WO2000038720A1 - Remedes contre la douleur - Google Patents
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- WO2000038720A1 WO2000038720A1 PCT/JP1999/007191 JP9907191W WO0038720A1 WO 2000038720 A1 WO2000038720 A1 WO 2000038720A1 JP 9907191 W JP9907191 W JP 9907191W WO 0038720 A1 WO0038720 A1 WO 0038720A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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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
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- 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
Definitions
- the present invention relates to a remedy for pain which exhibits a powerful morphine-like analgesic effect and suppresses side effects.
- the present invention also relates to a novel compound having a strong analgesic effect, and a medicament comprising a pharmaceutically acceptable salt thereof.
- Obioid analgesics such as morphine have long been known as powerful analgesics.
- Potent opioid analgesics act on opioid ⁇ receptors (agonist activity) and are effective against severe pain, but also cause side effects such as nausea and mental symptoms such as hallucinations * confusion.
- side effects such as nausea and mental symptoms such as hallucinations * confusion.
- strong opioid analgesics such as morphine are well known to form mental dependence, which is a major problem.
- psychiatric symptoms such as nausea and hallucinations, which are side effects of morphine
- dopamine D2 receptor antagonists such as haloperidol
- dopamine D2 antagonism required to simultaneously suppress nausea, psychiatric symptoms, and psychiatric dependence formation.
- the present inventors have studied various compounds in order to solve the above problems. Then, they have found that certain novel compounds have both the activity of obioid ⁇ receptor agonist and the activity of dopamine D2 receptor antagonist. A compound having both activities has not been reported yet, and it has been found that the compound exhibits a potent analgesic effect and does not exhibit a psycho-dependent and locomotor-promoting effect such as a strong obioid.
- a compound having an opioid ⁇ receptor agonist activity means a compound exhibiting a binding affinity in an opioid ⁇ receptor membrane binding test and exhibiting an analgesic activity by a hot plate method.
- [3 H] -DAMGO radioligand final concentration InM to label the receptor membrane fraction and ⁇ receptors made tone from rat forebrain ([D-Ala 2 , N-Me-Phe 4 , Gly-ol] -enkephalin)
- the strength of the test substance to displace [ 3 H] -DAMGO binding IC 5 of each compound.
- Non-linear least squares regression 2 The analgesic activity was determined by the mice to which the test substance was administered on a hot plate at 52 ° C.
- the Ki value was determined by analysis and determined using the Cheng and Prusoff equation. There can be represented by the effect indicating the avoidance behavior from thermal stimulation (refer to ED 5. value calculated minimum square method Nyo Li from dose-response of each compound).
- the term "compound having dopamine D2 receptor antagonist activity" refers to a compound that exhibits a binding affinity in a D2 receptor membrane binding test and also exhibits an activity of inhibiting apomorphine-induced climbing. is there. Specifically, 1) the binding affinity radioligand for labeling the de one dopamine D2 receptor membrane fraction and D2 receptors by rat striatal Li preparation (final concentration O. lnM [3 H] - in the presence of spiperone), the IC 5.
- the value of the intensity (the compound test substance replaced the binding of [3 H] -spiperone was determined by nonlinear least squares regression analysis, calculated using the formula Cheng and Prusoff 2)
- the apomorphine-induced climbing-inhibitory activity was determined by the characteristic climbing behavior caused by the administration of apomorphine to mice. can be represented by the climbing suppressing action strength (refer to ED 5. value calculated by the least square method from the dose-response of each compound).
- the same compound was used in the present invention for the binding affinity shown in the obioid receptor membrane binding test. The ratio between the above and the binding affinity shown in the D2 receptor membrane binding test is defined as the activity ratio.
- the compound was a compound having both the activity of the obioid ⁇ receptor agonist and the activity of the dopamine D2 receptor antagonist, If the activity ratio of the compounds is preferably 1: 1 to 1: 150, more preferably 1:10 to 1:30, the compound shows a strong analgesic effect while suppressing side effects, The present inventors have found that this can be a useful therapeutic agent for pain, and have completed the present invention.
- the present invention has the following configuration.
- a therapeutic agent for pain comprising as an active ingredient a compound having both the activity of obioid receptor agonist and the activity of dopamine D2 receptor antagonist.
- ring A represents a saturated 5- to 6-membered ring which may be substituted and may contain a heteroatom selected from S, N, and O;
- Ring B represents a 5- to 6-membered aromatic ring which may contain one heteroatom selected from N and ⁇ ,
- Ring C represents an optionally substituted benzene ring or pyridine ring
- D represents an aromatic ring which may be substituted and may contain a hetero atom selected from S, N, and O. ]
- D represents an aromatic ring which may be substituted and may contain a hetero atom selected from S, N, and ⁇ . ]
- ring A represents a saturated 5- to 6-membered ring which may be substituted and may contain a heteroatom selected from S, N, and ⁇ ;
- Ring B represents a 5- to 6-membered aromatic ring which may contain one heteroatom selected from N and O,
- Ring C represents an optionally substituted benzene ring or pyridine ring
- D represents an aromatic ring which may be substituted and may contain a hetero atom selected from S, N, and O. ]
- Ring A has the following general formula (a)-(e)
- Ring B has the following general formula (f) to (h)
- R 2 , R and R 4 are each independently a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a cyano group, a halogen atom, a hydroxy group, a carbamoyl group , A nitro group, or an amino group.
- U represents S, 0, or NR 5 (R 5 is H or a lower alkyl group).
- V represents a hydrogen atom, a chlorine atom, a fluorine atom or a methoxy group
- w represents a nitrogen atom or CH
- X represents NH or ⁇
- Y represents a hydrogen atom, a hydroxyl group or a methoxy group. Or a pharmacologically acceptable salt thereof.
- V represents a hydrogen atom or a chlorine atom
- W represents a nitrogen atom or CH
- X represents NH or O
- Y represents a CH or nitrogen atom
- Z represents a hydrogen atom or a methoxy group. Or a pharmacologically acceptable salt thereof.
- V represents a hydrogen atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group
- W represents a nitrogen atom or CH.
- W represents a nitrogen atom or CH.
- V represents a chlorine atom or a methoxy group
- W represents a nitrogen atom or C H. Or a pharmacologically acceptable salt thereof.
- An agent for treating pain comprising the compound according to any one of the above items 4 to 13, or a pharmacologically acceptable salt thereof.
- FIG. 1 is a diagram showing the conditional position preference of the compound of Example 14 and morphine.
- FIG. 2 is a diagram showing the conditional position preference of the compound of Example 16 and morphine.
- a lower alkyl as a group or a part of a group means a linear or branched alkyl having 1 to 6, preferably 1 to 4 carbon atoms, for example, methyl, ethyl, isopropyl, isobutyl. , T-butyl and the like.
- the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- Alkoxy means alkyloxy which may be substituted, and preferably represents alkyloxy having 1 to 4 carbon atoms, for example, linear or branched alkyloxy such as methoxy, ethoxy, isopropyloxy, etc.
- ring A represents a saturated 5- to 6-membered ring which may be substituted and may contain a heteroatom selected from S, N, and O;
- the rings represented by (a) to (e) are mentioned.
- R 1 represents a hydrogen atom or a lower alkyl group.
- Ring B represents a 5- or 6-membered aromatic ring which may contain one hetero atom selected from N and 0, and includes, for example, rings represented by the following general formulas (f) to (! 1) .
- Preferred examples include a benzene ring or a pyridine ring represented by the general formula (f), more preferably a benzene ring in which Z and L simultaneously represent CH.
- Ring C represents an optionally substituted benzene ring or pyridine ring, and a preferred example is a benzene ring.
- D represents an aromatic ring which may be substituted and may contain a heteroatom selected from S, N, and O, and includes, for example, aromatic rings represented by the general formulas (i) to (n).
- Preferred examples include a benzene ring represented by the general formula (i) or (j), Examples include a substituted benzene ring, a pyridine ring, or a substituted pyridine ring.
- the substituents R 2 , R 3 , and R 4 are each independently a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a cyano group, a halogen atom, a hydroxy group, Represents a group, a nitro group, or an amino group.
- the lower alkylthio group means a linear or branched alkylthio group having 1 to 4 carbon atoms such as methylthio, ethylthio, and isopropylthio.
- the lower alkoxycarbonyl group means an alkoxycarbonyl group having 1 to 4 carbon atoms such as methyloxycarbonyl, ethyloxycarbonyl and isopropyloxycarbonyl.
- R 2 , R and R 4 can be independently substituted for all hydrogen atoms on the ring.Even if they are not completely substituted with substituents other than hydrogen atoms, they are the same or different at one or more positions. May be substituted with a substituent other than a hydrogen atom.
- V represents a hydrogen atom, a chlorine atom, a fluorine atom or a methoxy group
- w represents a nitrogen atom or CH
- X represents NH or ⁇
- Y represents a hydrogen atom, a hydroxyl group or a methoxy group. Or a pharmacologically acceptable salt thereof.
- V represents a hydrogen atom or a chlorine atom
- W represents a nitrogen atom or CH
- X represents NH or ⁇
- Y represents a CH or nitrogen atom
- Z represents a hydrogen atom or a methoxy group. Or a pharmacologically acceptable salt thereof.
- the compound in Japanese Patent Application No. 116-136812, which is also an earlier application which also relates to the priority of the present application, the compound is referred to as a spiro hydrocarbon number, a heterocyclic atom number, and a unique ring number. As shown below, it was described as 14-benzylspiro [hydrobenzo [e] isobenzofuran-1,4,1-piperidine] -3-one.
- the novel compound of the present invention represented by the above general formula (I) can be produced by the following method.
- the compound of the above general formula (X) is reacted with 2-naphthonitrile in a solvent (eg, tetrahydrofuran, dimethyloxetane) which does not participate in the reaction, in a base (preferably, lithium 2,2,6,6-tetraphenyl).
- a solvent eg, tetrahydrofuran, dimethyloxetane
- a base preferably, lithium 2,2,6,6-tetraphenyl
- the compound of the general formula (XI) can be obtained as a commercially available reagent or can be obtained by the method described in Reference Examples 1 and 2 (J. Med. Chem. 37, 2729 (1994)), ie, the substitution of a commercially available compound.
- Ester such as methyl benzoate, substituted ethyl benzoate, substituted methyl nicotinate, substituted ethyl nicotinate is reduced with a reducing agent such as lithium aluminum hydride in a solvent that does not participate in the reaction (eg, tetrahydrofuran).
- the reaction can be carried out at a reaction temperature of about 50 ° C., preferably about 0 to 30 ° C. for 1 to 48 hours, preferably about 2 hours, and further obtained by oxidation with Swern oxidation or manganese dioxide.
- the compound of the general formula (I) according to the present invention is a compound of the above general formula (X) (wherein ring A, ring B and ring C represent the same meaning as defined in the above general formula (I) ) And a compound of the above general formula (XI) (where D represents the same meaning as defined in the above general formula (I))
- a solvent that does not participate eg, dichloroethane, tetrahydrofuran, dimethyl sulfoxide
- sodium triacetoxyborohydride in the presence of acetic acid at a reaction temperature of 20 to 50 ° C, preferably about 30 ° C.
- acetic acid eg, dichloroethane, tetrahydrofuran, dimethyl sulfoxide
- the purification of the target compound from the reaction mixture is carried out by a method commonly used in synthetic chemistry, that is, the reaction product is mixed with water and an organic solvent which is not arbitrarily mixed with water, for example, It is extracted by partitioning into benzene, toluene, ethyl acetate, butyl acetate, methyl isobutyl ketone, chloroform, dichloromethane, etc., and concentrated and crystallized.
- fractional purification by column chromatography using, for example, alumina or silica gel is also performed.
- the compound of the general formula (I) can be a pharmacologically acceptable salt thereof.
- Possible salt forms include acid addition salts with inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid and sulfuric acid, or aliphatic monocarboxylic acids, dicarboxylic acids, hydroxyalkanoic acids, hydroxyalkanediacids, amino acids, etc. And salts derived from non-toxic organic acids, such as aromatic acids, aliphatic and aromatic sulfonic acids.
- acid addition salts include hydrochloride, hydrobromide, nitrate, sulfate, hydrogen sulfate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, tartrate , Oxalate, malonate, succinate, fumarate, maleate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, toluenesulfonate, quenched Acid salts, lactates, malates, and glycomonolates.
- compounds other than the above-mentioned general formula (I), which have both an opioid ⁇ receptor agonist activity and a dopamine D2 receptor antagonist activity also show a strong analgesic effect, while exhibiting side effects ( In particular, dopamine-related behavior). Therefore, according to the present invention, a compound having both opioid; receptor agonist activity and dopamine D2 receptor antagonist activity (including the novel compound and a pharmacologically acceptable salt thereof) can be used as a new therapeutic agent for pain with suppressed side effects, that is, a useful therapeutic agent for pain with one agent.
- the compound having both the activity of the obioid ⁇ receptor agonist and the activity of the dopamine D2 receptor antagonist used in the present invention is represented by the above general formula (I)
- Other compounds can be used, for example, a compound represented by the general formula ( ⁇ ) or (III)
- D represents an aromatic ring which may be substituted and may contain a heteroatom selected from S, N, and 0. ]
- D represents an aromatic ring which may be substituted and may contain a hetero atom selected from S, N, and O. ]
- V represents a hydrogen atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group, and w represents a nitrogen atom or CH.
- W represents a nitrogen atom or CH.
- V represents a chlorine atom or a methoxy group
- W represents a nitrogen atom or C H.
- a pharmacologically acceptable salt thereof The compounds of the general formulas (II) and (III) will be described in more detail.
- Possible salt forms include acid addition salts with inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid and sulfuric acid, or aliphatic monocarboxylic acids, dicarboxylic acids, hydroxyalkanoic acids, hydroxyalkane diacids, amino Acids and salts derived from non-toxic organic acids such as aromatic acids, aliphatic and aromatic sulfonic acids.
- inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid and sulfuric acid
- aliphatic monocarboxylic acids dicarboxylic acids
- hydroxyalkanoic acids hydroxyalkane diacids
- amino Acids and salts derived from non-toxic organic acids such as aromatic acids, aliphatic and aromatic sulfonic acids.
- acid addition salts include hydrochloride, hydrobromide, nitrate, sulfate, hydrogen sulfate, monohydrogen phosphate, dihydrogen phosphate, acetate, propionate, tartrate , Oxalate, malonate, succinate, fumarate, maleate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate Salts, lactates, malates, glycolates and the like.
- the compound of the general formula (III) or (III) can be produced by the method shown below. That is, a compound represented by the general formulas ( ⁇ ) and (XIV) and a compound represented by the general formula (XIII) (where D is defined by the general formulas (I) to ( ⁇ ))
- a compound represented by the general formulas ( ⁇ ) and (XIV) and a compound represented by the general formula (XIII) (where D is defined by the general formulas (I) to ( ⁇ ))
- acetic acid in a solvent that does not participate in the reaction (eg, dichloroethane, tetrahydrofuran, dimethyl sulfoxide).
- ⁇ 50t It can be obtained by reacting at a reaction temperature of preferably about 30 ° C for 2 to 48 hours, preferably about 5 hours.
- the compounds of the general formulas (II) to (XIV) can be obtained as commercially available reagents. Further, the compound of the general formula (II) can also be synthesized by the methods described in Reference Examples 1 and 2 below. That is, an ester of a commercially available compound, such as substituted methyl benzoate, substituted ethyl benzoate, substituted methyl nicotinate, substituted ethyl nicotinate, is dissolved in a solvent (e.g., tetrahydrofuran) that does not participate in the reaction with lithium aluminum hydride or the like.
- a solvent e.g., tetrahydrofuran
- the pharmaceutical composition containing the compound of the present invention as an active ingredient can be administered orally or parenterally (for example, by intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, transdermal administration, intraspinal administration), It can be administered to humans and non-human animals. Therefore, according to the present invention, The pharmaceutical composition containing the compound as an active ingredient is in a form suitable for the administration route.
- oral preparations include tablets, capsules, powders, granules, syrups, and the like
- parenteral preparations include injections such as intravenous injections and intramuscular injections, rectal preparations, and oily occlusive preparations. Preparations, aqueous suppositories and the like. These various preparations can be produced by a conventional method using commonly used excipients, disintegrants, binders, lubricants, coloring agents and the like.
- Excipients include, for example, lactose, glucose, corn starch, sorbitol, crystalline cellulose, and the like. Dimethylcellulose, polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gelatin, hydroxypropylcellulose, polyvinylpyridone, and the like.
- lubricants include talc, magnesium stearate, polyethylene glycol, And hardened vegetable oils.
- the above preparations can be produced by adding a buffer, a pH adjuster, a stabilizer and the like, if necessary.
- the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, but is usually 0.1 to 50% by weight, preferably about 0.5 to 20% by weight in the whole composition. .
- the dosage will be determined as appropriate for each individual case, taking into account the patient's age, weight, gender, differences in disease, severity of symptoms, etc., but usually 1 to 100 mg / day for an adult. It is preferably 1 to 30 Omg, which is administered once or several times a day.
- Methyl 6-chloronicotinate (Lancaster) 0.20 g (1.17 mmo 1) anhydrous The solution was dissolved in 4 ml of tetrahydrofuran, and 0.045 g (1.17 ol) of lithium aluminum hydride was added in an ice bath, followed by stirring for 30 minutes. Sodium sulfate 10 hydrate was added to the reaction system until foaming stopped, and the mixture was stirred for 2 hours, and then filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 6-chloromouth pyridine-3-methyl alcohol 0.09 Og.
- the solution was dissolved in 25 ml, and 0.03 g (0.127 mmol) of camphorsulfonic acid was added thereto, followed by stirring. Two hours, 20 hours, and 44 hours after the start of the reaction, 0.03 g (0.127 mmol) of camphorsulfonic acid was further added thereto, and 0.1 ml of water was added 28 hours after the start of the reaction. Sixty six hours after the start of the reaction, 3 ml of chloroform and 2 ml of an aqueous solution of sodium hydrogencarbonate were added to perform extraction. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
- the reaction mixture was extracted with 1 Oml of form-form, 5 ml of water and 5 ml of a saturated aqueous solution of sodium hydrogen carbonate.
- the temperature of the reaction system was raised to 78 ° C., and 0.92 g of 2-naphthonitrile dissolved in 3 ml of anhydrous tetrahydrofuran was added dropwise to the reaction system, followed by stirring for 50 minutes. Subsequently, 1.25 g (6.6 Oraraol) of 4-benzylpiperidone dissolved in 5 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred for 2 hours, brought to 0 C, stirred for 1 hour, and then stirred at room temperature for 1 hour.
- Example 24 benzyl-7-methoxy (benzo [g] 1,3-dihydroisobenzofuran-1-spiro-1,4-piperidin) -13-one
- the compound obtained in Example 13 (A) 0.410 g (1 (0.1 mmol) was dissolved in 4.00 ml of methylene chloride, and 0.63 g (3.3 1 mmol) of P-toluenesulfonic acid monohydrate was added thereto, followed by stirring.
- Example 28 1,1-Benzyl-2,5-dihydrofuro [3,4-b] quinoline-5-spiro-1,4-piperidin-2-one
- compounds classified as the compound of the general formula (in) include compounds of the following general formula.
- the membrane fraction prepared from the rat forebrain was prepared as the membrane fraction for the Obioid ⁇ receptor.
- the rat forebrain was homogenized with a 10-fold amount of 0.32 ⁇ sucrose solution, and the resulting homogenate was 900 900 Centrifuged at g for 10 minutes. Subsequently, the supernatant is washed at 11500 X g for 20 minutes. After centrifugation, a sediment was obtained. The precipitate was washed by centrifugation with Atsey buffer (50 mM Tris-HCl, pH 7.4), and the finally obtained membrane fraction was used as the Obioid // receptor membrane fraction.
- Atsey buffer 50 mM Tris-HCl, pH 7.4
- Binding experiments in the presence of the resulting membrane fraction and the radioligand [3 H] £ test compound was performed using the -D AMGO, and [3 H] -DAMGO in the membrane fraction and the final concentration of InM added And incubated at 25 ° C for 90 minutes. The reaction was stopped by rapid filtration through a GF / B filter, and the plate was further washed with 5 ml of Atsushi buffer. Radioactivity was measured with a liquid scintillation counter. Non-specific binding was determined by 1 M DAMGO, and specific binding was calculated from the difference. IC 5 for each compound. After the values were determined by nonlinear least squares regression analysis, Ki values were calculated using the Cheng and Prusoff equation.
- the receptor affinity Ki value of the compound of Reference Example 15 was 100 OnM or more, whereas the ⁇ receptor affinity Ki value of the compound of the present invention was 5 OnM or less. It has been found that it has a strong affinity for the opioid ⁇ receptor.
- Test Example 2 Binding affinity with dopamine D2 receptor
- the membrane fraction prepared from rat striatum was prepared as a membrane fraction of dopamine D2 receptor.
- the rat striatum was first homogenized with a 10-fold amount of 0.32 ⁇ sucrose solution, and the obtained homogenate was centrifuged at 900 900g for 10 minutes. Subsequently, the supernatant was centrifuged at 11,500 X g for 20 minutes to obtain a sediment.
- the ⁇ dopamine D2 Atsuse I buffer 120mM NaCL 5mM KC1, ImM MgCl 2 and ImM 50mM Tris-HCl buffer containing CaCl 2, pH 7.4
- the fraction was defined as a dopamine D2 receptor membrane fraction.
- Binding experiments were performed using the obtained membrane fraction and the radioligand [ 3 H] -spiperone.
- the membrane fraction and the final concentration of O.lnM [ 3 H] -spiperone were added, and the mixture was incubated at 37 ° C for 30 minutes.
- the reaction was stopped by rapid filtration with a GF / B filter, and further washed with 5 ml of Atsushi buffer (50 mM Tris-HCl, pH 7.4). Radioactivity was measured with a liquid scintillation counter. Non-specific binding was determined by 10 M sulpiride, and specific binding was calculated from the difference. IC 5 of each of compounds.
- Ki values were calculated using the Cheng and Prusoff equation.
- Table 1 The results of measuring the binding affinities of the compounds of the present invention with the opioid; receptor and dopamine D2 receptor from Test Examples 1 and 2 are summarized in Table 1 below.
- the ratio of the dopamine D2 receptor antagonist activity to the obioid receptor agonist activity of the compound of the present invention falls within the range of 1: 1 to 1: 150, so that it has few side effects and is useful as a therapeutic agent for pain. It is. table 1
- Test Example 3 Analgesic effect by hot plate method
- This test is a general method for evaluating the analgesic effect of severe pain, and it is known that compounds having opioid ⁇ receptor agonist activity respond well to this test.
- This test was performed according to the method of Narita et al. (Jpn J Pharmacol. 1993; 62: 15-24). That is, using a ddY male mouse (weight 28-33 g), the drug was intraperitoneally administered to the mouse, and after 30 minutes the mouse was placed on a hot plate at 52 ° C, Latency before licking or jumping was measured. The latency before drug administration was measured at least one hour before the start of the experiment, and mice with a reaction time longer than 30 seconds were regarded as inappropriate for the experiment and excluded. The maximum latency was set to 60 seconds to avoid tissue burns.
- the analgesic effect was calculated by the following formula.
- the compound of the present invention has an analgesic effect equal to or stronger than that of morphine, and is presumed to have the activity of obioid ⁇ receptor agonist together with the results of Test Example 1.
- Test Example 4 Anti-dopamine effect on apomorphine-induced climbing behavior
- Administration of apomorphine, a dopamine receptor agonist, to mice induces continuous climbing behavior, and antagonism to this effect is commonly used to detect dopamine receptor antagonist.
- the mouse was placed in a cylindrical wire mesh (diameter 10 cm, height 14 cm) and allowed to familiarize for about 1 hour.
- the mouse was placed in a measurement cage (23 ⁇ 33 ⁇ 12.5 cm), and after acclimated to the cage, the test drug was intraperitoneally administered, and the locomotor activity was measured by an infrared sensor for 2 hours.
- Morphine showed a strong locomotor activity promoting effect.
- the compounds of the present invention (Examples 14 to 18 and 22 to 23) had no effect on locomotor activity. That is, the action of promoting dopamine release via the obioid ⁇ receptor was not expressed by the compound of the present invention having both the activities of the obioid receptor and the dopamine D 2 receptor antagonist. Therefore, it is presumed that the compound of the present invention suppresses side effects such as mental dependence, nausea, hallucinations and confusion, which are considered to be caused by dopamine release via the opioid ⁇ receptor.
- Sprague-Dawley rats (170-210 g) were used.
- the experimental equipment is a shuttle box with a color of 30 cm in width, 60 cm in length and 30 cm in height, colored white (uneven surface) and black (smooth surface without unevenness). used.
- rats were placed on the platform set in the center of the box without administering any drug or saline, and the time spent in each compartment for 15 minutes from the moment the rats got off the platform It was measured. The difference between the residence time in the compartment on the drug treatment side and the residence time in the compartment on the saline treatment side was calculated.
- novel compound represented by the general formula (I) and a pharmacologically acceptable salt thereof have both the obioid ⁇ receptor agonist activity and the dopamine D2 receptor antagonist activity, and have a pain with suppressed side effects. Useful as a therapeutic. All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety.
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Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99959951A EP1142587A1 (en) | 1998-12-24 | 1999-12-21 | Remedies for pain |
CA002356269A CA2356269A1 (en) | 1998-12-24 | 1999-12-21 | Pain control agent |
AU16915/00A AU1691500A (en) | 1998-12-24 | 1999-12-21 | Remedies for pain |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP36736698 | 1998-12-24 | ||
JP10/367366 | 1998-12-24 | ||
JP11/136812 | 1999-05-18 | ||
JP13681299 | 1999-05-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000038720A1 true WO2000038720A1 (fr) | 2000-07-06 |
Family
ID=26470311
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/007191 WO2000038720A1 (fr) | 1998-12-24 | 1999-12-21 | Remedes contre la douleur |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1142587A1 (ja) |
AU (1) | AU1691500A (ja) |
CA (1) | CA2356269A1 (ja) |
WO (1) | WO2000038720A1 (ja) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004525967A (ja) * | 2001-04-10 | 2004-08-26 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | Orl−1受容体介在障害の治療に有用な1,3,8−トリアザスピロ[4.5]デカン−4−オン誘導体 |
JP2009543825A (ja) * | 2006-07-18 | 2009-12-10 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | スピロ環状アザインドール誘導体 |
US7696201B2 (en) | 2006-08-15 | 2010-04-13 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
US7786107B2 (en) | 2006-08-18 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
US7786141B2 (en) | 2004-08-19 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Dihydrospiroindene modulators of muscarinic receptors |
US7858790B2 (en) | 2006-06-29 | 2010-12-28 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
US7858635B2 (en) | 2005-12-22 | 2010-12-28 | Vertex Pharmaceuticals Incorporated | Spiro compounds as modulators of muscarinic receptors |
US7863449B2 (en) | 2004-11-29 | 2011-01-04 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
JP2011016829A (ja) * | 2002-11-11 | 2011-01-27 | Gruenenthal Gmbh | スピロ環状シクロヘキサン誘導体 |
US7879834B2 (en) | 2004-08-19 | 2011-02-01 | Vertex Pharmaceuticals Incorporated | Spiroindoline modulators of muscarinic receptors |
US7973162B2 (en) | 2007-10-03 | 2011-07-05 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
US8263605B2 (en) | 2006-02-22 | 2012-09-11 | Vertex Pharmaceutical Incorporated | Modulators of muscarinic receptors |
US8304423B2 (en) | 2006-02-22 | 2012-11-06 | Vertex Pharmaceutical Incorporated | Modulators of muscarinic receptors |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6867222B2 (en) * | 2001-04-18 | 2005-03-15 | Euro-Celtique, S.A. | Nociceptin analogs |
DE10360792A1 (de) * | 2003-12-23 | 2005-07-28 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
DE10360793A1 (de) * | 2003-12-23 | 2005-07-28 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
DE102004039382A1 (de) | 2004-08-13 | 2006-02-23 | Grünenthal GmbH | Spirocyclische Cyclohexan-Derivate |
WO2015002755A2 (en) * | 2013-06-21 | 2015-01-08 | The Broad Institute, Inc. | Compounds for the treatment of malaria |
-
1999
- 1999-12-21 AU AU16915/00A patent/AU1691500A/en not_active Abandoned
- 1999-12-21 WO PCT/JP1999/007191 patent/WO2000038720A1/ja not_active Application Discontinuation
- 1999-12-21 CA CA002356269A patent/CA2356269A1/en not_active Abandoned
- 1999-12-21 EP EP99959951A patent/EP1142587A1/en not_active Withdrawn
Non-Patent Citations (4)
Title |
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CHEMICAL ABSTRACTS, vol. 93, 1980, Columbus, Ohio, US; abstract no. 107010A, SWAIN HENRY: "Annual Report: evaluation of new compounds for opioid activity" XP002924328 * |
JOSEE E. LEYSEN: "(3H)Sufentanil, a Superior Ligand for mu-Opiate receptors: Binding Properties and Regional Distribution in Rat Brain and Spinal Cord", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 87, no. 2-3, 1983, pages 209 - 225, XP002924330 * |
NIDA RES. MONOGR.,(PROB. DRUG DEPEND.), vol. 27, 1979, pages 356 - 398 * |
RAFAEL MALDONADO: "Absence of opiate rewarding effects in mice lacking dopamine D2 receptors", NATURE, vol. 388, no. 6642, 1997, pages 586 - 589, XP002924329 * |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2004525967A (ja) * | 2001-04-10 | 2004-08-26 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | Orl−1受容体介在障害の治療に有用な1,3,8−トリアザスピロ[4.5]デカン−4−オン誘導体 |
JP2011016829A (ja) * | 2002-11-11 | 2011-01-27 | Gruenenthal Gmbh | スピロ環状シクロヘキサン誘導体 |
US7786141B2 (en) | 2004-08-19 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Dihydrospiroindene modulators of muscarinic receptors |
US7879834B2 (en) | 2004-08-19 | 2011-02-01 | Vertex Pharmaceuticals Incorporated | Spiroindoline modulators of muscarinic receptors |
US8497295B2 (en) | 2004-08-19 | 2013-07-30 | Vertex Pharmaceuticals Incorporated | Spiroindoline modulators of muscarinic receptors |
US8367691B2 (en) | 2004-08-19 | 2013-02-05 | Vertex Pharmaceutical Incorporated | Modulators of muscarinic receptors |
US8258148B2 (en) | 2004-08-19 | 2012-09-04 | Vertex Pharmaceutical Incorporated | Spiroindoline modulators of muscarinic receptors |
US7863449B2 (en) | 2004-11-29 | 2011-01-04 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
US7858635B2 (en) | 2005-12-22 | 2010-12-28 | Vertex Pharmaceuticals Incorporated | Spiro compounds as modulators of muscarinic receptors |
US8263605B2 (en) | 2006-02-22 | 2012-09-11 | Vertex Pharmaceutical Incorporated | Modulators of muscarinic receptors |
US8304423B2 (en) | 2006-02-22 | 2012-11-06 | Vertex Pharmaceutical Incorporated | Modulators of muscarinic receptors |
US7858790B2 (en) | 2006-06-29 | 2010-12-28 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
JP2009543825A (ja) * | 2006-07-18 | 2009-12-10 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | スピロ環状アザインドール誘導体 |
US8399503B2 (en) | 2006-07-18 | 2013-03-19 | Gruenenthal Gmbh | Spirocyclic azaindole derivatives |
US7696201B2 (en) | 2006-08-15 | 2010-04-13 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
US7786107B2 (en) | 2006-08-18 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
US7973162B2 (en) | 2007-10-03 | 2011-07-05 | Vertex Pharmaceuticals Incorporated | Modulators of muscarinic receptors |
Also Published As
Publication number | Publication date |
---|---|
AU1691500A (en) | 2000-07-31 |
CA2356269A1 (en) | 2000-07-06 |
EP1142587A1 (en) | 2001-10-10 |
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