JPH01308290A - (cycloalkylamino)methylenebis(phosphonic acid) and medicine containing said compound as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R and R<1>-R<4> are H or lower alkyl; n is 3-10). EXAMPLE:Tetraethyl (cycloheptylamino) methylenebis (phosphonate) expressed by formula V. USE:An inhibitor for bone resorption, anti-inflammatory, antipyretic, analgesic and antirheumatic agents. PREPARATION:An aminocycloalkyl expressed by formula II is mixed with a lower alkyl orthoformate expressed by formula III and phosphorous acid expressed by formula IV or a lower alkyl ester thereof and reacted, preferably at about 150 deg.C for 10-60min. The resultant reaction mixture is then filled in a silica gel column and eluted with a mixed solvent of methanol-chloroform.

Description

[Detailed description of the invention] (Industrial application field) The present invention has anti-inflammatory effects in addition to bone resorption inhibiting tltlJ effects.

The present invention relates to (cycloalkylamino)methylenebis(phosphonic acid), its lower alkyl ester or non-interfering salt thereof, which is useful as a medicine having antirheumatic effects, etc., and a medicine containing the compound as an active ingredient.

(Prior art) (cycloalkylamino)methylenebis(), -thread
"i"'7"l!J2"')"As a P conductor, Schiff
Compounds having a delkyl group, a cyclopentyl group, or a cyclohexyl group are described in JP-A-54-37829, and compounds having a cyclohexyl group are each used as a pesticide, especially a herbicide. Although it is explained that it can be used in the prevention of precipitation in water or aqueous solutions.

There is no suggestion that it could be used as a medicine.

The compound of the present invention is characterized in its chemical structure in that the cycloal or kyl group is an unsubstituted or substituted 9-carbon Schiff convex alkyl group having 3 to 10 carbon atoms.

There are also compounds that can be used as bone resorption inhibitors.

(Problems to be solved by inventiveness and means of solving them)
That is, the medicament of the present invention is represented by the following general formula (
Bone absorption containing cycloalkylamino)methylenebis(, phosphonic acid), its lower argylinis-methyl, or its non-traditional salt as an active ingredient.

It is an astringent agent.

(In the formula, R, R'', R2, R3 and R4 represent a hydrogen atom or a lower alkyl group, and n represents an integer of 3 to 10. □The same applies hereinafter) In addition, one compound of the present invention is the above-mentioned compound. Compounds represented by the general formula (I) (4 compounds, where momme is 5 or 6).

゛R means a lower alkyl group. ), its lower argyl esters or its non-synthetic salts.

In the explanation of the 2-notation formula (D), the lower alkyl group is a straight-chain or branched □ carbon having 1 to 5 carbon atoms.

It is hydrogen gas. Representative lower alkyl groups include unsubstituted or substituted lower alkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group,
cyclooctyl group.

They are a cyclooctyl group, a cyclononyl group, and a cyclodecyl group.

The salt of compound (1) is a salt with a non-natural base. Suitable salts include storium salts.

Inorganic base salts such as potassium salts, ammonium salts.

Organic base salts such as triethylamine salts may be mentioned.

(Manufacturing method) The compound of the present invention can be manufactured by the method shown by the following reaction formula. ′(U),
(III) (IV) C (I) This method deals with the reaction of aminocycloargyl (n), orthoformic acid lower alkyl ester (III), and phosphorous acid or its lower alkyl ester (IV). Mix the amounts and react under heating. The reaction solvent is
Not particularly necessary. The reaction is usually carried out at 100 to 200°C, preferably around 150''C for 10 to 60 minutes.

In order to isolate and purify the reaction product thus obtained, it is sufficient to fill a silica gel tube with the reaction mixture and elute with a methanol-chloroform mixed solvent. In the above reaction, when phosphorous acid or its ester (■) is used, the corresponding divosboric acid or its ester can be obtained.

Next, the diphosphonic acid ester is hydrolyzed to form the corresponding diphosphonate rri, vc.
I can do it. This hydrolysis is usually carried out in concentrated hydrochloric acid.

Heat to reflux. In addition, the compound (
D can be treated with a strong acid or trimethylsilyl rogenide. This method usually uses commercially available hydrobromide/acetic acid as it is or diluted as appropriate, or trimethylsilane iodide dissolved in a solvent such as carbon tetrachloride, dimethylpolamide, chloroform, toluene, etc. Ru. The temperature for hydrolysis is either cooling or heating. For example, when using trimethylsilyl chloride under cooling at -10°C or lower, the target compound is partially hydrolyzed. is generated.

In order to convert diphosphonic acid into a salt, it is subjected to a conventional method using a base such as thorium hydroxide, potassium hydroxide, ammonia or an organic amine. (Effects of the Invention) The compound ('f) and its salt provided by the present invention have an effect of suppressing bone resorption and also have an effect of suppressing hypercalcemia caused by bone resorption. . It is also recognized to have excellent anti-inflammatory and antipyretic and analgesic effects.

Next, the hypercalcemia suppressing effect of one compound of the present invention will be shown together with a test method.

Hypercalcemia Suppressing Effect Using rats with hypercalcemia caused by administration of parathyroid hormone, the effect of reducing serum tunorsium levels when two compounds of the present invention were administered was measured.

Test method: Human 1-34 parathyroid hormone (p'rH) was administered to 5-week-old male twin star rats exposed to 8 pm.

Peptide Institute) was administered intravenously at 30 μg/kg.

PTI-I was dissolved in physiological saline containing 01% USA and administered at 5 ml/kg. Normal control group is 01%U
S.A.

Only the containing physiological saline was administered in the same manner. 45 minutes after the administration of PTH, the rats were anesthetized with ether and then opened, and blood was collected from the abdominal vena cava using a vacuum blood collection tube. Blood immediately changes to 4℃ and 3000 revolutions.

The serum was separated by centrifugation for 10 minutes. Immediately measure the level of ionized calcium (Ca'l+) in the serum with a Ca meter (
Horiba, Ltd., Cera 250).

The test compound was prepared using caustic soda and salt/acid.
, 4 was prepared and administered subcutaneously at 2 mt/kg 72 hours before PTH administration. normal control group,
Physiological saline was similarly administered to the control group. Also as a reference compound.

Measurement was performed using salmon calcitonin (SCT, 2000, Armor Inc.). SC, T was administered subcutaneously at 2 ml/kg 30 minutes before administration of PTI-I.

The results are expressed as mean ± S, E for each group, and comparisons between groups were tested using one-way analysis of variance.

Note that a risk rate of less than 5% was considered significant.

Results: The results of subcutaneous administration are shown in Table 1.

Table 1. Subcutaneous administration, mean clay S, E, *; P<0.05**;
It is clear that the compounds of the present invention inhibit bone resorption since the compounds of the present invention do not exhibit an excellent effect of lowering the serum calcium level when P<0.01 or more. P for diseases in which the origin of bone resorption is thought to play an important role in the pathology.
Aget disease hypercalcemia, bone metastasis of cancer, and osteoporosis. Furthermore, the origin of bone resorption (osteoporosis) associated with inflammatory joint diseases such as rheumatoid arthritis is also a major clinical problem. The compound of the present invention suppresses bone resorption for these diseases and pathological conditions.

It can be used as a drug that prevents a decrease in bone mass or prevents or lowers an increase in serum calcium level associated with normalization of bone resorption.

The compound m of the present invention and its salts may be used as such or in a known pharmaceutically acceptable carrier.

It is used as a pharmaceutical composition mixed with excipients and the like. Administration is by oral administration such as tablets, capsules, powders, granules, and radish, injections, and syrups.

Parenteral administration such as ointments and suppositories may be used.

The dosage varies depending on the subject, route of administration, symptoms, etc., but is usually 1 mg to 1 g per 11 adults. 01 to 1011 g is appropriate for nasal, intravenous, and crude drug administration.

(Prescription example) Next, an example of the prescription of the medicament of the present invention will be given.

tablet.

Compound of Example 8 5rr1g Lacto-
], 19mg corn starch 67111g hydroxyglopylcellulose 4mg carboxymethylcellulose calcium 4mg magnesium stearate Im
g Total amount 200n+g 5g of the compound of Example 8, 119g of lactose.

Mix 67g of corn starch evenly.

Add 10% hydroxyglopy cellulose (W/W) to the mixture.
) 40 ml of aqueous solution were added and the resulting mixture was wet granulated. The thus obtained granules were combined with 4 g of carboxymethylcellulose calcium and magnesium stearate]
g and compress the mixture into 2001 square tablets.

Capsule: Compound of Example 8 5 ■ Crystalline cellulose 50rl1g゛Crystalline lactose
144 TIg total amount 200
1,000 times the amount of each ingredient was mixed and filled into gelatin capsules to produce turnips and cells each weighing 200rl'1g.

(Example) Next, the method for producing the compound of the present invention will be explained with reference to Examples.

Example 1゜゜Cloheptylamine 40g, ethyl orthoformate 6
27g and diethyl phosphite, 19. ! 7g was stirred at 150 degrees for 15 hours. After cooling, the two reaction solutions were concentrated under reduced pressure.

After removing unreacted ethyl orthoformate and diethyl phosphite, the residue was purified by CYIJ Noahgel column chromatography (methanol/chloroform = 1/-49) to obtain tetraethyl (cycloheptylamino). ) methylene bis(phosphonate).

90 g were obtained as a pale yellow oil.゛The physical and chemical properties of this product are as follows.

I) Mass spectrometry value (FABMaSs) 400 (M+1)1
1) Nuclear magnetic resonance spectrum (δ value, in CDCl3) 1
．． 3'2 (1-2H, 'ocr-12c view, x4
) 3.36 (IT-I, -NHC view-) 400~
4.4.0 (8H, -QC, CH3X 4.) Using the same method as in Example 1, the following compound was synthesized.

Example 2 Tetraethyl(cyclopropylamino)methylenebis(
Phosphonate) Yellow oil 1) Mass spectrometry value (FA9 Mass) 344 (M
+1) 11) Nuclear magnetic resonance spectrum (δ value, CDCl
3 out of 3) 1.35 (12H, 0CH2C tan, x 4
) 1.94 (IH, -NH-) 3.40 (IH, -NC■-) 396-4.40 (8I-I, -4 in QCCDCl3
．． ) Example 3 Tetraethyl(cyclooctylamino)methylenebis(
1) Mass spectrometry value (FAB Mass) 414 (M
441) 11) Nuclear magnetic resonance spectrum (δ value, CD
in Cl3) 1.34. (12H, -ocH2c, ×4) 120-240 (14■ (, methylene H of cyclooctyl group) 3.04 (IH, 6) 3.36 (, IH, -NHCH-) 400-4
．． 48 (8H, -oc rule CH3X 4 ) 15 Example 4 Tetraethyl [(3-methylcyclohexyl)amine]
Methylene bis(phosphonate) 1) Mass spectrometry value ('
FAB Mass) 400 (M”+1)1
1) Nuclear magnetic resonance spectrum 3.44 (IH, -NC observation-) 4.00-4.
42 (8H, -QC, CH3X4)tetraethyl(cyclohebutylamino)methylenebis(phosphonate)
) 4. 1 g of C was dissolved in 40 ml of concentrated hydrochloric acid and refluxed for 25 hours. Next, after concentrating the core liquid of 1 incubation under reduced pressure to remove hydrochloric acid, 30 ml of purified water was added to the residue.

It was concentrated again under reduced pressure. The obtained oil was solidified with methanol and acetone, and then washed with acetone to remove 'P' to obtain (cyclohebutylamino)methylenebis(
2.5 g of Fumeshoninokuacinodo was obtained as a white solid.

The physical and chemical properties of this are as follows! It is.

i) Mass spectrometry value (FABMass) 288 (M+
+1) 11) Elemental analysis value (,C4H+gNO6Pt)
CI-I N F Theoretical value (%+ 33.46 6,67 4.88
21.57 actual measurement value (φ), 33,27 6,40
4.87', 21.54iii) Melting point (
'C)'2'32-233 (Recrystallized from MeOHH2O) The following compound was synthesized using the same method as in Example 5.

Example 6゜(cyclooctylamino)methylenebis(phosphonic acid) 1) Mass spectrometry value (FAB Ma, ss) 302
(M++1)11) Elemental analysis value (CoH21NOo
P2) CHN, P theoretical value (@ 35.89 7,03 4.65 2
0.57 actual value (@35,87 6,82 4.69
20.49111) Melting point ('C) 228-229
(Unpurified) Example 7 (Cyclobutylamino)methylenebis(phosphonic acid) 1) Elemental analysis value (C3HI3N06P2) CH'
N Theoretical value (@24,50 5.35 571 Actual value (
匍 24.41 5,23 5.6611)
Melting point (°c) 256-258 (Recrystallized from methanol) Example 8 [(3-methylcyclohexyl)amine]methylenebis(phosphonic acid) 1) Mass spectrometry value (FAB
Mass), 288 (M++1)11
) Elemental analysis value (caI (+oNOaP2・0.2H20
) CHN P Theoretical value (H) 33.04 6.72 j, 81.21
．． 30 actual measurement value (-3'2,88 6,47 4.77
21.32111) Melting point ('C) 220-221
(Unpurified) Example 9 [(2-Methylcyclohexyl)aminocomethylenebis(phosphonic acid) 1) Elemental analysis value (C8H
+oNO6Pz) C"H', N Theoretical value (@33,46 6,674.88 Actual value (Sneak 33.07 6.3c+ 4.86ii)
Melting point (0C) 238-240 (methane-
Example 10 [('4-Methylcyclohexyl)aminocomethylenebis(phosphonic acid) 1) Elemental analysis value (C3
H1llNOQP2 )CHN Theoretical value (-33, 46, 6,674, 88 Actual value (%J
”33.13 6/11 4.75111)
Melting point ('C) '25'5-258 (Recrystallized from methanol-water) Example 11゜Tetraethyl(cyclopropylamino)methylenebis(
1.28 g of phosphonate) was dissolved in 25% hydrobromic acid and acetic acid solution13. It was dissolved in rnl and stirred at 45°C for 2 hours. After concentrating the reaction solution under reduced pressure, 20 m of purified water was added to the residue.
1 was added thereto, and the mixture was again concentrated under reduced pressure. After solidifying the obtained oil with methanol and acetone.

By washing with acetone, (cyclopropylamino)methylenebis(phosphonic acid)
Obtained 0.42 g as a white solid.

The physical and chemical properties of this product are as follows.

1) Mass spectrometry value (FAB, Mass) '232
(M++1)11) Elemental analysis value (C1H++N0o
P2" 0.21-120) CHN P theoretical value (%l 20.47 4,89 5.9'6
26.39 Actual value (coefficient 1 20.45 4,73
5.83 26.33111) Melting point (°C) 21
4-216°C (unpurified) Example 12 Cyclopentylamine 3.0g, ethyl orthoate 6.2
A mixed solution of 194 g of diethyl phosphite and 194 g of diethyl phosphite was stirred at 150 degrees for 1.5 hours. After cooling, the reaction solution was concentrated under reduced pressure.

After removing unreacted ethyl orthoformate and diethyl phosphite, the residue was purified by silica gel column chromatography (methanol/chloroform-'/49) to obtain tetraethyl (cyclopentylamino) methylene bis(phosphonate) 10 Obtained .7 g as a pale yellow oil.

The physical and chemical properties of this product are as follows.

]) Mass spectrometry value (FAB Mass') 372 (
M++1) 11) Nuclear magnetic resonance spectrum (δ value, CD
in Cl3) 1.34. (12H, 0CH7C small x 4) 1.42-2.00. , (8H, methylene I-I of cyclopentyl group) 3.30' (4
H, -NHC limit-)400~4.36 (8H, -0C
H2CH3X4) The following compound was synthesized by the same method as in Example 12.

Example 13 Tetraethyl (cyclohexylamino)methylenebis(phosphonate) i) Mass spectrometry value (F A B Mass ) 38
6 (M++1)11) Nuclear magnetic resonance spectrum (δ value, in CDCl3) 1,. 32 12H, -0CH2C
I-I3X4).

12-2.0 (IOH, methylene H of cyclohexyl group) 2.90 (IH, NH-70) 3.44. (IH, NI-ICI-I
)4.00~4.4'O(811, -0CH2CII3
X 4 ) Example 14 8.0 g of tetraethyl (cyclopentylamino)methylenebis(fosunionate) was dissolved in 80 ml of concentrated hydrochloric acid and refluxed for 25 hours. After cooling, the two reaction solutions were concentrated under reduced pressure to remove hydrochloric acid, and 70 ml of purified water was added to the residue, followed by concentration under reduced pressure again. The obtained oil was solidified with acetone and acetonitrile, and then recrystallized from P-containing water-methanol to obtain 36 g of (cyclopentylamine)methylenebis(phosphonic acid) as white crystals.

The physical and chemical properties of this product are as follows.

1) Mass spectrometry value (FAB Mass) 260
(M”+1) ii) Elemental analysis value (C1H++N0
oP2・0. I H2O)C,HNP Theoretical value (@27,62 5,87 5.37 23.7
4 actual measurement value (φi' 27,42 5,67 5.4
8 23.66111) Melting point ('C,) 228~
229 A primary compound was synthesized in the same manner as in Example 14.

Example 15 (Cyclohexylamino)methylenebis(phosphonic acid) 1) Mass spectrometry value (F A B Mass ) 27
4 (M++1) II) Elemental analysis value (C7H, 7No
oP2) CHN P theoretical value (candy 1 30.78 6.27 513 22
．． 68 actual value (hate) 30..4.8 6,11 5.
16 22.17111) Melting point ('C) 267~
269 (Unrefined) Patent Applicant: Yamanouchi Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R, R^1, R^2, R^3 and R^4 are
n represents a hydrogen atom or a lower alkyl group, and n represents an integer of 3 to 10. ) Bone resorption inhibitor 2 containing (cycloalkylamino)methylenebis(phosphonic acid), its lower alkyl ester, or its non-toxic salt as an active ingredient, general formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (Formula Medium, R, R^1, R^2, R^3 and R^4 are
n represents a hydrogen atom or a lower alkyl group, and n represents an integer of 3 to 10. However, when n is 5 or 6, R means a lower alkyl group. ) (cycloalkylamino)methylenebis(phosphonic acid), its lower alkyl ester or its non-toxic salt