Background of the Invention Nitric oxide is produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes-constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time. two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs. an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been particularly implicated in the pathogenesis of inflammatory diseases. Regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states (J. E. Macdonald, Ann. Rep.

Med. Chem., 1996,31,221-230).

Considerable effort has been expended in efforts to identify compounds that act as specific inhibitors of one or more isoforms of the enzyme nitric oxide synthase. The use of such compounds in therapy has also been widely claimed. One group of these compounds incorporate within their structures a cyclic amidine moiety. Thus, WO 95/11231 discloses compounds of general formula: WO 96/33175 discloses compounds of general formula: WO 96/35677 discloses compounds of general formula:

and WO 97/16430 and US 5,629,322 describe cyclic amidines of general formula: and

respectively.

The compounds of the present invention are distinguished from those of the prior art by virtue of the nature of the particular substituents attached to the cyclic amidine ring.

Disclosure of the invention According to the present invention, there is provided a compound of formula (I) wherein: A, B and D are independently selected from C, N, O and S, at least one of A. B and D being N, O or S, so as to form a 5-membered heterocyclic aromatic ring; X represents CHo, NR, O or S (O) m ; or represents

R1 and representhydrogen,halogen,C1to6alkyl,NO2,OH,OR7,CN,independe ntly COoR, NR R or CONR R R3, R4, R5 and R6 independently represent hydrogen, C 1 to 8 alkyl. C 2 to 8 alkenyl, C 2 to 8 alkynyl, phenyl, or a 5-membered or 6-membered heterocyclic aromatic ring; said phenyl or a 5-membered or 6-membered heterocyclic aromatic ring being optionally substituted by halogen, C 1 to 6 alkyl or C 1 to 6 alkoxy; and said alkyl, alkenyl and alkynyl groups being optionally substituted by halogen, OH.

1to6alkoxy,aryl,aryloxy,aryl-C1to6-alkoxy,C1to6alkyl-S(O) m,NR8R9,C aryl-S (O) m, aryl-C 1 to 6 alkyl-S (O) m, wherein aryl represents phenyl, naphthyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl or a 5-membered or 6-membered heterocyclic aromatic ring optionally substituted by halogen, C 1 to 6 alkyl or C 1 to 6 alkoxy, OH, CN, NH2;NO2or or R4and can be joined together so as to form a 3 to 7 membered saturated ring optionally incorporating a nitrogen atom substituted by R or an oxygen atom; or R and R can be joined together so as to form a 3 to 7 membered saturated ring optionally incorporating a nitrogen atom substituted by R8 or an oxygen atom: or either of R4mayor be joined together with either of R5 or R6 so as to form a 3 to 7 membered saturated ring optionally nitrogena atom substituted by R8 or an oxygen atom; or, when X represents NR. R and R may together represent O;

R8 and R9 are independently selected from hydrogen, C 1 to 8 alkyl, C 1 to 6 alkylcarbonyl, C 1 to 6 alkylsulphonyl, aminocarbonyl, C 1 to 6 alkylaminocarbonyl, C 1 to 6 alkoxycarbonyl, aryl, arylcarbonyl, arylsulphonyl, arylaminocarbonyl and 3-arylacryloyl: wherein aryl represents phenyl, naphthyl, indolyl or a 5-membered or 6-membered heterocyclic aromatic ring optionally substituted by halogen. C 1 to 6 alkyl or C 1 to 6 alkoxy, OH, CN, NO,) or NH2; R, R and R independently represent hydrogen or C 1 to 6 alkyl; R12 represents hydrogen or CO,) R 13 wherein R13 represents C1 to 6 alkyl, 2, 2, 2- trichloroethyl or benzyl; m represents an integer 0,1 or 2; or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.

The compounds of formula (1) and their pharmaceutically acceptable salts, enantiomers, racemates and tautomers have the avantage that they are inhibitors of the enzyme nitric oxide synthase (NOS). In particular, the compounds of formula (1) and their pharmaceutically acceptable salts, enantiomers, racemates and tautomers have the advantage that they are inhibitors of the inducible isoform of the enzyme nitric oxide synthase (iNOS).

The invention further provides a process for the preparation of compounds of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.

According to the invention there is also provided a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof, for use as a medicament.

Another aspect of the invention provides the use of a compound of formula (1) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof, in the

manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial.

A more particular aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory disease.

According to the invention, there is also provided a method of treating, or reducing the risk of, diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.

More particularly, there is also provided a method of treating, or reducing the risk of, inflammatory disease in a person suffering from or at risk of, said disease, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.

The compounds of the present invention may also be used advantageously in combination with a second pharmaceutically active substance, particularly in combination with a selective inhibitor of the inducible isoform of cyclooxygenase (COX-2). Thus, in a further aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt. enantiomer, racemate or tautomer thereof, in combination with a COX-2 inhibitor for the treatment of inflammation, inflammatory disease and inflammatory related disorders. And there is also provided a method of treating, or reducing the risk of, inflammation, inflammatory disease and inflammatory related disorders in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof in combination with a COX-2 inhibitor.

Preferably in formula (I), A represents S, and B and D each represent carbon.

Alternatively it is preferred that in formula (I), B represents S, and A and D each represent carbon.

Preferably, X in formula (I) represents O or S.

Particular compounds of the invention include: 2,3-dihydro-thieno [2,3-f] [1,4]thiazepin-5-ylamine; 3-ethyl-2, 3-dihydro-thieno [2. 3-f] [1,4] thiazepin-5-ylamine; (3 S)-3-ethyl-2, 3-dihydro-thieno [2. 3-f] [1,4]thiazepin-5-ylamine; (3R)-3-ethyl-2,3-dihydro-thieno [2,3-f] [1, 4] thiazepin-5-ylamine; (3S)-3-benzyl-2,3-dihydro-thieno [2,3-fol [1, 4] thiazepin-5-ylamine; (3S)-3-phenyl-2,3-dihydro-thieno [2,3-f] 1,4] thiazepin-5-ylamine; (3S)-3-benzyloxymethyl-2,3-dihydro-thieno [2,3-f] [1, 4] thiazepin-5-ylamine; 3-ethyl-2,3-dihydro-thieno [2,3-f] [1,4] oxazepin-5-ylamine; (3S)-1,1-dioxo-3-benzyl-2,3-dihydro-thieno [2,3-f] [1,4] thiazepin-5-ylamine ; 3-propyl-2,3-dihydro-thieno [2, 3-f] [1,4] thiazepin-5-ylamine; 1,1-dioxo-3-propyl-2,3-dihydro-thieno [2, 3-f] [1,4] thiazepin-5-ylamine; 3-propyl-2,3-dihydro-thieno [2,3-f] [1,4] oxazepin-5-ylamine; (3-propan-2-yl)-2,3-dihydro-thieno [2,3-f] [1,4] thiazepin-5-ylamine; 2', 3'-dihydro-spiro [cyclopentane-1,3'-thieno [2,3-f] [1,4] thiazepin]-5'-ylamine ; 2', 3'-dihydro-spiro [cyclopentane-1, 2'-thieno [2,3-f] [1,4] thiazepin]-5'-ylamine; 3-butyl-2,3-dihydro-thieno [2,3-fol [1,4] oxazepin-5-ylamine; 3-but-2,3-dihydro-thieno [2.3-f] [1,4] thiazepin-5-ylamine; (3S)-3-phenyl-2,3-dihydro-thieno [2,3-f] [1,4] oxazepin-5-ylamine; (2S)-2-methyl-2,3-dihydro-thieno [2,3-f] [1,4] oxazepin-5-ylamine; (2R)-2-methyl-2,3-dihydro-thieno [2,3-f] [1,4] oxazepin-5-ylamine; (cis)-4a, 8,8a-hexahydro-thieno [3,2-b] benzoxazepin-10-ylamine ; (3S)-3- (2-methylpropyl)-2,3-dihydro-thieno [2,3-f] [1,4] oxazepin-5-ylamine;

2, 3-dihydro-thieno [2.3-f] [1,4] oxazepin-5-ylamine; 2-ehtyl-2,3-dihydro-thieno[2,3-f][1,4]oxazepin-5-ylamine; (3S)-3-(sec-butyl)-2,3-dihydro-thieno[2,3-f][1,4]oxazepi-5-y lamine; 2- (5-amino-2, 3-dihydro-thieno [2,3-f] oxazepin-3-ylmethoxy)-thiophene-2-carboxylic acid methyl ester; 8-bromo-3-butyl-2,3-dihydro-thieno [2,3-f] [1,4] oxazepin-5-ylamine; 7,8-dihydro-6H-thieno [3,2-c] azepin-4-ylamine; 6-allyl-7, 8-dihydro-6H-furo [3,2-c] azepin-4-ylamine ; 6-allyl-1-methyl-1,6,7,8-tetrahydro-pyrrolo[3,2-c]azepin-4-y lamine; 2-methyl-7,8-dihydro-6H-thiazolo[5,4-c]azepin-4-ylamine; 3-[(2-methylthio)ethyl]-2,3-dihydro-thieno[2,3-f][1,4]oxazep in-5-ylamine; 3-[(2-methylsulfonyl)ethyl]-2,3-dihydro-thieno[2,3-f][1,4]ox azepin-5-ylamine; 6-allyl-5, 6-dihydro-4H-furo [2,3-c] azepin-8-ylamine; 6-propyl-5,6-dihydro-4H-furo[2,3-c]acepin-8-ylamine; 3-allyl-2,3-dihydro-thieno [2, 3-f] [1, 4] oxazepin-5-ylamine ; 2-ethyl-2, 3-dihydro-thieno [3, 4-f] [1,4] oxazepin-5-ylamine ; 6-propyl-7,8-dihydro-6H-furo[2,3-c]azepin-4-ylamine; 6-allyl-7,8-dihydro-6H-thieno[2,3-c]azepin-4-ylamine; 6-propyl-7,8-dihydro-6H-thieno [3,2-c] azepin-4-ylamine ; 3-methyl-2,3-dihydro-thieno[2,3-f][1, 4] thiazepin-5-ylamine; 2-methyl-2,3-dihydro-thieno [2,3-f][1, 4] thiazepin-5-ylamine; (3S)-3-ethyl-2-methyl-2,3-dihydro-thieno [2, 3-f] 1. 4] oxazepin-5-ylamine; (3R)-3-ethyl-2-methyl-2,3-dihydro-thieno oxazepine-5-ylamine ; 2-phenyl-2,3-dihydro-thieno[2,4-f][1, 4] oxazepin-5-amine; 4a, 5,6,7,8,8a-hexahydro-thieno [3,2-b] [1,5] benzoxazepin-10-ylamine ; 3-butyl-8-chloro-2,3-dihydro-thieno[2,3-f][1,4]oxazepin-5-yl amine; 5-amino-3-butyl-2,3-dihydro-thieno[2,3-f][1, 4] oxazepine-8-carbonitrile; (5-amino-2,3-dihydro-thieno [2. 3-f][1, 4] oxazepin-3-yl)-methanol; 4- (5-amino-2, 3-dihydro-thieno [2, 3-f] [1,4] oxazepin-3-ylmethoxy)-benzonitrile; 3-(3-nitro-phenoxymethyl)-2,3-dihydro-thieno[2,3-f][1, 4] oxazepin-5-ylamine; 3-(3-amino-phenoxymethyl)-2,3-dihydro-thieno[2,3-f][1, 4] oxazepin-5-ylamine;

6-allyl-2-bromo-7,8-dihydro-6H-thieno [3,2-c] azepin-4-ylamine; 6-allyl-3-bromo-7, 8-dihydro-6H-thieno [3,2-c] azepin-4-ylamine; 3-(6-bromo-naphthalen-2-yloxymethyl)-2,3-dihydro-thieno[2,3- f][1,4]oxazepin-5-ylamine; 2,3-dihydro-1 H-thieno diazepin-5-ylamine; 2-(but-3-enyl)-2,3-dihydro-thieno [2,3-fez [1,4] oxazepin-5-ylamine ; 2-butyl-2, 3-dihydro-thieno oxazepin-5-ylamine ; [(2-but-3-enyl)-2, 3-dihydro-thieno [2, 3-f] [1,4] oxazepin-5-yl]-carbamic acid tert-butyl ester; 2- [ (3E)-4- (6-methoxy-pyridin-3-yl)-but-3-enyl]-2,3-dihydro-thieno [2, 3-f][1, 4] oxazepin-5- ylamine; <BR> <BR> <BR> <BR> 3- (1,2,3,4-tetrahydro-isoquinolin-7-yloxymethyl)-2, 3-dihydro-thieno [2, 3-f] [1,4] oxapin-5- ylamine; 2-aminomethyl-2,3-dihydro-thieno [2, 3-f] [1,4] oxazepin-5-ylamine; 2-methylaminomethyl-2, 3-dihydro-thieno [2, 3-f] [1,4] oxazepin-5-ylamine ; N- (5-amino-2, 3-dihydro-thieno [2,3 fJ [1, 4]oxazepin-2-ylmethyl)-benzenesulphonamide; N- (5-amino-2,3-dihydro-thieno [2, 3-f] [1, 4] oxazepin-2-ylmethyl)-methanesulphonamide; N- (5-amino-2,3-dihydro-thieno oxacepin-2-ylmethyl)-3-(1H-indol-3-yl)- acrylamide; N- (5-amino-2,3-dihydro-thieno oxazepin-2-ylmethyl)-acetamide; N- (5-amino-2,3-dihydro-thieno [2, 3-f] [1,4] oxazepin-2-ylmethyl)-benzamide; 3-amino-1H-pyrazole-4-carboxylic acid (5-Amino-2, 3-dihydro-thieno [2, 3-f] [1,4] oxazepin- 2-ylmethyl) amide; (5-amino-2,3-dihydro-thieno [2,3-fl [1,4] oxazepin-2-ylmethyl]-urea; 2-thiophen-2-yl-2,3-dihydro-thieno oxazepin-5-ylamine; 2- (2-amino-ethyl)-2,3-dihydro-thieno oxazepin-5-ylamine; N- [2- (5-amino-2, 3-dihydro-thieno oxazepin-2-yl) ethyl]-benzamide; and pharmaceutically acceptable salts, enantiomers, racemates or tautomers thereof.

Unless otherwise indicated, the term "C1 to 8 alkyl"referred to herein denotes a straight or branched chain alkyl group having from 1 to 8 carbon atoms or a cyclic alkyl group having from 3 to 8 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopentyl and cyclohexyl.

Unless otherwise indicated, the term"C2 to 8 alkenyl"referred to herein denotes a straight or branched chain alkyl group having from 2 to 8 carbon atoms or a cyclic alkyl group having from 3 to 8 carbon atoms, each incorporating at least one carbon-carbon double bond. Examples of such groups include ethenyl, propenyl, butenyl, cyclopentenyl and cyclohexenyl.

Unless otherwise indicated, the term"C2 to 8 alkynyl"referred to herein denotes a straight or branched chain alkyl group having from 2 to 8 carbon atoms and incorporating at least one carbon-carbon triple bond. Examples of such groups include ethynyl, propynyl, and butynyl.

Unless otherwise indicated. the term"C 1 to 6 alkoxy"referred to herein denotes a straight or branched chain alkoxy group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy and t-butoxy.

Examples of a five or six membered aromatic heterocyclic ring include furan, thiophene, pyrrole, thiazole, oxazole, imidazole, pyridine, pyrimidine, pyrazine and pyridazine.

According to the invention, we further provide a process for the preparation of compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof which comprises: (a) preparing compound of formula (I) wherein hydrogenrepresents by reaction of a compound of formula (II)

wherein R, R, R3'R, R,, R6, A, B, D and X are as defined above, withammonia; or (b) preparing a compound of formula (I) wherein hydrogenbyreactionofarepresents compound of formula (HI) or a salt thereof wherein R, R, R'R, R,. R6, A, B, D and X are as defined above and R represents methyl or ethyl, with ammonia or ammonium acetate; or (c) preparing a compound of formula (I) wherein hydrogenrepresents by cyclisation of a compound of formula (IV)

wherein R, R, R3'R, R, R, A, B, D and X are as defined above and PG represents a protecting group : or (d) preparing a compound of formula (I) wherein Rl-represents ConR13 and R13 is as defined above, by alkoxycarbonylation of a compound of formula (I) wherein R represents hydrogen ; and where desired or necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof, or vice versa, and where desired converting the resultant compound of formula (I) into an optical isomer thereof.

In process (a), the reaction will take place on mixing the reactants in a suitable organic solvent at a suitable temperature. The reaction time will depend inter alia on the solvent used and on the reaction temperature. In a preferred embodiment, a saturated solution of ammonia in methanol is used as reagent/solvent and the reaction is conducted at approximately 100 °C in a pressurised container.

In process (b), the reaction may be performed by combining the reactants in a organic solvent such as methanol or acetonitrile at a suitable temperature, generally between room temperature and the boiling point of the solvent. The reaction time will depend inter alia on the polarity of the solvent and the temperature of the reaction. The process may also be carried out as in the preferred embodiment of process (a) above.

In process (d), the reaction may be performed by treating the compound of formula (1) wherein R ~ represents hydrogen with a reagent such as a dialkyl dicarbonate under conditions that are well known in the art.

It will be apparent to a person skilled in the art that in the above processes it may be desirable to protect an amine or other potentially reactive group. Suitable protecting groups and details of processes for adding and removing such groups may be found by reference to the standard text"Protecting Groups in Organic Synthesis", 2nd Edition (1991) by Greene and Wuts.

The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic. succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

Salts of compounds of formula (I) may be formed by reacting the free base, or a salt, enantiomer, racemate or tautomer thereof, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuo or by freeze drying. The reaction may also be a metathetical process or it may be carried out on an ion exchange resin.

Novel intermediates of formulae (g), (E ? and (IV) form another aspect of the invention.

The preparation of compounds of formula (Ell) may be achieved by reaction of a compound of formula (II) with a compound R-L, wherein R is as defined above and L is a leaving group such as halogen, particularly iodide, or mesylate.

Compounds of formula (II) may be prepared by reaction of a compound of formula (V) with Lawesson's reagent.

Methods for the preparation of compounds of formula (V) are summarised in Schemes 1 to 5 : Scheme 1 Scheme 2

Scheme 3 R3 R30xone (0) mR4 R5 acetone-water S R5 D R2 R2 B NH R6 or B NH R6 B, > NH or B>Js NHR1 A ll 2) MCPBA/DCM R1 A f O O Scheme 4

R5 PUS R4 R6 R R6 OH R3 NHPG R3NHPG R2 OH OH OMe R2 ORME R1 O DEAD/P (Ph) 3 A 1) HCI/Dioxane or 2) TFA/DCM R5 R3 R4 J. R6 4 R3NH \ R Rl A Bp NH R6 R2 D R1 BJ\.,. Oe R1 A E OMe o (V) Scheme 5

R3 D 9 R4 N H20 H R3 R2 p R4 Ri A R6 B R5 R5 R1 A \R6 R1 A \ R6 N OH NaOH/Tosyl-Cl R3 R3 R3 R2 D Acetone D x R4 E ;J NH R6 g R5 A Reflux (V) Ri N"-LL OTs O N zoos ors Intermediate compounds may be used in protected form. Protecting groups and details of processes for their removal may be found by reference to the standard text"Protecting Groups in Organic Synthesis". 2nd Edition (1991) by Greene and Wuts.

The compounds of the invention and intermediates thereto may be isolated from their reaction mixtures and, if necessary further purified, by using standard techniques.

The compounds of formula I may exist in enantiomeric forms. Therefore, all enantiomers. diastereomers, racemates and mixtures thereof are included within the scope of the invention.

The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation, or HPLC.

Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures.

The compounds of formula (I) may exist in alternative tautomeric forms. Compounds of formula (I) are provided in another tautomeric form or as a mixture thereof.

The compounds of formula (I). and their pharmaceutically acceptable salts, enantiomers. racemates and tautomers, are useful because they possess pharmacological activity in animals. In particular, the compounds are active as inhibitors of the enzyme nitric oxide synthase. More particularly, they are inhibitors of the inducible isoform of the enzyme nitric oxide synthase and as such are predicted to be useful in therapy, for example, as anti-inflammatory agents. They may also have utility as inhibitors of the neuronal isoform of the enzyme nitric oxide synthase.

The compounds and their pharmaceutically acceptable salts, enantiomers. racemates and tautomers are indicated for use in the treatment or prophylaxis of diseases or conditions in which synthesis or oversynthesis of nitric oxide synthase forms a contributory part. In particular, the compounds are indicated for use in the treatment of inflammatory conditions in mammals including man.

Conditions that may be specifically mentioned are: osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, inflamed joints ; eczema, psoriasis, dermatitis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including uveitis, glaucoma and conjunctivitis; lung disorders in which inflammation is involved, for example, asthma. bronchitis, chronic obstructive pulmonary disease, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome ; bacteraemia. endotoxaemia (septic shock), aphthous ulcers, gingivitis, pyresis. pain and pancreatitis ; conditions of the gastrointestinal tract including inflammatory bowel disease, Crohn's disease. atrophic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis. peptic ulceration, irritable bowel syndrome, reflux oesophagitis, damage to the

gastrointestinal tract resulting from infections by, for example, Helicobacter pylori, or from treatments with non-steroidal anti-inflammatory drugs: and other conditions associated with inflammation.

The compounds will also be useful in the treatment and alleviation of acute pain or persistent inflammatory pain or neuropathic pain or pain of a central origin.

We are particularly interested in the conditions inflammatory bowel disease, rheumatoid arthritis, osteoarthritis. chronic obstructive pulmonary disease and pain.

The compounds of formula (1) and their pharmaceutically acceptable salts, enantiomers. racemates and tautomers may also be useful in the treatment or prophylaxis of diseases or conditions in addition to those mentioned above. For example, the compounds may be useful in the treatment of atherosclerosis, cystic fibrosis, hypotension associated with septic and/or toxic shock, in the treatment of dysfunction of the immune system, as an adjuvant to short- term immunosuppression in organ transplant therapy, in the control of onset of diabetes, in the maintenance of pancreatic function in diabetes, in the treatment of vascular complications associated with diabetes and in co-therapy with cytokines, for example TNF or interleukins.

The compounds of formula (I) may also be useful in the treatment of hypoxia, for example in cases of cardiac arrest and stroke, neurodegenerative disorders including nerve degeneration and/or nerve necrosis in disorders such as ischaemia, hypoxia, hypoglycaemia, epilepsy. and in external wounds (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia, for example pre-senile dementia, Alzheimer's disease and AIDS-related dementia, Sydenham's chorea. Parkinson's disease, Tourette's Syndrome, Huntington's dis- ease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Korsakoff's disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, pain, autism, seasonal affective disorder, jet-lag, depression or other symptoms associated with Premenstrual Syndrome (PMS), anxiety and septic shock. Compounds of formula (I) may also be expected to show activity in the prevention and reversal of drug addiction or tolerance to opiates and diazepines, treatment of drug addiction, treatment of migraine and

other vascular headaches, neurogenic inflammation, in the treatment of gastrointestinal motility disorders, cancer and in the induction of labour.

We are particularly interested in the conditions stroke, Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, schizophrenia, migraine, cancer, septic shock and pain.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of. the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

For the above mentioned therapeutic indications, the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired.

However, in general, satisfactory results are obtained when the compounds are administered at a dosage of the solid form of between 1 mg and 2000 mg per day.

The compounds of formula (1), and pharmaceutically acceptable derivatives thereof, may be used on their own, or in the form of appropriate pharmaceutical compositions in which the compound or derivative is in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Administration may be by, but is not limited to, enteral (including oral, sublingual or rectal), intranasal, intravenous, topical or other parenteral routes.

Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in. for example,"Pharmaceuticals-The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988. The pharmaceutical composition preferably comprises less than 80% and more preferably less than 509c of a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, racemate or tautomer thereof.

There is also provided a process for the preparation of such a pharmaceutical composition which comprises mixing the ingredients.

The compounds of formula (n, and pharmaceutically acceptable derivatives thereof, may also be advantageously used in combination with a COX-2 inhibitor. Particularly preferred COX-2 inhibitors are Celecoxib and MK-966. The NOS inhibitor and the COX-2 inhibitor may either be formulated together within the same pharmaceutical composition for administration in a single dosage unit, or each component may be individually formulated such that separate dosages may be administered either simultaneously or sequentially.

The invention is illustrated, but in no way limite, by the following examples: Example I 2.3-Dihydro-thienoF2. 3-flEI*41thiazepin-5-ylamine hydrochloride a) 3,4-Dihvdro-2H-thienoF2. 3-flE1. 41thiazepine-5-one To a solution of methyl 3-chlorothiophene-2-carboxylate (4.42 g. 25 mmol) and 2- aminoethanethiol hydrochloride (11. 36 g. 100 mmol) in dimethylformamide (100 ml) was added 1,8-diazabicyclo [5.4.0] undec-7-ene (30 ml 200 mmol). The solution was stirred for 1.5 hours at room temperature. The temperature was then increased to 70°C and the reaction stirred for 18 hours. The cooled reaction mixture was poured into 2M hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried (anhydrous MgSO4) and evaporated. The residue was passed down a silica gel column eluted with hexane: ethyl acetate (1: 3), then ethyl acetate, to give a white solid (1.51 g).

Mass spectrum: m/e 186 [M + H]; NMR: (CDC13): 3.25-3.28 (m, 2H), 3.60-3.78 (m. 2H), 6.85 (d, 1H). 7. 48 (d. 1H), 8.17 (bs, H). b) 3,4-Dihydro-2H-thieno[2,3-f][1,4]thiazepine-5-thione

The product from Example 1 (a) (1.12 g, 60 mmol) was suspended in anhydrous benzene (100 ml) and [2,4-bis (4-methoxyphenyl)-1,3-dithia-2.4-diphosphetane-2,4-disulfide ] (1. 47 g, 3.6 mmol) was added. The reaction was gently refluxed for 2 hours. After cooling the solvent was removed and the residue passed down a silica gel column eluted with hexane: ethyl acetate (2: 1) to afford a yellow solid (0.94 g).

Mass spectrum :m/e 202 [M + H] ; NMR: (CDCI3): 3.37-3.40 m. 2H). 3.86-3.90 (m. 2H), 6.90 (d, 1H). 7.72 (d. 1H). 8.68 (bs, 1H). c) 2.3-Dihydro-thienoF2. 3-ílLl. 41thiazepin-5-vlamine hvdrochloride The product From Example l (b) (0.15 g, 0.75 mmol) was dissolved in methanol (10 ml) saturated with ammonia and the resulting solution placed in a stainless steel finger bomb.

The bomb was sealed and heated at 100°C for 18 hours. After cooling the solvent was removed and the residue passed down a silica gel column eluted with dichloromethane: methanol (9: 1) to give a white solid which was converted into the hydrochloride salt with 1M hydrochloric acid in diethyl ether (0.08 g). M. p. 202-204 °C.

Mass spectrum:/e 185 [M + H]+; NMR: (DMSOd6): 3.48-3.54 (m, 2H), 3.78-3.82 (m, 2H), 7.13 (d, 1H), 7.86 (d, 1H). 8.17.

Example 2 3-Ethyl-2,3-dihydro-thieno[2,3-f][1,4]thiazepin-5-ylaminehyd rochloride a) (2-tert-Butvloxvcarbonylamino)-1-butanol To a solution of 2-amino-1-butanol (7.97 g, 89.5 mmol) and triethylamine (12.5 ml, 89.5 mmol) in tetrahydrofuran (120 ml) at 0°C was added di-tert-butyl dicarbonate (19. 53 g, 89.5 mmol) in one portion. The reaction was stirred at 0°C for 15 minutes then at room temperature for 18 hours. The solvent was removed on a rotary evaporator and the residue diluted with ethyl acetate (1 D0 ml). The organic phase was washed with water (3 x 50 mi). dried (anhydrous MgSO4) and evaporated to give a colourless oil (16.26 g).

NMR: (CDC13): 0.96 (t, 3H). 1.45 (s, 9H), 2. 42 (bs, 1H), 3.54-3. 57 (m. 2H). (m, 1H), 4.62 (bs, 1H). b) O-Tosvl- (2-tert-Butvloxvcarbonvlamino)-1-butanol To a solution of the product of Example 2 (a) (10.92 g, 57.7 mmol) and triethylamine (9.0 ml, 64.6 mmol) in dichloromethane (100 ml) at 0°C was added dropwise a solution of p-toluenesulphonyl chloride (12.38 g, 64.9 mmol) in dichloromethane (100 ml). The reaction was allowed to warm to room temperature and stirred for 18 hours. Water (50 ml) was added, the layers separated and the organic phase washed with water (2 x 50 ml). dried (anhydrous MgSO4) and evaporated. The residue was passed down a silica gel column eluted with hexane: diethyl ether (2: 1) to give a white solid (9.84 g).

NMR: (CDCl3) : 0.88 (t, 3H), 1.41 (s, 9H). 1.48-1.55 (m, 2H), 2.45 (s. 3H). 3.63 (m.

1H), 3.99-4.02 (m, 2H), 4.55 (bs, 1H), 7.35 (d, 2H). 7.78 (d. 2H). c) 3-f (2-tert-Butvloxvcarbonvlamino) butvlthiol-thiophene-2-carboxvlic acid 3-Mercaptothiophene-2-carboxylic acid (1.02 g, 6.37 mmol) was dissolved in dimethylformamide (50 ml) and caesium carbonate (4.57 g, 14.0 mmol) added and the mixture stirred at room temperature for 0.5 hours. The product of Example 2 (b) (2.19 g.

6.37 mmol) was then added and the reaction stirred for 18 hours at room temperature.

Water (100 ml) was added and the reaction extracted with ethyl acetate (3 x 80 ml). The combined organic extracts were washed with water (3 x 50 ml) dried (anhydrous MgSO2) and evaporated. The residue was passed down a silica gel column eluted with hexane: ethvl acetate (1: 1) to afford a deep red oil (0.58 g).

Mass spectrum:/e 330 [NI-11 d) 3-Ethvl-3. 4-dihydro-2H-thienof2. 3-fl 1. 41thiazepine-5-one The product of Example 2 (c) (0.47 g, 1.43 mmol) was dissolved in 4M hydrochloric acid in dioxane (5 ml) and stirred for 2 hours at room temperature. The solvent was removed and the residue dissolved in dimethylformamide (4 ml) and bromo-tris-pyrrolidinophosphonium hexafluorophosphate (1.33 g, 2.86 mmol) added. The solution was stirred for 15 minutes then N, N-diisopropylethylamine (0.92 g, 7.15 mmol)

added. The reaction was stirred at room temperature for 18 hours. Water (80 ml) was added and the reaction extracted with ethyl acetate (3 x 25 ml). The combined organic extracts were washed with water (2 x 10 ml), dried (anhydrous MgS04) and evaporated. The product was passed down a silica gel column eluted with hexane: ethyl acetate (2: 1) to give a white solid (0.13 g).

NMR: (CDC13): 1.06 (t. 3H), (m, 2H), 3.18 (d, 2H), (m. 1H).

6.13 (bs, IH), 6.85 (d, 1H). 7. 46 (d, 1H). e) 3-Ethyl-3,4-dihydro-2H-thieno[2,3-f][1,4]thiazepine-5-thione The product from Example 2 (d) (0.12 g. 0.56 mmol) was dissolved in benzene and [2, 4- bis (4-methoxyphenyl)-1.3-dithia-2.4-diphosphetane-2,4-disulfide ] (0.14 g. 0. 34 mmol) added. The reaction mixture was refluxed for 4 hours. The reaction was cooled and the solvent removed on a rotary evaporator. The residue was passed down a silica gel column eluted with hexane: ethyl acetate (3: 1) to afford the product as a yellow solid (0.13 g).

Mass spectrum :m/e 230 [M + H]; NMR: (CDC13): 1.09 (t. 3H), 1.77-1.89 (m. 2H), 3.26 (d, 2H), 3.80-3.90 (m, IH).

6.88 (d, 1H), 7.50 (d, 1H), 7.97 (bs. 1H). f) hydrochloride The product from Example 2 (e) (0.13 g. 0.54 mmol) was dissolved in methanol (20 ml) saturated with ammonia and the resulting solution placed in a stainless steel finger bomb.

The bomb was sealed and heated at 100°C for 24 hours. After cooling the solvent was removed and the residue passed down a silica gel column eluted with dichloromethane: methanol (19: 1) to give a white solid which was converted into the hydrochloride salt with 1M hydrochloric acid in diethyl ether (0.03 g). M. p. 189-190 °C.

Mass spectrum: [M+H]+;213 NMR: (DMSOd6): 1.13 (t. 3H), 1.78-1.98 (m. 2H), 3.39 (d. 2H), 3.64-3.74 (m. IH).

7.10 (d, 1H), 7.82 (d, 2H).

Example 3

(3S)-3-Ethyl-2. 3-dihydro-thienof2. 3-fif I, 41thiazepin-5-vlamine hvdrochloride Starting from (2S)-2-amino-1-butanol, the title compound was synthesised via the route used for Example 2.

Mass spectrum:/e 213 [M + H]+; NMR: (DMSOd6): 1.13 (t, 3H), 1.81-2.03 (m, 2H), 3.35-3.40 (m. 2H). 3.63-3.74 (m, 1H).

7.09 (d, 1H), 7.80 (d, 2H). 9.02 (bs, 2H), 10.63 (d, 1H).

Example 4 (3R)-3-Ethyl-2,3-dihydro-thieno[2,3-f][1,4]thiazepin-5-ylami nehydrochloride The synthetic sequence described for the preparation of Example 2 was applied to (2R)-2- amino-1-butanol to give the title compound.

Mass spectrum : m/e 213 [M + H] ; NMR: (DMSOd6): 0.97 (t, 3H), 1.71 (m, 2H), 3.37-3.50 (m, 2H), 3.64 (m, 1H), 7.26 (d.

1H), 8.65 (d, 2H), 9.8 (bs, 3H).

Example 5 (3S)-3-Renzyl-2,3-dihydro-thieno[2,3-f][1,4]thiazepin-5-ylam inehydrochloride The synthetic sequence described for the preparation of Example 2 was applied to (2S)-2- amino-3-phenyl-propanol to give the title compound. M. p. 234-235 °C.

Mass spectrum : m/e 275 [M + H] + ; NMR: (DMSOd6): 3.04 (m. 2H), 3.45 (m, 2H), 4.02 (m, 1H), 7.25 (d, 1H), 7.31 (m, 5H), 8.16 (d, 2H). 8.95 (bs, 2H). 10.13 (d, 1H).

Example 6

(3S)-3-Phenyl-2,3-dihydro-thieno[2,3-f][1,4]thiazepin-5-ylam inehydrochloride Starting from (2S)-2-phenyl-2-aminoethanol, the title compound was synthesised via the route described for Example 2. M. p. 221-223 °C.

Massspectrum :/e 261 [M+H] ; Cl3Hl3N2CIS2. 0. 5H2O requires: C, 51.1; H, 4.6; N, 9.2; S, 20. 9 %.

Found: C, 51.0; H, 4.7; N, 9.4; S, 21.3 %.

Example 7 (3S)-3-Benzyloxymethyl-2,3-dihydro-thieno[2,3-f][1,4]thiazep in-5-ylaminehydrochloride a) (2S)-3-BenzylOxy-O-mesvl-(2-tert-butvloxvcarbonvlamino)-prop an-1-ol (2S)-3-Benzyloxy- (2-tert-butyloxycarbonylamino)-propan-1-ol (prepared by the procedure described in Synth. Comm. 26 (13), 2511-22,1996), (5.6 g, 20 mmol) and triethylamine (3 ml) in dichloromethane (75 ml) were cooled to-10°C and treated with mesyl chloride (1.7 ml). The reaction mixture was stirred at 0°C for 2 hr then poured into aqueous 2M hydrochloric acid and the product extracted with ethyl acetate and isolated as a colourless oil (6.7 g).

Mass spectrum : m/e 360 [M-Boc] b) (2S)-3-f3-Benzvloxv- (2-tert-butvloxycarbonvlamino)-propylthiol-thiophene-2- carboxylic acid The mesylate produced in Example 7 (a) (3.1 g) and 3-mercaptothiophene-2-carboxylic acid (1.5 g) were subjected to the procedure described in Example 2 (c) to give the product as an oil (0.6 g).

Mass spectrum: [M-1]+;422 NMR: (DMSOd6/CDC13): 1.43 (s, 9H), 3.18-3.19 (d, 2H), 3.49-3.52 (m, 1H), 3.55-3.57 (m, 1H), 3.69-3.89 (m, 1H), 4.52 (s, 2H), 6.23 (d. 1H), 7.21-7.34 (m, 4H), 7.54-7.58 (m.

2H), 7.64 (d, 1H).

c) (2S)-3-f (3-Benzvloxy-2-amino) propylthiol-thiophene-2-carboxylic acid The product from Example 7 (b) (0.6 g) was deprotected by the procedure described in Example 2 (d) to afford the product as a gum (0.5 g).

Mass spectrum:/e 324 [M + H]. d)(3S)-3-benzyloxymethyl-3,4-dihydro-2H-thieno-[2,3-f][1,4]t hiazepin-5-one The product from Example 7 (c) (0.5 g) was cyclise by the procedure described in Example 2 (d) to afford the product as a colourless oil (0.15 g).

Mass spectrum:/e 306 [M + H]; NMR: (CDCl3) : 3.13-3.31 (m, 2H), 3.56-3.77 (m, 2H), 4.56 (bs, 2H), 6.62 (bs. IH).

6.85 (d, 1H), 7.29-7.38 (m. 5H), 7.47 (d, 1H). e) (3S)-3-Benzyloxymethvl-3.4-dihvdro-2H-thieno-F2. 3-fl f 1. 41thiazepin-5-thione The product from Example 7 (d) (0.15 g) was subjected to the procedure described in Example 2 (e) to afford the product as a yellow gum (0.1 g).

Mass spectrum : m/e 322 [M +H] ; NMR: (CDCl3) : 3.18-3.22 (dd, 1H), 3.47-3.53 (dd, 1H), 3.58-3.62 (dd, IH). 3.72- 3.75 (dd, IH), 4.06-4.12 (m, IH), 4.52-4.64 (dd, 2H), 6.62 (bs, IH), 6.87 (d, 1H). 7.32- 7.40 (m, 5H), 7.49 (d, 1H), 8.22 (bs, 1H). f) (3S)-3-Benzyloxymethyl-2,3-dihydro-thieno-[2,3-f][1,4]thiaze pin-5-ylamine hydrochloride The product from Example 7 (e) (0.1 g) in acetonitrile (5 ml) was treated with methyl iodide (0.5 ml) and stirred for 3 hr. The solvent was evaporated to leave a yellow gum. This was dissolved in methanol (5 ml), treated with ammonium acetate (0.1 g) and heated at reflux for 40 hrs. The solvent was evaporated and the residue passed down a silica gel column eluted with dichloromethane: methanol (10: 1, v/v and then 5: 1, v/v). A yellow solid

was obtained which was triturated with 1M ethereal hydrochloric acid to afford the product as a solid (0.035g). M. p. 175-179 °C.

Mass spectrum: m/e 305 [M + H] ; NMR: (DMSOd6): 3.48 (d. 2H), 3.70 (d. 2H), 3.72-3.75 (dd, 1H), (m. 1H).

4.52-4.61 (dd, 2H), 7.25 (d. 1H), 7.29-7.40 (m, 5H), 8.16 (d. 1H), 8.8-9.2 (bs, 3H).

Example 8 3-Ethyl-2.3-dihvdro-thieno [2. 3-fl f 1. 4 oxazepin-5-ylamine hvdrochloride a) Methvl 3-i (9-tert-butyloxvcarbonvlamino) butoxyl-thiophene-2-carboxvlate The product from Example 2 (b) (1.03 g, 3 mmol) and methyl 3-hydroxythiophene-2- carboxylate, (0.48 g, 3 mmol) in acetone (10 ml) were treated with potassium carbonate (0.5 g, 3.5 mmol) and a catalytic amount of potassium iodide and heated at reflux for 18 hrs. The mixture was poured into aqueous 2M hydrochloric acid and extracted with ethyl acetate. The extract was passed down a silica gel column eluted with hexane: ethyl acetate (7: 1, v/v) to afford an oil (0.12 g).

Mass spectrum : m/e 330 [M-Boc]; NMR: (CDCI3): 0.99 (t, 3H). 1.44 (s, 9H), 1.74-1.81 (m, 2H), 3.85 (s, 3H), 4.11-4.19 (m.

3H), 5.11 (bs, 1H), 6.85 (d, 1H), 7.40 (d, 2H). b) Methvl 3- (2-aminobutoxv)-thiophene-2-carboxvlate trifluoroacetate The product from Example 8 (a) (0.11 g) was dissolved in a mixture of dichloromethane: trifluoroacetic acid (4: 1, v/v) (10 ml) and stirred for 1.5 hr. The mixture was treated with toluene (10 ml) and the solvent was evaporated to dryness. This was repeated twice more to leave a gum (0.1 g).

Mass spectrum: m/e 228 [M-1] + c) 3-Ethyl-3, 4-dihydro-2H-thieno[2. 3-fol 41oxazepine-5-one

The product from Example 8 (b) was subjected to the procedure described in Example 12 (d) to afford the product as a gum.

Mass spectrum : m/e 196 [M-1] +. d)3-Ethyl-3.4-dihydro-2H-thienof2. 3-flf 1, 41oxazepine-5-thione The product from Example 8 (c) was subjected to the procedure described in Example 12 (e) to afford the product as a yellow gum.

Mass spectrum: [M+H]+.214 e) 3-Ethyl-2.3-dihydro-thienof2. 3-f][1,4]oxazepin-5-(methylthio) hydroiodide The product from Example 8 (d) was subjected to the procedure described in Example 12(f) to afford the product as a yellow solid.

Mass spectrum:/e 228 [M +H]. f) hydrochloride The product from Example 8 (e) (0.15 g) was treated with a saturated solution of ammonia in methanol as in Example 2 (f) to afford the product as a yellow solid (0.03 g). M. p. 194- 197 °C.

Mass spectrum : m/e 197 [M + H] + ; NMR: (DMSOd6): 0.99 (t. 3H), 1.49-1.59 (m, 2H), (m, 1H), 4.34-4.49 (m.

2H), 6.94 (d, 1H), 8.05 (d, 2H), 8.6 (bs, 3H).

Example 9 (3S)-1,1-Dioxo-3-benzyl-2,3-dihydro-thieno[2,3-f][1,4]thiaze pin-5-ylaminehydrochloride a) (3S)-1,1-Dioxo-3-benzyl-3,4-dihydro-2H-thieno-[2,3-f][1,4]th iazepin-5-one (3S)-3-Benzyl-3,4-dihydro-2H-thieno- [2, 3-f] [1,4] thiazepin-5-one (an intermediate in the preparation of Example 5) (0.1 g) in acetone (10 ml) and water (2 ml) was treated with oxone (1.0 g) and stirred at ambient temperature for 72 hr. The mixture was poured into

10% aqueous sodium metabisulphite and the product was extracted into ethyl acetate.

Evaporation of the solvent gave the product as a white solid (0.11 g).

Mass spectrum: [M+H]+;308 NMR: (DMSOd6): 3.06 (m. 2H), 3.55 (m, 1H), 3.68 (m, 1H), 4.38 (m. 1H), 6.31 (bs.

1H), 7.2-7.4 (m, 5H0, 7.56 (d. 1H). 7.66 (d, 1H). b) (3S)-1.1-Dioxo-3-benzvl-2. 3-dihvdro-thieno-f2. 3-flf 1. 41thiazepin-5-vlamine hydrochloride The product from Example 9 (a) was converted into the required product by the procedures described in Examples 2 (e) and 2 (f).

Mass spectrum:/e 307 [M + H] ; NMR: 07 (m, 2H), 3.81 (m, 1H), 4.09 (m, 2H), 7.6 (m. 5H). 7.63 (d.

1H), 8.26 (d, 1H).

Example 10 3-Propyl-2,3-dihydro-thieno[2,3-f][1,4]thiazepin-5-ylaminehy drochloride The synthetic sequence described for the preparation of Example 2 was applied to (2RS)-2- amino-pentanol to give the title compound. M. p. 219-220 °C.

Mass spectrum: [M+H]+;227 NMR: (DMSOd6): 0.86 (t. 3H), 1.40 (m, 1H). 1.65 (m, 1H), 3. 2-3.50 (m, 4H), 3.72 (m.

1H), 7.25 (d, 1H), 8.16 (d, 2H).

Example 11 1.1-Dioxo-3-propyl-2. 3-dihvdro-thienof ?. 3-flf 1. 41thiazepin-5-vlamine hvdrochloride 3-Propyl-3,4-dihydro-'H-thieno [2,3-f] [1, 4] thiazepine-5-one. an intermediate from Example 10, was oxidised to the sulphone, 1,1-dioxo-3-propyl-3,4-dihydro-2H-thieno [2.3-

f] [1, 4] thiazepine-5-one as described in Example 9 (a). The sulphone was converted into the required product by the synthetic procedure described in Examples 12 (f) and 12 (g).

M. p. 250-251 °C.

Mass spectrum:/e 259 [M + H] + ; NMR: (DMSOd6): 0.83 (t. 3H), 1.24-1.47 (m, 2H), 1.52-1.75 (m. 2H), (m.

1H), 3.90-4.05 (m, 2H). 7.64 (d, 1H), 8.30 (d, 2H).

Example 12 3-Propyl-2,3-dihydro-thieno[2,3-f][1,4]oxacepin-5-ylaminehyd rochloride a) (2-tert-Butyloxvcarbonvlamino)-1-pentanol (RS)-2-Aminopentanol (9.25 g, 90 mmol) was dissolved in dry tetrahydrofuran (100 ml) and treated with pyridine (7.9 g. 100 mmol). The solution was cooled in an ice-bath and stirred under an nitrogen atmosphere. Di-tert-butyldicarbonate (19.6 g. 90 mmol) was added and the mixture was allowed to warm up to ambient temperature over 18 hr with stirring. The mixture was poured into aqueous 2M hydrochloric acid and the product was extracted using ethyl acetate. The ethyl acetate was removed under reduced pressure to give the product as a clear oil (16.7 g).

Mass spectrum: [M-1]+;202 NMR: (CDC13): 0.93 (t. 3H), (m, 4H), 1.45 (s, 9H), 2.57 (bs. IH), 3.50- 3.56 (m, 1H). (m, 2H), 4.62 (bs, IH). b) Methyl 3-f (2-tert-Butvloxvcarbonvlamino) pentoxyl-thiophene-2-carboxvlate Methyl 3-hydroxythiophene-3-carboxylate (1. 58 g. 10 mmol), triphenylphosphine (2.62 g, 10 mmol) and the product of Example 12 (a) (2.03 g. 10 mmol) were dissolved in dry benzene (25 ml) and stirred under a nitrogen atmosphere. Diethyl azodicarboxylate (1.74 g, 10 mmol) was added and the mixture stirred for 3 hr at ambient temperature. The reaction

mixture was absorbed onto silica and passed down a silica gel column eluted with hexane: ethyl acetate (4: 1, v/v) to afford the product (2.8 g).

Mass spectrum: m/e 244 [M-Boc] ; NMR: (CDCl3) : 0.95 (t. 3H), 1.38-1.42 (m, 2H), 1.44 (s, 9H), 1.65-1.71 (m, 2H). 3.85 (s, 3H), 3.87-3.90 (m, 1H), 4.10-4.18 (m, 2H), 5.12 (bs, 1H), 6.85 (d, 1H), 7.40 (d, 2H). c) Methyl 3- (2-aminopentoxv)-thiophene-2-carboxylate hvdrochloride The product from Example 12 (b) (2.8 g, 8.2 mmol) was dissolved in 4M hydrochloric acid in dioxane (25 ml) and stirred for 2 hr. The solvent was removed under reduced pressure to give the product (2.3 g).

Mass spectrum : m/e 244 [ii + H] +. d) 3-Propyl-3,4-dihydro-2H-thieno[2,3-f][1,4]oxacepine-5-one The product from Example 12 (c) (2.3 g, 8 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (3 g, 20 mmol) were dissolved in dimethylformamide (50 ml) and heated at 110°C for 24 hr. The reaction mixture was poured into 2M hydrochloric acid and extracted with ethyl acetate which was evaporated under reduced pressure to give a gum. This crystallised from hexane/ethyl acetate to give the product as a white solid (1.1 g).

Mass spectrum : m/e 212 [M + H] ; NMR: (CDCl3) : 0.97 (t, 3H), 1.44-1.53 (m, 2H), 1.54-1.65 (m, 2H), 3.53-3.60 (m, 1H), 4.24-4.35 (m, 2H), 6.33 (bs, 1H), 6.87 (d, 1H), 7.38 (d, 2H). e) 3-Propyl-3. 4-dihvdro-2H-thienoF2. 3-fl F 1. 41Oxazepine-5-thione The product from Example 12 (d) (1 Q, 4.5 mmol) and [2,4-bis (4-methoxyphenyl)-1,3- dithia-2,4-diphosphetane-2,4-disulfide] (1.2 g, 3 mmol) in benzene (50 ml) were heated at reflux for 3 hr. The reaction mixture was absorbed onto silica and passed down a silica gel column eluted with hexane: ethyl acetate (4: 1, v/v) to afford the product as a yellow solid <BR> <BR> <BR> <BR> 0.77g<BR> (0. 77 g).

Mass spectrum: m/e 228 [M + H].

f) hydroiodide The product from Example 12 (e) (0.76 g, 3.3 mmol) was dissolved in acetonitrile (25 ml), treated with methyl iodide (3 g) and stirred at ambient temperature for 20 hr. The reaction mixture was evaporated to dryness to afford the product as a yellow solid (1.2 g) Mass spectrum:/e 949 [M + H]. g)hydrochloride The product from Example 12(f) (1.2 g. 3.25 mmol) and ammonium acetate (2.5 g, 33 mmol) in acetonitrile (25 ml) were heated at reflux for 6 hr. The mixture was poured into water (150 ml) and extracted with ethyl acetate. The aqueous layer was then basified with 2M NaOH to pH>12 and extracted with ethyl acetate (3 x 200 ml). The combined extracts were washed with saturated sodium bicarbonate, brine, dried (anhydrous MgSO4) and evaporated under reduced pressure to give a white solid. This solid was stirred with I M ethereal hydrochloric acid to give the product as a white solid (0.51 g). M. p. 223-224 °C.

Mass spectrum:/e 211 [Mspectrum:/e 211 [M + H] C10H15N2ClOS requires: C, 48.67; H, 6.13; N, 11.35 ; S, 12. 99 %.

Found: C, 48.86; H. 6.12 : N. 11.40; S, 12.56 (7c.

Example 13 (3-Propan-2-yl)-2,3-dihydro-thieno[2,3-f][1,4]thiazepin-5-yl aminehydrochloride Starting with 2-amino-3-methyl-1-butanol. the title compound was synthesised via the route described for Example 2. M. p. 233-236 °C.

Mass spectrum:/e'27 [M + H]+; C10H15N2ClS2.H2O requires : C, 42.8; H, 6.0; N, 10.0; S. 22.8 %.

Found: C, 43.2; H. 5. 5 : N, 10.0; S, 23.0 %.

Example 14

2'. 3'-Dihydro-spirofcyclopentane-1. 3'-thienor2. 3-f1 f 1. 41thiazepin1-5'-ylamine hvdrochloride a) 3- (1-tert-Butyvcarbonvlamino-cvrclopentylmethvlthiol-thiophene -2-carboxvlic acid and (b) 3-f 1- (tert-butvloxycarbonylamino-methyl)-cvclopentvlthiol-thiophe ne-2-carboxvlic acid 3-Mercapto-2-thiophene carboxylic acid (1. 04 g, 6.47 mmol) was dissolved in dimethylformamide (25 ml) and caesium carbonate (4.64 g, 14.23 mmol) added. The mixture was stirred for 15 minutes at room temperature. O-mesyl-(1-tert- butyloxycarbonylamino)-l-cyclopentane methanol (1.9 g, 6.47 mmol) as a solution in dimethylformamide (25 ml) was added dropwise and the reaction stirred for 48 hours at <BR> <BR> <BR> <BR> room temperature. Water (70 ml) was added and the reaction extracted with ethyl acetate (3 x 30 ml) and the extracts discarded. The reaction was acidified with aqueous 2M hydrochloric acid and extracted with ethyl acetate (3 x 70 ml). Combined extracts were washed with water (4 x 40 ml), dried (anhydrous MgS04) and evaporated. The residue contained the two isomeric products which were purified by chromatography The white solid obtained (0.80 g) was 3: 2 ratio of (a): (b) (by LC/MS).

Mass spectrum: [M-1]+.356 c) 3'. 4'-Dihydro-2'H-spirofcvclopentane-1,3'-thienoF2,3-flf 1. 41thiazepinl-5'-one and (d) 3'. 4'-Dihydro-2'H-spirorCvClopentane-1. 2'-thienor2, 3-flfl, 41thiazepinl-5'-one The mixture from Examples 14 (a) and 14 (b) was dissolved in 4M hydrochloric acid in dioxane and the solution stirred for 3 hours at room temperature. The solvent was removed on a rotary evaporator and the residue dissolved in dimethylformamide (40ml). Bromo-tris- pyrrolidinophosphonium hexafluorophosphate (2.09 g, 4.48 mmol) was added and the solution stirred for 0.5 hours at room temperature. N, N-Diisopropylethylamine (2.0 ml, 11.2 mmol) was then added and the reaction stirred for 18 hours at room temperature.

Water (50 ml) was added and the reaction extracted with ethyl acetate (3 x 70 ml).

Combined extracts were washed with water (4 x 40 ml), dried (anhydrous MgS04) and

evaporated. The residue was passed down a silica gel column eluted with hexane: ethyl acetate (1: 1) to afford the products 14 (c) (0.19 g) and 14 (d) (0.12 g).

Example 14 (c) Mass spectrum :m/e 240 [M + H]+; NMR: (CDCl3) : 1.74-1.98 (m, 8H), 3.18 (s, 2H), 6.19 (bs, 1H), 6.85 (d, 1H), 7.45 (d. 1H).

Example 14 (d) Mass spectrum : m/e 240 [M + H]+; NMR: (CDCl3) : 1.66-1.94 (m. 8H), 3.52 (s, 2H), 6.72 (bs, 1H), 6.82 (d, 1H), 7.47 (d. 1H). e) 3'. 4'-Dihydro-2'H-spirofcvclopentane-1. 3'-thienof2. 3-fl (1. 41thiazepinl-5'-thione The product from example 14 (c) (0.18 g, 0.74 mmol) was dissolved in benzene (25 ml) and [2,4-bis (4-methoxyphenyl)-1.3-dithia-2,4-diphosphetane-2,4-disulfide ] (181 mg, 0.45 mmol) added. The reaction was refluxed for 3.5 hours then after cooling the solvent removed on a rotary evaporator. The residue was purified by chromatography to afford the title compound as a yellow solid (0.17 g).

Mass spectrum: m/e 256 [M + H]+; NMR: (CDCl3) : 1.74-2.04 (m, 8H), 3.20 (s, 2H), 6.86 (d, 1H), 7.50 (d, 1H), 8.11 (bs, 1H). f) 2'. 3'-Dihydro-spiro[cyclopentane-1. 3'-thienof2. 3-f1fI. 41thiazepin1-5'-v) amine hydrochloride The product from Example 14 (e) (0.16 g, 0.63 mmol) was dissolved in acetonitrile (30 ml) and methyl iodide (1.0 ml) added. The solution was stirred for 24 hr at room temperature and then the solvent removed on a rotary evaporator. The residue was dissolved in acetonitrile (20 ml) and ammonium acetate (486 mg, 6.3 mmol) added. The reaction was refluxed for 36 hours. Water (40 ml) was added and the mixture acidified with aqueous 2M hydrochloric acid, extracted with ethyl acetate (3 x 20 ml) and these extracts discarded. The reaction was basified with aqueous 10% sodium hydroxide (pH>12) and extracted with ethyl acetate (3 x 50 ml). Combined extracts were washed with water (2 x 20 ml), dried (anhydrous MgSO4) and evaporated. The residue was dissolved in ethyl acetate and the solution treated with IM hydrochloric acid in diethyl ether. The precipitated solid was filtered off to give the title compound as a white solid (0.09 g). M. p. 260-263 °C.

Mass spectrum: maze 239 [M + H] + ;

CnH) 5N2ClS2 requires: C, 48.1; H, 5.5; N, 10.2; S, 23.3%.

Found: C, 47.9; H, 5.6; N, 10.6; S 24.2 %.

Example 15 2'.3'-Dihvdro-spirofcycIopentane-1,2'-thieno['2.3-f1f1.41thi azepin1-5'-vlamine hvdrochloride The title compound was synthesised via the route described in Examples 14 (e) and 14 (f) starting with the product from Example 14 (d).

Mass spectrum: m/e 239 [Ni + H] +; NMR: (DMSOd6): 1.71-2.04 (m, 8H), 3.48 (d, 2H), 7.06 (d, 1H), 7.76 (1H), 8.89 (bs. 1H), 9.09 (bs, 1H), 11.29 (bs, 1H).

Example 16 3-Butyl-2,3-dihydro-thieno[2,3-f][1,4]oxacepin-5-ylaminehydr ochloride Starting with (2RS)-2-aminohexanol the title compound was synthesised via the route described for Example 12. M. p. 193-195 °C.

Mass spectrum: [M+H]+;241.0833 NMR: (DMSOd6): 0.86 (t. 3H), 1.23-1.41 (m, 4H), 1.61-1.73 (m, 2H), 3.40-3.49 (m.

2H), 3.39 (m, 1H), 7.25 (d, 1H), 8.15 (d, 2H). 8.90 (bs, 2H), 10.1 (d. 1H).

Example 17 3-Buthl-2,3-dihydro-thieno[2,3-f][1,4]thiazepin-5-ylaminehyd rochloride Starting with (2RS)-2-aminohexanol the title compound was synthesised via the route described for Example 2. M. p. 214-215 °C.

Mass spectrum: [M+H]+;261 C11H17N2ClOS requires: C, 50.6; H, 6.6; N, 10.7; S, 12.3 %.

Found: C, 51.3; H, 6.8; N, 10.8; S, 12.0 %.

Example 18 (3S)-3-Phenyl-2,3-dihydro-thieno[2,3-f][1,4]oxazepin-5-ylami nehydrochloride Starting with (2S)-2-phenyl-2-aminoethanol the title compound was synthesised via the route described for Example 12. M. p. 217-219 °C.

Mass spectrum :m/e 245.0739 [M + H] +; Cl3Hl3N2CIOS requires: C, 55.6; H, 4.7; N, 10.0; S, 11.4%.

Found: C, 55.6; H, 4.3; N, 9.0; S, 11.1 %.

Example 19 (2S)-2-Methyl-2,3-dihydro-thieno[2,3-f][1,4]oxazepin-5-ylami nehydrochloride Starting with (R)-1-amino-2-propanol, the title compound was synthesised via the route described for Example 12. M. p. 210-212 °C.

Mass spectrum : m/e 183.0565 [M + H] + ; CgH"N2CIOS requires: C, 43.9; H, 5.1; N, 12.8; S, 14.7 %.

Found: C, 43.8; H, 5.1; N, 12.6; S, 14.5 %.

Example20 (2R)-2-Methyl-2,3-dihydro-thienof2. 3-fl fl. 41oxazepin-5-ylamine hydrochloride Starting with (S)-1-amino-2-propanol, the title compound was synthesised via the route described for Example 12. M. p. 211-212 °C.

Mass spectrum : m/e 183 [M + H] + ; C8H11N2ClOS requires: C, 43.9; H, 5.1; N, 12.8; S. 14.7 %.

Found: C, 43.5; H, 5.1; N, 12.8; S, 14.3 %.

Example 21 (cis)-4a. 5.6.7,8,8a-Hexahydro-thienof3. 2-blbenzoxazepin-10-ylamine hvdrochloride Starting with trans-2-aminocyclohexanol, the title compound was synthesised via the route described for Example 12. M. p. 245-246 °C.

Mass spectrum : m/e 259 [M + H] + ; C11H15N2ClOS requires: C, 51.1; H, 5.8; N, 10.8; S, 12.4 %.

Found: C, 51.1; H, 5.9; N, 10.7; S, 12.1 %.

Example 22 <BR> <BR> <BR> <BR> <BR> (3S)-3- (2-Methylpropyl)-2. 3-dihvdro-thienof 2. 3-f1 (1. 4 oxazepin-5-ylamine hydrochloride Starting with (S)- (+)-leucinol, the title compound was synthesised via the route described for Example 12. M. p. 209-210 °C.

Mass spectrum: m/e 261 [M + H]+; C11H17N2ClOS requires: C, 50.7; H, 6.6; N, 10. 7 %.

Found: C, 50.6; H, 6.5; N 10.6%.

Example 23 Starting with 2-aminoethanol, the title compound was synthesised via the route described for Example 12. It was isolated as the monohydrate. M. p. 113-114 °C.

Mass sepctrum: [M+H]+;169 C7H9N2CIOS. H2O requires: C, 37.8; H, 5.0 ; N, 12.6 ; S, 14.4 %.

Found: C, 38.0; H, 5.1; N, 12. 5; S, 14.1% Example 24 2-Ethyl-2.3-dihydro-thienor2. 3-fl f 1, 41oxazepin-5-ylamine hvdrochloride Starting with l-amino-butan-2-ol, the title compound was synthesised via the route described for Example 12. M. p. 185-187 °C.

Mass spectrum : m/e 197 [M + H] + ; C9H13N2ClOS requires: C, 46.4; H, 5.6; N, 12.0; S, 13.8 %.

Found: C, 46.0; H, 5.7; N, 12.1; S, 14.1%.

Example 25 (3S)-3- (sec-Butyl)-2. 3-dihvdro-thienof2, 3-flrl, 41oxazepin-5-ylamine hydrochloride Starting with (S)- (+)-isoleucinol, the title compound was synthesised via the route described for Example 12. M. p. 216-217 °C.

Mass spectrum : m/e 261 + H] + ; C11H17N2ClOS requires: C, 50.7; H, 6.6; N, 10.8 %.

Found: C, 50.8; H, 6.6; N, 10.8 %.

Example 26 <BR> <BR> <BR> <BR> <BR> 2- (5-Amino-2. 3-dihvdro-thienof2, 3-floxazepin-3-vlmethoxy)-thiophene-2-carboxylic acid methyl ester

a) 3-[2-tert-butyloxycarbonylamino-3-(2-methoxycarbonyl-thiophe n-3-yloxy)- propoxyl-thiophene-2-carboxvlate : b) Methvl 3- (2-tert-butyloxvcarbonylamino-3-hvdroxy-propoxv)-thiophene-2 -carboxvlate (2-tert-Butyloxycarbonylamino)-propane-1, 3-diol (prepared from 2-amino-propane-1,3- diol by the method described for Example 12 (a)) was reacted with methyl 3-hydroxy- thiophene-2-carboxylate by the method described in Example 12 (b). Two products were formed in the reaction which were separated by chromatography on silica gel eluted by hexane: ethyl acetate (4: 1).

The first product off the column was the sub-title compound 26 (a).

NMR: (CDCl3) : 1.47 (s, 9H). 3.83 (s, 6H), 4.11-4.33 (m, 3H), 4.49-4.53 (dd, 2H), 5.77 (bs, 1H), 6.95 (d, 2H), 7.41 (d, 2H).

The second product off the column was the sub-titled compound 26 (b).

Mass Spectrum: [M-1]+;330 NMR: (CDCl3) : 1.45 (s, 9H). 3.79-3.84 (m, 1H), 3.94 (s, 3H), 3.96-3.98 (m, 1H), 4.03-4.08 (m, 2H), 4.30 (d, 1H), 5.73 (bs, 1H), 6.42 (bs, 1H), 6.84 (d, 1H), 7.43 (d, 1H). c) 2- (5-Amino-2. 3-dihvdro-thieno [?. 3-floxazepin-3-vlmethoxv)-thiophene-2-carboxvlic acid methyl ester Starting with the product from Example 26 (a) the title compound was prepared by the route described for Examples 12 (c). 12 (d), 12 (e), 12 (f) and 12 (g). M. p. 170-175 °C.

Mass spectrum: [M+H]+;339 NMR: (DMSOd6): 3.75 (s. 3H), 4.2-4.23 (m, 1H0, 4.30-4.41 (m, 2H), 4.49-4.54 (m. 1H), 4.68 (d, 1H), 6.95 (d, 1H), 7.16 (d, 1H), 7.85 (d, 1H), 8.03 (d. 1H).

Example 27 8-Bromo-3-butyl-2,3-dihydro-thieno[2,3-f][1,4]oxazepin-5-yla minehydrochloride

Starting with (2RS)-2-aminohexanol and methyl 4-bromo-3-hydroxy-thiophene-2- carboxylate the title compound was synthesised via the route described for Example 12.

M. p.: 192-193 °C.

Mass spectrum:/e 303/305 [M + H] ; CllHl6N2BrCIOS requires: C, 38.9; H, 4.8; N, 8.3; S, 9.4 57c.

Found: C, 49.1 ; H, 4.7; N, S, 9.3 %.

Example 28 7,8-Dihydro-6H-thieno[2,3-c]azepin-4-ylaminehydrochloride The title compound was synthesised via the route described in Examples 14 (e) and 14 (f) starting with 5,6,7,8-tetrahydro-thieno [3,2-c] azepine-4-one. M. p. 178-180 °C.

Mass spectrum:/e 167 [M + H] ; NMR: (DMSOd6): 2.18-2.12 (m, 2H), 3.11 (dd, 2H), 3.29 (dd, 2H), 7.39 (d, 1H), 7.59 (d, 1H), 9.05 (bs, 2H), 9.83 (bs, 1H).

Example 29 6-Allyl-7,8-dihvdro-6H-furo 3. 2-clazepin-4-ylamine hydrochloride a) 5-Allyl-6,7-dihydro-SH-benzofuran-4-one.

To a stirred solution of lithium diisopropylamide [prepared from diisopropylamine (2.8 ml) and butyllithium (2.5M in hexanes, 8 ml)] in anhydrous tetrahydrofuran (20 ml) at -78 °C was added a solution of 6,7-dihydro-SH-benzofuran-4-one (2.5 g) in anhydrous tetrahydrofuran (5 ml). The resulting mixture was stirred at-78°C for 30 minutes and then allylbromide (2.6 ml) in anhydrous tetrahydrofuran (5 ml) was added dropwise. The resulting solution was allowed to warm to ambient temperature and was further stirred for 20 hours. The mixture was poured into saturated ammonium chloride solution and was extracted into ethyl acetate (3 x 50 ml), dried over anhydrous magnesium sulphate, filtered

and concentrated to afford an oil that was purified by chromatography on silica gel eluting with ether: hexane (1: 9) to afford the sub-title compound as an oil (1.91 g).

Mass spectrum:/e 176 [M + H] + ; NMR: (CDC13): 1.88-1.98 (m, 1H); 2.18-2.34 (m, 2H); 2.43-2.51 (m, 1H); 2.68-2.78 (m, 1H); 2.84-2.98 (m, 2H); 5.06 (dd, 1H); 5.09 (dd, 1H); 5.78 (dddd, 1H); 6.67 (d. 1H); 7.32 (d, 1H). b) 5-Allyl-6,7-dihydro-SH-benzofuran-4-one oxime.

Sodium acetate trihydrate (3.4 g) was added to a stirred mixture of 5-allyl-6,7-dihydro-SH- benzofuran-4-one (Example 29 (a)) (1.90 g) and hydroxylamine hydrochloride (1.39 g) in ethanol (20 ml) and water (8 ml) and the resulting mixture was heated to 70 °C for 6 hours.

The mixture was cooled and concentrated, the residue was diluted with water (30 ml) and extracted into ethyl acetate (3 x 50 ml), dried over anhydrous magnesium sulphate, filtered and concentrated to afford an oil (2.1 g) that was used directly in the next stage.

Mass spectrum:/e 192 [M + H] +; NMR: (CDC13): (Mixture of (E) and (Z) oximes) 1.86-2.25 (m, 3H); 2.38-2.45 (m, 1HO; 2.61-2.80 (m, 2H); 2.79-2.85 and 3.52-3.56 (2m, 1H); 5.04-5.11 (m, 2H); 5.78-5.91 (m.

1H); 6.53 and 7.10 (2d, 1H): 7.29 and 7.33 (2d, 1H). c) 6-Allyl-5,6,7.8-tetrahydro-furof3, 2-clazepin-4-one.

To a stirred solution of 5-allyl-6,7-dihydro-5H-benzofuran-4-one oxime (Example 29 (b)) (2.1 g) in acetone (50 ml) and aqueous sodium hydroxide solution (1M, 12 ml) was added dropwise with ice bath cooling benzenesulfonylchloride (1.53 ml). After stirring for 30 minutes at 0°C, the cooling bath was removed and the reaction allowed to stir at ambient temperature for 24 hours. The mixture was concentrated, the residue was diluted with water (30 ml) and extracted into ethyl acetate (3 x 50 ml), dried over anhydrous magnesium sulphate, filtered and concentrated to afford an oil that was dissolved in methanol and concentrated hydrochloric acid (2 ml) added. The resulting mixture was stirred at 90 °C for 5 hours. The mixture was cooled and concentrated, the residue was diluted with water (30 ml) and extracted into ethyl acetate (3 x 50 ml), dried over anhydrous magnesium sulphate,

filtered and concentrated to afford an oil that was purified by chromatography on silica gel eluting with ethyl acetate: hexane (1: 1) to afford the sub-titled product as a solid (1.2 g).

Mass spectrum : m/e 192 [M + H] NMR: (CDCl3) : 1.95-1.99 (m, 1H); 2.11-2.17 (m, 1H); 2.29-2.44 (m, 2H) : 2.92-3.07 (m, 2H); 3.48-3.53 (m, 1H): 5.19 (dd, 1H); 5.24 (dd, 1H); 5.75 (dddd. 1H); 5.83 (br, 1H) : 6.78 (d, IH); 7.28 (d, 1H). d) 6-Allyl-7, 8-dihydro-6H-furoF3.2-clazepin-4-ylamine hvdrochloride To a stirred solution of 6-allvl-5,6,7,8-tetrahydro-furo [3,2-c] azepin-4-one (Example 29 (c)) (1.2 g) in anhydrous toluene (30 ml) was added 2,4-bis (4-methoxyphenyl)-1,3-dithia-2. 4- diphosphetane-2,4-disulfide (1.52 g) and the resulting mixture heated to 110°C for 2 hours. cooled and was concentrated onto silica gel (5 g). The residue was poured onto the top of a column filled with silica gel and was purified by elution with ethyl acetate: hexane (1: 4) to afford a yellow oil that was immediately dissolved in acetonitrile (30 ml) and treated with iodomethane (3.7 ml). The resulting mixture was stirred for 20 hours and was concentrated.

The residue was re-dissolved in acetonitrile (100 ml) and ammonium acetate (10 g) added.

The resulting suspension was stirred at 80°C for 4 hours, cooled and concentrated. The residue was diluted with water (30 ml) and washed with diethyl ether (2 x 20 ml). The aqueous layer was basified to pH 10 with IN aqueous sodium hydroxide and was extracted into ethyl acetate (3 x 50 ml), dried over anhydrous magnesium sulphate, filtered and concentrated to afford an oil that was dissolved in acetonitrile (2 ml) and added to a rapidly stirred solution of ethereal hydrogen chloride (1 M, 30 ml). The resulting solid was filtered off to afford the title compound as a white solid (1. lg) Mass spectrum: maze 191 [M-HCl+1]+; NMR: (CDC13): 1.81-2.05 (m, 1H); 2.07-2.13 (m, 1H); 2.40-2.46 (m.? H) ; (m.

2H); 3.64-3.71 (m, 1H) ; 5.18 (dd, 1H) ; 5.22 (dd, 1H) ; 5.87 (dddd, 1 H) : 7.07 (s, 1 H) : 7.84 (d, 1H); 8.69 (br, 1H); 8.89 (br, 1H); 9.63 (d, 1H).

Example 30

6-Allyl-1-methyl-1,6,7 8-tetrahydro-pyrrolof3. 2-clazepin-4-vlamine hvdrochloride 1-Methyl-1,5.6,7-tetrahydro-indole-4-one was converted into the title compound by the procedure described for Example 29.

Mass spectrum :m/e 204.1494 [M + H]+; NMR: (DMSOd6): 1.79-1.86 (m, 1H); 2.08-2.17 (m, 1H); 2.34-2.44 (m, 2H); 2.92 (t, 2H), 3.50-3.60 (m, 1H); 3.56 (s, 3H), 5.14-5.25 (m, 2H) ; 5.82-5.95 (m, 1H) : 6.66 (d, 1H); 6.92 (d, 1H) ; 8.13 (br, 1H); 8.32 (br, 1H); 9.11 (br, 1H).

Example 31 2-Methyl-7.8-dihydro-6H-thiazolo 5. 4-clazepin-4-vlamine The title compound was synthesised via the route described in Examples 14 (e) and 14 (f) starting with [5,4-c] azepine-4-one. M. p. 253-254 °C.

Mass spectrum:/e 260 [M + H] + ; NMR: (DMSOd6): 2.07 (ddt, 2H), 2.74 (s, 3H), 3.14 (t, 2H), 3.41 (dt, 2H), 8.91 (bs, 2H), 10.03 (brt, H).

Example 32 3-[(2-Methylthio)ethyl]-2,3-dihydro-thieno[2,3-f][1,4]oxacep in-5-ylaminehydrochloride Starting with 2-amino-4-methylthio-1-butanol, the title compound was synthesised using the route described for Example 12.

M. p. 188-190 °C.

Mass spectrum : m/e 243 [M + H] +.

Example 33

3-f (2-Metlsulfonyl) ethyll-2. 3-dihvdro-thienof 2. 3-fl f 1. 41oxazepin-5-vlamine hydrochloride 3-[(2-Methylthio)[(2-Methylthio) ethyl]-2,3-dihydro-thieno [2,3-fez [1,4] oxazepin-5-ylamine hydrochloride (prepared in Example 32) was subjected to the reaction conditions described in Example 9 (a) to afford the title compound.

M. p. 223-225 °C.

Mass spectrum:/e 275 [M + H] +.

Example 34 6-Allyl-5.6-dihydro-4H-furof2, 3-clazepin-8-vlamine hvdrochloride a) 5.6-Dihydro-4H-benzofuran-7-one Chloroacetaldehyde (29.7 ml of a 50% weight solution in water, 0.234 mol) and sodium hydrogen carbonate (22.5 g. 0.268 mol) in water (175 ml) were stirred together and cooled (T < 5 °C). 1,2-Cylcohexanedione (25 g, 0.233 mol) dissolved in water (175 ml) was added dropwise over Ih and then the reaction mixture was stirred for 20 h at room temperature before dilution with ethyl acetate (225 ml). 10% Aqueous sulphuric acid was added to achieve pH 2 and the reaction was stirred for 2 h. Neutralisation (to pH 7) was achieved by cautious, portion-wise addition of solid sodium hydrogen carbonate. The reaction was extracted three times with ethyl acetate and the combined organic phases washed with brine and concentrated in vaclio. The residue was purified by flash chromatography, eluting with a gradient of 3: 1 to 2: 1 to 0: 1 isohexane: ethyl acetate to yield the sub-title compound as a brown solid (7.17 g), m. p. 59-62 °C.

Mass Spectrum: m/e 136 [M] +.

NMR (CDC13): 2.13 (m, 2H). 2.57 (t, 2H), 2.78 (t, 2H), 6.42 (d, IH), 7.56 (m, 1H). b) 6-Allyl-5. 6-dihydro-4H-furof2.3-clazepin-8-vlamine hvdrochloride

The product of Example 34 (a) was subjected to the procedures described in Example 29 to afford the title product as a white solid, m. p. 165-173 °C.

Mass Spectrum: [M+H]+.191 NMR (DMSOd6): 1.79 (m, IH), 2.06 (m, 1H), 2.37 (m, 2H), 2.86 (m, 2H). 3.68 (m. 1H).

(m, 2H), 5.83-5.96 (m, 1H), 6.80 (m, H), 8.14 (m, 1H), 8.91-8.98 (m, 2H), 9.89 (bs, 1H).

Example 35 6-Propyl-5,6-dihydro-4H-furo[2,3-c]azepin-8-ylaminehydrochlo ride The title product of Example 34 (b) (0.180 g, 0.946 mmol) (as the free base) was dissolved in ethanol (20 ml). This solution was added to a slurry of 10% palladium on charcoal (catalytic amount) in ethanol. The reaction mixture was stirred for 60 h at room temperature under a hydrogen atmosphere (4.0 bar). The reaction mixture was filtered and concentrated in vacuo. Anhxdrous hydrogen chloride (1M in diethyl ether) was added to the residue and the resulting white precipitate isolated by filtration. The product was washed with diethyl ether and dried in vacuo to yield the title compound (0.070 g), m. p.

147-149 °C.

Mass Spectrum: m/e 193 [NI + H] +.

NMR (DMSOd6): 0.90 (t, 3H), 1.38-1.66 (m, 4H), 1.83 (m, 1H), 2.01 (m. 1H), 2.86 (t, 2H), 3.58 (m, 1H), 6.80 (s, 1H), 8.13 (s, 1H), 8.63 (bs, 1H), 8.93 (bs, 1H), 9.65 (bd, 1H).

Example 36 3-Allyl-2,3-dihydro-thieno[2,3-f][1,4]oxacepin-5-ylamine.

Starting with 2-amino-pent-4-en-l-ol, the title compound was synthesised via the route described for Example 12.

M. p. 95.2-96.2 °C.

Mass Spectrum: [M+H]+.209 NMR (DMSOd6): 2.22-2.41 (m, 2H), 3.43 (m, 1H), 3.88 (m, 1H), 4.33 (m. 1H). 5.03-5.14 (m, 2H), 5.76 (bs, 2H), 5.86-6.00 (m, 1H), 6.71 (d. 1H), 7.52 (d. 1H).

Example 37 2-Ethyl-2,3-dihydro-thieno[2,3-f][1,4]oxacepin-5-ylaminehydr ochloride a) 4- (1- (tert-Butvloxvcarbonvlamino-methyl)-propoxvl-thiophene-3-car boxvlic acid methyl ester To a solution of triphenylphosphine (0.79 g) in dry tetrahydrofuran (10 ml) cooled to 0 °C was added diethyl azodicarboxylate (0.39 ml) and the resulting solution stirred for 10 minutes. A solution of (2-hydroxy-butyl)-carbamic acid tert-butyl ester (0. 38 g) in dry tetrahydrofuran (2 ml) was added dropwise. After complete addition a solution of 4- hydroxy-thiophene-3-carboxylic acid methyl ester (0.32 g) in dry tetrahydrofuran was added. The mixture was stirred for 20 hours and was concentrated onto silica gel (2 g).

The residue was purified by chromatography on silica gel eluting with ethyl acetate : hexane (1: 9) to (1: 4) to afford the sub-titled compound as an oil (0.35 g).

Mass spectrum : m/e 330 [M + H] +.

NMR (CDC13): 1.02 (t, 3H). 1.43 (s, 9H), 1.68-1.82 (m, 2H), 3. 3-3.50 (m. 2H), 3.86 (s.

3H), 4.10-4.18 (m, 1H), 5. 35-5. 45 (m, 1H), 6.44 (d, 1H), 7.96 (d, 1H). b) hydrochloride The compound from Example 37 (a) was subjected to the procedures described in Example 12 (c to g) to afford the title product as a white solid, m. p. 199-199.5 °C.

Mass spectrum : m/e 197 [M + H] +.

NMR (DMSOd6): 0.99 (t, 3H), 1.50-1.66 (m, 2H), 3.31-3.39 (m, 1H), 3.56-3.64 (m, 1H), 4.28-4.37 (m, 1H), 7.13 (d, 1H), 8.36 (dd, 1H), 9.02 (br, 1H), 9.33 (br, 1H). 9.96 (br, 1H).

Example 38

6-Propvl-7.8-dihvdro-6H-furof3, 2-clazepin-4-vlamine hvdrochloride 6-Allyl-7,8-dihydro-6H-furo [3,2-c]-azepin-4-ylamine hydrochloride (Example 29) was hydrogenated according to the procedure described in Example 35 to afford the title compound as a white solid, m. p. 168-169.5 °C.

Mass spectrum:/e 193 [M + H] +.

NMR (DMSOd6): 0.90 (t, 3H), 1.38-1.65 (m, 4H), 1.82-1.92 (m, 1H), 2. 05-2,10 (m, IH), 3.03-3.12 (m, 2H), (m, IH), 7.05 (d, IH), 7.84 (s, 1H), 8.65 (s, 1H), 8.84 (s, IH), 9.69 (s, 1H).

Example 39 6-Allvl-7.8-dihvdro-6H-thienof3.2-clazepin-4-ylamine hydrochloride Starting with 6,7-dihydro-SH-benzo [b] thiophen-4-one, the title compound was synthesised via the route described for Example 29.

M. p. 152-157 °C.

Mass spectrum:/e 207 [M + H] +.

NMR (DMSOd6): 2.02-2.19 (m, 2H), 2.33-2.46 (m, 2H), 2.98-3.09 (m, 1H), 3.13-3.21 (m, IH), 3.36-3.42 (m, IH), 5.09-5.21 (m, 2H), 5.76-5.87 (m, IH), 7.37 (d, IH), 7.59 (d, IH), 8.83 (bs, 1H), 9.12 (bs, 1H), 9.68 (d, 1H).

Example 40 6-Propvl-7.8-dihydro-6H-thienof3. 2-clazepin-4-vlamine hydrochloride Starting with the product of Example 39, the title compound was synthesised via the route described for Example 35.

M. p. 186-190 °C.

Mass spectrum : m/e 209 [M + H] +.

NMR (DMSOd6): 0.86 (t. 3H), (m, 4H), 2.04 (m. 1H), 2.18 (m, 1H). 3.02 (m.

1H), 3.15 (m, 1H), 3.40 (m. 1H), 7.37 (d, 1H), 7.58 (d, 1H).

Example 41 3-Methyl-2.3-dihvdro-thienoF2. 3-fl F 1. 41thiazepin-5-vlamine hvdrochloride a) (2-Hydroxy-l-methyl-ethvl)-carbamic acid tert-butyl ester 2-Amino-1-propanol (2.135 g, 28.4 mmol) was dissolved in tetrahydrofuran (80 ml) and triethylamine (4.4 ml) added. The solution was cooled to 0 °C and di-t-butyldicarbonate (6.82 g, 31.2 mmol) added in one portion. The reaction was stirred for 2 h at 0 °C, then at room temperature for 18 h. Water (100 ml) was added and the mixture extracted with diethyl ether (3 x 80 ml). The combined organic extracts were washed with water (3 x 30 ml), dried (Na2S04) and evaporated in vacaco to give the sub-title compound as a pale yellow oil, (4.49 g, 90%).

NMR (CDCl3) : 1.18 (d, 3H), 1.45 (s, 9H), 2.34 (s, 1H), 2.96-3.03 (m, 1H), 3.23-3.31 (m, 1H, 3.87-3.94 (m, 1H), 4.92 (m, 1H). b) Methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester The compound from Example 41 (a) (4.49 g, 25.6 mmol) was dissolved in dichloromethane (100 ml), triethylamine (4.5 ml) was added, and the solution cooled to 0 °C.

Methanesulfonyl chloride (2.5 ml, 32.0 mmol) in dichloromethane (30 ml) was added dropwise and the resultant solution stirred at 0 °C for 2 h, then room temperature for 18 h.

The reaction was diluted with dichloromethane (150 ml) and washed with water (3 x 60 ml) and brine (40 ml), dried (Na2SO4) and evaporated in vacuo to give the sub-title compound (5.85 g, 90%).

NMR (CDC13): 1.41 (d, 3H), 1.45 (s, 9H) 3.03 (s, 3H), 3.18-3.27 (m, 1H), (m, 1H), 4.84-4.91 (m, 2H).

c) 3- (2-tert-Butoxycarbonvlamino-propylthio)-thiophene-2-carboxyl ic acid and 3- (2-tert-Butoxycarbonylamino-1-methyl-ethylthio)-thiophene-2- carboxylic acid 3-Mercapto-2-thiophene carboxylic acid (1.15 g, 7.2 mmol) was dissolved in N, N- dimethylformamide (50 ml) and caesium carbonate (7.37 g, 22.6 mmol) added. The reaction was stirred for 0.5 h at room temperature and then the product from Example 41 (b) (3.64 g, 14.4 mmol) was added and the reaction stirred for 72 h. The reaction was poured into water (80 ml) and washed with ethyl acetate (3 x 40 ml). The aqueous portion was acidified with aqueous 2M hydrochloric acid and extracted with ethyl acetate (3 x 80 ml). The combined organic extracts were washed with water (3 x 40 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash silica column chromatography, eluting with hexane: ethyl acetate (3: 1), to afford an inseparable mixture of the isomeric sub-titled products (0.68 g. 30%) in a 2: 1 ratio (by LC/MS).

Mass spectrum:/e 316 [M-H]. d) 3-Methyl-3.4-dihvdro-2H-thienof2. 3-fl r 1. 41thiazepin-5-one and 2-Methvl-3. 4-dihvdro- 2H-thienof2. 3-flf 1. 41thiazepin-5-one The mixture of products from Example 41 (c) (0.68 g, 2.14 mmol) was dissolved in 4M hydrochloric acid in 1,4-dioxane and the solution stirred at room temperature for 3 h. The solvent was removed in vacuo. The residue (0.54 g, 2.14 mmol) was dissolved in N, N- dimethylformamide (75 ml) and PyBrop (2.0 g, 4.28 mmol) added in one portion. After stirring for 20 min at room temperature, Hunig's base (1.9 ml, 10.7 mmol) was added dropwise and the resulting solution stirred for 18 h. Water (100 ml) was added and the reaction mixture acidified with aqueous 2M hydrochloric acid, extracted with ethyl acetate (3 x 80 ml) and the combined organic extracts were washed with water (3 x 40 ml), dried (MgS04) and the solvent removed in vacuo. The residue was passed down a flash silica column, eluting with hexane: ethyl acetate (1: 2), to afford the sub-titled products (120 mg) and (60 mg) respectively as white solids.

3-Methyl-3,4-dihydro-2H-thieno thiazepin-5-one:

NMR (CDCI3 + DMSOd6): 1.40 (d, 3H), 3.17 (d, 2H), 3.93-3.99 (m, 1H), 6.86 (d, 1H), 7.07 (s, 1H), 7.47 (d, 1H).

2-Methyl-3,4-dihydro-2H-thieno[2,3-fJ [1, 4] thiazepin-5-one: NMR (CDC13 + DMSOd6): 1.39 (d, 3H), 3.42-3.52 (m, 1H), 3.55-3.72 (m, 2H), 6.85 (d, 1H), 7.47 (d, 1H), 7.51 (s, 1H). e) 3-Methyl-2.3-dihydro-thienof2. 3-flfl, 41thiazepin-5-ylamine hydrochloride 3-Methyl-3, 4-dihydro-2H-thieno [2,3-f] [1, 4] thiazepin-5-one [one of the products of Example 41 (d)] was subjected to the procedures described in Examples 12 (e-g) to afford the title product as a white solid, m. p. 233-237 °C.

Mass Spectrum : m/e 199 [M + H] +.

NMR (CDC13 + DMSOd6): 1.57 (d, 3H), 3.31-3.47 (m, 2H), 3.90-4.01 (m, 1H), 7.09 (d, 1H), 7.77 (d, 1H), 8.81-9.17 (m, 2H), 10.83-10.92 (m, 1H).

Example 42 2-Methvl-2, 3-dihvdro-thienof2. 3-fl f 1, 41thiazepin-5-vlamine hvdrochloride 2-Methyl-3,4-dihydro-2H-thieno [2, 3-f] [1,4] thiazepin-5-one [one product from Example 41 (d)] was subjected to the procedures described in Example 12 (e-g) to afford the title product as a white solid, m. p. 186-189 °C.

Mass 199[M+H]+.m/e NMR (CDCI3+ DMSOd6): 1.42 (d, 3H), 3.36-3.46 (m, 1H), 3.67-3.76 (m, 1H), (m, 1H), 7.08-7.13 (m, 1H), (m, 1H), 8.95-9.22 (m, 2H), (m, 1H).

Example 43 (3S)-3-Ethyl-2-methyl-2,3-dihydro-thieno[2,3-f][1,4]oxacepin -5-ylaminehydrochloride

a) f (1 S)-I-L (Methoxvmethvlamino) carbonyllpropvl}-carbamic acid tert-butyl ester (2S)-2-[[(tert-Butoxy)carbonyl] amino] butanoic acid (3.937 g, 19.4 mmol) was dissolved in dichloromethane (80 ml) and N-methylmorpholine (3.927 g. 38.8 mmol) added. The solution was cooled to-15 °C and iso-butylchloroformate (2.5 ml, 19.4 mmol) added. The reaction was stirred at-15 °C for 20 minutes, then N, O-dimethylhydroxylamine hydrochloride (1.95 g, 20.0 mmol) added. The mixture was stirred at-15 °C for I hour then allowed to warm to room temperature and stirred for 3.5 hours. Water (100 ml) was added and the layers separated. The aqueous portion was extracted with dichloromethane (2 x 80 ml) and the combined organic extracts washed with water (40 ml), dried (Na2SO4) and evaporated in vaclo to give the title compound as a white solid (3.55g, 74%).

NMR (CDC13): 0.92-0.96 (m. 3H), 1.44 (s, 9H) 1.54-1.61 (m, 1H), 1.74-1.79 (m, 1H), 3.21 (s, 3H), 3.77 (s, 3H), 4.64 (m, 1H), 5.18 (m, 1H). b) f (1S)-1-Ethyl-2-oxopropvll-carbamic acid tert-butyl ester The product of Example 43 (a) (2.13 g, 8.65 mmol) was dissolved in anhydrous tetrahydrofuran (80 ml) and cooled to 0 °C. Methyl magnesium bromide (3M in diethyl ether) (14.4 ml, 43.24 mmol) was added dropwise whilst maintaining a temperature of 0 °C. The reaction was allowed to warm to room temperature and stirred for 18 hours.

Aqueous 2M hydrochloric acid (40 ml) was added cautiously and the mixture extracted with ethyl acetate (3 x 70 ml). The combined organic extracts were washed with water (2 x 40 ml) and brine (30 ml), dried (Na, S04) and evaporated in vacaco to afford the title compound as a colourless oil (1.61 g, 93%).

NMR (CDC13): 0.89 (t, 3H). 1.44 (s, 9H), 1.54-1.66 (m, 1H), 1.90-1.99 (m, IH), 2.20 (s, 3H), 4.28-4.34 (m, 1H), 5.21 (s, 1 H). c) f (lS)-1-Ethyl-2-hvdroxyropvll-carbamic acid tert-butyl ester The product of Example 43 (b) (1.61 g, 8.0 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml) at 0 °C and sodium borohydride (0.726 g, 19.2 mmol) was added in one portion. The reaction was stirred for 2 hours at 0 °C, then room temperature for 18 h.

Water (80 ml) was added followed, cautiously, by aqueous 2M hydrochloric acid. The

mixture was stirred for 15 minutes then extracted with diethyl ether (3 x 100 ml). The combined organic extracts were washed with brine (40 ml), dried (Na, S04) and evaporated in vacuo to give the product as a 1: 3 mixture of diastereoisomers (by NMR). (1.3 g).

NMR (CDCl3) : (m, 3H), (2 x d, 3H), 1.2-1.4 (m, 1H). (2 x s.

9H), 1.50-1.65 (m, 1H), 2.7 (bs, 1H), 3.3-3.5 (2 x m, 1H), 3.7-3.9 (m, 1H), 4.50-4.70 (2 x m, 1H). d) hydrochloride Starting with the product from Example 43 (c), the title compound was synthesised via the route described for Example 12. The product was obtained as two diastereomers.

Diastereoisomer 1: M. p. 251-255 °C.

Mass Spectrum: m/e 211 [M + H] +.

NMR (CDCl3 + DMSOd6): 1.14 (t, 3H), 1.39 (d, 3H), 1.65-1.74 (m, 2H), (m, 1H), 4.57-4.63 (m, 1H), 6.77 (d, 1H), 7.71 (d, 1H), 8.62 (s, 2H), 10.70 (s, 1H) Diastereoisomer 2: M. p. 217-220 °C.

Mass Spectrum : m/e 211 [M + H] +.

NMR (CDC13+DMSOd6): 1.05 (t, 3H), 1.34 (d, 3H), 1.50-1.60 (m, 1H), 1.62-1.73 (m.

1H), 3.56-3.61 (m, 1H), 4.68-4.74 (m, 1H), 6.80 (d, 1H), 7.87 (d, 1H), 8.61 (s, 2H).

Example 44 (3R)-3-Ethyl-2-methvl-2. 3-dihydro-thienof2. 3-flflt, 41oxazepine-5-ylamine hvdrochloride a) (1R)-1-Ethyl-2-hydroxypropyl]-carbamic acid tert-butyl ester Starting with (2R)-2-[[(tert-butoxy) carbonyl] amino] butanoic acid, the sub-titled product was prepared by the procedure described in Examples 43 (a-c).

NMR (CDC13): (m, 3H), (2 x d, 3H), 1.25-1.4 (m, 1H), 1.45-1.50 (2 x s, 9H), 1.50-1.65 (m, 1H), 2.7-2.8 (bs, 1H), 3.3-3.5 (2 x m, 1H), 3.75-3.95 (m, 1H), 4.45-4.70 m,1H).(2x b) (3R)-3-Ethyl-2-methyl-2. 3-dihvdro-thienof2, 3-flf 1. 41oxazepin-5-vlamine hydrochloride Starting with the product from Example 44 (a), the title compound was synthesised via the route described for Example 12. The product was obtained as two diastereomers.

Diastereoisomer 1: M. p. 190-195 °C.

Mass Spectrum : m/e 211 [M + H] +.

NMR (CDCl3 + DMSOd6): 1.11 (t, 3H), 1.38 (d, 3H), 1.55-1.76 (m, 2H), 3.49-3.57 (m, 1H), 4.62-4.70 (m, 1H), 6.78 (d, 1H), 7.72 (d, 1H), 10.59 (s, 1H).

Diastereoisomer 2: M. p. 238-240 °C.

Mass Spectrum: m/e 21 1 [M + H]+.

NMR (CDC13 + DMSOd6): 1.14 (t, 3H), 1.39 (d, 3H), (m, 2H). 3.56-3.63 (m, 1H), 4.58 (d, 1H), 6.77 (d, lH), 7.70 (d, 1H), 10.70 (s, 1H).

Example 45 2-Phenyl-2.3-dihydro-thienor2. 3-f][ 1,41oxazepin-5-amine Starting with 2-amino-1-phenylethanol, the title compound was prepared following the procedure described in Example 12.

M. p. 142-145 °C.

Mass Spectrum: m/e 245 [M + H] +.

NMR (CDC13 + DMSOd6,): 3.81 (q, 1H), 4.01 (d, 1H), 4.24 (s, 2H), 5.19 (d, 1H), 6.80 (d.

1H), 7.29-7.41 (m, 6H).

Example 46 4a, 5.6.7.8.8a-Hexahvdro-thienof3. 2-bl r 1. 51benzoxazepin-10-ylamine hvdrochloride Starting with cis-2-aminocyclohexanol hydrochloride, the title compound was prepared following the procedure described in Example 12.

M. p. 278-279 °C.

Mass spectrum : m/e 223 [M + H] +.

NMR (DMSOd6): 1.24 (m, 2H), 1.45 (m, 2H), 1.69 (m, 2H), 2.18 (m, 2H), 3.48 (m, 1H), 4.24 (m, 1H), 6.86 (d, 1H), 7.92 (d, 1H), 8.38 (bs, 2H).

Example 47 3-Butyl-8-chloro-2.3-dihvdro-thienof2.3-fl F I. 41Oxazepin-5-vlamine hvdrochloride a) 8-Bromo-3-butyl-3,4-dihydro-2H-thieno[2,3-f][1,4]oxaceipin-5 -one The sub-title compound was prepared from methyl-4-bromo-3-hydroxythiophene-2- carboxylate and 2-amino-hexan-1-ol via the procedures described in Examples 12 (a-d).

Mass spectrum: m/z 304/305 [M + H] +.

NMR (CDCl3) : 0.92 (t, 3H), 1.41 (m, 4H), 1.62 (m, 2H), 3.59 (m, 1H), 4.34 (m, 1H), 4.44 (d, 1H), 6.29 (bs, 1H), 7.43 (s, 1H). b) 8-Chloro-3-butyl-3,4-dihydro-2H-thieno[2,3-f][1,4]oxacepin-5 -one The product from Example 47 (a) (0.61 g, 2. 0 mmol) and cuprous chloride (0.2 g, 2.0 mmol) were suspended in l-methyl-2-pyrrolidinone and the reaction mixture was heated at 200 °C for 3 days. After cooling, the reaction mixture was poured onto water (100 ml) and extracted with ethyl acetate (insoluble copper salts were removed via filtration through

glass fibre filter paper). The organic extracts were then dried (anhydrous magnesium sulphate) and evaporated. The residue was passed down a silica gel column eluted with hexane: ethyl acetate (1: 2) then ethyl acetate to give a pale yellow oil (0.43 g).

Mass spectrum:/e 260/262 [M + H] +. c) 3-ButvI-8-chIoro-2.3-dihvdro-thienof2.3-/1f1.41oxazepin-5-yl aminehydrochloride The product from Example 47 (b) was converted into the title compound via the procedures described in Example 12 (e-g).

M. p. 205-206 °C.

Mass spectrum:/e 259/261 [M + H] +.

NMR (DMSOd6): 0.88 (t, 3H), 1.32 (m, 2H), 1.42 (m, 2H), 1.57 (m, 2H), 3.89 (m, 1H), 4.56 (m, 2H), 8.25 (s, 1H), 8.80 (br s, 2H), 10.26 (br s, 1H).

Example 48 5-Amino-3-butyl-2. 3-dihydro-thienof2, 3-fl f 1, 4loxazepine-8-carbonitrile hydrochloride The product of Example 47 (a) and copper (I) cyanide were subjected to the reaction conditions described in Example 47 (b) to give a light brown oil. This was converted into the title compound via the route described for Example 12 (e-g).

M. p. 240-241 °C.

Mass spectrum:/e 250 [M + H]+.

NMR (DMSOd6): 0.88 (t, 3H), 1.33 (m, 4H), 1.61 (m, 2H), 3.92 (br s, 1H), 4.59 (m, 2H), 8.94 (br s, 2H), 9.00 (d, 1H), 10.34 (s, 1H).

Example 49 (5-Amino-2.3-dihydro-thienof2, 3-flFI, 41oxazepin-3-yl)-methanol hydrochloride a) 3-Hydroxymethyl-3,4-dihvdro-2 H-thienof2, 3-flf 1. 41oxazepin-5-one

Starting with 2-amino-1,3-propanediol, the sub-title compound was synthesised via the procedures described for Example 12 (a-d).

Mass spectrum:/e 199 [M] +. b) H-thieno[2,3-f][1,4]oxazepin- 5-one The product of Example 49 (a) (3.0 g, 15 mmol) was added to a solution of tert-butyldimethylsilyl chloride (2.5 g. 16.5 mmol) in a mixture of dimethylformamide (5 ml) and dichloromethane (50 ml). Imidazole (2.8 g, 41 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with 2M hydrochloric acid, water and brine. The organic phase was dried (anhydrous MgS04) and evaporated onto silica gel. The residue was passed down a silica gel column eluted with hexane: ethyl acetate (1: 3 to 1: 2) to give the sub-title compound as a white solid (3.3 g).

Mass spectrum : m/e 314 [M + H] +. c) (5-Amino-2,3-dihydro-thienor2. 3-fl f l, 41oxazepin-3-vl)-methanol hvdrochloride Starting with the product of Example 49 (b), the title compound was synthesised via the route described for Examples 12 (e-g), using ethanolic hydrochloric acid in the final step.

Mass spectrum:/e 199 [M + H]+.

NMR (DMSOd6): 3.57 (m, IH), 3.65 (m, 1H), 3.83 (m, 1H), 4.38 (m, 1H), 4.57 (d, 1H), 6.96 (d, 1H), 8.09 (d, 1H), 8.54 (br s, 2H), 9.78 (d, 1H).

Example 50 4- (5-Amino-2, 3-dihydro-thienof2. 3-flf 1.41oxazepin-3-ylmethoxy-benzonitrile a) 4- (5-Oxo-2 3.4.5-tetrahvdro-thienof2, 3-f][1, 41oxazepin-3-ylmethoxv)-benzonitrile Starting with the product of Example 49 (a) and 4-cyanophenol, the sub-title compound was synthesised via the procedure described in Example 12 (b).

Mass spectrum : m/e 299 [M-H]'. b) 4- (5-Amino-2, 3-dihydro-thienor2. 3-flrl, 41oxazepin-3-vlmethoxy)-benzonitrile Starting with the product of Example 50 (a), the title compound was synthesised via the route described for Example 12 (e-g).

M. p. 243-244 °C.

Mass spectrum : m/e 300 [M + H] +.

NMR (DMSOd6): 4.34 (m, 3H), 4.63 (m, 2H), 6.98 (d, 1H), 7.13 (d, 2H). 7.80 (d, 2H).

8.12 (d, 1H), 8.68 (br s, 2H), 10.12 (d, 1H).

Example 51 3- (3-Nitro-phenoxvmethyl)-2. 3-dihydro-thienof 2. 3-fl f 1, 41oxazepin-5-ylamine hydrochloride a) 3- (3-Nitro-phenoxymethyl)-3. 4-dihydro-2-thienof2, 3-f) fl, 41oxazepin-5-one Starting with the product of Example 49 (a) and 3-nitrophenol, the sub-title compound was synthesised via the procedure described in Example 12 (b).

Mass spectrum : m/e 320 [M] +. b) 3- (3-Nitro-phenoxvmethvl)-2. 3-dihydro-thienof2. 3-flfl. 41oxazepin-5-ylamine hydrochloride Starting with the product of Example 51 (a), the title compound was synthesised via the route described for Examples 12 (e-g).

M. p. 208-210 °C.

Mass spectrum: m/e 320 [M + H] +.

NMR (CDC13): 3.97 (m, 1H), 4.13 (m, 2H), 4.36 (m, 1H), 4.73 (d, 1H), 6.73 (d, 1H), 7.28 (m, 2H), 7.44 (t, 1H), 7.82 (m, 2H).

Example 52

3- (3-Amino-phenoxymethvl)-2. 3-dihydro-thieno f 2. 3-fl f 1. 41oxazepin-5-vlamine dihydrochloride A slurry of 10% palladium on charcoal (20 mg) in ethanol (5 ml) was added to a suspension of the product of Example 51 (b) (0.12 g) in a mixture of dry ethanol (20 ml) and methanol (5 ml). The reaction mixture was then stirred under 1 atmosphere of hydrogen for 16 h. Removal of the catalyst by filtration followed by evaporation of the filtrate gave a light grey solid (0.11 g). This solid was triturated with IM ethereal hydrochloric acid to give the title product as a light grey solid (0.1 g), m. p. 230-231 °C Mass spectrum:'/e 290 [M + H] +.

NMR (DMSOd6): 4.16 (m. 1H), 4.27 (m, 2H), 4.63 (m, 2H), 6.78 (d. 3H), 6.99 (d, 1H), 7.30 (t, 1H), 8.12 (d, 1H), 8.71 (br s, 2H), 10.20 (d, 1H).

Example 53 6-Allyl-2-bromo-7.8-dihydro-6H-thienoF3.2-clazepin-4-vlamine hvdrochloride Starting with 2-bromo-6,7-dihydro-5 H-benzo [b] thiophen-4-one (prepared by the procedure described in J. Chem. Soc. (C), 1969,2750), the title compound was synthesised via the route described for Example 29.

M. p. 222-228 °C.

Mass spectrum: m/e 285 [M + H] +.

NMR (DMSOd6): 2.05 (m, 1H), 2.15 (m, 1H), 2.35 (m, 2H), 2.99 (dt, 1H), 3.13 (ddd, 1H), 3.46 (1H, m), 5.14 (m, 2H). 5.82 (ddt, 1H), 7.49 (s, 1H), 9.26 (bs, 3H).

Example 54 6-Allyl-3-bromo-7,8-dihydro-6H-thieno[3,2-c]acepin-4-ylamine hydrochloride

a) 6-Allvl-3-bromo-5.6.7. 8-tetrahydro-thieno[3,2-c] azepin-4-one To 6-allyl-2-bromo-5,6,7,8-tetrahydro-thieno [3,2-c] azepin-4-one (an intermediate prepared in Example 53) (0.58 g, 2.01 mmol) in tetrahydrofuran (5 ml) was added sodium hydride (97 mg of a 60% dispersion in mineral oil, 2.4 mmol) and the reaction stirred for 1 h. After cooling to-78 °C, lithium diisopropylamide (1.2 ml of a 2M solution in tetrahydrofuran, 2.4 mmol) was added dropwise and the reaction warmed to-30 °C over 0.5 h. After re-cooling to-78 °C, methanol was added and the reaction was then warmed to room temperature. Aqueous 2M hydrochloric acid and ethyl acetate were added and the organic layer was separated. dried (anhydrous MgSO4) and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate: hexane (1: 2) and re- crystallisation from dichloromethane: hexane to afford the sub-titled product as a beige solid (0.3 g).

NMR (CDC13): 2.00 (m, 2H), 2.34 (m, 2H), 2.92 (ddd, 1H), 3.11 (ddd, 1H), 3.46 (m, 1H), 5.22-5.15 (m, 2H), 5.76 (m. 2H), 7.07 (s, 1H). b) 6-Allvl-3-bromo-7, 8-dihvdro-6H-thieno 3. 2-clazepin-4-vlamine hydrochloride The product of Example 54 (a) was subjected to the procedures described in Example 29 (d) to afford the product as a beige solid, m. p. 213-216 °C.

Mass spectrum : m/e 285 [M + H] +.

NMR (DMSOd6): 2.08 (m. 2H), 2.35 (m, 2H), 2.95 (m, 1H), 3.13 (dd, 1H), 3.34 (m. 1H), 5.15 (m, 2H), 5.79 (ddt, 1H), 7.77 (s, 1H), 9.01 (s, 1H), 9.20 (s, 1H), 10.08 (d, 1H).

Example 55 <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- (6-Bromo-naphthalen-2-vloxvmethyl)-2. 3-dihydro-thienof2. 3-fl ( 1 (4loxazepin-5-vlamine hydrochloride Starting with 6-bromo-naphthalen-2-ol and the product of Example 49 (a), the title compound was synthesised via the route described for Examples 12 (b) and 12 (e-g) to afford the title product as a yellow solid, m. p. 210 (dec) °C.

Mass spectrum:/e 403 [M + H] +.

NMR (CD30D): 4.39 (m, 2H), 4.46 (m, 1 H), 4.70 (m, 2H), 6.93 (d, 1 H), 7.21 (dd, 1H).

7.31 (s, 1H), 7.52 (dd, 1H). 7.70 (d, 1H), 7.74 (d, IH), 7.97 (s, 2H).

Example 56 2.3-Dihydro-1 H-thienoF3. -e lrl. 41diazepin-5-vlamine hydrochloride a) 3- (2-tert-Butoxvcarbonvlamino-ethvlamino)-thiophene-2-carboxvl ic acid methvl ester A mixture of 3-amino-thiophene-2-carboxylic acid methyl ester (3.14 g, 20 mmol) and 2- bromo-ethylamine hydrobromide (4.10 g, 20 mmol) in dioxane (20 ml) was heated at 100 °C for 16 h. After cooling to room temperature it was poured into ethyl acetate. The organic solution was washed sequentially with aqueous potassium carbonate solution, aqueous IN sodium hydroxide solution and brine. The solution was then dried (anhydrous MgSO4) and evaporated. The residue was taken up in dichloromethane (20 ml) and triethylamine (6.9 ml, 50 mmol), and solid di-tert-butyl dicarbonate (5.4 g, 24.9 mmol) was added in small portions. After 2 h at room temperature, the solvents were removed and the residue was purified by chromatography on silica gel eluting with dichloromethane: hexane (75 : 25 to 100: 0) to afford the sub-titled product as a yellow oil (1.0 g).

NMR (CDC13): 1.45 (s, 9H). 3.32 (m, 2H), 3.41 (dt, 2H), 3.81 (s, 3H), 4.80 (bs, 1H). 6.70 (d, 1H), 6.86 (bs, 1H), 7.34 (d, 1H). b) 1. 2, 3, 4-Tetrahydro-thienoF3, 2-e lrl. 41diazepin-5-one The product of Example 56 (a) was dissolved in 4N hydrogen chloride in 1,4-dioxane (40 ml) and stirred at room temperature for 16 h. The solvents were removed and the residue dissolved in methanol (10 ml). Sodium methoxide (2 ml of a 4.6M solution in methanol) was added and the reaction refluxed for 48 h. After cooling to room temperature the solvents were removed and the residue was purified by chromatography on silica gel eluting with dichloromethane: methanol (100: 0 to 90: 10) to afford the sub-titled product as a yellow solid (1.0 g).

NMR (DMSOd6): 3.32-3.21 (m, 4H), 6.49 (d, 1H), 7.01 (bs, 1H), 7.42 (d, 1H). 7.51 (bs, 1H). c) e][1,4]diazepin-5-ylaminehydrochlorideH-thieno[3,2- The product of Example 56 (b) was subjected to the procedures described in Example 12 (e- g) to afford the title product as a beige solid, m. p. 65 (dec) °C.

Mass spectrum : m/e 168 [M + H] +.

NMR (DMSOd6): 3.44 (bs. 2H), 3.51 (bs, 2H), 6.70 (d, 1H), 7.83 (d, 1H), 7.98 (bs, 2H), 8.30 (bs, 1H), 9.35 (bs, 1H).

Example 57 2-(But-3-enyl)-2. 3-dihvdro-thienor2. 3-fl F 1. 41 oxazepin-5-vlamine hvdrochloride a) 3- (1-Aminomethyl-pent-4-eny ov)-thiophene-2-carboxylic acid methyl ester To a solution of methyl 3-hydroxythiophenecarboxylate (3.01 g, 19 mmol), 1-azido-5- hexen-2-ol (2.82 g, 20 mmol) (as described in Tetrahedron Letters (1998), 39,4337-8), and triphenylphosphine (11.64 g, 44.4 mmol) in dry toluene (100 ml) under nitrogen at 0 °C. was added diethyl azodicarboxylate (3.65 g, 3.6 ml, 21 mmol). The mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was filtered and evaporated. The residue was dissolved in acetonitrile (50 ml) and water (25 ml) was added.

The solution was stirred at room temperature for 18 h. The crude reaction mixture was then concentrated in vacuo and partitioned between ethyl acetate and aqueous 2N hydrochloric acid. The aqueous phase was basified with aqueous 2N sodium hydroxide solution, and extracted with ethyl acetate. dried (Na2SO4) and evaporated to leave a pale yellow oil (2.2 g, 45%).

Mass spectrum: m/e 256 [Ii + H]+.

NMR (CDC13): 1.68-1.98 (m, 2H), 2.17-2.24 (m, 2H), 2.89-2.99 (m, 2H), 3.84 (s, 3H), 4.18-4.24 (m, 1H), 4.98-5.06 (m, 2H), 5.77-5.89 (m, 1H), 6.85 (d, 1H) and 7.39 (d, 1H).

b) hydrochloride The product of Example 57 (a) was converted into the title compound using the methods described in Example 12 (d-C).

M. p. 201-202 °C.

Mass spectrum:/e 223 [M + H]+.

NMR (DMSOd6): 1.72-1.82 (m, 2H), 2.18-2.25 (m, 2H), 3.50-3.82 (m, 2H), 4.42-4.48 (m.

1H), 5.00-5.11 (m, 2H), (m, 1H), 6.94 (d, 1H), 8.09 (d, 1H) and 8.20 (v br. s, 2H).

Example 58 2-Butyl-2,3-dihvdro-thienof2. 3-fl (l, 41oxazepin-5-vlamine hydrochloride The product from Example 57 (b) (0.095 g, 0.37 mmol) in ethanol (5 ml) containing 10% palladium on carbon (0.005 g) was subjected to 3 atmospheres of hydrogen for 16 h. The suspension was filtered and evaporated to dryness to leave the title compound as a white solid (0.091g, 95%), m. p. 207-208 °C.

Mass spectrum: m/e 225 [M + H] +.

NMR (CDC13): 0.94 (t, 3H). 1.35-1.57 (m, 3H), 1.64-1.88 (m, 3H), 3.39-3.83 (m, 2H), 4.27-4.34 (m, 1H), 6.79 (d, 1H) and 7.63 (d, 1H).

Example 59 r(2-But-3-enyI)-2.3-dihydro-lhienor2.3-/H'l.41oxazepin-5-yI1 -carbamic(2-But-3-enyI)-2.3-dihydro-lhienor2.3-/H'l.41oxazep in-5-yI1-carbamic acid tert-butvl ester To a solution of the product from Example 57 (b) (0.91 g, 3.52 mmol) in 10% aqueous potassium carbonate (50 ml). was added di-tert-butyl dicarbonate (0.77 g, 3.52 mmol). The reaction mixture was stirred at room temperature for 16 h, extracted with ethyl acetate, <BR> <BR> <BR> dried (Na2SO4) and evaporated to leave the title compound as a pale yellow gum (1.13 g, 100%).

Mass spectrum: [(M-BOC)+H]+.223 NMR (CDC13): 1.55 (s, 9H), 1.64-1.94 (m, 2H), 2.24-2.30 (m, 2H), 3.59-3.66 (m, 1H).

4.22-4.28 (m, 2H), 5.01-5.11 (2H), 5.77-5.91 (m, 1 H), 6.59 (d, 1 H), 7.25 (d, 1 H) and 9.13 (bd. s, 1H).

Example60 2-r(3E)-4-(6-Methoxy-pvridin-3-yl)-but-3-enyll-2. 3-dihvdro-thienoF2. 3-fl r 1. 41 oxazepin-5- ylamine hydrochloride To a solution of the product of Example 59 (0.161 g, 0.5 mmol), palladium (II) acetate (0.005 g, 4 mol%) and tri-o-tolylphosphine (0.006 g, 4 mol%) in triethylamine (5 ml) was added 5-iodo-2-methoxypyridine (0.117 g, 0.5 mmol). The mixture was heated at 70 C for 4 h, cooled to room temperature and concentrated in vacuo. Flash chromatography on silica gel eluting with triethylamine: ethyl acetate: dichloromethane, 1: 25: 74 afforded a pale yellow oil. This oil was triturated with IN hydrogen chloride in diethyl ether to leave the title compound as a pale yellow solid (0.062 g, 38%).

Mass spectrum : m/e 330 [M + H] +.

NMR (CDC13): 1.75-1.97 (m, 2H), 2.40-2.46 (m, 2H), 3.63-3.70 (m, 1H), 3.92 (s, 3H).

4.24-4.34 (m, 2H), 6.08-6.16 (m, 1H), 6.37 (d, 1H) 6.60 (d, 1H), 6.70 (d, 1H), 7.26 (d, 1H), 7.62 (dd, 1H) and 8.06 (d, 1H).

Example 61 3-(1,2,3,4-Tetrahydro-isoquinolin-7-yloxymethyl)-2,3-dihydro -thieno[2,3-f][1,4]oxapin-5- ylamine dihydrochloride a) 7- (5-Oxo-2.3.4. 5-tetrahydro-thieno[2,3-f][1,4]oxacepin-3-ylmethoxy)-3,4-dih ydro- (lH)-isoquinoline-2-carboxvlic tert-butyl ester.

Starting with the product of Example 49 (a) and 7-hydroxy-3, 4-dihydro-(1H)-isoquinoline- 2-carboxylic acid tert-butyl ester (1.27 g, 5.1 mmol) (prepared as described in J. Nled.

Chem. (1998), 41,4983-4994), the sub-title compound was prepared by the procedure described Example 12 (b).

Mass spectrum : m/e 331 [ (M-BOC) + H] +.

NMR (CDCl3) : 1.49 (s, 9H), 2.74-2.78 (m, 2H), 3.60-3.64 (m, 2H), 3.97-4.04 (m. 2H), 4.10-4.17 (m, 1H), 4.40-4.58 (m, 4H), 6.50 (bd. s, 1H), 6.64 (s, 1H), 6.68-6.75 (m. 2H), 7.05 (d, 1H) and 7.41 (d, 1H). b) 3-(1. 3- f 41Oxapin-5-vlamine dihvdrochloride Starting with the product of Example 61 (a), the title compound was prepared using the procedures described in Example 12 (e-g).

Mass spectrum : m/e 330 [M + H] +.

NMR (DMSOd6): 2.90-2.95 (m, 2H), 3.34-3.38 (m, 2H), 4.10-4.34 (m, 5H), 4.61-4.65 (m, 2H), 6.86-6.90 (m, 2H), 6.98 (d, 1H), 7.15 (d, 1H), 8.11 (d, 1H) 8.72 (bs, 2H), 9.37 (bs, 2H) and 10.16 (bs, 1H).

Example 62 2-Aminomethyl-2. 3-dihydro-thienof2. 3 1.41oxazepin-5-vlamine dihvdrochloride a) 3-(2-amino-1-aminomethyl-ethoxy)-thiophene-2-carboxylic acid methvl ester dihydrochloride Starting with (3-tert-butoxycarbonylamino-2-hydroxypropyl)-carbamic acid tert-butyl ester, the sub-titled compound was synthesised according to the procedures described in Examples 12 (b-c).

Mass spectrum : m/e 231 [M + H] +.

NMR (DMSOd6): 3.1-3.5 (m. 4H), 3.79 (s, 3H), 4.92 (quin, 1H), 7.46 (d, 1H), 7.91 (d, 1H), 8.39 (bs, 6H).

b)2-Aminomethyl-3,4-dihydro-2H-thieno[2,3-f][1,4]oxacepin-5- one Trimethylaluminium (2M in toluene, 0.86 ml, 1.73 mmol) was added to the product from Example 62 (a) (0.5 g, 1.73 mmol) in toluene (20 ml) at 0 °C under a nitrogen atmosphere.

The solution was stirred at 80 °C for 18h. Methanol (I ml) was added carefully and the resulting solution was concentrated onto silica and purified by column chromatography eluting with methanol: dichloromethane (1: 20) to leave a solid (0.1 g).

Mass spectrum:"'/z 199 [M + H] +.

NMR (DMSOd6): 1.68 (s, 2H), 2.70 (dd, 1H), 2.88 (dd, 1H), 3.21 (ddd, 1H), 3.53 (dd. IH), 4.03 (dt, 1H), 6.73 (d, 1H), 7.66 (d, 1H), 8.08 (d, 1H). c) (5-Oxo-2, 3, 4. 5-tetrahydro-thienor2, 3-filrl, 4loxazepin-2-ylmethyl)-carbamic acid tert- butvl ester A solution of the product from Example 62 (b) (3.5 g, 15 mmol), di-tert-butyl dicarbonate (4.0 g, 18 mmol) and triethylamine (10 ml, 70 mmol) in methanol: water (1: 1,200 ml) was stirred for 20 h. The solution was concentrated in vaccco and 2M hydrochloric acid was added. The mixture was extracted three times with ethyl acetate and the ethyl acetate phases were combined, dried (Na2SO4) and concentrated to a solid (4.2 g).

Mass spectrum: m/e 299 [M + H] +.

NMR (CDCl3) : 1.42 (s, 9H), 3.4-3.7 (m, 4H), 4.32 (dt, 1H), 4.99 (bt, 1H), 6.67 (d, 1H), 6.65 (bs, 1H), 7.40 (d, 1H). d) acid tert-butyl ester A mixture of the product from Example 62 (c) (4.2 g) and Lawesson's reagent (2.5 g, 6.2 mmol) in benzene (100 ml) was heated at 75 °C for 5h. The resulting mixture was concentrated onto silica and purified by column chromatography eluting with petrol: ethyl acetate (3: 1 to 1: 1) to leave a yellow solid (2.3 g).

Mass spectrum: maze 214 [M-100]-.

NMR (CDCl3) : 1.42 (s, 9H), 3.50 (dd, 2H), 3.59 (ddd, l H), 3.85 (dd, 1H), 4.36 (dt, 1H), 4.93 (bs, 1H), 6.68 (d, 1H), 7.50 (d, 1H), 8.30 (bs, 1H). e) acid tert-butvl ester A solution of the product from Example 62 (d) (2.2 g, 7.0 mmol) and iodomethane (2.2 ml, 35 mmol) in acetonitrile (40 ml) was stirred at room temperature overnight. Ammonium acetate (3.24 g, 42 mmol) was added and the suspension was heated at 70 °C for 3 h. The resulting mixture was cooled, concentrated onto silica and purified by column chromatography eluting with methanol: dichloromethane (2: 100) to leave a white solid (1.5 g).

Mass spectrum:/e 297 [M] +.

NMR (CDC13): 1.39 (s, 9H). 3.0-3.15 (m, 1H), 3.15-3.30 (m, 2H), 3.63 (dd, 1H), 4.00-4.10 (m, 1H), 5.80 (bs, 1H), 6.70 (d, 1H), 7.08 (bt, 1H), 7.50 (d, 1H). f) dihydrochloride The product from Example 62 (e) (1.5 g, 5 mmol) was stirred with 4M hydrogen chloride in dioxane (30 ml) at room temperature for 5 h. The resulting mixture was diluted with ether and the white solid product (1.07 g) was filtered off.

Mass spectrum: m/e 198 [M + H] +.

NMR (DMSOd6): 3.05-3.35 (m, 2H), 3.60 (ddd, 1H), 3.96 (dd, 1H), 4.7-4.8 (m, 1H), 6.95 (d, 1H), 8.12 (d, 1H), 8.55 (bs, 3H), 8.92 (bs, 2H), 10.20 (bs, 1H).

Example 63 2-Methylaminomethyl-2.3-dihvdro-thienoF2.3-flf 1. 41oxazepin-5-vlamine dihydrochloride To the product from Example 62 (e), (0.11 g, 0.37 mmol) in tetrahydrofuran (2 ml) was added sodium hydride (60% in oil, 15 mg, 0.39 mmol). After stirring for 0.5 h, iodomethane (0.023 ml, 0.37 mmol) was added and the mixture was left to stir for 17 h.

The resulting mixture was concentrated onto silica and purified by column chromatography eluting with methanol: dichloromethane (2: 100) to leave a white solid, which was stirred with 4M hydrogen chloride in dioxane (0.1 ml) in dichloromethane (1 ml) at room temperature for 5h. The resulting mixture was diluted with ether and the white solid product (25 mg) was filtered off.

Mass spectrum:/e 212 [M + H] +.

NMR (DMSOd6): 3.2-3.4 (m, 2H), 3.34 (s, 3H), 3.87 (dd, 1H), 4.10 (d, 1H), 4.85-4.95 (m, 1H), 6.96 (d, 1H), 8.08 (d, 1H), 8.49 (bs, 5H).

Example 64 N- (5-Amino-2. 3-dihydro-thienof 2, 3-fl f 1, 41oxazepin-2-vlmethyl)-benzenesulphonamide hydrochloride Benzenesulphonyl chloride (0.2 ml) was stirred with a solution of the product from Example 62 (f) (0.05 g, 0.19 mmol) in pyridine (3 ml) for 4 h. The resulting mixture was <BR> <BR> <BR> <BR> concentrated onto silica and purified by column chromatography eluting with methanol : dichloromethane (1: 100 to 5: 100) to leave a white solid (6 mg).

Mass spectrum:'tue 338 [M + H] +.

NMR (CDCI3 + DMSOd6): 3.2-3.4 (m, 2H), 3.45 (dd, 1H), 3.97 (d, 1H), 4.39 (dt, 1H). 6.72 (d, 1H), 7.5-7.65 (m, 3H), 7.73 (d, 1H), 7.9-7.95 (m, 5H). 8.75 (bs, 1H).

Example 65 <BR> <BR> <BR> <BR> <BR> <BR> <BR> N- (S-Amino-2. 3-dihydro-thienof2, 3-flf 1. 41oxazepin-2-ylmethyl)-methanesulphonamide hydrochloride Starting with the product from Example 62 (f) and methanesulfonyl chloride, the title compound was synthesised via the route described for Example 64.

Mass spectrum: m/e 276 [NI + H] +.

NMR (DMSOd6): 2.98 (s, 3H), 3.30-3.4 (m, 2H), 3.52 (ddd, 1H), 3.88 (dd, 1H), 4.48 (dt, 1H), 6.94 (d, 1H), 7.54 (t, 1H), 8.11 (d, 1H), 8.78 (s, 1H), 8.90 (bs, 1H), 9.97 (bs, 1H).

Example 66 N-(5-Amino-2,3-dihydro-thieno[2,3-f][1,4]oxacepin-2-ylmethyl )-3-(1H-indol-3-yl)- acrylamide A solution of 3- (IH-indol-3-yl)-acrylic acid (0.035 g, 0.19 mmol) and carbonyldiimidazole (0.03 g, 0.19 mmol) in N, N-dimethylformamide (1 ml) was stirred for 3h. Hunig's base (0.073 g, 0.57 mmol) and then the product from Example 62 (f) (0.05 g, 0.19 mmol) were added and the mixture was stirred for 19 h. The resulting mixture was concentrated onto silica and purified by column chromatography eluting with methanol: dichloromethane (1: 100 to 5: 100) to leave a white solid (0.025 g).

Mass spectrum : m/e 367 [M + H] +.

NMR (DMSOd6): 3.45-3.70 (m, 3H), 3.88 (d, 1H), 4.55 (dt, 1H), 6.67 (d, 1H), 6.97 (d, lH), 7.1-7.25 (m, 2H), 7.46 (d, 1H), 7.66 (d, 1H), 7.77 (s, 1H), 7.90 (d, 1H), 8.11 (d, 1H), 8.47 (t, 1H), 8.78 (s, 2H), 11.62 (bs, H).

Example 67 N-(5-amino-2,3-dihydro-thieno[2,3-f][1,4]oxacepin-2-ylmethyl )-acetamidehydrochloride Starting with acetic acid and the product from Example 62 (f), the title compound was synthesised via the route described for Example 66.

Mass spectrum : m/e 240 [M + H] +.

NMR (DMSOd6): 1.86 (s. 3H), 3.3-3.6 (m, 3H), 3.81 (d, 1H), 4.44 (dt, 1H). 6. 94 (d, 1H), 8.11 (d, 1H), 8.27 (bt, 1H), 8.74 (s, 2H).

Example 68

N- (5-Amino-2. 3-dihydro-thienof2. 3-flf 1, 41oxazepin-2-ylmethyl)-benzamide hydrochloride Starting with benzoic acid and the product from Example 62 (f), the title compound was synthesised via the route described for Example 66.

Mass spectrum : m/e 302 [M + H] +.

NMR (DMSOd6): 3.5-3.8 (m, 3H), 3.90 (dd, 1H), 4.60 (dt, 1H), 6.95 (d, 1H), 7.4-7.6 (m, 3H), 7.69 (s, 2H), 7.90 (d, 1H), 8.10 (d, 1H), 8.77 (s, 3H).

Example 69 3-Amino-lH-pvrazole-4-carboxylic acid 2-ylmethvl) amide Starting with 3-amino-lH-pyrazole-4-carboxylic acid and the product from Example 62 (f), the title compound was synthesised via the route described for Example 66.

Mass spectrum : m/e 307 [M + H] +.

NMR (DMSOd6): 3.4-3.65 m, 3H), 3.87 (d, 1H), 4.57 (dt, 1H), 5.31 (s, 2H), 5.78 (s, 1H), 6.93 (d, 1H), 7.91 (s, 1H), 8.02 (dd, 1H), 8.07 (d, 1H), 9.0 (bs, 2H).

Example 70 (5-Amino-2,3-dihydro-thieno[2,3-f][1,4]oxazepin-2-ylmethyl]- ureahydrochloride Trimethylsilyl isocyanate (0.15 ml, 1.1 mmol) was added to a solution of the product from Example 62 (f) (0.07 g, 0.26 mmol) in dimethylsulphoxide: N-methylpyrrolidone: Hunig's base (2: 10: 1,6.5 ml) and stirred for 4 h. The resulting mixture was concentrated onto silica and purified by column chromatography eluting with methanol: dichloromethane (1: 20 to 1: 5) to leave a white solid (0.011 g).

Mass spectrum: m/e 241 [M + H] +.

NMR (DMSOd6): 3.2-3.5 (m, 3H), 3.84 (d, 1H), 4.44 (dd, 2H), 4.90 (dd, 1H), 6.39 (t, 1H), 6.93 (d, 1H), 8.09 (d, 1H), 8.75 (bs, 3H).

Example 71 2-Thiophen-2-yl-2,3-dihydro-thieno[2,3-f][1,4]oxacepin-5-yla mine a) acid methyl ester Starting from (2-hydroxy-2-thiophen-2-yl-ethyl) carbamic acid tert-butyl ester, the sub- titled compound was synthesised according to the procedure in Example 12 (b).

Mass spectrum : m/e 383 [M] +.

NMR (CDC13): 1.43 (s, 9H). 3.5-3.6 (m, 1H), 3.7-3.8 (m, 1H), 3.89 (s, 3H), 5.38-5.50 (m, 1H), 5.8 (bs, 1H), 6.69 (d, 1H), 6.99 (dd, 1H), 7.08 (d, H), 7.28-7.31 (m, 2H). b) 2-Thiophen-2-vl-3.4-dihvdro-2H-thieno (2, 3-fl (1, 4loxazepin-5-one Sodium hydride (60% in oil. 0.17 g, 4.30 mmol) was added to the product from Example 71 (a) (1.5 g, 3.91 mmol) in tetrahydrofuran (30 ml) and the reaction stirred at room temperature for 2 h. Water (0.5 ml) was added and the mixture was concentrated onto silica and purified by column chromatography eluting with ethyl acetate: isohexane (1: 2) to leave a white solid (0.64 g).

Mass spectrum : m/e 251 [M] +.

NMR (CDC13): 3.7-3.9 (m. 2H), 5.55 (d, 1H), 6.6 (bs, 1H), 6.74 (d. 1H), 7.05 (dd, 1H), 7.12 (d, 1H), 7.36 (d, 1H), 7.43 (d, 1H). c) 2-Thiophen-2-vl-2.3-dihvdro-thieno (2. 3-fl f 1. 41oxazepin-5-ylamine A mixture of the product from Example 71 (b) (0.64 g, 2.55 mmol) and Lawesson's reagent (0.57 g, 1. 4 mmol) in toluene (20 ml) was heated at 75 °C for 16h. The resulting mixture <BR> <BR> <BR> was concentrated onto silica and purified by column chromatography eluting with petrol : ethyl acetate (3: 1 to 2: 1) to leave a yellow solid (0.64 g). A solution of this thioamide (0.64

g, 2. 4 mmol) and iodomethane (2.2 ml, 35 mmol) in acetonitrile (20 ml) was stirred at room temperature overnight. Ammonium acetate (2.0 g, 26 mmol) was added and the suspension was heated at 70 °C for 3 h. The resulting mixture was cooled, concentrated onto silica and purified by column chromatography eluting with methanol : dichloromethane (2: 100) to leave a white solid (0.28 g).

Mass spectrum: m/e 251 [M + H] +.

NMR (DMSOd6): 3.70 (dd, 1H), 3.85 (d, 1H), 5.54 (d, 1H). 5.80 (bs, 2H), 6.76 (d, 1H), 7.04 (dd, 1H), 7.16 (d, 1H). 7.52 (d, 1H), 7.57 (d, 1H).

Example 72 2- (2-Amino-ethyl)-2. 3-dihvdro-thienof2. 3-flf 1, 41oxazepin-5-vlamine dihvdrochloride Starting with (4-tert-butoxycarbonylamino-2-hydroxy-butyl)-carbamic acid tert-butyl ester, the title compound was synthesised according to the procedures described in Example 62.

Mass spectrum : m/e 212 [M + H] + NMR (DMSOd6): 2.00 (dt, 2H), (bs, 2H), 3.60 (dt, 1H), 3.84 (d, 1H), 4.64 (dd, 1H), 6.98 (d, 1H), 8.11 (d, 1H), 8.23 (bs, 3H), 8.87 (bs, 2H), 10.10 (t, 1H).

Example 73 N-r2- (5-Amino-2. 3-dihydro-thienof2. 3-flf 1. 41oxazepin-2-vl) ethvll-benzamide hydrochloride Starting with the product from Example 72 and benzoic acid, the title compound was synthesised according to the procedure described in Example 66.

Mass spectrum: m/e 316 [M + H] +.

NMR (DMSOd6): 1.94 (dt, 2H), 3.4-3.55 (m, 2H), 3.60 (dd, 1H), 3.80 (d, 1H), 4.57 (dd, 1H), 6.94 (d, 1H), 7.4-7.6 (m. 3H), 7.84 (d, 2H), 8.10 (d, 1H), 8.30 (s, 1H), 8.64 (t, 1H), 8.73 (bs, 2H).

Screens The pharmacological activity of compounds according to the invention was tested in the following screens.

Screen 1 The activity of compounds of formula (1), or a pharmaceutically acceptable salt, enantiomer or tautomer thereof, may be screened for nitric oxide synthase inhibiting activity by a procedure based on that of Forstermann et al., Eur. J. Pharm., 1992, 225, 161-165. Nitric oxide synthase converts 3H-L-arginine into 3H-L-citrulline which can be separated by cation exchange chromatography and quantified by liquid scintillation counting.

Enzyme is prepared, after induction, from the cultured murine macrophage cell line J774A-I (obtained from the laboratories of the Imperial Cancer Research Fund). J774A-1 cells are cultured in Dulbeccos Modified Eagles Medium (DMEM) supplemented with 10% foetal bovine serum, 4 mM L-glutamine and antibiotics (100 units/ml penicillin G, 100 mg/ml streptomycin & 0.25 mg/ml amphotericin B). Cells are routinely grown in 225 cm3 flasks containing 35 ml medium kept at 37 °C and in a humidified atmosphere containing 5% CO2.

Nitric oxide synthase is produced by cells in response to interferon-g (IFNg) and lipopolysaccharide (LPS). The medium from confluent culture flasks is removed and replaced with 25 ml (per flask) of fresh medium containing 1 mg/ml LPS and 10 units/ml IFNg.

After a period of 17-20 hours in culture, harvesting of cells is accomplished by scraping the cell sheet from the flask surface into the culture medium. Cells are collected by centrifugation (1000 g for 10 minutes) and lysate prepared by adding to the cell pellet a solution containing 50 mM Tris-HCI (pH 7.5 at 20 °C), 10% (v/v) glycerol, 0.1% (v/v) Triton-X-100,0.1 mM dithiothreitol and a cocktail of protease inhibitors comprising leupeptin (2 mg/ml), soya bean trypsin inhibitor (10 mg/ml), aprotinin (5 mg/ml) and phenylmethylsulphonyl fluoride (50 mg/ml).

For the assay, 25 1 of substrate cocktail (50 mM Tris-HCI (pH 7.5 at 20 °C), 400, uM NADPH, 20 RM flavin adenine dinucleotide, 20 lM flavin mononucleotide. 4 jj. M tetrahydrobiopterin, 12 lM L-arginine and 0.025 mCi L- [3H] arginine) is added to wells of a 96 well filter plate (0. 45µM pore size) containing 25 gel of a solution of test compound in 50 mM Tris-HCI. The reaction is started by adding 50 1 of cell Iysate (prepared as above) and after incubation for 1 hour at room temperature is terminated by addition of 50 il of an aqueous solution of 3 mM nitroarginine and 21 mM EDTA.

Labelled L-citrulline is separated from labelled L-arginine using Dowex AG-50W. 150 p. I of a 25% aqueous slurry of Dowex 50W (Na+ form) is added to the assay after which the whole is filtered into 96 well plates. 75 gl of filtrate is sampled and added to wells of 96 well plates containing solid scintillant. After allowing the samples to dry the L-citrulline is quantified by scintillation counting.

In a typical experiment basal activity is 300 dpm per 75 p. 1 sample which is increased to 1900 dpm in the reagent controls. Compound activity is expressed as IC50 (the concentration of drug substance which gives 50% enzyme inhibition in the assay) and aminoguanidine, which gives an IC50 (50% inhibitorv concentration) of 10 J. M, is tested as a standard to verify the procedure. Compounds are tested at a range of concentrations and from the inhibitions obtained IC50 values are calculated. Compounds that inhibit the enzyme by at least 25% at 100 pLM are classed as being active and are subjected to at least one retest.

In the above screen, the compounds of Examples 1 to 73 were tested and gave IC50 values of less than 25 JM indicating that they are expected to show useful therapeutic activity.

Screen 2 Compounds also show activity against the human form of induced nitric oxide synthase as can be demonstrated in the following assay.

The human colorectal carcinoma cell line, DLD-1 (obtained from the European Collection of Animal Cell Culture-cell line number 90102540) was routinely grown in RPMI 1640 supplemented with 10% (v/v) foetal bovine serum, and 2mM L-glutamine, at 37 °C in 5% COI).

Nitric oxide synthase was induced in cells by addition of medium containing human recombinant gamma-IFN (1000 units/ml), TNF-alpha (200 U/ml), IL-6 (200 U/ml) and IL-1-beta (250 U/ml). After incubation for 18 hours at 37 °C, the medium was removed and the cells washed with warm phosphate buffered saline. Cells were incubated for a further 5 hours at 37 °C/5% CO in RPMI 1640 containing 1001lM L-arginine and 100pM verapamil-HCI in the presence and absence of test compounds.

Nitrite accumulation was determined by mixing an equal volume of culture media with Griess reagent (10 mg/ml sulphanilamide, 1 mg N- (l-naphthyl) ethylenediamine in 1 ml 2.5% (v/v) phosphoric acid). Inhibition in the presence of compounds was calculated relative to the nitrite levels produced by untreated cells. IC50 values were estimated from a semi-log plot of % inhibition versus concentration of compound.

In this screen the compounds of Examples 1 to 73 gave IC50 values of less than 25 pM. indicating that they are predicted to show useful therapeutic activity.