JPS58219118A - Medicinal composition based on theophylline and substituted cinnamic acid amide therefor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to medicaments derived from theophylline that exhibit long-term activity.

Theophylline, also known as /, J-dimethylxanthine, has the following formula: Theophylline is a water-soluble, bitter-tasting white powder that is based on the relaxation of bronchial smooth muscle.

Shows bronchodilatory action; theophylline shows activity against all bronchial constrictors; in addition, theophylline partially inhibits degranulation and causes the release of histamine in response to hypersensitivity. It has an inhibitory effect on mast cells.

R, W, Butcher and B, W, 8uth
Arland Yoshi J.

Blol, Ohem, Volume 237#124t#
As shown on page 1210, this activity is associated with phosphogesterase, i.e., cyclic AMP (
cyclic adenosine °3/, zl-monophosphoric acid) j′-person M
It appears to be associated with a competitive inhibitory effect on enzymes that promote transfer to P. The result is an increase in tissue of cyclic AMP, which is responsible for theophylline activity.

Theophylline has long been used to treat asthma;
Its use is somewhat problematic; the compound is considered to be poorly tolerated and ineffective. Current measurement methods using high performance liquid phase chromatography and immunoenzymological methods allow the concentration of theophylline in blood to be determined easily and accurately. Medicinal drugs based on these methods are becoming important in the treatment of asthma.

Adrenocorticosteroids are sometimes used primarily as bronchodilators in the treatment of asthma, and therefore theophylline is clearly a bronchodilator.Theophylline is well absorbed orally. On the other hand, absorption from the rectum is extremely irregular. Intrapulmonary administration via aerosol has no effect.

The relationship between therapeutic efficacy and blood concentration has been determined.

As for the case where the concentration in blood is J-20 Cape/l.

The improvement in vital capacity is proportional to the logarithm of theophylline concentration. Signs of intolerance appear at concentrations above 1 owq/L; ie, indigestion, neurological disorders.

Heart failure is followed by neurological symptoms.

Most of theophylline is metabolized in the liver to produce inactive metabolites, which are eliminated by the kidneys.

Half-life varies slightly with age and individual. This half-life is close to an average of 4 hours in a normal adult, but a half-life of 3 hours is also normal. It is necessary for each dose to be absorbed. However, because asthma attacks are chronic - careful treatment by regular administration of frequent medications throughout the day is almost impossible.

Therefore, various galenical pharmaceuticals have been proposed, such as microgranular pharmaceuticals that slowly release theophylline into the digestive tract.

However, reducing the frequency of drug administration and also reducing fluctuations in theophylline concentration in the blood may make administration easier. It is desirable to obtain more persistent superficial blood theophylline concentrations.

Therefore, research is being conducted on compositions comprising theophylline and compounds that maintain the theophylline concentration in the blood within a therapeutically preferable range and exhibit long-term activity. We have recently developed a theophylline-containing composition that eliminates theophylline's shortcoming of a relatively short half-life, provides a stable theophylline concentration in the blood for a long period of time after administration, and exhibits a therapeutic effect for 21 hours. did.

According to the present invention, theophylline or a derivative thereof and the general formula (■): [wherein R represents hydrogen, halogen or an acetyl group; R1 represents hydrogen or a methyl group;
14-Of (IOH(ff) < R3 is hydrogen or methyl group); or R1 and the island are adjacent -3
- capable of forming an oxazolidinyl group] is provided.

Examples of substituted cinnamic acid amide compounds that can be used in combination with theophylline include N-(λ-hyproxethyl)cinnamic acid amide;
N-(2-hydroxyethyl)-guchlorocinnamic acid amide 13; N-methyl, N-(2-hydroxyethyl) cinnamic acid amide 7%; N-(,2-(/~droxyzolovir))]cinnamic acid amide; N-(,2-hydroxyethyl)-l-fluorocinnamic acid r; N-(2-hydroxyethyl)-guacetyl cinnamic acid +9
-chlorocinnamoyl), 2. ．． 2-dimethyloxazolidine; λ.

λ-dimethyl-j-(fluorosinnamoyl)oxazolidine and 3-cinnamoyl-2,-1-dimethyloxazolidine can be used.

Compounds in which R is a group of the above formula can be prepared by the method described in French Patent No. 1, oao, tri. For example, the general formula: al-NH-OH-OH,OH(t)C can be reacted with an amine of the above formula, 1t11 (3 and R3 have the same meanings as above). The reaction is carried out in an inert solvent such as dioxane, tetrahydrofuran or chloroform.
It may be carried out in the presence of an alkaline agent such as an alkali carbonate or bicarbonate, an organic base such as pyridine or triethylamine, or in an excess of 2M of the compound. The reaction may be carried out at a temperature ranging from θ°C to the boiling point of the solvent used.

Examples of such compounds are as follows: Compound I
:N-(λ~hydroxyethyl)cinnamic acid amino)' $
011H13NO2, M (molecular weight)=/riheλko.

Crystallized in the form of beautiful white crystals, melting point = 100. r~/
Toxicity LDs when administered orally to mice at 02.1°C
o-4000m97 to 9 [common name: idrosylamide (1 droc 口罐-mlde')].

Compound 11: N-(λ-hydroxyethyl)-
Hiro-chlorocinnamic acid amide, 0IIHI, (MNO,
M=22! , A.I.

White needle-like crystals, melting point t3y ~/3r, z℃, LD
50 (oral administration to mice) = /100 to /kf.

Compound ■: N-methyl e N-(2-hydroxyethyl)cinnamic acid amide, 0! Goose HIINL) 2, M-20
, 21° white powder, melting point = 72 ~ 1°C, LD,...
(oral administration to mice) = J 000 wq/kg.

Compound IV: N-(co(/-hydroxypropyl))
Cinnamic acid amino Y, 011H1sNOm, y=2o
Z, Koj.

Small white flakes, MjIt points: /[4(-/+A
°C, LDi.

(oral administration to mice) -= 3200 k80 compounds'
%l':N-(,2-hi#:"roxyethel)-p-fluorocinnamic acid amide#OllHlmFNOlm"
“Koy, -1.

Melting point = too-ioλ°C, LDIIo (oral administration to mice) = 3200 mp/kf or more.

Compound ■: N-/2-hydroxyethyl)-guar 7tylcinnamic acid amide *ots) (tsl'Jos l M
``Coco L, 2t.

Melting point=lλ≠~lλj°C, LD. Oral administration to mice)
Engineering J J 00119/kp.

Compounds ■ and ■ are described in the French Patent No. 1, 04/1O
.

/J'/ is a new compound not described in the specification.

The compound in which -NFLIRs is a λ,2-dimethyl-3-oxazolidinyl group can be obtained without condensing ethanolamine and acetone to produce an intermediate oxazolidine in the first step and then isolating it.

It can be prepared by reacting K with cinnamoyl chloride of the general formula (1) above. Advantageously, the reaction is carried out using an excess of ethanolamine. Examples of compounds prepared by this method are shown below.

Compound ■: j-(4I-chlorocinnamoyl)-2,2
-dimethyloxasilicif *Ot*Ht@0tNO
1.

M=2jj, 73. White crystals, melting point = 107. j,
109.1℃.

LDl@(oral administration to mice) = 3200 ~/hoof or above Compound ■: λ, 2-dimethyl-3-(≠-fluorocinnamoyl)oxazolidine* 0tiH1@FNQ□
M=J4tP, J7, melting point=/Qt-IOt℃,
LDm* (oral administration to 1 mouse): 2000 k/kf.

Compound ■: 3-cinnamoyl-11, cosimethyloxazolidi7e 014H1yNO2, M=Jj/, J
P.

Melting point = 107-10 °C, LD, oral administration to mice) = J200yq/10°C. ' Examples of the preparation of novel compounds according to the invention are shown below.

Example/: j-(4(-chlorocinnamoyl)-2°/
J, 44t (0, Jλ moles) of ethanolamine were added dropwise to 30cc of acetone and the mixture was heated.

After cooling to room temperature %/1.3? (0.02 mol) of darkchlorocinnamoyl chloride and J Oec in acetone, while reducing the temperature to /j-2.
The mixture was maintained at θ°C and stirred at room temperature for 2 hours. The reaction medium was diluted with water and the j-(4I-chlorocinnamoyl)-1, cordimethyloxazolidine was isolated as white crystals. The crystals were filtered, dried and recrystallized in heptane.

Melting point processing 107. j~10ri, 5℃.

Elemental analysis 014H,, ClN0. M Engineering 261.
73O% Hl 01% N% theoretical value t
3. KO P t, 07 / JL31 Yo λ7 actual measurement value
t3. it tko0 /1440 J:kotIR(
KBr) y (0=17)=/ , 4406B-'R
MN (ODOIm) δ= /, 7 p p
m (-heavy ring, $H) 17-Hiroshi 3 (multiplet, Hiroshi H) j, j (double ring, J = 74') f z # l
H) 12-7bu (complex dense term, 4CH) 2bu (double ring, J=/$Hg, IH).

Example Koni N-(co-hydroxyethyl)-Hiroshi-37a
A solution consisting of y (2.03 mol) of difluorocinnamoyl chloride and t of dioxane was mixed with λ 79 (
The mixture was added dropwise to a solution consisting of 17 mol of ethanolamine and 17 mol of dioxane at 0°C. The reaction mixture was stirred at room temperature for 3 hours, then dried overnight and concentrated under reduced pressure. The residue was dissolved in sodium bicarbonate solution. N-
The precipitate of (2-hydroxyethyl)-hyfluorocinnamic acid amide was filtered, washed with water and dried. Yield 3 pits
(Yield: t3chi). This product was recrystallized in ethyl acetate. Melting point = -ioo, io2℃ Elemental analysis olI Hl! PNO3M=koOri, λ
λ(4Hl Fl N% Theoretical value t3.ia jnear!or c7゜Actual value t3.OF yotr Name 3 bu, 7 ko I
R(KBr) j/ (0=0)=/, Ato6
R-1 Example J: N-(λ-hydroxyethyl)-≠-
1t (o, or mol) of l-acetylcinnamic acid (
G.

H,01eLand, J, Org, Ohem, ,
344, 74A4I (/94 F)], a mixture consisting of thionyl chloride of 301 and benzene of HiroOct was refluxed for 20 minutes. The reaction solution was concentrated under reduced pressure. The remaining solid was dissolved in 100 cc of dioxane and the solution was diluted to 2.3y (o, ismol).
was added dropwise at 20°C to a solution consisting of ethanolamine and dioxane. The reaction mixture was stirred at room temperature for 1 h, then mixed with 5 oot of ice water and J Occ of 10 NHO.
The mixture was poured into a mixture with L and extracted with chloroform. After washing the organic phase with water, it was dried over sulfuric acid. The solvent was evaporated under reduced pressure to give N-(cohydroxyethyl)-l-acetyl katamide, which was recrystallized in ethyl acetate. Melting point; lkoda~tsz°C. Collection
:Hiroshi, -2ノ (yield: 3%) 3 Elemental analysis olH1-N03M=233.2%
H% N coefficient theoretical value tt, y36.
pr t, oi actual measurement value 6mu to mu31 /,
, /2IR(KBr)j' (0=0)=/,610
and /, ttOan-” Starting from ginseng-fluorocinnamoyl chloride and working according to a method similar to Example 1, j-($-
For the production of (fluorocinnamoyl)-1,-dimethyloxazolidine. Yield near 7cm; melting point = toA, iol
'C (hexane-ethyl acetate).

Elemental analysis 0,4H8,FNO,M=2μri e-27C
% Hchi Fchi N eutheoretical value J74't J, 4t7712142 actual measurement value
&7443 Jjj 77/jNiaJ Starting from cinnamoyl chloride, 3-cinnamoylruco, 2-dimethyloxazolidine was prepared according to the same method as in Example 1. Yield: 7 excellent.

Melting point: 107-10 °C (recrystallized from hexane-ethyl acetate).

Elemental analysis 014H1, No3 M=, 23/, λ2C
Chi H Chi N Chi Theoretical value 7tljta 7≠/t, O4 actual value 7.
The tJ co Z4J t,Or animal model was selected and developed and treated with N-(j-hydroxyethyl)cinnamic acid amide (
The long-term effects of theophylline in combination with compound ■) were investigated.

A type of Wista, male rat with a weight of 0-24IO9,
After 74 hours of fasting, theophylline was administered in the form of an aqueous solution.

Half of the test rats were given theophylline at the same time as jl.
Rosilami F suspended in Arabian Jum at a concentration of
'' (Compound I) and the other half received Arabia'5
Theophylline suspended in 100% chloride was administered. Theophylline was administered at a dose of tzwg/kq and idrocilami)'Vi/ODart/kcy. Groups of nine rats were killed by cutting the carotid artery at 71 minutes, 30 minutes, 1 hour, 3 hours, and 1 hour after administering theophylline. . Rat blood was collected in heparinized tubes and centrifuged, and the plasma was then decanted. After plasma was removed, the theophylline concentration in the blood was measured by liquid phase chromatography.

The average value of theophylline concentration in the blood thus obtained and the pharmacodynamic (pharmacodynamic natlc) /'!
-) The calculated values of the meter are shown in Table 1.

Table 7 N8 = Not Significant, 8; Significant From Table 7 it can be observed that: I) The maximum concentration of theophylline in the blood wanted to increase: in the case of theophylline alone, 2o, lump.

7 when theophylline and iProsylamide are used together
7.7μ.

λ) What is the blood concentration of theophylline obtained when theophylline is used in combination with idrociland?

From 3 hours after administration to the end of the study, it is significantly greater than with theophylline alone; at 1 hour the concentration is 2.7 times greater.

3) The half-life calculated from the maximum value increases by % pH by co-administration of Ido-Dilami-P.

Area under the lytheophylline concentration one-hour curve (are
a) increases by 1 hour after administration and by 0.7% when extrapolated to infinity.

Figure 7 is a curve showing the relationship between theophylline concentration and time after administration of theophylline alone or together with Idrosylamide; this curve shows that when used in combination with Idrosylamide, the stability of theophylline is improved and the biochemical In Fig. 1, the concentration of theophylline expressed in %q/l is shown on the y-axis at t (hours) at 16 hours of administration, and the y-axis shows the concentration of theophylline. Curve 2 shows the concentration of theophylline when theophylline is used alone and when theophylline-hydrosylamide is used in combination.

From the above test examples, it can be seen that some of the structural homologs of N-(2-hydroxyethyl)cinnamic acid amide, when administered with theophylline (e.g., as shown in Figure 1) It has been speculated that it has the property of significantly increasing the area underneath. Various compounds of the present invention gave the results shown in Table 2 in the tests described above.

Various cinnamic acids were tested in the same manner as the tests described above, the results of which are shown in Table 1; the results are shown in Table 1. In this case, theophylline is /jv/k
f. Cinnamic acid amide was administered at a dose of 100wy7kq.

The mixture of theophylline and substituted cinnamic acid amide according to the present invention can be used as a medicine in the application of theophylline and its derivatives in the treatment of asthma.

A mixture of theophylline and a cinnamic acid amide compound polysubstituted with dimethyloxacylyl groups.

It has been found that mixtures of theophylline and J-(4!-chlorocinnamoyl)-1,2-dimethyloxazolidine or 3-cinnamoyl-2,2-dimethyloxazolidine are highly advantageous. .

The optimal proportion of substituted cinnamic acid amide derivative in the mixture will vary depending on the age and weight of the patient. Cinnamic acid amide derivatives exhibit effects on the metabolic concentration of theophylline even at small doses. Theophylline and cinnamic acid amide Vi, depending on the patient and the drug format, expressed as a molar ratio of thiophylline:cinnamic acid amide, approximately /:0. /~7. Preferably, they may be mixed in a weight ratio of 2', I-/:4A.

Theophylline in free form or in the form of derivatives.

For example, the form bound to ethylenediamine (euphyllin,
aminophylline) can be introduced into the mixture.

Additionally, both theophylline and aminophylline may be administered.

A unit dosage of theophylline or its derivatives heavy-transformed cinnamic acid amide P mixture may be 10-/200 tq. Preferably, the dose is administered twice per day p/hourly.

Some examples of formulations which can be used therapeutically are given below, consisting of a mixture of theophylline or aminophylline and a substituted cinnamic acid amide according to the invention. Amyl cinnamic acid in the mixture
The proportion of derivative may be varied taking into account, inter alia, the age and weight of the patient.

No, /tablet theophylline λ00q00～
Dermatamide CoOO■Lactose
3. Denzon
33mg gelatin
70 ■ Alginic acid
+20 dust magnesium stearate
3q00119 NO62 Tablets that can be cut into small cedar sticks Theophylline 200■ Substituted cinnamic acid amide'#00mg Lactose 10~, ゛Starch! 0tay gelatin /! my1wg
Alginic acid 30 ■ Magnesium stearate! ■7jOki No,j Sugar-coated tablet Human and Theophylline λoo Misaki 100mg Substituted cinnamic acid amide 100■ 100■
Lactose J7+y
4! Owq Starch 3rd Season θ ~ Gelatin rq
4wg alginic acid /
1IIql-211v Magnesium Stearate
3 da Kokigu oo da 300 ~ Sugar coating The whole AOOtq! Amount that becomes Q Key sugar coating agents: Sugar, Arabian man, gelatin, talc,
Same formulation as White Wax NoJ. However, before coating with sugar coating, an acetone-isoprono-7-nol solution of HyProxypyl methylcellulose phthalate was applied to make the tablets resistant to gastric juices.

No, j suppository aminophylline 300wg substituted cinnamic acid amide JOOwg semi-synthetic glycerai P 7 tablets 93sP No, A injection solution human and theophylline y
JOOwg jOrrq substituted cinnamic acid amide F″ /J da /j Misaki Sodium Anisate JOOwg /1
0 Misaki Ethanol (ri6°) 0,2
1wd O, Coj - Treatment Example I A series of comparative treatment trials were conducted. ! asthmatic patients (male,
200μ of theophylline and /DOη of idrosylamide were simultaneously administered orally to adult subjects, λ times a day, at the hour and one theta hour. After reaching an equilibrium state,
The concentration of theophylline in the blood of treated patients was measured at different times. The measurement was performed using high pressure liquid phase chromatography (Wat
ers equipment; adsorbent, Merck-IIichro
sorb RP/ff, methanol, formamide P,
Potassium phosphate solvent: U, V, spectrally detected). The average values obtained are shown in Table 3.

2 hours after morning medication //, J-μ
I l+2
# r # //, jz
/J#
10 From the above results, we can see the following:
.

l) What is the theophylline concentration in the blood before taking medicine in the morning? , zTng/l, that is, in the active concentration range. At this point, the longest time has elapsed since taking the drug, so theophylline mrx is at a low Jlt4), meaning that during the night the theophylline concentration is sufficient to exhibit therapeutic activity. do.

2) Throughout the whole day of the test, the concentration of theophylline in the blood increased moderately after morning administration, and remained within the range of 10 kg/l overall. Theophylline concentration is therefore stable.

'3) Seventy-two hours after the morning dose, and before the next morning's dose, the theophylline concentration is still 10 K/t, ie, a concentration sufficient to exhibit therapeutic activity.

Therefore, it can be concluded that when theophylline and ipromycin are used together, the theophylline concentration remains stable for a long period of time and exhibits a therapeutic effect during the daytime (-day).

In order to compare the results with treatment example IK, a test was conducted under the same conditions except that only 200 Cape theophylline was administered. The results are shown in the table below.

2 hours after morning dose ”'7-! II #
/Q, jit z
,zl lko l/,
3200mg theophylline alone or this and 10
Figure 2 summarizes the results obtained when administering 0 wg of iP rosylamide to humans at intervals of 2 hours every 7 days. In FIG. 4, the elapsed time (i) from morning dosing is shown on the X-axis; time O corresponds to the time of dosing of the μth dose. The 0 curve ■, which shows the theophylline concentration in blood on the y-axis, is thiophylline, and the 5 curve ■ is theophylline 2.
The results are shown when 00q and 100 mg of iP rosylimide were administered.

In addition to the fact that a stable theophylline concentration can be obtained by using Hydrocylamide P and theophylline in combination, in both cases of curves I and ■, even though theophylline of 000 cape was administered.

It can be seen that the area of curve 1 for the mixture is very large.

Theophylline absorption is very poor when administered orally.
The first reason is that the mechanism of action of the drug is related to the interference effect of idrosylamide on the metabolism of theophylline. As a result, the half-life of theophylline is shown to be increased. In adults with normal renal function, theophylline dosage varies from patient to patient, although absorption of this drug is good. This variation results from differences in the metabolic abilities of individuals. By using idrosilane, which acts at the metabolized level of theophylline, the mixture can be administered in uniform doses.

Treatment Example ■ Eleven other asthma patients were treated with theophylline-hydrosylamide mixture. There were no problems with tolerance, and the treatment results were good. In some cases, particularly good results have been obtained without the use of corticoids. −

[Brief explanation of the drawing]

FIG. 7 is a graph showing the relationship between thiopolylin concentration and time after administration. FIG. 2 is a graph showing the therapeutic effect according to the present invention.

Claims (1)

[Scope of Claims] t Theophylline and the general formula (1) [In the formula, R represents hydrogen, HQ, or an acetyl group; R represents hydrogen or a methyl group; - represents -0H-O
H, OH 1 (fl) (R*Vi is hydrogen or methyl group); or tortoise and R1 together with the adjacent nitrogen atom represent 2,
forming a 2-dimethyl-3-oxazolidinyl group]. Pharmaceutical compositions based on theophylline with long-term activity. Cinnamic acid amide is 3-(≠-chlorocinnamoyl)-
2,2-dimethyloxitezolidine. A composition according to claim 1. 3. Cinnamic acid amide is 3-cinnamoyl-2,,2-dimethyloxazolidine. A composition according to claim 1. France Amyl cinnamic acid is idrosylamide. A composition according to claim 7. or in unit dosage form consisting of 10-1'200 ql of said mixture. A composition according to claim 1. t Theophylline consists of aminophylline. A composition according to claim 7. 2 The unit dosage form consists of a tablet, injection ampoule or suppository. A composition according to claim 1. L General formula: (In the formula, %R represents hydrogen or halogen; R and R2
(forms a co,2-dimethyl-3-oxazolidinyl group with the adjacent nitrogen atom). ta N-(co-hydroxyethyl)-≠-acetyl cinnamic acid amide