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WO1992019253A1 - ANALOGUES DE CHOLECYSTOKININE CENTRALE (CCK) CONTENANT DES ACIDES AMINES α-SUBSTITUES - Google Patents

ANALOGUES DE CHOLECYSTOKININE CENTRALE (CCK) CONTENANT DES ACIDES AMINES α-SUBSTITUES Download PDF

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WO1992019253A1
WO1992019253A1 PCT/US1992/003015 US9203015W WO9219253A1 WO 1992019253 A1 WO1992019253 A1 WO 1992019253A1 US 9203015 W US9203015 W US 9203015W WO 9219253 A1 WO9219253 A1 WO 9219253A1
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fmoc
asp
met
phe
obu
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PCT/US1992/003015
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David Christopher Horwell
Reginald Stewart Richardson
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Warner-Lambert Company
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Priority to JP4510283A priority Critical patent/JPH06506941A/ja
Publication of WO1992019253A1 publication Critical patent/WO1992019253A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • 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
    • C07K14/575—Hormones
    • C07K14/595—Gastrins; Cholecystokinins [CCK]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • CCK central cholecystokinin
  • the CCK peptides are widely distributed in various organs of the body including the gastrointestinal tract, endocrine glands, and the nerves of the peripheral and central nervous systems.
  • Various biologically active forms have been identified including a 33-amino acid hormone and various carboxyl-terminus fragments of this peptide (e.g., the octapeptide CCK26-33 and the tetrapeptide (CCK30-33) . (G. J. Dockray, Br. Med. Bull., 38 (No. 3) :253-258, 1982) .
  • CCK peptides are thought to be involved in the control of smooth muscle contractility, exocrine and endocrine gland secretion, sensory nerve transmission, and numerous brain functions. Administration of the native peptides cause gall bladder contraction, amylase secretion, excitation of central neurons, inhibition of feeding, anticonvulsive actions, and other behavioral effects.
  • CCK peptides in many brain areas also indicate major brain functions for these peptides (G. J. Dockray, Br. Med. Bull., 38 (No. 3) :253-258, 1982) .
  • the most abundant form of brain CCK found is CCK26-33, although small quantities of CCK30-33 exist (Rehfeld and Gotterman, J. Neurochem. 32:1339-1341 (1979)).
  • the role of central nervous system CCK is not known with certainty, but it has been implicated in the control of feeding (Della-Fera and Baile, Science 206:471-473 (1979)).
  • appetite suppressant drugs either act peripherally, by increasing energy expenditure (such as th roxine) , or in some other manner (such as the biguanides) , or act by exerting a central effect on appetite or satiety.
  • CCK has been shown to increase the levels of insulin when administered to mammals (Rushakoff, et al, J. Clin. Endocrinol. Metab. 65:395 (1987)).
  • C-terminal fragments of CCK have recently been reported to function as CCK receptor antagonists (Jensen, et al, Biochem. Biophys. Acta 757:250 (1983); Spanarkel, J. Biol. Chem. 258:6746 (1983)).
  • Japanese patent application 70/10506 to Miyao, et al discloses a tetrapeptide derivative of the carboxy terminal sequence of gastrin (L-Trp-L-Lys-L-Asp-L-Phe-NH 2 ) which has antigastrin activity.
  • Centrally acting appetite suppressants either potentiate central catecholamine pathways and tend to be stimulants (for example, amphetamine) , or influence serotonergic pathways (for example, fenfluramine) .
  • Other forms of drug therapy include bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety.
  • WO 90/06937 covers derivatives of tetrapeptides as CCK agonists. The compounds are for treating gastrointestinal disorders, central nervous system disorders, insulin-related disorders, treatment of pain or regulating appetite.
  • the invention relates to novel compounds which are CCK ligands and are ⁇ , ⁇ -substituted mono-, di-, tri-, tetra-, or polypeptides of formula
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 17 , A, and n are as defined below.
  • the invention also relates to a pharmaceutical composition containing an effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for appetite suppression.
  • the invention further relates to a method of appetite suppression in mammals which comprises administering an amount effective to suppress appetite of the composition described above to a mammal in need of such treatment.
  • the invention further relates to methods of treating gastrointestinal disorders, central nervous system disorders such as CNS suppressants which can exhibit such effects as an ipsychotic, neuroleptic, anxiolytic, and anticonvulsant.
  • the invention further relates to methods of reducing gastric acid secretion and to treating gastrointestinal ulcers.
  • the invention further relates to blocking the reaction caused by withdrawal from drug or alcohol use and to potentiating the effects of morphine and other opioids in treating pain.
  • the invention further provides processes for the preparation of compounds of formula I.
  • the invention further provides novel intermediates useful in the preparation of compounds of formula I and also provides processes for the preparation of the intermediates.
  • Figure 1 shows Compound 2 is a partial agonist.
  • Figure 2 shows Compound 4 is an agonist and Compound 5 is a weak agonist.
  • Figure 3 shows Compound 6 is an agonist.
  • Figures 1 through 4 show CCK8s as agonist reference standards.
  • the compounds of the present invention are analogs of CCK 30-33 and CCK 26-33 which contain at least one residue of an amino acid which is ⁇ , ⁇ -disubstituted. These compounds differ from the mammalian genetically coded natural peptides in that the ⁇ -substituents cannot all simultaneously be hydroge .
  • R 1 is hydrogen, BOC, 1-Adoc, 2-Adoc, Z, FMOC,
  • A is a bond, Gly, ⁇ -ALA, GABA, DAVA, Aib,
  • 3-indazoyl or phenyl any of these can have from 0 to 3 substituents each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, methoxy, trifluoromethyl, nitro, hydroxy, NH 2 , and 0CF 3 ;
  • R 5 is lower alkyl, (CH 2 ) r S (CH 2 ) S CH 3 wherein r is an integer of from 1 to 6 and s is an integer of from 0 to 6;
  • n is an integer of from 1 to 3;
  • R 7 is -OH, -COOH, tetrazole, triazole, -COOR 16 , -CONR 10 R n , wherein R 16 is lower alkyl, and R 10 and R 11 are as described below;
  • R 9 is selected from R 3 above;
  • R 17 is -C-NR 10 R 1:L , CH 2 OR 18 or H wherein R 10 and R 11 are each independently hydrogen, lower alkyl, alkoxycarbonyl, carboxyalkyl, or R 10 and R- 1 together form a ring of from 3 to 10 atoms with the nitrogen to which they are attached which ring contains atoms selected from carbon, nitrogen, oxygen, and sulfur; and
  • R 18 is R 1 or CH 2 C0 2 H or CH 2 CONR 10 R 1:L or CONR 10 R ⁇ :L ;
  • R 2 and R 3 , R 4 and R 5 , R 6 and R 7 , R 8 and R 9 or R 9 and R 10 may together form a ring of from 3 to 8 atoms which atoms are selected from carbon, nitrogen, oxygen, and sulfur.
  • Preferred compounds of the instant invention are those of formula I wherein
  • R 1 is Fmoc, Z, Boc, or Me 3 Si(CH 2 ) 2 0C0-;
  • A is a bond, Gly, ⁇ -ALA, Aib, Asp-Tyr-Met-Gly, Asp-Tyr(OSO3H)-Met-Gly;
  • R 2 , R 4 , R 6 , and R 8 are each independently alkyl of from 1 to 3 carbon atoms, carboxyalkyl of 1 or 2 carbon atoms, or CH OH;
  • R 3 is 3-indazolyl, 3-benzothienyl, 2-benzofuran l, 3-benzofuranyl, or 2-bromo-
  • R 5 is isobutyl, sec-butylethyl, n-propyl, or i-propyl
  • R 7 is CONH 2 , CONMe 2 , or OH
  • R 9 is selected from R 3 ;
  • R 10 and R 11 are each independently alkyl of from 1 to 3 carbon atoms or together R 10 and R 11 form a ring of from 4 to 8 atoms including the nitrogen to which they are attached. More preferred compounds of the instant invention are those of formula wherein R 1 is hydrogen or BOC; A is a bond or ⁇ -ALA;
  • R 2 , R 4 , R 6 , and R 8 are each independently CH 3 or CH 2 C0 2 H;
  • R 3 is 3-indolyl, 1-naphthyl, or 2-naphthyl;
  • R 5 is n-butyl, n-pentyl, (CH ) 2 SCH 3 or
  • R 7 is OH, tetrazole, triazole, or C0 2 H
  • R 9 is phenyl, 1-naphthyl, or 2-naphthyl
  • R 1C and R 11 are each independently hydrogen, CH 3 or together R 10 and R 11 form a ring of 5 or 6 atoms including the nitrogen to which they are attached.
  • Especially preferred compounds of the instant invention are selected from the group consisting of: ⁇ -Methyl-DL-tryptophyl-L-methionyl-L- ⁇ -aspartyl- L-phenylalaninamide, ⁇ -Methyl-D-tryptophyl-L-methionyl-L- ⁇ -aspartyl-L- phenylalaninamide, ⁇ -Methyl-L-tryptophyl-L-methionyl-L- ⁇ -aspartyl-L- phenylalaninamide,
  • Preferred compounds are those wherein the ⁇ -amino acid residues are of the [L] configuration.
  • the compounds of the present invention can have multiple chiral centers depending on their structures. Centers of asymmetry may exist on carbon atoms bearing substituents R 1 in formula I and at R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R ⁇ , R 9 , and R 17 in formula I.
  • the compounds of the present invention may exist as diastereomers, mixtures of diastereomers, or as the mixed or the individual optical enantiomers.
  • the present invention contemplates all such forms of the compounds.
  • the mixtures of diastereomers are typically obtained as a result of the reactions described more fully below. Individual diastereomers may be separated from mixtures of the diastereomers by conventional techniques such as column chromatography or repetitive recrystallizations.
  • the compounds of the instant invention include the solvates and hydrates and pharmaceutically acceptable salts of formula I.
  • lower alkyl means straight or branched chain alkyl groups of from 1 to 6 carbon atoms unless otherwise specified.
  • alkoxycarbonyl means a carbon group of from 1 to 4 carbon atoms.
  • Preferred pharmaceutically acceptable salts are benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, diethylamine, and tromethane.
  • Especially preferred pharmaceutically acceptable salts are N-methylglucamine and sodium for acids and HC1, sulfate, and trifluoroacetate for bases.
  • the compounds of the present invention can be formed by coupling individual substituted ⁇ -amino acids by methods well known in the art. (See, for example, standard synthetic methods discussed in the multi-volume treatise "The Peptides, Analysis, Synthesis, Biology," by Gross and Meinhofer, Academic Press, New York.)
  • the individual substituted alpha amino acid starting materials are generally known or, if not known, may be synthesized and, if desired, resolved by methods within the skill of the art. (Synthesis of racemic [DL]- ⁇ -methy1 tryptophan methyl ester - see Bra ⁇ a, M. F., et al, J. Heterocvclic Chem. 17:829 (1980)) .
  • the invention also includes novel intermediates which are useful in the preparation of the final products.
  • These intermediates are the following compounds or the compound on the solid phase resin; for example, Fmoc-MePhe-Resin.
  • Trp-Met-Asp (OBu 1 )-MePhe-NH 2 Trp-Met-Asp (OBu 1 )-MePhe-NH 2 ,
  • Fmoc-MeAsp-Phe-NH 2 Fmoc-Met-MeAsp(OBu t ) -Phe-NH 2 , Fmoc-Trp-Met-MeAsp(OBu 1** )-Phe-NH 2 ,
  • Fmoc-MeAsp(OBu fc )OH Fmoc-MeAsp(OBu fc )OPFP.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
  • the powders and tablets preferably contain 5 to about 70% of the active component.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
  • Liquid form preparations include solutions, suspensions, and emulsions.
  • Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • the biological activity of compounds of the present invention was evaluated employing an initial screening test which rapidly and accurately measured the binding of the tested compound to be known CCK receptor sites.
  • Specific CCK receptors have been shown to exist in the central nervous system. (See Hays et al, Neuropeptides 1:53-62 (1980); and Satuer et al, Science 208:11555-56 (1980).
  • this screening test the cerebral cortices taken from male CFLP mice weighing between 30 to 40 g were dissected on ice, weighed, and homogenized in 10 volumes of 50 mM Tris-HCl buffer (pH 7.4 at 0-4°C) .
  • the resulting suspension was centrifuged, the supernate was discarded, and the pellet was washed by resuspension in Tris-HCl buffer followed by recentrifugatio .
  • the final pellet was resuspended in 20 volumes of 10 nM Hepes buffer (pH 7.2 at 23°C) containing 130 nM NaCl, 4.7 nM KC1, 5 nM MgCl 2 , 1 nM EDTA, 5 mg/mL bovine albumin, and bacitracin (0.25 mg/mL) .
  • cerebral cortical membranes were incubated at 23°C for 120 minutes in a final volume of 500 ⁇ liter of Hepes incubation buffer (pH 7.2) together with 0.2-20 nM tritiated- pentagastrin (Amersham International, England) .
  • membranes were incubated with a single concentration (2 nM) of ligand, together with increasing concentrations (10 -11 to 10 ⁇ 14 M) of competitive test compound. In each case, the nonspecific binding was defined as that persisting in the presence of the unlabeled octapeptide CCK 26 _ 33 (10 *6 M) .
  • radioactivity bound to membranes was separated from that free in solution by rapid filtration through Whatman GF/B filters and washed three times with 4 mL of ice cold Tris-HCl buffer. Filters from samples incubated with tritiated-pentagastrin were placed in polyethylene vials with 4 mL of scintillation cocktail, and the radioactivity was estimated by liquid scintillation spectrometry (efficiency 47-52%) .
  • the specific binding to CCK receptor sites was defined as the total bound tritiated-pentagastrin minus the amount of tritiated-pentagastrin bound in the presence of 10 ⁇ 6 octapeptide, CCK 26 _ 33 .
  • Figure 1 shows the dose response curve for CCK ⁇ s before and during exposure to compound (2) and a curve for compound (2) alone.
  • the curves represent the total number of action potentials occurring during a response to CCK ⁇ s or (2) and are plotted as counts (Y-axis) versus dose (X-axis) .
  • the curves for compound (2) indicate that this compound has partial agonist type properties in this experiment.
  • * is CCK-8s + (2)
  • Figure 2 shows the dose response curves for BH-CCK and CCK4 analogs on the same neurone in the VMH.
  • the total number of action potentials occurring during a response is plotted as counts (Y-axis) versus dose of ligand (X-axis) .
  • Compound (4) is equipotent with CCK8s while compound (6) possesses slightly lower electrophysiological activity and compound (5) has relatively low agonist activity.
  • Compound (2) is a partial agonist.
  • Compounds of the present invention are useful as appetite suppressants as based on the tests described hereinbelow.
  • MPE 50 values are obtained for the anorectic effects of these compounds.
  • the compounds of the instant invention are administered to the patient at dosage levels of from about 200 to about 2800 mg per day.
  • the compounds of the instant invention have therapeutic utility as appetite suppressants and, as antagonists, as agents in treating gastrointestinal disorders, central nervous system disorders such as CNS suppressants which can exhibit such effects as antipsychotics, neuroleptics, anxiolytics, and anticonvulsants.
  • the compounds of the instant invention are expected to have utility in reducing gastric acid secretion, in reducing anxiety, in treating gastrointestinal ulcers, in treating psychotic behavior, in blocking the reaction caused by withdrawal from drug, alcohol, cocaine, benzodiazepine, diazepam, or nicotine, and in potentiating the effects of morphine for treating pain.
  • CCK Analogs containing ⁇ -methyl amino acids were made by three methods. Method A is a solution phase procedure wherein the peptides were assembled using standard solution phase protocols yielding fully protected intermediates or standard salt coupling which yield aspartic acid side-chain deprote ⁇ ted intermediates. Examples 1 and 2 below illustrate Method A.
  • the peptides can also be prepared by Method B, a solid-phase method wherein peptides were constructed on solid-phase resins designed to produce C-terminal amides either by treatment of the resin with ammonia in methanol or by direct cleavage of an appropriately substituted resin using trifluoroacetic acid, with the required scavengers, giving the amides directly.
  • Method B a solid-phase method wherein peptides were constructed on solid-phase resins designed to produce C-terminal amides either by treatment of the resin with ammonia in methanol or by direct cleavage of an appropriately substituted resin using trifluoroacetic acid, with the required scavengers, giving the amides directly.
  • the latter protocol was used with DuPont RapidAmide ® or Nova Biochem Novasyn KR ® resins either in a simple bubbler apparatus (DuPont resin) or automated synthesizer (Nova Biochem resin) . This method is illustrated by Example 3 below.
  • the third method, Method C is a nonsolvent method whereby the amino component and a pentafluorophenyl ester are heated together without a solvent at 50° to 100°C for 10 to 120 minutes or more.
  • This method is illustrated by Example 4 below.
  • Male Hooded Lister rats (175-250 g) are housed individually and fasted overnight (free access to water) . They are anesthetized with urethane (1.5 g/kg IP) and the trachea cannulated to aid spontaneous respiration.
  • the stomach is perfused continuously using a modification of the original method of Ghosh & Schild in "Continuous recording of acid secretion in the rat", Br. J. Pharmac.
  • Pentagastrin is stored as a frozen aliquot and diluted to the required concentrations with sterile 0.9% w/v NaCl. Novel compounds are dissolved in sterile 0.9% w/v NaCl on the day of the experiment.
  • Drugs are administered IV through a cannulated jugular vein as a bolus in a dose volume of 1 mL/kg washed in with 0.15 mL 0.9% w/v NaCl. Basal pH is allowed to stabilize before administration of compounds is begun. Typically 30 minutes elapses between surgery and the first compound administration.
  • Compounds of the invention may also antagonize the stimulation of gastric acid secretion produced by a standard dose of 1 nmole/kg pentagastrin.
  • a compound also attenuates the amount of gastric acid secreted in response to a 1 nmole/kg dose of pentagastrin (initial pentagastrin response 254 ⁇ moles/1 H + , after the compound (cumulative dose of 1.1 ⁇ mole/kg) 128 ⁇ moles/1 H + ) .
  • pentagastrin initial pentagastrin response 254 ⁇ moles/1 H +
  • the compound cumulative dose of 1.1 ⁇ mole/kg 128 ⁇ moles/1 H +
  • the compounds of the instant invention are also useful as antiulcer agents as discussed hereinbelow.
  • Aspirin-induced gastric damage is assessed in groups of 10 rats each.
  • CMC carboxymethylcellulose
  • the animals are sacrificed five hours after aspirin administration and the stomachs removed and opened for examination.
  • the mean ulcer score in the saline control group is 12.1 ⁇ 6.85 ( ⁇ SD) .
  • Treatment with ranitidine (15 mg/kg PO) inhibits ulcer formation by 74% giving an ulcer score of 3.2 ⁇ 2.35 (p ⁇ 0.001 compared with controls) .
  • Treatment with a compound of the invention (10 mg/kg PO) results in an ulcer score of 6.3 ⁇ 4.14 (p ⁇ 0.05 compared with controls), a 48% reduction in ulcer formation.
  • the compounds of the instant invention are also useful as anxiolytic agents as described and discussed belo .
  • mice Anxiolytic activity is assessed in the light/dark exploration test in the mouse (B. J. Jones, et al, Br. J. Pharmacol. 93:985-993, 1988). The number of mice is 5 and the pretreatment time is 40 minutes. The compound is given p.o. in 0.1, 1, and 10 mg/kg doses.
  • the apparatus is an open-topped box, 45 cm long, 27 cm wide, and 27 cm high, divided into a small (2/5) area and a large (3/5) area by a partition that extends 20 cm above the walls. There is a 7.5 x 7.5 cm opening in the partition at floor level.
  • the small compartment is painted black and the large compartment white.
  • the floor of each compartment is marked into 9 cm squares.
  • the white compartment is illuminated by a 100-watt tungsten bulb 17 cm above the box and the black compartment by a similarly placed 60-watt red bulb.
  • the laboratory is illuminated with red light. All tests are performed between 13 hundred hours, 0 minutes and 18 hundred hours, 0 minutes. Each mouse is tested by placing it in the center of the white area and allowing it to explore the novel environment for five minutes.
  • mice Male Sprague Dawley (CD) Bradford strain rats are used. The rats are housed in groups of five at a temperature of 21 ⁇ 2 ⁇ C on a 12 hour light-dark cycle of lights-on between 07 hours 00 minutes and
  • Rats are fed CRM diet (Labsure) and allowed water ad libitum.
  • Rats are anesthetized with chloral hydrate (400 mg/kg SC) and placed in a Kopf stereotaxic frame.
  • Chronically indwelling guide cannulae (constructed of stainless steel tubing 0.65 mm diameter held bilaterally in Perspex holders) are implanted using standard stereotaxic techniques to terminate 3.5 mm above the center of the nucleus accumbens (Ant. 9.4, Vert. 0.0, Lat. 1.6) or 5.0 mm .above the central nucleus of the amygdala (An . 5.8, Ver . —1.8, Lat. ⁇ 4.5) (atlas of De Groot, 1959) .
  • the guides are kept patent during a 14-day recovery period using stainless steel stylets, 0.3 mm diameter, which extend 0.5 mm beyond the guide tips.
  • Rats are manually restrained and the stylets removed.
  • Intracerebral injection cannulae 0.3 mm diameter, are inserted and drugs delivered in a volume of 0.5 ⁇ l over 5 seconds (a further 55 seconds was allowed for deposition) from Hamilton syringes attached via polythene tubing to the injection units. Animals are used on a single occasion only.
  • locomotor activity follows the bilateral injection of amphetamine (20 ⁇ g) into the nucleus accumbens; peak hyperactivity (50 to 60 counts 5 minutes -1 ) occur 20 to 40 minutes after injection.
  • Intraperitoneal injection of the rats with a compound at 20 mg/kg or 30 mg/kg or at 10 mg/kg reduces the hyperactivity caused by the intra- accumbens injection of amphetamine. This test is known to be predictive of antipsychotic activity (Costall, Domeney & Naylor & Tyers, Brit J Pharmac 92:881-894) .
  • EXAMPLE 2 Also prepared by this method were ⁇ -methyl-L- tryptophyl-L-methionyl-I ⁇ - ⁇ -aspartyl-,L- phenylalaninamide
  • Trp-Met-Asp-DL-MePhe-NH 2 -CF 3 C0 2 H Trp-Met-DL-MeAsp-Phe-NH 2 -CF 3 C0 2 H.
  • the peptide was constructed from the C-terminus using Fmoc amino acid penta luorophenyl or DHBt esters and HOBt catalysis. Each residue was present in a fivefold excess to ensure rapid and complete acylation.
  • the peptide (4) was isolated following TFA cleavage (94% TFA, 5% anisole, 1% ethanedithiol) from the resin (2h, room temperature) in 46% yield (32 mg isolated).
  • HPLC C18, 20-80% MeCN-H 2 0 + 0.1% TFA
  • the preceding tetrapeptide was N-deprotected using 20% piperidine in DMF for 20 minutes then the solvent removed and the residue triturated with n-hexane, leaving the free amino tetrapeptide.
  • This was treated with thioanisole and ethanedithiol (100-250 ⁇ L/mmol and 50-100 ⁇ L/mmol) followed by 95% aqueous TFA (3-5 mL/mmol) for 5 minutes. All volatiles were removed and the residue triturated with diethyl ether, giving a white solid, purified by preparative HPLC.
  • Fmoc-DL-MeAsp(OBu fc )OPfp (1.46 g, 2.47 mmol) and H-Phe-NH 2 (0.41 g, 2.5 mmol) were dissolved in the minimum quantity of ethyl acetate to give a clear solution, then the solvent was immediately removed. The mixture was then heated at 100°C for 1 hour and cooled. Trituration of the residue with diethyl ether yielded the protected dipeptide, 993 mg, 71%.

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Abstract

L'invention se rapporte à de nouveaux peptides contenant au moins un acide aminé α,α-disubstitué. Les composés sont efficaes en tant qu'agents dans le traitement de l'obésité et des troubles gastro-intestinaux associés à la gastrine. Ils sont également efficaces dans le traitement de tumeurs dépendant de la gastrine ou en tant qu'antipsychotiques. De plus, les composés sont des agents anxiolytiques, anti-ulcéreux, antidépresseurs et sont des agents efficaces pour empêcher la réaction de sevrage produite par un traitement ou un usage chronique suivis de sevrage de nicotine, de diazépam, d'alcool, de cocaïne, de caféine ou d'opioïdes. Sont également décrits des procédés de préparation des composés, de nouveaux intermédiaires s'utilisant dans leur préparation, des compositions les contenant et des procédés d'utilisation desdits composés.
PCT/US1992/003015 1991-04-24 1992-04-15 ANALOGUES DE CHOLECYSTOKININE CENTRALE (CCK) CONTENANT DES ACIDES AMINES α-SUBSTITUES WO1992019253A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004011A3 (fr) * 1994-08-05 1996-05-02 Wisconsin Alumni Res Found Nouveau compose simulant un effet peptidique naturel
WO2002070546A3 (fr) * 2001-03-01 2002-12-05 Univ Ulster Peptide modifie
US7491699B2 (en) 2002-12-09 2009-02-17 Ramot At Tel Aviv University Ltd. Peptide nanostructures and methods of generating and using the same
US7504383B2 (en) 2003-01-07 2009-03-17 Ramot At Tel Aviv University Ltd. Peptide nanostructures encapsulating a foreign material and method of manufacturing same
US7625707B2 (en) 2003-10-02 2009-12-01 Ramot At Tel Aviv University Ltd. Antibacterial agents and methods of identifying and utilizing same
US7732479B2 (en) 2004-08-19 2010-06-08 Tel Aviv University Future Technology Development L.P. Compositions for treating amyloid associated diseases
US8372880B2 (en) 2003-09-25 2013-02-12 Tel Aviv University Future Technology Development L.P. Compositions and methods using same for treating amyloid-associated diseases
US8563273B2 (en) 2002-09-06 2013-10-22 Tel Aviv University Future Technology Development L.P. Method of screening for compounds that disaggregate amyloid aggregates
US8697634B2 (en) 2002-01-31 2014-04-15 Tel Aviv University Future Technology Development L.P. Peptides and methods using same for diagnosis and treatment of amyloid-associated disease
US9096645B2 (en) 2010-11-15 2015-08-04 Ramot At Tel-Aviv University Ltd. Dipeptide analogs for treating conditions associated with amyloid fibril formation
US10004828B2 (en) 2005-10-11 2018-06-26 Romat at Tel-Aviv University Ltd. Self-assembled Fmoc-ff hydrogels

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0226217A2 (fr) * 1985-12-19 1987-06-24 FISONS CORPORATION (a Massachusetts corporation) Peptides ayant des groupes ester-sulfate
WO1990012810A1 (fr) * 1989-04-25 1990-11-01 The Salk Institute For Biological Studies Analogues viia de facteurs de liberation d'hormones de croissance
US5013722A (en) * 1986-06-06 1991-05-07 Hoffmann-Laroche Inc. Cholecystokinin analogs for controlling appetite

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0226217A2 (fr) * 1985-12-19 1987-06-24 FISONS CORPORATION (a Massachusetts corporation) Peptides ayant des groupes ester-sulfate
US5013722A (en) * 1986-06-06 1991-05-07 Hoffmann-Laroche Inc. Cholecystokinin analogs for controlling appetite
WO1990012810A1 (fr) * 1989-04-25 1990-11-01 The Salk Institute For Biological Studies Analogues viia de facteurs de liberation d'hormones de croissance

Non-Patent Citations (1)

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Title
CHEMICAL AND PHARMACEUTICAL BULLETIN OF JAPAN, Volume 36(9), issued 1988, FUJII et al., "Studies on Peptides CLIX.1.2 Preparation of a Protected 33-Residue Peptide for the Synthesis of Human Cholecystokinin (hCCK-33)", pages 3271-3280. *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004011A3 (fr) * 1994-08-05 1996-05-02 Wisconsin Alumni Res Found Nouveau compose simulant un effet peptidique naturel
US5814316A (en) * 1994-08-05 1998-09-29 Wisconsin Alumni Research Foundation Compound to mimick a naturally occurring peptide's effect
WO2002070546A3 (fr) * 2001-03-01 2002-12-05 Univ Ulster Peptide modifie
AU2002238701B2 (en) * 2001-03-01 2008-01-24 Uutech Limited Modified derivatives of CCK-8
US8993510B2 (en) 2002-01-31 2015-03-31 Tel Aviv University Future Technology Development L.P. Peptides and methods using same for diagnosis and treatment of amyloid-associated disease
US8697634B2 (en) 2002-01-31 2014-04-15 Tel Aviv University Future Technology Development L.P. Peptides and methods using same for diagnosis and treatment of amyloid-associated disease
US8563273B2 (en) 2002-09-06 2013-10-22 Tel Aviv University Future Technology Development L.P. Method of screening for compounds that disaggregate amyloid aggregates
US7491699B2 (en) 2002-12-09 2009-02-17 Ramot At Tel Aviv University Ltd. Peptide nanostructures and methods of generating and using the same
US7504383B2 (en) 2003-01-07 2009-03-17 Ramot At Tel Aviv University Ltd. Peptide nanostructures encapsulating a foreign material and method of manufacturing same
US8372880B2 (en) 2003-09-25 2013-02-12 Tel Aviv University Future Technology Development L.P. Compositions and methods using same for treating amyloid-associated diseases
US7625707B2 (en) 2003-10-02 2009-12-01 Ramot At Tel Aviv University Ltd. Antibacterial agents and methods of identifying and utilizing same
US7732479B2 (en) 2004-08-19 2010-06-08 Tel Aviv University Future Technology Development L.P. Compositions for treating amyloid associated diseases
US10004828B2 (en) 2005-10-11 2018-06-26 Romat at Tel-Aviv University Ltd. Self-assembled Fmoc-ff hydrogels
US9096645B2 (en) 2010-11-15 2015-08-04 Ramot At Tel-Aviv University Ltd. Dipeptide analogs for treating conditions associated with amyloid fibril formation
US9630989B2 (en) 2010-11-15 2017-04-25 Ramot At Tel-Aviv University Ltd. Dipeptide analogs for treating conditions associated with amyloid fibril formation

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CA2106765A1 (fr) 1992-11-12
AU1879892A (en) 1992-12-21
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MX9201883A (es) 1992-10-01
JPH06506941A (ja) 1994-08-04
PT100427A (pt) 1993-08-31

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