JPS5913771A - 3-piperidino-substituted propiophenone derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (X is halogen; R1 is H, CH3, or C2H5; R2 is 1-4C alkoxy) and its acid addition salt. EXAMPLE:5'-Chloro-2'-methoxy-3-piperidinopropiophenone hydrochloride. USE:A remedy for spastic obdormition. PROCESS:A compound shown by the formula II is reacted with a formaldehyde and piperidine shown by the formula III or its salt preferably in a solvent such as ethyl acetate, etc. preferably at the reflux temperature of the solvent to give a compound shown by the formula I . Piperidine is usually used as a salt of mineral acid such as hydrochloric acid, hydrobromic acid, etc., but free piperidine can be used if the mineral acid is added to a reaction system to acidify it sufficiently.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to phenone derivatives and their pharmacologically acceptable acid salts.

Further K flYL. <In other words, the present invention is based on the general formula (1)
A novel 3- The present invention relates to piperinono-substituted globiof-non derivatives and pharmacologically acceptable acid addition salts thereof.

In the general formula (1) of the present invention, the carbon represented by R2 vL! ．．
Examples of the lower Alfkyne groups of 1 to 4 include methoxy, ethoxy, broboxy, and isopropoxy.

Examples include butoxy and isobutoquino groups, and examples of the halogen atom represented by X include 7 atoms, chlorine, breath, and atom.

If desired, the compound represented by the general formula (1) of the present invention can be converted into a pharmacologically acceptable acid addition salt, or the base can be liberated from the generated acid addition salt. You can also do that.

Examples of the pharmacologically acceptable phosphoric acid addition salts of the compound represented by the general formula (1) of the present invention include hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid mineral salts such as, or acetic acid.

Maleic acid, fumaric acid, citric acid, nchoic acid.

Examples include organic acid salts such as tartaric acid.

The novel 3-piperidino-substituted brobimephenone derivative of the present invention represented by the general formula (+) has the following general formula (m×12 (wherein, X, R, l and R2 represent the same meanings as above). It is produced by reacting a keto compound represented by the following with a polyaldehyde in a solvent and a piperidine represented by the formula (1) or a salt thereof by a method known per se (Mannich reaction).

Examples of the formaldehyde used include formaldehyde, and its linear and interlocking cyclic polymers, such as paraformaldehyde and trioquine.

In addition, piperidine is usually used in the presence of a mineral acid such as hydrochloric acid, hydrobromic acid, or nitric acid, but when using free piperidine, add enough mineral acid to make the reaction system sufficiently acidic. It can be implemented by

The reaction equivalent ratio can be selected as appropriate, but in particular, because it is necessary to eliminate residual piperinone in the post-reaction treatment, 1 equivalent of piperidine represented by the above formula (1) is compared with 1 equivalent of the piperidine represented by the above formula (1). At least 1 to 1 to 1, preferably 2 equivalents of the indicated keto compound are reacted with at least 1 equivalent, preferably 3 equivalents, of formaldehyde.

Examples of solvents used in the reaction include alcohols such as methanol, kudokunol, puwapanol, and impropatol, and nitromethane.

Nitroalkane solvents such as nitromethane, methyl acetate,
Examples include lower fatty acid lower alkyl ester solvents such as ethyl acetate and ethyl propimenate, and it is particularly preferable to use lower fatty acid lower alkyl nisful solvents.

Reaction I-1 The reaction is carried out in a room temperature or under a high flow rate, particularly under reflux humidity of the solvent used.

The novel 3-piperidi/substituted propyl A fluorinone derivative represented by the general formula (1) produced in this way and its pharmacologically acceptable salts have excellent anti-inflammatory properties. It has mesophasic muscle relaxing effects such as tremoline and anti-nicotinic effects, making it extremely useful as a therapeutic agent for spastic paralysis.

Note that the compound represented by the general formula (I), which is the starting material of the present invention, is described in, for example, the Journal of the India/Kumical Sorieti.
rl, l+r+1+-old IIn(!br++n1Cn1
8nrir+1. y), 17.65 (+9
40), 29,4 19 (+952), 55.50
It is a known substance described in (+978) etc.
29, 419 < 1952).

(In the formula, x, rtl and R2 have the same meanings as described above.) The present invention will be explained below with reference to Examples.

Example 1 5'-ri o t+ -2'-methoxy-3-piperidib 11 bial 7ff/n 4 hydrochloride 5'--ri n n -2'-meth↑diacet 7 manone 6
101 acid-resistant ethyl ethyl alcohol] - 60 #l solution, Bihelicine 1.40 #7, ? /l-
j person 1, ! i (1//) was added to the mixture. Next, the mixture was stirred, hydrogen chloride gas was introduced to make it acidic, and the mixture was heated for 25 hours. The aqueous layer is extracted with alkaline f/I', !: none, acetic acid ethyl ester using a lithium hydroxide aqueous solution.The ethyl acetate Nisder layer is washed with water,
dehydration.

The solvent is distilled off, and ethanol and constant hydrochloric acid are added to the resulting residue. The solvent was distilled off, and ethyl acetate was added to the resulting residue to precipitate crystals 45o2. IIru. Recrystallization from methyl ethyl ketone yields colorless I with a melting point of 164-165°.
Obtain crystals.

No e elementary analysis value (!1yJ120c11'1F)2
4fR,! 1 theoretical value <:, 56.61 ;ll,
6.65;N, 4.40Experiment &(C,5654:IT
, 6.78 IN, 4.58 Example 2 4'-chloro-27-medogine-3-piperidi/propiophenone C hydrochloride 4'-chloro-2'-notoquinoacetof.) 7600 g
1. piperidine to 60 m/solution of acid-resistant ethyl ester.
Add all 40&h and 150g of Barahorian altehyde.

Next, the mixture was cooled and stirred, chloride water gas was introduced to make it acidic, and the mixture was heated and rubbed with In+ for 1 hour. After the reaction, the precipitated crystals are converted to f'+
(I') crystallizes, melting point 169-170°
Colorless Φl-shaped product 393a (given).

Original zero analysis value (!151120(-1tV)24TCI
Ri M WI (!, 56.61 lII, 6.65
iN, 4.40 Experimental value C, 56, 47; II, 6
．． 79IN, 487 Example 3 5'-Tarolow 22-methoxy-2-methyl-3-piperidinopropioften hydrochloride 5'-chloro-22-
Add 40 esters of acetic acid of 440 acetic acid to the solution, and add 0.9 fi of 1 to 440 acetic acid! ? and parabomaldehyde 11,0 OR. l
Then, cool the mixture with stirring, introduce chloride water, and heat for 1.2.5 hours with a flow of 1-λ. Hydrochloric acid solution after reaction? Add life, shake, and remove the water layer for 111 minutes! 'if
Ru. The aqueous layer is extracted with sodium hydroxide and ethyl acetate. The acetic acid nibble ester layer was washed with water and dehydrated. The solvent was distilled off, and ethanol monohydrochloric acid was added to the resulting residue. ffg guy is like a seedling, ? Add the remaining tυko^1 acid niger ester and collect the precipitated crystals. The f1 fraction was recrystallized from ethanol to give colorless plate crystals with a melting point of 181-182°2. +9, +7? ! JZ].

J'l', ? A analysis ii? + (!1
6T122(:IN)24+(jl ・9r12(1 theory i11I (・, F17.06;I
I, ? , 0 3 ; N, 4.16 experimental value
(!, fi6.94; II, 7.+9; N,
4. B:1 Example 4-Chloro-2-methquine-2-methyl-3-biveridinopropyl 4-phthalocyanate ii acid 4'-Rio Rho 2
To 5 all of acetic acid ethyl ester/solution of metquin propylene chloride 15001, add piperidine 1302 and varaporno aldehyde 1' 1.401 t. 7
k I"C, cold J: (IN, PP F, I'-i
Hydrogen gas was introduced to make the mixture acidic, and the mixture was refluxed for 4 hours. Harahorno, aldehyde in the furnace 1. OOj? Add f, add 1 hour! Flow through JV, l+, and then add aqueous hydrochloric acid solution to separate the aqueous layer. The aqueous layer is made alkali with potassium carbonate and extracted with a needle mill. Needle layer i-1+ fA, FIiA water.The solvent was distilled off, and the resulting residue was purified using Calano Chromatograph-2.
250 g of treated L, a pale orange liquid, was obtained using E (silica gel, chloroporin). ? ! Ethanol and constant hydrochloric acid are added to the distilled liquid, and after distilling off the solvent, ethyl acetate is added to give precipitated crystals of 1.47β.

Recrystallized from alcohol-ether, melting point 148-1
A colorless @1-state crystal with an angle of 49° is obtained.

Ordinary analysis value 016H22(]IV12・rl(,!1
Theoretical value (U, 57.84; II, 6.98; N
, 4.22'noll/p]tIC,57,69i1
1.7.12iN, 4.21 Patent No. 11'1 Applicant: Hokuriku Pharmaceutical Co., Ltd. Procedural Rectification (Voluntary) March 27, 1980 Commissioner of the Patent Office Kazuo Wakasugi 1 Case Description Showa ff] 1957 Patent Item No. 1228
No. 37 No. 2 Title of the invention 3-H〈Rizino-substituted propyl A ph-non derivative 3 Relationship with the case of the person making the amendment Patent Issuer Office 1-rFI3-14, Tateyo-cho, Katsuyama City, Fukui Prefecture
4 Date of amendment order Initial 5 Number of inventions to be increased by amendment 6. Subject of amendment 7. Contents of amendment (1) The statement "centrality of action, etc." in the first line on page 6 of the specification was changed to 1. Antispasmodic effects such as effects, and muscle relaxation, 47@i anti-r
``Ni'' is corrected to ``central effects such as inhibitory effects''.

Contents of the amendments made on Akebono 7 of ``Detailed Explanation of the Invention in +I M 1'' as attached.

Claims (1)

[Scope of Claims] 1, -- General formula (wherein X represents a halogen atom, R1 represents an I atom, a methyl group or an ethyl group,
5: Represents a lower alkali having an IC number of 1 to 4. ) A 3-piperidino-purchased flopiof J-non derivative represented by the following formula, and its pharmacologically acceptable salt. 2- General formula (wherein, X represents a halogen atom, R1 is water T,
Characteristic R' represented by methyl group or ethyl A [representing 1°)
rClaim No. +rc”.