8-Hydroxy-hexahydronaphth[1',2':4,5]imidazo[2,1-b]thiazole and i

Details 8-Hydroxy-hexahydronaphth[1',2':4,5]imidazo[2,1-b]thiazole and i 8-Hydroxy-hexahydronaphth[1',2':4,5]imidazo[2,1-b]thiazole and i

1980-08-15

1982-08-31

Rollins, Alton D.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

424270, 424232, 548305, 564428, A61K 31425, C07D51304

Patent

active

043473695

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel compounds used as a medicine and veterinary drug and a method of preparing them. More particularly, the present invention relates to hexahydronaphth[1',2':4,5]imidazo[2,1-b]thiazole and its derivatives which are usable as a medicine for treating cancer or autoimmune diseases such as rheumatoid arthritis because of their immunostimulative and immunoregulative activities and as a veterinary anthelmintic and to a method of preparing them.


BACKGROUND ART

Tetramisole, or 2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole hydrochloride, is used as a veterinary anthelmintic and levamisol of formula (a) given below, that is, the levorotatory isomer of tetramisole, has immunostimulative and immunoregulative activities. ##STR3## Much attention has been paid to these activities for application to immunotherapy for cancer and treatment for autoimmune diseases such as rheumatoid arthritis.
Further, 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazole[3,2-a]benzimidazole-2-ace tic acid (NSC 208828), which has a chemical structure similar to levamisol as shown in formula (b), also has been known to have immunostimulative and carcinostatic activities. Although these activities are ##STR4## lower than in levamisole, its low toxicity has received considerable attention.
Their pharmaceutical effect, toxicity, etc., have yet to be elucidated definitely and thorough investigation has been expected on these compounds and their analogs with similar structure.
The present inventors, in an effort to find compounds having better immunostimulative and immunoregulative activities as compared with these known compounds aforementioned, have synthesized many kinds of novel compounds with basic structures analogous to that of the known compounds mentioned above, studied the pharmaceutical properties, and have come to achieve the present invention.


DISCLOSURE OF INVENTION

The present invention relates to hexahydronaphth [1',2':4,5]imidazo[2,1-b]thiazole and its derivatives which are shown as formula [I] ##STR5## (where X.sub.1 and X.sub.2 stand for hydrogen and halogen atoms; R represents a hydrogen atom, lower alkyl of 1 to 4 carbon atoms or carboxyl-substituted lower alkyl given as HOOC(CH.sub.2).sub.n --(n is an integral number of 1 to 3); A, B, C, and D symbolize the rings respectively and the configuration of rings B and C is trans).
According to the present invention, hexahydronaphth[1',2':4,5]imidazo[2,1-b]thiazole and its derivatives of formula [I] are prepared by reaction of tetrahydronaphthimidazoline-2-thiones (3a,4,5,9a-tetrahydronaphth[1,2-d]imidazoline-2-thione and its derivatives) of formula [II] ##STR6## (where X represents a hydrogen or halogen atom; A, B, and C symbolize the rings respectively; the configuration of rings B and C is trans) with .alpha.-haloketones of formula [III] ##STR7## (where X.sub.2 represents a hydrogen or halogen atom; X.sub.3 stands for a halogen atom; and R represents a hydrogen atom, lower alkyl of 1 to 4 carbon atoms, or carboxyl-substituted lower alkyl given as --(CH.sub.2).sub.n COOH (n is an integral number of 1 to 3)).


Best Mode of Carrying out the Invention

In formula [I] described above, X.sub.1 and X.sub.2 are hydrogen or halogen atoms, in which the halogen is preferably fluorine, chlorine or bromine. The position and number of the halogen substitution are not restricted in particular. R is a hydrogen atom, lower alkyl of 1 to 4 carbon atoms or carboxyl-substituted lower alkyl given as --(CH.sub.2).sub.n COOH (n is an integral number of 1 to 3) and especially a hydrogen atom, methyl, and carboxymethyl are preferred.
In the present invention, the configuration of rings B and C is trans-form. The synthesis of derivatives with cis-form in rings B and C is very difficult due to the steric hindrance of the phenyl group in the 8-position of formula [I]. The configuration of the substituents in the 8- and 9-positions is not restricted in particular in the present invention.
In the present invention, the hexahydronaphth[1', 2':4,5]imida

REFERENCES:
patent: 3954784 (1976-05-01), Acheson et al.
Knysh et al, Chemical Abstracts, vol. 76, Abstract No. 59209b (1972).
Radhakrishna et al, Chem. Abstracts, vol. 88, Abstract No. 136517y (1978).

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