Pharmaceutical for treatment of neurological and neuropsychiatric disorders
First Claim
Patent Images
1. A compound of the following formula:
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or a pharmaceutically acceptable salt thereof,wherein;
(1) C* is a substituted carbon;
(2) R2 (a) is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (C1-C6) alkylaminocarbonyl, or dialkylaminocarbonyl wherein each alkyl is independently C1 to C6, (b) comprises (where R1 is not aminoethylene, —
O—
R8 or —
S—
R8*) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon or nitrogen from one of either R1, Rxb or Ryb, (d) is R2a linked by R2b to C*, or (e) is ethylene forming a third bridging structure as set forth in (2iii)(b)(i);
(2i) Rx is Rxa linked by Rxb to C*;
(2ii) Ry is Rya linked by Ryb to C*;
(2iii) Rxa, Rya and R2a, are independently Ar, which is phenyl or naphthyl, or a 5 to 7-membered non-aromatic ring having 0 heteroatoms wherein;
(a) each of Rxa and Rya can be independently substituted with one of Rq, RrO—
or RsS—
, wherein each of Rq, Rr and Rs are independently Ar or adamantyl, and (b) Rxa, Rya, R2a, Rq, Rr and Rs can be substituted or additionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C12) alkyl, (C2-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl of dialkylamino is independently C1 to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, or amidino wherein the amidino can be independently substituted with up to three (C1-C6) alkyl groups, wherein;
(i.) the substitutions of Rxa and Rya can be combined to form a second bridge between Rxa and Rya comprising (1) methylene or ethylene, which methylene or ethylene can be substituted by an R2 when R2 is ethylene to form the third bridging structure, or (2) —
CH═
CH—
or wherein Rxa and Rya can be directly linked by a single bond;
(2iv) Rxb and R2b are independently a single bond or (C1-C2) alkylene;
(2v) Ryb is a single bond, oxy, (C1-C2) alkylene, ethenylene or —
CH═
(where the double bond is with C*), thio, methyleneoxy or methylenethio, or either —
N(R6) or —
CH2—
N(R6*)—
, wherein R6 and R6* are hydrogen or (C1-C6) alkyl;
(3) R1 comprises;
a straight-chained (C2-C3) aliphatic group;
═
N—
O-(ethylene), wherein the unmatched double bond is linked to C*;
—
O—
R8 or —
S—
R8* wherein R8 or R8* is a ethylene or ethenylene and O or S is bonded to C*;
aminoethylene where the amino is bonded to C*;
wherein R1 can be substituted with up to one hydroxy, up to one (C1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy or oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen;
wherein if R1 contributes a heteroatom linked to C*, then Ryb does not contribute a heteroatom linked to C*; and
wherein the alkyl or alkylidene substituents of R1 can be linked to form a 3 to 7-membered non-aromatic ring;
(4) R3 (a) is hydrogen, (C1-C6) alkyl, or phenyl or phenylalkyl wherein the alkyl is C1 to C6 and the phenyl or phenyl of phenylalkyl can be substituted with the same substituents defined above for the phenyl of Rxa, (b) is —
R12C(Rxx)(Ryy)(R11), wherein R12 is bonded to N, Rxx is independently the same as Rx, Ryy is independently the same as Ry, R11 is independently the same as R2 and R12 is independently the same as R1;
(5) R4 and R4* are independently hydrogen or (C1-C6) alkyl, or one of R4 and R4* can be (C1-C6) hydroxyalkyl; and
(6) R5 is (CO)NR13R14, (CO)OR15, (CO)SR16, (SO2)NR17R18, (PO)(OR19)(OR20), (CR22)(OR23)(OR24), CN or tetrazol-5-yl, wherein (a) R13, R14, R15, R16, R17, R18 R19 and R20 are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R15 or the sulfur of R16 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, Ar-alkyl wherein the alkyl is C1-C6, or Ar, and (b) R22 is hydrogen or OR25 and R23, R24 and R25 are independently (C1-C6) alkyl, phenyl, benzyl or acetyl or, the alkyls of R23 and R24 can be combined to include 1,3-dioxolane or 1,3-dioxane;
wherein the phenyl or naphthyl groups of R13, R14, R15, R16, R17, R18, R19, R20, R22, R23 or R24 can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, hydroxy, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1 -C6) alkyl, (C1-C6) alkylsulfonyl, or amidino that can substituted with up to three (C1-C6) alkyl;
wherein R13 and R14 together with the attached nitrogen can form a 5 to 7-membered ring;
and wherein further the following provisos apply;
if R15 is hydrogen and R1 is propylene, then at least one of the following applies (1) both Rxa and Rya are not fluorophenyl, (2) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, (3) R2 is R2a R2b—
, (4) R2 is not hydrogen, or (5) R3 is not hydrogen;
if R15 is hydrogen and R1 is ethylene or C*R1 is prop-1-enylene, then at least one of the following applies (1) an Ar of at least one of Rxa and Rya is substituted with a radical different from hydrogen, (2) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, (3) R2 is R2a R2b—
, (4) R2 is not hydrogen, or (5) R3 is not hydrogen;
if R5 is C(O)NR13R14 wherein R13 and R14 are hydrogen, (C1-C8) alkyl, phenyl or substituted phenyl, then at least one of the following applies (1) an Ar of at least one of Rx and Ry is substituted with a radical different from hydrogen, fluoro, chloro, or bromo (2) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, (3) R2 is R2a R2b—
, (4) R2 is not hydrogen, (5) R3 is not hydrogen, or (6) R1 is not ethylene;
if R2 is phenyl or p-methylphenyl, then at least one of the following applies (1) the Ar of Rx and Ry are not substituted with p-methylphenyl or p-methoxyphenyl, (2) an Ar of at least one of Rx and Ry is substituted with a radical different from hydrogen, (3) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, or (4) R1 is not aminoethylene, OR8 or SR8*;
if R2 is p-methoxyphenyl, then at least one of the following applies (1) an Ar of at least one of Rx and Ry is substituted with a radical different from hydrogen, (2) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, or (3) R1 is not OR8 or —
SR8*, and the compound is not N-(1,1-diphenylpropyl)-glycinamide or N-(1,1-diphenylpropyl)-glycinamide having one or more halo substitutions on one or more of the phenyls and differs therefrom by at least two of the following;
(a) substitutions or (b) differences in Rx, Ry, R1, R3, R4, R4* or R5.
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Abstract
The invention provides a pharmaceutical for treatment of neurological and neuropsychiatric disorders comprising a compound of the formula:
or a pharmaceutically acceptable salt thereof.
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Citations
28 Claims
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1. A compound of the following formula:
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or a pharmaceutically acceptable salt thereof, wherein; (1) C* is a substituted carbon;
(2) R2 (a) is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (C1-C6) alkylaminocarbonyl, or dialkylaminocarbonyl wherein each alkyl is independently C1 to C6, (b) comprises (where R1 is not aminoethylene, —
O—
R8 or —
S—
R8*) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon or nitrogen from one of either R1, Rxb or Ryb, (d) is R2a linked by R2b to C*, or (e) is ethylene forming a third bridging structure as set forth in (2iii)(b)(i);
(2i) Rx is Rxa linked by Rxb to C*;
(2ii) Ry is Rya linked by Ryb to C*;
(2iii) Rxa, Rya and R2a, are independently Ar, which is phenyl or naphthyl, or a 5 to 7-membered non-aromatic ring having 0 heteroatoms wherein;
(a) each of Rxa and Rya can be independently substituted with one of Rq, RrO—
or RsS—
, wherein each of Rq, Rr and Rs are independently Ar or adamantyl, and(b) Rxa, Rya, R2a, Rq, Rr and Rs can be substituted or additionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C12) alkyl, (C2-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl of dialkylamino is independently C1 to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, or amidino wherein the amidino can be independently substituted with up to three (C1-C6) alkyl groups, wherein;
(i.) the substitutions of Rxa and Rya can be combined to form a second bridge between Rxa and Rya comprising (1) methylene or ethylene, which methylene or ethylene can be substituted by an R2 when R2 is ethylene to form the third bridging structure, or (2) —
CH═
CH—
or wherein Rxa and Rya can be directly linked by a single bond;
(2iv) Rxb and R2b are independently a single bond or (C1-C2) alkylene;
(2v) Ryb is a single bond, oxy, (C1-C2) alkylene, ethenylene or —
CH═
(where the double bond is with C*), thio, methyleneoxy or methylenethio, or either —
N(R6) or —
CH2—
N(R6*)—
, wherein R6 and R6* are hydrogen or (C1-C6) alkyl;
(3) R1 comprises;
a straight-chained (C2-C3) aliphatic group;
═
N—
O-(ethylene), wherein the unmatched double bond is linked to C*;
—
O—
R8 or —
S—
R8* wherein R8 or R8* is a ethylene or ethenylene and O or S is bonded to C*;
aminoethylene where the amino is bonded to C*;
wherein R1 can be substituted with up to one hydroxy, up to one (C1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy or oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen;
wherein if R1 contributes a heteroatom linked to C*, then Ryb does not contribute a heteroatom linked to C*; and
wherein the alkyl or alkylidene substituents of R1 can be linked to form a 3 to 7-membered non-aromatic ring;
(4) R3 (a) is hydrogen, (C1-C6) alkyl, or phenyl or phenylalkyl wherein the alkyl is C1 to C6 and the phenyl or phenyl of phenylalkyl can be substituted with the same substituents defined above for the phenyl of Rxa, (b) is —
R12C(Rxx)(Ryy)(R11), wherein R12 is bonded to N, Rxx is independently the same as Rx, Ryy is independently the same as Ry, R11 is independently the same as R2 and R12 is independently the same as R1;
(5) R4 and R4* are independently hydrogen or (C1-C6) alkyl, or one of R4 and R4* can be (C1-C6) hydroxyalkyl; and
(6) R5 is (CO)NR13R14, (CO)OR15, (CO)SR16, (SO2)NR17R18, (PO)(OR19)(OR20), (CR22)(OR23)(OR24), CN or tetrazol-5-yl, wherein (a) R13, R14, R15, R16, R17, R18 R19 and R20 are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R15 or the sulfur of R16 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, Ar-alkyl wherein the alkyl is C1-C6, or Ar, and (b) R22 is hydrogen or OR25 and R23, R24 and R25 are independently (C1-C6) alkyl, phenyl, benzyl or acetyl or, the alkyls of R23 and R24 can be combined to include 1,3-dioxolane or 1,3-dioxane;
wherein the phenyl or naphthyl groups of R13, R14, R15, R16, R17, R18, R19, R20, R22, R23 or R24 can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, hydroxy, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1 -C6) alkyl, (C1-C6) alkylsulfonyl, or amidino that can substituted with up to three (C1-C6) alkyl;
wherein R13 and R14 together with the attached nitrogen can form a 5 to 7-membered ring;
and wherein further the following provisos apply;
if R15 is hydrogen and R1 is propylene, then at least one of the following applies (1) both Rxa and Rya are not fluorophenyl, (2) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, (3) R2 is R2a R2b—
, (4) R2 is not hydrogen, or (5) R3 is not hydrogen;
if R15 is hydrogen and R1 is ethylene or C*R1 is prop-1-enylene, then at least one of the following applies (1) an Ar of at least one of Rxa and Rya is substituted with a radical different from hydrogen, (2) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, (3) R2 is R2a R2b—
, (4) R2 is not hydrogen, or (5) R3 is not hydrogen;
if R5 is C(O)NR13R14 wherein R13 and R14 are hydrogen, (C1-C8) alkyl, phenyl or substituted phenyl, then at least one of the following applies (1) an Ar of at least one of Rx and Ry is substituted with a radical different from hydrogen, fluoro, chloro, or bromo (2) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, (3) R2 is R2a R2b—
, (4) R2 is not hydrogen, (5) R3 is not hydrogen, or (6) R1 is not ethylene;
if R2 is phenyl or p-methylphenyl, then at least one of the following applies (1) the Ar of Rx and Ry are not substituted with p-methylphenyl or p-methoxyphenyl, (2) an Ar of at least one of Rx and Ry is substituted with a radical different from hydrogen, (3) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, or (4) R1 is not aminoethylene, OR8 or SR8*;
if R2 is p-methoxyphenyl, then at least one of the following applies (1) an Ar of at least one of Rx and Ry is substituted with a radical different from hydrogen, (2) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, or (3) R1 is not OR8 or —
SR8*, andthe compound is not N-(1,1-diphenylpropyl)-glycinamide or N-(1,1-diphenylpropyl)-glycinamide having one or more halo substitutions on one or more of the phenyls and differs therefrom by at least two of the following;
(a) substitutions or (b) differences in Rx, Ry, R1, R3, R4, R4* or R5.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 26, 27, 28)
wherein A and B are Ar ring structures consistent with the definitions of Rxa and Rya, respectively, and Y is C* wherein R21 either (i.) completes a single bond linking two Ar rings of Rxa and Rya, or (ii.) is (C1-C2) alkylene or —
CH═
CH—
, and wherein Rxa and Rya can be substituted.
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14. The compound of claim 13, wherein R21 is CH2CH2 or CH═
- CH.
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15. The compound of claim 1, wherein Rxa and Rya together can be substituted with up to six substituents, R2a, Rq, Rr and Rs can each be substituted with up to 3 substituents, and wherein the presence of each of Rq, RrO—
- or RsS—
is considered a substitution to the respective ring structure of Rxa and Rya.
- or RsS—
-
16. The compound of claim 1, wherein a phenyl of R3 is substituted with up to three substituents.
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17. The compound of claim 1, wherein the Ar of R13, R14, R15, R16 R17, R18 R19 or R20 is substituted with up to three substituents.
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18. The compound of claim 1, wherein the compound is an optically pure enantiomer.
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19. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
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20. The pharmaceutical composition of claim 19, wherein the compound is present in an effective amount for:
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(1) treating schizophrenia, (2) treating epilepsy, (3) treating spasticity, (4) treating muscle spasm, (5) treating pain, (6) treating mood disorders, (7) enhancing memory or learning, or (8) treating learning disorders.
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21. The compound of claim 1 wherein:
-
(1) R2 is hydrogen, (2) Rxa and Rya are both phenyl and at least one of Rxa and Rya is substituted with one of phenyl, phenoxy, or phenylthio, (3) Rxb is a single bond and Ryb is a single bond or oxy, and (4) R5 is (CO)NR13R14 or (CO)OR15, wherein R13, R14, and R15 are independently hydrogen;
(C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of OR15 has no more than secondary branching;
(C2-C6) hydroxyalkyl or aminoalkyl mere the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyl or phenylalkyl, wherein the alkyl is C1-C6 and the phenyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, hydroxy, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino that can substituted with up to three (C1-C6) alkyl.
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26. The pharmaceutical composition of claim 19, wherein the compound is present in an effective amount for treating schizophrenia.
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27. The compound of claim 1, wherein R1 is a straight-chained (C2-C3) aliphatic group.
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28. The compound of claim 27, wherein R2 forms a double bond with an adjacent carbon from R1.
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22. A method of (1) treating schizophrenia comprising administering a schizophrenia treating effective amount of a compound, (2) of treating epilepsy comprising administering an epilepsy treating effective amount of a compound, (3) treating spasticity comprising administering a spasticity treating effective amount of a compound, (4) treating muscle spasm comprising administering a muscle spasm treating effective amount of a compound, (5) treating pain comprising administering a pain treating effective amount of a compound, (6) treating mood disorders comprising administering a mood disorder treating effective amount of a compound, (7) enhancing memory or learning comprising administering a memory or learning enhancing effective amount of a compound, or (8) treating learning disorders, comprising administering an amount effective for said treating or enhancing of a compound of formula:
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or a pharmaceutically acceptable salt thereof, wherein; (1) C* is a substituted carbon;
(2) R2 (a) is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (C1-C6) alkylaminocarbonyl, or dialkylaminocarbonyl wherein each alkyl is independently C1 to C6, (b) comprises (where R1 is not aminoethylene, —
O—
R8 or —
S—
R8*) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon or nitrogen from one of either R1, Rxb or Ryb, (d) is R2a linked by R2b to C*, or (e) is ethylene forming a third bridging structure as set forth in (2iii)(b)(i);
(2i) Rx is Rxa linked by Rxb to C*;
(2ii) Ry is Rya linked by Ryb to C*;
(2iii) Rxa, Rya and R2a, are independently Ar, which is phenyl or naphthyl, or a 5 to 7-membered non-aromatic ring having 0 heteroatoms wherein;
(a) each of Rxa and Rya can be independently substituted with one of Rq, RrO—
or RsS—
, wherein each of Rq, Rr and Rs are independently Ar or adamantyl , and(b) Rxa, Rya, R2a, Rq, Rr and Rs can be substituted or additionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C12) alkyl, (C2-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl of dialkylamino is independently C1 to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, or amidino wherein the amidino can be independently substituted with up to three (C1-C6) alkyl groups, wherein;
(i.) the substitutions of Rxa and Rya can be combined to form a second bridge between Rxa and Rya comprising (1) methylene or ethylene, which methylene or ethylene can be substituted by an R2 when R2 is ethylene to form the third bridging structure, or (2) —
CH═
CH—
or wherein Rxa and Rya can be directly linked by a single bond;
(2iv) Rxb and R2b are independently a single bond or (C1-C2) alkylene;
(2v) Ryb is a single bond, oxy, (C1-C2) alkylene, ethenylene or —
CH═
(where the double bond is with C*), thio, methyleneoxy or methylenethio, or either —
N(R6) or —
CH2—
N(R6*)—
, wherein R6 and R6* are hydrogen or (C1-C6) alkyl;
(3) R1 comprises;
a straight-chained (C2-C3) aliphatic group;
═
N—
O—
(ethylene), wherein the unmatched double bond is linked to C*;
—
O—
R8or —
S—
R8* wherein R8 or R8* is a ethylene or ethenylene and O or S is bonded to C*;
aminoethylene where the amino is bonded to C*;
wherein R1 can be substituted with up to one hydroxy, up to one (C1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy or oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen;
wherein if R1 contributes a heteroatom linked to C*, then Ryb does not contribute a heteroatom linked to C*; and
wherein the alkyl or alkylidene substituents of R1 can be linked to form a 3 to 7-membered non-aromatic ring;
(4) R3 (a) is hydrogen, (C1-C6) alkyl, or phenyl or phenylalkyl wherein the alkyl is C1 to C6 and the phenyl or phenyl of phenylalkyl can be substituted with the same substituents defined above for the phenyl of Rxa, (b) is —
R12C(Rxx)(Ryy)(R11), wherein R12 is bonded to N, Rxx is independently the same as Rx, Ryy is independently the same as Ry, R11 is independently the same as R2 and R12 is independently the same as R1;
(5) R4 and R4* are independently hydrogen or (C1-C6) alkyl, or one of R4 and R4* can be (C1-C6) hydroxyalkyl;
(6) R5 is (CO)NR13R14, (CO)OR15, (CO)SR16, (SO2)NR17R18, (PO)(OR19)(OR20), (CR22)(OR23)(OR24), CN or tetrazol-5-yl, wherein (a) R13, R14, R15, R16, R17, R18 R19 and R20 are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R15 or the sulfur of R16 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, Ar-alkyl wherein the alkyl is C1-C6, or Ar, and (b) R22 is hydrogen or OR25 and R23, R24 and R25 are independently (C1-C6) alkyl, phenyl, benzyl or acetyl or, the alkyls of R23 and R24 can be combined to include 1,3-dioxolane or 1,3-dioxane;
wherein the phenyl or naphthyl groups of R13, R14, R15, R16, R17, R18, R19, R20, R22, R23 or R24 can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, hydroxy, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1-C6) alkyl, (C1 -C6) alkylsulfonyl, or amidino that can substituted with up to three (C1-C6) alkyl wherein R13 and R14 together with the attached nitrogen can form a 5 to 7-membered ring;
and wherein further the following provisos apply;
if R5 is C(O)NR13R14 wherein R13 and R14 are hydrogen, (C1-C8) alkyl, phenyl or substituted phenyl, then at least one of the following applies (1) an Ar of at least one of Rx and Ry is substituted with a radical different from hydrogen, fluoro, chloro, or bromo (2) Ry is Ar—
(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—
N(R6)—
or Ar—
CH2—
N(R6*)—
, (3) R2 is R2a R2b—
, (4) R2 is not hydrogen (5) R3 is not hydrogen, or (6) R1 is not ethylene; and
the compound is not N-(1,1-diphenylpropyl)-glycinamide or N-(1,1-diphenylpropyl)-glycinamide having one or more halo substitutions on one or more of the phenols and differs therefrom by at least two of the following;
(a) substitutions or (b) differences in Rx, Ry, R1, R3, R4, R4* or R5.- View Dependent Claims (23, 24, 25)
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Specification