you guys have explored the isotretoin/anti-androgen effects on sebum...which comes out to answer the question: what stimulates the sebaceous glands? But, the following article will answer, How are sebaceous glands formed, and how can we reduce them? You guys should focuse more on how sebaceous glands are formed and how to reduce the formation activity, not what stimulates them. here you go. This is a new type of research that i was trying to get at....but I found someone that thought the same as me
Method for decreasing sebum production
The present invention is directed to the topical application of the malonamide ACAT inhibitors described by Formula I. Other aspects of the invention are directed to topical formulations of these diamides, their use to treat sebaceous gland disorders and their use to alleviate oily skin.
Agent: Warner-lambert Company - Ann Arbor, MI, US
Inventors: Catherine R. Kostlan, Raj Neil Raheja, Meera Tugnait, Kimberly Wade
Class: 424070100 (USPTO), A61K007/06 (Intl Class)
Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application 60/509,984 filed Oct. 9, 2003.
FIELD OF THE INVENTION
[0002] The present invention is directed to the topical application of a class of diamide ACAT inhibitors. Other aspects of the invention are directed to topical formulations of these diamides, their use to treat sebaceous gland disorders and their use to alleviate oily skin.
BACKGROUND OF THE INVENTION
[0003] Human skin is composed of three primary layers, the stratum corneum, the epidermis, and the dermis. The outer layer is the stratum corneum. Its primary function is to serve as a barrier to the external environment. Lipids are secreted to the surface of the stratum corneum. These lipids decrease the stratum corneum's water permeability. Sebum typically constitutes 95% of these lipids. Abramovits et al, Dermatologic Clinics, Vol 18, Number 4, October 2000.
[0004] Sebum is produced in the sebaceous glands. These glands are present over most of the surface of the body. The highest concentration of these glands occurs on the scalp, the forehead and the face. Despite the important physiological role that sebum plays, many individuals experience excess sebum production, especially in the facial area. Excess sebum is associated with an increased incidence of acne. Even in individuals without acne, sebum can make the skin look greasy, decreasing its attractiveness. Abramovits et al, supra.
[0005] Current treatments for excess sebum are less than optimal. Accutane (isotretinoin) reduces sebum secretion by up to 90%. However, isotretinoin is associated with a number of serious side effects. It causes serious birth defects and is contraindicated in women of childbearing age. Thus, isotretinoin is only utilized for severe acne. It is inappropriate to use this drug merely as a cosmetic aid.
[0006] Acyl CoA cholesterol acyl transferase (ACAT) inhibitors were initially evaluated to treat elevated cholesterol. U.S. Pat. No. 6,133,326 discloses that ACAT inhibitors also reduce the secretion of sebum. While the '326 patent is a valuable contribution to the art, such treatments are not commercially available at the present time. Currently, the most practical means of alleviating excess sebum is frequent washings. Thus, a need exists in the art for new treatments that will reduce the secretion of sebum by the sebaceous glands.
SUMMARY OF THE INVENTION
[0007] A new method for decreasing the secretion of sebum, by the sebaceous glands, has been discovered. A class of ACAT inhibitors that exhibit superior activity in the inhibition of sebum secretion has been discovered. These ACAT inhibitors may be represented by Formula I: 1
[0008] in which R.sup.1 and R.sup.2 are each independently represented by hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, NR.sup.5R.sup.6, or SR.sup.7; X is represented by --CR.sup.8R.sup.9--(CH.sub.2).sub.n; R.sup.3 is represented by hydrogen, C.sub.1-6 alkyl, --(CH.sub.2).sub.q-Ph, or --(CH.sub.2).sub.q-M; p is represented by an integer from 1 to 4; R.sup.4 is represented by a substituent selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, NR.sup.5R.sup.6, and SR.sup.7; R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are each independently represented by hydrogen or C.sub.1-6 alkyl; Ph is represented by a phenyl ring which may be optionally substituted; M is represented by a 5- or 6-membered heteroaryl ring, containing 1 hetero-atom selected from the group N, S, or O; n and q are each independently represented by an integer from 0-4; a pharmaceutically acceptable salt thereof, or a prodrug thereof.
[0009] The compounds of Formula I may be administered to a patient to decrease the amount of sebum secreted by their sebaceous glands. Typically, the compounds will be administered topically to the areas exhibiting excess sebum production. Decreasing sebum secretion will alleviate a number of dermatological disorders and cosmetic complaints. These conditions include oily skin, oily hair, shiny skin, acne, and seborrheic dermatits.
[0010] The invention is also directed to pharmaceutical compositions containing at least one of the compounds of Formula I in admixture with a carrier suitable for topical administration. In a further embodiment, the invention is directed to an article of manufacture containing a compound of Formula I, packaged for retail distribution, in association with instructions advising the consumer on how to use the compound to alleviate a condition associated with excess sebum production. An additional embodiment is directed to the use of a compound of Formula I as a diagnostic agent to detect inappropriate sebum production. Other aspects of the invention are directed to the use of a compound of Formula I in the manufacture of a medicament for seborrhea.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The headings within this document are only being utilized expedite its review by the reader. They should not be construed as limiting the invention or claims in any manner.
[0012] A) Definitions and Exemplification
[0013] As used throughout this application, including the claims, the following terms have the meanings defined below, unless specifically indicated otherwise. The plural and singular should be treated as interchangeable, other than the indication of number:
[0014] a. "C.sub.1-C.sub.6 alkyl" refers to a branched or straight chained alkyl group containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, etc.
[0015] b. "C.sub.1-C.sub.6 alkoxy" refers to a straight or branched chain alkoxy group containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentoxy, n-hexyloxy, etc.
[0016] c. "halogen" refers to a chlorine, fluorine or bromine atom.
[0017] d. "optionally substituted phenyl" refers to a phenyl (--C.sub.6H.sub.5) which may be substituted with up to 3 substituents, each substituent is independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, NR.sup.5R.sup.6, or SR.sup.7. These substituents may be the same or different and may be located at any of the ortho, meta, or para positions.
[0018] e. "heteroaryl" refers to aromatic ring having a single heteroatom selected from oxygen, nitrogen and sulfur. More specifically, it refers to a 5-, or 6-, membered ring containing 1 nitrogen atom, 1 oxygen atom, or 1 sulfur atom. The 5-membered ring has 2 double bonds and the 6-membered ring has 3 double bonds. Examples of such heteroaryl ring systems include, but is not limited to pyrrolyl, furanyl, thiophenyl, and pyridinyl.
[0019] f. "pharmaceutically acceptable salts" is intended to refer to either pharmaceutically acceptable acid addition salts" or "pharmaceutically acceptable basic addition salts" depending upon actual structure of the compound.
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