Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-01
2002-05-28
Seaman, D. Margaret (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S428000, C546S234000, C548S567000
Reexamination Certificate
active
06395759
ABSTRACT:
This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
U.S. Pat. No. 4,022,900 (Marion) discloses benzamido-tetrahydroisoquinolines having anti-hypertensive and vasodilator properties, including the compound 2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide.
The compound N-[2-(1-methyl-pyrrolidin-2-yl)-phenyl]benzamide is disclosed in JACS 1976, 98, p6321.
It has now been surprisingly found that benzamide compounds of formula (I) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, panic disorders and/or aggression.
Accordingly, the present invention provides a compound of formula (I) or pharmaceutically acceptable salt thereof.
where
G is a methylene or ethylene linkage;
R
1
is hydrogen, C
1-6
alkylO—;
R
2
is hydrogen, halogen, CN, N
3
, trifluoromethyldiazirinyl, CF
3
, CF
3
O—, CF
3
S—, CF
3
CO—, C
1-6
alkyl, C
3-6
cycloalkyl,C
3-6
cycloalkyl-C
1-4
alkyl-, C
1-6
alkylO—, C
1-6
alkylCO—, C
3-6
cycloalkylCO—, C
3-6
cycloalkyl-C
1-4
alkylCO—, phenyl,phenoxy, benzyloxy, benzoyl and substituted benzoyl, phenyl-C
1-4
alkyl-, C
1-6
alkylSO
2
—, (C
1-4
alkyl)
2
NSO
2
— or (C
1-4
alkyl)NHSO
2
—;
R
3
is hydrogen, halogen, CN, N
3
, trifluoromethyldiazirinyl, C
1-6
alkylO—, C
1-6
alkylS—, C
1-6
alkyl, C
3-6
cycloalkyl,C
3-6
cycloalkyl-C
1-4
alkyl-, C
1-6
alkenyl, C
1-6
alkynyl, CF
3
CO—, C
1-6
alkylCO—, C
3-6
cycloalkylCO—, C
3-6
cycloalkyl-C
1-4
alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C
1-4
alkyl-, or —NR
5
R
6
where R
5
is hydrogen or C
1-4
alkyl, and
R
6
is hydrogen, C
1-4
alkyl, —CHO, —CO
2
C
1-4
alkyl or —COC
1-4
alkyl;
R
4
is hydrogen, C
1-6
alkyl, C
1-6
alkenyl, or C
1-6
alkynyl.
The compounds of this invention are typically (2-pyrrolidin/2-piperidin-yl-phenyl)-benzamides.
In the formula (I), groups are typically based on straight chain alkyl groups, but in general alkyl groups may be straight chain or branched.
Suitable C
3-6
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further, it should be appreciated that whenever the term phenyl is mentioned above, the phenyl moiety is optionally substitued for example it is independently substituted one or more times by a substituent selected from the list comprising halogen, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylcarbonyl.
Suitable halo substituents include fluoro, chloro, iodo and bromo.
A suitable group of compounds of formula (I) have
R
1
as methoxy, ethoxy or n-propoxy
R
2
as hydrogen, methoxy, bromo, chloro, iodo, acetyl, benzoyl, trifluoromethyl, trifluoroacetyl.
R
3
as hydrogen, methyl, ethyl, n-butyl, t-butyl, phenyl, methoxy, ethoxy, isopropoxy, n-butoxy, benzyloxy, amino, acetylamino, benzoyl, chloro or azido
R
4
as hydrogen, methyl, ethyl or propyl.
Examples of compounds of formula (I) are:
2-[3-(4-tert-butyl-2-methoxy-benzoylamino)-phenyl]-pyrrolidine.
2-[3-(4-tert-butyl-2-methoxy-benzoylamino)-phenyl]-piperidine.
When synthesised, these compounds are often in salt form, typically the hydrochloride or trifluoroacetate, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts. The compounds and their salts may be obtained as solvates, such as hydrates, and these also form part of this invention. It should be appreciated that the present compounds possess a chiral centre, therefore the present invention extends to each enantiomer separately and to all mixtures of enantiomers including racemates.
The above compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
The administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual or transdermal administration.
An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 5000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 5000 mg, for example 1 to 1500 mg, that is in the range of approximately 0.01 to 70 mg/kg/day, for example 0.1 to 20 mg/kg/day.
It is greatly preferred that the compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral, including sub-lingual, rectal, topical or parenteral (especially intravenous) composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art.
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, pro
Thompson Mervyn
Vong Antonio Kuok Keong
Ward Robert William
Covington Raymond
Hall Linda E.
King William T.
Kinzig Charles M.
Seaman D. Margaret
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