EP1140099A1

EP1140099A1 - Utilisation of 2-substituted 1,2-benzisothiazole derivatives and 3-substituted tetrahydropyridopyrimidinone derivatives for the prophylaxis and therapy of cerebral ischaemia

Info

Publication number: EP1140099A1
Application number: EP99966990A
Authority: EP
Inventors: Gerd Steiner; Kurt Schellhaas; Wilfried Lubisch; Uta Holzenkamp; Dorothea Starck; Laszlo Szabo; Franz Emling; Francisco Javier Garcia-Ladona; Hans-Peter Hofmann; Liliane Unger
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1999-01-11
Filing date: 1999-12-22
Publication date: 2001-10-10
Also published as: CA2359390A1; KR20010101440A; DE19900544A1; NO20013408L; SK9682001A3; JP2002534467A; MXPA01006966A; HUP0200520A2; TR200102009T2; NO20013408D0; PL348916A1; BG105688A; HUP0200520A3; BR9916888A; AR029741A1; ZA200105473B; WO2000041697A1; AU2285100A; IL144145A0; CN1333685A

Abstract

The invention relates to the utilisation of compounds of formula (I) wherein the substituents have the meanings given in the description. The invention also relates to the salts thereof comprising pharmacologically compatible acids for producing medicaments for the prophylaxis and therapy of cerebral ischaemia and strokes.

Description

USE OF 2-SUBSTITUTED 1, 2-BENZISOTHIAZOLE DERIVATES AND OF 3-SUBSTITUTED TETRAHYDROPYRIDOPYRIMIDINONE DERIVATIVES FOR PROPHYLAXIS AND THERAPY OF CEREBRAL ISCHEMIA

5 Description

The invention relates to the use of compounds of formula I for the prophylaxis and therapy of cerebral ischemia

0 DE 19747063.7 describes 3-substituted tetrahydropyridopyrimidinone derivatives of the formula I

wherein

0 one of the two radicals X, Y represents CH ₂ and the other represents NR ¹ ,

R ¹ for hydrogen, (Cι_ ₆ ) Al yl branched or unbranched, CO- (Cι_ ₄ ) alkyl, C0 ₂ tBu, CO-aryl and a phenylalkyl- C ₁ -C ₄ -R.es, which in turn on the aromatic F, Cl, Br, I, 5 ₁ -C alkyl, C ₁ -C ₄ alkoxy, trifluoroethyl, hydroxy, amino, cyano or nitro may be substituted,

A is branched or unbranched (Cι-ιo) -alkylene or straight-chain or branched (C2 ₁₀₎ -alkylene which 0 comprises at least one group Z which is selected from 0, S, MR2, cyclopropyl, CHOH, a double or a triple bond,

R ^{2 represents} hydrogen and C ₁ -C ₄ alkyl, 5

B stands for 4-piperidine, 4-tetrahydro-l, 2, 3, 6 pyridine, 4-piperazine and the corresponding ring compounds enlarged by a methylene group, the linkage to A taking place via an N atom of B and 0

Ar for phenyl, which may be branched or unbranched by (Cι_ ₆ ) alkyl, O- (Cι_ ₆ ) alkyl branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR ² ₂ , C0 ₂ R ² , cyano or substituted phenyl, tetralin, indane, more highly condensed 5 aromatics such as naphthalene, which is optionally substituted by (C ^) alkyl or 0 (Cχ-) alkyl, anthracene or 5- or 6-membered aromatic heterocycles with 1 to 2 hetero - ato en, which are independently selected from O and N, which can be fused with other aromatic radicals.

These compounds of formula I can be prepared by using a compound of formula II,

in which A, X and Y have the meaning given above and Q represents a cleavable group (for example Cl, Br, I, alkanesulfonyloxy or arylsulfonyloxy), with a compound of the formula III,

H-B-Ar (III),

in which B and Ar have the meaning given above, are reacted in a manner known per se and the compound thus obtained is optionally converted into the acid addition salt of a physiologically tolerated acid. It is also possible to use a compound of formula IV

with a compound of formula V

Q- _A -B- _A r (v)

to implement in a manner known per se.

Another synthesis variant is the linking of a compound of formula VI

with a compound of formula III by a known reductive amination. Compounds of the formula III can be synthesized by

1. Linking compounds of general formula VII

WB ¹ (VII)

where B ^{1 is} piperazine or homopiperazine and W is hydrogen or one of the usual amino protecting groups (such as Boc or Cbz), with a compound of general formula VIII

P-Ar (VIII),

where P is B (OH) ₂ , SnR ₃ , OTf, Br, Cl, or I and R is iC ₄ -Al yl, in a known manner; or

the linking of compounds of general formula IX

_W _ _B 2_pl (iχ),

where B2 is 4-tetrahydro-l, 2, 3, 6-pyridine and the corresponding ring compounds enlarged by a methylene group and Pi is Cl, Br, I, SnR ₃ - where R is C 1 -C ₄ -alkyl, OTf with a compound of the general formula X

P-Ar (X),

where W, P and Ar each have the meaning given above and the reactions are carried out by known processes, such as described in

S.L. Buchwald et al. J. Am. Chem. Soc. 1996, 118, 7215,

J.F. Hartwig et al. Tetrahedron Lett. 1995, 36, 3604,

J.K. Stille et al. Appl. Chem. 1986, 98, 504,

S.L. Buchwald et al. Appl. Chem. 1995, 107, 1456 or

J.F. Hartwig et al. J.Am. Chem. Soc 1996, 118, 7217 or

J.F. Hartwig et al. J. Org. Chem. 1997, 62, 1268,

S.L. Buchwald et al. J. Org. Chem. 1997, 62, 1264 and literature cited therein or

S.L. Buchwald et al J.Am. Chem. Soc 1997, 119, 6054,

J.K. Silence, Angew. Chem. 1986, 98, 504 or

J.K. Stille et al. J. Org. Chem. 1990, 55, 3014,

M. Pereyre et al. "Tin in Organic Synthesis," Butterworth

1987; or 3. Reduction of compounds of the general formula (XI)

WB ² -Ar (XI),

where B ^{2 has} the meaning given above for compounds of the general formula XII

WB ³ -Ar (XII),

10 wherein B ^{3 represents} piperidines linked in the 1,4-position and the corresponding ring compounds enlarged by a methylene group; or

15 4. the cyclization of compounds of general formula XIII

WN- (C ₂ H ₄ Q) ₂ (XIII),

where W and Q have the meaning described above, with ^ 0 a compound of the general formula XIV

NH ₂ -Ar (XIV),

25 where Ar has the meaning given above, to compounds of the general formula XV

W-ß-Ar (XV).

30 The substances of the formulas III and V required as starting materials for the synthesis of the new compounds are known or can be prepared using the known processes (e.g. Organikum Barth Dt. Verl. Der Wiss. 1993 or AR Katritzky, CW Rees (ed. ) Comprehensive Heterocyclic Chemiεtry Pergamon Press) from analog

35 synthesize starting materials.

The further implementation of the compounds thus prepared after 1 to 4 with subsequent removal of any protective groups

^■ 40 HB-Ar (III)

to the compounds of the formula V is carried out by linking to compounds of the formula XVI

⁵ QAQ '(XVI), where Q and Q 'stand for leaving groups, under conditions known per se.

The substances of the formula II, IV, VI and the general formula P-Ar, NH ₂ -Ar, WB ¹ or -B ² - required as starting materials for the synthesis of the new compounds? ¹ are known or can be synthesized from analogous starting materials according to the production processes described in the literature (for example B. Dumaitre, N. Dodic J. Med. Chem. 1996, 39, 1635 or A. Yokoo et al. Bull. Chem. Soc. Jpn. 1956, 29, 631 or L. Börjeson et al. Acta Chem. Chem. 1991, 45, 621 or Organikum Barth Dt. Verl. Der Wiss. 1993 or AR Katritzky, CW Rees (ed.) Comprehensive Heterocyclic Chemistry Pergamon Press or The Chemistry of Heterocyclic Compounds J. Wiley & Sons Inc. NY and the literature cited there).

Example 1:

3- [2- [4- (2-Methoxyphenyl) -l-piperazinyl] ethyl] -5,6,7,8-tetra-hydro-6-benzylpyrido [4, 3-d] pyrimidine-4 (3H ) -on

Production of raw materials

a) 5,6,7,8-tetrahydro-6-benzyl-pyrido [4,3-d] pyrimidin-4 (3H) -one

4.7 g of sodium were allowed to react in small portions in 250 ml of ethanol, and a suspension of 14.2 g (0.05 mol) of N-benzyl-4-piperidone-3-carboxylic acid methyl ester was then added dropwise at 5-10 ° C. in ethanol. After stirring for 30 minutes, 6 g (0.075 mol) of formamidine hydrochloride were slowly added and the reaction mixture was heated under reflux for 10 h. The solvent was removed in vacuo and the residue was adjusted to pH = 6.5-7 in 100 ml of water with 2N hydrochloric acid, so that the product precipitated. The crystals were filtered off with suction, dried in a vacuum drying cabinet and 8 g (66%) were isolated in this way. Mp: 88 ° C.

5,6,7,8-tetrahydro-7-benzyl-pyrido- [3, 4-d] pyrimidin-4 (3H) -one (mp: 199 ° C.) and 5, 6, 7, 8 -Tetrahydro-pyrido [4,3-d] pyrimidine-4 (3H) -one-6-carboxylic acid methyl ester (mp: 160 ° C) obtained.

b) l- (2-methoxyphenyl) -4- (2-chloroeth-l-yl) piperazine

A solution of 19.2 g (0.1 mol) of o-methoxyphenylpiperazine and 13.8 g (0.1 mol) of potassium carbonate in 200 ml of DMF was initially introduced at room temperature and 30 ml (0.36 mol) were added after 30 minutes. l-bromo-2-chloroethane. The mixture was stirred at room temperature for 2 h. After pouring into ice water, the mixture was extracted with methyl tert-butyl ether, the organic phases were washed with water, dried with sodium sulfate and then concentrated. The hydrochloride was precipitated from the solution of the residue in ethyl acetate by adding 30% isopropanol / HCl solution, which was dried in a vacuum drying cabinet at 40 ° C. after suction. 17 g (67%) of substance were obtained. Mp ..- 200 ° C.

Analogously, 1- (2-methoxyphenyl) -4- (3-chloroprop-l-yl) piperazine (mp: 217 ° C., hydrochloride), 1- (3, 4-methylphenyl) -4- ( 2-chloroeth-l-yl) piperazine (mp: 260 ° C, hydrochloride), 1- (2-pyrimidyl) -4- (2-chloro-1-yl) piperazine (mp: 270 ° C, Hydrochloride), l- (naphth-l-yl) -4- (3-chloroprop-l-yl) piperazine (mp: 217 ° C., hydrochloride).

Two example syntheses are given below for the preparation of the piperazines.

l-tetralin-5-yl-piperazine

14.7 g (0.1 mol) of 5-aminotetralin was heated under reflux with 18 g (0.11 mol) of bis (β-chloroethyl) amine hydrochloride in 300 ml of n-butanol, and 5.4 g were added after cooling Sodium carbonate was added and heated under reflux for a further 20 h. The precipitate formed by cooling was filtered off with suction, taken up in water and treated with 2N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, if desired with water, dried over sodium sulfate and concentrated in vacuo. 10.7 g (50%) of the product could thus be isolated as an oil.

4-piperazin-l-yl-isoquinoline

4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of piperazine-N-carboxylic acid t-butyl ester, 0.1 g (0.11 mmol) of tris (dibenzylideneacetone) dipalladium, 0.11 g (0.18 mmol) of 2,2'-bis (diphenylphosphino) -l, 1'-binaphthyl and 2.92 g (30.4 mmol) of sodium t-butoxide in 50 ml of toluene and 2 h at 75 ° C stirred. The reaction mixture was poured onto ice / sodium chloride, extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was removed on a rotary evaporator. The product crystallized out, was filtered off and washed with pentane. 5.5 g (81%) of the Boc-protected piperazine (mp: 111 ° C.) were obtained. 5.2 g (16.6 mmol) of this substance were taken up in 17 ml dichloromethane and at 0 ° C slowly mixed with 17 ml (0.22 mol) of trifluoroacetic acid. The mixture was stirred at 0 ° C. for 4 h, poured onto ice water and extracted with dichloromethane. The aqueous phase was filtered, made alkaline and extracted with dichloromethane. After drying over sodium sulfate and extensive removal of the solvent, the mixture was diluted with diethyl ether and the hydrochloride was precipitated with ethereal hydrochloric acid. 3.2 g (67%) of the product were obtained. (Mp: 293 ° C).

The following compounds were prepared in analogy to the two processes described: 1-naphth-l-yl-azepan (85 ° C., hydrochloride), 1-naphth-l-ylmethyl-piperazine (oil), 4-piperazin-1-yl -indane (oil), 1-naphth-l-yl-piperazine (82 ° C), 4-chloro-l-piperazin-1-yl-phthalazine (205 ° C, dec.) and 4-piperazin-l-yl - quinazoline (320 ° C, hydrochloride). Other derivatives were commercially available.

Production of the end product

To a solution of 2.4 g (10 mmol) of tetrahydropyridopyrimidine

[a)] in 40 ml of DMF, 2.9 g (10 mmol) of chloroethylpiperazine [b)] and 2.8 g (20 mmol) of potassium carbonate were added. After two hours of reaction at 90 ° C, the reaction mixture was poured onto ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and the solvent was removed in vacuo. The remaining oil was taken up in acetone and the hydrochloride was precipitated with isopropanol / HCl. 4 g (75%) of the product were obtained (mp: 205 ° C.).

NMR: CDCl ₃ δ 8.0 (s, 1H), 7.4 - 7.2 (m, 5H), 7.1 - 6.8 (m, 4H), 4.0 (t, 2H), 3.8 (s, 3H), 3.7 (s, 2H) , 3.5 (s, 2H), 3.1 (br. S, 4H), 2.8 - 2.6 (m, 10H) ppm.

The following compounds were obtained in an analogous manner:

Example 2:

3- [2- [4- (2-Methoxyphenyl) -l-piperazinyl] ethyl] -5, 6, 7, 8-tetra-hydro-7-benzyl-pyrido [3,4-d] pyrimidine-4 (3H ) -one (mp: 181 ° C, hydrochloride).

Example 3:

3- [3- [4- (2-Methoxyphenyl) -l-piperazinyl] propyl] -5,6,7,8-tetra-hydro-6-benzylpyrido [4,3-d] pyrimidine-4 (3H ) -on (mp ..- 198 ° C, hydrochloride). Example 4:

3- [3- [4- (2-Methoxyphenyl) -l-piperazinyl] propyl] -5,6,7,8-tetra-hydro-7-benzylpyrido [3, 4-d] pyrimidine-4 (3H ) -one (mp: 190 ° C, hydrochloride).

Example 5:

3- [3- [4- (2-Methoxyphenyl) -l-piperazinyl] 2-hydroxypropyl] -5,6,7,8-tetrahydro-6-benzyl-pyrido [4, 3-d] pyrimidine-4- ( 3H) -on.

Example 6:

3- [2- [4- (naphth-l-yl) -l-piperazinyl] ethyl] - 5, 6, 7, 8-tetra-hydro-pyrido [4, 3-d] pyrimidin-4- (3H) -on-6-carboxylic acid t-butyl ester (mp: 170 ° C., hydrochloride).

Example 7:

3- [2- [4- (Isoquinolin-4-yl) -l-piperazinyl] ethyl] -5,6,7,8-tetra-hydro-6-benzylpyrido [4,3-d] pyrimidin-4 - (3H) -one (mp: 268 ° C, hydrochloride).

Example 8:

3- [2- [4- (Naphth-1-yl) -1-piperazinyl] ethyl] -5,6,7, 8-tetrahydropyrido [4,3-d] pyrimidin-4- (3H) -on (mp: 272 ° C, hydrochloride).

Example 9:

3- [2- [4- (Quinazolin-4-yl) -1-piperazinyl] ethyl] -5,6,7,8-tetra-hydro-6-benzyl-pyrido [4,3-d] pyrimidin-4 - (3H) -one (mp: 258 ° C, hydrochloride).

Example 10:

3- [2- [4- (Naphth-1-yl) -1-piperazinyl] ethyl] -5,6,7,8-tetra-hydro-6-benzyl-pyrido [4,3-d] pyrimidin-4 - (3H) -one (mp: 227 ° C, hydrochloride).

Example 11:

3- [2- [4- (Naphth-1-yl) tetrahydro-1,2,3,6-pyridin-l-yl] eth-l-yl] 5,6,7,8-tetrahydro-6- benzyl-pyrido [4, 3-d] pyrimidin-4- (3H) -one (mp: 216 ° C, hydrochloride). Synthesis of the starting materials

a) N-Boc-4- (trifluoromethanesulfonyloxy) tetrahydro-1,2,3,6-pyridine

A solution of 13.2 g (0.13 mol) of diisopropylamine in 200 ml of THF was deprotonated at -78 ° C. with 100 ml of nBuLi (1.6M in hexane) and after 30 minutes at this temperature 20.0 g (0.1 mol) of the N-Boc-piperidone-4 dissolved in 50 ml of THF was added dropwise. After another three hours at -78 ° C, one was given

Solution of 39.3 g (0.11 mol) of N, N, -bis rifluoromethanesulfonyl-aniline in 50 ml of THF and allowed to come to room temperature overnight. For working up, water was added, the mixture was extracted with ether, the organic phases were washed with NaHC0 ₃ solution and water, dried over sodium sulfate and the solvent was concentrated. The crude product was purified by means of flash chromatography (silica gel, eluent heptane / ethyl acetate = 3/1).

Yield: 20.2 g (60% of theory)

1H-NMR: (270 MHz, CDCl ₃ ) δ = 1.4 (s, 9H); 2.4 (m, 2H); 3.6 (t, 2H); 4.1 (m, 2H); 5.8 (m, lH) ppm

b) N-Boc-4-naphth-l-yl-tetrahydro-l, 2,3, 6-pyridine

14.7 g (44.4 mmol) of the compound described above dissolved in 115 ml of dirthhoxyethane were successively 22 ml of 2M sodium carbonate solution, 7.63 g (44.4 mmol) of naphthyl-1-boronic acid, 4.13 g (97.6 mmol ) Lithium chloride, 0.85 g (4.44 mmol) copper (I) iodide and 2.1 g (1.77 mmol) tetrakistriphenyl palladium were added and the mixture was heated to boiling for 4 h. For the work-up, with the addition of aqueous ammonia solution, the mixture was worked up extractively with water and ethyl acetate, dried over sodium sulfate and the residue obtained after evaporation of the solvent was purified by means of flash chromatography (silica gel, mobile phase heptane / ethyl acetate = 4/1).

Yield: 8.2 g (57% of theory)

1H-NMR (270 MHz, CDC1 ₃ ): δ = 1.4 (s, 9H); 2.5 (m, 2H); 3.7 (t, 2H); 4.1 (m, 2H); 5.8 (m, 1H); 7.2-7.5 (m, 3H); 7.3-8.0 (m, 3H) ppm. c) 4-Naphth-l-yl-tetrahydro-l, 2,3, 6-pyridine

7.84 g (25.3 mmol) of N-Boc-4-naphth-1-yl-tetrahydro-1, 2, 3, 6-pyridine were stirred overnight with 200 ml of ethereal hydrochloric acid at room temperature, the precipitated product was filtered off and dried.

Yield: 5.5 g (88% of theory).

d) representation of the final connection

0.51 g (2 mmol) of 4-naphth-l-yl-tetrahydro-l, 2, 3, 6-pyridine dissolved in 30 ml of dry DMF were mixed with 0.61 g (2 mmol) of 3- (2-chloro eth-l-yl) -3,5,7, 8-tetrahydro-4-oxo-6-benzylpyrido [4,3-d] pyrimidine and mixed with 2 ml (17 mmol) triethyla in and 5 h stirred at 120 ° C. The organic phase diluted with ether was washed with water, dried over sodium sulfate and the solvent was removed in vacuo. The crude product obtained was purified by chromatography and a white solid was obtained by precipitation of the salt with ethereal hydrochloric acid solution.

Yield: 0.2 g (20% of theory)

Mp: 237 ° C.

Example 12

3- [2- [4- (Naphth-1-yl) piperidin-1-yl] eth-l-yl] -5,6,7,8-tetra-hydro-6-benzylpyrido [4,3 -d] pyrimidine-4- (3H) -one

4-naphth-l-yl-piperidine

3.7 g (15.3 mmol) of 4-naphth-l-yl-tetrahydro-l, 2, 3, 6-pyridine dissolved in methanol were hydrogenated with the addition of 0.8 g of palladium on carbon with hydrogen at room temperature over 48 h. The catalyst was filtered off and the solvent was concentrated.

Yield: 1.8 g (56% of theory)

1H NMR (270 MHz, CDCl ₃ ) δ = 1.6-1.8 (m, 2H); 2.0 (.2H); 2.9 (dt, 2H); 3.3 (d, 2H); 3.5 (tt, IH); 7.4-7.6 (m, 4H); 7.7 (d, IH); 7.9 (d, IH); 8.1 (d, IH) ppm. Representation of the final connection

0.42 g (2 mmol) of 4-naphth-l-yl-piperidine, dissolved in 30 ml of dry DMF, were treated with 0.61 g (2 mmol) of 3- (2-chloro-eth-l-yl) -3.5 , 7, 8-tetrahydro-4-oxo-6-benzyl-pyrido [4, 3-d] pyrimidine and with 2 ml

(17 mmol) triethylamine were added and the mixture was stirred at 120 ° C. for 5 h. The organic phase diluted with ether was washed with water, dried over sodium sulfate and the solvent was removed in vacuo. The crude product obtained was purified by chromatography and a white solid was obtained by precipitation of the salt with ethereal hydrochloric acid solution.

Yield: 0.24 g (27% of theory)

1H-NMR (270 MHz, CDCl ₃ ) δ = 8.3 (s, IH), 8.0 (d, IH), 7.8 (d, IH), 7.7 (t, IH), 7.5 - 7.2 (m, 9H), 4.5 (s, 2H), 4.0 (s, 2H), 3.7 - 2.3 (m, 15H), 2.1 (d, 2H) ppm.

The following table lists further preferred compounds of the formula I according to the invention.

DE 19746612.5 describes 2-substituted 1,2-benzisothiazole derivatives of the formula I

wherein

R ¹ , R ² independently of one another represent (Cχ-ξ) alkyl,

R ³ , R ⁴ independently of one another for hydrogen, (Cι_ ₆ ) alkyl branched or unbranched, OH, 0- (Cι- ₆ ) alkyl branched or unbranched, F, Cl, Br, I, trifluoromethyl, NR ⁵ R ⁶ , C0 ₂ R ⁷ , nitro, cyano, pyrrole, for a phenylalkyl C ₁ -C ₄ radical, which in turn is aromatic on F, Cl, Br, I, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl , Hydroxy, amino, cyano or nitro can be substituted,

R ⁵ , R ⁶ independently of one another for hydrogen, (Cχ- ₆ ) alkyl branched or unbranched, COPh, C0 ₂ tBu, CO- (Cχ_ ₄ ) alkyl or together for a 5- or 6-membered ring which may optionally be a second N contains (e.g. piperazine),

R ^{7 represents} hydrogen and (Cι_g) alkyl branched or unbranched,

A represents branched or unbranched (Cι_ιo) alkylene or straight-chain or branched (C_ιo) alkylene which comprises at least one group Z which is selected from 0, S, NR ⁷ , cyclopropyl, CHOH, a double or a triple bond,

B represents 4-piperidine, 4-tetrahydro-l, 2, 3, 6 pyridine, 4-piperazine and the corresponding ring compounds enlarged by a methylene group, the linkage to A taking place via an N atom of B and

Ar for phenyl which is optionally branched or unbranched by (Ci-β) alkyl, 0- (Ci-β) alkyl branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR ⁵ R ⁶ , C0 ₂ R ^7, cyano or phenyl, tetralin, indan, highly condensed aromatics such as naphthalene, which is optionally substituted by (C ₁ - ₄₎ alkyl or 0 (Cι_ ₄₎ is substituted alkyl, anthracene or 5- or 6-membered aromatic heterocycles having 1 up to 2 heteroatoms, which are independently selected from 0 and N, and those with others aromatic residues can be fused, for example quinoline, isoquinoline, phthalazine, indole and quinazoline, which in turn can be substituted with phenyl,

stands as well as their salts with physiologically acceptable acids.

These compounds of formula I can be prepared by using a compound of formula II

in which R ¹ to R ⁴ and A have the meaning given above and Q represents a cleavable group (for example Cl, Br, I, alkanesulfonyloxy or arylsulfonyloxy), with a secondary amine of the formula III,

H-B-Ar III

in which B and Ar have the meaning given above, are reacted in a manner known per se and, if appropriate, the compound thus obtained is converted into the acid addition salt of a physiologically tolerated acid. It is also possible to use a compound of formula IV

R3 R

with a compound of formula V

Q-A-B-Ar V

to implement in a manner known per se. Another synthesis variant is the linking of a compound of formula VI

with a compound of formula III by a known reductive amination.

Compounds of the formula III can be synthesized by

5. Linking compounds of the general formula VII

WB ¹ (VII)

P-Ar (VIII),

where P is B (OH) ₂ , SnR ₃ , OTf, Br, Cl, or I and R is C 1 -C ₄ -alkyl, in a known manner; or

6. the linking of compounds of the general formula IX _ _B2 _pl ( _IX )

where B ² for 4-tetrahydro-l, 2, 3, 6-pyridine and the corresponding ring compounds enlarged by a methylene group and P ¹ for Cl, Br, I, SnR ₃ - where R for C ₁ -C ₄ alkyl stands -, OTf stands with a compound of the general formula X

P-Ar (X)

where W, P and Ar each have the meaning given above and the reactions are carried out by known processes, such as described in S.L. Buchwald et al. J. Am. Chem. Soc. 1996, 118, 7215 J.F. Hartwig et al. Tetrahedron Lett. 1995, 36, 3604 J.K. Stille et al. Appl. Chem. 1986, 98, 504 S.L. Buchwald et al. Appl. Chem. 1995, 107, 1456 or J.F. J.F. Hartwig et al. J.Am. Chem. Soc 1996, 118, 7217 or J.F. Hartwig et al. J.Org. Chem. 1997, 62, 1268 S.L. Buchwald et al. J.Org. Chem. 1997, 62, 1264 and literature cited therein or

SL Buchwald et al J.Am. Chem. Soc 1997, 119, 6054 JK Stille, Angew. Chem. 1986, 98, 504 or JKStille et al. J. Org. Chem. 1990, 55, 3014. M. Pereyre et al. "Tin in Organic Synthesis", Butterworth 1987; or 7. Reduction of compounds of the general formula (XI)

W-B-Ar (XI)

where 3 ^{2 has} the meaning given above for compounds of the general formula XII

WB ³ -Ar (XII)

wherein B ^{3 represents} piperidines linked in the 1,4-position and the corresponding ring compounds enlarged by a methylene group; or

the cyclization of compounds of general formula XIII

WN- (C ₂ H ₄ Q) ₂ (XIII),

where W and Q have the meaning described above, with a compound of general formula XIV

NH-Ar (XIV),

where Ar has the meaning given above, to compounds of the general formula XV

W-ß-Ar (XV).

The substances of the formulas III and V required as starting materials for the synthesis of the new compounds are known or can be prepared using the known processes (for example Organikum Barth Dt. Verl. Der Wiss. 1993 or AR Katritzky, CW Rees (ed.) Comprehensive heterocyclic chemistry Pergamon Press) from analogous starting materials.

H-B-Ar (III)

Q-A-Q '(XVI),

where Q and Q 'are leaving groups, under conditions known per se. The substances of the formula II, IV, VI and the general formula P-Ar, NH ₂ -Ar, WB ¹ and WB ² -P ¹ required as starting materials for the synthesis of the new compounds are known or can be according to those in the literature Synthesis described 5 synthesize from analogous starting materials (eg B. Schulze, K. Illgen J. Prakt. Chem. 1997, 339, 1 or K. Auer, E. Hungerbühler, RW Lang Chimia 1990, 44, 120 or A. Yokoo et al Bull. Chem. Soc. Jpn. 1956, 29, 631 or L. Börjeson et al. Acta Chem. Chem. 1991, 45, 621 or Organikum Barth Dt. Verl. Der Wiss. 1993 or AR 10 Katritzky, CW Rees ( ed.) Comprehensive Heterocyclic Chemistry Pergamon Press or The Chemistry of Heterocyclic Compounds J. Wiley & Sons Inc. NY and the literature cited there).

example 1

15

3,3-dimethyl-2- [3- (4-tetralin-5-yl-piperazine-1-yl) prop-1-yl] -2, 3-dihydro-1,2-benzisothiazole-1,1 -dioxide

Production of raw materials

20 a) 3,3-Dimethyl-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide

This compound was prepared in a manner known from the literature (K. Auer, E. Hungerbühler, R. W. Lang Chimia 1990, 44, 25 120). Analogously, 3,3-diethyl-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide (mp: 174 ° C.) and 3,3-dimethyl-6-nitro-2,3- dihydro-l, 2-benzisothiazole-l, l-dioxide (mp: 187 ° C.).

b) 2- (3-chloroprop-1-yl) -3, 3-dimethyl-2, 3-dihydro-l, 2-benziso-30-thiazole-1, 1-dioxide

A solution of 5.9 g (3 mmol) of 3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide in 150 ml DMF was placed in at room temperature and heated after the addition of 3.7 g (3.3 mmol)

35 potassium t-butoxide under nitrogen to 80 ° C. 14.2 g (9 mmol) of l-bromo-3-chloropropane were then rapidly added and the mixture was stirred at 100 ° C. for 30 min. After pouring into ice water, the mixture was etherified, the organic phases were washed with water, dried with sodium sulfate and then concentrated, so that the product was crystalline

40 failed and could be suctioned off. 6.7 g (82%) of substance were obtained. Mp .: 107 ° C.

In an analogous manner, 2- (3-chloroprop-l-yl) -3, 3-diethyl-2, 3-di-hydro-l, 2-benzisothiazole-l, 1-dioxide (mp: 70 ° C.) 2- (3-chloro-45 prop-l-yl) -3,3-dimethyl-6-nitro-2, 3-dihydro-l, 2-benzisothiazole-l, l-dioxide (mp: 146 ° C), 2- (2-chloroethyl) -3,3-diethyl-2, 3-dihydro-l, 2-benzisothiazole-l, 1-dioxide (Oil), 2- (2-chloroethyl) -4-chloro-3,3-dimethyl-2,3-dihydro-l, 2-benz-isothiazole-1, 1-dioxide (oil), 2- (3- Chloro-2-methylene-prop-1-yl) -3, 3-dimethyl-2, 3-dihydro-l, 2-benzisothiazole-l, 1-dioxide (mp: 115 ° C) and 2- (3- Chlorprop-l-yl) -3, 3-dimethyl-6-nitro-2, 3-di-hydro-1, 2-benzisothiazol-1, 1-dioxide (mp: 146 ° C).

c) l-tetralin-5-yl-piperazine

14.7 g (0.1 mol) of 5-aminotetralin was heated under reflux with 18 g (0.11 mol) of bis (β-chloroethyl) amine hydrochloride in 300 ml of n-butanol, 5.4 g of sodium carbonate were added after cooling and the mixture was heated again for 20 hours Reflux. The precipitate formed by cooling was filtered off with suction, taken up in water and treated with 2N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated in vacuo. 10.7 g (50%) of the product could be isolated as an oil.

4-piperazin-l-yl-isoquinoline

4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of t-butyl piperazine-N-carboxylate, 0.1 g (0.11 mmol) of tris (dibenzylideneacetone) dipalladium, 0.11 g (0.18 mmol) 2, 2'-bis (diphenylphosphino) -1, 1'-binaphthyl and 2.92 g (30.4 mmol) sodium t-butoxide in 50 ml toluene and stirred at 75 ° C for 2 h. The reaction mixture was poured onto ice / sodium chloride, extracted with ethyl acetate, the organic phase was dried over sodium sulfate and the solvent was removed on a rotary evaporator. The product crystallized out, was suction filtered and washed with pentane. 5.5 g (81%) of the Boc-protected piperazine were obtained (mp: 111 ° C.). 5.2 g (16.6 mmol) of this substance were taken up in 17 ml of dichloromethane, and 17 ml (0.22 mol) of trifluoroacetic acid were added slowly at 0 ° C. The mixture was stirred at 0 ° C. for 4 h, poured onto ice water and extracted with dichloromethane. The aqueous phase was filtered, made alkaline and extracted with dichloromethane. After drying over sodium sulfate and extensive removal of the solvent, the mixture was diluted with diethyl ether and the hydrochloride was precipitated with ethereal hydrochloric acid. 3.2 g (67%) of the product were obtained. (Mp: 293 ° C).

The following compounds were prepared in analogy to the two processes described: 1-naphth-l-yl-diazepan (85 ° C., hydrochloride), 1-naphth-l-ylmethyl-piperazine (oil), 4-piperazin-l-yl -indan (oil), 1-naphth-l-yl-piperazine (82 ° C), 4-chloro-l-piperazin-l-yl-phthalazine (205 ° C, dec.) and 4-piperazin-l-yl-quinazoline (320 ° C, hydrochloride). Other derivatives were commercially available.

Production of the end product

To a solution of 1.64 g (6.0 mmol) of 2- (3-chloroprop-1-yl) -3, 3-dimethyl-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide in 40 ml DMF was added to 1.1 g (5.2 mmol) of l-tetralin-5-yl-piperazine, 1.5 ml of triethylamine and a trace of potassium iodide. After a reaction for four hours at 100 ° C., the reaction mixture was poured onto ice water and the precipitate formed was filtered off with suction. The purification was carried out by recrystallization from isopropanol and 1 g (43%) of the product (mp: 140 ° C.).

NMR: CDC1 ₃ δ 7.8 (d, IH), 7.6 (dd, IH), 7.5 (dd, IH), 7.4 (d, IH), 7.1 (dd, IH), 6.9 (d, IH), 6.8 (d , IH), 3.4 (t, 2H), 3.0-2.5 (m, 14H), 2.1 (tt, 2H), 1.8-1.7 (m, 4H), 1.5 (s, 6H) ppm.

The following compounds were obtained in an analogous manner:

Example 2: 3, 3-Dimethyl-2- [3- (4- (2-phenylquinazoline-4-yl) piperazin-1-yl) prop-1-yl] -2, 3-dihydro-l, 2-benzisothiazole-1,1-dioxide (mp: 269 ° C., hydrochloride).

Example 3: 3, 3-Dimethyl-2- [3- (4-quinolin-2-yl-piperazine-l-yl) prop-1-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide (mp: 63 ° C).

Example 4: 3, 3-Dimethyl-2- [3- (4-naphth-l-yl-l, 4-diazapan-l-yl) prop-l-yl] -2, 3-dihydro-l, 2-benzisothiazole-l, 1-dioxide (mp: 126 ° C, hydrochloride).

Example 5: 3,3-dimethyl-2- [3- (4- (4-chlorophthalazin-l-yl) piperazin-1-yl) eth-l-yl] -2, 3-dihydro-l, 2-benzisothiazole-l, l-dioxide (mp: 190 ° C.).

Example 6: 3, 3-Dimethyl-2- [3- (4-naphth-l-yl-piperazine-l-yl) -2-methylene prop-l-yl] -2, 3-dihydro-1,2 -benzisothiazole-l, l-dioxide (mp: 193 ° C).

Example 7: 3, 3-Dimethyl-2- [2- (4-quinazolin-4-yl-piperazine-1-yl) eth-1-yl] -2, 3-dihydro-1, 2-benzisothiazole- l, 1-dioxide (mp: 178 ° C, hydrochloride). Example 8: 3, 3-Dimethyl-2- [2- (4-naphth-l-yl-piperazine-l-yl) eth-l-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide (mp: 282 ° C, hydrochloride).

Example 9: 3, 3-Dimethyl-2- [2- (4-isoquinolin-4-yl) piperazin-1-yl) eth-l-yl] -2, 3-dihydro-l, 2-benziso - thiazole-1,1-dioxide (mp: 243 ° C, hydrochloride).

Example 10: 3,3-Diethyl-2- [2- (4-naphth-l-yl-piperazine-l-yl) eth-l-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide (oil).

Example 11: 3,3-Dimethyl-2- [3- (4-naphth-l-yl-piperazine-l-yl) prop-1-yl] -6-pyrrole-l-yl-2,3- dihydro-l, 2-benzisothiazole-l, l-dioxide (mp: 269 ° C., hydrochloride).

The pyrrole ring was formed by reacting 3, 3-dimethyl-2- [3- (4-naphth-l-yl-piperazine-l-yl) prop-l-yl] -6-amino-2, 3-dihydro -l, 2-benzisothiazole-1, 1-dioxide with 2, 5-dimethoxytetrahydrofuran in glacial acetic acid at 100 ° C (1 h) in 86% yield.

Example 12: 3, 3-Dimethyl-2- [3- (4-naphth-l-yl-piperazine-l-yl) prop-l-yl] -6-benzoylamido-2, 3-dihydro-l, 2-benzisothiazole-1,1-dioxide (mp: 127 ° C.).

Example 13: 3, 3-Dimethyl-2- [3- (4-naphth-1-yl-piperazine-1-yl) prop-1-yl] -6-nitro-2, 3-dihydro-1, 2-benzisothiazole-1,1-dioxide (mp: 203 ° C.).

Example 14: 3,3-Dimethyl-2- [2- (4- (2,3-dimethylphenyl) piperazin-1-yl) eth-l-yl] -2,3-dihydro-1,2 benzisothiazole-l, l-dioxide (mp: 291 ° C., hydrochloride).

Example 15: 3, 3-Dimethyl-2- [2- (4-indan-4-yl-piperazine-1-yl) eth-1-yl] -2, 3-dihydro-1, 2-benzisothiazole- l, 1-dioxide (mp: 271 ° C, hydrochloride).

Example 16: 3, 3-Dimethyl-2- [3- (4- (4-chloro-naphth-1-yl) piperazin-1-yl) prop-1-yl] -2, 3-dihydro-l, 2-benzisothiazole-l, l-dioxide (mp: 151 ° C.).

Example 17: 3, 3-Dimethyl-2- [3- (4-pyrimidin-2-yl-piperazine-l-yl) prop-l-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide (mp: 263 ° C, hydrochloride). Example 18: 3,3-Dimethyl-2- [2- (4- (4-methoxyphenyl) piperazin-l-yl) eth-l-yl] -2, 3-dihydro-l, 2-benzoiso- thiazole-1,1-dioxide (mp: 207 ° C, hydrochloride).

Example 19: 3,3-Dimethyl-2- [3- (4- (2-methoxyphenyl) piperazin-1-yl) -2-hydroxy-prop-l-yl] -2, 3-dihydro -l, 2-benzisothiazole-l, 1-dioxide (mp: 160 ° C).

Example 20: 3,3-diethyl-2- [3- (4-naphth-l-yl-piperazine-l-yl) prop-l-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide (mp: 179 ° C).

Example 21: 3,3-Dimethyl-2- [3- (4- (2,5-dimethylphenyl) piperazin-1-yl) prop-1-yl] -2,3-dihydro-1,2 benzisothiazole-1,1-dioxide (mp: 218 ° C., hydrochloride).

Example 22: 3,3-Dimethyl-2- [2- (4- (2-cyano-phenyl) -piperazin-1-yl) -eth-1-yl] -2, 3-dihydro-1,2-benziso - thiazole-1,1-dioxide (mp: 228 ° C, hydrochloride).

Example 23: 3,3-Dimethyl-2- [2- (4-naphth-1-yl-piperazine-1-yl) eth-1-yl] -4-chloro-2, 3-dihydro-1, 2-benzisothiazole-1,1-dioxide

Production of raw materials

a) 4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide. This compound was prepared analogously to Example 1 a). Yield 7.8 g (70%). (Mp: 121 ° C)

b) 2- (2,2-Diethoxyeth-l-yl) -4-chloro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide

7.7 g (33 mmol) of 4-chloro-3, 3-dimethyl-2, 3-dihydro-l, 2-benzisothiazol-1, 1-dioxide, 8.25 ml (55 mmol) of bromoacetaldehyde diethylacetal and 7.0 g of potassium carbonate were added taken up in 100 ml of dry DMF and stirred at 120 ° C for 5 h. After pouring the reaction mixture into ice water, the mixture was extracted with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the crude product was purified by column chromatography. 7.5 g (65%) of the product were thus obtained as an oil.

c) 2- (2-Oxoeth-l-yl) -4-chloro-3,3-dimethyl-2,3-dihydro-l, 2-benzisothiazol-1, 1-dioxide 7.5 g (21.5 mmol) of 2- (2, 2-diethoxyeth-l-yl) -4-chloro-3, 3-dimethyl-2, 3-dihydro-l, 2-benzisothiazole-l, 1-dioxide and 25 ml conc. Hydrochloric acid was taken up in 25 ml of water and 150 ml of THF and the mixture was stirred at 40 ° C. for 1.5 hours. The reaction mixture was neutralized with sodium hydroxide solution, etherified, the organic phase was dried over sodium sulfate and concentrated in vacuo. In this way 5.8 g (98%) of the product could be isolated as an oil.

Production of the end product

1.5 g (5.5 mmol) of the aldehyde 24 c), 1.06 g (5 mmol) of naphthylpiperazine (prepared analogously to Example 1 c)) and 0.42 g (7 mmol) of glacial acetic acid in 50 ml of ethanol were added, and the mixture was stirred at room temperature for 30 minutes and then slowly added 0.5 g (8 mmol) sodium cyanoborohydride. After the reaction mixture was stirred at room temperature for 2 hours, it was poured onto an ice / brine mixture and extracted with dichloromethane. Drying with sodium sulfate, distilling off the solvent and subsequent recrystallization from ethanol gave 0.9 g (39%) of colorless crystals (mp: 156 ° C.).

NMR: CDC1 ₃ δ = 8.3 (m, IH), 7.8 (m, IH), 7.7 (d, IH), 7.6 - 7.3 (m, 6H), 7.1 (d, IH), 3.5 (t, 2H), 3.2 (, 4H), 3.0 - 2.8 (m, 6H), 1.8 (s, 6H) ppm.

Example 24

Preparation of 3,3-dimethyl-2- [2- (4-naphth-l-yl-tetrahydro-1,2,3,6-pyridin-l-yl) -eth-l-yl] 2,3 dihydro-1,2-benzisothiazole-1,1-dioxide

Synthesis of the starting materials

a) N-Boc-4- (trifluoromethanesulfonyloxy) tetrahydro-1,2,3,6-pyridine

A solution of 13.2 g (0.13 mol) diisopropylamine in 200 ml THF was deprotonated at -78 ° C with 100 ml nBuLi (1.6M in hexane) and after 30 minutes at this temperature 20.0 g (0.1 mol) of the in

50 ml of THF dissolved N-Boc-piperidone was added dropwise. After a further three hours at -78 ° C., a solution of 39.3 g (0.11 mol) of N, N, -bistrifluoromethanesulfonyl-aniline in 50 ml of THF was added and the mixture was allowed to come to room temperature overnight. For working up, water was added, the mixture was extracted with ether and the organic were washed

Phases with NaHC0 ₃ solution and water, dried over sodium sulfate and concentrated the solvent. The crude product was Flash chromatography (silica gel, eluent heptane / ethyl acetate = 3/1) cleaned. Yield: 20.2 g (60% of theory) iH-NMR: (270 MHz, CDC13) δ = 1.4 (s, 9H); 2.4 (m, 2H); 3.6 (t, 2H); 4.1 (m, 2H); 5.8 (m, lH) ppm.

b) N-Boc-4-naphth-l-yl-tetrahydro-1,2,3,6-pyridine

14.7 g (44.4 mmol) of the compound described above dissolved in 115 ml of dimethoxyethane were successively 22 ml of 2M sodium carbonate solution, 7.63 g (44.4 mmol) of naphthyl-1-boronic acid, 4.13 g (97.6 mmol) of lithium chloride, 0.85 g (4.44 mmol) copper (I) iodide and 2.1 g (1.77 mmoD tetrakistriphenyl-palladium added and heated to boiling for 4 h. For working up, extraction was carried out with the addition of aqueous ammonia solution with water and ethyl acetate, drying over sodium sulfate and that after evaporation the residue obtained from the solvent was purified by means of flash chromatography (silica gel, mobile phase heptane / ethyl acetate = 4/1) .Yield: 8.2 g (57% of theory)

^ - MR (270 MHz, CDC13): δ = 1.4 (s, 9H); 2.5 (m, 2H); 3.7 (t, 2H); 4.1 (m, 2H); 5.8 (m, IH); 7.2-7.5 (m, 3H); 7.3-8.0 (m, 3H) ppm.

c) 4-Naphth-l-yl-tetrahydro-1,2,3,6-pyridine

7.84 g (25.3 mmol) of N-Boc-4-naphth-1-yl-3, 6-dihydro-2H-pyridine were stirred overnight with 200 ml of ethereal hydrochloric acid at room temperature, the precipitated product was filtered off and dried. Yield: 5.5 g (88% of theory).

d) representation of the final connection

1.0 g (4.1 mmol) of the compound 24c described above dissolved in 20 ml of methanol was in the presence of 2.22 g (16.8 mmol)

Zinc (II) chloride first with 1.27g (5.3 mmol) of the example

23c described aldehyde and mixed with 0.5g (8.14 mmol) sodium cyanoborohydride. After 16 hours at room temperature, the mixture was worked up as described and the crude product obtained was purified by chromatography (silica gel, mobile phase dichloromethane / methanol =

97/3). Precipitation of the salt with ethereal hydrochloric acid solution gave a white solid.

Yield: 0.9 g (47% of theory) ⁱ H-MR (270 MHz, DMSO-d6): δ = 1.6 (m, 6H); 2.6 (m, IH); 3.1 (m, IH); 3.4-3.6 (m, 6H); 4.0-4.2 (m, 2H); 5.8 (sbr, IH), - 7.6-8.0 (m,

7H); 8.2 (d, IH); 12.0 (s, IH) ppm. Example 25

Preparation of 3,3-dimethyl-2- [2- (4-naphth-l-yl-piperidine-l-yl) -eth-l-yl] -2, 3-dihydro-l, 2-benzisothiazole- l, 1-dioxide

a) 4-Naphth-l-yl-piperidine

3.7 g (15.3 mmol) of 4-naphth-1-yl-tetrahydro-1, 2, 3, 6-pyridine dissolved in methanol were hydrogenated with the addition of 0.8 g of palladium on carbon with hydrogen at room temperature over 48 h. The catalyst was filtered off and the solvent was concentrated. Yield: 1.8 g (56% of theory)

^X H NMR (270 MHz, CDC13) δ = 1.6-1.8 (m, 2H); 2.0 (m, 2H); 2.9 (dt, 2H); 3.3 (d, 2H); 3.5 (tt, IH); 7.4-7.6 (m, 4H); 7.7 (d, IH); 7.9 (d, IH); 8.1 (d, IH) ppm.

Representation of the final connection

A solution of 1.5 g (7.1 mmol) of the amine 25a in 20 ml of methanol was first mixed with 3.8 g (28.4 mmol) of zinc chloride and 2.21 g

(9.2 mmol) of the aldehyde dissolved in 15 ml of methanol described in Example 23 c are added, and 0.89 g (14.2 mmol) of sodium cyanoborohydride are then added in portions. After stirring for six hours, the undissolved solution was filtered off, the mother liquor was concentrated and taken up in ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and a yellowish oil was obtained on concentration.

Yield: 2.2 g (65% of theory) ^! H-NMR (270 MHz, CDC1 ₃ ): δ = 1.7-1.9 (m, 8H); 2.0 (m, 2H); 2.7-3.0 (m, 4H); 3.2 (m, 2H); 3.5 (m, IH); 3.7 (t. 2H); 7.1 (d, IH); 7.3-7.7 (m, 9H); 8.2 (d, IH) ppm.

are suitable for the manufacture of medicaments for the prophylaxis and therapy of neurodegeneration, brain trauma and cerebral ischemia, in particular stroke, or the secondary diseases caused by these diseases.

One use according to the invention also relates to neuroprotection.

The preparation of these compounds is described in the patents mentioned at the beginning. The preparation as a medicament is carried out with a compound of the formula I or its pharmacologically acceptable acid addition salt as an active ingredient, together with conventional carriers and diluents.

The use according to the invention can take place in the usual way orally or parenterally, intravenously or intramuscularly.

The dosage depends on the age, condition and weight of the patient and on the type of application. As a rule, the daily dose of active substance is between approximately 1 and 100 mg / kg body weight when administered orally and between 0.1 and 10 mg / kg body weight when administered parenterally.

The medicines can be used in common galenical forms of application in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way. The active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et. Al: Pharmaceuticals Technology, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain the active ingredient in an amount of 1 to 99% by weight.

These compounds are useful for the treatment of central nervous disorders such as seasonal mood disorders and dysthymia. This includes anxiety such as generalized anxiety, panic attacks, sociophobia, obsessive-compulsive disorders and post-traumatic stress symptoms, memory disorders including dementia, amnesias and age-related memory loss as well as psychogenic eating disorders such as anorexia nervosa and bulimia nervosa.

It has now been found that compounds of the formula I

(N— A B Ar (I)

wherein

A represents branched or unbranched (Cι_ ₁₀ ) alkylene or straight-chain or branched (C ₂ -ιo) alkylene which comprises at least one group Z which is selected from 0, S, NRs, cyclopropyl, C0 ₂ , CHOH , a double or a triple bond,

B represents 4-piperidine, 4-tetrahydro-l, 2, 3, 6 pyridine, 4-piperazine or the corresponding ring compounds enlarged by a methylene group, the linkage to A taking place via an N atom of B and

Ar for phenyl, which is branched or unbranched by (Cι_ ₅ ) alkyl, O- (Ci_ ₆ ) alkyl branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR ² ₂ , C0 ₂ R ² , cyano or substituted phenyl, tetralin, indane, more highly condensed aromatics such as naphthalene, which is optionally substituted by (C ^) alkyl or 0 (Cι_-ι) alkyl, anthracene or 5- or 6-membered aromatic heterocycles having 1 to 2 heteroatoms, the are independently selected from O and N, which can also be fused with other aromatic radicals,

stands, one of the two Resce X, Y stands for CH ₂ and the other for NR ⁹ ,

R ^ R ² independently of one another are -CC ₆ alkyl,

R ³ , R ⁴ independently of one another for hydrogen, (Cι_ ₆ ) alkyl branched or unbranched, OH, O- (Cι- ₆ ) alkyl branched or unbranched, F, Cl, Br, I, trifluoromethyl, NR ⁵ R ⁶ , C0R ⁷ , nitro, cyano, pyrrole, for a phenylalkyl C ₁ -C ₄ radical, which in turn is aromatic on F, Cl, Br, I, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, hydroxy, amino , Cyano or nitro may be substituted, R ⁵ , R ⁶ independently of one another for hydrogen, (Cι_ ₆ ) alkyl branched or unbranched, COPh, C0 ₂ tBu, CO- (C ₁ -. ₄ ) alkyl or together for a 5- or 6-membered ring which optionally contains a second N (for example piperazine),

R ^{7 represents} hydrogen and (Cι_ ₆ ) alkyl branched or unbranched,

R ^{8 represents} hydrogen and C ₁ -C ₄ alkyl,

R ⁹ for hydrogen, (Cι_ ₆ ) alkyl branched or unbranched, CO- (C ₁ -) alkyl, C0 ₂ tBu, CO-aryl and a phenylalkyl -C-C ₄ radical, which in turn on the aromatic through F, Cl, Br, I, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, hydroxy, amino, cyano or nitro can be substituted,

and their salts,

suitable for the production of medicaments for the prophylaxis and therapy of neurodegeneration, brain trauma and cerebral ischemia, in particular stroke, or the secondary diseases caused by these diseases.

One use according to the invention also relates to neuroprotection.

The preparation of these pyrimidine derivatives is described in the patents mentioned at the beginning.

The preparation as a medicament is carried out with a compound of the formula I or its pharmacologically acceptable acid addition salt as an active ingredient, together with customary carrier and diluent. The use according to the invention can take place in the usual way orally or parenterally, intravenously or intramuscularly.

The drugs can be used in common galenical forms of administration, solid or liquid, e.g. as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way. The active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et. Al: Pharmaceuticals Technology, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain the active ingredient in an amount of 1 to 99% by weight.

Claims

Claim

1. Use of compounds of formula I.

(N— A B Ar (I)

wherein

A represents branched or unbranched (Cx-io) alkylene or straight-chain or branched (C ₂ -ιo) alkylene which comprises at least one group Z which is selected from O, S, NR ⁸ , cyclopropyl, C0 ₂ , CHOH , a double or a triple bond,

B for 4-piperidine, 4-tetrahydro-1,2,3,6 pyridine,

4-piperazine or the corresponding ring compounds enlarged by a methylene group, the linkage to A taking place via an N atom of B and

Ar for phenyl which is optionally branched or unbranched by (C _x - ₆ ) alkyl, 0- (C _ι - ₆ ) alkyl branched or unbranched, OH, F, Cl, Br, I, trifluoromethyl, NR ² ₂ , C0 ₂ R ² , cyano or phenyl is substituted, tetralin, indane, more highly condensed aromatics such as naphthalene, which is optionally substituted by (Cι- ₄ ) alkyl or 0 (d- ₄ ) alkyl, anthracene or 5- or 6-membered aromatic heterocycles with 1 up to 2 heteroatoms, which are selected independently of one another from 0 and N, which can also be fused with further aromatic radicals,

C- stands for or

one of the two radicals X, Y represents CH ₂ and the other represents NR ⁹ ,

R ^ R ² independently of one another represent Ci-Ce-alkyl, R ³ , R ⁴ independently of one another for hydrogen, (Ci-ε) alkyl branched or unbranched, OH, 0- (Ci-g) alkyl branched or unbranched, F, Cl, Br, I, trifluoromethyl, NR ⁵ R ⁵ , C0R ⁷ , nitro, cyano, pyrrole, for a phenylalkyl C ₁ -C ₄ radical, which in turn is substituted on the aromatic by F, Cl, Br, I, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, hydroxy, Amino, cyano or nitro can be substituted,

R ^5, R ⁶ independently represent hydrogen, (Cχ_ ₆₎ branched alkyl or unbranched, COPh, C0 ₂ tBu, CO (C ₁ - ₄₎ alkyl or together represent a 5- or 6-membered ring, optionally containing one contains second N (e.g. piperazine),

R ^{7 represents} hydrogen and (Cι_ ₆ ) alkyl branched or unbranched,

R ^{8 represents} hydrogen and C ₁ -C ₄ alkyl,

R ⁹ for hydrogen, (Ci-β) alkyl branched or unbranched, CO- (C ₁ - ₄ ) alkyl, C0 ₂ tBu, CO-aryl and a phenylalkyl-Cι-C radical, which in turn on the aromatic through F, Cl, Br, I, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, trifluoromethyl, hydroxy, amino, cyano or nitro can be substituted,

and their salts with pharmacologically acceptable acids for the manufacture of medicaments for the prophylaxis and therapy of cerebral ischemia and stroke.