FI63937B - FREQUENCY REQUIREMENT FOR THERAPEUTIC USE OF THERAPEUTIC TREATMENT - Google Patents

Description

55 ^ * 1 ΓΒ1 NOTICE -,

JgTg (1) UTLÄGGNINGSSKRIFT 639 3 7 (51) K..H..W3 O ° 7 D 405/06, 409/06, '' 41J / 06, 417/06 ENGLISH I - Fl N LAN D (21) P * unttlh »kemu« - PK «ttMwekiiin | 771287 (22) H »k * ml« p «v» - Afweknlnpdac 22. OL.77 (23) AlkupUvi - GlItlfhetKUf 22.0 ^ .77 (41) Become Public— Whrit off «ntH | oK in 77

Pstantti- and rakiatarihleikeld ...., _ -,,. . . (44) Date of issue and of the date of issue. - rstent- och nglitvityrdaan Antäkan utisfd odi utljkrtften public * r »4 3i.05.83 (32) (33) (31) Requested privilege — e * j» rd prtorttet 23.0U. 76

England-England (GB) 16526/76 (71) Lilly Industries Limited, Henrietta House, Henrietta Place,

London Wl, England-England (GB) (72) John Pomfret Verge, Henley on the Thames, Oxfordshire, William Boffey Jamieson, Woking, Surrey, England-England (GB) (7I +) Ltd Kolster Ah (5 * 0 Method for the use of therapeutically useful phenylpiperazines - Förfarande för fraraställning av therapeutiskt användhara phenylylpiperaziner

The invention relates to a process for the preparation of novel phenylpiperazine derivatives. The compounds according to the invention have useful pharmacological activity, in particular antiallergic activity.

The invention relates to a process for the preparation of therapeutically useful phenylpiperazine derivatives of the formula

R1-Q- (CH2) m- (CHR3) n-N2-R2

wherein R is benzyl, chlorobenzyl, C 1-4 alkyl, phenyl or substituted phenyl having 1-2 halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy, C 1-4 alkoxy, or nitro substituents; r 2 is 2,63937 phenyl having 1-2 halogen, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 2-4 alkanoylamino, hydroxy, C 1-4 alkoxy, nitro or alkyylisulfonamidosubstituenttia; R 1 is hydrogen or C 1-6 alkyl; Q is furan, thiophene, oxazole or thiazole; m is 1-3 and n is 0 or 1, provided that when m is 2 and n is 0, it cannot be methyl if Q is thiazol-5-yl; and pharmaceutically acceptable salts thereof.

The term "C 1-4 alkyl" is used to mean a straight or branched chain alkyl group having 1 to 4 carbon atoms, e.g., methyl, ethyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. "C 1-4 haloalkyl" means the aforementioned C 1-4 alkyl group substituted with one or more fluorine, chlorine, bromine, or iodine atoms, for example, trifluoromethyl or pentachloroethyl group. Accordingly, "C 1-4 alkoxy" means a C 1-4 alkyl group, as defined above, attached to the phenyl group via an oxygen atom.

PL Patent Publication No. 78,185 discloses phenylpiperazine derivatives of the general formula R 1 r - v y - ^ S-p-R 3 - "Λν,

However, they are not reported to be antiallergically active.

DE-A-1 957 371 discloses antiallergically active phenylpiperazine derivatives. They differ considerably from the compounds of the formula I considerably, inter alia, because the formula contains an -NHCO group.

Preferred compounds of formula (I) are those having one or more of the following properties: (a) m is 1 and n is 0; (b) Q is thiazole (c) Q is oxazole (d) Q is thiophene (e) Q is furan (f) R 1 is C 1-2 alkyl such as methyl or isopropyl; (g) R 1 is phenyl (h) R 2 is benzyl (i) R is phenyl substituted with one or two methyl groups.

li 63937 3

Particularly active members of the phenylpiperazine derivatives of formula (I) are furans of the formula

R (CH_) m- N N-R II

wherein R x is phenyl optionally substituted with one or two radicals suitable for halogen, C 1-4 alkyl, 2-L · * 4 → C 1-4 alkoxy and C 1-4 haloalkyl; R is phenyl optionally substituted with C 1-4 alkyl, amino, C 1-4 alkylsulfonamido and C 1-4 alkoxy, and wherein m is 1 or 3, with the exception of compounds wherein R is unsubstituted phenyl, m is 1 and R is unsubstituted phenyl; or wherein R is methyl, m is 1 and R is phenyl optionally substituted with a single radical which is halogen; C 1-6 alkyl, C 1-4 alkoxy or C 1-4 haloalkyl, or its substituents are two C 1-4 alkyl radicals; thiophenes of formula (III): XV ΛΛ 2 R 1 (CH 2) - (CHR 3) - / R 111 2 m n \ / 1 2 '' wherein R is phenyl; R is phenyl, substituted with one C 1-4 alkyl or C 1-4 haloalkyl group, or substituted with two radicals suitable for halogen, C 1-4 haloalkyl and C 1-4 alkyl, substituted phenyl, and wherein m is 1 or 2 and n = 0; or wherein 3 m is 1, n is 1 and R is ethyl; oxazoles of formula (IV); JX ΓΛ,

R XCH0) -N N -R IV

2 wherein R 1 is 2 ± -4-phenyl substituted by C 1-4 alkoxy or halogen; R is phenyl optionally substituted with C 1-4 alkyl, C 1-4 haloalkyl, halogen, amino or C 2-4 alkanoylamino and m is 1 or 2; Thiazoles of formula (V): 63937 / \ 2 N-π- CH „-N N-R v XT ^

R 1 is wherein R is benzyl, R is phenyl or p-halophenyl; or Thiazoles of the formula: Ή ^,

CH "-N N-R

2 w wherein R 1 is C 1-4 alkyl or phenyl optionally substituted with C 1-4 alkyl, C 1-4 alkoxy, nitro and C 1-4 haloalkyl and R 4 is phenyl which is optionally substituted with C 1-4 haloalkyl, and pharmaceutically acceptable salts thereof In the above compounds, m is preferably 1.

The process according to the invention is characterized in that, (A) a compound of formula is condensed

R1-Q '(CH-) - (CHR3) -L VI

m n where L is a leaving group, and a compound of formula ΛΛ 2

HN ^ _ ^ ί-R VII

(B) reducing a compound of formula

(i) R1-Q- (CH2) m-C1-C11-R2-R2

a compound of formula I wherein n is 0; or reducing a compound of formula ϋ 63937 5 1 3 (+) / \ 2

(ii) R -Q- (CHO) Tn-CRJ = 1 'N N-K IX

2 m \ / for a compound of formula I wherein n is 1; or (C) cyclizing using a dehydrating agent a compound of formula 1 3/2 R -CCO-CH 0 -NH-CO- (CH 2) - (CHR) -N NR X 2 2 mn \ / to a compound of formula I wherein Q is oxazole.

The above condensation (A) is preferably carried out in the presence of a proton acceptor such as sodium carbonate base. Polar solvents such as alcohols, e.g. ethanol, are suitable solvents for this reaction, which is preferably carried out at the reflux temperature of the reaction mixture. The cleavable group L can be any radical known to function in such condensation reactions; for example halogen atoms such as chlorine, or methylsulfonyl or substituted benzenesulfonyl groups are suitable meanings of L in this reaction. The reaction is preferably carried out at a temperature in the range of 20 to 150 ° C. The compounds of formula (VI) are either known (see J.A.C.S. 56 470-1 (1934) and 53 1470-3 (1931)) or can be prepared by known methods.

The amide of formula (VIII) may be reduced with chemical reducing agents such as 132 μl or lithium aluminum hydride. The reaction preferably uses an ether solvent such as tetrahydrofuran and is carried out at a temperature in the range of 0 to 80 ° C.

Amides of formula (VIII) can be prepared by reacting an acid chloride (prepared e.g. by reaction of the corresponding acid with thionyl chloride) of formula 6,63937 ° C.

R1-Q- (CH2, m-1-i-C1 to react with phenylpiperazine of formula

H |

Compounds of formula (IX) may be reduced under the reaction conditions described in J.A.C.S. 93, 2897-2904 (1971) or Synthesis 135-146 (1975). The reduction is preferably carried out with sodium cyanoborohydride, but other reduction methods, e.g. catalytic hydrogenation, or other suitable chemical reducing agents may also be used. The reduction is preferably carried out in the temperature range 0 to 80 ° C.

The reaction conditions in the cyclization reaction (C) are generally known. The subject is discussed, for example, in Chemical Reviews, 75, 389-437 (1975) and Advances in Heterocyclic Chemistry 17 (1974).

As the dehydrating agent, for example, polyphosphoric acid, phosphorus oxychloride or concentrated sulfuric acid are used to give compounds of the following formula rv <CH2> nr (CHR> n -yJV1 * 2

The reaction is best carried out at a temperature in the range of 80-180 ° C.

63937 7

Compounds of formula (X) may be prepared by giving a formula

R1-CO-CH--NH-CO- (CH-) - (CHR3) -Br XI

2 2. m n according to the bromine derivative react with the formula / “\ 2

· _N ^ H-R

in the presence of an acid scavenger such as sodium carbonate.

Compounds of formula (XI) may be prepared by reacting an amine of formula r1coch2nh2 with an acid chloride of formula C1O0 (CH0) - (CHR3) Cl2 m n and using dimethylformamide as a solvent.

The compounds of formula (I) prepared by the above methods may be isolated as such or in the form of an acid addition salt.

Acid addition salts are preferably salts of pharmaceutically acceptable, non-toxic acids, such as inorganic acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acid, or organic acids, such as glycolic, maleic, hydroxymaleic, malic, tartaric, salts of citric, salicylic, o-acetobenzoic, nicotinic or isonicotinic acid or organic sulfonic acids, e.g. methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, toluene-p-sulfonic, or naphthalene-2-sulfonic acid. In addition to pharmaceutically acceptable acid addition salts, other salts, such as picric and oxalic acid salts, are within the scope of the invention, as they can be used to purify compounds or to prepare pharmaceutically acceptable acid addition salts, as well as to identify and characterize bases.

The acid addition salt may be converted into the free compound in a known manner, e.g. by treatment with a base such as a metal hydroxide or a metal alcoholate, e.g. a time hydroxide or an alkaline earth metal hydroxide, e.g. lithium, sodium, potassium or calcium hydroxide; a metal carbonate such as an alkali metal or alkaline earth metal carbonate or bicarbonate; ammonia; or by hydroxyl ion exchange, or any other suitable reagent.

The acid addition salt can also be converted to another acid addition salt in a known manner; for example, a salt of an inorganic acid may be treated with the sodium, barium or silver salt of the desired acid in a suitable solvent in which the inorganic salt formed is insoluble. The acid addition salt can also be converted to another acid addition salt by an ion exchange method.

To demonstrate the antiallergic activity of the compounds of formula I, pharmacological tests were performed by the method described by Herxheimer (Journal of Physiology, London, 177, 251, 1952).

Male guinea pigs were sensitized to egg albumin by fusing with a Wright nebulizer at a pressure of about 100 kPa a 1% egg albumin solution for inhalation by the guinea pigs. As a result of this exposure, the guinea pigs' breathing deepened and accelerated, and they lacked oxygen, with symptoms manifested in the eyes and skin, as well as a typical cough. The time interval between antigen exposure and the onset of cough is the so-called a "collapse time" that is typical and reproducible in a particular animal. The antihistamine mepyramine was used to detect the non-histamine component of bronchoconstrictor mediators. The results are shown in the following table.

Table R1 - Q - <CH2) m --- / \ - R2 v_ / 1 2 1 2 3 R Q m R Dose M / C D / C M + D / „

M

N - CH3- // 1 m-BrPh- 100 3.2 5.5 3.8 \ gs 9 63937 pH-CH2 N -S 1 £ -ClPh- 50 5.0 1, 1 1, 7 M \ xs t-Bu- N - / 1 Ph- 50 5.8 0.7 1.9 X_ £ -NO2Ph- X- N 1 Ph- 100 5.8 2.0 2

{X

S

Ph- Ti Λ 1 m-CF2Ph- 50 5.6 1, 7 3, 8 ~ ..................

Ph- jj ^ 1 3,4-diMePh- 50 3, 4 0.6 3.5

S

Me Jj ^ 1 m-ClPh- 50 5.6 2.0 2.0 10 63937 £ OMe-Ph- rn 1 Ph- 50 4.7 1.1 1.7 / \ 0A ........ ........

Ph h A 3 £ -MePh- 50 6.2 1.7 2.5 / A0 / \ CHO-Ph- ή A 1 £ -MePh- 50 5.4 1.1 2.4

Ph- h N 1 Ph- 100 5.7 4.7 2.2 ΛΑ 0

f-N

Ph jj 1 m-CF3Ph- 100 5.7 1, 4 2.2

Ph- 2 Ph ~ 100 6.6 7.3 1, 6 * = mg / kg p.p. 2 hours before exposure C = control (mean collapse time) H = mepyramine dose 0.5 mg / kg s.c. 0.5 hours before exposure (mean collapse time) D = compound of the invention (mean collapse time)

Column 1 shows the protective effect obtained with mepyramine. Correspondingly, column 2 shows the protective effect obtained with the compound of the invention. Column 3 shows, in terms of ratio, the additional protective effect achieved by administering the test compound and mepyramine to the animal.

li 11 63937

The following examples illustrate the invention.

Example 1 (a) 2-Acetoxythioacetamide

Dry hydrogen sulfide is allowed to flow rapidly into a solution of 2-acetoxyacetonitrile (150 g; 1.52 moles) and triethanolamine (20 mL) in dry ethanol (500 mL) with vigorous stirring. The internal temperature rose to about 55 ° C.

The gas flow was continued for about three hours, after which G.L.C analysis showed the reaction to be complete. Excess H 2 S gas was removed with a stream of nitrogen and the ethanol solvent was evaporated. The remaining sticky crystalline mass was extracted with boiling ether and a small insoluble residue was discarded. The combined extracts were treated with decolorizing carbon, filtered and evaporated to a volume of about 400 ml. Cooling to 0 ° C gave about 170 g of slightly tough 2-acetoxythioacetamide. This will be used in the next step without further investigation.

(b) 2-Hydroxymethyl-4-phenylthiazole 2-Bromoacetophenone (39.9 g; 0.2 mol) and 2-acetoxythioacetamide (30 g; 0.225 mol) were dissolved in dioxane (150 ml). The mixture was stirred and heated on a steam bath for 15 minutes to form a series of crystals. Aqueous 5 N HCl (40 mL) was added and heating was continued for 30 min. The dioxane was evaporated in vacuo and the residue was neutralized with aqueous n. The solid was collected, washed with water and imaged. After recrystallization of the product from benzene, the yield was 33.5 g (87%) and the m.p. was 88-9 ° C.

63937 12 (c) 2-Chloromethyl-4-phenylthiazole

Phenyl chloride (6.25 g, 0.052 mol) was added dropwise with stirring to a solution of 2-hydroxymethyl-4-phenylthiazole (9.55 g; 0.05 mol) and dry pynidine (4.0 g; 0.051 mol) in dry benzene (60 ml). ), at room temperature. The mixture was stirred and heated to boiling for one hour. The cooled reaction mixture was then shaken with 2 x 70 mL and dried over anhydrous MgSO 4. The solvent was removed in vacuo and the residual red oil was extracted at 40-60 ° C with petroleum ether (100 mL), a slight, tarry residue was discarded. The extract was treated with decolorizing carbon, filtered and evaporated to leave a yellow oil which was crystallized on cooling. Yield 9.9 g 94.5%.

No further purification was performed and the material was used for the next step.

(d) 1- (4-phenyl-2-thiazolylmethyl) -4-phenylpiperazine Crude 2-chloromethyl-4-phenylthiazole (4.19 g; 0.02 mol) and N-phenylpiperazine (3.24 g; 0.02 mol) and a mixture of finely ground anhydrous sodium carbonate in absolute ethanol (60 ml) was stirred and refluxed for 8 hours. The solvent was evaporated, the solid residue was suspended in water (100 ml) and then extracted with 2 x 100 ml of CH 2 Cl 2. The extracts were washed with water and dried over anhydrous MgSO 4. Evaporation of the solvent and recrystallization of the residue from benzene / 60-80 ° C petroleum ether (using carbon) gave the required product (5.03 g; 75%), m.p. 142-3 ° C.

Examples 2-19

In a similar manner there were prepared: (2) 1- (4-phenyl-2-thiazolylmethyl) -4- (3-bromophenyl) piperazine, m.p. 127.5 to 128.5 ° C.

(3) 1- (4-phenyl-2-thiazolylmethyl) -4- (3,4-dichlorophenyl) piperazine, m.p. 144-6 ° C.

(4) 1- (4-phenyl-2-thiazolylmethyl) -4- (3-trifluoromethylphenyl) piperazine, m.p. 112-3 ° C.

(5) 1- (4-phenyl-2-thiazolylmethyl) -4- (4-chloro-3-trifluoromethylphenyl) piperazine, m.p. 117-9 ° C.

(6) 1- (4-phenyl-2-thiazolylmethyl) -4- (4-methylphenyl) piperazine, m.p. 141-3 ° C.

63937 13 (7) 1- (4-phenyl-2-thiazolylmethyl) -4- (4-methoxyphenyl) piperazine, m.p. 148-9 ° C.

(8) 1- [4- (4-chlorophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, m.p. 164-5 ° C.

(9) 1- [4- (4-chlorophenyl) -2-thiazolylmethyl] -4- (3-bromophenyl) piperazine, m.p. 100-101 ° C.

(10) 1- [4- (4-bromophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, m.p. 166 ° C.

(11) 1- [4- (3-chlorophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, m.p. 129-131 ° C.

(12) 1- / 4- (2-chlorophenyl) -2-thiazolylmethyl-7-4-phenylpiperazine, m.p. 100-101 ° C.

(13) 1- [4- (3,4-dichlorophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, m.p. 138 to 139.5 ° C.

(14) 1- [4- (3-trifluoromethylphenyl) -2-thiazolylmethyl] -4-phenylpiperazine, m.p. 110-111 ° C.

(15) 1- [4- (4-methoxyphenyl) -2-thiazolylmethyl] -4-phenylpiperazine .HCl, m.p. 201 ° C.

(16) 1- [4- (4-methylphenyl) -2-thiazolylmethyl] -4-phenyl-piperazine .HCl, m.p. 175-180 ° C.

(17) 1- [4- (3-methylphenyl) -2-thiazolylmethyl] -4-4-phenylpiperazine, m.p. 113 to 113.5 ° C.

(18) 1- [4- (4-hydroxyphenyl) -2-thiazolylmethyl] -4-phenylpiperazine, m.p. 228-230 ° C.

(19) 1- [4- (4-nitrophenyl) -2-thiazolylmethyl] -4-phenylpiperazine, m.p. 195-8 ° C.

Example 20 (a) N-Phenylchloroacetamide

Chloroacetyl chloride (25 g; 0.226 mol) was added slowly to a stirred solution of phenacylamine hydrochloride (25.9 g; 0.151 mol) in anhydrous dimethylformamide (DMF) (80 ml) at room temperature. The temperature of the mixture rose to about '40 ° C. After the addition, the mixture was stirred for four hours and most of the DMF was evaporated in vacuo. The residue was treated with water (200 ml) and the crystalline precipitate was collected, washed with water and dried. Yield 27.75 g (88%), m.p. 118-119 ° C.

63937 14 (b) 2-Chloromethyl-5-phenyloxazole N-Phenylchloroacetamide (22.6 g; 0.107 mol) was mixed with polyphosphoric acid (200 g) and the mass was heated with stirring for 30 minutes at 150 ° C. The hot solution was poured into water (800 mL) with vigorous stirring. The mixture thus formed was extracted with 3 x 100 ml of chloroform, the extracts were washed by shaking with water and dried over magnesium sulfate. The CHCl 3 was removed by evaporation and the residual oil was extracted with 400 ml of boiling petroleum ether at 60-80 ° C. The resulting solution was treated with decolorizing carbon to remove tarry material and evaporated to give a crude yellow oil which crystallized rapidly. Yield 18.8 g (91%), m.p. 70-l ° C.

(c) 1- (5-phenyl-oxyrazol-2-ylmethyl) -4-phenylpiperazine 2-chloromethyl-5-phenyloxazole (3.87 g; 0.02 mol) and N-phenylpiperazine (3, 25 g; 0.02 mol) of a solution in anhydrous ethanol (60 ml) was boiled and stirred with finely ground anhydrous sodium carbonate (5 g) for 6 hours. The solution was evaporated to dryness and treated with water (60 ml). The suspension thus obtained was extracted with 2 x 70 ml of dichloromethane. The extracts were dried over magnesium sulfate and evaporated to dryness. A solid residue was recrystallized from petroleum ether at 80-100 ° C using decolorizing charcoal.

Yield H.67 g, m.p. 96 ° C.

Examples 21-35

In a similar manner there were prepared: (21) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (4-methyl-phenyl) -piperazine, m.p. 113-114 ° C.

(22) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (3-chloro-phenyl) -piperazine, m.p. 73 ° C.

(23) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (4-chloro-phenyl) -piperazine, m.p. 125-6 ° C.

(24) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (3-trifluoromethyl-phenyl) -piperazine m.p. 69-70 ° C.

(25) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (3,4-dichloro-phenyl) -piperazine, m.p. 134-5 ° C.

(26) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (4-methoxy-phenyl) -piperazine, m.p. 121-2 ° C

(27) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (3-methoxy-phenyl) -piperazine, m.p. 100 ° C.

(28) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (2,4-dimethoxy-phenyl) -piperazine, m.p. 89-91 ° C, 15 · 639 37 (29) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (3,4-dimethoxy-phenyl) -piperazine, m.p. 93-5 ° C.

(30) 1- (5-phenyl-oxazol-2-ylmethyl) -4- (4-ethoxy-phenyl) -piperazine, m.p. 98 ° C.

(31) 1 - [(5- (4-fluorophenyl) oxo] s-2-ylmethyl] -4-phenylpiperazine, mp 114-116 ° C.

(32) 1- (5- (4-fluorophenyl) oxa-2-ylmethyl-4- (4-methoxyphenyl) piperazine, mp 112 ° C.

(33) 1- (5- (4-methoxyphenyl) oxazol-2-ylmethyl] -4-phenylpiperazine, mp 112-115 ° C.

(34) 1- (5- (4-methoxyphenyl) oxazol-2-ylmethyl] -4- (4-methoxyphenyl) piperazine, mp 148-50 ° C.

(35) 1- (5-phenyloxazol-2-ylmethyl) -4- (4-nitrophenyl) piperazine, m.p. 170-2 ° C.

Example 36 1- (5-Phenyl-oxazol-2-ylmethyl) -4- (4-aminophenyl) -piperazine 1- (5-Phenyloxazol-2-ylmethyl) -4- (4-nitro-phenyl) -piperazine (7.28 g, 0.02 mol) in glacial acetic acid (50 ml) was hydrogenated with 5% palladium on carbon catalyst (100 mg) at atmospheric pressure and room temperature until hydrogenation was complete. The solvent was removed by evaporation in vacuo and the residue was treated with aqueous sodium bicarbonate solution to give a white crystalline solid. Weight after drying = 6.54 g (98%), m.p. 130 ° C.

Example 37 1- (5-Phenyloxazol-2-ylmethyl) -4- (4-acetamidophenyl) piperazine

The 4-aminophenyl compound prepared in Example 36 was heated on a steam bath with glacial acetic acid (5 mL) and acetic anhydride (10 mL) for one hour. The mixture was poured into water (200 ml), stirred well and the collected precipitate was washed with water and dried. After recrystallization from methanol, the product weighed 2.45 g and melted at 196-7 ° C.

63937 16

Example 38 1- (5-Phenyloxazol-2-ylmethyl) -4- (4-hydroxyphenyl) piperazine

Propane-1-thiol (5.0q; 0.066 mol) was added slowly with stirring to a suspension of 50% sodium hydride / mineral oil (3.17 g; 0.066 mol) in anhydrous dimethylformamide (140 ml). To a solution of the sodium propane-1-thiolate thus formed was added 1- (5-phenyl-oxazol-2-ylmethyl) -4- (4-methoxy-phenyl) -piperazine (7.7 g; 0.022 mol). The solution was heated in a reflux condenser with an oil bath for 10 hours under a nitrogen atmosphere. The mixture was then poured into water (600 ml) and extracted with 3 x 200 ml of ethyl acetate. The extracts were shaken several times with water, dried and evaporated until a white evaporation residue formed. After recrystallization from dioxane / 60-80 ° C from Petro ether, the product weighed 5.5 g (74-, 5%), m.p. 189-190 ° C.

Example 39 1- [2- (5-Phenyloxazol-2-yl) -ethyl] -4-phenylpiperazine (a) N-Phenyl-3-bromopropanamide 3-Bromopropionyl chloride (25 g; 0.146 mol) was added slowly with stirring at room temperature. a suspension of phenacylamine hydrochloride (17.15 g; 0.1 mol) in dry dimethylformamide (50 ml). The temperature of the mixture rose to about 40 ° C. The mixture was stirred for 2 hours and the dimethylformamide (DMF) was removed in vacuo. The residue was diluted with water (200 mL) and the crystalline solid was collected, washed with water and dried. Product weight = 9.49 g (35%), m.p. 114 ° C.

(b) N-Phenyl-3- (4-phenylpiperazin-1-yl) -propanamide A solution of N-phenyl-3-bromopropanamide (10.2 g; 0.038 mol) and N-phenylpiperazine in dry DMF (100 ml) was stirred. with anhydrous, finely ground sodium carbonate (15.0 g) for 18 hours at room temperature. The temperature was then raised to 80 ° C and maintained for 12 hours to complete the reaction. The DMF was removed by evaporation in vacuo and the residue was diluted with water (100 ml). The mixture was extracted with chloroform (3 x 100 mL). The extracts were shaken with 2 x 100 mL of 2 N HCl and the organic layer was discarded. The aqueous layer was adjusted to pH 9 with NaOH solution and extracted with 3 x 75 mL of CHCl 3. The extracts were washed with water and dried.

63937 17

After removal of the solvent, the remaining tough gum was triturated dry with ether to give a tan solid. After recrystallization from xsopropanol, the product weighed 6.0 g and melted at 126 ° C.

(c) 1- [2- (5-Phenyl-oxazol-2-yl) -ethyl} -4-phenyl-piperazine N-Phenyl-3- (4-phenyl-piperazin-1-yl) -propionamide (* + .03 g 0.011 mol) was mixed with polyphosphoric acid (36 g) and heated at 140 ° C for 30 minutes with stirring. The mixture was dissolved in water (100 ml), cooled and extracted (2 x 30 ml of chloroform). The extracts were discarded and the pH of the aqueous phase was adjusted to 9 with 50% NaOH solution. The resulting emulsion was extracted with 3 x 100 ml of chloroform, the extracts were dried and evaporated. The crystalline residue was recrystallized from petroleum ether at 60-80 ° C. Yield 2.6 g, m.p. S-84 ° C.

Example 40 1- [5- (3-Trifluoromethylphenyl) -furan-2-ylmethyl] -4-, phenylpiperazine (a) 2-hydroxymethyl-5- (3-trifluoromethylphenyl) -furan 2- (3-trifluoromethylphenyl ) -furan (J. Chem. Soc. (c) 1968, 2737 and Acta Chem. Scand. 24, 2379 (1970)) (21.2 g; 0.1 mol) was stirred in tetrahydrofuran (100 ml), cooled to 40 ° To C and n-butyllithium (0.1 mol, hexane solution) were added dropwise. After stirring for one hour at -40 ° C, paraformal dehyde (3.3 g; 0.11 moles) was gradually added. The mixture was stirred at -40 ° C for 30 min, then the temperature was allowed to rise. The exothermic reaction started at 10 ° C and the temperature gradually rose to 40 ° C (over 10 minutes), then gradually dropped back to 20 ° C. After stirring for the next 1 hour, the clear brown solution was poured into ice / water, the pH was adjusted to about 4 with hydrochloric acid and extraction with ethyl acetate was performed. The acetate extract was dried over MgSO 4 and evaporated to give a brownish yellow viscous oil which was distilled in vacuo to give 2-hydroxymethyl-5- (3-trifluoromethylphenyl) -furan as a colorless solution, b.p. 125 ° C / 0.5 mm, (16.2 g), and which on standing formed crystals, m.p. 45 ° C.

63937 18 (b) .2-Bromomethyl-5- (3-trifluoromethylphenyl) -furan The hydroxymethyl compound (4.84 g; 0.02 mol) prepared according to (a) above was dissolved in dimethylformamide (30 ml), cooled to Q-5 ° C and thionyl bromide (1.7 ml; 0.02 mol) was added dropwise with stirring. After 2 hours, the greenish-yellow solution was poured onto ice / water and extracted with diethyl ether. The ether extract was washed with NaCl (saturated solution), dried over molecular sieve 3A and evaporated to give a light brown oil which crystallized slowly (4.6 g).

(e) 1- {5- (3-Trifluoromethylphenyl) -furan-2-ylmethyl] -4-phenylpiperazine

The bromomethyl product (0.015 mol) from (b) above was stirred in dioxane (50 ml) with N-phenylpiperazine (2.75 g; 0.017 mol) in the presence of anhydrous sodium carbonate (1.5 g) and the mixture was heated at reflux for 7 hours. ice / water and extracted with chloroform. The chloroform extract was washed with water, then brine, and finally evaporated to give an oil which, on treatment with volatile hydrochloric acid, formed a cream-colored crystalline solid (2.1 g). This hydroxide (2 g) was dissolved in chloroform (15 ml), mixed with water (15 ml), and saturated sodium carbonate solution was added dropwise until the mixture was alkaline. The phases were separated and the chloroform layer was evaporated to give a straw-colored oil (1.7 g) which slowly crystallized and recrystallized from petroleum ether at 60/80 ° C to give the title compound 1- [5- (3-trifluoromethylphenyl) -furan-2- ylmethyl-4-phenylpiperazine, 1.2 g, m.p. 94 ° C.

In a similar manner, the following compounds were prepared except that the intermediate hydroxymethyl compounds were converted to chloromethyl compounds with thionyl chloride.

Example 41 1- [5- (4-Chloro-phenyl) -furan-2-ylmethyl-1,7-phenyl-piperazine

Sp. 140 ° C.

Example 42 1- [5- (4-Chloro-phenyl) -furan-2-ylmethyl] -4- (3-trifluoromethyl-phenyl) -piperazine Monohydrochloride The free base was obtained from the step as a viscous oil and converted to the monohydrochloride. i, sp. 22 () ° C.

0 '19 63937

Example 43 1- [N- (4-Chloro-phenyl-furan-2-ylmethyl] -4- (3-chloro-phenyl) -piperazine monohydrochloride M.p. 215 ° C.

Example 4 4 '- [(4- (Chlorophenyl) furan-2-ylmethyl) -4- (3-bromophenyl) piperazine 5- (4-chlorophenyl) -2-furancarboxylic acid (Australian Journal of Chemistry, 26 , 1147 (1973)) (6.67 g; 0.03 mol) was refluxed in benzene (100 ml) with thionyl chloride (4.5 ml) for 1.5 hours. After the excess thionyl chloride was removed, the remaining acid chloride in benzene was added dropwise with stirring and cooling to N- (3-bromophenyl) piperazine (7.23 g / 0.03 mol) and triethylamine (4.5 ml, about 0.03 mol). ) in a mixture of benzene (100 ml).

After stirring at room temperature for one hour, the mixture was shaken with water (100 ml). The separated benzene phase was further washed with brine and evaporated to give an oil which readily crystallized. The product was recrystallized from ethyl acetate / 60-80 ° C from petroleum ether (1/3 v / v) to give 1-, N- (4-chlorophenyl) -2-furoyl-4- (3-bromophenyl) piperazine (12.3 g), m.p. 130 ° C.

The above tertiary amide (4.45 g; 0.01 mol) was dissolved in dry tetrahydrofuran (30 ml) and added dropwise, with stirring and cooling to 0 ° C, to a solution of diborane in tetrahydrofuran (20 ml, 1M solution). the reaction was performed under a nitrogen atmosphere). The temperature rose to about 8 ° C and the resulting cloudy solution was refluxed for one hour. After the clear, pale yellow solution cooled, it was heated on a steam bath for 15 min with 15 N HCl (20 mL). After repeated cooling, the solution was made alkaline (4N NaOH) and extracted with diethyl ether. After drying, the ether extract was evaporated to give an oil which was converted to the title compound as its monohydrochloride (2.8 g), m.p. 217 ° C.

In a similar manner the following were prepared: 63937 20

Example M 5 1- {5- (4-Chloro-phenyl) -furan-2-ylmethyl, 7-4- (3-trifluoromethyl-4-chloro-phenyl) -piperazine M.p. 104 ° C.

Example 46 1- (5- (4-Methyl-phenyl) -furan-2-ylmethyl) -4-phenyl-piperazine M.p. 8 7 ° C.

Example 47 1- [5- (2-Methylphenyl) -furan-2-ylmethyl-N-phenylpiperazine

Sp. 67 ° C.

Example 4 8 1- {5- (3,4-Dichloro-phenyl) -furan-2-ylmethyl-4-phenyl-piperazine M.p. 9 2 ° C.

Example 49 1- [N- (3-Trifluoromethyl-4-chlorophenyl) -furan-2-ylmethyl] -4-phenylpiperazine M.p. 102 ° C.

Example 50 1- [5- (3-Trifluoromethyl-4-chloro-phenyl) -furan-2-ylmethyl] -4- (3-chloro-phenyl) -piperazine monohydrochloride M.p. 216 ° C.

Example 51 1- [5- (3-Trifluoromethyl-4-chloro-phenyl) -furan-2-ylmethyl] -4- (4-methyl-phenyl) -piperazine M.p. 126 ° C.

Example 52 1- (5-Phenyl-furan-2-ylmethyl) -4- (3-chloro-phenyl) -piperazine monohydrochloride

Sp. 208 ° C.

In the following Examples 53-58, the final reduction step was performed using the following internal reduction method · K.M. Biswas and A.H. Jackson, Tetrahedron 24, 1145 (1967).

63937 21

Example 53 1- (5-Phenyl-furan-2-ylmethyl) -4- (3-trifluoromethyl-phenyl) -piperazine 1- (5-phenyl-2-furoyl) -4- (3-trifluoromethyl-phenyl) -piperazine (6 .0 g, 0.015 mol) and sodium borohydride (1.28 g, 0.034 mol) were stirred in a diglyme (25 ml) under a nitrogen atmosphere, and redistilled boron trifluoride etherate (6 ml; 0.045 mol) in a diglyme (20 ml) was added dropwise with constant stirring. The resulting clear solution was stirred at room temperature for three hours and then evaporated to remove diglyme. The residue was carefully diluted with water (100 mL), 5N HCl (20 mL) was added and the mixture was heated on a steam bath for 15 minutes. The mixture was cooled and made alkaline (4N NaOH) and extracted with diethyl ether. The dried ether extract (MgSO 4) was evaporated to give an oil which failed to crystallize. The product was converted to the hydrochloride and then reconverted to the free base as in Example 40. The base formed was a light oil which crystallized very vigorously on cooling, m.p. 56 ° C.

The following were prepared in the same way *

Example 54 * - [(5-Phenyluran-2-ylmethyl) -4- (3,4-dichloro-phenyl) -piperazine

Sp. 150 ° C.

Example 5 1- (5-Phenyl furan-2-ylmethyl) -4-phenylpiperazine M.p. 10 6 ° C.

Example 56 1- (5-Phenyl-furan-2-ylmethyl) -4- (4-methyl-phenyl) -piperazine

Sp. 114 ° C.

Example 57 1- [5- (3,4-Dimethyl-phenyl) -furan-2-ylmethyl] -4- (3-trifluoromethyl-4-chloro-phenyl) -piperazine

Sp. 80 ° C.

63937 22

Example 58 1- {5- (3,4-Dimethyl-phenyl) -furan-2-ylmethyl--4- (3-methoxy) -piperazine M.p. 2 Q 0 ° C.

Example 59 1- ('5- (U-Methoxyphenyl) -furan-2-ylmethyl) -4- (3-trifluoromethyl-4-chlorophenyl) piperazine M.p. 100 ° C.

Example 60 1- [5- (4-Methoxyphenyl) furan-2-ylmethyl] -4-phenylpiperazine

Sp. 96 ° C.

Example 61 1- {5- (4-Methoxyphenyl) furan-2-ylmethyl 11,7-4- (3-trifluoromethylphenyl) piperazine M.p. 7 4 ° C.

Example 62 1- (5-Phenyl-thiophen-2-ylmethyl) -4-phenyl-piperazine 5-Phenyl-2-thiophenecarbonyl acid (Khim G. heterosikl Soedin, 1967, 1020 (Ven.)) Reacted as in Example 44 to give the title compound. compound (recrystallized from 60/80 ° C petroleum ether containing some drops of ethyl acetate). Sp. At 88 ° C.

Example 63 1- (5-Phenylthiophen-2-ylmethyl) -4- (3-chlorophenyl) piperazine 5-Phenyl-2-thiophenecarbonyl acid, as in Example 44, was reacted to the amide, which was then reduced to the title compound as in Example 53. Sp. 115 ° C.

In a similar manner, the following were prepared:

Example 64 1- (5-Phenylthiophen-2-ylmethyl) -4- (4-methoxyphenyl) piperazine

Sp. 136 ° C.

Example 65 1- (5-Phenyl-thiophen-2-ylmethyl) -4- (3-trifluoromethyl-4-chloro-phenyl) -piperazine M.p. 114 ° C.

Il 63937 23

-EgJ mark i 6 R

1- (5-Phenylthiophen-2-ylmethyl) -N (ethyl) -phenyl-phenyl] -piperazine

Sp. 13 5 ° C.

Example 67 1- (5-Phenylthiophen-2-ylmethyl) .1) (3-Trifluoro, ethyl).

phenyl) piperazine M.p. 94 ° C.

Example KR

1- (5-Phenylthiophen-2-ylmethyl) -4- (4-fluorophenyl) piperazine

Sp. 128 ° C.

Example 69 1 "(5-Phenylthiophen-2-ylmethyl) -4- (3,4-dimethylphenyl) piperazine

Sp. 130 ° C.

Example 70 1- [5- (3,4-Dimethyl-phenyl) -furan-2-ylmethyl} -4-phenyl-piperazine 5- (3,4-Dimethyl-phenyl) -furan-2-carboxaldehyde (4.0 g; 0.02 mol) ) prepared by CS Davis and G.S. Lougheed J.Het.Chem. 4.153, (1967), was added with rapid stirring to a solution of N-phenylpiperazine (3.2 g; 0.02 mol) in methanol (30 mL) adjusted to pH 7 (using MeOH / HCl). After 30 minutes, a solution of sodium cyanaborohydride (0.48 g; 0.0075 mol) in methanol (10 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After the methanol was removed by evaporation, the evaporation residue was purified by silica gel chromatography. Fractions containing the desired compound were combined, evaporated and the resulting crystalline evaporation residue recrystallized from petroleum ether at 60/80 ° C to give the title compound, m.p. 110 ° C.

In a similar manner the following were prepared: 24 '63937

Example 71 1- (5- (3-Trifluoromethyl-H-chlorophenyl) -furan-2-ylmethyl-4- (4- (4-fluorophenyl) piperazine M.p. 94 ° C.

Example 7? 1- (5- (4-chlorophenyl) -furan-2-ylmethyl] -4- (4-nitrophenyl) piperazine M.p. 149 ° C.

Example 73 1- [5- (4-Methoxyphenyl) furan-2-ylmethyl] -4- (4-methylphenyl) piperazine M.p. 138 ° C.

Example 74 1- (5- (3,4-Dichlorophenyl) furan-2-ylmethyl] -4- (3-trifluoromethylphenyl) piperazine monohydrochloride M.p. 210 ° C.

Example 75 1- (5-Phenylthiophen-2-ylmethyl) -4- (3,4-dichlorophenyl) piperazine

Sp. 140 ° C.

Example 76 1- (5-Methyl-furan-2-ylmethyl) -4- (3-chloro-phenyl) -piperazine 2-Methyl-2-furancarboxylic acid prepared from D.J. By the method of Chadwick et al., J.C.S. Perkin I, 1766 (1973), reacted as in Example 44 to give the title compound.

bp 145 ° C / 0.01 mm (Kugelrohr).

Example 77 1- (5-Methylfuran-2-ylmethyl) -4-phenylpiperazine 2-Methyl-2-furancarboxylic acid was converted, as in Example 44, to the amide, which was reduced to the title compound, as in Example 53. K.p. 115 ° C / 0.01 mm (Kugelrohr).

Example 78 1- (5-Methyl-furan-2-ylmethyl) -4- (4-methyl-phenyl) -piperazine

Sp. 52 ° C.

Il 63937 25

Example 7 9 1- (5-Methyl-furan-2-yl-imyl) -4- (4-methyl-phenyl) -piperazine

Sp. 85 ° C.

Example 80 1- (5-Methylfuran-2-ylmethyl) -4- (4-chlorophenyl) piperazine M.p. 78 ° C.

Example 81 1- (5-Methylfuran-2-ylmethyl) -4- (3-trifluoromethyl-4-chlorophenyl) piperazine

A pale yellow oil which partially decomposed on distillation.

Example 82 1- (5-Methylfuran-2-ylmethyl) -4- (3-trifluoromethylphenyl) piperazine K.p. 10 5 ° C / 0.02 mm (Kugelrhr).

Example 83 (a) 1- (5-Methylfuran-2-ylmethyl) -4- (4-fluorophenyl) piperazine M.p. 50 ° C.

Example 83 (b) 1- (5-Methylfuran-2-ylmethyl) -4- (3,4-dimethylphenyl) piperazine

Sp. 47 ° C.

Example 84 1- (5-tert-Butyl furan-2-ylmethyl) -4-phenylpiperazine 5-tert-Butyl-2-furancarboxylic acid, Bull. Soc. Chim.

France 1166 (1962), reacted as in Example 77 to give the title compound against m.p. 48 ° C.

In a similar manner, the following were prepared:

Example 85 1- (5-tert-Butyl-furan-2-ylmethyl) -4- (4-methyl-phenyl) -piperazine

Sp. 6 2 ° C.

63937 26

Example 86 1- (5-tert-Butyl-furan-2-ylmethyl) -1 + - (3-chloro-phenyl) -piperazine K.p. 140 ° C / 0.01 mm (Kugelrohr).

Example 87 1- (5-tert-Butyl-furan-2-ylmethyl) -4- (4-methoxy-phenyl) -piperazine

Sp. 7 ° C.

Example 88 1- (5-tert-Butylfuran-2-ylmethyl) -4- (3-trifluoromethyl-N-chlorophenyl) piperazine K.p. 130 ° C / 0.01 mm (Kugelrohr).

Example 89 1- (5-tert-Butyl-furan-2-ylmethyl) -4- (3-trifluoromethyl-phenyl) -piperazine Pale yellow oil.

Example 90 1- (5-tert-Butyl-furan-2-ylmethyl) -4- (4-fluoro-phenyl) -piperazine

Light yellow oil.

Example 91 1- (5-tert-Butyl-lifuran-2-ylmethyl) -14- (3,4-dimethyl-phenyl) -piperazine M.p. 70 ° C.

Example 92 1- [3- (5-Phenylfuran-2-yl) -prop-1-yl] -4-phenyl] -piperazine 5-Phenyl-2-furan-propionic acid, J.Heterocyc. Chem. 6, 713, (1969) reacted as in Example 77 to give the title compound m.p. 95 C. The following were prepared in the same way:

Example 93 1- [3- (S-Phenylfuran-2-yl) prop-1-yl} -1 '- (1- + methylmethyl) piperazine M.p. 92 ° C.

Example '27 63937.Example 94 - (O- (5-phenylfuran-2-yl) prop-1-yl) -4- (3-trifluoromethylphenyl) pipepazine M.p. 56 ° C.

Example 95 1- [3- (5- (U-Chlorophenyl) furan-2-yl) prop-1-yl] -4- (4-methylphenyl) piperazine

Sp. 130 ° C.

Example 96 E 3- (5- (3,4-dichlorophenyl) furan-2-yl) prop-1-yl] -4- (4-methylphenyl) piperazine M.p. 100 ° C.

Example 97 1- [3- (5-Phenylphen-2-yl) prop-1-yl] -4- (4-methylphenyl) piperazine M.p. 9 2 ° C.

Example 98 (a) 5-Phenyl-2- (2-hydroxyethyl) thiophene 2-Phenylthiophene (16.0 g; 0.1 mol) reacted in the same manner as in Example 40, but using ethylene oxide (10 ml; 0.2 mol) instead of paraformaldehyde. The title compound was obtained as a pale yellow crystalline solid, m.p. 74 ° C.

(b) 1- (2- (5-phenylthiophen-2-yl) ethyl O-4-phenylpiperazine A hydroxyethyl compound (6.13 g; 0.03 mol) prepared according to the above (a). reacted as in Example 40 (b), but using thionyl chloride instead of thionyl bromide The chloroethyl compound was obtained as an oily oil (6.2 g) which crystallized on standing, mp 40 ° C. This product was stirred in dioxane (50 ml) to give N- with phenylpiperazine (4.8 g; 0.03 mol) in the presence of anhydrous sodium carbonate, and the mixture was heated under reflux for 24 hours. ° C to Petro-ether and filtered through a column of silica gel using benzene / ethyl acetate 4: 1 v / v as the developing solvent.The first fast moving zone contained an unreacted chloroethyl compound (3.5 g). the zone was in the title said compound having, after recrystallization from ethyl acetate, m.p. 124 C. In the same way was prepared: 28 6 3 9 3 7

Example 99 1- {2- (5-Phenylthiophen-2-yl) ethyl] -4- (4-methylphenyl) piperazine

Sp. 15 8 ° C.

Example 100 (a) 1 "(5-Phenylfuran-2-ylmethyl) -4- (4-nitrophenyl) piperazine 5-Phenyl-2-furancarboxylic acid was reacted as in Example 44 to give the title amide, which was reduced to the title compound as in Example 53. 170 ° C.

(b) 1- (5-Phenylfuran-2-ylmethyl) -4- (4-aminophenylpiperazine

The product prepared according to (a) was hydrogenated and treated as in Example 36. M.p. 102 ° C.

(c) 1- (5-Phenyl-furan-2-ylmethyl) -4- (4-methanesulfonamido-phenyl) -piperazine

The product prepared according to (b) (2.9 g; 0.009 mol) was stirred in anhydrous ether (50 ml) at room temperature, and reacted with methanesulfonyl chloride (0.68 ml) in the presence of triethylamine (1.2 ml). The mixture was stirred overnight, then the ether was evaporated to give an evaporation residue which was extracted with water and chloroform. The chloroform extract was washed with saturated sodium chloride solution and evaporated to give the title compound as a crystalline evaporation residue which was recrystallized from ethyl acetate, m.p. 178 ° C. In the same way it was made:

Example 101 1- (5-Phenylthiophen-2-ylmethyl) -4- (4-methanesulfonamidophenyl) piperazine

Sp. 18 8 ° C.

Example 102 (a) 5-Phenyl-2- (2-hydroxypropyl) furan-2-phenylfuran (14.4 g, 0.1 mol) reacted in the same manner as in Example 40, but using propylene oxide (9 mL, 0.13 moles). The title compound was obtained as an oily oil (16.0 g), b.p. 145 ° C / 0.05 mm where the compound decomposes.

29 63937 (b) 1- {2- (5-phenylfuran-2-yl) prop-1-yl] -4-phenylpiperazine monohydrochloride

The hydroxypropyl compound (8.0 g; 0.04 mol) was oxidized to the corresponding ketone S.L. By the method of Huang et al., J.O.C. 41, 3329 (1976). The ketone was obtained as a brown oil (4.0 g) which reacted with N-phenylpiperazine and sodium cyanoborohydride as in Example 70, but the reaction took three days. After purification by flash chromatography, the title compound was obtained as a pale yellow oil which failed to crystallize and was converted to its monohydrochloride (ethyl acetate hydrochloride) (1.3 g) m.p. 206 ° C.

In the same way the following had been prepared:

Example 103 1- [2- (5-Phenylthiophen-2-yl) prop-1-yl] -4-phenylpiperazine:

Sp. 89 ° C.

Example 104 1- {2- (5-Phenylthiophen-2-yl) but-1-yl] -4-phenylpiperazine monohydrochloride

Sp. 200 ° C.

Example 105 1- (2-Methylthiazol-4-ylmethyl) -4- (3-bromophenyl) piperazine 4-Chloromethyl-2-methylthioazole (7.4 g; 0.05 mol), 1- (3-bromophenyl) piperazine ( A mixture of 12.05 g; 0.05 mol) and anhydrous sodium carbonate (10 g) was suspended in absolute ethanol (150 ml). The mixture was stirred and refluxed for 8 hours. The solvent was then completely evaporated and water (100 ml) was added. The emulsion thus formed was extracted with dichloromethane, the organic extracts dried over magnesium sulphate and evaporated to give an oil. The oil was dissolved in hot benzene, treated with decolorizing carbon and filtered. The filtrate was evaporated to give the title compound as an oil which crystallized completely, m.p. 82 ° C (ether). In the same way the following had been prepared: 30 '63937 T--

Example. 106 1- (2-methylthiazol-4-ylmethyl) -1- (3-trifluoromethylphenyl) piperazine, dihydrochloride M.p. 176-8 ° C ..

Example 107 1- (2-Methylthiazol-4-ylmethyl) -4- (3-chlorophenyl) piperazine M.p. 71-2 ° C.

Example 108 1- (2-Methylthiazol-4-ylmethyl) -4- (3-methoxyphenyl) piperazine M.p. 71, S-7 2.5 ° C.

Example 109 1- (2-Methylthiazol-4-ylmethyl) -N- (4-bromophenyl) piperazine

Sp. 114-115 ° C.

Example 110 1- (2-Methylazol-4-ylmethyl) -4- (2-bromophenyl) piperazine

Sp. 85 to 86.5 ° C.

Example 111 1- (2-Methylazol-4-ylmethyl) -4- (3,4-dichlorophenyl) piperazine dihydrochloride M.p. 17 5-17 6 ° C.

Example 112 1- (2-Methylthiazol-4-ylmethyl) -4- (3-nitrotenyl) piperazine hydrochloride M.p. 218-222 ° C.

Example 113 1- (2-Methylazol-4-ylmethyl) -4- (4-methylphenyl) piperazine hydrochloride M.p. 190-2 ° C.

Example 114 1- (2-Methylazol-4-ylmethyl) -4- (3-methylphenyl) piperazine hydrochloride M.p. 158-160 ° C.

31

Example 115 6 3 9 3V

1- (2-Methylthiazol-4-ylmethyl) -4- (4-chlorophenyl) piperazine

Sp. 98 ° C.

Example 116 1- (2-Methylthiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethylphenyl) piperazine hydrochloride M.p. 185-7 ° C.

Example 117 1- (2-Methylthiazol-4-ylmethyl) -4- (4-methoxyphenyl) piperazine hydrochloride M.p. 134-5 ° C.

Example 118 1- (2-n-Propylthiazol-4-ylmethyl) -4-phenylpiperazine 2-n-propyl-4-chloromethylthiazole hydrochloride (3.18 g; 0.015 mol), 1-phenylpiperazine (2.43 g; 0.015 mol) ) and sodium carbonate (anhydrous, 10 g) in absolute ethanol (60 ml) were stirred and refluxed for 6 hours. The suspension was filtered and the filtrate evaporated to give a yellow oil which was dissolved in boiling benzene and treated with decolorizing carbon. After filtration, benzene was removed to give a yellow oil which crystallized 4.27 g. The solid was recrystallized from petroleum ether (b.p. 60-80 ° C) at 0 ° C to give a crystalline solid (m.p. 38-39 ° C).

Preparation of starting material (a) 2-n-propyl-4-chloromethylthiazole

To a solution of thiobutanamide (30.96 g, 0.3 mol) in absolute ethanol (200 mL) was added a solution of 1,3-dichloroacetone (38.1 g; 0.3 mol) in ethanol (100 mL). The mixture was refluxed for one hour and the solvent was evaporated. The residue was treated with excess saturated sodium bicarbonate solution and extracted with ether. The extracts were dried and evaporated to give a brown oil which was distilled in vacuo to give a pale yellow oil, b.p. 50 ° C / 0.06 mm Hg. This was converted to the title compound (hydrochloride salt) with volatile hydrogen chloride, m.p. 60 ° C decomposes. In a similar manner there were prepared: 32 6 3 9 3 7 (b) 2-benzyl-4-chloromethylthiazole K.p. 116-118 ° C / 0.09 mm Hg.

(c) 2-isopropyl-4-chloromethylthiazole hydrochloride M.p. 58 ° C (decomposes).

The following compounds were prepared by the method described in Example 118:

Example 119 1- (2-n-Propylthiazol-4-ylmethyl) -4- (4-chlorophenyl) piperazine

Sp. 51-54 ° C.

Example 120 1- (2-n-Propylthiazol-4-ylmethyl) -4- (4-methylphenyl) piperazine

Sp. 41-44 ° C. ......

Example 121 1- (2-n-Propylthiazol-4-ylmethyl) -4- (4-methoxyphenyl) piperazine

Sp. 46-47 ° C.

Example 122 1- (2-n-Propylthiazol-4-ylmethyl) -4- (3-trifluoromethyl-phenyl) piperazine hydrochloride M.p. 162-6 ° C.

Example 123 1- (2-n-Propylthiazol-4-ylmethyl) -4- (3,4-dichlorophenyl) piperazine dihydrochloride M.p. 158-160 ° C.

Example 124 1- (2-n-Propylthiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethylphenyl) piperazine dihydrochloride M.p. 174-8 ° C.

Example 125 1- (2-Benzylthiazol-4-ylmethyl) -4-phenylpiperazine M.p. 60-62 ° C.

Example 126 1- (2-Benzyl-thiazol-4-ylmethyl) -4- (4-chloro-phenyl) -piperazine

Sp. 74 ° C.

33 - 63937

Example I- (2-Benzylthiazol-4-ylmethyl) -4- (4-methoxyphenyl) -piperazine M.p. 6 5 ° C.

Example 128 1- (2-Benzylthiazol-4-ylmethyl) -4- (3-chlorophenyl) -piperazine M.p. 69 ° C.

Example T29 1- (2-Benzyl-thiazol-4-ylmethyl) -4- (4-chloro-3-trifluoromethyl-phenyl) -piperazine Colorless oil.

Example 130 (4-Chloro-benzyl) -thiazol-H-ylmethyl-4-phenyl-piperazine dihydrochloride M.p. 150 ° C (decomposes).

Example 131 1- (2-Isopropyl-thiazol-4-ylmethyl) -4- (4-chloro-phenyl) -piperazine M.p. 54 ° C.

Example 132 1- (2-Isopropyl-thiazol-4-ylmethyl) -4-phenyl-piperazine

Sp. 42 ° C.

Example 133 1- (2-Isopropyl-thiazol-4-ylmethyl) -4- (3-methoxy-phenyl) -piperazine

Sp. 6 5 ° C.

Example 134 1- (2-Isopropyl-thiazol-4-ylmethyl) -4- (3-bromo-phenyl) -piperazine Colorless oil.

Example 135 1- (2-Isopropylthiazol-H-ylmethyl) -N- (n-chloro-3-trifluoromethylphenylpiperazine Colorless oil.

Claims (3)

A process for the preparation of therapeutically useful phenylpiperazine derivatives of the formula R 1 -Q- (CH 2) - (CHR 3) -t / N 2 R 2 N 2 n wherein y R 1 is benzyl, chlorobenzyl, C 1-6 alkyl, phenyl or substituted phenyl having 1-2 halo, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy, C 1-4 alkoxy, or nitro substituent-2- R is a phenyl group having 1-2 halo, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 1-4 alkanoylamino, hydroxy, C 1-4 alkoxy, nitro or C 1-4 alkyl C 1-4 alkylsulfonamido substituent, R is hydrogen or C 1-4 alkyl, Q is furan, thiophene, oxazole or thiazole, m is 1-3 and n is 0 or 1, provided that when m is 2 and n is 0, then R 1 is not methyl if Q is thiazol-5-yl, and for the preparation of their pharmaceutically acceptable salts, characterized in that (A) a compound of formula R 1 -Q- (CH) - (CHR 3) -L VI 2 is condensed where L is a leaving group with the compound, j (b) reducing a compound of formula (i) R 1 -Q- (CH 2 -, - - - (/ V-R 2 VIII 2 -) to a compound of formula I wherein n is 0; or reducing a compound of formula (ii) R 1 -Q- (CH 2) m -CR 3 = (+) N 1 --R 2 IX 2 m 2 / 35,63937 to a compound of formula I wherein n is 1; or (C) cyclizing a compound of formula 1 using a dehydrating agent R 2 -CO-CH 0 -NH-CO- (CH 2) - (CHR) -N N -R X i m n \ / to a compound of formula I wherein Q is oxazole. For the manufacture of a therapeutic agent for phenylpiperazine with formula 1 3 / N 2 Rx-Q- (CH2) m- (CHR'3) nN ^ _ ^ NR ^ I color R1-benzyl, chlorobenzyl, C1-6-alkyl, phenyl or substituted phenyl, som har 1 -2-halo, C 1-4 alkyl, C 1-4 haloalkyl, hydroxy, C 1-4 alkoxy or nitro substituents; R 1 is phenyl, having 1 to 2 halogen, C 1-4 alkyl, C 1-4 haloalkyl, amino, C 2-4 alkanoylamino, hydroxy, C 1-4 alkoxy, nitro or C 1-4 alkylsulfonamido substituent; R 3 is hydrogen or C 1-4 alkyl; Q is furan, thiophene, oxazole or thiazole; m is 1-3 and is 0 or 1, is not 2, is 0, R1 is methyl, is Q, thiazol-5-yl, is a pharmaceutical product, is not known, att man (A) condenser in the form of formulas R1-Q-iCH_) - (CHR3) -L VI 2. n color L is a group of compounds in the form of Γ \ 2 HN NR VII (B) reducer in the form with formula (i) R 1 -Q- ^ N-R 2 VIII is as defined in formula I, i is selected from 0; or reducers and formulations