subcutaneously with the peptide is carried out as reported in C. Rivier et al. Biol. Reproduc.. 1983. 29, 374-378. The peptides are first dissolved at a concentration of 1.0 or 10 mg/ml in bacteriostatic water and then further diluted in 0.04 M phosphate buffer containing 0.1% BSA. Subsequent dilutions are made in phosphate buffer. The peptides are injected sc, and blood samples (300 μl) are collected under metotane anesthesia. Sera (50 μl) are tested for LH levels in duplicate using reagents provided by the National Pituitary and Hormone Distribution Program of the NIDDK. Testing shows that a dosage of 50 μg of peptide per rat suppresses LH secretion to levels that are less than 50% of control levels for the first 3 days, which levels are about the same as the LH levels exhibited by rats similarly injected with a dose of 50 micrograms of Acyline. However, 96 hours following injection, the LH levels are only about 75% of those of the Acyline-injected rats. Examination of the rats shows that the peptide was very well tolerated, with no significant gelling at the point of injection being detectable. Experience gained from the testing of a large number of GnRH antagonists shows that a peptide exhibiting such long-acting suppression of LH would, if assayed in vivo in mature female Sprague-Dawley rats, fully block ovulation at a dosage of 2.5 micrograms. EXAMPLE 2 A portion of the peptidoresin intermediate synthesized in Example 1 is used to create [D-Dpr (Cbm) 3 ] -Acyline. After removal of the Fmoc protecting group from the side chain of the D-Dpr residue as in Example 1, the intermediate is treated with t-butyl isocyanate for about 6 hours at room temperature. Cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1, which results in removal of the t-butyl, leaving the carbamoyl group substituted upon the amino side chain of the D-Dpr residue. The peptide Ac-D-2Nal-D-4Cpa-D-Dpr (carbamoyl) -Ser-4Aph (acetyl) - D-4Aph (acetyl) -Leu-Lys (isopropyl) -Pro-D-Ala-NH 2 (Peptide No. 2) is obtained in the RP-HPLC purification. It is judged to be substantially homogeneous, and its purity is estimated to be greater than 98 percent. MS analysis shows a mass of 1513.7 Da, which is in agreement with the calculated mass of 1513.7 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Peptide No. 1. Assaying this peptide in the standard in vivo rat test as in Example 1, shows that, at a dosage of 50 micrograms, the peptide is bioactive, being about as effective for the suppression of LH as Peptide No. 1. EXAMPLE 2A A portion of the peptidoresin intermediate prepared in the synthesis set forth in Example 1 is utilized herein to form [D-Dpr (EtCb ) 3 ] -Acyline. After removal of the Fmoc protecting group from the side chain of the D-Dpr residue as in Example 1, the intermediate is treated with ethyl isocyanate for about 60 minutes at room temperature in the presence of DIEA to form an ethylurea group with the amino side chain of the D-Dpr residue. Cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Dpr (ethylcarbamoyl) -Ser-4Aph(acetyl) -D-4Aph(acetyl) - Leu-Lys(isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. It is judged to be substantially homogeneous, and its purity is estimated to be greater than 98 percent. MS analysis shows a mass of 1541.4 Da, which is in agreement with the calculated mass of 1541.8 Da. From the HPLC results, it can be seen that this peptide is about as hydrophilic as Acyline. Assaying this peptide in the standard in vivo rat test as in Example 1, shows that, at a dosage of 50 micrograms, the peptide is bioactive, being about as effective as Peptide No. 2 for the suppression of LH. EXAMPLE 2B Another portion of the peptidoresin intermediate prepared in Example 1 is utilized to form the decapeptide [D-Dpr (iprCbm) 3 ] -Acyline. After removal of the Fmoc protecting group from the side chain of the D-Dpr residue as in Example 1, the intermediate is treated with isopropylisocyanate for about 30 minutes at room temperature in the presence of DIEA to form an isopropylurea group with the amino side chain of the D-Dpr residue. Cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Dpr (isopropylcarbamoyl) -Ser-4Aph(acetyl) -D-4Aph(acetyl) - Leu-Lys(isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. It is judged to be substantially homogeneous, and its purity is estimated to be greater than 95 percent. MS analysis shows a mass of 1555.5 Da, which is in agreement with the calculated mass of 1555.8 Da. Assaying this peptide in the standard in vivo rat test as in Example 1, shows that, at a dosage of 50 micrograms, the peptide is bioactive, being about as effective an Acyline for 2 days. At 3 days, it is less effective than Acyline for the suppression of LH. EXAMPLE 2C The synthesis set forth in Example 1 is generally used to form a decapeptide intermediate wherein the D-Dpr, 4Aph and D-4Aph residues all remain protected by Fmoc. After acetylation of the N-terminus and then removal of the Fmoc protecting groups from the three side chains as in Example 1, the intermediate is treated with methyl isocyanate for about 2 hours at room temperature in the presence of DIEA to form methylurea groups with the three amino side chains. Cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D-Dpr (methylcarbamoyl) - Ser-4Aph(methylcarbamoyl) -D-4Aph (methylcarbamoyl) -Leu- Lys(isopropyl)-Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. It is judged to be substantially homogeneous and to be more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat test as in Example 1, shows that, at a dosage of 50 micrograms, the peptide is bioactive, and about as effective as Acyline for the suppression of LH. EXAMPLE 3 An analog of the peptide Cetrorelix having the formula Ac-D-2Nal-D-4Cpa-D-Dpr (methylcarbamoyl) -Ser-Tyr-D-Cit- Leu-Arg-Pro-D-Ala-NH 2 is synthesized using the synthesis as generally set forth in Example 1. Instead of coupling N α Boc-D-4Aph and 4Aph in the 6- and 5-positions, N β Boc-D-Cit is coupled in the 6-position, and N a Boc-Tyr (2BrZ) is coupled in the 5-position. N a Boc-Arg(Tos) is used instead of N a Boc- Lys(ipr, Z) . Alternatively, N a Boc-D-Orn(Fmoc) is coupled in the 6-position, and the chain elongation is temporarily halted following the addition of. Boc-Tyr (2BrZ) in the 5- position, having obtained the following peptide intermediate : Boc-Tyr (2BrZ) -D-Orn (Fmoc) -Leu-Arg (Tos) -Pro-D-Ala-NH- [MBHA resin support] . The amino side chain on the Orn residue is then deprotected by removal of the Fmoc protection as in Example 1, and the intermediate is treated with excess t- butyl isocyanate in DMF for about 6 hours at room temperature to react with the side chain of the Orn residue. The completion of the synthesis of the decapeptide intermediate is then carried out as in Example 1, followed by deprotection of the D-Dpr side chain and reaction with methyl isocyanate. The peptidoresin is then subjected to the standard wash, and cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Dpr (methylcarbamoyl) -Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH 2 (Peptide No. 3) is obtained following RP-HPLC purification. The peptide is considered to be more hydrophilic than Acyline and to have longer duration of in vivo suppression of LH than Cetrorelix. EXAMPLE 3A The synthesis set forth in Example 3 is repeated, substituting N a Boc-D-Hci for N a Boc-D-Cit and ILys 8 for Arg 8 to synthesize an analog of the decapeptide Antarelix. Following deprotection of the D-Dpr side chain, reaction is carried out with methyl isocyanate. Cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-β-D-2Nal-D-4Cpa-D-Dpr (methylcarbamoyl) -Ser-Tyr-D-Hci- Leu-ILys-Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. This peptide has substantially the same ability to suppress the in vivo secretion of LH as does Peptide No. 3. EXAMPLE 4 An analog of the peptide Antide having the formula Ac-D-2Nal-D-4Cpa-D-Dpr (methylcarbamoyl) -Ser- Lys (nicotinoyl) -D-Lys (nicotinoyl) -Leu-Lys (ipr) -Pro-D-Ala- NH 2 is synthesized using the synthesis as generally set forth in Example 1 of U.S. Patent No. 5,169,935, but substituting N a Boc-D-Dpr (Fmoc) for D-3Pal. Following the completion of the synthesis of the decapeptide intermediate, deprotection of the D-Dpr side chain and reaction with methyl isocyanate are carried out as in Example 1. The peptidoresin is then subjected to the standard wash; then cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Dpr (methylcarbamoyl) -Ser-Lys (Nic) -D-Lys (Nic) -Leu-ILys- Pro-D-Ala-NH 2 (Peptide No. 4) is obtained in the RP-HPLC purification. The peptide exhibits longer duration of in vivo suppression of LH secretion than Antide. EXAMPLE 5 An analog of the peptide Azaline B having the formula Ac-D-2Nal-D-4Cpa-D-Dpr (methylcarbamoyl) -Ser-4Aph(atz) -D- 4Aph(atz) -Leu-ILys-Pro-D-Ala-NH 2 is synthesized using the synthesis as generally set forth in Example VIII of U.S. Patent No. 5,269,468. Instead of coupling N a Boc-D-3Pal in the 3-position, N a Boc-D-Dpr (Fmoc) is substituted. Following the completion of the synthesis of the decapeptide intermediate, deprotection of the D-Dpr side chain and reaction with methyl isocyanate are carried out as in Example 1. The peptidoresin is then subjected to the standard wash, and cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Dpr (methylcarbamoyl) -Ser-4Aph(atz) -D-4Aph(atz) -Leu-ILys- Pro-D-Ala-NH 2 (Peptide No. 5) is obtained in the RP-HPLC purification. This peptide is more hydrophilic than Acyline and exhibits longer duration of in vivo suppression of LH secretion than Azaline B. EXAMPLE 5A An analog of the peptide Antide, [D-Dpr (methylcarbamoyl) 3 , 4Aph(Gab) (atz) 5 , D- 4Aph(Gab) (atz) 6 ] -Antide is synthesized using the synthesis as generally set forth in Example 1. After coupling N a Boc- D-4Aph(Fmoc) and N a Boc-4Aph(Fmoc) in the 6- and 5-positions, the chain elongation is temporarily halted and reaction with side chain-protected gamma-amino butyric acid (Gab) is carried out followed by the building of the triazole modifications as taught in Example 1 of U.S. Patent No. 5,506,207. Following the completion of the synthesis of the decapeptide intermediate, deprotection of the D-Dpr side chain and reaction with methyl isocyanate are carried out as in Example 1. The peptidoresin is then subjected to the standard wash, and cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Dpr (methylcarbamoyl) -Ser-4Aph (Gab) (atz) -D-4Aph(Gab) (atz)- Leu-ILys-Pro-D-Ala-NH 2 (Peptide No. 5A) is obtained in the RP-HPLC purification. This peptide is more hydrophilic than Antide and exhibits longer duration of in vivo suppression of LH secretion than Acyline. EXAMPLE 5B Another analog of the peptide Antide [D-Dpr (methylcarbamoyl) 3 , 4Aph(β-Ala) (atz) 5 , D-4Aph(β- Ala) (atz) 6 ] -Antide is synthesized using the synthesis as generally set forth in Example 5A. Instead of reacting the side chain amino groups of D-4Aph and 4Aph in the 6- and 5- positions with Gab, the initial reaction is carried out with N β Fmoc-β-Ala. The remainder of the synthesis is the same. Following the completion of the synthesis of the decapeptide intermediate, deprotection of the D-Dpr side chain and reaction with methyl isocyanate are carried out as in Example 1. The peptidoresin is then subjected to the standard wash, and cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Dpr (methylcarbamoyl) -Ser-4Aph(β-Ala) (atz) -D-4Aph(β- Ala) (atz)-Leu-ILys-Pro-D-Ala-NH 2 (Peptide No. 5B) is obtained in the RP-HPLC purification. This peptide is more hydrophilic than Antide and exhibits longer duration of in vivo suppression of LH secretion than Antide. EXAMPLE 5C Another analog of the peptide Antide, [D-Dpr (methylcarbamoyl) 3 , 4Aph(For) 5 , D-4Aph (For) 6 ] -Antide is synthesized using the synthesis as generally set forth in Example 1. Instead of reacting the side chain amino groups of D-4Aph and 4Aph in the 6- and 5-positions with acetic anhydride, the reaction is carried out with a mixture of formic acid and acetic anhydride. Following the completion of the synthesis of the decapeptide intermediate, deprotection of the D-Dpr side chain and reaction with methyl isocyanate are carried out as in Example 1. The peptidoresin is then subjected to the standard wash, and cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Dpr (methylcarbamoyl) -Ser-4Aph(For) -D-4Aph(For) -Leu-ILyε- Pro-D-Ala-NH 2 (Peptide No. 5C) is obtained in the RP-HPLC purification. The peptide exhibits longer duration of in vivo suppression of LH secretion than Antide. EXAMPLE 5D The analog [D-Dpr (MeCbm) 3 , 4Aph (Hor) 5 ] -Acyline is synthesized as generally set forth in Example 1. The 6- position D-4Aph is acetylated prior to the addition to the chain of N α Boc-4Aph(Fmoc) . Following deprotection of the 4Aph side chain, a reaction is carried out with hydroorotic acid (CN 2 H 5 (0) 2 COOH) in the presence of DIC and HOBt in DMF for about 8 hours at room temperature. Completion of the synthesis, cleavage from the resin and deprotection, followed by purification, are then carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D-Dpr (MeCbm) - Ser-4Aph(Hor) -D-4Aph(acetyl) -Leu-Lys (isopropyl) -Pro-D-Ala- NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 99 percent. MS analysis shows a mass of 1625.5 Da which compares favorably to the expected mass of 1625.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH Suppression test shows that, at a dosage of 50 micrograms, it is substantially as active as Acyline in suppressing LH level for 2 days, and at 3 days it shows suppression of LH to levels less than Acyline. EXAMPLE 5E The analog [D-Dpr (MeCbm) 3 , 4Aph(Hor) 5 , D-4Aph (Hor) 6 ] - Acyline is synthesized as generally set forth in Example 5D. The 6-position D-4Aph and the 5-position 4Aph residues are reacted simultaneously. Following deprotection of the two 4Aph side chains, the reaction is carried out with hydroorotic acid, and completion of the synthesis, cleavage from the resin and deprotection, and purification are then carried out as in Example 5D. The peptide Ac-D-2Nal-D- 4Cpa-D-Dpr (methylcarbamoyl) -Ser-4Aph (Hor) -D-4Aph (Hor) -Leu- Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 95 percent. MS analysis shows a mass of 1735.5 Da which compares favorably to the expected mass of 1735.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH Suppression test shows that, at a dosage of 50 micrograms, it is substantially as active as Acyline in suppressing LH level at 1, 2 and 3 days, and is considered to be long- acting. EXAMPLE 5F The analog [D-Dbu (MeCbm) 3 , 4Aph (Hor) 5 ] -Acyline is synthesized as generally set forth in Example 5D, substituting N a Boc-D-Dbu(Fmoc) for N a Boc-D-Dpr (Fmoc) . Completion of the synthesis, cleavage from the resin and deprotection, followed by purification, are then carried out as described in Example 1. The peptide Ac-D-2Nal-D- 4Cpa-D-Dbu (MeCbm) -Ser-4Aph (Hor) -D-4Aph (acetyl) -Leu- Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. The compound is bioactive in suppressing the secretion of LH. EXAMPLE 5G The analog [D-Dpr (MeCbm) 3 , 4Aph(Hor) 5 , D-4Amf (Cbm) 6 ] - Acyline is synthesized as generally set forth in Example 5D, substituting N α Boc-D-4Amf (Fmoc) for N a Boc-D-4Aph(Fmoc) for the 6-position residue and then reacting its deprotected side chain with t-butyl isocyanate prior to the addition of N α Boc-4Aph(Fmoc) . Completion of the synthesis, cleavage from the resin and deprotection, followed by purification, are then carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D-Dpr (MeCbm) -Ser- 4Aph(Hor) -D-4Amf (Cbm) -Leu-Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. The compound is bioactive in suppressing the secretion of LH. EXAMPLE 6 The synthesis set forth in Example 1 is repeated to form the peptide [D-Dpr (MeCbm) 3 , 4Aph(Cbm) 5 , D-4Aph(Cbm) 6 ]- Antide. Instead of reacting the side chain amino groups of 4Aph and D-4Aph with acetic anhydride, they are both reacted with t-butyl isocyanate; removal of Boc then permits further extension of the peptide chain. Following acetylation of the N-terminus and then deprotection of the D-Dpr side chain, reaction with methyl isocyanate is carried out. Cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1 and result in removal of the t-butyl moieties. The peptide Ac-D-2Nal-D-4Cpa-D-Dpr (methylcarbamoyl) - Ser-4Aph(carbamoyl) -D-4Aph (carbamoyl) -Leu-Lys (isopropyl) - Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 98 percent. MS analysis shows a mass of 1529.9 Da which compares favorably to the expected mass of 1529.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH Suppression test shows that, at a dosage of 50 micrograms, it is substantially as long acting as Acyline. EXAMPLE 6A A synthesis as generally set forth in Example 5G is carried out to form the peptide [D-Dpr (Cbm) 3 , 4Aph(Hor) 5 , D- 4Amf (Cbm) 6 ] -Antide. The side chain amino group of D-4Amf is reacted with t-butyl isocyanate. After removal of Boc, N a Boc-4Aph(Fmoc) is added to the peptide chain. After removal of Fmoc, reaction with hydroorotic acid is carried out. Following acetylation of the N-terminus and then deprotection of the D-Dpr side chain, reaction with t-butyl isocyanate is carried out. Cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Dpr (carbamoyl) -Ser-4Aph (L-hydrooroty1) -D-4Amf (carbamoyl) - Leu-Lys ( isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. This peptide is bioactive in suppressing the secretion of LH. EXAMPLE 7 The peptide analog [D-Gln 3 ] -Acyline is synthesized using the synthesis as generally set forth in Example 1. Instead of coupling N a Boc-D-Dpr (Fmoc) in the 3-position, N a Boc-D-Gln is used. Optionally, N a Boc-D-Gln(Xan) is used; however, preferably D-Gln is coupled without side chain protection. Following the completion of the synthesis of the decapeptide intermediate, the peptidoresin is subjected to the standard wash; then, cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Gln-Ser-4Aph (Ac) -D-4Aph (Ac) -Leu-ILys-Pro-D-Ala-NH 2 (Peptide No. 7) is obtained in the RP-HPLC purification. It is judged to be substantially homogeneous, and its purity is estimated to be greater than 99 percent. LSIMS analysis shows measured mass of 1512.9 Da which is in agreement with the calculated mass of 1512.7 Da for this peptide. When tested in vivo for suppression of LH secretion as in Example 1, the peptide exhibits about the same duration of bioactivity as Acyline over 3 days. EXAMPLE 7A The analog [D-Gln 3 , 4Aph (Hor) 5 ] -Acyline is synthesized as generally set forth in Examples 5D and 7. The 6- position D-4Aph is acetylated prior to the addition to the chain of N a Boc-4Aph(Fmoc) . Following deprotection of the 4Aph side chain, a reaction is carried out with hydroorotic acid as in Example 5D. Following completion of the synthesis and purification, the peptide Ac-D-2Nal-D-4Cpa- D-Gln-Ser-4Aph(L-hydroorotyl) -D-4Aph (acetyl) -Leu- Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 95 percent. MS analysis shows a mass of 1610.9 Da which compares favorably to the expected mass of 1610.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH Suppression test shows that, at a dosage of 50 micrograms, it is substantially as active as Acyline in suppressing LH level at 1, 2 and 3 days, and at 96 hours it shows suppression of LH to levels well below Acyline. It is considered to be very long-acting. EXAMPLE 7B The synthesis set forth in Example 7A is repeated to create a peptide which substitutes D-Gln (Me) 3 for D-Gln 3 . A simple substitution of N α Boc-D-Gln(Me) for N a Boc-D-Gln may be used. Alternatively, following addition of Boc-D- Glu(OFm) and the removal of the fluorenylmethyl ester side chain protecting group, a reaction is carried out with NH 2 CH 3 -HC1 in the presence of DIEA and BOP (benzotriazoyl-N- oxytris (dimethylamino) phosphonium hexafluorophosphate) to form the N-methylamide. Cleavage from the resin and deprotection, followed by purification, are carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Gln (methyl) -Ser-4Aph (L-hydrooroty1) -D-4Aph (acetyl) -Leu- Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 98 percent. MS analysis shows a mass of 1624.8 Da which compares favorably to the expected mass of 1624.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH Suppression test shows that, at a dosage of 50 micrograms, it is substantially as long acting as Acyline; it is equipotent for 3 days and slightly less effective through day 4. EXAMPLE 7C The synthesis set forth in Example 7A is repeated, substituting N α Boc-D-4Amf (Fmoc) for N a Boc-D-4Aph(Fmoc) and then reacting its deprotected side chain with t-butyl isocyanate prior to the addition of N a Boc-4Aph(Fmoc) . The peptide Ac-D-2Nal-D-4Cpa-D-Gln-Ser-4Aph(L-hydroorotyl) - D-4Amf (carbamoyl) -Leu-Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 98 percent. MS analysis shows a mass of 1625.8 Da which compares favorably to the expected mass of 1625.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH suppression test shows that, at a dosage of 50 micrograms, it is substantially as effective as Acyline for 2 to 3 days. EXAMPLE 7D The synthesis of Example 7C is generally followed to make [N-MeCbm-D-2Nal 1 , D-Gln 3 , 4Aph(Hor) 5 , D-4Amf (Cbm) 6 ] - Antide; however, Fmoc protection is not removed from 4Aph until after the N-terminus has been modified. Following deprotection of the N-terminus, the α-amino group is reacted with methyl isocyanate. Then, Fmoc protection is removed, and 4Aph is reacted with L-hydroorotic acid as in Example 7A. Cleavage from the resin and deprotection, followed by purification, are then carried out as described in Example 1. The peptide N-methylcarbamoyl-D-2Nal-D- 4Cpa-D-Gln-Ser-4Aph(L-hydroorotyl) -D-4Amf (carbamoyl) -Leu- Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 99 percent. MS analysis shows a mass of 1640.8 Da which compares favorably to the expected mass of 1640.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH suppression test shows that, at a dosage of 50 micrograms, it is substantially as effective as Acyline for 2 to 3 days. EXAMPLE 7E The synthesis set forth in Example 7C is repeated, substituting methyl isocyanate for t-butyl isocyanate in carrying out the reaction with the deprotected side chain of D-4Amf. Cleavage from the resin and deprotection, followed by purification, are subsequently carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D- Gln-Ser-4Aph(L-hydroorotyl) -D-4Amf (methylcarbamoyl) -Leu- Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 99 percent. MS analysis shows a mass of 1639.7 Da which compares favorably to the expected mass of 1639.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH suppression test shows that, at a dosage of 50 micrograms, it is substantially as effective as Acyline for 2 to 3 days. EXAMPLE 7F The synthesis set forth in Example 7C is repeated, substituting N a Boc-4Amf (Fmoc) for N a Boc-4Aph(Fmoc) to create the analog of [D-Gln 3 , 4Amf(Hor) 5 , D-4Amf (Cbm) 6 ] -Antide. Cleavage from the resin and deprotection, followed by purification, are subsequently carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D-Gln-Ser-4Amf (L- hydrooroty1) -D-4Amf (carbamoyl) -Leu-Lys ( isopropyl) -Pro-D- Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 98 percent. MS analysis shows a mass of 1639.7 Da which compares favorably to the expected mass of 1639.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH suppression test shows that, at a dosage of 50 micrograms, it remains effective and is slightly better than Acyline after 4 days. EXAMPLE 7G The synthesis set forth in Example 7D is repeated, substituting D-hydroorotic acid for L-hydroorotic acid in the reaction with the deprotected side chain of 4Aph to create the analog [N-MeCbm-D-2Nal 1 , D-Gln 3 , 4Aph(D-Hor) 5 , D-4Amf (Cbm) 6 ] -Antide. Should an alternative protocol be used wherein the peptidoresin would contain the hydroorotyl group when the reaction with an isocyanate is to take place, the base, e.g. DIEA, is not added and only 3 eq. of the particular isocyanate is employed. Cleavage from the resin and deprotection, followed by purification, are subsequently carried out as described in Example 1. The peptide N-methylcarbamoyl-D-2Nal-D-4Cpa-D-Gln-Ser-4Aph (D- hydroorotyl)-D-4Amf (carbamoyl) -Leu-Lys (isopropyl) -Pro-D- Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 98 percent. MS analysis shows a mass of 1640.7 Da which compares favorably to the expected mass of 1640.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH suppression test shows that, at a dosage of 50 micrograms, it is short-acting, being nearly as effective as Acyline for 1 day and then fairly quickly losing its effectiveness. EXAMPLE 7H The synthesis set forth in Example 7D is repeated, substituting L-Imz for L-hydroorotic acid in the reaction with the deprotected side chain of 4Aph to create the analog D-Gln 3 , 4Aph(Imz) 5 , D-4Amf (Cbm) 6 ] - Antide. Cleavage from the resin and deprotection, followed by purification, are subsequently carried out as described in Example 1. The peptide N-methylcarbamoyl-D-2Nal-D-4Cpa- D-Gln-Ser-4Aph(Imz) -D-4Amf (carbamoyl) -Leu-Lys (isopropyl) - Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. This peptide is more hydrophilic than Acyline and is substantially as effective as Acyline for 2 to 3 days in LH suppression. EXAMPLE 71 The synthesis set forth in Example 7F is repeated, substituting methyl isocyanate for t-butyl isocyanate in carrying out the reaction with the deprotected side chain of D-4Amf to create the analog of [D-Gln 3 , 4Amf(Hor) 5 , D- 4Amf (MeCbm) 6 ] -Antide. Cleavage from the resin and deprotection, followed by purification, are subsequently carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-D-Gln-Ser-4Amf (L-hydroorotyl) - D-4Amf (methylcarbamoyl) -Leu-Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 98 percent. MS analysis shows a mass of 1653.7 Da which compares favorably to the expected mass of 1653.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH suppression test shows that, at a dosage of 50 micrograms, it is substantially as effective as Acyline for 3 days and remains effective through day 4. EXAMPLE 7J The synthesis set forth in Example 7A is repeated, substituting N a Boc-4Amf (Fmoc) for N a Boc-4Aph(Fmoc) to create the analog of [D-Gln 3 , 4Amf (Hor) 5 ] -Acyline. The peptide Ac-D-2Nal-D-4Cpa-D-Gln-Ser-4Amf (L-hydroorotyl) -D- 4Aph(acetyl) -Leu-Lys ( isopropyl)-Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be greater than 99 percent. MS analysis shows a mass of 1624.8 Da which compares favorably to the expected mass of 1624.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH suppression test shows that, at a dosage of 50 micrograms, it is nearly as effective as Acyline both after 3 days and after 4 days. EXAMPLE 7K The analog [D-Asn 3 , 4Aph (Hor) 5 ] -Acyline is synthesized as generally set forth in Example 7A, except that N a Boc-D- Asn is used instead of N a Boc-D-Gln. The peptide Ac-D-2Nal-D-4Cpa-D-Asn-Ser-4Aph (Hor) -D-Aph (acetyl) -Leu- Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be about 99 percent. MS analysis shows a mass of 1596.9 Da which compares favorably to the expected mass of 1596.7 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH Suppression test shows that, at a dosage of 50 micrograms, it is substantially as active as Acyline in suppressing LH level for 2 days, and at 3 days it shows suppression of LH to levels less than Acyline. EXAMPLE 7L The analog [D-Asn 3 , 4Aph(Hor) 5 , D-4Amf (Cbm) 6 ] -Acyline is synthesized as generally set forth in Example 7K, except that D-4Amf is used as the 6-position residue. After D- 4Amf is deprotected, it is reacted with t-butyl isocyanate, prior to removal of Boc to extend the chain. The peptide Ac-D-2Nal-D-4Cpa-D-Asn-Ser-4Aph (Hor) -D-Amf (Cbm) -Leu- Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. The peptide is bioactive in suppressing the secretion of LH. EXAMPLE 8 The peptide [Gin 3 ] -Acyline is synthesized by repeating the synthesis set forth in Example 7 but coupling N a Boc-Gln in the 3-position instead of N a Boc-D-Gln. The peptide Ac-D-2Nal-D-4Cpa-Gln-Ser-4Aph (Ac) -D-4Aph (Ac) -Leu-ILys-Pro- D-Ala-NH 2 (Peptide No. 8) is obtained in the RP-HPLC purification. It is judged to be substantially homogeneous, and its purity is estimated to be greater than 99 percent. LSIMS analysis shows measured mass of 1512.7 Da which is in agreement with the calculated mass of 1512.7 Da for this peptide. The peptide exhibits about the same duration of bioactivity as Acyline when tested in vivo for suppression of LH secretion as in Example 1, being about equal to Acyline over 4 days. It is considered to be long- acting. EXAMPLE 8A The analog [Gin 3 , 4Aph (Hor) 5 ] -Acyline is synthesized as set forth in Example 7A, substituting N a Boc-Gln for N a Boc-D- Gln. The peptide Ac-D-2Nal-D-4Cpa-Gln-Ser-4Aph(Hor) -D- 4Aph (acetyl) -Leu-Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification and judged to be substantially homogeneous, with its purity estimated to be about 99 percent. MS analysis shows a mass of 1610.7 Da which compares favorably to the calculated mass of 1610.8 Da. From the HPLC results, it can be seen that this peptide is more hydrophilic than Acyline. Assaying this peptide in the standard in vivo rat LH Suppression test shows that, at a dosage of 50 micrograms, it is substantially as active as Acyline in suppressing LH levels over 4 days. It is considered to be long-acting. EXAMPLE 8B The synthesis set forth in Example 7A is repeated to create a peptide which substitutes Gin (Me) 3 for D-Gln 3 . A simple substitution of N a Boc-Gln(Me) for N a Boc-D-Gln is used. The peptide Ac-D-2Nal-D-4Cpa-Gln (methyl) -Ser- 4Aph(L-hydroorotyl) -D-4Aph (acetyl) -Leu-Lys (isopropyl) -Pro- D-Ala-NH- is obtained in the RP-HPLC purification. This peptide is more hydrophilic than Acyline. At a dosage of 50 micrograms, it is substantially as long acting as Acyline. EXAMPLE 8C The synthesis set forth in Example 8A is repeated, substituting N a Boc-D-4Amf (Fmoc) for N a Boc-D-4Aph(Fmoc) and then reacting its deprotected side chain with t-butyl isocyanate. The peptide Ac-D-2Nal-D-4Cpa-Gln-Ser- 4Aph(L-hydroorotyl) -D-4Amf (carbamoyl) -Leu-Lys (isopropyl) - Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. This peptide is more hydrophilic than Acyline. It is judged to be substantially homogeneous, and its purity is estimated to be greater than 99 percent. MS analysis shows a mass of 1625.6 Da, which is in agreement with the calculated mass of 1625.8 Da. Assaying this peptide in the standard in vivo rat test as in Example 1, shows that, at a dosage of 50 micrograms, the peptide is bioactive, being about as effective as Acyline for 24 hours. At 2 days, it is somewhat less effective than Acyline for the suppression of LH and its effectiveness declines rapidly thereafter. EXAMPLE 8D The synthesis set forth in Example 8C is repeated, substituting methyl isocyanate for t-butyl isocyanate in carrying out the reaction with the deprotected side chain of D-4Amf. Cleavage from the resin and deprotection, followed by purification, are subsequently carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-Gln- Ser-4Aph (L-hydroorotyl) -D-4Amf (methylcarbamoyl) -Leu- Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. This peptide is more hydrophilic than Acyline. At a dosage of 50 micrograms, it is substantially as effective as Acyline for 2 to 3 days. EXAMPLE 8E The synthesis set forth in Example 8C is repeated, substituting N a Boc-4Amf (Fmoc) for N a Boc-4Aph(Fmoc) to create the peptide [Gin 3 , 4Amf(Hor) 5 , D-4Amf (Cbm) 6 ] -Antide. Cleavage from the resin and deprotection, followed by purification, are subsequently carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-Gln-Ser-4Amf (L- hydroorotyl) -D-4Amf (carbamoyl) -Leu-Lys (isopropyl) -Pro D-Ala-NH 2 is obtained in the RP-HPLC purification. This peptide is more hydrophilic than Acyline. At a dosage of 50 micrograms, it is about as effective as Acyline over 4 days. EXAMPLE 8F The synthesis set forth in Example 8E is repeated, substituting methyl isocyanate for t-butyl isocyanate in carrying out the reaction with the deprotected side chain of D-4Amf. Cleavage from the resin and deprotection, followed by purification, are subsequently carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-Gln- Ser-4Amf (L-hydroorotyl) -D-4Amf (methylcarbamoyl) -Leu- Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. This peptide is more hydrophilic than Acyline. At a dosage of 50 micrograms, it is substantially as effective as Acyline for 3 days. EXAMPLE 8G The synthesis set forth in Example 8A is repeated, substituting N a Boc-4Amf (Fmoc) for N a Boc-4Aph (Fmoc) to create the analog of [Gin 3 , 4Amf (Hor) 5 ] -Acyline. Cleavage from the resin and deprotection, followed by purification, are subsequently carried out as described in Example 1. The peptide Ac-D-2Nal-D-4Cpa-Gln-Ser-4Amf (L-hydroorotyl) -D- 4Aph(acetyl) -Leu-Lys (isopropyl) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purification. This peptide is more hydrophilic than Acyline. At a dosage of 50 micrograms, it is about as effective as Acyline over 3 days. EXAMPLE 8H The synthesis set forth in Example 7A is repeated to create a peptide which substitutes Asn 3 for D-Gln 3 . A simple substitution of N a Boc-Asn for N Boc-D-Gln is used . The peptide Ac-D-2Nal-D-4Cpa-Asn-Ser-4Aph (L-hydroorotyl ) - D-4Aph ( acetyl) -Leu-Lys ( isopropyl ) -Pro-D-Ala-NH 2 is obtained in the RP-HPLC purif ication . This peptide is more hydrophilic than Acyline . At a dosage of 50 micrograms , it is substantially as long acting as Acyline . EXAMPLE 9 Using the procedures as generally set forth in Examples 1 to 8, the following GnRH antagonist peptides are also prepared: Acr-D-2Nal 1 , 4FD-Phe 2 , D-Dpr (MeCbm) 3 ] -Acyline Bz-D-2Nal 1 , 4N0 2 D-Phe 2 , D-Dpr (MeCbm) 3 , 4Aph (Hor) 5 ] -Acyline For-D-2Nal 1 , 40CH 3 D-Phe 2 , D-Dpr (MeCbm) 3 , 4Amf (Hor ) 5 ] -Acyline Bz-D-2Nal 1 , 4BrD-Phe 2 , D-Dpr (MeCbm) 3 , D-4Aph ( Imz ) 6 ] -Acyline [ Pn-D-2Nal 1 , 4CH 3 D-Phe 2 , D-Dpr (MeCbm) 3 , 4Aph (MeCbm) 5 ] -Acyline By-D-2Nal 1 , 3 , 4Cl 2 D-Phe 2 , D-Dpr (MeCbm) 3 , 4Aph (Cbm) 5 ] -Acyline Vl-D-2Nal 1 , 4N0 2 D-Phe , D-Gln 3 , D-4Aph (Cbm) 6 ] -Acyline Vac-D-2Nal 1 , C a Me4ClD-Phe 2 , D-Gln 3 , 4Aph (Hor) 5 ] -Acyline Pn-D-2Nal 1 , D-Gln 3 , 3Aph ( Imz ) 5 , D-3Amf (Hor) 6 , Agl 10 ] -Antide [Acr-D-2Nal 1 , D-Gln 3 , 4Ahp (Hor) 5 ,Arg 8 , D-Agl (Me) 10 ] -Acyline MeCbm-D-2Nal 1 , D-Gln 3 , 4Aph (Cbm) 5 , Agl (Me) 10 ] -Acyline Cbm-D-2Nal 1 , D-Dpr (MeCbm) 3 , 4Amf (MeCbm) 5 , D-Agl 10 ] -Acyline EtCbm-D-2Nal 1 , D-Dpr (MeCbm) 3 , 4Amf ( iprCbm) 5 , Pro NHCH 2 CH 3 ] - Acyline r Acr-D-2Nal 1 , D-Gln 3 , 4Aph ( Imz ) 5 , D-4Amf ( Cbm) 6 , Ala 10 ] -Antide Cbm-D-2Nal , D-Dpr (Cbm) 3 , 4Aph (MeCbm) 5 , Arg (Et 2 ) 8 ] -Acyline D-Dpr (Cbm) 3 , 4Ahp (Hor) 5 , D-4Ahp ( Imz ) 6 , D-Agl 10 ] -Ant ide Ac-D-lNal 1 , D-Gln 3 , 3Amf (Hor) 5 , D-4Amf (Hor ) 6 , Arg 8 ] -Antide PrCbm-D-2Nal 1 , D-Gln 3 , D-3 Aph ( EtCbm) 6 , Pro 9 NHCH 2 CH 3 ] -Acyl ine D-Dpr (MeCbm) 3 , 4Amf (Hor) 5 , AzaGly 10 ] -Antide D-Dpr (Cbm) 3 , 4Amf (Hor) 5 , D-Cit 6 , Har 8 ] -Acyline D-Dpr ( EtCbm) 3 , 4Aph ( Hor ) 5 , D-4 Aph ( D-Imz ) 6 , Gly 10 ] -Antide D-Dpr (Cbm) 3 , D-Hci 6 , Agl (Me) 10 ] -Antide D-Gln 3 , 4Aph (Hor) 5 , D-2Pal 6 , Har 8 , Ala 10 ] -Antide D-Dpr (Cbm) 3 , 4Aph (Hor) 5 , D-4Aph (For ) 6 , D-Agl (Me) 10 ] -Antide D-Dpr (EtCbm) , 4Aph (Hor) 5 , D-4Aph (atz ) 6 , Har (Et 2 ) 8 ] -Antide D-Gln 3 , 4Aph (Hor) 5 , D-4Aph ( iprCbm) 6 , D-Agl 10 ] -Antide For-D-lNal 1 , D-Dpr (EtCbm) 3 , 4Amf (Hor) 5 , D-4Amf (atz ) 6 ] -Antide These peptides are biopotent in inhibiting the secretion of LH. EXAMPLE 10 Using the procedures as generally set forth in Examples 1 to 8 and in U.S. Patent No. 5,491,217, the following GnRH antagonist peptides are also prepared: ; D-Dpr (MeCbm) 3 , N a Me4Aph ( Ac) 5 ] -Acyline D-Dpr (Cbm) 3 ,N a Me4Aph( Ac) 5 ] -Acyline D-Dpr (EtCbm) 3 ,N a Me4Aph (Ac) 5 ] -Acyline [D-Dpr ( iPrCbm) 3 , N a Me4Aph (Ac) 5 ] -Acyline D-Dpr (MeCbm) 3 ,N α Me4Aph (Hor) 5 ] -Acyline D-Dpr (MeCbm) 3 , N a Me4Aph (Hor) 5 , D-Aph (Hor) 6 ] -Acyline D-Dbu (MeCbm) 3 ,N a Me4Aph (Hor) 5 ] -Acyline D-Dpr (MeCbm) 3 , N a Me4Aph (Hor) 5 , D-4Amf (Cbm) 6 ] -Acyline [Dpr (MeCbm) 3 , N a Me4 Aph (Cbm) 5 , D-4Aph (Cbm) 6 ] -Acyline Dpr (Cbm) 3 , N a Me4Aph (Hor ) 5 , D-4Amf (Cbm) 6 ] -Acyline D-Gln 3 , N α Me4Aph (Ac) 5 ] -Acyline D-Gln 3 , N α Me4Aph (Hor ) 5 ] -Acyline D-Gln 3 (Me) , N a Me4 Aph (Hor ) 5 ] -Acyline r D-Gln 3 , N a Me4Aph (Hor ) 5 ,D-4Amf (Cbm) 6 ] -Acyline N a MeCbm 1 , D-Gln 3 , N a Me4Aph (Hor) 5 , D-4Amf (Cbm) 6 ] -Acyline D-Gln 3 , N a Me4Aph (Hor ) 5 , D-4Amf (MeCbm) 6 ] -Acyline D-Gln 3 , N α Me4Amf (Hor ) 5 , D-4Amf (Cbm) 6 ] -Acyline N a MeCbm 1 , D-Gln 3 , N a Me4Aph (D-Hor ) 5 , D-4Amf (Cbm) 6 ] -Acyline [ D-Gln 3 , N α Me4Aph( Imz ) 5 ,D-4Amf( Cbm) 6 ] -Acyline D-Gln 3 , N α Me4Amf (Hor) 5 , D-4Amf (MeCbm) 6 ] -Acyline D-Gln 3 , N α Me4Amf (Hor ) 5 ] -Acyline D-Asn 3 , N α Me4Aph (Hor ) 5 ] -Acyline D-Asn 3 , N α Me4Aph (Hor) 5 , D-4Amf (Cbm) 6 ] -Acyline [Gln 3 ,N a Me4Aph(Ac) 5 ]-Acyline Gin 3 , N a Me4Aph (Hor ) 5 ] -Acyline Gin 3 (Me) , N α Me4Aph (Hor ) 5 ] -Acyline Gin 3 , N a Me4Aph (Hor ) 5 ,D-4Amf (Cbm) 6 ] -Acyline Gin 3 , N a Me4Aph (Hor ) 5 , D-4Amf (MeCbm) 6 ] -Acyline TGln 3 , N a Me4Amf (Hor ) 5 , D-4Amf (Cbm) 6 ] -Acyline Gin 3 , N a Me4Amf (Hor ) 5 , D-4Amf (MeCbm) 6 ] -Acyline Gin 3 , N α Me4 Amf (Hor ) 5 ] -Acyline Asn 3 , N a Me4Aph (Hor ) 5 ] -Acyline These peptides are biopotent in inhibiting the secretion of LH and exhibit very good solubility at physiologic pH. EXAMPLE 11 Using the procedures as generally set forth in Examples 1 to 8, the following GnRH antagonist peptides are also prepared: [For-D-2Nal 1 , 4CH 3 D-Phe 2 , Gin 3 , 4Amf (Hor) 5 ] -Acyline [Bz-D-2Nal 1 ,4BrD-Phe 2 , Gin 3 , D-4Aph (Imz) 6 ] -Acyline [Acr-D-2Nal 1 , Gin 3 , 4Ahp (Hor) 5 , Arg 8 , D-Agl (Me) 10 ] -Acyline [For-D-2Nal 1 ,4N0 2 D-Phe 2 , Gin 3 , D-4Aph(Cbm) 6 ] -Acyline [Bz-D-2Nal 1 , C a Me4ClD-Phe 2 , Gin 3 , 4Aph (Hor) 5 ] -Acyline [Pn-D-lNal 1 , Gin 3 , 3Aph (Imz) 5 ,D-3Amf (Hor) 6 , Agl 10 ] -Antide [MeCbm-D-2Nal 1 , Gin 3 , 4Aph (Cbm) 5 , Agl (Me) 10 ] -Acyline [PrCbm-D-2Nal 1 , Gin 3 , D-4Aph (EtCbm) 6 , Pro 9 NHCH 2 CH 3 ] -Acyline [Gin 3 , 4Aph (Hor) 5 , D-4Aph ( iprCbm) 6 , D-Agl 10 ] -Antide [Gin 3 , 4Aph (Hor) 5 , D-3Pal 6 , Har 8 , Ala 10 ] -Antide [Ac-D-lNal 1 , Gin 3 , 4Amf (Hor) 5 , D-4Amf (Hor) 6 , Arg 8 ] -Antide [Gin 3 , 3Amf (Hor) 5 , D-Cit 6 ,Har 8 ] -Acyline [Gin 3 , 4Aph (Hor) 5 , D-4Aph (atz ) 6 , Har (Et 2 ) 8 ] -Antide [ For-D-lNal 1 , Gin 3 , 3Amf (Hor) 5 , D-4Amf (atz ) 6 ] -Antide [Acr-D-2Nal 1 , Gin 3 , 4Aph (Imz ) 5 , D-4Amf (Cbm) 6 , Ala 10 ] -Antide These peptides are biopotent in inhibiting the secretion of LH. The foregoing compounds that were tested exhibited biological potency, from the standpoint of suppression of LH, at least generally comparable to the GnRH antagonist peptide known as Acyline, of which each is an analog. As a result of extensive testing in this area for over a decade, biopotency determined in this widely accepted test constitutes evidence as to biopotency of such compounds to suppress gonadotropin secretion and thus to have anti- ovulatory and antigonadal effect. Based upon superior solubility, resistance to in vivo gelling, long duration of bioactivity and other properties, these compounds are considered to be generally useful to suppress the secretion of gonadotropins and inhibit the release of steroids by the gonads, e.g. as anti-ovulatory agents. The compounds of the invention are often administered in the form of pharmaceutically acceptable, nontoxic salts, such as acid addition salts, or of metal complexes, e.g., with zinc, barium, calcium, magnesium, aluminum or the like (which are considered as addition salts for purposes of this application) , or of combinations of the two. Illustrative of such acid addition salts are hydrochloride, hydrobromide, sulphate, phosphate, nitrate, oxalate, fumarate, gluconate, tannate, pamoate, maleate, acetate, citrate, benzoate, succinate, alginate, malate, ascorbate, tartrate and the like; acetate and pamoate, the salt of pamoic acid, may be preferred. If the active ingredient is to be administered in tablet form, the tablet may contain a pharmaceutically-acceptable, nontoxic diluent which includes a binder, such as tragacanth, corn starch or gelatin; a disintegrating agent, such as alginic acid; and a lubricant, such as magnesium stearate. If administration in liquid form is desired, sweetening and/or flavoring may be used as part of the pharmaceutically-acceptable diluent, and intravenous administration in isotonic saline, phosphate buffer solutions or the like may be effected. The pharmaceutical compositions will usually contain an effective amount of the peptide in conjunction with a conventional, pharmaceutically-acceptable carrier or diluent. Usually, the dosage will be from about 10 micrograms to about 2.5 milligrams of the peptide per kilogram of the body weight of the host when given intravenously. The nature of these compounds may permit effective oral administration; however, oral dosages might be higher. Overall, treatment of subjects with these peptides is generally carried out in the same manner as the clinical treatment using other antagonists of GnRH, using a suitable carrier in which the compound is soluble and administering a dosage sufficient to suppress LH and FSH levels in the patient. It may also be desirable to deliver the GnRH analog over prolonged periods of time, for example, for periods of one week to one year from a single administration, and slow release, depot or implant dosage forms may be utilized. These compounds can be administered to mammals intravenously, subcutaneously, intramuscularly, orally, percutaneously, intranasally, intrapulmonarily, intrarectally or intravaginally generally to suppress the secretion of the gonadotropins, e.g. to achieve fertility inhibition and/or control and also in applications calling for reversible suppression of gonadal activity, such as for the management of precocious puberty or during radiation or chemotherapy. They are also useful for treatment of steroid-dependent tumors. Effective dosages will vary with the form of administration and the particular species of mammal being treated. An example of one typical dosage form is a bacteriostatic water solution at a pH of about 6 containing the peptide which solution is administered parenterally to provide an effective dose in the range of about 0.1 to about 2.5 mg/kg of body weight per day. These compounds are considered to be well-tolerated in vivo and to resist gelling; accordingly, they are considered to be particularly well-suited for administration by subcutaneous injection in a bacteriostatic water solution at appropriate concentrations, above about 0.75 mg/ml and even above about 1.0 mg/ml, without danger of gelling at the point of injection. These GnRH antagonist peptides are also useful diagnostically, both in vivo and in vitro . These peptides can be injected in vivo followed by assaying the bloodstream of a patient to determine the extent of decrease of hormonal secretion, e.g. LH secretion. In vitro assays can be carried out to determine whether certain tumor cells are sensitive to GnRH. In such assays, tumor cell cultures are treated with the GnRH antagonist peptides and then monitored for hormonal secretions and cell proliferation. Although the invention has been described with regard to its preferred embodiments, it should be understood that changes and modifications as would be obvious to one having the ordinary skill in this art may be made without departing from the scope of the invention which is set forth in the claims which are appended hereto. For example, alternatively in the synthesis, an isocyanate can be reacted with the amino side chain prior to coupling the α-amino protected amino acid into the peptide chain rather than modifying it while a part of the chain. Other substitutions known in the art which do not significantly detract from the effectiveness of the peptides may also be employed in the peptides of the invention. Whereas the N- terminus may be left unsubstituted or other equivalent acylating groups can be used, either acetyl or substituted or unsubstituted carbamoyl is preferred. Instead of 4Aph(Ac), the aminoPhe group can be treated with alternative acylating agents as disclosed in U.S. Patent No. 5,506,207, such as formic acid, β-Ala(atz) and gamma- aminobutyric acid (atz), which as indicated in the examples likewise result in GnRH antagonists that exhibit long- acting duration; thus, these are considered equivalents of D- and L-4Aph(Ac) , respectively. Instead of Aph or D-Aph, Ahp(aminohomophenylalanine) or D-Ahp can be used in the 5- and 6-positions, respectively. Both Lys(Bu) and Lys(Et 2 ) are considered to be equivalents of ILys, as are Arg, Arg(Et 2 ), Har, and Har(Et 2 ); however, ILys is most preferred. Other hydrophobic amino acid residues can also be employed in the 1-position and in the 6-position (as mentioned hereinbefore) , preferably in D-isomer form, and are considered equivalents of those specified. Instead of D-Ala-NH 2 at the C-terminus, D-Ala-ol or Ala-ol may be used as an equivalent. Moreover, the antagonists can be administered in the form of their pharmaceutically or veterinarially acceptable, nontoxic salts, as indicated hereinbefore, which are considered equivalents.

Claims: CLAIMS : 1. A linear GnRH antagonist peptide having the formula: X-D-Nal- (A) D-Phe-Xaa 3 -Ser-Xaa 5 -Xaa 6 -Leu-Xaa 8 -Pro- Xaa 10 or a pharmaceutically acceptable salt thereof wherein: X is an acyl group of 7 carbon atoms or less or Q, 0 with Q being - C -NHR, with R being H or lower alkyl; A is 4C1, 4F, 4Br, 4N0 2 , 4CH 3 , 40CH 3 , 3,4C1 2 or C a Me4Cl; Xaa 3 is D-Gln, Gin, D-Asn, Asn or D-Dpr(Q); Xaa 5 is Tyr, Aph(Q-,) , AmfCQ-,) or Lys(Nic) , with Q 1 being Q, For, Ac, 3-amino-l, 2 , 4-triazole, β- Ala(3-amino-l,2,4-triazole) , Gab(3-amino-l, 2 , 4-triazole) , r L-Hor) (D- or L-Imz) Xaa 6 is D-Aph(Q 2 J, D-Amf(Q 2 ), D-Lys(Nic) , D-Cit, D-Hci or D-Pal, with Q 2 being independently any of the members of Xaa 8 is Lys(ipr), Arg, Har, Har(Et 2 ) , or Arg(Et 2 ) ; and Xaa 10 is D-Ala-NH 2 , NHCH 2 CH 3 , Gly-NH 2 , AzaGly-NH 2 , Ala- NH 2 , Agl-NH 2 , D-Agl-NH 2 , Agl(Me)-NH 2 or D-Agl (Me) -NH 2 , provided however that the α-amino group of Xaa 5 may be methylated. 2. A GnRH antagonist peptide according to claim 1 wherein: X is For, Ac, Acr, Pn, By, VI, Vac, Bz or Q, Xaa 5 is Aph(Q-,) or Amf (Q-,) with Q-, being Ac, 3-amino- 1,2 ,4-triazole, Q or (D- or L-Imz ) ; Xaa 6 is D-Aph(Q 2 ), D-Amf(Q 2 ), D-Lys(Nic), D-Cit, D-Hci or D-Pal, with Q 2 being For, Ac, 3-amino-l, 2 , 4-triazole, Q or (D- or L-Imz) and with Q, A, Xaa 3 , Xaa 8 and Xaa 10 being defined as in claim 1 , provided however that the α-amino group of Xaa 5 may be methylated. 3. A GnRH antagonist peptide according to claim 1 having the formula: X-D-Nal-D-4Cpa-Xaa 3 -Ser-Xaa 5 -Xaa 6 -Leu- Lys(ipr) -Pro-D-Ala-NH 2 or a pharmaceutically acceptable salt thereof wherein: X is an acyl group of 7 carbon atoms or less or Q, 0 with Q being -c-NHR, with R being H or methyl or ethyl; Xaa 3 is D-Gln, Gin or D-Dpr(Q); Xaa 5 is Aph(Ac), Aph(Q) , Amf(Q), or Aph(atz) ; and Xaa 6 is D-Aph(Ac), D-Amf(Q), D-Aph(Q) or D-Aph(atz). 4. A GnRH antagonist according to claim 1 or claim 2 wherein X is Ac, Xaa 5 is 4Aph(Q 2 ) or 4Amf(Q 2 ), Xaa 6 is D- 4Aph(Q 2 ) or D-4Amf (Q 2 ) , Xaa 8 is Lys(ipr) and Xaa 10 is D-Ala- NH 2 . 5. A GnRH antagonist according to any one of claims 1-3 wherein Xaa 5 is 4Aph(Ac) and Xaa 6 is D-4Aph(Ac) or wherein Xaa 5 is 4Aph(atz) and Xaa 6 is D-4Aph(atz) . 6. A GnRH antagonist according to claim 1 or claim 2 wherein Xaa 5 is Tyr and Xaa 6 is D-Cit; or Xaa 5 is Lys (Nic) and Xaa 6 is D-Lys (Nic); or Xaa 5 is Tyr and Xaa 6 is D-Hci. 7. A GnRH antagonist according to any one of claims 1-6 wherein Xaa 3 is D-Gln. 8. A GnRH antagonist according to any one of claims 1-6 wherein Xaa 3 is Gin. 9. A GnRH antagonist according to any one of claims 1-6 wherein Xaa 3 is D-Dpr (Q) and R is H, Me or Et. 10. A GnRH antagonist according to claim 1 having one of the following formulas: Ac-D-2Nal-D-4Cpa-D-Dpr (MeCbm) - Ser-4Aph(Ac) -D-4Aph(Ac) -Leu-Lys (ipr) -Pro-D-Ala-NH 2 ; Ac-D- 2Nal-D-4Cpa-D-Dpr (MeCbm) -Ser-4Aph (Cbm) -D-4Aph (Cbm) -Leu- Lys (ipr) -Pro-D-Ala-NH 2 ; and Ac-D-2Nal-D-4Cpa-Xaa 3 -Ser- 4Aph(Hor) -D-4Aph(Ac) -Leu-Lys (ipr) -Pro-D-Ala-NH 2 , wherein Xaa 3 is D-Gln or Gin. 11. A pharmaceutical composition for inhibiting the secretion of gonadotropins in mammals comprising, as an active ingredient, an effective amount of a GnRH antagonist according to any one of the preceding claims in association with a nontoxic diluent. 12. A method for in vivo or in vitro diagnosis of a condition where GnRH is causing excess hormonal secretion or tumor growth, which method comprises administering a GnRH antagonist peptide according to any one of the preceding claims and monitoring for hormonal secretion or for tumor cell proliferation. 13. A method for inhibiting the secretion of gonadotropins in mammals comprising administering an effective amount of a pharmaceutical composition according to claim 11 which effects a substantial decrease in LH and FSH levels.

Inventors: JIANG GUANGCHENG, SEMPLE GRAEME, JIANG, GUANGCHENG, SEMPLE, GRAEME
Applicants: FERRING BV, JIANG GUANGCHENG, SEMPLE GRAEME, JIANG, GUANGCHENG, SEMPLE, GRAEME
Application year: 1998
Main classification: C07K7
IPC codes: A61K38, A61P15, A61P35, A61P43, C07K7, G01N33