Derivatives of 4-aryl-1-(indenmity or dihydrobenzofuranyl)piperidine- -tetrahydropyridine or piperazine and pharmaceutical composition

 

(57) Abstract:

Describes new derivatives of 4-aryl-1-(indenmity or dihydrobenzofuranyl)piperidine, tetrahydropyridine or piperazine of the formula I, where the values of R1-R8, Ar, X, Y, Z are specified in paragraph 1 of the formula acting on Central serotonergic receptors. They are used in the form of pharmaceutical compositions in the treatment of some mental and neurological diseases. 2 S. and 9 C.p. f-crystals, 1 PL.

The invention relates to a new class of derivatives of 4-aryl-1-(indenmity, dihydrobenzofuranyl or dihydrobenzofuranyl)piperidine, tetrahydropyridine or piperazine acting on Central serotonergic receptors. Therefore, these melaminovye compounds are useful in the treatment of some mental and neurological disorders.

Several of the prior art known to a small number of derivative aminomethane-dihydrobenzofuran and-dihydrobenzofuran.

Thus, in the patent EP 0281261 described derivatives of 1-aminopyridine, 3-aminomethyltransferase and 3-aminomethylbenzoic with a hydroxy-group or substituted by a hydroxy-group in the 6-position (indan) or 5-position will stifle activity in particular, the influence presynaptic dopamine receptors.

In U.S. patent N 4500543 we are talking about some of the compounds 1-aminotetralin that demonstrate adrenergic actions and in accordance with this antihypertensive properties and to reduce the frequency of heart contractions. To the specified patent are primarily compounds having substituents in the 5-, 6 - and/or 7-position.

In EP 0325963 A1 describes, among other compounds, a class derived 1-aminopyridine in which the aminomethyl group can contain 1-pyrrolidinyloxy group, which is substituted by tanila or phenyl. As stated, the compounds are2antagonists used in the treatment of depression, metabolic disorders, glaucoma, migraine and hypertension.

In addition, in EP 0490772 A1 describes a class 4-benzofuranyl - or 4-benzodioxane-1-indanylaminopropane derivatives which are 5-HT1Athe ligands.

EP 0428437 mainly applies to a very broad class of 1,2-benzisoxazole derivatives, including some 3-[1-[(1-indenyl)methyl]-1,2-benzisoxazole. However, only one such connection is shown in the examples, but in this case, no data was provided

U.S. patent N 3886168 relates to derivatives of 1-[(indan-1-yl)-methyl]piperidine derivatives having antihypertensive activity.

It is known that compounds which are ligands for the different subtypes of serotonin receptors have different actions. As for the 5-HT2Areceptor, which was previously identified as 5-HT2receptor, reported on his next action.

It is shown that ritanserin, which is an antagonist of 5-HT2A(Meert, T. F., Janssen, P. A. Drug. Dev. Res. 1989, 18, 119), effective in the treatment state of fear and depression, presumably by improving sleep quality. In addition, it was found that selective, centrally acting 5-HT2Aantagonists, have effect in relation to negative symptoms of schizophrenia and reduce extrapyramidal side effects caused by treatment with classical antipsychotics in patients with schizophrenia (Gelders, Y. G., British J. Psychiatry, 1989, 155 (suppl. 5), 33). Finally, selective 5-HT2Aantagonists could be effective in the prevention and in the treatment of migraine, since it is known that 5-HT is involved in the migraine attack. Relationship between 5-HT and migraine attacks are different, and they suggest a number of mechanisms by which mo is A antagonist, MDL 100 907 (Sorensen, S. M. et al., J. Pharmacol. Exp. Ther. 1993, 266, 684-691) and some derivatives in the range of 1-felininty (WO 93/12790) and 3-phenylindole derivatives (WO 93/14758) showed antipsychotic activity in animal models, indicating a predisposition to extrapyramidal side effects (EPP, EPS).

Clinical studies known 5-HT1Apartial agonists, such as buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinil-]-butyl]-8-azaspiro[4,5] decane-7,9-dione, gepirone, 4,4-dimethyl-1-[4-[4-(2-pyrimidyl)-1-piperazinil] butyl] -2,6-piperidinedione, and ipsapirone, 2-[4-[4-(2-pyrimidyl)-1-piperazinil] butyl] -1,2-benzothiazol-3-(2H)-one-1,1-dioxide, showed that 5-HT2Apartial agonists useful in the treatment of disorders associated with fear, such as generalized disorder associated with anxiety disorder, caused by panic, and disorder called compulsive obsessie (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies have shown that, in addition, full agonists used in the treatment of the above-mentioned related fear disorders (Schipper, Human Psychopharmacol., 1991, 6, S53).

In addition, there is evidence both for clinical and non-clinical support positive who is ellenia alcohol (van Hest, Psychopharmacol., 1992, 107, 474; Schipper et al., Human Psychopharmacol., 1991, 6, S53; Cervo et al., Eur. J. Pharm., 1988, 158, 53; Glitz, D. A., Pohl, R., Drugs 1991, 41, 11; Grof et al., Int Clin. Psychopharmacol. , 1993, 8, 167-172; Ansseau et al., Human Psychopharmacol., 1993, 8, 279-283).

5-HT1aagonists and partial agonists inhibit caused by isolation aggression in mice (males), indicating that these compounds are useful in the treatment of aggression (Sanchez et al., Psychopharmacology, 1993, 110, 53-59).

In addition, 5-HT1Aligands reportedly show antipsychotic activity in animal models (Wadenberg and Ahlenius, J. Neural. Transm., 1991, 83, 43; Ahlenius, Pharmacol &Toxicol., 1989, 64, 3; Lowe et al., J. Med. Chem. , 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147; and Martin et al., J. Med. Chem., 1989, 32, 1052).

In addition, recent studies have shown that 5-HT1Areceptors important in serotonergic modulation caused by haloperidol catalepsy (Hicks, Life Science 1990, 47, 1609, Wadenberg et al., Pharmacol. Biochem. & Behav. 1994, 47, 509-513), which suggests that 5-HT1Aagonists useful in the treatment of EPP EPS (extrapyramidal side effects) caused by conventional antipsychotic agents like haloperidol.

In addition, 5-HT1Aagonists are neuroprotective properties in rodent models with local and global cerebral ischemia and therefore they maracalagonis research which showed that 5-HT1Aantagonists useful in the treatment of senile dementia (Bowen et al., Trends Neur. Sci. 1992, 15, 84).

As in animal models and in clinical trials it was shown that 5-HT1Aagonists exert an antihypertensive effect via a Central mechanism (Saxena and Villalon, Trends Pharm. Sci. 1990, 11, 95; Gillis et al., J. Pharm. Exp. Ther. 1989, 248, 851). Therefore, 5-HT1Athe ligands may be useful in the treatment of cardiovascular disorders.

Inhibitors of 5-HT reverse absorption (reuptake) are well-known antidepressant drugs.

Because the classes of compounds which are ligands of 5-HT1Aand 5-HT2Areceptors and inhibitors of 5-HT reverse takeover, have different activity in different animal models, demonstrating antisolitons and protivougrevoe action (Perregaard et al., recent Developments in Anxioolytics. Current in Therapeutic Patents 1993, 1, 101-128), and/or models showing the effect of other mental disorders, it could also successfully treat complex state of fear, depression or other mental illness with drugs, which has combined serotonergic actions.

Would piperidine, -tetrahydropyridine or piperazines effectively interact with Central serotonergic receptors, in particular 5-HT1Aand/or 5-HT2Athe receptors.

Accordingly, this invention relates to new compounds of the formula I

< / BR>
where one of X and Y is CH2and the other is selected from the group consisting of CH2, O and S;

the dotted line emanating from Z indicates an optional bond; when the bond is not specified, Z is N, CH or SON, and when the link is specified, Z is C;

Ar represents phenyl, 2-thienyl, 3-thienyl, 3-furanyl, 3-furanyl, 2 pirimidil, 1-indolyl, 2-indolyl, 3-indolyl, 1-indole-2-IMT, 3-indole-2-IMT, 2 - or 3-benzofuranyl, 2 - or 3-benzothiophene, 1-naphthyl or 2-naphthyl, each arbitrarily substituted with halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, trifluoromethyl, tripterocalyx, cycloalkyl, cycloalkyl-lower alkyl, nitro, amino, lower alkylamino, di-lower alkylamino, acylamino or C1-2alkylenedioxy;

R1represents hydrogen, lower alkyl, lower alkenyl, lower quinil, recloak(EN)yl, recloak(EN) yl-lower ALK(EN/in)yl, aryl-lower alkyl, acyl, thioacyl, nepredstavlyaet O or S and R9represents lower alkyl, cycloalkyl, cycloalkyl-lower alkyl or aryl, or

R1is the group R10R11NCO or R10R11NCS-, where R10and R11are independently hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl or aryl, or R10and R11together with N-atom to which they are bound, form pyrrolidinyl, piperidinyl or peligrosamente group;

R2represents hydrogen, lower alkyl, cycloalkyl or cycloalkyl-lower alkyl;

or R1and R2together with N-atom to which they are attached, form a group

< / BR>
in which Q is C=O, C=S or CH2; T is NH, S, O or CH2; m is 1-4, inclusive;

R3-R5are independently hydrogen, halogen, lower alkyl, lower alkylsulphonyl, phenylcarbinol, halogen, substituted phenylcarbamoyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, trifluoromethyl, cycloalkyl, cycloalkyl-lower alkyl or nitro;

R6and R7are each hydrogen or lower alkyl, or they are connected together with the formation of a 3-7-membered carbocyclic ring;

R8is hydrogen or lower alkyl;

each one is xerophagy, which, in addition, optional tarifitsirovana aliphatic or aromatic carboxylic acid: any aryl present Deputy optionally substituted with halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, lower alkylsulfonyl, cyano, trifluoromethyl, tripterocalyx, cycloalkyl, cycloalkyl-lower alkyl or nitro;

and their pharmaceutically acceptable salts accession acid.

It is established that the compounds of this invention have a strong affinity for 5-HT1Areceptors and/or 5-HT2Athe receptors. In addition to acting on these receptor subtypes, some of these compounds also exhibit the effect of inhibiting 5-HT reverse takeover.

Accordingly, the compounds of this invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, state of fear, such as diseases caused by fear, panic, and obsessive compulsive disorders, depression, alcohol abuse, diseases associated with motivational control, aggression, side effects caused by conventional antipsychotics is Ucrania sleep.

In another aspect the invention provides a pharmaceutical composition, at least one the above compound of formula I or its pharmaceutically acceptable salt accession acid or prodrug to a therapeutically effective amount or in combination with one or more pharmaceutically acceptable carriers or diluents.

The following aspect of this invention relates to the use of compounds of formula I, above, or its salt accession acid or prodrugs to obtain a pharmaceutical preparation for the treatment of the aforementioned disorders.

Compounds of General formula (I) can exist in the form of their optical isomers, and such optical isomers are also included in the scope of the invention.

Prodrugs of compounds of General formula (I) are also included in the scope of the invention.

The term cycloalkyl denotes a carbocyclic ring having 3-8 carbon atoms, inclusive, or a bicyclic or tricyclic carbocycle, such as substituted.

The term lower alkyl refers to an unbranched and branched alkyl group having from one to six carbon atoms, inclusive, such as methyl, ethyl, a is hydroxy, lower alkylthio, lower alkylsulfonyl, lower alkylamino, lower alkylsulphonyl etc. designate such groups in which the alkyl group is a lower alkyl group as described above. Similarly, lower alkenyl and quinil respectively denote groups having from two to six carbon atoms inclusive. The preferred groups are groups having up to four carbon atoms.

The term aryl refers to mono - or bicyclic carbocyclic or heterocyclic aromatic group, such as phenyl, indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, benzofuranyl, benzothiazol, pyridyl, naphthyl and furanyl, in particular phenyl, pyrimidyl, indolyl and thienyl.

Halogen means fluorine, chlorine, bromine or iodine.

Used herein, the term acyl refers to formyl, lower ALK(EN/in)ylcarbonyl, arylcarboxylic, aryl-lower ALK(EN/in)ylcarbonyl, cycloalkylcarbonyl or cycloalkyl-lower ALK(EN/in)ylcarbonyl group.

The term thioacyl means corresponding acyl group in which a carbonyl group substituted thiocarbonyl group.

The expression of ALK(E. the X preferably represents CH2or S, and Y preferably is CH2and, most preferably, they are both CH2.

R1preferably represents an acyl, lower alkyl, lower alkoxy group, R10R11NCO or R10R11NCS-, in which R10is hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl or aryl and R11is hydrogen or lower alkyl, or R10and R11together with N-atom to which they are connected, form pyrrolidinyl, piperidinyl or peligrosamente group. Most preferably, R1represents formyl, acetyl, methylaminomethyl, methylaminomethyl, dimethylaminoethyl, dimethylaminostyryl, methylsulphonyl, aminocarbonyl, cyclopropanecarbonyl, methyl, pyrrolidinylcarbonyl or 4-ftorpolimernoj.

R2is preferably hydrogen or lower alkyl, most preferably hydrogen or methyl, or R1and R2connected together, form a 5-7-membered unsubstituted ring lactam or pyrrolidinyl, piperidinyl or peligrosas.

R3-R5are preferably hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl or acetyl, and R6-R8the 1-indolium, or pirimidinom or phenyl, 3-indolium, 1-indolium or pirimidinom substituted by halogen.

A preferred subclass of compounds are compounds in which R1is acetyl and R2is H and, in particular, such compounds in which Ar is indolium or phenyl substituted by halogen, especially chlorine. If Ar is 3-indolium, it is preferably substituted in 6-position, and if he is phenyl, it is preferably substituted in the 4-position.

Another preferred subclass of compounds of the invention are those in which R1is the group R10R11NCO or R10R11NCS-, in which R10is hydrogen or lower alkyl, cycloalkyl, cycloalkyl-lower alkyl or aryl, and R11is hydrogen or lower alkyl, and R2is hydrogen.

In yet another preferred subclass of compounds R1represents hydrogen, lower alkyl or lower alkylsulfonyl, in particular methyl or methylsulphonyl, and R2represents hydrogen or lower alkyl, in particular methyl, or R1and R2joined together, forming pyrrolidinone ring or pyrrolidinyl ring.

Site (+)-1-(6-Acetaminophen-1-ylmethyl)-4-(4-forfinal)piperidine.

(-)-1-(6-Acetaminophen-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-5-Florinda-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-4-Florinda-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-4-bromantan-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-4-nitrogen-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-4-canaidan-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-5-Clorinda-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-5-bromantan-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-5-canaidan-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-7-Clorinda-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-7-Florinda-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(5-Acetyl-6-acetaminophen-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetylamino-1-methylinden-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(3-forfinal)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(2-forfinal)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(4-were)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(4-dimethylaminophenyl-1-ylmethyl)-4-(3-triptoreline)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(5-Acetylamino-2,3-dihydrobenzofuran-3-ylmethyl)-4-(4-forfinal) piperidine.

1-(6-Acetylamino-1,3-dihydrobenzofuran-1-ylmethyl)-4-(4-forfinal) piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(4-chlorophenyl)piperazine.

1-(6-Acetaminophen-1-ylmethyl)-4-(3-chlorophenyl)piperazine.

1-(6-Acetaminophen-1-ylmethyl)-4-(2-chlorophenyl)piperazine.

1-(6-Acetaminophen-1-ylmethyl)-4-(4-triftormetilfullerenov) piperazine.

1-(6-Acetaminophen-1-ylmethyl)-4-(3,4-dichlorophenyl)piperazine.

1-(6-Acetaminophen-1-ylmethyl)-4-(3,4-dichlorophenyl)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(2-methoxyphenyl)piperazine.

1-(6-Acetaminophen-1-ylmethyl)-4-(4-forfinal)-1,2,3,6 - tetrahydropyridine.

1-(6-Acetaminophen-1-ylmethyl)-4-(4-chlorophenyl)-1,2,3,6 - tetrahydropyridine.

1-(6-Acetaminophen-1-ylmethyl)-4-(2-pyrimidyl)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(2-pyrimidyl)piperazine.

1-(6-Acetaminophen-1-ylmethyl)-4-(2-pyridinyl)piperazine.

1-(6-Acetaminophen-1-ylmethyl)-4-(3-thienyl)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(2-thienyl lmutil)-4-(1-naphthyl)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(2-naphthyl)piperidine.

1-(6-Butanilicaine-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Formylamino-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Formylamino-1-ylmethyl)-4-(4-forfinal)piperazine.

4-(4-Forfinal)-1-(6-methanesulfonylaminoethyl-1-ylmethyl)piperidine.

1-(6-Cyclopropanecarbonitrile-1-ylmethyl)-4-(4-forfinal) piperidine.

1-(6-Cyclopentanecarbonitrile-1-ylmethyl)-4-(4-forfinal)piperidine.

4-(4-Forfinal)-1-(6-methylaminoanthraquinone-1-ylmethyl)piperidine.

1-(6-(4-Forfinal)aminocarbonylmethyl-1-ylmethyl] -4-(4-forfinal) piperidine.

4-(4-Forfinal)-1-(6-methylenedioxyaniline - 1-ylmethyl)piperidine.

1-(6-Dimethylaminocarbonylmethyl-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Dimethylaminocarbonylmethyl-1-ylmethyl)-4-(4-forfinal) piperidine.

4-(4-Forfinal)-1-[6-(1-pyrrolidinyl)carboalumination-1-ylmethyl] piperidine.

1-(6-Aminocarbonylmethyl-1-ylmethyl)-4-(4-forfinal)piperidine.

1-(6-Ethoxycarbonylmethyl-1-ylmethyl)-4-(4-forfinal)piperidine.

1-[6-(N,N-dimethylamino)indan-1-ylmethyl]-4-(4-fluoro who CLASS="ptx2">

3-[1-(5-Acetylamino-2,3-dihydrobenzofuran-3-ylmethyl)-1,2,3,6 - tetrahydropyridine-4-yl]-5-chloro-1H-indole.

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl]-5-fluorescent-1H-indole.

3-[1-(6-Acetylamino-2,3-dihydrobenzofuran-3-ylmethyl)-1,2,3,6 - tetrahydropyridine-4-yl]-5-fluorescent-1H-indole.

3-[1-(6-Acetaminophen-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl] -6 - chloro-1H-indole.

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl]-6-chloro-1H-indole.

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl] -6-chloro-1 - methyl-1H-indole.

1-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl]-6-chloro-1H-indole.

1-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl]-5-chloro-1H-indole.

3-[1-(6-Acetaminophen-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl] -5 - chloro-1H-indole.

4-(4-Forfinal)-1-[6-(1-pyrrolidin-2-IMT)indan-1-ylmethyl)piperidine.

4-(4-Forfinal)-1-[6-(1-piperidine-2-IMT)indan-1-ylmethyl)piperidine.

1-[6-(4-Forgenerating)indan-1-ylmethyl]4-(4-forfinal)piperidine.

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl]-6-chloro-benzothiophen.

3-[1-(6-Acetaminophen-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl] -6 - chloro-benzothiophen.

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-and the

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl]-6-chloro-benzofuran.

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl] -6-chloro-1H-indole-2-it.

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl] -6-chloro-methyl-1H-indole-2-it.

3-[1-(6-Acetaminophen-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl] -6 - chloro-1-methyl-1H-indole-2-it.

2-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl]-6-chloro-1H-indole.

1-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl] -5-chloro-1H-indole-2-it.

3-[1-(6-Methylaminoanthraquinone-1-ylmethyl)piperidine-4-yl] -5-chloro-1H-indole.

3-[1-(6-Methylaminoanthraquinone-1-ylmethyl)-1,2,3,6 - tetrahydropyridine-4-yl]-6-chloro-1H-indole.

1-(6-Acetaminophen-1-ylmethyl)-4-(4-bromophenyl)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-hydroxy-(4-chlorophenyl) piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(3-trifluoromethyl-4-chlorophenyl)piperazine.

1-(6-Acetaminophen-1-ylmethyl)-4-(2-chloro-3-thienyl)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(4-chloro-2-thienyl)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(3,4-methylenedioxyphenyl)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-(3,4-methylenedioxyphenyl)piperazine.

1-(6-what-ylmethyl)-4-hydroxy-4-(3-trifluoromethyl-4 - chlorophenyl)piperidine.

1-(6-Acetaminophen-1-ylmethyl)-4-atomic charges-4-(3-trifluoromethyl-4 - chlorophenyl)piperidine.

5-chloro-1-[1-(6-methylaminoanthraquinone-1-ylmethyl)piperidine-4-yl] - 1H-indole.

Salt accession acid according to the invention are pharmaceutically acceptable salts of compounds of formula I formed with non-toxic acids. Examples of such organic salts are salts with maleic, fumaric, benzoic, ascorbic, monowai (embonic), succinic, oxalic, bis-methylanilinium, methansulfonate, econsultancy, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, almond, cinnamon, tarakanovas, aspartic, stearic, palmitic, takenaway, glycolic, p-aminobenzoic, glutamic, benzosulfimide, Tefillin acetic acid, and 8-valuevillage, for example 8-remotefilename. Examples of such inorganic salts are salts with hydrochloric, Hydrobromic, sulfuric, sulfonovoj (sulfamic), phosphoric and nitric acids.

The pharmaceutical compositions according to this invention or pharmaceutical compositions obtained in accordance with this invention can be any podhodjawego for injection. For obtaining such compositions can be used in ways well known in this field, and can be used with any pharmaceutically acceptable carriers, diluents, fillers, or other commonly used in the art excipients.

Convenient to the compounds of this invention was administered in a single dosage form containing specified compound in an amount of from about 0.01 to 100 mg

The total daily dose is normally in the range of about 0.05-500 mg, and most preferably, from about 0.1 to 50 mg of active compound of the invention.

In addition, the invention relates to a method for production of new 4-aryl-1-[aminoindan, dihydrobenzofuran and dihydrobenzofuran)methyl] piperidine-tetrahydropyridine or piperazines of formula I, including:

(a) the interaction of the amino derivatives of the following formula II

< / BR>
where R2-R3X, Y, Z, Ar and the dotted line is such as previously defined, with a reagent of formula R1'-Gal or R1'-OCOR, and in these formulas Gal is halogen, R is alkyl, aryl or alkoxy, and R1is acyl, diazelam, the group R9VCO-, or R10R11NCO or R10R11 or R11cannot be hydrogen, or lower alkylsulfonates, triftormetilfullerenov, or isocyanate, or thioisocyanate formula R10-N=C=O or R10-N=C=S, where R10is as defined above;

b) in order to obtain the compound of formula I, in which R1is lower ALK(EN/in)Il, recloak(EN)yl-lower ALK(EN)yl or aryl-lower alkyl, alkylation of the amino derivatives of formula II alkylating agent, such as alkylhalogenide R1'-Gal mesilate R1"OSO2CH3toilet R1"OSO2C2H4-CH3or similar alkylating reagent with the appropriate atmasamyama groups, and R1represents lower alkyl, lower alkenyl, lower quinil, recloak(EN)yl, recloak(EN)yl-lower ALK(EN/in)yl or aryl-lower alkyl;

C) the restoration of the double bond of tetrahydropyridine derivatives of the following formula III

< / BR>
where R1-R8X, Y and Ar are such as defined previously; or

d) alkylation arylpiperazine, arylpiperazine or arylmethylidene formula V alkylating derivative of the formula IV

< / BR>
where R1-R8X, Y, Z, Ar and the dotted line such as that previously defined, and W soedineniya formula I, in which the substituents R1and R2together form a ring, the closure of the cycle (cyclization of a derivative of formula VI

< / BR>
where R3-R8X, Y, Z, Ar, m, Q, T, and the dashed line, such as that previously defined, and W is tsepliaeva group, such as, for example, halogen, mesilate or tosylate; or

e) in order to obtain the compound of formula I, in which R1is lower ALK(EN/in)Il, recloak(EN)yl, recloak(EN)yl-lower ALK(EN)yl or aryl lower alkyl, reduction of carbonyl group of the amide derivative of the following formula VII:

< / BR>
where R2-R8X, Y, Z, Ar and the dotted line such as that previously defined, and R1"'is this group that the group R1"'CH2is lower ALK(EN/in)Il, recloak(EN)yl, recloak(EN)yl-lower ALK(EN)yl or aryl-lower alkyl, covered by the definition of R1; or

g) introduction of substituent R3, R4or R5by reacting compounds of the following formula VIII

< / BR>
where one of R3'-R5'is hydrogen and the other two are the corresponding R3, R4or R5as defined previously, and R1, R2, R6-R8X, Y, Z, Ar and the dotted line such as defined by ray agent, or reactive agent that generates ions Carbonia (RCO+, R), where R is alkyl quinil, the aryl cycloalkyl, or cyclol(EN/in)yl; or

C) the restoration of the double bond in the compound of the following formula IX

< / BR>
where R1-R8X, Y, Z and Ar are such as defined previously, and one of the two dotted lines represents a double bond; or

and recovering the amide carbonyl in compound of the following formula X:

< / BR>
where R1-R5, R8X, Y, Z, Ar and the dotted line such as that previously defined,

after which the compound of formula I is isolated in the form of free base or pharmaceutically acceptable acid salts of the merger.

The interaction according to the method (a) is carried out at low temperature (e.g., below room temperature) in an inert solvent, such as acetone, dichloromethane, tetrahydrofuran or dimethoxyethane when using a reactive carboxylic acid anhydrides, isocyanates or isothiocyanates. Formirovanie amines are obtained from the corresponding amines by reaction of formic acid with esters of formic acid or by reacting a mixed anhydride of formic acid produced in situ. Usually the Cove.

The alkylation according to methods b) and C) is usually carried out by boiling under reflux in a suitable solvent, such as acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol or 2-propanol in the presence of a base such as triethylamine or potassium carbonate.

Restoration of double bonds according to methods b) and C) is usually carried out by catalytic hydrogenation at low pressure (< 3 ATM) in a Parr apparatus (Paar), or by using reducing agents such as DIBORANE in an inert solvent, such as tetrahydrofuran, dioxane or diethyl ether.

Recovery according to the methods (e) and (and usually is carried out by using LiAlH4, AlBH3or DIBORANE in an inert solvent, such as tetrahydrofuran, dioxane or diethyl ether, at room temperature or at slightly elevated temperature.

Halogenoalkane according to method g) is usually carried out using chlorine, bromine or N-chlorosuccinimide, N-bromosuccinimide or other halogenated molecule, the precursor, typically in the presence of a catalyst, such as Fe ions or mineral acid.

1-Unsubstituted 4-arylpiperazine formula V (Z=N) or com and c boiling reflux in a high boiling point solvents, as for example chlorobenzene, usually within 2-3 days according to the methods described by Martin et al., J. Med. Chem. 1989, 32 1052-1056.

4-Arylpiperazine formula V (Z= CH) are either commercially available, or they receive, as described, for example, in U.S. Pat. USA N 2891066; McElvain et al., J. Amer. Chem. Soc. 1950, 72, 3134; Bally et al., Chem. Ber. 1887, 20, 2590. The corresponding 4-aryl-1,2,3,6-tetrahydropyridine formula V (Z=C) receives from the N-protected 4-piperidinol by adding the appropriately substituted alliteration or arylalkylamines with subsequent acid catalyzed water elimination. Finally, the N-protective group of carbamate, benzyl, sulfonyl, acetyl) removed in the usual way.

Synthesis of 3-(4-piperidinyl)-1H-indoles and 3-(1,2,3,6-tetrahydropyridine-4-yl) 1-indoles described in the experimental section.

Key intermediates such as 1-indocaribbean acid (V. Asham and W. H. Linnell, J. Chem. Soc. 1954, 4691-4693, Hansen et al., Helv. Chim. Acta 1982, 33, 325-343) and 5-nitro-3-benzodiazepinova acid (application for Heb. Pat. EP N 88-301073 CA (110 (9); u) and references cited therein) are obtained according to well known literature procedures.

EXPERIMENTAL SECTION

Below, the invention is additionally illustrated by the examples, which, however, is not with edalat on a Buchi SMP-20 apparatus. The melting temperature are unadjusted.1H NMR spectra were recorded at 250 MHz spectrometer Bruker AC 250. As solvents used deuterated chloroform (99.8% of D) and dimethylsulfoxide (99.9% of D). TMS was used as internal standard. The values of chemical shifts are expressed in M. D. Used the following abbreviations for sets of NMR signals: s= singlet, d=doublet, t=triplet, K=Quartet, kV=quintet, g=septet, DD= doublet of doublets, dt=doublet of triplets, DC=doublet of quartets, TT=triplet of triplets, m=multiplet.

Primer

6-Nitro-1-indocaribbean acid, 1a

A solution of 1-intakebadboy acid (30 g) obtained according to the method of Hansen et al. , Helv. Chim. Acta 1982, 325-343, in dichloromethane (50 ml) is mixed with concentrated sulfuric acid (300 ml) at -10oC. a Mixture of 100% NHO3(11.4 g) and concentrated H2SO4(96 ml) is added dropwise under vigorous stirring below -10oC. After stirring for one hour at 10oC the mixture was poured on ice. Extraction with ethyl acetate (2 x 300 ml), drying (betw. MgSO4and, finally, evaporation of the organic solvent to give 42 g of the named compound. So pl.: 126-130oC.

5-Nitro-3-benzotiofenului acid produces the (CA110(9): W (1988), J. Amer. Chem. Soc. 1948, 70,1955 and J. Chem. Soc. (C) 1967, 1899.

Example 2 (method "and")

1-(6-Aminoindan-1-ylmethyl)-4-(4-forfinal)piperidine, 2a.

Dimethylformamide (DMF, 1 ml) was added to a solution of 6-nitro-1-intakebadboy acid 1A (13 g) and thionyl chloride (18 ml) in dichloromethane (125 ml). The mixture is refluxed for 4 hours Add the toluene and volatile matter is evaporated in vacuum. Thus obtained acid chloride of carboxylic acid are dissolved in dichloromethane (100 ml) and added dropwise to a solution of 4-(4-forfinal)piperidine (19.5 g) and triethylamine (7 ml) in dichloromethane (100 ml) at 0-5oC. the Mixture is stirred at room temperature for an additional 1.5 hours, water is Added, the organic phase is separated, washed with brine, dried (betw. MgSO4), filtered and the dichloromethane is evaporated in vacuum, obtaining the crude derivative of 6-nitrogen-1-carboxamide in the form of oil (35 g). Purification of column chromatography on silica gel (elute with a mixture 1:1 of ethyl acetate and heptane) gives 12 g of pure carboxamide in the form of oil. All this oil is dissolved by boiling under reflux in 90% ethanol (350 ml). Fe-powder (10 g) and concentrated aqueous HCl (1 ml) are successively added in small portions in throwaway, while the mixture is still hot, and the ethanol is evaporated in a vacuum. Add dilute aqueous NH4OH to achieve a pH > 9. Extraction with ethyl acetate (2 x 200 ml) and the processing of the organic phase, as mentioned above, gives 8 g of the derivative of 6-aminoindan-1-carboxamide. So pl. 144-145oC. To a suspension of LiAlH4(2.7 g) in dry tetrahydrofuran (THF, 125 ml) is added dropwise a solution just carboxamide in THF (125 ml). The mixture is heated at a low boil under reflux for 2 hours, After cooling to 10oC water (10 ml) and 15% aqueous NaOH solution carefully added to destroy excess LiAIH4. The inorganic salt is filtered off and washed thoroughly with THF. The combined THF solution is evaporated, getting 6.5 g of the named compound 2a in the form of oil. Hydrochloric salt crystallized from 2-propanol. So pl. 198-201oC.

1H NMR (DMSO-d6): 1.85 to 2.40 a (m, 6H); 2,60-2,90 (m, 3H); 3.00 and is 3.15 (m, 3H); at 3.35 (broad s, 3H), 3.45 points-of 3.60 (m, 2H); 3,65 of 3.75 (m, 1H); of 6.45 (d, 1H); 6,50 (s, 1H); to 6.95 (d, 1H); to 7.15 (t, 2H); 7,25-7,35 (m, 2H).

In a similar way we obtain the following aniline derivatives:

1-(6-Aminoindan-1-ylmethyl)-4-(2-methoxyphenyl)piperazine, 2B in the form of oil,

1-(6-Aminoindan-1-ylmethyl)-4-(2-chlorophenyl)piperazine, 2B in the form of oil,

1-(6-Amino, so pl.: 98-109oC,

1-(5-Amino-2,3-dihydrobenzofuran-3-ylmethyl)-4-(4-forfinal)- piperidine, 2E in the form of oil,

1-(6-Aminoindan-1-ylmethyl)-4-(4-forfinal)-1,2,3,6-tetrahydropyridine, 2ZH, so pl.: 78-84oC,

1-(6-Aminoindan-1-ylmethyl)-4-(3,4-dichlorophenyl)piperazine, 2H, T. pl. : 156-158oC (washed with diethyl ether).

1H NMR (CDCl3): 1,70-1,90 (m, 1H); 2,20-of 2.30 (m, 1H); of 2.45 (DD, 1H); 2,55 is 2.75 (m, 6H); 2,75-2,90 (m, 2H); 3,20 (t, 4H); 3,20-to 3.35 (m, 1H); 3,55 (broad s, 2H); 6,50 (DD, 1H); 6,70-to 6.80 (m, 2H); 6.90 to-7,00 (m, 2H); to 7.25 (d, 1H);

1-(6-Aminoindan-1-ylmethyl)-4-(3,4-methylenedioxyphenyl)piperazine, 2i in the form of oil

1-(6-Aminoindan-1-ylmethyl)-4-hydroxy-4-(3-vermeil-4-chlorophenyl)piperidine, 2K in the form of oil

1-(6-Aminoindan-1-ylmethyl)-4-(4-were)piperidine, 2l in the form of oil

1-(6-Aminoindan-1-ylmethyl)-4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine, 2m in the form of butter.

Example 3 (method "and")

1-(6-Aminoindan-1-ylmethyl)-4-(4-forfinal)piperazine, 3A.

1-Endocarpon acid (20 g), DMF (2 ml) and thionyl chloride (53 g) in dichloromethane (250 ml) is refluxed for 4 hours Volatile substance is evaporated in vacuum and the remaining thionyl chloride is removed by evaporation with toluene in vacuo. The remaining acid chloride of carboxylic acid are dissolved in dichloromethane (200 ml) and to the project for 1.5 h at room temperature the organic phase is washed successively with water and with brine and, finally, after treatment of the organic phase, as described above, receive 66 g of crude carboxamide. Purification of column chromatography on silica gel (elute with a mixture of 1:1 ethyl acetate/heptane) to give 36 g of crystalline product with so pl. 119-124oC. All of this product is dissolved in concentrated H2SO4(170 ml) at -10oC. a Mixture of 100% HNO3(6,9 g) in concentrated H2SO4(55 ml) is added dropwise under vigorous stirring below -10oC. the Mixture is stirred for a further one hour at -5oC. the Mixture was poured on ice (500 g) and add a mixture of 1:1 dichloromethane and ethyl acetate (300 ml). The organic phase is separated and washed with diluted aqueous Na2CO3(2 x 200 ml) and with brine (200 ml). Treatment of the organic phase, as described above, gives 35 g of the crude derivative of 6-nitrogen-1-carboxamide in the form of oil. The crude product is dissolved in 90% ethanol by boiling. Fe powder (31,5 g) and concentrated aqueous HCl (3.1 ml) are added sequentially in small portions during 30 minutes the resulting mixture is refluxed for another 2.5 hours Inorganic salt is filtered off while the mixture is still hot, and the ethanol is evaporated in a vacuum. Add razbavlyat indicated above, give 31 g of crystalline derivative of 6-aminoindan-1-carboxamide. So pl. 143-149oC. To a suspension of LiAlH4(10.4 g) in dry THF (400 ml) is added dropwise a solution just carboxamide in THF (400 ml). The mixture is heated at a low boil under reflux for 2.5 hours After cooling to 15oC carefully add water (40 ml) and 15% aqueous NaOH solution (10.4 ml) to destroy excess LiAlH4. The inorganic salt is filtered off and washed thoroughly with THF. The combined THF solutions evaporated, receiving 23.7 g of the named compound 3A in the form of butter.

Example 4 (method a)

1-(6-Acetaminophen-1-ylmethyl)-4-(4-forfinal)piperidine, 4A.

To a solution of 1-(6-aminoindan-1-ylmethyl)-4-(4-forfinal)piperidine 2A (6.5 g) and triethylamine (3 ml) in dichloromethane (150 ml), cooled to 0oC, is added dropwise a solution of acetylchloride (1.7 g) in dichloromethane (50 ml). The mixture is stirred for one hour at room temperature. Add water (500 ml), the organic phase is separated, washed with brine (2 x 50 ml) and then treated as above. Selected so named product was then purified column chromatography on silica gel (elute with a mixture of ethyl acetate/heptane/triethylamine 75:SS="ptx2">

1H NMR (CDCl3): 1,70-1,90 (m, 5H); 2,00-of 2.15 (m, 1H); of 2.15 (s, 3H); 2,20-of 2.30 (m, 1H); 2,35-of 2.50 (m, 2H); 2,60 (DD, 1H); 2,70-2,90 (m, 2H); 2.95 and is 3.15 (m, 2H); of 3.45 (q, 1H); to 6.95 (t, 2H); 7,05-7,25 (m, 5H); at 7.55 (s, 1H).

The appropriate method will receive the following acylamino, thioacetamide, sulfonylamino derivatives:

1-(6-Acetaminophen-1-ylmethyl)-4-(4-forfinal)piperazine 4B, so pl. 179-187oC (ethanol).

1H NMR (DMSO-d6): 1,70-of 1.85 (m, 1H); 2,00 (s, 3H); 2,10-of 2.25 (m, 1H); 2,35 (DD, 1H); 2,50-2,60 (m, 5H); 2,65-2,90 (m, 2H); 3,10 (t, 4H); 3,35 (kV, 1H); 6.90 to-7,10 (m, 5H); 7,30 (d, 1H); of 7.60 (s, 1H); of 9.75 (s, 1H).

1-(6-Acetylamino-2,3-dihydrobenzofuran-3-ylmethyl)-4-(4-forfinal)piperidine 4B, so pl. 140-142oC (washed with diethyl ether).

1H NMR (DMSO-d6): 1,55-1,75 (m, 4H); 1,95 (s, 3H); 1,90-2,05 (m, 1H); 2,05-of 2.20 (dt, 1H); 2,35 (DD, 1H); 2.40 a is 2.55 (m, 3H); 2.95 and (d, 1H); 3.15 in (d, 1H); 3,20-to 3.35 (m, 1H); of 3.45 (t, 1H); 3,55-3,70 (m, 1H); 7,05-to 7.15 (m, 3H); 7,25-7,35 (m, 3H); the 7.65 (s, 1H); 9,85 (s, 1H).

1-(6-Acetaminophen-1-ylmethyl)-4-(4-chlorophenyl)piperazine 4G, so pl. 191-194oC (acetone).

1H NMR (CDCl3): 1,80-of 1.95 (m, 1H); 2,10 (s, 3H); of 2.20 to 2.35 (m, 1H); of 2.45 (DD, 1H); 2,60-2,70 (m, 5H); 2,80-2,95 (m, 2H); 3.15 in (t, 4H); 3,35 (kV, 1H); 6,85 (d, 2H); 7,05-7,25 (m, 5H); at 7.55 (s, 1H).

1-(6-Acetaminophen-1-ylmethyl)-4-(3-chlorophenyl)piperazine 4D, so pl. 176-178oC (acetone).

1H NMR (CDCl3): 1,75-1,90 (m, 1H); 2,">

1-(6-Acetaminophen-1-ylmethyl)-4-(2-chlorophenyl)piperazine, hydrochloride, 4E, so pl. 195-203oC (acetone).

1H NMR (DMSO-d6): 2,00 (s, 3H); 2,00-of 2.15 (m, 1H); 2,30 at 2.45 (m, 1H); of 2,75 2,95 (m, 2H); 3,20-of 3.80 (m, 11H); 7,05-7,40 (m, 5H); was 7.45 (d, 1H); the 7.65 (s, 1H); 10,00 (s, 1H); 10,95 (broad s, 1H).

1-(6-Acetaminophen-1-ylmethyl)-4-(2-methoxyphenyl)piperazine, oxalate, j, so pl. 210-213oC (acetone/ethanol 1:1).

1H NMR (DMSO-d6): 1,85-2,00 (m, 1H); is 2.05 (s, 3H); 2,25-to 2.40 (m, 1H); 2,65 was 3.05 (m, 3H); of 3.25 (broad s, 8H); 3,45-of 3.60 (m, 1H); of 3.80 (s, 3H); 6,85-7,05 (m, 4H); to 7.15 (d, 1H); 7,30 (d, 1H); of 7.60 (s, 1H); for 9.90 (s, 1H).

1-(6-Acetaminophen-1-ylmethyl)-4-(4-forfinal)-1,2,3,6 - tetrahydropyridine s, so pl. 156-161oC (washed with diethyl ether).

1H NMR (CDCl3): 1,80-of 1.95 (m, 1H); of 2.15 (s, 3H); of 2.20 to 2.35 (m, 1H); 2,45-2,60 (m, 3H); 2,65-3,00 (m, 5H); 3,20 (broad s, 2H); 3.30 is is-3.45 (m, 1H); 6,05 (broad s, 1H); to 6.95 (t, 2H); to 7.15 (d, 1H); 7,15-7,25 (m, 2H); to 7.35 (DD, 2H); to 7.50 (s, 1H).

4-(4-Forfinal)-1-(6-methanesulfonylaminoethyl-1-ylmethyl) piperidine 4I, so pl. 152-155oC (diethyl ether).

1H NMR (CDCl3): 1,70-1.,90 (m, 5H); 2,00-of 2.20 (m, 2H); of 2.20 to 2.35 (m, 1H); 2.40 a-2,70 (m, 3H); of 2,75 2,95 (m, 2H); 3,00 (s, 3H); 3,10 (t, 2H); of 3.25 to 3.45 (m, 1H); 6,70 (broad s, 1H); 6.90 to-7,05 (m, 3H); 7,15-7,25 (m, 3H); to 7.35 (s, 1H).

1-(6-Cyclopropanecarbonitrile-1-ylmethyl)-4- (4-forfinal)piperidine 4K, so pl. 134-140

1-(6-Cyclopropanecarbonitrile-1-ylmethyl)-4- (4-forfinal)piperidine 4L, so pl. 177-178oC (diethyl ether).

1H NMR (CDCl3): 1,50-1,70 (m, 2H); 1.70 to 1,95 (m, 11H); 2,00-of 2.15 (m, 2H); of 2.20 to 2.35 (m, 1H); 2,35-of 2.50 (m, 2H); 2,60-of 2.75 (m, 2H); of 2,75 2,95 (m, 2H); 2.95 and is 3.15 (m, 2H); 3,35 (kV, 1H); to 6.95 (t, 2H); 7,10-7,25 (m, 5H); the 7.65 (s, 1H).

1-(6-Ethoxycarbonylmethyl-1-ylmethyl)-4-(4-forfinal)-piperidine fumarate, 4m, so pl. 191-193oC (ethanol/acetone 2:1)

1H NMR (DMSO-d6): to 1.15 (s, 3H); 1,70-1,90 (m, 5H); 2,10-of 2.30 (m, 3H); 2.40 a-2,90 (m, 5H); of 3.10-3.20 (m, 2H); of 3.25 to 3.35 (m, 1H); 4,15 (K, 1H); 6,60 (s, 1.5 H); 7,00-to 7.15 (m, 4H); to 7.35 (DD, 2H); at 7.55 (s, 1H); to 9.45 (s, 1H).

4-(4-Chlorophenyl)-1-(6-methanesulfonylaminoethyl-1-ylmethyl)- 1,2,3,6-tetrahydropyridine, oxalate 4h, so pl. 176-178oC (from ethanol).

1H NMR (DMSO-d6): 1,90-2,00 (m, 1H); 2,30-to 2.40 (m, 1H): 2,95 (s, 3H); 2,65-3,10 (m, 5H); 3,20-3,30 (m, 3H); 3,50-3,60 (m, 1H); of 3.75 (broad s, 2H); and 6.25 (broad s, 1H); 7,05 (DD, 1H); 7,15-7,25 (m, 2H); was 7.45 (d, 2H); at 7.55 (d, 2H); a 9.60 (broad s, 1H).

1-(6-Acetaminophen-1-ylmethyl)-4-(4-were)piperidine o, so pl. 173-175oC (washed with diethyl ether).

1H NMR (CDCl3): 1,70-of 1.95 (m, 5H); 2,10 (s, 3H); 2,20-of 2.30 (m, 1H); 2,30 (s, 3H); 2,35-of 2.50 (m, 2H); to 2.65 (DD, 1H); arvanil)piperazine 4P, so pl. 160-163oC (washed with diethyl ether).

1H NMR (CDCl3): 1,80-1,90 (m, 1H); 2,10 (s, 3H); 2,15-of 2.30 (m, 1H); of 2.45 (DD, 1H); 2,55-2,70 (m, 5H); 2,70-3,00 (m, 2H); 3,20 (t, 4H); 3,35 (kV, 1H); of 6.25 (DD, 1H); to 6.95 (d, 1H); 7,10 (d, 1H); then 7.20 (d, 1H); to 7.25 (d, 1H); 7,40 (broad s, 1H); of 7.60 (s, 1H).

1-(6-Acetaminophen-1-ylmethyl)-4-(4-chlorophenyl)-1,2,3,6 - tetrahydropyridine, oxalate 4P, so pl. 223-226oC (from acetone).

1H NMR (DMSO-d6): 1,80-of 1.95 (m, 1H); is 2.05 (s, 3H): 2,20-2,40 (m, 1H); 2,65-3,00 (m, 5H); 3,15-3,30 (m, 3H); 3,50-3,60 (m, 1H); 3,70 (broad s, 2H); and 6.25 (broad s, 1H); to 7.15 (d, 1H); 7,30 (d, 1H); 7,40 (d, 2H); 7,50 (d, 2H); the 7.65 (s, 1H).

1-(6-Acetaminophen-1-ylmethyl)-4-(3,4-methylenedioxyphenyl)piperazine, 4-h, so pl. 188-189oC (washed with diethyl ether).

1H NMR (CDCl3): 1,70-of 1.95 (m, 1H); of 2.15 (s, 3H); 2,15-2,30, (m, 1H); of 2.45 (DD, 1H); 2,60-2,70 (m, 5H); 2,70-2,90 (m, 2H); 3,10 (t, 4H); 3.40 in (q, 1H); to 5.85 (s, 2H); 6,45 (DD, 1H); 6,55 (d, 1H); 6,70 (d, 1H); to 7.15 (d, 1H); 7,20-7,35 (m, 2H); at 7.55 (s, 1H).

1-(6-Acetaminophen-1-ylmethyl)-4-hydroxy-4-(3-trifluoromethyl - 4-chlorophenyl)piperidine, poloxamer 4T, so pl. 163-165oC (acetone).

1H NMR (DMSO-d6): 1,65-of 1.95 (m, 3H); is 2.05 (s, 3H); 2,15-of 2.30 (m, 3H); 2,65-3,30 (m, 8H); 3,40-to 3.50 (m, 1H); to 7.15 (d, 1H); to 7.25 (d, 1H); 7,70-a 7.85 (m, 3H); 8,00 (s, 1H).

Example 5 (method a)

4-(4-Forfinal)-1-(6-methylaminoanthraquinone-1-ylmethyl) piperidine, 5A.

1H NMR (CDCl3): 1,70-1,90 (m, 5H); 2,00-of 2.15 (m, 2H); of 2.20 to 2.35 (m, 1H); 2,35 is 2.55 (m, 2H); 2,60 (DD, 1H); 2,80 (d, 3H); of 2,75 2,95 (m, 2H); 3,05 (broad d, 2H); 3,30 (kV, 1H); 4.95 points (K, 1H); 6,55 (s, 1H); 6.90 to-7,00 (m, 3H); 7,10-7,25 (m, 3H); to 7.35 (s, 1H).

In a similar way we obtain the following derivative of urea or thiourea.

1-[6-(4-Forfinal)aminocarbonylmethyl-1-ylmethyl] -4-(4-forfinal)piperidine, 5B, so pl. 235-238oC (CH2Cl2).

1H NMR (DMSO-d6): 1.55V and 1.80 (m, 5H); 2,20-of 2.30 (m, 3H); 2,35 (DD, 1H); 2,45-2,60 (m, 2H); 2,60-to 2.85 (m, 2H); 3,05 (broad d, 2H); 3,30 (kV, 1H); 7,05-to 7.15 (m, 6H); 7,25-to 7.35 (DD, 2H); 7,40 is 7.50 (DD, 2H); at 7.55 (s, 1H); and 8.50 (s, 1H); 8,65 (s, 1H).

4-(4-Forfinal)-1-(6-methylenedioxyaniline-1-ylmethyl)piperidine, 5V, so pl. 181-183oC (ethanol/acetone, 1:1).

1H NMR (DMSO-d6): 1,70-1,90 (m, 5H); 2,15-2,95 (m, 8H); 2,90 (d, 3H); 3,20-3,30 (m, 2H); 3.40 in (q, 1H); of 6.20 (s, 2H); 7,05-7,20 (m, 4H); 7,30 (DD, 2H); 7,40 (s, 1H); 7,80 (broad s, 1H); 9,60 (broad s, 1H).

1-(6-Metiram).

1H NMR (DMSO-d6): 1,70-of 1.85 (m, 1H); 2,15-of 2.30 (m, 1H); 2,60 (d, 3H); 2,70-3,00 (m, 3H); 3,20 (m, 4H); 3,35-of 3.46 (m, 1H); 5,90 (s, 2H); 6,00-6,10 (m, 1H); 6,40 (DD, 1H); 6,70 (d, 1H); to 6.80 (d, 1H); 7,05 (d, 1H); 7,10 (d, 1H); 7,45 (s, 1H); to 8.40 (s, 1H).

Example 6 (method a)

1-(6-Dimethylaminocarbonylmethyl-1-ylmethyl)-4-(4-forfinal) piperidine, 6A.

1-(6-Aminoindan-1-ylmethyl)-4-(4-forfinal)piperidine, 2A (3 g) dissolved in THF (50 ml) and add triethylamine (2 g). When 5oC is added dropwise dimethylcarbamoyl (1 g) in THF (15 ml). Upon completion of the addition the mixture is refluxed for 1.5 hours THF evaporated. Add water and extraction with dichloromethane (2 x 50 ml) and processed as described above, the combined organic phases give the crude titled product, which was purified column chromatography on silica gel (elute with 4% triethylamine in a mixture 1: 1 of ethyl acetate and heptane). The purified titled compound 6A is crystallized from diethyl ether.

Yield: 1.4 g, so pl. 141-144oC.

1H NMR (CDCl3): 1,65-to 2.55 (m, 10H); 2,70 (DD, 1H); 2,70-2,95 (m, 2H); 2.95 and was 3.05 (m, 1H); 3,05 (s, 6H); 3.15 in (broad d, 1H); 3,35 (kV, 1H); and 6.25 (s, 1H); 6,95-7,25 (m, 6H); 7,45 (s, 1H).

Similarly obtain the following derivatives of urea and thiourea:

1-(6-Dimethylaminoisopropyl is UP>H NMR (CDCl3): 1,65-of 1.95 (m, 5H); 2,00-of 2.15 (m, 2H); of 2.20 to 2.35 (m, 1H); 2,35 is 2.55 (m, 2H); 2,60 (DD, 1H); 2,70-2,90 (m, 2H); 3,05 is 3.15 (m, 2H); 3,85 (s, 6H); 3.40 in (q, 1H); 6,95-7,10 (m, 4H); 7,15-7,30 (m, 4H).

4-(4-Forfinal)-1-[6-(1-pyrrolidine)carboalumination-1 - ylmethyl] piperidine, 6V, so pl. 190-193oC (washed with diethyl ether).

1H NMR (CDCl3): 1,65-to 2.55 (m, 14H); to 2.65 (DD, 1H); 2,75-2,90 (m, 2H); 3,00 (broad d, 1H); 3.15 in (broad d, 1H); 3,35 (kV, 1H); of 3.45 (t, 4H); x 6.15 (s, 1H); to 6.95 (t, 2H); 7,00-7,10 (m, 2H); then 7.20 (DD, 2H); to 7.50 (s, 1H).

Example 7 (method a)

1-(6-Aminocarbonylmethyl-1-ylmethyl)-4-(4-forfinal) piperidine, hemifumarate, 7a.

A solution of potassium isocyanate (1.5 g) dissolved in dichloromethane (20 ml), cooled to 5oC and added dropwise a solution of triperoxonane acid (1.9 g) in dichloromethane (20 ml). To the resulting mixture is added dropwise a solution of 1-(6-aminoindan-1-ylmethyl)-4-(4-forfinal)piperidine, 2A (3 g) in dichloromethane (10 ml). Temperatures give the opportunity to rise to room temperature. After stirring for a further 3 h, the mixture was poured on ice (500 g) and add dilute aqueous NH4OH to achieve a pH > 9. The organic phase is separated and treated as described above. The crude product named purified column chromatography on silica gel (elute 4% three the oru fumaric acid (0.6 g) in ethanol (20 ml). Landed salt hemifumarate filtered and dried. Yield 1.6 g, so pl. 172-174oC.

1H NMR (DMSO-d6): 1,65-1,90 (m, 5H); of 2.10 to 2.35 (m, 3H); 2,45-2,90 (m, 5H); 3,10-of 3.25 (m, 2H); of 3.45 (q, 1H); 6,85 (s, 2H); 6,60 (s, 1H); 7,00-to 7.15 (m, 4H); 7,30 (DD, 2H); 7,45 (s, 1H); to 8.45 (s, 1H).

Example 8

5-Chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole, 8A.

A mixture of 5 chloro-1H-indole (25 g), piperidine-4-one, hydrate, hydrochloride (71 g) and potassium hydroxide (38 g) in ethanol (450 ml) boil c reflux for 6 hours After cooling, the inorganic salts filtered off and the ethanol evaporated in vacuo. To the remaining oil add salt solution (500 ml) and ethyl acetate (2 x 200 ml). The organic phase is separated and treated as described above. Yield of the crude titled product: 45g (semi-crystalline).

The appropriate method will receive the following 3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indoles.

6-Chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole, 8b.

5-fluoro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole, 8b.

Example 9

5-Chloro-3-(4-piperidinyl)-1H-indole, 9a.

The crude 5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole, 8A (26 g) was dissolved in glacial acetic acid (330 ml) and add PtO2(0.7 g). The mixture hydronaut in apparaat water and the pH adjusted to > 9 by adding dilute aqueous NH4OH. Extraction with ethyl acetate (2 x 200 ml) and processing the combined organic phases gives 19 g of the crude titled compound as a viscous oil.

The appropriate method will receive the following 3-(4-piperidinyl)-1H-indoles.

6-Chloro-3-(4-piperidinyl)-1H-indole, 9b.

5-fluoro-3-(4-piperidinyl)-1H-indole, 9b.

Example 10

3-[1-(5-Amino-2,3-dihydrobenzofuran-3-ylmethyl)piperidine-4-yl] -5-chloro-1H-indole, 10a.

5-Nitro-3-benzotiofenului acid 1B (20 g) is transformed into the corresponding acid chloride of the carboxylic acid, as in example 2. The acid chloride of the acid dissolved in THF (200 ml) and added dropwise to a solution of 5-chloro-3-(4-piperidinyl-1H-indole, 9a (19 g) and triethylamine (10 ml) in THF (200 ml) at 0-5oC. the Mixture is stirred over night at room temperature. THF is evaporated. To the remaining oil add water. Extraction with dichloromethane (2 x 100 ml) and treatment with organic extracts leads to obtain the crude amide 5-nitro-3-benzotiofenului acid that subsequently purified column chromatography on silica gel (elute with a mixture of ethyl acetate/heptane 1: 1). Yield 6.6 g, so pl. 243-250oC. All amide are dissolved in 90%and consequently in small portions over 10 minutes The resulting mixture was refluxed for another 2.5 hours Inorganic salt is filtered off and the ethanol evaporated in vacuo. Add water to the remaining oil and bring the pH to > 9 by the addition of dilute aqueous NH4OH. Extraction with dichloromethane (2 x 100 ml), and the subsequent processing of the organic phase gives 4 g of amide 5-amino-3-benzotiofenului acid in the form of oil. All this oil is dissolved in methanol (100 ml), add 0.5 g of Mg shavings. When heated to 35oC starts an exothermic reaction. Mg shavings add small portions (3 x 0.5 g), keeping the temperature below 45oC. Finally, the mixture was poured into an aqueous solution of NH4Cl and added concentrated aqueous HCl (1 ml). Extraction with dichloromethane (2 x 50 ml) and treatment with organic extracts, as described above, results in 2 g of amide 5-amino-2,3-dihydrobenzofuran-3 - carboxylic acid in the form of oil. To a suspension of LiAlH4(0.6 g) in dry THF (50 ml) is added dropwise a solution just carboxamide in THF (50 ml). The mixture is heated under low boiling under reflux for 2 hours, After cooling to 10oC water (2.4 ml) and 15% aqueous NaOH solution carefully added to destroy the excess LiAlH4. Inorganic-2,3-dihydrobenzofuran-3-ylmethyl) piperidine-4-yl] -5-chloro-1H-indole in the form of butter.

In a similar way we obtain the following derivatives of aniline:

3-[1-(5-amino-2,3-dihydrobenzofuran-3-ylmethyl)- 1,2,3,6-tetrahydropyridine-4-yl]-5-chloro-1H-indole, 10B in the form of butter;

3-[1-(5-amino-2,3-dihydrobenzofuran-3-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-5-fluoro-1H-indole, 10B in the form of butter.

The corresponding 1-(6-aminoindan-1-ylmethyl)-substituted 4-(3-intellipedia and 4-(3-indolyl)-1,2,3,6-tetrahydropyridine obtained from the corresponding 1-indocarbocyanine, which are sequentially subjected to nitration in the 6-position, restoration of microsatelites and restoration of the carbonyl group carboxamide. The sequence of reactions described in example 3. Get the following derivative indana:

3-[1-(6-Aminoindan-1-ylmethyl)piperidine-4-yl]-5-fluoro-1H-indole, 10g in the form of butter;

3-[1-(6-Aminoindan-1-ylmethyl)piperidine-4-yl]-6-chloro-1H-indole, 10D in the form of butter;

3-[1-(6-Aminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl] -5-chloro-1H-indole, 10th in the form of butter;

3-[1-(6-Aminoindan-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl] -6-chloro-1H-indole, j in the form of butter;

1-[1-(6-Aminoindan-1-ylmethyl)piperidine-4-yl]-5-chloro-1H-indole, 10a in the form of butter.

Example 11

3-[1-(5-Acetylamino-2,3-dihydrobenzofuran-3-ylmethyl)-piperidine-4-and the Dol, 10A (1.9 grams) and triethylamine (2 ml) in dichloromethane (50) ml) maintained at 0oC, is added dropwise a solution of acetylchloride (0.4 g) in dichloromethane (10 ml). The mixture is stirred at room temperature for 2 hours, water is Added and the organic phase is treated as described above. The crude titled compound purified column chromatography on silica gel (elute with 4% triethylamine in ethyl acetate). The output of 0.8, the Oxalate salt of the above compound is crystallized from a 1:1 mixture of acetone and ethanol. So pl. 168-174oC.

1H NMR (DMSO-d6): 2,00 (s, 3H); 1,95-2,15 (m, 4H); 2,85-of 3.25 (m, 5H); 3.40 in-3,50 (m, 2H); 3,55-3,70 (m, 2H); 3,90-4,00 (m, 1H); 7,00-7,40 (m, 6H); of 7.70 (s, 1H); of 7.70 (broad s, 2H); 9,95 (broad s, 1H); 11,10 (broad s, 1H).

In a similar way we obtain the following derivatives of indole.

3-[1-(5-Acetylamino-2,3-dihydrobenzofuran-3-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl]-5-chloro-1H-indole, oxalate, 11b. so pl. 214-216oC (ethanol).

1H NMR (DMSO-d6): 2,00 (s, 3H); to 2.75 (broad s, 2H); 2.95 and is 3.40 (m, 5H); 3,50-of 3.80 (m, 3H); 3,95 (broad s, 1H); x 6.15 (broad s, 1H); to 7.15 (t, 2H); to 7.25 (d, 1H); was 7.45 (d, 1H); of 7.60 (s, 1H); the 7.65 (s, 1H); a 7.85 (s, 1H); 9,95 (s, 1H); 11,50 (s, 1H).

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl] -5-fluoro - 1H-indole, oxalate, 11V, so pl. 145-149oC (acetone).(d, 1H); 7,40 (DD, 1H); was 7.45 (DD, 1H); of 7.70 (s, 1H); 9,95 (s, 1H); 11,05 (s, 1H).

3-[1-(5-Acetylamino-2,3-dihydrobenzofuran-3-ylmethyl)-1,2,3,6 - tetrahydropyridine-4-yl]-5-fluoro-1H-indole, oxalate, 11g, so pl. 155-165oC (acetone).

1H NMR (DMSO-d6): 2,00 (s, 3H); to 2.75 (broad s, 2H); 2.95 and is-3.45 (m, 5H); 3,50-of 3.80 (m, 3H); 3,95 (broad s, 1H); x 6.15 (broad s, 1H); to 6.95 (t, 1H); then 7.20 (d, 1H); 7,30 (d, 1H); 7,45 (m, 1H); 7,55-of 7.70 (m, 3H); 9,95 (s, 1H); of 11.45 (s, 1H).

3-[1-(6-Acetaminophen-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl] -6-chloro-1H-indole, oxalate hemihydrate 11, so pl. 151-164oC (acetone).

1H NMR (DMSO-d6): 1,95-2,10 (m, 1H); 2,00 (s, 3H); 2,30 at 2.45 (m, 1H); 2,70-2,90 (m, 4H); 3.15 in (t, 1H): 3,35-to 3.50 (m, 3H); 3,55-3,70 (m, 1H); 3,95 (broad s, 2H); x 6.15 (s, 1H); 7,05 (DD, 1H); to 7.15 (d, 1H); to 7.25 (d, 1H); was 7.45 (d, 1H); at 7.55 (d, 1H); of 7.60 (s, 1H); a 7.85 (d, 1H); 9,95 (s, 1H); for 11.55 (s, 1H).

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl] -6-chloro - 1H-indole, oxalate, 11th, so pl. 122-130oC (acetone).

1H NMR (DMSO-d6): 1,90-of 2.15 (m, 6H); 2,00 (s, 3H); 2,25-to 2.40 (m, 1H); 2,70-3,10 (m, 6H); 3,35 (d, 1H); 3.45 points-of 3.65 (m, 2H); 7,00 (DD, 1H); 7,15-7,25 (m, 2H); 7,30 (d, 1H); 7,40 (s, 1H); 7,60-of 7.70 (m, 2H); for 9.90 (s, 1H); 11,05 (c, 1H).

3-[1-(6-Acetaminophen-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl] -5-chloro-1H-indole, oxalate g, so pl. 220-223oC (acetone/ethanol 5:1).

1H NMR (DMSO-d6): 1,95-2,10 (m, 1H); 2,00 (s, 3H); 2,30 at 2.45 (m, 1H); 2,70-2,95 (m, 4H); 11,50 (s, 1H).

3-[1-(6-Acetaminophen-1-ylmethyl)piperidine-4-yl]-5-chloro-1H-indole, s, so pl. 189-191oC (ethyl acetate).

1H NMR (CDCl3): 1,80-2,00 (m, 1H); 2.05 is-is 2.40 (m, 7H); of 2.20 (s, 3H); 2.50 each (DD, 1H); to 2.65 (DD, 1H); 2,80-2,95 (m, 2H); 3.15 in (broad t, 2H); 3,35 (kV, 1H); 4,20-4,30 (m, 1H); of 6.45 (d, 1H); 7,20-7,35 (m, 4H); 7,30-7,40 (m, 2H); of 7.60 (d, 1H); of 7.70 (broad s, 1H).

Example 12 (method e)

4-(4-Forfinal)-1-[6-(1-pyrrolidin-2-IMT)indan-1-ylmethyl] piperidine fumarate, 12A.

To a solution of 1-(6-aminoindan-1-ylmethyl)-4-(4-forfinal)piperidine, 2A (3 g) and triethylamine (2 ml) in dichloromethane (50 ml) at 0oC is added dropwise a solution of acid chloride of 4-harpalani acid (1.4 g) in dichloromethane (15 ml). Finally the mixture is stirred for 5 h at room temperature. Add ice dilute aqueous NaOH solution and the organic phase is successively processed as described above. Crude 1-[6-(4-chlorotoluene)indan-1-ylmethyl] -4-(4-forfinal)piperidine purified column chromatography on silica gel (elute with 4% triethylamine in a 1:3 mixture of ethyl acetate and heptane). The yield of crystalline product: 2.4 g with so pl. 129-135oC (washed with diethyl ether). The solution selected thus derived 4-chlorobutanol (1 g) and tert-butoxide potassium (0.4 g) in water NH4OH and dichloromethane and the organic phase is then treated as described above. The remaining oil (1 g) dissolved in acetone (10 ml) and added to a hot solution of fumaric acid (0.3 g) in ethanol (15 ml). After cooling in the refrigerator over night landed fumaric salt is filtered off and dried. Yield 0.7 g, so pl. 177-179oC.

1H NMR (DMSO-d6): 1,70-1,90 (m, 5H); 2,10 (q, 2H); 2,20-2,40 (m, 3H); 2,45-to 2.65 (m, 4H); 2,70-2,95 (m, 3H); 3,20 (broad t, 2H); 3.40 in (q, 1H); 3,70-3,90 (m, 2H); 6,60 (s, 2H); to 7.15 (t, 2H); then 7.20 (d, 1H); 7,30 (DD, 2H); 7,40 (DD, 1H); the 7.65 (s, 1H).

Example 13

(+)-6-Nitro-1-indocaribbean acid, 13A.

A solution of 6-nitro-1-intakebadboy acid (1a) (96 g) and brucine hydrate (200 g) is heated in acetone (1.25 l) until then, until you get a clear solution. The solution is stored overnight in the refrigerator. Landed brucine salt is filtered off. Output: 159,1, by Recrystallization from 2-propanol obtain 103 g of pure brucine salt of (+)-6-Nitro-1-intakebadboy acid. Salt is dissolved in water and add dilute hydrochloric acid. The diethyl ether extraction and processing, as described above, gives to 29.8 g of the named compound 13A. So pl. 92-94oC []D= +83,3o(C = 1, methanol).

Example 14

(+)-1-(6-Acetylaminobenzoic acid, 13A according to the methods in examples 2 and 4. So pl. 145-146oC.

1H NMR (CDCl3): 1,70-1,90 (m, 5H); 2,00-of 2.15 (m, 1H); of 2.15 (s, 3H); 2,20-of 2.30 (m, 1H); 2,35-of 2.50 (m, 2H); 2,60 (DD, 1H); 2,70-2,90 (m, 2H); 2.95 and is 3.15 (m, 2H); of 3.45 (q, 1H); to 6.95 (t, 2H); 7,05-7,25 (m, 5H); at 7.55 (s, 1H). []D= +24,3o(c = 1, methanol).

Example 15

3-[1-(6-Acetaminophen-1-ylmethyl)-1,2,3,6-tetrahydropyridine-4-yl] -6-chloro-1-methyl-1H-indole, 15A.

3-[1-(6-Nitrogen-1-ylcarbonyl)-1,2,3,6-tetrahydropyridine-4-yl] -6-chloro-1H-indole (23 g), obtained according to the method in example 10, was dissolved in dry DMF (300 ml) and added dropwise tert-piperonyl potassium (7,3 g) in 10oC. are added dropwise within 30 min methyliodide (23,2 g). The mixture is left overnight at room temperature. Add water and diethyl ether and the organic phase is treated as described above. The crude N-methylated indole purified column chromatography on silica gel (elute with a mixture 1:1 of ethyl acetate and heptane). The output of 2.75, Recovery nitro Fe in 90% acidified ethanol, followed by reduction of the carbonyl group of amide and, finally, acylation of aniline groups according to the method in examples 10 and 11 give the named compound 15A. So pl. 189-193oC, washed with diethyl ether).

1H NMR (CDCl3is rocky with, 1H); 7,00 (s, 1H); 7,10 (DD, 1H); to 7.15 (d, 1H); 7,20-7,30 (m, 3H); to 7.50 (s, 1H); 7,80 (d, 1H).

Catalytic hydrogenation of compounds 15A according to the method in example 9 gives:

3-[1-(6-acetaminophen-1-ylmethyl)piperidine-4-yl] -6-chloro-1-methyl-1H-indole, oxalate 15B, so pl. 202-205 areoC (acetone).

1H NMR (DMSO-d6): 1,90-of 2.15 (m, 5H); 2,00 (s, 3H); 2,30-to 2.40 (m, 1H); 2,70 is 3.15 (m, 6H); 3,35 (d, 1H); 3,50-3,70 (m, 2H); of 3.75 (s, 3H); 7,00 (DD, 1H); 7,10-7,30 (m, 3H); at 7.55 (d, 1H); the 7.65 (s, 1H); the 7.65 (d, 1H); 9,90 (s, 1H).

Example 16 (method f)

4-(4-Forfinal)-1-(6-methylaminoethanol-1-ylmethyl)piperidine, 1,5 oxalate 16A.

To a solution of 4-(4-forfinal)-1-(6-methylaminoethanol-1-ylmethyl)piperidine, 2A (4 g) and triethylamine (3 ml) in dichloromethane is added dropwise at 0-5oC solution of ethyl chloroformate (1.5 g) in dichloromethane (15 ml). The mixture is stirred at room temperature for 2 h and poured into saturated saline solution (500 ml). The organic phase is separated and treated as described previously. The yield of ethyl carbamate in the form of oil-in 4.3, To a suspension of LiAlH4(1.2 g) in dry diethyl ether (20 ml) at 5oC is added dropwise a solution of all of ethyl carbamate in dry THF (25 ml). The mixture is stirred for a further one hour at 5oC and then at room temperature for 5 hours, the Excess LiAlH4s salt is filtered off and the solvents evaporated in vacuo. The crude titled compound purified column chromatography on silica gel (elute with a mixture of 1:1 heptane and ethyl acetate). Yield 1.5 g in the form of oil, 1.5 g of oxalate salt 16A crystallized from 1:1-mixture of acetone and ethanol. So pl. 84-86oC.

1H NMR (DMSO-d6): 1,75-2,10 (m, 5H); 2,20-2,40 (m, 1H); 2,60 (s, 3H); 2,60-2,90 (m, 3H); 3.00 and is 3.15 (m, 3H); 3,40-of 3.80 (m, 4H); 6,40 (DD, 1H); 6,50 (d, 1H); to 6.95 (d, 1H); to 7.15 (t, 2H); to 7.35 (DD, 2H).

Example 17

5-Chloro-1-(4-piperidinyl)-1H-indole, 17a.

To a solution of 5-chloro-1H-indole (20 g) in N-methyl-2-pyrrolidone (450 ml) is added potassium carbonate (82 g), CuBr (7.5 g) and Cu bronze (3 g). The mixture is heated to 140oC and (add) 4-bromopyridin, hydrochloride (22 g). The mixture is heated for 1 h at 150oC and add another 4-bromopyridin, hydrochloride (15 g). This procedure is repeated twice and the mixture is finally heated overnight at 150oC. After cooling, the deposited inorganic salts filtered off. Add water (2 l), ethyl acetate (500 ml) and dilute aqueous ammonia (500 ml). Nerastvorimaya substance is filtered off and discarded. The organic phase is treated as indicated previously, receiving 34 g of 5-chloro-1-(4-pyridyl)-1H-indole with so pl. 153 to 155oC. the Entire product without further purification was dissolved in dimethoxyethane (350 ml) at 60-70ooC. All pyridinium salt is suspended in ethanol (450 ml) and water (50 ml). Added NaBH4(16 g) in small portions over 1.5 h with stirring. After stirring for a further 1.5 h the greater part of the ethanol is evaporated in vacuum at room temperature. Add ethyl acetate (300 ml) and water (500 ml) and the organic phase is treated as described previously. Output 5-chloro-1-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole; 17 g in the form of oil. To a solution of the derived tetrahydropyridine (15 g) in glacial acetic acid (150 ml) is added PtO2and the mixture hydronaut in a Parr apparatus at 3 ATM for 7 hours the Catalyst is filtered off, most of the acetic acid is evaporated in a vacuum and, finally, the crude 5-chloro-1-(1-methyl-4-piperidinyl)-1H-indole extracted with ethyl acetate from the alkaline aqueous solution. Exit 13 g in the form of oil. Any remaining water in the crude product (10 g) is removed by distillation with toluene. Finally, the oil is dissolved in 1,1,1-trichloroethane (200 ml). While boiling under reflux is added dropwise 2,2,2 - trihloretilamina (6.5 ml), dissolved in 1,1,1-trichloroethane (20 ml). The mixture is refluxed for 2 hours, add sodium carbonate (2 g) and continue g crude derived carbamate. To a solution of carbamate (6 g) in 90% aqueous acetic acid (110 ml) is added finely ground powder Zn (12 g) in small portions at 45oC for 1 h the Mixture is heated for another hour at 50oC. Zn-salt is filtered off and most of the acetic acid is evaporated in a vacuum. The remaining oil is dissolved in water (200 ml) and ethyl acetate (200 ml). the pH of the aqueous phase is brought to pH > 9 by the addition of dilute aqueous ammonia. The organic phase is finally processed, as indicated previously, obtaining 3.5 g of the crude titled product 17A in the form of oil, which is used without further purification for connection s.

Example 18

1-(6-Acetaminophen-1-ylmethyl)-4-atomic charges-4-(3-trifluoromethyl-4-chlorophenyl)piperidine, 18a.

To a solution of 1-(6-aminoindan-1-ylmethyl)-4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl) piperidine, 2K, (6.7 g) and triethylamine (4 ml) in dichloromethane (100 ml) is added dropwise at 0-5oC solution chloroacetanilide (2.6 ml) in dichloromethane (50 ml). The mixture is stirred over night at room temperature. Add water and bring the pH to > 9. The organic phase is separated and treated as described previously. The crude product is purified column chromatography on silica gel (elute 4% is indocarbocyanine-1-ylmethyl)-piperidine-4-yl] -1H-indole, 19a.

To a solution of 1-[1-(6-aminoindan-1-ylmethyl)piperidine-4-yl]-5-chloro-1H-indole, 108 (0.9 g) in dichloromethane (10 ml) was added methyl isocyanate (0.2 ml). The mixture is stirred at room temperature for 16 hours Dichloromethane is evaporated. After adding ethyl acetate named connection 19a crystallized. The crystalline product is filtered and dried over night at 80oC in vacuum. The output of 0.6, So pl. 193-195oC.

1H NMR (DMSO-d6): 1,70-of 1.85 (m, 1H); 1,90 to 2.35 (m, 7H); 2,35-to 2.85 (m, 4H); to 2.65 (d, 3H); 3,05 is 3.15 (m, 2H), 3,25, (kV, 1H); 4,35 is 4.45 (m, 1H); 5,95 (dt, 1H); of 6.45 (d, 1H); 7,00-7,20 (m, 3H); 7,50-the 7.65 (m, 4H); 8,35 (s, 1H).

Pharmacological tests

Compounds of the invention were tested in accordance with the well known and reliable methods. Well-known MDL100,907, an antagonist of 5-HT2Aand well-known buspirone, an antagonist of 5-HT1Aincluded in the tests as the reference compounds. Tests were carried out as described below and the results are given in the table.

Inhibition of 3H-8-OH-DPAT binding to serotonin 5-HT1Areceptors in the brain of the rat in vitro.

Using this method, determine the in vitro inhibition of drug binding to 5-HT1Aagonist3H-8-OH-DPAT (1 nm) with 5m with affinity for 5-HT1Athe receptor. The test is carried out as described by Hyttel et al., Drug. Dev. Res. 1988, 15-389-404.

Inhibition of binding3H-Ketanserina with 5-HT2receptors in the cerebral cortex of the rat in vitro.

Using this method, determine the in vitro inhibition of drug binding3H-Ketanserina (0.5 nm) 5-HT2Areceptors in the membranes of rats. This method is described by J. Hyttel, Pharmacology & Toxicology, 61, 126-129, 1987.

In addition to the above tests, the compounds of this invention were tested in respect of affinity for the dopamine D2the receptor by determining their ability to inhibit binding3H-spiroperidol with D2receptors on the way Hyttel et al., J. Neurochem., 1985, 44, 1615. In addition, they were tested for their inhibitory effect on 5-HT re-uptake by measuring their ability to inhibit the absorption of3H-serotonin in Siapakah brain of the rat in vitro according to the method described by Hyttel and Larsen, Acta Pharmacol. Tox., 1985, 56, suppl. 1, 146-153.

In General, the compounds of this invention, as installed, strongly inhibit both the binding of the treated 8-hydroxy-2-dipropylenetriamine (8-OH-DPAT) and 5-HT1Areceptors and binding3H-ketanserina is Ceptor, 5-HT1Aor 5-HT2A. In addition to these impacts, a number of compounds, as is proved, have the additional advantage of a strong inhibitory effect of 5-HT reuptake. So, for example, compounds in which R1is acetyl, R2is H and Ar is 3-indolyl, substituted by halogen in the 6-position or 5-position, or compounds in which Ar is phenyl, substituted Cl in the 4-position, exhibit IC50values in the lower nanomolar region (1-65 nm).

In accordance with these compounds according to the invention are considered useful for the treatment of positive and negative symptoms of schizophrenia, other psychoses, state of fear, such as diseases caused by fear, panic, and obsessive compulsive disorders, depression, alcohol abuse, diseases associated with motivational control, aggression, side effects caused by conventional antipsychotic means, States, coronary artery disease, migraine, dementia and cardiovascular disorders, and to improve sleep.

Examples of preparation of medicines.

Pharmaceutical formulations of the invention m by mixing the active ingredient with ordinary adjuvants and/or diluents and then pressing the mixture in a conventional teletrauma car. Examples of adjuvants or diluents are: corn starch, potato starch, talc, magnesium stearate, gelatine, lactose, gums, etc. Some other adjuvants or additives commonly used for such purposes, such as colorants, perfumes, preservatives, etc. may be used provided that they are compatible with the active ingredients.

Injectable solutions can be obtained by dissolving the active ingredient and possible additives in a part of the solution for injection, preferably sterile water, bringing the solution to the desired volume, sterilization of the solution and filling in suitable ampoules or vials. Can be added to any suitable additive usually used in this field, such as toning agents, preservatives, antoxidant, etc.

Typical examples of recipes formulations of the invention are as follows.

1) Tablets containing 5.0 mg of compound 4A in the calculation of the free base:

Compound 4A - 5.0 mg

Lactose 60 mg

Corn starch 30 mg

Hydroxypropylcellulose - 2.4 mg

Microcrystalline cellulose is 19.2 mg

Sodium croscamellose type a - 2.4 mg

Magnesium stearate - 0.84 mg

2) Mal - 46,9 mg

Corn starch - 23,5 mg

Povidone - 1.8 mg

Microcrystalline cellulose is 14.4 mg

Sodium croscamellose type a - 1.8 mg

Magnesium stearate - 0,63 mg

3) Syrup, containing in 1 ml:

Compound 11e - 25 mg

Sorbitol 500 mg

Hydroxypropylcellulose 15 mg

Glycerin 50 mg

Methyl paraben 1 mg

Propyl-paraben 0.1 mg

Ethanol - 0,005 ml

Odorant - 0.05 mg

Saccharin carbonated 0.5 mg

Water Up to 1 ml

4) Solution for injection containing per 1 ml:

Compound 4a - 0.5 mg

Sorbitol - 5.1 mg

Acetic acid - 0.08 mg

Water for injection Up to 1 MAV

1. Derivatives of 4-aryl-1-(indenmity or dihydrobenzofuranyl)-piperidine, tetrahydropyridine or piperazine of General formula I

< / BR>
where one of X and Y is CH2and the other is selected from the group including CH2and S;

the dotted line emanating from Z indicates an optional bond; when the bond is not specified,

Z represents N, CH or SON, and the OH group can be optionally etherification, and when the link is specified, Z represents S;

Ar is phenyl, 1-indolyl, 2-indolyl, 3-indolyl, 1-indole-2-IMT, 3-indole-2-IMT, 1-naphthyl or 2-naphthyl, each optionally is UP>1
represents hydrogen, lower alkyl, acyl, lower alkylsulfonyl;

R1is the group R9VCO, where V is O and R9represents lower alkyl, cycloalkyl, cycloalkyl-lower alkyl or phenyl, or

R1is the group R10R11NCO or R10R11NCS where R10and R11are, independently, hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl or phenyl, or R10and R11together with N-atom to which they are attached, form pyrrolidinyl group;

R2represents hydrogen, lower alkyl;

or R1and R2together with N-atom to which they are attached, form a group

< / BR>
where Q is C=O or CH2;

T represents NH or CH2;

m = 1-4, inclusive;

R3- R5represent, independently, hydrogen, halogen, lower alkyl, cycloalkyl-lower alkyl or nitro;

R6and R7are each hydrogen or lower alkyl or they are connected together to form a 3-clanlogo carbocyclic ring;

R8is hydrogen or lower alkyl,

moreover, any present alkyl, cycloalkyl or cycloalkenyl group is optional for the and R11optionally substituted with halogen, lower alkyl, lower alkoxy,

and its pharmaceutically acceptable salt accession acid.

2. Connection on p. 1, wherein X is CH2or S and Y is CH2.

3. Connection under item 1 or 2, wherein R1represents acyl, lower alkyl group, R10R11NCO or R10R11NCS-, where R10is hydrogen, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl or phenyl and R11is hydrogen or lower alkyl, R10and R11together with N-atom to which they are bound, form pyrrolidinyloxy group.

4. Connection on p. 3, wherein R1represents acetyl, methylaminomethyl, methylenedioxybenzyl, dimethylaminoethyl, dimethylaminostyryl, methylsulphonyl, aminocarbonyl, cyclopropanecarbonyl, methyl, pyrrolidinylcarbonyl or 4-ftorpolimernoj.

5. The compound according to any one of paragraphs.1-4, wherein R2is hydrogen or lower alkyl.

6. Connection under item 1 or 2, wherein R1and R2linked together, form a 5-7-membered unsubstituted lactam ring or pyrrolidinyl.

6- R8all are hydrogen.

8. The compound according to any one of paragraphs.1-4, characterized in that Ar represents phenyl, 3-indolyl, 1-indolyl or phenyl, 3-indolyl, 1-indolyl, substituted with halogen.

9. The compound according to any one of paragraphs. 1-5 and 7-8, wherein R1represents acetyl, R2is H and Ar is indolyl or phenyl, substituted by halogen.

10. Connection on p. 9, wherein Ar is 3-indolyl, substituted 5 - or 6-position by chlorine or fluorine, or phenyl substituted in the 4-position by chlorine.

11. The pharmaceutical composition exerting an action on the Central serotonergic receptors, characterized in that it contains a compound according to any one of paragraphs.1-10 in therapeutically effective amounts in combination with one or more pharmaceutically acceptable carriers or diluents.

 

Same patents:

The invention relates to new pyrimidine derivative of the formula (I-1) and (I-2), where R1and R5that may be the same or different, independently represent hydrogen or C1-C3alkyl group or, taken together, form cyclopentene or tsiklogeksilnogo ring; a represents a group of formula (II) in which R1and R2represent independently from each other hydrogen or C1-C3alkyl group, and R3represents hydrogen, C1-C3alkyl group or halogen; B is 1-(substituted) -1,2,3,4-tetrahydroisoquinoline-2-yl of the formula (III-1) or 7-(substituted) -4,5,6,7-tetrahydrothieno(2,3-C)-pyridine-6-yl of the formula (III-2), where R6is hydrogen or C1-C3alkyl group, and their pharmaceutically acceptable salts, which have excellent antisecretory activity, to pharmaceutical compositions that contain the specified active ingredient, and a new intermediate compounds and processes for their preparation

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to new 2-imidazolin-2-yl)thieno - foroperational compounds, to intermediates used to obtain these compounds, and the way of dealing with these compounds with unwanted annual and perennial plants, namely 6-(2-imidazolin-2-yl)thieno - and furo[2,3-b] and 5-(2-imidazolin-2-yl)thieno - and furo[3,2-b]the pyridine compounds and the corresponding 2,3-dihydrothieno and 2,3-dihydropyrimidine with structural formulas (Ia) and (Ib):

< / BR>
whererepresents a single or double bond; R1represents a C1-C4alkyl; R2represents a C1-C4alkyl or C3-C6cycloalkyl; R1and R2together with the carbon atom to which they are joined, can form WITH3-C6cycloalkyl, optionally substituted stands; And represents СООR3CHO, CH2OH, COCH2HE, CONHCH2CH2OH, CONHOH or

R3hydrogen, C1-C12alkyl, which can be broken od is alkoxy, halogen, hydroxyl, C3-C6cycloalkyl, benzyloxy, fullam, phenyl, furfuryl, galopera, lower alkylphenyl, lower alkoxyphenyl, nitrophenyl, carboxyla, lower alkoxycarbonyl, cyano, C1-C4alkylthio or three (lower) alkylammonium; C3-C6alkenyl, optionally substituted by one of the following groups:1-C3alkoxy, phenyl, halogen or two WITH1-C3alkoxygroup or two halogen groups; C3-C6cyclooctyl, optionally substituted by one or two1-C3alkyl groups; C3-C10quinil, optionally substituted by phenyl, halogen or CH2IT; or the cation of an alkali metal or alkaline-earth metal (CA, BA) manganese, copper, iron, ammonium, or organic ammonium; RWITHand RDrepresent N or CH3; Represents N; COR4or SO2R5provided that when a represents a COR4or SO2R5and is a СOOR3the radical R3cannot be hydrogen or a salt-forming cation; R4represents a C1-C11alkyl, chloromethyl or phenyl, optionally substituted A5 alkyl or phenyl, optionally substituted one metalno, chloro - or nitro-group; W represents 0 or S; X represents 0, S or whenis a single bond, the group S 0; Y and Y', Z and Z' represent hydrogen, halogen, C1-C6alkyl, C1-C4hydroxy (lower) alkyl, C1-C6alkoxy, C1-C6acyloxy, benzoyloxy, optionally substituted by one or two1-C4alkyl, C1-C4alkoxygroup or halogen; C1-C4alkylthio, phenoxy,1-C4haloalkyl,1-C4haloalkoxy, nitro, cyano, C1-C4alkylamino,1-C4dialkylamino,1-C4alkylsulfonyl or phenyl, optionally substituted by one or more1-C4the alkyl, C1-C4alkoxy, halogen, or any combination of these two groups, where Y and Z are the same provided that Y and Z represent hydrogen, halogen, alkyl or alkoxy, and when Y and Y' or Z and Z' are the same group they are hydrogen or alkyl; and taken together, Y and Z form a ring in which YZ has the structural formula -(CH2)n- where n являе/www.fips.ru/fullimg/rupat2/19962/004.dwl/2058313-8t.gif" ALIGN="ABSMIDDLE">-=where L, M, Q, and R7each represent hydrogen, halogen, nitro, C1-C4lower alkyl, C1-C4lower alkoxy, methoxy, phenyl, phenoxy, provided that only one of the radicals L, M, Q or R7may have a value different from hydrogen, halogen, C1-C4the alkyl or C1-C4alkoxy; or a pyridine-N-oxides, when W represents oxygen or sulfur and a is COOR3; and when R1and R2not the same, the optical isomers of these compounds, except for the case when R3represents a salt-forming cation, their salts kislotoustoichivam

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(I) with an antidepressant

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< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

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R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

The invention relates to new derivatives of arylsulfonamides having, in particular, valuable pharmacological properties, more particularly to a derivative of arylsulfonamides General formula (I)

< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

R2a hydrogen atom, methyl,

R3pyridyl,

R4and R5hydrogen atoms or together denote a carbon-uglerodnoi communication,

R6hydroxyl, methoxyl,

A group of the formula

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene group

X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

their mixtures, isomers or individual isomers and physiologically tolerated additive salts with bases, if R6means hydroxyl, which

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

The invention relates to the field of organic chemistry and relates to a method of obtaining new derivatives of imidazole
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