JPS5948445A - Biphenylylpropionic acid derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is 1-15C alkylcarbonyloxy or alkenylcarbonyloxymethyl). EXAMPLE:Acetyloxymethyl 2-(2-fluoro-4-biphenylyl)propionate. USE:An antiphlogistic and analgesic agent. Useful as a drug having rapid activity, high safety, and wide application range. PROCESS:The compound of formula I can be prepared by the esterification reaction of the 2-(2-fluoro-4-biphenylyl)propionic acid of formula II or its salt with the alkyl- or alkenylcarbonyloxymethyl halide of formula XR (X is F, Cl, Br, or I). The reaction is carried out preferably in DMSO, etc. in the absence of presence of usually K2CO3, Na2CO3, NaOH, etc. The compound of formula I has high rate of hydrolysis in the body.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to alkylcarbonyloxymethyl esters and alkenylcarbonyloxymethyl ester derivatives of lylupropionic acid and processes for their production.

2-(2-Fluoro-4-biphenylyl)propionic acid (Flurubidiafen, hereinafter referred to as FP) is already commercially available as a powerful anti-inflammatory, m-Q IA'r, 1T thermal agent.

However, since FP has poor solubility in water, it is necessary to make it into an alkali gold form such as ALfl, etc. to make it into an aqueous solution. Moreover, the biggest drawback is that the aqueous solution of the salt is irritating. Therefore, it is difficult to use it for injections, eye drops, etc.; 4 (f).

The present inventors have conducted extensive research to solve these problems, and as a result, they have completed the present invention by attempting to change the physicochemical properties of FP.

That is, the stinging property was eliminated by converting FP into an ester compound and increasing its lipophilicity. Moreover, the compound of the present invention is not only non-stinging, but also lipophilic, so it is more effective in in vivo distribution after administration than FP! And the destination 1 is transformed into a fire, and as a result, the inflammation bureau 19 [σpe'
:! : +1''/J6., which increases the medicinal efficacy because the high 5V per liter increases.For example, in the rat carrageenan foot edema test, the H.l;lj efficacy FP increases by about 6 times. The compound of the present invention is a safe compound because it causes less ulcer formation, which is one of the factors that occur during crop production.On the other hand, in general, the increase in lipophilicity and non-irritant property of the curved material are compared with those of carboxylic acids. Alkyl esterification is carried out, but simple alkyl esters have the disadvantage that their decomposition rate in the body is slow and it is difficult to develop medicinal efficacy.However, when the compound of the present invention is compared with FP ethyl ester, The decomposition rate is more than 10 times higher than that of herbs, and the medicinal efficacy of the herb is rapidly expressed.Also, since the compound of the present invention is hypophilic, it can be expected that the medicinal efficacy will last longer when combined with an oily base. 1t'1% Since it has a high affinity for tissues such as mucous membranes, rapid in-vivo absorption can be expected.

From the above, the compound of the present invention is a sharp compound, FP.
It is non-irritating compared to
It is an excellent product with a high safety margin.

Therefore, an object of the present invention is to provide a novel FP derivative that has excellent anti-inflammatory and analgesic properties, is fast-acting, is highly safe, and is extremely useful as a pharmaceutical with a wide range of applications, and a method for producing the same. .

The compound of the present invention has the formula (II): FP or a salt thereof≠11 and the general formula (
■): XR (If /.j is obtained by esterifying an alkyl or alkenyl carbonyloxymethyl halide represented by (representing a child) with t. Such an esterification reaction can be carried out using any conventionally known method. Although not particularly limited, it is preferable to use the reaction shown in (J) from the viewpoint of yield and industrialization.

That is, this reaction usually involves alkali gold X no 1 carbonate Ll,
X (potassium charcoal, sodium carbonate, rotorium bicarbonate, potassium bicarbonate, etc.), alkali hydroxide (sodium hydroxide, potassium hydroxide, etc.), alkali metal hydride (hydrogenation) IJum, hydride potassium, lithium hydride, etc.) and aprotic organic solvents (N
, N-dimethylformamide, dimethyl sulfoxide,
Hexamethylphosphonyltriamide, etc.). As the FP salt, metal salts such as silver, copper, lithium, sodium, potassium, etc. are used. It is also possible to use a mixed solvent of the above-mentioned solvents and a solvent such as ether, tetrahydrofuran or acetone.

General formula (l11): Alkyl or alkenylcarbonyloxymethyl halide represented by the formula %() (in the formula, R and X are the same as in the iff notation) 13. The use of ゛−°−；゛ ij'i, is II・P
Or its J-fu, &Lord's protection ≠ shout out ☆ f- mole or more, preferably 7 or 1.0 to 1.5 (H'1 mole is economically equivalent to 1 profit) The reaction temperature is not particularly limited, but is usually 10 to 12
Preferably, it is carried out at 0°0.

The reaction time depends on the solvent used, "i+'r jl!i II.
1 (median) and (month i1i effect (varies depending on γ, but generally 1 to 24 hours) ends as I).

i' The misfire that is brought about by the book of Il [1] σ
) FPσ) ゛Alkyl or hydroxyloxymethane, both of the f and i forms (showing anti-inflammatory, multi-Q1 effects, and hydration in the body)゛] Cocoon tA also ((°, ゛J1. and Q.

Next, the chemical effect of the compound of the present invention is 1! :, min 1'J
'll rate 1LD5o values are shown in Table 1.

Table 1 1) Rat carrageenan float 11tl < 50% 11+1
;Ill throw, 1lF (branch) rat helmet 7'J: 50
% formation11. l.

(2) Hydrolyzed grouper in human blood 37°O% 1hr incubation, substrate Q: mol l corresponding to yP501z 1) iv) 50% lethal dose of compound 1 niacetyloxymethyl 2-(2- fluor r1
-4-biphenylyl)propionate 2: Propionyl A xymethyl 2-(2-7l]-
rho 4-biphenylyl)propi 4 years old, -1. ) Propionate // 5: 3,3-Dimethyl-acryloyl]xymethyl 2-(2-fluoro-4-biphenylyl) propionate biphenylyl) propionate 7: Bivaloyloxymethyl 2-(2-fluoro-acryloyl) -biphenylyl/I/)probionate Compound 8: Ethyl 2-(2-fluoro-4-biphenylyl)propionate//9: FP 10: Indomethacin As shown in Table 1, the compounds of the present invention are comparative examples. It shows superior mulberry effect compared to pp and indomethacin. For example, acetyloxymethyl 2-(2-fluoro-4-biphenylyl)propionate (compound 1
) has a carrageenin floating inhibitory effect (intravenous injection) compared to the comparative example FP (
3.8 times more than compound 9), indomethacin (compound 10)
It is 15 to 6 times more effective. Furthermore, comparative example FP ethyl ester (compound 8) which is a simple alkyl ester
Comparing the decomposition rate in human plasma, Compound 1 has a decomposition rate approximately 11 times higher than that of Compound 1, so rapid synergistic expression in the human body is expected. Furthermore, when compared with FP, the incidence of gastrointestinal ulcer formation, which is one of the side effects of acidic anti-inflammatory drugs, is about 1/3, and the safety margin expressed as the ratio of drug efficacy to side effects is about 11 times higher. Also, L D 5o (m q/k
42 body weight) is about twice that of FP, and its toxicity is also low.

Next, examples will be given to explain the compounds of the present invention! 1 and the manufacturing method will be described in detail, but the present invention is not limited only to those examples.

Practical example 1 (acetyloxymethyl 2-(2-fluoro-4-biphenylyl) propionate (compound or jl)) 2-(2-fluoro-4-biphenylyl) propion l' 11″ (hereinafter referred to as FP) 7.329 (
1 mmol/') was dissolved in 100 ml of aqueous dimethylpolamide, and while cooling with water, 2 g (t5 mmor) of anhydrous 1.-7f phosphorous potassium was added and stirred for 1 hour. Next, distilled distillate ij+'l acetyloxymethyl chloride 6 and filter 9 (3Dm mo/) were added at 0 to 5°.
It took 10 minutes at C to remove the sieve. 6i: After finishing the process, it was stirred at 2:11 in the room. The reaction mixture was cooled with water;
After the inorganic matter was separated in the furnace, the solvent lost H:, WI. Diethyl ether 150m7 for remaining lf'F! Add water,
Next, j:t' was washed with 10% sodium carbonate water and saturated saline, and the μ layer was dried over anhydrous magnesium sulfate. After that, the dissolved ρ:, (was distilled off under reduced pressure to form an oily layer. 8.24° of the target product (crude yield: δ6.9%) was obtained.

Further, this product was distilled under reduced pressure under a nitrogen atmosphere to obtain an oily target product 6.5B9 (yield: 69.1%, b
p=196-197°O10,4 mm) 1 g) was obtained.

Next, the characteristic values of Compound 1 are shown.

Original analysis value = (C engineering, H□7c4F SMW: 316
) Subtraction value (%): 068.35 HB, 3B
Actual value (%): C! 68.42 HB, 51NMR
Spectrum (in Oce4, TMS), (ppm) δ1
．． 49 (d, 31L 〉011-0 pressure,) δ2.0
0 (8,3H, -000-0 and) δ3.74 (q
, IH,0H3-OH) δ5.71 (8,2H
1-0-OH2-0-) δ7.03 to 7.56 (m,
81 (, aromatio H) mass spectrum (2
DeV), (Diloct) m/e 316 (M
m/e 226 ([M-00H20AO)”) m/e
199 (base peak, [MC!0
2CHOAc)+m/e 73 [-an2oAc'
]"m/e 4ro [-000H3]"Eng R spectrum (Neat) 3'l(][]~2B50cm (aromatiQ
lalkyl LIO-H) 1760am-1 (Sea
0 (IOR) 1625~1420 am-' (aro
matio, νc=c) 1370 am""
(v -000H3) Refractive index nD -1,5488 UVIJ and yield λmax = 248 nm Example 2 (Propynyloxymethyl 2-(2-fluoro-4-
11 of biphenylyl) propionate (compound 2).・
'Iii! ffi) FP 7-32g (30mm
) was dissolved in 100 mp of anhydrous dimethylpolamide and cooled on ice (HB
Add 9 (15 mmo74) to 111. ++-1i2
Stirred. Next, propionyl A made by steaming fdi fit
4.78g of oxymethyl chloride (39mm(+1
) was lowered i1:i:i under ice-cooling, stirred at room temperature for 2 hours after the addition, and further heated at 6o~70oO for 1 hour.
The reaction was completed by stirring. The reaction mixture was cooled on ice and the solvent was distilled off under reduced pressure. 150ml of dimethyl ether was added to the residue, washed successively with water, 10% aqueous sodium carbonate, and saturated brine, and the organic layer was dehydrated. After drying with magnesium sulfate, the solvent was distilled off, and this product was distilled off under reduced pressure in a nitrogen atmosphere to obtain the target substance 7.359 as a colorless oil.
(Yield: 74.2%, bp 194-196°C/Q
, i3mmHri) was obtained.

Next, 1 of compound 2, IC property ((< is shown.

Elemental analysis value (C engineering, H□, 04F, MW: 330
) Calculated value (support): C69, D9 H5,76
Actual value (%): 069.33 H5,98HMR spectrum (in a cl!4, TMS) (ppm) δ
i −o a (t 13H1-OH2-as3)/ δ1.52 ((IX3)L C!13-OH\) δ2
．． 26 ((L, 2)T, -CH2-(!It3
)δ3-72 (qs IH,0H3-OH,)δ5.
69 (B, 2H1-0-0dan, -o-) δ7.0
6-7.55 (m, 8H1aromatic H)
Mass spectrum (20eV) (irireot) m/
e 330 (M±) 11+ m/e 226 (1:M-ocH2ocIC
tt+ )11+ m/e 199 (CM -(:+020)r20
(j E t ) )11+ m/e 87 ([-CHp -00E t )
)11+ m/e 57 (baIIIe pea',
[-cF8t'3) Engineering R spectrum (Neat) 3100-2850cm (aroma;
c, a, 1kyl vC-H) 1 1760cm (SiR-000-R) 1
625-1420cm (aroma, tic
νo = (refractive index n = 1.5431 U [and λmax = 248 nm
Production of biphenylyl) propionate (compound 3)) F
P 7-32g (+0m mol), anhydrous dimethylformamide 70me, anhydrous potassium carbonate 2.1g (1
5m mol) and inbutyryloxymethyl chloride 4.08g (30mmol) were reacted, post-treated and purified in the same manner as in Example 2 to obtain an oily target product of 7.29° (yield: 70.6 %, 'bp' 188
~190' (!10.4mm1 (9) was obtained.

Next, the characteristic values of compound B are shown.

Elemental analysis I: jj (C20H2104h', MW:
344) Calculated value (%): C69,77H6,
1゜Actual 4111 value (sub) door 070.03 H6,08
HMR spectrum < ace4, TMS), (ppm
) δ1.50 (d, 3H, shout, -OHgu) δ5.
69 (s, 2H1-o-C!1i2-0-)
δ7.0 [] ~ 7.60 (m, 8H, aromat
ic H) Mass spectrum (2QeV) (Diroc
t) m/e Otsu 44 (M') 1 m/e 243 (CM-aH3oaaH(an3
)2)+)1 m/e 226 (CM-oaI(2occI((
aH3)2))1 m/e 199 (base piah, (M-co
2an2oCen(aH3)2) )1 m/e 101 ([-0H20(!0II(1:!
H3), ] )m/e 71 ((-aocu(c
a,)2) )m/e 43((-aHrOH3)
2. ]) Engineering R spectrum (tJeat) 6100~2B50cm (aromati, c 5
alkyl-v (!-H)1 1755cm (shiR-Coo-R)16
25~142 [1cm (aroma, tic va
=c) Flex 4J1 index 6 n = 1.5409 Actual bl'Ii Example 4 (Crotonoyloxymethyl 2-(2-fluoro-4-
Production of biphenylyl) propionate (compound 4) F
P7.529 (30 mmol, anhydrous dimethylformamide 100 m/, anhydrous carbon T'I:2 potassium 2.
Example 2 using 19 (15 mmol) and 4 g (30 mmol) of crotonoyloxymethyl chloride
5-57 g of oily target product (yield: 54.3%, bp = 217-2
19°Cj10, 4 mmH9).

Next, the characteristic values of Compound 4 are shown.

Elemental analysis value: (02oH0,04F, MY:
542) Nai t! I value (%): C70,18H5
,55 Actual value (%): C70,46H5,79NMR
Spectrum (a in C14, TMS), (ppm) δ1
．． 52 (a, 2.u, 053-OHgu) δ1.68
~1.95 (m, 3H, olefini, c (
! H,) δ3.73 (q, 1H,0H3-0 and) δ5.67-5.94 (m-, IH% olefi
nic H) δ5.75 (s, 2H, -0-0dan, -
o-) δ6-80~6.98 (m, IH, ole
fina H) δ7.00~7, 52 (m58H
% aromatic H) mass spectrum (20eV
) (Diroct) m/e 542 (M') 1 m/e 226 ((M-oau2oacH=cu
aH3) )1 m/e 199 (Cu-ao2aH2oaaH=an
an3] ) m/e 69 (basepeak, (
-cocn=cqtc■(3'))EngR spectrum (N
ea, t) 3100-2850cm (aromaL;ic
1 alky ν (j-H)1 1740cm (vR-000-R)11
t(Li-1'fl<n = 1.5525 uvyn 11'J.

λmax=248 nm Example 5 (3,3-dimethylacryloyloxymethyl 2-(2
-Fluoro-4-biphenylyl)propionate (f'4 structure of compound 5) FP7.329 (Omno/), anhydrous dimethylpho/
The same procedure as in Example 2 was carried out using 5.89 (39 mmol) of 1/mu7lide (9'i), and 6.57 g (yield: 61.5 %,
bp: 210-214°V0.5mmH9).

Next, the characteristic values of Compound 5 are shown.

Elemental analysis value: (C2□H2□04F, MW: 3
56) Calculated value (%): 07[1,79H5,90
Actual value (%): 071.12 H6,25 NMR spectrum (in Co/4, Tr, qs) (ppm) δ1
．． 52 (a, 3H, cH3-cHri) δ1.94 (
s, 511, olefinic 0H3) δ2,10
(8,3H1olefinic cH3)δ3.70
(q, 1) 1, C! H3-0 ■) δ5.55-5
．． 69 (m N IH, olefinic H) δ5
．． 72 (S, 2H1-o -cH2-0-)δ7.
00~7.51 (m, 8H, aromatic H
)Mass spectrum (20eV) (Direct)m
/e 356 (M) 1R spectrum (Neat) 3100-2850cm (aroma, tics
alk;yl ν(!-H)1 1745cm (vR-Coo-R) 4
1i;:i<n=1.5535 Example 6 (palmitoyloxymethyl 2-(2-fluoro-4-
Production of biphenylyl) propionate (compound 6)) F
P7.32g (30m no/'), JIK water dimethylformamide 50m/, anhydrous disease 11 dipotassium 2
．． 19 (15 mmol) and balmitoyloxymethylchloride l' 11.99 (39 mmol) in ether solution! j The reaction and post-treatment were carried out in the same manner as in Example 2 to obtain the first white crystal [its target substance 9.79
(phase rate: 73.1%). This material was also subjected to liquid chromatography (carrier: KT 2106, Elue
nt = Cyclohexane: Dichlo
romethane (1:1)) as white crystals showing a zero point of 45.5-48°C 7.3. (yield: 47.5%).

Next, the characteristic values of compound B are shown.

Elemental analysis value: (a32H, 04F, MW: 512
) Calculated value (%): C75,D H8,79 Actual 11n value (%): c 75.34 H9,04FMR
Spectrum (CC!/, Medium 1TMS) (ppm) δ
0.8B (t, Hu, -(!H2-0■3)δ1.11
~1.42 (m, 26H, aekyl H) δ1
．． 51 (a, 3rr, CH, 3-CjH<)δ2.
23 (t, chu, -oco -CH2-mouth, -) δ3.
71 (q, IH, CH3-knock) δ5.65 (s
, 2H1-o-CH2-o-) δ7.00-7.67
(m, OH1aromatic H) Mass spectrum (20eV) (Direct) m/θ 512
(M) 1 m/e 244 (CM-OH2oa (CH2),
4aH3) ) m/6 239 [-Co(CH2)
, OH3]”1 rn/e 199 (base pθah , Cu
-co2aH2oc(OH2)14cIi3) ) Engineering R
Spectrum (Neat) 3100-2800cm (aromatic, a,
13g1νo-H)1 1755cm (R-Coo-R)1 1625~1420cm (aromaticνc=
D) Example 7 (Hyhaloyloxymethyl 2-(2-fluoro-4-biphenylyl)propionate (compound ¥) 7)
) FP7.32g (30mmol, f+((water dimethylpolmu γmid 100mz, force IF water ice charcoal)
! y potassium 2.1 g (15 m m mol) and pivaloyloxymethyl chloride 4.519 (30 m m
or) 'E, the reaction, post-treatment, and purification were carried out in the same manner as in Example 2 to obtain the oily target product t(7,739 (yield:
72.0%, bp: 191-194°O10-4mm
HG+) was obtained.

Next is Compound 7, Part 1! Shows r-sexuality 1/1.

Elemental analysis value: (C2□H23FO4, MW: 358
) Vagina value (%): 070.45 H6,49
Actual measurement C69,73H6,88 FMR spectrum (in ccz4, 'XMS) (pp
m) δ1.10 (a, %, -a(CH3)3) δ1.
50 (d, 3HS Cape, -OHri) δ3.72 (q
% 1H-0H3-hit) δ5.69 (s, z+,
-0-0! ! 2-0-) δ7. OO~7.60 (m
s OH% aromatic H) mass spectrum (
20eV) (Direct)m/e! 158
(M') 1 m/e 243 (CM-OH2oca(CH3)
3) )1 m/e227 ([M-OCH20CC(CI(3)3]
)11+ m/e 199 (base peak, [M-
co2an, oCC(OH3)3) )1 m/e 115 [-0H2000(OH3)3]”m
/e 85 (Coo(C!H3)3')"+ m/e 57 [-C(CH3)3)E spectrum (Neat) 5100-2850cm (aromatic, al
kylνc! -H)1 1755cm (Ll -00OR)16
25~1420cm (aromaticνo=o)
Refraction ¥26 n = 1.53913 UV absorption λma, x = 248nlTl Actual KIL example 8 (Acedeloxymethyl 2-(2-fur 10-4-biphenylyl) propionate (Shigyu 511) 11.1
11τl1) Potassium J of FP! 2 and 8 were added with 1.2 g of dimethylformdialdehyde chloride and heated for 1 hour in a chamber/:l:f. Post-treatment and purification were carried out in the same manner as in Example 1.
11 to obtain 2.56 g (Q, yield: 81%) of the target compound. The characteristic values of this item are actual riji example 1
It matched the value shown in .

Procedural amendment (spontaneous) October 14, 1980 1 Indication of case 1988 Patent application No. 158578 2 Name of invention Biphenylyl propion Cm Wt263 and its III! ! Relationship with the case of the person making the third amendment to the Act Patent applicant Tamotsu Omori ”+ 0.
L3 representative Tamotsu Omori), 1. -'' 4 Agent 〒540 5 Subject of amendment (1) "Yl (ill) of the invention" in the specification; (
1i'-5 bright''(1; J6 ft1i positive content (IJ 'IIJ #llIS S'', i page 8, line 4 (7) l'-1[1j Q ``O, J,!= il
l Correct.

(2) In the same page 9, 81\table 1, second from the left (
1) I, 41ill and O, 6th if+l, respectively, ``)1・-! Intracavitary administration'' are all replaced with ``oral administration Jjj''.

(3) [(rA-0020HOA
c)+'' to [(M-co, 0H20Ac)+)
Add j.

(4) "Dimethyl go-thyl-1" on page 15, line 1 is corrected to "diethyl ether."

to correct.

(0) "Liquid" in the first line of page 23 is corrected to "quick hair/liquid."

('7) "Aldehyde" in lines 8-9 of page 26 is corrected to "amide."

From −]−

Claims (1)

[Claims] 1. Biphenylylpropionic acid represented by the general formula (I): (wherein R represents an alkylcarbonyloxymethyl group or an alkenylcarbonyloxymethyl group having 1 to 15 carbon atoms) Alkyl carbonyloxymethyl ester derivatives and alkenyl carbonyloxymethyl ester derivatives. 2 The above R consists of an acetyloxymethyl group, a propionyloxymethyl group, an isobutyryloxymethyl group, a pivaloyloxymethyl group, a convex palmitoyloxymethyl group, a crotonoyloxymethyl group, and a 6,3-dimethylacryloyloxymethyl group 8μ conductor according to claim 1, which is a substituent selected from fliY:. 6 Formula (I+): 2-(2-fluoro-4-biphenylyl)
Propionic acid or its J/, [and general formula (■): (representing a halogen atom such as chlorine, bromine or iodine) with the general formula (■): (wherein R is alkylcarbonyloxymethyl having 1 to 15 carbon atoms) 11. Alkylcarbonyloxymethyl esters and alkenylcarbonyloxymethyl esters of biphenylylpropionic acid represented by carbonyl or alkenylcarbonyloxymethyl groups; i'i, HAX
How to prepare your body in the morning.