CN1046853C - (Cycloalkyl amine) methylene di (phosphonic acid) and drug taking this compound as active component - Google Patents
(Cycloalkyl amine) methylene di (phosphonic acid) and drug taking this compound as active component Download PDFInfo
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- CN1046853C CN1046853C CN92114203A CN92114203A CN1046853C CN 1046853 C CN1046853 C CN 1046853C CN 92114203 A CN92114203 A CN 92114203A CN 92114203 A CN92114203 A CN 92114203A CN 1046853 C CN1046853 C CN 1046853C
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Abstract
(Cycloalkylamino)methylenebisphosphonic acids and esters (I) and salts thereof <CHEM> (wherein R, R<1>, R<2>, R<3> and R<4> are hydrogen or lower alkyl and n is an integer from 3 to 10) are bone-resorption inhibitor and anti-arthritic agents.
Description
The present invention relates to and have bone resorption inhibition activity and/or the active preparation of drug combination method of arthritis.
Many derivants of (cycloalkyl amido) di-2-ethylhexylphosphine oxide (phosphonic acids) are known.Japanese patent laid-open publication gazette N.O37,829/79 discloses a compounds, and they contain a unsubstituted cyclopenta or cyclohexyl groups.The open NO12 of Japan Patent, 319/80 correspondingly discloses a kind of chemical compound, and this chemical compound contains a cyclohexyl as group of naphthene base.These Japanese patent gazette point out that these chemical compounds can be used used as pesticides, especially can be used as herbicide, also can be used in the sedimentary method of anti-sealing and aqueous solution, but do not mention as medicine with this chemical compound.
The object of the invention provides an analog derivative of (cycloalkyl amido) di-2-ethylhexylphosphine oxide (phosphonic acids), and they contain the cycloalkyl that does not replace or replace that carbon number is 3-10, can be used as bone resorption inhibitor and anti-arthritic.
The invention provides a kind of (cycloalkyl amido) di-2-ethylhexylphosphine oxide (phosphonic acids) that contains following general formula representative, it lower alkyl esters or its pharmaceutical salt as the pharmaceutical composition of active ingredient.
Wherein R, R
1, R
2, R
3And R
4Represent a hydrogen atom or a low alkyl group.N represents the integer of 3-10.
The present invention also provides a kind of bone resorption inhibitor and a kind of anti-arthritic, and its active ingredient contains chemical compound, its lower alkyl esters and the pharmaceutical salt thereof of general molecular formula for (I).
The present invention also provides a kind of noval chemical compound, its lower alkyl esters and pharmaceutical salt with general molecular formula (I) expression.R, R in the formula
1, R
2, R
3, R
4Represent a hydrogen atom or a low alkyl group.N represents the integer of 3-10, but when n was 5 or 6, R represented a lower alkyl esters.
Lower alkyl esters in the general molecular formula I be have 1-5 carbon former in the hydrocarbyl group of straight or branched.Typical low alkyl group is that methyl, ethyl, propyl group or isopropyl, chemical constitution are
Group in general molecular formula (I), represent a cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, ring nonyl or ring decyl, they are replaced by a low alkyl group or are not substituted.
The salt of chemical compounds I is pharmaceutically acceptable salt.Ideal as a comparison salt, it can be the salt that has inorganic base, as sodium salt, potassium salt or similar salt, also can be the salt that has organic base as: amine salt, triethylamine salt and class are saloid.
The preparation of chemical compound of the present invention is carried out according to following reaction equation:
In this reaction, Cycloalkyl amine (II), the positive formates of low alkyl group (II), phosphoric acid or its lower alkyl esters (IV) are mixed and heat according to corresponding response magnitude separately, reaction needn't be carried out under dissolution conditions, but this reaction is generally carried out under 100-200 ℃, preferably under about 150 ℃, reacted 10-60 minute
Must separate and purification the product that so obtains, for example, reactant mixture is packed in the silica dioxide gel post, and with methanol-chloroform mixed liquor eluting, with the form of above-mentioned reaction, can also obtain corresponding two phosphonic acids or diphosphonate respectively from phosphoric acid or its ester (IV).
By hydrolysis, diphosphonate can be converted to corresponding two phosphonic acids, and this hydrolysis can be undertaken by reflux diphosphonate in concentrated hydrochloric acid.In addition, also available strong acid or three silicyl halogenide are handled diphosphonate in anhydrous solvent, in the method, generally can directly or with appropriate weak solution form use discuss the dehydration hydrobromic acid of selling in acetic acid, or be dissolved in solution in a kind of solvent, these solvents such as carbon tetrachloride, dimethyl formamide, chloroform, toluene etc. with three silicyl iodide.As for reaction temperature, this hydrolysis all can carry out under low temperature or heating condition.For example under low temperature-10 ℃ even lower temperature, can obtain the partly product of hydrolysis during hydrolysis with three silicyl halogenide when this ester.
If make two phosphonic acids transform salify, then handle with alkali such as sodium hydroxide, potassium hydroxide, ammonia or organic amine etc. in due form.
Chemical compound provided by the invention (I) and salt thereof have the bone resorption inhibitory action, but also the hypercalcemia that causes because of bone resorption is had inhibitory action, have confirmed that in addition it has tangible antiinflammatory, analgesic, analgesic activity.
For confirming the inhibitory action of chemical compound provided by the invention (I) and salt pair hypercalcemia thereof, introduce some experiment test method and test results below.
(1) to the inhibitory action of Mus hypercalcemia
Induce the hypercalcemia of Mus with parathyroid hormone.And measure the minimizing value use Mus serum calcium content behind this chemical compound.Assay method:
The people 1-34 parathyroid hormone (PTH that is dissolved in 0.1% the bovine serum albumin normal saline solution, the Peptide pharmaceutical factory produces) (content of PTH is 6 μ g/ml), give 5 all male Wistar rats of 20 hours of fasting according to the 30 μ g/Kg amount intravenous injection of (being equivalent to this solution 5ml/Kg).And only inject 0.1% bovine serum albumin normal saline solution to normal control group white mouse with the same manner.Injection parathyroid hormone after 45 minutes with white mouse anesthesia and cut open the belly, is collected blood with vacuum test tube from abdominal vein with ether.With the blood gathered immediately at 4 ℃, under the 3000rpm condition centrifugal 10 minutes, separation of serum, and use Ca
++Detector (Sera250, Horiba manufacturing company produces) is measured the calcium ion (Ca in the serum immediately
++) concentration.
With sodium hydroxide and hydrochloric acid with compound dissolution provided by the present invention (pH7.4) in normal saline, according to the dosage subcutaneous administration of 2ml/kg.At injection parathyroid hormone injection in preceding 72 hours The compounds of this invention.With the same manner to normal control group and matched group injecting normal saline or distilled water.As having used salmon calcitonin (SCT, Armour company produce) in this assay method of reference compound, inject the preceding 30 minutes dosage according to 2ml/kg to this calcitonin of rat skin lower injection at parathyroid hormone.
Each is organized the result and represents that with the form of mean+/-standard error the folk prescription of employing variance compares each group to analytic process.Significance level gets 5%.The result: table 1 has been represented the data that obtain after the subcutaneous medication
The subcutaneous medication test result of table 1
Attention: mean+/-standard error
*: P＜0.05
*: P＜0.01
| Tested chemical compound dosage (mg/kg) | N | Serum Ca ++ (mmole/l) |
| The chemical compound 1.5 of chemical compound 0.3 preparation example 8 of normal control group-matched group-preparation example 8 | 5 5 5 5 | 1.42±0.02 1.48±0.03 1.25±0.02 ** 1.12±0.02 ** |
| The chemical compound 0.1 of chemical compound 0.03 preparation example 15 of normal control group-matched group-preparation example 15 | 5 5 5 5 | 1.41±0.02 ** 1.46±0.02 1.37±0.02 ** 1.20±0.02 ** |
| The chemical compound of the compound example 5 of the compound example 5 of the compound example 14 of normal control group matched group preparation example 14 | - - 0.1 0.3 0.1 0.3 | 5 5 5 5 5 5 | 1.34±0.02 ** 1.43±0.01 1.34±0.02 ** 1.21±0.01 ** 1.12±0.01 ** 0.97±0.02 ** |
| The chemical compound of the compound example 10 of the compound example 10 of the compound example 9 of normal control group matched group preparation example 9 | - - 0.1 0.3 0.1 0.3 | 5 5 5 5 5 5 | 1.36±0.01 ** 1.45±0.02 1.31±0.01 ** 1.19±0.01 ** 1.35±0.01 ** 1.22±0.01 ** |
| The compound of the compound preparation example 6 of the compound preparation example 6 of the compound preparation example 7 of the compound Normal group control group preparation example 7 of Normal group control group preparation example 11 | - - 1.0 - - 0.3 1.0 0.3 1.0 | 5 5 5 5 5 5 5 5 5 | 1.35±0.02 ** 1.44±0.01 1.35±0.02 ** 1.38±0.01 ** 1.48±0.02 1.40±0.02 ** 1.29±0.01 ** 1.33±0.03 ** 1.12±0.03 ** |
| Normal control group matched group calcitonin | - - 0.3IU | 5 5 5 | 1.38±0.01 ** 1.49±0.00 1.07±0.02 ** |
(2) parathyroid hormone is induced rat hypercalcemia method
Give rat (Wistar kind, male, about 3 weeks make) intravenous injection with parathyroid hormone (people PTH1-34,30 μ g/kg), inject blood sampling after 45 minutes, use Ca
++Detector is measured serum calcium ion (Ca
++) concentration.
The injection parathyroid hormone before 3 days with test compound subcutaneous and oral administration, measurement result is represented with mean+/-standard error, analyzes the statistical significance of these values to the ANOVA method with folk prescription.(
*: P＜0.05,
*: P＜0.01) result
Parathyroid hormone may be by stimulating skeleton to discharge the rising serum Ca of calcium
++Level.Diphosphonate, chemical compound of preparation example 5 (following represent) and APD with YM-21175-1
*Gave rat skin lower injection before 3 days or can suppress the increase of the content of serum calcium when oral at the injection parathyroid hormone, suppress relevant with application dosage.No matter be subcutaneous injection or oral, YM-21175-1 is than 10 times of the strong drug actions of APD.
Table 2 YM-21175-1 and APD are to the influence of the inductive rat hypercalcemia of parathyroid hormone
| Dosage (mg/kg) | N | Serum calcium (mmole/l) | |
| Normal group (PTH) matched group (+PTH) APD APD YM-21175-1 | 0.03 subcutaneous 0.1 subcutaneous 0.3 subcutaneous 30 per os, 100 per os, 300 per os 0.01 subcutaneous 0.03 subcutaneous 0.01 are subcutaneous | 5 5 5 5 5 5 5 5 5 5 5 | 1.42±0.02 1.49±0.02 1.49±0.02 1.46±0.01 1.41±0.02 * 1.50±0.02 1.42±0.02 1.22±0.02 ** 1.44±0.02 1.36±0.02 ** 1.15±0.01 ** |
| Normal group (PTH) matched group (+PTH) YM-21175-1 | --10 per os 30 per os 100 per os | 5 5 5 5 5 | 1.35±0.02 1.45±0.02 1.37±0.02 1.23±0.05 ** 1.05±0.04 ** |
*:APD(Ciba-Geigy)；
(a kind of commercially available be used for the treatment of pagetic medicine)
(3) by excision rat neuroinduction skeleton disuse atrophy method
The brachial plexus nerve cut-out of rat (wistar, male, 6 weeks made) is caused the useless usefulness of left forearm.Take off its left humerus after two weeks, remove the soft tissue around the os purum bone, with skeleton with ethanol and acetone dewater in succession, defat.And take by weighing the dry weight of skeleton.
The dispenser of chemical compound per os continued for two weeks once a day.The result represents with mean+/-standard error, with folk prescription to the ANOVA criterion analyze these numerical value statistical significance (
*: P＜0.05,
*P＜0.01) result:
Humerus dry weight that denervates and sham cut are removed the person and are alleviated apparent in viewly, oral diphosphonate, YM-21175-1 and APD, and the minimizing that shows the humerus dry weight that suppresses to denervate suppresses relevant with dosage, and the drug effect of YM-21175-1 is stronger 30 times than APD.
Table 3YM-21175-1 and APD induce denervating in the rat
Useless with the property osteanabrosis influence
| Dosage (mg/kg) | N | Key heavy (mg) |
| Sham cut is except nerve-control group-APD 10 30 100 YM-21175-1 0.3 13 10 | 6 6 5 5 6 6 6 6 6 | 154±3 ** 113±2 126±3 128±4 * 135±2 ** 126±2 132±6 ** 135±3 ** 150±4 ** |
(4) adjuvant brings out the rat arthritis method
The oil suspension of deactivation bacillus is injected under the left back pawl corium of rat (Lewis, male, 5 weeks made).From injection, begin to give rat oral every day chemical compound, continued for 5 weeks.Measure the thickness of left back pawl, and take off the fl of rat in next day of last dose.With skeleton dehydration, defat.And take by weighing its dry weight.After incinerating, the skeleton combustion takes by weighing the weight of bone ash then.
Calculate the content of its skeleton inorganic matter with the heavy ratio of bone ash and backbone, data are analyzed its statistical significance with mean+/-standard error (N=6) expression with unidirectional ANOVA criterion.(
*: P＜0.01) result:
The arthritis that adjuvant brings out is a kind of model of human body rheumatoid arthritis commonly used.The injection adjuvant induces arthritic rat not only to show as joints of foot swelling, and also has the minimizing of skeleton inorganic content.This be considered to because of bone resorption increase and/or hind leg useless in causing.
The indometacin of 1mg/kg suppresses the swelling of hind leg significantly, owing to suppressed arthritic development, has also just suppressed the minimizing of skeleton inorganic content.YM-21175-1 only just suppresses swelling when heavy dose, and can suppress the minimizing of skeleton inorganic content when 1mg/kg, and therefore, indometacin and YM-21175-1 may exist difference aspect anti-inflammation detumescence.YM-21175-1 is stronger than the drug effect of APD.
Table 4
YM-21175-1 and APD bring out adjuvant
The influence of rat arthritis
| Dosage (mg/kg) | N | Pawl thick (mm) | Bone ash weight/backbone heavy (%) | |
| Normal group matched group indometacin APD YM-21175-1 | - - 1 1 3 10 30 100 0.3 1 3 10 30 | 6 6 6 6 6 6 6 6 6 6 6 6 5 | 6.4±0.0 13.5±0.1 7.6±0.1 ** 12.1±0.6 11.6±0.7 10.8±0.6 ** 12.1±0.3 9.3±0.3 ** 12.3±0.6 11.7±0.1 12.3±0.8 10.5±0.7 ** 9.5±0.2 ** | 54.8±0.1 ** 49.5±0.4 52.3±0.2 ** 50.4±0.3 51.2±0.4 ** 52.1±0.5 ** 53.3±0.3 ** 56.6±0.3 ** 50.7±0.6 52.1±0.8 ** 53.1±0.4 ** 55.9±0.3 ** 57.6±0.3 ** |
To the inhibitory action of bone loss and being compared of APD, as the result of three kinds of tests, YM-21175-1 is considered to can be used for treating osteopetrosis, rheumatoid arthritis and the enhanced disease of other bone resorption with YM-21175-1.Confirm also that in addition YM-21175-1 is stronger than the drug effect of APD.
Result of the test proves that chemical compound provided by the present invention has the effect that reduces serum calcium cancentration significantly.Therefore, affirmed that further chemical compound of the present invention has the bone resorption inhibitory action.Some disease is because of excessive bone resorption causes, and what this can mention Paget (scleromalacia), hypercalcemia, metastatic tumor of bone and fragilitas ossium is arranged.Moreover, as the stronger bone resorption after inflammatory arthritis such as the chronic rheumatoid arthritis, see it is a very important problem from clinical point.Chemical compound provided by the present invention can be used as this sick medicine, in order to suppressing bone resorption and to prevent the bone loss, or prevents that the serum calcium value that causes because of stronger bone resorption from rising, or reduction blood calcium value.
Chemical compound provided by the present invention (I) and salt thereof can mix with other any pharmaceutical carriers, excipient, diluent etc. and forms compositions, as tablet, capsule, powder, granule, pill etc., be used for oral injection, syrup; The agent shape of other non-oral medications such as suppository, unguentum.Although according to differences such as route of administration, patient symptoms, compound amount provided by the present invention also changes.But generally speaking, oral administration adult consumption is 1mg/ days to 1g/ days, and non-oral consumption is 0.1-10mg/ days.
Chemical compound of the present invention is as follows as the formula examples of medicine: (1) tablet
The chemical compound 5mg of preparation example 8
Lactose 119mg
Corn starch 67mg
Hydroxy propyl cellulose 4mg
Carboxymethylcellulose calcium 4mg
Magnesium stearate 1mg
Amount to 200mg
Chemical compound with 5 gram preparation examples 8,119 gram lactose and 67 gram corn starch uniform mixing, the hydroxy propyl cellulose aqueous solution that adds 40ml 10% (W/W), said mixture is made wet granular then with resulting granules and 4 gram carboxymethylcellulose calciums and 1 gram magnesium stearate mixing, this mixture is processed into tablet, every weight 200mg.(2) capsule
The chemical compound 5mg of preparation example 8
Crystalline cellulose 50mg
Crystallization lactose 144mg
Magnesium stearate 1mg
Amount to 200mg
Above-mentioned composition is mixed according to the amount of 1000 times of above-mentioned amounts, and the gelatine capsule of packing into, every capsule contains said mixture 200mg.
In following preparation example, will the manufacture method of The compounds of this invention be described: preparation example 1
With 4.0 gram cycloheptylaminos, the mixture of 6.27 gram ethyl orthoformates and 19.5 gram diethyl phosphinates was 150 ℃ of following agitating heating 1.5 hours.After the cooling, under reduced pressure, reactant liquor is concentrated, to get rid of unreacted ethyl phosphinate and ethyl orthoformate.Then residue is carried out purification with silica gel column chromatography.(methanol/chloroform=1/49) obtains tetraethyl (suberyl amido) di-2-ethylhexylphosphine oxide (phosphonate) that 9.0 grams are light yellow oil sample.
The physicochemical properties of this product are as follows:
(ⅰ) mass spectrum (FAB Mass) 400 (M
++ 1)
(ⅱ) (δZhi is at CDCl for nuclear magnetic resoance spectrum
3In)
1.32 (12H,OCH
2CH
3×4)
(1.20-2.08 12H, the methylene H in the suberyl)
2.96
(1H,
3.36 (1H,-NHCH-)
4.00-4.40 (8H,-OCH
2CH
3×4)
Method with same with preparation example can prepare following compounds.Preparation example 2
The xanchromatic oil of tetraethyl (cyclopropyl amido) di-2-ethylhexylphosphine oxide (phosphonate)
(ⅰ) mass spectrum (FAB Mass) 344 (M
++ 1)
(ⅱ) (δZhi is at CDCl for nuclear magnetic resoance spectrum
3In)
0.36-0.56 (4H,
1.35 (12H,OCH
2CH
8×4)
1.94 (1H,-NH-)
2.65 (1H,
3.40 (1H,-NCH-)
3.96-4.40 (8H ,-OCH
2CH
3* 4) preparation example 3
Tetraethyl (ring octyl group amido) di-2-ethylhexylphosphine oxide (phosphonic acids)
(ⅰ) mass spectrum (FAB Mass) 414 (M
++ 1)
(ⅱ) (δZhi is at CDCl for nuclear magnetic resoance spectrum
3In)
1.34 (12H,-OCH
2CH
3×4)
(1.20-2.40 14H, the methylene H in the ring octyl group)
3.04 (1H,
3.36 (1H,-NHCH-)
4.00-4.48 (8H ,-OCH
2CH
3* 4) preparation example 4
Tetraethyl ((3-methylcyclohexyl) amido) di-2-ethylhexylphosphine oxide (phosphonate)
(ⅰ) mass spectrum (FAB Mass) 400 (M
++ 1)
(ⅱ) nuclear magnetic resoance spectrum
0.92 (3H,
1.34 (12H,-OCH
2CH
3×4)
1.20-2.40 (9H,
2.80 (1H,
3.44 (1H,-NCH-)
4.00-4.42 (8H ,-OCH
2CH
3* 4) preparation example 5
4.0g tetraethyl (suberyl amido) di-2-ethylhexylphosphine oxide (phosphonate) is dissolved in the 40ml concentrated hydrochloric acid, reflux 2.5 hours, after the cooling, concentration of reaction solution is removed hydrochloric acid under reduced pressure.In residue, add the 30ml pure water then.Again this mixed liquor is concentrated under reduced pressure, use methanol and acetone with its solid state to the oil sample product that this method obtains, and filter.Use the washing with acetone residue at last, obtain 2.5g (suberyl amido) di-2-ethylhexylphosphine oxide (phosphonic acids) white solid.
This material has following physicochemical properties
(ⅰ) mass spectrum (FAB Mass) 288 (M
++ 1)
(ⅱ) elementary analysis (C
8H
10NO
6P
2)
C H N P
Value of calculation (%): 33.46 6.67 4.88 21.57
Measured value (%): 33.27 6.40 4.87 21.54
(ⅲ) fusing point: 232-233 ℃ (from MeOH-H
2Recrystallization among the O)
Method with same with preparation example 5 also can prepare following compounds.Preparation example 6
(ring octyl group amido) di-2-ethylhexylphosphine oxide (phosphonic acids)
(ⅰ) mass spectrum (FAB Mass) 302 (M
++ 1)
(ⅱ) elementary analysis (C
9H
21NO
6P
2)
C H N P
Value of calculation (%): 35.89 7.03 4.65 20.57
Measured value (%): 35.87 6.82 4.69 20.49
(ⅲ) fusing point (℃) 228-229 (unpurified) preparation example 7
(cyclobutyl amido) di-2-ethylhexylphosphine oxide (phosphonic acids)
(ⅰ) elementary analysis (C
6H
13NO
5P
2)
C H N
Value of calculation (%): 24.50 5.35 5.71
Measured value (%): 24.41 5.23 5.66
(ⅱ) fusing point (℃) 256-258 (using the methanol recrystallize) preparation example 8
((3-methylcyclohexyl) amido) di-2-ethylhexylphosphine oxide (phosphonic acids)
(ⅰ) mass spectrum (FAB Mass) 288 (M
++ 1)
(ⅱ) elementary analysis (C
8H
19NO
6P
20.2H
2O)
C H N P
Value of calculation (%): 33.04 6.72 4.81 21.30
Measured value (%): 32.88 6.47 4.77 21.32
(ⅲ) fusing point (℃) 220-221 (unpurified) preparation example 9
(cis-trans mixture)
((2-methyl cyclohexyl) amido) di-2-ethylhexylphosphine oxide (phosphonic acids)
(ⅰ) elementary analysis (C
8H
10NO
6P
2)
C H N
Value of calculation (%): 33.46 6.67 4.88
Measured value (%): 33.07 6.39 4.86
(ⅱ) fusing point (℃): 238-240 (with methanol-acetone recrystallize) preparation example 10
((4-methylcyclohexyl) amido) di-2-ethylhexylphosphine oxide (phosphonic acids)
(ⅰ) elementary analysis (C
8H
10NO
6P
2)
C H N
Value of calculation (%): 33.46 6.67 4.88
Measured value (%): 33.13 6.41 4.75
(ⅱ) fusing point (℃): 255-258 (using the methanol-water recrystallization) preparation example 11
1.28 gram tetraethyl (cyclopropyl amido) di-2-ethylhexylphosphine oxides (phosphonate) are dissolved in the hydrogen bromide acetic acid solution of 13ml 25%, above-mentioned mixed liquor was stirred 2 hours down at 45 ℃, under reduced pressure reactant liquor is concentrated, and adding 20ml purifies waste water.And then under reduced pressure this mixture is concentrated once more.The oil sample product solid state that will obtain like this with methanol and acetone also filters.Use the washing with acetone crystalline solid, obtain 0.42 gram (cyclopropyl amido) di-2-ethylhexylphosphine oxide (phosphonic acids) white solid.
The physicochemical properties of this product are as follows:
(ⅰ) mass spectrum (FAB Mass) 232 (M
++ 1)
(ⅱ) elementary analysis (C
4H
11NO
6P
20.2H
2O)
C H N P
Value of calculation (%): 20.47 4.89 5.96 26.39
Measured value (%): 20.45 4.73 5.83 26.33
(ⅲ) fusing point (℃): 214-216 (unpurified) preparation example 12
With 3.0 gram cyclopenta amine, 6.2 gram positive formates of ethyl and 19.4 gram diethyl phosphinates after the cooling, under reduced pressure concentrate positive formates of ethyl and the diethyl phosphinate that removal does not react with reactant liquor 150 ℃ of following agitating heating 1.5 hours.Use silica gel column chromatography (methanol/chloroform=1/49) with the residue purification then, obtain tetraethyl (cyclopenta amido) di-2-ethylhexylphosphine oxide (phosphonate) of the light yellow oil sample of 10.7 grams.
The physicochemical properties of this material are as follows:
(ⅰ) mass spectrum (FAB Mass): 372 (M
++ 1)
(ⅱ) (δZhi is at CDCl for nuclear magnetic resoance spectrum
3In)
1.34 (12H,OCH
2CH
3×4)
(1.42-2.00 8H, the methylene H in the cyclopenta)
3.30 (1H,-NHCH-)
3.48 (1H,
4.00-4.36 (8H,-OCH
2CH
3×4)
Also can prepare following compounds with the same mode of preparation example 12.Preparation example 13
Tetraethyl (cyclohexyl amido) di-2-ethylhexylphosphine oxide (phosphonate)
(ⅰ) mass spectrum (FAB Mass) 386 (M
++ 1)
(ⅱ) (δZhi is at CDCl for nuclear magnetic resoance spectrum
3)
1.32 (12,-OCH
2CH
3×4)
(1.2-2.0 10H, the methylene H in the cyclohexyl)
2.90 (1H,
3.44 (1H,NHCH)
4.00-4.40 (8H ,-OCH
2CH
3* 4) preparation example 14
8.0 gram tetraethyl (cyclopenta amido) di-2-ethylhexylphosphine oxides (phosphonate) are dissolved in the 80ml concentrated hydrochloric acid, reflux 2.5 hours after the cooling, under reduced pressure concentrates reactant liquor and removes hydrochloric acid, add the 70ml pure water in the residue, under reduced pressure above-mentioned mixed liquor is concentrated again.The oil sample product that obtains is also filtered its solid state with acetone and acetonitrile.And then in methanol aqueous solution recrystallization, produce (cyclopenta amido) di-2-ethylhexylphosphine oxide (phosphonic acids) white crystals of 3.6 grams.
The physicochemical properties of this material are as follows:
(ⅰ) mass spectrum (FAB Mass) 260 (M
++ 1)
(ⅱ) elementary analysis (C
6H
15NO
6P
20.1H
2O)
C H N P
Value of calculation (%): 27.62 5.87 5.37 23.74
Measured value (%): 27.62 5.67 5.48 23.66
(ⅲ) fusing point (℃) 228-229 ℃
Can also the production following compounds in preparation example 14 same modes.Preparation example 15
(cyclohexyl amido) di-2-ethylhexylphosphine oxide (phosphonic acids)
(ⅰ) mass spectrum (FAB Mass) 274 (M
++ 1)
(ⅱ) elementary analysis (C
7H
17NO
6P
2)
C H N P
Value of calculation (%): 30.78 6.27 5.13 22.68
Measured value (%): 30.48 6.11 5.16 22.17
(ⅲ) fusing point (℃) 267-269 ℃ (unpurified)
Claims (2)
1. preparation has the method that bone resorption suppresses activity and/or the active Pharmaceutical composition of arthritis, it is characterized in that following formula (cycloalkyl amido) di-2-ethylhexylphosphine oxide (phosphonic acids), its lower alkyl esters or its pharmaceutical salts as active component
Wherein R, R
1, R
2, R
3And R
4Represent hydrogen atom or low alkyl group; N represents 3 to 10 integer; With pharmaceutical carrier and/or other mixed with excipients, and this mixture changed into the Pharmaceutical composition form.
2. method according to claim 1 is characterized in that using (suberyl amido) di-2-ethylhexylphosphine oxide (phosphonic acids) as active component.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1165688 | 1988-01-20 | ||
| JP11656/88 | 1988-01-20 | ||
| CN89101539A CN1022630C (en) | 1988-01-20 | 1989-01-20 | (Cycloalkylamino) methylenebis cphosphonic acid, and medicines containing the same as an active ingredient |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN89101539A Division CN1022630C (en) | 1988-01-20 | 1989-01-20 | (Cycloalkylamino) methylenebis cphosphonic acid, and medicines containing the same as an active ingredient |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1072594A CN1072594A (en) | 1993-06-02 |
| CN1046853C true CN1046853C (en) | 1999-12-01 |
Family
ID=25742552
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92114203A Expired - Fee Related CN1046853C (en) | 1988-01-20 | 1992-12-11 | (Cycloalkyl amine) methylene di (phosphonic acid) and drug taking this compound as active component |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1046853C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061661C (en) * | 1997-12-24 | 2001-02-07 | 国家医药管理局上海医药工业研究院 | Method for preparation of (cycloheptyl amido) methylene diphospho disodium-hydrate |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5646134A (en) * | 1994-04-21 | 1997-07-08 | Merck & Co., Inc. | Alendronate therapy to prevent loosening of, or pain associated with, orthopedic implant devices |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5437829A (en) * | 1977-08-29 | 1979-03-20 | Nissan Chem Ind Ltd | Disulfonic acid type herbicidal and insecticidal agents |
-
1992
- 1992-12-11 CN CN92114203A patent/CN1046853C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5437829A (en) * | 1977-08-29 | 1979-03-20 | Nissan Chem Ind Ltd | Disulfonic acid type herbicidal and insecticidal agents |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061661C (en) * | 1997-12-24 | 2001-02-07 | 国家医药管理局上海医药工业研究院 | Method for preparation of (cycloheptyl amido) methylene diphospho disodium-hydrate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1072594A (en) | 1993-06-02 |
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