Claims
- 1. A compound of the formula: ##STR288## wherein: R.sub.1 and R.sub.2 are different, and are selected from the group consisting of hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons or together represent a methylene group --(CH.sub.2).sub.n -- where n is a whole number of from 1 to 6;
- R.sub.3 represents one or more substituents up to five selected from the group consisting of:
- hydrogen, halogen, haloalkyl of 1-12 carbons, alkyl of 1-12 carbons, alkoxy of 1-12 carbons, alkenyl of 2-12 carbons, cycloalkyl of 3-12 carbons, mono- or dicyclic aryl,
- --ZR.sub.5 where Z is O, S, S(O) or SO.sub.2 and R.sub.5 is hydrogen, alkyl of 1-18 carbons, cycloalkyl of 3-12 carbons or phenyl;
- --NR.sub.6 R.sub.7 where R.sub.6 and R.sub.7 may be the same or different and may be hydrogen, alkyl of 1-12 carbons, cycloalkyl of 3-6 carbons, phenyl, alkoxy of 1-12 carbons, acyl of the formula --C(O)R.sub.8 where R.sub.8 is alkyl of 1-12 carbons, cycloalkyl of 3-12 carbons, phenyl, CH.sub.3 OC(O)CH.sub.2 CH.sub.2 --, HOOCCH.sub.2 CH.sub.2 --, NaO.sub.3 SCH.sub.2 CH.sub.2 NHC(O) CH.sub.2 CH.sub.2 --, or R.sub.6 and R.sub.7 together may represent --C(O)CH.sub.2 CH.sub.2 (O)--, --C(O)--C.sub.6 H.sub.4 --C(O)-- or --(CH.sub.2).sub.x -- where x is 2, 3, 4, 5 or 6;
- morpholino imidazole or piperazino joined to the phenyl ring through a nitrogen atom; or
- R.sub.3 represents the atoms necessary to complete between adjacent ring carbons a further 3, 4, 5, 7, or 8 membered carbocyclic ring; a 6 membered non-aromatic carbocyclic ring or a 5-6 membered heterocyclic ring including one or more O, S or N rings atoms; and
- R.sub.4 is from one to five substituents selected from halogen, nitro, --C(O)CH.sub.3, S(O).sub.p R.sub.9 where p is 0, 1 or 2 and R.sub.9 is hydroxy, --ONa, or optionally substituted alkyl of 1-12 carbons or optionally substituted cycloalkyl, or
- a nontoxic pharmaceutically acceptable salt of said compound, provided that R.sub.3 and R.sub.4 are not both hydrogen and provided further that when R.sub.3 is phenoxy or represents the atoms necessary to complete between adjacent ring carbons a further carbocyclic ring, R.sub.4 is nitro or S(O).sub.p R.sub.9.
- 2. A compound according to claim 1 wherein: one of R.sub.1 and R.sub.2 is hydrogen and the other is an alkyl of 1-6 carbon atoms;
- R.sub.3 represents one or more substituents up to five selected from the group consisting of:
- hydrogen, lower alkyl or cycloalkyl, lower alkoxy, phenyl, the atoms necessary to complete a ring with adjacent carbon atoms of the phenyl ring; NR.sub.6 R.sub.7 where R.sub.6 is hydrogen and R.sub.7 is C(O)R.sub.8 where R.sub.8 is phenyl or R.sub.6 and R.sub.7 together represent --(CH.sub.2).sub.x -- where x is 2-6;
- R.sub.4 is S(O).sub.p R.sub.5 where p is 0, 1 or 2 and R.sub.5 is a lower alkyl carboxylic acid group; or
- a nontoxic pharmaceutically acceptable salt thereof.
- 3. A compound according to claim 2 wherein R.sub.4 is --SCH.sub.2 C(CH.sub.3).sub.2 COOH, --S(O)CH.sub.2 C(CH.sub.3).sub.2 CO.sub.2 H or --SO.sub.2 CH.sub.2 C(CH.sub.3)CO.sub.2 H.
- 4. A compound according to claim 3 wherein R.sub.4 is in the para position.
- 5. A compound of the formula: ##STR289## wherein: R.sub.1 and R.sub.2 are both methyl or ethyl; or are selected from the group consisting of alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons or together represent a methylene group --(CH.sub.2).sub.n -- where n is a whole number of from 2 to 6, so that together with an adjacent carbon they form a cycloalkyl ring;
- R.sub.3 represents one or more substituents up to five selected from the group consisting of:
- hydrogen, halogen, haloalkyl of 1-12 carbons, alkyl of 1-12 carbons, alkoxy of 1-12 carbons, alkenyl of 2-12 carbons, cycloalkyl of 3-12 carbons, mono- or dicyclic aryl,
- --ZR.sub.5 where Z is O, S, S(O) or SO.sub.2 and R.sub.5 is hydrogen, alkyl of 1-18 carbons, cycloalkyl of 3-12 carbons or phenyl;
- --NR.sub.6 R.sub.7 where R.sub.6 and R.sub.7 may be the same or different and may be hydrogen, alkyl of 1-12 carbons, cycloalkyl of 3-6 carbons, phenyl, alkoxy of 1-12 carbons, acyl of the formula --C(O)R.sub.8 where R.sub.8 is alkyl of 1-12 carbons, cycloalkyl of 3-12 carbons, phenyl, CH.sub.3 OC(O)CH.sub.2 CH.sub.2 --, HOOCCH.sub.2 CH.sub.2 --, NaO.sub.3 SCH.sub.2 CH.sub.2 NHC(O)CH.sub.2 CH.sub.2 --, or R.sub.6 and R.sub.7 together may represent --C(O)CH.sub.2 CH.sub.2 (O)--, --C(O)--C.sub.6 H.sub.4 --C(O)-- or --(CH.sub.2).sub.x -- where x is 2, 3, 4, 5 or 6;
- morpholino imidazole or piperazino joined to the phenyl ring through a nitrogen atom; or
- R.sub.3 represents the atoms necessary to complete between adjacent ring carbons a further 3, 4, 5, 7, or 8 membered carbocyclic ring; a 6 membered non-aromatic carbocyclic ring or a 5-6 membered heterocyclic ring including one or more O, S or N rings atoms; and
- R.sub.4 is from one to five substituents selected from halogen, nitro, --C(O)CH.sub.3, S(O).sub.p R.sub.9 where p is 0, 1 or 2 and R.sub.9 is hydroxy, --ONa, or optionally substituted alkyl of 1-12 carbons or optionally substituted cycloalkyl, or
- the nontoxic pharmaceutically acceptable salts of the compound of Formula IV provided that R.sub.3 and R.sub.4 are not both hydrogen and provided further that when R.sub.3 is phenoxy or represents the atoms necessary to complete between adjacent ring carbons a further carbocyclic ring, R.sub.4 is nitro or S(O).sub.p R.sub.9.
- 6. A compound according to claim 5 wherein R.sub.1 is CH.sub.3, R.sub.2 is CH.sub.3, R.sub.3 is C.sub.2 H.sub.5 at position 3 and C.sub.2 H.sub.5 at position 4, and R.sub.4 is --SCH.sub.2 C(CH.sub.3).sub.2 CO.sub.2 H connected at phenyl ring position 4.
- 7. A compound according to claim 5 wherein R.sub.1 is CH.sub.3, R.sub.2 is CH.sub.3, R.sub.3 is C.sub.2 H.sub.5 at phenyl ring position 3 and C.sub.2 H.sub.5 at phenyl ring position 4, and R.sub.4 is S(O)CH.sub.2 C(CH.sub.3).sub.2 CO.sub.2 H connected at phenyl ring position 4.
- 8. A compound according to claim 5 wherein R.sub.1 is CH.sub.3, R.sub.2 is CH.sub.3, R.sub.3 is C.sub.2 H.sub.5 at phenyl ring position 3 and C.sub.2 H.sub.5 at phenyl ring position 4, and R.sub.4 is S(O.sub.2)CH.sub.2 C(CH.sub.3).sub.2 CO.sub.2 H connected at phenyl ring position 4.
- 9. A compound according to claim 5 wherein R.sub.1 and R.sub.2 together represent the methylene group --(CH.sub.2).sub.3 --, R.sub.3 is a carbocyclic ring of the formula --(CH.sub.2).sub.4 -- connected at phenyl ring positions 3 and 4, and R.sub.4 is --SCH.sub.2 C(CH.sub.3).sub.2 CO.sub.2 H connected at phenyl ring position 4.
- 10. A compound according to claim 5 wherein R.sub.1 and R.sub.2 together represent the methylene group --(CH.sub.2).sub.3 --, R.sub.3 is a carbocyclic ring of the formula --(CH.sub.2).sub.4 -- connected at phenyl ring positions 3 and 4, and R.sub.4 is --S(O)CH.sub.2 C(CH.sub.3).sub.2 CO.sub.2 H connected at phenyl ring position 4.
- 11. A compound according to claim 5 wherein R.sub.1 and R.sub.2 together represent the methylene group --(CH.sub.2).sub.3 --, R.sub.3 is a carbocyclic ring of the formula --(CH.sub.2).sub.4 -- connected at phenyl ring positions 3 and 4, and R.sub.4 is --S(O.sub.2)CH.sub.2 C(CH.sub.3).sub.2 CO.sub.2 H connected at phenyl ring position 4.
- 12. A compound of claim 5, the compound being 4-(2'-Carboxy-2'-methylpropylsulfinyl)phenyl 2-(3',4'-diethyl-phenyl)isobutyric acid.
- 13. A compound of claim 5, the compound being 4-(2'-Carboxy-2'-methylpropylsulfonyl)phenyl 2-(3',4'-diethyl-phenyl)isobutyric acid.
- 14. A pharmaceutical composition for inhibiting undesired elastase activity comprising an effective amount of a compound of the formula: ##STR290## wherein: R.sub.1 and R.sub.2, which may be the same or different, are selected from the group consisting of hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons or together represent a methylene group --(CH.sub.2).sub.n -- where n is a whole number of from 1 to 6;
- R.sub.3 represents one or more substituents up to five selected from the group consisting of:
- hydrogen, halogen, haloalkyl of 1-12 carbons, alkyl of 1-12 carbons, alkoxy of 1-12 carbons, alkenyl of 2-12 carbons, cycloalkyl of 3-12 carbons, mono- or dicyclic aryl,
- --ZR.sub.5 where Z is O, S, S(O) or SO.sub.2 and R.sub.5 is hydrogen, alkyl of 1-18 carbons, cycloalkyl of 3-12 carbons or phenyl;
- --NR.sub.6 R.sub.7 where R.sub.6 and R.sub.7 may be the same or different and may be hydrogen, alkyl of 1-12 carbons, cycloalkyl of 3-6 carbons, phenyl, alkoxy of 1-12 carbons, acyl of the formula --C(O)R.sub.8 where R.sub.8 is alkyl of 1-12 carbons, cyclolakyl of 3-12 carbons, phenyl CH.sub.3 OC(O)CH.sub.2 CH.sub.2 --, HOOCCH.sub.2 CH.sub.2 --, NaO.sub.3 SCH.sub.2 CH.sub.2 NHC(O)CH.sub.2 CH.sub.2 --, or R.sub.6 and R.sub.7 together may represent --C(O)CH.sub.2 CH.sub.2 (O)--, --C(O)--C.sub.6 H.sub.4)C(O)-- or --(CH.sub.2x -- where x is 2, 3, 4, 5 or 6;
- morpholino imidazole or piperazino joined to the phenyl ring through a nitrogen atom; or
- R.sub.3 represents the atoms necessary to complete between adjacent ring carbons a further carbocyclic ring of from 1 to 6 carbons or a 5-6 membered heterocyclic ring including one or more O, S or N ring atoms; and
- R.sub.4 is from one to five substituents selected from hydrogen, halogen, nitro, --C(O)CH.sub.3, S(O).sub.p R.sub.9 where p is 0, 1 or 2 and R.sub.9 is hydroxy, --ONa, or optionally substituted alkyl of 1-12 carbons or optionally substituted cycloalkyl, or
- the nontoxic pharmaceutically acceptable salts of the compound of Formula IV provided that R.sub.3 and R.sub.4 are not both hydrogen and a carrier therefor.
- 15. A method of inhibiting elastase activity which comprises administering to a subject in need of such inhibition, a compound of the formula: ##STR291## wherein: R.sub.1 and R.sub.2, which may be the same or different, are selected from the group consisting of hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons or together represent a methylene group --(CH.sub.2).sub.n -- where n is a whole number of from 1 to 6;
- R.sub.3 represents one or more substituents up to five selected from the group consisting of:
- hydrogen, halogen, haloalkyl of 1-12 carbons, alkyl of 1-12 carbons, alkoxy of 1-12 carbons, alkenyl of 2-12 carbons, cycloalkyl of 3-12 carbons, mono- or dicyclic aryl,
- --ZR.sub.5 where Z is O, S, S(O) or SO.sub.2 and R.sub.5 is hydrogen, alkyl of 1-18 carbons, cycloalkyl of 3-12 carbons or phenyl;
- --NR.sub.6 R.sub.7 where R.sub.6 and R.sub.7 may be the same or different and may be hydrogen, alkyl of 1-12 carbons, cycloalkyl of 3-6 carbons, phenyl, alkoxy of 1-12 carbons, acyl of the formula --C(O)R.sub.8 where R.sub.8 is alkyl of 1-12 carbons, cyclolakyl of 3-12 carbons, phenyl CH.sub.3 OC (O)CH.sub.2 CH.sub.2 --, HOOCCH.sub.2 CH.sub.2 --, NaO.sub.3 SCH.sub.2 CH.sub.2 NHC(O) CH.sub.2 CH.sub.2 --, or R.sub.6 and R.sub.7 together may represent --C(O)CH.sub.2 CH.sub.2 (O)--, --C(O)--C.sub.6 H.sub.4)C(O)-- or --(CH.sub.2x -- where x is 2, 3, 4, 5 or 6;
- morpholino imidazole or piperazino joined to the phenyl ring through a nitrogen atom; or
- R.sub.3 represents the atoms necessary to complete between adjacent ring carbons a further carbocyclic ring of from 1 to 6 carbons or a 5-6 membered heterocyclic ring including one or more O, S or N ring atoms; and
- R.sub.4 is from one to five substituents selected from hydrogen, halogen, nitro, --C(O)CH.sub.3, S(O).sub.p R.sub.9 where p is 0, 1 or 2 and R.sub.9 is hydroxy, --ONa, or optionally substituted alkyl of 1-12 carbons or optionally substituted cycloalkyl, or
- the nontoxic pharmaceutically acceptable salts of the compound of Formula IV provided that R.sub.3 and R.sub.5 are not both hydrogen.
- 16. A method of treating adult respiratory distress syndrome which comprises administering to a subject in need of such therapy a compound of the formula: ##STR292## wherein: R.sub.1 and R.sub.2, which may be the same or different, are selected from the group consisting of hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons or together represent a methylene group --(CH.sub.2).sub.n -- where n is a whole number of from 1 to 6;
- R.sub.3 represents one or more substituents up to five selected from the group consisting of:
- hydrogen, halogen, haloalkyl of 1-12 carbons, alkyl of 1-12 carbons, alkoxy of 1-12 carbons, alkenyl of 2-12 carbons, cycloalkyl of 3-12 carbons, mono- or dicyclic aryl,
- --ZR.sub.5 where Z is O, S, S(O) or SO.sub.2 and R.sub.5 is hydrogen, alkyl of 1-18 carbons, cycloalkyl of 3-12 carbons or phenyl;
- --NR.sub.6 R.sub.7 where R.sub.6 and R.sub.7 may be the same or different and may be hydrogen, alkyl of 1-12 carbons, cycloalkyl of 3-6 carbons, phenyl, alkoxy of 1-12 carbons, acyl of the formula --C (O)R.sub.8 where R.sub.8 is alkyl of 1-12 carbons, cyclolakyl of 3-12 carbons, phenyl CH.sub.3 OC(O)CH.sub.2 CH.sub.2 --, HOOCCH.sub.2 CH.sub.2 --, NaO.sub.3 SCH.sub.2 CH.sub.2 NHC(O) CH.sub.2 CH.sub.2 --, or R.sub.6 and R.sub.7 together may represent --C(O)CH.sub.2 CH.sub.2 (O)--, --C(O)--C.sub.6 H.sub.4)C(O)-- or --(CH.sub.2x -- where x is 2, 3, 4, 5 or 6;
- morpholino imidazole or piperazino joined to the phenyl ring through a nitrogen atom; or
- R.sub.3 represents the atoms necessary to complete between adjacent ring carbons a further carbocyclic ring of from 1 to 6 carbons or 5-6 membered heterocyclic ring including one or more O, S or N ring atoms; and
- R.sub.4 is from one to five substituents selected from hydrogen, halogen, nitro, --C(O)CH.sub.3, S(O).sub.p R.sub.9 where p is 0, 1 or 2 and R.sub.9 is hydroxy, --ONa, or optionally substituted alkyl of 1-12 carbons or optionally substituted cycloalkyl, or
- the nontoxic pharmaceutically acceptable salts of the compound of Formula IV provided that R.sub.3 and R.sub.4 are not both hydrogen.
- 17. A method of treating myocardial infarction which comprises administering to a subject in need of such therapy a compound of the formula: ##STR293## wherein: R.sub.1 and R.sub.2, which may be the same or different, are selected from the group consisting of hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons or together represent a methylene group --(CH.sub.2).sub.n -- where n is a whole number of from 1 to 6;
- R.sub.3 represents one or more substituents up to five selected from the group consisting of:
- hydrogen, halogen, haloalkyl of 1-12 carbons, alkyl of 1-12 carbons, alkoxy of 1-12 carbons, alkenyl of 2-12 carbons, cycloalkyl of 3-12 carbons, mono- or dicyclic aryl,
- --ZR.sub.6 where Z is O, S, S(O) or SO.sub.2 and R.sub.5 is hydrogen, alkyl of 1-18 carbons, cycloalkyl of 3-12 carbons or phenyl;
- --NR.sub.6 R.sub.7 where R.sub.6 and R.sub.7 may be the same or different and may be hydrogen, alkyl of 1-12 carbons, cycloalkyl of 3-6 carbons, phenyl, alkoxy of 1-12 carbons, acyl of the formula --C(O)R.sub.8 where R.sub.8 is alkyl of 1-12 carbons, cyclolakyl of 3-12 carbons, phenyl CH.sub.3 OC(O)CH.sub.2 CH.sub.2 --, HOOCCH.sub.2 CH.sub.2 --, NaO.sub.3 SCH.sub.2 CH.sub.2 NHC(O)CH.sub.2 CH.sub.2 --, or R.sub.6 and R.sub.7 together may represent --C(O)CH.sub.2 CH.sub.2 (O)--, --C(O)--C.sub.6 H.sub.4) C(O)-- or --(CH.sub.2x -- where x is 2, 3, 4, 5 or 6;
- morpholino imidazole or piperazino joined to the phenyl ring through a nitrogen atom; or
- R.sub.3 represents the atoms necessary to complete between adjacent ring carbons a further carbocyclic ring of from 1 to 6 carbons or a 5-6 membered heterocyclic ring including one or more O, S or N ring atoms; and
- R.sub.4 is from one to five substituents selected from hydrogen, halogen, nitro, --C(O)CH.sub.3, S(O).sub.p R.sub.9 where p is 0, 1 or 2 and R.sub.9 is hydroxy, --ONa, or optionally substituted alkyl of 1-12 carbons or optionally substituted cycloalkyl, or
- the nontoxic pharmaceutically acceptable salts of the compound of Formula IV provided that R.sub.3 and R.sub.4 are not both hydrogen.
- 18. A method of treating periodontal disease which comprises administering to a subject in need of such therapy a compound of the formula: ##STR294## wherein: R.sub.1 and R.sub.2, which may be the same or different, are selected from the group consisting of hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons or together represent a methylene group --(CH.sub.2).sub.n -- where n is a whole number of from 1 to 6;
- R.sub.3 represents one or more substituents up to five selected from the group consisting of:
- hydrogen, halogen, haloalkyl of 1-12 carbons, alkyl of 1-12 carbons, alkoxy of 1-12 carbons, alkenyl of 2-12 carbons, cycloalkyl of 3-12 carbons, mono- or dicyclic aryl,
- --ZR.sub.5 where Z is O, S, S(O) or SO.sub.2 and R.sub.5 is hydrogen, alkyl of 1-18 carbons, cycloalkyl of 3-12 carbons or phenyl;
- --NR.sub.6 R.sub.7 where R.sub.6 and R.sub.7 may be the same or different and may be hydrogen, alkyl of 1-12 carbons, cycloalkyl of 3-6 carbons, phenyl, alkoxy of 1-12 carbons, acyl of the formula --C(O)R.sub.8 where R.sub.8 is alkyl of 1-12 carbons, cyclolakyl of 3-12 carbons, phenyl CH.sub.3 OC(O)CH.sub.2 CH.sub.2 --, HOOCCH.sub.2 CH.sub.2 --, NaO.sub.3 SCH.sub.2 CH.sub.2 NHC(O)CH.sub.2 CH.sub.2 --, or R.sub.6 and R.sub.7 together may represent --C(O)CH.sub.2 CH.sub.2 (O)--, --C(O)--C.sub.6 H.sub.4)C(O)-- or --(CH.sub.2x -- where x is 2, 3, 4, 5 or 6;
- morpholino imidazole or piperazino joined to the phenyl ring through a nitrogen atom; or
- R.sub.3 represents the atoms necessary to complete between adjacent ring carbons a further carbocyclic ring of from 1 to 6 carbons or a 5-6 membered heterocyclic ring including one or more O, S or N ring atoms; and
- R.sub.4 is from one to five substituents selected from hydrogen, halogen, nitro, --C(O)CH.sub.3, S(O).sub.p R.sub.9 where p is 0, 1 or 2 and R.sub.9 is hydroxy, --ONa, or optionally substituted alkyl of 1-12 carbons or optionally substituted cycloalkyl, or
- the nontoxic pharmaceutically acceptable salts of the compound of Formula IV provided that R.sub.3 and R.sub.4 are not both hydrogen.
- 19. A compound of the formula: ##STR295## wherein: R.sub.1 and R.sub.2, which may be the same or different, are selected from the group consisting of hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons or together represent a methylene group --(CH.sub.2).sub.n -- where n is a whole number of from 1 to 6;
- R.sub.3 represents one or more substituents up to five selected from the group consisting of:
- hydrogen, halogen, haloalkyl of 1-12 carbons, alkyl of 1-12 carbons, alkoxy of 1-12 carbons, alkenyl of 2-12 carbons, cycloalkyl of 3-12 carbons, mono- or dicyclic aryl,
- --ZR.sub.5 where Z is O, S, S(O) or SO.sub.2 and R.sub.5 is hydrogen, alkyl of 1-18 carbons, cycloalkyl of 3-12 carbons or phenyl;
- --NR.sub.6 R.sub.7 where R.sub.6 and R.sub.7 may be the same or different and may be hydrogen, alkyl of 1-12 carbons, cycloalkyl of 3-6 carbons, phenyl, alkoxy of 1-12 carbons, acyl of the formula --C(O)R.sub.8 where R.sub.8 is alkyl of 1-12 carbons, cycloalkyl of 3-12 carbons, phenyl, CH.sub.3 OC(O)CH.sub.2 CH.sub.2 --, HOOCCH.sub.3 CH.sub.2 --, NaO.sub.3 SCH.sub.2 CH.sub.2 NHC(O)CH.sub.2 CH.sub.2 --, or R.sub.6 and R.sub.7 together may represent --C(O)CH.sub.2 CH.sub.2 (O)--, --C(O)--C.sub.6 H.sub.4 --C(O)-- or --(CH.sub.2).sub.x -- where x is 2, 3, 4, 5 or 6;
- morpholino imidazole or piperazino joined to the phenyl ring through a nitrogen atom; or
- R.sub.3 represents the atoms necessary to complete between adjacent ring carbons a further 3, 4, 5, 7, or 8 membered carbocyclic ring; a 6 membered non-aromatic carbocyclic ring or a 5-6 membered heterocyclic ring including one or more O, S or N rings atoms; and
- R.sub.4 is --SCH.sub.3 in the ortho or para position; or the nontoxic pharmaceutically acceptable salts of the compound of Formula IV.
- 20. The compound of claim 1 wherein R.sub.1 and R.sub.2 together with an adjacent carbon atom form a cyclobutyl or cyclopentyl ring.
- 21. The compound of claim 5 wherein R.sub.1 and R.sub.2 are both methyl groups.
- 22. The compound of claim 5 wherein R.sub.1 and R.sub.2 are both ethyl groups.
- 23. A process for preparing a compound of the formula: ##STR296## wherein: R.sub.1 and R.sub.2, which may be the same or different, are selected from the group consisting of alkyl of 1-6 carbons, cycloalkyl of 3-6 carbons or together represent a methylene group --(CH.sub.2).sub.n -- where n is a whole number of from 1 to 6;
- R'.sub.3 represents R.sub.3 or R.sub.3 P.sub.g, wherein Pg is an appropriate protecting group, wherein
- R.sub.3 represents one or more substituents up to five selected from the group consisting of:
- hydrogen, halogen, haloalkyl of 1-12 carbons, alkyl of 1-12 carbons, alkoxy of 1-12 carbons, alkenyl of 2-12 carbons, cycloalkyl of 3-12 carbons, mono- or dicyclic aryl,
- --ZR.sub.5 where Z is O, S, S(O) or SO.sub.2 and R.sub.5 is hydrogen, alkyl of 1-18 carbons, cycloalkyl of 3-12 carbons or phenyl;
- --NR.sub.6 R.sub.7 where R.sub.6 and R.sub.7 may be the same or different and may be hydrogen, alkyl of 1-12 carbons, cycloalkyl of 3-6 carbons, phenyl, alkoxy of 1-12 carbons, acyl of the formula --C(O)R.sub.8 is alkyl of 1-12 carbons, cycloalkyl of 3-12 carbons, phenyl, CH.sub.3 OC(O)CH.sub.2 CH.sub.2 --, HOOCCH.sub.2 CH.sub.2 --, NaO.sub.3 SCH.sub.2 CH.sub.2 NHC(O)CH.sub.2 CH.sub.2 -- or R.sub.6 and R.sub.7 together may represent --C(O)CH.sub.2 CH.sub.2 C(O)--, --C(O)--C.sub.6 H.sub.4 --C(O)-- or --(CH.sub.2).sub.x -- where x is 2,3,4,5 or 6;
- morpholino, imidazole or piperazino joined to the phenyl ring through a .nitrogen atom; or
- R.sub.3 represents the atoms necessary to complete between adjacent ring carbons a further carbocyclic ring of from 1 to 6 carbons or a 5-6 membered heterocyclic ring including one or more O, S or N ring atoms;
- R'.sub.4 is R.sub.4 or R.sub.4 P.sub.g, wherein
- R.sub.4 is from one to five substituents selected from hydrogen halogen, nitro, --C(O)CH.sub.3, S(O).sub.p R.sub.9 where p is 0, 1 or 2 and R is hydroxy, --ONa or optionally substituted alkyl of 1-12 carbons or optionally substituted cycloalkyl; or
- the nontoxic pharmaceutically acceptable salts of the compound of formula VI,
- which comprises:
- (a) reacting a phenylacetic acid having the formula: ##STR297## with an alcohol ROH in the presence of an acid to obtain the compound having the formula: ##STR298## (b) when R.sub.1 or R.sub.2 is not hydrogen, treating the compound of formula XXIX with R.sub.1 X and/or R.sub.2 X, wherein X is a halide to obtain the compound having the formula: ##STR299## (c) reacting the compound of formula XXX with an alcohol to produce a phenylalkanoic acid derivative, and then chlorinating the phenylalkanoic acid derivative to produce an acid chloride derivative having the formula: ##STR300## (d) reacting the compound of formula II, in the presence of a suitable organic base, with a compound having the formula: ##STR301## (e) optionally removing Pg groups; (f) optionally oxidizing the compound to the sulfoxide or the sulfone derivative when R'.sub.4 contains a sulfur atom; and
- (g) optionally forming an acceptable non-toxic salt.
CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation of application Ser. No. 07 7841,608, filed on Feb. 25, 1992, which was abandoned upon the filing hereof, which is a continuation in part application of Ser. No. 07/692,322 filed May 2, 1991, now abandoned which is a continuation-in-part application of Ser. No. 07/528,967 filed May 22, 1990, now U.S. Pat. No. 5,214,191.
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Entry |
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(3) CA 105 (17):153057k (1986). |
Abstrats Of: EP 181568-A; EP 106565-A; EP 179487-A; WO 8909765-A; EP 178826-A; WO 8400545-A; J58038243-A; U.S. 3,526,653 and U.S. 3,318,682. |
Chemical Abstracts CA 112(7):55219q1989. |
Continuations (1)
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Number |
Date |
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Parent |
841608 |
Feb 1992 |
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Continuation in Parts (2)
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Number |
Date |
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Parent |
692322 |
May 1991 |
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Parent |
528967 |
May 1990 |
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