EP0702681A1 - Azacycles spirosubstitues antagonistes de la neurokinine - Google Patents

Azacycles spirosubstitues antagonistes de la neurokinine

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Publication number
EP0702681A1
EP0702681A1 EP95901979A EP95901979A EP0702681A1 EP 0702681 A1 EP0702681 A1 EP 0702681A1 EP 95901979 A EP95901979 A EP 95901979A EP 95901979 A EP95901979 A EP 95901979A EP 0702681 A1 EP0702681 A1 EP 0702681A1
Authority
EP
European Patent Office
Prior art keywords
spiro
piperidine
dichlorophenyl
methylamino
butyl
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.)
Ceased
Application number
EP95901979A
Other languages
German (de)
English (en)
Inventor
Malcolm Maccoss
Sander G. Mills
Shrenik K. Shah
Yuan-Ching P. Chiang
Patrick T. Dunn
Hiroo Koyama
Paul E. Finke
Hongbo Qi
Albert J. Robichaud
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.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
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 Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0702681A1 publication Critical patent/EP0702681A1/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • the invention disclosed herein is directed to certain spiro- substituted azacycles useful as tachykinin receptor antagonists.
  • the compounds disclosed herein are neurokinin receptor antagonists.
  • tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB), are structurally similar members of a family of neuropeptides. Each of these is an agonist of the receptor types, neurokinin-1 receptor (NK-1), neuorokinin-2 receptor (NK-2) and neuorokinin-3 receptor (NK-3), which are so defined according to their relative abilities to bind tachykinins with high affinity and to be activated by the natural agonists SP, NKA and NKB respectively.
  • SP substance P
  • NKA neurokinin A
  • NKB neurokinin B
  • NK-3 neurokinin-3 receptor
  • the tachykinins are distinguished by a conserved carboxyl- terminal sequence Phe-X-Gly-Leu-Met-NH2. More specifically, substance P is a pharmacologically-active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence:
  • Neurokinin A possesses the following amino acid sequence:
  • Neurokinin B possesses the following amino acid sequence:
  • the neurokinin receptors are widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. This includes sensory perception of olfaction, vision, audition and pain, movement control, gastric motility, vasodilation, salivation, and micturition (B. Pernow, Pharmacol. Rev., 1983, 35, 85- 141).
  • the NK1 and NK2 receptor subtypes are implicated in synaptic transmission (Laneuville et al, Life Sci., 42: 1295-1305 (1988)).
  • Substance P acts as a vasodilator, a depressant, stimulates salivation and produces increased capillary permeability. It is also capable of producing both analgesia and hyperalgesia in animals, depending on dose and pain responsiveness of the animal (see R.C.A. Frederickson et al, Science, 199, 1359 (1978); P. Oehme et al, Science, 208, 305 (1980)) and plays a role in sensory transmission and pain perception (T.M. Jessell, Advan. Biochem. Psychopharmacol. 28, 189 (1981)). In particular, substance P has been shown to be involved in the transmission of pain in migraine (see B.E.B. Sandberg et al, Journal of Medicinal Chemistry, 25, 1009 (1982)), and in arthritis (Levine et al Science, (1984) 226, 547-549).
  • NK1 receptors are associated with microvascular leakage and mucus secretion, while NK2 receptors regulate smooth muscle contraction.
  • substance P and neurokinin A are effective in inducing airway constriction and edema. Based on such findings, it is believed that substance P and neurokinin A may be involved in the pathogenesis of neurogenic inflammation, including allergic diseases such as asthma. (Frossard et al, Life Sci., 49, 1941-1953 (1991); Advenier, et al, Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)).
  • sensory neuropeptides especially tachykinins such as substance P and neurokinin A
  • tachykinins such as substance P and neurokinin A
  • Neurokinin A is a very potent constrictor of human airways in vitro
  • substance P causes mucus secretion in the airways.
  • bradykinin causes bronchoconstriction in asthmatic patients but not in normal subjects.
  • Inhalation of bradykinin causes bronchoconstriction in asthmatic patients but not in normal subjects.
  • bradykinin-induced bronchoconstriction is partly opposed by anticholinergic agents and since bradykinin is only a weak constrictor of human airways in vitro, it has been suggested that the bronchoconstrictor response is partly mediated by a neural reflex. Bradykinin stimulates vagal afferent C fibers and causes broncho ⁇ constriction in dogs.
  • bradykinin causes a bronchoconstrictor response by way of cholinergic and sensory-nerve-mediated mechanisms.
  • Bradykinin-induced bronchoconstriction in human airways may therefore be due partly to tachykinin released from sensory nerve terminals via axon reflex mechanisms.
  • a dual NK-l/NK-2 antagonist such as FK-224 protects against bradykinin induced bronchocontriction in asthmatic patients. (Ichinoe, M. et al, Lancet, , vol. 340, pp 1248-1251 (1992)).
  • tachykinins have also been implicated in gastro ⁇ intestinal (GI) disorders and diseases of the GI tract, such as inflammatory bowel disease, ulcerative colitis and Crohn's disease, etc. (see Mantyh et al, Neuroscience, 25 (3), 817-37 (1988) and D. Regoli in "Trends in Cluster Headache” Ed. F. Sicuteri et al, Elsevier Scientific Publishers, Amsterdam, 1987, pp. 85-95).
  • GI gastro ⁇ intestinal
  • tachykinin antagonists are believed to be useful are allergic conditions (Hamelet et al, Can. J. Pharmacol. Physiol. (1988) 66, 1361-7), immunoregulation (Lotz et al, Science (1988) 241, 1218-21, Kimball et al, J. Immunol. (1988) 141 (10) 3564-9 and A. Perianin, et al, Biochem. Biophys. Res. Commun.
  • Antagonists selective for the substance P and/or the neurokinin A receptor may be useful in the treatment of asthmatic disease (Frossard et al, Life Sci., 49, 1941-1953 (1991); Advenier, et al, Biochem. Biophys. Res. Comm., 184(3), 1418-1424 (1992)).
  • This invention is directed to compounds of formula I.
  • the invention is also concerned with pharmaceutical formulations with these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders.
  • the compounds of this invention are tachykinin receptor antagonists and are useful in the treatment of inflammatory diseases, pain or migraine and asthma.
  • This invention is directed to compounds of formula I.
  • Rl is selected from a group consisting of: (1) hydrogen, (2) linear or branched C ⁇ _8 alkyl, linear or branched C2-8 alkenyl, or linear or branched C2-8 alkynyl, wherein the Cl-8 alkyl, C2-8 alkenyl or C2-8 alkynyl is optionally mono, di, tri or tetra substituted, the substitutents independently selected from: (a) hydroxy,
  • halogen which is defined to include Br, CI, I, and F,
  • R6 and R7 are 10 independently selected from:
  • heteroaryl wherein heteroaryl is selected from the group consisting of:
  • heteroaryl wherein heteroaryl is selected from the group consisting of:
  • Rl 2(g) is optionally quatemized with Cl-4alkyl or phenylCl-4alkyl or is optionally present as the N-oxide (N+0-);
  • W is selected from the group consisting of
  • X is selected from the group consisting of (1) a covalent bond
  • said ring being an phenyl, naphthyl or heteroaryl group, with the heteroaryls selected from the group consisting of:
  • heteroaryl wherein heteroaryl is selected from the
  • One subclass of this invention consists of structures tabulated below linked to Rl (as detailed immediately above) via the broken bond, and optionally substituted at the positions indicated by numbers 1-8 with
  • the above compounds may be co-administered with a ⁇ 2-agonist such as Bambuterol, US 4,419,364 issued to Draco on 12/6/83; Bitolterol mesylate, US 4,138,581 issued to Sterling 2/6 79; Carbuterol, US 3,763,232 issued to SmithKline 10/2/73; Clenbuterol, US 3,536,712 issued to Boehringer Ingelheim 10/27/70; Dopexamine, US 4,645,768 issued to Fisons 2/24/87; Formoterol, US 3,994,974 issued to Yamanouchi 11/30/76; Mabuterol, US 4,119,710 issued to Boehringer Ingelheim 10/10/78; Pirbuterol hydrochloride US 3,700,681 issued to Pfizer 10/24 72; Procaterol hydrochloride US 4,026,897 issued to Otsuka 5/31/77; Ritodrine hydrochloride US
  • the compounds of formula I are particularly useful in the treatment of diseases or conditions that are advantageously treated by concomitant antagonism of both NKl and NK2 receptors or NKl, NK2 and NK3 receptors.
  • diseases include neuropathy, such as diabetic or peripheral neuropathy and chemotherapy-induced neuropathy; asthma; osteoarthritis; rheumatoid arthritis; and migraine.
  • the compounds of formula I may be co-administered with another NKl or NK2 antagonist such as those described in
  • EP-347802 filed 20-Jun-88, Pub. 27-Dec-89; Appln No. EP-412542, filed 10-Aug-89, Pub. 13-Feb-91; Appln No. WO9005729, filed 23- Nov-88, Pub. 31- May-90; Appln No. WO9005525, filed 23-Nov-88, Pub. 31- May-90; Appln No. EP-436334, filed 04-Jan-90, Pub. 10-Jul- 91; Appln No. W09118878, filed 31- May-90, Pub. 12-Dec-91; Appln No. W09118899, filed Ol-Jun-90, Pub. 12-Dec-91; Appln No.
  • the compounds of formula I are useful in the prevention and treatment of a wide variety of clinical conditions (as detailed in this specification) which are characterized by overstimulation of the tachykinin receptors, in particular NKl, NK2 and NK3.
  • These conditions may include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic or peripheral neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy, and neuralgia; respiratory diseases such as chronic obstructive airways disease, bronchopneumonia, bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis,
  • the compounds of the present invention are particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example: neuropathy, such as diabetic or peripheral neuropathy and chemotherapy-induced neuropathy; asthma; osteoarthritis; rheumatoid arthritis; and migraine.
  • compounds of Formula I may be administered orally, topically, parenterally, ICV, 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, intracistemal injection or infusion techniques.
  • the compounds of the invention are effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethyl- cellulose, sodium alginate, polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • topical use creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • an appropriate dosage level will generally be about 0.001 to 50 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level may be about 0.001 to 25 mg/kg per day, about 0.005 to 10 mg/kg per day, or about 0.005 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the compounds of this invention are useful for antagonizing tachykinins, in particular substance P and neurokinin A in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, pain or migraine and asthma in a mammal in need of such treatment. This activity can be demonstrated by the following assay.
  • the cDNA for the human NK1R was cloned into the expression vector pCDM9 which was derived from pCDM8 (INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+) into the Sac II site.
  • Transfection of 20 ⁇ g of the plasmid DNA into 10 million COS cells was achieved by electroporation in 800 ⁇ l of transfection buffer (135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 uF using the IBI GENEZAPPER (IBI, New Haven, CT).
  • the cells were incubated in 10% fetal calf serum, 2 mM glutamine, lOOU/ml penicillin- streptomycin, and 90% DMEM media (GIBCO, Grand Island, NY) in 5% C02 at 37°C for three days before the binding assay. Similar methods were used to express the NK2 receptor.
  • the cDNA was subcloned into the vector pRcCMV (INVITROGEN).
  • Transfection of 20 ⁇ g of the plasmid DNA into CHO cells was achieved by electroporation in 800 ⁇ l of transfection buffer suplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 uF using the IBI GENEZAPPER (IBI).
  • the transfected cells were incubated in CHO media (10% fetal calf serum, 100 U/ml pennicilin- streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml G418 (GIBCO)) in 5% C ⁇ 2 at 37°C until colonies were visible. Each colony was separated and propagated. The cell clone with the highest number of human NK1R was selected for subsequent applications such as drug screening. Similar methods were used to express the human NK2 receptor.
  • CHO media 10% fetal calf serum, 100 U/ml pennicilin- streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml G418 (GIBCO)
  • the binding assay of human NK1R expressed in either COS or CHO cells is based on the use of - ⁇ I-substance P ( ⁇ - ⁇ I-SP, from DU PONT, Boston, MA) as a radioactively labeled ligand which competes with unlabeled substance P or any other ligand for binding to the human NK1R.
  • - ⁇ I-substance P ⁇ - ⁇ I-SP, from DU PONT, Boston, MA
  • Monolayer cell cultures of COS or CHO 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 MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.02 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 ⁇ I-SP binding (approximately 50,000 to 200,000 cells).
  • the binding buffer 50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.02 mg/ml BSA, 0.01 mM phosphoramidon
  • the activation of phospholipase C by NK1R may also be measured in CHO cells expressing the human NK1R by determining the accumulation of inositol monophosphate which is a degradation product of IP3.
  • CHO cells are seeded in 12- well plate at 250,000 cells per well. After incubating in CHO media for 4 days, cells are loaded with 0.025 uCi/ml of ⁇ H-myoinositol by overnight incubation. The extracellular radioactivity is removed by washing with phosphate buffered saline. LiCl is added to the well at final concentration of 0.1 mM with or without the test compound, and incubation is continued at 37°C for 15 min.
  • Substance P is added to the well at final concentration of 0.3 nM to activate the human NK1R. After 30 min of incubation at 37°C, the media is removed and 0.1 N HCI is added. Each well is sonicated at 4°C and extracted with CHCl3/methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG 1X8 ion exchange column. The column is washed with 0.1 N formic acid followed by 0.025 M ammonium formate-0.1 N formic acid. The inositol monophosphate is eluted with 0.2 M ammonium formate-0.1 N formic acid and quantitated by beta counter. Similar methods were used to assess antagonism at the NK2 receptor, except NKA was used as the stimulating agonist.
  • the compounds of of Formula I as Exemplified in the EXAMPLES below have been found to displace radioactive ligand for the NK-1 receptor at a concentration range of 0.01 nM to 1.0 ⁇ M, for the NK-2 receptor, 0.01 nM to 5 ⁇ M, and for the NK-3 receptor, 1.0 nM to 10 ⁇ M.
  • the required azacycle starting materials are prepared using methods described in the literature; such as described in Ong, H. H. et al, Journal of Medicinal Chemistry, 1983,26, 981-986, and Nargund, R. et al, USSN 08/147,226 (November 3, 1993), EP 93309867.5 hereby encorporated by reference. None of the compounds in these references are claimed to be neurokinin antagonists.
  • the aldehyde needed for this reaction can be prepared by methods generally known in the chemical literature; for the purposes of the present invention the preparation of a representative aldehyde is described in Hale, J.J.; Finke, P.E.; MacCoss, M. Bioorganic & Medicinal Chemistry Letters 1993,3, 319-322.
  • the alkyl halide or alkyl sulfonate needed for this reaction can be prepared by methods generally known in the chemical literature; for the purposes of the present invention an aldehyde, prepared as described above, can be reduced to an alcohol with sodium borohydride, diisobutylaluminum hydride or lithium aluminum hydride, and the product alcohol converted to either the alkyl halide using methods described in March J.
  • a strong reducing agent e.g. diborane including borane dimethylsulfide; and, lithium aluminum hydride
  • the product amide can in and of itself be a neurokinin antagonist or can be reduced with a strong reducing agent, such as diborane or lithium aluminum hydride, to give the ter
  • compound 1 formed in the alkylation step may be further modified in subsequent reactions.
  • the aldehyde fragment contained a t-butoxycarbonylamino group (Example 2).
  • the t-butoxycarbonyl protecting group is removed by treatment with a strong acid such as trifluoroacetic acid or formic acid and the resulting amine is acylated to furnish the desired compounds (Example 3).
  • the protecting group may also be present in the azacycle portion as illustrated with a benzyloxycarbonyl group in Example 6.
  • the allyl acid 2 (described in Hale et al, see above) can be converted into the N-methyl methoxy amide 3, which is then treated with an alkyl or aryl metal reagent, for example methyllithium or butyllithium, to provide the ketone 4 (Scheme 2).
  • the ketone can be converted into an imine which can then be reduced to secondary amine 5 chemically, (e.g using sodium cyanoborohydride or sodium borohydride), or catalytically (e.g. using hydrogen and palladium on carbon or Raney nickel catalyst).
  • secondary amine 5 chemically, (e.g using sodium cyanoborohydride or sodium borohydride), or catalytically (e.g. using hydrogen and palladium on carbon or Raney nickel catalyst).
  • the allyl group in 6 can be oxidatively cleaved to aldehyde 7 with osmium tetroxide followed by sodium periodate or with ozone at low temperature. Reductive amination of aldehyde 7 with azacycle 1 can then be carried out under the conditions described above.
  • Substituted spiro(indoline-3,4'-piperidine) derivatives can be prepared as shown in Scheme 3 starting from the appropriately substituted phenylhydrazines. Following the Fischer indole reaction and reduction of the intermediate imine with a mild reducing agent such as sodium borohydride, the indoline nitrogen can be reacted with an electrophile such as an acyl chloride or a sulfonyl chloride.
  • the protecting group on the piperidine nitrogen for example a benzyloxycarbonyl group, can be removed by treatment with hydrogen in the presence of palladium on carbon or by exposure to trimethylsilyl iodide, to give the deprotected substituted spiro(indoline-3,4'- piperidine).
  • Displacement of the chloride with functionalized 2-bromothiophenol provides the allylic sulfide, which can be cyclized under radical conditions to give the illustrated spiro(2,3-dihydrobenzothio ⁇ hene-3,4'- piperidine).
  • Spiro(2,3-dihydrobenzofuran-3 ,4'-piperidine) derivatives can be prepared as illustrated in Scheme 5.
  • Treatment of an appropiately substituted ester of 2-fluorophenylacetate with mechlorethamine hydrochloride under basic conditions provides the piperidine product, which on treatment with a strong reducing agent such as lithium aluminum hydride produces the corresponding 4- (hydroxymethyl) compound.
  • Cyclization with base provides the benzofuran derivative, and cleavage of the N-methyl group can then be carried out using 1 -chloroethyl chloroformate or other suitable N- demethylating agents.
  • ketone derivatives can be prepared by an extension of the chemistry given above, as shown in Scheme 7.
  • a second Amdt-Eistert chain extension provides the illustrated heptenoic acid derivative, which after conversion into its N-methoxy-N-methyl amide, can be reacted with an aryl organometalhc reagent, such as an aryl magnesium bromide, to provide the ketone.
  • Routine oxidative cleavage then gives the desired aldehyde, which can be coupled with a spiro-piperidine derivative as described above.
  • Alcohol containing antagonists can be prepared according to procedures given in Scheme 8. Formation of the N-methyl-N- methoxy amide of the indicated acid followed by oxidative cleavage of the olefin provides the intermediate aldehyde. Coupling with a spiro(indoline-3,4'-piperidine) derivative followed by addition of an organometalhc reagent to the amide provides the illustrated ketone. Treatment with a hydride reducing agent, such as sodium borohydride, then yields the desired alcohol derivatives.
  • a hydride reducing agent such as sodium borohydride
  • heterocycle substituted antagonists can be carried out according to the procedure given in Scheme 9 for substituted imidazoles.
  • Reduction of the allyl acid with a strong reducing agent such as lithium aluminum hydride followed by in situ formation of the trifluoromethanesulfonate of the formed alcohol allows for displacement of the triflate with a nucleophile such as 2- phenylimidazole.
  • Oxidative cleavage under standard conditions provides the indicated aldehyde which can then be coupled under the conditions described above to the appropriate spiro derivative.
  • Spiro(2-oxo-l,2,3,4-tetrahydroquinoline-4,4'-piperidine) and spiro( 1-oxo-l, 2,3 ,4-tetrahydroisoquinoline-4,4'-piperidine) can be prepared as shown in Scheme 10.
  • Scheme 10 Starting from the indicated spiro(2- oxoindane-3,4'-pi ⁇ eridine) (described in Claremon, D.A. et al, European Patent 0 431 943 943 A2. Evans, B.E. et al U.S. Patent 5.091.387. Davis, L. et al, U.S. Patent 4.420.485.
  • deprotection of the piperidine nitrogen is carried out by treatment with acid, for example trifluoroacetic acid, followed by protection as the trifluoroacetamide, and the product is exposed to hydrazoic acid in the presence of sulfuric acid. Heating of this mixture effects a Schmidt rearrangement, to provide both the tetrahydroquinoline and the tetrahydroisoquinoline derivatives.
  • Neurokinin antagonists with ether substituents can also be prepared by the route shown in Scheme 11.
  • the allyl acid discussed earlier can be reduced to the corresponding alcohol with, for example, lithium aluminum hydride.
  • This alcohol can be alkylated by a Williamson ether synthesis, by deprotonation with a strong base such as sodium hydride or sodium hexamethyldisilazide followed by reaction with a benzyl halide such as benzyl bromide.
  • the product can be processed through the oxidative cleavage steps described earlier to provide the aldehyde, which can then be coupled with a spirocycle ismer reductive amination conditions or else by reduction to the corresponding alcohol and conversion to the bromide, the bromide can then be used to alkylate a spirocycle under the conditions detailed above.
  • the invention encompasses a process of making compounds of formula I
  • a suitable solvent such as acetonitrile or dimethylacetamide with a compound of formula Rl-Xl wherein Xl is a leaving group such as bromo, chloro, tosyl or mesyl optionally in the presence of a suitable base such as trialkylamine; or
  • Step A l'-(3-((S)-(3,4-dichlorophenyl))-4-(methylamino)butyl)-l- methanesulfonyl-spirofindoline-S ⁇ '-piperidine)
  • Step B l'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5- dimethylbenzoyl)(methylamino))butyl)- 1 -methanesulfony 1- spiroCindoline-3 ⁇ '-piperidine
  • Mass Spectmm 200, 202, 228, 230, 279, 308, 310, 494, 496, 670, 672
  • the yellow oil was dissolved in 800 mL of 1,2- dichloroethane and cooled in ice bath as 50 mL (463 mmol) of 1- chloroethyl chloroformate keeping the temperature below 10°C. The resulting solution was heated to reflux. Gas evolution was noticed when the reaction temperature reached 70-75 °C. After 1 h the solution was cooled, concentrated to ca. 250 mL in vacuo and 700 mL of methanol was added. The mixture was refluxed for 1.5 h and gas evolution was observed. The reaction was cooled to room temperature and concentrated in vacuo to a wet solid. The solid was slurried with cold methanol, the solid was filtered, washed with cold methanol and dried.
  • the filtrate was concentrated to a thick oil and the oil was dissolved in 40 mL of EtOH.
  • Acetic acid (3 mL) and 0.8 g of 10% Pd/C were added to the solution and the resulting mixture was hydrogenated on a Parr apparatus for 3 h.
  • the catalyst was filtered and washed with EtOAc and the combined filtrate was concentrated.
  • the residue was partitioned between CH2CI2 and water and 2N NaOH was added to this mixture until the aqueous layer was basic.
  • the layers were separated and the aqueous layer was extracted with CH2CI2.
  • the combined organic layer was washed with brine, dried over Na2S ⁇ 4 and the filtrate was concentrated to give 2.93 g (77%) of the title compound sufficiently pure for use in the next reaction.
  • Step 1 N-Methoxy-N-methyl-2-(S)-(3,4-dichlorophenyl)-4- pentenamide
  • Step 2 3-(S - .4-dichlorophenylV5-hexen-2-one
  • Step 3 N-Methyl 3-(S)-(3,4-dichlorophenyl)-5-hexen-2-(RS)- amine
  • Step 4 N-Methyl-N-t-butoxycarbonyl-3-(S)-(3,4-dichlorophenyl)-
  • Step 5 N-Methyl-N-t-butoxycarbonyl-3-(S)-(3 ,4-dichlorophenyl)-
  • Step 6 l'-(3-(S)-(3,4-Dichlorophenyl)-4-(N-(R or S)-(t-butoxy- carbonyl)(methylamino))pentyl)- 1 -methanesulfonyl- spiro(indoline-3 ,4'-piperidine
  • Step 7 l'-(3-(S)-(3,4-Dichlorophenyl)-4-(N-(R or S)- fmethylamino ⁇ pentyl 1 -methanesulfonyl-spirofindoline- 3.4'-piperidine
  • Step 8 l'-(3-(S)-(3,4-Dichlorophenyl)-4-(N-(R or S)-(3-methyl- benzoyl)(methylamino))pentyl)- 1 -methanesulfonyl- spirofindoline-3.4'-piperidine
  • the title compound was prepared from l'-(3-(S)-(3,4- dichlorophenyl)-4-(R or S)-(methylamino)pentyl)-l-methanesulfonyl- spiro(indoline-3,4'-piperidine) (from Step 7 above) using a procedure identical to Example 3, Step (b), substituting m-toluoyl chloride for 3,5-dimethylbenzoyl chloride.
  • the title compound was prepared from l'-(3-(S)-(3,4- dichlorophenyl)-4-(R or S)-(methylamino)pentyl)- 1 -methanesulfonyl- spiro(indoline-3,4'-piperidine) (from Example 1, Step 7 above) using a procedure identical to Example 3 Step (b), substituting 3,5- bis(trifluoromethyl)benzoyl chloride for 3,5-dimethylbenzoyl chloride.
  • the filtrate was concentrated and the residue which was a mixture of the desired acid and the aldehyde was dissolved in 3 mL of acetone.
  • the solution was treated with 6 N Jones reagent until the orange color persisted. After stirring for 20 min the excess reagent was destroyed by adding few drops of i-PrOH.
  • the solution was diluted with water and extracted with CH2CI2.
  • the CH2CI2 layer was washed with brine, dried and the filtrate was concentrated.
  • the residue was purified by prep TLC using 0.5:30:69.5 of HOAc:EtOAc:hexane to isolate 0.14 g (45 %) of 3-bromo-5-methylbenzoic acid.
  • Step B l'-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3-bromo-5- methy lbenzoyl)(methylamino))buty 1)- 1 -methanesulf onyl- spiro(indoline-3.4'-piperidine
  • Step A 1.r-Dimethyl-spiro( ⁇ ndol-2-one-3.4'-piperidine)
  • Step B l-Methyl-spiro( ' indol-2-one-3.4'-piperidine
  • Step C l '-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethyl- benzoyl)(methylamino))butyl)-l-methyl-spiro(indol-2-one-
  • Step A 1 '-Trifluoroacetyl-spirod -indanone-3.4'-piperidine
  • Step B l'-Trifluoroactyl-spiro-(2-oxo- 1,2,3, 4-tetrahydro- quinoline-4,4'-piperidine) and r-trifluoroactyl-spiro-(l- oxo-1.2.3.4-tetrahydroisoquinoline-4.4'-piperidine
  • a mixture of 1.09 g (16.8 mmol) of Sodium azide in 1.2 mL of water and 6.6 mL of CHCI3 was added 0.46 mL of concentrated H2SO4 (36 N) keeping the temperature between 0-5°C.
  • Step C Spiro-(2-oxo-1.2.3.4-tetrahydroquinoline-4.4'-piperidine
  • Step D l'-(3-((S)-(3,4-Dichlorophenyl))-4-(N-(3,5-dimethyl- benzoyl)(methylamino))butyl)-spiro(2-oxo-tetrahydro-
  • Step A 1 -Methy l-spiro-(2-oxo-l ,2,3,4-tetrahydroquinoline-4,4'- piperidine
  • Step B l '-(3-((S)-(3,4-dichlorophenyl))-4-(N-(3,5-dichloro- benzoy l)(methylamino))buty 1)- 1 -methyl-spiro(2-oxo- tetrahydroquinoline-4.4'-piperidine
  • Step A 3-(S)-(4-Fluorophenyl)-4-(N-(3,5- bistrifluoromethylbenzoyl)methylamino)butanol.
  • Step B 4-Bromo-2-(S)-(4-fluorophenyl)-l-(N-(3,5- bistrifluoromethylbenzoyl)methylamino)butane.
  • Example 22 The compounds in Examples 22-26 were prepared as in Example 21 from the requisite bromide, prepared from the corresponding phenylacetic acid as described in Example 20, and the required 1- substituted-spiro(indoline-3,4'-piperidine).
  • the title compound was prepared as in Example 21 from 4-bromo-2- (S)-(4-chlorophenyl)-l -(N-(3,5- bistrifluoromethylbenzoyl)methylamino)butane and spiro(2,3- dihydrobenzothiophene-3,4'-piperidine) hydrochloride except that 3 eq. of diisopropylethylamine were used.
  • the title compound was prepared from 3-(S)-(4-pyridyl)-4-(N-(3,5- bistrifluoromethyl-benzoyl)methylamino)butanal (prepared from 4- pyridylacetic acid as described by J. Hale et. al., Bioorganic & Medicinal Chemistry Letters 1993,5, 319-322) by reductive amination as described in Example 2.
  • Step A 4-Bromo-2-(S)-(3 ,4-dichlorophenyl)- 1 -(N-(3 ,5- dimethylbenzoyl)methylamino)butane.
  • the title compound was prepared as in Example 20, Steps A and B, from 3-(S)-(3,4-dichlorophenyl)-4-(N-(3,5-dimethyl- benzoyl)ethylamino)butanal (prepared from 3,4-dichlorophenylacetic acid as described by J. Hale et. al., (Bioorganic & Medicinal Chemistry Letters 1993,5, 319-322) using ethylamine rather than methylamine to form the intermediate amide).
  • Step B 1 '-(3-(S)-(3,4-Dichlorophenyl)-4-(N-(3,5- dimethylbenzoyl)-(ethylamino))butyl)- 1 -methanesulfonyl- spiro(indoline-3 ,4'-piperidine).
  • the title compound was prepared from the bromide prepared in Step A and l-acetyl-spiro(indoline-3,4'-piperidine) as described in Example 21.
  • Step 2) 4-(2,5-Difluorophenyl)-4-hydroxymethyl-l -methylpiperidine
  • EtOH (5.1 mL, 86 mmol) was added to 0.5 M LiAlH4 in glyme (82 mL, 41 mmol) at 0°C.
  • 4-(2,5-difluorophenyl)-4-methoxycarbonyl-l- methylpiperidine (3.45 g, 12.8 mmol) in glyme (4 mL) was added.
  • Saturated aqueous sodium potassium tartrate (50 mL) was added along with Celite (10 g), and the mixture was mechanically stirred 1 h at room temp. The slurry was filtered, and the organic layer was extracted with IN HCI. The HCI was washed with EtOAc and then basified with 3N NaOH.
  • n-Butyl lithium (9.57 mL, 2.45M in hexane, 23.7 mmol) was added to a -78°C solution of diisopropylamine (3.32 mL, 23.7 mmol) in THF (15 mL). After 30 min at -78°C, methyl phenyl sulfoxide (3.32 g, 23.7 mmol) in THF (4 mL) was added. The solution was warmed to 0°C and cooled back down to -78°C. l-t-butoxycarbonyl-4-piperidinone (4.69 g, 23.7 mmol) in THF (20 mL) was added.
  • Step 2) 1 -t-Butoxycarbonyl-3,4-didehydro-4-(chloromethyl)piperidine
  • the allylic chloride (330 mg, 1.43 mmole) was dissolved in acetone (10 mL) and 2-bromothiophenol (172 ml, 1.43 mmole) and K2CO3 (390 mg, 2.86 mmole) were added.
  • the reaction mixture was heated to 60°C for 1 h and then filtered though silica gel ( ether).
  • the organic layer was concentrated in vacuo and purified by column chromatography (silica gel 60, hexanes/ethyl acetate 10/1) to give the title compound in 84% yield (460 mg).
  • Step 4) 1 '-t-Butoxycarbonyl-spiro(2,3-dihydrobenzothiophene-3,4'- piperidine).
  • the intermediate adduct from step 3 above 450 mg, 1.17 mmole was dissolved in benzene (60 mL) and AIBN (10 mg) and tributyltin hydride (644 mL, 2.39 mmole) were added. This mixmre was refluxed for 2 h and concentrated. The residue was dissolved in Et2 ⁇ and Br2 was added until the reaction solution turned to a brownish color. To this brownish solution at room temp was added DBU (650 mL) dropwise.
  • the title compound was prepared by oxidizing l'-(3-((S)-(3,4- dichlorophenyl))-4-(N-(t-butoxycarbonyl)-(methylamino))butyl)- spiro(2,3-dihydrobenzothiophene-3,4'-piperidine) as described in Example 47 above, and then removing the BOC group and N- benzoylating according to the procedures given in Example 3, Steps A and B.
  • the title compound was prepared by the oxone oxidation method described in Example 53.
  • the title compound was prepared by the oxone oxidation method described in Example 51.
  • Substituted indoline spiropiperidine derivatives were obtained by employing substituted phenyl hydrazines and 1- benzyloxycarbonylpiperidine-4-carboxyaldehyde in the Fisher indole synthesis. When regioisomers were formed, they were separated as the 1 '-benzyloxy carbonyl- 1 -methanesulf onyl-spiro(indoline-3 ,4'-piperidine) derivative by chromatography (silica gel 60, THF/hexane). Preparation of a representative substituted spiro(indoline-3,4'-piperidinium) hydrochloride is described below:
  • Step 1) 1 '-Benzyloxycarbonyl-5-fluoro-l -methanesulf onyl- spiro(indoline-3 ,4'-piperidine)
  • N-Napthoyl- methylamino derivatives (Examples 91 -101 ) were prepared by analogy to the benzoyl derivatives, employing commercially available 1-napthoyl chlorides in place of benzoyl chlorides:
  • Benzylamine derivatives could be synthesized by reducing the benzamide of the 1 -methanesulfony l-spiro(indoline-3,4'-piperidine) derivatives described in some of the Examples.
  • the methanesulfonyl group could be removed by heating with HBr/acetic acid/phenol and then be replaced with an acetyl group by treating with acetic anhydride/pyridine. Representative procedures and compounds are given in Examples 102 and 103 below:
  • Step 1) l-Bromo-4-fluoro-3,5-dimethylbenzene
  • 4-Bromo-2,6-dimethylaniline 8.3 g, 42 mmol
  • H2 ⁇ 50 mL
  • cone H2SO4 6.25 mL
  • NaN ⁇ 2 4.1 g
  • Water (30 mL) was added to make the mixture homogeneous.
  • HBF4 50%, 13.7 g was added dropwise with stirring.
  • the resultant white precipitate was collected by vacuum filtration, washed with H2 ⁇ (30 mL), MeOH (30 mL), and Et2 ⁇ (60 mL), and dried over P2O5 under vacuum for 16 h. The solid was then heated in a glass flask with an open flame until all the solid had decomposed. The remaining liquid was diluted with Et2 ⁇ (50 mL) and 0.5 M NaOH (30 mL).

Abstract

Azacycles spirosubstitués de la formule I, antagonistes des récepteurs de la tachykinine, utiles dans le traitement de maladies inflammatoires, de la douleur ou de la migraine et de l'asthme. Et, en particulier, composés de la formule (I) s'avérant antagonistes de la neurokinine.
EP95901979A 1993-06-07 1994-05-17 Azacycles spirosubstitues antagonistes de la neurokinine Ceased EP0702681A1 (fr)

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WO1994029309A1 (fr) 1994-12-22
AU7201194A (en) 1995-01-03
ZA943946B (en) 1995-01-20
CA2163995A1 (fr) 1994-12-22
HRP940337A2 (en) 1997-04-30
JPH08511522A (ja) 1996-12-03
AU680020B2 (en) 1997-07-17
IL109836A0 (en) 1994-08-26

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