TWI307338B - Novel antidiuretic agents - Google Patents

Description

L3〇7338 V. DESCRIPTION OF THE INVENTION (Inventory of the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperatives, Field of the Invention) The present invention relates to a new class of peptide hormonal vasopressin, which is converted into an entity. Therefore, it can be used to treat certain human diseases characterized by urinary urinary tract. It can also be used to control urinary incontinence and bleeding disorders. BACKGROUND OF THE INVENTION Angiotensin is a peptide hormone secreted by the posterior lobe of the pituitary gland. The county flow of water thus reduces the amount of urine. Therefore, the reason is blood = calfin, the name "anti-diuretic hormone". It also acts on the vascular bed to produce the same blood pressure effect. The mediators of these two roles have determined their characteristics. The antidiuretic effect is the second type of blood called the corpus callosum. The agent that can interact with the V2 receptor and activate the receptor in the same way is called the v2 receptor agonist v2 synergist. The anti-receptive two-receptor interaction is not the same as that of other blood vessels. It will have the effect of hypertension with vasoconstriction. This is the main queen test I and let these drugs have the effect of treating fine polyuria. Human disease characterized by excessive urine production)

Text Paper Money® National Standard (CNS) A4 Specification (210 X 297) 1307338

V. Description of invention (

^NH

'NH S, 〇V N1H, Η〇^ΗΚ,—°

^»s, 乂γΝ.

This drug has been used in the treatment of humans. Desmoprisin (desmop sin in) (also known as serotonin, miniton, DDAVP) is a peptide analog of angiotensin, which is a selective effect of % receptors. Agent. Dispeptricin is used to treat central diabetes insipidus, a disease caused by a deficiency in the secretion of angiotensin. It is also used to control nighttime beds and to control nighttime polyuria. But Des Moprisin is not an ideal agent for every facet. Even the current best synthesis methods are still lengthy, and Dissimoprisin is not suitable for the most convenient purification techniques such as knots. As a result, dissimoprisin is quite expensive with very low oral bioavailability and this parameter varies slightly.

BB rate, loading --- (please read the notes on the back and fill out this page) -

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

Dispreprisin therefore requires a selective angiotensin V2 receptor co-agent for easy preparation and purification' and highly predictable oral bioavailability

1307338 A7 _B7 _ V. Description of invention (3) (Please read the notes on the back and fill out this page). These properties are most likely obtained using non-peptide compounds. These considerations led to other research groups investigating non-peptide tubular vasopressin V2 synergists, and the results of the study are disclosed, for example, in International Patent Application Nos. W097/22591, W099/06403, W099/06409, WOOO/46224, WOOO/46225, WOOO/46227 and WOOO/46228. However, the compounds disclosed in these documents are not ideal. In particular, its oral bioavailability is poor, in part because of its low solubility in water. The present invention provides compounds having improved solubility and bioavailability. In addition to its antidiuretic effect, dissimoprisin is used to increase the blood coagulation protein concentration in blood, which is called factor VIII and von Willebrand factor. This is the clinical use of DispMoprisin for the treatment of hemophilia A and Weng Bleu disease. The non-peptide synergists of the present invention are also suitable for the same use. SUMMARY OF THE INVENTION As disclosed herein, the present invention relates to a series of non-peptide agonists of angiotensin and is selective for V2 receptor subtypes. The compound can be represented by the formula 1.

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives: A is a bicyclic or paracyclic azaindole derivative selected from the general formulas 2 to 7. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 7 1307338

V. Description of invention (4)

5 6 7

Ai, A4, A7 and A10 are selected from Ch2, 〇 and nr8 respectively; A2 'A3 ' A9 ' A11 ' A13 ' A14 and A15 are respectively selected from CH and N; A5 is a covalent bond and A6 is S, Or A5 is N=CH and A6 is a covalent bond; A8 and A12 are each selected from NH and S; A16 and A17 are both CH2' or one of A16 and A17 is CH2 and the other is selected from 0, S0X And NR8; V1 and V2 are both Η, OMe or F, or one of V1 and V2 is Br, Cl, F, OH, OMe, OBn, 〇Ph, 0- fluorenyl, N3, NH2, ΝΗΒη or NH - 醯 而 and the other is H, or V1 and V2 are =0, -0(CH2)p0- or -S(CH2)pS-; W1 is 0 or S; X1 and X2 are both H, or common Is =0 or =S; Y is OR5 or NR6R7; Z is S or -CH=CH-;

Ri, R2, R3 and R4 are respectively selected from the group consisting of hydrazine, lower alkyl, and lower alkoxy. The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). (Please read the notes on the back first. Fill in this page)

Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printing A7 B7 1307338 i'Inventive Note (5) Base, F, Cl and Br; R5 is selected from lanthanum and lower alkyl; R6 and R7 are selected from lanthanum and low carbon, respectively. Alkyl, or a combination of _(CH2)n_, R8 is deuterium or lower alkyl; η = 3, 4, 5 or 6; ρ is 2 or 3; and X is 0, 1 or 2. The invention further comprises a pharmaceutical composition in combination with such an angiotensin synergist, which composition is particularly useful for the treatment of central diabetes insipidus, nocturnal enuresis, and nocturnal polyuria. DESCRIPTION OF THE INVENTION The present invention comprises each of the indole-octylaminocarbamyl groups defined by Formula 1. (Please read the phonetic on the back first? Then fill in this page)

In the printed version of the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, Α represents a bicyclic or sulfhydryl aza base according to one of the formulae 2-7. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public hair Γ 7^---- 1307338 A7 B7 5. Invention description (6 0O5, 2 3 Α13=Λ14〇C, odf

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, A1 'A4' A7 and Ai〇 are selected from the group consisting of methylene (_Ch2_), oxygen (_〇_) and substituted nitrogen (-NR8-). A2, A3, A9' A11, A13, VIII14 and A16 represent a nitrogen atom (_N=) or a low fluorenyl group (_ch=). A5 represents a covalent bond, and in this case, A6 represents a sulfur atom (-S-), and thus the ring including the diradical is an oxime ring. Further, A5 may represent a _n=CH- group, in which case a represents a covalent bond, and thus the ring of the two groups is an acridine ring. A8 and A12 represent -NH- or a sulfur atom (_s_). A16 and A17 represent a divalent group. The two may be an anthracenylene group (_CH2_)4, which is a methylene group and the other is selected from the group consisting of hydroxymethylene (-CH(OH)-), difluoromethylene (-CF2-), oxygen ( -〇-), substituted nitrogen (_nr5-) and sulfur or sulfur oxide (_s_,_s〇_ or -S〇2_). V1 and V2 may each be hydrogen, methoxy or fluorine, or one may be selected from the group consisting of bromine, chlorine, fluorine, hydroxyl, lower alkoxy, benzindenyl, phenoxy, decyloxy, azide, Amino, benzylamino and decylamino (Br, C1, F, OH, fluorene-lower alkyl, 〇Bn, 〇ph, 〇-mercapto, Nh2, NHBn and NH-fluorenyl) but One is hydrogen, or vi and v2 together represent an oxygen atom such that the CW2 segment is a carbonyl group (〇〇). Vi and v2 may also be ethyl or propyl-dioxy or dithiol chains (_0(ch2)2o-, -〇(CH2)3〇_,^ s(ch2)2s-'- s(ch2)3s-) Therefore cW2 is ι,3-dioxos, 1;3_

, install i I (please read the notes on the back and fill out this page)

1307338 A7

V. Description of the invention (7) Dioxane, 1,3-dithio-sulfonium or anthracene, 3-dioxane ring. W1 is an oxygen or sulfur atom. X and X旮 are hydrogen' or collectively represent an oxygen or sulfur atom, and thus the CX X2 segment is a few groups or a thiol group (C=〇 or d). Y is _〇R5 group or -NR6r7 group; Z represents a sulfur atom, so the ring containing 2 is a thiophene ring, or represents a _CH=CH- group, so the ring is a benzene ring. R1 'R2' R3 and R4 are each independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, and halogen, i.e., fluorine, chlorine, and bromine. R5 is a hydrogen atom or a low carbon alkyl group. R6 and R7 are each a hydrogen atom or a lower alkyl group, or may form a chain of 3 to 6 fluorenylene groups, and thus, together with the nitrogen atom to which they are attached, form aziridine, torolidine, hexahydroacridine or Hydrogen-nitrogen ring. R8 is hydrogen or a lower alkyl group. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives In the present disclosure, the term "lower alkyl" is intended to include straight-chain and branched alkyl and cycloalkyl groups having from 1 to 6 carbon atoms. For example, methyl, ethyl, isopropyl, t-butyl, neopentyl, and cyclohexyl are all described in the context of low carbon alkyl. The term "mercapto" means low; ε charcoal carbonyl such as ethenyl, pentamidine, cyclopropylcarbonyl and the like. Hypermethyl ketone is also considered a thiol. Certain compounds of formula 1 can form salts with acids or assays. For example, a compound containing one or more nitrogen atoms may form an addition salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, limonic acid or benzoic acid as well as an organic acid. The compound containing an acidic group can form a salt with a base. Such salts include, for example, sodium, potassium, calcium, triethylammonium, and tetraethylammonium salts. In addition, the paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 11

5. [307338 Description of the Invention (8 Compounds having both an acidic group and a basic group may form an internal salt (zwitterionic). To date, such salts are pharmaceutically acceptable and are included in the scope of the present invention. All of the compounds of formula 1 have at least one stereogenic center (tetrahedral carbon atom with four different substituents) and thus may exist as optical isomers such as enantiomers and diastereomers. Isoforms and mixtures thereof are all intended to be included within the scope of the invention. In a preferred embodiment of the invention, A is a group according to formula 2.

In another preferred embodiment of the invention, A is a group according to formula 3. A is a group according to Formula 4. A is a group according to Formula 5. a is a group according to Formula 6. A is a group according to Formula 7. In a more preferred embodiment, octatetrahydrocarbazide-1-yl is also a group according to formula 7, wherein both A16 and A17 are methylene. In another preferred embodiment, one of R1 and R2 is chloro or methyl and the other is hydrogen. Both R3 and R4 are also hydrogen. In another preferred embodiment, one of νι and V2 is methoxy or benzyloxy and the other is hydrogen. In still another preferred embodiment, Χι and X2 together represent an oxygen atom and hydrazine is -NR6R7. Particularly preferred embodiments of the invention are combinations of the two or more specific embodiments described above. A still further preferred embodiment of the invention is a compound of formula 8. ^装--- (Please read the notes on the back and fill out this page).

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printed 12 I3〇7338

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 297 297 mm) 13 1307338

In the formula 9, R5 and R6 are as defined above, wherein one of 1DRa&Rb is hydrogen and the other is chlorine or methyl. Still more preferred are compounds according to formula 9A wherein the stereochemistry is as shown.

Individual preferred compounds within the scope of the invention include, but are not limited to, the following (please read the notes on the back and fill out this page)

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative - (2-mercapto-4-(2,3,4,5-tetrahydro-1-benzoazepine_丨-ylcarbonyl)benzylaminocarbamidine -L-proline-indole, hydrazine-dimethyl decylamine, (4R)-4-hydroxy-1-(2-mercapto-4-(2,3,4,5-tetrahydro-1) _benzoazepinecarbonyl)benzylaminocarbazyl)-L-proline-N,N-didecylguanamine, (4R)-l-(3-chloro-4-(2, 3,4,5-tetrahydro-1-benzoazepine-1-ylcarbonyl)benzylaminoindenyl)-4-oxo-L-proline-N,N-dimercaptopurine Amine, (4R)-l-(2-milo-4-(2,3,4,5-tetrahydro-1-benzazepine-1-yl)benzylaminomethylmercapto)-4 -Methoxy-L-proline-N,N-dimethyldecylamine, (411)-4-benzyloxy-1-(2-mercapto-4-(2,3,4,5-tetrahydro) -1- benzoazepine_1-ylcarbonyl)benzylaminoindenyl)-L-proline-N,N-dimethyl-brontan, (4R)_4-methoxy-1-( 2-mercapto-4-(2,3,4,5-tetrazole-1-benzoazepine_ι_ylcarbonyl)benzylaminoindenyl)-L-proline-N,N -Dimethyl decylamine, (4R)-4-indolyl-1-(3-mercapto-4-(2,3,4,5-tetrahydro-1-benzazepine basic paper scale for China) National Standard (CNS) A4 Specification (210 X 297 mm)

14 A7 1307338 ^^ ---gL____ $, invention description (n) carbonyl)benzylaminomethylmercapto)-L-proline-N,N-dimethyldecylamine, (4R)-l-( 2-Chloro-4-(5,6,7,8-tetrahydro-4H-indeno[3,2-b]azepin-4-yl)benzylaminomethylcarbyl)-4 -Methoxy-L-proline _N,N-dimethyl decylamine, (411)-1-(4-(10,11-dihydro-511-portylpyrrolo[2,1-(; (1,4) benzodiazepine-10-ylidyl)-2-methyl-benzylaminomethyl) oxime _L_proline _ Ν, Ν-dimercapto Amine, (4R)-l-(2-chloro-4-(10,11-dihydro-5Η-fluorenyl[2,i_c](1,4) benzodiazepine-10-ylcarbonyl)千基胺基曱醯)_4_曱氧_L_proline _ N,N-dimercaptoamine, and (4R)-l-(4-(10,ll-dihydro-5H-pyrrole) And [2,1-c](i,4) benzodiazepine-10-ylcarbonyl)-2-mercapto-benzylaminoindenyl)_4_methoxy_L_proline _ N,N-Dimercaptothioguanamine. The compounds of the invention can be prepared by methods generally known in the art. The compounds of formula 1 can be considered to consist of (AC) three-block linkages.

This two is separately prepared and then combined in the later stages of synthesis. The mt of the various bases (R'-R4, V1, V2'X1, X2, etc.) may be incompatible with such assembly. Therefore, it is necessary to use a protecting group. The use of the protection base is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). (Please read the notes on the back and fill out this page)

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative 15 307338 A7 B7 V. INSTRUCTIONS (12) Well-known (see, for example, "Organic Synthesis Protection Group", T W Greene, Willy Technology Corporation" (1981). Specific groups to be protected are amines (protected as guanamines or amine phthalates), alcohols (protected as esters or bonds), and carboxylic acids (protected as S-types). Used here for discussion, it is presumed that these required protections are in place. Groups A, B, and C are based on a combination of two strategies to obtain a hydrazine compound. The first strategy, A and B segments are linked to obtain a segment corresponding to AB, and then C# is combined. In the table of the younger brother, the B and C segments are linked to obtain the segment corresponding to bc, and then the segment A is combined. The chemistry involved in the condensation of A and B and the condensation of B and C are the same regardless of the strategy used. The inventors have found that the first strategy is more flexible when small-scale operations and specially selected compounds are made. In spite of this, the second strategy is dominant in large-scale operation to prepare selected compounds. The formation of the fragment AB, loaded - (please read the notes on the back and fill out this page) Order · Λ {A},,}

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. (A) and (B) respectively represent the structure of the A&B segment. The formation of guanamines by condensation of carboxylic acid with amines is well known in the art. Usually, the acid and the amine are combined with a sulfonium I. a rhenogenic agent such as methyl chloride or dimethylformamide in the presence of a condensing agent, for example, a dimethylimine (for example, "water-soluble quinone diimine". 'It is Ν 'ethyl Ν, · (3 dimethylaminopropyl) dimethyl imidate) or a reactive phosphorus derivative (such as "ΒΟΡ" which is hexa(tetra) acid (stupid and three sigma sitting _ 1 -yloxy) ginseng (-nonylamino) scale). The reaction can be selectively catalyzed by a tertiary amine such as triamine or 4· decylamine n (t $ catalyzed. In addition, the carboxylic acid can be converted into a more anti-hypermixed paper size _+0 mesh X 297 PCT) 16 1307338 A7 V. INSTRUCTIONS (13) Derivatives of sex such as hydrazine. This hydrochloride is then reacted with the aforementioned amine without the use of a condensing agent. Fragment BC LG^LG ϊ P}' {B}, τ Form B or C between the formation of anti-bond or sulfur brick bond most easily through the corresponding b-stage of the first-stage amine and carbonic acid derivatives such as phosgene (where LG is achieved by reacting chloro) or carbonyldiimidazole (wherein LG is 1-imidazolyl) to form an intermediate amine decanoic acid derivative. When W1 is sulfur rather than oxygen, thiophosgene or thiocarbonyldiimidazole is used. The reaction is conveniently carried out in the presence of a third-grade amine such as triethylamine or N,N-diisopropylethylamine in an aprotic solvent such as dioxane or dimethylamine. After the intermediate is formed for a period of time sufficient, the corresponding second stage amine is added to the reaction mixture. There is no need to separate the intermediate amino acid formic acid derivative, the Ministry of Economic Affairs, the Intellectual Property Office, the employee consumption cooperative, and the change method of the method, which can reverse the order of addition of the amines corresponding to the 6 and c stages, so the amino phthalate ester is Secondary amine formation, followed by the addition of a first amine. In summary, the following intermediates are required for the synthesis of the compounds of the invention. The private paper scale applies to Chinese specifications (10)

Armored --- (Please read the notes on the back and fill out this page) Order _ -J.

1307338 A7 _B7 V. Description of invention (14) i) for segment A

Printed by the Intellectual Property Office of the Ministry of Economic Affairs and the Consumer Consortium. The fused azepines according to these formulas can be prepared according to the methods reported in the references. See, for example, Aranapakam et al., Bloorg. 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., Journal of Bioorganic Pharmacology 23, 1980, 878; Chakrabarti et al., J. Med. Chem. 23, 1980, 884; Chakrabarti et al., J. Med. Chem. 32, 1989, 2573; Chimirri et al., Heterocycle 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 et al., Heterocyclic Chemistry Journal 19, 1982, 1501; Wright et al., J. Med. Chem. 23, 1980, 462; Yamamoto et al., Tetrahedron Letters 24, 1983, 471 1; and International Patent Application, Publication No. WO99/06403. Some of them are commodities. (Please read the notes on the back and fill out this page.) Order, this paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 18

1307338 V. Description of invention (15)

η) for segment B

OH Since the first-grade amine and the carboxylic acid are unknown - they are not separately phased, they must be developed separately and insured. The substituted benzoic acid is well known and the carboxylic acid is conveniently protected as methyl vinegar. The first primary amine can be obtained from a bismuth-a S (by reduction) or an alcohol (via replacement with a nucleophilic group using nitrogen).昜 琅 The best method is based on the substituent R1_R4

The nature of the decision. Iii) For the clip C ^ Pack·· I (please read the notes on the back and fill out this page)

« ·

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives This type of pyrrolidine derivative was prepared according to the method described in the literature. See, for example, Dugave et al., Tetrahedron Letters π, 1S > 98, 1169; Petriu〇 et al., J. Med. Chem. 31, 1988, 1148; and Smith et al., Journal of Medicinal Chemistry 31, 1988, 875. The proline and hydroxyproline derivatives having the defined stereochemistry are commercially available as a convenient starting material. The invention further comprises a pharmaceutical composition comprising at least one compound according to the foregoing as an active ingredient. The composition may also include a second agent such as the paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 19 1307338 A7 B7 V. Invention Description (16) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing The anticancer agent or the material channel is known to improve bladder dysfunction. Preferred compositions include only - (iv) sexual ingredients. The compositions include agents selected from the group consisting of binders, extenders, dispersants, solvents, stabilizers, and the like: excipients, which are generally known in the art. The use of the agent will depend on the intended properties of the formulation, and the nature of the formulation will be determined by the route of administration. The time of administration is oral, transmucosal (e.g., sublingual, buccal, (iv), vaginal, and rectal), transdermal or injection (e.g., subcutaneous, intramuscular, and intravenous). Oral administration is usually preferred for oral administration, and the preparation is a tablet or capsule. Other formulating agents include dry powders, solutions, suspensions, elixirs, and the like. The present invention is a method of treating or controlling π physiological dysfunction in some people. Such a method comprises administering to a patient in need of such treatment an effective amount of a pharmaceutically acceptable compound comprising the compound according to the foregoing as an active ingredient. The compound can be used to reduce the amount of urine, and thus the present invention can be applied to any problem caused by an increase in urine volume. Compounds can also increase the production of coagulation proteins called the Vth phenotype and the Weng's leucine blue factor, thus treating bleeding disorders. In a preferred embodiment, diabetes insipidus can be treated. In this case, the body is unable to produce and secrete physiologically active angiotensin, and as a result, the reabsorption of water is greatly reduced to produce a large amount of urine. Alternatively, the condition treatable in the preferred embodiment is nocturnal enuresis. These definitions define the bladder emptying during personal sleep. This type of patient is mainly in the child and its etiology involves a number of factors. In another preferred embodiment, the condition to be treated is nighttime polyuria. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 packages).

'^褒--- n K _ - J. (Please read the notes on the back and fill out this page)

297 mm) 20 1307338 V. Description of invention (17) Jade: The condition can be defined as the amount of urine produced at night so that the individual must wake up to urinate. Again, this is the result of the sage. In another preferred embodiment, the condition being treated is incontinence. This is due to the reduced bladder capacity and reduced bladder control, so non-autonomous urination occurs unless the bladder is often evacuated. Loss of eight cases, namely stress incontinence and urgent incontinence, rape = multiple causes. In accordance with the present invention, the system can delay the emptying of the bladder ("empty delay"), allowing the incontinent patient to have a drying time of up to several hours (eg, up to four hours). This delay in emptying can also be used for non-incontinence groups, such as those who need to attend meetings for a long time. In another preferred embodiment, the condition to be treated is sputum type blood disease or Weng Bleu's disease. The reduction in the production of the νιη coagulation factor or the onion blue factor of these patients has resulted in prolonged bleeding in the individual. 'Alternatively, in a preferred embodiment, such a composition is administered to a surgery (including a dental operation) to increase the clotting ability of the lye and thereby reduce the time of postoperative dynasty. The administration is usually carried out by a physician. The physician can determine the amount of the composition to be administered and the dosage plan, taking into account the patient's condition and /D treatment target. For adult diabetes insipidus patients, the typical dose is From milligrams to 1 gram of active compound, daily oral-spin or at most four-bonds are used for routes other than oral administration, and the amount of the compound is reduced. The original use of non-oral (4) can more effectively transfer (4) to the system and circulation; Alpha treatment of type A hemophilia and Weng's microbrilli disease, the amount of compound is higher than that of diabetes insipidus.

Because of the need for the paper ruler 21 1307338 A7 B7 V. Description of the invention (18) The foregoing general description will be further illustrated by the following non-limiting examples. Example Abbreviation Use the following abbreviations. Ac acetylated LIBN arsenazo (isobutyl hydrazine) Bn benzyl BOC tert-butoxycarbonyl (B0C) 20 dibutyl butyl dicarbonate DMF decyl decylamine Et ethyl EtOAc ethyl acetate I PA Propanol iPr isopropyl MS mass spectrometry Me thiol NBS N-bromobutaneimine pet. Ether petroleum ether, boiling point 60-80 ° C fraction Ph phenyl tBu third butyl THF tetrahydro vent South WSCDI water soluble Preparation of bismuthimine intermediates (please read the notes on the back and fill out this page) Binding -

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. The reagents corresponding to Groups A and C are commercially available or can be prepared according to established procedures, except for the details detailed in the special case. The reactants corresponding to the B stage were prepared as follows. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). 22 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print A7 ------------B7 V. Invention Description (19 )

Methyl chloroformate 1307338 Add NBS (5.8 g, 32.0 mM) to a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in four gas fossil (50 ml) Mohr) and AIBN (0.442 g ' 2.70 mmol). The mixture was stirred at reflux for 18 hours. Allow the contents to cool to room temperature and then vacuum; The residue was purified by gel chromatography (flash ethyl acetate: petroleum ether 0:100 to 5:95); yield: 5.96 g (84%). A2. 4-(Tertidinoxycarbonylaminomethyl)-3-chlorobenzoic acid was added to a saturated solution of ammonia in ethanol (170 mL). Methyl decanoate (5.5 g, 20.9 mmol). The mixture was stirred at room temperature for 1 hour then concentrated in vacuo. The residue was triturated with ethyl acetate and the obtained white crystals were filtered and washed with diethyl ether. This solid is added to a solution of water (1 mL) (BOC) 2 Torr (5.0 g '23.0 mmol) in dioxane (100 mL) and sodium hydroxide (1.86 g, 46.0 mmol). A solution of water (1 ml). The mixture was stirred at room temperature for 18 h then concentrated in vacuo. The aqueous residue was acidified with citric acid and extracted with a gas/IPA. The organic layer is based on i paper size _ towel _ home standard (CNS) A4 size (210 X 297 mm) (please read the back of the note before you fill out this page)

23 1307338 A7 B7

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives. V. INSTRUCTIONS (20) Washing, dehydration with magnesium sulfate and concentration in vacuo gave a white solid; yield 2.8 g (67%). Example B. 4-cyano-3-methylbenzoic acid

</ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 4.48 ml, 11.2 mmol) solution. The mixture was stirred at -78 &lt;0&gt;C for 1 h then poured into EtOAc (EtOAc) Allow the mixture to warm to room temperature. Water (200 ml) was added and the mixture was extracted with diethyl ether (3 times). The aqueous layer was acidified by addition of concentrated hydrochloric acid and extracted with chloroform (3 times). The combined chloroform extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to give a white solid. Example C. 4-cyano-2-methylbenzoic acid

CN This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

24 1307338 A7 B7 V. Description of the invention (21) 4-bromo-3-methylbenzonitrile (2.0 g ' 10.2 mmol) was obtained according to the procedure of Example B to give a yellow solid. The yield was 0.96 g (59%). The following specific examples were obtained for the combination of reactants corresponding to the A, B and C stages. Example 1. 1-(2-Methyl-4-(2,3,4,5-tetrahydro-1 -benzazepine-1 - a heteropoly) 芊I night - _ carbyl fluorenyl)- L-proline-N,N-dimethyl decylamine

〇ACC«Y〇Ο Λ- ο -I · I (please read the notes on the back and fill out this page) -J _ order 1Α· 2-曱基-4-((2,3,4,5-four Hydrogen-1Η-benzo[b]azepine-indole-carbonyl)_ benzoiconitrile 2,3,4,5-tetrahydro-1Η-stupid [b]|t 萆(〇·8〇克, 5.44 mmol, 4-cyano-3-methylbenzoic acid (0.96 g, 5.95 mmol), triethylamine (0.60 g, 5.95 mmol) in a solution of di-methane (50 mL) Ear), 4-(dimethylamino)acridine (0.73 g '5·95 mmol) and WSCDI (1.24 g, 6.48 mmol). The mixture was stirred at reflux for 8 hours, cooled and evaporated in vacuo. The residue was partitioned between ethyl acetate and 1% potassium hydrogen sulfate. The organic layer was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate and vacuum. The crude material was purified by flash chromatography on silica gel (solvent ethyl acetate: petroleum ether 30:70); yield 丨·1 g (70%). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printing 25 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printing 1307338 A7 _____ B7 V. Invention Description ( 22) 1Β· 1-(4-(Aminomethyl)-3-methylacetylmethyl)-2,3,4,5-tetrahydro-1H-mosa[b]azepine hydrochloride To a solution of the cyanobenzodiazepine (1.10 g, 3.79 mmol) of Example 1A in methanol (50 mL) was added to saturated hydrochloric acid (0.98 mL, 11.3 mmol) and 10% palladium/carbon. (0.80 g). Hydrogen was passed through the mixture for 5 hours at room temperature. The catalyst was removed by filtration through a pad of ceiite and the filtrate was evaporated; yield: &lt;RTIgt; 1C. 1-(2-Mercapto-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylaminocarbazyl)-L-decylamine Acid-N,N-dimercaptoguanamine was added to a solution of the amine of Example lb (0.10 g, 0.302 mmol) in DMF (10 mL). N,N-diisopropylethyl Indoleamine (43 mg '0.332 mmol) and carbonyl diimidazole (0.074 g, 0.453 mmol). The mixture was stirred at room temperature for 40 minutes. A solution of the valine-N,N-dimethyl-branamine (〇_1〇7 g '0.756 mmol) in DMF (1 mL) was added. The mixture was stirred for a further 16 hours at room temperature. The solvent was removed in vacuo and the crude material was purified by flash chromatography (solvent: methanol: methylene chloride: 5:95); yield: 0.115 g (82%). *H NMR (CDC13): 5 1.35-1.55 (1H, m), 1.74-2.10 (3H, m), 2.11 (3H, S), 2.17-2.35 (1H, m), 2.60-2.82 (2H, m) , 2.86 (3H, s), 2.90-3.14 (2H, m), 3.05 (3H, s), 3.26 (1H, dd, J = 14.9 &amp; 7.2 Hz), 3.40-3.53 (1H, m), 3.64- 3.84 (1H, m), 4.03-4.19 (1H, m), 4.29-4.42 (1H, m), 4.55-4.68 (1H, m), 4.74- 4.81 (1H, m), 4.85-4.98 (1H, m ), 6.58 (1H, d, J=7.7Hz), 6.75- 6.89 (2H, m), 6.91-7.06 (3H, m), 7.16 (1H, d, J=6.5Hz), the paper size applies to China Standard (CNS) A4 specification (210 X 297 mm) _______!·Installation.1 (Please read the note on the back and fill out this page) .SJ··

26 A7 1307338 ______B7______ V. Description of invention (23) 7.93-B.03 (1H, m) ppm. M.S.: calculated value m/e=462.26; measured value [Μ+Η], 463·2 Example 2.

[4R]-4-(-1-(2-(2-, 4-, 4-, 4-tetrahydro-1-benzoindole-yl) benzylaminomethyl) -L-proline--Ν,Ν-二曱曱

2Α. L-trans-4-hydroxyproline-indole, Ν-dimercaptoamine hydrochloride in BOC-hydroxyproline (2.99 g ' 13.89 mmol) in dioxane (100 ml) To the solution was added hydrazine, hydrazine-diisopropylethylamine (3.7 ml, 21.24 mmol), 4-(dimethylamino) bite (1.74 g, 14.24 mmol) of 'dimethylamine salt. Acid salt (1.72 g, 21.09 mmol) and WSCDI (3.17 g, 16.68 mmol). The mixture was stirred at room temperature for 30 hours. The mixture was diluted with methylene chloride (EtOAc) (EtOAc)EtOAc. The crude material was taken up in EtOAc (EtOAc m. The residue was azeotroped with toluene and diethyl ether to afford a white solid: 0.45 g (17%). 28. (4 ft)-4-1,4-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzoazepine-1 ylcarbonyl)benzylamino hydrazine醯-)-L-proline-oxime, Ν-dimercaptoamine Example 1 Β amine (0.10 g '0.302 mmol) and Example 2 Α amine This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 mm) (Please read the notes on the back and fill out this page)

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 27 1307338 V. Description of the Invention (24) (0.153 mg, 〇j85 mmol) According to the method (1). The product was purified by flash chromatography on a silica gel (solvent chloroform·methanol·acetic acid 95:4:1); yield: 0.95 g (66%). H NMR (CDC13): (5 1.65-1.80 (2H, m)5 1.85-2.00 (3H, m), 2.05-2.25 (1H, m), 2.10 (3H, s), 2.80-3.10 (3H, m) , 2.85 (3H, s), 3.00 (3H, s), 3.40-3.30 (1H, m), 3.45-3.55 (1H, m), 3- 65-3.95 (1H, m), 4.00-4.10 (1H, m), 4.30-4.55 (1H, m), 4- 91 (1H, t, J=7.7Hz)s 5.15-5.30 (1H, m), 6.10-6.20 (1H, m), 6.55-6.65 (1H, m), 6.85-7.50 (5H, m) ppm. Ms..calculated value m/e=478.26; measured value [M+H]+=479 2 Example 3-116 Other examples listed in the following tables use similar methods preparation.

Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Example Number R/S V8 XY [M+H]+ 3 S Η h2 OMe 436.4 4 R Η h2 OMe 436.2 5 R/S OPh 0 OH 528.3 6 R/S OPh 0 NMe2 555.3 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 28 1307338 A7 B7 V. Description of invention (25)

Example No. R1 R1 V1 V* XY [M+H]* 7 Η Me HH 0 OtBu 492.5 B Η Me HH 0 OH 436.3 9 Η Me H OH 〇OMe 466.0 --Shang--------Book· ( Please read the notes on the back and fill out this page.)

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

-—a I 29 1307338 A7 B7 V. INSTRUCTIONS (26) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Example Number R1 R2 V1 V2 XY [Μ+ΗΓ 10 Η Me H OAc 0 NMe2 521.0 11 Η Me =〇0 ΝΜβ2 477.3 12 Η Me H OH 0 OEt 480.2 13 Η Me H OCOcCjHs 0 NMe2 547.3 14 Η Me H OMe 0 NMez 493.5 15 Η Cl HH 0 NMe2 483.4 16 Η Me HH s NMe2 479.2 17 Η Me HH 0 NMeEt 477.2 18 Η OMe HH o NMe2 479.2 19 Η Me H OMe 0 OMe 480.2 20 Η Me HH 0 OiPr 478.2 21 Η Me H OH 0 OH 452.1 22 Η Me H OBn 0 OiPr 584.2 23 Η Me H OH 0 OiPr 494.1 24 Η Me H OBn 0 NMez 569.2 25 Me HHH o NMe2 463.2 26 Η Me H OMe o OH 466.2 27 CI HHH o NM62 483.1 28 Η Et HH 0 NMez 477,3 29 Η Cl HH s NMea 499.2 30 Η Cl H OBn 0 NMe2 589.2 31 Η C! H OH 0 NMe2 499.2 32 Η Me H OEt 0 NMe2 507.3 33 Η Me Br H o NMe2 -541.1 34 Η Me H Cl 0 OMe 4S4.1 35 Η Me FF o ΝΜβ2 499.2 36 Η Me H Cl 0 OH 470.1 37 Η Me HN , 0 NMe2 504.3 38 Η Me H Cl 0 NMe2 497.2 39 Η Me H OtBu 0 NMe2 535.3 40 Η Me Cl H 0 NMe2 497.2 41 Η Me H OPh 0 OMe 542.3 42 Η Me HF 0 OMe 468.3 Pack - (Please read the notes on the back and fill out this page) Order: Line. This paper size applies to China National Standard (CNS) A4 specifications ( 210 X 297 mm) 30 1307338 ΚΙ Β7 V. Invention description (27) Example number R1 R* V1 V2 XY [Μ+ΗΓ 43 Η Me HF 0 OH 454.4 44 Η Me HF 0 NMe2 481.3 45 Η Me H NHBn 0 NMez 568.0 46 Η Me OMe OMe 0 OMe 510.3 47 Η Me OMe OMe 0 OH 496.2 48 Η Me OMe OMe 0 ΝΜθ2 523.3

Example No R2 V2 X [M+H]* 49 Cl H 0 489.1 50 Me H 0 469.2 51 Me OH 0 485.0 52 Cl OMe 0 519.3 53 Me OMe o 499.3 54 Cl OMe s 535.1 Ministry of Economic Affairs Intellectual Property Office Staff Consumption Cooperative Printed system

χ^·ΝΜβ2

Example No R* V2 w1 X [M+H]* 55 H H S 0 479.4 56 H OH s 0 495.0 (Please read the notes on the back and fill out this page)

This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 31 1307338 A7 B7 V. Invention description (28) Example number R3 V2 W1 X [Μ+Η]* 57 Η Η SS 495.1 58 Me Η 0 ο 477.2 59 Η ΟΒη S ο 585.2 60 Η ΟΒη 0 S 585.0

V2 V

(Please read the note on the back and fill out this page) Example No. A, · A17 Ra V2 [M+H]* 61 NEt CHa Me OMe 522.4 62 NH CHa Me OMe 494.3 63 ch2 NiPr Me OMe 536.4 64 ch2 NH Me OMe 494.5 65 0 ch2 Cl OMe 515.2 66 CH(OH) ch2 Me H 479.2 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

A

32 1307338 A7 _B7 V. Description of invention (29) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

(Please read the notes on the back and fill out this page)

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). 33 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1307338 _B7 V. Invention description (30)

(Please read the precautions on the back and fill out this page.) This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 34 1307338 A7 B7 V. Description of invention (31: Example number

A V4 [M+Hf 83

Ν ο

6 Μο 2 9· 54 84

ΗΝ Ν

e Μο 2 8· 54 85

Μθο 2 6 5 (Please read the notes on the back and fill out this page) -J- I I I _ 装 ο. 86

Ν e Μο ·2 90· 5 .- Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

• Line · θ Μ

Example No. V1 V2 XY [M+H]* 87 Η Η s NMe2 516,2 88 Η OBn 0 ΝΜβ2 606.3 89 Η OH 0 NMe2 507.3 90 Η ΟΜθ 0 ΝΜθ2 530.3 91 —OOHjCH^O- 0 OMe 545.3 92 OMe OMe 0 OMe 547.3 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 35 1307338 A7 —__ B7 V. Invention description (32) Example number V1 V» XY [ΝΙ+ΗΓ 93 -och2ch2o- 0 NMez 558.3 94 —SCH2CHtS~ 0 ΝΜθ2 590.2

(Please read the note on the back and then fill out this page.) Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives Printed Example Number R* V1 V» XY [R/ΗΉΓ 95 Me H OH 〇NMe2 516.1 96 Me HH s NMe2 516.2 97 Me H OMe 0 NMe2 530.4 98 Me -och2ch2o- 0 OMe 545.3 99 Me -och2ch2o- 0 OH 531.3 100 Me —OCH2CH2OTM 0 NMe« 558.3 101 a HH 0 NMe2 551.5 102 Me H OMe 0 NEt2 558.3 103 Me H OMe 0 〇570.3 104 Me H OMe s NMe2 546.2 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 36 1307338 A7 B7 V. Description of invention (33)

12 Example No. A10 R* V2 X [Μ+ΗΓ 105 0 Me H 0 519.3 106 NMe Me H 0 532.3 107 NMe Me OH 0 546.1 108 ΝΜθ Me OBn 0 638.2 109 NMe Me OMe 0 562.3 110 0 Me OMe 0 549.2 111 NMe Me Cl 0 566.2 112 ΝΜθ Me OMe s 578.2 113 0 Cl OMe 0 569.1 114 0 Me OMe s 565.2 115 0 Cl OMe s 585.1 116 NH Me OMe 0 548.2 Pack -------- set. (Please read the back first Note: Please fill out this page) -4· ϋ I- n WT . Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed on this paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 37 1307338 A7 _B7 V. Description of invention (34) Printing by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). {Please read the notes on the back and fill out this page.)

38 1307338 A7 B7 V. INSTRUCTIONS (35) EXAMPLE 117. ACTIVATED ACTIVITY The compound of the present invention is a selective agonist of the receptor. In the two-ligand displacement assay, the Ki value of the compound to the V2 receptor: β Μ. 』仏ιυ Example 118. ' ----&quot; — Applicable to the test; ... ^Special, '隹 (Brattleb〇ro) rats are known ▲ tuberculosis defect research model (related The review is based on FD Grant, "The genetic model of vasopressin deficiency," physiology 85. 203S-209S &gt; 2000) ° Animals do not secrete vasopressin results in large dilutions of urine. The sigma of the present invention was administered to Brett-containing rats (0.1-10 mg/kg orally in methylcellulose). Urine was collected every hour and its volume was compared to control animals. Animals are free to access food and water during the 13⁄4 process. Representative results are not in the table. The results of the Des Moprisin are for comparison. Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs (please read the notes on the back and fill out this page)

I x 297 mm) 39 1307338 A7 B7 V. INSTRUCTIONS (36) Example compound dose urine volume inhibition percentage ___P hour) 1 mg/kg _82 ~Ϊ4~~ _ 1 mg/kg 84 ~52 ~~ _ 1 Mg/kg ~54~~ _ 1 mg/kg 68 —-- 1 mg/kg 63 ~9〇~~ 1 mg/kg 60 1 mg/kg 74 ~Ϊ04~~ 1 mg/kg 81 109 1 mg/kg 73 1 mg / kg 80 ΤΪ 2~~·~~ 1 mg / kg 75 1 mg / kg 85 ^ 115 ~ ~ ~ ~ 1 mg / kg 88 Dissimoprisin 0.1 mg / kg 37 1 mg / kg 100 10 MG/kg 100 Example 119. Record: The pharmaceutical group contains 100 mg of the compound of Example 1 as the active agent. The following is the package--- (please read the phonetic on the back? Please fill out this page) _ Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed Sub-preparation: Example 1 Compound Corn Starch Hydroxypropyl Cellulose Methylcellulose Dance Magnesium Stearate Total Amount 200.0 g 71.0 g 18.0 g 13.0 g 3.0 g 195.0 g 500.0 The gram material is mixed and then compressed to obtain 2 〇〇〇 ingot 25 〇 tablets, each containing Applicable Standard iV Chinese Zhang Scale (CNS) A4 size (2i〇 well _ x 297 ") 40 V. invention is described in (37) 100 mg of compound of Example 5. BRIEF DESCRIPTION OF THE INVENTION The compounds of the present invention are verified to facilitate the preparation of such compounds using standard chemical techniques. The substance has the expected biological properties for the V2 receptor co-agent. In particular, these compounds are powerful anti-diuretics in the animal model of vascular growth. This can be used to treat human diseases currently treated with dissimoprisin, such as #枢尿尿症, enuresis and nocturia. Further suggest that antidiuretics such as dissimoprisin can be used for certain types of urinary incontinence. Such differentiation will also extend to the compounds of the invention. Dissiprisin is also used to treat certain blood clotting disorders. There is clear evidence that this effect is through V2 receptor mediators (eg, refer to JE Kaufm et al.: "Angiotensin-induced endothelial cell secretion of Weng's microbubble factor involves V2 receptor and CAMP" 107-116 , 2000; A Bernat et al., "V2 Receptor Antagonism in the Induction of Blood Constant Factor Release in Conscious Canines," Grade _^JLi! 282, 597-602, 1997) b. This is expected to be a useful pre-coagulation of the compounds of the present invention. Agent. The scope of the invention is further defined in the scope of the following patent application.

Claims (1)

1307338 VI. Scope of Application for Patent Application No. 90100209 Patent Application Revised Patent Application No. May 20, 1997 1. A compound of formula 1 or a pharmaceutically acceptable salt thereof, Wherein: A is a bicyclic or paracyclic nitrogen weed derivative selected from the group consisting of formulas 2, 3, 5, and 7. A1 is CH2; A2 and A3 are CH; A4 is NR8; A5 is a covalent bond and A6 is S, or A5 is N=CH and A6 is a covalent bond; A10 is Ο; A11 is CH; 42 1307338 Patent range A12 is S; A16 and A17 are both CH2, or A16 is NR8 and A17 is CH2; V1 and V2 are both Η or F, or one of V1 and V2 is OH, OMe or OBn and the other is η W1 is 〇 or S; X1 and X2 are =0 or =S together; Y is OR5 or NR6R7; Z is S or -CH=CH-; R1 'R2, R3 and R4 are respectively selected from Η 'Cw alkyl And Cl; R5 is hydrazine and Cw alkyl; R6 and R7 are respectively selected from 11 and (: 1-4 alkyl; and R8 is hydrazine or Cm alkyl. 2. The compound of claim 1 or its medicinal Receptive salt, wherein A is a group of the formula 2. 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is a group of the formula 3. 4 Or a pharmaceutically acceptable salt thereof, wherein A is a group of the formula 5, or a pharmaceutically acceptable salt thereof, wherein A is a group of the formula 7. 6_If applying for a patent The compound of the above formula 1, or a pharmaceutically acceptable salt thereof, wherein A is a group according to Formula 7, and 2 is -(:11=(:11 and 八和灰) are both CH2. The compound of the scope of the third aspect or a pharmaceutically acceptable salt thereof, 43 307 338, wherein the one of R1 and R2 is Cl or Me and the other is η, and R3 &amp; r4 are both hydrogen. The compound of the above item 1, or a pharmaceutically acceptable salt thereof, wherein one of V1 and V2 is 〇Me or OBn and the other is H. 9. A compound according to claim 1 or a pharmaceutical acceptableness thereof a salt, wherein X1 and X2 together are =〇 and γ is NR6R7. 〇·If the compound of claim 1 or the pharmaceutically acceptable salt thereof, Wherein W1 is 0 or s; one of Ra&amp;Rb is C1 or fluorenyl and the other is H; ... is a fluorenyl or benzyl group; R6 and R7 are each selected from the group consisting of hydrazine and (^_4 alkyl). U. The compound of claim i or the pharmaceutically acceptable salt thereof is -44 - 1307338 VI. Application for patent scope Wherein W1 is 0 or S; one of Ra&amp;Rb is C1 or methyl and the other is hydrazine; 1^ is fluorenyl or benzyl; and R6 and R7 are each selected from hydrazine and Ci_4 alkyl. 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein both V1 and V2 are H. 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein X1 and X2 together are hydrazine and Y is NR6R7. 14. A compound of claim 1 or a pharmaceutically acceptable salt thereof, which is Of which 45 1307338 6. The scope of application for patent w1 is 〇 or S; one of Ra&amp;Rb is 01 or methyl and the other is Η; R6 and R7 are respectively selected from hydrazine and Cl_4 alkyl. A compound of any one of claims 1 to 5 to 7 or 12 to 14 or a pharmaceutically acceptable salt thereof, which is W1 is 〇 or S; one of Ra&amp;Rb is C1 or methyl and the other is η; R6 and R7 are respectively selected from fluorene and Cm alkyl. 16. The compound of claim 1, wherein the compound is selected from the group consisting of 1-(2-mercapto-4-(2,3,4,5-tetrahydro-1) benzoazepine-1-ylcarbonyl Benzylaminomethylmercapto)-L-proline-indole, hydrazine-dimethyl decylamine, (4 ft)-4-hydroxy-1-(2-methyl-4-(2,3, 4,5-tetrahydro-1-benzoazepine-1-ylcarbonyl)benzylaminoindenyl)-L-proline-indole, hydrazine-dimethyl decylamine, (4R)-l -(3-Chloro-4-(2,3,4,5-tetrahydro-1_ benzoazepine-1-ylcarbonyl)benzylaminomethylmercapto)-4-methoxy-L-oxime Amino acid _n,N-dimethyl amidoxime oxime (4 ft)-1-(2-gas-4-(2,3,4,5-tetrahydro-1_benzoazepine _1_1 yl) Carbonyl) benzylaminomethylmercapto)-4-methoxy-L-proline _ν, Ν-dimethyl decylamine, 46 1307338 VI. Patent scope (4R)-4-benzyloxy_i- (2-Methyl-4_(2,3,4,5-tetrahydro-1-benzazepine-1-ylcarbonyl)benzylaminocarbazyl)-L-proline-N,N - dimethyl decylamine, (4R)-4-methoxy-1-(2-mercapto-4-(2,3,4,5-tetrahydro-1-benzazepine-1-ylcarbonyl) Benzylaminomethylmercapto)-L-proline-indole, hydrazine-dimethyl-branched amine, (4R)-4-methoxy-1-(3-methyl-4-(2,3, 4,5-tetrahydro-1-benzoazepine-1-ylcarbonyl)benzylaminopurine )-L-proline-indole, Ν-dimercaptodecylamine, (4R)-l-(2- gas-4-(5,6,7,8-tetrahydro-4114 seleton [3, 2-15]azepine-4-ylcarbonyl)benzylaminocarbazyl)-4-oxo-L-proline-N,N-didecylguanamine, (4R)-l-( 4-(l〇,ll-dihydro-5H-indolo[2,lc](l,4)benzodiazepine-10-ylcarbonyl)-2-methyl-benzylaminoformamidine ))-4-oxo-L-proline-N,N-didecyl decylamine, (411)-1-(2-chloro-4-(10,11-dihydro-511^ And [2,1-(;](1,4) benzo-milk decyl-10-carbyl) nicylaminomethyl aryl)-4·-methoxy_L-acantine-N, N-dimercaptodecylamine, and (4 ft)-1-(4-(1〇,11-dihydro-511_ fluoren[2,1-(:](1,4) benzodiazepine Weed-10-pyridyl)-2-methyl-flatylaminoindenyl)_4_曱oxy_l_proline-indole, hydrazine-dimethylthioguanamine or a pharmaceutically acceptable salt thereof 17. A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use as a component of a pharmaceutical composition and which acts as a agonist of an angiotensin V2 receptor. For the treatment of enuresis, nocturia, due to the infertility caused by diabetes Urinary incontinence and bleeding disorders of the pharmaceutical composition, which comprises 47 six special applications like, the scope of patented drug acceptability benefits range 16 to 1 or a compound of any one of the doctors salt thereof. A pharmaceutical composition which acts as a co-agent for a vasopressin V2 receptor, which comprises an active agent selected from a compound of any two of the above-mentioned claims, to a pharmaceutical product, and a pharmaceutically acceptable The active agent of the salt. 2. A pharmaceutical composition according to claim 19, which is for the treatment of polyuria. 21. The pharmaceutical composition of claim 19, which is for use in the control of urinary incontinence. 22. The pharmaceutical composition of claim 19, wherein the composition is used for delayed emptying. 23. The pharmaceutical composition of claim 19, which is for use in the treatment of bleeding disorders. 24. Use of a compound as claimed in claim 1 for the manufacture of a pharmaceutical composition for the treatment of enuresis, nocturia, polyuria due to central diabetes insipidus, urinary incontinence, and bleeding disorders.