WO1990007503A1 - Substituted 3-azabicyclo[3.1.1]heptanes, their production and use - Google Patents

Substituted 3-azabicyclo[3.1.1]heptanes, their production and use Download PDF

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WO1990007503A1
WO1990007503A1 PCT/EP1989/001544 EP8901544W WO9007503A1 WO 1990007503 A1 WO1990007503 A1 WO 1990007503A1 EP 8901544 W EP8901544 W EP 8901544W WO 9007503 A1 WO9007503 A1 WO 9007503A1
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alkyl
phenyl
substituted
azabicyclo
mono
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PCT/EP1989/001544
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German (de)
French (fr)
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Rolf Banholzer
Erich Lehr
Wolf-Dietrich Bechtel
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Boehringer Ingelheim Kg
Boehringer Ingelheim International Gmbh
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D221/00Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22Bridged ring systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Novel 3-azabicyclo[3.1.1]heptanes of formula (I), where the substituents R, R' and R'' are defined in the description, can be produced by processes known per se. These compounds are useful as drugs. Intermediate products are also described.

Description

substituted 3-Azabicvclo Ϊ 3 .1. llheptane, their preparation and their use

The invention relates to novel 3-azabicyclo [3.1.l] heptane, which are in 1-, 3- and 5-position is optionally substituted, their preparation according to known methods and their use in the treatment of certain diseases.

The new compounds correspond to the formula

Figure imgf000003_0001

mean in your

R, R '(which may be identical or different), lkyl- an A or alkoxyalkyl group having up to 6

C- A Tomen, a C 3 -C 7 -cycloalkyl, saturated or mono-unsaturated and optionally substituted by one or two

C - C .- A lkylreste may be substituted;

1 4 is a phenyl radical which is mono- or polysubstituted by Alike h e or different radicals from the group

C1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy,

C, 1-Co 0 acyloxy, amino,

C, -C alkylamino,

Di- (C 1 -C 4 alkyl) amino,

C - C - A cy l amino, nitro, halogen, CN or mono- o r me h rfach halosubstituted

C -C alkyl may be substituted; or a heteroaromatic or saturated heterocyclic radical, which be mono- or polysubstituted by identical or different radicals from the

Group C ^^ - alkyl, C ^^ - Alko, phenyl, halogen, mono- or polyhalosubstituted C.-C.-alkyl,

C, -C 4 alkylamino or

Di- (C, -C 4 alkyl) amino may be substituted; R also "is hydrogen;

R * is hydrogen, an optionally

Oxygen-interrupted C -, - C fi alkyl; an alkenyl or alkynyl group having up to 6 carbon atoms; a by phenyl, an optionally monounsaturated C _, - substituted C 7 -Cycloaliphaten, a heteroaromatic or non-aromatic heterocycle C, -C 4 alkyl, wherein the respective cyclic radical may be mono- or polysubstituted by identical or different substituents from the group C, -C 4 alkyl (mono- or which can be multiply substituted with halogen), C, -C 4 alkoxy, halogen, hydroxy, amino, C 1 -C 4 -alkylamino /

Di- (C - C.-alkyl) amino, C, -C acyloxy, 'C -_L-Co 0 acylamino, nitro, cyano, CONH -__.

CONH- (C 1 -C 4 alkyl) S0 2 NH 2,

S0 2 NH- (C 1 -C 4 -Alky1), HCO 2 H,

NHS0 2 (C 1 -C 4 alkyl) or phenyl may be substituted, and their salts, preferably with physiologically acceptable acids.

In the above definitions are with "halogen", fluorine, chlorine and bromine, respectively. Fluorine and chlorine are preferred. The aliphatic groups having more carbon atoms can be straight or branched •. Preferably, they contain up to 3, especially 1 or 2 C-atoms. As the unsaturated groups allyl and propargyl are to be emphasized, as cycloaliphatics cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl. As "heteroaromatic" are here referred in particular pyridine, pyrazine, pyrimidine, thiophene, pyrrole, furan, imidazole, pyrazole, triazole, tetrazole.

"Non-aromatic heterocycles" in the sense of the invention, the corresponding partially or completely hydrogenated compounds, further five- and six-membered heterocycles with one to three identical or different hetero atoms (N, S, 0) and corresponding substituted compounds.

In case of multiple substitution, especially phenyl groups are generally only halogen atoms, alkyl and alkoxy before up to three times. The übrigen- substituents are just simple, no more than two times generally present.

Typical substituents for the purposes of the above definitions are CH 3, OCH 3, N0 2, CN, (CH 3) 2, N (C 2 H 5) 2, NH 2, N (CH 3) (C 2 H 5), NHC ^, NHCH 3, HS0 2 CH 3, NHCOCH 3, CF 3, S0 2 NH 2, CONH 2, F, Cl, CGH. 5

These compounds in which R "is hydrogen or methyl, R 'is (optionally substituted in the context of the above definitions) phenylalkyl, and R are phenyl is. For salt formation with the compounds of formula I, suitable acids are for example hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, citric acid acid, fumaric acid, methanesulfonic acid. If the compounds of formula I are to be further reacted, they can of course be used as salts any other acids.

To produce the novel compounds of the following methods may be used:

1) reducing a compound of the formula

Figure imgf000006_0001

R '

in which R, R 'and R "are those radicals according to the above definitions are available under the

Reducing conditions are sufficiently stable, with sodium bis (2-methoxyethoxy) aluminum dihydride.

The reaction is carried out in an inert organic solvent, for example toluene, at elevated temperature, preferably between about 60 ° C and 120 ° C and the boiling temperature of the reaction mixture. Advantageous to use an inert gas. 2) substituting a compound of formula

Figure imgf000007_0001

H

wherein R and R "have the above significance, at the nitrogen by a group R '.

The introduction of the group R 'is achieved with sufficient reactive compounds capable of formula

R '- X (IV),

wherein R 'has the above meaning and X is a by introducing R' cleavable amino group in the group ( "leaving group"), for example chlorine, bromine,. the method of reductive alkylation comes as an alternative in the usual manner into consideration, where it must be ensured that run side reactions not to a disturbing degree.

The compounds obtained by a) or b), insofar as they are not known, obtained according to known methods, for example according to the following scheme: R

Figure imgf000008_0001

Figure imgf000008_0002

(I)

If one starts from compounds of the formula VI, wherein R "is benzyl, the benzyl group from the resulting compound of formula I can hydrogenoly ish be cleaved by conventional methods.

The compounds of formula III thus obtained can then be substituted in the desired manner on the nitrogen. In the compounds of the formula III R and / or R "is phenyl, one can by hydrogenation under suitable conditions to those compounds of the formula III obtained, the R / R" in the meaning hexyl. Before the removal of the benzyl other groups contained in R or R "can be changed if necessary (eg modification of functional groups, reduction of nitro groups). The new compounds are suitable for use as active ingredients in medicinal products, including psychotropic drugs, .and can before mainly be used therapeutically to treat Despressionen.

The new compounds show a pronounced antidepressant effect. In terms of potency is detect some multiple superiority over the commercial product imipramine example. A particular advantage is the lack of side effects in doses that are much higher than that. antidepressive effective dose. The absence of side effects represents a significant therapeutic advance in the field of anti-depressants.

the new compounds in a conventional manner with conventional auxiliary ^ and / or excipients are processed to conventional pharmaceutical compositions for application, such as tablets, capsules, dragees, solutions, suppositories, syrups.

The Appdikation done orally or parenterally. Except as preparations with immediate Wirksto -Freisetzung the active ingredients can be used in sustained release forms. micronized powders, solutions or suspensions for spraying are used in liquefied propellant gases in containers for Doεierventil also possible nasal application. Formulierunσsbeispiele

1. tablets

Composition:

Active substance according to invention 30 parts by weight

Stearic acid 6 parts by weight

Glucose 564 parts by weight

The ingredients are processed in a customary manner to give tablets of 600 mg weight. If desired, the active compound content can be increased or reduced and the quantity of glucose or increased accordingly.

2. suppositories

Composition:

Active substance according to invention 80 parts by weight

Powdered lactose 45 parts by weight

Cocoa butter 1575 parts by weight

The ingredients are processed in the usual way to form suppositories weighing 1.7 g.

The following examples illustrate the invention described above, but without limiting its scope.

Production of Ausganqsstoffen

a) acrylic acid α-phenylacrylic acid-N-benzylamide

88.00 g (0.60 mol) of α-Phenylacrylεäure be abs in 400 ml. Methylene chloride, admixed with 0.88 g (0.012 mol) abs. Dimethylformamide, and at room temperature to gradually 114.24 g (0.90 mol) of oxalyl chloride dropwise. Here, the evolution of gas a clear, yellow solution. This is followed by a 3-hour post-reaction connects at 30 ° C. The reaction solution is finally evaporated under reduced pressure to a yellow oil, which is used by chromatographic and spectroscopic control for the next synthesis stage.

80, (61 g (0.50 mol) of N-Benzylacrylsäureamid and 121.4 g (1.2 mol) abs. Triethylamine in 750 ml abs. Methylene chloride and dissolved under cooling to a solution of the above prepared α-Phenylacrylsäurechlorid in 150 ml of abs. added dropwise methylene chloride so that the internal temperature of 10 ° C is not exceeded. in this case, gradually triethylamine hydrochloride precipitates in crystalline form. after a one hour reaction at room temperature, the reaction is completed in chromatographiεcher control. after addition of 300 ml water the phases after thorough mixing are separated, dried and the methylene chloride phases over sodium sulfate, and then distilled off the solvent under reduced pressure. for the removal of triethylamine, α-phenylacrylic and dimerization, a cleaning process follows, which eventually leads to a residue of 131.36 g of brown oil which was a yield of 90.2% of theory of the title compound corresponds and Chromatog is raphisch and spectroscopy.

Analog can be produced:

Acrylic acid-α- (m-methoxyphenyl) -acrylic acid-N- benzylamide

Acrylic acid-a- (p-methoxyphenyl) -acrylic acid-N- benzylamide

Acrylεäure- - (m-tolyl) acrylic acid-N-benzylamide

Methacrylεäure-α-phenylacrylic acid-N-benzylamide

c N-Benzyl-l-phenyl-3-azabicvclof3.1. llheptan-2,4-dione

131.36 g (0.45 mol) of acrylic acid-α-phenyl-N-benzylamide acrylεäure dissolved in 2500 ml of xylene, heated under reflux.

After about 10 hours reaction time, the chromatographic control indicates a practically quantitative conversion. Thereafter daε xylene is distilled off under reduced pressure. The distillation residue, a brown oil is used for chromatographic and spectroscopic examination for the next synthesis stage. It is possible for this compound from toluene in the form of white crystals of melting point 113 - 114 ° C to obtain. Analog can be produced:

N-benzyl-lm-methoxyρhenyl-3-azabicyclo [-3.1.1] heptane-2,4-dione

N-benzyl-lp-methoxyphenyl-3-azabicyclo [3.1.l] heptane-2,4-dione

N-benzyl-lm-tolyl-3-azabicyclo [3.1.l] heptane-2,4-dione

N-Benzyl-l-phenyl-5-methyl-3-azabicyclo [3.ll] heρtan- 2,4-dione F. 108-111 ° C.

Example 1

N-Benzyl-l-phenyl-3-azabicycloT3.1.11heptan-hydro- chloride

A solution of 131.36 g (0.45 mol) abs N-benzyl-1-phenyl-3-azabicyclo [3.1.l] heptane-2,4-dione in 200 ml. Toluene (to a solution of 630 ml of a 70% solution of sodium bis (2-methoxy-ethoxy) -. (Aluminum dihydride in toluene abs 2.25 mol), diluted with 500 ml of absolute toluene, below. be nitrogen at 100 ° C dropwise within 45 minutes. After a postreaction time of 30 minutes, the Chrornatogramm indicates a quantitative reaction. the reaction solution is stirred under ice cooling into a mixture consisting of 500 g of ice and 100 ml of conc. sodium hydroxide solution. for further dilution additionally added 500 ml of toluene, the aqueous phases are separated, dried over sodium sulfate and the toluene removed by distillation after drying the toluene under reduced pressure. from the 11

Distillation residue prepared in the usual manner the hydrochloride.

65.63 g (. 48.6% d, Th) white crystals (ethanol), m.p. 226 -. 229 ° C (dec.).

Elemental analysis and spectroscopic examination confirms the presence of this compound.

Analog lasεen be produced:

N-benzyl-lm-methoxyphenyl-3-azabicyclo [3.1. l] heptane hydrochloride,

Mp 210 -. 214 ° C (dec.)

N-benzyl-lp-methoxyphenyl-3-azabicyclo [3.1.1] heptane hydrochloride,

Mp 216 -. 219 ° C (dec.)

N-benzyl-Im-tolyl-3-azabicyclo [3.1.1] heptane hydrochloride,

Mp 232 -. 235 ° C (dec.) * R

N-Benzyl-l-phenyl-5-methyl-3-azabicyclo [3.1. l] heptane hydrochloride,

Mp 228 -. 232 ° C (dec.)

example 2

l-phenyl-3-azabicyclor3.1. ll eptan-hydrochloride

40.00 g (0.15 mol) N-Benzyl-l-phenyl-3-azabicyclo [3.1.1] heptane are dissolved in 1.4 1 of methanol, 12 g of palladium / active carbon 10% under a hydrogen pressure of 5 bar shaken for 2 hours at 20 ° C in a Hydrierbirne. If the chromatographic control indicates a quantitative reaction, the catalyst is filtered off and the solvent was distilled off under reduced pressure. From the light yellow distillation residue is daε in the usual manner l-phenyl-3-azabicyclo [3.1. l] heptane hydrochloride prepared.

29.74 g (93.4% d. Th.) Of white crystals (ethanol), mp. 253 -254 ° C (dec.).

The elementaranalytiεche and spectroscopic examination confirms the presence of this compound.

Analog can be prepared:

l-Phenyl-5-methyl-3-azabicyclo [3.1. l] heptane hydrochloride,

Mp 182 -. 183 ° C

Example 3 c

Nm-methoxybenzyl-l-phenyl-3-azabicycloT3.1.11 eptan- hydrochloride

0.94 g (0.0045 mol) of l-phenyl-3-azabicyclo [3.1.1] heptane hydrochloride are suspended in 25 ml of acetonitrile and, after addition of 0.78 g (0.005 mol) of m-methoxybenzyl chloride and 1.6 g (0.01 mol) of sodium 2 - heated for 3 hours under reflux. As soon as the chromatographic control indicates a quantitative reaction, the solvent is distilled off under reduced pressure, the offset Deεtillations residue with ether and water and the collected ether phases after extraction with l <r

Sodium sulfate. After drying, the sodium sulfate is separated, the solvent was distilled off and made of the light yellow distillation residue in the usual manner the hydrochloride.

1.34 g (90.5% d. Th.) Of white crystals (isopropanol), mp. 184 -188 ° C (dec.).

Elemental analysis and spectroscopic examination confirms the presence of this compound.

Analog can be produced:

Np-chlorobenzyl-l-phenyl-3-azabicyclo [3.1.l] heptane hydrochloride,

Mp 231 -. 236 ° C (dec.)

Np-methylbenzyl-l-phenyl-3-azabicyclo [3.1.1] heptane hydrochloride,

Mp 221 -. 225 ° C (dec.)

No-Fluorberizyl-l-phenyl-3-azabicyclo [3.1.1] heptane hydrochloride,

Mp 212 -. 215 ° C (dec.)

Np-fluorobenzyl-l-phenyl-3-azabicyclo [3.1.1] heptane hydrochloride,

Mp 244 -. 246 ° C (dec.)

Nm-methylbenzyl-l-phenyl-3-azabicyclo [3.1.1] heptane hydrochloride,

Mp 209 -. 210 ° C (dec.)

No-methylbenzyl-l-phenyl-3-azabicyclo [3.1.l] heptane hydrochloride,

Fp. 196 - 199 ° C (dec.) N-cyclohexylmethyl-l-phenyl-3-azabicyclo [3.1.1] heptane hydrochloride,

Mp 220 -. 225 ° C (dec.)

Nm-trifluoromethyl-l-phenyl-3-azabicyclo [3.1.1] heptane hydrochloride,

Mp 216 -. 220 ° C (dec.)

No-trifluoromethyl-l-phenyl-3-azabicyclo [3.1. l] heptane hydrochloride,

Fp. 144 - 146 ° C

Np-methylbenzyl-l-phenyl-5-methyl-3-azabicyclo [3.1.1] - heptane hydrogen oxalate, mp 160 ° C (dec.).

Np-methoxybenzyl-l-phenyl-5-methyl-3-azabicyclo [3.1.1] heptane hydrochloride,

Mp. 187 - 189 ° C

No-fluorobenzyl-l-phenyl-5-methyl-3-azabicyclo [3.1.13- heptane iydrochlorid,

Fp. 165 - 167 ° C

example 4

a) N-2-furancarbonyl-l-phenyl-5-methyl-3-azabicvclo- T3.l.llheptan

2.22 g (0.01 mol) of l-phenyl-5-methyl-3-azabicyclo [3.1.13heptan hydrochloride and 2.02 g (0.02 mol) abs. Of triethylamine in 25 ml abs. Methylene chloride and thereto within 10 minutes a solution of 1.31 g (0.01 mol) of 2-Furancarbonsäurechlorid in 5 ml abs. 16

Of methylene chloride. After a chromatographic control indicates quantitative Umsetzun, water is added and after extraction, the methylene chloride phase over Natriumsulf t-dried. The solvent was evaporated under reduced pressure and the yellow crystalline Destillationsrückεtand umkristllisiert auε acetone. 2.39 g (.. 85.7% of theory) of white crystals (acetone), mp. 139 - 141 ° C.

Elemental analysis and spectroscopic examination confirms the presence of this compound.

Analog can be produced:

N-3-furancarbonyl-l-phenyl-3-azabicyclo [3.1.1 heptane, mp 142 -. 143 ° C

N-2-thiophenecarbonyl-l-phenyl-3-azabicyclo [3.1.13heptan mp 127 -. 128 ° C

b) N-2-furanmethyl-l-phenyl-5-methyl-3-azabicyclo Ϊ3. 1 .1] heptane hydrochloride

A solution of 2.05 g (0.0073 mol) of N-2-furancarbonyl-l-phenyl-5-methyl-3-azabicyclo [3.1.1 heptane in 40 ml of abs.

Toluene is added to a solution of 5.1 ml of a 70%

Solution of sodium bis (2-methoxy-ethoxy) aluminum dihydride in abs. Toluene (0.0182 mol), diluted with 5 ml of abs. Toluene under nitrogen at 100 C C within

15 minutes dropped. After a reaction time of

15 minutes shows the chromatogram of a quantitative

Implementation.

Working up the reaction solution is in

Example 1. π

From the distillation residue is produced in the usual way, the un hydrochloride. 1.51 g (68.2% of theory..) Of white crystals (ethyl acetate / ether), m.p. 138 -. 139 ° C.

Elemental analysis and verification spektroskopiεche beεtätigt daε presence of this compound.

Analog can be produced:

N-3-furanmethyl-l-phenyl-3-azabicyclo [3.1.1] heptanch-lor mp 219 -. 221 ° C (dec.)

N-2-Thiophenmethyl-l-phenyl-3-azabicyclo [3.1.1] heptane hydrochloride, mp 221 -. 223 ° C (dec.)

example 5

l-Cyclohexyl-3-azabicyclo Ϊ3 .1.11heptan hydrochloride r

to 3.15 g (0.015 mol) of l-phenyl-3-azabicyclo [3.1.1] heptane hydrochloride dissolved in 50 ml of ethanol, 0.3 g of PtO / RhO "(20% platinum / 46% rhodium) produced by Vorhydrieren catalyst under a hydrogen pressure of 5 bar for 3.5 hours at 20 ° C in a. Hydrierbirne shaked, whereby a slightly acidic reaction is advantageous. If the chromatographic control indicates a quantitative reaction, the catalyst is filtered off and the solvent was distilled off under reduced pressure. 2.62 g (80.9% of theory..) Of white crystals (acetonitrile), mp 189 -. 190 ° C.

Elemental analysis and spectroscopic examination confirms the presence of this compound. 18

example 6

N-Benzyl-l-cvclohexyl-3-azabicvclo [3.1.llheptan- hvdrochlorid

1.08 g (0.005 mol) of l-cyclohexyl-3-azabicyclo [3.1.13- heptan-hydrochloride are suspended in 25 ml of acetonitrile and, after addition of 0.63 g (0.005 ml) of benzyl chloride and 1.06 g (0, 01 mol) of sodium 2 - heated for 3 hours under reflux. As soon as the chromatographic control indicates a quantitative reaction, the Lösungεmittel is abdeεtilliert under reduced pressure, the Destillationεrückεtand treated with ether and water and dried, the collected ether phases after extraction with sodium sulfate. After drying, the solvent is distilled off under reduced pressure and the hydrochloride prepared from the light brown Destillationεrückεtand in the usual manner. 1.24 g (81.1% of theory..) Of white crystals (ethanol), m.p. 259 -. 260 ° C (dec.). c Elemental analysis and spectroscopic examination confirms the presence of this compound.

Analog can be prepared:

Np-chlorobenzyl-l-cyclohexyl-3-azabicyclo [3.1.13heptan- hydro chlord

Mp 245 -. 251 ° C (dec.)

Claims

13Patentansprüche
3-azabicyclo [3.ll] heptanes of the formula
Figure imgf000021_0001
in the
R, R '(which may be identical or different), an alkyl or alkoxyalkyl group having biε to
6 C atoms, a C 3 -C 7 -cycloalkyl, saturated or mono-unsaturated and optionally substituted by one or two ι
C, -C 4 alkyl radicals may be substituted; a phenyl radical which is monosubstituted or polysubstituted by identical or different radicals from the
Group C 1 -C 4 alkyl, C, -C 4 -alkoxy,
Hydroxy, C1, -Co 0 acyloxy, amino,
C - C 4 alkylamino,
Di- (C, -C 4 alkyl) amino,
C1, -Co 0 acylamino, nitro, halogen, CN or mono- or polysubstituted halogensubεtituiertes C, -C 4 -alkyl may be substituted; or a heteroaromatic or saturated heterocycliεchen radical mono- or polysubstituted by identical or different radicals from the group C, -C 4 alkyl, C ^^ - Alko y, phenyl, halogen, mono- or poly-halo-substituted C ^^ - alkyl, C, -C 4 alkylamino or zo
Di (C.-C 4 alkyl) amino may be substituted; R also "is hydrogen;
R 'is hydrogen, an optionally
Oxygen-interrupted C, -Co alkyl; an alkenyl or Alkinylres having up to 6
Carbon atoms; an unsaturated by phenyl, optionally mono-
C -.- C-cycloaliphatics, a
Heteroaromatic or non-aromatic
heterocycle substituted
C, -C 4 alkyl, wherein the respective cyclic radical may be mono- or polysubstituted by identical or verεchiedene Subεtituenten from the group C, -C 4 alkyl (which may also be singly or multiply halogen-substituted),
C, -C 4 alkoxy, halogen, hydroxy, amino,
C - C 4 alkylamino,
Di- (C, -C 4 alkyl) amino, C, -C R acyloxy,
CX, -Cα 0 acylamino, nitro, cyano, CONH ".Z,
CONH- (C ^ C ^ alkyl), S0 2 H 2, c S0 £ NH- (C 1 -C 4 alkyl), NHC0NH 2, NHS0 2 (C 1 -C 4 alkyl), or phenyl to be subεtituiert may mean, and their salts with acids.
2. Compounds according to claim 1, wherein R is phenyl, R 'is optionally substituted phenyl εubstituiertes
(C 1 -C 3 alkyl), and R "stands for Wasεerεtoff or methyl.
3. Compounds according to claim 1 or 2, wherein R is phenyl, R 'is benzyl and R "is hydrogen or methyl.
4. A pharmaceutical composition characterized by a content of a compound according to claim 1, 2 or 3rd
5. antidepressant, characterized by a content of a compound according to claim 1, 2 or 3rd
6. Use of compounds according to claim 1, 2 or 3 in the treatment of Despressionen.
7. Use of compounds according to claim 1, 2 or 3 in the manufacture of medicaments.
8. Use of compounds according Anεpruch 1, 2 or 3 in the preparation of antidepressant agents.
9. A process for the preparation of compounds according to claim 1, 2 or 3, characterized in that in manner known per se
a) a compound of formula
(II)
Figure imgf000023_0001
zz
reduced, or in that
b) a compound of formula
Figure imgf000024_0001
wherein R and R "have the above .Bedeutung substituted on the nitrogen by the group R '
and the compounds obtained by a) or b) if desired, converted according to their nature into free bases or into salts in Säureadditionsεalze physiologiεch acceptable acids.
10. Compounds of formula
Figure imgf000024_0002
and
Figure imgf000024_0003
wherein R, R 'and R "have the meaning given in Anεpruch. 1
PCT/EP1989/001544 1988-12-23 1989-12-15 Substituted 3-azabicyclo[3.1.1]heptanes, their production and use WO1990007503A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011054885A1 (en) 2009-11-04 2011-05-12 Universiteit Gent 1-substituted 2-azabicyclo [3.1.1] heptyl derivatives useful as nicotinic acetylcholine receptor modulators for treating neurologic disorders
US8389561B2 (en) 2008-04-30 2013-03-05 Universiteit Gent Substituted 7-azabicyclo[2.2.1]heptyl derivatives useful for making pharmaceutical compositions
US8809365B2 (en) 2009-11-04 2014-08-19 Universiteit Gent 1-substituted 2-azabicyclo [3.1.1] heptyl derivatives useful as nicotinic acetylcholine receptor modulators for treating neurologic disorders

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EP0166692A2 (en) * 1984-06-20 1986-01-02 Ciba-Geigy Ag Substituted azabicycloheptanes, their use, pharmaceutical compositions comprising them and process for the preparation of the compounds
EP0272208A1 (en) * 1986-11-21 1988-06-22 Ciba-Geigy Ag Aromatically substituted azacyclo-alkylalkanediphosphonic acids
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Publication number Priority date Publication date Assignee Title
US8389561B2 (en) 2008-04-30 2013-03-05 Universiteit Gent Substituted 7-azabicyclo[2.2.1]heptyl derivatives useful for making pharmaceutical compositions
WO2011054885A1 (en) 2009-11-04 2011-05-12 Universiteit Gent 1-substituted 2-azabicyclo [3.1.1] heptyl derivatives useful as nicotinic acetylcholine receptor modulators for treating neurologic disorders
US8809365B2 (en) 2009-11-04 2014-08-19 Universiteit Gent 1-substituted 2-azabicyclo [3.1.1] heptyl derivatives useful as nicotinic acetylcholine receptor modulators for treating neurologic disorders

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