(Acyloxyalkoxy)carbonyl derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs

• US 4,760,057 A
• Filed: 04/22/1985
• Issued: 07/26/1988
• Est. Priority Date: 06/23/1983
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Alexander, Jose
• Primary Examiner(s): Hollrah, Glennon H.
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US06/725,605
• Time in Patent Office: 1,191 Days
• Field of Search: 544/363, 544/358, 544/121, 544/135, 544/358, 544/363, 544/365, 560/165, 514/187, 548/146, 548/181, 548/201, 548/204
• US Class Current: 514/187
• CPC Class Codes: C07D 215/56 with oxygen atoms in position 4
• CPC Class Codes: C07D 285/10 1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

This invention relates to novel (acyloxyalkoxy)carbonyl derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs having a primary or secondary amine function thereon. Hydrolytic enzymes are used to trigger the regeneration of the parent amine drug of the carbamate prodrug moiety. The case also contains pharmaceutical composition, method of treatment and process claims.

Claims

1. A compound of the formula:

##STR4## wherein RR'"'"'N represents an amino substituted primary or secondary amine pharmaceutical;

R₁ and R₂ are selected from the group consisting of hydrogen, and substituted C_1-6 alkyl or alkyl wherein the substituents are carboxy or C_1-5 alkoxy carbonyl

R₃ is selected from the group consisting of

C_1-20 alkyl

C_2-20 alkenyl

C_2-5 alkynyl

aryl

C_6-8 aralkyl

C_3-8 cycloalkyl

C_3-10 cycloalkenyl

carboxy C_2-20 alkyl

carboxy C_5-20 cycloalkyl

halo (C_2-20) alkyl.

2. A compound of claim 1 wherein the RR'"'"'N group is an amino substituted primary or secondary amine pharmaceutical;

R₁ and R₂ are the same or different and are selected from the group consisting of

hydrogen and

C_1-5 alkyl and

R₃ is selected from the group consisting of

C_1-10 alkyl

carboxy C_2-10 alkyl and

C_1-5 alkoxy carboxyl C_2-10 alkyl.

3. A compound of claim 1 wherein the RR'"'"'N primary or secondary amine pharmaceutical is selected from the group consisting of timolol, thiabendazole, norfloxacin, dimethoxyphenethylamine, propranolol, atenolol, pindolol, methyldopa, epinephrine, dopamine, metoprolol, cartelolol, pipemidic acid, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid and 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperezinyl)-3-quinolinecarboxylic acid.

4. A compound of claim 1 which is 1-(Acetoxymethoxy)carbonyl-2-(4-thiazolyl)benzimidazole.

5. A compound of claim 1 which is 3-[3-(N-acetoxymethoxycarbonyl)tert-butylamino-2-hydroxypropoxy]-4-morpholino-l,2,5-thiadiazole.

6. A compound of claim 1 which is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(acetoxymethoxycarbonyl-1-piperazinyl]-3-quinolinecarboxylic acid.

7. A compound of claim 1 which is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[(4-octanoyloxymethoxycarbonyl)1-piperazinyl]-3-quinolinecarboxylic acid.

8. A compound of claim 1 which is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(1-acetoxyethoxycarbonyl)-1-piperazinyl]-3-quinolinecarboxylic acid.

9. A compound of claim 1 which is 1-[N-(1-acetoxyethoxycarbonyl)isopropylamino]-3-(1-naphthloxy)-2-propanol.

10. A pharmaceutical composition comprising a compound of claim 1 and a suitable pharmaceutical carrier.

11. A pharmaceutical composition comprising a compound of claim 2 and a suitable pharmaceutical carrier.

12. A pharmaceutical composition comprising a compound of claim 3 and a suitable pharmaceutical carrier.

13. A method for alleviating pain or disease symptoms in a warm-blooded animal exhibiting pain or disease symptoms which comprises administering thereto an anti-pain or anti-disease symptom effective amount of a compound of claim 1.

14. A method for alleviating pain or disease symptoms in or on a warm-blooded animal exhibiting pain or disease symptoms which comprises administering thereto an anti-pain or anti-disease symptom effective amount of a compound of claim 2.

15. A method for alleviating pain or disease symptoms in or on a warm-blooded animal exhibiting pain or disease symptoms which comprises administering thereto an anti-pain or anti-disease symptom effective amount of a compound of claim 3.