# Combination of a Steroid Sulfatase Inhibitor and an Ascomycin

Imported: 10 Mar '17 | Published: 27 Nov '08

Josef Gottfried Meingassner

USPTO - Utility Patents

## Abstract

A combination of a steroid sulfatase inhibitor and an ascomycin, which combination is useful as a pharmaceutical.

## Description

The present invention relates to a combination of a steroid sulfatase inhibitor and an ascomycin.

In one aspect the present invention provides a combination of a steroid sulfatase inhibitor and an ascomycin.

An ascomycin (ascomycins) includes ascomycin as such, and derivatives thereof. A derivative is to be understood as being an antagonist, agonist or analogue of the parent compound which retains the basic structure and modulates at least one of the biological, for example immunological, properties of the parent compound. e.g. obtainable by fermentation techniques. Such derivatives are e.g. obtainable by chemical derivatisation or fermentation manipulation procedures of naturally occurring ascomycins.

Appropriate ascomycins are hereinafter designated as ascomycin(s) of (according to) the present invention and e.g. include compounds as disclosed in U.S. Pat. No. 3,244,592, EP349061, EP184162, EP315978, EP323042, EP423714, EP427680, EP465426, EP474126, WO9113889, WO9119495, EP484936, EP523088, EP532089, EP569337, EP626385, WO935059, WO978182;

such as

• ascomycin;
• tacrolimus (FK506; PrografR);
• imidazolylmethoxyascomycin (WO978182, compound of formula I, e.g. of Example 1);
• 32-O-(1-hydroxyethylindol-5-yl)ascomycin (L-732531) (Transplantation 65 [1998] 10-18, 18-26, on page 11, FIG. 1;
• (32-desoxy,32-epi-N1-tetrazolyl)ascomycin (ABT-281) (J. Invest. Dermatol. 12 [1999] 729-738, on page 730, FIG. 1);
• {1R,5Z,9S,12S-[1E-(1R,3R,4R)],13R,14S,17R,18E,21S,23S,24R,25S,27R}-17-ethyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-5,18-diene-2,3,10,16-tetraone (Example 8 in EP626385), hereinafter referred to as 5,6-dehydroascomycin;
• {1E-(1R,3R,4R)]1R,4S,5R,6S,9R,10E,13S,15S,16R,17S,19S,20S}-9-ethyl-6,16,20-trihydroxy-4-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-15,17-dimethoxy-5,11,13,19-tetramethyl-3-oxa-22-azatricyclo[18.6.1.0(1,22)]heptacos-10-ene-2,8,21,27-tetraone (Examples 6d and 71 in EP569337), hereinafter referred to as ASD 732; and
• pimecrolimus (INN recommended) (ASM981; Elidel), i.e {[1E-(1R,3R,4S)]1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R}-12-[2-(4-chloro-3-methoxycyclohexyl)-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28,dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetraone of formula

such as disclosed in EP 427 680 (33-epi-33-chloro-FR 520 of example 66a.

Appropriate steroid sulfatase inhibitors are hereinafter designated as steroid sulfatase inhibitors of (according to) the present invention and e.g. include compounds of formula

wherein

R1 is (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 selected from the group consisting of
• halogen, nitro, di(C1-4)alkylamino, cyano, (C1-6)alkyl, (C1-4)haloalkyl, unsubstituted phenylcarbonylamino(C1-4)alkyl, (C1-4)alkoxy, (C1-4)haloalkoxy, aminocarbonyl, di(C1-4)alkylaminocarbonyl, (C1-4)alkylcarbonyl, (C1-4)alkoxycarbonyl, unsubstituted phenyl, carboxyl, and phenyl-substituted phenylcarbonylamino(C1-4)alkyl or substituted phenyl, wherein the phenyl-substitutents are selected from the group consisting of
• halogen, nitro, di(C1-4)alkylamino, cyano, (C1-6)alkyl, (C1-4)haloalkyl, (C1-4)alkoxy, (C1-4)haloalkoxy, aminocarbonyl, di(C1-4)alkylaminocarbonyl, (C1-4)alkylcarbonyl, (C1-4)alkoxycarbonyl and carboxyl, or

R1 is a group of formula

R2 is a group of formula

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,
• R11 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,
• (C1-6)alkoxycarbonyl((C1-4)alkyl)amino,
• (C1-6)alkoxycarbonyl((C2-4)alkenyl)amino,
• (C3-8)cycloalkylcarbonylamino,
• (C3-8)cycloalkylcarbonyl((C1-4)alkyl)amino,
• (C3-8)cycloalkylcarbonyl((C2-4)alkenyl)amino,
• (C1-6)alkoxycarbonyloxy,
• phenyl(C1-4)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(C1-4)alkyl,
• (C3-8)cycloalkoxycarbonyl(C1-4)alkyl,
• (C1-6)alkoxycarbonylamino(C1-4)alkyl,
• (C3-8)cycloalkylcarbonylamino(C1-4)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,
• (C3-8)cycloalkoxycarbonyl,
• (C3-8)cycloalkyl(C1-4)alkylcarbonyl, wherein cycloalkyl is unsubstituted or substituted by hydroxy,
• phenylcarbonyl, wherein phenyl is unsubstituted or substituted and wherein the substituents are defined as above for substituted phenyl,
• (C3-8)cycloalkylaminocarbonyl,
• (C3-8)cycloalkyl((C1-4)alkyl)aminocarbonyl,
• (C3-8)cycloalkyl((C2-4)alkenyl)aminocarbonyl, and
• (C1-8)alkoxycarbonyl,

R3, R8, R13 and R18 independently of each other are hydrogen, hydroxy, halogen, cyano, (C1-4)alkyl, (C1-4)alkoxy, phenyl or phenoxy,

EITHER

R8 or R18, respectively, independently of each other are hydrogen, hydroxy, halogen, cyano, (C1-4)alkyl, (C1-4)alkoxy, phenyl or phenoxy, and at lest 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,

independently of each other have the meaning of R4 and R5 together with the carbon atom to which they are attached, as defined above,

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)cycloalkyl, and

R8 or R18, respectively, independently of each other are a substituted

• bridged cycloalkyl system, (C4-8)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 defined 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

• R1, 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 bridged heterocyclyl ring system, wherein the substituents are as defined above for the corresponding groups, or if R1 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

IF

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; and

IF

m is 0, n is 0 and R1 and/or R2 are substituted (C4-8)cycloalkyl,

THEN

(C4-8)cycloalkyl is substituted as defined above with the exception of phenyl and substituted phenyl as a substituent,

with the proviso that

in a compound of formula I at least one substituent selected from the group consisting of a substituted bridged cycloalkyl ring system, substituted (C4-8)cycloalkyl, substituted piperidine, substituted tetrahydropyridine, substituted piperazine, or a substituted bridged 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.g. (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)cycloalkyl, such as (C6-8)cycloalkyl, wherein the bridge optionally comprises a heteroatom, such as N, e.g. including cycloalkyl anellated 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 CH2CH2 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 CH2NHCH2 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 CH2NHCH2 group and which bridged cycloheptyl is further anellated 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 or substituted 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 (C1-4)alkoxy. Chromanyl, e.g. includes chroman-6-yl, e.g, substituted by (C1-4)alkyl. Pyridine includes pyridine substituted by halogen and is bound to the (optionally (CH2)m or n)carbonyl or (optionally (CH2)m or n)sulfonyl group in a compound of formula I via a carbon atom.

A steroid sulfatase inhibitor of the present invention includes 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
• R15

is substituted (C4-8)cycloalkyl, wherein the substituents are as defined above for substituted cycloalkyl, with the exception of phenyl and substituted phenyl as a substituent, and the other substitutents are as defined above, such as a compound of formula IP2, IP6, IP7 or IP10 as defined below.

A steroid sulfatase inhibitor of the present invention also includes 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
• R15

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 substituted piperazine, wherein the substituents are as defined above for substituted piperidine, substituted tetrahydropyridine, a substituted bridged heterocyclic system and wherein piperazine is substituted by groups as defined for substituted piperidine, and the other substitutents are as defined above, such as a compound of formula IP1, IP4, IP5, IP8, IP9, IP12, IP13 or IP14 as defined below.

A steroid sulfatase inhibitor of the present invention also includes a compound of formula I, which is a compound of formula

wherein R1P1 has the meaning as defined in R1 above, and R16P1 and R17P1 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 IP1 preferably

R1P1 is substituted or unsubstituted thienyl, benzthiazolyl, chromanyl, phenyl or naphthyl,

R16P1 and R17P1 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)alkoxycarbonyl, e.g. BOC (i.e. tert.butoxycarbonyl),
• (C1-6)alkoxycarbonyl(C1-4)alkyl, e.g. tert.butoxycarbonylmethyl,
• unsubstituted or substituted phenyl, wherein the substituents are as defined for phenyl above,
• (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,
• 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 (C1-4)alkyl,

and

R18P1 is hydrogen, phenyl or (C1-4)alkyl, more preferably hydrogen or phenyl.

A steroid sulfatase inhibitor of the present invention also includes 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)cycloalkyl, wherein the substituents are as defined above for substituted cycloalkyl with the exception of phenyl or substituted phenyl as a substituent, and R18P2 has the meaning of R18 as defined above.

In a compound of formula IP2 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
• (C1-6)alkoxycarbonylamino(C1-4)alkyl, (C1-6)alkoxycarbonylamino, (C1-6)alkoxycarbonyl-((C1-4)alkyl)amino, (C1-6)alkoxycarbonyl((C2-4)alkenyl)amino, (C3-8)cycloalkylcarbonyl-((C1-4)alkyl)amino, (C3-8)cycloalkylcarbonylamino(C1-4)alkyl, (C1-6)alkylcarbonylamino-(C1-4)alkyl, (C3-8)cycloalkyl(C1-4)alkyl-carbonyloxy, (C3-8)cycloalkyl(C1-4)alkylcarbonyloxy, (C3-8)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 (C1-6)alkoxycarbonylamino(C1-4)alkyl or (C1-6)alkoxycarbonylamino,

R18P2 is hydrogen

A steroid sulfatase inhibitor of the present invention also includes a compound of formula I, which is a compound of formula

wherein R1P3 has the meaning of R1 as defined above, R16P3 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 R18P3 has the meaning of R18 as defined above.

In a compound of formula IP3 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
• (C4-12)alkyl,
• (C1-6)alkyl, substituted by hydroxy, phenyl,
• unsubstituted phenyl and substituted phenyl, wherein the substituents are as defined above for substituted phenyl,
• (C1-6)alkoxycarbonylamino, e.g. tert.butoxycarbonylamino,
• (C1-6)alkoxycarbonyl(C1-6)alkyl,
• (C3-8)cycloalkylcarbonyl(C1-6)alkyl,
• (C3-8)cycloalkoxycarbonyl(C1-6)alkyl,
• (C1-6)alkylcarbonyl wherein alkyl is unsubstituted or substituted, e.g. by hydroxy,
• (C3-8)cycloalkyl,
• (C3-8)cycloalkylamino(C1-6)alkyl,

more preferably substituted by (C1-6)alkoxycarbonyl, such as BOC, (C4-8)alkyl, such as pentyl or (C1-6)alkoxycarbonylamino, e.g. tert.butoxycarbonylamino.

• R18P3 is hydrogen, such as a compound of formula

or of formula

including pure isomers of formula

and mixtures thereof.

Compounds comprising a group of formula

normally are obtained in the configuration of a compound of formula EX217.

A steroid sulfatase inhibitor of the present invention also includes 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 IP4 preferably

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 cycloalkyl ring system, substituted piperidine or substituted bridged piperidine, more preferably a substituted bridged cycloalkyl 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,
• (C1-4)alkylcarbonyloxy(C1-4)alkyl, 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

or of formula

or of formula

A steroid sulfatase inhibitor of the present invention also includes a compound of formula I, which is a compound of formula

wherein

R1P5 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 R11 and R12 as defined above.

In a compound of formula IP5 preferably

• R1P5 is unsubstituted or substituted phenyl or thienyl
• R11P5 and R12P5 together with the carbon atom to which they are attached are piperidine, methylpiperidine or a bridged cycloalkyl ring system substituted by
• (C1-6)alkoxycarbonyl, e.g. tert.butoxycarbonyl;
• unsubstituted or substituted phenyl, wherein the substituents are as defined above for phenyl,
• (C1-8)alkylcarbonyloxy, such as tert.butyl-methylcarbonyloxy,
• more preferably substitutents are selected from (C1-8)alkoxycarbonyl, such as BOC, or (C1-6)alkyl-carbonyloxy, such as tert.butylmethylcarbonyloxy,
• R3P5 is hydrogen, halogen or cyano.

A steroid sulfatase inhibitor of the present invention also includes a compound of formula I, which is a compound of formula

wherein

R1P6 has the meaning of R1 as defined above,

R16P6 and R17P6 together with the carbon atom to which they are attached are substituted (C4-8)cycloalkyl,

R18P6 has the meaning of R18 as defined above, and

mP6 is 1, 2, 3 or 4.

In a compound of formula IP6 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.

A steroid sulfatase inhibitor of the present invention also includes 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, wherein the substituents are as defined above for substituted (C4-8)cycloalkyl with the exception of phenyl or substituted phenyl as a substituent,

R18P7 has the meaning of R18 as defined above, and

mP7 is 1, 2, 3 or 4.

In a compound of formula IP7 preferably

• R1P7 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
• mP7 is 1.

A steroid sulfatase inhibitor of the present invention also includes a compound of formula I, which is a compound of formula

wherein

R1P8 has the meaning of R1 as defined above,

R16P8 and R17P8 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,

mP8 is 1 and nP8 is 1,

In a compound of formula IP8 preferably

• R1P8 is unsubstituted or substituted phenyl,
• R16P8 and R17P8 together with the carbon atom to which they are attached are piperidine substituted by (C1-6)alkoxycarbonyl.
• R18P8 is hydrogen.
• mP8 is 1.
• nP8 is 1.

A steroid sulfatase inhibitor of the present invention also includes a compound of formula I, which is a compound of formula

wherein R1P9, R6P9 and R7P9 have the index-number corresponding meaning of R1, R6 and R7 as defined above and wherein at least one substituent selected from the group consisting of a substituted bridged cycloalkyl ring system, substituted (C4-8)cycloalkyl, substituted piperidine, substituted tetrahydropyridine, substituted piperazine, or a substituted bridged heterocyclyl ring system, wherein the substituents are as defined above for the corresponding groups, is present.

In a compound of formula IP9 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)cycloalkylaminocarbonyl or (C1-6)alkoxycarbonyl, or amino substituted by substituted piperidine,

and wherein at least one substituent is such substituted piperidinyl.

A steroid sulfatase inhibitor of the present invention also includes a compound of formula I, which is a compound of formula

wherein

wherein R1P10 has the meaning of R1,

R8P10 is a substituted

• bridged cycloalkyl system, (C4-8)cycloalkyl, substituted piperidine, tetrahydropyridine, or a bridged heterocyclic system,

wherein the substitutents are as defined above for the corresponding groups, and

R9P10 and R10P10 together with the carbon atom to which they are attached are (C4-8)cycloalkyl.

In a compound of formula IP10 preferably

• R1P10 is substituted or unsubstituted phenyl.
• R8P10 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.

A steroid sulfatase inhibitor of the present invention also includes a compound of formula I, which is a compound of formula

wherein

R1P11 has the meaning of R1,

R11P11 and R12P11 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 of R13, and

mP11 is 1, 2, 3 or 4.

In a compound of formula IP11 preferably

• R1P11 is substituted or unsubstituted phenyl.
• R11P11 and R12P11 together with the carbon atom to which they are attached are a substituted bridged cycloalkyl ring system.
• mP11 is 1.

A steroid sulfatase inhibitor of the present invention also includes 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,

R8P12 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 IP12 preferably

• R2P12 is substituted or unsubstituted phenyl.
• R8P12 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)alkylcarbonyl, 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

A steroid sulfatase inhibitor of the present invention also includes a compound of formula I, which is 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 R12 as defined above, and

R13P13 has the meaning of R13 as defined above.

In a compound of formula IP13 preferably

• R2P13 is unsubstituted or substituted phenyl.
• R11P13 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.

A steroid sulfatase inhibitor of the present invention also includes a compound of formula I, which is a compound of formula

wherein R1P14 is (C6-18)aryl, and R2P14 is (C6-18)arylsulfondioxideamino.

In a compound of formula IP14 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(C1-3)alkyl, (C1-3)alkoxy, halogen(C1-3)alkoxy, or halogen.

A compound of formula I includes a compound of formula IP1, IP2, IP3, IP4, IP5, IP6, IP7, IP8, IP9, IP10, IP11, IP12, IP13 and IP14. Steroid sulfatase inhibitors include 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 steroid sulfatase inhibitor 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.

A salt of a steroid sulfatase inhibitor of the present invention includes a pharmaceutically 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. HCl; amine salts include salts of a compound of formula I with an amine.

A steroid sulfatase inhibitor of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa. A steroid sulfatase inhibitor 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.

Such steroid sulfatase inhibitors may exist in the form of isomers and mixtures thereof, e.g. such compounds may 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 R1 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. Steroid sulfatase inhibitors of the present invention include a compound in any isomeric form and in any isomeric mixture.

Any compound described herein may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as specified herein. A steroid sulfatase inhibitor of the present invention, such as a compound of formula I may e.g. be prepared by reaction of a compound of formula

wherein R1 and n are as defined above, with 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 with 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 R2H, 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)2OPCHRxCOOR, 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-PCRxCOOC2H5, 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 NCCH2COOR, wherein R is as defined above, in a solvent, e.g. dimethylformamide, in the presence of a catalyst, e.g. piperidine and -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/H2O, 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 seborrhea. 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-O-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, seborrhea, 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, asthma and organ rejection following transplantation, psoriasis, lichen planus, atopic dermatitis, allergic-, irritant-contact dermatitis, eczematous dermatitis, graft versus host disease. 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-HCl, pH 7.4, 0.25 M sucrose). The homogenate obtained is centrifuged at 10,000g 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 (100,000g, 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-HCl, pH 7.4 and stored at 20 C. until further work-up.

After thawing, microsomes are collected by ultracentrifugation (as described above) and are suspended in 50 ml of buffer B (10 mM Tris-HCl, 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 (100,000g, 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 (2.620 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 (1.610 cm) equilibrated in buffer C (20 mM Tris-HCl, pH 7.4, 0.1% Triton X-100, 0.5 M NaCl). 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-HCl, 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 (0.810 cm) equilibrated with buffer D; which column is washed and elution is carried out with a linear gradient of buffer D to 2 M NaCl 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 l substrate solution (1.5 mM 4-methylumbelliferyl sulfate in 0.1 M Tris-HCl, pH 7.5)
• 2) 50 l test compound dilution in 0.1 M Tris-HCl, 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 l 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 M in 0.1 M Tris-HCl, 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 l 0.2 M NaOH. Fluorescence intensity is determined in a Titertek Fluoroskan II instrument with ex=355 nm and em=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% (IC50) is calculated using the equation:

$I = I 100 1 + ( c / IC 50 ) 5$

wherein I100 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:

$rel IC 50 = IC 50 of test compound IC 50 of estrone sulfamate$

According to our testing and calculation estrone sulfamate shows an IC50 value of approximately 60 nM.

The steroid sulfatase inhibitors 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 l/well 0.5 mM 4-methylumbelliferyl sulfate (MUS), dissolved in 0.1M Tris-HCl, pH 7.5. The enzyme reaction is carried out at 37 C. for 30 minutes. Then 50 l/well stop solution (1M Tris-HCl, 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-O-sulfamate is run as a reference compound, and the IC50 values are normalized to estrone 3-O-sulfamate (relative IC50=IC50 compound/IC50 estrone 3-O-sulfamate).

The steroid sulfatase inhibitors 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 11 mm) using sharp scissors. The pieces obtained are suspended in ten volumes (w/w) of buffer (20 mM Tris-HCl, 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 C/ml [3H]DHEAS, specific activity: about 60 Ci/mmol, and 20 M unlabeled DHEAS). Samples are incubated for 18 hrs at 37 C. At the end of the incubation period, 50 l 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 steroid sulfatase inhibitors of the present invention show activity in that described assay (IC50 in the range of 0.03 to 10 M).

The steroid sulfatase inhibitor of the present invention show activity in test systems as defined above. A steroid sulfatase inhibitor 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 steroid sulfatase inhibitor of the present invention are therefore indicated for use as steroid sulfatase inhibitors 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;
• cognitive dysfunctions, such as senile dementia including Alzheimer's disease.

The steroid sulfatase inhibitor of the present invention are preferably used in the treatment of acne, seborrhea, androgenetic alopecia, hirsutism; estrogen, e.g. and androgen-dependent cancers, more preferably in the treatment of acne. 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 IC50 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 IC50 in the range of 0.03 to 0.27 M and are thus highly active steroid 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 M.

We have now surprisingly found, that a steroid sulfatase inhibitor, e.g. a compound of Example 217 and a compound of Example 218, show anti-inflammatory activity in combination with an ascomycin, e.g. pimecrolimus.

Activity in inflammatory diseases may be e.g. shown in the following test system

Anti-Inflammatory Test System

The test sites on the inner surface of the right external ears of mice, e.g. strain NMRI, (8 per group) are treated with 10 l of the dissolved test compound or with the vehicle (a 4:4:2 mixture of ethanol/acetone/dimethylacetamide) alone. The test compounds are applied alone or in combination at concentrations shown in the TEST RESULT TABLE. Thirty minutes after the treatment irritant contact dermatitis is elicitated at the treated auricular sites with 10 l 0.005% tetradecanoylphorbol-13-acetate (TPA).

Skin inflammation is assessed 6 hours after the elicitation by determination of the auricular weights, as a measure of inflammatory swelling. The animals are killed and both ears are cut off and weighed. Inhibitory activity of test compounds is calculated from differences in right and left ears (internal controls) in mice treated with the test compounds compared with animals treated with the vehicle only. Results obtained are as set out in TEST RESULT TABLE below:

TEST RESULT TABLE compound of example 217 or of example 218 pimecrolimus 0 0.1 0.3 1.0 3.0 10 0 20 36 45 0.1 15 18 35 49 0.3 29 52 1.0 30 58 70 3.0 31 54 10 42 60

In the TEST RESULT TABLE the concentrations of the compounds (in bold) used are indicated in micromol/litre. The values given in the TEST RESULT TABLE (in regular letters) are the inhibition in % determined according to the ANTI-INFLAMMATORY TEST SYSTEM used.

From the TEST RESULT TABLE it is evident that a combination of a steroid sulfatase inhibitor with an ascomycin is useful as an anti-inflammatory agent.

In another aspect the present invention provides a combination of a steroid sulfatase inhibitor with an ascomycin for use as a pharmaceutical.

In a further aspect the present invention provides the use of a combination of a steroid sulfatase inhibitor with an ascomycin in the preparation of a medicament for the treatment of inflammatory disorders.

In another aspect the present invention provides a method of treating inflammatory disorders comprising administering a therapeutically effective amount of a combination of a steroid sulfatase inhibitor with an ascomycin to a subject in need of such treatment.

Treatment includes treatment and prophylaxis. For such treatment the term a steroid sulfatase inhibitor includes one or more steroid sulfatase inhibitors, preferably one; and the term an ascomycin includes one or more ascomycins, preferably one.

An appropriate mol ratio of an ascomycin of the present invention to a steroid sulfatase inhibitor of the present invention in combination includes a mol ratio of 0.1:100 to 1:0.1, such as 1:100 to 1:0.5.

In another aspect the present invention provides a pharmaceutical composition comprising, in association with at least one pharmaceutically acceptable excipient, a pharmaceutically effective amount of at least one steroid sulfatase inhibitor in combination with at least one ascomycin.

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.

Such pharmaceutical compositions may be manufactured according, e.g. analogously to a method as conventional, e.g. by mixing, granulating, coating, dissolving or lyophilizing processes. Pharmaceutically acceptable excipient includes e.g. appropriate carrier and/or diluent, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers.

A pharmaceutical composition of the present invention may comprise as active ingredients a steroid sulfatase inhibitor of the present invention and an ascomycin of the present invention alone, or a combination of the present invention and additionally one or more other pharmaceutically active agents. Such further pharmaceutically active agents include e.g. other anti-inflammatory active compounds.

In the following examples all temperatures are given 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

TFA trifluoroacetic acid

THF tetrahydrofurane

Procedures

### a. 4-Bromo-2,5-dichloro-thiophene-3-sulfonamide

90 ml of an aqueous solution of NH3 (32%) are added at RT to a solution of 8.88 g of 4-bromo-2,5-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 HCl and H2O, and dried. Solvent of the organic phase obtained is evaporated.

4-Bromo-2,5-dichloro-thiophene-3-sulfonamide is obtained.

m.p. 113-117; 13C-NMR (CDCl3): =108.287; 125.342; 130.404; 135.716.

### b. 4-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylaminocarbonyl)-piperidine-1-carboxylic 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 230 mg of 1-(tert.butyloxycarbonyl)-piperidine-4-carboxylic acid in 8 ml of DMF. The mixture obtained is stirred for ca. 16 hours at ca. 30, solvent is evaporated and the evaporation residue obtained is treated with EtAc. The mixture obtained is washed with aqueous 1 N HCl, aqueous saturated NaHCO3 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-carboxylic acid tert.-butyl ester is obtained and lyophilized from 1,4-dioxane.

### 4-(3,5-Bis-trifluoromethyl-benzenesulfonylaminocarbonyl)-trans-3-methyl-piperidine-1-carboxylic acid tert.-butyl ester (compound of Example 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 HCl, saturated aqueous NaHCO3 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 Nal 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 HCl, saturated aqueous NaHCO3 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/H2O (1:1) are stirred at RT and diluted with EtAc. The mixture obtained is extracted with aqueous 1M HCl. The organic layer obtained is dried, solvent is evaporated and the evaporation 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 3,5-bis(trifluoromethyl)phenylsulfonamide, 94 mg of EDC and 30 mg of DMAP in 2 ml of DMF and 84 l 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/H2O (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.

### a. N-(Piperidine-4-carbonyl)-3,5-bis-trifluoromethyl-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 CH2Cl2. The mixture obtained is treated at RT with 20 ml of 3 N HCl in (C2H5)2O 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-[1-(2-Nitro-phenyl)-piperidine-4-carbonyl]-3,5-bis-trifluoromethyl-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 hours at 80, solvent is evaporated and the evaporation residue obtained 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.

### 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-2,5-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 obtained is washed with 1 N HCl and H2O, and dried. Solvent of the organic solution obtained is evaporated. 4-Bromo-2,5-dichloro-thiophene-3-sulfonamide is obtained.

m.p. 113-117 C., 13C-NMR: =108.287; 125.342; 130.404; 135.716.

### b. trans-[4-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylaminocarbonyl)-cyclohexylmethyl]-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 HCl, saturated NaHCO3 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-sulfonylaminocarbonyl)-cyclohexylmethyl]-carbamic acid tert.-butyl ester is obtained.

### 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 hours at RT and solvent from the mixture obtained is evaporated. The evaporation residue obtained is dissolved in EtAc and washed with 1 N HCl, saturated NaHCO3 solution and brine, and the organic phase obtained is dried. Solvent of the organic phase obtained is evaporated and the evaporation residue obtained is subjected to chromatography.

4-Chloro-N-(4-pentyl-bicyclo[2.2.2]octane-1-carbonyl)-benzenesulfonamide is obtained.

### a. 10-Oxo-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester

25 g of 8-methyl-8-aza-bicyclo[4.3.1]decan-10-one in the form of a hydrobromide are dissolved in H2O and a pH of 11 is adjusted by addition of 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 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 evaporation residue obtained together with 18 g of K2CO3 and 28.4 g of di-tert.-butyldicarbonate is treated with 240 ml of THF/H2O (5:1) and stirred at RT. The mixture obtained is concentrated and diluted with EtAc. The mixture obtained is extracted with H2O, 1M HCl, aqueous, saturated NaHCO3 solution and brine. The organic layer obtained is dried and solvent is evaporated. The evaporation residue obtained is subjected to filtration over silica gel with EtAc/c-Hex (1:3).

10-Oxo-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester is obtained.

m.p.: 50-52; 13C-NMR: 211.99, 154.82, 80.20, 48.70, 28.44, 26.40.

### b. 10-Methoxymethylene-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester

To a suspension of 9.54 g of methoxymethyltriphenylphosphonium chloride in 25 ml of dry THF, 13.8 ml of a sodium bis(trimethylsilyl)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 ml of THF are slowly added and stirring at 0 is continued. The mixture obtaineddiluted with EtAcis extracted with aqueous 1M HCl, aqueous saturated NaHCO3 solution and brine. The organic layer obtained is dried and solvent is evaporated. The evaporation residue obtained is subjected to filtration over silica gel with EtAc/c-Hex (1:9). 10-Methoxymethylene-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester is obtained.

13C-NMR: 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-Formyl-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester

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 Nal are added and the mixture obtained is stirred at 40 overnight. From the mixture obtained solvent is evaporated and the evaporation residue obtained is dissolved in EtAc. The mixture obtained is extracted with aqueous 1M HCl, aqueous, saturated NaHCO3 solution and brine. The organic layer obtained is dried, solvent is evaporated and the evaporation residue obtained is subjected to filtration over silica gel with EtAc/c-Hex (1:41:2).

10-Formyl-8-aza-bicyclo[4.3.1]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-bicyclo[4.3.1]decane-8,10-dicarboxylic acid 8-tert-butyl ester

2.86 g of 10-formyl-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester and 5.8 g of magnesium monoperoxyphthalic acid hexahydrate in 170 ml of EtOH/H2O (1:1) are stirred at RT. The mixture obtained is diluted with EtAc. The mixture obtained is extracted with aqueous 1M HCl and brine. The organic layer obtained is dried, solvent is evaporated and the evaporation residue is crystallized from MeOH/H2O.

8-aza-bicyclo[4.3.1]decane-8,10-dicarboxylic acid 8-tert-butyl ester is obtained. m.p.: 218-222; 13C-NMR: 179.88, 155.31, 80.00, 52.43, 50.98, 47.63, 33.14, 32.31, 28.91, 27.06.

### e. 10-(3,5-Bis-trifluoromethyl-benzenesulfonylaminocarbonyl)-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester

6.1 ml of a 50% PPA solution in DMF, 633 mg of DMAP in 50 ml of dimethylamine and 1.8 ml of DIEA are added to a solution of 1.5 g of 8-aza-bicyclo[4.3.1]decane-8,10-dicarboxylic acid 8-tert-butyl ester, 2.3 g of 3,5-bis(trifluoromethyl)phenylsulfonamide, the mixture obtained is stirred at 40 and diluted with EtAc. The mixture obtained is extracted with aqueous 1M NaHSO4 solution, saturated NaHCO3 solution and brine. From the mixture obtained solvent is distilled off. The distillation residue obtained is purified by filtration over silica gel with EtAc/c-Hex/MeOH (5:5:1) and the residue obtained is subjected to crystallization from CH3CN:H2O (4:6). 10-(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 HCl and H2O, the phases obtained are separated, the organic layer obtained is dried and solvent is evaporated. 10-(3,5-bis-trifluoromethyl-benzene-sulfonylaminocarbonyl)-8-aza-bicyclo[4.3.1]decane-8-carboxylic acid tert-butyl ester is obtained.

### a. 3,5-Bis-(trifluoromethyl)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 HCl and H2O, and dried. Solvent of the organic solution obtained is evaporated.

3,5-Bis-trifluoromethyl-benzene sulfonamide is obtained.

### b. 2-{4-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-ethyl]-piperidin-1-yl}-4-trifluoromethyl-benzamide

0.46 g of 2-fluoro-4-(trifluoromethyl)benzamide are added to a suspension of 1.8 g K2CO3 and 0.8 g of piperidin-4-yl acetic acid hydrochloride in 12 ml of DMSO, the mixture obtained is stirred for 4 hours 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 and the evaporation residue obtained is treated with EtAc. The mixture obtained is washed with 1 N HCl, saturated aqueous NaHCO3 solution and brine, dried, concentrated and subjected to chromatography on silica gel. 2-{4-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-ethyl]-piperidin-1-yl}-4-trifluoromethyl-benzamide is obtained.

### a. 3-Oxo-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl 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. To the evaporation residue obtained, 18 g of K2CO3 and 28.4 g of di-tert.-butyldicarbonate are added and treated with 250 ml of THF/H2O, the mixture obtained is stirred at RT for 3 hours, concentrated and diluted with EtAc. The mixture obtained is washed with H2O, 1M HCl, saturated NaHCO3 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. 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-Ethoxycarbonylmethylene-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl 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 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-Ethoxycarbonylmethylene-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester is obtained. 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-Ethoxycarbonylmethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl 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 PtO2 as a catalyst. From the mixture obtained 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-Carboxymethyl-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl 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 HCl. 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 is obtained.

13C-NMR: 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-[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

69 l 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 l 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 is obtained.

### a. 9-Oxo-3-aza-bicyclo[3.3.1]decane-3-carboxylic acid tert-butyl 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, diluted with EtAc and washed with H2O, 1M HCl, saturated aqueous NaHCO3 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.

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-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl 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 NaH2PO4 and saturated aqueous NaHCO3 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.

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-(Carboxy-fluoro-methylene)-3-aza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl 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 HCl, the organic layer obtained is dried and solvent is evaporated. 9-(Carboxy-fluoro-methylene)-3-aza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester 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-[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

69 l 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-trichloro-thiophene-3-sulfonyl amide, 233 l of PPA and 24 mg of DMAP in 2 ml of DMA, and the mixture obtained 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 LH20 (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 is obtained.

### a. 3-(Cyano-methoxycarbonyl-methylene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

A solution of 2 g of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 1.2 ml of cyano-acetic acid methyl ester, 130 l of piperidine and 38 mg of -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 evaporated and the residue obtained is subjected to chromatography on silica gel. 3-(cyano-methoxycarbonyl-methylene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester is obtained

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-bicyclo[3.2.1]octane-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 is obtained.

13C-NMR: 165.14, 153.83, 115.12, 107.51, 81.23, 28.82.

### c. 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

120 l of DIEA are added to a solution of 102 mg of 3-(carboxy-cyano-methylene)-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 l 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 evaporated 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-ethylidene]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester is obtained.

### a. 3,3-Dimethyl-butyric 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 CH2Cl2 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 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-butyric acid 4-(fluoro-ethoxycarbonyl-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.

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-butyric acid 4-(carboxy-fluoro-methylene)-adamantan-1-yl ester

3,3-dimethyl-butyric acid 4-(fluoro-ethoxycarbonyl-methylene)-adamantan-1-yl ester is saponified analogously to the method as described in example J c. 3,3-Dimethyl-butyric acid 4-(carboxy-fluoro-methylene)-adamantan-1-yl ester 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-butyric acid 4-[2-(4-bromo-2,5-dichloro-thiophene-3-sulfonylamino)-1-fluoro-2-oxo-ethylidene]-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 c. 3,3-Dimethyl-butyric acid 4-[2-(4-bromo-2,5-dichloro-thiophene-3-sulfonylamino)-1-fluoro-2-oxo-ethylidene]-adamantan-1-yl ester is obtained.

### a. 3,5-Bis-(trifluoromethyl)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 obtained are separated, the organic layer obtained is washed with 1 N HCl and H2O, and dried.

Solvent of the organic solution obtained is evaporated.

3,5-Bis-trifluoromethyl-benzene sulfonamide is obtained.

### b. 4-cis/trans-(3,5-Bis-(trifluoromethyl)-benzenesulfonylaminocarbonylmethyl)-cyclohexyl]-carbamic acid tert.-butyl ester

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-sulfonamide 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 hours 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 HCl, saturated NaHCO3 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)-cyclohexyl]-carbamic acid tert.-butyl ester in the form of an isomeric mixture is obtained.

### 1-[2-(3,5-Bis-trifluoromethyl-benzenesulfonylamino)-2-oxo-(4-chloro-phenyl)-ethyl]-piperidine-4-carboxylic 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-chlorophenyl)-(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.

### 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.

### a. 1-Pyridin-4-yl-cyclopentanecarboxylic acid ethyl ester

25 ml of a n-butyllithium 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 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 obtained is washed with H2O, saturated NaHCO3 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-cyclopentanecarboxylic acid ethyl ester are dissolved in a mixture of 100 ml of MeOH and aqueous HCl (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 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-Ethoxycarbonyl-cyclopentyl)-piperidine-1-carboxylic acid tert-butyl ester

2.0 g of 1-piperidin-4-yl-cyclopentanecarboxylic acid ethyl ester in the form of a hydrochloride are 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-carboxylic 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)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 1.2 g of 4-(1-ethoxycarbonyl-cyclopentyl)-piperidine-1-carboxylic 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 separated. The aqueous layer obtained is acidified with HCl (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.

### a. 4-[(benzhydryl-sulfamoyl)-methyl]-4-hydroxy-piperidine-1-carboxylic acid tert.-butyl ester

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 HCl, 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 is obtained. m.p. 121-123.

### b. 4-Hydroxy-4-sulfamoylmethyl-piperidine-1-carboxylic acid tert.-butyl ester

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 l 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 tert.-butyl ester are obtained. m.p. 176-180.

### c. 4-[(3,5-bis-trifluoromethyl-benzoylsulfamoyl)-methyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

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-sulfamoylmethyl-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 HCl, saturated, aqueous NaHCO3 solution and brine, the organic layer obtained is dried and subjected to chromatography on silica gel. 4-[(3,5-bis-trifluoromethyl-benzoylsulfamoyl)-methyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester is obtained. m.p. 154-159.

### d. 4-[(3,5-bis-trifluoromethyl-benzoylsulfamoyl)-methylene]-piperidine-1-carboxylic acid tert.-butyl ester

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 CH2Cl2. 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 chromatography on silica gel.

4-[(3,5-bis-trifluoromethyl-benzoylsulfamoyl)-methylene]-piperidine-1-carboxylic acid tert.-butyl ester is obtained. m.p. 132-136.

### e. 4-[(3,5-bis-trifluoromethyl-benzoylsulfamoyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester

A solution of 880 mg of 4-[(3,5-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]-piperidine-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

wherein R18 is hydrogen and R1 and R16+R17 are as defined in TABLE 1 (compounds of formula I, wherein m is 0, n is 0, and R1 is a group of formula VII) are obtained, if not otherwise indicated in TABLE 1. If not otherwise indicated, in TABLE 1 13C-NMR and 1H-NMR data are determined in CDCl3.

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R18 is hydrogen and R1 and R16+R17 are as defined in TABLE 2 (compounds of formula I, wherein m is 0, n is 0, and R1 is a group of formula VII) are obtained. If not otherwise indicated in TABLE 2 1HNMR and 13C-NMR data are determined in CDCl3.

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R18 is hydrogen and R1 and R16+R17 are as defined in TABLE 3 (compounds of formula I, wherein m is 0, n is 0, and R1 is a group of formula VII) are obtained. If not otherwise indicated in TABLE 3 13C-NMR and 1HNMR data are determined in CDCl3.

TABLE 3 EX R1 R16 + R17 m.p./1HNMR/13C-NMR 186 (DMSO-d6): = 0.80-0.95(m,3 H); 0.95-1.40(m, 10 H); 1.50-1.75(m, 8 H); 7.62/7.82(AB, 4 H) 187 322-333 188 98-100/(DMSO-d6): 1.38/1.40(s, 9 H), 1.60-2.10(m, 12 H); 3.41-3.57(m, 1 H); 6.68/6.80(bd,1 H); 8.36/8.40(s, 2 H); 8.48/8.50(s, 1 H) 189 1.47(s, 9 H); 1.51-2.13(m,12 H); 3.72(m, 1 H); 4.81(d,1 H); 7.60(s, 1 H); 8.30(s, 1 H) 190 132-133 191 2 rotamers, selected signals:8.55(s, 2 H), 8.35 + 8.32(2 br,s, 1 H), 8.16(s, 1 H), 3.87 + 3.82 s, 1 H), 3.05 + 3.00(2 s, 3 H);2.40 + 2.32(2 s, 2 H), 1.47(s, 9 H) 192 (DMSO-d6): 173.12, 170.12,150.43, 136.52, 135.24, 133.86,131.29, 130.04, 129.79, 129.19,128.87, 128.47, 125.10, 122.94,117.86, 115.85, 60.09, 47.76,32.80, 31.60, 26.06 193 (DMSO-d6): 170.59, 150.93,136.92, 135.02, 134.99, 130.44,130.20, 129.63, 126.47, 125.56,118.24, 116.16, 60.62, 48.20,33.27, 32.02, 26.55 194 (CDCl3/DMSO-d6): 173.42,170.56, 151.37, 142.90, 134.67132.89, 132.61, 130.16, 129.31,128.97, 128.51, 126.99, 119.30,116.91, 61.47, 48.66, 33.60,32.09, 26.78 195 (CDCl3/DMSO-d6): 173.72,170.83, 152.28, 143.07, 136.26,132.79, 132.52, 130.78, 130.13,128.95, 127.04, 122.48, 121.83,120.56, 61.41, 48.74, 33.65,32.13, 26.82 196 173.14, 167.61, 149.63, 142.55,133.06, 132.70, 132.46, 132.37,129.13, 127.26, 124.99, 124.20,123.54, 60.42, 48.87, 40.38,33.78, 32.27, 27.00 197 171.33, 141.88, 133.33, 133.06,129.38, 127.69, 123.86, 62.30,33.47, 31.79, 26.45 198 203.85, 171.03, 150.68, 141.52,133.44, 133.17, 129.45, 128.13,127.90, 119.82, 118.09, 61.87,48.42, 33.89, 32.13, 31.92,26.61 199 170.40, 154.09, 140.96, 138.32,134.78, 133.31, 133.04, 132.76,132.48, 129.06, 129.03, 127.61,125.55, 123.38, 121.20, 117.12,115.07, 112.97, 101.03, 55.60,48.45, 33.07, 32.28, 26.09 200 170.68, 155.72, 141.43, 136.12,135.92, 133.49, 133.21, 132.93,129.47, 127.98, 123.81, 121.63,118.99, 118.97, 117.80, 116.45,116.42, 109.19, 60.26, 48.41,33.75, 32.02, 26.87 201 95-98 202 170.44, 132.95, 132.68, 132.41,132.13, 127.36, 126.23, 125.66,124.07, 121.89, 119.71, 81.09,62.52, 61.35, 50.29, 33.16,28.43, 27.16 203 8.53(s, 2 H), 8.11(s, 2 H), 5.25(m, 1 H), 3.56(s, 2 H), 3.13(bd,2 H), 2.98(bs, 1 H), 2.88(bs,1 H), 2.67(bs, 2 H), 2.21(s, 1 H),2.02(m, 2 H), 1.83(m, 2 H),1.78-1.58(m, 10 H), 1.40(m, 2 H) 204 173.01, 171.44, 142.73, 133.31,133.03, 132.76, 132.49, 129.07,129.05, 127.18, 127.15, 127.12,126.11, 123.93, 121.76, 119.59,54.84, 49.82, 48.82, 45.09,33.42, 32.25, 30.38, 27.01,26.24 205 173.15, 142.63, 132.91, 132.56,132.22, 128.98, 127.10, 124.14,121.42, 53.68, 49.63, 48.88,33.08, 32.61, 32.28, 28.89,26.96, 26.25, 19.02 206 172.71, 171.25, 141.71, 136.26,134.33, 127.18, 127.11, 53.92,49.49, 49.15, 39.74, 36.96,33.50, 33.18, 32.72, 32.32,32.11, 26.99, 26.20, 25.34 207 172.45, 171.36, 138.44, 135.99,135.85, 132.09, 130.50, 128.07,53.80, 49.61, 49.18, 39.74,36.89, 33.63, 33.24, 33.19,32.08, 27.01, 26.32, 25.34 208 173.15, 171.18, 141.69, 133.40,133.12, 132.85, 129.35, 127.82,123.82, 121.64, 54.00, 49.41,49.25, 39.67, 37.02, 33.53,33.21, 33.14, 32.26, 32.04,26.92, 26.13, 25.29 209 172.78, 172.45, 142.56, 133.41,133.07, 132.72, 132.38, 129.10,127.25, 124.18, 121.46, 80.1953.66, 49.62, 48.74, 42.62,33.21, 33.08, 32.37, 32.26,30.05, 27.02, 26.21, 24.28,24.18 210 172.78, 171.30, 141.74, 133.38,133.10, 129.37, 127.78, 123.83,54.12, 49.46, 49.24, 41.21,35.46, 33.82, 33.54, 33.23,32.29, 32.01, 26.92, 26.54,26.49, 26.12 211 173.83, 171.03, 141.51, 133.77,133.42, 133.08, 132.73, 129.39,127.91, 126.77, 124.06, 121.34,118.82, 54.21, 49.48, 49.22,41.58, 37.19, 35.15, 35.08, 33.48,33.13, 32.19, 31.93, 28.533,26.89, 26.51, 26.44, 26.07 212 171.16, 155.61, 141.55, 133.42,133.14, 129.39, 127.87, 123.81,69.31, 49.48, 33.34, 32.03,26.60, 22.61 213 130.45, 130.21, 129.74, 129.65,80.35, 49.41, 32.09, 28.86 mix 214 171.46, 155.14, 138.41, 135.99,135.85, 132.10, 130.49, 128.07,80.40, 49.65, 33.28, 32.01,28.86, 26.67 215 171.26, 155.28, 141.51, 136.30,134.42, 127.21, 127.04, 80.69,49.49, 33.21, 32.08, 28.86,26.58 216 Diastereoisomeric mixture ofcompounds of Example 217 andExample 218 217 170.84, 154.71, 141.06, 133.27,132.99, 132.99, 132.72, 132.44,129.03, 129.00, 127.54, 127.52,123.39, 121.22, 80.07, 49.04,32.83, 31.66, 28.45, 26.15 218 173.68, 155.62, 141.76, 133.75,133.41, 133.07, 132.72, 129.26,127.89, 124.09, 121.37, 80.23,61.00, 44.81, 34.22, 33.21,28.93, 28.89, 26.82 219 173.79, 155.30, 80.49, 45.50,44.28, 37.87, 30.93, 30.63,28.90, 28.83, 27.82, 13.83 220 171.37, 156.23, 141.64, 133.68,133.41, 133.13, 132.85, 129.34,127.83, 123.81, 121.64, 65.96,51.73, 49.44, 33.21, 32.11,31.48, 26.61, 19.53, 14.03 221 171.50, 156.20, 141.72, 133.68,133.40, 133.13, 132.85, 129.33,127.79, 123.82, 121.65, 119.47,72.28, 49.47, 33.23, 32.12,28.41, 26.62, 19.41 222 171.10, 156.11, 141.55, 133.71,133.44, 133.16, 132.88, 129.41,127.88, 123.81, 121.63, 75.56,49.40, 33.25, 32.12, 31.88,26.87, 26.63 223 171.26, 155.81, 141.52, 133.76,133.41, 133.07, 132.72, 129.40,127.87, 124.06, 121.35, 118.63,51.20, 49.41, 33.29, 32.08,26.60, 23.96 224 173.17, 157.69, 142.62, 133.03,132.69, 129.06, 127.21, 124.20,121.48, 53.07, 51.98, 49.66,34.01, 33.20, 33.12, 32.49,26.63, 24.03 225 171.86, 171.29, 155.31, 155.12,141.65, 133.43, 133.08, 129.35,127.93, 124.07, 121.35, 80.49,80.21, 47.63, 47.30, 28.87,26.44, 19.90, 19.43 226 155.48, 132.98, 132.64, 132.30,131.96, 127.76, 127.13, 125.79,124.41, 121.70, 118.98, 79.63,48.08, 45.69, 44.59, 40.33,40.12, 32.82, 32.70, 30.55,30.40, 28.88, 20.16 227 171.68, 171.14, 155.27, 155.10,141.23, 137.28, 130.35, 130.26,129.78, 129.73, 80.38, 80.10,47.58, 47.24, 28.89, 26.44,19.94, 19.47 mix 228 171.78, 171.30, 136.09, 136.04,131.99, 131.91, 128.12, 80.34,80.03, 47.73, 47.38, 28.89,26.38, 19.46 229 172.12, 171.64, 155.11, 131.24,108.50, 80.42, 80.13, 50.94,47.81, 47.43, 30.43, 28.90,26.49, 19.95, 19.49 230 171.96, 153.20, 141.06, 133.03,132.69, 128.99, 127.59, 80.04,36.97, 28.45 231 174.00, 153.35, 139.11, 135.50,135.37, 131.59, 130.46, 127.77,79.63, 40.66, 40.45, 40.24,40.04, 36.49, 32.90, 28.81 232 172.19, 153.03, 137.04, 130.71,125.99, 108.01, 79.83, 36.68,32.67, 28.48 233 170.84, 155.33, 141.38, 138.52,133.61, 133.26, 132.92, 132.57,129.61, 129.42, 127.87, 126.98,124.13, 121.41, 118.69, 80.37,50.56, 49.24, 48.24, 35.17,31.36, 31.05, 28.66 234 171.09, 154.50, 138.81, 138.36,136.07, 135.96, 132.06, 130.53,129.88, 128.35, 128.07, 127.09,126.94, 79.87, 50.88, 48.44,47.60, 36.29, 31.26, 30.97, 28.61 235 171.49, 154.44, 138.78, 138.65,137.68, 131.04, 129.90, 129.38,127.09, 126.90, 126.33, 108.55,79.87, 50.95, 48.37, 47.51,36.45, 31.20, 30.82, 28.61 236 273.58, 171.44, 155.56, 155.21,138.38, 136.03, 136.00, 135.85,132.09, 131.85, 130.47, 128.11,128.08, 80.54, 80.23, 49.60,44.82, 33.17, 32.01, 28.89,28.86, 26.83 237 171.57, 155.09, 50.39, 49.69,33.15, 32.01, 28.09 238 173.55, 155.37, 142.08, 133.28,132.94, 129.23, 127.63, 124.13,121.42, 80.83, 45.58, 44.58,37.76, 30.86, 30.55, 29.39,28.87, 27.50, 13.73 239 172.84, 154.11, 138.23, 136.07,135.96, 131.90, 131.82, 130.46,128.07, 80.03, 46.23, 44.69,39.57, 31.81, 29.31, 28.88,28.84, 20.37 240 173.14, 154.11, 137.49, 131.08,126.35, 108.46, 80.83, 46.20,44.66, 39.61, 31.90, 31.74,29.34, 28.83, 28.86, 20.41

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R1, R16+R17 are as defined in TABLE 4 and R18 is hydrogen or is as defined in TABLE 4 (compounds of formula I, wherein m is 0, n is 1, and R1 is a group of formula VII) are obtained. If not otherwise indicated in TABLE 4, characterisation data is 1HNMR data, and 13C-NMR and 1HNMR data are determined in CDCl3.

TABLE 4 EX R1 R16 + R17/R18 m.p./1H-NMR/13C-NMR 241 (DMSO-d6): = 1.25(dq, 2 H);1.59(d, 2 H); 1.70(m, 1 H); 1.97(d, 2 H); 2.66(t, 2 H); 3.12(d,2 H); 7.30(s, 1 H); 7.35(d, 1 H);7.62(s, 1 H); 7.73(d, 1 H); 8.19(s, 1 H); 8.27(s, 1 H); 8.29(s, 2 H). 242 170.39, 170.31, 155.44,154.43, 131.45, 126.22,108.68, 79.91, 79.80, 47.36,45.93, 45.86, 45.67, 44.61,42.52, 36.84, 36.46, 32.10,31.95, 31.25, 30.90, 30.08,29.29, 29.17, 28.92, 27.53,20.44, 14.02 243 (DMSO-d6): 0.92(m, 2 H);1.35(s, 9 H); 1.42(m, 2 H);1.74(m, 1 H); 2.10(d, 2 H);2.54-2.70(m, 2 H); 3.77-3.88(d, 2 H); 7.80(d, 2 H); 7.97(t, 1 H) 244 1.02-1.15(m, 2 H); 1.44(s,9 H); 1.56-1.68(m, 2 H); 1.83-1.95(m, 1 H); 2.12-2.25(m,2 H); 2.57-2.73((m, 2 H); 3.91-4.10(m, 2 H); 7.56(s, 1 H);8.23(s, 1 H) 245 (DMSO-d6): 1.20(dq, 2 H);1.51(d, 2 H); 1.73(m, 1 H);2.20(d, 2 H); 2.70(dt, 2 H);3.06(d, 2 H); 7.05(t, 1 H);7.24(d, 1 H); 7.52(t, 1 H);7.74(d, 1 H); 8.41(s, 2 H); 8.53(s, 1 H) 246 (DMSO-d6): 1.09(dq, 2 H);1.43(d, 2 H); 1.63(m, 1 H);2.09(d, 2 H); 2.51(t, 2 H);2.97(d, 2 H); 6.95(t, 1 H);7.14(d, 1 H); 7.42(ddd,1 H); 7.64(dd, 1 H); 7.72(d,2 H); 7.90(t, 1 H) 247 1.03-1.14(m, 2 H); 1.44(s,9 H); 1.55-1.65(m, 2 H); 1.88-1.96(m, 1 H); 2.16-2.23(m,2 H); 2.61-2.77(m, 2 H); 3.98-4.10(m, 2 H); 8.12(s, 1 H);8.50(s, 2 H) 248 247-251 249 195-198 250 149-152 251 243-246 252 179-183 253 92-95 254 81-83 255 150-153 256 174-178 257 129-133 258 93-96 259 1.10(q, 2 H), 1.52-1.61(m,3 H), 1.93(d, 2 H), 2.25(t, 2 H),3.48(d, 2 H), 7.89-7.94(m,2 H), 8.05(broad d, 1 H), 8.12(broad d, 1 H), 9.29(broad s,2 H), 8.30(broad s, 1 H) 260 98-101 261 170.70, 170.43, 155.84, 155.24,41.82, 141.76, 133.73, 133.38,133.03, 132.69, 129.27, 127.80,126.60, 124.08, 121.37, 80.47,80.32, 43.61, 41.02, 39.59,36.32, 32.34, 28.79, 16.68 262 170.77, 170.45, 155.71, 155.13,138.41, 135.99, 135.93, 131.90,131.87, 130.57, 130.54, 128.03,80.16, 80.03, 43.61, 40.73,39.54, 36.03, 35.82, 32.22,31.56, 28.82, 26.66, 16.72, 11.66 263 160-165 264 140-150 265 170.88, 170.52, 155.65,155.07, 137.33, 137.25,131.35, 126.34, 108.63,108.58, 80.11, 79.96, 40.78,39.51, 36.04, 35.73, 32.25,31.69, 28.83, 16.78 266 153-156 267 (DMSO-d6): 1.42-1.65(m, 4 H),2.85-3.05(m, 4 H), 3.55(s,2 H), 5.72(s, 1 H, OH), 7.32(s,1 H), 7.34(d, 1 H), 7.59 and8.18(2 s, 2 H, NH), 7.72(d,1 H), 8.18(s, 1 H), 8.26(s, 2 H) 268 170.85, 170.22, 153.88, 142.03,133.25, 132.91, 129.31, 127.60,121.42, 80.45, 43.90, 43.58,35.59, 28.92, 28.81, 28.18,26.72, 25.67 269 170.22, 153.77, 138.56,135.99, 138.88, 131.82,130.62, 128.03, 127.96,80.00, 44.08, 43.57, 28.94,28.86, 26.25, 25.44 270 170.73, 170.55, 153.81,137.00, 131.56, 108.75,80.13, 44.04, 43.54, 28.97,28.88, 28.26, 26.25, 25.40 271 170.46, 155.24, 138.35,136.06, 135.99, 131.84, 130.54,128.07, 79.90, 40.33, 39.46,35.56, 31.25, 28.92, 26.67 272 170.42, 155.35, 141.71,136.36, 134.41, 127.09,80.05, 40.34, 39.48, 35.60,31.31, 28.92, 26.67 273 170.38, 155.51, 141.74,133.47, 133.19, 129.28,127.91, 123.81, 80.38, 46.00,40.45, 39.53, 35.60, 31.36,28.90, 26.60 274 (CDCl3/DMSO-d6): 171.89,170.37, 129.15, 135.54,135.42, 131.74, 130.82,130.56, 127.80, 116.87,61.83, 39.27, 38.78, 36.13,31.29, 26.91 275 170.41, 141.73, 136.35,134.40, 131.01, 127.11,62.23, 38.98, 38.86, 35.89,31.06, 26.83 276 170.81, 141.77, 133.41,133.06, 130.83, 129.27,127.88, 62.07, 39.04, 35.97,31.11, 26.84 277 173.06, 170.82, 142.22, 136.26,134.16, 127.05, 54.43, 49.85,40.20, 39.81, 39.09, 37.17,35.86, 35.64, 33.19, 31.58,31.43, 26.97, 26.37, 25.37, 25.33 278 172.69, 170.42, 138.53,135.97, 131.79, 130.56,128.05, 54.27, 49.69, 40.18,39.76, 39.14, 37.04, 35.66,33.16, 31.44, 26.99, 26.36,25.37, 25.33 279 173.27, 171.15, 142.24, 133.63,133.28, 132.94, 132.59, 129.18,127.60, 124.14, 121.42,118.70, 54.45, 49.86, 40.19,39.79, 39.02, 37.21, 35.89,35.53, 33.13, 31.58, 31.33,26.93, 26.33, 25.30, 25.25 280 171.84, 154.00, 142.66, 139.62,139.35, 133.05, 132.71, 129.95,129.40, 129.01, 127.27, 126.74,126.46, 124.16, 79.03, 48.41,7.62, 40.39, 38.63, 35.96, 33.16,32.74, 30.00, 28.50 281 171.57, 154.08, 139.84,139.53, 139.15, 135.59,135.45, 131.75, 130.55,129.98, 129.41, 127.84,126.70, 126.45, 79.01, 48.47,47.71, 40.18, 38.51, 36.04,35.99, 33.13, 32.76, 30.04,28.54 282 169.93, 155.06, 139.30,139.00, 138.41, 136.03,135.98, 131.83, 130.57,129.80, 129.25, 128.09,126.93, 79.70, 42.00, 41.11,39.58, 32.81, 32.40, 28.64 283 171.17, 153.90, 139.116,138.83, 136.06, 131.42,129.54, 128.97, 126.33,126.07, 125.43, 108.28,79.03, 48.00, 47.22, 39.44,38.08, 35.34, 35.32, 32.76,32.19, 29.55, 27.99 284 170.09, 154.68, 138.96, 138.66,136.71, 131.04, 129.42,128.86, 126.58, 126.48,125.87, 108.28, 79.38, 41.52,41.09, 40.94, 40.71, 39.16,32.38, 32.03, 28.24 285 170.76, 170.43, 155.94,154.64, 142.05, 141.88,132.96, 132.61, 129.27,127.68, 126.83, 124.13,121.39, 80.36, 80.29,47.50, 46.12, 45.61, 44.94,42.52, 36.93, 36.39, 32.14,31.85, 31.13, 30.88, 30.08,29.42, 29.29, 29.23, 27.81,20.29, 13.87 mix 286 239-240 287 85-90

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R2, R3 and R4+R5 are as defined in TABLE 5 (compounds of formula I, wherein m is 0, n is 0, and R1 is a group of formula II) are obtained.

If not otherwise indicated in TABLE 5 1C-NMR and 13C-NMR data are determined in CDCl3.

TABLE 5 EX R2 R4 + R5/R3 m.p./1H-NMR/13C-NMR 288 158.34, 157.96, 154.94, 144.81, 141.33,137.70, 133.48, 133.13, 129.59, 128.15,124.08, 121.36, 80.53, 50.60, 49.55,49.33, 33.51, 32.01, 31.94, 31.39, 28.85 289 153.65, 116.14, 109.03, 80.82, 28.77 290 171.96, 158.46, 158.09, 145.82, 145.72,139.92, 137.48, 131.21, 126.25, 108.85,78.20, 49.55, 42.06, 41.65, 40.65, 38.38,38.08, 33.12, 33.03, 32.36, 32.34, 31.13,30.38, 30.02 291 1.44(s, 9 H); 2.25(t, 2 H); 2.41(s,3 H); 2.58(s, 3 H); 2.85(t, 2 H); 3.40(t,2 H); 3.48(t, 2 H); 5.62(s, 1 H); 7.30(s,1 H); 8.02(s, 1 H); 8.06(broad, 1 H) 292 (DMSO-d6) 1.25(s, 9 H); 2.02-2.08(m,2 H); 2.56-2.64(m, 2 H); 3.38-3.20(m,4 H); 5.61(m, 1 H); 8.30(s, 2 H); 8.42(s,1 H) 293 (DMSO-d6): 2.40(m, 2 H), 2.91(m, 2 H),3.01(m, 2 H), 3.08(m, 2 H), 5.78(s, 1 H),7.26(s, 1 H), 7.34(d, 1 H), 7.62 and 8.07(2 s, 2 H, NH), 7.66(d, 1 H), 8.45(s, 2 H),8.58(s, 1 H) 294 1.46(s, 9 H); 2.26(t, 2 H); 2.90(t, 2 H);3.41(t, 2 H); 3.47(t, 2 H); 5.76(s, 1 H);7.56(t, 1 H); 7.90(d, 2 H) 295 1.44(s, 9 H); 2.28(m, 2 H); 2.85(m, 2 H);3.42(m, 2 H); 3.50(m, 2 H); 5.62(s, 1 H);7.63(s, 1 H); 8.18(broad, 1 H); 8.35(s, 1 H) 296 168.16, 163.00, 141.84, 133.36, 133.01,129.40, 127.82, 121.40, 112.34, 80.55,28.76 297 167.39, 163.23, 155.07, 138.64, 135.94,135.88, 131.72, 130.71, 127.99, 112.60,80.45, 28.77 298 169.84, 168.85, 154.55, 154.50, 134.83,122.96, 121.40, 79.32, 43.86, 42.49,28.24, 28.09 299 167.43, 155.08, 131.89, 126.13, 108.82,80.45, 39.78, 28.78 300 162.46, 141.87, 133.34, 133.00, 129.37,127.83, 121.40, 118.03, 80.40, 54.13,30.08, 28.82 301 153.69, 145.66, 143.194, 141.23,135.04, 134.92, 133.82, 133.47, 133.13,132.78, 129.57, 128.16, 126.78, 124.06,121.34, 80.38, 52.97, 28.80 302 162.6, 161.2, 157.6, 141.04, 137.58,130.31, 129.69, 118.37, 80.27, 33.4,31.7, 29.8, 28.83 303 161.89, 138.63, 135.92, 131.71, 128.02,118.17, 80.26, 30.08, 28.83 304 127.89, 28.78 305 153.69, 145.69, 143.35, 138.13, 136.14,136.01, 134.35, 134.22, 131.92, 130.82,128.02, 80.30, 55.01, 28.81 306 136.80, 117.99, 80.31, 54.15, 30.08,28.85 307 145.74, 143.27, 134.69, 126.27, 108.73,80.33, 53.53, 53.13, 28.82 308 172.88, 163.03, 155.29, 141.98, 133.32,132.98, 129.32, 127.75, 126.85, 124.14,121.42, 118.71, 109.95, 80.75, 42.11,28.88, 28.60 309 171.98, 162.62, 138.27, 135.52, 135.46,131.28, 130.34, 127.63, 109.60, 80.19,51.18, 50.59, 50.29, 49.56, 41.62, 34.52,34.36, 33.65, 33.48, 33.31, 28.48, 19.76 310 (DMSO-d6): 12.11(s, 1 H), 8.35(s, 1 H),8.25(t, J = 1.7 Hz, 1 H), 8.17-8.22(m, 2 H),8.02(dt, J = 1.7 + 8 Hz, 1 H), 7.79(t, J = 8 Hz,1 H), 5.77(s, 1 H), 3.98-4.18(m, 2 H), 3.78(br.s, 1 H), 2.70-2.98(m, 2 H), 2.24(br.s,1 H), 1.52-1.96(m, 6 H), 1.37(s, 9 H) 311 172.41, 163.25, 155.17, 134.96, 132.34,127.84, 109.97, 80.50, 51.60, 51.08,50.74, 50.03, 42.07, 34.80, 34.11, 33.91,30.07, 28.89, 20.20 312 170.31, 164.59, 135.38, 132.50, 125.43,110.85, 109.01, 80.05, 51.55, 51.00,50.66, 49.95, 41.73, 34.64, 33.73, 33.56,28.80, 20.16 313 169.30, 163.66, 154.10, 133.70, 130.31,122.51, 121.09, 109.85, 79.26, 50.61,50.02, 49.68, 49.01, 40.74, 33.72, 32.70,27.77, 19.17 314 D25 = 4.1 (optical rotation)Pure (+) isomer of unknownstereochemestry 315 D25 = +7.9 (optical rotation)Pure () isomer of unknown sterochem. 316 171.24, 170.90, 163.49, 150.58, 136.63,134.44, 134.11, 131.78, 131.40, 130.94,126.18, 125.23, 122.52, 119.73, 116.99,111.22, 108.84, 59.63, 58.06, 42.49,34.37, 34.28, 33.44, 19.45 317 144.81, 141.33, 137.70, 133.48, 133.13,129.59, 128.15, 124.08, 121.36, 80.53,50.60, 49.55, 49.33, 33.51, 32.01, 31.94,31.39, 28.85, 19.85 318 171.43, 163.10, 150.47, 142.01, 134.47,133.36, 133.09, 131.31, 130.53, 129.32,127.82, 123.88, 121.70, 117.16, 111.31,59.57, 58.16, 42.39, 34.33, 34.26, 33.32,19.39 319 169.02, 141.94, 133.36, 133.02, 130.01,128.69, 80.42, 44.05, 36.25, 29.37,29.37, 28.86, 28.32 320 157.93, 157.56, 155.27, 144.25, 141.33,140.98, 140.88, 133.81, 133.47, 133.12,132.78, 130.25, 130.04, 129.63, 129.51,129.05, 128.87, 128.60, 128.30, 127.99,126.79, 124.07, 121.36, 118.64, 80.65,49.87, 33.80, 33.72, 33.63, 33.54, 33.20,33.05, 29.54, 29.33, 28.83, 28.30, 28.10 321 167.91, 162.70, 155.31, 138.69, 135.94,135.90, 135.77, 130.72, 128.77, 127.34,80.39, 43.88, 36.17, 36.02, 29.57, 29.37,28.89, 28.38, 28.16 322 155.15, 141.89, 140.47, 140.38, 138.21,136.13, 136.02, 131.87, 130.84, 128.06,80.40, 33.69, 33.61, 33.06, 28.84, 26.64 323 168.05, 162.89, 155.36, 134.99, 132.24,127.87, 127.83, 116.30, 80.41, 53.80,49.57, 43.96, 36.17, 30.07, 28.87, 26.73,26.54 324 155.15, 144.33, 141.86, 140.61, 140.51,134.31, 133.1, 127.96, 127.85, 80.38,33.71, 33.63, 33.11, 32.96, 28.86, 26.68 325 168.30, 162.87, 155.31, 136.66, 131.80,126.17, 108.77, 80.40, 43.97, 36.23,36.11, 29.60, 29.38, 28.88, 28.36, 28.14 326 157.93, 157.57, 155.18, 144.29, 141.82,140.73, 140.64, 131.16, 126.25, 108.73,80.43, 33.82, 33.73, 33.57, 33.09, 32 327 163.98, 129.19, 128.90, 126.74, 126.40,114.47, 79.43, 42.71, 42.50, 38.31,33.72, 33.50, 29.53, 28.17, 22.54 328 162.79, 138.58, 135.83, 131.66, 129.12,127.98, 127.68, 127.37, 115.07, 80.37,43.22, 37.65, 36.81, 28.71 329 172.04, 158.62, 158.25, 145.09, 145.00,140.10, 138.36, 137.65, 135.96, 135.90,130.79, 127.27, 78.30, 49.56, 42.02,40.52, 38.18, 37.10, 33.08, 33.02, 32.33,32.26, 31.11, 30.66, 30.37, 29.93, 29.71 330 172.02, 158.27, 157.91, 141.29, 139.85,137.41, 133.48, 133.14, 132.79, 130.34,49.54, 32.25, 31.13, 30.33, 29.93

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R18 is hydrogen and R1 and R16+R17 are as defined 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.

TABLE 6 EX R1 R16 + R17 m.p./1H-NMR/13C-NMR 331 93-96 332 0.93(q, 2 H); 1.03(q, 2 H); 1.34(s, 9 H); 1.40-1.50(m, 3 H); 1.65(d, 2 H); 2.07(d, 2 H); 3.07(m,1 H); 4.50(broad, 1 H); 8.12(s,1 H); 8.52(s, 2 H) 333 1.12-1.28(m, 2 H);1.45(s, 9 H);1.40-1.70(m, 6 H); 1.83-1.94(m1 H); 2.21(d, 2 H); 3.62-3.76(m,1 H); 4.60(broad, 1 H); 5.33(broad, 1 H); 8.12(s, 1 H); 8.50(s, 2 H) 334 0.90(q, 1 H); 1.07(q, 1 H); 1.20-1.52(m, 6 H); 1.37/1.39(s, 9 H);1.63-1.78(m, 1 H); 2.10/2.17(d,2 H); 2.38(s, 3 H); 2.52(s, 3 H);3.10/3.40(m, 1 H); 7.15/7.21(d,1 H); 7.52(s, 1 H); 7.80(s, 1 H);12.18/12.22(s, 1 H) 335 0.88(q, 2 H); 1.05(q, 2 H); 1.18-1.54(m, 6 H); 1.36/1.37(s, 9 H);1.63-1.78(m, 1 H); 2.12/2.18(d,2 H); 3.10/3.40(m, 1 H); 6.63/6.70(d, 1 H); 7.88-8.04(m, 3 H);8.30(m, 1 H); 12.36(s, 1 H) 336 0.88(d, 1 H); 1.07(d, 1 H); 1.18-1.53(m, 6 H); 1.36/1.38(s, 9 H);1.64-1.79(m, 1 H); 2.10/2.17(d,2 H); 3.33-3.41(m, 1 H); 6.30(broad, 1 H); 7.56(dt, 1 H); 7.91(dd, 1 H); 8.04(dd, 1 H); 12.3(broad, 1 H) 337 0.90(q, 1 H); 1.08(q, 1 H); 1.20-1.30(m, 2 H); 1.30-1.54(m, 4 H);1.37/1.38(s, 9 H); 1.65-1.81(m,1 H); 2.13/2.20(d, 2 H); 3.10/3.40(m, 1 H); 6.63/6.70(d, 1 H); 7.73(d, 1 H); 7.81(d, 1 H); 8.03(s, 1 H) 338 0.91(q, 1 H); 1.08(q, 1 H); 1.18-1.32(m, 2 H); 1.36(s, 9 H); 1.35-1.56(m, 3 H); 1.65-1.80(m, 2 H);2.13/2.17(d, 2 H); 3.10/3.41(m,1 H); 6.62-6.73(m, 1 H); 7.85(s,2 H); 8.06(s, 1 H); 12.0(broad, 1 H) 339 1.12(q, 1 H); 1.27(q, 1 H); 1.30-1.50(m, 2 H); 1.56/1.57(s, 9 H);1.60-1.75(m, 3 H); 1.84-2.02(m,2 H); 2.34/2.40(d, 2 H); 3.31/3.61(m, 1 H); 6.85/6.91(d,1 H); 8.13(d,1 H); 8.29(d, 1 H); 12.4(broad, 1 H) 340 0.90(q, 1 H); 1.08(q, 1 H); 1.20-1.32(m, 2 H); 1.37/1.38(s, 9 H);1.35-1.55(m, 3 H); 1.66-1.80(m,2 H); 2.12/2.18(d, 2 H); 3.10/3.40(m, 1 H); 6.64/6.70(d, 1 H); 8.15(s,1 H); 8.16(s, 1H); 12.7(broad, 1 H) 341 (CDCl3): 170.84, 141.87,133.31, 132.97, 132.62, 129.30,127.73, 124.11, 121.39, 47.03,44.35, 38.28, 35.32, 32.48,30.38, 28.80 342 (CDCl3): 170.90, 141.79,133.32, 132.97, 129.31, 127.73,124.10, 44.28, 35.90, 32.74,28.78, 28.43, 26.43 343 (CDCl3): 153.06, 132.95,132.67, 128.63, 127.31, 123.40,121.23, 82.06, 75.40, 43.47,33.48, 31.03, 30.50, 27.78 344 (CDCl3): 169.97, 153.49,141.64, 133.73, 133.45, 133.18,132.90, 129.37, 127.94, 123.81,121.64, 82.27, 72.32, 43.62,33.61, 29.49, 28.24, 27.24 345 0.95(q, 1 H); 1.11(q, 1 H); 1.22-1.36(m, 2 H); 1.38(s, 9 H); 1.40-1.60(m,3 H); 1.68-1.87(m, 2 H); 2.15/2.21(d, 2 H); 3.13/3.44(m, 1 H); 6.73/6.68(d, 1 H); 12.8(broad, 1 H) 346 0.97(q, 2 H); 1.15(q, 2 H), 1.55-1.68(m, 3 H), 1.77(d, 2 H), 2.18-(d, 2 H), 3.12-3.22(m, 1 H), 6.71(d, 1 H, NH) 347 (CDCl3): 170.55, 153.54,137.42, 131.23, 126.33, 108.60,82.22, 72.46, 72.40, 43.40,33.39, 29.53, 28.31, 28.24,27.28 348 (CDCl3): 169.93, 153.01,137.07, 130.76, 129.02, 128.22,126.01, 125.29, 108.13, 81.96,75.37, 42.90, 33.25, 31.09,30.53, 27.80, 21.44

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R18 is hydrogen and R1 and R16+R17 are as defined in TABLE 7 (compounds of formula I, wherein m is 1, n is 0, and R1 is a group of formula VII) are obtained. If not otherwise indicated in TABLE 7 13C-NMR and 1HNMR data in TABLE 7 are determined in CDCl3.

TABLE 7 EX R1 R16 + R17 m.p./1H-NMR 349 m.p. = 212-215 350 (DMSO-d6): 11.52(s, 1 H), 7.70(d, J = 8.4 Hz, 1 H), 7.50(d, J = 2 Hz,1 H), 7.26(dd, J = 8.4 + 2 Hz, 1 H),4.73(s, 2 H), 3.72(br.s, 1 H),2.62(s, 3 H), 2.06-2.14(m,1 H), 1.36-1.80(m, 8 H), 1.37(s, 9 H) 351 (DMSO-d6): 11.33(s, 1 H), 7.68(d, J = 8.3 Hz, 1 H); 7.51(d, J =2 Hz, 1 H), 7.26(dd, J = 2 + 8.3Hz, 1 H), 6.74(br.d, J = 6.6 Hz,1 H), 4.73(s, 2 H), 3.43(br.s,1 H), 2.19-2.28(m, 1 H), 1.40-1.77(m, 8 H), 1.37(s, 9 H) 352 m.p.: 211-215 353 8.40(s, 1 H), 7.39(s,1 H), 7.24(s, 2 H), 4.63(s, 2 H), 3.69(br.s, 1 H), 2.30(br.s, 1 H), 1.55-1.78(br.m, 8 H), 1.44(s, 9 H) 354 (DMSO-d6): 11.50(s, 1 H), 7.66(t, J = 1.9 Hz, 1 H), 7.29(d, J =1.9 Hz, 2 H), 6.68(d, J = 7.8 Hz,1 H), 4.73(s, 2 H), 3.10-3.20(br.s, 1 H), 2.05(tt, J = 3.3 +11.9 Hz, 1 H), 1.63-1.82(m,4 H), 1.28-1.42(m, 2 H), 1.35(s, 9 H), 1.00-1.14(m, 2 H) 355 (DMSO-d6): 11.49(s, 1 H), 7.66(s, 1 H), 7.29(s, 2 H), 6.78(t, J =5.6 Hz, 1 H), 4.72(s, 2 H), 2.73(t, J = 6.3 Hz, 2 H), 2.08(t, J =11.8 Hz, 1 H), 1.63-1.73(m,4 H), 1.35(s, 9 H), 1.22-1.35(m, 2 H), 0.73-0.86(m, 2 H) 356 (DMSO-d6) 11.52(s, 1 H), 8.18(s, 1 H), 7.95(s, 2 H), 6.66(d, J =7.3 Hz, 1 H), 4.97(s, 2 H), 3.07-3.18(m, 1 H), 2.04(tt, J = 3.2 +8.6 Hz), 1.62-1.80(m, 4 H),1.35(s, 9 H), 1.26-1.35(m,2 H), 0.98-1.11(m, 2 H) 357 204-207 358 0.93(s, 9 H); 1.42(s, 9 H); 1.23-1.62(m, 3 H); 1.78-2.14(m, 5 H);2.98(t, 2 H); 4.58(broad, 1 H);4.64(s, 2 H); 7.26-7.40(m, 5 H);7.58(s, 1 H) 359 0.98(q, 2 H); 1.42(s, 9 H); 1.52-2.20(m, 8 H); 2.99(t, 2 H); 4.59(broad, 1 H); 5.24(s, 2 H); 7.40-7.65(m, 3 H); 8.01(d, 1 H); 8.14(s, 1 H) 360 1.42(s, 9 H); 1.40-1.78(m, 4 H);2.21(m, 1 H); 2.92(t, 2 H); 4.06(d, 2 H); 4.68(s, 2 H); 7.30-7.40(m, 5 H); 7.75(s, 1 H) 361 1.44(s, 9 H); 1.45-1.90(m, 4 H);2.33(m, 1 H); 2.78(t, 2 H); 4.10(d, 2 H); 5.22(s, 2 H); 7.42-7.70(m, 3 H); 7.92(broad, 1 H); 8.03(d, 1 H)

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R18 is hydrogen and R1 and R16+R17 are as defined in TABLE 8 (compound of formula I, wherein m is 1, n is 1, and R2 is a group of formula VII) are obtained.

TABLE 8 EX R1 R16 + R17 1HNMR 362 (DMSO-d6): 11.63(s, 1 H), 8.18(s,1 H), 7.99(s, 2 H), 5.00(s, 2 H), 3.86(d, J = 12.7 Hz, 2 H), 2.67(br.s, 1 H),2.13(d, J = 7 Hz, 2 H), 1.76-1.89(m, 1 H), 1.50-1.60(m, 2 H), 1.37(s, 9 H), 0.88-1.03(m, 2 H)

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R1, R14 and R15 are as defined in TABLE 9 (compounds of formula I, wherein m is 0, n is 0, and R1 is a group of formula VI) are obtained. If not otherwise indicated 13C-NMR and 1HNMR data in TABLE 9 are determined in DMSO-d6.

TABLE 9 EX R14 R15 R1 m.p./1HNMR 363 150-154 364 CF3 171-175 365 169-171 366 140-145 367 229-231Racemate 368 9.7(s, br NH), 8.19(s, 1 H),8.0(s, 2 H), 7.73(d, J = 8 Hz,NH), 7.5(d, J = 8.5 Hz, 2 H),7.37(d, J = 8.5 Hz, 2 H),4.95(s, 1 H), 3.46(m, 2 H),2.85(m, 2 H), 2.71(m, 1 H),2.27(m, 1 H), 1.85(m, 3 H),1.67(m, 4 H), 1.53(m, 1 H),1.16(m, 6 H) 369 9.76(s, br, NH), 8.19(s, 1 H),8.08(s, 2 H), 7.73(d, J = 8 Hz,NH), 7.54(d, J = 8.5 Hz, 2 H),7.37(d, J = 8.5 Hz, 2 H), 4.95(s, 1 H), 3.46(m, 2 H), 2.85(m, 2 H), 2.71(m, 1 H), 2.27(m, 1 H), 1.85(m, 3 H), 1.67(m, 4 H), 1.53(m, 1 H), 1.16(m, 6 H) 370 250-254 371 254-257 372 249-251 373 7.89(s, br, 3 H), 7.72(d,J = 8.1 Hz, 2 H), 7.63(d,J = 8.2 Hz, 2 H), 7.53(s, br,1 H), 3.85(s, br, 1 H),3.47(m, 1 H), 2.77(s, 1 H),2.50(s, br, 1 H), 1.99(s,br, 2 H), 1.88(s, br, 1 H),1.65(m, 4 H), 1.52(m,4 H), 1.21(m, 3 H), 1.16(m, 3 H)

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R1, R16+R17 and R18 are as defined in TABLE 10 (compounds of formula I, wherein m is 0, n is 0, and R2 is a group of formula VII) are obtained

TABLE 10 EX R16 + R17 R18 R1 1HNMR/13C-NMR 374 175.20, 168.92, 152.57,135.26, 134.93, 133.67,133.33, 132.98, 132.83,132.63, 129.88, 129.27,127.71, 126.82, 125.06,124.10, 122.35, 121.99,121.38, 117.92, 59.79,54.81, 43.10, 32.94,28.94, 25.10 375 174.98, 155.00, 141.65,133.42, 133.07, 129.25,127.83, 121.33, 80.13,59.57, 44.31, 44.10,32.40, 28.77, 28.11,25.45

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R13 is hydrogen and R1 and R11+R12 are as 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.

TABLE 11 EX R11 + R12 R1 1HNMR 376 (CDCl3): 7.92(s, 1 H), 7.83(s, 2 H), 7.50(br.s, 1 H), 5.46(s, 1 H), 4.81(s, 2 H),4.04-4.42(m, 2 H), 2.92-3.13(m,2 H), 1.40-.30(m, 8 H) 1.46(s, 9)

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

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, R1 is a group of formula VII) are obtained.

TABLE 12 EX R9 + R10 R2 m.p./1HNMR 377 (DMSO-d6): 1.12(dq, 2 H), 1.40(s, 9 H),1.85(dd, 2 H), 2.03(m, 1 H), 2.65-2.71(m, 2 H), 3.07(d, 2 H), 3.87(broad d,2 H), 7.29(dd, 1 H), 7.32(dd, 1 H), 7.51(dd, 1 H) 378 (DMSO-d6): 8.45(s, 2 H), 8.12(s, 1 H),3.80(br.d, J = 12.5 Hz, 2 H), 2.46(d, J =6.3 Hz, 2 H), 2.70(br. s, 2 H), 1.90-1.98(m, 1 H), 1.80(br.d, J = 13.3 Hz,2 H), 1.00-1.12(m, 2 H) 379 m.p.: 268-273 380 m.p.: 173-176 381 m.p.: 154-159 382 (DMSO-d6): 1.38(s, 9 H), 1.59(d, 2 H),1.70(m, 2 H), 3.05(broad, 2 H), 3.35(s,2 H), 3.60(broad d, 2 H), 4.91(s, 1 H,OH), 8.18(s, 1 H), 8.46(s, 2 H) 383 (CDCl3): 2 rotamers, selected signals:11.30(br.s, 1 H), 8.62(s, 2 H), 8.08(s,1 H), 4.60 + 3.95(2 br.d, J = 13 Hz, 2 1 H), 3.16 + 3.13(2 d, J = 12 Hz, 2 H),2.63(t, J = 12 Hz, 1 H) 384 (DMSO-d6): 0.78(s, 3 H), 1.04(s, 3 H),1.32(m, 1 H), 1.40(m, 1 H), 1.84-1.92(m, 2 H), 1.97 m, 1 H), 2.29(m, 1 H), 2.62(m, 1 H), 3.26 and 3.47(AB, 2 H), 8.15(broad, 1 H), 8.48(broad, 2 H)

Analogously to methods as described in the PROCEDURES (Examples A to Q), but using appropriate starting materials, compounds of formula

wherein R3 is hydrogen, and R2 and R4+R5 are as defined in TABLE 13 (compounds of formula I, wherein m is 0, n is 0, R1 is a group of formula II, and R2 is (C6-18)aryl), are obtained.

TABLE 13 EX R4 + R5 R2 1H-NMR 385 (DMSO-d6): 1.42(s, 9 H), 2.33(t, 2 H),2.82(t, 2 H), 3.44(broad, 4 H), 6.61(s,1 H), 8.41(s, 1 H), 8.57(s, 2 H) 386 (DMSO-d6): 2.40(m, 2 H), 2.93-3.10(m,6 H), 6.44(s, 1 H), 7.27(s, 1 H), 7.36(d,1 H), 7.66(s, 1 H), 7.70(s, 1 H), 8.15(d,2 H, NH), 8.48(s, 2 H)

## Claims

1. A composition comprising an ascomycin and a steroid sulfatase inhibitor.
2-3. (canceled)
4. A method of treating inflammatory disorders comprising administering a therapeutically effective amount of a combination of a steroid sulfatase inhibitor with an ascomycin to a subject in need of such treatment.
5. A pharmaceutical composition comprising, in association with at least one pharmaceutically acceptable excipient, a pharmaceutically effective amount of at least one steroid sulfatase inhibitor in combination with at least one ascomycin.
6. A composition according to claim 1 wherein said ascomycin is a compound of formula
7. A composition according to claim 1 wherein said steroid sulfatase inhibitor is a compound of formula