Nimodipine Water-Soluble Derivative, And Preparation Method And Use Thereof
20180303810 ยท 2018-10-25
Assignee
Inventors
Cpc classification
A61K31/444
HUMAN NECESSITIES
C07D211/90
CHEMISTRY; METALLURGY
A61K31/675
HUMAN NECESSITIES
A61K31/44
HUMAN NECESSITIES
A61P9/10
HUMAN NECESSITIES
A61K31/4439
HUMAN NECESSITIES
International classification
A61K31/4422
HUMAN NECESSITIES
A61P9/10
HUMAN NECESSITIES
A61K31/4439
HUMAN NECESSITIES
Abstract
Provided are a nimodipine water-soluble derivative, and a preparation method and a use thereof, belonging to the field of pharmaceutical chemistry. The nimodipine water-soluble derivative has the structural feature of general formula I and has a relatively high water solubility, and can be converted into nimodipine by an internal enzyme in blood or in the body, so that the nimodipine water-soluble derivative can be used as a nimodipine prodrug and a calcium ion antagonist for treating cardiovascular and cerebrovascular diseases.
##STR00001##
Claims
1. A water-soluble Nimodipine derivative having a structural characteristic of formula I or a pharmaceutically acceptable salt thereof: ##STR00062## wherein: W is selected from CO, CS, or SO.sub.2; or W is absent; A is selected from O or S; or A is absent; B is C(R.sub.4)(R.sub.5), or absent; each of R.sub.4 and R.sub.5 is independently selected from hydrogen, deuterium, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkyl substituted by R.sub.15, aryl, or aryl substituted by R.sub.15, and R.sub.4 and R.sub.5 together with the atom to which they are attached can form a 4 to 6-membered ring; R.sub.15 is selected from O, carboxyl, or amino; T is selected from CO, SO.sub.2, SO.sub.3R.sub.6, PO.sub.3R.sub.7R.sub.8, or PO.sub.2R.sub.17(NHR.sub.18); or T is absent; each of R.sub.6, R.sub.7, and R.sub.8 is independently selected from H, a metal ion, or an ammonium ion; R.sub.17 is selected from aryl, substituted aryl, naphthyl or substituted naphthyl; NHR.sub.18 is an amino acid group; U is selected from C.sub.1-C.sub.8 alkyl, carboxyl-containing C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, aryl, alkenyl, alkynyl, nitrogen-containing heterocycloalkyl, guanidyl-containing C.sub.1-C.sub.8 alkyl, amide-containing C.sub.1-C.sub.8 alkyl, 2-4 peptide alkyl, C.sub.1-C.sub.8 alkyl substituted by R.sub.16, C.sub.3-C.sub.8 cycloalkyl substituted by R.sub.15, aryl substituted by R.sub.15, alkenyl substituted by R.sub.15, or alkynyl substituted by R.sub.15; or U is absent; R.sub.16 is selected from amino, carboxyl, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, substituted C.sub.3-C.sub.7 cycloalkyl, aryl, substituted aryl, heterocyclyl containing O, N, or S heteroatom, substituted heterocyclyl containing O, N, or S heteroatom, heteroaryl containing O, N, or S heteroatom, substituted heteroaryl containing O, N, or S heteroatom, or a side chain group of a natural amino acid; V is selected from NR.sub.9R.sub.10, COOR.sub.11, PO.sub.3R.sub.12R.sub.13 or SO.sub.3R.sub.14; or V is absent; each of R.sub.9 and R.sub.10 is independently selected from hydrogen, C.sub.1-C.sub.8 alkyl, or C.sub.1-C.sub.8 alkyl substituted by R.sub.15, and R.sub.9 and R.sub.10 together with the atom to which they are attached can form a 4 to 8-membered ring; each of R.sub.11, R.sub.12, R.sub.13, and R.sub.14 is independently selected from H, a metal cation, or an ammonium ion; and the metal cation is selected from sodium ion, potassium ion, lithium ion, calcium ion, or magnesium ion.
2. The water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the water-soluble Nimodipine derivative is selected from a structure represented by the following formula II: ##STR00063## B is C(R.sub.4)(R.sub.5); and each of R.sub.4 and R.sub.5 is independently selected from hydrogen, deuterium, or C.sub.1-C.sub.3 alkyl.
3. The water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the water-soluble Nimodipine derivative is selected from a structure represented by the following formula III: ##STR00064## R.sub.4 is selected from hydrogen, deuterium, or C.sub.1-C.sub.3 alkyl.
4. The water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof according to claim 3, wherein U is selected from C.sub.1-C.sub.8 alkyl, alkenyl, or C.sub.1-C.sub.8 alkyl substituted by R.sub.16; R.sub.16 is selected from amino, or carboxyl; V is selected from NR.sub.9R.sub.10, or COOR.sub.11; or V is absent; and each of R.sub.9 and R.sub.10 is independently selected from hydrogen, or C.sub.1-C.sub.8 alkyl.
5. The water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein U is selected from C.sub.1-C.sub.8 alkyl, alkenyl, nitrogen-containing heterocycloalkyl, guanidyl-containing C.sub.1-C.sub.8 alkyl, amide-containing C.sub.1-C.sub.8 alkyl, 2-4 peptide alkyl, or C.sub.1-C.sub.8 alkyl substituted by R.sub.16; or U is absent; R.sub.16 is selected from amino, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, substituted C.sub.3-C.sub.7 cycloalkyl, aryl, substituted aryl, heterocyclyl containing O, N, or S heteroatom, substituted heterocyclyl containing O, N, or S heteroatom, heteroaryl containing O, N, or S heteroatom, substituted heteroaryl containing O, N, or S heteroatom, or a side chain group of a natural amino acid; V is selected from NR.sub.9R.sub.10, COOR.sub.11 or PO.sub.3R.sub.12R.sub.13; or V is absent; and each of R.sub.9 and R.sub.10 is independently selected from hydrogen, or C.sub.1-C.sub.8 alkyl.
6. The water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof according to claim 4, wherein U together with V can form one of the following groups: ##STR00065##
7. The water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the water-soluble Nimodipine derivative is selected from a structure represented by the following formula IV: ##STR00066## wherein: when X is H, Y is selected from OH ##STR00067## when X is O, Y is selected from ##STR00068## R.sub.1 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, or substituted C.sub.1-C.sub.6 alkyl; R.sub.2 is selected from one of the following groups: ##STR00069## R.sub.3 is selected from hydrogen, C.sub.1-C.sub.6 alkyl, substituted C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, substituted C.sub.3-C.sub.7 cycloalkyl, aryl, substituted aryl, heterocyclyl containing O, N, or S heteroatom, substituted heterocyclyl containing O, N, or S heteroatom, heteroaryl containing O, N, or S heteroatom, substituted heteroaryl containing O, N, or S heteroatom, or a side chain group of a natural amino acid; m is selected from 0, 1, 2, or 3; and n is selected from 0, 1, or 2.
8. The water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof according to claim 7, wherein the natural amino acid is selected from lysine, arginine, or histidine.
9. The water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof according to claim 7, wherein the pharmaceutically acceptable salt is selected from sodium salt, potassium salt, calcium salt, magnesium salt, lithium salt, lysine salt, arginine salt, aspartic acid, glutamic acid, tromethamine salt, ethanolamine salt, hydrochloride, sulfate, phosphate, citrate, acetate, maleate, lactate, methanesulfonate, oxalate, fumarate, hydrobromide, p-toluenesulfonate, benzenesulfonate, or nitrate.
10. The water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof according to claim 7, wherein R.sub.1 is selected from hydrogen, or Me; and U together with V can form one of the following groups: ##STR00070##
11. The water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein the water-soluble Nimodipine derivative is selected from one of the following compounds: ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## wherein M and N are independently selected from 1, 2, 3, 4, 5, or 6; and M is selected from 0, 1, 2, 3, 4, 5, or 6.
12. A method of preparing the water-soluble Nimodipine derivative according to claim 7, wherein the method comprises: reacting Nimodipine with halogenate chloroformate to form an amide; then reacting the amide with the corresponding carboxylic acid, amino acid or phosphoric acid derivative to form an ester, deprotecting, so as to yield the water-soluble Nimodipine derivative, the reaction route is shown as below: ##STR00076## or the method comprises: reacting Nimodipine with di-tert-butyl chloromethyl phosphate to form a methylene phosphate, then deprotecting, so as to yield the water-soluble Nimodipine derivative, the reaction route is shown as below.
13. A method for treating or preventing cardiovascular disease in a mammal in need thereof which comprises administering to the mammal an effective amount of the water-soluble Nimodipine derivative or the pharmaceutically acceptable salt thereof of claim 1.
Description
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0062] In the compounds described herein, the line drawn from the substituent into the ring system indicates that the indicated bond can be linked to any ring atom that can be substituted.
[0063] The term alkyl as used herein is intended to include a branched and straight chain saturated aliphatic hydrocarbon group having a particular number of carbon atoms. For example, the definition of C.sub.1-C.sub.6 in C.sub.1-C.sub.6 alkyl includes a group having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight chain or a branched chain. For example, C.sub.1-C.sub.6 alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.
[0064] The term cycloalkyl refers to a saturated monocyclic aliphatic hydrocarbon group having a specific number of carbon atoms. For example, cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.
[0065] The term aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused fashion, and include an aromatic group such as phenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl. The more preferred aryl is phenyl.
[0066] The term alkenyl refers to a hydrocarbon group having an unsaturated alkenyl group, such as CHCH.
[0067] The term alkynyl refers to a hydrocarbon group having an unsaturated alkynyl group, such as CC.
[0068] The term heterocyclyl groups includes saturated heteroatom-containing cycloalkyl and heteroaryl, wherein the heteroatom may be selected from nitrogen, sulfur, and oxygen, and any oxidation state forms of the nitrogen, sulfur, and phosphorus.
[0069] Examples of saturated heterocycloalkyl groups include a 3 to 8-membered saturated heteromonocyclic group containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl; a 3 to 8-membered saturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as morpholinyl; a 3 to 8-membered saturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl. Nitrogen-containing heterocycloalkyl refers to a 3 to 8-membered saturated heteromonocyclic group containing 1 to 4 nitrogen atoms.
[0070] The term amide-containing alkyl refers to a branched or straight chain hydrocarbon group including an amide linkage and having a specific number of carbon atoms, for example isoglutamine, dipeptide alkyl, tripeptide alkyl, and the like.
[0071] The term alkyl containing 2 to 4 peptides refers to a small molecule peptide consisted of 2 to 4 amino acids, preferably a small molecule peptide consisted of 2 amino acids.
[0072] The term guanidyl-containing alkyl refers to alkyl substituted by guanidyl.
[0073] Examples of heteroaryl include a 5 to 8-membered unsaturated heteromonocyclic group containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyrazolyl, 4-pyridyl, pyrimidyl, pyrazinyl, and pyridazinyl; triazolyl, such as 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl; a 5 to 8-membered unsaturated heteromonocyclic group containing one oxygen atom, such as pyranyl, 2-furyl, 3-furyl, and the like; a 5 to 8-membered unsaturated heteromonocyclic group containing one sulfur atom, such as 2-thienyl, 3-thienyl, and the like; a 5 to 8-membered unsaturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, and oxadiazolyl; a 5 to 8-membered unsaturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl.
[0074] Particular examples of nitrogen-free heteroaryl include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuranyl, benzothienyl, and the like.
[0075] Cycloalkyl group may contain 3 to 20 ring-forming atoms and may be either monocyclic or polycyclic if an appropriate number of atoms that are membered a ring is present. Examples of cycloalkyl group are cyclopropyl, cyclopentyl, cyclohexyl and adamantyl groups.
[0076] The term substituted means that hydrogen on the carbon chain is substituted with halogen (ie, fluorine, chlorine, bromine or iodine atom) or an amino group. For example, substituted C.sub.1-C.sub.3 alkyl means chloromethyl, bromoethyl, 3-chloropropyl, 4-chlorobutyl, and the like.
[0077] The term a side chain group of a natural amino acid means an alkyl group, aryl group, heterocyclic moiety linked to the alpha carbon atom of an amino acid. For example, a side chain group of lysine, arginine or histidine refers to one of the following groups:
##STR00018##
[0078] The term absent means that there is no substituent listed in the general formula of the structural formula, and the two moieties adjacent to the substituent are directly linked, as Formula II is the case in which W and A are selected as absent.
[0079] In addition to the standard methods that are known from the literature or exemplified in laboratory procedures, the compound of the present disclosure can be prepared by the reactions shown in the following schemes. Accordingly, the following illustrative schemes are shown for the purpose of illustration and will not be limited to the listed compounds or any specific substituents, and the methods are intended to be merely illustrative and not limit to the scope of the present disclosure.
[0080] Wherein THF refers to tetrahydrofuran, TLC refers to thin layer chromatography, PE refers to petroleum ether, EA refers to ethyl acetate, DMF refers to dimethylformamide, TBAI refers to tetrabutylammonium iodide, DCM refers to dichloromethane, Boc refers to tert-butyloxycarbonyl, and eq refers to equivalent.
Example 1 Preparation of Compound 3
[0081] The reaction was preformed according to the following route:
##STR00019##
(1) Preparation of Compound 2
[0082] To a solution of dry THF was added NaH (10 g, 240 mmol), followed by 300 mL of Nimodipine (compound 1) in THF (50 g, 120 mmol) in dropwise in an ice bath under nitrogen atmosphere. After half an hour, chloromethyl chloroformate (15 mL, 150 mmol) was added dropwise. The reaction was warmed to room temperature. After completion of the reaction (monitored by TLC), a saturated solution of ammonium chloride was added, and then the reaction mixture was extracted with EtOAc (ethyl acetate), washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE/EA=3:1) to afford compound 2 as yellow oil (57.9 g, 95%).
[0083] The characterization data for the product: .sup.1H-NMR (400 MHz, CDCl.sub.3) (8.06 (s, 1H, H-2), 8.03 (d, 1H, J=8.0 Hz, H-4), 7.60 (d, 1H, J=8.0 Hz, H-6), 7.37 (t, 1H, J=8.0 Hz, H-5), 5.79 (s, 2H, CH.sub.2), 5.28 (s, 1H, H-4), 5.10 (m, 1H, CH(CH.sub.3).sub.2), 4.37-4.11 (m, 2H, OCH.sub.2CH.sub.2O), 3.63 (s, 2H, OCH.sub.2CH.sub.2O), 3.36 (s, 3H, OMe), 2.56 (s, 3H, Me), 2.53 (s, 3H, Me), 1.32-1.24 (m, 6H, CH(CH.sub.3).sub.2).
(2) Preparation of Compound 3
[0084] To a flask was added compound 2 (2.15 g, 4.2 mmol), followed by monosodium fumarate (1.2 eq) and 20 mL of DMF. The mixture was heated at 120 C. for 3 hours, and then rotary evaporated for removal of DMF. The residue was purified by column chromatography (PE/EA=2:1) to afford compound 3 as yellow oil (1.34 g, 54%).
[0085] The characterization data for the product: .sup.1H-NMR (400 MHz, CDCl.sub.3) 8.02 (m, 2H, H-2, H-4), 7.60 (d, 1H, J=8.0 Hz, H-6), 7.37 (t, 1H, J=8.0 Hz, H-5), 6.89 (m, 2H), 5.92 (s, 2H, CH.sub.2), 5.30 (s, 1H, H-4), 5.10 (m, 1H, CH(CH.sub.3).sub.2), 4.37-4.11 (m, 2H, OCH.sub.2CH.sub.2O), 3.63 (s, 2H, OCH.sub.2CH.sub.2O), 3.36 (s, 3H, OMe), 2.56 (s, 3H, Me), 2.53 (s, 3H, Me), 1.32-1.24 (m, 6H, CH(CH.sub.3).sub.2).
Example 2 Preparation of Compound 6
[0086] The reaction was preformed according to the following route:
##STR00020##
[0087] Compound 3 (590 mg, 1 mmol) was dissolved in 5 mL of ethanol, and 0.5 mL of lysine aqueous solution (1.5 eq) was added dropwise at 40 C. After 0.5 h, 10 mL of ethanol was added. The reaction was cooled to 0 C. overnight. The reaction solution was filtered to afford compound 6 as a white solid (210 mg, 35%).
[0088] Compound 6 has a solubility of 120 mg/mL in water at room temperature. A portion of compound 6 was throughly mixed with rat anticoagulated plasma and incubated at 37 C. The drug was extracted with acetonitrile at different time points for HPLC analysis. The half-life for converting compound 6 into Nimodipine in blood was determined to be approximately 1.5 hour.
Example 3 Preparation of Compound 7
[0089] The reaction was preformed according to the following route:
##STR00021##
(1) Preparation of Compound 4
[0090] To a 100 mL reaction flask were added compound 2 (2.15 g, 4.2 mmol), potassium carbonate (2 eq), and TBAI 0.2 eq, followed by 25 mL of dry 1,4-dioxane. Di-tert-butyl phosphate (1.6 eq) was added under nitrogen atmosphere and the mixture was reacted at 80 C. overnight. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with ethyl acetate, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA=3:1) to afford compound 4 as yellow oil (2.52 g, 87%).
[0091] The characterization data for the product: .sup.1H-NMR (400 MHz, CDCl.sub.3) 8.06 (s, 1H, H-2), 8.03 (d, 1H, J=8.0 Hz, H-4), 7.56 (d, 1H, J=8.0 Hz, H-6), 7.42 (t, 1H, J=8.0 Hz, H-5), 5.68, 5.65 (2s, 1H, CH.sub.2), 5.29 (s, 1H, H-4), 5.10 (m, 1H, CH(CH.sub.3).sub.2), 4.37-4.11 (m, 2H, OCH.sub.2CH.sub.2O), 3.63 (s, 2H, OCH.sub.2CH.sub.2O), 3.36 (s, 3H, OMe), 2.56 (s, 3H, Me), 2.53 (s, 3H, Me), 1.47 (s, 18H, tBu), 1.32-1.24 (m, 6H, CH(CH.sub.3).sub.2).
(2) Preparation of Compound 7
[0092] Compound 4 (2 g, 2.9 mmol) was dissolved in 15 mL of 5% TFA in DCM solution in an ice bath. After the reaction was completed, the reaction mixture was concentrated in vacuo, toluene was added and then concentrated (repeat twice) to afford compound 7 as yellow oil (1.88 g, 95%).
[0093] The characterization data for the product: .sup.1H-NMR (400 MHz, CDCl.sub.3) 9.04 (brs, 2H, OH), 8.04 (s, 1H, H-2), 7.98 (d, 1H, J=8.0 Hz, H-4), 7.53 (d, 1H, J=8.0 Hz, H-6), 7.40 (t, 1H, J=8.0 Hz, H-5), 5.70, 5.66 (2s, 1H, CH.sub.2), 5.29 (s, 1H, H-4), 5.10 (m, 1H, CH(CH.sub.3).sub.2), 4.39-4.28 (m, 2H, OCH.sub.2CH.sub.2O), 3.63 (s, 2H, OCH.sub.2CH.sub.2O), 3.36 (s, 3H, OMe), 2.56 (s, 3H, Me), 2.53 (s, 3H, Me), 1.32-1.24 (m, 6H, CH(CH.sub.3).sub.2).
Example 4 Preparation of Compound 8
[0094] The reaction was preformed according to the following route:
##STR00022##
[0095] Compound 7 (1 g, 1.4 mmol) was dissolved in 7 mL of ethanol, and 0.7 mL of lysine aqueous solution (1.5 eq) was added dropwise at 40 C. After 0.5 h, 14 mL of ethanol was added, and the reaction was cooled to 0 C. overnight. The reaction solution was filtered to afford compound 8 as a white solid (633 mg, 63%).
[0096] Compound 8 has a solubility of 105 mg/mL in water at room temperature. A portion of compound 8 was throughly mixed with rat anticoagulated plasma and incubated at 37 C. The drug was extracted with acetonitrile at different time points for HPLC analysis. The half-life for converting compound 8 into Nimodipine in blood was determined to be approximately 1.5 hour.
Example 5 Preparation of Compound 9
[0097] The reaction was preformed according to the following route:
##STR00023##
(1) Preparation of Compound 5
[0098] To a reaction flask were added potassium carbonate (276 mg, 2 mmol), TBAI (73 mg, 0.2 mol), and compound 2 (449 mg, 1.3 eq), followed by 6 mL of 1,4-dioxane. The reaction solution was stirred for 0.5 h at room temperature. Boc-protected lysine (510 mg, 1 mmol) was added and the reaction was performed at 90 C. for 3 h. After completion of the reaction (monitored by TLC), the reaction solution was cooled to room temperature, extracted with EA, washed once with saturated NaCl, dried, filtered, concentrated, and the residue was purified by column chromatography (PE:EA=3:1) to afford compound 5 as yellow oil (680 mg, 83%).
[0099] The characterization data for the product: .sup.1H-NMR (400 MHz, CDCl.sub.3) 8.03 (m, 2H, ArH), 7.58 (d, 1H, J=8.0 Hz, ArH), 7.40 (t, 1H, ArH), 5.87 (m, 2H, OCH.sub.2O), 5.29 (s, 1H, H-4), 5.09 (m, 2H, OCH(CH.sub.3).sub.2, H-1.sub.1ys), 4.60 (s, 1H, NH), 4.39-4.26 (m, 3H, OCH.sub.2, NH), 3.63 (m, 2H, OCH.sub.2), 3.36 (s, 1H, OMe), 3.08 (2H, H-4.sub.1ys), 2.51 (2s, 6H, Me), 1.64-1.23 (m, 30H, 3CH.sub.2, 2Boc, 2Me).
(2) Preparation of Compound 9
[0100] Compound 5 (820 mg, 1.0 mmol) was dissolved in 4 mL of EA, and 1 mL of hydrochloric acid was added. The reaction was carried out at room temperature for two hours. After completion of the reaction (monitored by TLC), the solvent was evaporated and ethyl ether was added, then a white precipitate was formed, filtered to afford compound 9 as a white solid (630 mg, 82%).
[0101] The characterization data for the product: .sup.1H NMR (400 MHz, DMSO) 8.75 (s, 2H, NH.sub.2), 8.12 (d, 1H, ArH), 8.02 (s, 2H, NH.sub.2), 7.90 (s, 1H, ArH), 7.62 (t, 1H, ArH), 7.53 (d, 1H, ArH), 5.88 (s, 2H, OCH.sub.2O), 5.23 (s, 1H, H-4), 5.00 (s, 1H, OCH(CH.sub.3).sub.2, 4.30 (m, 2H, OCH.sub.2), 4.08 (s, 1H, H-1.sub.1ys3), 3.57 (m, 2H, OCH.sub.2), 3.25 (s, 1H, OMe), 2.73 (2H, H-4.sub.1ys), 2.50 (2s, 6H, Me), 1.84-1.64 (m, 6H, 3CH.sub.2), 1.48 (m, 6H, 2Me).
[0102] Compound 9 has a solubility of 230 mg/mL in water at room temperature. A portion of compound 9 was throughly mixed with rat anticoagulated plasma and incubated at 37 C. The drug was extracted with acetonitrile at different time points for HPLC analysis. The half-life for converting compound 9 into Nimodipine in blood was determined to be approximately 2.5 hours.
Example 6 Preparation of Compound 11
[0103] The reaction was preformed according to the following route:
##STR00024##
(1) Preparation of Compound 10
[0104] To a solution of dry THF was added NaH (1 g, 25 mmol), followed by 30 mL of Nimodipine (compound 1) in THF (5 g, 12 mmol) and TBAI (0.44 g, 1.2 mmol) in dropwise in an ice bath under nitrogen atmosphere. After half an hour, di-tert-butyl chloromethyl phosphate (3.7 g, 14 mmol) was added dropwise. The reaction was warmed to room temperature for 5 h. After completion of the reaction (monitored by TLC), a saturated solution of ammonium chloride was added, and then the reaction mixture was extracted with EtOAc, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (PE/EA=3:1) to afford compound 10 as yellow oil (4.2 g, 55%).
[0105] The characterization data for the product: .sup.1H-NMR (400 MHz, CDCl.sub.3) 8.07 (s, 1H, H-2), 8.03 (d, 1H, J=8.0 Hz, H-4), 7.54 (d, 1H, J=8.0 Hz, H-6), 7.41 (t, 1H, J=8.0 Hz, H-5), 5.29 (s, 1H, H-4), 5.39 (s, 2H) 5.09 (m, 1H, CH(CH.sub.3).sub.2), 4.37-4.11 (m, 2H, OCH.sub.2CH.sub.2O), 3.63 (s, 2H, OCH.sub.2CH.sub.2O), 3.36 (s, 3H, OMe), 2.56 (s, 3H, Me), 2.53 (s, 3H, Me), 1.47 (s, 18H, tBu), 1.32-1.24 (m, 6H, CH(CH.sub.3).sub.2).
(2) Preparation of Compound 11
[0106] Compound 10 (2 g, 3.1 mmol) was dissolved in 15 mL of 5% TFA in DCM solution in an ice bath. After the reaction was completed, the reaction mixture was concentrated in vacuo, toluene was added and then concentrated (repeat twice) to afford compound 11 as yellow oil (1.58 g, 96%).
[0107] The characterization data for the product: .sup.1H-NMR (400 MHz, CDCl.sub.3) 9.04 (brs, 2H, OH), 8.03 (s, 1H, H-2), 7.97 (d, 1H, J=8.0 Hz, H-4), 7.54 (d, 1H, J=8.0 Hz, H-6), 7.41 (t, 1H, J=8.0 Hz, H-5), 5.38 (s, 2H, CH.sub.2), 5.29 (s, 1H, H-4), 5.10 (m, 1H, CH(CH.sub.3).sub.2), 4.39-4.28 (m, 2H, OCH.sub.2CH.sub.2O), 3.63 (s, 2H, OCH.sub.2CH.sub.2O), 3.36 (s, 3H, OMe), 2.56 (s, 3H, Me), 2.53 (s, 3H, Me), 1.32-1.24 (m, 6H, CH(CH.sub.3).sub.2).
Example 7 Preparation of Compound 12
[0108] The reaction was preformed according to the following route:
##STR00025##
[0109] Compound 11 (1 g, 1.4 mmol) was dissolved in 7 mL of ethanol, and 0.7 mL of lysine aqueous solution (1.5 eq) was added dropwise at 40 C. After 0.5 h, 14 mL of ethanol was added, and the reaction was cooled to 0 C. overnight. The reaction mixture was filtered to afford compound 12 as a white solid (533 mg, 56%).
[0110] Compound 12 has a solubility of 80 mg/mL in water at room temperature. A portion of compound 12 was throughly mixed with rat anticoagulated plasma and incubated at 37 C. The drug was extracted with acetonitrile at different time points for HPLC analysis. The half-life for converting compound 12 into Nimodipine in blood was determined to be less than 30 mins.
Example 8 Preparation of Compound 14
[0111] ##STR00026##
[0112] To a solution of potassium N-BOC-glycinate (0.52 g, 2.45 mmol), TBAI (144 mg, 0.39 mmol) and 8 mL of dioxane was added compound 2 (1.0 g, 1.96 mmol), The mixture was stirred at 55-60 C. for 5 hours. The reaction solution was subjected to rotary evaporation and concentrated in vacuo. The concentrate was added with ethyl acetate (40 mL for dissolution), washed with water (15 ml3), followed by saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The concentrate was purified by silica-gel column chromatography (petroleum ether/ethyl acetate 3:1) to obtain an intermediate 13 as a light yellow syrup (1.24 g, 97.6%).
[0113] The characterization data for the product: ESI-MS, C.sub.30H.sub.39N.sub.3O.sub.13 (649.2), found 672.2 [M+Na].sup.+.
[0114] Compound 13 (1.12 g) was dissolved in ethyl acetate (4 mL), a solution of HCl in dioxane (5.2 mol/L, 6 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated in vacuo, and acetonitrile was added and then concentrated for removal of the residual hydrogen chloride. 20 ml of isopropyl ether was added and the mixture was stirred overnight. Isopropyl ether was poured off, and the solid was dissolved in 15 ml of chloroform and filtered. The filtrate was rotary evaporated to afford compound 14 as a light brown solid (0.64 g, 64%).
[0115] The characterization data for the product: ESI-MS: C.sub.25H.sub.31N.sub.3O.sub.11 (549.2) found 550.2 [M+H].sup.+. HNMR (500 MHz, CDCl.sub.3) 8.67 (brs, 2H), 7.99-7.96 (m, 2H), 7.59 (m, 1H), 7.40-7.36 (m, 1H), 5.92 (s, 2H), 5.55 (brs, 1H), 5.52 (s, 1H), 5.10-5.05 (m, 1H), 4.35-4.26 (m, 2H), 4.08 (s, 2H), 3.61 (m, 2H), 2.53 (s, 3H), 2.51 (s, 3H), 1.29 (d, J=6.2 Hz, 3H).
Example 9 Preparation of Compound 16
[0116] ##STR00027##
[0117] To a solution of potassium N-BOC-sarcosinate (0.56 g, 2.45 mmol), TBAI (144 mg, 0.39 mmol) and 8 mL of dioxane was added compound 2 (1.0 g, 1.96 mmol). The mixture was stirred at 55-60 C. overnight. The reaction solution was subjected to rotary evaporation and concentrated in vacuo. The concentrate was dissolved in ethyl acetate (30 mL), washed with water (15 ml3), followed by saturated sodium chloride (15 mL2), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford an intermediate 15 as a light brown syrup (1.24 g, 95.3%).
[0118] The characterization data for the product: ESI-MS, C.sub.31H.sub.41N.sub.3O.sub.13 (663.2), found 564.1[MBoc+H].sup.+.
[0119] Compound 15 (1.09 g) was dissolved in ethyl acetate (4 mL), a solution of HCl in dioxane (5.2 mol/L, 6 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo and acetonitrile was added and then concentrated for removal of the residual hydrogen chloride. 20 ml of isopropyl ether was added and the reaction mixture was stirred overnight. Isopropyl ether was poured off, and the solid was dissolved in 15 ml of chloroform, filtered. The filtrate was rotary evaporated to afford compound 16 as a light brown solid (0.65 g, 66.0%).
[0120] The characterization data for the product: ESI-MS, C.sub.26H.sub.33N.sub.3O.sub.11 (563.2), found 564.1 [M+H].sup.+. .sup.1H-NMR (500 MHz, CDCl.sub.3) 10.06 (brs, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.93 (t, J=1.75 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.42 (t, J=7.95, 1H), 5.93 (s, 1H), 5.30 (s, 1H), 5.10 (m, 1H), 4.37 (m, 1H), 4.29 (m, 1H), 3.92 (s, 2H), 3.63 (m, 2H), 3.36 (s, 3H), 2.86 (s, 3H), 2.56 (s, 3H), 2.54 (s, 3H), 1.30 (d, J=6.3 Hz, 3H), 1.26 (d, J=6.3 Hz, 3H).
Example 10 Preparation of Compound 18
[0121] ##STR00028##
[0122] To a solution of potassium BOC-L-alaninate (0.56 g, 2.45 mmol), TBAI (144 mg, 0.39 mmol) and 8 mL of dioxane was added compound 2 (1.0 g, 1.96 mmol). The mixture was stirred at 55-60 C. for 4 hours. The reaction solution was subjected to rotary evaporation and concentrated in vacuo. The concentrate was dissolved in ethyl acetate (30 mL), washed with water (15 ml2), followed by saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford an intermediate 17 as a light brown syrup (1.25 g, 96.1.0%).
[0123] The characterization data for the product: ESI-MS, C.sub.31H.sub.41N.sub.3O.sub.13 (663.2), found 686.2 [M+Na].sup.+.
[0124] Compound 17 (1.15 g) was dissolved in ethyl acetate (6 mL), a solution of HCl in dioxane (5.2 mol/L, 6 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo and acetonitrile was added and then concentrated for removal of the residual hydrogen chloride. 15 ml of isopropyl ether was added and the reaction mixture was stirred at 50 C. for 5 mins. Isopropyl ether was poured off, and 15 ml of isopropyl ether was added and the reaction mixture was stirred at 50 C. for another 5 mins. Isopropyl ether was poured off, and the solid was dissolved in 20 ml of chloroform, filtered. The filtrate was rotary evaporated to afford compound 18 as a light brown solid (0.61 g, 58.7%).
[0125] The characterization data for the product: ESI-MS, C.sub.26H.sub.33N.sub.3O.sub.11 (563.2), found 564.1 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 500 MHz) 8.85 (brs, 2H), 8.00 (m, 1H), 7.97 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 5.97 (dd, J=5.8, 1.0 Hz, 1H), 5.87 (dd, J=5.8, 1.0 Hz, 1H), 5.30 (s, 1H), 5.09 (m, 1H), 4.35 (m, 1H), 4.28 (m, 1H), 3.61 (m, 2H), 3.351 (s, 1.5H), 3.349 (s, 1.5H), 2.54 (s, 1.5H), 2.53 (s, 1.5H), 2.53 (s, 1.5H), 2.51 (s, 1.5H), 1.71 (d, J=7.2 Hz, 3H), 1.30 (d, J=6.3 Hz, 3H), 1.26 (m, 3H).
Example 11 Preparation of Compound 20
[0126] ##STR00029##
[0127] To a solution of potassium BOC-L-leucinate (605 mg, 2.45 mmol), TBAI (144 mg, 0.39 mmol) and 8 mL of dioxane was added compound 2 (1.0 g, 1.96 mmol). The mixture was stirred at 55-60 C. overnight. The reaction solution was subjected to rotary evaporation and concentrated in vacuo. The concentrate was dissolved in ethyl acetate (30 mL), washed with water (15 ml2), followed by saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain an intermediate 19 as a light brown syrup (1.5 g, 108.7%).
[0128] The characterization data for the product: ESI-MS, C.sub.34H.sub.47N.sub.3O.sub.13 (705.3), found 728.3[M+Na].sup.+.
[0129] Compound 19 (1.35 g) was dissolved in THF (10 mL), a solution of HCl in dioxane (5.2 mol/L, 5 mL) was added and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated in vacuo and acetonitrile was added and then concentrated for removal of the residual hydrogen chloride. 15 ml of isopropyl ether was added and the mixture was stirred at room temperature overnight. The solid was dissolved in 10 ml of chloroform, filtered. The filtrate was rotary evaporated to afford compound 20 as a light brown solid (1.0 g, 81.3%).
[0130] The characterization data for the product: ESI-MS, C.sub.29H.sub.39N.sub.3O.sub.11 (605.2), found 606.2 [M+Na].sup.+. .sup.1H-NMR (500 MHz, CDCl.sub.3) 8.94 (brs, 2H) 8.02-7.98 (m, 2H), 7.58 (d, J=7.6 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 5.97 (d, J=5.9 Hz, 1H), 5.85 (d, J=5.9 Hz, 1H), 5.29 (s, 1H), 5.09 (m, 1H), 4.36 (m, 1H), 4.28 (m, 1H), 3.61 (m, 2H), 3.35 (s, 3H), 4.14 (m, 1H), 2.54 (d, J=1.4 Hz, 3H), 2.52 (d, J=2.15 Hz, 3H), 1.99-1.92 (m, 2H), 1.83 (m, 1H), 1.30 (d, J=6.3 Hz, 3H), 1.26 (d, J=6.3 Hz, 3H), 0.98-0.94 (m, 6H).
Example 12 Preparation of Compound 21
[0131] ##STR00030##
[0132] To a solution of Nimodipine (1) (4.5 g, 10.76 mmol) in tetrahydrofuran (17 mL) was added NaH (60%) (0.76 g, 19.0 mmol) at 0 C. The mixture was stirred for 30 minutes, and the reaction was cooled to 40 C. 1-chloroethyl chloroformate (2.07 g, 14.48 mmol) was added dropwise. After the addition in dropwise is completed, the reaction solution was stirred at 40 C. for 20 minutes, and allowed to spontaneously warmed to room temperature and stirred overnight. The reaction solution was concentrated in vacuo, and the residue was dissolved in 60 mL of ethyl acetate, washed with saturated sodium bicarbonate (20 mL2), followed by saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, rotary evaporated, and purified by silica-gel column chromatography (PE/EA 5:1) to afford compound 21 as a light yellow syrup (2.97 g, 52.7%).
[0133] The characterization data for the product: ESI-MS, C.sub.24H.sub.29ClN.sub.2O.sub.9 (524.1), found 525.1[M+H].sup.+. .sup.1H-NMR (500 MHz, CDCl.sub.3) 8.05 (dd, J=3.8, 1.8 Hz, 1H), 8.02 (m, 1H), 7.53 (m, 1H), 7.38 (t, J=8.0 Hz, 1H), 6.53 (q, J=5.8 Hz, 1H), 5.30 (s, 1H), 5.12 (m, 1H), 4.38 (m, 1H), 4.31 (m, 1H), 3.63 (m, 2H), 3.37 (s, 1.5H), 3.36 (s, 1.5H), 2.59 (s, 1.5H), 2.57 (s, 1.5H), 2.568 (s, 1.5H), 2.55 (s, 1.5H), 1.83 (d, J=5.8 Hz, 1.5H), 1.82 (d, J=5.8 Hz, 1.5H), 1.32 (d, J=6.3 Hz, 1.5H), 1.317 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.3 Hz, 1.5H), 1.26 (d, J=6.3 Hz, 1.5H).
Example 13 Preparation of Compound 23
[0134] ##STR00031##
[0135] To a solution of potassium BOC-L-alaninate (540 mg, 2.38 mmol), TBAI (144 mg, 0.38 mmol) and 8 mL of dioxane was added compound 21 (1.0 g, 1.9 mmol). The mixture was stirred at 55-60 C. for 4 hours. The reaction solution was subjected to rotary evaporation and concentrated in vacuo. The residue was purified by silica-gel column chromatography (PE/EA 5:1) to obtain an intermediate 22 as a colorless syrup (0.78 g, 60.5%).
[0136] The characterization data for the product: ESI-MS, C32H43N3O13 (677.2), found 700.2[M+Na].sup.+.
[0137] Compound 22 (0.62 g) was dissolved in ethyl acetate (4 mL), a solution of HCl in dioxane (5.2 mol/L, 4 mL) was added and the mixture was stirred at room temperature for 6 hours. The reaction solution was concentrated in vacuo and acetonitrile (10 mL) was added and then concentrated for removal of the residual hydrogen chloride. The concentrate was dissolved in 1.5 mL of THF and precipitated from 20 mL of isopropyl ether. The supernatant was decanted and the solid was treated with THF/isopropyl ether for three times. The resulting precipitate was dissolved in 10 ml of chloroform, filtered. The filtrate was rotary evaporated to afford compound 23 as an off-white foam-like solid (0.416 g, 74.3%).
[0138] The characterization data for the product: ESI-Ms, C.sub.27H.sub.35N.sub.3O.sub.11 (577.2), found 578.2[M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 500 MHz) 8.80 (s, 2H), 8.03 (m, 2H), 7.55 (m, 1H), 7.41 (m, 1H), 6.90 (m, 1H), 5.30 (s, 0.5H), 5.29 (s, 0.5H), 5.10 (m, 1H), 4.36 (m, 1H), 4.29 (m, 1H), 4.20 (m, 1H), 3.62 (m, 2H), 3.36 (m, 3H), 2.55-2.47 (m, 6H), 1.71 (d, J=6.4 Hz, 1.5H), 1.60 (d, J=6.4 Hz, 1.5H), 1.53 (m, 3H), 1.29 (m, 6H).
Example 14 Preparation of Compound 24
[0139] ##STR00032##
[0140] To a solution of fumaric acid (212 mg, 1.82 mmol), DIPEA (234 mg, 1.82 mmol), TBAI (140 mg, 0.38 mmol) and 8 mL of acetonitrile was added compound 21 (0.8 g, 1.52 mmol). The mixture was stirred at 55-60 C. overnight. The reaction solution was subjected to rotary evaporation and concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with 0.5 mol/L hydrochloric acid (6 ml2), followed by saturated sodium chloride (18 mL5), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and dissolved in methanol (10 mL). The pH was adjusted to about 7.0 by adding KOH in methanol (40 mg of KOH dissolved in 5 mL of methanol). The solution was rotary evaporated, and the residue was dissolved in 1.5 ml of THE 20 mL of isopropyl ether was added for precipitation. The supernatant was decanted, and the solid was further treated with THF/isopropyl ether for three times. The resulting precipitate was dissolved in 10 ml of chloroform, filtered. The filtrate was rotary evaporated to afford compound 24 as a light brown solid (0.310 g, 31.7%).
[0141] The characterization data for the product: ESI-MS, C.sub.28H.sub.31KN.sub.2O.sub.13 (642.1), found 603.2[MK].sup.. .sup.1H-NMR (CDCl.sub.3, 500 MHz) 8.00 (m, 2H), 7.52 (d, J=7.6 Hz, 1H), 7.37 (td, J=7.8, 1.9 Hz, 1H), 6.85 (dd, J=15.8, 2.5 Hz, 1H) 6.79 (q, J=5.5 Hz, 1H), 6.40 (dd, J=15.8, 1.9 Hz, 1H), 5.27 (s, 1H), 5.08 (m, 1H), 4.34 (m, 1H), 4.27 (m, 1H), 3.60 (m, 2H), 3.33 (s, 1.5H), 3.31 (s, 1.5H), 2.51 (s, 1.5H), 2.50 (s, 1.5H), 2.44 (s, 1.5H), 2.43 (s, 1.5H), 1.40 (m, 3H), 1.27 (m, 6H).
Example 15 Preparation of Compound 26
[0142] ##STR00033##
[0143] To a solution of potassium BOC-beta-alaninate (0.56 g, 2.45 mmol), TBAI (144 mg, 0.39 mmol) and 8 mL of dioxane was added compound 2 (1.0 g, 1.96 mmol). The mixture was stirred at 55-60 C. overnight. The reaction solution was subjected to rotary evaporation and concentrated in vacuo. The residue was added with ethyl acetate (35 mL for dissolution), washed with water (15 ml2), followed by saturated sodium chloride (15 mL2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an intermediate 25 as a light brown syrup (1.36 g, 104.6%).
[0144] The characterization data for the product: ESI-MS, C.sub.31H.sub.41N.sub.3O.sub.13 (663.2), found 564.2[MBoc+H].sup.+.
[0145] Compound 25 (1.24 g) was dissolved in ethyl acetate (4 mL), a solution of HCl in dioxane (5.2 mol/L, 6 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo and 15 mL of acetonitrile was added and then concentrated for removal of the residual hydrogen chloride. 20 ml of isopropyl ether was then added and the mixture was stirred overnight. Isopropyl ether was poured off, and the solid was dissolved in 15 ml of chloroform, filtered. The filtrate was rotary evaporated to afford compound 26 as a light brown solid (0.72 g, 64.3%).
[0146] The characterization data for the product: ESI-MS, C.sub.26H.sub.33N.sub.3O.sub.11 (563.2), found 564.1 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 500 MHz) 8.25 (brs, 2H), 8.02 (m, 1H), 7.97 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 5.84 (s, 2H), 5.28 (s, 1H), 5.09 (m, 1H), 4.35 (m, 1H), 4.28 (m, 1H), 3.61 (m, 2H), 3.38 (m, 2H), 3.35 (s, 3H), 3.00 (t, J=6.4 Hz, 2H), 2.53 (s, 3H), 2.51 (s, 3H), 1.29 (d, J=6.3 Hz, 3H), 1.25 (d, J=6.3 Hz, 3H).
Example 16 Preparation of Compound 28
[0147] ##STR00034##
[0148] To a solution of potassium BOC-gamma-aminobutyrate (0.287 g, 1.19 mmol), TBAI (70 mg, 0.19 mmol) and 10 mL of dioxane was added compound 21 (0.50 g, 0.95 mmol). The mixture was stirred at 60 C. for 8 hour. The reaction solution was subjected to rotary evaporation and concentrated in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with saturated NaHCO.sub.3 (10 ml3), followed by saturated sodium chloride (10 mL2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain an intermediate 27 as a light brown syrup (700 mg, 106.2%).
[0149] The characterization data for the product: ESI-MS, C.sub.33H.sub.45N.sub.3O.sub.13 (691.3), found 592.1 [M+Cl].sup..
[0150] To a solution of HCl in dioxane (5.2 mol/L, 8 mL) was added compound 27 (700 mg). The mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated in vacuo. The residue was dissolved in acetonitrile (1.5 mL), and precipitated from 15 ml of isopropyl ether, then the supernatant was poured off and the precipitate was dissolved in acetonitrile, and then precipitated from isopropyl ether, which were repeated five times. The precipitate was dried in vacuo to afford compound 28 as a light brown solid (90 mg, 15.1%).
[0151] The characterization data for the product: ESI-MS, C.sub.28H.sub.37N.sub.3O.sub.11 (591.1), found 592.1 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 400 MHz) 8.25 (brs, 2H), 8.05 (m, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 6.81 (q, J=5.2 Hz, 1H), 5.30 (s, 1H), 5.11 (m, 1H), 4.37 (m, 1H), 4.30 (m, 1H), 3.63 (m, 2H), 3.363 (s, 1.5H), 3.357 (s, 1.5H), 3.11 (m, 2H), 2.56 (s, 1.5H), 2.54 (s, 1.5H), 2.51 (s, 1.5H), 2.48 (s, 1.5H), 2.47 (m, 2H), 2.10 (m, 2H), 1.47 (d, J=5.3 Hz, 3H), 1.31 (d, J=6.2 Hz, 3H), 1.27 (m, 3H).
Example 17 Preparation of Compound 30
[0152] ##STR00035##
[0153] To a solution of potassium BOC-gamma-aminobutyrate (0.301 g, 1.25 mmol), TBAI (74 mg, 0.2 mmol) and 10 mL of dioxane was added compound 2 (0.50 g, 0.98 mmol). The mixture was stirred at 60 C. overnight. The reaction solution was subjected to rotary evaporation and concentrated in vacuo. The residue was dissolved in ethyl acetate (35 mL), washed with saturated NaHCO.sub.3 (10 ml3), followed by saturated sodium chloride (10 mL2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an intermediate 29 as a light brown syrup (730 mg, 112.3%).
[0154] The characterization data for the product: ESI-MS, C.sub.32H.sub.43N.sub.3O.sub.13 (677.3), found 712.2 [M+Cl].sup..
[0155] Compound 29 (720 mg) was dissolved in tetrahydrofuran (6 mL), a solution of HCl in dioxane solution (5.2 mol/L, 6 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated in vacuo, and the residue was dissolved in 15 mL of acetonitrile, filtered. The filtrate was rotary evaporated. The concentrate was dissolved in tetrahydrofuran (1.5 mL), and precipitated from 20 ml of isopropyl ether, then the isopropyl ether was poured off, and the precipitate was dissolved in tetrahydrofuran, and then precipitated from isopropyl ether, which were repeated five times. The precipitate was dried in vacuo to afford compound 30 as a light yellow solid (0.300 g, 64.3%).
[0156] The characterization data for the product: ESI-MS, C.sub.27H.sub.35N.sub.3O.sub.11 (577.2), found 578.2 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 400 MHz) 8.19 (brs, 2H), 8.01 (m, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 5.79 (s, 2H), 5.29 (s, 1H), 5.10 (m, 1H), 4.36 (m, 1H), 4.29 (m, 1H), 3.62 (m, 2H), 3.35 (s, 3H), 3.13 (s, 2H), 2.57 (t, J=6.9 Hz, 2H), 2.54 (s, 3H), 2.52 (s, 3H), 2.13 (t, J=6.9 Hz, 2H), 1.30 (d, J=6.2 Hz, 3H), 1.26 (d, J=6.2 Hz, 3H).
Example 18 Preparation of Compound 32
[0157] ##STR00036##
[0158] To a solution of potassium BOC-4-piperidine formate (0.334 g, 1.25 mmol), TBAI (74 mg, 0.2 mmol) and 10 mL of dioxane was added compound 2 (0.50 g, 0.98 mmol). The mixture was stirred at 60 C. overnight. The reaction solution was subjected to rotary evaporation and concentrated in vacuo. The residue was dissolved in ethyl acetate (40 mL), washed with saturated NaHCO.sub.3 (15 ml3), followed by saturated sodium chloride (15 mL2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an intermediate 31 as light brown syrup (750 mg, 109.0%).
[0159] To a solution of HCl in dioxane (5.2 mol/L, 8 mL) was added compound 31 (750 mg), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated in vacuo. The residue was dissoloved in acetonitrile (1.5 mL), and precipitated from 20 ml of isopropyl ether, then the supernatant was poured off and the precipitate was dissolved in acetonitrile, and then precipitated from isopropyl ether, which were repeated five times. The precipitate was dried in vacuo to afford compound 32 as a light brown solid (0.320 g, 54.3%).
[0160] The characterization data for the product: ESI-MS, C.sub.29H.sub.37N.sub.3O.sub.11 (603.2), found 604.2 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 400 MHz) 9.66 (brs, 1H), 9.44 (brs, 1H), 8.04 (m, 1H), 7.97 (t, J=1.92 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 5.82 (s, 2H), 5.30 (s, 1H), 5.11 (m, 1H), 4.38 (m, 1H), 4.30 (m, 1H), 3.63 (m, 2H), 3.43 (m, 2H), 3.36 (s, 3H), 3.05 (m, 2H), 2.65 (m, 1H), 2.54 (s, 3H), 2.52 (s, 3H), 2.19 (m, 2H), 2.10 (m, 2H), 1.31 (d, J=6.2 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H).
Example 19 Preparation of Compound 34
[0161] ##STR00037##
[0162] To a solution of potassium BOC-6-aminocaproate (0.337 g, 1.25 mmol), TBAI (74 mg, 0.2 mmol) and 10 mL of dioxane was added compound 2 (0.50 g, 0.98 mmol). The mixture was stirred at 60 C. for 8 hours and then rotary evaporated for removal of the solvent. The concentrate was dissolved in ethyl acetate (40 mL), washed with saturated NaHCO.sub.3 (10 ml3), followed by saturated sodium chloride (10 mL2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an intermediate 33 as a light brown syrup (670 mg, 97.0%).
[0163] The characterization data for the product: ESI-MS, C.sub.34H.sub.47N.sub.3O.sub.13 (705.3), found 740.3 [M+Cl].sup..
[0164] To a solution of HCl in dioxane (5.2 mol/L, 8 mL) was added compound 33 (665 mg) and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated in vacuo and then 10 mL of acetonitrile was added and then concentrated for removal of the hydrogen chloride remained in the second steps. The concentrate was dissolved in acetonitrile (1.5 mL), and precipitated from isopropyl ether (20 ml), then the supernatant was poured off and the precipitate was dissolved in acetonitrile, and then precipitated from isopropyl ether, where were repeated five times. The precipitate was dissolved in acetonitrile (2 mL), filtered, and concentrated to afford compound 34 as a light brown solid (0.16 mg, 27.0%).
[0165] The characterization data for the product: ESI-MS, C.sub.29H.sub.39N.sub.3O.sub.11 (605.3), found 606.1 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 400 MHz) 8.23 (brs, 2H), 8.04 (m, 2H), 7.58 (d, J=7.7 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 5.79 (s, 2H), 5.29 (s, 1H), 5.11 (m, 1H), 4.37 (m, 1H), 4.30 (m, 1H), 3.63 (t, J=4.6 Hz 2H), 3.36 (s, 3H), 3.01 (m, 2H), 2.55 (s, 3H), 2.52 (s, 3H), 2.37 (t, J=7.2 Hz, 2H), 1.81 (m, 2H), 1.66 (m, 2H), 1.45 (m, 2H), 1.31 (d, J=6.2 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H).
Example 20 Preparation of Compound 36
[0166] ##STR00038##
[0167] To a solution of potassium BOC-7-aminoheptanoate (0.354 g, 1.25 mmol), TBAI (74 mg, 0.2 mmol) and 10 mL of dioxane was added compound 2 (0.50 g, 0.98 mmol). The mixture was stirred at 60 C. for 8 hours, and then rotary evaporated for removal of the solvent. The concentrate was dissolved in ethyl acetate (40 mL), washed with saturated NaHCO.sub.3 (10 ml3), followed by saturated sodium chloride (10 mL2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an intermediate 35 as a light brown syrup (710 mg, 100.0%).
[0168] The characterization data for the product: ESI-MS, C.sub.35H.sub.49N.sub.3O.sub.13 (719.3), found 736.4 [M+OH].sup..
[0169] To a solution of HCl in dioxane (5.2 mol/L, 8 mL) was added compound 35 (705 mg) and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated in vacuo and acetonitrile (10 mL) was added and then concentrated for removal of the hydrogen chloride remained in the second steps. The concentrate was dissolved in acetonitrile (1.5 mL), and precipitated from isopropyl ether (20 ml), then the supernatant was poured off and the precipitate was dissolved in acetonitrile and then precipitated from isopropyl ethe, which were repeated five times. The precipitate was dissolved in acetonitrile (2 mL), filtered, and concentrated to afford compound 36 as a light brown solid (0.329 mg, 54.3%).
[0170] The characterization data for the product: ESI-MS, C.sub.30H.sub.41N.sub.3O.sub.11 (619.3), found 620.1 [M+H].sup.+. HNMR (CDCl.sub.3, 400 MHz) 8.22 (brs, 2H), 8.04 (m, 2H), 7.58 (d, J=7.7 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 5.79 (s, 2H), 5.29 (s, 1H), 5.11 (m, 1H), 4.37 (m, 1H), 4.30 (m, 1H), 3.63 (t, J=4.8 Hz 2H), 3.36 (s, 3H), 3.00 (m, 2H), 2.55 (s, 3H), 2.52 (s, 3H), 2.34 (m, 2H), 1.78 (m, 2H), 1.63 (m, 2H), 1.39 (m, 2H), 1.31 (d, J=6.2 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H).
Example 21 Preparation of Compound 38
[0171] ##STR00039##
[0172] To a solution of potassium BOC-6-piperidineacetate (0.352 g, 1.25 mmol), TBAI (74 mg, 0.2 mmol) and 10 mL of dioxane was added compound 2 (0.50 g, 0.98 mmol). The mixture was stirred at 60 C. for 7 hours, and then rotary evaporated for removal of the solvent. The residue was dissolved in ethyl acetate (40 mL), washed with saturated NaHCO.sub.3 (10 ml3), followed by saturated sodium chloride (10 mL2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an intermediate 37 as a light brown syrup (785 mg, 111.8%).
[0173] The characterization data for the product: ESI-MS, C.sub.35H.sub.47N.sub.3O.sub.13 (717.3), found 618.1 [MBoc+H].sup.+.
[0174] To a solution of HCl in dioxane (5.2 mol/L, 8 mL) was added compound 37 (780 mg) and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated in vacuo and acetonitrile (10 mL) was added and then concentrated for removal of the hydrogen chloride remained in the second steps. The concentrate was dissolved in acetonitrile (1.5 mL), and precipitated from isopropyl ether (20 ml), then the supernatant was poured off and the precipitate was dissolved in acetonitrile and then precipitated from isopropyl ether, which were repeated five times. The precipitate was dissolved in acetonitrile (2 mL), filtered, and concentrated to afford compound 38 as a light brown solid (0.500 g, 78.1%).
[0175] The characterization data for the product: ESI-MS, C.sub.30H.sub.39N.sub.3O.sub.11 (617.3), found 618.1 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 400 MHz) 9.61 (brs, 2H), 8.04 (m, 1H), 7.99 (m, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H), 5.80 (s, 2H), 5.30 (s, 1H), 5.11 (m, 1H), 4.37 (m, 1H), 4.30 (m, 1H), 3.62 (m, 2H), 3.50 (m, 2H), 3.36 (s, 3H), 2.88 (m, 2H), 2.54 (s, 3H), 2.52 (s, 3H), 2.35 (d, J=6.9 Hz, 2H), 2.27 (m, 1H), 1.96 (m, 2H), 1.72 (m, 2H), 1.31 (d, J=6.2 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H).
Example 22 Preparation of Compound 39
[0176] ##STR00040##
[0177] Compound 3 (350 mg) was dissolved in 5 mL of methanol, and the pH was carefully adjusted to approximately 7.0 with 0.5 mol/L of a solution of sodium hydroxide in methanol. The solvent was rotary evaporated. The concentrate was dissolved in 1.5 mL of THF, and precipitated from 15 mL of isopropyl ether. The supernatant was decanted and the solid was treated with THF/isopropyl ether for three times. The resulting precipitate was dissolved in 10 mL of chloroform, filtered. The filtrate was rotary evaporated to afford compound 39 as a light brown solid (0.250 g, 68.9%).
[0178] The characterization data for the product: .sup.1H-NMR (500 MHz, CDCl.sub.3) 7.96 (m, 2H), 7.54 (d, J=7.8 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 6.90 (d, J=15.8 Hz, 1H) 6.44 (q, J=5.5 Hz, 1H), 5.77 (t, J=6.8 Hz, 2H), 5.26 (s, 1H), 5.07 (m, 1H), 4.33 (m, 1H), 4.26 (m, 1H), 3.59 (t, J=5.0 Hz, 2H), 3.32 (s, 3H), 2.49 (s, 3H), 2.47 (s, 3H), 1.27 (d, J=6.2 Hz, 3H), 1.23 (d, J=6.2 Hz, 3H).
Example 23 Preparation of Compound 41
[0179] ##STR00041##
[0180] To a solution of potassium BOC-L-isoglutamate (0.355 g, 1.25 mmol), TBAI (74 mg, 0.2 mmol) and 10 mL of dioxane was added compound 2 (0.50 g, 0.98 mmol) The mixture was stirred at 60 C. overnight, and then rotary evaporated for removal of the solvent. The residue was dissolved in ethyl acetate (40 mL), washed with saturated NaHCO.sub.3 (15 mL3), followed by saturated sodium chloride (15 mL2), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an intermediate 40 as a light brown syrup (650 mg, 92.2%).
[0181] The characterization data for the product: ESI-MS, C.sub.33H.sub.44N.sub.4O.sub.14 (720.3), found 621.3 [MBoc+H].sup.+.
[0182] To a solution of HCl in dioxane solution (5.2 mol/L, 8 mL) was added compound 40 (630 mg) and the mixture was stirred overnight at room temperature. The reaction solution was concentrated in vacuo and then acetonitrile (15 mL) was added and then concentrated for removal of the hydrogen chloride remained in the second steps. The concentrate was dissolved in acetonitrile (1.5 mL), and precipitated from isopropyl ether (20 ml), then the supernatant was poured off and the precipitate was dissolved in acetonitrile, and then precipitated from isopropyl ether, which were repeated five times. The precipitate was dissolved in acetonitrile (2 mL), filtered, and concentrated to afford compound 41 as a light brown solid (100 mg, 15.6%).
[0183] The characterization data for the product: ESI-MS, C.sub.28H.sub.37ClN.sub.4O.sub.12 (656.2), found 621.2 [MCl].sup.+.
EXAMPLE
[0184] Solubility of Nimodipine derivatives in water and release rate thereof into plasma
[0185] 1. Solubility in Water
[0186] The compound sample prepared according to the above examples was accurately weighed in an appropriate amount, and pure water was added dropwise with a microsyringe while shaking until the solution became clear. The amounts of the sample and pure water were recorded and converted into mg/mL, as the solubility of the sample. The result was shown in the following table, and the original drug, i.e. Nimodipine, was used as a control.
[0187] 2. Release Rate into Plasma
[0188] The compound sample prepared according to the above examples was dissolved in brine in an appropriate amount to formulate into a stock solution between 0.3 and 0.4 mg/mL. 20 L of stock solution was added into the rat anticoagulated plasma previously incubated at 37 C. for 2 mins, which were throughly mixed, and incubated at 37 C. 100 L of samples were taken at different time points, and an equal amount of acetonitrile was added to precipitate proteins, then centrifugated and the supernatant was sampled for HPLC analysis. The half-life t.sub.1/2 (min) was calculated and the results were shown in table 1.
TABLE-US-00001 TABLE 1 Solubility of Nimodipine Derivatives in Water and Release Rate thereof into Plasma release rate solubility into plasma Example No. Compound No. structure (mg/mL) t.sub.1/2(min) 2 6
[0189] As can be seen from the above table, Nimodipine derivatives described above have an excellent solubility in water and can be quickly converted into Nimodipine in plasma.
[0190] The foregoing embodiments merely represent several embodiments of the present disclosure, which are described in particular and details, but should not be understood as being limited to the scope of the present disclosure. It should be noted that, for those skilled in the art, several variations and improvements may be made without departing from the concept of the present disclosure, and these are all within the protection scope of the present disclosure. Therefore, the protection scope of the present disclosure shall be subject to the appended claims.