GB2101125A - Novel amidinopiperidine derivatives and processes for producing them - Google Patents

Novel amidinopiperidine derivatives and processes for producing them Download PDF

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GB2101125A
GB2101125A GB08215069A GB8215069A GB2101125A GB 2101125 A GB2101125 A GB 2101125A GB 08215069 A GB08215069 A GB 08215069A GB 8215069 A GB8215069 A GB 8215069A GB 2101125 A GB2101125 A GB 2101125A
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amidino
hydrochloride
mixture
crystals
ether
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Mutsumi Muramatsu
Hiroyasu Sekine
Atsushi Tendo
Toshio Satoh
Yoshio Kikawa
Kaname Kondo
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Nippon Chemiphar Co Ltd
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Nippon Chemiphar Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Compounds of the following formula, and pharmaceutically acceptable salts thereof: <IMAGE> wherein R represents a hydrogen atom, a naphthyl, indanyl, tetrahydronaphthyl or pyridyl group, or a phenyl group which may have 1 to 3 substituents selected from halogen atoms, and alkyl, alkenyl, alkoxy, alkanoyl, cyano, formyl, trifluoromethyl, phenyl, phenylalkyl, alkanoylamino, aminosulfonyl, carboxyl, alkoxycarbonyl, benzyloxycarbonyl, benzoylvinyl, phenylvinylcarbonyl, carboxyvinyl, and diphenylmethyloxycarbonylvinyl groups, A represents an oxygen or sulfur atom, and n represents zero or an integer of 1 to 3, with the proviso that when n is zero, R must not be a hydrogen atom, are highly effective for inhibiting a complement reaction, inflammation caused by an allergic reaction, and platelet aggregation. Processes for manufacturing the compounds are described.

Description

SPECIFICATION Novel amidinopiperidine derivatives and processes for producing them This invention relates to novel amidinopiperidine derivatives and to process for producing such derivatives.
Hamanaka and Frnest, S. have reported that 1-amidino-3-piperidinecarboxylic acid and 1-amidino-4piperidine-carboxylic acid are useful as materials for synthetic penicillins (U.S. Patents 3,870,709, 3,933,797 and 3,972,872). However, no research has been made into the pharmacological action of 1-amidino-3piperidine-carboxylic acid.
A number of different amidinopiperidine derivatives have now been studied, resulting in the present invention.
It is accordingly, one object of the present invention to provide novel amidinopiperidine derivatives which exhibit strong inhibitory effects on a complement reaction, inflammation caused by an allergic reaction, and platelet aggregation.
It is another object of the invention to provide processes for producing these novel amidinopoperidine derivatives.
According to one aspect of the invention, there are provided compounds of the formula (I) below and pharmaceutically acceptable salts thereof,
wherein R represents a hydrogen atom, a naphthyl, indanyl, tetrahydronaphthyl or pyridyl group, or a phenyl group which may have 1 to 3 substituents selected from the group consisting of hydrogen atoms, and an alkyl, alkenyl, alkoxy, alkanoyl, cyano, formyl, trifluoromethyl, phenyl, phenylalkyl, alkanoylamino, aminosulfonyl, carboxyl, alkoxycarbonyl, benzyloxycarbonyl, benzoylvinyl, phenylvinylcarboxyl, carboxyvinyl, and diphenylmethyloxycarbonylvinyl group, A represents an oxygen or sulfur atom, and n represents zero or an integer of 1 to 3, provided that when n is zero, R must not be a hydrogen atom.The compounds of the formula (I) have been found to possess excellent inhibitory effects on a complement reaction, inflammation caused by an allergic reaction, and platelet aggregation.
In particular, compounds of the formula (la) below, and pharmaceutically acceptable salts thereof,
wherein R and n are as defined above, are excellent in their pharmacological action on the conditions referred to above.
R in the formula (I) may be a hydrogen atom, a naphthyl, indanyl, tetrahydronaphthyl or pyridyl group, or a phenyl group which may have 1 to 3 substituents selected from halogen atoms, and alkyl, alkenyl, alkoxy, alkanoyl, cyano, formyl, trifluoromethyl, phenyl, phenylalkyl, acetamino, sulfonylamino, carboxyl, alkoxycarbonyl, benzyloxycarbonyl, benzoylvinyl, phenylvinylcarbonyl, carboxyvinyl, and diphenyl methyloxycar- bonylvinyl groups.Examples of phenyl groups suitable as the group R include phenyl, p-methylphenyl, o-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,4,6-trimethylphenyl, p-isopropylphenyl, p-tbutylphenyl, p-cyclohexylphenyl, p-chlorophenyl, p-fluorophenyl, p-bromophenyl, 2,4-dichlorophenyl, 2-chloro-4-t-butylphenyl, p-methoxyphenyl, o-ethoxyphenyl, p-propoxyphenyl, o-allylphenyl, 4-allyl-2methoxyphenyl, p-acetylphenyl, p-propanoylphenyl, o-propanoylphenyl, p-cyanophenyl, o-cyanophenyl, p-formylphenyl, o-formylphenyl, m-trifluoromethylphenyl, p-phenylphenyl, o-phenylphenyl, p aminosulfonyiphenyl, o-aminosulfonylphenyl, p-acetaminophenyl, o-acetaminophenyl, 4-formyl-2methoxyphenyl, p-benzylphenyl, p-(a,a-dimethylbenzyl)phenyl, p-carboxyphenyl, p methoxycarbonylphenyl, o-benzyloxycarbonylphenyl, o-carboxyphenyl, o-cynnamoylphenyl, o-(ss- phenylcarbonylethenyl)phenyl p-(ss-diphenylmethyloxywarbonyl)ethenylphenyl, p-(ss- carboxy)ethenylphenyl, and 3-methoxy-4-( & arboxyethenyl)phenyl. Other suitable groups for use as R include 1-naphthyl, 2-naphthyl, 5-indanyl, 5, 6, 7, 8, -tetrahydro-2-naphthyl, and 3-pyridyl.
A in the formula (I) may be of an oxygen or sulfor atom, and n is zero or an integer of 1 to 3. However, when n is zero, R must not be a hydrogen atom.
Pharmaceutically acceptable salts of the compounds of the present invention include acid salts derived from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, and p-toluenesulfonic acid.
In accordance with a further aspect of the invention, compounds of the formula (II),
wherein m is an integer of 1 to 3, are produced by reacting compounds of the formula (III),
wherein m is as defined above, with an alkyl-isourea or alkyl-isothiourea, or a salt thereof.
This reaction is carried out with stirring at room temperature for 5 to 20 hours in the presence of sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, or the like. The compounds of the formula (III) may be produced by hydrogenation of the corresponding pyridylcarboxylic acid or pyridyl-fatty acid in the presence of a catalyst, such as platinum.
According to another aspect of the invention, compounds of the formula (lb) below and pharmaceutically acceptable salts thereof.
wherein R' is a naphthyl, indanyl, tetrahydronaphthyl or pyridyl group, or a phenyl group which may have 1 to 3 substituents selected from halogen atoms, and alkyl, alkenyl, alkoxy, alkanoyl, cyano, formyl, trifluoromethyl, phenyl, phenylalkyl, alkanoylamino, aminosulfonyl, carboxyl, alkoxycarbonyl, benzyloxycarbonyl, benzoylvinyl, phenylvinylcarbonyl, and diphenylmethyloxycarbonylvinyl groups, and A and n are the same as defined above, are produced by reacting compounds of the formula (IV),
wherein n is the same as defined above, or reactive derivatives thereof, with compounds of the formula (V) R'-A-H (V) wherein R' and A are the same as defined above, or sulfite derivatives thereof.
Suitable reactive derivatives of the compounds of the formula (IV) include acid halides such as acid chloride, acid bromide and the like, and mixed anhydrides of ethylchloroformate. Suitable sulfite derivatives of the compounds of the formula (V) include diarylsulfite derivatives such as dephenylsulfite, and bis-(p-chlorophenyl)sulfite.
The reaction of the compounds of the formula (IV) with the compounds of the formula (V) may be carried out with stirring at room temperature for 1 to 20 hours. Suitable solvents which may be used include dimethylformamide, dimethylacetamide, and pyridine.
The reaction of the reactive derivatives of the compounds of the formula (IV) with the compounds of the formula (V) may be effected with stirring at a temperature of from room temperature to the boiling point of the solvent. Suitable solvents which may be used include dimethylformamide, dimethylacetamide, pyridine, dichloromethane, dichloroethane, chloroform, and acetonitrile. In such instance, it is sometimes recommended to use an acid-binding agent such, for example, as triethylamine, dimethylaniline or pyridine.
When the compounds of the formula (IV) are reacted directly without conversion to any reactive intermediates thereof, the reaction is preferably carried out in the presence of a condensing agent, for example, a carbodiimide such as dicyclohexylcarbodiimide, or a Lewis acid such as phosphorus oxychloride or boron trifluoride. The reaction is effected using a solvent such, for example, as toluene, xylene or dimethylformamide, or a solvent mentioned above, or a mixture thereof, at a temperature of from room temperature to the boiling point of the solvent.
Of the compounds of the formula (I), when a compound having a carboxyphenyl or carboxyvinylphenyl group is desired, a compound may first be obtained having a benzyloxycarbonyl or diphenylmethyloxycarbonylvinyl group which may be hydrogenated in the presence of a catalyst such as paradium-carbon.
Further, suitable acid salts of the compounds of the formula (I) can be isolated from the reaction mixture by known methods.
The thus obtained compounds of the formula (I) have some excellent pharmacological activities. Such compounds are markedly effective in inhibiting a complement reaction. The compounds also exert marked effects on the inhibition of inflammation caused by an allergic reaction, i.e. the inhibition of the Arthus reaction and delayed type hypersensitivity. Moreover, the compounds are effective as inhibitors of platelet aggregation.
1. Inhibition of hemolysis by complement 1) Inhibition of hemolysis by classical pathway of complement A mixture of fresh human (or guinea pig) plasma and a test sample solution was incubated at 37"C for 30 minutes, and the mixture was then cooled to 4"C. To the mixture were added a geletin-veronal buffer and then an EA (sheep erythrocytes-anti-sheep erythrocytes) suspension, and the resulting mixture was incubated at 37"C for 90 minutes. The mixture was centrifuged at 4"C for 5 minutes (2,500 rpm), and the supernatant was determined from the absorbance at 541 nm.
The inhibitory effects are shown in Table 1 as the 50 percent inhibition concentration [CH50(mM)].
2) Inhibition of hemolysis by alternative pathway of complement A mixture of fresh human (or guinea pig) plasma and a test sample solution was incubated at 37"C for 30 minutes. To the mixture was added a rabbit erythrocytes suspension, and the resulting mixture was incubated at 370C for 40 minutes. EDTA was added to the mixture. The resulting mixture was centrifuged for 5 minutes (2,500 rpm), and the supernatant was determined from the absorbence at 413 nm.
The inhibitory effects are shown in Table 1 as the 50 percent inhibition concentration [ACH50(mM)].
TABLE 1 Inhibition of homolysis by complement Test Compound CH50 (mM) ACH50 (mM) 1 0.44 0.40 2 0.44 0.28 3 0.57 0.19 4 0.17 0.25 5 0.23 0.18 6 0.20 0.10 7 1 < 0.10 8 1 < 0.31 9 1 < 0.30 10 0.67 0.26 11 1 < 0.30 12 0.20 0.21 13 1 < 0.17 14 0.27 0.34 15 0.32 0.32 16 1 < 0.30 17 0.86 0.08 18 1 < 0.26 Compound 1: Phenyl 1-amidino-4-piperidinecarboxylate hydrochloride 2: p-Methylphenyl 1 -a midi no-4-pi peridenecarboxylate hydrochloride 3: p-Methoxyphenyl 1 -amidino-4-piperidinecarboxylate hydrochloride 4: p-Chlorophenyl 1 -amidino-4-piperidinecarboxylate hydrochloride 5: 2,4-Dichlorophenyl 1 -amidino-4-piperidinecarboxylate hydrochloride 6: p-t-Butylphenyl 1 -am idino-4-pi peridinecarboxylate hydrochloride 7:Phenyl 1-amidino-4-piperidenepropionate hydrochloride 8: p-Methoxyphenyl 1-amidino-4-piperidinepropionate hydrochloride 9: p-Chlorophenyl 1 -amidino-4-piperidenepropionate hydrochloride 10: 2,4-Dichlorophenyl 1-amidino-4-piperidenepropionate hydrochloride 11: 2-Chloro-4-t-butylphenyl 1-amidino-4-piperidinepropionate hydrochloride 12: p-Acetylphenyl 1-amidino-4-piperidenepropionate hydrochloride 13: p-Acetaminophenyl 1-amidino-4-piperidinepropionate hydrochloride 14: 1-Naphthyl 1-amidino-4-piperidineproptionate hydrochloride 15: 2-Naphthyl 1-amidino-4-piperidineproprionate hydrochloride 16: p-Fluorophenyl 1-amidino-4-piperidenepropionate hydrochloride 17: p-Aminosulfonylphenyl 1-amidino-4-piperidinepropionate hydrochloride 18: 3-Pyridyl 1-amidino-4-piperidinepropionate hydrochloride 2. Inhibition of Edema by allergic reaction 1) Inhibition of edema by reverse Arthus reaction in guinea pigs Egg albumin with saline (20 mglmlkg) was intravenously injected into the fore limb of a guinea pig. 15 minutes later, 0.05 me of rabbit anti-egg albumin serum was subcutaneously injected into the back of the guinea pig. 3 hours later, the reddening and edema area (mm2) was measured. Test samples were administered per os 1 hour prior to the antigen injection.
The results obtained are shown in Table 2 as the inhibition percent.
TABLE 2 Inhibitory effects on reverse arthus reaction Dose Inhibition Test Compound (mgikg, P.O.) (%) 6 500 90.08 12 50 49.97 15 50 67.26 17 50 47.64 18 50 63.75 19 50 50.16 20 50 63.56 21 50 55.07 22 50 53.18 23 50 41.60 24 50 71.52 25 50 50.53 26 50 67.72 27 50 59.41 28 50 57.65 29 50 49.97 30 50 55.70 31 50 73.20 Compounds 6, 12, 15, 17 and 18:Same as defined in Table 1 Compound 19: p-lsopropylphenyl 1-amidino-4-piperidineproprionate hydrochloride 20: o-Allylphenyl 1 -amidinoA-piperidinepropionate hydrochloride 21: p-t-Butylphenyl 1-amidino-4-piperidinepropionate hydrochloride 22: p-(a,a-Dimethylbenzyl)phenyl 1-amidino-4-piperidinepropionate hydrochloride 23: p-Fluorophenyl 1-amidino-4-piperidinepropionate hydrochloride 24: p-Formylphenyl 1-amidino-4-piperidinepropionate hydrochloride 25: p-Phenylphenyl 1 -amidino-4-piperidinepropionate hydrochloride 26: o-Methylphenyl 1 -amidino-4-piperidinepropionate hydrochloride 27: o-Cyanophenyl 1 -amidino-4-piperidinepropionate hydrochloride 28: o-Phenylphenyl 1 -amidino-4-piperidinepropionate hydrochloride 29: m-Trifluoromethylphenyl 1-amidino-4-piperidinepropionate hydrochloride 30: 4-Formyl-2-methoxylphenyl 1 -amidinoA-piperidinepropionate hydrochloride 31: 5,6,7,8-Tetrahydro-2-naphthyl 1 -amidino-4-piperidinepropionate hydrochloride 2) Inhibition of edema by delayed type hypersensitivity in mice ICR strain female mice were sensitized with BCG (1 mg/animal) with saline (subcutaneously injected into the back of each mouse). After the lapse of 6 days, the thickness of the foot was measured, and each animal was sensitized once more with BCG (1 mg/animal) with saline (subcutaneously injected into the hind paw).
The thickness of the foot injected was measured again. Test samples were administered per os daily for 6 days from the sensitization.
The results obtained are shown in Table 3 as the inhibition percent.
TABLE 3 Inhibitory effects an delayed type hypersensitivity Dose Inhibition Test Compound (mg/kglday, P.O.) (%) 6 10 54.75 6 5 30.77 20 10 62.67 21 10 55.20 21 5 50.23 22 10 43.56 31 10 60.61 32 10 54.69 33 10 39.18 34 10 48.98 35 10 52.24 36 10 45.25 36 5 33.03 Compounds 6,20,21,22 and 31: Same as defined in Tables 1 and 2 Compound 32: 2,4-Dimethylphenyl 1 -amidino-4-piperidinecarboxylate hydrochloride 33: p-Cyclohexylphenyl 1 -a midi no-4-piperidi necarboxylate hydrochloride 34: o-Carboxyphenyl 1 -amidino-4-piperidinepropionate hydrochloride 35: 5-lndanyl 1-amidino-4-piperidinepropionate hydrochloride 36:Phenyl 1-amidino-4-piperidineacetate hydrochloride As stated above, the present compounds exhibit excellent inhibitory effects on platelet aggregation. For example, 2',4'-dimethylphenyl 1-amidino-4-piperidinepropionate hydrochloride and 4'-allyl-2'methoxyphenyl 1-amidino-4-piperidinepropionate hydrochloride completely blocked arachidonic acidinduced and collagen-induced platelet aggregation in vitro with use of rabbit platelet-rich plasma at a concentration of 5 Fg/m.
The invention is illustrated by the following specific examples which are presented herein for purposes of illustration only and are not to be construed as limiting the invention.
Example 1 1-Amidino-4-piperidinepropionic acid: 20 me of 2N sodium hydroxide was stirred with ice-cooling, and 3.4 g of o-methylisourea sulfate and 3.1 g of piperidine-4-propionic acid were added to the aqeuous sodium hydroxide solution. To the mixture was then added 5 me of water, and the resulting mixture was stirred at room temperature for 19 hours. The product precipitated was separated by filtration and washed with a small amount of cold water three times, then with acetone and finally with ether to obtain 2.0 g of 1-amidino-4-piperidinepropionicacid as colorless crystals having a melting point of 294"C (decomposed).
Example 2 1-Amidino-4-piperidinepropionic acid hydrochloride: 2.0 g of 1 -amidino-4-piperidinepropionic acid prepared as in Example 1 was dissolved in 15 me of 1 N hydrochloric acid. To the solution was added 0.2 g of activated charcoal, and the resulting mixture was stirred for 30 minutes. After removal of activated charcoal by filtration, the filtrate was concentrated under reduced pressure. Acetone was added to the residue to give crystals which were then washed with acetone and further with ether and dried to obtain 1.7 g of 1 -amidino-4-piperidinepropionic acid hydrochloride as prisms having a melting point of 199.5 to 202"C.
The thus obtained prisms were further purified to give crystals having a melting point of 203 to 204"C.
IRvKBr cm-s : 1710(C=O) max Example 3 Phenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 707 mg of 1 -amidino-4-piperidinepropionic acid hydrochloride and 1.1 g of diphenyl sulfite was stirred overnight at room temperature in a mixture of 8 me of dry dimethylformamide and 3 me of dry pyridine. The solvent was removed under reduced pressure, and the residue was washed twice with 20 me of ether to give crystals. The crystals were washed with acetone and dissolved in 4 me of methanol. The resulting solution was added to a solution of 20 me of ether and 30 me of acetone to give crystals.The crystals were washed twice with hot ethyl acetate to obtain 643 mg (yield: 69%) of phenyl 1-amidino-4piperidinepropionate hydrochloride as colorless crystals having a melting point of 167 to 170.5"C.
IR VKBr cm1 : 1735 (C=O) max NMR(CD,OD)G : 1.00 - 4.00 (1 3H, m, piperidine protons and CH2CH2CO) 6.90 - 7.40 (5H, m, aromatic protons) Example 4 o-Benzyloxycarbonylphenyi 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 707 mg of 1-amidino-4-piperidinepropionic acid hydrochloride and 2.3 g of bis-(o benzyloxycarbonylphenyl)sulfite was stirred overnight at room temperature in a mixture of 8 m4 of dry dimethylformamide and 3 mk of dry pyridine. The solvent was removed under reduced pressure, and the residue was washed with 20 mf of ether three times and then with 20 mf of ethyl acetate to give crystals.
The crystals were recrystallized from isopropanol to obtain 710 mg (yield: 51%) of o-benzyloxycarbonyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 148 to 150"C.
IR vK3r cm-l : 1750, 1705 (C=O) max NMR(CD30D)b: 1.00-4.00 (13H, m, piperidine protons CH2CH2CO) 5.20 (2H, s, CH2-Ph) 6.96 - 8.96 (9H, m, aromatic protons) Example 5 o-Hydroxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride: 5.5 g of o-benzyloxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride was dissolved in a mixture of 60 m( of t-butyl alcohol and 60 m4 of water. 225 mg of 10% paradium-carbon was added to the solution, and the mixture was stirred at room temperature for 1 hour in the presence of hydrogen (starting pressure: 2.4 kg/cm2). The catalyst was removed by filtration, and the solvent was removed.The residue was washed with t-butyl alcohol to obtain 3.5 g (yield: 79.7%) of o-hydroxycarbonylphenyl 1-amidino-4piperidinepropionate hydrochloride as colorless needles having a melting point of 192 to 194"C.
IR yKB' Cm-7 : 1745, 1725 (C=O) max NMR(DMSO-d6)b: 0.8 - 2.0 (7H, m, 3- and 5-H2, 4-H, p-H2) 2.65 (2H, distorted t, a-H2) 2.8 - 4.2 (4H, m, 2- and 6-H2) 7.2 - 8.3 (4H, m, aromatic protons) Example 6 2',4'-Dichlorophenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 1.7 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 4.0 g bis-(2,4dichlorophenyl)sulfite was stirred at room temperature for 45 minutes in a mixture of 10 m4 of dry dimethylformamide and 3t of dry pyridine. The solvent was removed under reduced pressure, and 30 me of ethyl acetate was added to the residue. The mixture was then stimulated to give crystals.The crystals were washed with ethyl acetate and then with ether to obtain 2.0 g (yield: 73%) of 2',4'-dichlorophenyl 1 -amidino-4-piperidinepropionate hydrochloride as colorless powder having a melting point of 152 to 1 56"C.
IR VKB' Cm-7 : 1760(C=O) NMR(CD3OD)6 : 1.10-4.00 (13H, m, piperidine protons and CH2CH2CO) 7.20 -7.70 (3H, m, aromatic protons) Example 7 p-Chlorophenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 1.5 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 7.7 g of bis-(pchlorophenyl)sulfite was stirred at room temperature for 30 minutes in a mixture of 12 m4 of dry dimethylformamide and 6 mt of dry pyridine. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals.The crystals were washed with ether twice and then with ethyl acetate and recrystallized from methanol-ether to obtain 1.75 g (yield: 79.5%) of p-chlorophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 173 to 176 C.
IR #KBrmax cm- : 1753 (C=O) max NMR(CD30D)o: : 1.08 - 4.05 (13H, m, piperidine protons and CH2CH2CO) 7.15 - 7.67 (4H, m, aromatic protons) Example 8 p-Methylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 1.5 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 6.7 g of bis-(pmethylphenyl)sulfite was stirred at room temperature for 2 hours in a mixture of 12 ml of dry dimethylformamide and 6 mt of dry pyridine. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals.The crystals were washed with ether twice and then with ethyl acetate and recrystallized from isopropyl alcohol-isopropyl ether to obtain 1.87 g (yield: 90%) of p-methylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 182 to 184 C.
IR Vmax cm : 1743 (C=O) NMR(CD30D)b: 1.00 -4.00 (13H, m, piperidine protons and CH2CH2CO) 2.29 (3H, s, -CH3) 6.61 - 7.20 (4H, m, aromatic protons) Example 9 p-Methoxyphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 1.5 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 6.8 g of bis-(pmethoxyphenyl)sulfite was stirred at room temperature for 35 hours in a mixture of 14 mt of dry dimethylformamide and 7 me of dry pyridine. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals.The crystals were washed with ether twice and then with ethyl acetate and recrystallized from isopropyl alcohol-isopropyl ether to obtain 1.25 g (yield: 57%) of p-methoxyphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 148 to 151 C.
IRVKmBax cm : 1754 (C=O) NMR(CD30D)b: : 1.00 - 4.00 (13H, m, piperidine protons and CH2CH2CO) 3.75 (3H, s, OCH3) 6.63 - 7.04 (4H, m aromatic protons) Example 10 p-t-Butylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 5.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 9.2 g of bis-(p-tbutylphenyl)sulfite was stirred at room temperature for 3 hours in a mixture of 40t of dry dimethylformamide and 20 mt of dry pyridine. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals. The crystals were washed with ether and then with acetone and dissolved in methanol. After removal of any insoluble materials, ether was added to the solution to obtain 7.2 g (yield: 92%) of p-t-butylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 159 to 1630C.
IRVKmBx cm-1: 1748 (C=O) NMR(CD30D)6: : 0.84 - 3.84 (13H, m, piperidine protons and CH2CH2CO) 1.29 (9H, s, CH(CH3)3) 6.84 - 7.14 (4H, m, aromatic protons) Example 11 p-Acetaminophenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 2.0 g of 1-amidino-4-piperidinepropionic aicd hydrochloride and 1.29 g of p-acetaminophenol was dissolved in 20 mf of dry pyridine. To the solution was added with stirring and ice-cooling 1.75 g of dicyclohexylcarbodiimide, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered to give crystals which were then washed with ethyl acetate and further with ether and dried.The crystals were refluxed with 600 mt of dichloromethane, and the resulting mixture was filtered to give an insoluble substance. The substance was washed with dichloromethane and recrystallized from methanol-ethyl acetate to obtain 1.5 g (yield: 48.4%) of p-acetaminophenyl 1-amidino-4piperidineproiponate hydrochloride as colorless crystals having a melting point of 258 to 261"C.
IRv cm : 1761 (C=O) NMR(CD30D)b: : 0.89 - 4.05 (13H, m, piperidine protons and CH2CH2CO) 2.10 (3H, s, COCH3) 7.01 - 7.70 (4H, m, aromatic protons) Example 12 o-Allyphenyl 1-amidino-4-piperidinepropionate hydrochloride: 3.7 g of bis-(o-allylphenyl)sulfite prepared from o-allylphenol and thionyl chloride was dissolved in a mixture of 16 mt of dry dimethylformamide and 8 m of dry pyridine. 2.0 g of 1-amidino-4piperidinepropionic acid hydrochloride was added with stirring to the resulting solution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with acetone. The mixture was poured with stirring into ether to give crystals.The crystals were washed in turn with ether, acetone and ether and dried to obtain 2.3 g (yield: 77.2%) of o-allyphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 116 to 119"C.
The thus obtained crystals were further purified to give crystals having a melting point of 122 to 124"C.
lR"'KBr cm : 1762 (C=O) NMR(CDCr3) : 1.01 - 4.42 (13H, m, piperidine protons and CH2CH2CO) 3.36 (2H, d, CH2-Ph) 5.03 - 5.34 (2H, m, =CH2) 5.82 - 6.23 (1 H, m, -CH=) 6.98 - 7.77 (4H, m, aromatic protons) Example 13 p-Acetylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 2.00 g of 1-amidino-4-piperidinopropionic acid hydrochloride and 1.15 g of p-acetylphenol was suspended in 20 mk of dry pyridine. 1.74 g of dicyclohexylcarbodiimide was added with ice-cooling to the suspension, and the mixture was stirred at room temperature for 2 days. After removal of any insoluble materials, the solvent was removed under reduced pressure.Ethyl acetate was added to the residue to give crystals which were then recrystaliized from ethanol-ethyl acetate to obtain 2.2 g (yield: 73.3%) of p-acetylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 104 to 106 C.
IR VKB' cm : 1768 (C=O) NMR(CD30D)6 : 0.83 - 4.20 (13H, m, piperidine protons and CH2CH2CO) 2.69 (3H, s, COCH3) 7.30 - 8.49 (4H, m, aromatic protons) Example 14 2'-Chloro-'-t-butylphenyl 1-amidino-4-piperidinepropionate hydrochloride: 5.3 g bis-(2-chloro-4-t-butylphenyl)sulfite prepared from 2-chloro-4-t-butylphenol and thionyl chloride was dissolved in a mixture of 16 mt of dry dimethylformamide end 8 mt of dry pyridine, and 2.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride was added with stirring to the resulting solution, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure.
Ether was added to the residue, and the mixture was stirred to give crystals. The crystals were air-dried at room temperature and recrystallized from methanol-ethyl acetate to obtain 2.2 g (yield: 64.7%) of 2'-chloro-4'-t-butylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 186 to 189 C.
IR #KBrmax cm- : 1769 (C=O) NMR(CD30D)6: 0.94 - 3.99 (13H, m, piperidine protons and CH2CH2CO) 1.34 (9H, s, C(CH3)3) 7.00 - 7.49 (3H, m, aromatic protons) Example 15 p-lsopropylphenyl 1-amidino-4-piperidinepropionate hydrochloride A mixture of 2 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 4.05 g of bis-(pisopropylphenyl)sulfite prepared from p-isopropylphenyl and thionyl chloride, 10 mt of dry dimethylformamide and 5 mf of dry pyridine was stirred at room temparature for 1 hour. The solvent was removed, and ether was added to the residue to give crystals.The crystals were washed with ether and then with ethyl acetate and recrystallized from isopropyl alcohol-ethyl acetate-ether to obtain 2.9 g (yield: 97%) of p-isopropylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 119 to 121 C.
IR VK'3ar cm-: 1755 (C=O) NMR(CD30D)6: 1.24 (6H, d, J=7.2Hz, CH3 x 2) 1.0 - 2.0 (7H, m, p-H2, 3- and 5-H2, 4-H) 2.7 - 4.0 (5H, m, 2- and 6-H2, CH < ) 6.99,7.26 (each 2H, each d, J=8.4Hz, aromatic protons) Example 16 2'-Naphthyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 2 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 4.3 g of bis-(2-naphthyl)sulfite prepared from p-naphthol and thionyl chloride, 10 me of dry dimethylformamide and 5 me of dry pyridine was stirred at room temperature for 3 hours. The solvent was removed, and ether was added to the residue to give crystals.The crystals were recrystallized from methanol-ether to obtain 2.4 g (yield: 78%) of 2'-naphthyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 185 to 187 C.
IRKBr cm : 1745(C=O) max NMR(CD30D)b: : 1.0 - 2.0 (7H, m, p-H2, 3- and 5-H2, 4-H) 2.68 (2H, t, J=7,8Hz, a-H2) 2.9 - 4.0 (4H, m, 2- and 6-H2) 7.1 - 8.0 (7H, m, aromatic protons) Example 17 1 '-Naphthyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 2 g of 1-midino-4-piperidinepropionic acid acid hydrochloride, 4.25 g of bis-(1-naphthyl)sulfite prepared from a-naphthol and thionyl chloride, 10 me of dry dimethylformamide and 4 mt of dry pyridine was stirred at room temperature for 1 hour. The solvent was removed, and the residue was treated with ethyl acetate to give crystals. The crystals were washed with ethyl acetate to obtain 2.9 g (yield: 94%) of '-naphtyl 1-amidino-4-piperidinepropionate hydrochloride as light brown needles having a melting point of 187 to 190 C.
IRvKBr cm~1: 1755(C=O) max NMR(CD30D)b: : 1.0 - 2.0 (7H, m, ss-H2,3- and 5-H2, 4-H) 2.78 (2H, t, J=7.2Hz, a-H2) 3.0 - 4.0 (4H, m, 2- and 6-H2) 7.1 - 8.0 (7H, m, aromatic protons) Example 18 2',4'-Dimethylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4.0 g of 1 -amidino-4-piperidinepropionic acid hydochloride and 6.9 of bis-(2,4dimethylphenyl)sulfite prepared from 2,4-dimethylphenol and thionyl chloride was added to a mixture of 34 mt of dry dimethylformamide and 17 mt of dry pyridine, and the resulting mixture was allowed to stand at room temperature for 6 hours.The solvent was removed under reduced pressure, and ethyl acetate was added to the residue to give crystals. The crystals were recrystallized from methanol-ether to obtain 4.5 g (yield: 78%) of 2',4'-dimethylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 191 to 193"C.
IR KBr cm : 1745(C=O) max NMR(CD,OD)G : 0.96 - 3.96 (13H, m, piperidine protons and CH2CH2CO) 2.08 (3H, s, 4'-CH3) 2.26 (3H, s, 2'-CH3) 6.66 - 7.04 (3H, m, aromatic protons) Example 19 p-Fluorophenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 2.00 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 0.95 g of p-fluorophenol was suspended in 20 m6 of dry pyridine. To the suspension was added with stirring and ice-cooling 1.74 g of dicyclohexylcarbodiimide and the resulting mixture was allowed to stand at room temperature for 4 days.
After removal of any insoluble materials, the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue to give crystals which were then recrystallized from methanol-ether to obtain 1.4 g (yield: 50.0%) of p-fluorophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 131 to 133"C.
IR VKBr cml : 1750 (C=O) max NMR(CD,OD)G : 0.88 - 3.96 (13H, m, piperidine protons and CH2CH2CO) 6.80 - 7.15 (4H, m, aromatic protons) Example 20 p-Cyclohexylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 8 g of bis-(p-cyclohexylphenyl)sulfite prepared from p-cyclohexylphenol and thionyl chloride and 4 g of 1-amidino-4-piperidinepropionic acid hydrochloride was dissolved in a mixture of 20 mt of dry dimethylformamide and 8 mw of dry pyridine, and the resulting solution was stirred at room temperature for 2.5 hour. The solvent was removed, and the residue was treated with ethyl acetate to give crystals.The crystals were recrystallized from isopropanol-ether to obtain 5.6 g (yield: 83.6%) of p-cyclohexylphenyl 1amidino-4-piperidine propionate hydrochloride as colorless crystals having a melting point of 115 to 11 6"C.
IR v,KBarx cam : 1760 (C=O) NMR(CD2OD)6 : 1.00 - 4.00 (24H, m, piperidine protons, cyclohexane protons and CH2CH2CO) 6.8 - 7.20 (4H, m, aromatic protons) Example 21 p-(a,a-Dimethylbenzyl)phenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 9.6 g of bis-[p-(a,a-dimethylbenzyl)phenyl]-sulfite prepared from p-(a,adimethylbenzyl)phenol and thionyl chloride and 4 g of 1-amidino-4-piperidinepropionic acid hydrochloride was added to a mixture of 20 mt of dry dimethylformamide and 8 mb of dry pyridine, and the resulting solution was stirred at room temperature for 2.5 hours.After removal of the solvent, ethyl acetate was added to the residue, and the mixture was stirred to give crystals. The crystals were washed with ethyl acetate and then with ether and recrystallized from isopropanol-etherto obtain 5.5 g (yield: 75.3%) of p-(a,adimethylbenzyl)phenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 155 to 1 560C.
The thus obtained crystals were recrystallized twice to give crystals having a melting point of 195 to 1 96aC.
IR yKB' cm1 : 1765(C=O) max NMR(CD2OD)5: 1.0 - 4.0 (13H, m, piperidine protons and CH2CH2CO) 1.64 (6H, s, > C(CH3)2) 6.80 - 7.30 (4H, m, aromatic protons) Example 22 4'-Formyl-2'-methoxyphenyl 1 -am idino-4-piperidinepropionate hydrochloride: A mixture of 4.7 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 3 g of vaniline, 4.1 g of dicyclohexylcarbodiimide, 20 me of dry dimethylformamide and 10 me of dry pyridine was stirred at room temperature for 24 hours. After removal of any insoluble materials, the solvent was removed. The residue was treated with ethyl acetate to give white powder.The powder was washed with ethyl acetate and then with ether and recrystallized from isopropanol-etherto obtain 5.8 g (yield: 79.5%) of 4'formyl-2'- methoxyphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 98 to 105 C.
IRVKmBaxcml : 1700,1750,1770 (C=O) NMR(CD2OD)6: 1.04 - 4.20 (13H, m, piperidine protons and CH2CH2CO) 3.95 (3H, s, OCH3) 7.50 - 8.0 (3H, m, aromatic protons) 10.4(1 H, s, CHO) Example 23 p-Aminosulfonylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4.7 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 3.5 g of p-hydroxybenzene sulfonamide, 4.1 g of dicyclohexylcarbodiimide, 10 mt of dry dimethylformamide and 20 me of dry pyridine was stirred at room temperature for 24 hours. After removal of any insoluble materials, the solvent was removed. The residue was treated with ethyl acetate and then with ether to give crystals. The crystals were dissolved in methanol, and any insoluble materials were removed by filtration. Ether was added to the filtrate to obtain 4.5 g (yield: 57.7%) of p-aminosulfonylphenyl 1-amidino-4-piperidinepropionate hydrochloride as yellow crystals having a melting point of 206 to 2090C.
I R Vmax cm 1760 (C=O) NMR(CD3OD)6: 1.04 - 4.20 (13H, m, piperidine protons and CH2CH2CO) 7.44 - 8.28 (4H, m, aromatic protons) Example 24 m-Trifluoromethylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4.0 g of 1 -amidino-4-piperidinepropionic acid hydrochloride and 2.75 g of mtrifluoromethylphenol was suspended in 27 mk of dry pyridine. To the suspension was added 3.5 g of dicyclohexylcarbodiimide, and the resulting mixture was stirred at room temperature for 6 hours. After removal of any insoluble materials, the solvent was removed. The residue was washed with ether, dissolved in chloroform and then stirred.After removal of any insoluble materials, the filtrate was washed twice with a saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 4.0 g (yield: 62.0%) of m-trifluoromethylphenyl 1-amidino-4piperidinepropionate hydrochloride as colorless crystals having a melting point of 97 to 100"C.
IR VKBr cm1: 1760 (C=O) max NMR(CDC43)6 : 0.92 - 4.52 (13H, m, piperidine protons and CH2CH2CO) 7.20 - 7.92 (4H, m, aromatic protons) Example 25 p-Formylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 2.1 g of phydroxybenzaldehyde was suspended in 20 mt of dry pyridine. 3.5 g of dicyclohexylcarbodiimide was added with stirring to the suspension, and the resulting mixture was stirred overnight at room temperature.
After removal of any insoluble materials, the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was stirred to give crystals. The crystals were recrystallized from methanol-etherto obtain 2.1 g (yield: 36.4%) of p-formylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 144 to 147"C.
IR VKBr cm-': 1700,1760 (C=O) max NMR(CD3OD)5: 0.92 - 4.16 (13H, m, piperidine protons and CH2CH2CO) 7.40 - 8.20 (4H, m, aromatic protons) 10.16 (1H, s, CHO) Example 26 p-Cyanophenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4.0 g of 1 -amidino-4-piperidinepropionic acid hydrochloride, 2.0 g of p-cyanophenol and 3.5 g of dicyclohexylcarbodiimide was stirred overnight at room temperature in 20 mt of dry pyridine. Any insoluble materials were filtered, washed with pyridine and extracted with a mixture of 20 mk of water and 20 m4 of t-butanol, followed by stirring for about 20 minutes.The filtrate, washings and extract were combined together, and the solvent was removed under reduced pressure. The residue was recrystallized from water to obtain 3.4 g (yield: 59%) of p-cyanophenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 164.5 to 169"C.
lRVKmBx cm1 : 2240 (CN), 1765 (C=O) NMR(CD30D)b: 1.00 - 4.10 (13H, m, piperidine protons and CH2CH2CO) 7.40 - (4H, m, aromatic protons) Example 27 o-Cyanophenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.0 g of o-cyanophenol and 3.5 g of dicyclohexylcarbodiimide was stirred at room temperature for 24 hours in 20 m6 of dry pyridine. Any insoluble materials were filtered and washed with dry pyridine. The filtrate and washings were combined together, and the solvent was removed under reduced pressure.Ethyl acetate was added to the residue to give crystals which were then recrystallized from water to obtain 2.1 g (yield: 37%) of o-cyanophenyl 1 -amidino-4-piperidinepropionate as colorless crystals having a melting point of 159.5 to 1 62.5"C.
IR vmBarXcm-1: 2240 (CN), 1775 (C=O) NMR(CD,OD)G : 1.00-4.10 (13H, m, piperidine protons and CH2CH2CO) 7.40 - 8.00 (4H, m, aromatic protons) Example 28 o-Methylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 6.7 g of bis-(o-methylphenyl)sulfite prepared from o-methylphenol and thionyl chloride, 4 g of 1-amidino-4-piperidinepropionic acid hydrochloride was stirred at room temperature for 24 hours in a mixture of 20 me of dry dimethylformamide and 6 me of dry pyridine. The solvent was removed under reduced pressure, and 50 me of ethyl acetate and 20 me of ether was added to the residue to give crystals.
The crystals were recrystallized in turn from isopropanol-ether, methanol-ether and water to obtain 2.1 g (yield: 38%) of o-methylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 184 to 185.5"C.
IR VKBr cm1 : 1750 (C=O) max NMR(CD30D)6: : 1.00 - 4.05 (13H, m, piperidine protons and CH2CH2CO) 2.14 (3H, s, CH3) 6.90 - 7.30 (4H, m, aromatic protons) Example 29 o-Methylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 1.9 g of o-methylphenol, 3.5 g of dicyclohexylcarbodiimide and 20 me of dry pyridine was stirred overnight at room temperature. Any insoluble materials were filtered and washed with pyridine. The filtrate and washings were combined together, and the solvent was removed under reduced pressure. Ethyl acetate and ether were added to the residue to give crystals.After being air-dried, the crystals were recrystallized from water to obtain 3 g (yield: 54%) of o-methylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless prisms having a melting point of 184 to 1 85.50C. The IR and N MR spectra of the compound were identical with those of the compound obtained in Example 28.
Example 30 3'-Pyridyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4.71 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 1.95 g of 3-hydroxypyridine, 4.13 g of dicyclohexylcarbodiimide, 40 me of dry dimethylformamide and 20 me of dry pyridine was stirred at room temperature for 19 hours. After removal of any insoluble materials, the solvent was removed. The residue was washed with ethyl acetate and dissolved in methanol. Any insoluble materials were removed by filtration, and ethyl acetate was added to the filtrate to give crystals. The crystals were washed with ethyl acetate and then with ether to obtain 6.2 g (yield: 99%) of 3'-pyridyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 177 to 179"C.
IR VKB' cm-' : 1765(C=O) max NMR(CD30D)6: : 1.0 - 2.1 (7H, m, and 5-H2, 4-H and ss-H2) 2.84 (2H, t, J = 7.6Hz, a-H2) 3.0 - 4.2 (4H, m, 2- and 6-H2) 7.7 - 8.9 (4H, m, pyridine protons) Example 31 o-Phenylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 9.3 g of bis-(ophenylphenyl)sulfite prepared from o-phenylphenol and thionyl chloride, 40 me of dry dimethylformamide and 20 me of dry pyridine was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and the residue was recrystallized from water and washed with ethyl acetate and then with ether to obtain 3.45 g (yield: 52%) of o-phenylphenyl 1 -amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 160 to 162"C.
IR vm cm : 1755 (C=O) NMR(CD3OD)6: 0.8 - 1.9 (7H, m, and 5-H2, 4-H and P-H2) 2.52 (2H, t, J = 7.0Hz, a-H2) 2.8 - 4.1 (4H, m, and 6-H2) 7.3 - 7.9 (9H, m, aromatic protons) Example 32 p-Phenylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 9.3 g of bis-(pphenylphenyl)suifite prepared from p-phenylphenol and thionyl chloride, 40 me of dry dimethylformamide and 8 mf of dry pyridine was stirred at room temperature for 3 hours.The solvent was removed under reduced pressure, and the residue was recrystallized from methanol-ethyl acetate to obtain 4 g (yield: 61%) of p-phenylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 200 to 2030C.
IR vKBr cm : 1755 (C=O) max NMR(CD30D)o: : 1.0 - 2.0 (7H, m, and 5-H2, 4-H and P-H2) 2.61 (2H, t, J = 6.8Hz, a-H2) 2.8 - 4.0 (4H, m, 2- and 6-H2) 7.0 - 7.6 (9H, m, aromatic protons) Example 33 2',4',6'-Trimethylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4 g of 1 -amidino-4-piperidinepropionic acid hydrochloride, 2.3 g of 2,4,6-trimethylphenol and 3.5 g of dicyclohexylcarbodiimide was stirred overnight at room temperature in dry pyridine. Any insoluble materials were filtered and washed with dry pyridine and then with a mixture of of 25 m( of t-butanol and 25 m6 of water. The filtrate and washings were combined together and concentrated under reduced pressure.
50 me of ethyl acetate was added to the residue, and the mixture was stirred to give crystals. The crystals were recrystallized from water to obtain 3.3 g (yield: 55%) of 2', 4', 6'-trimethylphenyl 1-amidino-4piperidinepropionate hydrochloride as colorless crystals having a melting point of 220 to 223"C.
IR 'KBr cm : 1750 (C=O) max NMR(CD30D)G : 1.00 - 4.16 (13H, m, piperidine protons and CH2CH2CO) 2.12 (6H, s, 2,6-CH3) 2.26 (3H, s, 4-CH3) 6.92 (2H, s, aromatic protons) Example 34 2',6'-Dimethylphenyl 1-amidino-4-piperidinepropionate hydrochloride: 7.4 g of bis-(2,6-dimethylphenyl)sulfite prepared from 2.6-dimethylphenol and thionyl chloride was dissolved in a mixture of 36 mi of dry dimethylformamide and 18 m of dry pyridine. To the solution was added with stirring 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride, and the resulting mixture was allowed to stand at room temperature for 4 days. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals.The crystals were washed with ether and then with ethyl acetate and recrystallized from water to obtain 3.3 g (yield: 57%) of 2',6'-dimethylphenyl 1-amidino-4piperidinepropionate hydrochloride as pale yellow crystals having a melting point of 191 to 194"C.
lRVKmBax cm : 1740 (C=O) NMR(CD30D)o: 0.96 - 4.32 (13H, m, piperidine protons and CH2CH2CO) 2.24 (6H, s, 2,6-CH3) 7.24 - 7.60 (3H, m, aromatic protons) Example 35 5'-lndanyl 1-amidino-4-piperidinepropionate hydrochloride: 7.0 g of bis-(5-indanyl)sulfite prepared from 5-indanol and thionyl chloride was dissolved in a mixture of 25 mt of dry dimethylformamide and 12 mt of dry pyridine. To the solution was added with stirring 3.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride, and the resulting mixture was allowed to stand for 4 hours. The solvent was removed under reduced pressure, and ethyl acetate was added to the residue to give crystals.The crystals were washed with ethyl acetate and then with ether and recrystallized from methanol-etherto obtain 3.6 g (yield: 80%) of 5'-indanyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 184 to 188"C.
IR vKBr cm : 1760 (C=O) max NMR(CD30D)6: : 0.84-4.32 (19H, m, piperidine protons, CH2CH2CO and CH2CH2CH) 7.00 - 7.64 (3H, m, aromatic protons) Example 36 p-Methoxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 5 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 3.23 g of methyl phydroxybenzoate, 4.38 g of dicyclohexylcarbodiimide, 100 mb of dry dimethylformamide and 20 mb of dry pyridine was stirred at room temperature for 24 hours, and the mixture was treated by the same procedure as in Example 11.The crystals obtained were recrystallized from isopropanol-ether to obtain 5.7 g (yield: 72.7%) of p-methoxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 163 to 164.5"C.
IRvmBarXcm-1: 1700, 1730, 1755 (C=O) Example 37 o-Acetaminophenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4.0 g of 1 -amidino-4-piperidinepropionic acid hydrochloride, 2.6 g of o-acetaminophenol was dissolved in 40 mt of dry pyridine. To the solution was added with ice-cooling and stirring 3.5 g of dicyclohexylcarbodiimide, and the resulting mixture was allowed to stand at room temperature for 44 hours.
After removal of any insoluble materials, the solvent was removed under reduced pressure. The residue was washed with ethyl acetate, and dry ether was then added to the residue to give crystals. The crystals were washed with ether several times, then with warm dichloromethane and finally with ethyl acetate. Dry ether was added to the crystals, and the mixture was evaporated to dryness to obtain 5.8 g (yield: 92.7%) of o-acetaminophenyl 1-amidino-4-piperidinepropionate hydrochloride as hygroscopic crystals.
lRvK:axcml : 1750 (C=O) max NMR(CD30D)o: 0.92 - 4.26 (13H, m, piperidine protons and CH2CH2CO) 2.40 (3H, s, COCH3) 7.28 - 8.20 (4H, m, aromatic protons) Example 38 5',6',7',8'-Tetrahydro-2'-naphthyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 4 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.5 g of 5,6,7,8-tetrahydro-2naphthol, 4 g of dicyclohexylcarbodiimide and 25 me of dry pyridine was stirred on an oil bath at room temperature for 1 day and then at 50"C for 6 hours. After removal of any insoluble materials, the solvent was removed under reduced pressure. The residue was washed with ethyl acetate and then with ether and dissolved in a small amount of isopropanol. Water was added to the solution to give crystals which were then washed with ethyl acetate and further with ether to obtain 3.5 g (yield: 56.5%) of 5',6',7',8'-tetrahydro2'-naphthyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 113to 115 C.
IR v cm 1 1758(C=O) NMR(CD30D)o: : 1.70 - 1.94 (8H, m, -(CH2)4-) 1.04 - 4.20 (13H, m, piperidine protons and CH2CH2CO) 7.00 - 7.44 (3H, m, aromatic protons) Example 39 p-Nitrophenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 5.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 7.6 g of bis-(p-nitrophenyl)sulfite prepared from p-nitrophenol and thionyl chloride, 20 m( of dry dimethylformamide and 6 mt of dry pyridine was stirred at room temperature for 22 hours. The solvent was removed under reduced pressure, and 70 me of ethyl acetate and 30 ml of ether were added to the residue. The mixture was well stirred, and the supernatant solution was removed by decantation. 50 m( of ether was added to the residue.Followed by sufficient stirring of the mixture, the supernatant solution was removed by decantation. A small amount of water was added to the residue, and the mixture was stimulated to give crystals. Acetone was added to the crystals, and the mixture was stirred, thereby separating the crystals by filtration. The crystals were washed with acetone and then with ether and dried to obtain 3.2 g of p-nitrophenyl 1 -amidino-4- piperidinepropionate hydrochloride as colorless crystals having a melting point of 131 to 136"C.
IR v cm : 1770 (C=O) max NMR(DMSO-d6)o: 0.92 - 4.08 (13H, m, piperidine protons and CH2CH2CO) 6.90 - 7.10 (6H, m, NH2 and aromatic protons) 7.80 - 8.00 (2H, m, aromatic protons) Example 40 Phenylthio 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 2.4 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 1.1 g of thiophenol, 2.1 g of dicyclohexylcarbodiimide and 15 mf of dry dimethylformamide was stirred at room temperature for 17 hours. After removal of any insoluble materials, the solvent was removed.The residue was washed with ether and then with t-butanol to obtain 1.2 g (yield: 36.4%) of phenylthio 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 168 to 170"C.
IR vKBr cm-' 1710 (C=O) max NMR(CD30D)b : 1.0 - 4.16 (13H, m, piperidine protons and CH2CH2CO) 7.56 (5H, s, aromatic protons) Example 41 p-t-Butylphenylthio 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 3 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 2.2 g of p-t-butyl thiophenol, 2.6 g of dicyclohexylcarbodiimide and 18 mf of dry dimethylformamide was stirred at room temperature for 10 hours. After removal of any insoluble materials, the solvent was removed under reduced pressure. The residue was washed with ether and dissolved in t-butanol. Ether was added to the solution to give an oily substance.Water was added to the oily substance, and the mixture was allowed to stand overnight in cold conditions to give crystals. The crystals were washed with ethyl acetate and then with ether and air-dried to obtain 2.3 g (yield: 46.9%) of p-t-butylphenylthio 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point at 86 to 88"C.
iRvKBr cm-l : 1710 (C=O) NMR(CD,OD)G : 1.00 - 4.10 (13H, m, piperidine protons and CH2CH2CO) 1.40 (9H, s, C(CH3)3) 7.50 - 7.84 (4H, m, aromatic protons) Example 42 Phenyl 1 -amidino-4-piperidinecarboxylate hydrochloride: A mixture of 826 mg of 1-amidino-4-piperidinecarboxylic acid hydrochloride and 1.4 g of diphenyl sulfite was stirred overnight at room temperature in a mixture of 10 me of dry dimethylformamide and 4 mt of dry pyridine. The solvent was removed under reduced pressure, and the residue was washed three times with 20 mt of ether. 10 mf of acetone was added to the residue, and the mixture was stirred to give crystals.The crystals were washed with acetone and dried to obtain 600 mg (yield: 53% of phenyl 1-amidino-4piperidinecarboxylate hydrochloride as crystalline powder having a melting point of 155.5 to 161.5"C.
IR yKB' cm : 1750 (C=O) NMR(CD3OD)5 : 1.50 - 4.00 (9H, m, piperidine protons) 6.90 - 7.40 (5H, m, aromatic protons) Example 43 o-Benzyloxycarbonylphenyl 1-amidino-4-piperidinecarboxylate hydrochloride: A mixture of 826 mg of 1-amidino-4-piperidinecarboxylic acid hydrochloride and 3.0 g of bis-(o benzyloxycarbonylphenyl)sulfite was stirred overnight at room temperature in a mixture of 10 mt of dry dimethylformamide and 4 me of dry pyridine. The solvent was removed under reduced pressure, and the residue was washed three times with ether. 10 me of acetone and 30 me of ethyl acetate were added to the residue, and the mixture was stimulated to give crystals.The crystals were washed with hot ethyl acetate to obtain 1,015 mg (yield: 61%) of o-benzyloxycarbonylphenyl 1-amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 140.5 to 1 47aC.
IR VKBr cm-1 : 1740,1710(C=O) max NMR(CD3OD)5: 1.50 - 4.00 (9H, m, piperidine protons) 5.20 (2H, s, CH2-Ph) 6.96 - 8.00 (9H, m, aromatic protons) Example 44 2',4'-Dichlorophenyl 1-amidino-4-piperidinecarboxylate hydrochloride: A mixture of 2.0 g of 1-amidino-4-piperidinecarboxylic acid hydrochloride and 7.2 g of bis-(2,4dichlorophenyl)sulfite was stirred at room temperature for 4 hours in a mixture of 18 mt of dry dimethylformamide and 9 me of dry pyridine. The solvent was removed under reduced pressure, and the residue was washed three times with ether. Acetone was added to the residue, and the mixture was stirred to give crystals.The crystals were washed with ethyl acetate and then with ether and recrystallized from methanol-ether to obtain 1.27 g (yield: 37.4%) of 2',4'-dichlorophenyl 1-amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 215 to 21 8.5aC.
gRVKBr cm1 : 1762 (C=O) max NMR(CD30D)6: : 1.67-4.28 (9H, m, piperidine protons) 7.31 - 7.82 (3H, m, aromatic protons) Example 45 p-Chlorophenyl 1-amidino-4-piperidinecarboxylate hydrochloride: A mixture of 1.5 g of 1-amidino-4-piperidinecarboxylic acid hydrochloride and 8.8 g of bis-(p chlorophenyl)su Ifite was stirred at room temperature for 1 hour in a mixture of 14 me of dry dimethylformamide and 7 me of dry pyridine. The solvent was removed under reduced pressure, and the residue was washed twice with dry ether. Acetone was added to the residue to give crystals.The crystals were washed with ether and then with ethyl acetate and recrystallized from methanol-ether to obtain 1.62 g (yield: 70.4%) of p-chlorophenyl 1-amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 196 to 198 C.
IR #KBr cm-: 1744(C=O) max NMR(CD30D)o: : 1.65 - 4.15 (9H, m, piperidine protons) 7.19 -7.72 (4H, m, aromatic protons) Example 46 p-Methylphenyl 1-amidino-4-piperidinecarboxylate hydrochloride: A mixture of 1.5 g of 1-amidino-4-piperidinecarboxylic acid hydrochloride and 7.6 g of bis-(pmethylphenyl)sulfite was stirred at room temperature for 1.5 hours in a mixture of 7 m4 of dry dimethylformamide and 7 mt of dry pyridine. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals. After being washed with ether and then with ethyl acetate, the crystals were reprecipitated from methanol-ether and recrystallized from isopropanol-isopropyl ether to obtain 2.15 g (yield: 99.6%) of p-methylphenyl 1 -amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 187 to 189"C.
IR #KBr cm- : 1742 (C=O) NMR(CD30D)6: : 1.50 - 4.00 (9H, m, piperidine protons) 2.30 (3H, s, CH3) 6.61 - 7.23 (4H, m, aromatic protons) Example 47 p-Methoxyphenyl 1-amidino-4-piperidinecarboxylate hydrochloride: A mixture of 1.5 g of 1-amidino-4-piperidinecarboxylic acid hydrochloride and 7.7 g of bis-(pmethoxyphenyl)sulfite was stirred at room temperature for 18 hours in a mixture of 16 mf of dry dimethylformamide and 8 mt of dry pyridine. The solvent was removed under reduced pressure and ether was added to the residue to give crystals.The crystals were washed with ether twice and then with ethyl acetate and recrystallized from methonal-ether to obtain 1.9 g (yield: 83.7%) of p-methoxyphenyl 1 -amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 198 to 203aC.
IR yKB' cm : 1739 (C=O) NMR(CD30D)o: : 1.48 - 4.01 (9H, m, piperidine protons) 3.75 (3H, s, OCH3) 6.73 - 7.05 (4H, m, aromatic protons) Example 48 p-t-Butylphenyl 1-amidino-4-piperidinecarboxylate hydrochloride: A mixture of 1.0 g of 1-amidino-4-piperidinecarboxylic acid hydrochloride and 3.3 g of bis-(p-tbutylphenyl)sulfite was stirred at room temperature for 2.5 hours in a mixture of 10 mf of dry dimethylformamide and 5 mf of dry pyridine. The solvent was removed under reduced pressure, and dry ether was added to the residue to give crystals.The crystals were washed with dry ether and then with ethyl acetate and recrystallized from methanol-ether to obtain 1.0 g (yield: 61.4%) of p-t-butylphenyl 1-amidino-4piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 211 to 213"C.
The thus obtained crystals were recrystallized twice to give crystals having a melting point of 222 to 223"C.
IR yKB' cm : 1742 (C=O) NMR(CD3OD)6: 1.38 (9H, s, C(CH3)3) 1.65 - 4.15 (9H, m, piperidine protons) 7.04 - 7.74 (4H, m, aromatic protons) Example 49 p-(a,a-Dimethylbenzyl)phenyl 1-amidino-4-piperidinecarboxylate hydrochloride: A mixture of 10.9 g of bis[p-(a,a-dimethylbenzyl)phenyl]suifite prepared from p (a,a,dimethylbenzyl)phenol and thionyl chloride, 4 g of 1-amidino-4-piperidinecarboxylic acid hydrochloride, 20 m( of dry dimethylformamide and 8 mt of dry pyridine was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to give an oily substance which was then treated with ethyl acetate to give powder.The powder was recrystallized from isopropanol-ether to obtain 5.3 g (yield: 68.8%) of p-(a,a-dimethylbenzyl)phenyl 1-amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 166 to 168"C.
IR vma cm : 1758 (C=O) NMR(CD30D)o: : 1.74 (6H, s, > C(CH3)2) 1.50 - 4.18 (9H, m, piperidine protons) 7.18 - 7.60 (9H, m, aromatic protons) Example 50 p-Cyclohexylphenyl 1-amidino-4-piperidinecarboxylate hydrochloride: A mixture of 9.2 g of bis-(p-cyclohexylphenyl)sulfite, 4 g of 1-amidino-4-piperidinecarboxylic acid hydrochloride, 20 mf of dry dimethylformamide and 8 mk of dry pyridine was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the residue was treated with ethyl acetate to give crystals.The crystals were recrystallized from isopropanol-ether to obtain 2.9 g (yield: 40.8%) of p-cyclohexylphenyl 1-amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 226 to 230"C.
IR yKB' cm : 1760 (C=O) NMR(CD30D)G : 1.20 - 4.30 (20H, m, piperidine protons and cyclohexane protons) 7.16 - 7.64 (4H, m, aromatic protons) Example 51 2',4'-Dimethylphenyl 1-amidino-4-piperidinecarboxylate hydrochloride: 8.4 g of bis-(2,4-dimethylphenyl)sulfite was dissolved in a mixture of 36 m4 of dry dimethylformamide and 18 mt of dry pyridine. To the solution was added 4.0 g of 1-amidino-4-piperidinecarboxylic acid hydrochloride, and the resulting mixture was stirred at room temperature for 4 hours.The solvent was removed under reduced pressure, and ether was added to the residue to obtain 5.8 g (yield: 96.7%) of 2',4'-dimethylphenyl 1-amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 198 to 2010C.
The thus obtained crystals were further purified to give crystals having a melting point of 205 to 2070C.
IRK BY cm : 1745 (C=O) NMR(CD3OD)6: : 1.60 - 4.36 (9H, m, piperidine protons) 2.24 (3H, s, 4-CH3) 2.40 (3H, s, 2-CH3) 7.02 - 7.56 (3H, m, aromatic protons) Example 52 o-Allylphenyl 1-amidino-4-piperidinecarboxylate hydrochloride: 2.4 g of bis-(o-allylphenyl)sulfite was dissolved in a mixture of 10 me of dry dimethylformamide and 5 mt of dry pyridine. To the solution was added 1.0 g of 1 -amidino-4-piperidinecarboxylic acid hydrochloride, and the resulting mixture was allowed to stand at room temperature for 3 hours. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals.The crystals were recrystallized from isopropanol-ether to obtain 950 mg (yield: 61.3%) of o-allylphenyl 1-amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 151 to 153aC.
IR #KBrmax cm- : 1740 (C=O) NMR(CDCt3)6: : 1.60 - 4.52(11 H, m, piperidine protons and CH2-Ph) 5.04 - 5.48 (2H, m, =CH2) 5.88 - 6.40 (1 H, m, -CH=) 7.24- 8.08 (4H, m, aromatic protons) Example 53 Piperidine-4-acetic acid hydrochloride: 15 g of 4-pyridyl acid hydrochloride was dissolved in 180 mt of water. To the solution was added 0.6 g of platinum dioxide, and the resulting mixture was subject to catalytic reduction at an initial hydrogen pressure of 4.85 kg/cm2. The reaction was terminated when 6.2 t of hydrogen gas was absorbed, and the catalyst was removed by filtration. The filtrate was evaporate to dryness under reduced pressure, and a small amount of ethanol was added to the residue.The solid in the mixture was crushed, and a large amount of ether was added to the mixture. Subsequent filtration of the resulting mixture gave 14.6 g of piperidine-4-acetic acid hydrochloride as a white solid having a melting point of 136 to 141"C.
lRKBr cm : 1710(C=O) NMR(CD3OD)6: 1.20 - 3.44(11 H, m) Example 54 1-Amidino-4-piperidineacetic acid: A mixture of 14 g of piperidine-4-acetic acid and 10.9 g of s-methylisothiourea 1/2 sulfate was added to 40 me of a 4N sodium hydroxide solution, and the mixture was stirred at room temperature for 20 hours.
Methyl mercaptan formed was filtered to give crystals. The crystals were washed with ice-water and then with acetone and dried to obtain 12 g (yield: 83%) of 1-amidino-4-piperidineacetic acid as colorless powder having a melting point of over 310"C.
I R vmBarx cm - 1: 1570,1410 Example 55 1-Amidino-4-piperidineacetic acid hydrochloride: 11.5 g of 1 -amidino-4-piperidineacetic acid prepared as in Example 54 was dissolved in 100 mt of a 1 N hydrochloric acid solution, and the solution was treated with activated charcoal and concentrated. Acetone was added to the residue to obtain 12.7 g (yield: 92%) of 1 -amidino-4-piperidineacteic acid hydrochloride as colorless prisms having a melting point of 213 to 215.5"C.
IR Vmrx cm : 1720 (C=O) Example 56 Phenyl 1-amidino-4-piperidineacetate hydrochloride: A mixture of 2 g of 1 -amidino-4-piperidineacetic acid hydrochloride and 3.2 g of diphenylsulfite was stirred at room temperature for 1.5 hours in a mixture of 10 mt of dry dimethylformamide and 3 m4 of dry pyridine.
The solvent was removed under reduced pressure, and the residue was washed several times with ether to give crystals. The crystals were washed with ethyl acetate and then with ether to obtain 2.4 g (yield: 89%) of phenyl 1-amidino-4-piperidineacetate hydrochloride as colorless crystalline powder having a melting point of 131 to 136.5 C.
I R vm x c m 1750 (C=O) NMR(CD30D)#: 1.20 - 4.10 (9H, m, piperidine protons) 2.60 (2H, d, J=6Hz, CH2CO) 6.90 - 7.40 (5H, m, aromatic protons) Example 57 4'-Methoxyphenyl 1-amidino-4-piperidineacetate hydrochloride: A mixture of 2 g of 1 -amidino-4-piperidineacetic acid hydrochloride and 4 g of bis-(pmethoxyphenyl)sulfite was stirred at room temperature for 4 hours in a mixture of 10 ml of dry dimethylformamide and 3 mf of dry pyridine. The solvent was removed under reduced pressure, and the residue was washed several times with ether to give crystals.The crystals were washed with ethyl acetate and then with ether to obtain 2.9 g (quantitative) of 4'-methoxyphenyl 1 -amidino-4-piperidineacetate hydrochloride as colorless crystalline powder having a melting point of 159 to 162 C.
IR VKBr cm1 : 1740 (C=O) max NMR(CD30D)#: 1.20 - 4.10 (9H, m, piperidine protons) 2.56 (2H, d, J=6Hz, CH2CO) 3.80 (3H, s, OCH3) 6.90 - 7.20 (4H, m, aromatic protons) Example 58 4'-Chlorophenyl 1-amidino-4-piperidineacetate hydrochloride: A mixture of 2.0 g of 1-amidino-4-piperidineacetic acid hydrochloride and 4.6 g of bis-(p chlorophenyl)sulfite was stirred at room temperature for 2 hours in a mixture of 10 m( of dry dimethylformamide and 3 ml of dry pyridine. The solvent was removed under reduced pressure, and 30 mt of ether was added to the residue, and the mixture was stimulated to give crystals.The crystals were washed with ethyl acetate and then with ether to obtain 2.7 g (yield: 90%) of 4'-chlorophenyl 1-amidino-4piperidineacetate hydrochloride as colorless crystals having a melting point of 186.5 to 190.5 C.
lRVKmBax cm : 1760 (C=O) NMR(CD30D)6 : 1.10 - 4.10 (9H, m, piperidine protons) 2.60 (2H, d, J=6Hz, CH2CO) 7.04 - 7.60 (4H, m, aromatic protons) Example 59 4'-Methylphenyl 1 -amidino-4-piperidi neacetate hydrochloride: A mixture of 2.0 g of 1-amidino-4-piperidineacetic acid hydrochloride and 3.5 g of bis-(pmethylphenyl)sulfite was stirred at room temperature for 2 hours in a mixture of 10 mt of dry dimethylformamide and 3 me of dry pyridine. The solvent was removed under reduced pressure, and 20 me of ether was added to the residue. Thereafter, the mixture was stimulated to give crystals.The crystals were washed with ethyl acetate and then with ether to obtain 2.8 g (quantitative) of 4'-methylphenyl 1-amidino-4-piperidineacetate hydrochloride as colorless crystals having a melting point of 167 to 173aC.
IR v cm : 1750 (C=O) NMR(CD3OD)6: 1.20 -4.10 (9H, m, piperidine protons) 2.38 (3H, s, CH3) 2.62 (2H, d, J=6Hz, CH2CO) 6.90 - 7.40 (4H, m, aromatic protons) Example 60 2',4'-Dichlorophenyl 1-amidino-4-piperidineacetate hydrochloride: A mixture of 2.0 g of 1-amidino-4-piperidineacetic acid hydrochloride and 5.0 g of bis-(2,4dichlorophenyl)sulfite prepared from 2,4-dichlorophenol and thionyl chloride was stirred at room temperature for 1 hour in a mixture of 10 mt of dry dimethylformamide and 3 me of dry pyridine. The solvent was removed under reduced pressure, and 20 me of ether was added to the residue. The mixture was then stimulated to give crystals.The crystals were washed with ethyl acetate and then with ether and stirred for 10 minutes in 20 me of acetone. The crystals were washed with ether to obtain 2.6 g (yield: 79%) of 2',4'-dichlorophenyl 1-amidino-4-piperidineacetate hydrochloride as colorless crystals having a melting point of 177.5 to 181.5 C.
lRvKBr cm1 : 1765 (C=O) NMR(CD3OD)6: : 1.20 - 4.10 (9H, m, piperidine protons) 2.70 (2H, d, J=6Hz, CH2CO) 7.20 - 7.70 (3H, m, aromatic protons) Example 61 4'-t-Butylphenyl 1-amidino-4-piperidineacetate hydrochloride: A mixture of 1.2 g of 1-amidino-4-piperidineacetic acid hydrochloride and 2.6 g of bis-(p-tbutylphenyl)sulfite was stirred at room temperature for 2 hours in a solution of 5 me of dry dimethylformamide and 2 me of dry pyridine. The solvent was removed, and to the residue were added with stirring 20 me of ethyl acetate and 100 me of ether to give crystals. The crystals were recrystallized from methanol-ether to obtain 1.42 g (yield: 74%) of 4'-t-butylphenyl 1 -amidino-4-piperidineacetate hydrochloride as colorless crystalline powder having a melting point of 183.5 to 187"C.
lR"'KBr cm : 1755 (C=O) NMR(CD3OD)6: 1.10 - 4.00 (9H, m, piperidine protons) 1.33 (9H, s, C(CH3)3 2.56 (2H, d, J=6Hz, CH2CO) 6.84 - 7.44 (4H, m, aromatic protons) Example 62 1-Amidino-3-piperidinepropionic acid hydrochloride: 15.7 g of piperidine-3-propionic acid was dissolved in 100 ml of a 1 N sodium hydroxide solution, and 14 g of s-methylisothiourea sulfate was added to the solution, and the resulting mixture was stirred slowly at room temperature for 20 hours. Methyl mercaptan formed was absorbed into a potassium manganate solution under reduced pressure. The crystals deposited were separated by filtration, washed with a small amount of cold water and dissolved in 117 me of a 1 N hydrochloric acid solution. The solvent was removed, and the residue was dissolved in isopropyl alcohol.Isopropyl ether was added to the solution to give crystals which were then recrystallized from water to obtain 14 g (yield: 59%) of 1-amidino-3-piperidinepropionic acid hydrochloride as colorless crystals having a melting point of 220 to 222"C.
IRVKBr cm1 : 1715(C=O) max NMR(CD30D)o: : 1.0 - 2.0 (7H, m, p-H2, 3-H, and 5-H2) 2.36 (2H, t, J=6.4 Hz, a-H2) 2.64 - 3.84 (4H, m, 2-H2 and 6-H2) Example 63 Phenyl 1-amidino-3-piperidinepropionate hydrochloride: 3 g of 1-amidino-3-piperidinepropionic acid hydrochloride was dissolved in a mixture of 30 mt of dry dimethylformamide and 3 mt of dry pyridine. To the solution was add 4.5 g of diphenyl sulfite, and the resulting mixture was stirred at room temperature for 29 hours. The solvent was removed, and the residue was washed with dry ether and treated with ethyl acetate to give light brown powder.The powder was recrystallized from ethanol-etherto obtain 3.1 g (yield: 78%) of phenyl 1-amidino-3-piperidinepropionate hydrochloride as light brown powder having a melting point of 101 to 112"C.
IR VKB' cm 1: 1760 (C=O) max NMR (CD30D)o: : 1.0 - 2.1 (7H, m, p-H2, a-H, and 5-H2) 2.64 (2H, t, J=7.2 Hz, a-H2) 6.9 - 7.4 (5H, m, aromatic protons) Example 64 4'-Methoxyphenyl 1-amidino-3-piperidinepropionate hydrochloride: 3 g of 1-amidino-3-piperidinepropionic acid hydrochloride, 5.6 g of bis-(p-methoxyphenyl)sulfite, 30 me of dry dimethyl-formamide and 3 mk of dry pyridine were reacted for 17 hours by the same procedure as in Example 63. The solvent was removed, and the residue was washed with dry ether to give crystals.The crystals were recrystallized from methanol-ether to obtain 3.9 g (yield: 93%) of 4'-methoxyphenyl 1-amidino-3-piperidine-propionate hydrochloride as colorless needles having a melting point of 214 to 216"C.
IR#KBrmax cm-: 1760 (C=O) NMR(CD30D)4 1.0 - 2.1 (7H, m, p-H2, 3-H, and 5-H2) 2.6 (2H, t, J=7.2 Hz, a-H2) 3.72 (3H, s, OCH3) 6.83 (4H, s, aromatic proton) Example 65 4'-Chlorophenyl 1-amidino-3-piperidinepropionate hydrochloride: 2 g of 1-amidino-3-piperidinepropionic acid hydrochloride, 10.3 g of bis-(p-chlorophenyl)sulfite, 20 mt of dry dimethyl-formamide and 5 me of dry pyridine were reacted at room temperature for 1 hour, and the reaction mixture was treated by the same procedure as in Example 63.The product thus obtained was recrystallized from methanol-ether to obtain 2.4 9 (yield: 82%) of4'-chlorophenyl 1-amidino-3-piperidinepropionate hydrochloride as light brown needles having a melting point of 168 to 170"C.
IR v cm : 1750 (C=O) NMR(CD30D)o: : 1.0 - 2.1 (7H, m, p-H2, a-H, and 5-H2) 2.67 (2H, t, J=6.8 Hz, a-H2) 2.8 - 3.9 (4H, m, 2- and 6-H2) 7.0 - 7.4 (4H, m, aromatic protons) Example 66 4'-Methylphenyl 1-amidino-3-piperidinepropionate hydrochloride: 2.5 g of 1-amidino-3-piperidinepropionic acid hydrochloride, 9 g of bis-(p-methylphenyl)sulfite, 25 me of dry dimethylformamide and 8 me of dry pyridine were reacted at room temperature for 2 hours, and the reaction mixture was treated by the same procedure as in Example 63. The product thus obtained was recrystallized from ethanol-etherto obtain 3 g (yield: 87%) of 4'-methylphenyl 1-amidino-3-piperidinepropionate hydrochloride as colorless needles having a melting point of 189 to 192 C.
IR Vmax cm : 1750 (C=O) NMR(CD2OD)5: 1.1 - 2.1 (7H, m, p-H2, 3-H, and 5-H2) 2.36 (3H, s, -CH3) 2.70 (2H, d, J=6.8 Hz, a-H2) 2.80 - 4.0 (4H, m, and 6-H2) 7.0 - 7.4 (4H, m, aromatic protons) Example 67 2',4'-Dichlorophenyl 1-amidino-3-piperidinepropionate hydrochloride: 2 g of 1 -amidino-3-piperidinepropionic acid hydrochloride was suspended in 10 me of dry dimethylformamide. To the suspension were added with cooling on a water bath 4.8 g of bis-(2,4-dichlorophenyl)sulfite and 3 me of dry pyridine, and the resulting mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and ether was added to the residue. Thereafter, the mixture was stimulated to give crystals.The crystals were washed with ethyl acetate and then with ether and recrystallized from isopropanol to obtain 2.2 g (yield: 68%) of 2',4'-dichlorophenyl 1-amidino-3 piperidinepropionate hydrochloride as colorless crystals having a melting point of 170.5 to 174"C.
I R Vmax cm : 1770 (C=O) NMR(CD30D)o: 1.10 - 4.00 (13H, m, piperidine protons and CH2CH2CO) 7.20 - 7.70 (3H, m, aromatic protons) Example 68 4'-t-Butylphenyl 1-amidino-3-piperidinepropionate hydrochloride: 1 g of 1-amidino-3-piperidinepropionic acid hydrochloride was suspended in a mixture of 10 me of dry dimethylformamide and 5 mt of dry pyridine. To the suspension was added 1.76 g of bis-(p-tbutylphenyl)sulfite, and the resulting mixture was stirred at room temperature for 2.5 hours. The solvent was removed under reduced pressure to give crystals.The crystals were washed with dry ether and recrystallized three times from ethanol-etherto obtain 1 g (yield: 64%) of 4'-t-butylphenyl 1-amidino-3piperidinepropionate hydrochloride as colorless needles having a melting point of 212 to 2140C.
IR #KBrmax cm1: : 1740(C=O) NMR(CD3OD)6: 1.0 - 2.1 (7H, m, p-H2, 3-H, and 5-H2) 1.35 (9H, s, C(CH3)3) 2.5-4.1 (6H, m, a-, 2- and 6-H2 7.0 - 7.7 (4H, m, aromatic protons) Example 69 1-Amidino-3-piperidinebutyric acid acid hydrochloride: 1) 20 g of 3-pyridylbutyric acid was suspended in 250 me of water, and the suspension was shaken in a stream of hydrogen (5 to 6 kg/cm2) in the presence of 1 g of platinum dioxide. When the absorption of hydrogen was terminated, the catalyst was removed by filtration. The filtrate was washed with water, and the solvent was removed to give powder. The powder was recrystallized from ethanol to obtain 19 g of 3-piperidine-butyric acid as colorless needles having a metling point of 208 to 210"C.
IR yKB' cm : : 1760 (C=O) max NMR(CD3OD)5: 1.0 - 2.0 (9H, m, ss- andy-H2, 3-H, 4-H2 and 5-H2) 2.13 (2H,t,J=6.4Hz,a-H2) 2.4 - 3.46 (4H, m, 2-H2 and 6-H2) 2) 20 g of 3-piperidinebutyric acid prepared as in 1) above was dissolved in 117 mt of a 1 N sodium hydroxide solution. To the solution was added 16.3 g of S-methylisothiourea sulfate, and the resulting mixture was stirred slowly at room temperature for 20 hours. Methyl mercaptan formed was absorbed into a potassium manganate solution under reduced pressure. The crystals deposited were separated by filtration, washed with a small amount of cold water and dissolved in 117 mk of a 1 N hydrochloric acid solution.The solvent was removed, and the residue was dissolved in isopropyl alcohol, and isopropyl ether was then added to the solution to obtain 18.3 g (yield: 63%) of 1 -amidino-3-piperidinebutyric acid hydrochloride as colorless needles having a melting point of 112 to 115"C.
IRvKBr cm-: 1700 (C=O) max NMR(CD3OD)#: 1.0 - 2.0 (9H, m, p-and -H2, 3-H, 4-H2 and 5-H2) 2.24 (2H, t, J=6.4 Hz, a-H2) 2.52 - 3.76 (4H, m, 2-H2 and 6-H2) Example 70 Phenyl 1-amidino-3-piperidinebutyrate hydrochloride: 3 g of 1-amidino-3-piperidinebutyric acid hydrochloride, 4.2 g of diphenylsulfite, 30 mC of dry dimethylformamide and 3 m( of dry pyridine were reacted for 19.5 hours in accordance with the procedure employed in Example 63. The solvent was removed, and the residue was washed with dry ether to obtain 3.9 g of phenyl 1-amidino-3-piperidinebutyrate hydrochloride as an oil.
lRvnaatcml : 1760 (C=O) max NMR(CD30D)G : 1.0 - 2.0 (9H, m, p-H2, "-H2, 3-H, 4-H2 and 5-H2) 2.48 (2H, t, J=6.4 Hz, a-H2) 2.5 - 3.8 (4H, m, 2- and 6-H2) 6.6 - 7.3 (5H, m, aromatic protons) Example 71 4'-Methoxyphenyl 1-amidino-3-piperidinebutyrate hydrochloride: 3 g of 1-amidino-3-piperidinebutyric acid hydrochloride and 5.3 g of bis-(p-methoxyphenyl) sulfite were reacted for 17 hours in accordance with the procedure employed in Example 63. The solvent was removed, and the residue was washed with dry ether and dissolved in chloroform. Ethyl acetate was added to the solution to obtain 2.9 g (yield: 68%) of 4'-methoxyphenyl 1-amidino-3-piperidinebutyrate hydrochloride as colorless powder having a melting point of 122 to 130"C.
IRv cm . 1760 (C=O) max NMR(CD30D)G : 1.0 - 2.0 (9H, m, ss-, y-H2, 3-H, and 5-H2) 2.5 (2H, t, J=6.4 Hz, a-H2) 3.68 (3H, s, OCH3) 6.79 (4H, s, aromatic proton) Example 72 4'-Chlorophenyl 1-amidino-3-piperidinebutyrate hydrochloride: 3 g of 1-amidino-3-piperidinebutyric acid hydrochloride, 7.3 g of bis-(p-chlorophenyl) sulfite, 30 m4 of dry dimethyl-formamide and 10 mC of dry pyridine were reacted and treated in accordance with the procedure employed in Example 63 to obtain 3 g (yield: 69%) of 4'-chlorophenyl 1-amidino-3-piperidinebutyrate hydrochloride as light brown needles having a melting point of 155 to 157"C.
IRvKBr cm1 : 1744(C=O) max NMR(CD30D)G : 1.1-2.1 (9H, m, p-, y-H2, 3-H, 4- and 5-H2) 2.66 (2H, t, J=6.8 Hz, a-H2) 2.8 - 4.0 (4H, m, 2- and 6-H2) 7.2 - 7.6 (4H, m, aromatic protons) Example 73 2', 4'-Dichlorophenyl 1-amidino-3-piperidinebutyrate hydrochloride: 2 g of 1-amidino-3-piperidinebutyric acid hydrochlorice was suspended in 10 me of dry dimethylformamide. To the suspension were added 4.5 g of bis-(2,4-dichlorophenyl)sulfite and 3 mt of dry pyridine, and the resulting mixture was stirred at room temperature for 2 hours.The solvent was removed under reduced pressure, and the residue was washed three times with 20 mt of ether and then stimulated to give crystals.
The crystals were washed with ethyl acetate and then with ether to obtain 2.4 g (yield: 76%) of 2', 4'-dichlorophenyl 1-amidino-3-piperidinebutyrate hydrochloride as colorless crystals having a melting point of 138 to 141"C.
IR v cm : 1780 (C=O) max NMR(CD3OD)5: 1.20 - 4.00 (15H, m, piperidine protons and CH2CH2CO) 7.20 - 7.70 (3H, m, aromatic protons) Example 74 4'-Methylphenyl 1 -am idino-3-piperidinebutyrate hydrochloride: A mixture of 3 g of 1-amidino-3-piperidinebutyric acid hydrochloride, 4.7 g of bis-(p-methylphenyl)sulfite, 15 mt or dry dimethylformamide and 5 mt of dry pyridine was stirred at room temperature for 2 hours. The solvent was removed, and the residue was treated with ethyl acetate to give a solid substance.The substance was washed several times with ethyl acetate and then with ether and dried to obtain 3.7 g (yield: 90%) of 4'-methylphenyl 1-amidino-3-piperidinebutyrate hydrochloride as colorless crystals having a melting point of 138 to 140"C.
IR vKBr cm : 1750 (C=O) max NMR(CD3OD): 1.10 - 2.10 (9H, m, ss-, y-H2, 3-H, and 5-H2) 2.52 (3H, s, CH3) 2.60 (2H, t, J=8Hz, a-H2) 2.76 - 4.00 (4H, m, 2- and 6-H2) 6.90 - 7.40 (4H, m, aromatic protons) Example 75 4'-t-Butylphenyl 1-amidino-3-piperidinebutyrate hydrochloride: A mixture of 2 g of 1 -amidino-3-piperidinebutyric acid hydrochloride, 4.16 g of bis-(p-t-butylphenyl)sulfite, 20 mt of dry dimethylformamide and 10 me of dry pyridine was stirred at room temperature for 16 hours.
The solvent was removed under reduced pressure, and the residue was washed with dry ether and then dissolved in isopropyl alcohol. Water was added to the solution, and the mixture was cooled to give colorless crystals. The crystals were washed with cold water and dried to obtain 1.9 g (yield: 62%) of 4'-t-butylphenyl 1-amidino-3-piperidinebutyrate hydrochloride as colorless crystals having a melting point of 164 to 169 C.
IR #KBrmax cm- : 1755 (C=O) max NMR(CD30D)o: 1.0-2.1 (9H, m, 3-H, ss-, 4- and 5-H2) 1.32 (9H, s, C)CH3)3) 2.3 - 3.9 (6H, m, a-, and 6-H2) 6.96- 7.5 (4H, m, aromatic protons) Example 76 1-Amidino-4-piperidinebutyric acid hydrochloride: A mixture of 13.0 g of o-methylisourea sulfate and 15.7 g of 4-piperidinebutyric acid hydrochloride was dissolved with stirring and ice-cooling in 60 m4 of a 4N sodium hydroxide solution. To the solution was added 20 mt of water, and the resulting mixture was stirred at room temperature for 64 hours.The crystals obtained were washed with 300 m4 of ice-water and dehydrated with acetone and further washed with ether.
The crystals were dissolved in 90 mC of a 1N hydrochloric acid solution, and the solution was dried under reduced pressure. The residue was washed with acetone and then with ether and air-dried to obtain 16.3 g (yield: 86.7%) of 1-amidino-4-piperidinebutyrate hydrochloride as colorless crystals having a melting point of 178to 1800C.
IR VKBr cm : 1624,1726 max NMR(CD30D)G : 0.96 - 1.94 (9H, m, p-H2, y-H2, 4-H and 5-H2) 2.27 (2H, t, a-H2) 2.86 - 3.98 (4H, m, 2-H2, 6-H2) Example 77 Phenyl 1-amidino-4-piperidinebutyrate hydrochloride: A mixture of 2.5 g of 1-amidino-4-piperidinebutyric acid hydrochloride and 2.9 g of diphenylsulfite was stirred at room temperature for 3 hours in a mixture of 14 m6 of dry dimethylformamide and 7 m4 of dry pyridine. The solvent was removed under reduced pressure. Dry ether was added to the residue, and the mixture was stirred overnight to give crystals.The crystals were recrystallized from methanol-ether to obtain 2.3 g (yield: 70%) of phenyl 1-amidino-4-piperidinebutyrate hydrochloride as pale yellow crystals having a melting point of 166 to 167or.
IR vKB' cm : 1612,1754 max NMR(CD30D)G : 0.97 - 1.96 (9H, m, p-H2, -H2, a-H2, 4-H and 5-H2) 2.55 (2H, t, a-H2) 2.84 - 3.96 (4H, m, 2-H2, 6-H2) 6.90 - 7.44 (5H, m, aromatic protons) Example 78 4'-Methylphenyl 1-amidino-4-piperidinebutyrate hydrochloride: 5 m4 of dry pyridine was added to a mixture of 3 g of 1 -amidino-4-piperidinebutyric acid hydrochloride, 15 mC of dry dimethylformamide and 4.4 g of bis-(p-methylphenyl)sulfite, and the resulting mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and ethyl acetate was added to the residue to give crystals.The crystals were washed with ethyl acetate and then with ether and recrystallized from methanol-ether to obtain 3.8 g (yield: 92.7%) of 4'-methylphenyl 1-amidino-4piperidinebutyrate hydrochloride as yellow needles having a melting point of 160 to 163 C.
IR VKBr cm1 : 1760 max NMR(CD30D)o: : 1.00 - 2.00 (9H, m, ss-H2, y-H2,3-H2,4-H and 5-H2) 2.30 (3H, s, CH3) 2.52 (2H, t, J=7Hz, CH2CO) 2.80 - 4.00 (4H, m, 2-H2, 6-H2) 6.80 - 7.20 (4H, m, aromatic protons) Example 79 4'-Methoxyphenyl 1-amidino-4-piperidinebutyrate hydrochloride: 3 g of 1 -amidino-4-piperidinebutyric acid hydrochloride was dissolved in a mixture of 15 ml of dry dimethylformamide and 5 ml of dry pyridine. 5.3 g of bis-(p-methoxyphenyl)sulfite was added to the solution, and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was treated by the same procedure as in Example 63.The crystals obtained were recrystallized from methanol-ether to obtain 4 g (yield: 93.6%) of 4'-methoxyphenyl 1 -amidino-4-piperidinebutyrate hydrochloride as colorless needles having a melting point of 173 to 176"C.
lRvKmSx cm- : 1760 (C=O) NMR(CD3OD)b: : 0.8 - 2.0 (9H, m, p-H2, y-H2, 3-H2, 4-H and 5-H2) 2.24 (2H, t, J=6.8 Hz, a-H2) 2.80 - 3.95 (4H, m, 2-H2, 6-H2) 3.71 (3H,s,O-CH3) 6.82 (4H, s, aromatic proton) Example 80 4'-Chlorophenyl 1 -amidino-4-piperidinebutyrate hydrochloride: A mixture of 3 g of 1-amidino-4-piperidiniebutyric acid hydrochloride, 5.1 g of bis-(p-chlorophenyl)sulfite, 15 ml of dry dimethylformamide and 5 me of dry pyridine was stirred at room temperature for 2.5 hours.
The reaction mixture was treated by the same procedure as in Example 65. The crystals obtained were recrystallized from methanol-ether to obtain 2.9 g (yield: 67%) of 4'-chlorophenyl 1-amidino-4piperidinebutyrate hydrochloride as colorless needles having a melting point of 166 to 168"C.
IR #KBrmax cm : 1765 NMR(CD3OD)6: 0.9 - 2.9 (9H, m, p-H2, y-H2, a-H2, 4-H and 5-H2) 2.52 (2H, t, J=7.4 Hz, a-H2) 2.8 - 3.9 (4H, m, 2-H2 and 6-H2) 6.96 - 7.48 (4H, m, aromatic protons) Example 81 4'-t-Butylphenyl 1-amidino-4-piperidinebutyrate hydrochloride: A mixture of 2.5 g of 1-amidino-4-piperidinebutyric acid hydrochloride and 4.3 g of bis-(p-tbutylphenyl)sulfite was stirred at room temperature for 6 hours in a mixture of 14 me of dry dimethylformamide and 7 ml of dry pyridine. The solvent was removed under reduced pressure, and dry ether was added to the residue to give crystals. The crystals were recrystallized from ethanol-ether acetate to obtain 2.2 g (yield: 58%) of 4'-t-butylphenyl 1-amidino-4-piperidine-butyrate hydrochloride as colorless crystals having a melting point of 147 to 1490C.
IRvKBr cm-': 1621,1642,1758 max NMR(CD3OD6: : 0.97 - 1.96 (9H, m, p-H2, y-H2, 3-H2, 4-H and 5-H2) 1.32 (9H, s, -C(CH3)3) 2.54 (2H, t, a-H2) 2.81 - 3.96 (4H, m, 2-H2, 6H2) 6.83 - 7.42 (4H, m, aromatic protons) Example 82 2',4'-Dichlorophenyl 1-amidino-4-piperidinebutyrate hydrochloride: 18 mC of dry pyridine was added on an ice bath to a mixture of 5 g of 1-amidino-4-piperidinebutyric acid hydrochloride, 25 mk of dry dimethylformamide and 10.7 g of bsx-(2,4-dichlorophenyl)sulfite, and the resulting mixture was stirred at room temperature for 1 hour.The solvent was removed under reduced pressure, and the residue was washed several times with ether and treated with ethyl acetate to give crystals. The crystals were washed in turn with ethyl acetate, ether and acetone and then recrystallized from isopropanol-etherto obtain 4.2 g (yield: 49%) of 2',4'-dichlorophenyl 1-amidino-4-piperidinebutyrate hydrochloride as yellow powder having a melting point of 122 to 124"C.
IR VKBr cm1 : 1770 max NMR(CD30D)o: : 1.00 - 2.00 (9H, m, p-H2, -H2, 3-H2, 4-H and 5-H2) 2.60 (2H, t, J=7Hz, a-H2) 2.80 - 4.00 (4H, m, 2-H2, 6-H2) 7.00 - 7.50 (3H, m, aromatic protons) Example 83 2'-Cynnamoylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 5 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 4.8 g of 2'-hydroxychalcone, 4.4 g of N,N'-dicyclohexylcarbodiimide and 30 mt of dry pyridine was stirred at room temperature for 46 hours.
After removal of any insoluble materials, the solvent was removed under reduced pressure to give a yellow oil. The oil was washed with ethyl acetate to give a gummy substance. The substance was dissolved in water. Thereafter, diethyl ether was added to the mixture, and the resulting mixture was stirred and allowed to stand overnight in cold conditions. The solid obtained was washed several times with diethyl ether and then with water to obtain 1.8 g of 2'-cynnamoylphenyl 1 -amidino-4-piperidinepropionate hydrochloride as white powder having a melting point of 103 to 105"C.
lRvKBr cm1 : 1765,1660 (C=O) NMR(CD30D)o: 0.9 - 4.0 (13H, m,
6.6 - 7.6 (11 H, m, -CH=CH- and aromatic protons) Example 84 2'-(p-Phenylcarbonyl)ethenylphenyl 1-amidino-4-piperidinepropionate hydrochloride: A mixture of 5 g of 1 -amidino-4-piperidinepropionic acid hydrochloride, 4.8 g of 2-hydroxychalcone, 4.4 g of dicyclohexylcarbodiimide and 30 mf of dry pyridine was stirred at room temperature for 46 hours. After removal of any insoluble materials by filtration, the solvent was removed under reduced pressure to give an oily substance. The substance was washed with ethyl acetate to give a gummy substance which was then dissolved in water.To this mixture was added ethyl acetate, and the resulting mixture was stirred and allowed to stand overnight in cold conditions. The solid substance obtained was washed several times with diethyl ether and then with water to obtain 3 g (yield: 32.3%) of 2'-(B-phenylcarbonyl)ethenylphenyl 1-amidino-4-piperidinepropionate hyd-ochloride as yellow needles having a melting point of 85"C.
IR VKB' cm-l : 1755, 1660 (C=O) NMR(CD30D)G 1.0 : 1.0-3.66(13H,m,
6.5 - 8.0 (11 H, m, -CH=CH- and aromatic protons) Example 85 4'-(p-Diphenylmethyloxycarbonyl)ethenylphenyl 1 -amidino-4-piperidinepropionate hydrochloride: 9.9 g of p-coumaric acid diphenylmethyl ester prepared from p-coumaric acid and diphenyldiazomethane was dissolved in 70 mt of dry pyridine.To the solution were added 6.4 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 5.6 g of N,N-dicyclohexylcarboniimide, and the resulting mixture was stirred for 3 days at room temperature and overnight at 45"C. Thereafter, 1.4 g of N,N-dicyclohexylcarbodiimide was added to the reaction mixture, and the mixture was stirred overnight at 45"C. After cooling, the crystals separated by filtration were washed with cold pyridine several times, then with ethyl acetate and finally with ether and then air-dried at room temperature. The crystals were stirred in 100 mk of dichloromethane, and any insoluble materials were removed by filtration. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals.The crystals were washed with ethyl acetate and then with ether and air-dried to obtain 6.4 g (yield: 43%) of 4'-(ss-diphenylmethyloxycarbonyl)-ethenylphenyl 1 -amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 135 to 138 C.
IR #KBrmax cm- : 1710,1760(C=O) NMR(CDCt3)6: 1.10-4.34(13H, m, piperidine,-(CH2)2-)
6.96(1 H, s, COOCH < ) 6.80 -7.70 (14H, m, aromatic protons)
Example 86 4'-(p-Carboxy)ethenylphenyl 1 -amidino-4-piperidine-propionate hydrochloride: 2.6 g of 4'-(ss-diphenylmethyloxycarbonyl)ethenylphenyl 1-amidino-4-piperidinepropionate hydrochloride was dissolved in 50 mf of formic acid, and the solution was stirred at 40 C for 2 hours. The solvent was removed under reduced pressure, and ether was added to the residue to give crystals.The crystals were washed several times with ether to obtain 1.7 g (yield: 94%) of 4'-(p-carboxy)ethenylphenyl 1 -amidino-4- piperidinepropionate hydrochloride as colorless crystals having a melting point of 249 to 250"C.
NMR(CD3OD)6: 1.00 - 4.34 (13H, m, piperidine, -(CH2)2-)
7.04 - 7.82 (4H, m, aromatic protons) Example 87 2'-Methoxy-4'-(p-diphenylmethoxycarbonyl)ethenylphenyl 1-amidinio-4-piperidinepropionate hydrochloride:: A mixture of 6 g of 1 -amidino-4-piperidinepropionate hydrochloride, 10 g of 4-hydroxy-3methoxycinnamic acid diphenylmethyl ester, 5.6 g of N,N'-dicyclohexylcarbodiimide and 50 ml of dry dimethylformamide was stirred at room temperature for 66 hours and at 60 C for another 1 hour. After removal of any insoluble materials by filtration, the solvent was removed to give an oily substance. The substance was treated with ethyl acetate and diethyl ether to give a solid. Water was added to the solid to deposit crystals. The crystals were washed with acetone and then with diethyl ether and recrystallized from methanol-diethyl ether to obtain 2.8 g (yield: 19.4%) of 2'-methoxy-4'-(ss-diphenylmethoxy- carbonyl)ethenylphenyl 1-amidino-4-piperidinepropionate hydrochloride as white powder having a melting pointof 118to 120"C.
IR #KBrmax cm-: 1760,1720(C=O) NMR(CD3OD)6: 0.9-4.06(13H,m,
3.61 (3H, -OCH3) 6.50 (1H,d,J=16 Hz, =CH-COO) 6.75(1 H, s, COOCH c) 6.94 - 7.30 (13H, m, aromatic protons) 7.54(1H,d,J=16Hz,-CH=) Example 88 4'-(p-Hydroxycarbonylethenyl)-2'-methoxyphenyl 1-amidino-4-piperidinepropionate hydrochloride: A solution of 1.6 g of 2'-methoxy-4'-(p-diphenyl-methoxycarbonyl)ethylphenyl 1-amidino-4piperidinepropionate hydrochloride and 30 mk of formic acid was stirred at 50"C for 1 hour.After concentration and cooling of the reaction mixture, a sufficient amount of diethyl ether was added to the residue. The mixture was allowed to stand overnight in cold conditions to give crystals. The crystals were washed with diethyl ether and air-dried to obtain 1.1 g of 4'-(P-hydroxycarbonylethenyl)-2'-methoxyphenyl 1 -amidino-4-piperidinepropionate hydrochloride as white powder having a melting point of 198 to 200aC.
lRvKSr cm-: 1740,1720 (C=O) NMR(CF3COOH)â: 1.00 - 4.10 (13H, m,
3.81(3H,s,-OCH3) 6.47 (1 H, d, J=16 Hz, =CHCOO) 7.78 (1H, d,J=16 -CH=) 8.15 - 8.50 (3H, m, aromatic protons) Example 89 4'-Allyl-2'-methoxyphenyl 1-amidino-4-piperidine-propionate hydrochloride: A mixture of 2.0 g of 1 -amidino-4-piperidinepropionic acid hydrochloride and 1.4 g of eugenol was dissolved in 30 mt of dry pyridine. To the solution was added 1.75 g of N,N'-dicyclohexylcarbodiimide, and the resulting mixture was stirred at room temperature for 5 days.Subsequently, 1.0 g of N,N'dicyclohexylcarbodiimide was added to the reaction mixture, and the resulting mixture was stirred overnight at 40"C. After removal of any insoluble materials by filtration, the filtrate was concentrated under reduced pressure. 50 mC of water was added to the residue, and the solution was allowed to stand for 2 days to give crystals. The crystals were washed with a small amount of water and then with ether and dried to obtain 1.35 g (yield: 42%) of 4'-allyl-2'-methoxyphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 83 to 86"C.
IR v cm NMR(CDCC3):
3.80 (3H, s, -O-CH3) 4.92 - 4.24 (2H, m, -CH2-CH=CH2 5.72 - 6.16 (1H, m, -CH2-CH=CH2) 6.64 - 7.04 (3H, m, aromatic protons) Example 90 1-Amidino-3-piperidinecarboxylic acid hydrochloride: 22 g of s-methylisothiourea 1/2 sulfuric acid was added with ice-cooling to a solution of 6.5 g of sodium hydroxide in 120 mk of water. To the mixture was added 20 g of nipecotic acid, and the resulting mixture was stirred at room temperature for 40 hours. The reaction mixture was filtered to give crystals. The crystals were washed in turn with cold water, acetone and ether.Thereafter, the crystals were dissolved in 110 me of 1 N hydrochloride, and the resulting solution was stirred at room temperature for 45 minutes. After removal of any insoluble materials by filtration, the filtrate was concentrated under reduced pressure to give white powder, and the powder was dissolved in methanol. Ether was added to the solution to give crystals which were then washed with ether to obtain 10 g of 1 -amidino-3-piperidinecarboxylic acid hydrochloride as white powder having a melting point of 234 to 236"C.
IR yKB' cm-' . 1710 (C=O) NMR(CD3OD)6: 1.40 - 3.80 (9H, m, piperidine protons) Example 91 Phenyl 1-amidino-3-piperidinecarboxylate hydrochloride: A mixture of 3 g of 1-amidino-3-piperidinecarboxylic acid hydrochloride, 1.4 g of phenol, 3 g of dicyclohexycarbodiimide and 40 mt of dry pyridine was stirred at room temperature for 2 days. After removal of any insoluble materials, the solvent was removed under reduced pressure to give a light yellow oil. The oil was washed twice with ethyl acetate to give white powder. The powder was washed with dry ether and dried under reduced pressure to obtain 3 g of phenyl 1-amidino-3-piperidinecarboxylate hydrochloride as hygroscopic white powder having a melting point of 54 to 60 C.
lRvmKsrx cm1 : 1750 (C=O) NMR(CD3OD)â: : 1.40 - 4.00 (9H, m, piperidine protons) 6.80 - 7.40 (5H, m, aromatic protons) Example 92 4'-Methoxyphenyl 1-amidino-3-piperidinecarboxylate hydrochloride: A mixture of 2 g of 1 -amidino-3-piperidinecarboxylic acid hydrochloride, 1.2 g of p-methoxyphenol, 2 g of dicyclo-hexylcarbodiimide and 30 mt of dry pyridine was stirred at room temperature for 2 days. After removal of any insoluble materials, the solvent was removed under reduced pressure to give an oily substance. The substance was washed with ice-cooling with ethyl acetate to give a solid substance. The solid was dissolved in methanol, and any insoluble materials were removed by filtration.Ether was added to the solution, and the resulting mixture was allowed to stand overnight in cold conditions. The crystals obtained were washed with ether and then dried to obtain 2.5 g (yield: 83%) of 4'-methoxyphenyl 1-amidino-3piperidinecarboxylate hydrochloride as light orange powder having a melting point of 140 to 143 C.
IR yKB' cm-l : 1740 (C=O) max NMR(CD3OD)â: : 1.50 - 4.00 (9H, m, piperidine protons) 3.70 (3H, s, OCH3) 6.50 - 7.00 (4H, m, aromatic protons) Example 93 4'-Methylphenyl 1 -am idino-3-piperidinecarboxylate hydrochloride: A mixture of 3 g of 1 -amidino-3-piperidinecarboxylic acid, 5.6 g of bis-(p-methylphenyl)sulfite, 15 mt of dry dimethylformamide and 5 mt of dry pyridine was stirred at room temperature for 2.5 hours. The solvent was removed under reduced pressure.The residue was washed with ethyl acetate and then with ether several times and dried under reduced pressure to obtain 3.2 g (yield: 74%) of 4'-methylphenyl 1-amidino-3-piperidinecarboxylate hydrochloride as hygroscopic pale orange powder having a melting point of 103 to 110 C. The powder was further washed with ether to give powder having a melting point of 138 to 140 C.
I R Vmax cm 1 1760 (C=O) NMR(CD3OD)a: 1.50 - 4.00 (9H, m, piperidine protons) 2.32 (3H, s, CH3) 6.90 - 7.40 (4H, aromatic protons) Example 94 4'-Chlorophenyl 1-amidino-3-piperidinecarboxylate hydrochloride: The same procedure as in Example 93 was followed using 3 g of 1-amidino-3-piperidinecarboxylic acid hydrochloride, 6.6 g of bis-(p-chlorophenyl)sulfite, 15 me of dry dimethylformamide and 5 me of dry pyridine, thereby obtaining 2.9 g (yield: 64%) of 4'-chlorophenyl 1-amidino-3-piperidine-carboxylate hydrochloride as light orange powder having a melting point of 160 to 163 C.
IRVKmSax cm : 1760 (C=O) max NMR(CD3OD)â: 1.60-4.00 (9H, m, piperidine protons) 7.08 - 7.50 (4H, m, aromatic protons) Example 95 2',4'-Dichlorophenyl 1-amidino-3-piperidinecarboxylate hydrochloride: The same procedure as in Example 93 was followed using 3.1 g of 1 -amidino-3-piperidinecarboxylic acid hydrochloride, 8.4 g of bis-(2,4-dichlorophenyl)sulfite, 1 5mC of dry dimethylformamide and 5 mC of dry pyridine, thereby obtaining 1.8 g (yield: 34%) of 2', 4'-dichlorophenyl 1-amidino-3-piperidinecarboxylate hydrochloride as white powder having a melting point of 164 to 1 66"C.
I R vm x cm : 1760 (CO) NMR(CD3OD)â: 1.50 - 4.00 (9H, m, piperidine protons) 7.20 - 7.00 (3H, m, aromatic protons) Example 96 4'-t-Butylphenyl 1-amidino-3-piperidinecarboxylate hydrochloride: The same procedure as in Example 93 was followed using 1 g of 1-amidino-3-piperidinecarboxylic acid hydrochloride, 2 g of bis-(p-t-butylphenyl)sulfite, 5 m4 of dry dimethyl-formamide and 1.5 mC of dry pyridine, thereby obtaining 0.9 g (yield: 56%) of 4'-t-butylphenyl 1-amidino-3-piperidinecarboxylate hydrochloride as white powder having a melting point of 178 to 182"C.
IRVKBr cm1 : 1750 (C=O) max NMR(CD3OD)â: : 1.34 (9H, s, C(CH3)3) 1.60 - 4.00 (9H, m, piperidine protons) 6.90 - 7.50 (4H, m, aromatic protons)

Claims (7)

1. A compound of the following formula or a pharmaceutically acceptable salt thereof,
wherein R represents a hydrogen atom, a naphthyl, indanyl, tetrahydronaphthyl or pyridyl group, or a phenyl group which may have 1 to 3 substitutents selected from halogen atoms, and alkyl, alkenyl, alkoxy, alkanoyl, cyano, formyl, trifluoromethyl, phenyl, phenylalkyl, alkanyl-amino, aminosulfonyl, carboxyl, alkoxycarbonyl, benzyl-oxycarbonyl, benzoylvi nyl, phenylvinylcarbonyl, carboxyvinyl, and diphenylmethyloxycarbonylvinyl groups, A represents an oxygen or sulfur atom, and n represents zero or an integer of 1 to 3, provided that when n is zero, R must not a hydrogen atom.
2. A compound of the following formula or a pharmaceutically acceptable salt thereof,
wherein R represents a hydrogen atom, a naphthyl, indanyl, tetrahydronaphthyl or pyridyl group, or a phenyl group which may have 1 to 3 substitutents selected from halogen atoms, and alkyl, alkenyl, alkoxy, alkanoyl, cyano formyl, trifluoromethyl, phenyl, phenylalkyl, alkanoyl-amino, aminosulfonyl, carboxyl, alkoxycarbonyl, benzyloxycarbonyl, benzoylvinyl, phenylvinylcarbonyl, carboxyvinyl, and diphenylmethyloxycarbonylvinyl groups, A represents an oxygen or sulfur atom, and n represents zero or an integer of 1 to 3, provided that when n is zero, R must not be a hydrogen atom.
3. A compound of the following formula or a pharmaceutically acceptable salt thereof,
wherein R represents a naphthyl, indanyl, tetrahydronaphthyl or pyridyl group, or a phenyl group which may have 1 to 3 substituents selected from halogen atoms, and alkyl, alkenyl, alkoxy, alkanoyl, cyano, formyl, trifluoromethyl, phenyl, phenylalkyl, alkanoylamino, aminosulfonyl, carboxyl, alkoxycarbonyl, benzyloxycarbonyl, benzoylvinyl, phenylvinylcarboxyl, carboxyvinyl, and diphenylmethyl-oxycarbonylvinyl groups.
4. A compound as claimed in Claim 1 substantially as described with reference to any of the foregoing Examples.
5. A process for producing a compound of the formula.
wherein m represents an integer of 1 to 3, or an acid salt thereof, which comprises reacting a compound of the formula,
wherein m is as defined above, with an alkyl-isourea or alkyl-isothiourea, or a salt thereof.
6. A process for producing a compound of the following formula or a pharmaceutically acceptable salt thereof,
wherein R' represents a naphthyl, indanyl, tetrahydronaphthyl or pyridyl group, or a phenyl group which may have 1 to 3 substituents selected from halogen atoms, and alkyl, alkenyl, alkoxy, alkanoyl, cyano, formyl, trifluoromethyl, phenyl, phenylalkyl, alkanoylamino, aminosulfonyl, carboxyl, alkoxycarbonyl, benzyloxycarbonyl, benzoylvinyl, phenylvinylcarbonyl, carboxyvinyl, and diphenyl methyl-oxycarbonylvinyl groups, A represents an oxygen or sulfur atom, and n represents zero or an integer of 1 to 3, which comorises reactino a comnound of the formula.
wherein n represents zero or an integer of 1 to 3, or a reactive derivative thereof with a compound of the formula, R"-A-H wherein R" represents a naphthyl, indanyl, tetrahydronaphthyl or pyridyl group, or a phenyl group which may have 1 to 3 substituents selected from the group consisting of halogen atoms, and alkyl, alkenyl, alkoxy, alkanoyl, cyano, formyl, trifluoromethyl, phenyl, phenylalkyl, alkanoylamino, aminosulfonyl, alkoxycarbonyl, benzyloxycarbonyl, benzoylvinyl, phenylvinylcarbonyl, and diphenylmethyloxycarbonylvinyl groups, and A represents an oxygen or sulfur atom, or a sulfite derivative thereof, and where R' is required to be a phenyl group substituted by 1 to 3 carboxyl orcarboxyvinyl groups, producing these groups by hydrogenation of the compounds containing corresponding benzyloxycarbonyl or diphenylmethyloxycarbonyl groups with catalytically activated hydrogen.
7. A process for producing a compound as claimed in Claim 1 substantially as described with reference to any of the foregoing Examples.
GB08215069A 1981-05-25 1982-05-24 Novel amidinopiperidine derivatives and processes for producing them Expired GB2101125B (en)

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JP7814381A JPS57193456A (en) 1981-05-25 1981-05-25 Novel amidinopiperidine derivative and its preparation
JP56078142A JPS57193457A (en) 1981-05-25 1981-05-25 Amidinopiperidine derivative and its preparation

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