CN103664726A - Deuterated bimatoprost or derivative thereof and preparation method and application of deuterated bimatoprost or derivative thereof - Google Patents
Deuterated bimatoprost or derivative thereof and preparation method and application of deuterated bimatoprost or derivative thereof Download PDFInfo
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Abstract
The invention relates to deuterated bimatoprost or a derivative thereof. A novel deuterated drug compound is formed by substituting an isotopic nuclide deuterium atom (D) for a hydrogen atom (H) contained in a bimatoprost structure and changing the chemical molecular structure and bond energy of the bimatoprost structure. The deuterated drug compound can be used for pharmacokinetic research, achieves obviously enhanced drug property and reduces the toxic side effect of a drug. The invention also relates to a preparation method and application of the deuterated bimatoprost or the derivative thereof.
Description
Technical field
The present invention relates to a kind of deuterated medical compounds, its preparation method and application thereof, particularly relate to a kind of deuterated bimatoprost or derivatives thereof, their preparation method and application thereof.
Background technology
Bimatoprost, (Z)-7-[(1R, 2R, 3R, 5S)-3,5-dihydroxyl-2-[(E, 3S)-3-hydroxyl-5-phenyl penta-1-thiazolinyl] cyclopentyl]-N-ethyl heptan-5-alkene acid amides, be considered to fall at present the strongest local anti-glaucoma medicine of IOP effect, all effective to normal people, POAG and OHT patient, be mainly used in tolerating other and fall IOP medicine or use other to fall POAG or the OHT patient that IOP medicine is invalid.
In organic compound molecule structure, hydrocarbon structure is the most basic structure, the C-H (C-H) forming is also the most basic chemical bond, hydrogen bond is with X-H ... Y represents, and distance between X-Y is decided to be to the bond distance of hydrogen bond, hydrogen bond has bond energy, and the structural parameter of hydrogen bond, as bond distance, bond angle, asking property of side can change in quite on a large scale, affect bond energy, bond distance is shorter, and hydrogen bond is stronger.Although the bond energy of hydrogen bond is little, very large on the impact of physical property, reason has two: 1. form maximum hydrogen bond principles, material inside becomes to asking in as far as possible hydrogen bonds that generate to reduce the energy of system more.2. because hydrogen bond energy is little, its formation and to destroy required activation energy also little, material interior molecules ask with molecule in constantly under motion change condition, hydrogen bond constantly ruptures and forms, and keeps the hydrogen bonded of some amount in material.The formation of hydrogen bond all can have deep effect to the various physicochemical property of material, also plays a part very important in the mankind and vegeto-animal physiology, biological process.Therefore, change chemical bond and hydrogen bond energy in medical compounds molecular structure, can change physics, chemistry, the pharmaceutical properties of medical compounds.
Hydrogen has three kinds of isotropic substances: the protium that nucleidic mass is 1 (H); Nucleidic mass is the tritium (T) that 2 deuterium (D) and nucleidic mass are 3.Deuterium is as a kind of stable form isotropic substance of hydrogen, and its nucleus is comprised of a proton and a neutron.Compared with the many neutrons of hydrogen nuclei, cause C-D chemical bond compared with stable (fast 6 times than C-D key of the c h bond breakdown rates of c h bond; (Nature News home, Published online 16March 2009; Chemistry & Industry 2009.March.9; 24-26).Such as, when medical compounds chemical structure methyl c h bond is replaced by C-D, hydrogen bond energy grow, strengthened the stability of individual molecule, although very small with regard to individual molecule bond energy, but hundreds of millions molecules are combined in and form simultaneously material, under kinetic isotope effect (Kinetic Isotope Effect) effect, finally change significantly chemistry, the pharmacology pharmacokinetics character of medical compounds.Obtain beyond thought effect, the medicine that significantly slows down is degradation rate by liver P450 enzyme, optimizes drug pharmacokinetics, obviously strengthens medicine effect, increases medicine new indication.Drug effect enhancing causes reducing medicine dosage, reduces this drug metabolite, reduces medicine toxicity, side effect, forms the novel isotropic substance of a class and replaces medicine, i.e. deuterated medicine.
The important feature of deuterium is that its shape in drug molecule is substantially the same with hydrogen with volume, that is to say, if the hydrogen in drug molecule is by the deuterium that replaces with of selectivity, deuterated medicine generally also can retain original biological activity and selectivity. experimental results show that, the combination of carbon-deuterium key is more stable than C-H. and carry the deuterium of neutron and carbon-deuterium key of carbon formation at lower frequency vibration, thereby be better than C-H.The increase of this intensity, can directly affect the attributes such as absorption, distribution, metabolism and excretion of some drugs, thereby improves curative effect, security and the tolerance of medicine.Therefore theory is thought, if certain the specific C-H being decomposed will be delayed to its decomposition course by deuterated for after corresponding carbon-deuterium key in drug molecule, the time that deuterated medicine is acted in health is longer, and effect is more better than original medicine.
Deuterium is a kind of stable non radioactive isotope of hydrogen, and weight is 2.0144.To introducing deuterium in compound, mainly contain two kinds of approach, the one, by carrying out proton exchange with hydrogen; The 2nd, by using deuterated raw material synthetic.More conventional with second method at present.Because the deuterium content in the deuterated compound generating is far away higher than the content of occurring in nature 0.015%, so can be regarded as a kind of novel compound.Deuterated effect has been widely used in the pharmacokinetic in mankind's clinical study and medicament research and development process.
The toxicity of deuterium is very low, and unicellular organism can survive, grow up in the environment of full deuterium.The low forms of life comprise fish and tadpole, can in 30% deuterium-oxide, survive. for mouse and dog, although the deuterium content in body can not be higher than 25%, in body, the hydrogen of 10%-15% can't produce significantly impact to its physical appearance when deuterated.The mankind also can bear the deuterium that has high density in blood, and the deuterium of concentration between 15%-20% can not produce significantly impact to human body.
From the angle of drug development, deuterated effect one of the most noticeable feature is exactly the powerful especially combining form of deuterium and carbon.As far back as the sixties, Elison with regard to find by the N-methyl hydrogen in morphine (Morphine) carry out deuterated after not only usefulness reduce, and N-demethyl rate reduces, and the restraint force of enzyme active center is also obviously weakened.Shao etc. participate in by deuterated the transformation period that metabolic molecular locus extends anodyne U-26225A (Tramadol) in vivo.
It is generally acknowledged, the deuterated advantage acting in drug research is some difficult points that can solve in medicament research and development process, optimizes the undesirable medicine of some effects, such as:
1) cause the medicine of bad metabolism;
2) from blood, remove too fast medicine;
3) after gi tract or liver metabolism degraded, could arrive the medicine of blood;
4) medicine that disturbs other drug to remove.
The CTP-347 of Concert company is the two deuterium model molecules to thymoleptic paroxetine (Paroxetine).Paroxetine is the non-hormone class medicine for the treatment of hectic fever, but some patient who is taking other drug can not use simultaneously, because the irreversible inactivation cytochrome C YP2D6 enzyme of its energy, makes the other drug that patient is taking reach a breakneck concentration level in blood.Experiment showed, CYP2D6 enzyme can eliminate paroxetine methylenedioxy group two hydrogen and generate Cabbeen; And highly active Cabbeen can with the heme iron irreversible fixation of CYP2D6 enzyme, make this enzyme deactivation.If these two hydrogen are deuterated, can greatly reduce the formation of Cabbeen, thereby reduce the inactivation of enzyme, can use with other drug widely simultaneously.
Venlafaxine (Venlafaxine) is a kind of selectivity serotonin NRI class (SNRIs) thymoleptic, and a methoxyl group in its molecule can be converted into rapidly hydroxyl in liver; Meanwhile, the dimethylamine group in molecule also can be converted to rapidly primary amine.SD-254 is the deuterated compound of Venlafaxine.First phase clinical experiment shows, the accretion rate of SD-254 is half of Venlafaxine, thus its in vivo lasting time longer than Venlafaxine, curative effect is also more obvious. this has proved the superiority of deuterated product aspect treatment disease to a certain extent.
Use deuterated medicine to have following advantage for inquiring into pharmacokinetics:
(1) overcome individual difference in experiment, improved the credibility of test precision and experimental data;
(2) highly sensitive means of testing, has reduced the demand of blood plasma, urine and tissue samples;
(3) higher data statistics confidence level, has reduced experimenter's number, has saved experiment spending;
(4) experimenter's tested time and test sample time have been shortened;
(5) be applicable to the Gestation period and neonatal patient.
Deuterated medicine also has important effect aspect pharmacology, and main manifestations is following three aspects:
(1) reduce System Cleaning rate, increase the biological half-life of compound.This advantage of deuterated medicine can keep identical treatment level when reducing using dosage, thereby reduces side effect, heightens the effect of a treatment;
(2) reduce the metabolic ratio of medicine in gi tract or liver, make most of not medicines of metabolism enter into body circulation.Deuterated medicine can reduce the requirement of drug dose, produces lower metabolic burden, improves the tolerance of medicine;
(3) reduce harmful metabolism, strengthen the drug effect of medicine.
Summary of the invention
The object of the present invention is to provide a kind of deuterated medical compounds, deuterated bimatoprost and derivative thereof, have under the prerequisite of bimatoprost characteristic, to have more superiority than the former in pharmaceutical activity, stability and safety.
Another object of the present invention is to provide described deuterated bimatoprost and the synthetic method of derivative thereof.
A further object of the present invention is to provide described deuterated bimatoprost and the application of derivative thereof.
The technical solution used in the present invention is as follows:
A deuterated bimatoprost or derivatives thereof, has suc as formula the structure shown in I:
R wherein
1alkyl, phenyl, substituted-phenyl, aralkyl or substituted aralkyl for C1～30.
Wherein, described R
1preferable methyl, ethyl, propyl group, sec.-propyl, butyl or the tertiary butyl.
The preparation method of deuterated compound of the present invention is by the intermediate ester with formula II structure (II) and deuterated alkylamine R
1nD
2direct aminolysis, or in deuterated solvent, carry out aminolysis reaction, obtain the deuterated bimatoprost or derivatives thereof of target compound (I);
Wherein, R
1for alkyl, phenyl or substituted-phenyl, aralkyl or the substituted aralkyl of C1～30, R
2for alkyl.
In described method, the preferred deuterated methylamine of deuterated alkylamine, deuterated ethamine, deuterated propylamine, deuterated Isopropylamine, deuterated butylamine or deuterated TERTIARY BUTYL AMINE.
In described method, intermediate ester (II) has following formula (II) structure,
R wherein
2for alkyl, the alkyl of preferred C1～C4.
Described preparation method specifically comprises the steps:
A) by ester (II) and deuterated alkylamine R
1nD
2directly or mix in deuterated solvent;
B), by the mixed solution of step (A) gained, be controlled at certain temperature and carry out aminolysis reaction, until react completely;
C) will after the reaction product processing of step (B) gained, obtain target compound.
Described aminolysis reaction temperature is 0-100 ℃, preferably 40-70 ℃.
Described deuterated solvent comprises heavy water, deuterated four deuterium furans, deuterated toluene, deuterated DMF or deuterated DMSO etc., preferably D
2o, deuterated DMF or deuterated DMSO.
Described deuterated bimatoprost or derivatives thereof has the characteristic of bimatoprost, and have more superiority on pharmaceutical activity, effectiveness and reliability, can replace bimatoprost in the Application Areas of bimatoprost, therefore deuterated compound of the present invention can be applied in household chemicals, medicine, particularly in household chemicals, applies.
Be below household chemicals, pharmaceutical applications field, described deuterated bimatoprost and the comparison of bimatoprost in relevant main characteristic.
Table 1: transformation period contrast:
Table 2: eyelash growing effect comparison:
Note: two groups are carried out double blinding contrast, the formula of same concentrations actives, contrast in 2 months, 20 people/group.
Table 3: toxicity contrast:
The hair papilla cell active (n=3) of the deuterated bimatoprost of table 4:
Note: 1) Positive control:DMEM supplemented with 5%FBS;
2)Significant?difference?against?un-treated?cells；
Black：Significant?increase。
Therefore, the invention still further relates to described deuterated compound as the application of hair growth liquor.
The invention still further relates to another purposes that described deuterated compound is done, i.e. application in the glaucomatous medicine of preparation treatment.
Hair growth liquor is the main Application Areas of the deuterated compound of the present invention.Because described deuterated bimatoprost compound has as above these features, therefore, application prospect is very extensive, as Mascara, growing liquid, natural on-off cycles of hair growth liquid etc., also can be applied to shampoo etc., hair conditioner etc.
The deuterated compound agent of the present invention can also be used for the treatment of glaucoma as glaucoma drug candidate, because its toxic side effect is little, uses safer.
Beneficial effect of the present invention: the deuterated compound of the present invention, except thering is the characteristic of bimatoprost, as to hair and skin action temperature and, low stimulation, foaming and emulsifying property is good, soil removability strong, safe, the biodegradability of environmental and biological materials well beyond, but also there is the character that is better than bimatoprost:
1) biological half-life of compound is longer.This advantage can reduce using dosage, thereby reduces toxic side effect, strengthens and extend curative effect;
2) reduce medicine metabolism ratio in vivo and in vitro, make not metabolism partly enter into body circulation, reduce drug dose, produce lower metabolic burden, improve tolerance;
3) reduce harmful metabolism, strengthen the drug effect of medicine.
Embodiment:
The preparation (1) of the deuterated thing of embodiment 1 (I1)
By the methyl esters (R of formula II structure
2for methyl) 12.5g (31mmol), 70% deuterated methylamine (30%D
2o) 150mL is added in 250ml flask, under room temperature condition, stirs 50h, it is complete that HPLC detects raw material reaction, is concentrated into 80mL, with the aqueous solution of saturated sodium pyrosulfate, is neutralized to pH value neutrality, ethyl acetate is extracted (300mL) 3 times, saturated sodium-chloride water solution washing 3 times, anhydrous sodium sulfate drying, suction filtration is also concentrated into dryly, adds isopropyl ether appropriate, stirs 1h, suction filtration, dry, obtain 10.0g, yield 80.0%.
1HNMR(CDCl
3)δ：7.17-7.41(Ar
H-，m，5H)；5.11-5.62(-CH＝C
H-，m，4H)；4.22-4.24(-O
H，m，3H)；3.17-3.55(C
H-，m，3H)；3.08(C
H 2-，m，2H)；2.63(C
H-，m，1H)；2.73(C
H 2-，m，2H)；2.13-2.38(C
H-，m，10H)；1.52-1.84(C
H 2-，m，2H)；1.56(C
H-，m，1H)；1.28(C
H 3-，m，1H)。
The preparation (2) of the deuterated thing of embodiment 2 (I1)
By the methyl esters (R of formula II structure
2for methyl) 12.5g (31mmol), deuterated methylamine (99%) 100mL be added in 250ml flask, stirs 30h at 50 ℃, and it is complete that HPLC detects raw material reaction, be concentrated into 50mL, with the aqueous solution of saturated sodium pyrosulfate, be neutralized to pH value neutrality, ethyl acetate is extracted (300mL) 3 times, saturated sodium-chloride water solution washing 3 times, anhydrous sodium sulfate drying, suction filtration is also concentrated into dry, add isopropyl ether appropriate, stir 1h, suction filtration, dry, obtain 10.5g, yield 82.0%.
1HNMR(CDCl
3)δ：7.25-7.41(Ar
H-，m，5H)；5.22-5.57(-CH＝C
H-，m，4H)；4.11-4.38(-O
H，m，3H)；3.17-3.69(C
H-，m，3H)；3.07(C
H 2-，m，2H)；2.85(C
H-，m，1H)；2.66(C
H 2-，m，2H)；2.13-2.37(C
H-，m，10H)；1.57-1.83(C
H 2-，m，2H)；1.67(C
H-，m，1H)；1.25(C
H 3-，m，1H)。
The preparation (1) of the deuterated bimatoprost of embodiment 3 (I2)
By the methyl esters (R of formula II structure
2for methyl) 12.5g (31mmol), deuterated ethamine (99%) 100mL be added in 250ml flask, stirs 30h at 50 ℃, and it is complete that HPLC detects raw material reaction, be concentrated into 50mL, with the aqueous solution of saturated sodium pyrosulfate, be neutralized to pH value neutrality, ethyl acetate is extracted (300mL) 3 times, saturated sodium-chloride water solution washing 3 times, anhydrous sodium sulfate drying, suction filtration is also concentrated into dry, add isopropyl ether appropriate, stir 1h, suction filtration, dry, obtain 10.9g, yield 84.3%.
1HNMR(CDCl
3)δ：7.25-7.41(Ar
H-，m，5H)；5.22-5.57(-CH＝C
H-，m，4H)；4.11-4.38(-O
H，m，3H)；3.17-3.69(C
H-，m，3H)；3.01(C
H 2-，m，2H)；2.85(C
H-，m，1H)；2.66(C
H 2-，m，2H)；2.13-2.37(C
H-，m，10H)；1.57-1.83(C
H 2-，m，2H)；1.67(C
H-，m，1H)；1.25(C
H 3-，m，1H)。
The preparation (2) of the deuterated bimatoprost of embodiment 4 (I2)
By the methyl esters (R of formula II structure
2for methyl) 12.5g (31mmol), 70% deuterated ethamine (30%D
2o) 150mL is added in 250ml flask, under room temperature condition, stirs 50h, it is complete that HPLC detects raw material reaction, is concentrated into 80mL, with the aqueous solution of saturated sodium pyrosulfate, is neutralized to pH value neutrality, ethyl acetate is extracted (300mL) 3 times, saturated sodium-chloride water solution washing 3 times, anhydrous sodium sulfate drying, suction filtration is also concentrated into dryly, adds isopropyl ether appropriate, stirs 1h, suction filtration, dry, obtain 11.2g, yield 86.6%.
1HNMR(CDCl
3)δ：7.27-7.40(Ar
H-，m，5H)；5.12-5.52(-CH＝C
H-，m，4H)；4.12-4.28(-O
H，m，3H)；3.16-3.65(C
H-，m，3H)；3.05(C
H 2-，m，2H)；2.83(C
H-，m，1H)；2.63(C
H 2-，m，2H)；2.13-2.35(C
H-，m，10H)；1.56-1.83(C
H 2-，m，2H)；1.66(C
H-，m，1H)；1.23(C
H 3-，m，1H)。
The preparation of the deuterated thing of embodiment 5 (I3-I6)
With reference to the method for embodiment 1 with different R
1substituent deuterated alkylamine carries out the preparation of deuterated thing (I3-I6).
The result of embodiment 1-5 is as shown in the table.
Claims (10)
1. a deuterated bimatoprost or derivatives thereof, its structural formula is suc as formula shown in I:
Wherein, R
1alkyl, phenyl or substituted-phenyl, aralkyl or substituted aralkyl for C1～30.
2. deuterated bimatoprost or derivatives thereof according to claim 1, is characterized in that described R
1be selected from methyl, ethyl, propyl group, sec.-propyl, butyl or the tertiary butyl.
3. a synthetic method for deuterated bimatoprost or derivatives thereof, is characterized in that: the intermediate ester (II) and deuterated alkylamine R with formula II structure
1nD
2direct aminolysis, or in deuterated solvent, carry out aminolysis reaction, obtain the deuterated bimatoprost or derivatives thereof of target compound (I);
R wherein
1for alkyl, phenyl or substituted-phenyl, aralkyl or the substituted aralkyl of C1～30, R
2alkyl.
4. the synthetic method of deuterated bimatoprost or derivatives thereof according to claim 3, is characterized in that: described deuterated alkylamine R
1nD
2in, R
1be selected from methyl, ethyl, propyl group, sec.-propyl, butyl or the tertiary butyl, in intermediate ester (II), R
2alkyl for C1～C4.
5. the synthetic method of deuterated bimatoprost or derivatives thereof according to claim 3, is characterized in that: described aminolysis reaction temperature is 0-100 ℃.
6. the synthetic method of deuterated bimatoprost or derivatives thereof according to claim 5, is characterized in that: described aminolysis reaction temperature is 40-70 ℃.
7. the synthetic method of deuterated bimatoprost or derivatives thereof according to claim 3, is characterized in that: described deuterated solvent, refers to heavy water, deuterated four deuterium furans, deuterated toluene, deuterated DMF, deuterated DMSO.
8. the synthetic method of deuterated bimatoprost or derivatives thereof according to claim 7, is characterized in that: described deuterated solvent is D
2o, deuterated DMF or deuterated DMSO.
9. deuterated bimatoprost or derivatives thereof claimed in claim 1 is as the application of hair growth agent.
10. the application of deuterated bimatoprost or derivatives thereof claimed in claim 1 in the glaucomatous medicine of preparation treatment.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109851638A (en) * | 2018-02-07 | 2019-06-07 | 深圳市塔吉瑞生物医药有限公司 | Substituted diaminopyrimidine compounds |
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| CN101969772A (en) * | 2007-10-31 | 2011-02-09 | 帕梅拉·立普金 | Prostaglandin analog compositions and methods to treat epithelial-related conditions |
| WO2012100347A1 (en) * | 2011-01-24 | 2012-08-02 | Inceptum Research & Therapeutics, Inc. | Compositions comprising a prostaglandin for treating neuropsychiatric conditions |
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Application publication date: 20140326 |