CN104031098A - Hypoglycemic medicine - Google Patents

Hypoglycemic medicine Download PDF

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Publication number
CN104031098A
CN104031098A CN201410281397.6A CN201410281397A CN104031098A CN 104031098 A CN104031098 A CN 104031098A CN 201410281397 A CN201410281397 A CN 201410281397A CN 104031098 A CN104031098 A CN 104031098A
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Prior art keywords
compound
formula
lipid acid
solvate
acceptable salts
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李友香
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Beijing Kaili economic and Trade Co., Ltd.
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李友香
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Abstract

The invention relates to a hypoglycemic medicine and a composition, and in particular relates to a compound as shown in the formula I or a solvate thereof. The structure of the composition is described in the specification. The invention further relates to a medicine composition comprising the compound and application of the medicine composition and the compound. The compound or the composition is an excellent hypoglycemic medicine.

Description

Ofhypoglycemic medicine
Technical field
The present invention relates to a kind of hypoglycemic drug and comprise its composition, particularly relate to compound and its composition of formula I, using and as therapeutical agent particularly as the purposes of sodium dependent glucose translocator (SGLT) inhibitor.
Background technology
At the commitment for the treatment of diabetes, dietary control and kinesitherapy are first-selected glycemic control protocols.In the time that these methods are difficult to realize to the control of blood sugar, need to use Regular Insulin or orally-taken blood sugar reducing class medicine to treat.At present existing multiple ofhypoglycemic medicine, for clinical treatment, comprises biguanide compound, sulfonyl urea compound, insulin resistant activator and alpha-glucosidase inhibitor etc.But said medicine, due to different separately side effects, all cannot meet the needs of long-term treatment.For example, biguanide compound easily causes lactic acidosis; Sulfonyl urea compound can cause hypoglycemia symptom; Insulin resistant activator easily brings out oedema and cardiac failure, and alpha-glucosidase inhibitor can cause the symptoms such as stomachache, abdominal distension, diarrhoea.In view of the foregoing, people urgently wish to develop a kind of safer effective novel ofhypoglycemic medicine in order to meet the treatment needs of diabetes.
Research finds, cell is mainly realized by urging glucose transporter (GLUTs) (passive transport) and Na-dependent glucose these two the protein family members of albumen (SGLTs) (active transport) that cotransport the adjusting of glucose transport process.The member wherein in SGLTs family with glucose transport function is mainly distributed in the positions such as the proximal tubule of enteron aisle and kidney, and then infer in the process such as reuptake of its absorption at intestines glucose and kidney glucose and all bringing into play keying action, thereby become one of potential target spot of ideal for the treatment of diabetes.
Particularly, family member SGLT-1 albumen is mainly distributed in the intestinal mucosa cell of small intestine, in cardiac muscle and kidney, also has a small amount of expression.It is the intestinal absorption process of collaborative GLUTs albumen adjusting glucose mainly.And another member SGLT-2, because of its high level expression in kidney, the main adjusting of being responsible for glucose kidney reuptake process, the glucose in urine can initiatively be attached to renal cells and be transported in born of the same parents and be re-used by SGLT-2 albumen when through glomerular filtration.In this course, SGLT-2 has been responsible for 90% heavy absorption process, and remaining 10% has by SGLT-1 and completes.SGLT-2 has also obtained further confirmation as this theory of main translocator in animal experiment.By using specificity SGLT-2 antisense oligonucleotide to suppress the SGLT-2mRNA level in renal cortex of rats cell, can obviously suppress the kidney glucose reuptake process of rat.Find to infer based on these researchs, if develop a kind of SGLTs (SGLT-1/SGLT-2) protein inhibitor, by regulating its glucose transport function, can realize on the one hand the absorption of controlling enteron aisle glucose, can suppress on the other hand the reuptake of kidney glucose, strengthen the discharge of glucose from urine, bring into play comparatively systematic blood sugar reducing function, thereby become the ideal medicament for the treatment of diabetes.
In addition, research also finds that SGLTs protein inhibitor can be for the treatment of diabetes related complication.As retinopathy, neuropathy, ephrosis, insulin resistant that glucose metabolism disorder causes, hyperinsulinemia, hyperlipidemia, obesity etc.SGLTs protein inhibitor also can be combined use with existing medicine simultaneously, as sulphonamide, thiazolidinedione, N1,N1-Dimethylbiguanide and Regular Insulin etc., in the situation that not affecting drug effect, reduce dosage, thereby avoid or alleviated the generation of untoward reaction, improved the conformability of patient to treatment.
In sum, SGLTs protein inhibitor, particularly SGLT-2 protein inhibitor has good DEVELOPMENT PROSPECT as novel Remedies for diabetes.The method of new treatment diabetes is still expected to have in this area.
Summary of the invention
The object of the invention is to provide for this area a kind of method of new treatment diabetes.Have been surprisingly found that compound or the composition with feature of the present invention present advantage of the present invention, the present invention is based on this discovery and be accomplished.
In a first aspect of the present invention, a kind of compound is provided, it is with compound shown in following formula I:
Or its solvate.
According to the compound of first aspect present invention, wherein said solvate is hydrate.
According to the compound of first aspect present invention, wherein said solvate is monohydrate.
According to the compound of first aspect present invention, the chemical name of wherein said formula I compound can be for example: (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE mixture.Its molecular formula is typically C22H24ClO7FC5H9NO2, and molecular weight is typically about Mr=570.01.
According to the compound of first aspect present invention, it is with following formula Ia compound:
According to the compound of first aspect present invention, the chemical name of wherein said formula Ia compound can be for example: (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE, one water complex.
According to the compound of first aspect present invention, wherein said formula Ia compound is (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, the mole ratio 1:1:1 mixture that 3,4-triol and L-PROLINE and water form.Its molecular formula is typically C22H24ClO7FC5H9NO2H2O, and molecular weight is typically about Mr=588.03.
According to the compound of first aspect present invention, it is formula Ia compound compound, and it is in the time of relative humidity 10%～90%, and water content is 2.5%～3.5%, and for example water content is 2.8%～3.3%.
According to the compound of first aspect present invention, it is formula Ia compound compound, and it is exposed under relative humidity 80% condition after 10 hours at 30 DEG C, and moisture absorption weightening finish is less than 1%, for example, be less than 0.5%, for example, be less than 0.3% (w/w).In this article, term " moisture absorption weightening finish " is well known to a person skilled in the art, and typically refers under this condition determination, and when sample starts in the time of 10 hours and 0 hour time, the weight of the difference of weight when starting is multiplied by the result of 100% gained again.
According to the compound of first aspect present invention, it is formula Ia compound compound, it is in the weight-loss curve of thermogravimetric analysis (conventionally can referred to as TGA) test, the weightless <1% (for example <0.5%, for example <0.25%) of weight-loss curve within the scope of from 50 DEG C to 110 DEG C; And/or the weightlessness of weight-loss curve within the scope of from 100 DEG C to 220 DEG C is 2～4% (for example 2.5%～3.5%, for example 2.8%～3.3%, for example 2.9%～3.1%, for example approximately 3%).
In a second aspect of the present invention, provide the compound of first aspect present invention in the purposes of preparing in sodium dependent glucose transporter inhibitors.
In a second aspect of the present invention, the compound that first aspect present invention is provided is for the preparation for the treatment of or delay the purposes in the medicine of following advancing of disease or outbreak, and wherein said disease is selected from level, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or the hypertension of the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine.
In a third aspect of the present invention, a kind of solid composite medicament is provided, wherein comprise:
(a) as activeconstituents with following formula I compound or its solvate:
(b) lipid acid or its pharmacologically acceptable salts; And optional
(c) pharmaceutical excipient.
According to the solid composite medicament of third aspect present invention, wherein said solvate is hydrate.
According to the solid composite medicament of third aspect present invention, wherein said solvate is monohydrate.
According to the solid composite medicament of third aspect present invention, the chemical name of wherein said formula I compound can be for example: (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE mixture.
According to the solid composite medicament of third aspect present invention, wherein said formula I compound is with following formula Ia compound:
According to the solid composite medicament of third aspect present invention, the chemical name of wherein said formula Ia compound can be for example: (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE, one water complex.
According to the solid composite medicament of third aspect present invention, wherein said formula Ia compound is (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, the mole ratio 1:1:1 mixture that 3,4-triol and L-PROLINE and water form.
According to the solid composite medicament of third aspect present invention, wherein said lipid acid is stearic acid.
According to the solid composite medicament of third aspect present invention, the pharmacologically acceptable salts of wherein said lipid acid is the magnesium salts of lipid acid, sodium salt, calcium salt, zinc salt.
According to the solid composite medicament of third aspect present invention, wherein said lipid acid or its pharmacologically acceptable salts are selected from: stearic acid, Magnesium Stearate, calcium stearate, sodium stearate, Zinic stearas and combination thereof.
According to the solid composite medicament of third aspect present invention, wherein said lipid acid or its pharmacologically acceptable salts are selected from: stearic acid, Magnesium Stearate, calcium stearate and combination thereof.
The inventor has been surprisingly found that, in the time that being prepared together with lipid acid or its pharmacologically acceptable salts, formula I compound there is beat all good result, the particularly effect of stability, and this effect can not disappear for preparations shaping object other pharmaceutical excipient used because of adding other.Therefore, solid composite medicament of the present invention can be the solid composite medicament that comprises formula I compound of the present invention or its solvate and lipid acid of the present invention or its pharmacologically acceptable salts, can also be to comprise further the conventional conventional pharmaceutical excipient of other optional pharmaceutics.
According to the solid composite medicament of third aspect present invention, wherein said pharmaceutical excipient includes but not limited to thinner or weighting agent, disintegrating agent, tackiness agent, lubricant or glidant.
According to the solid composite medicament of third aspect present invention, wherein said thinner or weighting agent include but not limited to: starch is W-Gum, dextrin, Microcrystalline Cellulose, modified starch, pregelatinized Starch, N.F,USP MANNITOL, lactose, sucrose, sorbyl alcohol, D-glucitol, erythritol, Xylitol, fructose etc. such as.Preferred N.F,USP MANNITOL and/or the lactose of comprising.Have been surprisingly found that gelling phenomenon tablet stripping can be overcome valuably in the time that thinner or weighting agent use sugar alcohol of the present invention (this sugar alcohol is selected from: N.F,USP MANNITOL, lactose or its combination) time.In one embodiment, described solid composite medicament comprises sugar alcohol (it is selected from: lactose, N.F,USP MANNITOL or its combination).In one embodiment, the weight ratio of formula I compound or its solvate (taking formula Io compound weighing scale) and described sugar alcohol is as 1:1～100, for example 1:2～100, for example 1:2～50, for example 1:2～20.
According to the solid composite medicament of third aspect present invention, wherein said pharmaceutical excipient comprises and is selected from following thinner or weighting agent: N.F,USP MANNITOL, lactose or its combination.
According to the solid composite medicament of third aspect present invention, wherein said pharmaceutical excipient also optionally comprises and is selected from following thinner or weighting agent: starch is W-Gum, dextrin, Microcrystalline Cellulose, modified starch, pregelatinized Starch, sucrose, sorbyl alcohol, D-glucitol, erythritol, Xylitol, fructose and combination thereof for example.
According to the solid composite medicament of third aspect present invention, wherein said disintegrating agent includes but not limited to: low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, cross-linked carboxymethyl cellulose sodium, starch etc.
According to the solid composite medicament of third aspect present invention, wherein said tackiness agent is such as but not limited to hydroxypropylcellulose, Vltra tears, polyvinylpyrrolidone, polyvinyl alcohol, etc.The preferred hydroxypropylcellulose that comprises, Vltra tears, polyvinylpyrrolidone or polyvinyl alcohol.Described tackiness agent can use separately, also can two or more combine use.Described water-soluble copolymer adhesive combined amount be for example tablet total weight amount 0.5 to 10wt%, preferably l to 5wt%.The oral preparations of employing pharmaceutical compositions of the present invention refers to and is mixed with tablet, capsule, particle or fine grain pharmaceutical preparation.Described preparation can the application of the invention formula etc. be made tablet, capsule, particle or fine particle through traditional method.
In the present invention, lubricant and glidant can rise and be referred to as lubricant.Lubricant includes but not limited to: Liquid Paraffin, polyoxyethylene glycol, silicon-dioxide, colloid silica, micropowder silica gel, talcum powder, hydrogenated vegetable wet goods or its combination.
According to the solid composite medicament of third aspect present invention, the weight ratio of wherein said formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.01～100, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.02～50, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～20, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～10, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～5, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～2, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～1.In one embodiment, described lipid acid or its pharmacologically acceptable salts account for as 0.5～10% of tablet weight, particularly account for 0.5～5% of tablet weight, particularly account for 0.5～2.5% of tablet weight.
According to the solid composite medicament of third aspect present invention, wherein said pharmaceutical excipient accounts for 0～99.5% of said composition weight, for example described pharmaceutical excipient accounts for 10～99% of said composition weight, for example described pharmaceutical excipient accounts for 25～99% of said composition weight, for example described pharmaceutical excipient accounts for 50～98% of said composition weight, and for example described pharmaceutical excipient accounts for 75～95% of said composition weight.The consumption of described pharmaceutical excipient can rule of thumb easily be determined according to those skilled in the art.For example, as disintegrating agent, its gross weight in composition conventionally can be in 3～30% scopes, for example conventionally can be in 5～20% scopes.Again for example, as tackiness agent, its gross weight in composition conventionally can be in 2～20% scopes, for example conventionally can be in 5～10% scopes.Again for example, as thinner or weighting agent, it typically is and made the medicament can moulding, therefore its amount can not determined especially, and for example its gross weight in composition conventionally can be in 1～95% scope, for example conventionally can be in 10～90% scopes.Again for example, as lubricant, its gross weight in composition conventionally can be in 1～20% scope, for example conventionally can be in 1～10% scope, and for example conventionally can be in 1～8% scope; But, because lipid acid used in the present composition or its pharmacologically acceptable salts may produce enough lubrications, therefore can not add in addition in the present invention lubricant.
According to the solid composite medicament of third aspect present invention, it is the dosage form that is tablet, capsule, granule, piller etc.In one embodiment, described solid composite medicament is the dosage form that is tablet, capsule, granule.In one embodiment, described solid composite medicament is the dosage form that is tablet or capsule.
According to the solid composite medicament of third aspect present invention, it is the unit dose formulations form that is tablet, capsule, granule, piller etc.Term " unit dose formulations form " for example refers to the dosage form an of tablet, a seed lac wafer etc.In one embodiment, in described each " unit dose formulations form ", the amount of contained I compound or its solvate is amounted to into (1S, 2S, 3S, 4R, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5S)-5-[4-) methyl] phenyl]-1-(methylol)-6, 8-dioxa dicyclo is [3.2.1] octane-2 also, 3, 4-triol L-PROLINE is counted 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.For example in every tablet, the amount of contained I compound or its solvate is amounted to into (1S, 2S, 3S, 4R, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5S)-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE is counted 0.1～100mg, be for example 0.1～50mg, being for example 0.1～25mg, for example, is 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
According to the solid composite medicament of third aspect present invention, method in its first method (taking Xiu Shi method) it " A. volumetric precipitation method " in two annex VIIIM aquametries of Chinese Pharmacopoeia version in 2010 is measured, this solid composite medicament contains the moisture that is greater than 0.1%, for example contain the moisture that is greater than 0.2%, for example, contain 0.2%～5% moisture.
In the pharmaceutical composition of preparing as bulk drug using activeconstituents formula I compound of the present invention or formula Ia compound, formula Io compound wherein and L-PROLINE all can be measured and be obtained by for example the method for the invention of ordinary method, and both ratios (mol ratio or weight ratio) can be not influenced because of the interpolation of auxiliary material, for example can use taking formula Io compound as reference substance HPLC method of the present invention to measure the content that obtains present composition Chinese style Io compound, can also use the inventive method to measure the content that obtains L-PROLINE in composition.Therefore, according to the solid composite medicament of third aspect present invention, wherein contain formula Io compound and L-PROLINE, the two mol ratio of formula Io compound and L-PROLINE is that 1:0.9～1.1, particularly mol ratio are 1:0.95～1.05.
In a fourth aspect of the present invention, a kind of solid composite medicament is provided, wherein comprise:
(a) as activeconstituents with following formula I compound or itself or its solvate:
(b) sugar alcohol; And optional
(c) pharmaceutical excipient.
According to the solid composite medicament of fourth aspect present invention, wherein said solvate is hydrate.
According to the solid composite medicament of fourth aspect present invention, wherein said solvate is monohydrate.
According to the solid composite medicament of fourth aspect present invention, the chemical name of wherein said formula I compound can be for example: (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE mixture.
According to the solid composite medicament of fourth aspect present invention, wherein said formula I compound is with following formula Ia compound:
According to the solid composite medicament of fourth aspect present invention, the chemical name of wherein said formula Ia compound can be for example: (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE, one water complex.
According to the solid composite medicament of fourth aspect present invention, wherein said formula Ia compound is (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, the mole ratio 1:1:1 mixture that 3,4-triol and L-PROLINE and water form.
According to the solid composite medicament of fourth aspect present invention, wherein said sugar alcohol is selected from: N.F,USP MANNITOL, lactose, sorbyl alcohol, D-glucitol, erythritol, Xylitol, fructose or its combination.According to the solid composite medicament of fourth aspect present invention, wherein said sugar alcohol is selected from: N.F,USP MANNITOL, lactose or its combination.Have been surprisingly found that gelling phenomenon tablet stripping can be overcome valuably in the time using sugar alcohol of the present invention time.In one embodiment, described solid composite medicament comprises sugar alcohol (it is selected from: lactose, N.F,USP MANNITOL or its combination).In one embodiment, the weight ratio of formula I compound or its solvate (taking formula Io compound weighing scale) and described sugar alcohol is as 1:1～100, for example 1:2～100, for example 1:2～50, for example 1:2～20.
According to the solid composite medicament of fourth aspect present invention, wherein also comprise lipid acid or its pharmacologically acceptable salts.
According to the solid composite medicament of fourth aspect present invention, wherein said lipid acid is stearic acid.
According to the solid composite medicament of fourth aspect present invention, the pharmacologically acceptable salts of wherein said lipid acid is the magnesium salts of lipid acid, sodium salt, calcium salt, zinc salt.
According to the solid composite medicament of fourth aspect present invention, wherein said lipid acid or its pharmacologically acceptable salts are selected from: stearic acid, Magnesium Stearate, calcium stearate, sodium stearate, Zinic stearas and combination thereof.
According to the solid composite medicament of fourth aspect present invention, wherein said lipid acid or its pharmacologically acceptable salts are selected from: stearic acid, Magnesium Stearate, calcium stearate and combination thereof.
According to the solid composite medicament of fourth aspect present invention, the weight ratio of wherein said formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.01～100, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.02～50, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～20, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～10, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～5, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～2, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～1.In one embodiment, described lipid acid or its pharmacologically acceptable salts account for as 0.5～10% of tablet weight, particularly account for 0.5～5% of tablet weight, particularly account for 0.5～2.5% of tablet weight.
The inventor has been surprisingly found that, in the time that being prepared together with lipid acid or its pharmacologically acceptable salts, formula I compound or its solvate there is beat all good result, the particularly effect of stability, and this effect can not disappear for preparations shaping object other pharmaceutical excipient used because of adding other.Therefore, solid composite medicament of the present invention can be the solid composite medicament that comprises formula I compound of the present invention or its solvate and lipid acid of the present invention or its pharmacologically acceptable salts, can also be to comprise further the conventional conventional pharmaceutical excipient of other optional pharmaceutics.
According to the solid composite medicament of fourth aspect present invention, wherein said pharmaceutical excipient includes but not limited to thinner or weighting agent, disintegrating agent, tackiness agent, lubricant or glidant.
According to the solid composite medicament of fourth aspect present invention, wherein said thinner or weighting agent include but not limited to: starch is W-Gum, dextrin, Microcrystalline Cellulose, modified starch, pregelatinized Starch, N.F,USP MANNITOL, lactose, sucrose, sorbyl alcohol, D-glucitol, erythritol, Xylitol, fructose etc. such as.And above related N.F,USP MANNITOL and/or lactose its also there is the effect of thinner or weighting agent.Therefore, according to the solid composite medicament of fourth aspect present invention, wherein state pharmaceutical excipient except described sugar alcohol with place and also optionally comprise and be selected from following thinner or weighting agent: starch is W-Gum, dextrin, Microcrystalline Cellulose, modified starch, pregelatinized Starch, sucrose, sorbyl alcohol, D-glucitol, erythritol, Xylitol, fructose and combination thereof for example.
According to the solid composite medicament of fourth aspect present invention, wherein said disintegrating agent includes but not limited to: low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, cross-linked carboxymethyl cellulose sodium, starch etc.
According to the solid composite medicament of fourth aspect present invention, wherein said tackiness agent is such as but not limited to hydroxypropylcellulose, Vltra tears, polyvinylpyrrolidone, polyvinyl alcohol, etc.The preferred hydroxypropylcellulose that comprises, Vltra tears, polyvinylpyrrolidone or polyvinyl alcohol.Described tackiness agent can use separately, also can two or more combine use.Described water-soluble copolymer adhesive combined amount be for example tablet total weight amount 0.5 to 10wt%, preferably l to 5wt%.The oral preparations of employing pharmaceutical compositions of the present invention refers to and is mixed with tablet, capsule, particle or fine grain pharmaceutical preparation.Described preparation can the application of the invention formula etc. be made tablet, capsule, particle or fine particle through traditional method.
In the present invention, lubricant and glidant can rise and be referred to as lubricant.Lubricant includes but not limited to: Liquid Paraffin, polyoxyethylene glycol, silicon-dioxide, colloid silica, micropowder silica gel, talcum powder, hydrogenated vegetable wet goods or its combination.
According to the solid composite medicament of fourth aspect present invention, wherein said pharmaceutical excipient accounts for 0～99.5% of said composition weight, for example described pharmaceutical excipient accounts for 10～99% of said composition weight, for example described pharmaceutical excipient accounts for 25～99% of said composition weight, for example described pharmaceutical excipient accounts for 50～98% of said composition weight, and for example described pharmaceutical excipient accounts for 75～95% of said composition weight.The consumption of described pharmaceutical excipient can rule of thumb easily be determined according to those skilled in the art.For example, as disintegrating agent, its gross weight in composition conventionally can be in 3～30% scopes, for example conventionally can be in 5～20% scopes.Again for example, as tackiness agent, its gross weight in composition conventionally can be in 2～20% scopes, for example conventionally can be in 5～10% scopes.Again for example, as thinner or weighting agent, it typically is and made the medicament can moulding, therefore its amount can not determined especially, and for example its gross weight in composition conventionally can be in 1～95% scope, for example conventionally can be in 10～90% scopes.Again for example, as lubricant, its gross weight in composition conventionally can be in 1～20% scope, for example conventionally can be in 1～10% scope, and for example conventionally can be in 1～8% scope; But, because lipid acid used in the present composition or its pharmacologically acceptable salts may produce enough lubrications, therefore can not add in addition in the present invention lubricant.
According to the solid composite medicament of fourth aspect present invention, it is the dosage form that is tablet, capsule, granule, piller etc.In one embodiment, described solid composite medicament is the dosage form that is tablet, capsule, granule.In one embodiment, described solid composite medicament is the dosage form that is tablet or capsule.
According to the solid composite medicament of fourth aspect present invention, it is the unit dose formulations form that is tablet, capsule, granule, piller etc.Term " unit dose formulations form " for example refers to the dosage form an of tablet, a seed lac wafer etc.In one embodiment, in described each " unit dose formulations form ", the amount of contained I compound or its solvate is amounted to into (1S, 2S, 3S, 4R, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5S)-5-[4-) methyl] phenyl]-1-(methylol)-6, 8-dioxa dicyclo is [3.2.1] octane-2 also, 3, 4-triol L-PROLINE is counted 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.For example in every tablet, the amount of contained I compound or its solvate is amounted to into (1S, 2S, 3S, 4R, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5S)-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE is counted 0.1～100mg, be for example 0.1～50mg, being for example 0.1～25mg, for example, is 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
According to the solid composite medicament of fourth aspect present invention, method in its first method (taking Xiu Shi method) it " A. volumetric precipitation method " in two annex VIIIM aquametries of Chinese Pharmacopoeia version in 2010 is measured, this solid composite medicament contains the moisture that is greater than 0.1%, for example contain the moisture that is greater than 0.2%, for example, contain 0.2%～5% moisture.
In the pharmaceutical composition of preparing as bulk drug using activeconstituents formula I compound of the present invention or formula Ia compound, formula Io compound wherein and L-PROLINE all can be measured and be obtained by for example the method for the invention of ordinary method, and both ratios (mol ratio or weight ratio) can be not influenced because of the interpolation of auxiliary material, for example can use taking formula Io compound as reference substance HPLC method of the present invention to measure the content that obtains present composition Chinese style Io compound, can also use the inventive method to measure the content that obtains L-PROLINE in composition.Therefore, according to the solid composite medicament of fourth aspect present invention, wherein contain formula Io compound and L-PROLINE, the two mol ratio of formula Io compound and L-PROLINE is that 1:0.9～1.1, particularly mol ratio are 1:0.95～1.05.
Fifth aspect present invention provides the method for preparing solid composite medicament described in third aspect present invention any one, and it comprises following steps:
(i) provide formula I compound or its solvate, lipid acid or its pharmacologically acceptable salts and optional pharmaceutical excipient;
(ii) formula I compound or its solvate and lipid acid or its pharmacologically acceptable salts and optional pharmaceutical excipient are mixed with random order, obtain mixture;
(iii) mixture of step (ii) is made to pharmaceutical preparation according to the mode of preparation unit dose formulations form.
For example, for preparing tablet, have been found that the hybrid mode of formula I compound or its solvate and lipid acid or its pharmacologically acceptable salts is on realizing the object of the invention there are no impact; For example formula I compound or its solvate and lipid acid or its pharmacologically acceptable salts is pre-mixed and then mix with other pharmaceutical excipient, finally be pressed into again tablet, with formula I compound or its solvate are first mixed finally and are mixed with lipid acid or its pharmacologically acceptable salts with other pharmaceutical excipient, finally be pressed into tablet, two kinds of mode gained tablets all show good character again.
Sixth aspect present invention provides the method for preparing solid composite medicament described in fourth aspect present invention any one, and it comprises following steps:
(i) provide formula I compound or its solvate, sugar alcohol and optional pharmaceutical excipient;
(ii) formula I compound or its solvate and sugar alcohol and optional pharmaceutical excipient are mixed with random order, obtain mixture;
(iii) mixture of step (ii) is made to pharmaceutical preparation according to the mode of preparation unit dose formulations form.
For example, for preparing tablet, have been found that the hybrid mode of formula I compound or its solvate and sugar alcohol is on realizing the object of the invention there are no impact; For example formula I compound or its solvate are pre-mixed with sugar alcohol and then mix with other pharmaceutical excipient, finally be pressed into again tablet, with formula I compound or its solvate are first mixed finally and are mixed with sugar alcohol with other pharmaceutical excipient, finally be pressed into tablet, two kinds of mode gained tablets all show good character again.
Sixth aspect present invention provides the method for preparing compound described in first aspect present invention any one, it comprises following steps: make the i.e. (1S of formula Io compound, 2S, 3S, 4R, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5S)-5-[4-) methyl] phenyl]-1-(methylol)-6, 8-dioxa dicyclo is [3.2.1] octane-2 also, 3, 4-triol reacts with L-PROLINE in solvent, form the i.e. (1S of formula I compound, 2S, 3S, 4R, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5S)-5-[4-) methyl] phenyl]-1-(methylol)-6, 8-dioxa dicyclo is [3.2.1] octane-2 also, 3, 4-triol L-PROLINE mixture (1:1), or form the i.e. (1S of its monohydrate formula Ia compound, 2S, 3S, 4R, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5S)-5-[4-) methyl] phenyl]-1-(methylol)-6, 8-dioxa dicyclo is [3.2.1] octane-2 also, 3, 4-triol L-PROLINE one water complex (1:1:1).
According to the method for sixth aspect present invention, wherein said solvent is water-containing solvent.In one embodiment, wherein said solvent is the mixture of second alcohol and water.In one embodiment, wherein said solvent is 90～99% ethanol.In one embodiment, wherein said solvent is 95～99% ethanol.In one embodiment, wherein said solvent is approximately 98% ethanol.
According to the method for sixth aspect present invention, it comprises the following steps: 0.23 weight part L-PROLINE is dissolved in 90% ethanol/water of 1.2 weight parts, this solution is heated to micro-boiling, then adds the solution that is dissolved in 0.23 weight part formula Io compound in 4 parts by weight of ethanol; Make gained solution be cooled to-20 DEG C and reach 2 hours, can form during this period solid; This solution is at room temperature placed 2 days; Make this container centrifugal, remove supernatant liquor; Remaining solid washs with normal hexane, makes this solid dry under vacuum, and obtaining white solid is the mole ratio 1:1 mixture of Compound I o and L-PROLINE, i.e. formula I compound.
According to the method for sixth aspect present invention, it comprises the following steps: 0.23 weight part L-PROLINE is dissolved in 90% ethanol/water of 1.2 weight parts, this solution is heated to micro-boiling, add again the solution that is dissolved in 0.23 weight part formula Io compound in 4 parts by weight of ethanol, slowly add acetone to 5～15% of cumulative volume; Make gained solution be cooled to-20 DEG C and reach 2 hours, can form during this period solid; This solution is at room temperature placed 2 days; Make this container centrifugal, remove supernatant liquor; Remaining solid washs with normal hexane, makes this solid dry under vacuum, and obtaining white solid is the mole ratio 1:1:1 mixture of Compound I o and L-PROLINE and water, i.e. formula Ia compound.
Arbitrary technical characterictic that arbitrary embodiment of either side of the present invention has goes for or is combined in arbitrary embodiment of either side equally, as long as these are suitable for or combination can be not conflicting, certainly, in the time being suitable for each other or combining, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
In the present invention, compound (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol can be described as formula Io compound,
formula Io compound.
In the present invention, compound (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE 1:1 mixture can be described as formula I compound,
formula I compound.
In the present invention, compound (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, the 1:1:1 mixture of 3,4-triol L-PROLINE monohydrate can be described as formula Ia compound,
formula Ia compound.
The formula Io compound that the formula I compound that first aspect present invention relates to or formula Ia compound and the present invention mention, all can be used as in essence medicinal raw material medicine and uses, although may there is the difference of quality aspect as described in the present invention between them.
Brief description of the drawings
Fig. 1 be formula Ia compound at the moisture sorption isotherm of 30 DEG C.
Embodiment
Can conduct further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to 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 working method that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.In compound synthetic, reagent used, intermediate all can obtain by prior art for example synthetic with reference to prior art or buy from market.
While preparing composition below in listed prescription, while feeding intake with formula Io, I or Ia compound, if not otherwise indicated, its calculated amount is all calculated with the form of the formula Io compound of its corresponding equivalent, and listed formula is the amount of for example, in per unit dosage particles (every tablet, every seed lac wafer) contained formula Io compound; While preparing composition below, every batch of preparation amount is the amount of 10000 unit dose formulations, for example, feed intake with the amount of 10,000 or 10,000 seed lac wafers.
In the various HPLC stratographic analyses of the present invention, when not specified, the chromatographic peak that proline(Pro) and water show is all ignored in the time calculating.
one, analysis test method
1, HPLC measures
Below [HPLC method A] can be used for measuring the content with formula Io characterization of compound in the various materials of the present invention (comprising the bulk drug of contained Io, formula I or formula Ia compound or the composition that comprises them), or foreign matter content wherein and their changing conditions.In view of proline(Pro) and water, inconvenient accurate recording in this HPLC system shows chromatographic peak, and therefore if not otherwise indicated, the content in any material all can adopt the content of formula Io characterization of compound, and can be especially taking formula Io compound as contrast.
[HPLC method A]: anti-phase C18 post (Gemini post), 5 μ m × 4.6mm × 150mm, flow rate 1ml/ minute, moving phase is acetonitrile: water: trifluoroacetic acid=400:600: 1, UV detects 220nm.Taking synthesize and the formula Io compound of purified (chromatographic purity >99.8%) as reference substance, be mixed with containing the solution within the scope of its 0.001～0.1mg/ml product solution in contrast by moving phase; Trial-product uses suitably flow phased soln dilution to make to be equivalent to containing the also solution suitable with reference substance solution concentration of formula Io compound concentration according to the amount of its Chinese style Io, formula I or formula Ia compound, with external standard method with in calculated by peak area trial-product with formula Io, the formula I of formula Io compound metering or the amount of formula Ia compound.
2, the mensuration of L-PROLINE
Present method can be used for measuring the particularly content of the L-PROLINE in the material of formula I or formula Ia compound and in the composition that comprises them and their changing conditions of the various materials of the present invention.
Like that with reference to model the method that the document (Fan Ailing, etc., the content of spectrophotometry proline(Pro), Taiyuan Normal University's journal (natural science edition), 2004,3 (4): 48-50) of the tinkling of pieces of jade is recorded carries out.Taking the L-PROLINE of content >99.8% as reference substance, do replicate(determination), so that the L-PROLINE content in the various materials that comprise L-PROLINE (for example, as the formula I of bulk drug or formula Ia compound or the pharmaceutical composition that comprises them) is calculated in contrast.
3, moisture determination
For formula Io, the formula I or the formula Ia compound that can be used as medicinal raw material medicine, their determination of moisture method is as follows: first the material of tile (thickness is less than 0.5cm) is placed 24 hours under 50 DEG C, vacuum condition, use again the method in the first method (expense Xiu Shi method) it " A. volumetric precipitation method " in two annex VIIIM aquametries of Chinese Pharmacopoeia version in 2010, measure the moisture content in these bulk drugs.
For the pharmaceutical composition that comprises pharmaceutical excipient, their determination of moisture method is as follows: first composition is ground into fine powder, tiling (thickness is less than 0.25cm), under 70 DEG C, vacuum condition, place 24 hours, use again the method in the first method (expense Xiu Shi method) it " A. volumetric precipitation method " in two annex VIIIM aquametries of Chinese Pharmacopoeia version in 2010, measure the moisture content in these compositions.In view of bulk drug is diluted in composition, and in composition, some auxiliary material used may contain crystal water.Therefore, if the present composition uses formula Ia, compound is raw material (its moisture content approximately 3%), and when the deal of this raw material formula Ia compound in composition is 10%, measure by aforesaid method, conventionally can be measured to and contain the moisture that is greater than 0.1%, for example contain the moisture that is greater than 0.2%, for example, contain 0.2%～5% moisture.
two, compound preparation example
The monitoring of the reaction process in the each example of the present invention adopts tlc (TLC), the system of the developping agent that reaction is used has: methylene dichloride and methanol system, normal hexane and ethyl acetate system, the volume ratio of solvent regulates according to the polarity of compound is different.
The system of eluent and the developping agent system of tlc of the column chromatography that purifying compounds adopts comprise: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, the volume ratio of solvent regulates according to the polarity of compound is different, also can add a small amount of alkalescence such as triethylamine and acetic acid or acid reagent to regulate.When the bulk drug of using as pharmaceutical composition uses, can amplify and produce to obtain abundant material by this method below.
preparation example 1:the fluoro-benzene of preparation 1-oxyethyl group-2-
2-fluorophenol (6.7g, 60mmol) is dissolved in 66mL acetone, adds iodoethane (6.3mL, 78mmol) and salt of wormwood (12.4g, 90mmol), back flow reaction 5 hours in oil bath.Concentrating under reduced pressure reaction solution, add 100mL ethyl acetate and 60mL water, separatory, water is extracted with ethyl acetate (30mL × 2), merges organic phase, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, obtains the fluoro-benzene of title product 1-oxyethyl group-2-(6.88g, red oil).MS?m/z(ESI)：280.2[2M+1]
preparation example 2:preparation (the chloro-phenyl of the bromo-2-of 5-)-(the fluoro-phenyl of 4-oxyethyl group-3-) ketone
The bromo-5-chloro-Benzoyl chloride of 2-(12.4g, 48.8mmol) is dissolved in 100mL methylene dichloride, adds the fluoro-benzene (6.84g of 1-oxyethyl group-2-, 48.8mmol), be chilled to 0 DEG C, add aluminum chloride (5.86g in batches, 44mmol), reaction 16 hours.In ice bath downhill reaction liquid, drip the hydrochloric acid soln of 20mL2M, separatory, water 30mL dichloromethane extraction, merge organic phase, anhydrous magnesium sulfate drying, filters concentrating under reduced pressure filtrate, obtain title product (the chloro-phenyl of the bromo-2-of 5-)-(the fluoro-phenyl of 4-oxyethyl group-3-) ketone (12.8g, yellow solid).MS?m/z(ESI)：358.9[M+1]。
preparation example 3:preparation (the chloro-phenyl of the bromo-2-of 5-)-(the fluoro-phenyl of 4-oxyethyl group-3-) methyl alcohol
By (the chloro-phenyl of the bromo-2-of 5-)-(the fluoro-phenyl of 4-oxyethyl group-3-) ketone (12.7g, 35.5mmol) be dissolved in the mixed solvent of 100mL tetrahydrofuran (THF) and methyl alcohol (v:v=1:1), under ice bath, add sodium borohydride (2.68g in batches, 70mmol), under room temperature, react 30 minutes.Add 15mL acetone, concentrating under reduced pressure reaction solution, add 150mL acetic acid ethyl dissolution resistates, with saturated nacl aqueous solution washing (50mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, obtains title product (the chloro-phenyl of the bromo-2-of 5-)-(the fluoro-phenyl of 4-oxyethyl group-3-) methyl alcohol (12.65g, safran oily matter), be directly used in next step reaction without separation.
preparation example 4:the chloro-phenyl of the preparation bromo-2-of 4-[(5-) methyl]-fluoro-the benzene of 1-oxyethyl group-2-
By (the chloro-phenyl of the bromo-2-of 5-)-(the fluoro-phenyl of 4-oxyethyl group-3-) methyl alcohol (12.7g, 35.3mmol) be dissolved in 100mL methylene dichloride, add triethyl silicane (16.9mL, 106mmol), drip boron trifluoride diethyl etherate (8.95mL, 70.6mmol), reaction 3 hours.Add 50mL saturated sodium bicarbonate solution, separatory, water is extracted with ethyl acetate (100mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filters, concentrating under reduced pressure filtrate, purify gained resistates with silica gel column chromatography with eluent system B, obtain the chloro-phenyl of the bromo-2-of title product 4-[(5-) methyl]-fluoro-the benzene of 1-oxyethyl group-2-(10.2g, faint yellow oily matter). 1H?NMR(400MHz，CDCl3)：δ7.33-7.27(m，3H)，6.95-6.90(m，3H)，4.14(q，2H)，4.01(s，2H)，1.49(t，3H)。
preparation example 5:the fluoro-phenyl of the preparation chloro-3-[(4-oxyethyl group-3-of (2S, 3R, 4S, 5S, 6R)-2-[4-) methyl] phenyl]-6-(methylol)-2-methoxyl group-tetrahydropyrans-3,4,5-triol
By the chloro-phenyl of bromo-4-[(5-2-) methyl] the fluoro-benzene (7.36g of-1-oxyethyl group-2-, 21.4mmol) be dissolved in 30mL tetrahydrofuran (THF), be chilled to-78 DEG C, drip the hexane solution (10.27mL of n-Butyl Lithium, 25.7mmol), at-78 DEG C, react 1 hour, drip 20mL (3R, 4S, 5R, 6R)-3, 4, 5-tri-(trimethylsiloxy group)-6-(trimethylsiloxy group methyl) tetrahydropyrans-2-ketone (11g, tetrahydrofuran solution 23.6mmol), at-78 DEG C, react 2 hours, add 2.8mL methylsulfonic acid and 71mL methyl alcohol, under room temperature, react 16 hours.Add 100mL saturated sodium carbonate solution, concentrating under reduced pressure reaction solution, in resistates, add 50mL saturated nacl aqueous solution, be extracted with ethyl acetate (100mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filters, concentrating under reduced pressure filtrate, purify gained resistates with silica gel column chromatography with eluent system A, obtain title product (2S, 3R, 4S, 5S, 6R) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-2-[4-) methyl] phenyl]-6-(methylol)-2-methoxyl group-tetrahydropyrans-3,4,5-triol (5.73g, white solid). 1H?NMR(400MHz，CD3OD)：δ7.56(s，1H)，7.48(dd，1H)，7.37(dd，1H)，6.95-6.87(m，3H)，4.08-4.07(m，4H)，3.91(m，1H)，3.93-3.73(m，2H)，3.56-3.53(m，1H)，3.45-3.43(m，1H)，3.30(s，2H)，3.08(s，3H)，1.35(t，3H。
preparation example 6:preparation (2S, 3R, 4S, 5S, the 6R)-6-[(tertiary butyl (dimethyl) silylation) oxygen methyl] the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-2-[4-) methyl] phenyl]-2-methoxyl group-tetrahydropyrans-3,4,5-triol
By (2S, 3R, 4S, 5S, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 6R)-2-[4-) methyl] phenyl]-6-(methylol)-2-methoxyl group-tetrahydropyrans-3,4,5-triol (5.7g, 12.5mmol) is dissolved in 50mL pyridine, add successively TERT-BUTYL DIMETHYL CHLORO SILANE (2.26g, 15mmol) and DMAP (305mg, 2.5mmol), react 16 hours.Concentrating under reduced pressure reaction solution, add 200mL ethyl acetate, with copper/saturated copper sulphate solution washing (50mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, obtains title product (2S, 3R, 4S, 5S, 6R)-6-[(the tertiary butyl (dimethyl) silylation) oxygen methyl] the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-2-[4-) methyl] phenyl]-2-methoxyl group-tetrahydropyrans-3,4,5-triol (7.1g, colorless oil), is directly used in next step reaction without separation.
preparation example 7:preparation [[(2R, 3R, 4S, 5R, 6S)-3,4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-6-methoxyl group-tetrahydropyrans-2-yl] methoxyl group]-the tertiary butyl-dimethylsilane
By (2S, 3R, 4S, 5S, the 6R)-6-[(tertiary butyl (dimethyl) silylation) oxygen methyl] the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-2-[4-) methyl] phenyl]-2-methoxyl group-tetrahydropyrans-3,4,5-triol (7.14g, 12.5mmol) is dissolved in 100mL DMF, under ice bath, add 60% sodium hydride (2.5g, 62.5mmol), finish under room temperature and react 40 minutes, add cylite (7.5mL, 62.5mmol), reaction 16 hours.Add 20mL methyl alcohol, concentrating under reduced pressure reaction solution, add 200mL ethyl acetate and 50mL water dissolution resistates, separatory, water is extracted with ethyl acetate (50mL), organic phase is water (50mL) successively, saturated nacl aqueous solution washing (50mL), merge organic phase, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, obtain title product [[(2R, 3R, 4S, 5R, 6S)-3, 4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-6-methoxyl group-tetrahydropyrans-2-yl] methoxyl group]-the tertiary butyl-dimethylsilane (10.44g, yellow oil).
preparation example 8:preparation [(2R, 3R, 4S, 5R, 6S)-3,4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-6-methoxyl group-tetrahydropyrans-2-yl] methyl alcohol
By [[(2R, 3R, 4S, 5R, 6S)-3,4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-6-methoxyl group-tetrahydropyrans-2-yl] methoxyl group]-the tertiary butyl-dimethylsilane (10.52g, 12.5mmol) is dissolved in 50mL methyl alcohol, drips Acetyl Chloride 98Min. (0.13mL, 1.9mmol), reaction 1 hour.Concentrating under reduced pressure reaction solution, purify gained resistates with eluent system B with silica gel column chromatography, obtain title product [(2R, 3R, 4S, 5R, 6S)-3, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 4,5-, tri-benzyloxies-6-[4-) methyl] phenyl]-6-methoxyl group-tetrahydropyrans-2-yl] methyl alcohol (7.56g, yellow oil).
preparation example 9:preparation (2S, 3S, 4S, 5R, 6S)-3,4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-6-methoxyl group-tetrahydropyrans-2-formaldehyde
By oxalyl chloride (1.17mL, 13.6mmol) be dissolved in 20mL methylene dichloride, be chilled to-78 DEG C, drip successively 20mL methyl-sulphoxide (1.56mL, dichloromethane solution 21.9mmol) and 50mL[(2R, 3R, 4S, 5R, 6S)-3, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 4,5-, tri-benzyloxies-6-[4-) methyl] phenyl]-6-methoxyl group-tetrahydropyrans-2-yl] dichloromethane solution of methyl alcohol (7.6g, 10.45mmol), at-78 DEG C, react 30 minutes, add triethylamine (7.25mL, 52.3mmol), under room temperature, react 2 hours.Add the hydrochloric acid soln of 50mL1M, separatory, saturated nacl aqueous solution washing (50mL × 2) for organic phase, dichloromethane extraction for water (50mL), merge organic phase, anhydrous magnesium sulfate drying, filters, concentrating under reduced pressure filtrate, obtain title product (2S, 3S, 4S, 5R, 6S)-3,4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-6-methoxyl group-tetrahydropyrans-2-formaldehyde (7.54g, colorless oil), be directly used in next step reaction without separation.
preparation example 10:preparation (2S, 3S, 4S, 5R, 6S)-3,4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-2-(methylol)-6-methoxyl group-tetrahydropyrans-2-formaldehyde
By (2S, 3S, 4S, 5R, 6S)-3, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 4,5-, tri-benzyloxies-6-[4-) methyl] phenyl]-6-methoxyl group-tetrahydropyrans-2-formaldehyde (7.6g, 10.45mmol) is dissolved in 80mL1, in 4-dioxane, the formalin and the sodium hydroxide solution (31.35mL, 31.35mmol) that add successively 15.8mL37% react 16 hours at 70 DEG C.Add 50mL saturated nacl aqueous solution, be extracted with ethyl acetate (50mL × 4), organic phase is used saturated sodium bicarbonate solution (50mL) successively, saturated nacl aqueous solution washing (50mL), merge organic phase, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, obtain title product (2S, 3S, 4S, 5R, 6S)-3, 4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-2-(methylol)-6-methoxyl group-tetrahydropyrans-2-formaldehyde (7.88g, colorless oil), be directly used in next step reaction without separation.
preparation example 11:preparation [(3S, 4S, 5R, 6S)-3,4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-2-(methylol)-6-methoxyl group-tetrahydropyrans-2-yl] methyl alcohol
By (2S, 3S, 4S, 5R, 6S)-3,4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-2-(methylol)-6-methoxyl group-tetrahydropyrans-2-formaldehyde (7.9g, 10.45mmol) is dissolved in the mixed solvent of 50mL tetrahydrofuran (THF) and methyl alcohol (v:v=2:3), adds sodium borohydride (794mg, 20.9mmol), reaction 30 minutes.Add a small amount of acetone, concentrating under reduced pressure reaction solution, purify gained resistates with eluent system A with silica gel column chromatography, obtain title product [(3S, 4S, 5R, 6S)-3, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 4,5-, tri-benzyloxies-6-[4-) methyl] phenyl]-2-(methylol)-6-methoxyl group-tetrahydropyrans-2-yl] methyl alcohol (1.14g, colorless oil).
preparation example 12:preparation [(1S, 2S, 3S, 4R, 5S)-2,3, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 4-tri-benzyloxies-5-[4-) methyl] phenyl]-6,8-dioxa dicyclo is [3.2.1] octane-1-yl also] methyl alcohol
By [(3S, 4S, 5R, 6S)-3,4, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5-tri-benzyloxies-6-[4-) methyl] phenyl]-2-(methylol)-6-methoxyl group-tetrahydropyrans-2-yl] methyl alcohol (1.11g, 1.46mmol) be dissolved in 20mL methylene dichloride, be chilled to-10 DEG C, add trifluoroacetic acid (0.23mL, 3mmol), under room temperature, react 2 hours.Add 20mL saturated sodium bicarbonate solution, separatory, dichloromethane extraction for water (20mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filters concentrating under reduced pressure filtrate, purify gained resistates with eluent system B with silica gel column chromatography, obtain title product [(1S, 2S, 3S, 4R, 5S)-2,3, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 4-tri-benzyloxies-5-[4-) methyl] phenyl]-6,8-dioxa dicyclo is [3.2.1] octane-1-yl also] methyl alcohol (836mg, colorless oil).MS?m/z(ESI)：742.3[M+18]。
preparation example 13:preparation (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol (being formula Io compound)
formula Io compound
By [(1S, 2S, 3S, 4R, 5S)-2,3, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 4-tri-benzyloxies-5-[4-) methyl] phenyl]-6,8-dioxa dicyclo is [3.2.1] octane-1-yl also] methyl alcohol (830mg, 1.14mmol) is dissolved in the mixed solvent of 20mL tetrahydrofuran (THF) and methyl alcohol (v:v=1:1), adds orthodichlorobenzene (1.3mL, 11.4mmol) and palladium/carbon (500mg, 10%), hydrogen exchange three times, reacts 3 hours.Filtering reacting liquid, with a small amount of ethyl acetate drip washing, concentrating under reduced pressure filtrate, purify gained resistates with eluent system A with silica gel column chromatography, obtain title product (1S, 2S, 3S, 4R, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5S)-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, and 3,4-triol (414mg, white solid).[HPLC method A] chromatographic purity 99.4%.MS?m/z(ESI)：472.2[M+18]。1H?NMR(400MHz，CD3OD)：δ7.47(s，1H)，7.42-7.35(m，2H)，6.95-6.87(m，3H)，4.16-4.14(m，1H)，4.06-4.02(m，4H)，3.85-3.70(m，2H)，3.67-3.54(m，4H)，1.37(t，3H)。
preparation example 14:preparation I compound, i.e. (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE mixture (1:1)
L-PROLINE (0.23g, 2mmol) is dissolved in 90% ethanol/water of 1.2mL, this solution is heated to micro-boiling, then add the solution of the Compound I o (0.5mmol) being dissolved in 4mL ethanol.Make gained solution be cooled to-20 DEG C and reach 2 hours, can form during this period solid.This solution is at room temperature placed 2 days.Make this container centrifugal, remove supernatant liquor.Remaining solid washs with normal hexane, makes this solid dry under vacuum, obtains white solid (0.044g), and it is the mole ratio 1:1 mixture of Compound I o and L-PROLINE, i.e. formula I compound.
Ultimate analysis, measured value: C, 56.75%; H, 5.83%; O, 25.29%.C27H33ClO9FN theoretical value C, 56.84%; H, 5.79%; O, 25.26%.
[HPLC method A] measures chromatographic purity 99.53%.
Moisture content: 0.07%, can ignore.
[HPLC method A] and PA method are measured also as calculated, this mixture Chinese style Io compound: the mol ratio of proline(Pro) is 1:1.02.
Above measurement result shows, this preparation example products therefrom is the 1:1 mixture of Compound I o and L-PROLINE.
preparation example 15:preparation formula Ia compound, i.e. (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE, one water complex (1:1:1)
L-PROLINE (0.23g, 2mmol) is dissolved in 90% ethanol/water of 1.2mL, this solution is heated to micro-boiling, then add the solution of the Compound I o (0.5mmol) being dissolved in 4mL ethanol.Slowly add acetone to 10% of cumulative volume, make gained solution be cooled to-20 DEG C and reach 2 hours, can form during this period solid.This solution is at room temperature placed 2 days.Make this container centrifugal, remove supernatant liquor.Remaining solid washs with normal hexane, makes this solid dry under vacuum, obtains white solid (0.057g), and it is the 1:1:1 mixture of Compound I o and L-PROLINE and a crystal water, i.e. formula Ia compound.
Ultimate analysis, measured value: C, 55.12%; H, 5.91%; O, 27.25%.C27H35ClO10FN theoretical value C, 55.10%; H, 5.95%; O, 27.21%.
[HPLC method A] measures chromatographic purity 99.53%.
Moisture content: 3.09%.
[HPLC method A] and PA method are measured also as calculated, this mixture Chinese style Io compound: the mol ratio of proline(Pro) is 1:0.99.
In addition, make this preparation example gained formula Ia compound carry out thermogravimetric analysis (TGA), result is presented at the weight loss (noncrystalline water) that only has <0.12% within the scope of 50 DEG C～110 DEG C, but within the scope of 110 DEG C～250 DEG C, there is typically losing the curve of crystal water, the weightlessness that weight-loss curve calculates in from 100 DEG C (being substantially platform within the scope of 50～110 DEG C) to 220 DEG C of (dehydration, now having reached plateau) scopes is about 3.14%.This result shows that this preparation example gained formula Ia compound is monohydrate equally, and result is consistent with Ka Er-Fei Xiushi moisture determination result 3.09%.
Above measurement result shows, this preparation example products therefrom is Compound I o and L-PROLINE and the water mixture with mole ratio 1:1:1 ratio, and molecular formula is the compound of formula C22H24ClO7FC5H9NO2H2O.
preparation example 16:preparation formula Ia compound, i.e. (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE, one water complex (1:1:1)
L-PROLINE (0.23g, 2mmol) is dissolved in 90% ethanol/water of 1.2mL, this solution is heated to micro-boiling, then add the solution of the Compound I o (0.5mmol) being dissolved in 4mL ethanol.Slowly add acetone to 5% of cumulative volume, make gained solution be cooled to-20 DEG C and reach 3 hours, can form during this period solid.This solution is at room temperature placed 1.5 days.Make this container centrifugal, remove supernatant liquor.Remaining solid washs with normal hexane, makes this solid dry under vacuum, obtains white solid (0.053g), and it is the 1:1:1 mixture of Compound I o and L-PROLINE and a crystal water, i.e. formula Ia compound.
Ultimate analysis, measured value: C, 55.15%; H, 5.92%; O, 27.24%; [HPLC method A] measures chromatographic purity 99.64%; Moisture content: 3.17%; Mixture Chinese style Io compound: the mol ratio of proline(Pro) is 1:0.98; TGA analyzes, the weightless <0.22% of weight-loss curve within the scope of from 50 DEG C to 110 DEG C, and the weightlessness of weight-loss curve within the scope of from 100 DEG C to 220 DEG C is about 3.06%.Result shows, this preparation example products therefrom is Compound I o and L-PROLINE and the water mixture with 1:1:1 ratio.
preparation example 17:preparation formula Ia compound, i.e. (1S, 2S, 3S, 4R, 5S) the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of-5-[4-) methyl] phenyl]-1-(methylol)-6,8-dioxa dicyclo is [3.2.1] octane-2 also, 3,4-triol L-PROLINE, one water complex (1:1:1)
L-PROLINE (0.23g, 2mmol) is dissolved in 90% ethanol/water of 1.2mL, this solution is heated to micro-boiling, then add the solution of the Compound I o (0.5mmol) being dissolved in 4mL ethanol.Slowly add acetone to 15% of cumulative volume, make gained solution be cooled to-20 DEG C and reach 2 hours, can form during this period solid.This solution is at room temperature placed 2.5 days.Make this container centrifugal, remove supernatant liquor.Remaining solid washs with normal hexane, makes this solid dry under vacuum, obtains white solid (0.062g), and it is the 1:1:1 mixture of Compound I o and L-PROLINE and a crystal water, i.e. formula Ia compound.
Ultimate analysis, measured value: C, 55.13%; H, 5.97%; O, 27.22%; [HPLC method A] measures chromatographic purity 99.48%; Moisture content: 3.03%; Mixture Chinese style Io compound: the mol ratio of proline(Pro) is 1:0.98; TGA analyzes, the weightless <0.17% of weight-loss curve within the scope of from 50 DEG C to 110 DEG C, and the weightlessness of weight-loss curve within the scope of from 100 DEG C to 220 DEG C is about 3.01%.Result shows, this preparation example products therefrom is Compound I o and L-PROLINE and the water mixture with 1:1:1 ratio.
preparation example 21:preparation Compound I o-L-proline(Pro)-water=1:1:1.5 mixture
With reference to the method for preparation example 15, different is slowly to add acetone to 25% of cumulative volume in the time adding acetone.This sample after measured, is following formula: compound C22H24ClO7FC5H9NO23/2H2O, and Compound I o and L-PROLINE and water are with the mixture of mole ratio 1:1:1.5 ratio.Test result is as follows: ultimate analysis, measured value: C, 54.23%; H, 6.04%; O, 28.12%; [HPLC method A] measures chromatographic purity 99.48%; Moisture content: 4.63%; Mixture Chinese style Io compound: the mol ratio of proline(Pro) is 1:1.05; The weightlessness of thermogravimetric analysis (TGA) weight-loss curve within the scope of from 100 DEG C to 220 DEG C is about 4.56%.
preparation example 22:preparation Compound I o-L-proline(Pro)-water=1:1:2 mixture
With reference to the method for preparation example 15, different is slowly to add acetone to 35% of cumulative volume in the time adding acetone.This sample after measured, is following formula: compound C22H24ClO7FC5H9NO22H2O, and Compound I o and L-PROLINE and water are with the mixture of mole ratio 1:1:2 ratio.Test result is as follows: ultimate analysis measured value: C, 53.44%; H, 6.09%; O, 29.02%; [HPLC method A] measures chromatographic purity 99.51%; Moisture content: 6.06%; Mixture Chinese style Io compound: the mol ratio of proline(Pro) is 1:1.02; The weightlessness of thermogravimetric analysis (TGA) weight-loss curve within the scope of from 100 DEG C to 220 DEG C is about 5.98%.
Visible according to above preparation example 14～preparation example 17 and preparation example 21～22, while adding in the methods of the invention appropriate acetone, can form the mixture containing crystal water, and the amount of crystal water is obviously relevant with the addition of acetone.
preparation example 23:prepare following formula Xo compound
formula Xo compound,
To { (2S, 3S)-2, the chloro-3-of 3,4-, tri--benzyloxy-5-[4-(4-ethoxy benzyl)-phenyl]-6,8-dioxa-dicyclo [3.2.1] is pungent-1-yl } (it can obtain by art methods-methyl alcohol, 335mg) at ethanol/tetrahydrofuran (THF) (10ml, 4/1) in the solution in, continuous adding formic acid (420 μ l, 22 equivalents) and palladium black (208mg, 4 equivalents), and formed mixture is at room temperature stirred.After 1 hour, add other formic acid (420 μ l, 22 equivalents) and palladium black (208mg, 4 equivalents), and mixture is at room temperature stirred one hour again.Filter palladium, then make the crude mixture obtaining after evaporating solvent by preparation HPLC purifying.
Preparation HPLC: anti-phase C18 post (Gemini post), 5 μ m × 30mm × 100mm, 40ml/min, gradient is acetonitrile/0.1% formic acid: water/0.1% formic acid; 25 to 50% acetonitrile/0.1% formic acid, go through 18 minutes; UV detects: 220nm.There are two essentially identical chromatographic peaks of peak area in retention time 12.4 minutes and 13.2min place, intercept the elutriant that retention time is located for 12.4 minutes, the fraction that contains product is under reduced pressure concentrated.Crude material is precipitated from vinyl acetic monomer and heptane.By formed white solid with heptane wash 2 times, and drying under reduced pressure (62mg).For following formula Xo compound:
formula Xo compound,
Formula Xo compound is the chloro-3-of (1S, 2S, 3S, 4R, 5S)-5-[4-(4-ethoxy benzyl)-phenyl]-1-methylol-6,8-dioxa-dicyclo [3.2.1] octane-2,3,4-triol.MS (LCMS) 437.2 (M+H+; Holotype); 481.4 (M+HCO2-; Negative mode).1H NMR (400MHz, methyl alcohol-d4) δ 7.43 (d, 1H, J=1.9Hz), 7.36 (dd, 1H, J=8.3 and 2Hz), 7.32 (d, 1H, J=8.3Hz), 7.08-7.04 (m, 2H), 6.79-6.75 (m, 2H), 4.12 (d, 1H, J=7.5Hz), 4.00 (s, 2H), 3.96 (q, 2H, J=7.0Hz), 3.81 (d, 1H, J=12.5Hz), 3.75 (dd, 1H, J=8.3 and 1.3Hz), 3.65 (d, 1H, J=12.5Hz), 3.63 (t, 1H, J=8.2Hz), 3.57 (dd, 1H, J=7.5 and 1.3Hz), 3.52 (d, 1H, J=8.0Hz), 1.33 (t, 3H, J=6.9Hz).To the HRMS calculated value 437.1361 of C22H26O7Cl (M+H+), measured value 437.1362.
preparation example 24:prepare following formula X compound
formula X compound
Use preparation example 23 gained formula Xo compounds to prepare (1S according to the method for preparation example 14 of the present invention for raw material, 2S, 3S, 4R, the chloro-3-of 5S)-5-[4-(4-ethoxy benzyl)-phenyl]-1-methylol-6,8-dioxa-dicyclo [3.2.1] octane-2,3,4-triol L-PROLINE mixture (1:1), is formula X compound.Ultimate analysis, measured value: C, 58.75%; H, 6.13%; O, 26.07%.C27H34ClO9N theoretical value C, 58.70%; H, 6.16%; O, 26.09%.[HPLC method A] measures chromatographic purity 99.53%.Moisture content: 0.11%, can ignore.[HPLC method A] and PA method are measured also as calculated, this mixture Chinese style Io compound: the mol ratio of proline(Pro) is 1:1.02.Above measurement result shows, this preparation example gained formula X compound is the 1:1 mixture of formula Xo compound and L-PROLINE.
preparation example 25:prepare following formula Xa compound
formula Xa compound
Taking preparation example 24 gained formula X compounds as raw material, according to the method for preparation example 15 of the present invention, but in the time adding acetone, slowly add acetone to 40% of cumulative volume, can obtain target product formula Xa compound is white solid (0.03g).Results of elemental analyses shows that itself and the title compound that is monohydrate coincide.[HPLC method A] measures chromatographic purity 99.45%.Moisture content: 3.18%, TGA shows dehydration 3.23%.[HPLC method A] and PA method are measured also as calculated, this mixture Chinese style Xo compound: the mol ratio of proline(Pro) is 1:1.07.Above measurement result shows, this preparation example products therefrom is formula Xo compound and L-PROLINE and the water mixture with 1:1:1 ratio, and molecular formula is the compound of formula C22H24ClO7FC5H9NO2H2O.
three, test example part
test example 1: rat pharmacokinetics test
(1) reagent: formula Io compound (preparation example 13 makes), formula I compound (preparation example 14 makes), formula Ia compound (preparation example 15 makes), formula Xo compound (preparation example 23 makes), formula X compound (preparation example 24 makes), formula Xa compound (preparation example 25 makes), each reagent is dissolved into the concentration of suitable administration with the aqueous solution that contains 20%PEG400 and 25% HYDROXYPROPYL BETA-CYCLODEXTRIN.
(2) method: according to CN102149717A (CN200980135661.2) specification sheets [0517] to [0535] section institute support method, animal rat (～300g) is divided into 6 groups at random, every group 5, each animal groups is oral one of the above-mentioned 6 kinds of compounds (dosage is 20 μ mol/kg body weight) that give respectively, respectively at 0 hour (before administration), 0.25h after administration, 0.5h, 0.75h, 1h, 2h, 4h, 6h, 8h, 12h, 18h, 24h is from 0.2 milliliter of blood of jugular vein sampling, process blood sample according to literature method, and use LC-MS/MS to analyze to measure the concentration (taking formula Io compound or formula Xo compound as reference substance) of different time blood sample Chinese style Io compound or formula Xo compound.
For each group, calculate the average blood plasma drug level (representing with nmol/ml) of each time point, then draw respectively its drug-time curve to each group, calculate under the drug-time curve of each group area and be AUC value (0->24 hour interval, with nmol × hour/ml represents).
(3) result: for every a series of medicine, calculate the relative AUC of mixture group with respect to its corresponding non-complexes group, for example, the relative AUC=of formula I compound group (formula I compound group AUC ÷ formula Io compound group AUC) × 100%; The relative AUC=(formula Ia compound group AUC ÷ formula Io compound group AUC) × 100% of formula Ia compound group; The relative AUC=(formula Xa compound group AUC ÷ formula Xo compound group AUC) × 100% of formula Xa compound group; Relative AUC=(formula Xo compound group AUC ÷ formula Xo compound group the AUC) × 100%=100% of formula Xo compound group.AUC value shows that more greatly this Compound Phase has larger bioavailability for its non-complexes relatively.Result is as table 1.
Table 1:
Group AUC relatively
Formula Io compound (Io) 100％
Formula I compound (Io/P, 1:1) 184％
Formula Ia compound (Io/P/W, 1:1:1) 191％
Formula Xo compound (Xo) 100％
Formula X compound (Xo/P, 1:1) 92％
Formula Xa compound (Xo/P/W, 1:1:1) 112％
In table bracket, for reagent annotates, for example (Io/P/W, 1:1:1) expression Ia compound is formula I compound: L-PROLINE: water is the mixture of mole ratio 1:1:1, and the similar statement in all the other or other place of the present invention all has similar meaning.Unexpectedly show, formula I compound of the present invention or formula Ia compound have than in obviously higher bioavailability of its non-complexes.
test example 2: external activity detects
(1) reagent: with test example 1
(2) method and result: according to CN102149717A (CN200980135661.2) specification sheets [0500] to [0511] section institute support method, every kind of compound is at least measured 10 times hSGLT1 and hSGLT2, shows that calculating IC50 value (representing with nmol/L) gets its average.Result is as table 2.
Table 2:
Compound IC50(nmol/L，hSGLT1) IC50(nmol/L，hSGLT2)
Formula Io compound (Io) 1437 4.23
Formula I compound (Io/P, 1:1) 1621 3.85
Formula Ia compound (Io/P/W, 1:1:1) 1484 4.42
Formula Xo compound (Xo) 1834 5.23
Formula X compound (Xo/P, 1:1) 1641 5.73
Formula Xa compound (Xo/P/W, 1:1:1) 1585 5.14
Above result shows, as proline(Pro) mixture or its further hydrate, its chemically reactive original shape medicine corresponding with it (Io or Xo) is suitable, further can not affect pharmaceutical activity with water formation mixture with proline(Pro) formation mixture or its.
test example 3: medicine draws moist
From the angle of biologic activity, formula Io compound, formula I compound, formula Ia compound are all the options feasible as material medicine.But those skilled in the art still expect that they have good pharmacy performance, for example, have low water absorbability.
Adopt Surface Measurements System Ltd., Dynamic Vapour Sorption (DVS) the automatic absorbing analyser DVS-1 instrument that UK produces, the water absorbability of some hydrates prepared by mensuration the present invention.
The test material of about 25mg is accurately weighed and is placed in sample disc.Be exposed in the humidity environment of relative humidity 0～90%.Within the scope of 0～15%RH, adopt 1%RH gradient to carry out detailed analysis, within the scope of 15～90%RH, adopt 15%RH gradient to carry out detailed analysis.Analysis temperature is 30 DEG C, and nitrogen flow rate is 200 cubic centimetres/min.
Fig. 1 has shown the moisture sorption isotherm of the formula Ia compound that preparation example 15 obtains.When this thermoisopleth shows about 8%RH, sample forms monohydrate, but this material has lost the water of approximately 3% (w/w) all in its monohydrate molecular structure in the time of 0%RH.Once formation monohydrate, even if also seldom moisture absorption under high humidity environment has for example only absorbed the water lower than 0.3% (w/w) in the scope of 10%-90%RH, this result shows that formula Ia compound of the present invention is nonhygroscopic substantially.In addition, also show that the sorption and desorption curve of formula Ia compound of the present invention is quite identical, further proved that the water absorbability of formula Ia compound of the present invention is low.
In addition, also can be by the above-mentioned character of following simple moisture absorption weightening finish percentage ratio evidence: make the about 2g of formula Ia compound of precise weighing be placed in 30 DEG C, relative humidity 80% condition and assign 10 hours, weight difference before and after processing with this calculates the moisture absorption weightening finish percentage ratio of material, and the weight of forward and backward increase in 10 hours is multiplied by the percentage ratio of 100% gained again divided by material initial weight.Result shows that formula Ia compound that this preparation example 15 obtains moisture absorption weightening finish percentage ratio is with this understanding 0.26%.
In addition, moisture absorption weightening finish percentage ratio (weightening finish %, 30 DEG C-RH80%-10h) and their the crystal water changing conditions (DVS) of some compounds that test the present invention obtains, result is as table 3.
Table 3:
Compound Weightening finish % Crystal water changes
Formula I compound (preparation example 14, I/P/W=1/1/0) 2.76％ Sorption and desorption curve is misfitted, water yield when absorption finishes > 6%
Formula Ia compound (preparation example 15, I/P/W=1/1/1) 0.28％ Sorption and desorption curves, the crystallization water yield is unchanged
Formula Ia compound (preparation example 16, I/P/W=1/1/1) 0.33％ Sorption and desorption curves, the crystallization water yield is unchanged
Formula Ia compound (preparation example 17, I/P/W=1/1/1) 0.16 Sorption and desorption curves, the crystallization water yield is unchanged
Preparation example 21 compounds (I/P/W=1:1:1.5) 3.22％ Sorption and desorption curve is misfitted, water yield when absorption finishes > 8%
Preparation example 22 compounds (I/P/W=1:1:2) 4.16％ Sorption and desorption curve is misfitted, water yield when absorption finishes > 8%
Formula X compound (preparation example 24, X/P/W=1/1/0) 2.45％ Sorption and desorption curve is misfitted, water yield when absorption finishes > 6%
Formula Xa compound (preparation example 25, X/P/W=1/1/1) 3.02％ Sorption and desorption curve is misfitted, water yield when absorption finishes > 6%
Above result demonstration, the mixture of the present invention that contains a crystal water has good agent of low hygroscopicity energy, and anhydride or more high water content hydrate easily present larger moisture absorption, this is totally unfavorable for drug manufacture.
test example 4: the chemical stability of medicine
The compounds of this invention vial is sealed, be placed under 40 DEG C of conditions and place 6 months, measure the content of each sample Chinese style Xo compound with HPLC method A, the remaining percentage amounts while calculating when June with respect to 0 month, June, content was multiplied by the percentage ratio of 100% gained again divided by 0 month content.Result is as table 4.
Table 4:
Compound June remaining percentage amounts
Formula Io compound (preparation example 13, I) 95.4％
Formula I compound (preparation example 14, I/P/W=1/1/0) 94.7％
Formula Ia compound (preparation example 15, I/P/W=1/1/1) 96.3％
Formula Ia compound (preparation example 16, I/P/W=1/1/1) 95.8％
Formula Ia compound (preparation example 17, I/P/W=1/1/1) 95.3％
Preparation example 21 compounds (I/P/W=1:1:1.5) 92.1％
Preparation example 22 compounds (I/P/W=1:1:2) 90.5％
Above result shows, formula Io compound or itself and L-PROLINE form mixture or further form a water complex with water, their chemical stability is without obvious difference, but in the time that crystal water continues to increase, exhibit stabilization reduces significantly, approaches 90% defective limit.
test example 5: formula Ia compound and lipid acid composite test
In various composition test examples of the present invention, if not otherwise specified, the activeconstituents of use and complementary composition are all can pass through 80 object fine powders through pulverizing to form.
Getting can be by the formula Ia compound of 80 order fine powder states (preparation example 15 makes), separately get and can pass through stearic acid or the Magnesium Stearate of 80 order fine powder states, formula Ia compound (each mixture is at least used the amount of 10g) is ground well in mortar with a certain amount of stearic acid as shown in the table or salt, pack in aluminum-plastic composite membrane sack, then each sample is placed in to 50 DEG C of thermostat containers and places 4 months (can dispose referred to as " 50 DEG C of April " in the present invention).For each sample, use [HPLC method A] to measure their maximum single contaminant content and total impurities content in the time of 0 month, and measure their maximum single contaminant content and total impurities content in the time of 50 DEG C of April, calculating respectively maximum single contaminant by following formula increases percentage ratio and total impurities increase percentage ratio:
Maximum single contaminant increases percentage ratio=[(50 DEG C of maximum single contaminant in April content-0 month maximum single contaminant content) 0 month maximum single contaminant content of ÷] × 100%
Total impurities increases percentage ratio=[(50 DEG C of total impurities in April content-0 month total impurities content) 0 month total impurities content of ÷] × 100%
The results are shown in Table 5.
Table 5:
The two weight ratio of stearic acid: Ia when the first hurdle in upper table " stearic acid: Ia " represents to mix, for example this value is to represent that 0 part of stearic acid mixes with 1 part of Ia at 0 o'clock, this value is to represent that 0.01 part of stearic acid mixes with 1 part of Ia at 0.01 o'clock, and this value is to represent that 200 parts of stearic acid mix with 1 part of Ia at 200 o'clock, etc.; The 4th hurdle also has similar meaning similarly.
Visible according to upper table result, withstand high temperatures environment better when the combination of formula Ia compound and stearic acid or stearyl ester magnesium, be particularly in the scope of 1:0.05～2 in the weight ratio of formula Ia compound and described lipid acid or its pharmacologically acceptable salts, there is the result of obvious excellence, although the weight ratio of formula I compound and described lipid acid or its pharmacologically acceptable salts is that in the scope of 1:3～10, impurity increase is not remarkable, but excessive lipid acid or its pharmacologically acceptable salts are present in for example compressing tablet performance of other performance that may have influence on medicine in formula, conventionally consumption is tablet weight 0.5～10% particularly in 0.5～5% scope particularly in 0.5～2.5% scope, because the inventive example can be 1～50mg as being the every amount containing activeconstituents in the composition of tablet, therefore the above-mentioned ratio that lipid acid or the amount of its pharmacologically acceptable salts in tablet both can meet itself and activeconstituents also can meet the ratio of itself and tablet total weight.
supplementary test example 51:with reference to the method for above test example 5, different is only that active medicine is used instead as formula I compound (preparation example 14 gained anhydrides).Basic identical in result and table 5, maximum single contaminant increases (%) and total impurities and increases in (%) and table 5 corresponding proportioning acquired results and differ and be all no more than 8 percentage points (weight ratio of formula I compound and described lipid acid or its salt is in the scope of 1:0.05～2) or be all no more than 16 percentage points (weight ratio of formula I compound and described lipid acid or its salt is that 1:0～0.02 scope is interior) or be all no more than 14 percentage points (weight ratio of formula I compound and described lipid acid or its salt is that 1:3～10 scope is interior).For example, stearic acid: in I=0.2:1 proportioning, maximum single contaminant increases (%) and total impurities increase (%) is respectively 27% and 34%.
supplementary test example 52:with reference to the method for above test example 5, different is only that active medicine is used instead as preparation example 22 gained dihydrates (mixture of formula Io/L-proline(Pro)/water=1:1:2).Basic identical in result and table 5, maximum single contaminant increases (%) and total impurities and increases in (%) and table 5 corresponding proportioning acquired results and differ and be all no more than 9 percentage points (weight ratio of active medicine and described lipid acid or its salt is in the scope of 1:0.05～2) or be all no more than 16 percentage points (weight ratio of active medicine and described lipid acid or its salt is that 1:0～0.02 scope is interior) or be all no more than 14 percentage points (weight ratio of active medicine and described lipid acid or its salt is that 1:3～10 scope is interior).For example, Magnesium Stearate: in active medicine=0.2:1 proportioning, maximum single contaminant increases (%) and total impurities increase (%) is respectively 26% and 39%.
supplementary test example 53:with reference to the method for above test example 5, different is only that active medicine is used instead as preparation example 25 gained formula Xa compounds (mixture of formula Xo/L-proline(Pro)/water=1:1:1).Result shows and does not present completely and variation tendency shown in table 5: under various mixed ratio conditions maximum single contaminant increase (%) all in 128～271% scopes and with mixed ratio irregularities; Under various mixed ratio conditions total impurities increase (%) all in 161～312% scopes and with mixed ratio irregularities.For example, stearic acid: in Xa=0.2:1 proportioning, maximum single contaminant increases (%) and total impurities increase (%) is respectively 174% and 226%.
supplementary test example 54:with reference to No.3, the No.7 of above test example 5 tables 5, formula and the method for No.12, No.14, different is only that stearic acid is wherein replaced with to PEG 8000, obtains four samples; With reference to No.3, the No.7 of above test example 5, formula and the method for No.12, No.14, different is only that stearic acid is wherein replaced with to colloid silica, obtains four samples; With reference to No.3, the No.7 of above test example 5, formula and the method for No.12, No.14, different is only that stearic acid is wherein replaced with to talcum powder, obtains four samples.Dispose to investigate maximum single contaminant increase percentage ratio and the total impurities increase percentage ratio of each sample 50 DEG C of April that these 12 samples are shone to test example 5.Result shows and does not present completely and variation tendency shown in table 5: when formula Ia compound mixes with PEG, colloid silica or talcum powder, maximum single contaminant increase (%) all in 142～263% scopes and with mixed ratio irregularities; When formula Ia compound mixes with PEG, colloid silica or talcum powder, total impurities increase (%) all in 172～306% scopes and with mixed ratio irregularities.
test example 6: the test of formula Ia compound, lipid acid and pharmaceutical excipient combination
Getting can be by the formula Ia compound of 80 order fine powder states (preparation example 15 makes), separately gets and can pass through stearic acid or the Magnesium Stearate of 80 order fine powder states, and can pass through the pharmaceutical excipient described below of 80 order fine powder states.By weight formula Ia compound: stearic acid or salt: starch: Microcrystalline Cellulose: lactose=1:(0,0.05,0.2,2 or 5): 3:3:3, in mortar, these materials are ground well, pack in aluminum-plastic composite membrane sack, then each sample is placed in to 50 DEG C of thermostat containers and places 4 months.Measure the maximum single contaminant of each sample after 50 DEG C of April with reference to the method for test example 5 and increase percentage ratio and total impurities increase percentage ratio.The result of the corresponding proportioning group of result and table 5 Chinese style Ia compound and stearic acid or its salt is basic identical, and maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 5: the corresponding proportioning acquired results of stearic acid or salt differs and is all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.05,0.2 or 2) or is all no more than 20 percentage points (formula Ia compounds: stearic acid or salt=0) or is all no more than 18 percentage points (formula Ia compounds: stearic acid or salt=5).For example, comprise Ia: in the mixture of stearic acid=1:0.2 proportioning, maximum single contaminant increases (%) and total impurities increase (%) is respectively 26% and 35%.
supplementary test example 61:with reference to the method for above test example 6, different is only that active medicine is used instead as formula I compound (preparation example 14 gained anhydrides).The result of the corresponding proportioning group of result and table 5 Chinese style Ia compound and stearic acid or its salt is basic identical, and maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 5: the corresponding proportioning acquired results of stearic acid or salt differs and is all no more than 9 percentage points (formula Ia compounds: stearic acid or salt=0.05,0.2 or 2) or is all no more than 18 percentage points (formula Ia compounds: stearic acid or salt=0) or is all no more than 17 percentage points (formula Ia compounds: stearic acid or salt=5).
supplementary test example 62:with reference to the method for above test example 6, different is only that active medicine is used instead as preparation example 22 gained dihydrates (mixture of formula Io/L-proline(Pro)/water=1:1:2).The result of the corresponding proportioning group of result and table 5 Chinese style Ia compound and stearic acid or its salt is basic identical, and maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 5: the corresponding proportioning acquired results of stearic acid or salt differs and is all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.05,0.2 or 2) or is all no more than 19 percentage points (formula Ia compounds: stearic acid or salt=0) or is all no more than 21 percentage points (formula Ia compounds: stearic acid or salt=5).
supplementary test example 63:with reference to the method for above test example 6, different is only that active medicine is used instead as preparation example 25 gained formula Xa compounds (mixture of formula Xo/L-proline(Pro)/water=1:1:1).Result shows and does not present completely and variation tendency shown in table 5: under various mixed ratio conditions maximum single contaminant increase (%) all in 135～286% scopes and with mixed ratio irregularities; Under various mixed ratio conditions total impurities increase (%) all in 155～334% scopes and with mixed ratio irregularities.For example, Xa: stearic acid: starch: Microcrystalline Cellulose: in lactose=1:0.2:3:3:3 proportioning, maximum single contaminant increases (%) and total impurities increase (%) is respectively 18%6 and 235%.
test example 7: formula Ia compound and sugar alcohol composite test
(preparation example 15 makes modus ponens Ia compound, lower same), separately get lactose and/or N.F,USP MANNITOL (the two summation is called sugar alcohol), formula Ia compound and a certain amount of sugar alcohol as shown in the table are ground well in mortar, be pressed into tablet, every contains activeconstituents in formula Io compound 10mg (very few for supplementary product consumption, to press the heavy 100mg compacting of sheet for every).
Modus ponens Ia compound, separately get lactose and/or N.F,USP MANNITOL (the two summation is called sugar alcohol) and other conventional pharmaceutical excipient, formula Ia compound and a certain amount of sugar alcohol as shown in the table and other pharmaceutical excipient are ground well in mortar, be pressed into tablet, every contains activeconstituents in formula Io compound 10mg (very few for supplementary product consumption, to press the heavy 100mg compacting of sheet for every).
Modus ponens Ia compound, separately get other the conventional pharmaceutical excipient except lactose and N.F,USP MANNITOL, formula Ia compound and a certain amount of conventional pharmaceutical excipient as shown in the table are ground well in mortar, be pressed into tablet, every contains activeconstituents in formula Io compound 10mg (very few for supplementary product consumption, to press the heavy 100mg compacting of sheet for every).
The tablet of these different ingredients is carried out to dissolution rate test, according to Chinese Pharmacopoeia two annex XC dissolution method the second methods of version (oar method) in 2010, taking 500ml water as dissolution medium, stirring velocity 50rpm, 45min sampling and measuring dissolution rate.The results are shown in Table 6.
Table 6:
No. * prepares burden/compares Dissolution rate/stripping phenomenon No. * prepares burden/compares Dissolution rate/stripping phenomenon
1 Ia/ breast=10/0 44%, serious gelling 18 Ia/ Xylitol=10/50 38%, serious gelling
2 Ia/ breast=10/10 61%, there is gelling 19 Ia/ dextrin=10/50 41%, serious gelling
3 Ia/ breast=10/20 89%, collapse and clear entirely 20 Ia/MCC＝10/50 51%, serious gelling
4 Ia/ breast=10/50 93%, collapse and clear entirely 21 Ia/ starch=10/50 46%, serious gelling
5 Ia/ breast=10/100 88%, collapse and clear entirely 22 Ia/ forms sediment in advance=and 10/50 42%, serious gelling
6 Ia/ breast=10/200 91%, collapse and clear entirely 23 Form sediment in advance/SDS=10/50/2 of Ia/ 48%, serious gelling
7 Ia/ is sweet=and 10/10 59%, there is gelling 24 Hydroxyl=10/50/10, Ia/ sorbyl alcohol/shallow lake 43%, serious gelling
8 Ia/ is sweet=and 10/20 86%, collapse and clear entirely 25 Ia/ breast/MCC=10/50/50 93%, collapse and clear entirely
9 Ia/ is sweet=and 10/60 92%, collapse and clear entirely 26 Hydroxyl=10/50/50/10, Ia/ breast/MCC/ shallow lake 95%, collapse and clear entirely
10 Ia/ is sweet=and 10/120 89%, collapse and clear entirely 27 Ia/ breast/starch=10/50/50 89%, collapse and clear entirely
11 Ia/ is sweet=and 10/200 93%, collapse and clear entirely 28 Ia/ breast/dextrin=10/50/50 95%, collapse and clear entirely
12 Ia/ breast/sweet=10/10/10 89%, collapse and clear entirely 29 Ia/ is sweet/MCC=10/50/50 92%, collapse and clear entirely
13 Ia/ breast/sweet=10/25/25 93%, collapse and clear entirely 30 Ia/ is sweet/starch=10/50/50 88%, collapse and clear entirely
14 Ia/ breast/sweet=10/50/50 88%, collapse and clear entirely 31 Ia/ is sweet/dextrin=10/50/50 91%, collapse and clear entirely
15 Ia/ breast/sweet=10/100/100 94%, collapse and clear entirely 32 Ia/ breast/sweet/MCC=10/25/25/50 94%, collapse and clear entirely
16 Ia/ sucrose=10/50 39%, serious gelling 33 Ia/ breast/sweet/starch=10/25/25/50 90%, collapse and clear entirely
17 Ia/ sorbyl alcohol=10/50 46%, serious gelling 34 Ia/ is sweet/starch/SDS=10/50/50/2 94%, collapse and clear entirely
* ratio of components is weight ratio, and wherein the amount of Ia is with Io weighing scale; " breast " represents lactose, and " sweet " represents N.F,USP MANNITOL; MCC represents Microcrystalline Cellulose; " starch " represents W-Gum; " form sediment in advance " and represent pregelatinized Starch; " shallow lake hydroxyl " represents sodium starch glycolate, and it is a kind of classical, efficient disintegrating agent; SDS be sodium lauryl sulphate its be a kind of classical efficient solubilizing agents." there is gelling " and refer to forming in tablet process in leaching bulk thing as a form of gel and in whole process in leaching tablet can not leach; " collapse and clear entirely " and represent that tablet collapses loose beading completely and is typical good stripping phenomenon in process in leaching.
As everyone knows, above-mentioned dissolution rate testing method is the particularly dissolution rate testing method of tablet of typical solid pharmaceutical preparation, typically with this understanding the dissolution rate result of test to be greater than 75% be gratifying while being particularly greater than 80%, and when dissolution rate result is less than 70%, can not make us acceptance.According to above result, as Ia: the tablet being pressed into is being gratifying aspect dissolving out capability when sugar alcohol=1:2～the 20.And sugar alcohol can be because not adding pharmaceutical excipient to change to result of extraction; And if do not use sugar alcohol, even if add superdisintegrantes or efficient solubilizing agents as shown in No.23, No.24, also can not obtain equally good result of extraction.
supplementary test example 71:
With reference to formula and the method for above test example 7, different is only the formula I compound (preparation example 14 makes, lower same) that the formula Ia compound wherein using is replaced with to equivalent.Result shows, from the tablet (being only that activeconstituents is different) obtaining in the corresponding various batching situations of table 6, in their dissolution rate and stripping phenomenon and table 6, the result of corresponding batching tablet is basic identical, for example No.1, No.16～24 all occur that serious gelling and dissolution rate are all in 33～52% scopes, No.2, No.7 all occur that gelling and dissolution rate are all in 55～65% scopes, and other sample all collapses and clears complete and dissolution rate all in 85～97% scopes.
supplementary test example 72:
With reference to formula and the method for above test example 7, different is only the formula Xa compound (preparation example 25 makes) that the formula Ia compound wherein using is replaced with to equivalent.Result shows, gelling does not all appear in the gained tablet of all preparing burden, but dissolution rate is all in 57～81% scopes and there are no regularity.
four, composition Preparation Example part
Following examples preparation is the solids composition of the present invention of pharmaceutical dosage forms.
In following instance, use ordinary method to prepare tablet or capsule, the addition manner of the conventional thinner that wherein sugar alcohol of the present invention can photo agent/capsule adds in suitable processing step, stearic acid of the present invention or its salt can photo agent/capsule the addition manner of traditional lubrication agent agent in suitable processing step, add, for example, and other has diluting effect auxiliary material (Microcrystalline Cellulose), disintegration auxiliary material (for example crosslinked carboxymethyl fecula sodium), or adhesive effect auxiliary material (for example HPMC) also adds in suitable processing step with its usual manner.
embodiment 1:prepare tablet of the present invention or capsule
Formula (every amount, mg):
Formula Ia compound 10
Stearic acid 5
Lactose 50
Microcrystalline Cellulose 35
Crosslinked carboxymethyl fecula sodium 5
HPMC 2
Method for making: 100 mesh sieves are pulverized respectively and crossed to each material.HPMC is made into 5% aqueous solution for subsequent use as tackiness agent.Activeconstituents, sugar alcohol and other thinner are fully mixed, with tackiness agent softwood processed, granulate, dry.Dry gained particle is mixed with stearic acid and crosslinked carboxymethyl fecula sodium, is eventually mixed particle.Mixed 2/3 end particle is pressed into tablet, counts 10mg containing formula Ia compound with formula Io compound for every.Mixed other 1/3 end particle is directly filled in hard capsule case, and every capsules is counted 10mg containing formula Ia compound with formula I compound.
embodiment 2:prepare tablet of the present invention or capsule
Formula (every amount, mg):
Formula Ia compound 10
Stearic acid 10
N.F,USP MANNITOL 35
Starch 50
Low-substituted hydroxypropyl cellulose 5
PVP?K30 3
Method for making: 100 mesh sieves are pulverized respectively and crossed to each material.PVP K30 is made into 5% aqueous solution for subsequent use as tackiness agent.By formula I compound with partly measure stearic acid and mix, more fully mix with starch, N.F,USP MANNITOL, with tackiness agent softwood processed, granulate, dry.Dry gained particle is mixed with surplus Magnesium Stearate and low-substituted hydroxypropyl cellulose, is eventually mixed particle.Mixed 2/3 end particle is pressed into tablet, counts 10mg containing formula Ia compound with formula Io compound for every.Mixed other 1/3 end particle is directly filled in hard capsule case, and every capsules is counted 10mg containing formula Ia compound with formula I compound.
embodiment 3:prepare tablet of the present invention or capsule
Formula (every amount, mg):
Formula Ia compound 10
Stearic acid 2
N.F,USP MANNITOL 80
Lactose 120
Low-substituted hydroxypropyl cellulose 5
Colloid silica 2
PVP?K30 3
Method for making: 100 mesh sieves are pulverized respectively and crossed to each material.PVP K30 is made into 5% aqueous solution for subsequent use as tackiness agent.Formula I compound is mixed with stearic acid, more fully mix with N.F,USP MANNITOL, lactose, with tackiness agent softwood processed, granulate, dry.Dry gained particle is mixed with colloid silica and low-substituted hydroxypropyl cellulose, is eventually mixed particle.Mixed 1/2 end particle is pressed into tablet, counts 10mg containing formula Ia compound with formula I compound for every.Mixed other 1/2 end particle is directly filled in hard capsule case, and every capsules is counted 10mg containing formula Ia compound with formula Io compound.
embodiment 4:prepare tablet of the present invention or capsule
Formula (every amount, mg):
Formula Ia compound 10
Stearic acid 0.5
N.F,USP MANNITOL 20
Dextrin 50
Starch 30
Low-substituted hydroxypropyl cellulose 5
Colloid silica 5
PVP?K30 3
Method for making: 100 mesh sieves are pulverized respectively and crossed to each material.Formula Ia compound being divided and mixed with stearic acid, more fully mix with each material, suppressed large stretch of block, then be broken into and can pass through 18 object particles, is eventually mixed particle.Mixed 2/3 end particle is pressed into tablet, counts 10mg containing formula Ia compound with formula I compound for every.Mixed other 1/3 end particle is directly filled in hard capsule case, and every capsules is counted 10mg containing formula Ia compound with formula I compound.
embodiment 5:prepare tablet of the present invention or capsule
Formula (every amount, mg):
Formula Ia compound 5
Calcium stearate 2
MCC 50
Lactose 35
Low-substituted hydroxypropyl cellulose 5
Colloid silica 5
PVP?K30 2
Method for making: the method for reference example 4 is prepared tablet or capsule.Count 5mg containing formula Ia compound with formula I compound for every, every capsules is counted 5mg containing formula Ia compound with formula I compound.
embodiment 6:the formula of reference example 1 and method for making, different is only stearic acid wherein to be replaced with to Magnesium Stearate.
embodiment 7:the formula of reference example 2 and method for making, different is only stearic acid wherein to be replaced with to Magnesium Stearate.
embodiment 8:the formula of reference example 3 and method for making, different is only stearic acid wherein to be replaced with to Magnesium Stearate.
embodiment 9:the formula of reference example 4 and method for making, different is only stearic acid wherein to be replaced with to Magnesium Stearate.
embodiment 10:the formula of reference example 5 and method for making, different is only stearic acid wherein to be replaced with to Magnesium Stearate.
embodiment 11:the formula of reference example 1 and method for making, different is only formula Ia compound wherein to be replaced with to formula I compound.
embodiment 12:the formula of reference example 2 and method for making, different is only formula Ia compound wherein to be replaced with to formula I compound.
embodiment 13:the formula of reference example 3 and method for making, different is only formula Ia compound wherein to be replaced with to formula I compound.
embodiment 14:the formula of reference example 4 and method for making, different is only formula Ia compound wherein to be replaced with to formula I compound.
embodiment 15:the formula of reference example 5 and method for making, different is only formula Ia compound wherein to be replaced with to formula I compound.
embodiment 16:the formula of reference example 6 and method for making, different is only formula Ia compound wherein to be replaced with to formula I compound.
embodiment 17:the formula of reference example 7 and method for making, different is only formula Ia compound wherein to be replaced with to formula I compound.
embodiment 18:the formula of reference example 8 and method for making, different is only formula Ia compound wherein to be replaced with to formula I compound.
embodiment 19:the formula of reference example 9 and method for making, different is only formula Ia compound wherein to be replaced with to formula I compound.
embodiment 20:the formula of reference example 10 and method for making, different is only formula Ia compound wherein to be replaced with to formula I compound.
test example 8:the dissolving out capability test of solid composite medicament
Get the Tablet and Capsula agent that above embodiment 1～20 obtains, respectively according to the dissolution rate testing method of test example 7 above, measure the dissolution rate of these samples.Result: all the dissolution rate of Tablet and Capsula agent in the time of 45min all in 85～95% scopes, and all collapses clear complete, non-gelling phenomenon.
test example 9: solid composite medicament study on the stability
Get the tablet that above embodiment 1～20 obtains, pack in aluminum-plastic composite membrane sack, then each sample is placed in to 45 DEG C of thermostat containers and places 5 months (can dispose referred to as " 45 DEG C of Mays " in the present invention).The reference method of test example 5 above, for each sample, use [HPLC method A] to measure their maximum single contaminant content and total impurities content in the time of 0 month, and measure their maximum single contaminant content and total impurities content in the time of 45 DEG C of Mays, the maximum single contaminant that calculates respectively each sample increases percentage ratio and total impurities increase percentage ratio.The whole tablets of result: embodiment 1～20, maximum single contaminant increases percentage ratio and is all less than 50%, all in 22～46% scopes; Total impurities increases percentage ratio and is all less than 60%, all in 29～62% scopes.Show that these compositions have satisfactory stability.

Claims (10)

1. compound shown in formula I:
Or its solvate.
2. the compound of claim 1, wherein said solvate is hydrate; It is for example monohydrate; Be for example with following formula Ia compound:
3. the compound of claim 1, is characterized in that following any one or multinomial:
(1) it is formula Ia compound compound, and it is in the time of relative humidity 10%～90%, and water content is 2.5%～3.5%, and for example water content is 2.8%～3.3%;
(2) it is formula Ia compound compound, and it is exposed under relative humidity 80% condition after 10 hours at 30 DEG C, and moisture absorption weightening finish is less than 1%, for example, be less than 0.5%, for example, be less than 0.3% (w/w);
(3) it is in the weight-loss curve of thermogravimetric analysis (conventionally can referred to as TGA) test, the weightless <1% (for example <0.5%, for example <0.25%) of weight-loss curve within the scope of from 50 DEG C to 110 DEG C;
(4) it is in the weight-loss curve of thermogravimetric analysis (conventionally can referred to as TGA) test, the weightlessness of weight-loss curve within the scope of from 100 DEG C to 220 DEG C is 2～4% (for example 2.5%～3.5%, for example 2.8%～3.3%, for example 2.9%～3.1%, for example approximately 3%).
4. the compound of claim 1～3 any one is in the purposes of preparing in sodium dependent glucose transporter inhibitors; Or the compound of claim 1～3 any one is for the preparation for the treatment of or delay the purposes in the medicine of following advancing of disease or outbreak: level, hyperlipidaemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication or atherosclerosis or the hypertension of the rising of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, lipid acid or glycerine.
5. a solid composite medicament, wherein comprises:
(a) as activeconstituents with following formula I compound or its solvate:
(b) lipid acid or its pharmacologically acceptable salts; And optional
(c) pharmaceutical excipient, or further, described formula I compound or its solvate are the compounds described in claim 1～3 any one.
6. the solid composite medicament of claim 5, is characterized in that following any one or multinomial:
(1) wherein said lipid acid is stearic acid, the pharmacologically acceptable salts of for example described lipid acid is magnesium salts, sodium salt, calcium salt, the zinc salt of lipid acid, for example described lipid acid or its pharmacologically acceptable salts are selected from: stearic acid, Magnesium Stearate, calcium stearate, sodium stearate, Zinic stearas and combination thereof, and for example described lipid acid or its pharmacologically acceptable salts are selected from: stearic acid, Magnesium Stearate, calcium stearate and combination thereof;
(2) wherein said pharmaceutical excipient includes but not limited to thinner or weighting agent, disintegrating agent, tackiness agent, lubricant or glidant;
(3) wherein said thinner or weighting agent include but not limited to: starch is W-Gum, dextrin, Microcrystalline Cellulose, modified starch, pregelatinized Starch, N.F,USP MANNITOL, lactose, sucrose, sorbyl alcohol, D-glucitol, erythritol, Xylitol, fructose etc. such as;
(4) described solid composite medicament comprises sugar alcohol (it is selected from: lactose, N.F,USP MANNITOL or its combination);
(5) weight ratio of formula I compound or its solvate (taking formula Io compound weighing scale) and described sugar alcohol is as 1:1～100, for example 1:2～100, for example 1:2～50, for example 1:2～20;
(6) wherein said pharmaceutical excipient also optionally comprises and is selected from following thinner or weighting agent: starch is W-Gum, dextrin, Microcrystalline Cellulose, modified starch, pregelatinized Starch, sucrose, sorbyl alcohol, D-glucitol, erythritol, Xylitol, fructose and combination thereof for example;
(7) wherein said disintegrating agent includes but not limited to: low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, cross-linked carboxymethyl cellulose sodium, starch;
(8) wherein said tackiness agent is such as but not limited to hydroxypropylcellulose, Vltra tears, polyvinylpyrrolidone, polyvinyl alcohol;
(9) wherein said lubricant includes but not limited to: Liquid Paraffin, polyoxyethylene glycol, silicon-dioxide, colloid silica, micropowder silica gel, talcum powder, hydrogenated vegetable wet goods or its combination;
(10) weight ratio of described formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.01～100;
(11) described lipid acid or its pharmacologically acceptable salts account for as 0.5～10% of tablet weight;
(12) described pharmaceutical excipient accounts for 0～99.5% of said composition weight;
(13) it is the dosage form that is tablet, capsule, granule, piller etc.;
(14) it is to be tablet, capsule, granule, the unit dose formulations form of piller etc., in described each unit dose formulations form, the amount of contained I compound or its solvate is amounted to into (1S, 2S, 3S, 4R, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5S)-5-[4-) methyl] phenyl]-1-(methylol)-6, 8-dioxa dicyclo is [3.2.1] octane-2 also, 3, 4-triol L-PROLINE is counted 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
7. the solid composite medicament of claim 5, is characterized in that following any one or multinomial:
(1) method in its first method (taking Xiu Shi method) it " A. volumetric precipitation method " in two annex VIIIM aquametries of Chinese Pharmacopoeia version in 2010 is measured, this solid composite medicament contains the moisture that is greater than 0.1%, for example contain the moisture that is greater than 0.2%, for example, contain 0.2%～5% moisture;
(2) wherein contain formula Io compound and L-PROLINE, the two mol ratio of formula Io compound and L-PROLINE is that 1:0.9～1.1, particularly mol ratio are 1:0.95～1.05.
8. solid composite medicament, wherein comprises:
(a) as activeconstituents with following formula I compound or itself or its solvate:
(b) sugar alcohol; And optional
(c) pharmaceutical excipient, or further, described formula I compound or its solvate are the compounds described in claim 1～3 any one.
9. the solid composite medicament of claim 8, is characterized in that following any one or multinomial:
(1) wherein said sugar alcohol is selected from: N.F,USP MANNITOL, lactose, sorbyl alcohol, D-glucitol, erythritol, Xylitol, fructose or its combination;
(2) wherein said sugar alcohol is selected from: N.F,USP MANNITOL, lactose or its combination;
(3) weight ratio of formula I compound or its solvate (taking formula Io compound weighing scale) and described sugar alcohol is as 1:1～100, for example 1:2～100, for example 1:2～50, for example 1:2～20;
(4) wherein said pharmaceutical excipient includes but not limited to thinner or weighting agent, disintegrating agent, tackiness agent, lubricant or glidant;
(5) wherein said thinner or weighting agent include but not limited to: starch is W-Gum, dextrin, Microcrystalline Cellulose, modified starch, pregelatinized Starch, N.F,USP MANNITOL, lactose, sucrose, sorbyl alcohol, D-glucitol, erythritol, Xylitol, fructose etc. such as;
(6) wherein said disintegrating agent includes but not limited to: low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, cross-linked carboxymethyl cellulose sodium, starch etc.;
(7) wherein said tackiness agent is such as but not limited to hydroxypropylcellulose, Vltra tears, polyvinylpyrrolidone, polyvinyl alcohol, etc.;
(8) lubricant includes but not limited to: Liquid Paraffin, polyoxyethylene glycol, silicon-dioxide, colloid silica, micropowder silica gel, talcum powder, hydrogenated vegetable wet goods or its combination;
(9) wherein said pharmaceutical excipient accounts for 0～99.5% of said composition weight;
(10) it is the dosage form that is tablet, capsule, granule, piller etc.;
(11) it is to be tablet, capsule, granule, the unit dose formulations form of piller etc., in described each unit dose formulations form, the amount of contained I compound or its solvate is amounted to into (1S, 2S, 3S, 4R, the fluoro-phenyl of the chloro-3-[(4-oxyethyl group-3-of 5S)-5-[4-) methyl] phenyl]-1-(methylol)-6, 8-dioxa dicyclo is [3.2.1] octane-2 also, 3, 4-triol L-PROLINE is counted 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg,
(12) method in its first method (taking Xiu Shi method) it " A. volumetric precipitation method " in two annex VIIIM aquametries of Chinese Pharmacopoeia version in 2010 is measured, this solid composite medicament contains the moisture that is greater than 0.1%, for example contain the moisture that is greater than 0.2%, for example, contain 0.2%～5% moisture;
(13) wherein contain formula Io compound and L-PROLINE, the two mol ratio of formula Io compound and L-PROLINE is that 1:0.9～1.1, particularly mol ratio are 1:0.95～1.05.
10. the solid composite medicament of claim 8, is characterized in that following any one or multinomial:
(1) wherein also comprise lipid acid or its pharmacologically acceptable salts;
(2) wherein said lipid acid is stearic acid;
(3) pharmacologically acceptable salts of wherein said lipid acid is magnesium salts, sodium salt, calcium salt, the zinc salt of lipid acid;
(4) wherein said lipid acid or its pharmacologically acceptable salts are selected from: stearic acid, Magnesium Stearate, calcium stearate, sodium stearate, Zinic stearas and combination thereof;
(5) wherein said lipid acid or its pharmacologically acceptable salts are selected from: stearic acid, Magnesium Stearate, calcium stearate and combination thereof;
(6) weight ratio of wherein said formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.01～100, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.02～50, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～20, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～10, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～5, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～2, the weight ratio of for example formula I compound or its solvate and described lipid acid or its pharmacologically acceptable salts is 1:0.05～1,
(7) described lipid acid or its pharmacologically acceptable salts account for as 0.5～10% of tablet weight, particularly account for 0.5～5% of tablet weight, particularly account for 0.5～2.5% of tablet weight.
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CN112375087A (en) * 2020-11-27 2021-02-19 浙江天宇药业股份有限公司 Synthesis method of praline Henggliflozin
CN113880701A (en) * 2021-10-10 2022-01-04 浙江司太立制药股份有限公司 Antidiabetic drug intermediate and preparation method thereof

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