The present invention relates to organic compounds, a process for their production and pharmaceutical compositions containing them.
More particularly the present invention provides a compound of formula I:
each of m and n, independently, is 1, 2 or 3;
X is O or a direct bond;
a phenylalkyl wherein alkyl is a straight- or branched (C6-20)carbon chain; or
a phenylalkyl wherein alkyl is a straight- or branched (C1-30)carbon chain wherein said phenylalkyl is substituted at the phenyl residue by
a straight- or branched (C6-20)carbon chain optionally substituted by halogen,
a straight- or branched (C6-20)alkoxy chain optionally substitued by halogen,
a straight- or branched (C6-20)alkenyloxy,
phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl,
cycloalkylalkyl substituted by C6-20alkyl,
heteroarylalkyl substituted by C6-20alkyl,
heterocyclic C6-20alkyl or
heterocyclic alkyl substituted by C2-20alkyl,
the alkyl moiety may have
in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR5, wherein R5 is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and
as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy, or carboxy, and
wherein each of R3 and R4, independently, is H or C1-4alkyl, wherein alkyl is optionally substituted by 1, 2 or 3 halogen atoms;
in free form or in salt form.
Halogen is F, Cl, Br or I. Alkyl or alkoxy may be straight or branched chain.
Cycloalkyl is preferably C3-10cycloalkyl, more preferably C3-8cycloalkyl and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Acyl may be a residue Ry—CO— wherein Ry is C1-6alkyl, C3-6cycloalkyl, phenyl or phenyl-C1-4alkyl.
When in the compounds of formula I the carbon chain as R1 is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy. When the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted. When the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.
In the compounds of the invention, the following significances are preferred individually or in any sub-combination:
1. m and n are each 1 or 2, preferably 1.
2. X is O.
3. R1 is C13-20alkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R1 is phenylalkyl substituted by C6-14-alkyl chain optionally substituted by halogen and the alkyl moiety is a C1-6alkyl optionally substituted by hydroxy. More preferably, R1 is phenyl-C1-6alkyl, e.g. phenyl-C1-6alkyl, e.g. phenyl-C2alkyl, substituted on the phenyl by a straight or branched, preferably straight, C6-14alkyl chain. The C6-14alkyl chain may be in ortho, meta or para, preferably in para.
4. each of R3 and R4 is H.
A particularly preferred compound is phosphoric acid mono-[2-hydroxymethyl-4-(4-octyl-phenyl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-butyl]ester.
Compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. inorganic acids, such as hydrochloride, hydrobromide or sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or benzenesulfonate salts; when R3 or R4 is H, R2 may also be present in salt form, e.g. an ammonium salt or salts with metals such as sodium, potassium, calcium, zinc or magnesium, or a mixture thereof. Compounds of formula I and their salts in hydrate or solvate forms are also part of the invention.
The compounds of formula I have one or more asymmetric centers in the molecule, and thus various optical isomers may be obtained. The present invention also encompasses enantiomers, racemates, diastereoisomers and mixtures thereof. The central asymmetric carbon atom may have the R or S configuration. Moreover, when the compounds of formula I include geometric isomers, the present invention embraces cis-compounds, trans-compounds and mixtures thereof. Similar considerations apply in relation to starting materials exhibiting asymmetric carbon atoms or unsaturated bonds as mentioned above.
A compound of formula I may be prepared by reacting a compound of formula II:
wherein m, n, X, R1 and R2 are as defined in formula I;
with an aromatic 1,2-dicarbaldehyde, e.g. benzene-1,2-dicarbaldehyde, and recovering the resulting compound of formula I in free or salt form.
The process may be performed according to methods known in the art, e.g. as described in the examples.
A compound of formula II (e.g. a racemic mixture thereof) may be obtained as described in WO 02/18395 or WO 02/076995.
The present invention also provides a compound of formula I or formula II, wherein greater than 70% by weight of the compound is in the form of the S enantiomer, or greater than 70% by weight of the compound is in the form of the R enantiomer, e.g. greater than 90% is in the form of the R or S enantiomer. More preferably greater than 95% by weight, e.g. greater than 99% by weight of the compound is in the form of the R or S enantiomer. Thus the invention may relate to the substantially pure R or S enantiomer (e.g. the S enantiomer substantially free of the R enantiomer or vice versa), preferably the S enantiomer, of a compound of formula I or formula II. Particularly preferred are the substantially pure (e.g. greater than 99% by weight) R or S enantiomers, especially the S enantiomers, of phosphoric acid mono-[2-amino-2-hydroxymethyl-4-(4-octyl-phenyl)-butyl]ester (FTY720-phosphate) and phosphoric acid mono-[2-hydroxymethyl-4-(4-octyl-phenyl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-butyl]ester.
Compounds having the following 3-dimensional configuration are generally preferred:
Enantiomers of the compounds of formula I and II cannot be satisfactorily separated by standard methods. According to the present invention, separation of the enantiomers is achieved by the use of novel separation techniques and synthesis strategies.
A compound of formula I, wherein greater than 70% by weight of the compound is in the form of the R or S enantiomer, e.g. the substantially pure R or S enantiomer, may be obtained by:
a) separation of the S enantiomer from the R enantiomer in a racemic mixture of a compound of formula I, using chromatography on a chiral stationary phase; or
b) reacting a compound of formula II, wherein greater than 70% by weight of the compound is in the form of the R or S enantiomer, e.g. the substantially pure R or S enantiomer of a compound of formula II, with an aromatic 1,2-dicarbaldehyde e.g. benzene-1,2-dicarbaldehyde.
According to method a), the chromatographic separation is preferably carried out using a chiral ion-exchange phase based on quinine carbamate or quinidine carbamate as chiral selector, e.g. a quinine carbamate phase (8S,9R) available commercially under the tradename ProntoSIL Chiral AX QN-1: