Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Patent
1999-02-16
2000-08-08
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
544 89, 548486, C07D26512, C07D20934
Patent
active
061003972
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a new synthetic process to a compound having pharmacological activity.
WO93/18036 (SmithKline Beecham plc) describes compounds having 5-HT.sub.4 receptor antagonist activity of formula (I), or a pharmaceutically acceptable salt thereof: ##STR2## wherein X is O, S, SO, SO.sub.2, CH.sub.2, CH or NR wherein R is hydrogen or C.sub.1-6 alkyl; alkyl; ##STR3## wherein (CH.sub.2).sub.z -R.sub.10 wherein z is 2 or 3 and R.sub.10 is selected from cyano, hydroxyl, C.sub.1-6 alkoxy, phenoxy, C(O)C.sub.1-6 alkoxy, COC.sub.6 H.sub.5, -CONR.sub.11 R.sub.12, NR.sub.11 COR.sub.12, SO.sub.2 NR.sub.11 R.sub.12 or NR.sub.11 SO.sub.2 R.sub.12 wherein R.sub.11 and R.sub.12 are hydrogen or C.sub.1-6 alkyl; and and heterocyclic bioisostere;
Examples of alkyl or alkyl containing groups described herein include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11 or C.sub.12 branched, straight or cyclic alkyl, as appropriate. C.sub.1-4 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulfuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, maleic, citric, succinic, benzoic, ascorbic, methanesulfonic, .alpha.-keto glutaric, .alpha.-glycerophosphoric, and glucose-1-phosphoric acids.
Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds R.sub.x -T wherein R.sub.x is C.sub.1-6 alkyl, phenyl-C.sub.1-6 alkyl or C.sub.5-7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of R.sub.x include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples of T include halide such as chloride, bromide and iodide.
Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.
The compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is referred to.
Example 3 describes the hydrochoride salt of the compound of formula (I): ##STR4##
This compound is N-[(1-.sup.n butyl4-piperidyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carbo xamide SB 207266, (the hydrochloride salt is SB 207266-A) which is being developed by SmithKline Beecham plc as the active ingredient in a medicament for treatment of irritable bowel syndrome.
Example 3 of WO93/18036 describes a method of preparation of SB 207266-A from N-[(1-.sup.n butyl4-piperidyl)methyl]indole-3-carboxamide (i.e. the compound corresponding to SB 207266, without the oxazino moiety), by reacting with N-chlorosuccinimide and 3-bromo-1-propanol, followed by treatment with sodium carbonate. N-[(1-.sup.n butyl-4-piperidyl)methyl]indole-3-carboxamide is prepared by coupling N-(1-.sup.n butyl-4-piperidyl)methylamine with a indole-3-carboxylic acid.
An alternative process for preparing SB 207266-A has now been discovered which involves the use of the N-(1-.sup.n butyl4-piperidyl)methylamine intermediate at a later stage in the process thus resulting in an increased yield of SB 207266-A relative to the amount of this intermediate, which is relatively expensive to produce.
Accordingly, the present invention provides a process for the preparation of SB 207266 or a pharmaceutically acceptable salt thereof, which process comprises the reaction of of N-(1-.sup.n butyl-4-piperidyl)methylamine with a compound of formula (A): ##STR5## wherein R is alkyl, such as methyl or ethyl.
The compound of formula (A) wherein R is methyl is methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate.
The conditions and reage
REFERENCES:
patent: 5705498 (1998-01-01), Gaster et al.
Faster, et al. J. Med. Chem., 1995, 38, pp. 4760-4763.
Wayman, et al., Bioorganic & Medicinal Chemistry vol. 4, No. 2, 1996, pp. 255-260.
Fedouloff Michael
Guest David William
Smith Gillian Elizabeth
Strachan John Bryce
King William T.
Kinzig Charles M.
Raymond Richard L.
Schroeder Ben
Simon Soma G.
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