FUSED AZEPINE DERIVATIVES AND THEIR USE AS ANTIDIURETIC AGENTS

Abstract: Compounds according to general formulae (1 and 2), wherein G<1> is an azepine derivative and G<2> is a group according to general formulae (9 - 11) are new. Compounds according to the invention are vasopressin V2 receptor agonists. Pharmaceutical compositions of the compounds are useful as antidiuretic agents.

Description: FUSED AZEPINE DERIVATIVES AND THEIR USE AS ANTIDIURETIC AGENTS FIELD OF INVENTION The present invention relates to a class of novel chemical entities which act as agonists of the peptide hormone vasopressin. They reduce urine output from the kidneys and so are useful in the treatment of certain human diseases characterised by polyuria. They are also useful in the control of urinary incontinence and bleeding disorders. BACKGROUND TO THE INVENTION Vasopressin is a peptide hormone secreted by the posterior pituitary gland. It acts on the kidney to increase water retention and so reduce urine output. For this reason, vasopressin is alternatively known as "antidiuretic hormone". It also acts on the vasculature, where it produces a hypertensive effect. The cellular receptors that mediate these two actions have been characterised and shown to be different. The antidiuretic action is mediated by the type-2 vasopressin receptor, commonly called the V 2 receptor. Agents that can interact with the V 2 receptor and activate it in the same way as vasopressin are called V receptor agonists (or simply V 2 agonists). Such agents will have an antidiuretic action. If these agents interact selectively with the V 2 receptor and not the other vasopressin receptor subtypes, then they will not have the hypertensive effect of vasopressin. This would be an important safety consideration and make such agents attractive for the treatment of human disease conditions characterised by polyuria (which is herein taken to mean excessive urine production). Vasopressin In fact, such an agent is already in use in human therapy. Desmopressin (otherwise [1- desamino, D-Arg 8 ]vasopressin, Minirin™, DDAVP™, Octostim™) is a peptide analogue of vasopressin which is selectively an agonist at the V 2 receptor. It is used in the treatment of central diabetes insipidus, which is a condition that results from defective secretion of vasopressin. It is also employed in the control of nocturnal enuresis and may also be of use in the control of nocturia. However, desmopressin is not an ideal agent in all respects. Even the best current syntheses of the agent are lengthy, and desmopressin is not amenable to the most convenient of purification techniques such as crystallisation. Consequently, desmopressin is relatively expensive. It has a very low oral bioavailability, and there is some variability in this parameter. Desmopressin Overall then, there is a recognised need for a selective vasopressin V 2 receptor agonist that is easy to prepare and purify, and that has a high and predictable oral bioavailability. Such properties are most likely to be obtained with a non-peptide compound. Examples of such compounds are disclosed by Ogawa et al. in International Patent Application PCT/JP96/03652 (WO97/22591), by Failli et al. in PCT/US98/15487 (WO99/06403), PCT/USOO/00885 (WOOO/46224), and PCT/US00/00358 (WO00/46227), by Dusza et al. in PCT/US98/15495 (WO99/06409), and by Steffan and Failli in PCT/US00/00886 (WO00/46225), and PCT/US00/00658 (WO00/46228). However the compounds disclosed in these documents are not ideal drug candidates. For example, some have only moderate selectivity for the V 2 receptor and many have only very limited oral bioavailability, probably because they are poorly soluble in aqueous media. The present invention provides compounds that show a better combination of properties. The anti-diuretic action of desmopressin results in a decrease in the osmolarity of the blood, and this has been shown to be useful in the treatment and prophylaxis of sickle- cell disease. Besides its antidiuretic actions, desmopressin is used to increase the concentration in the blood of the coagulation proteins known as Faktor VIII and von Willebrand factor. In the clinical context, this makes desmopressin useful in the treatment of haemophilia A and von Willebrand's disease. Desmopressin has also been reported to show effects in the central nervous system. For example, it has been reported to be effective in the treatment of Tourette's disease and to be useful in the management of cocaine addiction. Similar applications would be open to the non- peptide agonists of the present invention. SUMMARY OF THE INVENTION The present invention relates to a series of compounds according to general formulae 1 and 2, and to salts and tautomers thereof, that are non-peptide agonists of vasopressin and which are selective for the V 2 receptor subtype. 1 2 wherein: W is either N or C-R 4 ; R 1 - R 4 are independently selected from H, F, Cl, Br, alkyl, CF 3 , phenyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2> NO 2 and CN, or R 2 and R 3 together can be -CH=CH-CH=CH-; G 1 is a bicyclic or tricyclic fused azepine derivative selected from general formulae 3 to 8, in which A 1 , A 4 , A 7 and A 10 are each independently selected from CH 2 , O and NR 5 ; A 2 , A 3 , A 9 , A 11 , A 13 , A 14 and A 15 are each independently selected from CH and N; either A 5 is a covalent bond and A 6 is S, or A 5 is N=CH and A 6 is a covalent bond; A 8 and A 12 are each independently selected from NH, N-CH 3 and S; A 16 and A 17 are both CH 2 , or one of A 16 and A 17 is CH 2 and the other is selected from CH(OH), CF 2 , O, SO a and NR 5 ; R 5 is selected from H, alkyl and (CH 2 ) b R e ; R 6 is selected from phenyl, pyridyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 , CO 2 H and CN; a is 0, 1 or 2; b is 1, 2, 3 or 4; Y is CH or N; Z is CH=CH or S; and G 2 is a group selected from general formulae 9 to 11, 10 11 in which Ar is selected from phenyl, pyridyl, naphthyl and mono- or polysubstituted phenyl or pyridyl wherein the substituents are selected from F, Cl, Br, alkyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 and CN; D is a covalent bond or NH; E 1 and E 2 are both H, OMe or F, or one of E 1 and E 2 is OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N 3 , NH 2 , NHBn or NHAc and the other is H, or E 1 and E 2 together are =O, -O(CH 2 ) g O- or -S(CH 2 ) g S-; F 1 and F 2 are both H, or together are =O or =S; L is selected from OH, O-alkyl, NH 2 , NH-alkyl and NR 9 R 10 ; R 7 is selected from H, alkyl, alkenyl and COR 8 ; R 8 is selected from OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , pyrrolidinyl and piperidinyl; R 9 and R 10 are both alkyl, or together are -(CH 2 ) h - or -(CH 2 ) 2 O(CH 2 )r; V is 0, N-CN or S; c is 0 or 1 ; d is 0 or 1 ; e is 0 or 1 ; f is O, 1, 2, 3 or 4; g is 2 or 3; and h is 3, 4 or 5, provided that d and e are not both 0. The invention further comprises pharmaceutical compositions incorporating these vasopressin agonists, which compositions are particularly useful in the treatment of central diabetes insipidus, nocturnal enuresis and nocturia. DESCRIPTION OF THE INVENTION In a first aspect, the present invention comprises novel 4-(aminomethyl)benzamide and 6-(aminomethyl)nicotinamide derivatives according to general formulae 1 and 2. 1 2 In general formula 1, W represents either a nitrogen atom (N) or a substituted carbon atom (C-R 4 ). The substituents R 1 - R 4 are each independently selected from hydrogen (H), fluorine (F), chlorine (Cl) and bromine (Br) atoms, and alkyl, trifluoromethyl (CF 3 ), phenyl (Ph), hydroxyl (OH), alkoxy (O-alkyl), primary amino (NH 2 ), monoalkylamino (NH-alkyl), dialkylamino (N(alkyl) 2 ), nitro (NO 2 ) and cyano (CN) groups. Alternatively, R 2 and R 3 together can be -CH=CH-CH=CH- such that together with the ring to which they are attached they form a naphthalene, isoquinoline or isoquinolin-3-one fused ring system. The relationship between the two general formulae above is clear when one considers the compound of general formula 1 in which W is nitrogen and R 1 is hydroxyl. The resulting 2-hydroxypyridine can also exist as its 2-pyridone tautomer. In this tautomeric form the nitrogen atom is able to carry a substituent equivalent to R 4 , and such a compound is represented by general formula 2. The group G 1 is a bicyclic or tricyclic fused azepine derivative selected from general formulae 3 to 8. It is joined to the carbonyl group of the parent molecule (1 or 2) through the nitrogen atom of the azepine ring common to all of 3 to 8, so as to form an amide bond. In these formulae, A 1 , A 4 , A 7 and A 10 each represent an oxygen atom (-O-) or a methylene (-CH 2 -) or substituted imino (-NR 5 -) group. A 2 , A 3 , A 9 , A 11 , A 13 , A 14 and A 15 each represent a methine group (=CH-) or a nitrogen atom (=N-). Where two or more of these occur in the same group, each is independent of the others. Thus, for example, in formula 3, A 2 and A 3 may both be nitrogen, both methine, or one may be methine and the other nitrogen. A 5 and A 6 are chosen together such that either A 5 is a covalent bond and A 6 is a sulphur atom (-S-), to give a thiophene ring, or A 5 is a group -N=CH- and A 8 is a covalent bond to give a pyridine ring. A 8 and A 12 each represent an imino group (-NH-), an N-methyl imino group (-NCH 3 -) or a sulphur atom (-S-). A 16 and A 17 may both represent a methylene group (-CH 2 -) or one of A 16 and A 17 may represent a methylene group while the other represents a hydroxymethylene group (-CH(OH)-), a difluoromethylene group (-CF^), a substituted imino group (-NR 5 -), an oxygen atom (-O-), or an optionally oxidised sulphur atom (-SO a -), where a is zero, 1 or 2. The group R 5 represents a hydrogen atom (H), an alkyl group, or a group -(CH 2 )bR 6 , where b is 1 , 2, 3 or 4. The group R 8 represents a group selected from phenyl, pyridyl, hydroxy (-OH), alkoxy (-O-alkyl), primary amino (-NH 2 ), mono- and dialkylamino (-NH-alkyl and N(alkyl) 2 ), nitro (-NO 2 ), carboxy (-CO 2 H) and cyano (-CN) groups. Y represents either a methine group (=CH-) or a nitrogen atom (=N-). Z represents either a sulphur atom (-S-) or a group -CH=CH-. The group G 2 is selected from general formulae 9 to 11. 9 10 11 In these formulae, V represents a divalent residue selected from oxygen (=O) and sulphur (=S) atoms and a cyanimide (=N-CN) group. In general formula 9, Ar represents an aromatic group selected from phenyl, pyridyl, naphthyl and mono- or polysubstituted phenyl and pyridyl groups, wherein the substituents are selected from fluorine (F), chlorine (Cl) and bromine (Br) atoms and alkyl, hydroxy (-OH), alkoxy (-O-alkyl), primary amino (-NH 2 ), mono- and dialkylamino (-NH-alkyl and N(alkyl) 2 ), nitro (-NO 2 ), carboxy (-CO 2 H) and cyano (-CN) groups. The values of c, d and e are independently zero or 1 , provided that d and e are not both zero. In general formula 10, D represents a covalent bond or an imino group (-NH-). The group R 7 represents a hydrogen atom (H), an alkyl or alkenyl group, or a group -COR 8 , in which R 8 represents a hydroxy (-OH), alkoxy (-O-alkyl), primary amino (-NH 2 ) or mono- or dialkylamino (-NH-alkyl and N(alkyl) 2 ) group, or a cyclic amino group selected from pyrrolidinyl (-N(CH 2 ) ) and piperidinyl (-N(CH 2 )s). The value of f is zero, 1 , 2, 3 or 4. In general formula 11, E 1 and E 2 represent either two monovalent atoms or groups, which may be the same or different, or together they represent a divalent atom or group. When E 1 and E 2 represent monovalent atoms or groups, these may both simultaneously be hydrogen (H) or fluorine (F) atoms or methoxy (-OMe) groups, or one may be a fluorine (F), chlorine (Cl) or bromine (Br) atom, or a hydroxy (-OH), alkoxy (-O-alkyl), benzyloxy (-OBn), phenoxy (-OPh), acetoxy (-OAc), azido (-N 3 ), primary amino (-NH 2 ), benzylamino (-NHBn) or acetamido (-NHAc) group and the other is a hydrogen atom (H). When E 1 and E 2 together represent a divalent atom or group, this may be an oxygen atom (=O) or an α,ω-dioxa- or dithiapolymethylene group (-O(CH 2 ) g O- or -S(CH 2 ) g S-), in which the value of g is either 2 or 3. F 1 and F 2 may both represent a hydrogen (H) atom. Alternatively, they may together represent an oxygen (=O) or sulphur (=S) atom. L represents a group selected from hydroxy (-OH), alkoxy (-O-alkyl), primary amino (-NH 2 ) and monoalkylamino (-NH-alkyl) groups and -NR 9 R 10 , wherein either R 9 and R 10 each represent alkyl groups which may be the same or different, or together they represent a polymethylene group (-(CH 2 ) h -) in which h can be 3, 4 or 5, or -(CH 2 ) 2 O(CH 2 )r- As used herein, the term "alkyl" includes saturated hydrocarbon residues, including linear, branched and cyclic groups, with up to six carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, ferf-butyl, neopentyl and cyclohexyl groups. The term "alkenyl" includes mono-unsaturated hydrocarbon residues, including linear, branched and cyclic groups, of between two and six carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, allyl, 2-methyl-2-propenyl, 2- butenyl, 3-cyclopentenyl and 2,3-dimethyl-2-butenyl groups. Certain compounds within the scope of the present invention may exist as tautomers. For example, when W is nitrogen and R 1 or R 2 is a hydroxy group, or when Ar is pyridyl further substituted by a hydroxy group, the resulting hydroxypyridine can exist as the pyridone tautomer. All such tautomers are considered to be within the scope of the present invention. Certain compounds of general formula 1 are capable of forming salts with acids or bases. For example, compounds containing one or more basic nitrogen atoms can form addition salts with mineral and organic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulphonic acid, citric acid and benzoic acid. Compounds containing acidic groups can form salts with bases. Examples of such salts include the sodium, potassium, calcium, triethylammonium and tetraethylammonium salts. Furthermore, compounds that have both acidic and basic groups can form internal salts (zwiterions). Insofar as these salts are pharmaceutically acceptable, they are included within the scope of the invention. A preferred embodiment of the invention is a compound according to general formula 1. More preferred is a compound according to general formula 1 in which W is C-R 4 . Even more preferred is such a compound in which at least one of R 1 - R 4 is other than hydrogen. Most preferred is a compound in which one of R 1 - R 4 is methyl, chlorine or fluorine and the other three are hydrogen. Another preferred embodiment of the invention is a compound according to general formula 2. More preferred is a compound according to general formula 2 in which R 2 and R 3 are both hydrogen. Another preferred embodiment of the invention is a compound according to general formulae 1 or 2 in which G 1 is a group according to any of general formulae 3 to 7. More preferred is a compound in which Y is CH. Even more preferred is a compound in which Z is -CH=CH- so as to complete a benzenoid ring. Alternatively, Z may be S to complete a thiophene ring. When Y is N it is particularly preferred that Z be -CH=CH- so as to complete a pyridine ring. Within the foregoing preferred embodiment, more preferred compounds are those wherein G 1 is a group according to general formula 3, particularly those wherein A 1 is CH 2 and both A 2 and A 3 are CH, and compounds wherein G 1 is a group according to general formula 6, particularly those wherein A 11 is CH and A 12 is S. Another preferred embodiment of the invention is a compound according to general formulae 1 or 2 in which G is a group according to general formula 8. More preferred is a compound in which one of A 16 and A 17 is CH 2 . Even more preferred is a compound in which both A 18 and A 17 are CH 2 . Another preferred embodiment of the invention is a compound according to general formulae 1 or 2 in which G 2 is a group according to general formula 9. More preferred are those compounds wherein Ar is mono- or polysubstituted phenyl. Even more preferred are phenyl groups with at least two halogen (fluorine or chlorine) substituents. Most preferably, Ar is 2,6-difluorophenyl. Another preferred embodiment of the invention is a compound according to general formulae 1 or 2 in which G 2 is a group according to general formula 10. More preferred are those compounds wherein R 7 is COR 8 . Most preferred are those compounds wherein R 8 is N(alkyl) 2 . Another preferred embodiment of the invention is a compound according to general formulae 1 or 2 in which G 2 is a group according to general formula 11. More preferred are those compounds wherein F 1 and F 2 together are =O. Also preferred are those compounds wherein both E 1 and E 2 are H, or one is H and the other is O-alkyl. For those compounds wherein one of E 1 and E 2 is H and the other is O-alkyl, it is preferred that the stereochemistry at the CE 1 E 2 centre be of the R absolute configuration. It is further preferred that the stereochemistry adjacent to the ring nitrogen atom be of the S absolute configuration. These configurations are illustrated below. alkyl To the extent that the features of the foregoing preferred embodiments are independent of each other they may be combined in embodiments that are more preferred. Thus, highly preferred embodiments of the invention are those compounds that combine the preferred options for W and R 1 - R 4 with the preferred options for G 1 and G 2 . A most preferred embodiment of the invention is a compound selected from the following. 1-(4-[3-(2-Chloro-6-fluorophenyl)ureidomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1- benzazepine 1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-5-(3-pyridyl)methyl-2,3 l 4,5- tetrahydro-1 H-1 ,5-benzodiazepine 1-(3-Chloro-4-[3-(2-chloro-6-fluorophenyl)ureidomethyl]benzoyl)-5-ethyl-2,3,4,5- tetrahydro-1 H-1 ,5-benzodiazepine 4-(3-Chloro-4-[3-(2,6-difluorophenyl)ureidomethyl]benzoyl)-5,6,7,8-tetrahydrothieno[3,2- ibjazepine 1-(3-Chloro-4-(3-(methyloxycarbonyl)propanoylaminomethyl)benzoyl)-2,3,4,5-tetrahydro- 1-benzazepine n 1-(2-Methyl-4-(5-(3-pyridylmethyl)-2,3,4,5-tetrahydro-1,5-benzodiazepin-1- ylcarbonyl)benzyl)-3-(methyloxycarbonylmethyl)urea 1-(2-Methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline- Λ/,Λ/-dimethylamide (4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl- carbamoyl)-L-proline-Λ/,Λ/-dimethylamide (4/?)-1 -(3-Chloro-4-(2,3,4,5-tetrahydro-1 -benzazepin-1 -ylcarbonyl)benzylcarbamoyl)-4- methoxy-L-proline-Λ/,Λ/-dimethylamide (4R)-1-(2-Chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4- methoxy-L-proline-Λ/,Λ/-dimethylamide (4f?)-4-Benzyloxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl- carbamoyl)-L-proline-Λ/,Λ/-dimethylamide (4R)-4-Methoxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1 -benzazepin-1 -ylcarbonyl)benzyl- carbamoyl)-L-proline-Λ/,Λ/-dimethylamide (4 ?)-4-Methoxy-1-(3-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl- carbamoyl)-L-proline-Λ/,Λ/-dimethylamide (4/?)-1-(2-Chloro-4-(5,6,7,8-tetrahydro-4H-thieno[3,2-6]azepin-4-ylcarbonyl)benzyl- carbamoyl)-4-methoxy-L-proline-/V,Λ/-dimethylamide (4R)-1-(4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1 ,4)benzodiazepin-10-yl carbonyl)-2-methyl- benzylcarbamoyl)-4-methoxy-L-proline-Λ/,Λ/-dimethylamide (4R)-1-(2-Chloro-4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)- benzylcarbamoyl)-4-methoxy-L-proline-Λ/,Λ/-dimethylamide (4R)-1-(4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-2-methyl- benzylcarbamoyl)-4-methoxy-L-proline-Λ ,Λ/-dimethylthioamide Within this set of compounds, two which show an optimal balance of properties are 1-(2- methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-/V,Λ/- dimethylamide and (4R)-4-hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1 -benzazepin-1 - ylcarbonyl)benzylcarbamoyl)-L-proline-Λ/,Λ/-dimethylamide. The present invention further comprises pharmaceutical compositions that include at least one compound according to the foregoing description as an active constituent. The composition may also include a second pharmacological agent such as a spasmolytic or a potassium channel blocker, these agents being known in the art to ameliorate bladder dysfunction. Preferably, the composition includes only one active constituent. The composition will include excipients selected from binding agents, bulking agents, dispersants, solvents, stabilising agents and the like, such excipients being generally known in the art. The excipients used will depend on the intended nature of the formulation, which will, in turn, depend on the intended route of administration. Administration may be oral, transmucosal (such as sublingual, buccal, intranasal, vaginal and rectal), transdermal or by injection (such as subcutaneous, intramuscular and intravenous). Oral administration is generally preferred. For oral administration, the formulation will be a tablet or capsule. Other formulations include dry powders, solutions, suspensions, suppositories and the like. In a further aspect, the present invention is a method of treating or controlling certain human physiological dysfunctions. This method comprises the administration to the person in need of such treatment of an effective amount of a pharmaceutical composition, which composition contains a compound according to the foregoing description as an active constituent. The compounds act to reduce urine output, and so the method of the invention can be applied to all conditions in which elevated urine output is a contributory factor. The compounds also increase the production of the blood coagulation proteins known as Factor VIII and von Willebrand factor, and so the treatment of bleeding disorders can be undertaken. In a preferred embodiment, the condition treated is central diabetes insipidus. This is a condition caused by an inability of the body to produce and secrete physiologically active vasopressin, with the result that water re-uptake is greatly reduced and large volumes of urine are produced. In another preferred embodiment, the condition treated is nocturnal enuresis. This is defined as bladder emptying while the individual is sleeping. It is a condition that mainly affects children and a number of factors may be involved in its etiology. In another preferred embodiment, the condition treated is nocturia. This is defined as production of sufficient urine during the night to require the individual to wake and empty his (or her) bladder. Again, this condition may be the result of a number of factors. In another preferred embodiment, the condition treated is incontinence. This condition is characterised, in part, by reduced bladder capacity and control such that involuntary urination occurs unless the bladder is emptied frequently. Incontinence has been divided into two conditions, stress incontinence and urge incontinence. A number of etiological factors are thought to be involved. Treatment according to the invention is particularly useful for delaying the need for bladder emptying ("voiding postponement") in order to allow the incontinent subject a dry period of a few hours (such as up to four hours). Such voiding postponement may also be useful for the non-incontinent population, for example for people obliged to remain in meetings for extended periods. In another preferred embodiment, the condition treated is haemophilia A or von Willebrand's disease. This is a condition in which Factor VIII or von Willebrand factor production is reduced and the individual suffers from prolonged bleeding. In another preferred embodiment, the composition is administered prior to surgery (including dental surgery) to increase the coagulability of the blood and so reduce peri- operative blood loss. The administration of the compositions of the present invention will generally be under the control of a physician. The physician will determine the amount of composition to be administered and the dosing schedule, taking into account the patient's physical condition and the therapeutic goals. For an adult diabetes insipidus patient, a typical dose might be between 50mg and 1g of the active compound per day, taken as a single tablet or as up to four tablets throughout the day. For routes of administration other than the oral route, the amount of compound will be reduced, since non-oral routes tend to be more efficient in terms of delivering therapeutic agents into the systemic circulation. For the treatment of von Willebrand's disease and haemophilia A, the amount of compound may need to be higher than for the treatment of diabetes insipidus. The compounds of the present invention can be prepared using methods generally known in the art. The compounds of general formulae 1 and 2 can be considered to be composed of three linked fragments, G\ G 2 and the central aromatic moiety (which will be referred to here as the "core"). Reagents corresponding to the three fragments will generally be prepared separately and then combined at a late stage in the synthesis. Some instances of the various groups and substituents might be incompatible with this assembly and so will require the use of protecting groups. The use of protecting groups is well known in the art (see for example "Protective Groups in Organic Synthesis", T.W. Greene, Wiley-lnterscience, 1981). Particular groups that may require protection are amines (protected as amides or carbamates), alcohols (protected as esters or ethers) and carboxylic acids (protected as esters). For the purposes of this discussion, it will be assumed that such protecting groups as are necessary are in place. The three fragments can be combined according to two strategies to give the compounds of formulae 1 and 2. In the first, the fragments corresponding to G 1 and the core are linked to give a fragment corresponding to core-G , which is then combined with fragment G 2 . In the second, the fragments the fragments corresponding to the core and G 2 are linked to give a fragment corresponding to G 2 -core, which is then combined with fragment G 1 . The chemistry involved in the condensation of fragment G 1 with the core fragment, and that involved in the condensation of the core fragment with fragment G 2 , will be the same whichever strategy is followed. Formation of fragment core- G 1 The synthesis of this fragment requires the formation of an amide bond between the two moieties. Reactions of this type are well known in the art. Most conveniently, an acid chloride corresponding to the core fragment may be allowed to react with the free secondary amino group of the G 1 azepine ring. Such a reaction generally is performed in an aprotic solvent such as dichloromethane or dimethylformamide at or slightly below room temperature. A tertiary amine base such as triethylamine or dimethylaminopyridine is usually added. Alternatively, the carboxylic acid corresponding to the core fragment may be condensed with the secondary amino group using one of the many reagents that have been developed for the formation of amide bonds in the field of peptide chemistry. Examples of such reagents include DCC (dicyclohexylcarbodiimide), BOP ((benzotriazol- 1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate), PyBOP ® ((benzotriazol- 1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), PyBroP ® (bromotripyrrolidino- phosphonium hexafluorophosphate) and HBTU (O-(benzotriazol-1-yl)-N,N,N',N- tetramethyluronium hexafluorophosphate). Other reagents are also known. The details of the synthetic method will depend on the particular reagent selected, but will generaly involve the use of an aprotic solvent and a tertiary amine base, as described above. Either the reagent is added to a mixture of the carboxylic acid and the azepine, or the carboxylic acid and the reagent are premixed to form a reactive intermediate (which is not isolated) to which is added the azepine. Formation of fragment G 2 -core Depending on the nature of G 2 , the G 2 -core bond can be part of an amide or thioamide, a sulphonamide, a urea or thiourea, a sulphonylurea or sulphonylthiourea, or a cyanoamidine, cyanoguanidine or sulphonylcyanoguanidine. The chemistry involved in the preparation of the G2-core bond will be different for each of these. (i.a) Amides {G 2 = 10, D = covalent bond, V = O} These compounds can be formed by the reaction of a carboxylic acid or acid chloride corresponding to fragment G 2 with the primary amino group of the core fragment. Conditions for the reaction will generally be similar to those described for the formation of the core-G 1 bond, except that the primary amine is more reactive than the azepine nitrogen and so lower temperatures and shorter reaction times may be used. (i.b) Thioamides {G 2 = 10, D = covalent bond, V = S} These compounds can be formed by the reaction of a suitable thiocarbonyl compound such as a dithioester (RCS 2 R') with the primary amine in a manner analogous to that described for the corresponding amides above. Alternatively, they may be prepared from the corresponding amides (V = O) by reaction with Lawesson's reagent. (ii) Sulphonamides {G = 9, d = 1 , e = zero} These compounds are generally prepared by the reaction of the sulphonyl chloride corresponding to the G 2 fragment with the primary amine of the core fragment. The reaction is generally performed under conditions similar to those described above for the reaction of a carboxylic acid chloride with the primary amine that gives the amides. (iii.a) Ureas{G = 9, d = zero, e = 1, V = O; G^ = 10, D = NH, V = O; * = 11, V = 0} These compounds can be prepared by the reaction of an amine with an isocyanate or an equivalent thereof. Due to the symmetry of the urea functional group, there is the possibility to choose which component acts as the amine and which as the isocyanate. Most simply, when G 2 is a group according to 9 or 10, the corresponding isocyanate is readily accessible. It can conveniently be reacted with the primary amine of the core fragment in an aprotic solvent without the need for additional reagents. When G 2 is a group according to 11, the isocyanate is not available, and the carbamoyl chloride can be used in its place. The carbamoyl chloride is generally prepared immediately prior to use by treating the corresponding secondary amine with phosgene or an equivalent reagent such as diphogene or triphogene. Alternatively, the use of carbonyl diimidazole leads to the formation of a carbamoyl imidazole derivative that can be used in place of the carbamoyl chloride. The reaction of the carbamoyl chloride with the primary amine generally requires the addition of a tertiary amine base to neutralise the hydrogen chloride formed. In some cases, it may be preferable to treat the primary amine corresponding to the core fragment with phosgene (or carbonyl diimidazole) to form an isocyanate that can subsequently be reacted with the primary or secondary amine corresponding to the G 2 fragment. (iii.b) Thioureas {G 2 = 9, d = zero, e = 1 , V = S; G 2 = 10, D = NH, V = S; G 2 = 11 , V = S} These compounds can be prepared by methods analogous to those described above for the ureas, simply by using the corresponding isothiocyanate and thiophosgene compounds. (hi. a) Sulphonylureas {G 2 = 9, d = 1 , e = 1 , V = O} These compounds can be prepared by the reaction of the primary amine corresponding to the core fragment with an appropriate sulphonyl isocyanate. The reaction conditions are similar to those described above for the reaction of an amine with an isocyanate to prepare the ureas. (iv.b) Sulphonylthioureas {G^ = 9, d = 1 , e = 1 , V = S} These compounds can be prepared analogously to the sulphonylureas by the reaction of the primary amine corresponding to the core fragment with an appropriate sulphonyl isothiocyanate. (v.a) Cyanoamidines {G = 10, D = covalent bond, V = N-CN} These compounds can be prepared by the reaction of the primary amine of the core fragment with an >-cyanothioamide or an Λ/-cyanothioimidate corresponding to the G 2 fragment. (v.b) Cyanoguanidines {G 2 = 9, d = zero, e = 1 , V = N-CN; G 2 = 10, D = NH, V = N-CN; G 2 = 11, V = N-CN} These compounds can be prepared by the reaction of the primary amine of the core fragment with a cyanothiourea corresponding to the G 2 fragment in the presence of a carbodiimide. (v.c) Sulphonylcyanoguanidines {G 2 = 9, d = 1 , e = 1 , V = N-CN} These compounds can be prepared in an analogous manner by the reaction of the primary amine of the core fragment with an /V-sulphonyl-ΛT-cyanothiourea corresponding to the G 2 fragment in the presence of a carbodiimide. The reagents corresponding to the fragments are commercially available, or they can be prepared by methods described in the literature. Particularly relevant leading references include the following. Synthesis of fused azepine derivatives for G 1 : Aranapakam et al., Bioorg. Med. Chem. Lett. 1993, 1733; Artico et al., Farmaco. Ed. Sci. 24, 1969, 276; Artico et al., Farmaco. Ed. Sci. 32, 1977, 339; Chakrabarti et al., J. Med. Chem. 23, 1980, 878; Chakrabarti et al., J. Med. Chem. 23, 1980, 884; Chakrabarti et al., J. Med. Chem. 32, 1989, 2573; Chimirri et al., Heterocycles 36, 1993, 601; Grunewald et al., J. Med. Chem. 39, 1996, 3539; Klunder et al., J. Med. Chem. 35, 1992, 1887; Liegeois et al., J. Med. Chem. 37, 1994, 519; Olagbemiro ef al., J. Het. Chem. 19, 1982, 1501; Wright et al., J. Med. Chem. 23, 1980, 462; Yamamoto et al., Tet. Lett. 24, 1983, 4711; and International patent application, publication number WO99/06403. Synthesis of amidine transfer reagents for G 2 , V = N-CN Mestres et al., Synthesis, 1980, 755; Petersen et al., J. Med. Chem. 21, 1978, 773; and Cord, J. Chem. Soc, 1948, 1620. Synthesis ofproline derivatives for G 2 = group according to 11 Dugave et al., Tet. Lett. 39, 1998, 1169; Petrillo et al., J. Med. Chem. 31, 1988, 1148; and Smith etal., J. Med. Chem. 31, 1988, 875. The foregoing general description is further illustrated below with a number of non-limiting examples. EXAMPLES Abbreviations The following abbreviations have been used. AIBN Azo-ιb/s-(isobutyronitrile) BOC terf-Butyloxycarbonyl (BOC) 2 O Di-.erf-butyl dicarbonate DMF Dimethylformamide EtOAc Ethyl acetate IPA Isopropanol M.S. Mass spectrometry NBS N-Bromosuccinimide pet. ether petroleum ether, fraction boiling at 60-80°C THF Tetrahydrofuran WSCDI Water-soluble carbodiimide Preparation of Intermediates Reagents corresponding to fragments G 1 and G 2 were commercially available or prepared according to the published procedures except where detailed in the specific Examples. Reagents corresponding to the core fragment were prepared as detailed below. Example A 4-(terf-Butyloxycarbonylaminomethyl)-3-chlorobenzoic acid A1. Methyl 4-bromomethyl-3-chlorobenzoate To a solution of methyl 3-chloro-4-methylbenzoate (5.0g, 27.1 mmol) in carbon tetrachloride (50ml) were added NBS (5.8g, 32.0mmol) and AIBN (0.442g, 2.70mmol). The mixture was stirred at reflux for 18h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96g (84%). A2.4-(terf-Butyloxycarbonylaminomethyl)-3-chlorobenzoic acid To a saturated solution of ammonia in ethanol (170ml) was added methyl 4-bromomethyl- 3-chlorobenzoate from Example A1 (5.5g, 20.9mmol). The mixture was stirred at room temperature for 1 hr and then concentrated in vacuo. The residue was triturated with diethyl ether and the resultant white crystals were filtered off and washed with more diethyl ether. To a solution of this solid in water (100ml) were added solutions of (BOC) 2 O (5.0g, 23.0mmol) in dioxan (100ml) and sodium hydroxide (1.86g, 46.0mmol) in water (100ml). The mixture was stirred at room temperature for 18h and then concentrated in vacuo. The aqueous residue was acidified with citric acid and extracted with chloroform/I PA. The organic layer was washed with water, dried over MgSO 4 , and concentrated in vacuo to give a white solid; yield 2.8g (67%). Example B 4-(tert-Butyloxycarbonylaminomethyl)-3-nitrobenzoic acid 4-Bromomethyl-3-nitrobenzoic acid (4.75g, 18.2mmol) was reacted following the method of Example A2 to give a yellow solid; yield 2.6g (49%). Example C 4-Cyano-3-methylbenzoic acid To a solution of 4-bromo-2-methylbenzonitrile (2.0g, 10.2mmol) in THF (100ml) at -78°C under a nitrogen atmosphere was added dropwise a 2.5M solution of π-butyl lithium (4.48ml, 11.2mmol). The mixture was stirred at -78°C for 1h and then poured onto solid carbon dioxide (5g) in THF (50ml). The mixture was allowed to warm to room temperature. Water was added (200ml) and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated HCI and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over MgSO 4> and concentrated in vacuo to give a white solid; yield 1.2g (73%). Example P 4-Cvano-2-methylbenzoic acid 4-Bromo-3-methylbenzonitrile (2.0g, 10.2mmol) was reacted following the method of Example C to give a yellow solid which was triturated with hexane and filtered off; yield 0.96g (59%). Example E 4-(fe/f-Butyloxycarbonylaminomethyl)-2-fluorobenzoic acid E1. 2-Fluoro-4-methylbenzoic acid 4-Bromo-3-fluorotoluene (8.33g, 44.07mmol) was reacted following the method of Example C to give a white solid; 4.89g (72%). E2. Methyl 2-fluoro-4-methylbenzoate To a solution of 2-fluoro-4-methylbenzoic acid from Example E1 (6.04g, 39.18mmol) in toluene (80ml) was added thionyl chloride (65ml, 89.11 mmol). The mixture was heated at reflux for 2.5h, cooled and concentrated in vacuo. The residue was dissolved in dichloromethane (50ml) and methanol (50ml) was added. The mixture was stirred at room temperature for 2.5h and then concentrated in vacuo. The residue was dissolved in dichloromethane (100ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO 4 , and concentrated in vacuo to give a tan solid; yield 5.07g (77%). E3. Methyl 4-bromomethyl-2-fluorobenzoate Methyl 2-fluoro-4-methylbenzoate from Example E2 (5.07g, 30.16mmol) was reacted following the method of Example of A1. The product was purified by flash chromatography on silica (eluant EtOAσ.pet. ether 20:80); yield 5.9g (80%). E4. 4-(ferf-Butyloxycarbonylaminomethyl)-2-fluorobenzoic acid Methyl 4-bromomethyl-2-fluorobenzoate from Example E3 (5.9g, 24.13mmol) was reacted following the method of Example A2. The product was recrystallised from dioxan/pet. ether to give white crystals; yield 2.46g (38%). Example F 6-(ferf-Butyloxycarbonylaminomethyl)-2-chloronicotinic acid F1. Methyl 2-chloro-6-methylnicotinate To a suspension of 2-chloro-6-methylnicotinic acid (5.3g, 30.8mmol) in dichloromethane (100ml) at 0°C were added DMF (1ml) and oxalyl chloride (3.2ml, 36.9mmol). The mixture was allowed to warm to room temperature and stirred for 5h. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (50ml) and methanol (50ml). The mixture was stirred at room temperature for 18h and then concentrated in vacuo. The residue was dissolved in chloroform, washed with saturated sodium bicarbonate solution and brine, dried over MgSO 4 , and concentrated in vacuo to give a brown oil; yield 5.70g (100%). F2. Methyl 6-bromomethyl-2-chloronicotinate Methyl 2-chloro-6-methylnicotinate from Example F1 (5.70g, 30.8mmol) was reacted following the method of Example of A1. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 20:80); yield 4.8g (58%). F3. Methyl 6-(terf-butyloxycarbonylaminomethyl)-2-chloronicotinate Methyl 6-bromomethyl-2-chloronicotinate from Example F2 (4.8g, 18.0mmol) was reacted following the method of Example of A2 to give an off white solid; yield 1.45g (28%). Example G 6-(fert-Butyloxycarbonylaminomethyl)nicotinic acid G1. Methyl 6-(bromomethyl)nicotinate Methyl 6-methylnicotinate (5.0g, 33.0mmol) was reacted following the method of Example A1. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 20:80); yield 3.7g (49%). G2. Methyl 6-(azidomethyl)nicotinate To a solution of methyl 6-(bromomethyl)nicotinate from Example G1 (2.0g, 8.60mmol) in DMF (15ml) was added sodium azide (0.84g, 12.9mmol). The mixture was stirred at room temperature for 18h. EtOAc (100ml) was added and the mixture was washed with water (3 times), dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 20:80) to give a yellow gum; yield 1.55g (93%). G3. Methyl 6-(ferf-butyloxycarbonylaminomethyl)nicotinate To a degassed solution of methyl 6-(azidomethyl)nicotinate from Example G2 (1.6g, 8.30mmol) in methanol (50ml) was added 10% palladium-on-carbon (0.15g). Hydrogen gas was bubbled through the mixture for 2h at room temperature. The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane and cooled to 0°C. To this solution were added triethylamine (1.67g, 16.0mmol) and (BOC) 2 O (2.17g, 9.96mmol). The mixture was allowed to warm to room temperature and stirred for 18h, then concentrated in vacuo. The residue was dissolved in EtOAc and washed with water, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50) to give a yellow solid; yield 1.57g (71%). G4. 6-(ferf-Butyloxycarbonylaminomethyl)nicotinic acid To a solution of methyl 6-(te/ϊ-butyloxycarbonylaminomethyl)nicotinate from Example G3 (1.56g, 5.84mmol) in THF (20ml) and water (5ml) was added lithium hydroxide monohydrate (0.37g, 8.76mmol). The mixture was stirred at room temperature for 18h and then concentrated in vacuo. The aqueous residue was acidified by addition of 1 M citric acid solution and extracted with chloroform/IPA (3 times). The combined organic extracts were washed with brine, dried over MgSO 4 , and evaporated in vacuo to give a white solid; yield 1.38g (94%). Example H 4/5-Bromo-6-(førf-butyloxycarbonylaminomethyl)-1-methyl-2-oxo-1,2-dihvdro- pyridine-3-carboxylic acid H1. Methyl 1 ,6-dimethyl-2-oxo-1.2-dihvdropyridine-3-carboxylate To a solution of 3-hydroxy-6-methylnicotinic acid (10g, 65.0mmol) in DMF (100ml) at 0°C was added sodium hydride (4.83g, 60% dispersion, 140mmol). The mixture was stirred at 0°C for 1.5h, then methyl iodide (12.4ml, 195mmol) was added and the mixture was allowed to warm to room temperature, stirring for a further 18h. The mixture was partitioned between water and EtOAc and the aqueous layer acidified to pH 5. The layers were separated and the organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant dichloromethane/methanol 95:5) to give a white solid. This was recrystallised from methanol and the filtrate was evaporated in vacuo to give the desired product; yield 6.1g (52%). H2. Methyl 4/5-bromo-6-bromomethyl-1-methyl-2-oxo-1.2-dihvdropyridine-3-carboxylate Methyl 1 ,6-dimethyl-2-oxo-1 ,2-dihydropyridine-3-carboxylate of Example H1 (6.0g, 33.0mmol) was reacted following the method of Example of A1. The product was purified by flash chromatography on silica (eluant dichloromethane/methanol 95:5); yield 5.2g (46%). H3. 4/5-Bromo-6-(tert-butyloxycarbonylaminomethyl)-1-methyl-2-oxo-1.2-dihvdropyridine- 3-carboχylic acid Methyl 4/5-bromo-6-bromomethyl-1-methyl-2-oxo-1 ,2-dihydropyridine-3-carboxylate of Example H2 (5.2g, 14.8mmol) was reacted following the method of Example A2 to give a brown gum; yield 1.3g (24%). Example I 4-Cvano-3.5-dimethylbenzoic acid 11. 4-Bromo-2.6-dimethylbenzonitrile 4-Bromo-2,6-dimethylaniline (4.49g, 22.4mmol) was taken up in water (25ml) and concentrated hydrochloric acid (8.0ml) was added. The mixture was sonicated to form a fine suspension and then cooled to 0°C. A solution of sodium nitrite (1.67g, 24.2mmol) in water (5ml) was then added dropwise so as to maintain the temperature of the reaction between 0-5°C. The mixture was stirred at 0-5°C for 1/2h and then neutralised by addition of solid sodium carbonate. The resulting solution was then added portionwise to a solution of copper cyanide (2.42g, 27.0mmol) and potassium cyanide (3.65g, 56.1 mmol) in water (25ml) at 70°C. The mixture was stirred at 70°C for 1/2h, allowed to cool and then extracted with toluene (2 times). The combined extracts were washed with water and brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 5:95) to give an orange solid; yield 3.2g (68%). 12.4-Cvano-3.5-dimethylbenzoic acid 4-Bromo-2,6-dimethylbenzonitrile from Example 11 (3.20g, 15.2mmol) was reacted following the method of Example C to give a tan solid; yield 1.5g (56%). Reagents corresponding to fragments A, B and C were combined to give the specific Examples as detailed below. Example 1 1-(4-r3-(2.6-Difluorophenyl)ureidomethyllbenzovn-2.3.4.5-tetrahvdro-1H-1- benzazepine 1 A. 1 -(4-Cvanobenzoyl)-2.3.4.5-tetrahvdro-1 H-1 -benzazepine To a solution of 2,3,4,5-tetrahydro-1 H-1 -benzazepine (1.05g, 7.14mmol) in dichloromethane (40ml) were added 4-cyanobenzoic acid (1.26g, 8.57mmol), triethylamine (1.00g, 7.14mmol), 4-(dimethylamino)pyridine (0.87g, 7.14mmol) and WSCDI (2.86g, 14.28mmol). The mixture was stirred at reflux for 18h, cooled and evaporated in vacuo. The residue was partitioned between EtOAc and 1 M KHSO 4 . The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO 4 , and concentrated in vacuo to give a white solid; yield 1.50g (76%). 1 B. 1-(4-(Aminomethyl)benzoyl)-2.3.4.5-tetrahvdro-1 H-1 -benzazepine To a degassed solution of the cyanobenzoyl benzazepine from Example 1A (1.50g, 5.43mmol) in methanol (50ml) were added concentrated hydrochloric acid (1.4ml, 16.2mmol) and 10% palladium-on-carbon (1.15g). Hydrogen gas was bubbled through the mixture for 5h at room temperature. The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated in vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was basified by addition of saturated sodium bicarbonate solution and extracted with dichloromethane (2 times). The combined organic extracts were washed with brine, dried over MgSO 4 , and concentrated in vacuo to give a white solid; yield 1.12g (74%). 1C. 1-(4-r3-(2.6-Difluorophenyl)ureidomethvπbenzoyl)-2.3.4.5-tetrahvdro-1H-1- benzazepine To a solution of the amine from Example 1B (0.50g, 1.79mmol) in dichloromethane (20ml) were added triethylamine (0.27ml, 1.97mmol) and 2,6-difluorophenylisocyanate (0.31g, 1.97mmol). The mixture was stirred at room temperature for 2h and then evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50) to give a white solid; yield 0.62g (80%). M.S.: calc m/e=435.18; found [M+H] + = 436. Example 2. 1 -(4-r3-(2.6-Difluorophenvπcvanoquanidinomethvnbenzoyl)-2.3Λ5-tetrahvdro-1 H-1 ■ benzazepine To a solution of the amine from Example 1B (0.12g, 0.379mmol) in DMF (20ml) were added 1-(2,6-difluoro-phenyl)-3-cyano-thiourea (0.16g, 0.758mmol, prepared according to Atwal et. al., Tetrahedron Lett., 30, p7313, 1989.), diisopropylethylamine (0.16ml, 0.947mmol) and WSCDI (0.087g, 0.455mmol). The mixture was stirred at room temperature for 72h and then evaporated in vacuo. The residue was partitioned between dichloromethane and 1M KHSO 4 . The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50- 70:30) to give a white solid; yield 0.084g (48%). M.S.: calc m/e=459.19; found [M+H] + = 460.0 Example 3. 1-(6-f3-(2.6-Difluorophenvnureidomethyllnicotinoyl)-2.3,4.5-tetrahvdro-1H-1- benzazepine 3A. 1 -r6-(te/f-Bυtyloxycarbonylaminomethyl)nicotinovn-2.3.4.5-tetrahvdro-1 H-1 - benzazepine The carboxylic acid from Example G4 (1.38g, 5.45mmol) was reacted with 2,3,4,5- tetrahydro-1 H-1 -benzazepine (0.80g, 5.50mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70-70:30); yield 1.14g (55%). 3B. 1-r6-(Aminomethyl)nicotinoyll-2.3.4.5-tetrahvdro-1 H-1 -benzazepine hvdrochloride The BOC amine from Example 3A (1.14g, 2.98mmol) was dissolved in 4N HCI/dioxan, stirred at room temperature for 1h and then evaporated in vacuo, azeotroping with toluene, to give an off white solid; yield 1.0g (quantitative). 3C. 1 -(6-r3-(2.6-Dif luorophenyl)ureidomethvnnicotinoyl)-2.3.4.5-tetrahvdro-1 H-1 - benzazepine The amine hydrochloride from Example 3B (0.070g, 0.220mmol) was reacted with 2,6- difluorophenylisocyanate (0.038g, 0.242mmol) according to the procedure in Example 1C. The product was purified by trituration with diethyl ether to give a white solid; yield 0.060g (63%). M.S.: calc m/e=436.47; found [M+H] + = 437.2 Example 4. 1-(3-Chloro-4-r3-(3-methoxyphenyl)ureidomethvπbenzovπ-2.3.4.5-tetrahvdro-1H-1- benzazepine 4A. 1-(4-rferf-Butyloxycarbonylaminomethyll-3-chlorobenzoyl)-2.3.4.5-tetrahydro-1H-1- benzazepine The carboxylic acid from Example A2 (1.0g, 3.50mmol) was reacted with 2,3,4,5- tetrahydro-1 H-1 -benzazepine (0.47g, 3.20mmol) according to the procedure in Example 1 A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70-40:60); yield 0.88g (66%). 4B. 1-(4-fAminomethvπ-3-chlorobenzoyl)-2,3.4.5-tetrahvdro-1 H-1 -benzazepine hvdrochloride The BOC amine from Example 4A (0.88g, 2.10mmol) was dissolved in 4N HCI/dioxan and stirred at room temperature for 1h, then evaporated in vacuo, azeotroping with toluene, to give a white solid; yield 0.70g (95%). 4C. 1-(3-Chloro-4-r3-(3-methoχyphenyl)ureidomethyllbenzoyl)-2.3.4.5-tetrahvdro-1H-1- beπzazepine The amine hydrochloride from Example 4B (0.050g, 0.140mmol) was reacted with 3- methoxyphenylisocyanate (0.021g, 0.140mmol) according to the procedure in Example 1C. The product was purified by trituration with diethyl ether to give a white solid; yield 0.060g (93%). M.S.: calc m/e=463.17; found [M+H] + = 464.2. Example 5. 1-(3-Chloro-4-r3-(2-chlorophenyl)ureidomethvnbenzoyl)-2,3,4.5-tetrahvdro-1H-1- benzazepine The amine hydrochloride from Example 4B (0.050g, 0.140mmol) was reacted with 2- chlorophenylisocyanate (0.022g, 0.140mmol) according to the procedure in Example 1C. The product was purified by trituration with diethyl ether to give a white solid; yield 0.063g (98%). M.S.: calc m/e=467.12; found [M+H] + ; J0 CI = 468.1 Example 6. 1-(3-Chloro-4-r3-(2,6-difluorophenyl)thioureidomethvπbenzoyl)-2,3,4,5-tetrahvdro- 1 H-1 -benzazepine The amine hydrochloride from Example 4B (0.075g, 0.214mmol) was reacted with 2,6-difluorophenylisothiocyanate (0.054g, 0.320mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAαpet. ether 30:70-45:55); yield 0.068g (66%). M.S.: calc m/e=485.11 ; found [M+H] + ; *CI = 486.2, [M+H] ■ > + +;. 37CMl = - 488.1 Example 7. 1-(4-r3-(2.6-Difluorophenvnureidomethvπ-2-methylbenzovπ-2.3A5-tetrahvdro-1H-1- benzazepine 7A. 1-(4-Cvano-2-methylbenzoyl)-2.3.4.5-tetrahvdro-1 H-1 -benzazepine The carboxylic acid from Example D (0.96g, 5.95mmol) was reacted with 2,3,4,5- tetrahydro-1 H-1 -benzazepine (0.80g, 5.44mmol) according to the procedure in Example 1 A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 0.59g (38%). 7B. 1-(4-rAminomethvn-2-methylbenzoyl)-2.3.4.5-tetrahvdro-1 H-1 -benzazepine hydrochloride The cyanobenzoyl benzazepine from Example 7A (0.59g, 2.03mmol) was hydrogenated according to the procedure in Example 1 B. The product was isolated as the HCI salt; yield 0.55g (82%). 7C. 1-(4-r3-(2.6-Difluorophenyl)ureidomethyll-2-methylbenzoyl)-2.3.4.5-tetrahvdro-1H-1- benzazepine The amine hydrochloride from Example 7B (0.050g, 0.151 mmol) was reacted with 2,6-difluorophenylisocyanate (0.028g, 0.181mmol) according to the procedure in Example 1 C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50); yield 0.041 g (62%). M.S.: calc m/e=449.19; found [M+H] + = 450.1. Example 8. 1-(3-Methyl-4-f3-(phenylsulfonyl)ureidomethvnbenzoyl)-2.3.4.5-tetrahvdro-1H-1- benzazepine 8A. 1-(4-Cvano-3-methylbenzoyl)-2.3.4,5-tetrahvdro-1H-1-benzazepine The carboxylic acid from Example C (0.96g, 5.95mmol) was reacted with 2,3,4,5- tetrahydro-1 H-1 -benzazepine (0.80g, 5.44mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 1.1 Og (70%). 8B. 1-(4-rAminomethyll-3-methylbenzoyl)-2.3.4.5-tetrahvdro-1 H-1 -benzazepine hydrochloride The cyanobenzoyl benzazepine from Example 8A (1.10g, 3.79mmol) was hydrogenated according to the procedure in Example 1B. The product was isolated as the HCI salt; yield 1.23g (98%). 8C. 1-(3-Methyl-4-r3-(phenylsulfonyl)ureidomethyllbenzoyl)-2.3.4.5-tetrahvdro-1H-1- benzazepine The amine hydrochloride from Example 8B (0.050g, 0.151 mmol) was reacted with phenylsulphonylisocyanate (0.028g, 0.151 mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOA .pet. ether 80:20); yield 0.026g (22%). M.S.: calc m/e=477.17; found [M+H] + = 478.2. Example 9. 1-(3-Methyl-4-r3-(2-oxo-1.2-dihvdropyrid-3-yl)ureidomethvnbenzovn-2.3.4.5- tetrahvdro-1 H-1 -benzazepine To a suspension of 2-hydroxynicotinic acid (95mg, 0.68mmol) in dioxan (5ml) were added triethylamine (0.11ml, 0.771mmol) and diphenylphosphoryl azide (0.16ml, 0.725mmol). The mixture was stirred at reflux for 3h. The amine hydrochloride from Example 8B (0.1 δg, 0.4δ3mmol) and triethylamine (0.09δml, 0.680mmol) were added and the mixture was stirred at reflux for a further 18h, cooled and evaporated in vacuo. The residue was partitioned between dichloromethane and 1M KHSO . The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant methanol:dichloromethane 2:98-δ:9δ) to give a white solid; yield 0.084g (43%). M.S.: calc m/e=430.20; found [M+H] + = 431.1. Example 10. 1-(4-r3-f2.6-Difluorophenvnureιdomethvn-3-methylbenzoyl)-2.3Λ5-tetrahvdro-1H-1- benzazepine The amine hydrochloride from Example 8B (0.050g, 0.151 mmol) was reacted with 2,6-difluorophenylisocyanate (0.028g, 0.181mmol) according to the procedure in Example 1 C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:60); yield 0.044g (65%). M.S.: calc m/e=449.19; found [M+H] + = 450.1. Example 11. 1-(3-Nitro-4-r2-nitrobenvzlsulfonylaminomethvnbenzoyl)-2.3.4.5-tetrahvdro-1H-1- benzazepine 11 A. 1-(4-rfe/f-Butyloxycarbonylaminomethyll-3-nitrobenzoyl)-2.3.4.δ-tetrahvdro-1 H-1- benzazepine The carboxylic acid from Example B (0.911g, 3.08mmol) was reacted with 2,3,4,6- tetrahydro-1 H-1 -benzazepine (0.4δ3g, 3.08mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOA pet. ether 60:60); yield O.δδg (43%). 11 B. 1-(4-fAminomethv π -3-nitrobenzoyl)-2.3 Aδ-tetrahvdro-1H-1-benzazepine hydrochloride The BOC-aminomethylbenzoyl benzazepine from Example 11A (0.33g, 0.764mmol) was reacted according to the procedure in Example 4B. The product was isolated as the HCI salt; yield 0.27g (98%). 11C. 1-(3-Nitro-4-f2-nitrobenyzlsulfonylaminomethvnbenzoyl)-2.3.4.5-tetrahydro-1H-1- benzazepine The amine hydrochloride from Example 11B (0.068g, 0.188mmol) was reacted with 2-nitrobenzylsulphonyl chloride (0.033g, 0.226mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 25:76-60:50); yield 0.01 Og (10%). M.S.: calc m/e=524.14; found [M+H] + = 526.2. Example 12. 1 -(3-Amino-4-r3-(2.6-difluorophenyl)ureidomethvnbenzovn-2.3.4.5-tetrahvdro-1 H-1 - benzazepine 12A. 1-(3-Amino-4-ftert-butyloxycarbonylaminomethvnbenzoyl)-2.3,4.5-tetrahvdro-1H-1- benzazepine To a degassed solution of the nitrobenzoyl benzazepine from Example 11A (0.30g, 0.700mmol) in methanol (δOml) was added 10% palladium-on-carbon (0.1 Og). Hydrogen gas was bubbled through the mixture for 1.δh at room temperature. The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated in vacuo; yield 0.2δ4g (92%). 12B. 1-(3-Amino-4-raminomethvnbenzoyl)-2.3.4.δ-tetrahvdro-1 H-1 -benzazepine dihvdrochloride The BOC-aminomethylbenzoyl benzazepine from Example 12A (0.14g, 0.3δ4mmol) was reacted according to the procedure in Example 4B. The product was isolated as the diHCI salt; yield 0.098g (75%). 12C. 1-(3-Amino-4-r3-(2.6-difluorophenyl)ureidomethyllbenzoyl)-2.3.4.5-tetrahvdro-1H-1- benzazepine The amine hydrochloride from Example 12B (0.132g, 0.3δmmol) was reacted with 2,6-difluorophenylisocyanate (O.Oδδg, 0.35mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 70:30) and then by preparative HPLC (gradient water:acetonitrile 80:20-20:80; 0.1% TFA). The HPLC fractions were freeze-dried to give a white solid; yield 0.027g (17%). M.S.: calc m/e=4δ0.19; found [M+H] + = 461.2. Example 13. 1-(4-r3-(2.6-Difluorophenvπureidomethvn-3-dimethylaminobenzoyl)-2.3.4.5- tetrahvdro-1 H-1 -benzazepine 13A. 1 -(4-rfeff-Bυtyloxycarbonylaminomethvn-3-dimethylaminobenzoyl)-2.3.4.δ- tetrahydro-1 H-1 -benzazepine To an ice cold solution of the amine from Example 12A (0.16g, 0.40mmol) in 1% acetic acid/methanol (2δml) was added formaldehyde (37% solution in water, O.OδOml, 0.60mmol). The mixture was stirred at 0°C for 10min and then sodium borohydride (O.OδOg, 0.80mmol) was added. The mixture was allowed to warm to room temperature with stirring over 1h. and then evaporated in vacuo. The residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70-70:30) to give a white solid; yield 0.091 g (66%). 13B. 1-(4-rAminomethyll-3-dimethylaminobenzoyl)-2.3.4.δ-tetrahvdro-1 H-1 -benzazepine The BOC-aminomethylbenzoyl benzazepine from Example 13A (0.089g, 0.22δmmol) was reacted according to the procedure in Example 4B. The product was isolated as the HCI salt; yield 0.07δg (97%). 13C. 1-(4-r3-(2.6-Difluorophenyl)ureidomethvn-3-dimethylaminobenzoyl)-2.3.4.δ- tetrahvdro-1 H-1 -benzazepine The amine hydrochloride from Example 13B (0.07δg, 0.20mmol) was reacted with 2,6-difluorophenylisocyanate (0.032g, 0.20mmol) according to the procedure in Example 1 C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 90:10); yield 0.044g (6δ%). M.S.: calc m/e=478.22; found [M+H] + = 479.2. Example 14. 1 -(4-r3-(2.6-Difluorophenyl)ureidomethvn-2-fluorobenzovπ-2.3.4.5-tetrahvdro-1 H-1 - benzazepine 14A. 1 -(4-rteAf-Butyloxycarbonylaminomethvn-2-fluorobenzoyl)-2,3.4,δ-tetrahvdro-1 H-1 • benzazepine The carboxylic acid from Example E4 (0.60g, 2.22mmol) was reacted with 2,3,4,δ- tetrahydro-1H-1-benzazepine (0.28g, 1.89mmol) according to the procedure in Example . 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 40:60); yield O.δδg (77%). 14B. 1-(4-rAminomethylI-2-fluorobenzoyl)-2.3.4.δ-tetrahvdro-1H-1-benzazepine The BOC-aminomethylbenzoyl benzazepine from Example 14A (O.δδg, 1.42mmol) was reacted according to the procedure in Example 4B. The product was isolated as the HCI salt; yield 0.29g (60%). 14C. 1-(4-f3-(2.6-Difluorophenyl)ureidomethvn-2-fluorobenzoyl)-2.3.4.δ-tetrahvdro-1H-1- benzazepine The amine hydrochloride from Example 14B (0.040g, 0.12mmol) was reacted with 2,6-difluorophenylisocyanate (0.020g, 0.13mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 40:60-100:0); yield 0.038g (70%). M.S.: calc m/e=4δ3.17; found [M+H] + = 464.1. Example 15. 1-(4-r3-(2.6-Difluorophenvπureidomethyll-3-methylbenzovn-2.3.4.5-tetrahvdro-1H- 1 ,5-benzodiazepine 1 δA. 2.3.4.5-Tetrahvdro-1H-1.5-benzodiazepine To an ice cold solution of lithium aluminium hydride (4.6δg, 123mmol) in dry THF (100ml), under a nitrogen atmosphere, was added dropwise a solution of 2,3,4,δ-tetrahydro-1H- 1 ,6-benzodiazepin-2-one (δ.Og, 30.9mmol) in dry THF (60ml). The mixture was allowed to warm to room temperature and then heated at reflux for 2h. The mixture was then cooled to 0°C and a solution of aqueous ammonium hydroxide (10ml) in THF (60ml) was added dropwise. The resultant suspension was stirred for 1h and then filtered through a pad of celite. The filtrate was evaporated in vacuo to give a tan solid; yield 4.36g (9δ%). 1 δB. 1 -(4-Cvano-3-methylbenzoyl)-2.3.4.δ-tetrahvdro-1 H-1.δ-benzodiazepine The carboxylic acid from Example C (0.6δg, 4.03mmol) was reacted with 2,3,4,δ- tetrahydro-1 H-1, δ-benzodiazepine from Example 1δA (O.δOg, 3.36mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:δ0); yield 0.36g (37%). 1 δC. 1 -(4-rAminomethyl1-3-methylbenzoyl)-2,3,4.δ-tetrahydro-1 H-1.δ-benzodiazepine hydrochloride The cyanobenzoyl benzodiazepine from Example 1δB (0.36g, 1.24mmol) was hydrogenated according to the procedure in Example 1B. The product was isolated as the HCI salt; yield 0.17g (40%). 1 δD. 1 -(4-f3-(2.6-Difluorophenyl)ureidomethyl1-3-methylbenzoyl)-2.3.4.δ-tetrahvdro-1 H- 1.δ-benzodiazepine The amine hydrochloride from Example 1δC (0.170g, 0.46mmol) was reacted with 2,6-difluorophenylisocyanate (0.071 g, 0.46mmol) according to the procedure in Example 1 C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:20); yield 0.089g (43%). M.S.: calc m/e=460.19; found [M+H] + = 461.2. Example 16. 1-(4-f3-(2,6-Difluorophenyl)ureidomethvn-3-methylbenzoyl)-5-(3-pyridyl)methyl- 2,3A5-tetrahvdro-1 H-1 ,5-benzodiazepine 16A. 1-(3-Pyridyl)methyl-2.3.4.δ-tetrahydro-1 H-1.δ-benzodiazepine To solution of 2,3,4,δ-tetrahydro-1 H-1, δ-benzodiazepine from Example 1δA (O.δOg, 3.3δmmol) in 1% acetic acid/methanol (2δml), at room temperature, was added pyridine- 3-carboxaldehyde (0.3δml, 03.72mmol). The mixture was stirred at reflux for 1 δh and then allowed to cool to room temperature. Sodium borohydride (O.OδOg, O.δOmmol) was added. The mixture was stirred for 2h and then evaporated in vacuo. The residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc) to give a white solid; yield 0.3δ6g (40%). 16B. 1-(4-Cvano-3-methylbenzoyl)-δ-(3-pyridyl)methyl-2.3.4.δ-tetrahvdro-1H-1,δ- benzodiazepine The carboxylic acid from Example C (0.31 g, 1.93mmol) was reacted with 1-(3- pyridyl)methyl-2,3,4,δ-tetrahydro-1 H-1, δ-benzodiazepine from Example 16A (0.39g, 1.61 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc); yield 0.2δg (4δ%). 16C. 1-(4-Aminomethyl-3-methylbenzoyl)-δ-(3-pyridyl)methyl-2.3.4.δ-tetrahvdro-1H-1.δ- benzodiazepine To a solution of the nitrile from Example 16B (0.2δg, 0.72mmol) in methanol (20ml) were added cobaltous chloride (0.33δg, 1.42mmol) and sodium borohydride (0.27g, 7.20mmol). The mixture was stirred at room temperature for 1h and then saturated aqueous ammonium chloride solution (10ml) was added. The mixture was concentrated in vacuo and the aqueous residue was partitioned between diethyl ether and water. The aqueous layer was basified by addition of saturated sodium bicarbonate solution and extracted with chloroform (3 times). The combined organic extracts were washed with brine, dried over MgSO 4 , and concentrated in vacuo to give a white solid; yield 0.20g (72%). 16D. 1-(4-r3-(2.6-Difluorophenyl)ureidomethvn-3-methylbenzoyl)-δ-(3-pyridyl)methyl- 2.3.4.δ-tetrahvdro-1 H-1.δ-benzodiazepine The amine from Example 16C (0.06δg, 0.168mmol) was reacted with 2,6-difluorophenylisocyanate (0.027g, 0.17mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc); yield 0.068g (75%). M.S.: calc m/e=541.23; found [M+H] + = 642.2. Example 17. 1-(4-r3-(2.6-Difluorophenyl)ureidomethvπ-3-methylbenzovπ-5-(2-hvdroxyethyl)- 2,3,4.5-tetrahvdro-1 H-1 ,5-benzodiazepine 17A. Methyl (2-oxo-2.3.4.δ-tetrahydro-1H-1.δ-benzodiazepin-1-yl)acetate To a solution of 1 ,3,4,δ-tetrahydro-benzo[ό][1 ,4]diazepin-2-one (δ.Og, 30.8mmol) in DMF (30ml), at -10°C, was added sodium hydride (1.3δg, 60% dispersion, 33.9mmol). The mixture was stirred at -10°C for 1δmin, then methyl bromoacetate (2.92ml, 30.δmmol) was added. The mixture was stirred at -10°C for a further 1h and then concentrated in vacuo. The residue was taken up in EtOAc and washed with brine (3 times), dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc) to give a white solid; yield 7.0δg (9δ%). 17B. 2-(2.3.4.δ-Tetrahvdro-1H-1.δ-benzodiazepin-1-yl)ethanol Methyl (2-oxo-[1,3,4,δ-tetrahydro-benzo[6]1,4]diazepin-1-yl)-acetate from Example 17A (7.08g, 30.2mmol) was reduced with lithium aluminium hydride according to the procedure in Example 1δA; yield 4.33g (7δ%). 17C. 1 -(4-Cvano-3-methylbenzoyl)-δ-(2-hvdroxyethyl)-2.3.4.δ-tetrahvdro-1 H-1.5- benzodiazepine To a solution of the carboxylic acid from Example 1C (1.38g, δ.δδmmol) in dichloromethane (δOml) was added thionyl chloride (3.33ml, 43.0mmol). The mixture was stirred at reflux for 2h and then evaporated in vacuo, azeotroping with toluene (2 times). The residue was dissolved in dichloromethane (60ml) and 2-(2,3,4,δ-tetrahydro- 1H-1 ,δ-benzodiazepin-1-yl)ethanol from Example 17B (1.δg, 7.δ0mmol) was added. The mixture was stirred at room temperature for 1δh and then evaporated in vacuo. The residue was partitioned between EtOAc and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo. The residue was triturated with EtOAc and the resultant solid filtered off; yield 1.2δg (4δ%). 17D. 1 -(4-Aminomethyl-3-methylbenzoyl)-δ-(2-hvdroxyethyl)-2.3.4.δ-tetrahvdro-1 H-1.6- benzodiazepine The cyanobenzoyl benzodiazepine from Example 17C (1.2δg, 3.73mmol) was hydrogenated according to the procedure in Example 1B. The product was isolated as the free base; yield 0.94g (74%). 17E. 1-(4-f3-(2.6-Difluorophenyl)υreidomethvn-3-methylbenzoyl)-δ-(2-hvdroxyethyl)- 2.3.4.δ-tetrahvdro-1 H-1.δ-benzodiazepine The amine from Example 17D (0.94g, 2.76mmol) was reacted with 2,6-difluorophenylisocyanate (0.47g, 3.04mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc); yield 0.068g (75%). M.S.: calc m/e=494.21; found [M+H] + = 495.2. Example 18. 1-(3-Chloro-4-r3-(2.6-difluorophenyl)ureidomethvnbenzoyl)-5-methyl-2.3.4.5- tetrahvdro-1 H-1 ,5-benzodiazepine 18A. 1 -Methyl-2-oxo-2.3.4.δ-tetrahvdro-1 H-1.δ-benzodiazepine To a solution of 2,3,4,δ-tetrahydro-1H-1,δ-benzodiazepin-2-one (2.0g, 12.3mmol) in DMF (30ml), at -10°C, was added sodium hydride (0.δ4g, 60% dispersion, 13.6mmol). The mixture was stirred at -10°C for 1δmin, then methyl iodide (0.77ml, 12.3mmol) was added. The mixture was stirred at -10°C for a further 1 h and then concentrated in vacuo. The residue was taken up in EtOAc and washed with brine (3 times), dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc) to give a white solid; yield 1.70g (7δ%). 1 δB. 1-Methyl-2.3.4.δ-tetrahvdro-1H-1.δ-benzodiazepine 1-Methyl-2-oxo-2,3,4,δ-tetrahydro-1 H-1, δ-benzodiazepine from Example 18A (1.7g, 9.6δmmol) was reduced with lithium aluminium hydride according to the procedure in Example 1δA; yield 1.34g (86%). 18C. 1-(4-rteff-Butyloxycarbonylaminomethvπ-3-chlorobenzoyl)-δ-methyl-2.3.4.δ- tetrahvdro-1 H-1.δ-benzodiazepine The carboxylic acid from Example A2 (0.δ06g, 1.77mmol) was reacted with 1-methyl- 2,3,4,δ-tetrahydro-1H-1,δ-benzodiazepine from Example 18B (0.24g, 1.48mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:δ0); yield 0.30g (47%). 16D. 1-(4-Aminomethyl-3-chlorobenzoyl)-δ-methyl-2.3.4.δ-tetrahvdro-1H-1.δ- benzodiazepine The BOC-aminomethylbenzoyl benzazodiazepine from Example 1δC (0.30g, 0.698mmol) was reacted according to the procedure in Example 4B. The product was isolated as the HCI salt; yield 0.2δg (98%). 18E. 1 -(3-Chloro-4-r3-(2.6-difluorophenyl)ureidomethvnbenzoyl)-δ-methyl-2.3.4.δ- tetrahvdro-1 H-1.δ-benzodiazepine The amine hydrochloride from Example 1δD (0.060g, 0.164mmol) was reacted with 2,6-difluorophenylisocyanate (0.021g, 0.164mmol) according to the procedure in Example 1C. The product was purified by trituration with diethyl ether to give a white solid; yield O.Oδδg (87%). M.S.: calc m/e=484.1δ; found [M+H] + ; J0 CI = 486.1 Example 19. 1-(4-r3-(2.6-Difluorophenyl)ureidomethvn-2-methylbenzovn-5-methyl-2.3.4.5- tetrahvdro-1 H-1 ,5-benzodiazepine 19A. 1 -(4-Cvano-2-methylbenzoyl)-δ-methyl-2.3.4.δ-tetrahvdro-1 H-1.δ-benzodiazepine hydrochloride The carboxylic acid from Example D (O.δOg, 3.10mmol) was reacted with 1-methyl- 2,3,4,δ-tetrahydro-1 H-1, δ-benzodiazepine from Example 1δB (0.46g, 2.δ0mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70-70:30); yield 0.27g (32%). 19B. 1-(4-Aminomethyl-2-methylbenzoyl)-δ-methyl-2.3.4,δ-tetrahvdro-1 H-1.δ- benzodiazepine hydrochloride The cyanobenzoyl benzazepine from Example 19A (0.26g, O.δδmmol) was hydrogenated according to the procedure in Example 1B. The product was isolated as the HCI salt; yield 0.30g (99%). 19C. 1-(4-r3-(2.6-Difluorophenyl)ureidomethvn-2-methylbenzoyl)-δ-methyl-2.3.4.δ- tetrahvdro-1 H-1.δ-benzodiazepine The amine hydrochloride from Example 19B (0.060g, 0.17mmol) was reacted with 2,6-difluorophenylisocyanate (0.027g, 0.17mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:20); yield 0.070g (93%). M.S.: calc m/e=464.20; found [M+H] + = 466.2. Example 20. 1-(4-r3-(2.6-Difluorophenyl)ureidomethyll-3.5-dimethylfaenzoyl)-2.3.4.5-tetrahvdro- 1 H-1 -benzazepine 20A. 1-(4-Cvano-3.5-dimethylbenzoyl)-2.3.4.δ-tetrahvdro-1H-1-benzazepine The carboxylic acid from Example 12 (0.49g, 2.δ0mmol) was reacted with 2,3,4,δ- tetrahydro-1 H-1 -benzazepine (0.39g, 2.63mmol) according to the procedure in Example 17C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 0.66g (77%). 20B. 1-(4-Aminomethyl-3.δ-dimethylbenzoyl)-2.3,4.δ-tetrahydro-1H-1-benzazepine The nitrile from Example 20A (0.6δg, 2.12mmol) was reduced according to the procedure in Example 16C; yield 0.42g (64%). 20C. 1-(4-r3-(2.6-Difluorophenyl)ureidomethvn-3.δ-dimethylbenzoyl)-2.3.4.δ-tetrahvdro- 1 H-1 -benzazepine The amine from Example 20B (0.070g, 0.23mmol) was reacted with 2,6-difluorophenylisocyanate (0.043g, 0.2δmmol) according to the procedure in Example 1 C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 40:60); yield 0.033g (31%). M.S.: calc m/e=463.21 ; found [M+H] + = 464.2. Example 21. 1-(2-Chloro-6-r3-f2,6-difluorophenvnureidomethvnnicotinoyl)-2.3,4,5-tetrahvdro-1H- 1 -benzazepine 21A. 1-(6-rte/f-Butylaminomethyll-2-chloronicotinoyl)-2.3.4.δ-tetrahvdro-1H-1- benzazepine The carboxylic acid from Example F3 (O.δOg, 1.74mmol) was reacted with 2,3,4,5- tetrahydro-1 H-1 -benzazepine (0.26g, 1.74mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 65:45); yield 0.038g (5%). 21 B. 1-(6-Aminomethyl-2-chloronicotinoyl)-2.3.4.δ-tetrahvdro-1H-1-benzazepine hydrochloride The BOC-aminomethylnicotinoyl benzazepine from Example 21A (0.036g, 0.074mmol) was reacted according to the procedure in Example 4B. The product was isolated as the HCl salt; yield 0.026g (98%). 21C. 1-(2-Chloro-6-r3-(2.6-difluorophenyl)ureidomethvnnicotinoyl)-2.3.4.δ-tetrahvdro-1H- 1 -benzazepine The amine hydrochloride from Example 21 B (0.026g, 0.073mmol) was reacted with 2,6-difluorophenylisocyanate (0.014g, O.Oδmmol) according to the procedure in Example 1 C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 90:10); yield 0.031 g (90%). M.S.: calc m/e=470.13; found [M+H] + ; X C\ = 471.1. Example 22. 1 -(6-r3-(2.6-Difluorophenyl)ureidomethyl1-1 -methyl-2-oxo-1 ,2-dihvdropyridyl-3- carbonyl)-2,3,4,5-tetrahvdro-1 H-1 -benzazepine 22A. 1 -(4/δ-Bromo-6-rterf-butyloxycarbonylaminomethvπ-1 -methyl-2-oxo-1.2- dihydropyridyl-3-carbonyl)-2.3.4.δ-tetrahvdro-1H-1-benzazepine The carboxylic acid from Example H3 (1.30g, 3.60mmol) was reacted with 2,3,4,6- tetrahydro-1H-1-benzazepine (0.63g, 3.60mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOA pet. ether 60:40); yield 0.70g (40%). 22B. 1-(4/δ-Bromo-6-rfe/f-butyloxycarbonylaminomethvπ-1-methyl-2-oxo-1.2- dihvdropyridyl-3-carbonyl)-2,3,4,δ-tetrahvdro-1H-1-benzazepine The benzazepine from Example 22A (0.60g, 1.23mmol) was hydrogenated according to the procedure in Example 12A; yield O.δOg (99%). 22C. 1-(6-Aminomethyl-1-methyl-2-oxo-1.2-dihvdropyridyl-3-carbonyl)-2.3.4.δ-tetrahvdro- 1 H-1 -benzazepine hydrochloride The BOC-aminomethyl pyridone from Example 22B (O.δOg, 1.22mmol) was reacted according to the procedure in Example 4B. The product was isolated as the HCI salt; yield 0.43g (99%). 22D. 1-(6-r3-(2.6-Difluorophenyl)ureidomethyll-1-methyl-2-oxo-1.2-dihvdropyridyl-3- carbonyl)-2.3,4.5-tetrahvdro-1 H-1 -benzazepine The amine hydrochloride from Example 22C (0.050g, 0.144mmol) was reacted with 2,6-difluorophenylisocyanate (0.025g, 0.144mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc:methanol 90:10); yield 0.064g (96%). M.S.: calc m/e=466.18; found [M+H] + = 467.2. Example 23. 1-(4-r3-f2.6-Difluorophenvπureidomethvn-3-methylbenzovπ-5-ethyl-2.3.4.5- tetrahvdro-1 H-1 ,5-benzodiazepine 23A. 1-Ethyl-2-oxo-2.3.4.δ-tetrahvdro-1H-1.δ-benzodiazepine 2-Oxo-2,3,4,δ-tetrahydro-1 H-1, δ-benzodiazepine (1.9δg, 11.96mmol) was reacted with ethyl iodide ( 1.4ml, 17.δmmol) according to the procedure in Example 18A. The product was purified by flash chromatography on silica (eluant EtOAc); yield 1.70g (76%). 23B. 1-Ethyl-2.3.4.δ-tetrahvdro-1 H-1.δ-benzodiazepine 1-Ethyl-2-oxo-2,3,4,δ-tetrahydro-1 H-1, δ-benzodiazepine from Example 23A (1.7g, 8.94mmol) was reduced with lithium aluminium hydride according to the procedure in Example 1δA; yield l.δδg (98%). 23C. 1 -(4-Cvano-3-methylbenzoyl)-δ-ethyl-2.3.4.δ-tetrahvdro-1 H-1.δ-benzodiazepine The carboxylic acid from Example C (0.63g, 3.29mmoi) was reacted with 1-ethyl-2,3,4,δ- tetrahydro-1H-1 ,δ-benzodiazepine from Example 23B (0.614g, 2.92mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:40); yield O.δδg (69%). 23D. 1 -(4-Aminomethyl-3-methylbenzoyl)-δ-ethyl-2.3.4.δ-tetrahvdro-1 H-1.6- benzodiazepine hydrochloride The nitrile from Example 23C (O.δδg, 1.73mmol) was hydrogenated according to the procedure in Example 1 B. The product was isolated as the HCI salt; yield O.δOg (96%). 23E. 1-(4-f3-(2.6-Difluorophenyl)ureidomethvn-3-methylbenzoyl)-δ-ethyl-2.3.4.δ- tetrahvdro-1 H-1.δ-benzodiazepine The amine hydrochloride from Example 23D (0.071 g, 0.20mmol) was reacted with 2,6-difluorophenylisocyanate (0.038g, 0.2δmmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:60-100:0); yield 0.044g (46%). M.S.: calc m/e=47δ.22; found [M+H] + = 479.2. Example 24. 5-(4-r3-(2.6-Difluorophenvπureidomethvn-3-methylbenzoyl)-6.7.8.9-tetrahvdro-5H- pyridor2,3-o1azepine 24A. 6-(4-Cvano-3-methylbenzoyl)-6.7.8.9-tetrahvdro-6H-pyridor2.3-d1azepine The carboxylic acid from Example C (0.36g, 2.26mmol) was reacted with 6,7,6,9- tetrahydro-δH-pyrido[2,3-ό]azepine (0.33g, 2.23mmol) according to the procedure in Example 17C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:20); yield 0.47g (73%). 24B. 6-(4-Aminomethyl-3-methylbenzoyl)-6.7.8.9-tetrahvdro-6H-pyridor2.3-i lazepine The cyanobenzoyl pyridoazepine from Example 24A (0.46g, l.δδmmol) was hydrogenated according to the procedure in Example 1B. The product was isolated as the free base; yield 0.28g (60%). 24C. δ-(4-f3-(2.6-Difluorophenyl)ureidomethyll-3-methylbenzoyl)-6.7.δ.9-tetrahvdro-δH- pyridof2.3- ?1azepine The amine from Example 24B (0.071 g, 0.20mmol) was reacted with 2,6-difluorophenylisocyanate (0.03δg, 0.23mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc); yield 0.020g (19%). M.S.: calc m/e=460.19; found [M+Hf= 461.2 Example 25. 5-(4-r3-(2.6-Difluorophenvnureidomethyll-3-methylbenzovn-1-oxo-1λ 4 -2.3.4.5- tetrahvdro-1 ,5-benzothiazepine 2δA. δ-(4-Cvano-3-methylbenzoyl)-2,3.4.δ-tetrahvdro-1.δ-benzothiazepine The carboxylic acid from Example C (0.27g, l.δδmmol) was reacted with 2,3,4,6- tetrahydro-1 ,5-benzothiazepine (0.2δg, 1.70mmol) according to the procedure in Example 1 A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:40); yield 0.43g (84%). 25B. δ-(4-Aminomethyl-3-methylbenzoyl)-2.3.4.δ-tetrahvdro-1.δ-benzothiazepine The cyanobenzoyl benzothiazepine from Example 26A (0.43g, 1.40mmol) was hydrogenated according to the procedure in Example 1B. The product was isolated as the free base; yield 0.1 Og (29%). 25C. δ-(4-f3-(2.6-Difluorophenyl)ureidomethvn-3-methylbenzoyl)-2.3.4.5-tetrahvdro-1.δ- benzothiazepine The amine from Example 26B (0.1 Og, 0.32mmol) was reacted with 2,6-difluorophenylisocyanate (0.061g, 0.39mmol) according to the procedure in Example 1C. The product was purified by trituration with diethyl ether to give a white solid; yield 0.112g (7δ%). 2δD. δ-(4-r3-(2.6-Difluorophenyl)ureidomethyll-3-methylbenzoyl)-1 -oxo-1 λ -2.3.4.δ- tetrahvdro-1.δ-benzothiazepine To a suspension of the thiazepine from Example 26C (O.lδg, 0.33mmol) in methanol (40ml), dichloromethane (10ml) and water (10ml) was added sodium periodate (0.21 g, 0.99mmol). The mixture was stirred at room temperature for 70h and then filtered. The filtrate was evaporated in vacuo and the residue was purified by flash chromatography on silica (eluant EtOAc); yield 0.013g (8%). M.S.: calc m/e=483.14; found [M+H] + = 484.1. Example 26. 4-(4-r3-(2.6-Difluorophenyl)ureidomethyll-3-methylbenzoyl)-5.6.7.8-tetrahvdro-4H- thienof3.2-o1azepine 26A. 4-(4-Cvano-3-methylbenzoyl)-5.6.7.8-tetrahvdro-4H-thienor3.2-f?lazepine The carboxylic acid from Example C (O.δOg, 3.10mmol) was reacted with δ,6,7,δ- tetrahydro-4H-thieno[3,2-d]azepine (0.4δg, 2.9δmmol) according to the procedure in Example 1A. The product was purified by recrystallisation from EtOAc:pet. ether; yield 0.4δg (δδ%). 26B. 4-(4-Aminomethyl-3-methylbenzoyl)-δ.6.7.δ-tetrahvdro-4H-thienor3.2-61azepine The nitrile from Example 26A (0.4δg, l.δOmmol) was reduced according to the procedure in Example 16C; yield 0.16g (33%). 26C. 4-(4-f3-(2.6-Difluorophenyl)ureidomethvn-3-methylbenzoyl)-5.6.7.8-tetrahvdro-4H- thienof3.2-frlazepine The amine from Example 26B (0.05g, 0.18mmol) was reacted with 2,6-difluorophenylisocyanate (0.027g, O.lδmmol) according to the procedure in Example 1C. The product was purified by trituration with diethyl ether to give a white solid; yield 0.052g (67%). M.S.: calc m/e=4δδ.15 found [M+H] + = 456.1. Example 27. 4-(3-Methyl-4-r3-(2.3.5.6-tetrafluorophenyl)ureidomethvπbenzovn-5.6.7.8-tetrahvdro- 4H-thienor3.2-frlazepine The amine from Example 26B (0.062g, 0.206mmol) was reacted with 2,3,5,6- tetrafluorophenylisocyanate (0.079g, 0.413mmol, prepared from the aniline according to the procedure of Kurita. K, et. al., J. Org. Chem., 41, 1976, p2070.) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 50:50); yield 0.045g (44%). M.S.: calc m/e=491.13 found [M+Hf= 492.1 Example 28. 1-(4-rN-(4-Methoxy-4-oxobutanoyl)aminomethvn-3-methylbenzoyl)-2,3,4,5- tetrahvdro-1 H-1 -benzazepine 28A. 1-(4-Cyano-3-methylbenzoyl)-2.3.4.δ-tetrahydro-1H-1-benzazepine To a solution of 2,3,4,δ-tetrahydro-1 H-1 -benzazepine (0.80g, δ.44mmol) in dichloromethane (40ml) were added 4-cyano-3-methylbenzoic acid from example C (0.96g, δ.9δmmol), triethylamine (0.76g, δ.44mmol), 4-(dimethylamino)pyridine (O.δδg, δ.44mmol) and WSCDI (2.17g, 10.88mmol). The mixture was stirred at reflux for 18h, cooled and evaporated in vacuo. The residue was partitioned between EtOAc and 1M KHSO 4 . The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 1.1 Og (70%). 28B. 1-(4-rAminomethvn-3-methylbenzoyl)-2.3.4.δ-tetrahvdro-1 H-1 -benzazepine hydrochloride To a degassed solution of the cyanobenzoyl benzazepine from Example 28A (1.10g, 3.79mmol) in methanol (40ml) were added concentrated hydrochloric acid (0.98ml, 11.3mmol) and 10% palladium-on-carbon (O.δOg). Hydrogen gas was bubbled through the mixture for δh at room temperature. The catalyst was removed by filtration through a pad of celite and the filtrate was evaporated in vacuo to give the product as the HCI salt; yield 1.23g (9δ%). 28C. 1-(4-fN-(4-Methoxy-4-oxobutanoyl)aminomethvπ-3-methylbenzoyl)-2.3.4.δ- tetrahvdro-1 H-1 -benzazepine To a solution of the amine from Example 28B (0.1 Og, 0.30mmol) in dichloromethane (10ml) were added triethylamine (0.061ml, 0.90mmol) and 3-carbomethoxy propionyl chloride (0.046g, 0.30mmol). The mixture was stirred at room temperature for 1δh and then washed with 1M KHSO (3 times), water and brine, dried over Na 2 SO 4 , and concentrated in vacuo to give a white solid; yield 0.10g (δ1%). M.S.: calc m/e=40δ; found [M+H] + = 409. Example 29 1-(4-rN-(2-Methoxy-2-oxoethanoyl)aminomethvn-3-methylbenzoyl)-2.3.4.5- tetrahvdro-1 H-1 -benzazepine The amine hydrochloride from Example 2δB (0.1 Og, 0.30mmol) was reacted with methyl oxalyl chloride (0.037g, 0.30mmol) according to the procedure in Example 2δC to give a white solid; yield O.Oδδg (76%). M.S.: calc m/e=3δ0; found [M+H] + = 361. Example 30 1-(4-rN-(2-Hvdroxy-2-oxoethanoyl)aminomethvn-3-methylbenzoyl)-2,3.4.5- tetrahvdro-1 H-1 -benzazepine To a solution of the methyl ester from Example 29 (0.045g, 0.11δmmol) in THF (10ml) and water (δml) was added lithium hydroxide monohydrate (0.01 Og, 0.23mmoi). The mixture was stirred at room temperature for 2h, acidified to pH1 by addition of 1M HCI and extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo to give a white solid; yield 0.034g (76%). M.S.: calc m/e=366; found [M+H] + = 367. Example 31 1-(4-rN-(5-Methoxy-5-oxopentanoyl)aminomethvn-3-methylbenzoyl)-2,3,4.5- tetrahvdro-1 H-1 -benzazepine The amine hydrochloride from Example 2δB (0.1 Og, 0.30mmol) was reacted with methyl 4-(chloroformyl) butyrate (O.OδOg,.0.30mmol) according to the procedure in Example 1 C to give a white solid; yield 0.061 g (4δ%). M.S.: calc m/e=422; found [M+H] + = 423. Example 32 1-(4-rN-f2-Ethoxy-2-oxoethylcarbamoyl)aminomethvn-3-methylbenzovπ-2,3,4,5- tetrahvdro-1 H-1 -benzazepine To a solution of the amine from Example 2δB (0.1 Og, 0.30mmol) in dichloromethane (10ml) were added triethylamine (0.061ml, 0.90mmol) and ethyl isocyanatoacetate (0.0δ9g, 0.4δmmol). The mixture was stirred at room temperature for 1δh and then washed with 1 M KHSO 4 (3 times), water and brine, dried over Na 2 SO , and concentrated in vacuo to give a white solid; yield 0.1 Og (61%). M.S.: calc m/e=423; found [M+H] + = 424. Example 33 1-(4-rN-(Carboxymethylcarbamoyl)aminomethvn-3-methylbenzoyl)-2 T 3,4,5- tetrahvdro-1 H-1 -benzazepine To a solution of the ethyl ester from Example 32 (O.OδOg, O.IOmmol) in THF (20ml) and water (δml) was added lithium hydroxide monohydrate (0.020g, 0.4δmmol). The mixture was stirred at room temperature for 4h. The mixture was concentrated in vacuo and the residue diluted with water then washed with diethyl ether. The aqueous layer was acidified to pH 1 by addition of 1M HCI and extracted with EtOAc (3 times). The combined organic extracts were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo to give a white solid; yield 0.046g (99%). M.S.: calc m/e=39δ; found [M+H] + = 396. Example 34 1-(4-rN-(2-Methylamino-2-oxoethylcarbamoyl)aminomethvn-3-methylbenzovπ- 2,3.4,5-tetrahvdro-1 H-1 -benzazepine To a solution of the carboxylic acid from Example 33 (0.1 Og, 0.25mmol) in dichloromethane (2δml) was added DIEA (0.221ml, 1.26mmol) and PyBroP (0.129g, 0.278mmol). The mixture was stirred at room temperature for 10min and then methylamine hydrochloride (O.Oδδg, 1.26mmol) was added. Stirring was continued for a further 3h. The mixture was then washed with 1M KHSO 4 (3 times), saturated sodium bicarbonate solution (3 times) and brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant dichloromethane:methanol 96:4) to give a white solid; yield 0.01 δg (17%). M.S.: calc m/e=40δ; found [M+H] + = 409. Example 35 1-(4-rN-(2-Dimethylamino-2-oxoethylcarbamoyl)aminomethvn-3-methylbenzoyl)- 2,3,4,5-tetrahvdro-1 H-1 -benzazepine The carboxylic acid from Example 33 (0.07g, 0.18mmol) was reacted with dimethylamine hydrochloride (0.072g, O.δδmmol) according to the procedure in Example 7. The product was purified by flash chromatography on silica (eluant chloroform:methanol:acetic acid 98:1:1) to give a white solid; yield O.Oδg (11%). M.S.: calc m/e=422; found [M+H] + = 423. Example 36 1-(4-rN-(2-Methoχy-2-oxoethylcarbamoyl)am8nomethvπ-3-methylbenzov0-2.3,4,5- tetrahvdro-1 H-1 -benzazepine To a solution of the carboxylic acid from Example 33 (O.OδOg, 0.20mmol) under a nitrogen atmosphere in dichloromethane (25ml) at 0°C were added DMF (20DI) and oxalyl chloride (31 mg, 0.24mmol). The mixture was stirred at 0°C to room temperature for 2h and then concentrated in vacuo. The residue was dissolved in methanol (4ml) and dichloromethane (16ml) and the mixture stirred at room temperature for 16h. The mixture was then washed with 1M KHSO 4 (3 times), saturated sodium bicarbonate solution (3 times) and brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant dichloromethane: methanol 96:4) to give a white solid; yield 0.049g (60%). M.S.: calc m/e=409; found [M+H = 410. Example 37 1-(4-fN-(2-Amino-2-oxoethylcarbamoyl)aminomethvπ-3-methylbenzovπ-2,3,4,5- tetrahvdro-1 H-1 -benzazepine To a solution of the carboxylic acid from Example 33 (0.1 Og, 0.25mmol) in dichloromethane (20ml) were added hydroxybenzotriazole (34mg, 0.2δmmol) and WSCDI (61 mg, 0.2δmmol). The mixture was stirred at room temperature for 10min. Ammonia 880 (O.δml) was then added and stirring continued for a further 16h. The mixture was concentrated in vacuo and the residue purified by flash chromatography on silica (eluant ethyl acetate) to give a white solid; yield O.OOδg (8%). M.S.: calc m/e=394; found [M+H] + = 396. Example 38 4- ( 4-rN- ( 4-Methoxy-4-oxobutanoyl ) aminomethvπ-3-chlorobenzoyl ) -5,6,7,8- tetrahvdro-4H-thienof3.2-b1azepine 38A. 4-(4-rN-(te/f-Butyloxycarbonyl)aminomethvn-3-chlorobenzoyl)-δ.6,7.8-tetrahvdro-4H- The carboxylic acid from Example A2 (O.δOg, 2.10mmol) was reacted with 5,6,7,8- tetrahydro-4H-thieno[3,2-6]azepine (0.28g, l.δOmmol) according to the procedure in example 2δA. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 40:60) to give a yellow solid. 3δB. 4-(4-rAminomethvn-3-chlorobenzoyl)-5.6.7.δ-tetrahvdro-4H-thienof3,2-άlazepine hydrochloride The BOC amine from Example 3δA was dissolved in 4N HCI/dioxan (30 ml). The mixture was stirred at room temperature for 40min then concentrated in vacuo to leave a tan solid; yield 0.41 g (63%, for 2 steps). 36C. 4-(4-fN-(4-Methoxy-4-oxobutanoyl)aminomethyl1-3-chlorobenzoyl)-δ.6.7.δ- tetrahydro-4H-thienor3.2-ά1azepine To a solution of the amine from Example 3δB (0.032g, O.Oδmmol) in dichloromethane (10ml) were added triethylamine (0.02δml, O.lδmmol) and 3-carbomethoxypropionyl chloride (0.014g, O.Oδmmol). The mixture was stirred at room temperature for 1δh and then washed with 1M KHSO 4 (3 times), water and brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:50-90:10); yield 0.022g (56%). M.S.: calc m/e=434; found [M+H] + 35 CI = 435. Example 39 1 -(2-Methyl-4-(2,3.4.5-tetrahvdro-1 -benzazepin-1 -ylcarbonyl)benzylcarbamoyl)-L- proline-ΛUV-dimethylamide 39A. 2-Methyl-4-((2.3.4.δ-tetrahydro-1H-benzord1azepine)-1-carbonyl)-benzonitrile. To a solution of 2,3,4,δ-tetrahydro-1H-benzo[/)]azepine (O.δOg, δ.44mmol) in dichloromethane (60ml) were added 4-cyano-3-methylbenzoic acid (0.96g, δ.9δmmol), triethylamine (0.60g, δ.9δmmol), 4-(dimethylamino)pyridine (0.73g, δ.9δmmol) and WSCDI (1.24g, 6.4δmmol). The mixture was stirred at reflux for 1δh, cooled and evaporated in vacuo. The residue was partitioned between EtOAc and 1 M KHSO 4 . The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO 4 , and concentrated in vacuo. The crude material was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 1.1 Og (70%). 39B. 1 -(4-(Aminomethyl)-3-methylbenzoyl)-2.3.4.δ-tetrahvdro-1 H-benzoffrlazepine hydrochloride. To a degassed solution of the cyanobenzazepine of Example 39A (1.1 Og, 3.79mmol) in methanol (60ml) were added concentrated hydrochloric acid (0.9δml, 11.3mmol) and 10% palladium on carbon (O.δOg). Hydrogen gas was bubbled through the mixture for δh at room temperature. The catalyst was removed by filtering through a pad of celite and the filtrate was evaporated; yield 1.23g (9δ%). 39C. 1-(2-Methyl-4-(2.3.4.δ-tetrahvdro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L- proline-Λ/.Λ-dimethylamide To a solution of the amine of Example 39B (0.10g, 0.302mmol) in DMF (10ml), under a nitrogen atmosphere, were added Λ/,Λ/-diisopropylethylamine (43mg, 0.332mmol) and carbonyl diimidazole (0.074g, 0.4δ3mmol). The mixture was stirred at room temperature for 40 minutes. A solution of proline-Λ/,Λ/-dimethylamide (0.107g, 0.756mmol) in DMF (1 ml) was added. The mixture was stirred at room temperature for a further 16 hr. The solvent was removed in vacuo and the crude material was purified by flash chromatography on silica (eluant methanohdichloromethane 5:96); yield 0.115g (82%). M.S.: calc m/e=462.26; found [M+H] + = 463.2 Example 40 ( R)-4-Hvdroxy-1 -(2-methyl-4-(2,3.4,5-tetrahvdro-1 -benzazepin-1 -ylcarbonvDbenzyl- carbamoyl)-L-proline-ΛϋV-dimethylamide 40A. L-frans-4-Hydroxyproline-Λ/,Λ/-dimethylamide hydrochloride To a solution of BOC-hydroxyproline (2.99g, 13.δ9mmol) in dichloromethane (100ml) were added Λ/,/V-diisopropylethylamine (3.7ml, 21.24mmol), 4-(dimethylamino)pyridine (1.74g, 14.24mmol), dimethylamine hydrochloride (1.72g, 21.09mmol) and WSCDI (3.17g, 16.68mmol). The mixture was stirred at room temperature for 30h. The mixture was diluted with dichloromethane (100ml) and washed with 0.3M KHSO 4 , saturated sodium bicarbonate solution and brine, dried over MgSO 4 , and concentrated in vacuo to give a colourless gum. This crude material was taken up in 4N HCI/dioxan (50ml) and stirred at room temperature for 1hr and then concentrated in vacuo. The residue was azeotroped with toluene and diethyl ether to give a white solid; yield 0.45g (17%). 40B. (4R)-4-Hvdroxy-1-(2-methyl-4-(2.3.4.5-tetrahvdro-1-benzazepin-1-ylcarbonyl)benzyl- carbamoyl)-L-proline-Λ/.Λ/-dimethylamide. The amine of Example 39B (0.10g, 0.302mmol) was reacted with the amine of Example 40A (0.153mg, OJδδmmol) following the method of Example 39C. The product was purified by flash chromatography on silica (eluant chloroform:methanol:acetic acid 95:4:1); yield 0.95g (66%). M.S.: calc m/e=47δ.26; found [M+H] + = 479.2 Following the above methods, the following compounds were also prepared. Table A - Examples 41 - 44 Table B - Examples 45 - 55 Table C - Examples 56 - 57 Table D - Examples 58 - 61 Table E - Examples 62 - 70 Table F - Examples 71 - 77 Table G - Examples 78 - 90 Table H - Examples 91-106 Table I - Examples 107-124 Table J - Examples 125-153 Table K - Examples 154-159 Table L - Examples 160-164 Table M - Examples 165-170 Table N - Examples 171-177 Table O- Examples 178-182 Table P- Examples 183 - 190 Table Q - Representative NMR data Ex. No 1 H NMR (CDCI 3 ) 28 δ 1.40-1.60 (1H, m), 1.84-2.20 (3H, m), 2.16 (3H, s), 2.40-2.64 (2H, m), 2.δδ-2.92 (4H, m), 2.94-3.10 (1H, m), 3.66 (3H, s), 4.30 (2H, d, J=δ.6Hz), 4.99 (1H, d, J=12.9Hz), 5.90 (1H, s), 6.62 (1H, d, J=7.9Hz), 6.76-6.96 Example 191. Determination of V? receptor agonist activity in vitro Agonist activity was determined for all compounds and is reported as an EC 50 value, being that concentration of compound necessary to cause a half-maximal cellular activation. All the compounds had EC 50 values of 10μM or less, and typical results are listed in Table R. Table R - EC 50 values for typical compounds Example 192. Determination of antidiuretic activity in vivo The Brattleboro rat is a recognised model for vasopressin deficiency (for a review see FD Grant, "Genetic models of vasopressin deficiency", Exp. Phvsiol. 85, 203S-209S, 2000). The animals do not secrete vasopressin and consequently produce large volumes of dilute urine. Compounds of the invention were administered to Brattleboro rats (0.1- 10mg/kg p.o. in methylcellulose. Urine was collected hourly and volumes were compared with control animals. Animals had free access to food and water throughout the experiment. Representative results are given in Table S. Results for Desmopressin are given for comparison. Table S - Antidiuretic activity Example 193. Pharmaceutical composition for tablet Tablets containing 100mg of the compound of Example 39 as the active agent are prepared from the following: Compound of Example 39 200.0g Corn starch 71.Og Hydroxypropylcellulose 18.0g Carboxymethylcellulose calcium 13.0g Magnesium stearate 3.0g Lactose 195.0g _____ 500. Og The materials are blended and then pressed to give 2000 tablets of 2δ0mg, each containing 100mg of the compound of Example 39. The foregoing Examples demonstrate that compounds within the scope of the invention are readily prepared using standard chemical techniques, and that these compounds have the biological properties that would be expected of V 2 receptor agonists. In particular, the compounds are potent antidiuretics in an animal model of vasopressin deficiency. Thus it is clear that they may be useful in the treatment of human diseases that are currently treatable with Desmopressin, such as central diabetes insipidus, nocturnal enuresis and nocturia. It has further been suggested that antidiuretics such as Desmopressin may be useful in certain types of urinary incontinence. These arguments would also extend to the compounds of the present invention. Desmopressin is also used in the treatment of certain coagulation disorders. There is good evidence to suggest that this action is also mediated through the V 2 receptor (see for example JE Kaufmann et al., "Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V 2 receptors and cAMP", J. Clin. Invest. 106, 107-116, 2000; A Bernat et al., "V 2 receptor antagonism of DDAVP-induced release of hemostasis factors in conscious dogs", J. Pharmacol. Exp. Ther. 282, 697-602, 1997), and hence it would be expected that the compounds of the present invention should be useful pro- coagulants. The scope of the present invention is further defined in the following Claims.

Claims: CLAIMS A compound according to general formula 1 or 2, or a tautomer or a pharmaceutically acceptable salt thereof, wherein: W is either N or C-R 4 ; R 1 - R 4 are independently selected from H, F, Cl, Br, alkyl, CF 3 , phenyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 and CN, or R 2 and R 3 together can be -CH=CH-CH=CH-; G 1 is a bicyclic or tricyclic fused azepine derivative selected from general formulae 3 to 8, 6 7 8 in which A 1 , A 4 , A 7 and A 10 are each independently selected from CH 2 , O and NR 5 ; A 2 , A 3 , A 9 A 11 , A 13 , A 14 and A 15 are each independently selected from CH and N; either A 5 is a covalent bond and A 6 is S, or A 5 is N=CH and A 8 is a covalent bond; A 8 and A 12 are each independently selected from NH, NCH 3 and S; A 16 and A 17 are both CH 2 , or one of A 16 and A 17 is CH 2 and the other is selected from CH(OH), CF 2 , O, SO a and NR 5 ; R 5 is selected from H, alkyl, CO-alkyl and (CH 2 ) b R 6 ; R 8 is selected from phenyl, pyridyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 , CO 2 H and CN; a is 0, 1 or 2; b is 1, 2, 3 or 4; Y is CH or N; Z is CH=CH or S; and G 2 is a group selected from general formulae 9 to 11, 10 11 in which Ar is selected from phenyl, pyridyl, naphthyl and mono- or polysubstituted phenyl or pyridyl wherein the substituents are selected from F, Cl, Br, alkyl, OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , NO 2 and CN; D is a covalent bond or NH; E 1 and E 2 are both H, OMe or F, or one of E 1 and E 2 is OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N 3 , NH 2 , NHBn or NHAc and the other is H, or E 1 and E 2 together are =O, -O(CH 2 )gO- or -S(CH 2 ) g S-; F and F 2 are both H, or together are =O or =S; L is selected from OH, O-alkyl, NH 2 , NH-alkyl and NR 9 R 10 ; R 7 is selected from H, alkyl, alkenyl and COR 8 ; R 8 is selected from OH, O-alkyl, NH 2 , NH-alkyl, N(alkyl) 2 , pyrrolidinyl and piperidinyl; R 9 and R 10 are both alkyl, or together are -(CH 2 ) h - or -(CH 2 ) 2 O(CH 2 ) 2 -; V is O, N-CN or S; c is 0 or 1 ; d is 0 or 1 ; e is 0 or 1 ; f is O, 1, 2, 3 or 4; g is 2 or 3; and h is 3, 4 or 6, provided that d and e are not both 0. A compound according to Claim 1 , or a tautomer or pharmaceutically acceptable salt thereof, wherein the compound is a compound according to general formula 1. A compound according to Claim 2, or a tautomer or pharmaceutically acceptable salt thereof, wherein W is C-R 4 . A compound according to Claim 3, or a tautomer or pharmaceutically acceptable salt thereof, wherein at least one of R 1 - R 4 is not H. A compound according to Claim 4, or a tautomer or pharmaceutically acceptable salt thereof, wherein one of R 1 - R 4 is methyl, F or Cl and the others are all H. A compound according to Claim 1 , or a tautomer or pharmaceutically acceptable salt thereof, wherein the compound is a compound according to general formula 2. A compound according to any preceding Claim, or a tautomer or pharmaceutically acceptable salt thereof, wherein G 1 is a group according to one of general formulae 3 to 7. A compound according to Claim 7, or a tautomer or pharmaceutically acceptable salt thereof, wherein Y is CH. A compound according to Claim 8, or a tautomer or pharmaceutically acceptable salt thereof, wherein Z is -CH=CH-. A compound according to Claim 8, or a tautomer or pharmaceutically acceptable salt thereof, wherein Z is S. A compound according to Claim 7, or a tautomer or pharmaceutically acceptable salt thereof, wherein Y is N and Z is -CH=CH-. A compound according to any of Claims 7 to 11 , or a tautomer or pharmaceutically acceptable salt thereof, wherein G 1 is a group according to general formula 3. A compound according to Claim 12, or a tautomer or pharmaceutically acceptable salt thereof, wherein A 1 is CH 2 and A 2 and A 3 are both CH. A compound according to any of Claims 7 to 11 , or a tautomer or pharmaceutically acceptable salt thereof, wherein G is a group according to general formula 6. A compound according to Claim 14, or a tautomer or pharmaceutically acceptable salt thereof, wherein A 11 is CH and A 12 is S. A compound according to any of Claims 1 to 6, or a tautomer or pharmaceutically acceptable salt thereof, wherein G 1 is a group according to general formula 8. A compound according to Claim 16, or a tautomer or pharmaceutically acceptable salt thereof, wherein A 17 is CH 2 . A compound according to either Claim 16 or 17, or a tautomer or pharmaceutically acceptable salt thereof, wherein A 18 is CH 2 . A compound according to any preceding Claim, or a tautomer or pharmaceutically acceptable salt thereof, wherein G 2 is a group according to general formula 9. A compound according to Claim 19, or a tautomer or pharmaceutically acceptable salt thereof, wherein Ar is mono- or polysubstituted phenyl. A compound according to either Claim 19 or 20, or a tautomer or pharmaceutically acceptable salt thereof, wherein Ar is phenyl substituted with at least two halogen atoms selected from F and Cl. A compound according to any of Claims 19 to 21 , or a tautomer or pharmaceutically acceptable salt thereof, wherein Ar is 2,6-difluorophenyl. A compound according to any of Claims 1 to 18, or a tautomer or pharmaceutically acceptable salt thereof, wherein G 2 is a group according to general formula 10. A compound according to Claim 23, or a tautomer or pharmaceutically acceptable salt thereof, wherein R 7 is COR 8 . A compound according to Claim 24, or a tautomer or pharmaceutically acceptable salt thereof, wherein R 8 is N(alkyl) 2 . A compound according to any of Claims 1 to 18, or a tautomer or pharmaceutically acceptable salt thereof, wherein G 2 is a group according to general formula 11. A compound according to Claim 26, or a tautomer or pharmaceutically acceptable salt thereof, wherein F 1 and F 2 together are =O. A compound according to either Claim 26 or 27, or a tautomer or pharmaceutically acceptable salt thereof, wherein E 1 and E 2 are both H or one is H and the other is O-alkyl. A compound according to any of Claims 26 to 28, or a tautomer or pharmaceutically acceptable salt thereof, wherein one of E 1 and E 2 is H and the other is O-alkyl, and the stereochemistry at the CE 1 E 2 centre is of the R absolute configuration. A compound according to any of Claims 26 to 29, or a tautomer or pharmaceutically acceptable salt thereof, wherein the stereochemistry adjacent to the ring nitrogen is of the S absolute configuration. A compound according to Claim 1, or a tautomer or pharmaceutically acceptable salt thereof, selected from 1-(4-[3-(2-Chloro-6-fluorophenyl)ureidomethyl]-3-methylbenzoyl)-2,3,4,δ-tetrahydro-1H- 1 -benzazepine, 1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-δ-(3-pyridyl)methyl-2,3,4,δ- tetrahydro-1 H-1 ,δ-benzodiazepine, 1-(3-Chloro-4-[3-(2-chloro-6-fluorophenyl)ureidomethyl]benzoyl)-δ-ethyl-2,3,4,δ- tetrahydro-1 H-1 ,6-benzodiazepine, 4-(3-Chloro-4-[3-(2,6-difluorophenyl)ureidomethyl]benzoyl)-δ,6,7,δ-tetrahydrothieno[3,2- Jbjazepine, 1-(3-Chloro-4-(3-(methyloxycarbonyl)propanoylaminomethyl)benzoyl)-2, 3,4,6- tetrahydro-1 -benzazepine, 1-(2-Methyl-4-(δ-(3-pyridylmethyl)-2 I 3,4,δ-tetrahydro-1,δ-benzodiazepin-1- ylcarbonyl)benzyl)-3-(methyloxycarbonylmethyl)urea, 1-(2-Methyl-4-(2,3,4,δ-tetrahydro-1 -benzazepin-1 -ylcarbonyl)benzylcarbamoyl)-L- proline-Λ/,Λ/-dimethylamide, (4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,δ-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl- carbamoyl)-L-proline-/V,Λ/-dimethylamide, (4R)-1-(3-Chloro-4-(2,3,4,δ-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4- methoxy-L-proline-Λ/,Λ/-dimethylamide, (4R)-1-(2-Chloro-4-(2,3,4,δ-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4- methoxy-L-proline-Λ/,Λ-dimethylamide, (4R)-4-Benzyloxy-1-(2-methyl-4-(2,3,4,δ-tetrahydro-1-benzazepin-1-yicarbonyl)benzyl- carbamoyl)-L-proline-Λ/,Λ/-dimethylamide, (4R)-4-Methoxy-1-(2-methyl-4-(2,3,4,δ-tetrahydro-1 -benzazepin-1 -ylcarbonyl)benzyl- carbamoyl)-L-proline-/V,Λ/-dimethylamide, (4/?)-4-Methoxy-1-(3-methyl-4-(2,3,4,δ-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl- carbamoyl)-L-proline-Λ/,Λ/-dimethylamide, (4R)-1-(2-Chloro-4-(δ,6,7,δ-tetrahydro-4H-thieno[3,2- ?]azepin-4-ylcarbonyl)benzyl- carbamoyl)-4-methoxy-L-proline-Λ/,/V-dimethylamide, (4R)-1-(4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1 ,4)benzodiazepin-10-yl carbonyl)-2-methyl- benzylcarbamoyl)-4-methoxy-L-proline-Λ/,Λ/-dimethylamide, (4 )-1 -(2-Chloro-4-(10,11 -Dihydro-5H-pyrrolo[2, 1 -c](1 ,4)benzodiazepin-10-ylcarbonyl)- benzylcarbamoyl)-4-methoxy-L-proline-Λ/,Λ/-dimethylamide, and (4f?)-1 -(4-(10, 11-Dihydro-δH-pyrrolo[2, 1 -c](1 ,4)benzodiazepin-10-ylcarbonyl)-2-methyl- benzylcarbamoyl)-4-methoxy-L-proline-Λ/,Λ/-dimethylthioamide. A compound according to Claim 1 , or a tautomer or pharmaceutically acceptable salt thereof, selected from 1-(2-Methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L- proline-Λ/,Λ/-dimethylamide, and (4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl- carbamoyl)-L-proline-Λ/,Λ/-dimethylamide. A use for a compound according to any of Claims 1 to 32 or a pharmaceutically acceptable salt thereof, which use is as a component of a pharmaceutical composition. A use for a compound according to any of Claims 1 to 32 or a pharmaceutically acceptable salt thereof, which use is as a therapeutic agent for the treatment of nocturnal enuresis, nocturia, polyuria resulting from central diabetes insipidus, urinary incontinence or bleeding disorders. A pharmaceutical composition which comprises, as an active agent, a compound according to any of Claims 1 to 32. A pharmaceutical composition according to Claim 36, which composition is to be used for the treatment of polyuria. A pharmaceutical composition according to Claim 35, which composition is to be used for the control of urinary incontinence. A pharmaceutical composition according to Claim 37, which composition is for voiding postponement. A pharmaceutical composition according to Claim 36, which composition is to be used for the treatment of bleeding disorders. A method of treatment of nocturnal enuresis, nocturia and diabetes insipidus, which method comprises the administration to a person in need of such treatment of an effective amount of a composition according to Claim 36. A method for the control of urinary incontinence, which method comprises the administration to a person in need of such treatment of an effective amount of a composition according to Claim 3δ. A method for the control of urinary incontinence according to Claim 41 , wherein the treatment results in voiding postponement. A method for the treatment of bleeding disorders, which method comprises the administration to a person in need of such treatment of an effective amount of a composition according to Claim 36.

Inventors: ASHWORTH DOREEN MARY, FRANKLIN RICHARD JEREMY, HUDSON PETER, PITT GARY ROBERT WILLIAM, SEMPLE GRAEME, YEA CHRISTOPHER MARTYN, ASHWORTH, DOREEN, MARY, FRANKLIN, RICHARD, JEREMY, HUDSON, PETER, PITT, GARY, ROBERT, WILLIAM, SEMPLE, GRAEME, YEA, CHRISTOPHER, MARTYN
Applicants: ASHWORTH DOREEN MARY, FERRING BV, FRANKLIN RICHARD JEREMY, HUDSON PETER, PITT GARY ROBERT WILLIAM, SEMPLE GRAEME, YEA CHRISTOPHER MARTYN, ASHWORTH, DOREEN, MARY, FERRING B.V., FRANKLIN, RICHARD, JEREMY, HUDSON, PETER, PITT, GARY, ROBERT, WILLIAM, SEMPLE, GRAEME, YEA, CHRISTOPHER, MARTYN
Application year: 2001
Main classification: C07D223
IPC codes: A61K31, A61P13, A61P25, A61P43, C07D223, C07D243, C07D255, C07D267, C07D281, C07D401, C07D403, C07D413, C07D471, C07D487, C07D495, C07D498, C07D519