EP0641312A1 - Synthetische arylpolyamine als antagonisten von anregbaren aminosäure-neurotransmittern - Google Patents

Synthetische arylpolyamine als antagonisten von anregbaren aminosäure-neurotransmittern

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Publication number
EP0641312A1
EP0641312A1 EP92916921A EP92916921A EP0641312A1 EP 0641312 A1 EP0641312 A1 EP 0641312A1 EP 92916921 A EP92916921 A EP 92916921A EP 92916921 A EP92916921 A EP 92916921A EP 0641312 A1 EP0641312 A1 EP 0641312A1
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EP
European Patent Office
Prior art keywords
boc
compound
alkyl
pharmaceutically acceptable
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92916921A
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English (en)
French (fr)
Inventor
Nicholas Alex Saccomano
Robert Alfred Volkmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shire NPS Pharmaceuticals Inc
Pfizer Inc
Original Assignee
Pfizer Inc
NPS Pharmaceuticals Inc
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Application filed by Pfizer Inc, NPS Pharmaceuticals Inc filed Critical Pfizer Inc
Publication of EP0641312A1 publication Critical patent/EP0641312A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F17/00—Metallocenes
    • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table

Definitions

  • This invention relates to a class of aryl polyamines and the pharmaceutically acceptable salts thereof which are antagonists of excitatory amino acid neurotransmitters. These neurotransmitters affect neuronal cells of a variety of organisms including invertebrates and vertebrates.
  • the polyamines of the present invention are synthetic analogs of certain polyamines found to be present in the venom of the A ⁇ elenopsis aperta spider.
  • This invention also relates to the use of such polyamines and their salts in antagonizing excitatory amino acid neurotransmitters. These neurotransmitters affect cells such as cells in the nervous system of an organism.
  • This invention further relates to the use of such polyamines and their salts in the treatment of excitatory amino acid neurotransmitter- mediated diseases and conditions in a mammal, in control of invertebrate pests, and to compositions comprising said polyamines and salts thereof.
  • This invention also relates to methods of producing such polyamines.
  • toxin is reported to block presynaptic transmission and it has been suggested that the toxin blocks calcium channels associated with the release of neurotransmi tter.
  • Certain polyamines found to be present in the venom of the Aqelenopsis aperta spider are disclosed in U.S. patent no. 5,037,846, filed April 28, 1989 and assigned to the assignees hereof.
  • Those polyamines and the pharmaceutically acceptable salts thereof are disclosed therein as blockers of excitatory amino acid receptors in cells and one such polyamine, B therein, is also disclosed as a blocker of calcium channels.
  • Excitatory amino acid neurotransmitter antagonists have a variety of utilities.
  • Excitatory amino acid neurotransmitter antagonists are useful in the treatment of such conditions as stroke, cerebral ischemia, neuronal degenerative disorders such as Alzheimer's disease and epilepsy and as psychotherapeutants, among others. See Excitatory Amino Acids In Health and Disease. D. Lodge, E., John Wiley and Sons Ltd., New York, NY 1988, the teachings of which are incorporated herein by reference. Further, such compounds are useful in the study of the physiology of cells such as neuronal cells and in the control of invertebrate pests.
  • Glutamate is the major excitatory neurotransmitter in mammalian brain. There has been a great deal of excitement in the past decade as the developing pharmacology of glutamate receptors has suggested their differentiation into several subtypes.
  • the glutamate receptor subtype classified by the selective action of the exogenous agonist N-methyl-D- aspartate (NMDA) has been the subject of intense research since these receptors have been proposed to play a role in a variety of neurological pathologies including stroke, epilepsy, and neurodegenerative disorders such as Alzheimers's disease.
  • NMDA receptor antagonists There are currently two broad classes of NMDA receptor antagonists that are being aggressively pursued in search of clinically useful drugs. The first class consists of competitive antagonists which interfere with binding of glutamate to its receptor site.
  • the compounds are characterized as highly polar compounds such as the phosphonate compounds AP7 and AP5.
  • the highly charged structure of the competitive agents render them unable to penetrate the blood/brain barrier and limits their therapeutic utility.
  • the second class consists of noncompetitive antagonists which block NMDA receptor function by acting at the ion channel associated with the NMDA receptor complex.
  • These compounds include MK-801 and phencyclidine (PCP).
  • PCP phencyclidine
  • Arylamine structures isolated from the venom of A ⁇ elenopsis aperta that show potent and specific antagonism of mammalian NMDA receptors are disclosed in U.S. patent application serial no. 554,311 , filed July 17, 1990 and in U.S. patent no. 5,037,846, filed July 31, 1990.
  • the arylamines isolated from A ⁇ elenopsis aperta venom are composite structures built up from an aromatic acid and polyamine fragments bonded together by amide bonds.
  • polyamine AGEL 416 disclosed in aforementioned patent no. 5,037,846, is disclosed as having the following structure.
  • spider venom arylamines provide a novel class of antagonist compounds at the NMDA receptor. Given the benefit of the disclosure herein with respect to the naturally- occurring compounds it is now possible to obtain said compounds by methods other than through isolation/purification from whole venom of A ⁇ elenopsis aperta. and correspondingly, it is also possible to synthesize analogous compounds of the same class which are not naturally-occurring.
  • This application concerns a class of synthetic aryl polyamines of the formula R-(CH 2 ) m -CO-R', wherein R is a 5 to 7 member carbocyclic system or an 8 to 11 member carbobicyclic system, or any of the above systems substituted with one or more substituents independently selected from F, Cl, Br, OH, C1 to C4 alkyl, C1 to C4 alkoxy, CF 3 , phenyl, amino, C1 to C4 alkylamino and di(C1 to C4)alkylamino; m is 0 or 1 ; R' is -[NH(CH 2 )J X NH 2 ; each n is independently 2 to 5; and x is 1 to 6.
  • This invention also relates those compounds of the formula R-(CH 2 ) m -CO-R', or a pharmaceutically acceptable acid addition salt thereof wherein R is a 5 to 7 member carbocyclic system or an 8 to 11 member carbobicyclic system, or any of the above systems substituted with one or more substituents independently selected from F, Cl, Br, OH, C1 to C4 alkyl, C1 to C4 alkoxy, CF 3 , phenyl, amino, C1 to C4 alkylamino and di(C1 to C4)alkylamino; m is 0 or 1 ;
  • each n is independently 2 to 5;x is 0 to 4; y and z are each independently 1 to 5; and the sum of x and the greater of y and z is 1 to 5.
  • This application further relates to compounds of the formula R-(CH 2 ) m -CO-R', or a pharmaceutically acceptable acid addition salt thereof wherein R is a 5 to 7 member carbocyclic system or an 8 to 11 member carbobicyclic system, or any of the above systems substituted with one or more substituents independently selected from F, Cl, Br, OH, C1 to C4 alkyl, C1 to C4 alkoxy, CF 3 , phenyl, amino, C1 to C4 alkylamino and di (C1 to C4) alkylamino; m is 0 or 1 ; R is
  • each b is the same and is 2 to 5; each n is independently 2 to 5; x is 0 to 3; each y is the same and is 0 or 1 ; z is 0 to 3; and x + y + z is 0 to 4.
  • the carbocyclic systems of the present invention can be saturated, unsaturated or aromatic, with the aromatic systems being preferred. With regard to the monocyclic systems, phenyl is preferred.
  • the bicyclic systems can be fused or bridged, with 9 or 10-membered fused systems being preferred, for example, naphthyl and indene. Of the aforementioned bicyclics, naphthyl is particularly preferred.
  • R' groups are those wherein x is 4 or 5 and each n is independently 3 or 4. Particularly preferred R' groups are -[NH(CH 2 ) 3 ] 5 NH 2 and -[NH(CH 2 ) 3 ] 3 NH(CH 2 ) 4 NH(CH 2 ) 3 NH 2 .
  • the polyamines of this invention and the pharmaceutically acceptable salts thereof are antagonists of excitatory amino acid neurotransmitters.
  • said polyamines are useful in antagonizing such excitatory amino acid neurotransmitters, per se.
  • the polyamines of this invention are also useful in the control of invertebrate pests and in the treatment of diseases and conditions in a mammal mediated by excitatory amino acid neurotransmit ⁇ ters. Said polyamines are useful also as mammalian psychotherapeutants.
  • This invention also concerns pharmaceutical compositions comprising said polyamines, methods of administering said polyamines and methods of making said polyamines.
  • Detailed Description of the Invention A synthetic scheme for production of a polyamine of the formula
  • the polyamines of this invention reversibly antagonize excitatory amino acid neurotransmitters, which neurotransmitters affect cells such as cells in the nervous system of a variety of organisms including invertebrates and vertebrates.
  • vertebrates as used throughout is meant to include mammals.
  • invertebrates as used throughout is meant to include for example, insects, ectoparasites and endoparasites.
  • NMDA N-methyl-D-aspartic acid
  • the resulting pieces of cerebellum are transferred to 100 ml of Krebs/bicarbonate buffer at 37°C which is continuously equilibrated with 95:5 0 2 /CO 2 .
  • the pieces of cerebellum are incubated in such a manner for ninety minutes with three changes of the buffer.
  • the buffer then is decanted, the tissue centrifuged (1 min., 3200 rpm) and the tissue resuspended in 20 mi of the Krebs/bicarbonate buffer. Then, 250 ⁇ aliquots (approximately 2 mg) are removed and placed in 1.5 ml microfuge tubes.
  • cGMP cyclic GMP
  • Cerebellar granule cells are prepared from the cerebellum of 8 day old rats (Wilkin, G. P. et al., Brain Res:115: 181-199, 1976). Squares (1 cm 2 ) of Aclar (Proplastics Inc., 5033 Industrial Ave., Wall, NJ, 07719) are coated with poly- L-lysine and placed in 12-well dishes that contain 1 ml of Eagles Basal Medium.
  • the cells are dissociated and aliquots containing 6.25 x 10 ⁇ cells are added to each well containing the squares of Aclar. Cytosine-beta-D- arabino furanoside (final concentration 10 ⁇ M) is added 24 hours post plating. The cells are used for fura2 analysis at 6, 7 and 8 days of culture. The cells (attached to the Aclar squares) are transferred to 12-well dishes containing 1 ml of 2 ⁇ M fura2/AM (Molecular Probes Inc., Eugene, OR) in HEPES buffer (containing 0.1% bovine serum albumin, 0.1% dextrose, pH 7.4, magnesium-free).
  • the cells are incubated for 40 minutes at 37 °C; the fura2/AM containing buffer was removed and replaced with 1 ml of the same buffer without fura2/AM.
  • To a quartz cuvette is added 2.0 ml of prewarmed (37° C) buffer.
  • the cells on the Aclar are placed in the cuvette and the cuvette is inserted in a thermostated (37 °C) holder equipped with a magnetic stirrer and the fluorescence is measured with a fluorescence spectrophotometer (Biomedical Instrument Group, University of Pennsyl ⁇ vania). The fluorescence signal is allowed to stabilize for about 2 minutes.
  • cytosolic free calcium represented by an increase in fluorescence
  • An increase in cytosolic free calcium is produced by the addition of 50 ⁇ M NMDA and 1 ⁇ M glycine. Then 5-20 ⁇ of a stock solution of the compound under study in phosphate-buffered saline (PBS, pH 7.4) at appropriate concentrations are added to the cuvette. Calibration of the fluorescent signals and fura2/AM leakage correction are performed using the established procedures of
  • the polyamines of this invention are useful in antagonizing excitatory amino acid neurotransmitters, per se.
  • the polyamines are also useful in the control of invertebrate pests in the treatment of excitatory amino acid neurotransmitters-mediated diseases and conditions in a mammal such as stroke, cerebral ischemia, neuronal degenerative disorders such as Alzheimer's disease and epilepsy.
  • Said polyamines also are useful as psychotherapeutants in a mammal and, further, in the study of the physiology of cells including, but not limited to, cells of the nervous system.
  • the pharmaceutically acceptable salts of the polyamines of this invention are formed by methods well know to those skilled in the art.
  • acid addition salts of the polyamines can be prepared according to conventional methods.
  • Acid addition salts of the polyamines such as hydrochloric and trifluoroacetic acid addition salts thereof are preferred.
  • Hydrochloric acid addition salts of the polyamines are particularly preferred.
  • a polyamine or a pharmaceutically acceptable salt thereof of this invention When a polyamine or a pharmaceutically acceptable salt thereof of this invention is to be administered to a mammal, it can be administered alone or in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard practice.
  • the poly ⁇ amines or pharmaceuticaliy-acceptable salts thereof can be administered orally or parenterally.
  • Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration.
  • the compound can be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and com starch, and lubricating agents, such as magnesium stear- ate, are commonly added.
  • useful diluents are lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, sweetening or flavoring agents can be used.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions is suitably adjusted and buffered.
  • total concentration of solutes can be controlled to render the preparation isotonic.
  • a polyamine or salt thereof of this invention is used in a human subject, the daily dosage will normally be determined by the prescribing physician.
  • suitable dosages for the polyamines of this invention are from about 1 to 30 mg/kg/day.
  • the dosage will vary according to the age, weight and response of the individual patient, as well as the severity of the patients's symptoms and the potency of the particular compound being administered. Therefore, dosages outside the range given above are possible and are within the scope of this invention.
  • a polyamine or salt thereof of this invention When a polyamine or salt thereof of this invention is used in control of invertebrate pests, said compound is administered to said invertebrate directly or provided to the environment of said invertebrate.
  • a compound of this invention can be sprayed as a solution onto said invertebrate. The amount of compound necessary for control of said invertebrate will vary according to the invertebrate and environmental conditions and will be determined by the person applying the compound.
  • a polyamine or salt thereof of this invention is used in the physiological study of cells
  • said compound is administered to the cells according to methods well known to those skilled in the art.
  • said compound can be administered to cells in an appropriate physiological buffer.
  • An appropriate concentration of the compounds of this invention for use in such studies is 100 ⁇ M.
  • the concentration of said compounds in such studies may be greater than or much less than 100 ⁇ M.
  • the amount of the compound administered will be determined by the person skilled in the art according to the well known methods.
  • the product was purified by fiash chromatography (SiO 2 , 20-»100% ethylacetate in hexane) to provide the product N-Boc-nitrile 9 as a clear oil (14 g, 24% yield).
  • N-Boc-amine 14 was prepared from N-Boc-nitrile 13 as N-Boc-amine 11 was prepared from N-Boc-nitrile 9 in 99% yield (30 g).
  • Nitrite 15 was prepared from N-Boc-amine 14 as nitrite 12 was prepared from N-Boc-amine 11 in 90% yield.
  • Step 8 Procedure Type A
  • N-Boc-nitrile 16 was prepared from nitrite 15 as N-Boc-nitrile 13 was prepared from nitrite 12 as a clear colorless oil (30 g, 87% yield).
  • N-Boc-amine 17 was prepared from N-Boc-nitrile 16 as N-Boc-amine 11 was prepared from N-Boc-nitrile 9 in 74% yield (2.61 g).
  • Nitrite 18 was prepared from N-Boc-amine 17 as nitrite 12 was prepared from N-Boc-amine 11 in 91% yield (19 g), and was used without further purification.
  • N-Boc-nitrile 19 was prepared from nitrite 18 as N-Boc-nitrile 13 was prepared from nitrite 12 (16 g, 74% yield).
  • N-Boc-amine 20 was prepared from N-Boc-nitrile 19 as N-Boc-amine 11 was prepared from N-Boc-nitrile 9 (17 g, 99% yield).
  • NMR 300 MHz, CDCI 3 ) ⁇ 3.24-2.95 (m, 18H), 2.6 (t, 2H, J -6H), 1.72-1.52 (m, 10H), 1.42-1.32 (m, 45H).
  • Nitrite 21 was prepared from N-Boc-amine 20 as nitrite 12 was prepared from N-Boc-amine 11 in 99% yield.
  • Step 14 Procedure Type A
  • N-Boc-nitrile 22 was prepared from nitrite 21 as N-Boc-nitrile 13 was prepared from nitrite 12 in 99% yield.
  • N-Boc-amine 23 was prepared from N-Boc-nitrile 22 as N-Boc-amine 11 was prepared from N-Boc-nitrile 9 (8 g, 99% yield).
  • Nitrite 24 was prepared from N-Boc-amine 23 as nitrite 12 was prepared from N-Boc-amine 11 in 99% yield.
  • N-Boc-nitrile 25 was prepared from nitrite 24 as N-Boc-nitrile 13 was prepared from nitrite 12 (5.5 g, 74% yield).
  • N-Boc-amine 26 was prepared from N-Boc-nitrile 25 as N-Boc-amine 11 was prepared from N-Boc-nitrile 9 (5.01 g, 91% yield).
  • Step 1 Amide Bond Formation - Procedure Type D1
  • 0.19 g ferrocene carboxylic acid (0.82 mmol, 1.1 eq)
  • 0.12 g hydroxybenzotriazole (0.89 mmol, 1.2 eq)
  • 0.17 g 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HCI salt, 0.90 mmol, 1.2 eq
  • 10 ml CH 2 CI 2 0.61 g of N-Boc-amine 27 (0.75 mmol, 1.0 eq., see Example 5a herein for preparation) was added to the solution.
  • Step 2 Polyamine Deprotection - Procedure Type F Trifluoroacetic acid (30 ml) was degassed with a dry N 2 bubble stream (via Teflon tubing) in a 100 ml one neck RBF at 0°C.
  • the ferrocene carboxamide polyamine of step 1 above (712 mg, 0.69 mmol) was dissolved in 2 ml CH 2 CI 2 and transferred to the stirring TFA with 3 x 2 ml CH 2 CI 2 rinses. After 30 minutes, the ice bath was removed; after an additional 30 minutes, the solvents were removed under reduced pressure, then by Hi- Vac.
  • Step 1 Amide Bond Formation - Procedure Type D3
  • the hydrochloride salt of 2-pyridylacetic acid (0.105 g, 0.60 mmol, 1.0) was combined with 0.16 ml TEA (1.15 mmol, 2 eq) and 4 ml CH 2 CI 2 .
  • DEC (0.12 g, 0.62 mmol, 1.0 eq)
  • 0.09 g HOBt (0.66 mmol, 1.1 eq) were added and the mixture was stirred for 2 hours.
  • N-Boc- amine 27 (0.44 g, 0.54 mmol, 0.9 eq) was added and reaction stirred an additional 10 hours.
  • the reaction was diluted to 100 ml with CH 2 CI 2 and washed with aqueous 20% NH 4 OH (2 x 100 ml).
  • the base layers were extracted with CH 2 CI 2 (3 x 50 ml); all the CH 2 CI 2 fractions were combined, then washed with brine (50 ml) dried over K 2 C0 3 , filtered and the solvents removed to yield 281 mg (>100% yield) crude material.
  • Pure product was isolated via flash silica gel chromatography (12 g slurried in CH 2 CI 2 and eluted with a 0-10% MeOH/CH 2 CI 2 gradient) as a white, waxy, solid (190 mg, 88% yield).
  • Step 2 Polyamine Deprotection - Procedure Type F Triflouroacetic acid (30 ml) was degasssed with a continuous N 2 bubble stream (via Teflon tubing) at 0°C.
  • the biphenylacetamine of step 1 above 150 mg, 0.15 mmol was added as a dry powder to the stirring TFA. After 40 minutes, the ice bath was removed; after an additional 20 minutes the solvents were removed under reduced pressure, then Hi-Vac. After 2 hours, the resulting tan oil was mashed with Et 2 O (3 x 30 ml); a white solid formed and was collected under positive N 2 pressure on a porosity "C" frit. The solid was dissolved in water, rinsed through the frit and freeze dried to yield 136 mg (99% yield) of product as a white solid.
  • the compound of formula I was prepared from diaminobutane and acrylonitrile according to the published procedure of Yamamoto, Hisashi, J. Am. Chem. Soc. 103:6133-6136 (1981 ).
  • N-cyanoethyl-1 ,4-diaminobutane (6.44 g, 0.0457 mol) in acetonitrile (200 ml) under a nitrogen atmosphere was added KF/Celite (1 1 g) followed by the dropwise addition over a 7 hour period of N-(tert-butoxycarbonyl)-3-bromopropylamine (10.87 g, 0.0457 mol).
  • the reaction was allowed to stir for 1 6 hours at ambient temperature and was then heated to 70 °C for 24 hours. The reaction was allowed to cool and was filtered and concentrated in vacuo.
  • N-Boc amine 27 having the following structure, was made.
  • Nitrite XIII was prepared from N-Boc amine VIII as nitrite VI was prepared from N-Boc amine V (Example 5, Step 5), giving 1 .00 g of product (93% yield).
  • N-Boc nitrite XIV was prepared from nitrite XIII via amine protection using procedure A.
  • Step 10a N-Boc amine 27 was prepared by hydrogenation of N-Boc nitrite XIV as N-Boc amine VIII was prepared from N-Boc nitrite VII (step 7 of this example).
  • R(CH 2 ) m CO[NH(CH 2 ) 3 ] 3 NH(CH 2 ) 4 NH(CH 2 ) 3 NH 2 *5HCI (from procedure E) or R(CH 2 ) m CO[NH(CH 2 ) 3 ] 3 NH(CH 2 ) 4 NH(CH 2 ) 3 NH 2 *5TFA (from procedure F) were prepared via the following procedures.
  • N-cyanoethyi-1 ,4-diaminobutane (6.44 g, 0.0457 mol) in acetonitrile (200 ml) under a nitrogen atmosphere was added KF/Celite (11 g) followed by the dropwise addition, over 7 hours, of N-(fe/ - butoxycarbonyl)-3-bromopropylamine (10.87 g, 0.0457 mol).
  • the reaction mixture was stirred for 16 hours at ambient temperature, was heated to 70°C for 24 hours and was then cooled, filtered and concentrated ]n vacuo.
  • the product was chromatographed on 800 g silica gel using 4:1 hexane/ethylacetate and the fractions were monitored by hexane/ethylacetate and the fractions were monitored by TLC (KMNO ⁇ y.
  • the fractions containing the product were combined, concentrated in vacuo, chased twice with 50 ml dichloromethane and purged with high vacuum to yield 25.8 g of the product of this preparation.

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EP92916921A 1991-08-23 1992-08-10 Synthetische arylpolyamine als antagonisten von anregbaren aminosäure-neurotransmittern Withdrawn EP0641312A1 (de)

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US74901491A 1991-08-23 1991-08-23
US749014 1991-08-23
PCT/US1992/006482 WO1993004036A1 (en) 1991-08-23 1992-08-10 Synthetic aryl polyamines as excitatory amino acid neurotransmitter antagonists

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EP (1) EP0641312A1 (de)
JP (1) JPH06505996A (de)
CN (1) CN1069969A (de)
AU (1) AU2426392A (de)
BR (1) BR9206403A (de)
CA (1) CA2114798A1 (de)
CZ (1) CZ39994A3 (de)
FI (1) FI940833A0 (de)
HU (1) HU9400503D0 (de)
IL (1) IL102835A0 (de)
MX (1) MX9204866A (de)
PT (1) PT100801A (de)
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US7087765B2 (en) 1995-06-07 2006-08-08 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US6211245B1 (en) 1993-02-08 2001-04-03 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US6750244B2 (en) 1993-02-08 2004-06-15 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US6071970A (en) * 1993-02-08 2000-06-06 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US6017965A (en) * 1993-02-08 2000-01-25 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
ES2156162T3 (es) * 1994-02-08 2001-06-16 Nps Pharma Inc Compuestos activos en un nuevo sitio sobre canales del calcio accionados por un receptor, utiles para el tratamiento de trastornos y enfermedades neurologicas.
US20010004460A1 (en) * 1995-06-08 2001-06-21 Carla Rasmussen Klittich Process for the preparation of rice seed for sowing
US7087648B1 (en) * 1997-10-27 2006-08-08 The Regents Of The University Of California Methods for modulating macrophage proliferation using polyamine analogs
AU2003231670B2 (en) * 1997-10-27 2006-06-08 Slil Biomedical Corporation Methods for modulating macrophage proliferation using polyamine analogs
US8198334B2 (en) 1997-10-27 2012-06-12 Pathologica Llc Methods for modulating macrophage proliferation in ocular disease using polyamine analogs
EP1436246A1 (de) 2001-10-16 2004-07-14 SLIL Biomedical Corporation Oligoamin-verbindungen und ihre derivate für die krebstherapie
JP2007505044A (ja) * 2003-09-09 2007-03-08 ユニバーシティ オブ フロリダ リサーチ ファウンデイション、インコーポレイテッド ポリアミン−金属キレーター接合体
CN103073448B (zh) * 2012-12-29 2015-11-18 河南大学 含芳环结构的多胺衍生物及其制备方法和应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5037846A (en) * 1990-01-02 1991-08-06 Pfizer Inc. Indolyl-3 polyamines and their use as antagonists of excitatory amino acid neurotransmitters

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9304036A1 *

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JPH06505996A (ja) 1994-07-07
FI940833A (fi) 1994-02-22
IL102835A0 (en) 1993-01-31
AU2426392A (en) 1993-03-16
WO1993004036A1 (en) 1993-03-04
CZ39994A3 (en) 1994-11-16
PT100801A (pt) 1993-09-30
ZA926314B (en) 1994-02-21
CA2114798A1 (en) 1993-03-04
HU9400503D0 (en) 1994-05-30
MX9204866A (es) 1993-04-01
BR9206403A (pt) 1994-12-27
FI940833A0 (fi) 1994-02-22

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