Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-25
2004-12-14
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S937000, C424S452000, C424S455000
Reexamination Certificate
active
06831079
ABSTRACT:
This applications concerns new formulations for a class of tricyclic vasopressin agonist compounds, and pharmaceutically acceptable salts thereof, as well as processes for manufacturing the formulations. The invention particularly relates to orally administered formulations of these compounds.
Background of the Invention
The art describes many methods of producing liquid or semi-solid encapsulated pharmaceutical formulations. In Bull. Tech./Gattefosse Rep. (1996), 89, 27-38, authors Shah et al. describe hard gelatin capsule technology, particularly for use in enhancing the bioavailability of poorly soluble or poorly absorbed drugs.
U.S. Pat. No. 4,620,974 (Hersh et al.) teaches a hard gelatin capsule comprising a telescoping two-piece cap with a lubricant comprising a polyethylene glycol of a molecular weight between about 200 and about 900 present in admixture with the composition at a concentration of from about 0.5 to about 25 weight percent.
WO 96/40071 (Lamberti) discloses methods and devices for producing minimal volume capsules. WO 96/41622 (Tanner et al.) teaches suspensions suitable for encapsulation in gelatin capsules, particularly including a solid phase of solid particles and a liquid phase capable of suspending the solid phase.
U.S. Pat. No. 5,641,512 (Cimiluca) teaches soft gelatin encapsulated analgesics in which the shell contains a xanthine derivative, such as caffeine.
U.S. Pat. No. 4,578,391 (Kawata et al.) describes oily compositions for antitumor agents comprising at least one sparingly oil soluble or water-soluble antitumor drug, at least one fat or oil, and at least one solubilizing adjuvant in an oily vehicle, selected from crown ether, lecithin, polyethylene glycol, propylene glycol, vitamin E, polyoxyehtylene alkylether, and sucrose esters of fatty acids.
EP 0 815 854 A1 discloses a substantially translucent, semi-solid fill material for a soft gelatin capsule, the semi-solid material being sufficiently viscous that it cannot be expelled from the capsule with a syringe at room temperature.
U.S. Pat. No. 4,744,988 (Brox) teaches soft gelatin capsules comprising a shell of gelatin, a softener and a filling of a polyethylene glycol and a low polyhydric alcohol and at least one active substance, characterized in that the shell contains 4 to 40 percent sorbital or sorbitanes, at least half of the weight of polyethylene glycol used is a polyethylene glycol having a mean molecular weight of 600, and the capsule filling comprises up to 20% by weight of glycerol and/or 1,2-propylene glycol.
WO 95/19579 (Dhabhar) teaches a process for solubilizing difficulty soluble pharmaceutical agents in a mixture of polyethylene glycol and propylene glycol by using a polyvinylpyrrolidone with a specific viscosity average molecular weight of from about 5,000 to about 25,000.
SUMMARY OF THE INVENTION
This invention provides orally administerable formulations for tricyclic vasopressin agonist compounds, or the pharmaceutically acceptable salts thereof, singularly or collectively optionally referred to herein as “active ingredient”, which have the structure:
wherein:
A, B, E, G are, independently, CH or nitrogen;
D is, independently, C—W or nitrogen;
R
1
is alkanoyl of 2 to 7 carbon atoms, a group selected from CN, COOH, CONH
2
,
or a moiety selected from the group:
R
2
, R
3
and R
5
are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6 carbons;
R
4
is hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxyalkyl of 2 to 7 carbon atoms, or an acyl substituent selected from the group consisting of alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, cycloalkanoyl of 3 to 7 carbon atoms, aroyl, or arylalkanoyl;
and Y are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, perfluoroalkyl of 1 to 6 carbons, alkoxyalkyl of 2 to 7 carbon atoms, halogen (including chlorine, bromine, fluorine, and iodine), alkoxy of 1 to 6 carbons, hydroxy, CF
3
, or perfluoroalkyl of 2 to 6 carbons;
W is hydrogen, halogen (preferably chloro, bromo or iodo), alkyl, alkoxyalkyl of 2 to 7 carbons, hydroxyalkyl of 1 to 6 carbons, or CH
2
NR
6
R
7
;
R
6
and R
7
are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms; or, taken together with the nitrogen atom of CH
2
NR
6
R
7
, R
6
and R
7
form a five or six membered ring optionally containing one or more additional heteroatoms such as, but not limited to, those of the group:
R
8
is a straight chain alkyl of 1 to 6 carbon atoms
R
9
is independently hydrogen, trimethylsilyl or a straight chain alkyl of 1 to 6 carbon atoms;
or a pharmaceutically acceptable salt, ester or prodrug form thereof.
Among the more preferred active ingredient compounds of the formulations of this invention are those of the formula:
wherein:
A and B are, independently, CH or nitrogen;
D is C—W or nitrogen;
R
1
is alkanoyl of 2 to 7 carbon atoms or a group selected from
R
2
, R
3
and R
5
are, independently, hydrogen, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or perfluoroalkyl of 1 to 6 carbons;
R
4
, X, Y, W, R
6
, R
7
and R
8
are as defined above;
or a pharmaceutically acceptable salt thereof.
For the compounds defined above and referred to herein, unless otherwise noted, aroyl groups include, for example, benzoyl, naphthoyl which can be substituted independently with one or more substituents from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbons, CF
3
, or phenyl.
Heteroaroyl groups herein refer to a carbonyl (radical ) directly bonded to a carbon atom of a five membered heterocyclic ring having one or two heteroatoms selected from nitrogen, oxygen, sulfur, for example 2-thienoyl. The heterocyclic ring of the heteroaroyl groups may also include, but are not limited to, groups in which the aryl portion is a furan, pyrrole, 2H-pyrrole, imidazole, pyrazole, isothiazole, isoxazole, thiophene, pyrazoline, imidazolidine or pyrazolidine group. The heteroaryl groups herein can be substituted independently with one or more substituents from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, or branched chain alkyl of 3 to 7 carbon atoms.
The arylalkanoyl groups herein refer to a carbonyl group or radical directly bonded to an alkyl group of 1 to 6 carbon atoms which is terminally substituted by an aryl group, for example, phenylacetic acid. The aryl group can be substituted independently with one or more substituents from the group of hydrogen, halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbons, CF
3
, or phenyl or substituted phenyl where the substituents are selected from halogen, cyano, straight chain alkyl of 1 to 6 carbon atoms, branched chain alkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbons, CF
3
.
The halogens referred to herein may be selected from fluorine, chlorine, bromine or iodine, unless otherwise specified.
It is understood by those practicing the art that the definition of the compounds of formula (I), when R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, X, or Y contain symmetric carbons, encompass all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses any optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof, which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques. It is also understoo
Fawzi Mahdi
Saunders Richard W
Yoon Joseph K.
American Cyanamid Company
Fay Zohreh
Kwon Brian-Yong
Mazzarese Joseph M.
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