CN102040627A - Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity - Google Patents
Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity Download PDFInfo
- Publication number
- CN102040627A CN102040627A CN2009101862743A CN200910186274A CN102040627A CN 102040627 A CN102040627 A CN 102040627A CN 2009101862743 A CN2009101862743 A CN 2009101862743A CN 200910186274 A CN200910186274 A CN 200910186274A CN 102040627 A CN102040627 A CN 102040627A
- Authority
- CN
- China
- Prior art keywords
- contained compound
- deuterium
- treatment
- group
- phosphorus
- 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.)
- Pending
Links
- 0 *C(*)(C(*)(*)O)[n]1c(S)nc(*)c1* Chemical compound *C(*)(C(*)(*)O)[n]1c(S)nc(*)c1* 0.000 description 5
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity. Compared with bisphosphonates of existing structures, the compound in the invention can decrease oxidative metabolism, and increase the effective bioavailability. In addition, applying the compound for treatment of bone metabolism abnormity, can reduce the dosage and side effects. The phosphorus-containing compound in the invention is especially suitable for the treatment of hypercalcemia diseases.
Description
Technical field
The invention belongs to the pharmaceutical compound field, particularly a kind of P contained compound, its preparation method and the application in preparation abnormal bone metabolism medicine.
Background technology
Metastatic bone lesions is the modal severe complication of cancer patients, and 80% multiple myeloma patients is arranged, 70% mammary cancer and patients with prostate cancer generation metastatic bone lesions.According to different tumor type, patient's median survival time take place behind the metastatic bone lesions be not wait in 6～48 months.Bone photos such as the ostalgia that metastatic bone lesions causes, pathologic fracture, hypercalcemia, spinal compression close incident and bring great misery to the patient, have a strong impact on patient's quality of life.
In the prior art, the most frequently used medicine of treatment metastatic bone lesions is two phosphonic acids (salt).Two phosphonic acids (salt) are the organic synthesis compounds that similar natural coke phosphonic one class has unique biological Mars, comprise the structure that two phosphonyl groups form " P-C-P " on the central carbon atom, therefore can resist the effect of lytic enzyme in the body, be efficient bone resorption inhibitor.The two phosphonic acids of a new generation, " Zoledronic acid " treatment malignant tumour metastatic bone lesions has stronger effect, has become a clinical generation and has selected." Zoledronic acid " has that very strong potency, long action time, dosage are little, patient tolerates easily, is the more satisfactory treatment hypercalcemia and the medicine of metastatic bone lesions.This medicine can reduce cancer patient bone and soft tissue metastasis rate, can be used for assisting therapy metastatic bone lesions cancer patient, to alleviate the danger of hypercalcemia, ostalgia and fracture, also can be used for delaying the generation of metastatic bone lesions, its mechanism of action is to suppress bone resorption and the release or the anticancer that reduce bone an aromatic plant metioned in ancient books matter somatomedin adheres to bone an aromatic plant metioned in ancient books matter.
Though two phosphonic acids (salt) are the active drugs of existing treatment metastatic bone lesions, but two phosphonic acids (salt) have more side effect as a kind of intravenous administration clinical, comprise: heating, flu-like symptom, arthrodynia, myalgia, hypocalcemia, also have renal insufficiency in addition, the latter and dosage, amount of infusion, transfusion frequency are relevant.Therefore, need the researchist further the bisphosphonates compound structure to be optimized, improve its drug effect and pharmacokinetics and metabolism performance.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, and a kind of P contained compound of texture improvement is provided, and this P contained compound is used for the treatment of metastatic bone lesions and has higher drug effect, more excellent pharmacokinetics and metabolism performance.
For solving above technical problem, the present invention takes following technical scheme:
A kind of P contained compound with general formula (I):
Wherein, R
1, R
2In at least one be phosphine ester group or phosphono, another is a phosphonate group, phosphine ester group or phosphono R
3, R
4, R
5, R
6, R
7Be hydrogen or deuterium individually.
According to an aspect of the present invention, R
1, R
2In at least one be the group of general formula (II) expression:
In the general formula, R
1', R
2' be that hydrogen or deuterium M, L are O or NR individually
3', R
3' be hydrogen or deuterium; N is the integer between the 1-5, is preferably 2 or 3, wherein representational compound for example: a kind of in the following compounds:
According to another aspect of the invention, R
1, R
2In at least one be the group of general formula (III) expression:
Wherein, R
4', R
5' be OR individually
6' or NR
7' R
8', R
6', R
7', R
8' be C individually
1-6Straight or branched fat alkane base or their deuterium for thing; C
1-4Alkoxyl group, the methylene radical of carbonyl substituted or their deuterium are for thing.
Wherein, representational P contained compound has
Deuterium described in the present invention has represented for thing that all or part of hydrogen is the compound of its isotropic substance deuterium (D) in the compound, for example-and CH
2CH
3Deuterium for thing can be-CD
2CD
3,-CD
2CH
3Or-CH
2CD
3
Owing to take technique scheme, the present invention compared with prior art has following advantage:
P contained compound of the present invention is used for the treatment of metastatic bone lesions and has higher drug effect, more excellent pharmacokinetics and metabolism performance, has the advantage that using dosage is little, side effect is little.
Embodiment
Below the specific embodiment of the present invention is described, but be not limited to these embodiment.
Embodiment 1
A kind of P contained compound, chemical name is: two-1,3-two ethanedioyl-2,2-two deuterium generation-1-hydroxyl-2-(1H-imidazoles-1-ester) ethane-1,1-diester bisphosphate, its structural formula is as follows:
Above-mentioned P contained compound can prepare as follows:
(1), in 2-(1H-imidazoles-1-ester) acetate and deuterated methanol, add salt of wormwood, stirred 18 hours under the room temperature, be concentrated into dried.Resistates is dissolved in the ethyl acetate, water and saturated common salt water washing successively, anhydrous sodium sulfate drying filters, and concentrates and obtains 2-(1H-imidazoles-1-ester)-two deuteriums for acetate (intermediate 1-1).
(2), stir and to drip phosphorus trichloride down to the suspension of intermediate 1-1 and methylsulfonic acid (98-99%) in, add water, 55 ℃ of following back flow reaction 12 hours, reaction solution was cooled to 10 ℃ and also slowly adds water.Reaction solution at 3 hours internal heating to 105-112 ℃.Reaction solution is cooled to room temperature, filters, and transfers pH to 0.25 with sodium hydroxide solution (50%W/V).The cooling reaction solution filters to 0-5 ℃, water and methanol wash secondary successively, and 50-60 ℃ of following drying obtains 2,2-two deuterium generation-1-hydroxyl-2-(1H-imidazoles-1-ester) ethane-1,1-diester bisphosphate (intermediate 1-2).
(3), under 0 ℃, to intermediate 1-2, slowly add 1 in the mixed solution of triethylamine and pyridine, 3-propylene dichloride, reaction solution are back to room temperature and at room temperature stirred 18 hours, are concentrated into dried.Resistates is dissolved in the ethyl acetate, uses dilute hydrochloric acid (1M) successively, saturated sodium carbonate, water and saturated common salt water washing.Anhydrous sodium sulfate drying filters, and concentrates and promptly gets product.
Said process is expressed as follows with chemical equation:
Embodiment 2
A kind of P contained compound, chemical name is: tetramethyl-[1-hydroxyl-2-(1H-imidazoles-1-ester)-2,2-two deuterium generation-ethane-1,1-diester) bisphosphate, can prepare by the following method:
Under 0 ℃, to 2,2-two deuterium generation-1-hydroxyl-2-(1H-imidazoles-1-ester) ethane-1,1-diester bisphosphate slowly adds methyl-iodide in the mixed solution of triethylamine and pyridine, and reaction solution is back to room temperature and at room temperature stirred 4 hours, is concentrated into dried.Resistates is dissolved in the ethyl acetate, uses dilute hydrochloric acid (1M) successively, saturated sodium carbonate, water and saturated common salt water washing.Anhydrous sodium sulfate drying filters, and concentrates and promptly gets product.
Embodiment 3
A kind of P contained compound, chemical name is: 2-(1H-imidazoles-1-ester)-1,1-two (2-oxidation-1,3,2-endoxan-2-ester)-2,2-ethanol can prepare by the following method:
Under 0 ℃, to 2,2-two deuterium generation-1-hydroxyl-2-(1H-imidazoles-1-ester) ethane-1,1-diester bisphosphate slowly adds phosphorus oxychloride in the mixed solution of triethylamine and pyridine, and reaction solution is back to room temperature and at room temperature stirred 1 hour.Cooling reaction solution to 0 ℃ slowly adds the 3-aminopropanol, is back to room temperature, stirs 1 hour; Add water, stirred 1 hour, be concentrated into dried.Resistates is dissolved in the ethyl acetate, uses dilute hydrochloric acid (1M) successively, saturated sodium carbonate, water and saturated common salt water washing.Anhydrous sodium sulfate drying filters, and concentrates and obtains product.
Embodiment 4
A kind of P contained compound, chemical name is: dimethyl N, N '-1-hydroxyl-2-(1H-imidazoles-1-ester)-2,2-two deuterium generation-ethane-1,1-diester) two (N-methyl phosphamides), can prepare by the following method:
Under 0 ℃, to 2,2-two deuterium generation-1-hydroxyl-2-(1H-imidazoles-1-ester) ethane-1 slowly adds methyl-iodide (0.5eq) in the mixed solution of 1-diester bisphosphate and acetone, and reaction solution is back to room temperature and at room temperature stirred 4 hours, is concentrated into dried.Resistates is dissolved in the pyridine, filters.Be cooled to 0 ℃, add triethylamine and phosphorus oxychloride successively, be back to room temperature, stirred 1 hour.Add ethamine, stirred 1 hour, be concentrated into dried.Resistates is dissolved in the ethyl acetate, uses dilute hydrochloric acid (1M) successively, saturated sodium carbonate, water and saturated common salt water washing.Anhydrous sodium sulfate drying filters, and concentrates the P contained compound that obtains present embodiment.
More than the present invention has been done detailed description; its purpose is to allow the personage that is familiar with this art can understand content of the present invention and is implemented; can not limit protection scope of the present invention with this; all equivalences of doing according to spirit of the present invention change or modify, and all should be encompassed in protection scope of the present invention.
Claims (8)
1. the P contained compound that has general formula (I):
Wherein, R
1, R
2In at least one be phosphine ester group or phosphono, another is a phosphonate group, phosphine ester group or phosphono; R
3, R
4, R
5, R
6, R
7Be hydrogen or deuterium individually.
2. P contained compound according to claim 1 is characterized in that: R
1, R
2In at least one group of representing for logical formula II:
In the general formula, R
1', R
2' be hydrogen or deuterium; M, L are O or NR individually
3', R
3' be hydrogen or deuterium; N is the integer between the 1-5.
3. P contained compound according to claim 1 is characterized in that: n is 2 or 3.
4. P contained compound according to claim 2 is characterized in that: described P contained compound is a kind of in the following compounds:
5. P contained compound according to claim 1 is characterized in that: R
1, R
2In at least one be the group of general formula (III) expression:
Wherein, R
4', R
5' be OR individually
6' or NR
7' R
8', R
6', R
7', R
8' be C individually
1-6Straight or branched fat alkane base or their deuterium for thing; C
1-4Alkoxyl group, the methylene radical of carbonyl substituted or their deuterium are for thing.
6. P contained compound according to claim 5 is characterized in that: described P contained compound is a kind of in following:
7. the medicinal application of each described P contained compound in the treatment abnormal bone metabolism in the claim 1 to 6.
8. the medicinal application of each described P contained compound in treatment hypercalcemia disease in the claim 1 to 6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101862743A CN102040627A (en) | 2009-10-16 | 2009-10-16 | Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101862743A CN102040627A (en) | 2009-10-16 | 2009-10-16 | Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102040627A true CN102040627A (en) | 2011-05-04 |
Family
ID=43907190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101862743A Pending CN102040627A (en) | 2009-10-16 | 2009-10-16 | Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102040627A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102190684A (en) * | 2010-03-15 | 2011-09-21 | 南通波锐生物医药有限公司 | Phosphorus-containing compound having drug actions, and preparation and application thereof |
| IT202200003758A1 (en) * | 2022-03-01 | 2023-09-01 | Irccs Ospedale Policlinico San Martino | Drug conjugates in cancer therapy. |
-
2009
- 2009-10-16 CN CN2009101862743A patent/CN102040627A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102190684A (en) * | 2010-03-15 | 2011-09-21 | 南通波锐生物医药有限公司 | Phosphorus-containing compound having drug actions, and preparation and application thereof |
| IT202200003758A1 (en) * | 2022-03-01 | 2023-09-01 | Irccs Ospedale Policlinico San Martino | Drug conjugates in cancer therapy. |
| WO2023166535A1 (en) * | 2022-03-01 | 2023-09-07 | Irccs "Ospedale Policlinico San Martino" | Pharmacological conjugates in cancer therapy |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6932227B2 (en) | Carbidopa and L-dopa prodrugs and how to use them | |
| CN101074189B (en) | Styrene acid derivative and use in preparation of various blood-vessels target agent medicine | |
| CN102731580A (en) | Binuclear platinum (II)-diphosphonic acid coordination compound, preparation method and application thereof | |
| CN104558035B (en) | A kind of purification process of tenofovir prodrug | |
| CN102040627A (en) | Phosphorus-containing compound and its medicament application for treatment of bone metabolism abnormity | |
| CN105481946A (en) | Conjugate of 5-aminolevulinic acid and 3-pyridone-4-ketone and preparation method as well as use thereof | |
| JPH10500977A (en) | Therapeutic active agents comprising pyridylbisphosphonates | |
| CN101985456B (en) | Bone-seeking 99mTc-IPrDP coordination compound as well as preparation method and application thereof | |
| CN102190684A (en) | Phosphorus-containing compound having drug actions, and preparation and application thereof | |
| CN102875606B (en) | Copper diphosphonate complex and preparation method and application thereof | |
| WO2009059448A1 (en) | Styrene-acid derivative and use in manufacturing blood-vessel targeted-agent drugs | |
| CN102659840B (en) | Imidazole diphosphonie acid compound and pharmaceutically-acceptable salt and medicinal application thereof | |
| CN103232374A (en) | Side-chain aromatic ring-modified active vitamin D3 analog, as well as preparation method and application thereof | |
| CN102503897B (en) | 5-fluorouracil iodized oil derivative as well as preparation method and application thereof | |
| WO2008076826A1 (en) | Pyrophosphoramide alkylators | |
| CA2610647C (en) | Novel inhibitors of pyruvate kinase as therapeutic agents for cancer | |
| CN111944005B (en) | Cholic acid-hexyl-triphenyl phosphonium bromide and preparation method and application thereof | |
| CN105566147A (en) | Compound, preparation method and application thereof and corresponding targeted drug delivery system and chemotherapy drugs | |
| JP7164206B2 (en) | Ibandronate Conjugates of Nucleoside Antimetabolites | |
| CN105732758B (en) | Cholic acid α aminophosphonate ester derivatives and its synthetic method | |
| EP3351250A2 (en) | Phosphate management with small molecules | |
| CN107365330B (en) | Dihydromyricetin two banks mono-sodium salt derivative and its preparation method and application | |
| CN102603812A (en) | Binuclear platinum (II)-zoledronate complex and preparation and application thereof | |
| CN112585149A (en) | Phosphine transition metal complex, method for producing same, and anticancer agent | |
| TWI535690B (en) | Hepatocellular cancer therapeutic agent precursor and its manufacturing method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110504 |