JPH06510545A - Compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Compound field of invention The present invention provides novel substitutions 2.3.4 having α-adrenergic receptor antagonistic activity. ゜Relating to 5-tetrahydro-IH-3-benzazepine compounds.

Background of the invention The autonomic nervous system is divided into the cholinergic nervous system and the adrenergic nervous system. Ru. Norepinephrine, a neurotransmitter in the adrenergic nervous system, is responsible for to organs or nerve endings by interaction with receptors (adrenergic receptors). exerts its activity. Adrenergic receptors are of two main types: alpha and beta has. Based on receptor selectivity for a range of agonists and antagonists, Renarin receptors have been subdivided into C1 and α2 subtypes.

Much experimental evidence now indicates that the α2 subtype is a heterogeneous class of adrenergic receptors. I support the view that [For general scrutiny, see Timmermans & ・Van Zviet (Timmermans and Van Zviet) en), Journal of Medicinal Chemistry (J, Mad, Chem, ), 25.1289 (1982). 6-chloro-9-( 3-Methyl-2-butenyloxy)-3-methyl-2,3,4,5-tetrahydride Experiments using lo-IH-3-benzazepine (SK&F 104078) Classical adrenergic receptors are heterogeneous and SK&F 104078-insensitive α2 adrenergic receptors and SK&F 104078 - sensitive α2 adrenergic showed that it can be divided into two receptors. The latter individually, after conjugation (po adrenergic receptors, or, preferably, α , as adrenergic receptors, U, S, P 4.683,229 (1987 July 28th).

α-adrenergic receptors, one of the main regulators of peripheral vascular tone, are , it has long been recognized that alteration of vascular resistance yields therapeutic benefit in treating diseases such as hypertension. Attempts to develop drugs effective in altering vascular tone for use in It was a target. In clinical use, it functions through interaction with adrenergic receptors. Current antihypertensive compounds include methyldopa, clonidine, and prazosin. Examples include: Regulates sympathetic tone through interaction with adrenergic receptors By trying to do hat or α! Interacts somewhat selectively with adrenergic receptors Several compounds were obtained. As a selective agonist, it preferentially targets C1 receptors. Activates phenylephrine and methoxamine: and alpha, adrenergic receptors clonidine, alpha-methyl-norepinephrine, and drugs that preferentially activate the body. One example is ramazoline. Examples of selective α-adrenoceptor antagonists include: Prazosin with high selectivity for C1-adrenergic receptors: and C2 - selective blockers - yohimbine and rauvolsine ne).

U, S, P 4,469.634 (September 4, 1984) contains α2 adrenaline Ants useful as intermediates for the production of phosphorus receptor affinity resins and as antihypertensive drugs. ruoxy- and allylthio-2,3,4,5-tetrahydro-IH-3-ben Zoazepine is disclosed.

U, S, P 4.683.229 (July 28, 1987) includes C1 selective 6-halo-9-alkenyloxy-2,3,4,5-tetrahydrogen with antagonistic activity Dro-IH-3-benzazepines are disclosed.

tl, s, P 4.265.890 (May 5, 1981) contains dopamine Mercapto-substituted-2,3,4,5-tetrahydride with receptor blocking activity Lo-IH-3-benzazepines are disclosed.

Kaiser et al., Journal of Mesointernal Chemistry -, 23, 975-976 (1980), which is a dopamine receptor antagonist. 6-(phenylthio)-substituted-2,3,4,5-tetrahydro-IH-3-ben The production of zoazepine is disclosed.

Ku et al., Journal of Organic Chemistry (J, Org) Chem, ), 47: 3862-3865 (1982) contains certain Arylthio-substituted-2,3,4,5-tetrahydro-IH-3-benzazepi The synthesis of the compound is disclosed in detail. These compounds are dopamine receptor antagonists It is a neuroleptic drug that acts as a neuroleptic.

Summary of the invention The present invention provides certain substituted -2,3,4,5-tetrahydro-IH-3-benzoa It belongs to the discovery that zepine compounds are alpha-adrenergic receptor antagonists. Main departure Preferred compounds include the following compounds: 6-chloro2.3 ．． 4.5-tetrahydro-3-methyl-9-phenoxy-IH-3-benzoase pin.

6-chloro-2,3,4,5-tetrahydro-9-[(4-methquinphenyl) methoxy]-3-methyl-IH-3-benzazepine, 6-chloro-9-[(2 ,6-dimethoxyphenyl)methoxy]-2,3,4,5-tetrahydro-3- Methyl-IH-3-benzazepine, 6-chloro-9-4(4-chlorophenyl ) methoxy]-2.3,4.5-tetrahydro-3-methyl-IH-3-benzo Azepine, 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(2 -phenylethquine)-18-3-benzazepine, 6-chloro-2,3,4, 5-tetrahydro-9-[2-(2-methoxyphenyl)ethquine]-3-methy Ru-IH-3-benzazepine, 6-chloro-2,3,4,5-tetrahydro- 9-C2-(3-methoxyphenyl)ethquin]-3-methyl-IH-3-ben Zoazepine, 6-chloro-2,3,4,5-tetrahydro-9-[2-(3,4 -dimethoxyphenyl)ethquin]-3-methyl-IH-3-benzazepine, 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-4(3-phenyl -2-propenyl)oxy]-LH-3-benzazepine, 6-propenyl)2. 3.4.5-Tetrahydro-3-methyl-9-[2-phenoquinethoxy]-L H-3-benzazepine: 6-chloro-9-[2-(2,6-dimethquinephenol) ethquin]-2,3,4゜5-tetrahydro-3-methyl-IH-3-be nzazepine, 6-chloro-2,3,4,5-tetrahydro-3-methyl-9- [4-(4-nitrophenyl)butoquino]-1H-3-benzazepine, 9-[ 4-(4-aminophenyl)butquin-6-chloro-2,3,4,5-tetra Hydro-3-methyl-IH-3-benzazepine, 9-[4-(4-amino-3 -iodophenyl)butquin-6-chloro-2,3゜4.5-tetrahydro- 3-Methyl-IH-3-benzazepine, 6-chloro-2,3,4,5-tetra Hydro-3-methyl-9-[((3-(4-nitrophenyl)propyl)carbo oxy]-1H-3-benzazepine, 9-[((3-(4-aminophene) (propyl)carbonyl)oxy]-6-chloro-2,3,4,5-tetra hydro-3-methyl-IH-3-benzazepine, and 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(3-phenyl propyl)-LH-3-benzazepine: or a pharmaceutically acceptable salt thereof .

The most preferred compound of the invention is 6-chloro-2,3,4,5-tetrahydro- 3-methyl-9-(2-phenylethoxy)-1H-3-benzazepine or It is a pharmaceutically acceptable salt thereof.

In a further aspect, the invention provides substituted 2.3.4.5-tetrahydro-IH-3- a human subject, characterized in that an effective amount of a benzazepine compound is administered internally to a subject; The present invention provides a method for antagonizing adrenergic receptors in mammals, including:

The present invention is characterized in that it consists of a compound useful in the method of the invention and a suitable pharmaceutical carrier. A pharmaceutical composition having the following characteristics. Preferably, these compositions are adrenergic receptors. containing an effective amount of a compound useful in the methods of the invention that is used to produce antagonism in the body. have

Detailed description of the invention is an alpha-adrenergic receptor antagonist or an alpha-adrenergic receptor antagonist The compound of the present invention useful for the production of is represented by the following formula (1): [wherein, X is H, CL Br, F, L CF3, C1-, alkyl, COR', C O2R", C0NR"R", CN, NO2, NR3R', OR3,5RISSC F, is a possible combination of up to three substituents of Mataha solera.

R is H, c+-a alkyl, or C5-, alkenyl: B is present None or present as O or S.

A is -0CO(CH2)l-4-1OCH2CH=CH-1C0z(CH2 )1-4-1-(CH,). -8- or -(CH2). Z(CH2)-- , where, if B does not exist, n is O~4, m is 0~5, and only and m and n are together less than or equal to 5, and when B is present, n is O~4. and m is 1 to 5, provided that m and n are together 5 or less.

Z is O or S: Each R1 is independently C1-6 alkyl or (CHz). -6 phenyl can be.

R2 is each independently HSC+-a alkyl, or (CH-6-6 phenyl It is: R' is H, C+-a7J'v kill, C)(o, COR'* or 5O2R' 'l); R4 is H or C1-6 alkyl;

Xl is H, CL Br, F, L CFs, C1-6 alkyl, COR', CO 2R2, C0NR2R2, CN5NCh, NR1R', OR', SR", 5CF s, or possible combinations of up to five substituents thereof.

However, HSCL with 3 X Br5F, CF3, CH,, ○CH,, GOC H,,OH,)0HSNO2,NH,,QC(0)C+-sfulkyl,Mataha If GC○(0)C1-a alkyl, then B is absent, A is S, and X l is 5 H, Cj, GCI, F, 0HSNot, CHs, CF, or 0C Other than R3] or a pharmaceutically acceptable salt thereof.

As used herein, CI-. Alkyl is a straight line having 1 to 6 carbon atoms. C3-1 alkenyl means linear or branched alkyl, and C3-1 alkenyl has 3 to 5 carbon atoms. means a straight-chain or branched alkenyl having atoms "possible combinations thereof" The word ``se'' refers to a compound on the phenyl group that is available by chemical synthesis and is stable. Refers to combinations of up to three substituents.

Formula (Ia) [In the formula, X is H, CI, Br, F, I, CF3, C1-6 alkyl, COR', CCh R2, C0NR"R", CN, No,, NRIR', OR1, SRI or SC F, and R is H, CI-a alkyl, or C8-, alkenyl: B is absent or present as 0 or S.

A is -0CO(CHz)+-low 1-0 CH2CH=CH-1-CO2( CH2)l-, -1-(CHz). -6-1 or -(CH, Z(CH2), -, where if B is absent, n is 0 to 4, m is O to 5, and , where m and n are together less than or equal to 5, and if B is present, n is 0 ~4, and m is 1 to 5, provided that m and n together are 5 or less. the law of nature.

Z is 0 or S: R1 is each independently Cl-6 alkyl or (CHJ.-, phenyl); R1 is each independently HSC, alkyl, or (CH2). -6f is enil: R3 is H, C, alkyl, CHO, COR'! +': is 5OxR't'J' ); R4 is H or C1-6 alkyl: XI is H, CL Br, F, I, CF, , C1-, alkyl, C0RI, CO, R2, C0NR"R", CN , No! , NR"R', OR", SRI, SF3, Mataha solerano up to 5 locations Possible combinations of substituents: where X is HSCl, Br, F, CF, , CH, , OCH3,0HSN○1, NR2, or QC(0)CI-s alkyl , B does not exist and A is S, then XI has 5 H, CI, G C1, F, O H, No! , CH,, CF, or ○CH, C character. be] The compound represented by formula (1) or a pharmaceutically acceptable salt thereof is preferably This invention includes the compound of the present invention.

Preferred compounds have the formula ( This is a compound represented by Ia).

The benzazepine represented by formula (1) is described in the Journal of Mesointernal Chemistry. Disclosed in published literature such as or can be easily pounded using known methods. According to reaction scheme I Sodium hydride, etc., in a suitable organic solvent, such as dimethylformamide, A starting material of formula (1) is added to a suitable base such as an alkali metal hydride. Add. Next, 2-phenylethyl bromide, nannamil chloride, 2-(phenyl bromide) enoxy)ethyl, or 2-(2-methquinophenyl)ethyl-4-methylbenzene Suitably substituted halides or sulfonates such as benzenesulfonate is reacted with the intermediate obtained above to give the formula (1) [wherein A is -o(cHl)l- 3- or OCHz CH=CH-, B is absent or O is also or exists as S].

The compound represented by formula (1) [wherein B is absent and A is -〇-] is steel and a suitable salt such as triethylamine in a suitable solvent such as methanol The compound of formula (I) in the presence of nphenyliodonium chloride By reacting with XI-substituted diphenyliodonium halides such as Manufactured by

Formula (I) [wherein A is OCO(CH2) + -4T] Compounds are also prepared from compounds of formula (1). In this method, chloride Starting in the presence of a base such as triethylamine in a suitable solvent such as methylene Alcohol compounds such as 4-(4-nitrobenzene)butanoyl chloride ( React with XI-substituted-phenyl)alkanoyl halide.

The benzazepine represented by formula (2) is known in the art [Journal Le of Mesoinnal Chemistry, 27, 918-921 (1984) 1 or can be synthesized by a known method. According to reaction formula H, For example, using sodium nitrate in acetic acid, water, and sulfuric acid, diazotize the primary amine compound. The diazonium salt is, for example, cyanated. By reacting with a cyanide such as potassium, the corresponding formula (3) can be obtained. Conversion to cyano compounds is carried out. The cyano compound represented by this formula (3), in the presence of barium hydroxide in a suitable solvent such as a mixture of ethanol and water. By reacting, a carboxylic acid compound represented by formula (4) is produced. profit of sodium hydride in a suitable solvent such as dimethylformamide. and a suitable base such as an alkali metal hydride. Then 4-chloro -For reaction with suitably substituted halides such as 1-chloromethylbenzene Therefore, it is represented by the formula (1) [wherein A is -Co2(CHz)+-4-] A compound represented by formula (5) is obtained.

Scheme 1 illustrates the preparation of further compounds of formula (I). Reaction formula■ Thus, for example, at a temperature of about 5°C to about 100°C, preferably about 100°C, Using Raney nickel in a suitable solvent such as an acid, the formula (3 ) is converted into the corresponding aldehyde derivative represented by formula (6). exchange.

From the aldehyde compound represented by this formula (6), for example, about 35°C to about 35°C, Preferably, in a suitable solvent such as methanol at a temperature of about 10°C to about 24°C. Using sodium hydride, the hydroxyl represented by formula (7) is prepared by a reduction method. Manufactures methylbenzazepine. From the benzazepine shown by this formula (7) , using the method described in Reaction Formula 1, the compound represented by Formula (1), Formula (8) A benzazepine shown by is manufactured.

Reaction formula (1) is also represented by formula (1) [where A is (CHz)3-s-, and B is , not present] is also shown. According to reaction formula ■, in formula (6) The indicated aldehyde compound is heated at a temperature of about 0°C to about 110°C, preferably 11 triphenylphosphoranylideneacetate in a suitable solvent such as toluene at 0°C. with phosphorus ylides such as aldehydes or with triethylphosphonoacetate. by reacting with an alkylphosphonic acid ester such as tetrahydrofuran. Phosphonate in reaction with a suitable base such as sodium hydride in a suitable solvent. For example, each -CH=CH-CH=CH-C The corresponding alkenyl derivatives such as H○ or -CH=CHCCh ethyl are obtained. It will be done. The vinyl intermediate thus obtained can be used, for example, in a suitable solvent such as ethanol. by hydrogenation in a suitable solvent and in the presence of a suitable catalyst such as platinum oxide. reduced to a saturated analogue. This terminal ester or formyl group can be reagents, e.g. ester reducing agents such as lithium aluminum hydride, or the corresponding alcohol using a formyl reducing agent such as sodium borohydride Reduce to derivatives. The alcohol is reacted with a l) chloride colorant such as thionyl chloride. Accordingly, -(CHz)ss halobenzazepine is obtained. Bromide tank – presence of copper For reaction with ＼lopenzazebin Xl-substituted phenyllithium compounds in the presence of Therefore, formula (I) [wherein A is -(CHzh-s- and B is absent] ] is obtained.

Pharmaceutically acceptable non-toxic acid addition salts of formula (I) with free base availability include Formed with inorganic or organic acids by methods well known in the art .

Representative examples of suitable acids are maleic acid, fumaric acid, benzoic acid, ascorbic acid, Pamoic acid, succinic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfur Phonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, acetic acid, Spartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p- Aminobenzoic acid, glutamic acid, benzenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid , cyclohexylsulfamic acid, phosphoric acid and nitric acid.

Since the compound represented by formula (I) is an α-adrenergic antagonist, the compound represented by formula (I) The compound is associated with hypertension, pulmonary hypertension, excited heart failure, peripheral vascular disease, myocardial ischemia, and angina. It is useful in the treatment of cardiovascular diseases in which changes in vascular resistance are desirable, including cardiovascular disease. Formula (I ) is also used to treat benign prostatic hyperplasia, diabetes, glaucoma, ocular hypertension, Disorders of gastrointestinal motility, including hypertrophy, colonic stress, irritable bowel syndrome, and constipation, Also useful in the treatment of central nervous system disorders such as senile dementia and senile dementia. It is for use. Furthermore, the compounds of the present invention can be used to treat diseases resulting from inappropriate platelet aggregation. It is useful for

The alpha-adrenergic receptor activity of certain compounds of the invention was determined in the following in vitro study. Measured using ro system.

α1 adrenergic receptor antagonistic activity was measured using rabbit aorta. maleness New sealant white rabbits (2 to 4 in 9) were euthanized by neck shaking. chest A 4 cm section of the aorta was removed and placed in cold (10°C) Krebs-Hensleit ( Krebs-Hensleit) solution. fat from tissue and connective tissue was removed and cut into pieces approximately 3 mm in length. These fragments were divided into 0. 10 m1 of tissue was inserted through a hanger consisting of 251 m of tungsten wire. I hung it on. One hanger is fixed to a support in the air, and the other is connected to a silk thread to change the force. connected to a position transducer.

The tissue sections were allowed to equilibrate for 2 hours before being drug tested, during which time the base tension was maintained at 29 did. During this equilibration, the tissue was washed every 30 minutes. Krebs-Hensleit solution The solution contains cocaine (6 iM) and β-adrenergic to block neural uptake. Propranolol (1mM) was included to block the receptor. During the equilibration , the tissue is typically challenged with norepinephrine (0,1+mM) - times to test for viability. I investigated.

Obtain a cumulative concentration-response curve for norepinephrine in each aortic segment. Ta. Adrenergic receptor antagonists to be tested after washing out norepinephrine was added to the bath. After contacting the tissue with the antagonist for 30-60 minutes, the presence of the antagonist Bottom, norepinephrine concentration response curve was repeated. Then wash the tissue again , a 10-fold higher concentration of antagonist was added. After equilibration (30-60 minutes), the antagonist A third norepinephrine concentration-response curve was measured in the presence of .

The receptor dissociation constant (K,) for antagonists was determined using the following relationship: Furchgott, R,F, /-Ndobutsu Ku of Experimental 7 Who 7:10 Gee (Handbook of Experimentalp Pharmacology), Eichler (E) 1chler et al., pp. 283-335 (Sbringer 1972)]. each antagonist The Ki values obtained at drug concentrations were averaged to give an average of 1 for each experiment.

The α2-adrenoceptor antagonistic activity of the compound was demonstrated in isolated hyperperfused guinea pigs. Measurements were made using the left atrium of Soto. That is, pentono-rubital anesthetized males. Remove the heart from a sex guinea pig. Isolate the left atrium and keep it free of adherent tissue. An incision was made and placed in a 2 mA' hyperperfusion chamber. 30 noguru of the tissue/ pace), field stimulation (field stimulation) ion) to stimulate the sympathetic nervous system every 6 minutes. The response to nerve stimulation is It is measured as the difference in contractile force between the main contraction and the peak contraction after nerve stimulation. each consecutive By administering increasing concentrations of B-HT 920 (a known α2 agonist) after stimulation. Therefore, a concentration-response curve for B-HT 920 is created. Then, the tissue is overfed for 30 minutes with the α-adrenergic receptor antagonist to be tested, then B-) I7920 concentration-effect curve was repeated in the presence of antagonist. Data is , in the above definition, is reported as. Further details of this test system can be found in Heeble, Hieble, J.P. and R.G. Pendleton ( R, G, Pendleton), Arch, Pharmacol, 309 : 217-224 (1979).

α3 adrenergic receptor antagonist receptor activity was determined using canine saphenous vein (DS) as a test system. V). This test system was developed by Srivian, A.T. ivan.

A, T, ) and G.M.Drev, Arch. In Phara+aco10.314/249-58 (1980), is a suitable preparation for characterizing post-naptic α2 (α3) adrenergic receptors. It was shown that This test system involves removing the lateral saphenous vein from an anesthetized dog and then The vein is then prepared by cutting the vein into four length pieces. solid cormorant The fragments were placed as described for the heron aorta.

The α, adrenergic receptor antagonistic activity of the compounds of the present invention is determined by the compound being tested. To measure the shift in the induced specific agonist dose-response curve Therefore, it is measured. When testing the compounds listed in Table 1, α2, α3 agonist The drug B-HT 920 was used.

Representative compounds of formula (I) tested using the above in VitrO test system The compounds are listed in Table 1. Each of the compounds tested has one or more α-adrenergic It was found that it has antagonistic activity on the receptor subtype.

No. 1 schedule 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-phenoquine-I H-3-benzazepine: 6-ri-4-2.3.4.5-tetrahydro-9-[(4-methoxyphenyl) Metquin]-3-methyl-IH-3-benzazepine.

6-chloro-9-[(2,6-shiftquinphenyl)methoxyco-2,3,4, 5-tetrahydro-3-methyl-IH-3-benzazepine: 6-chloro-9- [(4-chlorophenyl)methquine] 2.3.4.5-tetrahydro-3-methine Chil-IH-3-benzazepine, 6-chloro-2,3,4,5-tetrahydro -3-methyl-9-(2-phenylethoxy)-1H-3-benzazepine, 6 -chloro-2,3,4,5-tetrahydro-9-[2-(2-methoxyphenyl ) ethoxy]-3-methyl-IH-3-benzazepine, 6-chloro-2,3, 4,5-tetrahydro-9-[2-(3-methoxyphenyl)ethoxy]-3- Methyl-IH-3-benzazepine, 6-chloro-2,3,4,5-tetrahydride rho-9-[2-(3,4-dimethoxyphenyl)ethomushroom-3-methyl-IH -3-benzazepine, 6-chloro-2,3,4,5-tetrahydro-3-methy -9-[(3-phenyl-2-propenyl)oxy]-LH-3-benzaze pin, 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-ph enoxyethquin]-1H-3-benzazepine, 6-chloro-9-[2-(2 ,6-Simethoxyphenoxy)ethquin]-2,3,4゜5-tetrahydro-3 -Methyl-IH-3-benzazepine, 6-chloro-2,3,4,5-tet lahydro-3-methyl-9-[4-(4-nitrophenyl)butoxy]-LH- 3-benzazepine, 9-[4-(4-aminophenyl)butoxy]-6-chloro rho-2,3,4,5-tetrahydro-3-methyl-IH-3-benzazepine, 9-[4-(4-amino-3-iodophenyl)butquin]-6-chloro-2, 3゜4.5-tetrahydro-3-methyl-IH-3-benzazepine, 6-chloro rho-2,3,4,5-tetrahydro-3-methyl-9-[((3-(4-nitro phenyl)propyl)carbonyl)oxy]-1H-3-benzazepine, 9- [((3-(4-aminophenyl)propyl)carbonyl)oxy]-6-chloro rho-2,3,4,5-tetrahydro-3-methyl-IH-3-benzazepine, and 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(3-phenyl propyl)-18-3-benzazepine, or a pharmaceutically acceptable salt thereof .

A spontaneous hypertensive rat model was used to evaluate the antihypertensive activity of certain compounds of the invention. It was measured. For more information on this in ViV□ test, check out wrestler J.M. (Roe sler, J.

M.) et al., Journal of Pharmacology and Experimental Therapeutics (J, P harmacol, E xp, Ther , ), 236:1-7 (1986).

The compound may be combined with a pharmaceutical carrier in a capsule, tablet or injectable preparation. When combined into convenient dosage forms, novel pharmaceutical compositions are obtained. solid or liquid Pharmaceutical carriers can be used. Solid carriers include starch, lactose, Calcium sulfate dihydrate, clay, euclose, talc, gelatin, agar, Pectin, gum arabic, magnesium stearate and stearic acid are listed. It will be done. Liquid carriers include syrup, peanut oil, olive oil, saline and water. can be mentioned. Similarly, as a carrier or diluent, alone or with wax , sustained release such as glyceryl monostearate or glyceryl distearate Examples include substances. The amount of solid carrier varies within a wide range, but preferably It is about 251 to about 1 g per position. If a liquid carrier is used, the preparation formulations, elixirs, emulsions, soft gelatin capsules, sterile injectable solutions or is in the form of an aqueous or non-aqueous suspension or solution.

For tablet form, the pharmaceutical preparation can be mixed, optionally granulated, and then compressed. Alternatively, the ingredients may be mixed, filled, and then dissolved as desired. according to the conventional techniques of medicinal chemists, including obtaining the desired oral or parenteral products. It is prepared well.

The dosage of the compound present in the pharmaceutical administration carrier ranges from 0.1 to 100 m g7kg, preferably a non-toxic working amount selected from the range 01-50u/&+g It is. The selected dosage is administered orally to human patients in need of treatment from 1 to 6 times per day. orally, rectally, topically, by inhalation or injection, or by infusion Administered sequentially. However, oral administration is more convenient for patients Therefore, it is preferable.

The following examples illustrate the preparation of compounds of formula (1). The example is These definitions and the following claims are not intended to limit the scope of the invention.

Example 1 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-phenoxy-I H-3-benzazepine 9-chloro-2,3,4,5-tetrahydro-IH-3-benzazepine-6- All (633 iris 9.3 01), diphenyliodonium chloride (1,79 , 5,4 mmol), triethylamine (13 wings and copper powder (200-9) A warm mixture of methanol (2Qm/) was stirred at 40°C for 18 hours. Filter the mixture and the filtrate was concentrated. Dissolve the residue in ethyl acetate and add 10% sodium hydroxide. , washed with water and saline. The organic phase was extracted with dilute hydrochloric acid and the aqueous phase was brought to pH 7.5. It was basified and then extracted with ethyl acetate. The organic phase was washed with brine and washed with sulfuric acid. Dry over magnesium, concentrate and then treat with hydrogen chloride to obtain 6-chloro-2, 3,4,5-tetrahydro-3-methyl 9-phenoquine-IH-3-benzaze Pin hydrochloride was obtained. Melting point: 215-217°C.

Example 2 6-chloro-2,3,4,5-tetrahydro-9-[(4-methoxyphenyl) methoxy]-3-methyl-IH-3-benzazepine 9-chloro-2,3,4, 5-tetrahydro-3-methyl-IH-3-benzazepin-6-ol (0, A solution of 849,4m+aol) in dimethylformamide (1(bj')) was heated with hydrogen. treated with a 50% dispersion of sodium chloride in mineral oil (0,239,4,9+nol) , stirred for 10 minutes, then dimethylforma of 4-methoxybenzyl chloride It was treated with a solution in Mido (4 m/). The mixture was heated to 60°C for 2 hours and cooled. It was poured into an aqueous sodium hydroxide solution and extracted with ethyl acetate. Dry the organic phase and concentrate The residue was then chromatographed on silica gel and chromatographed in methanol. The mixture was eluted with a gradient of 199 to 3.5:96.'5 of methylene chloride. Generate The fractions containing the product were pooled, concentrated and then treated with maleic acid to give 6 -chloro-2,3,4,5-tetrahydro-9-C(4-methquinphenyl)methyl Toquin]-3-methyl-IH-3-benzazepine maleate was obtained. melting point 177-179°C.

Examples 3-12 6-chloro-9-[(2,6-dimethoxyphenyl)metquinco-2,3,4, 5-tetrahydro-3-methyl-IH-3-benzazepine 6-chloro-9-[ (4-chlorophenyl)methoxy]-2,3,4,5-tetrahydro-3-methy Ru-IH-3-benzazepine 6-chloro-2,3,4,5-tetrahydro-3 -Methyl-9-(2-phenylethoxy)-1H-3-benzazepine 6-chloro-2,3,4,5-tetrahydro-9-(2-(2-methoxyphenylphenyl) ) ethoxy/]-3-methyl-IH-3-benzazepine 6-chloro-2,3, 4,5-tetrahydro-9-[2-(3-methoxyphenyl)ethoxyco3- Methyl-IH-3-benzazepine 6-chloro-2,3,4,5-tetrahydro -9-[2-(3,4-dimethoxyphenyl)ethoxy]-3-methyl-IH- 3-benzazepine 6-di-4-2.3.4.5-tetrahydro-3-methyl- 9-[(3-phenyl-2-propenyl)oxy]-1H-3-benzazepine 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-phenokyl ethoxy]-1H-3-benzazepine 6-chloro-9-[2-(2,6-ethoxy) phenoquine) ethquine]-2,3,4゜5-tetrahydro-3-methyl -IH-3-benzazepine 6-chloro-9-[2,3-dihydropenzodioxide Syn-2-yl)methokino]-2,3,4,5-tetrahydro-3-methyl-I H-3-Benzazepine Using the general method of Example 2, 4-methquine chlorobenzyl chloride, 4-chlorobenzyl chloride 2-phenylethylbromide, 2-(2-methquinphenyl)ethyl 4-methyl Thilbenzenesulfoner h, 2-(3-methoxyphenyl)ethyl 4-methylbenzene Zenesulfonate, 2-(3,4-dimethoxyphenyl)ethyl chloride, Nnamyl chloride, 2-(phenoquine)ethylbromide, 2-(2,6-dimethod) xyphenyl)ethyl bromide and 2,3-dihydrobenzodioxin-2- In place of methanol methanesulfonate, the following compounds were obtained: 6-chloro-9-[(2,6-cymethoxyphenyl)methquine]-2,3,4, 5-Tetrahydro-3-methyl-IH-3-benzazepine maleate, fused Point 112.5-113.5°C.

6-chloro-9-[(4-chlorophenyl)methoxy]-2,3,4,5-tet Lahydro-3-methyl-IH-3-benzazepine maleate: melting point 189 -190℃.

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(2-phenyl ethoxy)-1H-3-benzazepine hydrochloride; melting point 185-186.5°C.

6-chloro-2,3,4,5-tetrahydro-9-[2-(2-methquinphenylacetate) ) Ethomushroom-3-methyl-IH-3-benzazepine maleate; melting point 153.5-155°C.

6-chloro-2,3,4,5-tetrahydro-9-[3-(3-methoxyphenylon) ) ethoxy]-3-methyl-IH-3-benzazepine maleate: melting point 101-104.5°C.

6-chloro-2,3,4,5-tetrahydro-9-[2-(3,4-dimethoxy phenyl)ethquin]-3-methyl-IH-3-benzazepine hydrochloride, melting point 70℃.

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[(3-phenyl -2-propenyl)oxy]-LH-3-benzazepine hydrochloride; 157- 5-1625℃.

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(2-phenokyl )-1H-3-benzazepine hydrochloride: 150-152°C.

6-chloro-9-[2-(2,6-shiftquinphenoxy)ethoxy]-2,3 , 4゜5-tetrahydro-3-methyl-IH-3-benzazepine hydrochloride, molten Point 157-159°C.

6-chloro-9-[2,3-dihydropenzonooxin-2-yl)methoxy] -2,3,4,5-tetrahydro-3-methyl-IH-3-benzazepine Leate salt: melting point 58-60°C.

Special table flat e-5, to545 (8) Example 13 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[4-(4-ni trophenyl)butoxy]-1H-3-benzazepine 4-(4-nitrobenze ) butanol (2.17 g, l1m) and benzyltriethylmethane A solution of nium chloride (0.1 g) in methylene chloride (20% strength) was dissolved in 30% sodium hydroxide. Treated with thorium, stirred and cooled to -5°C, then treated with methylene chloride (10 wt. The solution was treated with methanesulfonyl chloride (1,99,16,7 mmol). Applicable The mixture was stirred at -5°C and then at 25°C for 16 hours. Wash the organic phase with water, Dry over sodium sulfate, then concentrate. the residue with ethyl ether 4-(4-nitrobenzene)butyl methanesulfonate (methanol) ) was obtained: melting point 48.5-49.5°C.

Using the general method of Example 2, 4-methoxybenzyl chloride was converted to 4-(4- 6-chloro-2,3 instead of nitrobenzene)butanol methanesulfonate ゜4.5-Tetrahydro-3-methyl-9-[4-(4-nitrophenyl)buto xy]-IH-3-benzazepine (methanol) was obtained. Melting point 79-80°C.

Example 14 9-[4-(4-aminophenyl)butoxo]-6-chloro-2,3,4,5- Tetrahydro-3-methyl-IH-3-benzazepine 6-chloro-2,3,4 ,5-tetrahydro-3-methyl-9-[4-(4-nitrophenyl)butoxy ]-LH-3-benzazepine (0,289, Q, 7 mmol) and platinum oxide The mixture in ethanol was shaken under hydrogen for 1 h, filtered, and the filtrate was concentrated. , dissolved in ethyl ether and then treated with ethereal hydrogen chloride to give 9-[4 -(4-aminophenyl)butquin-6-chloro-2,3,4,5-tetrahy Dro-3-methyl-IH-3-benzazepine dihydrochloride hydrate (methanol -ethyl acetate) was obtained. Melting point: 150°C (decomposed).

9-[4-(4-amino-3-iodophenyl)butoxy-6-chloro-2, 3゜9-[4-(4-aminophenyl)butoxy-6-chloro-2,3,4, 5-tetrahydro-3-methyl-IH-3-benzazepine (227 mg, 0. A stirred solution of 5 mmol) of acetic acid <Sat> was dissolved in sodium iodide (10 01g, 0.611IIIo1) and 30% hydrogen peroxide (97%, 0, 85 m1Ial) and then stirred for 2 hours. Sodium iodide mixture (25 u, 0.15 mmol) and hydrogen peroxide (25 u, 0.15 mmol) 1), stirred for 1 hour, and then treated with sodium metabisulfite in water (1 hour). (120 votesg). Basify the mixture with concentrated ammonium hydroxide and salt Extracted with methylene chloride, washed the organic phase with brine and diluted with sodium sulfate and potassium carbonate. and then concentrated. The residue was dissolved in methanol-ethyl acetate-hydroxide. Chromatograph on a thin layer of silica gel plate developed with ammonium (5.95:1). The product was eluted with the same solvent. Concentrate the filtrate and evaporate the residue. dissolved in alcohol and treated with ethereal hydrogen chloride to give 9-[4-(4-amino-3 -iodophenyl)butoxy-6-chloro-2,3,4,5-tetrahydro- 3-Methyl-IH-3-benzazepine dihydrochloride hydrate (methanol-ethyl ether) was obtained. Melting point 151.5-152°C (decomposed).

Example 16 Rhochloro2.3.4.5-tetrahydro-3-methyl-9-(((3-(4 -nitrophenyl)propyl)carbonyl)oxy]-LH-3-benzazepi 9-chloro-2,3,4,5-tetrahydro-IH-3-benzazepine-6 -ol (29,9,4 mmol), 4-(4-nitrobenzene)butanoyl loride (289,12,3IImol) and triethylamine (1,7mA, 12.3 mmol) in methylene chloride was stirred and heated to reflux for 16 hours, then It was then concentrated. Dissolve the residue in ethyl ether and add 10% sodium hydroxide and and water, then dried over sodium sulfate to give 6-chloro-2,3,4 ,5-tetrahydro-3-methyl-9-[((3-(4-nitrophenyl)pro carbonyl)oxo]-1H-3-benzazepine (ethyl ether) xane) was obtained. Melting point 91-93.5°C.

Example 17 9-[((3-(4-aminophenyl)propyl)carbonyl)oxyph-6- Chloro-2,3,4,5-tetrahydro-3-methyl-IH-3-benzazepi Using the general method of Example 14, 6-chloro-2,3,4,5-tetrahydrogen Dro-3-methyl-9-[4-(4-nitrophenyl)butoxy]-LH-3- Benzazepine is converted into 6-chloro-2,3,4,5-tetrahydro-3-methyl-9 -[((3-(4-nitrophenyl)propyl)carbonyl)oxy]-LH- Instead of 3-benzazepine, 9-[((3-(4-aminophenyl)propyl) ) carbonyl) oxyph-6-chloro-2,3,4,5-tetrahydro-3-methane Chil-IH-3-benzazepine hydrochloride was obtained.

9-chloro-2,3,4,5-tetrahydro-3-methyl-IH-3-benzoa Zepin-6-amine (10 g, 47.5 mmol) in acetic acid (34 ml) and water ( The solution in 2011) was stirred, treated with sulfuric acid (7.5 mj), cooled to 5 °C, and then Sodium nitrite (3,659,53II■ 01) in water (7.5 ml). The mixture was diluted with water at 50-55°C. Cupric sulfate trihydrate (14,29,57m++ol) in (35,1), Potassium salt (15,49,240 mmol), ice (249), water (36 mmol) of sodium bicarbonate (31,89,380 mmol) and toluene (35 m /) below the surface of the stirred mixture prepared. The mixture was heated at 50°C for 15 minutes. , then stirred for 1 hour at 25°C and diluted with sodium bicarbonate (709) in water (700 ml) to pH 8 and then 10% sodium hydroxide (300,/ml) to pH 8. ) was processed. The mixture was extracted with ethyl acetate, and the organic phase was dissolved in aqueous sodium hydroxide. Washed with liquid and brine, dried over magnesium sulfate, then concentrated. residual The oil was treated with ethereal hydrogen chloride to give 9-chloro-2,3,4°5-tetra Hydro-3-methyl-IH-3-benzazepine-6-carponitrile 8.39 (68%). Melting point 288-290°C.

9-chloro-2,3,4,5-tetrahydro-3-methyl-IH-3-benzoa Zepine-6-carbonitrile (3, 19, 14 mmol) in 90% formic acid (40 m l) treating the solution with Raney' nickel (3,19) and stirring; Then, the mixture was heated under reflux for 3 hours. Additional Raney Nickel (17g) and 90% Formic acid (85,1) was added over 12 hours and the mixture was stirred for a further 3 hours. Mixed The mixture was cooled and filtered, then the filter cake was washed with 45% formic acid. Concentrate the filtrate. Condensed, basified with 10% sodium hydroxide, extracted with ethyl acetate, and washed the organic phase. Clean, dry and concentrate to give 9-chloro-2,3,4,5-tetrahydro -3-Methyl-IH-3-benzazepine-6-carboxaldehyde 3g was obtained. Ta.

Tetrahydrof triethylphosphonoacetate (1,9y, 8.6 mmol) The solution in run (200,1) was stirred and a 50% dispersion of sodium hydride in mineral oil ( 0,459,9,4++5ol), stirred for 15 minutes, then treated with 9-chloro rho-2,3,4゜5-tetrahydro-3-methyl-IH-3-benzazepine- 6-carboxaldehyde (2,29,90 o1) in tetrahydrofuran (2 70 μl) solution. The mixture was stirred for 16 hours, concentrated and diluted with ethyl ether. and then washed with water and brine. Organic phase with magnesium sulfate Dry, then concentrate to give (E)-3-(9-chloro-2,3,4,5-tetho lahydro-3-methyl-IH-3-benzazepin-6-yl)-2-propene 2.6 g of ethyl acid was obtained.

(E)-3-(9-chloro-2,3,4,5-tetrahydro-3-methyl-IH -3-benzazepin-6-yl)-2-propenoic acid ethyl (269,8,9 city A solution of o1) in ethanol (150 gj') was mixed with concentrated hydrochloric acid (18 drops) and platinum oxide. (0.11 g), then shaken under hydrogen (40 psi) for 2 hours and filtered. and then concentrated. The residue was cooled with ethyl acetate-ethyl ether (3: IO300, r) and 5% sodium bicarbonate. The organic phase is mixed with water and Washed with brine, dried over magnesium sulfate/rum, then concentrated to give 9-chloro- 2,3,4,5-tetrahydro-3-methyl-IH-3-benzazepine-6- 2.5 g (96%) of ethyl propanoate was obtained.

Lithium aluminum hydride (0.55 g, 14.6 mmol) in tetrahydro The suspension in furan (20,1) was stirred and heated to reflux to give 9-chloro-2,3,4, 5-tetrahydro-3-methyl-IH-3-benzazepine-6-propanoic acid Solution of chill (2°1 g, 7 II + aol) in tetrahydrofuran (25,i) Processed with. The mixture was stirred at reflux for 3 hours, cooled and then diluted with water (1 , 65mj) and treated with care with 10% sodium hydroxide (0,55+f') did. The mixture was stirred at 25°C, filtered, and the filtrate was concentrated. vinegar residue Dissolved in acid ethyl ether (4:1 Washed with thorium and water, filtered, dried over magnesium sulfate, then concentrated did. The residue was partitioned between ethyl acetate-ethyl ether (21) and 3N hydrochloric acid. . The aqueous phase was washed with ethyl ether, basified with aqueous sodium hydroxide and then Then, the mixture was extracted with ethyl acetate-ethyl ether (2:1). The organic phase is mixed with water and Washed with brine, dried over magnesium sulfate, then concentrated. Remove the residue 9-chloro-2, dissolved in ether and then treated with ethereal hydrogen chloride to ,3,4,5-tetrahydro-3-methyl-IH-3-benzazepine-6-propylene Ropanol hydrochloride was obtained. 218.5-223.5°C.

9-chloro-2,3,4,5-tetrahydro-3-methyl-IH-3-benzoa Zepin-6-propanol (0,89,3+5ol) in methylene chloride (3017 The solution in ) was stirred at 5°C and then treated with thionyl chloride (40mj'). Applicable The mixture was heated at 5°C for 10 minutes, at 25°C for 15 minutes, at 55°C for 3 hours, then at 25°C. The mixture was stirred for 16 hours. The mixture was concentrated to give 6-chloro-9-(3-chloropropropylene). Pill)-2,3゜4.5-tetrahydro-3-methyl-IH-3-benzazepi 0.969 of N. hydrochloride was obtained.

Cuprous bromide (0,359,2,5 mmol) in tetrahydrofuran (7d>medium temperature) The mixture was stirred, cooled to -25°C and diluted with chlorohexane-ethyl ether (7.3X 3. z, 5.91111101) and then Stir for 20 minutes.

The mixture was converted into 6-chloro-9-(3-chloropropyl)-2',3,4°5-tetra Hydro-3-methyl-IH-3-benzazepine hydrochloride (0,279,087 Close. 1) and stirred at -25°C for 20 minutes and then at 25°C for 1 hour. Mixed The mixture was heated to 75°C for 3 hours and then stirred at 25°C for 16 hours. the mixture Treated with water-ammonium hydroxide (2:IO20ml) and extracted with ethyl ether. I put it out. The organic phase was washed with 10% sodium hydroxide, water and brine, washed with sulfuric acid mag Dry over nesium then concentrate. The residue was dissolved in ethyl acetate-hexane (1: Chromatography was performed on the alumina-GF preparative thin layer plate developed in 9). did. The product was eluted with ethyl acetate, concentrated, dissolved in ethyl ether, then , treatment with ethereal hydrogen chloride gave a rubber. Decant the supernatant and evaporate the gum. 6-chloro-2,3,4,5-tetrahydro-3 -Methyl-9-(3-phenylpropyl)-1H-3-benzazepine was obtained.

Melting point 118.5-126°C.

Example 19 The ingredients are screened and mixed in the proportions shown in Table n below, and then added to gelatin. Oral administration for administering compounds of the invention by filling in hard capsules Make the morphology rA.

Atsushi front Ingredients Usage amount Magnesium stearate 5. .

Neuculose, calcium sulfate dihydrate and formula (1) shown in Table m below ) are mixed and granulated together with a 10% gelatin solution. wet granules screened, dried and mixed with starch, talc and stearic acid, Screen and then compress into tablets.

Table m Ingredients Usage amount Calcium sulfate dihydrate 1:+O’u Krose 2o recommendation 9 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(2-phenyl Etoki/)-1H-3-benzazepine 75g was dispersed in 25g of normal saline. Prepare the injection preparation.

Although preferred embodiments of the invention are described above, the invention is described herein. All variations that come within the scope of the following claims, including but not limited to the precise instructions contained herein. Rights to examples are also reserved.

Continuation of front page Cinnaminson, Sussex, New Chassis 08077, United States Live number 201

Claims (1)

[Claims] 1. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X is H, Cl, Br, F, I, CF3, C1-6 alkyl, COR1, CO2 R2, CONR2R2, CN, NO2, NR3R4, OR3, SR1, SCF3 , or possible combinations of up to three substituents thereof; R is H, C1-6 alkyl, or C3-5 alkenyl; B is absent or O or exists as S; A is -OCO(CH2)1-4-, -OCH2CH =CH-, -CO2(CH2)1-4-, -(CH2)0-6- or -(CH 2) nZ(CH2)m-, where if B is absent, n is 0 to 4. , m is 0 to 5, provided that m and n are together 5 or less, and B is If present, n is 0-4 and m is 1-5, with the proviso that m and n are equal to together are 5 or less; Z is O or S; R1 is each independently C1-6 alkyl or (CH2)0-6 phenyl Yes; R2 is each independently H, C1-6 alkyl, or (CH2)0- 6 phenyl; R3 is H, C1-6 alkyl, CHO, COR1 or SO2R1; 4 is H or C1-6 alkyl; X1 is H, Cl, Br, F, I, C F3, C1-6 alkyl, COR1, CO2R2, CONR2R2, CN, NO 2, NR3R4, OR3, SR1, SCF3, or up to 5 substituents thereof possible combinations; provided that X is 3 H, Cl, Br, F, CF3, CH 3, OCH3, di-OCH3, OH, di-OH, NO2, NH2, OC(O)C 1-6 alkyl, or di-CO(O)C1-6 alkyl, and B is absent , when A is S, X1 is 5 H, Cl, di-Cl, F, OH, NO2, C Other than H3, CF3 or OCH3] A compound represented by or a pharmaceutically acceptable salt thereof. 2. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X is H, Cl, Br, F, I, CF3, C1-6 alkyl, COR1, CO2 R2, CONR2R2, CN, NO2, NR3R4, OR3, SR1 or SC is F3; R is H, C1-6 alkyl, or C3-5 alkenyl; B is absent or present as O or S; A is -OCO(CH 2) 1-4-, -OCH2CH=CH-, -CO2(CH2)1-4-, -(C H2)0-6-, or -(CH2)nZ(CH2)m-, where B is If absent, n is 0-4 and m is 0-5, with the proviso that m and n are taken together less than or equal to 5, and when B is present, n is 0 to 4 and m is 1 to 5 , where m and n are together less than or equal to 5; Z is O or S; can be; R1 is each independently C1-6 alkyl or (CH2)0-6 phenyl Yes; R2 is each independently H, C1-6 alkyl, or (CH2)0- 6 phenyl; R3 is H, C1-6 alkyl, CHO, COR1 or SO2R1; 4 is H or C1-6 alkyl: X1 is H, Cl, Br, F, I, C F3, C1-6 alkyl, COR1, CO2R2, CONR2R2, CN, NO 2, NR3R4, OR3, SR1, SF3, or up to five substituents thereof Possible combinations; provided that X is H, Cl, Br, F, CF3, CH3, OC H3, OH, NO2, NH2, or OC(O)C1-6 alkyl, and B is If not present and A is S, X1 is 5 H, Cl, di-Cl, F, OH, N other than O2, CH3, CF3, or OCH3] The compound according to claim 1, which is represented by: 3. 3. A compound according to claim 2, wherein X is Cl, Br, F or I. 4. 4. A compound according to claim 3, wherein R is CH3. 5.6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(2-phene (nilethoxy)-1H-3-benzazepine or a pharmaceutically acceptable salt thereof 5. A compound according to claim 4. 6.6-chloro-2,3,4,5-tetrahydro-3-methyl-9-phenoxy -1H-3-benzazepine; 6-chloro-2,3,4.5-tetrahydro-9-[(4-methoxyphenyl) methoxy]-3-methyl-1H-3-benzazepine; 6-chloro-9-[(2 ,6-dimethoxyphenyl)methoxy]-2,3,4,5-tetrahydro-3- Methyl-1H-3-benzazepine; 6-chloro-9-[(4-chlorophenyl ) methoxy]-2,3,4,5-tetrahydro-3-methyl-1H-3-benzo Azepine; 6-chloro-2,3,4,5-tetrahydro-9-[2-(2-meth) xyphenyl)ethoxy]-3-methyl-1H-3-benzazepine; 6-chloro rho-2,3,4,5-tetrahydro-9-[2-(3-methoxyphenyl)eth xy]-3-methyl-1H-3-benzazepine; 6-chloro-2,3,4,5 -tetrahydro-9-[2-(3,4-dimethoxyphenyl)ethoxy]-3- Methyl-1H-3-benzazepine; 6-chloro-2,3,4,5-tetrahydride rho-3-methyl-9-[(3-phenyl-2-propenyl)oxy]-1H-3 -Benzazepine; 6-chloro-2,3,4,5-tetrahydro-3-methyl- 9-[2-phenoxyethoxy]-1H-3-benzazepine; 6-chloro-9 -[2-(2,6-dimethoxyphenoxy)ethoxy]-2,3,4,5-tet lahydro-3-methyl-1H-3-benzazepine; 6-chloro-2,3,4, 5-tetrahydro-3-methyl-9-[4-(4-nitrophenyl)butoxy] -1H-3-benzazepine; 9-[4-(4-aminophenyl)butoxy]- 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzoa Zepine; 9-[4-(4-amino-3-iodophenyl)butoxy]-6-chloro rho-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine; 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[((3-(4 -nitrophenyl)propyl)carbonyl)oxy]-1H-3-benzazepi 9-[((3-(4-aminophenyl)propyl)carbonyl)oxy]- 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzoa Zepin; or 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(3-phenyl propyl)-1H-3-benzazepine; or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 4. 7. A medicament comprising a compound according to claim 1 and a suitable pharmaceutical carrier. Composition. 8. The compound is 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-( 2-phenylethoxy)-1H-3-benzazepine or its pharmaceutically acceptable The pharmaceutical composition according to claim 7, which is a salt of 9. The compound is 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-phenoxy-1 H-3-benzazepine; 6-chloro-2,3,4,5-tetrahydro-9-[(4-methoxyphenyl) methoxy]-3-methyl-1H-3-benzazepine; 6-chloro-9-[(2 ,6-dimethoxyphenyl)methoxy]-2,3,4,5-tetrahydro-3- Methyl-1H-3-benzazepine; 6-chloro-9-[(4-chlorophenyl ) methoxy]-2,3,4,5-tetrahydro-3-methyl-1H-3-benzo Azepine; 6-chloro-2,3,4,5-tetrahydro-9-[2-(2-meth) xyphenyl)ethoxy]-3-methyl-1H-3-benzazepine; 6-chloro rho-2,3,4,5-tetrahydro-9-[2-(3-methoxyphenyl)eth xy]-3-methyl-1H-3-benzazepine; 6-chloro-2,3,4,5 -tetrahydro-9-[2-(3,4-dimethoxyphenyl)ethoxy]-3- Methyl-1H-3-benzazepine; 6-chloro-2,3,4,5-tetrahydride rho-3-methyl-9-[(3-phenyl-2-propenyl)oxy]-1H-3 -Benzazepine; 6-chloro-2,3,4,5-tetrahydro-3-methyl- 9-[2-phenoxyethoxy]-1H-3-benzazepine; 6-chloro-9 -[2-(2,6-dimethoxyphenoxy)ethoxy]-2,3,4,5-tet lahydro-3-methyl-1H-3-benzazepine; 6-chloro-2,3,4, 5-tetrahydro-3-methyl-9-[4-(4-nitrophenyl)butoxy] -1H-3-benzazepine; 9-[4-(4-aminophenyl)butoxy]- 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzoa Zepine; 9-[4-(4-amino-3-iodophenyl)butoxy]-6-chloro rho-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine; 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[((3-(4 -nitrophenyl)propyl)carbonyl)oxy]-1H-3-benzazepi 9-[((3-(4-aminophenyl)propyl)carbonyl)oxy]- 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzoa Zepin; or 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(3-phenyl propyl)-1H-3-benzazepine; or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 7. 10. characterized in that an effective amount of the compound according to claim 1 is administered to a subject in need thereof. A method for antagonizing α-adrenergic receptors in mammals. H. The compound is 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-( 2-phenylethoxy)-1H-3-benzazepine or its pharmaceutically acceptable 11. The method according to claim 10, wherein the salt is 12. The compound is 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-phenoxy-1 H-3-benzazepine; 6-chloro-2,3,4,5-tetrahydro-9-[(4-methoxyphenyl) methoxy]-3-methyl-1H-3-benzazepine; 6-chloro-9-[(2 ,6-dimethoxyphenyl)methoxy]-2,3,4,5-tetrahydro-3- Methyl-1H-3-benzazepine; 6-chloro-9-[(4-chlorophenyl ) methoxy]-2,3,4,5-tetrahydro-3-methyl-1H-3-benzo Azepine; 6-chloro-2,3,4,5-tetrahydro-9-[2-(2-meth) xyphenyl)ethoxy]-3-methyl-1H-3-benzazepine; 6-chloro rho-2,3,4,5-tetrahydro-9-[2-(3-methoxyphenyl)eth xy]-3-methyl-1H-3-benzazepine; 6-chloro-2,3,4,5 -tetrahydro-9-[2-(3,4-dimethoxyphenyl)ethoxy]-3- Methyl-1H-3-benzazepine; 6-chloro-2,3,4,5-tetrahydride rho-3-methyl-9-[(3-phenyl-2-propenyl)oxy]-1H-3 -Benzazepine; 6-chloro-2,3,4,5-tetrahydro-3-methyl- 9-[2-phenoxyethoxy]-1H-3-benzazepine; 6-chloro-9 -[2-(2,6-dimethoxyphenoxy)ethoxy]-2,3,4,5-tet lahydro-3-methyl-1H-3-benzazepine; 6-chloro-2,3,4, 5-tetrahydro-3-methyl-9-[4-(4-nitrophenyl)butoxy] -1H-3-benzazepine; 9-[4-(4-aminophenyl)butoxy]- 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzoa Zepine; 9-[4-(4-amino-3-iodophenyl)butoxy]-6-chloro rho-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine; 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[((3-(4 -nitrophenyl)propyl)carbonyl)oxy]-1H-3-benzazepi 9-[((3-(4-aminophenyl)propyl)carbonyl)oxy]- 6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzoa Zepin; or 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(3-phenyl propyl)-1H-3-benzazepine; or a pharmaceutically acceptable salt thereof. 11. The method according to claim 10. 13. characterized in that an effective amount of the compound according to claim 1 is administered to a subject in need thereof. A method for treating hypertension in a mammal. 14. characterized in that an effective amount of the compound according to claim 1 is administered to a subject in need thereof. A method for treating congestive heart failure in a mammal. 15. characterized in that an effective amount of the compound according to claim 1 is administered to a subject in need thereof. A method for treating peripheral vascular disease in a mammal. 16. characterized in that an effective amount of the compound according to claim 1 is administered to a subject in need thereof. A method for treating benign prostatic hyperplasia in a mammal.