1. A method of treating a human suffering from or susceptible to hot flashes, menopausal vasomotor symptoms with sleep disturbances, menopausal vasomotor symptoms with major depressive disorder, or menopausal vasomotor symptoms with general anxiety disorder, comprising the step of administering to the human in need thereof a pharmaceutically acceptable composition comprising:
a. an effective amount of a compound of formula I:
or a salt, hydrate, or solvate thereof; wherein:
D is deuterium; and
each Y is independently selected from deuterium and hydrogen; and
b. a pharmaceutically acceptable carrier.
2. The method of claim 1, wherein Y1 is deuterium.
3. The method of claim 1 or 2, wherein at least one of Y2 and Y3 is deuterium.
4. The method of claim 3, wherein Y2 and Y3 are simultaneously deuterium.
5. The method of claim 1, wherein each hydrogen atom on the fluorophenyl ring is replaced with deuterium.
6. The method of claim 1, wherein any atom not designated as deuterium is present at its naturally abundant isotopic state.
7. The method of claim 1, wherein the compound is selected from any one of:
or a salt, hydrate, or solvate thereof; wherein all hydrogen atoms and all carbon atoms are present at their natural isotopic abundance.
8. The method of claim 1 comprising the additional step of administering to the human a second therapeutic agent that is metabolized by cytochrome P450 2D6.
9. The method of claim 8, wherein the second therapeutic agent is selected from nortriptyline, amitriptyline, imipramine, desipramine, fluoxetine, phenothiazines, propafenone, flecainide, encainide, risperidone, thioridazine, tamoxifen, and atomoxetine.
10. The method of claim 1, wherein the composition is dosed on an as-needed basis.
11. The method of claim 1 or 10, wherein the amount of the compound administered to the human on a daily basis is greater than 20 mgday and less than about 150 mgday in an instant release formulation, or greater than 25 mgday and less than about 150 mgday in a controlled release formulation.
12. The method of claim 11, wherein the amount of the compound administered to the human on a daily basis is greater than 60 mgday in an instant release formulation, or greater than 75 mgday in a controlled release formulation.
13. A method of treating a human or non-human subject suffering from or susceptible to a disease or disorder selected from depression; obsessive-compulsive disorder; generalized anxiety; post-traumatic stress; major depression; panic disorder; social phobia; premenstrual syndrome; cardiac disorders; non-cardiac chest pain; smoking addiction (to cause cessation or prevent relapses); reducing platelet activation states; alcoholism and alcohol dependence; psychiatric syndromes including anger, rejection sensitivity, and lack of mental of physical energy; late luteal phase dysphoric disorder; premature ejaculation; senile dementia; obesity; Parkinson’s disease; canine affective aggression; cancer cell growth, osteoporosis, dermatological diseases or disorders such as hyperproliferative or inflammatory skin diseases, and premature female orgasm; said method comprising the steps of:
a. administering to the subject in need thereof a composition comprising:
i. an effective amount of a compound of formula I:
or a salt, hydrate, or solvate thereof; wherein:
D is deuterium; and
each Y is independently selected from deuterium and hydrogen; and
ii. a pharmaceutically acceptable carrier; and
b. administering to the subject in need thereof an effective amount of a second therapeutic agent that is metabolized by cytochrome P450 2D6.
14. The method of claim 13, wherein the second therapeutic agent is selected from nortriptyline, amitriptyline, imipramine, desipramine, fluoxetine, phenothiazines, propafenone, flecainide, encainide, risperidone, thioridazine, tamoxifen, and atomoxetine.
15. The method of claim 13 or 14, wherein the subject is suffering from or susceptible to a disease or disorder selected from major depressive disorder, obsessive compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder, or premenstrual dysphoric disorder
16. The method of claim 15, wherein the subject is a human and the amount of the compound administered to the human on a daily basis is greater than 60 mgday and less than about 150 mgday in an instant release formulation, or greater than 75 mgday and less than about 150 mgday in a controlled release formulation.
17. A method of treating a subject suffering from or susceptible to tinnitus or social anxiety disorder, comprising the steps of:
a. administering to the subject in need thereof a composition comprising:
i. an effective amount of a compound of formula I:
or a salt, hydrate, or solvate thereof; wherein:
D is deuterium; and
each Y is independently selected from deuterium and hydrogen; and
ii. a pharmaceutically acceptable carrier; and
b. administering to the subject in need thereof an effective amount of clozapine.
18. A method of treating a subject suffering from or susceptible to panic disorder, post-traumatic stress disorder, depression or depressive mood, comprising the steps of:
a. administering to the subject in need thereof a composition comprising:
i. an effective amount of a compound of formula I:
or a salt, hydrate, or solvate thereof; wherein:
D is deuterium; and
each Y is independently selected from deuterium and hydrogen; and
ii. a pharmaceutically acceptable carrier; and
b. administering to the subject in need thereof an effective amount of vestipitant.
19. A method of treating a subject suffering from or susceptible to general anxiety disorder or post-traumatic stress disorder, comprising the steps of: administering to the subject in need thereof:
a. a composition comprising:
i. an effective amount of a compound of formula I:
or a salt, hydrate, or solvate thereof; wherein:
D is deuterium; and
each Y is independently selected from deuterium and hydrogen; and
ii. a pharmaceutically acceptable carrier; and
b. administering to the subject in need thereof an effective amount of quetiapine.
20. A method of treating a subject suffering from or susceptible to alcoholism or alcohol dependence, comprising the steps of: administering to the subject in need thereof:
a. a composition comprising:
i. an effective amount of a compound of formula I:
or a salt, hydrate, or solvate thereof; wherein:
D is deuterium; and
each Y is independently selected from deuterium and hydrogen; and
ii. a pharmaceutically acceptable carrier; and
b. administering to the subject in need thereof an effective amount of naltrexone.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method of making a fused heterocycle, comprising:
carboxylating the 3 position of a compound of formula I or a suitably protected derivative thereof
to form a dicarboxylic acid compound; and
converting the dicarbocylic acid compound to a fused heterocycle of formula (II)
wherein X1 is S, O, N\u2014R1, or P\u2014R2, wherein R1 is hydrogen or a nitrogen protecting group, and R2 is hydrogen or a phosphorus protecting group;
X2 is S, O, N\u2014R1, or P\u2014R2 where R1 and R2 are as previously defined; and
R is hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, aryl, heteroaryl, C1-C20 alkoxy, C1-C20 haloalkoxy, aryloxy, \u2014C1-C10 alkyl-O\u2014C1-C10 alkyl, \u2014C1-C10 alkyl-O-aryl, nitro, halo, amino, or mono- or di alkyl amino.
2. The method of claim 1, wherein X1 is S or O and X2 is S or O such that compounds according to formula II are
3. The method of claim 1, wherein R is hydrogen or C1-C20 alkyl.
4. The method of claim 1, wherein R is C6-C12 alkyl.
5. The method of claim 1, further comprising:
reducing the carboxylic acid groups of the dicarboxylic acid compound to form a compound comprising hydroxyl groups;
converting the hydroxyl groups into leaving groups to form an intermediate compound;
cyclizing the intermediate compound to form a dihydro derivative of formula II; and
aromatizing the dihydro derivative of formula II to form a fused heterocycle of formula II.
6. The method of claim 1, wherein the carboxylating is carried out with carbon dioxide, formic acid, or a chloroesterformate.
7. The method of claim 5, wherein the reducing is carried out using lithium aluminum hydride (LiAlH4), borane, aluminum hydride, or samarium (II) iodide (SmI2) in basic media.
8. The method of claim 5, wherein the converting the hydroxyl groups to leaving groups involves
halogenation using thionyl chloride, PCl3, PCl5, POCl3, PBr3, PBr5, the combination of PPh3 and CCl4 or the combination of PPh3 and CBr4; or
the preparation of alkyl or aryl sulfonates.
9. The method of claim 5, wherein the cyclizing to form
a dihydrothienyl moiety involves treatment of the intermediate compound with sodium sulfide or a hydrate thereof, or hydrogen sulfide;
a dihydrofuranyl moiety involves treatment of the intermediate compound with hydroxide or an oxide ion;
a dihydropyrrolyl moiety involves treatment of the intermediate compound with a sodium or calcium salt of cyanamide NH2\u2014CN; or
a dihydrophospholyl moiety involves treatment of the intermediate compound with a phosphine or a monoalkylsubstituted phosphine.
10. The method of claim 5, wherein the aromatizing of the dihydro derivative of formula II involves use of 2,3-dichloro5,6-dicyano-1,4-benzoquinone (DDQ), 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil), oxygen, MnO2, SeO2, or chromic acid.
11. The method of claim 5, further comprising derivatizing the dicarboxylic acid compound at the 5 position.
12. The method of claim 11, wherein the derivatizing is carried out using electrophilic or nucleophilic chemistries.
13. The method of claim 11, wherein the derivatizing is carried out by a metallation reaction followed by an alkylation using a haloalkyl having 1-20 carbon atoms.
14. The method of claim 5, further comprising protecting the 5 position of the compound of formula I prior to carboxylating; and deprotecting the 5 position prior to aromatizing or prior to reducing the carboxylic acid groups.
15. The method of claim 5, wherein the 5 position is protected with a silyl protecting group.
16. The method of claim 14, further comprising derivatizing the dicarboxylic acid compound at the 5 position after deprotecting.
17. The method of claim 16, wherein the derivatizing is carried out using electrophilic or nucleophilic chemistries.
18. The method of claim 16, wherein the derivatizing is carried out by a metallation reaction followed by an alkylation using a haloalkyl having 1-20 carbon atoms.
19. A regioregular polymer, comprising:
a regioregular fused heterocycle polymer of formula (III)
wherein X1 is S, O, N\u2014R1 or P\u2014R2, wherein R1 is hydrogen or a nitrogen protecting group, and R2 is hydrogen or a phosphorus protecting group;
X2 is S, O, N\u2014R1, or P\u2014R2 where R1 and R2 are as previously defined; and
R is C1-C20 alkyl, C1-C20 haloalkyl, aryl, heteroaryl, C1-C20 alkoxy, C1-C20 haloalkoxy, aryloxy, \u2014C1-C10 alkyl-O\u2014C1-C10 alkyl, \u2014C1-C10 alkyl-O-aryl, nitro, halo, amino, or mono- or di alkyl amino.
20. An article comprising the polymer of claim 19.