WO1998001121A1 - Antagoniste des canaux calciques de type p/q - Google Patents

Antagoniste des canaux calciques de type p/q Download PDF

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Publication number
WO1998001121A1
WO1998001121A1 PCT/JP1996/001871 JP9601871W WO9801121A1 WO 1998001121 A1 WO1998001121 A1 WO 1998001121A1 JP 9601871 W JP9601871 W JP 9601871W WO 9801121 A1 WO9801121 A1 WO 9801121A1
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WIPO (PCT)
Prior art keywords
compound
hydrogen
ring
lower alkyl
solution
Prior art date
Application number
PCT/JP1996/001871
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English (en)
Japanese (ja)
Inventor
Toshiyuki Kanemasa
Kiyomi Kagawa
Kazuyuki Minagawa
Yoshitaka Araki
Original Assignee
Shionogi & Co., Ltd.
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 Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to PCT/JP1996/001871 priority Critical patent/WO1998001121A1/fr
Priority to AU63191/96A priority patent/AU6319196A/en
Publication of WO1998001121A1 publication Critical patent/WO1998001121A1/fr

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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
    • A61K31/13—Amines
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
    • C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
    • C07C13/16—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a six-membered ring
    • C07C13/18—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a six-membered ring with a cyclohexane ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a P-type or Q-type calcium channel antagonist and a novel compound having a P-type or Q-type calcium channel antagonism.
  • calcium channels that control calcium metabolism in various parts of the body are classified into L-type, T-type, N-type, P-type, and Q-type by pharmacological and electrophysiological methods. .
  • N-type, P-type and Q-type calcium channels are known to exist only in the nervous system and to be involved in the release of neurotransmitters. Normally, this neurotransmitter is stored in synaptic vesicles at the nerve endings.However, when the nerve action potential reaches the nerve endings by signal transmission, calcium channels are activated and calcium Ions flow in, causing synaptic vesicles to fuse to the presynaptic membrane and release neurotransmitters. Released neurotransmitters act on postsynaptic membrane receptors and participate in synaptic transmission.
  • PZQ-type calcium channels N-type calcium channels and P-type or Q-type calcium channels (hereinafter referred to as PZQ-type calcium channels). It is said that the former is mainly present in the peripheral nerves and the latter is mainly present in the central nervous system.
  • PZQ-type calcium channel antagonists are very effective for diseases caused by excessive release of neurotransmitters in the nervous system.
  • ⁇ -agatoxin IVA extracted from spider venom is known (Nature, (Vol. 355, pp. 827-p. 829, 1992) is a polypeptide with a large molecular weight, shows negative pathological dependence, and is active in normal times. However, it has problems such as the possibility that the activity may be weakened during the disease state.
  • non-peptide selective PZQ-type calcium channel antagonists include FTX (International Patent Application Publication No. WO9132777), a plant alkaloid, daurisoline (Neuroreport) (N euroreport), pp. 1499-1492, pp. 199-2) have only been reported to have P-type calcium channel antagonism, and they inhibit P-type calcium channel inhibition.
  • IC 5 Was several mM for FTX and 35 ⁇ for daurizoline, which was not always satisfactory as a pharmaceutical.
  • ⁇ -eudesmol has a type II calcium channel antagonistic action.
  • the ring ⁇ may have a substituent and may have a double bond; a 6-membered carbon ring; R 1 is hydrogen or lower alkyl, and R 2 is hydrogen; Or R 1 and R 2 may together form one CH 2 CH 2 —;
  • R 3 is hydrogen, — CR 5 R 6 OH, — CR s R 6 O S0 7 R 7 ,-CR 5 R 6 COR 7 .
  • One CR 5 CH 2 ,-CORK ⁇ COOH,
  • One CONHR 5 , One CHR 5 R 6 , CR 5 R 6 ,
  • One CR 5 N ⁇ H or lower alkyloxylanil;
  • R 4 is hydrogen or lower alkyl
  • R 5 and R 6 are each independently hydrogen or a lower alkyl which may have a substituent
  • R 7 is a lower alkyl optionally having substituent (s);
  • R 8 is hydrogen or lower acyl
  • the present invention provides a method for treating a disease caused by excessive release of a neurotransmitter in the central nervous system, which comprises administering the compound (I).
  • a method for treating a disease caused by excessive release of a neurotransmitter in the central nervous system which comprises administering the compound (I).
  • compound (I) for the manufacture of a medicament for a disease caused by excessive release of a neurotransmitter in the central nervous system.
  • R 2 ′ is hydrogen and R 3 ′ is — CR 5 ′ R 6 ′ 0 SO 2 R 7 ′ -CR 5 ′ CH 2 , one C ONHR 5 ′ or one CO OH and R 1 ′ RR 5 R 6 R 7 'R 9 ' R 10 'and R 11 ' are each synonymous with R 'R 4 R 5 R 6 R 7 , R 9 , and R 11 ,
  • R 2 ′ is hydrogen;
  • R 3 ′ is —CR 5 “R 6 ” OH, wherein R 5 ′′ and R 6 ′′ are each independently a lower alkyl which may have a substituent; ), — CR 5 “'R 6 “' ⁇ SO 2 R 7 "or one CR 5 '" R 6, "NHR 8 ' (where R ⁇ "'and R 6 each independently represent hydrogen or a substituent R 7 "is lower alkyl which may have a substituent; R 8 'is lower acyl), and a broken line indicates that a double bond is not present on both; 1 'R 4 ' and R 1 1 'are synonymous with RR 4 and R 1 ', respectively
  • R 9 ′ and R 10 ′ are each independently hydrogen, —O CH 2 C ⁇ R 17 ′ or —NHCOR 19 ′ COOR 20 ′;
  • R 15 ′ and R 16 ′ may together form one O—
  • R 1 ', R 2 ', R ', R 5 ', R 6 ', R 7 ', R 13 ', R 14 ', R 17 ', R 18 ', R 19 ', R 2 0 'and R 2 1' are each RR 2, R 4, R 5 , R 6, R 7, R 1 3, R 1 4, R 1 7, R 1 8, R 1 9, R 2 0 and R 2
  • a compound having the same meaning as 1 , a pharmaceutically acceptable salt thereof or a hydrate thereof is provided.
  • the present invention also provides a pharmaceutical composition containing the compound (1 ′) as an active ingredient.
  • the “carbon 6-membered ring optionally having a double bond” includes a cyclohexane ring, a cyclohexene ring, a cyclohexadiene ring, a benzene ring and the like.
  • “Lower alkyl” means a straight or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. —Butyl, n-pentyl, isopentyl, veopentyl and hexyl. “Lower alkyl optionally having substituent (s)” may be substituted with hydroxy, halogen and the like.
  • lower acyl means an acyl having 1 to 6 carbon atoms, and includes acetyl, propionyl, butyryl, isobutyryl, valeryl, vivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonyl and the like.
  • the “lower alkylene” includes alkylene having 1 to 6 carbon atoms and includes, for example, methylene, ethylene, trimethylene, tetramethylene, propylene, ethylethylene and the like.
  • the “lower alkenylene” includes alkenylene having 2 to 6 carbon atoms, for example, vinylene, probenylene, butenylene, pentenylene, hexenylene, probezienylene, butegenylene and the like. be able to.
  • references to “the compound according to the present invention” also include pharmaceutically acceptable salts of compound (I).
  • salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid
  • organic acids such as formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, and succinic acid Salts of acids
  • salts of organic bases such as ammonium, trimethylammonium, and triethylammonium
  • salts of alkali metals such as sodium and potassium
  • salts of alkaline earth metals such as calcium and magnesium.
  • the compound according to the present invention also includes a hydrate thereof, and one molecule of the compound (I) may be bound to one or more water molecules.
  • All the compounds represented by the above formula (I) have a PZQ-type calcium channel antagonistic action and are useful as a PZQ-type calcium channel antagonist or a pharmaceutical composition.
  • R 9 , R 1 ° and R 15 are each independently hydrogen, hydroxy, lower alkyl, lower alkyloxy, lower acyloxy, lower alkylsulfonyloxy, OCH 2 COR 17 (R 17 human Dorokishi, lower Arukiruokishi or NH 2), - NHR 1 8 (R 1 8 is hydrogen, arsenate Dorokishi, lower alkyl, lower Ashiru or lower alk alkylsulfonyl), or a NHCOR 1 9 C_ ⁇ _OR 2.
  • R 19 is lower alkylene or lower alkenylene; R 2 Q is lower alkyl
  • R 11 , R 12 , R 13 , R 14 and R 16 are each independently hydrogen or lower alkyl which may have a substituent.
  • R 1 is lower alkyl
  • R 2 is hydrogen
  • R 3 is —CR 5 R 6 ⁇ H
  • —CR 5 R 6 OS 0 2 R 7 0 2 R 7
  • R 3 is -CR 5 R 6 OH, -CR 5 R 6 OS 0 2 R 7 CR 5 R 6 C ⁇ R one CR 5 R 6 NHR 8 or one COR 5 ;
  • RR 2 and R 3 are hydrogen, or
  • ring A is
  • R 1 and R 2 together form _CH 2 CH 2 —
  • R 1 is lower alkyl and R 2 is hydrogen or R 1 and R
  • R 4 is hydrogen
  • the compound (I) according to the present invention includes known compounds and novel compounds, and the literatures or commercially available products in which the known compounds are described below indicate the name of the sales company.
  • Helvetica 'Your strength' actor (Helv. Cim. Acta) 1 9 7 3, 5 6, 6 4 1
  • Helvetica 'Your strength' actor (Helv.Chim.Acta) 1 9 7 3,5,6,1 6 6 2
  • Tetrahedron 'Letters (T e t r a h e d r o n L e t t e r s) 1 9 7 2, 5 0 3 5
  • the above-mentioned group of known compounds has a known structure, but was never known to have P / Q-type calcium channel antagonistic activity.
  • a new group of compounds can be represented by the above general formula (I ′).
  • the new compound group (1 ′) is classified into the above groups a) to e) as described above.
  • R 4 ′ is hydrogen
  • 'I a compound in which one is one NH 2 , one NHC ⁇ CH 3 or —NHS ⁇ 2 CH 3 and the other is hydrogen
  • R 3 ′ is —C (CH 3 ) 2 OH, one CH (CH 3 ) ⁇ S 0 2 CH 3 , one CH (CH 3) NHR 8 ′ (where R 8 ′ is lower acyl)
  • R 2 ′ and R 3 ′ are hydrogen, R 4 ′ is lower alkyl, R 9 ′ and R 10 ′ are one hydrogen and the other is one OCH 2 COR 17 ′ or A compound that is one NHCOR 19 'COOR 20 '
  • R 1 1' and R 1 6 ' are each independently A compound which is hydrogen or lower alkyl optionally having substituent (s),
  • Specific examples of the preferred embodiment of the compound (1 ′) include compounds 3c, 5b, 5c, 5d, 5e, 5g, 5h, and 5i in the specific examples of the preferred embodiment of the compound (I). , 5 j, 6 e, 8 b, 8 c, 8 d, 18, 19, 20, 23 b, 23 d, 23 f, 23 g, 24 c, 25 a, 25 b, 25 c, 26 a, 26 b.26 c, 29 a.29 b, 29 c, 29 e, 30 c, 30 d, 31 b, 31 c, 31 d, 31 e, 3 2b, 32 c and 32 d. More preferably, 5b, 5c, 5d.5e, 6e, 20, 23b, 23d, 23f, 23g, 24c, 25a, 26c, 30c And 31 e, most preferably 5 b.
  • novel compounds (1 ') have strong PZQ-type calcium channel antagonistic activity and can be used as PZQ-type calcium channel antagonists or pharmaceutical compositions.
  • the new compound group (1 ′) can be synthesized from a known compound by a conventional method using, for example, the following method.
  • a compound having a suitable hydroxy compound (compounds 5a, 23c, 25b, etc.) is reacted with an azidating agent such as diphenylphosphoryl azide or hydrazic acid under Mitsunobu reaction conditions.
  • a sulfonyl compound such as 23d is reacted with an azide such as sodium azide to form an azide compound, which is then reduced using a reducing agent such as lithium aluminum hydride, tin chloride, magnesium enol, and triphenylphosphine.
  • a method for obtaining an amino compound (compounds 5b, 23e, 25c, etc.)
  • Oxime compounds (compounds 5 g, 30 c, etc.) were treated with sodium hydroxide, lithium aluminum hydride, sodium cyanoborohydride, titanium trichloride, and borax.
  • a method for obtaining a hydroxyamino compound and an amino compound by reducing with an appropriate reducing agent such as Z-trifluoroacetic acid (compounds 5i, 31b, 31d, 32b, 32d, etc.)
  • the P / Q-type calcium channel antagonist of the present invention can be applied to diseases caused by excessive release of neurotransmitters. Glutamate, aspartate and the like are known as neurotransmitters whose release is related to the PZQ-type calcium channel, such as diseases to which antagonist glutamate can be applied. Can be used for
  • ischemic neuronal damage such as stroke, spasticity, epilepsy, head trauma (TBI), Huntington's disease amyotrophic lateral sclerosis (ALS), dementia due to Alzheimer's disease, AIDS Can cause dementia and migraines.
  • TBI head trauma
  • ALS Huntington's disease amyotrophic lateral sclerosis
  • dementia due to Alzheimer's disease AIDS Can cause dementia and migraines.
  • ⁇ -agatoxin IVA which is a P / Q type calcium channel antagonist
  • the ⁇ / Q type calcium channel antagonist of the present invention is also used as an analgesic. Can be applied.
  • the PZQ-type calcium channel antagonist of the present invention is administered as a medicine, it can be safely administered by either the oral or parenteral method.
  • Oral administration may be carried out according to a conventional method by preparing a tablet, granule, powder, capsule, pill, solution, suspension, syrup, buccal or sublingual formulation, and administering the formulation.
  • any commonly used dosage form such as injections for intramuscular administration, suppositories, transdermal absorbents, inhalants, etc., can be suitably administered. Administration is preferred.
  • the pharmaceutical composition of the present invention requires various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants and diluents suitable for the final dosage form in an effective amount of the active ingredient.
  • lactose sucrose, glucose, starch, calcium carbonate or crystalline cellulose, etc.
  • a binder methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, etc.
  • Disintegrators include carboxymethyl cellulose, sodium carboxymethyl cellulose, starch, sodium alginate, powdered agar or sodium lauryl sulfate, and lubricants include talc, magnesium stearate or macrogol.
  • cocoa butter, macrogol, methylcellulose, or the like can be used.
  • lJg to 200 mg / kg / day may be administered once or several times a day, and when administered parenterally, it may vary greatly depending on the administration route. 1 g to 20 mg / kg / day may be administered once or several times a day.
  • Example 5 Synthesis of Compound 5e (1 ⁇ , m) ⁇ ⁇ m.
  • a solution of compound 5b (10 mg, 0.045 mmo 1) in chloroform (1 ml) was added a saturated aqueous solution of sodium hydrogen carbonate (0.8 ml), methanesulfonyl chloride (0.8 ⁇ 1, 0.1 mmO1) was added, and the mixture was stirred at room temperature for 10 hours.
  • the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate.
  • Hydroxyamine hydrochloride 49 mg, 0.70 mmo1
  • pyridine a solution of compound 4c (51 mg, 0.234 mmol) in ethanol (0.5 ml) at room temperature under a nitrogen atmosphere. (7.5.09.33 mmo 1) was added and stirred for 3 hours. Further, hydroxyamine hydrochloride (49 mg, 0.70 mmo 1) and pyridine (75.51> 0.933 mmo 1) were added, and the mixture was stirred for 4 hours. After concentration, water was added to the residue, and the mixture was extracted with ethyl acetate.
  • Lithium (26.0 mg, 3.75 mmo 1) was added to and dissolved in liquid ammonia (20 ml) under a nitrogen atmosphere at 178 t.
  • a THF solution (2 ml) of compound 4e (232 mg) and t-butyl alcohol (64.6 mg, 0.87 mmol) was added, and after refluxing for 3 hours, THF (10 ml) was added.
  • the reaction solution was heated to room temperature to distill off liquid ammonia, and further heated under reflux for 10 minutes. After cooling on ice, getyl phosphate (0.69 ml, 4.8 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours.
  • getyl phosphate (0.31 ml, 2.2 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was converted into a saturated aqueous ammonium chloride solution (20 ml). Poured and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 6d (19 mg, 8%).
  • Triclomouth acetic acid 400 mg, 2.4 mmo 1
  • the mixture was added at room temperature. Stirred for hours.
  • the reaction solution was partitioned between hexane and water, and the hexane transition was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate.
  • IR vmax (CD C 1 3 ) 3 606, 2 93 8, 2 8 68, 1 64 5, 1 4 6 7, 1 4 5 2, 1 3 8 1, 1 2 3 9, 1 1 4 7, 90 7
  • a mixture of selinene 1a ( ⁇ : / 3 about 1: 9) (204 mg, 1 mmo 1) in dry dichloromethane (2 ml) solution of sodium bicarbonate (50 mg) and 80% meta-chloroperbenzoic acid ( 208 mg (1 mmo1) was added, and the mixture was stirred under ice cooling for 1.5 hours.
  • the reaction solution was poured into ice water and extracted with S-ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and dried over anhydrous sodium sulfate.
  • reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 20 (113 mg, 14%).
  • Ozone gas was passed through a solution of compound 2a (600 mg, 2.7 mmo1) in dry ethyl acetate (20 ml) under cooling at _78 for 20 minutes, and then nitrogen gas was passed for 10 minutes.
  • triethylamine (7501, 5.4 mmo1) was added to the reaction solution, and the mixture was returned to room temperature and stirred for 2 hours.
  • the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate.
  • Synaptosomes were prepared from the cerebrum of Sprague-Dawely male rats (21-28 days old). The cerebrum was homogenized with the prepared solution (32 OmM sucrose, 15 mM HEPES, 5 mM EDTA, pH 7.4), and the cells were collected.
  • Compound (1) was added to synaptosomes and incubated at 30 for 1 minute.
  • Potassium channel currents were recorded as whole-cell force-stream currents from pituitary-derived GH3 cells by the whole-cell patch clamp method.
  • the extracellular fluid 1 5 0 mM N a C 1 , 5 mM KCU 1 mM M g C 1 2, 2 mM C a C 1 2> 1 0 m M glucose, l OmM HE PE S, p H 7. 4
  • a solution having a composition of 70 mM KC 1, 70 mM K aspartate, 5 mM MgCl 2 , 10 mM HE PES and pH 7.4 was used as the internal solution of the pipette.
  • Potassium channel current (A current + Delayed rectifier) was measured by applying a voltage-clamp to cells at -9 OmV and applying a depolarizing stimulus up to 80 msec and +10 mV. After the outward current due to the depolarization stimulation was stabilized, the compound (I) was added by replacing the extracellular solution with an extracellular solution containing 45 mM of the compound (I). The specificity of the compound (I) was expressed as a percentage with the current value before treatment being 100%, and it was judged that the specificity was 70% or more.
  • Table 1 shows the test results.
  • the compound (I) according to the present invention is useful as a PZQ-type calcium channel antagonist and can be used for treating a disease caused by excessive release of a neurotransmitter.

Abstract

Antagoniste des canaux calciques de type P/Q comprenant un composé représenté par la formule générale (I) ou un de ses sels en tant que principe actif (I); médicament permettant de lutter contre des maladies provoquées par la libération excessive de neurotransmetteurs dans le système nerveux et contenant ledit composé (I) en tant que principe actif; procédé de traitement de ces maladies au moyen de l'administration du composé (I); utilisation du composé (I) dans la préparation de médicaments contre ces maladies; nouveaux composés utiles pour traiter ces maladies.
PCT/JP1996/001871 1996-07-05 1996-07-05 Antagoniste des canaux calciques de type p/q WO1998001121A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP1996/001871 WO1998001121A1 (fr) 1996-07-05 1996-07-05 Antagoniste des canaux calciques de type p/q
AU63191/96A AU6319196A (en) 1996-07-05 1996-07-05 P/q type calcium channel antagonist

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Application Number Priority Date Filing Date Title
PCT/JP1996/001871 WO1998001121A1 (fr) 1996-07-05 1996-07-05 Antagoniste des canaux calciques de type p/q

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
US20110003784A1 (en) * 2009-06-16 2011-01-06 Garvey David S Opsin-binding ligands, compositions and methods of use

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110003784A1 (en) * 2009-06-16 2011-01-06 Garvey David S Opsin-binding ligands, compositions and methods of use
EP2442644A4 (fr) * 2009-06-16 2013-05-22 Bikam Pharmaceuticals Inc Ligands de liaison à l'opsine, compositions et procédés d'utilisation
EP3100723A1 (fr) * 2009-06-16 2016-12-07 Bikam Pharmaceuticals, Inc. Ligands de liaison a l'opsine, compositions et procedes d'utilisation
US9562022B2 (en) * 2009-06-16 2017-02-07 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use

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