DESCRIPTION

NOVEL ALKYLAMINO DERIVATIVES AS SIGMA 2 SELECTIVE LIGANDS

Technical Field

The present invention relates to novel alkylamino derivatives, pharmaceutical 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 pharmaceutically active compounds of this invention are highly selective and high affinity sigma 2 ligands.

Background Art

The recently identified brain sigma receptors/binding sites are potential targets for development of antjpsychotic 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, Pharmacological Reviews, 1990, 42, 355-402; G. Debonnel, J.

Psychiatr. Neurosci., 1993, 18, 4, 157-172]. The term "receptor" as used 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 classification 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. Tarn and D.P. Taylor, TiPS, 1992, 13, 85-86].

Sigma 1 binding sites are characterized by high affinity for haloperidol, Di-o- Tolyl Guanidine (DTG) and (+) benzomorphans such as (+) pentazocine. Sigma 2 binding sites are characterized by high affinity for haloperidol and DTG but low affinity for the (+) benzomorphans. Sigma 1 ligands have shown gastro-intestinal effects ; moreover, sigma 1 sites appear to mediate the inhibition by sigma ligands of the muscarinic acetylcholine receptor

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 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, LA. Paul and B. DeCosta, Eur. J. Pharmacol. Mol. Pharm. 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. Weissmann 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 pH] 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 association of sigma 2 binding sites with cortical 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. 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. Christoffersen, K.A. Serpa, T.A. Pugsley, A. Razmpour and T.G. Heffner, Neuropharmacology, 1992, 31 , 9, 961 -967].The clinically effective dopaminergic antipsychotic haloperidol shows a high affinity to the 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, distribution and function of sigma 2 binding sites has been hampered by the lack of selective agents.

Few agents bind with 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 selectivity for sigma 2 sites but it binds also to polyamine and alpha-1 receptors [K. Hashimoto, C.R. Mantione, M.R. Spada, J.L. Neumayer and E.D. London, Eur. J. Pharmacol. Mol. Pharm. Sect, 1994, 266, 66-77]. pH] BIMU has been proposed as a selective 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 selectivity 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 their sigma 1/ sigma 2 selectivity; three compounds present an interesting sigma 2 selectivity, they belong to the 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, abstract 763.16], but no data on their sigma selectivity has been shown and they also bind to alpha 1 receptor with a moderate to high affinity. The 5, 6, 7, 8, 9, 10-hexahydro-7,10-iminocyclohept[b]indoles have been identified as selective sigma 2 ligands [R.E. Mewshaw, R.G. Sherrill, R.M. Mathew, C. Kaiser, M.A. Bailey and E.W. Karbon, J. Med. Chem., 1993, 36, 343-352] with moderate to high affinity. A new approach to sigma 2 ligands has been recently disclosed: the polyamino sigma ligands described were moderatly potent and selective for sigma 2 site [B.R. DeCosta, X.S. He, C. Dominguez, J. Cutts, W. Williams and W.D. Bowen, J. Med. Chem., 1994, 37, 314-321].

Extensive literature exists relating to heteroaryl alkylamino derivatives; however there is very little data concerning heteroaryl groups like the naphtosultam ring. EP 546388 discloses heteroaryl methyl piperidino derivatives of chromanes, without examples of naphtosultam compounds. Alkylamino naphtosultam derivatives are described with examples in EP 352613, these compounds are claimed as 5-HT1 A ligands. EP 350403, EP

429341 and WO 91/16323 disclose series of naphtosultam derivatives as 5- HT2 antagonists and 5-HT reuptake inhibitors.

The present invention relates to a substituted (preferentially adamantyl, cycloalkyl)hydroxy-amino and diamino derivatives. Numerous phenyl ethanolamino derivatives exhibit important pharmaceuticals properties [Pharmaceutical Chemistry Vol. 1 : drug synthesis, H.J. Roth, A. Kleemann and T. Beisswenger, Ellis Horwood limited, Chichester England, 37-69]. For example, benzyl-piperidino derivatives like Ifenprodil and its derivatives belong to this class and are known to interact with sigma, adrenergic and glutamatergic 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, 3085-3090]. Surprisingly, the cycloalkyi and adamantyl ethanolamino derivatives of the present invention show a completely different and selective binding profile. EP 518 216 discloses certain N-[arylethyl]-N-alkyl-2-(1 -pyrrolidinyl)ethylamine compounds for CNS disorders. WO 93/22279 discloses 3-phenyl-1 ,2- propanediamine derivatives having selective affinity for sigma receptors. These compounds are potent preferentially sigma 1 ligands; no heteroaromatic derivatives are described and they are not substituted in a position by a cycloalkyi group. WO 93/10073 relates to ethylenediamine derivatives as substance P receptor antagonists; the general formula refers to secondary amino compounds. US 5,039,706 describes benzylamine derivatives having phospholipase A2 inhibiting properties, some examples of phenyl-propane diamino compounds are given.

The compounds described above do not show the sigma 2 receptor selectivity and affinity demonstrated by the compounds of the present invention.

The present invention resides in the discovery of a group of selective and high affinity sigma 2 binding site ligands. The inhibition constant Ki for sigma 2 binding site is of at least 50 nM and these new ligands have at least a 5 fold greater affinity 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.

Disclosure of Invention

Novel alkylamino derivatives of the invention which conform to the formula :

When X represents cycloalkylalkyl or adamantyl, Y represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkylalkyl, adamantyl, aryl, arylalkyi, heteroaryl or heteroarylalkyi; 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, cydoalkyl, alkenyl, alkyl optionally substituted with one to three fluorine atoms, hydroxy, alkoxy opfonally substituted with one to three fluorine atoms, phenyl, amino, alkylamino, carbamoyl, sulfamoyl, carboxyalkyi, cyano oralkynyl.

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

A represents the group -O-RΘ in which R9 represents hydrogen, alkyl, cycloalkyi, cycloalkylalkyl, alkenyl, aryl, arylalkyi, hydroxyalkyi, carboxyalkyi or carboxyaryl;

or A represents the group

Rioand R11 represent independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyi, hydroxyalkyi, carboxyalkyi, haloalkyl, haloalkoxyalkyl, aryl, arylalkyi,

heteroaryl or heteroarylalkyi; 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, cycloalkyi, 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, carboxyalkyi, cyano or alkynyl.

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

-(CH2) -D-(CH2)m-

where D represents a single bond, oxygen, sulfur or a nitrogen atom substituted by hydrogen, alkyl, cycloalkyi, alkenyl, cycloalkylalkyl, aryl or arylalkyi;

m is a number selected from 1 to 3;

Rio and Rn 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, cycloalkyi, 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.

R-i and R ₂ which may be the same or different, are hydrogen, alkyl, cycloalkyi, hydroxyalkyi or alkenyl.

R ₃ represents alkyl, cycloalkyi, hydroxyalkyi or alkenyl;

R ₄ represents the group -(CH2)p-B where p is a number selected from 3 to 8;

or R ₃ and R ₄ together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (II) :

where R ₅ and Re represent independently hydrogen or alkyl;

or R ₅ and B _& together with the intervening atom represent a 5 to 7 heterocyclic ring.

B is a heteroaryl group of formula

R7 and Re are independently selected from hydrogen, halo, nitro, cycloalkyi, 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, carboxyalkyi, 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(Ri3), -N(Ri3)-CH2-, N(Ri3)-S(O)2-, C(=O), -C(=O)-CH2-, -C(=O)-O- or -C(=O)-N(Ri3)-;

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 is heteroaryl group.

R13 represents hydrogen or alkyl.

In the above definition, "alkyl" includes C1-C6 alkyl group such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group or the like.

"Cycloalkyi" includes C3-C6 cycloalkyi group such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group or the like.

"Cycloalkyalkyl" includes C3-C6 cycloalkyl-Cι-C3 alkyl group such as cyclopropyl methyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclobutylmethyl group, cyclobutylethyl group, cyclopentylmethyl group, cyclohexylmethyl group or the like.

"Alkenyl" includes C3-C6 alkenyl group such as 1 -propenyl group, allyl group, isopropenyl group, 1-butenyl group, 3-butenyl group, 1-pentenyl 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 group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert- butoxy group, pentyloxy group, hexyloxy 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 group, ethylamino group, propylamino group, butylamino group, pentylamino group, hexylamino group, dimethylamino group, methylethylamino group, diethylamino group, dipropylamino group or the like.

"Carboxyalkyi" includes carboxy-Ci-Cε alkyl group such as carboxymethyl group, 2-carboxyethyl group, 3-carboxypropyl group, 4- carboxybutyl group, 5-carboxypentyl group, 6-carboxyhexyl group or the like.

"Hydroxyalkyi" 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-Cι-C3 alkyl group such as chloromethyl group, dichloromethyl group, trichloromethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, bromomethyl group, 1 -chloroethyl group, 1 ,1 -dichloroethyl group, 2-chloroethyl group, 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-bromopropyl group or the like. "Haloalkoxyalkyl" includes halogenated-Cι-C3 alkoxy-Cι-C3 alkyl group such as chloromethoxymethyl group, chloromethoxyethyl group, chloromethoxypropyl group, fluoromethoxymethyl group, fluoromethoxyethyl group, trifluoromethoxymethyl group, trifluoromethoxyetiyl group, trifluoromethoxypropyl group, bromomelhoxymethyl group, bromomefioxyethyl group, bromome ioxypropyl group, 1 -chloroethoxymethyl group, 2- chbroelhoxymethyl group, 2-chloroethoxyethyl group, 2-chloroethoxypropyl group, 2-1uoroethoxymethyl group, 2-1uoroethoxyethyl group, 2- fluoroetioxypropyl group, 2,2,2-trifluoroethoxymethyl group, 3- chbropropoxymethyl group, 3-lluoropropoxymelhyl group orthe like. "Aryl" includes Cε-Cio aryl group such as phenyl group, 1 -naphtyl group, 2-naphtyl group or the like.

"Arylalkyi" includes Cβ-Cio aryl-Cι-C3 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-Cιo 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, 1 ,5-dicarboxy-2-naphthyl group or the like.

"Heteroary Jncludes 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), benzothiophenyl group (benzothiophene ring), pyrrolyl group (pyrrole ring), imidazolyl group (irridazole ring), pyrazolyl group (pyrazole ring), thiazolyl group (thiazole ring), isothiazolyl group (isothiazole ring), triazolyl group (triazole ring), tefrazolyl group (tetrazde ring), pyridyl group (pyridine ring), pyiazynyl group (pyrazine ring), pyrimidinyl group (pyrimidine ring), pyridazinyl group (pyridazine ring), indolyl group (indole ring), isoindolyl group (isoindole ring), benzoimidazolyl group (benzoinidazole ring), purinyl group (purine ring),

quinolyl group (quinoline ring), phtalazinyl group (phtalazine ring), naphtyridinyl group (naphtyridine ring), quinoxalinyl group (quinoxaline ring), cinnolinyl group (cinnoline ring), pteridinyl group (pteridine ring), oxazolyl group (oxazole ring), isooxazolyl group (isooxazole ring), benzooxazolyl group (benzooxazole ring), furazanyl group (furazan ring) or the like.

"Heteroarylalkyi" includes heteroaryl-Cι-C3 alkyl group, wherein examples of heteroaryl are the same as those illustrated in the above definition, such as 2-furylmethyl group, 3-furylmethyl group, 2-thienylmethyl group, 3-thienylmethyl group, 1 -imidazolylmethyl group, 2-imidazolylmethyl group, 2-thiazolylmethyl group, 1 -pyridylmethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 1 -quinolylmethyl group, 2- quinolylmethyl group or the like.

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

When X represents C3-C6 cycloalkyl-Cι-C3-alkyl or adamantyl, Y represents hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, Cs-Cβ cycloalkyi, C3-C6 cycloalkyl-Cι-C3-alkyl, adamantyl, aryl selected from phenyl and naphthyl, aryl-Cι-C3-alkyl; wherein each of said aryl group may optionally be substituted wifri one to three substituents, each of the said substituents being independently selected from halo, ni1ro, C3-C6 cycloalkyi, C3-C6 alkenyl, Ci-Ce 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-Ci-Cβ-alkyl, cyano or C3-C6 alkynyl.

When X represents C3-C6 cycloalkyi, Y represents hydrogen, C1-C6 alkyl, C3-C6 alkenyl or C3-C6 cycloalkyi.

A represents the group -O-R9 in which R9 represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyi, C3-C6 cydoalkyl-Cι-C3-alkyl, C3-C6 alkenyl, phenyl, phenyl-Ci -C3-alkyl , hydroxy-C2-C6-alkyl , carboxy-C 1 -C3-alkyl or carboxyphenyl;

or A represents the group

R10 and Rn represent independently hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyi, phenyl or phenyl-Cι-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) -

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.

R-i and R ₂ which may be the same or different, are hydrogen, C1-C3 alkyl, C3-C6 cycloalkyi, hydroxy-C2-C3 alkyl or C3-C6 alkenyl.

R ₃ represents C1-C3 alkyl, C3-C6 cycloalkyi, hydroxy-C2-C3-alkyl or C3- Cβ-alkenyl;

R ₄ represents the group -(CH2)p-B where p is a number selected from 3 to 6;

or R ₃ and R together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (II) :

(II)

where R ₅ and Re represent independently hydrogen or C1-C3 alkyl;

B is a heteroaryl group of formula

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

R12 is selected from hydrogen or Ci-Cβ 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(Ri3), -N(Ri3)-CH2-, - N(Ri3)-S(O)2-, C(=O), -C(=O)-CH2-, -C(=O)-O- or -C(=O)-N(Ri3)-.

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.

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

When X represents C3-C6 cycloalkyl-Cι-C3-alkyl, adamantyl or C3-C6 cycloalkyi, Y represents hydrogen, C1-C6 alkyl, C3-C6 alkenyl or C3-C6 cycloalkyi.

A represents the group -O-R9 in which R9 represents hydrogen, C1-C4 alkyl, C3-C6 alkenyl or hydroxy-C2-C4-alkyl; or A represents amino, C1-C3 alkylamino, phenyl-Cι-C3-alkylamino, C3-C6 alkenylamino, C2-C6 dialkylamino,

C4-C5 cydoalkylamino, C4-C7 alkylalkenylamino, piperidino, piperazino, C1-C3 alkylpiperazino ormorpholino;

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

R-i and R _∑ which may be the same or different, are hydrogen or C1-C3 alkyl.

R ₃ represents C1-C3 alkyl;

R ₄ represents the group -(CH2)p-B where p is a number selected from 3 to 6; or R ₃ and R ₄ together with the intervening nitrogen atom represent a piperidine ring which is substituted as depicted in formula (II) :

where R ₅ and Re represent hydrogen;

B is a heteroaryl group of formula

R7 and Re 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(Ri3), -N(Ri3)-CH2-, - N(Ri3)-S(O)2-, C(=O), -C(=O)-CH2-, -C(=O)-O- or -C(=O)-N(Ri3)-;

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

W and represent independently a benzene ring or heteroary 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.

Preferable B is

Rr and Re 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;

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(Ri3), -N(Rιa)-CH2-, - N(Ri3)-S(O)2-, C(=O), -C(=O)-CH2-, -C(=O)-O- or -C(=O)-N(Ri3)-;

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

R13 represents hydrogen or C1-C6 alkyl.

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

TABLE I

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

R ₃ B

H -OCH ₃ -CH ₃

O- H -0(CH ₂ ) ₂ CH ₃ -CH ₃

JP- H -OH -CH ₃

JP- H -OCH ₃ -CH-*

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

R ₃ B

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

Y R3 B

JO- H -OCH ₂ CH=CH ₂ -CH ₃

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

R ₃ B

^ ^H -OCH ₃ -CH ₃ o ^ ^" ^

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

R ₃ B

TABLE I : (continued)

TABLE I : (continued)

TABLE I : (continued)

Y R ₃ B

^^ -CH ₂ CH ₃ -O H -CH ₃ b

TABLE i : (continued)

TABLE I : (continued)

Y R ₃

TABLE

TABLE II : (continued)

TABLE

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III ; (continued)

B

JO- H -OCH ₃

JO- H -OCH2CH ₃

JP- H -0(CH ) ₂ CH ₃

JO- H

-OCH2CH=CH ₂

H O- -0(CH2) ₂ OH

JP- H -OH

J^ H -0(CH ₂ ) ₂ CH ₃

JO- H -OCH ₂ CH=CH ₂

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

H -0(CH ₂ ) ₂ OH

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

B

Jp- H -OC H ₂ CH=CH ₂ 0=S v-Ntt o

TABLE III : (continued)

TABLE III : (continued)

TABLE III: (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

TABLE III : (continued)

B

A^ -O -OH

O

AT^ -CH. -OH - N

TABLE III: (continued)

TABLE IV :

TABLE IV : (continued)

TABLE IV : (continued)

TABLE IV : (continued)

TABLE IV : (continued)

Specifically preferred compounds are :

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

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

2-[[1-[2-(1-Adamantyl)-2-oximinoethyl]-4-piperidinyl]meth yl]-2H-naphth[1 ,8- cdjisothiazole 1 ,1 -dioxide;

1-(1 -Adamantyl)-2-[4-(2H-naphth[1 ,8-c ]isothiazol-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-cc|isothiazol-2- yl)butyl]amino]ethylamine S,S-dioxide;

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

2-(1 -Adamantyl)-N-methyl-N-[4-(2H-naphth[1 ,8-cc(|isothiazol-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-c ]isothiazole 1 ,1 -dioxide;

1 -(1 -Adamantyl)-2-[N-methyl-N-[4-[5H-phenanthhdin-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-ccjisothiazol-2-ylmethyl)pipe din-1 - yl]ethylamine S,S-dioxide;

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

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

2-[1 -[2-(1 -Adamantyl)-2-pyrrolidin-1 -ylethyl]piperidin-4-ylmet yl]-2H- naphth[1 ,8-ccflisothiazole 1 ,1 -dioxide;

2-[1-[2-(1 -Adamantyl)-2-(4-methyl)piperazin-1 -ylethyl]pipe din-4-ylmethyl]- 2H-naphth[1 ,8-cαflisothiazole 1 J -dioxide;

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

1 -(1 -Adamantyl)-N-allyl-N-methyl-2-[4-(2H-naphth[1 ,8-cd]isothiazol-2- ylmethyl)pipehdin-1 -yljethylamine S,S-dioxide;

2-[1 -[2-(1 -Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1 ,8- ccήisothiazole 1 ,1 -dioxide;

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

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

1 -Cyclohexyl-2-[4-(2H-naphth[1 ,8-cαdisothiazol-2-ylmethyl)piperidin-1 - yljethanol S,S-dioxide;

1 -(1 -Adamantyl)-2-[4-(2-chlorophenothiazin-10-ylmethyl)piperidin -1 -ylj¬ ethanol;

1 -(1 -Adamantyl)-2-[4-(phenothiazin-10-ylmethyl)piperidin-1 -yljethanol;

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

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

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

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

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

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

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

1-(1 -Adamantyl)-2-[4-(5,6,H ,12-tetrahydrodibenz[b,f]azocin-6-oxo-5- ylmethyl)piperidin-1 -yljethanol;

1-(1-Adamantyl)-2-[4-(5,6,H ,12-tetrahydrodibenz[b,fJazocin-5- ylmethyl)piperidin-1 -yljethanol;

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

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

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

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

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

1-(1-Adamantyl)-2-[N-methyl-N-[4-(10,H -dihydrodibenz[b,f][1 ,4]-oxazepin- 11 -oxo-10-yl)butyljamino]ethanol;

10-[4-[N-[2-(1 -Adamantyl)-2-methoxyethylJ-N-methylamino]butyl]-10,11 - dihydrodibenz[b,fJ[1 ,4Joxazepin-11 -one;

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

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

5-[4-[N-[2-(1-Adamantyl)-2-methoxyethyl]-N-methylamino]bu tyl]-5H- phenanthridin-6-one;

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

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

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

Compounds of the present invention can exist as optical isomers and both the racemic mixture of the isomers as well as the individual optical isomers are within the scope of this invention. The racemic mixtures can be separated into their individual isomers by techniques well known to those skilled in the art.

The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula (I) or pharmaceutically acceptable carriers or diluents.

The present invention relates to 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.

The present invention relates to a method of treating or preventing a condition 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 and memory impairment, hypertension, arrhythmia and angina.

The present invention relates to pharmaceutical compositions which provide from about 0.01 to 100 mg of the active ingredient per unit dose. The compositions may be administered by any suitable route. For example orally in the form of tablets or capsules, etc., parenterally in the form of solutions for injection, topically in the form of onguents or lotions, ocularly in the form of eye-lotion. For preparing such compositions, methods well known in the art may be used; the nature of the pharmaceutical composition employed will depend on the desired route of administration.The total daily dose usually ranges from about 0.05 - 500 mg.

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

Method A :

Scheme A1 illustrates the preparation of compounds of the formula (I). A compound of the formula III where Q includes halides such as Cl, Br, I or tosylate, mesylate, is reacted with the nucleophilic amino derivative IV to yield the corresponding 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 dimethylformamide, acetonitrile.

Scheme A1

IV

V

(1 )

The amino-keto derivative may be reduced to give the hydroxy derivative of formula (I) of the invention where A = OH and Y = H. The reduction is generally accomplished by using sodium borohydride in ethanol, methanol or tetrahydrofuran at room temperature.

The amino-keto derivative may be converted into aminoalcohols by reaction 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 description of formula (I).

Alkoxy molecules may be prepared by standard methods familiar to those skilled in the art by converting the 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, 264-317J; the solvolysis of a chiral sulfonyl ester derivative in the above ethanolamine 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 Preparation Vol. Ill [S.R. Sandlerand W. Karo, Academic Press, London, 1989, 430-481].

The keto derivative V may be the precursor of the amino derivatives of formula (I) where Y = H and A = -N (Ri o, Rl 1) via reductive amination [Comprehensive organic transformatbns, R.C. Larock, VCH Publishers, New York, 1989, 421 - 425] or by the Leuckart reaction [M.L Moore, Org. Reactions, 1949, 5, 7, 301]. Such amino derivatives may be prepared from the hydroxy derivative of formula (I) where A = OH by the Mitsunobu reaction [O. Mitsunobu, Synthesis, 1981 , 1 - 28J. The conversion by standard methods of the hydroxy group to a leaving group like Q (e.g. halide, mesylate) and subsequent substitution by an amino group to give an amino derivative is also a general method of synthesis.

The reaction of substitution may be carried out with sodium azide to give an azide. The azido derivative may be reduced to give primary amine [Comprehensive organic transformations, R.C. Larock, VCH Publishers, New York, 1989, 409-410]. The oximino derivative prepared as described above can also be reduced to give the free amino derivative by standard reduction process like catalytic hydrogenation over platinum oxide or palladium on carbon or chemical reduction with lithium aluminum hydride.

Scheme A 2

VIM

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

The target amino derivative VIII has been chosen in the piperidino series, however, acyclic amino derivatives may be obtained according to the same process. The P substituent in the compounds of formula VI and VIII represents 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 give the piperidino analogue of formula 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 sulfate or other suitable salt. This route of synthesis can be extended to other heteroaryl rings of formula B as depicted in the description of invention.

The heteroaryl ring of formula B may be purchased from commercial sources or they may be prepared via known methods. The synthesis of ring substituted

6H-dibenzo[c,e][1 ,2Jthiazine S,S-dioxide may be accomplished by employing the method described by F. Ullmann and C. Grob in Chem. Ber. 1910, 43,2694 for unsubstituted sultam.

Another route of synthesis of the starting amino compound IV is illustrated in scheme A3. The N-alkylatbn of the naphthosultam VII may be conducted acccording 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. 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 description of invention.

Q' is generally another electrophilic group which could be interconverted to Q and reacted with the N-protected amino derivative XI to give XII. The removal of the protective group from the amino precursors VIM and XII is accomplished by standard process and gives the resulting amine IV.

Scheme A3

Method 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 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, Tetrahedron Letters, 1990, 31 ,32,4661-4664]. The e poxy derivative XIII may be obtained according to different usual methods : oxidation of an alkenyl derivative, dehydrohalogenation of a halohydrin, synthesis starting from a carboxaldehyde.

Scheme B1

X-C T— C-R ₂ + H- Λ X ,C-C ?- ¹ N: R ₃ ³

\ R n„. A 1 R ₄

*2

When the starting epoxy derivative XIII is used in an optically active form, the final amino alcohol (I) is obtained in an optically active form.

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

The desired optically active enantiomer 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 pharmaceutically acceptable salts with various inorganic and organic acids. These salts are readily prepared by treating the base compound with a substancially equivalent amount of the chosen mineral or organic acid in a suitable organic solvent such as methanol, ethanol or isopropanol.

Best Mode for Carrying Out the Invention

In the folbwinntion 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 chromatography (TLC) was carried out on Merck 0.2 mm silica gel 6OF254 plates (Art 1.05735);

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

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

(iv) solvent ratios are given in volume:volume terms;

(v) Η-NMR: 200 MHz, δ in ppm.

EXAMPLE 1

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

a) 2-(4-lodobutyl)-2H-naphth[1 ,8-cd]isothiazole 1 , 1 -dioxide.

2-(4-Chlorobutyl)-2H-naphth[1 ,8-cd]isothiazole 1 ,1 -dioxide (62.9 g, 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. Martin, P. Moutin, A. Viroulaud, D. Allam and J. Betschart, J. Med. 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 concentrated in vacuo. Resulted syrup was poured into water (500 ml) and extracted three times with ethyl acetate. Combined organic extracts were dried over sodium sulfate, 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 g, 81%) as a yellowish powder, m.p. : 82-84 °C.

b) 2-(4-N-Methylaminobutyl)-2H-naphth[1 ,8-cc]isothiazole 1 ,1 -dioxide. To a solution of N-methyltrifl uoroacetamide (7.6 g, 60 mmol) in dimethylformamide (50 ml), was added in small portions sodium hydride (60% dispersion in oil) (2.0 g, 50 mmol). The solution was stirred for 20 min under nitrogen at room temp. Then iodo derivative 1 (a) (19.4 g, 50 mmol) in dimethylformamide (50 ml) was slowly added dropwise ove r 20 min . Resulted mixture was sti rred for 2 hou rs and then pou red into water. Extraction with ethyl acetate and standard work-up gave a brown semi- sol id which was subjected to flash chromatography (silica gel , ethyl acetate / hexane 3:7).yielding the corresponding trifluoroacetamide (9.3 g, 40 %) 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 g, 24 mmol) in methanol (210 ml) was treated with 10% solution of potassium carbonate in methanol/water (7:3) (75 ml) and the reaction mixture stirred for 2 hours. Methanol was evaporated and the residue extracted with ethyl acetate. Standard workup gave amine 1 (b) (5.3 g, 76%) as a green oil.

c)(R,S)-2-[4-[2-(1-Adamantyl)-2-oxoethyl]methylamino]buty l]-2H- naphth[1 ,8-cα sothiazole 1 ,1-dioxide.

A solution of amine 1 (b) (4.4 g, 15 mmol), 1 -(bromoacetyl)- adamantane (4.1 1 g, 16 mmol) and anhydrous potassium carbonate (2.16 g, 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 chloride. The organic solution was dried over sodium sulfate and the solvent was evaporated. The residue was chromatographed (silica gel, ethyl acetate/methylene chloride 1 :1 , Rf = 0.4) to produce aminoketone 1 (c) (4.0 g, 57%) as an orange oil.

d)(R,S)-1 -(1 -Adamantyl)-2-[N-methyl-N-[4-(2H-naphth[1 ,8-cαf]isothiazol-

2-yl)butylJaminoJethanol S,S-dioxide, fumarate.

A solution of aminoketone 1 (c) (4.0 g, 8.6 mmol) in ethanol (100ml) was treated with sodium borohydride (1.2 g, 30 mmol). The mixture was stirred for 4 hours at room temperature and then concentrated 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

under Removal of solvent under vacuum left the title aminoalcohol 1 (d) (3.4 g, 85%) as an oil. TLC: Rf = 0.3 (methanol/ methylene chloride 5:95). The aminoalcohol 1 (d) (3.4 g, 7.3 mmol) on treatment with fumaric acid (1.16 g, 10 mmol) in isopropanol was converted into its fumarate salt (3.1 g, 73%), m.p.: 166-168°C. MS: 468 (M+). Anal. Calc'd for C ₃₁ H ₄₀ N ₂ O ₇ S: C63.68; H,6.90;

N,4.79. Found: C63.48; H.6.98; N.,4.74.

EXAMPLE 2

(R,S)-2-[[1 -[2-(1 -Adamantyl)-2-oxoethylJ-4-piperidinyl]methyl]-2H-naphth[1 ,8- cα sothiazole 1 ,1 -dioxide, hydrochloride.

a) N-tert-Butoxycarbonyl isonipecotic acid. Di-ferf-Butyl dicarbonate (101.1 g, 464 mmol) was added dropwise to a stirred solution of isonipecotic acid (60 g, 464 mmol) and sodium hyd roxide (37.6 g, 940 mmol) in a mixture of water (86 ml) and tert- butanol (176 ml). After the addition was completed, terf-butanol (100 ml) was added and the mixture was sti rred for 3 hours at room temperature. The solution was diluted with water (200 ml) and extracted two times with pentane (150 ml). The aqueous phase was acidified with cooling with potassium hydrogen sulfate (70 g) and extracted with ethyl acetate. Standard workup gave N-Boc-protected iconipecotic acid 2(a) (102.3 g, 96%) as a white powder, m.p.: 144-146 °C.

b) N-ferfButoxycarbonyl-4-hydroxymethylpiperidine.

To a cold (-1 5°C) solution of 2(a) (13.74 g, 60 mmol) in 1 ,2- dimethoxyethane (60 ml) was added N-methylmorpholine (6.66 ml, 60 mmol) fol lowed by isobutyl chloroformate (8.16 ml, 60 mmol). After 10 min of stirring, the precipitate was filtered off and washed with 1 ,2- dimethoxyethane (60 ml) . To the cooled (ice - salt bath) filtrate was slowly added a solution of sodium borohydride (3.42 g, 90 mmol) in water (30 ml) . The mixture was stirred for 45 min., then diluted with water (800 ml) and extracted with of ethyl acetate (400 ml) . Organic solution was washed with 0.05 N hydrochloric acid, water and finally with a saturated aqueous solution of sodium bicarbonate. The solution was dried and the solvent

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

c) N-tert-Butoxycarbonyl-4-[2-(2H-naphth[1 ,8-cαf]isothiazol)methyl]- piperidine S,S-dioxide.

To an ice-cooled solution of alcohol 2(b) (26.8 g, 125 mmol) and triethylamine (19.1 ml, 137.5 mmol) in dry tetrahydrofuran (350 ml), methanesulfonyl chloride (11.3 ml, 137.5 mmol) was added dropwise. After stirring for 20 min, water was added and the reaction mixture was extracted with ethyl acetate. Combined organic extracts were washed with saturated aqueous solution of sodium bicarbonate, dried and evaporated producing N-tert- butoxycarbonyl-4-(methanesulfonyloxymethyl)piperidine in quantitative yield (36.6 g) as a white solid, m.p.: 72-74°C, To the suspensbn of sodium hydride (60 % dispersion in oil) (5.94 g, 148.5 mmol) dry dimethylformamide (60 ml) was added a solution of 1 ,8-naphtosultam (27.7 g, 135 mmol) in dimethylformamide (80 ml) and the reaction mixture was stirred at room temperature under nitrogen for 20 min. Then sodium iodide (6.00 g, 40 mmol) was added folbwed by the above methanesulfonyloxymethyl-N-Boc-piperidine (36.6 g, 125 mmol) in dimethylformamide (80 ml) and the reaction was conducted at 80°C for 4 hours. After cooling, the reactbn mixture was poured into water and extracted with ethyl acetate. The standard workup afforded a brownish oil which was subjected to column chromatography (silica gel, methylene chloride) giving the title compound 2(c) ( 43.5 g) in 80 % yield, m.p.: 1 12-1 14°C. TLC: Rf = 0.3 (ethyl acetate/hexane 3:7).

d) 4-[2-(2H-naphth[1 ,8-cα]isothiazol)methyl]piperidine S,S-dioxide.

N-Boc derivative 2(c) (36.0 g, 83.1 mmol) in ethyl acetate (400 ml) was treated with 4N hydrochloride solution in dioxane (83 ml) at room temperature overnight. Resulted white precipitate of 2(d) hydrochloride was filtered off and washed carefully with ethyl acetate. Quantitative yield, m.p. > 280 °C.

This hydrochloride was converted quantitatively into the free piperidine 2(d) by treatment with 0.5N sodium hydroxide aqueous solution and subsequent extraction with methylene chloride. A green oil was obtained which crystallized on standing at cold, m.p.: 188-190 °C.

e)(R,S)-2-[[1 -[2-(1 -Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]-2H- naphth[1 ,8-cc sothiazole 1 ,1-dioxide, hydrochloride.

The aminoketone 2(e) was synthesized from piperidine 2(d) (1 1.2 g, 37 mmol) and 1 -(bromoacetyl)adamantane (10.28 g, 40 mmol) folbwing 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 washed with ethanol and collected by filtration to give pure aminoketone 2(e) (13.6 g, 75%), m.p.: 168-170°C. TLC: Rf = 0.4 (ethyl acetate/ methylene chloride 1 :1 ). To the aminoketone 2(e) (1.5 g, 3.1 mmol) in ethanol (50 ml) was added 4N hydrogen chloride solution in dioxane (1.55 ml). Resulted solution was diluted with dry diethyl ether and left for crystallization. Precipitate was filtered off and dried under vacuum. Hydrochloride 2(e) (1.1 g, 69 %) was obtained as a grey powder, m.p.: 261 -263°C . MS: 479 (M+1 ). Anal. Calc'd for C ₂₈ H ₃₅ CIN ₂ O ₃ S: C65.29; H.6.85; N,5.44; Cl.6.88. Found : C.64.69; H.7.03; N.5.41 ; Cl.6.69.

EXAMPLE 3

(R,S)-2-[[1-[2-(1-Adamantyl)-2-oximinoethyl]-4-piperidiny l]methylJ-2H- naphth[1 ,8-c |isothiazole 1 ,1 -dioxide, hydrochloride.

The aminoketone 2(e) (1.46 g, 3 mmol) dissolved in a mixture of methanol (15 ml) and of tetrahydrofuran (5 ml) was reacted with hydroxylamine sulfate (0.540 g, 3.3 mmol) in presence of sodium acetate (0.540 g, 6.6 mmol) over 4 hours under reflux and then for 48 hours at room temperature. The single oxime product was formed ; TLC: Rf = 0.6 (Ethyl acetate / methylene chloride 1 : 1 ). Reaction mixture was diluted with ethanol (30 ml), filtered and filtrate treated with 4M hydrogen chloride 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 g, 57%) as a white crystalline powder.m.p.: 196- 198°C. MS: 494 (M + 1 ). Anal. Calc'd for C ₂₈ H ₃₆ CIN ₃ O ₃ S + 1.2 H ₂ O: C60.95;

H.7.02; N.7.62; Cl,6.43. Found : C.60.94; H.7.20; N.7.40; Cl.6.81.

EXAMPLE 4

(R,S)-1 -(1 -Adamantyl)-2-[4-(2H-naphth[1 ,8-c ]isothiazol-2-ylmethyl)piperidin- 1 -yljethanol S,S-dioxide, hydrochloride.

The aminoketone 2(e) (3.0 g, 6.1 mmol) was reduced following the method described in Example 1 (d) yielding the aminoalcohol 4 (2.2 g, 74%) as a white powder, m.p.: 207-209°C. TLC: Rf = 0.5 (methanol/ methylene chloride 5:95). ¹ H-NMR (CDCI ₃ ,200 MHz) δ (ppm): 8.05 (d,1 H); 7.9 (d,1 H); 7.75 (dd, 1H); 7.6-7.4 (m, 2H); 6.74 (d,1 H); 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 hydrochbride salt was prepared from aminoalcohol 4 (2.0 g, 4.15 mmol) following procedure described in Example 2(e). Recrystallisation from methanol afforded pure product (1.2 g, 56 %) as a white crystalline solid, m.p.: 280°C (dec). MS: 315 (M - 165). Anal. Calc'd for C ₂₈ H ₃₇ CIN ₂ 0 ₃ S: 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.

EXAMPLE 5

(R,S)-1-(1-Adamantyl)-2-[4-(9-carbazolyl)methylpiperidin- 1 -yljethanol, hydrochloride.

a) N-fen ^* -Butyloxycarbonyl-4-[9-(carbazolyl)methyl]piperidine. The title compound 5(a) was prepared from carbazole (8.35 g, 50 mmol) and N-tert-Butyloxycarbonyl- (methanesulfonyloxymethyl) piperidine (15.0 g, 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 ethyl acetate / hexane to give pure product 5(a) (7.16 g, 39%), m.p.: 165-167°C. TLC: Rf = 0.2 (diethyl ether/ hexane 2:8).

b) 4-[9-(Carbazolyl)methyl]piperidine.

Removal of the tert-butyloxycarbonyl protecting group from 5(a) was performed 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.

c) 9-[[1 -[(1 -Adamantyl)-2-oxoethyl]-4-piperidinyl]methyl]carbazole.

The amine 5(b) (3.6 g, 13.6 mmol) and 1 - (bromoacetyl)adamantane (3.85 g, 15 mmol) were reacted together in acetonitrile containing potassium carbonate following the procedure described in Example 1 (c). The aminoketone 5(c) (3.5 g, 59%) was isolated as a white powder, m.p.: 1 70-172°C. TLC: Rf = 0.6 (ethyl acetate/ methylene chloride 1 :1 ).

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

Reduction of the aminoketone ketone 5(c) following the method described in Example 1 (d) gave quantitatively the aminoalcohol 5(d) as a white solid, m.p.: 197-199°C. TLC: Rf = 0.3 (ethyl acetate / methylene chloride 1 :1 ). The title hydrochloride salt was prepared according to the procedure described in Example 2(e) starting from aminoalcohol 5(d) (2.7 g, 6.1 mmol). Recrystallization from isopropyl alcohol / diethyl ether gave the salt (1.7 g, 58%) as a white powder, m.p.: 268-270°C. MS: 442 (M ⁺ ). Anal. Calc'd for C ₃₀ H ₃₉ CIN ₂ OS: 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.

EXAMPLE 6

(R,S)-1 -(1 -Adamantyl)-2-[N-methyl-N-[4-(2H-naphth[1 ,8-cc sothiazol-2- yl)butyl]amino]ethylamine S,S-dioxide, tartrate.

a)2-[N-methyl-N-4-[(2-(1-Adamantyl)-2-methanesulfonyloxye thyl)- amino]butyl]-2H-naphth[1 ,8-ccflisothiazole 1 ,1 -dioxide.

To a solution of aminoalcohol 1 (d) (9.33 g, 20 mmol) in tetrahydrofuran (200 ml) cooled in an ice-water bath was added triethylamine (2.23 g, 22 mmol) followed by methanesulfonyl chloride (1.8 ml, 22 mmol). After stirring for 30 min., the mixture was quenched with water and extracted with methylene chbride. The combined organic extracts were washed with water, and saturated aqueous solution of sodium b arbonate, then dried and the solvent was evaporated. A colorless viscous oil of methanesulfonate 6(a) was obtained in quantitative yield. TLC: Rf = 0.21 (ethyl acetate / hexane 3:7).

b)(R,S)-1 -(1 -Adamantyl)-1 -azido-2-[N-methyl-N-[4-(2H-naphth[1 ,8- ccφsothiazol-2-yl)butyl]amino]ethylamine S,S-dioxide.

A mixture of methanesulfonate 6(a) (5.18 g, 9.5 mmol) and sodium azide (0.690 g, 10.6 mmol) in dry dimethylformamide (100 ml) was stirred overnight 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. Purification of the residue by flash chromatography (silica gel, ethyl acetate/hexane 3:7) gave the title azide 6(b) (4.02 g, 86%) as an oil which crystallized as a white solid on 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 C ₂₇ H ₃₅ N ₅ O ₂ S: 0,65.69;

H.7.15; NJ4.19. Found: C.65.41 ; H,7.23; NJ3.95.

c)(R,S)-1-(1 -Adamantyl)-2-[N-methyl-N-[4-(2H-naphth[1 ,8-cc]isothiazol- 2-yl)butyl]amino]ethylamine S,S-dioxide, tartrate.

A solution of azide 6(b) (1.85 g, 3.7 mmol) in ethanol (100 ml) and tetrahydrofurane (20 ml) was hydrogenated with shaking over 10% Pd/C (2.2 g) 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 g, 65%) as a slightly yellow foam. TLC: Rf = 0.2 (methanol/methylene chloride 1 :9).

Diamine 6(c) on treatment with (R,S) tartaric acid (2.2 equiv.) in ethanol was converted in 54% yield into the title tartrate salt 6(c), m.p.: 215-217°C. Anal. Calc'd for C31H43N3O8S + H2O: C.58.56; H.7J3; N.6.61. Found: C.58.37; H,6.89; N,6.61.

EXAMPLE 7

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

a)1-(1 -Adamantyl)-N-methyl-N-trifluoroacetamido-2-[N-methyl-N-[4-( 2H- naphth[1 ,8-cα sothiazol-2-yl)butyl]amino]ethylamine S,S-dioxide.

A solution of methanesulfonate 6(a) (3.79 g, 6.9 mmol) in dry dimethylformamide (10 ml) was added to a pre-reacted over 20 min. mixture of

N-methyltrifluoroacetamide (1.09 g, 8.4 mmol) and sodium hydride (60% suspension in oil) ( 0.280 g, 7 mmol) in dry dimethylformamide (10 ml) and then

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, ethyl acetate/hexane 1 :3) gave the title compound 7(a) (2.89 g, 74%) as an oil. TLC: 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- cαφsothiazol-2-yl)butyl]amino]ethylamine S,S-dioxide, fumarate.

The hydrolysis of the trifluoroacetamido group in 7(a) (2.89 g, 5.16 mmol) was performed in aqueous methanol in the presence of potassium carbonate (1.64 g, 11.9 mmol) as described in Example 1 (b). After stirring overnight at room temperature, the reaction mixture was extracted with methylene chloride and worked-up as usual yielding free diamine 7(b) ( 1.76 g, 71 %) as an oil, TLC: Rf = 0.3 (methanol/methylene chloride 1 :9). Folbwing the usual procedure (Examples 1 (d) and 6(c)) the title fumarate salt was crystallized from ethanol in 42% yield. M.p.: 168-170°C. Anal. Calc'd for C32H43N3O6S: C64.30; H.7.25; N.7.03. Found: C.64.03; H.7.30; N.7.08.

EXAMPLE 8

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

A mixture of mesylate 6(a) (2.72 g, 5 mmol), pyrrolidine (0.83 ml, 10 mmol), anhydrous potassium carbonate (1.14 g, 8.2 mmol), and sodium iodide (0.225 g, 1.5 mmol) was stirred and heated under reflux over 2 hours under nitrogen. After cooling, the mixture was diluted with water and extracted with methylene chloride. Standard work-up furnished free diamine 8 (1.9 g, 73%) as a yellow oil, TLC: Rf = 0.2 (methanol/methylene chloride 1 :9).

The fumarate salt 8 was crystallized from ethanol in 44% yield following the usual procedure (Examples 1 (d) and 6(c)). M.p.: 190-191 °C. Anal. Calc'd for C35H47N3O6S: C.65.91 ; H,7.43; N.6.59. Found: C65.79; H.7.48; N.6.67.

EXAMPLE 9

(R,S)-2-[4-[N-[2-(1-Adamantyl)-2-methoxyethyl]-N-methylam ino]butyl]-2H- naphth[1 ,8-cαf]isothiazole 1 ,1-dioxide, tartrate.

The methanolysis of mesylate 6(a) ( 2.72 g, 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 solution washed with

0.025M aqueous sodium hydroxide, water and saturated aqueous sodium bicarbonate. The organic phase was dried and concentrated and the residual material purified by chromatography (silica gel, ethyl acetate/methylene chloride /methanol 10:10:1 ) to give methyl ether 9 (0.770 g, 33 %) 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 was crystallized from ethanol as a white solid, m.p.: 124-126°C. MS: 303 (M-

179). Anal. Calc'd for C32H44N2O9S + 1/3 H2O: C.60.14; H.6.99; N.4.38.

Found : C.60.14; H.7.18; N, 4.59.

EXAMPLE 10

(R,S)-1 -(1-Adamantyl)-2-[N-methyl-N-[4-[5H-phenanthridin-6-oxo-5-yl ]butyl]- aminojethanol, hydrochloride.

a) 4-(N-tert- ^β utoxycarbonyl-N-methylamino)butyric acid.

This compound was prepared from 4-(N-methylamino)butyric acid hydrochloride (23 g, 150 mmol) and di-tert-butyl dicarbonate (32.7 g, 150 mmol) according to the method described in Example 2(a). The product 10(a) (31 g, 95%) was obtained as an oil.

b) N- terf-Butoxycarbonyl-N-methyl-4-hydroxybutylamine.

Reduction of the carboxylic acid 10(a) (31 g, 142 mmol) via its mixed carboxylic-carbonic anhydride, following the procedure presented in Example 2(b), produced alcohol 10(b) (19.5 g, 64%) as an oil.

c) N-Methyl-N-[(5H-phenanthridin-6-oxo-5-yl)butyl]amine.

Folbwing the procedure described in Example 2(c) the alcohol 10(b) was first converted into the mesylate in 98% yield. Reaction of the above mesylate (5.6 g, 20 mmol) with dihydro(5H)-phenanthridinone (4.3 g, 22 mmol) in the presence of sodium hydride in dimethylformamide furnished N-tert- butoxycarbonyl-N-methyl-N-[(5H-phenanthridin-6-oxo-5- yl)butyl]amine (4.5 g, 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 g, 1 1.4 mmol) was performed following the procedure 2(d). The title amine 10(c) (2.8 g, 88%) was obtained as a colorless oil.

d)5-[4-[2-(1-Adamantyl)-2-oxoethyl]methylamino]butyl]-6(5 H)- phenanthridinone.

The amine 10(c) (2.8 g, 10 mmol) and l -(bromoacetyl) adamantane (2.83 g, 11 mmol) were reacted together, according to procedure presented in Example 1 (c), to produce the title ketone 10(d) (3.31 g, 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-phenanthridin-6-oxo-5- yl)butyl]amino]ethanol, hydrochloride.

Ketone 10(d) (3.2 g, 7.0 mmol) was reduced with sodium borohydride in ethanol, folbwing the procedure described in Example 1 (d), yielding the free aminoalcohol 10(e) (3.0 g, 94%) as an oil. TLC: Rf = 0.3 (methanol / methylene chloride 1 :9). The title hydrochbride was prepared according to the procedure described in Example 2(e). Starting from aminoalcohol 10(e) (2 g, 4.3 mmol) and after recrystallizatbn from ethanol / diethyl ether the salt 10(e) (1.4 g, 63%) was obtained as a white hygroscopic powder; m.p.: 127-129°C. MS: 293 (M - 165). Anal. Calc'd for C30H39CIN2O2 + H2O: C.70.22; H.8.05; N,5.46; Cl.6.91. Found: C.70.48; H,7.95; N.5.59; Cl.7.27.

EXAMPLE 11

(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.

a) N -Methyl-N-[4-[6-(6H-dibenzo[ce][1 ,2]thiazin)]butyl]amine S,S- dioxide.

The synthesis of amine 11(a) was performed folbwing the sequence of reactbns described in Example 10(c). Alkylation of 6H- dibenzo[ce]-1 ,2-thiazine-5,5-dioxide (4.16 g, 18 mmol) with mesylate of 10(b) (5.06 g, 18 mmol) gave N-tert-butoxycarbonyl-N-methyl-N-[4-[6-(6H- dibenzo[ce][1 ,2]thiazin)]butyl]amine S,S-dioxide (6.45 g, 77%) as a viscous oil. TLC: Rf = 0.3 (ethyl acetate /hexane 3:7). Next, removal of N-tert- butoxycarbonyl group and basic work-up furnished the title amine 11(a) (4.3 g, 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 solution of the amine 11(a) (0.886 g, 2.8 mmol) in ethanol (15 ml) was added (l -adamantyl)ethylene oxide (0.500 g, 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, methanol / methylene chloride 1 :20) to give the title aminoalcohol 11(b) (1 g, 72 %) as a white foam. TLC: Rf = 0.25 (methanol / methylene chbride 1 :20). Anal. Calc'd for C29H38N2O3S + 0.5 H2O: C.69.09; H.7.74; N,5.55. Found: C.68.79; H.7.70; N, 5.50.

(I -Adamantyl)ethylene oxide was prepared according to Shiryaev A.K. etal., Khim. Farm. Zh., 1990, 24, 23-25.

EXAMPLE 12

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

a)1 -(1-Adamantyl)-1-methanesulfonyloxy-2-[4-(2H-naphth[1 ,8- cclisothiazol-2-ylmethyl)piperidin-1 -yl]ethane S,S-dioxide.

Folbwing procedure described in Example 6(a) reaction of methanesulfonyl chloride with aminoalcohol 4 produced the title mesylate 12(a) in 96% yield as a white solid, m.p.: 175.5-176.5°C. TLC: Rf = 0.21 (ethyl acetate/hexane 3:7).

b) 1 -(1-Adamantyl)-1 -azido-2-[4-(2H-naphth[1 ,8-cα sothiazol-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 in Example 6(b) and afforded azide 12(b) in 45% 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-ccf]isothiazol-2-ylmethyl)- piperidin-1-yl]ethylamine S,S-dioxide, tartrate.

Folbwing 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 ethanol in 40% yield as a white powder, m.p.: 189-190°C. Anal. Calc'd for C32H43N3O8S + 1.2 H2O: C.59.01; H.7.03; N,6.45. Found: C.58.74; H.6.66; N, 6.40.

EXAMPLE 13

(R,S)-1 -(1 -Adamantyl)-N-methyl-2-[4-(2H-naphth[1 ,8-cc |isothiazol-2- ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide, maleate.

a) 1 -(1-Adamantyl)-N-methyl-N-trifluoroacetamido-2-[4-(2 V-naphth[1 ,8- cαf]isothiazol-2-ylmethyl)piperidin-1 -yl]ethylamine S,S-dioxide.

Reaction 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-cαfjisothiazol-2- ylmethyl)piperidin-1-yl]ethylamine S,S-dioxide, maleate.

Hydrolysis of the trifluoroacetamide 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% yield. White

powder, m.p.: 191 -193°C. Anal. Calc'd for C33H43N3O6S + 0.5 H2O: C64.08; H.7.11 ; N.6.80. Found: C64.08; H.7.H ; N.6.90.

EXAMPLE 14

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

Reaction of mesylate 12(a) with pyrrolidine, 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. Calc'd for C36H47N3O6S + 0.25 H2O: C66.05; H.7.26; N.6.42. Found: C65.92; H.7.31; N,6.49.

EXAMPLE 15

(R,S)-2-[1-[2-(1-Adamantyl)-2-morpholin-4-ylethyl]piperid in-4-ylmethyl]-2H- naphth[1 ,8-cc/]isothiazole 1 ,1 -dioxide, dihydrochloride.

Folbwing procedure described in Example 8, reactbn 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 dihydrochloride salt was prepared in 61% yield, according to the procedure 2(e), as a white hygroscopic solid, m.p.: 182-184°C. Anal. Calc'd for C32H45CI2N3O3S + H2O: C.59.99; H,7.39; N.6.56. Found: C.60.41 ; H.7.74; N.6.64.

EXAMPLE 16

(R,S)-2-[1-[2-(1-Adamantyl)-2-(4-methyl)piperazin-1-yleth yl]piperidin-4- ylmethyl]-2H-naphth[1 ,8-cd]isothiazole 1 J -dioxide, hydrochloride.

Mesylate 12(a) and N-methylpiperazine were reacted under conditions analogous to Example 8 and gave the title triamine 16 in 86% yield as a white solid, m.p.: 1 14.9-1 15.5°C. TLC: Rf = 0.3 (methanol/methylene chloride 1 :9).

The hydrochloride salt was prepared in 48 % yield, according to the procedure 2(e), as a white solid, m.p.: 213.5-214.3°C. Anal. Calc'd for C33H46N4O2S + 2.8 HCI +1.5 H2O: C.57.19; H.7.58; N,8.09; 01,14.35. Found: 0,57.26; H.7.73; N.8.07; Cl.14.23.

EXAMPLE 17

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

Mesylate 12(a) and diethylamine were reacted together, under conditions 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 procedure, in 48% yield as a white solid, m.p.: 221.5-222.3°C. Anal. Calc'd for C36H49N3O6S + 1/3 H2O: 0,65.75; H.7.55; N.6.39. Found: 0,65.77; H,7.66; N.6.39.

EXAMPLE 18

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

Folbwing typicall procedure (Example 8), reaction of mesylate

12(a) with N-methylallylamine furnished diamino compound 18 in 20 % yield as a white solidified foam. TLC: Rf = 0.5 (ethyl acetate).

Diamine 18, on the usual treatment with fumaric acid in ethanol, gave the title salt 18 in 49% yield as a white solid, m.p.: 191.7-192.8°C. Anal. Calc'd for C36H47N3O6S + H2O: 0,64.74; H.7.40; N,6.29. Found: C.64.61 ; H,7.26; N.6.14.

EXAMPLE 19

(* )-(S)-1 -(1-Adamantyl)-2-[4-(2H-naphth[1 ,8-cα]isothiazol-2-ylmethyl)piperidin- 1 -yljethanol S,S-dioxide.

Reaction of 4-[2-(2H-naphth[1 ,8-cc(]isothiazol-1 ,1 -dbxide)methyl] piperidine 2(d) (0.151 g, 0.5 mmol) with (+)-S-(1 -adamantyl)ethylene oxide (0.089 g, 0.5 mmol) was conducted folbwing procedure described in Example 11 (b), but over 72 hrs. Column chromatography (silica gel, methylene chloride/ methanol 20: 1) gave pure aminoalcohol 19 (0.155 g, 65%) as a solidified foam, m.p.: 202.5 - 204.5°C. [a] _D ²⁰ = +24.7° (c 1.3, CHCI3). ¹ H-NMR (CDCI3): identical to that of a racemic aminoalcohol 4.

The (+)-S-(1 -adamantyl)ethylene oxide ([a] _D ²⁰ = + 13.3° (c 1.6, CHCI3)) was prepared according to De Ninno M.P. etal. (J. Org. Chem., 1992, 57, 7115-7118), but starting with the opposite enantiomer of the catalyst.

EXAMPLE 20

(-)-(R)-1-(1-Adamantyl)-2-[4-(2H-naphth[1 ,8-ccTlisothiazol-2-ylmethyl)piperidin- 1 -yljethanol S,S-dioxide.

Following procedure 1 1(b), (-)-R-(1-adamantyl)ethylene oxide (0.500 g,

2.8 mmol) and piperidine 2(d) (0.845 g, 2.8 mmol) were reacted together, but over 54 hrs. Purification by column chromatography furnished aminoalcohol 20

(0.710 g, 55%) as a white solid, m.p.: 204.5 - 205.5°C. [a] _D ²⁰ = - 29.3° (c 1 ,

CHCI3). ¹ H-NMR (CDCI3): identical to that of aminoalcohol 4. The (-)-R-(1 -adamantyl)ethylene oxbe ([a] _D ²⁰ = - 14.7° (c 1 , CHCI3)) was prepared according to De Ninno M.P. etal. (J. Org. Chem., 1992, 57, 71 15- 7118).

EXAMPLE 21

(R,S)-2-[1 -[2-(1 -Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-2H- naphth[1 ,8-cdJisothiazole 1 ,1 -dioxide, hydrochloride.

Sodium hydride (60 % dispersion in oil) (0.6 g, 14 mmol) was added to a solution of aminoalcohol 4 (3.0 g, 2.7 mmol) in dry tetrahydrofuran (60 ml) at room temperature under nitrogen, and the resulted mixture was stirred for 20 min. Next, dimethyl sulfate (0.6 ml, 2.7 mmol) was added and stirring continued overnight. Reaction was quenched with water (50 ml) and extracted with methylene chloride. The combined organic extracts were dried and evaporated.

The residue was chromatographed (silica gel, methylene chloride / ethyl acetate

6:4, then 1 :1 ) to give methyl ether 21 (1.0 g, 30%) as a white solid, m.p.: 169-

171 °C. TLC: Rf = 0.65 (methylene chloride /ethyl acetate 7:3). H-NMR (CDCI ₃ ): 8.06 (d,1 H); 7.97 (d,1 H); 7.75 (ddJ H); 7.53 (ddJ H); 7.45 (d,1 H); 6.74

(dJ H); 3.68 (d,2H); 3.48 (s,3H); 3.04-2.95 (m,2H); 2.73 (dd,1H); 2.49-2.33 (m,2H); 2J 0-1.34 (m, 22 H). MS: 315(M-179). Anal. Calc'd for C29H38N2O3S: 0,70.41 ; H.7.74; N.5.66. Found: C,70J7; 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.Cab'd for C29H38N2O3S + Hα + 0.5 H2O: C64.44; H.7.41 ; N.5J8; Cl.6.57. Found: C.64.09; H.7.35; N.4.96; 01,6.38.

EXAMPLE 22

(+)-(S)-2-[1-[2-(1 -Adamantyl)-2-methoxyethyl]piperidin-4-ylmethylJ-2H- naphth[1 ,8-cc ]isothiazole 1 J-dioxide, hydrochloride.

The O-methylatbn of the (+)-S-aminoalcohol 19 was performed as described in the Example 21. Methyl ether 22 was obtained in 42 % 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 C29H38N2O3S + HCI + 0.5 H2O: C.64.44; H.7.41 ; N,5J8; CI.6.57. Found: 0,64.29; H,7.61 ; N.5.11 ; Cl, 6.56 . [a] _D ²⁰ = + 13.2° (c 1 , CHCl3).

EXAMPLE 23

(-)-(R)-2-[1 -[2-(1 -Adamantyl)-2-methoxyethyl]piperidin-4-ylmethyl]-2H- naphth[1 ,8-ccφsothiazole 1 ,1 -dioxide, hydrochloride.

The O-methylation of the (-)-R-aminoalcohol 20 was performed as described in the Example 21. Methyl ether 23 was obtained in 55 % yield. ¹ H- NMR (CDCI3): identical to that of racemic methyl ether 21.

The hydrochbride salt was prepared according to the procedure 2 (e) as a white hygroscopic foam. Anal.Cab'd for C29H38N2O3S + HCI + H2O: 0,63.38; H.7.47; N.,5.10; 01,6.47. Found: 0,63.60; H.7.51 ; N.5.13; Cl.6.55. [a] _D o = - 17.3° (c 1 , CHCI ₃ ).

EXAMPLE 24

(R,S)-2-[1-[2-(1-Adamantyl)-2-ethoxyethyl]piperidin-4-ylm ethyl]-2H- naphth[1 ,8-cc sothiazole 1 ,1-dioxide, fumarate.

A solution of the mesylate 12(a) (2.5 g, 45 mmol) in efianol (50 ml) was heated under reflux for 2 hrs. After evaporation 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 bicarbonate. The organb phase was dried and concentrated. Residue was chromatographed (silica gel, methylene chloride / methanol 95:5) to give a white solid (0.76 g) which was recrystallized from ethyl acetate yielding eliyl etιer 24 (0.55 g, 31%). Mp.: 1623-

1633 °C. TLC: Rf= 02 (ethyl acetate /hexane 3:7).

¹ H-NMR (CDCI3): 8.06 (d,1 H); 7.97 (d,1 H); 7.75 (dd,1H); 7.53 (dd,1H); 7.45

(d,1 H); 6.74 (d,1 H); 3.8 (m,1 H); 3.68 (d,2H); 3.5 (m,1 H); 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.: 206.7-207.4°C. Anal. Calc'd for C34H44N2O7S: C.65.36; H.7.10; N.4.48. Found: 0,65.25; H.6.99; N.4.59.

EXAMPLE 25

(-)-2-[1 -[2-(1 -Adamantyl)-2-ethoxyethyl]piperidin-4-ylmethyl]-2H-naphth[1 ,8- ccφsothiazole 1 ,1 -dioxide.

a) (-)-1 -(1-Adamantyl)-1 -camphosulfonyloxy-2-[4-(2H-naphth[1,8-

co]isothiazol-2-ylmethyl)piperidin-1 -yljethane S,S-dioxide.

The sulfonylatbn of the racemic aminoalcohol 4 (5.8 g, 12.08 mmol) with (1 S)-(+)-10-camphorsulphonyl chloride (4.54 g, 18 mmol) was conducted in tetrahydrofuran (180 ml) in the presence of triethylamine (2.52 ml, 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 g, 14.2 %) was eluted first (Rf = 0.46) and crystallized as a white solid, mp : 201-203 °C. [a] ²⁴ = - 40° (c 1 , CHCI3).

b)(-)-2-[1 -[2-(1 -Adamantyl)-2-ethoxyethyl]piperidin-4-ylmethyl]-2H- naphth[1 ,8-cα sothiazole 1 J -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 evaporatbn of the solvent, the residue was diluted with methylene chbride and treated with 0.025 M aqueous sodium hydroxide, then water and saturated aqueous sodium bicarbonate. The organb phase was dried, concentrated under vacuum and the resulting solid was purified by silicagel chromatography (eluent : methylene chbride /methanol 95:5) to give 200 mg (54.5 %) of a white solid, mp : 159.3- 161 °C. TLC: Rf = 0.2 (ethyl acetate/hexane 3:7). The ¹ H-NMR (CDCI3) was identical to that of the Example 24. [ab ²⁴ = 27° (c 1 , CHCI3).

EXAMPLE 26

(R,S)-1-(1-Adamantyl)-1-methyl-2-[4-(2H-naphth[1 ,8-cc|isothiazol-2- ylmethyl)piperidin-1 -yljethanol S,S-dioxide, hydrochloride.

Methyl lithium (1.4 M in ether, 6.0 ml, 8.4 mmol) was slowly added dropwise at 0°C to a stirred suspension of aminoketone 2(e) (4.0 g, 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 added.

Resulted red solution was stirred for 3 h and during that time the red cobur disappeared. Reaction was quenched with water (20 ml) followed by ethyl acetate (100 ml) and brine (30 ml). The layers were separated and the aqueous one was extracted with methylene chbride (50 ml). The combined

organic phases were dried and concentrated. Residue was purified by column chromatography (silica gel, hexane / ethyl acetate 6:4, then methylene chbride /ethyle acetate 1 :1 ) to afford aminoalcohol 26 (0.5 g, 12 %) as a white solid, m.p.: 78-81 °C. TLC: Rf = 0.66 (hexane / ethyl acetate 6:4). MS: 315 (M-179). Anal. Calc'd for C29H38N2O3S: 0,70.41 ; 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 C29H38N2O3S + Hα +1.1 H2O: C.63.22; H.7.54; N.5.08; 01,6.43. Found: C.63.26; H.7.48; N _. 5.01 ; Cl _. 6.25.

EXAMPLE 27

(R,S)-1 -Cyclohexyl-2-[4-(2H-naphth[1 ,8-cc(]isothiazol-2-ylmethyl)piperidin-1 - yljethanol S,S-dioxide, hydrochloride.

a) 1 -Cyclohexyl-2-chloroethan-1 -one.

A solution of cyclohexanecarbonyl chloride (2.0 ml, 15 mmol) in diethyl ether (6 ml) was slowly added at room temp, over 30 min. to the etheral solution of diazomethane (prepared from Diazald (Aldrich) (10.0 g, 46.7 mmol) according to Hudlicky M. J. Org. Chem., 1980, 45, 5377-5378). The reaction was conducted for 1 h. Next, hydrogen chbride 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 carbonate solution. Organic solution was dried and evaporated. Residual liquid was treated with saturated aqueous sodium bicarbonate solution and stirred for 2 h. Mixture was extracted with ether, combined extracts were dried and evaporated to give fairly pure chloromethylketone 27(a) (1.1 g, 46%) as a yellow liquid.

b)2-[(1-(2-Cyclohexyl-2-oxoethyl)-4-piperidinyl)methyl]-2 H-naphth[1 ,8- cc sothiazole 1 ,1 -dioxide.

A mixture of chloromethylketone 27(a) (1.4 g, 8.3 mmol), hydrochloride 2(d) (2.5 g, 7.3 mmol), anhydrous potassium carbonate (1.2 g, 8.3 mmol) and sodium iodide (1.4 g, 8.3 mmol) in 30 ml of acetonitrile was vigorously stirred under reflux for 3 h. After cooling, water (60 ml) was added, resulted mixture stirred for 20 min., and then extracted twice with methylene

chbride (100 ml). The combined organic layers were dried and evaporated to give crude aminoketone 27(b) (3.0 g, 100%) which was sufficiently pure for the next step.

c)(R,S)-1 -Cyclohexyl-2-[4-(2H-naphth[1 ,8-cd]isothiazole-2- ylmethyl)piperidin-1 -yljethanol S,S-dioxide, hydrochloride.

Reduction of the aminoketone 27(b) (3.0 g, 7 mmol), according to the method described in Example 1 (d), folbwed by purification by column chromatography (silica gel, methylene chbride / ethyl acetate 7:3, then 1 :1 ) gave aminoalcohol 27(c) (1.9 g, 63%) as a white solid, m.p.: 148-150 °C. TLC:

Rf = 0.12 (methylene chbride / ethyl acetate (98:2). MS: 429 (M+1 ). Anal.

Calc'd for C24H32N2O3S: 0,67.26; H.7.53; N.6.54. Found: 0,67.11 ; H.7.57;

N.6.40.

The hydrochbride salt was prepared according to the usual procedure 2(e) as a white solid, m.p.: 262.7-264 °C. Anal.Cab'd for C24H32N2O3S + 1.75 HO:

C58.54; H.6.91 ; N,5.69; CIJ2.60. Found: C.58.38; H,6.89; N,5.64; 01,12.69.

EXAMPLE 28

(R,S)-1 -(1 -Adamantyl)-2-[4-(2-chlorophenothiazin-10-ylmethyl)piperidin -1 -ylj¬ ethanol, hydrochloride.

a) N- ten ^* -Butoxycarbonyl-4-[10-(2-chlorophenothiazyl)methylJpip eridine. Compound 28(a) was prepared from 2-chlorophenothiazine (5 g,

21.4 mmol) and N-tet -butoxycarbonyl-4-(methanesulphonyloxymethyl) piperidine (15.0 g, 50 mmol) according to the method described in Example 2(c), but reactbn was performed in boiling p-xylene over 40 hrs and without addition of sodium iodide. The crude product, obtained after usual extractive work-up of the reactbn mixture, was chromatographed (silica gel, ethyl acetate / hexane 1 :9) yielding 28(a) (3.5 g, 38%) as a slightly yellow foam.

b) 4-[10-(2-Chlorophenothiazyl)methylJpiperidine hydrochloride.

Removal of the N-tert-butoxycarbonyl protecting group from 28(a) was performed in the presence of hydrogen chbride as described in Example 2(d). The title piperidine hydrochloride 28(b) was obtained in 96% yield as a white solid, m.p.: 248-250 °C.

c)10-[(1 -(2-(1 -Adamantyl)-2-oxoethyl)-4-piperidinyl)methyl]-2-chloro- phenothiazine.

Hydrochloride 28(b) (3.19 g, 8.69 mmol) and l -(bromoacetyl) adamantane (2.38g, 9.25 mmol) were reacted in boiling acetonitrile (35 ml) in the presence of anhydrous potassium carbonate (1.25 g, 9.04 mmol) folbwing the method descrbed in Example 1 (c). The aminoketone 27(c) (3.4 g, 77 %) was obtained as a cream colored solid, m.p.: 178-181 °C.

d)(R,S)-1-(1-Adamantyl)-2-[4-(2-chlorophenothiazin-10-ylm ethyl)- piperidin-1 -yljethanol, hydrochloride.

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 chbride 5:95, then 10:90) afforded aminoalcohol 28(d) in 90% yield as a white solid, m.p.: 215-217 °C. TLC: Rf = 0.5 (ethyl acetate / hexane 1 :1 ). MS: 343 (M-165). Anal. Calc'd for C30H37CIN2OS: C.70.77; H,7.32; N.5.50. Found: C71.07; H.7.54; N.5.45. The title hydrochloride salt was prepared following the usual procedure 2(e) as a white solid, m.p.: 256-258 °C. Anal. Calc'd for C30H37CIN2O1S + Hα: C66.04; H.7.02; N.5.13; 01,13.00. Found: 0,65.86; H.6.97; N,5.10; CIJ3.02.

EXAMPLE 29

(R,S)-1 -(1 -Adamantyl)-2-[4-(phenothiazin-10-ylmethyl)piperidin-1 -yljethanol, hydrochloride.

a) N-fert-Butoxycarbonyl-4-[(10-phenothiazyl)methyl]piperidine. Compound 29(a) was prepared from phenothiazine (4.4 g, 22 mmol) and N-fet -Butoxycarbonyl-4-(methanesulphonyloxymethyl)piperidine (6.0 g, 20 mmol) according to the method described in Example 2(c). Column chromatography (silica gel, ethyl acetate / hexane 15:85, Rf = 0.3) gave 29(a) (8 g, 97%) as a brown solid, m.p.: 104-106 °C.

b) 4-[(10-Phenothiazyl)methyl]piperidine.

Removal of the N-tert-butoxycarbonyl protecting group in 29(a) was performed with hydrogen chbride, as described in Example 2(d), to produce 29(b) hydrochloride salt in 87 % yield as a white solid, m.p.: 137-139 °C. The basic work-up gave the title free amine 29(b) in 95% yield as a white solid, m.p.: 83-85 °C.

c)10-[[1-[2-(1-Adamantyl)-2-oxoethyl]-4-piperidinyl]rneth yl]- phenothiazine. Amine 29(b) (4.7 g, 15 mmol) and 1 -(bromoacetyl)adamantane

(4.8 g, 18 mmol) were converted to the aminoketone 29(c) (5.9 g, 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 chbride 1 :1).

d) (R,S)-1 -(1-Adamantyl)-2-[4-(phenothiazin-10-ylmethyl)piperidin-1 -ylj¬ ethanol, hydrochloride.

Aminoketone 29(c) was reduced according to the procedure described in the Example 1 (d). Crude product was recrystallized from chbroforme / diethyl ether to give pure aminoalcohol 29(d) in 73% yield as a white solid, m.p.: 254-256°C. TLC: Rf = 0.2 (ethyl acetate/methylene chloride

1 :1 ).

Folbwing procedure 2(e), the hydrochbride salt 29(d) was prepared in 50% yield after recrystallisation from ethanol / diethyl ether. A white solid, m.p.: 266- 268°C. MS: 474 (M ⁺ ). Anal. Calc'd for C30H39CIN2OS: C,70.49; H.7.69; N, 5.48; 01,6.94. Found: C.70.39; H.7.70; N.5.57; Cl.6.82.

EXAMPLE 30

(R,S)-1-(1-Adamantyl)-2-[4-(phenoxazin-10-ylmethyl)piperi din-1 -yljethanol, fumarate.

a) N-terf-Butoxycarbonyl-4-[(10-phenoxazyl)methyl]piperidine. Compound 30(a) was prepared from phenoxazine (2.91 g, 15.9 mmol) and N-tert-Butoxycarbonyl-4-(methanesulphonyloxymethyl)piperidin e (4.16 g, 14 mmol) according to the method described in Example 2(c). The

crude product was chromatographed (silica gel, ethyl acetate / hexane 15:85, Rf = 0.3) to afford 30(a) (3.0 g, 54%) as a grey solid, m.p.: 156-158°C.

b) 4-[(10-Phenoxazyl)methyl]piperidine. Removal of the N-tert-butoxycarbonyl protecting group in 30(a) was performed with hydrogen chbride, as described in Example 2(d), to produce 30(b) hydrochbride salt in 77 % yield as a white solid, m.p.: 252- 254°C.

The free amine 30(b) was obtained in usual manner in quantitative yield as a white solid, m.p.: 131-133°C.

c)10-[[1 -[2-(1 -Adamantyl)-2-oxoethyl]-4-piperidinylJmethylJ- phenoxazine.

Amine 30(b) (1.6 g, 5.5 mmol) and 1 -(bromoacetyl)adamantane (1.6 g, 6.05 mmol) were converted to aminoketone 30(c) (2 g, 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-10-ylmethyl)piperidin-1-ylJ- ethanol, fumarate.

Reduction of the aminoketone 30(c) was performed folbwing the method described in Example 1 (d). Purification by chromatography (silica gel, ethyl acetate / methylene chbride 3:7) furnished aminoalcohol 30(d) in 87% yield as a solid, m.p.: 180-182°C. TLC: Rf = 0.3 (ethyl acetate / methylene chloride 3:7).

The fumarate salt was crystallized from ethanol in 37% 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 C ₃₄ H ₄₂ N ₂ O ₆ : C,71.06; H.7.37; N.4.87. Found: 0,71.38;

H.7.87; N.4.96. Fumarate salt 30(d) contained ca. 5 % of ethanol (basis on ¹ H-NMR). The salt decomposed slowly when exposed to light.

EXAMPLE 31

(R,S)-1 -(1 -Adamantyl)-2-[4-(5H-dibenz[b,f]azepin-5-ylmethyl)piperidin- 1 - yljethanol, fumarate.

a) N-fert-Butoxycarbonyl-4-[5-(5H-dibenz[b,fJazepinyl)methyl]pi peridine.

Compound 31(a) was prepared from 5/--dibenz[b,f]azepine (4.25 g, 22 mmol) and N-tert-butoxycarbonyl-4-(methanesulfonyloxymethyl) piperidine (6.54 g, 22 mmol) according to the method described in Example 2(c). The crude product was chromatographed (silicagel, methylene chbride / hexane 7:3) to give 31 (a) (3.9 g, 45 %) as a viscous oil.

b) 4-[5-(5H-Dibenz[b,f]azepinyl)methylJpiperidine.

Removal of the N-tert-butoxycarbonyl protecting group in 31(a) was performed with hydrogen chloride, as described in Example 2(d), to give 31 (b) hydrochloride quantitative yield as a gummy solid. The free amine 31 (b) was obtained after usual basic work-up in 79 % yield as a yellow oil.

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

1 -yljethanol, fumarate.

Reaction of the (l -adamantyl)ethylene oxide (0.865 g, 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. Purif ation by column chromatography (silica gel, methylene chloride/methanol 9:1 ) afforded aminoalcohol 31(c) (0.630 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 % as a yellow powder, m.p.: 225-227°C. MS: 468 (M ⁺ ). Anal. Calc'd for C36H44N2O5: 0,73.94; H,7.58; N.4.79. Found: 0,73.66; H.7.65;

N.5.05.

EXAMPLE 32

(R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihydro-5H-dibenz[b,f]a zepin-5-ylmethyl)- piperidin-1 -yljethanol, fumarate.

a) N-tert-Butoxycarbonyl-4-[5-(10,11 -dihydro-5H-dibenz[b,f]azepinyl) methyljpiperidine.

Compound 32(a) was prepared from 10,11 -dihydro-5H- dibenz[b,fjazepine (4.43 g, 22 mmol) and N-tert-Butoxycarbonyl-4- (methanesulfonybxymethyl)piperidine (6 g, 20 mmol) according to the method described in Example 2(c). The crude product was chromatographed (silica gel, methylene chloride / hexane 8:2, Rf = 0.3) to give 32(a) (6.6 g, 76%).

b) 4-[5-(10,11-dihydro-5H-dibenz[b,f]azepinyl)methyl]piperidine . Removal of the N-tert-butoxycarbonyl protecting group in 32(a) was performed with hydrogen chbride, as described in Example 2(d), giving piperidine 32(b) hydrochloride in 79 % 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-(10,1 1 -dihydro-5H-dibenz[b,f]azepin-5- ylmethyl)piperidin-1 -yljethanol, fumarate.

Reaction of the (l -adamantyl)ethylene oxide (0.980 g, 5 mmol) with piperidine 32(b) (1.46 g, 5 mmol) was conducted according to the method described in the Example 1 1(b), but over 7 hrs. Purification by column chromatography (silica gel, methylene chbride / methanol 9:1 ) furnished the title aminoalcohol 32(c) (1.2 g, 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 % yield as a white solid, m.p.: 192-194°C. MS: 471 (M+1 ). Anal. Calc'd for C36H46N2O5 + H2O: C.71.50; H,8.00; N.4.63. Found: C.71.70;

H,7.91 ; N,4.95.

EXAMPLE 33

(R,S)-1-(1 -Adamantyl)-2-[4-(5H-phenanthridin-6-oxo-5-ylmethyl)piperidi n-1 * yljethanol, hydrochloride.

a) N-tert-Butoxycarbonyl-4-[5H-phenanthridin-6-oxo-5-yl)methylJ - piperidine.

Compound 33(a) was prepared from 6-(5H)-phenanthridinone

(4.3 g, 22 mmol) and N-tert-butoxycarbonyl-4-(methanesulfonyloxymethyl) piperidine (6.0 g, 20 mM) according to the method described in Example 2(c).

The crude product was chromatographed (silica gel, ethyl acetate / hexane 3:7,

Rf = 0.25) to give 33(a) (4.5 g, 57%) as a white solid, m.p.: 76-79 °C.

b) 4-[5H-Phenanthridin-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 % 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.

c) 5-[[1 -[2-(1 -Adamantyl)-2-oxoethyl]-4-piperidinylJmethyl]-6-(5H)- phenanthridinone.

Folbwing procedure 1 (c), amine 33(b) hydrochloride (3.7 g, 11.3 mmol) and 1 -(bromoacetyl)adamantane (3.4 g, 13 mmol) were reacted together in acetonitrile (60 ml) containing potassium carbonate (1.7g, 12 mmol). Column chromatography (silica gel, hexane / ethyl acetate / triethylamine 12:8: 1) gave aminoketone 33(c) (3.1 g, 59%) as a pale pink solid, m.p.: 98-100 °C.

d)(R,S)-1-(1-Adamantyl)-2-[4-(5H-phenanthridin-6-oxo-5-yl methyl)- piperidin-1 -yljethanol, hydrochloride.

Aminoketone 33(c) was reduced folbwing the method described in the Example 1 (d). Purification by column chromatography (silica gel, methylene chbride / ethyl acetate / methanol 50:50:1 ) afforded aminoalcohol 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). H-NMR (CDCI ₃ ): 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,1H); 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.Cab'd for C31H38N2O2: C.79.11 ; H.8.14; N.5.95. Found: C.79.28; H.8.28; N.5.77.

The title hydrochbride salt was prepared according to example 2(e) in 50 % yield as a white solid, m.p.: 193.5-194.5 °C. Anal. Calc'd for C31H38N2O2 +

(HCI)1.75: 0,69.67; H,7.50; N,5.24; 01,11.61 . Found: C69.67; H,7.57; N,5.23;

01,11.56.

¹ H-NMR (CDCI ₃ ): 10.55 (bsJ H); 8.45 (dd, 1 H); 8.25 (m, 2H); 7.75 (t, 1 H);

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);

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).

EXAMPLE 34

(+)-(S)-1-(1-Adamantyl)-2-[4-(5H-phenanthridin-6-oxo-5-yl methyl)piperidin-1- yljethanol, hydrochloride.

Reaction of (+)-S-(1 -adamantyl)ethylene oxide (0.500 g, 2.8 mmol) with piperidine 33(b) (0.818 g, 2.8 mmol) was conducted according to the method described in the Example 1 1(b), but over 72 hrs. Column chromatography

(silica gel, methylene chbride / methanol 20:1) gave aminoalcohol 34 (0.980 g,

75%) as a foam. [a] _D ²⁰ = + 28.8° (c 1.1 , CHCI ₃ ). TLC: Rf = 0.2 (methylene chloride / methanol 20:1). ¹ H-NMR (CDCI3): identical to that of racemic aminoalcohol 33(d).

The hydrochloride salt 34 was prepared in 90 % yield according to the usual procedure 2(e). White powder, m.p.: 195-197 °C. [a] _D ²⁰ = + 14.2 ° (c 1 ,

CHCI ₃ ). ¹ H-NMR (CDCI3): identical to that of hydrochloride salt 33(d). Anal. Calc'd for C31H38N2O2 + HO + H2O: 0,70.90; H.7.87; N.5.33; Cl.6.75. Found: 0,70.59; H.7.82; N.5.26; 01,6.81.

EXAMPLE 35

(-)-(R)-1-(1-Adamantyl)-2-[4-(5H-phenanthridin-6-oxo-5-yl methyl)piperidin-1- yljethanol, hydrochloride.

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

20:1)to give aminoalcohol 35 (0.980 g, 74%) as a white powder, m.p.: 101 - 103°C. [a] _D ²⁰ = - 30.5 ° (c 1 , CHCI ₃ ). TLC: Rf = 0.2 (methylene chbride / methanol 20:1 ). ¹ H-NMR (CDCI3): identical to that of aminoalcohol 33(d).

The hydrochbride salt 35 was prepared in 90 % yield according to the usual method 2(e). White powder, m p : 269-271 °C. [a] _D ² ° = - 18.5 ° (c 1 , CHCI ₃ ).

¹ H-NMR (CDCI3): identical to that of hydrochloride 33(d).

Anal. Calc'd for C31H38N2O2 + HCI + 1.3 H2O: 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.

EXAMPLE 36

(R,S)-1 -(1 -Adamantyl)-2-[4-(10,11 -dihydrodibenz[b,f][1 ,4]oxazepin-11 -oxo-10- ylmethyl)piperidin-1 -yljethanol, hemitartrate.

a) N-tert-Butoxycarbonyl-4-[(10,11 -dihydrodibenz[b,fJ[1 ,4Joxazepin-11- oxo-10-yl)methyl]piperidine.

Compound 36(a) was prepared from 10,11 - dihydrodibenz[b,f][1 ,4]-oxazepin-1 1-one (4.3 g, 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 chbride 1 :9) affording 36(a) (6 g, 74 %) as an orange oil. TLC: Rf = 0.3 (ethyl acetate /methylene chloride 1 :9).

b) 4-[(10,11 -Dihydrodibenz[b,f][1 ,4]oxazepin-11 -oxo-10-yl)methylJ piperidine.

Removal of the N-tert-butoxycarbonyl protecting group in 36(a) was performed with hydrogen chbride, as described in Example 2(d), to give piperidine 36(b) hydrochloride in 53% yield as a white powder, m.p.: > 250 °C. The free amine 36(b) was obtained, after usual basic work-up, in 90 % yield as a foam.

c)10-[[1 -[2-(1 -Adamantyl)-2-oxoethyl]-4-piperidinyl]methylJ-10,11 - dihydrodibenz[b,f][1 ,4]oxazepin-11 -one.

Piperidine 36(b) (2.7 g, 8.8 mmol) and l -(bromoacetyl) adamantane (2.83 g, 11 mmol) were converted to aminoketone 36(c) (3 g,

70%), as described in Example 1 (c). The pure product was obtained after chromatography (silica gel, hexane / ethyl acetate 1 :1 ) as a pale yellow oil. TLC: Rf = 0.2 (hexane / ethyl acetate 1 :1). d) (R,S)-1-(1-Adamantyl)-2-[4-(10,H -dihydrodibenz[b,f][1 ,4]oxazepin- 11 -oxo-10-ylmethyl)piperidin-1 -yljethanol, hemitartrate.

Aminoketone 36(c) (3 g, 6 mmol) was reduced folbwing the procedure 1 (d). Column chromatography (silica gel, methylene chbride / methanol 95:5) gave aminoalcohol (1.7 g, 58%) as a foam. TLC: Rf = 0.5 (methylene chloride / methanol 9:1 ).

The hemitartrate salt 36(d) was crystallized, in a usual way, from ethanol in 69% yield as a white solid, m.p.: 221 J -223.4°C. MS: 321 (M-165). Anal. Calc'd for C33H41N2O6 + 1.25 H2O: C67.78; H.7.45; N.4.81. Found: 0,67.70; H,7.29; N.4.81.

EXAMPLE 37

(R,S)-1 -(1 -Adamantyl)-2-[4-(10,11 -dihydrodibenzo[b,eJ[1 ,4]diazepin-11 -oxo- 10-ylmethyl)piperidin-1 -yljethanol, hydrochloride.

a) N-fert-Butoxycarbonyl-4-[(10,H-dihydrodibenzo[b,f][1 ,4]diazepin-11- oxo-10-yl)methyl]piperidine.

Compound 37(a) was prepared from 10,11 - dihydrodibenzo[b,e][1 ,4]diazepin-11 -one (4.6 g, 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 chbride 1 :9) yielding 37(a) (3.2 g, 39 %) as an oil. TLC: Rf = 0.4 (diethyl ether / methylene chbride 2:8).

The starting 10, 11 -dihydrodibenzo[b,e][1 ,4jdiazepin-11 -one was prepared according to Monro A.M. et al.[J. Med. Chem. 1963, 255-261 j.

b) 4-[(10,11-Dihydrodibenzo[b,e][1 ,4]diazepin-1 l -oxo-10- yl)methyl]piperidine.

Removal of the tert-butybxycarbonyl protecting group in 37(a) was performed with hydrogen chloride, as described in Example 2(d), to give piperidine 37(b) hydrochloride in quantitative yield as a powder, m.p.: > 250 °C.

The free amine 37(b) was obtained in a usual way, in quantitative yield as a foam. c) (R,S)-1-(1-Adamantyl)-2-[4-(10,11-dihydrodibenzo[b,eJ[1 ,4Jdiazepin- 11-OXO-10-ylmethyl)piperidin-1 -yljethanol, hydrochloride. Reaction of the (l -adamantyl)ethylene oxide (0.500 g, 2.8 mmol) with piperidine 37(b) (0.860 g, 5 mmol) was conducted according to the method described in Example 11(b), but over 48 hrs. Purification by column chromatography (silica gel, methylene chbride / methanol 20: 1) afforded aminoalcohol 37(c) (1.04 g, 77%) as a white foam. TLC: Rf = 0.44 (methylene chloride / methanol 9:1 ).

The hydrochloride salt 37(c) was prepared, following general procedure 2(e), in 69% yield as a white solid, m.p.: 196-198°C. MS: 320 (M-165). Anal. Calc'd for C31H39N3O2 + Hα + 0.5 H2O: C70.06; H.7.72; N,7.90;CI,6.68. Found : 0,70.07; H.7.94; N,7.76;CI,6.77.

EXAMPLE 38

(R,S)-1 -(1 -Adamantyl)-2-[4-(10, 11 -dihydrodibenzo[b,f][1 ,4]thiazepin-11 -oxo- 10-ylmethyl)piperidin-1 -yljethanol, fumarate.

a) N-tert-Butoxycarbonyl-4-[(10,H-dihydrodibenzo[b,f][1 ,4]thiazepin-11- oxo-11-yl)methyl]piperidine.

Compound 38(a) was prepared from 10,11 - dihydrodibenzo[b,f][1,4Jthiazepin-11 -one (2.27 g, 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 subjected to column chromatography (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-dihydrodibenzo[b,fJ[1,4Jthiazepin-11-one was prepared according to JAQUES etal. [Helv. Chim. Acta 1959, 1265J.

b) 4-[(10,11 -Dihydrodibenzo[b,f][1 ,4]thiazepin-11 -oxo-10-yl)methyl] piperidine.

Removal of the tert-butybxycarbonyl protecting group in 38(a) was performed with hydrogen chbride, as described in Example 2(d), to give piperidine 38(b) hydrochbride in 84 % 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,H-dihydrodibenzo[b,f][1 ,4]thiazepin- 11-0X0-10-ylmethyl)piperidin-1 -yljethanol, fumarate.

Reaction of the (l -Adamantyl)ethylene oxide (0.470 g, 2.6 mmol) with piperidine 38(b) (0.860 g, 2.6 mmol) was conducted according to the method described in Example 1 1(b), but over 72 hrs. Column chromatography (silica gel, methylene chloride / methanol 9:1 ) gave aminoalcohol 38(c) (0.800 g, 61 %) as a white solid, m.p.: 217-220°C. TLC: Rf = 0.2 (methylene chbride / methanol 20:1).

The fumarate salt 38(c) was crystallized from ethanol, folbwing usual procedure, in 72 % yield as a white solid, m.p.: 207-209°C. MS: 337 (M-165). Anal. Calc'd for C35 H42N2O6S : 0,67.94; H.6.84; N.4.53. Found: 0,67.73; H.6.85; N.4.43.

EXAMPLE 39

(R,S)-1 -(1-Adamantyl)-2-[4-(5,6,H J2-tetrahydrodibenz[b,f]azocin-6-oxo-5- ylmethyl)piperidin-1 -yljethanol, maleate.

a) N-tert-Butoxycarbonyl-4-[(5,6,11 ,12-tetrahydrodibenz[b,f]azocin-6- oxo-5-yl)methyl]piperidine. Compound 39(a) was prepared from 5,6,1 ,12- tetrahydrodibenzo[b,f]azocin-6-one (5 g, 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 (silica gel, ethyl acetate / methylene chloride 1 :9) to produce 39(a) (7.8 g, 90%) as a white solid, m.p.: 122-124°C. TLC: Rf = 0.7 (ethyl acetate / methylene chloride 1 :9).

b) 4-[(5,6,11 J2-tetrahydrodibenz[b,f]azocin-6-oxo-5-yl)methyl] piperidine.

Removal of the N-tert-butoxycarbonyl protecting group in 39(a) was performed with hydrogen chbride, as described in Example 2(d), to give piperidine 39(b) hydrochloride as a white powdered solid, m.p.: 154-156°C. The usual basic work-up afforded free amine 39(b) (4g, 67%) as a white solid, m.p.: 114-116°C.

c) 5-[[1 -[2-(1 -AdamantylJ^-oxoethylJ^-piperidinylJmethylJ-δ.β, 11 ,12- tetrahydrodibenz[b,fJazocin-6-one.

The piperidine 39(b) (3.9 g, 11.7 mmol) and l-(bromoacetyl) adamantane (3.6 g, 14 mmol) were converted to the aminoketone 39(c) (3.1 g,

53%) folbwing the procedure 1 (c). The pure product was obtained after column chromatography (silica gel, methylene chbride / ethyl acetate 1 J ) as a pale yellow oil. TLC: Rf = 0J5 (hexane / ethyl acetate 1 :1).

d) (R,S)-1 -(1-Adamantyl)-2-[4-(5,6, 11 J2-tetrahydrodibenz[b,fJazocin-6- oxo-5-ylmethyl)piperidin-1 -yljethanol, maleate.

Aminoketone 39(c) (3 g, 6 mmol) was reduced according to procedure 1 (d). Purifbation by column chromatography (silica gel, methanol/methylene chbride 5:95) gave aminoalcohol 39(d) in quantitative yield as a white solid, m.p.: 162.5-164.4 °C. TLC: Rf = 0.5 (methylene chbride

/ methanol 9:1 ).

The maleate salt 39(d) was crystallized from ethanol / diethyl ether, in a usual way, in 81% yield as a white solid, m.p.: 224.5-225.5°C. MS: 333 (M-165). Anal.

Calc'd for C37H46N2O6 + 0.25 H2O: 0,71.84; H.7.54; N.4.56. Found: C,71.80;

H.7.65; N.4.68.

EXAMPLE 40

(R,S)-1-(1-Adamantyl)-2-[4-(5,6,H J2-tetrahydrodibenz[b,f]azocin-5- ylmethyl)piperidin-1 -yljethanol, fumarate.

a) N-tert-Butoxycarbonyl-4-[(5,6J 1,12-tetrahydrodibenz[b,f|azocin-5- yl)methyl]piperidine.

Compound 40(a) was prepared from 5,6,1 1, 12- tetrahydrodibenzo[b,f]azocine ( 3.81 g, 18 mmol) and N-tert-butoxycarbonyl-4-

(methanesulfonybxymethyl)piperidine (5.41 g, 20 mmol) according to the method described in Example 2(c). Column chromatography (silica gel, ethyl acetate / methylene chloride 1 :9) gave 40(a) in 80 % yield.

b) 4-[(5,6,11 J2-tetrahydrodibenz[b,f]azocin-5-yl)methyl]piperidine.

Removal of the tert-butoxycarbonyl protecting group in 40(a) was performed with hydrogen chloride, as described in Example 2(d), to give piperidine 40(b) hydrochloride as an oil. The usual basic work-up furnished free amine 40(b) as a foam in 80 % overall yield.

c) 5-[[1-[2-(1-Adamantyl)-2-oxoethyl]-4-piperidinyl]methylJ-5,6 ,11 ,12- tetrahydrodibenz[b,f]azocine. The piperidine 40(b) (3.49 g, 11.4 mmol) was reacted with 1 -

(bromoacetyl)adamantane (3.2 g, 12.5 mmol) folbwing the procedure 1 (c).

Purification by column chromatography (silica gel, methylene chbride / methanol 97:3) afforded aminoketone 40(c) (1.4 g, 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 ,12Jetrahydrodibenz[b,fJazocin-5- ylmethyl)piperidin-1 -yljethanol, fumarate.

Reduction of the aminoketone 40(c) (1.36 g, 2.8 mmol), according to the method described in Example 1 (d), folbwed by column chromatography (silica gel, methylene chloride / ethyl acetate 5:1 ) gave aminoalcohol (0.57 g,

42%) as a white solid, m.p.: 153.7-154.8°C. TLC: Rf = 0.6 (methylene chloride/methanol 9:1 ).

Folbwing the usual way, fumarate salt 40(d) was crystallized from ethanol in

52 % yield as a white solid, m.p.: 182.0-183.4°C. MS: 319 (M-165). Anal. Calc'd for C37H48N2O5 + H2O: 0,71.82; H,8.14; N.4.53. Found: 0,71.80; H.8.20; N,

4.46.

EXAMPLE 41

(R,S)-1 -(1 -Adamantyl)-2-[4-(6H-dibenzo[c,e][1 ,2]thiazin-6-ylmethyl)piperidin-1 - yljethanol S,S-dioxide, hydrochloride.

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 g, 20 mmol) and N-tert-Butoxycarbonyl-4- (methanesulfonybxymethyl)piperidine (6.0 g, 20 mmol) according to the method described in Example 2(c). Column chromatography (silicagel, ethyl acetate / hexane 3:7, TLC: Rf = 0.2) furnished 41(a) (5.21 g, 61%) as a white solid.

6-(6H-Dibenzo[c,eJ[1 ,2]thiazine 5,5-dioxide was prepared according to Ullmann 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 chbride, as described in Example 2(d), to give piperidine 41(b) hydrochbride 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]methyl]-6H-dibenzo-

[c,e][1 ,2]thiazine 5,5-dioxide.

Reaction of amine 41(b) (2.4 g, 7.4 mmol) with 1 -

(bromoacetyl)adamantane (2.1 g, 8.1 mmol) was performed as described in

Example 1 (c). Column chromatography (silicagel, methylene chbride / ethyl acetate 1 :1 , TLC: Rf = 0.27) gave aminoketone 41(c) (2.7 g, 72%) as a white solidified foam.

d) (R,S)-1 -(1-Adamantyl)-2-[4-(6H-dibenzo[c,eJ[1 ,2Jthiazin-6- ylmethyl)piperidin-1 -yljethanol S,S-dioxide, hydrochloride. Reduction of aminoketone 41 (c) (2.6 g, 5.1 mmol), according to the method descri bed in Example 1 (d), followed by column chromatography (silicagel, methylene chloride / ethyl acetate 1 :1 ) gave aminoalcohol 41 (d) (1.8 g, 70%) as a solidified foam. TLC: Rf = 0.3 (ethyl acetate / methylene chloride 1 :1 ). ¹ H-NMR (CDCI ₃ ): 8.00 (m, 3H); 7.70 (t, 1 H); 7.55 (t,1 H); 7.45 (d, 1 H); 7.35 (m,2H); 3.85 (d, 2 H); 3.15 (dd, 1 H); 3.00 (bd, 1 H); 2.7 (bd, 1 H); 2.4-1.2 (m, 24 H). Folbwing procedure 2(e), the title hydrochloride salt 41(d) was prepared in

62% yield as a white solid, m.p.: 242-244°C. Anal. Calc'd for C ₃₀ H ₃₉ CIN ₂ O ₃ S: 0,66.34; 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). ¹ H-NMR (CDCI ₃ ): 10.3 (bs, 1 H); 8.00 (m, 3H); 7.75 (m, 1 H); 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, 2H); 2.2-1.4 (m, 19 H).

EXAMPLE 42

(+)-(S)-1 -(1 -Adamantyl)-2-[4-(6H-dibenzo[c,e][1 ,2]thiazin-6-ylmethyl)piperidin- 1 -yljethanol S.S-dioxide, hydrochloride.

Reaction of (+)-(S)-(1-adamantyl)ethylene oxide (0.500 g, 2.8 mmol) with piperidine 41(b) (0.923 g, 2.8 mmol) was conducted according to the method described in Example 11 (b), but over 72 hrs. Column chromatography (silicagel, methanol / methylene chloride 20:1 ) furnished aminoalcohol 42 (1.13 g, 80%) as a solidified foam. [a] _D 0 = + 22.8° (c 1.1 , CHCI ₃ ). TLC: Rf = 0.3 (methanol / methylene chbride 1 :20). ¹ H-NMR (CDCI3): identical to that of the racemic aminoalcohol 41 (d). 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] _D ²⁰ = + 12.5° (c 0.7, CHCI ₃ ). ¹ H-NMR

(CDCI3): identical to that of the hydrochloride 41 (d).

Anal. Calc'd for CaoHagCINsOgS: C.66.34; H.7.24; N,5.16; Cl,6.53. Found:

0,66.17; H.7.25; N.5.12; Cl.6.50.

EXAMPLE 43

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

Reaction of the (-)-(R)-(1-adamantyl)ethylene oxide (0.500 g, 2.8 mmol) with piperidine 41(b) (0.923 g, 2.8 mmol) was performed according to the procedure described in Example 1 1(b), but over 60 hrs. Purifbation by column chromatography (silicagel, methanol / methylene chbride 20: 1) afforded aminoalcohol 43 (0.970 g, 68%) as a solidified foam, [ajo ²⁰ = - 27.4° (c 1 ,

CHCI ₃ ). TLC: Rf = 0.3 (methanol / methylene chbride 1 :20). 1 H-NMR (CDCI3): identical to that of the aminoalcohol 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. [ajo ²⁰ = - 15.3° (c 1.1 ,

CHCI ₃ ). ¹ H-NMR (CDCI3): identical to that of the hydrochloride 41 (d).

Anal. Calc'd for C ₃₀ H ₃₈ N ₂ O ₃ S + HCI + 0.3 H ₂ O : 0,65.57; H,7.21; N _. 5.10;

Cl.6.47. Found: 0,65.64; H,7.29; N.5.11 ; Cl.6.44.

EXAMPLE 44

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

The O-methylatbn of the (+)-S-aminoalcohol 42 (0.450 g, 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 (0.200 g, 44%) was obtained as a white solidified foam . ¹ H-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); 2.0-1.2 (m, 22 H).

The hydrochbride salt 44 was prepared according to the usual method 2(e) as a white foam. [a] _D ²⁰ = + 12.1° (c 1 , CHCI ₃ ). MS 341 (M-179).

Anal. Calc'd for C^ H^N- S + HCI + 1.3 H ₂ O: C.64.03; H.7.51; N.4.82; 01,6.11. Found: 0,64.06; H.7.59; N.4.54; 01,6.12.

EXAMPLE 45

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

The O-methylatbn of (-)-R-aminoalcohol 43 (0.450 g, 0.89 mmol) was performed as described in Example 21. Column chromatography (silicagel, ethyl acetate / methylene chloride 2:3, TLC: Rf = 0.2) afforded the title methyl ether 45 (0.170 g, 37%) as a white foam. ¹ H-NMR (CDCI3): identical to that of methyl ether 44.

The hydrochloride salt 45 was prepared according to the usual method 2(e) as a foam. [aj _D ² 0 = - 15.0° (c 1 , CHCI ₃ ).

Anal. Calc'd for + HCI + 1.3 H ₂ O: C64.03; H.7.51 ; N.4.82;

01,6.11. Found: C.63.85; H.7.48; N,4.74; 01,6.31.

EXAMPLE 46

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

a) 8-Fluoro-6H-dibenzo[c,eJ[1 ,2]-thiazine 5,5-dioxide.

To a stirred solution of 3-fluoroaniline (11.11 g, 100 mmol) in ethyl acetate (40 ml) and pyridine (8.2 ml, 100 mmol) was slowly added dropwise a solution of 2-nitrobenzenesulfonyl chbride (22.16 g, 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. After cooling, the reaction mixture was filtered and the solid washed with ethyl acetate. The organic solution was washed with 2N hydrochloric acid, then dried and evaporated. The residue was purified by filtration through a silica pad (hexane / ethyl acetate 1 :1 ). Evaporation of the solvent and recrystallization from toluene-hexane gave 2-nitrobenzenesulfon- 3'-fluoroanilide (23.5 g, 79 %) as pinky crystals, mp : 130.2-132 °C. To a solution of the above o-nitrobenzenesulfonamide (22.2 g, 75 mmol) in ethyl acetate (200 ml) was added tin (II) chloride dihydrate (84.5 g, 375 mmol) and resulted mixture heated at 80°C for 2 hrs. After cooling, the reaction mixture was poured into water (400 ml), the solution was basified with 2N sodium hydroxyde and extracted with ethyl acetate. Combined organb extracts were dried and evaporated to give a waxy solid of 2-aminobenzenesulfon-3'- fluoroanilide (19.97 g, 100%) which was used in the next step without further purification.

To a solution of the above o-aminobenzenesulfonamide (10.65 g, 40 mmol) in acetic acid (30 ml) was added concentrated hydrochloric acid (60 ml). Then, on cooling below 10 °C, a solution of sodium nitrite (3.04 g, 44 mmol) in water (15 ml) was slowly added dropwise. The reactbn mixture was vigorously stirred for 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 extracts were washed with water, dried and evaporated. Residual solid

was purified by filtration through a silica pad (hexane / ethyl acetate 1 :2) and recrystallized from ethanol / hexane yielding fluoro-sultam 46(a) (1.74 g, 18%) as an orange crystalline solid, m.p.: 205.8-206.8 °C. TLC: Rf = 0.43 (hexane / ethyl acetate 1 :1). ¹ H-NMR (DMSO-De): 11.67 (bs, 1 H), 8.30 (dd, I H-C10); 8.22 (dd, 1 H-C4); 7.96 (dd,1 H-Cι); 7.81 (dt, 1 H-C3); 7.65 (dt,1H-C2); 7.18 (dt, 1 H-C9); 7.00 (dd, 1 H-C7). The proton signals were assigned with the aid of H.H-COSY experiment.

b) 4-(8-Fluoro-6H-dibenzo[c,e][1,2Jthiazin-6-ylmethyl)piperidin e S,S- dioxide.

Starting from fluoro-sultam 46(a) and N-tert-butoxycarbonyl-4- (metanesulfonyloxymethyl)piperidine and folbwing 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 -yljethanol S.S-dioxide, fumarate.

Reaction of the (l-adamantyl)ethylene oxide (0.890 g, 5 mmol) with piperidine 46(b) (1.75 g, 5 mmol) was conducted according to the method described in Example 11 (b), but over 12 hrs. Column chromatography (silicagel, methylene chbride / methanol 9:1 , TLC: Rf = 0.54) furnished the title aminoalcohol 46(c) (0.75 g, 28%) as a white solid, m.p.: 247.2-247.8 °C. The fumarate salt 46(c) was crystallized from ethanol / diethyl ether, according to the usual procedure, as a white hygroscopic solid, m.p.: 138.7-140.2 °C. MS: 359 (M-165). Anal. Calc'd for C ₃₄ H ₄₁ FN ₂ O ₇ S + 1/2 H ₂ O: 0,62.77; H,6.46;

N.4.31. Found: C.62.65; H,6.65; N.4.31.

EXAMPLE 47

(R,S)-1 -(1 -Adamantyl)-2-[4-(9-fluoro-6H-dibenzo[c,e][1 ,2Jthiazin-6-ylmethyl)- piperidin- 1 -yljethanol S.S-dioxide, hydrochloride.

a) 9-Fluoro-6H-dibenzo[c,e][1 ,2]thiazine 5,5-dioxide.

The title fluoro-sultam 47(a) was synthesized from 4-fluoroaniline folbwing the sequence of reactbns described in Example 46(a). Reaction with

2-nitrobenzenesulfonyl chbride gave 2-nitrobenzenesulfon-4'-fluoroanilide in 66% yield as a solid, m.p.: 104.7-105.9°C. Next, reduction of the nitro group provided crude 2-aminobenzenesulfon-4'-fluoroanilide in 88% yield. Finally, decomposition of diazonium salt and recrystallization from ethyl acetate / 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)piperidin e S,S- dioxide. Starting from fluoro-sultam 47(a) and N-tert-butoxycarbonyl-4-

(methanesulfonybxymethyl)piperidine and folbwing the usual procedures described in Examples 2(c) and 2(d), the piperidine 47(b) hydrochloride was obtained in 70 % 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-fiuoro-6H-dibenzo[c,e][1 ,2]thiazin-6- ylmethyl)-piperidin-1 -yl]ethanol S.S-dioxide, hydrochloride.

Reaction of (l -adamantyl)ethylene oxide (1.33 g, 7.5 mmol) with piperidine 47(b) (2.6 g, 7.5 mmol) was conducted folbwing the method described in Example 11(b), but over 18 hrs. Purification by column chromatography (silica gel, methylene chbride / methanol 9:1 , TLC: Rf = 0.56) furnished aminoalcohol 47(c) ( 1.4 g, 35%) 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- 165). Anal. Calc'd for C ₃₀ H ₃₈ CIFN ₂ O ₃ S: 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.

EXAMPLE 48

(R,S)-1 -(1 -Adamantyl)-2-[4-(7-fluoro-6H-dibenzo[c,e][1 ,2Jthiazin-6-ylmethyl)- piperidin-1 -yljethanol S.S-dioxide, hydrochloride.

a)7-Fluoro-6H-dibenzo[c,e][1 ,2]thiazine 5,5-dioxide.

The title fluoro-sultam 48(a) was prepared from 2-fluoroaniline folbwing the sequence of reactbns described in Example 46(a). Reaction with 2-nitrobenzenesulfonyl chbride gave 2-nitrobenzenesulfon-2'-fluoroanilide in 54% yield as a pink solid, m.p.: 110.3-1 12.6 °C. Next, reduction of the nitro group provided crude 2-aminobenzenesulfon-2'-fluoroanilide in 88% yield. Finally, decomposition of diazonium salt and recrystallization 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)piperidin e S,S- dioxide.

Starting from fluoro-sultam 48(a) and N-tert-butoxycarbonyl-4-

(methanesulfonybxymethyl)piperidine and folbwing procedures described in

Examples 2(c) and 2(d) , the piperidine 48(b) hydrochloride was prepared in 72 % 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]thi azin-6- ylmethyl)piperidin-1 -yljethanol S.S-dioxide, hydrochloride. Reaction of the (l -adamantyl)ethylene oxide (0.566 g, 3.2 mmol) piperidine 48(b) (1.10 g, 3.2 mmol) was performed according to the method described in the Example 1 1(b), but over 67 hrs. Column chromatography (silica gel, methylene chbride / methanol 20:1, TLC: Rf = 0.32) provided aminoalcohol 48(c) (1.34 g, 80%) as a solidified foam. The hydrochloride salt 48(c) was prepared according to the procedure described in Example 2(e) as a white solid, m.p.: 228.2-230J°C. MS: 359 (M- 165). Anal. Calc'd for C ₃₀ H ₃₈ CIFN ₂ O ₃ S: C64.21 ; H,6.83; N.4.99; Cl.6.32.

Found: C.63.96; H,6.94; N.4.83; Cl,6.40.

EXAMPLE 49

(R,S)-1-(1-Adamantyl)-2-[4-(8-chloro-6H-dibenzo[c,e][1 ,2]thiazin-6-ylmethyl)- piperidin-1 -yljethanol S.S-dioxide, hydrochloride.

a) 8-Chloro-6H-dibenzo[c,e][1 ,2jthiazine 5,5-dioxide.

The title chloro-sultam 49(a) was synthesized from 3-chloroaniline

folbwing the sequence of reactbns described in Example 46(a). Reaction with 2-nitrobenzenesulfonyl chbride gave 2-nitrobenzenesulfon-3'-chbroanilide 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 67% yield. Finally, decomposition of diazonium salt and recrystallizatbn from methylene chbride / hexane afforded chbro-sultam 49(a) in 27% yield as a white crystalline solid, m.p.: 219-220 °C. TLC: Rf = 0.51 (ethyl acetate / hexane 1 :1 ). ¹ H-NMR (DMSO-De) : 11.6 (bs, 1 H), 8.13 (dd, 1 H-C4); 8.12 (dd, 1 H-Cιo); 7.95 (dd,1 H-Cι); 7.82 (dt, 1 H-C3); 7.68 (dt,1 H-C2); 7.35 (dd, 1 H-C9); 7.21 (d, 1 H-C7).

b) 4-(8-Chforo-6H-dibenzo[c,e][1 ,2]thiazin-6-ylmethyl)piperidine S,S- dioxide.

Starting from chbro-sultam 49(a) and N-tert-butoxycarbonyl-4- (methanesulfonybxymethyl)piperidine and folbwing usual process described in the Examples 2(c) and 2(d), the piperidine 49(b) hydrochloride was prepared in 63 % 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-adamantyl)-2-[4-(8-chbro-6H-dibenzo[c,e][1 ,2]thiazin-6- ylmethyl)-piperidin-1-yl]-ethanol S.S-dioxide.

Reaction of (l -adamantyl)ethylene oxide (0.5 g, 2.8 mmol) with piperidine 49(b) (1.016 g, 2.8 mmol) was conducted according to the method described in the Example 11(b), but over 68 hrs. Purifbation by column chromatography (silica gel, methylene chloride / methanol 20:1 , TLC: Rf=0.39) furnished the title aminoalcohol 49(c) (0.910 g, 60 %) as a white solidified foam.

The hydrochloride salt 49(c) was prepared according to the procedure described in Example 2(d), as a white solid, m.p.: 176-177°C. MS: 375 (M-165). Anal. Calc'd for CaoH^CIsN^ S + 2/3 H ₂ O: C,61.01 ; H.6.66; N.4.74; 01,12.03. Found: C,61.03; H.6.98; N.4.62; 01,12.16.

EXAMPLE 50

(R,S)-1-(1 -Adamantyl)-2-[4-(8-methoxy-6H-dibenzo[c,e][1 ,2Jthiazin-6- ylmethyl)piperidin-1 -yljethanol S.S-dioxide, hydrochloride.

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 folbwing the sequence of reactbns described in Example 46(a). Reaction with 2-nitrobenzenesulfonyl chbride gave 2-nitrobenzenesulfon-3'- methoxyanilide in 75% 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% yield. Finally, decomposition of diazonium salt and recrystallizatbn from ethyl acetate / hexane provided methoxy-sultam 50(a) in 28 % yield as a white crystalline solid, m.p.: 168.9-170°C. TLC: Rf = 0.65 (ethyl acetate hexane 1 :1 ).

¹ H-NMR (DMSO-De): 11.32 (bs, 1 H), 8.13 (dd, 1 H-C4); 8.12 (dd, I H-C10); 7.88 (dd,1 H-Cι); 7.77 (dt, 1 H-C3); 7.58 (dt,1 H-C2); 6.90 (dd, 1 H-C9); 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-4-

(methanesulfonybxymethyl)piperidine and folbwing typicall procedures described in Examples 2(c) and 2(d), the title piperidine 50(b) hydrochbride was prepared in 86 % yield as a white solid.

Usual basic work-up gave free piperidine 50(b) as a slightly yellow paste.

c) (R,S)-1 -(1-Adamantyl)-2-[4-(8-methoxy-6H-dibenzo[c,eJ[1 ,2]thiazin-6- ylmethyl)piperidin-1 -yljethanol S.S-dioxide, hydrochloride. Reaction of (l-adamantyl)ethylene oxide ( 0.890 g, 5 mmol) with piperidine 50(b) (1.9 g, 5.3 mmol) was conducted according to the method described in the Example 1 1(b), but over 48 hrs. Purification by column chromatography (silica gel, methylene chbride / methanol 9:1 , TLC: Rf = 0.63) provided t he title aminoalcohol (1.36 g, 51 %) as a pinky solid, m.p.: 193- 194°C.

The hydrochloride salt 50(c) was prepared folbwing 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 C ₃₁ H ₄₁ CIN ₂ O ₄ S + 2/3 H ₂ O: C63.58; H.7.23; N.4.79; Cl.6.07.

Found: 0,63.72; H,7.32; N.4.76; Cl,6.15.

EXAMPLE 51

(R,S)-5-[4-[N-[2-(1-Adamantyl)-2-methoxyethyl]-N-methylam ino]butyl]-5H- phenanthridin-6-one, hydrochloride.

The O-methylatbn of the aminoalcohol 10(e) (1.05 g, 2.3mmd) was performed folbwing procedure described in the Example 21. Column chromatography (silica gel, methylene chloride / methanol 10:90, TLC: Rf = 0.2) provided the title methyl ether (0.400 g, 40%) as a viscous oil. The hydrochloride salt was prepared according to the procedure described in Example 2(d), as a white hygroscopic foam. MS: 293 (M-179). Anal. Calc'd for C ₃₁ H ₄₀ N ₂ O ₂ + 1.1 HCI + 1.5 H ₂ O: C.68.98; H.8.24; N.5.19; Cl.7.22. Found: 0,69.14; H.8.30; N.5.20; Cl.7.17.

EXAMPLE 52

(R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(10,H-dihydrodiben z[b,fJ[1 ,4J- oxazepin-11-OXO-10-yl)butyl]aminojethanol, hydrochloride.

a)N-Methyl-N-4-[10-(10,H-dihydrodibenz[b,f][1 ,4Joxazepin-11 -oxo)] butylamine. Reaction of 10,1 1 -dihydrodibenz[b,f][1 ,4]oxazepin-1 1-one (422 g,

20 mmd) and mesylate of the aloohol 10(b) (5.6 g, 20 mmd) was performed according to procedure described in Example 10(c) and gave N-tet - butoxycarbonyl-N-methyl-N-4-{10-(10J 1-dihydrodibenz[b,f][1 ,4]oxazepin-1 1- oxo)]butylamine (5.8 g, 73%) as an oil. TLC: Rf= 0.3 (e1hyl acetate /hexane 3:7). Subsequent 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 % overall yield as a colorless oil.

b) 1 -(1-Adamantyl)-2-[N-methyl-N-[4-(10, 11 -dihydrodibenz[b,f][1 ,4]- oxazepin- 11 -oxo-10-yl)butyl]amino]methylketone.

Amine 52(a) (2.0 g, 6.7 mmol) and 1 -(bromoacetyl)adamantane (1.85 g, 7.2 mmol) were reacted together, according to procedure described in

Example 1 (c), to produce aminoketone 51(b) (2.85 g, 90%) as an orange oil. TLC: Rf = 0.6 (methanol / methylene chloride 1 :9). c) 1 -(1-Adamantyl)-2-[N-methyl-N-[4-(10,H -dihydrodibenz[b,f][1,4J- oxazepin-11-OXO-10-yl)butyljamino]ethanol, hydrochloride. Reduction of aminoketone 52(b), according to the method described in Example 1 (d), gave the title aminoalcohol 52(c) in 95% 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 a white hygroscopic foam. MS: 309 (M-165). Anal. Calc'd for C ₃₀ H ₃₉ CIN ₂ O ₃ + 2/3 H ₂ O: C ,68.83; H,7.71;

N.5.29; 01,6.79. Found: 0,68.78; H,7.91 ;N, 5.35; Cl,6.96.

EXAMPLE 53

(R,S)-10-[4-[N-[2-(1 -Adamantyl)-2-methoxyethyl]-N-methylamino]butylJ-10,11- dihydrodibenz[b,fJ[1 ,4]oxazepin-11-one, hydrochloride.

Reaction of aminoalcohol 52(c) with methanesulfonyl chbride, performed as described in Example 6(a) and followed by column chromatography (silica gel, hexane / ethyl acetate 7:3, TLC: Rf = 0.3), produced corresponding mesylate in 53% yield as a colorless viscous oil.

Methanolysis of the above mesylate was conducted as described in Example 9.

Purification by column chromatography (silica gel, methylene chbride / methanol 9:1 , TLC: Rf = 0.4) provided methyl ether 53 in 31% yield as a foam.

The title methyl ether 53 hydrochbride 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 C ₃₁ H ₄₁ CIN ₂ O ₃ + H ₂ O: 0,68.55; H,7.98;

N.5.16; Cl.6.53. Found: C68.52; H,8.05; N.5.21 ; Cl.6.53.

EXAMPLE 54

(R,S)-1-(1-Adamantyl)-2-[N-methyl-N-[4-(10,H-dihydrodiben zo[b,f][1 ,4]- thiazepin-11 -oxo-10-yl)butyl]amino]ethanol, hydrochloride.

a) N-Methyl-N-4-[10-(10,11 -dihydrodibenzo[b,f][1,4Jthiazepin-11-oxo)J

butylamine.

Reaction of 10,11 -dihydrodibenzo[b,fJ[1,4]thiazepin-11 -one (7.49 g, 33 mmol) and mesylate derivative of alcohol 10(b) (8.43 g, 30 mmol) was performed according to procedure described in Example 10(c) and gave N- tert-butoxycarbonyl-N-methyl-N-4-[10-(1O,11 -dihydrodibenzo[b,f][1 ,4]- thiazepin-11-oxo)]butylamine (10.33 g, 83%) as an oil. TLC: Rf = 0.3 (ethyl acetate / hexane 3:7).

Next, removal of N-Boc protecting group gave amine 54(a) hydrochbride 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,H -dihydrodibenzo- [b,fJ[1 ,4J- thiazepin-11-oxo-10-yl)butyl]amino]methylketone. Amine 54(a) (6.3 g, 20.5 mmol) and 1 -(bromoacetyl) adamantane

(5.66 g, 22 mmol) were reacted together, according to procedure described in Example 1 (c), to produce aminoketone 54(b) (9.67 g, 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-dihydrodi benzo-

[b,fj[1 ,4]-thiazepin-11-OXO-10-yl)butyl]amino]ethanol, hydrochloride.

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 hydrochloride salt was prepared according to the procedure described in Example 2(e), but in methylene chbride / diethyl ether, as a white hygroscopic foam. MS: 325 (M-165). Anal. Calc'd for C ₃₀ H ₃₉ CIN ₂ O ₂ S+ 2/3 H ₂ O: 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.

EXAMPLE 55

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

Folbwing the procedure described in Example 6(a), the mesylate

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. Cdumn chromatography (silica gel, methylene chbride / methanol

20:1 , TLC: Rf = 0.3) furnished methyl ether 55 in 37% 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 C ₃₁ H ₄₁ CIN ₂ O ₂ S+ 2/3 H ₂ O: C.67.27; H.7.65;

N.5.06; Cl.6.42. Found : C.67.22; H,7.96; N.5.13; 01,6.31.

PHARMACOLOGY

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

SIGMA RECEPTORS BINDING ASSAY

The sigma 1 selective binding assay was performed using [ ³ H]-(+) pentazocine (3 nM final, 35 Ci/mmol, New England Nuclear, Dupont de Nemours) as the radioligand according to the method described by D.L. DeHaven-Hudkins, L.C. Fleissner and F.Y. Ford Rbe (European Journal of Pharmacology - Molecular Pharmacology Section, 1992, 227, 371 -378). Crude P2 membrane fraction 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 concentrations of the reference compound (Haloperidol 10 ^{"1 0} to 10" ⁶ M) or of the test ligand (10- ¹⁰ to 10" 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 filtration through Whatman GF/B filters. Prior to use, filters were soaked in 0.5 % pdyethyleneimine for 1 hour. After filtration using a Brandell cell harvester, filters were washed four times with ice cold incubation buffer. Non specific binding was determined using Haloperidol 1 μM. The radioactivity on the filters was determined by scintillation spectrometry using Formula 989 (New England Nuclear, Dupont de Nemours) as scintillator liquid and a counter LS 6000 TA (Becmann). Competition curves were analyzed with the curve fitting program Ligand (G.A. Mc Pherson, Computer Programs in Biomedicine, 1983, 17, 107). Ki and IC 50 values were calculated. Kd value for [ ³ H]-(+) pentazocine was 3nM. Values are averages ± SEM of three experiments, each carried out in duplicate.

The sigma 2 selective binding assay was performed using [ ³ H]-Di-o-

Tolyl-Guanidine (DTG) (1 nM final, 37 Ci/mmd, New England Nuclear, Dupont de Nemours) as the radioligand. Crude P2 membrane fraction was prepared

from the livers of male Sprague-Dawley rats according to the method 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 and of various concentrations of the reference compound (Haloperidol 10 ^~1 0 to 10" ⁶ M) or of the test ligand (10 ^{" 0} to 10 ^-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 filtration through Whatman GF/B filters. Prior to use, filters were soaked in 0.5 % polyethyleneimine for 1 hour. After filtration using a Brandell cell harvester, filters were washed four times with ice cold incubation buffer. Non specific binding was determined using Haloperidol 1 μM. Scintillation counting and curve analysis were determined as previously described. Kd value for [ ³ H]- DTG was predetermined and equal to 6.9 nM.

TABLE V :

TABLE V: (continued)

Example Sigma 1 Sigma 2 S2/S1 ratio n° Ki (nM ± SEM) Ki (nM ± SEM)

The binding data presented in the above table, based on at least 3 determinations, show that the molecules of the present invention are moderatly to highly potent sigma 2 ligands and that they show a high selectivity for this site.

The binding of these compounds to dopaminergic receptors was measured according to the method described by M. Terai, K. Hidaka and Y. Nakamura [Eur. J. Pharmacol. 1989, 173, 177] using rat striata. The affinity of these compounds towards serotoninergic 5-HT2 receptors was also evaluated folbwing 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 VI :

TABLE VI

TABLE VI : (continued)

Additionally, some compounds of the invention were tested on alpha 1 adrenergic, beta 1 and 2 adrenergic, D1, 5-HT1 , 5-HT1A, 5-HT3 and

phencyclidine receptors. For most compounds, the selectivity was very high : IC50 X/ IC50 Sigma 2 > 100. X : D1 , D2, 5-HT1 , 5-HT1A, 5-HT2, 5-HT3, alphal adrenergic, beta 1 and 2 adrenergic and phencyclidine receptors.

IN VIVO PHARMACOLOGY

The psychotropic properties of the compounds have been determined by some standard tests exploring dopaminergic, serotonergic and glutamatergic mechanisms, which are all involved in schizophrenic pathogenia.

Mescaline induced scratching in Mice

This is a modification of the method of Cook L., Tarn S.W. and Rohrbach K.W. [J. Pharmacol. Exp. Ther. 1992, 263, 1 159-1166]. In mice, compounds (10 animals /dose) were administered per os 60 min before 10 mg/kg i.p. of Mescaline. 10 minutes after the challenge, mice were observed during a 10 min period and the number of scratching were counted. The ED50 was defined as the dose of the test compound that protected 50 % of the scratching number.

TABLE VII

Table VII shows that compounds of the inventbn 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 mice by oral administration by the 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 effect was observed with these compounds.

FORMULATION EXAMPLES

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

Typical examples of recipes for the formulation of the invention are as follows:

in this example, the compound 2 can be replaced by the same amount of any of the described examples 1 to 55.

2) Suspension :

An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the described example, 50 mg of sodium carboxymethyl cellubse, 1 mg of sodium benzoate , 500 mg of sorbitol and water ad 1 ml.

3) Injectable :

A parenteral composition is prepared by stirring 1.5 % by weight of active ingredient in 10 % by volume propylene glycol and water. 4) Ointment :

Compound of the example 2 5 to 1000 mg

Stearyl alcohol 3 g

Lanoline 5 g

White petroleum 15 g Water ad 100 g in this example, the compound 2 can be replaced by the same amount of any of the described examples 1 to 55.

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

Industrial Applicability

The compounds of the present invention exhibit a high selectivity and 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.