Intermediates useful in a process for synthesizing COX-2...

Details Intermediates useful in a process for synthesizing COX-2... Intermediates useful in a process for synthesizing COX-2...

2000-01-21

2001-06-26

Davis, Zinna Northington (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S510000, C564S511000

Reexamination Certificate

active

06252116

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for synthesizing certain COX-2 inhibiting compounds. Additionally certain intermediate compounds are included.
Cyclooxygenase-2 (COX-2) is an enzyme that is implicated in pain, inflammation, hormone-induced uterine contrations and certain types of cancer growth. Until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. Recently the gene for a second inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1. COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. While the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow, the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will reduce fever, inhibit the inflammatory process, counteract hormone-induced uterine contractions and have potential anti-cancer effects,along with a diminished ability to induce some of the mechanism-based side effects.
One object of the present invention is to provide a synthesis scheme for COX-2 inhibiting compounds which utilizes reduced temperatures in the synthesis.
Another object of the present invention is to utilize a synthetic route that provides high yields.
Another object of the present invention is to provide a synthesis scheme that utilizes a minimum of process steps.
These and other objects will be apparent to those of ordinary skill from the teachings contained herein.
SUMMARY OF THE INVENTION
A process for synthesizing a compound of the formula I:
is disclosed wherein:
0-2 R groups are present;
each R, R′ and R″ independently represents C
1-10
alkyl, C
6-10
aryl, aralkyl, halo, —S(O)
m
H, —S(O)
m
C
1-6
alkyl, —S(O)
m
aryl, nitro, amino, C
1-6
alkylamino, di-C
1-6
alkylamino, —S(O)
m
NH
2
, —S(O)
m
NHC
1-6
alkyl, —S(O)
m
NHC(O)CF
3
and cyano,
the alkyl and aryl groups, and the alkyl and aryl portions of aralkyl, —S(O)
m
C
-6
alkyl, —S(O)
m
aryl, C
1-6
alkylamino, di-C
1-6
alkylamino and —S(O)
m
NHC
1-6
alkyl being optionally substituted with 1-3 groups selected from C
1-4
alkyl, aryl, halo, hydroxyl, —S(O)
m
H, —S(O)
mC
-6
alkyl, —CN, C
1-6
alkoxy, amino, C
1-6
alkylamino, di-C
1-6
alkylamino, —S(O)
m
NH
2
, —S(O)
m
NHC
1-6
alkyl, —S(O)
m
NHC(O)CF
3
and aryloxy;
Y is C or N;
and m is 0, 1 or 2,
comprising reacting a compound of formula II:
wherein R
2
through R
5
each independently represent C
1-6
alkyl, aryl or aralkyl, and X
−
represents a suitable counterion,
with a compound of the formula III:
wherein R, R′ and Y are as previously defined,
in the presence of a base to produce a compound of formula I.
Certain intermediate compounds are also included.
DETAILED DESCRIPTION OF THE INVENTION
The invention is described in detail using the terms defined below unless otherwise specified.
The term “alkyl” refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following:
wherein: x plus y=from 0-10 and w plus z=from 0-9.
The alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
The term “alkoxy” refers to those groups of the designated length in either a straight or branched configuration. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term “halogen” is intended to include fluorine, chlorine, bromine and iodine.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl. Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl. Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
X
−
represents a suitable counterion. Hence, the intermediates of formula II are salt forms which may or may not be “pharmaceutically acceptable” as defined below. A subset of values of X
−
which are of particular interest includes the following: phosphates, e.g., hexafluorophosphate and the like; sulfates; sulfonates, e.g., mesylate, tosylate, triflate and the like; acetates, e.g., acetate, trifluoroacetate and the like; perchlorate; borate, e.g., tetrafluoroborate, tetraphenylborate and the like; antimonate, e.g., hexafluoroantimonate; halide, e.g., Cl, F, Br and I; benzoate and napsylate.
Preferred values of X
−
which is used in the process described herein are selected from the group consisting of: hexafluorophosphate; the halides; sulfate; the sulfonates; trifluoroacetate; perchlorate; tetrafluoroborate; tetraphenylborate and hexafluoroantimonate.
Salts encompassed within the term “pharmaceutically acceptable salts” refer to substantially non-toxic salts of the compounds which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following:
acetate, benzoate, the halides; napsylate and phosphate/diphosphate.
Preferred values of X
−
which pertain to the novel intermediates described herein include: hexafluorophosphate, tetrafluoroborate, tetraphenylborate and hexafluoroantimonate.
The compounds used in the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are useful within the scope of the present invention. When a compound is chiral, the separate enantiomers, substantially free of the other, are included along with mixtures of the enantiomers. Also are polymorphs and hydrates of the compounds.
The compounds of formula I can be administered in oral dosage forms such as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered parenterally, e.g., by intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular injection.
The following abbreviations are used:
Me═methyl
Et═ethyl
n-Pr, Pr═normal propyl
i-Pr═isopropyl
n-Bu, Bu═normal butyl
i-Bu═isobutyl
s-Bu═secondary butyl
t-Bu═tertiary butyl
c-Pr═cyclopropyl
c-Bu═cyclobutyl
c-Pen═cyclopentyl
c-Hex═cyclohexyl
Bn benzyl
BOC, Boc t-butyloxycarbonyl
BOP Benzotriazol-1-yloxy tris/dimethylamino)-phosphonium hexafluorophosphate
calc. calculated
CBZ, Cbz Benzyloxycarbonyl
CDI N,N′-carbonyldiimidazole
DCC Dicyclohexylcarbodiimide
DCM dichloromethane
DIEA diisopropylethylamine
DMF N,N-dimethylformamide
DMAP 4-Dimethylaminopyridine
DSC N,N′-disuccinimidyl carbonate
EDC 1-(3-dimeth

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