Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-23
2001-03-20
Kight, John (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S323000, C546S199000, C546S201000
Reexamination Certificate
active
06204274
ABSTRACT:
This invention concerns a series of novel heteroaryl-&bgr;-hydroxypropylamines which are effective pharmaceuticals for the treatment of conditions related to or are affected by the reuptake of serotonin. The compounds are particularly useful for the treatment of depression, anxiety, drug withdrawal, eating and sexual disorders and other conditions for which serotonin reuptake inhibitors are used.
BACKGROUND TO THE INVENTION
In their article “4-(Indolyl-3)-1-(benzimidazolonylalkyl)-piperidines, a Novel Group of Potential Antiallergy Compounds”, Arzneim.-Forsch, 35 (1), 272-276 (1985), Freter et al. disclose compounds of the formula:
as anti-allergy agents by virtue of their histamine H1-blocking actions in addition to weak mast cell stabilizing properties.
SUMMARY OF THE INVENTION
Depression is a psychiatric condition thought to be associated with decreased serotonin release. Most antidepressant agents (e.g. fluoxetine) potentiate the effects of serotonin by blocking the termination of its activity through reuptake into nerve terminals. The present invention provides a series of novel indolyl derivatives which inhibit the reuptake of serotonin, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy for the treatment of central nervous system disorders, particularly depression.
Compounds of the present invention are represented by the general formula (1):
wherein:
R
1
and R
2
each independently represent hydrogen, hydroxy, F, Cl, Br, I, CN, 1 to 6 carbon alkyl, 1 to 6 carbon alkoxy, nitro, CF
3
and phenyloxy or benzyloxy, in which the aromatic ring can be optionally substituted by from 1 to 3 groups selected from C
1
-C
6
alkoxy (preferably OMe), F, Cl, Br, I, and CF
3
;
R
3
and R
4
are each independently a hydrogen, a 1 to 6 carbon alkyl or a CH
2
Ph in which the phenyl ring can be optionally substituted by from 1 to 3 groups selected from C
1
-C
6
alkoxy (preferably OMe), F, Cl, Br, I, and CF
3
;
Y is selected from CH
2
or CH and,
X is selected from a group represented by N, CR
3
, CHR
3
, CHCH;
or a pharmaceutically acceptable salt thereof.
A preferred group of compounds of this invention are those in which X is N and R
1
, R
2
, R
3
, R
4
and Y are as defined above. Another preferred group herein comprises compounds wherein X is CR
3
, CHR
3
or CHCH and R
1
, R
2
, R
3
, R
4
and Y are as defined above.
The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable inorganic acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, fumaric, acetic, lactic or methanesulfonic acid.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the present invention may be prepared using conventional methods. For example, treatment of the indole or benzimidazole derivative (2) with glycidyl tosylate affords the epoxide (3). Reaction of the epoxide with the piperidine or tetrahydropyridine derivatives (4) and (5) affords the respective products (1).
The preparation of the appropriately substituted 3-(4-piperidinyl)indoles and 3-(4-tetrahydro pyridinyl) indoles can be achieved by known and conventional methods. For example, the reaction of an optionally substituted indole with 4-piperidone affords the 3-(4-tetrahydropyridinyl)indole (5). This can be reduced using standard catalytic hydrogenation methodology to afford a 3-(4-piperidinyl)indole (4). Such methodology is described in C. Gueremy et al., J. Med. Chem., 1980, 23, 1306-1310, J-L. Malleron et al., J. Med. Chem., 1993, 36, 1194-1202 and J. Bergman, J. Heterocyclic. Chem., 1970, 1071-1076.
The present invention provides methods for inhibiting the reuptake of serotonin in mammals, preferably in humans. Compounds of the present invention inhibit with very high affinity the binding of paroxetine to the serotonin transporter, and consequently, they are useful for the treatment of central nervous system disorders such as depression, anxiety, including generalized anxiety disorder, sleep disorders, sexual dysfunction, obsessive-compulsive disorders, obesity, bulimia nervosa, migraine, chronic fatigue syndrome, pain, particularly neuropathic pain, panic disorder, post traumatic stress disorder, late luteal phase dysphoric disorder (also referred to a premenstrual syndrome), Tourette's syndrome, alcohol and cocaine addiction, Parkinson's disease, schizophrenia and for cognition enhancement such as in Alzheimer's disease.
It is understood that the therapeutically effective dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. Variables involved include the specific psychosis or state of anxiety and the size, age and response pattern of the patient. The novel method of the invention for treating conditions related to or are affected by the reuptake of serotonin comprise administering to warm-blooded animals, including humans, an effective amount of at least one compound of this invention or a non-toxic, pharmaceutically acceptable addition salt thereof. The compounds may be administered orally, rectally, parenterally, or topically to the skin and mucosa. The usual daily dose is depending on the specific compound, method of treatment and condition treated. An effective dose of 0.01-1000 mg/Kg may be used for oral application, preferably 0.5-500 mg/Kg, and an effective amount of 0.1-100 mg/Kg may be used for parenteral application, preferably 0.5-50 mg/Kg. The therapeutically effective dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. The variables involved include the specific malady or disorder and the size, age and response pattern of the patient.
The present invention also includes pharmaceutical compositions containing a compound of this invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Applicable solid carriers or excipients can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins. Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. Liquid pharmaceutical compositions
Kang Young H.
Kelly Michael G.
American Home Products Corporation
Covington Raymond
Eck Steven R.
Kight John
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