Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-03-28
2002-05-14
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C544S058200, C544S098000, C544S386000, C562S426000, C562S433000, C562S443000, C564S218000, C564S305000
Reexamination Certificate
active
06388127
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing cyclic thioamides useful for preparing aralkyl and aralkylidene heterocyclic lactams and imides, which are selective agonists and antagonists of serotonin 1 (5-HT
1
) receptors, specifically, of one or both of the 5-HT
1A
and 5-HT
1D
receptors, useful in treating or preventing migraine, depression and other disorders for which a 5-HT
1
agonist or antagonist is indicated.
European Patent Publication 434,561, published on Jun. 26, 1991, refers to 7-alkyl, alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT
1
agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.
European Patent Publication 343,050, published on Nov. 23, 1989, refers to 7-unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes as useful 5-HT
1A
ligand therapeutics.
PCT publication WO 94/21619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT
1
agonists and antagonists.
PCT publication WO 96/00720, published Jan. 11, 1996, refers to naphthyl ethers as useful 5-HT
1
agonists and antagonists.
European Patent Publication 701,819, published Mar. 20, 1996, refers to the use of 5-HT
1
agonists and antagonists in combination with a 5-HT re-uptake inhibitor.
Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT
1
ligand in their article “5-HT
1D
Serotonin Receptors”,
Clinical Drug Res. Dev.,
22, 25-36 (1991).
Glennon's article “Serotonin Receptors: Clinical Implications”,
Neuroscience and Behavioral Reviews,
14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease.
World Patent Application WO 95/31988, published Nov. 30, 1995, refers to the use of a 5-HTD
1D
antagonist in combination with a 5-HT
1A
antagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson's disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.
G. Maura et al.,
J. Neurochem,
66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HT
1A
receptors or for both 5-HT
1A
and 5-HT
1D
receptors might represent a great improvement in the treatment of human cerebellar ataxias, a multifaceted syndrome for which no established therapy is available.
European Patent Publication 666,261, published Aug. 9, 1995 refers to thiazine and thiomorpholine derivatives which are claimed to be useful for the treatment of cataracts.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a compound of the formula
wherein b is 0, 1, 2 or 3; Y is oxygen, sulfur, NH or N-acetyl; and each R
3
is independently selected from the group consisting of halo, cyano, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy and trifluoromethyl; comprising reacting a compound of the formula
with a dehydrating agent.
The present invention also relates to a more preferred process for preparing the compound of formula I, wherein the dehydrating agent is acetic anhydride.
The present invention also relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with haloacetic acid in the presence of a base.
The present invention also relates to a more preferred process for preparing the compound of formula II, wherein the haloacetic acid is bromoacetic acid.
The present invention also relates to a more preferred process for preparing the compound of formula II, wherein the base is potassium hydroxide.
The present invention also relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with a reducing agent and reacting the compound so formed with hydrochloric acid.
The present invention also relates to a more preferred process for preparing the compound of formula III, wherein the reducing agent is borane tetrahydrofuran complex.
The present invention also relates to a process for preparing a compound of the formula
comprising reacting a compound of the formula
with hydroxyacetic acid, mercaptoacetic acid or 2-aminoacetic acid.
The present invention also relates to a more preferred process for preparing the compound of formula IV, wherein the compound of formula V is reacted with mercaptoacetic acid.
The present invention also relates to a process for preparing a compound of the formula
wherein b is 0, 1, 2 or 3; Y is oxygen, sulfur, NH or N-acetyl; and each R
3
is independently selected from the group consisting of halo, cyano, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy and trifluoromethyl; comprising
(a) reacting a compound of the formula
with hydroxyacetic acid, mercaptoacetic acid or 2-aminoacetic acid;
(b) reacting a compound of formula IV so formed
with a reducing agent and reacting the intermediate compound so formed with hydrochloric acid;
(c) reacting a compound of formula III so formed
with haloacetic acid in the presence of a base; and
(d) reacting a compound of formula II so formed
with a dehydrating agent.
The present invention also relates to a more preferred process for preparing the compound of formula I, wherein the compound of formula V is reacted with mercaptoacetic acid; the reducing agent is borane tetrahydrofuran complex; the base is potassium hydroxide; the haloacetic acid is bromoacetic acid; and the dehydrating agent is acetic anhydride.
The present invention also relates to a compound of the formula
The present invention also relates to a compound of the formula
The present invention also relates to a compound of the formula
DETAILED DESCRIPTION OF THE INVENTION
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, b, Y and R
3
in the reaction Schemes and the discussion that follow are defined as above.
In reaction 1 of Scheme 1, the aniline compound of formula V is converted to the corresponding compound of formula IV, wherein Y is oxygen, sulfur, NH or N-acetyl, by reacting V with hydroxyacetic acid, mercaptoacetic acid or 2-aminoacetic acid, in the presence of an aprotic solvent, such as toluene. The reaction mixture so formed is heated to reflux for a time period between 16 hours to about 24 hours, preferably about 20 hours.
In reaction 2 of Scheme 1, the compound of formula IV is converted to the corresponding compound of formula III by reducing IV with a reducing agent, such as borane tetrahydrofuran complex. The compound so formed is then treated with anhydrous hydrochloric acid in the presence of a polar protic solvent, such as ethanol. The reaction is carried out at a temperature between about 10° C. to about 20° C., preferably about 15° C., for a time period between about 2 hours to about 4 hours, preferably about 3 hours.
In reaction 3 of Scheme 1, the compound of formula III is converted to the corresponding compound of formula II by first treating III with a base, such as potassium hydroxide, under inert atmosphere, in the presence of a polar protic solvent, such as ethanol, at a temperature between about 0°C. to about 20° C., preferably about 10° C., for a time period between about 0.5 hours to about 2 hours, preferably about 1 hour. Alkylation of the intermediate compound so formed is carried out with the addition of bromoacetic acid. The reaction mixture is then stirred for an additional time period between about 2 hours to about 4 hours, p
Hill Paul D.
Quallich George Joseph
Raggon Jeffrey William
Ginsburg Paul H.
Killos Paul J.
Pfizer INC
Richardson Peter C.
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