Claims
- 1. A tetrahydrofuran or tetrahydrothiophene of the formula ##STR23## wherein X stands for O of S;
- n is an integer from 1 to 6;
- R stands for a straight or branched C.sub.1 -C.sub.13 alkyl, a C.sub.5 -C.sub.10 cycloalkyl, a phenyl or a substituted phenyl having the formula: ##STR24## R.sub.1 to R.sub.5 is H, CH.sub.3 or OCH.sub.3 and Z.sup..crclbar. is a pharmaceutically acceptable anion.
- 2. A therapeutic composition of matter, comprising as an essential ingredient therein an effective amount of a compound according to claim 1 in admixture with the appropriate diluent or carrier.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 8712693 |
May 1987 |
GBX |
|
Parent Case Info
This application is a continuation-in-part of application Ser. No. 199,948 filed May 27, 1988, now abandoned.
The present invention relates to new 5-(.omega.-ammonio acyloxy methylene) tetrahydrofurans and tetrahydrothiophenes of the general formula: ##STR2## wherein
X stands for O or S;
n is an integer from 1 to 6;
R stands for a straight or branched C.sub.1 -C.sub.13 alkyl, a C.sub.5 -C.sub.10 cycloalkyl, an optionally substituted phenyl or an optionally substituted phenyl alkyl with 1 to 5 carbon atoms in the alkyl moiety, the substitutions R.sub.1 to R.sub.5 of the phenyl ring, of formula: ##STR3## being CH.sub.3 or OCH.sub.3 and Z.sup..crclbar. is a pharmaceutically acceptable anion.
The invention relates to these compounds under the form of each of their possible stereoisomers or of any mixture of the same.
These compounds are more particularly interesting as anti PAF agents (P A F means platelets aggregation factor) with the corresponding activity as anti-anaphylactic, antithrombotic, anti-ischemic, immunodepressors and acting also against immune alteration of kidney, against various shocks, against skin allergies and intestinal ulcers induced by endotoxine for instance.
The compounds according to the invention may be prepared by reacting a compound of formula I: ##STR4## with a compound of formula II: ##STR5## wherein X, n and R are as defined above and Y is an halogen.
The reaction is suitably carried out in an inert solvent such as dry CHCl.sub.3 at room temperature in the presence of triisopropylbenzenesulfonylchloride and pyridine and lead to the intermediate formula III: ##STR6## wherein X, n, R and Y are as defined above; this compound is further treated by pyridine for the obtention of the title compounds.
The compound of formula I may be synthesized according to the following steps:
An intermediate triol is prepared in accordance with the following steps: ##STR7##
This reaction is carried out under standard Grignard reaction conditions. The Grignard reagent is suitably prepared in situ by using dry magnesium turnings in dry ether and adding the brominated butene thereto. The substituted formaldehyde is added to the Grignard reagent. The substituted formaldehyde may be added by a stream of nitrogen gas into the solution of the Grignard reagent. The reaction is stopped by the addition of ice and dilute sulfuric acid, thus making the intermediate compound (A).
(A) is reacted with benzyl chloride (BzCl) to form the compound (B). ##STR8##
(B) is oxidized by cold dilute potassium permanganate (KMnO.sub.4) to form (C), the triol intermediate: ##STR9##
The triol (C) can be cyclized into a tetrahydrofuran or tetrahydrothiophene ring using protecting groups, mesylation and treatment either by water or Na.sub.2 S, the different synthesis methods depending on whether R is aromatic or aliphatic, and whether X is oxygen or sulfur.
(1) When R is aromatic and X=O, (C) is cyclized by hydrogenation with H.sub.2 /Pd under standard acidic conditions, forming the substituted tetrahydrofuran (D) of formula I: ##STR10## where R is aromatic.
(2) When R is aliphatic and X=O, the compound of formula I is made as follows:
(C) from above is hydrogenated with H.sub.2 /Pd. Here, cyclization is prevented by performing the hydrogenation under basic conditions such as by adding calcium carbonate (CaCO.sub.3), forming the triol: ##STR11##
The primary hydroxyl is substituted with the protecting group triphenylmethyl chloride (Tr) [(C.sub.6 H.sub.5).sub.3 CCl] and the other hydroxyl groups are substituted with mesyl chloride (MS) (CH.sub.3 SO.sub.2 Cl) to form the compound (E): ##STR12##
(E) is then cyclized in water and hexametapol (HMPT) to form the following compound: ##STR13## which is hydrogenated with H.sub.2 /Pd to form the substituted tetrahydrofuran (F) where R is aliphatic: ##STR14##
(3) To form the compound of formula I where X=S and R is aliphatic or aromatic, the foregoing steps up to compound (E) are followed. The sulfur is introduced into the ring by the addition of Na.sub.2 S in HMPT to form the compound: ##STR15##
The triphenylmethyl chloride is removed by adding formic acid to form the substituted tetrahydrothiophene (G): ##STR16## where R may be aliphatic or aromatic.
(D), (F) and (G) as described above are all variants of the substituted tetrahydrofurans and tetrahydrothiophenes of formula I used as the starting materials in the present invention.
Non-Patent Literature Citations (2)
| Entry |
| Chemical Abstracts, vol. 110 (No. 21) abst. No. 192,663-c; May 22, 1989. |
| Chemical Abstracts, vol. 110 (No. 25) abst. No. 231,446f Jun. 19,1989. |
Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
199948 |
May 1988 |
|
Patent Grant
5017588
