Claims
- 1. An acyclic bisphosphonate of the formula
- R.sub.2 --X--(CW).sub.m1 --CR.sub.3 R.sub.4 -CH.sub.2 --CM[PO--(OR.sub.1).sub.2 ].sub.2 (III)
- where
- (I) m.sub.1 is 0 or 1;
- (II) M is --H, --Cl or --CH.sub.3 ;
- (III) where both --OR.sub.1 on the same P are taken together along with --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --CH.sub.2 -- or --CH.sub.2 --C(CH.sub.3).sub.2 --CH.sub.2 -- to form a heterocyclic ring containing one --P--, two --O-- and two or three carbon atoms;
- (IV) R.sub.2 is
- (A) --.phi. optionally substituted with 1 or 2 --.phi. or with 1 thru 3
- (1) --F,
- (2) --Cl,
- (3) --Br,
- (4) --I,
- (5) --NO.sub.2,
- (6) --CN,
- (7) --CF.sub.3,
- (8) C.sub.1 -C.sub.10 alkyl,
- (9) C.sub.3 -C.sub.7 cycloalkyl,
- (10) --OH,
- (11) C.sub.1 -C.sub.4 alkoxy,
- (12) --SH,
- (13) --NH.sub.2,
- (14) --O--CO--R.sub.2-1 where R.sub.2-1 is
- (a) C.sub.1 -C.sub.10 alkyl,
- (b) C.sub.3 -C.sub.7 cycloalkyl,
- (15) --(CH.sub.2).sub.n1 --COO--R.sub.2-2 where n.sub.1 is 1 thru 3 and R.sub.2-2 is
- (a) --H,
- (b) C.sub.1 -C.sub.6 alkyl,
- (c) --CH.sub.2 --.phi.,
- (d) --N--CO--R.sub.2-3 where R.sub.2-3 is
- (i) C.sub.1 -C.sub.10 alkyl,
- (ii) C.sub.3 -C.sub.7 cycloalkyl,
- (e) --(CH.sub.2).sub.n4 --COO--R.sub.2-9 where n.sub.4 is 1 thru 3 and R.sub.2-9 is
- (i) --H,
- (ii) C.sub.1 -C.sub.6 alkyl,
- (iii) --.phi.,
- (16) --O--S(O).sub.2 --R.sub.2-4 where R.sub.2-4 is
- (a) C.sub.1 -C.sub.10 alkyl,
- (b) --.phi. optionally substituted with 1 thru 3
- (i) --F,
- (ii) --Cl,
- (iii) --Br,
- (iv) --I,
- (v) --NO.sub.2,
- (vi) --CN,
- (vii) --CF.sub.3,
- (viii) C.sub.1 -C.sub.10 alkyl,
- (ix) --OH,
- (x) C.sub.1 -C.sub.4 alkoxy,
- (xi) --O--.phi.,
- (xii) C.sub.1 -C.sub.4 alkylthio,
- (xiii) --N--CO--R.sub.2-3 where R.sub.2-3 is as defined above,
- (17) --N(R.sub.2-5)(R.sub.2-6) where R.sub.2-5 and R.sub.2-6 are the same or different and are (a) --H,
- (b) C.sub.1 -C.sub.6 alkyl,
- (c) C.sub.3 -C.sub.7 cycloalkyl,
- (d) --.phi.,
- (18) --N(R.sub.2-7)--CO--R.sub.2-3 where R.sub.2-7 is
- (a) --H,
- (b) C.sub.1 -C.sub.6 alkyl,
- (c) C.sub.3 -C.sub.7 cycloalkyl,
- (d) --.phi. and where R.sub.2-3 is as defined above,
- (19) --N(R.sub.2-7)--CO--O--R.sub.2-s where R.sub.2-8 is
- (a) --H,
- (b) C.sub.1 -C.sub.6 alkyl,
- (c) C.sub.3 -C.sub.7 cycloalkyl,
- (d) --.phi. and
- (e)--CH.sub.2 --.phi., and where R.sub.2-7 is as defined above,
- (20) --N(R.sub.2-7)--CO--N(R.sub.2-5)(R.sub.2-6) where R.sub.2-5, R.sub.2-6 and R.sub.2-7 are as defined above,
- (21) --N(R.sub.2-7)--SO.sub.2 --R.sub.2-4 where R.sub.2-4 and R.sub.2-7 are as defined above,
- (V) R.sub.3 and R.sub.4 are:
- (A) R.sub.3 and R.sub.4 together with the attached carbon atom form a cycloalkyl ring of 3 thru 7 carbon atoms,
- (B) R.sub.3 is --H and R.sub.4 is:
- (1) --H,
- (2) R.sub.2-4,
- (3) --CO--O-- R.sub.2-8,
- (4) --CO--R.sub.2,
- (5) --CN,
- (6) --CO--NH--R.sub.2,
- (7) --NH--CO--R.sub.2-1,
- (8) --S--R.sub.2-x,
- (C) R.sub.3 is --H and R.sub.4 is:
- (1) --F,
- (2) --Cl,
- (3) --Br,
- (4) --I,
- (D) R.sub.3 and R.sub.4 are the same or different and are C.sub.1 -C.sub.10 alkyl;
- (VI) W.sub.1 is:
- (A) .dbd.O,
- (B) .dbd.S,
- (C) .dbd.N--N(R.sub.2-7).sub.2 where R.sub.2-7 is as defined above,
- (D) W.sub.1-1 :W.sub.1-2 where W.sub.1-1 and W.sub.1-2 are the same and are
- (1) C.sub.1 -C.sub.4 alkoxy,
- (E) W.sub.1 is --H:--W.sub.1-5 where W.sub.1-5 is:
- (1) --OH,
- (2) --SH,
- (3) --NH.sub.2,
- (4) --S--W.sub.1-6 where W.sub.1-6 is C.sub.1 -C.sub.4 alkyl,
- (5) --O--CO--R.sub.2-1 where R.sub.2-1 is as defined above,
- (6) --O--S(O).sub.2 --R.sub.2-4 where R.sub.2-4 is as defined above,
- (7) --N(R.sub.2-5)(R.sub.2-6) where R.sub.2-5 and R.sub.2-6 are as defined above,
- (8) --N(R.sub.2-7)--CO--R.sub.2-1 where R.sub.2-1 and R.sub.2-7 are as defined above,
- (9) --N(R.sub.2-5)--CO--O--R.sub.2-8 where R.sub.2-5 and R.sub.2-8 are as defined above,
- (10) --N(R.sub.2-7)--CO--N(R.sub.2-5)(R.sub.2-6) where R.sub.2-5, R.sub.2-6 and R.sub.2-7 are as defined above,
- (11) --N(R.sub.2-7)--SO.sub.2 --R.sub.2-4 where R.sub.2-6 and R.sub.2-7 are as defined above;
- (VII) X is --(CH.sub.2).sub.n2 -- or --(CH.dbd.CH).sub.n3 -- where n.sub.2 is 0 thus 5 and n.sub.3 is 0 thru 2, with the proviso that when R.sub.4 is --R.sub.2-4, m.sub.1 is 1, or pharmaceutically acceptable salts thereof.
- 2. An acyclic bisphosphonate of formula (III) according to claim 1 where m.sub.1 is 1.
- 3. An acyclic bisphosphonate of formula (III) according to claim 1 where R.sub.1 is --CH.sub.2 --C(CH.sub.3).sub.2 --CH.sub.2 --.
- 4. An acyclic bisphosphonate of formula (III) according to claim 1 where R.sub.3 is --H.
- 5. An acyclic bisphosphonate of formula (III) according to claim 1 where R.sub.4 is --H, R.sub.2-4, --CO--O--R.sub.2-8, --CO--R.sub.2, --CN and --CO--NH--R.sub.2.
- 6. An acyclic bisphosphonate of formula (III) according to claim 1 where W is .dbd.O.
- 7. An acyclic bisphosphonate of formula (III) according to claim 1 where n.sub.2 and n.sub.3 are 0.
- 8. An acyclic bisphosphonate of formula (III) according to claim 1 where the acyclic bisphosphonate is selected from the group consisting of
- [4-oxo-3,4-diphenylbutylidene]-2,2'-methylenebis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-phenylbutylidene]-2,2'-methylenebis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(3-fluorophenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(3-fluorophenyl)-(3,3-dimethyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphofinane],
- [4-oxo-4-(4-fluorophenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(2-fluorophenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(2,5-difluorophenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(2,6-difluorophenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(4-trifluoromethyl-phenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(3-trifluoromethyl-phenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(2-trifluoromethyl-phenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(2,4-difluorophenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(3-methoxyphenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane],
- [4-oxo-4-(2,3-difluorophenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane].
- 9. An acyclic bisphosphonate or formula (III) according to claim 8 which is [4-oxo-4-3-fluorophenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane].
- 10. (3-Methoxy-4-oxo-4-phenyl)-butylidene]-2,2'-bis[5,5-dimethyl-2,2'-dioxide 1,3,2-dioxaphosphorinane].
CROSS-REFERENCE TO RELATED APPLICATIONS
The present patent application is a divisional application of U.S. patent application Ser. No. 08/019,964, filed Feb. 19, 1993, U.S. Pat. No. 5,412,141, which is a continuation (national phase) application of PCT application PCT/US91Y05554, filed Aug. 9, 1991 which is a continuation-in-part of U.S. patent application Ser. No. 07/570,274, filed Aug. 21, 1990, now abandoned.
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3683080 |
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4746654 |
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Foreign Referenced Citations (1)
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Divisions (1)
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Number |
Date |
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Parent |
19964 |
Feb 1993 |
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Continuation in Parts (1)
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Number |
Date |
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Parent |
570274 |
Aug 1990 |
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