CN103420994A - Dabigatran derivative used as prodrug, and preparation method and application thereof - Google Patents
Dabigatran derivative used as prodrug, and preparation method and application thereof Download PDFInfo
- Publication number
- CN103420994A CN103420994A CN2012101647221A CN201210164722A CN103420994A CN 103420994 A CN103420994 A CN 103420994A CN 2012101647221 A CN2012101647221 A CN 2012101647221A CN 201210164722 A CN201210164722 A CN 201210164722A CN 103420994 A CN103420994 A CN 103420994A
- Authority
- CN
- China
- Prior art keywords
- dabigatran
- pharmaceutically acceptable
- formula
- derivative
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical class N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 229940002612 prodrug Drugs 0.000 title description 4
- 239000000651 prodrug Substances 0.000 title description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 239000003868 thrombin inhibitor Substances 0.000 claims abstract description 6
- 229940122388 Thrombin inhibitor Drugs 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 69
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 38
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 claims description 14
- -1 ester derivative of dabigatran Chemical class 0.000 claims description 11
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 10
- 229960000288 dabigatran etexilate Drugs 0.000 claims description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 229960003850 dabigatran Drugs 0.000 claims description 7
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 7
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- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
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Abstract
The invention relates to a preparation method of a benzimidazole derivative shown as a general formula I, wherein R1, R2 and R3 are defined as in the specification. The invention relates to a Dabigatran derivative shown as the general formula I and non-toxic pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing these compounds as active components, and application of the compounds and the pharmaceutical composition as thrombin inhibitors.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to dabigatran etexilate derivatives and a preparation method thereof, a pharmaceutical composition containing the derivatives and application of the compound and the pharmaceutical composition as thrombin inhibitors.
Background
Dabigatran etexilate is a novel synthetic direct thrombin inhibitor, is a prodrug of dabigatran, belongs to a non-peptide thrombin inhibitor, and is developed by the company brigreville, germany. In 4 months 2008, first marketed in germany and uk under the trade name Pradaxa, for the prevention and treatment of acute Venous Thrombosis (VTE). The new anticoagulant oral drug is the first new anticoagulant oral drug on the market 50 years after warfarin, and has the characteristics of strong effect, no need of special drug monitoring, less drug interaction and the like. In vitro and in vivo tests and clinical researches all suggest that the product has good curative effect and pharmacokinetic characteristics, and is a milestone breakthrough in the field of anticoagulant therapy and the field of potential lethal thrombus prevention. Pradaxa capsules (dabigatran etexilate) were approved by the U.S. food and drug administration at 10/19/2010 for the prevention of stroke and clotting in patients with cardiac arrhythmias (atrial fibrillation).
Thrombin plays an important role in the coagulation process, being an extracellular insulin-like serine protease, which, on the one hand, is capable of cleaving fibrinogen into fibrin, which participates in the formation of an insoluble thrombotic matrix; on the other hand, it can induce platelet activation and aggregation, which in turn triggers a series of secondary coagulation cascades. Dabigatran is a prodrug, which is converted into active dabigatran in vivo, and dabigatran exerts an anticoagulant effect by directly inhibiting thrombin. After oral gastrointestinal absorption, the dabigatran etexilate is converted into dabigatran with direct anticoagulant activity in vivo. The drug binds to the fibrin specific binding site of thrombin, preventing the cleavage of fibrinogen into fibrin, thereby blocking the final step of coagulation cascade network and thrombus formation.
However, oral bioavailability of dabigatran etexilate is low (< 6.5%), and thus further improvements are desired.
Disclosure of Invention
The invention relates to dabigatran etexilate derivatives shown in a structural formula I, non-toxic pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compounds as active ingredients, and application of the compounds and the pharmaceutical composition as thrombin inhibitors.
Accordingly, in a first aspect, the present invention provides an ester derivative of dabigatran represented by formula i:
wherein,
R1represents H or C1-C5Alkyl or substituted alkyl of (a); r2Represents H or C1-C3Alkyl or substituted alkyl of (a); r3Represents C1-C6Alkyl or substituted alkyl of (a).
Preferably, the present invention provides an ester derivative of dabigatran represented by formula I or a pharmaceutically acceptable salt thereof, wherein R is1Represents H, methyl or ethyl, R2Represents H or CH3，R3Represents a group, ethyl, propyl, butyl, pentyl or n-hexyl.
More preferably, the present invention provides an ester derivative of dabigatran represented by formula i or a pharmaceutically acceptable salt thereof selected from the group consisting of compounds represented by the following structural formulae:
the substituents of a particular target compound are each defined as follows:
I1：R1is-CH3，R2is-H, R3is-CH3；
I2：R1is-CH3，R2is-H, R3is-CH2CH3；
I3：R1is-CH3，R2is-H, R3is-CH2CH2CH3；
I4：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH3；
I5：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH2CH3；
I6：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH2CH2CH3；
I7：R1is-CH2CH3，R2is-H, R3Is R3-CH3；
I8：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH3；
I9：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH3；
I10：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH2CH3；
I11：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH2CH2CH3；
I12：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH2CH2CH2CH3；
I13：R1is-CH3，R2is-CH3，R3is-CH3；
I14：R1is-CH3，R2is-CH3，R3is-CH2CH3；
I15：R1is-CH3，R2is-CH3，R3is-CH2CH2CH3；
I16：R1is-CH3，R2is-CH3，R3is-CH2CH2CH2CH3；
I17：R1is-CH3，R2is-CH3，R3is-CH2CH2CH2CH2CH3；
I18：R1is-CH3，R2is-CH3，R3is-CH2CH2CH2CH2CH2CH3；
I19：R1is-CH2CH3，R2is-CH3，R3Is R3-CH3；
I20：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH3；
I21：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH3；
I22：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH2CH3；
I23：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH2CH2CH3；
I24：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH2CH2CH2CH3；
A second aspect of the invention relates to a pharmaceutical composition, which comprises at least one ester derivative of dabigatran represented by formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
The second aspect of the invention relates to an ester derivative of dabigatran shown as a formula I and non-toxic pharmaceutically acceptable salts thereof, and application of a pharmaceutical composition containing the ester derivative of dabigatran shown as the formula I and the non-toxic pharmaceutically acceptable salts thereof as active ingredients as anticoagulation.
The compounds represented by formula i can form pharmaceutically acceptable salts with inorganic acids, such as sulfates, phosphates, hydrochlorides, hydrobromides; pharmaceutically acceptable salts can also be formed with organic acids such as acetates, oxalates, citrates, succinates, gluconates, tartrates, p-toluenesulfonates, benzenesulfonates, methanesulfonates, benzoates, lactates, maleates, and the like. The selection and preparation of suitable salts is well known to those skilled in the art.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered alone or in the form of pharmaceutical compositions. The pharmaceutical composition of the present invention can be formulated into various suitable dosage forms according to the administration route. The use of one or more physiologically acceptable carriers, including excipients and auxiliaries, facilitates processing of the active compounds into preparations which can be used pharmaceutically. The appropriate formulation will depend on the route of administration chosen and may be prepared in accordance with common general knowledge in the art.
The administration route can be oral, parenteral or topical, preferably oral and injectable. The oral pharmaceutical preparation comprises capsules, tablets and the like. The compounds of the invention may also be formulated for parenteral or transdermal or transmucosal administration, or by means of suppositories or implants. It will be appreciated by those skilled in the art that the compounds of the present invention may employ a suitable Drug Delivery System (DDS) to achieve a more beneficial effect.
Detailed Description
The following examples are presented to enable those skilled in the art to more fully understand the present invention and are not intended to limit the invention in any way.
Dabigatran etexilate and ester derivatives of dabigatran shown in formula I are synthesized by the methods of references (Hauel NH, Nar H, Prepke H, et al.Structure-Based Design of Novel patent polypeptide Thrombin inhibitors. J.Med.Chem.2002; 45: 1757-:
R1=H，-CH3，-CH2CH3；R2=H，CH3，R3 = C1-C6alkyl or substituted alkyl of (a).
Taking a compound 1 as a starting material, and carrying out amidation and condensation to obtain an intermediate 2; reacting the intermediate 2 with sodium hydroxide and then reacting with chloralkane to obtain an intermediate 3, wherein the intermediate 3 reacts with acetylThe hydroxamic acid is reacted to obtain an intermediate 4, the intermediate 4 is reacted with different substituted activated esters to obtain the dabigatran derivative (I)1-32）
EXAMPLE 13 methyl- (2- (((3- ((methoxycarbonyl) amino) benzisoxazol-5-yl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamido) propionate (I1) Preparation of
1) Synthesis of ethyl 3- (2- (((3-cyano-4-fluorophenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamido) propionate (2A)
2- ((3-cyano-4-fluorobenzene) amino) acetic acid (1.77g,0.0lmo1), EDC1(1.9g, 0.01mo1), 1-hydroxybenzotriazole (1.35g, 0.01mo1) were dissolved in a mixture of THF (35mL) and DMF (5 mL). The mixture was stirred in an ice-water bath for 35min, warmed to room temperature, and a solution of 1(3.1g, 0.009mo1) in THF (15mL) was slowly added dropwise. Stirring for 6h after the addition. The solvent was evaporated, dichloromethane (30mL) was added, washing was performed with saturated brine (5mLx3), drying was performed with anhydrous sodium sulfate, then filtration was performed, the filtrate was concentrated to dryness, glacial acetic acid (45mL) was added to the residue, heating was performed under reflux for 2 h, concentration was performed under reduced pressure to dryness, concentrated aqueous ammonia (15mL) was added to the residue, the solvent was evaporated by stirring at room temperature for 30min, dichloromethane (25mL) was added to the residue, washing was performed with saturated brine (5mL x3), drying was performed with anhydrous sodium sulfate, then filtration was performed, the filtrate was concentrated to dryness, and the residue was purified by column chromatography to obtain 3.1g of an amorphous yellow solid.
2) Synthesis of methyl 3- (2- (((3-cyano-4-fluorophenyl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamido) propionate (3 Aa)
Dissolving 5.0 g of intermediate 2A in 200mL of ethanol, adding 10 mL of 1N sodium hydroxide solution, stirring at room temperature to react until hydrolysis is complete, evaporating to dryness, dissolving with 20mL of DMF, adding 1.86 g of methyl iodide, stirring at room temperature for 24 hours, concentrating, and performing column separation to obtain 4.0g of target intermediate.
3) Synthesis of methyl 3- (2- (((3-aminobenzisoxazol-5-yl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamido) propionate (4 Aa)
4.0g of intermediate 3Aa was dissolved in 80 mL of DMF, and potassium carbonate (4.8 g,0.036 mol) was dissolved in 24 mL of water and added to the solution, followed by stirring at room temperature. Acetohydroxamic acid (1.632 g,0.024 mol) was weighed and added to the above reaction solution, reacted at room temperature for 3 days, filtered off the solid and evaporated to dryness, and passed through a column to obtain 2.5 g of pure product.
4) Methyl 3- (2- (((3- ((methoxycarbonyl) amino) benzisoxazol-5-yl) amino) methyl) -1-methyl-N- (pyridin-2-yl) -1H-benzimidazole-5-carboxamido) propionate (I1) Synthesis of (2)
The product (4 Aa) obtained in the above step was dissolved in tetrahydrofuran (50mL), and methyl chloroformate (0.519 g) and DIEA (3mL) were added thereto, and the mixture was stirred at room temperature overnight, evaporated to dryness, and purified by column chromatography to obtain 1.8g of a white aimed product.1H NMR(DMSO-d6,400 MHz)δ: 2.68(t, J=7.1Hz, 2H, CH2), 3.68(s, 3H, CH3), 3.72(s, 3H, CH3), 4.22(t, J=7.1 Hz, 2H, CH2), 3. 8(s, 3H, CH3), 5.33(s,2H, CH2), 6.27(br t, 1H, NH), 6.89~6.95(m, 2H, ArH), 7.09~7.12(m, 1H, ArH), 7.19~7.22(m, 2H, ArH), 7.47(d, J=8.4, 1H, ArH), 7.5~7.56(m, 2H, ArH), 7.67(d, J=8.4, 1H, ArH), 8.37(m, 1H), 8.97(br s, 1H, NH), ESI-MS: m/z 558 [M+H]+。
Examples 2 to 24
Referring to the procedure of example 1, except that different phenoxyacetic acids were selected, different carboxylic acid esters were reacted with different activated ester side chains to give the compounds of formula I below.
Example 25 evaluation of anticoagulant Activity-determination of activated partial Thromboplastin time (aPPT)
Kunming mice, 18-20g in mass, were randomly grouped into groups of 10 mice each, fasted overnight. Suspending or dissolving dabigatran etexilate and a target compound to be detected in 1% sodium carboxymethylcellulose water solution to prepare 1mg/mL concentration, performing intragastric administration according to a dose of 10mg/Kg (calculated by being converted into dabigatran), after half an hour, taking blood through cardiac puncture, adding a 4% sodium lycii solution to a final concentration of 0.4% for anticoagulation, centrifuging for 5 minutes at 12000r/min, taking 0.1mL of plasma, adding 0.1mL of aPPT reagent, pre-heating at 37 ℃ for 3 minutes, adding 0.1mL of calcium chloride solution pre-heated at 37 ℃, and determining the coagulation time by using a platelet aggregation coagulation factor analyzer to obtain the aPPT value. The results are shown in Table 1.
TABLE 1 measurement of activated partial thromboplastin time (aPPT)
| Compound (I) | aPPT(sec) |
| Physiological saline | 21.4±4.3 |
| Dabigatran etexilate | 75.3±2.1 |
| Ⅰ3 | 72.1±2.5 |
| Ⅰ4 | 160.1±2.6 |
| Ⅰ5 | 140.2±4.2 |
| Ⅰ10 | 142.6±3.3 |
| Ⅰ12 | 130.9±2.7 |
| Ⅰ13 | 117.4±3.6 |
| Ⅰ14 | 75.9±3.3 |
| Ⅰ16 | 97.4±2.7 |
| Ⅰ17 | 90.9±2.9 |
| Ⅰ18 | 160.2±4.4 |
| Ⅰ22 | 122.6±3.0 |
| Ⅰ23 | 63.5±3.4 |
| Ⅰ24 | 100.9±2.8 |
Claims (7)
1. An ester derivative of dabigatran having the structure of formula i or a pharmaceutically acceptable salt thereof:
wherein,
R1is H or C1-C5Alkyl or substituted alkyl of (a); r2Is H or C1-C3Alkyl or substituted alkyl of (a); r3Is C1-C6Alkyl or substituted alkyl of (a).
2. The derivative of an ester of dabigatran according to claim 1, having the structure of formula i:
wherein,
R1is H, methyl or ethyl; r2Is H or CH3；R3Is methyl, ethyl, propyl, butyl, pentyl or n-hexyl.
3. The derivative of an ester of dabigatran etexilate having the structure of formula i or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, selected from the group consisting of compounds represented by the following structural formulae:
wherein R is1、R2And R3Are respectively defined as follows:
I1：R1is-CH3，R2is-H, R3is-CH3；
I2：R1is-CH3，R2is-H, R3is-CH2CH3；
I3：R1is-CH3，R2is-H, R3is-CH2CH2CH3；
I4：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH3；
I5：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH2CH3；
I6：R1is-CH3，R2is-H, R3is-CH2CH2CH2CH2CH2CH3；
I7：R1is-CH2CH3，R2is-H, R3Is R3-CH3；
I8：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH3；
I9：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH3；
I10：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH2CH3；
I11：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH2CH2CH3；
I12：R1is-CH2CH3，R2is-H, R3Is R3-CH2CH2CH2CH2CH2CH3；
I13：R1is-CH3，R2is-CH3，R3is-CH3；
I14：R1is-CH3，R2is-CH3，R3is-CH2CH3；
I15：R1is-CH3，R2is-CH3，R3is-CH2CH2CH3；
I16：R1is-CH3，R2is-CH3，R3is-CH2CH2CH2CH3；
I17：R1is-CH3，R2is-CH3，R3is-CH2CH2CH2CH2CH3；
I18：R1is-CH3，R2is-CH3，R3is-CH2CH2CH2CH2CH2CH3；
I19：R1is-CH2CH3，R2is-CH3，R3Is R3-CH3；
I20：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH3；
I21：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH3；
I22：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH2CH3；
I23：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH2CH2CH3；
I24：R1is-CH2CH3，R2is-CH3，R3Is R3-CH2CH2CH2CH2CH2CH3。
4. The dabigatran etexilate derivative with the structure of the formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the salt is formed by the dabigatran etexilate derivative with the structure of the formula I and an organic acid or an inorganic acid.
5. The ester derivative of dabigatran or its pharmaceutically acceptable salt according to claim 4, wherein the salt may be sulfate, phosphate, hydrochloride, hydrobromide, acetate, oxalate, citrate, succinate, gluconate, tartrate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, benzoate, lactate, maleate.
6. A pharmaceutical composition comprising at least one ester derivative of dabigatran etexilate having the structure of formula i or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, and one or more pharmaceutically acceptable carriers or excipients.
7. Use of the dabigatran etexilate derivative having the structure of formula i or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 for the preparation of thrombin inhibitors.
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