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A dopamine-modified, bioinspired gellan gum hydrogel (STM-148B) with improved physicochemical and biological characteristics, suitable for minimally invasive cell delivery and retention in the context of cartilage repair, is herein presented. STM-148B's putative game-changing design characteristics include a highly biocompatible, animal-free and chemically defined composition, reproducibility of manufacture and ease of formulation. STM-148B undergoes rapid ionic crossinking by physiologically relevant mono and divalent cations to form stable 3D hydrogels that possess excellent tissue adhesiveness, such that additional fixation aids are rendered superfluous. STM-148B hydrogels maintain viability of mammalian cells and further promote up-regulation of the expression of healthy chondrogenic extracellular matrix markers upon stimulation. STM-148B is currently undergoing pre-clinical safety and efficacy assessment as a medical device for cell delivery and retention focussing on regeneration of hyaline-like cartilage and may represent a valuable addition to the armamentarium of tissue-engineering therapies for treatment of focal cartilage lesions.

7,8-Dichloro-1,2,3,4,5,6-hexahydrobenzo[ f ]quinolin-3-one 10 (R = H) is obtained by reaction of 5,6-dichloro-3,4-dihydronaphthalen-2(1H)-one pyrrolidine enamine 9 with acrylamide and is N-alkylated to 7,8-dichloro-1,2,3,4,5,6-hexahydro-4-propylbenzo[ f ]quinolin-3-one 10 (R = Prn). 6,7,8,9-Tetrahydro-2-methoxy-5H-benzo[7]annulen-6-one 5 (R = H) is converted to N,N-dipropyl(6,7,8,9-tetrahydro-2-methoxy-5H -benzo[7]annulen-6-yl)amine 8 and via the pyrrolidine enamine is reacted with acrylamide to give 2,3,4,5,6,7-hexahydro-9-methoxy-1H-benzo[3,4]cyclohepta[1,2- b]pyridin-3-one 11 (R = H) and 2,3,4,4a,5,6-hexahydro-8-methoxy-1H-benzo[5,6]cyclohepta[1,2- b]pyridin-2-one 12 (R = H). Each of these is N-alkylated to give 11 (R = Prn) and 12 (R = Prn) which are reduced individually to 2,3,4,4a,5,6,7,11b-octahydro-9-methoxy-4-propyl-1H-benzo[3,4] cyclohepta[1,2-b]pyridine 14 (X = Y = H) and 2,3,4,4a,5,6,11,11a-octahydro-8-methoxy-1-propyl-1H-benzo[5,6] cyclohepta[1,2-b]pyridine 15 (X = Y = H) respectively. The hydroxyimino derivative 19 (R = H) of 6,7,8,9-tetrahydro-1,2-dimethoxy-5H-benzo[7]annulen-5-one 18 is methylated to give 19 (R = Me) which with ethyl lithiopropiolate yields ethyl 3-(6,7,8,9-tetrahydro-5-hydroxy-1,2-dimethoxy-6-methoxyimino-5H -benzo[7]annulen-5-yl)propiolate 20 which is catalytically reduced to 21. 6,7,8,9-Tetrahydro-1,2-dimethoxy-6-propionamido-5H-benzo[7] annulen-5-one 22 prepared from 19 (R = H) is reacted with sodium borohydride to give both cis- and trans-6,7,8,9-tetrahydro-5-hydroxy-1,2-dimethoxy-6- propionamido-5H-benzo[7]annulen-5-ol 24 and 23 which are separately reduced by BH3–THF to cis- and trans-6,7,8,9-tetrahydro-5-hydroxy-1,2-dimethoxy-6- propylamino-5H-benzo[7]annulen-5-ol 26 and 25. The latter is reacted with chloroacetyl chloride and thence in two steps gives trans-2,3,4,4a,5,6,7,11b-octahydro-8,9-dimethoxy-4- propylbenzo[6,7]cyclohept[1,2-b][1,4]oxazine 29.

1,2,3,4-Tetrahydro-6- and -7-methoxy-4-oxo-1-(p-tolylsulfonyl)quinolines 3 (R = tosyl, X = 6- and 7-OMe) and 1-ethoxycarbonylmethyl-1,2,3,4-tetrahydro-7-methoxy-4-oxoquinoline 3 (R = CH2CO2Et, X = 7-OMe) have been ring-expanded in two steps to 2,3,4,5-tetrahydro-7- and -8-methoxy-4-oxo-1-(p-tolylsulfonyl)-1H-1-benzazepines 2 (R = tosyl, X = 7- and -8-OMe) and 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-8-methoxy-4-oxo-1H-1-benzazepine 2 (R = CH2CO2Et, X = 8-OMe). Reduction of the oximes gives 4-amino-2,3,4,5-tetrahydro-7-methoxy-1-(p-tolylsulfonyl)-1H-1-benzazepine 1 (R = tosyl, X = 7-OMe), 4-amino-2,3,4,5-tetrahydro-8-methoxy-1H-1-benzazepine 1 (R = H, X = 8-OMe) and 4-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-8-methoxy-1H-1-benzazepine 1 (R = CH2CO2Et, X = 8-OMe). From these, several N-substituted and N,N-disubstituted compounds have been obtained and 3-amino-2,3,4,5-tetrahydro-1-(p-tolylsulfonyl)-1H-1-benzazepine 12 (X = NH2, Y = H) has been made by similar means. Two routes are described to 2,3,4,5-tetrahydro-8-methoxy-5-oxo-1-(p-tolylsulfonyl)-1H-1-benzazepine 13 (R1 = tosyl, R2 = H) which is converted to 2,3,4,5-tetrahydro-8-methoxy-4-methoxyimino-5-oxo-1-(p-tolylsulfonyl)-1H-1-benzazepine 17 (R = Me) and thence to 5-[2-(ethoxycarbonyl)ethynyl]-2,3,4,5-tetrahydro-5-hydroxy-8-methoxy-4-methoxyimino-1-(p-tolylsulfonyl)-1H-1-benzazepine 18 (R = CCCO2Et) and 5-[2-(ethoxycarbonyl)ethyl]-2,3,4,5-tetrahydro-5-hydroxy-8-methoxy-4-methoxyimino-1-(p-tolylsulfonyl)-1H-benzazepine 18 [R = (CH2)2CO2Et]. Reduction of oximino ketone 17 (R = H) in two steps gives both cis- and trans-4-acetamido-2,3,4,5-tetrahydro-5-hydroxy-8-methoxy-1-(p-tolylsulfonyl)-1H-1-benzazepines 22 and 21 which are separately deacetylated and cyclised with ethyl chloroacetate to cis- and trans-2,3,4,4a,5,6,7,11b-octahydro-9-methoxy-3-oxo-7-(p-tolylsulfonyl)[1,4]oxazino[3,2-d][1]benzazepine 26 and 25. By similar methodology cis- and trans-2,3,4,5-tetrahydro-5-hydroxy-8-methoxy-4-propionamido-1-(p-tolylsulfonyl)-1H-1-benzazepines 28 and 27 have been obtained, separated and the latter reduced to trans-2,3,4,5-tetrahydro-5-hydroxy-8-methoxy-4-(n-propylamino)-1-(p-tolylsulfonyl)-1H-1-benzazepine 29. In three steps the latter is converted to trans-2,3,4,4a,5,6,7,11b-octahydro-9-methoxy-4-(n-propyl)-7-(p-tolylsulfonyl)[1,4]oxazino[3,2-d][1]benzazepine 33.

Novel 5-aryloxy substituted 3-phenyl-1,3,4-oxadiazol-2(3H)-ones were prepared and identified as potent inhibitors of FAAH. In vitro SAR are discussed. Structural variations of the selected lead compound were explored in order to optimise in vivo efficacy and selectivity.