Derivatives of piperazine and piperidine derivatives and method of production thereof

 

(57) Abstract:

The invention relates to a derivative of piperazine and piperidine derivatives of General formula (a) where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S; R1denotes hydrogen or fluorine; R2denotes oxoprop or1-4alkyl and p = 0 or 1; Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon; R3and R4independently of one another denote hydrogen or C1-4alkyl; n = 1 or 2; R5stands WITH1-4alkoxy, C1-4alkyl, halogen or hydroxy, and q = 0 or 1; Y represents phenyl, substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylamino-carbonyl; furyl or thienyl and their salts. It also describes the method of obtaining these compounds. The claimed compounds possess a high degree of affinity to the receptors of dopamine D2and receptors serotonin 5-HT1A. 2 S. and 4 C. p. F.-ly, 6 PL.

The invention relates to a group of new compounds, piperazine and piperidine derivatives, which have titbits which denotes a heterocyclic group with 5-7 atoms in the ring, containing 1-2 heteroatoms from the group O, N and S;

R1denotes hydrogen or fluorine;

R2represents C1-4-alkyl or oxoprop and p is 0, 1 or 2;

Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon;

R3and R4independently represent hydrogen or C1-4alkyl;

n is 1 or 2;

R5denotes halogen, hydroxy, C1-4alkoxy or C1-4alkyl, and q is 0, 1,.

Y represents phenyl which may be substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylaminocarbonyl; or furyl, or thienyl and their salts possess interesting pharmacological properties.

Preferred compounds according to this invention are the compounds of formula (a), in which A together with the phenyl group denotes a group of formula b-m

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in which R1, (R2)p, R3, R4, (R5)q, Y and Z have the abovementioned meanings and n is equal to 1, and their salts.

Especially preferred are the compounds of formula (a), in which A together is, Y represents phenyl which may be substituted as mentioned above, n is 1, R3and R4denote hydrogen, R5denotes a hydroxy, methoxy or halogen, q is 0 or 1, Z represents nitrogen, and their salts.

Even more preferred are the compounds of formula (a), in which A together with the phenyl group is a group of the formula (I), substituted in heteroclite exography, q is 0, and Y denotes phenyl, and their salts.

From European patent N 0650964 it is known that compounds of the formula

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where R0represents C1-4alkyl which may be substituted in the phenyl group, and/or heterocyclic group, and/or piperazino group, affect the Central nervous system by binding to receptors 5-HT. These compounds, in particular, are associated with subtypes of receptors 5-HT, i.e. receptors 5-HT1Aand 5-HT1D.

Now unexpectedly found that compounds of this invention show a high degree of affinity to the receptors of dopamine D2and receptors serotonin 5-HT1A(in the range of pKi 7,0-9,5 to receptors of both types). This combination of properties useful for the treatment of schizophrenia and other psychotic the MOU, negative symptoms and deficits in cognitive abilities).

These compounds exhibit different activity as partial agonists or antagonists at the receptor dopamine D2D3and D4. Some compounds have an impact on the dopamine receptors, such agonists, however, they have a strong antagonistic effect on caused by apomorphine behavior of climbing in mice (values ED50< 1 mg/kg by oral administration). These compounds have different effects as agonists of the receptors 5-HT1Aand cause signs of a behavioral syndrome, characteristic of serotinin, with varying degrees of intensity.

These compounds are active in therapeutic models that are sensitive to applied in the clinic antipsychotic agents (for example, when treating of the reaction due to avoidance; Van der Heyden & Bradford, Behav. Brain Res. , 1988, 31: 61-67), antidepressants (for example, when differential amplification slow reactions; Van Hest et al. , Psychopharmacology, 1992, 107: 474-479) and anxiolytics (e.g., suppression of stress-induced reactions enhance voice; Van der Poel et al. , Psychopharmacology, 1989, 97: 147-148).

Unlike used in clinics is to provide catalepsy in rodents, and therefore, probably cause less extrapyramidal side effects than existing antipsychotics.

Inherent in these compounds agonism to the receptors 5-HT1Ayou can explain that they have a reduced tendency to cause extrapyramidal and therapeutic effects observed in behavioral models, sensitive, or antidepressants or anxiolytics.

These compounds probably are of value for the treatment of disorders or diseases of the Central nervous system caused by disturbances in the dopaminergic or serotonergically systems, such as Parkinson's disease, aggression, fear, autism, vertigo, depression, disorders of cognitive ability or memory, and particularly schizophrenia and other psychotic disorders.

Suitable acids with which the compounds can form pharmaceutically acceptable salt accession acids are, for example, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, partywall the ways to produce drugs for injection with the use of auxiliary substances, such as liquid and solid media.

Compounds according to this invention can be obtained by using some of the following methods (A-E). Piperazines, homopiperazine and piperidine used in the implementation of these methods are denoted by I-H to the nineteenth-H, where Roman numerals from I to XIX lists the following groups:

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Piperidine XVIII-H and nineteenth-H (Fig. A1) used in the preparation of the compounds of this invention are synthesized according to the procedure similar to that described in WO 94-GB 1507.

Synthesis of piperazines (Fig. A1) used in the preparation of the compounds according to this invention, is described in ER, with the exception of compounds XI-H, XIII-H and XV-H (see below).

Homopiperazin XI-H and piperazines XIII-H and XV-H are novel compounds, and methods for their preparation are given below (scheme A. i - A. (iii).

The way to obtain compound XI-H (see diagram A. i presented at the end of the description).

The method of obtaining compounds XIII-H (see figure A. ii, presented at the end of the description).

Stage 1-3 (scheme A. ii)

7-Nitroindole described With. M Parmerter and others (S. M. Parmerter et al. , J. Am. Chem. Soc. 80, (1958), 4621-2). Stage 1, 2 and 3 are performed analogously to synthesis, predstavlennuyu at the end of the description).

Stages 1-3 of scheme A. i and stage 1 scheme A. iii is described in detail in the examples, and procedures stage 2 and 3 of scheme A. iii are similar to those described in the European patent EPO 189612.

The hydrogen atom of the fragment of the N-H compounds I-H XIX-H can be replaced by a group Q five different chemical methods (A, B, C, D and E, see below), the implementation of which receive connections of the invention. Figure A2 shows the values of the groups Q1 through Q34 (see end of description)

Method of synthesis of A

Compounds A1-A14 and A16-A28 received in accordance with the method of synthesis is shown in figure A1 (see the end of the description). Piperazine (compound I-H VI-H and VIII-H XVII-H) were subjected to interaction with the compound Q-X (X= Cl, Br, OMs) in acetonitrile with Et(i-Pr)2N acting as a base, and in some cases added K1. Instead of Et(iPr)2N you can use Et3N

The following methods of synthesis Is not limited to the obtaining of piperazines, they can also be used to obtain piperidinol.

Method for the synthesis of B

These compounds can also be obtained in accordance with the method of synthesis depicted in scheme B1 (see the end of the description). Piperazine I-N were subjected to interaction with 2-phenylphenol and formaldehyde in EtOH.

The si method the Scriptures). Phenylpiperazine were subjected to interaction with multiple anhydrides measuremenu vinylbenzoic acid, yielding the corresponding amides. Amides were then recovered in connection C1-C4 using LiAlH4.

Connection C2 and C3 were obtained as shown in scheme C2 (see the end of the description).

Method for the synthesis of D

Connection D1-D18 and D21-D23 was obtained in accordance with the method of synthesis depicted in scheme D1 (see the end of the description). Arylboronic acid were subjected to interaction with the aromatic bromide in alkaline conditions in the presence of catalytic amount of Pd(PPh3)4. As a result of implementation of the so-called reaction "Suzuki" received final products D with the carbon-carbon bond.

Connection D19 and D20 was obtained in accordance with a modified method of synthesis, which is depicted in the diagram D2 (see the end of the description).

After making the above Suzuki reaction with additional hydrolysis removes the protective benzyl group using standard techniques (for example, using hot concentrated HCl), see, for example, procedure E2 (figure E2).

Method for the synthesis of E

Connections E2 and E3 obtained in accordance with the method the second method of synthesis of D, although the intermediate compounds are different.

Compound E1 was obtained in accordance with a modified method of synthesis, which is depicted in the diagram E2 (see the end of the description). An additional stage to the method of synthesis is shown in scheme E1, was the hydrolysis of the benzyl protective group.

The examples below details ways to produce compounds of formula (a) and the number of intermediate connections.

Example 1

Procedure A1 (scheme A1)

To 20 ml of CH3CN was added 1.0 g (4.3 mmol) of piperazine III-N and 1.2 g (4.7 mmol) of the compound Q1-Br, after which was added 0.52 g (5.1 mmol) Et3N and a small amount of K1. The reaction mixture is stirred and heated under reflux in nitrogen atmosphere for 16 hours. After cooling the mixture, the solvent was removed in vacuo, leaving a residue that was dissolved in CH2Cl2and successively washed with 0.5 N. NaOH solution and saturated salt solution (2 times). The organic fraction was dried on MgSO4. After removal of the drying agent, the solvent was removed under vacuum giving a residue. The resulting residue gave, after flash chromatography on columns (SiO2, eluent: a mixture of CH2Cl2and MeOH, 99: 1) A11 connection is NT 1 standards. HCl EtOH. The precipitation gave 0,98 g (2.3 mmol, 52%) of pure compound A11. HCl, etc., 228-230oC.

1H-NMR (CDCl3, ): 2.18 (m, 2H), 3.09 (broad, 2H), 3.3-3.7 (broad cluster, 6H), 4.21 (m, 4H), 4.30 (s, 2H), 6.59 (DD, J= 1 and 8 Hz, 1H), 6.71 (DD, J= 1 and 8 Hz, 1H), 6.82 (t, J= 8 Hz, 1H), 7.37 (m, 1H), 7.47 (m, 2H), 7.53 (t, J= 8 Hz, 1H), 7.62-7.74 (cluster, 4H), 7.90 (t, J= 2 Hz, 1H), 12.9 (broad, 1H).

In accordance with the above described method is similarly received connection A1-A14 and A16-A28, which are shown in table A1. Connection A15 received from connections A14 by restoring a mixture of LiAlH4THF analogously to the procedure A5 (see below, recovery A14 was carried out at the boiling point under reflux instead of room temperature).

An example of obtaining compounds of Q2-OH (see figure A2 in the end of the description).

Arylboronic acid were subjected to interaction with the aromatic bromide in alkaline conditions in the presence of catalytic amount of Pd(PPh3)4. As a result of implementation of the so-called reaction "Suzuki" received intermediate compound Q-OH with the carbon-carbon bond. Used boranova acid can be easily obtained by using the corresponding bromides. General methods of obtaining described in article D. Janietz et al. , Synthesis, (1993), 33 item fridge in a nitrogen atmosphere, then the solvent was left to cool. Added to 0.85 ml (1,43 g, 8,8 mmol) of 2-bromothiophene and within 10 minutes the solution was barbotirovany nitrogen. Then to the solution was added 0.4 g (0.35 mmol, 0.04 to EQ. Pd(PPh3)4. After stirring for 10 minutes to the reaction mixture was added to 8.5 ml of 2 standards. Na2CO3/H2O and 1.25 g (8.2 mmol) of 3-(hydroxymethyl)phenylboronic acid, dissolved in about 2 ml of EtOH. The reaction mixture was heated and kept heated at the boiling point under reflux for 4 hours, then heating was stopped, the reaction mixture is stirred for another 16 hours at room temperature. The precipitate was filtered through celite, and the filter was rinsed with a mixture of EtOAc/H2O. the Filtrate was extracted EtOAc, the combined organic fractions were dried on MgSO4. After removal of the drying agent, the filtrate gave after evaporation of the solvent 2.1 g of oil. Flash chromatography (SiO2, eluent: a mixture of tert-butyl methyl ether and hexane, 1: 1) gave 0,85 g (4.5 mmol, 51%) of the desired product Q2-OH.

Similarly received the following metsamasina benzyl alcohols Q-HE combination of aromatic bromides and Baranovich acids listed in TA using standard procedures (for example, using MsCl and Et3N in EtOAc). However, in the case of compounds Q8-OH and Q9-OH received no mesylates, and the corresponding chlorides Q8-Cl and Q9-Cl due to processing 2 standards. HCl. The last two compounds were also excellent alkylating agents when carrying out the reaction depicted in scheme A1.

The intermediate connection Q1-Br (see figure A3 in the end of the description).

Metafilter (S1= H) was premirovalsya through the action of N-bromosuccinimide (NBS) in the presence of catalytic amounts of dibenzoylperoxide.

Procedure A3 (diagram A3)

Connection Q1-Br

3 g (29,8 mmol)3-vinyltoluene and 5.3 g (29,8 mmol) of N-bromosuccinimide (NBS) was dissolved in 30 ml of CCl4. Added a small amount of dibenzoylperoxide, and the reaction mixture was heated under reflux for 10 hours. During this period was additionally added a little dibenzoylperoxide. After cooling, the reaction mixture was diluted CCl4and water. Two-phase system was podslushivaet 2 standards. NaOH, after which it was mixed. The organic layer was washed 1 standards. NaOH and water and subsequently dried over MgSO4. After removal of the drying agent, the solvent was removed in vacuo, yielding 8.0 g of residue. and, 1: 9) to give 5.3 g (21.5 mmol, 72%) of pure intermediate compound Q1-Br.

In the case of compound Q10-Br the desired 2-fluoro-5-panelcolor (S1= F) was obtained from phenylboronic acid and 2-fluoro-5-bromthymol on the Suzuki reaction is analogous to the procedure A2. Cm. scheme A3.

Connection Q4

Example get (Q4-OH) (see figure A4 in the end of the description).

Demethylation of 3-phenyl-4-hydroxybenzoic acid (method of obtaining, see U.S. patent N 4873367) under the action of Mel/KOtBu gave the corresponding methyl ester methoxybenzoic acid, which in turn can be restored (LiAlH4in connection Q4-OH.

Procedure A4 (diagram A4)

Stage 1

4.0 g (19 mmol) of 3-phenyl-4-hydroxybenzoic acid was dissolved in 70 ml of DMF, to which was added 4.6 g (41 mmol) KOtBu, and the mixture is stirred for 30 minutes. After this was added 3.0 g (21 mmol) Mel, and the reaction mixture is stirred for 14 hours at room temperature, during this period, was added a second equivalent of Mel. The solvent was removed under vacuum giving a residue that was dissolved in EtOAc. The resulting solution was shaken with 2 standards. NaOH. The organic fraction was dried over Na2SO4. After removal of the drying agent and process the second portion was used without further purification for recovery describes procedures for A5.

Procedure A5 (diagram A4)

Stage 2

of 0.68 g (18 mmol) of LiAlH4was added to 20 ml dry THF and stirred under nitrogen atmosphere. Then to the mixture LiAlH4and THF was added dropwise 3,65 g (16.0 mmol) of methyl ester of Z-phenyl-4-methoxybenzoic acid, dissolved in 60 ml of dry THF. Stirring is continued for 1 hour at room temperature. The reaction mixture was cooled (water mixed with ice) and was added 0.7 ml of water in a mixture of THF and 1.4 ml of 2 standards. NaOH. Then the mixture was heated under reflux for 10 minutes, after which it was filtered to remove salts. The salts were washed with hot THF, and the wash water was combined with the filtrate. After removal of the solvent in vacuo was obtained 3.1 g (14.5 mmol, 90%) pure enough Q4-OH. This portion was used without further purification for receiving nelfinavir Q4-OMs, which in turn was used in the reaction depicted in scheme A1, giving the A8 connection.

Example 2

Procedure B1 (diagram B1)

3,74 g in (17.0 mmol) of piperazine I-H and 3.0 g in (17.0 mmol) of 2-phenylphenol was dissolved in 80 ml of absolute ethanol. Under stirring solution was added 2.0 ml (24,0 mmol) of a mixture of 37% CH2O/H2O continued to mix in Ry was subjected to flash chromatography on a column (SiO2, eluent: a mixture of CH2Cl2and petroleum ether, 1: 1). First separated unreacted part 2-phenylphenol when replacing the eluent, starting with 100% CH2Cl2to a mixture of CH2Cl2and MeOH, 99: 1, giving 1.70 g (4.2 mmol, 25%) of compound B1 in the form of a free base, etc., 174-175oC.

1H-NMR(CDCl3, ): 2.65 (cluster, 8H), 3.83 (s, 2H), 4.27 (m, 4H), 6.48 (DD, J= 1.5 and J= 8 Hz, 1H), 6.59 (DD, J= 1.5 and J= 8 Hz, 1H), 6.76 (t, J= 8 Hz, 1H), 6.87 (t, J = 8 Hz, 1H), 7.05 (DD, J= 1.5 and J= 8 Hz, 1H), 7.28 (DD, J = 1.5 and J= 8 Hz, 1H), 7.32 (m, 1H) 7.42 (t, J= 8 Hz, 2H), 7.61 (m, 2H), 11.4 (broad s, 1H).

Example 3

Procedure C1 (figure C1).

Stage 1.

In the atmosphere of nitrogen 0.8 g (3.4 mmol)of 3-(3-methoxyphenyl)benzoic acid was dissolved in 15 ml of dry THF along with 0,65 ml Et3N. the Solution was cooled to 0oC was mixed with the addition of 0.42 ml of ISO-ButO(CO)Cl. After 30 minutes, to the resulting solution was added 0.71 g (3.2 mmol) of I-N, dissolved in 5 ml of dry THF. The reaction mixture was left to warm to room temperature and stirring continued for 16 hours. After the reaction mixture was processed 2 standards. NaOH, after which a two-phase system was extracted with EtOAc. The organic fraction was dried over MgSO4. After removal of the drying agent and udalit: a mixture of EtOAc and petroleum ether, 1: 1), yielding 0.75 g (1.7 mmol, 52%) of the corresponding amide.

Stage 2

0.9 g LiAlH4was suspendibility in 20 ml of dry THF, the suspension was brought to the boiling temperature under reflux, after which was added 0.7 g (1.6 mmol) of amide (product of stage 1), dissolved in 15 ml of dry THF. The reaction mixture was continued heating under reflux for 15 minutes, after which the mixture was cooled (water mixed with ice) and very carefully dropwise added 0.9 g H2O. Then was added to 1.8 ml of 2 standards. NaOH and 0.9 g H2O, after which the mixture is again brought to the boiling temperature under reflux for 20 minutes. Cooling to room temperature and filtration gave a residue that was filtered by EtOAc. The combined filtrate and wash water were dried over MgSO4. After removal of the drying agent and removal of the solvent in vacuo remained a residue, which was subjected to chromatography on a column (SiO2, eluent: EtOAc), giving 0,57 g (1.4 mmol, 85%) of pure free base C1. The base was dissolved in EtOAc and was turned into a chloride-hydrogen salt by addition of one equivalent of 1 norms. HCl/methanol, yielding 0.50 g of pure ClHCl, so pl. 165-167oC (decomposition).

1is C, 2H), 6.79 (t, J= 8 Hz, 1H), 6.93 (m, 1H), 7.23 (m, 2H), 7.38 (t, J= 8 Hz, 1H), 7.52 (t, J= 8 Hz, 1H), 7.65 (broad D. J= 8 Hz, 1H), 7.69 (broad D. J= 8 Hz, 1H), 7.92 (broad C. 1H), 13.2 (broad, 1H).

Procedure C2 (scheme C2)

Stage 1 and 2

These reactions are similar to the C1 stage 1 and 2 (figure C1).

Stage 3

1.1 g (2.4 mmol) of the ester of acetic acid was suspendibility in 150 ml of ethanol with 15 ml of H2O, after which was added 1.5 g (37.5 mmol) of NaOH. The reaction mixture was stirred for 16 hours, after which the ethanol was removed in vacuum. The remaining fraction was treated with a saturated solution of NH4Cl and was extracted with CH2Cl2. The combined organic fractions were washed with saturated NaHCO3, dried over MgSO4. After removal of the drying agent and removal of the solvent in vacuo was 0.97 g (2.3 mmol, 97%) of the residue containing the corresponding net derivative of phenol.

Stage 4

0,98 g (2.3 mmol) of the derivative of phenol (obtained in stage 3) was dissolved in 15 ml of acetone, to which was added 1.5 g of powder K2CO3. Under stirring was added 0.3 ml (CH3)2SO4, after which the reaction mixture was heated under reflux for 2 hours. After the reaction mixture has reached the camping was subsequently boiled for 45 minutes. After cooling, the mixture was extracted CH2Cl2organic fraction was dried over MgSO4. After removal of the drying agent and removal of the solvent in vacuo remained the rest of 0.95 g (2.2 mmol, 96%) of the corresponding pure O-methylated derivative of phenol.

Compound C4 was synthesized according to the procedure similar to that described for compound C2.

Table C shows the obtained compounds.

Intermediate compounds used in the method C

3-(3-Methoxyphenyl)benzoic acid (see scheme C3 at the end of the description) was obtained according to a similar procedure described by W. G. Dauben et al. , J. Am. Chem. Soc. , 75(1953), 4969-73. 3-Phenyl-4-acetoxybenzoic acid (scheme C3) were obtained using standard procedures from 3-phenyl-4-hydroxybenzoic acid (see figure C3). The synthesis of the latter compound is described in U.S. patent N 4873367.

Example 4

Procedure D1 (figure D1)

In the atmosphere of nitrogen, 0.4 g (2.8 mmol) of 4-bromophenol was dissolved in 5 ml of toluene. To the resulting solution was added to 97.5 mg (0,084 mmol, 0.03 equiv. Pd(PPh3)4and 2.8 ml of 2 N. Na2CO3and 1.0 g (2.8 mmol) Bronevoy acid d1 (S5= H), dissolved in 5 ml of hot ethanol. Obtained by the change of temperature, she was diluted EtOAc and a small amount of water. Then extraction was carried out EtOAc, the combined organic fractions were washed with saturated salt solution and dried over MgSO4. After removal of the drying agent and removal of the solvent in vacuo remained 1.52 g of residue, which was subjected to chromatography on a column (SiO2, eluent: a mixture of EtOAc and petroleum ether, 1: 1), giving of 0.53 g (1.3 mmol, 47%) of pure free base D22. The free base was turned into his dihydrochloride salt (crystallization from a mixture of EtOAc and simple ether), giving compound D222HCl, so pl. 222-227oC.

1H-NMR (d16-DMSO/CDCl34/1, ): 3.14-3.30 (broad cluster, 4H), 3.34-3.56 (broad cluster, 4H), 4.23 (m, 4H), 4.42 (doctor J= 4 Hz, 2H), 6.46-6.58 (cluster, 2H), 6.73 (t, J= 8 Hz, 1H), 6.89 (m, 2H), 7.47 (t, J= 7 Hz, 1H), 7.52-7.66 (cluster, 4H), 7.99 (t, J= 1 Hz, 1H), 9.40 (broad ), 11.5 (broad, 1H).

According to the above synthesis was obtained the following compounds (table D).

Intermediate compounds used in the method D

Bromides, used in the circuit of D1 and D2, can be easily obtained by standard methods or purchased commercially. Boranova acid used in the diagrams D1 and D2, can be easily obtained through the corresponding bromides (see the CLASS="ptx2">

Used bromides (S5= H, OCH2Ph diagram D3) is synthesized in accordance with the procedure similar to that described in procedure E3 (figure E3).

Example 5

Procedure E1 (figure E1)

to 5.1 g (12,0 mmol) 1-[(2-methoxy-5-bromophenyl)methyl] -4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine was dissolved in 20 ml of toluene, to which was added 12 ml of 2 N. Na2CO3/H2O and 0.45 g (0,39 mmol, 0.03 equiv. Pd(PPh3)4. Then to the solution was added 1,46 g (12,0 mmol) of phenylboronic acid dissolved in 3 ml of warm ethanol. The reaction mixture was vigorously stirred at 85oC. After 4 hours the two-phase reaction mixture was left to reach room temperature, then separated organic fraction (toluene). The aqueous layer was extracted with EtOAc. The combined toluene and EtOAc fractions, respectively, washed with water and saturated salt solution, then the organic fraction was dried over Na2SO4. After removal of the drying agent and subsequent removal of the solvent in vacuo remained a residue, which was subjected to chromatography on a column (SiO2, eluent: a mixture of EtOAc and petroleum ether, 1: 2). Selected pure free base of compound E2 was dissolved in a mixture of EtOAc and ethanol (1: 1) and obtained theC (decomposition).

1H-NMR (d6-DMCO/CDCl34/1, ): 3.1-3.3 (cluster, 4H), 3.48 (cluster, 4H), 3.93 (C. 3H), 4.23 (m, 4H), 4.41 (doctor J= 5 Hz, 2H), 6.48 (DD. J= 1 Hz, J= 8 Hz, 1H), 6.55 (DD, J= 1 Hz, J= 8 Hz, 1H), 6.73 (t, J= 8 Hz, 1H), 7.20 (doctor J= 9 Hz, 1H), 7.32 (m, 1H), 7.40 (t, J= 8 Hz, 2H), 7.71 (m, 2H), 7.75 (DD, J= 2 Hz, J= 9 Hz, 1H), 8.04 (doctor J= 2 Hz, 1H), 11.1 (broad, 1H).

Procedure E2 (figure E2)

3.0 g (5.9 mmol) of O-benzyl-protected compound E1 was dissolved in 35 ml of concentrated HCl, then the mixture is stirred and brought to the boiling temperature under reflux. After 45 minutes the addition was added 30 ml of concentrated HCl and heated under reflux was continued for another 45 minutes. Then the reaction mixture was left to cool to room temperature, and the solvent was removed in vacuum. The residue is treated with saturated solution of NaHCO3and the solution was extracted EtOAc. The organic fraction was washed with saturated salt solution, dried over MgSO4. After removal of the drying agent and subsequent removal of the solvent in vacuo remained a residue that was subjected to flash chromatography on a column (SiO2eluent: CH2Cl2/MeOH, 95: 5). Free base E1 separated and turned into the HCl salt by treatment with a mixture of 1 N. HCl/EtOH. Perkristian are shown in table E.

Intermediate compounds used in the method E

Bromides used to make the Suzuki reaction depicted in scheme E1, it is possible to synthesize from phenylpiperazine and the corresponding substituted 3-brompheniramine-X intermediate compounds in which X can be Cl, Br or OMs (see figure E3 at the end of the description).

Procedure E3 (figure E3)

To 80 ml of CH3CN added 6.6 g (23,0 mmol) (2-methoxy-5-bromophenyl)-bromide and 5.4 g (21 mmol) of I-HCl, then enter 5,2 g (51,0 mmol) Et3N and a small amount of KI. The reaction mixture is stirred and maintained at the boiling point under reflux for 16 hours. Then the mixture is filtered and the filtrate concentrated in vacuo. The residue is subjected to chromatography on a column (SiO2, eluent: EtOAc/petroleum ether, 1: 2), which gives a value of 5.1 g (12.2 mmol, 58%) of pure 1-[(2-methoxy-5-bromophenyl)methyl] -4- (2,3-dihydro-1,4-benzodioxin-5-yl)piperazine.

Used boranova acid is easily obtained by using the corresponding bromides, for example, in accordance with the General procedures described D. Janietz et. al. , Synthesis, (1993), 33, and these links.

Obtaining the intermediate XI-H in accordance with the scheme A. i

the see Dickerman et. al. , J. Org. Chem. , 19, (1954), 1855-61)) and 7,39 g (37.5 mmol) of 7-bromobenzophenone together from 3.45 g (25 mmol) of the dried K2CO3and of 0.48 g (2.5 mmol) Cul are placed in the flask and the resulting mixture, stirring, heated at a temperature of 120oC for 90 hours. After the reaction mixture was brought to room temperature, was added 40 ml of toluene. The resulting suspension is filtered through celite and the residue is washed with warm toluene. The combined wash water and the filtrate is evaporated in vacuum, obtaining 12.4 g of brown oil. The oil was diluted with CH2Cl2and consistently handle 2 N. NaOH, NaHCO3(saturated) and water. The organic fraction is dried over MgSO4. After removal of the drying agent and evaporation of the solvent in vacuo was an 11.7 g of brown oil. The obtained residue was subjected to flash chromatography on a column (SiO2, eluent: CH2Cl2/MeOH, 98: 2) to give 5.7 g (83%) of the desired product.

Stage 2 (scheme. A. i)

5.9 g (to 18.6 mmol) of the product of stage 1, dissolved in 40 ml of dry THF, are added dropwise to a mixture of 2.14 g (55,8 mmol) of LiAlH4in 100 ml of Et2O and stirred for 3 hours. Then the reaction mixture was sequentially treated with 2.1 ml of H2O in THF, 4,2 ml 2 N. NaOH and 2.4 m is correctly washed with THF and CH2Cl2. The combined wash water and the filtrate evaporated in vacuum to obtain 5.4 g of a brown oil. The resulting residue is subjected to flash chromatography on a column (SiO2, eluent: CH2Cl2/MeOH, 98: 1), which gives 4.83 g (85%) of the analogue of diazepine.

Stage 3 (scheme A. i)

4.83 g (15.8 mmol) of the product of stage 2 are dissolved with stirring in 65 ml of 1,2-dichloroethane. In nitrogen atmosphere at 2-4oC for 10 minutes, to the resulting solution was added 2.3 g (15.8 mmol) Cl(CO)O(CHCl)CH3 (ACE-chloride"), dissolved in 25 ml of 1,2-dichloroethane. Then the reaction mixture is heated under reflux for 10 hours and concentrated in vacuo to obtain a 5.1 g of residue. The residue is diluted with methanol and the resulting solution heated under reflux for 16 hours. After the reaction mixture was brought to room temperature, the solvent is removed in vacuum with the receipt of 4.2 g of residue, which was subjected to flash chromatography on a column (SiO2, eluent: CH2Cl2/MeOH/NH4OH, 92: 7,5 level: 0.5), which gives 2.8 g (82%) of 1-(7-benzofuranyl)hexahydro-1,4-diazepine.

Obtaining XV-H, see diagram A. iii

Stage 1 (scheme A. iii)

3.94 g (21.9 mmol) of 7-nitro-2-benzoxazolinone (for review with the method obtained the t 1,72 g 85% KOH powder (to 26.2 mmol). To the obtained solution under stirring and cooling (water) for 10 minutes, added dropwise and 3.72 g (26,2 mmol) Mel dissolved in 6 ml of DMSO. The reaction mixture continued to stir at room temperature for 16 hours, during the last period add an additional amount Mel (0.5 g). After the reaction, the reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic fractions washed sequentially with water and saturated salt solution, then the organic fraction is dried over MgSO4. After removal of the drying agent and evaporation of the solvent in vacuo obtain 4.1 g of the solid residue. Flash chromatography of the latter on the column (SiO2, eluent: CH2Cl2gives 3.6 g (85%) of pure 3-methyl-7-nitro-2-benzoxazolinone.

1. Derivatives of piperazine and piperidine derivatives of the formula (a)

< / BR>
where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S;

R1denotes hydrogen or fluorine;

R2denotes oxoprop or C1-4alkyl;

p = 0 or 1;

Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and t is t hydrogen or C1-4alkyl;

n = 1 or 2;

R5represents C1-4alkoxy, C1-4alkyl, halogen or hydroxy;

q = 0 or 1;

Y represents phenyl substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylaminocarbonyl; furyl or thienyl and their salts.

2. Connection on p. 1, characterized in that together with the phenyl group is a group of formula b-m

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
in which R1and (R2)phave the values listed in paragraph (1, n = 1, R3, R4, (R5)q, Y and Z have the values listed in paragraph 1, and their salts.

3. Connection on p. 2, characterized in that together with the phenyl group is a group of formula (b) or a group of the formula (l), which is substituted in heteroclite exography, Y denotes phenyl which may be substituted, as indicated in paragraph 1, and Z represents nitrogen and their salts.

4. Connection on p. 3, wherein R3and R4denote hydrogen, R5denotes hydrogen, hydroxy, methoxy or halogen and Y have the values listed in paragraph 3, and their salts.

5. Connection on p. 4, characterized in that together with the phenyl group is a group of formula (l), which is 6. The method of obtaining the compounds stated in paragraph 1, namely, that the connection formulas

< / BR>
subjected to interaction with the compound of the formula

< / BR>
in which X is tsepliaeva group.

 

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The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

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The invention relates to new chemical compounds, in particular derivatives (1,2,3-triazolyl)-1,2,5-oxadiazole General formula I, where R = NH2or< / BR>
and, if R1= N, R2lowest hydroxyalkyl, or, if R1- lower alkyl, lower hydroxyalkyl, aryl, R2= N, the lower hydroxyalkyl or a radical of General formula-C(O)R3where R3= HE, NH2, lower alkyl or lower alkoxyl, potentiating NO-dependent activation of the soluble form of guanylate cyclase (RGC)

The invention relates to compounds of formula I:

< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

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-OH; Y = -(CH2)f; R1, R2independently selected from the group including hydrogen, lower alkyl, halogen, -OZ, -NO2, -NH2; R3selected from the group including hydrogen, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkyl-carboxylic acid; f = 1 - 6; n = 0 to 2; b = 0 - 2; m = 1 to 3; Z represents lower alkyl, phenyl, or their pharmaceutically acceptable salts, esters, Amida
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