CN101768155A - Derivatives containing (aminomethyl-five-membered heterocyclo-4-carbonyl)-pyrrolidine-2-carboxylic acid, preparation method thereof and use thereof - Google Patents
Derivatives containing (aminomethyl-five-membered heterocyclo-4-carbonyl)-pyrrolidine-2-carboxylic acid, preparation method thereof and use thereof Download PDFInfo
- Publication number
- CN101768155A CN101768155A CN200810154646A CN200810154646A CN101768155A CN 101768155 A CN101768155 A CN 101768155A CN 200810154646 A CN200810154646 A CN 200810154646A CN 200810154646 A CN200810154646 A CN 200810154646A CN 101768155 A CN101768155 A CN 101768155A
- Authority
- CN
- China
- Prior art keywords
- pyrrolidine
- carbonyl
- aminomethyl
- oxazole
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicaments for treating tumors and thrombus and particularly relates to derivatives containing (aminomethyl-five-membered heterocyclo-4-carbonyl)-pyrrolidine-2-carboxylic acid, preparation method thereof, medicinal composition thereof and use thereof in the preparation of anti-tumor and antithrombotic medicaments, wherein the groups are defined in the description.
Description
Technical Field
The invention relates to the field of medicaments related to tumors and thrombus, in particular to a derivative containing (aminomethyl-five-membered heteroaromatic ring-4-carbonyl) -pyrrolidine-2-carboxylic acid with the functions of an anti-tumor medicament and an anti-thrombus medicament, a preparation method thereof, a pharmaceutical composition thereof and application thereof in preparing the anti-tumor medicament and the anti-thrombus medicament.
Background
Cancer is the leading disease threatening human life, and according to statistics, the total number of cancer deaths in the world reaches 700 million people every year, and more than 100 million patients who die of tumor in China every year are gradually increased, and the cancer is the first cause of death of urban population. At present, the traditional medicines for treating cancer diseases clinically in China comprise: alkylating agents (such as phosphoramide), antimetabolites (such as 5-fluorouracil), antibiotics (such as idarubicin), and anticancer plant drugs (such as hydroxycamptothecin). They have obvious clinical treatment effect, but have the following disadvantages: low specificity and poor selectivity, causes obvious toxic and side effects, and is easy to generate serious multi-drug resistance phenomena of cancers.
With the development of molecular biology, the current anti-cancer drugs are developing from traditional cytotoxic drugs to novel anti-cancer drugs aiming at multi-link mechanism, and one of the important new targets of the current anti-cancer effect concerned at home and abroad is protein tyrosine kinase (xanthone, butyl key, new target of anti-tumor drugs, Chinese prescription drugs, 2006, 12(57), 10-15). More than 20 receptor tyrosine kinases and non-receptor tyrosine kinases belonging to different families are currently used as targets for screening anticancer drugs, inhibitors of the protein tyrosine kinases have been on the market, and in order to find drugs with better activity, molecular targeted anticancer drug therapy also provides another challenging concept in recent years: the strategy of multiple target tyrosine kinase inhibition (multiple targeted tyrosine kinase inhibition) is an important direction for anti-tumor. On the basis of researching the crystal structures of various tyrosine kinases, an aminomethyl five-membered aromatic heterocyclic 4-carboxylic acid derivative is designed, has a good matching mode with a plurality of target structures, has good anti-tumor activity after in vitro cell strain screening, and also has an anti-thrombus effect through in vivo anti-thrombus tests.
Disclosure of Invention
The invention aims to search a medicament with better activity from a new structure class aiming at the current situation that the anti-tumor and anti-thrombus medicaments cannot meet the clinical requirement. Compounds having the general formula I or pharmaceutically acceptable salts thereof are provided.
The invention also aims to provide a preparation method of the compound with the structure of the general formula I or the pharmaceutically acceptable salt thereof.
It is still another object of the present invention to provide a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient, in combination with one or more pharmaceutically acceptable carriers, excipients or diluents, and its use in the prevention and treatment of tumors and thrombotic disorders.
The invention will now be described, one by one, with reference to the objects of the invention:
the compounds of formula I of the present invention have the following structural formula:
wherein,
Y＝O、NH、S；
R1is H, contains C1-C4Linear or branched alkyl of (a);
R2is H or C1-C5Straight OR branched alkyl, -OR ', -SR', -halogen, -CN, -NHCOR ', -N (R')2、-NO2A substituent group such as-COOR ', CONR ', and the like, wherein R ' is H, C1-C5Linear or branched alkyl of (a);
R3is composed of
Wherein R is4Is H or C1-C5Straight or branched alkyl, C1-C5Acyl group, -CH, linked to a linear or branched alkyl group of2OH；R5Is H or C1-C5Straight OR branched chain alkyl, -OR', -halogen, -CN.
The compound of the general formula I contains one or two chiral centers, can generate two or four optical isomers, and the invention comprises any optical isomer and diastereoisomer mixture thereof.
Preference is given to compounds of the general formula I or pharmaceutically acceptable salts thereof, in which,
Y＝O、NH、S；
R1comprises the following steps: H. isopropyl, methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl;
R2is H or C1-C5Straight OR branched alkyl, -OR ', -SR', -halogen, -CN, -NHCOR ', -N (R')2、-NO2Substituent groups such as-COOR ' and CONR ', wherein R ' is H, isopropyl, methyl, ethyl, n-propyl, n-butyl, isobutyl and tert-butyl;
R3is composed of
Wherein R is4Is H or isopropyl, methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, isopropionyl, formyl, acetyl, n-propionyl, n-butyryl, isobutyryl, tert-butyryl, -CH2OH；R5Is H or C1-C5Straight OR branched chain alkyl, -OR', -halogen, -CN.
More preferred compounds of formula I according to the invention are selected from:
n- (4-Morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- (4-Morpholin-4-yl-phenyl) - (R) -1- [2- ((R) -1-amino-ethyl) -oxazole-4-carbonyl ] -pyrrolidine-2-carboxylic acid amide
N- (4-Morpholin-4-yl-phenyl) - (R) -1- [2- ((S) -1-amino-ethyl) -oxazole-4-carbonyl ] -pyrrolidine-2-carboxylic acid amide
N- (4-morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-thiazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- (4-morpholin-4-yl-phenyl) - (S) -1- (2-aminomethyl-1H-imidazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- (4-Morpholin-4-yl-phenyl) - (S) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [4- (4-methyl-piperazin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [4- (4-hydroxymethyl-piperazin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [4- (4-acetyl-piperazin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [4- (5-hydroxymethyl-isoxazol-3-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [4- (3-methyl-2, 4-dione-imidazolidin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido
N- [4- (piperidin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [ 3-methyl-4- (piperidin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [ 3-chloro-4- (piperidin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [ biphenyl-4-yl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [ 4' -cyano-biphenyl-4-yl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido
N- [ 4' -chloro-biphenyl-4-yl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido
N- [ 4' -acetyl-biphenyl-4-yl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido
N- (4-Morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido hydrochloride
N- (4-Morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamidato oxalate
The compound of the general formula I is synthesized by the following general formula steps:
the starting material VII (aminomethyl 5-membered heteroaromatic 4-carboxylic acid derivative, which can be produced by the method described in patent CN200710057661.8 filed by the present inventors "1, 3-dihetero five-membered ring-containing hydroxamic acid derivative and use thereof") of the present invention was used. In the reactant IV of the synthetic route, part of the compounds are synthesized according to the methods of the prior patents (CN200510015371.8, CN200710057464.6) of the inventor.
The aminomethyl 5-membered aromatic heterocyclic 4-carboxylic acid compound (VI) protected by amino reacts with proline methyl ester in the presence of a catalyst (DCC/HBOt or CDMT/NMM and the like) to obtain a compound V. The compound V is subjected to deesterification to form acid (IV), then condensed with compound III in the presence of a catalyst (DCC/HBOt or CDMT/NMM and the like) to obtain a compound (II), and subjected to deamination protection to obtain a product I.
Wherein: r1、R2、R3As defined above.
The pharmaceutically acceptable salts of the compounds of formula I according to the present invention may contain basic groups depending on the derivative, and may form salts with various inorganic acids (such as, but not limited to, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or organic acids (such as, but not limited to, formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, amino acids, etc.).
The compound of formula I or the pharmaceutically acceptable salt thereof can be prepared into a pharmaceutical composition together with one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition can be made into solid oral preparation, liquid oral preparation, injection, etc. The solid and liquid oral formulations comprise: tablet, dispersible tablet, sugar-coated preparation, granule, dry powder, capsule and solution. The injection comprises: small needle, large infusion solution, lyophilized powder for injection, etc.
The composition of the invention, the pharmaceutically or dietetically acceptable auxiliary materials are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials, or other excipients.
The composition of the invention, and the pharmaceutically or dietetically acceptable auxiliary materials. The filler is one or more of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and microcrystalline cellulose; the adhesive comprises one or a combination of more of sucrose, starch, polyvidone, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, medicinal ethanol and water; the disintegrating agent comprises one or more of starch, cross-linked polyvidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and effervescent disintegrating agent.
The compound of the general formula I or the salt thereof has the anti-tumor effect and the anti-thrombus effect in biological experiments, and can be used as an effective component for preparing medicaments for treating tumor or thrombotic diseases.
The compounds of formula I of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, divided into one or more administrations. The actual dosage of the compounds of formula I to be administered according to the invention can be determined by the physician in the light of the relevant circumstances. These include: the physical state of the subject, the route of administration, the age, body weight, individual response to the drug, severity of the symptoms, and the like.
Detailed Description
The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.
EXAMPLE 1 preparation of (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl ] -pyrrolidine-2-carboxylic acid
VI (2-Cbz-aminomethyl-oxazole-4-carboxylic acid: 1.52g, 5.5mmol) was dissolved in dry THF, 1-hydroxybenzotriazole (0.82g, 6.05mmol) was added, DCC (1.2g, 5.8mmol) was added portionwise at 0 deg.C, allowed to warm to room temperature naturally for 3h, filtered, VII (R) -proline methyl ester was added to the filtrate: 0.71g, 5.5mmol), reaction at room temperature for 7h, filtration, concentration of the filtrate under reduced pressure, and crude separation of the residue on a silica gel column (petroleum ether: ethyl acetate 1: 1) to give 1.23g (v) of a pale yellow solid in 60% yield.
And (3) mixing the product obtained in the previous step: 0.5g in MeOH/H2O (8mL, 1/1), LiOH.H.was added at 0 deg.C2O (150mg, 2.52mmol), warmed to room temperature naturally, followed by TLC detection, 4.5h before completion of the reaction, 20mL of water was added, PH 2 was adjusted with 1N hydrochloric acid, and the mixture was extracted with dichloromethane (15mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 0.4g (iv) of a pale yellow solid.
Examples 2 to 6
The synthetic procedure of reference example 1, with different VI and VII being substituted, gives a different IV.
| VI | VII | IV | |
| Example 2 | 2- ((R) -1-Cbz-amino-ethyl) -oxazole-4-carboxylic acid | (R) -proline methyl ester | (R) -1- [2- ((R) -1-Cbz-amino-ethyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid |
| VI | VII | IV | |
| Example 3 | 2- ((S) -1-Cbz-amino-ethyl) -oxazole-4-carboxylic acid | (R) -proline methyl ester | (R) -1- [2- ((S) -1-Cbz-amino-ethyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid |
| Example 4 | 2-Cbz-aminomethyl-thiazole-4-carboxylic acid | (R) -proline methyl ester | (R) -1- [2- (Cbz-amino-methyl) -thiazole-4-carbonyl]-pyrrolidine-2-carboxylic acid |
| Example 5 | 2-Cbz-aminomethyl-1H-imidazole-4-carboxylic acid | (S) -proline methyl ester | (S) -1- [2- (Cbz-amino-methyl) -1H-imidazole-4-carbonyl]-pyrrolidine-2-carboxylic acid |
| Example 6 | 2-Cbz-aminomethyl-oxazole-4-carboxylic acid | (S) -proline methyl ester | (S) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid |
EXAMPLE 7 preparation of N- (4-morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido
IV (product 1.87g, 5mmol from example 1) and III (4-morpholin-4-yl-aniline: 0.98g, 5.5mmol) were dissolved in THF (20mL), HOBt (0.92mg, 6.8mmol) was added, DCC (1.06g, 5.1mmol) was added under ice bath, the mixture was allowed to warm to room temperature naturally, reacted for 20h, filtered, concentrated under reduced pressure, the residue was dissolved in dichloromethane (30mL), washed with saturated sodium bicarbonate and brine in sequence, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure, and the residue was separated on a silica gel column (petroleum ether: ethyl acetate ═ 3: 1) to give 1.4g (II) of a colorless viscous liquid with a yield of 70%.
Dissolve 0.5g of the product from the previous step in methanol (15mL), add 5% Pd/C145 mg, H at atmospheric pressure2Reducing, checking the reaction of raw materials by TLC after 3h, filtering to remove Pd/C, decompressing and concentrating the filtrate to obtain off-white solid 0.4g (I) and mp148-151 ℃.
Examples 8 to 24
The synthetic procedure of reference example 7, with different IV and III being substituted, gives different I.
| IV | III | I | mp(℃) | |
| Example 8 | (R) -1- [2- ((R) -1-Cbz-amino-ethyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4-morpholin-4-yl-anilines | N- (4-Morpholin-4-yl-phenyl) - (R) -1- [2- ((R) -1-amino-ethyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxamides | 155-157 |
| Example 9 | (R) -1- [2- ((S) -1-Cbz-amino-ethyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4-morpholin-4-yl-anilines | N- (4-Morpholin-4-yl-phenyl) - (R) -1- [2- ((S) -1-amino-ethyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxamides | 149-152 |
| Example 10 | (R) -1- [2- (Cbz-amino-methyl) -thiazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4-morpholin-4-yl-anilines | N- (4-morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-thiazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 165-167 |
| Example 11 | (S) -1- [2- (Cbz-amino-methyl) -1H-imidazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4-morpholin-4-yl-anilines | N- (4-morpholin-4-yl-phenyl) - (S) -1- (2-aminomethyl-1H-imidazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 177-179 |
| Example 12 | (S) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4-morpholine-4-yl-anilines | N- (4-Morpholin-4-yl-phenyl) - (S) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 141-144 |
| Example 13 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4- (4-methyl-piperazin-1-yl) -aniline | N- [4- (4-methyl-piperazin-1-yl) -phenyl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 168-170 |
| IV | III | I | mp(℃) | |
| Example 14 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4- (4-hydroxymethyl-piperazin-1-yl) -aniline | N-[4- (4-hydroxymethyl-piperazin-1-yl) -phenyl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 185-187 |
| Example 15 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4- (4-acetyl-piperazin-1-yl) -aniline | N- [4- (4-acetyl-piperazin-1-yl) -phenyl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 177-179 |
| Example 16 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4- (5-hydroxymethyl-isoxazol-3-yl) -phenylamine | N- [4- (5-hydroxymethyl-isoxazol-3-yl) -phenyl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 165-167 |
| Examples | (R) -1- [2- (Cbz-amino- | 4- (3-methyl) | N- [4- (3-methyl-2, 4-dione-imidazole) | 187-190 |
| 17 | Methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | -2, 4-dione-imidazolidin-1-yl) -aniline | Alk-1-yl) -phenyl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | |
| Example 18 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4-piperidin-1-yl-anilines | N- [4- (piperidin-1-yl) -phenyl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 137-139 |
| IV | III | I | mp(℃) | |
| Example 19 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4- (piperidin-1-yl) -3-methyl-anilines | N- [ 3-methyl-4- (piperidin-1-yl) -phenyl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 146-149 |
| Example 20 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 3-chloro-4-piperidin-1-yl-anilines | N- [ 3-chloro-4- (piperidin-1-yl) -phenyl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 141-145 |
| Example 21 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4-aminobiphenylene | N- [ biphenyl-4-yl]- (RR) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 127-129 |
| Example 22 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4' -cyano-4-aminobiphenyl | N- [ 4' -cyano-biphenyl-4-yl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 133-137 |
| Example 23 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4' -chloro-4-aminobiphenyl | N- [ 4' -chloro-biphenyl-4-yl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 141-144 |
| Example 24 | (R) -1- [2- (Cbz-amino-methyl) -oxazole-4-carbonyl]-pyrrolidine-2-carboxylic acid | 4' -acetyl-4-aminobiphenyl | N- [ 4' -acetyl-biphenyl-4-yl]- (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide | 137-139 |
Example 25
0.2 g of the product obtained in example 7 was taken, an appropriate amount of hydrochloric acid (1mol/L) was added thereto, the mixture was dissolved by gentle heating, an equal volume of anhydrous ethanol was added thereto, the mixture was allowed to stand and sufficiently crystallized, and N- (4-morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamide hydrochloride was collected.
Example 26
0.2 g of the product obtained in example 7 was taken, an appropriate amount of oxalic acid (1mol/L) solution was added thereto, the mixture was dissolved by gentle heating, and an equal volume of anhydrous ethanol was added thereto, followed by standing, and sufficient crystallization was carried out to collect N- (4-morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamidato oxalate.
Example 27
Dosage/tablet
Example 7 sample 100mg
Microcrystalline cellulose 100mg
Pregelatinized starch 45mg
Polyvinylpyrrolidone 3mg
Carboxymethyl starch sodium salt 5mg
Magnesium stearate 1mg
Talcum powder 1mg
Sieving active ingredients, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft mass, sieving, making wet granule, drying at 50-60 deg.C, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci, adding into the above granule, and tabletting.
Example 28
Dosage/granule
Example 16 sample 50mg
Microcrystalline cellulose 60mg
Pregelatinized starch 45mg
Polyvinylpyrrolidone 3mg
Magnesium stearate 2mg
Talcum powder 1mg
Sieving active ingredients, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft material, sieving, making wet granule, drying at 50-60 deg.C, sieving magnesium stearate and pulvis Talci, adding into the above granule, and making into capsule.
Example 29
The dosage is 50ml
Example 25 sample 100mg
Citric acid 100mg
Appropriate amount of NaOH (adjusting pH to 4.0-5.0)
50ml of distilled water
Adding distilled water and citric acid into distilled water, stirring for dissolving, adding sample, slightly heating for dissolving, adjusting pH to 4.0-5.0, adding 0.2 g of activated carbon, stirring at room temperature for 20min, filtering, measuring solution concentration by central control, packaging at 2 ml per ampoule, and sterilizing at high temperature for 30min to obtain injection.
Example 30
(1) Material
Cell lines: leukemia HL-60 cells, gastric adenocarcinoma SGC-7901 cells, breast cancer MCF-7 cells and lung cancer A-549 cells, which are all purchased from Shanghai cell research institute of Chinese academy of sciences.
Reagent: MTT, Amresco split, batch No.: 04M 0904; DMEM medium, Gibco, lot number: 1290007, respectively; calf serum, lakehou marine life, lot number: 20080218, respectively; trypsin, Amresco dispensed, batch No.: 016B 0604; fluorouracil injection, 0.25g/10ml (ramus), tianjin jin Yao amino acids Limited, lot number: 0512022.
the instrument comprises the following steps: clean bench, Suzhou clean plant; CO 22Incubator, Thermo corporation, model: HERA Cell 150; inverted microscope, Carl Zeiss, type: axiovert 200; enzyme linked immunosorbent assay, TECAN, type: sunrise; centrifuge, Kerdro corporation, model: heraeus.
(2) Method of producing a composite material
Cell culture: tumor cells were inoculated into 10% calf serum, 100IU/ml penicillin G sodium saltAnd 100ug/ml streptomycin sulfate in DMEM culture solution at 37 deg.C and 100% relative humidity and containing 5% CO2The culture box of (5), passage 3 times for standby.
Determination by MTT method: cells in logarithmic growth phase are taken, digested by 0.25% trypsin (suspension cells are not required to be digested), suspended in DMEM culture solution containing 10% calf serum, slightly blown by a glass dropper to form single cell suspension, and counted by a blood cell counting plate under a microscope. The 96-well culture plate was inoculated with 90. mu.l of cell suspension per well (cell concentration was adjusted to 6 to 8X 10)4Pieces/ml) at 37 deg.C, 100% relative humidity, 5% CO2After 24 hours of incubation in a 95% air incubator, 10. mu.l of the drug solution (final concentration: 20. mu.g/ml) was added to each well. In addition, each concentration was set with a negative control (equal concentration of DMSO) and a blank background (no cells added), and each group was set with 6 replicate wells. The culture was continued for another 48h, then 10. mu.l of 5mg/ml MTT solution was added to each well and after further 4h of culture, the supernatant was carefully aspirated (suspension cells, centrifugation was required before aspiration of the supernatant). Add 100. mu.l DMSO into each well, shake in a micro-oscillator to dissolve the crystal completely, and test OD value by single-wavelength colorimetry with a 492nm microplate reader. The cell growth inhibition rate was calculated as an evaluation index in the following manner.
The inhibition ratio (%) was [1- (experimental OD mean-blank OD mean)/(control OD mean-blank OD mean) ] × 100%.
(3) Results
Inhibition ratio (%) of sample (concentration 20. mu.g/ml) to in vitro cultured tumor cells
(4) Conclusion
From the results of the in vitro tests, it can be seen that the compound of the general formula I has certain inhibition effect on 3 human cancer cells after being acted for 48 hours in vitro at the concentration of 20 mu g/ml.
Example 31
Wistar rats with the weight of 200-220 g are taken, the rats are randomly grouped according to the weight, 6 rats are taken in each group, males are subjected to intragastric administration, 1 time is taken every day for 3 times, 30min after the last administration, 3% sodium pentobarbital is injected into the abdominal cavity of the rats for 35mg/kg of anesthesia, the rats are fixed in a supine mode, the skin of the neck is cut, the left carotid artery and the right external jugular vein are separated and connected with a bypass pipe, and a No. 4 surgical silk thread with the length of 7cm is placed in the pipe. And (4) after the operation is finished, opening the blood flow for 20min, then taking out the silk thread, weighing, and subtracting the weight of the silk thread to obtain the wet weight of the thrombus. The mean and standard deviation of each experimental group were calculated and compared with the saline group using the t-test.
Effect of samples on thrombosis
*: compared with the model group, p is less than 0.05.
The result shows that the compound of the general formula I has obvious antithrombotic activity.
Claims (8)
1. Compound with general formula I or pharmaceutically acceptable salt thereof, and synthesis method and application thereof
Wherein,
Y＝O、NH、S；
R1is H, contains C1-C4Linear or branched alkyl of (a);
R2is H or C1-C5Straight OR branched alkyl, -OR ', -SR', -halogen, -CN, -NHCOR ', -N (R')2、-NO2A substituent group such as-COOR ', CONR ', and the like, wherein R ' is H, C1-C5Linear or branched alkyl of (a);
R3is composed of
Wherein R is4Is H or C1-C5Straight or branched alkyl, C1-C5Acyl group, -CH, linked to a linear or branched alkyl group of2OH；R5Is H or C1-C5Straight OR branched chain alkyl, -OR', -halogen, -CN.
The compound of the general formula I contains one or two chiral centers, can generate two or four optical isomers, and the invention comprises any optical isomer and diastereoisomer mixture thereof.
2. A compound of the general formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, wherein,
Y＝O、NH、S；
R1comprises the following steps: H. isopropyl, methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl;
R2is H or C1-C5Straight OR branched alkyl, -OR ', -SR', -halogen, -CN, -NHCOR ', -N (R')2、-NO2Substituent groups such as-COOR ' and CONR ', wherein R ' is H, isopropyl, methyl, ethyl, n-propyl, n-butyl, isobutyl and tert-butyl;
R3is composed of
Wherein R is4Is H or isopropyl, methyl, ethyl, n-propyl, n-butyl, isobutyl, tert-butyl, isopropionyl, formyl, acetyl, n-propionyl, n-butyryl, isobutyryl, tert-butyryl, -CH2OH；R5Is H or C1-C5Straight OR branched chain alkyl, -OR', -halogen, -CN.
3. A compound of general formula I as defined in claim 2, or a pharmaceutically acceptable salt thereof, selected from:
n- (4-Morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- (4-Morpholin-4-yl-phenyl) - (R) -1- [2- ((R) -1-amino-ethyl) -oxazole-4-carbonyl ] -pyrrolidine-2-carboxylic acid amide
N- (4-Morpholin-4-yl-phenyl) - (R) -1- [2- ((S) -1-amino-ethyl) -oxazole-4-carbonyl ] -pyrrolidine-2-carboxylic acid amide
N- (4-morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-thiazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- (4-morpholin-4-yl-phenyl) - (S) -1- (2-aminomethyl-1H-imidazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- (4-Morpholin-4-yl-phenyl) - (S) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [4- (4-methyl-piperazin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [4- (4-hydroxymethyl-piperazin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [4- (4-acetyl-piperazin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [4- (5-hydroxymethyl-isoxazol-3-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [4- (3-methyl-2, 4-dione-imidazolidin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido
N- [4- (piperidin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [ 3-methyl-4- (piperidin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [ 3-chloro-4- (piperidin-1-yl) -phenyl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [ biphenyl-4-yl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide
N- [ 4' -cyano-biphenyl-4-yl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido
N- [ 4' -chloro-biphenyl-4-yl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido
N- [ 4' -acetyl-biphenyl-4-yl ] - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido
N- (4-Morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxamido hydrochloride
N- (4-morpholin-4-yl-phenyl) - (R) -1- (2-aminomethyl-oxazole-4-carbonyl) -pyrrolidine-2-carboxylic acid amide oxalate.
4. A process for the synthesis of a compound of general formula I according to any one of claims 1 to 3, comprising the steps of:
the aminomethyl 5-membered aromatic heterocyclic 4-carboxylic acid compound (VI) protected by amino reacts with proline methyl ester in the presence of a catalyst (DCC/HBOt or CDMT/NMM and the like) to obtain a compound V. The compound V is subjected to deesterification to form acid (IV), then condensed with compound III in the presence of a catalyst (DCC/HBOt or CDMT/NMM and the like) to obtain a compound (II), and subjected to deamination protection to obtain a product I.
Wherein: r1、R2、R3As defined above.
5. Use of a compound of general formula I as defined in claims 1 to 3 or a pharmaceutically acceptable salt thereof for the preparation of anti-tumour and anti-thrombotic medicaments.
6. A pharmaceutical composition comprising a compound of general formula I according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, together with a suitable carrier or excipient.
7. The pharmaceutical composition of claim 6, wherein the composition is a solid oral preparation, a liquid oral preparation or an injection.
8. The solid and liquid oral formulation of claim 7 comprising: the injection preparation comprises injection water injection, injection freeze-dried powder injection, large infusion and small infusion.
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