WO1993017032A1 - Techniques et intermediaires de preparation de peptidomimetismes non peptidiques - Google Patents

Techniques et intermediaires de preparation de peptidomimetismes non peptidiques Download PDF

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WO1993017032A1
WO1993017032A1 PCT/US1993/001201 US9301201W WO9317032A1 WO 1993017032 A1 WO1993017032 A1 WO 1993017032A1 US 9301201 W US9301201 W US 9301201W WO 9317032 A1 WO9317032 A1 WO 9317032A1
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carbon atoms
compound
benzyl
integer
mmol
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PCT/US1993/001201
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Ralph Hirschmann
Ellen Leahy
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The Trustees Of The University Of Pennsylvania
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to synthetic compounds which mimic or inhibit the biological and/or chemical activity of peptides, including compounds which are bound by G-protein-linked receptors. This invention also relates to techniques and intermediates useful in preparing in these synthetic compounds.
  • G-proteins activate or inhibit different effector enzymes, modulating the levels of intracellular secondary messengers.
  • G-protein-linked receptors At least 50 sub-types of G-protein-linked receptors have been identified, among them the ⁇ -adrenergic, ⁇ -adrenergic, muscarinic, cholinergic, dopamine, histamine, adenosine, serotonin, prostaglandin, leukotriene, thromboxane, prostacyclin, PAF, cAMP, enkephalin, ehdorphin, cholecystokinin, bombesin, substance K, substance P, neuromedin, bradykinin, FMLP, C5a, C3a, vasopressin, oxytocin, angiotensin, VIP, parathyroid hormone, calcitonin, neurotensin, TRH, somatostatin, rhodopsin, epinephrine, norepinephrine, acetylcholine, S-hydroxytryptamine, thyrotropin
  • the transmembrane signaling pathway used by G-protein-linked receptors represents one of the major mechanism of signal transduction in cellular systems. It is known, for example, that substance P acts as a vasodilator, a depressant, stimulates salivation, and produces increased capillary permeability. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. In addition to substance P (neurokinin-1, NK-1), the known mammalian tachykinins include neurokinin A (NK-2) and neurokinin B (NK-2). The tachykinins have been implicated in gastrointestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease, ulcerative colitis and Crohn's disease.
  • GI gastrointestinal
  • Substance P is known to produce both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal and plays a role in sensory transmission and pain perception. Substance P also is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis. Other disease areas where the tachykinins are believed to be involved include allergic conditions, immunoregulation, bronchospasm, reflex or neuronal control of the viscera, and Alzheimer's disease and Downs Syndrome.
  • Protease Inhibitors Barrett and Selveson, eds., Elsevier (1986) has been to design peptide mimics through the application of the transition state analog concept in enzyme inhibitor design.
  • the secondary alcohol of statine mimics the tetrahedral transition state of the scissile amide bond of the pepsin substrate.
  • increased potency rather than decreased susceptibility to peptidases or increased bioavailability was the principal objective.
  • the transition state analog concept has no apparent relevance to hormone agonist/antagonist design.
  • compositions of matter which mimic or inhibit the biological and/or chemical activity of peptides.
  • compositions which are chemically more stable than naturally-occurring peptides, particularly under conditions such as found in the human body. It is a further object to provide compositions which function as hormone agonists or hormone antagonists.
  • peptide analogs which contain no peptide bonds yet which mimic or inhibit the chemical and/or biological activity of peptides.
  • the peptide analogs have structure (3):
  • peptide analogs invention have structure (4) and, more preferably, structure (5):
  • the present invention also provides processes and chemical intermediates useful in preparing the peptide analogs.
  • 4-deoxy peptide analogs are prepared by processes that include providing a first compound having structure (14):
  • R 1 , R 2 , and R 3 are the same or different and are hydroxyl protecting groups.
  • R 1 , R 2 , and R 3 are as above, R F has structure (16) or (17), R G and R H are, independently, alkyl or alkenyl having from one to about 10 carbon atoms, and p is an integer from 0 to about 10.
  • Protected amine (15) is then contacted with a base that does not remove the hydroxyl protecting groups to form primary amine (18).
  • the invention also provides methods for producing a prophylactic or therapeutic response in a mammal by administering to the mammal a pharmaceutically effective amount of one or more peptide analogs of the invention.
  • the present invention provides methods for producing such responses by modulating the activity of at least one mammalian G-protein-linked receptor by administering an effective amount of one or more peptide analogs of the invention.
  • non-peptide compounds which mimic or inhibit the chemical and/or biological activity of a variety of peptides can be produced by appending to certain core species such as the tetrahydropyranyl ring of structure (3) chemical functional groups which cause the compounds to be at least partially crossreactive with the peptide.
  • compounds which mimic or inhibit peptides are to varying degrees crossreactive therewith.
  • crossreactive moieties are those which compete with one another in binding G-protein-linked receptors through one of the many chemical reaction phenomena known in the art such as, for example, complexation, crystallization, or ionic, hydrogen, or covalent bonding.
  • crossreactive include both agonism and antagonism.
  • a substance which competes with a peptide ligand in cell receptor binding is described as an agonist if the response of the cell is the same as or mimics the action of the peptide ligand.
  • a substance that competes with the peptide ligand in receptor binding is referred to as antagonist if it blocks or inhibits the action of the cell to the action of the ligand.
  • Structural analysis of a peptide generally provides a large body of data which in preferred embodiments comprises the amino acid sequence of the peptide as well as the three-dimensional positioning of its atomic components. It is believed that only certain of these components, which are known both individually and collectively as chemical functionality, participate in any given reaction phenomena. It will be appreciated that the participation of a chemical functional group in peptide reactivity is manifested by the linkage or coordination of the functional group with at least a portion of a complementary reactive moiety such as a hormone receptor. Such linkage or binding may be effected through a covalent, ionic, or hydrogen bond or some weaker atomic coordination effect such as complexation or crystallization.
  • peptide chemical functionality which participates in binding is identified by one of the many techniques known in the art. For example, such identification can be effected through a stepwise process wherein one or more peptide analogs are prepared.
  • peptide analogs having structure (3) can be prepared by substitution at certain of the positions R 1 -R 5 with chemical functionalities which are crossreactive with functionalities found in the peptide. The activity of the analog in a binding assay is then compared with that of the peptide. The degree to which the binding of the analog corresponds with that of the peptide indicates the degree to which the substituents participate in the binding phenomena.
  • one important criterion in preparing peptide analogs according to the present invention is the respective chemical similarity of the side chains found in the peptide and any potential substitutes therefor appended to the core structure in the analog.
  • the chemical functional group in the peptide of interest and its substitute in at least one of the peptide analogs be somewhat chemically dissimilar.
  • the substitute is chemically dissimilar from the peptide side chain, it will generally be easier to elucidate the contribution, if any, of side chain to activity of the peptide.
  • somatostatin also known as somatotropin release inhibiting factor or SRIF
  • SRIF somatotropin release inhibiting factor
  • the cyclic hexapeptide L-363,301 (structure (6a)), disclosed by Veber and Hirschmann, et al . , Life Sciences, 1984, 34 , 1371 and the cyclic hexapeptide MK-678 (structure (6b)), disclosed by Veber and Hirschmann, et al., Nature, 1981, 292, accomplish the proper orientation via the segments Phe-N-Me-Ala or Phe-Pro, respectively.
  • peptide analogs having structure (3) were further simplified by including only three adjacent side chains of the four amino acids of the ⁇ -turn. These side chains are attached to rigid frameworks devoid of peptide bonds.
  • the frameworks were developed through molecular modeling to orient the side chains appropriately and/or to permit the receptor to induce the proper fit.
  • the phenylalanine residue in the dipeptide segments Phe-N-Me-Ala or Phe-Pro appears to add an important hydrophobic binding element. For this reason, the present synthetic analogs of somatostatin contain a corresponding aromatic residue. Increased hydrophobicity also should prove helpful in improving the duration of action and activity via oral administration of such compounds.
  • Participatory chemical functionality includes any of the wide variety of functional groups known in the art.
  • the side chains of naturally-occurring amino acids provide examples of suitable participatory functionality.
  • Representative participatory chemical functionality which may be contained within groups R 1 -R 5 is set forth in Table 1.
  • one or more of R 1 -R 5 can have the structure Z-(CH 2 )y- or Z-O-, where y is from 0 to about 5 and Z is one of the side chains of Table 1
  • non-peptide analogs preferably possess the general structure (3):
  • R 1 is -O(CH 2 ) n R A , -OC(O) (CH 2 ) n R A , -(CH 2 ) n R A , or
  • R A is -H, alkyl or alkenyl having from about 1 to about 14 carbon atoms and up to about 4 nitrogen atoms, or aryl having from about 6 to about 14 carbon atoms and up to about 4 nitrogen atoms, and n is an integer from 0 to about
  • R 2 , R 3 , and R 4 independently, is -O(CH 2 ) m R B , -OC(O) (CH 2 ) m R B , -(CH 2 ) m R B or -C(O) (CH 2 ) m R B where R B is -H or aryl, and m is an integer from 0 to about 5; and
  • R 5 is -O(CH 2 ) p NHR c , -OC(O) (CH 2 ) p NHR c , -O(CH 2 ) p R D , -OC(O) (CH 2 ) p R D , -(CH 2 ) p NHR c , -C(O) (CH 2 ) p NHR c , -(CH 2 ) p R D or -C(O)(CH 2 ) p R D , where:
  • p is an integer from 0 to about 10;
  • R c is -R E or -C(O)R E ;
  • R D is -H, -OR E , or -C(O)R E ;
  • R E is -H, alkyl or alkenyl having from about 1 to about 14 carbon atoms and up to about 4 nitrogen atoms, or aryl having from about 6 to about 14 carbon atoms and up to about 4 nitrogen atoms;
  • R 1 -R 5 depends intimately upon the peptide of interest whose biological and/or chemical activity is to be mimicked or inhibited.
  • R A should be an aryl functional group, preferably an nitrogen-substituted aryl group such as pyridine or indole. More preferably, R A is a 3-substituted indole.
  • n should be 2 and R B should be phenyl.
  • the integer m should be zero or, preferably, 1.
  • R 5 should be -O(CH 2 ) p NH 2 or -O(CH 2 ) p NHR c , where p is from about 2 to about 8, preferably 3 to about 6, more preferably 5.
  • R c can be, for example, a phenyl, benzyl or nitrogen heterocyclic moiety. Where substitution is possible at more than one position of these and other R c , it is intended that the present invention include each of resulting peptide analogs. For example, it is intended that the invention include analogs wherein R c is a pyridine or isonicotinic acid residue having one of the following structures:
  • R c is -C(O)CH 3 .
  • preferred peptide analogs have structures (8) -(13).
  • peptide analogs are preferred to the extent that they selectively and effectively are bound by G-proteins-linked receptors such as the somatostatin receptor, the ⁇ -adrenergic receptor, and the substance P receptor.
  • G-proteins-linked receptors such as the somatostatin receptor, the ⁇ -adrenergic receptor, and the substance P receptor.
  • the potency of a compound commonly is expressed as its inhibitory concentration (IC), the concentration at which the compound is able to displace a predetermined portion ⁇ typically 50% ⁇ of another compound which is already bound by a particular receptor.
  • IC inhibitory concentration
  • the compound that is displaced is a radioactive agonist or antagonist at the receptor under study.
  • a peptide analog possess a clinically effective IC 50 in at least one mammal; that is, it should possess an IC 50 which is low enough to inhibit binding of radioactive agonist or antagonist to a given G-protein linked receptor while causing a minimum of unacceptable side effects in the mammal.
  • clinically effective inhibitory concentrations vary depending on a number of factors, such as the pharmacokinetic characteristics and stability of the compound under study and thus must be determined empirically for each analog and each factor.
  • the clinically effective concentration for the somatostatin receptor is about 50-500 nM, but for the in vitro system the potency is about 1-10 nM.
  • the potency of a compound of the invention be as great as possible, preferably greater than or equal to the native hormone.
  • Selectivity or specificity is manifested for a compound of the present invention by its tendency to be bound by one particular G-protein-linked receptor but not other G-protein-linked receptors.
  • selectivity is manifested where a compound is bound by a particular receptor when placed in contact or close proximity with a medium containing at least one other receptor.
  • specificity is expressed as a ratio of the potency or activity of a compound for two different receptors.
  • a compound having an IC 50 of 100 ⁇ m for compound A and IC 50 of 200 ⁇ M for compound B can be said be two times more selective for compound A.
  • the selectivity of the peptide analogs of the present invention should be as great as possible.
  • the present invention provides a wide variety of peptide analogs which effectively and selectively are bound by individual G-protein-linked receptors.
  • the peptide analogs which bear amino groups are capable of forming salts with various inorganic and organic acids and such salts are also within the scope of this invention.
  • acid addition salts include acetate, adipate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, ethanesulfonate, fumarate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, methanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, picrate, pivalate, propionate, succinate, sulfate, tartrate, tosylate, and undecanoate.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is later removed in vacuo or by freeze drying.
  • the salts also may be formed by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
  • 4-Deoxy, 6-alkoxyamino peptide analogs according to the invention can be prepared by processes that include treating a 4-deoxy, 6-hydroxy glucopyranoside bearing hydroxyl protecting groups at positions 1, 2, and 3 with a base under conditions that do not remove the hydroxyl protecting groups.
  • Preferred protected, 4-deoxy, 6-hydroxy glucopyranosides have structure (14):
  • R 1 , R 2 , and R 3 are the same or different and are hydroxyl protecting.
  • Representative hydroxyl protecting groups include 2-(1-phenylsulfonyl)-indol-3-yl-ethyl or benzyl groups.
  • Preferred protecting groups for a 1-position hydroxyl group include 2-(1-phenylsulfonyl)-indol-3-yl-ethyl groups.
  • Preferred protecting groups for a 2- and/or 3-position hydroxyl include benzyl groups. It is particularly preferred that R 1 is 2-(1-phenylsulfonyl)-indol-3-yl-ethyl and R 2 and R 3 are benzyl.
  • Bases that can be used to abstract the 6-hydroxyl proton include 2,6-di-tert-butyl-4-methylpyridine and 2,4,6-trimethylpyridine. Those skilled in the art will be able to identify other useful bases through routine experimentation.
  • nucleophilic 4-deoxy glucopyranoside is coupled with a protected alkylamine that bears a suitable leaving group, resulting in structure (15):
  • R 1 , R 2 , and R 3 are as above, R F has structure (16) or (17), R G and R H are, independently, alkyl or alkenyl having from one to about 10 carbon atoms, and p is an integer from 0 to about 10.
  • the protected glucopyranoside nucleophile is reacted with a compound having structure: or
  • L is a leaving groups such as a O-trifluoromethanesulfonyl group.
  • R G and R H comprise up to about 3 carbon atoms. It is particularly preferred that the amine function in structure R F is protected as a phthalimide group.
  • Protected amine compounds (15) are converted to primary amines (18) through treatment with a suitable base under conditions that do not remove groups R 1 , R 2 and R 3 .
  • Suitable bases are those that can remove amide protecting groups from the amine function of structure R F but cannot remove hydroxyl protecting groups R 1 , R 2 , and R 3 .
  • Useful bases for deprotection reactions of this type include sodium methoxide and sodium ethoxide. Those skilled in the art will be able to identify other useful bases through routine experimentation.
  • compositions which comprise one or more peptide analogs.
  • compositions which comprise individual peptide analogs which are bound by certain receptors, the compositions will likely also be bound by the same receptors.
  • the analogs themselves may be present in the compositions in any of a wide variety of forms. For example, two or more peptide analogs may be merely mixed together or may be more closely associated through complexation, crystallization, or ionic or covalent bonding.
  • prophylactic, diagnostic, and therapeutic treatments may be prepared from the synthetic compounds and compositions of the invention, due in large part to the crossreactivity ⁇ that is, agonism or antagonism ⁇ of these moieties with one or more naturally-occurring peptides.
  • prophylactic or therapeutic responses can be produced in a human or some other type mammal.
  • Preferred responses are produced by modulating ⁇ that is, increasing, decreasing or otherwise modifying ⁇ the activity of at least one G-protein-linked receptor. It will be appreciated that the production of prophylactic or therapeutic responses includes the initiation or enhancement of desirable responses, as well as the cessation or suppression of undesirable responses.
  • Certain preferred peptide analogs of the present invention exhibit significant substance P receptor-binding activity and therefore, are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin, in particular substance P, activity.
  • disorders of the central nervous system such as anxiety, psychosis and schizophrenia; neurodegenerative disorders such as senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; respiratory diseases such as bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immunological reactions such as rejection of transplanted tissues; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; disordeis of blood flow caused by vasodilation; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions or the transmission of pain in migraine.
  • compositions for use in the methods of this invention can be in the form of a solid, semisolid or liquid form and can include one or more of peptide analogs as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications.
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes maybe used.
  • the active ingredient is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • Solid compositions .of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of said compounds in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered (preferably pH>8) if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
  • a compound of the invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compounds of the present invention may be administered on an intermittent basis; i.e., at semi-weekly, weekly, semi-monthly or monthly intervals.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon tne host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 mg of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain from about 0.5 mg to about 500 mg of active ingredient.
  • a preparation containing a 1-3% concentration of active agent may be utilized.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects provided that such higher dose levels are first divided into several small doses for administration throughout the day.
  • reaction mixture was diluted with 250 mi of ethyl acetate and washed with H 2 O (1 ⁇ 100 ml), saturated aqueous NaCl (1 ⁇ 100 ml), and dried over magnesium sulfate. Concentration and flash chromatography (silica, 5% methanol in dichloromethane) provided pure target compound (9.15 g, 85%) as a white foam.
  • Triethylamine (1.6 ml, 1.6 equiv, 11.6 mmol) was added to room temperature followed by acetic anhydride (0.9 ml, 1.3 equiv, 9.45 mmol) and the reaction mixture was stirred an additional night. Concentration and flash chromatography (silica, 7% CH 3 OH/EtOAc) afforded N-CH 3 CO-5-amino-pentanol (1 g, 100%).
  • reaction mixture was stirred at 0°C for 30 minutes and then warmed to room temperature. After stirring 24 hours, the reaction was cooled to 0°C and quenched with 40 ml of saturated aqueous ammonium chloride. The resulting solution was diluted with ethyl acetate (400 ml) and washed with H 2 O (1 ⁇ 150 ml), saturated aqueous NaCl (1 ⁇ 150 ml) and dried over magnesium sulfate.
  • Methyl 2 , 3 , 6 - tri -O-benzoyl - 4 - (methylthio)thiocarbonyl- ⁇ -D-glucopyranoside To a solution of the methyl 2,3, 6-tri-O-benzoyl- ⁇ -D-glucopyranoside (5.00 g, 9.87 mmol) in 100 ml of dry THF at -78°C was added carbon disulfide (0.45 ml, 7.48 mmol) followed by sodium bis (trimethylsilyl)amide (10.5 ml, 51.8 mmol). The solution was stirred at -78°C for 20 minutes.
  • Methyl iodide To a solution of the methyl 2,3, 6-tri-O-benzoyl- ⁇ -D-glucopyranoside (5.00 g, 9.87 mmol) in 100 ml of dry THF at -78°C was added carbon disulfide (0.45 ml, 7.48 mmol) followed by sodium bis (trimethyl
  • NKIR human neurokinin-1 receptor
  • the cells were incubated in 10% fetal calf serum, 2 mM glutamine, 100 U/ml penicillin-streptomycin, and 90% DMEM media (Gibco, Grand Island, NY) in 5% CO 2 at 37°C for three days before the binding assay.
  • the binding assay of human NKIR expressed in COS cells is based on the use of 125 I-substance P ( 125 I-SP, from DuPont, Boston, MA) as a radioactively labeled ligand which competes with unlabeled substance P or any other ligand for binding to the human NKIR.
  • 125 I-substance P 125 I-SP, from DuPont, Boston, MA
  • Monolayer cell cultures of COS were dissociated by the non-enzymatic solution (Specialty Media, Lavallette, NJ) and resuspended in appropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl 2 , 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon) such that 200 ⁇ l of the cell suspension would give rise to about 10,000 cpm of specific 125 I-SP binding (approximately 50,000 to 200,000 cells).
  • the binding buffer 50 mM Tris pH 7.5, 5 mM MnCl 2 , 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon
  • the binding assay 200 ⁇ l of cells were added to a tube containing 20 ⁇ l of 1.5 to 2.5 nM of 125 I-SP and 20 ⁇ l of unlabeled substance P or any other test compound. The tubes were incubated at 4°C or at room temperature for 1 hour with gentle shaking. The bound radioactivity was separated from unbound radioactivity by GF/C filter (Brandel, Gaithersburg, MD) which was pre-wetted with 0.1 polyethylenimine . The filter was washed with 3 ml of wash buffer (50 Tris pH 7.5, 5 mM MnCl 2 , 150 mM NaCl) three times and its radioactivity was determined by gamma counter.
  • wash buffer 50 Tris pH 7.5, 5 mM MnCl 2 , 150 mM NaCl
  • the affinity of a variety of compounds for the SRIF receptor was determined by studying the displacement of 125 I-CGP-23996 from AtT-20 cells using a method generally in accordance with that disclosed by Raynor and Reisine, Journal of Pharmacology and Experimental Therapeutics, 1989, 251; 2 , 510. The following data were obtained:
  • the peptide analogs of the present invention are selectively bound by certain receptors.
  • structure (1) exhibits approximately 14-fold greater selectivity than structure (8) for the substance P receptor, while structure (8) is bound by the substance P and SRIF receptors but is not bound by the ⁇ -adrenergic receptor.

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Abstract

L'invention concerne des composés ayant une réaction croisée avec des peptides tels que ceux fixés par des récepteurs liés par la protéine G, ainsi que leurs procédés de préparation et d'emploi thérapeutique. Dans certains modes de réalisation, on prépare des 4-désoxy, 6-alkylamino glucopyranosides par couplage d'un 4-désoxy, 6-hydroxy glucopyranoside avec une alkylamine protégée, puis élimination du groupe protecteur d'alkylamine.
PCT/US1993/001201 1992-02-24 1993-02-10 Techniques et intermediaires de preparation de peptidomimetismes non peptidiques WO1993017032A1 (fr)

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0728007A1 (fr) * 1993-10-28 1996-08-28 The Trustees Of The University Of Pennsylvania Composes non peptidiques imitant l'activite de peptides
US5830866A (en) * 1994-09-12 1998-11-03 The Trustees Of The University Of Pennsylvania Corticotropin release inhibiting factor and methods of using same
WO2000014097A2 (fr) * 1998-09-04 2000-03-16 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouvelles pyranoses
US6039956A (en) * 1994-09-12 2000-03-21 Pennsylvania, Trustees Of The University Of, The Corticotropin release inhibiting factor and methods of using same for treating behavioral symptoms in an anxiety disorder
US6150179A (en) * 1995-03-31 2000-11-21 Curagen Corporation Method of using solid state NMR to measure distances between nuclei in compounds attached to a surface
US6251671B1 (en) 1996-02-28 2001-06-26 Vanderbilt University Compositions and methods of making embryonic stem cells
US7153684B1 (en) 1992-10-08 2006-12-26 Vanderbilt University Pluripotential embryonic stem cells and methods of making same
US7994140B2 (en) 2002-10-11 2011-08-09 Alchemia Limited Classes of compounds that interact with GPCRs
US8222381B2 (en) 2002-08-08 2012-07-17 Alchemia Limited Derivatives of monosaccharides for drug discovery
WO2013004766A1 (fr) 2011-07-04 2013-01-10 Ferrari Giulio Antagonistes des récepteurs nk-1 pour traiter une néovascularisation cornéenne
WO2019162519A1 (fr) 2018-02-26 2019-08-29 Ospedale San Raffaele S.R.L. Antagonistes nk-1 destinés à être utilisés dans le traitement de la douleur oculaire
WO2021180885A1 (fr) 2020-03-11 2021-09-16 Ospedale San Raffaele S.R.L. Traitement d'une déficience en cellules souches

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7153684B1 (en) 1992-10-08 2006-12-26 Vanderbilt University Pluripotential embryonic stem cells and methods of making same
EP0728007A1 (fr) * 1993-10-28 1996-08-28 The Trustees Of The University Of Pennsylvania Composes non peptidiques imitant l'activite de peptides
EP0728007A4 (fr) * 1993-10-28 1998-09-02 Univ Pennsylvania Composes non peptidiques imitant l'activite de peptides
US5830866A (en) * 1994-09-12 1998-11-03 The Trustees Of The University Of Pennsylvania Corticotropin release inhibiting factor and methods of using same
US6039956A (en) * 1994-09-12 2000-03-21 Pennsylvania, Trustees Of The University Of, The Corticotropin release inhibiting factor and methods of using same for treating behavioral symptoms in an anxiety disorder
US6341256B1 (en) 1995-03-31 2002-01-22 Curagen Corporation Consensus configurational bias Monte Carlo method and system for pharmacophore structure determination
US6150179A (en) * 1995-03-31 2000-11-21 Curagen Corporation Method of using solid state NMR to measure distances between nuclei in compounds attached to a surface
US6251671B1 (en) 1996-02-28 2001-06-26 Vanderbilt University Compositions and methods of making embryonic stem cells
WO2000014097A3 (fr) * 1998-09-04 2000-07-20 Byk Gulden Lomberg Chem Fab Nouvelles pyranoses
WO2000014097A2 (fr) * 1998-09-04 2000-03-16 Byk Gulden Lomberg Chemische Fabrik Gmbh Nouvelles pyranoses
US8222381B2 (en) 2002-08-08 2012-07-17 Alchemia Limited Derivatives of monosaccharides for drug discovery
US7994140B2 (en) 2002-10-11 2011-08-09 Alchemia Limited Classes of compounds that interact with GPCRs
WO2013004766A1 (fr) 2011-07-04 2013-01-10 Ferrari Giulio Antagonistes des récepteurs nk-1 pour traiter une néovascularisation cornéenne
WO2019162519A1 (fr) 2018-02-26 2019-08-29 Ospedale San Raffaele S.R.L. Antagonistes nk-1 destinés à être utilisés dans le traitement de la douleur oculaire
EP4371613A2 (fr) 2018-02-26 2024-05-22 Ospedale San Raffaele S.r.l. Composés destinés à être utilisés dans le traitement de la douleur oculaire
WO2021180885A1 (fr) 2020-03-11 2021-09-16 Ospedale San Raffaele S.R.L. Traitement d'une déficience en cellules souches

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