Process for production of piperidine derivatives

Details Process for production of piperidine derivatives Process for production of piperidine derivatives

1995-12-21

2001-03-13

Chang, Ceila (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S209000, C546S239000, C546S240000, C548S146000, C548S187000, C548S230000, C548S237000, C548S322500, C514S317000

Reexamination Certificate

active

06201124

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to processes for the production of piperidine derivatives.
BACKGROUND OF THE INVENTION
Terfenadine, 1-(p-tert-butylphenyl)-4-[4′-(&agr;-hydroxydiphenylmethyl)-1′-piperidinyl]-butanol is a non-sedating anti-histamine. It is reported to be a specific H
1
-receptor antagonist that is also devoid of any anticholingeric, anti-serotoninergic, and anti-adrenergic effects both in vitro and in vivo. See D. McTavish, K. L. Goa, M. Ferrill,
Drugs,
1990, 39, 552; C. R. Kingsolving, N. L. Monroe, A. A. Carr,
Pharmacologist,
1973, 15, 221; J. K. Woodward, N. L. Munro,
Arzneim-Forsch,
1982, 32, 1154; K. V. Mann, K. J. Tietze,
Clin. Pharm.
1989, 6, 331. A great deal of effort has been made investigating structure-activity relationships of terfenadine analogs, and this is reflected in the large number of U.S. patents disclosing this compound and related structures as follows:
U.S. Pat. No. 3,687,956 to Zivkovic
U.S. Pat. No. 3,806,526 to Carr, et. al.
U.S. Pat. No. 3,829,433 to Carr, et. al.
U.S. Pat. No. 3,862,173 to Carr, et. al.
U.S. Pat. No. 3,878,217 to Carr, et. al.
U.S. Pat. No. 3,922,276 to Duncan, et. al.
U.S. Pat. No. 3,931,197 to Carr, et. al.
U.S. Pat. No. 3,941,795 to Carr, et. al.
U.S. Pat. No. 3,946,022 to Carr, et. al.
U.S. Pat. No. 3,956,296 to Duncan, et. al.
U.S. Pat. No. 3,965,257 to Carr, et. al.
U.S. Pat. No. 4,742,175 to Fawcett, et. al.
In animal and human metabolic studies, terfenadine has been shown to undergo extensive hepatic first-pass metabolism, and after usual dosages it cannot be detected in plasma unless very sensitive assays are used. A specific hepatic cytochrome P-450 enzyme converts terfenadine to the major metabolite 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-&agr;-&agr;-dimethylphenylacetic acid, also known as terfenadine carboxylic acid metabolite. This metabolite can be readily detected in plasma and is considered to be the active form of orally administered terfenadine.
Side effects reported with terfenadine are cardiac arrhythmias (ventricular tachyarrhythmias, torsades de points, ventricular fibrillation), sedation, GI distress, dry mouth, constipation and/or diarrhea. The most serious of these, and potentially life threatening, are cardiac arrhythmias, which are related to terfenadine's ability to prolong the cardiac QT interval, and are only reported in patients administered terfenadine with liver disease or who also take the antifungal drug ketoconazole or the antibiotic erythromycin. As a result of these adverse events, the FDA, in 1992, required terfenadine to include a warning label. Although OTC formulations of terfenadine are purportedly being developed, the potentially serious side effects seen in some patients will be a significant obstacle for regulatory approval.
Since cardiac side effects of terfenadine have been reported in patients with impaired liver function, as well as in patients also taking antibiotics known to suppress hepatic enzyme function, it was speculated that the cardiac side effects were due to accumulation of terfenadine and not due to accumulation of terfenadine carboxylic acid metabolite. Patch clamp studies in isolated feline ventricular myocytes support the contention that terfenadine, and not the carboxylic acid metabolite, is responsible for cardiac side effects. At a concentration of 1 &mgr;M, terfenadine caused a greater than 90% inhibition of the delayed rectifier potassium current. At concentrations up to 5 &mgr;M, the terfenadine carboxylic acid metabolite had no significant effect on the potassium current in this assay (See R. L. Woosley, Y. Chen, J. P. Frieman, and R. A. Gillis,
JAMA
1993, 269, 1532). Since inhibition of ion transport has been linked to cardiac abnormalities such as arrhythmias, these results indicate that terfenadine carboxylic acid is likely not liable to cause cardiac arrhythmias, at dose levels at which there is a distinct risk of such a side effect being caused by terfenadine itself.
Carebastine, 4-[4-[4-(diphenylmethoxy)-1-piperidinyl]-1-oxobutyl]-&agr;,&agr;-dimethylphenylacetic acid, is the carboxylic acid metabolite of ebastine, 1-(p-tert-butylphenyl)-4 -[4′-(&agr;-diphenylmethoxy)-1′-piperidinyl]-butanol. Both compounds possess potent selective histamine H
1
-receptor blocking and calcium antagonist properties and should prove useful in the treatment of a variety of respiratory, allergic, and cardiovascular disease states.
These compounds relax bronchial and vascular smooth muscle in vitro and in vivo and inhibit the constrictor influence of noradrenaline, potassium ions, and various other agonist drugs. The compounds also inhibit responses of intestinal and tracheal preparations to histamine, acetylcholine, and barium chloride and block the bronchoconstriction induced by histamine aerosol in guinea pigs in doses less than 1 mg/kg animal body weight administered orally. They also possess antianaphylactin properties in the rat, inhibit the skin lesions to a variety of anaphylactic mediators (histamine, 5-hydroxytryptamine, bradykinin, LCD
4
, etc.), and antagonize the Schultz-Dale response in the sensitive guinea-pig.
Piperidine derivatives related to the terfenadine carboxylic acid metabolite are disclosed in the following U.S. patents:
U.S. Pat. No. 4,254,129 to Carr, et. al.
U.S. Pat. No. 4,254,130 to Carr, et. al.
U.S. Pat. No. 4,285,957 to Carr, et. al.
U.S. Pat. No. 4,285,958 to Carr, et. al.
In these patents, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-&agr;,&agr;-dimethylbenzeneacetic acid and related compounds are prepared by alkylation of a substituted piperidine derivative of the formula:
with an &ohgr;-haloalkyl substituted phenyl ketone of the formula:
wherein the substituents halo, R
1
, R
2
, n, Z, and R
6
are described in column 6 of U.S. Pat. No. 4,254,130.
In similar fashion, U.S. Pat. No. 4,550,116 to Soto et al. describes preparation of piperidine derivatives related to carebastine by reacting the &ohgr;-haloalkyl substituted phenyl ketone with a substituted hydroxypiperidine derivative of the formula:
U.S. Pat. No. 4,254,130 indicates that &ohgr;-haloalkyl substituted phenyl ketones, wherein Z is hydrogen, are prepared by reacting an appropriate straight or branched lower alkyl C
1-6
ester of &agr;-&agr;-dimethylphenylacetic acid with a compound of the following formula:
under the general conditions of a Friedel-Crafts acylation, wherein halo and m are described in column 11 of U.S. Pat. No. 4,254,129. The reaction is carried out in carbon disulfide as the preferred solvent.
Other procedures for producing terfenadine carboxylic acid metabolite are disclosed in PCT Application Nos. WO95/00492, WO94/03170, and WO95/00480.
The present invention is directed toward an improved process for preparation of terfenadine carboxylic acid metabolite and carebastine derivatives.
SUMMARY OF THE INVENTION
The present invention is directed to processes for preparing piperidine derivative compounds of the formulae:
wherein
n is 0 or 1;
R
1
is hydrogen or hydroxy;
R
2
is hydrogen;
or, when n is 0, R
1
and R
2
taken together form a second bond between the carbon atoms bearing R
1
and R
2
, provided that when n is 1, R
1
and R
2
are each hydrogen;
R
3
is —COOH or —COOR
4
;
R
4
is an alkyl or aryl moiety;
A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents
or a salt thereof.
In one aspect of the invention, the piperidine derivative compound is prepared by providing a regioisomer having the following formula:
wherein
Z is —CG
1
G
2
G
3
,
m is an integer from 1 to 6;
Q and Y are the same or different and are selected from the group consisting of O, S, and NR
5
;
G
1
, G
2
, and G
3
are the same or different and are selected from the group consisting of OR
8
, SR
8
, and NR
8
R
9
;
X
3
is halogen, OR
15
, S

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