Title of Invention

ACYLSULFONAMIDES AS INHIBITORS OF STEROID SULFATASE

Abstract

The present invention relates to a compound of formula (I) wherein R<SUB>1</SUB> is haloalkyl, alkenyl, phenyl, thienyl, pyridine, benzthiazolyl, chromanyl (1,2-dihydrobenzopyranyl) or (6-18)aryl, and R<SUB>1</SUB> or R<SUB>2</SUB> independently of each other are substituted (C<SUB>4</SUB>-<SUB>8</SUB>)cycloalkyl, a substituted bridged cycloalkyl system, substituted piperidine, substituted tetrahydropyridine, or a substituted bridged heterocyclic system, useful as a pharmaceutical.

Full Text

Acylsulfonamides The present invention relates to acylsulfonamides, e.g. useful in the treatment of disorders mediated by the action of steroid sulfatase. wherein R3 and R13 independently of each other are hydrogen, hydroxy, halogen, cyano, (C1-4)-alkyl, (C1-4)alkoxy, phenyl or phenoxy, at least one of - R4 and R5 together with the carbon atom to which they are attached, - Rn and R12 together with the carbon atom to which they are attached, independently of each other are a substituted - bridged cycloalkyl system, - (C4-8)cycloalkyl, - piperidine, tetrahydropyridine, or - bridged heterocyclic system, wherein the substitutents are selected from the group consisting of (C1-6)alkoxycarbonylamino, (C1-6alkoxycarbonyl((C1-4)alkyl)amino, (C1-6)alkoxycarbonyl((C2-4)alkenyl)amino, (C3-8)cycloalkylcarbonylamino, (C3-8)cycloalkylcarbonyI((C1-4)alkyl)amino, (C3-8)cycloalkylcarbonyI((C2-4)alkenyl)amino, (C1-6)alkoxycarbonyloxy, phenyl(Ci.4)alkylcarbonyloxy, wherein phenyl is unsubstituted or substituted and wherein the substituents are as defined above for substituted phenyl, phenylsulphonyl, wherein phenyl is unsubstituted or substituted and wherein the substituents are defined as above for substituted phenyl, (C4.8)alkyl, e.g. (C5.8)alkyl, (C1-4)hydroxyalkyl, (C1-4)hydroxyalkyl substituted by phenyl, wherein phenyl is unsubstituted or substituted and wherein the substituents are as defined above for substituted phenyl, (C1-6)alkoxycarbonyl(Ci.4)alkyl, (C3-8)cycloalkoxycarbonyl(C1-4)alkyl, (C1-6)alkoxycarbonylaminof(C1-4)alkyl, (C3.8)cycloalkylcarbonyIamino(Ci.4)alkyl, phenyl or substituted phenyl, wherein the substituents are as defined above for substituted phenyl, heterocyclyl having 5- or 6-ring members and 1 to 4 heteroatoms selected from N, O, S, e.g. oxadiazolyl, OR at least one of - R9 and R10 together with the carbon atom to which they are attached, - R16 and R17 together with the carbon atom to which they are attached, are (C3-8)cycioalkyl, and R8 or R18, respectively, independently of each other are a substituted - bridged cycloalkyl system, (C^cycloalkyl, substituted piperidine, tetrahydropyridine, or a bridged heterocyclic system, wherein the substitutents are as defined above for the corresponding groups, R6 and R15 independently of each other are (C1_6)haloalkyl, unsubstituted or substituted (C6-18)aryl, wherein the aryl-substitutents are as defind above, or a substituted - bridged cycloalkyl system, (C4-8)cycloalkyl, piperidine, tetrahydropyridine, or bridged heterocyclic system, wherein the substitutents are as defined above for the corresponding groups, or R6 and R15 independently of each other are amino substituted by a substituted - bridged cycloalkyl system, (C4.8)cycloalkyl, piperidine, tetrahydropyridine, or bridged heterocyclic system, wherein the substitutents are as defined above for the corresponding group, R7 and R14 independently of each other are a substituted - bridged cycloalkyl system, (C4-8)cycloalkyl, piperidine, tetrahydropyridine, or bridged heterocyclic system, wherein the substitutents are as defined above for the corresponding groups, or R7 and R14 independently of each other are amino substituted by a substituted - bridged cycloalkyl system, (C4-8)cycloalkyl, piperidine, tetrahydropyridine, or bridged heterocyclic system, wherein the substitutents are as defined above for the corresponding group, m is 0, 1, 2, 3 or 4, such as 0 or 1, n is 0, 1, 2, 3 or 4, such as 0 or 1, and IF m and/or n are other than 0, THEN - Ri, if m is other than 0, and R2, if n is other than 0, independently of each other have the meaning as defined above and additionally may be substituted piperazine, wherein the substitutents are as defined above for substituted piperidine above; and - a substituted bridged cycloalkyl system is substituted as defined above for a substituted bridged cycloalkyl system, and additionally may be substituted by oxo and/or (C1-4)alkyl; and IF ^R1 is a substituted - bridged cycloalkyl ring system, (C4.8)cycloalkyl, piperidine, tetrahydropyridine, or a brigded heterocyclyl ring system, wherein the substituents are as defined above for the corresponding groups, or if Ri is additionally piperazine, if m is other than 0, THEN R2 has the meaning as defined above and additionally may be (C1-.6)haloalkyl, unsubstituted (C2-6)alkenyl, (C2-6)alkenyl substituted by phenyl, unsubstituted or by 1 to 5 substitutents substituted - thienyl, pyridine, benzthiazolyl, chromanyl (i.e. 1,2-dihydrobenzopyranyl) or (C6-18)aryl, wherein the substituents are as defined above for the corresponding groups, and m is 0, n is 0 and R2 is substituted (C4-8)cycloalkyl or a substituted bridged cycloalkyl ring system, wherein the substituents are as defined above, THEN R1 is other than (C1-6)haloalkyl. In a compound of formula I at least one substituent selected from the group consisting of a substituted bridged cycloalkyl ring system, substituted (C4-8cycloalkyl, substituted piperidine, substituted tetrahydropyridine, substituted piperazine, or a substituted brigded heterocyclyl ring system, wherein the substituents are as defined above for the corresponding groups, is present. In a compound of formula I m is preferably 0 or 1, and n is preferably 0 or 1. If not otherwise specified herein - cycloalkyl includes e.g. non-bridged (C3-8)cycloalkyl, such as (C4-8)cycloalkyl, - heterocyclyl includes heterocyclyl having 5 to 6 ring members and 1 to 4 heteroatoms selected from N, S or O, optionally anellated with another ring (system), such as piperidine, tetrahydropyridine, pyridine, piperazine, thienyl, pyridine, benzthiazolyl, chromanyl, oxadiazolyl, aryl includes (C6-18)aryl, e-9- (C6-12)aryl,such as naphthyl, phenyl. A substituent attached to cyclohexyl, a piperidine, tetrahydropyridine or piperazine ring in a compound of formula I may be in any position with respect to the sulfonamide group, or with respect to a group -(CH2)m- or -(CH2)n-, also attached to said ring, e.g. in 2, 3 or 4 position; and is preferably in 3 or in 4 position. A bridged cycloalkyl system includes bridged (C5-12)cycloaIkyl, such as (C6-8)cycloalkyl, wherein the bridge optionally comprises a heteroatom, such as N, e.g. including cycloalkyl annelleted with another ring system, e.g. anellated with a (C5.12)cycloalkyl, such as decalin and/or phenyl, e.g. including - decalin bridged by alkyl, e.g. methyl, such as adamantyl, - cyclohexyl or cycloheptyl, bridged by (C1-4)alkyl, e.g. bridged by a -CH2- CH2- group, - cycloheptyl or cyclooctyl bridged by an amine group, - cyclohexyl or cycloheptyl bridged by an alkyl chain, e.g. (C2.4)alkyl chain interrupted by a hetero atom, such as nitrogen, e.g. a -CH2-NH-CH2- group, - cycloheptyl bridged by an alkyl chain, e.g. (C2-4)alkyl chain, which is interrupted by a hetero atom, such as nitrogen, e.g. a -CH2-NH-CH2- group and which bridged cycloheptyl is further annelleted with phenyl. A bridged substituted bridged heterocyclic system includes a bridged piperidine, e.g. bridged by (C1-4)alkylene, such as ethylene. Naphthyl includes e.g. naph-1-yl, naphth-2-yl, e.g. unsubstituted orsubsituted by di(C1-4)alkylamino. Thiophenyl, includes e.g. thiophen-2-yl and thiophen-3-yl, e.g. substituted by 1 to 3 halogen. Benzthiazolyl, e.g. includes benzthiazol-2-yl, e.g. substituted by (C2-4)alkoxy. Chromanyl, e.g. includes chroman-6-yl, e.g, substituted by (C2-4)alkyl. Pyridine includes pyridine substituted by halogen and is bound to the (optionally (CH2)mor n)carbonyl or (optionally (CH2)mor n)sulfonyl group in a compound of formula I via a carbon atom. In another aspect the present invention provides a compound of formula I, wherein at least one of - R4 and R5 together with the carbon atom to which they are attached, - R9 and R10 together with the carbon atom to which they are attached, - Rn and R12 together with the carbon atom to which they are attached, - R16 and R17 together with the carbon atom to which they are attached, ■ R14, or •Rl5 s a substituted bridged cycloalkyi system, and the other substitutents are as defined above, such as a compound of formula lP3, IP4, Ips, Ipu, or lPi2 as defined below. n another aspect the present invention provides a compound of formula I, wherein at least 3ne of ? R4 and R5 together with the carbon atom to which they are attached, ? R9 and R10 together with the carbon atom to which they are attached, • Rn and Ri2 together with the carbon atom to which they are attached, or ■ R16 and Ri7 together with the carbon atom to which they are attached, ■ R61 •R7, - R14, or " Rl5 is substituted (C4-8)cycloalkyl, and the other substitutents are as defined above, such as a compound of formula lP2, ip6, W or lP10 as defined below. In another aspect the present invention provides a compound of formula I, wherein at least one of - R4 and R5 together with the carbon atom to which they are attached, - R9 and R10 together with the carbon atom to which they are attached, - R11 and R12 together with the carbon atom to which they are attached, or - R16 and R17 together with the carbon atom to which they are attached, R6, -R7, - R14, or " Rl5 is substituted piperidine, substituted tetrahydropyridine, or a substituted bridged heterocyclic system, and, if m is other than 0 and/or n is other than 0, additionally may be piperazine, and the other substitutents are as defined above, such as a compound of formula lP1, lP4, Ip5, Ip8, Ip9, Ip12, Ip13 or lP14.as defined below. In another aspect the present invention provides a compound of formula I which is a compound of formula wherein RiPi has the meaning as defined in Ri above, and R16Pt and R17Pi together with the carbon atom to which they are attached are substituted piperidine or substituted tetrahydropyridine, wherein the substituents are as defined above for substituted piperidine. In a compound of formula lP1 preferably RIPI is substituted or unsubstituted thienyl, benzthiazolyl, chromanyl, phenyl or naphthyl, R16P1 and RnP1 together with the carbon atom to which they are attached are piperidine or tetrahydropyridine, preferably piperidine, substituted a) at the nitrogen atom of the ring by substituents selected from the group consisting of - (C1-6)alkoxycarbonyI, e.g. BOC (i.e. tert.butoxycarbonyl), - (C1-6)alkoxycarbonyl(C1-4)alkyl, e.g. tertbutoxycarbonylmethyl, - unsubstituted or substituted phenyl, wherein the substituents are as defined for phenyl above, - (C1-6)alkylcarbonyl or phenylcarbonyl, (C3.8)cycloaIkyl(C1-4)alkylcarbonyl, - heterocyclyl, e.g. pyridine, such as pyridin-2-yl, e.g. substituted by nitro, more preferably piperidine substituted at the nitrogen atom by BOC, or unsubstituted or substituted phenyl, and optionally b) further substituted at a carbon atom of the ring by (Chalky!, and Rispi is hydrogen, phenyl or (C1.4)alkyl, more preferably hydrogen or phenyl. In another aspect the present invention provides a compound of formula I which is a compound of formula wherein R1P2 has the meaning of R1 as defined above, R16P2 and R17P2 together with the carbon atom to which they are attached are substituted (C4-7)cycloaikyl, wherein the substituents are as defined above for substituted cycloalkyl, and R18P2 has the meaning of Ris as defined above. In a compound of formula lP2 preferably - R1p2 is substituted or unsubstituted phenyl, naphthyl, alkenyl (e.g. substituted by phenyl), or thienyl. - R16P2 and R17P2 together with the carbon atom to which they are attached are cyclohexyl substituted by (C3.B)cycloalkyl((C1-4)alkyl)aminocarbonyl, phenylcarbonyl, or heterocyclyl having 5- or 6-ring members and 1 to 4 heteroatoms selected from N.O, S, e.g. oxadiazolyl, more preferably substituted by (C-65)alkoxycarbonylaminofCi^alkyl or (C1-6alkoxycarbonylamino, R18P2 is hydrogen In another aspect the present invention provides a compound of formula I which is a compound of formula wherein R1P3 has the meaning of Rt as defined above, RI6FP3 and R17P3 together with the carbon atom to which they are attached are a substituted bridged cycloalkyl ring system, wherein the substituents are as defined above for a bridged cycloalkyl ring system, and RISP3 has the meaning of Ri8 as defined above. In a compound of formula lP3 preferably - R1P3 is unsubstituted or substituted phenyl or thienyl. - R16P3 and R17P3 together with the carbon atom to which they are attached are a bridged cycloalkyl ring system which is substituted by In another aspect the present invention provides a compound of formula I which is a compound of formula wherein R1P4 has the meaning of R1 as defined above, R16P4 and R17p4 together with the carbon atom to which they are attached are a substituted bridged cycloalkyl ring system or substituted piperidine, a substituted bridged heterocyclic system, substituted piperazine, or substituted tetrahydropyridine, wherein the substitutents are as defined above for corresponding groups and wherein piperazine is substituted by groups as defined for substituted piperidine above, R18P4 has the meaning of R18 as defined above, and mP4 is 1, 2, 3 or 4. In a compound of formula lP4 preferably R1P4 is unsubstituted or substituted phenyl orthienyl. R16P4 and R17P4 together with the carbon atom to which they are attached are a substituted bridged cycloyalkyl ring system, substituted piperidine or substituted bridged piperidine, more preferably a substituted bridged cycloyalkyl ring system or substituted piperidine, wherein substitutents are selected from a) - C1-6)alkoxycarbonyl, e.g. BOC, - (C1-6)alkoxycarbonyl(C1-4)alkyl, e.g. tert.butoxycarbonylmethyl, - (C1-6alkylcarbonyloxy(C1-4alkyl, e.g. unsubstituted or substituted by phenyl, - unsubstituted or substituted phenyl, wherein the substituents are as defined above for phenyl, - (C1-6)alkylcarbonyl or phenylcarbonyl, (C3-8)cycloalkyl(C1-4)alkylcarbonyl, - heterocyclyl, e.g. pyridine, such as pyridin-2-yl, e.g. substituted by nitro, and optionally b) (C1-4)alkyl at a carbon atom of a ring, more preferably substitutents are selected from (C1-6)alkoxycarbonyl, e.g. BOC, phenyl, unsubstituted phenyl and substituted phenyl, e.g. substituted by groups as defined above for substituted phenyls, such as nitro, (C1-4)alkyl, (C1-4)haloalkyl, e.g. trifluoromethyl, aminocarbonyl. - R18P4 is hydrogen or hydroxy, more preferably hydrogen. - mP4 is 1, such as compounds of formula wherein RIPS has the meaning of R1 as defined above, R13P5 has the meaning of R13 as defined above, and R11P5 and R12P5 together with the carbon atom to which they are attached have the meaning of Rn and R12as defined above. In a compound of formula lP5 preferably - R1P5 is unsubstituted or substituted phenyl or thienyl. - R11P5 and R12PS together with the carbon atom to which they are attached are piperidine, methylpiperidine or a bridged cyclolalkyl ring system substituted by - (Cv6)alkoxycarbonyI, e.g. teitbutoxycarbonyl; - unsubstituted or substituted phenyl, wherein the substituents are as defined above for phenyl, - (C1-8)alkyicarbonyloxy, such as tert.butyl-methylcarbonyloxy, more preferably substitutents are selected from (d.8)alkoxycarbonyl, such as BOC, or (C1-6alkyl-carbonyloxy, such as tert.butylmethylcarbonyloxy, - R3P5 is hydrogen, halogen or cyano. In another aspect the present invention provides a compound of formula I which is a compound of formula wherein R1P6 has the meaning of R1 as defined above, Riepe and R17pe together with the carbon atom to which they are attached are substituted (C4-8)cycloalkyl, Rispe has the meaning of R18 as defined above, and mP6 is 1, 2, 3 or 4. In a compound of formula lP6 preferably - R1P6 is unsubstituted or substituted phenyl or thienyl. R16p6 and R17P6 together with the carbon atom to which they are attached are cyclohexyl, substituted by (C1-6)alkoxycarbonyloxy or (C1-6)alkoxycarbonylamino. - mP6 is 1. In another aspect the present invention provides a compound of formula I which is a compound of formula wherein R1p7 has the meaning of R1 as defined above, R16P7 and R17p7 together with the carbon atom to which they are attached are substituted (C4-8)cycloalkyl, R18P7 has the meaning of Ri8 as defined above, and mP7 is 1, 2, 3 or 4. In a compound of formula lP7 preferably - Rip7 is unsubstituted or substituted phenyl, - R16P7 and R17P7 together with the carbon atom to which they are attached are cyclohexyl substituted by (C1.6)alkoxycarbonylamino(C1.4)alkyl),or (C1-.6)alkoxycarbonylamino, wherein the amine group is optionally further substituted by (C1-4)alkyl. - R18P7 is hydrogen, and - m P7 is 1. In another aspect the present invention provides a compound of formula I which is a compound of formula wherein R1P8 has the meaning of R1 as defined above, R16P8 and R17ps together with the carbon atom to which they are attached are substituted piperidine, tetrahydropyridine or piperazine, wherein the substitutents are as defined above for piperidine, R18P8 has the meaning of R18 as defined above, m P8 is 1 and n P8 is 1, In a compound of formula lP8 preferably - R1P8 is unsubstituted or substituted phenyl, - R16pe and R17P8 together with the carbon atom to which they are attached are piperidine substituted by (Ci_6)alkoxycarbonyi. R18P8 is hydrogen. - m ps is 1. - n p8 is 1. In another aspect the present invention provides a compound of formula I, which is a compound of formula wherein R1P9, R6p8 and R7P9 have the index-number corresponding meaning meaning of R1f R6and R7as defined above. In a compound of formula lP9 preferably - R1P9 is unsubstituted or substituted phenyl, - R6P9 and R7P9 independently of each other are (C1-6)haloalkyl, unsubstituted or substituted phenyl, piperidinyl substituted by (C3-8)cyclyolalkylaminocarbonyl or (C1-6)alkoxycarbonyl, or amino substitued by substituted piperidine. In another aspect the present invention provides a compound of formula wherein wherein R1P10 has the meaning meaning of R1, R8p10 an has the meaning meaning of R8, and R9P10 and R10P10 together with the carbon atom to which they are attached are (C4.8)cycloalkyl. In a compound of formula lP10 preferably - RIP10 is substituted or unsubstituted phenyl. - RSPIO is piperidine substituted by (C1-6)alkoxycarbonyl or unsubstituted or substituted phenyl. - R9P10 and R10P10 together with the carbon atom to which they are attached are (C4.7)cycloalkyl. In another aspect the present invention provides a compound of formula I, which is a compound of formula wherein R1P11 has the meaning meaning of R1, R11P11 and R12pn together with the carbon atom to which they are attached have the meaning of R11 and R12 together with the carbon atom to which they are attached, R13P11 has the meaning meaning of R13, and mP11 is 1, 2, 3 or 4. In a compound of formula lP11 preferably - R1P11 is substituted or unsubstituted phenyl. - RUPII and R12P11 together with the carbon atom to which they are attached are a substituted brigded cycloalkyl ring system. - mpii is 1. In another aspect the present invention provides a compound of formula I, which is a compound of formula wherein R2P12 has the meaning of R8 as defined above and additionally is unsubstituted or substituted (C6.18)aryl wherein substituents are as defined above for aryl-substituents, RBP12 has the meaning of R8 as defined above, R9P12 and R10P12 have the meaning of R9 and R10 as defined above, and mP12 is 1, 2, 3 or 4. In a compound of formula lP12 preferably - R2P12 is substituted or unsubstituted phenyl. - RSPI2 is hydrogen or hydroxy. - R9P12 and R10P12 together with the carbon atom to which they are attached are - A) piperidine substituted at the nitrogen atom of the ring by (C1-6)alkoxycarbonyl, (C3-8)cycloalkyl(C1-4)alkyIcarbonyl, or unsubstituted or substituted phenyl, - B) a bridged cycloalkyl ring system substituted by oxo, e.g. and (C1-4)alkyl. - mP12 is 1, such as a compound of formula wherein R2P13 has the meaning of R2 as defined above, and additionally is unsubstituted or substituted (C6-18)aryl wherein substituents are as defined above for aryl-substituents, R11P13 and R12P13 have the meaning of R11 and Ri2 as defined above, and R13P13 has the meaning of R13 as defined above. In a compound of formula lP13 preferably R2P13 is unsubstituted or substituted phenyl. - RHPI3 and R12P13 together with the carbon atom to which they are attached are piperidine substituted by unsubstituted or substituted phenyl, or substituted by ( c1-6)alkoxycarbonyl. - R13P13 is hydrogen. In another aspect the present invention provides a compound of formula I, which is a compound of formula In a compound of formula lP14 preferably - R1P14 is phenyl substituted by trifluoromethyl or halogen, and - R2P14 is (C3-18)arylsulfondioxideamino, such as phenylsulfondioxideamino, unsubstituted or substituted by (C1-6)alkyl, or halogen(Ci.3)alkyl, (Ci.3)alkoxy, halogen(C1-3)alkoxy, or halogen. A compound of formula I includes a compound of formula lP1, lP2, Ip3, Ip4. Ips, Ipe, IP7. Ips, U. Ip10. Ip11. Ip12. Ip13 and lP14. Compounds provided by the present invention are hereinafter designated as "compound(s) of the present invention". A compound of the present invention includes a compound in any form, e.g. in free form, in the form of a salt, in the form of a solvate and in the form of a salt and a solvate. In a compound of the present invention substituents indicated are unsubstituted, if not otherwise (specifically) defined. Each single substituent defined above in a compound of formula I may be per se a preferred substituent, independently of the other substituents defined. In another aspect the present invention provides a compound of the present invention in the form of a salt, e.g. and in the form of a salt and in the form of a solvate, or in the form of a solvate. A salt of a compound of the present invention includes a pharmaceutical^ acceptable salt, e.g. including a metal salt, an acid addition salt or an amine salt. Metal salts include for example alkali or earth alkali salts; acid addition salts include salts of a compound of formula I with an acid, e.g. HCI; amine salts include salts of a compound of formula I with an amine. A compound of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa. A compound of the present invention in free form or in the form of a salt and in the form of a solvate may be converted into a corresponding compound in free form or in the form of a salt in unsolvated form; and vice versa. A compound of the present invention may exist in the form of isomers and mixtures thereof. A compound of the present invention may e.g. contain asymmetric carbon atoms and may thus exist in the form of diastereoisomeres and mixtures thereof. Substituents in a non-aromatic ring may be in the cis or in the trans configuration in respect to each other. E.g. if R1 or R2 includes a substituted piperidine or tetrahydropyridine which is additionally substituted by a further substitutent at a carbon atom of said ring, said further substitutent may be in the cis or in the trans configuration with respect to the (optionally -(CH2)m-or -(CH2)n)sulfonamide group also attached to said piperidine or tetrahydropyridine; and if F^ or R2 includes a substituted cyclohexyl, said substitutent may be in the cis or in trans configuration with respect to the (optionally -(CH2)m-or -(CH2)n)sulfonamide group also attached to said cyclohexyl ring. Isomeric mixtures may be separated as appropriate, e.g. according to a method as conventional, to obtain pure isomers. The present invention includes a compound of the present invention in any isomeric form and in any isomeric mixture. Any compound described herein, e.g. a compound of the present invention, may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as specified herein. In another aspect the present invention provides a process for the production of a compound of formula I comprising reacting a compound of formula wherein R2 and m are as defined above, e.g. in an activated form, e.g. and/or in the presence of a coupling agent; and isolating a compound of formula I, wherein R1, R2, m and n are as described above from the reaction mixture obtained, e.g. if a compound of formula I comprises a group of formula II or of formula V, a compound of formula VIII may be reacted a compound of formula wherein the substituents are as defined above, e.g. in an activated form, e.g. and/or in the presence of a coupling agent, to obtain a compound of formula I, wherein the substitutents are as defined above. The above reaction is an acylation reaction and may be carried out as appropriate, e.g. in appropriate solvent and at appropriate temperatures, e.g. according, e.g. analogously, to a method as conventional or according, e.g. analogously, to a method as described herein. If in a compound of formula I a piperidine, tetrahydropyridine or piperazine, or a bridged cycloalkyl ring system comprising a nitrogen atom in a bridge, is unsubstituted present, such ring may be e.g. substituted at the nitrogen atom, e.g. by acylation to introduce a carbonyl containing residue, e.g. or by reaction with a fluoro containing phenyl wherein fluoro acts as a leaving group for N-phenylation (similarly, a heterocyclyl group may be attached to the nitrogen with a corresponding heterocyclic ring which is substituted by chloro as a leaving group). An ester group obtained by a reaction step may be saponified to obtain a carboxylic acid group, or vice versa. Compounds of formula VIII, IX, X and XI are known or may be obtained as appropriate, e.g. according, e.g. analogously, to a method as conventional or as described herein. A compound of formula VIII, for example may be obtained from a compound of formula by treatment with (aqueous) NH3. A compound of formula X or XI may be obtained e.g. by reacting a compound R2-H, wherein R2 is a group of formula II or of formula V, which carries an oxo group at one of the carbon atoms of the (bridged) ring system, with - (RO)2OP-CHRx-COO-R, wherein R is alkyl, such as (C1-4)alkyl, e.g. methyl or ethyl and Rx is R3 or R8 as defined above, in a solvent, e.g. tetrahydrofurane in the presence of a base e.g. sodium hydride; or - Ph3-P-CRx-COO-C2H5, wherein Rx is as defined above, in a solvent such as toluene, e.g. at temperatures above room temperature, or, - if Rx is hydrogen, by reaction with NC-CH2-COOR, wherein R is as defined above, in a solvent, e.g. dimethylformamide, in the presence of a catalyst, e.g. piperidine and 3-alanine, e.g. at temperatures above room temperature; and subsequent treatment of the compound obtained with NaOH or LiOH, in a solvent such as tetrahydrofurane/H20, e.g. at temperatures above room temperature. Steroidal hormones in particular tissues are associated with several diseases, such as tumors of breast, endometrium and prostate and disorders of the pilosebaceous unit, e.g. acne, androgenetic alopecia, and hirsutism. Important precursors for the local production of these steroid hormones are steroid 3-O-sulfates which are desulfated by the enzyme steroid sulfatase in the target tissues. Inhibition of this enzyme results in reduced local levels of the corresponding active steroidal hormones, which is expected to be of therapeutic relevance. Furthermore, steroid sulfatase inhibitors may be useful as immunosuppressive agents, and have been shown to enhance memory when delivered to the brain. Acne is a polyetiological disease caused by the interplay of numerous factors, such as inheritance, sebum, hormones, and bacteria. The most important causative factor in acne is sebum production; in almost all acne patients sebaceous glands are larger and more sebum is produced than in persons with healthy skin. The development of the sebaceous gland and the extent of sebum production is controlled hormonally by androgens; therefore, androgens play a crucial role in the pathogenesis of acne. In man, there are two major sources supplying androgens to target tissues: (i) the gonades which secrete testosterone, (ii) the adrenals producing dehydroepiandrosterone (DHEA) which is secreted as the sulfate conjugate (DHEAS). Testosterone and DHEAS are both converted to the most active androgen, dihydrotestosterone (DHT), in the target tissue, e.g. in the skin. There is evidence that these pathways of local synthesis of DHT in the skin are more important than direct supply with active androgens from the circulation. Therefore, reduction of endogeneous levels of androgens in the target tissue by specific inhibitors should be of therapeutic benefit in acne and seborrhoea. Furthermore, it opens the perspective to treat these disorders through modulation of local androgen levels by topical treatment, rather than influencing circulating hormone levels by systemic therapies. Androgenetic male alopecia is very common in the white races, accounting for about 95% of all types of alopecia. Male-pattern baldness is caused by an increased number of hair follicles in the scalp entering the telogen phase and by the telogen phase lasting longer. It is a genetically determined hair loss effected through androgens. Elevated serum DHEA but normal testosterone levels have been reported in balding men compared with non-balding controls, implying that target tissue androgen production is important in androgenetic alopecia. Hirsutism is the pathological thickening and strengthening of the hair which is characterized by a masculine pattern of hair growth in children and women. Hirsutism is androgen induced, either by increased formation of androgens or by increased sensitivity of the hair follicle to androgens. Therefore, a therapy resulting in reduction of endogeneous levels of androgens and/or estrogens in the target tissue (skin) should be effective in acne, androgenetic alopecia and hirsutism. As described above, DHT, the most active androgen, is synthesized in the skin from the abundant systemic precursor DHEAS and the first step in the metabolic pathway from DHEAS to DHT is desulfatation of DHEAS by the enzyme steroid sulfatase to produce DHEA. The presence of the enzyme in keratinocytes and in skin-derived fibroblasts has been described. The potential use of steroid sulfatase inhibitors for the reduction of endogenous levels of steroid hormones in the skin was confirmed using known steroid sulfatase inhibitors, such as estrone 3-O-sulfamate and 4-methylumbelliferyl-7-0-sulfamate. We have found that inhibitors of placental steroid sulfatase also inhibit steroid sulfatase prepared from either a human keratinocyte (HaCaT) or a human skin-derived fibroblast cell line (1BR3GN). Such inhibitors were also shown to block steroid sulfatase in intact monolayers of the HaCaT keratinocytes. Therefore, inhibitors of steroid sulfatase may be used to reduce androgen and estrogen levels in the skin. They can be used as inhibitors of the enzyme steroid sulfatase for the local treatment of androgen-dependent disorders of the pilosebaceous unit (such as acne, seborrhoea, androgenetic alopecia, hirsutism) and for the local treatment of squamous cell carcinoma. Furthermore non-steroidal steroid sulfatase inhibitors are expected to be useful for the treatment of disorders mediated by the action of steroid hormones in which the steroidal products of the sulfatase cleavage play a role. Indications for these new kind of inhibitors include androgen-dependent disorders of the pilosebaceous unit (such as acne, seborrhea, androgenetic alopecia, hirsutism); estrogen- or androgen-dependent tumors, such as squamous cell carcinoma and neoplasms, e.g. of the breast, endometrium, and prostate; inflammatory and autoimmune diseases, such as rheumatoid arthritis, type I and II diabetes, systemic lupus erythematosus, multiple sclerosis, myastenia gravis, thyroiditis, vasculitis, ulcerative colitis, and Crohn's disease, psoriasis, contact dermatitis, graft versus host disease, eczema, asthma and organ rejection following transplantation. Steroid sulfatase inhibitors are also useful for the treatment of cancer, especially for the treatment of estrogen- and androgen-dependent cancers, such as cancer of the breast and endometrium and squamous cell carcinoma, and cancer of the prostata. Steroid sulfatase inhibitors are also useful for the enhancement of cognitive function, especially in the treatment of senile dementia, including Alzheimer's disease, by increasing the DHEAS levels in the central nervous system. Activities of compounds in inhibiting the activity of steroid sulfatase may be shown in the following test systems: Purification of human steroid sulfatase Human placenta is obtained freshly after delivery and stripped of membranes and connective tissues. For storage, the material is frozen at -70°C. After thawing, all further steps are carried out at 4°C, while pH values are adjusted at 20°C. 400 g of the tissue is homogenized in 1.2 I of buffer A (50 mM Tris-HCI, pH 7.4, 0.25 M sucrose). The homogenate obtained is centrifuged at 10,000xg for 45 minutes. The supernatant is set aside and the pellet obtained is re-homogenized in 500 ml of buffer A. After centrifugation, the two supernatants obtained are combined and subjected to ultracentrifugation (100,000xg, 1 hour). The pellet obtained is resuspended in buffer A and centrifugation is repeated. The pellet obtained is suspended in 50 ml of 50 mM Tris-HCI, pH 7.4 and stored at -20°C until further work-up. After thawing, microsomes are collected by ultracentrifugation (as descrobed above) and are suspended in 50 ml of buffer B (10 mM Tris-HCI, pH 7.0,1 mM EDTA, 2 mM 2-mercaptoethanol, 1 % Triton X-100, 0.1 % aprotinin). After 1 hour on ice with gentle agitation, the suspension is centrifuged (100,000xg, 1 hour). The supernatant containing the enzyme activity is collected and the pH is adjusted to 8.0 with 1 M Tris. The solution obtained is applied to a hydroxy apatite column (2.6x20 cm) and equilibrated with buffer B, pH 8.0. The column is washed with buffer B at a flow rate of 2 ml/min. The activity is recovered in the flow-through. The pool is adjusted to pH 7.4 and subjected to chromatography on a concanavalin A sepharose column (1.6x10 cm) equilibrated in buffer C (20 mM Tris-HCI, pH 7.4, 0.1 % Triton X-100, 0.5 M NaCI). The column is washed with buffer C, and the bound protein is eluted with 10 % methyl mannoside in buffer C. Active fractions are pooled and dialysed against buffer D (20 mM Tris-HCI, pH 8.0,1 mM EDTA, 0.1 % Triton X-100, 10 % glycerol (v/v)). The retentate obtained is applied to a blue sepharose column (0.8x10 cm) equilibrated with buffer D; which column is washed and elution is carried out with a linear gradient of buffer D to 2 M NaCI in buffer D. Active fractions are pooled, concentrated as required (Centricon 10), dialysed against buffer D and stored in aliquots at -20°C. Assay of Human Steroid Sulfatase It is known that purified human steroid sulfatase not only is capable to cleave steroid sulfates, but also readily cleaves aryl sulfates such as 4-methylumbelliferyl sulfate which is used in the present test system as an activity indicator. Assay mixtures are prepared by consecutively dispensing the following solutions into the wells of white microtiter plates: 1) 50 pi substrate solution (1.5 mM 4-methylumbelliferyl sulfate in 0.1 M Tris-HCI, pH 7.5) 2) 50 pi test compound dilution in 0.1 M Tris-HCI, pH 7.5, 0.1 % Triton X-100 (stock solutions of the test compounds are prepared in DMSO; final concentrations of the solvent in the assay mixture not exceeding 1 %) 3) 50 pi enzyme dilution (approximately 12 enzyme units/ml) We define one enzyme unit as the amount of steroid sulfatase that hydrolyses 1 nmol of 4-methylumbelliferyl sulfate per hour at an initial substrate concentration of 500 pM in 0.1 M Tris-HCI, pH 7.5, 0.1 % Triton X-100, at 37°C. Plates are incubated at 37°C for 1 hour. Then the reaction is stopped by addition of 100 pi 0.2 M NaOH. Fluorescence intensity is determined in a Titertek Fluoroskan II instrument with X-ex = 355 nm and Xen = 460 nm. Calculation of relative IC50 values From the fluorescence intensity data (I) obtained at different concentrations (c) of the test compound in the human steroid sulfatase assay as described above, the concentration inhibiting the enzymatic activity by 50 % (IC5o) is calculated using the equation: wherein l10o is the intensity observed in the absence of inhibitor and s is a slope factor. Estrone sulfamate is used as a reference compound and its IC50 value is determined in parallel to all other test compounds. Relative IC50 values are defined as follows: According to our testing and calculation estrone sulfamate shows an IC50 value of approximately 60 nM. The compounds of the present invention show activity in that described assay (rel IC50 in the range of 0.0046 to 10). CHO/STS Assay CHO cells stably transfected with human steroid sulfatase (CHO/STS) are seeded into microtiter plates. After reaching approximately 90% confluency, they are incubated overnight with graded concentrations of test substances (e.g. compounds of the present invention). They are then fixed with 4% paraformaldehyde for 10 minutes at room temperature and washed 4 times with PBS, before incubation with 100 μl/well 0.5 mM 4-methylumbelliferyl sulfate (MUS), dissolved in 0.1 M Tris-HCI, pH 7.5. The enzyme reaction is carried out at 37°Cfor 30 minutes. Then 50μl/well stop solution (1M Tris-HCI, pH 10.4) are added. The enzyme reaction solutions are transferred to white plates (Microfluor, Dynex, Chantilly, VA) and read in a Fluoroskan II fluorescence microtiter plate reader. Reagent blanks are subtracted from all values. For drug testing, the fluorescence units (FU) are divided by the optical density readings after staining cellular protein with sulforhodamine B (OD550), in order to correct for variations in cell number. IC50 values are determined by linear interpolation between two bracketing points. In each assay with inhibitors, estrone 3-0- sulfamate is run as a reference compound, and the IC50 values are normalized to estrone 3-O-sulfamate (relative IC5o = IC50 compound / IC50 estrone 3-O-sulfamate). The compounds of the present invention show activity in that described assay (rel IC50 in the range of 0.05 to 10). Assay Using Human Skin Homogenate Frozen specimens of human cadaver skin (about 100 mg per sample) are minced into small pieces (about 1x1 mm) using sharp scissors. The pieces obtained are suspended in ten volumes (w/w) of buffer (20 mM Tris-HCI, pH 7.5), containing 0.1 % Triton X-100. Test compounds (e.g. compounds of the present invention) are added at graded concentrations from stock solutions in ethanol or DMSO. Second, DHEAS as the substrate is added (1 μC/ml [3H]DHEAS, specific activity: about 60 Ci/mmol, and 20 ΜM unlabeled DHEAS). Samples are incubated for 18 hrs at 37°C. At the end of the incubation period, 50 pi of 1 M Tris, pH 10.4 and 3 ml of toluene are added. A 1-ml aliquot of the organic phase is removed and subjected to liquid scintillation counting. The determined dpm-values in the aliquots are converted to nmol of DHEA cleaved per g of skin per hour. The compounds of the present invention show activity in that described assay (IC50 in the range of 0.03 to 10 μM). The compounds of the present invention show activity in test systems as defined above. A compound of the present invention in salt and/or solvate form exhibits the same order of activity as a compound of the present invention in free and/or non-solvated form. The compounds of the present invention are therefore indicated for use as steroid sulfatase inhibitor in the treatment of disorders mediated by the action of steroid sulfatase, e.g. including androgen-dependent disorders of the pilosebaceous unit, such as acne, seborrhea, androgenetic alopecia, hirsutism; cancers, such as estrogen and androgen-dependent cancers; and cognitive dysfunctions, such as senile dementia including Alzheimer's disease. Treatment includes therapeutical treatment and prophylaxis. Preferred compounds of the present invention include a compound of Example 208, a compound of Example 217 and Example 218, a compound of Example 248, a compound of Example 249, a compound of Example 251, and a compound of Example 379. These compounds show in the Human Steroid Sulfatase Assay a rel IC5o in the range of 0.0046 to 0.29, in the CHO/STS Assay a rel IC50 in the range of 0.05 to 0.18, and in the Assay Using Human Skin Homogenate of an IC5o in the range of 0.03 to 0.27 pM and are thus highly active steroide sulfatase inhibitors. Even more preferred is the compound of Example 217 and Example 218, which show in the Assay of Human Steroid Sulfatase a rel IC50 of 0.29, in the CHO/STS Assay a rel IC50 of 0.08 and in the Assay Using Human Skin Homogenate an IC50 of 0.27 μM. In another aspect the present invention provides a compound of formula I for use as a pharmaceutical, e.g. in the treatment of disorders mediated by the action of steroid sulfatase. In a further aspect the present invention provides a compound of formula I for use in the preparation of a medicament for treatment of disorders mediated by the action of steroid sulfatase. In another aspect the present invention provides a method of treating disorders mediated by the action of steroid sulfatase comprising administering a therapeutically effective amount of a compound of formula I to a subject in need of such treatment. For such use the dosage to be used will vary, of course, depending e.g. on the particular compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results may be obtained if the compounds are administered at a daily dose of from about 0.1 mg/kg to about 100 mg/kg animal body weight, e.g. conveniently administered in divided doses two to four times daily. For most large mammals the total daily dosage is from about 5 mg to about 5000 mg, conveniently administered, for example, in divided doses up to four times a day or in retarded form. Unit dosage forms comprise, e.g. from about 1.25 mg to about 2000 mg of a compound of a present invention in admixture with at least one pharmaceutically acceptable excipient, e.g. carrier, diluent. The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt, e.g. an acid addition salt, metal salt, amine salt; or in free form; optionally in the form of a solvate. The compounds of the present invention may be administered in similar manner to known standards for use in such indications. The compounds of the present invention may be admixed with conventional, e.g. pharmaceutically acceptable, excipients, such as carriers and diluents and optionally further excipients. The compounds of the present invention may be administered, e.g. in the form of pharmaceutical compositions, - orally, e.g. in the form of tablets, capsules; - parenterally, intravenously, e.g. in the form of liquids, such as solutions, suspensions; - topically, e.g. in the form of ointments, creams. The concentrations of the active substance in a pharmaceutical composition will of course vary, e.g. depending on the compound used, the treatment desired and the nature of the composition used. In general, satisfactory results may be obtained at concentrations of from about 0.05 to about 5 % such as from about 0.1 to about 1% w/w in topical compositions, and by about 1% w/w to about 90% w/w in oral, parenteral or intravenous compositions. In another aspect the present invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of the present invention in association with at least one pharmaceutically acceptable excipient. A pharmaceutical composition of the present invention may comprise as an active ingredient one or more compounds of the present invention, e.g. at least one, and one or more other pharmaceutically active agents. At least one compound of the present invention thus may be used for pharmaceutical treatment alone, or in combination with one or more further pharmaceutically active agents. Such further pharmaceutically active agents include e.g. retinoids, e.g. retinoic acid, such as isotretinoin; tretinoin (Roche); adapalene (6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid); oral contraceptives, e.g. 19- nor-17a-pregna-1,3,5(10)-trien-20-in-3,17-diol, 6-Chlor-17-hydroxy-1a,2a-methylen-4,6- pregnadien-3,20- dion, such as Diane® (Schering), antibacterials, such as erythromycins, including erythromycin A, azithromycin, clarithromycin, roxythromycin; tetracyclines, lincosamid-antibiotics, such as clindamycin (methyl 7-chlor-6,7,8-tridesoxy-6-(trans-1-methyl-4-propyl-L-2-pyrrolidin-carboxamido)-1 -thio-L-threo-a-D-galacto-octopyranosid), azelaic acid (nonanedionic acid), nadifloxacin; benzoyl peroxide. Combinations include - fixed combinations, in which two or more pharmaceutically active agents are in the same pharmaceutical composition, - kits, in which two or more pharmaceutically active agents in separate compositions are sold in the same package, e.g. with instruction for co-administration; and - free combinations in which the pharmaceutically active agents are packaged separately, but instruction for simultaneous or sequential administration are given. In another aspect the present invention provides a compound of the present invention in combination with at least one other pharmaceutically effective agent for use as a pharmaceutical, such as a pharmaceutical composition comprising a combination of at least one compound of the present invention with at least one other pharmaceutically effective agent in association with at least one pharmaceutical acceptable excipient. In the following examples all temperatures are in degree Centigrade and are uncorrected. The following abbreviations are used: DIEA: diisopropylethylamine DMA: N,N-dimethylacetamide DMAP: N,N-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: dimethylsulfoxide EDC: 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide in the form of a hydrochloride EtAc: ethyl acetate EX: Example HEX: n-hexane c-HEX: cyclohexane m.p.: melting point PPA: propanephosphonic acid anhydride RT: room temperature THF: tetrahydrofurane PROCEDURES Example A 4-(4-Bromo-2,5-dichloro-thiophene-3-sulfonyIaminocarbonyl)-piperidine-1-carboxylic acid tert.-butyl ester (compound of Example 1) a. 4-Bromo-2,5-dichloro-thiophene-3-sulfonamide 90 ml of an aqueous solution of NH3 (32%) is added at room temperature to a solution of 8.88 g of 4-bromo-2l5-dichloro-thiophene-3-sulfonylchloride in 120 ml of EtAc. The mixture obtained is stirred for ca. 15 hours.Two phases obtained are separated, the organic layer is washed with 1 N HCI and H20, and dried. Solvent of the organic phase obtained is evaporated. 4-Bromo-2,5-dichloro-thiophene-3-sulfonamide is obtained in the form of a white powder, m.p. 113-117 °; 13C-NMR (CDCI3): 8= 108.287; 125.342; 130.404; 135.716. b. 4-(4-Bromo-2,5-dichloro-thiophene-3-sulfonvlaminocarbonvl)-piperidine-1 -carboxvlic acid tert.-butvl ester 60 mg of DMAP, 130 mg of DIEA and 192 mg of EDC are added to a solution of 155 mg of 4-bromo-2,5-dichloro-thiophene-3-sulfonamide and 230 mg of l-(tert.butyloxycarbonyl)-piperidine-4-carboxylic acid in 8 ml of DMF. The mixture obtained is stirred for ca. 16 h at ca. 30°, solvent is evaporated and the evaporation residue is treated with EtAc. The mixture obtained is washed with aqueous 1 N HCI, aqueous saturated NaHC03 and brine, and dried. Solvent from the organic phase obtained is evaporated and the evaporation residue is subjected to chromatography. 4-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylaminocarbonyl)-piperidine-1-carboxy!ic acid tert.-butyl ester is obtained and lyophilized from 1,4-dioxane. Example B 4-(3,5-Bis-trifluoromethyl-benzenesulfonylaminocarbonyl)-cis-3-methyl-piperldlne-1- carboxylic acid tert.-butyl ester (compound of Example 72) and 4-(3,5- Bls-trifluoromethyl-benzenesulfonylaminocarbonyl)-trans-3-methyl-plperidine-1- carboxylic acid tert.-butyl ester (compound of Examuple 73) 18 ml of a sodium bis(trimethylsilyl)amide solution (2M) in THF are added to a suspension of 12.4 g of methoxymethyltriphenylphosphonium chloride in 25 ml of dry THF at 0°. To the mixture obtained, 5.87 g of 3-methyl-4-oxo-piperidine-1-carboxylic acid tert.butyl ester in 25 ml of THF are slowly added, the mixture obtained is stirred at 0°, diluted with EtAc and extracted with aqueous 1M HCI, saturated aqueous NaHC03 solution and brine. The organic layer obtained is dried and solvent is evaporated. The evaporation residue obtained is subjected to filtration over silica gel and solvent of the filtrate obtained is evaporated. 3.6 g of the filtration residue obtained are dissolved in 150 ml of CH3CN, 1.68 g of cerium trichloride heptahydrate and 337 mg of sodium iodide are added and the resulting mixture is stirred at 40° overnight. From the mixture obtained solvent is evaporated and the evaporation residue obtained is treated with EtAc. The mixture obtained is extracted with aqueous 1M HCI, saturated aqueous NaHC03 solution and brine. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to filtration over silica gel and solvent of the filtrate obtained is evaporated. 494 mg of the evaporation residue obtained and 1.18 g of magnesium monoperoxyphthalic acid hexahydrate in 36 ml of EtOH/H20 (1:1) are stirred at RT and diluted with EtAc. The mixture obtained is extracted with aqueous 1M HCI. The organic layer obtained is dried, solvent is evaporated and the evaporatation residue is subjected to filtration and solvent of the filtrate obtained is evaporated. To a solution of 60 mg of the evaporation residue obtained, 71 mg of S^-bis^rifluoromethyOphenylsulfonamide, 94 mg of EDC and 30 mg of DMAP in 2 ml of DMF and 84 pi of DIEA are added and the mixture obtained is shaked at RT. From the mixture obtained solvent is removed and the concentrated residue obtained is subjected to preparative HPLC on an RP-18 column (CH3CN/H20 (0.1% TFA). 4-(3,5- Bis-trifluoromethyl-benzenesulfonylaminocarbonyl)-cis -3-methyl-piperidine-1-carboxylic acid tert.-butyl ester and 4-(3,5- Bis-trifluoromethyl-benzenesulfonyl-aminocarbonyl)-trans-3-methyl-piperidine-1-carboxylic acid tert.-butyl ester are obtained. Example C N-[1-(2-Nitro-phenyl)-piperidine-4-carbonyl]-3,5-bis-trifluoromethyI-benzenesulfonamide (compound of Example 81) a. N-(Piperidine-4-carbonyl)-3t5-bis-trifluoromethvl-benzenesulfonamide in the form of a hydrochloride 2 g of 4-(3,5-bis-trifluoromethyl-benzenesulfonylaminocarbonyl)-piperidine-1-carboxylic acid tert.-butyl ester are dissolved in a mixture of 1 ml MeOH and 9 ml of CH2CI2. The resulting mixture is treated at RT with 20 ml of 3 N HCI in (C2H5)20 for ca. 16 hours. Solvent is evaporated and N-(piperidine-4-carbonyl)-3,5-bis-trifluoromethyl-benzenesulfonamide in the form of a hydrochloride is obtained, m.p. 285-291°. b. N-n-(2-Nitro-phenyl)-"Diperidine-4-carbonvn-3.5-bis-trifluoromethvl-benzenesulfonamide 0.13 g of DIEA and 0.07 g of 1-fluoro-2-nitrobenzene are added to a solution of 0.22 g N-(piperidine-4-carbonyl)-3,5-bis-trifluoromethyl-benzenesulfonamide in the form of a hydrochloride in 4 ml of DMSO. The mixture obtained is stirred for ca. 18 h at 80°, solvent is evaporated and the evaporation residue is subjected to flash chromatography on silica gel (eluent: EtAc). N-[1 -(2-Nitro-phenyl)-piperidine-4-carbonyl]-3,5-bis-trifluoromethyl-benzenesulfonamide is obtained. Example D trans-[4-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylaminocarbonyl)-cyclohexylmethyl]-carbamic acid terf-butyl ester (compound of Example 109) a. 4-Bromo-2.5-dichloro-thiophene-3-sulfonamide 90 ml of an aqueous solution of NH3 (32%) is added at RT to a solution of 8.88 g of 4-bromo-2f5-dichloro-thiophene-3-sulfonylchloride in 120 ml of EtAc. The mixture obtained is stirred for ca. 15 h and two phases obtained are separated. The organic layer is washed with 1 N HCI and H20, and dried. Solvent of the organic solution obtained is evaporated. 4-Bromo-2,5-dichloro-thiophene-3-sulfonamide in the form of a white powder is obtained, m.p. 113-117 °C, 13C-NMR: 8 = 108.287; 125.342; 130.404; 135.716. b. trans-r4-(4-Bromo-2.5-dichloro-thiophene-3-sulfonvlaminocarbonvl)-cvclohexvlmethvn- carbamic acid tert.-butyl ester 60 mg of DMAP, 130 mg of DIEA and 192 mg of EDC are added to a solution of 155 mg of 4-bromo-2,5-dichloro-thiophene-3-sulfonamide and 257 mg of trans-1-(tert.butyloxycarbonyl-aminomethyl)cyclohexane-4-carboxylic acid in 8 ml of DMF and the mixture obtained is stirred for ca. 16 hours at ca. 30°. From the mixture obtained solvent is evaporated and the evaporation residue obtained is dissolved in EtAc. The solution obtained is washed with 1 N HCI, saturated NaHC03 solution and brine and dried. From the organic phase obtained solvent is evaporated and the evaporation residue obtained is subjected to chromatography. trans-[4-(4-Bromo-2,5-dichloro-thiophene-3-sulfonyIaminocarbonyl)-cyclohexylmethyl]-carbamic acid tert.-butyl ester is obtained. Example E 4-Chloro-N-(4-pentyl-bicyclo[2.2.2]octane-1-carbonyl)-benzenesulfonamide (compound of Example 186) 0.42 g of 4-chlorophenylsulfonamide| 60 mg of DMAP and 0.42 g of EDC are added to a solution of 0.5 g of 4-pentyl-bicyclo[2 2.2]octan-1-carboxylic acid in 8 ml of DMF, the mixture obtained is stirred for ca.16 h at RT and solvent from the mixture obtained is evaporated. The evaporation residue obtained is dissolved in EtAc and washed with 1 N HCIf saturated NaHC03 solution and brine and the organic phase obtained is dried. Solvent of the organic phase obtained is evaporated and thi evaporation residue obtained is subjected to chromatography. 4-Chloro-N-(4-pent} I- bicydo[2.2.2]octane-1-carbonyl)-benzenesulfonamide is obtained in the form of a white powder; Example F 10-(3,5-bis-trifluoromethyI-benzene >ulfonylaminocarbonyl)-8-aza-bicyc!o[4.3.1]deca- ne-8-carboxylic acid tert-butyl estei (compound of Example 217) a. 10-Oxo-8-aza-bicvclor4.3.11decane-8-carboxvlic acid tert-butvl ester 25 g of 8-methyl-8-aza-bicyclo[4.3.1]c ecan-10-one in the form of a hydrobromide are dissolved in H20 and a pH of -11 is adjusted by addition of aqueous NaOH solution. The mixture obtained is extracted with (C2 H5)2O. The organic layer obtained is dried and solvent is evaporated. The evaporation residte obtained is dissolved in 50 ml of dichloroethane, 23.7 ml of 1-chloroethyl chloroformate are added at 0° and the mixture obtained is stirred at 80°, cooled to RT, and 50 ml of MeOh are added. The mixture obtained is stirred at 60°, solvent is evaporated and the evapon tion residue obtained together with 18 g of K2C03 and 28.4 g of di-tert.-butyldicarbonate is treated with 240 ml of THF/H20 (5:1) and stirred at RT. The mixture obtained is concentrated under reduced pressure and diluted with EtAc. The mixture obtained is extracted with H20,1M HCI, aqueous, saturated NaHC03 solution and brine. The organic layer obtained s dried and solvent is evaporated. The evaporation residue is subjected to filtration over s lica gel with EtAc/c-Hex (1:3). 1O-Oxo-8-aza-bicyclo[4.3.1]decane-8-carboxylic acic tert-butyl ester is obtained, m.p.: 50-52°; 13C-NMR: 211.99, 154.82, 80.20, 48.70, 28.44, ' b. 10-Methoxvmethvlene-8-aza-bicvcl( !4.3.11decane-8-carboxvlic acid tert-butvl ester To a suspension of 9.54 g of methoxy nethyltriphenylphosphonium chloride in 25 ml of dry THF, 13.8 ml of a sodium bis(trimethyl3ilyl)amide solution (2M) in THF are added at 0° under stirring. To the mixture obtained 5.40 g of 10-oxo-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester in 25 m of THF are slowly added and stirring at 0° is continued. The mixture obtained - dilu ed with EtAc - is extracted with aqueous 1M HCI, aqueous saturated NaHC03 solution And brine. The organic layer obtained is dried and solvent is evaporated. The evaporatio i residue obtained is subjected to filtration over silica gel with EtAc/c-Hex (1:9). 10-Methoxy Tiethylene-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester is obtained. 13C-N VlR: 155.54, 142.46,118.38, 79.58, 59.82, 52.17, 50.89, 49.54, 36.93, 35.53, 34.91, 33 80, 33.50, 32.08, 28.94, 27.30, 27.18. c. 10-Formvl-8-aza-bicvclor4.3.11decane-8-carboxvlic acid tert-butvl ester -> 1:2). 10-Formyl-8-aza-bicydo[4.3.1 4.8 g of 10-methoxymethylene-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester are dissolved in 180 ml of CH3CN, 1.94 g of cerium trichloride heptahydrate and 390 mg of sodium iodide are added and the mixtue obtained is stirred at 40° overnight. From the mixture obtained solvent is evaporate I and the evaporation residue otained is dissolved in EtAc. The mixture obtained is extracts d with aqueous 1M HCI, aqueous, saturated NaHCO3-solution and brine. The orga lie layer obtained is dried, solvent is evaporated and the evaporation residue obtained is si bjected to filtration over silica gel with EtAc/c-Hex (1:4 2.86 g of 10-formyI-8-aza-bicyclo[4.3. magnesium monoperoxyphthalic acid at RT. The mixture obtained is diluted decane-8-carboxylic acid tert-butyl ester is obtained, m.p.: 55-60°; 13C-NMR: 204.53, 155.28 , 78.00, 55.40, 32.44, 32.12, 30.06, 28.89, 27.29. d. 8-Aza-bicvclof4.3.11decane-8t10-dicarboxvlic acid 8-tert-butvl ester ]decane-8-carboxylic acid tert-butyl ester and 5.8 g of lexahydrate in 170 ml of EtOH/H20 (1:1) are stirred with EtAc. The mixture obtained is extracted with aqueous 1M HCI and brine. The orgar ic layer obtained is dried, solvent is evaporated and the evaporation residue is cristallised rom MeOH/H20. 8-aza-bicyclo[4.3.1]decane-8,10- . 13, dicarboxylic acid 8-tert-butyl ester is ol >tained. m.p.: 218-222°; 1JC-NMR: 179.88, 155.31, 80.00, 52.43, 50.98, 47.63, 33.14, 32. 11, 28.91, 27.06. e. 10-(3t5-Bis-trifluoromethyl-benzenesulfonvlaminocarbonvl)-8-aza-bicyclor4.3.ndecane-8- carboxylic acid tert-butyl ester ml of DIEA are added to a solution of 6.1 ml of a 50% PPA solution in DMF,|633 mg of DMAP in 50 ml of dimethylamine and 1.8 .5 g of 8-aza-bicyclo[4.3.1]decane-8,10-dicarboxylic acid 8-tert-butyl ester, 2.3 g of 3,5-bis(trifIuoromethyl)phenyisulfonamide, the mixture obtained is stirred at 40° and diluted with EtAc. The mixture obtained is extracted with aqueous 1M NaHSO4-solution, saturat9d NaHCO3-solution and brine. From the mixture obtained solvent is distilled off. The dis filiation residue obtained is purified by filtration over silica gel with EtAc/c-Hex/MeOH (5:5:1) and the purified residue is subjected to crystallization from CH3CN:H20 (4:6). 0-(3,5-Bis-trifluoromethylbenzenesulfonylamino-carbonyl)-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester in the form of a sodium salt is obtained which is dissolved in EtAc and 1 M aqueous HCI and H2O, the phases obtained are separated, the organic layer obtained is dried and solvent is evaporated. 10(3,4-bis-trifluoromethyl-benzene-sulfonylaminocarbonyl)-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester is obtained. Example G 2-{4-[2-(3,5-Bis-trifIuoromethyI-benzenesulfonylam trifiuoromethyl-benzamide (compound of Example 241) a. 3.5-Bis-(trifluoromethvl)benzene-sulfonamide An aqueous solution of NH3 (32%) is added at RT to a solution of 3,5-bis(trifluoromethyl)-benzene-sulfonylchloride in EtAc. The mixture obtained is stirred and two phases are obtained and are separated. The organic layer obtained is washed with 1 N HCI and H2O, and dried. Solvent of the organic solution obtained is evaporated. 3,5-Bis-trifluoromethyl-benzene sulfonamide is obtained. b. 2"(4-f2-(3,5-Bis-trifluoromethvl-benzenesulfonvlamino)-2-oxo-ethvl1-piperidin'1-yl)-4- trifluoromethvl-benzamide 0.46 g of 2-fluoro-4-(trif luoromethyl)benzamide are added to a suspension of 1.8 g K2C03 and 0.8 g of piperidin-4-yl acetic acid hydrochloride in 12 ml of DMSO, the mixture obtained is stirred for 4 h at 150°, solvent is evaporated, the evaporation residue obtained is suspended in MeOH and filtrated. The filtrate obtained is concentrated and subjected to chromatography on silica gel. [1-(2-Carbamoyl-5-trifluoromethyl-phenyl)-piperidin«4-yl]-acetic acid is obtained. 300 mg of EDC are added to a solution of 260 mg of [1-(2-carbamoyl-5-trifluoromethyl-phenyl)-piperidin-4-yl]-acetic acid, 230 mg of 3,5-bis-trifluoromethyl-benzenesulfonamide, 200 mg of DIEA and 90 mg of DMAP in 4 ml of DMF. The mixture obtained is stirred for 3 days at RT, solvent is evaporated in vacuo and the evaporation residue obtained is treated with EtAc. The mixture obtained is washed with 1 N HCI, saturated aqueous NaHCO3 solution and brine, dried, concentrated in vacuo and subjected to chromatography on silica gel. 2-{4-[2-(3,5-Bis-trifluoromethyI-benzenesulfonylamino)-2-oxo-ethyl]-piperidin-1 -yl}-4-trifluoromethyl-benzamide is obtained. Example H 3-r2-(4-Bromo-2 a. 3-Oxo-9-aza-bicvclof3.3.nnonane-9-carboxvlic acid tert-butvl ester 19.1 g of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one in the form of a hydrochloride are suspended in 150 ml of dichloroethane and 26 ml of DIEA are added slowly at 0°. The mixture obtained is stirred for 1 hour at 0°, to the mixture obtained 27 ml of 1-chloroethyl chloroformate are added and the mixture obtained is stirred at 80° for 8 hours and cooled to RT. To the mixture obtained 100 ml of MeOH are added, the mixture obtained is stirred at 60° for 5 hours and solvent is evaporated. The evaporation residue obtained, 18 g of K2C03 and 28.4 g of di-tert.-butyldicarbonate are treated with 250 ml of THF/H2O, the mixture obtained is stirred at RT for 3 hours, concentrated under reduced pressure and diluted with EtAc. The mixture obtained is washed with H2O,1M HCI, saturated NaHC03 solution and brine, the organic layer obtained is dried and solvent is evaporated. The evaporation residue obtained is subjected to filtration over silica gel. 3-Oxo-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester is obtained in the form of an oil and is crystallized. 13C-NMR: 209.94, 168.09, 154.33, 80.56, 48.90, 47.58, 45.81, 45.61, 30.95, 30.67, 28.81, 16.67. b. 3-Ethoxvcarbonvlmethvlene-9-aza-bicvclor3.3.nnonane-9-carboxvlic acid tert-butvl ester 0.54 ml of (diethoxy-phosphoryl)-acetic acid ethyl ester are added dropwise to a suspension of 108 mg of NaH (55% in mineral oil) in 5 ml of THF at 0°. The mixture obtained is stirred and 650 mg of 3-oxo-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in 5 ml of THF are slowly added. The mixture obtained is stirred at 60°C for 3 days, diluted with c-HEX and washed with 1M aqueous NaH2PO4 and saturated aqueous NaHCO3 solution. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography on silica gel. 3-EthoxycarbonyImethylene-9-aza- bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester is obtained in the form of an oil. 13C- NMR: 171.79, 154.45, 154.27, 133.38, 132.77, 127.11, 126.30, 79.64, 79.54, 61.03, 61.00, 48.59, 47.20, 46.81, 45.22, 42.72, 33.61, 33.42, 32.59, 32.17, 30.73, 30.07, 28.87, 28.57, 28.13, 16.48, 14.59. c. 3-Ethoxvcarbonvlmethvl-9-aza-bicvclof3.3.11nonane-9-carboxvlic acid tert-butvl ester 390 mg of 3-ethoxycarbonylmethylene-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert- butyl ester are dissolved in 50 ml of EtOH and hydrogenated (50 bar, RT) in the presence of 100 mg of Pt02 as a catalyst. From the mixture opbtained the catalyst is filtrated off and 3- ethoxycarbonylmethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in the form of a mixture of the syn and anti isomers is obtained. 13C-NMR: 172.95, 172.88, 155.55, 154.44, 79.46, 79.42. 60.63. 47.40. 45.96. 45.88, 44.60. 43.77, 40.69, 37.01, 36.63. 32.24, 32.03, 31.40, 31.02, 29.61. 29.21. 29.17, 27.43. 20.60. 14.65. 14.07. d. 3-Carboxvmethvl-9-aza-bicvclof3.3.nnonane-9-carboxvlic acid tert-butvl ester 10 ml of 1M aqueous NaOH are added to a solution of 3-ethoxycarbonylmethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in 20 ml of THF and the mixture obtained is stirred at RT. To the mixture obtained 10 ml of brine and 70 ml of EtAc are added, and the mixture obtained is washed with 1M aqueous HCI. The organic layer obtained is dried and solvent is evaporated. 3-Carboxymethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in the form of an oil is obtained. 13ONMR: 178.47, 177.28, 155.61, 154.50, 79.70, 79.63, 47.39, 45.88. 43.39, 40.31. 36.92. 32.22. 31.98. 31.37, 30.99, 30.74, 30.64, 30.08, 29.59, 29.20, 21.15, 20.60, 14.05. e. 3-f2-(4-Bromo-2.5-dichloro-thiophene-3-sulfonvlamino)-2-oxo-ethvn-9-aza- bicvclof3.3.1lnonane-9-carboxvlic acid tert-butvl ester 69 \}\ of DIEA are added to a solution of 57 mg of 3-carboxymethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester, 93 mg of 2,4,5-trichloro-thiophene-3-sulfonic acid amide, 233 pi of PPA and 24 mg of DMAP in 2 ml of DMA, and the mixture obtained is stirred at RT for 48 hours. From the mixture obtained solvent is evaporated and the evaporation residue obtained is subjected to preparative HPLC on an RP-18 column followed by lyophilisation from dioxane. 3-[2-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylamino)-2-oxo-ethyl]-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester in the form of a powder is obtained. Example J 9-[1-Fluoro-2-oxo-2«(2,4,5-trichloro-thiophene-3-sulfonylamino)-ethylidene]-3-aza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (compound of Example 288) a. 9-Oxo-3-aza-bicvclor3.3.ndecane-3-carboxvlic acid tert-butvl ester 20 g of 3-methyl~3-aza-bicyclo[3.3.1]decan-10-one oxalate are dissolved in H2O and the pH is adjusted to -11 by addition of 1M aqueous NaOH solution. The mixture obtained is extracted with (C2H5)2O, the organic layer obtained is dried and solvent is evaporated. The evaporation residue obtained is dissolved in 100 ml of dichloroethane, 22.5 ml of 1-chloroethyl chloroformate are added at 0°, the mixture obtained is stirred at 80°, cooled to RT and 100 ml of MeOH are added. The mixture obtained is stirred at 60° and solvent is evaporated. The evaporation residue obtained, 14.8 g of K2CO3 and 23.4 g of di-tert.-butyldicarbonate are treated with 300 ml of THF/H2O and stirred at RT. The mixture obtained is concentrated under reduced pressure, diluted with EtAc and washed with H2O, 1M HCI, saturated aqueous NaHC03 solution and brine. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is subjected to filtration over silica gel with EtAc/c-HEX. 9-Oxo-3-aza-bicyclo[3.3.1]decane-3-carboxylic acid tert-butyl ester is obtained in crystalline form. 13C-NMR: 216.58, 154.49, 80.36, 51.00, 50.15, 47.11, 34.08, 28.45, 19.49. b. 9-(Fluoro-Ethoxycarbonylmethylene-3-aza-bicyclor3.3.nnonane-3-carboxylic acid tert- butvl ester 1.14 ml of (diethoxy-phosphoryl)-fluoro-acetic acid ethyl ester are added dropwise to a suspension of 244 mg of NaH (55% in mineral oil) in THF at 0°, the mixture obtained is stirred, 918 mg of 9-oxo-3-aza-bicyclo[3.3.1]decane-3-carboxylic acid tert-butyl ester in 10 ml of THF are added slowly and the mixture obtained is stirred at RT overnight.The mixture obtained is diluted with c-HEX and the diluted mixture obtained is washed with 1M aqueous NaH2P04 and saturated aqueous NaHC03 solution. The organic layer obtained is dried, solvent is removed by distillation and the distillation residue obtained is subjected to chromatography on silica gel. 9-(Fluoro-ethoxycarbonylmethylene-3-aza-bicyclo[3.3.1]-nonane-3-carboxylic acid tert-butyl ester is obtained in the form of an oil. 13C-NMR: 161.43, 161.15, 154.65, 139.95, 139.4, 137.97,79.79,61.15,50.33,49.98, 48.97, 48.53, 31.39, 31.04, 30.98, 28.54, 28.49, 19.70, 14.14. c. 9-(Carboxv-fluoro-methvlene)-3-aza-bicvclof3.3.1lnonane-3-carboxvlic acid tert-butvl ester 10 ml of 1M aqueous NaOH are added to a solution of 9-(fluoro-ethoxycarbonylmethylene-3-aza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester in 20 ml of THF, the mixture obtained is stirred at 40°, 10 ml of brine are added and the mixture obtained is diluted with EtAc. The diluted mixture obtained is washed with 1M aqueous HCI, the organic layer obtained is dried and solvent is evaporated. 9-(Carboxy-fIuoro-methylene)-3-aza-bicyclo[3.3.1]nonane-3-carboxy!ic acid tert-butyl ester in the form of an oil is obtained. 13C-NMR: 165.25, 164.96, 154.81, 142.21, 139.37, 137.42, 80.23, 50.39, 50.03, 49.37, 49.05, 33.21, 33.10, 32.94, 32.81, 31.74, 31.73, 31.37, 31.31, 28.51, 19.64. d. 9-ri-Fluoro-2-oxo-2-(2.4,5-trichloro-thiophene-3-sulfonvlamino)-ethvlidene1-3-aza- bicvclor3.3.nnonane-3-carboxylic acid tert-butyl ester 69 pi of DIEA are added to a solution of 60 mg of 9-(carboxy-fluoro-methylene)-3-aza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester, 71 mg of 2,4,5-trichIoro-thiophene-3-sulfonyl amide, 233 |jl of PPA and 24 mg of DMAP in 2 ml of DMA, and the mixture otained is stirred at 40° overnight. The mixture obtained is diluted with 10 ml of EtAc/c-HEX, and washed with 1M NaHSO4 solution. The organic layer obtained is dried and solvent is evaporated. The evaporation residue obtained is subjected to chromatography on silica gel and on Sephadex LH2O (MeOH) and relevant fractions obtained from chromatography are subjected to lyophilisation from dioxane. 9-[1-Fluoro-2-oxo-2-(2,4,5-trichloro-thiophene-3-sulfonylamino)»ethylidene]-3-aza"bicyclo[3.3.1]nonane-3-carboxylic acid tert.-butyl ester in the form of a powder is obtained. Example K 3-[2-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylamino)-1-cyano-2-oxo-ethylidene]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (compound of Exampl 289) a. 3-(Cyano-methoxycarbonvl-methylene)-8-aza-bicyclor3.2.noctane'8-carboxylic acid tert- butylester A solution of 2 g of 3-oxo-8-aza-bicycIo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 1.2 ml of cyano-acetic acid methyl ester, 130μl of piperidine and 38 mg of β-alanine in 4 ml of DMF is stirred at 70°C for 48 hours, the mixture obtained is diluted with EtAc, washed with H2O and brine, the organic layer obtained is dried, solvent is removed in vacuo and the residue obtained is subjected to chromatography on silica gel. 3-(cyano-methoxycarbonyI-methylene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester is obtained in the form of an oil. 13C-NMR: 174.13, 162.27, 153.68, 115.37, 107.45, 80.70, 53.92, 53.08, 28.81. b. 3-(Carboxy-Cyano-methylene)-8-aza-bicyclof3.2.noctane-8-carboxylic acid tert-butyl ester 3-(cyano-methoxycarbonyl-methylene)-8-aza-bicyclo[3.2.1 ]octane-8-carboxylic acid tert- butyl ester is saponified analogously to the method described in example J, c). 3-(Carboxy- cyano-methylene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in the form of a foam is obtained. 13C-NMR: 165.14, 153.83, 115.12, 107.51, 81.23, 28.82. c. 3-r2-(4-Bromo-2.5-dichloro-thiophene-3-sulfonvlamino)-1-Cyano-2-oxo-ethylidene1-8-aza- bicyclof3.2.1loctane-8-carboxylic acid tert-butylester 120 μl of DIEA are added to a solution of 102 mg of 3-(carboxy-cyano-methyIene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 162 mg of 4-bromo-2,5-dichloro-thiophene-3-sulfonamide, 583 pi of PPA in DMF (50%) and 43 mg of DMAP in 4 ml of DMA, and the mixture obtained is stirred at RT for 48 hours. From the mixture obtained solvent is removed in vacuo and the residue obtained is subjected to preparative HPLC on an RP-18 column. 3-[2-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylamino)-1-cyano-2-oxo-ethyIidene]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in the form of a foam is obtained. Example L 3,3-Dimethyl-butyric acid 4-[2-(4-bromo-2,5-dichloro-thiophene~3-sulfonylamino)-1 - fluoro-2-oxo-ethylidene]-adamantan-1-yl ester (compound of Example 290) a. 3,3-Dimethyl-butvric acid 4-oxo-adamantan-1-yl ester A solution of 1.03 g of 5-hydroxy-2-adamantanone, 1.83 g of DMAP and 1.9 ml of 3,3-dimethylbutanoyl chloride in 10 ml of CH2CI2 is stirred at 40°C for 48 hours, 6 ml of aqueous 1M KH2PO4 solution are added and the mixture obtained is stirred. The layers obtained are separated, from the organic layer obtained solvent is evaporated and the evaporation residue obtained is subjected to chromatography. 3,3-Dimethyl-butyric acid 4-oxo-adamantan-1-yl ester in the form of an oil is obtained. 13C-NMR: 215.61, 171.52, 49.10, 47.02, 41.38, 39.93, 38.17, 30.74, 29.79, 29.62. b. 3,3-Dimethyl-butvric acid 4-(fluoro-ethoxycarbonvl-methylene)-adamantan-1-yl ester 1.48 ml of (diethoxy-phosphoryl)-fluoro-acetic acid ethyl ester are added dropwise to a suspension of 317 mg of NaH (55% in mineral oil) in 30 ml of THF at 0°. The mixture obtained is stirred, 1.37 g of 3,3-dimethyl-butyric acid 4-oxo-adamantan-1-yl ester in 10 ml of THF are added slowly and the mixture obtained is stirred at RT overnight.The mixture obtained is diluted with EtAc and the diluted mixture obtained is washed with 1M aqueous NaH2PO4 and saturated aqueous NaHCO3 solution. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to chromatography on silica gel. 3,3-Dimethyl-butyric acid 4-(fluoro-ethoxycarbonyl-methylene)-adamantan-1-yl ester is obtained in the form of an oil. 13C-NMR: 171.54, 161.64, 140.78, 140.66, 139.92, 137.45, 78.28, 61.06, 49.23, 41.82, 41.80, 41.46, 40.27, 37.78, 37.54, 32.41, 32.39, 32.19, 30.72, 30.20, 29.63, 14.21. c. 3,3-Dimethyl-butvric acid 4-(cattooxy-fluoro-methylene)-adamantan-1-yl ester 3,3-dimethyl-butyric acid 4-(fluoro-ethoxycarbonyl-methylene)-adamantan-1-yI ester is saponified analogously to the method as described in example J c. 3,3-Dimethyl-butyric acid 4-(carboxy-fluoro-methyIene)-adamantan-1-yl ester in the form of a foam is obtained. 13C-NMR: 172.09, 166.50, 166.13, 144.79, 144.67, 139.55, 137.13, 78.52, 49.62, 42.22, 42.20, 41.83, 40.55, 38.31, 37.96, 33.12, 33.10, 32.95, 32.87, 31.94, 31.15, 30.52, 30.10, 30.04. d. 3.3-Dimethyl-butvric acid 4-r2-(4-bromo-2,5-dichloro-thiophene-3-sulfonvlamino)-1-fluoro- 2-oxo-ethylidene1-adamantan-1 -yl ester Coupling of 3,3-dimethyl-butyric acid 4-(carboxy-fluoro-methylene)-adamantan-1-yl ester with 4-bromo-2,5-dichloro-thiophene-3-sulfonamide and isolation is performed analogously to the method as described in Example K a. 3,3-DimethyI-butyric acid 4-[2-(4-bromo-2,5- dichloro-thiophene-3-sulfonylamino)-1 -fluoro-2-oxo-ethylidene]-adamantan-1 -yl ester is obtained. Example M [4-cis/trans-(3,5-Bis-(trifIuoro carbamic acid tert.-butyl ester (compound of Example 331) a. 3.5-Bis-(trifluoromethyl)benzene-sulfonamide An aqueous solution of NH3 (32%) is added at room temperature to a solution of 3,5-bis-(trifluoromethyl)benzene-sulfonylchloride in EtAc. The mixture obtained is stirred and two phases obtained are separated, the organic layer obtained is washed with 1 N HCI and H2O, and dried. Solvent of the organic solution obtained is evaporated. 3,5-Bis-trifluoromethyl-benzene sulfonamide is obtained. b. f4-cis/trans-(3 carbamic acid tert.-butylester 60 mg of DMAP, 130 mg of DIEA and 192 mg of EDC are added to a solution of 293 mg of 3,5-bis-trifluoromethyl-benzene-suifonamide and 257 mg of cis/trans-1-(tert.butyloxy-carbonylamino)cyclohexane-4-acetic acid in 10 ml of DMF, and the mixture obtained is stirred for 16 h at ca. 30°. Solvent from the mixture obtained is evaporated and the evaporation residue obtained is dissolved in EtAc. The solution obtained is washed with 1 N HCI, saturated NaHC03 solution and brine, and dried. From the organic phase obtained solvent is evaporated and the evaporation residue obtained is subjected to chromatography. [4-cis/trans-(3,5-bis-(trifluoromethyl)-benzenesulfonylaminocarbonylethyl)-cyclohexylj-carbamic acid tert.-butyl ester in the form of an isomeric mixture is obtained. Example N 1-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-(4-chloro-phenyl)-ethyl]-piperidine-4-carboxyiic acid cyclohexylamide (compound of Example 371) 140 mg of triethylamine and 0.32 ml of 50% propylphosphonic acid anhydride (solution in DMF) are added to a solution of 150 mg of (4-chlorophenyI)-(4-cyclohexylcarbamoyl-piperidin1-yl)-acetic acid, 174 mg of 3,5-bis(trifluoromethyl)-benzenesulfonamide and 24 mg of DMAP in 6 ml of anhydrous DMF at 10°. The mixture obtained is stirred for ca. 60 hours at RT, solvent is evaporated off and the evaporation residue obtained is treated with EtAc and H2O. Two phases obtained are separated and the organic layer obtained is washed, dried and solvent is evaporated. The evaporation residue obtained is subjected to chromatography on silica gel. 1-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-(4-chloro-phenyl)-ethyl]-piperidine-4-carboxylic acid cyclohexylamide is obtained. Example O 1-[2-Benzenesulfonylamino-1-(3,5- bistrifluoromethyl-phenyl)-2-oxo-ethyl]-piperidine- 4-carboxylic acid cyclohexylamide (compound of Example 365) A solution of 500 mg of bromo-(4-chlorophenyl)-acetic acid methyl ester in 1.3 ml of CH3CN is added to a solution of 288 mg piperidine-4-carboxylic acid cyclohexylamide and 0.239 ml DIEA in 4 ml of CH3CN at RT, the mixture obtained is stirred for ca. 24 hours at RT, solvent is evaporated and the evaporation residue obtained is treated with EtAc and H2O. The organic phase obtained is washed, dried and solvent is evaporated. 1-[2-Benzenesulfonylamino-1-(3,5-bistrifluoromethyl--phenyl)-2-oxo-ethyl]-piperidine-4-carboxylic acid cyclohexylamide is obtained. Example P (compound of Example 375) 4-(1-Carboxy-cyclopentyl)-piper»dine-1 -carboxylic acid tert-butyl ester a. 1-Pvridin-4-yl-cyclopentanecarboxylicacid ethyl ester 25 ml of a n-buthyllithium solution in HEX (1.6M) is slowly added to a solution of 2.17 ml of pyridin-4-yl-acetic acid ethyl ester in 200 ml of THF, the mixture obtained is stirred at RT for 30 minutes, is cooled to -78 °C and treated with 2.8 ml of 1,4-dibromobutane in 20 ml of THF. The mixture obtained is allowed to warm up to RT overnight, is treated with EtAc, the organic layer obtaiend is washed with water, saturated NaHC03 solution and brine, dried and solvent is evaporated. The evaporation residue obtained is subjected to chromatography. 1-Pyridin-4-yl-cyclopentanecarboxylic acid ethyl ester is obtained. 13C-NMR: 175.05,152.68, 150.15, 122.44, 61.63, 59.18, 36.19, 24.06, 14.33. b. 1-Piperidin-4-yl-cyclopentanecarboxylic acid ethyl ester in the form of a hydrochloride 1.75 g of 1-pyridin-4-yl-cycIopentanecarboxylic acid ethyl ester are dissolved in a mixture of 100 ml of MeOH and aqueous HCI (32%) and the mixture obtained is hydrogenated in the presence of 175 mg of PtO2 as a catalyst under pressure for 5 hours. From the mixture obtained the catalyst is removed by filtration and solvent is evaporated. 1-Piperidin-4-yl- cyclopentanecarboxylic acid ethyl ester in the form of a hydrochloride salt is obtained. 13C- NMR (CD3OD): 176.73, 61.33, 57.71, 45.08, 45.00, 42.14, 33.80, 25.49, 25.43, 25.36, 14.58. c. 4-(1-Ethoxycarbonvl-cyclopentyl)-piperidine-1-carboxylic acid tert-butylester 2.0 g of 1-piperidin-4-yl-cyclopentanecarboxylic acid ethyl ester in the form of a hydrochloride is converted into 4-(1-ethoxycarbonyl-cyclopentyl)-piperidine-1-carboxylic acid tert-butyl ester analogously to the procedure as described in Example F, c 4-(1-Ethoxycarbonyl-cyclopentyl)-piperidine-1-carboxyIic acid tert-butyl ester is obtained. 13C-NMR: 177.22, 155.16, 79.67, 60.75, 58.22, 44.77, 44.46, 33.73, 28.83, 28.67, 25.34, 14.66. d. 4-(1-Carboxy-cyclopentyl)-O-piperidine-1-carboxylic acid tert-butylester A solution of 1.2 g of 4-(1-ethoxycarbonyl-cyclopentyl)-piperidine-1-carboxyIic acid tert-butyl ester in a mixture of 100 ml of EtOH and 50 ml of an 1M aqueous NaOH is stirred at 70 ° for 14 days, EtAc is added and two phases obtained are are separated. The aqueous layer obtained is acidified with hydrochloric acid (pH 2-3) and extracted with EtAc. The organic layer obtained is washed with brine, dried and solvent is evaporated. 4-(1-Carboxy-cyclopentyl)-piperidine-1-carboxylic acid tert-butyl ester is obtained. Example Q 4-[(3,5-bis-trifluoromethyl-benzoylsulfamoyl)-methyl]-piperidine-1 -carboxylic acid tert-butyl ester (compound of Example 378) a, 4-r(benzhvdrvl-sulfamovl)-methvn-4-hvdroxy-piperidine-1-carboxylic acid tert.-butylester 28 ml of n-butyllithium (1.6 N solution in HEX) are added at -70° to a solution of 5.22 g of N-(diphenylmethyl)-methanesulfonamide in 120 ml of THF. The mixture is warmed to 0°, cooled to -30° and treated with 4 g of BOC-piperidin-4-one in 15 ml of THF. The mixture obtained is stirred at RT overnight, solvent is evaporated, the evaporation residue obtained is treated with EtAc, washed with 1 N HCI, saturated, aqueous NaHCO3 solution and brine, the organic layer obtained is dried and solvent is evaporated. The evaporation residue obtained is subjected to chromatography on silica gel. 4-[(Benzhydryl-sulfamoyl)-methyl]-4-hydroxy-piperidine-1-carboxylic acid tert.-butyl ester in the form of a powder is obtained, .m.p. 121 -123°. b. 4-Hydroxy-4-sulfamovlmethyl-Piperidine-1-carboxylic acid tert-butylester 5.19 g of 4-[(benzhydryl-sulfamoyl)-methyl]-4-hydroxy-piperidine-1-carboxylic acid tert.-butyl ester in 150 ml of MeOH are treated with 100 pi of triethylamine and the mixture obtained is hydrogenated overnight at RT with 10 % Pd/C as a catalyst. From the mixture obtained the catalyst is filtrated off, solvent is evaporated and the evaporation residue is subjected to chromatography on silica gel. 4-Hydroxy-4-sulfamoylmethyl-piperidine-1-carboxylic acid i tert.-butyl ester are obtained, m.p. 176 -180°. c. 4-rf3,5-bis-trifluoromethyl-benzovlsulfamovl)-methvn-4-hvdroxy-piperidine-1-carboxylic acid tert-butylester 1510 mg of 3,5-bis-(trifluoromethyl)-benzoic acid, 477 mg of DMAP, 1010 mg of DIEA and 1500 mg of EDC are added to a solution of 1150 mg of 4-hydroxy-4-suIfamoylmethyl-piperidine-1-carboxylic acid tert-butyl ester. The mixture obtained is stirred for 16 hours, solvent is evaporated and the evaporation residue is treated with EtAc, washed with 1 N HCI, saturated, aqueous NaHC03 solution and brine, the organic layer obtained is dried and subjected to chromatography on silica gel. 4-[(3l5-bis-trifIuoromethyl-benzoylsulfamoyl)-methyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester are obtained, m.p. 154 -159°. d. 4-r(3,5-bis-trifluoromethyl-benzovlsulfamovl)-methylene]-piperidine-1-carboxylic acid tert.- butylester 1510 mg of Martin Sulfurane dehydrating agent are added to 300 mg of 4-[(3,5-bis-trifluoromethyl-benzoylsulfamoyl)-methyl]-4-hydroxy-piperidine-1 -carboxylic acid tert.-butyl ester in 5 ml of CH2CI2. The mixture obtained is stirred in a microwave oven at 100° for 15 minutes, from the mixture obtained solvent is evaporated and the evaporation residue is subjected to chromatogry on silica gel. 4-[(3,5-bis-trifluoromethyl-benzoyIsulfamoyl)-methylene]-piperidine-1 -carboxylic acid tert.-butyl ester is obtained, m.p. 132 -136°. e. 4-r(3,5-bis-trifluoromethyl-benzovlsulfamovl)-methyl1-piperidine-1 -carboxylic acid tert-butylester A solution of 880 mg of 4-[(3I5-bis-trifluoromethyl-benzoylsulfamoyl)-methylene]-piperidine-1-carboxylic acid tert.-butyl ester in 100 ml of MeOH is hydrogenated (10 % Pd/C as a catalyst). From the mixture obtained the catalyst is filtrated off and solvent is evaporated. 4-[(3,5-Bis-trifluoromethyl-benzoylsulfamoyl)-methyl]-pipericline-1 -carboxylic acid tert-butyl ester is obtained. Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula TABLE 2 (compounds of formula I, wherein m is 0, n is 0, and Ri is a group of formula VII) are obtained. If not otherwise indicated in TABLE 2 1HNMR and 13C-NMR data are determined in CDCI3. TABLE 3 (compounds of formula I, wherein m is 0, n is 0, and R, is a group of formula VII) are obtained. If not otherwise indicated in TABLE 3 13C-NMR and 1HNMR data are determined in CDCI3. hydrogen or is as defined in TABLE 4 (compounds of formula I, wherein m is 0, n is 1, and Ri is a group of formula VII) are obtained. If not otherwise indicated in TABLE 4, characterisation data is 'HNMR data, and 13C-NMR and 1HNMR data are determined in CDCI3. / (compounds of formula I, wherein m is 0, n is 0, and Ri is a group of formula II) are obtained. If not otherwise indicated in TABLE 5 'C-NMR and 13C-NMR data are determined in CDCI3. in TABLE 6 (compounds of formula I, wherein m is 0, n is 1, and R2 is a group of formula VII) are obtained. If not otherwise indicated 13C-NMR and 1HNMR data in TABLE 6 are determined in DMSO-d6. defined in TABLE 7 (compounds of formula I, wherein m is 1, n is 0, and Ri is a group of formula VII) are obtained. If not otherwise indicated in TABLE 7 13C-NMR and 'HNMR data in TABLE 7 are determined in CDCI3. Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula 1 Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula defined in TABLE 11 (compounds of formula I, wherein m is 1, n is 0, and R2 is a group of formula V) are obtained. wherein R8 is hydrogen or is as defined in TABLE 12 and R2 and R9 + R10 are as defined in TABLE 12 (compounds of formula I, wherein m is 0, n is 1, Ri is a group of formula VII) are obtained. TABLE 13 (compounds of formula I, wherein m is 0, n is 0, Rt is a group of formula II, and R2 is (C6-i8)aryl). are obtained. WE CLAIM: 1. A compound of formula wherein R1p4 is unsubstituted or substituted phenyl or thienyl, R16P4 and R17P4 together with the carbon atom to which they are attached are a substituted bridged (C5_12)cycloyalkyl ring system, substituted piperidine or substituted bridged piperidine, Ri8P4 is hydrogen or hydroxyl, more preferably hydrogen, mP4 is 1. 3. A compound of any one of claims 1 or 2 for use as a pharmaceutical. 4. A compound of any one of claims 1 to 3 for use in the preparation of a medicament for treatment of disorders mediated by the action of steroid sulfatase. Dated this 5th day of April 2004

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