WO1983002113A1 - Propenylamine derivatives and drug containing same - Google Patents

Abstract

Propenylamine derivatives represented by the following general formula: $ (8,) $ AD where R1 and R2 may be the same or different and each represent hydrogen, an alkyl, an alkenyl, a cycloalkyl, an aryl or an aralkyl or, taken together , R1 and R2 represent a hetero ring with the adjacent nitrogen atom, R3 represents hydrogen, a halogen, an alkyl or alkoxy, A and B can be identical or different and each represent a hydrogen atom or an aryl , Z represents oxygen or a sulfur atom, q represents an alkylene or a group represented by - (CH2) n X1- (CH2) m- (where X1 represents an oxygen atom or a sulfur atom, n represents an integer between 1 and 3, and m represents an integer between 2 and 4), R4 represents H, $ (4,) $ (where R5 represents H, an alkyl, an alkenyl, an alkynyl, an alkoxy alkyl, a cycloalkyl, aryl or aralkyl, and E represents oxygen or a sulfur atom, = NR6 (where R6 represents H, cyano, nitro, alkyl, aryl, alkylsulfonyl or aryl sulfonyl) or = CHR7 (where R7 represents nitro, alkyl sulfonyl or aryl sulfonyl) or a group represented by the following formula: $ (8,) $ (where X2 represents an oxygen atom or a sulfur atom, Y represents an aryl or a pyridyl optionally substituted by 1 to 5 lower alkyl or lower alkoxy substituents in arbitrary positions, R8 represents H or an alkyl, and p represents 0 or an integer from 1 to 5), the aryl and the aralkyl being optionally substituted in an arbitrary position of the aromatic nucleus by at least one substituent selected between a halogen, an alkyl, an alkoxy, a trifluoromethyl, and a methylene dioxy BD, as well as their pharmaceutically acceptable acid addition salts. These compounds are useful as medicaments for the digestive system, medicaments for the circulatory organs, analgesics, anti-inflammatory agents, or intermediates for their synthesis.

Description

 Clear oath

Technical Field of the Invention and Disclosure of the Invention The present invention relates to a general formula useful as a pharmaceutical or a synthetic intermediate thereof.

 The brominated amine derivative represented by A or a pharmaceutically acceptable acid addition salt thereof and a drug containing the same

In the above formula, β ¹ and R ² are the same or different and represent a hydrogen-alkyl, an alkyl, a cycloazole, an aryl or an alkyl, R is hydrogen, nitrogen alkyl or alkoxy, and A and B are the same or different. Represents hydrogen, alkyl or aryl, Z represents an oxygen atom or a sulfur atom, and Q represents alkylene or the formula (CH 2) _n X ¹ (CH ₂ ) _m A group (where X ¹ is an oxygen atom or a sulfur atom, π is a ^ number of 0 or 13, m is _ff , an integer of 2 to 4), R * is hydrogen, formula _, _iHR A group represented by 5 [where β ^δ is hydrogen, alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, aryl Rule The other is the § La Le key Lumpur: Β is ¾ atom, Sulfur atom, group represented by the formula- ⁶ (where B ⁶ is hydrogen, cyano, nitro, azolekyl, aryl, alkyl sulfonyl) or represents a § Li one ls e le e d Le) or the formula -. in group (here the at G HR ⁷ is I Table, R ⁷ is two collected by filtration, 5 a Le key ls e le e d Indicates a file or file.

io で表わされる基 （ ここで、 X ²は酸素原子又は硫黄原子を 、 Yはァ リ ールまたは任意の位置が 1 〜 5 倔の低級ァ ル キ ル も し く は低級ア ル コ キ シで箧換さ れ て い て も よ い ピ リ ジ ルを、 B ⁸ は水素またはアルキルを、 p は 0 ま たは 1 〜 5 の整数を示す。 ） を示す。 . :). Or equation _χ 2

a group represented by io (where X ² represents an oxygen atom or a sulfur atom, Y represents aryl or lower alkyl or lower alkoxy having any position of 1 to 5 tones) Represents a pyridine which may be replaced by B, B ⁸ represents hydrogen or alkyl, and p represents 0 or an integer of 1 to 5).

is In the above definition, an aryl and an arylalkyl may be a nitrogen, an alkyl, an alkoxy, a trifluoride at any position on the aromatic nucleus. It may be substituted by at least one substituent which is encountered with the methyl and methyl oxy groups.

 20 In the present specification, alkyl refers to a linear or branched linear group having 1 to 8 strontium atoms, for example, methyl, ethyl, propyl, and a. So-propyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and octyl.Alkenyl is a carbon atom containing 2 carbon atoms. Linear or minute with ~ 8 values

26 Since it is a branch, for example,

O PI

/ IPO 8

 These are aryl, butenyl, and hexenyl.Alkynyl has 2 to 8 carbon atoms, for example, ethynyl, pu / rugi. , 1-methyl-2-provinyl, alkoxy 'is a straight or branched chain having 1 to 8 carbon atoms, for example, methoxy. , Ethoxy, pro-box, iso-pro-box, buttocks, pent-ro-ki, hex-ro-xi, ok-ro-ki, A cycloalkyl is one having 3 to 7 carbon atoms, such as cyclopropyl, cyclopenticole, and cyclohexyl. An aryl is phenyl, naphthyl, etc., an aryl is benzyl, phenyl, etc., and an alkylene is carbon number. 1 5 pieces, for example, methylene, ethylene, trimethylene, propylene, tetramethylene, 2 — methyltrimethylene And pentamethylene. Halogen is chlorine, bromine, fluorine, etc. The lower alkyl and lower alkoxy are the above-mentioned alkyl and alkoxy, respectively. Refers to those of ~ 4.

β ¹ your good beauty R ² represents the condensation was not good even though aliphatic heterocyclic of instantaneous Sessu that nitrogen atom and 5 to 1 0-membered ring is a heterocyclic ring that be formed to also be Further, the ring may contain an oxygen atom, a sulfur atom, or a nitrogen atom, or may have one double bond. Examples of these include pyrrolidine, pyridyne, hexamethylenimine, morpholin, thiomolholin, and fourth place. Lekyl-alkenyl, f OMPI ヽ Piperazine, tetrahydropyridin, tetraura substituted with aryle, arylene, arylenezine (cinnamil, etc.) Examples include hydroazepines.

 The present invention includes all tautomers and geometric isomers of the compound of the general formula (1).

 The compound of the general formula (1) of the present invention is produced, for example, by the following method.

Manufacturing method 1

 This method is applied when is hydrogen in the general formula α).

 ① General formula

(I)

 B (In the formula, each symbol is the same as defined above.)

Is converted to a metal salt such as lithium salt in a solvent such as tetrahydrofuran or ethyl, and a compound represented by the general formula

L-Q- 0Π)

 (In the formula, Q is as defined above, and L is halogen, methylyloxynoxy, trilithoxylinoxy, or acyloxy. The active residues are shown.)

Reacting a compound of the formula

O PI

(In the formula, each symbol is as defined above.)

 Is decomposed by hydrazine hydrate or the like, or

 ② The one-step (B) compound of Jinwu salt and the general formula

 L one Q— L (V)

 (Wherein each symbol is as defined above)

Is reacted with the compound under cooling or at a temperature up to 1 δ 0, and the resulting general formula is obtained.

(In the formula, each symbol is as defined above.)

The compound of the formula (1) is reacted with an ammonium salt in a suitable solvent (water, alcohols, etc.) at room temperature or with heating, or is reacted with hexamethylene. A method of reacting with tramine and then hydrolyzing with acid.

 The compound of the general formula (II), which is a starting material, can be obtained by the following process.

Ko fe Α 1

 This is applied when A and B are both hydrogen in the general formula (D).

ΟΜΡΙ

 (In the formula, each symbol is as defined above.)

 ②

HOCH 9-compound (H)

(Wherein the symbols are as defined above.)

 Process formula 2

 This applies to the case where one of A and B is hydrogen and the other is alkyl or aryl in the general formula (Π).

 ① A force ί Alkyl or aryl,: 水 素 indicates hydrogen

OMPI (In the formula, A Ri der Ri through the title, and the other symbols are the the阆₀₎

® When A represents hydrogen and B represents alkyl or aryl: R ³

R ³

Dehydration f ⁴ !

(In the formula, B is as described above, and other symbols are as defined above.)

Manufacturing method 2

In this method, in general formula (I), R ⁴ is hydrogen and Q is a group represented by the formula (CH ₂ pX ¹ (0H ₂ ) _m — (where X ¹ , m

 , n are as defined above. ) Is applied.

の化合物と 、 一般式 ① ー crotch type „3

And a compound of the general formula

L ² (OH ₂ ) _m NH ₂ m

(In formulas and formulas, ^one of L ¹ and L ² is a hydroxyl group, a thiol

The other is a reactive residue (halogen, methyl sulfonyloxy-triethyl sulfonyloxy, acyloxy)

OMPI W ^IP And other symbols are as defined above. ]

 Is reacted with a metal salt such as a sodium salt or a potassium salt in the presence of a dehydrating agent such as hydrochloric acid or sulfuric acid, or

δ ② General formula for m 2

 (Wherein each symbol is as defined above.)

Method for reacting compound 0 with ethyleneimine

—A starting material compound of the general formula δ¾, for example, a compound of n−1, L ¹ -hydroxyl group or a reactive residue, is obtained by combining the compound of the general formula (II) with η—butyl lithium -React with phenol-formaldehyde or vinegar-formalin, etc.

R]

(Wherein the symbols are as defined above.)

By reducing the compound of ©, it is converted into a 2-methylol form, and this is converted to a reactive active residue by halogenation or the like as necessary. Manufactured.

 Manufacturing method 3

 E

In this way the general formula (I), R * has the formula -GNKR ⁵ (this ⁵ this; E, R ⁵ is the a Ru synonymous der.) A group represented by

 OMPI

Picture wi Commonly used in some cases, general formula

 R

 R〗

 The compound of A B and the general formula

Β ^δ — W ² Oil

 A method of reacting a compound with.

In formulas (00) and (¾), ^one of W ¹ and W ² is amino, and the other is isocyanate, isochionat, or formula NiiC ^ (here in, P is a reactive residue (C b gain down, Al co key sheet, alkylene Ruchi O, etc.) and, V is the formula = NH ^beta or - at C HR ⁷ (here, R ^beta, R ⁷ is the And the group represented by). And the other symbols are as defined above.

 This reaction is carried out without a solvent, preferably in a solvent, at a temperature ranging from cooling to 200 ° C., under normal pressure or reduced pressure. Examples of the solvent include water, alcohols (eg, methanol, ethanol, isopro- nol), ethers (eg, ethanol). Ethyl ether, dioxane, tetrahydrofuran, etc.), hydrocarbons (hexane, benzene, toluene, etc.), keto Compounds (such as acetate and methyl ketone), amides (such as dimethylformamide, dimethylacetamide), Examples thereof include dimethyl alcohol sulfide, tertiary amines (eg, pyridin, trimethylamine), and a mixed solvent thereof. The reaction is

OMPI If necessary, a heavy metal salt such as silver nitrate or mercuric chloride can be used as a catalyst.

The general formula (XD of the raw material compounds钧, was example place is Lee Sochi. O '* Ana Todea Ru compound, the compound w ¹ is Ru § Mi Nodea, Ri by the conventional method, were example, if disulfide It is produced by reacting hydrogen and alkyl hydroxide, followed by reaction with ethyl chlorate, and W ¹ is represented by the formula -NHG <^ (where P, V is Ru as defined above der. compounds of groups I Table in), the compounds W ¹ is Ru Ah in Amino general formula

(Wherein P and V have the same meanings as described above), and in a suitable solvent at room temperature or under heating. Manufacturing method 4 ―

E-In this method, in the general formula (I), is a group represented by the formula — CNHB ⁵ (E and H ^U are as defined above), and Q is a group represented by the formula (GH ₂ S (0H ₂ ) _m — (where n and m have the same meanings as above.): Applied when the group is represented by the general formula

(In the formula, L ³ is a hydroxyl group or its reactive group (halogen, methyl sulfonyloxy, trisulfonyloxy) IX

 Etc.), and other symbols are as defined above. ) And the compound of formula

 E

HS (CH ₂ ) _m NH0NHR ⁶ (XV)

 (In the formula, each symbol is as defined above.)

 A method of reacting with a compound of the formula

This reaction is carried out in the presence of a dehydrating agent such as hydrochloric acid, sulfuric acid, or the like, or with an alkali metal salt of thiol (cxy) (such as sodium salt or potassium salt). It is done. The reaction in Do solvent will I mentioned production method 8, is from under cooling carried out in 2 0 0 ^e C until the temperature at the.

 Manufacturing method δ

In this method, in general formula (I),

(Where each symbol is the same as defined above for ₀ ) and Q is a group represented by the formula (CH ₂ ^ nX ¹ (CH ₂ ) _m — (where each symbol is This is the same as the above.) It is applied when the group is represented by

① General formula

 Compound of A B and general formula

O PI z w CH 2) pnY OT)

A method of reacting with a compound of the formula

In the above formulas 0M) and »), W ³ represents a case in which W * is a decone group such as nitroamino, halogen, lower alkylthio, benzylthio, etc. When W * is amino, a group represented by the formula —X ¹ (0H ₂ ) _m NH ₂ (where each symbol is as defined above) is represented by the formula -X ¹ (GH ₂ ) _m L * (where,

It represents a reactive residue such as melogen, methyl sulfoxyloxy, trisulfuroxyloxyloxy, etc., and other symbols are as defined above. In the case where is a group represented by the formula -ΝΗ (( ₂ (where each symbol is as defined above)), halogen, methylsulfur W ^{k represents} the reactive residues such as rox, tri-res, ho-n-re, and a-

-NH (CH ₂ ) _m L ⁶ (where; L ⁵ is halogen, methyl sul ijt dioxy, trilus krejoni oxy, aci oxy, etc. In the case of a group represented by), it represents a hydroxyl group or a thiol group, and other symbols are as defined above.

The reaction is solvent-free or favored by rather is carried out in a solvent and normal pressure or under reduced pressure in a range of temperatures up to under cooling or et 2 0 0 ^e C. Solvents include, for example, water, alcohol granules (eg, methanol, ethanol, isobronol).

OMPI

, Ί WIPO 18 Ethers (diethyl ether, dioxan, tetrahydrofuran, etc .; hydrogen hydrides (hexan, benzene, toxin) Ruthenes), ketones (aceton, methylethyl ^ ton, etc.), amides (dimethylformamide, dimethyl) Acetamide, etc.), dimethylsulphoxide, tertiary amine (pyridin, triethylamine, etc.), or. The reaction may be carried out, if necessary, in the presence of a dehydrating agent such as hydrochloric acid, sulfuric acid, hydrobromic acid, or a tertiary solvent such as pyridin or tritylamine. Proceeds in the presence of metal salts of aluminum or mineral such as sodium carbonate, sodium hydroxide, sodium hydroxide, sodium hydroxide, etc. To. ② over general formula _

(Wherein each symbol is as defined above.)

 0

K ⁹ OC

, GH— (CH ₂ ) _p Y (ΧΚ)

R ⁸ C

(Wherein, beta ⁹ is indicates alkyl le, pen di Le, E two relay, the other symbols are of the Ru synonymous der.) A method of reacting a compound of.

 The reaction is carried out, preferably in a solvent such as alcohols, in gold.

OMPI Done by heating in the presence of alcoholic acid. >>

Manufacturing method β

This method is based on the general formula (1) where R * is

 (Here, each symbol is as defined above.) This is used when Q is alkylene.

の化合物と一般式 ) _ΡΥGeneral formula n]

Compounds with the general formula) _[rho Upsilon

の化合物を反応させる方法。

Reacting the compound of

In the above formula OS) and (XXI), L ^E is L ⁷ are two filtrated A Mi Bruno, c b gain down, lower A Le key Le Ji Oh, with base down di Le Chi O of any leaving group When a certain amino acid is used, and if it is an amino, it is possible to use a gene, a methyl resin, a polyethylene resin, a tris j, a resin, an acyl. the O key sheet of any reactive residues, Q ¹ represents an a Le key les down, and the other symbols Ru as defined above der.

The reaction is performed in the same manner as in Production method 5-①. Manufacturing method 7

In this method, in the single-split type (1),

(Where each symbol is as defined above). The compound obtained by Production Methods 5 and 6 is used ubiquitously for the compound represented by the formula: Preferably, it is produced by reacting phosphorus pentasulfide with ^ benzene, toluene, dioxane, pyridin, dimethyl sulfoxide and the like under heating. Is performed.

 The compound represented by the general formula ω according to the present invention can be used as a free or acid addition salt or a hydrate as a medicament. Acceptable acid addition salts include hydrochloric, sulfuric, hydrobromic, phosphoric, formic, acetic, oxalic, fumaric, maleic, quinone, tartaric, Inorganic salts such as linoleic acid, mandelic acid, methansulphonic acid, and toluenesulphonic acid, and salts of organic acids.

The compound (1) of the present invention, a pharmaceutically acceptable acid addition salt thereof and a hydrate thereof can be used, for example, in mammals (eg, humans, rats, mice, mice, and mice). Has an inhibitory effect on gastric secretion, an antihypertensive effect, an anti-inflammatory effect, an analgesic effect, etc., for example, a gastrointestinal drug, a cardiovascular drug, an analgesic, an anti-inflammatory drug, or an intermediate between drugs. Useful as a body. For example, human static Mi emissions jB ₂ -遷択inhibits this receptor

OMPI As a result, gastric acid secretion inhibitors, anti-cancer drugs, and allergic disease drugs that use histamine as a medium reduce blood pressure or increase heart rate due to histamine. Useful as a drug that acts on the cardiovascular system to suppress.

Pharmacological experiment

 The effect of the compound of the present invention on histamine-induced gastric acid secretion was determined by the method of Gausch and Silt (Μ · Ν · Ghosh &

H.0. S ch h i e 1 d, B r! t .J .Pharmaco lgy, 13, 54.

 1958).

Male rats weighing about 200 to 25 Off were fasted for 20 hours and then anesthetized with urethane 1.5 fA ^ subcutaneously. Yone went. A polystyrene tube for inflow of gastric perfusate was inserted from the mouth to the cardia and fixed under the trachea. Open the abdomen to expose the stomach, make a small incision in the duodenum 1 £ »below the pyloric sphincter, insert a polystyrene tube for perfusate outflow into the stomach, fix the incision. Physiological saline heated to the combined _β 37 ^e C was perfused in the stomach at a rate of 0.7 lightning, and effluent was collected at 10-minute intervals. Histamine 1 ^ Zk9 was administered from the crotch vein at 1 o'clock to induce gastric acid secretion. The test compound was dissolved in physiological saline or diluted hydrochloric acid, and administered via the crotch vein 5 minutes before administration of histamine. I酵of perfusate using an automatic titrator was measured by titration to pH 7.0 with 5 X 10 one ^3N hydroxide Na Application Benefits © beam solution. A dose of the test compound was administered to 4 rats to reduce the rate of inhibition of gastric acid secretion.

Ο ΡΙ I asked.

Test compound:

 A: N-C2-[5-(3-methylamino-1-1 profile)-2-1-methylmethylthio] ethyl] 1-meter Chill 2 1 1 1 1-Ethylene diamine 32 Fumarate

 Β: Ν-C 2-C 5-(3-dimethylamino 11-pro-nyl)-12-furyl-methyl-methyl] 1) Chile 2 1 2 1 mouth 1 · 1-pentadiamine amine maleate

 0 · Ν — [2 — [5-(3 — Pyrrolidino 1-11 Prinyl) 1 2 — Chenyl methyl) ethyl) — Ν, メTitanium 1-toro 1- 1-ethanediamine succinate 12-hydrate

 D: Ν-C 2 — [.5 — (3 — (4 1 benzene-1 pi-radio) 1-1 porinoin] 1-1-methyl methane [Thio] ethyl] 1-methyl 2 nitro 1, 1-ethanediamine, 2 oxalic acid

Ε: 5 — (3 1 pyridyl methyl) 1 2 —! : 2-C 5 1 (3-pyrrolidine 11-pronyl) 1 2-chloromethylthio] ethylamino]-4 (1

Η) — pyrimidinone

Ϊ ¹ : 5-(3-pyridyl methyl) 1 2-[2-[5-1 (3-pyrrolidino ^1- pro-le)-2- Furyl methylthio] ethylamino] ー 4 (1H)

2-[2-1-4-Methyl 5-(3-Pyrrolidino 1-1-o-v)-1-2- ] 1-5 — (3 — pyridyl methyl) 1 4 (1H) 1 pyrimidinone

O PI Result

χο

S

0

Five

OMPI When the compound of the present invention is used as a medicament, it can be administered orally or parenterally, but in the case of oral, it is admixed with a pharmacologically acceptable carrier, excipient, and powder or tablet. It is used as a capsule, troche, troche, solution, capsule, and granule. For parenteral use, used as an aqueous solution or non-aqueous suspension, as an injection such as intravenous, intramuscular, or subcutaneous injection, or as a shaving or cream ointment . In the case of oral administration, preferably, each unit contains 1 to 20 active ingredients and is administered 2 to 4 times a day, and a daily dose of 50 to 1200 W is preferable. . Formulation example

2 tablets are prepared with the following composition: _β

 Compound of the present invention '25 .0 «5»

 Lactose 49.5 ^

 Contour 30.0

 Microcrystalline cellulose 1 Q. 0 ^

 Talk 5.0 «¾ *

 Magnesium stearate 0.5 0.5 «ί?

 1 2 0. 0

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. Example 1

(a) 2-(3 — 口 口 口 1 ー ー ー ニ ゾ) Dissolve 31.7 f in dimethylformamide 60 and At 54 ° C, add 54% aqueous dimethylamine solution at 7 ° C. Stir for 1 hour o Pour the reaction mixture into water, extract with ethyl acetate, wash with water, evaporate the solvent, and distill to the boiling point.

8 δ to 87 ^e C / 4 »» H g 2 — (3-dimethylamino 1-1-bromo) thiophene 2 S. 4 f is obtained ₀ (b) 2 — (3—Dimethylamino 1-prole) Thiophene 16.7 f is dissolved in anhydrous tetrahydrofuran 67 7 »? Hexane solution of n-butyllithium (15% W / W) 68 was added dropwise at 15 to 0'C in an air stream, and the mixture was stirred at room temperature for 2 hours. Add aldehyde 8.6 at 1.0 to 15'C and stir at room temperature for 1 hour. The reaction mixture was poured into ice water, extracted with a quenching medium, the solvent was distilled off, and the residual oil was removed from the mixture using a silica gel, silica gel, gross form: methanol Purification with -10-1: 1) yields 5-(3-dimethylamino-1-1-vinyl)-2-thiophene with a melting point of 77-79 ° C.一 ル

 (c) Dissolve 5 (3-dimethylamino 1 puronyl)-12 thiophenemetanol 27 in the c-mouth hole 18 5) ^, At room temperature, 3 to 7 ° C was added dropwise, and after stirring at room temperature for 1 hour, the mixture was concentrated to dryness, acetonitrile was added to the obtained crystals, suction-filtered, and dried. 2- — π-opening methyl 5 -— (8-dimethylamino-1,1-pronyl) hydrochloride of thiophene is obtained. Anhydrous ethanol 1

Dissolve metal sodium 4.4 in 20 »and add 9.5% ^ of cysteine hydrochloride to anhydrous ethanol 85 in a nitrogen stream. The solution was added dropwise at 0 ° C and stirred for 1.5 hours, and then 2-methyl α-methyl-5- (3—dimethylamino-1-ob ovyl) Add 10.5 of thiophene hydrochloride at -5 to 0 and stir at room temperature for 8 hours. The solvent is distilled off under reduced pressure, water is added, and the mixture is extracted with a black hole home, the α-hole home is washed with water, the solvent is distilled off under reduced pressure, and the residual oil is ethanol. In the case of hydrochloride, 2- (5-((8-dimethylamino-1-one-brodinyl) -12-chloromethyl) with a melting point of 163-166. [Rio] ethylamine hydrochloride to give 9.9 _β

 The following compounds can be obtained by the method described in Example 1 and the specification.

 @ 2-C 5-(8-dimethylamino-11-p-vinyl) 1-2-furylmethylthio] ethylamine, a pale brown oil.

 Nuclear magnetic resonance spectrum (3, ppm in deuterium π-holm): 5.98 to 6.28 (m, 4H), 3.69 (s, 2H), 3.04 (d, 2 H), 2.86 (t, 2 H), 2.66 (t, 2 »), 2.28 (s» 6 Η), 1.48 (s, 2 Β!, Disappeared in heavy water)

 Value (silica gel, black mouth home: methanol: 28% ammonia water: i = 45: 5: 2): 0.7

© 2-C 5 — (3 — pyrrolidino, 11-pronyl) 12 — chloromethylthio) ethylamine 2 oxalate, fused ^ 16 0 ~ 16 3 ° G (decomposition) ^! ^

 O PI

'' WIPO 28

© 2-[5-(8-piperidinone 11-pro-vinyl) 1-2-phenylmethylthio] ethylamine dihydrochloride, melting point 1888 ~ 1 9 1 ^e C '

 © 2-[5-(8-morpholino 1-pronil)-1 δ2-1 -methylmethylthio] ethylamine dihydrochloride, melting point 1 90-192. C

 @) 2 — [5-1 (8-1 (4-methylazine 1-piperazinyl) -1 1-loop α-phenyl) 1 2—Chenylmethylthio] ethyl Vanadium oxalate, melting point 174-178 ° C (decomposition)

© 2-[5-[3-(4 benzene-1 piperazine) 1-1 broth: le]-2-phenyl methyl thiol A Mi emission-2 Shi Yu c acid salt, mp ^{1 6 8 ~ 1 6 7 e} C ( decomposition)

 © 2-[5-(8-N-Nylon; N-Methyl-amino 1, program)-1-2-Cheninole Metchile] Min * 2 oxalate, melting point 1668-172. C (decomposition

 © 2-C 5 — (3 — Methyl Amino 1-1 Prinyl) 1-2-1-Methyl Amino Retio) ヱ Chilamine

 ◎ 2-[5-[3-(1,2,3,6-Tetrahydropyridine 1-11 yl) 1 1 1 1 1 1 10]] 1 2-divinyl (Methylthio) ethylamine

© 2-C 5 — (31-pyrrolidinous 11-pronyl) 1-2-furylmethylthio) ethylamine © 2-[5-(8-N-methyl: N-phenyl)-1-2-methylmethyl] ethyla Min

 ◎ 2-[5-(8-10)

 ) 1-2-CH2 METRYLUIO]

 © 4-[5-(3-bilolidinino 1-bronilyl)-1 2-phenyl] butylamine

 ◎ 3— [5— (8—Dimethylamine Minor 1 Browelle

 ) 1-2-CH 2 R 2) propyl amine

© 2-5-I 3 1 (41 m-black mouth ferrule-1 piperazinyl) 1-1 pro (<^ レ) 1-2 1-channel methyl)ヱ Chilean

Example 2

: (A) Dissolve sodium hydroxide 18.2 f in water 160 s, and add 8 —methyl 2 —thiophenaldehyde 6 7

 Dissolve in ethanol 20.0a and add it to the solution at 0 to 5 ° C and add acetoaldehyde 55 to water 8 8ι ^

The dissolved solution is dropped at 5 o'clock. After the dropwise addition, the mixture was stirred for 1 Toki閭0 to 5 ^e C, added酡酸to the reaction solution, and the p H 7. Add water, extract with ethyl acetate, wash the organic layer with saturated saline, dry over sodium sulfate, distill off the solvent under reduced pressure, and distill off the residual oil to give a boiling point of 115 to 125 °. 0 / 0.3 Hir's 3 (3-Methyl 1-2 Chenyl) 1-2-Pro?:?

 () 3 — (3 — Methyl 2 — Chenille) 1 2 — Pro

(OMPI- The reduction of nal 28.5 f with sodium borohydride in ethanol yields 8 — (8-methyl 2 — phenyl) 1 2 — Propeller 1 1 1 Allo get ₀

 Hf value (silica gel ♦ Cloth mouth hologram: Metanole = 9

 9: 1): 0.2

 (c) While stirring Ether 75 and Sanhao Phosphorus 13.2 f, stir 0. At 0, 8 1 (8-methyl 2-channel) 1 2-propene 1 -all 1 8.6, pyridin 2.7 f and ether Of the mixture is added dropwise. 0. Stir at C for 10 minutes, add water, separate the ether layer, and wash with water. Add 17.2 f of pyridine to the ether at 0 to δ ° C and stir at room temperature for 2 hours. The ether layer is washed with water, dried with sodium sulfate, shrinked, and calum chromatographed (silica gel, black mouth form: methanol = 10: 1). Purification yields 3-methyl-2- (8-viridinyl-11-prole) thiophene as a pale yellow oil.

 Hf value (silica gel) Chloroholm: Metanor-5: 1

 ): 0.3

 (d) 3 -methyl 2-(8-1 pyrrolidino 1-1 p-vinyl) Toffphen 10. δf is replaced with anhydrous tetrahydrofuran

6) In a stream of nitrogen, hexane solution of π-butyllithium (15% W / W) 3.9 »is dropped at“ 5 to 0. C ”for 2 hours. you攙拌. then added parametric e le arm a Lud arsenide de 1. 6 f in 5 ~ 1 0 ^e C, and stirred for 1 hour at room temperature, this Mi poured into ice water, click b Π e le Extract under reduced pressure. The solvent is distilled off, and the residual oil is purified by column chromatography (silica gel, black mouth hole: methanol-10: 1). Melting point is 94-96 when recrystallized from guinea pig. 4-methyl-5-1 (3—pyrrolidinol 1-brogel) 1-2—thiophene methanol is obtained.

 (e) 4-methyl-5- (3—pyrrolidino-1-pro

-1) Dissolve 9.1 ^ in π-piform 50 *, add dropwise thiol chloride 16-9 f at 0 • C, and allow to cool at room temperature. After stirring for 1 hour and concentrating to dryness, 2-chloromethane / —4-methyl-5— (3—pilogino 1-pro: le) Thiophene Gives the hydrochloride of

Dissolve 1.5 f of metallic sodium in 30 mi of anhydrous ethanol, and 3.2 f of cysteine hydrochloride in 80 ml of anhydrous ethanol in a nitrogen stream. dissolved even to the dropwise at 0 ^e C, 1. 5 hours攙拌, 2 - click o ₀ menu Chi les -4 chromatography menu Chi le -5 - (3 - pin b Li Gino -1-flop port Bae the two Le) Chio full e down hydrochloride 4 f - 5 ~ added at 0 ^e C, stirred at room temperature for 8 hours. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with a black hole solution. Water was removed, and the solvent was distilled off under reduced pressure to obtain a light yellow oily 2- [4-methyl-5 — (3 — pyrrolidino: I-propyl) 1-2 — chenyl methylthio] ethyl amine

 Nuclear magnetic resonance spectrum (3, pm in heavy chlorine): 6.5 6 (s, 1H), 6.55 (d, lH),

5.9 4 (m, l H) _t 3.7 8 (s _t 2H), 3.2 2 (d,

O PI . 2H), 2.82 (t, 2H), 2.64~2.44 (m, 6 Η), 2.18 (8, 8H) disappeared 1.92 (s _f 2H i heavy water) · 1.92~; L70 (m, 4Η)

 The following compounds are obtained by the method described in Example 2 and in the specification II.

 ◎ 2 — [4-Methyl 5-(8-pyrroligin 1-Pro-Pininole)] 1-2-Free Methyl Retino] Ethylene Amine, pale yellow oil object

 Nuclear magnetic resonance spectrum (3, ppm in deuterium port): 6.30 (d, IH) 6.0 & (m, 1H), 5.96 (s, 1H), 8.68 (s » 2H), 3.22 (d, 2H), 2.84 (t2Η), 2.7 δ to 2.15 (m, 6Η), 2.02 (s, 3Η), 1.95 to 1.56 (m, 6Η \ 2 disappears in heavy water)

 @ 2-[3-Methyl 5-(8-1 pillory resin)-2-CELL METHYL CHIO] Ethylamine, light Brown oil

 Nuclear magnetic resonance spectrum (3, ppm in deuterium port): 6.58 (s, 1H), 6.52 (d, 1H), 6.02 (m, IH), 3.78 (s , 2Η) 3.20 (d, 2Η), 2.84 (t, 2Η), 2.68 ^ -2.40 (m, 6Η), 2.13 (s, 3Η)

, 1.92〜1 ・ 64 (m, 6Η {2 Η disappeared in heavy water

◎ 2-[5-(3-dimethylamino 1-p-vinyl)-14-meth oxy 1-2-phenyl methyl thio] ethyl amide N

© 2 — [4-Bloom 5 — (8 — n ぺ ル 一 2 2 — Thiel-methyl thiol) ethylamine Example 8

 (a) 2-(11-phenyl-8-pi-oligo- 11-pronyl) thiophene 41.8 f with anhydrous tetrahydrofuran 2 0 0 «dissolved in hexane, and a hexane solution of η-butyllithium (15 ^ W / W) 1 19 in a nitrogen stream was added dropwise at -5 to 0, and at room temperature for 1 hour. Mix. Next, the values of valaaldehyde 4 and 9 are 10 to 15. Add with C and stir at room temperature for 1 hour. The reaction mixture was poured into water, extracted with chloroform, the solvent was distilled off, and the residual oil was removed from column chromato gel (silica gel, chromatophore: methanol). When purified as oxalate in ethanol, the oxalate in the ethanol has a melting point of 142 to 144 4, and has a melting point of 5— (11-phenyl-0.8—pyro).

• J ノ ノ 一 一 2 2 — 2 — 2 2 — —.

(b) 5-(1 Ferrule 8-Pi α Resin 1-Prole-1) 1-2- It was dissolved in beam 1 0 0 ml, one 5 ~:? 1 0 ^e C with dropwise 2 0 * chloride Chi O d Le, after 1 hour攙拌at room temperature, if you concentrated to dryness, 2 Qu b b Methyl 5 — (11-phenyl 3 — pyrrolidino-11-pronil) Thiophene hydrochloride is obtained.

Dissolve 7.6 f of metallic sodium in anhydrous ethanol 170 W, and add 16.6 f of cysteamine hydrochloride in anhydrous nitrogen in a nitrogen stream. What was dissolved in 50 a was added dropwise at 0 ° C. 1. After stirring for δ hours, 2-chloromethyl-5- (11-phenyl-8-pyrrolidino-11-pronil) the 2 6 f - 5 ~ 8 hours攞拌at room temperature was added at 0 ^e C. The solvent is distilled off under reduced pressure, water is added, and the mixture is extracted with a black hole home. The mouth layer layer was washed with water, and the solvent was distilled off under reduced pressure. The residual oil was converted into oxalate in methanol, and its melting point was 172-174 (decomposition). [5- (1-Phenyl-8-pyrrolidino-11-p-vinyl) -1-2-Polymethyl-methylthio] ethylamine, oxalate Power is obtained. .

 Example 4

 (a) 2—methyl 3— (2—cell) 1 2—pron 50 f dissolved in ethanol 800 ** and hydrogenated hydrogen sodium 3.7, stir the mixture for 1 hour, concentrate the reaction mixture, add water and water, extract the oil with ethyl acetate, wash with water, dry, distill off the solvent, and remove the residual oil into petroleum. Recrystallization from ether gives 2-methyl-8— (21-phenylene) -12-propene-11-ol with a melting point of 48-50. Can be

(b) 2-methyl 3-1 (2-channel)-1-2-prone-1-4-5 f and pyrimidine 26. Dissolve in chloroform 280 », and add 39 ml of titanium chloride under ice cooling, stir at room temperature for 1 hour, wash the reaction solution with water, dry and evaporate the solvent under reduced pressure. Dissolve the residual oil in dimethylformamide 80 «^ and add pyrrolidine 39.2 ^. 80

After stirring in the room for 2 hours, pour into ice water and extract with ethyl acetate. The extract is washed with water, dried, and distilled, yielding a boiling point of 108 to 105 * C / 0.1 JSg 2- (2-methyl-8-pyrrolidino) -Le) Chief fen s 5 is obtained. Thereafter, when treated in the same manner as in Example 8, the melting point of 207 to 209'C 2 — [5 — (2 — methyl 3 — bi-α- lyzino-1-1-vinylene) 1 2 — CH2 dimethyl methacrylate] _β to obtain ethylammonium oxalate

 The following compounds can be obtained from ltt by the methods described in Examples 8 and 4 and in the specification.

 © 2-[5-(2-Ferrule 3-Pyrrolidinone 1-α α-) 1 2-Chen Reme Chile] Chilamine 2 Oxalate, melting point 1776-: 179 (decomposition) © 2-[5-(8-dimethylamino-2-methyl 1

15 part B Bae d le) one 2 inch E two Le main Chi Le Chi O] E Chi le § Mi emission-2 Shi Yu c acid salt, mp ^{1 8 6~: 1 8 9 e} C ( decomposition) © 2 — [5-1 (3-methylamino-1 methyl, 11-propyl) 12-cell methylthio] ethyl-lamin-2 c acid salt, mp ^{1 7 5~ 1 7 7 e C} ( decomposition)

20 © 2 — [5-(3 — dimethylamino, 11-phenyl)

 1-Prodini-sol) 1-2-Chenylmethylthio] ethylamine * 2 oxalate, melting point 177-179. C (decomposition) © 2 — [5 (1 ferrule 3'—piperidino 11-pronil) 1-2, chenille meth]ァ

25 ン · 2 oxalate, melting point 17 2 〜: L 78 'C (decomposition) 81

 © 2-[5-(8-also ホ ホ ホ 一 一 一) 1 2-2 二 メ ェ ェ ァ チOxalate, mp 179-180. C (decomposition)

◎ 2-[5-(2-Methyl 8-Pyrrolidine-1 bronil)-1-2-Furyl methylthio]

◎ 2-[5-[11 (ρ-methoxyl) 18-pyrrolidino 11-1 pro) 1 2-Chen Etchamine

 © 4-1 C 5-1 (1-1 (P-methyl benzene))-3-(4-1 butyl-1) [Cheer] Butylamine

 ® 2-C 5-(3 phenyl amine 1 ell-1 pill) 1 2-furyl methyl thioethylamine

◎ 8-[5-1 (2-Methyl-3-(1, 2, 8, 6-tetrahydro o pyridine-1-yl)-1-1 p) 2-CHENIRIO)

 © 2-1 [5-1 (2, methyl 8 «methyl amino 1-ap α-phenyl)-1 2 1 full-methyl methyl] ethyl @ 2 [ 5 — (11 ferrules, 3 pyrrolizinos 11 plonyl) 12 chemi-methods)

2 — (5 — (3 — pyrrolidino 11-pronyl)) 12-methyl thiol methyl ethyl amine 8, 1-methyl amino 1-1-methylio 1-2-2 Trotten 5 9 82

And ethanol 80 Z Z is refluxed at 4 o'clock and concentrated to dryness under reduced pressure. This is used as a calak mouth mat (silica gel, black mouth hole). M: methanol-10: 1), purified as oxalate in ethanol and recrystallized from ethanol-water, the melting point is 99-10. 2 * C Ν-methyl) Τ [2-[5-(& -Pyrrolidino 1-1 bronil) 1 2-チ · ■ メ メ メ〕〕〕〕〕 [Ethyl] 1-1-1-Port-1 1,1-Ethylenediamine / oxalate / 1Z2 hydrate is obtained.

Example 6 '

 2 to [51 (8-methyl methyl)

 ) 1 2 1 furyl methyl ratio] ethyl amide 4.8, 1-methyl amide 1 -11-methyl litho 1-2-2

 Reflux 3.8 f and ethanol 50 for 5 hours, concentrate under reduced pressure, and remove the remaining g of oil from the calum lip mouth mat (silica gel, chlorophore: Purification by methanol Λ-10: 1) and the formation of maleate in ethanol gave N-methyl with a melting point of 101 to 1003.5 • C (decomposition). -[2-C5-(3-dimethylamino-1-bromide) 1 2-furylmethyl] ethyl] 1 2-^ Tro 1 , 1

 · Maleate is obtained.

Example 7

2 — [5 — (8-methylmethylamino-1 1-vinyl) 1 2 —Chenylmethylthio] ethylamine 4.59,1 ーMethylamine 1-methylthio1-2-2 nitrone 2.99 _% ethanol 35 I ^ and water 3.5 to 60-

OMPI 88

In 6 5 ^e C you 5 hours携拌. The reaction mixture is strained under reduced pressure, concentrated to dryness, and the residual oil is converted to fumarate in methanol. The melting point is 187.5 to 13.8.5'C (decomposition) N- [2- [δ- (3—dimethylene)] 1 2—Che2 δlmethine]] N'- Methyl 221

 1, I-ethenediamine · 8/2 fumarate 6.1 ^ force 5 is obtained.

 Example 8

 (a) 2 1 [5 1 (δ-dimethylamino 1-1 p-vinyl) 1-2-phenylmethylthio] ethylamine 1 19

Then, dissolve the cyanothioimid dimethyl carbonate 7.5 ^ in ethanol 90 »?, And stir at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, and recrystallized from isopropyl ether-ethanol to give Ν-cyanone with a melting point of 89 to 93 XJ. 2-[δ-1 (8-dimethylamine 1-1-port)-1-1-methyl-methyl]-ethyl] 1-S-methyl isobutyl Urea 11.5 is obtained.

(b) N-1 (2-5) (3-dimethylamino)-1-2 diphenyl (methyl) ) — S-methylisothiourea 3.59 ethanol 1 OB and ethanol containing 29% methylamine · 20 is at room temperature The reaction solution is concentrated to dryness and converted to oxalate in ethanol. The melting point is 125 to 127. (, Cyano, Ν 'of C (decomposition) [2-[5-(3-dimethylamino, 1-pro-vinyl)-1-2- 84

8.6 f of dimethylthio] ethyl] guanidine oxalate is obtained.

Example 9

2 [5-(8-dimethylamino 1-pi ぺ ニ nil) 1 2-二 2 J メ メ ル〕 チ 2 δ 9 リStir Luisotiothionate 1, 1 and Acetonitrile 1 at room temperature for 5 hours. The reaction solution was concentrated to dryness under reduced pressure, and the residual oil was converted to oxalate in methanol. The melting point was 188-; 140- (decomposed) of Ν-aryl-1N'-1. [2-[5-C3-dimethylamine] (11-butyl) 1-1-chloromethylthio] ethyl] thiourea oxalate 2.6 _Β is obtained

 The following compounds can be obtained by the methods described in Examples 5 to 9 and the specification.

 1 [2-[5-1 (8-1 mol holino 1-1 p-vinyl)-1-2-methyl-------------------------------------------------- Nitro, 1,1, ethendiamin oxalate

, Melting point 110-: Lia 'c (decomposition)

Benzyl N '-[21- [5- (3-dimethylamine 1 bronil) 2] -Chenylmethylthio] ethyl] thiourea shea Yu c acid salt, mp ^{1 0 2~ 1 0 5 e C} ( decomposition),

© N—Methyl N ', [2— [5— (3—Piperidino 1-Pop π ぺ Ni)) 1.2—Chenylmethylthio] Chill] 2 — Nitro 1, 1-ethenediamin oxalate, 85

Melting point 1 2 2 ^e C (decomposition)

 ◎ Cyclohexyl N'- [2-[δ-(8-dimethylamino 1-1-divinyl)] 2-chenille methyl] Tile] urea oxalate, melting point 129-13-131 'C (decomposed)'

© Ν — Methyl 1 [2-[5-[3-(4 1 1 1 1 1 1 V. Radial) 1 1 1 1 B-1] 1-2-Chal Chi Zorechi O] e Chi le] one 2 - two collected by filtration one 1, 1 over e Te emissions di A Mi emission-2 push from © salt, mp ^{1 δ 0 ~ 1 8 3 e} C ( decomposition)

® N ~ C 2-[5-(8-1; N-benzyl-N-methylamino-11-brole)-1-2-phenylmethylthio] ethylenol 1; N, -methyl- 1 2-2-toro 1,1-ethanediamine oxalate Melting point 127-130'C (decomposition) © N ~ C 2-C 5-C 8 1 (41 pillows)-1-bronile] 1-2-二 レ — ク レ〕) one; - main Chi le -2 twelve collected by filtration one 1, 1 over e Te emissions di § emission-2 push from © salt, mp ^{1 7 2 ~ 1 7 5 e} C ( decomposition)

◎ N-[2-[5 [3-(4-Methyl 1 piperazine) 1-1 Pl 2] 2-Chenyl Methyl Chlo]] Enyl urea, oxalate, melting point 1993 ~: 196¾ (decomposition)

 © N-[2-[5-[3-(4-m-Black mouth fin-1-1 pipe-radial)-1-1 Pl-vinyl] 1-2-1

One OMPI 86

N-methyl methacrylate 2—Nitro 1, 1 ethene diamine oxalate, melting point 1668 or more

 I 6 4 Ό (decomposition)

 ® N-m-Trifluoromethyl N'1- [21- (5— (8-Pyrrolidine 11-Bro-L) -1 2—Cheny Rumethylthio] ethyl] 1-2-2-toro-1,1-phenethene diammine maleate, melting point 1447-148 (decomposition)

 — Methyl N'— [2— [5— [3— (1,2,3,6-tetraethyl pyridine) ) 1-2-chloromethylthio) ethyl] 1-2-nitro 1,1-ethanediamine oxalate, point 140

~ 1 4 8 'C (decomposition)

© N—Isobutyl IT-1 (: 2-C5 — (3—Bilirolino 11-Prop.) 1-21 Methyl Methylthio) Etch Sole] one 2 - two collected by filtration one 1, 1 Ichiwe Te emissions di § Mi emissions shea Yu c acid salt, monohydrate, mp ^{1 3 8~ 1 4 0 e C} ( decomposition)

 Hata Bropargil IT [21-5-(3-Pyrrolidino 11-11 Principle) 《2-Chen Methyl Mio] Echinore] 1 2 122 mouth-1,1 ethenediamin sulphate, melting point 1447-150 (decomposition)

◎ N — Aryl one N 'one! : 2-C 5 (3-pillory resin

1 1-Pr-vinyl) 1, 2,2-methylmethylthio] ethyl] -2 12-toro 1, 1 -ethenediamin oxalate, melting point 1 4 1 to: 1 4 3 ^e C (decomposition)

O PI WIPO " 87

(g) N-C 2 to C 5-(8-dimethylamine 1-divinyl) 1-2 1-2-2-1-1-1 Pro / Glygyl 1—2—Port 1 1,1-ethenediamin maleate, melting point 11 1 to 1 18 ^e C (decomposition)

 s © N-1 m — Trifluoromethyl ferrite IT-1 [2 1 [5-(3-dimethylamino 1-1 port opening ニ nil) 1 2 1 CHENYL METHYL CHIO] ETHINO LENNOW 2 — Nitto 1, 1 1 1 1 1 1 1, 1, 11, 11 Disassembly )

 0 ◎ N — ethyl; N '— [2-C5-(3-pyrrolidino-1-1-propionyl)-1 2-chloromethylthio] ethyl 1) 2-1-2 trol 1,1-ethanediamine oxalate, melting point 134--1886 1 (decomposition)

© 11—Prop; Lu; — [2— [5— (3—Pyrrolidino s-1-1-Pr-Pinyl) -12-Chenyl-Methyl-Lio] Le] one 2 - two filtrated over 1 »1 e Te emissions di § Mi emissions shea Yu c acid salt, mp ^{1 3 6 ~ 1 8 8 e} C ( decomposition)

 © N Benzyru N'— [2-C51 (3—pyrrolidinone I-one profile)] 0 liters] — 2 nitro-1,1 ethenediamin maleic acid 融 点, melting point 123-126. C (decomposition)

 © NC 2 — [5 — (3 — Pyrrolidino 1 P

 1) p-Methoxysilane 2-2-chloro-1, 2-ethylmethylthiol

ΟΙνίΡΙ 88

 ◎ N—Methyl-N'— [2-C5— (3—Pyrrolidine 1-Brownine) 1 2 1 Fully-methylthio] ethyl) 1 2 — Two-to-one

 © N-Methyl N '1 [2-1 [5-(3 1 N-Methyl-N-phenylamine-1-1)-2-Chenyl Methyl Chio] Echile] 1-2 = Troll 1, 1-Ethylenediamine

 @ N-C2— [5— (8—dicyclohexylamino) 11-2—Chenylmethylthio] ethyl] 1);ー Methyl ー 2 — Two-row 1, 1-

 © Ν — methyl ル Τ 1-4-5-(8-pyrrolidino 1-1-1-vinyl) 1 2-二 2-butyl) 1-2-2 trol 1, 1

 © N-[2-[5-(8-methylamino 1-1-pronil) 1-2-1-methylmethylthio]-ethyl) 1-N '-nit α Guinegin

 ® '— Dimethyl N "— !: 2 1 [5-(3-Dimethylamino 1-1-broth-sole) 1 2-Chenyl methylinorecho] Echimere]' Guanidine

 — [2 — [5 — (8 — dimethylamin 1-propionyl

) 1-2 ^ thienylmethylthio) 1: 1-phenyl-anidin

 ◎ N — Methyl N '— (: 2-C5-1 (3-pyrrolidine 1-1-propyl) 2-1-methyl-methyl-thio) 1 2 — METANCE FREMONY 1,1

OMPI

W0PO 89

 © N-Methane sulfone N'-Methyl-N "[2-[5-(3-Pyrrolidine 1-Prinyl) 1 2-CH2 Lumethylthio) ethyl) guanidine

 © N-Benzensulhonru N'-methyl-[215] [51 (31 pyrrolizinone-1-prongyl)-1-2- Reciprocal chio]

 ◎ N— [2— [5— (3—pyrrolidinone-one> 12-one-channel-methyl-thio] ethyl) -21-one-pentene Sur Honiley I, 1

to © N-Methyl-1-5-(3-dimethylamino1-1-prole) 2-------------------- Tro 1, 1—Engagement

 © Belgian 1-C 2 1 [5 (8-pyrrolidino 1-1-1 pro-le) 1 2 — Thie-methyl methylthio] ethyl 6 re] " -2 1 1 1 1 1

 © Ν1 methyl 1 N '[2 "[5-(3-lipo-resinino, 11-pronyl) 2 cis-methyl] methyl] 1 2 ---- One-one 1.1

 ◎ Ν — (: 2 — [5-(3 — lipoline 1 · tape α ニ ぺ 0 0 0 2 2 2 2) 2 2 2 2〕) © Ν き 〔2 5 5 5 5 5 5 5 5 5 5 5 5 5 5 — — 5 — — — — — — — — — — — Chill 2 1 2 1 1, 1-Engineering

 © Ν — Methyl N'— [2 [5--(3 thiomhol hol 5 5 1-1 pronil)] 1, 2, methylene thiol]

OMPI Chill 1 2 — 2 Troll 1 · 1-

◎ N-methyl N'- [2-[5-[3-(4 -cinyl 1-piperazine)] 1-1 π ぺ ぺ ジ 1-2-Chereme Chil Chio) Etchl) 1 2--Draw 1, 1

 ◎ Methyl IT-1 (: 2-[2-C5-(3-pyrrolidinone 1-bromide)-1 2-CHENYL] チ CHILLIO , 1 2: Tokuguchi · 1 1.

 -2-C 5-[3-(4-1-piperazine) 1-1-bronze] 1-2-methylene-methyl ] 1-Methyl 2 2 1 2 α--

 © N — (2 — methoxymethyl)-Ν'-1-- (2-C5-(3 — pyrrolizinone) Lucio]-1) 2-2

 © Ν-methyl-N '— [2— [5-1 (3-methylamylone-one-brownyl) 1-21-chloromethylthio] ethylile) 1 2 1 2 tro 1, 1 ェ テ ジ ジ

Example 10

2 — [3 — Methyl 5 — (3 — Pyrrolidine 1 — Proplonyl) 1 2 — Furyl methylthio] Ethyl amine 4 9 _% 1 1-methylamino 1-methylthio 1-2-2 nitrone 2.6 f and ethanol 40 were refluxed for 5 hours, concentrated under reduced pressure, and the residue was removed. Add oil to π mat (silica)

OMPI And chloro mouth: methanol:-10: 1) to give oxalate in methanol, the melting point is 139-1.

4 0.5 ^e C N—methyl; N '— [2— [4—methyl 5 1 (8—pyrrolidino 1 1—brown) 1 2—f Ryl methylthio] ethyl] 1 2 —-trol 1, 1-ethenediamine, oxalate can be obtained n

 Example Γ t

 2 — [4-methyl 5-1 (3-pyrrole resin 1-o-o-nil) 1 2--chel-methyl-thiol]-chillamine 3.9 9-1 1-methylamino 1-methylthio 1--2 2-troentene 2.3 and ethanol 40 reflux for 5 hours. Semi-shrink under reduced pressure, add black mouth film, wash with water, dry the black mouth layer with sodium sulfate, concentrate it, and remove the residual oil from the chromium gel (silica gel, black Rolophosolem: purified with methanol = 10: 1), and the fumarate in methanol has a melting point of 100-108 (decomposition). N-methyl ー '-2-[4-methyl 5-(8-pyrrolidino 1-1 α-vinyl) 1 2 1 -methyl [Ethyl]

-2 1 1 1 and 1 1-ethenediamine 3/2 fumarate is obtained.

 The following compounds are obtained by the methods described in Examples 10 and 11 and the description in the above specification.

◎ N-methyl N'— [2-C3—methyl-5— (31-piridino-1-1-pronyl) 1-2—Chenylmethylchi Ί レ 二 二 二 二 1 1 1 1 1 1 • oxalate, mp 129-181 ° C (decomposed)

◎ N-[2-[4-Methyl-5-1 (8-Dimethyl-A-1-Pi n-nil) 1-1-2-C2-C2-C1-2] 1-2 -Nitro 1, 1-

© N-Methyl-[2-C4-Methyl 5-(8-piperidinone 11-1 pronil)] Thiourea ''

 ◎ N-arylue N'— [2- [4-measurement machine 5—C3-C4 1-methyl-1-biperazine) 1 1 1 ] 一--レ レ レ レ ォ レ 尿素

◎ N- (Ρ- ク mouth α benzene) 1 N '1 [2-[3 1 meth oxy 1 5 — (: 3-(1, 2, 3, 6-tetrahydro) Pigment I-yl) 1 1 οv ニ ル ル ル 2 一 一 一 二〕〕 尿素 尿素

© N-(m-trifluoromethyl J refenyl) i N '-[

2-[4-Methyl 5-(3

13） 一 2 一 一 一 2 2 一 一 v v v v v v v 一 v

 ◎ N-C 2-C 4 1-5-(3-pyrrolidine 1-cr cr ぺ · = · レ) 1-2 methyl-

] IT-Pu r α j j lay 2 1 2 1 1 1

— Cyanone N, — Methyl: — [2C4 Methyl 5— (3—Pyrrolidine 1-Pole) 2-Frylmethylthio Ί ethyl) 48

 @ N-[2-[4-Bromo 5-(3-dimethylamino)-1-2-furylmethylthio] ethyl] 1Ν 'r — methyl methyl

 © N-C 8-C 5-(3-dimethylamino 1-one-pro- nyl)-1-4-methyl-2-phenyl-propyl) guani gin

 © N-C 2-C 4-Methyl 5-(3-pyrrolidino 1-bromide) 1-Z-methylene-methyl) 1) N 12 Trojan

 © N — METHANOL N N 'メ y レ N N 〔— 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1) 1 2 1 CH 2 NOMELETCHETCHYL] GANJININE @ N-[2-[4-Port Mouth 5-(3-Dimethylamino) 1-π ぺ ニ ル ル 一 2 — — — 2 2 フ 2 — 2 一 ~ ー ー ~ チ ル 2 メ 一 一 レ j レ ニ ニ, 1 Min

 © N-C 2 [4-Mouth mode 5-(3-dimethyl amino) 1-2 'レ レ レ レ レ〕 One-way relay 2 One venture hole 1, 1-

 © N — Methyl N '[4 [4-Methyl 5-1 (8-Pyrrolidino << 11 Pl)-2-Chenyl] Butinole J, 2- 1, 2, 1

— Methyl N'—! : 2 [4-Methyl 5-(3-pyrrolidino 1-1-pi ぺ ぺ 一) 1 2-CHEN 1) 2-2 Troll 1, 1-Agent

Example 12

 2 — (5 — (2 — methyl 3 — virgin resin 1 — n) n 2) 1 2 — benzene methyl thio) ethyl amine

 9.1, 1-methylamino 1-methylthio1-2-2 σ ヱ tent 5.4 and ethanol 8 Ο β are refluxed for 4 hours, and concentrated under reduced pressure. Add on-water and wash with water.

After drying the no-holm layer, the brown oil obtained by concentrating the gel was purified with a calum chromatogram (silica gel, black mouth foam: methanol-15: Purification by 1) yields N- [2-C51- (2—methyl 8—pi-lysinol 11-propyl) 12—2-chloromethylthio] [Ethyl]

2 A light yellow oil of 1,2-1,1-ethanediazine is obtained. _Β This is considered to be a oxalate in ethanol, and its melting point is 144 to 144 °. G (decomposed) oxalate is obtained.

 According to the method described in Example 12 and the specification, the following

Is obtained.

 © N — Methyl IT-1 (: 2 — [5 — (1 Methyl 3 — Bilo-Risino 1-Vorve)) 2 — Chenyl Methylヱ till], 221 trol 1, 1

 * Oxalate, melting point 1339 ~ 141 (decomposition)

© N-[2-[5-(3-dimethylamine 2-methylamine 1-pro- nyl) 1-2-chloromethylthio] ethyl j 1 2 1 2 Trouble 1,1-

/ O PI> Acid salt, melting point 165-; I ^{67 e} C (decomposition)

 ◎ N — Methyl N'— (: 2-C5 — (8 — Dimethylamino 1-1-methylene 1-1-vinyl) 1 2-Chen2me [Chirthio] ethyl] 121-Ethro-1,1-ethanediamine 8/2 oxalate, melting point 152-14-154'C (decomposition)

◎ N-methyl: 1 [2-C5-(2 1 ferrule 8 1 pyrrolidino 1 1 1 pro-le) 1 2-chenille methylchi E) Ethyl] 1-2-2-toro 1, 1-ethenediamine fumarate * monohydrate, melting point 102-105 (decomposition)

 © N-methyl; 1 [2-[5-(1-1-3-vinyl-1-1--------------------------------------------------------- [Thio] ethyl] 1 2 —-trol 1,1-ethanediamine oxalate monohydrate, melting point 122 to 12 $ ° C (decomposition)

-Methyl-N'-1 [2-1-5-1 (11-vinyl-1-vinyl-1 1 «pronil) 1--2 methyl-methyl-thio] [Ethyl] 2-'~ Toro ~ 1, 1-ethenediamine * oxalate, hemihydrate, melting point 10 2 ~ 10 5 ^e C (decomposition)

 © N-1 [2-5] ((3-N-1 benzene) N-1 methyl amide. (Chenisole methylthio) ethyl] 1 N'-methyl 221

1,1-Ethylenediamine oxalate, at points 140 to 142 (decomposed)

OMPI © N-Methyl-L '-(: 2-[5-(2-Methyl-8-Pyrrolidino 1-1)-1-2-Furyl Methyl [Ethyl] 1 2-2 Trowl 1, 1-

 -Cyanone N '— [2— [5— (8-Methylmethylamino2—Methylsolene 11-Pronylene) 12, Chenylmethylyl E) ethyl] one N "—methylguanidine

◎ N-[2-[5--[11 (p-methoxyphenyl)-1 8-bilolizino-11-bronil]-2-chenilleme [Chiruchio] ethyl] iT-methyl 2-2

 -Agent

 ◎ N-Methyl-L; N '-[4-1- [5-1- (p-methylphenyl) -13- (4-methyl-1-piperazinil)]ブ ぺ 2 2 — 2 — 2 — — — 2 — 2 2 2 — —

 : G

◎ N 1 [2-[5-(3 1 j ria clear amino 1 1 1 1 1 1 1 2 3 4 1 2 3 4 5 6 5 6 7 8 9 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 20 25 30 25 20 25 20 25 30 25 20 25 30 25 20 25 20 25 30 25 20) 2-Free j — (M — Tri-Fir

2 1 α- 1 »1 — Engineering

 ◎ N (m-cloth phenyl) 1 [2-[5-(3-morholino 1 1 ^^ Fernray 1, Plonisole) ""

2, 1, 2, 1, 2, 1, 2, 1, 1, 1

 © N-ary Ν '"[3-[5-[2-Methyl-31 (1, 2, 3, 6-Tetrahydropyridine-1-yl)] -1-bronilyl) 1 2-C. zenil thiop π pill]

Γ ΟΜΠ urea

 ◎ N, Ν'-one methyl Ν Ν "-1 [2-[5-(2-methyl 1-8-methyl amino 1-1 p-vinyl) 1 2-frill Methyl Chidole)

 @ Ν -C 2 — [5-(8-dimethylamino-2-, dimethyl-1-c)-2-phenyl-methyl] ethyl ]; 1; —Bronoregile 1—2—2

 ◎ Ν メ ー Ν 〔〔〔〔メ メ メ メ メ メ メ メ メ メ メ メ メ メ Ν-Methyl 一-2-1 (5-1 (2-Methyl 3-1-Port Lisino 1-1 η ぺ 一)-1-2-Cell Methyl) Chill) urea

 © Ν — [2-C5— (3—methyl amino 2—methyl 1-vinyl) —2-furyl methyl etch] Anijin

© Ν-[2-[5 (8-dimethylamino 11-methyl 11-pro- nyl) 1-21 N'12 Trojan

 ◎ Ν C C 2 C C 5 （(& ジ メ ア ミ 一 一 一 一 一 2 2 2) ] 1>, METHANOL

 @ Ν — Methyl N'1 [2-1 [5-(2-Methyl 3 -2-pyrrolidino 1-1-propyl) 2-Frill y Chillcho] [Ethyl] 1-2-METHANES

OMPI orchid © N-methyl-N '~ C 2-[5-1 (1 -methyl 8 -'pi-zigino-1-1-pronyl) 1-2 -Chenyl-methyl-cho [Ethyl] 12 1 Benzens Kurehonirei 1, 1-Ethenylamine s (§) N- _methyl - _Ν , — [〔-C5-(1 One final 3

 1-Pyrrolidine 1-1-vinyl) 1-2-dimethylmethacrylate-1-2-2 1-1, 1-10- — Benzil Ν '-[2 — [5 — (2 — Methyl

 1-pyrrolidino-1 1-bromophenyl) 1 2—Chenylmethyl α-L-thio] ethyl] Thiourea

 Example 13

2-(5-(8-pyrrolidine)

 2 1-Chenylmethylthio) ethylamine 5 ^ and 21: g. Α-amidium 5 — (3—pyridylmethyl) 1-4 (S1 H) — Add pyrimidinone 4.4 to ethanol 50 and reflux for 20 hours. The ethanol was distilled off under reduced pressure, and the residual oil was dissolved in porcine, washed with water and dried over sodium sulfate, and the porcine was distilled off under reduced pressure. When recrystallized, the melting point is 114 to 118. 5-(3-0 pyridylmethyl)-2-C2 of C-[5-(3-

 一 1-1 π ぺ ぺ ル ル 2 — — — — — — — — — — — — — — — — — — — — — — — — — — —. Example 1

 2 — (4 — Methyl 5 — (3 — Pill

 · Π · ぺ レ 一 2 一 一 一 2 一 2 一

 O PI

, W! PT " _¾t 5 f and 21-trominominor δ — (8—pyridylmethyl) 14 (1H) — pyrimidinon 3. And reflux for 24 hours. Ethanol is distilled off under reduced pressure, and the residual oil is dissolved in black hole foam, washed with water, and dried with sodium sulfate. The o-pi film is distilled off under reduced pressure to remove the residual oil. Purified by column chromatography (silica gel, black hole: medanol-10: 1), and re-purified from ethyl acetate-isopropyl ether Crystals have a melting point of 12.9-1

3 2 ^e C 2 — [2 — [4-methyl 5-(3-biloli gino-1-pro-nickel) 1 2-free-methyl- (No)] 1-5 — (3 — vinyl methyl) 14 (1H) — pyrimidinone force s is obtained.

Example 1 δ

 2 to [5— (3—dimethylamine) I 2—thiethylmethylthio] ethylamine 5.9 ぉ and 2 — Methyl methyl 5 — (3 — pyridyl methyl) 1

4 (1 Η) 1-pyrimidinone 5.4 Reflux of f in isoamyl alcohol for 30 hours. The solvent was distilled off under reduced pressure, and the residual oil was purified by column chromatography (silica gel, black hole: methanol = r1 = 1). When the hydrochloric acid salt in ethanol is used, its melting point is 2 19 to 22 2 (decomposed), and it is 2- [2— [5— (3 dimethylamine). 2 — dimethyl methylthio) ethyl amino] 1 5 — (

3 — pyridylmethyl) 1-4 (1H) — pyrimidinone, 8-hydrochloride is obtained. The following compounds can be obtained by the methods described in Examples 18 to 15 and in the specification II.

 ◎ 5 — (3 — pyridyl methyl) 1 2 τ · (2 — [5 — 8 8 — pyridinone 1-bronile) 1 2 — furyl methyl chi E) ethylamino] 14 (1H)-pyrimidinone, melting point 74-78'C

© 5-(ρ-Fluorobenzyl) 1 2 1 [2-[5-1 (3 1 pyrrolidino ^ 1 1 bronil) 1 2-Furyl methyl ratio] Chi le § Mi Bruno] one 4 (1 Η) one pin Li Mi di Bruno emissions, mp 9 0 ~ 9 4 ^e G

 © 2-[2-[5-(.2-Methyl 8-Pyrrolidino 1-1 Pl)-2-Chenyl Methyl Chio] Mino] 1-5-(3-pyridylmethyl) 1-4 (1H) 1-pyrimidinone, with a transition point of 119-122. C

© 2 — [2 — [51-1 (2-methyl 3-amino-1-bronil) 1-2 1 2 Mino] 1-5 — (3-pyridylmethyl) 1-4 (1H) 1-pyri I dinonone trihydrochloride, mp 22 & ~ 280 0 (decomposition)

© 2-[2-1 [5-1 (1-methyl 3-dimethyl amino 1-α-α-phenyl)-1-2-phenyl methyl thiol] チAmino] 1-5 (31 pyridyl methyl) 14 (1 1) -pyrimidinone, melting point 13 2 〜: L36 6

® 2-Γ 2-C 5 — (2 — Ferro 8 — Pyrrolidino 11-1-Pro-Ni-Ni) 1 2 — Chen 2

O PI Rumino] 1 5 1 (8 1 pyridyl methyl) 1 4 (1H

) One piece of ') dinonone, melting point 1 28 to 1 26 ^C C

 ◎ 2-[2-[5-(1 ferrule-8 pillorino)

 1-11 (Prinyl) 1 2—Chenylmethylthio] each

B rumino] 1 5 — (8-Villyl methyl) 1 4 (1H

 ) -Pyrimidinone ♦ 8 oxalate, melting point 13 δ ~ 18

 8 ¾ (disassembly)

 © 2-[2-[5-(3-dimethylamine) Amino] 1-5 (3-pyridyl methyl) 1 4 (

 1 g) — pyrimidinone, with a melting point of 125 to 127

 ® 2-C 2 1 [5-(3-dimethylamine 1-1-1-propyl)-1-2-furylmethylthio] ethyla Mino] one 5 — (3 — pyridyl methyl) one 4 (1

 H) — pyrimidinone * 3 hydrochloride, mp 208-210 (decomposition)

 ◎ 5-1 (p-fluorobenzene) 1 2-[2-[5-

 (& Methyl methylamino-1-1 ferrule-1-vinyl)-1-2-chloromethylthio) ethyl-1-4

 (1 &) — pyrimidinone * 2 hydrochloride, mp 169-1

 7 Hi 'C

 © 2 — [2 — [5-(3 — Morhol 1

 1 1 プ π ぺ ジ ジ ジ 一 一 2 '一' '' 一 'π' 1 一 '' '' '2' '1 一 一 一 一 一' 2 '' '' '

 ) One pyrimidinone, melting point 1 1 1 to 1 1 2 ° C

OMPI WIPO ^ ν © 2 — [2 — [5-(8-dimethylamino 1-11-1-pronyl)-1-2-chloromethylthio] Lumino] 1-5 — (8,4-methylbenzene) 14 (1H) 1 pyrimidinonone dihydrochloride, mp 1559- 1 6 2 ^e C

 © 2 1 [2-[5-(3-N 1 benzene: N 1 methyl amino 1-1 phenyl-1 propyl) 1-2-CH2 5-(3-pyridylmethyl) 14 (1H)-pyrimidinone, melting point 88-90 * C

 ◎ 2-[2-[5-(1-ferro 3-bi-peridino-1-1-prog-nil)-2------------------------ 5) (3-pyridylmethyl) 14 (1H) 1-pyridinone * 3 hydrochloride dihydrate, melting point 107 to 109 * C

 © 2-2 — [4-Methyl 5-(2-Methyl 3-Virolidine 1-Bromine) 1 2-Chenyl Methyl] Lumino 1 5 — (8 — pyridylmethyl)-4 (1H) — pyrimidinone, melting point 1886 or more: ® 2 -C2 with L38 — 4 -Methyl 5-(8-pyrrolidine 1-1 mouth opening) 1 2-Chenyl methyl ratio] ethyl solamino] 1 5 1 (3- Bisyl methyl) 14 (1H) pyrimidinone, melting point 189-142'C (decomposition)

© 5-(6-methyl 8-pyridyl methyl) 1 2-2-[5-(3-bilolizino 1-1 plodnyl) 1 2 58

 1-Chenylmethylthio) ヱ Chylamino] 1-4 (1H)

 © 5 — (6 — methyl 3 — pyridyl methyl) 1 2-[

2 1 [4-methyl δ-(8-bi-resin-1-probe) 1-2-furyl-methyl-] ethyl-1-4 (1 Η) — pyrimidinone

 ◎ 2 [2 1 [5 1 (3-dimethylamino) 1-2-Frisolate methylthio] echidylamino 1- (6-methyl-8-1-methyl-methyl) 1-4 (1 ~) ~ bilimidinone

 ◎ 2 — (: 2 — [5 — (3 — dimethylamine) 11 2 1 2 1 2 3 2

 One δ — (6 — methyl 3 — pyridyl methyl) One (1Η)-bill? Zinon

© 2 — [2-[4-Met xy 5-[3-(4-Met cray 1-Pipe radii-)] 1 1 1 1 1-2-Change (Methyl thiol) ethyl amino) 5-1 (41 pyridyl methyl) to 4 (1)) — bilimidinone

 ◎ 2 — [2 — [3 — Metaxis 5 — [8 — (1, 2, 3, 6 to Tetrahydrobiline 1 1) 1 1 1 π ぺ] 1-2-CHENYL METHYL CHIO] CHETYL AMINO]-5-(2 pyridyl methyl) 4 (1 Η) pyrimidinone

 © 2-C 2 [8-Methyl 1 5 (3-Pyrrolidino 1-α α)] 1-2 Methyl Methyl

OMPI Mino :) 1-5-(8-pyridyl methyl) 1-4 (1H)-Pyrimidinone

 © 2-[2-[5-(8-Garyl Amino 1-1)-1-2-Chenyl Methyl-Chio] Acetamino-1-5 -Ferrule 4 (1 H).-Pyrimidinone

, ② 5-1 (p-methyl pentyl) 1-2 1 [2-[5-(3-1-N-methyl relay N-phenyl- ) 1-2-chloromethylthio) ethylamino]-4 (1H)-pyrimidinone

 ◎ 2-[2-[5-(3 dimethylamino 1-1 c-vinyl)-1-2--------------------------------------------- 8 — pyridyl methyl) 1 4 (1H) — pyrimidine zion

 ◎ 2-[2-[4-Bloom 5-(8-Pyrrolidine 1-Pronil)] 1-2------------------------------- 1) 5 — (3 — pyridyl) 1 4 (1H) — pyrimidinone

 ◎ 2-[2-[3-Bromo 5-(3-Dimethylamino 1-Brodel) 1-2-Chenylmethylthio] Rumino] one 5 (3-pyridyl methyl) one 4 (1

H)-Billy I

◎ 5-(3-pyridyl methyl) 2-[4 [5-(3-pyridinyl 1-1 propylene) 1 2-Chenirile methyl ] Butyramino] 1-4 (1H)-pyrimidinone © 2-C 2-[5-(8-dimethylamino 11-one-prongil)-one-two full-metal]-ヱ8 — pyridyl methyl) 1 4 (1H) 1 pyrimidinone

 ◎ 2-[2-[δ-(8-dimethylamino) 11-1 furylmethylthio] ethylamine] 1 6- Methyl 5 — (8 — pyridyl methyl) 1 4 (1 Η) 1 pyridinone

 ◎ 5-(8,4-dimension benzene) 1 2 — (: 2 — [5 — [1 (ρ — methoxysilane) 1 8 — pyrrole No. 1 1 口 口 ジ 2 2 2 2 — — — — — — — — 1 — — — — — — —

© 5 — (ρ — Chlorbenzyl) 1 2 — [8 1 1 5 – [8— 1 1 1 (ρ-Methyl ref-1) 1 1- Α ぺ ぺ 一 4 4 4 4 4 4 4 4 4 4 (4 (

 ◎ 2 [2-C 5-(3, dimethylamino-1-1-vinyl)-1-furylmethylthio] ethylamino-1 5-( 6—Methoxy 3—Visil methyl) 1 4 (1 1) —Pyrimidinone

 © 2-C 2 — [5-(3--dimethylamino 11-1-vinyl) 1-2-methyl-methyl] 1-alkyl-1-5 — (5 »6-dimethyl 8 — pyridyl methyl) 1-4 (1 Η) — pyrimidinone

-'The invention is described in the above specification and the practice encompassed by it.

(、 ΟΜΠ WIPO Although fully described in the examples, various modifications and decorations can be made without departing from the spirit and scope of the present invention.

Claims

The scope of the claims  1 General λ R ⁸

 A α-phenylamine derivative or a pharmaceutical thereof represented by the formula:  Pharmaceutically acceptable acid addition salts. In the above formulas, E ¹ and H ² are the same or different and each represents hydrogen, alkydile, alkenyl, siginal kill, aryl or aralkyl, or adjacent R ³ represents hydrogen, halogen, alkaryl or alkyloxy, and A and B represent the same groups which form a heterocyclic ring together with the nitrogen atom. Is hydrogen, alkyl or aryl, Z is an oxygen atom or a sulfur atom, and Q is an alkylene or formula (OH ₂ ^ nX ¹ (C! H ₂ ) _m - in a group (here, which is I Table, X ¹ is ^oxygen: the atom or a sulfur atom, n is 0 or is from 1 to 3 And m represents an integer of 2 to. ), H ⁴ is hydrogen, formula —! A group represented by _HR 5 (where H ⁵ is hydrogen, alkyl, alkyl, alkyl, alkyloxy, Files, sick files, files or files. E is an oxygen atom, a sulfur atom, a group represented by the formula-; NR ^e ( In here, the E ^beta represents hydrogen, Shiano, two collected by filtration, A Le key Le, § Li Lumpur, the A Le key ls e le e was double le or the § Li Ichiru scan le e d Honoré. ) Also f or formula - in 0HR ⁷ in the group (here, which is I Table , H ⁷ are two collected by filtration, A Le key ls e le e d le or is § Li Ichiru scan OMPI. Indicates Le Honil. 〉 Indicates or expression

a group represented by s (where X ² is an oxygen atom or sulfur atom; Y is aryl or lower alkyl or lower alkyl having 1 to δ arbitrary positions) A pyridyl which may be substituted by alkoxy, a ⁸ is hydrogen or alkyl, and Ρ is Indicates 0 or an integer from 1 to 5. ) Indicates ά ιο In the above definition, aryl and aralkyl may be located at any position on the aromatic nucleus such as rho, gen, alkyl, arkoxy, and trifluorene. It may be substituted by at least one substituent selected from acetyl and methyloxy. 15 2. Ν—Methyl IT-1 [2— [5— (3—Pyrrolidino 1- 1-Brown) 1- 1-Chenylile-methyl] 1-Cyl] 1 2—2 The compound _{β according to} claim 1, which is tro-1,1'-ethenediamin or a pharmaceutically acceptable acid salt thereof.  20 3 · 5 (8-pyridylmethyl) 1 2 1 [2-[5-(3-bilolizino-1 1pronique) 1 2-phenylmethylthio [Ethylamino] The compound according to claim 1, which is 1-4 (1H) -pyrimidinone or a pharmaceutically acceptable acid addition salt thereof. 25 4. N—Methyl-L [2— [4-Methyl-L 1-pyrrolidino 1-broule) 1 2—Chenirile methylthio] ethyl] 1 2—2-Troll 1, 1-Ethylene ami  2. The compound according to claim 1, which is a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable acid addition salt thereof.  5. 2— [2— [5— (3—Dimethylamino 1  π ぺ レ レ 一 2 1-1-methylmethylthio) ethylamino) 一 5-(3-pyridylmethyl) -14 (1H)-pyrimidinone or its 2. The compound according to claim 1, which is a pharmaceutically acceptable acid addition salt.  10 6.2-[2-[4-Methyl-1-- 1 1 ο ぺ ぺ レ レ 2 2 — — — — — — — — — — — 5 1 5 — 5 レ 5 2 2 2 2 — — 5 1 5 — 5 レ 2 2 2 — 5 5 di Bruno down or compound of claims claim 1 wherein a pharmaceutically acceptable acid addition salt ₀  I S 7. -Methyl-N'-1 [2-[4 -Methyl 5-1 (3  1-pyrrolidino-1 1-alpha-phenylene) 1-2-free-melt-one]  Or the compound according to claim 1, which is a pharmaceutically acceptable acid addition salt thereof.  0 8. Ν — Methyl 1 [2-[5-(2 — Methyl 8  1-pyrrolidino 1-1-1-vinyl) 1-2-1-methyl-1-1-1-1-  2. The compound according to claim 1, which is a pharmaceutically acceptable salt or a pharmaceutically acceptable addition salt thereof.  5 9. Ν — Methyl N 'one! : 2-C 5 — (3 — Dimethyla O PI- Minnow 11-Brownyl) 1 2-Furylmethylthio] ethyl] 1 2-Nitro 1, 1-etheneamine or its pharmaceuticals 2. The compound according to claim 1, which is an acid salt which is acceptable. 10. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable excipient. OMPI drawing