Tetracyclic compounds

Details Tetracyclic compounds Tetracyclic compounds

1993-12-22

1994-12-06

Richter, Johann

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

A61K 3144, C07D22118

Patent

active

053712250

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP93/00527 filed Apr. 23, 1993.


TECHNICAL FIELD

The present invention relates to novel tetracyclic compounds which are useful as immunosuppresive agents.


PRIOR ART

A compound represented by the formula ##STR2## (where R.sup.1 represents CO.sub.2 H, etc.; R.sup.2 and R.sup.3 independently represent H, F, etc.; and R.sup.4 and R.sup.5 independently represent H, etc.) is disclosed in Japanese Published Unexamined Patent Application No. 233661/90 corresponding to U.S. Pat. No. 4,918,077 as being effective as a cancer chemotherapeutic agent, and in WO 92/00739, it is mentioned as being useful as an immunosuppresive agent.
The compound sodium 2- (2 '-fluoro-1, 1'-biphenyl-4-yl) -6-fluoro-3-methyl-4-quinoline carboxyl disclosed in Japanese Published Unexamined Patent Application No. 313428/89 corresponding to U.S. Pat. No. 5,084,462 as being useful as an immunosuppresive agent.
The compounds 5H-indeno [1,2-b]quinoline-6-carboxylic acid; 6, 7-dihydro-5H-benzo[6, 7]cyclohepta [1,2-b]quinoline-8-carboxylic acid and 5, 6, 7,8-tetrahydrobenzo [7,8]cycloocta[1,2-b]quinoline-9-carboxylic acid have been reported, but their pharmacological effects are unknown [(Liebigs Ann. Chem., 610, 57 (1957) ].


DISCLOSURE OF THE INVENTION

According to the present invention, there are provided novel tetracyclic compounds represented by formula (I) ##STR3## (wherein X.sup.1 and X.sup.2 independently represent hydrogen or lower alkyl; and n represents an integer of 1 t6 4) and pharmaceutically acceptable salts thereof.
In the definition of the respective groups in formula (I), the lower alkyl includes straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertbutyl, pentyl, neopentyl, hexyl, etc.
The pharmaceutically acceptable salts of Compound (I) include metal salts, ammonium salts, organic amine addition salts and amino acid addition salts.
As the pharmaceutically acceptable metal salts of Compound (I) include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salts and zinc salt; as the pharmaceutically acceptable ammonium salts include salts of ammonium and tetramethylammonium; as the pharmaceutically acceptable organic amine addition salts include addition salts with morpholine and piperidine; and as the pharmaceutically acceptable amino acid addition salt include addition salts with lysine, glycine and phenylalanine. The processes for producing the compounds of the present invention are described below.


PROCESS 1

Compound (I-a), Compound (I) wherein X.sup.1 and X.sup.2 are both hydrogen, can be obtained by the following reaction steps. ##STR4## (In the above formulae, n has the same meaning as defined above.)


STEP 1

Compound (III) can be obtained by treating Compound (II) with a dehydrating agent in the absence of a solvent usually at 50.degree. to 120.degree. C. for 1 to 6 hours.
The dehydrating agent includes polyphosphoric acid, methanesulfonic acid and sulfuric acid.


STEP 2

Compound (IV) can be obtained by reacting Compound (III) with 2 to 3 equivalents of triethylsilane in trifluoroacetic acid usually at room temperature to 70.degree. C. for 5 minutes to 6 hours.


STEP 3

Compound (V) can be obtained by reacting Compound (IV) with 1 to 4 equivalents of chromic acid in a mixed solvent of acetic acid/propionic acid usually at 0.degree. C. to room temperature for 1 to 6 hours.


STEP 4

Compound (I-a) can be obtained by reacting Compound (V) with an equivalent amount of Compound (VI) (product of Aldrich Co.) in a mixed solvent of ethanol/water under the alkaline condition where potassium hydroxide, sodium hydroxide, etc. are used usually at room temperature to 100.degree. C. for 12 to 120 hours. Compound (II) can be obtained by the following reaction steps. ##STR5## (In the above formulae, n has the same meaning as defined above. )


STEP 5

Compound (IX) can be obtained by reacting Compound (VII) (product o

REFERENCES:
patent: 4918077 (1990-04-01), Behrens
patent: 5084462 (1992-01-01), Ackerman et al.
Huisgen et al., Liebigs Ann. Chem., vol. 610 (1957) 57-66.

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