Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1993-03-16
1994-12-20
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D22314, C07D22316, C07D22318
Patent
active
053747224
DESCRIPTION:
DESCRIPTION
DETAILED DESCRIPTION OF THE INVENTION
It is noted that, when R.sub.1 and R.sub.2 on the same carbon atom are different, e.g., H and CH.sub.3, respectively, stereoisomers of the following formulas exist: ##STR6##
All such isomeric forms and mixtures thereof are within the scope of the present invention. Unless otherwise indicated, the methods of preparation disclosed herein may result in product distributions which include all possible structural isomers, although it is understood that physiological response may vary according to stereochemical structure. The isomers may be separated by conventional means such as fractional crystallization or HPLC (high performance liquid chromatography),
Compounds of formulas I or II can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of this invention. All such forms are within the scope of this invention.
The compounds of formulas I or II may form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfide, phosphoric, acetic, citric, malonic, saliiicylic, malic, fumaric, succinic, ascorbic, maleic, methanesuIfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms and are within the scope of this invention.
When utilized herein and in the appended claims, the following terms, unless otherwise specified, have the following meanings:
alkyl (including the alkyl portions of alkoxy, hydroxyalkyi haloalkyl, etc.)- represents a straight or branched, saturated hydrocarbon chain having from 1 to 8. preferably from 1 to 6, carbon atoms (The number of carbon atoms can be designated. For example, C.sub.1 -C.sub.4 alkyl" represents a straight or branched, saturated hydrocarbon having from 1 to 4 carbon atoms.);
alkoxy - represents an alkyl group attached to a molecule through an oxygen atom (alkyl--O--);
allyl - represents the groups --CH.sub.2 --CH=CH.sub.2,--CH=CH--CH.sub.3, or--C(CH.sub.3).dbd.CH.sub.2 ;
halo - represents fluoro, chloro, bromo or iodo;
haloalkyl - represents an alkyi group as defined above wherein 1 to 3 hydrogens thereof have been replaced with a halo moiety, e.g., trifluoromethyl, 2-chloroethyl, etc.; and
substituted phenyl - represents a phenyl group in which 1 to 3 hydrogen atoms thereof are replaced by the same or different sustituents independently chosen from hydroxy, alkyl, halo, nitro, alkoxy, haloalkyl including trifluoromethyl, cyano, cycloalkyl, SH, or S(O)pR.sup.a [wherein p is 0, 1 or 2 and R.sup.a is alkyl].
As used herein degrees or ".degree." refers to degrees Celsius unless otherwise indicated.
The compounds of formula I above may be prepared by the methods described below with reference to Schemes 1 and 2, wherein G, Y, Z and R, R.sub.1, and R.sub.2 are as defined above, unless otherwise indicated: ##STR7##
wherein R.sub.3, R.sub.4, Y and Z are as described above and R' is ##STR8## H, alkyl or
wherein R, R.sub.3, R.sub.4, Y and Z are as described above, and R.sub.1 and R.sub.2 are the same as R.sub.1 and R.sub.2 respectively as previously define, but with the proviso that R.sub.1 and R.sub.2 cannot both be H. Hal is halogen. ##STR9##
Starting materials of formulas, III, III', III", or III"', are known, or may be prepared as disclosed in EPA 0285,919 or by methods analogous to those disclosed therein. EPA 0285,919
REFERENCES:
patent: 4769368 (1988-09-01), Kaiser et al.
patent: 4957914 (1990-09-01), Clark et al.
Weinstock et al. J. Med. Chem., (1987), 30, pp. 1303-1308.
CA 107:58826(t), Weinstock et al (1987).
CA 108:37670(t), Kaiser et al (1987).
Annals of the New York Academy of Sciences, vol. 66, pp. 740-752 (1957), Cook et al.
Clark et al., J. Med. Chem., (1990), 33, pp. 633-641.
Berger Joel G.
Chang Wei K.
Clader John W.
Boxer Matthew
Datlow P. I.
Dicker Eric S.
Mazer Edward
Schering Corporation
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