CN100500644C - Interconnected medicine precursor of gabapentin and pregabalin and its medicinal use - Google Patents

Interconnected medicine precursor of gabapentin and pregabalin and its medicinal use Download PDF

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CN100500644C
CN100500644C CNB2004100298017A CN200410029801A CN100500644C CN 100500644 C CN100500644 C CN 100500644C CN B2004100298017 A CNB2004100298017 A CN B2004100298017A CN 200410029801 A CN200410029801 A CN 200410029801A CN 100500644 C CN100500644 C CN 100500644C
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gabapentin
pregabalin
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CN1673212A (en
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仲伯华
史卫国
杨红菊
刘河
郑建全
赵楠
李万华
陈兰福
宫泽辉
罗质璞
龚正华
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Institute of Pharmacology and Toxicology of AMMS
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Abstract

The present invention relates to the interconnected medicine precursor of gabapentin and pregabalin and its non-toxic pharmaceutically acceptable salt and their use in preparing medicines for treating epilepsy, neurogenic pain and/or anxiety neurosis.

Description

Mutual prodrug of gabapentin and pregabalin and medical application thereof
Technical Field
The present invention relates to mutual prodrugs of Gabapentin (Gabapentin) and Pregabalin (Pregabalin), non-toxic pharmaceutically acceptable salts thereof and their use in the preparation of medicaments for the treatment of epilepsy, neuropathic pain, and/or anxiety.
Technical Field
Neuropathic pain is a serious disease seriously threatening human life and health, and the incidence rate is up to 1%. Neuropathic pain refers to pain caused by damage or pathological changes of the nervous system, including intractable pain due to tumor compression, polyneuritis pain in diabetic patients, trigeminal neuralgia, herpes zoster neuralgia, and pain caused by spinal cord or nerve root compression in spinal disease patients. Neuropathic pain is often long-term and chronic, lasting days or months, as opposed to acute pain due to tissue damage. Persistent pain seriously affects the quality of life of people. The clinical causes of neuropathic pain are wide, the symptoms are various, the pathological mechanism is complex, and the conventional analgesics such as opioid potent narcotic analgesics and non-steroidal anti-inflammatory drugs have no obvious curative effect on the neuropathic pain, so the neuropathic pain becomes one of the difficulties of clinical treatment.
The treatment of epilepsy is also a problem to be solved in medicine today. The incidence of active epilepsy is about 0.7% of the general population, and the population is 400 tens of thousands of patients worldwide. Similar to neuropathic pain, the pathogenesis of epilepsy is also complex.
Although research into therapeutic drugs for neuropathic pain and epilepsy has made significant progress, research to find new compounds is slow due to the complex pathological mechanisms of both, which may involve various receptors, pathways and neurotransmitters, and difficulty in mechanism-based drug design; however, the existing medicines have limited curative effect, and no single medicine can completely eliminate any pain symptom.
Gabapentin (Gabapentin, shown in formula I) and Pregabalin (Pregabalin, shown in formula II) are effective drugs for treating neuropathic pain and epilepsy, but because of large polarity, the Gabapentin and Pregabalin are difficult to pass through a blood brain barrier, large-dose administration is required, and large-dose administration generates large toxic and side effects, such as dizziness, somnolence, nystagmus, sedation and the like, so that the tolerance of a patient is influenced; moreover, the medicine needs to be taken 3-4 times a day because of the short effective time in the body and the inconvenient taking.
In addition, lactam impurities are easily formed during the preparation and storage of I and II. Acids, bases or certain excipients may accelerate the formation of lactam by-products, resulting in uncontrollable drug quality.
Figure C200410029801D00042
Disclosure of Invention
The invention discovers that molecules of gabapentin and pregabalin both contain free amido and carboxyl, and the molecules are converted into a precursor form of amide or ester, so that lipophilicity can be increased, penetrability to blood brain barrier is increased, distribution in brain tissue is improved, dosage is reduced, and side effect is avoided; but also can prolong the action time.
Therefore, the mutual prodrug formed between gabapentin and pregabalin and the non-toxic pharmaceutically acceptable salt thereof have better activity of resisting epilepsy and treating neuropathic pain, the biological half-life period is obviously prolonged, and the lactam byproduct is not generated after long-term storage.
Accordingly, a first aspect of the invention provides a mutual prodrug of formula III:
Figure C200410029801D00051
wherein,
R1＝H，
Figure C200410029801D00052
or
Figure C200410029801D00053
R4＝H
Figure C200410029801D00054
Or
Figure C200410029801D00055
X is O or NH, n-1-6, R3Is straight-chain or branched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms.
In another aspect, the invention relates to a pharmaceutical composition comprising a mutual prodrug of formula III or a non-toxic pharmaceutically acceptable salt or pharmaceutically acceptable salt thereof as an active ingredient in combination with a pharmaceutically acceptable excipient.
The invention also relates to the use of a compound of formula III for the preparation of a medicament for the treatment of neuropathic pain and epilepsy.
According to the invention, the mutual prodrugs of the invention are compounds represented by formula III.
According to the invention, pharmaceutically acceptable salts of compounds of formula III include salts with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids such as: formic acid, acetic acid, methanesulfonic acid, benzoic acid, tartaric acid, maleic acid or fumaric acid; examples of the alkali metal include lithium, sodium or potassium, and examples of the alkaline earth metal include calcium and magnesium; examples of the inorganic base include sodium hydroxide, potassium hydroxide and aqueous ammonia; examples of organic bases are methylamine, ethylamine, triethylamine or dimethylethylamine.
According to the present invention, the pharmaceutical composition of the present invention can be used in the form of an oral or parenteral dosage form, such as a tablet, a capsule or an injection.
The compound III of the present invention can be prepared by the following synthetic route:
Figure C200410029801D00061
wherein,
R1＝Hor
Figure C200410029801D00063
R4＝H
Figure C200410029801D00064
Or
Figure C200410029801D00065
X is O or NH, n-1-6, R3Is straight-chain or branched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms.
In the above reaction route, gabapentin or pregabalin is used as a raw material, and tert-Butyloxycarbonyl (BOC) is used for protecting amino to obtain IV; IV reacts with diol under the action of DCC at room temperature or low temperature to obtain monoester V; condensing V and BOC protected gabapentin or pregabalin under the action of DCC to generate protected diester VI; VI, removing the protecting group by hydrochloric acid to obtain the target compound III.
Detailed Description
The present invention can be more specifically explained by the following examples. However, the scope of the present invention is not limited to the following examples.
EXAMPLE 1 tert-Butoxycarbonyl (BOC) protected gabapentin (IV)1) Synthesis of (2)
0.80g (0.02mol) of NaOH was added to a 250ml eggplant-shaped bottle, 20ml of water was added to dissolve the solution, the mixture was cooled in an ice bath and stirred magnetically, 3.42g (0.02mol) of gabapentin was further added, and after the solid was completely dissolved, a solution of 5.24g (0.024m0l) of BOC anhydride in 30ml of dioxane and a solution of 0.88g of NaOH in 30ml of water were alternately added to keep the pH of the reaction solution at about 9 and the reaction solution was added over about 30 minutes. After the addition was completed, the reaction was carried out in ice bath for 2 hours and then at room temperature for 2 hours. The reaction was complete. Extracting excess BOC anhydride with diethyl ether for 30ml × 5 times, discarding diethyl ether layer, adding 5% citric acid into water layer under stirring to pH3, separating solid, adding 80ml ethyl acetate to extract precipitate for 80ml × 3 times, mixing organic phases, washing ethyl acetate layer with water for 30ml × 2 times, and saturating NaClWashing with 30ml of water, 3 times, anhydrous MgSO4Drying for 4-6 hours. Then filtering out the drying agent, evaporating the solvent to obtain III14.7g of white solid, yield 86.72%, mp: 129-130 ℃,1H-NMR(CDCl3，400MHz，δ ppm)：1.45(s，9H，-C(CH3)3) 1.2-1.55(d, 10H), 2.32(s, 2H), 3.17(d, 2H), 5.0(s, 1H, CO-NH-), 11.5(s, 1H, -COOH); TLC: petroleum ether as developing agent EtAc CH3OH(5:2:0.5)，Rf＝0.34。
Example 2 Tert-Butoxycarbonyl (BOC) protected Pregabalin (IV)2) Synthesis of (2)
With reference to the procedure of example 1, pregabalin was reacted with BOC anhydride to obtain III as a white solid2Yield 90.73%, mp: 70-71 ℃; MS (ESI, m/e): 258.4(M-1), 260.3(M +1), 282.3(M + Na);
TLC: petroleum ether as developing agent EtAc CH3OH(5:2:0.5)，Rf＝0.34。
EXAMPLE 3 Synthesis of t-butyloxycarbonyl-protected gabapentin ethylene glycol Mono ester (V)1) Synthesis of (2)
Adding IV into 100ml eggplant-shaped bottle12.5g (0.00922mol), anhydrous CH2Cl220ml of the solution was stirred magnetically in an ice bath to dissolve the solid, and a solution of 3.43g (0.00922 mol. times.6) of ethylene glycol in 5ml of anhydrous DMF was added. After cooling to 0 ℃ DCC1.99g (0.00922 mol. times.1.05) was dissolved in 5ml of anhydrous CH dropwise2Cl2After reacting in ice bath for 1 hour, 0.25g of DMAP was added, and then the ice bath was removed and the reaction was carried out at room temperature for 12 hours. After the reaction, the precipitated DCU was filtered off, the solvent was distilled off under reduced pressure, EtAc100ml was added for dissolution, the precipitated DCU was filtered off again, and the EtAc layer was separately washed with 5% NaHCO3Wash 30ml X3 times, 5% citric acid wash 25ml X2 times, 5% NaHCO3Washing 30ml × 3 times, washing 30ml × 3 times with saturated NaCl, adding anhydrous MgSO4Drying for 4-6 hours. Then, the drying agent was filtered off, and the solvent was distilled off to obtain 3.0g of a colorless viscous liquid. Passing through a silica gel column, eluting: petroleum ether EtAc CH3OH 5:2:0.5 to obtain V12.8g, yield: 96.2 percent; TLC: petroleum ether as developing agent EtAc CH3OH(5:2:0.5)，Rf＝0.59；MS(ESI，m/e)：316.2(M+1)。
Example 4 Synthesis of t-butyloxycarbonyl-protected pregabalin ethylene glycol Mono-ester (V)2) Synthesis of (2)
Method according to example 3, IV2Condensation with ethylene glycol under the action of DCC to obtain V2The yield is as follows: 95.4 percent of the total weight of the mixture,
TLC: petroleum ether as developing agent EtAc CH3OH(5:2:0.5)，Rf＝0.57；MS(ESI，m/e)：326(M+Na)。
EXAMPLE 5 Synthesis of 1, 3-propanediol gabapentin monoester protected with tert-butyloxycarbonyl group (V)3) Synthesis of (2)
Method according to example 3, IV1Condensation with 1, 3-propanediol under the action of DCC to obtain V3The yield is as follows: 97.5 percent.
EXAMPLE 6 Synthesis of 1, 4-butanediol gabapentin monoester protected with tert-butyloxycarbonyl group (V)4) Synthesis of (2)
Method according to example 3, IV1Condensing with 1, 4-butanediol under the action of DCC to obtain V4The yield is as follows: 97.8 percent.
EXAMPLE 7 Synthesis of tert-Butoxycarbonyl protected gabapentin 1, 5-pentanediol monoester (V)5) Synthesis of (2)
Method according to example 3, IV1Condensation with 1, 5-pentanediol under the action of DCC to obtain V5The yield is as follows: 93.8 percent.
EXAMPLE 8 Synthesis of tert-Butoxycarbonyl protected gabapentin 1, 6-hexanediol monoester (V)6) Synthesis of (2)
Method according to example 3, IV1Condensation with 1, 6-hexanediol under the action of DCC to give V6The yield is as follows: 93.4 percent.
EXAMPLE 9 Synthesis of 1, 3-propanediol monoester of pregabalin protected with tert-butyloxycarbonyl group (V)7) Synthesis of (2)
Method according to example 3, IV2Condensation with 1, 3-propanediol under the action of DCC to obtain V7The yield is as follows: 96.7 percent.
EXAMPLE 10 Synthesis of 1, 4-butanediol monoester of pregabalin protected by t-butyloxycarbonyl (V)8) Synthesis of (2)
Method according to example 3, IV2Condensing with 1, 4-butanediol under the action of DCC to obtain V8The yield is as follows: 94.1 percent.
EXAMPLE 11 Synthesis of 1, 2-propanediol gabapentin monoester protected with tert-butyloxycarbonyl group (V)9) Synthesis of (2)
Method according to example 3, IV1Condensation with 1, 2-propanediol under the action of DCC to obtain V9The yield is as follows: 96.5 percent.
EXAMPLE 12 Synthesis of 1, 2-butanediol gabapentin monoester protected with tert-butyloxycarbonyl group (V)10) Synthesis of (2)
Method according to example 3, IV1Condensation with 1, 2-butanediol under the action of DCC to obtain V10The yield is as follows: 95.9 percent.
EXAMPLE 13 Synthesis of 1, 3-butanediol gabapentin monoester protected with tert-Butoxycarbonyl group (V)11) Synthesis of (2)
Method according to example 3, IV1Condensation with 1, 3-butanediol under the action of DCC to obtain V11The yield is as follows: 96.4 percent.
EXAMPLE 14 Synthesis of t-butyloxycarbonyl-protected gabapentin neopentyl glycol monoester (V)12) Synthesis of (2)
Method according to example 3, IV1Condensation with neopentyl glycol under the action of DCC to give V12The yield is as follows: 91.4 percent.
EXAMPLE 15 Synthesis of t-butyloxycarbonyl-protected gabapentin ethylene glycol diester (VI)1) Synthesis of (2)
Adding V into 100ml eggplant-shaped bottle11.7g (0.00553mol), anhydrous CH2Cl220ml, ice bath, electromagnetic stirring and then adding IV11.5g (0.00553 mol). After cooling to 0 ℃ DCC1.20g (0.00553 mol. times.1.05) was added dropwise to the solution, which was dissolved in 5ml of anhydrous CH2Cl2After reacting in ice bath for 1 hour, 0.1g of DMAP was added, and then the ice bath was removed and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, precipitated DCU was filtered off, the solvent was distilled off under reduced pressure, EtAc100ml was added for dissolution, precipitated DCU was filtered off again, and EtAc layers were each separated with 5% NaHCO3Wash 30ml X3 times, 5% citric acid wash 25ml X2 times, 5% NaHCO3Washing 30ml × 3 times, washing 30ml × 3 times with saturated NaCl, adding anhydrous MgSO4Drying for 4-6 hours. Then, the drying agent was filtered off, and the solvent was distilled off to obtain 3.0g of a colorless viscous liquid. Passing through silica gel column, and adding petroleum ether EtAc CH3Eluting with mixed solvent of OH 5:1.5:0.5 to obtain VI12.7 g. Yield: 88.2 percent; TLC: petroleum ether as developing agent EtAc CH3OH(5:1.5:0.5)，Rf＝0.65；MS(ESI，m/e)：569.4(M+1)。
EXAMPLE 16 Synthesis of t-butyloxycarbonyl-protected pregabalin ethylene glycol diester (VI)2) Synthesis of (2)
Method according to example 15, V2Condensation with IV2 under the action of DCC to give VI2The yield is as follows: 91.3 percent;
TLC: petroleum ether as developing agent EtAc CH3OH(5:1.5:0.5)，Rf＝0.66；MS(ESI，m/e)：545.5(M+1)，567.5(M+Na)。
EXAMPLE 17 Synthesis of t-butyloxycarbonyl-protected gabapentin/pregabalin ethyleneglycol heterodiester (VI)3) Synthesis of (2)
Method according to example 15, V1Under the action of DCC, with IV2Condensation to give VI3The yield is as follows: the mass ratio of the mixture to the mixed solution is 87.6 percent,
TLC: petroleum ether as developing agent EtAc CH3OH(5:1.5:0.5)，Rf＝0.65；MS(ESI，m/e)：557.2。
EXAMPLE 18 Synthesis of 1, 3-propanediol gabapentin protected by tert-Butoxycarbonyl group (VI)4) Synthesis of (2)
Method according to example 15, V3Under the action of DCC, with IV1Condensation to give VI4The yield is as follows: 93.7 percent.
EXAMPLE 19 Synthesis of tert-Butoxycarbonyl protected gabapentin 1, 4-butanediol diester (VI)5) Synthesis of (2)
Method according to example 15, V4Under the action of DCC, with IV1Condensation to give VI5The yield is as follows: 94.3 percent.
EXAMPLE 20 Synthesis of tert-Butoxycarbonyl protected gabapentin 1, 5-pentanediol diester (VI)6) Synthesis of (2)
Method according to example 15, V4Under the action of DCC, with IV1Condensation to give VI6The yield is as follows: 92.3 percent.
EXAMPLE 21 Synthesis of tert-Butoxycarbonyl-protected gabapentin 1, 6-hexanediol diester (VI)7) Synthesis of (2)
Method according to example 24, V5Under the action of DCC, with IV1Condensation to give VI7The yield is as follows: 90.9 percent.
EXAMPLE 22 Boc-protected gabapentin/pregabalin 1, 3-propanediol heterodiester (VI)8) Synthesis of (2)
Method according to example 15, V3Under the action of DCC, with IV2Condensation to give VI7The yield is as follows: 88.7 percent.
EXAMPLE 23 Boc-protected gabapentin/pregabalin 1, 4-butanediol Heterodiester (VI)9) Synthesis of (2)
Method according to example 15, V4Under the action of DCC, with IV2Condensation to give VI9The yield is as follows: 86.8 percent.
EXAMPLE 24 Boc-protected gabapentin/pregabalin 1, 5-pentanediol heterodiester (VI)10) Synthesis of (2)
Method according to example 15, V5Under the action of DCC, with IV2Condensation to give VI10The yield is as follows: 86.8 percent.
EXAMPLE 25 Boc-protected gabapentin/pregabalin 1, 6-hexanediol heterodiester (VI)11) Synthesis of (2)
Method according to example 15, V6Under the action of DCC, with IV2Condensation to give VI11The yield is as follows: 83.4 percent.
EXAMPLE 26 tert-Butoxycarbonyl protected pregabalin 1, 3-propanediol diester (VI)12) Synthesis of (2)
Method according to example 15, V7Under the action of DCC, with IV2Condensation to give VI11The yield is as follows: 92.5 percent.
EXAMPLE 27 Boc-protected pregabalin 1, 4-butanediol diester (VI)13) Synthesis of (2)
Method according to example 15, V8Under the action of DCC, with IV2Condensation to give VI13The yield is as follows: 92.5 percent.
EXAMPLE 28 Boc-protected gabapentin 1, 2-propanediol diester (VI)14) Synthesis of (2)
Method according to example 24, V9Under the action of DCC, with IV1Condensation to give VI14The yield is as follows: 93.9 percent.
Example 29 t-butyloxycarbonyl protected gabapentin 1,2-butanediol diester (VI)15) Synthesis of (2)
Method according to example 15, V10Under the action of DCC, with IV1Condensation to give VI15The yield is as follows: 91.4 percent.
EXAMPLE 30 tert-Butoxycarbonyl protected gabapentin 1, 3-butanediol diester (VI)16) Synthesis of (2)
Method according to example 15, V11Under the action of DCC, with IV1Condensation to give VI16The yield is as follows: 92.1 percent.
EXAMPLE 31 tert-Butoxycarbonyl protected gabapentin neopentyl glycol diester (VI)17) Synthesis of (2)
Method according to example 15, V12Under the action of DCC, with IV1Condensation to give VI17The yield is as follows: 93.1 percent.
EXAMPLE 32 Boc-protected gabapentin/pregabalin 1, 2-propanediol heterodiester (VI)18) Synthesis of (2)
Method according to example 15, V9Under the action of DCC, with IV2Condensation to give VI18The yield is as follows: 84.3 percent.
EXAMPLE 33 Boc-protected gabapentin/pregabalin 1, 2-butanediol Heterodiester (VI)19) Synthesis of (2)
Method according to example 15, V10Under the action of DCC, with IV2Condensation to give VI19The yield is as follows: 83.8 percent.
Example 34 tert-Butoxycarbonyl protected gabapentin/pregabalin 1, 3-butanediol Heterodiester (VI)20) Synthesis of (2)
Method according to example 15, V11Under the action of DCC, with IV2Condensation to give VI20The yield is as follows: 81.3 percent.
Example 35Boc protected gabapentin/pregabalin neopentyl glycol heterodiester (VI)21) Synthesis of (2)
Method according to example 15, V12Under the action of DCC, with IV2Condensation to give VI21The yield is as follows: 83.5 percent.
EXAMPLE 36 Synthesis of gabapentin/gabapentin ethylene glycol hydrochloride (III)1) Synthesis of (2)
VI is mixed with1The reaction mixture was dissolved in 20ml of anhydrous EtAc with stirring, and 20ml of 4N HCl/EtAc solution was added thereto, followed by stirring at room temperature. White solid began to precipitate after 15min of reaction, and the reaction was continued for 1 hour and stopped. The precipitate was filtered off, washed with cold EtAc and dry ether, respectively, and dried in vacuo. To obtain III11.75g, mp: 176-178 ℃, yield: 100 percent; elemental analysis (C)20H38N2O4Cl2): calculated values: 54.42% of C, 8.62% of H and 6.35% of N; experimental values: c54.01%, H9.05%, N6.04%;1H-NMR(CD3OD，600MHz，δ ppm)：1.41-1.56(d，20H)，2.57(s，4H)，3.07(s，4H)，4.34(s，4H)；MS(ESI，m/e)：368.9(M+1)。
example 37 Synthesis of Pregabalin/Pregabalin ethylene glycol diacetate hydrochloride (III)2) Synthesis of (2)
Method according to example 36, VI2Deprotection with hydrochloric acid to give III2mp: 154-155 ℃, yield: 100 percent; elemental analysis (C)18H38N2O4Cl2): calculated values: c51.80%, H9.11%, N6.71%; experimental values: c51.35%, H9.26%, N6.65%;1H-NMR(CD3OD，600MHz，δ ppm)：0.92-0.95(dd，12H，J＝6.6Hz)，1.27(m，4H)，1.66(m，2H)，2.24(m，2H)，2.48(d，4H)，2.98(m，4H)，4.33(s，4H)；MS(m/e)：345.2(M+1)。
example 38 gabapentin/pregabalin ethylene glycol Heterodiester hydrochloride (III)3) Synthesis of
Method according to example 36, VI3Deprotection with hydrochloric acid to give III3Mp: 101-103 ℃, yield: 100 percent; elemental analysis (C)19H38N2O4Cl2): calculated values: c53.14%, H8.86%, N6.53%; experimental values: 53.22% of C, 8.83% of H and 6.44% of N;1H-NMR(CD3OD，600MHz，δ ppm)：0.92-0.95(dd，12H，J＝6.6Hz)，1.27(m，4H)，1.41-1.56(d，10H)，1.66(m，2H)，2.24(m，2H)，2.48(d，4H)，2.57(s，4H)，2.98(m，4H)，3.07(s，4H)，4.33(s，4H)；MS(ESI，m/e)：357.4(M+1)。
EXAMPLE 39 Synthesis of gabapentin/gabapentin 1, 3-propanediol diester hydrochloride (III)4) Synthesis of (2)
Method according to example 36, VI4Deprotection with hydrochloric acid to give III4The yield is as follows: 100%, mp: 179-181 ℃ and elemental analysis (C)21H40N2O4Cl2): calculated values: c55.38%, H8.79%, N6.15%; experimental values: c55.05%, H8.88%, N6.06%;1H-NMR(CD3OD，600MHz，δ ppm)：1.46-1.59(m，20H)，2.00(m，2H)，2.67(s，4H)，3.09(s，4H)，4.27(t，4H)，8.33(s，6H，-NH 2 HCl)。
EXAMPLE 40 Synthesis of gabapentin/gabapentin 1, 4-butanediol diester hydrochloride (III)5) Synthesis of (2)
Method according to example 36, VI5Deprotection with hydrochloric acid to give III5The yield is as follows: 100%, mp: 171-173 ℃ and element analysis (C)22H42N2O4Cl2): calculated values: c56.29%, H8.95%, N5.97%; experimental values: 56.50% of C, 8.83% of H and 5.82% of N;1H-NMR(CD3OD，600MHz，δ ppm)：1.44-1.56(d，20H)，2.65(s，4H)，3.02(s，4H)，4.15(s，4H)，8.44(s，6H，-NH 2 HCl)。
EXAMPLE 41 Synthesis of gabapentin/gabapentin 1, 5-pentanediol diester hydrochloride (III)6) Synthesis of (2)
Method according to example 36, VI6Deprotection with hydrochloric acid to give III6The yield is as follows: 100%, mp: 177 to 179 ℃; elemental analysis (C)23H44N2O4Cl2): calculated values: c57.14%, H9.11%, N5.80%; experimental values: c57.08%, H9.17%, N6.68%;1H-NMR(CD3OD，400MHz，δ ppm)：1.38-1.72(m，26H)，2.62(s，4H)，3.09(s，4H)，4.15(t，4H)，8.42(s，6H，-NH 2 HCl)％。
EXAMPLE 42 Synthesis of gabapentin/gabapentin 1, 6-hexanediol diester hydrochloride (III)7) Synthesis of (2)
Method according to example 36, VI7Deprotection with hydrochloric acid to give III7The yield is as follows: 100%, mp: 177 to 179 ℃; elemental analysis (C)24H46N2O4Cl2): calculated values: c57.95%, H9.25%, N5.63%; experimental values: c57.80%, H9.29%, N5.49%;1H-NMR(CD3OD，400MHz，δ ppm)：1.37-1.69(m，28H)，2.59(s，4H)，3.09(s，4H)，4.11(t，4H)，8.41(s，6H，-NH 2 HCl)。
example 43 gabapentin/pregabalin 1, 3-propanediol heterodiester hydrochloride (III)8) Synthesis of (2)
Method according to example 36, VI8Deprotection with hydrochloric acid to give III7Yield: 100%, mp: 116-118 ℃; elemental analysis (C)20H40N2O4Cl2): calculated values: c54.17%, H9.03%, N6.32%; experimental values: 54.15% of C, 9.03% of H and 6.39% of N;1H-NMR(CD3OD，600MHz，δ ppm)：0.90-0.93(t，6H)，1.22-1.65(m，13H)，1.99(t，2H)，2.56(s，1H)，2.56-2.65(m，4H)，3.12-3.13(m，4H)，4.24(t，4H)，8.30(s，6H，-NH 2 HCl)。
example 44 gabapentin/pregabalin 1, 4-butanediol Heterodiester hydrochloride (III)9) Synthesis of (2)
Method according to example 36, VI9Deprotection with hydrochloric acid to give III9The yield is as follows: 100%, mp: 105-107 ℃; elemental analysis (C)21H42N2O4Cl2): calculated values: c55.14%, H9.19%, N6.12%; experimental values: 54.99% of C, 9.40% of H and 6.18% of N;1H-NMR(CD3OD，600MHz，δ ppm)：0.91-0.93(d，6H)，1.21-1.77(m，17H)，2.35-2.67(m，5H)，3.06(s，4H)，4.15(s，4H)，8.36-8.49(d，6H，-NH 2 HCl)。
example 45 gabapentin/pregabalin 1, 5-pentanediol heterodiester hydrochloride (III)10) Synthesis of (2)
Method according to example 36, VI10Deprotection with hydrochloric acid to give III10The yield is as follows: 100%, mp: 109-111 ℃; elemental analysis (C)22H44N2O4Cl2): calculated values: c56.06%, H9.34%, N5.94%; experimental values: 56.09% of C, 9.69% of H and 6.14% of N;1H-NMR(CD3OD，400MHz，δ ppm)：0.91-0.93(d，6H)，1.19-1.78(m，19H)，2.33(m，1H)，2.55-2.61(m，4H)，3.05-3.12(d，4H)，4.15(s，4H)，8.34-8.48(d，6H，-NH 2 HCl)。
example 46 gabapentin/pregabalin 1, 6-hexanediol heterodiester hydrochloride (III)11) Synthesis of (2)
Method according to example 36, VI11Deprotection with hydrochloric acid to give III11The yield is as follows: 100%, mp: 88-90 ℃; elemental analysis (C)23H46N2O4Cl2): calculated values: 56.91% of C, 9.48% of H and 5.77% of N; experimental values: c56.90%, H9.63%, N5.87%;1H-NMR(CD3OD，400MHz，δ ppm)：0.91-0.93(d，6H)，1.18-1.68(m，21H)，2.35(m，1H)，2.53-2.58(d，4H)，3.05-3.12(d，4H)，4.12(s，4H)，8.34-8.50(d，6H，-NH 2 HCl)。
example 47 Pregabalin/Pregabalin 1, 3-propanediol diester hydrochloride (III)12) Synthesis of (2)
Method according to example 36, VI12Deprotection with hydrochloric acid to give III12The yield is as follows: 100%, mp: 132-134 ℃; elemental analysis (C)19H40N2O4Cl2): calculated values: c52.90%, H9.28%, N6.50%; experimental values: c52.90%, H9.54%, N6.28%;1H-NMR(CD3OD，400MHz，δ ppm)：0.91-0.94(m，12H)，1.20-1.37(m，4H)，1.66(m，2H)，2.01(s，2H)，2.39(s，2H)，2.56(m，4H)，3.05(d，4H)，4.23(m，4H)，8.31(s，6H，-NH 2 HCl)。
example 48 Pregabalin/Pregabalin 1, 4-butanediol diester hydrochloride (III)13) Synthesis of (2)
Method according to example 36, VI13Deprotection with hydrochloric acid to give III13The yield is as follows: 100%, mp: 114-116 ℃; elemental analysis (C)20H42N2O4Cl2): calculated values: 53.93% of C, 9.44% of H and 6.29% of N; experimental values: c53.40%, H9.48%, N6.22%;1H-NMR(CD3OD，400MHz，δ ppm)：0.91-0.94(t，12H)，1.20-1.37(m，4H)，1.66(m，2H)，2.05(s，2H)，2.36(s，2H)，2.51-2.62(d，4H)，3.05(d，4H)，4.20(d，4H)，8.38(s，6H，-NH 2 HCl)。
example 49 gabapentin/gabapentin 1, 2-propanediol bisEster hydrochloride (III)14) Synthesis of (2)
Method according to example 36, VI14Deprotection with hydrochloric acid to give III14The yield is as follows: 100%, mp: 128-130 ℃; elemental analysis (C)20H38N2O4Cl2): calculated values: c55.38%, H8.79%, N6.15%; experimental values: c55.40%, H8.79%, N6.33%;1H-NMR(CD3OD，400MHz，δ ppm)：1.19-1.64(m，23H)，2.66-2.98(m，4H)，3.00-3.17(m，4H)，4.12-4.30(d，2H)，5.21-5.24(m，1H)，8.37(s，6H，-NH 2 HCl)。
example 50 gabapentin/gabapentin 1, 2-butanediol diester hydrochloride (III)15) Synthesis of (2)
Method according to example 36, VI15Deprotection with hydrochloric acid to give III15The yield is as follows: 100%, mp: 92-95 ℃; elemental analysis (C)22H42N2O4Cl2): calculated values: c56.29%, H8.95%, N5.97%; experimental values: 55.77% of C, 9.29% of H and 5.97% of N;1H-NMR(CD3OD，400MHz，δ ppm)：0.91-0.95(t，3H)，1.19-1.67(m，22H)，2.61-2.88(m，4H)，3.03-3.21(m，4H)，4.07-4.33(d，2H)，5.05-5.10(m，1H)，8.34(s，6H，-NH 2 HCl)。
example 51 gabapentin/gabapentin 1, 3-butanediol diester hydrochloride (III)16) Synthesis of (2)
Method according to example 36, VI16Deprotection with hydrochloric acid to give III16Yield: 100%, mp: 176-178 ℃; elemental analysis (C)22H42N2O4Cl2): calculated values: c56.29%, H8.95%, N5.97%; experimental values: 55.99% of C, 9.03% of H and 6.04% of N;1H-NMR(CD3OD，400MHz，δ ppm)：1.19-1.57(m，23H)，1.88-1.97(m，2H)，2.57-2.75(m，4H)，3.03-3.26(m，4H)，4.13-4.28(d，2H)，5.08-5.09(m，1H)，8.30(s，6H，-NH 2 HCl)。
example 52 gabapentin/gabapentin neopentyl glycol diester hydrochloride (III)17) Synthesis of (2)
Method according to example 36, VI17Deprotection with hydrochloric acid to give III17The yield is as follows: 100%, mp: 138-140 ℃; elemental analysis (C)23H44N2O4Cl2): calculated values: c57.14%, H9.11%, N5.80%; experimental values: c57.35%, H9.56%, N5.79%;1H-NMR(CD3OD，400MHz，δ ppm)：0.94s，6H)，1.35-1.60(m，20H)，2.67(s，4H)，3.11(s，4H)，3.97(s，4H)，8.33(s，6H，-NH 2 HCl)。
example 53 gabapentin/pregabalin 1, 2-propanediol heterodiester hydrochloride (III)18) Synthesis of (2)
Method according to example 36, VI18Deprotection with hydrochloric acid to give III18The yield is as follows: 100%, mp: 87-89 ℃; elemental analysis (C)20H40N2O4Cl2): calculated values: c54.17%, H9.03%, N6.32%; experimental values: 53.76% of C, 9.02% of H and 6.27% of N;1H-NMR(CD3OD，400MHz，δ ppm)：0.91-0.93(d，6H)，1.19-1.65(m，16H)，2.38-3.19(m，9H)，3.96-4.40(d，2H)，5.18-5.23(m，1H)，8.30(s，6H，-NH 2 HCl)。
example 54 gabapentin/pregabalin 1, 2-butanediol Heterodiester hydrochloride (III)19) Synthesis of (2)
Method according to example 36, VI19Deprotection with hydrochloric acid to give III19The yield is as follows: 100%, mp: 88-90 ℃; elemental analysis (C)21H42N2O4Cl2): calculated values: c55.14%, H9.19%, N6.12%; experimental values: c55.01％，H 9.15％，N 6.31％；1H-NMR(CD3OD，600MHz，δ ppm)：0.91-0.96(s，9H)，1.19-1.68(m，12H)，2.08(s，1H)，2.35-3.20(m，8H)，4.06-4.10(d，1H)，4.37-4.49(d，1H)，5.01-5.05(m，1H)，8.29-8.40(d，6H，-NH 2 HCl)。
Example 55 gabapentin/pregabalin 1, 3-butanediol Heterodiester hydrochloride (III)20) Synthesis of (2)
Method according to example 36, VI20Deprotection with hydrochloric acid to give III20The yield is as follows: 100%, mp: 86-88 ℃; elemental analysis (C)21H42N2O4Cl2): calculated values: c55.14%, H9.19%, N6.12%; experimental values: 55.56% of C, 9.06% of H and 6.56% of N;1H-NMR(CD3OD，600MHz，δ ppm)：0.86-0.93(s，6H)，1.17-1.68(m，18H)，1.90-1.95(m，1H)，2.39-2.68(m，4H)，3.02-3.17(m，4H)，4.11-4.39(d，1H)，5.04-5.07(m，1H)，8.26-8.38(d，6H，-NH 2 HCl)。
example 56 gabapentin/pregabalin neopentyl glycol heterodiester hydrochloride (III)21) Synthesis of (2)
Method according to example 36, VI21Deprotection with hydrochloric acid to give III21The yield is as follows: 100%, mp: 148-150 ℃; elemental analysis (C)22H44N2O4Cl2): calculated values: c56.06%, H9.34%, N5.94%; experimental values: c56.04%, H9.61%, N5.94%;1H-NMR(CD3OD，600MHz，δ ppm)：0.90-0.98(m，12H)，1.01-1.67(m，13H)，2.50(s，1H)，2.53-2.75(m，4H)，3.02-3.16(m，4H)，3.90-3.99(m，4H)，8.29(s，6H，-NH 2 HCl)。
biological activity assay
The compounds of interest were subjected to preliminary evaluation of anti-neuropathic pain activity and anti-epileptic activity.
1. Anti-neuropathic pain Activity
Pharmacodynamic evaluation of the target compounds against neuropathic pain was performed using a model of chronic compressive neuralgia of the sciatic nerve (CCI). The method comprises the following steps:
SD rats, male, weighing 160-. Separating sciatic nerve from peripheral tissue with sterile glass hook, loosely tying 4 rings with sterile chromium catgut (No. 4, diameter 0.15mm), spacing 1-2mm between each ring, locally scattering penicillin powder, suturing muscle tissue and skin, and placing in cage with cork dust. The sham group exposed only the sciatic nerve, and the other treatments were as above.
Rats of different days after surgery were placed in a metal cage and their soles were stimulated with different gram weights of cellosilk, 5 seconds apart for each stimulation, until a cellosilk was found that caused 4 to 6 rat foot-lifting reactions out of 10, and their gram weights were recorded and set as a threshold (unit: g). And simultaneously recording the times of raising the feet of the animals when the cellosilk with different gram weights is stimulated for 10 times, and setting the highest threshold value to be 26 g.
The compound was administered intraperitoneally (60mg/kg) 1 hour prior to the experiment, 5-6 animals per group, and the effect of the drug on pain threshold after administration was observed. The threshold statistics adopts nonparametric Test WilcoVon2-Sample Test and Kruskal-Wallis Test; data analysis was performed using SASS data processing software.
Maximum analgesic percentage (%) - (threshold after drug treatment-threshold before drug treatment)/(threshold maximum analgesic value-threshold before drug treatment) ×%.
The results are shown in Table 1.
TABLE 1 Experimental observations of hypersensitivity to pain of rat CCI model
Figure C200410029801D00211
Figure C200410029801D0021172232QIETU
，，
2. Anti-epileptic activity
The anti-epileptic effect of the target compounds was evaluated using a mouse maximal electroshock seizure model and a mouse pentaazane convulsive Model (MET). The former is a well-known experimental model of epileptic grand mal, and the latter is an experimental animal model for observing the curative effect of the anti-epileptic grand mal.
2.1 mouse maximal electroshock attack Model (MES)
Kunming mice, 20 +/-2 mg in body weight, male and female, are divided into groups randomly, and each group comprises 10 animals. Firstly, immersing the dentate clamp electrodes in physiological saline, respectively clamping the dentate clamp electrodes on two ears of a mouse, then introducing currents (mA) with different intensities, and taking MES as MES of the mouse which generates hindlimb rigid extension and flexion and then twins, thereby determining that the current intensity of MES generated by more than 97 percent of mice is 8.02 mA.
On the basis of the above experiment, different doses of samples to be tested are given at p.o 0.5h before the experiment, normal saline is used as a control to observe the MES resistance, and the Bless method is adopted to calculate the anti-startling effect ED50The value is obtained. In addition, 90% of the effective dose is administered, the anti-MES effect is observed at different intervals, and the 50% effective time t is determined1/2. The results are shown in Table 2.
TABLE 2 anti-maximal electroshock onset effect in mice
Figure C200410029801D00221
2.2 mouse model of convulsion due to Penetracycline (MET)
Kunming mice, 20 +/-2 mg in body weight, male and female, are divided into groups randomly, and each group comprises 10 animals. Injecting pentylenetetrazol sc, and determining the dose value of pentylenetetrazol of more than 97% of animals producing convulsion as 92.1mg kg-1 with twinning convulsion of animals lasting for more than 3 seconds within 30min as final index.
On the basis of the above experiment, different doses of samples to be tested are given at p.o 0.5h before the experiment, normal saline is used as a control to observe the anti-MET effect and the anti-MES effect, and the Bless method is adopted to calculate the anti-fright effect ED50The value is obtained. In addition, 90% of the effective dose is administered, the anti-MES effect is observed at different intervals, and the 50% effective time t is determined1/2. The results are shown in Table 3.
TABLE 3 anticonvulsant action against pentaerythrine in mice
Figure C200410029801D00231

Claims (3)

1. Mutual prodrug of gabapentin and pregabalin represented by formula III
Figure C200410029801C00021
Wherein,
Figure C200410029801C00022
or
Figure C200410029801C00023
Figure C200410029801C00024
Or
Figure C200410029801C00025
X is O, n is 1-6, R3Is straight-chain or branched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms.
2. A pharmaceutical composition comprising a compound of formula III according to claim 1 as an active ingredient, and a pharmaceutically acceptable excipient.
3. Use of the mutual prodrug of claim 1 for the manufacture of a medicament for the treatment of neuropathic pain or epilepsy.
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Title
加巴喷丁用于神经病理性疼痛治疗的研究进展. 刘国凯等.中国临床药理学与治疗学，第8卷第3期. 2003
加巴喷丁用于神经病理性疼痛治疗的研究进展. 刘国凯等.中国临床药理学与治疗学，第8卷第3期. 2003 *
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