JPS5832865A - Novel amidinopiperidine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:An amidinopiperidine derivative shown by the formulaI(A is O or S; R is phenyl, pyridyl, naphthyl, indanyl, or tetrahydronaphthyl which may have 1-3 substituent groups selected from halogen, alkyl, alkenyl, aralkyl, alkoxy, alkanoylamino, nitro, cyano, etc.; n is 0-2) and its acid addition salt. EXAMPLE:1-Amidino-4-piperidinepropionic acid phenyl ester hydrochloride. USE:Having an anticomplementary action, allergic inflammation suppressing action, protease inhibiting action, etc., useful as a drug. PROCESS:A compound shown by the formula II or its salt or its reactive derivative is reacted with a compound shown by the formula III (R<1> is halogen, etc.) or its sulfite derivative, and, if necessary, hydrogenated, to give a compound shown by the formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel piperidine derivatives, particularly those having the following general formula (1
) (wherein A is an oxygen atom or a sulfur atom, R is a halogen atom, an alkyl group, an alkenyl group, an aralkyl group,
1 to 1 selected from alkoxy group, alkanoyl group 1, alkanoylamino group, nitro group, cyano group, formyl group, aminosulfonyl group, trihalogenomethyl group, alkoxycarbonyl group, benzyloxycarbonyl group, carboxyl group, aryl group A novel amidinopiperidine derivative represented by a phenyl group, a pyridyl group, a naphthyl group, an indanyl group, or a tetrahydronaphthyl group which may have three substituents, where n is 0 or an integer of 2. and its acid addition salt and its production method.

The present inventors have developed all piperidine-based compounds over a long period of time and investigated their pharmacological effects.
The present invention has been completed based on the discovery that a novel amidinopiperidine derivative represented by () and its acid addition salt have excellent anti-complement effect, allergic inflammation suppressing effect, protease inhibiting effect, etc.

Therefore, an object of the present invention is to provide a novel compound represented by the general formula (1) and its acid addition salts having excellent pharmacological action.

Another object of the present invention is to provide a method for producing the novel compound represented by the general formula (1).

Groups that can be substituted with the phenyl group, pyridyl group, naphthyl group, indanyl group, or tetrahydronaphthyl group represented by R of the novel amidinopiperidine derivative represented by the general formula (1) include halogen atoms such as chlorine, bromine, and fluorine. , alkyl groups such as methyl, ethyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, alkenyl groups such as allyl group, aralkyl groups such as benzyl 7-enethyl, α, α-dimethylbenzyl, phenylpropyl nato, methoxy, ethoxy, propoxy, butyloxy Alkoxy groups such as acetyl, alkanoyl groups such as propanoyl groups, trihalogenomethyl groups such as trifluoromethyl groups, alkanoylamino groups, nitro groups, cyano groups, formyl groups, aminosulfonyl groups, alkoxycarbonyl groups, penzyloxy carbonyl group,
Examples include carboxyl group and aryol group. In addition, not only one substituent but also up to three substituents may be used in various combinations.

In addition, acid addition salts of the compound of general formula (1) include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, p
-Acid addition salts with toluenesulfonic acid etc. can be mentioned.

The novel amidinopiperidine derivative of general formula (1) and its acid addition salt of the present invention are produced as follows.

(In the formula, R1 is a halogen atom, an alkyl group, an alkenyl group, an aralkyl group, an alkoxy group, an alkanoyl group, an alkanoylamino group, a nitro group, a cyano group, a formyl group, an aminosulfonyl group, a trihalogenomethyl group, an alkoxycarbonyl group, A phenyl group, pyridyl group, naphthyl group, indanyl group or tetrahydronaphthyl group selected from benzyloxycarbonyl group and aryl group and optionally having 1 to 3 substituents, A, R and n are as above. In other words, the novel amidinopiperidine derivative of general formula (1) is a compound of general formula (If), a salt thereof or a reactive derivative thereof, and the compound tri represented by general formula (2) is a sulfite derivative thereof. When it is desired to obtain a compound having a carboxyl group as a substituent in the group represented by R as a desired product by reaction, it is preferable to subject a compound having a benzyloxycarbonyl group to a hydrogenation reaction. be done.

7- General formula (Reactive derivatives of the compound of IQ include acid halides such as acid chloride and acid bromide, mixed acid anhydrides and active esters such as chloroethyl carbonate and chlorobutyl carbonate ester. General formula ( The sulfite derivative of the compound 2) can be easily obtained by reacting the compound of the general formula (2) with thionyl chloride in the presence of a tertiary amine.

Reaction combinations include reaction of a reactive derivative of a compound of general formula (IF) and a compound of general formula (2), and reaction of a compound of general formula (n)
reaction of the compound or its salt with the compound of general formula (2),
Examples include reactions between the compound of general formula (1) or a salt thereof and the sulfite derivative of the compound of general formula (2).

The reaction between the reactive derivative of the compound of general formula (n) and the compound of general formula (2) is carried out at -10°C to room temperature (stirring for 15 to 5 hours).As the reaction solvent, dimethylformamide is used. , dichloromethane, dichloroethane,
Examples include chloroform and acetonitrile, and it is preferable to carry out the reaction in the presence of a tertiary amine such as triethylamine and dimethylaniline.

The reaction between the compound of general formula (n) or a salt thereof and the compound of general formula (to) is preferably carried out using a carbodiimide such as dicyclohexylcarbodiimide as a condensing agent and stirring at room temperature for 5 hours to 5 days. As a solvent, dimethylformamide, dimethylacetamide, pyridine,
Toluene, xylene, dimethyl sulfoxide, etc. or mixtures thereof are preferred.

In addition, the reaction between the salt of the compound of the general formula (10) and the sulfite derivative of the compound of the general formula (IID) is carried out in a solvent such as dimethylformamide, dimethylacetamide, pyridine, or a mixed solvent thereof at 0°C to room temperature. The mixture was stirred for 10 hours.

In addition, when a compound having a benzyloxycarbonyl group in a single group among the compounds of general formula (1) is obtained by the above condensation reaction, a carboxyl group can be obtained by subjecting it to an erihydrogenation reaction as desired. It can be converted to .

The hydrogenation method is easily carried out by adding hydrogen in the presence of palladium etc. When obtaining the acid addition salt of the novel amidinopiperidine derivative of the general formula (1), the raw material of the general formula (If ) It is preferable to use the acid addition salt of the compound to obtain the target compound in the form of the salt.

The compound of general formula (II) which is a raw material is 4-piperidinecarboxylic acid or Fi, 4-piperidinepropionic acid.
-Methylisourea or fc is S-methylisothiourea.vcL9 can be easily obtained by reacting at room temperature for 5 to 20 hours. , has suppressive effects on allergic inflammation such as suppressing Arthus reaction and suppressing hypersensitivity, as well as proteolytic enzyme inhibitory effects, and is useful as a medicine.

The effect on complement was investigated using fresh human and guinea pig serum to determine how the compounds of the present invention inhibit hemolytic reactions via the classical pathway and the alternative pathway. That is, the classical route was tested by adding gelatin veronal buffer, sheep red blood cells, and anti-sheep red blood cell antibodies to fresh human or guinea pig serum to cause a hemolytic reaction. The second route was tested by adding rabbit red blood cells to fresh human or guinea pig serum to cause a hemolytic reaction.

The 50% inhibitory concentration for the classical pathway (OHso) and the 50% inhibitory concentration for the alternative pathway (AO]1Iso) thus obtained are shown in Table 1.

Table 1 Anti-complement effect of the compounds of the present invention 12- Test compound 1: Compound obtained in Example 1.

Test compound 2: Compound obtained in Example 7.

Test compound 3: Compound obtained in Example 5.

Test compound 4: Compound obtained in Example 4.

Test compound 5: Compound obtained in Example 12.

Test compound 6: Compound obtained in Example 11.

Test compound 7: Compound obtained in Example 9.

Test compound 8: Compound obtained in Example 15.

Test compound 9: Compound obtained in Example 17.

Test compound 10: Compound obtained in Example 21.

Test compound 11: Compound obtained in Example 40.

Test compound 12: Compound obtained in Example 44.

Test compound 13: Compound obtained in Example 45.

Test compound 14: Compound obtained in Example 43.

Test compound 15: Compound obtained in Example 42.

Test compound 16: Compound obtained in Example 46.

The effect on allergic inflammation was investigated by testing how the compounds of the present invention inhibit Arthus reaction and Delayed hypersensitivity.

Regarding Arthus reaction, guinea pigs were tested in reverse passive mode. That is, oval albumin was administered as an antigen into the forelimb vein, and 15 minutes later, rabbit antiserum, which had been collected in advance, was injected into the dorsal region. Observations were made over time.

The test compound was orally administered 1 hour before antigen administration. Observations were made by measuring the major axis x minor axis of redness and edema, and the inhibition rate (expressed as function) relative to the control. The results are shown in Table 2.

Table 2 Effect of compounds of the present invention on reverse passive Arthus phenomenon in guinea pigs Test compound 9: Same as above.

Test compound 10: Same as above.

Test compound 16: Same as above.

Test compound 17: Compound obtained in Example 8.

Test compound 18: Compound obtained in Example 19.

Test compound 19: Compound obtained in Example 25.

Test compound 20: Compound obtained in Example 30.

Test compound 21: Compound obtained in Example 26.

Test compound 22: Compound obtained in Example 25.

Test compound 23: Compound obtained in Example 29.

Test compound 24: Compound obtained in Example 22.

Test compound 25: Compound obtained in Example 20.

Test compound 26: Compound obtained in Example 28.

For delayed-type hypersensitivity, IOR mice were sensitized to dorsal dorsal administration using live BOG bacteria, and 6 days later they were given BOG again.
Live bacteria were administered to the front of the legs to induce the infection. Thickness of foot swelling'
(The test compound was measured 24 hours after the intradermal administration of l-BOG live bacteria. The test compound was orally administered for 6 consecutive days from the day after sensitization. The results were determined from the difference in foot thickness from the control. Table 3 Effect of the compound of the present invention on delayed-type hypersensitivity Test compound 16: Same as above.

Test compound 17: Same as above.

Test compound 18: Same as above.

Test compound 25: Same as above.

Test compound 27: Compound obtained in Example 10.

Regarding the protease inhibitory effect, the effect of the compounds of the present invention on the ice-melting ability of synthetic substrates such as trypsin, chymotrigsin, plasmin, kallikrein, thrombin, and urokinase was investigated.

As a result, the compound of the present invention showed particularly strong inhibition against trypsin, chymotrypsin, and urokinase.

As a result of the above, the compounds of the present invention are useful as prophylactic or therapeutic agents for allergic inflammation and inflammation.

19- However, the present invention is not limited thereby in any way.

Example 1 1-amidino-4-piperidine propionic acid phenyl ester m acid w: 1-amidino-4-piperidine propionic acid hydrochloride 70
7q and diphenyl sulfite 1.1f' with 8t of anhydrous dimethylformamide! 1t and anhydrous pyridine 3-
After stirring overnight at room temperature, the solvent was distilled off under reduced pressure, the residue was washed twice with 20 wt of ether, and the resulting crystal 'LP was collected and washed with acetone. This was dissolved in 4 tIt of total methanol, added to a solution of 2O-ether and 30 wt of acetone, and crystallized. The precipitated crystals were collected and washed twice with hot ethyl acetate to give a melting point of 167-17[L5℃].
1-amidino-4-piperidine propionic acid phenyl ester hydrochloride as colorless crystals 643η (yield 69%)
I got it.

2O-IRyKB"cvr-': 1735 (0=0
) ax NMR (CD30D) δ: 1.00 to 4.00 (1
5H,m, piperidine hydrogen and CdiCH2C0) &90-7.40 (5H,m, aromatic hydrogen), Example 2 1-amidino-4-biperidineprobion VO-benzyloxycarbonylphenyl ester hydrochloride: 1-amidino-4-piperidine propionic hydrochloride 7Q
7q and bis-(0-benzyloxycarbonylphenyl)sulfite 2.5 ti anhydrous dimethylformamide 8- and anhydrous pyridine 3111 were stirred overnight at room temperature.

The solvent was distilled off under reduced pressure, and the residue was washed three times with ether 20-. Next, when washed with 20% of ethyl acetate, crystals were precipitated, and these were recrystallized with isopropyl alcohol with a melting point of 148.
10jlv (yield: 51h) of 1-amidino-4-piperidinepropionic acid 0-benzyloxycarbonylphenyl ester salt Wl salt was obtained as colorless crystals at ~150°C.

Engineering RvKBrcy-': 1750, 1705 (0=O)
ax NMR (CD30D) δ: 1.00S-4,00(1
5H,m, piperidine hydrogen and Cμ202,C0) 5.20(2H,s,O40ph) 6.96-a96 (911,m, aromatic hydrogen) Example 5 1-amidino-4-piperidinepropion [0- H)”
Roxycarbonylphenyl ester hydrochloride: 1-amidino-4-piperidinepropion #o-benzyloxycarbonylphenyl ester hydrochloride 5.5f1
The mixture was dissolved in a mixture of 60 wt of kt-butyl alcohol and 60 wt of water, 225 lv'i of 10-chipalladium-carbon was added, and the mixture was shaken at room temperature for 1 hour in the presence of hydrogen at an initial pressure of 2.4 Kf/cIi. The catalyst 'kF was removed and the solvent was completely distilled off. The residue was washed with t-butyl alcohol, and the melting point was 192-1.
1-amidino-4-piperidinepropionic acid O-hydroxygalbonylphenyl ester hydrochloride 55f (yield 797%) was obtained as colorless needle crystals at 94°C.

EngineeringRvKBrm-': 1745,1725((!-0
)ax NMR (DM80-tl,)δ: [L8-2.0 (
71H,m, 3- and 5-112°4-H9β-
H2) 2.65 (2H, distorted t, a-H2)
2.8~4.2 (4H, m, 2-work 6-H2
)7.2-&Q4H,m, aromatic hydrogen) Example 4 1-amidino-4-piperidinepropion [21,4+
-dichlorophenyl ester [ll[: 1-amidino-4-piperidine propionic hydrochloride 1.7t and bis-(2,4-dichlorophenyl)sulfai) a,
Stirred at room temperature for 45 minutes in 10 ml of dimethylformamide and 3 d of anhydrous pyridine. The solvent was distilled off under reduced pressure, and 50% of ethyl acetate was added to the residue, which was then washed with ethyl acetate and ether to obtain 1-amicino-4-piperidinepropion R''t4'-dichloro as a colorless powder with a melting point of 152-156°C. Phenyl ester hydrochloride 2.
o2 (yield 73) O IRyKBrm-': 1760 (0□) ax NMR (CD30D) δ: 1.1 to 4.00 (13H
,m, piperidine hydrogen and Cμ2CH2CO) 7.20-7.70 (3H,m, aromatic hydrogen) Example 5 1-7midino 4-piperidi/propionic acid P-chlorophenyl ester ms salt: 1-amidino-4 - in a mixture of 1.5 g of piperidine propionic hydrochloride and bis-(p-chlorophenyl) sulfite 7, yt2 anhydrous di-1-y-lformamide 12- and anhydrous pyridine 6-;
Stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and ether was added to the residue to collect the precipitated crystals. After washing with ether twice and further with ethyl acetate, the crystals were recrystallized from methanol-ether to give colorless crystals with a melting point of 173-176°C. 1-amidino-4-biveridinbu, ropionic acid p-chlorphenyl ester hydrochloride 1.75 ? (Yield 79
．． 5%).

IR)l""z-': 1753(0=O)aX NMR(CD30D)δ: 1.0&S-4,05(1
3)1. m, piperidine hydrogen and 0H20μ2CO) 7,1)-7,67 (4H, m, aromatic hydrogen) Example 6 1-amidino-4-piperidine propionic acid p-methylphenyl ester hydrochloride = 1-amidino-4- In a mixture of 1.5 t of piperidine propionic acid hydrochloride and 12 g of anhydrous dimethylformamide and 6 t of anhydrous pyridine,
The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals were collected, washed twice with ether and further with ethyl acetate, and then recrystallized from isopropyl alcohol-isopropyl ether to give a melting point of 182-184°C. 1-amidino-4-piperidinepropionic acid p-methylphenyl ester hydrochloride 1.5ytC (yield: 90%) was obtained as colorless crystals.

IRν"r5-': 1743 (0=0) ax NMR (CD60D) δ: 1.00-4.00 (13
H, m, piperidine hydrogen processing C Dan2CH2CO) 2.29 (3H, s, published) &61~7.20 (4) 1. m, aromatic hydrogen) Example 7 1-amidino-4-piperidine propionic acid p-methoxyphenyl ester hydrochloride: 1.5 g of 1-amidino-4-piperidine propionic acid hydrochloride and bis-(p-methoxyphenyl) sulfur Phyto&82 was stirred at room temperature for 35 hours in a mixture of anhydrous dimethylformamide 14tRt and anhydrous pyridine 7-. The solvent was completely distilled off under reduced pressure, and ether was added to the residue to collect the precipitated crystal 'kF. After washing twice with ether and further with ethyl acetate, it was recrystallized from isopropyl alcohol-inpropyl ether to give a melting point of 1.
1-amidino-4-piperidine probiotic acid p-methoxyphenyl ester hydrochloride [1,24 M (yield 57 qA)'e was obtained as colorless crystals at 48-151°C. 0) ax NMR (CD, OD) δ; 1.0 to 4.0 (13H
, m, piperidine hydrogen and 0 companies, 0H200) 4.68 (3H, a , OOH,) 6.6) -7,04 (411, m, aromatic hydrogen) Example 8 1-amidino-4-piperidine Propion: j[pt-butylphenyl ester mum: 1-amidino-4 nibiveridine probion 27-hydrochloride 5. The mixture was stirred in Of and bis(pt-butylene) at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and ether was added to the residue to collect precipitated crystals, which were washed successively with ether and acetone. The obtained crystals were dissolved in a small amount of methanol, and after separating the insoluble matter tF, ether was added to precipitate crystals 'kF, which were collected as colorless crystals with a melting point of 159-163°C. 1-amidino-4-piperidinepropionic acid p- t-
Butylphe silkworm ester hydrochloride 7.2 f (yield 92
h) was obtained.

IRvKBrcm-':174B(0=O)ax NMR(CD30D)δ: (184-JL84(15
H, m, piperidine hydrogen and 2 (3H2co) 1.29 (9H, s, O (O di) 3) &48-7.14 (4H, m, aromatic hydrogen) Example? 1-amidino-4- Piperidine propionic acid p-acetaminophenyl ester hydrochloride: 1-amidino-4-piperidine propionophyl hydrochloride 2.Of and p-acetaminophenol 1.2.9 f J anhydrous pyridine 20
1.75 tk of dicyclohexylcal and posiimide were added to the mixture under water-cooling and stirring, and the mixture was stirred overnight at room temperature. The precipitated crystals t=F were collected, washed with ethyl acetate and ether in that order, and air-dried. 600w of dichloromethane with the obtained friend crystals
1 was refluxed in a medium, the insoluble matter was removed, washed with dichloromethane, and further recrystallized from methanol-ethyl acetate to give 1-amidino-
4-piperidinepropion [p-ace, doaminophenyl ester [l[tJil, 5f (yield 4&4t)'t
-I got it.

Engineering Rν drawing, 1761 (0=0) AX NMR (CD30D) δ: α89~405 (13H, m
, piperidine hydrogen C solid 2CH2C2.10 (3H, g, 0OOH) 7.01-7.70 (4H, m, aromatic hydrogen) z8 Example 10 1-Amidino-4-piperidinepropionate 0-allyl Phenyl ester hydrochloride Bis-(0-allylphenyl) prepared from 20-allylphenol and thionyl chloride
Sulfite 17tff anhydrous dimethylformamide 16
1-amidino-4-piperidine propionic hydrochloride 2 was dissolved in a mixture of W1t and anhydrous pyridine 8- and was stirred.
．． Off was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and diluted with acetone. This was poured into ether with stirring, and the precipitated crystals, total ether, acetone, and ether, were washed in this order and dried, with a melting point of 116-11.
1-amidino-4-piperidinepropionic acid 0-allylphenyl ester hydrochloride ffl 2 as colorless crystals at 9°C
．． 3f (yield 77.2cm) was obtained.

XRvKBram-': 1762 (0:O) at NMR (CDCl2) δ: 1.01-4.42 (13
H, m, piperidine hydrogen OH, OH, Co) 536 (2H, d, 0112-Ph) 5.0 ) -5,34 (217, m, = O solid,) 5
．． 82q23 (IH, m, -0H=) & 9 doors, 77 (
4H, m, aromatic hydrogen) Example 11 1-amidino-4-piperidine propionic acid p-acetylphenyl ester m acid m: 1-amidino-4-piperidine propionic acid hydrochloride 2.00 t and p-acetylphenol 1. 15fi-Anhydrous pyridine 20- Suspended in dicyclohexylcarbodiimide 1.74f under water cooling
' and stirred at room temperature for 2 nights. Precipitated crystal 'kF
The solvent was distilled off under reduced pressure.

Add ethyl acetate to the residue, collect the precipitated crystals t-F, and recrystallize from ethanol-ethyl acetate to give a melting point of 104-10.
1-amidi-4-piperidine propion & p-acetylphenyl ester hydrochloride 2.2 as colorless crystals at 6°C
t (yield 755To) was obtained.

XRyKBrz-1: 1768 (Jin 0) ax 11MR (CD30D) δ: Q, 8C-20 (15
H, m, piperidine hydrogen and eel, Cμ2CO) 2.69 (!IH, 8, Coo solid,) 7.3 to 49 (4H, m, aromatic hydrogen) Example 12 1-amidino-4-piperidine propion [2'-Chloro-4'-t-butylphenyl ester hydrochloride: Bis-(2-ria) prepared from 2-chloro-4-t-butylphenol and thionyl chloride.

-4-t-butylphenyl) sulfite a31P'z
Anhydrous dimethylformamide 16- and anhydrous pyridine 8
1-amidino-4-piperidine propionic hydrochloride hydrochloride 2. Of'ji was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, ether was added to the residue, and the mixture was stirred and the precipitated crystals 't-F were collected.

After air drying, recrystallize from methanol/ethyl acetate to a melting point of 18.
1-amidi-4-piperidinepropionic acid 21-chloro-4'-t-butylphenyl ester hydrochloride 2.2F (yield: 6 years, 7%) was obtained as a colorless powder bed at 6 to 189°C.

Engineering RyKB"cNl-': 1769 (0-0) ax 11MR (CD, OD) δ: [194S, !L99 (
13H, m, piperidine hydrogen ↓ and C20 dico) 1.54 (9H, a, O (O2, )3) 1 mouth 0-149
(5H, m, aromatic hydrogen) Example 15 1-amidino-4-piperidineprobion & p-isopropylphenyl ester mum: 1-amidino-4-piperidinepropionic acid hydrochloride 2f, p-isopropylphenol and thionyl chloride After stirring a mixture of 4.05 t1 of anhydrous dimethylformamide 10 and anhydrous pyridine 5 at room temperature for 1 hour, the solvent was distilled off. Ether was added to the residue to collect the precipitated crystals, washed with ether and ethyl acetate in that order, and washed with isopropyl alcohol.
Recrystallized from ethyl acetate-ether, melting point 119-12
1-amidino-4-piperidinepropionic acid p-isopropylphenyl ester as colorless needles at 1°C! acid!
2.9 f (yield: 97 g) was obtained.

KBr -L Engineering R, 17m, Xcm, 1755 ((3=O)N
MR (CD, OD) δ: 1.24 (6H, d, J==
7.2Hz, 0H3X2)1, toe 2.0 (7H,
m, β-H2,3- and 5-IH2,4-H) 2.7S-4,0(5H, m, 2- and 6-H2
゜Cdan≦)゛&99,7.26 (each 2H, each d.

J=44H2, aromatic hydrogen) Example 14 1-amidino-4-piperidinepropionic acid 21-su7
Tyl ester hydrochloride: 1-amidino-4-piperidine propionic hydrochloride 22
, - bis7 toll and thionyl chloride ↓9 -
A mixed solution of (2-su7thyl)sulfite 4.3f, anhydrous dimethylformamide 10- and anhydrous pyridine 5- was stirred at room temperature for 3 hours, and then the solvent was distilled off. The residue was powdered with ether and then recrystallized from methanol-ether to give 2.4 f of 1-amidino-4-piperidinepropionic acid 21-naphthyl ester hydrochloride as colorless needle crystals with a melting point of 185-187°C (yield: 7B%) 'I got OIRyKB'
m-': 1745 (0=0)lLX NMR (CD30D) δ: 1. O~2.0 (7H,
m, fi -H2* 3-work 5-H2,4-H
) z, 6a (zn, t, J=7.8Hz, a-H2)2
．． 9-4.0 (4H, m, 2- and 6-H2)
7.1-JO (7H, m, aromatic hydrogen) Example 15 1-amidino-4-piperidinepropion i!1!1'
Bis-(1-naphthyl) sulfite prepared from α-naphthol and thionyl chloride 4.25? , anhydrous dimethylformamide 10- and anhydrous pyridine 4- were stirred at room temperature for 1 hour. After distilling off the solvent, the residue was treated with total ethyl acetate to precipitate crystals.

Wash the crystal with ethyl acetate, melting point 187-190℃
1-amidino-4-piperidinepropionic acid 11-naphthyl ester hydrochloride 2.9f (yield 94g) was obtained as pale brown needle crystals of 7'C.

IRpKBrcm': 1755 (0=O)mfL! NMR (0D60D) δ: 1. [)%-2,0(7H
, m , β-H2,3-Okoji 5-II2.4-H) 2.78 (2H, t, J=7.2Hz, α-H2) Gono-,0 (4H, m, 2- Work 6-H2) 7.1-JO
(7H, m, aromatic hydrogen) Example 16 1-amidino-4-piperidinepropion [21,4+
-Dimethylphenyl ester hydrochloride: 1-amidino-4
-Piperidine propionic hydrochloride 4. Of and bis-
(2,4-dimethylphenyl)sulfa'f) 494(
(Adjusted from 2,4-dimethylphenol and thionyl chloride)
It was added to a mixed solution of 34 wt of all anhydrous dimethylformamide and 17 wt of anhydrous pyridine, and left at room temperature VC for 6 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue to precipitate crystals. The obtained crystals were recrystallized from methanol-ether to give 1-amidino-4-piperidinepropion I12' as colorless needle crystals with a melting point of 191-195°C.
, 4'-dimethylphenyl ester hydrochloride 4.5?
(Yield 78%) t-4⇠OIRI/KBrm-': 1
745(0=O)ax NMR (CD30D) δ: [1,96""496(1
3H, m, piperidine hydrogen and C2Cμ200) 2.08 (1, s, 4'-0, 5) 2.26 (jH, 8,2'-OH,) &66-7.04 (3H, m , aromatic hydrogen) Example 17 1-amidino-4-piperidine propionic acid p-fluorophenyl ester hydrochloride: 1-amidino-4-piperidine propionic acid hydrochloride 2.0 t and p-fluorophenol α95f'i anhydrous The suspension was suspended in pyridine (20%), and 1.741 Ft of dicyclohexylcarbodiimide was added thereto while stirring under water cooling, and the mixture was left at room temperature for 4 days. The precipitated dicyclohexyl urea was separated, and the p liquid was concentrated under reduced pressure. Add ethyl acetate to the residue, collect the precipitated crystals, and recrystallize the crystals from methanol-ether to give a melting point of 131-1.
1-amidino-4-piperidinepropionic acid p-fluorophenyl ester tjL acid j as colorless crystals at 33°C
X 1.4 t (yield sa 0%) was obtained.

IRyKBrm-': 1750 (0=O)ax NMR (CD30D) δ: 0. BB-! c96(13
H,m, piperidine hydrogen and Cμ20μ2co) &8(1-7,15(4H,m, aromatic hydrogen) Example 1
8 1-amidino-4-piperidine propionic acid p-cyclohexylphenyl ester hydrochloride: p-cyclohexylphenol and thiochloride, bis-(p-cyclohexylphenyl]sulfite 8t and 1-amidino-4-piperidine prepared by Nilyosu Propionic hydrochloride 4ft-Anhydrous dimethylformamide 20+d
and anhydrous pyridine 8- and stirred at room temperature for 2.5 hours. The solvent was completely distilled off, and the residue was treated with total ethyl acetate to precipitate crystals. This was recrystallized from isopropanol-ether to give colorless crystals with a melting point of 115-116°C.
)' got it.

IRWKB" 3-1: 1760 (Wataru) "ax NMR (CD50D) δ: 1.0 t4.00 (2
H, m, piperidi/hydrogen cyclohexane hydrogen and a
H20H2Co ) & 8-7.26 (4H, m, aromatic hydrogen) Example 19 1-amidino-4-piperidinepropionic acid p-(α,
α-dimethylbenzyl)phenyl ester hydrochloride: bis-(p-(α,α-dimethylbenzyl)phenyl)sulfite θ6f and 1-amidino- prepared from p-(α,α-dimethylbenzyl)phenol and thionyl chloride. 4-piperidine propionic acid hydrochloride 4tt was added to a mixture of anhydrous dimethylformamide 20- and anhydrous pyridine 8d, and stirred at room temperature for 2.5 hours.The solvent was distilled off, and ethyl acetate was added to the residue, which was stirred to crystallize. I let it happen.

After washing with ethyl acetate and ether in that order, recrystallization from isopropanol-ether gives colorless crystals with a melting point of 155-156°C.1-amidino-4-piperidinepropionic acid p-(α,α-dimethylbenzyl)phenyl ester hydrochloride 5.5 tons of salt (yield: 75.3 tons) was obtained.

IRyKBrm-': 1765(0=O)ax NMR (CD30D) δ: 1. [h-4,0(13H
, m, piperidine hydrogen and O! ,! OH200) 164 (6R, e, nc(oμ3)2) 48 doors 4
0 (4H, m, aromatic hydrogen) Example 20 1-amidino-4-piperidinepropionic acid 41-formyl-2'-methoxyphenyl ester hydrochloride: 1-amidino-4-piperidinepropionic acid hydrochloride 4.
7f, vanillin 5? , dicyclohexylcarbodiimide 4.1F, anhydrous dimethylformamide 20dL and anhydrous pyridi/10- were stirred at room temperature for 24 hours. After separating the precipitated dicyclohexylurea kF, the solvent was distilled off and 7
'CQ residue was treated with ethyl acetate to obtain a white powder'f
c. After washing with ethyl acetate and ether in that order, recrystallization from isopropanol-ether gives a melting point of 98-105°C.
1-amidino-4-piperidinepropionic acid 41-formyl-21-methoxyphenyl ester hydrochloride as colorless crystals! 1Lar (yield 795cm) was obtained'fC-OIRy''rcm-': 1700,1750.1770
(0=O)lLX NMR (CD, OD) δ: 1.04-4.20 (1
3H, m, piperidine hydrogen and Cdan2C. co) 4.04 (5H, a, 00 days,) 7.5O-aO (3H, m, aromatic hydrogen) 10.4 (I
H,s,0HO) Example 21 1-amidino-4-piperidinepropionic acid p-aminosulfonylphenyl ester hydrochloride: 1-amidino-4-piperidinepropionic fl! salt 11
salt ty t, p-hydroxybenzenesulfonamide i5f, dicyclohexylcarbodiimide 4.11F
, anhydrous dimethylformamide 10- and anhydrous pyridine 20- were stirred at room temperature for 24 hours. After separating the precipitated dicyclohexyl urea in a furnace, the solvent was distilled off.

The residue was treated with ethyl acetate followed by ether to give crystals. After dissolving this in methanol and removing all insoluble matter,
The crystals precipitated by adding ether had a melting point of 206 kF.
1-amidino-4-piperidinepropionic acid p-aminosulfonylphenyl ester hydrochloride 4.59 (yield 57.79 b)' was obtained as yellow crystals at ~209°C.

IR)/KBr3″-1: 17/10(0-0)2L
x NMR (CD30D) δ: 1.04N4.20 (1
3H,m, piperidine/hydrogen↓andC2Cdan2CO) 7.44-C28 (4H,m, aromatic hydrogen) Example 22 1-amidino-4-piperidinepropionic acid m-)! J
Fluoromethylphenyl ester hydrochloride: 1-amidino-4-piperidine propionic hydrochloride 4.
Of and m-trifluoromethylphenol 2.7
5 was suspended in 27 g of completely anhydrous pyridine, 5 ft of dicyclohexylcarbodiimide was added thereto, and the mixture was stirred at room temperature for 6 hours.

The precipitated dicyclohexylurea'kF was separated, the solvent was distilled off, and the residue was washed with ether, dissolved in chloroform, and stirred. After separating the insoluble matter 'kF', it was washed twice with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1-amidino-
4-Piperidinepropionic acid m-trifluoromethylphenyl ester hydrochloride 4.0? (yield: 62.0%).

Engineering RuKBr5+-1=1760(C=O]ax NMR(OD013) δ:452(13H, m
, piperidine hydrogen and 0 units 2C giant, C0) 7.2 (h-7,92 (4H, m, aromatic hydrogen) Example 25 1-amidino-4-piperidine propionic acid p-formylphenyl ester salt m salt: 1 -amidino-4-piperidine propionic acid hydrochloride 4.0t and p-hydroxybenz, aldehyde 2.1fTh suspended in anhydrous pyridine 20- and dicyclohexylcarbodiimide 5.0t under stirring.
5 ft- was added and stirred overnight at room temperature. Separating the precipitated dicyclohexylurea'kF, Pt1. Ethyl acetate was added to the residue obtained by concentrating under reduced pressure, and the mixture was stirred to precipitate crystals. The obtained crystals were recrystallized from methanol-ether to give 1-amidino-
4-piperidinepropion flip-formylphenyl ester hydrochloride tJL 2.1y (yield 364%) was obtained.
-o) 1LX NMR (CD30D) δ: α92=-416 (13H,
m, piperidine hydrogen and 0H20H2Co) 7.4O-C20 (4B, m, aromatic hydrogen) 1α16 (
IH,s,Cl0) Example 24 1-amidino-4-piperidinepropionic acid p-77 nophenyl ester hydrochloride = 1-amidino-4-piperidinepropionate hydrochloride 4fXp-cyanophenol2.
Of and dicyclohexylcarbodiimide 5 tf anhydrous pyridine 20++d! Stir overnight at 7'C.

The reaction mixture was filtered and washed with pyridine. Further, the crystallization water on the filter was extracted by stirring for about 20 minutes in a mixed solvent of 20 d-t-butanol and 7' cm.The above-mentioned p solution, washing solution and extract were combined, and the solvent was distilled off under reduced pressure. The residue was recrystallized from water and had a melting point of 164.5-169. 1-amidino-4-piperidinepropion [
p-cyanophenyl ester hydrochloride 14f (yield: 59cm)'IRWKBrm-': 2240 (ON), 1765
(0=O)maNMR(C!D30D)δ: 1.00-4.10(1
5H, m, piperidine hydrogen ↓ and CH2O, co) 7.40-&10 (4H, m, aromatic hydrogen) Example 25 1-amidino-4-piperidine propionic acid 0-cyanophenyl ester [acid acid: 1 -amidino-4-piperidine propionic hydrochloride 4.
0? , 0-cyanophenol 2.0? and dicyclohexylcarbodiimide 5 Sfi was stirred in anhydrous pyridine 20 for 24 hours. The precipitated dicyclohexyl [l] was filtered and washed with anhydrous pyridine. Combine the p solution and washing solution,
The solvent was removed under reduced pressure. Ethyl acetate was added to the residue for crystallization. The obtained crystals were recrystallized with water and had a melting point of 159.
．． 1-amidino-4 as colorless crystals at 5-162.5°C
-Piperidine propionic acid 0-cyanophenyl ester hydrochloride 2.1F (yield 37%) was obtained.

47-ERvKBrm-': 2240 (ON), 1775
(C=sax NMR (CD30D) δ: 1.0 to 4.10 (13H
, m, piperidine hydrogen and CH2 eel, C0) 7.40400 (4H, m, aromatic hydrogen) Example 26 1-amidino-4-piperidine propionic acid O-methylphenyl ester hydrochloride: 0-methylphenol and thionyl chloride 6.7 t of the prepared bis-(0-methylphenyl)sulfite and 4 t of 1-amidino-4-piperidine propionic acid hydrochloride (stirred in a mixed solvent of 20-anhydrous dimethylformamide and 6-anhydrous pyridine for 2.4 hours) The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (55%).
0- and ether 20tQ- were added for crystallization. The crystals were collected and recrystallized from inpropanol-ether and then from methanol-ether. The product was further recrystallized in water to give 1-amidino-4-piperidinepropionic acid 〇-methylphenyl ester salt II as colorless crystals with a melting point of 184-185.5°C (yield: 58°C).

IRvKBrm-': 1750 (0=0) lLX NMR (CD30D) δ: 1.00-i, 05 (15
H, m, piperidine hydrogen and hydrogen, C0) 2.14 (3H, a, Odan 3) &9O-7JO (4H, m, aromatic hydrogen) Example 27 1-amidino-4-piperidine propionic acid 0 -Methyl phenyl ester hydrochloride = 1-amidino-4-piperidine propionic hydrochloride 41. o-Methylphenol 1.
A mixture of 9f dicyclohexylcarbodiimide & 5f anhydrous pyridine was stirred at room temperature overnight. The precipitated crystals were separated and washed with pyridine. The solution and washing solution were combined, and the solvent was distilled off under reduced pressure. The residue was poured with ethyl acetate and ether to precipitate crystals. Take crystal kF,
The mixture was washed with ethyl acetate and ether in this order.

After air drying, recrystallize from water to obtain colorless prismatic crystals with a melting point of 184-185L at 5°C.1-amidino-4-piperidinepropionic acid 0-methylphenyl ester hydrochloride, salt 5f
(yield s 4%) was obtained. The chemical resistance and NMR were consistent with the compound obtained in Example 26.

Example 28 1-amidino-4-piperidinepropionic acid 31-pyridyl ester hydrochloride: 1-amidino-4-piperidinepropionic acid salt salt 4.
A mixture of 71t, S-hydroxypyridine 1.95F, dicyclohexylcarbodiimide 4.131F, anhydrous dimethylformamide 40- and anhydrous pyridine 20- was stirred at room temperature for 19 hours. After separating the precipitated dicyclohexylurea'kF, the solvent was distilled off. The residue was washed with ethyl acetate and then dissolved in methanol. Separate insoluble matter 'kF,
Ethyl acetate was added.

The precipitated crystals were washed with all ethyl acetate and then with ether to obtain colorless needle crystals with a melting point of 177-179°C, 1-amidino-4-piperidinepropionic acid 3'-pyridyl ester hydrochloride &2t (yield: 99cm) I got it.

IRyKB"cm-': 1765 (0=O)ma! NMR (CD30D) δ: 1.Ox2.1 (7H,
m, 3-and 5-H2゜4-H and β-H2) 2.84 (2H, t, J=7.6Hz, α-H2) 50
q2 (4H, m, 2- and 6-H2) 7.7 to 89 (
4H, m, pyridine hydrogen] Example 29 1-amidino-4-piperidine propionic acid 0-phenylphenyl ester mmm: 1-amidino-4-piperidine propionic acid hydrochloride 49. A mixture of 9.5 f of bis-(0-phenylphenyl) sulfite (made from o-phenylphenylated and thionyl chloride), 40 ml of anhydrous dimethylformamide, and 20 ml of anhydrous pyridine was stirred at room temperature for 4 hours, and then the solvent was removed. It was completely distilled off under reduced pressure. The residue was recrystallized from water and washed with ethyl acetate and then with ether to give 1-amidino-4-piperidinepropionic acid 〇-phenylphenyl ester hydrochloride 145f (yield 52ch) All obtained.

IRvKB"m-': 1755 (0=O) ax NMR (CD30D) δ: [Lt1.9 (71K
, m, 3- and 5-H2゜4-H and β-H2
] 2.52 (2H, t, J=7.0Hz, a-H2
)2-&-4,1(4H,m,2- and 6-H2)7
．． 3x7.9 (9H, m, aromatic hydrogen) Example 30 1-amidino-4-piperidinepropionic acid p-phenylphenyl ester hydrochloride: 52- 1-amidino-4-piperidinepropionic acid hydrochloride 4t
, bis-(p-phenylphenyl) sulfite 9.3
After stirring a mixture of t (made from p-phenylphenol and thionyl chloride), anhydrous dimethylformamide 40 and anhydrous pyridine 8 at room temperature for 3 hours, the solvent was distilled off under reduced pressure. The residue was recrystallized from total methanol-ethyl acetate to give 1-
Amidino-4-piperidinepropionic acid p-phenylphenyl ester hydrochloride 41F (yield 61%) was obtained.

Engineering RV"" am-1: 1755 (0:O) ax NMR (CD, OD) δ: 1. OS2.0 (7H,
m, 3-work 5-H214-) I and β-I (
2) L61 (2H*t-J=&8H2*a-H2)
2, 4.0 (41, m, 2-work 6-H2)7.
0=7.6 (9H, m, aromatic hydrogen) Example 31 1-amidino-4-piperidinepropionic acid 21,41
161-trimethylphenyl ester hydrochloride: 1-amidino-4-piperidine propionic hydrochloride 4f
, 2,4.6-)limethylphenol 2.5? and 15 ft of dicyclohexylcarbodiimide - stirred in anhydrous pyridine at room temperature overnight. The precipitated crystals were filtered and washed with a small amount of anhydrous pyridine. Furthermore, t-butanol 2
It was thoroughly washed with a mixed solvent of 5-1 water and 25-2. The p solution and washing solution were combined and concentrated under reduced pressure. Add 50d' of ethyl acetate to this
i and stirred well to crystallize. Take the crystal 'kF,
1-amidino-4-piperidinepropion [2't
4'e 6'-) Limethylphenyl ester hydrochloride 53
f (yield: 55 cm)'t'' was obtained.

IRyKB"m-': 1750 ax NMR (CD30D) δ: 1.0 to 4.16 (13H,
m, piperidine hydrogen and eel, aH2co) 2-12 (6H, s, 2.6-0...3) 2.26 (5H
, e, 4-C...3) &92 (2H, s, aromatic hydrogen) Example 32 1-amidino-4-piperidinepropionic acid 2'+b'
#) f sulfenyl ester salt l: bis-(2,6-cynotyl phenyl) sulfite made from 2,6-cynotylphenol and thionyl chloride 7,4 t' (anhydrous dimethylformamide 36- and anhydrous pyridine 18- 4.0 f k of 1-7midino-4-piperidineprobionic hydrochloride was dissolved in the mixed solution and stirred, and the mixture was left at room temperature for 4 days.The solvent was distilled off under reduced pressure, and ether was added to the residue.
The precipitated crystal was taken from the furnace and washed with ether and ethyl acetate in that order. Recrystallized from water, melting point 191-1941...
・(1-amidino-4-pi=55-veridinepropionic acid 2+,64-dimethylphenyl ester hydrochloride 53t (yield 57%) was obtained as pale yellow crystals at 1°C.

Engineering RyKB” m-1: 1740 (0=O) ax NMR (C!D30D) δ: α96S-4,32 (15
H, m, piperidine hydrogen and C dan, Cichi 2CO) 2.24 (6H, e, 2.6-0 dan,) 7.24 to 7.
60 (3H, m, aromatic hydrogen) Example 33 1-amidino-4-piperidinepropionic acid 51-indanyl ester hydrochloride: 5-indanol and thionyl chloride
(5-indanyl]sul7ai) 7. Of'? was dissolved in a mixture of 25 wt of anhydrous dimethylformamide and 12-wt of anhydrous pyridine, 1-amidino-4-piperidine propionic acid hydrochloride 5 at-i (at-i) was added under stirring, and the mixture was left to stand for 4 hours. The solvent was distilled off under reduced pressure. Then, 56 ml of ethyl acetate was added to the residue to precipitate crystals.The obtained crystals were washed with ethyl acetate and ether in that order, and recrystallized from methanol-ether to give 1- as colorless crystals with a melting point of 184-188°C. Acicino 4-piperidinepropionic acid 51-indanyl ester hydrochloride 161F (yield 80%)' was obtained.

■RvKB"cm""': 1760 (0=O) ax NMR (CD30D) δ: α84-4.32 (19H,
m, piperidine hydrogen.

C,,0H200 and C,C,C,) 7.0 toz64 (3H, m, aromatic hydrogen) Example 34 1-amidino-4-piperidinepropion 11p-,)
') Oxycarbonylphenyl ester hydrochloride: 1-amidino-4-piperidinopropionate hydrochloride 52
A mixed solution of 1251 tons of methyl p-hydroxybenzoate, 4.38 tons of dicyclohexylcarbodiimide, 100 tons of anhydrous dimethylformamide, and 20 tons of anhydrous pyridine was stirred at room temperature for 24 hours, and then treated in the same manner as in Example 9. The obtained crystals were recrystallized from inpropanol ether to give colorless needle crystals with a melting point of 16'5 to 164.5°C.1-amidino-4-piperidinepropionic acid p-methoxycarbonylphenyl ester salt ff salt 5.7F (Yield 72.
7To) was obtained.

NMR (CD30D) δ: 1. OS2.2 (7H,
m, 3- and 5-H2゜4-■,--H2) 2.84 (2H,t, J=7.2Hz, a-H
2) String, 4.5 (4H, m, 2 and 6-H2) 4.1
6 (also 311, θ, 0-C) 7.68 and a58 (each 2H, eacb4°J”a8Hz, aromatic hydrogen) Example 35 1-Amicino 4-piperidine propionic acid 0-acetaminophenyl ester hydrochloride: 1-amidino-4-piperidinepropionic acid hydrochloride 4.Of and 2.6 t of 0-acetaminophenol were dissolved in 40% of anhydrous pyridine, and 595% of dicyclohexylcarbodiimide was added with stirring while cooling with water, and the mixture was heated at room temperature for 44 hours. I left it alone.

The precipitated dicyclohexylurea t-F was separated, and the solvent was completely distilled off under reduced pressure. After washing the residual liquid with ethyl acetate, anhydrous ether was added to precipitate crystals, which were washed several times with ether. After washing with warm dichloromethane and ethyl acetate,
Anhydrous ether was added and evaporated to dryness to give 1-amidino-4-piperidinepropionic acid 0-acetaminophenyl ester K [acid salt 5.8F (yield 92.7) as hygroscopic crystals.
h) obtained.

IRyKBrm-': 1750((3=0)ax NMR((!D30D)δ: a92~4.2s(13
H, m, piperidine hydrogen CH2C dan 2CO] 2.40 (3H, a, 000 dan,) 7.2 to a20 (4H, m, aromatic hydrogen) 59 Example 36 1-amidino-4-piperidine propionic acid 5', 6
', 7', 8'-Tetrahydro-2'-naphthyl ester hydrochloride: 1-amidino-4-piperidine propionic hydrochloride 4, 5, 6, 7. B-tetrahydro-2-naphthol2.
5? , dicyclohexylcarbodiimide 4t and anhydrous pyridine 25- were stirred at room temperature for 1 day and further stirred in a 50°C oil bath for 6 hours. After separating the precipitated dicyclohexylurea'kF, the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate and ether in that order, dissolved in a small amount of isopropanol, and water was added to precipitate crystals. The obtained crystals were washed with ethyl acetate and ether in that order until the melting point was 1.
1-amidino-4-piperidinepropionic acid s+, 61, 7+, a as colorless powder at 13-115°C
l-tetrahydro-21-naphthyl ester hydrochloride &5
f (yield 5 &5%)'1ji- was obtained.

60-ERνKBrcM''': 175B (C=sax NMR (CDSOD) δ: 1.7t 1.94 (8H,
m, -(OH2)4-)1.04A-4,20(15
H, m, piperidine hydrogen and C and 20 and 2CO) 7, Odoor, 44 (S H, m, aromatic hydrogen) Example 37 1-amidino-4-piperidine propionic acid p-nitrophenyl ester hydrochloride: 1 - amidino-4-piperidine propionic hydrochloride S, at, bis-(p-nitrophenyl) sulfite 7.6 t (made from p-ditrophenol and thionyl chloride), anhydrous dimethylformamide 20- and anhydrous pyridine 6-Mixture of 'Q'
Stirred at room temperature for 22 hours.

The solvent was distilled off under reduced pressure, and 70 ml of ethyl acetate and 50 ml of ether were added to the residue, stirred well, and removed using a decantation pipe. Further, 500-t of ether was added, stirred and decanted in the same manner, and the supernatant was removed. A small amount of water was added to the residue to stimulate crystallization. After further adding acetone and stirring, crystals 't-F were collected. The resulting crystals were washed with acetone and ether and dried to give 1-amidino-
4-piperidinepropionic acid p-nitrophenyl ester hydrochloride 52fi was obtained.

IRyKB"am-': 1770 ((3=O)ax NMR (DMSO-t16) δ: 192S-4.08(
13H,m, piperidine hydrogen and Cdan, 0H2CO) &9door, 10 (6H,m, Ndan, and aromatic hydrogen) 7.8 ToseoO (2H,m, aromatic hydrogen) Example 38 1-amidino- 4-Piperidine propionic acid phenylthioester hydrochloride 2' 1-amidino-4-piperidine propionic acid hydrochloride 2.
4t, thiophenol i, 1f, dicyclohexycarbodiimide 2.12 and anhydrous dimethylformamide 15
- The mixture was stirred for 217 hours. After separating the precipitated dicyclohexylurea'tF, the solvent was distilled off. The residue was washed with ether and t-butanol, mp 168-1.
1-amidino-4-piperidine propionic acid phenylthioester hydrochloride as colorless crystals at 70°C 1.2 f
(Yield 5&4%) was obtained.

IRvKBrm-': 1710 (0=O)ax NMR (CD30D) δ: 1. [)%4.16 (1
3H, m, piperidine hydrogen and Cdan2cu2
C0) 7.56 (5H, a, aromatic hydrogen) Example 59 1-amidino-4-piperidinepropionic acid p -t-
Butylphenylthioester hydrochloride:
・: 1-amidino-4-piperidine propionic hydrochloride 5?
, p-(t,-butyl)thiophenol 2.2t, dicyclohexylcarbodiimide 2.6f and anhydrous dimethylformamide 1B- was stirred at room temperature for 10 hours.

After separating the precipitated dicyclohexylurea'kF, the solvent was distilled off under reduced pressure and the resulting oily substance was washed with ether. Water? Then, leave it in a cool place overnight. Precipitated crystal 'k
After removing F and washing with ethyl acetate and ether in that order, air drying gave 1-amidino-4 as colorless crystals with a melting point of 86-88°C.
-Piperidine propionic acid pt-butylphenylthioester hydrochloride 21f (yield 4&9%) was obtained.

Engineering RyKBroll-': 1710 ((3-0) ax NMR (CD30D) δ: 1.0 to 4.10 (13H
, m, piperidine hydrogen and 0H20H,! OO) 1.40(,9H,s,C(C!dan,)3)7.5(1
-7,84 (4H, m, aromatic hydrogen) 63 - Example 40 1-amidino-4-piperidinecarboxylic acid phenyl ester hydrochloric acid [: 1-amidino-4-piperidinecarboxylic acid salt al[a2
The mixture was stirred overnight at room temperature in 1.41F'i of anhydrous dimethylformamide and 4d of anhydrous pyridine. The solvent was distilled off under reduced pressure, and the residue was washed with 20 ml of ether three times, then washed with 10 wt. of acetone.
1-amidino-4-piperidinecarboxylic acid phenyl ester hydrochloride 600 wf (harvested) was obtained as powdered crystals with a melting point of 15 & 5 to 161 and a temperature of 5°C. rate 53%)k
Obtain'fc,.

IRyKB"cm-': 1750 (0-0) ax NMR (CD60D) δ: 1.5OS-4,00 (9
H, m s piperidine hydrogen) & 9 door, 40 (5H, m
, aromatic water
q and bis-1-〇-benzyloxycarbonylphenyl) sulfite Kof'l (stirred in anhydrous dimethylformamide and anhydrous pyridine overnight at room temperature, then evaporated the solvent under reduced pressure and the residue !10- was washed with ether three times. Next, acetone (10-) and ethyl acetate (30-) were added to give a stimulus to precipitate crystals. The crystals were collected and washed with hot ethyl acetate to give a melting point of 14 (15). ~
1-7midino-4-piperidinecarboxylic acid 0-benzyloxycarbonylphenyl ester as a colorless powder at 147°C! 1015 ml of acid (yield 61%) was obtained.

IRyKBr3-': 1740, 1770 (C=o)
ax NMR (CD30D) δ: 1-5 4-00 (9
Hm m *piperidine hydrogen) & 20 (2H, s, 0 g Ph) 496-aoO (9H, m, aromatic hydrogen) Example 42 1-amicino 4-piperidine carboxylic acid 21, 4+
-Dichlorophenyl ester salt u salt: 1-7 Midino 4
-Piperidine carboxylic hydrochloride 2. Of and bis-(
2+ 4- V ri”, ruphenyl) sulfite 7
, 2 f 5 anhydrous dimethylformamide 18- and anhydrous pyridine 9 wt., and stirred at room temperature for 4 hours.

The solvent was distilled off under reduced pressure, and the resulting residue was washed three times with ether. Acetone was added to the residue and stirred, and the precipitated crystal kF was collected and washed with ethyl acetate and ether.

This crystal is recrystallized from methanol-ether and has a melting point of 2.
1-Amicino 4- as colorless crystals at 15-21a5℃
Piperidine carbon rlt "t" -dichlorophenyl ester salt RjX 1.27 f (yield 37.
4%).

EngineeringRvKBrffi-': 1762((3=O)'
ax NMR (CD50D) δ: 1.67-%4.28 (
9H, m, piperidine hydrogen) 741-7.82 (3H
, m, aromatic hydrogen) 1-amidino-4-piperidinecarboxylic acid p-chlorophenyl ester hydrochloric acid [: 1-amidino-4-piperidinecarboxylic acid hydrochloride 1.5
f-cooked bis-(p-chlorophenyl) sulfite a
In a mixture of anhydrous dimethylformamide 14d and anhydrous pyridine 7g, stir at room temperature for 1 hour.
. The solvent was distilled off under reduced pressure, and the residual liquid was washed twice with anhydrous ether, and then acetone was added to precipitate crystals. Take crystal tp,
After washing with ether and ethyl acetate, it was recrystallized from methanol-ether to give 1-amidino-4-piperidinecarboxylic acid p-chlorophenyl ester hydrochloride 1.62f (yield 7114%) as colorless crystals with a melting point of 196-198°C.
I got it.

Engineering RνKBr cfR-': 1744 (0=snax NMR(CDsOD) a: 1.65S
-4,15 (9H* m + piperidine hydrogen) 7,19
~7.72 (4H, m, aromatic hydrogen) Example 44 1-amidino-4-piperidinecarboxylic acid p-methylphenyl ester m acid n: 1-7 midino-4-piperidinecarboxylic acid hydrochloride 1,5
tOkobis-(p-methylphenyl)sulfite 7
, 6t'i was stirred at room temperature for 1.5 hours in a mixture of anhydrous dimethylformamide and anhydrous pyridine 7-. The solvent was distilled off under reduced pressure, and ether was added to the residue to precipitate all the crystals. The precipitated crystals were washed with ether and ethyl acetate in that order, then reprecipitated with methanol-ether ether, and recrystallized from inglobanol-isoglobil ether to give a melting point of 187.
1-7midino-4-piperidinecarboxylic acid p-methylphenyl ester hydrochloride as colorless crystals at ~189°C2.
15f (yield 99.6%) was obtained.

Engineering RvKB"cIN-': 1742 (0 = O) ax NMR (CD60D) δ: to tso 4.Q O (9H,
piperidine hydrogen) 2.30 (3Hts, CHs
)&61-123 (4H, m, aromatic hydrogen) Example 4
5 1-amidino-4-piperidinecarboxylic acid p-methoxyphenyl ester m acid w: 1-amidino-4-piperidinecarboxylic hydrochloride hydrochloride 1.5t Separated bis-(p-methoxyphenyl) sulfite 7,7 f t-Anhydrous dimethylformamide 16- and anhydrous pyridine 81Rt were stirred at room temperature for 18 hours. Remove the solvent under reduced pressure,
Crystallized by adding ether to the residue? After washing the precipitated crystals twice with ether and then with ethyl acetate,
Recrystallized methanol-ether, melting point 198-2
1-amidino-4-piperidinecarboxylic acid p-methoxyphenyl ester hydrochloride as colorless crystals at 03°C 1.9
f (yield 83.7%) was obtained.

IR)/KBrm-': 1739 (0=O) ax NMR (CD, OD) δ: 1.4 t4.01 (9H
, m t piperidine hydrogen) 4.67 (3H, s, O-0
) &76~7.05 (4H1m, aromatic hydrogen) Example 46 1-amidino-4-piperidinecarboxylic acid pt-7'
Tylphenyl ester hydrochloride: 1-amidino-4-piperidinecarboxylic hydrochloride 1. Of and bis-(p-t
The mixture was stirred at room temperature for 2.5 hours in a mixture of anhydrous dimethylformamide 10- and anhydrous pyridine 5-butyl, phenyl) sulfite 5-tf. The solvent was distilled off under reduced pressure, and anhydrous ether was added to the residue to precipitate crystals.

The obtained crystals were washed with anhydrous ether and then with ethyl acetate, and then recrystallized from methanol-ether to give a melting point of 211.
1-amidino-4-piperidinecarvone flip-t-butylphenyl ester [
Acid [1,Of (115161, 4%) was obtained.

Engineering RvKB"ff1-': 1742 ((3=O)a
x NMR (CD30D) δ: 1.58 (9H, s, c (
an,),) 1.65-4.15 (94m, piperidine water,
, α-dimethylbenzyl) phenyl ester hydrochloride: Bis-[p-(α, α-dimethylbenzyl) phenyl] sulfite IQ, 9f, prepared by p-(α, α-dimethylbenzyl)phenol and thionyl chloride↓, 1-amidino-4-piperidinecarboxylic hydrochloride 41. Stirred over a mixture of anhydrous dimethylformamide 20d and anhydrous pyridine 8 at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the resulting oil was treated with ethyl acetate to give a powder. This was recrystallized from isopropanol ether with a melting point of 166~
1-amidino-4-piperidinecarvone [p-(α,α-dimethylbenzyl)phenyl ester]i12 salt 5.5f (yield 6a8%) was obtained as colorless crystals at 168°C.

NMR (CD30D) δ: 1.74 (6H,8,=C(
0 days, ) 2) 1.5 to 4.1 B (9H, m, piperidine hydrogen) 7,18-7.60 (9H, m, aromatic hydrogen) Example 48 1-amidino-4-piperidinecarboxylic acid p-Cyclohexylphenyl ester hydrochloric acid m: mixture of bis-(p-cyclohexylphenyl) sulfite 9.2F, 1-amidino-4-piperidinecarboxylic hydrochloride 41, anhydrous dimethylformamide 20- and anhydrous pyridine 8-
Stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was treated with ethyl acetate to crystallize. The precipitated crystals were recrystallized from inpropanol ether to give 1-amidino-4-piperidinecarboxylic acid p-cyclohexylphenyl ester hydrochloride as colorless crystals with a melting point of 226-25[L°C] 2.91
F (yield 4IIL8%) was obtained.

Engineering RyKBrttn-': 1760 (0=SlLX NMR (CD30D) δ: 1.2+) 4.30 (20
H, m, piperidine hydrogen and cyclohexane hydrogen) 7,11r-7,64 (4H, m, aromatic hydrogen) Example 49 1-amidino-4-piperidinecarboxylic acid 21, a
l-Dimethylphenyl ester hydrochloride: bis-(2,4
-dimethylphenyl) sulfite &4f'i anhydrous dimethylformamide 36W1t and anhydrous pyridine 18d
4. Dissolve in a mixture of 1-amidino-4-piperidinecarphonic acid hydrochloride. Of'i was added and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and ether was added to the residue to collect the precipitated crystals. 1-amidino-4-piperidinecarboxylic acid 2 was obtained as colorless crystals with a melting point of 198-201°C.
1,4+-dimethylphenyl ester hydrochloride &81F
(ILK rate 9&7%) was obtained.

IRWKB"1?ll+-': 1745 (C=O)
ax NMR (CD30D) δ: 1.60-4.36 (9
H, m, piperidine hydrogen) 2.24 (3H, s e
4-OHs) 2.40 (3H,s, 2-0d,
) 7,02-7.56 (3H, m, aromatic hydrogen) Example 50 1-amidino-4-piperidinecarboxylic acid 0-arylphenyl ester jJ[[:bisu(0-allylphenyl)sulfite 2 .4tk anhydrous dimethylformamide 1
Dissolved in a mixture of 0- and anhydrous pyridine 5-, and added 1 to this.
-amidino-4-piperidinecarboxylic hydrochloride 1.01
F'i (added and left at room temperature for 3 hours. The solvent was completely distilled off under reduced pressure, and ether was added to the residue to precipitate crystals'?t.
I got an F. Dilute the obtained crystals with isopropanol ether? ! 950q (yield: 61.3q) of 1-amidino-4-piperidinecarboxylic acid 0-allylphenyl ester hydrochloride was crystallized as colorless crystals with a melting point of 151-153°C.

Engineering RyKBrcIR-': 1740 (0=SlLX NMR (CDCl2) δ: 1.65S-4,52 (1
1H, m, piperidine hydrogen and -Cμ2-ph) 5.04-5.48 (2Ht m + =CH2)5
．． 8t & 40 (IH, m, -OH-") 7.24q08
(4H, m, aromatic hydrogen) That's it.

Patent applicant Nippon Chemifa Co., Ltd. Page 1 continued 0 Inventor Kondo Yoko 4-47 Noborito-cho, Koshigaya-shi Procedural amendment (spontaneous) October 12, 1980 Haruki Shimada, Commissioner of the Japan Patent Office 1. Indication of the case; 1982 Patent Application No. 'f30856λ Title of Invention Novel amidinopiperidine derivatives and process for producing the same.

V. Relationship with the case of the person making the amendment Patent applicant address 2-2-3 Iwamoto-cho, Chiyoda-ku, Tokyo & Engraving of application and specification to be amended (no change in content) 0 & Contents of amendment Procedural amendment ( (Voluntary) May 21, 1930 Haruki Shimada, Commissioner of the Japan Patent Office 1. Indication of the case 1982 Patent Application No. 130856 2. Title of the invention: Novel amidinopiperidine derivatives and process for producing the same.
Relationship with the case of the person making the amendment Patent Applicant Address 2-2-3-4 Iwamoto-cho, Chiyoda-ku, Tokyo Date of amendment order Voluntary i 1iIO of “Detailed Description of the Invention” of the specification to be amended: & Attached sheet of amendment details.

Contents of the amendment (1) r4.68 (3H, s, 00 days 3)" is r175
(5H, s, 0OH3) Correct as J.

(2) Same as above, page 28, line 3, replaces "Cylformamide and anhydrous pyridine..." with "Cylformamide 40d and anhydrous pyridine..."
I am corrected.

(3) Same as above, on page 30, line 17, it says "(Yield 7y, 2%) was obtained."
Insert the next sentence.

"When this product was further purified, it became colorless crystals with a melting point of 122-124°C." (4) Same as above, page 39, line 19, r++*a1. Q o~a, o o (2H, m, *
・J means “---1,00~4.00 (24H,
Correct it as m, ---j.

(5) Same as above, page 40, bottom line: [s, st (yield 75.3 cm) was obtained. ” and then insert the following sentence.

``If you repeat the recrystallization process, the melting point of this substance will be 195 ~
It became colorless crystals at 196°C. (6) Same as above, on page 41, line 4, correct [164 (6H, a, n c (cp3) 2) J to rt64 (6H, s, n 0 (CH3) 2) J.

(No. Same as above, on page 42, line 8, r 4.04 (3H, e, 0OH3) J is corrected to ``595 (3H, s, 00dan 3).''

(8) Same as above, on page 48, line 13, the phrase "...stirred in a mixed solvent for 2.4 hours..." was corrected to "...stirred in a mixed solvent for 24 hours..." Do0 (9) Same as above, page 58, line 9 says, "I got a)." Next, change the line and insert the following sentence.

"Engineering Rv cIR-1: 1700.1730.175
5(0=O) jtLX 0 Same as above, page 58, line 10, "NMR (OD50D) δ:tO~2.2---J to line 16 rJw & 8Hz, aromatic hydrogen)" deleted do.

(11) Same as above, p. 66, line 17, replaces r”・scar-1:1740.1770 (0=O) J with “…cm-1:1740.1710 (0=O) J
I am corrected.

(12) Same as above, on page 70, line 19, the statement "r 4.67 (5H,s, O-0dan3)" is corrected to "575 (3H,s, 0-0H3) J.

(13) Same as above, on page 71, line 16, after the statement "61.4% obtained 9.", insert the following sentence.

``If you repeat the recrystallization process, the melting point will be 222 ~
It appeared as colorless crystals at 223°C. (14) Ibid., No. 74
Page, line 17, after it says "96.7%) was obtained," insert the following sentence.

“When this substance is further purified, it has a melting point of 205-207°C.
It became a colorless crystal. (15) Same as above, page 76, line 1, "...δ: 1.65-4.52 (11H,...") was replaced with "...δ: 1./i0-4. 52 (11B,・
0 or more 5- JP-A-58-32865 (22) 460-

Claims (2)

[Claims] (1) General formula (wherein A represents an oxygen atom or a sulfur atom, R represents a halogen atom, an alkyl group, an alkenyl group, an aralkyl group,
Alkoxy group, alkanoyl group, alkanoylamino group, nitro group, cyano group, formyl group, aminosulfonyl group, trihalokenomethyl group, alkoxycarbonyl group,
Represents a phenyl group, a pyridyl group, a naphthyl group, an indanyl group, or a tetrahydronaphthyl group, which may have 1 to 3 substituents selected from a benzyloxycarbonyl group, a carboxyl group, and an aryl group, and n is 0 or 2. indicates an integer. ) A novel amidinopiperidine derivative and its acid addition salt. (2) A compound represented by the general formula (wherein n represents an integer of 0 or 2), a salt thereof, or a reactive derivative thereof with the general formula R'-A-H (wherein M is an oxygen atom or Ro represents a sulfur atom, a halogen atom, an alkyl group, an alkenyl group, an aralkyl group, an alkoxy group, a plucyl group, an alkanoylamino group, a nitro group, a cyano group, a formyl group, an aminesulfonyl group, a torinologenomethyl group, an alkoxycarbonyl group , a phenyl group, a pyridyl group, a naphthyl group, an indanyl group, or a tetrahydronaphthyl group selected from a benzyloxycarbonyl group, an aryl group and optionally having 7'C1 to 3 substituents] or The sulfite derivative is reacted, and if desired, the product is subjected to a hydrogenation reaction. Alkanoylamino group, nitro group, cyano group, formyl group,
Aminosulfonyl group "□, trilogenomethyl group, alkoxycarbonyl group, benzyloxycarbonyl group,
represents a phenyl group, a pyridyl group, a naphthyl group, an indanyl group, or a tetrahydronaphthyl group, which may have 1 to 3 substituents selected from carboxyl groups and aryl groups, and A and n are the same as above] A method for producing the novel amidinopiperidine derivative or its acid addition salt.