WO2005123677A1

WO2005123677A1 - 4-carbonyl substituted 1,1,2-trimethyl-1a,4,5,5a-tetrahydro-1h-4-aza-cyclopropa'a!pentalene derivatives as agonists for the g-protein-coupled receptor s1p1/edg1 and immunosuppressive agents

Info

Publication number: WO2005123677A1
Application number: PCT/EP2005/006348
Authority: WO
Inventors: Martin Bolli; Daniel Bur; Martine Clozel; Walter Fischli; David Lehmann; Boris Mathys; Claus Mueller; Olivier Nayler; Michael Scherz; Thomas Weller
Original assignee: Actelion Pharmaceuticals Ltd
Priority date: 2004-06-16
Filing date: 2005-06-14
Publication date: 2005-12-29

Abstract

The invention relates to novel pyrrole compounds of the formula (I) wherein A represents -CH2CH2-, -CH=CH-, or -NH-CH2; Ar represents phenyl; mono-, di-, or tri-substituted phenyl, wherein the substituents are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkoxy, 1-glyceryl, 2-glyceryl, cycloalkyl, mono- or di-lower alkylamino, methylenedioxy, ethylenedioxy, trifluoromethyl and trifluoromethoxy; or unsubstituted mono- or di-substituted 2-, 3- or 4-pyridyl, wherein the substituents are independently selected from lower alkoxy and hydroxy-lower alkoxy. The present invention provides novel compounds of formulae (I), (II) and (III) that are agonists for the G protein-coupled receptor S1P1/EDG1 and have a powerful and long-lasting immunosuppressive effect which is achieved by reducing the number of cirulating and infiltrating T- and B-lymphocytes, whitout affecting their maturation, memory or expansion. The reduction of circulating T-/B-lymphocytes as a result of S1P1/EDG1 agonism, possibly in combination with the observed improvement of endothelial cell layer function associated with S1P1/EDG1 activation, makes such compounds useful to treat uncontrolled inflammatory disease and to improve vascular functionality.

Description

4 -CARBONYL SUBSTITUTED 1 , 1 , 2 -TRIMETHYL-1A, 4 , 5 , 5A-TETRAHYDRO-1H-4 -AZA-CYCLOPROPA ' A I PENTALENE DERIVATIVES AS AGONISTS FOR THE G-PROTEIN-COUPLED RECEPTOR SlPl /EDGl AND IMMUNOSUPPRESSIVE AGENTS

5 Field of the invention

The present invention relates to S1 P1/EDG1 receptor agonists of 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 10 the preparation of the compounds, pharmaceutical compositions containing compounds of the Formula (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.

15 Background of the invention

The human immune system is designed to defend the body against foreign microorganisms and substances that cause infection or disease. Complex regulatory mechanisms ensure that the immune response is targeted against the intruding

20 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

25 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. Alternative treatments include agents that activate

30 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 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 P17EDG1 receptor are known in the art and are published in e.g.: Hla, T., and Maciag, T. J. Biol Chem. 265 (1990), 9308-9313; WO 91/15583 published 17 October 1991 ; WO 99/46277 published 16 September 1999. The potency and efficacy of the compounds of Formulae (I), (II) and (III) are assessed using a GTPγS assay to determine EC₅o values and by measuring the circulating lymphocytes in the rat after oral administration, respectively (see Examples).

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.

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, π-propyl, /^'so-propyl, n-butyl, /so-butyl, sec-butyl, err-butyl, n-pentyl, n-hexyl or n-heptyl. The term lower alkoxy means an R-O group, wherein R is lower alkyl. Preferred examples of lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso- butoxy, sec-butoxy or terf-butoxy.

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

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

The term cycloalkyl alone or in combination, means a saturated cyclic hydrocarbon ring system with 3 to 7 carbon atoms, preferably three to five carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Salts are preferably the pharmaceutically acceptable salts of the compounds of Formula (I), (II) or (III).

Salt-forming groups are groups or radicals having basic or acidic properties. Compounds having at least one basic group or at least one basic radical, for example amino, a secondary amino group not forming a peptide bond or a pyridyl radical, may form acid addition salts, for example with inorganic acids. When several basic groups are present mono- or poly-acid addition salts may be formed.

Compounds having acidic groups, such as a carboxy group or a phenolic hydroxy group, may form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri-(2-hydroxyethyl)-amine, or heterocyclic bases, for example Λ/-ethyl-piperidine or Λ/,Λ/'-dimethylpiperazine. Mixtures of salts are possible. Compounds having both acidic and basic groups can form internal salts.

For the purposes of isolation or purification, as well as in the case of compounds that are used further as intermediates, it is also possible to use pharmaceutically unacceptable salts, e.g. the picrates. Only pharmaceutically acceptable, non-toxic salts may be used for therapeutic purposes, however, and those salts are therefore preferred.

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 a compound of Formula (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., Wiley 1977; P. L. Gould, Salt selection of basic drugs, Int. J. Pharmaceutics 33 (1986), 201-217).

i) The invention relates to novel pyrrole compounds of the Formula (I),

Formula (I)

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

Ar represents phenyl; mono-, di-, or tri-substituted phenyl, wherein the substituents are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkoxy, 1-glyceryl, 2-glyceryl, cycloalkyl, mono- or di-lower alkylamino, methylenedioxy, ethylenedioxy, trifluoromethyl and trifluoromethoxy; or unsubstituted, mono- or di-substituted 2-, 3- or 4-pyridyl, wherein the substituents are independently selected from lower alkoxy and hydroxy-lower alkoxy;

and configurational isomers such as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts and solvents of such compounds, and morphological forms.

The general terms used hereinbefore and hereinafter preferably have, within this disclosure, the following meanings, unless otherwise indicated:

A preferably represents -CH₂CH₂-.

Ar preferably represents phenyl; mono-, di-, or tri-substituted phenyl, wherein the substituents are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkoxy, 1-glyceryl, 2-glyceryl, cycloalkyl, mono- or di-lower alkylamino, methylenedioxy, ethylenedioxy, trifluoromethyl and trifluoromethoxy; most preferably Ar represents phenyl or mono- or di-substituted phenyl, wherein the substituents are independently selected from halogen and lower alkoxy.

Compounds of Formula (II) as described below are preferred. Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.

Any reference hereinbefore or hereinafter to a compound of Formula (I), (II) or (III) is to be understood as referring also to configurational isomers, such as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts and solvents of such compounds, and morphological forms, as appropriate and expedient.

ii) A preferred embodiment of the invention relates to pyrrole compounds according to embodiment i) above, wherein A represents -CH₂CH₂-.

iii) Another preferred embodiment of the invention relates to pyrrole compounds according to embodiment i) above, wherein A represents -CH=CH-.

iv) Another preferred embodiment of the invention relates to pyrrole compounds according to embodiment i) above, wherein A represents -NH-CH₂-.

v) Another preferred embodiment of the invention relates to pyrrole compounds according to any one of embodiments i) to iv) above, wherein Ar represents a mono- or di-substituted phenyl ring, wherein the substituents are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy-lower alkyl, hydroxy- lower alkoxy, 2-glyceryl, 1-glyceryl, methylenedioxy and ethylenedioxy.

vi) Another preferred embodiment of the invention relates to pyrrole compounds according to any one of embodiments i) to v) above, wherein Ar represents a mono- or di-substituted phenyl ring with one substituent in the ortho position.

vii) Another preferred embodiment of the invention relates to pyrrole compounds according to any one of embodiments i) to iv) above, wherein Ar represents a mono- or di-substituted phenyl ring substituted with lower alkoxy. viii) In another preferred embodiment, the invention relates to pyrrole compounds of the Formula (II)

Formula (II)

according to any one of embodiments i) to vii) above.

ix) In further preferred embodiment, the invention relates to pyrrole compounds of the Formula (III)

Formula (III)

according to any one of embodiments i) to vii) above.

Specific pyrrole compounds according to Formula (I) are: 3-Phenyl-1-((1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-4-aza- cyclopropa[a]pentalen-4-yl)-propan-1 -one; 3-(2-Methoxy-phenyl)-1 -((1 aS,5aR)-1 , 1 ,2-trimethyM , 1 a,5,5a-tetrahydro-4- aza-cyclopropa[a]pentalen-4-yl)-propan-1-one; 3-(3-Methoxy-phenyl)-1 -((1 aS,5aR)-1 , 1 ,2-trimethyl-1 , 1 a,5,5a-tetrahydro-4- aza-cyclopropa[a]pentalen-4-yl)-propan-1-one; 3-(4-Methoxy-phenyl)-1 -((1 aS,5aR)-1 , 1 ,2-trimethyl-1 , 1 a,5,5a-tetrahydro-4- aza-cyclopropa[a]pentalen-4-yl)-propan-1 -one; and 3-(2,5-Difluoro-phenyl)-1 -((1 aS,5aR)-1 , 1 ,2-trimethyl-1 , 1 a,5,5a-tetrahydro-4- aza-cyclopropa[a]pentalen-4-yl)-propan-1-one.

The compounds of Formulae (I), (II) and (III) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions 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 Formula (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 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, very especially about 5 mg to about 200 mg, comes into consideration for the treatment of disorders associated with an activated immune system. Depending oh 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 Formula (I), (II) or (III).

The above-mentioned pharmaceutical composition is useful for the prevention and treatment of diseases or 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; photoallergic 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 or disorders to be prevented or treated with the compounds of the present invention are rejection of transplanted organs, tissue or cells and graft-versus-host diseases brought about by transplantation.

Also preferred diseases or disorders to be prevented or treated with the compounds of the present invention are 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. The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a patient a pharmaceutically active amount of a compound of Formula (I), (II) or (III).

Furthermore, compounds of the Formulae (I), (II) and (III) are also useful, in combination with one or several immunomodulating agents, for the prevention or treatment of the diseases and disorders mentioned herein. According to a preferred embodiment of the invention, said agent is selected from the group consisting of immunosuppressants, corticosteroids, NSAID's, cytotoxic drugs, adhesion molecule inhibitors, cytokines, cytokine inhibitors, cytokine receptor antagonists and recombinant cytokine receptors.

In particular, compounds of the Formulae (I), (II) and (III) are useful in combination with one or several agents selected from the group comprising or consisting of cyclosporin, monoclonal antibodies such as daclizumab and basiliximab, everolimus, tacrolimus (FK506), sirolimus, azathioprine, leflunomide, 15- deoxyspergualin, mycophenolate mofetil, methothrexate, and 5-aminosalicylic acid.

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

The present invention also relates to the use of a compound of Formula (I), (II) or (III) for the preparation of a pharmaceutical composition, optionally for use in combination with one or several immunomodulating agents, for the prevention or treatment of the diseases and disorders mentioned herein.

The present invention also relates to pro-drugs of a compound of Formula (I), (II) or (III) that convert in vivo to the compound of Formula (I), (II) or (III) as such. Any reference to a compound of Formula (I), (II) or (III) is therefore to be understood as referring also to the corresponding pro-drugs of the compound of Formula (I), (II) or (III), as appropriate and expedient.

The compounds of 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 Formula (II) 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 Formula (II) are described.

Structure 2

Structure 1

Compounds of the Formula (II) may be prepared by reacting the compound of Structure 1 with a compound of Structure 2 in the presence or absence of a base such as Li-, Na-, or K-HMDS, sodium hydride, potassium tert. butoxide, triethyl amine, etc. in a solvent such as THF, dioxane, DMF, DCM, etc.. In Structure 2, the moiety CO-X represents an activated carboxylic acid derivative, such as a carboxylic acid chloride, a carboxylic acid bromide, a carboxylic acid anhydride e.g. a mixed anhydride with acetic acid, an adduct with an activating agent such as EDC, DCC, etc. or an activated ester such as a pentafluorophenyl ester. The compounds of Structure 2 are either commercially available or are prepared according to procedures known to a person skilled in the art.

Structure 3 Structure 1

The compound of Structure 1 may be prepared by reacting a compound of Structure 3 with an aqueous base such as LiOH, NaOH, or KOH in the presence of one or more additional solvents such as methanol, ethanol, THF, dioxane, etc. at ambient or elevated temperature, followed by decarboxylating the intermediate pyrrole-2-carboxylic acid by treatment with an acid such as TFA in a solvent such as DCM or 1 ,2-dichloroethane.

Structure 4 Structure 3

The compounds of Structure 3 may be prepared by reacting the compound of Structure 4 with an aminomalonic acid ester or its hydrochloride salt in the presence of a base such as sodium methylate, sodium ethylate, etc. in a solvent such as methanol, ethanol, THF, DMF or mixtures thereof.

The compound of Structure 4 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 5

The compounds of Formula (I) may be prepared in analogy to the reaction sequence outlined above for the compounds of Formula (II) by starting from the racemic form of the compound of Structure 4 (Structure 5). The racemic form of Structure 4 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 Formula (III) may be obtained by resolving the racemic mixture of a compound of Formula (I) or one of its precursors (e.g. Structure 5) 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 °C. 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 (used hereinbefore or hereinafter) abs. absolute aq. aqueous

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(s)

HMDS hexamethyldisilazane

HPLC high performance liquid chromatography

LC-MS liquid chromatography - mass spectrometry min minute(s) prep. Preparative

TFA trifluoroacetic acid

THF tetrahydrofuran rt room temperature sat. saturated

S1 P sphingosine 1 -phosphate t_R retention time

TLC thin layer chromatography

(1aS,5aR)-1,1,2-Trimethyl-1a,4,5,5a-tetrahydro-7H-4-aza-cyclopropa[a]- pentalene (Pyrrole template, Structure 1)

a) To a solution of diethyl aminomalonate hydrochloride (1.17 g, 5.5 mmol) in abs. ethanol (20 mL), is added a 1 M solution of sodium in abs. ethanol (11 mL, 11 mmol). The mixture is stirred at rt for 15 min before (1S, 5R)-2-(1-chloro-(E)- ethylidene)-6,6-dimethyl-bicyclo[3.1.0]hexan-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) (923 mg, 5.0 mmol) is added. Stirring is continued for 30 min, the mixture is diluted with water (75 mL) and extracted with DCM (100 mL). The organic extract is dried over MgS0₄ and evaporated to give crude (1aS,5aR)-1 ,1 ,2-trimethyl- 1 a,4,5,5a-tetrahydro-1 H-4-aza-cyclopropa[a]pentalene-3-carboxylic acid ethyl ester (1.10 g) as a yellow oil. An analytical sample is purified by prep. HPLC to furnish (1aS,5aR)-1 ,1 ,2-trimethyl-1a,4,5,5a-tetrahydro-1 H-4-aza-cyclo- propa[a]pentalene-3-carboxylic acid ethyl ester as a pale yellow oil. LC-MS: tR = 1.03 min, [M+1]⁺ = 234.11. ¹H NMR (CDCI₃): δ 8.41 (s br, 1H), 4.27 (q, J = 7.6 Hz, 2H), 2.81 (dd, J = 7.0, 17.0 Hz, 1 H), 2.49 (d, J = 17.0 Hz, 1 H), 2.29 (s, 3H), 1.86 (dd, J = 1.2, 6.4 Hz, 1 H), 1.67-1.60 (m, 1 H), 1.34 (t, J = 7.6 Hz, 3H), 1.10 (s, 3H), 0.61 (s, 3H).

b) To a solution of the above (1aS,5aR)-1 ,1 ,2-trimethyl-1a,4,5,5a-tetrahydro-1 H-4- aza-cyclopropa[a]pentalene-3-carboxylic acid ethyl ester (1.17 g, 5.0 mmol) in ethanol (70 mL) is added a 2 N aq. LiOH solution. The reaction mixture is stirred at 75°C for 16 h. The mixture is cooled to rt, diluted with water (250 mL), acidified by adding 10% aq. citric acid (75 mL) and extracted with DCM (125 mL). The organic extract is treated with TFA (1.5 mL) and allowed to stand at rt for 15 min before it is washed with sat. aq. NaHC0₃ (100 mL), dried over Na₂SO and evaporated. The crude product is purified by HPLC (X-terra RP C18, as above, gradient of acetonitrile in water containing 0.5% sat. aq. ammonium hydroxide) to give (1aS,5aR)-1 ,1 ,2-trimethyl-1a,4,5,5a-tetrahydro-1 H-4-aza-cyclopropa[a]pentalene (250 mg) as a rose-coloured solid. LC-MS: t_R = 0.65 min, [M+1]⁺ = 162.24. ¹H NMR (CDCI₃): δ 7.38 (s br, 1 H), 6.32 (s, 1 H), 2.80 (dd, J = 7.0, 16.4 Hz, 1 H), 2.45 (d, J = 15.8 Hz, 1 H), 2.05 (s, 3H), 1.88-1.82 (m, 1 H), 1.62-1.54 (m, 1 H), 1.08 (s, 3H), 0.60 (s, 3H).

Example 1

A mixture of 3-phenyl-propionic acid (150 mg, 1 mmol) and phosphorus trichloride

(55 mg, 0.4 mmol) is allowed to stand at rt for 20 h. Of this mixture, an aliquot of 3- phenyl-propionic acid (0.31 mmol) is added to a solution of (1aS,5aR)-1 ,1 ,2- trimethyl-1a,4,5,5a-tetrahydro-1 H-4-aza-cyclopropa[a]pentalene (25 mg, 0.154 mmol) and NaHMDS (230 μL of a 2 M solution in THF, 0.465 mmol) in dioxane (1 mL). The reaction mixture is allowed to stand at rt for 15 min before it is directly purified by prep. HPLC (X-terra RP C18, as above, gradient of acetonitrile in water containing 0.5% sat. aq. ammonium hydroxide) to yield 3-phenyl-1-((1aS, 5aR)- 1 , 1 ,2-trimethyl-1 , 1 a,5,5a-tetrahydro-4-aza-cyclopropa[a]pentalen-4-yl)-propan-1 ■ one (5.5 mg) as a colourless oil. LC-MS: t_R = 1.15 min, [M+1]⁺ = 294.12.

Example 2

A mixture of 3-(2-methoxyphenyl)propionic acid (890 mg, 4.9 mmol) and phosphorus trichloride (247 mg, 1.8 mmol) is allowed to stand at rt for 20 h before it is added to a solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1a,4,5,5a-tetrahydro-1 H-4- aza-cyclopropa[a]pentalene (360 mg, 2.23 mmol) and NaHMDS (3.35 mL of a 2 M solution in THF, 6.7 mmol) in dioxane (7.5 mL). The reaction mixture is allowed to stand at rt for 10 min. The mixture is directly subjected to prep. HPLC purification (X-terra RP C18, as above, gradient of acetonitrile in water containing 0.5% sat. aq. ammonium hydroxide) to yield 3-(2-methoxy-phenyl)-1-((1aS,5aR)-1 ,1 ,2- trimethyl-1 ,1a,5,5a-tetrahydro-4-aza-cyclopropa[a]pentalen-4-yl)-propan-1-one (100 mg) as a brownish oil. LC-MS: t_R = 1.16 min, [M+1]⁺ = 324.11 ; ¹H NMR (CDCI₃): δ 7.23-7.14 (m, 2H), 6.91-6.77 (m, 3H), 3.83 (s, 3H), 3.06-2.91 (m, 5H), 2.74 (d, J = 17.6 Hz, 1 H), 1.99 (s, 3H), 1.76 (dd, J = 1.8, 6.4 Hz, 1 H), 1.65-1.58 (m, 1 H), 1.08 (s, 3H), 0.63 (s, 3H).

Alternative route: A mixture of pentafluorophenol (1.85 g, 10 mmol), 3-(2- methoxyphenyl)propionic acid (1.80 g, 10 mmol) and DCC (2.15 g, 10.5 mmol) in acetonitrile (40 mL) is stirred at rt for 45 min before it is diluted with diethyl ether (250 mL). The precipitate is removed by filtration and the filtrate is evaporated to yield 3-(2-methoxy-phenyl)-propionic acid pentafluorophenyl ester (3.40 g) as a white solid. A solution of (1aS,5aR)-1 ,1 ,2-trimethyl-1a,4,5,5a-tetrahydro-1 H-4-aza- cyclopropa[a]pentalene (1.20 g, 7.5 mmol) in abs. THF (40 mL) is treated with NaHMDS (8 mL of a 1 M solution in THF, 8 mmol). After stirring the mixture at rt for 2 min, a solution of the above 3-(2-methoxy-phenyl)-propionic acid pentafluorophenyl ester (3.40 g, 9.82 mmol) in THF (40 mL) is added. The mixture is allowed to stand at rt for 5 min, is diluted with water (500 mL) and extracted twice with DCM (120 mL). The organic extracts are dried over Na₂S0₄ and the solvent is evaporated. The crude product is purified by prep. HPLC (X-terra RP C18, 100x30 mm, 5 μm particle size, gradient of acetonitrile in water containing 0.5% sat. aq. ammonium hydroxide) to furnish 3-(2-methoxy-phenyl)-1- ((1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-4-aza-cyclopropa[a]pentalen-4-yl)- propan-1-one (830 mg) as a brownish oil with identical analytical data as the material prepared above.

Example 3

3-(3-Methoxy-phenyl)-1 -((1 aS,5aR)-1 , 1 ,2-trimethyl-1 , 1 a,5,5a-tetrahydro-4-aza- cyclopropa[a]pentalen-4-yl)-propan-1-one (5.1 mg) is obtained as a colourless oil following the procedure given in Example 1 and starting from (1aS,5aR)-1 ,1 ,2- trimethyl-1a,4,5,5a-tetrahydro-1 H-4-aza-cyclopropa[a]pentalene (25 mg, 0.155 mmol) and 3-(3-methoxyphenyl)propionic acid (56 mg, 0.31 mmol). LC-MS: t_R = 1.15 min, [M+1]⁺ = 324.13.

Example 4

3-(4-Methoxy-phenyl)-1 -((1 aS,5aR)-1 , 1 ,2-trimethyl-1 , 1 a,5,5a-tetrahydro-4-aza- cyclopropa[a]pentalen-4-yl)-propan-1-one (5.1 mg) is obtained as a colourless oil following the procedure given in Example 1 and starting from (1aS,5aR)-1 ,1 ,2- trimethyl-1a,4,5,5a-tetrahydro-1 H-4-aza-cyclopropa[a]pentalene (25 mg, 0.155 mmol) and 3-(4-methoxyphenyl)propionic acid (56 mg, 0.31 mmol). LC-MS: t_R = 1.15 min, [M+1]⁺ = 324.12.

Example 5

3-(2,5-Difluorophenyl)-1 -((1 aS,5aR)-1 , 1 ,2-trimethyl-1 , 1 a,5,5a-tetrahydro-4-aza- cyclopropa[a]pentalen-4-yl)-propan-1-one (5.1 mg) is obtained as a colourless oil following the procedure given in Example 1 and starting from (1aS,5aR)-1 ,1 ,2- trimethyl-1a,4,5,5a-tetrahydro-1 H-4-aza-cyclopropa[a]pentalene (25 mg, 0.155 mmol) and 3-(2,5-difluorophenyl)propionic acid (58 mg, 0.31 mmol). LC-MS: t_R =

1.16 min, [M+1]⁺ = 330.14.

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

a) To a suspension of (+)-3-carene (82 g, 0.6 mol) and CaC0₃ (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. Na₂S₂O (2x500 mL), and dried over Na₂S0₄. 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 (1 S,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, 1 H), 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 Ag₂0 (156.4 g, 0.675 mol). The resulting suspension 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 Na₂S0 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 MgS0₄ and the solvent is removed in vacuo to furnish acetic acid (1S,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 MgSO 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 (1 S,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 (s, 3H).

Example 6: GTPγS assay to determine EC₅₀ 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 NaCl (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-GTPγS (Amersham Biosciences, SJ1320). The pH is 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-GTPγS, 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 Na₂HPO₄/NaH₂PO (70%/30%), dried, sealed at the bottom and, after addition of 25 μl MicroScint20 (Packard Biosciences, order no. 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.

The EC₅o values of the compounds of Examples 1 to 5 determined as described above are in the range of 20 to 500 nM.

Table 1 shows the EC₅₀ value of Example 2 determined as described above:

Table 1 : Compound of Example EC50 [nM] 2 31

Example 7: Assessment of In Vivo Efficacy

The efficacy of the compounds of Formulae (I), (II) and (III) is assessed by measuring the circulating lymphocytes after oral administration of 30 mg/kg of a compound of Formula (I), (II) or (III) 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 a compound 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 2 -47 ± 5% (p<0.001)

Claims

1. A compound selected from the group consisting of pyrroles of the Formula (I),

Formula (I) wherein

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

Ar represents phenyl; mono-, di-, or tri-substituted phenyl, wherein the substituents are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkoxy, 1-glyceryl,

2-glyceryl, cycloalkyl, mono- or di-lower alkylamino, methylenedioxy, ethylenedioxy, trifluoromethyl and trifluoromethoxy; or unsubstituted, mono- or di-substituted 2-, 3- or 4-pyridyl, wherein the substituents are independently selected from lower alkoxy and hydroxy-lower alkoxy;

and optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts and solvents of such compounds, and morphological forms.

A compound according to claim 1 wherein A represents -CH₂CH₂-.

3. A compound according to claim 1 wherein A represents -CH=CH-.

4. A compound according to claim 1 wherein A represents -NH-CH₂-.

5. A compound according to any one of claims 1 to 4 wherein Ar represents a mono- or di-substituted phenyl ring, wherein the substituents are independently selected from halogen, lower alkyl, lower alkoxy, hydroxy-lower alkyl, hydroxy- lower alkoxy, 2-glyceryl, 1-glyceryl, methylenedioxy and ethylenedioxy.

6. A compound according to any one of claims 1 to 5 wherein Ar represents a mono- or di-substituted phenyl ring with one substituent in the ortho position.

7. A compound according to any one of claims 1 to 4 wherein Ar represents a mono- or di-substituted phenyl ring substituted with lower alkoxy.

8. A compound of the Formula (II)

Formula (II)

according to any one of claims 1 to 7.

9. A compound of the Formula (III)

Formula (III)

according to any one of claims 1 to 7.

10. A compound according to claim 1 selected from the group consisting of: 3-Phenyl-1-((1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-4-aza- cyclopropa[a]pentalen-4-yl)-propan-1-one; 3-(2-Methoxy-phenyl)-1-((1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-4- aza-cyclopropa[a]pentalen-4-yl)-propan-1 -one; 3-(3-Methoxy-phenyl)-1-((1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-4- aza-cyclopropa[a]pentalen-4-yl)-propan-1-one; 3-(4-Methoxy-phenyl)-1-((1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-4- aza-cyclopropa[a]pentalen-4-yl)-propan-1 -one; and 3-(2,5-Difluoro-phenyl)-1-((1aS,5aR)-1 ,1 ,2-trimethyl-1 ,1a,5,5a-tetrahydro-4- aza-cyclopropa[a]pentalen-4-yl)-propan-1-one.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier material.

12. A compound according to any one of claims 1 to 10, or composition according to claim 11 , for use as a medicament.

13. Use of a compound according to any one of claims 1 to 10 for the preparation of a pharmaceutical composition for the prevention or treatment of diseases or disorders associated with an activated immune system.