Carbamates of 6-chloro-7,8-dihydroxy-1-(4'-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benz azepine as prodrugs

• US 4,861,771 A
• Filed: 01/27/1989
• Issued: 08/29/1989
• Est. Priority Date: 01/27/1989
• Status: Expired due to Term

• Current Assignee: Neurex Corp. (Perrigo Company PLC)
• Original Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Inventors: Mico, Bruce, Weinstock, Joseph, Gaitanopoulos, Dimitri
• Primary Examiner(s): Springer, David B.
• Application Number:
  US07/303,519
• Time in Patent Office: 214 Days
• Field of Search: 540/595, 514/213
• US Class Current: 514/217.02
• CPC Class Codes: A61P 5/42 for decreasing, blocking or antagonising the activity of mineralocorticosteroids
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 223/16 Benzazepines; Hydrogenated benzazepines

Abstract

Prodrug carbamate derivatives of fenoldopam which provide fenoldopam plasma levels of similar magnitude and over a much longer period of time than the parent compound. An absence of a high initial peak effect associated with the parent compound is noted. A lead compound of the series is 6-chloro-7,8-diethylcarbamoyl-1-(4'"'"'-ethylcarbamoylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine. The R-enantiomers are the most biologically active and preferred compounds.

Claims

1. A compound of the structural formula:

##STR3## in which;

R₆ is halo; and

R₇, R₈ and R₄ are each independently hydrogen or --CONHR wherein R is lower alkyl having from one to four carbon atoms;

or a nontoxic pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1 in which R₆ is chloro.

3. The compound of claim 2 in which R₄, R₇ and R₈ are --CONHR.

4. The compound of claim 3 being 6-chloro-7,8-diethylcarbamoyl-1-(4'"'"'-ethylcarbamoylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine or one of its pharmaceutically acceptable acid addition salts.

5. The compound of claim 4 being the R-enantiomer.

6. The compound of claim 4 being the hydrochloride salt.

7. The compound of claim 4 being the free base.

8. The compound of claim 2 in which R₇ and R₈ are CONHR and R₄ is hydrogen.

9. The compound of claim 8 being 6-chloro 7,8-diethylcarbamoyl-1-(4'"'"'-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine or one ot its nontoxic pharmaceutically acceptable acid addition salts.

10. The method of inducing peripheral dopaminergic activity in a subject in need thereof comprising administering orally a nontoxic dopaminergic quantity of a compound of claim 1.

11. The method of inducing antihypertensive activity in a subject in need thereof comprising administering orally or by injection a nontoxic antihypertensive quantity of a compound of claim 1.

12. The method of claim 10 in which the compound is (R)-6-chloro-7,8-diethylcarbamoyl-(4'"'"'-ethylcarbamoylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine or one of its nontoxic pharmaceutically acceptable acid addition salts.

13. The method of claim 11 in which the route of administration is oral and the dosage unit is from about 50 to about 500 mg. of the compound.

14. A pharmaceutical composition having antihypertensive activity comprising a nontoxic antihypertensive quantity of a compound of claim 1.

15. The composition of claim 14 in which the compound is 6-chloro-7,8-diethylcarbamoyl-(4'"'"'-ethylcarbamoylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine or one of its pharmaceutically acceptable acid addition salts.

16. The composition of claim 15 in which the compound is present as the R-enantiomer.