Derivatives of n-substituted 3-azabicyclo(3.2.0) heptanol


(57) Abstract:

Describes new derivatives of N-substituted 3-azabicyclo[3.2.0]heptanol formula I, where R means naftalina or phenanthroline group, which can be mono - or tizamidine halogen atoms, a represents a residue of the formula or naftalina group which may be substituted by halogen, or their salts with physiologically acceptable acids which can be used as adjunct tools. 1 C.p. f-crystals.

< / BR>

The invention relates to new derivatives of azabicycloalkanes possessing biological activity, in particular to derivatives of N - substituted 3-azabicyclo[3.2.0]heptanol.

Known derivatives of N-substituted azabicycloalkanes with antipsychotic activity (see application DE N 42 19 973, CL 07 D 209/52, A 61 K 31/40, 23.12.1993,).

The objective of the invention is to expand the Arsenal of derivatives of N-substituted 3-azabicyclo[3.2.0]heptanol with antipsychotic activity.

The problem is solved proposed derivatives of N - substituted 3-azabicyclo[3.2.0]heptanol formula (I)

< / BR>
where R means naftalina or phenanthroline group, which can be mono - or tizamidine atoms is and halogen, or their salts with physiologically acceptable acids.

The compounds of formula I can be obtained by the fact that the compounds of formula (II)


in which a has the above values and Nu is a nucleophilic waste group, is subjected to the interaction with the derived 3-azabicyclo- [3.2.0]heptane of the formula (III)

< / BR>
where R means naftalina or phenanthroline group which may be mono - or tizamidine halogen,

and the compound obtained, if necessary, transferred to salt treatment physiologically acceptable acid.

Nucleophilic exhaust group Nu atoms are preferably halogen, in particular bromine or chlorine.

The interaction should be carried out in the presence of an inert base, such as triethylamine or potassium carbonate as acid binding means, and in an inert solvent such as a cyclic saturated simple ether, in particular tetrahydrofuran or dioxane, or a hydrocarbon of the benzene series, such as toluene or xylene.

Interaction occurs, as a rule, at temperatures from 20 to 150oC, in particular from 80 to 140oC, and ends usually within 1-10 hours

Saedi, preferably lower alcohols, such as ethanol, or column chromatography.

The racemate is separated into the enantiomers simple way classical splitting with optically active carboxylic acids, for example derivatives of tartaric acid, in an inert solvent, for example lower alcohols.

Available derivatives of 3-azabicyclo [3.2.0.] heptane of the formula (I) can be converted in the usual manner in salt accession pharmacologically tolerable acids, preferably by mixing the solution with the equivalent of the appropriate acid. Pharmaceutically tolerated acids are, for example, hydrochloric acid, phosphoric acid, sulfuric acid, methane-acid, amidosulfonic, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.

Used for the synthesis of new compounds, the compounds of formula (II) are known.

The compounds of formula (III) receive the fact that the amine of formula (IV),

< / BR>
where R has the above meaning and R1means hydrogen, acetyl, benzyl or TRIFLUOROACETYL, is subjected to a photochemical [2+2] ticlopidine and, if necessary, otscheplaut acyl or benzyl group.

P>C. as a light source is well suited mercury lamp high pressure. Sometimes it is preferable to photocyclization in a quartz apparatus in an atmosphere of nitrogen with the addition of about one mole of hydrochloric acid per mole of amine.

Photocyclization occurs in most cases with a high degree of diastereoselectivity to bicyclic compounds (III) with asocolflores relatively R:

< / BR>
Splitting of the racemate, for example, optically active derivatives of tartaric acid are separate enantiomers.

Acyl group, R1it is advisable to split by known methods. The same is valid for the removal of benzyl groups.

Amines of formula (IV) are known from the literature or obtained by the fact that the aldehyde R-CHO subjected to interaction with winimageoryou to obtain the allyl alcohol of formula (V)

< / BR>
then subjected to a rearrangement of hydrogen chloride to allyl chloride of the formula (VI)

< / BR>
and then subjected to the interaction with the corresponding allylamino formula (VII),

< / BR>
or cinnamic aldehyde of formula (VIII)

< / BR>
directly subjected to reductive aminating with the allyl AMIA the above formula (I) possess antipsychotic activity and can therefore be used as a neuroleptic funds (in particular, atypical), antidepressants, sedatives, hypnotics, which protects the Central nervous system tools or muscle relaxants.

The affinity of compounds of the above formula (I) to the subtype of 4.2 D4-dopamine receptor is illustrated by the following experience.

The experiment for the determination of affinity for subtype 4.2 D4-dopamine receptor

Lysed cells (Cos cells exhibiting stable expression of cloned human D4.2-receptor), re-suspended in incubation buffer (50 mmol Tris-HCl, pH 7,4) containing 5 mmol EDUC, 1.5 mmol of potassium chloride, 120 nmol of sodium chloride and 5 mmol of magnesium chloride. The concentration of the cells was 105/experience. Incubation was carried out at 25oC in the presence or absence of the compounds using 50 pmol of [125J] spiperone. Nonspecific binding was determined using haloperidol, taken at a concentration of 10-6mol. After 60-minute incubation, bound and free radioactivity were separated by filtration using a glass filter GF/B firm Woodman, GB, using the device Skadron to collect cells. The filter was washed with cold buffer Tris-HCl, pH 7, the b was determined by liquid scintillation using device Packard 2200 CA. Values FORi(nmol/l) of the studied compounds were determined by nonlinear regression analysis using the program Ligand. Your results:

The means for subtype 4.2 D4-dopamine receptor

The compound of example N - Ki(nmol/l)

1 - 6,7

2 - 4,5

3 - 19

4 - 1,8

6 - 5,1

7 - 4,3

8 - 4,4

10 - 31

Compounds according to the invention belong to the category of low-toxic substances.

Compounds according to the invention can be administered in the usual manner orally, parenterally, intravenously or intramuscularly.

The dosage depends on age, condition and weight of the patient, and the type of injection. As a rule, the daily dose of active substance is from 1 to 100 mg/kg in oral introduction and from 0.1 to 10 mg/kg of body weight at parenteral administration.

Compounds according to the invention can be used in conventional solid or liquid pharmaceutical forms, such as tablets, coated tablets, capsules, powder, granules, pills, suppositories, solutions, ointments, creams or sprays. These forms are made in the usual way. The active substance is processed with normal, pharmaceuticals subsidiary among katorumi, wetting agents, dispersing agents, emulsifiers, solvents, retarding the release of active substances means, antioxidants and/or working gases (see N. Sucker etc., Pharmazeutische Technologie, ed. Tieme, Stuttgart, 1978).

Thus obtained forms usually contain the active substance in an amount of from 1 to 99 wt.%.

The following examples serve to explain the invention.

A. Obtaining parent compounds

aa) 1-(1-naphthyl)-allyl alcohol

In a two-liter flask is poured in a nitrogen atmosphere 277 ml (360 mm) 1.3 M solution of vinylmania in tetrahydrofuran. Then added under stirring in nitrogen atmosphere, 50 g (320 mm) 1-naphthaldehyde dissolved in 250 ml of tetrahydrofuran (THF) for 60 min at 30-35oC. the Reaction mixture is stirred for another 4.5 hours in a nitrogen atmosphere at room temperature. Then, under stirring and ice cooling was added 90 ml of a saturated solution of ammonium chloride, sucked off and the filter residue washed three times using 150 ml of tetrahydrofuran. The filtrates are combined, dried over sodium sulfate and concentrated. Get 58,3 g (99%) of crude product as a brown oil;

AB) 3-(1-naphthyl)-allylchloride of 58.3 g (317 mm) 1-(1-naphthyl)- allyl alcohol races the temperature rises to 37oC. and Then stirred for one hour. After washing with 200 ml ice water, the organic phase is dried over sodium sulfate and concentrated. Get 59,2 g (92%) of a brownish solid;

AB) N-allyl-N-[3-(1-naphthyl)-allyl]-amine

To 167 g (2.9 M) allylamine add to 59.2 g (0,29 M)3-(1-naphthyl)-allylchloride dissolved in 250 ml of toluene, at reflux for one hour. The mixture continued to stir for two hours at the temperature of the return stream. Then the reaction mixture was concentrated, the residue consume 250 ml of water and set to pH 12 with 50% caustic soda. The aqueous phase is extracted with dichloromethane, the organic phase is dried over sodium sulfate and concentrated.

Output: 67,6 g (97%) of a dark brown oil;

AG) Exo-6-(1-naphthyl)-3-azabicyclo[3.2.0]heptane

50.0 g (193 mm) of N-allyl-N-[3-(1-naphthyl)-allyl]ameriglide dissolved in 1600 ml of acetone and mixed with 210 ml of 10% hydrochloric acid. Transparent yellow solution is irradiated in nitrogen atmosphere mercury lamp high pressure power 700 watts in a quartz apparatus for four hours at room temperature. After this reaction solution was concentrated, the residue absorb water and set to pH 12 with povstancheskaya phase is dried over sodium sulfate and concentrated.

Dark brown oily residue (43,2 g) dissolved in 150 ml of isopropanol and mixed with 25,5 g (220 mm) of maleic acid dissolved in 220 ml of isopropanol. Loose maleinate sucked off, washed with isopropanol and dried in a vacuum drying Cabinet at 40oC during the night.

Output: 43,9 g (67%) of colourless powder with so pl. 162-164oC (malaikat).

In a similar way we obtain the following connections:

ad) Exo-6-(2-naphthyl)-3-azabicyclo[3.2.0]heptane,

so pl.: 145-147oC (malaikat)

AE) Exo-6-(6-chloro-2-naphthyl)-3-azabicyclo[3.2.0]heptane,

so pl.: 164-165oC.

B. Obtain the target compounds

Example 1

M-[2-(Exo-6-(1-naphthyl)-3-azabicyclo[3.2.0]heptane-3-yl)- ethyl]-benzamide

4.0 g (17,8 mm) Exo-6-(1-naphthyl)-3-azabicyclo[3.2.0]heptane in 70 ml of toluene is mixed with 6.6 g (35,2 mm) of N-(2-chloroethyl)- benzamide, and with 2.5 g (18,1 mm) crushed into fine powder of potassium carbonate and 0.5 g of potassium iodide and refluxed under good stirring for 6 hours, After cooling, concentrated on a rotary evaporator and the residue is distributed between methylene chloride and water. The aqueous phase is extracted twice with methylene chloride and concentrated the organic phase after drying with sodium sulfate. wearing 96:4). The free base (3.0 g) is dissolved in 100 ml of tert.-butyl methyl ether and mixed under ice cooling with excess ethereal hydrochloric acid. Precipitated hydrochloride is sucked off in a nitrogen atmosphere, washed with a large quantity of tert.-butyl methyl ether and dried by suction in a stream of nitrogen. Obtain 2.6 g of the product as hydrochloride with so pl. 184-186oC (yield 35%).

Similarly receive the following connections:

2. N-12-(Exo-6-(2-naphthyl)-3-azabicyclo[3.2.0]heptane-3 - yl)ethyl]-benzamide, so pl. 233-235oC (hydrochloride),

3. 3-[2-(1-naphthyl)ethyl]-Exo-6-(1-naphthyl)-3 - azabicyclo[3.2.0]heptane, so pl. 227-229oC (hydrochloride),

4. 3-[2-(1-naphthyl)ethyl]-Exo-6-(2-naphthyl)-3 - azabicyclo[3.2.0]heptane, so pl. 208-210oC (hydrochloride),

5. 1-[2-(Exo-6-(1-naphthyl)-3-azabicyclo[3.2.0]heptane-3 - yl)ethyl]-1H-beneo-[cd]indol-2-it, so pl. 174-176oC (hydrochloride),

6. 1-[2-(Exo-6-(2-naphthyl)-3-azabicyclo[3.2.0]heptane-3 - yl)ethyl]-1H-benzo-[cd]indol-2-it, so pl. 258-260oC (hydrochloride),

7. 3,3-dimethyl-1-[2-(Exo-6-(2-naphthyl)-3 - azabicyclo[3.2.0] heptane-3-yl)ethyl]-1,3-dihydroindol-2-it, so pl. 124-125oC,

8. amide 5-chloro-M-[2-(Exo-6-(1-naphthyl)-3 - azabicyclo[3.2.0]heptane-3-yl)-ethyl]-2-thiophencarboxylic acid, so pl. 160-162oC,

9. N-[2-(Exo-6-(6-chloro-2-lo[3.2.0]heptane-3-yl)-ethyl]-benzamide, so pl. 110-112oC (hydrochloride).

1. Derivatives of N-substituted 3-azabicyclo (3.2.0)heptanol formula I

< / BR>
where R means naftalina or phenanthroline group, which can be mono - or tizamidine atoms, halogen,

A represents the residue of a formula

< / BR>
< / BR>
or naftalina group which may be substituted by halogen, or their salts with physiologically acceptable acids.

2. Derivatives of N-substituted 3-azabicyclo (3.2.0)heptanol formula I on p. 1, showing antipsychotic activity.


Same patents:

The invention relates to new derivatives of azetidinone General formula (I) in which R, R1, Ar1-Ar3X, Y, m, n, q and r are specified in the claims values, and their pharmaceutically acceptable salts, which are the active ingredient of the pharmaceutical composition with anti-atherosclerotic or hypocholesterolemic activity

The invention relates to benzothiophene compounds of formula I, where R1-H, - OH, -O(C1-C4alkyl), - EA6H5-, OCO(C1-C6alkyl), or-OSO2(C2-C6alkyl);

R2IS-H, -OH, -O(C1-C4alkyl), EA6H5, CCA(C1-C6alkyl) , -OSO2(C2-C6alkyl), or halogen; R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, diisopropylamino or 1 hexamethyleneimino; n = 2 or 3; Z Is-O - or-S-, or their pharmaceutically acceptable salts

The invention relates to a derived aydinonat or salts thereof, useful for use as a medicine, particularly as an inhibitor of activated factor X coagulation

The invention relates to certain CIS - and TRANS-benzopyrane having substituted benzamide in position C-4, and to their use for the treatment and/or prevention (prophylaxis) of certain CNS disorders

The invention relates to new derivatives of benzimidazole and their salts formed by the addition of acids, the way they are received and microbicide tool based on them

The invention relates to hydrobromide salts 3-(N-methyl-2(R)-pyrrolidinyloxy)-5-(2-phenylsulfonyl)-1H-indole having the formula (I)

< / BR>
Preferably the invention relates to a specific polymorphic form, referred to hereinafter as the alpha form above hydrobromide salt

The invention relates to therapeutic tools, specifically setidentityproviderid N-substituted nitrogenous heterocyclic compounds and methods of producing such compounds, intermediate products used in obtaining, compositions containing such compounds and the use of such heterocycles

The invention relates to a new series of 4-phenylpiperazine, 4-phenylpiperidines and 4-phenyl-1,2,3,6-tetrahydropyridine

The invention relates to new chemical compounds with valuable biological properties, in particular to derive hinolan and naphthyridinone acids with antibacterial activity, as well as to the isoindole derivative as starting compounds for obtaining the derivatives hinolan and naphthyridinone acid