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Substituted thioacetamidesRelated Patent Categories: Organic Compounds -- Part Of The Class 532-570 Series, Azo Compounds Containing Formaldehyde Reaction Product As The Coupling Component, Carbohydrates Or Derivatives, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbons, Chalcogen Bonded Directly To Ring Carbon Of The Six-membered Hetero Ring, Plural Chalcogens Bonded Directly To Ring Carbons Of The Six-membered Hetero RingSubstituted thioacetamides description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080027228, Substituted thioacetamides. Brief Patent Description - Full Patent Description - Patent Application Claims
REFERENCE TO RELATED APPLICATIONS [0001] The present application is a divisional of U.S. application Ser. No. 11/116,755, filed Apr. 28, 2005, which is a continuation of U.S. application Ser. No. 10/716,238, filed Nov. 18, 2003, now U.S. Pat. No. 6,919,367, which is a divisional of U.S. application Ser. No. 10/014,645 filed Oct. 26, 2001, now U.S. Pat. No. 6,670,358, which is a continuation-in-part of U.S. application Ser. No. 09/855,228 filed May 15, 2001, now U.S. Pat. No. 6,492,396, which claims priority to U.S. Provisional Application Ser. No. 60/204,789, filed May 16, 2000 and U.S. Provisional Application No. 60/268,283, filed Feb. 13, 2001. The disclosure of each of these applications and patents is hereby incorporated herein by reference in their entireties. FIELD OF THE INVENTION [0002] The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions that include substituted thioacetamides, and their use in the treatment of diseases, including treatment of sleepiness, promotion of wakefulness, treatment of Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation of appetite and weight gain, treatment of attention deficit hyperactivity disorder ("ADHD"), enhancing function in disorders associated with hypofunctionality of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic fatigue syndrome, and improvement of cognitive dysfunction. BACKGROUND OF THE INVENTION [0003] The compounds disclosed herein are related to the biological and chemical analogs of modafinil. Modafinil, C.sub.15H.sub.15NO.sub.2S, also known as 2-(benzhydrylsulfinyl)acetamide, or 2-[(diphenylmethyl) sulfinyl] acetamide, is a synthetic acetamide derivative with wake-promoting activity, the structure of which has been described in French Patent No. 78 05 510 and in U.S. Pat. No. 4,177,290 ('290), and which has been approved by the United States Food and Drug Administration for use in the treatment of excessive daytime sleepiness associated with narcolepsy. Modafinil has been tested for treatment of several behavioral conditions in combination with various agents including apomorphine, amphetamine, reserpine, oxotremorine, hypnotics, yohimbine, 5-hydroxytryptophan, and monoamine oxidase inhibitors, as described in the cited patents. A method of preparation of a racemic mixture is described in the '290 patent and a method of preparation of a levorotatory isomer is described in U.S. Pat. No. 4,927,855 (both incorporated herein by reference). The levorotatory isomer is reported to be useful for treatment of hypersomnia, depression, Alzheimer's disease and to have activity towards the symptoms of dementia and loss of memory, especially in the elderly. [0004] The primary pharmacological activity of modafinil is to promote wakefulness. Modafinil promotes wakefulness in rats (Touret et al., 1995; Edgar and Seidel, 1997), cats (Lin et al., 1992), canines (Shelton et al., 1995) and non-human primates (Hernant et al, 1991) as well as in models mimicking clinical situations, such as sleep apnea (English bulldog sleep disordered breathing model) (Panckeri et al, 1996) and narcolepsy (narcoleptic canine) (Shelton et al, 1995). [0005] Modafinil has also been described as an agent with activity in the central nervous system, and as a useful agent in the treatment of Parkinson's disease (U.S. Pat. No. 5,180,745); in the protection of cerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in the treatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776); and in the treatment of sleep apneas and disorders of central origin (U.S. Pat. No. 5,612,379). U.S. Pat. No. 5,618,845 describes modafinil preparations of a defined particle size less than about 200 microns. In addition, modafinil may be used in the treatment of eating disorders, or to promote weight gain or stimulate appetite in humans or animals (U.S. Provisional Patent Application No. 60/150,071, incorporated herein by reference), or in the treatment of attention deficit hyperactivity disorder (ADHD), or fatigue, especially fatigue associated with multiple sclerosis (U.S. Provisional Patent Application No. 60/149,612, incorporated herein by reference). [0006] Several published patent applications describe derivative forms of modafinil and the use of modafinil derivatives in the treatment of various disorders. For example, PCT publication WO 99/25329 describes analogs of modafinil in which the phenyl groups are substituted with a F, Cl, Br, CF.sub.3, NO.sub.2, NH.sub.2, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, or methylenedioxy, and in which the amide is substituted with OH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 hydroxyalkyl, or a C.sub.1-C.sub.4 hydrocarbon radical. These compositions are described as being useful for treating drug-induced sleepiness, especially sleepiness associated with administration of morphine to cancer patients. [0007] Similarly, U.S. Pat. No. 4,066,686 describes benzhydrylsulphinyl derivatives, including modafinil derivatives with an extended alkyl chain between the sulfinyl and carbonyl groups and where NR.sub.3R.sub.4 is NHOH. These compounds are described as being useful in therapy for treating disturbances of the central nervous system. [0008] PCT publication WO 95/01333 describes modafinil derivatives that are useful for modifying feeding behavior. The modifications to modafinil described include a chloro group at the 3 position of one of the phenyl groups, and a pyridyl substituted for the second phenyl, substitution of one or two methyl groups for hydrogens at the 2-carbon position, the amide hydrogens may be substituted with one or two groups selected from H, a pyridyl-methyl or ethyl groups, and further where the sulfur may not be oxidized. [0009] PCT publication WO 95/01171 also describes modified modafinil compounds that are said to be useful for modifying eating behavior. The described compounds include substitutions of 4-fluoro-, 3-fluoro-, and 4 chloro- in a first phenyl group and 4-fluoro- or 3-fluoro-substitutions in the second phenyl. Also described are substitutions in which the amide contains substitutions with an OH or isopropyl group. [0010] Terauchi, H, et al. described nicotinamide derivatives useful as ATP-ase inhibitors (Terauchi, H, et al, J. Med. Chem., 1997, 40, 313-321). In particular, several N-alkyl substituted 2-(Benzhydrylsulfinyl)nicotinamides are described. [0011] U.S. Pat. Nos. 4,980,372 and 4,935,240 describe benzoylaminophenoxybutanoic acid derivatives. In particular, sulfide derivatives of modafinil containing a phenyl and substituted phenyl linker between the sulfide and carbonyl, and a substituted aryl in the terminal amide position, are disclosed. [0012] Other modafinil derivatives have been disclosed wherein the terminal phenyl groups are constrained by a linking group. For example, in U.S. Pat. No. 5,563,169, certain xanthenyl and thiaxanthenyl derivatives having a substituted aryl in the terminal amide position are reported. [0013] Other xanthenyl and thiaxanthenyl derivatives are disclosed in Annis, I; Barany, G. Pept. Proc. Am. Pept. Symp. 15.sup.th (Meeting Date 1997) 343-344, 1999 (preparation of a xanthenyl derivative of Ellman's Reagent, useful as a reagent in peptide synthesis); Han, Y.; Barany, G. J. Org. Chem., 1997, 62, 3841-3848 (preparation of S-xanthenyl protected cysteine derivatives, useful as a reagent in peptide synthesis); and El-Sakka, I. A., et al. Arch. Pharm. (Weinheim), 1994, 327, 133-135 (thiaxanthenol derivatives of thioglycolic acid). [0014] Thus, there is a need for novel classes of compounds that possess beneficial properties. It has been discovered that a class of compounds, referred to herein as substituted thioacetamides, are useful as agents for treating or preventing diseases or disorders, including treatment of sleepiness, promotion of wakefulness, treatment of Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation of appetite and weight gain, treatment of attention deficit hyperactivity disorder, enhancing function in disorders associated with hypofunctionality of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic fatigue syndrome, and improvement of cognitive dysfunction. The present invention is directed to these, as well as other, important ends. SUMMARY OF THE INVENTION [0015] One aspect of the present invention provides, in part, various novel substituted thioacetamides. Other aspects of the invention also include their pharmaceutical compositions, methods of their preparation, and use of the compounds in the treatment of diseases. [0016] In one aspect of the invention, there are provided compounds of formula (I-A): Constituent members and preferred embodiments are disclosed in detail infra. [0017] In another aspect of the invention, there are provided compounds of formula (I): Constituent members and preferred embodiments are disclosed in detail infra. [0018] Another object of the present invention is to provide compounds of formula (II-A): Constituent members and preferred embodiments are disclosed in detail infra. [0019] An additional object of the present invention is to provide compounds of formula (II): Constituent members and preferred embodiments are disclosed in detail infra. [0020] Another object of the present invention is to provide methods of treating or preventing diseases or disorders, including treatment of sleepiness, promotion of wakefulness, treatment of Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation of appetite and weight gain, treatment of attention deficit hyperactivity disorder, enhancing function in disorders associated with hypofunctionality of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic fatigue syndrome, and improvement of cognitive dysfunction. Continue reading about Substituted thioacetamides... 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