Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-08-03
2001-07-10
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S228200, C514S235200, C514S254090, C514S414000, C544S143000, C544S373000, C544S062000, C548S454000
Reexamination Certificate
active
06258800
ABSTRACT:
BACKGROUND OF THE INVENTION
Substance-P, widely distributed throughout the periphery and central nervous system, is believed to mediate a variety of biological actions, via an interaction with three receptor types referred to as NK
1
, NK
2
, and NK
3
, including smooth muscle contraction, pain transmission, neuronal excitation, secretion of saliva, angiogenesis, broncho-constriction, activation of the immune system and neurogenic inflammation.
Accordingly, compounds capable of antagonizing the effects of substance-P at NK
1
receptors will be useful in treating or preventing a variety of brain disorders including pain, anxiety, panic, depression, schizophrenia, neuralgia, and addiction disorders; inflammatory diseases such as arthritis, asthma, and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome, and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including Parkinson's disease, multiple sclerosis, and Alzheimer's disease; and ophthalmic diseases including scleroderma.
The compounds of the invention provide NK
1
receptor antagonists useful as anti-angiogenic agents for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis, and tumor cell growth. They will also be useful as agents for imaging NK
1
receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.
The compound, 2-benzofuranylmethyl [R-(R*,S*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]carbamate (hereinafter compound 1) is a highly selective NK
1
antagonist useful as a pharmacologic agent in the treatment of, for example, emesis. The chemical structure of compound 1 is
Compound 1, processes for its preparation, and methods of using it are claimed in U.S. Pat. No. 5,594,022 hereby incorporated by reference. U.S. patent application Ser. No. 60/021030 claims the use of compound 1 as an antiemetic; it is hereby incorporated by reference.
Compound 1 is poorly soluble in water (less than 1 &mgr;g/mL). Therefore, a suitable pharmaceutical formulation, especially an intravenous formulation, is not conveniently achievable using the parent drug substance. The instant invention is a solution to this problem; it is a prodrug of compound 1 with increased aqueous solubility, good solution stability, and high conversion rate to the parent compound in vivo by an enzyme such as an alkaline phosphotase or an esterase. The instant invention utilizes an attachment to the parent molecule, directly or indirectly, of biocleavable, ionizable group(s) such as a phosphate or an amino acid derivative for enhancing aqueous solubility. Due to the lack of readily derivatized functional groups, the only available sites of attachment on compound 1 are the nitrogen of the amide bond; the carbamate bond, and the indole moiety. Although prodrugs derived from amide and carbamate functionalities have been studied in the past, the nitrogen of the indole ring was selected as a more favorable site for prodrug derivatization due to its pKa, chemical reactivity, and relatively less steric encumbrance.
The use of indole nitrogen as the functional group for the preparation of prodrugs is not known in literature. It is the intention of this application to provide a novel prodrug approach by utilizing the indole nitrogen for the preparation of prodrugs. We have now discovered that a hydrophilic and ionizable group, such as a phosphate or an amino acid derivative attached directly or indirectly to an indole nitrogen, can be cleaved enzymatically in vivo. In the indirect attachment approach, a variety of self-cleavable linkers, which were reported to be useful for the hydroxy and amino functional groups in the preparation of prodrugs, were found to be also successful for the indole nitrogen. These linkers include hydroxymethyl (Varia S. A., Schuller S., Sloan K. B., Stella V. J., “Phenytoin prodrugs III: water-soluble prodrugs for oral and/or parenteral use,”
J. Pharm. Sci.,
1984;73: 1068-1073; TenHoor C. N., Stewart B. H., “Reconversion of fosphenytoin in the presence of intestinal alkaline phosphatase,”
Pharm. Res.,
1995;12:1806-1809), hydroxymethoxycarbonyI (Safadi M., Oliyai R., Stella V. J., “Phosphoryloxymethyl carbamates and carbonates-novel water-soluble prodrugs for amines and hindered alcohol,”
Pharmaceutical Res.,
1993;10:1350-1355), and masked lactones (Amsberry K. L., Borchardt R. T., “The lactonization of 2′-hydroxyhydrocinnamic acid amides: a potential prodrug for amines,”
J. Org. Chem.,
1990;55:5867-5877; Amsberry K. L., Gerstenberger A. E., Borchardt R. T., “Amine prodrugs which utilize hydroxy amide lactonization. II. A potential esterase-sensitive amide prodrug,”
Pharmaceutical Res.,
1991;8:455-461; Nicolaou M. G., Yuan C-S., Borchardt R. T., “Phosphate prodrugs for amines utilizing a fast intramolecular hydroxy amide lactonization,”
J Org. Chem.,
1996;61 :8636-8641). We have now also discovered that prodrugs of compound 1 derived from both phosphate and amino acid derivatives provide reasonable aqueous solubility and good bio-conversion to the parent compound in vivo.
SUMMARY OF THE INVENTION
The invention covers tachykinin antagonists. The compounds are nonpeptides which have proved to be highly selective and functional tachykinin antagonists. These compounds are unique in the alkylation/substitution pattern along their back bone.
Compounds of the invention are those of Formula I
or a pharmaceutically acceptable salt therof wherein
R is
—CH
2
OZ;
—C(═O)OCH
2
OZ or Z;
wherein Z is
—P(═O)(OH)
2
, or
—C(═O)Q;
n is an integer of from 0 to 3;
m is an integer of from 0 to 1;
R
3
and R
4
are each independently hydrogen or alkyl of from 1 to 6 carbons or R
3
and R
4
are taken together with the carbon to which they are attached to form a cycloalkylidene of from 3 to 6 carbons;
R
5
-R
9
are each independently hydrogen, halogen, alkyl, or alkoxy and one of R
5
-R
9
is —OC(═O)Q, OP(═O)(OH)
2
, —CH
2
OC(C═O)Q, —CH
2
OP(═O)(OH)
2
, —OH, CH
2
NR
1
R
2
, or NR
1
R
2
;
Q is alkyl optionally substituted by —OH, phosphono, phosphooxy, carboxy, or amino, monoalkylamino, or dialkylamino;
R
1
and R
2
are each independently hydrogen, alkyl optionally substituted with —OH, phosphono, phosphonooxy, carboxy, amino, monoalkylamino, or dialkyl amino or NR
1
R
2
is
Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat respiratory disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
Another aspect of the invention is a method for treating respiratory disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I.
Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat inflammation in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
Another aspect of the invention is a method for treating inflammation in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I.
Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat gastrointestinal disorders in a mammal suffering therefrom, and a pharmaceutically acceptable carrier.
Another aspect of the invention is a method for treating gastrointestinal disorders in a mammal such as a human comprising administering a therapeutically effective amount of a compound according to Formula I.
Another aspect of the invention is a pharmaceutical composition comprising an amount of a compound according to Formula I effective to treat eye diseases such as dry eye and conjunctivitis in a mammal suffering therefrom, and a pharmaceutically acceptable ca
Chan Oilun Helen
Chen Michael Huai Gu
Goel Om Prakash
Hershenson Fred M.
Zhu Zhijian
Anderson Elizabeth M.
Ashbrook Charles W.
D'Souza Andrea
Lambkin Deborah C.
Warner-Lambert & Company
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