AU3964393A

AU3964393A - Novel amidoalkyl- and imidoalkyl-piperazines

Info

Publication number: AU3964393A
Application number: AU39643/93A
Authority: AU
Inventors: Christina Akesson; Stefan Bengtsson; Lennart Florvall; Gerd Hallnemo; David Jackson; Svante Ross; Bo-Ragnar Tolf; Bengt Ulff; Lian Zhang
Original assignee: Astra AB
Current assignee: AstraZeneca AB
Priority date: 1992-04-09
Filing date: 1993-04-06
Publication date: 1993-11-18
Anticipated expiration: 2013-04-06
Also published as: SE9201138D0; SI9300191A; CA2109816A1; WO1993021179A1; CZ270193A3; FI935494A0; EP0594813A1; NO180794C; AU665825B2; BG98281A; NO934426L; NO180794B; FI935494A; HUT68891A; SK138993A3; JPH06508378A; NO934426D0; CN1099752A

Description

Novel amidoalkyl- and imidoalkyl-piperazines Field of the invention

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

The object of the present invention is to provide novel compounds that will be useful in the treatment of psychiatric disorders such as schizophrenia and other psychoses, anxiety, depression and manic-depressive psychosis.

Prior art Buspirone is a known substance that has been recently tested in a variety of central nervous system diseases including depression. It has affinity for both 5HT1A receptors and for D2 receptors. Glennon and colleagues (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] that bind to 5HT1A receptors as labelled by (3H)-8-hydroxyDPAT. In another report, the same group (Raghuparthi RK, Rydelek-Fitzgerald L, Teitler M, Glennon RA: Journal of Medicical Chemistry 1991, 34, 2633-2638) describe some analogs of the 5HT1A agonist NAN190 that have affinity at 5HT1A receptors, as well as some binding affinity at αl receptors. Further synthetic work in a related area 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).

Disclosure of the invention

According to the present invention it has been found that new compounds of the general formula

or pharmaceutically acceptable salts thereof, wherein R is a hydrogen atom or a phenyl group, m is an integer 3 to 8,

R₄ is situated in the meta or para position of the ring and represents an NO₂-group or a group NR₇R₈ wherein R₇ and R₈ are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms,

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

R₆ is situated in 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, an alkoxy group having 1-3 carbon atoms, 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, in racemic or optically active form, or as a mixture of diastereomers, provided that 1) when W is an optionally substituted aromatic ring(s) then

R, m, R₄, R₅, and Rg are as defined above,

n₁ is 0 or 1,

n₂ is 0 or 1,

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

B is a hydrogen atom or

A and B together constitute a carbonyl group,

2) when W is a carbocyclic ring(s) or a heterocyclic ring then

R, m, R₄, R₅, and R₆ are as defined above,

n₁ is 0 or 1,

n₂ is 0 or 1,

A and B are hydrogen atoms or A and B together constitute a carbonyl group,

3) when W is an optionally substituted methylene group then

R, m, R₄, R₅, and R₆ are as defined above,

n₁ and n ₂ are 1 or

n₁ is 1 and n₂ is 0 or

n₁ is 0 and n₂ is 1,

A and B together constitute a carbonyl group, exhibit an affinity for D₂ and 5HT1A receptors. This effect makes it possible to use the compounds defined above in the treatment of mental disturbances e.g. psychosis, schizophrenia and depression.

An aromatic ring(s) in the definition above is preferably phenyl or naphthyl and is mono- or disubstituted, wherein the substituents are preferably chosen from the following: a hydrogen atom, a halogen atom, a hydroxy group, CF₃, an alkyl group (s) having 1-3 carbon atoms, or an alkoxy group (s) having 1-3 carbon atoms.

Heterocyclic ring in the definition above is preferably furyl, thienyl, pyrrolyl, pyridyl, or indolyl.

A carbocyclic ring(s) in the definition above is preferably mono, bi, or polycyclic rings having 3-12 carbon atoms. The substituents on the carbocyclic ring(s) in the definition above are preferably a hydrogen atom or an alkyl group having 1-3 carbon atoms.

The substituent on the methylene group in the definition above is preferably a hydrogen atom or an alkyl group having 1-4 carbon atoms. Halogen in the definition above is preferably a chlorine, bromine, or fluorine atom.

A preferred group of compounds are those of the general formula

or pharmaceutically acceptable salts thereof, wherein

R₁ is situated in the 3- or 4-position and represents a hydrogen atom, a halogen atom, CF₃, an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, NO₂, COCH₃, or NR₂R₃ wherein R₂ and R₃ are the same or different and each represents a hydrogen atom or an alkyl group having 1-6 carbon atoms, m is an integer 3 to 8,

R₄ is situated in the meta or para position of the ring and represents an NO₂ group or a group NR₇R₈ wherein R₇ and R₈ are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms,

R₅ is situated in the ortho, meta, or para position of the ring and represents a hydrogen atom, a halogen atom, or CF₃, R₆ is situated in the ortho, meta, or para position of the ring and represents a halogen atom or CF₃

W is preferably chosen from the following groups : the substituents preferably being a halogen atom, a hydroxy group, or a methoxy group, mcst preferred are bromine, hydroxy, or methoxy in the ortho and/or meta positions.

the substituents being a halogen atom or a methoxy group

When W is chosen from one of the groups i-xi, then m is preferably 4-6,

R₄ is preferably NH₂,

most preferred R₄ is NH₂ in the meta or para positions,

R₅ is preferably hydrogen or halogen,

particularly preferred are compounds where R₅ is hydrogen, chlorine, or bromine,

most preferred R₅ are hydrogen or chlorine in the meta or para positions,

R₆ is preferably CF₃ or halogen,

further preferred are compounds where R₆ is CF₃ or chlorine,

most preferred R₆ are CF₃ or chlorine in the meta position.

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

n₁ is preferably 0 and n₂ is preferably 0 or 1, most preferred n₂ is 0,

A is preferably hydrogen, methoxy, or hydroxy in the ortho position.

When W is ii, then

n₁ is preferably 0.

When W is iii-vii, then

n₁ is preferably 0,

A is preferably a hydrogen atom or an alkyl group with 1- 3 carbon atoms,

and B is preferably a hydrogen atom. When W is viii, then

n₁ and n₂ are preferably 0 and

A and B preferably constitute a carbonyl group. When W is ix, then

n₁ and n₂ are preferably 1 and

A and B preferably constitute a carbonyl group,

When W is x, then

n₁ and n₂ are preferably 0 and

A and B preferably constitute a carbonyl group

Most preferred are the following compounds

and

and and

and

Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, pamoic, ethanedisulfonic, sulfamic, succinic, propionic, glycollic, malic, mandelic acid, gluconic, pyruvic, phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic, naphthalenesulfonic, ascorbic, cyclohexylsulfamic, fumaric, maleic and benzoic acids. These are readily prepared by methods known in the art. Preparation

The compounds of the general formula I

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

R₄ is situated in the meta or para position of the ring and represents an NC₂-group or a group NR₇R₈ wherein R₇ and R₈ are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms,

R₆ is situated in 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,

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, in racemic or optically active form, or as a mixture of diastereomers, provided that 1) when W is an optionally substituted aromatic ring(s) then

R, m, R₄, R₅, and R₆ are as defined above,

n₁ is 0 or 1,

n₂ is 0 or 1,

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

B is a hydrogen atom or

A and B together constitute a carbonyl group,

2) when W is a carbocyclic ring(s) or a heterocyclic ring then

R, m, R₄, R₅, and R₆ are as defined above,

n₁ is 0 or 1,

n₂ is 0 or 1,

A and B are hydrogen atoms or

A and B together constitute a carbonyl group, 3) when W is an optionally substituted methylene group then

R, m, R₄, R₅, and R₆ are as defined above, n₁ and n₂ are 1 or

n₁ is 1 and n₂ is 0 or

n₁ is 0 and n₂ is 1,

A and B together constitute a carbonyl group, are prepared by any of the following alternative methods

A) Reaction of a compound of the general formula II

wherein R, m, W, A, B, n₁ and n₂ are as defined above and X is a suitable leaving group such as halogen, arylsulfonate or alkylsulfonate, with a compound of the general formula III

wherein R₄, R₅ and R₆ are as defined above in a suitable solvent, such as an alcohol, DMF, acetonitrile or DMSO in the presence of a base such as triethylamine, sodium hydroxide, or potassium carbonate and a catalytic amount of a sodium or potassium halide, such as KI at ambient or higher temperature for a prolonged time. B) Conversion of a compound, of the general formula IV

wherein R, m, R₅, R₆, W, A, B, n₁ and n₂ are as defined above and Y is situated in the meta or para position and represents a group which can be transformed to a group R₄ , where R₄ is situated in the meta or para position of the ring and represents a group NR₇R₈, wherein R₇ and R₈ are as defined above, by a suitable hydrolytic, reductive, electrochemical or other known processes. Compounds of the formula IV can be prepared according to Method A. Such a group Y may be chosen from easily cleaved amides, carbamates, imines, benzylic amines or other suitably protected amino groups. Such groups can be trifluoroacetamido, formamido, t-butoxycarbonylamino, or N-benzylamino .

In addition, Y can be a group such as nitro, azido, hydroxyamino, hydrazono, amido or imino, which can be transformed to R₄ ¹ by known reductive processes. C) Reaction of a compound of the general formula V

wherein R, m, W, A, B, n₁ and n₂ are as defined above and Z is hydrogen, hydroxy, halogen, or alkoxy, with a compound of the general formula III

wherein R₄, R₅ and R₆ are as defined above in the presence of a suitable reducing agent such as sodium cyanoborohydride or lithium aluminium hydride in a direct or stepwise manner.

D) Reaction of a compound of the general formula VI

wherein W, n₁, n₂, and A are as defined above, and T independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or heterocyclic acid or acid derivative, such as a halide, an ester, an imide, an anhydride, or other acid activating group, with a compound of the general formula VII

wherein m, R₄, R₅ and R₆ are as defined above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid, or tetrahydrofuran or neat at ambient or elevated temperature for a prolonged time.

E) Reaction of a compound of the general formula VIII

wherein R, m, R₄, W, A, B, n₁ and n₂ are as defined above and R₅ is H, halogen, or CF₃ with a suitable halogenating reagent such as sulfuryl chloride, or bromine in a suitable solvent such, as chloroform or dioxane. F) Reaction of a compound of the general formula IX

wherein W, n₁ and n₂ are as defined above, A and B together represent a carbonyl group, and M represents a suitable alkali metal such as sodium or potassium, with a compound of the general formula X

wherein X, R₄, R₅ and R₆ are as defined above in a suitable solvent such as DMF, acetonitrile, or DMSO in the presence of a base such as triethylamine, sodium hydroxide, or potassium carbonate at ambient or higher temperature for a prolonged time.

Intermediates

A compound of the general formula II wherein R, m, W, A, B, n₁, n₂ and X are as defined above, can be prepared by reacting a compound of the general formula VI

wherein W, n₁, n₂, and A are as defined above, and T independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or heterocyclic acid or acid derivative, such as a halide, an ester, an imide, an anhydride, or other acid activating group, with a compound of the general formula XI

H₂N—[CH₂]_m—O H X I wherein m is as defined above, in a suitable solvent such as dichloromethane, chloroform, toluene, acetic acid, or tetrahydrofuran or neat at ambient or elevated temperature for a prolonged time, and subsequently- reacting the intermediate of the general formula XII

wherein R, m, W, A, B, n₁ and n₂ are as defined above, with a suitable halogenating agent such as thionyl chloride, phosgene, oxalyl chloride, or phosphorous tribromide, or with a suitable sulfonating agent such as tosyl chloride or other arylsulfonyl chloride or alkylsulfonyl chloride.

A compound of the general formula III¹

wherein R₄ ¹, R₅ and R₆ are as defined above can be prepared from a compound of the general formula XIII

wherein Y, R₅ and R₆ are as defined above in analogy with method B.

A compound of the general formula XIII

wherein R₅ and R₆ are as defined above and Y is NO₂ can be prepared by reacting a compound of the general formula XIV

wherein R₅ and R₆ are as defined above, Y is NO₂ and U is a halogen, with piperazine or a suitably monosubstituted piperazine, where the substituent is easily removeable, such as a benzyl or an ethoxycarbonyl group,

or by reacting a compound of the general formula XV

wherein R₅ and R₆ are as defined above and Y is NO₂, with a compound of the general formula XVI

wherein X is as defined above and V is hydrogen or an easily removable group such as benzyl or ethoxycarbonyl.

A compound of the general formula X

wherein X, m, R₄ , R₅ and R₆ are as defined above , can be prepared by reacting a compound of the general formula

XVII

X— [ C H ₂]_m—X XV I I

wherein X and m are as defined above,

with a compound of the general formula III

wherein R₄, R₅ and R₆ are as defined above, under suitable reaction conditions analogous to method A.

Pharmaceutical formulations

According to the present invention the compounds of the formula I will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in association with a pharmaceutically acceptable dosage form. The dosage form may be a solid, semisolid or liquid preparation. Usually the active substance will constitute between 0.1 and 99 % by weight of the preparation, more specifically between 0.5 and 20 % by weight for preparations intended for injection and between 0.2 and 50 % by weight for preparations suitable for oral administration.

To produce pharmaceutical formulations containing a compound of the formula I in the form of dosage units for oral application the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet can be coated with a polymer well known in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents or in water. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compounds.

For the preparation of soft gelatine capsules, the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the active substance using either the above mentioned excipients for tablets e.g. saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.

Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.

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

Solutions for parenteral applications can 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 stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules .

Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are 50 - 500 mg by oral administration and up to 100 mg via parenteral administration.

It is especially preferred to administer a compound of the formula

or

EXAMPLES

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

A mixture of 3.18 g (0.01 mol) of 4-amino-3-trifluoromethylphenylpiperazine, a catalytic amount of KI, 4.1 g (0.03 mol) of potassium carbonate and 3.0 g

(0.01 mol) of N-(4-bromobutyl)phthalimide in 25 ml of DMF was stirred at 100ºC overnight. After addition of 500 ml of water, the mixture was extracted with ether. The extract was washed with water and extracted with dilute hydrochloric acid. The water layer was separated, made alkaline with sodium hydroxide and again extracted with ether. The extract was dried (Na₂SO₄) and acidified with hydrogen chloride in ether. The yielded precipitate was filtered off and recrystallized from ethanol-ether.

Yield 3.0 g (58%).

M.p. 226-227"C.

In an analogous way the following compounds (2-12) were prepared:

Example 2

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

M.p. 167-169ºC. Example 3

1-(4-Amino-3-trifluoromethylphenyl) -4-]5- (3-methoxyphthalimido)-1-centyl] piperazine oxalate

M.p. 114-118ºC.

Example 4 1-(4-Amino-3-trifluoromethylphenyl) -4-[4-(4-chlorophthalimido)-1-butyl]piperazine dihydrochloride.

M.p. 203-204ºC. Example 5

1-(4-Amino-3-trifluoromethylphenyl)-4-(5-phthalimido-1-pentyl)piperazine trihydrochloride. M.p. 109-113ºC.

Example 6

1-(4-Amino-3,5-dichlcrophenyl)-4-(4-phthalimido-1- butyl)pip erazine

M.p. 116-119ºC.

Example 7 1-(4-Amino-3-trifluoromethylphenyl) -4-[3- (1,8 naphthalimido)-1-propyl]piperazine

M.p. 156-158ºC. Example 8

1 - (4-Amino-3-trifluoromethylphenyl) -4- [4- (3 ,3-dimethylglutarimido)-1-butyl]piperazine dihydrochloride

M.p. 235-236ºC.

Example 9 1- (4-Amino-3-trifluoromethylphenyl) -4- [4- (3 ,3-tetramethyleneglutarimido) -1-butyl]piperazine dihydrochloride

M.p. 243-245ºC.

Example 10

1- (4-Amino-3-trifluoromethylphenyl) -4- [5- (3-phenylglutarimido)-1-pentyllpiperazine hydrochloride

M.p. 136-140ºC.

Example 11 1-(3-Amino-4-chlorophenyl)-4-[5-(2-furanecarboxamido)-1-pentyl]piperazine oxalate

M.p. 165-170ºC. Example 12

1- (4-Amino-3 -trifluoromethylphenyl ) -4- (4 cyclohexanecarboxamido-1-butyl)piperazine M.p. 127-128ºC. Example 13 (Method B)

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

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

M.p. 101-103ºC.

In an analogous way the following compounds (examples 14-24) were prepared:

Example 14

1-(4-Amino-3-trifluoromethylphenyl)-4-(6-phthalimido-1-hexyl)piperazine acetate

M.p. 125-127ºC.

Example 15

1-(4-Amino-3-trifluoromethylphenyl)-4-(8-phthalimido-1- octyl)piperazine acetate

M.p. 94-96ºC.

Example 16

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

M.p. 159-162ºC. Example 17

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

M.p. 149-150ºC.

Example 18 1-(4-Amino-3-methylphenyl)-4-(4-phthalimido-1-butyl)-piperazine acetate.

M.p. 123-126ºC. Example 19

1-(3-Amino-4-chlorophenyl)-4-[4-(3,3-tetramethylene-glutarimido)-1-butyl]piperazine M.p. 133-136ºC.

Example 20

1-(4-Amino-3-trifluoromethylphenyl)-4-f6-(3-phenoxybenzamido)-1-hexyl]piperazine acetate

M.p. 128-131ºC.

Example 21

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

M.p. 112-115ºC. Example 22

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

M.p. 123-125ºC.

Example 23 1-(4-Amino-3-trifluoromethylphenyl)-4-(4-adamantaneacetamido-1-butyl)piperazine

M.p. 115-116ºC. Example 24

1-(4-Amino-3-trifluoromethylphenyl)-4-(6-adamantanecarboxamido-1-hexyl)piperazine ¹H NMR (CDCl3) d 7.00 (s, 1 H), 6.96 (dd, 1 H), 6.70 (d,

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

Example 25 (Method B)

1-(4-Amino-2-trifluoromethylphenyl)-4-(4-phthalimido-1- butyl)piperazine dihydrochloride.

To a mixture of 1-(4-nitro-2-trifluoromethylphenyl)-4-(4- phthalimido-1-butyl)-piperazine (7.8 g, 0.01 mol) in 200 ml ethanol and 60 ml water, 11.2 g of sodium dithionite was added in portions while stirring and heating at 100ºC. The mixture was heated under reflux for 1 h and the ethanol was evaporated. The residual water solution was made basic with NaOH and extracted with ether. The extract was washed with water, dried and the ether was evaporated. The yielded oil was dissolved in 100 ml dry ether and the dihydrochloride was precipitated by the addition of hydrogen chloride in ether. The salt was recrystallized from ethanol-ether to give 2.3 g (44 %) of the target compound.

M.p. 243 -244ºC. Example 26 (Method B)

1-(4-piethylamino-3-trifluoromethylphenyl)-4-(4-phthalimido-1-butyl)-piperazine The product from Example 13 (1.0 g, 2 mmol), dissolved in 5 ml acetic acid, was added to a mixture of sodium borohydride (304 mg, 8 mmol) and 20 ml toluene. The mixture was heated for 6 h at 80ºC, cooled and added to 50 ml water and 50 ml ether and made alkaline with 2 M sodium hydroxide. The organic phase was dried and evaporated. The residue was recrystallized from hexane to yield 440 mg of the target product.

M.p. 70 - 71ºC. Example 27 (Method B)

1-(4-Amino-3-trifluoromethylphenyl)-4-(4-phthalimido-1- butyl)-piperazine. 4-(4-Acetamino-3-trifluoromethylphenyl)-1-(4-phthalimido- 1- butyl)-piperazine (4.9 mg, 0.01 mmol), dissolved in 2 ml ethanol and 0.2 ml 2 M hydrochloric acid, was heated for 5 h at 80ºC. The solvent was removed and the residue was shown by gas chromatography to be identical with the product in example 1. Example 28 (Method C)

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

To a refluxing solution of 4-phthalimido-1-butanal (0.713 g 3.25 mmol) and N-(4-amino-3-trifluoromethylphenyl)-piperazine (0.804 g, 3.25 mmol) in CHCI₃ (10 ml) was added dropwise 98% formic acid in CHCI₃ (10 ml) in 20 min. The solution was heated under reflux for 2 h. The solvent was removed and the residue purified by chromatography and shown by thin layer chromatography and gas chromatography to be identical to the product in example 1.

Example 29 (Method D)

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

4-(4-Amino-3-trifluoromethylphenyl)-1-(4-aminobutyl)-pipera zine(32 mg, 0.1 mmol) and phthalic anhydride (30 mg, 0.2 mmol) dissolved in 1 ml acetic acid were stirred at 75ºC for 3 hours. The solvent was removed and the residue was shown by gas chromatography and thin layer chromatography to be identical with the product in example 1.

Example 30 (Method D)

1-(4-Amino-3-trifluoromethylphenyl)-4-f4-(5-bromo-2,3- dimethoxybenzamido)-1-butyl]piperazine dioxalate

The product from example 1 (3.3 g, 6.4 mmol) was dissolved in 60 ml ethanol, made alkaline with 2 M NaOH, and the base was heated with hydrazine hydrate (2.0 ml) at 75°C for 3.5 h. After cooling, the solution was acidified with 27 ml 2 M HCl and evaporated. The residue was dissolved in 75 ml H₂O and 75 ml ether . The aqueous phase was made alkaline and extracted with chloroform. The solvent was evaporated to yield crude 1-(4- aminobutyl)-4-(4-amino-3-trifluoromethylphenyl)-piper azine. A solution of 5-bromo-2,3-dimethoxybenzoic acid (0.52 g, 2.0 mmol) in 10 ml toluene, thionylchloride (2 ml, 23 mmol), and a few drops of DMF 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 residual acyl chloride was dissolved in 15 ml dichloromethane and a solution of the crude amin from above (0.51 g, 1.6 mmol) and triethylamine (0.45 g, 3.2 mmol) in 10 ml dichloromethane was added with cooling. After stirring overnight the solvent was evaporated and the residue was partitioned between dil. HCl and ether. The organic phase was extracted with water and the combined water phases were made alkaline and extracted repeatedly with chloroform. Drying (Na₂SO₄) and evaporation gave 0.57 g of the product as an oil. The base was dissolved in aceton and treated with oxalic acid affording 0.95 g of the title product.

M.p. 174-175ºC. In an analogous way the following compounds (examples 31- 34) were prepared:

Example 31 1 - ( 4 -Amino-3 -trifluoromethylphenyl ) -4- ( 4-benzamido-1 - butyl ) piperazine

M.p . 117-120 º C . Example 32

1-(4-Amino-3-trifluoromethylphenyl)-4-[5-(5-broιtιo-2,3-dimethoxybenzamido)-1-pentyl]piperazine dioxalate

M.p. 151-154ºC.

Example 33 1- (4-Amino-3-trifluoromethylphenyl) -4- [4- (2-norbornanecarboxamido)-1-butyl]piperazine hydrochloride

M.p. 77-80ºC. Example 34

(R,endo)-1-(4-Amino-3-trifluoromethylphenyl)-4-[4-(2-norbornanecarboxamido)-1-butyl]piperazine hydrochloride M.p. 142-146ºC.

Example 35 (Method E)

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

The product in Example 13 (1.0 g, 2 mmol) was dissolved in 20 ml dioxane and 5 ml methanol. Bromine (350 mg, 2.2 mmol) dissolved in 3 ml dioxane was added and the mixture stirred at ambient temperature for 5 hours, the solvent evaporated, the residue made alkaline with 2 M aqueous NaOH and extracted with methylene chloride. The solvent was removed and the residue dissolved in diisopropyl ether and a precipitate of the title compound was obtained with oxalic acid dissolved in ethanol.

M.p. 172-175ºC. Example 36 (intermediate, compound II)

N-(5-Bromopentyl)-3-methoxyphthalimide 3-Methoxyphthalic anhydride (3.0 g, 16.8 mmol) and 5-amino-1-pentanol (1.7 g, 16.8 mmol) were mixed and heated to 120°C for 2 h. After cooling phosphorus tribromide (3.5 g, 13 mmol) was added and the mixture heated to 110°C for 2 h and poured into ice, extracted with ethyl acetate and the organic phase was separated, dried and the solvent evaporated. The residue was crystallized from ethyl acetate/hexane.

M.p. 65-67ºC. Example 37 (intermediate compound 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 toluene, thionyl chloride (6 ml, 70 mmol), and a few drops of DMF was heated at 60°C for 3 h. The solvent was evaporated, and the residue dissolved in 20 ml dichloromethane and evaporated again. The residual acid chloride was dissolved in 20 ml dichloromethane and added to a solution of 5-aminopentanol (1.8 g, 18 mmol) and triethylamine (4 ml, 28 mmol) in 30 ml dichloromethane at -35ºC and the temperature allowed to rise to 0ºC in 4 h. The solution was washed with dilute HCl, the organic phase separated, and the solvent removed to yield 2.2 g of a crude oil. This oil was dissolved in 20 ml dichloromethane, triethylamine (4 ml, 28 mmol) and tosylchloride (1.33 g, 7 mmol) were added, and the mixture was stirred at ambient temperature overnight. Ethyl ether (100 ml) was added and the organic phase washed with sodium carbonate solution and water. After drying, the organic solvent was evaporated to yield 2.7 g (5.5 mmol) of the title product as an oil. ¹H NMR(CDCL₃) d 7.9 (bs, 1 H), 7.81 (d, 1 H), 7.77 (d, 2 H), 7.34 (d, 2 H), 7.13 (d, 1 H), 4.03 (t, 2 H), 3.89 (s,3 H), 3.87 (s, 3 H), 3.42 (q, 2 H), 2.44 (s, 3 H), 1.73-1.40 (m, 6 H).

Example 38 (intermediate compound IV)

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

The compound from example 39 (8.5 g, 30 mmol), 4-bromobutylphthalimide (11.1 g, 40 mmol), potassium carbonate (5.0 g, 36 mmol) and a catalytic amount of potassium iodide were warmed to 90ºC in 80 ml DMF for 6 h. The mixture was poured into 500 ml water and extracted with methylene chloride. The organic phase was dried, the solvent evaporated and the residue triturated with ethanol/diisopropyl ether to yield a yellow, crystalline product.

M.p. 152-154º 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 catalytical amount of KI in 80 ml of 1-propanol was stirred and heated at 100ºC overnight. After cooling, 1 1 of ice-water was added with stirring. The yielded precipitate was filtered off , washed with water and dried.

Yield 26.6 g (94%). M.p. 81-83ºC. Example 40 (intermediate compound XIII)

4-Amino-2,6-dichlorophenylpiperazine 2,6-Dichloro-4-nitroaniline (10.4 g, 50 mmol), dissolved in 100 ml methanol and 10 ml 2 M HCl, was hydrogenated with platinum on carbon as catalyst at NTP in 8 h. The catalyst was filtered off and the solvent removed. The residue was dissolved in ether and made alkaline to yield 5.1 g (29 mmol) of a grey crystalline powder . This product was reacted with bis-(2-chloroethyl)amine hydrochloride (5.4 g, 30 mmol) with heating to 100ºC in n-butanol with 3×1 g sodium carbonate (30 mmol) for 26 h. The solvent was evaporated, the residue taken up in ether and made alkaline to yield 3.4 g (48 %) of product as an oil.

1H NMR(CDCL₃) d 6.82 (s, 2 H), 4.10 (s, 2 H), 3.02 (m, 8 H), 1.82 (s, 1 H). Pharmaceutical preparations

The following examples illustrate suitable pharmaceutical compositions to be used in the method of the invention. For the preparation of tablets the following compositions can be made.

Composition 1

Compound according to Example 1 50 g

Lactose 85 g

Potato starch 40 g

Polyvinylpyrrolidone 5 g

Microcrystalline cellulose 18 g

Magnesium stearate 2 g Composition 2

Compound according to Example 1 100 g

Lactose 90 g

Potato starch 50 g

Polyvinylpyrrolidone 5 g

Microcrystalline cellulose 23 g

Magnesium stearate 2 g

From the above compositions 1 000 tablets can be made, containing 50 mg and 100 mg of active substance, respectively. If desired, the obtained tablets can be film coated with e.g. hydroxypropyl methyl cellulose in an organic solvent or using water. Pharmacology

It is generally accepted that drugs that bind to dopamine D2 receptors and are antagonists at these receptors will be clinically effective as antipsychotic agents (for example in schizophrenia). It is also believed that a serotoninergic (5HT1A) receptor affinity as an agonist can be a useful property by reducing the incidence of extrapyramidal side effects and by increasing the efficacy of the substance in psychoses. These substances by having a certain ratio of D2 and 5HT1A binding will retain an antipsychotic effect at the same time as having a reduced incidence of side effects and improved efficacy. Table 1 illustrates the binding affinities (K_i values, nM) of several of the compounds at dopamine (D2) and serotonin (5HT1A) receptors and the ratios D2/5HT1A.

The pharmacological methods are described below. D2 Receptor Binding Assay

Tissue preparation: The rats are decapitated and the striata dissected out on ice. The tissue is homogenized at 0ºC in 20 ml 0.05 M Tris-HCl buffer pH 7.7, using a Branson B30 sonifier. The homogenate is centrifuged at 4ºC for 10 minutes at 48000 g, in a Sorvall RC-5B Refrigerated Superspeed Centrifuge. The pellet is resuspended and recentrifuged. The final pellet is 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, 1 mM MgCl₂ and 10 μM pargylin), to a final concentration of 2.5 mg wet weight/0.5 ml. The homogenate is preincubated for 10 min at 37ºC.

Receptor binding assay: Various concentrations of the test compound, the radioligand (InM H-Raclopride) and the homogenate are incubated for 60 min at room temperature. Non-specific binding is determined by the addition of 1 μM (+)-Butaclamol. The incubation is terminated by rapid filtration through glass fiber paper (Whatman GF/B) and subsequent washing with cold incubation buffer, using a cell harvester equipment. The radioactivity of the filters is measured in a Packard 2200CA liquid scintillation counter. Data is analyzed by non-linear regression using the LIGAND program, and presented as Ki values.

5-HT_1A Receptor binding Assay

Tissue preparation. Cerebral cortex + hippocampus from each rat was dissected and homogenized in 15 ml ice-cold 50mM Tris-HCl buffer 4.0 mM CaCl₂ and 5.7 mM ascorbic acid, pH 7.5 with an Ultra-Turrax (Janke & Kunkel, Staufen, FRG) for ten s. After centrifugation for 12.5 min at 17,000 rpm (39,800 × g in a Beckman centrifuge with a chilled JA-17 rotor (Beckman, Palo Alto, CA, USA), the pellets were resuspended in the same buffer and homogenization and centrifugation repeated. To each pellet 5 ml ice-cold 0.32 M sucrose were added and homogenized for 5 sec. These samples were kept frozen at -70ºC. When used they were diluted with the buffer to 8 mg tissue/ml and homogenized for 10 sec. The tissue homogenates were incubated for ten min at 37ºC and then supplied with 10 μM pargyline followed by reincubation for 10 min. The binding assay followed that described by Peroutka, J. Neurochem. 47, 529-540, (1986). The incubation mixture (2 ml) contained ³H-8-OH-DPAT (0.25 to 8 nM), 5 mg/ml tissue homogenate in 50 mM Tris-HCl buffer containing 4.0 mM CaCl₂ and 5.7 mM ascorbic acid, pH 7.5. Six different concentrations of ³H-8-OH-DPAT were analyzed. Binding experiments were started by the addition of tissue homogenate and followed by incubation at 37ºC for ten min. The incubation mixtures were filtered through Whatman GF/B glass filters with a Brandel Cell Harvester (Gaithersburgh, MD, USA). The filters were washed twice with 5 ml ice-cold 50 mM Tris-HCl buffer, pH 7.5, and counted with 5 ml Ultima Gold™ (Packard) in a Beckman LS 3801 scintillation counter. Non-specific binding was measured by the addition of 10 μM 5-HT to the reaction mixture. The binding data were processed by non-linear least squares computer analysis (Munson and Rodbard, Anal. Biochem. 107, 220-239, (1980). Data were presented as K_i values (nM).

Claims

1. A compound of the general formula

or pharmaceutically accetable salts thereof, wherein R is a hydrogen atom or a phenyl group, m is an integer 3 to 8,

R₅ is situated in the ortho, meta or para position and represents an hydrogen atom, a halogen atom or CF₃,

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

1) when W is an optionally substituted aromatic ring(s) then

R, m, R₄, R₅, and R₆ are as defined above,

n₁ is 0 or 1,

n₂ is 0 or 1,

B is a hydrogen atom or

A and B together constitute a carbonyl group,

2) when W is a carbocyclic ring(s) or a heterocyclic ring then

R, m, R₄, R₅, and R₆ are as defined above,

n₁ is 0 or 1, n₂ is 0 or 1 ,

A and B are hydrogen atoms or

A and B together constitute a carbonyl group,

3) when W is an optionally substituted methylene group then

R, m, R₄, R₅, and R₆ are as defined above,

n₁ and n₂ are 1 or

n₁ is 1 and n₂ is 0 or

n₁ is 0 and n₂ is 1,

A and B together constitute a carbonyl group,

2. A compound according to claim 1 having the formula

or

or or

or

3. A process for the preparation of a compound of the general formula I as defined in claim 1, characterized by

A) reaction of a compound of the general formula II

wherein R, m, W, A, B, n₁ and n₂ are as defined in claim 1 and X is a leaving group with a compound of the general formula III

wherein R₄, R₅ and R₆ are as defined in claim 1, or

B) conversion of a compound of the general formula IV

wherein R, m, R₅, R₆, W, A, B, n₁ and n₂ are as defined in claim 1 and Y is situated in the meta or para position and represents a group which can be transformed to a group R₄ ¹, where R₄ ¹ is situated in the meta or para position of the ring and represents a group NR₇R₈ as defined in claim 1, or

C) reaction of a compound of the general formula V

wherein R, m, W, A, B, n₁ and n₂ are as defined in claim 1 and Z is hydrogen, hydroxy, halogen, or alkoxy, with a compound of the general formula III

wherein R₄, R₅ and R₆ are as defined in claim 1, or

D) reaction of a compound of the general formula VI

wherein W, n_1, n₂ , and A are as defined in claim 1, and T independently or together with A represents a suitable derivative of an aliphatic, cycloaliphatic, aromatic or heterocyclic acid or acid derivative with a compound of the general formula VII

wherein m, R₄, R₅ and R₆ are as defined in claim 1, or

E) reaction of a compound of the general formula VIII

wherein R, m, R₄, W, A, B, n₁ and n₂ are as defined in claim 1 and R₅ is H, halogen, or CF₃ with a suitable halogenating reagent or F) reaction of a compound of the general formula IX

wherein W, n₁ and n₂ are as defined in claim 1, A and B together represent a carbonyl group, and M represents an alkali metal with a compound of the general formula X

wherein X, R₄, R₅ and R₆ are as defined in claim 1, whereafter, if so desired the compound obtained by any of the processes A)-F) is converted to a pharmaceutically acceptable salt thereof.

4. A process according to claim 3 characterized in that compound according to claim 2 is prepared.

5. A compound of the formula II

R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, 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, an alkoxy group having 1-3 carbon atoms, a phenyl group, or a phenoxy group, B is a hydrogen atom, or

1) when W is an optionally substituted aromatic ring(s) then R and m, are as defined above,

n₁ is 0 or 1,

n₂ is 0 or 1,

B is a hydrogen atom or

A and B together constitute a carbonyl group,

2) when W is a carbocyclic ring(s) or a heterocyclic ring then

R, and m, are as defined above,

n₁ is 0 or 1,

n₂ is 0 or 1,

A and B are hydrogen atoms or

A and B together constitute a carbonyl group,

3) when W is an optionally substituted methylene group then

R, and m, are as defined above,

n₁ and n₂ are 1 or

n₁ is 1 and n₂ is 0 or

n₁ is 0 and n₂ is 1,

A and B together constitute a carbonyl group.

6. A compound of the formula III¹

wherein R₄ ¹ is situated in the meta or para position of the ring and represents a group NR₇R₈ wherein R₇ and R₈ are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms,

R₆ is situated in the ortho, meta or para position and represents a halogen atom or CF₃.

7. A pharmaceutical preparation comprising as active ingredient a compound according to any of claims 1-2.

8. A pharmaceutical preparation according to claim 7 in dosage unit form.

9. A pharmaceutical preparation according to claims 8-9 comprising the active ingredient in association with a pharmaceutically acceptable carrier.

10. A compound according to any of claims 1-2 for use as a therapeutically active substance.

11. Use of a compound according to any of claims 1-2 for the preparation of medicaments with effect against mental disturbances.

12. A method for the treatment of mental disturbances in mammals, including man, characterized by the administration to a host in need of such treatment of an effective amount of a compound according to any of claims 1-2.

13. Compounds and processes and intermediates, for their preparation, pharmaceutical compositions containing them, and their use in the treatment of mental disturbances as claimed in claim 1-12 inclusive and substantially as described.