JPS59196849A - Novel carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is methyl or ethyl; R<2> and R<4> are H or 1-7C alkyl; R<3> is H, 1-4C alkyl, hydroxymethyl, mercaptomethyl, or 2-methylthioethyl; n is 1-5; provided that when n is 2-5, R<3> is H). EXAMPLE:N-(1-Methylcyclohexanecarbonyl)glycine ethyl ester. USE:Useful as a hepatic function improving agent, an antithrombotic agent, and a remedy for diseases caused by immune abnormality, e.g. arthrorheumatism, autoimmune diseases, allergic diseases such as asthma, nephritis, etc. PREPARATION:The compound of formula I can be prepared by reacting the compound of formula II with a halogenation agent (e.g. thionyl chloride, phosphorus pentachloride, etc.), and reacting the resultant compound of formula III with the compound of formula IV in the presence of a base (e.g. triethylamine).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula (1) (1) Hydrogen atom or carbon, number] ~7
(Rj (7) ll'J', #i'j仄(1) f
l (ij/<'7' rukyl group, ln is hydrogen) prince,
Charcoal, +', number 1~. l I +, ', l heavy chain or branched lower alkyl group, h]cyto1-dinotyl group 3 mercap (-methyl tethered, east 2-nonalnaonithyl group, n
is an integer between 1 and 5. (jl i.

If 11 is an integer from 2 to 5, the 1 sentence is hydrogen) 3;) Child +
i, :1. Taste-・)-ru) η[Ina Carboxylic Acid 1. Me', iE? It's about the body.

The compound of the present invention is a γj compound that has not been published in the literature.
It is a useful compound as an I9S chestnut product, having pharmacological effects such as anti-I9S, anti-+111 action and liver function improving action.

Traditionally, internal division? Bi-arrow disease, rheumatism ('t: disease, knee disease, kidney disease, blood disease, gastrointestinal disease, IIFI is harmful, skin disease, allergy such as bronchial asthma) Adrenocortical porn drug for disadvantages It is cured (medicine and L7 01. are used.

However, when used for a long period of time, stentoid preparations cause joint dyeing (11).
Induction or increase of i: U(, systemic 't: Z 114t,
Adrenal function on the body) 4 (various symptoms, gastrointestinal disorders, l'
It has a major drawback of causing side effects such as polyrhythmia.
7 and J6, these Ichikawas are currently blocked. The present inventors synthesized various compounds and examined their pharmacological effects, f=1, with the aim of developing a nonsteroidal antiallergic agent effective for the above-mentioned diseases.

Now, the compound represented by the general formula (1) has pharmacological effects such as 111 function modification action, anti-+Itt plugging action, immune function enhancement, and normalizing action, and is a liver function improving agent, an anti-mountain plugging agent,
It is a compound useful as a drug for treating diseases caused by abnormal immune function, such as rheumatoid arthritis, autoimmune diseases, asthma, nephritis, and other allergic diseases.

Therefore, the anti-allergic agents in the present invention include not only drugs that have anti-allergic effects in the narrow sense, but also drugs that have anti-allergic effects such as the above-mentioned 3R effects. Yuu: Is it something to taste? :).

The experimental methods and pharmacological experiment results for the compound of the present invention are shown below.

Experimental Example 1 Picrylic chloride daily contact skin in mice]/4 Effect on Ji that causes hypersensitivity Body weight 22-24 [?
Shave the abdomen of a ddY type 1-sex female and add 0.1 ml of 7% Kurilku 1 ml (1'(:) Utanol solution).
1 was applied to sensitize the cells. Apply 1% Pc ore t8't & 20 plJ to the 71J handlebars, apply 4" and 1
Nine shots. 24 I+, stomach i, jl then J
'￥sawo d ir+ I Ll+ 1ckncs:
; Measured using gaufXe, determined the pre-induction value; ; Two people doing it.

Secondary sensitization θ shoulder LI i & lIQ using 9 to 10 animals per group.
+ Induction was performed in the same way, and after 211 hours of light attraction, the lj of moon halo
, T-me was measured, and the thickening suppression rate was determined according to the formula below.

Test compound o, 5% 1-Lagant gum water soluble? +ν/gB, and 50 summer +ur/kg was orally administered over 21111 hours at the same time as photoinduction and 16 hours after induction.

In addition, a control group was given a plate of solvent.

Thickening degree - 24 hours of induction - 11- thickening before induction J-1's jγ paste - J's monthly thickness in the drug level 1] group J' 15! , Suppression of rice fertilization 11"
--- I want to suppress 1. IJ Z to 1
<-1゜"I) <0.0 5. *Large 1) <0.0
1 (compared to control Jl'l' in degree of hypertrophy and 2) Subtraction of 1st difference Experimental Example 2 Effect on delayed footprint response by sheep red blood cells in mice 1
Groups of 9 to 10 animals were used. 2.5 x 1 to starve the left hind limb of mice
The cells were sensitized by subcutaneous injection of 0.09/ml sheep red blood cells 40 JJJ. 4 After El, induction was performed by subcutaneously injecting 2.5 x 10/ml sheep red blood cells 40 squares into the right hind paw, and then dialling a 1-width-thick paw for 24 hours.
The hypertrophy due to induction was determined by subtracting the value before induction, and the inhibition rate of hypertrophy was calculated according to the following formula.

The test compound was suspended in 0.5% 1-Lagantogono-water/mixture, and t + 0 + ■/kg was administered orally twice (same as 4 injections), 5. Induction 1 (ill; twice after injection, did.

On the other hand, the vehicle 7) was administered to control 11r.

Thickening + C no' induction 2411.5 hours Thickness of foot kick before and after induction Thickness of foot 1 Ij of control group - Foot 1 υ゛ of drug administration group (degree of thickening Foot kick thickening wind hypertrophy j7 suppression rate ------- −−−−−−−−−−−−−
---×1o.

Control group foot rotation thickening melon The results are shown in the table below.

Table: Delay by sheep red blood cells in mice) 1) Effect on 1-leg response I) Column 1 (Represents the inhibition rate for group 1).

*p<0.05. Responsibility★p<0.01 (for both hypertrophic j and jj (compared to 7IIY, there is a difference) Experimental example 3 Effect on tsherculin response in mice C571 u - / 61i1' of body weight 21-231+
Eight to nine sex mice were used per group. K11led My
cobacLeriumLuberculosis
500 J9 to 0.05 n+ IO)
An emulsion was created by adding pl (4tetr dj u r a n L).
Sensitize it by injecting it into the back skin of ugly animals. 14L! After\p
ure purified protein dcri
v(+tivcs (PI'1l)125 no 1s/m
401J-0 was injected into the north of the right hind paw (induction was performed, and 24 hours later, the thickness of the kick was measured.
+ 1ckncss gauge, the pre-induction value was used to determine the degree of thickening induced by 21' pull, and the rate of inhibition of thickening was calculated according to the formula described in 1. 0.5% test compound
+L for Tragan I/rubber aqueous solution! Cloudy, 501■/k
g was orally administered twice, simultaneously with the induction and 16 hours after the induction. In addition, for control 711, IU of solvent (2) was administered,
L saw.

Thickening degree - Photoattraction 2415 Mouth 111 Induction 1iii
1 foot thicker foot after 117j! , the thickness of the control group - drug step Ji'l'' foot 1υ° & 1111 degrees foot 1θノ' (, HI 1!,'
: 1w thickening suppression rate = -X100 Illusion 1j71 The results of Ilr's foot QH1 thickening are shown in the following table.

Table Effect on tuberculin reaction in mice 1) vs. 1
14j 7i'l' suppression rate.

"p<0.05. Peak p<0.01 (fertilization) V, degrees vs. jjjj
IoloBouspassive cutancous
c) Rest of action of napbylaxis (PCA) Six to seven male Wistar rats weighing 160 to 180 g were used per group. One place on the left and right side of the rat's back has prickly hairs.
Using physiological saline (anti-1 diluted 30 times) NP-
Δs Ig IF, 1III supernatant 0. 1 ml was injected sarcastically. 48 hours fft, 2 mg DNP-
1 m of 0.25% Evans blue saline containing A s
1 was injected into the tail vein. 30 minutes later, he died of blood loss.
Out': S'jI (Cut off the skin j5 of j7, original 11
] et al.'s method (Arezukiba I-, 151-7 (1966))
Accordingly, the leaked dye [l] was converted to /l [ll], and the leaked dye suppression rate was determined according to the formula F.

The test compound was suspended at 0.5% in 1 to 1 liter of Lagant gum water and administered orally at 100 mg/kg 2 hours before induction.
)did. In addition, a control group received only the solvent.

Leakage dye suppression rate (%) - Dye leakage amount of control fir - 4 injections - I'J group
Amount of dye leakage: 1-------------------×1o.

Control group dye leakage amount The results are shown in the table below.

Table 48 hours homologous P C in Run 1
Effect on Δ: Reduce the suppression I that appears in 11 light 711'.

”I)<'f), (15,★★p<(1,01
(In leakage pigment 111, there is 7t:-Less compared to S・ljjHjl'r) Experimental Example 5 Sudden i'l in rats: 7!f Sex weight 95
~l 1. Og's Wistar yarn fltff i'l゛soso(-) was used per group of 6 animals.
The Tahi mortality rate was determined by observation for one week.

The results are shown in the table below.

Table Acute Toxicity Experiment Example 6 in Rats There were 8 Sichuan female Wistar rats of 4 sexes, 5 weeks old, in a group of 8 Sichuan rats. Test compound dose], 000 n*/kg at 1 [
' 1 time 2811 consecutive 1-1 injection) j (multiple, organ j
Measurement of 4x amounts (liver, kidney, kidney, kidney, thymus and adrenal glands) and liver biochemical tests (GOT activity, if! ) was carried out. Test compounds are Example I and Example 3.
and the compound of Example 11, both of which were used at 0.5% [Lagan I < 1 m water solution G]. Well, versus!
((Refrigerant was poured into the first group).

As a result, J? It's C too ff
1ftl and liver 41: Almost no effect was observed in chemical tests.

J:), From the above experimental results, the compound of the present invention is 'rl!
It has strong anti-allergic effect and low toxicity.
It is a compound for industrial use as a pharmaceutical.

Next, the method for producing the compound according to the present invention will be explained.
This is merely an example and, of course, it can be produced by other chemically similar methods.

To the production method, lower)' alkyl group, R is a hydrogen atom, a linear or branched lower argyl group having 1 to 4 carbon atoms, human! A oxymethyl group, a norcabutononal group, or a 2-methylf-thioethyl group, where n represents an integer of 1 to 5, and when n is an integer of 2 to 5, 1 is a hydrogen atom r.

Manufacturing method 1-3 3 2 (1) However, in the formula, ■? , 1, 1. ! , 1ze and 0 are 1ii
Same as Book I, seven fuss, and whitening of the truth.

Production method C 3 2 (1) (rl/) 3 2 (V) 11i, where R, R, R, R and 0' n are 1) 11
I will write about it and have a taste of it myself.

Furthermore, the general formula (11) is 〇'5 departure q to the Manufacturing Currency Law.
Compounds represented by (for example, 4 inventions"?:";';
・ni, upper - 2 te + l I9 no 1 sao 已: Rikiho (Japanese Patent Publication No. 1975)
4-98 '745) and ``IJ1 Kaisho t'l 5-
2<! to 43 and 5th class! i, C (synthesis deviation is good.

Regarding the above production method, i
11. Use an inert solvent (for example -
After introducing the halogenating agent 7,-- into a compound represented by the general formula (Ill) in a temperature range of ( ) to 120° C., 8. - Amino acids represented by general formula (IV) or u: ? ': In the presence of lower alkyl esters of amino acids and bases (e.g. 1-linalamine, bilin, cymenol aniline, ethyl aniline, sodium hydroxide, water rO, potassium chloride, etc.). Soup solvent (e.g. cyenal ether).

U-1 Shihi (-IJ furan, Shi4-nan, acetone,
(water, etc.) in the range of 0 to CiO''C.

In this case, the amino acids and lower amino acid esters may be optically active or racemic.

Production method [3 is to prepare the compound represented by the general formula (1) with a mineral acid (
(e.g., hydrochloric acid, sulfuric acid, nitric acid, etc.) or alkali (e.g., hydroxide, soot, hydroxide, potassium hydroxide, carbonate, potassium carbonate)? i: in an inert solvent (e.g. formic acid, acetic acid, 7N, ethanol, etc.), 20
・～・Hydrolyze at 120°C ↓ Good.

Production method C uses compounds represented by general formula (1) and fI bag formula (\lI), respectively, with a dehydrating agent (for example, sulfuric acid, -fluoride, silicon nitrate 1, phosphorus pentoxide, etc.) The compound (+) of the present invention may optionally be esterified using 1-norium, potassium, calcium, etc., and monoethanolamine, cy-tanolamine,
Triconitanolamine etc. J' II b,,'+
can lead to.

EXAMPLES The present invention will be explained in detail with reference to Examples below.

Example 1 1-Methyl cyclohexyl 7-hegizancarn 1° acid i 4.2
Dissolve 21.g of phosphorus pentachloride in 50ml of phosphorus pentachloride.
Gradually add Of+ to room/l (! After leaving for 30 minutes in
Time flows by. After the reaction was completed, the solvent was distilled off under reduced pressure and 1-notyl-cohexane was added.
．． I got 317.

Chrysin ethyl j nistil 20. t) g, l-lienalamine 20.0 tT and tetrahuman I cotran 200
The mixture 11ν of m1 is cooled to Q'C, and the acid 1-
Isl-1. Vf J+=” Gradually l+lii to h
' I ~ do. After stirring at room temperature for 4 hours.

At the end of the reaction, the solvent was distilled off, ice water was added to the residue, and the resulting crystals were collected. The crystals were washed with water, dried, and then crystallized from a mixed solvent of Enal-Eral and Hegizan, with a melting point of 61.
1.11 (Color prism product N-(1-Nonolschiff 1-1 to Gysan-force luponyl) Crine ethyl 20, !] l; - was 17 at -62°C.

h, ])', min)ha fll'L (C
1211, HN (13) CIt N Real #11 Lii 1? j (%) 63.
/I4 9.39 [i, 3'/■ A
, 1〆l'i ii1i11 (%) 63. /
II 9.31 6.16 Example 2 N-(1-ethyl-carbonyl)glycine 21. : 3 g was added to 100 ml of methanol, sulfuric acid] was added, left at room temperature for 12 hours, and then added at 60°C for 30 minutes. Do t. After the reaction path r, methane/l/ was distilled off, ice water was added to the residue, and the crystals were collected.

The crystals were washed with water, dried, and then mixed with ethyl eral in a 9' tube.
1) jg-colored needle crystals N-(1-ethylschiff UJ'\-
1-9・nkano]nohol)glycine menal ester 20.1 +: obtained.

Elemental analysis value (C, □112, N03) CII
N Actual value (%) 63.2G! 1.39 G, 371
Sato 1! I:ii 1171. (9A)
6J, 41 9.31 (i.
Grison Enal Esral 22.7 g, water f'+H
Lsl-')tsuA 4. (l r: , 15 ml of water and ethanol! 50 mIQ)? ll in cold temperature M2
0 II: Stir 111 1'1''. At the end of the reaction ((&l
The medium was distilled off, ice water was added to the residue, and the crystals were collected at t7.
8 points.

, the crystals were washed with water, (after drying Isoprop II Billerard) 111 crystals, colorless prismatic crystals N (1-notylcyclo IJ hexylcarbonyl) with a melting point of 107-108°C.
Chrysin l'/, G g (4I).

I/I (CIo 1117 NO3) CI
I N Actual value (%) 60.318.62 6.95 Theoretical value %') 60.28 8.60 7.03 or more -(・,
Follow the methods of Examples 1 to 3! 1 (t) The following compound was synthesized.

Example 4 N-(1-methylcyclohexane carbonyl)ε a.
, nocap) dinic acid Example 5 N-(1 methyl Schiff 1) hexane carbonyl) amount! ,−
Menaonin Example 6 N-(1-enalcyclohexane-carbonyl)glycine edyl ester Example 7 N-(1-ethylshiff1:J-\kizancarbonyl)glycine Example 8 N-(1-ethylcyclohexane-carbonyl)-L -Alanine notyl ester Example 9 N-(i-ethyl sulfinyl)-β-
Alanine Example 1O
l) L--alanine Example 1I N-(cis-1-methyl-4-n-bentylcylhexanecarbonyl)chrysinconinalconisral Example 12 N-(cis-1-methyl-4-n-pentylsif) 1-cohexane-(carbonyl)glycine Example 13 I-(cis-1-medyl-4-n)
l-\xincarbonyl)-ε aminokabu 1. Nonacid Example N (cis-1-phthyl-4-n-pentyl+:+
=, xanecarbonyl)-L,-methionine Melting points of the compounds of Examples 4 to 14, I! 11, +1 crystal f capacity and nitride analysis are shown in the following table.

Continued from page 1 0 Inventor Kunihiro Nakamura 833 Tashiro Daikan-cho, Tosu City 0 Inventor Nakatomibe Koho 205-1, 3-3 Fukumitsu Higashi, Gifu City 0 Inventor Yuji Shimozono Tashiro Daikan, Tosu City Town 833 0 Inventor Kanji Noda 93, 320 Oaza Tsunematsu, Chikushino City Procedure: ? c City official letter (spontaneous) Kazuo Wakasugi, Commissioner of the Patent Office1, Indication of the case, 1982 Patent Application No. 493612, Title of invention: Novel carboxylic acid derivative3, Relationship with the case to be amended Patent application Address: 408 Tashiro Daikancho, Tosu City, Saga Prefecture (■841
) (Contact address: Hideki Yamakawa, 09428-3-2101) 4. Date of amendment order Voluntary 5. Subject of amendment (1. 1. The third truth in the column "3. Detailed description of the invention" in the specification) In the third to fourth lines from the top, the words ``knee disease'' should be corrected to ``collagen disease''.

(2) Same book, r from lines 9 to 10 from just above No. 9
Freund's incompleLe adju
rantJ and [Fr++und's inco
Correct it as complete adjuvantJ.

Claims (1)

[Claims] General formula R3 2 (J (wherein 1 is a methyl group or
2 and R' are hydrogen Jl:f child or C51 with 1 to 7 carbon atoms in the form of 41 (class AJlbattno, (, 1?
3 is a hydrogen atom, 1 to 4 charcoal mebe numbers ("j fumata 4.
a lower argyl group, a 1-dioxynonal group, a norcabutonotyl group, or a 2-notylnaenoenalno group,
rl is an integer from 1 to 5. i11shi r1 is 2~
In the case of an integer of 5, 1-3 is hydrogen j prince +e, taste)
A new carbon f'i' (, iJ conductor).