1. An apparatus for applying an ink image to a receiving material which is adapted to be advanced in a predetermined direction which comprises an ink application mechanism for applying an ink image to a strip of receiving material, said ink application mechanism extending in a direction transverse to the direction of advance of the receiving material and
carrier means for keeping said strip in a predetermined position with respect to the ink application mechanism, said carrier means comprising a carrier plate for carrying said strip, said plate having channels extending in a direction substantially parallel to the direction of advance of the receiving material, wherein the carrier plate is provided with holes and air displacement means operatively associated with said holes for drawing air via said holes away from the space between the carrier plate and the strip of receiving material lying on the carrier plate
said holes appear in the carrier plate at least in a portion thereof in which a strip of the receiving material is maintained in a predetermined position with respect to the ink application mechanism.
2. The apparatus according to claim 1, wherein each channel has a width of between about 15 and 20 mm.
3. The apparatus according to claim 1, wherein the channels have channel walls which define an acute angle with a top surface of the carrier plate.
4. The apparatus according to claim 1, wherein the holes, when considered in the direction of advance of the receiving material, are situated predominantly at an upstream edge portion of the carrier plate.
5. The apparatus according to claim 1, wherein the holes are disposed in ribs which form the channels and lead into the top surface of each rib.
6. The apparatus according to claim 5, wherein the top surface of each rib is formed with a groove which extends from a hole provided in said rib to a downstream edge of the carrier plate.
7. The apparatus according to claim 1, wherein the carrier plate contains edge zones where side edges of a web of receiving material for processing may come into contact with the carrier plate, with the holes, when considered in the direction of advance of the receiving material, extending over the entire length of the carrier plate.
8. The apparatus according to claim 7, wherein the holes in the edge zones are formed in the channel walls which are situated on that side of the channels which is closest to the middle of the carrier plate.
9. The apparatus according to claim 8, wherein partitions are disposed in each channel in the edge zones at regular intervals from one another and extend transversely over the channel and their top is situated beneath the top edge of said channel.
10. The apparatus according to claim 9, wherein gutters are formed on the upstream and downstream sides of the edge zones and extend transversely with respect to the direction of advance of the receiving material and are in open communication with the channels in said edge zones.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1-15. (canceled)
16. A compound of Formula I
wherein:
R1, R2 denote H, Hal, CF3, OCF3, CN, or NO2,
W denotes CH or N,
Ra is Ar, Het, cycloalkyl having 3-7 atoms, A or NA2,
Rb is H, A, Hal, CF3, OCF3, OR3, CN, NO2, (CH2)nN(R3)2, OA, (CH2)nSO2N(R3)2, (CH2)nNR3SO2A, (CH2)nN(SO2A)2, NR3CON(R3)2, NR3COA or (CH2)nSO2R3,
Re denotes A, COA, CSA, COOA, CSOA, CON(R3)2 or CSN(R3)2,
A is branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, H-atoms may be replaced by Hal, or 1 to 7H-atoms may be replaced by OR3, CN or N(R3)2 and wherein one or more, preferably 1 to 7 non-adjacent CH2-groups may be replaced by O, NR3 or S andor by \u2014CH\u2550CH\u2014 or \u2014C\u2261C\u2014 groups, or denotes cycloalkyl or cycloalkylalkylene having 3-7 ring C atoms,
Hal is F, Cl, Br or I,
Ar denotes a monocyclic or bicyclic, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A, CH2OA, CH2N(R3)2, OR3, N(R3)2, NO2, N(SO2Me)2, CN, COOR3, CF3, OCF3, CON(R3)2, NR3COA, NR3CON(R3)2, NR3SO2A, COR3, SO2N(R3)2, SOA or SO2A, phenyl, pyridyl-C(R3)2n\u2014COOR3 andor \u2014OC(R3)2n\u2014CON(R3)2,
Het denotes a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic ring having 1 N andor 1 to 3O andor S atoms which may be unsubstituted or monosubstituted, disubstituted or trisubstituted by Hal, A, \u2014C(R3)2n\u2014Ar, \u2014C(R3)2n-cycloalkyl, CH2OA, CH2N(R3)2, OR3, CF3, OCF3, N(R3)2, N(SO2Me)2, NR3CON(R3)2, NO2, CN, \u2014C(R3)2n\u2014COOR3, \u2014C(R3)2n\u2014CON(R3)2, NR3COA, NR3SO2A, COR3, SO2N(R3)2, SOA, phenyl, pyridyl andor SO2A,
R3 is H or A,
and
n is 0, 1, 2, 3, 4, 5, 6, 7 or 8,
and pharmaceutically acceptable solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.
17. The compound according to claim 16, wherein Ra denotes Ar or Het.
18. The compound according to claim 17, wherein Ar denotes one of the following groups:
wherein X1, and X2 independently of one another F, OCH3, CH3, CF3, OCF3, OH, NO2, CN, andor phenyl.
19. The compound according to claim 17, wherein Het denotes one of the following groups:
wherein X1, and X2 denote independently of one another F, OCH3, CH3, CF3, OCF3, OH, NO2, CN, andor phenyl and R3 has the meaning given in claim 16.
20. The compound according to claim 17, wherein Ar or Het is substituted by methyl, trifluoromethyl or methoxy.
21. The compound according to claim 16, said compound being selected from:
and pharmaceutically acceptable solvates, tautomers, salts and stereoisomers thereof, including mixtures thereof in all ratios.
22. The compound according to claim 16, wherein said compound has an EC50 in GTP\u03b3S for the binding to the S1P1 receptor of less than about 5 \u03bcM.
23. A process for the preparation of a compound according to claim 16 comprising reacting:
a) a compound of formula A
wherein W, R, Ra and Rb have the meanings given above, and T is OH, or a leaving group, or the product of the reaction of isobutyl chloroformate with formula A, wherein T is OH; and
b) a compound of formula B
wherein R1, R2 and Rc have the meanings given in claim 16 in the presence of a base, or in case T is OH, in the presence of a suitable condensation reagent, and cyclizing the product,
and optionally converting the compound into a salt.
24. A pharmaceutical composition comprising at least one compound according to claim 16 and an excipient or adjuvant.
25. The pharmaceutical composition according to claim 24, further comprising at least one further active ingredient.
26. A kit consisting of separate packs of:
(a) an effective amount of a compound according to claim 16, and
(b) an effective amount of an additional active ingredient.
27. A method for the treatment andor prophylaxis of a sphingosine 1-phosphate associated disorder comprising the administration of a composition according to claim 24 to an individual having said disorder.
28. The method according to claim 27, wherein the sphingosine 1-phosphate-(1) associated disorder is an autoimmune disorder or condition associated with an overactive immune response.
29. The method according to claim 27, wherein said disorder is an immuneregulatory abnormality.
30. The method according to claim 29, wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: systemic lupus erythematosis, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener’s granulomatosis, ichthyosis, Graves opthalmopathy, bone marrow, organ transplant rejection or graft-versus-host disease, transplantation of organs or tissue, graft-versus-host diseases brought about by transplantation, autoimmune syndromes including, rheumatoid arthritis, Hashimoto’s thyroiditis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrhoeic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia greata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet’s disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren’s ulcer, scleritis, Graves’ opthalmopathy, 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, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture’s syndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre syndrome, Meniere’s disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow’s disease, 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, photoallergic sensitivity, cutaneous T cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener’s granuloma, Sjogren’s syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea dentis, glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair germination andor promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary’s syndrome, Addison’s disease, ischemia-reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and hypobaropathy, disease caused by histamine or leukotriene-C4 release, Behcet’s disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis, non-Anon-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, fulminant hepatic failure, late-onset hepatic failure, \u201cacute-on-chronic\u201dliver failure, augmentation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, and chronic bacterial infection and asthma.