CN103599155A - Novel method for treating migraine - Google Patents

Novel method for treating migraine Download PDF

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CN103599155A
CN103599155A CN201310618515.3A CN201310618515A CN103599155A CN 103599155 A CN103599155 A CN 103599155A CN 201310618515 A CN201310618515 A CN 201310618515A CN 103599155 A CN103599155 A CN 103599155A
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extract
radix raphani
described medicine
preparation
formula
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CN103599155B (en
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傅卫国
梅丹
王伟
朱家勇
吴舜彬
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Guangdong Jian Jian Pharmaceutical Co.,Ltd.
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GUANGZHOU ANJIAN INDUSTRIAL DEVELOPMENT Co Ltd
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Priority to CN201510396957.7A priority patent/CN104922127B/en
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Abstract

The invention relates to a novel method for treating migraine, and in particular relates to use of a radish extract in preparing a medicine for treating and/or preventing migraine and complications thereof. The invention further relates to use of a compound shown as formula 1 and a compound shown as formula 2 in preparing a medicine for treating and/or preventing migraine and complications thereof. Use of the extract or the compounds for treating and/or preventing migraine and complications thereof has already been found.

Description

Treat migrainous new method
Technical field
The invention belongs to medical technical field, relate to the migrainous new method for the treatment of, particularly relate to Radix Raphani extract or monomeric compound therefrom and treat migrainous new method.The invention still further relates to Radix Raphani extract or monomeric compound therefrom and treat and/or prevent the purposes in the medicine of migraine and complication thereof in preparation.
Background technology
Migraine is a kind of pulsatile headache of repeatedly showing effect, and belongs to " rich and influential family " in numerous headache types.Before outbreak, often there are the tendencys such as flash of light, blurred vision, numb limbs and tense tendons, simultaneously can be with neural, mental function disorder.It is a kind of disease that can progressively worsen, and frequency of disease development is conventionally more and more higher.
There is to about one hour the pain that a side head one is jumped in migraine approximate number minute, and aggravation gradually, until occur to feel sick, after vomiting, sensation just have take a turn for the better.In peace and quiet, dark surrounds or after sleep, headache is alleviated.Can be with neural, mental function disorder before headache occurs or while showing effect.Showing according to the study, more easily there is brain local damage in migraineur than usual people, and then causes apoplexy.Its migrainous number of times is more, and the region of brain damaged can be larger.
Migraine mainly comprises typicality migraine, common migraine and gathering together property migraine three major types.Typicality migraine feature is that most patients are periodical attack, and women is common.Can there is blurred vision, flash of light, photis, blind spot, ophthalmic bloated, emotional lability in premorbid most patients, nearly all patient keeps in dark place, and occurs a side headache after several minutes, and the positions such as great majority be take around head front portion, temples, eye socket, temple are as main.Can limit to a certain position, also can expand and prolong whole half sidely, during severe headache, can have vascular pulsation sense or eyeball to jump out sense.Pain generally peaked at 1～2 hour, continued 4～6 hours or tens hours, and severe one can be lasted a couple of days, and patient's headache is very painful unbearably.Common migraine accounts for migraineur's 80%, more common, premorbid can not have obvious premonitory symptom, has part patient in performances such as premorbid spiritedness obstacle, fatigue, yawn, inappetence, general malaises yet, women's menstrual onset, drink, also can Provocative pain when on an empty stomach hungry.Have a headache to be slowly more and increase the weight of, painful area can be a side or bilateral, and what also have is whole head, and the degree of pain is also light compared with typicality migraine.The migrainous feature of gathering together property is there is no premonitory symptom, and the time of each outbreak is roughly the same.Headache often starts suddenly, continues 30～120 minutes, in one day, can occur repeatedly, and clinical manifestation can occur that eye socket is swollen, shed tears, conjunctival congestion, nasal obstruction, perspiration, the burn feeling of pain side facial area etc., and it is thick, crooked etc. that the visible scalp vein of model case increases.In addition, migraine also comprises family's hemiplegic migraine, stomachache property migraine, neuropsychiatric migraine, BAM, retinal migraine and Menstrual migraine etc.
The conventional migrainous medicine that treats and/or prevents mainly contains the chemicals such as aspirin, ibuprofen, Ergotamine preparation, sumatriptan, Propranolol, pizotifen, methysergide, nimodipine, flunarizine, sodium valproate, amitriptyline, clonidine at present, yet people still expect there is the new migrainous method that treats and/or prevents, and particularly with natural product, treat and/or prevent migrainous method.
Summary of the invention
The object of the present invention is to provide and a kind ofly with natural product, treat and/or prevent migrainous method.The inventor finds to use Radix Raphani extract can effectively treat and/or prevent migraine and complication thereof or alleviate cephalagra.The present invention is based on this discovery and be accomplished.
For this reason, first aspect present invention provides Radix Raphani extract to treat and/or prevent the purposes in the medicine of migraine and complication thereof in preparation.
According to the purposes of first aspect present invention, wherein said Radix Raphani extract is the extract that Radix Raphani water extract or Radix Raphani juice obtain through n-butanol extraction.
According to the purposes of first aspect present invention, wherein said Radix Raphani extract is that Radix Raphani water extract or Radix Raphani juice are through being condensed into concentrated solution, or water suspendible becomes suspension after concentrate drying, the extract that gained concentrated solution or suspension further obtain through n-butanol extraction.
According to the purposes of first aspect present invention, wherein said Radix Raphani extract is that Radix Raphani water extract or Radix Raphani juice are through being condensed into concentrated solution, or after concentrate drying, water suspendible becomes suspension, gained concentrated solution or suspension further extract through following solvents successively: normal hexane, dichloromethane, ethyl acetate and n-butyl alcohol, and by the concentrated extract obtaining of n-butanol portion warp.
According to the purposes of first aspect present invention, wherein said Radix Raphani extract is that Radix Raphani water extract or Radix Raphani juice are through being condensed into concentrated solution, or after concentrate drying, water suspendible becomes suspension, gained concentrated solution or suspension further extract through following solvents successively: normal hexane (3 times), dichloromethane (3 times), ethyl acetate (3 times) and n-butyl alcohol (3 times), and by the concentrated extract obtaining of n-butanol portion warp of merging.
According to the purposes of first aspect present invention, wherein said concentrated solution or suspension, the weight that its every 1L is equivalent to fresh Radix Raphani is 20～100kg, for example 20～80kg, for example 30～75kg.
According to the purposes of first aspect present invention, volume ratio between wherein said concentrated solution or suspension and described extractant is that those skilled in the art rule of thumb can easily determine, and extractant consumption may affect extraction efficiency, but do not affect the essence that the invention provides new pharmaceutical applications.For example water (being concentrated solution or suspension) can be 1:(0.2～5 with the volume ratio of organic facies (being extractant)), be for example 1:(0.25～5), be for example 1:(0.5～5).
According to the purposes of first aspect present invention, wherein when extraction, every kind of extractant extracts 1～5 time, and for example 2～4 times, for example 3 times.Extraction times is also that those skilled in the art rule of thumb can easily determine, and extraction times may affect extraction efficiency, but does not affect the essence that the invention provides new pharmaceutical applications.
According to the purposes of first aspect present invention, wherein said Radix Raphani extract give mammal for example every daily dose of people normally with the amount of effective dose, use.In one embodiment, be the amount use can effectively treat and/or prevent migraine and complication thereof or to alleviate cephalagra.In one embodiment, be to use can effectively alleviate or alleviate the amount of cephalagra.In one embodiment, every daily dose that Radix Raphani extract is grown up, is converted to the weight of fresh Radix Raphani, is 0.001-1000g, for example 0.01-500g, for example 0.1-100g, for example 0.5-50g, for example 0.5-25g, for example 0.5-10g, for example 0.5-5g, for example 1-2g.In one embodiment, every daily dose that Radix Raphani extract is grown up, is converted to the weight of fresh Radix Raphani, is 0.001-1000g, for example 0.01-500g, for example 0.1-100g, for example 0.5-50g, for example 0.5-25g, for example 2-25g, for example 5-25g, for example 10-25g.In one embodiment, every daily dose that Radix Raphani extract is grown up, is converted to the weight of fresh Radix Raphani, is 0.01-1000g, for example 0.1-500g, for example 1-100g, for example 5-100g, for example 10-100g.
According to the purposes of first aspect present invention, wherein said medicine is preparations for oral administration or topical preparation.In one embodiment, described medicine is topical preparation.In one embodiment, described medicine is pernasal preparation.In one embodiment, described medicine is liquid or semi-solid preparation.In one embodiment, described medicine is solution or gel.In one embodiment, described medicine is selected from spray, nasal drop, gel, the agent of plug nose.
According to the purposes of first aspect present invention, wherein said medicine is the liquid preparation form that is nasal drop or nasal spray.
According to the purposes of first aspect present invention, when wherein said nasal drop or nasal spray give people experimenter, each dosage of this nasal drop or nasal spray can be 10-500ul, is preferably 10-250ul, more preferably 50-250ul.
According to the purposes of first aspect present invention, in the every ml of the liquid dosage form of wherein said nasal drop or nasal spray, the amount that contains Radix Raphani extract, is converted to the weighing scale of fresh Radix Raphani, is 1-1000g, for example 10-500g, for example 25-250g, for example 50-200g.
Further, the inventor extracts and obtains with following formula 1 compound from Radix Raphani,
Figure BDA0000423772670000041
Have been surprisingly found that, this formula 1 compound has significant migraine effect.
For this reason, second aspect present invention provides with following formula 1 compound and has treated and/or prevented the purposes in the medicine of migraine and complication thereof in preparation
Figure BDA0000423772670000042
Formula 1 compound, its CAS registration number 1310411-24-5, its chemistry is by name: (2S)-1-Methyl-2-azetidinemethanol, i.e. (2S)-1-methyl-2-azetidine methanol.
According to the purposes of second aspect present invention, wherein said formula 1 compound give mammal for example every daily dose of people normally with the amount of effective dose, use.In one embodiment, be the amount use can effectively treat and/or prevent migraine and complication thereof or to alleviate cephalagra.In one embodiment, be to use can effectively alleviate or alleviate the amount of cephalagra.In one embodiment, every daily dose that formula 1 compound is grown up, is 0.01-1000mg, for example 0.1-500mg, for example 0.1-250mg, for example 1-100mg.In one embodiment, every daily dose that formula 1 compound is grown up, is 0.1-1000mg, for example 1-500mg, for example 5-500mg, for example 10-500mg.In one embodiment, every daily dose that formula 1 compound is grown up, is 0.1-1000mg, for example 1-500mg, for example 5-250mg, for example 10-200mg.
According to the purposes of second aspect present invention, wherein said medicine is preparations for oral administration or topical preparation.In one embodiment, described medicine is preparations for oral administration, and in one embodiment, described medicine is the form that is tablet or capsule.In one embodiment, described medicine is topical preparation.In one embodiment, described medicine is pernasal preparation.In one embodiment, described medicine is liquid or semi-solid preparation.In one embodiment, described medicine is solution or gel.In one embodiment, described medicine is selected from spray, nasal drop, gel, the agent of plug nose.
Further, the inventor extracts and obtains with following formula 2 compounds from Radix Raphani,
Figure BDA0000423772670000051
Have been surprisingly found that, these formula 2 compounds have significant migraine effect.
For this reason, third aspect present invention provides with following formula 2 compounds and has treated and/or prevented the purposes in the medicine of migraine and complication thereof in preparation
Figure BDA0000423772670000052
Formula 2 compounds, its CAS registration number 286856-07-3, its chemistry is by name: 3,6-bis (1,1-dimethylethyl)-2,5-Piperazinedione, 3,6-bis-(1,1-dimethyl ethyl)-2,5-piperazinedione.
According to the purposes of second aspect present invention, wherein said formula 2 compounds give mammal for example every daily dose of people normally with the amount of effective dose, use.In one embodiment, be the amount use can effectively treat and/or prevent migraine and complication thereof or to alleviate cephalagra.In one embodiment, be to use can effectively alleviate or alleviate the amount of cephalagra.In one embodiment, every daily dose that formula 2 compounds are grown up, is 0.01-1000mg, for example 0.1-500mg, for example 0.1-250mg, for example 1-100mg.In one embodiment, every daily dose that formula 2 compounds are grown up, is 0.1-1000mg, for example 1-500mg, for example 5-500mg, for example 10-500mg.In one embodiment, every daily dose that formula 2 compounds are grown up, is 0.1-1000mg, for example 1-500mg, for example 5-250mg, for example 10-200mg.
According to the purposes of second aspect present invention, wherein said medicine is preparations for oral administration or topical preparation.In one embodiment, described medicine is preparations for oral administration, and in one embodiment, described medicine is the form that is tablet or capsule.In one embodiment, described medicine is topical preparation.In one embodiment, described medicine is pernasal preparation.In one embodiment, described medicine is liquid or semi-solid preparation.In one embodiment, described medicine is solution or gel.In one embodiment, described medicine is selected from spray, nasal drop, gel, the agent of plug nose.
Fourth aspect present invention provides a kind of pharmaceutical composition that can be used for treating and/or preventing migraine and complication thereof, comprising Radix Raphani extract and optional pharmaceutically acceptable carrier or excipient.
According to the pharmaceutical composition of fourth aspect present invention, wherein said Radix Raphani extract is the extract that Radix Raphani water extract or Radix Raphani juice obtain through n-butanol extraction.
According to the pharmaceutical composition of fourth aspect present invention, wherein said Radix Raphani extract is that Radix Raphani water extract or Radix Raphani juice are through being condensed into concentrated solution, or water suspendible becomes suspension after concentrate drying, the extract that gained concentrated solution or suspension further obtain through n-butanol extraction.
According to the pharmaceutical composition of fourth aspect present invention, wherein said Radix Raphani extract is that Radix Raphani water extract or Radix Raphani juice are through being condensed into concentrated solution, or after concentrate drying, water suspendible becomes suspension, gained concentrated solution or suspension further extract through following solvents successively: normal hexane, dichloromethane, ethyl acetate and n-butyl alcohol, and by the concentrated extract obtaining of n-butanol portion warp.
According to the pharmaceutical composition of fourth aspect present invention, wherein said Radix Raphani extract is that Radix Raphani water extract or Radix Raphani juice are through being condensed into concentrated solution, or after concentrate drying, water suspendible becomes suspension, gained concentrated solution or suspension further extract through following solvents successively: normal hexane (3 times), dichloromethane (3 times), ethyl acetate (3 times) and n-butyl alcohol (3 times), and by the concentrated extract obtaining of n-butanol portion warp of merging.
According to the pharmaceutical composition of fourth aspect present invention, wherein said concentrated solution or suspension, the weight that its every 1L is equivalent to fresh Radix Raphani is 20～100kg, for example 20～80kg, for example 30～75kg.
According to the pharmaceutical composition of fourth aspect present invention, volume ratio between wherein said concentrated solution or suspension and described extractant is that those skilled in the art rule of thumb can easily determine, and extractant consumption may affect extraction efficiency, but do not affect the essence that the invention provides new pharmaceutical applications.For example water (being concentrated solution or suspension) can be 1:(0.2～5 with the volume ratio of organic facies (being extractant)), be for example 1:(0.25～5), be for example 1:(0.5～5).
According to the pharmaceutical composition of fourth aspect present invention, wherein when extraction, every kind of extractant extracts 1～5 time, and for example 2～4 times, for example 3 times.Extraction times is also that those skilled in the art rule of thumb can easily determine, and extraction times may affect extraction efficiency, but does not affect the essence that the invention provides new pharmaceutical applications.
According to the pharmaceutical composition of fourth aspect present invention, it is preparations for oral administration or topical preparation.In one embodiment, described pharmaceutical composition is topical preparation.In one embodiment, described pharmaceutical composition is pernasal preparation.In one embodiment, described pharmaceutical composition is liquid or semi-solid preparation.In one embodiment, described pharmaceutical composition is solution or gel.In one embodiment, described pharmaceutical composition is selected from spray, nasal drop, gel, the agent of plug nose.
According to the pharmaceutical composition of fourth aspect present invention, wherein said pharmaceutical composition is the liquid preparation form that is nasal drop or nasal spray.
According to the pharmaceutical composition of fourth aspect present invention, when wherein said nasal drop or nasal spray give people experimenter, each dosage of this nasal drop or nasal spray can be 10-500ul, is preferably 10-250ul, more preferably 50-250ul.
According to the pharmaceutical composition of fourth aspect present invention, in the every ml of the liquid dosage form of wherein said nasal drop or nasal spray, the amount that contains Radix Raphani extract, is converted to the weighing scale of fresh Radix Raphani, is 1-1000g, for example 10-500g, for example 25-250g, for example 50-200g.
Further, fifth aspect present invention provides a kind of pharmaceutical composition that can be used for treating and/or preventing migraine and complication thereof, comprising with following formula 1 compound and optional pharmaceutically acceptable carrier or excipient,
Figure BDA0000423772670000071
According to the pharmaceutical composition of fifth aspect present invention, wherein said formula 1 compound give mammal for example every daily dose of people normally with the amount of effective dose, use.In one embodiment, be the amount use can effectively treat and/or prevent migraine and complication thereof or to alleviate cephalagra.In one embodiment, be to use can effectively alleviate or alleviate the amount of cephalagra.In one embodiment, every daily dose that formula 1 compound is grown up, is 0.01-1000mg, for example 0.1-500mg, for example 0.1-250mg, for example 1-100mg.In one embodiment, every daily dose that formula 1 compound is grown up, is 0.1-1000mg, for example 1-500mg, for example 5-500mg, for example 10-500mg.In one embodiment, every daily dose that formula 1 compound is grown up, is 0.1-1000mg, for example 1-500mg, for example 5-250mg, for example 10-200mg.
According to the pharmaceutical composition of fifth aspect present invention, wherein said pharmaceutical composition is preparations for oral administration or topical preparation.In one embodiment, described pharmaceutical composition is preparations for oral administration, and in one embodiment, described pharmaceutical composition is the form that is tablet or capsule.In one embodiment, described pharmaceutical composition is topical preparation.In one embodiment, described pharmaceutical composition is pernasal preparation.In one embodiment, described pharmaceutical composition is liquid or semi-solid preparation.In one embodiment, described pharmaceutical composition is solution or gel.In one embodiment, described pharmaceutical composition is selected from spray, nasal drop, gel, the agent of plug nose.
Further, sixth aspect present invention provides a kind of pharmaceutical composition that can be used for treating and/or preventing migraine and complication thereof, comprising with following formula 2 compounds and optional pharmaceutically acceptable carrier or excipient,
According to the pharmaceutical composition of sixth aspect present invention, wherein said formula 2 compounds give mammal for example every daily dose of people normally with the amount of effective dose, use.In one embodiment, be the amount use can effectively treat and/or prevent migraine and complication thereof or to alleviate cephalagra.In one embodiment, be to use can effectively alleviate or alleviate the amount of cephalagra.In one embodiment, every daily dose that formula 2 compounds are grown up, is 0.01-1000mg, for example 0.1-500mg, for example 0.1-250mg, for example 1-100mg.In one embodiment, every daily dose that formula 2 compounds are grown up, is 0.1-1000mg, for example 1-500mg, for example 5-500mg, for example 10-500mg.In one embodiment, every daily dose that formula 2 compounds are grown up, is 0.1-1000mg, for example 1-500mg, for example 5-250mg, for example 10-200mg.
According to the pharmaceutical composition of sixth aspect present invention, wherein said pharmaceutical composition is preparations for oral administration or topical preparation.In one embodiment, described pharmaceutical composition is preparations for oral administration, and in one embodiment, described pharmaceutical composition is the form that is tablet or capsule.In one embodiment, described pharmaceutical composition is topical preparation.In one embodiment, described pharmaceutical composition is pernasal preparation.In one embodiment, described pharmaceutical composition is liquid or semi-solid preparation.In one embodiment, described pharmaceutical composition is solution or gel.In one embodiment, described pharmaceutical composition is selected from spray, nasal drop, gel, the agent of plug nose.
The feature that arbitrary embodiment of either side of the present invention or this either side has is equally applicable to arbitrary other embodiment of this aspect, also be equally applicable to arbitrary embodiment of other either side or this other either side, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.
Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
Radix Raphani has another name called Radix Raphani ,Cai Tou， platymiscium circle, Cruciferae, Rhaphanus.Root meat, Long Circle, spherical or conical, root bark redness, green, white, pink or purple.Stem is upright, sturdy, cylindrical, and hollow, from base portion branch.Originate in China, all there is cultivation various places, and kind is extremely many, and common have Radix Dauci Sativae, green turnip, white turnip, summer radish and a red flesh etc.In the present invention, the term of mentioning " Radix Raphani " refers to the root of Radix Raphani.Especially, in the present invention, the term of mentioning " Radix Raphani " refers to the root of green turnip or white turnip.
In the present invention, the term of mentioning " complication ", migrainous complication, includes but not limited to the various symptoms relevant with migraine, such as but not limited to nauseating, vomiting, blurred vision, flash of light, photis, blind spot, ophthalmic bloated etc.
In the present invention, term " Radix Raphani extract " comprises the extract, particularly Radix Raphani extract as described in either side of the present invention that Radix Raphani obtains through any formal layout.
In the present invention, term " dry Radix Raphani " and " dry Radix Raphani ", the two is used interchangeably, they refer to Radix Raphani of the present invention, are optionally shredded, then through super-dry, such as drying, the mode such as oven dry, moisture content is wherein dropped to lower than 30%, for example, lower than 20%, for example, lower than 15%, 1-15% for example, 2-10% for example, 5-10% for example, the Radix Raphani being substantially dried obtaining thus.
In the present invention, every daily dose that described Radix Raphani extract gives people is normally used with the amount of effective dose.In one embodiment, be the amount use can effectively treat and/or prevent migraine and complication thereof or to alleviate cephalagra.In one embodiment, be to use can effectively alleviate or alleviate the amount of cephalagra.In one embodiment, every daily dose that Radix Raphani extract is grown up, is converted to the weight of fresh Radix Raphani, is 0.001-1000g, for example 0.01-500g, for example 0.1-100g, for example 0.5-50g, for example 0.5-25g, for example 0.5-10g, for example 0.5-5g, for example 1-2g.In one embodiment, every daily dose that Radix Raphani extract is grown up, is converted to the weight of fresh Radix Raphani, is 0.001-1000g, for example 0.01-500g, for example 0.1-100g, for example 0.5-50g, for example 0.5-25g, for example 2-25g, for example 5-25g, for example 10-25g.
In one embodiment, Radix Raphani extract gives people experimenter with the solution dosage of nasal drop or nasal spray, and each dosage of this nasal drop can be 10-500ul, is preferably 10-250ul, more preferably 20-200ul.In one embodiment, in the every ml of solution dosage of this nasal drop or nasal spray, the amount that contains Radix Raphani extract, is converted to the weighing scale of fresh Radix Raphani, for 0.001-1000g, for example 0.01-500g, for example 0.1-100g, for example 0.5-50g, 0.5-25g for example, for example 0.5-10g, for example 0.5-5g, for example 1-2g.In one embodiment, in the every ml of the solution dosage of this nasal drop or nasal spray, the amount that contains Radix Raphani extract, be converted to the weighing scale of fresh Radix Raphani, for 0.1-100g, for example 0.5-50g, for example 0.5-25g, 2-25g for example, for example 5-25g, for example 10-25g, for example 0.5-10g, for example 0.5-5g, for example 1-2g.
As described herein, term " effective dose " refers to and can in experimenter, realize the object dosage that prevents and/or treats disease of the present invention.Those skilled in the art, according to the context of the invention, can easily determine the using dosage of active component.Especially, according to the present invention, term " effective dose " can be understood as the Radix Raphani extract form of the compositions that comprises Radix Raphani extract (or with) with reasonable effect/risk of being applicable to any therapeutic treatment than sanatory q.s.But the total consumption per day that it should be understood that Radix Raphani extract of the present invention or its compositions can maked decision within the scope of medical judgment reliably by those skilled in the art.For any concrete experimenter, concrete prevention effective dose level must be determined according to many factors, and described factor comprises experimenter's age, body weight, general health situation, sex and diet; The concrete compositions adopting; Other therapeutic active substance of using or use simultaneously with Radix Raphani extract combination; And the known similar factor of medical field.
As described herein, term " pharmaceutical composition ", its can with " compositions " Alternate, wherein comprise active component Radix Raphani extract and optional pharmaceutically acceptable carrier or excipient.
As described herein, term " experimenter ", also can refer to " patient ", take this Radix Raphani extract " user " etc., the compositions that can refer to accept Radix Raphani extract of the present invention or comprise Radix Raphani extract is to prevent and/or treat the animal of disease of the present invention, mammal particularly, such as people, Canis familiaris L., monkey, cattle, horse etc.
As described herein, " % (w/w) ", unless otherwise noted, refers to the percentage ratio of weight by weight.
The invention provides the pharmaceutical composition that comprises the Radix Raphani extract formulated together with one or more nontoxic pharmaceutically acceptable carriers or formula 1 compound or formula 2 compounds.Described pharmaceutical composition can be mixed with especially specially with semisolid or liquid for oral administration or topical, particularly via intranasal application topical of liquid form particularly.In one embodiment, described Radix Raphani extract or formula 1 compound or formula 2 compounds and pharmaceutically acceptable carrier or excipient are mixed with the medicament for nasal-cavity administration, described pharmaceutically acceptable carrier or excipient such as but not limited to water, antiseptic agent if nipalgin alkyl esters, auxiliary agent such as propylene glycol, osmotic pressure regulator are if sodium chloride, thickening agent are as PVP-k30 etc.In addition, pharmaceutical composition of the present invention can be the form of Emulsion, solution or suspensoid.Pharmaceutical composition of the present invention can adopt and well known to a person skilled in the art routine techniques, by Radix Raphani extract of the present invention or formula 1 compound or formula 2 compounds, is that active component one of (or active component) preparation obtains.
The active substance of gained or reactive compound amount can change the actual dose level of each active component in pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response for concrete patient, compositions and administering mode.Dosage level must according to the activity of concrete active substance or compound, route of administration, the order of severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and medical history select.But the way of this area is, the dosage of active substance or compound is from lower than level that required therapeutic effect requires, increasing gradually dosage, until obtain required effect for obtaining.
When treating and/or preventing or other treatment and/or when prevention for above-mentioned, a kind of the compounds of this invention that treats and/or prevents effective dose can be applied with pure form, or with the acceptable ester of pharmacy or prodrug forms (in the situation that there are these forms) application.Or described compound can be accepted the pharmaceutical composition administration of excipient to contain this object compound and one or more medicines.The compounds of this invention that word " treats and/or prevents effective dose " refers to be applicable to the reasonable effect/risk of any therapeutic treatment and/or prevention than the compound of the q.s for the treatment of obstacle.But the total consumption per day that it should be understood that the compounds of this invention and compositions must maked decision within the scope of medical judgment reliably by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises the order of severity of treated obstacle He this obstacle; The activity of the particular compound adopting; The concrete compositions adopting; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound adopting, route of administration and excretion rate; The treatment persistent period; The medicine that is used in combination or uses simultaneously with adopted particular compound; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound is from lower than level that required therapeutic effect requires, increasing gradually dosage, until obtain required effect for obtaining.
Use the familiar pharmaceutical carrier of those skilled in the art can be prepared into the pharmaceutical composition containing the compounds of this invention of effective dose.Therefore the present invention also provides the pharmaceutical composition that comprises the compounds of this invention formulated together with one or more nontoxic drug acceptable carriers.That described pharmaceutical composition can be mixed with especially is specially for oral administration with solid or liquid form, for parenteral injection or for rectally.
Described pharmaceutical composition can be mixed with many dosage forms, is convenient to administration, for example, and oral formulations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, before injection, add injection water to use immediately).In described pharmaceutical composition, carrier comprises: the binding agent that oral formulations is used is (as starch, Semen Maydis normally, Semen Tritici aestivi or rice starch, gelatin, methylcellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone), diluent is (as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycerol), lubricant is (as silicon dioxide, Talcum, stearic acid or its salt, normally magnesium stearate or calcium stearate, and/or Polyethylene Glycol), if and needed, also contain disintegrating agent, as starch, agar, alginic acid or its salt, sodium alginate normally, and/or effervescent mixture, cosolvent, stabilizing agent, suspending agent, non-pigment, correctives etc., the antiseptic that injectable preparation is used, solubilizer, stabilizing agent etc., the substrate that topical formulations is used, diluent, lubricant, antiseptic etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenous, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under stomach condition, can be mixed with enteric coated tablets.
More particularly, pharmaceutical composition of the present invention can by oral, rectum, parenteral, pond, intravaginal, intraperitoneal, part (as by powder, ointment or drop), a mouthful cheek give the mankind and other mammals, or give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise intravenous, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and the administering mode of intra-articular injection and transfusion.
The compositions that is suitable for parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersant, suspensoid or Emulsion, and for the aseptic powder that reconstitutes sterile injectable solution agent or dispersant.Suitable moisture or nonaqueous carrier, diluent, solvent or vectorial example comprise that water, ethanol, polyhydric alcohol (propylene glycol, Polyethylene Glycol, glycerol etc.), vegetable oil (as olive oil), injectable organic ester are as ethyl oleate and their suitable mixture.
These compositionss also can contain adjuvant, as antiseptic, wetting agent, emulsifying agent and dispersant.By various antibacterial agents and antifungal, such as parabens, chlorobutanol, phenol, sorbic acid etc., can guarantee to prevent the effect of microorganism.Also expectation comprises isotonic agent, such as saccharide, sodium chloride etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin, can reach the prolongation absorption of injectable drug form.
In suspensoid, also can contain suspending agent except active ingredient beyond the region of objective existence, such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, bentonite, agar and Tragacanth or these materials partially.
In some cases, be the effect of prolong drug, expect to slow down absorption subcutaneous or intramuscular injection medicine.This can realize by the liquid suspension of the crystal with poorly water-soluble or amorphous substance.Like this, the infiltration rate of medicine depends on its dissolution velocity, and dissolution velocity can be depending on crystal size and crystal formation.Or, the delay of the medicament forms of parenteral absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.
Injectable depot formulations form can be prepared by form the microcapsule substrate of medicine in as polylactide-PGA (polylactide-polyglycolide) in biodegradable polymer.Can, according to the character of the ratio of medicine and polymer and the concrete polymer adopting, drug releasing rate be controlled.The example of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can by pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or microemulsion in prepare.
Injectable formulation can be for example by filtering or carry out sterilizing by mixing the biocide of aseptic solid composite form with bacteria filter, and described solid composite can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
The compounds of this invention or extract or its compositions can be by oral method or parenteral administration modes.Oral administration can be tablet, capsule, coating materials, and intestinal external application preparation has injection and suppository etc.These preparations are prepared according to method appreciated by those skilled in the art.In order to manufacture tablet, capsule, coating materials adjuvant used, it is the adjuvant of conventional use, for example starch, gelatin, arabic gum, Silicon stone, Polyethylene Glycol, liquid dosage form solvent used is as water, ethanol, propylene glycol, vegetable oil (as Semen Maydis oil, Oleum Arachidis hypogaeae semen, Fructus Canarii albi wet goods).In the preparation that contains the compounds of this invention, also has other adjuvant, surfactant for example, lubricant, disintegrating agent, antiseptic, correctives and pigment etc.The dosage that contains formula I compound of the present invention in tablet, capsule, coating materials, injection and suppository is that the compound amount existing in unit dosage form is calculated.In unit dosage form, the general content of formula I compound of the present invention is 0.01-5000mg, and preferred unit dosage form contains 0.1-500mg, and preferred unit dosage form contains 1-300mg.Specifically, the solid dosage forms for oral administration that the present invention can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage forms, reactive compound can be accepted excipient or carrier with the medicine of at least one inertia and mix as sodium citrate or dicalcium phosphate and/or following material: a) filler or extender are as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) binding agent is as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and Radix Acaciae senegalis; C) wetting agent is as glycerol; D) disintegrating agent is as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and sodium carbonate; E) solution blocker is as paraffin; F) absorb accelerator as quaternary ammonium compound; G) wetting agent is as spermol and glyceryl monostearate; H) adsorbent is as Kaolin and bentonite and i) lubricant is as Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.The in the situation that of capsule, tablet and pill, in described dosage form, also can comprise buffer agent.
The solid composite of similar type is used such as lactose and high molecular weight polyethylene glycol etc. of excipient, also can be used as the implant in soft capsule and hard capsule.
The solid dosage forms of tablet, dragee (dragees), capsule, pill and granule can be prepared together with coating and shell material other clothing materials as known in enteric coating material and field of medicine preparations.These solid dosage formss can optionally contain opacifier, and its form also can make it just or preferentially at certain position of intestinal optionally with delayed mode release of active ingredients.The example of operable embedding composition comprises polymer substance and wax class.If be applicable to, reactive compound also can be made into microcapsule form with one or more above-mentioned excipient.
Liquid dosage form for oral administration comprises the acceptable Emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain the conventional inert diluent in this area except containing reactive compound or extract, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), Polyethylene Glycol and the fatty acid ester of sorbitan and their mixture for example.Orally administered composition also can comprise adjuvant except comprising inert diluent, for example wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and flavouring agent.
The compositions of confession rectum or vagina administration is suppository preferably.Suppository can be by by the compounds of this invention and suitable non-irritating excipient or carrier, for example cocoa butter, Polyethylene Glycol or suppository wax mix to prepare, they are at room temperature solid, therefore but next at body temperature is liquid, can in rectal cavity or vaginal canal, melts and discharge reactive compound.
Compound of the present invention or extract and compositions thereof are also considered for topical.For the local dosage form that gives the compounds of this invention, comprise powder, spray, ointment and inhalant.Under aseptic condition by reactive compound and pharmaceutically acceptable carrier and any required antiseptic, buffer agent or propellants.Ophthalmic preparation, eye ointment, powder and solution are also considered within the scope of the present invention.
The compounds of this invention also can liposome form administration.As known in the art, liposome makes with phospholipid or other lipid materials conventionally.Liposome is formed by the single or multiple lift aquation liquid crystal being scattered in water-bearing media.On any nontoxic, physiology that can form liposome, can accept and metabolizable lipid all can be used.The present composition of liposome form, except containing the compounds of this invention, also can contain stabilizing agent, antiseptic, excipient etc.Preferred lipid is natural and synthetic phospholipid and phosphatidylcholine (lecithin), and they can use separately or together.The method that forms liposome is well known in the art.Referring to for example Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p.33.
The inventor finds that Radix Raphani extract of the present invention or formula 1 compound or formula 2 compounds have the effect that effectively treats and/or prevents migraine and complication thereof or alleviate cephalagra.
The specific embodiment
Below by specific embodiment/experimental example, further illustrate the present invention, still, should be understood to, these embodiment and experimental example are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention used, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and operational approach are well known in the art.
the preparation example part of A, extract and compound
preparation example 1: the juice squeezing from fresh Radix Raphani physics is prepared Radix Raphani extract
Fresh Radix Raphani (100kg) is squeezed to its juice (82kg), by this radish Juice concentrating under reduced pressure at 60 ℃, obtain dry extract (2424g).
Then this crude extract is suspended in to one-tenth suspension (3.3L) in water (2L), then uses successively normal hexane (3 times * 2L), dichloromethane (3 times * 2L), ethyl acetate (3 times * 2L) and n-butyl alcohol (3 times * 6L) extraction.By the n-butanol layer removal of solvent under reduced pressure merging, dry, obtain Radix Raphani extract.
In addition, normal hexane part wherein, dichloromethane part, ethyl acetate part merge respectively and removal of solvent under reduced pressure, dry, obtain respectively three kinds of Radix Raphani extracts, for follow-up biological test.
preparation example 2: the juice squeezing from fresh Radix Raphani physics is prepared Radix Raphani extract
Fresh Radix Raphani (75kg) is squeezed to its juice, this radish Juice concentrating under reduced pressure at 60 ℃ is become to concentrated solution (1L).
Then this concentrated solution is used successively to normal hexane (5L, 3L, 0.5L), dichloromethane (5L, 3L, 0.5L), ethyl acetate (5L, 3L, 0.5L) and n-butyl alcohol (3 times * 2L) extraction.By the n-butanol layer removal of solvent under reduced pressure merging, dry, obtain Radix Raphani extract.
preparation example 3: prepare Radix Raphani extract from dry Radix Raphani water extract
By the water boiling and extraction of 8 times of amounts 3 times for the Radix Raphani (10kg) that is dried to moisture to 8%, become every 1L to be equivalent to the concentrated solution of fresh Radix Raphani 50kg the water extraction liquid of merging concentrating under reduced pressure at 60 ℃.
Then this concentrated solution is used successively to normal hexane (1 times of volume, 3 times of volumes, 5 times of volumes), dichloromethane (2 times of volume * 1 time), ethyl acetate (2 times of volume * 2 time) and n-butyl alcohol (1 times of volume * 3 time) extraction.By the n-butanol layer removal of solvent under reduced pressure merging, dry, obtain Radix Raphani extract.
preparation example 4: preparation formula 1 compound and formula 2 compounds from Radix Raphani
According to preparation example 1 method, preparing end-product Radix Raphani extract is n-butyl alcohol fraction, is loaded into silicagel column (9 * 40cm; 200-300 order) on, carry out chromatography, gradient mixed liquor (100:1,100:2,100:3,100:5,100:7,100:15,100:20,100:30,100:50,100:75,100:100,75:100,50:100,25:100,0:100, water with methylene chloride-methanol, each 11L) carry out eluting, obtain 16 mix fraction (D-1, D-2 ..., D-16).
D-8 (1.817g) is loaded on silicagel column and carries out chromatography, obtain 9 fraction (D-8-1 to D-8-9).Fraction D-8-8 is loaded on silicagel column (Sephadex LH-20 post, 10 * 150mm) and carries out chromatography, uses methanol-eluted fractions to obtain 5 subfractions (D-8-8-1 to D-8-8-5).By preparation HPLC method, use 30% methanol/water to be further purified D-8-8-2, ultraviolet 254nm detects, and obtains compound 1 (6mg).
Fraction D-7-7 is loaded on silicagel column (Sephadex LH-20 post, 10 * 150mm) and carries out chromatography, use methanol-eluted fractions to obtain 3 subfractions (D-7-7-1 to D-7-7-3).D-7-7-2 is further purified and is obtained compound 2 (22mg) by recrystallization.
Can be by amplifying inventory and the chemical combination synthetic method by prior art obtains more compound 1 and compound 2.
Compound 1 and compound 2 characterize and structural identification:
Compound 1 is colourless acicular crystal, and its molecular formula obtaining through HR-ESI-MS data determination is C5H11NO (m/z102.1288, value of calculation C5H12NO, 102.0919).The structure of compound 1 shows below:
Figure BDA0000423772670000151
it can be described as formula 1 compound in the present invention.
In 1H NMR spectrum, provided the signal of 10 H that are connected with C, wherein δ 2.71 (3H, s, H-6) is methyl.In 13C NMR spectrum, 5 C signals have been provided.Therefore, prediction wherein only has a methyl, three methylene, and one of them is connected to hydroxyl and has higher chemical shift, has a methine in molecule.1H and 13C NMR data are confirmed (table 1 sees below) by HSQC and HMBC spectrum.The four-membered ring being formed by two methylene, methine and N is present in molecule, reason be wherein to have certain degree of unsaturation but without unsaturated bond.By the dependency between the δ 3.81 (1H, m, H-2) in HMBC spectrum and C-3 (δ 27.3), C-4 (δ 43.8) and C-5 (δ 59.2), can prove this conclusion.In addition, δ 2.71 (3H, s, H-6) is connected with N with the dependency announcement methyl between C-2 (δ 40.0), C-4 (δ 43.8).Therefore, (δ 59.2, C-5) are positioned at without doubt C-2 for CH2OH.
By NOESY, test the relative configuration of having determined formula 1 compound.According between CH3 and δ 3.02H-5a and CH3 and NOESY between H-5b intersect peak, and between H-2 and CH3, obviously do not have a dependency, two substituent groups of methyl and methylol, the two is all positioned at a side of four-membered ring.The configuration of 4 H of residue on two methylene can by between H-2 α in NOESY spectrum and H-4 α and the dependency between H-5 β and H-3 β determine.Therefore formula 1 compound is defined as following structure:
Figure BDA0000423772670000161
Its CAS registration number 1310411-24-5 has been included and given to this compound by CAS, chemistry is by name: (2S)-1-Methyl-2-azetidinemethanol, i.e. (2S)-1-methyl-2-azetidine methanol.
Compound 2 is white powder.Molecular formula is C12H22N2O2.The structural formula of compound 2 is as follows:
it can be described as formula 2 compounds in the present invention.
In 1H NMR spectrum (table 1 sees below), methine signal δ 3.67 (1H, s, H-3) and three overlapping methyl signals δ 2.56 (3H, s, Me-4) show wherein to exist the tert-butyl group.The explanation of four carbon signals that provide by 13C NMR is indicated as CH3 (δ 29.9), C (δ 49.1), CH (δ 52.3) and C (δ 176.3), and this information also can be confirmed by HSQC.Tentatively find out and wherein have amide structure segment and symmetrical structure.1H and 13C NMR spectroscopic data are provided in below table 1.
Dependency between H-3 ' (δ 3.67,1H, s, H-3) and C-1 ' (δ 176.3) is confirmed by HMBC.Result shows that compound 2 is a kind of cyclic dipeptides, encircle (4-methyl-valyl-4-methyl-valyl), so formula 2 compounds is defined as following structure:
Figure BDA0000423772670000171
Its CAS registration number 286856-07-3 has been included and given to this compound by CAS, chemistry is by name: and 3,6-bis (1,1-dimethylethyl)-2,5-Piperazinedione, 3,6-bis-(1,1-dimethyl ethyl)-2,5-piperazinedione.
Table 1: the spectroscopic data (CD3OD) of compound 1 and compound 2
b, compositions preparation example part
Compositions example 1: get preparation example 1 gained Radix Raphani extract, make solution with water dissolution, the weight that the medical material comprising in the every 1ml of this solution is converted to fresh Radix Raphani is counted 100g.This solution is packed in nasal drop bottle and makes nasal drop.
Compositions example 2: get preparation example 2 gained Radix Raphani extracts, make solution with water dissolution, add benzyl alcohol to concentration 0.9%, the weight that the medical material comprising in the every 1ml of this solution is converted to fresh Radix Raphani is counted 50g.This solution is packed in nasal spray bottle and makes nasal spray, select the atomizing pump of every spray 50,100, tri-kinds of specifications of 250ul, obtain the spray of every discharge rate 50,100, tri-kinds of specifications of 250ul.
Compositions example 3: get preparation example 3 gained Radix Raphani extracts, make solution with water dissolution, add chlorobutanol to concentration 0.5%, the weight that the medical material comprising in the every 1ml of this solution is converted to fresh Radix Raphani is counted 200g.This solution is packed in nasal drop bottle and makes nasal drop.
Compositions example 4: modus ponens 1 compound, with water dissolution, make solution, add benzyl alcohol to concentration 0.9%, drug level is 10mg/ml.This solution is packed in nasal drop bottle and makes nasal drop.
Compositions example 5: modus ponens 2 compounds, with water dissolution, make solution, add benzyl alcohol to concentration 0.9%, drug level is 5mg/ml.This solution is packed in nasal drop bottle and makes nasal drop.
Compositions example 6: modus ponens 1 compound 2g, lactose 30g, microcrystalline Cellulose 40g, low-substituted hydroxypropyl cellulose 4g, hydroxypropyl emthylcellulose 3g, magnesium stearate 1g.Method for making, modus ponens 1 compound, lactose and microcrystalline Cellulose mix homogeneously, be binding agent soft material processed with hydroxypropyl emthylcellulose aqueous solution (5%), granulate, dry, dry granule and other material are mixed, tabletting, every contains formula 1 compound 2mg, becomes the compositions of tablet form.
Reference composition example 1: the method for reference group compound example 1, different is to use preparation example 1 normal hexane part gained Radix Raphani extract above to replace n-butyl alcohol part gained Radix Raphani extract wherein, makes nasal drop.
Reference composition example 2: the method for reference group compound example 1, different is to use preparation example 1 dichloromethane part gained Radix Raphani extract above to replace n-butyl alcohol part gained Radix Raphani extract wherein, makes nasal drop.
Reference composition example 3: the method for reference group compound example 1, different is to use preparation example 1 ethyl acetate part gained Radix Raphani extract above to replace n-butyl alcohol part gained Radix Raphani extract wherein, makes nasal drop.
c, test of pesticide effectiveness example part
test of pesticide effectiveness example 1: medicine causes the impact of rat Nerve in Migraine Model on nitroglycerin
1, experimental principle: nitroglycerin is a kind of fat-soluble compound, easily sees through blood brain barrier, is the donor of nitric oxide (NO).After a period of time, can there is migraine-mimicking headache in migraineur's infusion nitroglycerin, and use NO NOS inhibitor can stop migrainous acute attack, this has illustrated that NO plays an important role in migrainous pathogenesis, this modeling method is simple, economical, massive duplication in a short time, and can under waking state, observe animal scratch one's head, get rid of first-class Behavioral reaction.
2, experiment grouping: the SD rat of random packet, 10 every group, concrete group comprises:
Model group (collunarium normal saline);
Nasal spray group: intranasal administration, reagent is respectively pharmaceutical composition of the present invention and the reference composition example 1-3 resulting composition of above-mentioned composition example 1-6 gained; The tablet of compositions example 6 before use with distilled water suspendible to facilitate collunarium to use.
Positive drug group (YANSUAN FUGUILIQIN JIAONANG, commercially available product, 5mg/ grain).
3, experimental technique: nasal spray group: rat intranasal administration, the dosage that the dosage of extract is converted to fresh Radix Raphani meter 1.5g/kg body weight or 3.0g/kg body weight, compound 1 and compound 2 is 0.2mg/kg body weight or 0.5mg/kg body weight (through microsampling product divided dose collunarium).Positive controls: YANSUAN FUGUILIQIN JIAONANG 2mg/kg (twice of clinical equivalent amount) gastric infusion.Model group is given and the isopyknic normal saline collunarium of nasal spray group.Each treated animal subcutaneous injection Nitro-Bid Ⅳ 10mg/kg, 0.2ml/100g, after modeling 2 minutes, Chinese medicine nasal spray group intranasal administration 1 time, the migraine reaction of 180 minutes rats of Continuous Observation after administration.
4, the observation of integral animal sign
From modeling, 30min is a period, adopts persistent period segmentation method, records respectively each period of rat difficult to tackle and climb the number of times of cage, calculates total cage number of times and total number of times difficult to tackle of climbing; Record rat simultaneously and occur for the first time time difficult to tackle and the red incidence rate of ear.Result is respectively in Table 2 and table 3.
Table 2, always climb cage number of times and total cumulative number difficult to tackle
Group/reagent Dosage Climb cage number of times Number of times difficult to tackle
Model group - 55 68
Positive drug group 2mg/kg 22 25
Compositions example 1 1.5g/kg 31 27
Compositions example 2 1.5g/kg 33 31
Compositions example 3 1.5g/kg 29 25
Compositions example 4 0.2mg/kg 24 27
Compositions example 5 0.2mg/kg 25 26
Compositions example 6 0.2mg/kg 25 29
Reference composition example 1 1.5g/kg 49 56
Reference composition example 2 1.5g/kg 45 53
Reference composition example 3 1.5g/kg 51 58
Compositions example 1 3.0g/kg 23 21
Compositions example 2 3.0g/kg 24 24
Compositions example 3 3.0g/kg 21 22
Compositions example 4 0.5mg/kg 20 29
Compositions example 5 0.5mg/kg 18 22
Compositions example 6 0.5mg/kg 22 20
Reference composition example 1 3.0g/kg 47 52
Reference composition example 2 3.0g/kg 46 54
Reference composition example 3 3.0g/kg 49 52
Table 3, time difficult to tackle and the red rate of ear for the first time
Group/reagent Dosage Time of occurrence (second) difficult to tackle for the first time The red incidence rate of ear (%)
Model group - 82 100
Positive drug group 2mg/kg 285 23
Compositions example 1 1.5g/kg 267 21
Compositions example 2 1.5g/kg 252 25
Compositions example 3 1.5g/kg 290 23
Compositions example 4 0.2mg/kg 275 27
Compositions example 5 0.2mg/kg 255 19
Compositions example 6 0.2mg/kg 260 24
Reference composition example 1 1.5g/kg 97 97
Reference composition example 2 1.5g/kg 89 89
Reference composition example 3 1.5g/kg 103 93
Compositions example 1 3.0g/kg 322 19
Compositions example 2 3.0g/kg 298 17
Compositions example 3 3.0g/kg 337 20
Compositions example 4 0.5mg/kg 306 18
Compositions example 5 0.5mg/kg 298 21
Compositions example 6 0.5mg/kg 302 20
Reference composition example 1 3.0g/kg 108 89
Reference composition example 2 3.0g/kg 96 92
Reference composition example 3 3.0g/kg 106 86
Above result shows: Radix Raphani extract of the present invention climb cage number of times, number of times difficult to tackle and the red incidence rate of ear lower than model group, and for the first time time of occurrence difficult to tackle than model group leader.
test of pesticide effectiveness example 2: the content of 5-HT, NA and DA in fluorescence spectrometry cerebral tissue and serum
After the behavioristics of the integral animal sign in test of pesticide effectiveness example 1 observes and finishes, each group rat is all plucked to eyeball and get blood, prepare serum; Broken end takes out cerebral tissue, on ice platform, carries out, and rejects cerebellum, removes meninges and blood vessel, with ice-cold normal saline flushing, removes bloodstain, and filter paper is wiped away dry, cuts hypothalamus part, adds ice-cold normal saline, preparation brain tissue homogenate.Measure the content of 5-HT, DA, NE in the brain of each treated animal and serum.In test, carry out normal group (do not carry out test of pesticide effectiveness example 1 is processed and the content of directly getting brain and determination of serum 5-HT, DA, NE) simultaneously.
Result is respectively in Table 4 and 5.
The content (ng/g) of table 4, cerebral tissue 5-HT, NA and DA
Group Dosage 5-HT NA DA
Model group — 710 515 1905
Normal group — 1460 663 2725
Positive drug group 2mg/kg 1330 633 2410
Compositions example 1 1.5g/kg 1362 645 2584
Compositions example 2 1.5g/kg 1410 622 2466
Compositions example 3 1.5g/kg 1397 646 2507
Compositions example 4 0.2mg/kg 1453 627 2473
Compositions example 5 0.2mg/kg 1383 615 2442
Compositions example 6 0.2mg/kg 2407 606 2518
Reference composition example 1 1.5g/kg 824 527 1974
Reference composition example 2 1.5g/kg 695 497 1889
Reference composition example 3 1.5g/kg 853 504 1953
Above result shows, uses after the present composition, the content of cerebral tissue 5-HT, NA and DA is had to the impact being highly profitable.
The content (ng/g) of table 5, serum 5-HT, NA and DA
Group Dosage 5-HT NA DA
Model group — 533 384 1705
Normal group — 980 620 2240
Positive drug group 2mg/kg 926 583 2078
Compositions example 1 1.5g/kg 894 579 2113
Compositions example 2 1.5g/kg 936 592 2032
Compositions example 3 1.5g/kg 903 563 1984
Compositions example 4 0.2mg/kg 912 584 2007
Compositions example 5 0.2mg/kg 895 548 2086
Compositions example 6 0.2mg/kg 920 584 2024
Reference composition example 1 1.5g/kg 568 379 1675
Reference composition example 2 1.5g/kg 584 396 1786
Reference composition example 3 1.5g/kg 542 405 1745
Above result shows, uses after the present composition, the content of serum 5-HT, NA and DA is had to the impact being highly profitable
clinical efficacy example:
6 migraineurs that have regular recurrence, when they for the first time migraine occur, use compositions example 1 compositions, and the weight that daily dose is converted to fresh Radix Raphani is 75g.Result is presented at after medication in 1 hour all cephalagra significantly and disappears.When there is migraine for the second time in these 6 patients, use compositions example 4 compositionss, daily dose is that formula 1 compound 10mg once takes.Result is presented at after medication in 1 hour all cephalagra significantly and disappears.When there is migraine for the second time in these 6 patients, use compositions example 5 compositionss, daily dose is that formula 1 compound 10mg once takes.Result is presented at after medication in 1 hour all cephalagra significantly and disappears.

Claims (15)

1. Radix Raphani extract treats and/or prevents the purposes in the medicine of migraine and complication thereof in preparation.
2. according to the purposes of claim 1, wherein said Radix Raphani extract is the extract that Radix Raphani water extract or Radix Raphani juice obtain through n-butanol extraction.
3. according to the purposes of claim 1, wherein said Radix Raphani extract be Radix Raphani water extract or Radix Raphani juice through being condensed into concentrated solution, or after concentrate drying, water suspendible becomes suspension, the extract that gained concentrated solution or suspension further obtain through n-butanol extraction.
4. according to the purposes of claim 1, wherein said Radix Raphani extract is that Radix Raphani water extract or Radix Raphani juice are through being condensed into concentrated solution, or after concentrate drying, water suspendible becomes suspension, gained concentrated solution or suspension further extract through following solvents successively: normal hexane, dichloromethane, ethyl acetate and n-butyl alcohol, and by the concentrated extract obtaining of n-butanol portion warp.
5. according to the purposes of claim 1, wherein said medicine is preparations for oral administration or topical preparation.In one embodiment, described medicine is topical preparation.In one embodiment, described medicine is pernasal preparation.In one embodiment, described medicine is liquid or semi-solid preparation.In one embodiment, described medicine is solution or gel.In one embodiment, described medicine is selected from spray, nasal drop, gel, the agent of plug nose.
6. with following formula 1 compound, in preparation, treat and/or prevent the purposes in the medicine of migraine and complication thereof
Figure FDA0000423772660000011
7. according to the purposes of claim 6, wherein said formula 1 compound give mammal for example every daily dose of people normally with the amount of effective dose, use.In one embodiment, be the amount use can effectively treat and/or prevent migraine and complication thereof or to alleviate cephalagra.In one embodiment, every daily dose that formula 1 compound is grown up, is 0.01-1000mg, for example 0.1-500mg, for example 0.1-250mg, for example 1-100mg.In one embodiment, every daily dose that formula 1 compound is grown up, is 0.1-1000mg, for example 1-500mg, for example 5-500mg, for example 10-500mg.In one embodiment, every daily dose that formula 1 compound is grown up, is 0.1-1000mg, for example 1-500mg, for example 5-250mg, for example 10-200mg.
8. according to the purposes of claim 5, wherein said medicine is preparations for oral administration or topical preparation.In one embodiment, described medicine is preparations for oral administration, and in one embodiment, described medicine is the form that is tablet or capsule.In one embodiment, described medicine is topical preparation.In one embodiment, described medicine is pernasal preparation.In one embodiment, described medicine is liquid or semi-solid preparation.In one embodiment, described medicine is solution or gel.In one embodiment, described medicine is selected from spray, nasal drop, gel, the agent of plug nose.
9. with following formula 2 compounds, in preparation, treat and/or prevent the purposes in the medicine of migraine and complication thereof
Figure FDA0000423772660000021
10. according to the purposes of claim 9, wherein said formula 2 compounds give mammal for example every daily dose of people normally with the amount of effective dose, use.In one embodiment, be the amount use can effectively treat and/or prevent migraine and complication thereof or to alleviate cephalagra.In one embodiment, be to use can effectively alleviate or alleviate the amount of cephalagra.In one embodiment, every daily dose that formula 2 compounds are grown up, is 0.01-1000mg, for example 0.1-500mg, for example 0.1-250mg, for example 1-100mg.In one embodiment, every daily dose that formula 2 compounds are grown up, is 0.1-1000mg, for example 1-500mg, for example 5-500mg, for example 10-500mg.In one embodiment, every daily dose that formula 2 compounds are grown up, is 0.1-1000mg, for example 1-500mg, for example 5-250mg, for example 10-200mg.
11. according to the purposes of claim 9, and wherein said medicine is preparations for oral administration or topical preparation.In one embodiment, described medicine is preparations for oral administration, and in one embodiment, described medicine is the form that is tablet or capsule.In one embodiment, described medicine is topical preparation.In one embodiment, described medicine is pernasal preparation.In one embodiment, described medicine is liquid or semi-solid preparation.In one embodiment, described medicine is solution or gel.In one embodiment, described medicine is selected from spray, nasal drop, gel, the agent of plug nose.
12. 1 kinds of pharmaceutical compositions that can be used for treating and/or preventing migraine and complication thereof, comprising Radix Raphani extract and optional pharmaceutically acceptable carrier or excipient.
13. according to the pharmaceutical composition of claim 12, and wherein said Radix Raphani extract is the extract that Radix Raphani water extract or Radix Raphani juice obtain through n-butanol extraction.
14. 1 kinds of pharmaceutical compositions that can be used for treating and/or preventing migraine and complication thereof, comprising with following formula 1 compound and optional pharmaceutically acceptable carrier or excipient,
Figure FDA0000423772660000031
15. 1 kinds of pharmaceutical compositions that can be used for treating and/or preventing migraine and complication thereof, comprising with following formula 2 compounds and optional pharmaceutically acceptable carrier or excipient,
Figure FDA0000423772660000032
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CN103200940A (en) * 2010-11-09 2013-07-10 曼金德公司 Composition comprising a serotonin receptor agonist and a diketopiperazine for treating migraines
CN103372044A (en) * 2012-04-16 2013-10-30 肖秋霞 Medicament for treating hemicranias, and application thereof in preparation of nose drop for treating hemicranias

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