CN101119728A - Indolomorphinan derivative having carboxy in 6'-position - Google Patents
Indolomorphinan derivative having carboxy in 6'-position Download PDFInfo
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- CN101119728A CN101119728A CNA2005800480811A CN200580048081A CN101119728A CN 101119728 A CN101119728 A CN 101119728A CN A2005800480811 A CNA2005800480811 A CN A2005800480811A CN 200580048081 A CN200580048081 A CN 200580048081A CN 101119728 A CN101119728 A CN 101119728A
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Abstract
A therapeutic and/or prophylactic agent for constipation induced by a compound having an opioid [mu] receptor agonist activity, which agent comprises as an effective ingredient a compound having an opioid ' receptor antagonist activity, e.g., a compound of Formula (I): (wherein R 1 represents hydrogen, lower alkyl, cycloalkyl lower alkyl or the like; R 2 and R 3 independently represent hydrogen, hydroxy or the like; R 4 is hydrogen, hydroxy or the like; R 5 is hydrogen; R 4 and R 5 may optionally form -O- or the like; R 6 represents hydrogen, lower alkyl or the like (wherein X represents -O- or -N(R 10 )-or the like; R 7 , R 8 , R 9a and R 9b independently represent hydrogen, lower alkyl, lower alkoxycarbonyl or the like; r represents an integer of 0 to 5; Y represents -CH- or the like; Z represents a crosslinkage composed of 2 to 5 atoms) or a pharmaceutically acceptable salt thereof or a solvate of either.
Description
Technical field
The present invention relates to can be used as nauseating, disgusting and/or vomiting, particularly by the indole that treats and/or prevents medicine and the morphinan derivative of feeling sick and/or vomitting that chemical compound brought out with opioid recdptor (for example opiates μ receptor) agonism.
Background technology
Opiates μ receptor stimulating agents such as morphine can be used as very effective analgesics and use for the cancer pain patient, but as side effect, bring out intensively feel sick, feel sick, vomiting, urine retention, pruritus etc.There are various Bendectins in clinical, to use, but all not talkative demonstration effect of sufficient, in order to improve patient's QOL, people wish that excellent relieving side effects medicine is arranged.
Put down in writing in the patent documentation 1～3 with the The compounds of this invention similar compounds for the treatment of feeling sick of being brought out of opiates MU agonist, vomiting or prevention effectively, but specifically do not put down in writing The compounds of this invention.
Patent documentation 1: the open WO2004/007503 pamphlet of international patent application
Patent documentation 2: the open WO95/31463 pamphlet of international patent application
Patent documentation 3: the open WO94/07896 pamphlet of international patent application
Summary of the invention
Invent problem to be solved
The invention provides and can be used as the indole that treat and/or prevent medicine and the morphinan derivative of feeling sick and/or vomitting relevant with opioid recdptor.
Solve the method for problem
The invention provides:
(1) chemical compound shown in the formula (I) or its pharmaceutically acceptable salt or their solvate:
(in the formula, R
1For hydrogen or-CHR
AR
B, R wherein
ABe group shown in elementary alkoxy carbonyl oxygen base, cyclo alkoxy carbonyl oxygen base, acyloxy or the following formula,
In the formula, R
2For hydrogen maybe can have substituent low alkyl group,
R
BBe hydrogen or methyl).
(2) chemical compound of above-mentioned (1) or its pharmaceutically acceptable salt or their solvate,
R wherein
1Be hydrogen.
(3) pharmaceutical composition is characterized in that: the chemical compound or its pharmaceutically acceptable salt or their solvate that contain above-mentioned (1).
(4) opioid receptor antagonists is characterized in that: the chemical compound or its pharmaceutically acceptable salt or their solvate that contain above-mentioned (1).
(5) pharmaceutical composition of above-mentioned (3), wherein, the chemical compound of above-mentioned (2) or its pharmaceutically acceptable salt or their solvate are active constituents of medicine.
(6) pharmaceutical composition of above-mentioned (3), its be feel sick and/or vomiting treat and/or prevent medicine.
(7) pharmaceutical composition of above-mentioned (3), it is alleviating and/or preventive drug by the side effect that chemical compound brought out with opioid recdptor agonism.
(8) above-mentioned (7) treat and/or prevent medicine, wherein side effect is to feel sick and/or vomiting.
(9) above-mentioned (7) or (8) treat and/or prevent medicine, the chemical compound that wherein has the opioid recdptor agonism is morphine, oxycodone, their pharmaceutically acceptable salt or their solvate.
(10) chemical compound of above-mentioned (1) or (2) or its pharmaceutically acceptable salt or their solvate have application in the medicine of opioid recdptor antagonism in preparation.
(11) chemical compound of above-mentioned (1) or (2) or its pharmaceutically acceptable salt or their solvate are used for the application of the medicine that treats and/or prevents of disgusting and/or vomiting in preparation.
(12) chemical compound of above-mentioned (1) or (2) or its pharmaceutically acceptable salt or their solvate are used for alleviating and/or prevent application by the medicine of the side effect that chemical compound brought out with opioid recdptor agonism in preparation.
(13) method of inhibition opioid recdptor is characterized in that: the chemical compound or its pharmaceutically acceptable salt or their solvate that give above-mentioned (1) or (2).
(14) method that treats and/or prevents of feeling sick and/or vomitting is characterized in that: the chemical compound or its pharmaceutically acceptable salt or their solvate that give above-mentioned (1) or (2).
(15) alleviate and/or prevent method, it is characterized in that: the chemical compound or its pharmaceutically acceptable salt or their solvate that give above-mentioned (1) or (2) by the side effect that chemical compound brought out with opioid recdptor agonism.
(16) analgesic, it is to be combined by the chemical compound of above-mentioned (1) or (2) of the effective dose that gives the side effect that this chemical compound brings out or its pharmaceutically acceptable salt or their solvate having the chemical compound of opioid recdptor agonism and being used to alleviate and/or preventing.
(17) analgesic, it is to be combined by the chemical compound of above-mentioned (1) or (2) of the effective dose of feeling sick of giving that this chemical compound brings out and/or vomiting or its pharmaceutically acceptable salt or their solvate having the chemical compound of opioid recdptor agonism and being used for the treatment of and/or preventing.
The invention effect
Chemical compound of the present invention (I) is to feeling sick and/or vomiting, particularly have the effect for the treatment of and/or preventing, can be used as the relieving side effects medicine of chemical compound that will have the opioid recdptor agonism or the patient who is giving by the disgusting and/or vomiting that chemical compound brought out with opioid recdptor (for example opiates μ receptor) agonism.
The best mode that carries out an invention
In this description, " halogen " comprises fluorine, chlorine, bromine and iodine.
" low alkyl group " comprises the straight or branched alkyl of carbon number 1～10, preferred carbon number 1～6, further preferred carbon number 1～3, and methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, hexyl, isohesyl, n-heptyl, different heptyl, n-octyl, iso-octyl, n-nonyl and positive decyl etc. are for example arranged.Preferable methyl or ethyl.
The substituent group that " can have substituent low alkyl group " has halogen, lower alkoxy, acyl group or acyloxy etc.
" lower alkoxy "; " elementary alkoxy carbonyl oxygen base "; " aromatic yl elementary alkyl "; " three low alkyl group silicyls "; " low alkyl group diaryl silicyl "; " triaryl low alkyl group silicyl "; " lower alkoxy low alkyl group "; " lower alkoxy lower alkoxy low alkyl group "; " lower alkylthio low alkyl group "; " aromatic yl elementary alkyl oxygen base low alkyl group "; the low alkyl group part of " low alkyl group sulfonyl " is same with above-mentioned " low alkyl group ".
The cycloalkanes of " cyclo alkoxy carbonyl oxygen base " partly comprises the ester ring type carbocyclic ring of carbon number 3～8, comprises cyclopropane, Tetramethylene., Pentamethylene., cyclohexane extraction, cycloheptane and cyclooctane.
" aryl " comprises phenyl, naphthyl, anthryl and phenanthryl etc., preferred especially phenyl.
The aryl moiety of " aryl carbonyl ", " aromatic yl elementary alkyl ", " low alkyl group diaryl silicyl ", " triaryl low alkyl group silicyl ", " aromatic yl elementary alkyl oxygen base low alkyl group ", " aryl sulfonyl " is identical with above-mentioned " aryl ".
" acyl group " comprises (1) carbon number 1～10, further preferred carbon number 1～6, most preferably the straight or branched alkyl-carbonyl or the alkenyl carbonyl of carbon number 1～4, (2) carbon number 4～9, the naphthene base carbonyl of preferred carbon number 4～7 and the aryl carbonyl of (3) carbon number 7～11.
The moieties of " alkyl-carbonyl " is identical with above-mentioned " low alkyl group " herein.
The alkenyl part of " alkenyl carbonyl " is included in arbitrarily has the carbon number 2～10 of two keys more than 1, preferred carbon number 2～8, the further preferably thiazolinyl of the straight or branched of carbon number 3～6 on the position.Specifically comprise vinyl, pi-allyl, acrylic, isopropenyl, cyclobutenyl, isobutenyl, isopentene group (Prenyl), butadienyl, pentenyl, isopentene group (isopentenyl), pentadienyl, hexenyl, dissident's thiazolinyl, hexadienyl, heptenyl, octenyl, nonene base and decene base etc.
The cycloalkyl moiety of " naphthene base carbonyl " is carbon number 3～10, preferred carbon number 3～8, the more preferably carbocylic radical of carbon number 4～8, for example comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, ring nonyl and ring decyl etc.
The object lesson of " acyl group " has: formoxyl, acetyl group, propiono, bytyry, isobutyryl, valeryl, valeryl, caproyl, acryloyl group, propioloyl, methacryl, crotonyl, cyclopropyl carbonyl, cyclohexyl-carbonyl, ring octyl group carbonyl and benzoyl etc.
The acyl moiety of " acyloxy " is identical with above-mentioned " acyl group ".
In this description, " solvate " for example comprises and the solvate of organic solvent, hydrate etc.When forming hydrate, can with the hydrone coordination of any amount.
Chemical compound (I) comprises pharmaceutically acceptable salt.For example have and alkali metal (lithium, sodium or potassium etc.), alkaline-earth metal (magnesium or calcium etc.), ammonium, organic base and amino acid whose salt, perhaps with the salt of mineral acid (hydrochloric acid, sulphuric acid, nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid etc.) and organic acid (acetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, 1,3-propanedicarboxylic acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid or ethyl sulfonic acid etc.).Preferred especially hydrochloric acid, phosphoric acid, tartaric acid or methanesulfonic acid etc.These salt can form according to the method for carrying out usually.
Chemical compound (I) is not limited to specific isomer, comprises all possible isomer or racemic modification.
Chemical compound of the present invention (I) can be according to following method preparation.
(in the formula, R
cBe hydrogen or low alkyl group, R
dBe the blocking group of hydroxyl, Z is hydroxyl or halogen,
Other symbol as hereinbefore).
At first, in appropriate solvent (for example methanol, ethanol, isopropyl alcohol, dimethyl formamide, dimethyl sulfoxide, acetic acid, propanoic acid or their mixture etc.), in the presence of acid (for example hydrochloric acid, sulphuric acid, phosphoric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, acetic acid, polyphosphoric acid etc.), near about 0 ℃～200 ℃, preferred about 20 ℃～150 ℃, make a known naltrexone (VII) and hydrazino-benzoic acid lower alkyl esters (VI) reaction about 5 minutes～about 24 hours, preferred about 1 hour～about about 5 hours, obtain chemical compound (V).
The R of gained chemical compound (V)
cDuring for low alkyl group, obtain chemical compound (I-1) by hydrolysis.Hydrolysis can be in appropriate solvent (two alkane, oxolane, methanol, ethanol, water or their mixture etc.), in the presence of alkali (sodium hydroxide, potassium hydroxide, Lithium hydrate, barium hydroxide, potassium carbonate, sodium carbonate etc.), reaction is about 5 minutes～about 24 hours near about 0 ℃～200 ℃, preferred about 30 ℃～about 100 ℃, preferred about 1 hour～about about 5 hours.
Then, the hydroxyl of the chemical compound (I-1) of gained is protected, obtained chemical compound (IV).
Blocking group to hydroxyl is not particularly limited, and for example can be low alkyl group (methyl; the tert-butyl group etc.); aromatic yl elementary alkyl (trityl group; benzyl etc.); three low alkyl group silicyl (trimethyl silyls; t-butyldimethylsilyl; triethylsilyl; triisopropyl silicyl etc.); low alkyl group diaryl silicyl (t-butyldiphenylsilyl etc.); triaryl low alkyl group silicyl (tribenzyl silicyl etc.); lower alkoxy low alkyl group (methoxy; the 1-ethoxyethyl group; 1-methyl isophthalic acid-methoxy ethyl etc.); lower alkoxy lower alkoxy low alkyl group (methoxy ethoxy methyl etc.); lower alkylthio low alkyl group (methylthiomethyl etc.); can be by the THP trtrahydropyranyl (Pentamethylene oxide .-2-base of replacements such as low alkyl group or lower alkoxy; 4-methoxyl group tetrahydropyran-4-base etc.); tetrahydrochysene sulfo-pyranose (tetrahydrochysene sulfo-pyrans-2-base etc.); tetrahydrofuran base (oxolane-2-base etc.); tetrahydrochysene thio-furan base (tetrahydrochysene thio-furan-2-base etc.); aromatic yl elementary alkyl oxygen base low alkyl group (benzyloxymethyl etc.); low alkyl group sulfonyl (mesyl; ethylsulfonyl etc.); acyl group (acetyl group etc.); perhaps can be by the aryl sulfonyl (p-toluenesulfonyl etc.) of replacements such as low alkyl group or lower alkoxy.
The importing reaction of protecting group can be carried out according to conventional method.For example; when using t-butyldimethylsilyl as blocking group; use dimethyl formamide, acetonitrile, oxolane, dimethyl formamide, dichloromethane, chloroform, toluene or their mixture etc. as solvent; at imidazoles, triethylamine, 2; 6-lutidines etc. exist down; with reactions such as tert-butyldimethylsilyl chloride, t-butyldimethylsilyl triflate, can obtain chemical compound (IV).Reacted near being reflected at-80 ℃～100 ℃ approximately, preferred about-20 ℃～about 25 ℃ about 5 minutes～about 24 hours, preferred about 1 hour～about about 10 hours.
The importing CHR of hydrolysis in vivo in gained chemical compound (IV)
AR
BGroup.
This reaction for example can following acquisition target compound: in appropriate solvent (dimethyl formamide, dimethyl sulfoxide, acetonitrile, oxolane, dichloromethane, diethyl ether, acetone etc.), at alkali (organic bases such as pyridine, triethylamine, diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium tert-butoxide, potassium carbonate, potassium bicarbonate or sodium bicarbonate) exist or do not exist down, make chemical compound (IV) and haloalkyl (III)-80 ℃～100 ℃ approximately, preferred-20 ℃～60 ℃ reactions about 5 minutes～about 24 hours down, preferred about 30 minutes～about about 3 hours.
Chemical compound (IV) can carry out esterification by dehydrating condensation with chemical compound (III) in the presence of acid (hydrochloric acid, sulphuric acid, methanesulfonic acid).
At last, the hydroxy-protective group of chemical compound (II) is carried out deprotection, obtain chemical compound (I ').
Deprotection reaction can adopt known method to carry out according to blocking group.When for example blocking group uses t-butyldimethylsilyl; can use oxolane, methanol, ethanol, acetic acid, water etc. as solvent; handle with fluorinated anionic (tetrabutyl ammonium fluoride, Fluohydric acid., Fluohydric acid .-pyridine, potassium fluoride etc.), perhaps handle with mineral acids such as organic acid such as acetic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or hydrochloric acid.Carried out near being reflected at-80 ℃～100 ℃ approximately, preferred about 0 ℃～about 40 ℃ about 5 minutes～about 24 hours, preferred about 30 minutes～about about 10 hours, and can obtain target compound (I ').
Chemical compound of the present invention is for acute dyspepsia, acute alcoholism, alimentary toxicosis, flu, gastric ulcer, duodenal ulcer, gastric cancer, intestinal obstruction, appendicitis, peritonitis, cholelithiasis, hepatitis, the liver inflammation, encephalitis, meningitis, cerebral increases, injury of head, carsick, vomiting during pregnancy, chemotherapeutic side effect, the side effect of actinotherapy, the side effect of anticarcinogen etc., the digestive tract that reasons such as the narrow or postoperative intestine adhesion of digestive tract compressing cause passes through obstacle, what the reasons such as cerebral rising that cerebroma cerebral hemorrhage meningitis brain radiation exposure etc. causes caused feels sick, treating and/or preventing effectively of vomiting, particularly for have by picked-up opioid recdptor (for example opiates μ receptor) agonism chemical compound brought out feels sick, feel sick and/or vomiting effectively.
" chemical compound with opioid recdptor agonism " specifically has morphine, oxycodone, fentanyl, methadone, codeine, paracodin, hydromorphone, levorphanol, Pethidine, the third oxygen sweet smell, dextropropoxyphene, tramadol, their pharmaceutically acceptable salt or their solvate, particularly for morphine, oxycodone, their pharmaceutically acceptable salt or their solvate, chemical compound of the present invention is effective especially.
The intensive opiates δ of compound exhibits of the present invention receptor antagonism.In addition, by test example described later as can be known, the dividing a word with a hyphen at the end of a line property of brain of The compounds of this invention is low, therefore can suppress hardly the disease that is attended by pain (cancer pain (bone transfer, nerve compression, intracranial hypertension, the pain that soft tissue soaks into or amyotrophy causes for example, pain around internal organs, muscular fascia, waist or the shoulder joint, the chronic pain of postoperative), AIDS etc.) the analgesic activity of the chemical compound that gives of patient with opioid recdptor agonism, to then showing the high effect that alleviates by the side effect that receptor stimulating agent brought out.And have high receptor-selective, high oral absorption, hypotoxicity, in human plasma feature such as high stability, high biological effectiveness, very effective as medicine.
When giving chemical compound of the present invention in order to alleviate the side effect of bringing out by chemical compound with opioid recdptor agonism, The compounds of this invention give can the chemical compound with opioid recdptor agonism give preceding, give the back or give simultaneously.
The interval that gives to these two kinds of medicines is not particularly limited.For example, when chemical compound of the present invention is given after the chemical compound with opioid recdptor agonism, as long as after just giving the opioid recdptor agonist～about 3 days with interior, preferably just given after～about 1 day in, just can more effectively play a role.In addition, when before giving the opioid recdptor agonist, giving chemical compound of the present invention, as long as face give the opioid recdptor agonist before～before about 1 day, preferably face give before～about 12 hours before, just can more effectively play a role.
Chemical compound of the present invention is as feeling sick and/or vomiting curative and/or preventive drug when giving, and also can feel sick with other and/or vomiting curative and/or preventive drug are united use.For example can unite use with Ondansetron Hydrochloride, adrenocortical steroid (methylprednisolone, prednisolone, dexamethasone etc.), prochlorperazine, haloperidol, timiperone, perphenazine, metoclopramide, domperidone, scopolamine, chlorpromazine hydrochloride, droperidol.
Chemical compound of the present invention can also be felt sick with the intermixture that combines with the chemical compound with opioid recdptor agonism, with other and/or the form of the intermixture that vomiting curative and/or preventive drug combine gives.
During with chemical compound administration of human of the present invention, can be with oral forms such as powder, granule, tablet, capsule, pill, liquid preparations, perhaps non-oral form administrations such as injection, suppository, transdermic absorbent, inhalant.Can be as required, medical additives such as the excipient that mixing and its dosage form adapt in the effective dose of this chemical compound, binding agent, wetting agent, disintegrating agent, lubricant are made pharmaceutical preparation.
Chemical compound of the present invention can also be made and mix chemical compound and/or other mixture disgusting and/or vomiting curative and/or preventive drug and various medical additives as required with opioid recdptor agonism.
Dosage is according to state, route of administration, patient's age or the body weight of disease and difference during to adult's oral administration, is generally 1 μ g～10g/ days, preferred 0.01～200mg/ days, during non-oral administration, is generally 0.1 μ g～1g/ days, preferred 0.1～2g/ days.
Below provide embodiment and test example, further describe the present invention, but the present invention is not limited by this.
Embodiment 1
17-cyclopropyl methyl-6,7-two dehydrogenations-4,5 α-epoxy radicals-3,14 beta-dihydroxy-6 '-carboxyl-6,7-2 ', 3 '-indole and morphinan
(first step) 17-cyclopropyl methyl-6,7-two dehydrogenations-4,5 α-epoxy radicals-3,14 beta-dihydroxy-6 '-ethoxy carbonyl-6,7-2 ', 3 '-indole and morphinan
Hydrazino-benzoic acid between known naltrexone hydrochloride of 500mg (1.32mmol) and 221mg (1.46mmol) is suspended in the 3ml ethanol, 50 ℃ of following heated and stirred.With 10 fens clock times to the 2ml alcoholic solution that wherein slowly drips 0.86ml (13.2mmol) methanesulfonic acid.After dripping end, under refluxing, continue to stir 2 hours.Be cooled to room temperature, add saturated sodium bicarbonate aqueous solution and ethyl acetate then in reactant liquor, separate organic layer, water and saturated aqueous common salt wash successively.Use the dried over sodium sulfate organic layer, heat up in a steamer then and desolvate.(chloroform: purification methanol=99: 1) obtains 379mg (59%) and is the title compound of faint yellow solid by silica gel column chromatography with residue.
NMR(300MHz、CDCl
3)
δ0.14-0.18(m，2H)，0.55-0.59(m，2H)，0.89(m，1H)，1.41(t，3H，J＝6.9Hz)，1.75(d，1H，J＝11.4Hz)，2.20-2.91(m，8H)，3.10(d，1H，J＝18.6Hz)，3.38(d，1H，J＝6.3Hz)，4.38(q，2H，J＝6.9Hz)，5.5(br s，1H)，5.69(s，1H)，6.46(d，1H，J＝8.1Hz)，6.55(d，1H，J＝8.1Hz)，7.34(d，J＝8.4Hz)，7.67(d，J＝8.4Hz)，7.92(s，1H)，8.36(s，1H).
(second step) 17-cyclopropyl methyl-6,7-two dehydrogenations-4,5 α-epoxy radicals-3,14 beta-dihydroxy-6 '-carboxyl-6,7-2 ', 3 '-indole and morphinan
Add 2.4ml 2mol/L sodium hydrate aqueous solution in the 2.4ml methanol solution of the chemical compound that in 654mg (1.20mmol) first step, obtains, reflux and stirred 1 hour down.Reactant liquor is cooled to room temperature, with the methanol dilution, is adjusted to pH 6.0 then with dilute hydrochloric acid.The crystal that leaching is separated out washes with water, drying, obtains 534mg (97%) and is the title compound of clear crystal.
NMR(300MHz，d6-DMSO)
δ0.14-0.18(m，2H)，0.48-0.54(m，2H)，0.90(m，1H)，1.59(d，1H，J＝11.7Hz)，2.09-2.82(m，8H)，3.07(d，1H，J＝18.6Hz)，5.55(s，1H)，6.49(d，1H，J＝7.8Hz)，6.52(d，1H，J＝7.8Hz)，7.42(d，J＝8.4Hz)，7.55(dd，J＝1.5，8.4Hz)，7.97(d，J＝1.5Hz，1H)，8.98(br s，1H)，11.54(s，1H).
Embodiment 2
(in the formula, TBS is a t-butyldimethylsilyl, and other symbol as hereinbefore)
(first step) 3-t-butyldimethylsilyloxy base-17-cyclopropyl methyl-6,7-two dehydrogenations-4,5 α-epoxy radicals-14 beta-hydroxy-6 '-carboxyl-6,7-2 ', 3 '-indole and morphinan
In 459mg (1mmol) embodiment 1, add 332mg (2.2mmol) tert-butyldimethylsilyl chloride and 170mg (2.5mmol) imidazoles in the 5ml dimethyl formamide solution of the chemical compound (I-1) of gained, at room temperature stir and spend the night.Reactant liquor is injected in frozen water-saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction.Organic layer is washed with saturated sodium-chloride water solution, use anhydrous sodium sulfate drying, then concentrating under reduced pressure.Gained grease 3-t-butyldimethylsilyloxy base-17-cyclopropyl methyl-6,7-two dehydrogenations-4,5 α-epoxy radicals-14 beta-hydroxy-6 '-t-butyldimethylsilyloxy base carbonyl-6,7-2 ', the not purified subsequent reaction that is used for of 3 '-indole and morphinan.In the mixed solution of the 2ml of above-mentioned grease oxolane and 2ml water, add 6ml acetic acid, at room temperature stirred 1.5 hours.Reactant liquor is injected in frozen water-2M aqueous sodium carbonate, is adjusted to pH=6～7, use ethyl acetate extraction.Wash organic layer with saturated sodium-chloride water solution, use anhydrous sodium sulfate drying, then concentrating under reduced pressure.Residue by silica gel column chromatography (chloroform/methanol=10/1 → 8/1 →/6/1) purification, is obtained the title compound that 405mg is a clear crystal (yield 71%).
1H NMR(DMSO-d
6，δppm)：0.07(s，3H)，0.02(s，3H)，0.11-0.21(m，2H)，0.45-0.57(m，2H)，0.84(s，9H)，0.88(m，1H)，1.58(d，J＝11.4Hz，1H)，2.03-2.88(m，9H)，3.10(d，J＝18.6Hz，1H)，4.75(br s，1H)，5.60(s，1H)，6.52(d，J＝8.1Hz，1H)，6.56(d，J＝8.1Hz，1H)，7.41(d，J＝8.4Hz，1H)，7.53(d，J＝8.4Hz，1H)，7.96(d，J＝0.6Hz，1H)，11.63(br s，1H)
(second step)
3-t-butyldimethylsilyloxy base-17-cyclopropyl methyl-6,7-two dehydrogenations-4,5 α-epoxy radicals-14 beta-hydroxy-6 '-1 "-(isopropoxy carbonyl oxygen base) ethoxy carbonyl-6,7-2 ', 3 '-indole and morphinan
Under ice-cooled, in 120mg (0.210mmol) first step, add 44mg (0.325mmol) potassium carbonate and 108mg (0.42mmol) 1-(isopropoxy carbonyl oxygen base) ethyl iodide in the 2ml dimethyl formamide solution of gained chemical compound, under this temperature, stirred 1 hour.Reactant liquor is injected in the frozen water, uses ethyl acetate extraction.Wash organic layer with saturated sodium-chloride water solution, use anhydrous sodium sulfate drying, then concentrating under reduced pressure.By silica gel column chromatography (chloroform/methanol=100/1 → 50/1 → 30/1 → 20/1) purification, obtaining 118mg is the foamy title compound of light orange (yield 80%) with residue.
1H NMR(CDCl
3，δppm)：0.02(d，J＝4.5Hz，3H)，0.02(d，J＝3.0Hz，3H)，0.13-0.25(m，2H)，0.53-0.65(m，2H)，0.88(d，J＝2.7Hz，9H)，0.95(m，1H)，1.29(d，J＝6.3Hz，6H)，1.66(d，J＝5.1Hz，3H)，1.79(d，J＝12.6Hz，1H)，2.22-2.97(m，8H)，3.15(d，J＝18.9Hz，1H)，3.39(br s，1H)，4.90(m，1H)，5.62(s，1H)，6.54(dd，J＝2.1，8.1Hz，1H)，6.58(dd，J＝2.1，8.1Hz，1H)，7.07(m，1H)，7.37(t，J＝8.1Hz，1H)，7.68(m，1H)，8.02(s，1H)，8.36(d，J＝4.8Hz，1H)
(third step) 17-cyclopropyl methyl-6,7-two dehydrogenations-4,5 α-epoxy radicals-14 beta-hydroxy-6 '-1 "-(isopropoxy carbonyl oxygen base) ethoxy carbonyl-6,7-2 ', 3 '-indole and morphinan
To 118mg (0.168mmol) 3-t-butyldimethylsilyloxy base-17-cyclopropyl methyl-6,7-two dehydrogenations-4,5 α-epoxy radicals-14 beta-hydroxy-6 '-1 "-(isopropoxy carbonyl oxygen base) ethoxy carbonyl-6; 7-2 '; add 252 μ l (0.252mmol) 1M tetrabutylammonium/tetrahydrofuran solutions in the 1.5ml tetrahydrofuran solution of 3 '-indole and morphinan, at room temperature stirred 1 hour.Reactant liquor is injected in frozen water-saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction.Wash organic layer with saturated sodium-chloride water solution, use anhydrous sodium sulfate drying, then concentrating under reduced pressure.Residue by silica gel column chromatography (chloroform/methanol=100/1 → 50/1 → 30/1 → 20/1) purification, by the hexane/ethyl acetate crystallization, is obtained the title compound that 67mg is a clear crystal (yield 68%).
1H NMR(CDCl
3，δppm)：0.10-0.22(m，2H)，0.50-0.64(m，2H)，0.88(m，1H)，1.30(d，J＝6.3Hz，6H)，1.67(d，J＝5.4Hz，3H)，1.76(d，J＝11.4Hz，1H)，2.20-2.92(m，8H)，3.13(d，J＝19.2Hz，1H)，3.37(d，J＝5.1Hz，1H)，4.91(m，1H)，5.30(brs，1H)，5.67(s，1H)，6.53(d，J＝8.1Hz，1H)，6.61(d，J＝8.1Hz，1H)，7.05(m，1H)，7.24(m，1H)，7.59(m，1H)，7.84(br s，1H)，8.43(br s，1H)
Synthetic other chemical compound (I) of same operation.Below represent structural formula and physical constant.
I-2
1H NMR(CDCl
3，δppm)：0.15-0.2(m，2H)，0.55-0.6(m，2H)，0.85-0.95(m，1H)，1.21(s，9H)，1.81(d，J＝13.5Hz，1H)，2.2-2.95(m，8H)，3.16(d，J＝18.3Hz，1H)，3.35-3.45(m，1H)，4.9-5.1(br s，1H)，5.70(s，1H)，5.99-6.03(ABq，J＝5.4Hz，2H)，6.57(d，J＝8.3Hz，1H)，6.64(d，J＝8.3Hz，1H)，7.41(d，J＝8.6Hz，1H)，7.73(d，J＝8.6Hz，1H)，8.07(s，1H)，8.47(br s，1H).
I-3
1H NMR(d
6-DMSO，6ppm)：0.1-0.2(m，2H)，0.45-0.6(m，2H)，0.85-0.95(m，1H)，1.60(d，J＝12.2Hz，1H)，2.1-2.85(m，11H)，3.07(d，J＝18.7Hz，1H)，3.25-3.35(m，1H)，4.78(br s，1H)，5.20(s，2H)，5.57(s，1H)，6.51(s，2H)，7.48(d，J＝8.3Hz，1H)，7.59(d，J＝8.3Hz，1H)，8.01(s，1H)，8.97(s，1H)，11.62(s，1H).
I-4
1H NMR(d
6-DMSO，δppm)：0.1-0.2(m，2H)，0.45-0.6(m，2H)，0.8-1.0(m，4H)，1.5-1.65(m，3H)，2.1-2.85(m，10H)，3.07(d，J＝17.6Hz，1H)，3.25-3.4(m，1H)，4.78(br s，1H)，5.57(s，1H)，5.95(s，2H)，6.51(s，2H)，7.49(d，J＝8.0Hz，1H)，7.55(d，J＝8.0Hz，1H)，8.01(s，1H)，8.97(s，1H)，11.67(s：1H).
I-6
1H NMR(CDCl
3，δppm)：0.15-0.2(m，2H)，0.55-0.6(m，2H)，0.85-0.95(m，1H)，1.25-1.35(m，3H)，1.67(d，J＝5.4Hz，3H)，1.75(d，J＝10.5Hz，1H)，2.2-2.9(m，8H)，3.13(d，J＝18.6Hz，1H)，3.35-3.45(m，1H)，4.23(q，J＝7.0Hz，2H)，5.1-5.3(br s，1H)，5.68(s，1H)，6.52(d，J＝8.1Hz，1H)，6.60(d，J＝8.1Hz，1H)，7.06(q，J＝5.3Hz，1H)，7.22，7.23(two d，J＝8.3Hz，1H)，7.56，7.60(two d，J＝8.4Hz，1H)，7.82(s，1H)，8.43(br s，1H).
I-7
1H NMR(d
6-DMSO，δppm)：0.1-0.2(m，2H)，0.45-0.6(m，2H)，0.85-0.95(m，1H)，1.15(s，9H)，1.57(d，J＝5.4Hz)，1.55-1.65(m，1H)，2.1-2.85(m，8H)，3.08(d，J＝18.0Hz，1H)，3.25-3.35(m，1H)，4.77(br s，1H)，5.57(s，1H)，6.51(s，2H)，6.96(q，J＝5.2Hz，1H)，7.47(d，J＝8.3Hz，1H)，7.56(d，J＝8.3Hz，1H)，7.99(s，1H)，8.98(s，1H)，11.65(s，1H).
I-8
1H NMR(CDCl
3，δppm)：0.15-0.2(m，2H)，0.55-0.6(m，2H)，0.85-0.95(m，1H)，1.63(d，J＝5.4Hz，3H)，1.77(d，J＝11.4Hz，1H)，2.10，2.11(two s，3H)，2.2-2.9(m，8H)，3.13(d，J＝18.6Hz，1H)，3.35-3.45(m，1H)，5.0-5.3(br s，1H)，5.68(s，1H)，6.53(d，J＝8.1Hz，1H)，6.60(d，J＝8.1Hz，1H)，7.1-7.2(m，1H)，7.31(d，J＝9.0Hz，1H)，7.62，7.65(two d，J＝8.0Hz，1H)，7.93(s，1H)，8.47(br s，1H).
I-9
1H NMR(CDCl
3，δppm)：0.15-0.2(m，2H)，0.55-0.6(m，2H)，0.85-0.95(m，1H)，1.15-1.25(m，6H)，1.62(d，J＝5.4Hz，3H)，1.78(d，J＝11.7Hz，1H)，2.2-2.9(m，9H)，3.14(d，J＝18.3Hz，1H)，3.35-3.4(m，1H)，5.0-5.2(br s，1H)，5.67(s，1H)，6.5-6.6(m，1H)，6.62(d，J＝7.8Hz，1H)，7.1-7.2(m，1H)，7.25，7.31(two d，J＝7.8Hz，1H)，7.56，7.51(two d，J＝8.4Hz，1H)，7.89，7.92(two s，1H)，8.40，8.45(twobr s，1H).
I-10
1H NMR(CDCl
3，δppm)：0.15-0.2(m，2H)，0.55-0.6(m，2H)，0.85-0.95(m，1H)，1.15-2.0(m，10H)，1.66(d，J＝5.7Hz，3H)，2.2-2.9(m，9H)，3.14(d，J＝18.3Hz，1H)，3.35-3.4(m，1H)，4.6-4.7(m，1H)，4.9-5.3(br s，1H)，5.67(s，1H)，6.5-6.6(m，1H)，6.63(d，J＝8.1Hz，1H)，7.0-7.1(m，1H)，7.28，7.31(two d，J＝9Hz，1H)，7.60，7.66(two d，J＝8.7Hz，1H)，7.91，7.92(two s，1H)，8.35，8.39(two br s，1H)
The influence of feeling sick, vomitting that 1 pair of morphine of test example brings out
1) tried material
Used above-claimed cpd (I-1).
2) test method
After ingesting about 30 minutes, ferret is transferred in the observation cage, tried material.Tried substance dissolves in containing 5%N, among 15%Solutol (registered trade mark) HS15 of N-dimethyl acetylamide, 5%N-methylglucosamine, given with 5mg/kg.Be subjected to give 0.6mg/kg morphine so that the amount of 1ml/kg is subcutaneous after the test solution 30 minutes, within 30 minutes, perusal is felt sick, symptoms of emesis after giving morphine.
To the total of feeling sick (the rhythmic contractile motion of abdominal part), vomitting (vomiting behavior or its similar behavior of drainage vomitus) and feeling sick and vomitting, add up its occurrence number, latent time (from giving the time of morphine) and persistent period (from the extremely final time of vomitting of first vomiting) respectively to the first appearance of symptoms of emesis.
Maximum when the latent time that the example of vomiting occurs finishes for observing 30 minutes for ease of statistics, vomiting will occur but the persistent period is lower than 1 minute example note does 1 minute.
The result is as shown in table 1.
[table 1]
| Administered dose (mg/kg) | Symptom number of individuals (symptom number of individuals/routine number) | Latent time (minute) | Persistent period (minute) | Occurrence number | ||
| Feel sick | Contrast a) | - | 3/3 | 3±1 | 9±2 | 47±13 |
| I-1 | 0.05 | 0/6 | 30±0 | 0±0 | 0±0 | |
| 0.5 | 0/6 | 30±0 | 0±0 | 0±0 | ||
| 5 | 0/6 | 30±0 | 0±0 | 0±0 | ||
| Vomiting | Contrast a) | - | 3/3 | 4±1 | 7±3 | 4±2 |
| I-1 | 0.05 | 0/6 | 30±0 | 0±0 | 0±0 | |
| 0.5 | 0/6 | 30±0 | 0±0 | 0±0 | ||
| 5 | 0/6 | 30±0 | 0±0 | 0±0 | ||
| Feel sick+vomiting | Contrast a) | - | 3/3 | 3±1 | 9±2 | 51±14 |
| I-1 | 0.05 | 0/6 | 30±0 | 0±0 | 0±0 | |
| 0.5 | 0/6 | 30±0 | 0±0 | 0±0 | ||
| 5 | 0/6 | 30±0 | 0±0 | 0±0 |
Each value is represented with mean+/-standard error.
A): contain 15%N, 15%Solutol (registered trade mark) HS15, the 0.25ml/kg of N-dimethyl acetylamide, 5%N-methylglucosamine
By above result as can be known, chemical compound (I) is for showing antagonism by feeling sick of giving that morphine brings out, vomiting.
2 dividing a word with a hyphen at the end of a line property of the brain tests of test example
1) test-compound
Used the mesylate of chemical compound (I-1).
2) using animal: Crj:CD (SD) IGS is 7 ages in week of male rat
3) give test fluid
In the 1mg test-compound, add 600 μ l N,N-dimethylacetamide (DMAA), make its dissolving, add 1.4ml propylene glycol (PG) then, fully stir.
4) gather sample: blood and brain
*
5) test method
Give test-compound with 0.5mg/ml/kg to not jejunitas rat (n=2) intravenous, give to take a blood sample by jugular vein after 30 minutes.Measure in brain and the blood plasma the not concentration of changing matter, calculating K p value.
Need to prove that rat, will be taken a blood sample and insert in the right jugular vein with flexible pipe during first three day in test, the normal raising.
6) sample processing method
Blood carries out centrifugalize (3000rpm, 10 minutes, 4 ℃), then isolating whole blood plasma is packed in the test tube, and brain is the form with 25% homogenate, by the LC/MS/MS standard measure.
7) result
Obtaining the Kp value by the concentration of gained, is 0.03.
Hence one can see that, and chemical compound of the present invention is difficult to by blood brain barrier, can not suppress the analgesic activity of opioid recdptor agonist, can alleviate feeling sick, vomitting as side effect.The assay method that combines of test example 3 and opioid recdptor
1) in conjunction with the preparation of measuring with film mark product
The rat brain (Slc:SD) that is kept at-80 ℃ is used for test.The 10mM Tris-HCl buffer (pH 7.0) that adds 20 times of ice-cooled amounts in the brain that has carried out gravimetry carries out homogenate (25000rpm, 30 seconds) with ヒ ス ト コ ロ Application (NITI-ON), with 36600 * g centrifugation 20 minutes.In the gained granule, add the identical buffer of 15ml, carry out ヒ ス ト コ ロ Application equally and handle centrifugation then.This washing operation is implemented twice.After the centrifugation, in the gained granule, add 15ml 50mM Tris-HCl buffer (pH 7.4), carry out ヒ ス ト コ ロ Application and handle, resuspending in this buffer of final 10 times of amounts, with it as membrane component (Life Sci.48,111～116,1991) slightly.The film specimen of preparation-80 ℃ of freezing preservations, is melted rapidly at the trial, carry out centrifugal and ヒ ス ト コ ロ Application same as described above and handle, use 50mM Tris-HCl buffer (pH 7.4) to be diluted to about 900 μ g/ml then, be used for testing.The determination of protein concentration of film specimen uses Micro BCA protein determination kit (PIERCE).
2) the δ receptors bind is measured implementation method and data analysis
In 10 μ l test-compounds of 10 times of segmentation dilutions, add 10 μ l ultimate densities and be 3nM [
3H]-DADLE (51.5Ci/mmol:PerkinElmer) is as part.To be added with 100mM choline chloride, 3mM MnCl
2Pack in the test tube with the 480 μ l rat brain membrane components of 100nM DAMGO, 25 ℃ of following incubations 2 hours.Behind the incubation, on the Whatman GF/C filter of handling with 0.5% polymine in advance, carry out suction strainer, with ice-cooled 2.5ml10mM Tris-HCl buffer (pH 7.4) washing four times.After the washing, filter is transferred in little phial that liquid scintillation counter uses, adds 5ml scintillator (Cleasol I), standing over night uses liquid scintillation counter Tri-Carb 2200CA (PACKARD) to measure 3 minutes radioactivity then.Use DMSO when mensuration is used for the total binding (TB) of data analysis, use 20 μ M levallorphans when measuring non-specific binding (NB), the Ki value of test-compound is used in advance KD value (2.93nM) calculating of the part of obtaining by the Scatchard map analysis.
The result is as shown in table 2.
[table 2]
| Chemical compound | Ki(nM) |
| I-1 | 0.62 |
| I-2 | 1.7 |
| I-3 | 1.06 |
| I-4 | 1.14 |
| I-8 | 1.38 |
| I-9 | 1.25 |
Formulation example 1
Preparation contains the granule of following composition.
Chemical compound 10mg shown in the empirical formula (I)
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
1000mg
Chemical compound shown in the formula (I) and lactose are crossed 60 purposes sieve.Corn starch is crossed 120 purposes sieve.They are mixed with V-Mixer.In mixed-powder, add HPC-L (low viscosity hyprolose) aqueous solution, carry out mixing, granulate (extrusion granulator, aperture 0.5～1mm), drying steps.The gained dried particles is sieved with vibrosieve (12/60), obtain granule.
Formulation example 2
Preparation contains the capsule filling granule of following composition.
Chemical compound 15mg shown in the empirical formula (I)
Lactose 90mg
Corn starch 42mg
HPC-L 3mg
150mg
Chemical compound, lactose shown in the formula (I) are crossed 60 purposes sieve.Corn starch is crossed 120 purposes sieve.They are mixed, in mixed-powder, add HPC-L solution, carry out mixing, granulation, drying.The gained dried particles is carried out granulate, then 150mg is filled in No. 4 hard gelatin capsules.
Formulation example 3
Preparation contains the tablet of following composition.
Chemical compound 10mg shown in the empirical formula (I)
Lactose 90mg
Microcrystalline Cellulose 30mg
CMC-Na 15mg
Magnesium stearate 5mg
150mg
Chemical compound shown in the formula (I), lactose, microcrystalline Cellulose, CMC-Na (sanlose) are crossed 60 purposes sieve, mix.In mixed-powder, mix magnesium stearate, obtain the film-making mixed-powder.With this mixed-powder direct compression, obtain the tablet of 150mg.
Formulation example 4
With the mixing of heating of following composition, injection is made in sterilization then.
Chemical compound 3mg shown in the empirical formula (I)
Non-ionic surface active agent 15mg
Injection pure water 1ml
Industrial applicability
Compound of the present invention can be used as feel sick and/or vomiting treat and/or prevent medicine, and the alleviating and/or preventive medicine of the side effect of opioid recdptor activator.
Claims (17)
1. the chemical compound shown in the formula (I) or its pharmaceutically acceptable salt or their solvate:
In the formula, R
1For hydrogen or-CHR
AR
B, R wherein
ABe group shown in elementary alkoxy carbonyl oxygen base, cyclo alkoxy carbonyl oxygen base, acyloxy or the following formula,
R in the formula
2For hydrogen maybe can have substituent low alkyl group;
R
BBe hydrogen or methyl.
2. the chemical compound of claim 1 or its pharmaceutically acceptable salt or their solvate, wherein R
1Be hydrogen.
3. pharmaceutical composition is characterized in that: the chemical compound or its pharmaceutically acceptable salt or their solvate that contain claim 1.
4. opioid receptor antagonists is characterized in that: the chemical compound or its pharmaceutically acceptable salt or their solvate that contain claim 1.
5. the pharmaceutical composition of claim 3, wherein, the chemical compound of claim 2 or its pharmaceutically acceptable salt or their solvate are active constituents of medicine.
6. the pharmaceutical composition of claim 3, its be feel sick and/or vomiting treat and/or prevent medicine.
7. the pharmaceutical composition of claim 3, it is alleviating and/or preventive drug by the side effect that chemical compound brought out with opioid recdptor agonism.
Claim 7 treat and/or prevent medicine, wherein side effect is to feel sick and/or vomiting.
Claim 7 or 8 treat and/or prevent medicine, the chemical compound that wherein has the opioid recdptor agonism is morphine, oxycodone, their pharmaceutically acceptable salt or their solvate.
10. claim 1 or 2 chemical compound or its pharmaceutically acceptable salt or their solvate have application in the medicine of opioid recdptor antagonism in preparation.
11. the chemical compound of claim 1 or 2 or its pharmaceutically acceptable salt or their solvate are used for the application of the medicine that treats and/or prevents of disgusting and/or vomiting in preparation.
12. the chemical compound of claim 1 or 2 or its pharmaceutically acceptable salt or their solvate are used for alleviating and/or prevent application by the medicine of the side effect that chemical compound brought out with opioid recdptor agonism in preparation.
13. suppress the method for opioid recdptor, it is characterized in that: the chemical compound or its pharmaceutically acceptable salt or their solvate that give claim 1 or 2.
14. the method that treats and/or prevents of feeling sick and/or vomitting is characterized in that: the chemical compound or its pharmaceutically acceptable salt or their solvate that give claim 1 or 2.
15. alleviate and/or prevent method, it is characterized in that: the chemical compound or its pharmaceutically acceptable salt or their solvate that give claim 1 or 2 by the side effect that chemical compound brought out with opioid recdptor agonism.
16. analgesic, it is the chemical compound that will have the opioid recdptor agonism, is combined by the chemical compound of the claim 1 of the effective dose that gives the side effect that this chemical compound brings out or 2 or its pharmaceutically acceptable salt or their solvate with alleviating and/or prevent.
17. analgesic, it is the chemical compound that will have the opioid recdptor agonism, is combined by the chemical compound of the claim 1 that gives the effective dose of feeling sick and/or vomitting that this chemical compound brings out or 2 or its pharmaceutically acceptable salt or their solvate with being used for the treatment of and/or prevent.
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