EP0413751A4 - Neurologically active compounds - Google Patents

Neurologically active compounds

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Publication number
EP0413751A4
EP0413751A4 EP19890905913 EP89905913A EP0413751A4 EP 0413751 A4 EP0413751 A4 EP 0413751A4 EP 19890905913 EP19890905913 EP 19890905913 EP 89905913 A EP89905913 A EP 89905913A EP 0413751 A4 EP0413751 A4 EP 0413751A4
Authority
EP
European Patent Office
Prior art keywords
group
compounds
guanidino
atoms
active compounds
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Withdrawn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
EP19890905913
Other languages
English (en)
French (fr)
Other versions
EP0413751A1 (de
Inventor
N. Eric Naftchi
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP0413751A1 publication Critical patent/EP0413751A1/de
Publication of EP0413751A4 publication Critical patent/EP0413751A4/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline

Definitions

  • This invention relates to a group of adrenergically active compounds and more particularly compounds which include a guanidino group.
  • guanidine derivatives have alpha 2 -adrenergic agonist activity in vivo.
  • a variety of guanidine derivatives have also been used clinically as anti-hypertensive agents, including clonidine, guanabenz, guanacline, guanadrel, guanazodine, guanethidine, guanfacine and guanochlor, guanoxabenz and guanoxan.
  • Clonidine and guanabenz two alpha 2 -adrenergic receptor agonists used in the earlier work, had limited usefulness as a result of desensitization of the subject upon long-term treatment, and the sedative, or sleep-inducing effect of these two agents which tended to reduce mobility and the ability to eat.
  • these compounds also result in drastic undesirable hypotensive effects, and syncopy, and further included constipation and rectal impaction in certain quadraplegic subjects, which can also result, paradoxically, in severe hypertension, a syndrome known as autonomic hyperreflexia.
  • novel compounds are provided which are effective as anti-spastic, or spasmolytic, agents for the control of spasticity caused as a result of neurological damage. These drugs would also produce little or no sedation and would not lower blood pressure.
  • pharmacologically active compounds having the capability of reestablishing previously destroyed neurological functions in a traumatized or diseased mammal.
  • These compounds comprise the reaction product of a guanidino, aminoguanidino, 2-imidazolino, 2-hydrazinoimidazolino or 2-guanidinobenzimidazolino group with a methylated xanthine group, which provide a combination of receptor activity designed to stimulate appropriate receptors in the brain and spinal cord and thus tonically stimulate motor neurons, in spite of a severely damaged central nervous system; they are highly lipophilic and thus capable of crossing the blood/CNS barrier.
  • These compounds preferably have the following general formula:
  • g and r can have a value of 0 or 1, to a total of one, h can be 0 or 1, and n is 0 or an integer of at least 1 and preferably not greater than 2; the R groups can be hydrogen or non-interfering organic groups.
  • R 1 and R 2 and R 3 preferably include alkyl groups or hydrogen atoms, at least one of R 1 and R 2 and/or R 3 most preferably comprising an alkyl group.
  • R 1 and/or R 3 can be the bridging group to the guanidino moiety outside of the brackets, and can be an aliphatic group, saturated or unsaturated, preferably including a carboxyl group or a carbonyl group, oxygen, nitrogen, sulfur, connected to a nitrogen atom of the guanidino group by a double bond.
  • R 1 and R 3 can preferably include acetyl, acetaldehyde, propionyl, hydroxyalkyl.
  • R 4 and R 5 can each be hydrogen, or any non-interfering organic group, preferably including lower alkyl, alkoxy, thioalkyl, alkenyl, aryl, aralkyl, or alkaryl or nucleoside group, or any such group substituted with NH 2 , OH, OCH 3 , or halogen, sulfur, oxygen, or NO 2 .
  • R 6 is a bridging group forming a closed heterocyclic ring compound with the two nitrogen atoms on the guanidino group, and can be any non-interfering organic group, which can include additional nitrogen atoms, halogen atoms, oxygen atoms, and can be aliphatic, cycloaliphatic, or aromatic, so as to form groups such as, e.g., imidazole, benzimidazole, triazine, thiopyrimidine, triazolethiol, diphenyl-2-imidazole-thiol.
  • novel compounds of the present invention have an alpha 2 -adrenergic receptor agonist moiety and a beta-adrenoceptor agonist moiety.
  • the beta-receptor agonist moiety is derived from a compound that has an indirect beta-adrenergic effect, such as the substituted xanthines, which enhance the metabolic effect of cyclic adenosine 3', 5',-monophosphate (c-AMP), by blocking c-AMP phosphodiesterase.
  • substituted xanthines which enhance the metabolic effect of cyclic adenosine 3', 5',-monophosphate (c-AMP)
  • c-AMP cyclic adenosine 3', 5',-monophosphate
  • alpha- 2 agonists have other direct physiological effects on the mammal being treated, which often are contraindicated following trauma such as spinal injury, e.g., the hypotensive effect of clonidine and quanabenz. It was recognized that such undesirable side effects can be counteracted by the simultaneous or sequential administration of an antagonist or a pressor agent, such as angiotensin II which could be titrated against the alpha 2 - agonist.
  • the compounds of the present invention which include the guanidino, 2-amino-imidazolino, 2-hydrazino-imidazolino, or 2-guanidinobenz-imidazolino 2,3,5-s-triazine moiety from alpha 2 agonist plus a beta-agonist moiety avoid any hypotensive effect, and result in an improved reactivation and reestablishment of the descending monoaminergic pathways and ascending nociceptive pathways while also improving upon and speeding up the affirmative process of restoring motor and sensory functions to almost one/third ofthe time required by the alpha2 agonists.
  • the indirect beta-agonists such as substituted xanthines act by inhibiting the enzyme phosphodiesterase, with the effect of increasing the ratio of c-AMP to c-GMP (cyclic guanosine-3,5-monophosphate).
  • moieties derived from direct acting beta-agonist such as 4-hydroxy-3- methoxymandelic acid, 3,4-dihydroxymandelic aldehyde, 3,4- dihydroxyphenyl(beta-hydroxy)-acetaldehyde may be combined through their aldehyde or carboxyl groups with guanidine, aminoguanidine, etc. to yield internally neutralized compounds which have similar effect.
  • the xanthine group is connected to the guanidino group through one of the guanidinonitrogen atoms.
  • one of the nitrogen atoms in the guanidino group shown in Formula 1 is replaced by a sulphur or an oxygen atom.
  • the compounds of the present invention can be used as medicaments for mammals in the form of pharmaceutical preparations suitable for administration orally, parenterally, intraperitoneally, intravenously or as nasal spray. These compounds can be administered in a substantially pure form, with other active ingredients which may be desirable, or merely with a suitable pharmaceutical vehicle.
  • the compounds are generally crystalline solids which may be at least partially soluble in commonly used organic salts. They are also generally soluble in liquid pharmaceutical vehicles, including water.
  • the compounds can be formed as physiologically acceptable salts including the salts of inorganic acids, such as hydrochloric, hydriodic, sulfuric or phosphoric, as well as organic acids including acetic, malic, ethionic, malonic, citric, benzoic and pamoic.
  • inorganic acids such as hydrochloric, hydriodic, sulfuric or phosphoric
  • organic acids including acetic, malic, ethionic, malonic, citric, benzoic and pamoic.
  • these acid addition salts are more soluble in water than the compounds per se.
  • Formulation in a pharmaceutical vehicle can be carried out in accordance with techniques and in vehicles which are wholly conventional to those skilled in the art for the intended mode of administration.
  • preparations for oral administration can be in either liquid or solid form, including for example syrups, elixirs, powders, capsules or tablets.
  • the materials are preferably prepared for unit dosage form as powders which are preferably pressed into tablets or suitably encapsulated in, for example, conventional gelatine capsules.
  • Any powders or compressed tablets can generally also comprise the usually suitable excipients and/or diluents, such as starch, lactose, stearic acid, magnesium stearate, dextrin or polyvinylpyrrolidone.
  • Suitable solid carriers include magnesium stearate, sicaryl alcohol, talc, vegetable oils or fats, alcohols such an benzyl alcohols, gums, waxes, alkylene or polyalkylene glycols, such as propylene glycol or polypropylene glycol and any other well known carriers.
  • Suitable sterile solutions or suspensions can be prepared for parenteral or intraperitoneal administration, e.g., intravenous, containing for example water, physiological saline, benzyl alcohol, ethyl oleate, methylcellulose, dimethyl sulfoxide, polyethylene glycol liquid, as well as other liquid excipients well known in the pharmaceutical or veterinary art.
  • auxiliary pharmaceutical materials which can be present include preservatives, stabilizers, wetting or emulsifying agents, or osmotic salts or buffering agents, as is well known to the pharmaceutical or veterinary art. As these formulations are generally well known and conventional, more specific instructions need not be presented for purposes of defining this invention.
  • the mixed alpha/beta receptor active compounds of the present invention are most effective in treating the undesirable after-effects of traumatic spinal injury, including even transection of spinal cord. Restoration of at least some normal sensory and motor control can be obtained as a result of treatment, especially if carried out within a relatively short time after injury to the spinal cord.
  • the compounds of the present invention do not have many of the undesirable side effects of utilizing the prior alpha 2 -adrenoreceptor agonists of the parent application, it is not necessary to postpone treatment using these novel compounds until after stabilization of the vital signs and recovery from the initial shock. Indeed, many of these compounds are also effective in treating the initial shock conditions by way of stabilizing or even slightly elevating arterial blood pressure and improving microprofusion pressure in the area of injury. Thus, the compounds of the present invention have positive hemodynamic effect as well as positive neurological effects.
  • the mixed agonists of this invention also have been found to interfere with the formation of undesirable scar tissue at the trauma site. It is believed that these mixed agonists interfere with triple helix formation in the synthesis of collagen protein, thus preventing or reducing the formation of hard scar tissue at the trauma site.
  • the plasma level of the compound in the blood stream of the mammal being treated be maintained as constant as feasible. This is especially important with respect to spinal injuries in order to reduce or substantially eliminate autonomic dysreflexia and spasticity during treatment until permanent return of sensory and motor function has been obtained.
  • These compounds generally should be administered in a proportion of at least about 10 mcg/kg of body weight, and preferably in an amount of at least 15 meg and preferably not more than about 100 mcg/kg of body weight, and most preferably not more than about 70 mcg/kg of body weight.
  • the optimal proportion in the blood is not directly proportional to body weight, but rather to a combination of factors including body weight and body superficial area.
  • these novel pharmacological agents may be preferable to administer these novel pharmacological agents using a sustained release form, for example, the conventionally available sustained release capsules or sustained release transdermal products.
  • a sustained release form for example, the conventionally available sustained release capsules or sustained release transdermal products.
  • these novel compounds can be administered regularly at relatively short intervals, for example, 2 to 4 times per day.
  • these compounds can, at least initially after the trauma, be administered intraperitoneally or intravenously to maintain a constant, tonic effect by slow administration of medication, or as a single injection, at intervals.
  • novel compounds of the present invention in accordance with Formula I above can be prepared by reacting a first compound ("A") including a guanidino group, which can be present as part of a heterocyclic group, e.g., an amino triazine group, an amino arylimidazole, e.g., an amino benzylimidazole, or an aminoimidazoline group, or an equivalent thio compound where one of the nitrogen atoms forming any of the above groups is replaced by a sulphur atom, with a second compound (“B”) comprising a direct or indirect beta-adrenergic receptor.
  • A a first compound
  • B comprising a direct or indirect beta-adrenergic receptor
  • a and B compounds preferably include a carboxyl group, an aldehyde (carbonyl) group, a hydroxyl group or an amino
  • the "A” compound reach through a primary or secondary amino nitrogen atom forming part of the guanidino or aminoguanidino moiety.
  • Suitable group A compounds include guanidine, guanidine hydrochloride, guanidine acetic acid, aminoguanidine (or its acid addition salts), 2-guanidinobenz imidazole hydrogen bromide acid addition salt, 2-amino-imidazoline, 2-aminodihydrothiazine, 2-hydrazinoimidazoline hydrogen bromide acid addition salt, 2,4,6-triamino-1,3,5-s-triazine, 2,4-diamino-6-phenyl-1,3,5-s-triazine, 2,4-bis (diethylamino)-6-hydrazino-1,3,5-s-triazine, 4-methyl-4H-1,2,4-triazole-3-thiole, 4,5,diphenyl-2-imidazole-thiole, 2-(4-aminophenyl-6-methyl-benzothiazole and their acid addition salts.
  • Useful B group compounds which are preferably direct or indirect beta-agonists can be, for example, theophylline, etofylline, theophylline 7-acetic acid, theophylline 7 acetaldehyde, 7-(2,3-dihydroxy)- propyltheophylline, 1-theobromine acetic acid, 1-theobromine acetaldehyde.
  • the final product is designated by a capital letter, to provide a shorthand identification for the compound in subsequent portions of this text.
  • the resulting mixture is stirred vigorously for thirty (30) minutes until a precipitate is completely formed.
  • the resultant yellow precipitate is filtered out by Whatman No. 1 filter paper; the filtered solid is admixed with water and the pH reduced to 8 by the addition of HCl.
  • the aqueous solution is again vacuum evaporated at 25°C, and the resultant dry yellow solid is dissolved in an alcohol solution of 80% ethanol and water and re ⁇ rystalized.
  • the resultant product has a molecular weight of 280.26 and has the formula shown in Table II.
  • the acylchloride of THAA is obtained by following the same procedure in EXAMPLE 1 above.
  • the ThAc 100 g.
  • the ThAc is then added dropwise to a solution of 2-guanidine-benzimidaz ⁇ le(GBI) (74 grams) in a mixture of benzene and pyridine (which is active both as a catalyst and to neutralize the by-product hydrogen chloride.
  • the reacting mixture is held overnight at room temperature (21oC); the benzene layer is then separated by decanting and washed with a 2 Normal aqueous solution of HCl (to remove any excess pyridine), subsequently washed with a 2 Normal aqueous solution of sodium hydroxide, and then washed with pure water, until substantially neutral (pH 6.8-7.2).
  • the benzene solution is then dried under vacuum (at 25°C.) and the resultant solid is dissolved and recrystalized from an aqueous solution of 80% ethanol.
  • the product has a molecular weight of 394.4 and has the formula shown in Table II.
  • novel compounds of the present invention have been tested and found to be extremely effective in treating severe neurological disorders of the type resulting from either severe traumatic injury to the spinal cord or from systemic diseases such as multiple sclerosis. These compounds are believed to act upon receptors at several sites. The stimulating of the receptors in the spinal cord, either directly or indirectly, tonically stimulates the motor neurons, thus preserving muscle mass. These drugs generally have longterm ameliorative effects, which apparently bring about a reorganization within the nervous system, providing for regaining of central nervous system control over lost functions in those portions of the body distal to the brain and below the damaged spinal cord site. These compounds reduce and result in control over spasticity in the distal bodily portions, for example, over the urinary tract or the legs; also significantly, the desirable results are obtained without sedating or lowering the blood pressure of the mammal.
  • a cat was anesthetized using intravenous pentobarbital (30 mg/kg) after which its arterial blood pressure was continuously monitored for at least two hours. After recording stable arterial blood pressure, a dorsal laminectomy was performed in the thoracic region of the cat from T 3 to T 5 ; after restoration of blood pressure, the cat was traumatized by means of a twenty gram weight being dropped from a height of twenty-five centimeters (500 g-cm force) on the exposed spinal column dura at the fourth thoracic segment.
  • the cat was not thereafter treated except to surgically clean the trauma region and assist in the healing of the surgery.
  • the cat was regularly observed over a four month period.
  • Somatosensory-evoked potentials were measured and recorded for this cat, immediately before the spinal trauma, 10, 20 and 30 minutes after the trauma, and two hours after the trauma, and then again 30 days after the trauma.
  • the SEPs were generated by stimulating the sciatic nerve by means of needle electrodes inserted through the posterior thighs. It is known that the recording of SEPs from the somatosensory cortex by stimulating lower extremities requires the presence of intact ascending pathways. The absence of SEPs indicates a complete disruption of the spinal cord tracks. Beginning 10 minutes after impact, the SEP was substantially completely absent from the thus injured cat.
  • the spinal cord of a group of rats was completely transected. After surgery, the rats were treated with guanabenz (4.0 milligrams per milliliter of dextrose in 5% water solution) was commenced 72 hours after the lesion. The drug (0.4 ml.) was given twice per day intraperitoneally.
  • the guanabenz was administered at a dosage rate of 5 mg/kg bid intraperitoneally. During the first two-week period there was substantially no restoration of proper plantar placement, weight bearing on the hind legs and/or control walking.
  • novel compounds of this invention are effective not only for the smaller mammals, but also for larger mammals including primates.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP19890905913 1988-05-02 1989-05-02 Neurologically active compounds Withdrawn EP0413751A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US18946488A 1988-05-02 1988-05-02
US189464 1988-05-02

Publications (2)

Publication Number Publication Date
EP0413751A1 EP0413751A1 (de) 1991-02-27
EP0413751A4 true EP0413751A4 (en) 1992-07-22

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EP19890905913 Withdrawn EP0413751A4 (en) 1988-05-02 1989-05-02 Neurologically active compounds

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EP (1) EP0413751A4 (de)
JP (1) JPH04503205A (de)
WO (1) WO1989010744A1 (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9401499D0 (sv) * 1994-05-02 1994-05-02 Item Dev Ab New method of treatment
EP1871420A4 (de) * 2005-04-15 2010-09-22 Univ North Carolina Verfahren zur ermöglichung des überlebens von zellen über neurotrophin-mimetika
US7671061B2 (en) 2005-12-22 2010-03-02 Hydra Biosciences, Inc. Methods and compositions for treating pain
AU2010319349B2 (en) 2009-11-12 2015-07-16 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US9944648B2 (en) * 2014-01-09 2018-04-17 Intra-Cellular Therapies, Inc. Organic compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0229897A1 (de) * 1985-12-26 1987-07-29 Siegfried Aktiengesellschaft Alpha1-adrenerg blockierende Theophyllinderivate

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1951560A1 (de) * 1969-10-09 1971-04-22 Klosa Josef Dr Rer Nat Dipl Ch Verfahren zur Herstellung von Xanthinguanylhydrazonen
US4696932A (en) * 1984-10-26 1987-09-29 The United States Of America As Represented By The Department Of Health And Human Services Biologically-active xanthine derivatives
US4612315A (en) * 1984-10-26 1986-09-16 The United States Of America As Represented By The Department Of Health And Human Services Biologically-active 1,3-dipropyl-8-phenylxanthine derivatives
US4783530A (en) * 1986-11-13 1988-11-08 Marion Laboratories, Inc. 8-arylxanthines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0229897A1 (de) * 1985-12-26 1987-07-29 Siegfried Aktiengesellschaft Alpha1-adrenerg blockierende Theophyllinderivate

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN, vol. 12, no. 22 (C-470)(2869), 22nd January 1988; & JP-A-62 175 483 (SUNTORY LTD) 01-08-1987 *
PHYSIOLOGIST, vol. 27, no. 4, August 1984, page 220, US; N.E. NAFTCHI et al.: "Histochemical correlates of behavioral effects of alpha-2 adrenergic agonist in spinal rats" *
See also references of WO8910744A1 *

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Publication number Publication date
WO1989010744A1 (en) 1989-11-16
JPH04503205A (ja) 1992-06-11
EP0413751A1 (de) 1991-02-27

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