CN104292221A - Novel amino acid cocrystal of (1S)-1, 5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol and application thereof - Google Patents
Novel amino acid cocrystal of (1S)-1, 5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol and application thereof Download PDFInfo
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- CN104292221A CN104292221A CN201410444525.4A CN201410444525A CN104292221A CN 104292221 A CN104292221 A CN 104292221A CN 201410444525 A CN201410444525 A CN 201410444525A CN 104292221 A CN104292221 A CN 104292221A
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- 0 Cc(c(Cc1ccc(-c(cc2)ccc2N)[n]1)c1)ccc1C(O[C@](COC)[C@]1O*)=C[C@]1OC Chemical compound Cc(c(Cc1ccc(-c(cc2)ccc2N)[n]1)c1)ccc1C(O[C@](COC)[C@]1O*)=C[C@]1OC 0.000 description 1
- KZAXJCFBBNFWJW-AJDVHMBISA-N Cc1ccc([C@@H](C[C@H]2O)OC(CO)[C@H]2O)cc1Cc1ccc(-c(cc2)ccc2F)[s]1 Chemical compound Cc1ccc([C@@H](C[C@H]2O)OC(CO)[C@H]2O)cc1Cc1ccc(-c(cc2)ccc2F)[s]1 KZAXJCFBBNFWJW-AJDVHMBISA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The invention relates to an L-proline cocrystal of (1S)-1, 5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol, a pharmaceutical composition containing the cocrystal, and application of the compounds in treatment of glucose related disorders like type 2 diabetes.
Description
Technical field
The present invention relates to (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl]-D-Glucose alcohol L-PROLINE eutectic, comprise described eutectiferous pharmaceutical composition and they are in the purposes for the treatment of glucose related disorder such as diabetes B.
Background technology
The metabolic disease of diabetes to be one group with hyperglycemia be feature.Hyperglycemia be then due to defect of insulin secretion or its biological action impaired, or both have concurrently and cause, thus cause glucose to accumulate in blood.Long-standing hyperglycemia during diabetes, causes various tissue, particularly eye, kidney, heart, blood vessel, neural chronic lesion, dysfunction.The most common form of diabetes is diabetes Bs, and be once called as maturity-onset diabetes or non insulin dependent diabetes (NIDDM), this can occupy > 90% in the diabetes of grownup.But along with young crowd becomes day by day overweight or fat, diabetes B is just becoming more and more general in teenager and children.Diabetes also can relate to gestational diabetes, type 1 diabetes or autoimmune diabetes, are once called as juvenile onset diabetes, are also referred to as the invisible autoimmune diabetes of grownup.
2 type glycosurias (non insulin dependent diabetes or NIDDM) are how the sequela of 35 ~ 40 years old.Be a kind of Metabolic disorder relating to abnormal glucose metabolism and insulin resistance and long-term complications, long-term complications relates to eyes, kidney, nerve and blood vessel.And be described to health can not prepare enough Regular Insulin (improper insulin secretion) or its can not effectively utilize Regular Insulin (target organ or tissue in insulin action, there is resistance).More particularly, the patient suffering from diabetes B has relative insulin and lacks.That is, in these patients, plasma insulin level with regard to absolute value for normally arriving height, but with regard to exist plasma glucose levels with regard to than estimate lower.
The feature of diabetes B is following clinical sign or symptom: the plasma glucose concentration or the hyperglycemia that continue rising; Diuresis; Polydipsia and/or eat more; Chronic microvascular complication is retinopathy, ephrosis and DPN such as; With macrovascular complications such as hyperlipidemia and hypertension, it can cause blind, end-stage renal disease, amputation and myocardial infarction.
The diagnosis of diabetes B comprises the assessment of symptom and the measurement to the glucose in urine and blood.It is necessary that blood glucose levels measures for making a definite diagnosis.More particularly, fasting blood glucose measures is used standard method.But oral glucose tolerance test (OGTT) is considered to sensitiveer than fasting blood glucose.Diabetes B is relevant to impaired oral glucose tolerance (OGT).Therefore, OGTT can contribute to the diagnosis of diabetes B, although this not to be diabetes diagnosis usually necessary (EMANCIPATOR K, Am J Clin Pathol1999 November; 665-674 page, the 112nd volume (5): 665-74; Type2Diabetes Mellitus, Decision Resources Inc., in March, 2000).OGTT allows to make an estimate to pancreatic β cell secreting function and insulin sensitivity, this contributes to the diagnosis of diabetes B and makes assessment (such as to the seriousness of this disease or progress, CAUMO, A. people is waited, J Clin Endocrinol Metab, 2000,4396-4402 page, the 85th volume (11)).More particularly, OGTT especially contributes to having multiple borders fasting blood glucose but the patient being not yet diagnosed as diabetes establishes the degree of hyperglycemia.In addition, OGTT can be used for detecting the patient with diabetes B symptom, and the possibility diagnosis of wherein improper carbohydrate metabolism is clearly established or negates.Therefore, glucose-tolerant sexual abnormality can be diagnosed in individuality, lower than required by diabetes B diagnosis of the fasting blood glucose of described individuality, but during OGTT, have the plasma glucose response between normal and diabetes.Glucose-tolerant sexual abnormality is considered to situation before diabetes, and glucose-tolerant sexual abnormality (being defined by OGTT) is potent forecast (HAFFNER, S.M., Diabet Med., in the August, 1997 of diabetes B development; 14Suppl3:S12-8).
Diabetes B is PD, and it is associated to pancreas miopragia and/or other processes relevant with Regular Insulin, and raises along with plasma glucose levels and worsen.Therefore, diabetes B has the long-term pre-diabetes stage usually, and multiple pathophysiological mechanism can cause hyperglycemia and the glucose-tolerant sexual abnormality of morbid state, the glucose utilization in such as pre-diabetes stage and validity, insulin action and/or Regular Insulin produce abnormal (GOLDBERG, R.B., Med Clin North Am, in July, 1998; 805-821 page, the 82nd volume (4)).The pre-diabetes stage relevant to glucose intolerance also can be inclined to abdominal obesity, insulin resistance, hyperlipidemia and hypertension (people such as GROOP L, Am J Hypertens, in September, 1997; 10 (9Pt2): 172S-180S; HAFFNER, S.M., JDiabetes Complications, in March, 1997-April; 69-76 page, the 11st volume (2); The people such as BECK-NIELSEN, H., Diabet Med, in September, 1996; 13 (9Suppl6): S78-84).Therefore, carbohydrate metabolism defect is to morbidity very crucial (DIUNNEEN, S.F., Diabet Med, in the August, 1997 of diabetes B and glucose-tolerant sexual abnormality; 14Suppl3:S19-24).In fact, exist from the abnormal continuous band to decisive diabetes B of glucose-tolerant sexual abnormality and fasting glucose tolerance (people such as RAMLO-HALSTED, B.A., Prim Care, in December, 1999; 771-789 page, the 26th volume (4)).The early intervention of people to the individuality of risky development diabetes B is paid close attention to and is reduced ill hyperglycemia or glucose-tolerant sexual abnormality, this early intervention can prevent or delay to diabetes B and related complication and.Therefore, by effectively treating the impaired and/or high blood glucose levels of oral glucose tolerance, people can prevent or suppress this imbalance to the progress of diabetes B.The typical treatment of people to the glucose disorders comprising diabetes B is paid close attention to and is maintained close to normal as far as possible by blood glucose levels, and comprise diet and motion, and as necessary, treat with antidiabetic, Regular Insulin or their combination.The diabetes B antidiabetic agents do not controlled by dietary management is treated, and described antidiabetic agents includes but not limited to: sulfonylurea (is such as not limited to first-generation medicine: P-607, tolazamide, tolbutamide; S-generation medicine: Glyburide, Glipizide; With third generation medicine: glimepiride), biguanides (such as, N1,N1-Dimethylbiguanide), thiazolidinediones (such as, rosiglitazone, pioglitazone, troglitazone), alpha-glucosidase inhibitor (such as, acarbose, miglitol), meglitinide (such as, repaglinide), other insulin sensitizing compounds and/or other antiobesity agents (such as, orlistat or sibutramine).Although such drug development progress is significantly, market and clinical still to providing effective treatment to there are needs for glucose related disorder such as such as high glucose level, diabetes Bs.Also still to for also slowing down or preventing the glucose related disorder of the progress of diabetes B and/or development from providing effective treatment to there are needs.
Summary of the invention
The present invention relates to the L-PROLINE eutectic of the compound of formula (I)
Preferably, the L-PROLINE eutectic of the compound of formula (I) is crystalloid.The invention still further relates to eutectiferous method of the compound of preparation formula (I), as described in more detail herein.
Example of the present invention is pharmaceutical composition, and it comprises the eutectic formation of the compound of pharmaceutically acceptable carrier and formula as herein described (I).Example of the present invention is the pharmaceutical composition being mixed by eutectic formation and the pharmaceutically acceptable carrier of the compound by formula as herein described (I) and prepared.Invention shows the method for pharmaceutical compositions, described method comprises the eutectic formation of the compound of formula as herein described (I) and the mixing of pharmaceutically acceptable carrier.
The invention still further relates to the method treating and/or preventing glucose related disorder, described method comprises the eutectic to the compound its experimenter in need being used to crystalloid formula (I) as herein described.
Embodiment
The present invention relates to the eutectic of the compound of formula (I)
More particularly, the present invention relates to the L-PROLINE eutectic of the compound of formula (I).In one embodiment of the invention, the L-PROLINE eutectic of the compound of formula (I) is crystalloid.
The compounds exhibit of formula (I) goes out the inhibit activities of the Na-dependent glucose transporter to such as SGLT2.The compound of formula (I) can the method disclosed in U.S. Patent Publication US2005/0233988A1 according to people such as Nomura, S. be prepared, and this patent disclosure was on October 20th, 2005, and it is incorporated herein by reference.
The invention still further relates to the method treating and/or preventing glucose related disorder (preferred diabetes B), described method comprises the eutectic to the compound its experimenter in need being used to formula as herein described (I).
Some crystalline forms of the compounds of this invention can exist by polymorphic form, and are intended to equally be included in the present invention.In addition, some compounds of the present invention can form solvate with water (i.e. hydrate) or ordinary organic solvents, and this type of solvate is also intended to be covered in scope of the present invention.
Unless otherwise stated, term used herein " form of separation " should mean compound to exist with the form of separating with any solid mixture of other compound formation, solvent system or coenocorrelation.In one embodiment of the present of invention, the L-PROLINE eutectic of the compound of formula (I) exists with the form be separated.
Except as otherwise noted, otherwise the molar percentage that term used herein " substantially pure form " should mean impurity in the crystallized form be separated is less than about 4 % by mole, preferably be less than about 2 % by mole, be more preferably less than about 0.4 % by mole, be most preferably less than about 0.1 % by mole.In one embodiment of the invention, the L-PROLINE eutectic of the compound of formula (I) exists in a substantially pure form.
The invention still further relates to treatment and prevent (preferably, the prevention of development) method of glucose related disorder, described method comprises the eutectic of the compound to any one formula as herein described (I) to its experimenter's administering therapeutic significant quantity in need.
Method of the present invention relates to the treating and/or preventing of " glucose related disorder " (comprising delaying of progress and morbidity).As used herein, term " glucose related disorder " should be defined as any imbalance being characterised in that or developing into high glucose level result.Glucose related disorder should comprise that diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing delay, insulin resistance, hyperglycemia, hyperinsulinemia, high blood fat sour water are flat, high blood glucose levels, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complication, atherosclerosis or hypertension.Especially, " glucose related disorder " is diabetes (1 type and diabetes B etc.), diabetic complication (as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), obesity or postprandial hyperglycemia.
In one embodiment of the invention, glucose related disorder is selected from that diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing delay, insulin resistance, hyperglycemia, hyperinsulinemia, high blood fat sour water are flat, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complication, atherosclerosis and hypertension.
In another embodiment of the present invention, glucose related disorder is selected from type 1 diabetes, diabetes B, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, obesity and postprandial hyperglycemia.In another embodiment of the present invention, glucose related disorder is selected from type 1 diabetes, diabetes B, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, obesity and wound healing delay.In another embodiment of the present invention, glucose related disorder is selected from bad glycemic control, diabetes B, X syndrome, gestational diabetes, insulin resistance, hyperglycemia.In another embodiment of the present invention, glucose related disorder is diabetes B.
In another embodiment, glucose related disorder is selected from high glucose level, pre-diabetes, impaired, the bad glycemic control of oral glucose tolerance, diabetes B, X syndrome (also referred to as metabolism syndrome), gestational diabetes, insulin resistance and hyperglycemia.The treatment of glucose related disorder can comprise reduction glucose level, improve glycemic control, reduces insulin resistance and/or prevent glucose related disorder from developing (such as prevent suffering from oral glucose tolerance patient evolution that is impaired or high glucose level and become diabetes B).
Except as otherwise noted, otherwise term used herein " treatment ", " treatment " etc. should comprise for resist disease, illness or imbalance object to experimenter or patient's (preferred mammal, more preferably people) carry out managing and nursing, and comprise and use compound of the present invention to prevent the outbreak of symptom or complication, mitigation symptoms or complication or to eliminate this disease, illness or imbalance.
Unless otherwise stated, term used herein " prevention " should comprise the frequency that (a) reduces one or more symptoms; B () reduces the severity of one or more symptoms; C () postpones or avoids the development of extra symptom; And/or (d) postpones or avoids the development of imbalance or illness.
One skilled in the art will realize that, the present invention relates to wherein in the situation of prevention method, experimenter in need (namely needing the experimenter carrying out preventing) should comprise any experienced or show to prevent imbalance, the experimenter of at least one symptom of disease or illness or patient (preferred mammal, more preferably people).In addition, experimenter in need can also be do not show to prevent imbalance, disease or illness any symptom, but the experimenter (preferred mammal, more preferably people) of risk having the described imbalance of development, disease or illness is thought by physician, clinician or other medical professions.Such as, due to the medical history of this experimenter, include but not limited to family history, easily ill physique, the imbalance coexisted or illness (morbid state simultaneously had), heredity test etc., this experimenter can be considered to develop the risk (and therefore needing prevention or prophylactic treatment) of imbalance, disease or illness.
As used herein, term " experimenter " refers to become treatment, observe or the animal of subjects, preferably refers to Mammals, most preferably refers to people.Preferably, experimenter has experienced and/or has shown at least one symptom of disease or the imbalance must treated and/or must prevent.
As used herein, the biology that term " treatment significant quantity " means to cause researchist, animal doctor, doctor or other clinicians seeking on tissue system, animal or human's body or the active compound of drug reaction (comprising the alleviation of the symptom of institute's disease therapy or imbalance) or the amount of medicament.
The optimal dose of administration is easy to be determined by those skilled in the art, and can change with the propelling of such as administering mode, formulation strengths, administering mode and illness.In addition, the factor relevant to the concrete patient treated, comprises patient age, body weight, diet and administration time, will cause needing adjust dosages.Those skilled in the art will recognize that, use suitable, known and in the body of received cell and/or animal model and in vitro tests can predict test compounds or collaborative therapy for treating or prevent the ability of given imbalance.Those of skill in the art also will appreciate that, the method that the human clinical trial's (comprising human body use-testing, Dosage test and clinical trial first) carried out in the patient of given disease in healthy patients and/or suffer from can know according to clinical and medical field come.
As used herein, term " composition " is intended to contain the product of the predetermined component comprising specified amount, and any predetermined component by combination specified amount and the product that directly or indirectly obtains.
In order to provide more succinct description, some quantitative expressions are stated as the scope that about X measures extremely about Y amount herein.Should be appreciated that described scope is not restricted to described boundary up and down when the scope of describing, and about X amount should be comprised to the gamut of about Y amount or any amount between them.
Describe more accurately to provide, some quantity statement provided herein is not modified by term " about ".Be to be understood that, no matter whether clearly use term " about ", each amount given in this article is intended to refer to actual set-point, and it is also intended to refer to can the approximation of these set-point that obtains of reasonable speculation according to this area general technology, comprise these set-point by the approximation of testing and/or caused by measuring condition.
Suitable solvent, alkali, temperature of reaction and other reaction parameters and component provide in detailed description hereafter.Those skilled in the art will recognize that enumerating of described example has no intention and should not be construed as the present invention limiting by any way and illustrate in claims which follow.
Those of skill in the art will recognize that if reactions steps of the present invention can be carried out in multi-solvents or solvent system, then described reactions steps also can be carried out in the mixture of suitable solvent or solvent system.If the method for the preparation of compound according to the present invention produces the mixture of steric isomer, then these isomer can be separated by the routine techniques of such as preparative chromatography and so on.Compound can racemic form be prepared, or indivedual enantiomorph is by the synthesis of mapping specificity or parsing preparation.Such as, compound resolves to its constituent enantiomers by standard technique, such as by the salt formation effect with optical activity acid (such as (-)--two toluoyl-D-tartrate and/or (+)-two toluoyls-L-TARTARIC ACID), afterwards by fractional crystallization and make free alkali regenerate and form diastereomer pair.Compound also by diastereomeric ester or acid amides formation, resolved by chromatographic separation and removing of chiral auxiliary(reagent) afterwards.Or described compound can use chirality HPLC column to resolve.In addition, enantiomeric excess per-cent (%ee) can be measured with chirality HPLC relative to standard substance.Enantiomeric excess can be calculated as follows: [(R mole-S mole)/(R mole+S mole)] × 100% wherein R mole and S mole is the molfraction of R and S enantiomorph in mixture, makes R mole+S mole=1.Alternatively, also the specific rotatory power by the mixture of required enantiomorph and preparation as described below enantiomeric excess: ee=([α-obs]/[α-maX]) × 100 can be calculated.
The present invention relates to the L-PROLINE eutectic of the compound of formula (I), the L-PROLINE eutectic of the compound of preferred crystalloid formula (I).
The preparation of crystalloid L-PROLINE:
Prepared by the part that the L-PROLINE eutectic of the compound of formula (I) screens as eutectic.In brief, join in each hole of 48 hole grinding blocks together with the eutectic formation (being L-PROLINE respectively) of the compound of about 15mg formula (I) and about 1 molar equivalent and 10 μ l solvents (being selected from acetone, ethanol, isopropyl acetate, toluene, water).Six (6) individual independent experiments (5 kinds of solvents and 1 dry hole) are carried out for each eutectic formation.Make aperture be subject to ball milling in 10 minutes, and and then carry out pXRD analysis.The L-PROLINE eutectic of the compound of crystalloid formula (I) additionally by make the compound of formula (I) (about 1g) and L-PROLINE with 1: 1.1 stoichiometry in acetone pulping prepare.
The eutectiferous physics and chemistry stability of L-PROLINE:
By under the following conditions about 10mg eutectic being stored in the eutectiferous physical stability of L-PROLINE of testing the compound of crystalloid formula (I) in 10mL serum gland bottle: (a) 5 DEG C, sealing; B () 25 DEG C/60%RH, opens; (c) 40 DEG C, sealing; D () 40 DEG C/75%RH, opens; (e) 60 DEG C, sealing; (f) 80 DEG C, sealing; Stability data is gathered the 1st day, the 1st week, the 2nd week and the 4th week.Find that the L-PROLINE eutectic of the compound of crystalloid formula (I) is under all of these conditions until 4 weeks is physically stable, simultaneously without visible colour-change.
Chemical stability/degraded is tested further through the L-PROLINE co-crystal sample of the compound of the crystalloid formula (I) of physical stability test the 1st day, the 1st week, the 2nd week and sampling in the 4th week.Water with 50: 50: acetonitrile solution (10mL) dilutes the L-PROLINE eutectic (about 10mg) of the compound of crystalloid formula (I), then dilutes 10 times further and measures for HPLC.At the 1st day, the 1st week, the 2nd week and the 4th week, all crystalloid L-PROLINE co-crystal sample all presented chemically stable.Do not observe degradation peak, and measured % area is consistent at each time point place.
PXRD, DSC, TGA and DVX measure:
The L-PROLINE eutectic of the compound of crystalloid formula (I) is characterized further by powder x-ray diffraction (pXRD), Dynamic Scanning Calometry (DSC), thermogravimetric analysis (TGA) and dynamic vapor sorption/desorb (DVS).
PXRD: use the Bruker AXS D8Discover X-ray diffractometer being furnished with GADDSTM (general area diffraction detection system), Bruker AXS HI-STAR area detector, in the distance of 15.05cm/ system calibrating, copper source, automatization X-y-z platform, and 0.5mm collimator obtains powder X-ray diffraction pattern.Sample is compacted into pellet form and is fixed on x-y-z platform.Arrange power 40kV and 40mA under reflective-mode, sample keeps fixing simultaneously, gathers diffractogram at ambient conditions.The open-assembly time of each sample is about 1 minute.Experience space remapping method obtains diffractogram with the geometry pincushion distortion of declare area detector, and then with the step-length of 0.02 degree, 2 θ along chi and the 2.1-37 degree of-118.8 to-61.8 degree quadrature, and setting bin normalization method is by its normalization method.Except using Jade software, using on EVA software observes Bruker machine and obtaining diffraction pattern.
DSC: the sample weighing aliquots containig is put in alumiseal sample disc.Sample disc be loaded in equipment (Q1000 differential scanning calorimeter, TA instrument), it is furnished with automatic sampler.By with 10 DEG C/min speed from T
min(usual room temperature) is to T
max(usual 300 DEG C) separately heated sample obtain Thermogram, use sky alumiseal dish in contrast.Dry nitrogen is used as sample purge gas and is set to the flow of 50ml/min.The analysis software using described instrument to provide is observed and is analyzed thermal transition.
TGA: the sample of aliquots containig is transferred in platinum sample disc.Described dish is placed on weighted platform, then uses control software design, it is automatically loaded in equipment (Q500 thermogravimeter, TA instrument).By with 10 DEG C/min from T
min(usual room temperature) is to T
max(usual 300 DEG C) obtain Thermogram by the sample purge flow of 60ml/min and the independent heated sample of balance purge flow rate of 40ml/min under the dry nitrogen of flowing.The analysis software using described instrument to provide is observed and is analyzed thermal transition (such as changes in weight).
DVS: water adsorption is in the upper sign of DVS-1 instrument (Surface Measurement Systems, Allentown, PA).In every case, from environment to 0% relative humidity (RH), then at 25 DEG C, 10%RH step draws the drying curve of sample through 2 circulations of adsorbing (0%RH to 90%RH) and desorb (90%RH to 0%RH).Allow each step sample to balance under specific %RH, thus carry out described method stable weight that is that increase or loss before next step at instrument.
Crystalloid L-PROLINE eutectic character:
The L-PROLINE eutectic of the compound of crystalloid formula (I) is characterized by powder x-ray diffraction (pXRD) pattern; The relatively pXRD pattern of eutectic pattern crystal composition together, more particularly, the pXRD of compound of formula (I) and the pXRD of L-PROLINE.
In one embodiment, the L-PROLINE eutectic of the compound of crystalloid formula (I) characterizes by its x-ray diffractogram of powder case, and this pattern comprises the peak listed in following table 1.
Table 1: the L-PROLINE eutectic of the compound of crystalloid formula (I)
Preferably, the L-PROLINE eutectic of the compound of crystalloid formula (I) is characterized by its pXRD pattern, and this pattern comprises the relative intensity having and be more than or equal to about 25%, preferably has the peak of the relative intensity being more than or equal to about 40%.
In another embodiment of the present invention, the L-PROLINE eutectic of the compound of crystalloid formula (I) characterizes by following pXRD peak ° 2 θ: 3.80,9.46,11.01,17.88,18.73,22.01,23.44 and 26.87.
The L-PROLINE eutectic of the compound of crystalloid formula (I) uses dsc (DSC) to characterize further, to measure from 25 DEG C to 300 DEG C with 10 DEG C/min and find that it shows the sharp melting point of 189 DEG C, and comparatively mild at 180 DEG C.
The L-PROLINE eutectic of the compound of crystalloid formula (I) uses thermogravimetric analysis (TGA) to characterize further, to measure from 25 DEG C to 300 DEG C with 10 DEG C/min and find that it shows until 1% weight loss (it is believed that this is the loss due to residual solvent) of 180 DEG C, then further until 25% weight loss of 280 DEG C, this corresponds to the loss of 1 molar equivalent L-PROLINE.
The L-PROLINE eutectic of the compound of crystalloid formula (I) uses dynamic vapor sorption (DVS) to characterize further, and at 25 DEG C, from 0%RH to 90%RH, (2 recycle to extinctions) measures.The L-PROLINE eutectic having found the compound of crystalloid formula (I) is moisture absorption, although until %RH has reached 40% does not all observe weight and increase.Between 40%RH and 90%RH, eutectiferous quality increases by 12%, and it is loss (having some delayed) during the desorption part measuring circulation.Show do not have irreversible form to transform with the pXRD that this sample observation gathers afterwards at DVS operation (being separated under 0%RH).
The present invention also comprises pharmaceutical composition, and it comprises the compound eutectic of any crystalloid formula (I) as herein described and pharmaceutically acceptable carrier.According to the pharmaceutical compounding techniques of routine, can prepare containing the pharmaceutical composition of one or more the compounds of this invention as herein described as activeconstituents by compound is closely mixed with pharmaceutical carrier.Depend on required route of administration (as oral, administered parenterally), carrier can take various ways.Thus for the liquid oral medicine of such as suspensoid, elixir and solution and so on, suitable carrier and additive comprise water, glycol, grease, alcohol, seasonings, sanitas, stablizer, tinting material etc.; For solid orally ingestible, such as powder, capsule and tablet, suitable carrier and additive comprise starch, sugar, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent etc.Solid orally ingestible also can be coated with the material of such as sugar and so on or be coated with enteric coating, to regulate main absorption site.Execute week for non-bowel, carrier will usually be made up of sterilized water and can add other compositions to increase solubleness or to carry out anticorrosion.Aqueous carrier also can be utilized to prepare suspension or solution together with suitable additive.
In order to prepare pharmaceutical composition of the present invention, according to the pharmaceutical compounding techniques of routine, closely mixed with pharmaceutical carrier by one or more present compositions as activeconstituents, described carrier depends on that the dosage form needed for administration (administered parenterally as oral administration or such as intramuscular administration and so on) can take various ways.When preparing the composition of oral dosage form, any conventional medicinal medium can be adopted.Thus, for liquid oral medicine such as suspensoid, elixir and solution, suitable carrier and additive comprise water, glycols, grease, alcohols, seasonings, sanitas, tinting material etc.; For solid orally ingestible such as powder, capsule, Caplet agent, soft capsule and tablet, suitable carrier and additive comprise starch, sugar, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent etc.Due to its accessibility in administration, Tablet and Capsula agent represents best oral unit dosage form, obviously adopts solid pharmaceutical carriers in this case.If needed, tablet is by the technology sugar coating or enteric coated of standard.For forms for parenteral administration, carrier will comprise sterilized water usually, but also can comprise other compositions, such as, dissolve or anticorrosion and so on object for such as helping.Can also suspension be prepared, in this case, suitable liquid carrier, suspending agent etc. can be adopted.The every dose unit of pharmaceutical composition herein (as every sheet, every capsules, every part of powder, often propping up injection, every bitter edible plant spoon etc.) is by containing promising amount of sending activeconstituents needed for above-mentioned effective dose.The every dosage unit unit of pharmaceutical composition herein (such as, every sheet, every capsules, every part of powder, often prop up injection, often prop up suppository, every bitter edible plant spoon etc.) about 0.1 to about 1000mg or any amount wherein or scope will be comprised, and can about 0.01 to about 500mg/kg/ day or any amount wherein or scope, the preferably dosed administration of about 0.5 to about 100mg/kg/ day or any amount wherein or scope.But the requirement depending on patient, the seriousness of illness for the treatment of and the compound adopted, dosage can change.Can adopt daily or all after date administrations (post-periodic dosing).
Preferably, these compositions are unit formulation, such as tablet, pill, capsule, powder, granula, parenteral sterile solution agent or suspensoid, metered aerosol or liquid spray, drops, ampulla, automated injection device or suppository; For parenteral oral administration, intranasal administration, sublingual or rectal administration, or for through suck or be blown into administration.Or composition goes for once in a week or the form of monthly administration exists; The such as insoluble salt of described active compound, as caprate, can be suitable for the depot preparation (depot preparation) being provided for intramuscularly.For preparing the solids composition of such as tablet and so on, by main activeconstituents and pharmaceutical carrier (as the tableting ingredients of routine, such as W-Gum, lactose, sucrose, sorbyl alcohol, talcum powder, stearic acid, Magnesium Stearate, Si Liaodengji dicalcium phosphate feed grade or natural gum) and other medicinal diluents (as water) mixing, to form the solid preformulation composition of the uniform mixture containing the compounds of this invention or its pharmaceutical salts.When being called even by these preformulation composition, it is dispersed in whole composition that it means activeconstituents, makes said composition easily can be subdivided into the equivalent dosage form of such as tablet, pill and capsule and so on.Then this solid preparation composition is subdivided into the unit dosage form of the above-mentioned type of inventive compound containing 0.01 to about 1,000mg or any amount wherein or scope.The tablet of this novel composition or pill can be carried out applying or otherwise compounding, to obtain the formulation that can provide long-acting advantage.Such as, tablet or pill can comprise internal dose component and outside dosage component, and the latter is the form of the covering covering the former.These two kinds of components can be separated by enteric layer, and this enteric layer plays the effect preventing disintegration under one's belt, thus make internal composition intactly enter duodenum or be able to delayed release.Have multiple material to can be used for this type of enteric layer or dressing, this type of material comprises and such as lac, the hexadecanol multiple polymeric acid material together with the material of cellulose acetate and so on.
Novel composition of the present invention can be mixed and comprise aqueous pharmaceutical, suitably seasoned syrup, water-based or Oil suspensions and the emulsion with edible oil (Oleum Gossypii semen, sesame oil, Oleum Cocois or peanut oil) seasoning for liquid preparation that is oral or drug administration by injection, and elixir and similar pharmaceutical media.The suitable dispersant or the suspension agent that are applicable to aqueous suspension comprise synthetical glue or natural gum (such as tragacanth gum, Sudan Gum-arabic, alginate, dextran, Xylo-Mucine, methylcellulose gum, polyvinylpyrrolidone or gelatin).
The method for the treatment of glucose related disorder of the present invention also can make pharmaceutical composition, and it comprises any compound defined herein and pharmaceutically acceptable carrier.Described pharmaceutical composition can comprise about 0.01mg and the compound about between 1000mg or any amount wherein or scope; The preferably compound of about 0.1mg to about 500mg, and any form being suitable for selected administering mode can be formed.Carrier comprises necessary with pharmaceutical excipient that is inertia, includes but not limited to tackiness agent, suspensoid, lubricant, flavouring agent, sweeting agent, sanitas, dyestuff and coating material.The composition being applicable to oral administration comprises solid form, such as pill, tablet, Caplet agent, capsule (respectively comprising quick-releasing type, time controlled released type and sustained releasing type), granula and powder; And liquid form, as solution, syrup, elixir, emulsion and suspensoid.The form that can be used for administered parenterally comprises sterile solution agent, emulsion and suspensoid.
Advantageously, composition of the present invention can the administration of single per daily dose, or total per daily dose can the divided dose administration of every day twice, three times or four times.In addition, compound of the present invention uses suitable intranasal vehicles with intranasal form administration by local, or by transdermal patch agent administration well known to those of ordinary skill in the art.Use with the form of transdermal delivery system, in whole dosage regimen, dosage is used yes continuous print instead of interruption.Such as, for oral in the form of a tablet or capsule, active medicine component and oral, avirulent medicinal inert carrier (such as ethanol, glycerine, water etc.) can be combined.In addition, in hope or if desired, also suitable tackiness agent, lubricant, disintegrating agent and tinting material can be mixed in mixture.Suitable disintegrating agent includes but not limited to starch, gelatin, natural carbohydrate (such as glucose or beta lactose), corn sweetener, natural gum (such as Sudan Gum-arabic, tragacanth gum) that is natural and synthesis or sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc.Disintegrating agent includes but not limited to starch, methylcellulose gum, agar, wilkinite, xanthan gum etc.
Liquid form is through suitably seasoned suspending agent or dispersion agent, such as, as synthesis and natural gum, tragacanth gum, Sudan Gum-arabic, methylcellulose gum etc.For administered parenterally, sterile suspensions and solution expect.When needs carry out intravenous administration, adopt the isotonic preparation usually containing suitable sanitas.
In order to prepare medicinal compositions of the present invention, according to the pharmaceutical compounding techniques of routine, closely mixed with pharmaceutical carrier by the compound of formula (I), depend on the dosage form that expectation is used (as oral or parenteral administration), this carrier can take various form.Suitable pharmaceutically acceptable carrier is known in the art.(can find in Pharmaceutical EXcipients at the The Handbook o of American Pharmaceutical Association and pharmaceutical society of Britain the description of some this kind of pharmaceutically acceptable carrier.
Described by the method for compounding pharmaceutical composition has had in many publications, the Pharmaceutical Dosage Forms:Tablets that the people such as the Lieberman that such as Marcel Dekker company publishes edit, the second edition, revision and extended version, 1-3 rolls up; The Pharmaceutical Dosage Forms:Parenteral Medications that the people such as Avisl edit, 1-2 roll up; And the Pharnaceutical Dosage Forms:Disperse Systems that the people such as Lieberman edits, 1-2 roll up.
Whenever needs glucose associated treatment, the eutectic of the compound of crystalloid formula (I) of the present invention can be used and according to the dose regimen administration of setting up in this area by any foregoing.
The per daily dose of product can change each adult every day about 0.01 to the wide region of about 1000mg, or change in any amount wherein or scope.For oral administration, composition preferably contains the tablet form of the activeconstituents of 0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0,50.0,100,150,200,250 and 500 milligram, according to the symptom adjust dosages of patient to be treated.
Preferably, the compound eutectic of crystalloid formula (I) is about 0.01mg to about 500mg with every kg body weight every day, or every day every kg body weight 0.01mg to about 200mg or the dosage level of any amount wherein or scope use.
Preferably, this scope be every day every kg body weight about 0.01 to about 50mg or any amount wherein or scope, more preferably from about 0.05mg to about 10mg or any amount wherein or scope, more preferably every day, every kg body weight about 1 was to about 5mg or any amount wherein or scope.In one embodiment, the eutectic of the compound of the crystalloid formula (I) of significant quantity provides with the dosage level of 10mg, 25mg, 50mg, 100mg, 150mg or 300mg or any amount wherein or scope.The eutectic of the compound of crystalloid formula (I) can every day the instructions about how to take medicine of 1 to 5 time use.
Those skilled in the art can easily determine optimal dose to be administered, and the progress with used particular compound, method of application, formulation strengths, method of application and disease condition changes by optimal dose.In addition, the factor relevant to the concrete patient treated, comprises patient age, body weight, diet and time of application, will cause needing adjust dosages.
Those skilled in the art will recognize that, use in the body of suitable, known and generally accepted cell and/or animal model and experiment in vitro all can prediction experiment compounds for treating or prevent the ability of given disease.
Those of skill in the art also will appreciate that, the method that the human clinical trial's (comprising human body use-testing, Dosage test and clinical trial first) carried out in the patient of given disease in healthy patients and/or suffer from can know according to clinical and medical field come.
Following instance provides to help to understand the present invention, is not intended to and should be interpreted as limiting by any way the present invention involved in example following claim book.
Example 1
The compound (20mg) of formula (I) joins in wig-L-bug bottle together with acetone (20 μ l) with L-PROLINE (5.2mg) (1: 1.1 molar equivalent API: CCF), mill ball by the L-PROLINE eutectic of the compound of crystalloid formula (I).Wig-L-bug is made to stand grinding in 10 minutes.After milling, the solid confirming to reclaim by pXRD is the L-PROLINE eutectic of the compound of desired crystalloid formula (I).
Example 2
The compound (50.18mg) of formula (I) joins in 4ml Erlenmeyer flask by the L-PROLINE eutectic of the compound of crystalloid formula (I) together with L-PROLINE (13.15mg) (1: 1.1 molar equivalent API: CCF), then adds acetone (0.5mL).The bottle heat gun of adding a cover simply is heated.From solution, be settled out white solid matter rapidly, and collect and confirm by pXRD the L-PROLINE eutectic that this material is the compound of desired crystalloid formula (I).
Example 3
Solid oral dosage form-imaginary routine example
As the specific embodiment of oral compositions, the L-PROLINE eutectic (preparation as described herein) of the compound of crystalloid for 100mg formula (I) and the lactose enough segmented are prepared to provide the total amount of 580 to 590mg to fill O shape hard capsule.
Although above-mentioned specification sheets has taught principle of the present invention to provide example for illustration of the mode of object, but should be appreciated that practice of the present invention covers all common variations within the scope of following patent requirement and equivalents thereof, changes form and/or modification.
Claims (5)
1. the L-PROLINE eutectic of the compound of a formula (I)
2. L-PROLINE eutectic according to claim 1, wherein said eutectic is crystalloid.
3. L-PROLINE eutectic according to claim 2, comprises following pXRD peak ° 2 θ: 3.80,9.46,11.01,17.88,18.73,22.01,23.44 and 26.87.
4. L-PROLINE eutectic according to claim 2, wherein said eutectic shows the fusing point of 189 DEG C recorded by DSC.
5. the L-PROLINE eutectic of the compound of a crystalloid formula (I)
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| CN201410444525.4A CN104292221A (en) | 2014-09-02 | 2014-09-02 | Novel amino acid cocrystal of (1S)-1, 5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol and application thereof |
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| CN112390792A (en) * | 2020-11-24 | 2021-02-23 | 浙江大学 | Puerarin-proline eutectic crystal and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112390792A (en) * | 2020-11-24 | 2021-02-23 | 浙江大学 | Puerarin-proline eutectic crystal and preparation method thereof |
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