AU665825B2 - Novel amidoalkyl- and imidoalkyl-piperazines - Google Patents

Description

1 OPI DATE 18/11/93 APPLN. ID 39643/93 Iill 11111111 lllll llllll AOJP DATE 27/01/94 PCT NUMBER PCT/SE93/00295 1111 11111 AU9339643 (51) International Patent Classification 5 C07D 403/06, 401/06, 405/06 C07D 295/073, 295/125, 295/135 C07D 209/48, C07C 309/73 A61K 31/495 (21) International Application Number: (22) International Filing Date: PCT/SE93/00295 6 April 1993 (06.04.93) Priority data: 9201138-6 9 April 1992 (09.04.92) SE (71)Applicant: AKTIEBOLAGET ASTRA [SE/SE]; S-151 85 S6dertilje (SE).

(72) Inventors: BENGTSSON, Stefan Pirongrand 4, S-151 68 S6dertalje FLORVALL, Lennart Snickarstigen 7, S-151 59 S6dertilje HALLNEMO, Gerd Nydalavigen 58, S-151 51 Sdertilje JACKSON, David Kimpevigen 31 11, S-151 54 Sodertailje ROSS, Svante Hedvigen 8, S-151 52 Sodertilje TOLF, Bo-Ragnar Kaptensgatan 3, S-619 00 Trosa (SE).

ULFF, Bengt Agostigen 19, S-151 54 S6dertfilje (SE).

ZHANG, Lian Karlhovsviigen 17, S-151 52 Sodertfilje AKESSON, Christina Kottestigen 87, S-147 43 Tumba (SE).

1) International Publication Number: WO 93/21179 3) International Publication Date: 28 October 1993 (28.10.93) (74) Agents: DANIELSSON, Sten et al.; Aktiebolaget Astra, Patent Department, S-151 85 Sodertilje (SE).

(81) Designated States: AU, BB, BG, BR, CA, CZ, FI, HU, JP, KP, KR, KZ, LK, MG, MN, MW, NO, NZ, PL, RO, RU, SD, SK, UA, VN, European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).

Published With international search report.

Before the expiration of the time limit for amending the claims and to he republished in the event of the receipt of amendments.

665825 i

I

(54)Title: NOVEL AMIDOALKYL- AND IMIDOALKYL-PIPERAZINES 0

II

W \N[CH 2 )N N CH1-A R I R R In2 (57) Abstract Compounds of general formula wherein R is a hydrogen atom or a phenyl group, m is an in'2ger 3 to 8, R 4 is an NO 2 group or a group NR 7

R

8 wherein R 7 and R 8 are the same or different and each is hydrogen or alkyl, R 5 is hydrogen, halogen or CF 3

R

6 is halogen, or CF 3 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, CF 3 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, nl is 0 or 1, and n, 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.

-I

r WO93/21179 PCT/SE93/00295 1 Novel amidoalkvl- and imidoalkvl-piperazines Field of the invention The present invention relates to novel, l-aryl-4 (-amido- 1-alkyl and c-imido-l-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.

1 Glennon and colleagues (Glennon RA, Naiman NA, Lyon RA, i Titeler M: Journal of Medicinal Chemistry, 1988, 31, 1968-1971) describe some aryl piperazine derivatives, Sincluding NAN190 [=l-(2-methoxyphenyl)-4-(4-(2i 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 al receptors. Further synthetic work in a related area is also described (Glennon RA, Naiman NA, Pierson ME, Smith 06.i WO 93/21179 PCT/SE93/00295 2 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 0 \N-[CH2] m -N

N-

.fCH-A B

R

900n 2 or pharmaceutically acceptable salts thereof, wherein j i S0 R is a hydrogen atom or a phenyl group, m is an integer 3 to 8, i I R4 is situated in the meta or para position of the 15 ring and represents a group NR 7

R

8 wherein R and R 8 are the same or different and each represents a j hydrogen atom or an alkyl group having 1-3 carbon atoms, is situated in the ortho, meta or para position and represents a hydrogen atom, a halogen atom, or CF 3 R6 is situated in the ortho, meta or para position and represents a halogen atom or CF 3 SW is an optionally substituted aromatic ring(s), a

I

WO 93/21179 PCT/SE93/00295 heterocyclic ring, a 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 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 n 2 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, R 4

R

5 and R6 are as defined above, n1 is 0 or 1, n2 is 0 or 1, A is a hydrogen atom, a halogen atom, CF 3 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, R 4

R

5 and R6 are as defined above, n 1 is 0 or 1, n 2 is 0 or 1, A and B are hydrogen atoms or r WO93/21179 PCT/SE93/00295 4 A and B together constitute a carbonyl group, 3) when W is an optionally substituted methylene group then R, m, R 4

R

5 and Rg are as defined above, ni and n2 are 1 or ni is 1 and n 2 is 0 or n1 is 0 and n 2 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, CF 3 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.

c -I 1 f i l- WO 93/21179 PCT/SE93/00295 Halogen in the definition above is preferably a chlorine, bromine, or fluorine atom.

A preferred group of compounds are those of the general formula

R

1 O

II

C\ R C 4

N-[CH

2 ]M-N N Ia C R II R I o or pharmaceutically acceptable salts thereof, wherein

R

1 is situated in the 3- or 4-position and represents a hydrogen atom, a halogen atom, CF 3 an alkyl group having 1-3 carbon atoms, an alkoxy group having 1-3 carbon atoms, NO 2

COCH

3 or NR 2

R

3 wherein R 2 an 1 R3 are the same or different and each represents a hydrogen atom or Ian alkyl group having 1-6 carbon atoms, Sm is an integer 3 to 8, K R 4 is situated in the meta or para position of the ring and represents an NO 2 group or a group NR 7 Rg wherein R 7 and Rg are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms,

R

5 is situated in the ortho, meta, or para position of the ring and represents a hydrogen atom, a halogen atom, or CF3, i. -c" WO 93/21179 PC/SE93/00295 Rg is situated in the ortho, meta, or para position of the ring and represents a halogen atom or CF 3 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.

iv ZI I 7 -7 WO 93/21179 PCr/SE93/00295 ixQ<] the substituents being a halogen atom or a methoxy group

X;

When W is chosen from one of the groups i-xi, then WO 93/21179 PCT/SE93/00295 8 m is preferably 4-6, R4 is preferably NH 2 most preferred R 4 is NH 2 in the meta or para positions,

R

5 is preferably hydrogen or nalogen, particularly preferred are compounds where R 5 is hydrogen, chlorine, or bromine, most preferred R 5 are hydrogen or chlorine in the meta or para positions,

R

6 is preferably CF 3 or halogen, further preferred are compounds where R6 is CF 3 or chlorine, most preferred '6 are CF 3 or chlorine in the meta position.

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

When W is i, then nI is preferably 0 and n 2 is preferably 0 or 1, most preferred n 2 is 0, A is preferably hydrogen, methoxy, or hydroxy in the ortho position.

When W is ii, then nI 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 iL. preferably a hydrogen atom.

When W is viii, then nI and n 2 are preferably 0 and A and B preferably constitute a carbonyl group.

WO 93/21179 PCT/SE93/00295 9 When W is ix, then n1 and n 2 are preferably 1 and A and B preferably constitute a carbonyl group.

When W is x, then n1 and n 2 are preferably 0 and A and B preferably constitute a carbonyl group.

Most preferred are the following compounds 0

C

N--[-CH

2 -N N- NH 2

C

0 CF3 and 0

C

C l II N-[CH] -N N NH 2]4 0 CF 3 and pp.~ 9, WO 93/21179 PC1'/SE93/00295 and

NH

2 and

F

NH.,

and C- /N

N-

N

NH

2

IL.

WO 93/21 179 PCr/SE93/00295 H11- N /N

NH

2

F

F

and

N

and and 7, I; ^S

S-.

WO 93/21179 PCT/SE93/00295

N

__J

-NH

2

F

and I N

N

CI

NH

2 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, 4aminosalicylic, 4-hydroxybenzoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic, naphthalenesulfonic, ascorbic, cyc.Lohexylsulfamic, fumaric, maleic and benzoic acids. These are readily prepared by methods known in the art.

r- pp -i WO 93/21179 PCr/SE93/00295 Preoaration The compounds of the general formula I 0

W

I

R n 2

N-[CH

2 ]m N N

B

,r I 4 5 I ft 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 a group NR 7

R

8 wherein R and R 8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms, is situated in the ortho, meta or para position and represents a hydrogen atom, a halogen atom, or CF 3

R

6 is situated in the ortho, meta or para position and represents a halogen atom, or CF 3 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, ^gR^ CF 3 an alkyl group having 1-3 carbon atoms, an'alkoxy C C

IL.

WO93/21179 PCT/SE93/00295 14 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 n 2 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, R 4

R

5 and R 6 are as defined above, n 1 is 0 or 1, n2 is 0 or 1, A is a hydrogen atom, a halogen atom, CF 3 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, R 4

R

5 and Rg are as defined above, n 1 is 0 or 1, n 2 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, R 4

R

5 and Rg are as defined above, pp V: I-,i I- ~P YY ~ILWL PCT/SE93/00295 WO 93/21179 ni and n 2 are 1 or n1 is 1 and n 2 is 0 or n1 is 0 and n 2 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 0 I I /[CH2]n-C, N-[CH2]m-X

I

CH-A

R

n 2 wherein R, m, W, A, B, n, and n 2 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 H-N N wherein R 4

R

5 and Rg 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.

r 7 'P 1 II---Y"s~PY'~CUI-- ;i~ WO 93/21179 .PCF/SE93/00295 B) Conversion of a compound of the general formula IV 0 I I [Cl

R

n2 N-[CH2]--N

N

B

R

wherein R, m, R 5

R

6 W, A, B, n, and n 2 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

R

4 1 where R 41 is situated in the meta or para position of the ring and represents a group NR 7

R

8 wherein R 7 and

R

8 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 R 4 1 by known reductive processes.

r j- 1 I

~I

WO 93/21179 P(7rSE93/00295 C) Reaction of a compound of the general formula V

/[CH

2 ]n -C, w CH A

R

N-[CH2]_ C-Z I 1 C wherein R, m, W, A, B, n I and n 2 are as defined above and Z is hydrogen, hydroxy, halogen, or alkoxy, with a compound of the general formula III H--N Nwherein R 4

R

5 and R 6 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

/[CH

2 ]n -C

T

CH-A

I

n2 i WO 93/21179 PCT/SE93/00295 wherein W, n 1 n 2 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

H

2 N-[CH 2--N N VII wherein m, R 4

R

5 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 [CH2] n

-C

W

/cw

CH-A

I

-7 /R4

N-[CH

2 ]m N N B R

VIII

wherein R, m, R 4 W, A, B, n 1 and n 2 are as defined above and R 5 is H,halo.gen, or CF 3 with a suitable halogenating reagent such as sulfuryl chloride, or bromine in a suitable solvent such as chloroform or dioxane.

L L~i- WO 93/21179 PCT/SE93/00295 19 F) Reaction of a compound of the general formula IX 0 S1

[CH

2 ]1 n-C W N-M IX

CH-A

2 wherein W, n 1 and n 2 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

X

[CH2] N N X S6 wherein X, R 4

R

5 and R 6 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 i WO 93/21179 PCT/SE93/00295

/[CH

2 ]n -C

CH-A

R

N [CH 2 m-X

I

wherein R, m, W, A, B, n n 2 and X are as defined above, can be prepared by reacting a compound of the general formula VI

/[CH

2 ]nl-C T I

CH-A

R

nn, wherein W, n 1 n 2 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-OH 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 L r L~ 7 1 F r?" r~ -T WO 93/21179 PCT/SE93/00295

/[CH

2 ]n -C,

CH-A

I

R

n, N-[CH2] -OH wherein R, m, W, A, B, n 1 and n 2 are as defined above, with a suitable halogenating agent such Es thiony.

chloride, phosgene, oxalyl chloride, or phosphorous tribromide, or with a suitable sulfornating agent such as tosyl chloride or other arylsulfonyl chloride or alkylsulfonyl chloride.

A compound of the general formula III 1 H-N N R6 1111 wherein R41, R 5 and R6 are as defined above can be prepared from a compound of the general formula XIII H-N N

R

6 X III r WO 93/21179 P(rSE93/00295 22 wherein Y, R 5 and Rg are as defined above in analogy with method B.

A compound of the general formula XIII H-N N

XIII

wherein R5 and Rg are as defined above and Y is NO 2 can be prepared by reacting a compound of the general formula

XIV

XIV

wherein R 5 and Rg are as defined above, Y is NO 2 and U is a halogen, with piperazine or a suitably monosubstituted piperazine; where the substituent is easily removeable, such as a Denzyl or an ethoxycarbonyl group, or by reacting a compound of the general formula XV

Y

H

2

^R

XV

I

k, WO 93/21179 PCT/SE93/00295 23 wherein R 5 and Rg are as defined above and Y is NO 2 with a compound of the general formula XVI

/CH

2

CH

2

X

V-N XVI

CH

2

CH

2

X

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 X- [CH 2 N- R X

R

6 wherein X, m, R 4

R

5 and Rg are as defined above, can be prepared by reacting a compound of the general formula

XVII

X-[CH

2 ]m-X XVI wherein X and m are as defined above, with a compound of the general formula III

R

4 H-N N R III WO 93/21179 PCT/SE93/00295 24 wherein R 4

R

5 and Rg 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, anda 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 L WO 93/21179 PCT/SE93/00295 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 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 L i a '74 WO 93/21179 PCY/SE93/00295 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

N-[CH

2 -N N

NH

2

CF

3 O N N

IH

2

F

F

WO093/21179 PCT/SE93/00295 27

EXAMPLES

Example 1 (method A) 1 (4 -Amino 3-tri fluoromethvlrohenyl) 4- (4 -Phthal imido -1 buv Diperazine dihvdrochloride A mixture of 3.18 a (0.01. mol) of 4-amino-3trifluoromethyiphenylpiperazine, a catalytic amount of KI, 4.1 g (0.03 mol) of potassium carbonate and 3.0 g 01 mol) of N- (4-bromobutyl) phthalimide in 25 ml of DMF was stirred at 100'C 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 (Na 2

SO

4 and acidified with hydrogen chloride in ether. The yielded precipitate was filtered off and recrystallized from ethanol-ether.

Yield 3.0 g M.p. 226-227'C.

In an analogous way the following compounds (2-12) were prepared: Example 2 1- (4-Amino-3-trifluoromethvlrhenyl)-4-(3-Tphthalimido-lpropyl) piperazine dihydrochloride.

M.p. 167-169"C.

WO 93/21179 WO 9321179PCT/SE93/00295 Example 3 1 4-Am ino -3 tr if or om e thv 1 nhe n v1 4- f5 (3 metho~cphthalimido) -1-rentv1]piperazine oxalate M.p. 114-118*C.

Example 4 1- 4-Am in-o--3-trif omethvlThenv 4chloro-ohthalinido) -1-bu:v1]lpiTerazine dihydrochloride.

M.o. 203-204*C.

Example 1-(4-Amino-3-t,-ifluoronethvlphenyl) ientvl)roiTerazine trihvdrochloride.

M.u. 109-113*C.

Example 6 1-(4-Amino-3,5-dichicroo~henyl)-4-(4-ohthalimido-lbutyl)pip erazine M.p. 116-119*C.

Example 7 1-(4-Amino-3-trifluoromethylphenyl)-4-F3-(1,8naThthalimrido) -l-propip1iperazine M.p. 156-158*C.

S-~

WO 93/21179 PCI'/SE93/00295 Example 8 1-(4--Amino-3--Lrifluoromethvl phen 1 dimethvlcilutarimido) -l-butvll-pioerazine dihydrochloride M.p. 235-236*C.

Example 9 1-(4-Amino-3-trifluoromethvlphenyl)-4-r4-(3,3tetramethyleneqlutarimido)-l-butvll1Derazine di hvdro chlor ide M.p. 243-245*C.

Example 1-(4-Amino-3-trifluoromethvlphenvl)-4-r5-(3phenvlalutarimido) -1-pentvliojoerazine hydrochloride M.p. 136-140'C.

Example 11 1-( 3 -Amino-4-chlorolphenyl)-4-[5-(2-furanecarboxamido)-lpentyllyiperazine oxalate M.p. 165-170*C.

Example 12 1- 4-Anino-3-trifluororneth 1 phen 1 cyclohexanecarboxamido-l-butyl iperazine M.p. 127-128*C.

06. WO 93/21179 PCT/SE93/00295 Example-13 (Method B) 1- (4 -Amino-3 tri fluoromethylphenvl) 4- (4 -phthal1imido 1butvl)-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 diisopropyle.ther and ethanol to yield 10.0 g of the title product.

M.p. 101-103'C.

in an analogous way the following compounds (examples 14- 24) were prepared: Example 14 l-(4-Amino-3-trifluoromethylrhenvl)-4- (6-phthalimido-lhexvl)piperazine acetate M.p. 125-127'C.

Example 1-(4-Amino-3-trifluoromethvlphenvl) (8-Dhthalitnido-loctvl)lpiperazine acetate M.p. 94-96*C.

Example 16 1- (3-Amino-4--chlorophenyl) -4-(4-p~hthalimido-l-butvl) Pinerazine acetate.

M.p. 159-162'C.

La WO 93/2 1179 PCJ'/SE93/00295 31 Example 17 1- (3-Arino-4-chloro-ohenvl) Pinerazine acetate.

M.p. 149-150*C.

Example 18 1- (4 -Amino 3 -ethv1]2henv1) (4-phthalimido-1--butyl)- Pioerazine acetate.

N.p. 123-126*C.

Example 19 1-(3-Amino-4-chlorophenyl)-4-r4-(3,3-tetramethvlenealutarirnido) -l-butylipipoerazine M.p. 133-136'C.

Example 1-(4-Akmino-3-trifluoromethvlphenyl)-4-F6- (3-p~henoxybenzamido)-l-hexvllpiperazine acetate M.p. 128-131'C.

Examle 21 1- (4-Aiino-3-trifluoromethylp~henvl)-4- (6-cyclohexanecarboxarnido-1 -hex-vl )piiperazine dihydrochloride M.p. 112-115*C.

I-

WO 93/21179 PCT/SE93/00295 32 Example 22 1-C4-Amino-3-trifluoromet hv1phenv)-4-(4-adamant carboxamido-l-butvl) Diperazine dihydrochioride M.p. 123-125*C.

Example 23 1-(4-Amino-3-trifluoromethvlohenyl)-4-(4-adamantaneacetamido-l-butyl) Dioerazine M.p. 115-116'C.

Example 24 l-(4-Amino-3-trifluoromethylphenyl)-4-(6-adamantanecarboxamido-l-hexvl)mpierazine HNR (CDC13) d 7.00 1 6 96 (dd, 1 6.70 (d, 1 5.57 (bs, 1 3.26 (bs, 2 3.24 2 3.08 Cm, 4 2.61 Cm, 4 2.39 Cm, 2 2.04 (bs, 3 H), 1. 84 (bs, 6 1.71 Cbs, 6H), 1.52 4 1.34 (m, 4 H).

Example 25 (Method B) i 1-C(4-Amino-2-trifluoromethylohenvl) -4-(4-Dhthalimido-lbutyl)piperazine dihvdrochloride.

To a mixture of I-C4-nitro-2-trif luoromethylphenyl) (4phthalimido-1-butyl) -piperazine- C7.8 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 l00*C. The mixture was heated under reflux for 1 h and the ethanol was evaporated. The residual water solution

L

.t WO 93/21179 PCT/SE93/00295 33 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 -244'C.

Example 26 (Method B) 1-(4-Diethvlamino-3-trifluoromethylphenvl)-4-(4phthalimido-l-butyl)-piDerazine The product from Example 13 (1.0 g, 2 mmol), dissolved in 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 80'C, cooled and added to 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 71'C.

Example 27 (Method B) 1-(4-Amino-3-trifluoromethylphenvl)-4-(4-phthalimido-lbutyl)-pioerazine.

4-(4-Acetamino-3-trifluoromethylphenyl)-l-(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 Fs for 5 h at 80'C. The solvent was removed and the residue was shown by gas chromatography to be identical with the product in example 1.

I

F,

WO 93/21179 34 PCT/SE93/00295 34 Example 28 (Method C) 4-(4-Amino-3-trifluoromethvlphenvl)-l-(4-phthalimido-lbutvyl)-piperazine To a refluxing solution of 4-phthalimido-l-butanal (0.713 g 3.25 mmol) and N-(4-amino-3-trifluoromethylphenyl)piperazine (0.804 g, 3.25 mmol) in CHC1 3 (10 ml) was added dropwise 98% formic acid in CHC13 (10 ml) in 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) l-(4-Amino-3-trifluoromethylphenvly-4-(4-phthalimidolbutvyl)piperazine 4-(4-Amino-3-trifluoromethylphenyl) l--(4-aminobutyl) pipera zine(32 mg, 0.1 mmol) and phthalic anhydride mg, 0.2 mmol) dissolved in 1 ml acetic acid were stirred at 75'C 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-trifluoromethylphenvl)-4-14-(5-bromo-2,3dimethoxvbenzamido)-l-butvllpiperazine 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 0 C for 3.5 h. After cooling, the solution was WO93/21179 PCT/SE93/00295 acidified with 27 ml 2 M HC1 and evaporated. The residue was dissolved in 75 ml H 2 0 and 75 ml ether. The aqueous phase was made alkaline and extracted with chloroform.

The solvent was evaporated to yield crude 1-(4aminobutyl)-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 0

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 (Na 2

SO

4 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 t-itle product.

M.p. 174-175'C.

In an analogous way the following compounds (examples 31- 34) were prepared: Example 31 l-( 4 -Amino-3-trifluoromethvlphenyl)-4-(4-benzamido-lbutyl)piperazine M.p. 117-120'C.

WO 93/21179 PC/SE93/00295 Example 32 l-(4-Amino-3-trifluoromethylphenyl)-4-[5-(5-bromo-23dimethoxybenzamido)-l-pentvl~oioerazine dioxalate M.p. 151-154*C.

Example 33 1 LK:.,Amino-3-tr fluoromethvylpheIv norbc:-r.aneca:Th)oxamido'I 1-butvloierazine hydrochloride M.p. 77-80'C.

Example 34 (R,endo)-l-(4-Amino-- rirluororiethylhenvl)-4-[4-(2norbornanecarboxamido)-1-*butvlloiperazine hydrochloride M.p. 142-146*C.

Example 35 (Method E) £-(4-Amino-5-bromo--3-trifluoromethylphenvl)-4jJ 4 ohthalimido-l-butyl)pperazine 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) dissclved in 3 ml dioxane was added and the mixture stirred at ambient temperatuyva for 5 hours, the solvent evaporated, the residue made alkaline with 2 M aqueous NaOR 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. 172-175*C.

WO 93/21179 .PCT/SE93/00295 37 Example 36 (intermediate, compound II) N-(5-Bromonentyl)-3-methoxyphthalimide 3-Methoxyphthalic anhydride (3.0 g, 16.8 mmol) and amino-1-pentanol(l.7 g, 16.8 mmol) were mixed and heated to 1200C for 2 h. After cooling phosphorus tribromide g, 13 mmol) was added and the mixture heated to 110 0 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. 65-67'C.

Example 37 (intermediate compound II) N-(5-Tosyloxvypentyl)-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, mmol), and a few drops of DMF was heated at 600C for 3 h.

The solvent was evaporated, and the residue dissolved in ml dichloromethane and evaporated again. The residual acid chloride was dissolved in 20 ml dichloromethane and added to a solution of 5-aminopentan. I (1.8 g, 18 mmol) and triethylamine (4 ml, 28 mmol) in 30 ml dichloromethane at -35'C and the temperature allowed to rise to O'C in 4 h. The solution was washed with dilute HC1, the organic phase separated, and the solvent removed to yield 2.2 g of a crude oil. This oil was dissolved in 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.

s WO 93/21179 PCT/SE93/00295 38 1 H NMR(CDCL 3 d 7.9 (bs, 1 7.81 1 7.77 2 7.34 2 7.13 1 4.03 2 3.89 (s, 3 3.87 3 3.42 2 2.44 3 1.73- 1.40 6 H).

Example 38 (intermediate compound IV) 1-(4-Nitro-3-trifluoromethylphenyl)-4-(phthalimido-1butyl)DiDerazine The compound from example 39 (8.5 g, 30 mmol), 4bromobutylphthalimide g, 40 mmol), potassium carbonate (5.0 g, 36 mmol) and a catalytic amount of potassium iodide were warmed to 90'C 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. 152-154'C.

Example 39 (intermediate compound XIII) 4 1-(4-Nitro-3-trifluoromethvlphenvl)Diperazine 4 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 1propanol was stirred and heated at 100'C 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 M.p. 81-83'C.

pr 7" WO 93/21179 PCT/SE93/00295 39 Example 40 (intermediate compound XIII) 4-Amino-2,6-dichlorophenvlpiperazine 2,6-Dichloro-4-nitroaniline (10.4 g, 50 mmol), dissolved in 100 ml methanol and 10 ml 2 M HC1, 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 100'C in n-butanol with 3x1 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.

iH NMR(CDCL 3 d 6.82 2 4.10 2 3.02 8 1.82 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 r

S

WO 93/21179 PCT/SE93/00295 Comoosition 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.

Pharmacoloqv 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.

L

I

WO93/21179 PCT/SE93/00295 41 D2 Receptor Binding Assay Tissue preparation: The rats are decapitated and the striata dissected out on ice. The tissue is homogenized at O'C in 20 ml 0.05 M Tris-HC1 buffer pH 7.7, using a Branson B30 sonifier. The homogenate is centrifuged at 4'C for 10 minutes at 48000 g, in a Sorvall Refrigerated Superspeed Centrifuge. The pellet is resuspended and recentrifuged. The final pellet is resuspended in incubation buffer (0.05 M Tris-HC1 pH 7.6 containing 0.1% ascorbic acid, 120 mM NaCl, 5 mM KC1, 2 mM CaC1 2 1 mM MgC12 and 10 LM pargylin), to a final concentration of 2.5 mg wet weight/0.5 ml. The homogenate is preincubated for 10 min at 37'C.

Receptor binding assay: Various concentrations of the test compound, the radioligand (InM 3 H-Raclopride) and the homogenate are incubated for 60 min at room temperature. Non-specific binding is determined by the addition of 1 M (+)-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 j presented as Ki values.

A Receptor binding Assay Tissue preparation. Cerebral cortex hippocampus from each rat was dissected and homogenized in 15 ml ice-cold Tris-HCl buffer 4.0 mM CaCl 2 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 x g in a Beckman centrifuge with a chilled JA-17 rotor (Beckman, Palo Alto, CA, USA), WO 93/21179 PCT/SE93/00295 42 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 -70"C. 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 37'C and then supplied with 10 tM 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 3 H-8-OH-DPAT (0.25 to 8 nM), 5 mg/ml tissue homogenate in 50 mM Tris-HCl buffer containing 4.0 mM CaCl 2 and 5.7 mM ascorbic acid, pH 7.5. Six different concentrations of 3 H-8-OH-DPAT were analyzed. Binding experiments were started by the addition of tissue homogenate and followed by incubation at 37'C 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- HC1 buffer, pH 7.5, and counted with 5 ml Ultima Gold

TM

(Packard) in a Beckman LS 3801 scintillation counter.

Non-specific binding was measured by the addition of pM 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 Ki values (nM).

p f' TABLE 1

R

Binding K, (nM) Ratio Ex. no. R ni n2 A B m R4 R5 R6 D2 5-HT1A D 2 /5HT1A 1 HOC 8 H 19 H fIi~ 0 0 0 0 1 1 0 0 0 4 4-NH 2 4 3-NH 2 4 3-NH 2 3-CF 3

H

4-Cl H 14 0.17 4-Cl H 13 220 0.06 22 H 0 0 H H 4 4-NH 2 31 H 0 0 H H 3-CF 3

H

3-CF 3 i H 4 4-NH 2 9 60 0.15 NAN 190 H IIi1II 0 0 11 04 H 2-MeO H 2

Claims (12)

1. A compound of the general formula CH2]--T C W FCH A n 2 N -CCH 2 ]m-N N B p a o a a 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 a group NR 7 Rg wherein R 7 and R 8 are the same or different and each represents a hydrogen atom or an alkyl group having 1-3 carbon atoms, is situated in the ortho, meta or para positioii and represents an hydrogen atom, a halogen atom or CF 3 R6 is situated in the ortho, meta or para position and represents a halogen atom or CF 3 r-I B f WO93/21179 PCT/SE93/00295 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, CF 3 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 n 2 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, R 4 R 5 and Rg are as defined above, n 1 is 0 or 1, n 2 is 0 or 1, A is a hydrogen atom, a halogen atom, CF 3 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, R 4 R 5 and R 6 are as defined above, n1 is 0 or 1, WO 93/21179 PCT/SE93/00295 46 n 2 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, R 4 R 5 and R6 are as defined above, ni and n 2 are 1 or n1 is 1 and n 2 is 0 or nI is 0 and n 2 is 1, A and B together constitute a carbonyl group,

2. A compound according to claim 1 having the formula 0 o N-[CH 2 N NH C II O CF 3 or N-[CH 2 N N NH 2 I C 2CF pp. WO 93/21179 PCr/SE93/00295 N N NH 2 0 N N NH 2 F NH 2 7, WO 93/21179 PCT/SE93/00295 NH 2 F F N NH 2 N N N H N2 F N H F F 0 or WO 93/21179 PCT/SE93/00295 -NH 2 F -CI NH 2

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 I I WO 93/21179 PCT/SE93/00295 /[CH 2 ]nl -C CH-A I R N [CH2Im--X I wherein R, m, W, A, B, n 1 and n 2 are as defined in claim 1 and X is a leaving group with a compound of tYz general formula III H-N wherein R 4 R 5 and R6 are as defined in claim 1, or B) conversion of a compound of the general formula IV 0 /CHni-C, W CH A I R n 2 \-27 N-fCH 2 ]m~-IN R 5 B R6 wherein R, m, R 5 Rg, W, A, B, n 1 and n 2 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 -III j i. L WO 93/21179 PCr/SE93/00295 group R4, where R4 is situated in the meta or para position of the ring and represents a group NR 7 R 8 as defined in claim 1, or C) reaction of a compound of the general formula V -C /[CH2]n -C CH -A R N-[CH 2 ]m C-Z I wherein R, m, W, A, B, n 1 and n 2 are as defined in claim 1 and Z is hydrogen, hydroxy, halogen, or alkoxy, with a compound of the general formula III H-N N' wherein R 4 Rs and R6 are as defined in claim 1, or D) reaction of a compound of the general formula VI i WO 93/21179 PCr/SE93/00295 0 I I /[CH 2 ]nl -CT I CH-A R n 2 wherein W, nl, n 2 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 H 2 N-[CH 2 ]m N N VII wherein m, R 4 R 5 and R6 are as defined in claim 1, or E) reaction of a compound of the general formula VIII 0 [CH 2 ]n l-C R I- W N-[CH 2 ]m-N N 8 5 B CI--A n VIII L 1 WO 93/21179 PCT/SE93/00295 wherein R, m, R 4 W, A, B, n and n 2 are as defined in claim 1 and Rg is H,halogen, or CF 3 with a suitable halogenating reagent or F) reaction of a compound of the general formula-IX 0 I I [CH 2 ]n -C W H A N-M I t rr t wherein W, ni 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 X-[CH L i ,K I *I R6 wherein X, R 4 R 5 and Rg are as defined in claim 1, whereafter, if so desired the compound obtained by any of the processes 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.

A compound of claim 1 or 2 when obtained by the process of claim 3 or 4, respectively. i do r WO 93/2117 PCT/SE93/00295 54

6. A pharmaceutical preparation comprising as active ingredient a compound according to any one of claims 1, 2 and in association with a pharmaceutically acceptable carrier.

7. A pharmaceutical preparation according to claim 6 in dosage unit form.

8. Use of a compound according to any one of claims 1, 2 and 5 in the preparation of medicaments with effect against mental disturbances.

9. 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 or pharmaceutical preparation according to any one of claims 1, 2 and 5-7, respectively. rr r r I: i tr: r :i 44 S DATED this 29th day of September 1995 ASTRA AKTIEBOLAG, By its Patent Attorneys, E. F. WELLINGTON COg, By: S W i S. Wellington)/ A/KA/3756 INTERNATIONAL SEARCH REPORT International application No. PCT/SE 93/00295 A. CLASSIFICATION OF SUBJECT MATTER C07D 403/06, C07D 401/06, C07D 405/06, C07D 295/073, C07D 295/125, C07D 295/135, C07D 209/48 C07C 309/73, A61K 31/495 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07D, C07C Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched SE,DK,FI,NO classes as above Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) CAS-ONLINE C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X J. Med. Chem., Volume 34, August 1991, 1-5,7-11 Revathi K. Raghupathi et al, "Analogues of the 1A Serotonin Antagonist 1-(2-Methoxy-phenyl)-4-/4-(2-phthalimido)butyl/pipe razine with Reduced alfal-Adrenergic Affinity", page 2633 page 2638, see especially compounds Ic, If and 2a-2c X J Indian Chem. Soc.,, Volume LVI, October 1979, 1-5,7-11 Samant et al, "Synthesis and Pharmacology of N-(N4-Aryl-N1-Piperaziny lalkyl)Phthalimides: CNS Depressants", page 1002 page 1005, see page 1004 Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: later document published after the international filing date or priority document defining the general state of the art which is not considered te ndnoin conlicti the a but cited to understan to be of particular relevance the principle or theory underlying the invention ertier document but published on or after the intemational filing date document of particular relevance: the claimed invention cannot be considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is onside en e documenot taen alondered to involve an inventive cited to establish the publication date of another citation or other special reason (as specified) document of particular relevance: the claimed invention cannot be document referring to an oral disclosure, use, exhibition or other considered to involve an inventive step when the document is means combined with one or more other such documents, such combination document published prior to the international filing date but later than being obvious to a person skilled in the art the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 14 Sept 1993 16 -09-199 Name and mailing address of the ISA/ Authorized officer Swedish Patent Office Box 5055, S-102 42 STOCKHOLM Giran Karlsson Facsimile No. 46 8 666 02 86 Telephone No. +46 8 782 25 00 Form PCT/ISA/210 (second sheet) (July 1992) 7 I INTERNATIONAL SEARCH REPORT International application No. PCT/SE 93/00295 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

WO, Al, 9109594 (VIRGINIA COMMONWEALTH UNIVERSITY), 11 July 1991 (11.07.91), see especially pages

11-17 and 66-97 J. Med. Chem., Volume 31, October 1988, Richard A. Glennon et al, "Arylpiperazine Derivatives as High-Affinity 5-HT1A Serotonin Ligands", page 1968 page 1971, see specially compounds 15-17 and 23-24 FR, A, 1537901 (LES LABORATOIRES BRUNEAU ET CIE), August 1968 (30.08.68) FR Addition 93884 (LES LABORATOIRES BRUNEAU ET CIE), May 1969 (30.05.69) GB, A, 1198459 (SHULTON INC.), 15 July 1970 (15.07.70) US, A, 3505338 (WILLIAM BLYTHE WRIGHT, JR ET AL), 7 April 1970 (07.04.70) US, A, 3940397 (WADE ET AL), 24 February 1976 (24.02.76) EP, Al, 0048045 (DUPHAR INTERNATIONAL RESEARCH 24 March 1982 (24.03.82), see especially page 3, example II compound 3) and example III compound 2) 1-4,7-11 1-5,7-11 1-4,7-11 1-4,7-11 1-4,7-11 1-5,7-11 1-5,7-11 J 1-4,7-11 Form PCT/ISA/20 (continuation of second sheet) (July 992) Form PCT/ISA/210 (continuation of second sheei) (July 1992) r I I INTERNATIONAL SEARCH REPORT International application No. PCT/SE 93/00295 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X P,X P,X X X X X X X GB, A, 2218988 (AMERICAN HOME PRODUCTS CORPORATION), 29 November 1989 (29.11.89), see especially example 8 and 19 US, A, 5143923 (HRIB ET AL), 1 Sept 1992 (01.09.92), see column 1-4 and exemple 1-4,7-11 EP, Al, 526434 3 February (BOEHRINGER INGELHEIM ITALIA S.P.A), 1993 (03.02.93), see especially example US, A, 4892943 (ABOU-GHARBIA), 9 January 1990 (09.01.90), see especially example 30-35 US, A, 4939137 (RUSSELL ET AL), 3 July 1990 (03.07.90) EP, A2, 212551 (KALI-CHEMIE PHARMA GMBH), 4 March 1987 (04.03.87), see especially compound 3116 and 3117 1-5,7-11 1-4,7-11 1-4,7-11 1-5,7-11 1-5,7-11 1-5,7-11 1-5,7-11 1-4,7-11 EP, A2, 0376633 (04.07.90), US, A, 3398151 (20.08.68) US, A, 3558777 (26.01.71) (SI"ITniR I TMTTFplt A .JulV 1q99 see pages 6-12 and 25-41 I (YAO HUA WU), 20 August 1968 (YAO HUA WU), 26 January 1971 Form PCT/ISA/210 (continuation of second sheet) (July 1992) pp f INTERNATIONAL SEARCH REPORT International application No. PCT/SE 93/00295 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A J. Med. Chem., Volume 32, August 1989, 1-4,7-11 Richard A. Glennon et al, "N-(Phthalimidoalkyl)Derivatives of Serotonergic Agents: A Common Interaction at 5-HT1A Serotonin Binding Sites?", page 1921 page 1926, see table II A Journal of Pharmaceutical Sciences, Volume 77, No 1-4,7-11 October 1988, Khalid A. Al-Rashood et al, "Antipsychotic Properties of New N-(4-Substituted-l-Piperazinylethyl)- and N-(4-Substituted-l-Piperidinylethyl)-Phthalimides", page 898 page 901, see table II X US, A, 3465080 (WILLIAM BLYTHE WRIGHT JR), 2 Sept 1969 (02.09.69), see exemple

12 X US, A, 4361565 (TEMPLE, JR. ET AL), November 1982 (30.11.82), see exemple 1-3 X Chemical Abstracts, Volume 80, No 1, 7 January 1974 (07.01.74), (Columbus, Ohio, USA), page 288, THE ABSTRACT No 37015m, FR, A, 2167355, (Carron, Claude L.C. et al) 28 Sept 1973 (28.09.73), see reg.no. 50845-96-0 X Chemical Abstracts, Volume 94, No 25, 22 June 1981 (22.06.81), (Columbus, Ohio, USA), Kormendy, Karoly et al, "Aminophthalazinone derivatives. VI. Synthesis of 4-(hydroxyalkylamino)l-(2H)-benzofglphthalazinones" ,page 594, THE ABSTRACT No 208787k, Acta Chim. Acad Sci. Hung. 1980, 105 175-188, see reg.no.

77766-48-4 Form PCT/ISA/210 (continuation of second sheet) (July 1992) n r- 7 i l- SUL-PI- 1_1 INTERNATIONAL SEARCH REPORT International application No. PCT/SE 93/00295 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X Chemical Abstracts, Volume 110, No 5, January 1989 (30.01.89), (Columbus, Ohio, USA), Giardina Dario et al, "Structure-activity relationships in prazosin-related compounds. Effect of replacing a piperazine ring with an alkanediamine moiety on xl-adrenoreceptor blocking activity", page 540, THE ABSTRACT No 38951p, J. Med. Chem. 1989, 32 50-55, see reg.no.

116784-96-4 I I Form PCT/ISA/210 (continuation of second sheet) (July 1992) I WWNW. This;, ternstional search repport has not been ertablished in respect ofccruzin claims under Article for the follow~ing reasons; 1. WX ClEirnsNos.: 12-13 becmuse they relae to subject matter not required to be searched by this Authcwity, namely. A method for treatment of the human or animal body by' therapy, see rule 39., 2. 9 CIa .s 1, 3 and becmuse they relate to pzrts of the international =ppllati'n Lhat do not comply with the presc. ibed requirements to Seuch z-n extent thai no meaningful international search can. be carried out, specica)"r. The scope of &laims 1,3 and 5 is so broadly formulated that many compounds of a very wide range of structures is included. The-SFearch has thus been limited to the compounds considered Dto be most relevant. 3. Clams:.Nos.: bemause they are dependent clims s-nd are not draf-td in a-ordanc with the second and third sententes of Rule Box 11 Observations where unity of invention is lacking (Continua~tion of item 2 of first sheet) This lnternsatior.2l Searching Authority found multiple inven4-cns in this international ;-pplicastion, L-s follows: 3.mF- As ;.1l recuired Lddition- search fees were timely paid by the applicant, this inlerratlons~l search report covers s-ll 2. F As 2ll searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. ~*DAs only some of the required additional search fees Were timely paid by the applicant, this internatior2al search report Fcovers only those clams for which fees were paid, specifically clams Nos.: 4. -I No eqird additional seach fees were timely paid by the a;p=ln. Consequentiy, this internatonal search report is resrce to the invention first mentioned in the clainS; it is Covered by clams Nos.:. Rem"r on Protest D The Ldditional search fees were accoompanied by the applicant's protest. E]No protest ;.ccompanied the payment of additional search feres. Form PCT/ISAj210 (continuation of first sheet. (July 1992) INTERNATIONAL SEARCH REPORT International application No. Information on patent family members 26/08/93 PCT/SE 93/00295 Patent document Publication Patent family Publication cited in search report date member(s) date WO-A1- 9109594 11/07/91 AU-A- 7168491 24/07/91 EP-A- 0507863 14/10/92 FR-A- 1537901 30/08/68 NONE GB-A- 1198459 15/07/70 CH-A- 505836 15/04/71 DE-A- 1695783 22/04/71 FR-A- 1570446 13/06/69 NL-A- 6713798 16/04/68 US-A- 3488352 06/01/70 US-A- 3574839 13/04/71 US-A- 3505338 07/04/70 BE-A- 707032 24/05/68 CH-A- 509311 30/06/71 CH-A- 509312 30/06/71 DE-A- 1670007 21/01/71 GB-A- 1166364 08/10/69 NL-A- 6715434 27/05/68 US-A- 3940397 24/02/76 CA-A- 1058178 10/07/79 DE-A- 2551062 26/05/76 FR-A,B- 2290903 11/06/76 GB-A- 1507709 19/04/78 EP-Al- 0048045 24/03/82 AU-A- 7502981 18/03/82 CA-A- 1155116 11/10/83 JP-A- 57081464 21/05/82 NL-A- 8005133 01/04/82 GB-A- 2218988 29/11/89 AU-B- 628341 17/09/92 AU-A- 3502589 30/11/89 EP-A- 0343961 29/11/89 JP-A- 2015059 18/01/90 US-A- 5143923 01/09/92 AU-A- 1518792 05/11/9. EP-A- 0511610 04/11/92 EP-Al- 526434 03/02/93 NONE US-A- 4892943 09/01/90 AU-B- 582906 13/04/89 AU-A- 6364586 30/04/87 EP-A- 0220873 06/05/87 GB-A,B- 2181731 29/04/87 US-A- 4939137 03/07/90 NONE EP-A2- 212551 04/03/87 NONE EP-A2- 0376633 04/07/90 AU-B- 630904 12/11/92 AU-A- 4726089 05/07/90 CA-A- 2006792 28/06/90 JP-A- 2256671 17/10/90 US-A- 5071845 10/12/91 Form PCT/ISA/210 (patent family annex) (July 1992) I pp. INJTERNATIONAL SEARCH REPORT Information on patent family members International application No. 26/08/93 PCT/SE 93/00295 Patent document cited in search report Publication dateI Patent family member(s) Publication date US-A- S'3'8151 20/08/68 BE-A- 693497 01/08/67 CH-A- 494766 15/08/70 CH-A- 495368 31/08/70 OE-A- 1695390 24/02/72 GB-A- 1164503 17/09/69 NL-A- 6701538 02/08/67 US-A- 3558777 26/01/71 NONE US-A- 3465080 02/09/69 NONE US-A- 4361565 30/11/82 AU-B- AU-A- BE-A- CA-A- CH-A, B- DE-A, C- FR-A,B- GB-A, B- JP-A- LU-A- NL-A- SE-B, C- SE-A- 560667 9108482 895505 1237722 653682 3248138 2518994 2114121 58118583 84562 8204974 449748 8207426 16/04/87 07/07/83 28/06/83 07/06/88 15/01/86 07/07/83 0 1/07/83 17/08/83 14/07/83 08/09/83 18/07/83 18/05/87 29/06/83 FR-A- 2167355 28/09/73 NONE I Form PCT/[SA/2l0 (patent family annex) (July 1992)