CN106946873B - Medicine for treating facial nerve injury and preparation method thereof - Google Patents
Medicine for treating facial nerve injury and preparation method thereof Download PDFInfo
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Abstract
The invention provides a benzothiazole compound with a structure shown in a formula (I):
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a medicine for treating nerve injury, which can treat nerve diseases related to nerve injury, such as facial nerve injury.
Background
The facial nerve injury is a kind of nerve disease, and can be classified into traumatic facial nerve injury (physical injuries such as traffic accidents, falling injuries, gunshot injuries, puncture injuries, fulguration injuries and the like) and iatrogenic injuries according to the etiology. The external force action modes can be classified into exposure, traction, extrusion, squeezing, sharp cutting injury, blunt friction injury and the like. Neurological diseases are associated with the death or damage of neuronal cells. Typical treatments for neurological diseases involve drugs that inhibit neuronal cell death. More recent approaches involve promoting nerve regeneration by promoting neuronal growth.
Nerve Growth Factor (NGF) is a nerve cell growth regulator with the biological functions of both neuron nourishment and neurite outgrowth, and has important regulation and control functions on the development, differentiation, growth, regeneration and expression of functional characteristics of central and peripheral neurons. For example, glial cell line-derived neurotrophic factor (GDNF) exhibits neurotrophic activity both in vitro and in vivo, and is being evaluated for its effect on parkinson's disease treatment. However, for the treatment of neurological diseases, the use of nerve growth factors can present several disadvantages. They do not rapidly cross the blood brain barrier and are unstable in plasma, and in addition, they have poor drug delivery properties.
In addition, studies have demonstrated that certain small molecules are capable of stimulating axonal growth in vivo, which protects neurons from further degeneration and promotes regeneration of nerve cells. For example, estrogens have been shown to promote axonal and dendritic growth (C.dominique Toran-Allerand et al, J.Steroid biochem.mol.biol., 1996, 56, pp.169-78; and B.S.McEwen et al, Brain Res.Dev.brain. Res., 1995, 87, pp.91-95). Compounds with affinity for FKBP12, which inhibits the gyrase activity of immunophilin proteins, have been reported to have nerve growth stimulating activity (Lyons et al, Proc. Natl. Acad. Sci. USA, 1994,91, pp.3191-3195). WO 96/41609 describes piperidine derivatives capable of stimulating the axon in nerve cells.
Although a wide variety of compounds have been described in the prior art for the treatment or prevention of neurodegenerative diseases, there are very few drugs that really enter clinical trials and are approved for marketing. Thus, there remains a need to find and design new compounds and compositions that can prevent and treat injuries associated with neurological diseases, such as facial nerve injury.
Disclosure of Invention
The present invention aims to provide a drug capable of having a therapeutic activity on nerve damage.
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
[ chemical formula 1]
In the formula (I), R1Selected from: hydrogen atom, halogen, cyano, nitro, amino, carboxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylamino, di (C1-C4 alkyl) amino, C1-C4 alkoxycarbonyl, C1-C4 alkylsulfonyl, phenyl, benzyl5-or 6-membered heterocycloalkyl and 5-or 6-membered heteroaryl;
R2、R3may be the same or different and are each independently selected from: hydrogen atom, halogen, cyano, nitro, amino, carboxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylamino, di (C1-C4 alkyl) amino, C1-C4 alkoxycarbonyl, C1-C4 alkylsulfonyl, phenyl, benzyl, 5-or 6-membered heterocycloalkyl, and 5-or 6-membered heteroaryl; or R2、R3May form a phenyl ring, or a 5-or 6-membered heteroaromatic ring together with the carbon atom to which it is attached;
R1、R2、R3the phenyl, benzyl, 5-or 6-membered heterocycloalkyl and 5-or 6-membered heteroaryl in (a) may be optionally substituted with 1 to 3 substituents selected from: halogen, hydroxy, nitro, cyano, carbamoyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, amino, C1-C4 alkylamino, di (C1-C4 alkyl) amino;
R4、R5may be the same or different and are each independently selected from: hydrogen atom, halogen, cyano, nitro, amino, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, di (C1-C4 alkyl) amino, C1-C4 alkoxycarbonyl, C1-C4 alkylsulfonyl.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may be used in a method of promoting nerve repair or preventing nerve damage in a patient or in vitro in a nerve cell.
In another embodiment, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diseases, including diseases associated with nerve damage. Examples of such diseases include facial nerve injury, peripheral nerve destruction due to physical injury or disease such as diabetes, neurological disorders due to neurodegeneration such as parkinson's disease, alzheimer's disease, and amyotrophic lateral sclerosis, and the like.
Hereinafter, the present invention will be described in detail.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned in this application are herein incorporated by reference.
The term "C1-C4 alkyl" is intended to denote a branched or straight chain and may contain 1-4, such as 1-3, such as 1-2, such as 2-3, saturated hydrocarbon groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
The term "halogen" is intended to mean fluorine, chlorine, bromine and iodine.
The term "5-or 6-membered heterocycloalkyl" is intended to denote a 5-or 6-membered monocyclic saturated ring group containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, such as pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, tetrahydrofuranyl, oxazolidinyl, morpholinyl, thiomorpholinyl and the like.
The term "5-or 6-membered heteroaryl" is intended to denote a 5-or 6-membered monocyclic aromatic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
In some embodiments of the compounds of the present invention, wherein R is1、R2、R3Represents hydrogen.
In some embodiments of the compounds of the present invention, wherein R is3Represents a 5-or 6-membered heterocycloalkyl group, preferably a pyrrolidinyl group.
In some embodiments of the compounds of the present invention, wherein R is4、R5Represents C1-C4 alkyl or C1-C4 alkoxy, preferably methyl or methoxy.
In some embodiments of the compounds of the present invention, wherein R is2、R3Together with the carbon atoms to which they are attached form a benzene ring.
In some embodiments of the compounds of the present invention, the compound is selected from the group consisting of:
the compounds of formula (I) described herein also include pharmaceutically acceptable derivatives thereof, such as any pharmaceutically acceptable salt, prodrug or salt of a prodrug of a compound of the invention, or any other compound that, upon administration to a patient, provides a compound of the invention.
The pharmaceutically acceptable salts of the compounds of formula (I) according to the invention are salts derived from inorganic or organic acids and bases. Such acid addition salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, hemisulfate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, nicotinate, oxalate, persulfate, picrate, pivalate, propionate, succinate, tartrate, tosylate, and undecanoate. Base addition salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, and salts with amino acids such as arginine, lysine, and the like.
The compounds of formula (I) of the present invention may also be modified by the addition of suitable functional groups to enhance selective biological characteristics. Such modifications are known in the art and include modifications to enhance the penetration of organisms into a given biological system (e.g., blood, lymphatic system, central nervous system), enhance oral availability, enhance solubility to allow administration by injection, alter metabolism and alter rate of excretion.
In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical composition may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally or via an implanted reservoir. The term "parenteral administration" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition may be administered orally, intraperitoneally, or intravenously.
The amount of the compound that can be combined with a pharmaceutically acceptable carrier to make a single dosage form will depend upon the patient being treated and the particular mode of administration. Preferably, the composition should be formulated so that a dose of 0.01-100mg/kg body weight/day of the compound can be administered.
Preparation method
The compounds of the present invention can be readily prepared by known synthetic methods.
For example, the compounds of formula (I) may be prepared by a process comprising the steps of:
the method comprises the following steps:
reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (IV);
the reaction is carried out in the presence of a palladium catalyst comprising bis (triphenylphosphino) palladium dichloride, palladium acetate, preferably bis (triphenylphosphino) palladium dichloride, and a base comprising potassium acetate, sodium acetate;
step two:
reacting a compound of formula (IV) with hydroxylamine to produce a compound of formula (V);
the reaction is carried out in the presence of a condensing agent comprising HBTU, TBTU, HATU or HCTU and a base; the base comprises triethylamine, pyridine or piperidine;
step three:
reacting a compound of formula (V) with a compound of formula (VI) to produce a compound of formula (I);
the reaction is carried out in the presence of a base including potassium alkoxides such as potassium tert-butoxide, sodium alkoxides such as sodium ethoxide, sodium hydride;
wherein R is1-R5As defined in claim 1, R represents a C1-C4 alkyl group, X1、X2Each independently represents a halogen atom, such as chlorine, bromine or iodine.
Advantageous effects
Compound of the present invention para CoCl2The resulting nerve cell damage has a very excellent protective activity and thus can be used for the treatment of diseases associated with nerve damage, such as facial nerve damage, peripheral nerve destruction due to physical injury or diseases such as diabetes, neurological disorders due to neurodegeneration such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and the like.
Detailed Description
Practical and presently preferred embodiments of the present invention are illustrated by the following examples.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
Example 1: (E) -3- (6- (3, 4-dimethyl-1H-pyrazol-5-yloxy) benzo [ d ] thiazol-2-yl) -N-hydroxyacrylamide (Compound 1)
The method comprises the following steps: under the protection of argon, 2-bromobenzo [ d ] thiazole-2-ol (4.56g), methyl acrylate (1 ml), potassium acetate (3.9 g) and bis (triphenylphosphine) palladium dichloride (0.1 g) are dissolved in DMF100ml, and the mixture is reacted for 6 hours under reflux and the reaction is completely detected by TLC. Water 200ml stirring 10min, DCM extraction, saturated saline water washing three times, anhydrous sodium sulfate drying, decompression evaporation of solvent to obtain white solid (E) -3- (6-hydroxy benzo [ d ] thiazole-2-yl) methyl acetate 3.83g, yield 81.2%.
Step two: 2.35g of methyl (E) -3- (6-hydroxybenzo [ d ] thiazol-2-yl) acetate, 2.8 g of HATU3 and 0.69g of hydroxylamine hydrochloride from step one were added to DCM500ml under an argon atmosphere, and the reaction mixture was stirred at 20 ℃ for 5 h. The mixture was poured into water, diluted with DCM, washed three times with water, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give (E) -N-hydroxy-3- (6-hydroxybenzo [ d ] thiazol-2-yl) acetamide as a white solid 1.78g, 75.4% yield.
Step three: adding 1.12g of potassium tert-butoxide into 200ml of DMF under the protection of argon, then slowly dropwise adding 1.18g of the solution of (E) -N-hydroxy-3- (6-hydroxybenzo [ d ] thiazol-2-yl) acetamide obtained in the step two dissolved in 30ml of DMF at the temperature lower than 40 ℃, continuously stirring for 30min after about 1H, adding 1.2g of 5-iodo-3, 4-dimethyl-1H-pyrazole, then slowly heating to 40 ℃, keeping the temperature and stirring for reaction for 2H. Cooled, filtered, the filtrate concentrated under reduced pressure, 1000ml of water added to the residue and then filtered to give the crude product. The crude product was recrystallized from a mixed solution of ethyl acetate-ethanol (1:1) to give the title compound as a white needle-like solid (1.31 g) in 79.5% yield.
ESI-MS：331.08[M+H]+
Elemental analysis: theoretical/measured values, C (54.53/54.59), H (4.27/4.20), N (16.96/16.88), O (14.53/14.58), S (9.71/9.68)
1H NMR(400MHz,CDCl3)δ13.75(s,1H),8.03(s,1H),7.73(d,1H),7.49(d,1H),7.31(s,1H),6.94(d,1H),6.76(d,1H),2.16(s,1H),2.06(s,3H),1.91(s,3H)。
Following a similar procedure, the following compounds were synthesized:
compound 2: (E) -3- (6- (3, 4-dimethyl-1H-pyrazol-5-yloxy) -4- (pyrrolidin-1-yl) benzo [ d ] thiazol-2-yl) -N-hydroxyacrylamide (compound 2)
ESI-MS：400.14[M+H]+
Elemental analysis: theoretical/measured values, C (57.13/57.19), H (5.30/5.20), N (17.53/17.58), O (12.02/12.08), S (8.03/7.95)
1H NMR(400MHz,CDCl3)δ13.75(s,1H),8.03(s,1H),7.73(d,1H),6.81(s,1H),6.34(s,1H),6.76(d,1H),3.46(t,4H),2.16(s,1H),2.06(s,3H),1.91(s,3H),1.82(t,4H)。
Compound 3: (E) -3- (5- (3, 4-dimethoxy-1H-pyrazol-5-yloxy) naphtho [1,2-d ] thiazol-2-yl) -N-hydroxyacrylamide (Compound 3)
ESI-MS：413.08[M+H]+
Elemental analysis: theoretical/measured values, C (55.33/55.29), H (3.91/3.80), N (13.58/13.52), O (19.40/19.48), S (7.77/7.91)
1H NMR(400MHz,CDCl3)δ13.45(s,1H),8.03(s,1H),7.99(d,1H),7.84(d,1H),7.51(m,2H),7.36(s,1H),7.76(d,1H),6.72(d,1H),4.06(s,3H),3.91(s,3H),2.16(s,1H)。
Next, pharmacological effects of representative compounds are specifically explained by experimental examples.
Test experimental example 1: neuroprotective assay for target compounds
Several cell culture assays known in the art can be used to determine the nerve growth stimulating activity of the compounds of the present invention. The present invention uses the pheochromocytoma PC12 branch-cell neurite assay to test the neuroprotective activity of the compounds of the present invention ("immunosuppresant FK506 proteins neural outgrowth in cultures of PC12cells and sensory great", Lyons w.e., et al, PNAS,1994,91, pp.3191-3195) as follows:
PC12cells grow to 80-90% confluence for passage, loose adherent cells are firstly lightly blown down by a disposable dropper, the culture solution is collected in a centrifuge tube of 15ml, and the rest adherent cells are digested by trypsinase digestive juice, wherein the digestive juice is 0.05 pancreatin and 0.02% EDTA. Observing the cell digestion state under an inverted microscope, immediately adding 2mL of complete culture medium to terminate digestion after cell gaps are enlarged and most cells become round, tapping the culture flask to ensure that all cells are detached, combining cell-containing culture solutions twice, centrifuging at 800rpm/min for 3min, discarding supernatant, re-suspending cells, adding the complete culture medium, inoculating into a new culture flask, and placing in a constant-temperature and saturated-humidity incubator at 37 ℃ to continue culture. PC12cells were cultured normally for 72 hours, and then the medium (RPMI1640 containing 5% HS + 10% FBS + 1% double antibody) was poured out and cultured in a serum-free medium (RPMI1640) for 12 to 16 hours for further use.
Preparing single cell suspension from serum starved PC12cells, and adjusting cell density to 7 × 104cells/mL, medium was changed to RPMI1640 with 10% FBS, and seeded into PLL-coated 96-well plates at 100. mu.L per well. NGF was added to 96-well plates at a final concentration of 50ng/mL and incubation was continued for 36 h.
After the cells are differentiated, the cells are divided into fine cellsThe cells are divided into a normal control group, an NGF group and an administration group, the cells are respectively added into a 96-well plate according to final concentrations of 3.75, 7.5, 15, 30 and 60nmol/L, each group comprises 6 multiple wells, the cells are cultured in an incubator for 24 hours, and then CoCl with the final concentration of 200 mu mol/L is added2The solution was added to a 96-well plate and incubation was continued for 12 h. mu.L of MTT (5mg/ml) was added to each well, and after 4h incubation, OD was measured at 490nm using a microplate reader.
The formula of the target compound for the proliferation of the damaged PC12cells at the corresponding concentration is as follows: [ OD490 (Compound) -OD490 (CoCl)2)]/[OD490(NGF)-OD490(CoCl2)]X is 100%; ultimate EC50The calculation formula of (2) is as follows: -pEC50 ═ logCmax-log2 × (Σp-0.75+0.25Pmax +0.25Pmin), where Cmax ═ maximum concentration, Σ P ═ total proliferation rate, Pmax ═ maximum proliferation rate, and Pmin ═ minimum proliferation rate. The results are shown in table 1 below:
table 1: protective Activity of target Compounds on damaged nerve cells
| Compound (I) | EC50(nm) |
| 1 | 43.5 |
| 2 | 52.7 |
| 3 | 29.0 |
The above results show that the compound of the present invention is para-CoCl2The induced nerve cell damage has excellent protective activity, so the method can be used for treating various nerve damage diseases, such as facial nerve damage.
The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.
Claims (16)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
[ chemical formula 1]
In the formula (I), R1Selected from: hydrogen atom, halogen, C1-C4 alkyl and C1-C4 haloalkyl;
R2、R3may be the same or different and are each independently selected from: a hydrogen atom, a C1-C4 alkylamino group, a di (C1-C4 alkyl) amino group and a 5-or 6-membered heterocycloalkyl group; or R2、R3May form a benzene ring together with the carbon atom to which it is attached;
R2、R3the 5-or 6-membered heterocycloalkyl group in (a) may be optionally substituted with 1 to 3 substituents selected from: halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl;
R4、R5may be the same or different and are each independently selected from: C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy;
wherein the 5-or 6-membered heterocycloalkyl is selected from the group consisting of pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl.
2. A compound of claim 1, wherein R is1、R2、R3Represents hydrogen.
3. A compound of claim 1, wherein R is3Represents a pyrrolidinyl group.
4. A compound of claim 1, wherein R is4、R5Represents a C1-C4 alkyl group or a C1-C4 alkoxy group.
5. A compound of claim 4, wherein R is4、R5Represents a methyl group or a methoxy group.
6. A compound of claim 1, wherein R is2、R3Together with the carbon atoms to which they are attached form a benzene ring.
7. The compound of claim 1, selected from the group consisting of:
8. a pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
9. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 in the manufacture of a medicament for the treatment of a disease associated with nerve damage.
10. The use according to claim 9, wherein the disease associated with nerve damage is selected from the group consisting of facial nerve damage, peripheral nerve destruction due to physical injury or disease, parkinson's disease, alzheimer's disease and amyotrophic lateral sclerosis.
11. The use according to claim 10, wherein the physical injury or disease is diabetes.
12. The use according to claim 9, wherein the medicament is for the treatment of facial nerve injury.
13. A process for the preparation of a compound of formula (I) according to claim 1, comprising the steps of:
the method comprises the following steps:
reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (IV);
the reaction is carried out in the presence of a palladium catalyst selected from bis (triphenylphosphino) palladium dichloride, palladium acetate and a base selected from potassium acetate, sodium acetate;
step two:
reacting a compound of formula (IV) with hydroxylamine to produce a compound of formula (V);
the reaction is carried out in the presence of a condensing agent selected from HBTU, TBTU, HATU or HCTU and a base; the base is selected from triethylamine, pyridine or piperidine;
step three:
reacting a compound of formula (V) with a compound of formula (VI) to produce a compound of formula (I);
the reaction is carried out in the presence of a base selected from potassium alkoxide, sodium hydride;
wherein R is1-R5As defined in claim 1, R represents a C1-C4 alkyl group, X1、X2Each independently represents a halogen atom.
14. The method of claim 13, wherein in step one, the palladium catalyst is bis (triphenylphosphino) palladium dichloride.
15. The process according to claim 13, wherein in step three, the base is selected from potassium tert-butoxide or sodium ethoxide.
16. The method of claim 13, wherein X is1、X2Each independently represents chlorine, bromine or iodine.
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