Itraconazole and saperconazole stereoisomers

Details Itraconazole and saperconazole stereoisomers Itraconazole and saperconazole stereoisomers

1995-01-26

2002-02-12

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S965000, C514S252010, C514S255030, C514S396000, C514S397000, C514S399000, C514S524000, C514S648000, C514S651000, C536S103000, C558S415000, C558S422000, C544S366000, C544S370000

Reexamination Certificate

active

06346518

ABSTRACT:

The present invention is concerned with the stereoisomeric forms of itraconazole and saperconazole, processes for preparing said stereoisomeric forms, the complexes thereof with cyclodextrin derivatives, pharmaceutical compositions comprising said complexes and methods of preparing said complexes and pharmaceutical compositions.
Itraconazole or (±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinylphenyl]-2,4-dihydro-2-(1-methyl-propyl)-3H-1,2,4-triazol-3-one, is a broadspectrum antifungal compound developed for oral, parenteral and topical use and is disclosed in U.S. Pat. No. 4,267,179. Its difluoro analog, saperconazole or (±)-cis-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxylphenyl]-1-piperazinyl]-phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one, has improved activity against Aspergillus spp. and is disclosed in U.S. Pat. No. 4,916,134. Both compounds exist as a mixture of four stereoisomers.
The development of efficaceous pharmaceutical compositions of itraconazole and saperconazole is hampered considerably by the fact that said compounds are only very sparingly soluble in water. The solubility of both compounds can be increased by complexation with cyclodextrins or derivatives thereof as described in WO 85/02767 and U.S. Pat. No. 4,764,604.
Unexpectedly, it has now been found that each of the individual stereoisomers of itraconazole and saperconazole have greater water solubility than the diastereomeric mixtures of said compounds, in particular when complexed with cyclodextrin or its derivatives. As a result, pharmaceutical compositions having good bioavailability, yet comprising less cyclodextrin as a complexing agent, can be prepared.
The present invention is concerned with the stereoisomeric forms of itraconazole (X=Cl) and saperconazole (X=F), which may be represented by the formula
and the pharmaceutically acceptable acid addition salt forms thereof. The three asterisks indicate the three chiral centers, and ‘cis’ means that the (1H-1,2,4triazol-1-ylmethyl) moiety and the substituted phenoxy moiety are located at the same side of the plane defined by the 1,3Aioxolane ring.
The four possible stereoisomeric cis forms can be described using various rules of nomenclature. The following tables show the correlation among the C.A. stereochemical descriptor, the absolute configuration at each of the chiral centers and the specific optical rotation [&agr;]
D
20
in 1% methanol (itraconazole; table I) (saperconazole; table II).
TABLE I

absolute configuration at
[&agr;]
D
20
C.A. descriptor
(a)
(b)
(c)
(1% CH
3
OH)
(+)-[2R-[2&agr;,4&agr;,4(R)]]
R
S
R
+14.15°
(+)-[2R-[2&agr;,4&agr;,4(S)]]
R
S
S
+19.08°
(−)-[2S-[2&agr;,4&agr;,4(R)]]
S
R
R
−18.78°
(−)-[2S-[2&agr;,4&agr;,4(S)]]
S
R
S
−13.46°
TABLE II

absolute configuration at
[&agr;]
D
20
C.A. descriptor
(a)
(b)
(c)
(1% CH
3
OH)
(+)-[2R-[2&agr;,4&agr;,4(R)]]
R
S
R
+9.00°
(+)-[2R-[2&agr;,4&agr;,4(S)]]
R
S
S
+14.13°
(−)-[2S-[2&agr;,4&agr;,4(R)]]
S
R
R
−13.55°
(−)-[2S-[2&agr;,4&agr;,4(S)]]
S
R
S
−8.41°
The term ‘stereoisomeric form’ as used herein concerns compounds having a stereoisomeric purity of at least 96% up to a stereoisomeric purity of 100%, in particular compounds having a stereoisomeric purity of 98% up to 100%. In particular, said stereoisomeric forms define compounds having an enantiomeric excess and a diastereomeric excess of at least 96% up to 100%, more particularly, having an enantiomeric excess and a diastereomeric excess of 98% up to 100%.
With regard to the intermediates described hereinafer, the term “enantiomerically pure” defines intermediates having an enantiomeric excess of at least 96% up to 100%, more particularly, having an enantiomeric excess of 98% up to 100%.
The stereoisomeric forms of the compounds of formula (I) have basic properties. The pharmaceutically acceptable acid addition salts as mentioned hereinabove comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. Said salt forms can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The term acid addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The four individual stereoisomeric forms of the compounds of formula (I) can be prepared by O-alkylating an enantiomerically pure phenol of formula (−)-(R)-(II) or (+)-(S)-(II) with an enantiomerically pure 1,3-dioxolane derivative of formula (−)-(2S,cis)-(III) or (+)-(2R,cis)-(III) wherein —OR represents a sulfonyloxy leaving group such as 4-methylbenzenesulfonyloxy (tosylate) or methanesulfonyloxy (mesylate).
Said O-alkylation reaction can conveniently be conducted following art-known procedures, e.g. by stirring and heating the reactants in an appropriate solvent such as a dipolar aprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide and the like, in the presence of a base such as, an alkali metal hydroxide, e.g. sodium or potassium hydroxide. The thus obtained stereoisomeric forms of the compound of formula cis-(I) may be purified further following art-known methodologies such as liquid chromatography and crystallization.
The relation between the stereochemistry of the stereoisomeric forms of the compound of formula (I) obtained in said O-alkylation reaction and the stereochemistry of the starting materials (II) and (III) is shown in the table herebelow.
cis-(I)
cis-(III)
(II)
(+) − [2R − [2&agr;,4&agr;,4(R)]]
(+) − (2R,cis) − (III)
(−) − (R) − (II)
(+) − [2R − [2&agr;,4&agr;,4(S)]]
(+) − (2R,cis) − (III)
(+) − (S) − (II)
(−) − [2S − [2&agr;,4&agr;,4(R)]]
(−) − (2S,cis) − (III)
(−) − (R) − (II)
(−) − [2S − [2&agr;,4&agr;,4(S)]]
(−) − (2S,cis) − (III)
(+) − (S) − (II)
The enantiomerically pure phenol of formula (−)-(R)-(II) can conveniently be prepared starting from (S)-2-butanol (IV). The enantiomeric (S)-butanol (IV) can be converted into a corresponding (S)-sulfonate (V) by reaction with 4-methylbenznesulfonyl chloride (R=Me) or 1-bromo-4-benzenesulfonyl chloride (R=Br) in pyridine.
Enantioselective coupling of the sulfonate (S)-(V) with the triazolone (VI) (prepared as described in Example XVII of U.S. Pat. No. 4,267,179) proceeds with inversion of configuration at the chiral center and yields (−)-(R)-(VII).
Said coupling reaction can be conducted in a reaction inert solvent such as a dipolar aprotic solvent, preferably N,N-dimethylformamide, in the presence of a base such as sodium hydride. The ena

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