The present invention relates to a class of heptapeptide analogs of LHRH. These compounds are useful in the treatment of disease conditions which are mediated by reproductive hormones, including benign prostate hyperplasia, prostate tumors, breast and ovaries tumors, cryptorchidism, hirsuitism, gastric motility disorders, dysmenorrhea, and endometriosis.

TECHNICAL FIELD OF INVENTION
 The present invention relates to novel analogs of LHRH. The novel analogs
 provide heptapeptides truncated from the C-terminus of LHRH antagonist
 peptides. The invention also relates to processes for preparing the
 disclosed compounds, pharmaceutical compounds containing such compounds,
 and use of such compounds for modulating levels of sex hormones in male or
 female mammals.
 BACKGROUND OF THE INVENTION
 Luteinizing hormone releasing hormone (LHRH) is released from the
 hypothalamus and binds to a receptor on the anterior pituitary gland
 causing the release of gonadotropin hormones. The gonadotropin hormones,
 luteinizing hormone (LH) and follicle-stimulating hormone (FSH), secreted
 from the anterior pituitary gland, regulate fundamental reproductive
 processes, such as ovarian release and gamete maturation. These play a
 major role in regulating the synthesis of the steroidal reproductive
 hormones from the gonads, ie. estrogen and progesterone in females and
 testosterone in males.
 The ongoing system of feedback between hypothalamus, the anterior pituitary
 gland, and the gonads modulates the fundamental processes related to the
 reproductive cycle. The feedback process, described by A. V. Schally et
 al., Fertility and Sterility, 22:11 (1971), provides a web of complex
 relationships related to reproductive functions. Pulsatile release of the
 gonadotropin hormones controls levels of steroidal hormone circulating in
 the mammalian reproductive cycle. Manipulation of the release of these
 hormones provides an avenue for the design of novel agents useful in
 treating various conditions related to dysfunction of the reproductive
 cycle and hormone dependent diseases. Several agonists of natural LHRH
 have been shown to be clinically useful.
 Natural mammalian releasing hormone LHRH isolated and purified from porcine
 and human hypothalami has been characterized as having the sequence:
 (Pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2
 as described in A. V. Schally, Science, 202:6 (1978). Substitutions and
 derivatizations of amino acyl residues have been developed to achieve
 novel compounds useful in treating various disorders related to mammalian
 reproductive systems.
 Synthetic analogs of LHRH have been described in a number of U.S. patents
 for exhibiting activity as LHRH agonists or as antagonists of LHRH. For
 the most part, these compounds contain nine or ten amino acyl residues,
 substituting naturally-occurring or non-naturally occurring amino acid
 residues at one or more positions in the natural sequence of LHRH. U.S.
 Pat. No. 5,110,904 describes nonapeptide and decapeptide LHRH antagonists
 wherein the nitrogen atom of at least one of the amide bonds has been
 alkylated. The decapeptide and undecapeptide analogs described in U.S.
 Pat. No. 5,502,035 have an acyl-substituted N-terminal nitrogen atom.
 Truncated peptide compounds have been developed as series of smaller
 peptide analogs also exhibiting biological activity and having the added
 advantage of possibly improved oral bioavailability. These reduced-size
 peptides, described in U.S. Pat. No. 5,140,009, exhibit effective LHRH
 agonist or antagonist activity. They are "pseudo" hexapeptide,
 heptapeptide, octapeptide and nonapeptide analogs of LHRH, which have 1 to
 3 amino acids eliminated from the N-terminus of a decapeptide antagonist
 sequence to achieve activity as LHRH antagonists. Distinctively, the
 peptides described in this invention have the 10 to 8 amino acids
 eliminated from the C-terminus. Copending U.S. application Ser. No.
 09/373,180 discloses and claims a class of pentapeptide LHRH analogs
 wherein the 1 to 3 amino acids are eliminated from the N-terminus and the
 10 to 8 amino acids from the C-terminus of a decapeptide LHRH antagonist.
 The development of synthetic LHRH antagonists truncated from the C-terminus
 having biological activity provides novel compounds for treatment of
 hormone dependent diseases in male and female mammals. Smaller synthetic
 peptide sequences provide significant advantages when compared to
 decapeptide LHRH analogs. These LHRH antagonists are useful in the
 treatment of a variety of clinical condition in which the suppression of
 sex steroids plays a major therapeutic role, including delay of puberty,
 treatment of benign prostatic hyperplasia, palliative treatment or
 remission of hormonal-dependent tumors of breast and ovaries, palliative
 treatment or remission of hormonal-dependent tumors of the prostate, the
 treatment of cryptorchidism, hirsutism in women, gastric motility
 disorders, dysmenorrhea, and endometriosis.
 SUMMARY OF THE INVENTION
 The compounds of the invention comprise a peptide of the formula:
 ##STR1##
 or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:
 R.sup.1 is of the formula R.sup.3 (C.dbd.O)--, wherein R.sup.3 is lower
 alkyl;
 A is an amino acyl residue selected from the group consisting of:
 3-(2-naphthyl)-D-alanyl;
 [3-(4-chloro)]-D-phenylalanyl; and
 sarcosyl;
 B is an amino acyl residue selected from the group consisting of:
 3-(1-naphthyl)-D-alanyl; and
 [3-(4-chloro)]-D-phenylalanyl;
 C is an amino acyl residue selected from the group consisting of:
 3-(3-pyridyl)-D-alanyl; and
 3-(1-naphthyl)-D-alanyl;
 D is seryl;
 E is an acyl group selected from the group consisting of:
 arginyl;
 (N-epsilon-nicotinyl)lysyl;
 N-methylphenylalanyl;
 [4-(3-amino-1,2,4-triazol-5-yl)]phenylalanyl;
 [4-(3-amino-1,2,4-triazol-5-yl)]-N-methylphenylalanyl;
 [4-(N-acetyl)]-N-methylphenylalanyl;
 [4-(N-nitro)]-N-methylphenylalanyl;
 [4-(N-acetyl)]-phenylalanyl;
 tyrosyl;
 N-methyltyrosyl; and
 1,2,3,4-tetrahydroisoquinoline-3-carbonyl;
 F is an amino acyl residue selected from the group consisting of:
 D-arginyl;
 D-asparaginyl;
 D-citrullyl;
 D-glutamyl;
 D-homocitrullyl;
 D-2-amino-6-N.sup.G,N.sup.G -diethylguanidinohexanoyl;
 (N-epsilon-nicotinyl)-D-lysyl;
 [4-(3-amino-1,2,4-triazol-5-yl)]-D-phenylalanyl;
 [4-(N-acetyl)]-D-phenylalanyl; and
 D-tryptyl;
 G is an amino acyl residue selected from the group consisting of:
 cyclohexylalanyl;
 leucyl; and
 N-methylleucyl; and
 R.sup.2 is of the formula --NR.sup.4 R.sup.5 ; wherein
 R.sup.4 is selected from the group consisting of:
 hydrogen;
 methyl; and
 ethyl;
 R.sup.5 is selected from the group consisting of:
 lower alkyl; and
 lower alkyl-R.sup.6 ; and
 R.sup.6 is selected from the group consisting of amino, guanidino,
 hydrogen, hydroxy, phenyl, morpholinyl, piperidinyl, pyrrolyl, pyridyl,
 pyrrolidinyl, pyrrolidinonyl, and quinuclidinyl; and wherein the
 piperidinyl, pyrrolyl, pyrrolidinyl, and pyrrolidinonyl groups are
 optionally substituted with a methyl group.
 Another aspect of the invention relates to pharmaceutical formulations
 comprising the compounds of the invention or pharmaceutically acceptable
 salts, esters, or prodrugs thereof.
 In another aspect, the invention relates to a method of modulating
 gonadotropin hormones in a mammal comprising administering to a mammal in
 need of such treatment a therapeutically effective amount of a compound as
 defined above.
 Yet another aspect of the invention relates to a process for preparing
 compounds of the invention or pharmaceutically acceptable salts, esters,
 or prodrugs thereof.
 DETAILED DESCRIPTION OF THE INVENTION
 The invention relates to novel LHRH analogs of seven amino acyl residues
 represented by the formula (I), wherein A, B, C, D, E, F, and G represent
 amino acyl residues as described above. A lower alkyl group of one to ten
 carbons, represented by R.sup.1, attaches via a carbonyl moiety to the
 N-terminal nitrogen atom of the representative amino acyl residue A. An
 N-alkylated nitrogen atom forms an amide bond with the C-terminal carbon
 atom of the representative amino acyl residue G.
 Compounds of the invention provide LHRH analogs wherein the 10 to 8 amino
 acids from the C-terminus carboxylic acid moiety of a decapeptide LHRH
 antagonist sequence is eliminated. The compounds exhibit effective LHRH
 antagonist activity and are useful in treating disorders related to high
 levels of reproductive hormones. The lower molecular weight of the present
 compounds allows for improved oral bioavailability in administering
 treatment for various hormone-dependent diseases.
 As used herein, the term "lower alkyl" refers to straight or branched chain
 alkyl radicals containing from 1 to 10 carbon atoms including, but not
 limited to methyl, ethyl, n-propyl, isopropyl (Isp), n-butyl (nBu),
 isobutyl, sec-butyl, t-butyl, diethyl, and the like.
 Unless otherwise indicated by the "D" prefix, the stereochemistry of the
 alpha-carbon atom of the amino acids and aminoacyl residues in peptides
 described in this specification and the appended claims is the natural or
 "L" configuration.
 As set forth above, the conventional abbreviations for the various common
 amino acids are used as generally accepted in the art and as recommended
 by the IU-IUB Commission on Biochemical Nomenclature, Biochemistry II,
 1726 (1972). These represent L-aminoacids, with the exception of the
 achiral amino acid glycine, and with the further exception of any
 unnatural or natural amino acids which are achiral, or otherwise
 designated as D-. All peptide sequences mentioned herein are written
 accordingly to the generally accepted convention whereby the N-terminal
 amino acid is on the left and the C-terminal amino acid is on the right.
 Further information on the nomenclature of peptides is described in Pure
 Appl. Chem., 56:595 (1984).
 Other abbreviations which are useful in describing the invention are the
 following:

Amino acids, protecting groups, reagents Abbreviation
 3-(1-naphthyl)-D-alanyl D1Nal
 3-(2-naphthyl)-D-alanyl D2Nal
 3-(3-pyridyl)-D-alanyl D3Pal
 N-acetyl-[3-(2-naphthyl)-D-alanyl] NAcD2Nal
 Arginyl Arg
 D-arginyl DArg
 D-asparaginyl DAsn
 D-citrullyl DCit
 Cyclohexylalanyl Cha
 D-glutamyl DGln
 D-2-amino-6-N.sup.G,N.sup.G -diethylguanidinohexanoyl DHarg(Et.sub.2)
 D-homocitrullyl DHcit
 (N-epsilon-nicotinyl)lysyl Lys(Nic)
 (N-epsilon-nicotinyl)-D-lysyl DLys(Nic)
 N-methyltyrosyl NMeTyr
 Leucyl Leu
 N-methylleucyl NMeLeu
 Phenylalanyl Phe
 [4-(N-acetyl)]-phenylalanyl Phe(4-NAc)
 [3-(4-chloro)]-D-phenylalanyl D4ClPhe
 N-methylphenylalanyl NMePhe
 [4-(N-acetyl)]-N-methylphenylalanyl NMePhe(4-NAc)
 [4-(N-nitro)]-N-methylphenylalanyl NMePhe(4-NO.sub.2)
 [4-(3-amino-1,2,4-triazol-5-yl)]-N-methylphenylalanyl NMePhe(4-Atza)
 [4-(N-acetyl)]-D-phenylalanyl DPhe(4-NAc)
 [4-(3-amino-1,2,4-triazol-5-yl)]phenylalanyl Phe(Atza)
 [4-(3-amino-1,2,4-triazol-5-yl)]-D-phenylalanyl DPhe(4-Atza)
 Sarcosyl Sar
 Seryl Ser
 1,2,3,4-tetrahydroisoquinoline-3-carbonyl Tic
 D-tryptyl DTrp
 Tyrosyl Tyr
 The compounds of the present invention are useful in modulating levels of
 gonadotropin and androgen secretion in mammals. The compounds are
 particularly useful for their activity as LHRH antagonists or agonists.
 The term "pharmaceutically acceptable salt" as used herein refers to acid
 addition salts of the compounds of formula (I) which are, within the scope
 of sound medical judgement, suitable for use in contact with the tissues
 of mammals, including humans and lower animals, without undue toxicity,
 irritation, allergic response, and the like commensurate with a reasonable
 benefit/risk ratio, and which are effective for their intended use.
 Pharmaceutically acceptable salts are well known in the art, and are
 summarized in S. M. Berge, et al., J. Pharmaceutical Sciences 66:1-19
 (1977). The salts can be prepared in situt during the final isolation and
 purification of the compounds of the invention, or separately by reacting
 the free base function with a suitable organic acid. Examples of
 pharmaceutically acceptable, nontoxic acid addition salts of an amino
 group formed with inorganic acids such as hydrochloric acid, hydrobromic
 acid, phosphoric acid, sulfuric acid and perchloric acid or with organic
 acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric
 acid, succinic acid or malonic acid or by using other methods used in the
 art such as ion exchange. Other pharmaceutically acceptable salts include
 adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
 bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
 cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,
 formate, fumarate, glucoheptonate, glycerophosphate, gluconate,
 hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate,
 lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate,
 methanesulfonate, 2-naphthalene-sulfonate, nicotinate, nitrate, oleate,
 oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate,
 phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,
 tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,
 and the like. Representative alkali or alkaline earth metal salts include
 sodium, lithium, potassium, calcium, magnesium, and the like. Further
 pharmaceutically acceptable salts include, when appropriate, non-toxic
 ammonium, quaternary ammonium, and amine cations formed using counterions
 such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate,
 loweralkylsulfonate and aryl sulfonate.
 The term "pharmaceutically acceptable ester" as used herein refers to
 non-toxic esters of the compounds of formula (I) derived by the
 condensation of a compound of the invention with an alcohol. Examples of
 pharmaceutically acceptable, non-toxic esters of the compounds of the
 invention include C.sub.1 to C.sub.6 alkanoyl esters wherein the alkanoyl
 group is a straight or branched chain, such as formate, acetate,
 propanoate, butyrate, isopropanoate, pentanoate, hexanoate, and the like.
 Esters of the compounds of the present invention may be prepared according
 to conventional methods.
 The term "pharmaceutically acceptable prodrug" as used herein refers to
 biolabile compounds or derivatives which, upon delivery or administration
 to a treatment subject, are converted to in vivo parent compounds of the
 formula (I) above. Prodrugs of compounds of the invention are suitable for
 use in contact with the tissues of mammals, including humans and lower
 animals, without undue toxicity, irritation, allergic response, and the
 like commensurate with a reasonable benefit/risk ratio as determined by
 one of ordinary skill in the medical arts within the scope of sound
 medical judgement, and which are effective for their intended use, as well
 as the zwitterionic forms, where possible, of the compounds of the
 invention. Prodrugs are well-known in the art, and generally refers to
 compounds that are rapidly transformed in vivo to yield the parent
 compound of formula (I), for example by hydrolysis in blood. A summary of
 the art is described in T. Higuchi and V. Stella, "Pro-drugs as Novel
 Delivery Systems," Vol. 14 of the A. C. S. Symposium Series and in
 Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American
 Pharmaceutical Association and Pergamon Press, 1987. Such prodrugs are
 readily apparent to one of ordinary skill in the art and can be regarded
 as functional equivalents of the compounds of the invention.
 Where appropriate, prodrugs of derivatives of compounds of the present
 invention may be prepared by any suitable method. For those compounds in
 which the prodrug moiety is an amino acid or peptide functionality, the
 condensation of the amino group with amino acids and peptides may effected
 in accordance with conventional condensation methods such as the azide
 method, the mixed acid anhydride method, the DCC
 (dicyclohexylcarbodiimide) method, the active ester method (p-nitrophenyl
 ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester
 method, and the like), the Woodward reagent K method, the DCC-HOBT
 (1-hydroxybenzotriazole) method and the like. Classical methods for amino
 acid condensation reactions are described in M. Bodansky, Y. S. Kausner
 and M. A. Ondetti, Peptide Synthesis, Second Edition, N.Y., 1976.
 Representative of the invention are compounds of formula (I), or a
 pharmaceutically acceptable salt, ester or prodrug thereof, wherein
 R.sup.1 is acetyl; A is 3-(2-naphthyl)-D-alanyl; B is
 [3-(4-chloro)]-D-phenylalanyl; C is 3-(3-pyridyl)-D-alanyl; D is seryl; E
 is N-methyltyrosyl; F is (N-epsilon-nicotinyl)-D-lysyl; G is leucyl; and
 R.sup.2 is of the formula --NR.sup.4 R.sup.5, wherein R.sup.4 is hydrogen,
 and R.sup.5 is selected from the group consisting of isopropyl, butyl,
 diethyl, and lower alkyl-R.sup.6, wherein R.sup.6 is selected from the
 group consisting of amino, guanidino, hydrogen, hydroxy, phenyl,
 morpholinyl, piperidinyl, methyl-piperidinyl, pyrrolyl, methylpyrrolyl,
 pyridyl, pyrrolidinyl, methylpyrrolidinyl, pyrrolidinonyl, and
 quinuclidinyl.
 Other representative compounds of the invention are compounds of formula
 (I), or a pharmaceutically acceptable salt, ester or prodrug thereof,
 wherein R.sup.1 is acetyl; A is 3-(2-naphthyl)-D-alanyl; B is
 [3-(4-chloro)]-D-phenylalanyl; C is 3-(3-pyridyl)-D-alanyl; D is seryl; E
 is an amino acyl residue selected from the group consisting of arginyl;
 (N-epsilon-nicotinyl)lysyl; N-methylphenylalanyl;
 [4-(3-amino-1,2,4-triazol-5-yl)]phenylalanyl;
 [4-(3-amino-1,2,4-triazol-5-yl)]-N-methylphenylalanyl;
 [4-(N-acetyl)]-N-methylphenylalanyl; [4-(N-nitro)]-N-methylphenylalanyl;
 [4-(N-acetyl)]-phenylalanyl; tyrosyl; and
 1,2,3,4-tetrahydroisoquinoline-3-carbonyl; F is an amino acyl residue
 selected from the group consisting of D-arginyl; D-asparaginyl;
 D-citrullyl; D-glutamyl; D-homocitrullyl; D-2-amino-6-N.sup.G N.sup.G
 -diethylguanidinohexanoyl;
 [4-(3-amino-1,2,4-triazol-5-yl)]-D-phenylalanyl;
 [4-(N-acetyl)]-D-phenylalanyl; and D-tryptyl; G is leucyl; and R.sup.2 is
 of the formula --NR.sup.4 R.sup.5, wherein R.sup.4 is hydrogen, and
 R.sup.5 is selected from the group consisting of isopropyl, butyl,
 diethyl, and lower alkyl-R.sup.6, wherein R.sup.6 is selected from the
 group consisting of amino, guanidino, hydrogen, hydroxy, phenyl,
 morpholinyl, piperidinyl, methylpiperidinyl, pyrrolyl, methylpyrrolyl,
 pyridyl, pyrrolidinyl, methylpyrrolidinyl, pyrrolidinonyl, and
 quinuclidinyl.
 Yet other representative compounds of the invention are compound of formula
 (I), or a pharmaceutically acceptable salt, ester or prodrug thereof,
 wherein R.sup.1 is acetyl; A is 3-(2-naphthyl)-D-alanyl; B is
 [3-(4-chloro)]-D-phenylalanyl; C is 3-(3-pyridyl)-D-alanyl; D is seryl; E
 is an amino acyl residue selected from the group consisting of arginyl;
 (N-epsilon-nicotinyl)lysyl; N-metihylpheniylalanyl;
 [4-(3-amino-1,2,4-triazol-5-yl)]phenylalanyl;
 [4-(3-amino-1,2,4-triazol-5-yl)]-N-methylphenylalanyl;
 [4-(N-acetyl)]-N-methylphenylalanyl; [4-(N-nitro)]-N-methylphenylalanyl;
 [4-(N-acetyl)]-phenylalanyl; tyrosyl; and
 1,2,3,4-tetrahydroisoquinoline-3-carbonyl; F is an amino acyl residue
 selected from the group consisting of D-arginyl: D-asparaginyl;
 D-citrullyl; D-glutamyl; D-homocitrullyl; D-2-amino-6-N.sup.G,N.sup.G
 -diethylcuanidinohexanoyl;
 [4-(3-amino-1,2,4-triazol-5-yl)]-D-phenylalanyl;
 [4-(N-acetyl)]-D-phenylalanyl; and D-tryptyl; G is leucyl; and R.sup.2 is
 a group of the formula --NH--(CH.sub.2).sub.2 -(1-pyrrolidine).
 Representative examples of compounds contemplated as within the scope of
 the present invention include, but are not limited to the following:
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH-nBu;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-N(CH.sub.2 CH.sub.3).sub.2
 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.6
 NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4
 NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 OH;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -phenyl;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH-isopropyl;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.7
 NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.6
 NH(C.dbd.NH)NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH-isopropyl;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH(C.dbd.NH)NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.3
 NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH(C.dbd.NH)NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.10
 NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.8
 NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NHCH.sub.3 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.8
 NH(C.dbd.NH)NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.10
 NH-isopropyl;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4
 NH(C.dbd.NH)NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4
 NH(C.dbd.NH)NH.sub.2 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 -(2-pyridine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 -(3-pyridine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(3-quinuclidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 -(1-piperidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 -(1-morpholine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 -(2-pyridine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 -[2-(1-methyl)pyrrole];
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 -[2-(1-methyl)pyrrolidine];
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 CH.sub.2 -(1-morpholine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 CH.sub.2 --N[(2-methyl)piperidine];
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 CH.sub.2 -(1-pyrrolidin-2-one);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 --CH.sub.2 CH.sub.2 OH;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH(CH.sub.2).sub.9 NH.sub.2
 ;
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DCit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DCit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-DLys(Nic)-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Arg-DTrp-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tic-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcSar-D4ClPhe-D1Nal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DArg-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-NAc)-DPhe(4-NAc)-Leu-NH--(CH.sub.2).
 sub.2 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-NO.sub.2)-DCit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Phe(4-Atza)-DPhe(4-Atza)-Leu-NH--(CH.sub.2).sub.
 2 -(1-pyrrolidine);
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-Atza)-DPhe(4-Atza)-Leu-NH--(CH.sub.2).
 sub.2 -(1-pyrrolidine); and
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Phe(4-NAc)-DPhe(4-NAc)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine).
 Another aspect of the present invention relates to pharmaceutical
 compositions comprising a compound of the present invention as the active
 ingredient and a pharmaceutically acceptable carrier. Pharmaceutically
 acceptable carriers suitable for the pharmaceutical compositions of the
 invention comprise non-toxic compatible substances useful for preparing a
 composition for administering the compound to a mammal in need of
 treatment.
 Suitable pharmaceutically acceptable carriers generally include, but are
 not limited to, non-toxic, inert solid, semi-solid, or liquid filler,
 diluent, encapsulating material or formulation auxiliary of any type.
 Exemplary material which can serve as pharmaceutically acceptable carriers
 are sugars, such as lactose, glucose, and sucrose; starches, such as corn
 starch and potato starch; cellulose and its derivatives, such as sodium
 carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered
 tragacanth; malt; gelatin; talc, excipients such as cocoa butter and
 suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil,
 sesame oil, olive oil, corn oil and soybean oil; glycols, such as
 propylene glycol; polyols such as glycerin, sorbitol, mannitol, and
 polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar;
 buffering agents such as magnesium hydroxide and aluminum hydroxide;
 alginic acid; pyrogen-free water; isotonic saline; Ringer's solution;
 ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic
 compatible substances used in pharmaceutical formulations. Wetting agents,
 emulsifiers and lubricants such as sodium lauryl sulfate and magnesium
 stearate, as well as coloring agents, releasing agents, coating agents,
 sweetening, flavoring and perfuming agents, preservatives and antioxidants
 can also be present in the pharmaceutically acceptable composition.
 In another aspect of the invention, the invention relates to a method of
 modulating gonadotropic hormones in a mammal comprising administering to a
 mammal in need of such treatment a therapeutically effective amount of a
 compound as defined above. Condition for which an amount of the compound
 may be effective can be described as excessive tissue swelling, precocious
 puberty, hormonal imbalance, and other related conditions. Exemplary known
 symptoms and conditions for which the compounds are useful in treating
 include, but are not limited to, benign prostate hypertrophy,
 dysmenorrhea, endometriosis, precocious puberty, prostate cancer, uterine
 fibroids, prostate necrosis, and other sex hormone dependent diseases.
 These compounds provide novel peptides for treatment regimens useful in
 treating such conditions.
 Compounds of the invention are administered to a mammal in need of such
 treatment by any of a variety of routes depending on the specific end use.
 Generally, the means for administering the peptide to a mammal will be a
 method selected from treatments consisting of oral, parenteral, vaginal,
 rectal, buccal (including sublingual), transdermal, and intranasal
 administration. Parental routes of administration include, but are not
 limited to subcutaneously, intramuscularly, and intravenously. The exact
 method and route of administration can be determined by one of ordinary
 skill in the medical arts having knowledge and the ability to develop a
 reasoned judgment as to the form of treatment administered to the mammal
 in need of treatment.
 The exact dose and regimen for administration may depend on a variety of
 any factors including, but not limited to, the need of the individual
 subject being treated, the type of treatment, the degree of affliction or
 need, and length and frequency of the treatment. Generally, dosage for the
 treatment is between about 0.01 and 10 milligram of the active ingredient
 per kilogram body weight per day. Preferably, in light of the general
 expediency of the treatment, the dose administered is from about 0.1 to
 about 5.0 mg/kg body weight per day. The administration may be
 accomplished in a single, daily administration or by distributing doses
 over several applications or by slow release in order to achieve the most
 effective results.
 GENERAL PROCEDURE FOR PEPTIDE SYNTHESIS
 Peptides of the present invention may be prepared by any techniques that
 are known to those skilled in the art. Commonly employed methods known in
 the art of peptide synthesis generally referred to as "solid phase"
 peptide synthesis, wherein sequential coupling of amino acids is
 accomplished attached to an inert solid support, and "solution phase"
 synthesis, the technique wherein amino acids are coupled in solution.
 Solid phase methods of synthesis on a support resin are described in J. M.
 Steward and J. D. Young, Solid Phase Peptide Synthesis, W. H. Freeman Co.,
 San Francisco, 1963; and J. Meienhofer, Hormonal Proteins and Peplides,
 Vol. 2, p. 46, Academic Press (New York), 1973. Summary of classical
 solution phase synthesis techniques is recited in G. Schroder and K.
 Lupke, The Peptides, vol. 1, Academic Pressure (New York), 1965, and "The
 Practice of Peptide Synthesis" by M. Bodansky and Bodansky, A.
 Starting materials used in these general methods of peptide synthesis
 comprise a suitable resin and one or more amino acids or derivatives
 thereof. Naturally occurring and commonly protected amino acids are
 commercially available or, alternatively, can be prepared with readily
 available starting materials by methods commonly known in the art.
 The peptide is synthesized in solution by methods known to those with skill
 in the art. The methods are described in "The Practice of Peptide
 Synthesis" by M. Bodansky and Bodansky, A. Briefly, an amino acid is
 N-protected with a protecting group and is coupled to the next N-free
 amino acid with a suitable coupling reagent (described below) at 0.degree.
 C. to ambient temperatures for about 1 to about 5 hours to afford a
 dipeptide fragment. The dipeptide fragment is deprotected to afford a free
 amine terminus and a subsequent protected amino acid is coupled to the
 fragment under the coupling conditions previously described.
 Suitable protecting groups are selected from the group consisting of
 hydroxy protecting groups. Exemplary suitable protecting groups include,
 but are not limited to, t-butyloxy-carbonyl (BOC), benzyloxycarbonyl
 (Cbz), biphenylisopropyloxycarbonyl, t-amyloxycarbonyl,
 isobornyloxycarbonyl,
 (alpha,alpha)-dimethyl-3,5-dimethoxybenzyloxycarbonyl,
 o-nitrophenylsulfenyl,
 2-cyano-t-butyloxycarbonyl-9-fluoroenylmethyloxycarbonyl (FMOC), and the
 like. The preferred protecting group is t-butyloxycarbonyl.
 Coupling reagents suitable for the amino acid coupling are selected from
 the group consisting of N,N'-dicyclohexylcarbodiimide or
 N,N'-diisopropylcarbodiimide (DIC) with or without 1-hydroxybenzotriazole
 (HOBT),
 benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium-hexafluorophosphate
 (BOP) and bis-(2-oxo-3-oxazolidinyl)phosphine chloride (BOPCl). The
 preferred reagent is N,N'-dicyclohexylcarbodiimide.
 Deprotecting reagents suitable for removing the protecting groups are
 anhydrous liquid hydrogen fluoride in the presence of anisole and
 dimcthylphosphite or other carbonium ion scavenger, hydrogen
 fluoride/pyridine complex, tris(tri-fluoroacetyl)boron and trifluoroacetic
 acid, hydrogen and palladium on carbon on polyvinylpyrrolidone, sodium in
 liquid ammonia. Preferably, the deprotecting agent is liquid hydrogen
 fluoride in the presence of anisole and dimethylphosphite.
 In the solid phase synthesis, a solid support provides an inert surface to
 which an amino acid is attached. The solid support materials, typically
 resins, are inert to the reagents and reaction conditions of the peptide
 linkage formation as well as conditions for cleaving the final peptide
 from the solid support. Suitable solid supports useful for the above
 synthesis are chloromethylpolystyrene-divinylbenzene polymer,
 hydroxymethylpolystyrene-divinylbenzene polvmer,
 benzyldrylaminopolystyrene-divinylbenzene polymer, and the like.
 Preferably, the support is chloromethyl-polystyrene-1% divinylbenzene
 polymer.
 Typically, the amino acid is protected or derivatized before attaching the
 amino acid to the resin. As used in the description of the general
 procedures for the peptide synthesis, the term "amino acid" refers to
 amino acids, salts, esters and derivatives thereof suitable for sequencing
 in a peptide synthesis as determined by one of ordinary skill in the art.
 The amino acid residues are attached to the resin or a formed polypeptide
 chain as a salt to synthesis the polypeptide chain having the desired
 sequence and having the desired length. Suitable salts of the amino acid
 are cesium, tetramethylammonium, triethyl-ammonium,
 1,5-diazabicyclo-[5.4.0]undec-5-ene salts, or the like. Preferably, the
 amino acid is coupled with the solid support as a cesium salt.
 Protecting groups preferred for preparing the peptides provide stable
 moieties for protecting the alpha-amino function of the amino acids. The
 protecting groups used generally have properties of being stable to
 conditions of peptide linkage formation and can be readily removed without
 destruction of the growing peptide chain or racemization of any of the
 chiral centers contained therein. Suitable protecting groups are hydroxy
 protecting groups as described in the solution phase synthesis.
 Coupling of the protected amino acid to the support is accomplished in an
 inert solvent. Solvents suitable for the coupling reaction include, but
 are not limited to, ethanol, dichloromethane, methylene chloride,
 acetonitrile. N,N-dimethyl-formamide (DMF), and the like, or a mixture
 thereof. Preferably, the solvent is ethanol or dimethylformamide.
 Typically, the reaction is carried out between about 40.degree. C. and
 60.degree. C., from about 12 to about 48 hours. The preferred reaction is
 accomplished in DMF at about 50.degree. C. for about 24 hours.
 Coupling of subsequent protected amino acid residues and derivatives can be
 accomplished using an automatic peptide synthesizer. These synthesizers
 are well-known in the art. Coupling of the attached amino acid and residue
 with additional amino acids involves reacting the attached amino acid with
 a suitable coupling reagent for about 1 to 24 hours. Preferably, the
 reaction is carried out for 12 hours at a temperature of between
 10.degree. C. and 50.degree. C. in the inert solvent. Each protected amino
 acid is introduced in 0.4 M concentration and approximately 3.5 molar
 excess. Preferably, the coupling reaction is carried out in a 1:1 mixture
 of dichloromethane and DMF at ambient temperatures. Suitable coupling
 agents are described in accordance with the preparation of compounds of
 the invention in solution phase.
 Cleaving the polypeptide chain by aminolysis removes the final peptide
 chain from the solid support. Preferred cleaving reagents are alkylamines
 or fluoroalkylamines in the presence or absence of boron tribromide. The
 most preferred is 1-(2-aminoethyl)-pyrrolidine.
 Deprotection is usually accomplished under anhydrous strong acidic
 conditions that remove the protecting groups without destroying the formed
 peptide chain or degrading the acid sensitive moieties present on the
 peptide chain. Preferred temperatures for carrying out the deprotection
 reaction are from about -10.degree. C. to about +10.degree. C. The most
 preferred reaction is carried out at 0.degree. C. for about 30 minutes
 with a deprotecting agent as described in the solution phase synthesis.

Procedures of the invention can be better understood in accordance with the
 Examples. The Examples are meant to merely illustrate compounds and
 processes which can be carried out in accordance with invention are not
 meant to be limiting in any way.
 EXAMPLES
 Example 1
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH-nBu
 A solution of
 NAcD2Nal-D4ClPhe-D3Pal-Ser(OBzl)-NMeTyr(OBzl)-DLys(Nic)-Leu-OH (0.266 g)
 in THF (5 ml), synthesized by conventional solution peptide synthesis
 methods as described in "The Practice of Peptide Synthesis" by M. Bodansky
 and Bodansky, A., which is herein incorporated by reference, was treated
 at -20.degree. C. with isobutylchloroformate (0.03 ml), triethylamine
 (0.075 ml) and n-butylamine (0.05 ml). The reaction mixture was stirred at
 room temperature for one hr, then poured into a saturated solution of
 sodium bicarbonate and stirred overnight. The solid precipitate was
 filtered, washed with water and dried in vacuo over P.sub.2 O.sub.5. The
 dried solid was treated with anhydrous anisole (1 ml) and anhydrous HF (5
 ml) at 0.degree. C. for 1 hour. The excess of reagent was removed in
 vacuo, the residue was washed with ether and then purified by HPLC using
 C-18 reverse phase column and running a gradient, over 30 minutes, of
 25-50% acetonitrile/water containing 0.1% trifluoroacetic acid. The
 desired product, NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH-nBu,
 was obtained as trifluoroacetate salt: R.sub.t =25.6 min; FAB Mass spec
 for C.sub.67 H.sub.82 N.sub.11 O.sub.11 Cl m/z 1252 (M+1); Amino Acid
 Anal: 0.35 Ser; 1.06 NMeTyr; 1.00 Leu; 0.78 3Pal; 1.29 4ClPhe; 1.00 Lys.
 Example 2
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH.sub.2
 A solution of
 NAcD2Nal-D4ClPhe-D3Pal-Ser(OBzl)-NMeTyr(OBzl)-DLys(Nic)-Leu-OBzl (0.2185
 g) in THF (3 ml), synthesized by conventional solution peptide synthesis
 methods, as described in "The Practice of Peptide Synthesis" by M.
 Bodansky and Bodansky, A., was treated at room temperature with
 diaminoethane (0.05 ml). The reaction mixture was stirred for three days
 at room temperature, then diluted with ethyl acetate, washed with
 bicarbonate and brine solutions, dried and concentrated in vacuo. The
 residue was dried over P.sub.2 O.sub.5 overnight and then was treated with
 anhydrous anisole (1 ml) and anhydrous HF (5 ml) at 0.degree. C. for 1
 hour. The excess of reagent was removed in vacuo, the residue was washed
 with ether and then purified by HPLC using C-18 reverse phase column and
 running a gradient, over 30 minutes, of 25-50% acetonitrile/water
 containing 0.1% trifluoroacetic acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =19.5 min; FAB
 Mass spec for C.sub.65 H.sub.79 N.sub.12 O.sub.11 Cl showed (M+1) @1239
 m/z; Amino Acid Anal.: 0.36 Ser; 1.01 NMeTyr; 1.06 Leu; 0.77 3Pal; 1.23
 4ClPhe; 1.00 Lys.
 Example 3
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 According to the procedure described in Example 1, a THF solution (3 ml) of
 NAcD2Nal-D4ClPhe-D3Pal-Ser(OBzl)-NMeTyr(OBzl)-DLys(Nic)-Leu-OH (0.234 g)
 was treated at -20 .degree. C. with isobutylchloroformate (0.03 ml),
 triethylamine (0.075 ml) and 1-(2-aminoethyl)pyrrolidine (0.03 ml). The
 reaction mixture was stirred at room temperature for ten days. The
 solvents and excess of reagents were removed in vacuo. The residue was
 dried in vacuo over P.sub.2 O.sub.5 and then treated with anhydrous
 anisole (1 ml) and anhydrous HF (5 ml) at 0.degree. C. for 1 hour. The
 excess of reagent was removed in vacuo, the residue was washed with ether
 and then purified by HPLC using C-18 reverse phase column and running a
 gradient, over 30 minutes, of 25-50% acetonitrile/water containing 0.1%
 trifluoroacetic acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), was obtained as trifluoroacetate salt: R.sub.t =21.2
 min; FAB Mass spec for C.sub.69 H.sub.85 N.sub.12 O.sub.11 Cl showed (M+H)
 @1293 m/z; Amino Acid Anal.: 0.36 Ser; 1.04 NMeTyr; 0.98 Leu; 0.78 3Pal;
 1.25 4ClPhe; 1.02 Lys.
 Example 4
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-N(CH.sub.2 CH.sub.3).sub.2
 According to the procedure described in Example 1, a THF (3.5 ml) solution
 of NAcD2Nal-D4ClPhe-D3Pal-Ser(OBzl)-NMeTyr(OBzl)-DLys(Nic)-Leu-OH (0.234
 g) was treated at -20.degree. C. with isobutylchloroformate (0.03 ml),
 triethylamine (0.075 ml) and diethylamine (0.03 ml). The reaction mixture
 was stirred at room temperature for ten days. The solvents and excess of
 reagents were removed in vacuo. The residue was dried in vacuo over
 P.sub.2 O.sub.5 and then treated with anhydrous anisole (1 ml) and
 anhydrous HF (5 ml) at 0.degree. C. for 1 hour. The excess of reagent was
 removed in vacuo, the residue was washed with ether and then purified by
 HPLC using C-18 reverse phase column and running a gradient, over 30
 minutes, of 25-50% acetonitrile/water containing 0.1% trifluoroacetic
 acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-N(CH.sub.2
 CH.sub.3).sub.2, was obtained as trifluoroacetate salt: R.sub.t =28.4 min;
 FAB Mass spec for C.sub.67 H.sub.82 N.sub.11 O.sub.11 Cl showed (M+H)
 @1252 m/z; Amino Acid Anal.: 0.37 Ser; 1.04 NMeTyr; 0.99 Leu; 0.79 3Pal;
 1.26 4ClPhe; 1.01 Lys.
 Example 5
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.6
 NH.sub.2
 According to the procedure described in Example 2, a DMF solution (3 ml) of
 NAcD2Nal-D4ClPhe-D3Pal-Ser(OBzl)-NMeTyr(OBzl)-DLys(Nic)-Leu-OBzl (0.2213
 g) was treated at room temperature with 1,6-diaminohexane (0.5 ml). The
 reaction mixture was stirred overnight, then poured into water, the
 precipitate was filtered and dried over P.sub.2 O.sub.5 overnight. The dry
 residue was treated with anhydrous anisole (1 ml) and anhydrous HF (5 ml)
 at 0.degree. C. for 1 hour. The excess of reagent was removed in vacuo,
 the residue was washed with ether and then purified by HPLC using C-18
 reverse phase column and running a gradient, over 30 minutes, of 25-50% of
 acetonitrile/water containing 0. 1% trifluoroacetic acid. The desired
 product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.6
 NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =20.2 min; FAB
 Mass spec for C.sub.69 H.sub.87 N.sub.12 O.sub.11 Cl showed (M+1) @1295
 m/z; Amino Acid Anal.: 0.36 Ser; 1.06 NMeTyr; 1.00 Leu; 0.78 3Pal; 1.24
 4ClPhe; 1.00 Lys.
 Example 6
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4
 NH.sub.2
 The procedure described in Example 5 was used, but substituting
 1,4-diamino-butane for 1,6-diaminohexane. After workup and drying of the
 product over P.sub.2 O.sub.5 overnight, the residue was treated with
 anhydrous anisole (1 ml) and anhydrous HF (5 ml) at 0.degree. C. for 1
 hour. The excess of reagent was removed in vacuo. The residue was washed
 with ether and then purified by HPLC using C-18 reverse phase column and
 running a gradient, over 30 minutes, of 25-50% acetonitrile/water
 containing 0.1% trifluoroacetic acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4
 NH.sub.2, was obtained as trifluoroacetate salt. R.sub.t =19.4 min; FAB
 Mass spec for C.sub.67 H.sub.83 N.sub.12 O.sub.11 Cl showed (M+1) @1267
 m/z; Amino Acid Anal.: 0.36 Ser; 1.06 NMeTyr; 0.99 Leu; 0.78 3Pal; 1.25
 4ClPhe; 1.01 Lys.
 Example 7
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 OH
 A solution of
 NAcD2Nal-D4ClPhe-D3Pal-Ser(OBzl)-NMeTyr(OBzl)-DLys(Nic)-Leu-OEt (0.2214 g)
 in DMF (1 ml), synthesized by conventional solution peptide synthesis
 methods as described in "The Practice of Peptide Synthesis" by M. Bodansky
 and Bodansky, A., was treated at room temperature with ethanolamine (1
 ml). The reaction mixture was stirred at room temperature for seven days,
 then poured into a 10% NaHCO.sub.3 solution and stirred for 5 min. The
 precipitate was filtered and then dried over P.sub.2 O.sub.5 overnight and
 then was treated with anhydrous anisole (1 ml) and anhydrous HF (5 ml) at
 0.degree. C. for 1 hour. The excess of reagent was removed in vacuo, the
 residue was washed with ether and then purified by HPLC using C-18 reverse
 phase column and running a gradient, over 30 minutes, of 25-50% of
 acetonitrile/water containing 0.1% trifluoroacetic acid. The desired
 product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 OH,
 was obtained as trifluoroacetate salt: R.sub.t =21.0 min; FAB Mass spec
 for C.sub.65 H.sub.78 N.sub.11 O.sub.12 Cl showed (M+1) @1240 m/z; Amino
 Acid Anal.: 0.38 Ser; 1.00 NMeTyr; 1.02 Leu; 0.66 3Pal; 1.00 4ClPhe; 0.98
 Lys.
 Example 8
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -phenyl
 The procedure described in Example 7 was used, but substituting
 phenethylamine for ethanolamine. After workup and drying over P.sub.2
 O.sub.5 overnight, the dry residue was treated with anhydrous anisole (1
 ml) and anhydrous HF (5 ml) at 0.degree. C. for 1 hour. The excess of
 reagent was removed in vacuo. The residue was washed with ether and then
 purified by HPLC using C-18 reverse phase column and running a gradient of
 25-50%, over 30 minutes, of acetonitrile/water containing 0.1%
 trifluoroacetic acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -phenyl, was obtained as trifluoroacetate salt: R.sub.t =30.4 min; FAB
 Mass spec for C.sub.71 1H.sub.82 N.sub.11 O.sub.11 Cl showed (M+1) @1300
 m/z; Amino Acid Anal.: 0.36 Ser; 1.06 NMeTyr; 0.99 Leu; 0.78 3Pal; 1.25
 4ClPhe; 1.01 Lys.
 Example 9
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH-isopropyl
 NAcD2Nal-D4ClPhe-D3Pal-Ser(OBzl)-NMeTyr(OBzl)-DLys(Nic)-Leu-OBzl (0.2213 g)
 was treated at room temperature with 2-aminoethyl-N-isopropylamine (1.0
 ml). The reaction mixture was stirred for two days, then was poured into
 10% NaHCO.sub.3 solution, the precipitate was filtered, dissolved in (1:1)
 acetonitrile/water and lyophilized. The dry residue was treated with
 anhydrous anisole (1 ml) and anhydrous HF (5 ml) at 0.degree. C. for 1
 hour. The excess of reagent was removed in vacuo, the residue was washed
 with ether and then purified by HPLC using C-18 reverse phase column and
 running a gradient, over 30 minutes, of 25-50% acetonitrile/water
 containing 0.1% trifluoroacetic acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH-isopropyl, was obtained as trifluoroacetate salt: R.sub.t =19.2 min;
 FAB Mass spec for C.sub.68 H.sub.85 N.sub.12 O.sub.11 Cl showed (M+1)
 @1281 m/z; Amino Acid Anal.: 0.39 Ser; 0.93 NMeTyr; 1.02 Leu; 0.65 3Pal;
 0.99 4ClPhe; 0.98 Lys.
 Example 10
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH2).sub.7 NH.sub.2
 The procedure described in Example 9 was used, but substituting
 1,7-diamino-heptane for 2-aminoethyl-N-isopropylamine (1.0 ml). The
 reaction mixture was stirred for two days, then was poured into 10%
 NaHCO.sub.3 solution, the precipitate was filtered, dissolved in (1:1)
 acetonitrile/water and lyophilized. The dry residue was treated with
 anhydrous anisole (1 ml) and anhydrous HF (5 ml) at 0.degree. C. for 1
 hour. The excess of reagent was removed in vacuo, the residue was washed
 with ether and then purified by HPLC using C-18 reverse phase column and
 running a gradient, over 30 minutes, of 25-50% acetonitrile/water
 containing 0.1% trifluoroacetic acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.7
 NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =21.0 min; FAB
 Mass spec for C.sub.70 H.sub.89 N.sub.12 O.sub.11 Cl showed (M+1) @1309
 m/z; Amino Acid Anal.: 0.38 Ser; 0.98 NMeTyr; 1.01 Leu; 0.66 3Pal; 1.00
 4ClPhe; 0.99 Lys.
 Example 11
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.6
 NH(C.dbd.NH)NH.sub.2
 A solution of
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.6
 NH.sub.2 (0.050 g) in DMF (1 ml) was treated with triethylamine (0.025 ml)
 and 3,5-dimethylpyrazole-1-carboxyamidine nitrate (0.050 g) at room
 temperature with stirring. The reaction mixture was stirred overnight and
 then concentrated in vacuo. The residue was poured into a 10% NaHCO.sub.3
 solution and stirred for 15 min. The precipitate was filtered and then
 dissolved in (1:1) acetonitrile/water and lyophilized. The dry residue was
 treated with anhydrous anisole (1 ml) and anhydrous HF (5 ml) at 0.degree.
 C. for 1 hour. The excess of reagent was removed in vacuo, the residue was
 washed with ether and then purified by HPLC using C-18 reverse phase
 column and rumning a gradient, over 30 minutes, of 25-50%
 acetonitrile/water containing 0.1% trifluoroacetic acid. The desired
 product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.6
 -NH(C.dbd.NH)NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t
 =21.6 min; FAB Mass spec for C.sub.70 H.sub.89 N.sub.14 O.sub.11 Cl showed
 (M+1) @1337 m/z; Amino Acid Anal.: 0.45 Ser; 1.05 NMeTyr; 1.01 Leu; 0.66
 3Pal; 1.00 4ClPhe; 0.99 Lys.
 Example 12
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-1-Leu-NH--(CH.sub.2).sub.5
 NH-isopropyl
 A solution of
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4
 NH.sub.2 (0.074g) in ethanol (1 ml) was treated with sodium
 cyanoborohydride (0.0145 g) in the presence of acetone (2 ml). The
 reaction mixture was stirred at room temperature overnight, then was
 poured into a 10% solution of NaHCO.sub.3 and stirred for 15 minutes. The
 precipitate was filtered, dissolved in (1:1) acetonitrile/water and
 lyophilized. The dry powder was treated with anhydrous anisole (1 ml) and
 anhydrous HF (5 ml) at 0.degree. C. for 1 hour. The excess of reagent was
 removed in vacuo. The residue was washed with ether and then purified by
 HPLC using C-18 reverse phase column and running a gradient, over 30
 minutes, of 25-50% acetonitrile/water containing 0.1% trifluoroacetic
 acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH-isopropyl, was obtained as trifluoroacetate salt: R.sub.t =21.1 min;
 FAB Mass spec for C.sub.71 H.sub.91 N.sub.12 O.sub.11 Cl showed (M+1)
 @1323 m/z; Amino Acid Anal.: 0.44 Ser; 0.98 NMeTyr; 1.01 Leu; 0.66 3Pal;
 1.01 4ClPhe; 0.99 Lys.
 Example 13
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH.sub.2
 The procedure described in Example 7 was used, but substituting
 1,5-diamino-pentane for ethanolamine. The reaction mixture was stirred at
 room temperature overnight, then was poured into a 10% solution of
 NaHCO.sub.3 and stirred for 15 minutes. The precipitate was filtered,
 dissolved in (1:1) acetonitrile/water and lyophilized. The dry powder was
 treated with anhydrous anisole (1 ml) and anhydrous HF (5 ml) at 0.degree.
 C. for 1 hour. The excess of reagent was removed in vacuo. The residue was
 washed with ether and then purified by HPLC using C-18 reverse phase
 column and running a gradient, over 30 minutes, of 25-50%
 acetonitrile/water containing 0.1% trifluoroacetic acid. The desired
 product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =19.7 min; FAB
 Mass spec for C.sub.6 H.sub.85 N.sub.12 O.sub.11 Cl showed (M+1) @1281
 m/z; Amino Acid Anal.: 0.44 Ser; 1.06 NMeTyr; 1.02 Leu; 0.65 3Pal; 1.11
 4ClPhe; 0.97 Lys.
 Example 14
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH(C.dbd.NH)NH.sub.2
 The procedure described in Example 11 was used, but substituting
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH.sub.2 for
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.6
 NH.sub.2. The guanidino derivative was obtained, and purified by HPLC
 using C-18 reverse phase column and running a gradient, over 30 minutes,
 of 25-50% acetonitrile/water containing 0.1% trifluoroacetic acid. The
 desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH(C.dbd.NH)NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =20.8
 min; FAB Mass spec for C.sub.69 H.sub.87 N.sub.14 O.sub.11 Cl showed (M+1)
 @1322 m/z; Amino Acid Anal.: 0.38 Ser; 0.98 NMeTyr; 1.01 Leu; 0.66 3Pal;
 0.99 4ClPhe; 0.98 Lys.
 Example 15
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.3
 NH.sub.2
 The procedure described in Example 10 was used, but substituting
 1,3-diamino-propane (1.0 ml) for 1,7-diaminoheptane. The reaction mixture
 was stirred for two days, then was poured into 10% NaHCO.sub.3 solution.
 The precipitate was filtered, dissolved in (1:1) acetonitrile/water and
 lyophilized. The dry residue was treated with anhydrous anisole (1 ml) and
 anhydrous HF (5 ml) at 0.degree. C. for 1 hour. The excess of reagent was
 removed in vacuo. The residue was washed with ether and then purified by
 HPLC using C-18 reverse phase column and running a gradient, over 30
 minutes, of 25-50% acetonitrile/water containing 0.1% trifluoroacetic
 acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.3
 NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =19.3 min; FAB
 Mass spec for C.sub.66 H.sub.81 N.sub.12 O.sub.11 Cl showed (M+1) @1253
 m/z; Amino Acid Anal.: 0.43 Ser; 1.04 NMeTyr; 1.02 Leu; 0.65 3Pal; 0.99
 4ClPhe; 0.98 Lys.
 Example 16
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH(C.dbd.NH)NH.sub.2
 Using the procedure described in Example 14, but substituting
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH.sub.2 for
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH.sub.2. The guanidino derivative was obtained, and purified by HPLC
 using C-18 reverse phase column and running a gradient, over 30 minutes,
 of 25-50% acetonitrile/water containing 0.1% trifluoroacetic acid. The
 desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH(C.dbd.NH)NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =19.5
 min; FAB Mass spec for C.sub.66 H.sub.81 N.sub.14 O.sub.11 Cl showed (M+1)
 @1281 m/z; Amino Acid Anal.: 0.42 Ser; 1.01 NMeTyr; 1.00 Leu; 0.67 3Pal;
 1.01 4ClPhe; 1.00 Lys.
 Example 17
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.10
 NH.sub.2
 The procedure described in Example 10 was used, but substituting
 1,10-diaminodecane (1.0 ml) for 1,7-diaminohexane. The reaction mixture
 was stirred for two days, then was poured into 10% NaHCO.sub.3 solution,
 the precipitate was filtered, dissolved in (1:1) acetonitrile/water and
 lyophilized. The dry residue was treated with anhydrous anisole (1 ml) and
 anhydrous HF (5 ml) at 0.degree. C. for 1 hour. The excess of reagent was
 removed in vacuo, the residue was washed with ether and then purified by
 HPLC using C-18 reverse phase column and running a gradient, over 30
 minutes, of 25-50% acetonitrile/water containing 0.1% trifluoroacetic
 acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.10
 NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =24.4 min; FAB
 Mass spec for C.sub.73 H.sub.95 N.sub.12 O.sub.11 Cl showed (M+1) @1351
 m/z; Amino Acid Anal.: 0.40 Ser; 0.95 NMeTyr; 1.00 Leu; 0.66 3Pal; 1.01
 4ClPhe; 0.99 Lys.
 Example 18
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.8
 NH.sub.2
 The procedure described in Example 10 was used, but substituting
 1,8-diamino-octane (1.0 ml) for 1,10-diaminodecane. The reaction mixture
 was stirred for two days, then was poured into 10% NaHCO.sub.3 solution.
 The precipitate was filtered, dissolved in (1:1) acetonitrile/water and
 lyophilized. The dry residue was treated with anhydrous anisole (1 ml) and
 anhydrous HF (5 ml) at 0.degree. C. for 1 hour. The excess of reagent was
 removed in vacuo, the residue was washed with ether and then purified by
 HPLC using C-18 reverse phase column and running a gradient, over 30
 minutes, of 25-50% acetonitrile/water containing 0.1% trifluoroacetic
 acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.8
 NH.sub.2, was obtained as trifluoroacetate: R.sub.t =21.50 min; FAB Mass
 spec for C.sub.71 H.sub.91 N.sub.12 O.sub.11 Cl showed (M+1) @1323 m/z;
 Amino Acid Anal.: 0.44 Ser; 1.05 NMeTyr; 1.01 Leu; 0.65 3Pal; 1.00 4ClPhe;
 0.99 Lys.
 Example 19
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NHCH.sub.3
 The procedure described in Example 9, was used but substituting
 N-methyl-1,2-diaminoethane (0.5 g) for 2-aminoethyl-N-isopropylamine. The
 reaction mixture was stirred for two days, then was poured into 10%
 NaHCO.sub.3 solution, the precipitate was filtered, dissolved in (1:1)
 acetonitrile/water and lyophilized. The dry residue was treated with
 anhydrous anisole (1 ml) and anhydrous HF (5 ml) at 0.degree. C. for 1
 hour. The excess of reagent was removed in vacuo. The residue was washed
 with ether and then purified by HPLC using C-18 reverse phase column and
 ruiming a gradient, over 30 minutes, of 25-50% acetonitrile/water
 containing 0.1% trifluoroacetic acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 NH--CH.sub.3, was obtained as trifluoroacetate salt: R.sub.t =19.8 min;
 FAB Mass spec for C.sub.66 H.sub.81 N.sub.12 O.sub.11 Cl showed (M+1)
 @1253 m/z; Amino Acid Anal.: 0.44 Ser; 1.03 NMeTyr; 1.01 Leu; 0.66 3Pal;
 1.00 4ClPhe; 0.99 Lys.
 Example 20
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.8
 NH(C.dbd.NH)NH.sub.2
 The procedure described in Example 16 was used, but substituting
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.8
 NH.sub.2 for NAcD
 2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2 NH.sub.2.
 The guanidino derivative was obtained, and purified by HPLC using C-18
 reverse phase column and running a gradient, over 30 minutes, of 25-50%
 acetonitrile/water containing 0.1% trifluoroacetic acid. The desired
 product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.8
 NH(C.dbd.NH)NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =23.8
 min; FAB Mass spec for C.sub.72 H.sub.93 N.sub.14 O.sub.11 Cl showed (M+1)
 @1365 m/z; Amino Acid Anal.: 0.47 Ser; 1.09 NMeTyr; 1.00 Leu; 1.06 3Pal;
 1.07 4ClPhe; 1.00 Lys.
 Example 21
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.10
 NH-isopropyl
 An solution of
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.10
 NH.sub.2 (0.074 g) in ethanol (1 ml) was treated with sodium
 cyanoborohydride (0.0159 g) in the presence of acetone (2 ml). The
 reaction mixture was stirred at room temperature overnight, then was
 poured into a 10% solution of NaHCO.sub.3 and stirred for 15 minutes. The
 precipitate was filtered, dissolved in (1:1) acetonitrile/water and
 lyophilized. The dry powder was treated with anhydrous anisole (1 ml) and
 anhydrous HF (5 ml) at 0.degree. C. for 1 hour. The excess of reagent wvas
 removed in vacuo. The residue was washed with ether and then purified by
 HPLC using C-18 reverse phase column and running a gradient, over 30
 minutes, of 25-50% acetonitrile/water containing 0.1% trifluoroacetic
 acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.10
 NH-isopropyl, was obtained as trifluoroacetate salt: R.sub.t =27.3 min;
 FAB Mass spec for C.sub.76 H.sub.102 N.sub.12 O.sub.11 Cl showed (M+1)
 @1394 m/z; Amino Acid Anal.: 0.48 Ser; 1.02 NMeTyr; 1.00 Leu; 1.06 3Pal;
 1.07 4ClPhe; 1.00 Lys.
 Example 22
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4
 NH(C.dbd.NH)NH.sub.2
 The procedure described in Example 14 was used, but substituting
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4
 NH.sub.2 for
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.5
 NH.sub.2. The guanidino derivative was obtained. and purified by HPLC
 using C-18 reverse phase column and running a gradient, over 30 minutes,
 of 25-50% acetonitrile/water containing 0. 1% trifluoroacetic acid. The
 desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.4
 NH(C.dbd.NH)NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =20.5
 min; FAB Mass spec for C.sub.68 H.sub.85 N.sub.14 O.sub.11 Cl showed (M+1)
 @1309 m/z; Amino Acid Anal.: 0.46 Ser; 1.02 NMeTyr; 1.00 Leu; 1.01 3Pal;
 1.03 4ClPhe; 1.00 Lys.
 Example 23
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 -(2-pyridine)
 A solution of
 NAcD2Nal-D4ClPhe-D3Pal-Ser(OBzl)-NMeTyr(OBzl)-DLys(Nic)-Leu-OBzl (0.154 g)
 in DMF (1 ml) was treated at room temperature with 2-amino-methylpyridine
 (1.0 ml). The reaction mixture was stirred for five days, then was poured
 into 10% NaHCO.sub.3 solution. The precipitate was filtered, dissolved in
 (1:1) acetonitrile/water and lyophilized. The dry residue was treated with
 anhydrous anisole (1 ml) and anhydrous HF (5 ml) at 0.degree. C. for 1
 hour. The excess of reagent was removed in vacuo. The residue was washed
 with ether and then purified by HPLC using C-18 reverse phase column and
 running a gradient, over 30 minutes, of 25-50% acetonitrile/water
 containing 0.1% trifluoroacetic acid. The desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2
 -(2-pyridine), was obtained as trifluoroacetate salt: R.sub.t =21.8 min;
 FAB Mass spec for C.sub.69 H.sub.79 N.sub.12 O.sub.11 Cl showed (M+1)
 @1287 m/z; Amino Acid Anal.: 0.42 Ser; 1.03 NMeTyr; 1.00 Leu; 1.00 3Pal;
 1.04 4ClPhe; 1.00 Lys.
 Example 24
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 -(3-pyridine)
 The procedure described in Example 23 was used, but substituting
 3-amino-methylpyridine for 2-aminomethylpyridine. After workup, cleaving
 of the protecting groups and HPLC purification, the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2
 -(3-pyridine), was obtained as trifluoroacetate salt: R.sub.t =21.2 min;
 FAB Mass spec for C.sub.69 H.sub.79 N.sub.12 O.sub.11 Cl showed (M+1)
 @1287 m/z; Amino Acid Anal.: 0.38 Ser; 0.94 NMeTyr; 0.99 Leu; 1.00 3Pal;
 1.04 4ClPhe; 1.00 Lys.
 Example 25
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-Dlys(Nic)-Leu-NH--(3-guinuclidine)
 A NAcD2Nal-D4ClPhc-D3Pal-Ser(OBzl)-NMeTyr(OBzl)-DLys(Nic)-Leu-OH (0.5171 g)
 in DMF (1 ml) was cooled to 0.degree. C. and 3-aminoquinuclidine
 hydrochloride (0.0886 g) was added, followed by diisopropylethylamine
 (0.25 ml) and
 benzotriazol-1-yloxytris(dimethylamino-phosphonium)hexafluorophosphate
 (0.1771 g). The reaction mixture was stirred for 1 hr at low temperature
 and then overight at room temperature. The mixture was poured into 20%
 NaHCO.sub.3 solution and stirred for 1 hour. The precipitate was filtered
 dissolved in methanol and the solution was concentrated in vacuo. The
 residue was dissolved in (1:1) acetonitrile/water and lyophilized. The dry
 powder was treated with anisole (1 ml) and then treated with anhydrous HF
 to remove the protecting groups as described in Example 1. HPLC
 purification of the crude material gave the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(3-quinuclidine),
 which was obtained as trifluoroacetate salt: R.sub.t =20.9 min; FAB Mass
 spec for C.sub.70 H.sub.85 N.sub.12 O.sub.11 Cl showed (M+1) @1304 m/z;
 Amino Acid Anal.: 0.37 Ser; 0.92 NMeTyr; 0.99 Leu; 0.93 3Pal; 1.08 4ClPhe;
 1.00 Lys.
 Example 26
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 --CH.sub.2
 -(1-piperidine)
 The procedure described in Example 23 was used, but substituting
 2-aminoethyl-1-piperidine for 2-aminomethylpyridine. After work up, the
 cleaving of the protecting groups and HPLC purification, the desired
 product, NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2
 --CH.sub.2 N-piperidine, was obtained as trifluoroacetate salt: R.sub.t
 =22.5 min; FAB Mass spec for C.sub.70 H.sub.87 N.sub.12 O.sub.11 Cl showed
 (M+1) @1307 m/z; Amino Acid Anal.: 0.43 Ser; 1.03 NMeTyr; 1.01 Leu; 1.01
 3Pal; 1.18 4ClPhe; 0.99 Lys.
 Example 27
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 --CH.sub.2
 -(1-norpholine)
 The procedure described in Example 26 was used, but substituting
 2-aminoethy-1-morpholine for 2-aminoethyl-1-piperidine. After work up, the
 cleaving of the protecting groups and HPLC purification, the desired
 product, NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2
 --CH.sub.2 -(1-morpholine), was obtained as trifluoroacetate salt: R.sub.t
 =20.9 min; FAB Mass spec for C.sub.69 H.sub.85 N.sub.12 O.sub.12 Cl showed
 (M+1) @1309 m/z; Amino Acid Anal.: 0.40 Ser; 0.89 NMeTyr; 0.99 Leu; 1.00
 3Pal; 1.08 4ClPhe; 1.07 Lys.
 Example 28
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 --CH.sub.2
 -(2-pyridine)
 The procedure described in Example 27 was used but substituting
 amino-ethylpyridine for aminoethylmorpholine. After work up, the cleaving
 of the protecting groups and HPLC purification, the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 --CH.sub.2
 -(2-pyridine), was obtained as trifluoroacetate salt: R.sub.t =22.2 min;
 FAB Mass spec for C.sub.70 H.sub.81 N.sub.12 O.sub.11 Cl showed (M+1)
 @1301 m/z; Amino Acid Anal.: 0.38 Ser; 1.07 NMeYyr; 0.99 Leu; 0.98 3Pal;
 1.10 4ClPhe; 1.00 Lys.
 Example 29
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 --CH.sub.2
 -[2-(1-methyl)pyrrole]
 The procedure described in Example 28 was used, but substituting
 2-(2-aminoethyl)-1-methyl-pyrrole for aminoethylpyridine. After work up,
 the cleaving of the protecting groups and HPLC purification, the desired
 product, NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2
 --CH.sub.2 -[2-(1-methyl)pyrrole], was obtained as trifluoroacetatc salt:
 R.sub.t =29.6 min; FAB Mass spec for C.sub.70 H.sub.83 N.sub.12 O.sub.11
 Cl showed (M+1) @ 1303 m/z; Amino Acid Anal.: 0.44 Ser; 1.11 NMeTyr; 0.47
 Leu; 1.06 3Pal; 1.22 4ClPhe; 1.00 Lys.
 Example 30
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 --CH.sub.2
 -[2-(1-methyl)pyrrolidine]
 The procedure described in Example 29 was used, but substituting
 2-(2-amino-ethyl)-1-methyl-pyrrolidine for
 2-(2-aminoethyl)-1-methyl-pyrrole. After workup, the cleaving of the
 protecting groups and HPLC purification, the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 --CH.sub.2
 -[2-(1-methyl)-pyrrolidine], was obtained as trifluoroacetate salt:
 R.sub.t =21.5 min; FAB Mass spec for C.sub.70 H.sub.87 N.sub.12 O.sub.11
 Cl showed (M+1) @ 1306 m/z; Amino Acid Anal.: 0.43 Ser; 1.08 NMeTyr; 1.01
 Leu; 1.01 3Pal; 1.17 4ClPhe; 0.99 Lys.
 Example 31
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 CH.sub.2 -(1-morpholine)
 The procedure described in Example 27 was used, but substituting
 4-(3-aminopropyl)morpholine for 2-aminoethylmorpholine. After work up, the
 cleaving of the protecting groups and HPLC purification, the desired
 product, NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2
 CH.sub.2 CH.sub.2 -(1-morpholine), was obtained as trifluoroacetate salt:
 R.sub.t =20.4 min; FAB Mass spec for C.sub.70 H.sub.87 N.sub.12 O.sub.12
 Cl showed (M+1) @1323 m/z; Amino Acid Anal.: 0.43 Ser; 1.00 NMeTyr; 1.00
 Leu; 1.02 3Pal; 1.18 4ClPhe; 1.00 Lys.
 Example 32
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 CH.sub.2 -[1-(2-methyl)piperidine]
 The procedure described in Example 31 was used, but substituting
 2-methylpiperidine for 4-(3-aminopropyl)morpholine. After work up, the
 cleaving of the protecting groups and HPLC purification, the desired
 product, NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2
 CH.sub.2 CH.sub.2 -[1-(2-methyl)piperidine], was obtained as
 trifluoroacetate salt: R.sub.t =23.3 min; FAB Mass spec for C.sub.72
 H.sub.91 N.sub.12 O.sub.11 Cl showed (M+1) @1335 m/z; Amino Acid Anal.:
 0.41 Ser; 1.34 NMeTyr; 1.00 Leu; 1.09 3Pal; 1.05 4ClPhe; 1.00 Lys.
 Example 33
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 CH.sub.2 -(1-pyrrolidin-2-one)
 The procedure described in Example 31 was used, but substituting
 1-(3-aminopropyl)pyrrolidin-2-one for aminopropylmorpholine. After work
 up, cleavage of protecting groups and HPLC purification, the desired
 product, NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2
 CH.sub.2 CH.sub.2 -(1-pyrrolidin-2-one), was obtained as trifluoroacetate
 salt: R.sub.t =25.7 min; FAB Mass spec for C.sub.70 H.sub.85 N.sub.12
 O.sub.11 Cl showed (M+1) @1321 m/z; Amino Acid Anal.: 0.27 Ser; 0.98
 NMeTyr; 1.00 Leu; 0.97 3Pal; 1.10 4ClPhe; 1.01 Lys.
 Example 34
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 CH.sub.2 CH.sub.2 OH
 The procedure described in Example 23 was used, but substituting
 4-amino-butanol for 2-aminomethylpyridine. After work up, cleavage of
 protecting groups and HPLC purification, the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH--CH.sub.2 CH.sub.2
 CH.sub.2 CH.sub.2 OH, was obtained as trifluoroacetate salt: R.sub.t =23.5
 min; FAB Mass spec for C.sub.67 H.sub.82 N.sub.11 O.sub.12 Cl showed (M+1)
 @(1268 m/z; Amino Acid Anal.: 0.42 Ser; 1.36 NMeTyr; 1.00 Leu; 1.00 3Pal;
 1.07 4ClPhe; 1.00 Lys.
 Example 35
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH(CH.sub.2).sub.9 NH.sub.2
 The procedure described in Example 34 was used, but substituting
 1,9-diaminononane for 4-aminobutanol. After work up, cleavage of
 protecting groups and HPLC purification, the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys(Nic)-Leu-NH(CH.sub.2).sub.9
 NH.sub.2, was obtained as trifluoroacetate salt: R.sub.t =24.1 min; FAB
 Mass spec for C.sub.72 H.sub.93 N.sub.12 O.sub.11 Cl showed (M+1) @1337
 m/z; Amino Acid Anal.: 0.45 Ser; 1.08 NMeTyr; 1.00 Leu; 1.01 3Pal; 1.17
 4ClPhe; 1.00 Lys.
 Example 36
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 In the reaction vessel of a Milligen-Biosearch 9500 peptide synthesizer was
 placed 1 g (0.42 mmol) of BOC-Leu-0-resin (Merrifield resin). Subsequent
 amino acids were added sequentially according to the following synthetic
 cycle:
 1. Deblocking, to remove the t-BOC oroup from the alpha-amino function of
 the peptide, was carried out using a solution of 45% trifluoroacetic acid
 (TFA), 2.5% anisole, 2.0% dimethyl phosphite, and 50.5% methylene
 chloride. The resin was prewashed with the deblocking solution for one
 minute and then the deblocking reaction was run for 20 minutes.
 2. Base wash, to remove and neutralize the TFA used for deprotection, was
 carried out using a solution of 10% N,N'-diisopropylethylamine in
 methylene chloride. The resin was washed with base three times for one
 minute each time after a deblocking step.
 3. Coupling reaction was carried out using a 3-fold molar excess of 0.3 M
 DMF solution of a t-BOC protected amino acid derivative along with a
 3-fold molar excess of 0.3 M methylene chloride solution of
 diisopropylcarbodiimide as activator. The activated amino acid was then
 coupled to the free alpha-amino grroup of the peptide-resin. The reaction
 time was as described in the synthesis protocol described below.
 4. Wash, each reaction step was followed by three washes of one minute
 each: one of methylene chloride, one of (1:1) methylene chloride/DMF, and
 one of DMF.
 Synthesis Protocol
 The amino acids were coupled to the resin according the following order,
 number and duration of couplings:

Order Number-Duration
 1. BOC-Leu two-1 h
 2. BOC-DLys(Nic) two-1 h
 3. BOC-Tyr(O-2-Br-Cbz) two-1 h
 4. BOC-Ser(OBzl) two-1 h
 5. BOC-D3Pal two-1 h
 6. BOC-D4C1Phe two-1 h
 7. BOC-D2Nal two-1 h
 Upon completion of the synthesis the peptide-resin was dried overnight over
 P.sub.2 O.sub.5, under vacuum and then was treated at room temperature
 with anhydrous methylene chloride (10 ml) with stirring under N.sub.2. To
 the slurry was added a 0.63 M solution of boron tribromide in methylene
 chloride (2 ml) and the mixture was stirred for one hr, then
 aminoethyl-N-pyrrolidine (0.3 ml) was added and stirring continued
 overnight. Methanol (1 ml) was added and the mixture was stirred for 15
 min and filtered. The resin was washed thoroughly with methanol three
 times and the filtrate and washes were combined and concentrated in vacuo.
 The residue was dried in vacuo over P.sub.2 O.sub.5 overnight and then
 treated with HF/anisole to remove protecting groups. After workup and
 lyophilization the crude product was purified by HPLC using C-18 reverse
 phase column and running a gradient of 25-50%, over 30 minutes, of
 acetonitrile/water containing 0.1% trifluoroacetic acid. The desired
 compound,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), was obtained as trifluoroacetate salt: R.sub.t =20.6
 min; FAB Mass spec for C.sub.68 H.sub.83 N.sub.12 O.sub.11 Cl showed (M+H)
 @(1278 m/z; Amino Acid Anal.: 0.47 Ser; 0.91 Tyr; 1.03 Leu; 0.94 3Pal;
 0.89 4ClPhe; 1.05 Lys.
 Example 37
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DCit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 36 was used, but substituting BOC-DCit
 for BOC-DLys(Nic). After workup and HPLC purification the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DCit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), was obtained as trifluoroacetate salt: R.sub.t =20.4
 min; FAB Mass spec for C.sub.62 H.sub.79 N.sub.12 O.sub.11 Cl showed (M+1)
 @1203 m/z; Amino Acid Anal.: 0.51 Ser; 0.99 Tyr; 1.00 Leu; 1.02 3Pal; 1.01
 4ClPhe; 1.01 Cit.
 Example 38
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 37 was used, but substituting BOC-DHcit
 for BOC-Cit. After workup and HPLC purification the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), was obtained as trifluoroacetate salt: R.sub.t =22.6
 min; FAB Mass spec for C.sub.63 H.sub.81 N.sub.12 O.sub.11 Cl showed (M+H)
 @1217 m/z; Amino Acid Anal.: 0.41 Ser; 0.95 Tyr; 1.00 Leu; 0.95 3Pal; 1.31
 4ClPhe.
 Example 39
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 36 is used, but substituting
 BOC-NMeTyr(OBzl) for BOC-Tyr(OBzl). After workup and HPLC purification the
 desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), is obtained as trifluoroacetate salt.
 Example 40
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Lys(Nic)-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 36 is used, but substituting
 BOC-Lys(Nic) for BOC-Tyr(OBzl). After workup and HPLC purification the
 desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Lys(Nic)-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), is obtained as trifluoroacetate salt.
 Example 41
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Arg-DTrp-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 36 is used, but substituting
 BOC-Arg(Ng-Tos) for BOC-Tyr(OBzl) and BOC-DTrp for BOC-DLys(Nic). After
 workup and HPLC purification the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Arg-DTrp-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), is obtained as trifluoroacetate salt.
 Example 42
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tic-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 36 is used, but substituting BOC-Tic for
 BOC-Tyr(OBzl). After workup and HPLC purification the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Tic-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), is obtained as trifluoroacetate salt.
 Example 43
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 36 is used, but substituting BOC-NMePhe
 for BOC-Tyr(OBzl). After workup and HPLC purification the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), is obtained as trifluoroacetate salt.
 Example 44
 NAcSar-D4ClPhe-D1Nal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 36 is used, but substituting BOC-Sar,
 BOC-D1Nal and BOC-NMeTyr(OBzl) for BOC-D2Nal, BOC-D3Pal and BOC-Tyr(OBzl),
 respectively. After workup and HPLC purification the desired product,
 NAcSar-D4ClPhe-D1Nal-Ser-NMeTyr-DLys(Nic)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), is obtained as trifluoroacetate salt.
 Example 45
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DArg-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 36 is used, but substituting
 BOC-NMeTyr(OBz) and BOC-DArg(Tos) for BOC-Tyr(OBzl) and BOC-DLys(Nic),
 respectively. After workup and HPLC purification the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DArg-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine), is obtained as trifluoroacetate salt.
 Example 46
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-NAc)-DPhe(4-NAc)-Leu-NH--(CH.sub.2).
 sub.2 -(1-Pyrrolidine)
 The procedure described in Example 36 is used, but substituting
 BOC-NMePhe-(4-NAc) and BOC-DPhe(4-NAc) for BOC-Tyr(OBzl) and BOC-DLys(Nic)
 respectively. After workup and HPLC purification the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-NAc)-DPhe(4-NAc)-Leu-NH--(CH.sub.2).
 sub.2 -(1-pyrrolidine), is obtained as trifluoroacetate salt.
 Example 47
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-NO.sub.2)-DCit-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 36 is used, but substituting
 BOC-NMePhe-(4-NO.sub.2) and BOC-DCit for BOC-Tyr(OBzl) and BOC-DLys(Nic)
 respectively. After workup and HPLC purification the desired product,
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-NO.sub.2)-DCit-Leu-NH--(CH.sub.2).sub.
 2 -(1-pyrrolidine), is obtained as trifluoroacetate salt.
 Example 48
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-Atza)-DPhe(4-Atza)-Leu-NH--(CH.sub.2).
 sub.2 -(1-pyrrolidine)
 The procedure described in Example 36 was used, but substituting
 BOC-NMePhe(4-N-FMOC) and BOC-DPhe(4-N-FMOC) for BOC-Tyr(OBzl) and
 BOC-DLys(Nic), respectively. After the completion of the synthesis the
 peptide-resin is treated with 30% piperidine/DMF for 2 to 24 hr, to cleave
 the FMOC protecting group from the 4-amino group on the phenyl rings of
 the side chains. The peptide-resin is washed 3 times with methylene
 chloride, 3 times with DMF and reacted with 10- to 20-fold excess of
 diphenylcyanocarbodiimidate in DMF overnight, washed 3 times with
 methylene chloride, 3 times with DMF, and then reacted with 20- to
 100-fold excess of hydrazine in DMF overnight. The peptide-resin is again
 washed, as previously described, dried over P.sub.2 O.sub.5, overnight and
 then is treated at room temperature with anhydrous methylene chloride (10
 ml) with stirring under N.sub.2. To the slurry is added a 0.63 M solution
 of boron tribromide in methylene chloride (2 ml) and the mixture is
 stirred for one hour, then aminoethyl-N-pyrrolidine (0.3 ml) is added and
 stirring continued overnight. Methanol (1 ml) is added and the mixture was
 stirred for 15 min and filtered. The resin was washed thoroughly with
 methanol three times and the filtrate and the washes are combined and
 concentrated in vacuo. The residue is dried in vacuo over P.sub.2 O.sub.5
 overnight and then treated with HF/anisole to remove protecting groups.
 After workup and lyophilization the crude product is purified by HPLC to
 give the desired product
 NAcD2Nal-D4ClPhe-D3Pal-Ser-NMePhe(4-Atza)-DPhe(4-Atza)-Leu-NH--(CH.sub.2).
 sub.2 -(1-pyrrolidine) as the trifluoroacetate salt.
 Example 49
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Phe(4-Atza)-DPhe(4-Atza)-Leu-NH--(CH.sub.2).sub.
 2 -(1-pyrrolidine)
 The procedure described in Example 48 is used, but substituting
 BOC-Phe-(4-N-FMOC) for BOC-NMePhe(4-N-FMOC). After workup and
 lyophilization the crude product is purified by HPLC to give the desired
 product
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Phe(4-Atza)-DPhe(4-Atza)-Leu-NH--(CH.sub.2).
 sub.2 -(1-pyrrolidine) as the tri fluoroacetate salt.
 Example 50
 NAcD2Nal-D4ClPhe-D3Pal-Ser-Phe(4-NAc)-DPhe(4-NAc)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine)
 The procedure described in Example 46 is used, but substituting
 BOC-Phe-(4-N-FMOC) for BOC-NMePhe(4-N-FMOC). After workup and
 lyophilization the crude product is purified by HPLC to give the desired
 product
 NAcD2Nal-D4ClPhe-D3Pat-Ser-Phe(4-NAc)-DPhe(4-NAc)-Leu-NH--(CH.sub.2).sub.2
 -(1-pyrrolidine) as the trifluoroacetate salt.
 LHRH ANTAGONIST ACTIVITY
 Representative compounds of the present invention were evaluated in vitro
 for inhibition of LH release from rat pituitary cells (pA.sub.2). Methods
 for the assay procedures arc described by F. Haviv, et al. J. Med. Chem.,
 32:2340-2344 (1989). Values of pA.sub.2 are the negative logarithms of the
 concentration of the particular antagonist test compound required to shift
 the response curve produced by the agonist leuprolide to two-fold higher
 concentration. Typically values of 7.0 or greater are indicative of good
 LHRH antagonist potency, with values of 8.0 or greater being preferred.
 Leuprolide LHRH agonist, disclosed and claimed in U.S. Pat. No. 4,005,063,
 has the structure 5-oxo-Pro.sup.1 -His.sup.2 -Trp.sup.3 -Ser.sup.4
 -Tyr.sup.5 -D-Leu.sup.6 -Leu.sup.7 -Arg.sup.8 -Pro.sup.9 -NHEt.
 Results for the assay of representative compounds in accordance with the
 invention are summarized in Table 1.
 TABLE 1
 LHRH Agonist Activity
 Example No. (pA.sub.2)
 1 7.90
 2 9.58
 3 11.27
 4 7.96
 5 9.91
 6 9.90
 7 8.95
 8 8.48
 9 10.21
 10 8.76
 11 9.10
 12 10.45
 13 9.30
 14 9.81
 15 8.70
 16 8.89
 17 7.63
 18 8.48
 19 9.70
 20 8.39
 21 8.42
 22 10.26
 23 9.18
 24 8.30
 25 10.02
 26 9.30
 27 8.30
 28 8.10
 29 8.30
 30 9.80
 31 9.30
 32 9.07
 33 8.30
 34 8.71