SI9300191A - New aminoalkyl- and iminoalkyl-piperazine derivatives - Google Patents

Abstract

Compounds of general formula (I) wherein R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, R4 is an NO2 group or a group NR7R8 wherein R7 and R8 are the same or different and each is hydrogen or alkyl, R5 is hydrogen, halogen or CF3, R6 is halogen, or CF3, W is an optionally substituted aromatic ring(s), a heterocyclic ring, a carbocyclic ring(s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group, an alkoxy group, a phenyl group, or a phenoxy group, B is a hydrogen atom, or A and B together constitute a carbonyl group, n1 is 0 or 1, and n2 is 0 or 1, processes and intermediates for their preparation, pharmaceutical preparation containing them and the use of the compounds in the treatment of mental disturbances.

Description

(57) Compounds of general formula:

Sl 9300191

in which R represents a hydrogen atom or a phenyl group, m is an integer from 3 to 8, R4 is an NC> 2-group or group

NR7R8 wherein R7 and Re are the same or different and each represents a hydrogen atom or alkyl, R5 is hydrogen, halogen or CF3, R6 is halogen or CF3, W is an optionally substituted aromatic ring (s), heterocyclic ring, carbocyclic ring (s) or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF ₃ , an alkyl group, an alkoxy group, a phenyl group or a phenoxy group, B a hydrogen atom or A and B together form a carbonyl group, it is not 0 or 1, and Π2 0 or 1, processes and intermediates for their preparation, pharmaceutical preparations containing them and use of these compounds in the treatment of mental disorders.

Nevi amidealkyl · - and ... imidealkyl-plperazines

Areas. of the invention

The invention relates to novel, 1-aryl-4 (ω-amido-1-alkyl and ω-imido1-alkyl) piperazines, intermediates and processes for their preparation, pharmaceutical preparations containing piperazines and the use of said compounds in therapy.

The subject of the invention is the preparation of new compounds that will be useful in the treatment of psychiatric disorders such as schizophrenia and other psychoses, anxiety, depression and manic depressive psychosis.

Condition, technique

Buspirone is a well-known substance that has recently been tested in various diseases of the central nervous system, including depression. It has an affinity for 5HT1A receptors and D2 receptors.

Glennon et al (Glennon RA, Naiman NA, Lyon RA, Titeler M: Journal of Medicinal Chemistry, 1988, 31, 1968-1971) describe some aryl piperazine derivatives, including NAN190 / = 1- (2-methoxyphenyl) -4- ( 4- (2-phthalimido) butyl) -piperazine /, which binds to (3H) -8hydroxyDPAT-labeled 5HT1A receptors. In another report, the same group (Raghuparthi RK, Rydelek-Fitzgerald L, Teitler M, Glennon RA: Journal of Medicinal Chemistry 1991, 34, 2633-2638) describes some analogues of 5HT1 agonist NAN190 having affinity for 5HT1A receptors, as well as a certain affinity for binding to al receptors. Further synthesis work in a related field is also described (Glennon RA, Naiman NA, Pierson ME, Smith JD, Ismaiel AM, Titeler M, Lyon RA: Journal of Medicinal Chemistry 1989, 32, 1921-1926).

Qpis of the invention

In accordance with the present invention, we have discovered that they have new compounds of general formula

Oh

or a pharmaceutically acceptable salt thereof, wherein

R is a hydrogen atom or a phenyl group, m is an integer from 3 to 8,

R4 is located at the meta or para position of the ring and represents the NC> 2-group or NR7R3 group where R7 and Rg are the same or different and each represents a hydrogen atom or an alkyl group of 1-3 carbon atoms,

R5 is located at the ortho, meta or para position and represents a hydrogen atom, a halogen atom or CF3,

Rg located at the ortho, meta or para position and represents a halogen atom or CF3,

W is an optionally substituted aromatic ring (s), a heterocyclic ring, a carbocyclic ring (s), or an optionally substituted methylene group,

A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group having 1-3 carbon atoms, a phenyl group or a phenoxy group,

B is a hydrogen atom, or

A and B together form a carbonyl group, not 0 or 1, and

02 0 or 1, in racemic or optically active form or as a mixture of diastereomers, provided that

1) if W is an optionally substituted aromatic ring (s), they have

R, m, R4, Rg and Rg have the same meaning as above, ηχ is 0 or 1,

Π2 is 0 or 1,

A is a hydrogen atom, a halogen atom, CF3, a hydroxy group, an alkyl group of 1-3 carbon atoms, an alkoxy group of 13 carbon atoms, a phenyl group or a phenoxy group, and B is a hydrogen atom or

A and B together form a carbonyl group,

2) if W is a carbocyclic ring (s) or a heterocyclic ring, they have

R, m, R4, Rg and Rg have the same meaning as above, not 0 or 1, n2 0 or 1,

A and B are hydrogen atoms or

A and B together form a carbonyl group,

3) if W is an optionally substituted methylene group, they have

R, m, R4, R5 and Rg have the same meaning as above, are not and n2 are 1 or not is 1 and Π2 is O or not is O and n2 is 1,

A and B together form a carbonyl group.

affinity for D2 and 5HT1A receptors. This effect allows the use of the compounds defined above in the treatment of mental disorders such as e. psychosis, schizophrenia and depression.

The aromatic ring (s) defined above is especially phenyl or naphthyl and is mono- or disubstituted, such that the substituents are selected in particular from the following: hydrogen atom, halogen atom, hydroxy group, CF3, alkyl group (s) with 1 -3 carbon atoms or alkoxy group (s) with 1-3 carbon atoms.

The heterocyclic ring defined above is particularly furyl, thienyl, pyrrolyl, pyridyl or indolyl.

The carbocyclic ring (s) defined above is particularly mono, bi, or polycyclic ring (s) of 3-12 carbon atoms.

The substituents on the carbocyclic ring (s) defined above are in particular a hydrogen atom or an alkyl group having 1-3 carbon atoms.

The substituent on the methylene group defined above is in particular a hydrogen atom or an alkyl group of 1-4 carbon atoms.

The halogen defined above is in particular a chlorine, bromine or fluorine atom.

Preferred group of compounds are those having the general formula

or pharmaceutically acceptable salts thereof, in which it is located at the 3- or 4- position and represents a hydrogen atom, a halogen atom, CF3, an alkyl group of 1-3 carbon atoms, an alkoxy group of 1-3 carbon atoms, NC> 2 / COCH3 or NR 2 R 3 wherein R 2 and R 3 are the same or different and each represents a hydrogen atom or an alkyl group of 1-6 carbon atoms, m is an integer from 3 to 8,

R4 is located at the meta or para position of the ring and represents the NO2 group or group NR7R3, where R7 and Rq are the same or different and each represents a hydrogen atom or an alkyl group of 1-3 carbon atoms,

R5 is located at the ortho, meta or para position of the ring and represents a hydrogen atom, a halogen atom or CF3,

Rg is located at the ortho, meta or para position of the ring and represents a halogen atom or CF3

W is selected in particular from the following groups:

I

the substituents are in particular a halogen atom, a hydroxy group or a methoxy group, preferably bromine, hydroxy or methoxy at the ortho and / or meta positions.

ii m

X

the substituents are a halogen atom or a methoxy group

If W is one of the groups i-xi, then m is mainly 4-6,

R4 is primarily NH2, preferred R4 is NII2 at the meta or para positions,

Rg is preferably hydrogen or halogen, compounds of which R5 is hydrogen, chlorine or bromine are preferred, R5 is hydrogen or chlorine at the meta or para positions,

Rg is preferably CF3 or halogen, further preferred are compounds wherein Rg is CF3 or chlorine, most preferably Rg is CF3 or chlorine at the meta position.

When W is i-x, then R is preferably H.

When W is i, n ^ is preferably 0 and n2 is preferably 0 or 1, most preferably n2 is 0,

A is preferably hydrogen, methoxy or hydroxy at the ortho position

When W is ii, n ^ is preferably 0.

When W is iii-vii, 0 is not preferred,

A is preferably a hydrogen atom or an alkyl group of 1-3 carbon atoms, and B is preferably a hydrogen atom.

When w is viii, n and n are preferably 0 and

A and B preferably form a carbonyl group.

When W is ix, ni and Π2 are preferably 1 and

A and B preferably form a carbonyl group.

When W is x, ni and Π2 are preferably 0 and

A and B preferably form a carbonyl group.

The following compounds are most preferred

Oh

II

F

F

F in

Both organic and inorganic acids can be used to form the non-toxic pharmaceutically acceptable acid addition salts of the present invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, pamoic, ethandisulfonic, sulfamic, succinic, propionic, glycolic, malic, almond, gluconic, aminocet, pyruvic, aminocet, pyruvic , anthranilic, salicylic, 4aminosalicylic, 4-hydroxybenzoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanyl, naphthalenesulfonic, ascorbic, cyclohexylsulfamine, fumaric, maleic and benzoic. These are easy to prepare using commonly known methods.

Preparation

Compounds of general formula I

Oh

II

r ~ \

v /

N

where R is a hydrogen atom or a phenyl group, m is an integer from 3 to 8,

R4 is located at the meta or para position of the ring and represents the NO2 group or NR7Rg group where R7 and Rg are the same or different and each represents a hydrogen atom or an alkyl group of 1-3 carbon atoms,

R5 is located at the ortho, meta or para position and represents a hydrogen atom, a halogen atom or CF3,

R5 is located at the ortho, meta or para position and represents a halogen atom or CF3,

W is an optionally substituted aromatic ring (s), a heterocyclic ring, a carbocyclic ring (s), or an optionally substituted methylene group,

A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group of 1-3 carbon atoms, an alkoxy group of 1-3 carbon atoms, a phenyl group or a phenoxy group,

B is a hydrogen atom or

A and Β together form a carbonyl group, ηχ 0 or 1, and

02 0 or 1, in racemic or optically active form or as a mixture of diastereomers, provided that

1) if W is an optionally substituted aromatic ring (s)

R, m, R4, R5 and Rg have the same meaning as above, ηχ is 0 or 1,

Π2 is 0 or 1,

A is a hydrogen atom, a halogen atom, CF3, a hydroxy group, an alkyl group of 1-3 carbon atoms, an alkoxy group of 13 carbon atoms, a phenyl group or a phenoxy group, and B is a hydrogen atom or

A and B together form a carbonyl group,

2) if W is a carbocyclic ring (s) or a heterocyclic ring, they have

R, m, R4, R5 and Rg have the same meaning as zgoi'aj, ηχ is 0 or 1,

Π2 is 0 or 1,

A and B are hydrogen atoms or

A and B together form a carbonyl group,

3) if W is an optionally substituted methylene group, they have

R, m, R4, R5 and Rg have the same meaning as above, ηχ and n2 are 1 or ηχ is 1 and Ώ.2 is 0 or ηχ is 0 and Π2 is 1,

A and B together form a carbonyl group, prepared by one of the following alternative methods.

I I

A) Reaction of a compound of general formula II

II

N- [CH ₂ ] _m -X

-A

CH — A

in which R, m, W, k, B, and Π2 have the same meaning as above and X is a suitable leaving group as halogen, arylsulfonate or alkylsulfonate, with a compound of general formula III

III in which R4, R5 and Rg have the same meaning as above in a suitable solvent as alcohol, DMF, acetonitrile or DMSO in the presence of a base such as triethylamine, sodium hydroxide or potassium carbonate and a catalytic amount of sodium or potassium halide than KJ for a longer time at room or higher temperatures.

B) Conversion of a compound of general formula IV

Oh

II

CH

A

B

IV in which R, m, R5, Rg, W, A, B, and n2 have the same meaning as above and Y is located at the meta or para position and represents a group which can be converted to a group R4I, wherein R4I is located at the meta or para position of the ring and represents the group NR7Rq in which R7 and Rg have the same meaning as above by suitable hydrolysis, reductive, electrochemical or other known methods.

The compounds of formula IV can be prepared according to method A. Tax group Y can be selected from readily cleavable amides, carbamates, imines, benzylamines or other suitably protected amino groups. Such groups may be trifluoroacetamido, formamido, t-butoxycarbonylamino or Nbenzylamino.

Y can also be groups such as nitro, azido, hydroxyamino, hydrazone, amido or imino, which can be converted to R4I by known reductive methods.

C) Reaction of a compound of the general formula V / ^CH 2 ^] n -C

Oh

II

-c-Z

CHf-A I

R 'n.

N-CCH ₂ ] _m . <

B in which R, m, A, B, n ^ and Π2 have the same meaning as above and Z is hydrogen, hydroxy, halogen or alkoxy, with a compound of general formula III

III

Ιό in which R4, R5 and Rg have the same meaning as above in the presence of a suitable reducing agent as sodium cyanoborohydride or lithium aluminum hydride in a direct or gradual manner.

D) Reaction of a compound of general formula VI

Oh

II / [ ^ΟΗ 23η _η “ ^ο

W \

VI

CH-A h ₂ in which W, ηχ, Π2 and A have the same meaning as above and T independently or together with A represents a suitable aliphatic, cycloaliphatic, aromatic or heterocyclic acid derivative or acid derivative such as halide, ester, imide, anhydride or other an acid activating group, with a compound of general formula VII

in which m, R4, R5 and Rg have the same meaning as above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid or tetrahydrofuran or without solvent for a longer time at room or elevated temperature.

E) Reaction of a compound of general formula VIII

Vlil —A

Cl ·

wherein R, m, R4, W, A, B, and n2 have the same meaning as above and R5 is hydrogen, halogen or CF3 with a suitable halogenating reagent as sulfuryl chloride or bromine in a suitable solvent such as chloroform or dioxane.

F) The reaction of the compounds of general formula IX

Oh

II / ^CH 23n “ ^c x

CH I

R —A

N — M I

B

IX in which W, ηχ and n2 have the same meaning as above, A and B together represent a carbonyl group and M represents a suitable alkali metal as sodium or potassium, with a compound of the general formula X

X in which X, R4, R5 and Rg have the same meaning as above in a suitable solvent as DMF, acetonitrile or DMSO in the presence of a base such as triethylamine, sodium hydroxide or potassium carbonate for a longer time at room or higher temperature.

Intermediates

A compound of general formula II

V /

CH

I

R

-A n «in which R, m, W, A, B can be prepared above so that ηχ, n2 and X have the same meaning as a compound of the general formula VI

Oh

II, t ^CH 2ln „- ^c

VI

CH ⁿ 2 in which W, np n2 and A have the same meaning as above and T independently or together with A represents a suitable aliphatic, cycloaliphatic, aromatic or heterocyclic acid derivative or an acid derivative such as halide, ester, imide, anhydride 'or other acid-activating acid a group having a compound of general formula XI

Η ₂ Ν - [CH ₂ ] _m -OH XI in which m has the same meaning as above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid or tetrahydrofuran or without solvent for a longer time at room or elevated temperature and then the intermediate is reacted with general formula XII

Oh

II

C ^CH 2ln ^ “ ^C s

CH l

R

N— [CH ₂ ] _m -OH B

XII

n.

in which R, m, W, A, B, n ^ and Π2 have the same meaning as above with a suitable halogenating reagent such as thionyl chloride, phosgene, oxalyl chloride or phosphorus tribromide or with a suitable sulfonation reagent as sued chloride or other arylsulfonyl chloride or alkylsulfonyl chloride.

A compound of the general formula 111 ^

in which R4 is ¹ , Rg and Rg have the same meaning as above can be prepared from a compound of general formula XIII

in which they have Y, by method B.

R5 and Rg have the same meaning as above by analogy

A compound of general formula XIII

in which R5 and Rg have the same meaning as above and Y is NCh can be prepared by metabolizing a compound of general formula XIV

XIV in which R5 and Rg have the same meaning as above, Y is NO2 and U is halogen, with piperazine or with appropriately monosubstituted piperazine, in which the substituent is easily removable, such as e.g. with a benzyl or ethoxycarbonyl group, or by reacting a compound of general formula XV

in which R5 and Rg have the same meaning as above and are Υ NO2 with a compound of the general formula XVI / GH ₂ CH ₂ X

V — N

XV »ch ₂ ch ₂ xv in which X has the same meaning as above and V is hydrogen or a readily removable group as benzyl or ethoxycarbonyl.

A compound of the general formula X

in which X, m, R4, R5 and Rg have the same meaning as above can be prepared by reacting a compound of general formula XVII

X— [CH ₂ ] _m -X XVII in which X and m have the same meaning as above with a compound of general formula III

III in which R4, R5 and Rg have the same meaning as above, under suitable reaction conditions, analogous to method A.

Pharmaceutical formulations

In accordance with the present invention, the compounds of formula I will typically be administered orally, rectally or by injection in the form of pharmaceutical compositions containing the active ingredient, or in the form of a free base or a pharmaceutically acceptable non-toxic acid addition salt, e.g. hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like. in a pharmaceutically acceptable dosage form. The dosage form can be a solid, semi-solid or liquid preparation. Typically, the active substance will form between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.

For the preparation of pharmaceutical formulations containing a compound of formula I in the form of dosage units for oral administration, the selected compound may be mixed with a solid carrier, e.g. lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, binders such as gelatin or polyvinylpyrrolidone, and glidants such as magnesium stearate, calcium stearate, paraethylene glycol, paraethylene glycol . If coated tablets are required, the kernels prepared as described above may be coated with a concentrated sugar solution which may contain e.g. arabic gum, gelatin, talc, titanium dioxide and the like. Alternatively, the tablet may be coated with a polymer as is commonly known in the art, dissolved in a volatile organic solvent or organic solvent mixture or in water. Dyes may be added to these coatings in order to allow the tablets containing different active substances or different amounts of active compounds to be well separated.

For the preparation of soft gelatin capsules, the active substance may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active substance using either the aforementioned tablet carriers, e.g. sucrose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. The active gelatin capsules can also be filled with the active substance in liquid or semi-solid state.

Dosage forms for rectal administration may be solutions or suspensions, or they may be formulated as suppositories containing the active substance in admixture with a neutral fatty base or gelatin rectal capsules containing the active substance in admixture with vegetable oil or paraffin oil.

Liquid preparations for oral administration may be in the form of syrups or suspensions, e.g. solutions containing from about 0.2% by weight to about 20% by weight of the active substance described herein, the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavors, saccharin and carboxymethylcellulose as a thickening agent or other well-known excipients.

Solutions for parenteral administration may be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabilizers and / or buffers and may conveniently be prepared as ampoules.

Suitable daily doses of the compounds of the present invention in human therapy are 50-500 mg for oral administration and up to 100 mg for parenteral administration.

Formula compounds are particularly preferred for the application

or

Implementation examples

Example 1 (Method A)

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine dihydrochloride

A mixture of 3.18 piperazine, potassium acid, washes.

g (0.01 mol) of 4-amino-3-trifluoromethylphenyl catalytic amount KJ, 4.1 g (0.03 mol) of carbonate and 3.0 g (0.01 mol) of N- (4bromobutyl) phthalimide in 5 ml of DMF were stirred at 100 ° C overnight. After addition of 500 ml of water, the mixture was extracted with ether. Extract with water and extract with dilute hydrochloric acid The aqueous phase is separated, basified with sodium hydroxide and extracted again with ether. The extract was dried (Na2SO4) and acidified with hydrogen chloride in ether. The resulting precipitate was filtered off and recrystallized from ethanol-ether.

Yield 3.0 g (58%).

Melting point 226-227 ° C.

The following compounds (2-12) were prepared in an analogous manner:

Example 2

1- (4-Amino-3-trifluoromethylphenyl) -4- (3-phthalimido-1-propyl) piperazine dihydrochloride.

Melting point 167-169 ° C.

Melting point 114-118 ° C.

Example 3

1- (4-Amino-3-trifluoromethylphenyl) -4-f 5- (3-methoxyphenyl imido) 1-pentylpiperazine oxalate

Example 4

1- (4-Amino-3-trifluoromethylphenyl) -4- [4- (4-chlorophthalimido) -1butylfeiperazine dihydrochloride.

Melting point 203-204 ° C.

Example 5

1- (4-Amino-3-trifluoromethylphenyl) -4- (5-phthalimido-1-pentyl) L.

piperazine trihydrochloride.,.

Melting point 109-113 ° C.

Example 6 1Z4-ylbenzyl-5-di-propylphenyl) -4-H-phthalroido-1-butylpiperazine

Melting point 116-119 ° C.

Example 7

1-14-Amino-3-trifluoromethylphenyl) -4-f3- (1,8-naphthalimido) -1propylpiperazine

Melting point 156-158 ° C.

Example 8

1- (4-Amino-3-trifluoromethylphenyl) -4--4- (3,3-dimethylglutarimido) -1-butylpiperazine dihydrochloride

Mp 235-236 ° C.

Example 9

1- (4-Amino-3-trifluoromethylphenyl) -4-4- (3,3-tetramethylenglutarimido) -1-butylpiperazine dihydrochloride

Melting point 243-245 ° C.

Example 10

1- (4-Amino-3-trifluoromethylphenyl) -4--5- (3-phenylalutarimido) 1-pentylpiperazine hydrochloride

Melting point 136-140 ° C.

Example n

1- (3-Amino-4-chlorophenyl) -4-5- (2-furancarboxamido) -1pentyl-piperazine oxalate

Melting point 165-170 ° C.

Prlmer.i2

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-cyclohexanecarboxamido-1-butyl) piperazine

Melting point 127-128 ° C.

Example 13 (Method B)

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-thymido-1-butyl) piperazine acetate.

The product of Example 38 (9.53 g, 20 mmol) was dissolved in 100 ml of ethanol and 50 ml of acetic acid and hydrogenated with Pd / C (1.0 g) as a catalyst for 5 h. The mixture was filtered, the solvent was evaporated and the residue was crystallized from diisopropylether and ethanol; 10.0 g of the title product are obtained.

Melting point 101-103 ° C.

The following compounds (Examples 14-24) were prepared in an analogous manner:

Primor 14

1- (4-Ando-3 ^ trifluoromethylphenyl) -4- (6-phthalimido-1-hexylpiperazine acetate.

Melting point 125-127 ° C.

Example 15 1- (4-Amino-3-trifluoromethylphenyl) -4- (8-phthalimido-1-octyl) piperazinacetate;

Melting point 94-96 ° C.

Example 16

1- (3-Anrino-4-chlorophenyl) -4- (4-phthalimido-1-butyl) piperazine acetate.

Melting point 159-162 ° C.

Example 17

1- (3-Amino-4-chlorophenyl) -4- (5-phthalimido-1-pentyl) piperazine acetate., ..

Melting point 149-150 ° C.

Example .. 18

1- (4-Amino-3-methylphenyl) -4- (4-phthalimido-1-butyl) piperazine acetate. ·

Melting point 123-126 ° C.

Example ..... 19

- (3-Amino-4-chlorophenyl 1) ~ 4- [4- (3,3-tetramethenyllutarimine) 1-butylpiperazine

Melting point 133-136 ° C.

Example 20

1- (4-Amino-3-trifluoromethyl and 1 phen and 1) -4- (6- (3-phenoxy benzamide) 1-hexylpiperazine acetate

Melting point 128-131 ° C.

Example 21

1- (4-Amino-3-trifluoromethylphenyl) -4- (6-cyclohexanecarboxamido-1-hexyl) piperazine dihydrochloride

Melting point 112-115 ° C.

Example 22

1- (4-7Unino-3-trifluoromethylphenyl) -4- (4-adamantanecarboxamido-1-butyl) piperazine dihydrochloride

Melting point 123-125 ° C.

Example 23

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-adamantanacetamido-1-butyl) piperazine

Melting point 115-116 ° C.

Example 24

1- (4-Amino-3-trifluoromethylphenyl) -4- (6-adamantanecarboxamido1-hexyl) piperazine

3-H NMR (CDCl3) d 7.00 (s, 1H), 6.96 (dd, and H), 6.70 (d, 1H),

5.57 (bs, 1H), 3.26 (bs , 2 H), 3.24 (m, 2H), 3.08 (m, 4H), 2.61 (m, 4H), 2.39 (m, 2H), 2.04 (bs, 3 H), 1.84 (bs, 6 H), 1.71 (bs, 6 H), 1.52 (m, 4 H), 1.34 (m, 4 H).

Example 25 (Method B) 1- [4- (4-AmiD.Q.-2-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine dihydrochloride,

To a mixture of 1- (4-nitro-2-trifluoromethylphenyl) -4- (4-phthalimido-butyl) piperazine (7.8 g, 0.01 mol) in 200 ml of ethanol and 60 ml of water was gradually added 11.2 g of sodium dithionite with stirring at 100 ° C. The mixture was refluxed for 1 h and the ethanol was evaporated. The remaining aqueous solution was basified with NaOH and extracted with ether. The extract was washed with water, dried and the ether evaporated. The resulting oil was dissolved in 100 ml of dry ether and the dihydrochloride was eliminated by the addition of hydrogen chloride in ether. The salt was recrystallized from ethanol-ether to give 2.3 g (44%) of the title compound.

Melting point 243-244 ° C.

Example 26 (Method B)

1- (4-Diethylamino-3-trifluoromethylphenyl) -4- (4-phthalimido-butyl) piperazine

The product of Example 13 (1.0 g, 2 mmol) dissolved in 5 ml of acetic acid was added to a mixture of sodium borohydride (304 mg, 8 mmol) in 20 ml of toluene. The mixture was heated at 80 ° C for 6 h, cooled and added to 50 ml of water and 50 ml of ether, basified with 2M sodium hydroxide. The organic phase is dried and evaporated. The residue was crystallized from hexane to give 440 mg of the title product.

Melting point 70-71 ° C.

Example 27 (Method B)

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl.) Piperazine.

4- (4-Acetamino-3-trifluoromethylphenyl) -1- {4-phthalimido-butyl) -piperazine (4.9 mg, 0.01 mmol) dissolved in 2 ml of ethanol and 0.2 ml of 2 M hydrochloric acid was heated at 80 ° C for 5 h. The solvent is removed; the residue is identical to the product in Example 1, as shown by gas chromatography.

Example 28 (Method Cl

4- (4-Amino-3-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine

To a refluxing solution of 4-phthalimido-1-butanal (0.713 g

98% (3.25 mmol) and N- (4-amino-3-trifluoromethylphenyl) piperazine (0.804 g, 3.25 mmol) in CHCl3 (10 ml) were added dropwise.

CHCl3 (10 ml) in 20 min 2 h. The solvent was removed and thinly so that the product was identical to formic acid and purified by reflux under reflux, showing the example 1.

Solution and residue and gas product v

Example 29 (Method D)

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-phthalimido-1-butyl) piperazine

A solution of 4- {4-amino-3-trifluoromethylphenyl) -1- (4-aminobutyl) piperazine (32 mg, 0.1 mmol) and phthalanhydride (30 mg, 0.2 mmol) in 1 ml of acetic acid was stirred at 75 ° C for 3 hours. The solvent was removed and gas and thin layer chromatography showed the residue to be identical to the product in Example 1.

Example 30 (Method Dl

1- (4-Amino-3-trifluoromethylphenyl) -4- (4- (5-bromo-2,3dimothoxybenzamido) -1-butylpiocrazine dioxalate

The product of Example 1 (3.3 g, 6.4 mmol) was dissolved in 60 ml of ethanol, basified with 2 M NaOH and the base was heated for 3.5 h with hydrazine hydrate (2.0 ml) at 75 ° C. After cooling, the solution was acidified with 27 ml of 2 M HCl and evaporated. The residue was dissolved in 75 ml H2O and 75 ml ether. The aqueous phase was basified and extracted with chloroform. The solvent was evaporated to give crude 1- (4-aminobutyl) 4- (4-amino-3-trifluoromethylphenyl) piperazine. A solution of 5bromo-2,3-dimethoxybenzoic acid (0.52 g, 2.0 mmol) in 10 ml of toluene, thionyl chloride (2 ml, 23 mmol) and a couple of DMF drops was heated at 60 ° C for 3 h. The solvent was evaporated and the residue was dissolved in 15 ml of dichloromethane and evaporated again. The remaining acyl chloride was dissolved in 15 ml of dichloromethane and a solution of the crude amine above (0.51 g,

1.6 mmol) and triethylamine (0.45 g, 3.2 mmol) in 10 ml of dichloromethane. After stirring overnight, the solvent was evaporated and the residue partitioned between dilute HCl and ether. The organic phase was extracted with water and the combined aqueous phases were basified and extracted several times with chloroform. Drying (Na2SO4) and evaporation gave 0.57 g of an oily product. The base was dissolved in acetone and oxalic acid was added to give 0.95 g of the title product.

Melting point 174 - 175 ° C.

The following compounds were prepared in an analogous manner (Examples 31 - 34):

Example 31

1- (4-Amino-3-trifluoromethylphenyl) -4- (4-benzamido-1-butyl) piperazine

Melting point 117-120 ° C.

Example 32

- (4-Anri ηο-3-trifluoromethyl and 1 phenyl 1) -4- [5- (5-chromo- ?, 3dimethoxybenzamido) -1-pentyl] piperazine dioxalate

Melting point 151-154 ° C.

Example 33

1- (4-Amino-3-trifluoromethyl 1-phen and 1) -4-f 4 - (2-norbornanecarboxamido) -1-butyl] piperazine hydrochloride

Melting point 77 - 80 ° C.

Example 34

IR.endo) -1- (4-Amino-3-trifluoromethyltenyl) -4-4- (2-norbornanecarboxamido) -1-butyl] piperazine hydrochloride

Melting point 142 - 146 ° C.

Example 35 (Method B)

1- (4-Amino-5-bromo-3-trifluoromethylphenyl) -4- (4-phthalimido-butyl) piperazine oxalate

The product of Example 13 (1.0 g, 2 mmol) was dissolved in 20 ml of dioxane and 5 ml of methanol. Bromine (350 mg, 2.2 mmol) was dissolved in 3 ml of dioxane and the mixture was stirred at room temperature for 5 hours, the solvent was evaporated, the residue was basified with 2 M aqueous NaOH and extracted with methylene chloride. The solvent was removed and the residue dissolved in diisopropylether and the title compound was eliminated with oxalic acid dissolved in ethanol.

Melting point 172 - 175 ° C.

Example 36 (Intermediate, Compound IX)

N- (5-Bromopentyl) -3-methoxyphthalimide

3-Methoxyphthalanhydride (3.0 g, 16.8 mmol) and 5-amino-pentanol (1.7 g, 16.8 mmol) were stirred and heated for 2 h to 120 ° C. After cooling, phosphorus tribromide (3.5 g, 13 mmol) was added and the mixture was heated to 110 ° C for 2 h, poured onto ice, extracted with ethyl acetate and the organic phase separated, dried and the solvent was evaporated. The residue was crystallized from ethyl acetate / hexane.

Melting point 65 - 67 ° C.

Example 37 (Intermediate sex II)

N- (5-Tosyloxypentyl) -5-bromo-2,3-dimethoxybenzamide

A solution of 5-bromo-2, 3-dimethoxybenzoic acid (1.56 g, 6.0 mmol) in 25 ml of toluene, thionyl chloride (6 ml, 70 mmol) and a couple of DMF drops was heated at 60 ° C for 3 h. The solvent was evaporated, the residue was dissolved in 20 ml of dichloromethane and evaporated again. Dissolve the remaining acid chloride in 20 ml of dichloromethane and add to a solution of 5-aminopentanol (1.8 g, 18 mmol) and triethylamine (4 ml, 28 mmol) in 30 ml of dichloromethane at -35 ° C and allow the temperature to rise for 4 h to 0 ° C. The solution was washed with dilute HCl, the organic phase separated and the solvent removed to give 2.2 g of crude oil. This oil was dissolved in 20 ml of dichloromethane, triethylamine (4 ml, 28 mmol) and tosyl chloride (1.33 g, 7 mmol) were added and the mixture was stirred overnight at room temperature. Ethyl ether (100 ml) was added and the organic phase was washed with sodium carbonate solution and water. After drying, the organic solvent was evaporated to give 2.7 g (5.5 mmol) of the oily title product.

^{Χ Η} NMR (CDCl3) d 7.9 (bs, 1 H) , 7.81 (d, 1H), 7.77 (d, 2 H), 7.34 (d, 2H), 7.13 (d, 1 H), 4.03 (t, 2H), 3.89 (s, 3 H), 3.87 (s, 3 II), 6 H). 3.42 (q, 2 II), 2.44 (s, 3 II), 1.73 - 1.40 (m,

Example 38 (Intermediate Compound IV)

1.7 {4-Nitrp-3-trifluoro-phenylphenyl) -4- (phthalimido-1-butylipiperazine

The compound of Example 39 (8.5 g, 30 mmol), 4-bromobutylphthalimide (11.1 g, 40 mmol), potassium carbonate (5.0 g, 36 mmol) and the catalytic amount of potassium iodide were heated 6 * h to 90 ° C in 80 ml of DMF. The mixture was poured into 500 ml of water and extracted with methylene chloride. The organic phase was dried, the solvent was evaporated and the residue was covered with ethanol / disopropyl ether to give a yellow, crystalline product.

Melting point 152-154 ° C.

Example 39 (Intermediate Compound XIII)

1- (4-Nitro-3-trifluoromethylphenyl) piperazine

A mixture of 22.4 g (0.1 mol) of 4-nitro-3-trifluoromethyl-1-chlorobenzene, 50.0 g (0.58 mol) of anhydrous piperazine and a catalytic amount of KJ in 80 ml of 1-propanol were stirred and heated at 100 ° C overnight. After cooling, 1 1 of ice water is added while stirring. The resulting precipitate was filtered off, filtered with water and dried.

Yield 26.6 g (94%). 81-83 ° C.

Example 40 (Intermediate Compound XIII)

4-Amino-2,6-dichlorophenylpiperazine

2,6-Dichloro-4-nitroaniline (10.4 g, 50 mmol) dissolved in 100 ml of methanol and 10 ml of 2 M IIC1 was hydrogenated with platinum to

NTP 8 h. Catalyst

The residue was dissolved in ether g (29 mmol) of gray carbon as a catalyst, filtered off and the solvent removed and basified to give 5.1 crystalline powder. This product was reacted with bis- (2-chloroethyl) amine hydrochloride (5.4 g, 30 mmol) by heating to 100 ° C in n-butanol with 3 χ 1 g of sodium carbonate (30 mmol) for 26 hours. The solvent was evaporated, the residue was dissolved to give 3.4 g (48%) of oily ether and the product was basified.

^X H NMR (CDCl 3) d 6.82 1.82 (s, 1H).

H), 4.10 (s, 2 H), 3.02 (m, 8 H),

The following examples illustrate suitable pharmaceutical compositions for use in the invention. The tablets may have the following composition.

Composition 1

Pharmaceutical preparations

Compound of Example 1 Lactose

Potato starch

Polyvinylpyrrolidone

Microcrystalline cellulose Magnesium stearate

Composition 2

Compound of Example 1 Lactose

Potato starch

Polyvinylpyrrolidone

Microcrystalline cellulose Magnesium stearate g 85 g 40 g g 18 g g

100 g g 50 g g

g 2 g

1000 tablets containing 50 mg and 100 mg of active substance can be prepared from the above compositions. If desired, the obtained tablets can be coated with a film of e.g. hydroxypropyl methyl cellulose in an organic solvent or using water.

Pharmacology

It is generally accepted that agents that bind to dopamine D2 receptors and have antagonists at these receptors to act clinically as antipsychotic agents (for example in schizophrenia). It is also widely believed that affinity and agonist effects on serotonergic (5HT1A) receptors may be beneficial properties for reducing the incidence of extrapyramidal side effects and for enhancing substance efficacy in psychoses. By having a specific binding ratio to D2 and 5HT1A, these substances will retain their antipsychotic effect while reducing the incidence of side effects and improved efficacy.

Table 1 illustrates the binding affinities (K4 values, nm) of some compounds to the dopamine (D2) and serotonin (5HT1A) receptors and the D2 / 5HT1A ratios.

The pharmacological methods are described below.

D2 receptor binding assay

Tissue preparation: Rats are beheaded and striated on ice. The tissue was homogenized at 0 ° C in 20 ml of 0.05 M Tris-HCl buffer ph 7.7 using a Branson B30 sonifier. The homogenate was centrifuged at 4 ° C for 10 minutes at 48000 g in a Gorvall RC-5B cooled ultracentrifuge. The sediment was resuspended and centrifuged. The final sediment was resuspended in incubation buffer (0.05 M Tris-HCl, pH 7.6 containing 0.1% ascorbic acid, 120 mM NaCl, 5 mM KCl, 2 mM CaCl2, lmM MgCl2 and 10 μΜ pargillin) to a final concentration of 2.5 mg wet weight / 0.5 ml. The homogenate was incubated for 10 min at 37 ° C.

Receptor binding assay; Different concentrations of the test compound, radioligand (1 nM ^ H-Raclopride) and homogenate were incubated for 60 min at room temperature. Non-specific binding is determined by the addition of 1 μΜ (+) - Butaclamol. The incubation is completed by rapid filtration through glass fiber paper (Whatman GF / B) and further washing with cold incubation buffer using a cell harvester.

The radioactivity of the filters is measured with a Packard 2200CA scintillation counter. Data are analyzed by nonlinear regression using LIGAND and presented as K ₂ values.

5-HTj ^ Receptor Binding Test

Tissue preparation. The cerebral cortex + hippocampus of each rat was excised and homogenized for 10 s in 15 ml of ice-cold 50 mM Tris-HCl buffer, 4.0 mM CaCl2 and 5.7 mM ascorbic acid, pH 7.5 with Ultra-Turrax (Janke & Kunkel, Staufen, ZRN). After 12.5 minutes of centrifugation at 17,000 rpm (39,800 x g in Beckman JA-17 Beckman-cooled rotor Beckman, Palo Alto, CA, USA), the sediments were resuspended in the same buffer and homogenized and centrifuged again. To each sediment was added 5 ml of ice-cold 0.32 M sucrose and homogenized for 5 sec. These samples were stored frozen at -70 ° C. When used, they are diluted with buffer to 8 mg tissue / ml and homogenized for 10 sec. The tissue homogenates were incubated for 10 min at 37 ° C and then 10 μΜ of pargillin were added, followed by incubation for 10 min. The binding assay was performed as described in Peroutka, J. Neurochem. 47, 529-540, (1986).

The incubation mixture (2 ml) contains ^ H-8-OH-DPAT (0.25 to 8 nM), 5 mg / ml tissue homogenate in 50 mM Tris-IICl buffer containing 4.0 mM CaCl2 and ⁿ 5.7 mM ascorbic acid, pH

7.5. Six different concentrations of ^ H-8-OH-DPAT are analyzed. In the binding experiments, tissue homogenisate was first added, then incubated at 37 ° C for 10 min. The incubation mixtures were filtered through Whatman GF / B glass filters with Brandel Celi Harvester (Gaithersburg, MD, USA). The filters were washed twice with 5 ml of ice-cold 50 mM Tris-HCl buffer, ph 7.5 and measured with 5 ml of Uitima Gold ™ IPackard) in Beckman's LS 3801 scintillation counter. Non-specific binding is measured by the addition of 10 μΜ 5-HT to the reaction mixture. Binding data are processed by nonlinear least squares computer analysis (Munson and Rodbard, Anal. Biochem, 107, 220-239, (1980)). We display the data as

Kj values (nM). For

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A compound of the general formula O or their pharmaceutically acceptable salts, where appropriate R is a hydrogen atom or a phenyl group, m is an integer from 3 to 8, R4 is located at the meta or para position of the ring and represents NC > R5 is located at the ortho, meta or para position and represents a hydrogen atom, a halogen atom or CF3, Rg located at the ortho, meta or para position and represents a halogen atom or CF3, W is an optionally substituted aromatic ring (s), a heterocyclic ring, a carbocyclic ring (s), or an optionally substituted methylene group, A is a hydrogen atom, a hydroxy group, a halogen atom, CF3, an alkyl group of 1-3 carbon atoms, an alkoxy group of 1-3 carbon atoms, a phenyl group or a phenoxy group, B is a hydrogen atom or A and B together form a carbonyl group, n ^ 0 or 1, and no 0 or 1, in racemic or optically active form or as a mixture of diastereomers, provided that 1) if W is an optionally substituted aromatic ring (s) R, m, R4, Rg and Rg have the same meaning as above, ηχ is 0 or 1, n2 is 0 or 1, A is a hydrogen atom, a halogen atom, CF3, a hydroxy group, an alkyl group of 1-3 carbon atoms, an alkoxy group of 13 carbon atoms, a phenyl group or a phenoxy group, and B is a hydrogen atom or A and B together form a carbonyl group, 2) if W is a carbocyclic ring (s) or a heterocyclic ring, they have R, m, R4, Rg and Rg have the same meaning as above, ηχ is 0 or 1, 112 is 0 or 1, A and B are hydrogen atoms or A and B together form a carbonyl group, 3) if W is an optionally substituted methylene group, they have R, m, R4, Rg and Rg have the same meaning as above; n ^ and n2 are 1 or n] _ is 1 and n ₂ is O or n ^ is O and n ₂ is 1, A and B together form a carbonyl group or or Oh II C N - ^CH 2 \ - ^N , / ~ y or