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  • 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
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  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
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Definitions

• Peptides form the main messenger systems within and between cells and they number more than a thousand. Over a hundred peptides are known to act as hormone, neurohormones, or neurotransmitters, and this number is growing rapidly. The potential for drug development is therefore vast. However, the great majority of peptide messengers are not suitable for use as pharmaceuticals in their natural state. The problems of natural peptides as drugs are lack of oral activity, failure to penetrate t" * -e blood-brain barrier, rapidly metabolized, no selectivity for receptor subclasses, ' antigenic properties, and expensive to make.
• modified peptides offer significant opportunities.
• the ⁇ , ⁇ -disubstituted amino acids are non-genetically coded synthetic analogues of natural mammalian ⁇ -amino acids and are incorporated at least once into the neuropeptides of this patent. So e examples of therapeutic applications of these modified peptides (peptoids) are given in Table I below.
• Adrenocorticotrophic Hormone Enhanced Alertness Enhanced Cognition ⁇ -Endorphin Decreased Awareness
• SP or NKA A dopamine behavioral syndrome i.e., increased locomotion, rearing
• the invention relates to novel compounds of formula
• 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 for appetite suppression.
• the invention also relates to a method for suppressing appetite in a mammal.
• the compounds of the invention are also useful for blocking the reaction caused by withdrawal from drug or alcohol use.
• the compounds of the invention are also useful in reducing gastric acid secretion, in treating gastrointestinal ulcers, in treating pain, treating and/or preventing stroke, treating inflammation, and in treating anxiety.
• the compounds of the invention are also useful in treating cognitive deficits, small cell lung cancer, colonic cancer, peptic ulcers, and are useful in contraceptio .
• the invention also relates to a pharmaceutical composition for reducing gastric acid secretion containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing gastric acid secretion.
• the invention also relates to a method for reducing gastric acid secretion in. ammals which comprises administering an amount effective for gastric acid secretion reduction of the composition described above to a mammal in need of such treatment.
• the invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for reducing anxiety.
• the invention also relates to a method for reducing anxiety in mammals which comprises administering an amount effective for anxiety reduction of the composition described above to a mammal in need of such treatment.
• the invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating gastrointestinal ulcers.
• the invention further relates to a method for treating gastrointestinal ulcers in mammals which comprises administering an amount effective for gastrointestinal ulcer treatment of the composition as described above to a mammal in need of such treatment.
• the invention also relates to a pharmaceutical composition containing an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier in unit dosage form effective for treating inflammation.
• the invention further relates to a method for treating inflammation in mammals which comprises administering an amount effective of a composition as described above to a mammal in need of such treatment.
• the invention also relates to a pharmaceutical composition for preventing the withdrawal response produced by chronic treatment or abuse of drugs or alcohol.
• the invention further relates to a method for treating the withdrawal response produced by withdrawal from chronic treatment or withdrawal from abuse of drugs or alcohol.
• drugs include benzodiazepines, especially diazepam, cocaine, caffeine, opioids, alcohol, and nicotine. Withdrawal symptoms are treated by administration of an effective withdrawal treating amount of a compound of the instant invention.
• This invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form for treating psychosis.
• the invention also relates to a method for treating psychosis in mammals which comprises administering an amount effective for treatment of the composition described above to a mammal in need of such treatment.
• This invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound according tc formula I in combination with a pharmaceutically acceptable carrier in unit dosage form for treating asthma.
• the invention also relates to a method for treating asthma in mammals which comprises administering an amount effective for treatment of the composition described above to a mammal in need of such treatment.
• This invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form for treating bladder dysfunction.
• the invention also relates to a method for treating bladder dysfunction in mammals which comprises administering an amount effective for treatment of the composition described above to a mammal in need of such treatment.
• This invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound according to formula I in combination with a pharmaceutically acceptable carrier in unit dosage form for treating arthritis and/or inflammatory pain.
• the invention also relates to a method for treating arthritis and/or inflammatory pain in mammals which comprises administering an amount effective for treatment of the composition described above to a mammal in need of such treatment.
• the invention further relates to methods of treating hypertension, heart failure, stroke, cognition, memory enhancement, spasticity, depression, and diabetes.
• 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.
• the invention also relates to a pharmaceutical composition for treating pain and to a method of using a compound of formula I for treating pain.
• the invention also relates to a pharmaceutical composition for treating and/or preventing stroke and to a method of using a compound of formula I for treating and/or preventing stroke.
• N-terminal protecting refers to those groups known to the art intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during a synthetic procedure or to prevent the attack of exopeptidases on the compounds or to increase the solubility of the compounds and includes, but is not limited to, sulfonyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc) , benzyloxycarbonyl (Cbz) , benzoyl, or an L- or D-aminoacyl residue, which may itself be N-protected similarly.
• C-terminal protecting group refers to those groups known to the art intended to protect the C—terminus of an amino acid or peptide, these include but are not limited to an amide, methyl ester, benzyl ester/ether, tert-butyl ester/ether. Other examples of side chains and protecting groups are those known in the art. .Any of those could be used.
• the compounds of the invention are represented by formula R2
• R is an N—terminal blocking group or from 0 to 4 amino acid residues or hydrogen
• R 2 is a si.dechai.n of a genetically coded amino acid except glycine;
• R 3 is a C—terminal blocking group or from 0 to
• n is an integer of from
• R is hydrogen or lower alkyl
• Ar is a mono— or polycyclic unsubstituted or substituted carbo- or heterocyclic aromatic or hydroaromatic moiety; neither R 2 nor R 4 can be hydrogen;
• R 1 plus R 3 cannot be greater than 4 amino acid residues in total.
• Preferred compounds of the invention are those rmula I selected from:
• Thr-Val-MeLeu More preferred compounds of the invention are those of formula I selected from:
• Most preferred compounds of the invention are those of formula I selected from: MeLys-Trp-Asp-Asn-Gln,
• Tyr-Pro-MeSer-Lys-Pro Tyr-Pro—Ser-MeLys-Pro, Tyr—Pro-Ser—Lys-MePro, MeThr-Arg-Gln-Arg-Tyr-NH 21 Thr-MeArg-Gln-Arg-Tyr-NH 2 , Thr-Arg-MeGln-Arg-Tyr-NH 2 , Thr-Arg-Gln-MeArg-Tyr-NH 2 ,
• MeLeu-Tyr-Gly-Leu-Ala-NH 2 Leu-MeTyr-Gly-Leu-Ala-NH , Leu-Tyr-Gly-MeLeu-Ala-NH 2 , Leu-Tyr-Gly-Leu-Aib-NH 2 , MePhe-Phe-Trp-Lys-Thr,
• the compounds include solvates, hydrates, and pharmaceutically acceptable salts of the compounds of formula I above.
• 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 colu n chromatography or repetitive recrystallizations.
• Individual enantiomers may be separated by conventional methods well known in the art such as conversion to a salt with an optically active compound, followed by separation by chromatography or recrystallization and reconversion to the nonsalt form.
• the compounds of the present invention may 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 Meienhofer, Academic Press, New York) . If known, the individual substituted alpha amino acid starting materials are synthesized by methods within the skill of the art. (Synthesized racemic [DL]- ⁇ -methyl tryptophan methyl ester — see Brana, M. F., et al, J. Hetero ⁇ yclic Chem. , 1980.
• 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 is a finely divided solid which is in a mixture with the finely divided active component.
• 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— elting 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.
• Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
• 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 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 capsules, cachet, or tablet itself, or it can be the appropriate number of any of these packaged • orms.
• Some of the peptides of the invention 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 Ultrasyn C ® resins either in a simple bubbler apparatus (DuPont resin) or automated synthesizer (Nova Biochem resin) .
• peptides of the invention can be made by the above method. Although any compatible resin may be used or, alternatively, solution phase synthesis may be used.
• Such peptides include but are not limited to the short chemotactic peptides, for example, for yl-Met—Leu—Phe-OBz, Met—enkephalin, enkephalinamides, leupeptin (Ac—Leu-Leu—Arginol) , Kyotorphin (Tyr— rg) , Morphiceptin (Tyr-Pro-Phe-Pro-NH 2 ) , Thymopoetin II (Arg-Lys-Asp-Val-Tyr) , Splenopentin (Arg—Lys-Glu-Val—Tyr) , Hamburger pentapeptide (Asp—Leu—Asp-Pro—Arg) , virus replication inhibiting peptide (Z-DPhe-Phe-Gly) , DNA binding peptide (Lys-Trp-Lys) , Molluscan cardioexcitatory peptide (Phe-Met-Arg-Phe-NH
• Preferred compounds are: IiTyr-Gly-Gly-a-MePhe-IjLeu (isomer 1) and
• L_Tyr-Gly-Gly- ⁇ -MePhe-LLeu (isomer 2) whose full chemical names are N-[ ⁇ -methyl-N-[N-(N—L— tyrosylglycyl)glycyl]-L-phenylalanyl]-L—leucine trifluoroacetate (1:1 salt) and N-[ ⁇ -methyl-N-[N-(N- L-tyrosylglycyl)glycyl]-D-phenylalanyl]-L-leucine trifluoroacetate (1:1 salt).
• a L659,874 is a standard NK 2 antagonist. Its chemical name is Glycinamide, N-acetyl-L-leucyl- L-methionyl— L— glutaminyl-L— ryptophyl— -phenylalanyl-Ac- Leu-LMet-LGln- Trp-LPhe-Gly-NH 2
• the peptide was prepared and separated as described above, using solid—phase methodology.
• EXftMPLE 2 N-(t-Butyloxycarbonyl)-DL- ⁇ -methylphenylalanine (1) DL- ⁇ -Methylphenylalanine (5.0 g, 28 mmol) was dissolved in warm 10% Na 2 C0 3 solution (60 mL) and then cooled to 0°C. t—Butyloxycarbonyl anhydride (6.39 g, 29.3 mmol) in dioxan (50 mL) was added dropwise and the mixture stirred at 0°C for 1 hour. The mixture was then allowed to warm to room temperature and stirred for a further 24 hours. The solvents were then distilled off in vacuo and the residue taken up in H 2 0.
• 1,3-Dicyclohexylcarbodiimide (4.95 g, 24 mmol) was added to a solution of 1 (6.70 g, 24 mmol) in THF (100 mL) at -15°C and allowed to stir for 5 minutes.
• 3-Hydroxy-1,2,3-benzotriazine—4-(3H)-one (3.91 g, 24 mmol) and an additional volume of THF (20 mL) were added and the mixture stirred at -10°C for 1 hour and at 0°C for 4 hours. After leaving overnight at 5°C a white solid precipitated.
• Hydrobenzotriazolyl tetramethyluronium hexachlorophosphate (0.19 g, 0.5 mmol) was added to a solution of Z-(L)-Trp (0.15 g, 0.5 mmol), 16 (0.17 g, 0.5 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.5 mmol) in DMF (3 mL) and stirred at room temperature for 45 minutes. Water was added and the mixture extracted with EtOAc. The organic layer was washed with 10% citric acid solution, saturated NaHC0 3 solution, H 2 0, and dried (MgS0 4 ) .
• HBTU Hydrobenzotriazolyl tetramethyluronium hexachlorophosphate
• Diisopropylethylamine (52 ⁇ L, 0.3 mmol) was added to a stirred solution of N-[ (1-naphthyl- methoxy)carbonyl]tryptophan (0.117 g, 0.3 mmol) and HBTU (0.114 g, 0.3 mmol) in DMF (5 mL) at room temperature. The mixture was stirred for 10 minutes, then 16 (0.105 g, 0.3 mmol) in DMF (5 mL) was added, followed by diisopropyl ethylamine (105 ⁇ L, 0.6 mmol) and the reaction mixture stirred for a further 18 hours.

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Family Applications (1)

Country Status (8)

Families Citing this family (15)

Family Cites Families (6)

• 1992
  • 1992-04-15 JP JP4511401A patent/JPH06507402A/ja active Pending
  • 1992-04-15 AU AU19072/92A patent/AU1907292A/en not_active Abandoned
  • 1992-04-15 EP EP92911434A patent/EP0668770A1/en not_active Withdrawn
  • 1992-04-15 CA CA002106764A patent/CA2106764A1/en not_active Abandoned
  • 1992-04-15 WO PCT/US1992/003119 patent/WO1992019254A1/en not_active Application Discontinuation
  • 1992-04-22 NZ NZ242441A patent/NZ242441A/en unknown
  • 1992-04-23 IE IE132192A patent/IE921321A1/en not_active Application Discontinuation
  • 1992-04-23 PT PT100422A patent/PT100422A/pt not_active Application Discontinuation

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