Labile quaternary ammonium salts as prodrugs

• US 4,727,151 A
• Filed: 11/22/1978
• Issued: 02/23/1988
• Est. Priority Date: 06/24/1974
• Status: Expired due to Term

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Interx Research Corporation
• Inventors: Bodor, Nicolae S.
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): WHITTENBAUGH, ROBERT
• Application Number:
  US05/962,948
• Time in Patent Office: 3,380 Days
• Field of Search: 549/68, 549/74, 549/77, 544/358, 544/42, 544/178, 544/41, 546/334, 546/216, 546/79, 546/197, 546/315, 546/221, 546/281, 546/127, 546/238, 546/156, 546/225, 546/224, 546/174, 546/335, 548/556, 548/427, 548/524, 548/568, 548/311, 540/485, 560/250, 560/253, 560/1, 560/187, 560/226, 560/229, 560/122, 560/123, 560/124, 560/228, 560/110, 560/19, 560/74, 560/58, 260/455 R
• US Class Current: 546/174
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 487/08 Bridged systems

Abstract

Labile quaternary ammonium salts of the following formula (I) and (II) are provided: ##STR1## wherein N represents a tertiary aliphatic amine; wherein N represents an unsaturated amine; wherein R represents a member selected from the group consisting of a hydrogen atom, a C₁ -C₈ open chain or cyclo alkyl group, a C₁ -C₈ alkoxyalkyl group, a C₁ -C₈ acyloxyalkyl group, a C₁ -C₈ haloalkyl group, a C₁ -C₈ carboxyalkyl group, a C₂ -C₈ alkenylphenyl group, an aryl group, and a substituted aryl group, whose substituents are selected from the group consisting of a halogen atom, an O-lower alkyl (C₁ -C₄) group, an O-acyl group, a nitro group, a carboxyl group, and a carboethoxy group; wherein R₁ which may be the same or different, represents any member defined by R above with the proviso that R₁ cannot be a hydrogen atom; wherein X is --O-- or --S--; and wherein Y represents a member selected from the group consisting of a halogen atom or any other organic or inorganic monovalent equivalent anion; with the further proviso that N and N, respectively cannot represent trimethylamine and pyridine or quinoline when R represents a hydrogen atom and R₁ represents a methyl group or a phenyl group. The compounds described above are characterized by their extreme solubility and resistance to oxidation, dealkylation, and protonation prior to chemical and/or enzymatic hydrolysis. Upon chemical and/or enzymatic hydrolysis, these compounds will "cleave," thus releasing their active constituent or constituents, according to the following general scheme(s): ##STR2## In other words, the title compounds hydrolyze (chemically or enzymatically) releasing a tertiary amine or unsaturated amine derivative, an aldehyde, a carboxylic acid and a hydrogen halide (HX) per the above reaction scheme.

Claims

1. A labile quaternary ammonium salt being capable of cleavage upon chemical or enzymatic hydrolysis to deliver a pharmacologically active tertiary amine and having the structural formulas (I) ##STR310## wherein N.sup.⊕

-- is a pharmacologically active tertiary amine moiety selected from the group consisting of

lidocaine;

3. The compound of claim 1 which is

(a) ω

-(Diethyl-benzoyloxymethyl-ammonium)-2,6-dimethylacetanilide chloride;

(b) ω

-(Diethyl-benzoyloxybenzoyl-ammonium)-2,6-dimethylacetanilide chloride;

(c) ω

-[Diethyl-(α

-benzoyloxyethyl)-ammonium]-2,6-dimethylacetanilide chloride;

(d) [6,8-Dichloro-α

-[dibutylaminomethyl]-2-[3'"'"',4'"'"'-dichlorophenyl-4-quinolinemethyl-N]-benzoyloxymethyl-[N,N-dimethylglycinate chloride];

(e) [6,8-Dichloro-α

-[dibutylaminomethyl]-2-[3'"'"',4'"'"'-dichlorophenyl]-4-quinolinemethyl-N]-[α

-benzoyloxybenzyl]-[N,N-dimethylglycinate chloride];

(f) 3-[Dibutylamino]-1-[(2,6-bis-trifluoromethylphenyl)-4-pyridyl]propanol-N-benzoyloxymethyl-N,N-dimethylglycinate chloride;

(g) 3-[Dibutylamino]-1-[(2,6-bis-trifluoromethylphenyl)-4-pyridyl]propanol-N-pivalyloxymethyl-N,N-dimethylglycinate chloride;

(h) N,N-Dimethyl-N-hexanoyloxymethyl-N'"'"'-phenyl-N'"'"'-(2-thenyl)ethylenediammonium chloride;

(i) β

-Dimethylaminoethyl (p-chloro-α

-methyl benzhydryl)ether-N-benzoyloxymethyl chloride;

(j) N-Ethylephedrine (α

-benzoyloxyethyl)chloride;

(k) 2-Diethylaminopropiophenone (α

-benzoyloxyethyl)chloride;

(l) (Bicyclohexyl)-1-carboxylic acid 2-(diethylamino)-ethyl ester N-hexanoyloxymethyl chloride;

(m) Diphenylthioacetic acid 5-(2-diethylaminoethyl)ester-N-thioacetyl chloride;

(n) 6-Dimethylamino-4,4-diphenyl-3-heptanone-N-(p-toluyloxymethyl)chloride;

2. 8-Dichloro-α

-[dibutylaminomethyl]-2-[3'"'"',4'"'"'-dichlorophenyl]-4-quinolinemethyl-N,N-dimethyl glycinate;

3-[Dibutylamino]-1-[2,6-bis-trifluoromethylphenyl)-4-pyridyl]propanol-N,N-dimethylglycinate;

N,N-Dimethyl-N'"'"'-phenyl-N'"'"'-(2-thienyl)-ethylenediammonium;

β

-Dimethylaminoethyl(p-chloro-α

-methyl benzhydryl)ether;

N-Ethylephedrine;

2-Diethylaminopropiophenone;

(Bicyclohexyl)-1-carboxylic acid 2-(diethylamino)-ethyl ester;

Diphenylthioacetic acid 5-(2-diethylaminoethyl)ester;

6-Dimethylamino-4,4-diphenyl-3-heptanone;

chlorcyclizine;

methapheniline;

pyrathiazine;

pyrilamine;

chlorophenoxamine;

clemastine;

diphenylpyraline;

doxylamine;

phenindamine;

cyclizine;

etafedrine acetate;

benzphetamine;

phendimetrazine;

cinnamedrine acetate;

piperoxan;

arecoline;

physostigmine;

adiphenine;

dicylomine;

piperidolate;

thiphenamil;

pipoxolan;

tremorine;

nicotine;

cocaine;

piperocaine;

dibucaine;

mepivacaine;

pyrrocaine;

fentanyl;

benzydamine;

methadone;

propoxyphene;

chlorpromazine;

diazepam;

or

cotinine;

R is hydrogen

C₁ -C₈ alkyl,

C₃ -C₈ cycloalkyl,

C₂ -C₈ alkoxyalkyl,

C₁ -C₈ haloalkyl,

C₆ -C₁₀ aryl or

substituted C₆ -C₁₀ aryl whose substituents are selected from the group consisting of

halogen,

C₁ -C₄ alkoxy,

nitro,

carboxyl, and

carboethoxy;

R₁ which can be the same as or different from R, is any member of the group defined by R above, with he proviso that R₁ cannot be a hydrogen atom;

X is --O-- or --S--; and

Y is halogen or an equivalent nontoxic pharmaceutically acceptable organic or inorganic monovalent anion.