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WO1991008759A1 - Pentapeptides d'acide penicillanique cycliques substitues par un alkyle - Google Patents

Pentapeptides d'acide penicillanique cycliques substitues par un alkyle Download PDF

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Publication number
WO1991008759A1
WO1991008759A1 PCT/US1990/007444 US9007444W WO9108759A1 WO 1991008759 A1 WO1991008759 A1 WO 1991008759A1 US 9007444 W US9007444 W US 9007444W WO 9108759 A1 WO9108759 A1 WO 9108759A1
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WO
WIPO (PCT)
Prior art keywords
compound
carbon atoms
boc
compoxmd
alkyl
Prior art date
Application number
PCT/US1990/007444
Other languages
English (en)
Inventor
Donna L. Hammond
Donald W. Hansen
Henry I. Mosberg
Original Assignee
G.D. Searle & Co.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by G.D. Searle & Co. filed Critical G.D. Searle & Co.
Publication of WO1991008759A1 publication Critical patent/WO1991008759A1/fr

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Classifications

    • 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
    • C07K14/70—Enkephalins
    • C07K14/702—Enkephalins with at least 1 amino acid in D-form
    • 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 provides novel compounds, compositions, methods of their use and methods of their manufacture. Such compounds are pharmacologically useful to induce analgesia in mammals. More specifically, the compounds of the present invention are antinociceptive pentapeptide mono and dimethyl tyrosyl penicillanic acid amides which, by acting as neurotransmitters or
  • neuromodulators in the central nervous system central pain-suppressant system induce analgesia.
  • Opioids are a group of drugs that are, to varying degrees, opium-like or morphine-like in their properties.
  • the opioids are employed primarily as analgesics, but they have many other pharmacological effects as well, and they share some of- the properties of certain naturally- occurring peptides.
  • researchers had concluded that the complex interactions among morphine-like drugs, morphine antagonists, and mixed morphine agonistantagonists could best be explained by postulating the existence of more than one type of receptor for the opioids and related drugs.
  • studies of the binding of opioid drugs and peptides to specific sites in brain and other organs has suggested the existence of perhaps as many as eight different types of opioid receptors, in the CNS there is reasonably firm evidence for three major categories of receptors,
  • naloxone The classical antagonist, naloxone, has been found to bind with high affinity to all opioid receptors.
  • Hughes and Kosterlitz described the isolation of two pentapeptides that exhibited morphine-like actions - actions that were specifically antagonized by naloxone.
  • Goldstein and colleagues reported the presence of peptide-like substances in the pituitary gland with opioid activity.
  • the peptide appears to act as a neurotransmitter or neuromodulator in the CNS.
  • the natural peptide binds stereospecifically to partially purified brain opiate receptor sites, see for example, Bradberry, et al., Nature, 260,793 (1976).
  • the natural peptide is also highly active in bioassays for opiate activity but exhibits only weak, fleeting analgesic activity when injected directly into the brain of the rat, see for example, Belluzi, et al., Nature, 260,625 (1976).
  • the compounds of this invention are cyclic,
  • pentapeptide tyrosyl substituted dipenicillanic acid opioid agonists that are selective for the ⁇ receptor.
  • the compounds of this invention have unexpected and surprisingly superior properties when compared to the non-cyclic di, tri, tetra and pentapeptides of the prior art.
  • the present invention provides new cyclic peptide derivatives which show improved potency and bioavailability as analgesic agents by central routes of administration.
  • the invention relates to novel compounds of the general formula I :
  • X is H, a halogen, nitro, lower alkyl or lower alkyl substituted by halogen or nitro, aralkyl or alkaryl or substituted aralkyl or alkaryl of from one to ten carbon atoms;
  • R 1 , R 2 , R 3 and R 4 are
  • R 4 , R 6 and R 7 are independently alkyl of from
  • R 5 is amino, hydroxy, alkoxy of from one to ten carbon atoms, alkyl amino or dialkylamino of from one to ten carbon atoms
  • R 8 is independantly H, alkyl of from one to ten carbon atoms, carboxyl, alkoxy carbonyl of from one to ten carbonyl, alkylamino carbonyl and dialkylamino carbonyl of from one to ten carbon atoms, or any of these R 8 constituents being aryl substituted thereon.
  • the compounds and pharmaceutical compositions thereof are useful in the analgesic methods of the invention.
  • the invention further provides dosage unit forms adapted for oral, topical or parenteral administration.
  • halogen shall include fluorine, chlorine, bromine or iodine.
  • alkyl shall mean branched or straight chain
  • Aryl shall mean substituted or unsubstituted phenyl.
  • the alkyl portion of "alkoxy” moieties shall be as defined above for alkyl.
  • pharmaceutically acceptable salts refers to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or which are prepared by reacting the free acid with a suitable base.
  • Representative salts include the hydrochloride,
  • analgesia shall mean the absence of sensibility to pain, designating particularly the relief of pain without loss of consciousness.
  • Compounds of the invention can be prepared readily according to one of the following reaction schemes or modifications thereof using readily available starting materials, reagents and conventional synthesis
  • TFA trifluoroacetic acid
  • DIEA diisopropylethylamine
  • DCC Dicyclohexylcarbodiimide
  • HOBT 1-hydroxybenzotriazole
  • DMF dimethylformamide
  • Boc t-butyloxycarbonyl (a)
  • pMBHA p-methyl-benzhydrylamine
  • oral dosage forms as oral tablets, sublingual tablets, capsules, pills, powders, granules, elixirs, tinctures, syrups, emulsions and suspensions.
  • the compounds may also be administered in intravenous, intraperitoneal, subcutaneous or intramuscular form, all using forms known to those of ordinary skill in the pharmaceutical arts.
  • the preferred form of administration is oral.
  • An effective but non-toxic amount of the compound is employed in the induction of
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including the type, species, age, weight, sex and medical condition of the patient. Other relevant factors are the severity of the condition to be treated, the route of administration, the renal and hepatic function of the patient, the route of
  • the invention when used for the indicated analgesic effects, will range between about 0.1 mg per kilogram of body weight per day (mg/kg/day) to about 1,000 mg/kg/day and preferably 10-100 mg/kg/day.
  • the mg/kg/day body weight per day
  • compounds of the present invention may be administered in a single daily dose or the total daily dosage may be administered in divided doses of 2, 3 or 4 times daily.
  • compositions and methods of the present invention will form the active ingredients and will typically be administered in admixture with suitable pharmaceutical diluents, excipients or carriers
  • carrier materials suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with an oral non-toxic pharmaceutically
  • inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form the active drug components may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as ethanol. glycerol, water and the like.
  • any oral non-toxic pharmaceutically acceptable inert carrier such as ethanol. glycerol, water and the like.
  • suitable flavoring carriers can be added such as cherry syrup and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated in the mixture.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate,
  • Lubricants for use in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.
  • transdermal skin patch administration daily dosage is continuous via the transdermal delivery system rather than divided, as in an oral delivery system.
  • the compounds of this invention exhibit analgesic properties useful in the treatment of pain.
  • the test procedures employed to measure this activity of the compounds of the present invention are described below.
  • mice Male Charles River albino mice (20-30g) or rats (250-300g) were used.
  • the heat induced tail flick (TF) response is a reflex reaction mediated at the level of the spinal cord.
  • the hind paw lick, (HP) however, is a more complex behavior requiring integration at higher centers in the brain.
  • the TF and HP tests provide two different methods of concurrently measuring analgesia. Compounds active in one test are not necessarily active in the other.
  • TFL tail flick latency
  • HPL hot plate latency
  • a Activity or Inactivity was determined by the significant increase in tail flick or hot plate latencies above normal latencies. Where applicable, the calculated effective dose (ED 50 ) was determined.
  • Subcutaneous (s.c) administration represented in mg/kg and mtracerbroventricular (i.c.v.) administration represented in meg.
  • s.c subcutaneous
  • i.c.v. mtracerbroventricular
  • N ⁇ -Boc-(S-pMeBzl)D-penicillamine was attached to the solid phase resin support via an ester linkage using a modification of the procedure of Gisin (Helv.) Chim. Acta, 56 1476 (1973)): N ⁇ -Boc-(S-pMeBzl)D-penicillamine
  • N ⁇ -Boc-(S-pMeBzl)D- penicillamine assessed by analytical HPLC which indicated >99% completion at 72 hr.
  • the product, N ⁇ -Boc-(S- pMeBzl)D-penicillamine-Merrifield resin was filtered, washed with 3x 75mL DMF, 3x 75mL DMF/H 2 O(9 : 1), ex 75mL DMF, and 3x 75mL ethanol(ETOH) and dried under vacuum.
  • ninhydrin test of Kaiser et al. (Anal. Bioch. 34, 595 (1970)). If test is positive, proceed to step 8, if negative repeat steps 3-7.
  • This compound was found to be >99% pure by analytical HPLC and have the appropriate molecular weight of 673 by analysis via FAB mass spectrometry.
  • Example 3 wherein a resin such as U.S. Biochemical
  • the title product is obtained by the method of Example 3 wherein the hydrofluoric acid(HF) cleavage of the peptide from the resin prior to the cyclization is carried out in a methanol slurry.
  • Example 3 wherein the Merrifield resin is treated with excess ethyl amine before N ⁇ -Boc-(S-pMeBzl)D- penicillamine is attached to the solid phase resin support via the amide linkage (Internat. Peptide Protein Res. 25, 1985, 414-420). The title peptide is isolated after HF cleavage from the resin, cyclization, and chromatographic purification..
  • Example 17 Example 17

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à de nouveaux composés de la formule générale (I) et à des sels pharmaceutiquement acceptables, où X est H, un halogène, nitro, alkyle inférieur ou alkyle inférieur substitué par halogène ou nitro, aralkyle ou alcaryle, ou aralkyle ou alcaryle substitués comportant de un à dix atomes de carbone: R?1, R2, R3 et R4¿ sont indépendamment H et, de plus, R?1, R2, R3, R4, R6 et R7¿ sont indépendamment alkyle comportant de un à dix atomes de carbone; R5 est amino, hydroxy, alcoxy comportant de un à dix atomes de carbone, alkylamino ou dialkylamino comportant de un à dix atomes de carbone; et R8 est indépendamment H, alkyle comportant de un à dix atomes de carbone, carboxyle, alcoxycarbonyle comportant de un à dix atomes de carbone, aminocarbonyle, alkylaminocarbonyle et dialkylaminocarbonyle comportant de un à dix atomes de carbone, ou bien n'importe lequel de ces constituants de R8 étant aryle substitué. Les composés et leurs compositions pharmaceutiques sont utiles dans les procédés analgésiques objets de l'invention.
PCT/US1990/007444 1989-12-15 1990-12-12 Pentapeptides d'acide penicillanique cycliques substitues par un alkyle WO1991008759A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US45129089A 1989-12-15 1989-12-15
US451,290 1989-12-15
US49783390A 1990-03-22 1990-03-22
US497,833 1990-03-22

Publications (1)

Publication Number Publication Date
WO1991008759A1 true WO1991008759A1 (fr) 1991-06-27

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5459181A (en) * 1993-07-23 1995-10-17 Weyerhaeuser Company Hydraulic binder composition and its uses
WO1996016982A3 (fr) * 1994-11-30 1996-10-24 Us Health Peptides ultra-selectifs simulant des opioides et leurs utilisations pharmacologiques et therapeutiques
US7484330B2 (en) 2006-02-09 2009-02-03 Terra-Mulch Products Llc Blended mulch product and method of making same
WO2012178063A1 (fr) * 2011-06-23 2012-12-27 The Regents Of The University Of Michigan Composé et procédé pour modulation d'activité de récepteur des opioïdes
US8742070B2 (en) 2003-02-27 2014-06-03 Pepscan Systems B.V. Method for selecting a candidate drug compound
WO2015011467A1 (fr) 2013-07-26 2015-01-29 Isis Innovation Limited Identification et affichage de ligands peptidiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4518711A (en) * 1983-05-16 1985-05-21 Gibson-Stephens Institute Conformationally constrained cyclic enkephalin analogs with delta receptor specificity
US4760180A (en) * 1986-02-14 1988-07-26 G. D. Searle & Co. N-terminally substituted dipeptide amides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4518711A (en) * 1983-05-16 1985-05-21 Gibson-Stephens Institute Conformationally constrained cyclic enkephalin analogs with delta receptor specificity
US4760180A (en) * 1986-02-14 1988-07-26 G. D. Searle & Co. N-terminally substituted dipeptide amides

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5459181A (en) * 1993-07-23 1995-10-17 Weyerhaeuser Company Hydraulic binder composition and its uses
WO1996016982A3 (fr) * 1994-11-30 1996-10-24 Us Health Peptides ultra-selectifs simulant des opioides et leurs utilisations pharmacologiques et therapeutiques
US8742070B2 (en) 2003-02-27 2014-06-03 Pepscan Systems B.V. Method for selecting a candidate drug compound
US8748105B2 (en) 2003-02-27 2014-06-10 Pepscan Systems B.V. Method for selecting a candidate drug compound
US9176127B2 (en) 2003-02-27 2015-11-03 Pepscan Systems B.V. Method for selecting a candidate drug compound
US7484330B2 (en) 2006-02-09 2009-02-03 Terra-Mulch Products Llc Blended mulch product and method of making same
WO2012178063A1 (fr) * 2011-06-23 2012-12-27 The Regents Of The University Of Michigan Composé et procédé pour modulation d'activité de récepteur des opioïdes
US9045526B2 (en) 2011-06-23 2015-06-02 The Regents Of The University Of Michigan Compound and method for modulating opioid receptor activity
WO2015011467A1 (fr) 2013-07-26 2015-01-29 Isis Innovation Limited Identification et affichage de ligands peptidiques
EP3483268A1 (fr) 2013-07-26 2019-05-15 Oxford University Innovation Limited Identification et affichage de ligands peptidiques
US10351847B2 (en) 2013-07-26 2019-07-16 Oxford University Innovation Limited Identification and display of peptide ligands

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