Title of Invention

PIPERAZINE OXIME DERIVATIVES HAVING NK-1 RECEPTOR ANTAGONISTIC ACTIVITY

Abstract wherein X represents phenyl or pyridyl substituted with 1 or 2 substituents from the group CH<sub>3</sub>, CF<sub>3</sub>, OCH<sub>3</sub>, halogen, cyano and 5-CF<sub>3</sub>-tetrazol-l-yl, Y represents 2- or 3- indolyl, phenyl, 7-aza-indol-3-yl or 3-indazolyl, 2-naphthyl, 3-benzo[b]thiophenyl or 2-benzofuranyl, which groups may be substituted with one or more halogen or alkyl (1-3C), 'n has the value 0-3, m has the value 0-2, R<sub>1</sub> represents NH<sub>2</sub>, NH-alkyl (1-3C), dialkyl (1-3C)N, morpholino or morpholino substituted with one or two methyl and/or ." methoxymethyl groups, thiomorpholino, 1,1 -dioxothiomorpholino, 2-, 3- or 4-pyridyl .or 4-CH<sub>3</sub>-piperazinyl, R<sub>2</sub> is hydrogen, alkyl (1-4C) or phenyl, or R<sub>2</sub> together with (CH<sub>2</sub>)<sub>m</sub> wherein m is 1, and the intermediate carbon, nitrogen and oxygen atoms forms an isoxazolyl or a 4,5-dihydroisoxazolyl group, R<sub>3</sub> and R<sub>4</sub> independently represent hydrogen or methyl, or R<sub>3</sub> and R<sub>4</sub> together are oxygen, and physiologically acceptable salts thereof.
Full Text The present invention relates to a group of novel piperazine oxime derivatives liaving interesting NK-1 antagonistic activity.
The invention also relates to a nnethod for the preparation of the novel compounds, and to pharmaceutical compositions comprising at least one of the novel compounds as an active ingredient, and the use of these compositions for the treatment of disorders in which neurokinin-1 receptors are involved.
EP 0899270 relates to 2-(3-indolylmethyl)-1-ben2oyl-4-[(2-(benzylamino)ethyl) aminocarbonyl)] piperazine derivatives having NK-1 antagonistic activity.
It has now been found that compounds wherein the [(benzylamino)ethyl aminocarbonyl] group at N-4 is replaced by an oxime group also have very interesting NK-1 antagonistic properties.
The invention relates to compounds of the general formula (1)

wherein:
- X represents phenyl or pyridyl substituted with 1 or 2 substituents from the group
CH3, CF3, OCH3, halogen, cyano and S-CFg-tetrazol-l-yl
- Y represents 2- or 3-indolyl, phenyl, 7-aza-indol-3-yl or 3-lndazolyl, 2-naphthyl,
3-benzo[b]thiophenyl or 2-benzofuranyl, which groups may be substituted with one or more halogen or alkyl (1-3C)
- n has the value 0-3
- m has the value 0-2

- Ri represents NHj, NH-alkyI (1-3C), dialkyl (1-3C)N, morpholino or morpholino
substituted with one or two methyl and/or methoxymethyl groups, thiomorpholino, 1,1-dioxothiomorpholino, 2-, 3- or4-pyridyl or 4-CH3-pipera2inyl
- Rj is hydrogen, alkyl {1-4C) or phenyl, or Rj together with (CHa)^ wherein m is 1,
and the intennediate carbon, nitrogen and oxygen atoms forms an isoxazoiyi or a 4,5-dihydroisoxazolyi group,
- Rg and R4 independently represent hydrogen or methyl, or R3 and R, together are
oxygen, and physiologically acceptable salts thereof.
In the description of the substituents the abbreviation "alkyi{1-3C)" means: "methyl, ethyl, n-propyl or isopropyl", and the abbreviation "alkyl(1-4C)" means "methyl, ethyl, n-propyl, isopropyl, 1-butyl, 2-butyl, 1-{2-methyl)-propyl and 2-{2-methy!)-pn>pyr.
The invention particularly relates to compounds having formula {1) wherein Y represents 2- or 3-indolyl, phenyl, 7-aza-indol-3-yl or 3-indazo!yl, which groups may be substituted with halogen or alkyl (1-3C); R, represents NHj, NH-alkyI (1-3C), dialkyl (1-3C)N, morpholino or morpholino substituted with one or two methyl and/or methoxymethyl groups, thiomorpholino, 2-, 3- or 4-pyridyl or 4-CH3-plpera2inyl, and R3 and R4 are hydrogen and X, n, m and R2 have the meanings given above.
More particularly the invention relates to compounds having formula (1) \A^erein X represents phenyl substituted with 2 substituents from the group CF3 and halogen, Y is 3-indolyl, m is 1 or 2, n is 1 or 2 and Ri, Ra, R3, and R4 have the meanings given above.
Still more particularly the invention relates to such compounds having formula (1) wherein X represents phenyl substituted at positions 3 and 5 with CF3 or halogen.
In this prefen-ed group of compounds having formula (1) m and n have the value 1 or 2, Ri is amino, dimethylamino or morpholino, Rj is hydrogen, methyl or phenyl, or R2 together with (CHz)^, wherein m = 1, and the intermediate carbon, nitrogen and oxygen atoms forms the isoxazoiyi group or dihydroisoxazotyl group.

Both compounds having formula (1) wherein the group -CH2-Y has the /?-configuration or the S-configuration, and the E- and Z- enantiomers of the oxime-etiier belong to the invention.
The compounds having formula (1) and their salts can be obtained according to at least one of the following methods known for compounds of this type.
Compound having fonnula (1) wherein n has the value 1-3 can be obtained by reaction of a compound having formula (2)

with a compound of the formula (3)

Wherein X, Y, m, R^ and R2 have the above meanings. This reaction is preferably carried out in a solvent such as methanol or ethanoi in the presence of sodium acetate.
Compounds having fonnula (1) wherein n = 0 can be obtained by reaction of a compound having fomiula (4)


with, N.N-dimethylformamide dimethylacetal, preferably in acetonitrile at reflux temperature, followed by reaction with a compound having formula (3) for example in THF at reflux temperature.
Compounds having formula (1) wherein n = 1, R2 is hydrogen, and Ri is morpholino can be obtained by reaction of a compound having formula {2) with a compound having fonnula (7)

This reaction can be carried out in a solvent such as acetonitrile in the presence of a base such as triethylamine and Kl at temperatures between room temperature and 80 ° C.
Compounds having formula (1) wherein R2 together with {CHa)^ and the intermediate atoms forms the isoxazolyl or4,5-dihydroisoxazolyl group can be obtained by reaction of a compound having formula (4) with a compound having formula (9)

wherein L is a so-called leaving group, for example chloro or bromo, and the dotted line is a bond or is absent.
The starting materials having formula (2) can be obtained
a) by reaction of a compound having formula (4) with a compound having formula (5)

wherein L is so-called leaving group, for example chloro or bromo. This reaction is carried out in a solvent such as acetonitrile in the presence of a base such as triethylamine and Kl at temperatures between room temperature and 80 " C; or
b) by acidic hydrolysis of a compound obtained from the reaction between a
compound having formula (4) with a compound having formula (6)

wherein the symbols have the above meanings.
The all c) by reaction of a compound having formula (4) with methyl vinyl ketone. This
reaction is preferably carried out in a solvent such as a toluene at room
temperature.
The starting compounds having formula {3) can be prepared
a) by reaction of a compound having formula (8)

with 1-phenyl ethanone-oxime, followed by acidic hydrolysis, in which formula L is a so-called leaving group, for example bromo or chloro.
The alkylation reaction can be carried out in a biphasic system consisting of a solvent such as toluene and aqueous NaOH and tetrabutylammonlum bromide, at a temperature of about 90° C. The hydrolysis can be carried out in 6 M HCI (aq.); or
b) according to the method described by Henmi et al. (Org. Prep. Proceed. Int. 1994,
26,111).
The starting compounds having formula (4) can be obtained from compounds having formula (10) in a similar manner as described in EP 0655442

The starting compounds having formula (7) can be obtained analogous to the synthesis of 1-chloro-2-methoxyiminoethane as described in J. Chem. Soc. Perkin Trans. 1,1991, 1721.

starting compounds having formula (9) can be obtained from 2-nitroetliyl 2-tetrahydropyranyl ether and ttie appropriate allyl- or propargylamine, analogous to ttie method described in J. Med. Chem. 1995, 38, 4198.
Starting connpounds having formula (10) can be obtained in a similar manner as described in EP 0655442, or from 4-ben2yi-pipera2ine-1-carboxylic acid tert-butyl ester by aikylation followed by acid treatment.
The aikylation of 4-benzyl-piperazine-1-carboxyiic acid terf-butyl ester (T.R. Herrin, J.M. Pauvlik. E.V. Schuber, A.O. Geiszler J. Med. Chem. 1975, 18,1216) can be done in diethylether by anion formation with a strong base, such as sec-butyl lithium in the presence of tetramethylethylenedlamine, at low temperature followed by the addition of a suitable alkylating agent of fonmula (11).
YCHjBr (11)
Removal of the fert-butyloxycarbonyl-group can be done using known procedures (T.W. Greene, P.G.I\4. Wuts Protective groups in organic synttiesis, 3"* ed., John Wiley & Sons, 1999).
The invention also provides a method of preparing compounds of the general formula

wherein R represents hydrogen, alkyl (1-4C) or 0-alkyl(l-4C) and Y has the meanings given in claim 1, characterised in that a solution of a compound of the general formula
in the presence of a coordinating di- or triamine, preferably tetramethyl-ethylenediamine, is treated with a solution of an alkyl lithium base, preferably sec-butyllithium, followed by the addition of a compound of the general formula
Y-CHzBr
to yield a compound of the general formula

and removal of the tert-butyloxycarbonyl group.
Suitable acid addition salts can be fornrwd with inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric add and nitric add, or with organic acids such as citric acid, fumaric acid, maleic acid, tartaric add, acetic acid, trifluoro acetic add, benzoic acid, p-toluene sulphonic acid, methanesulphonic add and naphthalene sulphonic acid.

The compounds of the invention of the general formula {1), as well as the salts thereof, have NK-1 antagonistic activity and show a good bioavailability. They are useful in the treatment of disorders in which neurokinins which interact with NK-1 receptors, e.g. neurokinin-1 {= Substance P) are involved, or that can be treated via manipulation of those receptors. For instance in acute and chronic pain, emesis, inflammatory diseases such as meningitis, arthritis, asthma, psoriasis and (sun)burns; gastro-intestinal disorders, in particular irritable bowel syndrome, inflammatory bowel disease (Crohn"s disease), ulcerative colitis; bladder or Gi tract hypermotility disorders, urinary tract inflammation; allergic responses such as eczema and rhinitis; cardio¬vascular disorders such as hypertension, atherosclerosis, edema, angina, cluster headache and migraine; cutaneous diseases such as urticaria, lupus erythematosus and pruritus; respiratory disorders including chronic obstructive pulmonary disease, bronchospams, bronchopneumonia, bronchitis, respiratory distress syndrome and cystic fibrosis; various neoplastic diseases; psychiatric and/or neurological disorders such as schizophrenia and other psychotic disorders; mood disorders such as bipolar I disorders, bipolar 11 disorders and unipolar depressive disorders like minor depression, seasonal affective disorder, postnatal depression dysthymia and major depression; anxiety disorders including panic disorder (with or without agoraphobia), social phobia, obsessive compulsive disorder (with or without co-morbid chronic tic or schizotypal disorder), posttraumatic stress disorder and generalized anxiety disorder; substance related disorders. Including substance use disorders (like dependence and abuse) and substance induced disorders (like substance withdrawal); pervasive development disorders including autistic disorder and Rett"s disorder; attention deficit and disruptive behavior disorders such as attention deficit hyperactivity disorder; impulse control disorders like agression, pathological gambling; eating disorders like anorexia nervosa and bulimia nervosa, obesity; sleep disorders like insomnia; tic disorders like Tourette"s disorder; restless legs syndrome; disorders characterized by impairment of cognition and memory such as Alzheimer"s disease, Creutzfeldt-Jacob disease, Huntington"s disease, Parkinson"s disease and neurorehabilitation (post-traumatic brain lesions)
The NK-1 antagonistic properties of the compounds of the invention were tested using the methods outlined below.
Pharmacological Methods

Receptor Binding for human NK-1 Receptors
Affinity of the compounds for human NK-1 receptors was assessed using radioreceptor binding assays. Membrane preparations were prepared from Chinese Hamster Ovarium fibroblast (CHO) cells in which the human NK-1 receptor was stably expressed. Membranes were incubated with pH]-substance P in the absence or the presence of specified concentrations of the compounds, diluted in a suitable buffer in presence of peptidase inhibitor for 10 min at 25°C. Separation of bound radioactivity from free was done by filtration over Whatman GF/B glass fiber filters with two 5 sec washings. Bound radioactivity was counted by liquid scintillation counting using a Betaplate counter. Measured radioactivity was plotted against the concentration of the displacing test compound and displacement curves were calculated by four-parameter logistic regression, resulting in IC50 values, i.e. that concentration of displacing compound by which 50% of the radioligand is displaced. Affinity pK| values were calculated by coaecting the IC50 values for radioligand concentration and its affinity for the human NK-1 receptor according to the Cheng-PrusolT equation:

in which the IC50 is as described above, S is the concentration pH]-substance P used in the assay expressed in mol/l, and Kj is the equilibrium dissociation constant of pHj-substance P for human NK-1 receptors (in mol/l).
In vitro functional metliods for NK-1 receptors
PI metabolism
The effects of test compounds on the turnover of phosphatidyl-inositol (PI) was assessed in CHO cells, stably expressing the cloned human neurokinin NK-1 receptors. In these cells, NK-1 receptors are positively linked to phospholipase C, liberating inositolphosphates from membrane phospholipids. Inositol phosphates can accumulate in cells when inositol-1-phosphatase is inhibited by preincubating cells with lithium. For tests, cells were cultured in 24-well plates and incubated overnight with pH]-myo- inositol which is metabolically incorporated in membrane phospholipids. After labeling, cells were rinsed twice with phosphate-buffered saline (pH 7.4) and incubated for 1 hr in a-DMEM. Thereafter, LiCI was added and 20 min later the test compounds

were added to the incubation medium and incubated for 1 hr. Botfi LiCI and substance P in the absence or presence of test compounds {at specified concentrations) were diluted to appropriate concentrations in serum-free a-DMEI\/l in such a way that LiCI had a final concentration of 5 mM.
After incubation, the medium was aspirated and cells were extracted with 5% trichloracetic acid. The inositol phosphates were recovered from the extract by sequential organic extraction using dichloromethane and water and ion-exchange chromatography over AG-1X2 DOWEX columns that were eluted by 1M ammonium fonnate (pH 7). Radioactivity in eluted fractions was counted using liquid scintillation counting and radioactivity was plotted against compound concentrations to construct concentration-effect relationships. Four-parameter logistic regression was done allowing estimates for potency and Intrinsic activity of compounds. ICso values, i.e. that compound concentration that antagonized 50% of substance P-induced accumulation of inositol phosphates, were obtained and antagonist potencies (pAj) values were calculated using:

in which the ICso of the test compound was obtained from concentration-effect relationships, [SP] is the concentration of substance P (in mol/l; typically 10 nM), and the ECsD is the potency of substance P at human cloned NK-1 receptors.
cAMP measurements
The effects of test compounds at formation of cyclic AMP (cM/lP) was assessed using CHO fibroblast cells, stably expressing cloned human NK-1 receptors. In addition to coupling to phospholipase C, human NK-1 receptors are also able to stimulate adenylate cyclase, which converts ATP into cAMP. For tests, cells were cultured in 24-well plates. Prior to experiments, medium was replaced by serum-free a-DMEM culture medium, containing pH]-adenine which is taken up by the cells and converted sequentially into radiolabeled adenosine, AMP, ADP and ultimately into radiolabeled ATP. After 2 hrs, cells were rinsed twice with phosphate-buffered saline (pH 7.4) in presence of 1 mM isobutylmethylxanthine (IBMX; inhibitor of phosphodiesterases that hydrolyse cAMP into AMP). Subsequently, cells were stimulated by 10 nM substance P in absence or presence of test compounds in appropriate dilutions In PBS/IBMX for 20 min. After stimulation, medium was aspirated and cells were extracted by 5% trichloracetic acid. Radiolabeled ATP and cAMP were recovered from the extracts

using sequential column chromatography. Extracts were separated by ion-exchange chromatography over DOWEX 50WX4 columns, allowing the recovery of ATP. Columns were subsequently put on top of aluminum oxide columns and eluted with water. Recovery of cAMP was performed by eluting the aluminum oxide columns with 100 mM imidazole (pH 7.4). Both ATP and cAMP fractions were counted for radioactivity using liquid scintillation counting and conversion ratios were calculated as:

Concentration-response relationships were constructed by plotting cAMP conversion against compound concentration and ICso concentrations were calculated by four-parameter logistic regression. Antagonist potencies (pAj) values were calculated using:

in which the IC50 of the test compound was obtained from concentration-effect relationships, [SP] is the concentration of substance P (in mol/l; typically 10 nM), and the EC50 is the potency of substance P at human cloned NK-1 receptors.
NK-1 agonist -induced gerbil Foot-Tapping
The ability of NK-1 antagonists to antagonise foot-tapping induced by centrally administered NK-1 agonists has been demonstrated (Rupniak and Williams, 1994 (Eur. J. Pharmacol. 265:179); Bristowand Young, 1994 (Eur. J. Pharmacol. 254:245)). Therefore, we have used this model to assess the in vivo activity of the compounds of the invention.
60 min prior to anaesthesia with NjO (O.SUmin), halothane (3%) and Oj (0.8 L/min) male gerbils (40-60 g; Charles River) received an injection of vehicle or test compound (pars orale). Upon successful narcosis the anaesthetic was adjusted to NjO (0.6L/min), halothane (1.5%) and O2 (0.6 L/min) and a midline scalp incision made. GR 73632 was infused into the cerebroventricular space (AP - 0.5mm, L -1.2 mm, and vertical -4.5mm from bregma). Following recovery from anaesthesia (about 3-4 min) the foot

tapping response was recorded for 5 minutes. Tlie predefined criteria for tfie antagonism of this response was defined as inhibition of foot tapping for > 5 minutes.
The compounds of the invention have a high affinity for NK-1 receptors in the binding assay described above. The compounds of the invention are also active in the cAIVlP assay, their pAz-values being in line with their pKrvalues. Some of the compounds belonging to the invention penetrate the blood brain barrier as is evident from their activity in the neurokinin-agonist induced gerbil foot tapping assay. This property maizes them useful in the treatment of CNS disorders.
The invention is further illustrated by means of the following specific examples. These examples are only intended to further illustrate the invention, in more detail, and therefore are not deemed to restrict the scope of the invention in any way.
Example 1
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-y[methyl)-4-(2-propanon-1-yl)piperazine (255 mg), 0-[2-{dimethyiamino)ethyi]hydroxylamine dihydrochloride {89 mg), sodium acetate (catalytically), and methanol (10 mL) was heated under reflux for 2 h. The solvent was removed in vacuo, and the residue was treated with dichloromethane and NaOH (aq, 2N). The layers were separated, the organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (SiOj, CH2Cl2/MeOH/NH40H 92/7.5/0.5) to afford 1-{(2/?)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yI}-2-propanone 0-[2-(dimethylamino)-ethyl]oxime 0.31 g (>95%) as an E/Z mixture. R, 0.26 {CH2Cl2/MeOH/NH40H 92/7.5/0.5).

The following compounds were obtained according to a similar manner:
1) 1-{{2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yimethyl)-piperazin-4-yl}-2-phenyl-2-ethanone 0-[2-(morpholin-4-yl)ethyl]oxime. MH* 702; R, 0.27 + 0.34 (E + Z isomer) (CHzCla/MeOH 95/5).
2) 1 -{(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1 H-indol-3-ylmethyl)-piperazin-4-yi}-2-phenyl-2-ethanone 0-[2-{dlmethyiamino)ethyl]oxime. MH* 660; R, 0.50 (CHjCij/MeOH/NH.OH 92/7.5/0.5).
3) 1 -{(2R)-1 -[3,5-bis(triftuoromethyl)ben2oyl]-2-{1 H-indol-3-ylmethyl)-pipera2in-4-yl}-2-phenyl-2-ethanone 0-[2-aminoethyl]oxime. R, 0.30 (CH2Cl2/MeOH/NH40H 92/7.5/0.5).
4) 1 -{(2R)-1-[3,5-bis(trifluoromethyl)benzoyri-2-{1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-phenyl-2-ethanone 0-[3-(morpholin-4-yl)propyl3oxime. MH* 716; /?,0.30 (CHjCla/MeOH 95/5).
4a) 1 -{{2f?)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-phenyl-2-ethanone 0-[3-{dimethylamino)propyl]oxime. MH* 674; R, 0.40 (CHjCla/MeOH/NH^OH 92/7.5/0.5).
5) 1 -{(2R)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(1 H-indol-3-ylmethyl)-piperazin-4-yI}-2-propanone O-methyloxime. MH* 541; R, 0.55 (EtOAc).
6) 1 -{(2/?)-1 -[3,5-bis{trifluoromethyl)benzoyl]-2-{1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-(morphoiin-4-yl)ethyl]oxime. MH* 640; R, 0.30 (CHjClz/MeOH 95/5).
7) 1 -{(2R)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(1 H-indol-3-ylmethyl)-piperazin-:-4-yi}-2-propanone 0-[2-(1-thiomorpholin-4-yl)ethyl]oxime. MH* 656; f?,0.70 (CHzCyMeOH/NH^OH 92/7.5/0.5).
8) 1-{{2f?)-1-[3,5-bis(trifluoromethyl)benzoy!]-2-(1W-lndol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-(4-methyl-1-piperazinyl)ethyl]oxime. MH* 653; R, 0.30 (CH2Cl2/MeOH/NH40H 92/7.5/0.5).
9) 1-{{2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-aminoethyGoxime. MH* 570.
10) 1-{(2R)-1 -[3,5-bis(trifluoromethy!)benzoyl]-2-(1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-(methyiamino)ethyi]oxime. MH* 584; R, 0.43 (CH2Cl2/MeOH/NH40H 85/15/1).
11) 1-{(2R)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(1 HHndoi-3-ylmethyl)-piperaztn-4-yl}-2-propanone 0-[3-(morpholin-4-yl)propyl]oxime. R, 0.35 (CHjClz/MeOH 95/5).

2) 1 -{(2R)-1 -[3,5-bis(trifluoromethyl)benzoyI]-2-(1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-
propanone 0-[3-(climethylamino)propyi]oxim6. MH* 611; R, 0.35
(CH2Cl2/MeOH/NH40H 92/7.5/0.5). 3)1-{(2f?)-1-[3,5-bJs(trif!uoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-3-
butanone 0-[2-{dimethylamino)ethyl]oxime. MH*612; R^OAO
(CH2Cl2/MeOH/NH40H 93/7/0.5). 4)1-{(2R)-1-[3,5-bis(trifluoromefhyl)benzoyl]-2-(1^/-indol-3-ylmethyl)-piperazin-4-yl}-3-
butanone 0-[2-{morpholin-4-yl)ethyl]oxime. MH* 654; R, 0.37
(CH2Cl2/MeOH/NH40H 93/7/0.5). 15) 1 -{(2/=?)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(1 W-indol-3-ylmethyl)-piperazin-4-yl}-3-
butanone 0-[2-aminoethyl]oxime. MH* 584; RfO.W (CHjCla/MeOH/NH^OH
93/7/0.5). l6)1-{(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-3-
butanone 0-[3-(dimethylamino)propyl]oxime. MH* 626; Rf0.20
(CHjCl^/MeOH/NH^OH 93/7/0.5). 17)1-{{2R)-1-[3.5-bis{trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-3-
butanone 0-[3-(morpholin-4-yl)propyl]oxime. MH"" 668; R,0.50
(CH2Cl2/MeOH/NH40H 93/7/0.5).
18) 1 -{{2R)-1 -[3.5-bis(trifluoromethyl)benzoyl]-2-(1 H-indol-3-ylmethyl)-piperazin-4-yl}-4-pentanone 0-[2-(morphoIin-4-yl)ethyI]oxiine. MH* 668; R, 0.33 (CHzClj/MeOH 8/2).
19) 3-{(2R)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(1 H-indo!-3-ylmethyl)-piperazin-4-yI}-propanal 0-[2-(dimethylamino)ethyl]oxime. MH* 598; Rf 0.29 (CH2Cl2/MeOH/NH40H 93/7/0.5).
20)3-{(2R)-1-[3,5-bis(trifluoromethy!)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yi}-
propanal 0-[2-(morpholin-4-yl)ethyI]oxime. MH*640; RfO.33 (CHzClz/MeOH 9/1). 21)1-{(2R)-1-[3,5-bis(trifIuoromethyl)benzoyl]-2-(1H-indol-3-ylmethyi)-piperazin-4-yI}-3-
phenyl-3-propanone 0-[2-(morpholin-4-yi)ethyl]oxime. MH* 716; R,0.26
(CH2Cl2/MeOH/NH40H 93/7/0.5). 22)1-{{2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1W-indol-3-ylmethyl)-piperazin-4-yl}-3-
phenyl-3-propanone 0-[3-(morpholin-4-yl)propyl]oxime. MH* 730; R, 0.23
(CHzClz/MeOH 95/5). 23) 1 -{(2R)-1 -[3,5-bis(trifluoromethyI)benzoyt]-2-(1 /V-indol-3-ylmethyl)-piperazin-4-yl}-2-
propanone 0-[2-(2-pyridyl)ethyl]oxime. MH* 632; R, 0.12 (CHzCla/MeOH 98/2).

24)1-{(2f?)-1-[3,5-bis(trifluoromethyl)ben2oyl]-2-{1H-indol-3-ylmethyl)-piperazin-4-yl}-2-
propanone 0-[2-pyridylmethyqoxime. MH* 618; Rf 0.24 (CHzClj/MeOH 97/3). 25)H(2R)-1-[3,5-bis(trifluoramethyl)benzoyl]-2-(1W-indol-3-ylnnethyl)-piperazin-4-yl}-2-
propanone 0-[3-pyridy!methyl]oxime. MH* 618; R, 0.27 (CHaClj/MeOH 97/3). 26)1-{{2f?)-1-[3,5-bis{trifluoromethyl}benzoyl]-2-{1H-indoI-3-yimethyl)-piperazin-4-yl}-2-
propanone 0-[4-pyridylmethyl]oxime. MH*618; R,0A9 (CHzCla/MeOH 97/3). 27)1-{(2/?)-1-[3,5-difluorobenzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-ylh2-propanone
0-[2-(morpholin-4-yl)ethyl]oxime. MH* 540; R,0.61 (CHzCla/MeOH/NH^OH
93/7/0.5). 28)1-{(2/?)-1-I3,5-dichlorobenzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone
0-[2.(morpholin-4-y!)ethyl]oxime. MH* 572; f?, 0.20 (CHjClj/MeOH 95/5).
29) 1 -{(2R)-1 -[3,5-dibromobenzoyl]-2-{1 H-indol-3-ylinethyl)-piperazin-4-yl}-2-propanone 0-[2-(morpholin-4-yl)ethyl]oxime. MH* 662; R, 0.44 (CH2Cl2/MeOH/NH40H 93/7/0.5).
30) 1 -{(2R)-1 -[3,5-dicyanobenzoyl]-2-(1 /^-indol-3-ylmethyl)-piperaan-4-yl}-2-propanone 0-[2-(morpholin-4-yl)ethyl]oxime. MH* 554.
31) 1 -{(2R)-1 -[2-methoxy-5-(5-trifluoromethyltetrazol-1 -yl)benzoyl]-2-(1 H-indol-3-ylmethyl)-piperazin-4-yI}-2-propanone 0-[2-(morpholin-4-yl)ethyl]oxime
32)1-{(2R)-1-[3-fluoro-5-(trifluoromethyl)benzoyI]-2-(1/V-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-(morpholin-4-yl)ethylloxime
33) 1 -{(2R)-1 -[{2,6-dichloropyridin-4-yl)carbonyI]-2-(1 Ay-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-{morpholin-4-yl)ethyl]oxime
34) 1-{(2R)-1 -[2,4-bis(trifluoromethyl)benzoyl]-2-(1 H-tndol-3-yImethyl)-piperazin-4-yi}-2-propanone 0-[2-(morphoIin-4-yl)ethyQoxime. MH* 640; R, 0.74 (CHjClz/MeOH 97/3).
35) 1 -{(2R)-1 -t2,5-bis(trifluoromettiyI)benzoyll-2-(1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-{morpholin-4-yl)ethyl]oxime. MH* 640; R, 0.64 (CHaClj/MeOH 97/3).
36)1-{(2R)-1-[3,5-dimethylbenzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-2-
propanone 0-[2-(morpholin-4-yl)ethyl]oxime. MH* 532; R, 0.57 (CHzClj/MeOH
97/3). 37)1-{(2R)-1-[2-chloro-5-(trifluoronriethyI)benzoyri-2-(1/^-indol-3-y!methy!)-piperazin-4-
yl}-2-propanone 0-[2-(morpholin-4-yl)etiiyi]oxime. MH* 606; R, 0.75 (CHjClz/MeOH
97/3).

38) 1 -{(2f?)-1 -[2-methoxybenzoyl]-2-(1 W-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-(morphoIin-4-yl)ethyrioxime. MH* 534; R, 0.63 (CHzCls/MeOH 97/3).
39) 1 -{1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(5-fluoro-1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-(morpholin-4-yl)ethyi]oxime. MH* 658; Rf 0.33 (CHaClj/MeOH 9/1).
40) 1 -{1 -[3,5-bis(trifluoromethyi)benzoyl]-2-(5-fluoro-1 /-/-indo!-3-ylmethyl)-piperazin-4-yl}-2-propanone 0[2-{dimethylamino)ethyl]oxime. MH* 616; f?,0.15 (CHzClj/MeOH 9/1).
41)1-{1-[3,5-bis(trifluoromethyl)benzoyr]-2-(5-methyl-1H-indol-3-ylmethyl)-piperazin-4-yi}-2-propanone O-[2-(morpholin-4-yl)ethy0oxime. MH" 654; R, 0.22 (CH2Cl2/MeOH/NH40H 92/7.5/0.5).
42) 1 -{1 -I3,5-bis(trifluoromethyl)benzoyl]-2-(5-methyl-1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-(dimethylamino)ethyl]oxime. MH* 612; f?,0.09 (CHjClz/MeOH/NHnOH 92/7.5/0.5).
43) 1-{1 -[3,5-bis(trifluoromethyl)benzoyI]-2-{7-aza-1 H-indol-3-ylmethy!)-piperazin-4-yl}-2-propanone 0-[2-(morpholin-4-yl)ethyI]oxime. MH* 641; R, 0.34 (CHaClz/MeOH 9/1).
44) 1-{1-[3,5-bis(trifluoromethyi)benzoyl]-2-benzyl-piperazin-4-yl}-2-propanone 0-[2-(morpholin-4-yt)ethyl]oxime. MH* 601; R, 0.45 (CHzCla/MeOH 97/3).
45)1-{1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1/Tf-indol-2-ylmetiiyl)-piperazin-4-yi}-2-propanone 0-[2-(nnorpholii>4-yl)ethyl]oxime. MH* 640; R, 0.46 (CHzCIj/MeOH/NHPH 93/7/0.5).
46)1-{{2R)-1-[3,5-bis{trifluoromethyl)benzoyl]-2-{1H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-t2-(morpholin-4-yl)-2-oxo-ethyl]oxime. R, 0.25 (CHsClj/MeOH 97/3).
47) 1 -{(2R)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2-( 1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-(morpholin-4-yl)propyl]oxime. MH*654; Rf0.19 (CHzCls/MeOH 97/3).
48) 1 -{(2R)-1 -[3,5-bis(trifluoromethyI)benzoyl]-2-(1 H-indol-3-yltnethyl)-piperazin-4-yI}-2-propanone 0-[2-methyl-2-(morpholin-4-yl)propyi]oxime. MH* 668; R, 0.45 (CHaClz/MeOH 97/3).
49)1-{(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyI)-piperazin-4-yl}-2-propanone O-[2-(2,6-dimethyl-morpholin-4-yl)ethy0-oxime. MH* 668; R, 0.34 (CH2Cl2/MeOH/NH40H 96/3.75/0.25).

50) 1 -{(2/?)-1 -[3.5-bis(trifluoromethyl)benzoyl]-2-(1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-I2-(1,1-dioxo-1-thiomorpholin-4-yl)ethyl]oxime. MH*688; R,0.34 (CH2Ci2/MeOH/NH40H 96/3.75/0.25).
51) 1 -{(2/?)-1 -[3,5-bis(trifluoromethyl)benzoyI]-2-(1 /V-indoI-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-{3,5-dimethyl-morpholin-4-yl)ethyl]-oxime (Isomer 1). MH* 668; Rf 0.20 + 0.28 (E + Z isomer) (CH2Cl2/MeOH/NH40H 96/3.75/0.25).
52) 1 -{(2f?)-1 -[3,5-bis(trifluoromethyl)benzoyi}-2-(1 /y-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-(3,5-dimethyl-morpholin-4-yl)-ethyl]-oxime (Isomer 2). MH* 668; R, 0.21 + 0.31 (E + Z isomer) (CH2Cl2/MeOH/NH40H 96/3.75/0.25).
53) 1 -{(2R)-1 -{3,5-bis(trifluoromethyI)benzoyI]-2-(1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanone 0-[2-(3-methoxymethyl-morpholin-4-yl)etiiyl]-oxime. MH* 684; R, 0.46 + 0.54 (E + Z isomer) (CH2Cl2/MeOH/NH40H 92/7.5/0.5).
54)1-{(2R)-1-[3.5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-y|}-2-propanone 0-[2-(c/s-3,5-bis-methoxymethyl-morpiiolin-4-yl)ethyl]-oxime. f?f 0.17 + 0.23 (E + Z isomer) (CH2Cl2/MeOH/NH40H 96/3.75/0.25).
55) 1 -{{2R)-^ -[3,5-bis(trifiuoromethyl)benzoyl]-2-(1 H-indol-3-ylmethyl)-piperazin-4-yl}-2-propanoneO-[2-(fra/JS-3,5-bis-methoxymethyl-morpholin-4-yl)ethyl]-oxime. MH* 728.
56) 1 -{1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)-piperazin-4-yl}-2-propanone 0-[2-(morpholin-4-yl)ettiyl]oxime. MH* 635; RfO.28 (CHaClj/MeOH 95/5).
57) 1-{1-[3,5-bis(trifluoromettiyl)benzoyl]-2-(3,4-dichlorobenzyl)-piperazin-4-yl}-2-propanone 0-[2-(morpholin-4-yl)ethyl]oxime. MH* 669; R, 0.63 (CHzClj/MeOH 95/5).
58)1-{1-[3,5-bis(trifiuoromethyt)benzoyl]-2-(naphthalen-2-ylmethyl)-piperazin-4-yl}-2-
propanone 0-[2-(morpholin-4-yl)ethyl]oxime. MH* 651; R, 0.65
(CH2Cl2/MeOH/NH40H 93/7/0.5). 59)1-{2-(benzo[b]thiophen-3-ylmethyl)-1-[3,5-bis(trifluoromet!iyl)benzoyl]-piperazin-4-
yl}-2-propanone 0-[2-(morpholin-4-yl)ethyi]oxime. MH* 657; R, 0.30 (CHjClj/MeOH
95/5). 60)1-{1-[3,5-bis(trinuoromethyl)benzoyI]-2-(1H-indazo!-3-ylmethyl)-piperazin-4-yl}-2-
propanone 0-[2-(morplnolin-4-yl)ethyl]oxime. MH* 641; R,0.40
(CH2Cl2/MeOH/NH40H 93/7/0.5).

6l)1-{2-(benzofuran-2-ylmethyl)-1-[3,5-bis{trifluoromethyl)benzoyl]-piperazin-4-yl^2-propanone 0-[2-(morpholin-4-yl)ethyQoxime. MH* 641; R, 0.30 (CHjCIz/MeOH 95/5).
Example 2
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-{1H-indol-3-ylmethyI)-piperazine (0.47 g), A/,A/-dimethylformamide dimethyl acetal (0.12 g), and acetonitrile (15 mL) was heated under reflux for 24 h. After cooling to room temperature the volatiles were removed in vacuo. The residue was dissolved in dry tetrahydrofuran, 0-[2-(dlmethylamino)ethyl]hydroxylamin6 dihydrochloride (547 mg) and diisopropylethylamine (1.1 mL) were added, and the resulting mixture was heated under reflux for two hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (SiOa, CH2Cl2/MeOH/NH40H 85/15/1) to afford 1-{(2R)-1-[3,5-bis(trifluoromethyl)ben2oyl]-2-(1H-indol-3-ylmethyl)-piperazin-4-yl}-methanone 0-[2-(dimethylamino)ethyl]oxime 0.79 g as an E/Z mixture. MH* 570, R, 0.32 + 0.49 (E + Z isomer) (CH2Cl2/MeOH/NH40H 85/15/1).
Example 3
A mixture of 2-chioroethanal 0-[2-(morphoIin-4-yl)ethyl]oxime (0.13 g), (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-ylmethyl)piperazine (0.29 g), diisopropyl¬ethylamine (0.11 mL), and acetonitrile (10 mL) was heated under reflux overnight. After

cooling to room temperature the solvent was removed in vacuo, and the residue treated with dichioromethane and K2CO3 (aq). The layers were separated, the organic layer was dried (NazSO^), and concentrated in vacuo. The residue was purified by flash chromatography (SiOz, CHzClj/MeOH/NH.OH 92/7.570.5) to afford 2-{(2/?)-1-[3,5-bis(trifluoromethyI)benzoyl]-2-(1H-indol-3-ylmethyi)-pipera2in-4-yl}-ethanal 0-[2-(morphoiin-4-^)ethyl]oxime 0.38 g (95%) as an E/Z mixture. MH* 626, R, 0.53 + 0.66 (E + Z isomer) (CH2Cl2/MeOH/NH40H 92/7.5/0.5). The following compounds were obtained according to a similar manner:
1) 2-{(2f?)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(1 W-indol-3-ylmethyl)-piperazin-4-yl}-ethanal 0-[3-(morpholin-4-yl)propyl]oxime. R, 0.63 + 0.72 (E + Z isomer) (CH2Cl2/MeOH/NH40H 92/7.5/0.5).
2) (2f?)-1 -[3,5-bis(trlfluoromethyl)benzoyl]-2-{1 /-/-indol-3-ylmethyl)-4-{[5-((morpholin-4-yl)-methyl)-4,5-dihydro-isoxazol-3-yl]-methyi}-piperazine. MH* 638, Two isomers isolated R,0.51 (isomer 1) Rr0.61 (isomer 2) (CH2Cl2/MeOH/NH40H 96/3.75/0.25)
3) (2R)-1 -[3,5-bts(trifluoromethyl)benzoyl]-2-(1 H-indol-3-ylmethyl)-4-{[5-((morphoiin-4-y!)-methyl)-isoxazol-3-yl]-methyl}-piperazine. Isolated as HCl-salt: mp 182-184""C, MH* 636, R, 0.28 (CH2Cl2/MeOH/NH40H 96/3.75/0.25).
Example 4
Preparation of intermediates having formula (2>

A mixture of phenacyl bromide (0.88 g), (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1/-/-indol-3-ylmethyl)piperazine (2 g), potassium iodide (catalytical), diisopropyl-ethylamine (0.77 mL), and acetonitrile (20 mL) was stirred at room temperature overnight. After cooling to room temperature the solvent was removed in vacuo, and the residue treated with dichioromethane and NaOH (2N). The layers were separated, the organic layer was dried (Na2S04), and concentrated in vacuo. The residue was purified by flash

chromatography (SiOz, CHiClj/MeOH 97/3) to afford (2R)-1-[3,5-bis(trifluoromethyl)ben2oyl]-2-(1H-inclol-3-ylmethyl)-4-(2-phenyl-2-ethanon-1-yl)piperazine 2.16 g (85%). MH* 574, RrO.44 (CHjClz/MeOH 97/3).
The following compounds were obtained according to a similar manner:
(2R)-1 -[3,5-bis(trifluoromethyl)ben2oyl]-2-(1 H-indo!-3-ylmethyl)-4-(2-propanon-1 -
yOpiperazine. MH* 512, R, 0.38 (CHjCla/MeOH 97/3).
(2R)-1-[3,5-dlfluorobenzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-propanon-1-yl)piperazine. Rf
0.72 (CH2Cl2/MeOH/NH40H 93/7/0.5).
(2f?)-1-[3,5-dichlorobenzoyl3-2-(1H-indol-3-ylmethyl)-4-(2-propanon-1-yl)piperazine. R,
0.50 (CH2Cl2/MeOH/NH40H 93/7/0.5).
(2R)-1-[3,5-dibromobenzoyI3-2-(1H-indol-3-ylmethy!)-4-(2-propanon-1-yl)piperazine
(2/?)-1 -[2-methoxy-5-(5-trifluoromethyltetrazol-1 -yl)benzoyl]-2-(1 H-indol-3-ylmethyl)-4-
(2-propanon-1-y!)piperazine
(2f?)-1 -[3-fJuoro-5-(trifluoromethyt)ben2oyl]-2-(1 H-indol-3-yimethyl)-4-(2-propanon-1 -
yl)piperazine
(2/?)-1-[(2,6-dichIoropyridin-4-yl)carbonyl]-2-{1/^-indol-3-ylmethyi)-4-(2-propanon-1-
yl)piperazine
(2R)-1-{3,5-dicyanobenzoyl]-2-(1H-indoI-3-ylmethyl)-4-(2-propanon-1-yl)pipera2ine
(2f?)-1 -[2,4-bis(trifiuoromethyl)benzoyi]-2-(1 H-indol-3-ylmethyl)-4-(2-propanon-1 -
yl)plperazine
(2R)-1 -[3,5-dimethy!benzoyi]-2-(1 H-indol-3-ylmethyl)-4-(2-propanon-1 -yl)piperazine
{2R)-1-[2-chloro-5-(trifIuoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-propanon-1-
yl)piperazine
(2f?)-1 -[2,5-bis(trif luoromethyl)benzoyl]-2-(1 f/-indol-3-ylmethyl)-4-{2-propanon-1 -
yi)piperazine
(2f?)-1-[2-methoxybenzoyl]-2-(1H-indol-3-ylmethyl)-4-(2-propanon-1-yl)piperazine
1-[3,5-bis(trifluoromethyl)benzoyl]-2-benzyl-4-(2-propanon-1-yl)piperazine. MH^ 473, R,
0.65 (CHjClz/MeOH 97/3).
1-[3,5-bis(trifluoromethy!)benzoyl]-2-(4-chIorobenzy!)-4-(2-propanon-1-yl)piperazine.
MH* 507, /?f 0.89 (CHsCiz/MeOH 95/5).
1-[3,5-bis(trifluoromethyl)benzoy(]-2-(3,4-dichlorobenzyl)-4-(2-propanon-1-
yi)piperazine. R,0.63 (CHzClj/MeOH 95/5).

1-[3,5-bis(trifluoromethyl)benzoyl]-2-{naphaialen-2-ylmethyl)-4-(2-propanon-1-
yl)piperazine. R, 0.77 (CHaCyMeOH 95/5).
1-[3,5-bis(trifluoromethyl)ben2oyl]-2-(1W-indol-2-yimethyl)-4-(2-propanon-1-
yl)pip6razine
1 -[3r5-bis(trifluoromethyi)ben2oyt]-2-{5-fluoro-1 N-indol-3-ylmethyl)-4-(2-propanon-1 -
yl)piperazine
1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(5-methyl-1 H-inclol-3-ylmethyt)-4-{2-propanon-1 -
yl)piperazine. MH* 526; R, 0.52 (CH2Cl2/MeOH/NH40H 92/7.5/0.5).
1-[3,5-bis(trifluoromethyl)benzoyl]-2-(7-a2a-1fy-indol-3-ylmethyl)-4-(2-propanon-1-
yl)piperazine. MH* 513; R,0.38 {CH2Cl2/Me0H/NH4OH 93/7/0.5).
1-[3,5-bis(trifluoromethyl)ben2oyl]-2-(1W-inda2ol-3-ylmethyl)-4-(2-propanon-1-
yl)piperazine; MH* 513; f?,0.32 (CH2Cl2/Me0H/NH4OH 93/7/0.5).
2-(benzo[b]thiophen-3-ylmettiyI)-l-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-propanon-1-
yl)piperazine. R, 0.73 (CHjClj/MeOH 95/5).
2-(benzofuran-2-ylmethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-{2-propanon-1-
yl)piperazine.
(2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yimethyi)-4-(3-phenyl-3-
propanon-1-yl)piperazine. MH"" 588, R,0.50 (CHzClj/MeOH 95/5).
(2R)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2-{1 /^-indol-3-ylmethyl)-4-(3-bLrtanon-1 -
yl)piperazine
Example 5
A mixture of 5-chloro-2-pentanone ethylene ketai (0.54 g), (2f?)-1-[3,5-bis(trifluoro-methyl)benzoyri-2-(1 H-indol-3-ylmethyl)piperazine (1.37 g), diisopropylethylamine (0.6 mL), and dimethylformamide (25 mL) was heated overnight, at 90°C. After cooling to room temperature the mixture was poured in water and extracted with ethyl acetate. The organic layer was dried (Na2S04), and concentrated in vacuo. The residue was purified by flash chromatography (SiOa, CHzCla/MeOH 95/5) to afford (2R)-1-[3,5-

bis(trifluoromethyl)ben2oyl]-2-(1H-indoI-3-ylmethyl)-4-[3-(2-methyl-1,3-dioxolan-2-yl)propyilpipera2ine (0.7 g, 40%). MH* 584.
The following compound was obtained according to a similar manner:
(2R)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(1 H-indo!-3-y!mettiyI)-4-[2-(1,3-dioxolan-2-
yl)ethyl]plperazine. R,0.30 {CH2C!2/MeOH/NH40H 93/7/0.5).
Example 6
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(2-methyl-1,3-dioxolan-2-yl)propyl]piperazine (0.7 g), 1,4-dioxane (6 mL). and hydrochloric acid (6N, 5 mL) was heated at SCC for 2 h. After cooling to room temperature the mixture was poured into ammonium hydroxide and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo to afford crude (2f?)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2-(1 H-indol-3-ylmethyl)-4-(4-pentanon-1 -yl)piperazine which was used as such. MH* 540, R, 0.51 (CH2Cl2/MeOH/NH40H 93/7/0.5).
The following compound was obtained according to a similar manner:
(2R)-1 -[3,5-bis(trifluoromethyl)benzoyri-2-(1 H-indol-3-ylmethyl)-4-(3-propanal-1 -
yOpiperazine. R, 0.33 (CHjCla/MeOH 95/5).
Example 7


To a solution of (2R)-1-[3,5-bis(trifluoromethyl)ben2oyl]-2-{1H-indol-3-ylmethyl)-4-(4-pentanon-1-yl)piperazine (1.37 g) in toluene (15 mL) was added drop-wise methyl vinyl ketone (0.3 g). After 2.5 h at room temperature the solution was concentrated to afford crude (2R)-1 -[3,5-bis(trifluoromethyl)-benzoyl]-2-(1 H-indol-3-ylmethyl)-4-(3-butanon-1 -yOpiperazine which was used as such, f?, 0.55 (CHjCla/MeOH 95/5).
Example 8
Preparation of intermediates having formula (7)

A mixture of acetaldehyde (0.1 mL of a 50 wt% soln. in water), 0-[2-((morpholin-4-yl))ethyl]hydroxylamine dihydrochloride (0.14 g), NaOH (2N, 0.64 mL) and water (5 mL) was stin-ed at room temperature overnight. The solution was made basic with NaOH (IN) and extracted with dichloromethane. The organic layer was dried (Na2S04), and concentrated in vacuo to afford 2-chloroethanal 0-[2-((morpholin-4-yl))ethyl]oxime (0.13 g, -100%), which was used as such.
The following compound was obtained according to a similar manner: 2-chloroethanal 0-[3-((morpholin-4-yl))propyl]oxime
Example 9
Preparation of intermediates having formula (9)


To a solution of A/-allylmorpholine (0.76 g, 5.0 mmol) in toluene (10 mL) was added 2-(2-nitroethoxy)tetrahydropyran (1.34 g, 7.7 mmol), phenylisocyanate (2.43 g, 20.1 mmol), and triethylamine (52 mg; 0.5 mmol). The resulting mixture was heated at 55°C overnight. After cooling to room temperature the formed precipitate was removed by filtration and the remaining solution concentrated in vacuo. The residue was pUrified by flash chromatography (StOa, CH2Cl2/MeOH/NH40H 96/3.75/0.25) to yield 0,63 g (44%) of [5-((morpholjn-4-yI)methyl)-4,5-dlhydro-isoxazol^3-yl]methyl 2-tetrahyd ropyranyl ether. MH* 285, Rf 0.34 (CHzClj/MeOH/NH^OH 96/3.75/0.25). The following compound was obtained according to a similar manner: [5-((morpho!in-4-yl)methyl)isoxa2ol-3-yOmethyl 2-tetrahydropyranyi ether. f?f 0.18 (EtOAc/MeOH 99/1).
Example 10
A mixture of [5-((morpholJn-4-yl)methyt)-4,5-dihydro-isoxazol-3-yl]methyI 2-tetrahydropyranyl ether (0.63 g) with pyridinium p-toluenesulfonate (10 mol%) in methanol was heated under reflux for 24 h. After cooling to room temperature the solvent was removed in vacuo and the residue purified by flash chromatography (SiOj, CH2Cl2/MeOH/NH40H 92/7.5/0.5) to afford [5-((morpholin-4-yi)methyl)-4,5-dihydro-isoxazol-3-yl]methanol (95%). R,0.17 (CH2Cl2/MeOH/NH40H 92/7.5/0.5).
Example 11
[5-((morpholin-4-yl)methyl)isoxa2ol-3-yl]methyl 2-tetrahydropyranyl ether (1.0 g) was dissolved in methanol (2 mL) and treated with 1M HCI (aq. 10 mL). The mixture was

stirred at rcxjm temperature for 1 h, then basified with K2CO3, and extracted with dichloromethane. The organic layers were dried (Na2S04), and concentrated in vacuo. The residue was purified by flash chromatography (SiOz, CH2Cl2/MeOH/NH40H 92/7.5/0.5) to afford t5-((morpholin-4-yl)methyl)-isoxazol-3-yl]methanol (53%). MH* 199, Rf 0.24 (CHzCij/MeOH/NH^OH 92/7.5/0.5).
Example 12
To a solution of [5-(morpholin-4-ylmethyl)-4,5-dihydro-isoxazol-3-yl]methanql (0.38 g) in dichloromethane was added dropwise diisopropylethylamine (0.33 mL) and methanesulfonyl chloride (0.15 mL). The resulting solution was stirred at room temperature for 3 h and treated with water. The layers were separated and the organic layer was dried (Na2S04) en concentrated In vacuo to afford [5-((morpholin-4-yl)methyl)-4,5-dihydro-isoxazol-3-yl]methanol methanesulfonate, 0.52 g (-100%). R, 0.63 (CHzClz/MeOH/NKOH 92/7.5/0.5).
The following compound was obtained according to a similar manner: [5-((morpholin-4-yl)methyl)isoxazol-3-yl]methanol methanesulfonate. Rf 0.62 (CH2Cl2/MeOH/NH40H 96/3.75/0.25).
Example 13
Preparation of intermediates having formula (3)

To a solution of acetophenone oxime (20 g) in toluene (700 mL) was added subsequently tetrabutylammonium bromide (4.77 g), water (8 mL), 4-(2-chloroethyl)morpholine hydrochloride (30.31 g) and finally 50% sodium hydroxide (aq, 52 mL). The resulting mixture was heated at 75°C overnight. After cooling to room

temperature water was added, to dissolve all the salts, the layers were separated, and the aqueous layer was extracted with toluene. The organic layers were dried (l\/lgS04), and concentrated in vacuo. The residue was purified by flash chromatography {SiOj, CH2Clz/l\/leOH 95/5) to afford acetophenone 0-[2-({morphoIin-4-yI))ethyl]oxime as an oil. The obtained oil was dissolved in 6M HCI (aq, 500 mL) and heated under reflux for 5 hours and subsequently stirred overnight at room temperature. The mixture was extracted with ether and concentrated in vacuo. The residue was crystallized from ethanol, to afford 0-[2-((morpholin-4-yI))ethyQhydroxylamine dihydrochloride. 24.8 g (77%)
The following compounds were obtained according to a similar manner: 0-[2-(dimethylamino)ethyl]hydroxyIamine dihydrochloride 0-[2-(methylamino)ethyl]hydnDxylamine dihydrochloride 0-[3-(dimethylamino)propyflhydroxylamine dihydrochloride 0-[3-({morpholin-4-yl))propyl]hydroxylamine dihydrochloride 0-[2-pyridylmethyl]hydroxylamine dihydrochloride 0-[3-pyridylmethyl]hydroxylamine dihydrochloride
0-[4-pyridylmethyl]hydroxylamine dihydrochloride Example 14

To a solution of 4-benzyl-piperazlne-1-carb"cxy!!C acid fer/-butyl ester (2 g) In diethylether (35 mL) was added tetramethylethylenediamine (1.4 mL). The resulting mixture was cooled to -70"C and sec-butyllithium {7 mL of a 1.3 M solution) was added dropwise, after complete addition the solution was slowly wanned to-10°C, at which temperature the mixture was stirred for one hour. Subsequently, the mixture was

recooled to -70°C; then a solution of 2-(bromomethyl)naphthalene (2 g) in dietliylether was added dropwise and stirring continued at -70°C was continued for one hour. The resulting mixture was stin-ed and allowed to come to room temperature overnight, then partitioned between saturated ammonium chloride (aq) and ethyl acetate. The organic layer was dried over magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiOj, CHzCyMeOH 99/1) to afford 4-benzyl-2-(naphthalen-2-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester as an oil. 0.8 g (27 %) Rf 0.47 (CHzCyUeOH 99/1), MH" 417.
The following compounds were obtained according to a similar manner:
2-(7-aza-1 -{toluene-4-sulfonyl)-1 H-indol-3-ylmethyl)-4-benzylpiperazine-1 -carboxylic
acid fert-butyl ester; R, 0.28 (CHjClz/MeOH 99/1).
2,4-diben2ylpiperazine-1-carboxylic acid tert-butyl ester; MH* 367, R, 0.84
(CH2Cl2/MeOH/NH40H 93/7/0.5).
4-benzyl-2-(1-(toiuene-4-sulfonyl)-1 W-indol-2-ylmettiyI)piperazine-1-carboxylic acid fe;^-
butyl esten MH* 560, R, 0.70 (CHzClz/MeOH 95/5).4-benzyl-2-(4-
chlorobenzyl)piperazine-1-carboxylic acid ferf-butyl ester; MH* 401, f?, 0.26
(CHzClj/MeOH 99/1).
4-benzyl-2-(3,4-dichlorobenzyl)piperazine-1-carboxylic acid fe/t-butyl ester; R,0.77
(CH2Cl2/MeOH/NH40H 93/7/0.5).
2-(benzo[£)lthiophen-3-ylmethyl)-4-benzylpiperazine-1-carboxylic acid tert-butyl ester;
MH* 423; R, 0.30 (CHaCyMeOH 99/1).
3-(4-benzyl-1-fe/t-butoxycarbonyl-piperazin-2-ylmethyl)-indazole-1-carboxylicacid tert-
butyl ester, MH* 507.
2-(benzofuran-2-ylmethyl)-4-benzylpiperazine-1-carboxylic acid tert-butyl ester; MH*
407, R,0.33 (CHzClj/MeOH 99/1).
Example 15
Preparation of intermediates having fomiula (10)


To a solution of 4-benzyi-2-(naphthalen-2-yimethyl)piperazine-1-carboxylicacid tert-butyl ester (0.75 g) in dlchloromelhane (3 mL) was added dropwise trifluoroacetic acid (3 mL). After 75 min at room temperature the mixture was poured onto ice and made basic by the addition of ammonium hydroxide (25% solution). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo to afford 1-benzyl-3-(naphthalen-2-ylmethyl)piperazine as an oil; 0.53 g (93 %) MH* 317, R, 0.61 (CH2Cl2/MeOH/NH«0H 93/7/0.5), which was used as such.
The following compounds were obtained according to a similar manner:
3-{7-aza-1-(toluene-4-suifonyl)-1H-indol-3-ylmethyl)-1-benzylpiperazine; Rf0.13
(CHzClz/MeOH 95/5).
1,3-dibenzylpiperazine piperazine; MH* 267, Rf 0.19 (CH2C!2/MeOH/NH40H 93/7/0.5),
1-benzyl-3-(1-(toluene-4-sulfonyl)-1H-indol-2-ylmethyl)piperazine; MH* 460, R,0.56
(CH2Cl2/MeOH/NH40H 93/7/0.5).
1-benzyl-3-(4-chlorobenzyl)piperazine; MH* 301, R,0.26 (CHzCls/MeOH/NH^OH
95/4.5/0.5).
1-benzyl-3-(3,4-dichlorobenzyl)piperazine; MH* 335, Rf 0.35 (CH2Cl2/MeOH/NH40H
93/7/0.5).
3-(ben2o[ib]thiophen-3-y!methyl)-1-benzylpiperazine; MH* 323, R, 0.35 (CHsClz/MeOH/
NH4OH 95/4.5/0.5).
1-benzyl-3-(fH-indazol-3-y!methyl)piperazine; !\4H* 307, R,0.10 (CH2C(2/MeOH 9/1).
3-(ben2ofuran-2-ylmethyl)-1-benzylpiperazine; MH^ 307, R,0.26
(CH2Ci2/MeOH/NH40H 93/7/0.5).
Example 16


To a solution of 3-{7-aza-1-(toluene-4-sulfonyl)-1H-indol-3-ylmethyl)-1-benzyl-piperazine (0.65 g) in methanol (28 mL) was added 3 M aqueous sodium hydroxide (5.6 mL), and the resulting mixture was heated for 90 min at 60°C. After cooling to room temperature, most of the methanol was removed in vacuo and the residue extracted with dichloromethane. The organic layer was dried over magnesium sulphate, filtered, concentrated in vacuo and the residue purified by flash chromatography (SiOa, CH,Cl2/MeOH/NH40H 85/15/1) to afford 3-(7-aza-1H-indol-3-ylmethyl)-1-benzyl-piperazine (0.3 g); MH* 307, /?, 0.51 (CH2Cl2/MeOH/NH40H 85/15/1).
The following compound was obtained according to a similar manner: 1-benzyl-3-(1H-indol-2-ylmethyl)piperazine); MH* 306, R,0.32 (CH2Cl2/MeOH/NH40H 93/7/0.5).


WE CLAIM:

wherein:
X represents phenyl or pyridyl substituted with 1 or 2 substituents from the group
CH3, CF3, OCH3, halogen, cyano and 5-CFs-tetrazol-l-yl
Y represents 2- or 3-indolyl, phenyl, 7-aza-indol-3-yl or 3-indazolyl, 2-naphthyl,
3-benzo[b]thiophenyl or 2-benzofuranyl, which groups may be substituted with one or
more halogen or alkyl (1-3C)
n has the value 0-3
m has the value 0-2
R1 represents NH2, NH-alkyl (1-3C), dialkyl (1-3C)N, morpholino or morpholino
substituted with one or two methyl and/or methoxymethyl groups, thiomorpholino, 1,1
-dioxothiomorpholino, 2-, 3- or 4-pyridyl or 4-CH3-piperazinyl
R2 is hydrogen, alkyl (1-4C) or phenyl, or R2 together with (CH2)m wherein m is 1,
and the intermediate carbon, nitrogen and oxygen atoms forms an isoxazolyl or a 4,5-
dihydroisoxazolyl group,
R3 and R4 independently represent hydrogen or methyl, or R3 and R4 together are
oxygen,
and physiologically acceptable salts thereof

2. The compounds as claimed in claim 1 having formula (1) wherein Y represents 2-or 3-indolyl, phenyl, 7-aza-indol-3-yl or 3-iridazoIyl, which groups may be substituted with one or more halogen or alkyl (1-3C); R1 represents NH2, NH-alkyl (1-3C), dialkyl (1-3C)N, morpholino or morpholino substituted with one or two methyl and/or methoxymethyl groups, thiomorpholino, 2-, 3- or 4-pyridyl or 4-CH3-piperazinyl; R3 and R4 are hydrogen and X, n, m and R2 have the meanings given in claim 1.
3. The compounds having formula (1) wherein X represents phenyl substituted with 2 substituents from the group CF3 and halogen, Y is 3-indolyl, m is 1 or 2, n is 1 or 2 and R1, R2, R3, and R4 have the meanings given in claim 1, and physiologically acceptable salts thereof
4. The compounds as claimed in claim 3, wherein X represents phenyl substituted at
positions 3 and 5 with CF3 or halogen.

wherein R represents hydrogen, alkyl (1-4C) or 0-alkyl(l-4C) and Y has the meanings given in claim 1, characterised in that a solution of a compound of the general formula

in the presence of a coordinating di- or triamine, preferably tetramethyl-ethylenediamine, is treated with a solution of an alkyl lithium base, preferably sec-butyllithium, followed by the addition of a compound of the general formula
Y-CH2Br
to yield a compound of the general formula

and removal of the tert-butyloxycarbonyl group.
6. The method as claimed in claim 5 for the preparation of intermediates useful in the
synthesis of compounds as claimed in the claims 1 to 4.
7. Pharmaceutical compositions containing a pharmacologically active amount of at
least one compound as claimed in claims 1 to 4 as an active ingredient.
8. Method of preparing a composition as claimed in claim 7, characterized in that a
compound as claimed in claims 1 to 4 is brought into a form suitable for administration.

Documents:

0047-chenp-2004-abstract-duplicate.pdf

0047-chenp-2004-abstract.pdf

0047-chenp-2004-claims-duplicate.pdf

0047-chenp-2004-claims.pdf

0047-chenp-2004-correspondence-others.pdf

0047-chenp-2004-correspondence-po.pdf

0047-chenp-2004-description-(complete)-duplicate.pdf

0047-chenp-2004-description-(complete).pdf

0047-chenp-2004-form-1.pdf

0047-chenp-2004-form-18.pdf

0047-chenp-2004-form-26.pdf

0047-chenp-2004-form-3.pdf

0047-chenp-2004-form-5.pdf

0047-chenp-2004-other-document.pdf

0047-chenp-2004-others.pdf

0047-chenp-2004-pct.pdf

0047-chenp-2004.jpg


Patent Number 214343
Indian Patent Application Number 47/CHENP/2004
PG Journal Number 13/2008
Publication Date 31-Mar-2008
Grant Date 11-Feb-2008
Date of Filing 08-Jan-2004
Name of Patentee SOLVAY PHARMACEUTICALS B.V
Applicant Address C.J. Van Houtenlaan 36, NL-1381 CP Weesp,
Inventors:
# Inventor's Name Inventor's Address
1 VAN MAARSEVEEN, Jan, H c/o C.J. Van Houtenlaan 36, NL-1381 CP Weesp,
2 VAN SCHARRENBURG, Gustaaf, J., M c/o C.J. Van Houtenlaan 36, NL-1381 CP Weesp,
3 TULP, Martinus, Th., M. c/o C.J. Van Houtenlaan 36, NL-1381 CP Weesp,
4 HERREMANS, Arnoldus, H., J. c/o C.J. Van Houtenlaan 36, NL-1381 CP Weesp,
5 VAN DEN HOOGENBAND, Adrianus c/o C.J. Van Houtenlaan 36, NL-1381 CP Weesp,
6 MCCREARY, Andrew, C. c/o C.J. Van Houtenlaan 36, NL-1381 CP Weesp,
7 IWEMA BAKKER, Wouter, I. c/o C.J. Van Houtenlaan 36, NL-1381 CP Weesp,
8 COOLEN, Hein, K., A., C. c/o C.J. Van Houtenlaan 36, NL-1381 CP Weesp,
PCT International Classification Number C07D 241/04
PCT International Application Number PCT/EP2002/007472
PCT International Filing date 2002-07-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 01202631.6 2001-07-09 EUROPEAN UNION