Processes and intermediates for preparing benzo-fused...

Details Processes and intermediates for preparing benzo-fused... Processes and intermediates for preparing benzo-fused...

1998-12-04

2001-05-22

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Esters having the thiocarboxylate group, -cx-, wherein the...

C548S477000, C549S419000, C556S426000, C560S016000, C560S029000

Reexamination Certificate

active

06235922

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to novel benzo-fused azepinone and piperidinone compounds which are useful either as selective angiotensin converting enzyme inhibitors, or as dual inhibitors of both angiotensin converting enzyme and neutral endopeptidase. The present invention is also directed to pharmaceutical compositions containing such selective or dual action inhibitors and to methods of using such compositions, as well as to processes for preparing the novel inhibitors, novel intermediates, and processes for preparing such intermediates.
SUMMARY OF THE INVENTION
The novel compounds of this invention are benzo-fused, bicyclic oxa- or thiazepinones or piperidinones and include those compounds having the following formula I, and pharmaceutically acceptable salts thereof:
wherein:
Y
1
and Y
2
are each independently hydrogen, alkyl, aryl, halogen, or alkoxy;
X is O or S(O)
t
;
A is
R and R
6
are each independently hydrogen, alkyl, substituted alkyl, aryl-(CH
2
)
p
—, substituted aryl-(CH
2
)
p
—, heteroaryl-(CH
2
)
p
—, —CH(R
8
)—O—C(O)—R
9
, or
R
5
, R
5a
, and R
5b
are each independently hydrogen, alkyl, alkenyl, cycloalkyl, substituted alkyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, cycloalkyl-alkylene-, aryl-alkylene-, substituted aryl-alkylene-, and heteroaryl-alkylene-, or R
5a
and R
5b
may form, together with the carbon to which they are bonded, a 3 to 7 membered carbocyclic ring, where said ring is optionally substituted by alkyl, or by aryl which is fused or bonded by a single bond to said ring;
R
7
is hydrogen, R
8
—C(O)—, or R
12
—S—;
R
8
is hydrogen, alkyl, substituted alkyl, cycloalkyl-(CH
2
)
p
—, aryl-(CH
2
)
p
—, substituted aryl-(CH
2
)
p
—, heteroaryl-(CH
2
)
p
—, or
R
9
is hydrogen, alkyl, alkoxy, or aryl;
R
10
is alkyl, aryl-(CH
2
)
p
—, substituted aryl-(CH
2
)
p
—, or heteroaryl-(CH
2
)
p
—;
R
11
is alkyl, substituted alkyl, cycloalkyl-(CH
2
)
p
—, aryl-(CH
2
)
p
—, substituted aryl-(CH
2
)
p
—, or heteroaryl-(CH
2
)
p
—;
R
12
is hydrogen, alkyl, substituted alkyl, cycloalkyl-(CH
2
)
p
—, aryl-(CH
2
)
p
—, substituted aryl-(CH
2
)
p
—, or heteroaryl-(CH
2
)
p
—, or —S—R
12
completes a symmetrical disulfide wherein R
12
is
m is zero or one;
n is zero or one;
p is zero or an integer from 1 to 6;
t is zero, one or two;
q is zero or an integer from 1 to 3; and
r is zero or one.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described in further detail as follows.
Definitions
The term “alkyl” refers to straight or branched chain radicals having one to seven carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, tert-butyl, sec-butyl or n-butyl. The term “lower alkyl” refers to straight or branched chain radicals having one to four carbon atoms, and is a preferred subgrouping for the term alkyl.
The term “substituted alkyl” refers to such straight or branched chain radicals of 1 to 7 carbons wherein one or more, preferably one, two, or three, hydrogens have been replaced by a hydroxy, amino, cyano, halo, trifluoromethyl, —NH(lower alkyl), —N(lower alkyl)
2
, lower alkoxy, lower alkylthio, or carboxy group.
The term “alkylene” refers to divalent straight or branched chain radicals having one to seven carbon atoms, such as —CH
2
—, —(CH
2
)
2
—,
—(CH
2
)
3
—, —(CH
2
)
4
—, etc.
The terms “alkoxy” and “alkylthio” refer to such alkyl groups as defined above attached to an oxygen or sulfur, respectively.
The term “alkenyl” refers to straight or branched chain radicals of 2 to 7 carbon atoms having one or two double bonds. Preferred “alkenyl” groups are straight chain radicals of 3 to 5 carbons having one double bond.
The term “substituted alkenyl” refers to such straight or branched radicals of 2 to 7 carbons having one or two double bonds wherein a hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, —NH(lower alkyl), —N(lower alkyl)
2
, lower alkoxy, lower alkylthio, or carboxy group.
The term “cycloalkyl” refers to saturated rings of 3 to 7 carbon atoms with cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl being most preferred.
The term “carbocyclic ring” refers to a ring moiety wherein all of the ring atoms are carbon atoms.
The term “aryl” refers to phenyl, 1-naphthyl, and 2-naphthyl. The term “substituted aryl” refers to phenyl, 1-naphthyl, and 2-naphthyl having a substituent selected from lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, trifluoromethyl, amino, —NH(lower alkyl), or —N(lower alkyl)
2
, and di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, hydroxy, and amino.
The term “heteroaryl” refers to unsaturated rings of 5 or 6 atoms containing one or two O and/or S atoms and/or one to four N atoms provided that the total number of hetero atoms in the ring is 4 or less. The heteroaryl ring is attached by way of an available carbon or nitrogen atom. Preferred heteroaryl groups include 2-, 3-, or 4-pyridyl, 4-imidazolyl, 4-thiazolyl, 2- and 3-thienyl, and 2- and 3-furyl. The term heteroaryl also includes bicyclic rings wherein the five or six membered ring containing O, S, and/or N atoms as defined above is fused to a benzene or pyridyl ring. Preferred bicyclic rings are 2- and 3-indolyl and 4- and 5-quinolinyl. The mono or bicyclic heteroaryl ring can also be additionally substituted at an available carbon atom by a lower alkyl, halo, hydroxy, benzyl, or cyclohexylmethyl group. Also, if the mono- or bicyclic ring has an available N-atom, such N atom can also be substituted by an N-protecting group such as
2,4-dinitrophenyl, lower alkyl, benzyl, or benzhydryl.
The terms “halogen” or “halo” refer to chlorine, bromine, fluorine and iodine.
The term “acyl”, as used herein alone or as part of another group, denotes the moiety formed by the removal of the hydroxyl group from the group —COOH of an organic carboxylic acid.
The term “salt(s)” denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internal or inner salts) are included within the term “salt(s)” as used herein, as are quaternary ammonium salts such as alkylammonium salts. The nontoxic, pharmaceutically acceptable salts are preferred, although other salts may be useful, for example, in isolation or purification steps which may be employed during preparation.
Exemplary acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as amines (e.g., dicyclohexylamine, alkylamines such as t-butylamine and t-amylamine, substituted alkylamines, aryl-alkylamines such as benzylamine, dialkylamines, substituted dialkylamines such as N-methyl glucamine (especially, N-methyl-D-glucamine), trialkylamines, and substituted trialkylamines), and salts with amino acids such as arginine, lysine and so forth. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aryl-alkyl halides (e.g. benzyl and phenethyl bromides), and others.
Prodrugs and solvates of the inventive compounds are also contemplated herein. The term “prodrug”, as employed herein, denotes a compound which, upon admin

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