CN103304561A - Compounds with antithrombotic effects - Google Patents
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Abstract
The invention discloses compounds with antithrombotic effects with the structure of formula I and pharmaceutically acceptable salts thereof. According to the compound, R can be hydrogen, methyl, ethyl, propyl, isopropyl, nitro, cyano, halogen and trifluoromethyl. The invention also discloses a method for preparing the compounds, a pharmaceutical composition by taking the compounds and the pharmaceutically acceptable salts as active ingredients, and application of serving as antiplatelet drugs, particularly for preparation of medicines for preventing or treating the coronary syndrome, myocardial infarction, myocardial ischemia and other cardiovascular and cerebrovascular diseases caused by platelet aggregation.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to a class and have compound of anti thrombotic action and preparation method thereof, contain their pharmaceutical composition and as the purposes of antithrombotic reagent.
Background technology
In rising trend take coronary artery thrombus and cerebral thrombosis as the sickness rate of main thrombotic disease, the serious harm human health.Platelet aggregation is a key link in the normal clotting mechanism, so the medicine of anticoagulant becomes the focus of antithrombotic reagent research.
The Ticlopidine (Ticlopidine) of France Sanofi company exploitation listing be first adp receptor antagonist class antiplatelet drug, its by with the special sulfydryl receptors bind of P2Y type, antiplatelet aggregative activity is played in the activation of inhibition adp receptor.Because Ticlopidine not only suppresses a certain platelet aggregation incitant, and suppresses accumulation process itself, in clinical, used widely.Especially the prevention cerebral infarction, treat stenocardia, prevent and treat myocardial infarction and improve the aspect such as peripheral vascular occlusive disease evident in efficacy.But find in the follow-up research that Ticlopidine can cause neutrophil leucocyte minimizing, thrombopenia, bone marrow depression, the again side effects such as barrier, thrombotic thrombocytopenic purpura (TTP), in recent years less application.
Clopidogrel (Clopidogrel) is second Thienopyridines adp receptor antagonist pharmaceuticals of Sanofi company development, compares with Ticlopidine, and structure is many carboxymethyls on the side chain only, and its action intensity and tolerance all are higher than Ticlopidine.Be applied to clinically treat atheromatosis, acute coronary syndrome, prevention intracoronary stent and plant restenosis and thrombotic complications etc. in people's postoperative support.In multinomial broad scale research, clopidogrel is better than other drug aspect the prognosis that improves ischemic events, and ADR is few than Ticlopidine, and security is better than acetylsalicylic acid, thereby clopidogrel has replaced the application of Ticlopidine in many cases.TTP and hemolytic uremic syndrome (HUS) have also occurred but accept Effect of Clopidogrel in Treating, the report of simultaneously relevant clopidogrel Resistant also had increase in recent years.Simultaneously because clopidogrel is oily matter, alkalescence extremely a little less than, need and strong acid could salify, but it is unstable to meet moisture, and free alkali is separated out, purifying also has certain difficulty.And because its strongly-acid has been subject to certain restriction aspect preparation.
The prasugrel (Prasugrel) that Japan the one or three is total to company and Lilly Co., Eli.'s joint development is the new thienopyridine analog derivative of a class.Studies confirm that in a large number with clopidogrel and compare, the prasugrel activity is stronger, and onset is faster, and the response difference to this medicine between patient is less.The controlled clinical trial result of itself and clopidogrel also shows, it can reduce the death that non-lethality heart trouble and palsy cause effectively, but causes patient's bleeding more.Because this product still has some and the closely-related untoward reaction problem of its clinical efficacy, particularly because higher bleeding risk, therefore, although FDA has ratified the prasugrel listing, but require it must add in the new drug label that black surround warns to warn bleeding risk, and suggestion suffer from reactivity Pathology bleeding, transient ischemic attack or palsy medical history or need in the recent period operation comprise that the patient of coronary artery bypass surgery does not take this medicine.
Focus as antiplatelet drug research, the Thienopyridines that reaches mentioned above is aspect activity, side effect or all also there is certain deficiency in the physicochemical characteristic aspect, therefore, the present invention proposes the compound with antithrombotic acitivity that a class is different from the Thienopyridines antiplatelet drug, to obtaining safe and effective medicine.
Summary of the invention
One object of the present invention is, discloses the compound with anti thrombotic action and the pharmaceutical salts thereof of a class novel texture.
Another object of the present invention is, discloses a class and has the compound of anti thrombotic action and the preparation method of pharmaceutical salts thereof.
A further object of the present invention is, open have the compound of anti thrombotic action and pharmaceutical salts thereof as the pharmaceutical composition of main active ingredient take a class.
A further object of the invention is, disclose a class and have the compound of anti thrombotic action and pharmaceutical salts thereof as the application of antiplatelet drug aspect, particularly at the coronary syndrome that causes because of platelet aggregation for the preparation of prevention or treatment, myocardial infarction, the purposes of the cardiovascular and cerebrovascular diseases medicament aspects such as myocardial ischemia.
Now in conjunction with the object of the invention, content of the present invention is described in detail.
The present invention is specifically related to compound and the pharmacy acceptable salt thereof of formula I structure:
Wherein:
R can be hydrogen atom, methyl, ethyl, propyl group, sec.-propyl, nitro, cyano group, halogen atom, trifluoromethyl.
Wherein preferred following compound and pharmacy acceptable salt thereof:
Formula I compound pharmacy acceptable salt refers to: the salt that compound becomes with mineral acid, organic acid.Wherein preferred: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate; maleate, benzoate, succinate; tartrate; Citrate trianion, fumarate, taurate; gluconate, amino acid salts.
The syntheti c route of formula I compound is as follows:
Wherein compound ii, III are the commercially available prod, compound V reference literature (Indian Journal of Chemistry, 2006(45B), and the synthetic method in 1453-1462), the researchist in this area all can conveniently make.
Compound ii and III are in the presence of triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide, take methylene dichloride, trichloromethane, tetrahydrofuran (THF), dioxane, acetonitrile, DMF or toluene as solvent ,-10～80 ℃ of reactions make compounds Ⅳ; Compounds Ⅳ and compound V are take methyl alcohol or ethanol as solvent, and back flow reaction obtains the compound VI in the presence of Potassium ethanoate or sodium-acetate; Compound VI and diacetyl oxide VII are reacted under the effect of triethylamine, salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, sodium hydroxide or potassium hydroxide and are obtained chemical compounds I.
Reaction make various compounds or products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol or the DMSO drip mineral acid, organic acid is made pharmacy acceptable salt.
Specifically products therefrom is dissolved among DMF, acetone, methyl alcohol, ethanol or the DMSO, drips acidic alcohol to pH2, make hydrochloride.Or products therefrom is dissolved in DMF, acetone, methyl alcohol or ethanol, and add and wait a mole taurine, get its taurate.Also this compound can be dissolved among DMF, acetone, methyl alcohol, ethanol or the DMSO, drip the methanol solution of the vitriol oil, transfer pH2-3, make its vitriol, etc.
This compounds is effective for the human disease that causes because of platelet aggregation for the treatment of.Although compound of the present invention can be without the direct administration of any preparation, described various compounds preferably use with the form of pharmaceutical preparation, and route of administration can be non-enteron aisle approach (such as vein, muscle administration) and oral administration.
The pharmaceutical composition of the compounds of this invention is prepared as follows: Application standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis etc.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (the compounds of this invention) can specifically be applied according to patient's the state of an illness, the situation of diagnosis, and the amount of used compound or concentration are regulated in a wider scope.Usually, the weight range of active compound is 0.5～90%(weight of composition), another preferred scope is 0.5～70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention has obvious restraining effect aspect platelet aggregation, therefore can be used as potential antithrombotic reagent.
Further specify the antithrombotic acitivity of the compounds of this invention below by pharmacodynamic experiment.
Test materials:
Medicine and preparation: the compounds of this invention is made into suspension for animals administer with 1%CMCNa.
Animal: male rat, Tianjin Inst. of Materia Medica laboratory animal room provides, animal conformity certification number: No. the 001st, Tianjin animal word.
Test method:
Male Wistar rat, about body weight 300g, the per os gavage gives the compounds of this invention 1-7, dosage is 100mg/kg, successive administration 3 times, 1 hour anesthesia (vetanarcol after the last administration, 54mg/kg, ip) dorsal position fixes, and separates right common carotid artery and left external jugular vein.Put into the silk thread of a long 6cm in the stage casing of polyfluortetraethylene pipe, (50u/ml) is full of polyfluortetraethylene pipe with heparin-saline solution.After an end of polyfluortetraethylene pipe inserts left external jugular vein, injected exactly the anticoagulant heparin of 50u/kg by polyfluortetraethylene pipe, and then the other end of polyfluortetraethylene pipe is inserted right common carotid artery.Open bulldog clamp, blood flow in the polyfluortetraethylene pipe from right common carotid artery, returns left external jugular vein.Herba Clinopodii in behind the open blood flow 15min takes out rapidly silk thread and weighs, and gross weight deducts silk thread weight and namely gets wet weight of thrombus.Carry out statistics relatively with the t-check, the results are shown in following table:
The invention compound is on the impact of platelet aggregation
By test-results as seen, compound of the present invention can obviously suppress the formation of thrombus.Therefore, they can be used for preventing or treating the coronary syndrome that causes because of thrombosis, myocardial infarction, the cardiovascular and cerebrovascular diseases such as myocardial ischemia.
Simultaneously through stability study as can be known the compounds of this invention free alkali get final product stable existence, after being prepared into the mineral acid such as hydrochloride, taurate or organic acid salt, its preparation stability also all is higher than the hydrosulfate of clopidogrel to some extent.
Embodiment
The present invention is described further below in conjunction with embodiment, and embodiment only is indicative, means that never it limits the scope of the invention by any way.Described compound is through high performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum (
1H NMR,
13C NMR), mass spectrum (MS) etc. is further proved conclusively its structure.
Reference example 1:
The compound V
Get starting compound 2-cyano group-3-(2-thienyl) ethyl propenoate 50g(241mmol), thiosemicarbazide 22g(241mmol) and Anhydrous potassium carbonate 102g(724mmol) back flow reaction 4h in anhydrous methanol, let cool after the reaction, regulate pH to neutral with dilute hydrochloric acid solution, have solid to separate out.Filter, filter cake washing, drying obtain clear crystal V (30.7g), yield 68.7% with the benzene recrystallization.170 ℃ of fusing points conform to document, HPLC normalization method 98.9%.
Embodiment 1:
Compounds Ⅳ-1
Get compound ii-1(10g, 61mmol) be dissolved in the 50mL methylene dichloride.Stir fully dissolving.Be cooled to 0 ℃.Drip the dichloromethane solution of bromoacetyl bromide (III, 13.6g, 67mmol).Drip off rear maintenance thermotonus 4h.After the TLC detection reaction is complete, wash reaction solution with water (30mL * 3) three times, divide and get organic layer, drying is filtered, and revolves steaming.By the time light yellow oil without refining, namely can be used to cast single step reaction.The quality of products obtained therefrom is 16.5g, yield 95%, purity 98.3%(HPLC normalization method), MS (m/z) [M+H]
+: 284.0.
With reference to embodiment 1, can make following compound
Embodiment 2:
Compound VI-1
Get compounds Ⅳ-1(10g, 35mmol) be dissolved in 50mL ethanol, fully add Potassium ethanoate (10.3g, 105mmol) after the dissolving, be heated to backflow, behind the reaction 6h, the TLC detection reaction is complete.Reaction solution is let cool, in the impouring water, have solid to separate out.Filter, drying with ethyl acetate and sherwood oil 1:2 recrystallization, obtains product 10.5g, yield 80.8%, purity 99.1%(HPLC normalization method), MS (m/z) [M+H]
+: 371.1.
With reference to embodiment 2, can make following compound
Embodiment 3:
Chemical compounds I-1
Get compounds Ⅳ-1(5g, 13.5mmol), fully dissolve with the 30mL methylene dichloride.Be down to 0 ℃, add triethylamine (2g, 20mmol), drip diacetyl oxide (2.1g, 20mmol), keep thermotonus 3h.The TLC detection reaction finishes.In reaction solution impouring 30mL water, divide and get organic phase, wash again three times (30mL * 3).Organic layer is dry, filtration evaporate to dryness obtain brown oil.Stir with ethanol under the room temperature, obtain white solid, filter, filter cake is used cold ethanol drip washing again, obtains product 4.3g.Yield 77.2%, purity 99.4%(HPLC normalization method), MS (m/z) [M+H]
+: 413.1.
Embodiment 4:
Chemical compounds I-2
Get compounds Ⅳ-2(5g, 13mmol), fully dissolve with the 30mL methylene dichloride.Be down to 0 ℃, add triethylamine (2g, 20mmol), drip diacetyl oxide (2.1g, 20mmol), keep thermotonus 3h.The TLC detection reaction finishes.In reaction solution impouring 30mL water, divide and get organic phase, wash again three times (30mL * 3).Organic layer is dry, filtration evaporate to dryness obtain brown oil.Stir with ethanol under the room temperature, obtain white solid, filter, filter cake is used cold ethanol drip washing again, obtains product 4.6g.Yield 83.0%, purity 98.2%(HPLC normalization method), MS (m/z) [M+H]
+: 427.2.
Embodiment 5:
Chemical compounds I-3
Get compounds Ⅳ-3(5g, 13mmol), fully dissolve with the 40mL tetrahydrofuran (THF).Be down to-10 ℃, add sodium hydroxide (1g, 26mmol), then drip diacetyl oxide (2.1g, 20mmol), keep thermotonus 5h.The TLC detection reaction finishes.With reacting liquid filtering, the filtrate evaporate to dryness obtains reddish-brown oily matter.Stir with methyl alcohol under the room temperature, obtain white solid, filter, filter cake is used cold methanol drip washing again, obtains product 3.9g.Yield 70.3%, purity 97.3%(HPLC normalization method), MS (m/z) [M+H]
+: 427.1.
Embodiment 6:
Chemical compounds I-4
Get compounds Ⅳ-4(5g, 13mmol), fully dissolve with the 40mL tetrahydrofuran (THF).Be down to-10 ℃, add sodium hydroxide (1g, 26mmol), then drip diacetyl oxide (2.1g, 20mmol), keep thermotonus 5h.The TLC detection reaction finishes.With reacting liquid filtering, the filtrate evaporate to dryness obtains reddish-brown oily matter.Stir with methyl alcohol under the room temperature, obtain white solid, filter, filter cake is used cold methanol drip washing again, obtains product 3.9g.Yield 70.3%, purity 97.3%(HPLC normalization method), MS (m/z) [M+H]
+: 427.1.
Embodiment 7:
Chemical compounds I-5
Get compounds Ⅳ-5(5g, 11.1mmol), stir under the DMF room temperature with 20mL, fully dissolving.Add salt of wormwood (4.55g, 33mmol), then drip diacetyl oxide (2.2g, 22mmol), behind the reaction 3h, the TLC detection reaction finishes.With reacting liquid filtering, in the filtrate impouring water, use dichloromethane extraction.Divide and get organic layer, drying is filtered, and evaporated under reduced pressure obtains brown oil.Stir with methyl alcohol under the room temperature, obtain pale solid, filter, filter cake is used cold methanol drip washing again, obtains product 4.3g.Yield 78.8%, purity 98.0%(HPLC normalization method), MS (m/z) [M+H]
+: 491.0.
Embodiment 8:
Chemical compounds I-6
Get compounds Ⅳ-6(5g, 10.3mmol), stir under the DMF room temperature with 20mL, fully dissolving.Add yellow soda ash (4.2g, 30mmol), then drip diacetyl oxide (2.2g, 22mmol), behind the reaction 5h, the TLC detection reaction finishes.With reacting liquid filtering, in the filtrate impouring water, use dichloromethane extraction.Divide and get organic layer, drying is filtered, and evaporated under reduced pressure obtains brown oil.Stir with ethanol under the room temperature, obtain pale solid, filter, filter cake is used cold ethanol drip washing again, obtains product 4.0g.Yield 80.5%, purity 99.2%(HPLC normalization method), MS (m/z) [M+H]
+: 481.1.
Embodiment 9:
Chemical compounds I-7
Get compounds Ⅳ-7(5g, 12mmol), fully dissolve with the 30mL acetonitrile.Be warming up to 80 ℃, add saleratus (3.6g, 36mmol), then drip diacetyl oxide (2.5g, 24mmol), keep thermotonus 4h.The TLC detection reaction finishes.With reacting liquid filtering, the filtrate evaporate to dryness obtains brown oily foaming shape thing.Stir with ethanol under the room temperature, obtain light yellow solid, filter, filter cake is used cold ethanol drip washing again, obtains product 3.5g.Yield 63.7%, purity 98.5%(HPLC normalization method), MS (m/z) [M+H]
+: 458.1.
Embodiment 10:
Chemical compounds I-8
Get compounds Ⅳ-8(5g, 12.6mmol), fully dissolve with the 30mL methylene dichloride.Be down to 0 ℃, add triethylamine (2.6g, 25mmol), drip diacetyl oxide (2.1g, 20mmol), keep thermotonus 3h.The TLC detection reaction finishes.In reaction solution impouring 30mL water, divide and get organic phase, wash again three times (30mL * 3).Organic layer is dry, filtration evaporate to dryness obtain brown oil.Stir with ethanol under the room temperature, obtain light yellow solid, filter, filter cake is used cold ethanol drip washing again, obtains product 3.8g.Yield 69.1%, purity 99.3%(HPLC normalization method), MS (m/z) [M+H]
+: 438.3.
Embodiment 11:
Chemical compounds I-1 one-tenth hydrochloride: get chemical compounds I-1(1g), be dissolved in the 10mL dehydrated alcohol.Ice-water bath is cooled to 5 ℃, drip 11.1% ethanol solution hydrochloride to pH be 2, continue at stir about 1h under the ice-water bath.Filter, vacuum-drying gets the white solid powder.
Embodiment 12:
Chemical compounds I-3 one-tenth taurate: get chemical compounds I-3(2.0g), be dissolved in 20mL acetone.Adding waits a mole taurine after being heated to backflow, continues at approximately 1.5h of the lower stirring reaction of backflow.React complete, under room temperature, leave standstill 24h.Separate out white crystals, filter vacuum-drying.
Embodiment 13:
Chemical compounds I-5 one-tenth vitriol: get chemical compounds I-5 light yellow solid product (1.5g), be dissolved in 15mL methyl alcohol.Ice-water bath is cooled to 0 ℃, drip 10% sulfuric acid methanol solution to pH be 3, continue at stir about 1h under the ice-water bath.Filter, get white solid.
In order to illustrate that more fully a class of the present invention has the pharmaceutical composition of the compound of anti thrombotic action, the below provides following example of formulations, and described embodiment only is used for explanation, rather than is used for limiting the scope of the invention.Described preparation can use any active compound and the salt thereof in the compounds of this invention, preferably uses compound and salt thereof described in the embodiment 1-13.
Embodiment 14:
Prepare hard gelatin capsule with following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves for subsequent use.After pressing recipe quantity mentioned component being mixed, be packed in the hard gelatin capsule.
Embodiment 15:
Prepare tablet with following compositions:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves for subsequent use.First with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material, cross 20 mesh sieves, dry 2 h in 55 ℃ of ventilated drying ovens, dried particle cross the whole grain of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
Embodiment 16:
The preparation of injection liquid:
Preparation method: get activeconstituents and join in the water for injection that dissolves polysorbate and propylene glycol, add medicinal basic adjusting pH value to 4～8 and make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilization.
Embodiment 17:
The preparation of injection lyophilized powder:
The taurate 100mg of chemical compounds I-3
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-85%
Preparation method: get activeconstituents and add water for injection, regulate the pH value with medicinal basic and make its dissolving to 4-8.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, sealing, and get final product.
Claims (11)
1. the compound and the pharmacy acceptable salt thereof that have formula I structure:
Wherein:
R can be hydrogen, methyl, ethyl, propyl group, sec.-propyl, nitro, cyano group, halogen atom, trifluoromethyl.
2. formula I compound as described in claim 1 is following compound:
3. formula I compound as claimed in claim 1 or 2, pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.
4. formula I compound pharmacy acceptable salt as claimed in claim 3 is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate; maleate; benzoate, succinate, tartrate; Citrate trianion; fumarate, taurate, gluconate.
5. the preparation method of claim 1 Chinese style I compound, it is characterized in that: this preparation method is prepared by following three steps:
(1) compound ii and III are in the presence of acid binding agent, and reaction makes compounds Ⅳ in solvent;
(2) compounds Ⅳ and compound V are take methyl alcohol or ethanol as solvent, and back flow reaction obtains the compound VI in the presence of Potassium ethanoate or sodium-acetate;
(3) compound VI and acetic anhydride obtain chemical compounds I.
6. preparation method according to claim 5 is characterized in that, acid binding agent is selected from triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide in the step (1).
7. preparation method according to claim 5 is characterized in that, solvent is selected from methylene dichloride, trichloromethane, tetrahydrofuran (THF), dioxane, acetonitrile, DMF or toluene in the step (1).
8. preparation method according to claim 5 is characterized in that, the temperature of reaction in the step (1) is-10～80 ℃.
9. the pharmaceutical composition of a platelet aggregation-against, it comprises each formula I compound or its pharmacy acceptable salt and one or more pharmaceutical carriers of claim 1～2 for the treatment of significant quantity.
Claim 1～2 each formula I compound and pharmacy acceptable salt in the application aspect medicament for resisting platelet aggregation.
11. application as claimed in claim 7, the purposes aspect the cardiovascular and cerebrovascular diseases medicament that causes because of platelet aggregation for the preparation for the treatment of.
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2013
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| WO2000078754A1 (en) * | 1999-06-21 | 2000-12-28 | University Of Maryland, Baltimore | Thienylhydrazon with digitalis-like properties (positive inotropic effects) |
| CN101796033A (en) * | 2007-06-28 | 2010-08-04 | 英特维特国际股份有限公司 | As CB 1The piperazine of the replacement of antagonist |
| WO2009117421A2 (en) * | 2008-03-17 | 2009-09-24 | Kalypsys, Inc. | Heterocyclic modulators of gpr119 for treatment of disease |
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