Imidazo-benzazepine compounds, their compositions and uses

Details Imidazo-benzazepine compounds, their compositions and uses Imidazo-benzazepine compounds, their compositions and uses

1999-09-21

2002-11-05

Coleman, Brenda (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S579000

Reexamination Certificate

active

06476020

ABSTRACT:

FIELD OF THE INVENTION
The subject invention relates to novel N-phenylmethyl-5,6-dihydroimidazo[5,1-a]benzazepin-3-amine compounds, pharmaceutical compositions containing them, and their therapeutic or preventative use in the areas of cardiovascular, oncology, infectious and inflammatory diseases.
BACKGROUND
Certain imidazo-isoquinoline compounds are disclosed in U.S. Pat. No. 3,917,610 issued Nov. 4, 1975; they are reported to have certain cardiovascular activities. One such compound is further reported on in Borchard, Fox, and Greeff, “The Positive Inotropic, Antiarrhythmic and Na
+
, K
+
-ATPase Inhibitory Effects of the Isoquinoline Derivative, BIlA”,
Achives of Pharmacology,
vol. 312 (1980), pp. 187-192.
SUMMARY OF THE INVENTION
The subject invention includes compounds having the structure:
wherein:
(a) The bond between C
&agr;
and N
&bgr;
is a single bond, or a double bond whereby R2 (and H on C
&agr;
) are nil;
(b) the bond between C
5
and C
6
is a single bond, or a double bond whereby R13 and R15 are nil; the bond between C
6
and C
7
is a single bond, or a doublebond whereby R11 and R13 are nil; but the C
5
-C
6
and C
6
-C
7
bonds are not both double bonds;
(c) R1 is selected from alkyl, aryl, and heterocycle;
(d) R2, if not nil, is selected from hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl and arylsulfonyl;
(e) R3, R4 and R5 are each independently selected from hydrogen, halo, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl- or aryl- or heterocycle-substituted hydroxy, thio, amino, amide, formyl (acyl), carboxy, and carboxamide; or R3 and R4 together are alkylene or heteroalkylene attached to adjacent carbons of the phenyl to which R3 and R4 are attached, and R5 is as specified in (e) above;
(f) R6, R7 and R8 are each independently selected from the group consisting of hydrogen, halo, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl- or aryl- or heterocycle-substituted hydroxy, thio, amino, amide, sulfonamide, formyl (acyl), carboxy, and carboxamide; or R6 and R7 together are alkylene or heteroalkylene attached to adjacent carbons of the phenyl to which R6 and R7 are attached, and R8 is as specified in (f) above;
(g) R9 is selected from hydrogen, halo, alkyl, aryl, heterocycle, and carboxy and its alkyl and aryl esters and amides;
(h) R10, R12 and R14, and R11, R13 and R15, if not nil, are each independently selected from hydrogen, alkyl, and aryl;
and an optical isomer, diestereomer or enantiomer thereof, a pharmaceutically acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.
The subject invention also includes compositions comprising a subject compound and a pharmaceutically-acceptable excipient; and methods for treating or preventing diseases or disorders by administering to a human or lower animal in need thereof, a safe and effective amount of a subject compound.
DETAILED DESCRIPTION OF THE INVENTION
As used herein unless specified otherwise, “alkyl” means a hydrocarbon chain which is branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted. The term “alkyl” may be used alone or as part of another word where it may be shortened to “alk” (e.g., in alkoxy, alkylacyl). Preferred linear alkyl have from one to about twenty carbon atoms, more preferably from one to about ten carbon atoms, more preferably still from one to about six carbon atoms, still more preferably from one to about four carbon atoms; most preferred are methyl or ethyl. Preferred cyclic and branched alkyl have from three to about twenty carbon atoms, more preferably from three to about ten carbon atoms, more preferably still from three to about seven carbon atoms, still more preferably from three to about five carbon atoms. Preferred cyclic alkyl have one hydrocarbon ring, but may have two, three, or more, fused hydrocarbon rings. Preferred alkyl are unsaturated with from one to about three double or triple bonds, preferably double bonds; more preferably they are mono-unsaturated with one double bond. Still more preferred alkyl are saturated. Saturated alkyl are referred to herein as “alkanyl”. Alkyl unsaturated only with one or more double bonds (no triple bonds) are referred to herein as “alkenyl”. Preferred substituents of alkyl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted alkyl are preferred.
As used herein, “heteroatom” means a nitrogen, oxygen, or sulfur atom.
As used herein, “alkylene” means an alkyl which connects two other moieties, “heteroalkylene” means an alkylene having one or more heteroatoms in the connecting chain.
As used herein unless specified otherwise, “aryl” means an aromatic hydrocarbon ring (or fused rings) which is substituted or unsubstituted. The term “aryl” may be used alone or as part of another word (e.g., in aryloxy, arylacyl). Preferred aryl have from six to about fourteen, preferably to about ten, carbon atoms in the aromatic ring(s), and a total of from about six to about twenty, preferably to about twelve, carbon atoms. Preferred aryl is phenyl or naphthyl; most preferred is phenyl. Preferred substituents of aryl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted aryl are preferred.
As used herein unless specified otherwise, “heterocycle” means a saturated, unsaturated or aromatic cyclic hydrocarbon ring (or fused rings) with one or more heteroatoms in the hydrocarbon ring(s). Preferred heterocycles have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms in the ring(s). Preferred heterocycles have from three to about fourteen, preferably to about ten, carbon plus heteroatoms in the ring(s), more preferably from three to about seven, more preferably still five or six, carbon plus heteroatoms in the rings(s); and a total of from three to about twenty carbon plus heteroatoms, more preferably from three to about ten, more preferably still five or six, carbon plus heteroatoms. Preferred heterocycles have one ring, but may have two, three, or more, fused rings. More preferred heterocycle rings include those which are one ring with 5 or 6 carbon plus heteroatoms in the ring with no more than three ring heteroatoms, no more than two of which are O and S. Still more preferred are such 5- or 6-ring atom heterocycles with one or two ring atoms being O or S and the others being C; or with one, two or three ring atoms being N and the others being C. Such preferred 5- or 6-ring atom heterocycles are preferably saturated, unsaturated with one or two double bonds, or aromatic. Such preferred 5- or 6-ring atom heterocycles are preferably a single ring; or fused with a 3- to 6-ring atom hydrocarbon ring which is saturated, unsaturated with one double bond, or aromatic (phenyl); or fused with another such 5- or 6-ring atom heterocyclic ring. Heterocycles are unsubstituted or substituted. Preferred heterocycle substituents are the same as for alkyl.
COMPOUNDS OF THE INVENTION
The subject invention involves compounds having the following structure:
In structure 1, the bond between the &agr; carbon and the &bgr; nitrogen can be either a single bond, in which case R2 and the H attached to the &agr; carbon exist, or a double bond, in which case R2 and that H do not exist (are nil). This C
&agr;
-N
&bgr;
bond is preferably a single bond.
In structure 1, the bonds between carbons 5 and 6 and between carbons 6 and 7 can both be single bonds or one can be a double bond. If the C
5
-C
6
bond is a double bond, R13 and R15 do not exist (are nil). If the C
6
-C
7
bond is a double bond, R11 and R13 do not exist (are nil). Preferably, the C
5
-C
6
and C
6
-C
7
bonds are

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