JPS63185993A - 2-substituted-2-oxo-ethylene-1,1-diphosphonic acid - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (A is phenyl, naphtyl or monocyclic or bicyclic nitrogen-containing heterocyclic ring; R is H, halogen, lower alkoxy or lower alkyl; R<1>-R<4> are H or lower alkyl) or salt thereof. EXAMPLE:Ethyl 2-oxo-2-phenylethylene-1,1-diphosphonate. USE:Antiphlogistics and anti-rheumatics. PREPARATION:For example, a reactive derivative (e.g. benzoyl chloride, etc.) of carboxylic acid expressed by formula II is reacted with a reaction activator in the methylene group of a lower alkyl ester (e.g. ethyl methylenediphosphonate, etc.) of methylenediphosphonic acid expressed by formula III to provide the compound expressed by formula I.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to 2-substituted-2-oxo-ethylene-1,l-diphosphonic acid and its ester, which are useful as pharmaceuticals such as anti-inflammatory agents and anti-rheumatic agents. or its non-toxic salts.

(Prior art) As the ω-substituted alkylene-1,1-diphosphonic acid derivative, the substituent at the ω position is a phenylthio group having a substituent, or a 5- to 6-membered heterocyclic ring containing an unsubstituted nitrogen atom or a sulfur atom. A compound having a thio group (JP-A-59-42395) and a compound having an azole group which may have a substituent (JP-A-61-43197) have been reported.

The present invention has a chemical structure in that the substituent at the ω position (2nd position) is an oxo group, a phenyl group, a naphthyl group, or ethylene-1,1-diphosphonic acid, which is a nitrogen-containing monocyclic or bicyclic heterocyclic group. The present invention provides novel compounds having the above characteristics.

(Means for Solving the Invention) That is, the present invention is 2-substituted-2-oxo-ethylene-1,1-diphosphonic acid represented by the following general formula, an ester thereof, or a non-toxic salt thereof.

(In the formula, ■ represents a phenyl group, a naphthyl group, or a monocyclic or bicyclic nitrogen-containing heterocyclic group.

R is hydrogen atom, halogen atom, lower Alkoxy group, lower alkyl group.

R1, R2, R3 and R4 are the same or different and each represents a hydrogen atom or a lower alkyl group. ) In the explanation of the above formula (I), the monocyclic or bicyclic nitrogen-containing heterocyclic group is a heterocyclic group containing one nitrogen atom, and examples of the monocyclic group include a pyrrolyl group.

Isoxazolyl group is a substituent substituted at any position of a cyclic group such as 1-inch azolyl group, thiazolyl group, quinolinyl group, and inquinolinyl group.

Among these, the halogen atom is the chlorine atom.

Bromine atom, fluorine atom, iodine atom, as an alkyl group, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, isobutyl group, impentyl group, neopentyl group, It is a linear or branched one having 1 to 8 carbon atoms, such as an isohexyl group, and the lower alkoxy group is an alkoxy group having a lower alkyl chain similar to the above-mentioned lower alkyl group. The lower alkyl group represented by R1 to R4 is a linear or branched alkyl group having 1 to 5 carbon atoms. Preferable C. groups are methyl group, ethyl group, propyl group, isopropyl group, butyl group, and isobutyl group.

The lower alkyl groups of R1 to R4 can be different from each other. Further, among R1 to R4, for example, any two atoms may be hydrogen atoms and the other two atoms may be lower alkyl groups.

Examples of non-toxic salts of compound (I) include inorganic salts such as sodium salts and potassium salts, and organic base salts such as ammonium salts and triethylamine salts.

The compound of the present invention can be produced by the method shown in the reaction formula.

(TI) (m) Reactive derivative of (TI) (III) Reactive derivative (Otori) (In the above formula, I Re ■ R1 and R4 have the same meanings as above. X is a chlorine atom or a pyridylthio group.

etc., Y is Na, "MgBr
It means an active salt of methylene group such as. ) Compound (I) of the present invention is a reactive oil derivative of a carboxylic acid represented by the general formula (If) and a lower alkyl ester of methylene diphosphonic acid represented by the general formula (m) in the methylene group. It is produced by reacting with the following, and then, if necessary, hydrolyzing the reaction product.

Examples of reactive derivatives of the compound (IT) include acid halides such as acid chloride and acid bromide; active esters such as 2-pyridylthiol and N-hydroxybenzotriazole; p) mixed acid anhydrides with luenesulfonic acid, etc.; Acid azide: Examples include alkyl carbonic acid mixed acid anhydrides.

In addition, examples of reactive activators for the methylene group of compound (m) include alkali metal salts such as sodium salts and potassium salts, bromine magnesium salts ("MgBr.sub.2"), and the like.

The above-mentioned reactive derivatives and reactive derivatives, compound (II)
It may be prepared when reacting with (m).

In order to prepare an acid compound, a carboxylic acid (IF), thionyl chloride, phosphorus trihalide, etc. may be reacted by a conventional method, and in order to prepare a 2-pyridylthiol ester, for example, pretane, Op, The, Chemical, Society, Op.

Japafu (Bull, Chem, Sac, Japa
n) 1974, Volume 47.

Compound (II), phenylphosphine and 2,2'-pyridyl disulfide may be reacted according to the method described on page 1777. In addition, in order to prepare the salt of compound (m) from salt of compound (m), sodium chloride tetrahydride and Grignard reagent (for example,
C2H, MgBr) may be reacted by a conventional method.

This reaction is carried out in an organic solvent inert to the reaction using approximately equimolar proportions of both reactants or an excess of one of them. Examples of the solvent include pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, dimethylformamide, and ethyl acetate.

Acetonitrile etc. are used.

Depending on the type of reactive derivative or reactive substance, the addition of a base such as triethylamine, pyridine, bicoli/lutidine, N,N-dimethylaniline, potassium carbonate, or sodium hydroxide may help the reaction proceed smoothly. , it may be advantageous to do so.

The reaction temperature varies depending on the type of 9-reactive derivative and is not particularly limited.

Next, hydrolysis is performed on R1-R4 in compound (1).
This is a step of deesterifying a compound (phosphoric acid ester) in which part or all of is a lower alkyl group. Hydrolysis involves treating compound (I) with a strong acid or trimethylsilyl halide in a water-free solvent. Usually, commercially available hydrobromide and acetic acid as is or diluted as appropriate.

Chloroform, benzene, toluene, etc. saturated with soluble hydrogen halide gas, carbon tetrachloride, dimethylformamide, chloroform.

A solution of trimethylsilane iodide in a solvent such as toluene is used. The temperature for hydrolysis is either cooling or heating. For example, when trimethylsilyl halide is used under cooling at -10°C or less, the target compound is partially hydrolyzed. generate.

(Effects of the Invention) The compound (I) and its salts provided by the present invention have excellent anti-inflammatory action, antipyretic and analgesic action, and action to improve bone abnormalities caused by rheumatoid arthritis, arthritis, osteoporosis, etc. It is useful as an anti-inflammatory agent, antipyretic, analgesic, anti-rheumatic agent, anti-arthritic agent, and anti-osteoporosis agent.

The compound (I) of the present invention and its salts can be used as is or as a pharmaceutical composition mixed with known pharmaceutically acceptable carriers, excipients, and the like. Administration is by oral administration in tablets, capsules, powders, granules, pills, etc., injections,
syrups, ointments.

Parenteral administration such as suppositories may be used. The dosage varies depending on the subject, administration route, symptoms, etc., but is usually 1 to 500 mg per day for adults, preferably 10 to 1 mg per day.
100 IQ, which is administered orally or parenterally in 2 to 4 divided doses per day.

(Example) Next, the compound of the present invention and its manufacturability will be explained using examples.

Example 1 Sodium hydride (60% oil) 0.28g THF
Add 1 g of ethyl methylene diphosphonate to the 5 mt suspension.

The mixture was added dropwise at a temperature below 15°C. After stirring at room temperature for 1 hour, 0.5 g of benzoyl chloride was added dropwise at below 10°C. After stirring at room temperature for 1 hour, ice water was added to the two reaction solutions. After washing the aqueous layer with chloroform, concentrated salt syrup was added. The aqueous layer was extracted with chloroform, and the organic layer was dried over botanicals and the solvent was distilled off to obtain 1.3 g of liquid ethyl 2-oxo-2-phenylethylene-1,1-diphosphonate L-1c.

(1) Mass spectrometry value (FAB Masa) 393 (M
+1) (11) Nuclear magnetic resonance spectrum (CDCI, medium) δ: 1.32 (12H, C for X 4') 4.08
~4.44 (8HCH,X4)5.02 (IH
, t, C0CH< )7.4-7.6 and 7.
9-8.1 (5H, H in aromatic ring) Example 2 Ethyl 2-oxo-2-phenylethylene-1,1-
1.2 g of diphosphonate was dissolved in 20 ml of carbon tetrachloride and cooled with ice water. under an argon atmosphere.

L-c309 stirring 1. Concentrated dry. picture. , 27- After burning and repeating concentration several times, recrystallization from acetone-hexane yielded 0.6 g of hygroscopic 2-oxo-2-phenylethylene 7-1.1-diphosphonic acid. .

The physical and chemical properties of this compound are as shown.

(1) Melting point 155-157°C (asentohexane)
(11) Elemental analysis value (CIH+oOzPt ・I Hq
O) C (%) H (%) Theoretical value 32.23 4.06 Experimental value 32.22 4.04 (iii) Mass spectrometry value (FAB Mass) 2
81 (M+1)Gv) Nuclear magnetic resonance spectrum (
in D20) δ: 5.10 (LH, t, C0CH()
7.48-8.12 (5H, H of aromatic ring) Example 3 0.85 g of picolinic acid, triphenyl thread sphine 2
g, 2.2'-divirdyl disulfide 1.7 g
and 6 ml of toluene under an argon atmosphere.
Stir for hours. This solution was cooled with ice water. To a solution of 2 g of ethyl methylene diphosphonate in 10 mA of THF, 0.56 g of sodium hydride (60% oil) was added at 15° C. or lower. Two hours after the temperature was returned to room temperature, this solution was added to the toluene solution of picolinic acid active ester at 15° C. or lower. The mixture was further returned to room temperature and stirred overnight. 20 ml of ethyl acetate was added to the reaction solution, and the mixture was extracted three times with 10 ml of water. After washing the aqueous layer with chloroform, 3N hydrochloric acid was added to adjust the pH to below 1. This aqueous layer was extracted with chloroform, the organic layer was dried with Bottle salt, and the solvent was distilled off.
-0.5 g of diphosphonate was obtained as a liquid. The physical and chemical properties of this product are as follows.

(1) Mass spectrometry (FAB Mass) 394 (M+1
) (i+) Nuclear magnetic resonance spectrum (CDCI, medium) δ: 1.18-1.40 (12H, CH3X4
)4.04~4.40 (8H,CH,X4)6.46
(IH,t,C0CH()7.4~8.8 (4
H, H of pyridine ring) Example 4 Ethyl 2-oxo-2-(2-pyridyl)ethylene-
0.9 g of 1,1-diphosphonate was dissolved in 10 m of carbon tetrachloride, and a solution of 1.43 m of trimethylsilyl iodide in 2 ml of carbon tetrachloride was reacted in the same manner as in Example 2.
After reprecipitation with hot methanol, the hygroscopic 2-oxo-2
-(2-pyridyl)ethylene-1,1-cyphosphonic acid 0
．． 6 g was obtained. The physical and chemical properties of this product are as follows.

(1) Elemental analysis value (C1H0No, P2・0.3H, 0
) C (%) H (%) N (%) Theoretical value 29.35 3.38 4.89 Experimental value 29.29 3.28 4.73 (11) Nuclear magnetic resonance spectrum (in D20+NaOH) δ: 5. 2
8 (IH, t, C0CH()7.56~8.8
(4H, H of pyridine ring) Example 5 Ethyl methylene diphosphonate 2.88 g,
) Luen 20m7. Sodium hydride (60% oily) 0
．． 4g.

Example 1 using 1.9 g of 1-su7toyl chloride
React and treat in the same manner as ethyl 2-(1-naphthyl)
-2-oxo-ethylene-1,1-diphosphonate 1.
2g was obtained. Next, add 10ml of carbon tetrachloride.
Using 1.62 ml of trimethyl iodide.

Reacted and treated in the same manner as in Example 2 to give 2-(1-naphthyl)-
2-oxo-ethylene-1,1-cyphospho/acid 0.84
I got g. The physical and chemical properties of this product are as follows.

(1) Elemental analysis value (CI2 Ht207 P2 )C(
%) H (%) Theoretical value 43.65 3.66 Experimental value 43.26 3.57 (11) Mass spectrometry value (FAB Mass) 331
(M+1) (iii) Nuclear magnetic resonance spectrum (D,
(in O) δ: 7.44 to 8.6 (H in naphthalene ring)
Example 6 CI<) COCH<: Notice CM, CN ethyl methylene diphosphonate 5.76 g, ) run 25
ml? Hydrogenated sodium A (60% oil-based) 0.9 g
Using 3.5 g of tp-chlorobenzoyl chloride.

The reaction and treatment were carried out in the same manner as in Example 1 to obtain 1.67 g of ethyl 2-(4-chlorophenyl)-2-okine-ethyle/-1,1-diphosphonate). Subsequently, this was reacted and treated in the same manner as in Example 2 using 16 ml of carbon tetrachloride and 2.3 m7 of trimethyl iodide to obtain 2-(4-
(phenyl)-2-oxo-ethylene-1,1-diphosphonic acid was obtained. This was recrystallized from acetonitrile to obtain 0.9 g of acetonitrile solvated crystals.

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

(1) Melting point 160-161℃ (acetonitrile) (11) Elemental analysis value (C, H007P2C1, 0,9
0H,CN)C (%) H (%) N (%) Theoretical value 33.47 3.33 3.59 Experimental value 33
．． 26 3.29 3.71 (iii) Mass spectrometry value (FAB Mass) 315 (M+ 1) (
IV) Nuclear magnetic resonance spectrum (in D2o) δ:
2.05 (3I(,s,CH30N)5.07 (
IH,t, C0CH() 7.58 (2H, H of aromatic ring) 8.02 (2H, H of aromatic ring) Example 7 PO(OH)2 MeOOC0CH< p. (OH).

5.76 g of ethyl methylene diphosphonate,
Tol x y 25ml 1t Sodium hydride A (60% oily) 0.9g.

Using 3.4 g of anisoyl chloride, the reaction and treatment were carried out in the same manner as in Example 1 to obtain ethyl 2-(p-methoxyphenyl-2-oxo-ethylene-1,1-diphosphonate).
3.2g was obtained. Subsequently, this was dissolved in 30 ml of 25% acetic acid and left overnight at room temperature. The reaction solution was concentrated, azeotropically concentrated several times with toluene, dissolved in water, and purified using an HP-20 column. Collect fractions containing the target substance,
Concentrate to dryness to give hygroscopic 2-(p-methoxyphenyl)
1 g of -2-oxo-ethylene-1,1-diphosphonate was obtained as a colorless amorphous solid. The physical and chemical properties of this product are as follows.

(1) Elemental analysis value (Co Hat Oa Pt + 0
．． 6 H20) C (%) H (%) Theoretical value 33.68 4.15 Experimental value 33.40 3.82

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, [A] is a phenyl group, a naphthyl group, a monocyclic or bicyclic nitrogen-containing heterocyclic group, R is a hydrogen atom, halogen atom, lower alkoxy group, lower alkyl group, R^1, R^2, R^3 and R^4 are the same or different and mean a hydrogen atom or a lower alkyl group, respectively) 2- Substituted-2-oxo-ethylene-1,1-
Diphosphonic acid, its ester or its non-toxic salt.