6,9-disubstituted benzazepines having .alpha.-adrenoceptor blocking activity

5,639,748

08/193,075

February 04, 1994

Alpha-adrenergic receptor antagonists having the formula: ##STR1## which are useful to produce .alpha.-adrenoceptor antagonism, pharmaceutical compositions including these antagonists, and methods of using these antagonists to produce .alpha.-adrenoceptor antagonism in mammals.

DeMarinis, Robert Michael (Ardmore, PA); Pfeiffer, Francis Richard (Cinnaminson, NJ)

SmithKline Beecham Corporation (King of Prussia, PA)

What is claimed is

1. A method of treating hypertension in mammals which comprises administering to a subject in need thereof an effective amount of a compound having the formula: ##STR7## in which: X is H, Cl, Br, F, I, CF.sub.3, C.sub.1-6 alkyl, COR.sup.1, CO.sup.2 R.sup.2, CONR.sup.2 R.sup.2, CN, NO.sub.2, NR.sup.3 R.sup.4, OR.sup.3, SR.sup.1, SCF.sub.3, or any accessible combination thereof up to three substituents;

R is H, C.sub.1-6 alkyl, or C.sub.3-5 alkenyl;

A is --OCO(CH.sub.2).sub.1-4 --, --OCH.sub.2 CH.dbd.CH--, --CO.sub.2 (CH.sub.2).sub.1-4 --, --(CH.sub.2).sub.0-6 --, or --(CH.sub.2).sub.n Z(CH.sub.2).sub.m --, wherein n is 0-4 and m is 1-5, with the proviso that m and n taken together are no greater than 5;

Z is O;

each R.sup.1 independently is C.sub.1-6 alkyl or (CH.sub.2).sub.0-6 phenyl;

each R.sup.2 independently is H, C.sub.1-6 alkyl, or (CH.sub.2).sub.0-6 phenyl;

R.sup.3 is H, C.sub.1-6 alkyl, CHO, COR.sup.1, or SO.sub.2 R.sup.1 ;

R.sup.4 is H or C.sub.1-6 alkyl; and

Het is a heteroaryl group selected from thienyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, thiazolyl, pyridinyl, or tetrazolyl which are unsubstituted or substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, Cl, Br, F, I, NR.sup.3 R.sup.4, CO.sub.2 R.sup.2, CONR.sup.2 R.sup.2, CN, or NO.sub.2 ; or a pharmaceutically acceptable salt thereof.

2. A method according to claim 1 of the formula (Ia): ##STR8## in which: X is H, Cl, Br, F, I, CF.sub.3, C.sub.1-6 alkyl, COR.sup.1, CO2R.sup.2, CONR.sup.2 R.sup.2, CN, NO.sub.2, NR.sup.3 R.sup.4, OR.sup.3, SR.sup.1, SCF.sub.3, or any accessible combination thereof up to three substituents;

each R .sup.1 independently is C.sub.1-6 alkyl or (CH.sub.2).sub.0-6 phenyl;

3. A compound of claim 2 wherein X is Cl, Br, F, or I.

4. A compound of claim 3 wherein Het is pyrazolyl, furanyl, thienyl, triazolyl, pyridinyl, or pyrrolyl with each heteroaryl group being unsubstituted or substituted by Cl or CH.sub.3.

5. A compound of claim 4 wherein R is CH.sub.3.

6. A compound of claim 5 which is 6-chloro-9-(3-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine or a pharmaceutically acceptable salt thereof.

7. A compound of claim 5 which is

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrazol-1-ylmethoxy)-1H-3-benzaz epine;

6-chloro-9-(4-chloro-1H-pyrazol-1-ylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H -3-benzazepine;

6-chloro-9-(2-furanylmethoxy)-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine;

6-chloro-9-[3-(2-furanyl)-2-propenyloxy]-2,3,4,5-tetrahydro-3-methyl-1H-3-b enzazepine;

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(2-thienyl-methoxy)-1H-3-benzazepine

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(3-thienyl-methoxy)-1H-3-benzazepine ;

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-(1H-pyrazol-1-yl)ethoxy]-1H-3-ben zazepine;

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-1,2,4-triazol-1-ylmethoxy)-1H-3- benzazepine;

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(4-pyridinylmethoxy)-1H-3-benzazepin e;

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-[2-(1H-1,2,4-triazol-1-yl)ethoxy]-1H -3-benzazepine;

6-chloro-9-[(4-chloro-1H-pyrazol-1-ylmethoxy)-methyl]-2,3,4,5-tetrahydro-3- methyl-1H-3-benzazepine;

6-chloro-9-[(4-chloro-1H-pyrazol-1-ylmethoxy)-carbonyl]-2,3,4,5-tetrahydro- 3-methyl-1H-3-benzazepine;

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-yl)-1H-3-benzazepine;

6-chloro-9-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3,4,5-tetrahydro-3-methyl-1H-3-b enzazepine;

6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-ylmethyl)-1H-3-benzazep ine;

6-chloro-9-[3-(4-chloro-1H-pyrazol-1-yl)propyl]-2,3,4,5-tetrahydro-3-methyl -1H-3-benzazepine; or

6-chloro-9-[5-(4-chloro-1H-pyrazol-1-yl)pentyl]-2,3,4,5-tetrahydro-3-methyl -1H-3-benzazepine; or a pharmaceutically acceptable salt thereof.

514/213; 540/594

A61K 3155; C07D40112; C07D40312; C07D40512

4233217 November 1980 Shetty
4265890 May 1981 Holden et al.
4469634 September 1984 DeMarinis
4683229 July 1987 DeMarinis et al.

Medicinal Chemistry (2nd Ed.) by Alfred Burger (Editor), pp. 72-78 (1960).
Journal of Medicinal Chemistry, vol. 25, No. 12, pp. 1389-1401, 1982, Timmermans et al.
Journal of Medicinal Chemistry, vol. 27, No. 7, pp. 918-921, 1984, DeMarinis et al.

edspgr.05639748