CA2197172A1 - Novel alkylamino derivatives as sigma 2 selective ligands - Google Patents

Novel alkylamino derivatives as sigma 2 selective ligands

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CA2197172A1
CA2197172A1 CA002197172A CA2197172A CA2197172A1 CA 2197172 A1 CA2197172 A1 CA 2197172A1 CA 002197172 A CA002197172 A CA 002197172A CA 2197172 A CA2197172 A CA 2197172A CA 2197172 A1 CA2197172 A1 CA 2197172A1
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adamantyl
alkyl
ylmethyl
piperidin
group
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Jean-Philippe Rocher
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Mitsubishi Chemical Corp
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Abstract

The present invention relates to novel alkylamino derivatives of formula (I). These compounds exhibit a high selectivity and a high affinity for sigma 2 receptor and therefore are useful in the treatment of central nervous system disorders as well as other disorders modulated by this receptor.

Description

2 1 97 t 72 1-- wo 96/05185 PCT/JP95101~00 ~, DESCRIPTION

LIGANDS

Technical Field The present invention relates to novel alkylamino derivatives, phammaceutical compositions comprising such compounds and the use of such compounds in the treatment of central nervous system disorders as well as several other disorders. The phammaceutically active compounds of this 15 invention are highly selective and high affinity sigma 2 ligands.

Background Art The recently identified brain sigma receptors/binding sites are potential 20 targets for development of antipsychotic drugs that lack the adverse effects associated with currently available dopaminergic D2 antipsychotic agents [J.M. Walker, W.D. Bowen, F.O. Walker, R.R. Matsumoto, B. de Costa and K.C. Rice, Pha~"acological Reviews, 1990, 42, 355-402; G. Debonnel, J.
Psychiatr. Neurosci., 1993, 18, 4, 157-172]. The term "receptor~ as used 25 herein refers to membrane-bound receptors and to other binding sites. The existence of at least two sigma receptor subtypes, sigma 1 and sigma 2, has been confirmed and a clas~iGcaliol1 of sigma binding sites has been proposed [R. Quirion, W.D. Bowen, Y. Itzhak, J.L. Junien, J.M. Musacchio, R.B. Rothman, T.P. Su, W. Tam and D.P. Taylor, TiPS, 1992, 13, 85-86].

Sigma 1 binding sites are characterized by high afflnity for haloperidol, Di-o-Tolyl Guanidine (DTG) and (+) ben~ "or~ al1s such as (+) pentazocine.
Sigma 2 binding sites are ul,ard.:tt~ ed by high afflnity for haloperidol and 35 DTG but low afflnity for the (+) bel1~ul l IUI IJhanS. S igma 1 ligands have shown gastro-intestinal effects; moreover, sigma 1 sites appear to mediate the inhibition by sigma ligands of the muscarinic acetylcholine receptor 2 ~ ~7 i ~2 phosphoinositide response. Sigma 1 binding sites are not only present in the brain but also on splenocytes. Such sigma ligands may inadvertently suppress the immune system [H.H. Garza, S. Mayo, W.D. Bowen, B.R.
DeCosta and D.J.J. Carr, J. of Immunology,1993,151, 9,4672-4680]. Sigma 5 2 binding sites are abundant in liver [A.E. Bruce, S.B. Hellewell and W.D.
Bowen, Soc. Neurosci. Abstr., 1990, 16, 370; A.S. Basile, I.A. Paul and B.
DeCosta, Eur. J. Pharmacol. Mol. Phamm. Sect., 1992, 227, 95-98], kidney [W.D. Bowen, G. Feinstein and J.S . Orringer, Soc. Neurosci. Abstr.,1992, 18, 456, abstract 195.8] and heart [M. Dumont and S. Lemaire, Eur. J.
Pharmacol., 1991, 209, 245-248].

In the brain, sigma 2 binding sites are present in hypothalamus, cerebellum and pons medulla. In rat brain, they are more abundant than sigma 1 sites in hippocampus, frontal and posterior cortex [D. J. Mc Cann, A. D. V\'e;i:,",ann 15 and T.P. Su, Soc. Neurosci abstr. 1992, 18, 22, abstract 16.5]. Guinea pig hippocampus membranes possess also sigma 2 binding sites which are selectively labelled by [3H] BIMU [D.W. Bonhaus, D.N. Loury, L.B. Jakeman, Z. To, A. DeSouza, R.M. Eglen and E.H.F. Wong, J. Pharmacol. Exp. Ther., 1993,267, 2, 961 -970]. The ~c50~ of sigma 2 binding sites with cortical 20 and limbic areas provide support to the interest of such compounds in the treatment of psychiatric disorders [D.C. Mash and C.P. Zabetian, Synapse, 1992, 12, 195-205]. Sigma 2 binding sites have been suspected to mediate motor effects especially dystonia [R.R. Matsumoto, M.K. Hemstreet, N.L. Lai, A. Thurkauf, B.R. DeCosta, K.C. Rice, S.B. Hellewell, W.D. Bowen and J.M.
25 Walker, Pharmacol. Biochem. Behav., 1990, 36, 151-155]; however, there is no evidence for such effect in primate models of extrapyramidal dysfunction [L.T. Meltzer, C.L. Cl " i~l. ff~l:,en, K.A. Serpa, T.A. Pugsley, A. Razmpour and T.G. Heffner, Neuropharmacology, 1992, 31, 9, 961-967].The clinically effective dopaminergic anfipsychotic haloperidol shows a high affinity to the 30 two sigma subtypes; however, the CNS active reduced metabolite of haloperidol shows a better affinity and selectivity for sigma 2 receptors towards dopaminergic D2 receptors than haloperidol [J.C. Jaen, B.W.
Caprathe, T.A. Pugsley, L.D. Wise and H. Akunne, J. Med. Chem., 1993, 36, 3929-3936]. In fact, the understanding of the pharmacology, distribubon and 35 function of sigma 2 binding sites has been hampered by the lack of selective agents.

2 ~ q 17 ~ 72 - ~

Few agents bind wibh a high affinity to sigma 2 binding sites [M. Abou-< Gharbia, S.Y. Ablordeppey and R.A. Glennon, Annual Reports in Medicinal Chemistry, 1993, 28, 1-10]. Ifenprodil has a marked selecbvity for sigma 2 sitesbutitbindsalsoto polyamineandalpha-1 receptors[K.Hasl,MIoiu, C.R.
Manbone, M.R. Spada, J.L. Neumayer and E.D. London, Eur. J. Pharmacol.
Mol. Pharm. Sect., 1994, 266, 66-77]. [3H] BIMU has been proposed as a selecbve sigma 2 ligand with Ki = 32 nM [D.W. Bonhaus, D.N. Loury, L.B.
Jakeman, Z. To, A. DeSouza, R.M. Eglen and E.H.F. Wong, J. Pharmacol.
Exp. Ther., 1993, 267, 2, 961-970]; however, despite a good selecbvity towards sigma 2, this compound is also a highly potent 5-HT3 and 5-HT4 serotonin ligand. WO 93/00313 relates to sigma receptor ligands and bheir sigma 1/sigma 2 selecbvity; bhree compounds present an interesb'ng sigma 2 selecb'vity, bhey belong to bhe phenyl piperazine class and are also high affinity 5-HT1 A serotonin ligands [R.A. Glennon, N.A. Naiman, R.A. Lyon and M. Titeler, J. Med. Chem., 1988, 31, 1968-1971]. Sub-nanomolar affinity sigma binding sites ligands have been presented as sigma 2 ligands [J.
Perregaard, E.K. Moltzen, E. Meier, C. Sanchez and J. Hyttel, Soc. Neurosci.
Abstr.,1993,19, 1868, absbract 763.16], but no data on bheir sigma selecbvity has been shown and bhey also bind to alpha 1 receptor wibh a moderate to high affinity. The 5, 6, 7, 8, 9, 10-hexahydro-7,10-iminocyclohept[b]indoles have been idenbfied as selecbve sigma 2 ligands [R.E. Mewshaw, R.G.
Sherrill, R.M. Mathew, C. Kaiser, M.A. Bailey and E.W. Karbon, J. Med.
Chem.,1 993, 36, 343-352] wibh moderate to high affinity. A new approach to sigma 2 ligands has been recently di;,~.l"secl. bhe polyamino sigma ligands described were moderatly potent and selective for sigma 2 site [B.R.
DeCosta, X.S. He, C. Dominguez, J. Cub's, W. Williams and W.D. Bowen, J.
Med. Chem., 1994, 37, 314-321].

Extensive literabure exists relabng to heteroaryl alkylamino derivatives;
however there is very little data conceming heteroaryl groups like bhe naphtosultam ring. EP 546388 discloses heteroaryl methyl piperidino derivabves of chromanes, without examples of naphtosultam compounds.
Alkylamino naphtosultam derivabves are described wibh examples in EP
352613, bhese compounds are claimed as 5-HTlA ligands. EP 350403, EP

, , ,, . ,, .. , _ _ , . , . , .,, .. ,, .. , . _ _, _ . , , ... , .,, ,,,, _ . , ., . , _ _ _ _ , ,, , .. , _ _ 7r ~

429341 and WO 91/16323 disclose series of naphtosultam derivabves as 5-HT2 dl lldgo~ la and 5-HT reuptake inhibitors.
The present invention relates to a subsbtuted (preferenbally adamantyl, cycloalkyl)hydroxy-amino and diamino derivabves. Numerous phenyl ebhanolamino derivabves exhibit important phar".,.~ ~ubr~l.c properties [Pharmaceubcal Chemisby Vol. 1: drug synbhesis, H.J. Roth, A. Kleemann and T. Beisswenger, Ellis Horwood limited, Chichester England, 37-69]. For example, benzyl-piperidino derivabves like Ifenprodil and its derivabves belong to this class and are known to interact with sigma, adrenergic and gl~hl"dl~lyic receptors [B.L. Chenard, I.A. Shalaby, B.K. Koe, R.T. Ronau, T.W. Butler, M.A. Prochniak, A.W. Schmidt and C.B. Fox, J. Med. Chem., 1991, 34, 3û85-3090]. Surprisingly, bhe cycloalkyl and adamantyl ebhanolamino derivabves of bhe present invenbon show a completely different and selective binding profile.
EP518 216 disdoses certdin N-[arylethyl]-N-alkyl-2-(1-pyrrolidinyl)ebhylamine compounds for CNS disorders. WO 93/22275 discloses 3-phenyl-1,2-propanediamine derivabves having selecbve afffinity for sigma receptors.
These compounds are potent pr~ ""-"y sigma 1 ligands; no heteroaromabc derivatives are described and bhey are not 5llhshh~ted in a posifion by a cycloalkyl group. WO 93/10073 relates to ethylenediamine derivabves as substance P receptor dl ILd90n;.~b, bhe general formula refers to secondar,v amino compounds. US 5,039,706 describes benzylamine derivabves having phospl1oli~,ase A2 inhibiting properties, some examples of phenyl-propane diamino compounds are given.

The compounds described above do not show bhe sigma 2 receptor selectivity and affinity de",on~t,dl~d by bhe compounds of bhe present invention.
The present invenbon resides in bhe discovery of a group of selecbve and high afflnity sigma 2 binding site ligands. The inhibibon constant Ki for sigma 2 binding site is of at least 50 nM and these new ligands have at least a 5 foldgreater afffinity for sigma 2 than sigma 1 binding sites and dopaminergic (D1, D2), serotoninergic (5-HT1 A,5-HT2,5-HT3), adrenergic (alpha and beta) and phencyclidine (PCP) receptors. Such binding profile makes the compounds of the present invention advantageous over compounds of the prior art.

\:
WO 96/05185 2 1 9 7 t 72 PCT/JP9S/01600 Disclosure of Invention Novel alkylamino derivatives of the invention which conform to the formula:
x~r i~l ,R3 R2 (1) When X represents cycloalkylalkyl or adamantyl, Y represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, adamantyl, aryl,1~ arylalkyl, heteroaryl or heteroarylalkyl; wherein each of said aryl and heteroaryl g~ups may optionally be substituted with one or more substituents, each of the said subsbtuents being independently selected from halo, nitro, cydoalkyl, alkenyl, alkyl opb'onally substituted wilh one to three fluorine atoms, hydroxy, alkoxy opbonally sllhctih~od wibh one to three fluorine atoms, phenyl, 20 amino, alkylamino, carbamoyl, sulfamoyl, carboxyalkyl, cyano oralkynyl.

When X represents cycloalkyl, Y represents hydrogen, alkyl, alkenyl or cycloalkyl.

2~ A represents the group -O-Rs in which Rs represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, arylalkyl, hydroxyalkyl, carboxyalkyl or carboxyaryl;

or A ,~p~se"t~ the group --N~ 10 R1~

Rloand R11 represent independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkoxyalkyl, alyl, arylalkyl, .

~f~7~
WO 96/05185 l~CT/JP95/01600 heteroaryl or heteroarylalkyl; each of the said aryl and heteroaryl groups may optional!y be substibuted with one or more substibuents, each of the said substituents being independently selec~hed from halo, nitro, cycloalkyl, alkenyl, alkyl opbonally .sllh.stit~ltPd with from one to three fluorine atoms, 5 hydroxy, alkoxy opbonally subsbtuted with one to three fluorine atoms, phenyl, amino, alkylamino, carboxy, carbamoyl, sulfamoyl, carboxyalkyl, cyano or alkynyl.

R10 and R11 taken together may form a ring corresponding to the 1 0 formula:
-(CH2)m-D-(CH2)m-where D represents a single bond, oxygen, sulfur or a nitrogen atom 15 substituted by hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkylalkyl, aryl or arylalkyl;
m is a number selected from 1 to 3;

R10 and R11 taken together with the nitrogen atom may form a 3-10 atom unsaturated heterocyclic ring which opbonally contains 1 to 4 further ht,lurulllu,,, selected from oxygen, nitrogen and sulfur; such heterocyclic group may optionally be 5llhsbh-tPd with one or more subsbhuents, each of bhe said subsbtuents being independently selected from halo, nihro, cycloalkyl, alkenyl, alkyl optonally substituted with one to three fluorine atoms, hydroxy, alkoxy optionally sl ~' ~tPd with one to three fluorine atoms, phenyl, amino, alkylamino, carbamoyl, sulfamoyl, carboxy,carboxyalkyl, cyano or alkynyl.
or Y and A taken together may form oxo or hydroxyimino.

R~ and R2 which may be the same or different, are hydrogen, alkyl, cycloalkyl, hydroxyalkyl or alkenyl.
R3 ,t:p,~se"t~ alkyl, cycloalkyl, hydroxyalkyl or alkenyl;

2 1 q7i 72 WO 96/05185 . PCT/JP95/01600 J R4 represents the group -(CH2)p-B where p is a number selected from 3 to8;

or R3 and R4 together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (Il):

X~ Y ~ ~
~C--C--N~CH2--B (Il) where R5and R8representindependentlyhydrogen oralkyl;

or R~ and R8 together with the intervening atom represent a 5 to 7 heterocyclic ring.
B is a heteroaryl group of formula O-S~ ~R7 ~R7 o~ ~ ~ o ~o~ ~

~R7 ~R7 ~, R7 --N X' ~ X --N~, S~

o~ N/ R0''S''0 S
~0 ~ ~--O~N~ '~' ~N

~ , [~ or ~1 R7 and Rs are independently selected from hydrogen, halo, nitro, 5 cycloalkyl, alkenyl, alkyl optionally substituted with one to three fluorine atoms, hydroxy, alkoxy optionally substituted with one to three fluorine atoms, phenyl, amino, alkylamino, carbamoyl, sulfamoyl, carboxyalkyl, cyano or alkynyl.

R12 is selected from hydrogen or alkyl.

X' represents a single bond, -CH2-, -CH=CH-, -CH2-CH2-, S, -S-CH2-, -S(0)-,-S(0)2-, -S~0)-CH2-,-S(0)2-CH2-, 0, -0-CH2-, N(R13), -N(R13)-CH2-, -N(R13)-S(0)2-, C(=0), -C(=0)-CH2-, -C(=0)-0- or-C(=0)-N(R13)-;
Y' represents -CH2- or C(=0);

W and W' represent independently a benzene ring or heteroaryl group of 5 to 7 atoms which contains one oxygen atom, one sulfer atom or one or 20 two nitrogen atoms, provided that at least one of W and W' is heteroaryl group.

R13 ~5p~se"~s hydrogen or alkyl.

2 t ~7 t ~2 In the above definition, "alkyl" includes C1-C6 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl 5 group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group or the like.
"Cycloalkyl" includes C3-C6 cycloalkyl group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group or the like.
"Cycloalkyalkyl" includes C3-C6 cycloalkyl-C1-C3 alkyl group such as 10 cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclohexylmethyl group or the like.
~ AIkenyl" includes C3-C6 alkenyl group such as 1 -propenyl group, allyl group, isopropenyl group, 1-butenyl group, 3-butenyl group, 1-pentenyl 15 group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-hexenyl group, 2-hexenyl group or the like.
"Alkynyl" includes C3-C6 alkynyl group such as 2-propynyl group, 3-butynyl group, 4-pentynyl group, 5-hexynyl group or the like.
"Alkoxy" includes C1-C6 alkoxy group such as methoxy group, ethoxy 20 group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, hexy!oxy group or the like.
"Halo" includes atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom or the like.
"Alkylamino" includes C1-C6 alkylamino group such as methylamino 25 group, ethylamino group, propylamino group, butylamino group, pentylamino group, hexylamino group, dimethylamino group, methylethylamino group, diethylamino group, dipropylamino group or the like.
"Carboxyalkyl" includes carboxy-C1-C6 alkyl group such as carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4-30 carboxybutyl group, 5-carboxypentyl group, 6-carboxyhexyl group or the like.
"Hydroxyalkyl" includes hydroxy-C2-C6 alkyl group such as 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group or the like.
"Haloalkyl" includes halogenated-C1-C3 alkyl group such as 35 chlorullleulyl group, dichloromethyl group, trichloromethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, br-,,,,oll,~UIyl group, 1-chloroethyl group, 1,1 -dichloroethyl group, 2-chloroethyl group, 2,2-2 ~ 2 dichloroethyl group, 2,2,2-trichloroethyl group, 1-fluoroethyl group, 1,1-difluoroethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2-bromoethyl group, 3-chloropropyl group, 3-fluoropropyl group, 3-blullloplu~Jyl group or the like.
"Haloalkoxyalkyl" indudes halogenated-Cl-Cs alkoxy-C1-C3 alkyl group such as chlorul"~U,oxymethyl group, chloromethoxyethyl group, chloromethoxypropyl group, fluoromethoxymethyl group, fluolu,ll~tl,oxyethyl group, trifluoromethoxymethyl group, trifluo,v,,,eUIoxye~hyl group, trifluor~,lleU,uxypropyl group, b,u",o",eU,oxymethyl group, blulllollltl~loxyethyl group, bru",o",e~loxypropyl group, 1-chloroethoxymethryl group, 2-chloroefhoxymethyl group, 2-dhloroethoxyethyl group, 2-dhloroethoxypropyl group, 2-luoroethoxymethyl group, 2-f uoroethoxyethyl group, 2-fluoroehoxypropyl group, 2,2,2-trifluoroethoxymethyl group, 3-chloropropoxymethyl group, 3-1uoropropoxymethyl group orthe like.
"Aryl" includes Co-Clo aryl group such as phenyl group, 1-naphtyl group, 2-naphtyl group or the like.
"Arylalkyl" includes C6-Clo aryl-Cl-Cs alkyl group such as benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 1-naphtylmethyl group, 2-naphtylmethyl group or the like.
"Carboxyaryl' includes carboxy-C6-Clo aryl group such as 2-carboxyphenyl group, 3-carboxyphenyl group, 4-carboxyphenyl group, 2,6-dicarboxyphenyl group, 2,4,6-tricarboxyphenyl group, 2-carboxy-1-naphthyl group, 3-carboxy-1-naphthyl group, 4-carboxy-1-naphthyl group, 1-carboxy-2-naphthyl group, 3-carboxy-2-naphthyl group, 4-carboxy-2-naphthyl group, l ,5-dicarboxy-2-naphthyl group or the like.
'Heteroaryl" indudes 5-10 membered heterocyclic group containing 1 to 4 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom to form a ring such as furyl group (furan ring), benzofuranyl group (benzofuran ring), isobenzofuranyl group (isobenzofuran ring), thienyl group (thiophene ring), ben~ullliopllenyl group (benzothiophene ring), pyrrolyl group (pyrrole ring), imidazolyl group (imidazole ring), pyrazolyl group (pyrazole ring), thiazolyl group (thiazole ring), isothiazolyl group (isothiazole ring), triazolyl group (triazole ring), tetrazolyl group (tetrazde ring), pyridyl group (pyridine ring), pyrazynyl group (pyrazine ring), pyrimidinyl group (pyrimidine ring), pyridazinyl group (pyridazine ring), indolyl group (indole ring), isoindolyl group (isoindole ring), be,,~ui,,,idd~ulyl group (benzoimidazole ring), purinyl group (purine ring), 2 t q7 t 7~ ' quinolyl group (quinoline ring), phtalazinyl group (phtalazine ring), naphtyridinyl group (naphtyridine ring), quinoxalinyl group (quinoxaline ring), cinnolinyl group (cinnoline ring), pteridinyl group (pbridine ring), oxazolyl group (oxazole ring), isooxazolyl group (isooxazole ring), be,,~uo.~d~olyl group (ben7l o~701e ring), 5 furazanyl group (furazan ring) orbhe like.
"Heteroarylalkyl" includes heteroaryl-C1-C3 alkyl group, wherein examples of heteroaryl are the same as those illushrated in bhe above definib'on, such as 2-furylmethyl group, 3-furylmethyl group, 2-thienylmethyl group, 3-bhienylmebhyl group, 1-imidazolylmethyl group, 2-imidazolylmebhyl 10 group, 2-bhiazolylmebhyl group, 1-pyridylmebhyl group, 2-pyridylmethyl group,3-pyridylmethyl group, 4-pyridylmebhyl group, 1-quinolylmebhyl group, 2-quinolylmethyl group or the like.

Preferred compounds of the present invenbon are compounds of 15 formula (I) wherein:

When X represents C3-C6 cycloalkyl-Cl-C3-alkyl or adamantyl, Y
represents hydrogen, Cl-C3 alkyl, C3-C6 alkenyl, C3-Cs alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-Cl-C3-alkyl, adamantyl, aryl selected from phenyl and naphbhyl,20 aryl-Cl-C3-alkyl; wherein eadh of said aryl group may opbonally be sl Ihsbh ItPd wi~h onetothree subsb'tuents,eadh ofthe said subsUtuentsbeing independently selected from halo, nitro, C3-C6 cycloalkyl, C3-C3 alkenyl, Cl-C6 alkyl opb'onally subsb'tuted wibh one to three fluorine atoms, hydroxy, Cl-C6 alkoxy opbonally subsbtuted with one to bhree fluorine atoms, phenyl, amino, Cl-C6 alkylamino, 25 carbamoyl, sulfamoyl, carboxy-Cl-C6-alkyl, cyano or C3-C6 alkynyl.

When X represents C3-C6 cycloalkyl, Y represents hydrogen, Cl-C6 alkyl, C3-Cs alkenyl or C3-Cs cycloalkyl.

A represents bhe group -O-Rs in which R3 represents hydrogen, Cl-C
alkyl, C3-C6 cycloalkyl, C3-C6 cydoalkyl-C1-C3-alkyl, C3-C6 alkenyl, phenyl, phenyl-Cl-C3-alkyl, hydroxy-C2-C6-alkyl,carboxy~Cl-C3-alkyl orcarboxyphenyl;

or A, ~p, t:ser,l:, bhe group N~
R

2t~72 wo 96/05185 pCI/JPg5l0l~00 R10 and R11 represent independently hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, phenyl or phenyl-C1-C3-alkyl; phenyl group may opfionally be subsfituted with one to three subsfituents, each of the said subsfituents being independently selected from halo, nitro, C1-C6 alkyl, hydroxy, amino, carboxy or cyano;

R10 and R11 taken together may form a ring corresponding to the fommula:
1 0 -(CH2)m-D-(CH2)m-where D represents a single bond, oxygen, sulfur or a nitrogen atom ,hctit~ltl~d byhydrogen orC1-C3alkyl;
m is a number selected from 1 to 3;
or Y and A taken together may form oxo or hydroxyimino.

R~ and R2 which may be the same or different, are hydrogen, C1-C3 alkyl, C3-Co cycloalkyl, hydroxy-C2-C3 alkyl or C3-C6 alkenyi.

R3 represents C1-C3 alkyl, C3-Cs cycloalkyl, hydroxy-C2-C3-alkyl or C3-C6-alkenyl;
2~
R4 represents the group -(CH2)p-B where p is a number selected from 3 to6;

or R3 and R4 together with the intervening nitrogen atom represent a piperidine ring which is s~hct~llt.sd as depicted in fommula (11):

R Hs X~Y 1' L~ .
~C--C--N~CH2--B
R2 R (Il) where Rs and R6 represent independently hydrogen or C1-C3 alkyl;
B is a heteroaryl group of formula ~R7 ~ 7 0~

~S ~R7 ~R7 N~'R7 --N X' _~X' --N X' ~

o_~S~N ~" '~ ~"s~"~

~~ [~ ~--O~N~ '~' ~N~
~ ~ or X

2t9~72 R7 and Rs are independently selected from hydrogen, halo, nitro, C1-C6 alkyl optionally substituted with one to three fluorine atoms, hydroxy or C1-Cs alkoxy optionally Cllh~tllltpd with one to three fluorine atoms.

R12 is selected from hydrogen or C1-C6 alkyl.

X' represents a single bond, -CH2-, -CH=CH-, -CH2-CH2-, S, -S-CH2-, -S(0)-, -S(0)2-, -S(0)-CH2-, -S(0)2-CH2-, 0, -0-CH2-, N(R13), -N(R13)-CH2-, -N(R13)-S(0)2-, C(=0), -C(=0)-CH2-, -C(=0)-0- or -C(=0)-N(R13)-.

Y' ,~pl~er,l~-CH2-orC(=O).

W and W' represent independently a benzene ring or heteroaryl group of 5 to 7 atoms which contains one oxygen atom, one suifer atom or one or 15 two nitrogen atoms, provided that at least one of W and W' is heteroaryl group.

R13 represents hydrogen or Cl-Cs alkyl.

Particularly preferred compounds of the present invention are those compounds of formula (I) wherein:

When X represents C3-C6 cycloalkyl-C1-C3-alkyl, adamantyl or C3-C6 25 cycloalkyl, Y ~e:prt!ser~b hydrogen, C1-C6 alkyl, C3-C6 alkenyl or C3-Cs cycloalkyl.

A represents the group -0-Rs in which Rs r~pl~senl~ hydrogen, C1-C4 alkyl, C3-C6 alkenyl or hydroxy-C2-C4-alkyl; or A represents amino, Cl-C3 30 alkylamino, phenyl-C1-C3-alkylamino, C3-C6 alkenyiamino, C2-C6 dialkylamino, C4-Cs cydoalkylamino, C4-C7 alkylalkenylamino, piperidino, piperazino, C1-C3 alkylpiperazino ormorpholino;

or Y and A taken together may form oxo or hydroxyimino.
R~ and R2 which may be the same or different, are hydrogen or C1-C3 alkyl.

2 1 ~7 t ~2 R3 represents C1-C3 alkyl;

R4 represents the group -(CH2)p-B where p is a number selected from 3 5 to6;
or R3 and R4 together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (11):

Rs x~r ~t ~
~C--C--N~CH2--B

R2 R6 (Il) where Rs and R6 represent hydrogen;

B is a heteroaryl group of formula Nl~ y~R7 ~ 7 o , ~ o~S~

_X --N~X y~ o-~

~7~2 WO 96/05185 PCT/JP9~/01600 O~N 0=S--N~ ~N o g ~N
~,~1,~ ~~~

~3 or ~

R7 and Rs are independently selected from hydrogen, halo, nitro, C1-C6 alkyl optionally substituted with one to three fluorine atoms, hydroxy or C1-C6 5 alkoxy optionally sl Ihciti' ~'nd with one to three fluorine atoms;

R12 is selected from hydrogen or C1-C6 alkyl;

X' represents a single bond, -CH2-, -CH=CH-, -CH2-CH2-, S, -S-CH2-, -10S(0)-, -S(0)2-, -S(0)-CH2-, -S(0)2-CH2-, 0, -0-CH2-, N(R13), -N(R13)-CH2-, -N(R13)-S(0)2-, C(=0), -C(=0)-CH2-, -C(=0)-0- or-C(=0)-N(R13)-;

Y' represents -CH2- or C(=0);

15W and W' represent independently a benzene ring or heteroary group of 5 to 7 atoms which contains one oxygen atom, one sulter atom or one or two nitrogen atoms, provided that at least one of W and W' is heteroaryl group.

20 R13 represents hydrogen or C1-C6 alkyl.

2 t ~ 7 ! 72 Preferable B is R

N~ --N~ ~N

~ O Y~ O~,S,~ ~

R7 and R8 are independently selected from hydro9en, halo, nitro, C1-C6 alkyl optionally substituted with one to three fluorine atoms, hydroxy or C1-C6 alkoxy optionaily s~ t~d with one to three fluorine atoms;

X' represents a single bond, -CH2-, -CH=CH-, -CH2-CH2-, S, -S-CH2-, -S(0)-, -S(0)2-, -S(0)-CH2-,-S(0)2-CH2-, 0, -0-CH2-, N(R13), -N(R13)-CH2-, -N(R13)-S(0)2-, C(=0), -C(=0)-CH2-, -C(=0)-0- or -C(=0)-N(R13)-;

Y' ,ep,t,sel,~ -CH2-orC(=0);
R13 represents hydrogen or C1-C6 alkyl.

Examples of the compounds of the present invention are set forth in Table 1-IV.

WO9610518S 2 7 97 ~ 72 PCI/JP9S/01600 TABLE I .

~C/ CH2--N-(CH2)p--B

OH -CH3 3 o-S~8 ~_ -OH -CH3 4 o b~-- -OH --CH3 5 ~~-1~8 OH --CH3 6 o r~8 - C H3 -O H - C H3 4 0= r~

CH3 -OH --CH3 5 O,S~

-C HzCH3 -O H

-(cH2)zcH3 -OH --CH3 4 . O-S

_ -(CH2)3CH3 -OH -CH3 4 o wo 96/05185 PCT/JP95/OlG00 TABLE 1: ~continued) -(cH2)4cH3 -OH --CH3 4o-1~8 (CH2)scH3 -OH -CH3 4O-~S~

_ -CH2CH=CH2 -OH -CH3 oO~s~8 -(CH2)2CH=CH2 -OH --CH3 ~O, ~8 (CH2)3CH=CH2 -OH --CH3 OO~S

~_ -(CH2)4CH=CH2 -OH --CH3 O ~S ~

b~ OH --CH3 o//S~8 ~1_ ~ -OH -N~ ~

b~-- ~ - O H --C H3 4O= S~

~1_ -OH --CH2CH3 4O=~S~

~1 q7~ 77 wo 96/0~185 PcrlJP95 TABLE 1: (continued) -OH -(CH2)2CH3 4 o-S~

-OH -CH2CH=CH2 4 0 S~

-OH -(CH2)2CH=CH2 4 O--,S~

_ -OH -(CH2)3CH=CH2 4 0 S~8 H -OH -(CH2)4CH=CH2 4 0 ,S~

~_ -OCH3 -CH3 4 o-S~8 _ -OCH2CH3 -CH3 4 o-S~8 ~1_ -O(CH2)zCH3 -CH3 4 o/s~8 b~-- -O(CH2)3CH3 -CH3 4 o_ ~_ -OCH2CH=CH2 -CH3 O

21 q7 T 72 TABLE l:(continued) O(CH2)2CH=CH2 -CH3 4 o=, ,~_ -O(CH2)3CH=CH2 -CH3 4 0=s~

~_ -O(CH2)4CH=CH2 -CH3 4 o=s~8 _ -O(CH2)20H -CH3 4 ~ l~8 ~_ -O(CH2)30H -CH3 4 o-s~8 b~-- o(c H2)40 H -C H3 4 o=,s~

NH2 -CH3 4 0--~S~

~ H ~NHCH3 -CH3 4 o=,s~

-NHCH2CH3 -CH3 4 o=,s~

b~-- -NH(CH2)2CH3 -CH3 o=~S~8 ~l ~ q ~

TABLE 1: (continued) ~_ -NHCH2~ -CH3 O=,S~

b~-- -NH(cH2)2~3 -CH3 4 o-,s~8 H-NH(CH2)3~ -CH3 4 o=s~8 b~-- -NHCH2CH=CH2 -CH3 4 ~S~8 H-NH(cH2)2cH=cH2 -CH3 4 o-s~8 ~ H-NH(CH233CH=CH2 -CH3 4 o=~

b~ H-NH(CH2)4CH=CH2 -CH3 4 o-S~8 b~ -N(CH3)2 -CH3 4 o=~S~8 CH3 -CH3 4 O=,S ~

b~-- -N(CH2CH3)2 -CH3 4 o=s~8 21~7~

TABLE 1: (continued) ~_ -N(CH2CH2CH3)2 -CH3 O~S~

~_ -NH~ -CH3 4 o--S~8 -- -NH~ -CH3 4 o-S~8 NCHzCH=CH2 -CH3 o~,S~8 NcH2cH=cH2 -CH3 4 o-S~8 CH2CH3 /, H-N~ (CH2)2CH=CH2 -CH3 4 -S~
~-- CH2CH2CH3 ~/, b~-- H -b~-- -N~> CHs 4 O_S~

~_ -N~NH -CH3 4 O-S~

b~-- -N~NCH3 -CH3 4 2 1 q7 t, ~
WO 9610518!j 24 I?CT/JP9~101600 TABLE 1: (continued) ~_ -N NCH2CH3 -CH3 o=,S~

~_ -N N(CH2)2CH8 -CH3 4 O=~

~_ -N~O -C H3 OO, ~_ =0 -CH3 4 o=S~

OH -CH3 4 O=S

-OH -CH3 4 --N~

_ -OCH3 -CH3 4 --N~

~_ -OCHzCH3 -CH3 4 --N~

O(CH2)2CH3 -CH3 4 --~_ -OCH2CH=CH2 -CH3 4 --N~

2 1 97 ~ 72 W O 96/05185 PC~r/JP95/01600 T~LE 1: (continued) ~_ -o(CH2)20H -CH3 4 --N~

-OH -CH3 4 Clj~

_ -OCH3 -CH3 4 Cl;~

Cl;~
H-OC H2C H3 -C H3 4 --~s ~_ -O(CH2)2CH3 -CH3 4 --,~s ~_ -O C H2C H=C H2 -C H3 4 _ -O(CHz)20H -CH3 4 ~_ -O H -C H3 4 ---OC H3 -C H3 4 --N~

~_ -OCH2CH3 -CH3 4 --N~

WO 96/05185 .PCT/JP95/01600 TABLE l:(continued) ~_ -O(CH2)2CH3 -CH3 4--N~

~_ -OCH2CH=CH2 -CH3 4--N~

O(C H2)20 H -C H3 4--N S

H _0 H -C H3 4--~o -OCH3 -CH3 4 ~ ~~

~_ -OCH2CH3 -CH3 4--N O

b~-- -O(CH2)2CH3 -CH3 4--N O

~_ -OCH2CH=CH2 -CH3 4 ~ ~~

H-O(CH2)20H -CH3 4--~0 H _0 H -C H3 4 ~~3 2 ~ ~7 1 72 Wo 96/05185 PCTIJP95101~00 TABLE 1: (continued) OCH3 -CH3 4 -~}

OCH2CH3 -CH3 4 -~

~_ -O(CH2)2CH3 -CH3 4 ~g3 ~ H-OCH2CH=CH2 -CH3 4 --~3 b~-- -O(CH2)20H -CH3 4 -~!1 b~-- oH -CH3 4 ~~) ~_ -O C H3 -C H3 4 --b~-- -OCH2CH3 -CH3 4 -~

b~ H-O(CH2)2CH3 -CH3 4 ~~

~ H-OCH2CH=CH2 -CH3 4 -~

Wo 96105185 28 PCr/JP9s/01600 IA~ (continued) ~_ -O(CH2)20H --CH3 4 ~~) -O H -C H

_ -OCH3 -CH3 4 _~3 _ -OCH2CH3 -CH3 4 --oN~

O(CHz)2CH3 -CH3 4 _~

H-OCH2CH=CH2 --CH3 4 --oN~

~ -O(CH2)2OH -CH3 4 --b~ OH --CH3 b~-- -OCH2CH3 -CH3 4 21 97-1 7~
WO 96/051~5 PCT/JP95/01600 ABLE 1: (continued) _ H-O(CH2)2CH3 -CH3 4 ~ H-OCHzCH=CH2 -CH3 4 b~ -O(CH2)20H -CH3 4 b~ -O H -C H3 4 b~ H -OCH3 -CH3 4 ~_ -OCH2CH3 -CH3 4 -O(CH2)2CH3 -CH3 4 OCH2CH=CH2 -CH3 4 ~ -O(CH2)20H -CH3 4 b~-- OH -CH

~I q7~ 7?~-TABLE 1: (continued) OCH3 -CH3 4~5 OCH2CH3 -CH3 4--~s --O(CH2)zCH3 -CH3 4~s ~_ -OCH2CH=CH2 -CH3 4--~;gs ~_ -O(CH2)20H -CH3 4--~s ~_ -OCH3 -CH3 4 ~ H -OCH2CH3 -CH3 4 b~ H-O(CHz)2CH3 -CH3 4 H-OCH2CH=CH2 -CH3 4~~

2 1 97 ~ 7~
WO96/05185 P~,~IJ. _.~16~0 TABLE 1: (continued) ~1_ -O(CH2)20H -CH3 4 b~ OH -CH3 4 -OCH2CH3 -CH3 --,N~

-O(CH2)2CH3 -CH3 4~1 H-OCH2CH=CH2 -CH3 --N~ }

~ -O(CH2)20H -CH3 --,N~

b~ H -OH -CH3 4a~.

b~ H -OCHs -CH3 4 ~_ -OCH2CH3 -CHS 4 2 ~ ' Z' TABLE l:(continued) o(c H2)zC H3 -C H3 4o O~

b~ H-OCH2CH=CH2 -CH3 4 _ -O(CH2)20H -CH3 4 _ -O H -C H3 4 -OCH3 -CH3 o O~

_ -OCH2CH3 CH 4~~

O(CH2)2CH3 -CH3 4NJ¢
o5o~

~_ -OCH2CH=CH2 -CH3 4NJ¢
o~o~

~ H-O(CH2)20H -CH3 ~

wo 96/05185 PCT/JPss/01600 TABLE 1: (continued) b~ -OCH3 -CH3 4 -OCH2CH3 o"

O(CH2)2CH3 -CH3 4 ,~

H-OCH2CH=CH2 -CH3 O~,~

_ -O(CH2)20H -CH3 4 ~_ ~0 H -C H3 .~

b~-- -OCH3 -CH3 4 ,~F

b~ -OCH2CH3 -CH3 4 O~

t ~ ~

TABLE l:(continued) ~_ -O(CH2)2CH3 -CH3 4 ~F

H-OCH2CH=CH2 -CH3 4 05 -O(CH2)20H -CH3 o5'~

-OH -CH3 4 O~

-OCH3 -CH3 4 ,~F

-OCH2CH3 -CH3 4 ,~F

H-O(CHz)2CH3 -CH3 4 ~F

H-OCH2CH=CH2 -CH3 4 ~F

~_ -O(CH2)20H -CH3 o O~

2 1 ~7=t 72 wos6losl8s . .~I/J. l~oo , TABLE l:(continued) o~

~_ -OC H

Cl ~ -OCH2CH3 -CH3 4 b~ -O(CH2)2CH3 -CH3 ~_ -OCH2CH=CH2 -CH3 4 ~~
o~o~
Cl ~_ -O(CH2)20H -CH3 4 ,~ -OH -CH3 4 $

-OCH3 -CH3 4 0~

Zl~7t72 WO 96105185 36 PCl[lJP95/01600 ~L~L.;(continued) -OCH2CH3 -CH3 4 ~CH3 o5o~

,OCH3 O(CH2)2CH3 -CH3 4 0~

~_ -OCH2CH=CH2 -CH3 OCH3 osg O(CH2)20H -CH3 4 OH -CH3 4 ~~
o8~¢1 ~_ -OCH3 -CH3 4 ~~
o5o~

-OCH2CH3 -CH3 4 --~3 ~'o51~FI3 O(CH2)2CH3 -CH3 4 0~

2 ~ Y~ ~ 7~
PCI~/JP9510 1600 WO 96/0518~

TA~LE 1: (continued) H-OCH2CH=CH2 -CH3 ~3 O(CH2)20H -CH3 ~3 ~_ -OH -CH3 4 ~'0 ~_ -OC H3 -C H3 4 O~o -OCH2CH3 -CH3 4 ~.0 O(CH2)2CH3 -CH3 4 o~~

H-OCH2CH=CH2 -CH3 4 ~'o ~_ - O ( C H2)20 H - C H3 4 O~o ~ ~ 97 1 72~
WO 96/05185 PCIIJP95/OlGOO

TABLE l:(oontinued~

-O H -C H3 4 _ ~ 5=0 -O C H3 -C H3 4 - ~ s=o - O C H2C H3 -C H3 4 - ~ =O

-O(C H2kC H3 -C H3 4 - N~s=O

- O C H2C H=C H2 -C H3 4 - ~ ~

- O(C H~20 H -C H3 4 - N~o -O H -C H3 Q ~,~

- O C H3 -C H3 Q ~

WO 96/05185 2 1 q 7 ~ 72 PCT/JP95/01600 TABLE 1: (continued) b~ H -OCH2CH3 -CH3 4 --~o ~_ -O(CH2)2CH3 -CH3 -OCH2CH=CH2 -CH3 4 ~~'o _ -O(CH2)20H -CH3 4 ~ ~'o ~H3 -O(CH2)2CH3 -CH3 WO 96105185 ~ 1 ~ 7 ~ 7 2 PCT1JP95101/i00 TABLE 1: (continued) OCH2CH=CH2 -CH3 4 -N S

q~,3 b~-- -O(CH2)2OH -CH3 4 --N S

OH

~_ -OCH3 -CH3 OH

-OCH2CH3 -CH3 4 --NO~S

OH

~_ -o(cH2)zcH3 -CH3 4 --gs b~-- -OCH2CH=CH2 -CH3 ~

OH

~_ -O(CH2)20H -CH3 4 -N S

2 t ~ 2 ., TABLE 1: (continued) X y A R3 P 3 _ -OCH3 -CH3 4 os.

b~ -OCH2CH3 -CH3 4 O(CH2)2CH3 -CH3 4 --~_ -OCH2CH=CH2 -CH3 4 --N~3 H-o(cH2)2oH -CH3 4 b~ -O H -C H3 4 "s~

~ -OCH3 -CH3 4 ~8 ~ ~~
~ -OCH2CH3 -CH3 4 o' ~

2 ~ 7 2 Wo 96/0518~ PCrlJPsS/01600 TABLE l:(continued) ~_ -O(CH2)2CH3 -CH3 4 H-OCH2CH=CH2 -CH3 4 O"S~

~5~ -O(CH2)20H -CH3 ,,~

- O H C H 4 ~ s ~ -OC H3 -C H3 4 ~,5 ,~ -OCH2CH3 -CH3 4 ,s~

b~ -O(CH2)2CH3 -CH3 4 "3 ~_ H-OCH2CH=CH2 -CH3 ~"s~

_ -O(C H2)20H -C H3 4 O;

WO 96105185 2 1 q 7 1 7 2 PCT/JP95101600 TABLE 1: (continued) ~_ -OH ~"~

~_ -OCH3 -CH3 4 b~ -OCH2CH3 -CH3 4 ~

~_ -O(CH2)2CH3 -CH3 4 ~8 ~ ~~
-OCH2CH=CH2 3 4 o ,N~

O(CH2)20H -CH3 4 ~8 O~ ,0 H -OH -CH3 4 ~3 2 ~ q7 t 72 TABLE l;(continued) O C H2C H3 -C H3 4 ~3 o~ "o ~_ -O(CH2)2CH3 -CH3 4 ~3 ~_ -OCH2CH=CH2 -CH3 4 ~3 o~ "o -O(CH2)20H -CH3 4 ~3 ~ H -OH -CH3 4 o~

b~ -OCH3 -CH3 4 ,~

~_ -OC H2C H3 ~ ~

~_ -O(C H2)zCH3 --~8 Wo 96/05185 2 1 9 7 1 7 2 PCTIJP9~/01600 TABLE 1: (continued) ~_ -OCH2CH=CH2 -CH3 4 ~ -O(CH2)20H -CH3 4O,S-N~

b~ -O H -C H3 4j~

~ -OCH2CH3 -CH3 4 b~-- O (C H2)2C H3 -C H3 4Oj~

~_ -OCH2CH=CH2 -CH3 4~8 -O(CH2)20H -CH

-O H C H3 4o "~

--N~
~ H -OCH3 -CH3 40=~

WO 96/0~185 2 1 9 7 ~ 7 2 PCT~JP95101600 TABLE 1: (continued) HO C H2C H3 ~

H-o (C H2)2C H3 --H-OC HzC H=CH2 ~

Ho (C H2) OH --H OH -CH3 4 _C~5 H -OH -CH3 4 -~S

-O H - C H3 4 --~o H -O H - C H3 4 --~J

2Iq~7~

TABIJ~ l; (continued) H -OH -CH3 4 ~~) H -OH -CH3 4 ~H

H -OH -CH3 4 ~~o H -OH -CH3 4 --N~

WO 96105185 2 1 9 7 t 7 2 PCT/JP95/01600 TABLE 1: ~continued) H -O H -C H3 ~,~

H -O H -C H3 4 --~8 -C H3 -O H o-,s~

-CH2CH3 -OH --~8 --(CH2)2CH3 -OH -CH3 4 ~8 --(CH2)sCH3 -OH --~

-CH2CH=CH2 -OH --~8 -(cH2)4cH=cH2 -OH -CH3 4 o--s~

-O H --Wo 96105185 PCr/~P951016qO

TABLE 1: (continued) X y A R3 P B

- C H3 -O H -C H3 4 --N~

-CH2CH3 -OH -CH3 4 ~g -CH3 -OH -CH3 4 --~s -C H3 -O H -C H3 4 --N~O

-CH2CH3 -OH -CH3 4 -- o ~ ~ ~7 ~ 72 TABLE l:(continued) X y A R3 P B

-CH3 -OH -CH3 4 ~g -CHzCH3 -OH -CH3 4 ~/ H -OH -CH3 4 ~/ H -OCH3 -CH3 4 c~

~/ H -OCH2CH3 -CH3 4 ~/ H -O(CH2)2CH3 -CH3 4 -OCH2CH=CH2 -CH3 4 o _~
~/ -O(CH2)20H 3 4 O=,~

W096/05185 51 PCTllP95/OlfiOO

TABLE 1: (continued) ~/ H -OH -CH3 c ~/ H -OH -CH3 4 ~ s ~/ H -OH -CH3 4 -~5 ~~ -O H -C H3 4 --N~

~/ H -OH -CH3 4 --~}

~/ H -O H -C H3 4 --~/ H -OH -CH3 4 OJ~

H -OH -CH3 4 ~NH

wo 96/05185 ~ I q 7 ~ 7 ~ PCTIJP95/01600 TABLE l:(continued~

H -OH -CH3 4 NQo o~
~3 ~/ H -OH -CH3 4 ~s o ~

/ H -OH -CH3 4 O~

~~ -OH -CH3 4 ~) ~/ H -OH -CH3 4 ~/ H -OH -CH3 Co'~3 ~/ H -OH -CH3 4 O_~
o 2~q~1 72 WO 96/0!i18~ PCT/JP95/01600 TABLE 1: (continued) ~/ -C H2C H3 - O H -C H3 4 o- s~

- (C H2)2C H3 -O H -C H3 4 o-s~

-(CH2)sCH3 -OH -CH3 4 -CH2CH=CH2 -OH -CH3 4 o ~/ -(CH2)4CH=CH2 -OH -CH3 4 o-s~

~~ ~ -O H -C H3 0 ~/ -CH3 -OH -CH3 4 --WO96/05185 2 1 ~ 7 1 72 PCT/JP95/01600 TABLE 1: (continued) ~/ -C H3 -O H -C H3 4 ~/ -CH3 -OH -CH3 4 --N O

-CH2CH3 -OH -CH3 4 ~

-CH3 -OH -CH3 4 o='3~8 ~/ -CHzCH3 -OH -CH3 4 O-s~

Wo 96/05185 PCT/JP95101600 TABLE 1~ ntinued) X y A R3 P B

H -O H -C H3 4 o ,s~

H -OH -CH

~ H -OH -CH3 O H -OH -CH3 4 r~

2 1 ~7 t ~2 WO 96105185 PCT/JP95/OlliO0 TA~I_E 11 . _ 'CH--~--N-(CH2)p--B

OH -CH3 H 4O S~

-O H-C H2C H3 H 4~- ~8 -OH -(CH2)2CH3 H 4 O-S~

~1_ -O H -C H3 --C H3 ~ /~s~8 ,~ -OH -CHzCH3 --CH3 4o-S~8 b~ -OH -(CH2)2CH3 --CH3 4o-S~8 -OH -CH2CH3 -CH2CH3 4QS~8 -OH -(CH2)2CH3 -CH2CH3 O"S~

_ -OH -(CH2)2CH3 -(CH2)2CH3 4o--S~8 2 ~ ~7 1 7~

T~Rl F 11: (continued) X A Rl R2 P B

~_ -O H -C H3 H 4 b~-- oH -CH2CH3 4O,,~

_ -OH -(CH2)2CH3 H 4o~

O H -C H3 --C H3 4o~8 b~-- OH -CH3 H 4 _ -O H -C H2C H3 H 4,~

~_ -OH -(CH2)2CH 3 H 4 ~_ -O H -C H3 3 4a"~~~8 WO 96/05185 2 1 ~ 7 T ~ 2 PCT/JP9~/01~00 TABLE 111 . ~
X Y
C--CH2-N~CH2B

X Y A B

~_ H -OH O,S~

--CH3 -OH ~ ~8 -C H2C H3 - O H O-,S~

-(CHz)2cH3 -OH oO~N~8 ~_ - (C H2)3C H3 -O H oO,S~

-(CH2)4CH3 -OH O,S~

~_ -(CH2)5CH3 -OH o_~

~_ -CH2CH=CH2 -OH o-S~8 ~_ -(CH2)2CH=CH2 -OH O--S ~

WO 96/05185 2 1 9 7 ~ ~ PCTIJP95/01600 T~RI F 111: (continued) X Y A B

~_ -(CH2)3CH=CH2-OH O="S~

~_ -(CH2)4CH=CH2-OH o-/S~8 ~_ --< -O H o- S ~8 -O H oO~sN~8 O H o=s ~8 -OC H3 ~O~, -OCH2CH3 %~lN~

_ -O(CH2)2CH3 o--o,lN~8 1~ --IN~
-- -O(CH2)3CH3 O-S~

~_ -OC H2CH=CH2 ~ "5 WO 96/05185 2 1 9 7 t 7 2 PCT/JP95/01600 ~

~RI F 111: (, "9"~

X Y A B

O ( C H2~2C H=C H2 O-"S~

~_ -O(CH2)3CH=CH2 o-,S~8 O(CH2)4CH=CH2 --~ -O(CH2)20H ~o,,S~

~1_ -O( CH2)30H ods~8 ~_ -O(C H2)40 H 0-"S~

NH2 ~--O-~sr~

NHCH3 oo~sN~8 ~_ - N HC H2C H 3 ~--O~S

b~-- -NH(C H2)2C H3 --N~

2 1 97 ~ ~2 TABLE 111: (continued) X Y A B
~_ -NHCH2~ o~sr~8 ~_ -NH(cH2)2~ 0--o,sr~8 --N~
H -NH(CH2)3~ O-,S~

H -NHCH2CH=CH2 0-,5 NH(CH2)2CH=CH2 O--o"S~

~_ -NH(CH2)3CH=CH2 Oo"S~

~_ -NH(CH2)4CH=CH2 ~---r~
H -N(CH3)2 o-,s~

C H3 0~5 ~_ - N (C H2C H 3)2 O="S~

o 2 1 ~7 ~ 72 WO 96/05185 PCTIJP95/01~00 TABLE 111: (coninyed) X Y A B

~_ -N(CH2C H2cH3)2 O-,S~

~_ -NH~ o--oS~8 b~-- H -NH~ o--,S~

~_ - ,NCH2CH=CH2 o_ I ~

~_ -N~ CHZcH=cH2 o-s~8 C H2C H 3 O'~

J(cH2)2cH=cH2 --IN~
H C H2C H2C H 3 o--,s -N~ o~="lN~

~_ H -~ ~--O~ IN~8 _ H -~NH o~S~

b~-- -N NCH3 0 ,8~8 2 1 ~7 t 72 TAFI F 111: (continued) X Y A B

b~ -N NCH2CH3 ~O, b~-- -N~JN(CH2)2CH3 O-,S~

-N~O o-"s~8 ~ O 0- S~

=N-OH O=,S~

~ H -OH A~

b~-- H - O C H3 b~ OCH2CH3 O(CH2)2CH3 ~_ -OCH2CH=CH2 --N~

WO 96105185 2 1 ~ 7 1 7 2PCT/JP95/01600 TABLE 111: (continued) X Y A B

O(CH2)20H --~

b~-- H - O H --~S

b~ H -OCH3 j~

-O C H2C H3 cli~

~_ -O(CH2)2CH3 Cl;~

-OCHzCH=CH2 Cl;~

b~ H -O(CH2)20H --N~

b~-- H -OH ~5 b~ H -O C H3 . --~s O C H2C H 3 --N~S

2~7t7~
o 96/05185 PcT/JPss/ol~oo T~RI F 111: (continued) X Y A B

b~ H-O(CH2)2CH3 --~s ~_ -OCH2CH=CH2 --~s o ( c H2)2o H --I\ S

b~-- H -OH N~

b~ -O C H3 --N~O

~_ -O C H2C H3 --N O

~_ -O(CH2)2CH3 --N O

b~-- -ocH2cH=cH2 -O(CH2)20H . --~~

~_ H -O H _~3 ?1 ~7 WO 96/05185 ~ 1 7 2 pcTlJp9s/

IABLE 111: (coniinued) X Y A B

H -OCH3 -~D

OCHzCH3 -~

b~-- -O(CH2)2CH3 -~1 b~-- -OCH2CH=CH2 b~-- H -OtCH2)20H

-- H -OH -~

~_ H -O C H3 -~) ~_ H -OCH2CH3 -~

~1_ -O(CH2)2CH3 -~

~_ -OCH2CH=CH2 ~) 2 t q~ ~ ~2 TABLE IlI:(continued) X Y A B

~_ -O(C H2)20 H -~

_ H -OH -~

~_ H -OCH3 -~

~ H -OCH2CH3 ~~3 b~ -O(CH2)2CH3 -o~3 ~_ -OCHzcH=cH2 -~

-- -O(CH2)20H

-OH --o~ SNH

b~ -OC H3 ~H

-OCH2CH3 --o~NH

TABLE 111: (continued) X Y A B

b~ H -O(CH2)2CH

~_ -OCH2CH=CH2 ~_ H -O(CH2)20H

H -OH --~_ H -OCH3 --~ H -OCH2CH3 _~

b~-- -O (C H2)2C H3 ~_ -OCH2CH=CH2 o~

H -O(CH2)20H J~

~_ H -OH ~ Ss 2 l 9~ ~ ~2 TABL~ (continued) X Y A B

H~OCH3 o~

O C H2C H3 ~

H-O ( C H2)2C H 3 --o~S

~_ -OCH2CH=CH2 o~

H-O(CH2)20H

b~-- H- O H

~_ H-OCH3 0,~

~_ -OCH2CH3 oJ~

~_ -o(cH2)2cH3 O C H2C H =C H2 2~q7t7~
Wo 96/0sl8s PCT/JP95/01600 TABLE 111: (continued) X Y A B

O (C H2)20 H

_ H - O H N~
e~
b~-- H -OCH3 ~) -OCH2CH3 --N~

_ -O(CH2)2CH3 --~N~

~_ -OCH2CH=CH2 ~_ -O (C H2)20 H

~_ H -OH ~51~8 ~_ H -OCH3 o~

b~ OCH2CH3 2 1 ~ 1 72 TABLF 111: (continued) .X Y A B

~_ -O(CH2)2CH3 ~_ -OCH2CH=CH2 a~-d~3 H -O(CHz)20H ~~O~g H -OH o'-O~ g H -OCH3 0~

b~-- o c H2C H 3 a'O~

O(CH2)2CH3 ~ H -OCH2CH=CHz b~ H -O(C H2)20 H O., W096/05185 2 1 9 7 T 7~ PCT/JP95/01600 f~

TA~LE 111: (conboued) X Y A B

b~ H -O H

H -OCH

H -OCH2CH3 ,~

~_ -O(CH2)2CH3 ~_ -O C H2C H =C H2 ~1_ -O(CH2)20H

b~-- H -OH

~_ -OCH3 ~F

b~ ocH2CH 3 ,~F

2 ~ ~7 ~ ~

T~RLF I11: (continued) X Y A B

O ( C H2)2C H3 ~F

~_ H -OCH2CH=CH2 ~F

b~-- H -O(CH2)20H

H -O H aO~

-- -OCH3 aO~F

~_ -OCH2CH3 aogF

O(CH2)2CH3 ,~F

b~-- -OCH2CH=CH2 ~F

~_ -O(CH2)20H a~.o~F

WO 96/05185 PCTIJP95/01600 j~

TABLE 111: (continued) X Y A B

~_ H -OH ,;~

~_ -OCH3 ao~g Cl --o (c H2)2c H3 a~

~_ -OCH2CH=CH2 a~osl~l Cl ~_ H -O(CH2)20H c~

~C~b _ H - O H 0~

_ H -OC H3 2 1 97 t 72 TARI F 111: (continued) X '~ A B

b~-- H o~O~

~ -O(C H2)2C H3 ~

~_ H -OCH2CH=CH2 o"ll~

~CH3 O(CH2)20H ~~O~F3 H -OH ~

-O C H3 CF, H -O C H2C H3 o"

H -O(CH2)2CH3 2 1 ~7 t 72 WO 96105185 PCT/~P95101600 TARI F ~ (continued) X Y A B

H -O C H2CH=C H2 CF, H -O(C H2)20 H - ~4 ~'o~

H -OH ~ o H -OCH3 ~0 H -OCH2CH3 o~~

H -O(CH2)2CH3 0--~"o b~ H -OCH2CH=CH2 0--~'''o ,~_ - O ( C H8)20 H _NQ, o WO 96/0~18~ 2 1 ~ 7 1 7 2 PCT/JP95101600 [~L~ (continued) X Y A B

H -O H --N~l= O

b~ H -OCH3 --~s=o H -OCH2CH3 --N ~0 o(CH2)2CH3 --N~SO

H-OCH2CH=CH2 --N~O

-O(CH2)20H _~so b~ H -OH --N S' _ H -OCH3 --~' WO 96/05185 2 I 9 7 ~ 7 2 PCT/JP95/01600 TABLE 111: (oontinued) X Y A B

oc H2C H3 --N~S~

O(CH2)2CH3 --N~Oo _ H -OCH2CH=CH2 ~ ~N~S''o _ - o ( c Hz)20 H --~S~~O

~C~b H -OH --~s Q~b b~-- -OC H3 --N S

OC~

oc~

H -O(CH2)2CH3 --~s 2 ~ 9~ 1 72 TARI F 111: (continued) X 'I A B
-_ H -OCH2CH=CH2 -~s O~H3 H -O(CH2)20H --~S

OH

H -OH --N S

OH

~_ -O C H3 --N~S

OH

O(CH2)2CH3 --N~

b~-- OCH2cH=cH2 N~S

~_ -O(CH2)20H --N S

WO 96105185 2 ~ ~ 7 ~ ~ 2 PCT/JP951OIG00 ~

TABLE 111: (continu=ed) X Y A B

H -O H --N~

H -O C H3 05~3 b~ H -OCH2CH3 o,~3 O(CH2)2CH3 --N~

~_ -OCH2CH=CH2 O(CH2)20H o-,~S~

~_ H -O H "S~
Q~SN~

b~ H -OCH3 O~ N~

~ - O C H2C H3 "~

2 1 97 ~ ~2 T~RI F 111: (continued) . X Y A B

~_ -O(CH2)2CH3 ~,S~8 ~_ -O C H2C H=CH2 o NN~

b~ -O(CH2)20H ',S~8 ~¦_ H -O H ;,s -OCH3 "s CH

-O C H2C H 3 ~~c~

H -O(CH2)2CH

-OCH2CH=CH2 o~N~

~1_ -O(CH2)20H "S

~ I q ~ t ~ 2 pCT/JP95101600 TABLE 111: (continued) _ X Y A B
o~
~_ H -O H o' N~3 ~_ H -OCH3 o" ~

b~ ; H -O C HzC H3 '~

~_ -O(CH2)2CH3 ~_ -OCH2CH=CH2 "S~

H -O(CH2)20H

o~ "o ,~_ H -OH g~3 ~_ H OCH3 ~3 W O 96/05185 PC~r/JP9~/01600 TAFU F ~ ntinued) O~ "0 ~_ -O C H2C H3 H-O(CH2)2CH3 ~3 o~ "o H--OcHzcH=cH

o~ "o ~_ -O(CH2)20H

H -OH

~_ H -O C H3 o~

~_ -OCH2CH3 o"~

~_ -O(CH2)2CH3 o~

2 ~ 7 2 TABLE 111: (continued) X Y A B

~_ H -OCH2CH=CH2 o=s~

o(CH2)20H o=,sN- N~

H -OH

b~ H - O C H

-- -OCH2CH3 ol~

~_ -o(cH2)2cH3 o~8 ~_ -OCH2CH=CH2 oj~

-O(CH2)20H o~

H -OH O_~

2 1 ~ 2 8~i T~RI F 111: (continued) X Y A B

--N~
H -O C H2C H 3 0 ,5_~

H -O(CH2)2CH3 ~ ~8 H -OCH2CH=CH2 o "

H -O(CH2)0H c=,~

H -OH ~~

Cl H -OH -N S

H -OH - s H -OH -~o H -OH --~}

21~7~7~

TABLE 111: (continued) X Y A B

H -OH --H -OH

H -O H g~

H -OH ~
o~

H -OH s H -OH

H -OH

H -O H o-s~
o'~

2 ~ q7 ~ 72 TARI F 111: (continued) X Y A

H -OH --~

H -O H --~
oOs~

- C H3 - O H ¦

-C H2C H3 -O H --I ~8 -(CH2)2CH3 -OH o "s~

- (C H2)sC H 3-O H ---CH2CH=CH2 -OH ~ ~8 --(cH2)4cH=cH2-OH ~ ~S~8 WO96/05185 2 t q 7 ~ 7 ~ PCT/JP95/01600 TABLE 111: (continued) X Y A B

_ ~9 -CH3 -OH --N~

-CH2CH3 -OH --~' ~,9 -CH2CH3 -OH -- s ~/ 9 -C H3 -O H --N~O

o~

2 1 97 t 72 ¦~ WO 96/05185 PCT/JP95/01600 TABLE 111: (continued) X Y A

-C H3 -O H oO-"s3 -C H2C H 3 -O H ~O,,s~

~/ H -O H ~8 H -OCH3 ~.

~/ H -OCH2CH

~/ H -O(CH2) ~/ H -OCH2CH=CH

WO96/0518~ 2 1 ~ 2 PCT/JP95/01600 TARI F 111: (continued) X Y A B

--N~
~/ H -O(CH2)2 ~~ H -OH

~/ H -OH -- s ~7 H -OH
~s ~/ H - O H ~ ~~

H -O H --~

~/ H -OH _~}

H -OH

2 ~ 97 ~ 72 - TABLE 111: (continued) X Y A B

~/ H - O H --o~NH

~/ H -OH

~~ H -OH O--~/ H -OH ~1 H -OH ~) ,~/ H -OH o~8 ~/ H -OH ~

~C~b H -OH ~8 WO 96/05185 2 l ~ 7 ~ 7 2 PCTIJP9S/01600 ~

TABLE 111: (continued) X Y A B

~~ -C H3 -O H 1 ~8 -C H2C H3 -O H --I ~

-(CH2)2CH3 o-;3~8 ~/ -(cH2)5cH3 --~

~, -CHzCH=CH2 -OH ~8 -(CHz)4CH=CHz -OH o~,S~8 -CH3 -OH --~

T~ Rl F I 1 1: (continued) ~/ -CH2CH3 -OH --~

~/ -.CH3 -OH --N S

~/ -CH2CH3 -O H _ Q
~s ~/ -CH3 -OH
~o ~/ -CH2CH3 -OH N O

-C H 3 -O H ~g -CH2CH3 -OH O~

~/ -C H3 - O H (F, ~8 Wo 9610518~ 2 l ~ 7 ~ 7 2 Pcr1Jp95101600 ~

TABLE 1 11: (continucd) X Y A B

-- -C H2C H3 -O H ~g H -OH O_~
o r H -O H o~

C~ H -OH o=~8 ~~ H -OH

~~/ H -OH O=~

D~/ H -OH o-~8 Cl~ H -O H ~ "~

[~ H -OH

- T~RI F IV

X-C H-C~C H2- B

X A R1 R2 Rs R6 B

OH --CH3 H H H O--S~

-OH -CH2CH3 H H HO=,S~

_ -OH -(CH2)2CH3 H H o,S~8 ~_ - O H - C H3 --C H3 ~, ~

~_ -OH -CH2CH3 --CH3 H Ho-S~8 ~I_ -OH -(CH2)2CH3 --CH3 H HO-lS1~8 b~-- -OH -CH2CH3 -CH2CH3 H HO=,S~

b~-- -OH -(CH2)2CH3 -CH2CH3 H H O-S~

,~_ -OH -(CH2)2CH3 -(CH2)2CH3 H H O--S~

WO 96/05185 2 I q 7 t 7 2 PCT/JP95/OIG00 TA~I F IV: (continued~

X A R1 R2 Rs R6 B

--N~9 -OH H H --CH3 H O=

~_ -OH H H CH3 -CH3 O S~8 - O H --C H3 H --C H3 H o S~

-OH --CH3 H --CH3 --CH3 o=~

-OH -CH2CH3 H -CH3 H O=r~

b~ -OH -CH2CH3 H --CH3 --CH3 o-S~8 b~ -OH -(CH2)2CH3 H --CH3 H O-S~

~ -OH -(cH2)2cH3 H -CH3 CH 0~-S~

b~ -OH -CH3 -CH3 --CH3 H O~S~

~5~ -OH --CH3 --CH3 - CH3 --CH3 O~S~

21q71 72 WO 96105185 . PCTIJP95101600 TARl F IV: (continued~

X A R1 R2 Rs R6 a ~ -OH -CH2CH3 -CH3 --CH3 H o-,s~8 b~ -OH -CH2CH3 -CH3 CH~ -CH3 o=~S~

b~ -OH -(CH2)2CH3 --CH3 O

~_ -OH -(CH2)2CH3 --CH3 --CH3 --CH3 O=~

-OH -CH2CH3 -CH2CH3 - CH3 H o=

~ -OH -CH2CH3 -CH2CH3 --CH3 -CH3 o=1~8 b~ -OH -(CH2)2CH3 -CH2CH3 --CH3 H o-s~-8 ,~ -OH -(CH2)2CH3 -CH2CH3 --CH3 --CH3 0~-S~

-OH -(CHz)2CH3 -(CH2)2CH3 --CH3 H O-S~

~_ -O H-(CH2)2C H3 -(CH2)2C H3 --C H3--C H3 O--~S~

WO 96/05185 2 l ~ 7 t 7 2 PCT/JP95/01600 T,~RLF IV: (continuedl X A R1 R2 Rs R6 B

OH -CH2CH3 H H H ~8 b~-- OH-(CH7)2cH3 H H H

_ -OH H H --CH3 H

~ -OH H H --CH3 -CH

b~-- o H - C H3 --C H3 --C H3 --C H3 b~ -OH --CH3 H HH ~3~8 ~ -OH -CH2CH3 H H ~~

21971 ~2 WO 96/05185 PCT/JP95/OlliO0 TABLE IV: (continued) X A R1 R2 Hs R6 B

-- -OH -(CH2)2CH3 H H H o55 OH -CH3 -CH3 H H o55 ~_ - O H H H C 3 H o55 ~_ -OH H H --CH3 --CH3 o"5~g ~_ -OH -CH3 -CH3 --CH3 --CH3 o5,5,~

2~7~72 Specifically preferred compounds are: -1-(1 -Adamantyl)-2-[N-methyl-N-[4-(2H-naphth[1 ,8-c~;~,oll ,ia~c,1-2-yl)butyl]amino]ethanol S,S-dioxide;

2-[[1-[2-(1 -Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]-2H-naphth[1 ,8-cu;;~Jthidzole 1,1-dioxide;

2-[[1-[2-(1 -Adamantyl)-2-oximinoethyl]-4-piperidinyl]methyl]-2H-naphth[1 ,8-10 c~;~utl ,ia~ole 1,1 -dioxide;

1-(1 -Adamantyl)-2-[4-(2H-naphth[1 ~8-cuqi~ull ,id~ul-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide;

1-(1-Adamantyl)-2-[4-(9-carbazolyl)methylpiperidin-1-yl]ethanol;

1-(1-Adamantyl)-2~[N-methyl-N-[4-(2H-naphth[1,8-c~ uthidzol-2-yi)butyl]amino]ethylamine S,S-dioxide;

1-(1-Adamantyl)-N-methyl-2-[N-methyl-N-[4-(2H-naphth[1,8-cu;;~,lhid~ol-2-yl)butyl]amino]ethylamine S,S-dioxide;

2-(1 -Adamantyl)-N-methyl-N-[4-(2H-naphth[1 ,8-c~;~utl ,ia,ul-2-yl)butyl]-2-pyrrolidin-1-ylethylamine S,S-dioxide;
2-[4-[N-[2-(1 -Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-2H-naphth[1,8-cu,;~,lhiazole 1,1-dioxide;

1-(1 -Adamantyl)-2-[N-methyl-N-[4-[5H-IJh~naulhl idi"-6-oxo-5-yl]butyl]amino]ethanol;

1-(1 -Adamantyl)-2-[N-methyl-N-[4-(6H-dibenzo[ce][1 ,2]thiazin-6-yl)butyl]amino]ethanol S,S-dioxide;

1-(1 -Adamantyl)-2-[4-(2H-naphth[1 ,8-cu,;sull ~idzul-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide;

2 1 97 1 7~

1~ Adamantyl)-N-methyl-2-[4-(2H-naphth[1,8-c~isothiazol-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide;

2-[1 -[2-(1 -Adamantyl)-2-morpholin-4-ylethyl]piperidin-4-ylmethyl]-2H-5 naphth[1,8-cu~;~,oll,idzule 1,1-dioxide;

2-[1-[2-(1 -Adamantyl)-2-pyrrolidin-1 -ylethyl]piperidin-4-ylmethyl]-2H-naphth[1,8- cu5;~otl,id~ule 1,1-dioxide;

2-[1-[2-(1-Adamantyl)-2-(4-methyl)piperazin-1-ylethyl]piperidin-4-ylmethyl]-2H-naphth[1 ,8-c~ ull ,id~ule 1 ,1 -dioxide;

1-(1 -Adamantyl)-N,N-diethyl-2-[4-(2H-naphth[1 ,8-cu,;~7.,lhiazù1-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide;
1-(1 -Adamantyl)-N-allyl-N-methyl-2-[4-(2H-naphth[1 ,8-cuj;~uLl,id~ul-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide;

2-[1-[2-(1 -Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1 ,8-20 cL~;Oulllid~ole 1,1-dioxide;

2-[1-[2-(1 -Adamantyl)-2-ethoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1 ,8-c~;~,ùlhidzùle 1,1-dioxide;

1-(1-Adamantyl)-1-methyl-2-[4-(2H-naphth[1,8-c~;suLl,iazul-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide;

1 -Cyclohexyl-2-[4-(2H-naphth[1 ,8-c~5;sol1 ~idzul-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide;
1-(1 -Adamantyl)-2-[4-(2-chlorophenothiazin-1 0-ylmethyl)piperidin-1 -yl]-ethanol;

1 -(1 -Adamantyl)-2-[4-(phenull,ia~i"-1û-ylmethyl)piperidin-1-yl]ethanol;
1-(1 -Adamantyl)-2-[4-(phenoxazin-1 0-ylmethyl)piperidin-1 -yl]ethanol;

, .. , . . . . . . ~

2 t ~7 l ~2 WO 96/0518~ PC~IJP95/01~00 1 -(1 -Adamantyl)-2-[4-(5H-dibenz[b,f]azepin-5-ylmethyl)piperidin-1 -yl]ethanol;
1 -(1 -Adamantyl)-2-[4-(10,11 -dihydro-5H-dibenz[b,flazepin-5-ylmethyl)-piperidin-1 -yl]ethanol;

1 -(1 -Adamantyl)-2-[4-(5H-phenanthridin-6-oxo-5-ylmethyl)piperidin-1 -yl]ethanol;

1 -(1 -Adamantyl)-2-[4-(10,11 -dihydrodibenz[b,f][1,4]oxazepin-11 -oxo-10-10 ylmethyl)piperidin-1 -yl]ethanol;

1-(1-Adamantyl)-2-[4-(10,11-dihydrodibenzo[b,e][1,4]diazepin-11-oxo-10-ylmethyl)piperidin-1 -yl]ethanol;

1-(1-Adamantyl)-2-[4-(10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-oxo-10-ylmethyl)piperidin-1 -yl]ethanol;

1-(1-Adamantyl)-2-[4-(5,6,11,12-tetrahy-lludiben [b,f]azocin-6-oxo-5-ylmethyl)piperidin-1 -yl]ethanol;
1-(1-Adamantyl)-2-[4-(5,6,11,12-tetrahydrodibenz[b,f]azocin-5-ylmethyl)piperidin-1 -yllethanol;

1 -(1 -Adamantyl)-2-[4-(6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidin-1 -25 yl]ethanol S,S-dioxide;

6-[1 -[2-(1 -Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide;

30 1-(1-Adamantyl)-2-[4-(7-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide;

1 -(1 -Adamantyl)-2-[4-(8-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide;
1 -(1 -Adamantyl)-2-[4-(9-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide;

_ _ _ . _ . . . .. . . .

2 1 ~7 ~ 72 ~ WO 96105185 PCT/JP95/01600 1 -(1 -Adamantyl)-2-[N-methyl-N-[4-(10,11 -dihydrodibenz[b,fl[1,4]-oxazepin-11 -oxo-10-yl)butyl]amino]ethanol;

10-[4-[N-[2-(1-Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-10,11-dihydrodibenz[b,fl[1,4]oxazepin-11 -one;

1 -(1 -Adamantyl)-2-[N-methyl-N-[4-~10,11 -dihydrodibenzo[b,11[1,4]-thiazepin-11-oxo-10-yl)butyl]amino]ethanol;
10-[4-[N-[2-(1-Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-10,11-dihydrodibenzo[b,fl[1,4]thiazepin-11-one;

5-[4-[N-[2-(1 -Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-5H-pllell~"~l ,riui"-6-one;

1 -(1 -Adamantyl)-2-[4-(8-chloro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide;

1-(1-Adamantyl)-2-[4-(8-methoxy-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin- 1 -yl]ethanol S, S-dioxide;

Wherein said compounds are both the racemic mixture or the individual optical isomers.

WO 96/0518~ 2 i 9 7 1 7 2 PCT/JP95/01~00 Compounds of the present invenbon can exist as optical isomers and both the racemic mixture of the isomers as well as the individual optical isomers are within bhe scope of this invention. The racemic mixtures can be separated into bheir individual isomers by techniques well known to those skilled in the 5 art.

The present invenbon also relates to the pharmaceutically acceptable acid addiUon salts of compounds of the formula (I) or pharmaceubcally acceptable 10 carriers or diluents.

The present invenbon relates to a mebhod of treating or prevenUng a condition in a mammal, including a human, bhe treatment or prevenbon of which is affected or facilitated by the neuromodulatory effect of sigma 2 1 5 ligands.

The present invenUon relates to a mebhod of treating or prevenUng a condibon selected from the group consisbng of anxiety, depression or 20 dysthymic disorders, psychosis, pain, dyskinesia, ischaemia induced brain disorders, convulsions, stroke, epilepsy, demenba, pafhi"aon.s""
neuropathological disorders and memory impairment, hypertension, arrhythmia and angina.

The present invention relates to pharmaceuUcal composibons which provide from about 0.01 to 100 mg of the acbve ingredient per unit dose. The composibons may be administered by any suitable route. For example orally in the form of tablets or capsules, etc..., parenterally in the fomm of solubons for 30 injection, topically in the form of onguents or lotions, ocularly in the form of eye-lotion. For preparing such composibons, methods well known in the art may be used; bhe nabure of the phal",aceubcal composibon employed will depend on the desired route of adl"iniabdGon.The total daily dose usually ranges from about 0.05 - 500 mg.

2 1 ~ 2 The compounds of Formula (I) may be prepared by general route of synthesis as disclosed in the following methods.

5 Method A:

Scheme A1 illustrates the p,~pa,dtivn of compounds of the formula (I).
A compound of the formula lll where Q includes halides such as Cl Br I or tosylate mesylate is reacted with the nucleophilic amino derivabve IV to yield 10 the coll~fJol~ y compound V. The reaction is typically carried out in the presence of a base such as triethylamine or potassium carbonate in a polar solvent like dimethyl~u,l"a",ive act,lu"il,ile.

Scheme A1 ,C-C-Q + H--N~

lll I IV

"C-C-N'R3 I

x~ r ~ ~ R3 (1) - The amino-keto derivafive may be reduced to give the hydroxy derivative of fommula (I) of the invenfion where A = OH and Y = H. The reduction is generally 20 accu"~ i,ed by using sodium borohydride in ethanol mebhanol or tetrahydrofuran at room temperature.

WO 96/05185 2 ~ ~ 7 t 7 2 ~

The amino-keto derivative may be converted into aminoalcohols by re~tion with organometallic reagents such as Y-MgBr or Y-Li to give compounds of the invention where A = OH and Y as defined in the des~ liul l of fommula (I).

5 Alkoxy molecules may be prepared by standard methods familiar to those skilled in the art by converting 6he free hydroxy derivative; O-alkyl derivatives may be carried out by the solvolysis of a sulfonyl ester intermediate [Advanced Organic Chemistry, J. March, John Wiley & sons, New York, 1985, 264-317];
the solvolysis of a chiral sulfonyl ester derivative in the above ethanolamine 10 series of general structure (I) where A = OH, affords a chiral ether.

The oxime of the keto derivative V is prepared according to oximation method as described in Organic Functional Group Fl~,udl ~ Vol. lll [S.R. Sandlerand W. Karo, Academic Press, London, 1989, 430-481].
The keto deriva6ve V may be the precursor of the amino derivatives of formula (I) where Y = H and A = -N (Rlo, Rl l) via reductive amination ICo",,u,~ "~ive organic l~cln~ulllldliuns, R.C. Larock, VCH Publishers, New York, 1989, 421-425] or by 6he Leuckart re~tion [M.L. Moore, Org. Reacbons, 1949,5, 7,301].
20 Such amino derivatives may be prepared from the hydroxy derivative of formula(I) where A = OH by the Mitsunobu re~tion [O. Mitsunobu, Synthesis,1981,1 -28]. The conversion by standard methods of the hydroxy group to a leaving group like Q (e.g. halide, mesylate) and subsequent sl~hstitllti-n by an amino group to give an amino derivative is also a general method of synthesis.
The re~tion of substitu6cn may be carried out with sodium azide to give an azide. The azido deriva6ve may be reduced to give primary amine [Comprehensive organic ~na~u~ liuns, R.C. Larock, VCH Publishers, New York,1989, 409-410].
30 The oximino derivative prepared as described above can also be reduced to give 6he free amino derivahve by standard reduc6cn process like catalytic hydrogenation over platinum oxide or palladium on carbon or chemical reduction with lithium aluminum hydride.

2~971 72 SiWO 96/05185 PCT/JP9S/OIG00 - Scheme A 2 P--N~}CH2-Q + 1' Vl Vll P--N~CH2 R6 ~-o,sg~

Vlll s The synthesis of the starting amino compound IV presented in scheme A1 is depicted in the scheme A2.

The target amino derivative Vlll has been chosen in the piperidino series 10 however acyclic amino derivatives may be obtained according to the same process. The P substituent in the compounds of formula Vl and Vll I, t~ se, It~
a protective group like those described in Protective Groups in Organic Synthesis [T.W. Greene and P.G.M. Wuts John Wiley & Sons, New York 1991]. This protecting group is easily removed to 3ive the piperidino analogue 15 of fommula IV. The N-alkylation reaction is preferably conducted in dimethylformamide in the presence of sodium hydride as base and at a temperature above 50 ~C. The reaction can also be conducted under phase transfer process using toluene as solvent, sodium or potassium hydroxide as base in the presence of catalytic amount of tetrabutylammonium hydrogen 20 sulfate or other suitable salt. This route of synthesis can be extended to other heteroaryl rings of formula B as depicted in the desc, i,u ';JI I of invention.

The heteroaryl ring of fommula B may be purchased from cor"" ,er~ ial sources or25 they may be prepared via known methods. The synthesis of ring substituted .. . . . . . . .. . . .... . _ . .. . .. .... ... . . . . . . _ WO 96/0518~ 2 ~ ~ 7 ~ 7 2 PCT/JP95/01600 ~o 6H-dibenzo[c,e][1,2]thiazine S,S-dioxide may be accomplished by employing the method described by F. Ullmann and C. Grob in Chem. Ber. 1910, 43,2694 for unsl Ihctitl ~t~d sultam.

Another route of synthesis of the starting amino compound IV is illustrated in scheme A3. The N-alkylation of the naphthosultam Vll may be conducted accc~JIdilly to the process described by J.L. Malleron, M.T. Comte, C.
Gueremy, J.F. Peyronel, A. Truchon, J.C. Blanchard, A. Doble, O. Piot, J.L.
10 Zundel, C. Huon, B. Martin, P. Moutin, A. Viroulaud, D. Allam and J. Betschart [J. Med. Chem. 1991, 34, 2477-2483]. This route of synthesis can be extended to other heteroaryl rings of formula B as depicted in the des~ lion of invention.

Q' is genera!ly another electrophilic group which could be interconverted to Q
15 and reacted with the N-protected amino derivative Xl to 3ive Xll. The removalof the protective group from the amino precursors Vll I and Xll is accomplished by standard process and gives the resulting amine IV.

Scheme A3 H-N~
Q~--(CH2)p Q O_ lX I C

Q'--(CH2)F ~
~-,S~
o X

X + P--N--H P--N--(CH2) Xl Xll ~-,S~
o WO 96/0518~i PCT/JP9~/01600 - MethQd B

Another route for the preparation of the compounds of formula (I) where A =
OH is outlined in Scheme B1. The aminolysis of epoxy derivatives is a classical 5 reaction which is generally conducted by heating the reactives in a solvent like ethanol [N.S. Isaacs and R.E.Parker, J., 1960, 3497-3504]; aminolysis reaction may be performed by using metal salts as catalysts [M. Chini, P.Crotti and F.Macchia, T~iL dl ,e.l, un Letters,1990, 31,32,4661 -4664].
The epoxy derivative Xlll may be obtained according to different usual 10 methods: oxidaton of an alkenyl derivatve, dehydrohalogenation of a halohydrin, synthesis starting from a carboxaldehyde.

Scheme B1 X--C\--/C-R2 + H--N~ ,C-~-N' 3 Xlll IV (1) When the starting epoxy derivative Xll l is used in an optically active form, the final amino alcohol (I) is obtained in an optically active form.

The relevant starting material in hhe above-mentioned processes may be in racemic form or in the desired optically active form to give racemic or optically active compounds.

25 The desired optically active enanhomer may also be obtained by resolution according to conventional techniques.

The compounds of the formula (I) which are basic in nature can form a wide variety of different phd""aceutically ~cPpt~hle salts with various inorganic and30 organic acids. These salts are readily prepared by treating the base compoundwith a substancially equivalent amount of the chosen mineral or organic acid in - a suitable organic solvent such as mehhanol, ethanol or isop",panol.

2 t ~ ~ 7~
WO 96/05185 . Pt~TlJP95/OlliO0 Best Mode for Carrying Out the Invention In the ' "t ..i""Li~, is further illustrated by examples which, however, may not be consg, the invetrued as limiting:

(i) column chromatography was carried out on Merck Kieselgel (Art 9335); thin layer ulllulll~lL/yldphy (TLC) was carried out on Merck 0.2 mm silica gel 60F2~4plates (Art 1.05735);

10 (ii) in general, the course of reactions was followed by TLC and reaction times are given for illustration only;

(iii) melting points (m.p.) are uncorrected and (dec) indicates decomposition;

15 (iv) solvent ratios are given in volume:volume temms;

(v) 'H-NMR: 200 MHz, ~i in ppm.

(R~s)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(2H-naphth[1~8-~ tll~ ol-2 yl)butyl]amino]ethanol S,S-dioxide, fumarate.

a) 2-(4-lodobutyl)-2H-naphth[1,8-cd]i~,.ll,ia~ol~ 1,1-dioxide.
2-(4-Chlorobutyl)-2H-naphth[1 ,8-cd]isuthid~L~le 1 ,1-dioxide (62.9 9, 212.8 mmol) [prepared as described by J.L. Malleron, M.T. Comte, C. Gueremy, J.F. Peyronel, A. Truchon, J.C. Blanchard, A. Doble, O. Piot, J.L. Zundel, C.
Huon, B. Marlin, P. Moutin, A. Viroulaud, D. Allam and J. Betschart, J. Med.
30 Chem. 1991, 34, 2477-2483] was added to methylethylketone (400 ml) containing sodium iodide (64.5 g, 430 mmol). The heterogeneous mixture was heated under reflux for 4 hours. After cooling, the solution was filtered and cont,ellL,dl~d in vacuo. Resulted syrup was poured into water (500 ml) and extracted three times with ethyl acetate. Combined organic extracts were dried 35 over sodium suHate, and the solvent was evaporated. The solid residue was then washed with a mixture of diethyl ether - hexane (3:7) to give the title iodide 1 (a) (67 9, 81 %) as a yellowish powder, m.p.: 82-84 ~C.

2 ~ ~7 1 ~2 - b) 2-(4-N-Methylaminobutyl)-2H-naphth[1,8-c.~;~utllid~ule 1,1-dioxide.To a solution of N-methylbrifluoroacetamide (7.6 9, 60 mmol) in dimethylformamide (50 ml), was added in small porbons sodium hydride (60% dispersion in oil ) (2.0 9, 50 mmol). The sol ubon was sb rred for 20 min 5 undernitrogenatroomtemp.Theniododerivabve1(a)(19.4g,50mmol)in dimebhylformamide (50 ml) was slowly added dropwise over 20 min.
Resulted mixture was sbrred for 2 hours and then poured into water.
Extraction with ethyl acetate and standard work-up gave a brown semi-solid which was subjected to flash chromatography (silica gel, ethyl 10 acetate / hexane 3:7).yielding the corresponding trifluoroacetamide (9.3 9, 40 ~/O) as a white powder, m.p.: 83-85~C. TLC: Rf = 0.5 (ethyl acetate /
methylene chloride 5:95).
Solution of this amide (9.3 9,24 mmol) in methanol (210 ml) was treated with 10% solution of potassium carbonate in methanoVwater (7:3) (75 ml) and bhe 15 reaction mixture sbrred for 2 hours. Methanol was evaporated and bhe residue exbracted with ethyl acetate. Standard workup gave amine 1 (b) (5.3 9, 76%) as a green oil.

c)(R,S)-2-[4-[2-(1 -Adamantyl)-2-oxoethyl]methylamino]butyl]-2H-20 naphth[1~8-c~ ull,ia~ole 1,1-dioxide.
A soluUon of amine 1(b) (4.4 9, 15 mmol), 1-(u,u",oacetyl~-add",d"L~,e (4.11 9, 16 mmol) and anhydrous potassium carbonate (2.16 9, 15.6 mmol) in acetonitrile (60 ml) was heated under reflux over 3 hours. After cooling, the mixture was diluted with water and extracted with methylene 25 chloride. The organic solubon was dried over sodium sulfate and bhe solvent was evaporated. The residue was ~,hlulllaluyld,uiled (silica gel, ethyl acetate/methylene chloride 1 :1, Rf = 0.4) to produce aminoketone 1 (c) (4.0 9, 57~/O) as an orange oil.

d)(R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(2H-naphth[1,8-cul;~uthia~ul-2-yl)butyl]amino]ethanol S,S-dioxide, fumarate.
A solubon of aminoketone 1(c) (4.0 9, 8.6 mmol) in ethanol (100ml) was treated with sodium borohydride (1.2 y, 30 mmol). The mixture was sbrred for 4 hours at room temperature and bhen conce"lldl~d under reduced pressure. Water was added and the product was extracted with methylene chloride. The organic phase was washed twice with saturated aqueous solution of sodium bicarbonate and dried over sodium sulfate. Removal of solvent WO 96105185 2 ~ q 7 ~ 7 2 PCT/JP951OlG00 ~

under Removal of solvent under vacuum leftthe btle aminoalcohol 1 (d) (3.4 9, 85%) as an oil. TLC: Rf = 0.3 (methanol/ methylene chloride 5:95).
The " ,i, lo~lcol1ol 1 (d) (3.4 9, 7.3 mmol) on treatment with fumaric acid (1.16 9, 10 mmol) in isopropanol was converted into its fumarate salt (3.1 9, 73~/O), m.p.:
5 . 166-168~C. MS: 468 (M+). Anal. Calc'd for C3,H40N2O7S: C,63.68; H,6.90;
N,4.79. Found: C,63.48; H,6.98; N,4.74.

(R,S)-2-[[1-[2-(1 -Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]-2H-naphth[1 ,8-,uJ;~utlli~c,lt~ 1,1-dioxide, hydrochloride.

a) N- tert-Butoxycarbonyl isc "i,~ acid.
Di-tert-Butyl dicarbonate (101.1 9, 464 mmol) was added dropwise to a sbrred solution of isonipecotic acid (60 9, 464 mmol) and sodium hydroxide (37.6 9, 940 mmol) in a mixture of water(86 ml) and tert-butanol (176 ml). After the addib'on was completed, tert-butanol (100 ml) was added and the mixbure was sbrred for 3 hours at room temperature.
20 The solubon was diluted with water (200 ml) and extracted two b'mes with pentane (150 ml). The aqueous phase was acidifled with cooling with potassium hydrogen sulfate (70 9) and extracted with ebhyl acetate.
Standard workup gave N-Boc-protected iconipecob'c acid 2(a) (102.3 g, 96%) as a white powder, m.p.: 144-146 ~C.~5 b) N-tert-Butoxycarbonyl-4-hyd,u,.y,,,~dU,ylpiperidine.
To a cold (-1 5~C) soluUon of 2(a) (13.74 9, 60 mmol) in 1,2-dimethoxyebhane (60 ml) was added N-methylmorpholine (6.66 ml, 60 mmol) followed by isobutyl chloroformate (8.16 ml, 60 mmol). After 10 min 30 of sbrring, bhe precipitate was filtered off and washed with 1,2-dimebhoxyethane (60 ml) . To bhe cooled (ice - salt bath) f Itrate was slowly add ed a sol ution of sod ium borohydride (3.42 9, 90 mmol) in water (30 ml) .
The mixbure was stirred for 45 min., then diluted with water (800 ml) and extracted with of ethyl acetate (400 ml). Organic solubon was washed with 35 0.05 N hydrochloric acid, water and finally with a saturated aqueous solubon of sodium bicarbonate. The solubon was dried and the solvent WO 96/05185 PCI/JP95/OlGOO

evaporated to give the alcohol 2(b) (9.8 9, 75~/O) as a colorless oil which crystallized upon storing at room temperature, m.p.: 74-76~C.

c) N-tert-Butoxycarbonyl-4-[2-(2tl-naphth[1,8-co~isothiazol)methyl]-5 piperidine S,S-dioxide.
To an ice-cooled solution of alcohol 2(b) (26.8 9,125 mmol) and triethylamine (19.1 ml, 137.5 mmol) in dry tebrahydrofuran (350 ml), methanesulfonyl chloride (11.3 ml, 137.5 mmol) was aWed dropwise. Affer stirring for 20 min, water was added and the reaction mixture was extracted with10 ethyl acetate. Combined organic exbacts were washed with saburated aqueous solubon of sodium bicarbonate, dried and evaporated producing N-tert-butoxycarbonyl-4(methanesulfonyloxymebhyl)piperidine in quanbtative yield (36.6 9) as a white solid, m.p.: 72-74~C, To bhe suspension of sodium hydride (60 ~/O dispersion in oil) (5.94 9, 148.5 15 mmol)drydimethy,fvlllldl,,ide(60ml)wasaddedasolutionof1~8-naphtosultam (27.7 9, 135 mmol) in dimebhylformamide (80 ml) and the reaction mixture was sbrred at room temperabure under nitrogen for 20 min. Then sodium iodide (6.00 9, 40 mmol) was aWed followed by the above mebhanesulfonyloxymethyl-N-Boc-piperidine (36.6 9, 125 mmol) in 20 dimethylformamide (80 ml) and the reaction was conducted at 80~C for4 hours.
Affer cooling, bhe reaction mixture was pwred into water and extracted with eblyl acetate. The standard workup afforded a brownish oil which was subjected to column ~;hl~lldlu~ Jhy (silica gel, methylene chloride) giving the btle compound 2(c) ( 43.5 9) in 80 ~/O yield, m.p.: 112-114~C. TLC: Rf = 0.3 25 (ebhyl acetate/hexane 3:7).

d) 4-[2-(2H-naphth[1 ,8-c~ vthia201)methyl]piperidine S,S-dioxide.
N-Boc derivative 2(c) (36.0 9, 83.1 mmol) in ethyl acetate (400 ml) was breated with 4N hydrochloride solubon in dioxane (83 ml) at room 30 temperab~re overnight. Resulted white precipitate of 2(d) h~ lorid~ was filtered off and washed carefully with ethyl acetate. Quantitative yield, m.p. >280 ~C.
- This hydrochloride was converted quanbtatvely into bhe free piperidine 2(d) by breatment with 0.5N sodium hydroxide aqueous solubon and subsequent 35 exbracton with methylene chloride. A green oil was obtained which crystallized on standing at cold, m.p.: 188-190 ~C.

WO 96/05185 2 ~ 9 ~ ~ 7 2 PCTIJP9S/01600 ;~

e)(R,S)-2-[[1 -[2-(1 -Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]-2H-naphth[1,8-c~i;,ull,id~vle 1,1-dioxide, hyd~uullloride.
The aminoketone 2(e) was synthesized from piperidine 2(d) (11.2 9, 37 mmol) and 1-(b,u",oaculyl)addr"a"ld"e (10.28 9, 40 mmol) 5 following the procedure described in example 1(c). The crude product was isolated as an oil which crystallized on storing at room temp. Resulted orange powder was weshed with ethanol and collected by filtration to give pure dl l ~ okulune 2(e) (13.6 9,75~/O), m.p.: 168-170~C. TLC: Rf = 0.4 (ethyl acetate/
methylene chloride 1:1).
10 To the aminoketone 2(e) (1.5 9, 3.1 mmol) in ethanol (50 ml) was aWed 4N
hydrogen chloride solution in dioxane (1.55 ml). Resulted solution was diluted with dry diethyl ether and left for crystallization. Precipitate wes filtered off and dried under vacuum. Hydrochloride 2(e) (1.1 9, 69 ~~O) was obtained as a grey powder, m.p.: 261-263~C . MS: 479 (M+1). Anal. Calc'd for C28H3sClN2O3S:
15 C,65.29; H,6.85; N,5.44; Cl,6.88. Found: C,64.69; H,7.03; N,5.41; Cl,6.69.

FxAMPLF 3 20 (R,S)-2-[[1-[2-(1-Adamantyl)-2--"~;",i"c~,;;,yl]-4-piperidinyl]methyl]-2H-naphth[1,8-.,~;;.utl,id~ule 1,1-dioxide, hyd,u,,hlo,ide.

The aminoketone 2(e) (1.46 9, 3 mmol) dissolved in a mixture of methanol (15 ml) and of tetrahydrofuran (5 ml) was reacted with 25 hydroxylamine sulfate (0.540 9, 3.3 mmol) in presence of sodium acetate (0.540 9, 6.6 mmol) over 4 hours under reflux and then for 48 hours at room temperature. The single oxime product was formed; TLC: Rf = û.6 (Ethyl acetate / methylene chloride 1: 1). Reaction mixture was diluted with ethanol (30 ml), filtered and hltrate treated with 4M hydrogen chloride 30 solution in dioxane (2.5 ml). The precipitate was filtered off and recrystallized from ethanol / diethyl ether (90:10) to give the title hydrochloride 3 (0.950 9, 57~/O) as a white crystalline powder,m.p.: 196-198~C. MS: 494 (M + 1). Anal. Calc'd for C28H38CIN3O3S + 1.2 H2O: C,60.95;
H,7.02;N,7.62;CI,6.43.Found :C,60.94;H,7.20;N,7.40;CI,6.81.

2 ~ q ~ 2 WO 96/05185 PCT/3P9~/01~00 (R,S)-1-(1 -Adamantyl)-2-[4-(2H-naphth[1 ,8-cu,;~uthid~ul-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide, hydrochloride.

The ~" ,i, lok~lu"e 2(e) (3.û 9, 6.1 mmol) was reduced following the method described in Example 1 (d) yielding the aminoalcohol 4 (2.2 9, 74~/O) as a white powder, m.p.: 207-209~C. TLC: Rf = 0.5 (methanoV methylene chloride 5:95). 1H-NMR (CDCI3,200 MHz) ~ (ppm): 8.05 (d,1 H); 7.9 (d,1 H); 7.75 (dd,1H); 7.6-7.4 (m, 2H); 6.74 (d,1H); 3.7 (d,2H); 3.2 (dd,1H); 3.15-2.8 (m,4H);2.4 (m,3H); 2.15-1.2 (m, 20 H).
The title hydrochloride salt was prepared from aminoalcohol 4 (2.0 9, 4.15 mmol) following procedure described in Example 2(e). Recrystallisation from methanol afforded pure product (1.2 9, 56 ~/O) as a white crystalline solid, m.p.:
280~C (dec). MS: 315 (M - 165). Anal. Calc'd for C28H37CIN2O3S: C,65.03;
H,7.21; N,5.42; Cl,6.86. Found: C,64.79; H,7.18; N,5.38; Cl,7.08.

(R,S)-1-(1 -Adamantyl)-2-[4-(9-carbazolyl)methylpiperidin-1 -yl]ethanol, h~l u~l~lul i~e.

a) N-tert-Butyloxycarbonyl-4-[9-(carbazolyl)methyl]piperidine.
The btle compound 5(a) was prepared from carbazole (8.35 9, 50 mmol) and N-tert-Butyloxycarbonyl-4-(",~:ll,allusulfonyloxymethyl) piperidine (15.0 9, 50 mmol) according to the method described in Example 2(c). Usual work-up of the reaction mixture provided a solid which was recrystallized from ethylacetate/hexanetogivepureproduct5(a)(7.16g,39~/O),m.p.:165-167~C.
TLC: Rf = 0.2 (diethyl ether/ hexane 2:8).

b) 4-[9-(Carbazolyl)methyl]piperidine.
- Removal of the tertbutyloxycarbonyl protecting group from 5(a) was perfommed as described in Example 2(d). The title compound 5(b) was obtained as a white syrup and was used in the next step without purification.

WO 96/05185 2 ~ ~ 7 ~ 7 2 PCTIJP9~/01600 ~

c) 9-[[1-[(1-Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]carbazole.
The amine 5(b) (3.6 9, 13.6 mmol) and 1-(bromoacetyl)ad~"anl~n~ (3.85 9, 15 mmol) were reacted together in ac~lu~ lilt, containing potassium carbonate following bhe procedure described 5 in Example 1 (c). The aminoketone 5(c) (3.5 9, 59%) was isolated as a white powder, m.p.: 1 70-172~C. TLC: Rf = 0.6 (ebhyl acetate/ methylene chloride 1 1).

d)(R,S)-1 -(1 -Adamantyl)-2-[4-(9-carbazolyl)methylpiperidin-1 -yl]ethanol, 10 hydrochloride.
Reduction of bhe ~ inok~lu~e ketone 5(c) following the method described in Example 1 (d) gave quanbtabvely the aminoalcohol 5(d) as a white solid, m.p.: 197-199~C. TLC: Rf = 0.3 (ethyl acetate / methylene chloride 1 :1).The btle hydrochloride salt was prepared according to the procedure described 15 in Example 2(e) starting from aminoalcohol 5(d) (2.7 9, 6.1 mmol).
Recrystallkabon from isopropyl alcohol / diethyl ebher gave the salt (1.7 9, 58%) as a white powder, m.p.: 268-270~C. MS: 442 (M+). Anal. Calc'd for C30H39CIN2OS: C,75.21; H,8.20; N,5.85; Cl,7.40. Found: C,75.26; H,8.18;
N,5.99; Cl,7.63.

(R,S)-1 -(1 -Adamantyl)-2-[N-methyl-N-[4-(2H-naphth[1,8-~ uU lid~u1-2-25 yl)butyl]amino]ethylamine S,S-dioxide, tartrate.

a)2-[N-methyl-N-4-[(2-(1 -Adamantyl~-2-methanesulfonyloxyethyl)-amino]butyl]-2H-naphth[1,8-c~;~uthi~ule 1,1-dioxide.
To a solubon of aminoalcohol 1 (d) (9.33 9, 20 mmol) in 30 tetrahydrofuran (200 ml) cooled in an ice-water bath was added briebhylamine (2.23 9,22 mmol) followed by methanesulfonyl chloride (1.8 ml,22 mmol). After sbrring for 30 min., bhe mixbure was quenched with water and extracted with mebhylene chloride. The combined organic extracts were washed with water, and saburated aqueous solubon of sodium bicarbonate, then dried and the 35 solvent was evaporated. A colorless viscous oil of mebhanesulfonate 6(a) was obtained in quantitative yield. TLC: Rf = 0.21 (ethyl acetate / hexane 3:7).

2 ~ 2 b)(R,S)-1 -(1 -Adamantyl)-1 -azido-2-[N-methyl-N-[4-(2H-naphth[1,8-cu~;~,ull ,ic~ol-2-yl)butyl]amino]ethylamine S,S-dioxide.
A mixture of methanesulfonate 6(a) (5.18 9, 9.5 mmol) and sodium azide (0.690 9, 10.6 mmol) in dry dimethylformamide (100 ml) was stirred 5 ovemight under nitrogen at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with water, dried and concentrated under vacuum. Purificabon of the residue by flash chromatography (silica gel, ethyl acetate/hexane 3:7) gave the b'tle azide 6(b) (4.02 9, 86%) as an oil which crystallized as a white solid on 10 standing at cold, m.p.: 24~C. TLC: Rf = 0.5 (ethyl acetate /hexane 1:1). IR
(KBr): 2095 cm-1. MS: 494 (M + 1). Anal. Calc'd for C27H3sNsO2S: C,65.69;
H,7.15; N,14.19. Found: C,65.41; H,7.23; N,13.95.

c)(R,S)-1 -(1 -Adamantyl)-2-[N-methyl-N-[4-(2H-naphth[1,8-cu~;~ulhid~ul-15 2-yl)butyl]amino]ethylamine S,S-dioxide, tartrate.
A solution of azide 6(b) (1.85 9, 3.7 mmol) in ethanol (100 ml) and tetrahydrofurane (20 ml) was hydluy~ with shaking over 10% Pd/C (2.2 9) at 2 kPa for 3 h at room temp. The slurry was filtered through Celite and solvents evaporated to give free diamine 6(c) (1.15 9, 65%) as a slightly yellow20 foam. TLC: Rf = 0.2 (I l l~tl IdnGL/U It:~ll ,ylene chloride 1 :9).
Diamine 6(c) on treabment with (R,S) tartaric acid (2.2 equiv.) in ethanol was converted in 54~/O yield into the titie tartrate salt 6(c), m.p.: 215-217~C.
Anal. Calc'd for C31H43N3OsS + H20: C,58.56; H,7.13; N,6.61. Found: C,58.37;
H,6.89; N,6.61.

(R,S)-1 -(1 -Adamantyl)-N-methyl-2-[N-methyl-N-[4-(2H-naphth[1,8-30 ~,u~;~,ulI ,id~u1-2-yl)butyl]amino]ethylamine S,S-dioxide, fumarate.

a)1 -(1-Adamantyl)-N-methyl-N-trifluo,uaceld",kio-2-[N-methyl-N-[4-(2H-naphth[1,8-cu~;~vtl,id~ul-2-yl)butyl]amino]ethylamine S,S-dioxide.
A solution of methanesulfonate 6(a) (3.79 9, 6.9 mmol) in dry 35 dimethylformamide (10 ml) was added to a pre-reacted over 20 min. mixture of N-methyltrifluoroacetamide (1.09 9, 8.4 mmol) and sodium hydride (60%
suspension in oil) ( 0.280 9, 7 mmol) in dry dimethyl~u"~d",i(le (10 ml)andthen 2 ~ q7 ~ 72 heated overnight under nitrogen at 80 ~C. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried and evaporated. The residue on chromatography (silica gel, ebhyl acetate/hexane 1 :3) gave the btle compound 7(a) (2.89 9,74~/O) as an oil. TLC:
5 Rf = 0.8 (ethyl acetate/hexane 1 :1).

b)(R,S)-1 -(1 -Adamantyl)-N-methyl-2-[N -methyl-N-[4-(2H-naphth[1,8-c."k,~.~l ,ia~ol-2-yl)butyl]amino]ethylamine S,S-dioxide, fumarate.
The hydrolysis of the trifluu,uac~ld",ido group in 7(a) (2.89 9,5.16 10 mmol) was performed in aqueous methanol in the presence of potassium carbonate (1.64 9, 11.9 mmol) as described in Example 1(b). Aflter stirring overnight at room temperabure, bhe reaction mixture was extracted with methylene chloride and worked-up as usual yielding free diamine 7(b) ( 1.76 9, 71 ~/O) as an oil, TLC: Rf = 0.3 (methanol/methylene chloride 1 :9).
15 Following bhe usual procedure (Examples 1 (d) and 6(c)) bhe b'tle fumarate sait was crystallized from ethanol in 42% yield. M.p.: 168-170~C. Anal. Calc'd for C32H43N306S: C,64.30; H,7.25; N,7.03. Found: C,64.03; H,7.30; N,7.08.

(R,S)-2-(1-Adamantyl)-N-methyl-N-[4-(2H-naphth[1,8-c~ ,lhid~ol-2-yl)butyl]-2-pyrrolidin-1-ylethylamine S,S-dioxide, fumarate.

A mixbure of mesylate 6(a) (2.72 9, 5 mmol), pyrrolidine (0.83 ml, 10 mmol), anhydrous potassium carbonate (1.14 9, 8.2 mmol), and sodium iodide (0.225 9, 1.5 mmol) was sbrred and heated under reflux over 2 hours under nitrogen. After cooling, bhe mixture was diluted with water and extracted with methyiene chloride. Standard work-up furnished free diamine 8 (1.9 9, 73%) as a yellow oil, TLC: Rf =0.2 (methanol/methylene chloride 1 :9).
The fumarate salt 8 was crystallized from ethanol in 44~/0 yield following the usual procedure (Examples 1(d) and 6(c)). M.p.: 190-191~C. Anal. Calc'd for C3sH47N306S: C,65.91; H,7.43; N,6.59. Found: C,65.79; H,7.48; N,6.67.

2 ~ 2 WO 96/05185 . PCT/JP95/01600 EXAMpl F 9 (R,S)-2-[4-[N-[2-(1 -Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-2H-naphth[1,8-cuJ;~..ll,ia~ole 1,1-dioxide, tartrate.

The methanolysis of mesylate 6(a) ( 2.72 9, 4.8 mmol) was conducted in boiling methanol (70 ml) for 5 hours. After evaporation of the solvent, the residue was taken in methylene chloride and resulted soluton washed with 0.025M aqueous sodium hydroxide, water and saturated aqueous sodium 10 bicarbonate. The organic phase was dried and concer,l,dlt~d and the residual material purified by ch,~"alug,d~ y (silica gel, ethyl acetate/methylene chloride /methanol 10:10:1) to give methyl ether 9 (0.770 9, 33 ~/O) as an oil.
TLC: Rf = 0.3 (methylene chloride/methanol 95:5).
According to the standard procedure (Examples 1 (d) and 6(c)) the tartrate salt 15 was crystallized from ethanol as a white solid, m.p.: 124-126~C. MS: 303 (M-179). Anal. Calc'd for C32H44N2OsS + 1/3 H20: C,60.14; H,6.99; N,4.38.
Found: C,60.14; H,7.18; N, 4.59.

(R,S)-1-(1 -Adamantyl)-2-[N-methyl-N-[4-[5H-pht" laulhl i.li, i-6-oxo-5-yl]butyl]-amino]ethanol, hydl u~:hlo, i.le.

a) 4-(N-tert-Butoxycarbonyl-N-methylamino)butyric acid.
This compound was prepared from 4-(N-methylamino)butyric acid hyd,ucl1lo~kle (23 9,150 mmol) and di-tert-butyl diualbu"dl~ (32.7 g, 150mmol) according to the method described in Example 2(a). The product 10(a) (31 9, 95~/O) was obtained as an oil.
b) N-tert-Butoxycarbonyl-N-methyl-4-hydroxybutylamine.
Reduction of the carboxylic acid 10(a) (31 9, 142 mmol) via its mixed carboxylic-carbonic anhydride, following the procedure presented in Example 2(b), produced alcohol 10(b) (19.5 9, 64%) as an oil.

WO 96/05185 2 T q ~ ~ 7 2 PCTIJP95101600 ~

c) N-Methyl-N-[(5H-I,henal llhl i.lil ,-6-oxo-5-yl)butyl]amine.
Following the procedure described in Example 2(c) the alcohol 1 O(b) was first converted into the mesylate in 98% yield. Reaciion of the abovemesylate (5.6 9, 20 mmol) with dihydro(5H)-phenanthridinone (4.3 9, 22 mmol) 5 in the presence of sodium hydride in dimethylfu",l~"ide fumished N-tert-butoxycarbonyl-N-methyl-N-[(5H-phel1al llhl idi~ I-6-oxo-5-yl)butyl]amine (4.5 9, 59%)~ TLC: Rf = 0.35 (ethyl acetate /hexane 3:7).
Removal of the N-tert-butoxycarbonyl protecting group from above N-Boc derivative (4.4 9,11.4 mmol) was performed following the procedure 2(d). The 10 title amine 10(c) (2.8 9, 88%) was obtained as a colorless oil.

d)5-[4-[2-(1 -Adamantyl)-2-oxoethyl]methylamino]butyl]-6(5H)-pl1e,1al 111 ,ridi"on~.
The amine 10(c) (2.8 g, 10 mmol) and 1-(blulllod~.,.~l) 15 adamantane (2.83 9, 11 mmol) were reacted together, according to procedure presented in Example 1 (c), to produce the title ketone 1 O(d) (3.31 9, 73%) as a yellow oil. TLC: Rf = 0.5 (ethyl acetate/ methylene chloride 1:1).

e) (R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(5H-pht",d"Ll"i.li"-6-oxo-5-20 yl)butyl]amino]ethanol, hydlu~,l,lo,i.le.
Ketone 1 O(d) (3.2 9, 7.0 mmol) was reduced with sodium borohydride in ethanol, following the procedure described in Example 1(d), yielding the free a",illoalcollol 10(e) (3.0 9, 94~/O) as an oil. TLC: Rf = 0.3 (methanol / methylene chloride 1:9).
25 The title hydlu~;l,lurid~ was prepared according to the procedure described in Example 2(e). Starting from aminoalcohol 10(e) (2 9, 4.3 mmol) and after recry~Ldlli~dLiun from ethanol / diethyl ether the salt 10(e) (1.4 9, 63%) was obtained as a white hygroscopic powder; m.p.: 127-129~C. MS: 293 (M - 165).
Anal. Calc'd for C30H3sClN2O2 + H20: C,70.22; H,8.05; N,5.46; Cl,6.91. Found:
30 C,70.48; H,7.95; N,5.59; Cl,7.27.

35 (R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(6H-dibenzo[c,e][1,2]thiazin-6-yl)butyl]amino]ethanol S,S-dioxide.

WO 96/05185 PCT/JP95/OlfiOO

a) N -Methyl-N-[4-[6-(6H-dibenzo[ce][1,2]thiazin)]butyl]amine S,S-dioxide.
The synbhesis of amine 11(a) was performed following bhe sequence of reactions described in Example 10(c). Alkylabon of 6H-5 dibenzo[ce]-1,2-thiazine-5,5-dioxide (4.16 9, 18 mmol) with mesylate of 10(b) (5.06 9, 18 mmol) gave N-tert-butoxycarbonyl-N-methyl-N-[4[6-(6H-dibenzo[ce][1,2]bhiazin)]butyllamine S,S-dioxide (6.45 9, 77~/O) as a viscous oil.
TLC: Rf = 0.3 (ebhyl acetate /hexane 3:7). Next, removal of N-tert-butoxycarbonyl group and basic work-up furnished bhe btle amine 11(a) (4.3 9, 10 76% overall yield) as a yellowish oil.

b) (R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(6H-dibenzo[c,e] [1,2]thiazin-6-yl)butyl]amino]ethanol S,S-dioxide.
To a warm solubon of the amine 11(a) (0.886 9, 2.8 mmol) in 15 ebhanol (15 ml) was added (1-adamantyl)ethylene oxide (0.500 9, 2.8 mmol).
The mixture was refluxed over 48 hours under nitrogen. After cooling, the solvent was evaporated and the residue subjected to column chromatography (silica gel, mebhanol / methylene chloride 1:20) to give bhe bb'e a",i"oalcohol 11(b) (1 9, 72 ~/O) as a white foam. TLC: Rf = 0.25 (mebhanol / mebhylene 20 chloride 1:20). Anal. Calc'd for C2aH3sN2O3S + 0.5 H20: C,69.09; H,7.74;
N,5.55. Found: C,68.79; H,7.70; N, 5.50.
(1-Adamantyl)ebhylene oxide was prepared according to Shiryaev A.K. etaL, Khim. Farm. Zh.,1990, 24, 23-25.

~AMPLF 12 (R,S)-1 -(1 -Adamantyl)-2-[4-(2H-naphth[1,8-cu~;~uthi~ol-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide, tartrate.~0 a)1-(1 -Adamantyl)-1-~ thdl lesulfonyloxy-2-[4-(2H-naphth[1,8-hi~u1-2-ylmethyl)piperidin-1 -yl]ethane S,S-dioxide.
Following procedure described in Example 6(a) reaction of I"t:thdllesulfonyl chloride with aminoalcohol 4 produced the title mesylate 12(a) 35 in 96% yield as a white solid, m.p.: 175.5-176.5~C. TLC: Rf = 0.21 (ethyl acetate/hexane 3:7).

. .

WO 96/05185 2 1 9 ~ ~ 7 2 PCT/JP95/01600 ~

b) 1~ Adamantyl)-1-azido-2-[4-(2H-naphth[1,8-cL~;soll,iazol-2-ylmethyl)piperidin-1-yl]ethane S,S-dioxide.
Reaction of mesylate 12(a) with sodium azide in dimethylformamide was performed in a similar manner to that described 5 . in Example 6(b) and afforded azide 12(b) in 45~/O yield as a white solid, m.p.: 170.5-170.6~C. TLC: Rf = 0.7 (ethyl acetate/hexane 1:1). IR (KBr):
2096 cm~1.

c)(R,S)-1 -(1 -Adamantyl)-2-[4-(2H-naphth[1,8-cJ~;~vll ,id~ol-2-ylmethyl)-10 piperidin-1-yl]ethylamine S,S-dioxide, tartrate.
Following procedure described in Example 6(c) reduction of azide 12(b) gave diamino compound 12(c) in 36% yield as a viscous oil. TLC: Rf =
0.2 (methanol / methylene chloride 1 :9).
The title tartrate salt 12 was crystallized in a usual way (exp.1 (d) and 6(c)) from 15 ethanol in 40~/O yield as a white powder, m.p.: 189-190~C. Anal. Calc'd for C32H43N3OsS + 1.2 H20: C,59.01; H,7.03; N,6.45. Found: C,58.74; H,6.66; N, 6.40.

(R,S)-1 -(1 -Adamantyl)-N-methyl-2-[4-(2H-naphth[1,8-.,u~ vll lid~ol-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide, maleate.

a) 1-(1-Adamantyl)-N-methyl-N-trifluoroacetamido-2-[4-(2H-naphth[1,8-cu~;~vLhid~ol-2-ylmethyl)piperidin-l-yl]ethyiamine S,S-dioxide.
ReacUon of N-methyltrifluoroacetamide with mesylate 12(a), performed as described in Example 7(a), produced compound 13(a) in 65%
yield as an oil.
b) (R,S)-1-(1-Adamantyl)-N-methyl-2-[4-(2H-naphth[1,8-c~isothiazol-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide, maleate.
Hydrolysis of the trifluu,uacul~"ide 13(a) was conducted as previously described in Example 7(b) and gave the title free diamine in 65%
yield as a solidified foam. TLC: Rf = 0.5 (methanol / methylene chloride 1 :9).
On the usual treatment with an excess of maleic acid in ethanol / diethyl ether diamine 13(b) was converted into its maleate salt in 50~~O yield. White powder, m.p.: 191-153~C. Anai. Caic'd for C33H43N30sS + 0.5 H20: C,64.08;
H,7.11; N,6.80. Found: C,64.08; H,7.11; N,6.90.

(R,S)-2-[1 -[2-(1 -Adamantyl)-2-pyrrolidin-1 -ylethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-c~;~otl,id~ule 1,1-dioxide, fumarate.

Reaction of mesylate 12(a) with pyrroiidine, conducted as described in Example 8, afforded diamine 14 in 70% yield as a white solidified foam. TLC: Rf = 0.3 (methanol / methylene chloride 1 :9).
The fumarate salt was prepared in ethanol, according to the usual procedure, in 68% yield as a slightly brown powder, m.p.: 194-196~C. Anal. Caic'd for C36H47N306S + 0.25 H20: C,66.05; H,7.26; N,6.42. Found: C,65.92; H,7.31;
N,6.49.

(R,S)-2-[1 -[2-(1 -Adamantyl)-2-morpholin-4-ylethyi]piperidin-4-ylmethyl]-2H-naphth[1,8-.,u,;~,uLl,id~ule 1,1-dioxide, dihydlucl,lo,i.le.

Following procedure described in Example 8, reaction of mesylate 12(a) and morpholine gave diamine 15 in 71% yield as a white solidified foam. TLC: Rf = 0.3 (methanol/methylene chloride 1 :9).
The dih~n~,u1hlori.1e salt was prepared in 61% yield, according to the procedure2(e), as a white hygroscopic solid, m.p.: 182-184~C. Anai. Caic'd for C32H4sCL2N303S + H20: C,59.99; H,7.39; N,6.56. Found: C,60.41; H,7.74;
N,6.64.

35 (R,S)-2-[1-[2-(1-Adamantyl)-2-(4-methyl)piperazin-1-ylethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-c~i~uthid~ule 1,1-dioxide, h~dluulllorid~.

, . . . _ _ . .. . .. . . . . . _ .. . .. ... . _ WO 96/05185 2 ~ ~ 7 1 7 2 PCT/JP95/01600 ~

Mesylate 1 2(a) and N-methylpiperazine were reacted under condibons analogous to Example 8 and gave bhe btle triamine 16 in 86% yield as a white solid, m.p.: 114.9-115.5~C. TLC: Rf = 0.3 (methanoUmethylene chloride 1 :9).
5 The hydrochloride salt was prepared in 48 ~/0 yield, according to bhe procedure 2(e), as a white solid, m.p.: 213.5-214.3~C. Anal. Calc'd for C33H46N402S + 2.8 HCI +1.5 H20: C,57.19; H,7.58; N,8.09; Cl,14.35. Found: C,57.26; H,7.73;
N,8.07; Cl,14.23.

(R,S)-1-(1 -Adamantyl)-N,N-diethyl-2-[4-(2H-naphth[1 ,8-co~isothiazol-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide, fumanate.
Mesylate 12(a) and diethylamine were reacted together, under condibons described in Example 8, to give diamine 17 in 46% yield as an oil.
TLC: Rf = 0.3 (methanol / methylene chloride 1:9).
The fumarate salt was crystallized from ethanol, according to the usual 20 procedure, in 48% yield as a white solid, m.p.: 221 .5-222.3~C. Anal. Calc'd for C36H4sN306S + 1/3 H20: C,65.75; H,7.55; N,6.39. Found: C,65.77; H,7.66;
N ,6 .39 .

(R,S)-1-(1-Adamantyl)-N-allyl-N-methyl-2-[4-(2H-naphth[1,8-uu~ thid~ul-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide, fumarate.

Following typicall procedure (Example 8), reaction of mesylate 12(a) with N-methylallylamine furnished diamino compound 18 in 20 ~/0 yield as a white solidified foam. TLC: Rf = 0.5 (ethyl acetate).
Diamine 18, on bhe usual treatment with fumaric acid in ethanol, gave the btle salt 18 in 49~/0 yield as a white solid, m.p.: 191.7-192.8~C. Anal. Calc'd for C36H47N306S + H20: C,64.74; H,7.40; N,6.29. Found: C,64.61; H,7.26; N,6.14.

2 1 97 1 7~

(+)-(S)-1 -(1 -Adamantyl)-2-[4-(2H-naphth[1,8-cu~W.,Il ,ia~ol-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide.

Reacton of 4-[2-(2H-naphth[1,8-c~isothiazol-1,1-dioxide)methyll piperidine 2(d) (0.151 9, 0.5 mmol) with (+)-S-(1-adamantyl)ethylene oxide (0.089 g, 0.5 mmol) was conducted following procedure described in Example 11(b),butover72hrs.Columnchlullldluyldplly(silicagel~methylenechloride/
10 methanol 20:1) gave pure aminoalcohol 19 (0.155 9, 65%) as a solidified foam,m.p.: 202.5 - 204.5~C. [a]D2o = +24.7~ (c 1.3, CHCI3). 1H-NMR (CDCI3):
identical to that of a racemic aminoalcohol 4.
The (+)-S-(1-adamantyl)ethylene oxide ([a]D2o = + 13.3~ (c 1.6, CHCI3)) was prepared according to De Ninno M.P. etal. (J. Org. Chem., 1992, 57,7115-7118), 15 but starbng with the opposite ena" "el of the catalyst.

20 (-)-(R)-1-(1-Adamantyl)-2-[4-(2H-naphth[1,8-cu,;~,utl,id~ol-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide.

Following procedure 11(b), (-)-R-(1-adamantyl)ethylene oxide (0.500 9, 2.8 mmol) and piperidine 2(d) (0.845 9, 2.8 mmol) were reacted together, but 25 over 54 hrs. Purification by column ~,hru"alu~ hyfurnished alllilloalcol,ul 20 (0.710 9, 55~/O) as a white solid, m.p.: 204.5 - 205.5~C. [a]D2o = - 29.3~ (c 1,CHCI3) . 1 H-NMR (CDCI3): identical to that of dl l lil ,oalcohol 4.
The (-)-R-(1-adamantyl)ethylene oxWe ([a]D2o= - 14.7~ (c 1, CHCI3)) was prepared accordingto De Ninno M.P. etal. (J. Org.Chem., 1992, 57, 7115-80 7118).

35 (R,S)-2-[1-[2-(1-Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-cu~ vtl,id~ule 1,1-dioxide, hy-i,u~l,lolicle.

2~ ~7 ~ 72 Sodium hydride (60 ~/O dispersion in oil) (0.6 9,14 mmol) was added to a solution of aminoalcohol 4 (3.0 9, 2.7 mmol) in dry tetrahydrofuran (60 ml) at roorn temperature under nitrogen, and the resulted mixture was stirred for 20 min. Next, dimethylsulfate (0.6 ml,2.7 mmol) was added and stirring continued 5 overnight. Reaction was quenched with water (50 ml) and extracted with methylene chloride. The combined organic extracts were dried and evaporated.
The residue was ul " u" IdlUyl dp hed (silica gel, methylene chloride / ethyl acetate 6:4, then 1 :1) to give methyl ether 21 (1.0 9,30~/O) as a white solid, m.p.: 169-171~C. TLC: Rf = 0.65 (methylene chloride /ethyl acetate 7:3). ~H-NMR
(CDCI3): 8.06 (d,1 H); 7.97 (d,1 H); 7.75 (dd,1 H); 7.53 (dd,1 H); 7.45 (d,1 H); 6.74 (d,1H); 3.68 (d,2H); 3.48 (s,3H); 3.04-2.95 (m,2H); 2.73 (dd,1H); 2.49-2.33 (m,2H); 2.10-1.34 (m, 22 H). MS: 315(M-179). Anal. Calc'd for C2sH3sN2O3S:
C,70.41; H,7.74; N,5.66. Found: C,70.17; H,7.84; N, 5.60.
The hydrochloride salt was prepared according to the procedure 2(e) as a white solid, m.p.: 198-205 ~C. Anal.Calc'd for C2sH3sN2O3S + Ha + 0.5 H20:
C,64.44; H,7.41; N,5.18; Cl,6.57. Found: C,64.09; H,7.35; N,4.96; Cl,6.38.

EXAMPLE
(+)-(S)-2-[1 -[2-(1 -Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-~ ,ull,id~ole 1,1-dioxide, hydlu.;hlo~ide.

The O-methylation of the (+)-S-all,i"oalcollol 19 was performed as described in the Example 21. Methyl ether 22 was obtained in 42 ~/O yield.1 H-NMR (CDCI3): identical to that of racemic methyl ether 21.
The hydrochloride salt was prepared according to the procedure 2(e) as a white hygroscopic foam. Anal. Calc'd for C2sH3sN2O3S + HCI + 0.5 H20:
C,64.44; H,7.41; N,5.18; Cl,6.57. Found: C,64.29; H,7.61; N,5.11; Cl, 6.56 .
[a]D20 = + 13.2~ (c 1, CHCI3).

35 (-)-(R)-2-[1-[2-(1-Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl~-2H-naphth[1,8-uu~;~otl,i,~ule 1,1-dioxide, hydrochloride.

21~7~
WO 96/0518~ PCI/JP95/01600 7 The O-methylation of the (-)-R-aminoalcdhol 20 was perfommed as described in the Example 21. Methyl ether 23 was obtained in 55 ~/O yield.1 H-NMR (Ci~CI3): identical to that of racemic methyl ether 21.
The hy~llucl~lorid~ saH was prepared according to the procedure 2 (e) as a white hygroscopic foam. Anal.Calc'd for C2sH3sN2O3S + HCI + H20: C,63.38;
H,7.47; N,5.10; Cl,6.47. Found: C,63.60; H,7.51; N,5.13; Cl,6.55.
[a]D2o = - 17.3~ (c 1, CHCI3).

1û FXAMPLF 24 (R,S)-2-[1 -[2-(1 -Adamantyl)-2-ethoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-cu,;~,u~i,id~ulu 1,1-dioxide, fumarate.

A sdution of the mesyiate 12(a) (2.5 9,45 mmol) in ehand (50 ml) was heated under reflux for 2 hrs. Af~er evaporaiion of the solvent, the residue was diluted with methylene chloride and treated with 0.025 M aqueous sodium hydroxyde, then water and saturated aqueous sodium bicdli U"diU. The organic phase was dried and cu"wr~,dl2d. Residue was ~;hlullldtuyld~Jlled (silica gel, methylene chloride / methanol 95:5) to give a whib solid (û.76 9) which was recrystallized from ethyi aoe~ate yielding ehyl eher 24 (û.55 9, 31~/O). M4: 1623-1633~C.TLC:Rf=02(ethylaoetdte/hexane3:7).
1H-NMR (Ci~CI3): 8.06 (d,1H); 7.97 (d,1H); 7.75 (dd,1H); 7.53 (dd,1H); 7.45 (d,1H); 6.74 (d,1H); 3.8 (m,1 H); 3.68 (d,2H); 3.5 (m,1H); 3.1 (m,2H); 2.5 (m,2H); 2.05-1.5 (m, 24 H); 1.2 (t, 3 H).
The fumarate salt 24 was crystallized in a usual way, from ethanol in 64% yield as a white solid, m.p.: 206.7-2û7.4~C. Anai. Caic'd for C34H44N207S: C,65.36;
H,7.10; N,4.48. Found: C,65.25; H,6.99; N,4.59.

(-)-2-[1 -[2-(1 -Adamantyl)-2-ethoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-,"ri~,ull ,ia~ole 1,1 -dioxide.
a) (-)-1-(1-Adamantyl)-1-camphosulfonyloxy-2-[4-(2H-naphth[1,8-WO 96/0!i185 21 q 7 l 7 2 PCTIJP95101600 ~

uu~;~uthid~ol-2-ylmethyl)piperidin-1-yl]ethane S,S-dioxide.
The sulfonylation of the racemic aminoalcohol 4 (5.8 9, 12.08 mmol) wrth (1S~-(+)-10-camphorsulphonyl chloride (4.54 9, 18 mmol) was conducted in tetrahydrofuran (180 ml) in the presence of triethylamine (2.52 ml,5 18 mmol). After the usual work-up, the mixture of diastereoisomers was separated by chromatography (silica gel, ethyl acetate / hexane 2:8). The camphosulfonic ester (-)-25(a) (1.18 9,14.2 ~/O) was eluted first (Rf = 0.46) and crystallized as a white solid, mp: 201-203 ~C. [a]D24 = - 40~ (c 1, CHCI3).

b)(-)-2-[1-[2-(1-Adamantyl)-2-ethoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-cu,;~7utl,id~ule 1,1-dioxide A solution of the (-)-camphosulfonate 25(a) (0.500 g, 0.72 mmol) in of ethanol (50 ml) was heated under reflux for 3 hrs. After evaporation of the solvent, the residue was diluted with methylene chloride and treated whh 0.025 15 M aqueous sodium hydroxide, then water and saturated aqueous sodium bicarbonate. The organic phase was dried, concentrated under vacuum and the resulting solid was purified by silicagel c hru ~ld~uyld,uhy (eluent: methylene chloride /methanol 95:5) to give 200 mg (54.5 ~/O) of a white solid. mp: 159.3-161 ~C. TLC: Rf = 0.2 (ethyl acetate/hexane 3:7).
20 The 1 H-NMR (CDCI3) was identical to that of the Example 24.
[a]c24 = 27~ (c 1, CHCI3).

(R,S)-1 -(1 -Adamantyl)-1 -methyl-2-[4-(2H-naphth[1,8-cu~;~,uthid~u1-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide, hyd,ucl,lo,ide.

Methyl lithium (1.4 M in ether, 6.0 ml, 8.4 mmol) was slowly aWed 30 dropwise at 0~C to a stirred suspension of aminoketone 2(e) (4.0 9,8.4 mmol) in tetrahydrofuran (80 ml). The suspension gradually changed to a pink solution.Additional methyl lithium (1.4 M in ether, 2.0 ml, 2.8 mmol) was aWed.
Resulted red solution was stirred for 3 h and during that time the red colour disappeared. Reaction was quenched with water (20 ml) followed by ethyl 35 acetate (100 ml) and brine (30 ml). The layers were separated and the aqueous one was extracted with methylene chloride (50 ml). The combined 21~1t72 WO 9610S185 . PCT/JP9S101~00 organic phases were dried and con~,en~dl~d. Residue was purified by column chromatography (silica gel, hexane / ethyl acetate 6:4, hhen mehhylene chloride /ethyle acetate 1 :1) to afford aminoalcohol 26 (0.5 9, 12 ~/O) as a white solid, m.p.: 78-81 ~C. TLC: Rf = 0.66 (hexane / ethyl acetate 6:4). MS: 315 (M-179).
5 Anal. Calc'd for C2sH3ON2O3S: C,70.41; H,7.74; N,5.66. Found: C,70.14; H, 7.75; N, 5.66.
The hydrochloride salt was prepared, according to the general procedure 2(e), as a white solid, mp: 271.2-272 ~C. Anal. Calc'd for C2sH3r~N2O3S + HCI +1.1 H20: C,63.22; H,7.54; N,5.08; Cl,6.43. Found: C,63.26; H,7.48; N,5.01; Cl,6.25.

(R,S)-1 -Cyclohexyl-2-[4-(2H-naphth[1,8-cu~;~,uthid~ol-2-ylmethyl)piperidin-1 -15 yl]ethanol S,S-dioxide, hyd~uuhlorkle.

a) 1 -Cyclohexyl-2-~:hlo, u~ll ,an-1 -one.
A soluhon of cyclohexanecarbonyl chloride (2.0 ml, 15 mmol) in diehhyl ether (6 ml) was slowly added at room temp. over 30 min. to the etheral 20 solub'on of did~u",~ll,ane (prepared from Diazald (Aldrlch) (10.0 9,46.7 mmol) according to Hudlicky M. J. Org. Chem., 1980, 45,5377-5378). The reaction was conducted for 1 h. Next, hydrogen chloride was bubbled into the reaction mixture at 0~C for 20 min. Then water (50 ml) was added, layers were separated and the etheral one was washed with saturated aqueous sodium 25 carbonate soluhon. Organic soluhon was dried and evaporated. Residual liquid was treated with saturated aqueous sodium bicar~ondl~ solution and stirred for 2 h. Mixture was extracted wrth ether, combined extracts were dried and evaporated to give fairly pure ~;hlo~u~ lllylketone 27(a) (1.1 9, 46%) as a yellow liquid.
b)2-[(1 -(2-Cyclohexyl-2-oxoethyl)-4-piperidinyl)methyl]-2H-naphth[1,8-cL5;sulllid~ule 1,1-dioxide.
~ A mixture of chloromethylketone 27(a) (1.4 9, 8.3 mmol), hydluclllorkle 2(d) (2.5 9, 7.3 mmol), anhydrous potassium carbonate (1.2 9, 35 8.3 mmol) and sodium iodide (1.4 9, 8.3 mmol) in 30 ml of act:lu"il,il~ was vigorously shrred under reflux for 3 h. Aflter cooling, water (60 ml) was'added,resulted mixture shrred for 20 min., and then extracted twice with mehhylene WO 96/05185 2 ~ PCT/JP95/Ol~iO0 chloride (100 ml). The combined organic layers were dried and evaporated to give cnude aminoketone 27(b) (3.0 9, 100%) which was sufficiently pure for the next step.

c)(R,S)-1 -Cyclohexyl-2-[4-(2H-naphth[1 ,8-cu~i~,utl ,id~ole-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide, hydrochloride.
Reduction of the aminoketone 27(b) (3.0 9, 7 mmol), according to the method described in Example 1(d), followed by purification by column chromatography (silica gel, methylene chloride / ethyl acetate 7:3, then 1:1 ) gave aminoalcohol 27(c) (1.9 9, 63%) as a white solid, m.p.: 148-150 ~C. TLC:
Rf = 0.12 (methylene chloride / ethyl acetate (98:2). MS: 429 (M+1). Anal.
Calc'd for C24H32N203S: C,67.26; H,7.53; N,6.54. Found: C,67.11; H,7.57, N,6.40.
The hydrochloride salt was prepared according to the usual procedure 2(e) as a white solid, m.p.: 262.7-264 ~C. Anal.Calc'd for C24H32N2OsS + 1.75 HCI:
C,58.54; H,6.91; N,5.69; Cl,12.60. Found: C,58.38; H,6.89; N,5.64; Cl,12.69.

E)(AMPLF 28 (R,S)-1-(1 -Adamantyl)-2-[4-(2-,_hlo, upheuutl ,ia~ -1 0-ylmethyl)piperidin-1 -yl]-ethanol, hyd~u~hlodde.

a) N- ter~Butoxycarbonyl-4-[1 0-(2--,hlul u~.he"utl ,idzyl)methyl]piperidine.
Compound 28(a) was prepared from 2-chlorophenothiazine (5 9, 21.4 mmol) and N-tert butoxycarbonyl-4(methanesulphonyloxymethyl) piperidine (15.0 9, 50 mmol) according to the method described in Example 2(c), but reaction was performed in boiling p-xylene over 40 hrs and whhout addition of sodium iodide. The crude product, obtained after usual extractive work-up of the reaction mixture, was chromatographed (silica gel, ethyl acetate / hexane 1:9) yielding 28(a) (3.5 9, 38%) as a slightly yellow foam.

b) 4-[10-(2-Cl,lo,ulJhenutl,ia~yl)methyl]piperidine hydluullloricl~. -Removal of the N-tert-butoxycarbonyl protecting group from 28(a) was performed in the presence of hydrogen chloride as described in Example 2(d). The title piperidine hydluchlolid~ 28(b) was obtained in 96% yield as a white solid, m.p.: 248-250 ~C.

2 ~ 2 W0 96105185 P~ J. 1600 c)10-[(1-(2~ Adamantyl~-2-oxoethyl)-4-piperidinyl)methyl]-2-chloro-phenoLI lid~M e.
Hydrochloride 28(b) (3.19 9, 8.69 mmol) and 1-(blull,odc~yl) 5 adamantane (2.38g, 9.25 mmol) were reacted in boiling acetonitrile (35 ml) in the presence of anhydrous potassium carbonate (1.25 9,9.04 mmol) following the method descrbed in Example 1 (c). The aminoketone 27(c) (3.4 9, 77 o/O) was obtained as a cream colored solid, m.p.: 178-181 ~C.

d)(R,S)-1-(1-Adamantyl)-2-[4-(2-ulllo,upl1el1othiazin-10-ylmethyl)-piperidin-1 -yl]ethanol, hydl u~ luride.

The aminoketone 28(c) was reduced according to the method described in the Example 1(d). Purification by column chromatography (silica gel, ethyl acetate / methylene chloride 5:95, then 10:90) afforded aminoaicohol 28(d) in 90~/O yield as a white solid, m.p.: 215-217 ~C. TLC: Rf = 0.5 (ethyl acetate / hexane 1:1). MS: 343 (M-165). Anai. Calc'd for C30H37CIN2OS:
C,70.77; H,7.32; N,5.50. Found: C,71.07; H,7.54; N,5.45.
The title hydrochloride saH was prepared following the usual procedure 2(e) as a white solid, m.p.: 256-258 ~C. Anal. Caic'd for C30H37CIN2OlS + HCI:
C,66.04; H,7.02; N,5.13; Cl,13.00. Found: C,65.86; H,6.97; N,5.10; Cl,13.02.

(R,S)-1 -(1 -Adamantyl)-2-[4-(phenothiazin-10-ylmethyl)piperidin-1 -yl]ethanol, h~ uchloi icle.

a) N-tett-Butoxycarbonyl-4-[(10-phenu;; ,id~yl)methyl]piperidine.
Compound 29(a) was prepared from phenothiazine (4.4 g, 22 mmol) and N-tert-Butoxycarbonyl-4-(methanesulphonyloxymethyl)piperidine (6.0 9, 20 mmol) according to the method described in Exampie 2(c). Column - ullru,,,aLu~,dphy (silica gel, ethyl acetate / hexane 15:85, Rf = 0.3) gave 29(a) (8 9, 97~/O) as a brown solid, m.p.: 104-106 ~C.
b) 4-[(10-Pl ,enuti ,i 7yl)methyl]piperidine.

WO96/05185 21 q~ PCT/JP95/Ol~iO0 Removal of the N-tert-butoxycarbonyl protecting group in 29(a) was perfommed with hydrogen chloride, as described in Example 2(d), to produce 29(b) hydrochloride salt in 87 ~/O yield as a white solid. m.p.:137-139 ~C.
5 The basic work-up gave the title free amine 29(b) in 95~/O yield as a white solid, m.p.: 83-85 ~C.
c)10-[[1-[2-(1-Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]-phellUIl lid~;l ,e.
Amine 29(b) (4.7 9, 15 mmol) and 1-(b,u,,,od;elyl)adamantane (4.8 9, 18 mmol) were converted to the aminoketone 29(c) (5.9 9, 83%), according to the method described in Example 1 (c). A cream colored solid was obtained, m.p.: 177-179~C. TLC: Rf = 0.5 (ethyl acetate / methylene chloride 1 1).
d) (R,S)-1-(1-Adamantyl)-2-[4-(~l,enull,id~;"-10-ylmethyl)piperidin-1-yl]-ethanol, hydl uuhlol ide.
Alllillukl:Lull~ 29(c) was reduced according to the procedure described in the Example 1 (d). Crude product was recrystallized from 20 chloroforme / diethyl ether to give pure aminoalcohol 29(d) in 73~/O yield as a white solid, m.p.: 254-256~C. TLC: Rf = 0.2 (ethyl acetate/methylene chloride 1 1).
Following procedure 2(e), the hydlu~;l loridu salt 29(d) was prepared in 50~/O
yield after recry " ' on from ethanol / diethyl ether. A white solid, m.p.: 266-25 268~C. MS: 474 (M+). Anal. Calc'd for C30H3sClN2OS: C,70.49; H,7.69; N, 5.48; Cl,6.94. Found: C,70.39; H,7.70; N,5.57; Cl,6.82.

3û
(R,S)-1 -(1 -Adamantyl)-2-[4-(phenoxazin-10-ylmethyl)piperidin-1 -yl]ethanol, fumarate.

a) N-tert-Butoxycarbonyl-4-[(10-phenoxazyl)methyl]piperidine.
Compound 30(a) was prepared from pht!nu~d~ille (2.91 9, 15.9 mmol) and N-tert-Butoxycarbonyl-4-(methanesulphonyloxymethyl)piperidine (4.16 9, 14 mmol) according to the method described in Example 2(c). The s crude productwasulllullldluyldplled (silica gel, ethyl acetate/hexane 15:85, Rf = 0.3) to afford 30(a) (3.0 9, 54~/O) as a grey solid, m.p.: 156-158~C.

b) 4-[(10 ~i ,enuAd~yl)methyl]piperidine.
Removal of bhe N-tett-butoxycarbonyl protecting group in 30(a) was performed with hydrogen chloride, as described in Example 2(d), to produce 30(b) hydrochlûride salt in 77 ~/O yield as a white solid, m.p.: 252-254~C.
The free amine 30(b) was obtained in usual manner in quantitabve yield as a white solid, m.p.: 131 -133~C.

c)10-[[1-[2~ Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]-,llenuAd~;, ,e.
Amine 30(b) (1.6 9, 5.5 mmol) and 1-(b,ur"od.,ulyl)adamantane (1.6 9, 6.05 mmol) were converted to a~ ohulu~e 30(c) (2 9, 88%), as described in Example 1 (c). A colored solid was isolated, m.p.: 166-168~C. TLC:
Rf = 0.6 (ethyl acetate/methylene chloride 1 :1).

d) (R,S)-1 -(1-Adamantyl)-2-[4-(phenoxazin-1 0-ylmethyl)piperidin-1-yl]-ebhanol, fumarate.
Reduction of bhe aminoketone 30(c) was performed following bhe method described in Example 1 (d). Purificabon by ~,hlullldluyld,uhy (silica gel, ebhyl acetate / methylene chloride 3:7) furnished aminoalcohol 30(d) in 87%
yield as a solid, m.p.: 180-182~C. TLC: Rf = 0.3 (ethyl acetate I methylene chloride 3:7).
The fumarate salt was crystallized from ethanol in 37~/O yield following the usual procedure (Example 1 (d)). A yellow powder, m.p.: 134.5-135.5~C. MS: 459 (M
+ 1). Anal. Calc'd for C34H42N2O6: C,71.06; H,7.37; N,4.87. Found: C,71.38;
H,7.87; N,4.96.
Fumarate salt 30(d) contained ca. 5 ~/O of ethanol (basis on 1 H-NMR). The salt decu,, ,~,osed slowly when exposed to light.

WO 96/05185 2 1 9 7 t 7 2 ' PCT/JP95/01600 (R,S)-1 -(1 -Adamantyl)-2-[4-(5H-dibenz[b,flazepin-5-ylmethyl)piperidin-1 -yl]ethanol, fumarate.

a) N-tert-Butoxycarbonyl-4-[5-(5H-dibenz[b,flazepinyl)methyl]piperidine.
Compound 31(a) was prepared from 5H-dibenz[b,flazepine (4.25 9, 22 mmol) and N-tert-butoxycarbonyl~(methanesulfonyloxymethyl) piperidine (6.54 9, 22 mmol) according to the method described in Example 10 2(c). The crude product was chromatographed (silicagel, methylene chloride /
hexane 7:3) to give 31 (a) (3.9 9,45 ~/O) as a viscous oil.

b) 4-[5-(5H-Dibenz[b,flazepinyl)methyl]piperidine.
Removal of the N-tert-butoxycarbonyl protecting group in 31(a) 15 was performed with hydrogen chloride, as described in Example 2(d), to give 31 (b) h~dl u-,hlulide quantitative yield as a gummy solid.
The free amine 31 (b) was obtained after usual basic work-up in 79 ~/c yield as a yellow oil.

2û c)(R,S)-1-(1-Adamantyl)-2-[4-(5H-dibenz[b,flazepin-5-ylmethyl)piperidin-1-yl]ethanol, fumarate.
Reaction of the (1-adamantyl)ethylene oxide (0.865 9, 4.8 mmol) with piperidine 31(b) (1.4 g, 4.8 mmol) was conducted according to the method described in the Example 11(b), but over 5 hrs. Purification by column clllullldlu~u~ ully (silica gel, methylene chloride/methanol 9:1) afforded aminoalcohol 31(c) (0.63û g, 28%) as yellow crystals, m.p.: 216-218~C. TLC:
Rf = 0.5 (methylene chloride / methanol 9:1).
Following the usual procedure 1 (d) the fumarate salt 31 (c) was crystallized from ethanol in 66 ~/0 as a yellow powder, m.p.: 225-227~C. MS: 468 (M+). Anal.
Calc'd for C3sH44N20s: C,73.94; H,7.58; N,4.79. Found: C,73.66; H,7.65;
N,5.05.

2 1 ~7 ~ ~

(R,S)-1 -(1 -Adamantyl)-2-[4-(10,11 -dihydro-5H-dibenz[b,flazepin-5-ylmethyl)-piperidin-1-yl]ethanol, fumarate.

a) N- tert-Butoxycarbonyl-4-[5-(10.11 -dihydro-5H-dibenz[b,f]azepinyl) methyl]piperidine.
Compound 32(a) was prepared from 10,11-dihydro-5H-dibenz[b,flazepine (4.43 9, 22 mmol) and N-tert-Butoxycarbonyl-4-(methanesulfonyloxymethyl)piperidine (6 9, 20 mmol) according to the meffhod described in Example 2(c). The crude product was ~;hlul l Idluyldphed (silica gel, methylene chloride / hexane 8:2, Rf = 0.3) to give 32(a) (6.6 9, 76%).

b) 4-[5-(10,11-dihydro-5H-dibenz[b,flazepinyl)methyl]piperidine.
Removal of ffhe N-tert-butoxycarbonyl protecting group in 32(a) was performed with hydrogen chloride, as described in Example 2(d), giving piperidine 32(b) hydlu~:lllor;d~ in 79 ~/O yield as a gummy solid. The basic work-up afforded the title free amine 32(b) in 78% yield as a brown oil.

c) (R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihydro-5H-dibenz[b,flazepin-5-ylmethyl)piperidin-1-yl]ethanol, fumarate.
Reacffon of the (1-adamantyl)effhylene oxide (û.980 9, 5 mmol) with piperidine 32(b) (1.46 9, 5 mmol) was conducted according to the method described in ffhe Example 11(b), but over 7 hrs. Purificaffon by coiumn chromatography (silica gel, methylene chloride / methanol 9:1) furnished the title d",i"oalcohol 32(c) (1.2 9, 51%) as a white solid, m.p.: 172-175~C. TLC: Rf = 0.55 (methylene chloride / methanol 9:1).
According to typical procedure 1 (d) the fumarate salt 32(c) was crystallized from ethanol in 61 ~/0 yield as a white solid, m.p.: 192-1 94~C. MS: 471 (M+1). Anal.Calc'd for C36H4sN2Os + H20: C,71.50; H,8.00; N,4.63. Found: C,71.70;
H,7.91; N,4.95.

EXAMpl F 33 (R,S)-1 -(1 -Adamantyl)-2-[4- (5H-phendl l l, idi, ~-6-oxo-5-ylmethyl)piperidin-1 -yl]ethanol, h~d~u~,hlulide.

a) N-tert-Butoxycarbonyl-4-[5H-phellal,UI,kli"-6-oxo-5-yl)methyl]-piperidine.
Compound 33(a) was prepared from 6-(5H)-phdnd"U"idi"one (4.3 g, 22 mmol) and N-tert-butoxycarbonyl-4-(methanesulfonyloxymethyl) 5 piperidine (6.0 9, 20 mM) according to the method described in Example 2(c).
Thecrudeproductwas~;l"v",dLuy,dphed(silicagel, ethylacetate/hexane3:7, Rf = 0.25) to give 33(a) (4.5 9, 57~/O) as a white solid, m.p.: 76-79 ~C.

b) 4-[51 1 Phe"dl, '"idi"-6-oxo-5-yl)methyl]piperidine.
Removal of the N-tert-butoxycarbonyl protecting group in 33(a) was performed with hydrogen chloride, as described in Example 2(d), to give piperidine 33(b) hydrochloride in 93 ~/O yield as a white solid. m.p.: > 250 ~C
(dec).
The basic work-up produced free amine 33(b) in 89% yield as a white solid.~5 c) 5-[[1-[2-(l-Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]-6-(5H)-phe, Idl 1"11 i~.C, IC~ ne.
Folbwing procedure 1(c), amine 33(b) hydluclllorid~ (3.7 9, 11.3 mmol) and 1-(L,,u,,,oac~,tyl)add,,,a,,Ldi,e (3.4 9,13 mmol) werereactedtogether 20 in ac~lu, ,iL,ile (60 ml) containing potassium carbonate (1.79, 12 mmol). Column chromatography (silica gel, hexane / ethyl acetate / triethylamine 12:8:1) gave dl"i,n)k~Lulle33(c)(3.1 g,59~/O)asapalepinksolid,m.p.:98-100~C.

d)(R,S)-l-(l-Adamantyl)-2-[4-(5H-phel,d"ii"idi"-6-oxo-5-ylmethyl)-25 piperidin-1-yl]ethanol, hydrochloride.

All~ k~:Lull~ 33(c) was reduced following the method described in the Example 1 (d). Purification by column chromatography (silica gel, methylene chlûride / ethyl acetate / methanol 50:50:1) afforded aminoalcohol 30 33(d) in 64% yield as white solid, m.p.: 202-203 ~C. TLC: Rf = 0.2 (ethyl acetate / methylene chloride 1:1). MS: 305 (M-165)MH-NMR(CDCI3): 8.54 (dd, 1 H); 8.31-8.26 (m, 2H); 7.78-7.76 (m, 1 H); 7.73-7.57 (m, 2H); 7.39 (d,1 H); 7.31 (t,lH); 4.34 (bd, 2 H); 3.15 (dd, 1 H); 3.02 (d, 1 H); 2.76 (d, 1 H); 2.38-2.19 (m, 3H); 2.04-1.5 (m, 21 H). Anal .Calc'd for C31 H3sN2O2: C,79. 11; H ,8.14; N,5.95.
35 Found: C,79.28; H,8.28; N,5.77.
The title hydluchlùlid~ salt was prepared according to example 2(e) in 50 ~/O
yield as a white solid, m.p.: 193.5-194.5 ~C. Anal. Calc'd for C31H3sN2O2 +

2~1t72 (HC1)1.7~: C,6g.67; H,7.50; N,5.24; Cl,11.61. Found: C,69.67; H,7.57; N,5.23;
Cl,11.56.
1H-NMR (CDC13): 10.55 (bs,1H); 8.45 (dd, 1H); 8.25 (m, 2H); 7.75 (t, 1H);
7.60-7.40 (m, 3H); 7.30 (t,1H); 5.65 (bs,2H); 4.35 (bs, 2 H); 3.75-3.69 (m, 3H);5 3.20-3.00 (m,2H); 3.00-2.60 (m, 2H); 2.35 (bs, 3H); 1.95 (bs, 4H); 1.75-1.40 (m, 12 H) (+)-(S)-1 -(1 -Adamantyl)-2-[4-(5H-~,I ,end, Ithl i~,fil ,-6-oxo-~-ylmethyl)piperidin-1 -yl]ethanol, hydrochloride.

Reaction of (+)-S-(1-adamantyl)ethylene oxide (0.500 9, 2.8 mmol) with 15 piperidine 33(b) (0.818 9, 2.8 mmol) was conducted according to the method described in the Example 11(b), but over 72 hrs. Column chromatography (silica gel, methylene chloride / methanol 20:1) gave aminoalcohol 34 (0.980 9, 75~/O) as a foam. [a]D2o = + 28.8~ (c 1.1, CHCI3). TLC: Rf = 0.2 (methylene chloride / methanol 20:1).
20 1 H-NMR (CDCI3): identical to that of racemic a" ,i"oalcuhol 33(d).
The hydrochloride sae 34 was prepared in 90 ~/O yield according to the usual procedure 2(e). White powder, m.p.: 195-197 ~C. [a]D2o= + 14.2 ~ (c 1, CHCI3). 1 H-NMR (CDCI3): identical to that of hydl u~l ,lorid~ salt 33(d).
Anal. Calc'd for C3lH3sN2O2 + HCI + HzO: C,70.90; H,7.87; N,5.33; Cl,6.75.
25 Found: C,70.59; H,7.82; N,5.26; Cl,6.81.

EXAMpl F 35 30 (-)-(R)-1 -(1 -Adamantyl)-2-[4-(5H-phend" ' ~ ii, I-6-oxo-5-ylmethyl)piperidin-1 -yl]ethanol, hydrochloride.

- Reaction of the (-)-R-(1-adamantyl)ethylene oxide ( 0.500 9, 2.8 mmol) with piperidine 33(b) (0.818 9, 2.8 mmol) was conducted according to the 35 method described in Example 11(b), but over 35 hrs. Crude product was subjected to column clll~lldtuyldl~hy (silica gel, methylene chloride / methanol _ _ _ _ _ _ . _ _ _ _ _ _ _ . . . . . . .

2 I q7 1 72 WO 96/05185 PCTIJP95/OlfiOO

20:1)to give al"i"oalcollol 35 (0.980 9, 74~/0) as a white powder, m.p.: 101-103~C. [a]D2o= - 30.5 ~ (c 1, CHCI3). TLC: Rf = 0.2 (methylene chloride /
methanol 20: 1) 1 H-NMR (CDCI3): identical to that of al, lil ,oalcuhol 33(d).
The hydrochloride salt 35 was prepared in 90 ~/0 yield according to the usual method 2(e). White powder, m p: 269-271~C. [a]D2o= - 18.5 ~ (c 1, CHCI3).
1 H-NMR (CDCI3): identical to that of hyd,uuhlol ide 33(d).
Anal. Calc'd for C31 H3sN2O2 + HCI + 1.3 H20: C,70.20; H,7.79; N,5.28; Cl,6.70.
Found: C,70.20; H,7.66; N,5.19; Cl,6.69.

(R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihydrodibenz[b,f][1,4]oxazepin-11-oxo-10-ylmethyl)piperidin-1 -yl]ethanol, hel l lild, l, a) N-tert-Butoxycarbonyl-4-[(10,11 -dihydrodibenz[b,f][1,4]oxazepin-11-oxo-10-yl)methyl]piperidine.
Compound 36(a) was prepared from 10,11 -dihydrodibenz[b,f][1,4]-oxazepin-11-one (4.3 9, 22 mmol) and N-tert-Butoxycarbonyl-4-(methanesulfonyloxymethyl)piperidine (6.0 g, 20 mmol) according to the method described in Example 2(c). The crude product was chromatographed (silicagel, ethyl acetate / methylene chloride 1 :9) affording 36(a) (6 9, 74 ~/O) as an orange oil. TLC: Rf = 0.3 (ethyl acetate /methylene chloride 1 :9).
b) 4-[(10,11-Dihy-iludiuell~[b~f][1~4]oxazepin-11-oxo-10-yl)methyl]
piperidine.
Removal of the N-tert-butoxycarbonyl protecting group in 36(a) was performed with hydrogen chloride, as described in Example 2(d), to give piperidine 36(b) hy.ll uuhlo, i-le in 53~/O yield as a white powder, m.p.: > 250 ~C.
The free amine 36(b) was obtained, after usual basic work-up, in 90 ~/O yield asa foam.

c)10-[[1 -[2-(1-Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]-10,11-dih~,.l,udil,ul l~[b,f][1,4]oxazepin-11 -one.

2 1 ~ ~ 7~

Piperidine 36(b) (2.7 9, 8.8 mmol) and l-(ulullludLetyl) adamantane (2.83 9, 11 mmol) were converted to aminoketone 36(c) (3 g, 70~~O), as described in Example 1(c). The pure product was obtained after ~;hlurll.8vy,dl~1,y (silica gel, hexane/ethyl acetate 1:1) as a pale yellowoil.TLC:
Rf = 0.2 (hexane / ethyl acetate 1 :1).
d) (R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihydrodibenz[b,f][1,4]oxazepin-11 -oxo-10-ylmethyl)piperidin-1 -yl]ethanol, he" lildl lldlt!.
Aminoketone 36(c) (3 9, 6 mmol) was reduced following the procedure 1 (d). Cdumn chromatography (silica gel, methylene chloride /
methanol 95:5) gave aminoalcohol (1.7 g, 58%) as a foam. TLC: Rf = 0.5 (methylene chloride / methanol 9:1).
The ht",ildrt,dl~ salt 36(d) was crystallized, in a usual way, from ethanol in 69% yield as a white solid, m.p.: 221.1 -223.4~C. MS: 321 (M-165~. Anal. Calc'd for C3~H41N206 + 1.25 H20: C,67.78; H,7.45; N,4.81. Found: C,67.70; H,7.29;
N,4.81.

(R,S)-1 -(1 -Adamantyl)-2-[4-(10,11 -dihydrodibenzo[b,e][1,4]diazepin-11 -oxo-10-ylmethyl)piperidin-1-yl]ethanol, hydlu~:hlolide.

a) N-tert-Butoxycarbonyl-4-[(10,11 -dih~n~udibe~ l~o[b,f][1,4]diazepin-11 -oxo-10-yl)methyl]piperidine.
Compound 37(a) WdS prepared from 10,11 -dihydrodibenzo[b,e][1,4]diazepin-11-one (4.6 9, 22 mmol) and N-tert-Butoxycarbonyl-4-(methanesulfonyloxymethyl)piperidine (6.0 9, 2û mmol) according to the method described in Example 2(c). The crude product was ullrullldluyld~Jhed (silicagel, ethyl acetate / methylene chloride 1:9) yielding37(a) (3.2 9, 39 ~/O) as an oil. TLC: Rf = 0.4 (diethyl ether / methylene chloride 2:8).
The starting 10,11-dih~,d,cclil,enzo[b,e][1,4]diazepin-11-one was prepared according to Monro A.M. etaL[J. Med. Chem. 1963, 255-261].
b) 4-[(10,11 -DihydludilJel ~u[b,e][1,4]diazepin-11 -oxo-10-yl)methyl]piperidine.

, . .. . . . .. .. . . ... . .. . . . .

2 ~ 97 ~ 72 WO 96/05185 PCTlJP9!i/01600 Removal of the tert-butyloxycarbonyl protecting group in 37(a) was performed with hydrogen chloride, as described in Example 2~d), to give piperidine 37(b) hydluuhlo~ide in quantitative yield as a powder, m.p.: > 250 ~C.
The free amine 37(b) was obtained in a usual way, in quanttative yield as a 5 foam.
c) (R,S)-1 -(l -Adamantyl)-2-[4-(10,11 -dihydrodibenzo[b,e][1,4]diazepin-11 -oxo-10-ylmethyl)piperidin-1-yl]ethanol, hydrochloride.
Reaction of the (1-adamantyl)ethylene oxide (0.500 9, 2.8 mmol) with piperidine 37(b) (0.860 9, 5 mmol) was conducted according to the method 10 described in Example 11(b), but over 48 hrs. Purification by column ~,hrullld~uuld~Jhy (silica gel, methylene chloride / methanol 20:1) afforded aminoalcohol 37(c) (1.04 9, 77~/O) as a white foam. TLC: Rf = 0.44 (methylene chloride / methanol 9:1).
The h~dlu~lllolid-3 salt 37(c) was prepared, following general procedure 2(e), in 15 6g% yield as a white soad, m.p.: 196-198~C. MS: 320 (M-165). Anal . Calc'd for C31H3sN3O2 + HCI + 0.5 H20: C,70.06; H,7.72; N,7.90;CI,6.68. Found:
C,70.07; H,7.94; N,7.76;CI,6.77.

20 F)~AMPI F 38 (R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihydludiiJel,~u[b,f][1,43thiazepin-11-oxo-10-ylmethyl)piperidin-1-yl]ethanol, fumarate.

a) N-tert-Butoxycarbonyl-4-[(10,11 -dih~J~ udiue~ l~o[b,f][1,4]thiazepin-11 -oxo-11-yl)methyl]piperidine.
Compound 38(a) was prepared from 10,11 -dihyd~cliben~u[b,fl[1,4]thiazepin-11-one (2.27 9, 10 mmol) and N-tert-Butoxycarbonyl-4-(methanesulfonyloxymethyl)piperidine (2.93 g, 10 mmol) according to the method described in Example 2(c). The crude product was subjecte~ to column u hl u" IdiuU~I d,Uh y (silica gel, ethyl acetate / hexane 3:7, Rf =
0.25) to give 38(a) (2.92 g, 69%) as a white solid.
The starting 10,11-dihyd,~ u[b,f][1,4]thiazepin-11-one was prepared according to JAQUES et aL [Helv. Chim. Acta 1959,1265].

-2l ~7 1 72 WO 96/0518~ J. .

- b) 4-[(10,11-Dihydrodibenzo[b,f][1,4]thiazepin~oxo-10-yl)methyl]
piperidine.
Removal of the tert-butyloxycarbonyl protecting group in 38(a) was performed with hydrogen chloride, as described in Example 2(d), to give 5 piperidine 38(b) hydrochloride in 84 ~/O yield as a white powder, m.p.: 248.2- 250.2 ~C.
The usual basic work-up produced free amine 38(b) in quantitative yield as an oil.
c) (R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihyd,u-libe,,~u[b,f]l1,4]thiazepin-11-oxo-10-ylmethyl)piperidin-1-yl]ethanol, fumarate.
Reacton of the (1-Adamantyl)ethylene oxide (0.470 9, 2.6 mmol) with piperidine 38(b) (0.860 9, 2.6 mmol) was conducted according to the method described in Example 11(b), but over 72 hrs. Column 1hlullldtuyld,uhy (silica gel, methylene chloride / methanol 9:1) gave ar,,i,,ualcuhol 38(c) (0.800 9, 61 ~/O) as a white solid, m.p.: 217-220~C. TLC: Rf = 0.2 (methylene chloride /
methanol 20:1).
The fumarate salt 38(c) was crystallized from ethanol, following usual procedure, in 72 ~/O yield as a white solid, m.p.: 207-209~C. MS: 337 (M-165).
Anal. Calc'd for C35 H42N206S: C,67.94; H,6.84; N,4.53. Found: C,67.73;
H,6.85; N,4.43.

(R,S)-1-(1-Adamantyl)-2-[4-(5,6,11,12-tetrahyd,udibe,,~[b,f]azocin-6-oxo-5-ylmethyl)piperidin-1-yl]ethanol, maleate.

a) N-tert-Butoxycarbonyl-4-[(5,6,11,12-tetrahydludil,en~[b,f]azocin-6-oxo-5-yl)methyl]piperidine.
Compound 39(a) was prepared from 5,6,11,12-tetrahydrodibenzo[b,f]azocin-6-one (5 9, 22 mmol) and N-tert-Butoxycarbonyl-4-(methanesulfonyloxymethyl)piperidine (6.0 9, 20 mmol) according to the method described in Example 2(c). The crude product was chlu~dtuyld~hed (silica gel, ethyl acetate / methylene chloride 1 :9) to produce 39(a) (7.8 g,9û~/O) as a white solid, m.p.: 122-124~C. TLC: Rf = 0.7 (ethyl acetate / methylene chloride 1 :9).

2I q7t 72 b) 4-[(5,6,11,12-tetrahy.l,u.liL,e,l~[b,f]azocin-6-oxo-5-yl)methyl]
piperidine.
Removal of the N-tert-butoxycarbonyl protecting group in 39(a) was performed with hydrogen chloride, as described in Example 2(d), to give 5 piperidine 39(b) hyd,uc,hluride as a white powdered solid, m.p.: 154-156~C.
The usual basic work-up afforded free amine 39(b) (49, 67%) as a white solid, m.p.: 114-116~C.

c) 5-[[1 -[2-(1 -Adamantyl)-2-oxoethyl]-4-piperidinyl]methyll -5,6,11,12-10 tetrahyd,udibe"~[b,f]azocin-6-one.
The piperidine 39(b) (3.9 9, 11.7 mmol) and 1-(bromoacetyl) addr"ar,l~ ,e (3.6 9, 14 mmol) were converted to bhe a" ,i, loh~lul ,e 39(c) (3.1 9, 53~/O) following the procedure 1(c). The pure product was obtained after column chromatography (silica gel, mebhylene chloride / ethyl acetate 1 :1) as a15 pale yellow oil. TLC: Rf = 0.15 (hexane / ethyl acetate 1 :1).

d) (R,S)-1-(1-Adamantyl)-2-[4-(5,6,11,12-tetrahydrodibenz[b,f]azocin-6-oxo-5-ylmethyl)piperidin-1-yl]ethanol, maleate.
A,,,inùhelun~ 39(c) (3 9, 6 mmol) was reduced according to 20 procedure 1 (d). Purificabon by column chromatography (silica gel, mebhanoVmethylene chloride 5:95) gave aminoalcohol 39(d) in quanbtabve yield as a white solid, m.p.: 162.5-164.4 ~C. TLC: Rf = 0.5 (mebhylene chloride / methanol 9:1).
The maleate salt 39(d) was crystallized from ethanol / diethyl ebher, in a usual25 way, in 81% yield as a white solid, m.p.: 224.5-225.5CC. MS: 333 (M-165). Anal.
Calc'd for C37H46N206 + û.25 H20: C,71.84; H,7.54; N,4.56. Found: C,71.80;
H,7.65; N,4.68.

(R,S)-1-(1-Adamantyl)-2-[4-(5,6,11,12-tetrahydrodibenz[b,f]azocin-5-ylmethyl)piperidin-1-yl]ethanol, fumarate.

a) N-tert-Butoxycarbonyl-4-[(5,6,11,12-tebrahydrodibenz[b,f]azocin-5-yl)methyl]piperidine.

2 I q7 ~ 72 Compound 40(a) was prepared from 5,6,11,12-tetrahydrodibenzo[b,f]azocine ( 3.81 9, 18 mmol) and N-tert-butoxycarbonyl-4-(methanesulfonyloxymethyl)piperidine (5.41 g, 20 mmol) according to the method described in Example 2(c). Column ~:hrv~aluyld~Jhy (silica gel, ethyl 5 acetate / methylene chloride 1 :9) gave 40(a) in 80 ~/O yield.

b) 4-[(5,6,11,12-tetrahydlvdiLJell~[b,f]azocin-5-yl)methyl]piperidine.
Removal of the te~-butoxycarbonyl protecting group in 40(a) was performed with hydrogen chloride, as described in Example 2(d), to give 10 piperidine 40(b) hy~lluvl ,lvri.le as an oil. The usual basic work-up furnished free amine 40(b) as a foam in 80 ~/O overall yield.

c) 5-[[1 -[2-(1 -Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]-5,6,11,12-tetrahydrodibenz[b,f]azocine.
The piperidine 40(b) (3.49 9, 11.4 mmol) was reacted with 1-(bromoacetyl)adamantane (3.2 9, 12.5 mmol) following the procedure 1(c).
Purification by column chromatography (silica gel, methylene chloride /
methanol 97:3) afforded i~" ~ ukulul ~e 40(c) (1.4 9, 25%) as an orange oil. TLC:
Rf = 0.3 (methylene chloride / methanol 97:3).
d)(R,S)-1-(1-Adamantyl)-2-[4-(5,6,11,12-tetrahyd,udiL,e,,~[b,f]azocin-5-ylmethyl)piperidin-1-yl]ethanol, fumarate.
Reduction of the a",i"okuLvlle 40(c) (1.36 9, 2.8 mmol), according to the method described in Example 1 (d), followed by column chromatography (silica gel, methylene chloride / ethyl acetate 5:1) gave ~",i"oalcohol (0.57 9,42%) as a white solid, m.p.: 153.7-154.8~C. TLC: Rf = 0.6 (methylene chloride/methanol 9:1).
Following the usual way, fumarate salt 40(d) was crystallized from ethanol in 52 ~/O yield as a white solid, m.p.: 182.0-183.4~C. MS: 319 (M-165). Anal. Calc'd for Cs7H4ON2Os + H20: C,71.82; H,8.14; N,4.53. Found: C,71.80; H,8 ~0; N, 4.46.

(R,S)- 1 -(1 -Adamantyl)-2-[4-(6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidin-1 -yl]ethanol S,S-dioxide, hyd,u~;hloricle.

_ . . . .. . _ .. . .. . . _ .. . .. _ . ... . _ WO 96/05185 2 1 ~ 7 1 7 2 PCT/JP95101600 a)N-tert-Butoxycarbonyl-4-[6-(6H-dibenzo[c,e][1,2]thiazin)methyl]-piperidine S,S-dioxide.
Compound 41(a) was prepared from 6-(6H-dibenzo[c,e]
[1,2]thiazine 5,5-dioxide (4.62 9, 20 mmol) and N-tert-Butoxycarbonyl-4-5 (methanesulfonyloxymethyl)piperidine (6.0 9, 20 mmol) according to themethod described in Example 2(c). Column chromatography (silicagel, ethyl acetate / hexane 3:7, TLC: Rf = 0.2) fumished 41(a) (5.21 9, 61%) as a white solid.
6-(6H-Dibenzo[c,e][1,2]thiazine 5,5-dioxide was prepared according to Ullmann 10 F., Grob C., Chem. Ber., 1910, 43, 2694.

b) 4-[6-(6H-Dibenzo[c,e][1,2]thiazin)methyl]piperidine S,S-dioxide.
Removal of the N-tert-butoxycarbonyl protecting group in 41(a) was performed with hydrogen chloride, as described in Example 2(d), to give 15 piperidine 41(b) hydrochloride in quantitative yield as a white solid, m.p.: 128-130~C.
After the usual basic work-up, the free amine 41 (b) was isolated in 92% yield as a solidified foam.

c) 6-[[1-[2-(1-Adamantyl)-2-oxoethyl]-4-piperidinyl]methyq-6H-diben [c,e][1,2]thiazine 5,5-dioxide.
Reaction of amine 41(b) (2.4 9, 7.4 mmol) with 1-(b~u~oac~tyl)adamantane (2.1 9, 8.1 mmol) was perfommed as described in Example 1(c). Column chrornatography (silicagel, methylene chloride / ethyl acetate 1 :1, TLC: Rf = 0.27) gave aminoketone 41(c) (2.7 9, 72%) as a white solidified foam.

d) (R,S~-l-(l-Adamantyl)-2-[4-(6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide, hyd~u1hloride.
Reduction of aminoketone 41 (c) (2.6 9,5.1 mmol), accord ing to the method described in Example 1(d), followed bycolumn chromatography (silicagel, methylene chloride / ethyl acetate 1:1) gave aminoalcohol 41(d) (1.8 9, 70~/O) as a solidified foam. TLC: Rf = 0.3 (ethyl acetate / methylene chloride 1~ H-NMR (CDCI3): 8.00 (m, 3H); 7.70 (t, 1 H); 7.55 (t,1 H); 7.45 (d, 1H); 7.35 (m,2H); 3.85 (d, 2 H); 3.15 (dd, 1H); 3.00 (bd, 1H); 2.7 (bd, 1H);
2.4-1.2 (m,24 H).
Following procedure 2(e), the title hydrochloride salt 41(d) was prepared in 2 1 ~7 t 72 62% yield as a white solid, m.p.: 242-244~C. Anal. Calc'd for C30H39CIN203S:
C,66.34; H,7.24; N,5.16; Cl,6.53. Found: C,66.21; H,7.24; N,5.10; Cl,6.69. MS:
341 (M-165).1H-NMR (CDCI3): 10.3 (bs,1H); 8.00 (m, 3H); 7.75 (m, 1H); 7.60-7.30 (m,4H); 4.00 (d,1 H); 3.65 (m,4H); 3.30 (bm,1 H); 3.0 (bm, 3H); 2.65 (bm, 5 2H); 2.2-1.4 (m, 19 H).

10 (+)-(S)-1-(1-Adamantyl)-2-[4-(6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide, hyd~vchlvride.

Reaction of (+)-(S)-(1-adamantyl)ethylene oxide (0.500 9, 2.8 mmol) with piperidine 41(b) (0.923 9, 2.8 mmol) was conducted according to the method 15 describedinExample 11(b),butover72hrs.Columnul,,ur,,dlv~u,,dpl,y(silicagel, methanol / methylene chloride 20:1) furnished a" ~i, ,oalcùhol 42 (1.13 9, 80%) as a solidified foam. [a]D2o= + 22.8~ (c 1.1, CHCI3). TLC: Rf = 0.3 (methanol /
methylene chloride 1:20). 1H-NMR (CDCI3): identcal to that of the racemic aminoalcohol 41 (d).
20 The hydrochloride salt 42 was prepared, according to the usual method 2(e), as a white solid, m.p.: 209.3-210.6~C. [a]D2o = + 12.5~ (c 0.7, CHCI3). 1 H-NMR
(CDCI3): identical to that of the h~dluclllol i.le 41 (d).
Anal. Calc'd for C30H39CIN2O3S: C,66.34; H,7.24; N,5.16; Cl,6.53. Found:
C,66.17; H,7.25; N,5.12; Cl,6.50.

(-)-(R)-1 -(1 -Adamantyl)-2-[4-(6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidin-30 1-yl]ethanol S,S-dioxide, hyd~v~,hlo~;de.

Reaction of the (-)-(R)-(1-adamantyl)ethylene oxide (0.500 9, 2.8 mmol) - with piperidine 41(b) (0.923 9, 2.8 mmol) was performed according to the procedure described in Example 11(b), but over 60 hrs. Purification by column 35 chromatography (silicagel, methanol / methylens chloride 20:1) afforded aminoalcohol 43 (0.970 9, 68%) as a solidified foam. [a]D20 = 27.4~ (c 1, _ , . . . _ . .. . . . _ _ ... . _ .. .. . . _ _ .

WO 96/05185 2 I q ~ T 7 2 PCT/JP95/01600 CHCI3). TLC: Rf = 0.3 (methanol / methylene chloride 1 :20).1 H-NMR (CDCI3):
identical to that of the a" ,i, lOdlCOI IUI 41 (d).
The hydrochloride salt 43 was prepared, according to the usual method 2(e), as a white hygroscopic solid, m.p. = 209-210 ~C. [a]D2o = - 15.3~ (c 1.1, 5 CHCI3) 1 H-NMR (CDCI3): identical to that of the hydl uul ,loride 41 (d).
Anal. Calc'd for C30H33N2O3S + HCI + 0.3 H2O: C,65.57; H,7.21; N,5.10;
Cl,6.47. Found: C,65.64; H,7.29; N,5.11; Cl,6.44.

(+)-(S)-6-[1 -[2-(1-Adamantyl)-2-l"ell,oxycthyl]piperidin-4-ylmethyl]-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide, hydrochloride.

The O-methylation of the (+)-S-aminoalcohol 42 (0.450 9, 0.89 mmol) was performed as described in Example 21. After column chromatography (silica gel, ethyl acetate / methylene chloride 2:3, TLC: Rf = 0.2), the title methyl ether 44 (û.200 9, 44~/O) was obtained as a white solidified foam . lH-NMR
(CDCI3): 8.00 (m, 3H); 7.70 (t, 1 H); 7.55 (t,1H); 7.45 (d, 1 H); 7.35 (m,2H); 3.85 (d,2 H); 3.4 (s,3H); 2.7-2.2 (m, 5H); 2.û-1.2 (m, 22 H).
The hydrochloride salt 44 was prepared according to the usual method 2(e) as a white foam. la]D2o = + 12.1 ~ (c 1, CHCI3). MS 341 (M-179).
Ana. Calc'd for C3,H40N203S + HCI + 1.3 H20: C,64.03; H,7.51; N,4.82;
Cl,6.11. Found: C,64.06; H,7.59; N,4.54; Cl,6.12.

(-)-(R)-6-[1 -[2-(l -Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-6H-30 dibenzo[c,e][1,2]thiazine 5,5-dioxide, hydluchlo,ide.

The O-methylation of (-)-R-aminoalcohol 43 (0.450 9, 0.89 mmol) was performed as described in Example 21. Cdumn ul,rul"dLuy,~hy (silicagel, ethyl acetate / methylene chloride 2:3, TLC: Rf = 0.2) afforded the title methyl35 ether 45 (0.170 9, 37~/O) as a white foam. lH-NMR (CDCI3): identical to that of methyl ether 44.

~ ~ 97 ~ 72 The hydrochloride salt 45 was prepared according to the usual method 2(e) as a foam. [a]D2o = - 15.0~ (c 1, CHCI3).
Anal. Calc'd for C3,H40N2O3S + HCI + 1.3 H20: C,64.03; H,7.51; N,4.82;
Cl,6.11. Found: C,63.85; H,7.48; N,4.74; Cl,6.31.

(R,S)-1 -(1 -Adamantyl)-2-[4-(8-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-10 piperidin-1-yl]ethanol S,S-dioxide, fumarate.

a) 8-Fluoro-6H-dibenzo[c,e][1,2]-thiazine 5,5-dioxide.
To a stirred solution of 3-fluoroaniline (11.11 9,100 mmol) in ethyl acetate (40 ml) and pyridine (8.2 ml,100 mmoi) was slowly added dropwise a 15 solubon of 2-nitrobenzenesuHonyl chloride (22.16 9,100 mmol) in ethyl acetate(60 ml). The mixture was stirred for 5 hours at room temperature and then heated at 80~C for 15 min. Aflter cooling, the reaction mixture was filtered andthe solid washed with ethyl acetate. The organic soluhon was washed with 2N
hydrochloric acid, then dried and evaporated. The residue was purified by 20 filbration through a silica pad (hexane / ethyl acetate 1 :1). Evaporabon of bhe solvent and recrystallization from toluene-hexane gave 2-nitrobenzenesuHon-3'-fluoroanilide (23.5 9, 79 ~/O) as pinky crystals, mp: 130.2-132 ~C.
To a solution of the above o-nitrobenzenesuHonamide (22.2 9, 75 mmol) in ebhyl acetate (200 ml) was added tin (Il) chloride dihydrate (84.5 9, 375 mmol) 25 and resulted mixture heated at 80~C for 2 hrs. After cooling, the reaction mixture was poured into water (400 ml), the solubon was basihed with 2N
sodium hydroxyde and extracted with ethyl acetate. Combined organic exbracts were dried and evaporated to give a waxy solid of 2-aminobenzenesulfon-3'-fluoroanilide (19.97 9, 100%) which was used in the next step withoutfurther 30 purification.
To a solubon of the above o-aminobenzenesulfonamide (10.65 9, 40 mmoi) in acetic acid (30 ml) was added conc~, lL~ ,d hydrochloric acid (60 ml). Then, on cooling below 10 ~C, a solubon of sodium nitrite (3.04 9, 44 mmol) in water (15 ml) was slowly added dropwise. The reaction mixture was vigorously shrred for 35 45 min., then diluted with water (50 ml), filtered and the filtrate heated at 100~C
for 45 min. After cooling, the mixture was extracted with ethyl acetate, combined organic exbracts were washed with water, dried and evaporated. Residual solid ,,, . _, ... ,,, . , .. , . , . , . , .,, .,, ... _ . ,, . ,, .. _, .. _ _ . , , . _, . . ., ... ... ,, . , . .,, .
, . , .. , ,,,, . _ _ 2 ~ ~7 ~ 72 WO 96/05185 PCT/JP95/01~00 was purified by filtration through a silica pad (hexane / ethyl acetate 1:2) andrecrystallized from ethanol / hexane yielding fluoro-suHam 46(a) (1.74 9, 18%) as an orange crystalline solid, m.p.: 205.8-206.8 ~C. TLC: Rf = 0.43 (hexane /
ethyl acetate 1:1).
1H-NMR (DMSO-D6): 11.67 (bs, 1H), 8.30 (dd, 1H-C1c); 8.22 (dd, 1H-C4); 7.96 (dd,1H-Cl);7.81 (dt,1H-C3);7.65(dt,1H-C2);7:18(dt,1H-Cs);7.00 (dd,1H-Cz).
The proton signals were assigned with the aid of H,H-COSY experiment.

b) 4-(8-Fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidine S,S-dioxide.
Starting from fluoro-sultam 46(a) and N-tert-butoxycarbonyl~
(metanesulfonyloxymethyl)piperidine and following the usual procedures described in Examples 2(c) and 2(d) the piperidine 46(b) hydrochloride was synthesized in 51% yield as a pinky hygroscopic solid.
Typicall basic work-up afforded free amine 46(b) as an oil.

c) (R,S)-1-(1-Adamantyl)-2-[4-(8-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide, fumarate.
Reaction of the (1-adamantyl)ethylene oxide (0.890 9, 5 mmol) with piperidine 46(b) (1.75 9, 5 mmol) was conducted accordinp to the method describedinExample 11(b),butover12hrs.Columncl".""dluy,d~,l,y(silicagel, methylene chloride / methanol 9:1, TLC: Rf = 0.54) furnished the title a",i"oalcollol 46(c) (0.75 9, 28%) as a white solid, m.p.: 247.2-247.8 ~C.
The fumarate salt 46(c) was crystallized frûm ethanol / diethyl ether, accordingto the usual procedure, as a white hygroscopic solid, m.p.: 138.7-140.2 ~C.
MS: 359 (M-165). Anal. Calc'd forC34H41FN2O7S + 1/2 H2O: C,62.77; H,6.46;
N,4.31. Found: C,62.65; H,6.65; N,4.31.

(R,S)-1-(1 -Adamantyl)-2-[4-(9-fluoro-6H-dibenzo[c,e][1 ,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide, h~dl~;lllu~lde.

a) 9-Fluoro-6H-dibenzo[c,e][1 ,2]thiazine 5,5-dioxide.
The title fluorû-sultam 47(a) was synthesized from 4-fluoroaniline following the sequence of reactions described in Example 46(a). Reaction with 2 ~ q~ ~ 7~

- 2~ ubu,,~endsulfonyl chloride gave 2-nitrobenzenesulfon-4'-fluoroanilide in 66% yield as a solid, m.p.: 104.7-105.9~C. Next, reducton of the nitro group provided crude 2-aminobenzenesulfon-4'-fluoroanilide in 88% yield. Finally, decomposition of diazonium salt and recry~ ,,liun from ethyl acetate /
5 hexane afforded fluoro-sultam 47(a) in 25% yield as an orange crystalline solid, m.p.: 214.7-215.7~C. TLC: Rf = 0.55 (ethyl acetate / hexane 1 :1).

b) 4-(9-Fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidine S,S-dioxide.
10Starting from fluoro-sultam 47(a) and N-ter~butoxycarbonyl-4-(methanesulfonyloxymethyl)piperidine and following the usual procedures described in Examples 2(c) and 2(d), the piperidine 47(b) hydlu~llloridt~ was obtained in 70 ~/O yield as a white solid, m.p.: 186-190~C.
Typicall basic work-up provided free amine 47(b) as an oil.
c) (R,S)-1-(1-Adamantyl)-2-[4-(9-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide, hyd~u~;hlodcle.
Reacffon of (1-adamantyl)ethylene oxide (1.33 9, 7.5 mmol) with piperidine 47(b) (2.6 9, 7.5 mmol) was conducted following the method 20 described in Example 11(b), but over 18 hrs. Purification by column chromatography (silica gel, methylene chloride / methanol 9:1, TLC: Rf = 0.56) fumished a" ,il loal~iuhol 47(c) (1.4 9, 35~/O) as a white solid, m.p. :198-199~C.
The hydrochloride salt 47(c) was prepared according to the usual procedure described in Example 2(e) as a white solid, m.p.: 214.5-216.5~C. MS: 359 (M-25 165). Anal. Calc'd for C30H38CIFN2O3S: C,64.21; H,6.83; N,4.99; Cl,6.32.Found: C,63.91; H,6.87; N,4.97;CI,6.36.

(R,S)-1 -(1 -Adamantyl)-2-[4-(7-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin- 1 -yl]ethanol S,S-dioxide, hy~l uuhlul idu.
a)7-Fluoro-6H-dibenzo[c,e][1,2]thiazine 'i,5-dioxide.

WO 96/05185 2 1 q 7 t 7 2 PCT/JP95/01~00 The title fluoro-sultam 48(a) was prepared from 2-fluoroaniline following the sequence of reactions described in Example 46(a). Reaction with 2-nitrobenzenesulfonyl chloride gave 2-nitrobenzenesulfon-2'-fluoroanilide in 54~~O yield as a pink solid, m.p.: 110.3-112.6 ~C. Next, reduction of the nitro 5 grwp provided cnude 2-d~ uuen~enesulfon-2'-fluoroanilide in 88% yield.
Finally, decu" llJû~iliul l of diazonium salt and recry~ from ethyl acetate ~ hexane (3:7) afforded fluorosultam 48(a) in 26% as an orange solid, m.p.:
206.0-210.3~C. TLC: Rf = 0.25 (ethyl acetate / hexane 3:7).

b) 4-(7-Fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidine S,S-dioxide.
Starting from fluoro-sultam 48(a) and N-tert-butoxycarbonyl-4-(methanesulfonyloxymethyl)piperidine and following procedures described in Examples 2(c) and 2(d), the piperidine 48(b) hydlu~,l,lulid~ was prepared in 72 ~/0 yield as a white solid. m.p.: > 250 ~C.
Usual basic work-up gave free amine 48(b) in quantitative yield as an oil.

c) (R,S)-1-(1-Adamantyl)-2-[4-(7-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide, hydlu~;hlolide.
Reaction of the (1-adamantyl)ethylene oxide (0.566 9, 3.2 mmol) piperidine 48(b) (1.1û 9, 3.2 mmol) was perfommed according to the method described in the Example 11(b), but over 67 hrs. Column chlu~lldluy~d~l~y (silica gel, methylene chioride / methanol 2û:1, TLC: Rf = 0.32) provided al ninoalcohol 48(c) (1.34 9, 80%) as a solidified foam.
The h!~d,u.~ uli.l~ sa~ 48(c) was prepared according to the procedure described in Example 2(e) as a white solid, m.p.: 228.2-230.1 ~C. MS: 359 (M-165). Anal. Calc'd for C30H38CIFN2O3S: C,64.21; H,6.83; N,4.99; Cl,6.32.
Found: C,63.96; H,6.94; N,4.83; Cl,6.40.

(R,S)-1 -(1 -Adamantyl)-2-[4-(8-chloro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide, hyd~u~,hlu~ide.
a) 8-Chloro-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide.
The title chloro-sultam 49(a) was synthesized from 3-ul ,lo, ual H ,e 2 ~ 9~ ~ ~2 following the sequence of reactions described in Example 46(a). Reacbon with 2-nitrobenzenesulfonyl chloride gave 2-nitrobenzenesulfon-3'-chloroanilide in 52% yield as a yellow powder, m.p.: 122-123~C. Next, reduction of the nitro group provided crude 2-aminobenzenesulphon-3'-chloroanilide in 6P/o yield.
Finally, decor"~,uailion of diazonium saH and recrystallization from mebhylene chloride / hexane afforded chloro-sultam 49(a) in 2P/o yield as a white crystallinesolid,m.p.:219-220~C.TLC:Rf=0.51 (ebhylacetate/hexane1:1).
1H-NMR (DMSO-D3): 11.6 (bs,1H), 8.13 (dd, 1H-C4); 8.12 (dd, 1H-C19); 7.95 (dd,1H-C1); 7.82 (dt, 1H-C8); 7.68 (dt,1H-C8); 7.35 (dd,1H-Cs); 7.21 (d,1H-C7).
b) 4-(8-Chloro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidine S,S-dioxide.
Starting from chloro-sultam 49(a) and N-tert-butoxycarbonyl-4 (mebhanesulfonyloxymebhyl)piperidine and following usual process described in the Examples 2(c) and 2(d), bhe piperidine 49(b) hydrochloride was prepared in 63 ~/O yield as a white solid, m.p.: > 250 ~C.
Usual basic work-up provided free amine 49(b) as an oil.

c) (R,S)-1-(1-atl~"d"~1)-2-[4(8-chloro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1 -yl]-ethanol S,S-dioxide.
Reacbon of (1-adamantyl)ebhylene oxide (0.5 9, 2.8 mmol) with piperidine 49(b) (1.016 9, 2.8 mmol) was conducted according to bhe mebhod described in bhe Example 11(b), but over 68 hrs. Purificabon by column .,hl ul ~ IdtVyl dphy (silica gel, methylene chloride / methanol 20: 1, TLC: Rf = 0.39) furnished the btle ~I,i,,~.!c~lol 49(c) (0.910 9, 60 ~/O) as a white solidiFied foam.
The hydrochloride saH 49(c) was prepared according to bhe procedure described in Example 2(d), as a white solid, m.p.: 176-177~C. MS: 375 (M-165).
Anal. Calc'd for C30H38CI2N2O3S + 2/3 H2O: C,61.01; H,6.66; N,4.74; Cl,12.03.
Found: C,61.03; H,6.98; N,4.62; Cl,12.16.

EXAMpLF 59 35 (R,S)-1-(1-Adamantyl)-2-[4-(8-methoxy-6H-dibenzo[c,e][1,2]bhiazin-6-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide, hydlu~:llloride.

.. . . .. .. . . .... . ... .. _ . . .. .. .

WO 96105185 2 1 9 7 1 ~7 ~ PCT/JP95101600 a) 8-Methoxy-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide.
The title methoxy-sultam 50(a) was prepared from 3-methoxy aniline following the sequence of reactions described in Example 46(a).
Reaction with 2-nitrobenzenesuKonyl chloride gave 2-llil,ubt:"~enesuHon-3'-5 methoxyanilide in 75~/O yield as a yellow powder, m.p. 105.5-106.6~C. Next, reduction of the nitro group produced crude 2-aminobenzenesulfon-3'-methoxyanilide in 97~/O yield. hnally, decomposi6On of diazonium salt and recry: ' " " n from ethyl acetate / hexane provided methoxy-sultam 50(a) in 2B ~/O yield as a white crystalline solid, m.p.: 168.9-170~C. TLC: Rf = 0.65 (ethyl 10 acetate hexane 1:1).
1H-NMR (DMSO-D6): 11.32 (bs,1 H), 8.13 (dd, 1 H-C4); 8.12 (dd, 1 H-C10); 7.88 (dd,1 H-C1); 7.77 (dt, 1 H-C3); 7.58 (dt,1 H-C2); 6.90 (dd,1 H-Cs); 6.71 (d,1 H-C7);
3.81 (s, 3H).

b) 4-(8-Methoxy-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidine S,S-dioxide.
Starting from methoxy-sultam 50(a) and N-tert-butoxycarbonyl~
(methanesulfonyloxymethyl), i~ ~ridi"e and following typicall procedures described In Examples 2(c) and 2(d), the title plperidine 50(b) hydrochlorlde was prepared In 86 ~/O yield as a whlte solld.
Usual basic work-up gave free piperldlne ~O(b) as a sllghtly yellow paste.

c) (R,S)-1 -(1-Adamantyl)-2-[4-(8-methoxy-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide, hy,l"Jcl,lo,i.ie.
Reaction of (1-adamantyl)ethylene oxide ( 0.890 9, 5 mmol) with piperidine 50(b) (1.9 9, 5.3 mmol) was conducted according to the method described in the Example 11(b), but over 48 hrs. Purification by column chromatography (silica gel, methylene chloride / methanol 9:1, TLC: Rf = 0.63) provided the title ~r"i~alcohd (1.36 9, 51 ~/O) as a pinky solid, m.p.: 193-1 g4~C.
The hydrochloride salt 50(c) was prepared following the usual procedure described in Example 2(d), as a white solid, m.p.: 216-219~C. MS: 371 (M-165) .
Anal. Calc'd for C3~H4~CIN2O4S + 2/3 H2O: C,63.58; H,7.23; N,4.79; Cl,6.07.
Found: C,63.72; H,7.32; N,4.76; Cl,6.15.

21 97 ~ 72 WO 96105185 PCr1JP95101G00 (R,S)-5-[4-[N-[2-(l-Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-5H-phelld, ltl " i.li"-6-one, hydrochloride.

The O-methylation of the aminoalcohol 10(e) (1.05 g, 2.3mmd) was performed following procedure described in the Example 21. Cdumn I;hl ul I IdlUyl dpl Iy (silica gel, methylene chloride / methanol 10:90, TLC: Rf = 0.2) provided the title methyl ether (0.400 9, 40~/O) as a viscous oil.
The hydrochloride saH was prepared according to the procedure described in Example 2(d), as a white hygroscopic foam.
MS: 293 (M-179). Anal. Calc'd for C3,H40N2O2 + 1.1 HCI + 1.5 H2O: C,68.98;
H,8.24; N,5.19; Cl,7.22. Found: C,69.14; H,8.30; N,5.20; Cl,7.17.

(R,S)- 1 -(1 -Adamantyl)-2-[N-methyl-N-[4-(10,11 -dihydl udiL,ellz[b,f][1,4]-oxazepin-11-oxo-10-yl)butyl]amino]ethanol, hy~llu-,lllo~idtl.

a)N-Methyl-N-4-[10-(10,11 -dihydrodibenz[b,f][1,4]oxazepin-11 -oxo)]
butylamine.
Reaction of 10,11 -dihydrodibenz[b,fl[1,4]oxa~pin-11 -one (4 22 9, 20 mmd) and mesylate of the aloohol 10(b) (5.6 9, 20 mmd) was performed according to procedure described in Example 10(c) and gave N-telt-bubxycarbonyl-N-methyl-N-4110-(10,11-dihydrodibenz[b,f][1,4]oxazepin-11-oxo)]butylamine (5~ 9,73~/O) as an oil. TLC: Rf = 0.3 (elhyl acetate /hexane 3:7).
Suhceql l~nt removal of N-Boc protecting group gave amine 52(a) hydrochloride as a white powder, m.p.: 182-184~C. Usual basic work-up provided free amine in 87 ~/O overall yield as a colorless oil.

b) 1-(1-Adamantyl)-2-[N-methyl-N-[4-(10,11-dihyd" "' n~[b,fl[1,4]-oxazepin-11 -oxo-10-yl)butyl]amino]methylketone.
Amine 52(a) (2.0 g, 6.7 mmol) and 1-(b~uuloac~tyl)addrl,d,~,e (1.85 g, 7.2 mmol) were reacted together, according to procedure described in WO 96/OS185 2 ' ~ 7 ~ 7 2 PCI/JP9S/01600 Example 1 (c), to produce aminoketone 51(b) (2.85 9, 90~~0) as an orange oil.
TLC: Rf = 0.6 (methanol / methylene chloride 1 :9).
c) 1~ Adamantyl)-2-[N-methyl-N-[4-(10,11-dihydrodibenz[b,f][1,4]-oxazepin-11 -oxo-10-yl)butyl]amino]ethanol, hy~ll u1hlol ide.
Reduction of d"li"okt,lu,e 52(b), according to the method described in Example 1 (d), gave the title ar~ ~i, ,odlcuhul 52(c) in 95~/O yield as an oil. TLC: Rf = 0.3 (methanol / methylene chloride 1 :9).
The hydrochloride salt 52(c) was prepared according to Example 2(e), but in methylene chloride / diethyl ether, as 2 white hygroscopic foam.
MS: 309 (M-165). Anal. Calc'd for C30H39CIN2O3+ 2/3 H2O: C,68.83; H,7.71;
N,5.29; Cl,6.79. Found: C,68.78; H,7.91 ;N, 5.35; Cl,6.96.

(R,S)-10-[4-[N-[2-(1 -Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-10,11 -dihydludibe,l~[b,f][1,4]oxazepin-11 -one, hydlu,,hlulide.

Reaction of aminoalcohol 52(c) with methanesulfonyl chloride, performed as described in Example 6(a) and followed by column ~,hlUI ll~.'Vyldph y (silica gel, hexane / ethyl acetate 7:3, TLC: Rf = 0.3), produced COIl~ )Olldill9 mesylate in 53~/O yield as a colorless viscous oil.
Methanolysis of the above mesylate was conducted as described in Example 9.
Purification by column uhru",aLuy,d~hy (silica gel, methylene chloride /
25 methanol 9: 1, TLC: Rf = 0.4) provided methyl ether 53 in 31 % yield as a foam.
The title methyl ether 53 hydrochloride was prepared according to the usual procedure described in Example 2(d), as a white hygroscopic foam.
MS: 309 (M-179). Anal. Calc'd for C31H4~CIN2O3+ H2O: C,68.55; H,7.98;
N,5.16; Cl,6.53. Found: C,68.52; H,8.05; N,5.21; Cl,6.53.

(R,S)-1 -(1 -Adamantyl)-2-[N-methyl-N-[4-(10,11 -dihy.ll udibel l~u~b,f][1,4]-35 thiazepin-11-oxo-10-yl)butyl]amino]ethanol, hydlu~hlolide.

a) N-Methyl-N-4-[ l O-( l O,11 -dihy.i I ud;uen~u[b,f][1,4]thiazepin-11-oxo)]

2 ~ t 7 2 - butylamine.

Reaction of 10,11 -dihydrodibenzo[b,f][1,4]thiazepin-11 -one (7.49 9, 33 mmol) and mesylate derivative of alcohol 10(b) (8.43 9, 30 mmol) was performed according to procedure described in Example 10(c) and gave N-tertbutoxycarbonyl-N-methyl-N-4-[10-(10,11-dih~/d~udibe~ù[b,f][1,4]-thiazepin-11-oxo)]butylamine (10.33 9, 83%) as an oil. TLC: Rf = 0.3 (ethyl acetate / hexane 3:7).
Next, removal of N-Boc protecting group gave amine 54(a) hydrochloride as a white powder. Usual basic work-up provided free amine 54(a) in 82% overall yield as a colorless oil.

b) 1-(1-Adamantyl)-2-[N-methyl-N-[4-(10,11-dihydrodibenzo- [b,f][1,4]-thiazepin-11 -oxo- 10-yl)butyl]amino]methylketone.
Amine 54(a) (6.3 9,20.5 mmol) and 1-(bromoacetyl) ad~"anl~n~:
(5.66 9, 2Z mmol) were reacted together, according to procedure described in Example 1 (c), to produce aminoketone 54(b) (9.67 9, 96%) as a yellowish oil.
TLC: Rf.= 0.7 (methanol / methylene chloride 1 :9).

c)(R,S)-1 -(1 -Adamantyl)-2-[N-methyl-N-[4-(10,11 -dihydrodibenzo-[b,f][1,4]-thiazepin-11-oxo-10-yl)butyl]amino]ethanol, hyLlluclllulicle.
Reduction of aminoketone 54(b), according to the method described in Example 1 (d), gave the title aminoalcohol 54(c) in 52% yield as an oil. TLC: Rf = 0.15 (methanol / methylene chloride 1 :12).
The h~/d~u~,llloride salt was prepared according to the procedure described in Example 2(e), but in methylene chloride / diethyl ether, as a white hygroscopic foam.
MS: 325 (M-165). Anal. Calc'd for C30H39CIN2O2S+ 2/3 H2O: C,66.79; H,7.48;
N,5.19; Cl,6.58. Found: C,66.91; H,7.78; N,5.06; Cl,6.66.

EXAMpl F 55 (R,S)-10-[4-[N-[2-(1-Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one, hydluclllolide.

Following the procedure described in Example 6(a), the mesylate WO 96/05185 2 1 9 7 t ~ 2 PCI'IJP9S/01~00 of aminoalcohol 54(c) was prepared in quantitative yield as a colorless viscous oil; TLC: Rf = 0.2 (hexane / ethyl acetate 7:3).
Methanolysis of the above mesylate was performed as described in the Example 9. Column ~;I ,ru ~ Idtu!Jl d~.hy (silica gel, methylene chloride / methanol 5 20:1, TLC: Rf = 0.3) fumished methyl ether 55 in 37~/O yield as a foam.
The title hydrochloride 55 was prepared according to the usual procedure described in Example 2(e), as a hygroscopic foam.
MS: 325 (M-180). Anal. Calc'd for C31H4lCIN2O2S+ 2/3 H2O: C,67.27; H,7.65;
N,5.06; Cl,6.42. Found: C,67.22; H,7.96; N,5.13; Cl,6.31.

21~t.7~

_ W 0 96/05185 PCT/JP95/OlGOO

PHARMACOLOGY

Some of the compounds of Formula I have been tested according to the 5 following methods.

SIGMA RECEI' I ORS BINDING ASSAY

The sigma 1 selecbve binding assay was performed using [3H]-(+) pentazocine (3 nM final, 35 Ci/mmol, New England Nuclear, Dupont de Nemours) as the radioligand according to bhe method described by D.L.
DeHaven-Hudkins, L.C. Fleissner and F.Y. Ford Rice (European Joumal of Pharmacology- MolecularPhil-",acology Secbon, 1992, 227, 371-378). Crude 15 P2 membrane fracbon was prepared from Guinea pig brain whole membrane preparations as described by E. Weber, M. Sonders, S. Quarum, S. Mc Lean, S. Pou and J. F. Keana (Proc. Natl. Acad. Sci. 1986, 83, 8784-8788).
Membrane fractions (0.4 ml) were allowed to incubate 150 min at 37 ~C in the presence of various concentrabons of the reference compound (Haloperidol 10~10to10-6M)orofthetestligand(10-10to10-5M)andthel~ d,ina f nal volume of 0.5 ml of 50 mM Tris-HCI, pH 7.4. Assays were terminated by rapid filtration through Whatman GF/B filters. Prior to use, filters were soaked in 0.5 ~/O polyethyleneimine for 1 hour. After filtrabon using a Brandell cell harvester, filters were washed four bmes wrth ice cold incubation buffer. Non specific binding was d~t~ ,i"ed using Haloperidol 1 IlM. The radioactivity on the filters was determined by ~.:il, " " 1 spectrometry using Fommula 989 (New England Nuclear, Dupont de Nemours) as scintillator liquid and a counter LS
6000 TA (Becmann). Competibon curves were analyzed with the curve fibing program Ligand (G.A. Mc Pherson, Computer Programs in Biomedicine, 1983, 17, 107). Ki and IC 50 values were calculated. Kd value for [3H]-(+) pentazocine was 3nM. Values are averages ~ SEM of three experiments, each carried out in duplicate.

The sigma 2 selecbve binding assay was performed using [3H]-Di-o-Tolyl-Guanidine (DTG) (1 nM final, 37 Ci/mmol, New England Nuclear, Dupont de Nemours) as the rdd;t'~ Id. Crude P2 membrane fracbon was prepared . _ . ... .. . . . . . .. . _ _ _ . . . . . .

WO 96/05185 2 ~ q ~ PCT/JP95/01600 from the livers of male Sprague-Dawley rats according to the meUhod described by X. He, W.D. Bowen, K.S. Lee, W. Williams, D.R. Weinberger and B.R. de Costa (J. Med. Chem. 1993, 36, 566-571). Membrane fractions (0.4 ml~ were allowed to incubate 2 hours at 25 ~C in the presence of 500 nM of pentazocine 5 and of various concentrations of the reference compound (Haloperidol 10-1 ~ to10-6 M) or of the test ligand (1 o-1 ~ to 1 0-5 M) and the radioligand, in a final volume of 0.5 ml of 50 mM Tris-HCI, pH 7.4. Assays were terminated by rapid filtraUon through Whatman GF/B filters. Prior to use, filters were soaked in 0.5 ~/0 polyethyleneimine for 1 hour. After filtration using a Brandell cell 10 harvester, filters were washed four times with ice cold incubation buffer. Non specific binding was determined using Haloperidol 1 ~LM. Scintillation counting and curve analysis were determined as previously described. Kd value for [3H]-DTG was p,~d~L~""i"ed and equal to 6.9 nM.

TABLEV: ~

Example Sigma1 Sigma2 S2/S1 ratio no Ki (nM + SEM) Ki (nM i SEM) Haloperidol 1.5 ~ 0.1 36 i 1 24 740i 116 10~1 0.01 2 40i6 5.8iO.7 0.14 3 957 i 65 45 i 7 0.05 4 230 i 58 2.4 i 0.4 0.01 1 900i351 4.8i 0.6 0.002 9 1 400 i 58 3.7 i 0.6 0.003 7 333 i 2000 7.2 i 0.5 0.001 11 1 933i203 19i8 0.01 19 153i15 1.7iO.5 0.01 240i15 1.4iO.2 0.01 21 167 i 17 6.6 i 0.8 0.04 22 154 i 79 2.9 i 0.8 0.02 23 380 i 137 3.6 i 0.8 0.01 2 1 97 ~ 72 - TABLE V: (continued) Example Sigma 1 Sigma2 S2/S1 ratio n~ Ki (nM i SEM) Ki (nM i SEM) 24 200 i 21 4.5 i 0.8 0.02 637i 126 4.5iO.2 0.01 26 615i74 25i5 0.04 27 16i5 2iO.5 0.12 28 1 197i257 30i10 0.02 29 370 i 47 4.5 i 0.7 0.01 1 107i110 6.3i1.9 0.01 31 1 613 i 387 4.6 i 2.0 0.003 32 753 i 37 4.9 i 1.3 0.01 33 1 097 i 211 1.5 i 0.2 0.001 34 1 767i219 1.6iO.5 0.001 1 173 i 474 2.9 i 0.7 0.002 36 2 600 i 351 2.2 i 0.5 0.001 37 300i105 3.7iO.6 0.01 38 2 533 i 674 4.2 i 0.7 0.002 39 250i 15 2.3iO.3 0.01 200i 15 6.9iO.4 0.03 41 913 i 67 0.85 i 0.16 0.001 42 1 150i161 1iO.2 0.001 43 923i 390 3 1 i 0.9 0.003 44 877 i 320 4.9 i 1.8 0.006 1 900 i 451 4.3 i 0.2 0.002 46 1 423i345 3.1 iO.5 0.002 47 957i225 4.1 i 0.3 0.004 48 210i46 2.5iO.3 0.01 49 4 200 i 2 300 4.6 i 1.2 0.001 1 290i274 3.2i 0.6 0.002 51 9833i1 102 6.2iO.8 0.001 52 3 900 i 1 300 10.7 i 1.3 0.003 53 2900i700 5.1 iO.9 0.002 54 2 100 i 500 17.0 i 4.6 0.008 7200i1900 9.9 iO.6 0.001 _ _ , ... . .. . . . .

2 1 ~7 ~ 72 WO 96/0518~ PCT/JP95/01600 The binding data presented in the above table, based on at least 3 d~L~I ~ "i"dLiuns, show that the molecules of the present inven6cn are mode ratly to highly potent sigma 2 ligands and that they show a high selectivity for this 5 site.

The binding of these compounds to dopaminergic receptors was measured according to the method described by M. Terai, K. Hidaka and Y. Nakamura 10 [Eur. J. Pharmacol. 1989, 173, 177] using rat striata. The af~inity of these compounds towards serotoninergic 5-HT2 receptors was also evaluated following the method described by J.E. Leysen, C.J.E. Niemegeers, J.M. Van Nueten and P.M. Laduron [Molecular Pharmacology 1982, 21, 301-314] using rat frontal cortex. Results are presented in Table Vl:

T~RI F Vl:

ExampleDopamine D2 5-HT2 n~ IC50 (nM) IC50 (nM) ~ 10 000 6 200 2 > 10 000 2 500 3 > 10 000 > 10 000 > 10 000 6 000 9 > 10 000 7 000 >10000 5100 11 > 10 000 3 200 19 > 10 000 940 2 ~ q7 t ~72 T~RI F Vl: (continued) ExampleDopamine D2 5-HT2 n~ IC50 (nM) IC50 (nM) 46 ~ 10 000 300 51 ~ 10 000 8 200 52 ~ 10 000 1 700 53 ~ 10 000 1 500 54 ~ 10 000 4 600 ~ 10 000 6 900 Additionally, some compounds of the invention were tested on alpha 1 5 adrenergic, beta 1 and 2 adrenergic, D1, 5-HT1, 5-HT1A, 5-HT3 and _ . . , . ... .. .. . . . . . .. . .. . .. _ _ _ _ _ . . . . .

2~ ~7 ~ 72 WO 96105185 PCT/IP95101~00 phencyclidine receptors. For most compounds, the selectivity was very high:
IC50 X/ IC50 Sigma 2 > 100. X: D1, D2, 5-HT1, 5-HT1 A, 5-HT2, 5-HT3, alpha1 adrenergic, beta 1 and 2 adrenergic and phencyclidine receptors.

IN VIVO PHARMACOLOGY

10 The psychotropic properties of the compounds have been determined by some standard tests exploring dopaminergic, serotonergic and glutamatergic mechanisms, which are all involved in s~:hi~o~,l " ~"ic pdU ,oge, lid.

15 Mescaline induced scratching in Mice This is a modification of the method of Cook L., Tam S.W. and Rohrbach K.W.
[J. Pharmacol. Exp.Ther. 1992, 263, 1169-1166]. In mice, compounds (10 animals /dose) were adl"i"i~ ,t,d per os 6û min before 10 mg/kg i.p. of 20 Mescaline. 10 minutes after the challenge, mice were observed during a 10 minperiod and the number of scratching were counted. The ED50 was defined as the dose of the test compound that protected 50 ~/O of the scratching number.

TABLE \/II: _ EXAMPLE Mouse d"U, 1 . s s - ' ,e ED50 n~ (mglkg, per os) 0.3 4 0.2 2 ~ 97 t 72 Table Vll shows that compounds of the invention strongly antagonize the scratching behavior in mice. In this tests, these compounds had excellent oral psychotropic activity.

TOXICITY

The study of the toxicity of the products of the invention was determined on 10 mice byoral adl~,ini~llr~liul1 bythe approximate determination of their LD 50. It has been observed that the products of the invention generally had an acute toxicity or LD 50 greater than 1 000 mg/Kg. No cataleptic eflect was observed with these compounds.

FORMULATION EXAMPLES

20 . The pharmaceutical formulations of the invention may be prepared by conventional methods in the art.

Typical examples of recipes for the fommulation of the invenUon are as follows:
~5 1 ) Tablets:
Compound of the example 2 5 to 50 mg DiCalcium IJho~lldlu 20 mg Lactose 30 mg Talcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg in this example, the compound 2 can be replaced by the same amount of any of the described examples 1 to 55.

2 1 97 t 72 2) Suspension:
An aqueous suspension is prepared for oral admi~ b~tiu11 so 6hat each 1 milliliter contains 1 to 5 mg of one of 6he described example, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol 5 and water ad 1 ml.

3) Injectable:
A parenteral composition is prepared by s6rring 1.5 ~/0 by weight of active ingredient in 10 ~/0 by volume propylene glycol and water.
0 4) Ointment:
Compound of the example 2 5 to 1000 mg Stearyl alcohol 3 9 Lanoline 5 9 White petroleum 15 9 Water ad 100 9 in this example, the compound 2 can be replaced by the same amount of any of the described examples 1 to 55.

Reasonable vafia60ns are not to be regarded as a departure from the 20 scope of the inven60n. It will be obvious that the thus described invention may be varied in many ways by those skilled in the art.

Industrial A
The compounds of the present inven60n exhibit a high selec6vity and high afflnity for sigma 2 receptor and therefore are useful in the treatment of central nervous system disorders as well as other disorders modulated by this receptor.

Claims (15)

1. A compound which conforms to the general formula l:

When X represents cycloalkylalkyl or adamantyl, Y represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, adamantyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, each of the said substituents being independently selected from halo, nitro, cycloalkyl, alkenyl,alkyl optionally substituted with one to three fluorine atoms, hydroxy, alkoxy optionally substituted with one to three fluorine atoms, phenyl, amino, alkylamino, carbamoyl, sulfamoyl, carboxyalkyl, cyano or alkynyl;

When X represents cycloalkyl, Y represents hydrogen, alkyl, alkenyl or cycloalkyl;

A represents the group -O- R9 in which R9 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl, arylalkyl, hydroxyalkyl, carboxyalkyl or carboxyaryl;

or A represents the group R10 and R11 represent independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyalkyl, carboxyalkyl, haloalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; each of the said aryl and heteroaryl groups may optionally be substituted with one or more substituents, each of the said substituents being independently selected from halo, nitro, cycloalkyl, alkenyl,alkyl optionally substituted with from one to three fluorine atoms, hydroxy, alkoxy optionally substituted with one to three fluorine atoms, phenyl, amino, alkylamino, carboxy, carbamoyl, sulfamoyl, carboxyalkyl, cyano or alkynyl;

R10 and R11 taken together may form a ring corresponding to the formula:

-(CH2)m-D-(CH2)m-where D represents a single bond, oxygen, sulfur or a nitrogen atom substituted by hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkylalkyl, aryl or arylalkyl;
m is a number selected from 1 to 3;

R10 and R11 taken together with the nitrogen atom may form a 3-10-atom unsaturated heterocyclic ring which optionally contains 1 to 4 further heteroatom selected from oxygen, nitrogen and sulfur; such heterocyclic group may optionally be substituted with one or more substituents, each of the said substituents being independently selected from halo, nitro, cycloalkyl, alkenyl,alkyl optionally substituted with one to three fluorine atoms, hydroxy, alkoxy optionally substituted with one to three fluorine atoms, phenyl, amino, alkylamino, carbamoyl, sulfamoyl, carboxy, carboxyalkyl, cyano or alkynyl;
or Y and A taken together may form oxo or hydroxyimino;

R1 and R2 which may be the same or different, are hydrogen, alkyl, cycloalkyl, hydroxyalkyl or alkenyl;
R3 represents alkyl, cycloalkyl, hydroxyalkyl or alkenyl;

R4 represents the group -(CH2)p-B where p is a number selected from 3 to 8;

or R3 and R4 together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (II):

where R5 and R6 represent independently hydrogen or alkyl;

or R5 and R6 together with the intervening atom represent a 5 to 7 heterocyclic ring;
B is a heteroaryl group of formula , , , , , , , , , , or R7 and R8 are independently selected from hydrogen, halo, nitro, cycloalkyl, alkenyl, alkyl optionally substituted with one to three fluorine atoms, hydroxy, alkoxy optionally substituted with one to three fluorine atoms, phenyl,amino, alkylamino, carbamoyl, sulfamoyl, carboxyalkyl, cyano or alkynyl;

R12 is selected from hydrogen or alkyl;

X' represents a single bond, -CH2-, -CH=CH-, -CH2-CH2-, S, -S-CH2-, -S(O)-, -S(O)2-, -S(O)-CH2-, -S(O)2-CH2-, O,-O-CH2-, N(R13),-N(R13)-CH2-, -N(R13)-S(O)2-, C(=O), -C(=O)-CH2-, -C(=O)-O- or -C(=O)-N(R13)-;

Y' represents -CH2- or C(=O);

W and W' represent independently a benzene ring or heteroaryl group of 5 to 7 atoms which contains one oxygen atom, one sulfer atom or one or two nitrogen atoms, provided that at least one of W and W' is heteroaryl group.

R13 represents hydrogen or alkyl.;

or a pharmaceutically acceptable salt, hydrates or solvates of such compounds.
2. A compound according to claim 1 wherein:

When X represents C3-C6 cycloalkyl-C1-C3-alkyl or adamantyl, Y
represents hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3-alkyl, adamantyl, aryl selected from phenyl and naphthyl, aryl-C1-C3-alkyl; wherein each of said aryl group may optionally be substituted with one to three substituents, each of the said substituents being independently selected from halo, nitro, C3-C6 cycloalkyl, C3-C6 alkenyl, C1-C6 alkyl optionally substituted with one to three fluorine atoms, hydroxy, C1-C6 alkoxy optionally substituted with one to three fluorine atoms, phenyl, amino, C1-C6 alkylamino, carbamoyl, sulfamoyl, carboxy-C1-C6-alkyl, cyano or C3-C6 alkynyl;

When X represents C3-C6 cycloalkyl, Y represents hydrogen, C1-C6 alkyl, C3-C6 alkenyl or C3-C6 cycloalkyl;

A represents the group -O-R9 in which R9 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3-alkyl, C3-C6 alkenyl, phenyl, phenyl-C1-C3-alkyl, hydroxy-C2-C6-alkyl, carboxy-C1-C3-alkyl or carboxyphenyl;

or A represents the group R10 and R11 represent independently hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, phenyl or phenyl-C1-C3-alkyl; phenyl group may optionally be substituted with one to three substituents, each of the said substituents being independently selected from halo, nitro, C1-C6 alkyl, hydroxy, amino, carboxy or cyano;

R10 and R11 taken together may form a ring corresponding to the formula:

-(CH2)m-D-(CH2)m-where D represents a single bond, oxygen, sulfur or a nitrogen atom substituted by hydrogen or C1-C6 alkyl;
m is a number selected from 1 to 3;
or Y and A taken together may form oxo or hydroxyimino;

R1 and R2 which may be the same or different, are hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, hydroxy-C2-C3 alkyl or C3-C6 alkenyl.

R3 represents C1-C3 alkyl, C3-C6 cycloalkyl, hydroxy-C2-C3-alkyl or C3-C6-alkenyl;

R4 represents the group -(CH2)p-B where p is a number selected from 3 to 6;
or R3 and R4 together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (II):

where R5 and R6 represent independently hydrogen or C1-C3 alkyl;

B is a heteroaryl group of formula , , , , , , , , , , , or R7 and R8 are independently selected from hydrogen, halo, nitro, C1-C6 alkyl optionally substituted with one to three fluorine atoms, hydroxy or C1-C6 alkoxy optionally substituted with one to three fluorine atoms;

R12 is selected from hydrogen or C1-C6 alkyl;

X' represents a single bond, -CH2-, -CH=CH-, -CH2-CH2-, S, -S-CH2-, -S(O)-, -S(O)2-,-S(O)-CH2-, -S(O)2-CH2-, O,-O-CH2-, N(R13),-N(R13)-CH2-, -N(R13)-S(O)2-, C(=O), -C(=O)-CH2-, -C(=O)-O- or -C(=O)-N(R13)-;

Y' represents -CH2- or C(=O);

W and W' represent independently a benzene ring or heteroaryl group of 5 to 7 atoms which contains one oxygen atom, one suffer atom or one or two nitrogen atoms, provided that at least one of W and W' is heteroaryl group;

R13 represents hydrogen or C1-C6 alkyl;

or a pharmaceutically acceptable salt, hydrates or solvates of such compounds.
3.A compound according to claim 1 or 2 wherein When X represents C3-C6 cycloalkyl-C1-C3-alkyl, adamantyl or C3-C6 cycloalkyl, Y represents hydrogen, C1-C6 alkyl, C3-C6 alkenyl or C3-C6 cycloalkyl.;

A represents the group -O-R9 in which R9 represents hydrogen, C1-C4 alkyl, C3-C6 alkenyl or hydroxy-C2-C4-alkyl;

or Y and A taken together may form oxo or hydroxyimino;

R1 and R2 which may be the same or different, are hydrogen or C1-C3 alkyl;
R3 represents C1-C3 alkyl or C3-C6 alkenyl;

R4 represents the group -(CH2)p-B where p is a number selected from 3 to 6;
or R3 and R4 together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (II):

where R5 and R6 represent hydrogen or methyl;

B is a heteroaryl group of formula , , , , , , , , , , , or .

R7 and R8 are independently selected from hydrogen, halo, nitro, C1-C6 alkyl optionally substituted with one to three fluorine atoms, hydroxy or C1-C6 alkoxy optionally substituted with one to three fluorine atoms;

R12 is selected from hydrogen or C1-C6 alkyl;

X' represents a single bond, -CH2-, -CH=CH-, -CH2-CH2-, S, -S-CH2-, - S(O)-, -S(O)2-, -S(O)-CH2-, -S(O)2-CH2-, O, -O-CH2-, N(R13), -N(R13)-CH2-, - N(R13)-S(O)2-, C(=O), -C(=O)-CH2-, -C(=O)-O- or -C(=O)-N(R13)-;

Y' represents -CH2- or C(=O);

W and W' represent independently a benzene ring or heteroaryl group of 5 to 7 atoms which contains one oxygen atom, one sulfer atom or one or two nitrogen atoms, provided that at least one of W and W' is heteroaryl group;

R13 represents hydrogen or C1-C6 alkyl;

or a pharmaceutically acceptable salt, hydrates or solvates of such compounds.
4. A compound according to claim 1 or 2 wherein When X represents C3-C6 cycloalkyl-C1-C3-alkyl, adamantyl or C3-C6 cycloalkyl, Y represents hydrogen, C1-C6 alkyl, C3-C6 alkenyl or C3-C6 cycloalkyl.;

A represents amino, C1-C3 alkylamino, phenyl-C1-C3-alkylamino, C3-C6 alkenylamino, C2-C6 dialkylamino, C4-C5 cycloalkylamino, C4-C7 alkylalkenylamino, piperidino, piperazino, C1-C3 alkylpiperazino or morpholino;

R1 and R2 which may be the same or different, are hydrogen or C1-C3 alkyl;

R3 represents C1-C3 alkyl or C3-C6 alkenyl;

R4 represents the group -(CH2)p-B where p is a number selected from 3 to 6;

or R3 and R4 together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (II):

where R5 and R6 represent hydrogen or methyl;
B is a heteroaryl group of formula , , , , , , , , , , , or .

R7 and R8 are independently selected from hydrogen, halo, nitro, C1-C6 alkyl optionally substituted with one to three fluorine atoms, hydroxy or C1-C6 alkoxy optionally substituted with with one to three fluorine atoms;

R12 is selected from hydrogen or C1-C6 alkyl;
X' represents a single bond, -CH2-, -CH=CH-, -CH2-CH2-, S, -S-CH2-, - S(O)-, -S(O)2-, -S(O)-CH2-, -S(O)2-CH2-, O, -O-CH2-, N(R13), -N(R13)-CH2-, - N(R13)-S(O)2-, C(=O), -C(=O)-CH2-, -C(=O)-O- or -C(=O)-N(R13)-;

Y' represents -CH2- or C(=O);

W and W' represent independently a benzene ring or heteroaryl group of 5 to 7 atoms which contains one oxygen atom, one sulfer atom or one or two nitrogen atoms, provided that at least one of W and W' is heteroaryl group;

R13 represents hydrogen or C1-C6 alkyl;

or a pharmaceutically acceptable salt, hydrates or solvates of such compounds.
5. A compound according to claim 1, 2, 3 or 4 which can exist as optical isomers, wherein said compounds are both the racemic mixture or the individual optical isomers.
6. A compound according to claims 1 to 5, wherein said compound is selected from:

(R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(2H-naphth[1,8-cd]isothiazol-2-yl)butyl]amino]ethanol S,S-dioxide;

(R,S)-2-[[1-[2-(1-Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]-2H-naphth[1,8-cd]isothiazole 1,1-dioxide;

(R,S)-2-[[1-[2-(l-Adamantyl)-2-oximinoethyl]-4-piperidinyl]methyl]-2H-naphth[1,8-cd]isothiazole 1,1-dioxide;

(R,S)-1-(1-Adamantyl)-2-[4-(2H-naphth[1,8-cd]isothiazol-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide;

(R,S)-1-(1-Adamantyl)-2-[4-(9-carbazolyl)methylpiperidin-1-yl]ethanol;

(R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(2H-naphth[1,8-cd]isothiazol-2-yl)butyl]amino]ethylamine S,S-dioxide;

(R,S)-1-(1-Adamantyl)-N-methyl-2-[N-methyl-N-[4-(2H-naphth[1,8-cd]isothiazol-2-yl)butyl]amino]ethylamine S,S-dioxide;

(R,S)-2-(1-Adamantyl)-N-methyl-N-[4-(2H-naphth[1,8-cd]isothiazol-2-yl)butyl]-2-pyrrolidin-1-ylethylamine S,S-dioxide;

(R,S)-2-[4-[N-[2-(1-Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-2H-naphth[1,8-cd]isothiazol 1,1-dioxide;

(R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[5H-phenanthridin-6-oxo-5-yl]butyl]-amino]ethanol;

(R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(6H-dibenzo[ce][1,2]thiazin-6-yl)butyl]amino]ethanol S,S-dioxide;

(R,S)-1-(1-Adamantyl)-2-[4-(2H-naphth[1,8-cd]isothiazol-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide;

(R,S)-1-(1-Adamantyl)-N-methyl-2-[4-(2H-naphth[1,8-cd]isothiazol-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide;

(R,S)-2-[1-[2-(1-Adamantyl)-2-morpholin-4-ylethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-cd]isothiazole 1,1-dioxide;

(R,S)-2-[1-[2-(1-Adamantyl)-2-pyrrolidin-1-ylethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-cd]isothiazole 1,1-dioxide;

(R,S)-2-[1-[2-(1-Adamantyl)-2-(4-methyl)piperazin-1-ylethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-cd]isothiazole 1,1-dioxide;

(R,S)-1-(1-Adamantyl)-N,N-diethyl-2-[4-(2H-naphth[1,8-cd]isothiazol-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide;

(R,S)-1-(1-Adamantyl)-N-allyl-N-methyl-2-[4-(2H-naphth[1,8-cd]isothiazol-2-ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide;

(R,S)-2-[1-[2-(1-Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-cd]isothiazole 1,1-dioxide;

(R,S)-2-[1-[2-(1-Adamantyl)-2-ethoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1,8-cd]isothiazole 1,1-dioxide;

(R,S)-1-(1-Adamantyl)-1-methyl-2-[4-(2H-naphth[1-8-cd]isothiazol-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide;

(R,S)-1-Cyclohexyl-2-[4-(2H-naphth[1,8-cd]isothiazol-2-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide;

(R,S)-1-(1-Adamantyl)-2-[4-(2-chlorophenothiazin-10-ylmethyl)piperidin-1-yl]-ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(phenothiazin-10-ylmethyl)piperidin-1-yl]ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(phenoxazin-10-ylmethyl)piperidin-1-yl]ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(5H-dibenz[b,f]azepin-5-ylmethyl)piperidin-1-yl]
ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihydro-5H-dibenz[b,f]azepin-5-ylmethyl)-piperidin-1-yl]ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(5H-phenanthridin-6-oxo-5-ylmethyl)piperidin-1-yl]
ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihydrodibenz[b,f][1,4]oxazepin-11-oxo-10-ylmethyl)piperidin-1-yl]ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihydrodibenzo[b,e][1,4]diazepin-11-oxo-10-ylmethyl)piperidin-1-yl]ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-oxo-10-ylmethyl)piperidin-1-yl]ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(5,6,11,12-tetrahydrodibenz[b,f]azocin-6-oxo-5-ylmethyl)piperidin-1-yl]ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(5,6,11,12-tetrahydrodibenz[b,f]azocin-5-ylmethyl)piperidin-1-yl]ethanol;

(R,S)-1-(1-Adamantyl)-2-[4-(6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)piperidin-1-yl]ethanol S,S-dioxide;

(S)-6-[1-[2-(1-Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide;

(R)-6-[1-[2-(1-Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide;

(R,S)-1-(1-Adamantyl)-2-[4-(7-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide;

(R,S)-1-(1-Adamantyl)-2-[4-(8-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide;

(R,S)-1-(1-Adamantyl)-2-[4-(9-fluoro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide;

(R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(10,11-dihydrodibenz[b,f][1,4]-oxazepin-11-oxo-10-yl)butyl]amino]ethanol;

(R,S)-10-[4-[N-[2-(1-Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-10,11-dihydrodibenz[b,f][1,4]oxazepin-11-one;

(R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(10,11-dihydrodibenzo[b,f][1,4]-thiazepin-11-oxo-10-yl)butyl]amino]ethanol;

(R,S)-10-[4-[N-[2-(1-Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one;

(R,S)-5-[4-[N-[2-(1-Adamantyl)-2-methoxyethyl]-N-methylamino]butyl]-5H-phenanthridin-6-one;

(R,S)-1-(1-Adamantyl)-2-[4-(8-chloro-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide;

(R,S)-1-(1-Adamantyl)-2-[4-(8-methoxy-6H-dibenzo[c,e][1,2]thiazin-6-ylmethyl)-piperidin-1-yl]ethanol S,S-dioxide.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1 to 6 and pharmaceutically acceptable carriers and/or excipients.
8. A method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of sigma 2 ligands, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound according to claims 1 to 6.
9. A method useful for treating or preventing central nervous system disorders and cardiovascular disorders selected from the group consisting of: anxiety, depression or dysthymic disorders, psychosis, pain, dyskinesia, ischaemia-induced brain disorders, convulsions, stroke, epilepsy, dementia, parkinsonism, neuropathological disorders, memory impairment, hypertension, arrhythmia and angina, comprising administering an effective amount of a compound according to claims 1 to 6.
10. A method according to claim 8, wherein the sigma 2 receptor ligand has an inhibition constant Ki for sigma 2 receptor of at least 50 nM and has at least a 5 fold greater affinity for sigma 2 receptor relative to sigma 1 receptor and to dopaminergic, serotonin, PCP and adrenergic receptors.
11. The method according to claims 8 to 10 wherein the disease is psychosis.
12. The method according to claims 8 to 10 wherein the disease is anxiety.
13. A method of treating amphetamine abuse or addiction in a mammal, comprising administering to a mammal in need of such treatment, an effective amount of a compound according to claims 1 to 6.
14. The method according to claims 8 to 10 wherein the disease is ischaemia-induced brain disorders.
15. A method according to claims 8 to 10 wherein the disease is a cardiovascular disease like hypertension arrhythmia or angina.
CA002197172A 1994-08-16 1995-08-10 Novel alkylamino derivatives as sigma 2 selective ligands Abandoned CA2197172A1 (en)

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GB9416571.9 1994-08-16

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EP1297175A4 (en) * 2000-06-30 2005-02-02 Univ California Methods and compounds for modulating nuclear receptor coactivator binding
MXPA04005999A (en) * 2001-12-21 2005-07-13 Taisho Pharma Co Ltd Piperazine derivative.
WO2004110388A2 (en) * 2003-06-12 2004-12-23 Agy Therapeutics, Inc. Sigma ligands for neuronal regeneration and functional recovery
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
PL2739285T3 (en) 2011-08-02 2019-07-31 Helmholtz Zentrum München Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh) Selective inhibition of malt1 protease by phenothiazine derivatives
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WO1996005185A1 (en) 1996-02-22
CN1164856A (en) 1997-11-12

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