EP0592512A1 - Analogues non desensibilisants de gonadoliberine et d'autres ligands biologiquement actifs - Google Patents

Analogues non desensibilisants de gonadoliberine et d'autres ligands biologiquement actifs

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Publication number
EP0592512A1
EP0592512A1 EP92914041A EP92914041A EP0592512A1 EP 0592512 A1 EP0592512 A1 EP 0592512A1 EP 92914041 A EP92914041 A EP 92914041A EP 92914041 A EP92914041 A EP 92914041A EP 0592512 A1 EP0592512 A1 EP 0592512A1
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EP
European Patent Office
Prior art keywords
alkyl
phe
formula
analog
gnrh
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP92914041A
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German (de)
English (en)
Inventor
Graham J. Moore
Hamid R. Habibi
John M. Matsoukas
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University Technologies International Inc
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University Technologies International Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/14—Angiotensins: Related peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/042—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers characterised by the nature of the carrier
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/23—Luteinising hormone-releasing hormone [LHRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention is directed to novel non-desensitizing analogs of a biologically active ligand containing at least one 6-membered aromatic ring or 5-membered ring and a method for selecting non- desensitizing analogs of a biologically active ligand containing at least one 6-membered aromatic ring or 5- membered ring. Additionally, the present invention is directed to a novel method for treating a patient in a non-desensitizing fashion with a non-desensitizing analog of a biologically active ligand containing at least one 6-membered aromatic ring or 5-membered ring. Moreover, the present invention is directed to a novel method for making new and useful non-desensitizing analogs of GnRH and opiate peptides as well as the novel non-desensitizing compounds prepared thereby.
  • GnRH Gonadotropin-Releasing Hormone
  • GnRH is one such biologically active compound which has been modified to produce both agonistic and antagonistic analogs thereof.
  • GnRH stimulates the release of gonadotropins through interaction with membrane-associated high affinity receptors on the pituitary gonadotropes. Subsequently, these gonadotropins act on the gonads to stimulate the synthesis of steroid sex hormones. The pulsatile release of GnRH, and thereby the release of gonadotropins, controls the reproductive cycle in domestic animals and humans.
  • Acute doses of GnRH agonists administered in pulsatile fashion can increase the levels of
  • Luteinizing Hormone and steroid sex hormones in both animals and humans.
  • LH Luteinizing Hormone
  • steroid sex hormones in both animals and humans.
  • acute or chronic doses of these agonists can suppress the levels of LH and steroid hormones.
  • GnRH agonists can be to suppress estrogen formation in the female and suppress testosterone formation in the male. Accordingly, knowledge of the molecular process by which desensitization occurs would be extremely useful in the design of analogs of biologically active ligands in which said receptor desensitization effects are reduced.
  • Yet another object of the present invention is to provide a novel method for selecting non- desensitizing analogs of a biologically active ligand which contain at least one 6-membered aromatic ring or 5-membered ring.
  • Still another object of the present invention is to provide a novel method for treating a patient in a non-desensitizing fashion with a non-desensitizing analog of a biologically active ligand containing at least one 6-membered aromatic ring or 5-membered ring.
  • a further object of the present invention is to provide a novel method for producing new and useful analogs of GnRH and opiate peptides as well as the novel analogs produced thereby.
  • a method for selecting non- desensitizing analogs of a biologically active ligand containing at least one 6-membered aromatic ring or 5- embered ring comprises selecting an analog of a biologically active ligand containing a 6- membered aromatic ring according to Formula I or selecting a biologically active ligand containing a 5- membered ring according to Formula II:
  • X is selected from H, R 1 , -OR 1 , halide, -CN, -CHO, CChalide) 3 , -alk-OH, -alk-OR 1 , -alk-C0 2 H, -alk-C0 2 R l , -alk-SH, -alk-SR 1 , -alk-CONH 2 , -C0 2 H, -COjR 1 , -COR 1 , -OCONH 2 , -OCH 2 OH, -OCHjOR 1 , -OCOR 1 , -N 3 , -N 2 , -NHCOR 1 , -N0 2 , -NH 2 , -NHR 1 , -NR r 2 , -S0 3 H, -SO-R 1 , -SCOR 1 , -NCS, -SCSR 1 , -S0 2 NH 2
  • R 1 is selected from alkyl of 1-7 carbon atoms, alkenyl or alkynyl of 2-7 carbon atoms or cycloalkyl of 3-7 carbon atoms, optionally halogenated at one or more hydrogen.
  • R 2 , R 3 , R 4 , R s , R 6 , R 7 , R 8 and R 9 are groups selected from X or -OH. In the above, is selected from P, N, S, or C being in either the L- or D-configuration and ⁇ can be deleted or extended by 1-2 carbon atoms, substituted or unsubstituted.
  • the nitrogen atom attached to ⁇ can be substituted or unsubstituted C, S, O or P and the carbon atom attached to ⁇ and oxygen can be substituted or unsubstituted N, S, o, P or C.
  • the aromatic ring of Formula I or the ring of Formula II can contain 0-4 N, S or 0 atoms.
  • the aromatic ring of Formula I or ring of Formula II can be fused with a 6-membered aromatic ring which can contain 0-4 N, S or O atoms and which can be substituted in the same manner as the aromatic ring of Formula I.
  • D-tyrosine and D-histidine are also included within Formulas I and II.
  • the method comprises selecting an analog of a biologically active ligand containing a 6- membered aromatic ring according to Formula I, as defined above, or selecting a biologically active ligand containing a 5-membered ring according to
  • the next step in the method comprises administering to a patient in need thereof a composition comprising a pharmaceutically effective amount of the selected analog together with a pharmaceutically acceptable carrier.
  • X is L- or D-Pyr, N-acyl-amino acid, ⁇ -C-alkyl-Pyr, or N-acyl- ⁇ -C-alkyl-amino acid;
  • x 2 , X 3 , X 4 , X 6 , X 7 and X g are independently selected from natural, synthetic, protected or ⁇ -C-alkyl- amino acids, or X 6 -X 7 optionally contains a 7-lactam;
  • X resonance is an i ino acid or ⁇ -C-alkyl-imino acid;
  • X ⁇ 0 is -N(H)R wherein R is GlyNH 2 , azaGlyNH 2 , alkyl or alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl or aryl; and
  • X 5 is selected from Formulas I or II, as defined above.
  • the compounds excluded from the compounds according to Formulas I and II are
  • X is Pyr, N-acyl- amino acid, ⁇ -C-alkyl-Pyr , N-acyl- ⁇ -C-alkyl amino acid;
  • X 2 and X 3 are aromatic L-amino acids;
  • X 4 , X 7 and X 8 are independently natural, synthetic, protected or ⁇ -C-alkyl- amino acids;
  • X 6 is a natural, synthetic or protected D-amino acid, Gly, ⁇ -C-alkyl-amino acid; or X ⁇ -X 7 optionally contains a 7-lactam;
  • X 9 is imino acid or ⁇ -C-alkyl-imino acid;
  • X, 0 is -N(H)R wherein R is GlyNH 2 , azaGlyNH 2 , alkyl, alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl or aryl; and
  • X 5 is according to Formula III, where
  • non-desensitizing describes a biologically active ligand with at least partially reduced desensitizing properties.
  • biologically active ligand refers to a molecule which binds to a biologically active receptor molecule and which directly or indirectly affects the activity of the receptor molecule.
  • the binding of such ligands to the receptor (acceptor) molecule is accordingly a necessary precondition for initiating, terminating, altering or preventing the biological activity in the receptor molecule.
  • Any ligand which effects the biological activity of the receptor molecule is said to be a biologically active ligand.
  • the biologically active ligand can be a substrate, an agonist, an antagonist, an activator, an inhibitor, etc. Examples of biologically active ligands according to the present invention include GnRH, also known as Luteinizing
  • Hormone-Releasing Hormone LH-RH
  • Angiotensin II or III
  • Additional examples of biologically active ligands are well documented in the art.
  • the biologically active ligand can be either peptidic or non-peptidic in nature. Such ligands can be indigenous to the organism where the biologically active receptor is found. When the ligand is one which is naturally occurring in that organism, then that ligand is referred to as a naturally occurring biologically active ligand.
  • the biologically active ligands can be synthetic molecules which are complementary to the biologically active receptor and which affect the biological activity of the receptor. Thus, any molecule which is complementary to a biologically active receptor and which affects the biological activity of the receptor, is a biologically active ligand.
  • ligand refers to any organic compound for which a receptor naturally exists or can be prepared.
  • receptor refers to a molecule which binds the ligand.
  • the ligand When binding of the biologically active ligand to the biologically active receptor and the activation of the active site results in an alteration of the biological activity of the receptor, e.g., initiates, increases, decreases or terminates the biological activity of the receptor, the ligand is said to directly affect the activity of the receptor.
  • a biologically active ligand indirectly affects the activity of the biologically active receptor when the binding of the ligand to the receptor results in an inability to activate the receptor.
  • Activation of the active site of the naturally occurring biologically active ligand/receptor complex is generally accomplished by some sort of chemical interaction between the ligand and the receptor.
  • chemical interaction involves the transfer of charge from one residue to another wherein one of the residues is either a phenol or phenolate residue, the interaction is termed a charge-transfer interaction.
  • charge-transfer interactions are believed to result in the alteration of the structure of the ligand or ligand/receptor complex. Because such charge-transfer interactions can now be detected by the techniques employed in the present invention, it is now possible to incorporate such interactions into the model created for the naturally occurring biologically active ligand and to create agonists and antagonists which have reduced desensitizing properties at the complementary receptor.
  • Any biologically active ligand containing a phenolic group such as tyrosine, may utilize the phenolic group to desensitize a complementary receptor.
  • Methods for determining biologically active phenolate ligands using spectroscopic techniques have been described in detail in U.S. Ser No. 07/458,926 filed December 29, 1989, which is incorporated herein by reference.
  • the presence of a phenolate species in a biologically active ligand is ascertained by measuring the fluorescence lifetime due to said phenolate species in a suitable environment such as propylene glycol.
  • phenolate (tyrosinate) fluorescence is diagnostic of the occurrence of the active phenolate species which may cause receptor desensitization.
  • the long fluorescence lifetime is produced by intramolecular interactions within the biologically active ligand when the ligand is dissolved in a receptor-simulating solvent such as propylene glycol.
  • the lability of the phenolic OH proton may be determined by NMR spectroscopy of the biologically active ligand in a suitable solvent such as DMSO.
  • a suitable solvent such as DMSO.
  • modification or substitution of the phenolic OH group of a biologically active ligand provides a method for establishing the involvement of the phenolic OH group in a receptor desensitizing process, particularly when such modification results in a ligand with reduced receptor desensitizing properties, as exemplified herein for peptides based on Angiotensin II and GnRH.
  • agonist refers to a biologically active ligand which binds to its complementary biologically active receptor and activates the latter either to cause a biological response in the receptor or to enhance pre-existing biological activity of the receptor.
  • the agonist can be the naturally occurring biologically active ligand or it can be a synthetic molecule which can also activate the receptor.
  • Angiotensin II acts as an agonist for its complementary receptor, the Angiotensin II receptor.
  • Other examples of agonists for the Angiotensin II receptor include [Sar t ] Angiotensin II and the like.
  • a common characteristic of all ligands in this invention is that the charge-transfer interaction in the ligand which is necessary to desensitize the biologically active receptor is compromised. That is to say that the charge-transfer interaction is essentially inoperable in the ligand.
  • antagonist refers to a biologically active ligand which binds to its complementary biologically active receptor and either prevents the activation of the latter or deactivates the latter so as to either prevent or diminish the biological activity of the receptor.
  • non-peptides 2-n-butyl-l- [4-carboxybenzyl]-4-chloroimidazole-5-acetic acid) and (methyl 2-n-butyl-l-[4-(2-carboxybenzamido)-benzyl]-4- chloroimidazole-5-acetate) sodium salt act as antagonists of the Angiotensin II receptor.
  • Other examples of art-recognized antagonists to other biologically active receptors include propranolol for the /3-adrenergic receptor, cimetidine for the Histamine-H 2 receptor and the like.
  • Angiotensin II refers to the biologically active ligand which is an octapeptide represented by the amino acid sequence of: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe.
  • Angiotensin III refers to the biologically active ligand which is a heptapeptide represented by the amino acid sequence of: Arg-Val-Tyr-Ile-His-Pro-Phe.
  • Mtr 4-methoxy-2,3,6-Trimethylbenzenesulfonyl; Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl; Pr propyl t-Boc t-Butoxycarbonyl
  • TFA trifluoroacetic acid Tos tosyl group Trt trityl group TFA trifluoroacetic acid tos tosyl group Trt trityl group
  • the chemical interaction between the ligand and the receptor can cause the desensitization of the receptor such that a subsequent interaction of the ligand on the receptor results in attenuation of the subsequent biological response to the ligand.
  • GnRH biologically active ligand which serves to illustrate the effects of desensitization of a receptor.
  • GnRH is released from the hypothalamus and binds to a receptor on the pituitary gland, causing the release of LH (Luteinizing Hormone) and FSH (Follicle-Stimulating Hormone) .
  • GnRH has been puri ied and identified in mammals to be a decapeptide having the amino acid sequence: Pyr-His- Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 .
  • Gly-NH 2 Chicken GnRH-II: Pyr-His-Trp-Ser-Hj ⁇ -Gly-Trp_- ⁇ yr-Pro- Gly-NH 2 ; and
  • GnRH analogs synthesized previously have been designed on the basis of resistance to metabolic degradation, and have been particularly concerned with the incorporation of a D-amino acid into the GnRH peptide (as mentioned above) , or with N-methylation of one or more of the peptide bonds in order to invoke intestinal stability to enzymes (European Patent No. 0 328 090) .
  • the criteria for selection of the analogs described herein is distinctly different from previous work such as that of EP-0,328,090 in that selection is based on GnRH analogs with receptor desensitizing properties, achieved principally by modifying the Tyr 5 or His 5 residue of
  • the method comprises selecting an analog of a biologically active ligand containing a 6-membered aromatic ring according to Formula I or selecting an analog of a biologically active ligand containing a 5-membered ring according to Formula II:
  • X is selected from H, R 1 , -OR 1 , halide, -CN, -CHO, C(halide) 3 , -alk-OH, -alk-OR 1 , -alk-C0 2 H, -alk-CO ⁇ 1 , -alk-SH, -alk-SR 1 , -alk-C0NH 2 , -C0 2 H, -COjR 1 , -COR 1 , -OCONH 2 , -OCH-OH, -OCHzOR 1 , -OCOR 1 , -N 3 , -N 2 , -NHCOR 1 , -N0 2 , -NH 2/ -NHR 1 , -NR X 2 , -S0 3 H, -SO-R 1 , -SCOR 1 , -NCS, -SCSR 1 , -S0 2 NH 2 ,
  • R 1 is selected from alkyl of 1-7 carbon atoms, alkenyl or alkynyl of 2-7 carbon atoms or cycloalkyl of 3-7 carbon atoms, optionally halogenated at one or more hydrogen.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are groups selected from X or -OH.
  • the nitrogen atom attached to ⁇ can be substituted or unsubstituted C, S, O or P and the carbon atom attached to ⁇ and oxygen can be substituted or unsubstituted N, S, 0, P or C.
  • the aromatic ring of Formula I or the ring of Formula II can contain 0-4 N, S or O atoms.
  • aromatic ring of Formula I or ring of Formula II can be fused with a 6-membered aromatic ring which can contain 0-4 N, S or O atoms and which can be substituted in the same manner as the aromatic ring of Formula I.
  • D-tyrosine and D-Histidine are also included within Formulas I and II.
  • the analogs of a biologically active ligand are selected so as to contain a ring modified according to Formulas I or II and so that the resulting biologically active ligand has reduced desensitizing properties, i.e., the biologically active ligand is such that the subsequent interaction of the ligand with the receptor does not substantially attenuate the biological response.
  • the discovery and use of analogs according to Formulas I or II, and especially GnRH analogs according to Formulas I or II, with reduced desensitizing properties is new.
  • the analog of a biologically active ligand containing at least one 6-membered aromatic ring can be selected, for example, from the peptides Angiotensin (II or III) or GnRH.
  • one method according to the present invention is the selection of a non- desensitizing analog of the biologically active ligand GnRH wherein the tyrosine residue at the 5-position has been modified according to Formula I.
  • X ⁇ -X 10 are selected from the following: X, is Pyr or N-acyl-amino acid; X 2 is an aromatic amino acid; X 3 is an aromatic amino acid, X 4 is Ala, Thr, Ser, Hse, Ser(Me) , ⁇ -C-methyl-Ser(Me) , Aib; X s is Tyr(O-alkyl) , Phe(4'-halogen) ; Phe(4 r -alkyl) ; Xg is Gly, Aib, or D-amino acid (natural or synthetic, including an amino acid bearing a protecting group) , ⁇ -C-alkyl-amino acid; X 7 is Leu, lie, Trp, Cha, ⁇ -C-methyl-amino acid, Val; X g is Arg, Gin, Tyr, Leu; Xg is Pro, pipecolic acid, nipecotic acid, azet
  • Another particularly preferred embodiment is one in which the ⁇ -carbon atom of at least one of the amino acids is alkylated, in which case position 5 may be as described by Formulas I or II or may be ⁇ -C-meth ⁇ l-histidine or ⁇ -C-methyl-tyrosine, or the like.
  • the modifications illustrated for the tyrosine residue of GnRH are also applicable to other Tyr- containing peptides.
  • selection of a biologically active ligand having a phenolate group according to Formula I or a 5-membered ring according to Formula II may likewise favorably alter the duration of action of the ligand.
  • the duration of the biological response is increased.
  • [Tyr(Me) 5 ]-GnRH has a longer duration of action than GnRH. This increase in duration of action and the non-desensitizing nature of the analog [Tyr(Me) 5 ]-GnRH is illustrated in Example 2 and, infra.
  • the same method is also applicable to antagonist analogs of a ligand.
  • the duration of action is decreased.
  • angiotensin wherein methylation of the tyrosine OH of the angiotensin antagonist [Sar 1 lie 8 ] ANG II to give [Sar 1 Tyr(Me) 4 lie 8 ] ANG II results in a reduction of the desensitization properties and duration of action.
  • the decrease in the duration of action and the non- desensitizing nature of the above antagonistic analogs is illustrated in Example 1, infra.
  • the present invention is not limited to peptides such as GnRH and Angiotensin II or III, but may be applied to any desensitizing biologically active ligands having a 6-membered aromatic ring or 5-membered ring. Accordingly, other examples demonstrating the extensive applicability of the selection method according to the present invention are as follows.
  • non-desensitizing analogs of a biologically active ligand selected according to the present invention include, but are not limited to, the opioid ligands, wherein desensitization, tolerance, dependence, and withdrawal may be effectively reduced by modification of the phenolic group or conjugated hydroxyl group of an opiate peptide (which have the N-terminal sequence Tyr- Gly-Gly-Phe-Met/Leu such as enkephalins, dynorphins and endorphins) or non-peptide ligands.
  • methylation of a phenolic hydroxyl group of morphine produces the less active analog codeine.
  • GnRH is used as an example only, and that the structural odifications to the 6-member aromatic ring in GnRH can likewise be applied to any biologically active ligand having a 6-membered aromatic ring or 5-membered ring which can be modified according to Formulas I or II.
  • biologically active ligands are likewise not limited to merely the peptidic ligands but also include non-peptidic ligands. Consequently, the present invention is useful in selecting agonistic non-peptidic analogs of a biologically active ligand containing at least one 6- embered aromatic ring according to Formula I or 5- membered ring according to Formula II in which the interrelated properties of desensitization, tolerance, dependence, withdrawal and addiction are reduced.
  • non-peptidic ligands refer to the ring structures depicted in Formulas I and II wherein the peptide backbone has been removed.
  • GnRH will once again be used as a representative example to display the numerous advantages which can be achieved by the practice of the present invention.
  • GnRH analogs are useful for increasing sexual activity, fertility and egg yield and inducing ovulation in animals, and are useful for increasing productivity in the farming of fish, poultry and mammals, as well as for increasing fertility in humans.
  • GnRH analogs can also increase lifetime gamete production, and permit collection of gametes from pre- and post-natal, juvenile, prepubertal and mature mammals for natural and artificial fertilization.
  • GnRH analogs are also effective in the treatment of gonadotropin-related diseases such as prostatic cancer, breast cancer, endo etriosis and fibroid shrinkage.
  • GnRH agonistic and super agonistic analogs of GnRH often require continuous or rapid pulsatile dosing in order to avoid the potent desensitizing effects associated with these peptides.
  • the development of GnRH agonist analogs with reduced receptor desensitizing properties is advantageous because such analogs obviate the need or continuous or rapid pulsatile dosing methods and may be administered in a single dose or with considerably lower dose frequency.
  • the advantage of eliminating the need for pulsatile dosing likewise extends to all analogs of a biologically active ligand according to the present invention.
  • a non-desensitizing analog of a biologically active ligand quite surprisingly possesses the additional advantage of not requiring the continued use of solely the non-desensitizing analog but allows for the use of "normally" desensitizing analogs without the expected desensitizing effects upon the biologically active receptor.
  • a non-desensitizing GnRH analog may be administered alone or in combination with another normally desensitizing GnRH agonist since the desensitizing properties of the latter are suppressed by the presence of, or pretreatment with, the former.
  • a "normally" desensitizing analog is an analog of GnRH which has not been modified in a manner which reduces the desensitizing properties as illustrated in the present invention.
  • the use of a non-desensitizing GnRH analog in combination with normally desensitizing GnRH or synthetic analogs thereof is a preferred method aspect of the present invention.
  • a “biologically active receptor” is a molecule, having a specific binding site for its complementary ligand, and includes classical hormonal receptors, binding and/or transport proteins, enzymes, antibodies and the like.
  • a biologically active receptor includes membrane-bound proteins which control certain cellular processes in which themselves are regulated by the binding, or lack of binding of a complementary naturally occurring biologically active ligand. Because such membrane bound biologically active receptors are bound to membrane, it is believed that the conformation of the biologically active ligand necessary to activate such receptors are lipid induced.
  • there are other biologically active receptors which are not membrane bound. In such cases, such receptors may not require a lipid induced conformation of the biologically active ligand and, in fact, may require an aqueous induced conformation of the complementary biologically active ligand in order to activate such receptors.
  • biologically active receptors have been well documented in the art. Specific examples include insulin receptor (wherein the complementary ligand is insulin) and the Angiotensin II receptor (wherein the complementary ligand is Angiotensin II) , and the like.
  • non-desensitizing analogs of a biologically active ligand selected according to the present invention have a multitude of uses in humans and animals, either of which are considered “patients” as that term is employed in the present disclosure or claims.
  • Additional examples of desired uses of non-desensitizing GnRH analogs of a biologically active ligand selected according to the present invention include, for example, the ability to more readily synchronize estrus in livestock, e.g., cattle, sheep or swine, either in order to be able to mate all the females in a given group with a male of the desired genetic quality, or so as to be able to perform artificial insemination on a maximum number of females, both within a comparatively short period of time. It will be appreciated that such a method is of particular importance for breeders of race horses and show animals, where the fee is paid for the services of an exceptional male animal often amount to considerable sums of money.
  • the present invention is also directed to a method of treating a patient in a non-desensitizing fashion with a non-desensitizing analog of a biologically active ligand containing at least one 6-membered aromatic ring or 5-membered ring.
  • the method comprises first selecting an analog of a biologically active ligand containing a 6-membered aromatic ring according to Formula I or selecting an analog of a biologically active ligand containing a 5-membered ring according to Formula II:
  • X is selected from H, R 1 , -OR 1 , halide, -CN, -CHO, C(halide) 3 , -alk-OH, -alk-OR 1 , -alk-C0 2 H, -al -CO-R 1 , -alk-SH, -alk-SR 1 , -alk-CONH 2 , -C0 2 H, -CO-R 1 , -COR 1 , -OCONH 2 , -OCH 2 OH, -OC ⁇ OR 1 , -OCOR 1 , -N 3 , -N 2 , -NHCOR 1 , -N0 2 , -NH 2 , -NHR 1 , -NR 1 ;,, -S0 3 H, -SOjR 1 , -SCOR 1 , -NCS, -SCSR 1 , -S0 2 NH 2 ,
  • R 1 is selected from alkyl of 1-7 carbon atoms, alkenyl or alkynyl of 2-7 carbon atoms or cycloalkyl of 3-7 carbon atoms, optionally halogenated at one or more hydrogen.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are groups selected from X or -OH.
  • ⁇ is selected from P, N, S, or C being in either the L- or D-configuration and ⁇ can be deleted or extended by 1-2 carbon atoms, substituted or unsubstituted.
  • the nitrogen atom attached to ⁇ can be substituted or unsubstituted C, S, O or P and the carbon atom attached to ⁇ and oxygen can be substituted or unsubstituted N, S, O, P or C.
  • the aromatic ring of Formula I or the ring of Formula II can contain 0-4 N, S or O atoms.
  • Formula II can be fused with a 6-membered aromatic ring which can also contain 0-4 N, S or 0 atoms which can be substituted in the same manner as the aromatic ring of Formula I. Also included within Formulas I and II, above, are D-tyrosine and D-histidine.
  • Step two of the method comprises * administering to a patient in need thereof the selected analog of a biologically active ligand as a composition comprising (i) a pharmaceutically effective amount of the selected analog and (ii) a pharmaceutically acceptable carrier for the selected analog. While it is possible for the particular active ingredient to be administered as the raw chemical, it is preferable, in view of the potency thereof, to present it as pharmaceutical formulation containing an acceptable carrier.
  • At least one non- desensitizing analog of GnRH is given in combination with at least one normally desensitizing GnRH or synthetic analog thereof.
  • the non-desensitizing analog(s) of GnRH may be given before a normally desenstizing GnRH analog, simultaneously therewith, or both.
  • the amount of the analog of the biologically active ligand will, of course, vary both with the particular active ingredient and with the route of administration. In general, however, for each of these utilities the dosage for nasal or parental administration will be in the range of about 0.005 to 200 ⁇ g per kilogram body weight of the patient, preferably between about 0.01 and 100 ⁇ g/kg.
  • the dosage would generally be in the range of about 0.005 to lOOO ⁇ g/kg, preferably about 0.05 to 200 ⁇ g/kg. It is understood that all dosages are calculated with reference to the base peptide. These doses apply to both a non-desensitizing and normally desensitizing analog of GnRH when administered in one of the combination protocols described above.
  • non- desensitizing fashion treats a patient in a manner such that the patient does not need to be treated with the type of pulsatile dosing that was heretofore required in order to successfully achieve the hormonal changes in the body of animals and humans.
  • the analogs, alone or in combination with normally desensitizing analogs, according to the present invention obviate the need for continuous or rapid pulsatile dosing methods and thus may be administered in a single dose or with considerably lower dose frequency.
  • the formulations of the present invention comprise an active ingredient or combination thereof, as described above, together with one or more pharmaceutically acceptable carriers as well as other optional therapeutic ingredients.
  • the carriers must be pharmaceutically "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations should not include oxidizing agents and other substances with which peptides, or non-peptides, are known to be incompatible.
  • formulations include those suitable for oral, rectal, nasal, topical, vaginal or parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the more suitable route in any given case will depend upon the selected active ingredient.
  • an active ingredient(s) may be presented as a depot formulation having a slow-release characteristic suiting it for implantation in the body of the recipient, for example, sub-cutaneously, intramuscularly, intraperitoneally or intravaginally.
  • injections may be given in depot form with a slow release agent such as an emulsion, sesame oil, a 10% aqueous polyvinylpyrolidone, or in biodegradable microspheres such as polylactic/glycolic acid.
  • administration may be given with the aid of a mini-osmopump, located internally or externally.
  • administration may be optionally given with a dopamine antagonist such as do peridone.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typical methods include the step of bringing into association the active ingredient with the carrier which optionally contains one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; or as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-water liquid emulsion or a water- oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compressing or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert dilution, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powder compound moistened with an inert liquid diluent.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as coco-butter, while a suitable formulation for nasal administration is nasal drops comprising an active ingredient in an aqueous or oily solution.
  • Formulations suitable for oral administration include lozenges comprising the active ingredient in a flavored basis, usually sucrose or acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin, glycerine or sucrose and acacia.
  • Formulations suitable for vaginal administration may be presented as pessaries, creams, pastes, or spray formulations containing in addition to the active ingredients such carriers as are known in the art to be appropriate.
  • Formulations suitable for parental administration conveniently comprise sterile aqueous solutions of the active ingredient, which solutions are preferably isotonic with the blood of the recipient.
  • Such formulations may be conveniently prepared by dissolving a solid active ingredient in water to produce an aqueous solution, and rendering said solution sterile and isotonic with the blood of the recipient.
  • non-desensitizing analogs of biologically active ligands containing at least one 6-membered aromatic ring or 5- membered ring.
  • the non-desensitizing analogs of a biologically active ligand contain at least one 6- membered aromatic ring according to Formula I or 5-membered ring according to Formula II:
  • X is selected from H, R 1 , -OR 1 , halide, -CN, -CHO, C(halide) 3 , -alk-OH, -alk-OR 1 , -alk-C0 2 H, -alk-C0 2 R * , -alk-SH, -alk-SR 1 , -alk-CONH 2 , -C0 2 H, -COjR 1 , -COR 1 , -OCONH 2 , -OCH 2 OH, -OCH 2 OR * , -OCOR 1 , -N 3 , -N 2 , -NHCOR 1 , -N0 2 , -NH 2 , -NHR 1 , -NR ⁇ , -S0 3 H, -SO ⁇ 1 , -SCOR 1 , -NCS, -SCSR 1 , -S0 2 NH 2 , -SO
  • R 1 is selected from alkyl of 1-7 carbon atoms, alkenyl or alkynyl of 2-7 carbon atoms or cycloalkyl of 3-7 carbon atoms, optionally halogenated at one or more hydrogen.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are groups selected from X or -OH.
  • ⁇ is selected from P, N, S, or C being in either the L- or D-configuration and ⁇ can be deleted or extended by 1-2 carbon atoms, substituted or unsubstituted.
  • the nitrogen atom attached to ⁇ can be substituted or unsubstituted C, S, O or P and the carbon atom attached to ⁇ and oxygen can be substituted or unsubstituted N, S, 0, P or C.
  • the aromatic ring of Formula I or the ring of Formula II can contain 0-4 N, S or O atoms. Likewise, the aromatic ring of Formula I or ring of
  • Formula II can be fused with a 6-membered aromatic ring which can also contain 0-4 N, S or O atoms which can be substituted in the same manner as the aromatic ring of Formula I. Also included within the Formulas I and II, above, are D-tyrosine and D-histidine.
  • positions 1 is Pyr, N-acetyl, N-Pyr-imino acid, or (C ⁇ cycloalkyl)acyl
  • positions 2 and 3 are aliphatic or aromatic amino acid
  • position 4 is Ser, Thr or Ala
  • position 5 is aromatic amino acid His, Trp or Phe
  • position 8 is an amino acid with a basic sidechain
  • position 9 is imino acid or aliphatic amino acid
  • position 10 is GlyNH 2 , AlaNH 2 , NHEt, NHPr, NHCH 2 CH 2 0H;
  • GnRH analogs having the Formula III include GnRH analogs having the Formula III:
  • X]-X ⁇ 0 are selected from the following: X, is Pyr or N-acyl-amino acid; X 2 is an aromatic amino acid; X 3 is an aromatic amino acid, X 4 is Ala, Thr, Ser, Hse, Ser(Me) , ⁇ -C-methyl-Ser(Me) or Aib; X 5 is Tyr(O-alkyl) , Phe(4'-halogen) or Phe (A '-alkyl) ; X depot is Gly, Aib, or D-amino acid (natural or synthetic, including an amino acid bearing a protecting group) or ⁇ -C-alkyl-amino acid; X 7 is Leu, lie, Trp, Cha, Val or ⁇ -C-methyl-amino acid; X 8 is Arg, Gin, Tyr or Leu; Xg is Pro, pipecolic acid, nipecotic acid, azetidine-2- carb
  • Another preferred embodiment is one in which the ⁇ -carbon atom of at least one of the amino acids is alkylated, in which case position 5 may be as described by Formulas I or II or may be ⁇ -C-methyl-histidine or ⁇ -C-methy1-tyrosine.
  • GnRH analogs and other analogs of biologically active ligands containing ⁇ -C-alkyl-amino acids are new.
  • a particularly preferred embodiment includes GnRH analogs in which at least one of positions 4, 5, 6 and 7 contain an ⁇ -C-alkyl-amino acid. Such modifications are advantageous for promoting and stabilizing turns occurring in this region of the peptide backbone, and for limiting proteolysis of the peptide.
  • analogs of a biologically active ligand according to the present invention can be synthesized by the methods well-known to one skilled in the art.
  • compounds can be synthesized by the solid phase method by one or more strategies known to one skilled in the art (J. Stewart and J. Young, Solid Phase Peptide Synthesis. 2nd Ed. (1984) , Pierce Chemical Co.).
  • chloromethylated polystyrene or benzhydrylamine resin can be used with N-t-butyloxycarbonyl protected amino acids and sidechain protection such as His(Tos) , Ser(Bzl) and Arg(Tos) .
  • the peptide-resin bond may be cleaved and protecting groups removed by treatment with anhydrous HF, or the peptide-resin bond may be cleaved and aminoalkylated with alkylamine and the protecting groups subsequently removed with HF.
  • the peptide may then be purified by reversed-phase HPLC.
  • peptides can be accomplished, for example, with the use of a Varian HPLC system equipped with a Vista 401 micro-processor controller. Separations can be achieved, for example, on a Bio-Rad Hi-Pore 318 reverse-phase preparative column (25.0 x 2.15 cm) at 25°C with a stepped linear gradient of acetonitrile in 0.1% CF 3 C0 2 H at a flow rate of 7.5 ml/min. Automated repetitive injections of peptides (5 x 5 mg) can then be made from a nitrogen pressurized Rheodyne injector with a 2.0 ml sample loop. One-fifth of the total sample may then be injected during each run by lowering the flow rate to 4.
  • One cycle could thus consist of the following events : 0 - 10 min, 7.5 ml/min, 90% H 2 O/10% of 1% aqueous CF 3 C0 2 H; 10 - 11 min, 4 . 0 ml/min; 11 - 11. 1 min, "inject” ; 11.
  • the resin is a novel chloro-(orthochloro)-trityl-resin to which the FMOC- protected, terminal amino acid is attached in the presence of diethylpropylamine (1.1 equivalents) in methylene chloride for 1 hour.
  • stepwise synthesis of the peptide with FMOC-amino acids is carried out with DCC/HBT
  • Cys(t-butyl) and the like, remain intact when the peptide-resin bond is cleaved with trifluoromethanol/acetic acid/methylene chloride in a ratio of 7/1/2, respectively.
  • a peptide amide may be prepared by treating the liberated peptide with methanolic HCl for 1-4 hours to yield the methyl ester followed by aminolysis in methanolic ammonia for 4-24 hours.
  • treatment of the received peptide with monoalkylamine in the presence of a suitable coupling agent such as DCC/HBT in a suitable solvent such as DMF for 1-4 hours affords the peptide N-alkylamide. Removal of protecting groups may be accomplished with 50% TFA in chloroform for 30 min.
  • an acid- sensitive group is to be maintained, such as
  • D-His(Trt) the synthesis is carried out with "limited” sidechain protection, for example, Pyr-His-Trp-Ser(Me)- Tyr(Me)-D-His(Trt)-Leu-Arg-Pro-resin, or alternatively by fragment condensation of Pyr-His-Trp-Ser(Me)- Tyr(Me)-D-His(Trt)-LeuOH (prepared using the
  • novel compounds produced according to the novel process described above are analogs of GnRH, and other hormonal peptides, in which an acid-sensitive protecting group is maintained at the end of the synthesis as a result of the use of an extremely labile peptide-resin bond provided by the (ortrochloro)trityl- resin bond.
  • Such analogs include, but are not limited to, compounds having the Formula III:
  • X theft is D-His having the protecting group trityl, tosyl, dansyl, dinitrophenyl, benzyloxymethyl or optionally substituted benzyl; D-Ser/Thr having the protecting group trityl, t-butyl, acyl, optionally substituted benzyl or benzyloxycarbonyl; D-Cys having the protecting group trityl, t-butyl, tosyl, or optionally substituted benzyl; D-Tyr having the protecting group tosyl, trityl, acyl, t-butyl, optionally substituted benzyl or benzyloxycarbonyl; D-Arg having the protecting group Tos, Mtr or Pmc; D-Orn/Lys having the protecting group t-Boc, trityl or optionally substituted benzyloxycarbonyl; D-Asp/Glu having the protecting group
  • a particularly preferred set of compounds prepared by the novel process according to the present invention are the compounds according to Formula III, wherein Xg comprises an amino acid which contains an acid-sensitive sidechain protecting group.
  • the amino acids containing acid-sensitive protecting groups are a particularly preferred set of novel compounds which can be prepared by the novel synthesis method of the present invention as a result of the use of the extremely labile peptide-resin bond provided by the (orthochloro)trityl-resin bond.
  • the particularly preferred acid-sensitive protecting groups which are uniquely useful in the novel method described above are, for example, trityl, t-Boc, t-butyl, Mtr, Pmc or formyl.
  • the terms "acid-sensitive” and “sidechain protecting group” are used in accordance with their art recognized definition, to the extent not inconsistent with the principles of the present invention.
  • the novel method of the present invention is also particularly well suited for the preparation of analogs of a biologically active ligand having the Formula III, wherein X, is Pyr (L or D) , N-acyl-amino acid, ⁇ -C-Alkyl-Pyr or N-acyl- ⁇ -C-alkyl-amino acid; X 2 , X 3 , X 4 , X 6 , X 7 and X 8 are independently natural, synthetic, protected or ⁇ -C-alkyl- amino acid, or X 6 -X 7 optionally contains a 7-lactam; Xg is imino acid or ⁇ -C-alkyl-imino acid; X 10 is -N(H)R wherein R is GlyNH 2 , azaGlyNH 2 , alkyl, alkenyl, haloalkyl, hydroxyalkyl, cycloalkyl or aryl, wherein each alkyl, alkenyl or
  • the relative responsiveness of goldfish pituitary fragments to various salmon and mammalian GnRH analogs were determined by using a superfusion system based on that described previously (Mackenzie et al., 1984; Chang et al., 1984; Marchant et al., 1987). Briefly, goldfish pituitaries were removed, pars distalis were separated, and fragments were prepared ( ⁇ 0.5 mm 2 ) and placed between two 100- ⁇ l layers of Cytodex carrier beads in a 300- ⁇ l superfusion chamber (3 pituitary equivalents per chamber) .
  • the fragments were superfused (5 ml/h) overnight (10-12 h) with Medium 199 containing Hanks' basic salts (Gibco Laboratories, Grand Island, N.Y.) 25 mM 4-(l-hydroxyethyl)-l-piperazineethanesulfonic acid (HEPES) and 56 TJ/ml nystatin. Two hours prior to the experiment, the medium was switched to Hanks' basic salts solution, supplemented with 25 mM HEPES buffer and 0.1% BSA (HBSS), and the flow rate was increased to 15 ml/h.
  • Hanks' basic salts Gibco Laboratories, Grand Island, N.Y.
  • HEPES 4-(l-hydroxyethyl)-l-piperazineethanesulfonic acid
  • HBSS BSA
  • Example 3 Desensitization properties of GnRH agonists after 2 min pulses every 20 min in superfused goldfish pituitaries .in vitro according to the methods described in Example 2.
  • Rats were injected every 30 min with 1.5 ⁇ g of GnRH, [Tyr(Me) 5 ]GnRH, or GnRH+[Tyr(Me) 5 ]GnRH. The values are corrected for basal levels (1.1 units/50 ⁇ l) by subtraction.

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Abstract

L'invention se rapporte à de nouveaux analogues non désensibilisants d'un ligand biologiquement actif ayant au moins un cycle à six éléments ou un cycle à cinq éléments, ainsi qu'à un procédé permettant de sélectionner des analogues non désensibilisants d'un ligand biologiquement actif ayant au moins un cycle à six éléments ou un cycle à cinq éléments. L'invention décrit également un nouveau procédé pour traiter un patient de façon non désensibilisante au moyen d'un analogue non désensibilisant d'un ligand biologiquement actif ayant au moins un cycle à six éléments ou un cycle à cinq éléments. L'invention se rapporte en outre à un nouveau procédé pour produire à des fins utiles de nouveaux analogues non désensibilisants de gonadolibérine et de peptides d'opiacés, ainsi qu'à de nouvaux composés non désensibilisants et à des compositions préparées à partir de ces composés.
EP92914041A 1991-07-01 1992-07-02 Analogues non desensibilisants de gonadoliberine et d'autres ligands biologiquement actifs Withdrawn EP0592512A1 (fr)

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GB9100468D0 (en) * 1991-01-09 1991-02-20 Proteus Molecular Design Improvements in and relating to hormones
US5688506A (en) 1994-01-27 1997-11-18 Aphton Corp. Immunogens against gonadotropin releasing hormone
US5677184A (en) * 1994-04-19 1997-10-14 Takeda Chemical Industries, Ltd. CHO cells that express human LH-RH receptor
SI20424A (sl) * 1998-03-05 2001-06-30 Agouron Pharmaceuticals, Inc. Nepeptidna GnRH sredstva
HUP0103622A3 (en) 1998-08-20 2003-01-28 Agouron Pharmaceuticals Inc La Non-peptide gnrh agents, methods and intermediates for their preparation and medicaments containing them
DE60226419D1 (de) 2001-03-08 2008-06-19 Univ Tulane Somatostatin-antagonisten
AU2003202115A1 (en) 2002-02-12 2003-09-04 Pfizer Inc. Non-peptide compounds affecting the action of gonadotropin-releasing hormone (gnrh)
US6861236B2 (en) 2002-05-24 2005-03-01 Applied Nanosystems B.V. Export and modification of (poly)peptides in the lantibiotic way
JP2005538064A (ja) 2002-06-13 2005-12-15 ファイザー・インク 非ペプチドＧｎＲＨ剤、医薬組成物、およびそれらの使用方法
GB0307777D0 (en) 2003-04-04 2003-05-07 Medical Res Council Conjugate compounds
RU2554087C2 (ru) 2009-12-18 2015-06-27 Айденикс Фармасьютикалз, Инк. 5,5-конденсированные ариленовые или гетероариленовые ингибиторы вируса гепатита с
AU2011207432A1 (en) * 2010-01-25 2012-08-02 Cornell University Aromatic-cationic peptides and uses of same

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DE3333752A1 (de) * 1983-09-19 1985-04-11 Victor Dipl.- Chem. 8000 München Brantl Pharmakologisch aktive peptide
US5110904A (en) * 1989-08-07 1992-05-05 Abbott Laboratories Lhrh analogs
WO1991010140A2 (fr) * 1989-12-29 1991-07-11 University Technologies International Inc. Methodes de modelage des structures tertiaires de ligands biologiquement actifs, y compris leurs agonistes et antagonistes et nouveaux antagonistes synthetiques bases sur l'angiotensine

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