CN114105910B - Hydroxycarbamimidoyl phenylalanine derivative, pharmaceutical composition and application - Google Patents

Hydroxycarbamimidoyl phenylalanine derivative, pharmaceutical composition and application Download PDF

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CN114105910B
CN114105910B CN202111290730.6A CN202111290730A CN114105910B CN 114105910 B CN114105910 B CN 114105910B CN 202111290730 A CN202111290730 A CN 202111290730A CN 114105910 B CN114105910 B CN 114105910B
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compound
salt
pharmaceutical composition
tumor
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CN114105910A (en
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宋更申
魏俊明
刘兆国
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Beijing Youcare Kechuang Pharmaceutical Technology Co ltd
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Beijing Youcare Kechuang Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The present invention relates to a hydroxyamidino phenylalanine derivative or its salt, a pharmaceutical composition containing it and its use in medicine. The hydroxycarbamimidoyl phenylalanine derivative is a compound shown in the following structural formula I, wherein R is C1-6 straight-chain or branched-chain alkyl, cycloalkyl, heterocyclic group or aromatic group. Compared with the existing amidine urokinase inhibitor, the compound has obviously improved water solubility and enhanced stability, and has equivalent tumor inhibition activity as the existing inhibitor. The medicine prepared by using the compound can be used for treating and preventing tumors and treating and preventing tumor metastasis.

Description

Hydroxycarbamimidoyl phenylalanine derivative, pharmaceutical composition and application
Technical Field
The invention belongs to the field of medicines, and in particular relates to a hydroxyamidino phenylalanine derivative or a salt thereof, a pharmaceutical composition containing the same and application of the same in medicine.
Background
Urokinase-type plasminogen activator (uPA) is a serine protease in the trypsin/chymotrypsin family, a multifunctional protease that degrades extracellular matrix and basement membrane components such as laminin, fibronectin, fibrinogen, type IV collagen by directly or indirectly activating matrix metalloproteinases. Active uPA plays an important role in a range of physiological and pathological processes. Urokinase in tumor tissue specifically activates plasminogen to plasmin, thereby promoting degradation of extracellular matrix and basement membrane components such as fibrin, fibronectin, laminin, etc., which ultimately lead to tumor cell development, invasion and metastasis.
As early as 1978 scientists discovered a close relationship of uPA with tumors that play an important role in the growth of tumors (e.g., breast, stomach, bowel, pancreas, ovary, and other solid tumors, etc.). The main inhibition target of the uPA inhibitor is a uPA serine protease fragment, and the uPA inhibitor can block the metastasis of tumors and reduce the growth of the tumors by inhibiting a uPA system.
CN1265645a discloses an aryl amidine uPA inhibitor, the IC50 of this class of compounds for urokinase inhibition is in the order of μm. CN1795183B discloses that hydroxyamidine and hydroxyguanidine compounds as uPA inhibitors have improved bioavailability. However, these inhibitors have been reported to have low solubility in water and poor stability, which is disadvantageous for the preparation of the drug.
Thus, there is an urgent need in the art for new uPA inhibitors that can have improved solubility and stability in water, reduce hydrolysis and oxidation, and thereby meet the need for preparing pharmaceuticals.
Disclosure of Invention
In this regard, the present application addresses this problem. The present application provides a novel uPA inhibitor with improved solubility and stability in water, reduced hydrolysis and oxidation, and capable of meeting the need for preparing a drug. Meanwhile, the inhibitor has the tumor inhibition activity equivalent to that of the existing inhibitor. Therefore, can be used for preparing medicines for treating and preventing tumors and tumor metastasis.
The application provides a compound or salt thereof with a structure shown as a general formula I:
wherein R is selected from C1-6 straight chain or branched alkyl, cycloalkyl, heterocyclic group or aromatic group.
In one embodiment, in a compound or salt of the present application, the R is selected from any one of the following: c1-4 straight-chain or branched-chain amino substituted alkyl, amino substituted cycloalkyl, nitrogen-containing heterocyclic group or nitrogen-containing heteroaromatic group.
In one embodiment, R is selected from any one of the following: c1-4 straight-chain amino substituted alkyl, six-membered nitrogen-containing heterocyclic group or six-membered nitrogen-containing heteroaromatic group.
In a preferred embodiment, in a compound or salt of the present application, the R is selected from any one of the following: ethylamino, piperazino, pyrazino.
In another embodiment, in a compound or salt of the present application, the salt is selected from inorganic salts or organic salts.
Preferably, the inorganic salt is selected from any one of the following: hydrochloride, hydrobromide, phosphate, sulfate or bisulfate; the organic salt is selected from any one of the following: acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, citrate, maleate, tartrate, fumarate, citrate or lactate.
Further preferably, the inorganic salt is selected from bisulfate or hydrochloride.
In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application or a salt thereof, and a pharmaceutically acceptable carrier.
In a preferred embodiment, in the pharmaceutical compositions of the present application, the pharmaceutical compositions are formulated in the form of tablets, capsules, granules, emulsions, solutions, oral suspensions and injections.
In another aspect, the application also provides the use of the compound or salt thereof, a pharmaceutical composition for the preparation of a medicament for the treatment of urokinase related diseases.
In another aspect, the present application also provides the use of a compound or a salt thereof, a pharmaceutical composition for the manufacture of a medicament for the treatment and prevention of tumors and the treatment and prevention of tumor metastases.
According to the above use, the tumor is breast cancer or pancreatic cancer.
In a preferred embodiment, there is also provided a process for the preparation of a compound of formula I or a salt thereof by reacting compound D after bromination with a compound substituted with an R group;
preferably, R is selected from any one of C1-6 straight-chain or branched alkyl, cycloalkyl, heterocyclic or aryl;
preferably, the R is selected from any one of the following: c1-4 straight-chain or branched-chain amino substituted alkyl, amino substituted cycloalkyl, nitrogen-containing heterocyclic group or nitrogen-containing heteroaromatic group;
preferably, the R is selected from any one of the following: c1-4 straight-chain amino substituted alkyl, six-membered nitrogen-containing heterocyclic group or six-membered nitrogen-containing heteroaromatic group;
preferably, the R is selected from any one of the following: ethylamino, piperazino, pyrazino;
the structural formula of the compound D is as follows:
the hydroxycarbamimidoyl phenylalanine derivative or the salt thereof provided by the invention has the advantages that at least the following are provided:
1) The pharmaceutically acceptable salt of the inhibitor has remarkably enhanced water solubility, which is about 5-10 times that of the existing amidine type uPA inhibitor;
2) The stability to water and oxygen is enhanced, and the hydrolysis and oxidation are reduced;
3) Has the tumor inhibition activity equivalent to that of the existing uPA inhibitors of the same type, and has definite curative effect on tumors.
Detailed Description
The invention will be described in further detail with reference to the following examples.
Preparation example 1:
the compound was prepared and bisulfate salt was prepared by the synthetic method of example 1 (preparation of WX-671) with reference to patent CN1795183B to give 19.6g of Compound D in total.
Preparation example 2
The compound was prepared and the hydrochloride salt was prepared by the synthetic method of example 1, see patent CN 100369906C, giving 18.2g of compound E in total. Compounds D and E are representative prior aryl amidine uPA inhibitors of the same type, and have good inhibitory activity and tumor inhibitory activity on urokinase.
Example 1: preparation of the Compounds
3-aldehyde phenylalanine is used as a starting material to react with triisopropylbenzene sulfonyl chloride to obtain the sulfonamide compound. And then, using DCC/HOBt as a condensing agent to condense with ethoxycarbonyl piperazine. Then reacts with hydroxylamine to obtain an oximido compound, bromides are obtained through bromination, and the bromides respectively react with ethylenediamine, 2-aminopiperazine and 2-aminopyrazine to obtain compounds A, B and C. Compound A was prepared as a hydrogen sulfate white solid in accordance with the method in preparation example 1, 18.8g, compound B was prepared as a hydrochloride white solid in accordance with the method in preparation example 2, 19.2g, and compound C was prepared as a hydrochloride white solid in accordance with the method in preparation example 2, 19.5g.
Example 2: preparation of compound capsule
The preparation process comprises the following steps: weighing the compound, silicon dioxide, sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate according to the prescription amount respectively, and uniformly mixing; and filling into capsules to obtain the final product.
The formulation of the capsules is shown in table 1 below:
TABLE 1 content of various ingredients (10000 grains) for preparing capsules
Test example 1: water solubility test of Compounds
The solubility of each compound in water was determined according to conventional methods. The results are shown in Table 2.
Table 2 solubility of various compounds in water
Experimental results show that the series of compounds have good water solubility after salification, and the solubility is about 5-10 times that of the hydrogen sulfate salt and the hydrochloride salt of the compound D and the compound E disclosed in the prior art.
Test example 2: stability test of Compounds
Preparing a detection liquid: 10mg of each of the hydrogen sulfate salt of the compound A, the hydrogen sulfate salt of the compound B, the hydrogen sulfate salt of the compound C, the hydrogen sulfate salt of the compound D and the hydrogen chloride salt of the compound E was weighed, dissolved in 100mL of purified water, adjusted to pH7 with a 0.01mol/L sodium hydroxide solution, left at room temperature for 72 hours, and then detected.
And (3) detection: and (3) shaking the detection liquid uniformly, taking the detection liquid into a 25mL Nahner colorimetric tube, and comparing the color of the detection liquid tube with that of the standard colorimetric liquid tube by looking up under the condition that the detection liquid is placed on a white background with orange-yellow color tone No. 1-10 of the standard colorimetric liquid of 2015 of Chinese pharmacopoeia.
The test results are shown in table 3 below:
TABLE 3 determination of stability of various Compounds
Conclusion:
as can be seen from Table 3, compounds D and E were darker than compounds A, B and C, with corresponding color numbers 1 to 3 higher, indicating more degradation impurities were generated after 72h of room temperature standing at pH7 of the aqueous solution. This experiment shows that compounds A, B and C are more stable to water and oxygen than D and E. Test example 3: in vivo assay of uPA inhibitors for mouse tumor diffusion, tumor growth and tumor metastasis
Human breast cancer cells MCF-7 are inoculated under the skin of BALB/cA NUDE mice, and MCF-7 mice transplantation tumor is obtained. After 3 passages of continuous transmission, tumor tissue shear blocks in the vigorous growth period are taken and inoculated under the right armpit skin of the mice under the aseptic condition. The modeled mice were randomly divided into 6 groups of 8 mice after 72h inoculation. Mice were weighed and dosed by gavage at 1 mg/kg. Blank group is capsule without uPA inhibitor, control group 1 and 2 are capsule containing compound D and E, test group 1-3 are capsule containing compound A, B and C respectively. Mice were sacrificed 30 days later, tumor masses were peeled off, and the metastasis was observed, and tumor masses were weighed.
Tumor inhibition was calculated as average tumor weight. Tumor inhibition rate = [ (average tumor weight in blank group-average tumor weight in control group (or test group)/average tumor weight in blank group ] ×100%).
The test results are shown in table 4 below:
TABLE 4 inhibition of MCF-7 mouse transplantable tumors by various capsules
Conclusion:
as can be seen from table 4, at the end of treatment in the breast tumor model, the average tumor weight of the test group was reduced by more than 50% compared to the blank group, the effect of inhibiting tumor was comparable to that of the control groups 1 and 2, and no tumor metastasis was observed in other organs. The experiment shows that the effect of inhibiting the growth and diffusion of the tumor in the experimental group is equivalent to that of the amidine uPA inhibitor known in the prior art, has stronger tumor inhibiting effect, can inhibit the diffusion of the tumor, and can be used for preparing medicaments for treating or preventing the tumor or the tumor.
Finally, it should be noted that: the above embodiments are only for illustrating the technical scheme of the present invention, and are not limited thereto. Although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
The present invention is not to be limited in scope by the specific embodiments described herein, which are for illustrative purposes only. Functionally equivalent products, compositions and methods are clearly within the scope of the invention as described herein.

Claims (10)

1. A compound having a structure according to formula I:
wherein R is selected from any one of the following: ethylamino, piperazino, pyrazino.
2. The compound of claim 1, or a salt thereof, wherein the salt is selected from an inorganic salt or an organic salt.
3. The compound according to claim 2, or a salt thereof, wherein the inorganic salt is selected from any one of the following: hydrochloride, hydrobromide, phosphate, sulfate or bisulfate; the organic salt is selected from any one of the following: acetate, trifluoroacetate, methanesulfonate, p-toluenesulfonate, citrate, maleate, tartrate, fumarate or lactate.
4. A compound according to claim 3, or a salt thereof, wherein the salt is selected from bisulphate or hydrochloride.
5. A pharmaceutical composition comprising as claimed inA compound of any one of the claims, or a salt thereof, and a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is in the form of a formulation comprising a tablet, capsule, granule, emulsion, solution, oral suspension, and injection.
7. Claim and claimA compound according to any one of the claims->Use of a pharmaceutical composition according to any one of the claims for the preparation of a medicament for the treatment of urokinase related diseases.
8. Claim and claimA compound according to any one of the claims->Use of the pharmaceutical composition of any one of the above in the manufacture of a medicament for the treatment and prevention of tumors and the treatment and prevention of tumor metastases.
9. The use according to claim 8, wherein the tumor is breast or pancreatic cancer.
10. The process for producing a compound of formula I or a salt thereof according to claim 1, wherein the process comprises: 3-aldehyde phenylalanine is used as a starting material to react with triisopropylbenzene sulfonyl chloride to obtain a sulfonamide compound; then, using DCC/HOBt as condensing agent to condense with ethoxycarbonyl piperazine; then reacts with hydroxylamine to obtain an oximido compound, and bromides are obtained by bromination, and react with ethylenediamine, 2-aminopiperazine and 2-aminopyrazine respectively.
CN202111290730.6A 2021-11-02 2021-11-02 Hydroxycarbamimidoyl phenylalanine derivative, pharmaceutical composition and application Active CN114105910B (en)

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CN115192564B (en) * 2022-05-23 2023-11-17 四川大学华西医院 Phenylalanine derivative, pharmaceutical composition and application thereof in tumor treatment

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1639142A (en) * 2002-02-28 2005-07-13 彭特法姆股份公司 Method for producing 3-amidinophenylalanine derivatives
CN1795183A (en) * 2003-05-26 2006-06-28 威丽克斯股份公司 Hydroxyamidine and hydroxyguanidine compounds as urokinase inhibitors
CN102796140A (en) * 2012-08-21 2012-11-28 天津药物研究院 Phosphate-containing isoxazoline derivatives and their preparation method and use

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1639142A (en) * 2002-02-28 2005-07-13 彭特法姆股份公司 Method for producing 3-amidinophenylalanine derivatives
CN1795183A (en) * 2003-05-26 2006-06-28 威丽克斯股份公司 Hydroxyamidine and hydroxyguanidine compounds as urokinase inhibitors
CN102796140A (en) * 2012-08-21 2012-11-28 天津药物研究院 Phosphate-containing isoxazoline derivatives and their preparation method and use

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