Potentiation of drug response

Details Potentiation of drug response Potentiation of drug response

1996-11-25

2001-01-02

Celsa, Bennett (Department: 1627)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S415000, C514S183000, C514S211070, C514S224200, C514S230500, C514S259500, C514S268000, C514S269000, C514S271000, C514S312000, C514S367000, C514S373000, C514S375000, C514S387000, C514S394000, C514S406000, C514S443000, C514S651000

Utility Patent

active

06169105

ABSTRACT:

FIELD OF THE INVENTION
The present invention belongs to the fields of pharmacology, medicine and medicinal chemistry, and provides a method and compositions for increasing the availability of serotonin, norepinephrine and dopamine in the brain of patients to whom is administered citalopram, fluvoxamine or paroxetine.
BACKGROUND OF THE INVENTION
Over the past twenty years or more, the science of pharmacology has been particularly interested in the physiology of the neurons containing monoamines in the human brain. Discovery has followed discovery in the field and it has now been demonstrated that serotonin, norepinephrine and dopamine interact with a great number of receptors in the brain and control or affect processes which regulate many bodily organs and functions. Serotonin, particularly, has been found to be the key to a large number of processes which reveal themselves in both physiological and psychological functions.
Perhaps the most dramatic discovery in medicinal chemistry in the recent past are the serotonin reuptake inhibitors, which are extremely effective in the treatment of depression. They increase the availability of serotonin in the synapse by reducing the uptake of serotonin by the serotonin uptake carrier. Dysfunction of the serotonin neurons resulting from excessive uptake results in depression, as well as other pathologies of the central nervous system. Not only are these drugs spectacularly effective in depression, they are also effective in treating numerous other conditions.
Among the serotonin reuptake inhibitors are citalopram, fluvoxamine and paroxetine. While the primary activity of these drugs is the inhibition of the reuptake of serotonin, the cascade of monoamine processes in the brain connects serotonin with both norepinephrine and dopamine. Thus, the increase of availability of serotonin results in increased availability of norepinephrine and dopamine as well.
The present invention provides a method for increasing the availability of serotonin, norepinephrine and dopamine, even compared to the usual increased availability caused by citalopram, fluvoxamine and paroxetine, by potentiating the action of those drugs.
SUMMARY OF THE INVENTION
The invention provides a method for potentiating the action of a first component chosen from the group consisting of citalopram, fluvoxamine and paroxetine in increasing the availability of serotonin, norepinephrine and dopamine in the brain, comprising administering a first component in combination with a second component chosen from the group consisting of alprenolol, WAY 100135, WAY 100635, spiperone, pindolol, (S)-UH-301, penbutolol, propranolol, tertatolol, and a compound of the formula
R
1
is an optional methyl group substituted on one of the three connecting carbon atoms;
R
2
is hydrogen, C
1
-C
4
alkyl, trifluoromethyl, hydroxy, (C
1
-C
4
alkyl)-O—, (C
1
-C
4
alkyl)-S(O)
p
—, or halo;
R
3
is C
3
-C
8
cycloalkyl or a bicycloalkyl group of the formula
 where a and c are independently 1-5, b is 0-5, and (a+c) is greater than 2;
Z is a straight or branched C
4
-C
10
alkane, alkene, or alkyne group; (C
4
-C
8
cycloalkyl) optionally substituted with C
1
-C
4
alkyl or phenyl; a bicycloalkyl group of the formula
 wherein a and c are independently 1-5, b is 0-5, and (a+c) is greater than 2; optionally phenyl substituted C
2
-C
10
alkyl where the phenyl group can be optionally substituted with R
2
as previously defined; or (C
1
-C
4
alkylidene)-T-(C
1
-C
4
alkyl), where T is —O—, —S—, —SO—, or —SO
2
—;
where
each G is independently a bond or C
1
-C
4
alkylidene;
X is —H, —COY, —CN, or C
1
-C
4
alkyl;
Y is —OH, —O-(C
1
-C
4
alkyl), or —NH
2
;
R
a
and R
a′
are independently hydrogen or C
1
-C
3
alkyl, or when taken together with the carbon atom to which they are attached form a C
3
-C
8
cycloalkyl ring;
p is 0, 1, or 2;
A is —O—, —S—, —NH—, or —NCH
3
—; and
m is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof;
provided that when the first component is citalopram, the second component is not (S)-UH-301 or penbutolol; and provided that when the first component is paroxetine or fluvoxamine, the second component is not pindolol.
The invention also provides pharmaceutical compositions which comprise a first component in combination with one of the second component compounds named above. Further, it provides methods of treating a pathological condition which is created by or is dependent upon decreased availability of serotonin, dopamine or norepinephrine, which comprise administering to a patient in need of such treatment an adjunctive therapy comprising a first component and one of the compounds named above.
Still further, the invention provides a preferred manner of carrying out the above method of adjunctive therapy, wherein the provisos above are disregarded, wherein the second component is administered in a manner which provides a substantially constant blood level of the second component, which level is sufficient to provide a substantially constant degree of potentiation of the action of the first component. Compositions adapted for carrying out the preferred manner of the invention are also provided.
DESCRIPTION OF PREFERRED EMBODIMENTS
In this document, all temperatures are described in degrees Celsius, and all amounts, ratios of amounts and concentrations are described in weight units unless otherwise stated.
The Compounds
Citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile, is disclosed in U.S. Pat. No. 4,136,193 as a serotonin reuptake inhibitor. Its pharmacology was disclosed by Christensen et al.,
Eur. J. Pharmacol.
41, 153 (1977), and reports of its clinical effectiveness in depression may be found in Dufour et al.,
Int. Clin. Psychopharmacol.
2, 225 (1987), and Timmerman et al., ibid., 239.
Fluvoxamine, 5-methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone O-(2-aminoethyl)oxime, is taught by U.S. Pat. No. 4,085,225. Scientific articles about the drug have been published by Claassen et al.,
Brit. J. Pharmacol.
60, 505 (1977); and De Wilde et al.,
J. Affective Disord.
4, 249 (1982); and Benfield et al.,
Drugs
32, 313 (1986).
Paroxetine, trans-(−)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine, may be found in U.S. Pat. Nos. 3,912,743 and 4,007,196. Reports of the drug's activity are in Lassen,
Eur. J. Pharmacol.
47, 351 (1978); Hassan et al.,
Brit. J. Clin. Pharmacol.
19, 705 (1985); Laursen et al.,
Acta Psychiat. Scand.
71, 249 (1985); and Battegay et al.,
Neuropsychobiology
13, 31 (1985).
The first components are known to increase the availability of serotonin (5-HT), dopamine (DA) and norepinephrine (NE), and the second component drugs potentiate that valuable property. The second component drugs have in common the property of being antagonists of the serotonin 1A receptor.
(S)-UH-301 ((S)-5-fluoro-8-hydroxy-2-dipropylaminotetralin) is well known to pharmacologists and pharmaceutical chemists. Hillver et al. taught its synthesis in
J. Med. Chem.
33, 1541-44 (1990) and Moreau et al.,
Brain Res. Bull.
29, 901-04 (1992) provided considerable in vivo data about the compound.
Alprenolol (1-(1-methylethyl)amino-3-[2-(2-propenyl)phenoxy]-2-propanol) was disclosed by Brandstrom et al., U.S. Pat. No. 3,466,325, which shows its preparation as Example 5.
WAY 100135 (N-(t-butyl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylpropanamide) was disclosed by Abou-Gharbia et al., U.S. Pat. No. 4,988,814, who taught that the compound has affinity for the 5-HT
1A
receptor. Cliffe et al.,
J. Med. Chem.
36, 1509-10 (1993) showed that the compound is a 5-HT
1A
antagonist.
WAY 100635 (N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide) was put in the literature by Cliffe et al., European Patent Publication 0512755, published Nov. 11, 1992. A number of papers about the compound and its activity as a 5-HT
1A
antagonist were presented at the IUPHAR Satellite Meeting o

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