HK1109571A - Phenylpiperazine derivatives with a combination of partial dopamine-d2 receptor agonism and serotonin reuptake inhibition - Google Patents

Description

Having a portion of dopamine-D2Phenylpiperazine derivatives combining receptor agonism with serotonin reuptake inhibition

The present invention relates to a group of novel phenylpiperazine derivatives which have a dual mode of action: serotonin reuptake inhibition and partial dopamine-D₂Receptor agonism. The invention also relates to the use of a compound disclosed herein for the manufacture of a medicament for producing a beneficial effect. The benefits disclosed herein or otherwise apparent to those skilled in the art from this description and general knowledge in the art. The invention also relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition. Rather, the present invention relates to a novel use for the treatment of diseases or conditions as disclosed herein or as would be apparent to one of skill in the art in view of the present specification and general knowledge in the art. In an embodiment of the invention, certain compounds disclosed herein are used for the manufacture of a medicament useful for the treatment of disorders involving dopamine-D₂Receptors and serotonin reuptake sites, or can be treated via manipulation of these targets.

Has the function of dopamine-D₂Compounds which act both as antagonists and as serotonin reuptake inhibitors are known from WO 00/023441, WO 00/069424 and WO 01/014330. This combination of activities is useful for the treatment of schizophrenia and other psychotic disorders: it can more completely treat all diseasesSymptoms (e.g., positive and negative symptoms).

It is an object of the present invention to provide additional compounds that have dual effects, being part of dopamine-D2 antagonists and serotonin reuptake inhibitors.

The present invention relates to a novel group of compounds of formula (1):

wherein: x is S or O,

R₁is H, (C)₁-C₆) Alkyl, CF₃、CH₂CF₃OH or O- (C)₁-C₆) Alkyl radical

R₂Is H, (C)₁-C₆) Alkyl, halogen or cyano

R₃Is H or (C)₁-C₆) Alkyl radical

R₄Is H, (C)₁-C₆) Alkyl optionally substituted by halogen atoms

T is a saturated or unsaturated carbon chain of 2 to 7 atoms, in which one carbon atom may be replaced by a nitrogen atom (optionally replaced by (C)₁-C₃) Alkyl, CF₃Or CH₂CF₃Substituted with groups) or by an oxygen or sulphur atom, the chain being optionally substituted with one or more substituents selected from: (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, halogen, cyano, trifluoromethyl, OCF₃、SCF₃、OCHF₂And a nitro group,

ar is selected from the following groups:

the Ar group is optionally further substituted with one or more substituents selected from: (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, halogen, cyano, trifluoromethyl, OCF₃、SCF₃、OCHF₂And a nitro group,

wherein, in the Ar group containing a five-membered ring, the double bond in the five-membered ring may be saturated,

and tautomers, stereoisomers and N-oxides thereof, and pharmacologically acceptable salts, hydrates and solvates of said compounds of formula (1) and tautomers, stereoisomers and N-oxides thereof.

In the group 'Ar', the point represents the point of attachment of the group 'T'.

In the description of the substituents, abbreviation' (C)₁-C₃) Alkyl ' represents ' methyl, ethyl, n-propyl or isopropyl '.

Prodrugs of the above compounds are within the scope of the invention. Prodrugs are therapeutic agents that are inactive by themselves, but may be converted to one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules that are used to overcome some of the obstacles to the use of the parent drug molecule. These include, but are not limited to, solubility, permeability, stability, pre-system metabolism, and targeting limitations (Medicinal Chemistry: Principles and practice, 1994, ed.: f.d. king, p.215; j.stella, produgussa therapeutics ",Expert Opin.Ther.Patents， 14(3) 277-280, 2004; ettmayer et al, letters from marked and stimulated project ", J.Med.chem., 47, 2393-. Prodrugs, i.e. compounds which are metabolized to compounds having formula (1) when administered to a human by any known route, are encompassed by the present invention. In particular, this relates to compounds having primary or secondary amino groups or hydroxyl groups. Such compoundsThe compound may be reacted with an organic acid to give a compound having formula (1) wherein additional groups are present which are readily removable after administration, such as, but not limited to, amidines, enamines, mannich bases, hydroxy-methylene derivatives, O- (acyloxy-methylene carbamate) derivatives, carbamates, esters, amides or enaminones.

N-oxides of the above compounds are within the scope of the present invention. The tertiary amines may or may not form N-oxide metabolites. The possible range of N-oxidation occurring varies from trace amounts to almost quantitative conversions. N-oxides may be more or less active than their corresponding tertiary amines. Although N-oxides are readily reduced to their corresponding tertiary amines by chemical means, this conversion occurs to varying degrees in the human body. Some N-oxides undergo an almost quantitative reductive conversion to The corresponding tertiary amine, in other cases this conversion is only a trace reaction or even does not occur at all (M.H. Bickel: The pharmacological and biochemical of N-oxides ",Pharmaco-logical Reviews， 21(4)，325-355，1969)。

it has been found that the compounds according to the invention are para-dopamine-D₂Both the receptor and the serotonin reuptake site show high affinity. These compounds are p-dopamine-D₂The receptors show activity with varying degrees of agonism. All compounds showed activity as serotonin reuptake inhibitors, as they potentiate 5-HTP induced mouse behavior (b.l. jacobs, An animobehoviour model for student central serological synapses',Life Sci.，1976， 19(6)，777-785)。

with all-dopamine-D₂Use of receptor agonists or antagonists instead, partial dopamine-D₂The use of receptor agonists provides a dynamic drug therapy that can self-regulate on an immediate basis to adapt to the patient's intrinsic state. Thus, the required flexible regulation of the dopamine system can be provided, avoiding much of the total dopamine-D usage₂Receptor agonists or full dopamine-D₂Adverse effects of receptor antagonist treatment, the former being bromocriptine (hallucinations, nausea, vomiting, dyskinesias, orthostatic hypotension, somnolence) and the latter being haloperidol (mood dullness, dysphoria, tardive dyskinesia). Due to many of these adverse effects, full agonists and antagonists have found only very limited use in the therapy of depression and anxiety. Part of dopamine-D₂Receptor agonists not only show flexible regulatory effects and desirable side-effect behaviour, but they also have outstanding anxiolytic behaviour in relevant animal models (Drugs of the Future2001, 26 (2): 128-.

Partial dopamine-D according to the invention₂Receptor agonists are compounds that, when tested over a range of concentration responses, achieve activation in a functional cAMP cell-type assay (described below). Part of dopamine-D₂Receptor agonists in cases of low intrinsic synaptic tone of dopamine or in total dopamine-D₂The presence of receptor antagonists may act as agonists, in cases of higher intrinsic synaptic tone of dopamine or in total dopamine-D₂A receptor agonist, when present, may act as an antagonist. Partial dopamine-D like full agonists₂Receptor agonists are generally active in sensitizing systems. They induce contralateral rotation in rats with unilateral 6-hydroxy-dopamine (6-OHDA) lesions in the substantia nigra pars compacta. In MPTP-treated marmosets, they produced potent and long-lasting reversal of motor symptoms (Drugs of the Future2001, 26 (2): 128-132). However, in contrast to full agonists, partial dopamine-D₂Agonists are essentially less active in non-sensitized systems: they hardly reversed the hypokinesia induced by reserpine in rats.

For the treatment of CNS disorders involving hyperactivity of the dopaminergic system, a pharmaceutical preparation is recommended which combines a fraction of dopamine-D which has an intrinsically low functional activity₂Receptor agonistic activity and serotonin reuptake inhibitory activity. In the case of disorders involving dopamine insufficiency, the combination of an intrinsic functionHigh activity partial dopamine-D₂The pharmaceutical preparation of the invention, which has receptor agonistic activity and serotonin reuptake activity, has considerable advantages.

Disorders characterized by dynamic fluctuations in dopamine neurotransmission, like bipolar depression and addiction, would particularly benefit from a partial dopamine-D in pharmaceutical preparations₂Flexible modulation of the dopamine system by receptor agonists. Combining this "dopaminergic neurotransmission stabilizing" activity with serotonin reuptake inhibiting activity will enhance antidepressant and anxiolytic efficacy. These compounds can be used for the treatment of central nervous system disorders or diseases caused by disorders of the dopaminergic and serotonergic systems, such as: aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, parkinson's disease, in particular schizophrenia, and other psychotic disorders.

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by mixing a compound of the invention with a suitable acid, for example an inorganic acid (e.g. hydrochloric acid) or an organic acid. Pharmaceutical preparation

The compounds of the invention can be brought into a form suitable for administration by means of customary processes using auxiliary substances, for example liquid or solid carrier materials. The pharmaceutical compositions of the present invention may be administered enterally, orally, parenterally (intramuscularly or intravenously), rectally or topically (topically). They may be administered in the form of solutions, powders, tablets, capsules (including microcapsules), ointments (creams or gels), or suppositories. Suitable excipients for such formulations are the pharmaceutically customary liquid or solid fillers and fillers, solvents, emulsifiers, lubricants, flavoring agents, colorants and/or buffer substances. Common auxiliary substances which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils (e.g. cod liver oil, sunflower oil, peanut oil or sesame oil), polyethylene glycols and solvents (e.g. sterile water and mono-or polyhydric alcohols (e.g. glycerol)).

The compounds of the present invention are generally administered as pharmaceutical compositions, which are important and novel embodiments of the invention, because of the presence of these compounds, and more specifically the specific compounds disclosed herein. The types of pharmaceutical compositions that may be used include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions and other types disclosed herein or apparent to those skilled in the art in view of the present specification and general knowledge of the art. In an embodiment of the invention, a pharmaceutical package or kit is provided comprising one or more containers filled with one or more of the ingredients of the pharmaceutical composition of the invention. Various written materials may be provided with such containers, such as directions for use or notices issued by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human or veterinary administration of the pharmaceutical.

Pharmacological methods

para-dopamine-D₂In vitro affinity of receptors

Compound p-dopamine-D₂Receptor affinity is determined using e.g. i.creese, r.schneider and s.h.snyder: [³H]The receptor binding assay described in spiropordol labels dopaminerepitors in rat pituitary and brain ", Eur.J.Pharmacol., 46, 377-381, 1977.

In vitro affinity for serotonin reuptake sites

The affinity of the compounds for the serotonin reuptake site was determined using e.habert et al: characterisation of [ 2 ]³H]-the receptor binding to rat antibodies ", Eur.J. Pharmacol, 118, 107-114, 1985.

For forskolin induced [ 2 ]³H]Inhibition of cAMP accumulation

Compounds of the invention para-dopamine-D₂The in vitro functional activity of the receptor,Comprising an intrinsic activity (epsilon) by which forskolin induction is inhibited³H]-the capacity of cAMP accumulation.

Human dopamine D_2，LThe recipient was cloned in a fibroblast cell line CHO-K1, obtained from Dr. At 37 ℃ at 93% air/7% CO₂CHO cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum, 2mM glutamine, 1mM pyruvate, 5000 units/ml penicillin, 5000. mu.g/ml streptomycin and 200. mu.g/ml G-418. For incubation with test compounds, confluent cultures grown in 24-well plates were used. Tests were typically performed in quadruplicate for each condition or substance. Loading a cell with a solution containing 1. mu. Ci³H]-0.5 ml medium/well of adenine. After 2 hours, the cultures were washed with 0.5ml PBS containing the 1mM phosphodiesterase inhibitor Isobutylmethylxanthine (IBMX) and incubated for 20 minutes with 0.5ml PBS containing 1mM IBMX and forskolin with or without test compound. After aspiration, the reaction was stopped with 1ml of trichloroacetic acid 5% (w/v). Produced in a cell extract³H]-ATP and [ 2 ]³H]cAMP was tested as described in the following references: solomon Y, Landos C, Rodbell M, 1974, A highlyelectrostatic adenylyl cyclase assay, Anal Biochem 58: 541-: 869-874. 0.8ml of the extract was passed through Dowex (50 WX-4200-400 mesh) and alumina column, eluting with water and 0.1M imidazole (pH 7.5). The eluate was mixed with 7ml Insta-gel and the radioactivity was counted using a liquid scintillation counter. [³H]The orientation of ATP³H]Conversion of cAMP is expressed as a percentage of radioactivity in the cAMP fraction compared to the combined radioactivity in the cAMP and ATP fractions, and basal activity is subtracted to correct for spontaneous activity.

Stock solutions of test compounds at 10mM in 100% DMSO were prepared and diluted to the maximum in PBS/IBMXFinal concentration. Generally, the compounds are used at concentrations from 10^-10M to 10^-5And M is in the range. Drug-induced, receptor-mediated effects on the accumulation of the indicated second messengers were estimated as a percentage of the control value (forskolin-stimulated cAMP accumulation, minus basal activity) averaged from the quadruplicate data results. The mean values were plotted against drug concentration (in moles) using a non-linear curve fitting program INPLOT or Excel-add-in XL-Fit to construct a sigmoidal curve (four parameter log curve). Maximum inhibition (usually at 10) with forskolin-induced maximum stimulated transformation as the maximum^-6M or 10^-5M drug concentration) as the minimum, these values are fixed during the fitting process. Thus, the concentration of compound (EC) that results in 50% of the maximal inhibition of forskolin-induced cAMP accumulation₅₀) Averaged over several experiments and expressed as average pEC₅₀+ -SEM. Antagonist potency is assessed by incubating the cells with a fixed concentration of agonist and a specified concentration of antagonist. The curve fitting operation is equivalent to estimating EC₅₀Those used in the values. Thereby obtaining an IC₅₀The value, i.e. the concentration at which 50% of the maximum antagonism achieved by the compound is achieved. Correction of IC Using Cheng-Prussoff equation₅₀Values based on agonist concentration and EC obtained in the same experiment₅₀The value is corrected. Thus, K_b＝IC₅₀/(1+ [ agonist)]/EC₅₀An agonist). Corresponding pA₂The value is-log (K)_b). pEC can be estimated by concentration-response curve fitting₅₀Value and maximum achievable effect (intrinsic activity or efficacy (epsilon)). The epsilon of a full receptor agonist is 1, the epsilon of a full receptor antagonist is 0, and a partial receptor agonist has intermediate intrinsic activity. Dosage form

Compounds of the invention para-dopamine-D₂The affinity of the receptor and the serotonin reuptake site is determined as described above. From the binding affinities measured for a given compound of formula (1), one can estimate the theoretical minimum effective dose. At a value equal to measured K_iAt a compound concentration of two times the value, 100% of the receptors may be expected to be so convertedThe compound (I) was used. This concentration is converted to mg compound per kg of patient, giving the theoretical lowest effective dose, where ideal bioavailability is assumed. Pharmacokinetic, pharmacodynamic, and other considerations may alter the actual dosage administered, representing higher or lower values. Conveniently, the dose is from 0.001 to 1000mg/kg, preferably from 0.1 to 100mg/kg, of patient body weight.

Treatment of

The term "treatment" as used herein means any treatment of a condition or disease in a mammal, preferably a human, including: (1) preventing the occurrence of the disease or disorder in a subject who may be predisposed to the disease but has not yet been diagnosed as having the disease, (2) inhibiting the disease or disorder, i.e., arresting its progression, (3) ameliorating the disease or disorder, i.e., causing regression of the disorder, or (4) ameliorating the symptoms of the disorder caused by the disease, i.e., terminating the disease. Materials and methods

¹H and¹³c NMR spectra were recorded on a Bruker Avance DRX600 instrument (600MHz), a Varian UN400 instrument (400MHz), or a Varian VXR200 instrument (200MHz) using DMSO-D₆Or CDCl₃As solvent tetramethylsilane was used as internal standard. The chemical drift is given in ppm (delta scale) shifted down from tetramethylsilane. The peak shape in the NMR spectrum is represented by the following symbols: q (quartet), dq (doublet quartet), t (triplet), dt (doublet triplet), d (doublet), dd (doublet), s (singlet), bs (broad singlet), and m (multiplet). Flash chromatography was performed using silica gel 60(0.040-0.063mm, Merck). Column chromatography was performed using silica gel 60(0.063-0.200mm, Merck). Mass spectra were recorded on a Micromass QTOF-2 instrument and data acquisition and processing was performed using MassLynx application software. The accurate mass measurement is alignment of molecular ions [ M + H ]]⁺The method is carried out. Melting points are recorded on a B ü chi B-545 melting point apparatus. The yields relate to the isolated pure product.

The preparation of the compounds of formula (1) will now be described in more detail in the following examples.

Examples

The H-atom of the N-H moiety of the amines I-H to X-H can be replaced by Q in two different chemical ways, A and B, to give the compounds of the invention, as shown in Table 1 (below).

The method A comprises the following steps:

compounds were prepared via the synthesis depicted in scheme a 1: reaction of an amine (from fig. 1) with Q-X (X ═ leaving group, e.g. Cl, Br, I), for example in acetonitrile or butyronitrile, with Et (I-Pr)₂N acts as a base, and in some cases KI (or NaI) is added. Et can be used₃N instead of Et (i-Pr)₂N。

Process A1

Example 1:

process A2

Scheme a2, step i:

to a suspension of 0.6g (2.35mmol) piperazine hydrochloride I-H.HCl in 100ml acetonitrile were added 0.77g (2.35mmol) iodide, 0.71g (4.7mmol) NaI and 1.39ml (8mmol) DIPEA. The mixture was refluxed for 20 hours and concentrated in vacuo. The residue was dissolved in CH₂Cl₂And the resulting mixture was washed with water. The organic layer was washed with Na₂SO₄And (5) drying. The drying agent was removed by filtration and the solvent was concentrated in vacuo. The residue was purified by flash column chromatography (SiO)₂Eluent CH₂Cl₂/MeOH/NH₄OH 960/37.5/2.5). The product containing fractions were concentrated in vacuo to leave a residue, in diisopropylStirring in ether. The solid product was collected by filtration to give 0.79g (81%) of Compound 9. M.p.: 228 ℃ and 230 ℃.

The method B comprises the following steps:

compounds were prepared via the synthesis depicted in scheme B1: the amine (from FIG. 1) is alkylated by reductive alkylation. Q-OH is oxidized to the corresponding aldehyde Q' -CHO, followed by reductive alkylation. THF and DCE are suitable solvents for this type of reaction.

Example 2:

the Swern oxidation was performed as per the literature: manucuso, DanielSwern; synthesis, (1981) 165-184.

Process B2

Flow B2, step i:

in N₂A solution of oxalyl chloride (0.45ml, 5.2mmol) in 15ml DCM was placed under an atmosphere in a three-necked round bottom flask equipped with a thermometer and two pressure-equalizing dropping funnels containing 3ml of a solution of dimethyl sulfoxide (0.74ml, 10.4mmol) in DCM and 5ml of 3- (6-chloro-indazol-1-yl) propanol Q56-OH (1.0g, 4.7mmol) in DCM, respectively. Dimethyl sulfoxide was added to the stirred oxalyl chloride solution at-50 ℃ to-60 ℃. The reaction mixture was stirred for 2 minutes and the alcohol was added over 5 minutes; stirring was continued for another 15 minutes. Triethylamine (3.3ml, 23.73mmol) was added and the reaction mixture was stirred for 15 minutes and then warmed to room temperature. Water was added and the aqueous layer re-extracted with additional DCM. The organic layer was washed with 0.3N HCl, water, 5% NaHCO₃Washed with saturated NaCl solution and Na₂SO₄And (5) drying. The solution was filtered and evaporated to give the corresponding aldehyde.

Scheme B2. Step ii:

the crude product containing the aldehyde (from step i) was added to a stirred solution of 3-methyl-7-piperazin-1-yl-3H-benzoxazol-2-one.2 HCl (V.2HCl) (0.57g, 2.44mmol) and triethylamine (0.76ml, 5.38mmol) in 100ml of DCE. The reaction mixture was stirred for 1 hour, NaBH (OAc) was added₃(0.83g, 3.91 mmol). The mixture was stirred for another 8 hours. Water was added and the resulting fraction was extracted with DCM (3 times). The organic layers were combined and evaporated. The crude product was purified by flash chromatography on silica (eluent: DCM with 1.5% MeOH → DCM with 2% MeOH) to afford128As a crystalline solid, yield 58%. Melting point: 118 ℃ and 120 ℃.

Table 1: examples of the Compounds of the invention

The structures of the phenylpiperazine part of the compound of formula (1), herein referred to as "amine" and group Q are given below. In the column "method", the general method (A or B) is given, and in the case of method A, the next column gives the leaving group.

Compound nr.	Amines as pesticides	Q	Method of producing a composite material	L-radical	Salt (salt)	Melting point range of DEG C
1	I	1	A	I	Free base	194-196.5
							2	I	2	A	I	Free base	168-170
3	I	3	A	I	Free base	206.5-207.5
							4	I	4	A	I	Free base	173.5-175
5	I	5	A	I	Free base	173-176
							6	I	6	A	I	Free base	180-182
7	I	7	A	I	Free base	211-213
							8	I	8	A	I	Free base	193-195
9	I	9	A	I	Free base	228-230
							10	I	10	A	I	Free base	186-188
11	I	11	A	I	Free base	176-178
							12	I	12	A	I	Free base	212-214
13	I	13	A	I	Free base	183-184
							14	I	14	A	I	HCl	225-227
15	I	15	A	I	HCl	255-260
							16	I	16	A	I	Free base	143-145
17	I	17	A	I	Free base	152-157
							18	I	18	A	I	Free base	157-159
19	I	19	A	I	HCl	179-181
							20	I	20	A	I	Free base	174.5-177
21	I	21	A	Cl	Free base	180-183
							22	I	22	A	I	Free base	206-208
23	I	23	A	I	Free base	202-204
							24	I	25	A	I	Free base	154-156
25	I	29	A	I	Free base	Amorphous form
							26	I	30	A	I	Free base	177-179
27	I	31	A	I	Free base	153-156
							28	I	32	A	I	Free base	174-177
29	I	33	A	Br	Free base	187-190
							30	I	34	A	Br	Free base	190-192
31	I	35	A	Br	Free base	174-177
							32	I	36	A	Br	Free base	198-200

33	I	37	A	Br	Free base	194-195
							34	I	38	A	Br	Free base	137-138
35	I	39	A	Br	Free base	136-138
							36	I	40	A	Cl	Free base	121-123
37	I	41	A	Br	Free base	133-135
							38	I	42	A	Br	Free base	135-137
39	I	43	A	Cl	Free base	111-112
							40	I	44	B		Free base	200-202
41	I	45	A	Br	Free base	197-199
							42	I	46	A	Cl	Free base	162-164
43	I	47	A	Br	Free base	204-206
							44	I	48	A	Cl	Free base	162-164
45	I	49	A	Br	Free base	188-189
							46	I	50	A	Cl	Free base	146-149
47	I	51	A	Cl	Free base	109-113
							48	I	52	A	Br	Free base	75-105 amorphous
49	I	53	A	Br	Free base	209-210
							50	I	54	B		Free base	201-203
51	I	55	B		Free base	161-162
							52	I	56	B		Free base	203-204
53	I	57	B		Free base	83-86
							54	I	58	B		Free base	172-174
55	I	59	B		Free base	134-137
							56	I	60	A	Br	Free base	214-6
57	I	61	A	I	HCl	214-6
							58	I	62	A	I	HCl	275-7(d)
59	I	63	A	I	Free base	NMR**
							60	I	64	A	Cl	Free base	234-6
61	II	3	A	I	Free base	187-189
							62	II	5	A	I	Free base	157-159
63	II	6	A	I	Free base	154-156
							64	II	8	A	I	Free base	190-192
65	II	9	A	I	Free base	234-236
							66	II	11	A	I	Free base	176-178
67	II	13	A	I	Free base	236-239
							68	II	15	A	I	Free base	156-158
69	II	16	A	I	HCl	256-260
							70	II	17	A	I	HCl	244-246
71	II	26	A	I	HCl	232-5(d)
							72	II	29	A	I	Free base	157-158
73	II	31	A	I	Free base	190-1
							74	II	32	A	I	Free base	168-170
75	II	35	A	Br	Free base	170-173

76	II	36	A	Br	Free base	193-196
							77	II	45	A	Br	Free base	166-169
78	II	47	A	Br	Free base	108-113
							79	II	49	A	Br	Free base	168-170
80	II	50	A	Cl	Free base	194-7
							81	II	59	B		Free base	153-5
82	II	61	A	I	Free base	157-9
							83	III	16	A	I	Free base	153-154
84	IV	16	A	I	Free base	163-5
							85	V	1	A	I	Free base	125-127
86	V	3	A	I	Free base	153-155
							87	V	4	A	I	HCl	182-183
88	V	5	A	I	Free base	113-116
							89	V	6	A	I	Free base	162-164
90	V	8	A	I	Free base	119-121
							91	V	9	A	I	Free base	150-152
92	V	10	A	I	Free base	141-142
							93	V	11	A	I	Free base	124-126
94	V	12	A	I	Free base	184-186
							95	V	13	A	I	HCl	107
96	V	14	A	I	HCl	197-199
							97	V	15	A	I	HCl	216-218
98	V	16	A	I	HCl	199-201
							99	V	17	A	I	HCl	214-218
100	V	18	A	I	Free base	228-229
							101	V	19	A	I	Free base	132-134
102	V	20	A	I	Free base	138-140
							103	V	22	A	I	Free base	143-145
104	V	23	A	I	Free base	150-152
							105	V	24	A	I	Free base	179-181
106	V	25	A	I	HCl	197-199
							107	V	26	A	I	Free base	105-107
108	V	28	A	I	Free base	146-147
							109	V	31	A	I	Free base	119-21
110	V	33	A	Br	HCl	＞240d
							111	V	34	A	Br	Free base	108-111
112	V	35	A	Br	Free base	129-132
							113	V	36	A	Br	HCl	＞240d
114	V	37	A	Br	Free base	146-149
							115	V	41	A	Br	Free base	117-118
116	V	42	A	Br	Free base	110-112
							117	V	43	A	Cl	Free base	167-170
118	V	45	A	Br	Free base	111-113

119	V	46	A	Cl	Free base	88-91
							120	V	47	A	Br	Free base	131-133
121	V	49	A	Br	Free base	124-126
							122	V	50	A	Cl	Free base	103-105
123	V	51	A	Cl	Free base	112-115
							124	V	52	A	Br	Free base	203-205
125	V	53	A	Br	HCl	262-264
							126	V	54	B		Free base	116-118
127	V	55	B		Free base	104-107
							128	V	56	B		Free base	118-120
129	V	57	A	I	Free base	108-112
							130	V	58	B		Free base	102-104
131	V	59	B		Free base	125-128
							132	V	60	A	Br	Free base	202-3
133	V	61	A	I	HCl	194-7
							134	V	62	A	I	HCl	274-6(d)
135	V	63	A	I	Free base	NMR**
							136	V	64	A	Cl	Free base	154-5
137	VI	16	A	I	Free base	134-6
							138	VI	31	A	I	Free base	125-6
139	VI	50	A	Cl	Free base	116-8
							140	VI	59	B		Free base	130-2
141	VII	16	A	I	HCl	274-276
							142	VIII	16	A	I	Free base	135-137
143	IX	3	A	I	Free base	106-108
							144	IX	6	A	I	Free base	117-119
145	IX	49	A	Br	HCl	204-206
							146	IX	50	A	Cl	Free base	107-109

NMR, compound 59: (d, ppm)3.36(t, broad, Ph-N (C)H ₂CH₂)₂N-)

NMR, compound 135: (d, ppm)3.29(t, broad, Ph-N (C)H ₂CH₂)₂N-)

**)：CDCl₃/d⁶-DMSO＝1/4

The phenylpiperazine part of the compounds of formula (1) used in these methods is as shown in I-H to IX-H, wherein the point on the N-atom is the point of attachment of the group Q:

the synthesis of piperazines I-H, III-H and V-H is described in WO 97/36893.

Synthesis of amine II-H:

scheme II

The synthesis of the starting materials has been described (patent DE 487014).

Scheme II, step i:

30g (0.14mol) of the starting material are suspended in 600ml of MeOH. A small amount of Raney nickel was then added, after which hydrogenation (atmospheric pressure, room temperature) was started. After 24 hours, 7.2 l (9.4 l theoretical) of hydrogen were absorbed. 150ml of THF and a further small amount of Raney nickel were added to the reaction mixture. After 1 hour, the reaction mixture was filtered through hyflo and the residue was washed with THF. The filtrate was concentrated in vacuo to give 25.2g (98%) of the corresponding aniline.

Scheme II, step II:

24.2g (131.2mmol) of the aniline from the preceding step and 25.8g (144.3mmol) of bis (2-chloroethyl) amine are suspended in 675ml of chlorineIn benzene. While stirring, 25ml of solvent were distilled off by means of a Dean-Stark apparatus. After removing the Dean-Stark instrument, the reaction was refluxed for 48 hours. When the reaction mixture had reached room temperature, the mixture was decanted and the residue was taken up in Et₂O wash twice. 400ml of MeOH were then added, after which the mixture was allowed to warm until almost all of the residue had dissolved. Then 200ml of silica were added and the whole mixture was concentrated in vacuo. The residue was then placed on top of a flash chromatography column using DMA 0.75 as eluent. After removal of the solvent, the residue was isolated, suspended in about 100ml of acetonitrile and stirred for 4 hours. Filtration and drying afforded 17g of the desired piperazine II-H as the free base.

Synthesis of amine IV-H:

procedure IV

The toluene used in this experiment was degassed for 3 hours before use. 1.48g (1.61mmol) of Pd₂(dba)₃And 3.02g (4.85mmol) of BINAP were added to 400ml of toluene, and then the mixture was stirred, heated to 105 ℃ for 0.5 hour, after which the mixture was allowed to cool to room temperature. Next, to the reaction mixture was added: 27.

scheme IV, step i:

20.5g (81.3mmol) of dibromophenol and 20g of potassium carbonate are suspended in 400ml of acetone, and then 15.7ml of benzyl bromide are added. The reaction mixture was refluxed for 24 hours. After the mixture had reached room temperature, it was concentrated in vacuo. Followed by addition of water and CH₂Cl₂. The organic layer was filtered through a water-resistant filter, and the anhydrous filtrate was concentrated in vacuo and then dissolved again in 200ml of acetonitrile. Subsequently, 15ml of piperidine was added, and then the temperature was raised to 60 ℃ for 1 hour. The reaction mixture was concentrated in vacuo and CH was added₂Cl₂. The latter was washed with 1N HCl (3X), water, 2N NaOH and water. Filtering the organic layer with a water-resistant filterFiltration and concentration of the anhydrous filtrate in vacuo gave 27.6g (99%) of the corresponding benzylated phenol.

Scheme IV, step ii:

to the reaction mixture were added 6g (80.7mmol) of benzylated compound (step i) in 50ml of toluene, 9.2g (80.7mmol) of (. alpha. ) -dimethylpiperazine and 10.08g (104.9mmol) of sodium tert-butoxide. The resulting mixture was heated at 105 ℃ for 20 hours and then allowed to reach room temperature. Subjecting the mixture to CH₂Cl₂Diluted and then filtered through hyflo and concentrated in vacuo. The residue was placed on a flash chromatography column (SiO)₂) Top, elution with DMA 0.125. The product containing fractions were combined and concentrated in vacuo to yield 7.7g (26%) of almost pure phenylpiperazine.

Scheme IV, step iii:

this step is carried out analogously to the process described in the preceding step ii (scheme IV). In this case, benzylamine is used in the Buchwald reaction. The yield thereof was found to be 88%.

Scheme IV, step IV:

7ml (98mmol) of acetyl chloride were added dropwise to 70ml of cooled absolute ethanol and stirring was continued for 15 minutes. The latter solution is added to a solution of 11.5g (28.7mmol) of the step iii dibenzyl product in 250ml of methanol. 1.5g Pd/C (10%) were then added and the reaction mixture was hydrogenated for 24 hours. The mixture was filtered through hyflo and the filtrate was concentrated in vacuo. The residue containing the aminophenol HCl salt was used directly in step v.

Scheme IV, step v:

the residue from step iv (28.7mmol), 52ml DIPEA (298mmol) and 20.9g (129mmol) CDI were added to 750ml THF, and the mixture was refluxed under nitrogen for 20 h. After cooling to room temperature, the mixture was concentrated in vacuo and CH was added to the residue₂Cl₂And 5% NaHCO₃The whole mixture was left for 1 hour. By CH₂Cl₂Extraction (3X), concentration of the aqueous fraction, re-extraction (CH)₂Cl₂3 x). The organic fractions were combined and concentrated in vacuo, the residue containing appreciable amounts of imidazole. The whole product was dissolved in 120ml of acetonitrile and the solution was then brought to room temperature. The precipitate formed was filtered to give almost pure piperazine IV.

Synthesis of amine V-H:

procedure V

Scheme V, steps i, ii and iii:

the synthesis of V-H has been described in WO 97/36893. Steps i, ii and iii are performed analogously to steps i, ii and iii in scheme VI.

Synthesis of amines VI to H:

scheme VI

Scheme VI, step i:

while stirring, 3.8g (15mmol) of piperazine II-H were suspended in 5.48ml (31.5mmol) of DIPEA and the mixture was cooled to-40 ℃.30ml of CH with 3.14g (14.4mmol, 0.96eq) of Boc-anhydride are added dropwise over 100 min₂Cl₂And (3) solution. Stirring was continued at-40 deg.C (1 hour) and then at-30 deg.C (2 hours) to bring the reaction mixture to room temperature (16 hours). Then water and some MeOH are added, followed by CH₂Cl₂And (4) extracting. The organic fractions were combined, filtered through a water-resistant filter, the anhydrous filtrate was mixed with 50ml of silica, and the whole mixture was concentrated in vacuo. The residue is then left to drySpectrum column (SiO)₂) Top, using CH₂Cl₂MeOH (98/2) as eluent. Cutting off the column containing the product, and subjecting the product to CH₂Cl₂the/MeOH (98/2) was eluted from the column to give 3.55g (67%) of the desired N-Boc II.

Scheme VI, step ii:

4.5g (12.7mmol) N-Boc II and 5.8g (3.3eq) potassium carbonate were suspended in 100ml acetone. The reaction mixture was cooled to-10 ℃ while stirring, and then 0.87ml (14mmol, 1.1eq) of methyl iodide was added dropwise. After 15 minutes, the reaction mixture was allowed to reach room temperature and stirring was continued for 14 hours. Subsequently, the reaction mixture was concentrated in vacuo and the residue was taken up with water and CH₂Cl₂And (4) mixing. Separating the aqueous layer with CH₂Cl₂The extraction was performed twice. The combined organic layers were filtered through a water-resistant filter and the anhydrous filtrate was concentrated in vacuo to give 4.5g (98%) of the corresponding N' -methylated N-Boc II.

Scheme VI, step iii:

while stirring at-10 deg.C, 5ml of acetyl chloride (70.4mmol, 5.8eq) was added dropwise to 65ml of ethanol. The latter solution was added to 4.5g (12.2mmol) of N' -methylated N-Boc II isolated in step II. The resulting mixture was stirred at 55 ℃ for 3 hours, then the reaction mixture was allowed to reach room temperature and stirring was continued for 14 hours. Subsequently, the mixture was concentrated in vacuo, and the residue was suspended in diisopropyl ether and stirred for 2 hours. The precipitate was separated by filtration to give 3.6g (97%) of piperazine VI-H.HCl.

Synthesis of amines VII-H:

scheme VII

Scheme VII, step i:

this step is carried out analogously to step i in scheme IV. After chromatographic purification, an oil containing benzylated product was isolated in 88% yield. The oil solidified upon standing.

Scheme VII, step ii:

this step is carried out analogously to step ii in scheme IV. Boc-piperazine was used in the Buchwald reaction. Yield after chromatographic purification: 44% brown oil.

Scheme VII, step iii:

this step is carried out analogously to the process described in the preceding step ii (scheme VII). In this case, benzylamine is used in the Buchwald reaction. Yield after chromatographic purification: 73% brown oil.

Scheme VII, step iv:

11.91g (24.3mmol) of the dibenzylated product isolated in the preceding step iii (scheme VII) are suspended in a mixture of 110ml of ethanol, 72ml of water and 11ml of acetic acid. While stirring, 0.5g Pd (OH) was added₂C, hydrogenation was started for 6 days. After 1 and 3 days, a further small amount of Pd (OH) was added₂and/C. The reaction mixture was filtered through hyflo and the filtrate was concentrated in vacuo. The residue was treated with toluene, concentrated in vacuo and the process repeated to leave 7.9g (88%) of a dark syrup containing the aminophenol.

Scheme VII, step v:

this step (closing the ring with CDI) is performed analogously to step v in scheme IV. The crude product after treatment is chromatographed (flash column, SiO)₂Eluent DCM/MeOH 97/3) to give 7.6g of an impure brown foam. By a second chromatographic treatment (flash column, SiO)₂Eluent EtOAc/petroleum ether 1/2) to give 3.3g (42%) of a pure brown foam containing N-Boc protected benzoxazolinone piperazine.

Scheme VII, step vi:

this methylation step is carried out analogously to the procedure described in step ii (scheme VI). Yield: 98% brown foam, 97% pure.

Scheme VII, step VII:

this deprotection step is carried out analogously to the process described in step iii (scheme VI). Yield: 94% bright pink red solid with purity 98% containing the product VII-H.HCl.

Synthesis of amine VIII-H:

scheme VIII, step i:

the synthesis of the starting material has been described in EP 0189612. 4.91g (32.7mmol) of aniline (anilin) are suspended in 75ml of 48% HBr/water while cooling to-5 ℃. Subsequently, a solution of 2.27g (33mmol) of sodium nitrite in 4ml of water was added dropwise over a period of 15 minutes. Stirring was continued at 0 ℃ for 15 minutes.

Subsequently, the reaction mixture was added in one portion to 2.42g (16.9mmol) of CuBr in 20ml of 48% HBr/water at 0 ℃. After 30 minutes, the reaction mixture was heated to 85 ℃ for 1 hour, then allowed to reach room temperature and stirred for a further 14 hours. Diethyl ether and water were added to the mixture, and after shaking, the organic layer was separated and washed with water. The organic layer was concentrated in vacuo, along with some silica, and the residue was placed on a flash chromatography column (SiO)₂) Top using Et₂O/Petroleum Ether (1/1), then neat Et₂O as eluent. The product containing fractions were combined and concentrated in vacuo to give 3.3g (47%) of the desired corresponding bromo product.

Scheme VIII, step ii:

this step is carried out identically to step ii in scheme VI. Yield: 92% of the corresponding methylated brominated compound.

Scheme VIII, step iii:

6.82g (29.9mmol) of the methylated brominated compound, 4.03g (35.9mmol) of dimethylpiperazine, 13.6g (41.9mmol) of Cs were mixed in this order₂CO₃1.42g (2.99mmol) X-Phos (see Huang et al, J.Am.chem.Soc., 125(2003)6653) and 0.55g (0.6mmol) Pd₂(dba)₃Added to 225ml of toluene and the toluene degassed for 4 hours before use. While stirring, the temperature was raised to 100 ℃ for 20 hours under nitrogen atmosphere, and then to room temperature. Subjecting the mixture to CH₂Cl₂Diluted, then filtered and concentrated in vacuo. The residue was placed on a flash chromatography column (SiO)₂) Top, elution with DMA 0.25. The product containing fractions were combined and concentrated in vacuo to yield 0.73g (9%) of the desired pure piperazine VIII-H.

Amine IX-H containing:

procedure IX

Scheme IX, steps i, ii and iii:

the synthesis of I-H has been described in WO 97/36893. Steps i, ii and iii are performed analogously to steps i, ii and iii in scheme VI.

The different structures of Q1 to Q64 are given below:

in these formulae 'Q', the dots represent the linkage to the phenylpiperazine moiety of the compound of formula (1).Synthesis of Q1-6:

schemes 1-6

All starting materials (phenol and alkyne) were prepared according to the literature procedures:

alkyne: davison, Edwin c.; fox, Martin e.; chem, soc, perkin trans.1; 12(2002)1494-1514.Yu, Ming; Alonso-Alicia, m.; bioorg.med.chem.; 11(2003)2802-2822.

Phenol: buchan; McCombie; chem.soc.; 137(1931)144 Fingeret al; j.amer.chem.soc.; 81(1959)94, 95, 97. Berg; newbery; chem.soc.; (1949)642-645.

Schemes 1-6, step i:

R＝CN，n＝2

a stirred solution of silylated alcohol (3.35g, 10mmol) in 20ml dry THF was cooled to-70 ℃. 2.5M n-BuLi (4.8ml, 12mmol) was slowly added dropwise at such a rate that the temperature remained below-65 ℃. The solution was allowed to warm to-20 ℃ and stirring was continued for 1 hour, during which time the color of the solution changed from light yellow to dark yellow. The solution was again cooled to-70 ℃ and a solution of tert-butyldimethylsilyl chloride (1.66g, 11mmol) in 15ml of anhydrous THF was slowly added dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirring was continued for 20 hours. Adding saturated NH to the reaction mixture₄Quenching reaction with Cl, Et₂O extract 2 x. Merge Et₂O layer with 5% NaHCO₃(1x) and H₂O (1X) washing, drying (Na)₂SO₄). Et was concentrated under reduced pressure₂O fraction, residue chromatographed (SiO)₂) DMA/petroleum ether 1/5 was used as eluent to give 3.35g (75%) of silylated alkyne as a colorless oil.

Schemes 1-6, step ii:

4-cyano-2-iodophenol (1.23g, 5mmol), silylated alkyne (from step i) (2.18g, 5mmol), LiCl (0.21g, 5mmol) and Na were reacted by bubbling nitrogen through the solution for 2 hours₂CO₃A mixture of (2.38g, 22.5mmol) in 20ml DMF was degassed. Addition of Pd (OAc)₂(50mg, 0.20mmol) and the reaction mixture was stirred at 100 ℃ for 7 h. Addition of H₂O and hexane, and the mixture was filtered through hyflo. After separation of the hexane layer, the aqueous layer was extracted with hexane (1 ×). The hexane layers were combined and washed with H₂O (1x) and brine (1 x). The hexane fraction was partially evaporated under reduced pressure, 8g of silica gel were added and stirring was continued for 15 minutes. The silica was filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed (SiO)₂) Using Et₂O/Petroleum ether 1/9 as eluent gave 0.93g (35%) of the benzofuran derivative as a bright yellow oil.

Schemes 1-6, step iii:

cyclized Compound (29.58g, 52.17mmol), KF.2H₂O (14.73g, 156.51mmol), benzyltriethylammonium chloride (14.26g, 62.60mmol) in 450ml CH₃The mixture in CN was refluxed for 4 hours. After cooling to room temperature, CH₃CN was washed 2x with hexane. Evaporation of CH under reduced pressure₃And (3) CN fraction. Adding H to the residue₂O, extracted twice with EtOAc. Combining the organic layers, respectively with H₂O (1x) and brine (1 x). The organic layer was dried (Na)₂SO₄) And concentrated in vacuo. The residue was subjected to column chromatography (SiO)₂Eluent: EtOAc/petroleum ether 1: 3 → EtOAc/petroleum ether 1: 1) to yield 9.20g (82%) of the alcohol Q3-OH as a yellow oil.

Schemes 1-6, step iv:

mixing PPh₃(14.38g, 54.84mmol) and imidazole (3.73g, 54.84mmol) were dissolved in 160ml CH₂Cl₂. Iodine (13.92g, 54.84mmol) was added and the resulting suspension was stirred at room temperature for 20 min. 70ml of CH with the alcohol from step iii (9.07g, 42.19mmol) was added dropwise₂Cl₂The reaction mixture was stirred at room temperature for 20 hours. Adding water, separating H₂CH for O layer₂Cl₂And (4) extracting. The organic layers were combined and separately treated with 5% NaHSO₃Solutions (1X) and H₂O (1X) washing over Na₂SO₄And (5) drying. The drying agent was removed by filtration and the solvent was concentrated in vacuo. The residue was chromatographed (SiO)₂) Using CH₂Cl₂As eluent, 12.9g (94%) of iodide Q3-I was obtained as a thick oil which crystallized upon standing.

Synthesis of Q7-9:

schemes 7-9

5-bromobenzothiophene is according to Leclerc, V.; beaura in, n.; pharm pharmacol Commun, 6(2000) 61-66.

Scheme 7-9, step i:

sodium metal (4.5g, 195.9mmol) was added in chunks to 260ml of anhydrous EtOH. Malonate (116ml, 779mmol) was added and the reaction mixture was stirred under nitrogen for 30 min. A suspension of 5-bromobenzothiophene (29.5g, 97.2mmol) in 125ml of anhydrous EtOH was added and stirring continued at reflux for 18 h. The solvent was evaporated under reduced pressure and then 250ml H was added to the residue₂O and 15g NH₄And (4) Cl. CH for aqueous layer₂Cl₂Extraction (2 ×), combination of the organic layers, drying (water filter resistant) and concentration of the filtrate in vacuo (with the aid of an oil pump, 8 mbar). The residue was chromatographed (SiO)₂) By CH₂Cl₂Petroleum ether 3/2 gave 23.9g (64%) of the diester.

Scheme 7-9, step ii:

this step is performed similarly to step ii of scheme 51.

Schemes 7-9, step iii:

this step is performed similarly to step iii of scheme 51.

Schemes 7-9, step iv:

this step is carried out analogously to step iii of scheme 10-12.

Schemes 7-9, step v

This step is carried out analogously to step v of scheme 10-12.

Schemes 7-9, step vi:

this step is carried out analogously to scheme 1-6 step iv.

Derivatives of Q7 and Q8 were prepared analogously to the above procedure.

Synthesis of Q10-12:

all reagents are commercially available. 5-bromobenzothiophene was prepared according to Badger et al, j.chem.soc., (1957)2624, 2628.

Scheme 10-12, step i:

to a stirred mixture of 5-bromobenzothiophene (22.5g, 105.6mmol) and acid chloride (17.4ml, 141.3mmol) in 135ml of benzene at 0 deg.C was added SnCl over a period of 2 hours₄(43.1ml, 368 mmol). Stirring was continued at the same temperature for 4 hours. The reaction mixture was poured into a mixture of 95ml concentrated HCl (36-38%) in ice. The reaction mixture was extracted with EtOAc and the organic layer was washed with H₂O(3x)、1N NaOH(1x)、5％NaHCO₃And H₂O (2x) wash. The EtOAc fraction was dried (MgSO)₄)。The drying agent was removed by filtration and the solvent was evaporated under reduced pressure. The residue was recrystallized from 950ml MeOH, chromatographed, and Et₂O/Petroleum ether 1/1 as eluent gave 23.3g (68%) of acylated benzothiophene.

Schemes 10-12, step ii:

to a stirred mixture of acylated benzothiophene (23.3g, 71.3mmol) and crushed NaOH (23g, 575mmol) in 285ml diethylene glycol was added hydrazine hydrate (23ml, 474 mmol). Stirring was continued for 2 hours at 145 ℃ and then additional stirring at 180 ℃ was required for 2 hours to complete the conversion. The reaction mixture was poured onto ice and acidified with concentrated HCl (36-38%). The aqueous layer was washed with Et₂O extraction, organic layer H₂O (3x) and brine (1x) and dried (MgSO)₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure to give 19.7g (93%) of acid.

Schemes 10-12, step iii:

29ml of thionyl chloride were added dropwise to 250ml of MeOH over 30 minutes at-5 ℃. The mixture was stirred for 15 minutes, during which time the temperature was kept between-10 ℃ and-5 ℃. To the cooled solution was added acid (19.7g, 65.9mmol) in one portion. The reaction mixture was stirred for 1 hour, then warmed to room temperature and stirred for another 20 hours. The reaction mixture was concentrated in vacuo and the residue was chromatographed (SiO)₂) With CH₂Cl₂As eluent, 20.6g (100%) of methyl ester were obtained.

Schemes 10-12, step iv:

a mixture of methyl ester (20.6g, 65.8mmol) and zinc cyanide (4.64g, 39.5mmol) in 85ml of anhydrous DMF was degassed by passing nitrogen through the solution for 1 hour. Pd (PPh) was added under nitrogen atmosphere₃)₄(3.8g, 3.29mmol) and the reaction mixture was stirred at 90 ℃ for 16 h. The reaction mixture was diluted with 200ml of toluene and filtered through a pad of Hyflo. The organic layer was washed with 5% NaHCO₃Washed (2X) with brine (1X) and dried (MgSO)₄). For treatingThe drying agent was removed by filtration and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO)₂) Using CH₂Cl₂Petroleum ether 3/2 → CH₂Cl₂As eluent, 15.6g (92%) of 5-cyanobenzothiophene were obtained.

Scheme 10-12, step v:

to a stirred solution of 5-cyanobenzothiophene (15.6g, 60.2mmol) in 250ml 96% EtOH at 15 deg.C was added sodium borohydride (22.8g, 602mmol) in one portion. The reaction mixture was stirred at room temperature for 48 hours. Addition of H₂O, aqueous layer Et₂O extraction (3 ×). The organic layers were combined and washed with brine (1 ×). Adding Et₂O fraction dried (MgSO)₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO)₂) Et with₂O/CH₂Cl₂1/9 as eluent, 9.2g (66%) of alcohol Q12-OH was obtained.

Schemes 10-12, step vi:

prepared according to the procedure described in scheme 1-6, step iii.

Q10-OH and Q11-OH were similarly prepared using steps i, ii, iii and v, respectively.Synthesis of Q13-20:

schemes 13-20

All starting materials are commercially available.

Scheme 13-20 step i:

to a stirred solution of 3-nitro-p-tolunitrile (16.58g, 102.3mmol) in 55ml of DMF was added DMF-dimethyl acetal (15.24g, 128.1 mmol). The reaction mixture turned dark red and was stirred at 110 ℃ for 3 hours. Removing solvent under reduced pressure, dissolving in 30A mixture of 0ml EtOH and 300ml acetic acid. The reaction mixture was heated to 60 ℃ and iron powder (33g, 594mmol) was added portionwise. The reaction mixture was refluxed for 2 hours and filtered through a Hyflo pad. Et was added to the filtrate₂O, Et for acidic layer₂O extraction (1 ×). Et was concentrated in vacuo₂And (4) O fraction. The residue was chromatographed (SiO)₂) With CH₂Cl₂As eluent, 7.02g (48%) of a solid containing 6-cyanoindole was obtained.

Scheme 13-20 step ii:

to a stirred suspension of NaH (60%) (1.13g, 25.96mmol) in 60ml of DMF under nitrogen was added portionwise the 6-cyanoindole of step i (3.51g, 24.72 mmol). After stirring at room temperature for 1 hour, 1- (dimethyl-tert-butylsilyl) -3-bromopropane (6.30ml, 27.29mmol) was added dropwise at-5 ℃. The reaction mixture was stirred at room temperature for 20 hours. 400ml of H are added₂O and 400ml Et₂And O. Isolation of Et₂O layer, aqueous layer with Et₂O extract 1 x. Merge Et₂Layer O, concentrated in vacuo. The residue was chromatographed (SiO)₂) With CH₂Cl₂Petroleum ether 3/1 as eluent gave 5.50g (71%) of a bright yellow oil.

Scheme 13-20 step iii:

is carried out analogously to step iii in schemes 1-6 to yield Q19-OH.

Scheme 13-20 step iv:

the conversion of the resulting alcohol to the corresponding iodine derivative is carried out analogously to scheme 1-6 step iv.

The 6-cyanoindole derivative Q20-OH was prepared according to the above procedure.

Indole, 6-fluoroindole and 6-chloroindole are commercially available and are further converted to the indole derivative Q13-18-OH according to the procedure described above.

Of Q21Synthesizing:

scheme 21

Scheme 21, step i:

to a stirred suspension of NaH (55%) (0.48g, 20mmol) in 20ml of NMP was added dropwise a solution of benzimidazole (1.18g, 10mmol) in 20ml of NMP at room temperature. The reaction mixture turned bright red and hydrogen formation was observed. After stirring at room temperature for 30 minutes, a solution of 3-chlorobromopropane (1.08ml, 11mmol) in 10ml of NMP was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, and then the reaction mixture was heated at 100 ℃ for 2 hours. After stirring at room temperature for another 72 hours, H was added₂O and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2 ×). The combined organic layers were washed with brine (1 ×), dried (MgSO)₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure to give 2.9g Q21-Cl (150%, still in the presence of NMP) as an oil. Which is used for the coupling reaction with amines.

Synthesis of Q22-23:

schemes 22-23

All reagents are commercially available.

Scheme 22-23 step i:

to a stirred solution of 2, 4-difluoronitrobenzene (8g, 50.3mmol) in 100ml of CH₃CN solution 4-aminobutanol (5.61ml, 60.4mmol) and DIPEA (20.9ml, 120.7mmol) were added. The reaction mixture was stirred at room temperature for 72 hours. The solvent was evaporated under reduced pressure and CH was added to the residue₂Cl₂. Will CH₂Cl₂Fractional use of H₂O wash (2 ×), dry (water filter resistant) and evaporate filtrate under reduced pressure. The residue was chromatographed (SiO)₂) Et with₂O as eluent, 9.68g (84%) of amino-alkylated product was obtained.

Scheme 22-23 step ii:

to a solution of the amino-alkylated product (from step i) (9.68g, 42.5mmol) in 250ml EtOH (96%) was added 1g of 10% Pd/C, and the mixture was hydrogenated at room temperature (1atm) for 3 h. The reaction mixture was filtered through a pad of Hyflo and the black filtrate was concentrated under reduced pressure in vacuo to give 8.42g (100%) of the corresponding aniline.

Schemes 22-23, step iii:

a mixture of aniline (from step ii) (8.42g, 42.5mmol) in 25ml formic acid (96%) was refluxed for 2.5 hours and then cooled to room temperature. Addition of H₂O, after cooling, 50ml of 50% NaOH was added to the reaction mixture. After stirring for 2 hours, the aqueous layer was treated with CH₂Cl₂And (4) extracting. Will CH₂Cl₂The fractions were dried (water-resistant filter) and concentrated under reduced pressure in vacuo. The residue was chromatographed (SiO)₂) With CH₂Cl₂MeOH 9: 1 as eluent, 8.1g (92%) of benzimidazole were obtained.

Schemes 22-23, step iv:

the conversion of the resulting alcohol to the corresponding iodo derivative is carried out according to the procedure described in scheme 1-6 step iv. In this case, triphenylphosphine on a solid support is used.

Q22-OH was prepared via the same procedure described above.

Synthesis of Q24:

scheme 24

All reagents are commercially available.

Process 24, step i:

a suspension of sodium borate tetrahydrate (32.5g, 211.2mmol) in 195ml of acetic acid was heated until the temperature of the reaction mixture was above 50 ℃. The reaction temperature was maintained in this manner while adding 2-chloro-4-cyanoaniline (5.93g, 38.9mmol) portionwise over 1 hour. Stirring and heating were continued on the 62 ℃ oil bath for 2 hours. After cooling to room temperature, the reaction mixture was poured into 1L of ice water. Et for aqueous layer₂O extraction (3 ×). Combining the organic layers with H₂O washes (2X), dried (MgSO)₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO)₂) Et with₂O/Petroleum ether 1/3 as eluent gave 5.27g (74%) of the oxidized product.

Scheme 24 step ii:

a stirred solution of 2-chloro-4-cyanonitrobenzene from step i (2.48g, 13.6mmol) in 12ml DMF was cooled on ice. 4-aminobutanol (5.50ml, 59.3mmol) was added and the reaction mixture was allowed to warm slowly to room temperature and stirring was continued at room temperature for 72 h. Addition of H₂O, CH for aqueous layer₂Cl₂Extraction (2 x). Combining the organic layers with H₂O wash (3 ×), dry (water filter resistant) and evaporate under reduced pressure. The residue was chromatographed as Et₂O/Petroleum ether 4: 1 as eluent gave 2.6g (49%) of the amino-alkylated product.

Scheme 24, step iii:

prepared according to step ii of schemes 22-23.

Scheme 24 step iv:

prepared according to step iii of schemes 22-23.

Scheme 24, step v:

prepared according to step iv of schemes 22-23.

Synthesis of Q25-28:

schemes 25-28

All reagents are commercially available.

Scheme 25-28 Steps i:

to a stirred solution of 3-nitro-p-tolunitrile (8.1g, 50mmol) in 30ml of DMF was added DMF-dimethyl acetal (13.3ml, 100mmol) and the reaction mixture was stirred at 120 ℃ for 3 h. The solvent was evaporated under reduced pressure and the residue was dissolved in CH₂Cl₂. Will CH₂Cl₂Fractional use of H₂Wash with O (2 ×), dry (water resistant filter). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure to give 10.6g (98%) of the adduct.

Scheme 25-28 step ii:

to the stirred adduct (from step i) (6g, 27.6mmol) in 175ml Et₂O emulsion 8.1g NH₄Cl and 29g zinc particles (40 mesh). After stirring at room temperature for 2 hours, 100ml of THF was added to dissolve the starting material. After stirring for an additional 6 hours, the reaction mixture was filtered through a pad of Hyflo. Half of the filtrate was used in the next step.

Scheme 25-28 step iii:

2-Bromoethanol (7.9ml, 112mmol), the quaternary ammonium chloride Aliquat (0.6g, 10 mol%) and 90ml of 10% NaOH were added to the filtrate from the previous step ii. The reaction mixture was stirred at room temperature for 20 hours. After separation of the layers, the aqueous layer was washed with Et₂O extraction (1 ×). Combining the organic layers with H₂O wash (4X), dry (MgSO)₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure (by means of an oil pump). The residue was chromatographed (SiO)₂Eluent: CH (CH)₂Cl₂→CH₂Cl₂/Et₂O4: 1) to give 1g (36%) of the corresponding alcohol Q27-OH.

Scheme 25-28 Steps iv:

the conversion of the resulting alcohol to the corresponding iodo derivative is carried out according to the procedure described in scheme 1-6 step iv.

Q25-OH, Q26-OH and Q28-OH were prepared analogously to the above-described process.

Synthesis of Q29:

process 29

Naphthyl propanol was prepared according to Searles, j.amer.chem.soc., 73(1951) 124.

Flow 29 step i:

the conversion of the resulting alcohol to the corresponding iodo derivative is carried out according to the procedure described in scheme 1-6 step iv.

Synthesis of Q30:

2-chloro-7-iodonaphthalene is prepared according to the literature (Beattie; Whitmore; J.chem.Soc.1934, 50, 51, 52).

Flow 30, step i:

a100 mL round bottom flask was charged with 2-chloro-7-iodonaphthalene (11mmol, 3.60g), allyl-tributyltin (13mmol, 4.30g, 3.96mL), tetrakis (triphenylphosphine) palladium (0) (0.55mmol, 0.635g), and 10mL degassed benzene under a nitrogen atmosphere. The mixture was heated to reflux under nitrogen and after 20 h another portion of tetrakis (triphenylphosphine) palladium (0) (0.55mmol, 0.635g) was added. The mixture was again heated at reflux for 20 hours, then cooled to room temperature and then poured into 70ml of 10% KF-solution. After stirring at room temperature for 30 min, the suspension was passed through Hyflo Supercel^®And (5) filtering. The filtrate was washed with water, brine and dried (Na)₂SO₄). Column chromatography on silica gel (eluent 1/9 toluene/petroleum ether) gave nearly pure 2-allyl-7-chloronaphthalene (1.80g, 80%).

Scheme 30 step ii:

a100 mL three-necked round bottom flask was charged with 2-allyl-7-chloronaphthalene (1.80g, 8.9mmol) and 12mL anhydrous THF under a nitrogen atmosphere. The mixture was cooled in an ice bath and borane-THF (3.05mmol, 3.05ml of a 1.0M solution of borane in THF) was added dropwise over about 20 minutes. After the addition, the mixture was allowed to warm to room temperature and stirred for 20 hours. A3.0N NaOH solution (2.65mmol, 0.89ml) was then added to the solution and the mixture was cooled in a water bath while 30% hydrogen peroxide (10.62mmol, 1.1ml) was added dropwise at such a rate that the temperature did not exceed 30 ℃. After the addition, the mixture was stirred at room temperature for 6 hours.

Water and diethyl ether were added to separate an organic layer. The aqueous layer was extracted again with ether, the combined organic extracts were washed with water, brine and dried (Na)₂SO₄). The drying agent was removed by filtration and the solvent was evaporated in vacuo. Flash column chromatography on silica gel (eluent: 1/99 methanol/dichloromethane) afforded 3- (7-chloro-naphthalen-2-yl) propan-1-ol (0.79g, 40%) Q30-OH.

Scheme 30, step iii:

the conversion of the resulting alcohol to the corresponding iodo derivative is carried out according to the procedure described in step iii of schemes 79-84 to afford Q30-I.

Synthesis of Q31:

fluorobromonaphthalenes were prepared according to Adcock, W.et al, Aust.J.chem., 23(1970) 1921-1937.

Flow 31, step i:

to a stirred suspension of magnesium turnings (0.49g, 20mmol) and 0.1ml of 1, 2-dibromoethane in 20ml of THF was added fluoronaphthalene (0.45g, 2mmol) in one portion. After the Grignard reaction started, a solution of fluoronaphthalene (4.06g, 18mmol) in 25ml of THF was slowly added dropwise. The temperature rose to 40 ℃ during the addition. The reaction mixture was stirred at room temperature for 2 hours until all the magnesium had disappeared. Freshly prepared LiCl in THF with CuCN was added dropwise at-10 ℃ resulting in the formation of a dark green solution. A solution of allyl bromide (1.9ml, 22mmol) in 15ml of THF is added dropwise at the same temperature. After complete addition, the reaction mixture was stirred at-10-0 ℃ for 30 minutes. The green colour disappeared and stirring was continued at room temperature for 20 hours. The reaction mixture was poured into 200ml of saturated NH₄In Cl, with CH₂Cl₂Extraction (3X). The combined organic layers were washed with brine and dried (MgSO)₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO)₂) Using petroleum ether as eluent, 1.65g (44%) of the corresponding allylfluoro-naphthalene was obtained.

Scheme 31 step ii:

to a cooled stirred solution of allyl-fluoronaphthalene (1.65g, 8.8mmol) in 10ml THF at-5 deg.C was slowly added dropwise 3.05ml 1.0M borane THF-complex. After stirring at the same temperature for 20 minutes and further at room temperature, iodine (2.11g, 8.6mmol) was added in one portion. 3.1ml of a freshly prepared 2.7M solution of sodium metal in MeOH (exothermic) were slowly added dropwise and the reaction mixture was stirred at room temperature for 20 h.75ml of NaHSO was added₃CH for aqueous layer₂Cl₂Extraction (3X). The organic layer was washed with brine (1 ×), dried (MgSO)₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO)₂) Using petroleum ether as eluent, 1.25g (46%) of iodide Q31-I was obtained as a white solid.

Synthesis of Q32-39 and Q41-42:

scheme 32-39, 41-42 step i:

KOH particles (140g, 2.5mol) were admixed with 10ml of H₂The mixture of O in the nickel crucible was heated to 250 ℃ with a bunsen burner while stirring with a stainless steel stirrer. The flame was removed and 7-amino-2-naphthalenesulfonic acid sodium salt (0.245mol, 60.0g) was added in 3 portions to the clear liquid. The clear liquid turned into a thick black slurry, which was again heated vigorously with a bunsen burner. At about 280 ℃ with gas evolution, the temperature of the mixture rapidly rose to 310 ℃ and 320 ℃. The temperature was maintained for 8 minutes and then the mixture was cooled to about 200 ℃. The thick black paste was carefully transferred to a 3 liter beaker filled with ice. The 2 experimental products were combined and neutralized with concentrated HCl with ice-salt bath cooling. The suspension was filtered and the black solid washed with 4 portions of 500ml 1.0N HCl and discarded. The resulting brown clear filtrate was cooled in an ice-salt bath and KOH particles were added until a bright suspension was obtained. Adding saturated NH₄After the OAc solution, a green-gray solid completely precipitated out, which was collected by filtration and air dried to give 7-aminonaphthalene-2-ol (27.9g, 36%).

Scheme 32-39, step ii 41-42:

7-amino-naphthalen-2-ol (0.169mol, 27.0g) was suspended in 750ml DCM and TEA (0.169mol, 17.2g, 23.6ml) was added. The mixture was stirred at room temperature for 30 minutes and then cooled to-5 in an ice-salt bathDEG C. A solution of p-toluenesulfonyl chloride (0.17mol, 32.4g) in 250ml DCM was added over 2.5 hours at-5-0 deg.C. The mixture was stirred at-5-0 ℃ for 10 minutes, then warmed to room temperature and stirred for 18 hours. Adding 1L H to the mixture₂O, passing the resulting suspension through Hyflo Super Cel^®Filter and transfer the filtrate to a separatory funnel. After extraction of the organic layer, the aqueous layer was extracted again with DCM (2 ×). The combined organic layers were washed with brine and dried (Na)₂SO₄) Concentration in vacuo afforded 51.5g of a black oil which was purified by column chromatography on silica gel (eluent 1/1 ethyl acetate/petroleum ether) to afford toluene-4-sulfonic acid-7-amino-naphthalen-2-yl ester (12.1g, 23%).

Scheme 32-39, 41-42 step iii:

a500 ml three-neck round bottom flask made of PFA was charged with 100g of pyridine/HF complex (30: 70% w/w) and cooled to-10 ℃ with an ice/EtOH bath. Toluene-4-sulfonic acid-7-amino-naphthalen-2-yl ester (38.6mmol, 12.1g) was added in one portion and the mixture was stirred for 10 min before a clear purple solution was obtained. The solution was cooled to < -30 ℃ in a dry ice cooling bath and sodium nitrite (42.5mmol, 2.93g, heated at 140 ℃ for 3 days to dry) was added in one portion. The dry ice bath was replaced with a normal ice bath and the mixture was stirred at 0 ℃ for 20 minutes and then heated to 55-60 ℃ on an oil bath (evolution of nitrogen was observed). After 1.5 hours, the nitrogen evolution ceased and the mixture was allowed to cool to room temperature and poured into a large ice-filled beaker. The mixture was transferred to a separatory funnel and extracted 3 times with DCM. The organic layers were pooled together, washed with brine and dried (Na)₂SO₄). Concentration in vacuo afforded 10.4g of a red oil which was purified by flash column chromatography on silica gel (eluent 1/4 ethyl acetate/petroleum ether) to afford toluene-4-sulfonic acid-7-fluoro-naphthalen-2-yl ester (7.1g, 58%).

Scheme 32-39, step iv 41-42:

in the presence of CaCl₂Tube-protected 500ml round-bottom flask was charged with toluene-4-sulfonic acid-7-fluoro-naphthalen-2-yl ester (22.4mmol, 7.1g) and 200ml MeOH. Heating the suspension untilA clear solution was obtained, which was then cooled to room temperature in a water bath to give a fine suspension. Magnesium (179mmol, 4.36g) was added to the mixture, followed by stirring at room temperature for 4 hours. The brown suspension was cooled in an ice-Et OH bath, acidified with 6N HCl and concentrated in vacuo. The mixture was transferred to a separatory funnel and extracted 3 times with ether. The organic extracts were pooled together, washed with brine and dried (Na)₂SO₄). The drying agent was removed by filtration and the solvent was evaporated in vacuo. Flash column chromatography on silica gel (eluent dichloromethane) afforded impure 7-fluoronaphthalen-2-ol (4.69g) as an off-white solid. The solid was dissolved in DCM and extracted 3 times with 2N NaOH solution. The basic extracts were combined and acidified with 3N HCl while cooling with an ice bath. White crystals precipitated from the solution, collected by filtration and air dried to give pure 7-fluoro-naphthalen-2-ol (3.16g, 87%).

Scheme 38-45; 47-48, step v:

to a 30ml toluene suspension of 0.97g (6mmol) 2-hydroxy-7-fluoronaphthalene, 2.83g (10.8mmol) triphenylphosphine and 1.11ml (12.6mmol) 3-bromo-1-propanol stirred at-5 deg.C was added dropwise a solution of 2.13ml (10.8mmol) DIAD in 5ml toluene. The reaction mixture was allowed to reach room temperature and then stirring was continued overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in 30ml of diethyl ether. The mixture was filtered, the filtrate was concentrated in vacuo and the residue was subjected to flash column chromatography (SiO)₂Eluent: CH (CH)₂Cl₂Petroleum ether 1/5). 1.28g (75%) of Q37-Br were obtained.

Q32 was synthesized as Q32-I, and the Q33-36, Q38-39 and Q41-42 derivatives were prepared (as bromides) analogously to the above procedure.

Synthesis of Q40, Q43:

schemes 40, 43

Scheme 40, 43 step i:

7-fluoro-2-naphthol (see scheme 32-39, step iv 41-42) (0.62g, 3.82mmol), olefin (1.11ml, 9.56mmol) and K₂CO₃(1.58g, 11.5mmol) in 35ml CH₃The mixture in CN was refluxed for 3 hours, then cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in H₂O and Et₂O, with Et₂O extraction (2 ×). Combining the organic layers with H₂O (1x) and brine (1x) followed by drying (Na)₂SO₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO)₂) With CH₂Cl₂Petroleum ether 1/5 as eluent gave 0.56g (58%) of the fluoronaphthol derivative Q43-Cl as a colorless oil.

Synthesis of Q44:

process 44

Flow 44, step i:

for fluoronaphthols, see scheme 32-39, step iv, 41-42. The Mitsunobu reaction is carried out analogously to step v in schemes 32-39, 41-42.

Scheme 44 step ii:

this step can be carried out analogously to step iii in schemes 1-6 to give Q44-OH.

Scheme 44, step iii:

Q44-OH was oxidized according to the procedure of step i in scheme B2. The product Q' 44-C ═ O was used for reductive alkylation of amines.

Synthesis of Q45-50:

the starting acids and reagents are commercially available. Cl-C4-MgBr was prepared according to C.R.Hebd, Senaces acad.Ser.G, 268(1969) 1152-1154.

Scheme 45-50 step i:

to a solution of the acid (25g, 148.8mmol) in 140ml benzene was added 0.07ml DMF followed by oxalyl chloride in one portion. Immediate foaming of the reaction mixture was observed. The reaction mixture was stirred at room temperature for 18 hours and the solvent was removed by evaporation under reduced pressure. Acetonitrile was added to the residue to co-evaporate, and again removed by evaporation under reduced pressure to yield 27.75g (100%).

Scheme 45-50 step ii:

mixing AlCl₃(27.8g, 208mmol) was suspended in 200ml of 1, 2-dichloroethane. The mixture was cooled to 0-5 ℃ under nitrogen and a solution of the acid chloride (27.75g, 148.8mmol) in 140ml of 1, 2-dichloroethane was added dropwise over 1 hour. The cooling bath was removed and after stirring for 30 minutes stirring was continued at 70 ℃ for 2 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of ice and 330ml concentrated HCl (36-38%). CH for aqueous layer₂Cl₂Extracting, and subjecting the obtained organic layer to H₂O(2x)、5％NaHCO₃And a brine wash. The organic layer was dried (MgSO₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure to give 19.02g (85%).

Scheme 45-50 step iii:

to a 0.5M solution of cyclopropylmagnesium bromide in THF (100ml, 50mmol) cooled at 15 deg.C was added a solution of ketone (5.3g, 35.3mmol) in 40ml of THF. The reaction mixture was stirred at reflux for 2 hours and then cooled in an ice bath. 50ml of saturated NH are added dropwise₄Cl, aqueous layer with Et₂And (4) extracting. Adding Et₂Washing O with brine(1X), drying (MgSO)₄) And evaporated under reduced pressure. The residue was dissolved in 85ml of acetic acid and 62ml of 20% HBr solution were added. The reaction mixture was stirred for 20 hours. Addition of H₂O, CH for aqueous layer₂Cl₂And (4) extracting. The organic layer is further substituted with H₂O (1X) and 5% NaHCO₃(1x) washing. The organic layer was dried (water filter resistant) and evaporated under reduced pressure. The residue is chromatographed on CH₂Cl₂Petroleum ether 2.5/97.5 as eluent gave 4.44g (49%) of indene Q49-Br.

Scheme 45-50 step iv:

was prepared according to the procedure described in step iii to give Q50-Cl.

The Q45, Q46, Q47, and Q48 derivatives were prepared analogously to the above procedure.

Synthesis of Q51:

process 51

The starting materials are commercially available.

Flow 51 step i:

a mixture of Grignard reagent (90ml, 90mmol) and CuI (18mg, 0.02mmol) was stirred for 15 minutes and then cooled in an ice bath. A solution of the diester (18.9ml, 96.7mmol) in 25ml THF was added over 90 minutes and the reaction mixture was stirred at 0 ℃ for 2 hours. 100ml of saturated NH are added dropwise₄Cl, aqueous layer with Et₂And (4) extracting. Adding Et₂The O fraction was washed with brine (1X) and dried (MgSO)₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure. The residue is chromatographed on CH₂Cl₂Petroleum ether 1/1 as eluent gave 26.17g (98%) of the adduct.

Process 51Step ii:

to a stirred solution of the adduct (26.17g, 88.4mmol) in 222ml EtOH was added 265ml 10% NaOH. The reaction mixture was refluxed for 3 hours and the solvent was evaporated under reduced pressure. The residue was cooled in ice and acidified with concentrated HCl (36-38%). The aqueous layer was extracted with EtOAc. The EtOAc fraction was washed with brine (1 ×), dried (MgSO)₄). The drying agent was removed by filtration and the solvent was evaporated under reduced pressure to give 20.9g (99%) of the diacid.

Scheme 51 step iii:

reacting diacid (20.9g, 87.1mmol) with Cu₂O (0.62g, 4.34mmol) in 600ml CH₃The mixture in CN was refluxed for 16 hours. The solvent was removed by evaporation under reduced pressure and 125ml 3N HCl was added to the residue. The aqueous layer was extracted with EtOAc. The EtOAc fraction was washed with brine (1 ×), dried (MgSO)₄). The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure to give 16.9g (99%) of the decarboxylated product.

Scheme 51 step iv:

prepared according to scheme 45-50, step i.

Scheme 51, step v:

prepared according to step ii of schemes 45-50.

Scheme 51 step vi:

prepared according to step iii of schemes 45-50 to yield Q51-Cl.

Synthesis of Q52-53:

scheme 52-53 step i:

a3 liter beaker was charged with 2-amino-5-fluoro-benzoic acid (64mmol, 10g), 100ml H₂O and 110ml concentrated HCl, and the suspension was cooled to 0 ℃ in an ice/acetone bath. To the mixture was added dropwise sodium nitrite (64mmol, 4.44g) in 68ml of H₂O solution while maintaining the temperature below 3 ℃. After the addition was complete, the brown solution was added portionwise over a period of 20 minutes to 760ml of H saturated with sulfur dioxide cooled to 0-5 ℃ with an ice bath under a stream of sulfur dioxide₂In O solution. After the addition was complete, the ice bath was removed and the solution was allowed to warm to room temperature while maintaining a stream of sulfur dioxide. After 1 hour the supply of sulphur dioxide was interrupted and the solution was left overnight at room temperature. 620ml of concentrated HCl was added to the resulting dark yellow solution, and after cooling the yellow precipitate mixture was isolated and collected on a cooled Buchner funnel. The solid was suspended in 2ml of concentrated HCl and 200ml of H₂O, the mixture was heated to reflux. After a period of time the solid dissolved to give a clear solution. After 1.5 hours at reflux, an orange/brown solid crystallized out and the mixture was cooled to room temperature and concentrated in vacuo to about 50 ml. The solid was collected and air dried to give 5-fluoro-1, 2-dihydro-indazol-3-one (5.05g, 52%).

Scheme 52-53 step ii:

5-fluoro-1, 2-dihydro-indazol-3-one (32mmol, 5.05g) was suspended in 30ml of pyridine, and chloroethyl formate (64mmol, 6.94g, 6.09ml) was added dropwise under cooling in an ice bath. The mixture was heated to reflux for 3 hours, then cooled to room temperature and concentrated in vacuo to give a dark red oil which crystallized upon addition of water. The solid was filtered and air dried to give the corresponding urethane (5.52g, 77%). Scheme 52-53 step iii:

to 20ml of toluene was added under nitrogen a urethane derivative (from step ii) (0.45g, 2mmol), 3-bromopropanol (0.18ml, 2.1mmol), Bu₃P (0.40g, 2mmol) and ADDP (0.5g, 2 mmol). After addition of the ADDP, the solution became clear. The reaction mixture was heated at 85 ℃ for 20 hours and cooled to room temperature. 2N NaOH and EtOAc were added and the aqueous layer was extracted with EtOAc (2X). The organic layers were combined, washed with 2N NaOH (1X), H₂O (1x) and brine(1X) Wash, then dry EtOAc (Na)₂SO₄) And evaporated under reduced pressure. The residue is chromatographed on CH₂Cl₂MeOH 99: 1 as eluent, 0.22g (32%) of the alkylated indazol-3-one was obtained.

Scheme 52-53 steps iv:

was carried out according to the procedure described in scheme a2, step i.

Scheme 52-53 step v:

ethyl carbamate (0.38g, 0.79mmol) was reacted with K₂CO₃(0.38g, 2.74mmol) in 21ml MeOH/DME/H₂The mixture in O (5/1/1) was stirred at room temperature for 4 hours. The reaction mixture was further purified by SCX-column (ion exchange column) with 1N NH₃The product was washed off the column with MeOH as eluent. The eluent was evaporated under reduced pressure to leave a residue at 20ml CH₃Refluxing in CN. The suspension was filtered with suction to give 0.28g (86%) of the deprotected product as a bright orange solid containing compound 125, which was then converted to its mono HC1 salt (AcCl/MeOH), 125-HCl.

Analogs of Q53 can also be synthesized, as described above.

Compounds 48, 49 and 124 were prepared analogously to the procedure given above.

Synthesis of Q54-59:

schemes 54-59

Indazole according to Christoph ru chardt, Volkert hasslemann; chem.; (1980) 908-927.

Scheme 54-59, step i:

56；R＝Cl，n＝3：

in N₂NaH (55%) (2.14g, 49.15mmol) was suspended in 70ml of anhydrous DMF under an atmosphere. 6-Chloroandazole (7.5g, 49.15mmol) was added at room temperature. The mixture was stirred for 1 hour, then cooled with an ice bath and (3-bromopropoxy) tert-butyldimethylsilane (11.4ml, 49.15mmol) was added dropwise. After stirring for another 15 minutes, the mixture was allowed to reach room temperature and stirring was continued for another 8 hours. Subsequently, the mixture was concentrated in vacuo, the residue was dissolved in DCM and the organic layer was then washed with water (3 ×). The organic layer was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (SiO)₂Eluent: petroleum ether/diethyl ether 5/1 → 4/1) to give the N1 substituted indazole in 61% yield.

Scheme 54-59, step ii:

to stirred KF.2H₂A solution of O (4.3g, 45.24mmol) and benzyltriethylammonium chloride (7.6g, 33.18mmol) in 300ml acetonitrile was added N1 substituted indazole (from step i) (9.8g, 30.16 mmol). The mixture was warmed to reflux and stirred for 8 hours. The solvent was evaporated and DCM was added to the residue. The organic layer was washed with water (3 ×). The organic layer was concentrated in vacuo. The crude product was purified by flash chromatography on silica (eluent: diethyl ether → diethyl ether with 1% MeOH) to give 3- (indazol-1-yl) propanol in 95% yield.

Other indazolyl alcohols are prepared similarly. In step ii, instead of KF.2H, a THF solution of tetrabutylammonium chloride may be used₂Combination of O/benzyltriethylammonium chloride.

Synthesis of Q60:

Q60-Br was synthesized analogously to the syntheses depicted in schemes 52-53, using bromoethanol in Mitsunobu step iii.

Synthesis of Q61-62:

Q61-I and Q62-I were synthesized analogously to the syntheses depicted in schemes 13-20, steps ii, iii and iv.

Synthesis of Q63:

Q63-I was synthesized as described in scheme 63:

scheme 63

Scheme 63, step i:

to 15ml of Et containing fluorobromonaphthalene (0.90g, 4mmol), triphenylphosphine (0.21g, 0.8mmol) and dichlorobis (triphenylphosphine) palladium (0.28g, 0.4mmol)₃The N suspension was purged with nitrogen for 1 hour. 3-butyn-1-ol (0.42g, 0.45ml, 6mmol) was added and the mixture was heated to 40-50 ℃ on an oil bath. After stirring at this temperature for 15 minutes, CuI (0.15g, 0.8mmol) was added and the mixture was heated and stirred at 70 ℃ for 48 hours. The resulting black suspension was brought to room temperature and diethyl ether and water were added. The fractions were separated and the aqueous layer was extracted twice with diethyl ether. The combined organic extracts were washed with water, brine and dried (Na)₂SO₄). After removal of the drying agent by filtration and removal of the solvent by concentration in vacuo, the residue is subjected to flash chromatography (SiO)₂Eluent: DCM) to give Q63-OH, i.e. 4- (2-fluoro-naphthalen-7-yl) -3-butyn-1-ol (0.30g, 1.46 mmol).

Scheme 63, step ii:

step I the conversion of the alcohol to the corresponding iodo derivative is performed according to scheme 1-6 step iv to give Q63-I.

Synthesis of Q64:

process 64

In the process 64, the process is described,step i:

a solution of Red-Al (4.47ml of a 3.4M solution in toluene) in 25ml of anhydrous diethyl ether was cooled in an ice bath under nitrogen, and a solution of Q63-OH (1.90g, 9.5mmol) in 40ml of diethyl ether (anhydrous) was added dropwise thereto. After the addition was complete, the resulting mixture was stirred at 0 ℃ for 10 minutes, then allowed to reach room temperature and stirred for an additional 2.5 hours. The reaction mixture was cooled again in an ice bath and 50ml of 3.6M H were added carefully₂SO₄And (6) quenching. The reaction mixture was extracted three times with diethyl ether. The combined organic extracts were washed with water, brine and dried (Na)₂SO₄). After removal of the drying agent by filtration and removal of the solvent by concentration in vacuo, the residue is subjected to flash chromatography (SiO)₂Eluent: DCM) to give 1.17g Q64-OH, i.e. 4- (2-fluoro-naphthalen-7-yl) -3-buten-1-ol (5.8 mmol).

Scheme 64, step ii:

5ml of concentrated hydrochloric acid were added to a solution of Q64-OH (1.17g, 5.8mmol) in 5ml of THF. The mixture was stirred at room temperature for 4.5 hours, then another 2ml of concentrated hydrochloric acid and 2ml of THF were added. After a further 30 minutes diethyl ether and water were added and the resulting fractions were separated. The aqueous layer was extracted twice with diethyl ether. The combined organic fractions were washed with water, brine and dried (Na)₂SO₄). The drying agent was removed by filtration, the solvent was concentrated in vacuo and the residue was flash chromatographed (SiO)₂Eluent: DCM) gave 1.03g Q64-Cl (4.67 mmol).

The specific compounds synthesized as described above serve to further illustrate the invention in detail and are therefore not to be considered as limiting the scope of the invention in any way. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. Accordingly, the specification and examples are to be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Abbreviations

AcCl acetyl chloride

ADDP 1, 1' - (Azodicarbonyl) dipiperidine

CDI carbonyl diimidazole

Dba see Huang et al, J.am.chem.Soc., 125(2003)6653

DCE Dichloroethane

DCM dichloromethane

DIAD diazodicarboxylic acid diisopropyl ester

DIPE diisopropyl ether

DIPEA diisopropylethylamine

CH₂Cl₂(ml) MeOH(ml) NH₄OH(ml)

DMA 0.125 980 18.75 1.25

DMA 0.187 970 28.13 1.87

DMA 0.25 960 37.5 2.5

DMA 0.50 920 75.0 5.0

DMA 0.75 880 112.5 7.5

DMA 1.00 840 150.0 10.0

DMAP 4-dimethylaminopyridine

DME dimethoxyethane

DMF N, N-dimethylformamide

EtOH ethanol

MeOH methanol

MTBE methyl tert-butyl ether

NMP N-methylpyrrolidone

PA Petroleum Ether

TBAB tetrabutylammonium bromide

TBAC tetrabutylammonium chloride

TBAF tetrabutylammonium fluoride

THF tetrahydrofuran

XPHOS see Huang et al, J.Am.chem.Soc., 125(2003)6653

Example (b): formulations of compound 56 for animal studies

For oral (p.o.) administration: in a glass tube, add some glass beads to the desired amount (0.5-5mg) of solid compound 56 and grind the solid by vortexing for 2 minutes. After addition of 1ml of a 1% solution of methylcellulose in water and 2% (v/v) of poloxamer 188(Lutrol F68), the compound was suspended by vortexing for 10 minutes. The pH was adjusted to 7 with a few drops of aqueous NaOH (0.1N). The remaining particles in suspension were further suspended using an ultrasonic bath.

For intraperitoneal (i.p.) administration: in a glass tube, add some glass beads to the desired amount (0.5-15mg) of solid compound 56 and grind the solid by vortexing for 2 minutes. After addition of 1ml of 1% methylcellulose in 5% mannitol in water, the compound was suspended by vortexing for 10 minutes. Finally the pH was adjusted to 7.

Example (b): results of pharmacological tests

TABLE 2 in vitro affinity and functional Activity of the Compounds of the invention

dopamine-D obtained according to the protocol given above₂And serotonin reuptake receptor affinity data are shown in the table below. For cloned human dopamine D₂The in vitro functional activity of the L receptor is measured by accumulation of radiolabeled cAMP (potency: pEC)₅₀Intrinsic activity epsilon).

	dopamine-D2	5-HT reuptake	dopamine-D2
	Bonding of	Bonding of	cAMP accumulation
Compound (I)	pKi	pKi	Epsilon (intrinsic activity)
6	7.7	9.8	0.85
				7	8.2	8.5	0.39
8	8.3	8.9	0.10
				16	8.5	9.1	0.73
53	8.8	8.8	0.62
				56	8.9	8.1	0.38
79	7.1	8.5	0.10
				94	7.8	8.5	0.70
98	6.9	9.0	0.75
				102	7.4	9.0	0.81
108	7.7	8.1	0.95
				117	8.1	＞9.0	0.29
135	7.2	8.7	0.45
				140	7.0	7.3	0.24

Claims (10)

1. A compound of the general formula (1):

wherein: x is S or O,

R₁is H, (C)₁-C₆) Alkyl, CF₃、CH₂CF₃OH or O- (C)₁-C₆) Alkyl radical

R₂Is H, (C)₁-C₆) Alkyl, halogen orCyano radical

R₃Is H or (C)₁-C₆) Alkyl radical

R₄Is H, (C)₁-C₆) Alkyl optionally substituted by halogen atoms

T is a saturated or unsaturated carbon chain of 2 to 7 atoms, in which one carbon atom may be replaced by a nitrogen atom, optionally substituted by (C)₁-C₃) Alkyl, CF₃Or CH₂CF₃Substituted by a group, or by an oxygen or sulphur atom, the chain being optionally substituted by one or more substituents selected from: (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, halogen, cyano, trifluoromethyl, OCF₃、SCF₃、OCHF₂And a nitro group,

ar is selected from the following groups:

the Ar group is optionally further substituted with one or more substituents selected from: (C)₁-C₃) Alkyl, (C)₁-C₃) Alkoxy, halogen, cyano, trifluoromethyl, OCF₃、SCF₃、OCHF₂And a nitro group,

and in the Ar group containing a five-membered ring, the double bond in the five-membered ring may be saturated,

and tautomers, stereoisomers and N-oxides thereof, and pharmacologically acceptable salts, hydrates and solvates of said compounds of formula (1) and tautomers, stereoisomers and N-oxides thereof.

2. A compound of formula (1) as claimed in claim 1 wherein the phenylpiperazine part of the molecule is selected from the group consisting of:

in these formulae, the dots represent the linkage to ` T ` in formula (1),

and wherein the intramolecular second moiety represented by the symbol-T-Ar in the formula (1) is selected from the group consisting of:

in these formulae, the dots represent the attachment to the phenylpiperazine moiety of the compound of formula (1),

and tautomers, stereoisomers and N-oxides thereof, and pharmacologically acceptable salts, hydrates and solvates of said compounds of formula (1) and tautomers, stereoisomers and N-oxides thereof.

3. A pharmaceutical composition comprising, as an active ingredient, a pharmacologically active amount of at least one compound as claimed in claim 1 or a salt thereof in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance.

4. A process for the preparation of a composition as claimed in claim 3, characterized in that at least one compound according to claim 1 or a salt thereof is brought into a form suitable for administration.

5. A compound according to claim 1 or a salt thereof for use as a medicament.

6. Use of a compound according to claim 1 for the preparation of a pharmaceutical composition for the treatment of CNS disorders.

7. Use as claimed in claim 6, characterized in that the disorder is aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, Parkinson's disease, schizophrenia and other psychotic disorders.

8. Use as claimed in claim 6, characterized in that the disorder is depression.

9. Use as claimed in claim 6, characterized in that the disorders are schizophrenia and other psychotic disorders.

10. Use as claimed in claim 6, characterized in that the disorder is Parkinson's disease.