The present invention is directed to chemical compositions of substituted thioacetamides, processes for the preparation thereof and uses of the compositions in the treatment of diseases.
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wherein
wherein Ar1 and Ar2 are the same or different and are each selected from thiophene, isothiazole, phenyl, pyridyl, oxazole, isoxazole, thiazole, imidazole thienyl, isothiazolyl, phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, and other five or six membered heterocycles comprising 1-3 atoms of —N—, —O—, or —S—, provided that Ar1 and Ar2 are not both phenyl and when Ar1 is phenyl, Ar2 is not pyridyl;
R1-R4 are the same or different and are each selected from H, lower alkyl, —OH, and —CH(R6)—CONR6AR6B, or any of R1-4 R1-R4 can be taken together to form a 3-7 member carbocyclic or heterocyclic ring, provided that R3 and R4 are not both OH; R6 is H, C1-C4 alkyl, or the side chain of an α-amino acid; R6A and R6B are independently H or lower alkyl; and
n is 0, 1, or 2; and
in addition, each of Ar1 or Ar2 may be independently optionally substituted with one or more substituents independently selected from:
a) H, aryl, heterocyclyl, F, Cl, Br, I, —CN, —CF3, —NO2, —OH, —OR7, —O(CH2)pNR9R10, —OC(═O)R7, —OC(═O)NR9R10, —O(CH2)pOR8, —CH2OR8, —NR9R10, —NR8S(═O)2R7, —NR8C(═O)R7, or —NR8C(═S)R7;
b) —CH2OR11, where R11 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
c) —NR8C(═O)NR9R10, —NR8C(═S)NR9R10, —CO2R12, —C(═O)R12, —C(═O)NR9R10, —C(═S)NR9R10, —CH═NOR12, —CH═NR7, —(CH2)pNR9R10, —(CH2)pNHR11, or —CH═NNR12R12A, where R12 and R12A are the same or different and each are independently selected from H, alkyl of 1 to 4 carbons, —OH, alkoxy of 1 to 4 carbons, —OC(═O)R7, —OC(═O)NR9R10, —OC(═S)NR9R10, —O(CH2)pNR9R10, —O(CH2)pOR8, substituted or unsubstituted arylalkyl having from 6 to 10 carbons, and substituted or unsubstituted heterocyclylalkyl;
d) —S(O)yR12, —(CH2)pS(O)yR7, —CH2S(O)yR11 where y is 0, 1 or 2; and
e) alkyl of 1 to 8 carbons, alkenyl of 2 to 8 carbons, or alkynyl of 2 to 8 carbons, where:
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl or alkynyl group is substituted with 1 to 3 groups selected from aryl of 6 to 10 carbons, heterocyclyl, arylalkoxy, heterocycloalkoxy, hydroxylalkoxy, alkyloxyalkoxy, hydroxyalkylthio, alkoxy-alkylthio, F, Cl, Br, I, —CN, —NO2, —OH, —OR7, —X2(CH2)pNR9R10, —X2(CH2)pC(═O)NR9R10, —X2(CH2)pC(═S)NR9R10, —X2(CH2)pOC(═O)NR9R10, —X2(CH2)pCO2R7, —X2(CH2)pS(O)yR7, —X2(CH2)pNR8C(═O)NR9R10, —OC(═O)R7, —OC(═O)NHR12, O-tetrahydropyranyl, —NR9R10, —NR8CO2R7, —NR8C(═O)NR9R10, —NR8C(═S)NR9R10, —NHC(═NH)NH2, —NR8C(═O)R7, —NR8C(═S)R7, —NR8S(═O)2R7, —S(O)yR7, —CO2R12, —C(═O)NR9R10, —C(═S)NR9R10, —C(═O)R12, —CH2OR8, —CH═NNR12R12A, —CH═NOR12, —CH═NR7, —CH═NNHCH(N═NH)NH2, —S(═O)2NR12R12A, —P(═O)(OR8)2, —OR11, and a monosaccharide of 5 to 7 carbons where each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl of 1 to 4 carbons, alkylcarbonyloxy of 2 to 5 carbons, or alkoxy of 1 to 4 carbons, where X2 is O, S, or NR8; where
R7 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl;
R8 is H or alkyl having from 1 to 4 carbons;
p is from 1 to 4; and where either
1) R9 and R10 are each independently H, unsubstituted alkyl of 1 to 4 carbons, or substituted alkyl of 1 to 4 carbons; or
2) R9 and R10 together form a linking group of the formula —(CH2)2—X1—(CH2)2—, wherein X1 is selected from —O—, —S—, and —CH2—;
and the a stereoisomeric forms, mixtures form, mixture of a stereoisomeric forms, or form, pharmaceutically acceptable salt and form, or ester forms form thereof.
wherein:
Ar1 and Ar2 are each independently selected from C6-C10 aryl or heteroaryl;
wherein each of Ar1 or Ar2 may be independently optionally substituted with 1-3 substituents independently selected from:
a) H, C6-C10 aryl, heteroaryl, F, Cl, Br, I, —CN, —CF3, —NO2, —OH, —OR7, —O(CH2)pNR9R10, —OC(═O)R7, —OC(═O)NR9R10, —O(CH2)pOR8, —CH2OR8, —NR9R10, —NR8S(═O)2R7, —NR8C(═O)R7, or —NR8C(═S)R7;
b) —CH2OR11;
c) —NR8C(═O)NR9R10, —NR8C(═S)NR9R10, —CO2R12, —C(═O)R13, —C(═O)NR9R10, —C(═S)NR9R10, —CH═NOR12, —CH═NR7, —(CH2)pNR9R10, —(CH2)pNHR11, —CH═NNR12R12A, —C(═NR8)NR8AR8B, —NR8C(═NH)R8A, —NR8C(═NH)NR8AR8B,
##STR00079##
—NR8C(═NH)NR8AR8B,
d) —S(O)yR7, —(CH2)pS(O)yR7, —CH2S(O)yR7 ; and
f) e) C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl, where:
3) 1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
4) 2) each alkyl, alkenyl or alkynyl group is independently substituted with 1 to 3 groups independently selected from C6-C10 aryl, heteroaryl, F, Cl, Br, I, CF3, —CN, —NO2, —OH, —OR7, —CH2OR8, —NR9R10, —O—(CH2)p—OH, —S—(CH2)p—OH, —X1(CH2)pOR7, X1(CH2)pNR9R10, —X1(CH2)pC(═O)NR9R10, —X1(CH2)pC(═S)NR9R10, —X1(CH2)pOC(═O)NR9R10, —X1(CH2)pCO2R8, —X1(CH2)pS(O)yR7, —XS(CH2)pNR8C(═O)NR9R10 —X1(CH2)pNR8C(═O)NR9R10, —C(═O)R13, —CO2R12, —OC(═O)R7, —C(═O)NR9R10, —OC(═O)NR12R12A, O-tetrahydropyranyl, —C(═S)NR9R10, —CH═NNR12R12A, —CH═NOR12, —CH═NR7, —CH═NNHCHCN═NH)NH2 —CH═NNHCH(N═NH)NH2, —NR8CO2R7, —NR8C(═O)NR9R10, —NR8C(═S)NR9R10, —NHC(═NH)NH2, —NR8C(═O)R7, —NR8C(═S)R7, —NR8S(═O)2R7, —S(O)yR7, —S(═O)2NR12R12A, —P(═O)(OR8)2, —OR11, and a C5-C7 monosaccharide where each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, C1-C4 alkyl, C1-C4 alkoxy, or —O—C(═O)R7;
X1 is —O—, —S—, —N(R8)—;
Y is selected from C1-C4 alkylene, —C(R1)(R2)—, wherein R1 and R2 are each independently H or C1-C6 alkyl; or either R1 or R2 is combined with either R3 or R4 to form a 5-7 membered heterocyclic ring, C6-C10 arylene, heteroarylene, C3-C8 cycloalkylene, heterocyclylene, —O—, —N(R8)—, —S(O)y, —CR9A═CR8B— —CR8A═CR8B—, —CH═CH—CH(R8)—, —CH(R8)—CH═CH—, or and —C≡C—; with the proviso that when Y is —O—, —N(R8)—, or —S(O)y, m and n cannot be 0;
R3 and R4 are the same or different and are each selected from H, C1-C6 alkyl, —OH, and —CH(R6)—CONR8AR8B, provided that R3 and R4 are not both OH; or R3 and R4, together with the nitrogen to which they are attached, form a 3-7 member heterocyclyl ring;
R6 is H, C1-C4 alkyl or the side chain of an α-amino acid;
R7 is C1-C6 alkyl, C6-C10 aryl, or heteroaryl;
R8, R8A and R8B are each independently H, C1-C4 alkyl, or C6-C10 aryl;
R9 and R10 are independently selected from H, C1-C4 alkyl, and C6-C10 aryl; or R9 and R10 together with the nitrogen to which they are attached, form a 3-7 member heterocyclyl ring;
R11 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;
R12 and R12A are each independently selected from H, C1-C6 alkyl, cycloalkyl, C6-C10 aryl, and heteroaryl; or R12 and R12A, together with the nitrogen to which they are attached, form a 5-7 member heterocyclyl ring;
R13 is H, C1-C6 alkyl, cycloalkyl, C6-C10 aryl, heteroaryl, —C(═O)R7, —C(═O)NR9R10, or —C(═S)NR9R10;
m is 0, 1, 2 or 3;
n is 0, 1, 2 or 3;
p is from 1, 2, 3, or 4;
q is 0, 1, or 2;
t is 2, 3, or 4;
y is 0, 1 or 2;
with the proviso that when Ar1 is phenyl and Ar2 is phenyl or pyridyl, then Y cannot be C1-C4 alkylene, or C(R1R2), wherein R1 and R2 are H or C1-C6 alkyl;
with the further proviso that when Ar1 and Ar2 are phenyl, q=1, m and n=0, Y is
##STR00080##
and R3 is H, then R4 is not C1-C6 alkyl;
and the a stereoisomeric forms, mixtures form, mixture of a stereoisomeric forms, or form, pharmaceutically acceptable salt and form, or ester forms form thereof.
3. The compound of
5. The compound of
6. The compound of claim 5 1, wherein Ar1 and Ar2 are each independently selected from phenyl, thienyl, isothiazolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, and imidazolyl.
14. The compound of
15. A compound of claim 14 1, wherein Y is C(R1R2), m and n are 0, and either R1 or R2 can combine with either R3 or R4 to form a 5-7 membered heterocyclic ring.
17. The compound of
18. The compound of
19. The composition compound of
0. 20. A method of treating diseases or disorders in a subject in need thereof comprising administering a therapeutically effective amount of a compound of
21. The A method of
22. The method of claim 20 21, wherein the compound is administered for the treatment of disorders associated with hydrofunctionality hypofunctionality of the cerebral cortex.
23. The method of
24. A pharmaceutical composition comprising a compound of
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The present application claims priority to U.S. Provisional application Serial No. 60/204,789, filed May 16, 2000 and U.S. provisional application Serial No. 60/268,283, filed Feb. 13, 2001. The disclosure of each of these applications is hereby incorporated herein by reference in its entirety.
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.
The compounds disclosed herein are related to the biological and chemical analogs of modafinil. Modafinil, C15H15NO2S, 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.
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).
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).
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, CF3, NO2, NH2, C1-C4 alkyl, C1-C4 alkoxy, or methylenedioxy, and in which the amide is substituted with OH, C1-C4 alkyl, Cl-C4 hydroxyalkyl, or a C1-C4 hydrocarbon radical. These compositions are described as being useful for treating drug-induced sleepiness, especially sleepiness associated with administration of morphine to cancer patients.
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 NR3R4 is NHOH. These compounds are described as being useful in therapy for treating disturbances of the central nervous system.
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.
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.
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.
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.
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.
Other xanthenyl and thiaxanthenyl derivatives are disclosed in Annis, I; Barany, G. Pept. Proc. Am. Pept. Symp. 15th (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).
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.
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.
In one aspect of the invention, there are provided compounds of formula (I-A):
##STR00001##
Constituent members and preferred embodiments are disclosed in detail infra.
In another aspect of the invention, there are provided compounds of formula (I):
##STR00002##
Constituent members and preferred embodiments are disclosed in detail infra.
Another object of the present invention is to provide compounds of formula (II-A):
##STR00003##
Constituent members and preferred embodiments are disclosed in detail infra.
An additional object of the present invention is to provide compounds of formula (II):
##STR00004##
Constituent members and preferred embodiments are disclosed in detail infra.
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.
Another object of the present invention is to provide pharmaceutical compositions comprising the compounds of the present invention wherein the compositions comprise one or more pharmaceutically acceptable excipients and a therapeutically effective amount of at least one of the compounds of the present invention, or a pharmaceutically acceptable salt or ester form thereof.
These and other objects, features and advantages of the substituted thioacetamides will be disclosed in the following detailed description of the patent disclosure.
In one embodiment, the present invention provides novel compounds of formula (I-A):
##STR00005##
wherein:
In an additional embodiment of the invention, there are provided compounds of formula (I): ##STR00008##
wherein Ar1 and Ar2 are the same or different and are each selected from benzaldehye benzaldehyde in step 1. (M+H)=280.
Compounds I-1 through I-7 and I-26 through I-38 were prepared following the same multistep general method as described in Scheme A utilizing the appropriately substituted amine NHR3R4 in step 3b. The analytical data is represented by each compound's mass spectrum (M+H) as shown in the following Table 3.
TABLE 3
Example
Compound
(M + H)
20
I-1
300
21
I-2
328
22
I-3
328
23
I-4
371
24
I-5
328
25
I-6
362
26
I-7
356
27
I-26
330
28
I-27
397
29
I-28
399
30
I-29
322
(M + Na)
31
I-30
377
32
I-31
377
33
I-32
377
34
I-33
384
35
I-34
340
36
I-35
355
37
I-36
294
38
I-37
376
39
I-38
348
The following Examples 40-41 were synthesized according to Scheme 4.
##STR00076##
Preparation of Compound 43
A mixture of compound 41 (0.75 g)(Dondoni, A. et al. J. Org. Chem. 1988, pp. 1748-1761), acetic anhydride (3 equivalents) and anhydrous pyridine (2-3 mL/mmol of alcohol) was stirred overnight at room temperature, or until the reaction was complete by thin layer chromatography. The reaction mixture was then poured into cold water and extracted into ethyl acetate (3×25 mL). The combined organic phase was successively washed with saturated sodium bicarbonate solution, water, brine, dried (sodium sulfate) and concentrated to generate the desired product compound 43 (0.84 g). Analytical Data: Rf=0.6 (2.5% methanol/ethyl acetate); 1H—NMR (CDCl3) δ7.72 (s, 1H), 7.47 (m, 1H), 7.38-7.22 (m, 5H), 7.11 (s, 1H), 2.17 (s, 3H).
Preparation of Compound 44
Compound 42 (0.92 g) was reacted in a manner similar to that described above in the preparation of compound 41. The resulting crude ester was purified by flash chromatography (eluant: 4:1 hexane/ethyl acetate) to give 0.41 g of compound 44. Analytical Data: Rf=0.32 (4:1 hexane/ethyl acetate); 1H—NMR (CDCl3) δ7.83 (s, 1H), 7.42 (s, 1H), 7.36 (m, 1H), 7.17 (m, 1H), 7.00 (m, 1H), 2.19 (s, 3H).
Preparation of Compound 45
To a stirring solution of compound 43 (0.84 g) and methyl thioglycolate (1.2 equivalents) in anhydrous dichloromethane (4-5 mL/mmol) at 0° C. under argon was added trimethylsilyl trifluoromethane (TMS-triflate, 1 equivalent). The reaction mixture was allowed to warm to room temperature and stirred until complete (2-6 h). It was then diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried (sodium sulfate), concentrated and dried under high vacuum to give compound 45 (1.01 g) that was used directly in the next step without any further purification. Analytical Data: Rf=0.62 (2.5% methanol/ethyl acetate); 1H—NMR (CDCl3) δ7.75 (s, 1H), 7.5 (d, 1H), 7.38-7.27 (m, 5H), 5.72 (s, 1H), 3.69 (s, 3H), 3.25 (q, 2H).
Preparation of Compound 46
Compound 44 (0.41 g) was reacted in a manner similar to that described above in the preparation of compound 45 to give compound 46 (0.30 g). Analytical Data: Rf=0.62 (2.5% methanol/ethyl acetate); 1H NMR (CDCl3) δ7.75 (s, 1H), 7.39 (s, 1H), 7.36 (m, 1H), 7.17 (broad, 1H), 6.94 (m, 1H), 6.07 (s, 1H), 3.72 (s, 3H), 3.30 (q, 2H).
Preparation of Compound 47
Anhydrous ammonia was bubbled into a stirring solution of compound 45 (1.0 g) in methanol (10 mL/mmol) at 0° C. for 5-10 minutes. The reaction mixture was allowed to warm to room temperature, stirred for additional 5-7 h, concentrated under reduced pressure and dried under vacuum. The crude product was purified by flash chromatography (eluant: 5% methanol/ethyl acetate) to give 0.48 g of compound 47. Analytical Data: Rf=0.20 (5% methanol/ethyl acetate); 1H—NMR (CDCl3) δ7.77 (s, 1H), 7.47 (d, 1H), 7.44-7.27 (m, 5H), 5.53 (broad, 1H), 3.22 (q, 2H).
Preparation of Compound 48
Compound 46 (0.30 g) was reacted in a manner similar to that described above in the preparation of compound 47 to give compound 48 (0.25 g). Analytical Data: Rf=0.20 (5% methanol/ethyl acetate); 1H—NMR (CDCl3) δ7.72, (s, 1H), 7.31 (s, 1H), 7.28 (m, 1H), 7.17 (s, 1H), 6.97 (m, 1H), 6.84 (broad, 1H), 6.11 (broad, 1H), 5.86 (s, 1H), 3.25 (q, 2H).
To a stirring solution of compound 47 (0.48)in anhydrous dichoromethane (10 mL/mmol) at −78° C. was added a solution of m-CPBA (1.0 equivalent) in dichloromethane (5-8 mL/mmol). After an additional stirring for 1 h, the reaction mixture was allowed to warm to −30 to −40° C. and quenched with 10% aqueous Na2S2O3 solution. Separated organic phase was successively washed with saturated sodium bicarbonate solution, water and brine, dried (sodium sulfate), and concentrated to generate compound I-37 (0.31 g). Analytical Data: Rf=0.13 (5% methanol/ethyl acetate); 1H—NMR (CDCl3) major diastereomer: □7.92 (s, sei), 7.61 (m, 2f), 7.44-7.36 (m5H), 7.00 (broad, 1H), 5.61 (s, 1H), 3.42 (q, 2H); minor diastereomer: δ7.86 (s, 1H), 7.55 (m, 2H), 7.44-7.36 (m, 5H), 6.83 (broad, 1H), 5.55 (s, 1H), 3.61 (q, 2H).
Compound 48 (0.25 g) was reacted in a manner similar to that described above in the preparation of compound 47 to give compound I-39 (0.105 g) (diastereomeric mixture). Analytical Data: 1H—NMR (DMSO-d6) major diastereomer: δ8.03 (s, 1H), 7.92 (s, 1H), 7.78 (broad, 1H), 7.68 (s, 1H), 7.36 (broad, 1H)), 7.17 (m, 1H), 6.50 (s, 1H), 3.47 (q, 2H); minor diastereomer: δ7.97 (s, 1H), 7.86 (s, 1H), 7.78 (broad, 1H), 7,72 (s, 1H), 7.36 (broad, 1H), 7.22 (m, 1H), 6.39 (s, 1H), 3.36 (q, 2H).
Starting with 9-hydroxyfluorene, this compound was prepared following the same multistep general method as described in Scheme 3 above, and utilizing L-Alanine-NH2 in the amination step. Analytical Data: white solid (diastereomeric mixture); Rt 7.27 min and 7.41 min. 1H—NMR (DMSO-d6) δ8.40-7.00 (a series of m and d, 11H), 5.60 and 5.70 (2 sets of s, 1H), 4.20 (m, 1H), 3.20 and 3.00 (2 sets of dd, 2H), 1.20 (2 overlapping doublets, 3H).
Starting with 9-hydroxyfluorene, this compound was prepared following the same multistep general method as described in Scheme 3 above, and utilizing 28% aqueous ammonia in the amination step. Analytical Data: white solid; mp 178.5-180° C.; Rt 7.48 min. 1H—NMR (CDCl3) δ7.90-7.40 (a series of m, 8H), 6.60 (broad, 1H), 5.40 (s, 1H), 5.30 (broad, 1H), 2.80 (d, 1H), 2.60 (d, 1H).
Starting with dibenzosuberol, this compound was prepared following the same multistep general method as described in Scheme 3 above, and utilizing 28% aqueous ammonia in the amination step. Analytical Data: white solid; mp 182-190° C.; Rt 8.43 min. 1H—NMR (DMSO-d6) δ7.80 (d, 1H), 7.60 (d, 1H), 7.40 (m, 8H), 5.50 (s, 1H), 3.60 (m, 2H), 3.50 (d, 1H), 3.40 (d, 1H), 2.90 (m, 2H).
Starting with dibenzosuberol, this compound was prepared following the same multistep general method as described in Scheme 3 above, utilizing dimethylamine in the amination step. Analytical Data: white solid; mp 112.5-115° C.; Rt 10.36 min. 1H—NMR (DMSO-d6) δ7.60 (d, 1H), 7.40 (m, 7H), 5.50 (s, 1H), 4.00 (d, 1H), 3.60 (d, 1H), 3.50 (m, 2H), 2.90 (s, 3H), 2.80 (m, 2H), 2.70 (s, 3H).
Compounds II-6 through II-8, II-10 through II-15, II-24, II-27, II-30 through II-54, II-56 through II-91 were prepared following the same multistep general method as described in Scheme B incorporating the appropriate reactants to form the desired product. The analytical data is represented by each compound's mass spectrum (M+H) as shown in the following Table 4.
TABLE 4
Example
Compound
(M + H)
46
II-6
314
47
II-7
342
48
II-8
300
49
II-10
348
50
II-11
314
51
II-12
348
52
II-13
314
53
II-14
328
54
II-15
341
55
II-24
371
56
II-27
288
57
II-30
286
58
II-31
415
59
II-32
363
60
II-33
363
61
II-34
316
62
II-35
300
63
II-36
326
64
II-37
298
65
II-38
376
66
II-39
288
67
II-40
329
68
II-41
343
69
II-42
318
70
II-43
328
71
II-44
343
72
II-45
376
73
II-46
330
74
II-47
358
75
II-48
343
76
II-49
343
77
II-50
371
78
II-51
359
79
II-52
373
80
II-53
369
81
II-54
286
82
II-56
316
83
II-57
359
84
II-58
314
85
II-59
328
86
II-60
334
87
II-61
340
88
II-62
385
89
II-63
384
90
II-64
338
91
II-65
384
The following Example 92 was synthesized according to Scheme 5.
##STR00077##
Preparation of Compound M
A mixture of dimethyl phthalate (compound K, 10 g, 0.51 mol), 3,4-dimethoxyacetophenone (compound L, 9.74 g, 0.054 mol), and powdered sodium methoxide (2.76 g, 0.051 mol) was heated at reflux overnight, cooled to room temperature, and concentrated in vacuo. The yellow slurry was suspended in water (100 mL), stirred for 10 min, acidified with 6N HCl (pH −1-2), and filtered. The residue was placed in ethanol (200 mL), heated to reflux for 30 min, cooled to room temperature, and filtered. The residue was washed with cold ethanol and dried in vacuo to generate compound M as a bright yellow fluffy solid (4.1 g) that was used without any further purification. Analytical Data: 1H—NMR (CDCl3) δ3.99 (s, 3H), 4.02 (s, 3H), 6.99 (d, 1H), 7.68-7.75 (m, 2H), 7.85 (m, 2H), 8.07 (d, 1H), 8.09 (s, 1H); MS: (M+H)+=311.
Preparation of Compound N
A mixture of compound M (3.37 g, 0.011 mol), hydrazine (0.41 mL, 0.013 mol) and ethanol (250 mL) under nitrogen was heated to reflux for 6 h, cooled to room temperature and filtered. The residue was washed with ethanol and dried to give compound N as a yellow solid (2.0 g). Analytical Data: 1H NMR (CDCl3) δ3.85 (s, 3H), 3.89 (s, 3H), 7.17 (d, 1H), 7.38-7.43 (m, 1H), 7.55 (m, 2H), 7.60 (d, 1H), 7.85 (d, 1H), 7.95 (s, 1H); MS: (M+H)+=307.
Preparation of Compound O
To a stirred solution of compound N (0.084 g, 0.27 mmol) in THF/H2O (3:1, 8 mL) at room temperature under nitrogen was added solid sodium borohydride (0.029 g, 0.63 mmol) in one portion. The reaction mixture was cooled to 0° C., stirred for 1 h, warmed to room temperature, diluted with ethyl acetate and washed with water. The organic phase was dried (magnesium sulfate) and concentrated in vacuo. The residue, on trituration with ether, generated compound O (0.077 g) as a yellow solid that was used without further purification. Analytical Data: 1H NMR (CDCl3) δ3.86 (s, 3H), 3.87 (s, 3H), 5.53 (s, 1H), 6.79 (d, 1H), 7.29 (t, 2H), 7.46 (d, 1H), 7.50 (s, 2H), 7.58 (t, 1H); MS: (M+H)+=309.
Preparation of Compound P
To a stirred solution of compound O (1.55 g, 0.005 mol) in CH2Cl2 (40 mL) under nitrogen at 0° C. was added methyl thioglycolate (0.54 mL, 0.006 mmol). Next, trifluoroacetic anhydride (1.42 mL, 0.01 mol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0° C. for 0.5 h, warmed to room temperature, stirred overnight, quenched with saturated aqueous sodium bicarbonate and extracted into ethyl acetate (3×25 mL). The organic layer was washed with water, brine, dried (magnesium sulfate), and concentrated in vacuo to generate compound P as a yellow solid (1.75 g) that was used without any further purification. Analytical Data: 1H NMR (CDCl3) δ2.77 (q, 2H), 3.33 (s, 3H), 3.93 (s, 3H), 4.00 3H), 4.99 (s, 1H), 6.96 (d, 1H), 7.23-7.42 (m, 2H), 7.47 (d, 1H), 7.49 (d, 1H), 7.64 (d, 1H), 7.69 (d, 1H), 7.72 (d, 1H); MS: (M+H)+=397.
Starting from compound P, this compound was generated following the procedure as described above for the preparation of compound 47, and in Example 35 for the synthesis of compound I-37. Thus, 0.050 mg of compound P, on treatment with ammonia in the first step, followed by oxidation with m-CPBA in the next step, generated 0.011 g of compound II-66. Analytical Data: 1H—NMR (CDCl3) δ2.75 (d, 1H), 2.88 (d, 1H), 3.92 (s, 3H), 3.96 (s, 3H), 5.67 (s, 1H),6.80 (s, 1H), 6.94 (d, 1H), 7.37 (t, 1H), 7.45-7.52 (m, 2H), 7.58 (d, 1H), 7.64 (s, 1H), 7.79 (d, 1H); MS: (M+H)+=420.
The methodology utilized is as described by Edgar and Seidel, Journal of Pharmacology and Experimental Therapeutics, 283:757-769, 1997, incorporated herein in its entirety by reference.
Animal Surgery. Adult, male Wistar rats (275-320g from Charles River Laboratories, Wilmington, Mass.) were anesthetized (Nembutal, 60 mg/kg, ip) and surgically prepared with implants for recording of chronic EEG and EMG recording. The EEG implants consisted of stainless steel screws (2 frontal (+3.9 AP from bregma, ±2.0 ML) and 3 occipital (−6.4 AP, ±5.5 ML). Two Teflon-coated stainless steel wires were positioned under the nuchal trapezoid muscles for EMG recording. All leads were soldered to a miniature connector (Microtech, Boothwyn, Pa.) and gas sterilized with ethylene oxide before surgery. The implant assembly was affixed to the skull by the combined adhesion of the EEG recording screws, cyanoacrylate applied between the hermetically sealed implant connector and skull and dental acrylic. An antibiotic (Gentamycin) was administered for 3 to 5 days postsurgery. At least 3 weeks were allowed for postsurgical recovery.
Recording environment. Rats were housed individually within specially modified Nalgene microisolator cages equipped with a low-torque slip-ring commutator (Biella Engineering, Irvine, Calif.) and a custom polycarbonate filter-top rise. These cages were isolated in separate, ventilated compartments of a stainless steel sleep-wake recording chamber. Food and water were available ad libitum and ambient temperature was 24±1° C. A 24-h light-dark cycle (light/dark 12-12-) was maintained throughout the study by 4-watt fluorescent bulbs located approximately 5 cm from the top of each cage. Light intensity was 30 to 35 lux at midlevel inside the cage. Animals were undisturbed for 3 days both before and after the treatments.
Automated data collection. Sleep and wake stages were determined with SCORE, a microcomputer-based sleep-wake and physiological monitoring system. SCORE™ design features, validation in rodents and utility in preclinical drug evaluation have been reported elsewhere (Van Gelder, et al., 1991; Edgar, et al., 1991, 1997; Seidel, et al, 1995, incorporated by reference herein in their entirety). In the present study, the system monitored amplified (×10,000) EEG (bandpass, 1-30 Hz; digitization rate, 100 Hz) and integrated EMG (bandpass, 10-100 Hz, root mean square integration). Arousal states were classified on-line as NREM sleep, REM sleep, wake or theta-dominated wake every 10 s by use of EEG period and amplitude feature extraction and ranked membership, algorithm. Individually taught EEG-arousal-state templates and EMG criteria differentiated REM sleep from theta-dominated wakefulness (Welsh, et al., 1985, incorporated by reference herein in its entirety). Data quality was assured by frequent on-line inspection of the EEG and EMG signals. Raw data quality and sleep-wake scoring was scrutinized further by a combination of graphical and statistical assessments of the data as well as visual examination of the raw EEG wave forms and distribution of integrated EMG values.
Drug administration and study design. Compound I-9 was suspended in sterile 0.25% methylcellulose (pH=6.2; Upjohn Co., Kalamazoo, Mich.) or methylcellulose vehicle alone was injected intraperitoneally in a volume of 1 ml/kg. Sample size (n) was 13 animals per treatment group.
EEG spectral analysis. Each 10-s epoch of raw EEG signal was digitized (100 Hz) for 24 h and wakefulness was scored as described previously by Edgar and Seidel (1996), incorporated by reference herein in its entirety.
Data analysis and statistics. The principal variable recorded was minutes per hour of wake. Treatment groups were compared post-treatment by repeated-measures ANOVA. In the presence of a significant main effect, Dunnett's contracts (a=0.05) assessed differences between active treatment groups and vehicle controls, unless otherwise specified.
Results.
The methodology utilized is based on that described by Edgar and Seidel, Journal of Pharmacology and Experimental Therapeutics, 283:757-769, 1997, and incorporated herein in its entirety by reference.
Animal Surgery. Adult, male Wistar rats (275-320 g from Charles River Laboratories, Wilmington, Mass.) were anesthetized (Nembutal, 45 mg/kg, ip) and surgically prepared with implants for recording of chronic EEG and EMG recording. The EEG implants were made from commercially available components (Plastics One, Roanoke, Va.) EEG's were recorded from stainless steel screw electrodes (2 frontal (+3.0 mm AP from bregma, ±2.0 mm ML) and 2 occipital (−4.0 mm AP, ±2.0 mm ML)). Two Teflon-coated stainless steel wires were positioned under the nuchal trapezoid muscles for EMG recording. All electrode leads were inserted into a connector pedestal and the pedestal, screws, and wires affixed to the skull by application dental acrylic. Antibiotic was administered post surgically and antibiotic cream was applied to the wound edges to prevent infection. At least 1 week elapsed between surgery and recording. Animals are tested for approximately 6-8 weeks and then sacrificed.
Recording environment. Postsurgically, rats were housed individually in an isolated room. At least 24 hrs. prior to recording, they were placed in Nalgene containers (31×31×31 cm) with a wire-mesh top, and entry to the room was prohibited until after recording had ended except for dosing. The containers were placed on a 2-shelf rack, 4 per shelf. Food and water were available ad libitum, ambient temperature was 21° C., and humidity was 55%. White-noise was provided in the background (68 db inside the containers) to mask ambient sounds. Fluorescent overhead room lights were set to a 24 hr. light/dark cycle (on at 7 AM, off at 7 PM). Light levels inside the containers were 38 and 25 lux for the top and bottom shelves respectively.
Data acquisition. EEG and EMG signals were led via cables to a commutator (Plastics One) and then to preamplifiers (model 1700, A-M Systems, Carlsborg, Wash.). EEG and EMG signals were amplified (10K and 1K respectively) and bandpass filtered between 0.3 and 500 Hz for EEG, and between 10 and 500 Hz for EMG. These signals were digitized at 128 samples per second using ICELUS sleep research software (M. Opp, U. Texas; see Opp, Physiology and Behavior 63:67-74, 1998, and Imeri, Mancia, and Opp, Neuroscience 92:745-749, 1999, incorporated by reference herein in their entirety) running under Labview 5.1 software and data acquisition hardware (PCI-MIO-16E-4; National Instruments, Austin, Tex.). On the day of dosing, data was recorded from 11 AM to 6 PM.
Sleep/wake scoring. Sleep and wake stages were determined manually using ICELUS software. This program displays the EEG and EMG data in blocks of 6 sec. along with the EEG-FFT. Arousal state was scored as awake (WAK), rapid eye-movement (REM), or slow-wave or non-REM sleep (NREM) according to visual analysis of EEG frequency and amplitude characteristics and EMG activity (Opp and Krueger, American Journal of Physiology 266:R688-95, 1994; Van Gelder, et al., 1991; Edgar, et al., 1991, 1997; Seidel, et al, 1995, incorporated by reference herein in their entirety). Essentially, waking activity consists of relative low-amplitude EEG activity with relatively lower power in the lower frequency bands from 0.5-6 Hz, accompanied by moderate to high level EMG activity. In a particular waking state (“theta-waking”), EEG power can be relatively focused in the 6-9 Hz (theta) range, but significant EMG activity is always present. NREM sleep is characterized by relative high-amplitude EEG activity with relatively greater power in the low frequency bands from 0.5-6 Hz, accompanied by little or no EMG activity. REM sleep is characterized by moderate and constant amplitude EEG focused in the theta (6-9 Hz range), similar to waking theta, but with no EMG activity.
Drug administration and study design. Compounds were evaluated on groups of 4 or 8 rats which were tested in 2 sessions at least 2 days apart. Initial studies used a crossover design, such that rats received either vehicle or test compound during each session. Animals were pseudo-randomized so that they did not receive the same drug twice. Compound II-23 was suspended in sterile 0.25% methylcellulose (pH=6.2; Upjohn Co., Kalamazoo, Mich.) at 30 mg/ml. This study was carried out on 8 rats which were tested in 2 sessions 5 days apart (overall, 7 rats received compound II-23 and 6 methylcellulose vehicle). Dosing was carried out at noon, while the rats were predominantly asleep. Each rat was lifted out of its container, given an intraperitoneal. injection in a volume of 3.33 ml/kg, and replaced. Dosing required approximately 8 minutes.
Data analysis and statistics. The principal outcome measure was minutes per hour of wakefulness. The primary outcome measure for purposes of determining activity in these experiments consists of the total integrated wake time for the first 3 hours post dosing relative to vehicle control. Thus, vehicle treated animals typically average 20% wake time during the recording period, or a total of 0.2 * 180=36 min. A 2-tailed, unpaired t-test (Statview 5.0, SAS Institute, Inc., Cary, N.C.) was performed on the wake time values for drug and vehicle treated animals, and compounds with p<0.05 were deemed significantly wake-promoting. Waking activity was also evaluated for successive half-hour periods beginning with the time of dosing, and individual t-tests performed at each time point to establish the duration of significant wake-promoting activity.
Results.
References. The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated in their entirety herein by reference:
Although the present invention has been described in considerable detail, those skilled in the art will appreciate that numerous changes and modifications may be made to the embodiments and preferred embodiments of the invention and that such changes and modifications may be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all equivalent variations as fall within the scope of the invention.
Mallamo, John P., Miller, Matthew S., Chatterjee, Sankar, Bacon, Edward R., Dunn, Derek, Vaught, Jeffry L.
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