Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-04
2001-11-13
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S303000
Reexamination Certificate
active
06316631
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a process for converting 2,4-dichloropyridines into 2-aryloxy-4-chloropyridines. This process can be used to prepare 3,6-di-(C
1
-C
4
)alkyl-4-chloro-2-(2,4,6-trisubstitutedphenoxy)pyridines, which are intermediates in the synthesis of pharmaceutically active 2-phenoxy-pyridine derivatives that exhibit activity as corticotropin releasing factor (CRF) antagonists and are useful in the treatment of several neurological disorders. Such pharmaceutically active compounds, methods of preparing them and the neurological disorders that they are useful in treating are described in copending U.S. patent application No. 08/255,514, which was filed on Jun. 8, 1994, (now abandoned), which is a 371 of PCT/IB95/00439 filed Jun. 6, 1995, which issued as WO 953370 Dec. 14, 1995. This PCT International Application is incorporated herein by reference in its entirety.
SUMMARY OF THE INVENTION
This invention relates to a process for preparing a compound of the formula
wherein R
1
is (C
1
-C
4
)alkyl;
R
2
is methyl or ethyl; and R
3
, R
4
and R
5
are selected, independently, from (C
1
-C
4
)alkyl and (C
1
-C
4
)alkoxy; or a pharmaceutically acceptable salt thereof; comprising reacting a compound of the formula
wherein R
1
and R
2
are defined as above, with a compound of the formula
wherein R
3
, R
4
and R
5
are defined as above, in the presence of a base that is capable of deprotonating the compound of formula III, optionally in the presence of an organometallic halide or oxide and a suitable solvent, and then optionally converting the resulting compound of formula I into a pharmaceutically acceptable salt of such compound.
Suitable bases for this reaction include sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, ammonium hydroxide, n-butyllithium and lithium, sodium or potassium (C
1
-C
4
) alkoxide. Examples of suitable solvents are tetrahydrofuran (THF), dimethylsulfoxide (DMSO), acetonitrile, methylene chloride (CH
2
Cl
2
), 1-methyl-2-pyrrolidinone, pyridine, quinoline, N,N-dialkylformamide (e.g. N,N-dimethylformamide), hexamethyl phosphormamide and toluene. The reaction temperature may range from about 0° to about 180° C. and is preferably between about room temperature and about 150° C.
A preferred embodiment of this invention relates to the above process wherein the compound of formula I that is formed is a compound wherein all of R
1
, R
2
, R
3
and R
4
and R
5
are methyl, the solvent is pyridine, the organometallic halide or oxide is copper (I) iodide and the base is potassium t-butoxide.
Another embodiment of this invention relates to the above depicted reaction of a compound of the formula II with a compound of the formula III, wherein the solvent is selected from dimethylsulfoxide (DMSO), pyridine, 2,4,6-trimethylpyridine, quinoline, and mixtures of the foregoing solvents, the base is selected from potassium hydride, sodium hydride, sodium methoxide, potassium t-butoxide, and sodium t-butoxide, and the organometallic halide or oxide is selected from cuprous bromide, cuprous chloride and cuprous iodide.
Other embodiments of this invention relates to the above depicted reaction of the compound of formula II with a compound of the formula III, wherein:
(a) the solvent is pyridine, DMSO or a mixture of pyridine and DMSO; or
(b) the base is sodium hydride or potassium t-butoxide; or
(c) the organometallic halide or oxide is cuprous iodide, cuprous bromide or cuprous chloride;
(d) the solvent is pyridine, R
1
and R
2
in the compound of formula II are both methyl and R
3
, R
4
and R
5
in the compound of formula II are both methyl and R
3
, R
4
and R
5
in the compound of formula III are all methyl;
(e) the solvent is pyridine, R
1
through R
5
in formulae II and III are all methyl and the base is potassium t-butoxide; or
(f) the solvent is pyridine, R
1
through R
5
in formulae II and III are all methyl, and the organometallic halide or oxide is cuprous iodide, cuprous bromide or cuprous chloride.
DETAILED DESCRIPTION OF THIS INVENTION
Compound of the formula I are useful as intermediates in the synthesis of 2-phenoxy-pyridine derivatives that are cotricotropin releasing factor (CRF) antagonists and are useful in the treatment of disorders for which treatment can be effected or facilitated by antagonizing CRF. Examples of such disorders are those selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome, Crohn's disease; spastic colon; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of unappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal and cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; stroke; immune disfunctions including stress induced immune dysfunctions (e.g., porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrilation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; and hypoglycemia in mammals, including humans.
The pharmaceutically active CRF antagonists that can be prepared using the intermediates of formula I that are produced by the processes of this invention are depicted below.
In these compounds, B is —NR
6
R
7
, —NHCHR
6
R
7
, —OCHR
6
R
7
or —SCHR
6
R
7
;
R
1
through R
5
are defined as above;
R
6
is C
1
-C
6
alkyl which may optionally be substituted with one or two substituents R
8
independently selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, CF
3
and C
1
-C
4
alkoxy, and wherein said C
1
-C
6
alkyl and the (C
1
-C
4
)alkyl moiety of said C
1
-C
4
alkoxy may optionally contain one carbon-carbon double or triple bond; and
R
7
is C
1
-C
12
alkyl, aryl or —(C
1
-C
4
alkylene)aryl wherein said aryl is phenyl, napthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, or benzooxazolyl; 3- to 8-membered cycloalkyl or —(C
1
-C
6
alkylene)cycloalkyl, wherein one or two of the ring carbons of said cycloalkyl having at least 4 ring members and the cycloalkyl moiety of said —(C
1
-C
6
alkylene)cycloalkyl having at least 4 ring members may optionally be replaced by an oxygen or sulfur atom or by N—R
9
wherein R
9
is hydrogen or C
1
-C
4
alkyl; and wherein each of the foregoing R
7
groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro and C
1
-C
4
alkyl, or with one substituent selected from bromo, iodo, C
1
-C
6
alkoxy, —O—CO—(C
1
-C
6
alkyl), —O—CO—N(C
1
-C
4
alkyl)(C
1
-C
2
alkyl), —S(C
1
-C
6
alkyl), CN NO
2
, —SO(C
1
-C
4
alkyl), and —SO
2
(C
1
-C
4
alkyl), and wherein said C
1
-C
12
alkyl and the C
1
-C
4
alkyl
Chen Yuhpyng L.
Ruggeri Sally Gut
Fuller Jr. Grover F.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Rotman Alan L.
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