WO2006010379A1

WO2006010379A1 - Novel thiophene derivatives as immunosuppressive agents

Info

Publication number: WO2006010379A1
Application number: PCT/EP2004/008501
Authority: WO
Inventors: Martin Bolli; Daniel Bur; Martine Clozel; Walter Fischli; David Lehmann; Boris Matthys; Klaus Mueller; Oliver Nayler; Michael Scherz; Thomas Weller
Original assignee: Actelion Pharmaceuticals Ltd.
Priority date: 2004-07-29
Filing date: 2004-07-29
Publication date: 2006-02-02
Also published as: RU2386626C2; PL1805163T3; CN1993346B; JP4807884B2; AR050273A1; SI1805163T1; KR20070046849A; US7750040B2; CN1993346A; AU2005266529A1; DE602005010109D1; US20080064740A1; BRPI0513841A; DK1805163T3; ATE409697T1; NO20071095L; ZA200700535B; IL180962A0; ES2313391T3; TW200616994A

Abstract

The invention relates to novel thiophene derivatives, their preparation and their use as pharmaceutically active compounds. Said compounds particularly act as immunosuppressive agents.

Description

NOVEL THIOPHENE DERIVATIVES AS IMMUNOSUPPRESSIVE AGENTS

Field of the invention

The present invention relates to S1P1/EDG1 receptor agonists of General Formulae (I), (II) and (III) and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the General Formulae (I), (II) or (III), and their use as compounds improving vascular function and as immunomodulating agents, either alone or in combination with other active compounds or therapies.

Background of the invention

The human immune system is designed to defend the body against foreign micro¬ organisms and substances that cause infection or disease. Complex regulatory mechanisms ensure that the immune response is targeted against the intruding substance or organism and not against the host. In some cases, these control mechanisms are unregulated and autoimmune responses can develop. A consequence of the uncontrolled inflammatory response is severe organ, cell, tissue or joint damage. With current treatment, the whole immune system is usually suppressed and the body^'s ability to react to infections is also severely compromised. Typical drugs in this class include azathioprine, chlorambucil, cyclophosphamide, cyclosporin, or methotrexate. Corticosteroids which reduce inflammation and suppress the immune response, may cause side effects when used in long term treatment. Nonsteroidal anti-infammatory drugs (NSAIDs) can reduce pain and inflammation, however, exhibit considerable side effects. Alternative treatments include agents that activate or block cytokine signaling. Orally active compounds with immunomodulating properties, without compromising immune responses and with reduced side effects would significantly improve current treatments of uncontrolled inflammatory disease.

In the field of organ transplantation the host immune response must be suppressed to prevent organ rejection. Organ transplant recipients can experience some rejection even when they are taking immunosuppressive drugs. Rejection occurs most frequently in the first few weeks after transplantation, but rejection episodes can also happen months or even years after transplantation. Combinations of up to three or four medications are commonly used to give maximum protection against rejection while minimizing side effects. Current standard drugs used to treat the rejection of transplanted organs interfere with discrete intracellular pathways in the activation of T-type or B-type white blood cells. Examples of such drugs are cyclosporin, daclizumab, basiliximab, everolimus, or FK506, which interfere with cytokine release or signaling; azathioprine or leflunomide, which inhibit nucleotide synthesis; or 15- deoxyspergualin, an inhibitor of leukocyte differentiation.

The beneficial effects of broad immunosuppressive therapies relate to their effects; however, the generalized immunosuppression which these drugs produce diminishes the immune system's defense against infection and malignancies. Furthermore, standard immunosuppressive drugs are often used at high dosages and can cause or accelerate organ damage.

Description of the invention

The present invention provides novel compounds of General Formulae (I), (II) and (III) that are agonists for the G protein-coupled receptor S1 P1/EDG1 and have a powerful and long-lasting immunosuppressive effect which is achieved by reducing the number of circulating and infiltrating T- and B-lymphocytes, without affecting their maturation, memory, or expansion. The reduction of circulating T- / B- lymphocytes as a result of S1 P1/EDG1 agonism, possibly in combination with the observed improvement of endothelial cell layer function associated with S1 P1/EDG1 activation, makes such compounds useful to treat uncontrolled inflammatory disease and to improve vascular functionality.

The compounds of the present invention can be utilized alone or in combination with standard drugs inhibiting T-cell activation, to provide a new immunosuppressive therapy with a reduced propensity for infections when compared to standard immunosuppressive therapy. Furthermore, the compounds of the present invention can be used in combination with reduced dosages of traditional immunosuppressant therapies, to provide on the one hand effective immunosuppressive activity, while on the other hand reducing end organ damage associated with higher doses of standard immunosuppressive drugs. The observation of improved endothelial cell layer function associated with S1 P1/EDG1 activation provides additional benefits of compounds to improve vascular function.

The nucleotide sequence and the amino acid sequence for the human S1 P1/EDG1 receptor are known in the art and are published in e.g.: HIa, T., and Maciag, T. J. Biol Chem. 265 (1990), 9308-9313; WO91 /15583 published 17 October 1991 ; WO99/46277 published 16 September 1999. These references are incorporated herewith in their entirety The potency and efficacy of the compounds of General Formulae (I), (II) and (III) are assessed using the following tests:

GTPYS assay to determine ECsn values

GTPγS binding assays are performed in 96 well microtiter plates (Nunc, 442587) in a final volume of 200 μl, using membrane preparations of CHO cells expressing recombinant human S1 P1 receptor. Assay conditions are 20 mM Hepes (Fluka, 54461 ), 100 mM NaCI (Fluka, 71378), 5 mM MgCI₂ (Fluka, 63064), 0.1% BSA (Calbiochem, 126609), 1 μM GDP (Sigma, G-7127), 2.5% DMSO (Fluka, 41644), 50 pM ³⁵S-GTPyS (Amersham Biosciences, SJ1320). The pH was 7.4. Test compounds are dissolved and diluted in 100% DMSO and pre-incubated at room temperature for 30 min in 150 μl of the above assay buffer, in the absence of ³⁵S- GTPγS. After addition of 50 μl of ³⁵S-GTPyS, the assay is incubated for 1 h at room temperature. The assay is terminated by transfer of the reaction mixture to a Multiscreen plate (Millipore, MAHFC1 H60) using a cell harvester from Packard Biosciences, and the plates are washed with ice-cold 10 mM Na₂HPO₄ZNaH₂PO₄ (70%/30%), dried, sealed at the bottom and, after addition of 25 μl MicroScint20 (Packard Biosciences, order# 6013621), sealed on the top. Membrane-bound ³⁵S- GTPγS is measured with a TopCount from Packard Biosciences.

EC₅₀ is the concentration of agonist inducing 50 % of the maximal specific ³⁵S- GTPγS binding. Specific binding is determined by subtracting non-specific binding from maximal binding. Maximal binding is the amount of cpm bound to the Multiscreen plate in the presence of 10 μM of S1 P. Non-specific binding is the amount of binding in the absence of an agonist in the assay.

Table 1 shows the EC₅₀ value of some Examples determined as described above:

Table 1:

Compound of Example EC₅₀ [nM]

^~5 75

7 183

24 164

36 300

48 16

49 2

The compounds are within an EC₅₀ range of 1 to 300 nM. Assessment of In vivo Efficacy

The efficacy of the compounds of General Formulae (I), (II) and (III) is assessed by measuring the circulating lymphocytes after oral administration of 30 mg/kg of a compound of General Formula (I) to normotensive male Wistar rats. The animals are housed in climate-controlled conditions with a 12 h-light/dark cycle, and have free access to normal rat chow and drinking water. Blood is collected before and 3 and/or 6 h after drug administration. Full blood is subjected to hematology using Advia Hematology system (Bayer Diagnostics, Zurich, Switzerland).

All data are presented as mean ± SEM. Statistical analyses are performed by analysis of variance (ANOVA) using Statistica (StatSoft) and the Student- Newman-Keuls procedure for multiple comparisons. The null hypothesis is rejected when p < 0.05.

As an example, Table 2 shows the effect on lymphocyte counts 3 h after oral administration of 30 mg/kg of two compounds of the present invention to normotensive male Wistar rats as compared to a group of animals treated with vehicle only.

Table 2

Compound of Example Lymphocyte counts

^~7 -46±3%

24 -40±4%

The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition. These definitions may also be combined without any limitation. Also the substituents enumerated in the General Formulae (I), (II), and (III) may be the same or different.

The term lower alkyl, alone or in combination with other groups, means saturated, straight or branched chain groups with one to seven carbon atoms, preferably one to four carbon atoms. Examples of lower alkyl groups are methyl, ethyl, /7-propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, terf-butyl, /7-pentyl, π-hexyl or π-heptyl. Preferred combinations are fluoro-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy- lower alkyl)-lower alkyl and di-(hydroxy-lower alkyl)-lower alkoxy. Examples are fluoro-ethoxy, hydroxy-ethyloxy, di-hydroxy-propyloxy, di-(propyloxy)-methoxy etc. The term lower alkoxy means a R-O group, wherein R is a lower alkyl. Preferred examples of lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso- butoxy, sec-butoxy or fe/f-butoxy.

The term hydroxy-lower alkoxy means a straight or branched alkoxy chain bearing a hydroxy group whereby there are at least two carbon atoms between the hydroxy group and the oxygen of the lower alkoxy group. Examples of hydroxy- lower alkoxy groups are 2-hydroxy-ethoxy, 3-hydroxy-propoxy, 2-hydroxy-propoxy, 4-hydroxy-butoxy, 3-hydroxy-1-methyl-propoxy, 3-hydroxy-butoxy, etc.

The term mono- or di-lower alkylamino means a R'-NH- or a R'-NR"- group, wherein R¹ and R" are each independently a lower alkyl. Preferred examples of mono- or di-lower alkylamino groups are methylamino, ethylamino, N₁N- dimethylamino, or N-methyl-N-ethyl-amino.

The term halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

The expression pharmaceutically acceptable salts encompasses either salts with inorganic acids or organic acids like hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like that are non-toxic to living organisms. In case the compound of General Formulae (I), (II) or (III) is acidic in nature the expression encompasses salts with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, or with an organic base such as benzathine, choline, meglumine, and the like which are also non-toxic to living organisms (S. M. Berge, L. D. Bighley and D. C. Monkhouse, Pharmaceutical salts, J. Pharm. Sci., 66 (1977), 1-19; P. L. Gould, Salt selection of basic drugs, Int. J. Pharmaceutics 33 (1986), 201-217). The invention relates to novel thiophene derivatives of the General Formula (I),

General Formula (I) wherein

A represents -CH₂CH₂-; -CH=CH-, or -NH-CH₂-;

R¹ represents hydrogen, lower alkyl, and in the case X represents C-R⁴, R¹ in addition represents halogen;

R² represents hydrogen, lower alkoxy, fluoro-lower alkoxy, hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkyl, di-(hydroxy-lower alkyl)- lower alkoxy, 1 -glyceryl, 2-glyceryl, pyridin-3-yl-methoxy, pyridin-4-yl-methoxy;

R³ represents hydrogen, lower alkyl, mono- or di-lower alkylamino, trifluoromethyl, or trifluoromethoxy; and in the case X represents C-R⁴, R³ in addition represents halogen;

X represents N, or C-R ,'4.

R⁴ represents hydrogen, lower alkyl, lower alkoxy, halogen; and configurational isomers, diastereomers, mixtures of diastereomers, as well as pharmaceutically acceptable salts, solvent complexes, and morphological forms.

In a particular embodiment of the invention, A represents -CH=CH-, and R¹, R², R³, and X are as defined in General Formula (I) above.

In another particular embodiment of the invention, A represents -NH-CH₂-, and R¹, R², R³, and X are as defined in General Formula (I) above.

In a preferred embodiment of the invention, A represents -CH₂CH₂-, and R¹, R², R³, and X are as defined in General Formula (I) above.

In a particular embodiment of the invention, X represents N, and R¹, R², R³, and A are as defined in General Formula (I) above.

In another particular embodiment of the invention, X represents C-R⁴, and R¹, R², R³, R⁴, and A are as defined in General Formula (I) above.

In a preferred embodiment of the invention, X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, and R², R³, and A are as defined in General Formula (I) above.

In a further preferred embodiment of the invention, X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ and R³ both represent hydrogen, and R² and A are as defined in General Formula (I) above.

In another preferred embodiment of the invention, R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy- lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R¹, R³, A, and X are as defined in General Formula (I) above.

In a further preferred embodiment of the invention, R² represents an (S)-1 -glyceryl group, and R¹, R³, A and X are as defined in General Formula (I) above. In a further preferred embodiment of the invention, X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, R² represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1-glyceryl, 2-glyceryl, and R³ and A are as defined in General Formula (I) above.

In yet another preferred embodiment of the invention, X represents C-R⁴, whereby R⁴ represents hydrogen, R¹ and R³ both represent a methyl group, R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1-glyceryl, 2-g!yceryl, and A is as defined in General Formula (I) above.

In a particularly preferred embodiment of the invention, X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, A represents - CH₂-CH₂-, and R² and R³ are as defined in General Formula (I) above.

In a further particularly preferred embodiment of the invention, X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ and R³ both represent hydrogen, A represents -CH₂-CH₂-, and R² is as defined in General Formula (I) above.

In another particularly preferred embodiment of the invention, R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1-glyceryl, 2-glyceryl, A represents -CH₂-CH₂-, and R¹, R³, and X are as defined in General Formula (I) above.

In a further particularly preferred embodiment of the invention, R² represents an (S)-1 -glyceryl group, A represents -CH₂-CH₂-, and R¹, R³, and X are as defined in General Formula (I) above.

In a further particularly preferred embodiment of the invention, X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH₂-CH₂-, and R³ is as defined in General Formula (I) above.

In yet another particularly preferred embodiment of the invention, X represents C- R⁴, whereby R⁴ represents hydrogen, R¹ and R³ both represent a methyl group ortho to R², R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy- lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2- glyceryl, and A represents -CH₂-CH₂-.

A further embodiment of the invention are compounds of the General Formula (II)

General Formula (II)

wherein

A represents -CH₂CH₂-; -CH=CH-, or -NH-CH₂-;

R² represents hydrogen, lower alkoxy, fluoro-lower alkoxy, hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkyl, di-(hydroxy-lower alkyl)- lower alkoxy, 1 -glyceryl, 2-glyceryl, pyridin-3-yl-methoxy, pyridin-4-yl-methoxy; R³ represents hydrogen, lower alkyl, mono- or di-lower alkylamino, trifluoromethyl, or trifluoromethoxy; and in the case X represents C-R⁴, R³ in addition represents halogen;

X represents N, or C-R ι |4..

R⁴ represents hydrogen, lower alkyl, lower alkoxy, halogen;

and configurational isomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as pharmaceutically acceptable salts, solvent complexes, and morphological forms.

A further embodiment of the invention are compounds of the General Formula (III)

General Formula (III)

wherein

A represents -CH₂CH₂-; -CH=CH-, or -NH-CH₂-;

R¹ represents hydrogen, lower alkyl, and in the case X represents C-R⁴, R¹ in addition represents halogen; R² represents hydrogen, lower alkoxy, fluoro-lower alkoxy, hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkyl, di-(hydroxy-lower alkyl)- lower alkoxy, 1 -glyceryl, 2-glyceryl, pyridin-3-yl-methoxy, pyridin-4-yl-methoxy;

X represents N, or C-R⁴;

R⁴ represents hydrogen, lower alkyl, lower alkoxy, halogen;

and configu rational isomers, diastereomers, mixtures of diastereomers, as well as pharmaceutically acceptable salts, solvent complexes, and morphological forms.

Specific thiophene derivatives according to General Formula (I) are:

(1aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2,4-dimethoxy-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-ethoxy-2-methoxy-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methyl-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3,5- dimethyl-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyM ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3,5- dimethyl-benzylamide, (laS.SaRJ-i .i ^-trimethyl-i .ia.δ.δa-tetrahyclro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-2- methoxy-benzylamide,

(1 aS,5aR)-1 ,1 ₍2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-2- methoxy-benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3-methyl- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3-methyl- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3-chloro- benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3-chloro- benzylamide,

(1 aS,5aR)-1 ,1 ,2-tιϊmethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-2-chloro- benzylamide,

(1aS₍5aR)-1 ,1 ,2-trimethyl-1,1a,5,5a-tθtrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-2-chloro- benzylamide, (1 aS,5aR)-1 ,1 ,2-trimethyl-i ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)- benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3,5-dimethyl- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-2-methoxy- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydrc-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3-methyl- benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-i ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3-chloro- benzylamide, (1aS,5aR)-1 ,1 ,24rimethyl-1 ,1aA5a-tetrahydiO-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-2-chlorc- benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-benzylamide, (1 aS,5aR)-1 ,1 ,2-trimethyl-1 , 1 a,5,5a-t8trahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3,5- dimethyl-benzylamide,

(1 aS,5aR)- 1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-methoxy- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3-methyl- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3-chloro- benzylamidθ,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-chloro- benzylamide, (1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cycIopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-3,5-dimethyl- benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-2-methoxy- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-3-methyl- benzylamide, (1aS,5aR)-1,,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-3-chloro- benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-2-chloro- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-benzylamide,

(laS.δaR^I .I ^-trimethyl-i .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-fluoro-ethoxy)-3,5-dimethyl- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-fluoro-ethoxy)-2-methoxy- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-chloro-4-(2-fluoro-ethoxy)- benzylamide,

(1 aS,5aR)-1 , 1 ,2-trimethyl-1 , 1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-fluoro-ethoxy)-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-fluoro-propoxy.)-2-methoxy- benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-propoxy-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,δ,5a-tetrahydro-3-thia- cycloprop^'a[a]pentalene-4-carboxylic acid 2-methoxy-4-isopropoxy-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-isobutoxy-2-methoxy-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(6-hydroxy-hexyloxy)-2-methoxy- benzylamidθ,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-2-hydroxymethyl-propoxy)- 3,5-dimethyl-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-(pyridin-3-ylmethoxy)~ benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-(pyridin-4-ylmethoxy)- benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (pyridin-2-ylmethyl)-amide,

3-(2-methoxy-phenyl)-1 -((1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3- thia-cyclopropa[a]penta-len-4-yl)-propan-1 -one,

3-[4-((S)-2,3-dihydroxy-propoxy)-2-methoxy-phenyl]-1 -((1 aS,5aR)-1 ,1 ,2- trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1 -one,

3-[4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-1-((1 aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1 a.δ.δa-tetrahydro-S-thia-cyclopropafalpentalen^-yO-propan-i -one, 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1 ,1 ,2- trimethyl-1 ,1 a.δ.δa-tetrahydro-S-thia-cyclopropafalpentalen^-yO-propan-i -one,

3-[4-((R)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1 ,1 ,2- trimethyl-i .ia.δ.δa-tetrahydro-S-thia-cyclopropatalpentalen^-yO-propan-i-one,

3-[4-(2-hydroxy-ethoxy)-3,δ-dimethyl-phenyl]-1 -((1 aS,δaR)-1 ,1 ,2-trimethyl- 1 ,1 a,δ,δa-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one,

3-[4-(2-(R/S)-hydroxy-propoxy)-3,δ-dimethyl-phenyl]-1 -(1 , 1 ,2-trimethyl- 1 ,1 a.δ.δa-tetrahydro-S-thia-cyclopropafaJpentalen^-ylJ-propan-i -one, 3-[4-(2-(2-fluoroethoxy)-3,5-dimethyl-phenyl]-1-(1 ,1 ,2-trimethyl-i ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one,

3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(1 ,1 ,2-tiϊmethyl-i ,1 a,5,5a- tθtrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one.

The compounds of General Formulae (I), (II) and (III) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parental or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.

The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art (see for example Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the described compounds of General Formulae (I), (II) or (III) and their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

Suitable inert carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents, consistency- improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.

The dosage of the compounds of General Formulae (I), (II) and (III) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 0.5 mg to about 1000 mg, especially about 1 mg to about 500 mg, comes into consideration for the treatment of disorders associated with an activated immune system for adult patients. Depending on the dosage it may be convenient to administer the daily dosage in several dosage units.

The pharmaceutical preparations conveniently contain about 0.5 to 500 mg, preferably 1 to 250 mg, of a compound of General Formulae (I), (II) or (III).

The above-mentioned pharmaceutical composition is useful for the prevention and treatment of disorders associated with an activated immune system.

Such diseases or disorders are selected from the group consisting of rejection of transplanted organs, tissue or cells; graft-versus-host diseases brought about by transplantation; autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; antiphospholipid syndrome; Hashimoto's thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; episcleritis; scleritis; Kawasaki's disease, uveo-retinitis; posterior uveitis; uveitis associated with Behcet's disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; psoriatic arthritis; atopic dermatitis; myopathy; myositis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; scleroderma; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerative keratitis; scleritis;

Graves' ophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchiolitis; bronchitis; endometriosis; orchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac disease; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture's syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; tubulointerstitial nephritis; interstitial cystitis; multiple myositis;

Guillain-Barre syndrome; Meniere's disease; polyneuritis; multiple neuritis; myelitis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; autoimmune thrombocytopenia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa; Huntington's chorea; Sydenham's chorea; myocardosis; myocarditis; scleroderma; Wegener's granuloma; Sjogren's syndrome; adiposis; eosinophilic fascitis; lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis; male pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezary's syndrome; hypophysitis; chronic adrenal insufficiency; Addison's disease; ischemia-reperfusion injury of organs which occurs upon preservation; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal insufficiency; chronic renal insufficiency; lung solid cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemias; lymphoma; psoriasis; pulmonary emphysema; cataracta; siderosis; retinitis pigmentosa; senile macular degeneration; vitreal scarring; corneal alkali burn; dermatitis erythema; ballous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; peripheral artery disease; carcinogenesis; solid cancer tumors; metastasis of carcinoma; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial liver resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepatic failure; late-onset hepatic failure; "acute-on-chronic" liver failure.

Particularly preferred diseases comprise the group consisting of rejection of transplanted organs, tissue or cells; graft-versus-host diseases brought about by transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; asthma; type I diabetes; psoriasis; psoriatic arthritis; Crohn's disease; ulcerative colitis; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; solid cancer tumors; and metastasis.

Furthermore, compounds of the General Formulae (I), (II) and (III) are also useful, in combination with one or several immunosuppressant agents, for the treatment of disorders associated with an activated immune system and selected from the list as above-mentioned. According to a preferred embodiment of the invention, said immunosuppressant agent is selected from the group comprising or consisting of immunosuppressants, steroids, cytotoxic drugs, cytokines and cytokine receptor antagonists or inhibitors, such as cyclosporin, monoclonal antibodies, daclizumab, basiliximab, everolimus, tacrolimus (FK506), sirolimus, azathioprine, leflunomide, 15-deoxyspergualin, mycophenolate mofetil, corticosteroids, methothrexate, 5-aminosalicylic acid.

Still a further object of the present invention is a process to prepare a pharmaceutical composition comprising a compound of the General Formulae (I), (II) or (III) by mixing one or more active ingredients with inert excipients in a manner known perse.

The compounds of General Formulae (I), (II) and (III) can be manufactured by the methods given below, by the methods given in the Examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures.

Compounds of the General Formula (I) of the present invention can be prepared according to the general sequence of reactions outlined below. Only a few of the synthetic possibilities leading to compounds of General Formula (I) are described.

In case A represents -NH-CH₂-, the compounds of the General Formula (I) may be prepared by reacting the compound of Structure 1 with a compound of Structure 2 in the presence of an activating agent such as EDC, DCC, HOBt, BOP, PyBOP, BOP-CI, etc. in a solvent such as THF, dioxane, DMF, DCM, acetonitrile, etc. Depending on the nature of the functionalities present in the residues R¹ to R³, these functionalities may require temporary protection. Appropriate protecting groups are known to a person skilled in the art and include e.g. a benzyl or a trialkylsilyl group to protect an alcohol, a ketal to protect a diol, etc. These protecting groups may be employed according to standard methodology (e.g. T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^rd Edition, Wiley New York, 1991 ; P. J. Kocienski, Protecting Groups, Thieme Stuttgart, 1994). Alternatively, the desired residues R¹ to R³ may also be introduced in later steps that follow the reaction of a compound of Structure 1 with a suitable precursor of a compound of Structure 2. The compounds of Structure 2 are either commercially available or are prepared according to procedures known to a person skilled in the art.

In case A represents -CHa-CH₂-, the compounds of General Formula (I) may be prepared by reacting the compound of Structure 3 with a compound of Structure 4 under Grignard conditions, preferably at temperatures below rt. The Grignard reagent of Structure 4 is prepared according to standard methodology. As above, the functional groups present in the residues R¹ to R³ may require temporary protection or may even be introduced in additional steps that follow the Grignard reaction. The Weinreb amide compound of Structure 3 is prepared by treating the compound of Structure 1 with N,O-dimethylhydroxylamine hydrochloride in the presence of coupling reagent such as EDC, DCC, etc. (M. Mentzel, H. M. R. Hoffmann, N-Methoxy N-methyl amides (Weinreb amides) in modern organic synthesis, Journal fuer Praktische Chemie/Chemiker-Zeitung 339 (1997), 517-524; J. Singh, N. Satyamurthi, I. S. Aidhen, The growing synthetic utility of Weinreb's amide, Journal fuer Praktische Chemie (Weinheim, Germany) 342 (2000) 340- 347; V. K. Khlestkin, D. G. Mazhukin, Recent advances in the application of N,O- dialkylhydroxylamines in organic chemistry, Current Organic Chemistry 7 (2003), 967-993).

In case A represents -CH=CH-, the compounds of General Formula (I) may be prepared by reacting the compound of Structure 5 with a compound of Structure 6. Compounds of General Formula (I) wherein A represents -CH₂-CH₂- may also be prepared by reacting a compound of General Formula (I) wherein A represents - CH=CH- with hydrogen in the presence of a catalyst such as Pd/C, Pt/C, PtO₂, etc in a solvent such as ethanol, methanol, THF, etc.

Structure 6

Structure 5

The compound of Structure 5 may be prepared by treating the compound of Structure 1 with MeLi in a solvent such as THF, dioxane, diethyl ether at temperatures below it

The compound of Structure 1 may be prepared by reacting a compound of Structure 7 with an aqueous base such as aq. NaOH, aq. LiOH, aq. KOH, etc. or an acid such as aq. HCI, TFA, etc. in a solvent such as water, ethanol, methanol, THF, etc. or mixtures thereof.

Structure 7

The compounds of Structure 7 are prepared by treating a compound of Structure 8 with a non aqueous base such as NaOMe, NaOEt, KO-tert.-Bu, DBU, etc. in a solvent such as methanol, ethanol, THF, DMF, etc. or mixtures thereof preferably at elevated temperatures.

Structure 8 Structure 7

The compounds of Structure 8 are prepared by treating the compound of Structure 9 with a 2-mercaptoacetic acid ester in the presence of a base such a NaH in THF, dioxane, DMF, or mixtures thereof.

Structure 9 Structure 8

The compound of Structure 9 may be prepared starting from commercially available (+)-3-carene according to the procedures given in the literature (e.g. S. A. Popov, A. Yu. Denisov, Yu. V. Gatilov, I. Yu. Bagryanskaya and A. V. Tkachev, Tetrahedron Asymmetry 5 (1994), 479-489; S. A. Popov, A. V. Tkachev; Synthetic Commun. 31 (2001), 233-243).

Structure 10

The compounds of General Formula (II) may be prepared in analogy to the reaction sequence outlined above for the compounds of General Formula (I) by starting from the racemic form of the compound of Structure 9 (Structure 10). The racemic form of Structure 9 may be prepared starting from (+)-3-carene following the procedures given in the literature (W. Cocker, D. H. Grayson, Tetrahedron Lett. 51 (1969), 4451-4452; S. Lochynski; B. Jarosz, M. Walkowicz, K. Piatkowski, J. Prakt. Chem. (Leipzig) 330 (1988), 284-288; M. Walkowicz, H. Kuczynsky, C. Walkowicz, Roczniki Chemii Ann. Soc. Chim. Polonorum 41 (1967), 927-937; H. Kuczynski, M. Walkowicz, C. Walkowicz, K. Nowak, I. Z. Siemion, Roczniki Chemii Ann. Soc. Chim. Polonorum, 38 (1964), 1625-1633; A.V. Pol, V. G. Naik, H. R. Sonawane, Ind. J. Chem. Sect. B, 19 (1980) 603-604; S. A. Popov, A. Yu. Denisov, Yu. V. Gatilov, I. Yu. Bagryanskaya and A. V. Tkachev, Tetrahedron Asymmetry 5 (1994), 479-489; S. A. Popov, A. V. Tkachev; Synthetic Commun. 31 (2001 ), 233-243) and is exemplified below.

The compounds of the General Formula (III) may be obtained by resolving the racemic mixture of a compound of General Formula (II) or one of its precursors (e.g. Structure 10) into its pure enantiomers by a method known per se to a person skilled in the art, preferably by chromatography or crystallisation.

Examples

The following examples illustrate the invention but do not at all limit the scope thereof.

All temperatures are stated in ⁰C. Compounds are characterized by ¹H-NMR (300MHz) or ¹³C-NMR (75MHz) (Varian Oxford; chemical shifts are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet; p = pentuplet, hex = hexet, hept = heptet, m = multiplet, br = broad, coupling constants are given in Hz); by LC-MS (Finnigan Navigator with HP 1100 Binary Pump and DAD, column: 4.6x50 mm, Zorbax SB-AQ, 5 m, 120A, gradient: 5-95% acetonitrile in water, 1 min, with 0.04% trifluoroacetic acid, flow: 4.5 ml/min), t_R is given in min; by TLC (TLC-plates from Merck, Silica gel 60 F₂₅₄); or by melting point. Compounds are purified by preparative HPLC (column: X-terra RP18, 50x19 mm, 5 μm, gradient: 10-95% acetonitrile in water containing 0.5 % of formic acid) or by MPLC (Labomatic MD-80-100 pump, Linear UVIS-201 detector, column: 350x18 mm, Labogel-RP-18-5s-100, gradient: 10% methanol in water to 100% methanol).

Abbreviations aq. aqueous atm atmosphere

BOC-anhydride di-tert. butyl dicarbonate

BOP (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate

BOP-CI bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride

BSA bovine serum albumin

DCC dicyclohexyl carbodiimide

DCM dichloromethane

DMF dimethylformamide

DMSO dimethylsulfoxide

EA ethyl acetate

EDC N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide h hour

Hex hexane

HMDS hexamethyldisilazane

HOBt 1 -hydroxybenzotriazole

HV high vacuum conditions min minutes

PyBOP benzotriazol-1-yl-oxy-tris-pyrolidino-phosphonium-hexafluoro phosphat

TBTU 2-(1 H-benzotriazole-1 -yl)-1 ,2,3,3-tetramethyluronium tetrafluoroborate

THF tetrahydrofuran rt room temperature sat. saturated

S1 P sphingosine 1 -phosphate t_R retention time tic thin layer chromatography

(1 aS,5aR)-1 ,1 ,2-TrimethyI-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]penta- lene-4-carboxylic acid ethyl ester (Example of a compound of Structure 7)

a) NaH (7.0 g, 60% dispersion in mineral oil, 175 mmol) is washed with pentane (100 ml_) before it is suspended in THF (400 ml_). The suspension is cooled to 0⁰C and a solution of ethyl 2-mercaptoacetate (12.62 g, 105 mmol) in THF (50 ml_) is added over a period of 20 min. The temperature of the reaction is maintained at 5- 10⁰C. Upon completion of the addition, the cooling is removed and stirring is continued for 30 min. A solution of (1S, 5R)-2-(1-chloro-(E)-ethylidene)-6,6- dimethyl-bicyclo[3.1.0Jhexan-3-one (S. A. Popov, A. Yu. Denisov, Yu. V. Gatilov, I. Yu. Bagryanskaya and A. V. Tkachev, Tetrahedron Asymmetry 5 (1994), 479-489; S. A. Popov, A. V. Tkachev; Synthetic Commun. 31 (2001 ), 233-243) (12.93 g, 70 mmol) in THF (50 mL) is added to the suspension and the resulting mixture is stirred for 1.5 h at rt. The mixture is filtered, the filtrate is concentrated to about 100 mL, diluted with 1 M aq. NaOH (100 mL) and extracted twice with DCM (150 mL). The extracts are dried over Na₂SO₄ and evaporated to furnish a crude E/Z mixture of {1-[(1S,5R)-6,6-dimethyl-3-oxo-bicyclo[3.1.0]hexylidene]-ethylsulfanyl}- acetic acid ethyl ester (18.2 g) as a brown oil. LC-MS: t_R = 1.00 min, [M+1]⁺ = 269.13. ¹H NMR (CDCI₃): δ 4.22 (q, J = 7.0 Hz, 2H both isomers), 3.67 (d, J = 15.8 Hz, 1H major isomer), 3.63 (d, J = 15.8 Hz, 1H minor isomer), 3.58 (d, J = 15.8 Hz, 1 H major isomer), 3.54 (d, J = 15.8 Hz₁ 1 H, minor isomer), 2.67 (dd, J = 6.4, 19.4 Hz, 1 H minor isomer), 2.60 (dd, J = 7.0, 19.4 Hz, 1 H major isomer), 2.58 (s, 3H minor isomer), 2.52 (s, 3H major isomer), 2.36-2.32 (m, 1 H major isomer), 2.30- 2.26 (m, 1H major isomer, 1 H minor isomer), 2.18 (d, J = 7.0 Hz, 1 H minor isomer), 2.00 (d, J = 7.0 Hz, 1 H major isomer), 1.95 (d, J = 7.6 Hz, 1 H minor isomer), 1.30 (t, J = 7.0 Hz, 3H major isomer), 1.28 (t, J = 7.0 Hz, 3H minor isomer), 1.18 (s, 3H major isomer), 1.15 (s, 3H minor isomer), 0.89 (s, 3H minor isomer), 0.85 (s, 3H major isomer).

b) A solution of Na (1.70 g, 74.8 mmol) in abs. ethanol (75 mL) is heated to 6O⁰C before it is treated with a solution of crude {1-[(1S,5R)-6,6-dimethyl-3-oxo- bicyclo[3.1.0]hex-(2Z)-ylidene]-ethylsulfanyl}-acetic acid ethyl ester (18.2 g, 68.0 mmol) in abs. ethanol (200 mL). The mixture is stirred at 75°C for 20 min, then cooled to rt, diluted with 0.5 M aq. NaOH (500 mL) and extracted with DCM (450 +

200 mL). The combined extracts are dried over Na₂SO₄, filtered and the solvent is removed in vacuo. This yields crude (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (10.5 g) as a yellow oil of 87% puritiy (LC-MS, UV 280 nm). LC-MS: t_R = 1.11 min, [M+1]⁺ =

251.14; ¹H NMR (CDCI₃): δ 4.26 (q, J = 7.0 Hz, 2H), 2.95 (dp, J_d = 18.8 Hz, J_p =

3.5 Hz, 1 H), 2.79 (d, J = 19.3, 1 H), 2.37 (s, 3H)₁ 1.89-1.84 (m, 2H), 1.34 (t, J = 7.0 Hz, 3H), 1.12 (s, 3H), 0.72 (s, 3H).

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]penta- lene-4-carboxylic acid (Compound of Structure 1)

To a solution of crude (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentaiene-4-carboxylic acid ethyl ester (10.3 g, 41.2 mmol) in ethanol (200 mL) a solution of 2N aq. LiOH (300 ml_) is added. The resulting mixture is stirred at 70⁰C for 1 h, cooled to rt and diluted with water (250 mL). The aq. solution is extracted three times with DCM (125 mL) before it is acidified to pH 3 by adding citric acid. The acidified solution is extracted twice with DCM (2x250 mL), These second extracts are combinded, dried over Na₂SO₄, filtered and evaporated to leave (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (7.0 g) as a yellow solid. LC-MS: t_R = 0.95 min, [M+1]⁺ = 223.00. ¹H NMR (CDCI₃): δ 3.04-2.92 (m, 1 H), 2.83 (d, J = 19.3 Hz, 1 H), 2.39 (s, 3H), 1.91-1.87 (m, 2H), 1.13 (s, 3H), 0.73 (s, 3H).

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]penta- lene-4-carboxylic acid methoxy-methyl-amide (Compound of Structure 3)

A mixture of N,O-dimehtylhydroxylamine hydrochloride (158 mg, 1.62 mmol) and (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid (300 mg, 1.35 mmol) in DCM (30 mL) and acetonitrile (10 mL) is treated with diisopropylethylamine (209 mg, 1.62 mmol). To the resulting clear solution EDC HCI (311 mg, 1.62 mmol) is added and the mixture is stirred at rt for 18 h before it is diluted with DCM (50 mL) and washed with 1 N aq. HCI (2x50 ml) and 1 N aq. NaOH (50 mL). The organic layer is dried over Na₂SO₄ and evaporated. The crude product is purified by preparative HPLC (Phenomenex AQUA 30x75 mm, gradient of 20-95% acetonitril in water containing 0.5 % formic acid) to furnish (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid methoxy-methyl-amide (200 mg) as a pale yellow solid. LC-MS: t_R = 1.02 min, [M+1]⁺ = 266.04. ¹H NMR (CDCI₃): δ 3.75 (s, 3H), 3.29 (s, 3H), 3.12-3.01 (m, 1 H), 2.93 (d, J = 19.0 Hz, 1 H), 2.38 (s, 3H), 1.90-1.82 (m, 2H), 1.12 (s, 3H), 0.71 (s, 3H).

(1 aS,5aR)-1 -(1 ,1 ,2-Tιϊmethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pen- talen-4-yl)-ethanone (Compound of Structure 5)

To a solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (220 mg, 1.00 mmol) in diethyl ether (10 mL) is added a solution of MeLi (1.6 M, 1.4 mL, 2.10 mmol) in diethyl ether at such a pace that the reaction mixture is refluxing gently. Upon completion of the addition stirring is continued at rt for 30 min. The reaction is quenched by adding sat. aq. NH₄OI (3 mL). The organic layer is separated, dried over Na₂SO₄ and the solvent is evaporated to give the title compound (165 mg) as a pale yellow oil. LC- MS: t_R = 1.03 min, [M+1]⁺ = 221.20; ¹H NMR (CDCI₃): δ 3.00 (ddd, J = 1.8, 4.7, 18.8 Hz, 1 H), 2.80 (d, J = 18.8 Hz, 1 H), 2.38 (s, 6H), 1.93-1.90 (m, 2H), 1.14 (s, 3H), 0.74 (s, 3H).

rac-(1 S,5R)-2-[1 -ChIoro-eth-(E)-ylidene]-6,6-dϊmethyl-bicyclo[3.1.0]hexan-3- one (Structure 10)

rac

a) To a suspension of (+)-3-carene (82 g, 0.6 mol) and CaCU₃ (80 g, 0.8 mol) in water (300 ml_) and dioxan (600 mL) is added N-bromosuccinimide (142 g, 0.8 mol). The mixture is stirred at rt for 1 h, diluted with water (1500 mL) and extracted with diethyl ether (500 mL). The organic extract is washed with water (3x1000 mL) and 5% aq. Na₂S₂θ₃ (2x500 mL), and dried over Na₂SO₄. The solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel eluting with hexane/EA 4:1 to yield (1S,3R,4R,6R)-4- bromo-3,7,7-trimethyl-bicyclo[4.1.0]heptan-3-ol (48.3 g) as a beige solid. ¹H NMR(CDCI₃): δ 4.05 (dd, J = 7.6, 10.6 Hz, 1H), 2.48-2.36 (m, 2H), 2.20 (dd, J = 10.0, 14.7 Hz, 1 H), 1.42-1.38 (m, 1 H), 1.36 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.90-0.80 (m, 1 H), 0.72-0.66 (m, 1 H).

b) To a solution of (1S,3R,4R,6R)-4-bromo-3,7,7-trimethyl-bicyclo[4.1.0]heptan-3- ol (58.0 g, 0.25 mol) in water (120 mL) and dioxane (1600 mL) is added Ag₂O (156.4 g, 0.675 mol). The resulting suspenion is stirred at rt for 18 h before it is filtered over celite. The filtrate is evaporated under reduced pressure. The remaining solid is dissolved in diethyl ether (650 mL) and washed with water (2x 1000 mL). The organic extract is dried over Na₂SO₄ and the solvent is removed in vacuo to furnish 1-((1S,3S,5R)-6,6-dimethyl-bicyclo[3.1.0]hex-3-yl)-ethanone (36.6 g) as a pale yellow oil. ¹H NMR (CDCI₃: δ 2.83-2.70 (m, 1 H), 2.14-2.03 (m, 5H), 1.82 (dd, J = 10.0, 14.1 Hz, 2H), 1.16-1.13 (m, 2H), 0.95 (s, 6H).

c) To a solution of 1-((1S,3S,5R)-6,6-dimethyl-bicyclo[3.1.0]hex-3-yl)-ethanone (36.5 g, 0.24 mol) in DCM (700 mL) is added 70% m-chloroperbenzoic acid (77 g, 0.312 mol) in portions. The reaction mixture is stirred at rt for 36 h before it is washed with 0.2 N aq. NaOH (1000 mL). The wash solution is extracted back with DCM (2x300 ml_). The combined organic extracts are dried over MgSO₄ and the solvent is removed in vacuo to furnish acetic acid (1 S,3S,5R)-6,6-dimethyl- bicyclo[3.1.0]hex-3-yl ester (37.8 g) as a pale yellow oil. ¹H NMR (CDCI₃): δ 4.94 (hept. J = 3.5 Hz, 1 H), 2.02-1.93 (m, 5H), 1.87-1.78 (m, 2H), 1.22-1.15 (m, 2H), 0.95 (s, 3H), 0.83 (s, 3H).

d) A solution of acetic acid (1S,3S,5R)-6,6-dimethyl-bicyclo[3.1.0]hex-3-yl ester (37.85 g, 225 mmol) in ethanol (700 ml_) is treated with 2 N aq. LiOH (700 ml_). The mixture is stirred at rt for 1 h, diluted with water (600 mL) and extracted with EA (2x150 mL). The combined organic extracts are dried over MgSO₄ and evaporated to give (1S,3S,5R)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-ol (23.9 g) as a pale yellow oil. ¹H NMR (CDCI₃): δ 4.23 (hept, J = 2.9 Hz, 1 H), 1.87-1.70 (m, 4H), 1.23-1.20 (m, 2H), 0.96 (s, 3H), 0.81 (s, 3H).

e) To a mixture of pyridine (80 mL) and DCM (720 mL) is added CrO₃ (50 g, 0.5 mol). The mixture is stirred for 5 min before (1S,3S,5R)-6,6-dimethyl- bicyclo[3.1.0]hexan-3-ol (11.5 g, 0.08 mol) is added. Stirring is continued at rt for 2.5 h. The mixture is decanted from an oily residue, diluted with DCM (100 mL) and washed with 2 N aq. HCI (3x80 mL) followed by sat. aq. NaHCO₃ solution (80 mL). The separated organic phase is dried over NaSO₄ and the solvent is removed in vacuo to give (1S,5R)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one as a pale yellow oil. ¹H NMR (CDCI₃): δ 2.58-2.46 (m, 2H), 2.19-2.11 (m, 2H), 1.34-1.26 (m, 2H), 1.09 (s, 3H), 0.87 (S₁ 3H).

f) To a suspension of NaH (873 mg 55% dispersion in mineral oil, 20 mmol, washed with dioxane prior to use) in dioxane (15mL) is added methyl acetate (2.22 g, 30 mmol). The suspension is stirred for 5 min at rt and a solution of (1S,5R)-6,6- dimethyl-bicyclo[3.1.0]hexan-3-one (1.24 g, 10 mmol) in dioxane (5 mL) is added. The reaction mixture is stirred at 65°C overnight. The mixture is poured onto cold 10% aq. citric acid solution (75 mL), extracted with DCM (3x75 mL). The organic extracts are washed with water, dried over MgSO₄ and evaporated to give crude racemic (1R, 2R, 5R)-2-acetyl-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (2.45 g, contains dioxane) as a dark yellow liquid. ¹H NMR (CDCI₃): δ 2.61 (dd, J = 7.3, 19.6 Hz, 1 H), 2.34-2.20 (m, 1 H), 2.01 (s, 3H), 1.72 (d, J = 8.2 HZ, 1 H), 1.40-1.20 (m, 2H), 1.09 (s, 3H), 0.81 (s, 3H).

g) A mixture of the above yellow liquid (1.66 g, 10 mmol), triphenylphosphine (4.53 g, 17 mmol), CCI₄ (5 mL) in chloroform (15 mL) is heated to 65°C for 1 h. The mixture is concentrated and the remaining residue is stirred with pentane. The pentane is decanted, the remaining residue is once more treated with pentane. The pentane fractions are combined and concentrated to leave rac-(1S,5R)-2-[1- chloro-eth^EJ-ylideneJ-e.β-dimethyl-bicyclofS.I .Olhexan-S-one (1.9 g) as brownish oil. This material is used in the next step without further purification. LC-MS: t_R = 1.02 min, [M+1]⁺ = .

Example 1

To a solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (Compound of Structure 1) (4.0 mg, 0.018 mmol), TBTU (7.1 mg, 0.022 mmol) and ethyl-diisopropylamine (8.4 mg, 0.065 mmol) in DMF (0.5 mL) is added a solution of 2-methoxy-benzylamine (3.3 mg, 0.022 mmol) in DMF (0.2 mL). The mixture is allowed to stand at rt for 1 h before it is subjected to purification by prep. HPLC (Water Xterra Prep. RpC18, 19x5 mm, 5 μm particle size, gradient: 20 to 95% acetonitrile in water containing 0.5% sat. ammonium hydroxide). This give (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy- benzylamide (4.8 mg) a a colourless lyophilisate. LC-MS: t_R = 1.08 min, [M+1]⁺ = 342.12.

Example 2

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 2,4-dimethoxy-benzylamide (4.9 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (Compound of Structure 1) (4.4 mg, 0.020 mmol) and 2,4-dimethoxy benzylamine (4.0 mg, 0.024 mmol) following the procedure given in Example 1. LC-MS: t_R = 1.08 min, [M+1]⁺ = 372.18.

Example 3

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-ethoxy-2-methoxy-benzylamide (13.3 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (Compound of Structure 1) (12.2 mg, 0.055 mmol) and 4-ethoxy-2-methoxy-benzylamine hydrochloride (12.0 mg, 0.055 mmol) following the procedure given in Example 1. LC-MS: t_R = 1.10 min, [M+1]⁺ = 386.15.

Example 4

(1aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a4etrahydro-3-t.hia-cyclopropa[a]pentalene-4- carboxylic acid 2-methyl-benzylamide (4.5 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (Compound of Structure 1 ) (4.0 mg, 0.018 mmol) and 2-methylbenzyIamine (2.7 mg, 0.022 mmol) following the procedure given in Example 1. LC-MS: t_R = 1.09 min, [M+1]⁺ = 326.07.

Example 5

a) To a suspension of LiAIH₄ (1.51 g, 39.8 mmol) in diethyl ether (40 mL) a solution of 4-hydroxy-3,5-dimethylbenzonitrile (4.89 g, 33.2 mmol) in diethyl ether (20 mL) and THF (10 mL) is added dropwise at rt. The mixture is stirred at rt for 22 h before it is cooled with an ice-bath and carefully treated with water (10 mL), acidified with 25% aq. HCI and diluted with water (30 mL). The mixture is extracted with diethyl ether. The etheral extract is disgarded. The aqeous phase is basified to pH~8 by adding solid NaHCO₃, saturated with NaCI, and extracted with diethyl ether followed by EA. The combined organic extracts are dried over MgSO₄ and evaporated to leave 4-aminomethyl-2,6-dimethyl-phenol (1.20 g) as a solid. LC- MS: t_R = 0.51 min, [M+1]⁺ = 152.19.

b) A solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (67 mg, 0.30 mmol), TBTU (106 mg, 0.33 mmol) and ethyl-diisopropylamine (169 μL, 0.99 mmol) in DMF (2 mL) is allowed to stand at rt for 10 min. A solution of 4-aminomethyl-2,6-dimethyl-phenol (45 mg, 0.30 mmol) in DMF (0.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL) the mixture is separated by HPLC to afford (laS.δaR^I .I ^-trimethyl-i .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (100 mg) as a colourless oil. LC-MS: t_R = 1.03 min, [M+1]⁺ = 356.23.

c) To a solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzyIamide (8.9 mg, 0.025 mmol) in isopropanol (1 ml_) is added 2 N aq. NaOH (100 μl_), NaI (1 mg, 0.007 mmol) and (S)-3-chloro-propane-1 ,2-diol (11.1 mg, 0.1 mmol). The reaction mixture is heated to 9O⁰C and shaken for 8 h before it is cooled to it Formic acid (0.2 mL) is added and the reaction mixture is separated by prep. HPLC to give (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3,5- dimethyl-benzylamide (3.7 mg) as a colourless lyophilisate. LC-MS: t_R = 0.94 min, [M+1]⁺ = 430.27.

Example 6

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3,5-dimethyl-benzylamide (3.1 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy- 3,5-dimethyl-benzylamide (8.9 mg, 0.025 mmol, Example 5, step b) and (R)-3- chloro-propane-1 ,2-diol (11.1 mg, 0.1 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.94 min, [M+1]⁺ = 430.27.

Example 7

a) A solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (78 mg, 0.35 mmol), TBTU (124 mg, 0.39 mmol) and ethyldiisopropylamine (264 μl_, 1.54 mmol) in DMF (1.5 ml_) is allowed to stand at rt for 10 min before a solution of 4-aminomethyl-3-methoxy- phenol (73 mg, 0.39 mmol, prepared starting from 4-hydroxy-2-methoxy- benzaldehyde in analogy to literature procedures: J. Org. Chem. 53 (1988), 1064- 1071 ; J. Chem. Soc. Perkin Trans. 1 , 1992, 1709-1719) and ethyl-diisopropyl- amine (64 μl_, 0.39 mmol) in DMF (0.75 ml_) is added. The reaction mixture is allowed to stand for 3 h before it is separated by prep. HPLC. This yields (1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-hydroxy-2-methoxy-benzylamide (105 mg) as a colourless lyophilisate. LC-MS: t_R = 0.99 min, [M+1]⁺ = 358.13.

b) (1 aS,5aR)-1 ,1 ,2-Trimethyl-i ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene- 4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-2-methoxy-benzylamide (5.8 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2- methoxy-benzylamide (10.0 mg, 0.028 mmol) and (S)-3-chloro-propane-1 ,2-diol (12.4 mg, 0.11 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.92 min, [M+1]⁺ = 432.14; ¹H NMR (CDCI₃): δ 7.20 (d, J = 8.2 Hz, 1 H), 6.49 (d, J = 2.3 Hz, 1 H), 6.43 (dd, J = 2.3, 8.2 Hz, 1 H), 6.16 (t br, J = 5.6 Hz, 1 H), 4.47 (d, J = 5.9 Hz, 2H), 4.15-4.06 (m, 1 H), 4.05-4.00 (m, 2 H), 3.87 (s, 3H), 3.75 (dd, J = 5.3, 11.1 Hz, 1 H), 2.90 (dd, J = 5.3, 17.6 Hz, 1 H), 2.69 (d, J = 17.6 Hz, 1 H), 2.35 (s, 3H), 2.09 (s br, 2H), 1.91-1.85 (m, 2H), 1.11 (s, 3H), 0.72 (s, 3H). Example 8

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-2-methoxy-benzylamide (4.6 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl- 1.la.δ.δa-tetrahydro-S-thia-cyclopropafajpentalene^-carboxylic acid 4-hydroxy-2- methoxy-benzylamide (10.0 mg, 0.028 mmol, Example 7, step a) and (R)-3-chloro- propane-1 ,2-diol (12.4 mg, 0.11 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.92 min, [M+1]⁺ = 432.18.

Example 9

a) A solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μl_, 1.65 mmol) in DMF (15 ml_) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-2-methyl-phenol hydrochloride (96 mg, 0.55 mmol) and ethyl-diisopropylamine (94 μl_, 0.55 mmol) in DMF (1.5 ml_) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL), the mixture is separated by HPLC to afford (1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-hydroxy-3-methyl-benzylamide (86 mg) as a colourless oil. LC- MS: t_R = 0.99 min, [M+1]⁺ = 342.17. b) (1aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene- 4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3-methyl-benzylamide (1.9 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3- methyl-benzylamide (7.8 mg, 0.023 mmol) and (S)-3-chloro-propane-1 ,2-diol (10.2 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.93 min, [M+1]⁺ = 416.25.

Example 10

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3-methyl-benzylamide (2.4 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2- methoxy-benzylamide (7.8 mg, 0.023 mmol, Example 9, step a) and (R)-3-chloro- propane-1 ,2-diol (10.2 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.93 min, [M+1]⁺ = 416.30.

Example 11

a) A solution of (laS.δaRJ-i .i ^-trimethyl-i.ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μL, 1.65 mmol) in DMF (15 mL) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-2-chloro-phenol hydrochloride (104 mg, 0.55 mmol) and ethyl-diisopropylamine (94 μL, 0.55 mmol) in DMF (1.5 ml_) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 ml_), the mixture is separated by HPLC to afford (1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-hydroxy-3-chloro-benzylamide (114 mg) as a colourless oil. LC- MS: t_R = 1.00 min, [M+1]⁺ = 362.14.

b) (1aS,5aR)-1 ,1 ,2-Trimethyl-i ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene- 4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3-chloro-benzylamide (1.5 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-

1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3- chloro-benzylamide (8.3 mg, 0.023 mmol) and (S)-3-chloro-propane-1 ,2-diol (10.2 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.94 min, [M+1]⁺ = 436.20.

Example 12

(1aS,5aR)-1 ,1 ,2-TrimethyM ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3-chloro-benzylamide (1.6 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3- chloro-benzylamide (8.3 mg, 0.023 mmol, Example 11 , step a) and (R)-3-chloro- propane-1 ,2-diol (10.2 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.94 min, [M+1]⁺ = 436.19. Example 13

a) A solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μl_, 1.65 mmol) in DMF (15 ml_) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-3-chloro-phenol hydrochloride (104 mg, 0.55 mmol) and ethyl-diisopropylamine (94 μl_, 0.55 mmol) in DMF (1.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL), the mixture is separated by HPLC to afford (1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-hydroxy-2-chloro-benzylamide (51 mg) as a colourless oil. LC- MS: t_R = 1.01 min, [M+1]⁺ = 362.13.

b) (laS.δaRJ-i .i ^-Trimethyl-i .ia.δ.δa-tetrahydro-S-thia-cyclopropafalpentalene- 4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-2-chloro-benzylamide (1.6 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-

1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2- chloro-benzylamide (8.3 mg, 0.023 mmol) and (S)-3-chloro-propane-1 ,2-diol (10.2 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.95 min, [M+1]⁺ = 436.19.

Example 14

(laS.δaR^I .I ^-Trimethyl-i .ia.δ.δa-tetrahydro-S-thia-cyclopropa^pentalene-^ carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-2-chloro-benzylamide (1.5 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2- chloro-benzylamide (8.3 mg, 0.023 mmol, Example 13, step a) and (R)-3-chloro- propane-1 ,2-diol (10.2 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.95 min, [M+1]⁺ = 436.17.

Example 15

a) A solution of (1aS,5aR)-1 ,1,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μl_, 1.65 mmol) in DMF (15 ml_) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-phenol hydrochloride (88 mg, 0.55 mmol) and ethyl-diisopropylamine (94 μl_, 0.55 mmol) in DMF (1.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL), the mixture is separated by HPLC to afford (1aS,5aR)-1 ,1,2- trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4- hydroxy-benzylamide (45 mg) as a colourless oil. LC-MS: t_R = 0.96 min, [M+1]⁺ = 328.17.

b) (1aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene- 4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-benzylamide (2.1 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-benzylamide (7.5 mg, 0.023 mmol) and (S)-3-chloro-propane-1 ,2-diol (10.2 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t,_R = 0.91 min, [M+1]⁺ = 402.25. Example 16

(laS.SaRJ-i .i ^-Trimethyl-i .ia.δ.δa-tetrahydro-S-thia-cyclopropafaJpentalene^- carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-benzylamide (2.4 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2-chloro- benzylamide (7.5 mg, 0.023 mmol, Example 15, step a) and (R)-3-chloro-propane- 1 ,2-diol (10.2 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.90 min, [M+1]⁺ = 402.20.

Example 17

To a solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (100 mg) (8.9 mg, 0.025 mmol) in isopropanol (1 ml_) is added 2 N aq. NaOH (100 μl_), NaI (1 mg, 0.007 mmol) and 2-bromo-ethanol (12.5 mg, 0.1 mmol). The reaction mixture is heated to 9O⁰C and shaken for 8 h before it is cooled to rt. Formic acid (0.2 ml_) is added and the reaction mixture is separated by prep. HPLC to give (1aS,δaR)-1 Λ2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3,5-dimethyl- benzylamide (δ.4 mg) as a colourless lyophilisate. LC-MS: t_R = 1.00 min, [M+1]⁺ = 400.26. Example 18

a) To a solution of 4-aminomethyl-3-methoxy-phenol (5.0 g, 26.5 mmol, prepared starting from 4-hydroxy-2-methoxy-benzaldehyde in analogy to literature procedures: J. Org. Chem. 53 (1988), 1064-1071 ; J. Chem. Soc. Perkin Trans. 1 , 1992, 1709-1719) in methanol (140 mL) and 2 N aq. NaOH (70 ml_) is added BOC-anhydride (8.7 g, 39.8 mmmol). The mixture is stirred at rt for 2 h before further BOC-anhydride (5.8 g, 26.5 mmol) is added. Stirring is continued for 30 min and another portion of BOC-anhydride (5.8 g, 26.5 mmol) is added. The mixture is stirred for 30 min. The organic solvent is removed in vacuo, the remaining solution is diluted with 2 N aq. NaOH and extracted with DCM. The aq. phase is neutralised to pH 7 by adding 1 N aq. HCI and extracted with DCM (3x200 mL). These second organic extracts are combined, dried over Na₂SO₄, filtered and evaporated to give (4-hydroxy-2-methoxy-benzyl)-carbamic acid tert-butyl ester (2.9 g) as a beige solid. LC-MS: t_R = 1.20 min, [M+1]⁺ = 254.08; ¹H NMR (D₆- DMSO): δ 9.24 (s, 1 H), 6.95-6.85 (m, 2H), 6.33 (d, J = 2.3 Hz, 1H), 6.26 (dd, J = 2.3, 7.6, 1 H), 3.95 (d, J = 5.9 Hz, 2H), 3.69 (s, 3H), 1.37 (s, 9H).

b) To a stirred solution of (4-hydroxy-2-methoxy-benzyl)-carbamic acid tert-butyl ester (22.8 mg, 0.09 mmol) in 2-propanol (1 mL) and 2 N aq. NaOH (0.15 mL) is added 2-bromoethanol (22.5 mg, 0.18 mmol). The reaction mixture is heated to 85°C and stirred for 8 h. The mixture is cooled to rt and subjected to prep. HPLC purification to give [4-(2-hydroxy-ethoxy)-2-methoxy-benzyi]-carbamic acid tert- butyl ester (10.3 mg) as a colourless oil. LC-MS: t_R = 0.85 min, [M+1]⁺ = 298.07.

c) The above [4-(2-hydroxy-ethoxy)-2-methoxy-benzyl]-carbamic acid tert-butyl ester (10.3 mg, 0.35 mmol) is treated with 37% aq. HCI (0.1 mL) and acetic acid (1 ml_) for 1.5 h at rt. The solvents are removed by lyophilisation. The residue is dissolved in 2 N aq. NaOH (1 ml_) and ethanol (0.25 ml_) and heated to 80⁰C for 1 h. The mixture is cooled to rt and extracted twice with EA. The organic extracts are combined, dried over Na₂SO₄, filtered and evaporated to give 2-(4-aminomethyl-3- methoxy-phenoxy)-ethanol (6.4 mg) as a beige oil. LC-MS: t_R = 0.58 min, [M+1]⁺ = 198.11.

d) A solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (7.8 mg, 0.035 mmol), TBTU (11.2 mg, 0.035 mmol) and ethyl-diisopropylamine (18.0 μl_, 0.105 mmol) in DMF (1 ml_) is allowed to stand at rt for 30 min. The solution is added to 2-(4-aminomethyl-3- methoxy-phenoxy)-ethanol (6.4 mg, 0.035 mmol) and the mixture is allowed to stand at rt for 1 h. The mixture is separated by prep. HPLC to afford (1aS,5aR)- 1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-2-methoxy-benzylamide (7.6 mg) as a colourless lyophilisate. LC-MS: t_R = 0.98 min, [M+1]⁺ = 402.16.

Example 19

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cydopropa[a]pentalene-4- carboxylic acid 4-(2-hydroxy-ethoxy)-3-methyl-benzylamide (1.9 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3-methyl- benzylamide (7.9 mg, 0.023 mmol, Example 9, step a) and 2-bromoethanol (11.5 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: \R = 0.99 min, [M+1]⁺ = 386.27.

Example 20

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-34hia-cyclopropa[a]pentalene-4- carboxylic acid 4-(2-hydroxy-ethoxy)-3-chloro-benzylamide (1.2 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3-chloro- benzylamide (8.3 mg, 0.023 mmol, Example 11 , step a) and 2-bromoethanol (11.5 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.00 min, [M+1]⁺ = 406.24.

Example 21

(1 aS,5aR)-1 ,1 ,2-Trimethyl-i ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-(2-hydroxy-ethoxy)-2-chloro-benzylamide (1.3 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2-chloro- benzylamide (8.3 mg, 0.023 mmol, Example 13, step a) and 2-bromoethanol (11.5 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.01 min, [M+1]⁺ = 406.18.

Example 22

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-(2-hydroxy-ethoxy)-benzylamide (2.2 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-benzylamide (7.5 mg, 0.023 mmol, Example 15, step a) and 2-bromoethanol (11.5 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.96 min, [M+1]⁺ = 372.20.

Example 23

(1aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3,5-dimethyl-benzylamide (5.7 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy- 3,5-dimethyl-benzylamide (8.9 mg, 0.025 mmol, Example 5, step b) and (rac)-1- bromo-propan-2-ol (13.9 mg, 0.1 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.03 min, [M+1]⁺ = 414.26.

Example 24

a) (rac)-1-(4-Aminomethyl-3-methoxy-phenoxy)-propan-2-ol is prepared starting from 4-aminomethyl-3-methoxy-phenol and (rac)-1-bromo-propan-2-ol in analogy to the procedures given in Example 18, steps a to c. LC-MS: t_R = 0.66 min, [M+1]⁺ = 212.13.

b) A solution of (laS.δaRJ-i .i^-trimethyl-i .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid (9.6 mg, 0.043 mmol), TBTU (13.8 mg, 0.043 mmol) and ethyl-diisopropylamine (22 μl_, 0.129 mmol) in DMF (1 mL) is allowed to stand at rt for 30 min. The solution is added to (rac)-1-(4-aminomethyl- 3-methoxy-phenoxy)-propan-2-ol (9.1 mg, 0.043 mmol) and the mixture is allowed to stand at rt for 1 h. The mixture is separated by prep. HPLC to afford (1aS,5aR)- 1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-methoxy-benzylamide (7.6 mg) as a colourless oil. LC-MS: t_R = 0.98 min, [M+1]⁺ = 402.16; ¹H NMR (CDCI₃): δ 7.20 (d, J = 8.2 Hz₁ 1 H), 6.50 (d, J = 2.3 Hz, 1H), 6.44 (d, J = 8.2 Hz, 1H), 6.16 (t br, J = 5.3 Hz, 1 H), 4.47 (d, J = 5.9 Hz, 2H), 3.93 (del, J = 2.9, 11.1 Hz, 1 H), 3.87 (s, 3H), 3.82-3.72 (m, 1 H), 2.90 (dd, J = 5.3, 17.6 Hz, 1 H), 2.69 (d, J = 18.1 Hz, 1 H), 2.35 (s, 3H), 1.92-1.85 (m, 2H), 1.30 (d, J = 6.4 Hz, 3H), 1.11 (s, 3H), 0.72 (s, 3H).

Example 25

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3-methyl-benzylamide (1.7 mg) is obtained as a colourless resin starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3-methyl- benzylamide (7.9 mg, 0.023 mmol, Example 9, step a) and (rac)-1 -bromo-propan- 2-ol (12.8 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.02 min, [M+1]⁺ = 400.28.

Example 26

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3-chloro-benzylamide (1.0 mg) is obtained as a colourless resin starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3-chloro- benzylamide (8.3 mg, 0.023 mmol, Example 11 , step b) and (rac)-i-bromo- propan-2-ol (12.8 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.02 min, [M+1]⁺ = 420.22. Example 27

(1 aS,5aR)-1 ,1 ,2-Tιϊmethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-chloro-benzylamide (1.1 mg) is obtained as a colourless resin starting from (1aS,5aR)-1 ,1,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2-chloro- benzylamide (8.3 mg, 0.023 mmol, Example 13, step b) and (rac)-i-bromo- propan-2-ol (12.8 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.03 min, [M+1]⁺ = 420.13.

Example 28

(laS.δaRJ-i .i ^-Trimethyl-i .ia.δ.δa-tetrahydro-S-thia-cyclopropatajpentalene^- carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-benzylamide (1.86 mg) is obtained as a colourless resin starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3- thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-benzylamide (7.5 mg, 0.023 mmol, Example 15, step b) and (rac)-1-bromo-propan-2-ol (12.8 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: \R = 0.99 min, [M+1]⁺ = 386.25. Example 29

(1aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-(3-hydroxy-propoxy)-3,5-dimethyl-benzylamide (5.0 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy- 3,5-dimethyl-benzylamide (8.9 mg, 0.025 mmol, Example 5, step b) and 3-bromo- propanol (13.9 mg, 0.1 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.02 min, [M+1]⁺ = 414.23.

Example 30

a) 3-(4-Aminomethyl-3-methoxy-phenoxy)-propan-1-ol is prepared starting from 4- aminomethyl-3-methoxy-phenol and 1-bromo-propanol in analogy to the procedures given in Example 18, steps a to c. LC-MS: t_R = 0.67 min, [M+1]⁺ = 212.16.

b) A solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (8.2 mg, 0.037 mmol), TBTU (11.9 mg, 0.037 mmol) and ethyl-diisopropylamine (19 μL, 0.111 mmol) in DMF (1 mL) is allowed to stand at rt for 30 min. The solution is added to 1-(4-aminomethyl-3- methoxy-phenoxy)-propanol (7.8 mg, 0.037 mmol) and the mixture is allowed to stand at rt for 1 h. The mixture is separated by prep. HPLC to afford (1aS,5aR)- 1 ,1 ,2-tri methyl- 1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-2-methoxy-benzylamide (6.5 mg) as a colourless lyophilisate. LC-MS: t_R = 1.01 min, [M+1]⁺ = 416.12.

Example 31

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-(3-hydroxy-propoxy)-3-methyl-benzylamide (1.2 mg) is obtained as a colourless resin starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro- 3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3-methyl-benzylamide (7.9 mg, 0.023 mmol, Example 9, step b) and 3-bromo-propanol (12.8 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.02 min, [M+1]⁺ = 400.25.

Example 32

(laS.δaRJ-i .i ^-Trimethyl-i .ia.δ.δa-tetrahydro-S-thia-cyclopropafalpentalene^- carboxylic acid 4-(3-hydroxy-propoxy)-3-chloro-benzylamide (0.7 mg) is obtained as a colourless resin starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro- 3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3-chloro-benzylamide (8.3 mg, 0.023 mmol, Example 11 , step b) and 1-bromo-propanol (12.8 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.02 min, [M+1]⁺ = 420.22. Example 33

(laS.δaRVI .I ^-Trimethyl-i .i a.δ.δa-tetrahydro-S-thia-cyclopropa^pentalene^- carboxylic acid 4-(3-hydroxy-propoxy)-2-chloro-benzylamide (0.4 mg) is obtained as a colourless resin starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro- 3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2-chloro-benzylamide (8.3 mg, 0.023 mmol, Example 13, step b) and 1-bromo-propanol (12.8 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.03 min, [M+1]⁺ = 420.20.

Example 34

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-(3-hydroxy-propoxy)-benzylamide (0.9 mg) is obtained as a colourless resin starting from (1aS,5aR)-1,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3- thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-benzylamide (7.5 mg, 0.023 mmol, Example 15, step b) and 1-bromo-propanol (12.8 mg, 0.092 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 0.99 min, [M+1]⁺ = 386.30. Example 35

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-(2-fluoro-ethoxy)-3,5-dimethyl-benzylamide (4.6 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl~ benzylamide (8.9 mg, 0.025 mmol, Example 5, step b) and 1 -bromo-2-fluoro- ethane (12.7 mg, 0.1 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.10 min, [M+1]⁺ = 402.24.

Example 36

a) [4-(2-Fluoro-ethoxy)-2-methoxy-benzyl]-carbamic acid tert-butyl ester is prepared starting from 4-aminomethyl-3-methoxy-phenol and 1-bromo-2-fluoro- ethane in analogy to the procedure given in Example 18 step a and b. LC-MS: t_R = 0.97 min, [M+1]⁺ = 300.12.

b) The above [4-(2-fluoro-ethoxy)-2-methoxy-benzyl]-carbamic acid tert-butyl ester (9.9 mg, 0.33 mmol) is treated with 37% aq. HCI (0.1 mL) and acetic acid (1 mL) for 1.5 h at rt. The solvents are removed by lyophilisation to give 4-(2-fluoro- ethoxy)-2-methoxy-benzylamine hydrochloride (7.8 mg) as a beige resin. LC-MS: t_R = 0.73 min, [M+1]⁺ = 200.04. . c) (1aS,5aR)-1 ,1 ,2-Tri methyl- 1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene- 4-carboxylic acid 4-(2-fluoro-ethoxy)-2-methoxy-benzylamide (7.3 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (7.3 mg, 0.033 mmol) and 4-(2-fluoro-ethoxy)-2-methoxy-benzylamine hydrochloride (7.8 mg, 0.033 mmol) following the procedure given in Example 18 step d. LC-MS: t_R = 1.08 min, [M+1]⁺ = 404.18.

Example 37

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 2-chloro-4-(2-fluoro-ethoxy)-benzylamide (0.3 mg) is obtained as a colourless resin starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3- thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-2-chloro-benzylamide (8.3 mg, 0.023 mmol, Example 13, step b) and 1 -bromo-2-fluoro-ethane (11.7 mg, 0.92 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.09 min, [M+1]⁺ = 408.17.

Example 38

(1aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-(2-fluoro-ethoxy)-benzylamide (1.3 mg) is obtained as a colourless resin starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3- thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-benzylamide (7.5 mg, 0.023 mmol, Example 15, step b) and 1 -bromo-2-fluoro-ethane (11.7 mg, 0.92 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.05 min, [M+1]⁺ = 374.10.

Example 39

(1 aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-(3-fluoro-propoxy)-2-methoxy-benzylamide is prepared starting from 4-aminomethyl-3-methoxy-phenol, 1-bromo-3-fluoro-propane and (1aS,5aR)- 1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 36. LC-MS: t_R = 1.10 min, [M+1]⁺ = 418.14.

Example 40

(1 aS,5aR)-1 ,1 ,2-Trimethyl-i ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 2-methoxy-4-propoxy-benzylamide is prepared starting from 4- aminomethyl-3-methoxy-phenol, bromopropane and (1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 36. LC-MS: t_R = 1.13 min, [M+1]⁺ = 400.19. Example 41

(1aS,5aR)-1 ,1 ,2-Trimethyl-1.la.δ.δa-tetrahydro-S-thia-cyclopropafalpentalene^- carboxylic acid 2-methoxy-4-isopropoxy-benzylamide is prepared starting from 4- aminomethyl-3-methoxy-phenol, 2-iodopropane and (1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 36. LC-MS: t_R = 1.12 min, [M+1]⁺ = 400.17.

Example 42

(1aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-isobutoxy-2-methoxy-benzylamide is prepared starting from 4- aminomethyl-3-methoxy-phenol, 1-bromo-2-methyl-propane and (1aS,5aR)-1 ,1 ,2- trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 36. LC-MS: XR = 1.16 min, [M+1]⁺ = 414.17.

Example 43

(1aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 4-(6-hydroxy-hexyloxy)-2-methoxy-benzylamide is prepared starting from 4-aminomethyl-3-methoxy-phenol, 6-bromohexanol and (1aS,5aR)- 1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 18. LC-MS: t_R = 1.08 min, [M+1]⁺ = 458.25.

Example 44

a) To a solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (28.8 mg, 0.08 mmol, Example 5 step b) in isopropanol (3.5 ml_) and 2 N aq. NaOH (0.6 ml_) is added a catalytic amount of NaI followed by methanesulfonic acid 2,2-dimethyl-[1 ,3]dioxan-5-ylmethyl ester (90 mg, 0.40 mmol, B. Xu, G. Kirschenheuter, A. F. Greslin, X. Cheng, J. Sennelo, M. Cattaneo, M. L. Zighetti, A. Chen, S.-A, Kim, H. S. Kim, N. Bischofberger, G. Cook, K. A. Jacobson, J. Med. Chem. 45 (2002) 5694-5709). The reaction mixture is shaken at rt for 8 h, diluted 1 N aq. NaOH, and extracted twice with DCM. The organic extracts are dried over MgSO₄, filtered and evaporated. The residue is purified by prep. HPLC to give (laS.δaRJ-i .i ^-trimethyl-i .ia.δ.δa-tetrahydro-S-thia-cyclopropataJpentalene^- carboxylic acid 4-(2,2-dimethyl-[1 ,3]dioxan-5-ylmethoxy)-3,5-dimethyl-benzylamide (28 mg) as a colourless solid. LC-MS: t_R = 1.13 min, [M+1]⁺ = 484.34.

b) A solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2,2-dimethyl-[1 ,3]dioxan-5- ylmethoxy)-3,5-dimethyl-benzylamide (28 mg, 0.058 mmol) in acetic acid (1.6 mL) and water (0.4 mL) is stirred at rt for 1 h before it is separated by prep. HPLC to give (laS.δaR^I .I ^-trimethyl-i .ia.δ^a-tetrahydro-S-thia-cyclopropatalpentalene- 4-carboxylic acid 4-(3-hydroxy-2-hydroxymethyl-propoxy)-3,5-dimethyl- benzylamide (22 mg) as a colourless solid. LC-MS: t_R = 0.96 min, [M+1]⁺ = 444.30; ¹H NMR (CDCI₃): δ 6.95 (s, 2H), 5.77 (t br, J = 5.8 Hz, 1 H), 4.51-4.37 (m, 2H), 4.00 (d, J = 5.3 Hz, 4H)₁ 3.90 (d, J = 5.3 Hz, 2H), 2.93 (dd, J = 5.9, 17.6 Hz, 1 H) 2.73 (d, J = 17.6 Hz, 1 H), 2.36 (s, 3H), 2.33-2.20 (m, 9 H), 1.93-1.86 (m, 2H), 1.12 (s, 3H), 0.74 (s, 3H).

Example 45

(1 aS,5aR)-1 ,1 ,2-TrimethyM ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 2-methoxy-4-(pyridin-3-ylmethoxy)-benzylamide is prepared starting from 4-aminomethyl-3-methoxy-phenol, 3-bromomethyl-pyridinel hydrobromide and (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 36. LC-MS: t_R = 0.90 min, [M+1]⁺ = 449.20.

Example 46

(1aS,5aR)-1 ,1 ,2-Trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid 2-methoxy-4-(pyridin-4-ylmethoxy)-benzylamide is prepared starting from 4-aminomethyl-3-methoxy-phenol, 4-bromomethyl-pyridinel hydrobromide and (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 36. LC-MS: t_R = 0.88 min, [M+1]⁺ = 449.21.

Example 47

(1aS,5aR)-1 ,1 ,2-Trimethyl-i ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4- carboxylic acid (pyridin-2-ylmethyl)-amide (4.2 mg) is obtained as a colourless lyophilisate starting from (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid (Compound of Structure 1) (4.0 mg, 0.018 mmol) and C-pyridin-2-yl-methylamine (2.4 mg, 0.022 mmol) following the procedure given in Example 1. LC-MS: t_R = 0.79 min, [M+1]⁺ = 313.03.

Example 48

a) A mixture of triethylsilane (34.9 g, 0.3 mol), TFA (96 mL) and 2-bromo-1 -(2- methoxy-phenyl)-ethanone (6.9 g, 30 mmol) is stirred at rt for 30 min before it is poured onto an ice/water mixture (600 mL). The mixture is neutralised by adding 2 N aq. NaOH and sat. aq. NaHCO₃ (200 mL), and is extracted with DCM (2x200 mL). The combined organic extracts are dried over Na₂SO₄, filtered and evaporated. The obtained residue is purified by chromatography on silica gel (TBME:EA 40:1) to give 1-(2-bromo-ethyl)-2-methoxy-benzene (4.50 g) as a colourless liquid. LC: t_R = 1.00 min.

b) At rt, a solution of 1-(2-bromo-ethyl)-2-methoxy-benzene (1.0 g, 4.15 mmol) in abs. THF (5 mL) is added to Mg turnings (0.13 g, 5.35 mmol) suspended in abs. THF (5 mL) over a period of 20 min. The thus obtained Grignard reagent is then added at to an ice-cold solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro- 3-thia-cyclopropa[a]pentalene-4-carboxylic acid methoxy-methyl-amide (400 mg, 1.5 mmol) in THF (5 mL). The reaction mixture is stirred at rt for 1 h, quenched by adding sat. aq. NH₄CI (10 mL), diluted with water (100 mL) and extracted twice with DCM (100 mL). The combined organic extracts are dried over Na₂SO₄, filtered and evaporated . The resulting residue is purified by prep. HPLC to afford 3-(2- methoxy-phenyl)-1-((1aS,5aR)-1 ,1 ,2~trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]penta-len-4-yl)-propan-1-one (390 mg) as a colourless oil. LC-MS: t_R = 1.15 min, [M+1]⁺ = 341.21 ; ¹H NMR (CDCI₃): δ 7.22-7.14 (m, 2H), 6.90-6.81 (m, 2H), 3.82 (s, 3H), 3.20-2.90 (m, 5H), 2.79 (d, J = 18.8 Hz, 1 H), 2.38 (s, 3H), 1.88 (d, J = 2.9 Hz, 2H), 1.12 (s, 3H), 0.72 (s, 3H).

Example 49

a) A stirred solution of (1aS,5aR)-1-(1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pen-talen-4-yl)-ethanone (110 mg, 0.5 mmol), 4-hydroxy-2- methoxybenzaldehyde (150 mg, 0.99 mmol) and KOH (0.5 g, 8.9 mmol) in ethanol (5 mL) is heated to 6O⁰C for 6 h followed by 8O⁰C for 2 h. Formic acid (1 mL) is added and the mixture is separated by prep. HPLC to afford 3-(4-hydroxy-2- methoxy-phenyl)-1 -((1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclo- propa[a]pentalen-4-yl)-propenone (75 mg) as a yellow solid. LC-MS: t_R = 1.08 min, [M+1]⁺ = 355.15; ¹H NMR (D₆-DMSO): δ 10.15 (s, 1 H), 7.73 (d, J = 15.2 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.23 (d, J = 15.8 Hz, 1 H), 6.47-6.40 (m, 2H), 3.84 (s, 3H), 3.12 (dd, J = 6.4, 18.8 Hz, 1 H), 2.88 (d, J = 18.8 Hz, 1 H), 2.07 (s, 3H), 2.02-1.93 (m, 2H), 1.11 (s, 3H), 0.70 (s, 3H). b) To a solution of 3-(4-hydroxy-2-methoxy-phenyl)-1-((1aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1a,5,5a-tetrahydro-3-thia-cyclo-propa[a]pentalen-4-yl)-propenone (71 mg, 0.2 mmol) in ethanol (3.5 ml_) is added Pd/C (30 mg, 10% Pd). The resulting suspension is stirred at rt for 30 min under 1 atm H₂. The mixture is filtered over celite and the filtrate is evaporated. The residue is purified by prep. HPLC to give 3-(4-hydroxy-2-methoxy-phenyl)-1-((1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalen-4-yi)-propan-1-one (22 mg) as a slightly yellow resin. LC-MS: t_R = 1.06 min, [M+1]⁺ = 357.22; ¹H NMR (CD₃OD): δ 6.88 (d, J = 8.2 Hz, 1 H), 6.37 (d, J = 2.3 Hz, 1 H), 6.26 (dd, J = 2.3, 8.2 Hz, 1 H), 3.76 (s, 3H), 3.00-2.74 (m, 6H), 2.04 (s, 3H), 1.98-1.89 (m, 2H), 1.12 (s, 3H), 0.70 (s, 3H).

c) 3-[4-((S)-2,3-Dihydroxy-propoxy)-2-methoxy-phenyl]-1 -((1 aS,5aR)-1 , 1 ,2- trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1 -one (3.3 mg) is obtained as a colourless resin starting from the above 3-(4-hydroxy-2- methoxy-phenyl)-1-((1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]-pentalen-4-yl)-propan-1-one (8.9 mg, 0.025 mmol) and (S)-3-chloro- propane-1 ,2-diol (11.1 mg, 0.1 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.00 min, [M+1]⁺ = 431.26; ¹H NMR (CDCI₃): δ 7.06 (d, J = 8.02 Hz, 1H)₁ 6.45 (d, J = 2.3 Hz, 1 H), 6.40 (dd, J = 2.3, 8.2 Hz, 1 H), 4.14-4.06 (m, 1H), 4.05-4.01 (m, 2H), 3.85 (dd, J = 4.1 , 11.1 Hz, 1 H), 3.80 (s, 3H), 3.75 (dd, J = 5.3, 11.1 Hz, 1 H), 3.02-2.90 (m, 5H), 2.79 (d, J = 18.8 Hz, 1 H), 2.38 (s, 3H), 1.97 (s br, 2H), 1.91-1.85 (m, 2H), 1.12 (s, 3 H), 0.71 (s, 3H).

Example 50

3-[4-(2-Hydroxy-ethoxy)-2-methoxy-phenyl]-1 -((1 aS,5aR)-1 ,1 ,2-trimethyl- 1 ,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.9 mg) is obtained as a colourless resin starting from 3-(4-hydroxy-2-methoxy-phenyl)-1- ((1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia-cyclopropa[a]-pentalen-4- yl)-propan-1-one (8.9 mg, 0.025 mmol, Example 49, step b and 2-bromoethanol (12.5 mg, 0.1 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.06 min, [M+1]⁺ = 400.72; ¹H NMR (CDCI₃): δ 7.06 (d, J = 8.2 Hz, 1H), 6.47 (d, J =2.3 Hz, 1 H), 6.41 (dd, J = 2.3, 8.2 Hz, 1 H), 4.09-4.05 (m, 2H), 3.98-3.92 (m, 2H), 3.81 (s, 3H), 3.01-2.90 (m, 5H), 2.79 (d, J = 18.8 Hz, 1 H), 2.38 (s, 3H), 1.90- 1.86 (m, 2H), 1.12 (s, 3H), 0.72 (s, 3H).

Example 51

a) a) A stirred solution of (1aS,5aR)-1-(1,1,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pen-talen-4-yl)-ethanone (441 mg, 1.8 mmol), 4-hydroxy-3,5- dimethylbenzaldehyde (751 mg, 0.99 mmol) in ethanol (10 mL) and HCI (5 mL, 1 N in isopropanol) is stirred at rt for 80 min. The blue reaction mixture is separated by prep. HPLC to afford 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-((1aS,5aR)-1,1,2- trimethyl-1 ,1 a.δ.δa-tetrahydro-S-thia-cyclo-propatalpentalen^-yO-propenone (360 mg) as a yellow solid. LC-MS: t_R = 1.13 min, [M+1]⁺ = 353.17; ¹H NMR (CDCI₃): δ 7.62 (d, J = 15.2 Hz, 1 H), 7.24 (s, 2H), 7.06 (d, J = 15.2 Hz, 1H), 4.93 (s br, 1 H), 3.13 (dd, J = 6.4, 18.8 Hz, 1H), 2.96 (d, J = 18.8 Hz, 1H), 2.43 (s, 3H), 2.29 (s, 6H), 1.99-1.90 (m, 2H), 1.15 (s, 3H), 0.76 (s, 3H).

b) To a solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl- 1,1a,5,5a-tetrahydro-3-thia-cyclo-propa[a]pentalen-4-yl)-propenone (360 mg, 1.03 mmol) in ethanol (20 mL) is added Pd/C (450 mg, 10% Pd). The resulting suspension is stirred at rt for 4.5 h min under 1 atm H₂. The mixture is filtered over celite and the filtrate is evaporated. The residue is purified by prep. HPLC to give 3-(4-hydroxy-3,5-dimethyl-phenyl)-1 -((1 aS,5aR)-1 , 1 ,2-trimethyl-1 , 1 a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (280 mg) as a slightly yellow resin. LC-MS: t_R = 1.11 min, [M+1]⁺ = 355.20.

c) 3-[4-((S)-2,3-Dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1 ,1 ,2- trimethyl-i.ia.δ^a-tetrahydro-S-thia-cyclopropatalpentalen^-yO-propan-i-one (4.4 mg) is obtained as a colourless resin starting from the above 3-(4-hydroxy- 3,5-dimethyl-phenyl)-1-((1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]-pentalen-4-yl)-propan-1-one (8.9 mg, 0.025 mmol) and (S)-3-bromo- propane-1 ,2-diol (15.5 mg, 0.1 mmol) following the procedure given in Example 5, step c. LC-MS: t_R = 1.02 min, [M+1]⁺ = 429.25.

Example 52

3-[4-((R)-2,3-Dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2- trimethyl-i.ia.δ.Sa-tetrahydro-S-thia-cyclopropajatøentalen^-yO-propan-i-one

(5.4 mg) is obtained as a colourless lyophilisate starting from 3-(4-hydroxy-3,5- dimethyl-phenyl)-1 -((1 aS,5aR)-1 , 1 ,2-trimethyl-1 , 1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]-pentalen-4-yl)-propan-1-one (8.9 mg, 0.025 mmol) and (R)-3-bromo- propane-1 ,2-diol (15.5 mg, 0.1 mmol) in analogy to the procedures given in Example 51. LC-MS: t_R = 1.02 min, [M+1]⁺ = 429.29.

Example 53

S-^^-Hydroxy-ethoxyJ-S.δ-dimethyl-phenyO-i-CCIaS.SaRVI.I^-trimethyl- i .ia.δ.δa-tetrahydro-S-thia-cyclopropalalpentalen^-yO-propan-i-one (3.1 mg) is obtained as a colourless resin starting from 3-(4-hydroxy-3,5-dimethyl-phenyl)-1- ((laS.SaRJ-i.i ^-trimethyl-i .ia.δ.δa-tetrahydro-S-thia-cyclopropafal-pentalen-^ yl)-propan-1-one (8.9 mg, 0.025 mmol) and 2-bromoethanol (12.5 mg, 0.1 mmol) in analogy to the procedures given in Example 51. LC-MS: t_R = 1.09 min, [M+1]⁺ = 499.2.

Example 54

3-[4-(2-(R/S)-Hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(1,1,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.2 mg) is obtained as a colourless resin starting from 3-(4-hydroxy-3,δ-dimethyl-phenyl)-1-((1aS,δaR)- 1 ,1 ,2-trimethyl-1 ,1 a.δ.δa-tetrahydro-S-thia-cyclopropafaJ-pentalen^-yO-propan-i- one (8.9 mg, 0.026 mmol) and rac-1-bromo-propan-2-ol (13.9 mg, 0.1 mmol) in analogy to the procedures given in Example 51. LC-MS: t_R = 1.12 min, [M+1]⁺ = 413.24.

Example 55

3-[4-(2-(2-Fluoroethoxy)-3,5-dimethyl-phenyl]-1-(1 ,1 ,2-trimethyl-1 ,1a,5,δa- tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (3.1 mg) is obtained as a colourless resin starting from 3-(4-hydroxy-3,δ-dimethyl-phenyl)-1-((1aS,δaR)- i .i^-trimethyl-i .ia.δ.Sa-tetrahydro-S-thia-cyclopropa^-pentalen^-yO-propan-i- one (8.9 mg, 0.025 mmol) and 1-bromo-2-fluoroethane (12.7 mg, 0.1 mmol) in analogy to the procedures given in Example 51. LC-MS: t_R = 1.18 min, [M+1]⁺ = 401.25.

Example 56

3-[4-(3-Hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (3.4 mg) is obtained as a colourless resin starting from 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-((1aS,5aR)- 1 ,1 ,2-trimethyl-1.la.S.δa-tetrahydro-S-thia-cyclopropaJal-pentalen^-yO-propan-i- one (8.9 mg, 0.025 mmol) and 3-bromopropanol (13.9 mg, 0.1 mmol) in analogy to the procedures given in Example 51. LC-MS: t_R = 1.11 min, [M+1]⁺ = 413.23.

Claims

1. Novel thiophene derivatives of the General Formula (I),

General Formula (I) wherein

A represents -CH₂CH₂-; -CH=CH-, or -NH-CH₂-;

X represents N, or C-R 4 4.. R⁴ represents hydrogen, lower alkyl, lower alkoxy, halogen;

and configurational isomers, diastereomers, mixtures of diastereomers, as well as pharmaceutically acceptable salts, solvent complexes, and morphological forms.

2. Thiophene derivatives according to claim 1 wherein A represents -CH=CH-, and R¹, R², R³, and X are as defined in claim 1.

3. Thiophene derivatives according to claim 1 wherein A represents -NH-CH₂-, and R¹, R², R³, and X are as defined in claim 1.

4. Thiophene derivatives accoding to claim 1 wherein A represents -CH₂CH₂-, and R¹, R², R³, and X are as defined in claim 1.

5. Thiophene derivatives according to claim 1 wherein X represents N, and R¹, R², R³, and A are as defined in claim 1.

6. Thiophene derivatives according to claim 1 wherein X represents C-R⁴, and R¹, R², R³, R⁴, and A are as defined in claim 1.

7. Thiophene derivatives according to claim 1 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, and R², R³, and A are as defined in claim 1.

8. Thiophene derivatives according to claim 1 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ and R³ both represent hydrogen, and R² and A are as defined in claim 1.

9. Thiophene derivatives according to claim 1 wherein R² represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R¹, R³, A, and X are as defined in claim 1.

10. Thiophene derivatives according to claim 1 wherein R² represents an (S)-1- glyceryl group, and R¹, R³, A and X are as defined in claim 1.

11. Thiophene derivatives according to claim 1 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-Iower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R³ and A are as defined in claim 1.

12. Thiophene derivatives according to claim 1 wherein X represents C-R⁴, whereby R⁴ represents hydrogen, R¹ and R³ both represent a methyl group ortho to R², R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A is as defined in claim 1.

13. Thiophene derivatives according to claim 1 wherein X represents N, A represents -CH₂-CH2-, and R¹, R², and R³ are as defined in claim 1.

14. Thiophene derivatives according to claim 1 wherein X represents C-R⁴, A represents -CH₂-CH₂-, and R¹, R², R³, and R⁴ are as defined in claim 1.

15. Thiophene derivatives according to claim 1 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, A represents - CH₂-CH₂-, and R² and R³ are as defined in claim 1.

16. Thiophene derivatives according to claim 1 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ and R³ both represent hydrogen, A represents -CH₂-CH₂-, and R² is as defined in claim 1.

17. Thiophene derivatives according to claim 1 wherein R² represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH₂-CH₂-, and R¹, R³, and X are as defined in claim 1.

18. Thiophene derivatives according to claim 1 wherein R² represents an (S)-1- glyceryl group, A represents -CH₂-CH₂-, and R¹, R³, and X are as defined in claim 1.

19. Thiophene derivatives according to claim 1 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, R² represents hydroxy-lower alkoxy, hydroxy-lower alky!, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH₂-CH₂-, and R³ is as defined in claim 1.

20. Thiophene derivatives according to claim 1 wherein X represents C-R⁴, whereby R⁴ represents hydrogen, R¹ and R³ both represent a methyl group ortho to R², R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A represents -CH₂-CH₂-.

21. Novel thiophene derivatives of the General Formula (II),

General Formula (II)

wherein

A represents -CH₂CH₂-; -CH=CH-, or -NH-CH₂-; R¹ represents hydrogen, lower alkyl, and in the case X represents C-R⁴, R¹ in addition represents halogen;

X represents N, or C-R⁴;

R⁴ represents hydrogen, lower alkyl, lower alkoxy, halogen;

22. Thiophene derivatives according to claim 21 wherein A represents -CH=CH-, and R¹, R², R³, and X are as defined in claim 21.

23. Thiophene derivatives according to claim 21 wherein A represents -NH-CH₂-, and R¹, R², R³, and X are as defined in claim 21.

24. Thiophene derivatives accoding to claim 21 wherein A represents -CH₂CH₂-, and R¹, R², R³, and X are as defined in claim 21.

25. Thiophene derivatives according to claim 21 wherein X represents N, and R¹, R², R³, and A are as defined in claim 21.

26. Thiophene derivatives according to claim 21 wherein X represents C-R⁴, and R¹, R², R³, R⁴, and A are as defined in claim 21.

27. Thiophene derivatives according to claim 21 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, and R², R³, and

A are as defined in claim 21.

28. Thiophene derivatives according to claim 21 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ and R³ both represent hydrogen, and R² and A are as defined in claim 21.

29. Thiophene derivatives according to claim 21 wherein R² represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R¹, R³, A, and X are as defined in claim 21.

30. Thiophene derivatives according to claim 21 wherein R² represents an (S)-1- glyceryl group, and R¹, R³, A and X are as defined in claim 21.

31. Thiophene derivatives according to claim 21 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R³ and A are as defined in claim 21.

32. Thiophene derivatives according to claim 21 wherein X represents C-R⁴, whereby R⁴ represents hydrogen, R¹ and R³ both represent a methyl group ortho to R², R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower aikyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A is as defined in claim 21.

33. Thiophene derivatives according to claim 21 wherein X represents N, A represents -CH₂-CH₂-, and R¹, R², and R³ are as defined in claim 21.

34. Thiophene derivatives according to claim 21 wherein X represents C-R⁴, A represents -CH₂-CH₂-, and R¹, R², R³, and R⁴ are as defined in claim 21.

35. Thiophene derivatives according to claim 21 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, A represents - CH₂-CH₂-, and R² and R³ are as defined in claim 21.

36. Thiophene derivatives according to claim 21 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ and R³ both represent hydrogen, A represents -CH₂-CH₂-, and R² is as defined in claim 21.

37. Thiophene derivatives according to claim 21 wherein R² represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH₂-CH₂-, and R¹, R³, and X are as defined in claim 21.

38. Thiophene derivatives according to claim 21 wherein R² represents an (S)-1- glyceryl group, A represents -CH₂-CH₂-, and R¹, R³, and X are as defined in claim 21.

39. Thiophene derivatives according to claim 21 wherein X represents C-R⁴, whereby R⁴ represents a methoxy. group, R¹ represents hydrogen, R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH₂-CH₂-, and R³ is as defined in claim 21.

40. Thiophene derivatives according to claim 21 wherein X represents C-R⁴, whereby R⁴ represents hydrogen, R¹ and R³ both represent a methyl group ortho to R², R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A represents -CH₂-CH₂-.

41. Novel thiophene derivatives of the General Formula (III),

General Formula (III) wherein

A represents -CH₂CH₂-; -CH=CH-, or -NH-CH₂-;

X represents N, or C-R⁴;

42. Thiophene derivatives according to claim 41 wherein A represents -CH=CH-, and R¹, R², R³, and X are as defined in claim 41.

43. Thiophene derivatives according to claim 41 wherein A represents -NH-CH₂-, and R¹, R², R³, and X are as defined in claim 41.

44. Thiophene derivatives accoding to claim 41 wherein A represents -CH₂CH₂-, and R¹, R², R³, and X are as defined in claim 41.

45. Thiophene derivatives according to claim 41 wherein X represents N, and R¹, R², R³, and A are as defined in claim 41.

46. Thiophene derivatives according to claim 41 wherein X represents C-R⁴, and R¹, R², R³, R⁴, and A are as defined in claim 41.

47. Thiophene derivatives according to claim 41 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, and R², R³, and

A are as defined in claim 41.

48. Thiophene derivatives according to claim 41 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ and R³ both represent hydrogen, and R² and A are as defined in claim 41.

49. Thiophene derivatives according to claim 41 wherein R² represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R¹, R³, A, and X are as defined in claim 41.

50. Thiophene derivatives according to claim 41 wherein R² represents an (S)-1- glyceryl group, and R¹, R³, A and X are as defined in claim 41.

51. Thiophene derivatives according to claim 41 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyi)-lower alkyl, 1 -glyceryl, 2-glyceryl, and R³ and A are as defined in claim 41.

52. Thiophene derivatives according to claim 41 wherein X represents C-R⁴, whereby R⁴ represents hydrogen, R¹ and R³ both represent a methyl group ortho to R², R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A is as defined in claim 41.

53. Thiophene derivatives according to claim 41 wherein X represents N, A represents -CH2-CH₂-, and R¹, R², and R³ are as defined in claim 41.

54. Thiophene derivatives according to claim 41 wherein X represents C-R⁴, A represents -CH2-CH2-, and R¹, R², R³, and R⁴ are as defined in claim 41.

55. Thiophene derivatives according to claim 41 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, A represents - CH₂-CH₂-, and R² and R³ are as defined in claim 41.

56. Thiophene derivatives according to claim 41 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ and R³ both represent hydrogen, A represents -CH₂-CH₂-, and R² is as defined in claim 41.

57. Thiophene derivatives according to claim 41 wherein R² represents hydroxy- lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di- (hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, A represents -CH₂-CH₂-, and R¹, R³, and X are as defined in claim 41.

58. Thiophene derivatives according to claim 41 wherein R² represents an (S)-1- glyceryl group, A represents -CH₂-CH₂-, and R¹, R³, and X are as defined in claim 41.

59. Thiophene derivatives according to claim 41 wherein X represents C-R⁴, whereby R⁴ represents a methoxy group, R¹ represents hydrogen, R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-Iower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-gIyceryl, A represents -CH₂-CH₂-, and R³ is as defined in claim 41.

60. Thiophene derivatives according to claim 41 wherein X represents C-R⁴, whereby R⁴ represents hydrogen, R¹ and R³ both represent a methyl group ortho to R², R² represents hydroxy-lower alkoxy, hydroxy-lower alkyl, di-(hydroxy-lower alkyl)-lower alkoxy, di-(hydroxy-lower alkyl)-lower alkyl, 1 -glyceryl, 2-glyceryl, and A represents -CH₂-CH₂-.

61. A thiophene derivative according to any one of claims 1 to 20 selected from the group consisting of:

(1 aS,5aR)-1 ,1 ,2-Trimethyl-i ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2,4-dimethoxy-benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-ethoxy-2-methoxy-benzylamide, (1aS,5aR)-1 ,1,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methyl-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3,5- dimethyl-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3,5- dimethyl-benzylamide, (1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxy1ic acid 4-((S)-2,3-dihydroxy-propoxy)-2- methoxy-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-2- methoxy-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3-methyl- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3-methyl- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3-chloro- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-3-chloro- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-2-chloro- benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)-2-chloro- benzylamidθ, (1aS,5aR)-1 ,1 ,2-trimethyl-i ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)- benzylamide,

(laS.δaRJ-i .i ^-trimethyl-i .ia.δ.δa-tΘtrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R)-2,3-dihydroxy-propoxy)- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyM ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3,5-dimethyl- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-2-methoxy- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia-

5 cyclopropa[a]pentalene-4-carboxyIic acid 4-(2-hydroxy-ethoxy)-3-methyl- benzylamide,

(1aS,δaR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa4etrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-3-chloro- benzylamidθ, 0 (1aS,6aR)-1 ,1,2-trimethyl-1,1a,6,6a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-ethoxy)-2-chloro- benzylamidθ,

(laS.δaR^I .I^-trimethyl-i.ia.δ.δa-tetrahydro-S-thia- cyciopropa[a]pentalene-4-carboxylic acid 4-(2-hydroxy-θthoxy)-benzylamide, δ (1aS,δaR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3,δ- dimethyl-benzylamide,

(1aS,δaR)- 1 ,1,2-trimethyl-1,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-methoxy- 0 benzylamidθ,

(1 aS,δaR)-1 ,1 ,2-trimethyl-i ,1 a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3-methyl- benzylamide,

(1aS,δaR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- δ cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-3-chloro- benzylamide,

(laS.δaRJ-i .i ^-trimethyl-i .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)-2-chloro- benzylamide, 0 (1 aS,δaR)-1 ,1 ,2-trimethyl-1 ,1 a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-((R/S)-2-hydroxy-propoxy)- benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-3,5-dimethyl- benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-2-methoxy- benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-i ,1 a,5,5a-tθtrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-3-methyl- benzylamidθ, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-3-chloro- benzylamide,

(laS.δaRJ-i .i^-trimethyl-i.ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-2-chlorc- benzylamide,

(1aS,δaR)-1 Λ24rimethyl-1Ja,δ,δa-tetrahydrc>-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-propoxy)-benzylamide,

(1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-fluoro-ethoxy)-3,δ-dimethyl- benzylamide,

(1 aS,δaR)-1 ,1 ,2-trimethyl-i ,1 a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-fluoro-ethoxy)-2-methoxy- benzylamide,

(1aS,δaR)-1 ,1 ,2-trimethyl-i ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-chloro-4-(2-fluoro-ethoxy)- benzylamide,

(1 aS,δaR)-1 ,1 ,2-trimethyl-1 ,1 a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(2-fluoro-ethoxy)-benzylamide,

(1 aS,δaR)-1 ,1 ,2-trimethyl-1 ,1 a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxyIic acid 4-(3-fluoro-propoxy)-2-methoxy- benzylamide,

(1aS,δaR)-1 ,1 ,2-trimethyl-1 ,1 a,δ,δa-tetrahydro-3-thia- cyciopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-propoxy-benzylamide, (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-isopropoxy-benzylamide,

(1 aS,5aR)-1 ,1 ,2-trimethyl-1 ,1 a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-isobutoxy-2-methoxy-benzylamide, 5 (1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-3-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(6-hydroxy-hexyioxy)-2-methoxy- benzylamide,

(laS.δaRH .I ^rimethyM .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 4-(3-hydroxy-2-hydroxymethyl-propoxy)- 0 3,5-dimethyl-benzylamide,

(laS.δaRH.I^-trimethyM .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-(pyridin-3-ylmethoxy)- benzylamide,

(1aS,δaR)-1 ,1 ,2-trimethyl-1 ,1a,δ,δa-tetrahydro-3-thia- δ cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-(pyridin-4-ylmethoxy)- benzylamidθ,

(laS.δaR^I .I ^-trimethyl-i .ia.δ.δa-tetrahydro-S-thia- cyclopropa[a]pentalene-4-carboxyiic acid (pyridin-2-ylmethyl)-amidθ,

3-(2-methoxy-phenyl)-1 -((1 aS,δaR)-1 ,1 ,2-trimethyl-1 ,1 a,δ,δa-tetrahydro-3- 0 thia-cyclopropa[a]penta-len-4-yl)-propan-1 -one,

3-[4-((S)-2,3-dihydroxy-propoxy)-2-methoxy-phenyl]-1-((1aS,δaR)-1 ,1 ₎2- trimethyl-1 ,1 a.δ.δa-tθtrahydro-S-thia-cyclopropatalpentalen^-yD-propan-i -one,

3-[4-(2-hydroxy-ethoxy)-2-methoxy-phenyl]-1 -((1 aS,δaR)-1 ,1 ,2-trimethyl- 1 ,1 a,δ,δa-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1 -one, δ 3-[4-((S)-2,3-dihydroxy-propoxy)-3,δ-dimethyl-phenyl]-1-((1aS,δaR)-1 ,1 ,2- trimethyl-1 ,1 a,δ,δa-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1 -one,

3-[4-((R)-2,3-dihydroxy-propoxy)-3,δ-dimethyl-phenyl]-1 -((1 aS,δaR)-1 ,1 ,2- trimethyl-i .ia.δ.δa-tetrahydro-S-thia-cyclopropa^pentalen^-yO-propan-i-one,

3-[4-(2-hydroxy-ethoxy)-3,δ-dimethyl-phenyi]-1 -((1 aS,δaR)-1 ,1 ,2-trimethyl- 0 1 ,1 a.δ.δa-tetrahydro-S-thia-cyclopropatalpentalen^-ylJ-propan-i -one,

3-[4-(2-(R/S)-hydroxy-propoxy)-3,δ-dimethyl-phenyl]-1 -(1 ,1 ,2-trimethyl- 1 ,1 a,δ,δa-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1 -one, 3-[4-(2-(2-fluoroethoxy)-3,5-dimethyl-phenyI]-1-(1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one,

3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(1 ,1 ,2-trimethyl-1 ,1a,5,5a- tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one,

and pharmaceutically acceptable salts thereoff.

62. A thiophene derivative according to any of claims 1 to 61 for use as a medicament.

63. A process for the manufacture of compounds as claimed in any one of claims 1 to 61 , which process comprises

a) reacting the compound of Structure 9 or 10 with 2-mercaptoacetic acid in the presence of a base;

Structure 9 Structure 10

b) reacting a compound of Structure 8 with an non-aqueous base;

Structure 8

c) reacting a compound of Structure 7 with an aqueous base;

Structure 7

d) reacting a compound of Structure 1 with a compound of Structure 2 in the presence of activating agents,

Structure 2

e) reacting a compound of Structure 1 with N,O-dimethyIhydroxylamine in the presence of an activating agent;

f) reacting a compound of Structure 3 with a Grignard reagent of Structure 4;

Structure 4

g) reacting a compound of Structure 1 with methyllithium;

h) reacting a compound of Structure 5 with a compound of Structure 6 in the presence of a base;

Structure 5 Structure 6

i) reacting a compound of Structure 11 with hydrogen in the presence of a hydrogenation catalyst.

64. Pharmaceutical compositions containing a compound according to any of claims 1 to 61 and usual carrier materials and adjuvants for the prevention or treatment of disorders associated with an activated immune system.

65. Pharmaceutical compositions containing a compound according to any of claims 1 to 61 and usual carrier materials and adjuvants for the prevention or treatment of organ transplant rejection or graft-versus-host diseases.

66. Pharmaceutical compositions containing a compound according to any of claims 1 to 61 and usual carrier materials and adjuvants for the prevention or treatment of diseases or disorders associated with an activated immune system selected from the group consisting of autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; Hashimoto's thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; posterior uveitis; uveitis associated with Behcet's disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post¬ infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; atopic dermatitis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerative keratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac diseases; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; arteriosclerosis; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture's syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; multiple myositis; Guillain-Barre syndrome; Meniere's disease; polyneuritis; multiple neuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa; Huntington's chorea; Sydenham's chorea; myocardosis; scleroderma; Wegener's granuloma; Sjogren's syndrome; adiposis; eosinophilic fascitis; lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis; male pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezary's syndrome; chronic adrenal insufficiency; Addison's disease; ischemia-reperfusion injury of organs which occurs upon preservation; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal insufficiency; chronic renal insufficiency; lung cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemias; lymphoma; psoriasis; pulmonary emphysema; cataracta; siderosis; retinitis pigmentosa; senile macular degeneration; vitreal scarring; corneal alkali burn; dermatitis erythema; ballous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; carcinogenesis; metastasis of carcinoma; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial liver resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepatic failure; late-onset hepatic failure; "acute-on-chronic" liver failure.

67. Pharmaceutical compositions according to claim 66, for the treatment of prevention of disorders which are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; prevention of psoriasis; Crohn's disease; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and metastasis of carcinoma.

68. Use of one or more compounds of the General Formula (I) in claim 1 for the prevention or treatment of diseases or disorders associated with an activated immune system.

69. Use of one or more compounds of the General Formula (II) in claim 21 for the prevention or treatment of diseases or disorders associated with an activated immune system.

70. Use of one or more compounds of the General Formula (III) in claim 41 for the prevention or treatment of diseases or disorders associated with an activated immune system.

71. Use of one or more compounds of the General Formula (I) in claim 1 for the prevention or treatment of organ transplant rejection or graft-versus-host diseases.

72. Use of one or more compounds of the General Formula (II) in claim 21 for the prevention or treatment of organ transplant rejection or graft-versus-host diseases.

73. Use of one or more compounds of the General Formula (III) in claim 41 for the prevention or treatment of organ transplant rejection or graft-versus-host diseases.

74. Use of one or more compounds of General Formula (I) according to claim 68 for the treatment or prevention of diseases or disorders which are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; Hashimoto's thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; posterior uveitis; uveitis associated with Behcet's disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; atopic dermatitis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerative keratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac diseases; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; arteriosclerosis; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture's syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; multiple myositis; Guillain-Barre syndrome; Meniere's disease; polyneuritis; multiple neuritis; mononeuritis; radiculopathy; hyperthyroidism;

Basedow's disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa;

Huntington's chorea; Sydenham's chorea; myocardosis; scleroderma; Wegener's granuloma; Sjogren's syndrome; adiposis; eosinophilic fascitis; lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis; male pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezary's syndrome; chronic adrenal insufficiency; Addison's disease; ischemia-reperfusion injury of organs which occurs upon preservation; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal insufficiency; chronic renal insufficiency; lung cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemias; lymphoma; psoriasis; pulmonary emphysema; cataracta; siderosis; retinitis pigmentosa; senile macular degeneration; vitreal scarring; corneal alkali burn; dermatitis erythema; ballous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; carcinogenesis; metastasis of carcinoma; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial liver resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepatic failure; late-onset hepatic failure; "acute-on-chronic" liver failure.

75. Use of one or more compounds of General Formula (II) according to claim 69 for the treatment or prevention of diseases or disorders which are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; Hashimoto's thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; posterior uveitis; uveitis associated with Behcet's disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; atopic dermatitis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerative keratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac diseases; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; arteriosclerosis; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture's syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; multiple myositis; Guillain-Barre syndrome; Meniere's disease; polyneuritis; multiple neuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa;

76. Use of one or more compounds of General Formula (III) according to claim

70 for the treatment or prevention of diseases or disorders which are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; Hashimoto's thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I diabetes; uveitis; posterior uveitis; uveitis associated with Behcet's disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; atopic dermatitis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerative keratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late asthma and airway hyper-responsiveness; bronchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; necrotizing enterocolitis; intestinal lesions associated with thermal burns; coeliac diseases; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; cardiac infarction; arteriosclerosis; aortitis syndrome; cachexia due to viral disease; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture's syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; multiple myositis; Guillain-Barre syndrome; Meniere's disease; polyneuritis; multiple neuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergy sensitivity; cutaneous T cell lymphoma; polyarteritis nodosa; Huntington's chorea; Sydenham's chorea; myocardosis; scleroderma; Wegener's granuloma; Sjogren's syndrome; adiposis; eosinophilic fascitis; lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis; male pattern alopecia or alopecia senilis; muscular dystrophy; pyoderma; Sezary's syndrome; chronic adrenal insufficiency; Addison's disease; ischemia-reperfusion injury of organs which occurs upon preservation; endotoxin shock; pseudomembranous colitis; colitis caused by drug or radiation; ischemic acute renal insufficiency; chronic renal insufficiency; lung cancer; malignancy of lymphoid origin; acute or chronic lymphocytic leukemias; lymphoma; psoriasis; pulmonary emphysema; cataracta; siderosis; retinitis pigmentosa; senile macular degeneration; vitreal scarring; corneal alkali burn; dermatitis erythema; ballous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; carcinogenesis; metastasis of carcinoma; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial liver resection; acute liver necrosis; cirrhosis; alcoholic cirrhosis; hepatic failure; fulminant hepatic failure; late-onset hepatic failure; "acute-on-chronic" liver failure.

77. Use of one or more compounds of General Formula (I) according to claim

68 in which said disorders are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; prevention of psoriasis; Crohn's disease; post- infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and metastasis of carcinoma.

78. Use of one or more compounds of General Formula (II) according to claim

69 in which said disorders are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; prevention of psoriasis; Crohn's disease; post¬ infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and metastasis of carcinoma.

79. Use of one or more compounds of General Formula (III) according to claim

70 in which said disorders are selected from the group consisting of autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; prevention of psoriasis; Crohn's disease; post¬ infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and metastasis of carcinoma.

80. Use of one or more compounds of the General Formula (I) in claim 1 in combination with one or several immunosuppressant compounds for the treatment of disorders associated with an activated immune system.

81. Use of one or more compounds of the General Formula (II) in claim 21 in combination with one or several immunosuppressant compounds for the treatment of disorders associated with an activated immune system.

82. Use of one or more compounds of the General Formula (III) in claim 41 in combination with one or several immunosuppressant compounds for the treatment of disorders associated with an activated immune system.

83. Use of one or more compounds of General Formula (I) according to claim

80 wherein said other immunosuppressant compound is selected from the group consisting of cyclosporin, daclizumab, basiliximab, everolimus, tacrolimus (FK506), azathiopirene, leflunomide, 15-deoxysperguaIin, or other immunosuppressant drugs.

84. Use of one or more compounds of General Formula (II) according to claim

81 wherein said other immunosuppressant compound is selected from the group consisting of cyclosporin, daclizumab, basiliximab, everolimus, tacrolimus (FK506), azathiopirene, leflunomide, 15-deoxyspergualin, or other immunosuppressant drugs.

85. Use of one or more compounds of General Formula (III) according to claim

82 wherein said other immunosuppressant compound is selected from the group consisting of cyclosporin, daclizumab, basiliximab, everolimus, tacrolimus

(FK506), azathiopirene, leflunomide, 15-deoxyspergualin, or other immunosuppressant drugs.

86. A method for the prevention or treatment of disorders associated with an activated immune system comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (I) in claim 1.

87. A method for the prevention or treatment of disorders associated with an activated immune system comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (II) in claim 21.

88. A method for the prevention or treatment of disorders associated with an activated immune system comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (III) in claim 41.

89. A method for the prevention or treatment of disorders of organ transplant rejection or graft-versus-host diseases comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (I) in claim 1.

90. A method for the prevention or treatment of disorders of organ transplant rejection or graft-versus-host diseases comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (II) in claim 21.

91. A method for the prevention or treatment of disorders of organ transplant rejection or graft-versus-host diseases comprising the administration to the patient of a pharmaceutical composition containing at least one compound of the General Formula (III) in claim 41.

92. A method according to claim 86 or 89 by administering to a patient a dose of the thiophene derivative of the General Formula (I) in claim 1 between 0.5 mg and 1000 mg per day.

93. A method according to claim 87 or 90 by administering to a patient a dose of the thiophene derivative of the General Formula (II) in claim 21 between 0.5 mg and 1000 mg per day.

94. A method according to claim 88 or 91 by administering to a patient a dose of the thiophene derivative of the General Formula (III) in claim 41 between 0.5 mg and 1000 mg per day.

95. A method according to claim 92 by administering to a patient a dose of the thiophene derivative of the General Formula (I) between 1 mg and 500 mg per day.

96. A method according to claim 93 by administering to a patient a dose of the thiophene derivative of the General Formula (II) between 1 mg and 500 mg per day.

97. A method according to claim 94 by administering to a patient a dose of the thiophene derivative of the General Formula (III) between 1 mg and 500 mg per day.

98. A method according to claim 92 by administering to a patient a dose of the thiophene derivative of the General Formula (I) between 5 mg and 200 mg per day.

99. A method according to claim 93 by administering to a patient a dose of the thiophene derivative of the General Formula (II) between 5 mg and 200 mg per day.

100. A method according to claim 94 by administering to a patient a dose of the thiophene derivative of the General Formula (III) between 5 mg and 200 mg per day.

101. A process for the preparation of a pharmaceutical composition comprising a compound of the General Formula (I) in claim 1, characterized by mixing one or more active ingredients according to any one of claims 1 to 20, and 61 with inert excipients in a manner known per se.

102. A process for the preparation of a pharmaceutical composition comprising a compound of the General Formula (II) in claim 21, characterized by mixing one or more active ingredients according to any one of claims 21 to 40 with inert excipients in a manner known perse.

103. A process for the preparation of a pharmaceutical composition comprising a compound of the General Formula (III) in claim 41 , characterized by mixing one or more active ingredients according to any one of claims 41 to 60 with inert excipients in a manner known per se.