JPS5951260A - Manufacture of n-phenylamidine - 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] l-The invention is made by Medical J, %'5 ()1't''t'l k'
1: Concerning compounds and proboscises that produce ff and their production methods.

+The invention is a medicinal 4-old anti-inflammatory and diuretic, anti-fibrotic zymogen, semi-I muscle relaxant /
This article relates to a method to bring out the anti-inflammatory effect in breast milk.

Administration of the compounds of the invention to mammals produces diuretic, 1) IV aqueous, smooth muscle relaxing or anti-inflammatory effects therein. .

Diuretics are divided into four groups depending on their molecular structure. They were introduced as therapeutic agents in the year d1; target 11111"?; in which organic mercury compounds, decarboxylase light reduction, 6-chloro 7-sulfuryl-1,2,4-benzo Thiadiazine-1,1
Thiazide, which is substituted by dioxide (chloroliazide), is a common compound among the various groups of compounds. VC in a miscellaneous group of compounds is
4-ri170-N-furfuryl-5-sulfa'moylanthranyl H,H,'+2 (furosemic 1゛), 2,4
．． 74-lyamino-6-phenylpteridine (triamterene) and aldosterone are the same!
, , I+1 (steroid compound n). Chemistry 1'l
Ruled r 4 t! As 1. ! , the N-phenylamidine of the present invention is structurally different from the fl diuretic described above.

The primary function of diuretics is to reduce the Rt of external fluid to eliminate edema or prevent its occurrence. 1) [Excretion θ] Along with enhancement, diuretics generally result in the elimination of electrolytes such as sodium, chloride, potassium and carbonate ions. , there is a non-rock-selective 1noF removal of electricity PIII! quality, especially potassium hypokia V which leads to animals.
Regarding C, it leads to electrolyte imbalance.

This invention is a generation! The compound ゛fat as its medicine/tomy (1 unit for mortaring that can be used [however, 1. t in the formula) -,, J: D
Y i, German fr: L, "'C water tri, ha (1 care, trifluoromethyl, 1 to 4 (hard carbon 1 prince 1 person 4 to alkoxy-n, or 1 to 4 carbon atoms lower alkyl-C, b; alkyl is 1 to 2 carbons + g
It is an alkylene residue containing a + child; Z is phenyl,
2-chenyl, 2-furyl, or the formula (where R4 is hydrogen, lower alkyl or benzyl, 7
g) Su,/i! ' is hydrogen, halogen or lower alkoxy, and is represented by (1). R4 and R5
+d-converted 3-indole (with; A is (however, TL is 1 to 3'+1 is 1, /<'
[i-paralysis! Bi3 independently provides a method for producing a water cable or a lower-1 ruky group (with 1 to 4 carbon atoms); :/reacted with a carboxamide having the formula (wherein alkyl, X, Y, Z, R-Rs and n are as previously defined) in a suitable inert organic solvent in the presence of phosphorus oxychloride. It is characterized in that the compound of formula I is converted into iJ4.

The term "German-French" used throughout the specification means that the respective substituted parts (i.e., X and Y; lI'2 and l?3) may or may not be the same. do.

The "f-algylene residues that limit the alkyl are methylene (-C)12-), ethylene (-CIbCI1
2), then 1,1-ethylene ((,'/I3(pH
) Halogen iWt fractions that define X and/or Y include arsenic, Q, fluorine and iodine. ul
Of the halogen 11 exchanged with 'Iif', bromine/] (acid is also removed by 1 rain.

rAIIt, represented by the formula, LJI-pyrrolidine; 5-methyl-1-pyrrolidine; 5,5-dimethyl-1-pyrrolidine; 4-methyl-1-pyrrolidine;
3-Methyl-1-pyrrolidine; 8,4,5.6-tetrahydro-2H-azepine; 8,4,5.6-titrahydrobiridine; "lower alkyl" used above in Meisho II 'iii; [The term IL (alkoxy) is intended to consist of radicals containing straight, 1-'-branched carbon residues of 1 to 4 carbon atoms.

Examples of these carbon chain residues are methyl, ethyl, propylene
l, isopropyl, 1-butyl, l-methylpropyl,
2-methylpropyl, and tertiary-butyl.

Examples of acids used as non-toxic pharmaceuticals for N-phenylamidine of formula t include sulfuric acid, phosphoric acid, hydrochloric acid,
Hydrobromic acid, hydroiodic acid, sulfamic acid, acetic acid, lactic acid, malic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, gluconic acid, geltanic acid, ascorbic acid, benzoic acid, cinnamic acid and related salts of various inorganic and organic acids such as

According to the method of the present invention, 1.1' of phosphorus oxychloride in the presence of rf in a suitable inert organic solvent (wherein alkyl, Reacting the -i'ru1,T,1 γniline with a carboxamide of the formula, where R3 and R are lln as previously defined.

Among the suitable carboxamide reagents are 2-
Pyrrolidinone, 5-methyl-2-pyrrolidinone, 5.5
-dimethyl-2-pyrrolidinone, ε-caprolactam,
Included are δ-valerolactam, 4-methyl-2-pyrrolidinone, 8-methyl-2-pyrrolidinone, and the like.

In carrying out the process for the preparation of N-phenylamidine of formula I, it is necessary to carry out the process in an inert, aprotic solvent to obtain a chemically forgiving 1θ
Mix the converted aniline and a suitable carboxamide reagent such as nitoxy 1-benzene phosphorus. A suitable and preferred solvent for practicing the method is 1,2-dichloroethane. 11 of songs such as chloroform, charcoal, 1,1-dichloroethane, benzene, toluene, hegisan etc.
(10 liters) using a suitable solvent. Reactant f,'+A
The JJII format is important for implementing this method (:
【do not have. 1. A solution or suspension of the substituted aniline and carboxamide in 2-dichloroethane can be added to the solution of phosphorus oxychloride, or the order of addition can be reversed; A solution of phosphorus oxymonomide can be added to the liquid resistance of the liquid. Alternatively, the phosphorus chloride can be added to the oxyjA first to the aniline reactant and then the carboxyimide reactant. A suitable application of the process curve of the invention is the combination of phosphorus oxychloride with a carboxamide and the addition of this mixture to the aniline reactant. Tilt alignment of the reactants produces an exothermic reaction, and external cooling can be used to moderate the reaction. However, this is not necessary for successful completion of the reaction. When the reactants are combined, the reaction of the carboxamide with the aniline occurs easily, and is generally a mixture of the substituted aniline and the carboxyimide reactant during the reaction of the N-71 ninylamidine compound. Preferably, the reaction is carried out by adding phosphorus oxychloride to the mixture.

Although this reaction can be carried out at temperatures of about -35 to 100 °C, it is more efficient to carry out the combination of reactants in one chamber under stirring [7], then stir the mixture overnight. It is generally a good idea to isolate the product after [2].

Illustrative of a preferred method for preparing compounds of formula I is to prepare a solution of a 1,1-substituted aniline and an oxy-phoxyamide in a dihydric solvent.
(This is by adding phosphorous chloride.

In the case of N-phenyl 1'midine of formula i where Z is indole, the above-described method can be applied to 11 mol L"j:('J trienalamine such as The present inventors have found that it is possible to add a class amine]111.
Addition of ethylamine is essential for successful completion of the reaction.
-t/+', but in some cases it is preferred to increase the yield and obtain a purer product.

The compound of Mr. 1 is stable in 710 salts that can be used as pharmaceuticals such as its hydrochloride.

Conversion of N-phenylamidine free St% within the range of formula 1 to the corresponding acid addition which can be used as a non-toxic medical agent is ethanol, benzene, ethyl acetate, ether, halogenated hydrocarbon, etc. This is accomplished by mixing the base in an inert organic solvent such as the selected fit. One method is to treat N-phenylamidine with ethanolic hydrogen chloride in substantially the same chemical form as an ethanol bath (JI41); It is to precipitate the bridge from. Although the N-phenyl 1 midine 11 of the present invention is generally water-soluble, the 1M group has -C that is substantially insoluble in water.

Before the compound of formula ■, rlS L, ta! The Iν method is based on 1 Hubredeleck and 1(, Preprek, l?gr, '3
4, 2278-95 (1961): (',', A, 55
;278718 articles. In this document, lr1', 2-
nk carboxamides like pyrrolidinone? Acidine (2-phenyliminopyrrolidine) was prepared by treating with hydrin and then with aniline in a liquid pen.

This amidine is virtually inactive as a compound when tested by the post-VB repress method.

Unidentified compound I proboscis (4, SV, 1., ribs -↑1.l.

PharnmcoE, IGxpt, ,Therap,
79-, j+ 7 (1!343) was evaluated as a diuretic by 11k. Eat. Control 11 (, 14 ζ ton h! / 2 per
5 m#I:/)% food saving 12A solution (Ctl, fi test 11
,';i compound I'j ``j-r lota, l/)lc
Use i r+,,,"l#t/'i'f (Mo;Xr
4-u: + w, y water to E1 cargo 7. Ru.

1 to 1ftt1iPf;t DI, 16g per mountain! l
60 nq (11 niq) of urea is administered. Animals in the first group are treated with the test compound (20 niq) of the same amount per box. Immediately after treatment, the animals are placed in metabolic boxes (2 The volume of urine excreted from each pair is measured after this intercostal space and the pooled urine is analyzed for sodium, potassium and chloride ions. Results for test compounds are expressed as the volumetric weight of urine excreted in tJ during the experimental period relative to the urine of the control group, or as the ratio of the total 111 of the electrolytic chambers (i.e., sodium, potassium, and chloride ions). In this test, N-phenylamidine of the formula (1) was found to have 2.7 to 25 Ing of 1111.i per body jh4.
Administered iL+.

In the trial I cloud, the results of using N-phenylamidine of the present invention revealed that it is an effective diuretic in -f: show.

Firebox lv + large urine DiE, sodium and 'a
'fP' 40% after oral administration of 1 non-ionic and 1 non-ionic phenylazine.

One of the drawbacks associated with diuretics like thiazides is.

It is believed to originate primarily from the excretion of potassium ions, which increases simultaneously with the elimination of water. It is believed that this drawback is overcome using the N-phenylamidines of the present invention, where a favorable balance of sodium and potassium excretion is obtained with 11 IB of water exclusion. For example, 5-methyl-2-(N-phenylbenzylamino), which is a representative formula I C/')#'-phenylamidine.
-i-Pyrroline JMF Shunj Bon's body 6,25 per 11kg
Oral administration of q to rats resulted in a % volume excretion of 2.82 and a sodium ion excretion of 2.08 when compared to the urea control group. For potassium ion excretion, (11 of 1,75; no, it's a shame. The ratio of sodium ion JJliillU to potassium ion 49g is 2.0810.75, which is a pun of 2.7. It is equivalent to the well-known anti-inflammatory agent Hydrochlorothyaza R.
has a sodium to potassium ion excretion dlj(1) ratio of 165 for the same ff1. light + rllll
As mentioned above, the potassium ion filtrate during lti
1. IiIl! may cause an imbalance between +h' and i'iT'J', resulting in unfavorable side effects.

The compound of formula 1 is 0.1 to 1009 per t7'jkg
The optimal treatment is effective in the range of 1.1! , especially −
It exhibits a diuretic activity of 1 r, when administered orally to mammals in a non-toxic formulation ranging from 0.1 to 25 m/g of body weight per day. Although these substances can be administered parenterally, oral administration is preferred as a matter of convenience of administration and RF ease. 4, f, [:]4υ of N-phenylamidine to mice is 50-500 da7
'give /I Lt)a o f+tj in the range of 9.

Formula + (7) N-butinylnomidine is in the free base form -
Chi hat Maso + 17 making) 4 “I, zζ・ノ, Toji CI
'Jstl I, i4+ as a mammal 1 (-
Even in the (゛kiru. Either O) form, it is also used medically as a solid that has ``!'' or no (・German solid (combined with 1 family or Prescribe +41. dosage form of medicine: 1 lil snout 6-
1. - This can be done by 1°. The favorable δfIVC is [1
Rank, 11 C seal 1? 15 puIt l H! Approximately 0.1 to 11 g of body and tissue of mammals
11111111!7]; Consists of N-feninodibazine of the tlS of the cascade. Next, administer II′i, 1i′/:l 醇form I1°ri J) River■ to suckling-Jj1 [7 and diuresis 1. I'm sorry for the innuendo. 1. Considering the invention as pronation +1. Doctor 71! ≦Use r+7 products include 1llii preparation, powder, granule, capsule, 11. fifiirv,
! ,':Liquid ゛1 liquid can take 11 liters. ``A 4U body for medical purchase is corn starve 1 milk 11.1, phosphorus 11 skin calcium, stearin λ porini[boo L/
water, sesame oil, peanut oil, propylene glycol/l・'"'i' (January:・Eel solid i:
, :includes both liquids and liquids.

・The combination of 1 and 1 power! 1411 tf Koji: Ruhara l old 1 ni 1: ni λ・1 uru 11n song (, 1, horn, ~ature, river, 92 for (HIO2) t・V
-No.1Fla.I:1-N, J, Illi, Po,
t h, , 1, 44ti (1:1 scene 12) [
- Doriki i1+V, carried out according to the method described. This is essentially turbidimetry-C, adenosine niline r
+9. Epinephrine;
Using the ef 11 L causality 1''^1 strain as pigeons, changes in the 2nd level of platelet-rich serum samples were measured.

According to this test, the uninvented fP compound is about 30-10
0mc g/vat, with an effective anti-fibrotic zymogen at one time.

The smooth muscle relaxing activity of the compound of the present invention -〇 is the standard C1
, (Intraductal mortality) [Can be measured by internal drug embedding test. One such test is carried out as follows. Sections of rabbit ileum %) in Tyrode's solution! I childishly cast 3 words, and the electronic i1rokurn of equiangular + 17 contraction is ゛! Connect between L and Mibari transmission equipment. Barium chloride ((1,25 mq/me), chloride such as acetylcholine 14ide, etc.),
f! After establishment of the control response to f1, the test 1'+6 compound is added and the G1+, porcine, and 12° responses are remeasured in the presence of test 19. The mean response to the convulsant in the presence of the young fruit of the test compound (i, test-...,...!Compound's proboscis is measured as a 6-fold decrease from the response of the test compound's proboscis vs. !Advanced combination' 1 1 2 ~ 5 1'
For the concentration of 1 - t:, 6ψ low 4 trials 11 times are obtained. The data are expressed in the form of a response curve for the elbow A (11:) and then evaluate the E C! (0 degree which causes a 50% reduction in tissue response to the convulsant). In general,
The effect of compound 1, identified by formula 1, on rabbit ileum is similar to that of the commonly used smooth muscle relaxant, pave 11.

As expected, in some (・do compounds, the proboscis is more active than in the song one. For example, L is 8-[#-(5-methyl-1
-virolin-2-yl)゛γnilino]methyl J indole IA1.・? I! , Ru is 1.4 times more potent than Nono1°Perine, but a-(rA/-(1-virolin-2-yl)anilinocomethyl I-(:/l・-RuImanti)
] 1 (4 is ha 0/-? Belin's Strongman's 0.5 to about (1
, 817'<.

A song test to measure the flat-if costal laxity of the compound A of Hon Shumei,
In-tube test 1: [1] Essentially using a spiral, Lisch et al.

J, Pharrnacol, Exp, Therap,
129, 191 (1960). As a demonstration of the activity of the compounds of the invention in this test, 8-((N-1-pyrroline-2-
IluP-aniridino)methylcoindole, which is about 1.7 times more potent than aminophylline.

The 1,000 Ml muscle relaxant properties of the compound of the present invention can be demonstrated in vivo in dogs. In this trial, for the first time, dogs were anesthetized with sodium zentobarpital, and the intestinal tract was
+'A I+i# of jf[:record of t muscle activity in the usual manner.

(Kusodoman and Gilman, th, ePherm
ttcoloq? car 1htsis of Th
erapeutics.

2nd edition, -? Tsukumiran Company, 1960, 2:
1-Yoke). The intrastatic dosage of the compound of the invention according to formula I is 1 to 10 In9 per 7 g of body weight;
At 11, there is a marked effect; the child's muscle relaxation is impaired.

Intestinal smooth i16 relaxing activity was also found to be 4 in 1 product in vivo in cats.
3. Can be measured while standing. In this test,
Make a small incision in the stomach of an anesthetized cat and insert the balloon down into the duodenum to a point of about locm (7. Record the change in IIfP internal pressure. Administer into the duodenum approximately 2 cIn below the balloon placed for a 1:1 recording of the duodenum 111b with a volume of 1 ml per ~.

This means of administration mimics oral administration. Administering the test drug Gods IfJll, it suppressed intestinal relaxation by up to 50 degrees.
Ill do IKI! +Upper use: Determine 11~. This value is IDs. It is said that

As a bone dilator, 8-C(N-1-pyrrolin-2-yl-P-7' herring) methyl] "Ndo-Ishi'11.
! '・1+jll 7 ((1! Samurai has l; IIBI;. Histamine induces 1 to guinea pig n-rosol test・l
i77 Nidoite [Turner-1Screening
AlatlLotl in PhIrnnnco-l
og'/, 2141-'j (1965) (Academic Press, New York)], this compound is approximately 1.4 times more potent than aminophylline when administered orally.

The compound 'i:n of formula 1 exhibits anti-inflammatory activity as demonstrated by its activity in inhibiting the formation of Rr-11i1i after sole injection of carrageenan into the tail of rats. As a non-medicated control, 1/it': 111 animals were administered with the test compound intravenously 15 minutes before the induction of 10 animals c/) 1 group. l for history (
7. Performed on any one-year-old adult rat. Ru. 4 Ducks were bathed in 0.5% carrageenan RT to the right hindlimb.
It is induced by plantar injection of k o, 1 me. The port side is treated in the same way with (), 9 tons of saline Q, lm14. 4 hours ritual ((limb f): 4/ by forceps 1: ° the volume of water;
Decided by Chismocraf. floating 11iIQ,
) 1 juice is carrageenin lE injection I') foot f'+-t
Increasing white fraction from the foot of saline injection in h.C-1
MowaΔ, 11. Ru. ? '%Itlj's single bird per centage is
Dosing 11 tons of carrageenan for foot floatation! By dividing the average increase rate of by the average increase in non-role and multiplying by 1()0, we get the total 'i+? : To be done. Body'Q (^ro1s1
1) For Oyy use, compounds of Formula I generally produce inhibition of about 40-60 11 lungs.

The following example is one contemplated for carrying out the present invention.
1 full aspect of t-hi is shown. They are illustrative only and should not be construed as limiting the scope of the claims in any way.

Procedure 1. 2-dichloroethane 15 (N-IN in l me
Vl? Phosphorus oxychloride (0.1 mol) is added all at once to a mixture of 4aniline (0.1 mol) and the appropriate carboxamide (0.1 mol) with stirring. After stirring the reaction mixture for 16 hours, it was poured into 1110 ml of crushed ice and J20 soda. Add 1 minute dilution of ethane to 1,5 NIHnl 10 (l III
/, then water 1 (lI + fli at 1 m/). The divalent aqueous layer is made basic with 20% caustic soda solution to obtain an oil, which is transferred to ether. The ether extract is dried over magnesium sulfate. [2, then 7H) condensation to yield the N-phenylamidine product.

Purify by distillation through a "minor diameter" (approximately 10 cm) column at reduced Ft.

N-phenylamidine free base is dissolved in ethanol, the ethanol solution is acidified with ethanolic hydrogen chloride, and anhydrous ether is added until hydrochloric acid 1 precipitates from the solution.

Typical N-phenylamidines produced by the above-mentioned procedure are listed in column i''lj2 in Table 2. Analysis 11r1 and main infrared absorption peaks of N-phenylamidine shown in Table 1 are reported in Table H. -ru.

Table ■ (continued) A B
CDHk' 17-23 Further examples of the N-phenylamidine of the present invention are shown in Table III. They can be prepared by using phosphorus, Ii', and phosphorus in Example 1 (as shown in Example 1, according to the procedure shown below).

Product example last issue X Y 20 7l-CCIls) sco 11
21 tn Cll5Op CHs022ノIノI 28 II HA
Reactant ('Iil 24 Tablets) The N-phenylamidine of the present invention is formulated into tablets according to the following example.

Amino)-1-pyrroline 1λX acid salt Magnesium stearate 1
．． 3g cornstarch
12.4 Gelatin pre-processed cornstarch
1.8g lactose 188.2,
! Mixing the materials listed i'-F in a twin-shell mixer;
It is then granulated and pressed into tablets of 25 (l rng. Each tablet is 56.8 mg cl) 5-methyl-2-(N-phenylbenzylamino)-l mivirorin IAAl'i & sagyutake 50 mg. It represents a biologically active compound.

(Siri 25 capsules) 80 g of 5-methyl-2-pyrroline in hard gelatin capsules such that each capsule contains 50 my of the biologically active base, 5-methyl-2-(#-phenylbenzylamino)-1-pyrroline. (N-phenylbenzylamino)-1
- Fill with a mixture consisting of pyrroline and 120 g of cornstarch.

1.2-dichloroethane 39mj! 8-(p-anisidinomethyl)indole (2,51,0, (11 mol)
and 2-pyrrolidinone (0.85 g, 0.01 mol) and triethylamino (1,(11,!i+, 11.01 mol)) was added with stirring to a mixture of
, 0.01 mol) at once. Reaction γ1^ Mix the own ingredients for 3 hours with a stirring trowel, crushed ice and 50 liters of soda.
l(.

Pour the mixture. Dichloroethane 1 di1 to 1 minute [shi,
11.757V, 1. 'Extract with AIIin 10101l. l skin! :, lmi water IC! 4 was first extracted with ether, made basic with 20% caustic soda, and then extracted with ether. 'After drying over GM9 magnesium, the ether extract was concentrated to a residue of 1.8. ! 9 to 41. A basic substance having a temperature of νnp135-1; 38°C is obtained by crystallization from ethanol.

η=C11'' of the material obtained by the above operation 7
．． 19 was dissolved in ether and acidified with ethanolic hydrogen chloride to give 4 tl of the hydrochloride. The ethanol solvent was removed directly in the air, and the residue thus obtained was added to benzene in July, gently refluxed, and then mixed with benzene.
Distillation is continued for 4 to 5 hours, during which time benzene is added as necessary.
p 165-175-CIl) salt ti:2-'24?
, we get 1 d 9. Is this fraction the best? J.J.
=+A The solution was triturated with acetone, and then the product insoluble in gamma setone was crystallized from isopropanol ether. At 1″C, acetone
Further product was obtained from the precipitate, which also crystallized as isopropanol-Luni-Delcala. The isopropanol-ether crystallized fraction was recrystallized from ethanol-ether to give analytically pure 8-r(#-1-pyrrolin-2-yl-p-anisidino)methylcoindole hydrochloride. Obtained as a white solid of 1'/7'C (corrected).

Min 4Jr C20HnNs-HCII toshite meter nAI
M(1): C, li7.50: nol, 6.2
8 ; #, l 1.8 1 ; Ce,
9,9 6. Actual 1ij*b1j (%):
C, 61,'18; H, 6,08; /V, 11.6
4: (, 'e, 5), 96° infrared (0,5%kljr
cm-”):816 (+, 1660.1510.1
310.1260.104 (1,850,750°N
AIRδ(ppIn,) C(,'DCI!s, Tetramethylsilane target): 8.78(s, 8#), 5.8
1 (s, 27/), 3.94 (rrh, 21)) (
1) tO, l) O4,707+p+uii4()
: 3.52(s, d11'); 4, Fl
0 (a, 2/7): 8.57 (nt, 2#).

Example 27 8-(#-(1-pyrrolin-2-yl)anili 3-(anilinomethyl)indole (11,1,9,0,05 mol), 2-pyrrolidinone (4, 26g% (1,(15 mol)) and triethylamine (5,06g% 11.05
Oxy-dead phosphorus (7.67 g% 0.05 mole) is added in one portion to the mixture of 7.67 g% (0.05 mole) under stirring at water bath temperature.

Stirring is continued at that temperature for 15 minutes and then at the width of the chamber for about 16 hours. After quenching in crushed ice and aqueous caustic soda, the reaction oil mixture was filtered to yield the solid free base.2.
Obtain 5g% Kelp 115-117°C. Example 26
(The dichloroethane layer is then extracted with hydrochloric acid, then the 1'+I2 derivatives are extracted with ether, and then treated with caustic soda. !1;4+r/),1ill
4.19. To concentrate the dried and dried ether extract, add the second Yuko + i + Jinki fraction. 4.19. 0L Ka1114
~120°C in a 1:1 ratio. The free rjlIta group fractions are combined and 5.1 g of sample 1 is converted to 1,1 g in ethanol by treatment with ethanolic hydrogen chloride. 4. A residue was obtained by reducing the I'-2-hypertanol liquid to zero, and the residue was dissolved in water. t of solids are separated from house to house.

'Cool the PNV and basify with 10% aqueous caustic soda to obtain the free base and collect. 8.1 g, nl
p 118-120” free base reconstituted with C0 missing,
Ethanol 1"L1 old 1', hydrogen: 1 (convert to LJ Lia by the usual method in ethanol by stirring. Adding ethanol to the ethanol solution has an analytical effect! 1
~Frame 1°ψ3− (A/−(1-pyrrolin-2-yl)
Anilino) methyl] indole j crystal acid 1; tA, 2
．． 6g% +717J 1 (53, Fi ~ l fi
6. fi ”(-: (correction) is corrected.

lIJ analysis CofLoNs ・llCe and I7tei”f
liQ: Direct (%) : (: , 7 (+, +1.3
:// * h, 19; /1/ + 12.90
g Ce # 1 (1880'zQ!・', Qll
'j ('')'C,'10.08 :11.6.12
;N, 12.70 :C:e, 10.62° Infrared 1.
5% /i dar-') 118 (+, 1670.1600.
1480.1450, 1320% 750. TOO.

NAfRδ(ppm)CI')yo, 11DO-4,7
0 reference) = 8.65 (m, 2/7), 3.1 7
(FIL, 2//), 4.8 6
(s.

2//).

R-(7+-anilinomethyl)indole (5,114 gb+), 02 mol)% 5-
Methyl-2-pyrrolidinone (1,98g, (1,+12
mole) and triethylamide 7 (2,02,9,0,
1.2-dikuo to the m solution of 02mo#).

OxylAg1hyrine in 1tough1Q+ie (8,06
9,0,02 mol) in 20 minutes. Accompanying
Upon completion, the mixture was stirred at 3-4° C. for 5 hours and then filtered to obtain 2.4 g of the same product, which was crystallized from water to give 1.0
Obtain 2 g, m2 184-187°C. This fraction was analytically analyzed by combining it with 181 g of the fraction obtained as described above and crystallized from ethanol. il)-7 Fuanisidino]Methyl]Indole White 12
t=, mp 181.5-188.5°C (corrected) is obtained.

Analysis C2J12. Calculated value (%) as N, -1ice
:C, 68, 19; 11, 6.54; #, l
1.86 :(,'e, 呵1 (i 8 o
Jl:! ! ＋'發I Direct(tsu1;) :C, 68,08
;7-/, 6. fiO;A', 11.29;C(
? , 9.58° infrared (0.5% kBr cm-'):
8160.166 (1,1510n1450% 1a
oo, 1250.750°N Af 1i! δCp
7) m) (D20, 1100 4.7 oe light)
: 8.60°3.62 (sg, 8/-7, total) +
1.20.1.89 (d d, 8//.

-7,6,5ttz) ; 4.85.4.92(s
s, 2/7. all).

Example 29 3-[/V-(5-methyl-1-pyrroline-
Example 27 (in 1,2-dichloroethane 1110#I/in 1,2-dichloroethane reacted according to the 1,+ method)
, 67jj, 0.05 mol), 3-(anilinomethyl)
Indole (11.1 g, 0.05 mol), 5-methyl-2-pyrrolidinone (4.96, !i+, 0.05
mol) and triethylamine (5,06N, (1
, 05 mol) to 1 111M group at °C total yield (Hi7
．． 55 g of product are obtained.

A sample of 5.5 g of #1t^(E base) was mixed with kM r in ethanol using ethanolic hydrogen chloride.
Convert to RJa. Analytically pure 3-(ff-(5-methyl-1-pyrrolin-2-yl)anilino]methyl]indole salt is prepared by addition of ether to the acidified ethanol solution, llua +127.5-174°C. (Isan iE
) 3.49 I-obtain.

Poor 1 Hayabusa CJb+N,・IIce as 1 shift (%)
:C, 70,68:H, 6,58; N, 12.8
6; Ce, 10.4 B, Experimental IPT (%): C
,70,41;11.6.56 :N+ 12.66
;(,'/?, 10.25..

Red evening i, ((15% kHz rs-'):
8 1 6 (1, 1 (150, 1590, 14
9(1, 1450,74(1,7(1+l.

NAIIIδ(p7>rn) (/32(J, HD
O-4,70 ml! it): 1.10.1.85Cd
d, 811 total, 6.4 //Z): □1. n
2.1. ! + 5 (s s , 2 /I total).

1.2-nochlorohydrone'15me oxy-monophosphorus (4,6, +7.o, oa mol), 3-(anilinomethyl)-1-methyl indole (7,1,9%) 11.
08 mol), 2-pyrrolidinone (2.55 g, O, Oa
mole) 1? and l-ethylamine (8,114,9,
u, 08 mol) is diluted according to the procedure of Example 27. [Anti] Toss Ot1 compound 1()%h±・Isoda 1゛・
・Yohi ice middle school 2! Then, separate the organic layer with 100 mb of 7J1.5 #hydrochloric acid and then extract with 100 m6 of water. Combine the extracts from the jilt and wash with ether. , make salt Jb with caustic soda, extract with ether, dry the ether extract over magnesium sulfate, dry under reduced pressure, and remove 6.6 g of the remaining product, which forms a solid when crushed with ether. 8-[(N-(1-Pyrro11-2-yl)anilino)methyl J-1-methylindole 4.29 m p
Obtained as free base at 95-97°C. 2.2 of free base
Transfer the sample of No. 9 into ethanol, acidify with ethanolic hydrogen chloride, and concentrate the %M solution under reduced pressure. The residue thus obtained is refluxed with benzene and the benzene solution is gently distilled. Jjj(1i°'(then 1 analytically pure 8-[(Ii-(,1-birolin-2-yl)
anilino)methyl]-1-methylindole Episode 1 n? ,
iL rnl 150.5-154.5'C (decomposition) (
Correction) 1.7g is obtained.

Analysis Cwo Ht s A/ a ・IIcII and Te row Vatσ (%): C, 70, 68; fl, 6.5
8;N, 12.86:Ce, 10.4B, Experimental IM (%
):C,To,66:II,6.69:N,12.20
: Ce, 10.44° infrared (0.5% kBrcm-'
): 8 (100,1650°1590.150
0.1820.750,710°NMI? δ(Fp
rrL) CCDCes-tetramethylsilane):
2, :d9Ct, 211,6. ? #g); 1.79
(p, 2//): 8.25 (t, 2H, 6,87/g)
:4.81(s, 2H);f(,78(a, 8
7)).

3 in 80 ml of 1,2-dichloroethane at a salt water bath temperature
-(anilinomethyl)indole (11.1 g, t+,
05 mol) 5.5-dimethyl-2-pyrrolidinone (5,
66 g, 0.05 mol) and triethylamine (3,
069, (1,05 mol) in 1,2-dichloroethane 2
Phosphorus oxychloride (7,67p, 0.05 mol) in 0ml
Attach quickly. Stir the mixture for about 15 minutes (1'), remove the water bath and continue stirring at room temperature for 16 hours. Treat the reaction mixture as follows. The mixture is quenched in 100 Inl of 10% caustic soda and crushed ice, Separate the layers. The organic layer is extracted with 2111 ga/l of 1.5N salt, then 1 (l OMIT) of water. The combined extracts are washed with ether, made basic with 10% soda, and then
A solid will precipitate out and move it to the east.

Clarify from ethyl acetate. Collection 1i8.211, mp
1] (1 product at 124-126 DEG C.) The dichloroethane fraction is dried over magnesium sulfate, concentrated in vacuo, the residue (10.4 g) is triturated with water and filtered. The second lateral Jfj fraction, 3.19.

A sill p of 125-127°C is obtained. The +1.7 + 1 fractions of 21 solids were combined, dissolved in ethanol, and treated with ethanolic hydrogen chloride to yield 8.7 fl, rap.
Analytically pure 8-((#-(5,5-dimethyl-1-pyrrolin-2-yl)anilino]methyl]indole 4tY
I! Get the salt.

Analysis C2IHtsNs ・Calculated value as HCl1 (4
) :C,? 1.27 *H, e, s+; N, 1x,
s7; Ce, to, o2゜actual i, mhliff (%
) :ni',? 1.45; H, 6, 81; /l/, 11
．． 84;(,'/?, 9.L3° infrared ((1,5'%
kBr an-' ): 8120.1650.15
90.1500.1460.1760.720゜A/
M l? δC'1)T)nL)CDtO', 1ll
)0 4.705. see) blasphemy, 28 (s, 6B); 4.8
7(s', 2H).

1,2-dichloroethane 50 according to the drying process of 1128 seconds
Oxy 1 frost ratio phosphorus in rnt (1,58,51,0,01
mol), 3-(p-anisinnomethyl)indole (2
,52,! i', (1,01 mol)5.5-dimethyl-
2-pyrrolidinone (1,18g, (1,01 mol)
, as well as triethylamine (1.01 g, 0.01 mol). After standing for 6 hours at water bath temperature, the reaction mixture was filtered to obtain the crude monocrystalline salt of the product, nLp188.
~191''(,/k(!#ru.) [Coloethane MV was made JH-based with 10% caustic soda, separated, dried over magnesium sulfur, and made 11β-based with ethanolic hydrochloric acid. F.: Concrete. The residue obtained in this way is crushed with acetone and added to salt (0,76,1,?
Le p.

A4) 191-194℃. Combine 1 salt fraction and dissolve in water + 1 + ￥ L, In & with caustic soda.
(by making it raw and then opening it with ether)
Convert to r'f:iH:FFM store (mp 88-85-C). Transfer JJDiILphosphorus into ethanol,
With ethanol 1 or hydrogen tetrahydride, [Shun 1 raw and analytically pure 3-[[-(5,5-dimethyl-1-biroline-
2-yl)-p-anizidino]methyl]indole tM
f'i2 LHlmp 188.5-191), 5°C
By obtaining (decomposition) (correction);

Analysis C22/125 N, -HCe and ritn
Value (%): C, 6s, s2; 11.6.88: N, 1
0.95: Ce, 9.2B, 1st shift (person in charge): C
,68,69;Ii,6.77 :N,10.7ri;C
/', 9j16° infrared (0.5% kBrcm-' C
2980,1fi 5 (1,1510,1450,1
260,1180, l (+ 4 (1,'r45゜panonol/Rδ(nonnru) (1) Runo Sυ-d0. Tetramethylsilane theft; Q): +(72(s + 8 H
) ; 1.50 (8, 6// ) ; 5.27
(s +211); 11.88 (broad +s1
2//)-monovirolin-2-yl)anilino]methyl]
N-(3-indolylmethyl)-4-methoxy phosphorus (7,7,'7, 0.05 mol) in 120 ml of 1,2-dichloroethane at water bath temperature -2-methylaniline (
18.8g% 0.05mol), 2-pyrrolidinone C/
L3g, 0.05 mol) and triethylamine (5,
1,! 9. 11.05 mol) of the mixture with stirring. After the addition is complete, remove the cooling bath and store the mixture in room γ,
Stir for 16 hours, then quench in 200 g of crushed ice, and make basic with 40% aqueous caustic soda. Extract the organic layer with IO% aqueous tM (&) and wash the aqueous extract with ether. , basify the rubbery substance with aqueous caustic soda and dilute it to 11%. Add 11% of this with ether.
)111. I L, fLlte+ ether eluate
- Shun Magnesium 2.:yu::;'#L, I (18) to obtain a residue, add to ethanol 2 (Jmt) and acidify with ethanolic hydrogen chloride. Add the acidified solution. Dilution with ether yields analytically pure 8-r(4-methoxy-2-methyl-N-(1-pyrrolin-2-yl)anilino]methyl]indole hydrochloride, ηxp178-18
0°C (corrected) 2.849 is obtained.

Analysis Recited value (chi) as Cn1b, Ns・lIC8:
C, 68,18; H, 6,58; N, 11.58;
Ce, 9.65° Experimental value (%): C167,92; H2
6,46; N, 11.18; Ce, 9.72° infrared C0
,5% kBrcm-”): 8450% 3211
0.1660.1510, 1460.1820, 124
0.750°NMRδC't)pm)CDhfSO-d. , see Tetramethylsilane): 8.75 (s, 8) I)
;1.89(s, 8//) ;n, 28
(s, 2#).

N-phenylamidine h11f characterized by formula I, where Z is R4,/,!S-indole
1 t of 1,2-dicycloethane in MNE using triethylamine according to the procedure of ilJ26-88.
(Prepared by reacting anilinoindole, carboxamide reactant, and phosphorus oxychloride. The anilinoindole reactant is obtained according to methods well known to those skilled in the art. f=!I, 1', Schiff base, N-(8-methylene-1-methylindole)aniline for the condensation of 1-methylindole-8-carboxaldehyde with aniline in single flow toluene. J: 11. Co-(anilinomethyl) of Schiff base with sodium borohydride
-1-methylindole.

There are 4 intermediates! I get caught.

Honorable title X Y A.

88 II H-C) Reactant: 3
-(Anilinomenal 39 tn-CH* p
Cl-C) Reactant: 8- (?
p-dimethino 40 HII-C
tlt+reactant: 3-(anilinoethylniki R'
R' A1- )-1-isopropylindole and 2-pyrrolidinone t
- /anilinomethyltwindole and 2-pyrrolidinone blade 2 indole and 2-pyrrolidinone
Doko IG Firefly (commercial note).

1) Further i't, i l'chemistry t1f', M1m; 1
4. The method of claim 1 comprising mixing the reactants at 4°.

2) iJ4 Ni anti-Uc; wo-35'C~100℃0)
1 AIreKJ-I T Real #ii Sun) Koto” Niri Naru 1,! , rt li A method of self-report for the Aoki Yamaj Engineering 1.

3) Mr. 1's 111-person 1! %I) 1: Hj group inactive 1
The method according to claim 2, which comprises producing a 1M acidic acid by reacting it with an acid which can be used as a pharmaceutical in a solvent.

/l) Z is l? ' and l? 51i't4 central 3-
When it is indole, add the amine to the reaction system in the third wave of the reaction.
1lii Σ song 1lj91 city method of claim.

Bamboo, 9″F shaft A, / Risdol, Ma Years, Company Daijin j1 Ritokawa
RA Good Dissolution Volume [19j
Takashi Yoshino.

■Inventor Walter Gee Robetsk 6100 Feltman Drive, Evansville, Indiana, USA

Claims (1)

[Claims] A compound of formula I or a pharmaceutically usable acid addition salt thereof, wherein XtJ- and Y are independently hydrogen, halogen, or trifluoromethyl. 1 to 4 carbon atoms; lower alkoxy or 1
~4Illil carbon is one round lower alkyl; alkyl is an alkylene residue containing 1 to 21+, 'il carbon atoms; z(rty enyl, 2-chenyl, 2-furyl, or (- 1 formula (where R4 is hydrogen, lower alkyl or benzyl, 11
``is hydrogen, halogen or lower alkoxy) and 'R' substituted 8 to t in indole
1 is (where n is an integer from 1 to 8-, and 1I) 2 and R3 are independently hydrogen or lower alkyl of 1 to 4 carbon atoms). 4〆、Slightly ahead of time、Ding( r 4・Isuru+jRl+△ryōji・(・、Mexicanization 11 in the presence of appropriate futoshi 171 If 4 Ikuzoku Jr~
1-chu 1〕 (〃-dashi ujichu-furugi, X, Y, Z, R”,
) i3 and n are as previously defined 1[n, t, ru] by reacting with a carboxamide to form a compound of formula 1 ÷! Hazouzuo Koto wo'I! J1゛:゛′ (to be J)
i', mu.