Whitby Research, Inc.

Nelson Research & Development Company

Other

Discovery Therapeutics, Inc.

Aderis Pharmaceuticals, Inc.

Whitby, Inc.

Durham Pharmaceuticals LLC

Gevork Minaskanian

James V Peck

Vithal J Rajadhyaksha

Eric L Nelson

Mark C Sleevi

L Meredith Moses

Jonathan Hadgraft

Keith Rippel

Process for preparing nitrogen-substituted aminotetralins

Methods for preventing the penetration of toxic chemicals through the stratum corneum of the skin of a mammal are disclosed which employ, as a penetration prevention agent, at least one compound selected from the group consisting of compounds represented by the formula: ##STR1## wherein W.sub.1 is a divalent oxygen, sulfur or nitrogen radical, W.sub.2 and W.sub.3 are independently a divalent oxygen or sulfur radical, R' is an alkyl radical comprising from 1 to 4 carbon atoms, y is 0 or 1, R.sub.1 and R.sub.2 are alkyl radicals comprising from 1 to 10 carbon atoms and R and R.sub.3 are individually a hydrocarbyl radical containing from 1 to 20 carbon atoms or a heteroatom-substituted derivative thereof wherein at least one but not two adjacent carbon atoms may be replaced by a divalent oxygen or sulfur radical or by NR', wherein R' is hydrogen or R', n is an integer from 2 to 5 and compounds represented by the above formula in which the ring and/or R includes one to three carbon carbon double bonds.

Topical compositions useful as skin penetration barriers

Compounds, topical compositions and methods useful for preventing the penetration of toxic chemicals through the skin of a mammal are disclosed. The compounds of the invention provide an enhanced barrier for the skin of a mammal to further inhibit or decrease the passage of bioactive agents through the skin of a mammal either from the outside environment into the systems of said mammal or from the mammal into the outside environment.

Cyclic amides and derivatives thereof

This invention relates to compounds and a method for their use in carrying physiologically active agents through body membranes such as skin and for retaining these agents in body tissues. More specifically, the invention relates to carboxylic acid derivatives and salts thereof, which compounds are useful in topically administering a physiologically active agent to a human or animal via a composition comprising the agent and an effective amount of a compound represented in one embodiment by the general formulae: ##STR1## wherein W represents oxygen, sulfur, or two hydrogen radicals; Z represents oxygen, sulfur, or --CH.sub.2 --;

Transdermal penetration enhancers

This invention relates to a method for administering systemically active agents through the skin or mucosal membranes of humans and animals and into the bloodstream in a transdermal device or formulation comprising topically administrating with said systemic agent an effective amount of a membrane penetration enhancer having the structural formula ##STR1## or the pharmaceutically acceptable salt thereof wherein W represents oxygen, sulfur or two hydrogen radicals; Z represents --CH.sub.2 --; R represents alkyl optionally substituted with one to three double or triple bonds, --SR'', --OR'', --NHR'', or --COOR.sub.1 ; R'' represents alkyl, alkylthioalkyl, alkoxyalkyl, amino alkyl, optionally substituted with a phenyl, or benzoyl; R' represents hydrogen, alkyl, alkoxy, acyloxy, alkylthio, hydroxy or --(CH.sub.2).sub.y COOR.sub.1 ; R' represents hydrogen or --(CH.sub.2).sub.y COOR.sub.1 ; R.sub.1, in each instance, independently represents hydrogen or lower alkyl; y, in each instance, is between zero and 3, inclusive; m is between one and 3, inclusive; n is between one and 24, inclusive; and x is zero or one, inclusive; with the provisos that when R' is hydrogen, then W is two hydrogen radicals and R' is not hydrogen; and when R' is hydrogen, then R' is not hydrogen. It has been found that the penetration enhancers are sufficient to carry physiologically active agents through body membranes and into the bloodstream.

Penetration enhancers for transdermal delivery of systemic agents

This invention relates to a method for administering systemically active agents including therapeutic agents through the skin or mucosal membranes of humans and animals and into the blood stream in a transdermal device or formulation comprising topically administering with said systemic agent an effective amount of a membrane penetration enhancer.

Optically active or racemic compounds are provided having the formula ##STR1## where R.sub.1 is ##STR2## where Y is hydrogen, halogen or C.sub.1 to C.sub.6 linear or branched alkyl; R.sub.6 is C.sub.1 to C.sub.4 linear or branched alkyl; X is oxygen or sulfur; a is an integer from zero to 3; and n is an integer from 1 to 4. The compounds are capable of binding selectively to dopamine D.sub.2 receptors and are useful in treatment of disorders of the central nervous, cardiovascular and endocrine systems, such as intraocular pressure, schizophrenia and Parkinsonism, and for inducing anorexia and weight loss in humans and other mammals.

Substituted 2-aminotetralins

Optically active or racemic compounds represented by the formula ##STR1## where R.sub.2 is OA and R.sub.3 is selected from the group consisting of H and OA; where A is H or is selected from the group consisting of hydrocarbyl radicals comprising between 1 and 3 carbon atoms, as well as ##STR2## with the proviso that when R.sub.3 is OA, then R.sub.2 and R.sub.3 may be bonded together to form the group R.sub.4 is selected from the group consisting of alkyl and aromatic residues having from 1 to 20, preferably from 1 to 12, carbon atoms, for example, alkyl, optionally substituted with aromatic residues, and aromatic residues optionally substituted with alkyl radicals; n is an integer from 1 to 4; R.sub.5 is an unbranched alkyl chain comprising from 1 and 3 carbon atoms or a cyclopropylmethyl radical; R.sub.1 is alkoxy, cycloalkoxy and a cyclic ether of the formula ##STR3## where m is an integer from 3 to 5; with the proviso that when R.sub.1 is alkoxy, then R.sub.3 cannot be H; and pharmaceutically-acceptable salts thereof. These compounds are useful for alleviating Parkinsonism, glaucoma, hyperprolactinemia and for inducing weight loss in mammals.

Optically active or racemic compounds are provided having the formula ##STR1## where R.sub.2, R.sub.3 and R.sub.4 are selected from the group consisting of H and OA with the provision that at least one of R.sub.2, R.sub.3 and R.sub.4 is H, that R.sub.2 and R.sub.4 are not both OA; A is H or is selected from the group consisting of hydrocarbyl radicals, said hydrocarbyl radicals being further optionally substituted with radicals selected from the group consisting of ##STR2## R.sub.5 is selected from the group consisting of alkyl and aromatic residues, preferably radicals having between 1 and 12 carbon atoms, including alkyl, alkyl substituted with aryl radicals, and aryl radicals substituted with alkyl radicals; n is an integer between 1 and 4; R.sub.6 is an alkyl chain comprising between 1 and 4 carbon atoms; X is oxygen; and R.sub.1 is selected from the group consisting of ##STR3## wherein Y is as defined in the specification, and a is an integer of from zero to 3. These compounds are useful in treatment of disorders of the central nervous, cardiovascular, and endocrine systems, such as for inducing anorexia and weight loss in humans.

Optically active or racemic compounds are provided having the formula ##STR1## where R.sub.2, R.sub.3 and R.sub.4 are each selected from the group consisting of H and OH with the provision that at least one of R.sub.2, R.sub.3 and R.sub.4 is H, that R.sub.2 and R.sub.4 are not both OH; X is oxygen; and R.sub.1 is selected from the group consisting of ##STR2## wherein Z is oxygen, nitrogen or sulfur, wherein Y is selected from the group consisting of hydroxy, nitro, cyano, azido, amino, acylamino, carboxyamido, trifluoromethyl, sulfate, sulfonamido, halogen, hydrocarbyl and heteroatom-substituted hydrocarbyl radicals, wherein said heteroatoms are selected from the group consisting of halogen, nitrogen, oxygen, sulfur and phosphorus and said hydrocarbyl radicals comprise from 1 to 12 carbon atoms, and a is an integer of from zero to 3. These compounds are capable of binding selectivity of one or more dopamine D.sub.2 receptors, for instance, in humans. They are useful in treatment of disorders of the central nervous, cardiovascular, and endocrine systems, such as elevated intraocular pressure, schizophrenia and Parkinsonism, and for inducing anorexia and weight loss in humans and other mammals.

This invention relates to a method for administering systemically active agents, including therapeutic agents, through the skin or mucosal membranes of humans and animals in a transdermal device or formulation comprising topically administering with said systemic agent a non-toxic, effective, penetrating amount of a membrane penetration enhancer having the structural formula ##STR1## wherein X represents sulfur or two hydrogen atoms; R' is H or a lower alkyl group having 1-4 carbon atoms; m is 2-6; n is 0-18 and R is --CH.sub.3, ##STR2## wherein R' is H or halogen.

This invention provides compositions comprising a physiologically-active agent and a compound having the structural formula ##STR1## wherein X may represent sulfur or two hydrogen atoms; R' is H or a lower alkyl group having 1-4 carbon atoms; m is 2-6; n is 0-18 and R is --CH.sub.3, ##STR2## wherein R' is H or halogen, in an amount effective to enhance the penetration of the physiologically-active agent through the skin or other membrane of the body of an animal.

Compositions comprising 1-substituted azacycloalkanes

This invention relates to a method for administering systemically active agents including therapeutic agents through the skin or mucosal membranes of humans and animals and into the blood stream in a transdermal device or formulation comprising topically administering with said systemic agent an effective amount of a membrane penetration enhancer being a carboxylic acid derivative or a salt thereof represented in one embodiment by the general formula ##STR1## wherein W represents oxygen, sulfur, or two hydrogen radicals; wherein Z represents oxygen, sulfur, or --CH.sub.2 --;

This invention provides compositions comprising a physiologically-active agent and a compound having the structural formula ##STR1## wherein X may represent sulfur or two hydrogen atoms; R' is H or a lower alkyl group having 1-4 carbon atoms; m is 2-6; n is 0-18 and R is --CH.sub.3, ##STR2## wherein R'' is H or halogen, in an amount effective to enhance the penetration of the physiologically-active agent through the skin or other membrane of the body of an animal.

N-substituted thiolactams

This invention relates to a method for administering systemically active agents including therapeutic agents through the skin or mucosal membranes of humans and animals in a transdermal device or formulation comprising topically administering with said systemic agent an effective amount of a membrane penetration enhancer having the structural formula ##STR1## wherein X is selected from the group consisting of oxygen and sulfur; R' is H or a lower alkyl group having 1-4 carbon atoms; m is 2-6; n is 0-17 and R is --CH.sub.3 ; wherein R is H or a lower alkyl group, m is 5-7 and n is 0-17.

Growing community of inventors

Irvine, CA, United States of America

Gevork Minaskanian