Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-07-20
2001-07-17
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S187000
Reexamination Certificate
active
06262075
ABSTRACT:
This invention relates to piperidones. More particularly, this invention relates to 5-(3,4-dichlorophenyl)-5-(2-[3-(4-fluoropiperidin-1-yl)]azetidin-1-yl)ethylpiperidin-2-one derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and uses of, such derivatives.
These derivatives are antagonists of tachykinins, including NKA, NKB and Substance P, acting at the human neurokinin-1 (NK
1
), neurokinin-2 (NK
2
) or neurokinin-3 (NK
3
) receptor, or any combination thereof. The derivatives are therefore useful for preventing or treating an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a central nervous system (CNS) disorder such as anxiety, depression, dementia or psychosis, a gastro-intestinal (GI) disorder such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis or Crohn's disease, a disease caused by
Helicobacter pylori
or other urease-positive Gram negative bacteria, an urogenital tract disorder such as incontinence, impotence, hyperreflexia or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a vasospastic disease such as angina or Reynaud's disease, a fibrosing or collagen disease such as scleroderma or eosinophillic fascioliasis, reflux sympathetic dystrophy such as shoulder/hand syndrome, an addiction disorder such as alcoholism, a stress-related somatic disorder, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia or post-herpetic neuralgia, a neuropathological disorder such as Alzheimer's disease or multiple sclerosis, a disorder related to immune enhancement or suppression such as systemic lupus erythematosis, a rheumatic disease such as fibrositis, emesis, cough, acute or chronic pain, migraine, or an opthalmic disease such as proliferative retinopathy.
These derivatives are particularly potent and selective antagonists of tachykinins, including NKA, NKB and Substance P, acting at the human NK
2
receptor. They are particularly useful for treating or preventing an inflammatory disease such as arthritis, psoriasis, asthma or inflammatory bowel disease, a central nervous system (CNS) disorder such as anxiety, depression, dementia or psychosis, a gastrointestinal (GI) disorder such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis or Crohn's disease, an urogenital tract disorder such as incontinence, hyperreflexia or cystitis, a pulmonary disorder such as chronic obstructive airways disease, an allergy such as eczema, contact dermatitis or rhinitis, a hypersensitivity disorder such as to poison ivy, a peripheral neuropathy such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, a burn, herpetic neuralgia or post-herpetic neuralgia, cough or acute or chronic pain.
International Patent Application Publication no. WO96/05193 discloses azetidinylalkyllactam derivatives with tachykinin antagonist activity, including 1-cyclopropylmethyl-5-(3,4-dichlorophenyl)-5-(2-[3-(4-fluoropiperidin-1-yl)]azetidin-1-yl)ethylpiperidin-2-one and pharmaceutically acceptable salts thereof. EP-A-0512901 discloses cyclic amine derivatives which have neurokinin receptor antagonist activity. EP-A-0723959 describes lactam derivatives which have tachykinin receptor antagonist activity.
The present invention provides a compound of the formula:-
or a pharmaceutically acceptable acid addition salt thereof, wherein
X is a direct link or C
1
-C
4
alkylene; and
R is C
3
-C
7
cycloalkyl optionally substituted by 1 or 2 substituents each independently selected from fluoro and C
3
-C
7
cycloalkyl: with the proviso that X is not methylene when R is cyclopropyl.
In the above definition of a compound of the formula (I), an alkylene group containing 3 or 4 carbon atoms may be straight- or branched-chain.
Preferably, X is a direct link, methylene or ethylene.
Most preferably, X is methylene.
Preferably, R is C
3
-C
6
cycloalkyl optionally substituted by 1 or 2 substituents each independently selected from fluoro and C
3
-C
6
cycloalkyl, preferably cyclopropyl.
More preferably, R is cyclopropyl, 1-cyclopropylcyclopent-1-yl, cyclohexyl or 4,4-difluorocyclohexyl.
Most preferably, R is 4,4-difluorocyclohexyl.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples include the hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, benzoate, methanesulphonate, benzenesulphonate, p-toluenesulphonate, 5-sulphosalicylate and 10-camphorsulphonate salts. A preferred acid addition salt is the disuccinate salt.
For a review on suitable acid addition salts see Berge et al, J. Pharm. Sci., 66, 1-19 (1977).
A compound of the formula (I) contains at least one asymmetric carbon atom and therefore exists in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) and mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid.
The preferred compounds of the formula (I) have the (S)- stereochemistry at the 5-position of attachment of the 3,4-dichlorophenyl and 2-[3-(4-fluoropiperidin-1-yl)]azetidin-1-ylethyl groups to the piperidin-2-one ring, i.e.
wherein X and R are as previously defined for a compound of the formula (I).
Preferred examples of a compound of the formula (I) are those wherein:
(i) R—X— is 4,4-difluorocyclohexylmethyl;
(ii) R—X— is cyclohexyl;
(iii) R—X— is 1-cyclopropylcyclopent-1-yl; or
(iv) R—X— is 2-cyclopropylethyl:
or any such compound with the (S)- stereochemistry at the 5-position of the 2-piperidinone ring, or a pharmaceutically acceptable acid addition salt of any thereof.
A particularly preferred compound of the formula (I) is 5(S)-5-(3,4-dichlorophenyl)-1-(4,4-difluorocyclohexylmethyl)-5-(2-[3-(4-fluoropiperidin-1-yl)]azetidin-1-yl)ethylpiperidin-2-one or an acid addition salt thereof and preferably a disuccinate salt thereof.
The compounds of the formula (I) provided by the invention can be prepared by the following methods:
1) The compounds of the formula (I) can be prepared by reductive amination using as starting materials a compound of the formula:
where R and X are as previously defined for a compound of the formula (I), and a compound of the formula:
or an acid addition salt thereof. The reaction is preferably carried out in the presence of a suitable acid, e.g. acetic acid.
The reaction proceeds via the initial formation of an intermediate iminium salt of the formula:
where W is an anion (e.g. acetate) derived from a suitable acid (e.g. acetic acid), which may be stable and isolatable. The reaction is preferably carried out without isolation of the intermediate of the formula (IV), in which case it is reduced in situ to provide a compound of formula (I).
In a typical procedure, an aldehyde of the formula (II) is first reacted with an azetidine of the formula (III) in a suitable solvent, e.g. tetrahydrofuran, and the mixture is then treated with a suitable reducing agent, e.g. sodium triacetoxyborohydride or sodium cyanoborohydride, in the presence of a suitable acid, e.g. acetic acid, to
MacKenzie Alexander Roderick
Marchington Allan Patrick
Meadows Sandra Dora
Middleton Donald Stuart
Ginsburg Paul H.
Joran A. David
Morris Patricia L.
Pfizer Inc
Richardson Peter C.
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