CA2294046A1 - Glucagon antagonists/inverse agonists - Google Patents
Glucagon antagonists/inverse agonists Download PDFInfo
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- CA2294046A1 CA2294046A1 CA002294046A CA2294046A CA2294046A1 CA 2294046 A1 CA2294046 A1 CA 2294046A1 CA 002294046 A CA002294046 A CA 002294046A CA 2294046 A CA2294046 A CA 2294046A CA 2294046 A1 CA2294046 A1 CA 2294046A1
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Abstract
Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof. The compounds act to antagonize the action of the glucagon peptide hormone.
Description
s F
DEMANDES OU BREVETS VOLUMINEUX
l.A PRESENTS PART1E DE CETTE DE~VIANDE OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST LE TOME ~ DEZ
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THAN ONE VOLUME
. THIS IS VOLUME ,~l OF Z
NOTE: For additional volumes please contact 'the Ganadian.Patent Office GLUCAGON ANTAGONISTSIINVERSE AGONISTS
Field of the invention The present invention relates to agents that act to antagonize the action of the glucagon peptide hormone. It relates particularly to non-peptide glucagon antagonists or inverse ago-nists.
Background of the invention Glucagon is a key hormonal agent that, in cooperation with insulin, mediates homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall.
The action of gluca-gon is opposed by insulin which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.
Glucagon is produced in the alpha islet cells and insulin in the beta islet cells of the pancreas.
Diabetes mellitus, the common disorder of glucose metabolism, is characterized by hypergly-cemia, and can present as type I, insulin-dependent, or type I I, a form that is non-insulin-dependent in character. Subjects with type I diabetes are hyperglycemic and hypoinsulinemic, 2o and the conventional treatment for this form of the disease is to provide insulin. However, in some patients with type I or II diabetes, absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state. Both in healthy animals as well as in animal models of type I and II, removal of circulating glucagon with selective and specific anti-bodies has resulted in reduction of the glycemic level (Brand et al.
Diabetologia 37, 985 (1994);
Diabetes 43, [suppl 1], 172A (1994); Am J Physiol 269, E469-E477 (1995);
Diabetes 44 [suppl 1], 134A (1995); Diabetes 45, 1076 (1996)). These studies suggest that glucagon suppression or an action antagonistic to glucagon could be a useful adjunct to conventional antihypergly-cemia treatment of diabetes. The action of glucagon can be suppressed by providing an an-tagonist or an inverse agonist, substances that inhibit or prevent glucagon induced response.
The antagonist can be peptide or non-peptide in nature. Native glucagon is a 29 amino acid-containing peptide having the sequence:
DEMANDES OU BREVETS VOLUMINEUX
l.A PRESENTS PART1E DE CETTE DE~VIANDE OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST LE TOME ~ DEZ
NOTE: Pour les tomes additionels, veuillez contacter fe Bureau canadien des brevets THiS SECT10N OF THE APPLICAT10N/PATENT CONTAINS MORE
THAN ONE VOLUME
. THIS IS VOLUME ,~l OF Z
NOTE: For additional volumes please contact 'the Ganadian.Patent Office GLUCAGON ANTAGONISTSIINVERSE AGONISTS
Field of the invention The present invention relates to agents that act to antagonize the action of the glucagon peptide hormone. It relates particularly to non-peptide glucagon antagonists or inverse ago-nists.
Background of the invention Glucagon is a key hormonal agent that, in cooperation with insulin, mediates homeostatic regulation of the amount of glucose in the blood. Glucagon primarily acts by stimulating certain cells (mostly liver cells) to release glucose when blood glucose levels fall.
The action of gluca-gon is opposed by insulin which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.
Glucagon is produced in the alpha islet cells and insulin in the beta islet cells of the pancreas.
Diabetes mellitus, the common disorder of glucose metabolism, is characterized by hypergly-cemia, and can present as type I, insulin-dependent, or type I I, a form that is non-insulin-dependent in character. Subjects with type I diabetes are hyperglycemic and hypoinsulinemic, 2o and the conventional treatment for this form of the disease is to provide insulin. However, in some patients with type I or II diabetes, absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state. Both in healthy animals as well as in animal models of type I and II, removal of circulating glucagon with selective and specific anti-bodies has resulted in reduction of the glycemic level (Brand et al.
Diabetologia 37, 985 (1994);
Diabetes 43, [suppl 1], 172A (1994); Am J Physiol 269, E469-E477 (1995);
Diabetes 44 [suppl 1], 134A (1995); Diabetes 45, 1076 (1996)). These studies suggest that glucagon suppression or an action antagonistic to glucagon could be a useful adjunct to conventional antihypergly-cemia treatment of diabetes. The action of glucagon can be suppressed by providing an an-tagonist or an inverse agonist, substances that inhibit or prevent glucagon induced response.
The antagonist can be peptide or non-peptide in nature. Native glucagon is a 29 amino acid-containing peptide having the sequence:
His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH2.
Glucagon exerts its action by binding to and activating its receptor, which is part of the Glu-cagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family {Jelinek et ai. Science 259, 1614, (1993)). The receptor functions by activation of the adenylyl cycfase second messenger system and the result is an increase in cAMP levels.
Several publications disclose peptide antagonists. Probably, the most thoroughly character-ized antagonist is DesHis'[Glu9]-glucagon amide (Unson et al., Peptides 10, 1171 (1989);
Post et al., Proc. Natl. Acad. Sci. USA 90, 1662 (1993)). Other antagonists are eg DesHis',Phe6[Glu9]-glucagon amide (Azizh et al., Bioorganic & Medicinal Chem.
Lett. 16, 1849 (1995)) or NLeu9,Ala"~'6-glucagon amide (Unson et al., J. Biol. Chem.
269(17), 12548 (1994)).
Peptide antagonists of peptide hormones are often quite potent; however, they are defective as drugs because of degradation by physiological enzymes, and poor biodistribution. Therefore, non-peptide antagonists of the peptide hormones are preferred. Among the non-peptide glu-2o cagon antagonists, a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethyl-amino]-6,7-dichloroquinoxaline was found to displace glucagon from the rat liver receptor (Collins, J.L. et al. (1992) Bioorganic and Medicinal Chemistry Letters 2(9}:915-918). West, R.R: et al. (1994), WO 94/144.26 discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists.
Anderson, P.L., U.S. Patent No. 4,359,474 discloses the glucagon antagonistic properties of 1-phenyl pyrazole derivatives. Barcza, S., U.S. Patent No. 4,374,130, discloses substituted disi-lacyclohexanes as glucagon antagonists. WO 98/04528 (Bayer Corporation) discloses substi-tuted pyridines and biphenyls as glucagon antagonists. Furthermore, WO
97/16442 (Merck &
Co., Inc.) discloses substituted pyridyl pyrroles as glucagon antagonists and (Merck & Co., Inc.) discloses 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. These glucagon antagonists differ structurally from the present compounds.
Glucagon exerts its action by binding to and activating its receptor, which is part of the Glu-cagon-Secretin branch of the 7-transmembrane G-protein coupled receptor family {Jelinek et ai. Science 259, 1614, (1993)). The receptor functions by activation of the adenylyl cycfase second messenger system and the result is an increase in cAMP levels.
Several publications disclose peptide antagonists. Probably, the most thoroughly character-ized antagonist is DesHis'[Glu9]-glucagon amide (Unson et al., Peptides 10, 1171 (1989);
Post et al., Proc. Natl. Acad. Sci. USA 90, 1662 (1993)). Other antagonists are eg DesHis',Phe6[Glu9]-glucagon amide (Azizh et al., Bioorganic & Medicinal Chem.
Lett. 16, 1849 (1995)) or NLeu9,Ala"~'6-glucagon amide (Unson et al., J. Biol. Chem.
269(17), 12548 (1994)).
Peptide antagonists of peptide hormones are often quite potent; however, they are defective as drugs because of degradation by physiological enzymes, and poor biodistribution. Therefore, non-peptide antagonists of the peptide hormones are preferred. Among the non-peptide glu-2o cagon antagonists, a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethyl-amino]-6,7-dichloroquinoxaline was found to displace glucagon from the rat liver receptor (Collins, J.L. et al. (1992) Bioorganic and Medicinal Chemistry Letters 2(9}:915-918). West, R.R: et al. (1994), WO 94/144.26 discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists.
Anderson, P.L., U.S. Patent No. 4,359,474 discloses the glucagon antagonistic properties of 1-phenyl pyrazole derivatives. Barcza, S., U.S. Patent No. 4,374,130, discloses substituted disi-lacyclohexanes as glucagon antagonists. WO 98/04528 (Bayer Corporation) discloses substi-tuted pyridines and biphenyls as glucagon antagonists. Furthermore, WO
97/16442 (Merck &
Co., Inc.) discloses substituted pyridyl pyrroles as glucagon antagonists and (Merck & Co., Inc.) discloses 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. These glucagon antagonists differ structurally from the present compounds.
Description of the invention Definitions The following is a detailed definition of the terms used to describe the compounds of the inven-tion:
"Halogen" designates an atom selected from the group consisting of F, CI, Br or I.
The term "alkyl" in the present context designates a hydrocarbon chain or a ring that is either saturated or unsaturated (containing one or more double or triple bonds where feasible) of from 1 to 10 carbon atoms in either a linear or branched or cyclic configuration.
Thus, alkyl includes for example n-octyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, allyl, propargyi, 2-hexynyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclooctyl, 4-cyclohexylbutyl, and the like.
Further non-limiting examples are sec-butyl, n-pentyl, isopentyl, neopentyl, Pert-pentyl, n-hexyl, isohexyl, n-heptyl, n-nonyl, n-decyl, vinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 2,4-heptadienyl, 1-octenyl, 2,4-octadienyl, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyi, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-hepynyl, 1-octynyl, 2-decynyl, cyclobutyl, cyclopentyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclohexenylmethyl, 4-cyclohexyl-2-butenyl, 4-(1-cyclohexenyl)-vinyl and the like.
The term "lower alkyl" designates a hydrocarbon moiety specified above, of from 1 to 6 carbon atoms.
"Aryl" means an aromatic ring moiety, for example: phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, isothiazolyl, tetrazolyl, 1-H-tetrazol-5-yl, indolyl, quinolyl, quinazolinyl, benzofuryl, benzothiophenyl (thianaphthenyl) and the like.
Further non-limiting examples are biphenyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydrobenzofuryl, triazolyi, pyranyl, thiadiazinyl, isoindolyl, in-dazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, benzothienyl, benzimidazolyl, benzthiazolyl, ben-zisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinolizinyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl and the like.
The aryl moieties are optionally substituted by one or more substituents, for example selected from the group consisting of F, CI, I, and Br; tower alkyl; lower alkanoyl such as formyl, acetyl, propionyf, butyryl, valeryl, hexanoyl and the like; -OH; -NOz; -CN; -COZH; -O-lower alkyl; aryl;
aryl-lower alkyl; -COZCH3; -CONH2; -OCHZCONH2; -NHz; -N(CH3)2; -SOZNHz; -OCHFZ; -CF3;
-OCF3 and the like. A further non-limiting example is -NH-(C=S)-NH2.
Such aryl moieties may also be substituted by two substituents forming a bridge, for example -OCHZO-.
"Aryl-lower alkyl" means a lower alkyl as defined above, substituted by an aryl, for example:
~ ~ S , ~ ~
i , i ~ ~ i /~/
The aryl group is optionally substituted as described above.
Description of the invention The present invention is based on the unexpected observation that compounds having a se-lected nitrogen-bearing central motif and the general structural features disclosed below an-tagonize the action of glucagon.
Accordingly, the invention is concerned with compounds of the general formula I:
R' I
A~X\N~N NCH ~ g-~K~ p wherein:
R' and RZ independently are hydrogen or lower alkyl or together form a valence bond;
R3 and R' independently are hydrogen or lower alkyl;
n is 0, 1, 2 or 3;
mis0orl;
X is >C=O, >C=S, >C=NR5 or >SO2;
wherein R5 is hydrogen, lower alkyl, aryl-lower alkyl or -ORe;
wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
A is R' R' R' ' R
Ra \ Ra N~ Ra~N~ \
Ra / / N /
Rs ' Rs ~ Rs , Rs I \ Rio , /
R' Rio \ I
Ra v N R
Rs I \ Rio Re I N N ~ R
' Rs ~ ' Rio N Ra R'° Rio Rio Rio N R7 N R~ N N
a N.
Ra ~ R ~ > >
s r , N /.~ . R N , R N~ , R Rs Ra Ra Rio Ra O R~ O R' S R
R~ N~ I Re ~ Ra ' N ~ , ~' . a ~ , Ra Rs Rs R
Rio Rio Rio Ra S R I R~ N R~ N R~
.N
. N\ I , Ra ~ N , Ra ~ N
Rs a ~
R Re~~ Rs Rs Rio Rio N R~ N R~ N R~ R~ N
Ra ~ , Ra ~ , R-jj- R
8 ~ 8 \ , Rs ~N Rs N~ \N Rs , Rs / N Rio s Rio R~ N Rio R' N R~N~ R N
a \ ~ a ~ ~ i R Rs / i N ' R Rs / ~ N N / . Rio , R'___.~
R,o Ra Ra S O ~ O ~O
Ro_S~ , R'__-, R'or R' N
Ra R Ra R
wherein:
"Halogen" designates an atom selected from the group consisting of F, CI, Br or I.
The term "alkyl" in the present context designates a hydrocarbon chain or a ring that is either saturated or unsaturated (containing one or more double or triple bonds where feasible) of from 1 to 10 carbon atoms in either a linear or branched or cyclic configuration.
Thus, alkyl includes for example n-octyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, allyl, propargyi, 2-hexynyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclooctyl, 4-cyclohexylbutyl, and the like.
Further non-limiting examples are sec-butyl, n-pentyl, isopentyl, neopentyl, Pert-pentyl, n-hexyl, isohexyl, n-heptyl, n-nonyl, n-decyl, vinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 2,4-heptadienyl, 1-octenyl, 2,4-octadienyl, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyi, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-hepynyl, 1-octynyl, 2-decynyl, cyclobutyl, cyclopentyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cyclopropylethyl, cyclobutylmethyl, 2-cyclobutylethyl, cyclohexenylmethyl, 4-cyclohexyl-2-butenyl, 4-(1-cyclohexenyl)-vinyl and the like.
The term "lower alkyl" designates a hydrocarbon moiety specified above, of from 1 to 6 carbon atoms.
"Aryl" means an aromatic ring moiety, for example: phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, isothiazolyl, tetrazolyl, 1-H-tetrazol-5-yl, indolyl, quinolyl, quinazolinyl, benzofuryl, benzothiophenyl (thianaphthenyl) and the like.
Further non-limiting examples are biphenyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydrobenzofuryl, triazolyi, pyranyl, thiadiazinyl, isoindolyl, in-dazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, benzothienyl, benzimidazolyl, benzthiazolyl, ben-zisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinolizinyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl and the like.
The aryl moieties are optionally substituted by one or more substituents, for example selected from the group consisting of F, CI, I, and Br; tower alkyl; lower alkanoyl such as formyl, acetyl, propionyf, butyryl, valeryl, hexanoyl and the like; -OH; -NOz; -CN; -COZH; -O-lower alkyl; aryl;
aryl-lower alkyl; -COZCH3; -CONH2; -OCHZCONH2; -NHz; -N(CH3)2; -SOZNHz; -OCHFZ; -CF3;
-OCF3 and the like. A further non-limiting example is -NH-(C=S)-NH2.
Such aryl moieties may also be substituted by two substituents forming a bridge, for example -OCHZO-.
"Aryl-lower alkyl" means a lower alkyl as defined above, substituted by an aryl, for example:
~ ~ S , ~ ~
i , i ~ ~ i /~/
The aryl group is optionally substituted as described above.
Description of the invention The present invention is based on the unexpected observation that compounds having a se-lected nitrogen-bearing central motif and the general structural features disclosed below an-tagonize the action of glucagon.
Accordingly, the invention is concerned with compounds of the general formula I:
R' I
A~X\N~N NCH ~ g-~K~ p wherein:
R' and RZ independently are hydrogen or lower alkyl or together form a valence bond;
R3 and R' independently are hydrogen or lower alkyl;
n is 0, 1, 2 or 3;
mis0orl;
X is >C=O, >C=S, >C=NR5 or >SO2;
wherein R5 is hydrogen, lower alkyl, aryl-lower alkyl or -ORe;
wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
A is R' R' R' ' R
Ra \ Ra N~ Ra~N~ \
Ra / / N /
Rs ' Rs ~ Rs , Rs I \ Rio , /
R' Rio \ I
Ra v N R
Rs I \ Rio Re I N N ~ R
' Rs ~ ' Rio N Ra R'° Rio Rio Rio N R7 N R~ N N
a N.
Ra ~ R ~ > >
s r , N /.~ . R N , R N~ , R Rs Ra Ra Rio Ra O R~ O R' S R
R~ N~ I Re ~ Ra ' N ~ , ~' . a ~ , Ra Rs Rs R
Rio Rio Rio Ra S R I R~ N R~ N R~
.N
. N\ I , Ra ~ N , Ra ~ N
Rs a ~
R Re~~ Rs Rs Rio Rio N R~ N R~ N R~ R~ N
Ra ~ , Ra ~ , R-jj- R
8 ~ 8 \ , Rs ~N Rs N~ \N Rs , Rs / N Rio s Rio R~ N Rio R' N R~N~ R N
a \ ~ a ~ ~ i R Rs / i N ' R Rs / ~ N N / . Rio , R'___.~
R,o Ra Ra S O ~ O ~O
Ro_S~ , R'__-, R'or R' N
Ra R Ra R
wherein:
R' is hydrogen, halogen, -CN, -CF3, -OCF3, -OCHzCF3, -NOz, -OR", -NR"R'Z, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SOZNR"R'2, -SR", -CHFZ, -OCHF2, -OSOZR", -CONR"R'2, -OCH2CONR"R'2, -CHzOR", -CHZNR"R'2, -OCOR", -COzR'3 or -OSOZCF3;
R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NO2, -OR", -NR"R'z, lower alkyl, aryl, -SCF3, -SR", -CHF2, -OCHF2, -OSOZR", -CONR"R'2, -CHZOR", -CHZNR"R'2, -OCOR", -COzR'3 or -OSOZCF,, or RB and R9 together form a bridge -or -OCHZCH20-;
wherein R" and R'2 independently are hydrogen, -COR'3, -SOZR'3, lower alkyl or aryl;
wherein R'3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and R'° is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B iS
R1s W~ \ W.,' \ W
-I- ~ -I- ~ ~-R14 ' V ~ ~ R1s / V~14 1 R's / V \R14 .q R .q R,4 R1s \ W ~~7 R14 Y ~ ~ / ,s V3~ , ~ , ~- R , ~q R's \ q \ q W
R14~'~ ~Rls R'4 I -+-~2 / V
R,4 Rts R1s q W. ~ ' R14 \ I ~ Y I \ W;
14 -CR'~CR's / ,Z , ~ -~-R
R1s V / V ~Z
or a valence bond;
R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NO2, -OR", -NR"R'z, lower alkyl, aryl, -SCF3, -SR", -CHF2, -OCHF2, -OSOZR", -CONR"R'2, -CHZOR", -CHZNR"R'2, -OCOR", -COzR'3 or -OSOZCF,, or RB and R9 together form a bridge -or -OCHZCH20-;
wherein R" and R'2 independently are hydrogen, -COR'3, -SOZR'3, lower alkyl or aryl;
wherein R'3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and R'° is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B iS
R1s W~ \ W.,' \ W
-I- ~ -I- ~ ~-R14 ' V ~ ~ R1s / V~14 1 R's / V \R14 .q R .q R,4 R1s \ W ~~7 R14 Y ~ ~ / ,s V3~ , ~ , ~- R , ~q R's \ q \ q W
R14~'~ ~Rls R'4 I -+-~2 / V
R,4 Rts R1s q W. ~ ' R14 \ I ~ Y I \ W;
14 -CR'~CR's / ,Z , ~ -~-R
R1s V / V ~Z
or a valence bond;
wherein:
R" and R'S independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CHZ),CF3, -NOZ, -OR'6, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR's, -CHF2, -OCHFz, -OCFZCHFZ, -OSOZCF3, -CONR'6R", -(CHZ),CONR'sR", -O(CHZ),CONR'6R", -(CHZ),COR'6, -(CHZ),COR'6, -(CHZ),OR'6, -O(CHZ),OR'6, -(CHZ),NR'6R", -O(CHz),NR'eR", -OCOR'6, -COZR'8, -O(CHZ),COzR'8, -O(CHZ),CN, -O(CHZ),CI, or R'° and R'S together form a bridge -O(CHz),O- or -(CHZ)~-;
wherein I is 1, 2, 3 or 4;
R'6 and R" independently are hydrogen, -COR'8, -SOZR'8, lower alkyl, aryl, or R'6 and R"
together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
wherein R'e is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
W is -N= or -CR'9=;
Y is -N= or -CRZ°=;
Z is -N= or -CR2'=;
V is -N= or -CRzz=; and Q is -NR23-, -O- or -S-;
wherein:
R'9, RZ°, RZ' and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NO2, -ORz', -NRz'RZS, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR24, -CHF2, -OCHFZ, -OCFZCHF2,-OSOzCF3, -CONR2'Rzs, -CHzCONRz°R25, -OCHZCONRz°Rzs,-CHZOR24, -CHZNRz°RZS, -OCORZ° or -COzR2', or R'9and Rz°, RZ° and RZ', or RZ' and R22 together form a bridge -OCH20-;
R" and R'S independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CHZ),CF3, -NOZ, -OR'6, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR's, -CHF2, -OCHFz, -OCFZCHFZ, -OSOZCF3, -CONR'6R", -(CHZ),CONR'sR", -O(CHZ),CONR'6R", -(CHZ),COR'6, -(CHZ),COR'6, -(CHZ),OR'6, -O(CHZ),OR'6, -(CHZ),NR'6R", -O(CHz),NR'eR", -OCOR'6, -COZR'8, -O(CHZ),COzR'8, -O(CHZ),CN, -O(CHZ),CI, or R'° and R'S together form a bridge -O(CHz),O- or -(CHZ)~-;
wherein I is 1, 2, 3 or 4;
R'6 and R" independently are hydrogen, -COR'8, -SOZR'8, lower alkyl, aryl, or R'6 and R"
together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
wherein R'e is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
W is -N= or -CR'9=;
Y is -N= or -CRZ°=;
Z is -N= or -CR2'=;
V is -N= or -CRzz=; and Q is -NR23-, -O- or -S-;
wherein:
R'9, RZ°, RZ' and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NO2, -ORz', -NRz'RZS, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR24, -CHF2, -OCHFZ, -OCFZCHF2,-OSOzCF3, -CONR2'Rzs, -CHzCONRz°R25, -OCHZCONRz°Rzs,-CHZOR24, -CHZNRz°RZS, -OCORZ° or -COzR2', or R'9and Rz°, RZ° and RZ', or RZ' and R22 together form a bridge -OCH20-;
wherein Rz' and R25 independently are hydrogen, -COR26, -SOZRZ6, lower alkyl, aryl or aryl-lower alkyl;
.. 5 wherein R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is R3a R3b R4a R4b (L) (CH -\~ CH M
2)b P ( 2)a ( )f (CHZ)~ (CH2)d wherein:
R3a, R3b, R4a and R'b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF,, 15 -NO2, -ORZ<a, -NRzoaR2sa, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SRZ°a, -CHF2, -OCHF2, -OCFZCHF2.-OSOZCF3, -CONRz4aR2sa, -CHZCONRz4aRzsa, _OCHZCONRz4aR2sa,-CHZOR24a, -CHZNRZ°aRzsa -OCOR2°a or -COzRz4a;
wherein RZ'a and Rzsa independently are hydrogen, -COR2sa, -SOZRzsa, lower alkyl, aryl or 20 aryl-lower alkyl;
wherein RZSa is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
or R3a and R3b, R4a and R4b, or R'a and R4b together form a bridge -(CHZ); ;
Wherein i is 1, 2, 3 or 4;
a, b, c and d independently are 0, 1, 2, 3 or 4;
e, f and p independently are 0 or 1;
q is 0, 1 or 2; and 5 L and M independently are -O-, -S-, -CH=CH-, -C--_C-, -NRSa-, -CHZNRsa-, -CO-, -OCO-, -COO-, -CONRSa-, -CONRSe-, -NRSaCO-, -SO-, -SOZ-, -OSOZ-, -SOzNRSa-, -NRSaS02-, -NRSaCONRSb-, -CONRSaNRSb-, -NRSaCSNRS°-, -OCONRS°-, -CHzCONRSb-, -OCHZCONRsb-, -G"
-P(O)(ORSa)O-, -NRSaC(O)O- Or ~R~.
wherein Rsa and R5b independently are hydrogen, lower alkyl, -OH, -(CHZ)k-ORsa, -CORsa, -(CHz)k-CH(ORsa)z, -(CHZ)k-CN, -(CHZ)k-NRsaR6b, aryl, aryl-lower alkyl, -(CHZ)9 COOR43 or _ (CHZ)9 CF3i wherein k is 1, 2, 3 or 4;
R6a and Rsb independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
g is 0, 1, 2, 3 or 4;
R43 is hydrogen or lower alkyl;
G" is -OCHZCO-, -CHZCO-, -CO- or a valence bond; and E" is -CHZ , -CHZCHZ-, -CH=CH-, -CHzNH- or -CHzCHZNH-;
D is hydrogen, R ~~" w~~~~r Rzr w ' it Ra \ w :-fit- za W
Rza V'~~ , a / V''Z, ~ ~ ~%Z' , V' Z' , Rz Rz~
R~' w~Q' Rz~ w,iQ~ Rz' ,,W' ' w ~ ~Y, ~ ° Y,. ~ I w'1~
r . , ~ .
Rza Rze R (CHz)' V, ~, it y Rza w ~ w Rz~
w~-z~ I w '~ Y\\ , ~ \ a ze R (CHz~V.%Z~ , Z -V ~~ ~ ~ R Z'-V' ~ .
Rz' Rrr ze W~ \z)s . ~E ~ \F' RE~CHF)s ~ Rza 'f-G Rz~ . ~ , F I /' Q - ~G
Rza R ~ R~
(CH )~E~~Rz~ /E F E~(C~z)s~U)~
z s CH ~~ F' G ( 2)s ~. w ~~ .
Q,y,.~ ' V'~Z~Rze R28 \
(CHz)s E~ \ '(Cyz)S/(G),w ;(C~i).
~.y~~ R~~~Rz' Rza~Rz~
E F' F F .
R~
Rza RZ ~CHz), G
E E Rza or G I E, I ~ Rza ~~ cHz), F,~ I I
F ~E~V';Z
wherein:
ris0orl;
I
s is 0, 1, 2 or 3;
E, E', F, G and G' independently are -CHR38-, >C=O, >NR39, -O- or -S-;
F' is >CR38- or >N-;
Y' is -N= or -CR32=;
Z' is -N= or -CR33=;
V' is -N= or -CR~'=;
W' is -N= or -CR35=; and Q' is -NR36-, -O- or -S-;
wherein:
Rz', Rze, R32, R33, R~ and R35 independently are hydrogen, halogen, -CN, -CF3, -O{CH2)yCF3, -(CHz)yNHCOCF3, -NOZ, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR29, -CHF2, -OCHF2, -OCFZCHFz, -OSOZRZ9, -OSOZCF3, -(CHZ)YCONRZ9R3°, -O(CHz)yCONR29R3°, -(CHz)yOR2s, -(CHZ)YNRZ9R3°, -OCORz9, -CORz9 or -COZR~;
or RZ'and R28, R32 and R33, R33 and R°', or Rte' and R35 together form a bridge -O(CH2)YO-;
wherein y is 0, 1, 2, 3 or 4; and R29 and R3° independently are hydrogen, -COR3', -COZR3', -SOZR3', lower alkyl, aryl or aryl-lower alkyl;
wherein R" is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R'6 and R'9 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
and R38 is hydrogen, -OR°°, -NR°°R", lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR°°, -CHF2, -OCHF2, -OCFZCHF2, -CONR°°R", -(CHZ)xCONR°°R", -O(CHZ)XCONR°°R°', -{CHZ)xOR°°, -(CHZ)XNR°°R°,, -OCOR4° or -COZR°°;
wherein x is 1, 2, 3 or 4;
R'° and R" independently are hydrogen, -COR42, -SOZR°z, lower alkyl, aryl or aryl-lower aI-kyl;
wherein R'2 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
Where the formulae for B make it possible, R'9, R~°, Rz', R~ and Rte' may alternatively be re-placed by R" or R'S, respectively. In such case eg W may be selected from -N=, -CR'9- and _CR,4_ Similarly, where the fom~ulae for D make it possible, R3z, R", R'°, Rte, R36, R~° and R'9 may al-ternatively be replaced by RZ' or R28, respectively. In such case eg E may be selected from -CHR'~-, >C=O, >NR39, -O-, -S-, -CHRZ'- and >NRZ'.
In a preferred embodiment the invention relates to compounds of the following general formula O
A~N~N~ (CH2}~ .B-{Kj~ D (II) R R
wherein A, B, K, D, R', R', n and m are as defined for formula I.
In another preferred embodiment the invention relates to compounds of the following general formula III:
O
I I
A~S~N~N (CH2~B-(K~D (III) O Rs Ra wherein A, B, K, D, R3, R4, n and m are as defined for formula I.
In still another preferred embodiment the invention relates to compounds of the following formula IV:
O
H
A N~N~~~H2~" B (K)m D
R3 Ra wherein A, B, K, D, R3, R°, n and m are as defined for formula I.
In the compounds of the above formulae I to IV the following substituents are preferred:
R3 is preferably hydrogen.
R' is preferably hydrogen.
A is preferably selected from the group consisting of:
R~ R~ R~
N
Re Rg \ RB
/ /
Rs . Rs .
Rs I ~ Rio R~~ Rio Rio I
N.N N R~ ~N R~
R~,%' Re ~ and N
R Rs~ Rs Re wherein R', R8, R9 and R'° are as defined for formula I.
A is more preferably R' Rs 5 wherein R', R8 and R9 are as defined for formula I.
In the above embodiments of A, R' is preferably halogen, lower alkyl, -OH, -NO2, -CN, -COZH, -O-lower alkyl, aryl, aryl-lower alkyl, -COzCH3, -CONH2, -OCHZCONH2, -NH2, -N(CH3)2, -SOZNH2, -OCHFZ, -CF3 or -OCF3.
Preferably, R8 and R9 are independently hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, and R'° is hydrogen, lower alkyl or phenyl.
More preferably, R8 and R9 are independently selected from hydrogen, halogen such as -F and -CI, -O-lower alkyl such as methoxy and ethoxy, -NH2, -CN or -NO2, and R'° is hydrogen.
In a particularly preferred embodiment A is Rs HO
Rs wherein R8 and R9 independently are hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCHzCF3, -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, preferably hydrogen, halogen such as -F and -CI, -O-lower alkyl such as methoxy and ethoxy, -NH2, -CN or -NO2.
In a further particularly preferred embodiment A is \
HO ~ R9 wherein R8 is hydrogen, halogen such as -F or -CI, -O-lower alkyl such as -OCH3 or -OCzHs, -NHz, -CN or -NO2; and R9 is hydrogen or halogen such as -F or -CI.
In a preferred embodiment R8 is halogen and R9 is hydrogen.
In still a preferred embodiment the invention relates to compounds of the following formula V:
R$ O
\ NiN~B \K)fn D M
HO
1 o wherein R°, B, K, D and m are as defined for formula I and R8 and R9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.
B is preferably:
Ris W~, \ W 1. W
-i--%Z / /
V ' ~s V ' ~s V
R R R" R ~ ~e Q W Q W
R ( ~ R \ ~ ~ -CRu'CR~s / V~ , / ~ . .
Ru R's V
a .Q R .D Rie \ Q Ru Rub I ~ '~I
Y Y R,s , W I
Rya Ru W W~~Q
~R" ~~ R,a~R,s / V ~Z
wherein V, W, Z, Y and Q are as defined for formula I; and R'4 and R'S independently are hydrogen, halogen, -CF3, -OCF3, -OR'6, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -OSOzCF3, -CONR'gR", -CH20R'e, -CH2NR'6R", -OCOR'6 or -COZR'8;
or R'4 and R'S together form a bridge -OCHzO- or -(CHZ),-;
wherein I, R'6, R" and R'8 are as defined for formula I.
Q is preferably -O- or -NH-.
Particularly preferred compounds are those in which B is R,a \ \ R~s Rya R~s (~J~
/ / ~ , R,.~~~ ,s R~s R~s R,s R,s / R,a Ru / /
\ w+R~4 , O / , NH ~r NH
V~~ \
R~s wherein V, W, Z, Y and Q are as defined for formula !; and R'4and R'S independently are hydrogen, halogen, -CF3, -OCF3, -OR'B, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -OSOZCF3, -CONR'6R", -CHZOR'e, -CH2NR'6R", -OCOR'6 or -COZR'e;
or R" and R'S together form a bridge -OCH20- or -(CHZ)r;
wherein I, R'6, R" and R'8 are as defined for formula I.
Still more preferred are compounds of the following formula Vl:
Rya \ N. N w \ (K)m ~ (VI ) H R1s HO ~R9 as well as compounds of the following formula VII:
Rya R$ O
(K)rt, D (VII) H
HO
R R
as well as compounds of the general formulae Vllla or Vlllb:
Rs O ~ ~ 1K)fIi D
(Villa) or HO ,a R9 R R,s R'°
RB R,s O
~~N ~ \ ~NH(K)m D ~Illb) HO ~R ~s wherein R"and R'S independently are hydrogen, halogen, -CF3. -OCF3, -OR'6, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -OSOzCF3,-CONR'sR", -CHZOR'6, -CHZNR'sR", -OCOR'6 or -COZR'8; or R" and R'S together form a bridge -OCH20- or -(CHZ),-;
wherein I, R'6, R" and R'8 are as defined for formula I;
K, D and m are as defined for formula I; and R8 and R9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.
In the above formulae VI, VII and VIII, R'° and R'S are preferably independently hydrogen, halogen, lower alkyl, aryl such as phenyl, or -O-lower alkyl such as methoxy.
In the above formulae VI and VII, K is preferably bound in para-position and in the above for-mulae Vllla and Vlllb, K is preferably bound at the nitrogen atom of the indole group.
K is preferably selected from the group consisting of:
-(CHZ)p O-(CHz)a , -(CHz)b S-(CHZ)d , --(CHZ)p CH-CH-(CHZ)d-~ , O
-(CHZ)b (CHZ)a- , -(CHZ)b N-(CHz}d ~ -(CHZ?-~.L-.O-(CHZ)d , R~
sa O Rsa R~ Rao -(CH )~N-(CH )~(CH ) , -(CH ) N--~ CH ~ -(CHz)b O; N- CH
2 b 2 c 2 d 2 b I ( 2)d v O ( 2)a R~
O O
II II O
-(CHZ)b O-(CHz)d , -(CHZ)b S-(CHZ)d , -(CHZ}b O-IL-(CHz)d , O
I I
-O-O-(CH2)a , -(CHZ}a , O-(CHZ)p N~ (CH2)a , R
O
O-(CHZ)b CHR~ (CHz)a N (CHZ}d , -O-(CHZr-~I-N-(CHZ)d ' sa R~
O O
-O-(CHZ)b N~(CHZ~e-- , -O-(CHZr-I~-O-(CHz)d , R~
O
-O-H O-(CH2~ , -O-(CHZ p ~~(CHz)d O
O
-O-(CHz)ti O-(CHZ)a , -O-(CHZ~CHR~- , -O-(CHz}d O--~- i -(CHZ~ , Rso Raa Rdb -O-(CHz)b-N-(CH2)~~(CHz)a , -O-(CH2)p S-(CHZ)a R5a O
Raa Rat Raa Rad -(CHZ)p N-(CHZ)~~(CHz)a- , -(CHZ)d SO-(CHZ)~\~(CHZ)d , R~
Raa Rab O Raa Rao -(CHZ)e SOz (CHZ)~ \~(CHZ)d , -(CHZ)ti P-O-~(CHZ)a , ORS
O Raa Ran O
-O-(CH2)b P-O-~-(CHZ)o , - CHz b~(CH
ORS' ( ) Z)a , O Ray R3b O
-~-N-(CHz)b-O-(CHZ)a , -(CHZ)b~(CHZ)a~N-(CHZ)d , R~
O Rsa O Rsa -O-CHZ~N~~ ~ -O-CH~N~
OII R~ O Rs~
-O-CHZ~N~ -(CHz)C , -O-CHZ~N~-CHZ , O R~ O R~
O CH~..~-N'~(CHZ)b N-(CHZ)a , -O-CHI-~-N , R~
O R~ O O Rsa -O-CH2~ ~ -(CHZ)~- , -CHZ-~L- ~ -(CHz)e , O R~ O Rs~
-O-CHz~N~ -(CHZ)b i -(CHZ)d , --LLN~ -(CHZ)b R~
O R~ O
-CHZ--LL-N~~(CHZ)o , -O-CHZ~N~~/N-R~ , OI' OII ~
-CHz~N~ R~ , ~N~ Rsa O O
-O-CHz~-Rse (CHz)b S-(CHz)d , -CHz~-N-(CHz)b O-(CHz)d .
R~
Raa Rae .
-(CHz)b N-(CHz)~~(CHz)d -CHz N-(CHz)b N-(CHz)d , Rst Rsa Raa Rao -O-(CHz)ti N-(CHz)~~(CHz)d . N-(CHz)p N-(CHz)d .
Rsa Rso Rsa O R~ R3b O
-O"CH~R~ (CHz)~N-(CHz)a , -N-LL-(CHz)p O-(CHz)a R~ R~
O Raa Rae Raa Ran O R~
~~ ~~ R3o -Chlz'~N-(CHz)p~(CHz)~~(CHz)a , -LL--N-(CH2)~(CHz)~ S-(CHz)a Rso R~ , R~ R3b -CH N- CH -~- O Rte' Rte' O
z R~ ( z)d a (CH2)c O-(CHz)d ~ ---~Nsb (CHz)~(CHz)-~-N-(CHz)d R Rsa R3a Rab Raa Rao O
-CHZ R~ (CHz)-~-(CHz)~~-(CHz)d and -CHz~--.N~ (CHz)b N-(CHz)d R R~
wherein R3a, R3b, Raa~ R4b Rsa~ RSb, a, b, c, d, p and q are as defined for formula I.
More preferably, K is selected from the group consisting of:
-(CHz)b O-(CHZ)a ~ -(CHZ)b N-(CHZ)d ~ O-(CHZ)b N-(CHz)a , R~ R~
O
O-(CHz)b CHR~ (CHz)a N (CHz)d , -O-(CHZ~N-(CHZ)d , sa R~
O O
-O-(CH2~0-(CHZ)a , , -O-(CHz~(CHZ)d O O
-O-S-(CHZ)d , -(CHZ)a - , -O-(CHZ)e -O-~-N-(CHZ)d- , O Rsb O
-O-(CHz)b-CHR3a- , -(CHz)D O~(CHZ)a -(CHZ)b g-(CH2)d , p Rsa ~~ Raa~ Reb -(CHZ)--u-N-(CH2)~(CHZ)a , -4-(CHZ)b-N-(CHZ)~~(CHZ)a , R5a Raa Rnb Raa Rab -(CHZ)b N-(CHZ)~\~(CHZ)a - , -(CH2)b SO-(CH2)~ \~(CHZ)a R~
R;a R4b p Rqa R4b -(CHz)ti SOZ (CHZ)~ \~(CHz)d , -(CHZ)d P=O~(CHz)d , ORS
O R°a R°° O
-O-(CHZ)b P-O~(CH2)d , - CH
( z)b (CH2)d , ORS
O R3a R3b O
--~L-N-(CHZ)b-O-(CHZ)d , -(CHZ)b~(CHZ)a~N-(CHz)d R~
5a OII R~ OII Rs~
-O-CH~N\~ , -O-CH~N\' OII R~ O R~
-O-CH~N~ -(CHZ)b , -O-CN~N~-CHz , O Rs~
-O-CH ~~ O R~
~N'~~(CHZ)b N-(CH2)d , -O-CHI-~-N .
R~
R~'' -O-CH~N~RCHz)b-IL- , -C~--~-N~-(CHZ)6 .
U
O Rsa O Rsa O CHZ~ ~ (CHZ)b N-(CHZ)d , ~N~-(CHZ)b R~
O R~ O
-CH--~N~~(CHz)b , -O-CH~ ~ R~
O O
-CH~ U Rsa , ~N~ R~ .
U
O
-O-CH2-~-N-(CHZ)p S-(CH2)a , -O-(CH2~ O-(CHZ)d , Rse O R~ Rao O
-(CHZ)~-N-(CHZ)~~(CHZ)d , -CH~N_(CHZ)b N-(CHZ)d , R~ Rx' R~
O Raa Rae O
-O-(CH2)-~N-(CHZ)~- '~(CHz)d ~ ~NWCHZ)o N-(CHz)a , R~ R~' R~
O R~' R3e O
-O-CHZ~N-(CHZ)~N-(CH2)d , -N-~-(CH2)p O-(CHz)a , Rs° R~ R~
O R~ R3u Raa Rae O R3a R3e -CH2-~LN-(CFiz)b--~-~-}p (CHz)~(CHZ)a , -~L-.-N-(CHZ)~(CHz)~ S-(CHZ)d , Rse Rsa R~ R3e O R~ R~ O
-CHz N-(CHZ)--~-(CHz)~ O-(CHZ)d , -IL-N-(CHZ)~-(CHz)-~-N-(CHZ)a R~ Rse Rsa R3a R3e Raa Rae O
-CHz N~ (CHz)e-~--(CHz)~-~-(CHZ)d , -CH2-II--N-(CHZ)b N-(CH2)d R Rse Rsa O
and -CH2-~-N-(CHZ)b O-(CHz)a Rso wherein R'a, R3b, Raa~ Rat Rsa~ RSb~ a, b, c, d, p and q are as defined for formula I.
5 In a further preferred embodiment K is selected from the group consisting of:
i -(CH2)ti O-(CHZ)d , -(CHz}p N-(CHz)a- , -O-(CHZ)Z N-(CHZ)d , R~ R~
R5a O
-O-CHz CHR~ CHZ N-(CHZ)a ~ -O-CH--~-N-(CHz)d , I~
R
O
-O-CH---~O-(CHZ)z , -(CHZ)b S-(CHz)d , O O
I I
-O-5- . a valence bond , -O-(CHZ)-p-~-~- , O
O O
-O-(CHZ)b CHR3a , -O--~CHz -O-CH2--~- , ~RSa R4a R4b Raa R4b ~~I.I!
-(CHz)b N-(CH2)~(CHZ)a , -O-(CH2)2-H-(CHZ)~ \~(CHZ)a , -(CHZ)b H-CHR°a CHZ -CHZ SO-CR'aRa°-O Raa Rab -CHZ SOZ CR'aR°b- -(CHz)b IP-O~(CHz)d ORS
O Raa Rob O
-O-(CHZ)b P p~(CHZ)d . -(CHZ)°~(CHZ)d , OR
O O
-LLN-(CHZ)°-O-(CHZ)a , ~HR3°~N-(CHZ)d , R~
5a O
--CH2 , -CHZ N--LL-CR'aR°b O Rsa O R~
-O-CH2~N\~ , -O-CHz~N\'-~ , OI R~ OI Rs~
-O-CH~ ~ -(CHZ)b . -O-CH~N~-CHz , R~ O Rsa CH N~~(CHZ)b N-(CH2)a -O-CHZ-~-N~ .
R~
OI R~ O Rs~
-O-CH~ ~ -(CHZ)b~L- , -CHZ-~L ~ -(CHz)b , O Rsa O Rsa -O-CHz~N~ -(CHz)~ i -(CHz)a ~ ~ ~ -(CHZ)b .
R~
OII R~ O~~
-CHz~N\~(CHZ)p , -O-CH~N~~JN-R~ , OII OII ~
CH~ ~ R~ , ~N~ R~ , U
O
-O-CHZ--LL-N-(CHZ)b S-(CHZ)d , -O-(CHZ)b O-(CHZ)a , Rsb O Raa Rab O
-{CHZ)--~-R~ (CHZ)~-~(CH2)d . -CH~Rsb(CHZ)o R~ (CHz)d .
Raa Rab -O-(CHZ)b N-(CHZ)~~(CHz)d . N-(CHz)e N-(CHZ)d , Rsa Rsb Rsa O R~ R3b O
-O-CHZ-LI-Rsb (CHZ)~P--N-(CH2)d , -N-~(CHZ)b O-(CHZ)a , R~ R~
O R~ Rsb R~ Rab O
~~ \/ R~~ R
-CHz R~ (CHZ)b~(CHZ)~~(CHZ)d , ~--N-(CHZ)~(CHZ)~ S-(CH2)a R~
Ray Rsb O R~ R3o O
-CHi R~ (CHZ)b~(CHZ)~ O-(CHz}d , --IL-Nsb (CHZ}~(CHZ).-II-N-(CH2)d Rsa R3a Rsn Raa Rab O
CHZ N~ (CHz}b-~(CHZ)~-~--(CHZ)d , -CHZ~L--N-(CHZ)b N-(CHz)a R Rsb Rsa O
and -CHz-ll-N-(CHZ)b O-(CHZ)a Rso wherein R3a, R3b, Raa, Rab, Rea, Rsn, b, c, d, p and q are as defined for formula I.
In the above embodiments of K, Rsa and RS° are preferably independently hydrogen, lower alkyl, -OH, -{CHZ)kORsa, aryl, aryl-lower alkyl, -CHZCF3, -(CHz)g COORa3, -COORa3, -(CHZ)k-CN or -(CHz)k-NR6aRfib wherein g, k, Ra', Rfia and Rsb are as defined for formula I.
Preferably, g and k are independently 1, 2 or 3, and Rfia and Rsb are independently hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl, In the above embodiments of K, R3a and R3b are preferably independently hydrogen, halo-gen, -OH, -O-lower alkyl, -COO-lower alkyl, lower alkyl or aryl-lower alkyl.
In the above embodiments of K, R°a and R4b are preferably independently hydrogen, -CN, -CONH2, -(CHZ)-N(CH3)2, -O-lower alkyl, -CHZOH, -CH20-aryl, -N(CH3}2, -OH, -C02-lower alkyl or lower alkyl.
D is preferably hydrogen, r-z' Rz~ ~:~,' Q /(~z), W,/
,'Y' W' F
za ,:Z' ~ ~V'-Z ' ~,\Rz' , R V Rze R~ /
Rz' Rz' Rza F I ~
\ W':~ E/(C F)s 2s / V~~' ~ ~'~R2' ' R Rza z~
\ E~R W~Q' R~ G ~ Rz~
(CH~)s ~~ j"-za ~ Y~ , ' F R ~ Rza .-,28 E F
cH ~ ~~
( z)5 G /(~z)s (CH~)a E~,_(G~ W'. , / \ , , .Y. E F'...(G)r ~W' 29 ~ ~'~1 ~~ 29 R R2e Rz~ R V,_Z' R
CH ~E~~R~ Rz~
( z)5 G , Q~~ E ~~Rza o~ ~ E' W ,1,, t Rze G~F~(cHT)s /'E V'-~Z
R2a wherein s, r, R2', R2a, V', Y', Q', Z', W', E, E', F, F', G and G' are as defined for formula 1.
In still a further preferred embodiment D is hydrogen, I
Rrr ~: Y~ ~Q' Rz~
I W .Y. E
28 :Z' 1\ //
R V' ' v'-Z' ' ~ ~~C"2)' , F~ Rza Rz' W''Y' E/(C"~)S E Rze F F
R28 V, ~ ~~ Rz~ . G , R28 Rz~
E7~
CH ~
G / ~ ~ a)s E F~-(G)r w'. /~\Z)' I
I , I .~ , E F,~(G)r _W' 2a R V'~, ~ ~~y za R R2e Rz~ R V._z, R
E Rz' CH ~ ~~ W' z)s G W~cQ~ R~ Q,i Rz~
r w Q' i , Y'~Z' R2e Rze Rza Rz~
~CHz)S
Rz~
E E Rza or G I E, I ~Rza G\ cH2)S F~
F ~E~V,:Z
wherein s, r, R2', RZa, V', Y', Z', Q', Z', W', E, E', F, F', G and G' are as defined for formula I.
D is more preferably hydrogen, Rz' W, Q. Rv , !Y' ~ E~ (/
R28 _/ . ~._Z. . ~ / (CHZ)s / F
Rza n E ( ~2F E Rze R
I
~~ Rz~ . Rm . Rza / V; Z.
R
E
(CHs)/ /( \z)s w E F._(G). W, /(\~)s j :~ ~ E F'-(G)r Z
za Rz~ V~ , \ Rza R Rze Rn E RZ' (CHZ)/ W~cn' R2~ Q,iW Rzr ~ v\ / Y,- 't Q,. I Y, ~ , .
~Y, Z ~ Rza Rze ze RZ'~CHZ)s ~E R2~ R2~
E~E Rza ~ G ~ or G I E, I ~Rze G\ cH~), F Rza ~E V''Z, wherein E and E' independently are >CHR38, >NR39 or -O-; F, G and G' independently are >CHR38, >C=O or >NR39; F' is >CR38- or >N-; and s, r, RZ', R28, R38, R3s, V', Y', Z', Q' and W' are as defined for formula I.
RZ' and RZa are preferably independently hydrogen; halogen such as -CI, -Br or -F; -CF3;
-OCF3: -OCHF2; -OCHzCF3; -(CHZ)YNHCOCF3; -NHCOCF3; -CN; -NO2; -CORz9, -COORZ9, -(CHZ)yORz9 or -ORZ9 wherein Rz9 is hydrogen, aryl or lower alkyl and y is 1, 2, 3 or 4; lower alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl;
lower alkylthio;
-SCF3; aryl such as phenyl; -(CHZ)yNR29R'° or -NRZ9Rso wherein R29 and R3° independently are hydrogen, -COO-lower alkyl or lower alkyl and y is 1, 2, 3 or 4; or -CONH2; or RZ'and RZa together form a bridge -OCH20-; R38 is hydrogen; -OCHF2; -OR"° wherein R'° is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; Eower alkylthio; -SCF3;
-CHZOH; -COO-lower alkyl or -CONHz; and R39 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
In a further embodiment the invention relates to the compounds of the formula I wherein:
R' and Rz independently are hydrogen or lower alkyl or together form a valence bond;
R3 and R' independently are hydrogen or lower alkyl;
X is >C=O, >C=S, >C=NRS or >SO2;
n is 0, 1, 2 or 3;
mis0or1;
R5 is hydrogen, lower alkyl, aryl-lower alkyl, or -OR6;
wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
A is R' R' R' R' Ra \ Ra Nw Ra~Nw Ra \
/ / N /
Rs ' Rs ~ Rs . Rs I \ Rio R~ Rio Re \ N R~
Rs I \ Rt° , R
R~° Rio Rio Rio N R~ N R~ N N
Ra I Ra~ I Ra~ R ~ ~---N . N , N~ .
Ra Ra '-_ Rs Ra Rio Re O R~ O R~ S R
Rs Ra r..- Rs ~- Ra . N , , ~ .
Ra N / I Ra I Ra Rio Rio a S R R ~ I ~ t R~ ~N R N N R N R
\'N I N\ I Re I Ra I N
. , Rs Ra Ra ~ Ra ~ Rs _-Rio Rio N R7 N R7 a N~ R7 a R7 \ Nw Re I . Ra I . R ~ ~ R
Rs , Rs ~ N Ri°
Rs ' N Rs N
s R'°
Ra R' \ N\ Rio a R' N R~N~ R Ra N
\
R
i s ~ i N ~ a / i N N ~ Rto R s R Rio Ra ~ R
S O O O
Ra---~~ , Ra-. Ra N~ or Ra-~~
N
Ra Rs Rs Rs wherein R' is hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NO2, -OR", -NR"R'2, lower al-kyl, aryl, -SCF3, -SR", -CHF2, -OCHFz, -OSOZR", -CONR"R'2, -CHZOR", -CHZNR"R'Z, -OCOR", -COZR'3, -OSOZCF3;
5 R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NOz, -OR", -NR"R'z, lower alkyl, aryl, -SCF3, -SR", -CHF2, -OCHF2, -OS02R", -CONR"R'Z, -CHZOR", -CHZNR"R'Z, -OCOR", -COZR'3, -OSOZCF3, or Re and R9 together form a bridge -OCHZO-;
R" and R'2 independently are hydrogen, -COR'3, -SOZR", lower alkyl or aryl;
R'3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
R'° is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B is Rt5 W~Y \ w~.l' \ w -+- ( -~-- I +-R~4 ' V~ ' Rt5 / V~ta ~ R'S / V~ t4 R R
w. WQ R W,Q Rt4 R'S \Y R,4 Y ~ ~ ~ t5 ~'J~'\7' R , Rts \ Q W 1r Rt4~ -~v...RtS R'° I -+-Y . Yf Z /
Rts Rts Rts R,4 Q W..Y I ~ ~
\ WAY ,4 -CRt4=CR's ~~z . I t R ;
R~5 V / V
or a valence bond; preferably R,s W'' Y \ W 1' \ w'1r .~.- y R,a V ' Ru V~~a ' R1s / V~ ,a R
D W Q W
R,a \ I -y--- R,a \ I
v~ , ~ -CR''~CR's R,s R's .(~ R .Q R,a ~Q R,s R,a~
Y Y R,s R,a R" and R'S independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CHZ),CF3, -NOz, -OR's, -NR'6R", lower alkyl, aryl, -SCF3, -SR'6, -CHF2, -OCHFz, -OCFZCHFz, -OSOzCF3, 5 -CONR'6R", -(CHZ),CONR'6R", -O(CHZ),CONR'sR", -(CH2),COR'6, -O(CHZ),COR'S, -(CHZ)~OR'6, -O{CHZOOR's, -(CHZONR'6R", -O(CHZONR'6R", _OCOR'6, -COZR'8 , -O(CHZ),CN, -O(CH2),CI, or R" and R'S together form a bridge -O-CH2-O-;
R'4 and R'S preferably independently representing hydrogen, halogen, -CF3, -OCF3, 10 -OR'6, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -OSOZCF3, -CONR'6R", -CHZOR'6, -CHzNR'eR", -OCOR'S or -COzR'8; or together forming a bridge -OCH20-;
I is 9 , 2, 3 or 4;
15 R'6 and R" independently are hydrogen, -COR'8, -SOZR'8, lower alkyl, aryl, or R'6 and R" together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
R'e is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
W is -N= or -CR'9=;
Y is -N= or -CRZ°=;
Z is -N= or -CRZ'=
V is -N= or -CRS=;
Q is -NR23-, -O- or -S-;
wherein:
R'9, R~°, RZ' and R'~ independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NOZ, -OR24, -NRZ°R25, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SRZ°, -CHF2, -OCHF2, OCFzCHF2,-OSOZCF3, -CONR2°R25, -CHZCONRZ'R25, -OCHZCONR24R2s,-CHZORz4, -CHZNR24Rz5, -OCORZ° or -COZR24, or R'9and RZ°, R2° and RZ'or RZ' and R~ together form a bridge -OCH20-;
~ 5 R2° and R25 independently are hydrogen, -CORZ6, -SOZRZe, lower alkyl, aryl or aryl-lower alkyl;
R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is R3a R3b R4a R4b L CH -\~ CH M CH CH
2~b P ~ y~a ~ ~f ~ 2~~ ~ y~d wherein:
Rsa, R3b, R<a and R'b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NOz, -ORz4a, -NR24aRzsa, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SRZ°a, -CHFz, -OCHF2, -OCFZCHF2,-OSOZCF3, -CONRZ°aR2sa -CHZCONR24aRzsa -OCHZCONR2aaR2sa -CH20RZ'a, -CHZNRZ'aRzsa -pCORzaa pr -COZRZaa;
wherein Rz4a and R25a independently are hydrogen, -CORzsa, -SOZRZSa, lower alkyl, aryl or aryl-lower alkyl;
RZSa is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or R'a and R3b, R4a and R4b or R3a and R'b together form a bridge -(CHZ); , wherein iis1,2,3or4;
1 o a, b, c and d independently are 0, 1, 2, 3 or 4;
e, f, p and q independently are 0 or 7 ;
L and M independently are -O-, -S-, -CH=CH-, -C--__C-, -NRSa-, -COO-, -CONRSa-, -NRSaCO-, -SO-, -SOz , -OSOZ-, -SOZ-NRSa-, -NRSaS02-, -NRSaCONRsb-, -NRSaCSNRSb-, -OCONRS°- Or -NRSaC(O)O_ wherein Rsa and Rsb independently are hydrogen, lower alkyl, -(CHz)k-OH, -(CHZ)k-NRsaRsb, aryl or aryl-lower alkyl;
wherein k is 2, 3 or 4;
Rsa and Rsb independently are hydrogen, lower alkyl or aryl-lower alkyl;
K preferably representing -(CHz)b 0-(CHz)a , -(CHz)b CH-CH-(CHz)d- , -(CHz)b (CHz)d- , -(CHz)p N-(CHz)a , R~
O O
-(CHz)d O-ll-(CHz)d , -O-g-(CHz)a O-(CH )-N-(CH ) , II ~ 2 b I 2 C
O R~
O-(CHz)p CHR~''-(CHz)a N (CHz)d 0 -O-(CHzr-LI-N-(CHz)a , R~
O
O
-O-(CHz)b R-ll-(CHz)a- , -p-(CHz~O-(CHz)d , O
-O-H 0-(CHz~ or -O-(CHz p ~i-- ~ -(CHz)~
O
D is hydrogen or Rz7 \ W. "\Q, ~W,~Rr I / W ~~ Rza \ Z, W~V,- ~~~
V Rza ' R2e V' ' ' z7 V' ~ ' Z , R
Rza Rv W~C1' R2~ W,iQ' R27 W~~ W,Y' I ~Y, I Rz7 ( V,:Z' , I ~ .
(CH2)r R28 R28 ~ R28 , (C~"~2)r W V' Rzr W'_ W
,/ ./
Rze ' , Y\\ /
Rze 2'-V' Rz7 / Rze Rz7 W~(CH2)$ ' E~(\~2)5 RE~(~F2)5 ~ Rza 2~ or F
Q~ ~ R R G z7 ~ze R / R
R ~/
preferably hydrogen, W' s W, __~~ Rr , ,~~ R27 ' \ z7 R
Rza Rza I / ~ , V" za R
/
~(CH2)S \ ,E
~Rz7 ~ / R2e or NF I ~ R27 Rza Rza 5 wherein:
r and s independently are 1 or 2;
E, F and G independently are -CHR38-, >C=O, >NR39, -O- or -S-;
Y' is -N= or -CR32=;
Z' is -N= or -CRS=;
V' is -N= or -CR~°=;
W' is -N= or -CR'S=;
Q' is -NR38-, -O- or -S-;
wherein Rz', RZe, Rs2, Rs3, R34a~d R35 are independently hydrogen, halogen, -CN, -CF3, -OCF3, O(CH2)yCF3, -NO2, -OR29, -NRZ9R3°, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SRZS, -CHFZ, -OCHFz, -OCFZCHF2, -OSOZRz9, -OSOZCF3, -CONRz9R3°, -(CHZ)yCONR~'R~°, -O(CHZ)yCONR29Rs°,-(CHZ)yOR29, -(CHz)yNR29Rs°, -OCOR29, -COZR29~
or RZ'and R28, R32 and R33, Rs3 and R'~ or Rte' and R'S together form a bridge -OCHZO-;
Rz' and RZa preferably independently representing hydrogen, halogen,-CF3, -OCF3, -OCHZCF3, -ORz9, lower alkyl, aryl or aryl-lower alkyl, or together forming a bridge -OCHZO-;
y is 1, 2, 3 or 4;
R29 and R3° independently are hydrogen, -COR", -SOZR3', lower alkyl, aryl or aryl-lower alkyl;
R3'is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R3$ is hydrogen, -OR'°, -NR'°R4', lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR4°, -CHFz, -OCHFz, -OCFZCHFz, -CONR°°R~,, -(CHZ)xCONR4°R"', -O(CHZ)xCONR°°R°', -(CHZ)xOR°°, -(CHz)xNR'°R4', -OCOR'° Or -COZR'°;
xis1,2,3or4;
R'° and R" independently are hydrogen, -COR42, -SOZR'2, lower alkyl, aryl or aryl-lower alkyl; and R°z is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
In a further embodiment the invention relates to the compounds of the formula I wherein:
R' and RZ independently are hydrogen or lower alkyl or together form a valence bond;
R3 and R4 independently are hydrogen or lower alkyl;
nis0,1,2or3;
mis0or1;
X is >C=O, >C=S, >C=NRS or >SO2;
wherein R5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR6;
wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
A is R' R' R' R' Ra \ Ra Nw Ra~Nw Ra \
/ / N /
Rs ' ' Rs ~ Rs . Rs I \ Rio , R' Rio I
Ra \ N R R~
~N
Rs I \ Rio , Ra N Ra Rs ' R~o~
Re Rio Rio Rio Rio N R~ I R~ I I
N N ,N
Ra / Ra~ / R~~ R7 N
Rs ' Rs Ra Re R,o Ra O R~ O R~ S R
R~ N/ / Ra / Ra / .-.'' , ~ , a , Ra Rs Rs R
° Rio Rio a S R R ~ I ~ I
R~ ~N R N N R N R
'N ~ ~- . N~ ~ . Ra ~ , Ra ~ N , Rs Ra s Rs Re R
Rio Rio N R7 N R7 N~ R7 R7 \ Nw Ra ~ . Re ~ X . Ra~ ~ Re ~ , N Rs , Rs / N Rio .Ra ~N .Rs NJ
s R'°
RaR' \ N\ R,o R' N R~N~ R N
a \
Rs / i N ~ R s / i N N / . Rio ' R'___.~
R ' l'~~ Ja Rio Re R
S O ~O ~O
R~ , R'__ ~~ , R'~ o~ R~
N
Ra Ra Ra Re wherein:
R' is hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NO2, -OR", -NR"R'z, lower al-kyl, aryl, -SCF3, -SR", -CHFz, -OCHF2, -OSOZR", -CONR"R'2, -CHZOR", -CHZNR"R'2, -OCOR", -COZR'3 or -OS02CF3;
Re and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NOz, -OR", -NR"R'2, lower alkyl, aryl, -SCF3, -SR", -CHF2, -OCHF2, -OS02R", -CONR"R'2, -CHZOR", -CHzNR"R'2, -OCOR", -COZR"or -OSOZCF3, or R8 and R9 together form a bridge -OCH20- or - OCHZCHzO-;
wherein R" and R'Z independently are hydrogen, -COR'3, -SOZR'3, lower alkyl or aryl;
wherein R'3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and R'° is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B is R,s W~ ~ ~ W~~ ~ ~ W 1' i R14 V ' R,s V~~4 ~ R1s / V~ ,a R R
W .Q R .~l 14 R's \ ~ R,a~ ~ W / R
/ Y ~ R,s V , ~ .
,4 R1s ~Q~ Q W 1' ,<~- ~R,S R'4 Y . . R / Z . ~ v~
R14 R,s ' R,s Q W, ,4 I
~Z . I \ W~-~-R'° . -CR'~CR's R1s V~ / V~Z
or a valence bond; preferably R,s ~ ~ R,s , R~a R,s R,a R~s \
~ W ~ or -~--R,a O /
/ V' R,s wherein:
5 R'4 and R'S independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CHz),CF3, -NOz, -OR'6, -NR'BR", lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR's, -CHFz, -OCHFz, -OCFZCHFz, -OSOZCF3, -CONR'BR", -(CHz),CONR'sR", -O(CHz),CONR'eR", -(CHz)iCOR'6, -(CHz),COR'6, -(CHzOOR'6~ -O(CHz)iOR's, -(CHz)iNR'eR,~~ -O(Cl..~z)iNR'sRn~
-OCOR's, -COZR'8 , -O(CHz),COzR'8, -O(CHz),CN, -O(CHz),CI, or R'4 and R'S
together 10 form a bridge -OCH20-;
R" andR'S preferably independently representing hydrogen, halogen, -CF,, -OCF3, -OR'6, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -OS02CF3, -CONR'6R", -CHzOR'6, -CHZNR'sR", -OCOR'6 or -COzR'8; or together forming a bridge -OCH20-;
wherein I is 1, 2, 3 or 4;
R'6 and R" independently are hydrogen, -COR'8, -SOZR'8, lower alkyl, aryl, or R'e and R" together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
wherein R'8 is hydrogen, Power alkyl, aryl or aryl-lower alkyl;
W is -N= or -CR'9=
Y is -N= or -CRzo=;
Z is -N= or -CRz'=;
V is -N= or -CRzz=; and Q is -NRz3-, -O- or -S-;
wherein:
R'9, Rz°, Rz' and Rzz independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NOz, -ORz', -NRz'Rzs, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SRz4, -CHFz, -OCHFz, -OCFZCHFz, -OSOzCF3, -CONRz4Rzs _CHzCONRz'Rzs, -OCHzCONRz°Rzs, -CHZORz4 -CHZNRz4Rzs, _OCORz4 or -COZRz", or R'9and Rz°, Rz° and Rz'or Rz' and Rzz together form a bridge -OCH20-;
wherein Rz° and Rzs independently are hydrogen, -CORzs, -SO2Rz6, lower alkyl, aryl or aryl-lower alkyl;
wherein Rzs is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and Rz3 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is R3a R3b R4a R4b L1 (CH -~ CH M CH CH -( le 2~b P ( z~a ( ~( ( z~~
wherein:
R3a, R3b R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NOz, -ORz4a, -NRzaaRzsa, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SRz'a, -CHFz, -OCHFz, -OCFZCHFz,-OSOZCF3, -CONRzaaRzsa _CHzCONRz4aR2sa -OCH2CONRzaaRzsa -CHZORzaa -CHZNRzaaRzsa -OCORz4a or -C02Rzaa;
wherein RZ'a and RZSa independently are hydrogen, -CORZ6a, -SOZRzsa, lower alkyl, aryl or aryl-lower alkyl;
wherein Rya is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
Or R'a and R3b, R'a and R°b or R3a and R°b together form a bridge -(CHZ);-;
wherein i is 1, 2, 3 or 4;
a, b, c and d independently are 0, 1, 2, 3 or 4;
e, f and p independently are 0 or 1;
q is 0,1 or 2; and L and M independently are -O-, -S-, -CH=CH-, -C=C-, -NRsa-, -CO-, -OCO-, -COO-, -CONRSa-, -NR5aC0-, -SO-, -SOZ , -OSOZ , -SOZ NRsa-, -NRSaS02-, -NRSaCONRSb-, -NRSaCSNRSb-, -OCONRsb- or -NRSaC(O)O-;
wherein Rsa and Rsb independently are hydrogen, lower alkyl, -(CH2)k-OH, -(CHZ)k-NR6aRsb, aryl or aryl-lower alkyl;
wherein k is 2, 3 or 4; and Rsa and Rfib independently are hydrogen, lower alkyl or aryl-lower alkyl;
K preferably representing -O-(CHZ)d . - - , -O-(CHZ)Z N-(CHZ)d , R~' O
-O-CHz CHR~ CHZ H-CHZ . -O-CHZ--~--N-(CHZ)a , I~
R
O O
-O-CH-ll-O-(CHz)z , -O-CH--~
O O
-O-S- , a valence bond , -O-(CHZ)2-p-~-H- , O
O
O-CHR~ , -O~CHz R'~ R'°
-(CHZ)b N-(CHz)a and -O-(CHz)2-H-(CHZ)~\~(CHZ)~
D is hydrogen, Rz~ Rz~
~' Y' \ ~' Y' \
i -t- Rza ~~ ~ ~G, ~Y' za ~/~'Z~ , ~ ~ V.'-Z~ , ~ ,Z' V'-Z' R R Rz7 V' , , Rza Rzi W~cQ' Rz~ W ~Q' R2~ W:-r W:Y.
z~ i ~~., I , R (cHz)r V''Z, ~ Rza (cH ) .=Z~ , ~~ V
Rza Rza Y'-Z' W ~ ~V' z~
W'- W' R
Y\~ -v ~ Rza ' ~ Y\\ ~ ~ / , Rze Z'-V' Rz~ / Rza Rz~
za RW"\ ~Z)~ , E OAF RE~~"F~ ~ RZe F ~Rz~ . Rz~ , F
~'Q' '~i--z'e G~ ' ' za R / Rrr R \~/
(cH )~E~~Rz~ /E F E~(cH2):WG)r z . CH ~, F
G ( Z)' G of G~~~ \ ze Y' ~ ~ \ R
~Rza ~ Rz~
Rza /(\ ~).
~G)r R~' 1 Rza preferably hydrogen, Rz~
~Q' Rz~
wN ~%~ \
R28 / , b'-Z , ~ ~(CHz)f , G~R2e /(CHz)s E R2a E I \ \
Rz' z~
R28 R ' Rz~ ' /
Rza E
(CHz)~ /(~ z)s (CH ) E F,~~G~r / ~ z s ~'~ Wr , Rza , _.
Rza R2~ \ Rz~ \ Rza R2r or E Rz' (CHz)~
QvY ~Z, Rze wherein:
r and s independently are 0, 1 or 2;
E, F and G independently are -CHR38-, >C=O, >NR39, -O- or -S-;
10 F' is >CR38- or >N-;
Y' is -N= or -CR32=;
Z' is -N= or -CR33=;
V' is -N= or -CR~'=;
W' is -N= or -CR'S=; and Q' is -NR36-, -O- or -S-;
wherein:
RZ', Rze,Rsz, R33, R~and R35 are independently hydrogen, halogen, -CN, -CF3, -OCF3, -O(CHZ)yCF3, -NOz, -ORZg, -NR~'R3°, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR29, -CHFZ, -OCHF2, -OCFZCHF2, -OSOZR29, -OSOZCF3, -CONRZ9R3o, -(CHz)YCONR~''R3°, -O(CHz)YCONRZ9R'°, -(CHZ)yORz9, -(CHZ)yNR29R3o, _OCORZ9 or -C02RZS;
or R2'and R28, R32 and R3', R33 and R~ or Rte' and R35 together form a bridge -OCH20-;
RZ' and R28 preferably independently representing hydrogen; halogen such as -CI or -F;
-CF3; -OCF3; -OCHFz; -OCHzCF3; -ORz9 wherein Rz9 is hydrogen or lower alkyl;
lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF3; -CHzOH;
-COO-lower alkyl; aryl or -CONH2; or together forming a bridge -OCH20-;
wherein y is 1, 2, 3 or 4; and R29 and R3° independently are hydrogen, -COR3', -SOzR", lower alkyl, aryl or aryl-lower alkyl;
wherein R3' is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
and R38 is hydrogen, -OR°°, -NR°°R°', lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR°°, -CHF2, -OCHF2, -OCFZCHF2, -CONK'°R", -(CHz)XCONR4°R", -O(CHZ)xCONR4°R", -(CHZ)XOR'°, -(CHZ)XNR°°R°', -OCOR°° or -COZR°°;
wherein x is 1, 2, 3 or 4;
R°° and R4' independently are hydrogen, -COR42, -SO2R"2, lower alkyl, aryl or aryl-lower alkyl; and wherein R'2 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
Examples of specific compounds represented by the above general formula V are the follow-ing:
CHI CHI
I CHI O C\ ~ i CHI
O CH O~O w ~0 w H.N w i CI ' ~ H.N w ~ CI
HO ~ HO
CI CI
3-Chloro-4-hydroxybenzoic acid [5-chloro-2- 3-Chloro-4-hydroxybenzoic acid [3,5-dichloro-methoxy-4-(4-isopropylbenzyloxy)- 4-(4-isopropylbenzyloxy)benzylideneJhydrazide benzylidene]hydrazide CHI CHI
0 \ i I CHI O i I CHl O ~ O
H.N ~ I i pCH I ~ H.N ~ I i CI
HO ~ OCH~ ~ HO / CI
CI CI
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [2,3-dichloro-[2,3-dimethoxy-4-(4-isopropylbenzyloxy)- 4-(4-isopropylbenzyloxy)benzylidene]hydrazide benzylidene]hydrazide HOC CHl ~CH3 0 ~ 0 I \ H'N \ I / OCH3 HO
CI
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [3-isopropyl-4-[2,3-dimethyl-4-{4-isopropylbenzyloxy)- {4-isopropylbenzyloxy)-5-benzylidene]hydrazide methoxybenzylidene]hydrazide H3C CH3 , N
CHs ~ CH, O \ O \ O ~ i CH3 \ N.N w I i CH p I ~ o w H 3 ~ N~N ~ ~ OCH
HO ~ HO I ~ H
C) CI
3-Chloro-4-hydroxybenzoic acid [3-isopropyl- 3-Chloro-4-hydroxybenzoic acid 4-(4-isopropylbenzyloxy)-5- {3-[2-{ 1-pyrrolid ino)ethoxy)]-4-(4-methylbenzylidene)hydrazide isopropylbenzyloxy)-5-methoxybenzyiidene}hydrazide CH3 H3C~N~CH3 CH3 CH3 ~ I CH3 O ~ I ~CH3 C \ O \
o \ I
O N~N ~ ~ ~ OCH I \ H.N ~ ~ pCH3 HO CI
CI
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [3-(2-diethylaminoethoxy)-4-{4-isopropyl- [3-(2-diethylaminoethyl)-4-(4-benzyloxy)-5-methoxybenzy(idene]hydrazide isopropylbenzyloxy)-5-methoxybenzylidene]hydrazide ~---CH3 CH COZH CH3 H3C~N ~ I CH3 OJ i I CH3 O~~ ~ O \
O I O
H.N ~ ~ OCH~ I ~ H.N ~ ~ pCH3 HO ~ HO
CI CI
3-Chloro-4-hydroxybenzoic acid 5-[(3-Chloro-4-hydroxybenzoyl)hydrazono-[3-diethylaminomethyl-4-(4-isopropylbenzyl- methyl]-3-methoxy-2-(4-isopropylbenzyloxy)-oxy)-5-methoxybenzylidene]hydrazide phenoxyacetic acid OOH , I CH3 OOH , CH
O J \ O ~ O \ O \ ~ s H.N ~ ~ pCH3 I j H-N ~ ~ OOH
HO C HO
CI
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [3-(2-hydroxyethoxy)-4-(4-isopropyl- [3,5-bis-(2-hydroxyethoxy}-4-(4-benzyloxy)-5-methoxybenzylidene]hydrazide isopropylbenzyloxy)benzylideneJhydrazide CH3 OCH3 i CH3 O\ H O \ i CH3 O
O
N.N w ( ~ OCH ~ \ ~.N w ~ OCH3 HO I ~ H OCH3 HO
CI
CI
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [2,3,5-trimethoxy-4-(4-isopropylbenzyloxy)- [3,5-dimethoxy-4.-(4-n-propylbenzyloxy)-benzylidene]hydrazide benzyiidene]hydrazide OCH3 i I OvCH3 CH3 O I \ O \ OCH3 i I CH3 \ N.N w i OCH p \ O \
HO I ~ H I ~ H.N w I i OCH3 CI HO
F
3-Chloro-4-hydroxybenzoic acid 3-Fluoro-4-hydroxybenzoic acid [3,5-dimethoxy-4-{4-ethoxybenzyloxy)- [3,5-dimethoxy-4-(4-isopropylbenzyloxy)-benzylidene]hydrazide benzylidene]hydrazide OCH3 ~ I ~CFi3 OCH3 ~ CHs O ~ O w O ~ O
H.N ~ I i pCH3 ~ N.N ~ I ~ OCH
H ' HO HO
NOZ COZH
3-Nitro-4-hydroxybenzoic acid 3-Carboxy-4.-hydroxybenzoic acid [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- ben-benzylidene]hydrazide zylidene]hydrazide OCH3 ~ I CH3 OCHy ~ I CHI
O ~ O ~ O ~O
H.N ~ I i OCH i ~ H.N ~ (i ii' OCH
HO ~ HO
CONHZ CN
3-Carbamoyl-4-hydroxybenzoic acid 3-Cyano-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- [3,5-dimethoxy-4-(4-isopropylbenzyloxy)-benzylidene]hydrazide benzylidene]hydrazide OCH3 i I Ol OCH3 i OCF3 O ~ O ~ ICF3 O ~ O
CI
~.N ~ ~ OCH3 I ~ H.N ~ ~ OCH3 HO ~ HO
CI CI
3-Chloro-4-hydroxybenzoic acid 3-Chioro-4-hydroxybenzoic acid {3,5-dimethoxy-4-[4-(2,2,2-trifluoroethoxy}- [3,5-dimethoxy-4-(3-chloro-4-benzyloxy]-benzylidene}hydrazide trifluoromethoxybenzyloxy)benzylid-ene]hydrazide O w O w O w O w N.N ~ I / I / CI ~ N.N ~ I i I i CH3 H OCH3 ( H OCH3 HO ~ HO ~ CH3 CI CI
3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-chlorophenoxy) benzylid- dimethoxy-4-(4-isopropylphenoxy) benzylid-ene]hydrazide eneJhydrazide OCH N ~ CF3 OCH3 CH3 w O w ~ O w O CH3 O N.N ~ I ~ OCH I ~ H.N ~ I ~ OCH3 HO I ~ H HO
CI CI
3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-trifluoromethyl-2- dimethoxy-4-(6-methylheptyloxy) benzylid-pyridylmethoxy)- benzylidene]hydrazide ene)hydrazide O ~ O ~r~~
O I O ~ \ CHa H.N w ~ OCH3 I I ~ H.N ~ ~ OCH3 H3C CH3 HO ~ CHZ HO
CI Ci 3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(5-hexenyloxy) benzylid- dimethoxy-4-(5,5-dimethyl-3-hexynyloxy) ene]hydrazide benzylidene]hydrazide \ \
O ~ ( \ O ~ \ O ~ \ O \
\ .N w ~ \ .N w I i I i CH3 N OCF3 ~ N
HO I ~ H HO I ~ H CH3 3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(4-trifluoromethoxyphenoxy)-1- isopropylphenoxy)-1-naphthylmethylene]hydrazide naphthylmethylene]hydrazide OCH3 i CF3 O ~ \ w \ ~ H3 \ H~N ~ ~ OCH3 O
HO ~ ~ N.N
C1 ~ , H ' HO
Ci 3-Chloro-4-hydroxybenzoic acid {3,5- 3-Chloro-4-hydroxybenzoic acid {3,5-di-dimethoxy-4-[2-{4-E-trifluoromethylphenyl}- methoxy-4-[(4-isopropylphenyl)-ethenyl]benzylidene}hydrazide ethynyl]benzylidene}hydrazide O ~ \ / ~ \ H.N H3 \ N~N ~ ~ OCH3 HO
HO I ~ H CI CH3 CI
3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3-(2-dimethoxy-4- methoxy-4-methytphenyl)ethynyl-5-(cyclohexylethynyl)benzyfidene]hydrazide methoxybenzylidene]hydrazide I ~ F F F
O ~ OH
N.N ~ I ~ I \ I
H O I ~ O
HO .N ~ ~ F
CI \ I
HO
CI
3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1- 3-chloro-4-hydroxybenzoic acid [4-(3,5-bis-naphthylmethylene)hydrazide trifluoromethylbenzyloxy)-1-naphthylmethyleneJhydrazide o i I °~°I
_ ,N ~ w °
/ H ~ ~ , N.N w HO ~ I H
CI HO
3-chloro-4-hydroxybenzoic acid [4-(2- 4-Hydroxy-3-methoxybenzoic acid (2-chloroethoxy)-1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide O I I ~ OCH3 O CH
N.N w / , N.N w I ~ CH3 ~ I H ~ I H
HO HO
4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxy-3-methoxybenzoic acid (4-tert-methoxy-1-naphthylmethylene)hydrazide butylbenzylidene)hydrazide O I ~ CH3 N.N ~ / O
H , .N ~ I /
HO \ I H
OCH3 HO \
4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxy-3-methoxybenzoic acid (4-isopropylbenzylidene)hydrazide trifluoromethoxybenzylidene)hydrazide WO 99/01423 PCTlDK98/00287 ( ~ ~ Hs O I NH O I ~ N~CH3 ( ~.N w ~ , N.N ~
H
HO HO
4-Hydroxy-3-methoxybenzoic acid (1 H-indol-3- 4-Hydroxy-3-methoxybenzoic acid (4-ylmethylene)hydrazide dimethylamino-1-naphthylmethylene)hydrazide o ~~ ~ o H.N ~ i ~ N.N ~ i I H
HO HO
4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxybenzoic acid (1-phenylbenzylidene)hydrazide naphthylmethylene)hydrazide O I ~ OCH3 O I
.N~ / ,N~ I /
~ I 'H
HO ~ HO \
HO
4-Hydroxybenzoic acid (4-methoxy-1- 3,4-Dihydroxybenzoic acid (1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide ~ F F F
O
.N ~ I i HO
.N ~
L H
HO
4-Hydroxy-3-methoxybenzoic acid (1- 4-Hydroxy-3-methoxybenzoic acid [3-(3-tri-naphthyimethylene)hydrazide fluoromethylphenoxy)benzylidene]hydrazide FY F
I' F
O I ~N O~F
N.N ~ / O \
HO \ I H , N.N w ( /
OCH3 HO \ I H
4-Hydroxy-3-methoxybenzoic acid {4- 4-Hydroxybenzoic acid [3-(1,1,2,2-quinolinyimethylene)hydrazide tetrafluoroethoxy)benzylidene]hydrazide CH3 \
\ OH
o N.N w \ I ~ \CH' , O N.N w I /
HO \ I H CH HO \ I H
4-Hydroxybenzoic acid [3-(4-tert-butylphenyl)- 4-Hydroxy-3-methoxybenzoic acid (4-E-but-2-enylidenejhydrazide hydroxy-1-naphthyimethyiene)hydrazide O \ \
_ ,N~ I ~
o \
HO \ I ~ , N.N ~
I H
HO \
4-Hydroxybenzoic acid (benzylidene)hydrazide 4-Hydroxybenzoic acid {1-naphthylmethylene)hydrazide \ i \
o I \ o I \ off .N ~ / .N ~
~ I ~ ~ I ' HO ~ HO \
NHZ NHz 3-Amino-4-hydroxybenzoic acid (1- naphthyl- 3-Amino-4-hydroxybenzoic acid (4-hydroxy-methylene)hydrazide 1- naphthylmethylene)hydrazide O ~ F
N~N ~ I / O / F
~ I H ~ I O I ~
HO / N.N ~ /
H
HO
CI
4-Hydroxybenzoic acid [3-(3-trifluoro- 3-Chloro-4-hydroxybenzoic acid (1-methylbenzyloxy)benzylidene]hydrazide naphthylmethylene)hydrazide OH O I ~ OH
° Iw .N ~ / / .N ~ /
I I
HO
HO
CI
3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1- 4-Hydroxybenzoic acid (4-hydroxy-naphthylmethylene)hydrazide naphthylmethylene)hydrazide F F O HN-N
O I W O / I F / N.N w W /
/ .N ~ / ~ ~ I H
I ~ HO
HO
4-Hydroxybenzoic acid [4-{3- 4-Hydroxybenzoic acid (5-phenyl-3-trifluoromethylphenoxy)benzylidene]hydrazide pyrazolylmethylene)hydrazide I
I off O I ~ o -N~ ~ / .N~ /
I _ I 'H
HO ~ OH HO
f _.N.
O ~O
2,4-Dihydroxybenzoic acid (4-hydroxy-1- 4-Hydroxy-3-nitrobenzoic acid (1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide O I ~ OH O I ~ OH
/ N.N w I / / N,N ~ I /
H I H
HO \ HO
O-~N~O HO
4-Hydroxy-3-nitrobenzoic acid (4-hydroxy-1- 3,4-Dihydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide O I / O I ~ OH
/ N.N w I / CI / N,N ~ I /
H J H
HO ~ HO
CI
4-Hydroxybenzoic acid (6-methoxy-2- 3,5-Dichloro-4-hydroxybenzoic acid (4-naphthyimethylene)hydrazide hydroxy-1-naphthylmethylene)hydrazide CI
/ I H.N ~ O
O ~ N
/ I H'N \ / OCH3 HO
4-Hydroxy-3-methoxyberizoic acid (9-ethyl-9H- 4-Hydroxy-3-methoxybenzoic acid [5-{3-3-carbazolylmethylene)hydrazide chlorophenyl)-2-furanylmethylene]hydrazide o I~ I
/ I H.N ~ ~ / O ~ O
CHz HO ~ / 'N ~ I /
CI HO ~ I
CI
3-Chloro-4-hydroxybenzoic acid (3-phenyl-E- 3-Chloro-4-hydroxybenzoic acid (4-allyloxy-1-allylidene)hydrazide naphtylmethylene)hydrazide I y O~ I y O I /
/ O N.N w I / , O N.N w ( /
H I H
HO \ HO
CI CI
3-Chloro-4-hydroxybenzoic acid (4- 3-Chloro-4.-hydroxybenzoic acid (4-ethynylmethoxy-1- benzyloxy-1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide O
O I W O~NHz O I W CH3 .N ~ I / / N.N ~ I /
I _ I _H
HO ~ HO
CI CI
2-(4-[(3-Chloro-4-hydroxyben zoyl)hydra- zo- 3-Chloro-4-hydroxybenzoic acid (4-methyl-1-nomethyl]-1-naphthyloxy)acetamide naphthylmethylene)hydrazide O I ~ O I ~ OCH3 / .N ~ / / N.N ~
HO ~ I ~ OH HO ~ I 'H
CI CI
3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1- 3-Chloro-4-hydroxybenzoic acid (4-methoxy-naphthylmethylene)hydrazide 1-naphthylmethylene)hydrazide o o .NON I / O HO I
I ~ H ~ v / .N w I /
HO
C! I / Ho ~ I
CI
N-(2-[(3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid (1-hydroxy-hydroxybenzoyl)hydrazono]ethyl)-2,2- 2-naphthyimethyfene)hydrazide diphenylacetamide ~I
O W O I
° I~
-N w I H-N w ~ OCH3 'H ~ I w HO C HO
CI
3-Chloro-4-hydroxybenzoic acid (2,2- 3-Chloro-4-hydroxybenzoic acid (4-diphenylethylidene)hydrazide benzyloxy-3,5-dimethoxybenzylidene)hydrazide I W \CH O W CHs O ~ ~ .N~ I /
O I _ HO
-N ~ I / CI
~ I H
HO
CI
3-Chioro-4-hydroxybenzoic acid [3-(4-tert- 3-Chloro-4-hydroxybenzoic acid {4-methyl-1-butylphenoxy)benzylidene]hydrazide naphthylmethylene)hydrazide O I ~ OH O I ~ O~CH3 H-N ~ ~ Br / -N ~ I i II0 H
HO HO
CI CI
3-Chloro-4-hydroxybenzoic acid (3-bromo-4- Acetic acid 4-[(3-Chioro-4-hydroxy-1-naphthylmethylene)hydrazide hydroxybenzoyl)hydrazonomethyl]-1-naphthyf ester p~N I
o I~ p N-N ~ / / _ -N ~ I /
HO ~ I H HO ~ I ~ OH
CI CI
3-Chloro-4-hydroxybenzoic acid (4- 3-Chloro-4-hydroxybenzoic acid (2-hydroxy-cyanomethoxy-1- 1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide O
O ~ ~ OCH3 O I ~ , N.N~ I ~ I
N-N ~ ~ ~ I H o 'H HO
HO ~ CI
CI
3-Chforo-4-hydroxybenzoic acid (2,3- 3-Chloro-4-hydroxybenzoic acid [3-(4-methylenedioxybenzyiidene)hydrazide methoxyphenoxy)benzylidene]hydrazide I p o ~ o ~ o~'oH
I H'N~ ~ I ~ / -N~ I /
HO ~ ~ I
HO
CI CI
3-Chloro-4-hydroxybenzoic acid (9- 3-Chloro-4-hydroxybenzoic acid [4-(2-phenanthrenylmethylene)hydrazide hydroxyethoxy)-1-naphthylmethyiene]hydrazide O ~ OH O ~ O ~N
I
I H'N \ / / I ~-N \ I ~ O
HO ~ HO
Br CI
3-Bromo-4-hydroxybenzoic acid (4-hydroxy-1- Nicotinic acid 4-[(3-chloro-4-naphthylmethylene)hydrazide hydroxybenzoyl)hydrazonomethyl]-1-naphthyl ester o I ~ \ / I o O ~ OVN O
I
-N ~ I r O / I ~-N ~
I ~ HO
HO
C CI
3-Chioro-4-hydroxybenzoic acid [4-(1,3-dioxo- 3-Chloro-4-hydroxybenzoic acid [4-1,3-dihydroisoindol-2-ylmethoxy)-1-naphthyl- (cyclohexyfmethoxy)-1-methylene]hydrazide naphthyfmethylene]hydrazide O ~,.~N
O I O O I
.N w ~ .N w ~ I '~ ~ I ' HO ~ HO
CI CI
3-Chloro-4-hydroxybenzoic acid [4- 3-Chloro-4-hydroxybenzoic acid [4-(3-(tetrahydro-2-pyranylmethoxy)-1-naphthyl- pyridylmethoxy)-1-methylene]hydrazide naphthylmethyfene]hydrazide O Oy N,iO_ O I \ O~O~CH3 w .N ~ / O
/ N.N w I /
HO ~ ~ I H
CI HO
CI
4-[(3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid (3-hydroxybenzoyl)hydrazonomethyl]-1- nitrobenzylidene)hydrazide naphthyloxy)acetic acid ethyl ester O CI ~ CI
.N ~ I / I F
_N O W
HO \ I H , .N ~ I
CI HO ~
CI
3-Chloro-4-hydroxybenzoic acid (2,4- 3-Chloro-4-hydroxybenzoic acid (4-fluoro-dichlorobenzylidene)hydrazide naphthyfmethylene)hydrazide F I ~ F
O ~ OH O
.N ~ I / / N.N ~ I /
/ I '~ I H
HO
HO
F Cf 3-Fluoro-4-hydroxybenzoic acid (4-hydroxy-1- 3-Chloro-4-hydroxybenzoic acid [4-(2,4-naphthylmethylene)hydrazide difluorobenzyloxy)-1-naphthylmethylene]hydrazide I
Q ~ o ~ o .N ~ I / N.N ~ I /
' / I ,H
HO ~ HO
F Cl 3-Fluoro-4-hydroxybenzoic acid (1- 3-Chloro-4-hydroxybenzoic acid [4-(3-naphthylmethylene)hydrazide methoxybenzyloxy)-1-naphthylmethyiene]hydrazide ~ F ~ O
I ~ Q I / I o O O
/ N.N ~ I / / N.N ~ I /
H \ I H
HO \ HO
CI CI
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(2-fluorobenzyloxy)-1- tetrahydrofuranylmethoxy)-1-naphthyimethylene]hydrazide naphthylmethylene]hydrazide O ( \ OCH3 O I \ O O
\ \
/ N.N w I / Br / N.N w ( /
H I H
HO \ HO \
CI CI
3-Chloro-4-hydroxybenzoic acid (3-bromo-4- 3-Chloro-4-hydroxybenzoic acid [4-(3-methoxy-1-naphthylmethylene)hydrazide tetrahydrofuranylmethoxy)-1-naphthylmethyleneJhydrazide O O F
OCH3 \ ~
\ \ OCH3 O \ O I / ~F
O I ~ O I / / N.N w N,N \ I / \ I ~H OCH3 /
I 'H HO
HO \ CI
C!
4-(4-[3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid [3,5-hydroxybenzoyl)hydrazonomethyl]-1- dimethoxy-4-(4-trifluoromethoxybenzyloxy)-naphthyloxymethyl)benzoic acid methyl ester benzylidene]hydrazide \ \ O~ F I \ I \
O I \ O ~ / F' F O /
I p \
/ ~N \ / / N~N ~ I / CH
HO \ I ~ \ I H
CI HO
C
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(2-trifluoromethoxybenzyloxy)-1- methoxybenzyloxy)-1-naphthylmethylene]hydrazide naphthylmethylene]hydrazide WO 99/01423 PCTlDK98/00287 W W W FW
O ~ O i O ~ O i .N w I / F , N.N w I ~ F
'H
HO ~ HO
CI CI
3-Chioro-4-hydroxybenzoic acid [4-(2- 3-Chloro-4-hydroxybenzoic acid [4-(2,6-fluorobenzyloxy)-1- difluorobenzyioxy)-1-naphthyimethylene]hydrazide naphthylmethylene]hydrazide OMe CHI
HO / ~ O / ~ _ HO / ~ O / ~ _ CI H \ / ~ O ~ / OCF~ CI H \ / ~ O ~ / OCF~
H H a CI O
O HO / ~ O-CHI CH, / ~ / ~ _ _ HO -N ~ / OCF3 CI H / ~ O \ / CH
Cl \ / ~ O~ H
H O-CHa O O
HO-~ CI - CHI HO ~ ~ CH3 CH, C! H \ ~ ~ O \ ~ CHI CI H N ~ ~ O \ ~ CH
H ~ I H ~ Ha HO ~ ~ COZH CHI HO ~ ~ O-~ CHI
H N ~ ~ N N
CI \ ~ ~ O~CH~ CI H \ ~ ~ 0 ~ ~ CH
H H ~_ a Ha CHa HO ~ ~ O HO ~ ~ 0 ~ O
N- ~N-N OCF~
CI H CI H \ ~ ~ 0 H
HO~~ ~~ ~~ O ~ ~ HO ~ ~ O
~N-N OCF~ N-N
H \ ~ ~ O \ / CI H \ ~ ~ O \ / N(Et)z H H a 0 / O\/~N~ O H
\ NON w \ ~ ~ / \ NH-N
H I OCF3 ~ / / \
HO
HO ~ CI \ I /
CI CHI CH3 O ~NH
OCF~
HO ~ ~ 0 ~ ~ N OCFy HO ~ ~ O I
CI H N ~ ~ ~ ~ CI H \ ~ ~ NUO
H H
O H i--N(Et)z HO ~ ~ ~ ~ \N ~ ~ CFA CO
CI H ~ ~ HO ~ ~ N ~ ~ N ~ ~ CF' H ~ CI H
H
N(Et)z ~N(Et)2 HO / ~ O / ~ HO / ~ /O
H-N -_~N
CI \ / ~ O / ~ CFA CI H
H
CFA CHI
~N(Et)Z i--N(Et)2 0 / ~ ~O
HO / ~ OMe ~N ~ HO--~~~ OMe N
CI H \ / ~ O / ~ F H N /
H H
OMe CHI OMe OCF~
HOC
O
HO / \ OMe N
CI H N / \ /
H
OMe CHI
The most preferred specific compounds represented by the above general formula 111 are the following:
HO / ~ SO / ~ CFA
NON- H / -i N-N
O CI H \ /
/ ~ ~ H CFA
HO
CI
HO / ~ S O / ~ HO / ~ S O /
O~ ~N-N OCF3 O N-N CI
H
CI \ / ~ O F H \ /
H H \- /
O O
HO / ~ ~S\ OMe - HO / ~ ~S\ OMe CH3 CI O H \ / ~ O ~ / OCF~ CI O H \ / ~ O ~ / CH
H H s Me OMe The most preferred specific compounds represented by the above general formula IV are the following:
Ho / \ o / \ _ H / \ O \ / OCF~
CI
OCH~ O
HO / \ O / \ CH, HO / \ N / \ CH
__~~H-N / \ / CI H / \ O \ / C
CI ~J~'/ ~ \ O~CH3 O / \ O CFA
HO / \ H OCH~ HO--~~~ OCH~ _ N-N OCF N-N
CI H / \ O \ / ~ CI H / \ O \ /
CFA
OCH~ OCH3 O
HO / \ N-N OCH~ CHI
CI H / \ O \ /
OCH~
Preferred specific compounds represented by the formulae VI and VII are the following:
Me0 O
O ~ I ~N O Me0 ~ O~N ~ CI
N.N~ W ~ / S ~ N.N~ ~ I H I i I
I H ~ I H c HO ~ CI ~ HO
CI CI
O Me0 ~ O ~
N
N.N~ w I ~ I O Me0 ~ O~
N
HO I ~ 'H ~ N.N~ w I H
C1 HO I i H
~CI CI
O Ne0 \ I O~H~['~ I O Me0 , O~ OH
N
N.N~ W I
N ~ W
I i H I H ~I /~
HO HO ~ v 'CI
CI CI
Me0 0 N O ~O , p ~ N
O N.Nw W I ~H I ~ CI ~ N.Nw ~ I ~~ ~ CI
I / H I H ~I
HO HO ~ v 'Cl Cl CI
Me0 O N O Me0 ~ O ~ N
O N.N ~ w I ~ ~~ ~ ~ N.N ~ w I ~~ ~ OMe I , ,H I H
HO ~ CI HO
CI
CI
OH
O Me0 , O~N \ I I i OMe \ N.Nw \ I H OH ~ ~I
I / H O ~ O~N
HO CI I H N \ \ I OMe H
HO
~Br O Me0 , O ~ ~[' I C!
N,N\ \ I H
I , H I
HO
CI
O ~ O~N \
CI .N~ \ I H
O M~ / O~N \ I CI I H OMe ~ F
H HO
( \ H.Nw \ CI
HO
cl I
Me0 O
\ O N.N~ \ I ~H I / O.CF3 \ O .N~ \ I O~H I i I , H I N O~ ~CI
HO~ r H
CI HO
CI
OMe ~ I CI
O ~ O~N~CI ( \ .N. \ I H
I H CI O ~ O
HO \ N.N ~ \ I OMe N \
CI
OMe HO I ~ H
C!
O ~ O~N \ CI
\ .N~ \ I H I i .CF \
N CI ~O ' I
H i HO
CI O .Nw \ ( O~H I \ C!
( \ I \ H OMe ~ CI
HO
O ~ O~N / CI
\ N. N w \ I OMe \ I I \
I~ H
HO
CI O / I O
\l I \ I \ H.N~ \
OMe OMe HO
O / O~N \ I CI
OMe I \ H.N ~ \ I OMe CH3 HO
CI
I I
i CI
i O ~ O~N~ O ~ O~N \ I CI
I I H
\ H.N ' \ OMe N I ~ CI I ~ .N ' \
N OMe HO
CI HO
CI CI
\ \
I~ S
0 / I O'/~N~ O / I 0'/'H~\/
I \ H.N ' \ OMe vN I \ OMe I ~ N.N ' \ OMe HO ~ ~ HO
CI CI
I\ I~
O'/'N \
O , I O~N I ~ OMe ~ O N.N' \ I OMe H I i O,CF3 N,N ' \ O~ l~~ I ~ H
I , 'H OMe HO
CI
HO
CI I \
I
OH
I O / I O~H I \
O i O~N~ ~ N.N ' \ pMe i NHZ
I \ H.N' \ I OMe H OH I ~ H
HO
HO ~ CI
CI
\ O \ I O~N
I ~ ~ B~ \ .N' \ I
N \ / S
O ~ O~N \ I HO I ~ H Cl I i I H
( \ H.N ' \ OMe CI
HO
I
CI \ O N \ I O~ ~~ \ I O
\ .N' \ N
I / OH , CI HO I ~ H
O ~ O'/~N ~ I CI
I H
I H N ' \ OMe OH
HO
I
CI O \ O~N \
I \ H.N ' \ I H i ~
HO
CI
N \ i , OMe O \ I O.~~ N ~ I ~ O \ I °.~ N \ I
I \ .N~ \ I H \ .Na \ I H
I~ H
HO HO
CI CI
I
O .N~\\ I O~N \ I O .N~\ I I O~H I \
\ N \ N
I i H I H F
HO HO
CI CI
I
O \ O~N \ O \ I O~ N
N
\ N.N~ \ I I i \ N.N~ \ I H
i~ H I~ H U
HO HO
CI CI
I
O \ I O~N I \ \ I O
\ N.N w \ \ O N.N w \ I ~H I , I i H OH I / H
HO HO
CI CI
CI
O \ I O~N \ I O \ I O~N \
I H
I \ H.N~ \ I % H.N~ \ I H I , CF' HO ~ HO
CI CI
I ~I
I H N
\ O N.N~v O~N ~ OMe \ O N.N~v I O~H
I , H I H CI
HO HO
CI CI
OMe ° \ I I °'~N \ I oMe o \ I I °~'N~
H.N~ \ CHI I \ H.N~ ~ N I \
HO HO ~ v 'CI
CI CI
I
\ O~ ~CI
\ I o O N \
O ~N \ \ N.Nw \ I H I i \ N.N~ \ I I , I ~ H CI
HO
HO I H H~C~N~CH3 CI
CI
I cHy ~ I
O ~ O~N~ O w O~N
N.N~ w I H I i CI ~ N.N~ W ( ~N
~ H HO~ H I i CHI
HO
CI CI O
O ~ I O~N
I
N.N~ w I H w I O ~ I O'~N
( / H ~ N.N~ W
HO I , H I
CI HO
CI
O w I O.~N w I / I
N.N ~ ~ I H OH O ~ O~N ~ OMe H ~ N.N~ ~ I I ~ OMe HO I , H
CI HO
CI
w I 0~ ~ OH ~
o ~~ I
N.Nw w I N w I O ~ O~N
I 'H .N ~ W I H OH
HO ~ I \ H
CI HO
CI
I
O ~ O~N OH I
N.N w w I ~ O w O~N
I , H I , ~ N.N~ ~ I H I ~N
HO Cl I , H
CI HO
CI
o ~ I p~N \ ~ , Br .N ~ w I H I , O w I O~N W I
I / H NHZ ~ N.N ~ ~ I H
HO I / H
CI HO
CI
I O / OH / CI
O ~N~ I
N.N~ w I ~N ~ Cl O W O~N w HO I ~ H I ~ CI W N.N ~ W I H
I / H
CI HO
CI
~' CI
O N.N~ ~ I ~N ~ OMe O ~ I I O~H~r'~ I CI
I / H I , ~ N.Nw HO I / H
C!
i I S ~ OMe p \ I 0~~ O i I O~N
.N~ \ \ .N~ \ N
I \ H I H OMe ~ \ CI
HO ~ HO / I ~ CI
i I OMe ~ I Br 0 \ O~N \ O / O~N \
.N~ \ I H I \ .N~ \ I H
\ N ~O.CFa I H OMe I , H HO
HO
CI CI
OMe I O ~0 0 \ I 0~ ~~ ~ I CI \ N.N\~~/~\ I OMe H I ~ CHa \ N.N~ \ N \ I H
HO I ~ H HO~ CHaHa CI
CI
CI
OMe I
O \ I 0 0 ~ ~N \ CI
\ .N ~ \ I ~H I , CH N N ' \ I O~N
I H a I , H
HO ~ H C CHa HO
a CI
CI
O ~OMe O \ I 0~ I % H.N ~ \ I O~N I \
\ . N ~ \ I H I , NH HO " Br I N ~ z CI
H
HO ~ OMe CI O , 0~N \ CI
CI \ .N~ \ I H I i I N Br ~Cl \ , H
I , HO
OMe Ci 0 ~ I O~N I ~ OMe CHa I \ H.N ~ \ OMe S, 0 i I O~H I \
HO ~ ~ N.N~ \
Br CI
CI HO I , H
OMe CI
O
0 i ~N \ OMe \ .N~ \ I H I ~ ~ O~
I N OMe ~CI 0 N \
i H .N~ \ I H I
HO \ N Br ~ NH
CI I ~ H z HO
OMe CI
O ~ 0~N \ CI
\ .N~ \ I H I i I N OMe ~CI
H
HO
CI
OMe I \ I \ F
O / O~N~ o I \ p /
. N ~ \ I ~ N CI / 'N~ /
I \ H gr I \ \ I q HO
CI
I\ o o / NON I \ o ~N I /
I H I / q \
Ho \ \ I
Ho CI G
\ H,°,° ~o~F
I ~(I / F
p ~ O I \
/I
/ f N \
H
\ a G
F
I \ F~F
o I \ o I\ I\ °o / iN / O \ ° /
I q / .~, I /
HO \ \ I p G w a Ct p CEO 5 I\
O I \ ~ O \ O
/ I
/ I q'~ / .~ p \ I .q Ho G
G
\ o \ \ °YF
O I \ 0~0/\QS O I \ O / F
/ ,\ I / / I H,~ /
\ I ~~H
HO
a G
G
G
\ \
O ~ \ O I \ O I /
/ N~ \ I
H /I
F CI
\ F \ F \ G \ G
O I \ O I / O I \ O I /
/ q~. I / / I q.H\ I /
H~ \ I Ho G G
\ \ \ °
° I \ ° I / °-~ ° \ ° /
/ ,H I / / "~I I / \ I o hHi ~ I ~
HO F~F
a a F
\
o I \ o I / \
/ 'N~ I / ° I \ ° I /
Ho \ I _~ / I H~ \ I /
Ho w F
F FI _F
\ \ F \ x O~F
° I \ ° I / O ~ \ °\/\
H
/ ~~ I / / N~N\ I / \ I
\ ~ H
wI
a I \ I \ F
O \ ° / \ b I I o I/
/ F F F O I \
\ I / I ~N\ /
f~
CI H° \
CI
F
F F I \ I \
\ \ 0 \ 0 /
O I \ O I / F / H N~ ~ /
/ N ~ / F F
~H~ \ HO
FIO \
CI
a F
F F H~O~O \ O"F
I \ I \ O I \ O I / ~'FX__F
\ O / IJw O I I H
/ w HD \
I
a HO
a I \ ~c.o I \
o I \ o~s ° o /
n / o \
/ N O
I H \ G / HiN\ / BF
\ I H O
CI
CI
I \
\ \
O ~0~ GO
N I / 0 / I 0 I I \ 0 I /
\ I p'\ ° / ~\ / O 0 HD
CI F~F HO \
CI
\ F
o p/ \ I I \ ~\/\ / I l~lrC~O ~ F
0 I \ O
Hp \
F
a F / H N Oi~a \ I
CI
F F F F
\ F \ F \
o I \ o ~ / O I \ o I /
,N I I
/ iN /
\ /
\ I ~ \ I H
HO rp I a ot, I \
~o~o I \ ~ o I \ °w/\N~'v°5 o I \ o / I N I
N
~N~N~ / o~aS No \ \ o N ~
\ I a F~F
a 0 I \ °
p I \ O N/\~ o I ° N
I / N. ~ / ~N
/ .N\ / w I N
\ I a Na I \
No ~ a /
G /
I o o \ o \
I \\ o I / a \ .N. \ I L I /N
o I ~p / ~\ / w /
a Ho G
\ r 'o \
I 0 I / o I /
0 N I / o I \ ~c N.N\ / o.~
N
O
/ O~
O \ I O~N
I \ \ O I / \ . \ \ I ~N
p ~ Y
/ ~N\ I / ~ I / ~ /
a No w G
I \ o c \ ~~
N' 'o a5 o I \ o\J\ _ o I \ ° / / I r~-~ / \ /
. o.aS ~ \
/
I e~
No o' ~o 'Sc~o 0II
o~ o.~ / I OS
N~ ~ I / o~~ \ I o 0 0 \
NO \ F'F'F I \ ~ N~ \ O~da a ~p /
F
p °' J~
O 'N I / O~N~ \ O N/N\ \ I O'~I\N/\./\N
\/J[~ ~,'/~V/J1' " J
I N ~ Na / I N \ O.~S ~ \
~N
\ OI
HO
a c F
I \ °N \ r O\/\~/\/N
O N/
\ O\/~N / I
O 'NV I / \ H~N\ \ I
~N
"° a a / O~N \ O~F
° / °~~ / \ N \ I N I / Ff~C~F
\ ~ \ \ \ I / w \ I
a \ I Ho v N~O~
O / ~~/'~ ~ o / I 0 I \ N N \ i I I \ ~. \ \ I / I
\ ~ / \
O I
N~a I O~ ~S O
\ ° ~H \ I H FS° Oy ° H \
H \ \ \
H
"° I / I / \ I
HO
a a ~S
aS / I ~ o~a'4 / I aS
o / I ° \ ° / o \
I \ H' \ p~ I \ H'H\ \ I OW~
HD
H°
a O~F CFt~
O ~ O I 'F
I \ ~ N\ \ I °.~ I \ H~ \ \ I I / CI
~ /
a CI
0 0 / 0 Ni O / °.~ N \ I
\ ~~ \I I \ H ~ / I
I / b \ I NS ~ / \
HD
CI CI
CI
/
I ~ /
o \ o\/\ \ I
' I I / I H
I \ o b.N\ \ ! I~o Ho I / H . \ a5 / a HO
CI
0~~
o\/\ / o~~
\ o .H~ \ I b I / s o ~ \ I o\/\H / \
b ~ .N I
ro I / \ I F' I 'f I \ ~ \
F /
a Hp a o ~05 ° / I °~H ~ 0 / \ / I O\/\N I \
yFI
\ If \ \ I \ N \ O / O~f H
I / \ I / "o /
\ I
O
°'~
° / \
° \ I o \ o ~~N\ \ I I
° /I
N'N\ \ °'d, ~ /
I H
HO /
a ~ 0~~
F
° \\ I o \ I °kF o I \
N \ \ ~ \
\ ~ I/ I/
/ HD
F
a \ I o~ ° \
\ O N\ /\ I O N I / I I ~
\ ~ \
I H ~I/ I/
YO
a a o / I ° ° I \ °\/\N I \
° / ~N a / H.N
° I H I H
I \ N'~ "°~
~H a no /
a °'aS o \ / I °~'p I \ F
° \ N \ /
O~ ' / I y ~~ i0 F F
J[ N N\ \ O HD / HOC
I H CI
a I / ~, 0~ \
o . / I ~ I /
\ N \ \ 0 H
I / '0 \ O / O
S° I / ~ I \ ~ N\ \ I
c-o cl «I \
I/
/ I o \ I ° ~\ \ I °~" I .
\ N \ \ °'aS
H I \ H
Ho / a ro . aS
a a o / ~ \ a ° ° I \ °~N I \
N / /
I \ b'N\ \ I I / I \
/ CI
F
CI
a O~aS aS ° - \ / I °\/\N I \
° \ I \ N \ /
O / I I p O
' ~ HJ
\ N- ~O
H a HD / F
F
The most preferred specific compounds of formula f wherein A is a heterocyclic and/or bicyclic moiety are the following:
CF3 , CF3 O ~ O \ I 0 \ I
O \
I I
I \ H.N ~ I \ N~ I \ ~.N w I \
'N ~ i H
Indole-5-carboxylic acid [4-(4- Indazole-5-carboxylic acid [4-(4-trifluoromethylbenzyloxy)-1- trifluoromethyibenzyloxy)-1-naphthylmethylene]hydrazide naphthylmethylene]hydrazide O \ O \ I O \ I
O
.N ~ I
H I \ ~ H.N w I \
-N
N HO N i H
Pyrazole-3-carboxylic acid [4-(4- 3-Hydroxyisoxazole-5-carboxylic acid[4-(4-trifluoromethylbenzyloxy)-1- trifluoromethylbenzyloxy)-1-naphthylmethyleneJhydrazide naphthylmethyleneJhydrazide O
N~ ~ OMe CHI ~ O
- OMe _ CHI
Me0 H ~ ~ O ~ ~ CH H ~ ~ ~ O ~ ~ CH
OMe H
OMe O
N~
>~' N-N OCFs Me0 H
H /
OMe N O
Me0 ~ ~ OMe CHI
--~~N-N O I ~ OH
H \ ~_~ O ~ ~ cH I
H ' / / -N ~ i OMe HO ~ \ I
CHs CHs OMe ~ I CHs ~ I CH
O \ O \ s O ~ \ O ~ \
N
\ H~ ~ OMe N N ~ \ 'N ~
/ ~N / /
H
Especially preferred according to the present invention are the following compounds which show a particularly high affinity to the human glucagon receptor:
CH3 F~F
H C.O I \ CH T3 O I \ O , I \ O I \ O
.N~ .CHI O \
HO \ I H ' O / I H ~ N\
O~'O HO \
CI
CHI
\ O
H~C.O O I % CH O I I \ O
O \ ~N r \ I
/ .N ( i .CHI I H O
\
I H O HO
HO \ CI F F F
C!
I\ o'' I\
O I W O~N~ O~N~N
I H.N N / O ~N I , H
I H ' ~ /
HO \ ~ HO
CI I i CI
O
OJ
CI F
~CI F
\ \ \ \ F
O I \ O I / I 0 I ~
I ° I\
i I H~N~ ~ , N.N\
\ \ ~ H
HO HO
CI CI
F F F F F F
\ \ \ \
p I \ O I i F O I \ O I i I H N\ I / F F ~ ~N I
I H
HO HO
CI CI
I I \
o N.N~ I ~ o'o~ ~ o I ~ o~H ~ I
H \ I o ~ N.N~ / \
I H ~o HO \
HO \ F-F'F
CI F F CI
F F ~ ~CI
I ~ o i ~ p I I ~ o iI
O I ~ / N.N
. N ~r~ I H
I ,H ~ HO W
HO \ CI
CI
~CH~ w w I ~ p iI ~ I O I
0 0 ~ CI
N.N\ I i / .N I i I H I H
HO \ HO
CI CI
p 0 I w O I ~ O ~ I O~O~N W
I I H
I H.N' / I ~ H.N\
CH
HO ~ HO
CI CI
CHI
.CHI
O 0 ' I CH3 O , I O~H , I
O
.N ~ I .CH I ~ H.N\ ~ I
I , 'H ~ O ~ HO
HO CI
F
O jj N ~ I O
O .N w I OH O ~ I OV 'N I
H \ I ~ N~N
HO ~ ~ I I / H
CI ~ HO
CI
O.CHs , I CHI O.CH~ , I CHI
O W / O
0 .N w I .CHI 0 .N y I .CH
W s I H O I 'H O
HO ~ CI HO ~ F
CI F
0. CHH F F ~ I
N 0 ~ O
p .N ~ I I / F .N ~ I i ~ CH
~N ~ O ~ ~N ~
HO I ~ H CHa HO I ~ H CHI
CI CI
O
I W H~N~ ~ I ~ O .N y I N I
I _H w I
HO HO
CI Br CI
O''I-I~C CHI ~ i ~ Br O ~ ( O~N ~ I O ~ I O~0 ~ I
I ~ H.N\ ~ I CH3 \ .N
I 'H
HO
HO
CI CI
O w I O~N~N I w i I
N.N' ~ I H \ O .N \ ~ I H I , I ~ H I H ~ cl HO HO
CI CI
r CH3 i N CH I
O I F
N.N\ ~ O v ~ ~ O N.N' \ ~ I O I ~ F
I H I H O~F
HO ~ HO
CI CI
CHI
O.CHs ~CH I
0 \ I\ I 3 p ~ N~ ~ CI
O .N w I .CH \ N N~ I N I
I / H \ O ~ HO I ~ H
HO
CI
N
OH H ~ I OH H
0 ~ I O~N O ~ O~N
N.N' ~ I \ _ .N
I ~ H I H
HO HO
CI CI
~I oII
O ~ I OH O w O~N
H-N~ ~ I ~ .Nw ~ I ~N-CHI
I~ H
HO HO
CI CI
0 i 0 o ~~ ~ I
-- N _.
0 N.N ~ ~ I N~N ~ ~ ~ O N.N w ~ I ~N
I H I H
HO ~ p H HO ~ 0 CI CI
0 0 ~ ( O
O I ~N~ OMe O ~ I °~N~ OMe H.Nw W ~N I ~ I ~ H.Nw ~ N
I i HO HO
OMe CI CI
° ° ~ I o '~ ~ °~N
° N.N~ W ( W ~ 0 N.N~ W I W
I H ~I I H
HO ~ v ' CF3 HO ~ CH3 CI CI
O ~ O
° \ I O _ N ~ CI 0 \ I °v _N OH
N.Nw W I ~ I ~ N.Nw W I W
I ~ _H I ~ H I
HO HO
CI CI
O~ O i I O
O I v 'N OH O \ I °~N I
H.N ~ W ~ ~ N.N ~ W ~CH3 I H
HO ~ CI HO ~ N-CH3 CI CI
i OII I ~ i OI' W I O~ ~ 0 W I O~N N
0 N.N~ W I N N, ~ N.N~ W I ( H H HO I ~ H
HO ~ O
CI CI
i I 0'I CI i I O'' O w I O~H I w O w I O~N
H.N ~ ~ ~ CI ~ N.N ~
I~ H
HO HO
CI CI
0 N.CH~ , 0 O W I O~N~ O W I O~N.N
.N~ w I CHI ~ .N~ w I H
I H I 'H
HO ~ HO
CI CI
O ~ O N w O ~ I I O~N~CH~ O w I O~N~ I i N.N w W ~O ~ .N w ~ I H
I H T -N
HO CH' HO I ~ H
CI CI
O / O
O ' I O~N ~ CI O \ I Ov _N
N.N w W I H I , ~ N.N w ~ I HOJ I
I , H I H CI
HO HO
CI CI
~ ~O ~I OII
O \ I I O~N~N O ~ O~N O
I H~Nw W CHI ~ N.N~ ~ I CH~
I ~ H
HO ~ HO
CI CI
/ OfI / I OII CHa O W ( O~N~~O O W I O~H~N.CHa H.N ~ ~ I H C- vNH ~ .N ~
HO HO
CI CI
O O O~NHz/ I
O N p ~ ~ ~ i N.N~ ~ I H ~ N,N~ ~ ~ H
H
HO I ~ 'H HO
CI
CI
o ~I o O w I O~N~CHa O ~ p~N~N ~ I
H.N ~ W CH3 I ~ H.N ~ ~ I H CHI
HO ~ HO
Cl CI
i O,' i OII
O w I O~N~ ~ CFa O ~ I I O~N
I H II
N.Nw W ~/ ~ .Nw W N
I / H I _H ~CHz HO HO
CI CI
OMe ~ ~ ~ I ~ I ~ I
0 i 0 N N ~ 0 ~ O N CFA
.N. \ I H CHI .N~ \ I H
'H OMe I \ 'H
HO ~ HO
CI CI
0I CHI ~ O'' CHI
O \ ( O~N \ O \ I O~N \
.N~ \ I H I ~ .N~ \ I H I , \ \
I H CHI I H
HO ~ HO
CI CI
I / I .~ CH~
O O ~ O ~ 0 N
O ~ I O~N \ ~ N.N ~ \ ( H/~ I // CH3 ,N~ ~ I H I ~ I ~ H
N Cl HO
HO I ~ H CI
CI
0 CHI ~ O CH3 O ~ I O~N O ~ I OV 'N \
.N~ \ I H .N~ \ I H I , \ \
I H I H CI
HO ~ HO
CI CI
O ~ O
O \ I O~N \ 0 ~ I O~N~N-CH~
N.N. \ I H I / CF \ N.N~ \ I CHI
HO ~ HO
CI CI
O ~ O
O \ I O~N 0 \ I O~N
N.N. \ I ~ N.N~ \ I N y HO I ~ 'H HO I ~ 'H I ~ N
CI CI
\ 0 ' \ 0 p I N~ ~ ~ CHI 0 I N
\ N.N~ \ ~N \ .N~ \
H I ~ H CHI
HO ~ HO
CI CI
O / N / OII
0 \ I O~N \ I O \ I
I ~~ NOz I \ H.N~ \ I CHI \ .N~ \ N
N \
HO I ~ H
HO
CI CI
0 NHz 0Ii i i OII
O \ I O~N \ I O \ ( O~N
\ N.N w \ I H \ N,N w \ I
I H I H p HO ~ HO
CI CI
i I O OMe O
0 \ O~N~ CH 0 ~ ( O~N~ CH3 H.N~ \ I ~N I \3 CHy I % H.N~ \ p~ ~N I % CHI
i HO
HO
CI CI
i O i O
O~ CH O w I O
O I N~ a ~N
I \ H.N w \ ~N \ CH3 I ~ H.N w \ I ~~ ~NH3 a CH
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O I ~ OH ~ N.Nw W I ~~ ~ CI
I H I
/ I H~N~ / HO / /
CI
HO ~ CI
CI
I 0 .N~\~ I O~N~ / I 0 O / O~N~ ~ CI w N N~0 I H 'I I / 'H
H.N ~ ~ 0~ ~/ CI HO
/ CI
HO
CI
O ~ I O~N / 0 ~ I O~N
N.N~ ~ I ~ I ~ N.N~ ~ I I /
I H I H
HO / HO /
CI Ci CI
0 ~ I O~N \ 0 ~ I O~N
N.Nw ~ I I / ~ N.Nw ~ I H
HO I / H OH HO I / H
OMe p ~ I p~N \ p ~ I p~N ~ I
.N~ ~ I H I / OMe ~ N.N~ ~ I H
I H I H
HO / HO /
CI CI
i I
O \ O.~' N \ \ I O
\ N.N~ \ I H I ~ F \ O_N.N~ \ I ~H I / p) HO I ~ H I i H O
HO
CI CI
O \ O~N \ \ I O
\ N.N~ \ I H I i CFA W O N.N~ \ I ~H I , I H I H CI
HO ~ HO
CI CI
i /I
\ O~ I
O N O \ O~N ~ CI
I \ H.N~ \ I ~N I ~ I \ .N~ \ I H I / CI
N
HO ~ ~CI HO ~ H
CI CI
CHI i p .N v\ I p~H I ~ p .N v I I p~H ~ I
\
I N CI I \ H \
HO
HO
CI CI
I
O \ O~N \ I O \ I O~N
I \ H.N w \ I H OH \ N.N ~ \ I ~~ ~ CI
HO ~ HO I ~ H I
CI CI
CI
O \ O~N~ O \ I O~N
I
I \ H.N' \ ~N \ OMe \ .N~ \ I
I~ I~ H I~
HO HO
CI CI
i I i ~er O \ O~N ~ OMe O \ I O~ '- j~\ I
i I
\ .N~ \
I H ~ OMe I \ H.N ~ \
HO ~ HO
CI CI
O/~CI , / CI
O \ I O~N \ I O \ I O~N \ I CI
N.N~ w I H ~ .N~ ~ I H
I H I H
HO ~ HO
CI CI
p _ / \
O ~ O~N ~ HO / \ i \ /
.N ~ ~ I H I , CH N-N N
H '~~CH 3 CI H \ / H CH3 HO ~ HaC ' CI
O - O
HO / \ ~ \ / HO / \ ~ \ /
N-N N N-N N
CI H \ / / \ CI H \ / ~ / \
HO
O - / \ HO / \ O - HO
HO / \ i \ / _ N-N~ \ / N
H N CI H \ / H / \
CI \ / H C 'CH
O - O
HO / \ i \ / HO / \ i \ /
N-N N N-N N
CI H \ / H / \ CI H \ /
F HO
F F
HO / \ N-N \ / S~ ~~ HO / \ N-N \ / S~N'N
CI H \ / S CH3 CI H \ / N N
HOC
HO / \ H-N \ / H F HO / \ H-Ni \ /
CI \ / ~ CI \ / / \
CHI
HaC CH3 O
HO / \ O ' \ / \-_/ HO / \ N-N/ \ / N
~H N N CI H \ / H
CI \ / H \..J / \
F
O O
HO / \ i \ / HO / \
N_N ~N N-N \ I N
Cl H \ I ~ / \ CI H \ / /
CHb ~ \
HOC
O
Ho / \ -/ \ N-N~ \ / N HO N-N~ \ / ~H~
CI H H N _ \ I \ ~ O CI H \ I H \ /
Ho Ho / \ o - / \ o _ \ / N_CHs HON-N \ / N
CI \ / ~OH CI~/ ~H \ / H3C / \
O
HO / \ CI
N-Ni \ / N -CI H \ / H ~ CHs HO~\ / \/~' ~J~O \ /
~N_Ni \ / N
H
CI \ / H CHs HO / \ N-N \ / S~N~N HO / \ O-N \ /
CI H N ~ N
\ / NHz CI H \ / ~N
HO / \ O -~-Ni \ / H / \
CI _ \ / HO ~/ \ ~O O
\ / ~N-Ni \ / N--HsC 0 CI J'= ' H \ / H CHs / \ O -HO
H-Ni \ / H HO / \
CI \ / / \ F H-N \ /
CI \ /
/ \ O O - HO
HO H-N~ \ / H HO / \ N-N~ \ / N
CI \ / \ ~ O C! H \ / H C CHs CHs s O-CHs O
HO / \ N-N \ / S~S~ HO /_\ N_N~ \ / N
CI H N ~H
\ / CI \ / H
\ /
NHz / \ O
HO / \ O ~ N HO N_N \ / N
~N-N \ / ~ CI H
CI H \ / I / \ / / \
~H -HO / \ O i \ / / \
O
/ \
CI H N \ / H NH2 HO N-N~ \ / N
\ / CI H \ / H O
HO / \ O i \ / HO / \ O _ N-N N N-N~ \ / N
CI H \ / H // 'S CI H \ / H / 0 CHI
HO / \ O / \ / HO / \ O ~ \ / OH
N-N N N-N N
C1 H \ / H \ / CI H \ / H
HO~ / \ O i H~ N HO / \ O i N
~N-N \ / S~' ~ ~H-N \
CIr H \ / N CI \ / N
The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included in the scope of the invention.
Furthermore, one or more carbon-carbon or carbon-nitrogen double bonds may be present in the compounds which brings about geometric isomers. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the invention.
Furthermore, the compounds of the present invention may exist in different tautomeric forms, eg the following tautomeric forms:
A N~N~ CH -B-(K) -D A~N\N~(CH2)~ B-(K)m-D
( 2)n 'm ~ O .
O H
It is intended that any tautameric forms which the compounds are able to form are included in the scope of the present invention.
Owing to their efficacy in antagonizing the glucagon receptor the present compounds may be suitable for the treatment and/or prevention of any glucagon-mediated conditions and dis-eases.
Accordingly, the present compounds may be applicable for the treatment of hyperglycemia as-sociated with diabetes of any cause or associated with other diseases and conditions, eg im-paired glucose tolerance, insulin resistance syndromes, syndrome X, type l diabetes, type II
diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas, acute pancreatitis, cardiovascular diseases, cardiac hypertrophy, gastrointestinal disorders, diabetes as a conse-quence of obesity etc. Furthermore, they may be applicable as diagnostic agents for identifying patients having a defect in the glucagon receptor, as a therapy to increase gastric acid secre-tions, to reverse intestinal hypomobility due to glucagon administration, to reverse catabolism and nitrogen loss in states of negative nitrogen balance and protein wasting including all causes of type I and type II diabetes, fasting, AIDS, cancer, anorexia, aging and other condi-tions, for the treatment of any of the above conditions or diseases post-operative or during surgery and for decreasing saitety and increasing energy intake. Thus, in a further aspect the present invention relates to a pharmaceutical composition comprising, as an active ingredi-ent, at least one compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients.
The present invention furthermore relates to methods of treating type I or type If diabetes or hyperglycemia which methods comprise administering to a subject in need thereof an effec-tive amount of a compound according to the invention.
Moreover, the present invention relates to a method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to the invention.
The present invention is also concerned with the use of a compound according to the inven-tion for the manufacture of a medicament for treating type I or type If diabetes or hypergly-cemia, or for lowering blood glucose in a mammal.
Pharmaceutical formulations and administration methods The compounds according to the invention, which may also be referred to as an active ingredi-ent, may be administered for therapy by any suitable route including oral, rectal, nasal, pul-monal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal), the oral route being preferred. It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen active ingredient.
The compounds of the invention are effective over a wide dosage range. A
typical dosage is 1o in the range of from 0.05 to about 1000 mg, preferably of from about 0.1 to about 500 mg, such as of from about 0.5 mg to about 250 mg for administration one or more times per day such as 1 to 3 times per day. It should be understood that the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant 15 diseases to be treated as well as other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
2o For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administra-tion, typically doses are on the order of about 1/2 the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharma-ceutically acceptable salt thereof. One example is an acid addition salt of a compound having 25 the utility of a free base. When a compound of formula I contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of for-mula I with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids, for example: malefic, fumaric, benzoic, ascorbic, pamoic, succinic, bis-methylene salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, sali-3o cylic, citric, pyruvic, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluensulfonic, hydro-chloric, hydrobromic, sulfuric, phosphoric or nitric acids. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable ration such as sodium or ammonium ion.
The compounds of the invention may be administered alone or in combination with pharma-ceutically acceptable carriers, in either single or multiple doses.
For parenteral administration, solutions of the novel compounds of formula i in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cy-clodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage fom~s suitable for the disclosed routes of ad-ministration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as dis-crete units such as capsules or tablets, each containing a predetemlined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet which may be prepared by conventional tabletting techniques may contain:
Core:
Active compound (as free compound or salt 100 mg thereof) Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst. (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium stearate Coating:
HPMC approx. g mg *Mywacett 9-40 T approx. 0.9 mg 1o *Acylated monoglyceride used as plasticizer for film coating.
For nasal administration, the preparation may contain a compound of formula I
dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
Optionally, the pharmaceutical composition of the invention may comprise a compound of formula ! combined with one or more other pharmacologically active compounds, e.g. an an-tidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pato-physiological mechanism. Suitable antidiabetics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S) which is incorporated herein by refer-ence as well as orally active hypoglycaemic agents such as sulphonyfureas, e.g. glibencla-mide and glipizide; biguanides, e.g. metformin; benzoic acid derivatives, e.g.
repaglinide;
and thiazolidinediones, e.g. troglitazone and ciglitazone, as well as PPAR and RXR agonists.
EXPERIMENTAL
Giucagon binding In the following section binding assays as well as functional assays useful for evaluating the efficacy of the compounds of the invention are described.
Glucagon Binding Assa~r (Il 1o Binding of compounds to the glucagon receptor was determined in a competition binding as-say using the cloned human glucagon receptor.
In the screening setup, antagonism was determined as the ability of the compounds to inhibit the amount of cAMP formed in the presence of 5 nM glucagon.
For full characterization, antagonism was determined in a functional assay, measured as the ability of the compounds to right-shift the glucagon dose-response curve.
Using at least 3 different antagonist concentrations, the K; was calculated from a Schild plot.
Receptor binding was assayed using cloned human receptor (Lok et al, Gene 140, (1994)). The receptor inserted in the pLJ6' expression vector using EcoRl/SSt1 restriction sites (Lok et al) was expressed in a baby hamster kidney cell line (A3 BHK 570-25).
Clones were selected in the presence of 0.5 mg/ml G-418 and were shown to be stable for more than 40 passages. The Ka was shown to be 0.1 nM.
Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM
NaCI, 1 mM dithiothreitol, 5 mg/I leupeptin (Sigma), 5 mg/l pepstatin (Sigma), 100 mg/I baci-tracin (Sigma) and 15 mg/I recombinant aprotinin (Novo Nordisk)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation upon a layer of 41 w/v% sucrose at 95.000 * g for 75 min. The white band located between the two layers was diluted in buffer and centrifuged at 40.000 * g for 45 min. The precipitate containing the plasma membranes was suspended in buffer and stored at -80°C until required.
Glucagon was iodinated according to the chloramine T method (Hunter and Greenwood, Na-tune 194, 495 (1962)) and purified using anion exchange chromatography (Jorgensen et al, Hormone and Metab. Res. 4, 223-224 (1972). The specific activity was 460 uCi/p,g on day of iodination. Tracer was stored at -18°C in aliquots and were used immediately after thawing.
Binding assays were carried out in triplicate in filter microtiter plates (MADV N65, Millipore).
The buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1 % human serum albu-min (Sigma, grade V). Glucagon was dissolved in 0.05 M HCI, added equal amounts(w/w) of HSA and freeze-dried. On the day of use, it was dissolved in water and diluted in buffer to the desired concentrations.
175 ~I of sample (glucagon or test compounds) was added to each well. Tracer (50.000 cpm) was diluted in buffer and 15 p,l was added to each well. 0.5 ~g freshly thawed plasma mem-brave protein diluted in buffer was then added in 15 ~I to each well. Plates were incubated at 25°C for 2 hours. Non specific binding was determined with 10~ M
glucagon. Bound and un-bound tracer were then separated by vacuum filtration (Millipore vacuum manifold). The plates were washed once with 150 p.l buffer/ well. The plates were air dried for a couple of hours, whereafter filters were separated from the plates using a Millipore Puncher.
The filters were counted in a y counter.
Functional Assav 111 The functional assay was carried out in 96 well microtiter plates (tissue culture plates, Nunc).
The resulting buffer concentrations in the assay were 50 mM tris/HCI, 1 mM
EGTA, 1.5 mM
MgS04, 1.7 mM ATP, 20 ~M GTP, 2 mM /BMX, 0.02% tween-20 and 0.1 % HSA. pH was 7.4 Glucagon and proposed antagonist were added in 35 ~cl diluted in 50 mM
tris/HCI, 1 mM
EGTA, 1.85 mM MgS04, 0.0222 % tween-20 and 0.111 % HSA, pH 7.4. 20 ~I of 50 mM
trisIHCI, 1 mM EGTA, 1.5 mM MgS04, 11.8 mM ATP, 0.14 mM GTP, 14 mM iso-buthyl-methyl-xanthine (/BMX) and 0.1% HSA, pH 7.4 was added. GTP was dissolved immediately before the assay.
50 pl containing 5 pg plasma membrane protein was added in a tris/HCI, EGTA, MgS04, HSA
buffer (the actual concentrations were dependent upon the concentration of protein in the stored plasma membranes).
The total assay volume was 140 ~I. The assay was incubated for 2 hours at 37°C with continu-ous shaking. Reaction was terminated by addition of 25 X10.5 N HCI. cAMP was measured by the use of a scintillation proximity kit (Amersham).
GIUC24on Binding Assay (II1 Receptor binding was assayed using the cloned human receptor (Lok et al, Gene 140, 203-209 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok et ai) was expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg/ml G-418 and were shown to be stable for more than 40 passages. The Kd was shown to be 0.1 nM.
Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tr7s/HCl), pH 7.4 containing 30 mM
NaCI, 1 mM dithiothreitol, 5 mg/I leupeptin Sigma), 5 mg/i pepstatin (Sigma), 100 mg/I baci-tracin (Sigma} and 15 mg/I recombinant aprotinin {Novo Nordisk)), homogenization by two 10-s 2o bursts using a Polytron PT 10-35 homogenizer (Kinematics), and centrifugation. The ho-mogenate was resuspended and centrifuged again. The final precipitate containing the plasma membranes was suspended in buffer and stored at -80°C until required.
Binding assays were carried out in duplicate in polypropylene tubes or microtiter plates. The buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1 % bovine serum albumin (Sigma, fraction V). Sample (glucagon {Sachem CA) or test compounds) was added to each tube or well. Tracer (- 25000 cpm) was diluted in buffer and was added to each tube or well.
0.5 p,g freshly thawed plasma membrane protein diluted in buffer was then added in aliquots to each tube or well. Tubes or plates were incubated at 37°C for 1 hour.
Non specific binding was determined with 10'' M glucagon. Bound and unbound tracer were then separated by vacuum filtration (Brandel). The tubes or wells were washed twice with buffer. The filters or plates were counted in a gamma counter.
Functional Assav (Ill The functional assay determined the ability of the compounds to antagonize glucagon-stimulated formation of cAMP in a whole-cell assay. The assay was carried out in borosilicate glass 12 x 75 tubes. The buffer concentrations in the assay were 10 mM HEPES, 1 mM EGTA, 1.4 mM MgCl2, 0.1 mM IBMX, 30 mM NaCI, 4.7 mM KCI, 2.5 mM NaH2P04, 3mM glucose and 0.2% BSA. The pH was 7.4. Loose whole cells (0.5 ml, 106/ml) were pretreated with various concentrations of compounds for 10 min at 37°C, then challenged with glucagon for 20 min.
Some aliquots (500 pL) of cells were treated with test compounds (55 uL) alone to test for 1 o agonist activity. The reactions were terminated by centrifugation, followed by cell lysis with the addition of 500 p.l 0.1 % HCI. Cellular debris was pelleted and the supernatant containing CAMP
evaporated to dryness. CAMP was measured by the use of an RIA kit (NEN, NEK-033). Some assays were carried out utilizing the adenylate cyclase FIashPlate system from NEN.
Synthesis methods The following synthesis protocols refer to intermediate compounds and final products identi-fied in the specification and in the synthetic schemes. The preparation of the compounds of the present invention is described in detail using the following examples, but the chemical reactions described are disclosed in terms of their general applicability to the preparation of the glucagon antagonists of the invention. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifica-tions known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions.
Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative meth-ods, all starting materials are known or readily preparable from known starting materials. All temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight when referring to yields and all parts are by volume when refer-ring to solvents and eluents.
General procedures for the r~erJaration of alkylidene hydrazides:
The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme l, that is, by converting an ester of a carboxylic acid, for example, an aromatic acid to a hydrazide derivative and further reacting that product compound with a substituted aldehyde or ketone to yield a substituted alkylidene hydrazide.
SCHEME/
O-Ra solvent NHNHZ
A + NH2NH2 ---,- A--reflux O
O
4~--(CHz)~ B-(K)m D
R HN-N-~-(CHZ)~ B-(K)m D
A-~ R
solvent, reflux O
wherein A, B, K, D, m, n and R4 are as defined for formula I and Ra is lower alkyl.
Seneral procedure for the synthesis of rp ecur.SOr hydrazides ABC=O)-NHNH
The reaction is known (Org. Syn., Coll. Vol. li, A.H.BIatt, ed., John Wiley &
Sons, New York, 1943, p. 85; Org. Syn., Coll. Vol. IV, N. Rabjohn, ed., John Wiley & Sons, New York, 1963, p.
819) and is generally performed by stirring the corresponding ester (either methyl, ethyl or other lower alkyl ester) with 2-10 molar excess of hydrazine in the presence of a solvent such 2o as ethyl alcohol, methyl alcohol, isopropyl or tert-butyl alcohol or tetrahydrofuran, dioxane, DMSO, ethylene glycol, ethylene glycol dimethyl ester, benzene, toluene or a mixture of the above solvents or, in the absence of a solvent where excess of hydrazine acts as a solvent.
The reactions are performed between 0°C to 130°C, preferably between 20°C to 100°C, most preferably at or about the reflux temperature of the solvent. The reactions are preferably con-ducted under an inert atmosphere such as NZ or Ar. When the reaction is complete as judged by disappearance of the starting ester by TLC or HPLC, the solvent may be removed by con-centration at atmospheric or reduced pressure.
The product can be further purified by either recrystallization from a solvent such as ethyl alco-hol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent. The corresponding fractions are concentrated either at atmos-pheric pressure or in vacuo to provide the pure aroyl hydrazide.
Preparation of aromatic acid hydrazi ~Pw The methyl or ethyl ester of the corresponding aromatic acid, such as for example a substi-tuted benzoic acid ester, is dissolved in ethanol and hydrazine (5 eq) is added. The reaction is refluxed overnight under nitrogen. Upon cooling the substituted hydrazide derivative usually precipitates. After filtration the product is usually recrystallized from hot methanol, ethanol or isopropyl alcohol. In cases where the hydrazide does not precipitate, the reaction is concen-trated under vacuo and chromatographed over silica gel using dichloromethane/methanol as the eluent. Specific examples illustrating the preparation of aromatic hydrazides are provided below.
Precaration of 5-hydrox~rindole 2 carbo~rlic a i v razid To a sample of ethyl 5-hydroxyindole-2-carboxylate {5g, 24 mmol), dissolved in ethanol (250 mL) was added hydrazine (4 mt_, 121 mmol). The reaction was refluxed overnight under ni-trogen. Upon cooling the reaction vessel, the desired product crystallized.
The white solid was isolated by filtration. Recrystallization from hot ethanol gave the 5-hydroxyindole-3-carboxylic acid hydrazide in 85% yield.
HO
N
H
O
1 H NMR (DMSO-dg): 8 4.38 (s, 2H); 6.62 (dd, 1 H); 6.76 (dd, 2H); 7.13 (d, 1 H); 8.70 (s, 1 H);
9.57 (s, 1 H}; 11.21 (s, 1 H); MS (FAB): m/z 192 (M+H)+.
Per paration of 3-chloro-4-hvdroxybenzoic acid hvdrazide:
To a sample of methyl 3-chloro-4-hydroxybenzoate (2 g) dissolved in ethanol (50 mL) was added hydrazine (1.8 mL). The reaction was refluxed overnight under nitrogen.
Upon cooling the reaction vessel, the desired product crystallized out of solution. The white solid was iso-lated by filtration. Recrystallization from hot ethanol gave the 3-chloro-4-hydroxybenzoic acid hydrazide in 60% yield.
NHNHZ
HO
CI
1 H NMR (DMSO-d6): 8 4.49 (broad s, 2H), 7.05 (dd, 1 H), 7.71 (dd, 1 H), 7.89 (d, 1 H), 9.669 (s, 1 H), 10.72 (broad s, 1 H).
By use of the above methodology, other hydrazides useful as intermediates in preparing the compounds of the invention are prepared, for example:
HO
Br 3-Bromo-4-hydroxybenzoic acid hydrazide 1 H NMR (DMSO-d6): 8 9.95 (s, 1 H), 9.65 (d, 1 H), 9.61 (broad s, 1 H), 6.95 (d, 1 H), 4.40 (broad s, 2H); MS m/z 233.1.
O
~NHNH2 HO
3-Nitro-4-hydroxybenzoic acid hydrazide 1 H NMR (DMSO-dg): 8 9.28 (broad s,1 H), 8.28 (s, 1 H), 7.52 (d, 1 H), 6.41 (d, 1 H). MS m/z 198.
HO
F
3-Fluoro-4-hydroxybenzoic acid hydrazide 1 H NMR (DMSO-dg): 8 9.45 (broad s, 1 H), 7.5 (d, 1 H), 7.43 (d, 1 H), 6.85 (t, 1 H), 5.55 (broad s, 3H).
Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide, 2,3-dichloro-4-hydroxybenzoic acid hydrazide and 2,5-dichloro-4-hydroxybenzoic acid hydrazide.
B O
OH ~ I ~ OH ~ w OMe p ~ . NHZ
i HZN CI HO ~ CI HO I ~ CI ~ I , H
HO CI
i O O O O
I ~ H.NHz p I w O~ + CI ~ OMe p Cl ~ .NHS
HO ~ CI HO ~ Cl I i ~ I H
CI CI HO CI HO
Preparation of 2-chloro-4-hydroxyrbenzoic acid hyrdrazide Step A:
4-amino-2-chlorobenzoic acid (10 g, 58 mmol) was dissolved in H2S04 (12 N, 120 mL) with heating. After cooling the solution in an ice-bath aqueous NaN02 (2.5 M, 25 mL) was added 2o dropwise such that the internal temperature remained at 5 °C. Urea was added to the mixtu-re for after stirring for 15 minutes to destroy excess NaNOz (monitored by starch iodine test).
CuSO, (100-200 mg) was added and the mixture was heated to 90 °C until evolution of gas stopped. After cooling, the mixture was extracted with ethyl ether (3x). The combined orga-nic fractions were extracted with 3N NaOH (3x). The combined aqueous layer was acidified with conc. HCI and the product was extracted with ethyl ether (3x). The organic fractions were washed with water, brine, and dried over MgS04. The crude product was introduced into a silica gel column and eluted with ethyl acetate/hexane (1I1) to afford 2-chloro-4-hydroxybenzoic acid.
'H NMR (DMSO-D6): 8 6.97 (dd, 1 H), 7.05 (d, 1 H), 7.95 (d, 1 H), 10.90 (brd s, 1 H).
Step B:
To a solution 2-chloro-4-hydroxybenzoic acid in anhydrous methanol was added thionyl chlo-ride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgS04 and concentrated in vacuo to give methyl 2-chloro-4-hydroxybenzoate.
Step C:
To a solution of methyl 2-chioro-4-hydroxybenzoate (13.6 g, 73.1 mmol) in acetic acid (300 mL) was added N-chlorosuccinimide (9.8 g, 73.7 mmol). The solution was refluxed for 24 h and the solvent was evaporated under vasuo. The residue was taken up in chloroform, washed with water, brine, dried over magnesium sulfate, filtered and concentrated. Methyl 2,3-dichloro-4-hydroxybenzoate precipitated out of ethyl acetate.
Chromatography of the re-sidue using ethyl acetate/hexane (1l9 to 3/7) afforded methyl 2,5-dichloro-4-hydroxybenzoate (1.4 g, 60%) as well as an additional batch of methyl 2,3-dichloro-4-hydroxybenzoate isomer (total of 8.4 g, 10%).
Methyl 2,3-dichloro-4-hydroxybenzoate:
'H NMR (DMSO-D6) 8 3.81 (s, 3H), 7.02 (d, 1 H), 7.70 (d 1 H), 11.52 (s, 1 H);
MS (APCI):
221, 223.
Methyl 2,5-dichloro-4-hydroxybenzoate:
' H NMR (CDC13): 8 3.90 (s, 3H), 6.00 (s, 1 H), 7.14 (s, 1 H), 7.27 (s, 1 H), 7.96 (s, 1 H); MS
(APCI): 221.9.
Step D:
The title comb o~ and was prepared according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNHz.
'H NMR (DMSO-D6): 8 6.82 (dd, 1 H), 6.90 (d, 1 H), 7.79 (d, 1 H, 10.68 (brd s, 1 H).
Preparation of 2.3-Dichloro-4-hvdroxvbenzoic acid hy~drazide and 2 5 dichloro-hvdroxybenzoic acid hyrdrazide ~(stelp DO
The 2,3-dichloro-4-hydroxybenzoic acid hydrazide was prepared from the methyl 2,3-dichloro-4-hydroxybenzoate above according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNHZ with the exception that pentanol was the solvent of choice. The product was purified via silica gel column chromatography using CH2C12/MeOH
( 95/5 to 80/20), yield = 50%.
2,5-dichloro-4-hydroxybenzoic acid hydrazide was prepared in a similar way starting from 2,5-dichloro-4-hydroxybenzoate.
2.3-Dichloro-4-hydroxybenzoic acid hydrazide:
'H NMR (DMSO-D6) 8 4.41 (brd s, 2H), 6.99 (1, 1 H), 7.37 (s, 1 H), 9.46 (s, 1 H), 11.04 (s, 1 H).
2.5-Dichloro-4-h~ droxybenzoic acid hydrazide~
'H NMR (DMSO-D6) 8 4.48 (brd s, 3H), 6.92 (d, 2H), 7.18 (d, 2H), 9.45 (brd s, 1 H).
Preaaration of 2 3-difluoro-4-hydroxyrbenzoic acid h~drazide:
~~N O O O
A
I ~ ~ ~ OH B I ~ OMe C a ~ ~ H.NHZ
HO F HO ~ F HO ~ F HO ~ F
F F F F
Step A:
A mixture of 2,3-difluoro-4-cyanophenol (1 g, 6.45 mmol) in water (8 mL), HZS04 (8 mL), and acetic acid (8 mL) was refluxed for 48 hours. The solvents were removed by rotary evapo-ration to give a slurry which was poured onto ice. The product precipitated out of solution and filtered. The solid was washed with water and dried to give 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 71 %).
'H NMR (DMSO-Ds): 8 6.87 (t, 1 H), 7.60 (t, 1 H), 11.28 (s, 1 H), 12.53 (brd s, 1 H).
Step B:
To the 2,3-ditluoro-4-hydroxybenzoic acid (800 mg, 5.1 mmol) dissolved in anhydrous methanol {50 mL) was added thionyl chloride (0.55 mL, 7.3 mmol). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgS04 to give methyl 2,3-difluoro-4-hydroxybenzoate (540 mg, 62%).
'H NMR (CDCI3): S 3.92 (s, 3H), 6.34 (brd s, 1 H), 6.82 (dt, 1 H), 7.68 (dt, 1 H).
Step C:
The 2,3-difluoro-4-hydroxybenzoic acid hydrazide was prepared from the methyl 2,3-difluoro-4-hydroxybenzoate above according to the general procedure for the synthesis of precursor hydrazides A-{C=O)-NHNH2. The product was purified via silica gel column chromatography using CH2CI2/MeOH ( 95/5 to 80/20) to afford the title com op und.
'H NMR (DMSO-D6): 8 4.48 (s, 2H), 6.80 (m, 1 H), 7.22 (m, 1 H), 9.36 (s, 1 H), 10.89 (s, 1 H);
MS (APCI): 189.
Preparation of 3-cyano-4-hyrdroxybenzoic acid hydrazide trifluoroacetate:
OMe A i ~ OMe g I % 'O~ D I ~ OH
--a HO ~ ---~ HO ---~ HO
HO
N N
D
H-NHZ E N.N~O
HO ~ ~ HO I i H O
II II
N N
Step A:
Methyl-4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of warm (65 °C) acetic acid. A solution of iodine monochloride (37.8 g, 0.233 mol) in 50 mL of acetic acid was added slowly (40 minutes) to the methyl-4.-hydroxybenzoate solution, while maintaining a temperature of 65 °C and vigorous stirring. The product crystallizes from solution upon 1 o cooling to room temperature and standing overnight. The crystals were collected on a filter, washed with water, then dried under vacuum. Methyl-4-hydroxy-3-iodobenzoate was obtai-ned as white crystals (28.6 g, 44%).
'H NMR (DMSO-D6): 8 3.79 (s, 3H), 6.95 (d, J = 8.3, 1 H), 7.81 (dd, J = 8.3, 2.2, 1 H), 8.22 (d, J = 2.2, 1 H); '3C NMR (DMSO- D6) 8 52.8, 85.2, 115.5, 123.0, 132.0, 141.0, 161.9, 165.6.;
MS (APCI, peg): 277.
Step B:
Methyl-4-hydroxy-3-iodobenzoate (2.00 g, 7.2 mmol) was dissolved into 5 mL of dry DMF.
Copper(!) cyanide (0.72 g, 8.0 mmol) and a small crystal of sodium cyanide was added. The mixture was flushed with nitrogen, placed in an oil heating bath (100-110 °C), and stirred overnight. TLC indicated nearly complete reaction. The mixture was cooled and the solids removed by filtration. The solids were extracted with DMF (3 mL). The filtrate and washings were taken up in 100 mL of ethyl acetate, then washed with 3 portions of saturated sodium chloride solution. The solids and aqueous washings were combined, and shaken with a mixture of 50 mL of ethyl acetate and a ferric chloride solution (4 g of hydrated ferric chloride in 7 mL of conc. hydrochloric acid). The ethyl acetate layers were combined, washed with brine containing sodium metabisulfite, dried over sodium sulfate, filtered, and the solvent removed in vacuo. The resulting solids were purred by flash chromatography on silica gel (20% ethyl acetate/ hexane) to afford methyl-3-cyano-4-hydroxybenzoate, 0.93g (73%).
'H NMR (DMSO- Ds): 8 3.79 (s, 3H), 7.07 (d, J = 8.7, 1 H), 8.02 (dd, J = 8.7, 1.9, 1 H), 8.10 (d, J = 1.9, 1 H).
1 o Step C:
Methyl-3-cyano-4-hydroxybenzoate (2.71g, 15.3 mmol) was dissolved in 50 mL of THF. The solution was chilled in an ice bath, and 2.OM potassium hydroxide (17 mL, 34 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. TLC in-dicated complete reaction. The THF was removed by rotary evaporation. The aqueous re-sidue was acidified with aqueous trifluoroacetic acid and purified by reverse-phase HPLC (C-18, 0.1 % TFA in water and acetonitrile). 3-Cyano-4-hydroxybenzoic acid was obtained as a white powder (2.1 g, 84%) after lyophilization.
'H NMR (DMSO- DB): 8 7.09 (d, J = 9.0, 1 H), 8.00 (dd, J = 9.0, 2.3, 1 H), 8.07 (d, J = 2.3, 1 H) 12.50 (br s, 2H); MS (APCI, neg): 162. IR: 2252 cm-', CN.
Step D:
3-Cyano-4-hydroxybenzoic acid (1.888, 11.5 mmol) was dissolved in 20 mL of methylene chloride/DMF (1/1 ) and chilled in an ice-bath. Diisopropylethylamine (12 mL, 69 mmol), t-butyl carbazate (1.76g, 13.3 mmol), and PyBroP (bromo-tris-pyrrolidino-phosphonium he-xafluorophosphate, 6g, 12.9 mmol} were added, and the mixture was stirred to form a clear solution. The solution stood in the refrigerator overnight. TLC indicated that the reaction was not complete, so additional diisopropylethylamine (22 mL, 127 mmol), t-butyl carbazate (0.85g, 6.4 mmol) and PyBroP (3.Og, 6.4 mmol) were added. After 8 more hours at 0 °C, the 3o reaction was worked up as follows. The solution was reduced by rotary evaporation. The remaining DMF solution was diluted with 100 mL of ethyl acetate, and washed with several portions of 0.1 M HCI (until the wash remained acidic to litmus paper). The ethyl acetate layer was further washed with 3 portions of brine, dried over magnesium sulfate, filtered, and reduced to an oil in vacuo. The oil was purified by chromatography on silica gel (6:4 hexa-ne:ethyl acetate) to afford tert-butyioxycarbonyl (3-cyano-4-hydroxy)benzoic acid hydrazide as a white solid (1.8g, 56%).
'H NMR (DMSO- D6): b 1.42 (s, 9H), 7.09 (d, J = 8.7, 1 H), 7.98 (m, 1 H), 8.11 (br s, 1 H), 8.92 (s, 1 H), 10.15 (s, 1 H), 11.73 (br s, 1 H); MS (APCI, peg): 276; IR:
cm-', CN.
Step E:
The Boc-hydrazide (1.8g, 6.5 mmol) was suspended in 50 mL of chloroform and cooled in an ice-bath. Trifluoroacetic acid was added with stirring, and the resulting solution stood for 4 hours at 0 °C. TLC indicated complete reaction. Solvent and excess TFA
were removed by rotary evaporation. The remaining oii was purified by reverse-phase liquid chromatography (Aquasil C-18 column, water/acetonitrile/0.1 % TFA). The title comb and was obtained as a white solid (0.24 g, 13%).
'H NMR (DMSO- D6): 8 7.16 (d, J = 9.0, 1 H), 8.00 (dd, J = 1.5, 9.0, 1 H), 8.14 (d, J = 1.5, 1 H), 10.47 (br s, 5H); MS (APCI, peg): 176.
Preparation of 4-hydroxyn~phthoic acid by azid~
O H O OH O OMe O N, NH
i i -' ~ ---~ I W W C
i i i i ~ 1 i i OH OH OH
OH
Step A:
Silver nitrate (17 g, 0.1 moi) was dissolved in water (10 mL) and treated with 1 N NaOH (300 mL, 0.3 mol). The brown precipitate which was formed was stirred for 30 minutes and the supernatant was decanted. The brown silver oxide was washed with additional volumes of water (3x).
To the silver oxide above was added 1 N NaOH (150 mL) and 4-hydroxynaphthaldehyde (1 g, 6 mmol)). The mixture was heated to 70 °C for 10 minutes after which additional amounts of 4-hydroxynaphthaldehyde (5.5 g, 32 mmol) was added in portions. The mixture was kept at 80 °C for 16 hours. TLC analysis indicated incomplete conversion. An additional portion of silver oxide was prepared as above and added to the reaction mixture. After heating the mixture for an additional 6 hours, the mixture was cooled and acidified with 1 N HCI. The aqueous layer was extracted with ethyl acetate (3x) and upon concentration 4-hydroxynaphthoic acid precipitated (3.7 g, 60%) out of solution.
' H NMR (DMSO-D6): b 6.69 (d, 1 H), 7.28 (t, 1 H), 7.39 (t, 1 H), 7.93 (d, 1 H), 8.03 (d, 1 H), 8.82 (d, 1 H), 10.82 (s, 1 H), 12.29 (s, 1 H).
Step B:
To a solution 4-hydroxynaphthoic acid in anhydrous methanol at 0 °C was added thionyl chloride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgS04 to give methyl hydroxynaphthoate.
'H NMR (DMSO-D6): 8 3.87 (s, 3H), 6.92 (d, 1 H), 7.53 (t, 1 H), 7.65 (t, 1 H), 8.13 (d, 1 H), 8.26 (d, 1 H), 8.93 (d, 1 H), 11.16 (s, 1 H).
Step C:
The title com ound was prepared from methyl 4-hydroxynaphthoate according to the proce-dure for the synthesis of precursor hydrazides A-(C=O)-NHNHZ.
'H NMR (DMSO-D6): 8 6.60 (d, 1 H), 7.28 (m, 3H), 7.95 (d, 1 H), 8.07 (d, 1 H), 9.25 (brd s, 1 H).
Moreover, by use of the above methodology, the following hydrazides useful as intermediates in preparing the compounds of the invention may be prepared:
I
F ~NHNH2 HO ~ ~ NHNH2 HO
F
NHNHZ I ~ ~NHNH2 I ~ ~NHNH2 HO HO ~ HO
CI CI CI
OCH O
I 3 I I ~CH3 OCH O
~NHNH2 3 I ~ NHNH2 HO ~ I ~ ~NHNH2 HO
CI HO ~ F CI
~NHNH2 ~ ~NHNH2 NHNH2 HO ~ HO ~ HO
O O
CI Me0 NHNH2 i w ~NHNH2 I ~ ~NHNH2 HO HO ~ HO
CI CI
CI O
~ ~NHNH2 NHNHZ ~ NHNH2 HO ~ F HO OCH3 OH
HO
CI ~ NHNH2 I ~ ~NHNH2 O
O
~NHNH2 ~ NHNH2 ~NHNHZ
HO HO / F HO
OH
CI
O O
F ~ NHNH2 I ~ ~NHNH2 / HO /
HO
C OMe General procedure for the syrnthesis of ether-substituted aryl-aldehydes~
The ether-linked aldehydes may be prepared by 0-alkylation of the corresponding phenolic compounds using various electrophilic alkylating agents that introduce the -(K)m D moiety as 1 o defined above in a reaction generally known as Williamson ether synthesis (H. Fever, J. Hooz in The Chemistry of the Ether Linkage, S. Patai Ed., Wiley, New York 1967, p.
446-460).
SCHEME II
H R3a Rsb R4a R4b R'4 O
Lx-(CH2)b ~ (CH2)a-(M)f (CH2)~ q (CH ) D
2d R'S OH Base, solvent H
R' 4 O
R3a R3b R4a 4b R
R~5 O-(CH2)b p (CHZ)a-(M)f (CH2)~ q (CH2)d D
wherein Lx is a leaving group such as -CI, -Br, -I, -OSOZCH3, -OSOZp-tolyl or -OSOZCF3;
and R3e , R3b, R4a , R4b, a, b, c, d, f, p, q, D, M, R'4 and R'S are as defined for formula I.
According to Scheme II an ether-substituted aryl-aldehyde can be prepared by stirring hy-droxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as acetone, meth-ylethyl ketone, dimethylformamide, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above sol-vents with an equimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the pres-ence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxide, ethoxide or grt-butoxide, sodium, potas-sium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6-collidine or benzyldimethyl-ammonium methoxide or hydroxide. The reaction can be performed at 0°C to 150°C, preferably at 20°C to 100°C and preferably in an inert atmosphere of NZ or Ar. When the reaction is complete the mixture is filtered, concentrated in vacuo and the resulting product optionally purified by column chromatography on silica gel using ethyl acetatelhexane as eluent. The compound can also (when appropriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of ether-substituted aryl-aldehydes are provided below.
PrPnaration of 4-l2-tetrahydropyranylmethoxy)-1-naahthaldehyde:
A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 2-bromomethyl tetrahydropyran (1 g, 5.8 mmol) and powdered KZC03 (1.2 g, 8.7 mmol) in dimethyl formamide was stirred at 60°C
overnight. The mixture was taken up in water and ethyl acetate. The organic layer was sepa-rated and washed with water, brine, dried over MgSO,, filtered, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate/hexane.
H O
\ \
O
-O
'H NMR (DMSO-de): 8 1.48 (m, 4H), 1.74 (d, 1 H), 1.84 (m, 1 H), 3.44 (m, 1 H), 3.78 (m, 1 H), 3.92 (d, 1 H), 4.23 (m, 2H), 7.17 (d, 1 H), 7.64 (t, 1 H), 7.74 (t, 1 H), 8.11 (d, 1 H), 8.27 (d, 1 H), 9.22 (d, 1 H), 10.17 (s,1 H).
Preparation of 4-[(3.5-bis-trifluoromethyl benzylox~~]-1-naphthaldehyde:
A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 3,5-bis-trifluoromethylbenzyfbromide (1.8 g, 5.8 mmol), and powdered KZC03 (1.2 g, 8.7 mmol) was stirred in acetone (40 mL) over-night. The mixture was poured onto 200 mL of ice-chips and stirred until the ice melted. The yellow precipitate, 4-{(3,5-bis-trifluoromethyl)benzyloxy)-1-naphthaldehyde, was collected and 2o dried.
H O
\ \
O
CF3 \ CF3 'H NMR (DMSO-ds): 8 5.58 (s, 2H), 7.07 (d, 1 H), 7.22 (d, 1 H), 7.63 (t, 1 H), 7.69 (t, 1 H), 7.79 (d, 1 H), 7.86 (d, 1 H), 7.99 (s, 1 H), 8.14 (s, 1 H), 8.30 (s, 3H), 8.94 (s, 1 H), 8.97 (d, 1 H), 11.0 (broad s, 1H), 11.69 (s,1H); MS (ESI) m/z 675.2 (M+H)'.
Prej~aration of 4-(2-chloroethoxv -1-na htha ehyde~
To a solution of 4-hydroxy-1-naphthaldehyde (8.6 g, 50 mmoles) and potassium carbonate (13.8 g, 100 mmoles) in N,N-dimethylformamide (DMF)(40 mL) was added 1-bromo-2-chloroethane (7.4 g, 50 mmoles). The mixture was heated at 60°C
overnight. The solution was diluted with ethyl acetate (500 mL), extracted with water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated to obtain 12.1 g product (52 % yield).
O H
/ I \
\ /
O
SCI
MS (C(): 403, 405, 407. 'H NMR (CDCI3): 8 10.2 (s, 1 H), 9.3 (d, 1 H) 8.35 (d, 1 H), 7.85 (d, 1 H), 7.65 (m, 1 H), 7.5 (m, 1 H), 7.1 (d, 1 H), 4.35 (t, 2H), 4.15 (t, 2H).
The products were used as such in further transformations.
By application of the above methodology the following substituted aldehyde intermediates were synthesized:
/ \ OMe / \
O O \
/ \ O O / \ O
H H
4-carbomethoxymethoxy-1-naphthaldehyde 4-benzyioxy-1-naphthaldehyde m.p.: 115-116°C
/ \ / \
O / \ o \ / ~I o H ~/ H
4-(4-chlorobenzyloxy)-1-naphthaldehyde 4-allyloxy-1-naphthaldehyde CH
/ \ / \
O / \ \ / OCF3 O
O / \ O
H H ~J
4-(4-trifluoromethoxybenzyloxy}-1- 4-propargyloxy-1-naphthaldehyde naphthaldehyde / \ / \ NH2 O \ / CF3 O
/ \ O U O O
H ~-=J H
4-(4-trifluoromethylbenzyloxy)-1- 2-[(4-carboxaldehydo)-1 naphthaldehyde naphthyloxy]acetamide m.p. 174-175°C
\ CF3 OCF3 \ ~ ~ ~ \
O
H O
O O
4-(3-trifluoromethylbenzyloxy)-1-naphthaldehyde 4-(2-(4-trifluoromethoxyphenyl)-2-oxo-ethoxy)-1-naphthaldehyde m.p. 112-114°C
OMe O ~ \ \ ~ OCF3 ~ ~ O -N
O
H O ~ ~ O
OMe 4-(4-trifluoromethoxybenzyloxy)-3,5- Nicotinic acid 4-formyl-1-naphthyl ester dimethoxybenzaldehyde m. p. 142-143°C
OMe CHs O / \ O \ / ~H o 0 ° w OMe 4-(4-isopropylbenzyloxy)-3,5-4-(1,3-dioxo-1,3-dihydroisoindol-2-dimethoxybenzaldehyde yimethoxy)-1-naphthaldehyde (oil) m.p. 191-192°C
O O
O O
H H U
4-(4-isopropylbenzyloxy)-1-naphthaldehyde 4-(tetrahydro-2-pyranylmethoxy)-1-naphthaldehyde / \ F
H ~ F
4-(3,5-difluorobenzyloxy)-1-naphthaldehyde m. p. 100-101 °C
Preparation of 3-AIIXI-4-hydroxyr-5-methoxy-benzaldehude:
OH
--a -.r H
To a solution of vanillin (1.0 g, 6.57 mmol) in acetone (30 mL) was added potassium carbon-ate (4.50 g, 32.8 mmol) and allyl bromide (0.62 mL, 7.3 mmol). The mixture was heated un-der reflux for 6 h. TLC showed appearance of a new spot. Potassium salts were removed by filtration and the filtrate was concentrated to a syrup. A small sample was purified using prep TLC using hexane/ethyl acetate 7:3 as developing solvent. 1 H NMR (CDCI3) 8 =
3.94 (s, 3H), 4.67 - 4.83 (m, 2H), 5.30 - 5.55 (m, 2H), 6.01 - 6.21 (m, 1 H), 6.98 (d, J = 9 Hz, 1 H), 7.40 - 7.56 (m, 2H), 9.85 (s, 1 H); MS (APCI): 193.6 The crude syrup was heated neat in an oil bath at 200 °C for 6 h. The crude material was dissolved in chloroform and filtered through a pack of silica gel. The crude product (yield 72%) was used as is in the next step for O-alkylation. A small portion was purified using prep-TLC to give a pure sample of 3-allyl-4-hydroxy-5-methoxy-benzaldehyde. 1 H NMR
(CDC13) b = 3.46 (d, J = 6 Hz, 2 H), 3.96 (s, 3H), 5.02 - 5.22 (m, 2H), 5.94 -6.11 (m, 1 H), 6.30 (s, 1 H), 7.45 (s, 2H), 9.80 (s, 1 H); MS (APCI}: 193.3.
Preparation of 3-Allvl-4-(4-isonroovlbenzvloxv) 5 methoxyh~Pn~aldeh~~g The crude 3-allyl-4-hydroxy-5-methoxy-benzaldehyde was taken up in acetone and treated with 4-isopropylbenzyl chloride in the presence of potassium carbonate to give the desired product.
1 H NMR (CDCi3) b = 1.2fi (d, J = 7 Hz, 6 H), 2.92 (m, 1 H), 3.38 (d, J = 7 Hz, 2H), 3.95 (s, 3H), 4.98 - 5.12 (m, 4H), 5.93 - 5.75 (m, 1 H), 7.20 - 7.43 (m, 6H), 9.87 (s, 1 H).
General~rocedure for the synthesis of compounds of formulae IXa and IXb:
QH
CI N OHC~ IB
D~NH2 -~. CI~ -.. Cp \p -step A
0 O step B
H a \ NiNHx O H
O~B\O~N\D Ho a H a ~ N~N~B\O~N~D
H O R R HH
O
step D HO R9 Formula IXa step C ICZCO~
\ N~NHx O
R° H
Ho , ~ N~N~/B\N~D
O~B~N,D R Ra H H
H
H step D HO Rs Formula IXb In the above formulae 8, D, R8 and R9 have the same meanings as defined for formula I.
Step A:
To a solution of aniline (or an aniline derivative) (1 eq.) in THF was added dropwise chloroacetyl chloride (1.2 eq.). After stirring at room temperature overnight, 100 mL water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with dilute hydrochloric acid, twice with water, dried over MgSO, and then con-centrated to give pure product.
Step B:
To a solution of chloroacetanilide (or a derivative thereof) (1.2 eq.) and 2-methoxy-4-hydroxy benzaldehyde (or another aromatic aldehyde substituted with a hydroxy group) (1 eq.) in DMSO was added potassium carbonate (1.5 eq.). After stirring overnight at room temperature, 100 ml water was added. The mixture was extracted with ethyl acetate, the or-ganic extracts were washed twice with a satd. sodium bicarbonate solution, twice with water, and dried over MgS04. After concentration in vacuo, the product was obtained.
The following two aldehydes were prepared as examples of compounds that can be pre-pared using this methodology:
N-l4-Chloroohenvl)-2-l4-formv! ~ r"Ptho p noxy~acetamide C!
O / I
Me0 O
\N
H
O
H
'H NMR (CDC13 ): 8 4.28 (s, 3H), 5.01 (s, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.97 ( dd, J = 8.6, 2.1 Hz, 1 H), 7.67 ( d, J = 8.9Hz , 2H), 7.89 (d, J = 8.8 Hz, 2H), 8.20 (d, J =
8.6Hz, 1 H), 8.51 (s, 1 H), 10.66 ( s, 1 H); MS ( APCI ): 319.9 .
N- 4-iso r h n r I- -m th h n x cet mi O ~ I ~CH3 Me0 \ O
~ \N
O / H
H
'H NMR ( DMSO-D6): 8 2.07 (d, J = 6.9 Hz , 6H), 2.70 (m, J = 6.9 Hz, 1H), 3.77 (s, 3H), 4.68 (s, 2H), 6.56 (dd, J = 8.7, 2.1 Hz, 1 H), 6.66 ( d, J = 2.1 Hz, 1 H), 7.06 (d, J = 8.5Hz, 2H), 7.39 ( d, J = 8.50 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1 H), 9.93 (s, 1 H), 10.05 (s, 1 H); MS (APCI ): 328.
This type of aidehydes can be coupled to hydrazides using the methodology as described in step D to give a compound of formula IXa. Alternatively these compounds can undergo re-arrangement by treatment with base as described below (step C), followed by coupling to a hydrazide (step D) to give a compound of formula IXb.
WO 99/01423 PCT/DK98/0828'l Step C:
The mixture of aldehyde (1 eq.) and potassium carbonate (1.5 eq.) in acetonitrile was re-fluxed. The reaction was monitored by TLC (hexane : ethyl acetate = 2:1 ).
When TLC
showed almost complete conversion (about 48 h), 100 ml water was added. The mixture was extracted with ethyl acetate, the organic extracts were dried over MgSO,, and concen-trated to give the desired product which can be further purified by column chromatography, or used directly for the next step.
1 o The following two aldehydes were prepared as examples of compounds that can be pre-pared using this methodology:
4-~4-Chlorophenylamino)-2-methoxybenzaldehyde:
Prepared from N-(4-chlorophenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide using the pro-cedure described in step C above.
WO 99/01423 PCT/DK98/0028?
H
Me0 N
\ \
O ~ / ~ /
CI
H
'H NMR (CDC13 ): b 3.84 (s, 3 H), 6.14 (s, 1 H), 6.45 (d, J = 2.0 Hz, 1 H), 6.54 ( dd, J = 8.4, 1.BHz, 1 H), 7.14 (d, J = 8.7Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.74 (d, J =
8.5Hz, 1 H), 10.22 (s, 1 H); MS (APCI ): 261.9.
4-(4-Isopropyl henylamino}-2-methoxybenzal~Ph, Prepared from N-(4-isopropylphenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide using the procedure described in step C above.
H
Me0 N
\ ~ \
'H NMR (CDCI3) b 1.26 (d, J = 6.9Hz, 6H), 2.88 (m, J = 6.9Hz, 1 H), 3.84 (s, 3H), 6.50 (d, J =
1.9Hz, 1 H), 6.55 (dd, J = 8.6, 1.8Hz, 1 H), 6.96 (s, 1 H), 7.15 (d, 2H, J =
8.5Hz, 2H), 7.22 (d, J
= 8.5Hz, 2H), 7.69 (d, J = 8.5Hz, 1 H), 10.18 (s, 1 H); MS (APCI ): 269.
Step D:
The resulting carbonyl compounds are treated with the corresponding acylhydrazide in a sol-vent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, -butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloro-form, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction sol-vents. The product can also be isolated by concentration of the reaction mixture in vacuo, fol-lowed by column chromatography on silica gel using a solvent system such as chioro-form/methanol or dichloromethane/methanol or chloroform/ethyl acetate to give a compound of formula IXb.
The following compounds of formulae IXa or IXb according to the invention were prepared as examples of compounds that can be prepared using this methodology:
EXAMPLE 1:
3-Chloro-4-hydr~benzoic acid (4-(4-chloro~herJ~rlamin~,l-2-methoxybenzylidene]hydra-zide 'H NMR ( DMSO-D6 ): b 3.81 (s, 3H), 6.72-6.67 (m, 2H), 7.04 (d, J = 8.5Hz, 1 H), 7.17 ( d, J
= 8.7Hz, 2H) 7.31 (d, J = 8.7Hz, 2H), 7.77- 7.70 (m, 2H), 7.96 (d, J = 1.6Hz, 1 H), 8.65 {s, 1 H), 8.70 (s, 1 H), 10.87 (s, 1 H), 11.51 (s, 1 H); MS (APCI ): 430.
EXAMPLE 2:
3-Chloro-4-hxdroxubenzoic acid (~4-isopro~ylphenylamino}-2-methoxybenzylidene]h~
drazide 1 H NMR (DMSO-D6): 8 1.18 (2s, 6H), 2.86 (m, 1 H), 3.79 (s, 3H), 6.65 (m, 2H), 7.03 (d, 1 H), 7.11 (d, 2H), 7.19 (d, 2H), 7.70 (d, 1 H), 7.75 (dd, 1 H), 7.97 (s, 1 H), 8.49 (s, 1 H), 8.64 (s, 1 H}, 10.88 (s, 1 H), 11.48 (s, 1 H); MS {FAB): 438.16.
EXAMPLE 3:
2-~4-f(3-Chloro-4-hvdroxybenzoy)hydrazonomethyl] 3 methoxy~ henoxy} N~4 chloro~~henyl}acetamide cl o / I
o lw H
H
HO
CI
1 H NMR (DMSO-D6): 8 3.66 (s, 3H}, 4.57 (s, 2H), 6.48 (d, 1 H), 6.55 (s, 1 H), 6.83 (d, 1 H), 7.20 (d, 2H), 7.48 (d, 2H), 7.56 (dd, 1 H), 7.58 (d, 1 H), 7.77 (d, 1 H), 8.48 (s, 1 H), 10.05 (s, 1 H), 10.72 (brd s, 1 H}, 11.40 (s, 1 H); MS (APCI): 487.8.
EXAMPLE 4:
2-~4-f(3-Chloro-4.-hydroxybenzoyl~h~rdrazonomethyl]i 3 methoxv h noxy~ N~4 1 H NMR (DMSO-D6): b 1.17 (2 s, 6H), 2.85 (m, 1 H), 3.87 (s, 3H), 4.76 (s, 2H), 6.70 (d, 1 H), 6.76 (d, 1 H), 7.05 (d, 1 H), 7.20 (d, 2H), 7.55 (d, 2H), 7.77 (dd, 1 H), 7.80 (d, 1 H}, 7.98 (s, 1 H), 8.70 (s, 1 H), 10.03 (s, 1 H), 10.92 (s, 1 H), 11.62 (s, 1 H); MS (FAB):
496.16.
~prol~ylpheny)acetamide EXAMPLE 5:
~~4-j(~3-Chloro-4-hydro~cybenzoy~hvdrazonomethyl]-3-methoxyphenox~~3 5-dichlorophenyl)acetamide I
CH~O \ O~N \ CI
O I H
\ Ni ~ /
H
HO
CI
~ H NMR (DMSO-D6): 8 4.06 (s, 3H), 4.94 (s, 2H), 6.8 (d, 1 H), 6.88 (s, 1 H), 7.20 (d, 1 H), 7.45 (s, 1 H), 7.90 (m, 3H), 8.10 (s, 1 H), 8.82 (s, 1 H), 10.62 (s, 1 H), 11.07 (brd s, 1 H), 11.75 (s, 1 H); MS (APCI): 524.8.
General i~rocedure for the synthesis of alkylidene hydrazides of formula fl accordin4 to the 1 o invention:
The acylhydrazides are treated with the corresponding carbonyl compounds, such as aldehy-des or ketones, in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible ~ 5 mixture of two or more of the above solvents. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystal-lized if necessary from a solvent such as the above described reaction solvents. The product 2o can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/-methanol or di-chloromethanelmethanol or chlorofom~/ethy! acetate. The product is isolated by concentration in vacuo of the appropriate fractions. Specific examples illustrating the preparation of com-pounds according to the invention are provided below.
EXAMPLE 6:
3-Chloro-4-hvdroxvbenzoic acid (4-hvdroxy-1-naphth ly methylene)hydr 7id~P
OH
O I
/ .N ~ /
HO
CI
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 7.1 mmol) in DMSO (2 ml) was added 4-hydroxynaphthafdehyde and a catalytic amount of glacial acetic acid (5 drops).
The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine, and dried over MgS04. The or-ganic volume was concentrated in vacuo to give the crude product. The product was purified by silica gel column chromatography using CHzCh/MeOH as the mobile phase.
'H NMR (DMSO-d6): 8 6.89 (d, 2H), 7.02 (d, 1 H), 7.47 (t, 1 H), 7.58 (t, 1 H), 7.66 (d, 1 H), 7.73 (d, 1 H), 7.93 (s, 1 H), 8.17 (d, 1 H), 8.84 (s, 1 H), 8.88 (d, 1 H), 10.73 (s, 1 H), 10.88 (s, 1 H), 11.54 (s, 3 H); MS (ES1): m/z 341.04 (M+H)'.
EXAMPLE 7:
3-chloro-4-hvdroxvbenzoic acid f4-(3 5-bis-trifluoromethvlbenzyloxxl 1 naoht~lmethvl~~nP1 hydrazide F F F
O I ~ O I i F
/ N.N ~ I / F F
H
HO
CI
To a solution of 3-chloTO-4.-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 mL) was added 4-(3,5-bis-trifluoromethylbenzyloxy)-1-naphthaldehyde (440 mg, 1.1 mmol) and a catalytic amount of glacial acetic acid (5 drops). The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicar-bonate, water, brine, and dried over MgS04. The organic volume was concentrated under vacuo to give the crude product. The product was purified by silica gel column chromatogra-phy using CH2Ch/MeOH as the mobile phase.
'H NMR (DMSO-ds): 8 3.77 (s, 6H), 4.91 (s, 2H), 6.95 (s, 2H), 6.99 (d, 1 H), 7.30 (d, 2H), 7.52 (d, 2H), 7.68 (m, 1 H), 7.89 (s, 1 H), 8.29 (s, 1 H), 10.90 (broad s, 1 H), 11.69 (s, 1 H); MS (ESI):
mlz 525.37 (M+H)+.
EXAMPLE 8:
3-chloro-4-hydroxybenzoic acid G4-(2-chloroethox~,-1-naphthv li methylene]hy razid o / I O~CI
\ .Nw \
_H \
HO
A solution of 1-(4-chloroethoxy)naphthaldehyde (2.35 g, 10 mmoles), 3-chloro-4-hydroxy benzoic acid hydrazide (1.87g, 10 mmoles), glacial acetic acid (0.2 mL) and dimethylsulfox-ide (DMSO)(15 mL) was stirred at room temperature overnight. Ethyl acetate (100 mL) was added. The solution was extracted with water and brine which induced precipitation. The product (3.1 g, 77% yield) was obtained by suction filtration. The product was purified by recrystallization from ethyl acetate.
MS (CI): 235. 'H NMR (DMSO-de): 8 11.5 (s, 1 H), 10.7 (s, 1 H), 8.7 (bs, 2H), 8.1 (m, 1 H), 7.8 (s, 1 H), 7.6-7.3 (m, 2H), 7.0 (m, 2H), 4.3 (t, 2H), 3.7 (t, 2H).
2o By application of the above methodology the following compounds of the invention are synthe-sized employing the following general procedure:
To a solution of 1 mmol of an arylcarboxylic acid hydrazide in 2 ml of anhydrous DMSO was added 1 mmol of the carbonyl compound (an aldehyde or ketone), followed by a catalytic amount of glacial acetic acid. The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO,. Upon partial concentration of the solvent in vacuo, the alkyiene hydrazides usually precipitated. The alkylene hydrazides were further purified by recrystafliza-tion from hot ethanol or ethyl acetate, or chromatographed using CHZCh/MeOH as an eluent.
EXAMPLE 9:
4-Hvdroxv-3-methoxybenzoic acid l2-naphtt~lmetf~ylene}hv razi ~P
I
O
.N. I i HO
H3C.0 'H NMR (DMSO-ds) 8 3.66 (s, 3 H), 6.67 (d, J = 8.2 Hz, 1 H), 7.32 - 7.47 (m, 5 H), 7.74 (d, J
= 7.2 Hz, 1 H), 7.79 (d, J = 8.2 Hz, 2 H), 8.60 (d, J = 8.2 Hz, 1 H}, 9.11 (s, 1 H), 11.80 (s, 1 H).
APCI m/z: 321 EXAMPLE 10:
4-Hvdroxv-3-methoxvbenzoic acid l4-methoxy-1-nar~hthylmethylene}hvdra7ide O ~ O
N.N ~ I
H
HO
H3C.0 1H NMR (CDC13): 8 4.80 (s, 3 H), 3.86 (s, 3 H), 6.00 (s, 1 H), 6.59 (d, 1 H), 6.83 (d, 1 H), 7.39 (m, 3 H), 7.52 (s, 1 H), 7.73 (s, 1 H), 8.18 (d, 1 H), 8.58 {d, 1 H), 8.88 (s, 1 H), 9.95 (s,1 H). MS (APCI): 351.
EXAMPLE 11:
4-HydroxX 3-metho~benzoic acid (4-tert-but~rlbenzylidene)hydrazide O
N' N w I / CH3 ~ I 'H
HO
H3C'O
1 H NMR (CDC13): b 1.30 (s, 9 H), 3.91 (s, 3 H), 6.16 (s, 1 H), 6.88 (d, 1 H), 7.23 - 7.78 (m, 6 H), 8.28 (s, 1 H), 9.58 (s, 1 H). MS (APCI): 327.
EXAMPLE 12:
4-Hydroxy-3-methoxvbenzoic acid l4-iso ro~ylbenzylidene)hydrazide O I ~ ~CH3 'N ~ i H
HO
H3C'O
1 H NMR (CDC13) 8 1.29 (d, 6 H), 2.94 (q, 1 H), 3.98 (s, 3 H), 6.13 (s, 1 H), 6.97 (d, 1 H), 7.20 - 7.80 (m, 6 H), 8.29 (s, 1 H), 9.38 (s, 1 H). MS (APCI): 313 EXAMPLE 13:
4-Hvdroxv-3-methoxvbenzoic amid (4-trifluoromethoxvbenzylidene}hydrazide F~F
TO
O
.N ~ ~ /
HO
H3C.0 1 H NMR (DMSO-dg): 8 4.01 (s, 3 H), 7.04 (d, J = 8.1 Hz, 1 H}, 7.60 - 7.65 (m, 4 H), 8.01 (d, J = 8.4 Hz, 2 H), 8.63 (s, 1 H), 9.92 (s, 1 H), 11.89 (s, 1 H). MS (APCI):
355, 313, 222, 205.
EXAMPLE 14:
4-Hvdroxv-3-methoxvbenzoic acid (1 H indol 3 ylmeth I ne hydra id / \
O ' / ,N \ ~ NH
H
HO
H3C.0 1 H NMR (DMSO-dg) b 3.79 (s, 3 H), 6.80 (d, J = 8.2 Hz, 1 H), 7.11 (m, 2 H), 7.38 (m, 3 H), 7.73 (d, J = 2.0 Hz, 1 H), 8.53 (d, J = 7.5 Hz, 1 H), 8.53 (s, 1 H), 9.58 (s, 1 H), 11.23 (s, 1 H), 11.49 (s, 1 H). MS (APCI): 310.
EXAMPLE 15:
4-Hydroxy-3-methoxXbenzoic acid (4-dimethylarnino-1-naph~~ylmethyleneUf ,ydrazide I W CHs O I ~ N.CHs / .N w /
w I _H
HO
H3C.0 1 H NMR (DMSO-d6): 8 3.05 (s, 6 H), 4.03 (s, 3 H), 7.06 (d, J = 8.1 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.63 - 7.80 (m, 4 H), 7.97 (d, J = 8.0 Hz, 1 H), 8.38 (d, J = 7.9 Hz, 1 H), 9.10 (d, J
= 8.4 Hz, 1 H), 9.15 (s, 1 H), 9.90 (s, 1 H), 11.73 (s, 1 H). MS {APCI): 364.
EXAMPLE 16:
4-Hysiro~y-3-methoxvlbenzoic acid~4-phenylbenzylidene)h~rdrazide I
O ~ /
/ .N ~ I /
~I
HO
H3C.0 1 H NMR (DMSO-d6): 8 4.02 (s, 3 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.63 - 7.68 (m, 5 H), 7.88 -7.96 (m, 6 H), 8.64 (s, 1 H), 9.91 (s, 1 H), 11.83 (s, 1 H). MS (APCI): 347.
EXAMPLE 17:
4-Hydroxybenzoic acid (1-nab hit iylmeth~rlene,)t~y ra id W
O
.N ~ I i HO
1 H NMR (DMSO-d6): 8 6.82 (d, J = 8.2 Hz, 2 H), 7.48 - 7.68 (m, 3 H), 7.72 -7.88 (m, 3 H), 7.95 (d, J = 8.2 Hz, 2 H), 8.80 (d, 1 H), 9.04 (s, 1 H), 10.14 (s, 1 H). MS
{APCI): 291.
EXAMPLE 18:
4-Hydroxybenzoic acid~4-methoxy-1-naphthylmet ylene)hy drazid I ~ CH3 O I ~ O
.N ~ r ~ I H
HO
1 H NMR (DMSO-d6): 8 3.97 (s, 3 H), 6.82 (d, J = 8.6 Hz, 2 H), 7.04 (d, J =
8.2 Hz, 1 H), 7.52 (dd, J = 7.3, 7.7 Hz, 1 H), 7.62 (dd, J = 6.8, 7.7 Hz, 1 H}, 7.77 (d, J = 8.5 Hz, 3 H}, 8.19 (d, J
= 8.2 Hz, 1 H), 8.89 (m, 2 H), 10.06 (s, 1 H). MS {APCt): 321.
EXAMPLE 19:
3 4-Dihvdroxvbenzoic acid w(1-na~ht yfme t~ylene)hydrazide O
~ .N ~ I i HO
HO
~ H NMR (DMSO-d6): 8 6.64 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.19 (d, J = 2.0 Hz, 1 H), 7.36 - 7.42 {m, 3 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.80 (d, J = 8.2 Hz, 2 H), 8.65 (d, J =
8.2 Hz, 1 H), 8.88 (s, 1 H), 9.07 (s, 1 H), 9.46 (s, 1 H), 11.45 (s, 1 H). MS
(APCI): 307.
EXAMPLE 20:
4-~iydro~-3-methoxyrbenzoic acid ~1-na~hthyrlmethylene)hyr razide O
.N ~ ~ i HO
H3C.0 ~ H NMR (DMSO-dg) 8 3.94 (s, 3H), 6.74 (d, 1 H), 7.37-7.52 (m, 6H), 7.77 (d, 1 H), 7.89 (d, 2H), 8.67 (d, 1 H), 9.93 (s, 1 H), 10.90 (s, 1 H). MS (APCI): 321.
EXAMPLE 21:
4-Hydroxv-3-methoxvbenzoic a .iri ~~ i~-triffuoromethyl~ no y)benzylidene)ihy r zide F F F
I
O
O I
.N ~ /
HO
H3C.0 1 H NMR (DMSO-d6) 8 3.83 (s, 3H), 6.85 (d, 1 H), 7.16 (dd, 1 H), 7.36 (m, 5H), 7.44 (m, 3H), 7.61 (t, 1 H), 8.43 (s, 1 H), 1.75 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 431.
EXAMPLE 22:
4_-Hvdroxv-3-methoxvbenzoic acid (4~- ~uinoli~ met y ene)~drazide I
O ( ~' N
.N ~ i _H
HO
H3C.0 1 H NMR (DMSO-d6): 8 3.58 (s, 3 H), 6.52 (d, J = 8.0 Hz, 1 H), 7.28 (d, J =
7.8 Hz, 2 H), 7.47 (dd, J = J' = 8.1 Hz, 1 H), 7.59 (m, 2 H), 7.86 (d, J = 8.4 Hz, 1 H), 8.50 (d, J = 8.4 Hz, 1 H), 8.73 (d, J = 4.5 Hz, 1 H), 8.94 (s, 1 H). MS (APCI): 322.
EXAMPLE 23:
4-Hyr is roxybenzoic acid [~(1 1 2 2-tetrafluoroetho~y~be~~ylidene~hvdrazide F\ /F
TXF
O F
O
N.N w I /
H
HO
1 H NMR (DMSO-dg) 8 6.49-6.78 (m, 3H), 7.10 (d, 1 H), 7.32 (t, 1 H), 7.41 (m, 2H), 7.57 (d, 2H), 8.23 (s, 1 H), 10.01 (s, 1 H), 11.59 (s, 1 H). MS (APCI): 357.
EXAMPLE 24:
4-Hydroxybenzoic acid j3-l4-tert-butylr~henyl)but-2-enylidene]hydrazide O
\CH3 N.N ~ ~
HO ~ I H CH3 1 H NMR (DMSO-dg) 8 1.15 (s, 9H), 1.99 (s, 3H), 6.64 (s, 1 H), 6.17 (d, 2H), 7.29 (s, 4H), 7.64 (d, 2H), 8.06 (s, 1 H), 9.98 (s, 1 H), 11.36 (s, 1 H). MS (APCI): 337.
EXAMPLE 25:
4-Hvdroxy-3-methoxybenzoic acid l4-hydroxy-1-nahhthylmethylene}I~ydrazide off o ,N
w HO
H3C.0 1 H NMR (DMSO-d6): 8 3.90 (s, 3 H), 6.89 (d, 1 H), 6.99 (d, 1 H), 7.19 (d, 1 H), 7.45 - 7.80 (m, 5 H), 8.22 (d, 1 H), 8.90 (s, 2 H), 9.62 (s, 1 H), 10.68 (s, 1 H). MS
(APCI): 337.
EXAMPLE 26:
4-Hy roxybenzoic acid (benzylidene~hvdrazide O
.N ~ I ~
HO
1 H NMR (DMSO-d6): b 6.86 (d, 2 H), 7.41 - 7.52 (m, 3 H), 7.72 (m, 2 H), 7.82 (d, 2 H), 8.41 (s, 1 H}, 10.14 (s, 1 H). MS (APCI): 241.
EXAMPLE 27:
3-Amino-4-hydroxybenzoic acid {1-naohth_ytmethv li en_e)~hydrazide O
.N ~ ~ i HO
N HZ
1 H NMR {DMSO-d6): b 4.71 (bs, 2 H), 6.68 (d, J = 8.1 Hz, 1 H), 7.01 (dd, J =
2.0, 8.2 Hz, 1 H),7.17(d,J=2.OHz,1H),7.51-7.62(m,3H), 7.84(d,J=7.2Hz,1H),7.94(d,J=8.0 Hz, 2 H), 8.75 (d, J = 7.6 Hz, 1 H), 9.01 (s, 1 H), 9.70 (s, 1 H), 11.54 (s, 1 H). MS (APCI):
306.
EXAMPLE 28:
3-Amino-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethv li ene)hydrazide O ~ OH
N.N ~ I /
H
HO
NHZ
1 H NMR (DMSO-d6): 8 4.68 (bs, 2 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.91 {d, J =
7.3 Hz, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 7.15 (s, 1 H), 7.43 - 7.65 (m, 3 H), 8.16 (d, J =
8.2 Hz, 1 H), 8.83 (m, 2 H), 10.71 (s, 1 H), 11.34 (s, 1 H). MS (APCI): 322.
EXAMPLE 29:
4-Hvdroxybenzoic acid f3-l3-trifluoromethv I nz I y)b n~ylid neJhydrazide O .N ~ I i F F
H O ~~ ~ F
HO I
1 H NMR (DMSO-d6): 8 5.28 (s, 2 H), 6.88 (d, 2 H}, 7.12 (m, 1 H), 7.24 - 7.50 (m, 3 H), 7.55 - 7.92 (m, 6 H), 8.41 (s, 1 H), 10.16 (s, 1 H), 10.86 (s, 1 H). MS (APCI):
415.
EXAMPLE 30:
3-Chloro-4-hvdroxybenzoic acid (1-naphthylmethyl neLy r ~idP
I
O
.N ~ I i ~I
HO
CI
1 H NMR (DMSO-d6): 8 7.03 (d, J = 8.2 Hz, 1 H), 7.52 - 7.62 (m, 3 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.86 (d, J =7.0 Hz, 1 H), 7.96 (m, 3 H), 8.79 (d, J = 8.2 Hz, 1 H), 9.01 (s, 1 H), 10.94 (s, 1 H), 11.76 (s, 1 H). MS (APCI): 325.
EXAMPLE 31:
3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)t~ydrazide i~
O ~ OH
/ .N ~ I /
HO
CI
1 H NMR (DMSO-d6): 8 6.90 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.50 (dd, J = J' _ 7.8 Hz, 1 H), 7.58 (dd, J = 7.1, 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.93 (s, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J =8.5 Hz, 1 H), 10.73 (s, 1 H), 10.88 (s, 1 H), 11.54 (s, 1 H). MS (APCI): 343, 341.
EXAMPLE 32:
4-H~rdroxybenzoic acid~4-hydroxy-1-naJZylmethylene)hydrazide O ~ OH
/ .N
HO
1 H NMR (DMSO-d6): 8 6.88 (d, 2 H), 6.98 (d, 1 H), 7.55 (dd, 1 H), 7.64 (dd, 1 H), 7.71 (d, 1 H), 7.82 (d, 2 H), 8.22 (d, 1 H), 8.94 (m, 2 H), 10.11 (s, 1 H), 10.77 (s, 1 H). MS (APCI):
307.
EXAMPLE 33:
4-Hydroxybenzoic acid (4 (3-trifluoromethyll henoxv)benzylid~Pn~]hvdrazide F F
O ~ O i F
i .N~ I ~ ~ I
HO
1 H NMR (DMSO-d6): 8 6.81 (d, 2 H), 6.98 (d, 1 H), 7.13 (dd, 1 H), 7.30 - 7.48 (m, 3 H), 7.48 - 7.60 (m, 3 H), 7.68 (dd, 1 H), 7.81 (d, 2 H), 8.41 (s, 1 H). MS (APCI): 401.
EXAMPLE 34:
4-Hvdroxybenzoic acid (5-phenyl-3-Ryrazo~rlmethylene)~hydrazide O HN-N
.N
HO
1 H NMR (DMSO-d6): 8 6.81 (d, 2 H), 7.40 - 7.62 (m, 5 H), 7.78 (d, 2 H), 8.09 (s, 1 H), 8.50 (s, 1 H). MS (APCI): 307.
EXAMPLE 35:
2 4-Dihydroxybenzoic acid l4-hydroxy-1-na~h~rlmethKlene)hydrazide I
O ~ OH
N.N ~ I /
H
HO ~ OH
1 H NMR (DMSO-d6): 6.35 (s, 1 H), 6.39 (d, 1 H), 6.99 (d, 1 H), 7.51 (dd, 1 H), 7.65 (dd, 1 H), 7.73 (d, 1 H), 7.82 (d, 1 H), 8.26 (d, 1 H), 8.88 (s, 1 H}, 8.98 (d, 1 H), 10.0 - 11.0 (m, 4 H). MS (APCI): 323.
EXAMPLE 36:
4-Hydroxy-3-nitrobenzoic acid l1-nap~hyimethylen~hvdrazide I
O
N.N ~ I /
H
HO
_,N ~
O ~O
1 H NMR (DMSO-d6): 8 6.15 (d, J = 9.3 Hz, 1 H), 7.37 - 7.48 (m, 4 H), 6.70 (d, J = 7.1 Hz, 1 H), 7.78 - 7.82 (m, 2 H), 8.29 (s, 1 H), 8.43 (d, J = 8.5 Hz, 1 H), 8.85 (s, 1 H).
EXAMPLE 37:
4-H.ydrox~3-nitrobenzoic acid l4-h~rdrox~r-1-na~hthylmeth I~~hydrazide I ~ off N.N ~
H
HO \
O_.N~~O
1 H NMR (DMSO-d6): b 6.24 (d, J = 9.3 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 7.37 -7.52 (m, 3 H), 7.57 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 8.34 (s, 1 H), 8.76 (s, 1 H), 8.79 (s, 1 H), 10.57 (s, 1 H), 11.17 (m, 1 H).
EXAMPLE 38:
3 4-DihydroxKbenzoic acid (4-hydroxv -r 1na~hthylmethylene)hydrazide I ~ OH
O I
.N ~ i w I _H
HO
HO
1 H NMR (DMSO-d6): 8 6.86 (d, 1 H), 6.98 (d, 1 H), 7.32 (d, 1 H), 7.42 (s, 1 H), 7.56 (dd, 1 H), 7.63 (dd, 1 H}, 7.71 (d, 1 H), 8.24 (d, 1 H), 8.88 (s, 1 H), 8.92 (m, 2 H), 9.26 (s, 1 H), 9.54 (s, 1 H), 10.75 (s, 1 H). MS (APCI): 323.
EXAMPLE 39:
4-Hydroxybenzoic acid (6-methox~r-2-naohthylmethylene)hydrazid~P
I ~ O
O
N.N w I /
~ l H
HO
1 H NMR (DMSO-d6): b 3.89 (s, 3 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.22 (dd, J =
2.3, 8.9 Hz, 1 H), 7.37 (d, J = 2.3 Hz, 1 H), 7.80 - 7.93 (m, 6 H), 8.04 (s, 1 H), 8.53 (s, 1 H), 11.67 (s, 1 H}.
MS (APCI): 321.
EXAMPLE 40:
3 5-Dichloro-4-hvdroxvbenzoic acid (4-hydroxy 1 naphthylmethyleneLydr z' O ~ OH
CI / ".N w HO
CI
1 H NMR (DMSO-d6): 8 6.98 (d, 1 H), 7.58 (dd, 1 H), 7.68 (dd, 1 H), 7.78 (d, 1 H), 8.02 (s, 2 H), 8.27 (d, 1 H), 8.90 (s, 1 H), 8.96 (d, 1 H), 10.81 (s, 1 H), 10.98 (s, 1 H), 11.67 (s, 1 H).
MS (APCI): 375, 377.
EXAMPLE 41:
6-Hvdroxy-2-naphthoic acid~4-hydroxy 1 na~hthylmethylene~~_hydrazide O ~ OH
N.N w HO ~ ~ hiI
1 H NMR (DMSO-d6): 8 6.04 (d, 2 H), 6.33 (m, 1 H), 6.62 (dd, 2 H), 6.79 (dd, 2 H), 7.06 (d, 2 H), 7.44 (d, 2 H), 8.27 (d, 2 H), 8.39 (s, 2 H).
EXAMPLE 42:
4H~droxv-3-methoxvbenzoic acid l9-ethyl-9H-3-carha~o~,Imetflylene)hydrazide / \
N
O .N ~ ~ ~ CH3 HO
H3C_O
'H NMR (DMSO-dB) S 1.34 (t, J = 7.0 Hz, 3 H), 3.88 (s, 3 H), 4.47 (q, J = 7.0 Hz, 2 H), 6.90 (d, J = 8.0 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.47 - 7.54 (m, 3 H), 7.64 (d, J = 8.2 Hz, 1 H}, 7.69 (d, J = 8.5 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 8.24 (d, J = 7.7 Hz, 1 H), 8.45 (s, 1 H), 8.62 (s, 1 H) 9.62 (s, 1 H), 11.51 (s, 1 H). MS (APCI): 388.
EXAMPLE 43:
4-H ox - -meth x b n of id - 3- hl r n I - -furan (meth I n h r CI
O
i H~N \ O
HO
H3C.0 1 H NMR (DMSO-d6): ~ 3.93 (s, 3 H), 6.97 (d, J = 8.2 Hz, 1 H), 7.14 (d, J =
3.5 Hz, 1 H), 7.37 (d, J = 3.5 Hz, 1 H), 7.48 - 7.63 (m, 4 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.93 (s, 1 H), 8.47 (s, 1 H), 9.85 (s, 1 H), 11.75 (s, 1 H). MS (APCI): 371.
EXAMPLE 44:
3-Chloro-4-hvdroxybenzoic acid~~~~~lallylidene)hydr i O I
.N ~ ~ i HO
CI
1 H NMR (DMSO-d6): 8 7.00 (m, 3 H), 7.22 - 7.40 (m, 3 H), 7.57 (d, 2 H), 7.69 (d, 1 H), 7.89 (s, 1 H), 8.12 (d, 1 H), 11.0 (s, 1 H), 12.0 (s, 1 H). MS (APCI}: 301.
EXAMPLE 45:
3-Chloro-4-hvdroxvbenzoic acid l4-allyhx_y 1 na~ht I"~methylene)hydrazide O I ~ O~CH
/ .N ~ I /
HO
CI
1 H NMR (DMSO-d6): 8 4.68 (m, 2 H), 5.21 (d, 1 H), 5.38 (d, 1 H), 5.90 -6.10 (m, 1 H), 6.86 (dd, 2 H), 7.42 (dd, 1 H), 7.53 (dd, 1 H), 7.67 (dd, 2 H), 7.86 (s, 1 H), 8.18 (d, 1 H), 8.78 (s, 1 H), 8.82 (d, 1 H), 10.9 (s, 1 H), 12.0 (s, 1 H). MS (APCI): 381.
EXAMPLE 46:
3-Chloro-4-hydroxybenzoic acid l4-ethynylmethoxy-1-na~hthylmeth~riene)hydrazide O
O
/ N.N ~
H
HO \
CI
1 H NMR (DMSO-d6): 8 3.60 (s, 1 H), 5.06 (s, 2 H), 6.99 (d, 1 H), 7.12 (d, 1 H), 7.55 (t, 1 H), 7.66 (t, 1 H), 7.73 (t, 1 H), 7.93 (s, 1 H), 8.02 (d, 1 H), 8.16 (t, 1 H), 8.86 (d, 1 H), 9.27 (d, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 378.
EXAMPLE 47:
3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-1-naphthylmethvlenP,~ hvdrazide O I /
O .N ~ ~ /
HO \
CI
1 H NMR (DMSO-d6): 8 5.40 (s, 2 H), 7.08 (d, 1 H), 7.08 (s, 1 H), 7.39 (d, 1 H), 7.43 (m, 3 H), 7.70 (m, 5 H), 8.00 (s, 1 H), 8.01 (d, 1 H), 8.33 (t, 1 H), 8.94 (d, 1 H), 9.35 (d, 1 H), 10.98 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 431, 433.
EXAMPLE 48:
~-(4-f(3-Chloro-4-hvdroxybenzoyl)hydrazonomethyl] 1 naphthylox~~acPtamiclg I \ O
O I \ O~NHz / .N ~ /
\
HO
CI
1 H NMR (DMSO-d6): 8 4.68 (d, 2 H), 6.94 (d, 1 H), 6.98 (dd, 1 H), 7.40 - 7.86 (m, 5 H), 8.00 (m, 1 H), 8.48 (dd, 1 H), 8.93 (m, 1 H), 9.38 (m, 1 H). MS (APCI): 398.
EXAMPLE 49:
3-Chloro-4-hydroxubenzoic acid (4-methyl-1-naphthv Ir methyl neLydrazide I ~ CH3 O I
.N ~ /
HO
CI
1 H NMR (DMSO-d6): 8 2.70 (s, 3 H), 7.10 (d, 1 H}, 7.49 (d, 1 H), 7.67 (m, 2 H), 7.81 (m, 2 H), 8.00 (s, 1 H), 8.11 (d, 1 H), 8.88 (d, 1 H), 9.07 (s, 1 H), 11.0 (s, 1 H).
MS (APCI): 339, 341.
EXAMPLE 50:
3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1-na~hthylmethyiene)hXdrazide O
/ .N ~ I /
HO ~ I ~ OH
CI
1 H NMR (DMSO-d6): 8 6.98 (d, 1 H), 7.98 (d, 1 H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.69 {d, 1 H), 7.78 (dd, 2 H), 7.90 (s, 1 H), 8.06 (d, 1 H), 9.32 (s, 1 H), 11.00 (s, 1 H). MS (APCI):
341.
EXAMPLE 51:
3-Chloro-4-hydroxybenzoic acid {4-metho~y-1 naphthylmethyfene)hy razide I
O I ~ O.CH3 .N ~ /
w HO
CI
1 H NMR (DMSO-d6): b 4.05 (s, 3 H), 7.06 (m, 2 H), 7.59 (dd, 1 H), 7.70 (dd, 1 H), 7.81 (d, 1 H), 7.86 (d, 1 H), 8.00 (s, 1 H), 8.27 (d, 1 H), 8.93 (s, 1 H), 8.99 (d, 1 H), 11.00 (s, 1 H). MS
(APCI): 341, 339.
EXAMPLE 52:
~2-[(3-Chloro-4 hydroxybenzoyl)hydra~on2]ethyl) 2 2 di henylacet~imide 0 o I
I ~.N~~ /
HO
CI I
~ H NMR (DMSO-d6) 8 3.85 (t, 2 H), 4.93 (s, 2 H), 7.16 - 7.25 (m, 10 H), 7.26 (m, 1 H), 7.62 (d, 1 H), 7.82 (s, 1 H), 8.89 (t, 1 H), 10.85 (s, 1 H), 11.39 (s, 1 H). MS
(APCf): 422 EXAMPLE 53:
3-Chloro-4-hvdroxvbenzoic acid l1-h dro y-2-nahhthylmeth feneZh~drazide o Ho I
,N ' ~I
HO
CI
1 H NMR (DMSO-d6): b 6.99 (d, 1 H), 7.22 (d, 1 H), 7.37 -7.56 (m, 4 H), 7.68 (dd, 1 H), 7.77 (d, 1 H), 7.90 (s, 1 H), 8.19 (d, 1 H), 8.58 (s, 1 H), 11.00 (s, 1 H). MS
(APCI): 341.
EXAMPLE 54:
3-Chloro-4-hydroxybenzoic acid (2 2-di henylethvlidene~vdrazide i I
O
i 'N ' i Ho ~ I ~ ~
CI
1 H NMR {DMSO-d6): s 4.94 (d, 1 H), 6.98 (d, 1 H), 7.11 - 7.22 (m, 5 H), 7.22 -7.34 (m, 4 H), 7.68 (d, 1 H), 7.82 (s, 1 H), 8.19 (d, 1 H), 11.00 (s, 1 H). MS (APCI): 365, 367.
EXAMPLE 55:
3-Chloro-4-hydroxybenzoic acid l4-benzyloxy-3 5-dimethoxvbenzylidene)h~idrazide H3C.0 O
O
.N ~ I i O.CH3 HO
CI
1 H NMR (DMSO-d6): 8 3.86 (s, 6 H), 4.98 (s, 2 H), 7.03 (s, 2 H), 7.09 (d, 1 H), 7.25 - 7.33 (m, 3 H), 7.48 (m, 2 H), 7.89 (dd, 1 H), 7.99 (s, 1 H), 8.32 (s, 1 H), 11.00 (s, 1 H). MS
(APCI): 441.
EXAMPLE 56:
3-Chloro-4-hydroxybPnzioc did,j3-{4-tert-butvlahenoxy)benzylidene~hvdrazide l w ~cH3 N.N ~
l H
HO \
CI
1 H NMR (DMSO-d6): 8 1.05 (s, 9 H), 6.90 (m, 3 H), 7.09 (d, 1 H), 7.30 (t, 1 H), 7.40 (m, 3 H), 7.69 (m, 2 H), 7.88 {s, 1 H), 8.44 (s, 1 H), 10.60 (s, 1 H), 11.55 (s, 1 H). MS (APCI): 423.
EXAMPLE 57:
3-Chloro-4-hydroxybenzoic acid l4-methyl-1-nar~hthylmeth~ene)hydrazide O
N.N
H
HO
CI
1 H NMR (DMSO-d6): 8 2.64 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.41 (d, J =
7.4 Hz, 1 H), 7.58 (m, 2 H}, 7.78 (m, 2 H}, 7.95 (d, J = 2.0 Hz, 1 H), 8.06 (dd, J = 2.0, 8.0 Hz, 1 H), 8.82 (d, J =
8.0 Hz, 1 H), 9.07 (s, 1 H}, 10.93 (s, 1 H), 11.71 (s, 1 H). MS (APCI): 337.
339.
EXAMPLE 58:
3- r -4- r x nz is ci 3- -4- r -1- a th im h I n r i I
o I ~ off .N ~ ~ gr HO
CI
1 H NMR (CDC13): 8 7.02 (d, J = 8.5 Hz, 1 H), 7.51 - 7.62 (m, 4 H), 7.80 (dd, J = 2.0, 8.5 Hz, 1 H), 8.00 (d, J = 2.0 Hz, 1 H), 8.21 (s, 1 H), 8.59 (d, J = 8.5 Hz, 1 H), 8.91 (s, 1 H). MS
(APCi): 421, 423.
EXAMPLE 59:
Acetic acid 4-f(3-Chioro-4-hydroxybenzoyiLydrazonomethyl] 1 naphthyl ester I
O ~ O~CH3 N.N ~ I i IIO
H
HO
CI
1 H NMR (DMSO-d6): 8 2.63 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.36 (d, J =
8.0 Hz, 1 H), 7.60 (dd, J = 7.0, 7.5 Hz, 1 H), 7.68 (dd, J = 7.0, 8.0 Hz, 1 H), 7.75 (dd, J
= 1.4, 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 8.85 (d, J = 8.5 Hz, 1 H), 9.08 (s, 1 H), 11.0 (s, 1 H), 11.78 (s, 1 H). MS (APCI): 383.
EXAMPLE 60:
3-Chloro-4-hydroxybenzoic acid (4-cyanomethoxv-1-na~hthylmethv li eneLydrazi~g I o~N
.N. I i ~I
HO
CI
1 H NMR (DMSO-d6): 8 5.40 {s, 2 H), 7.00 (d, 1 H), 7.21 (d, 1 H), 7.58 - 7.80 (m, 3 H), 7.82 (d, 1 H), 7.96 (s, 1 H), 8.18 (d, 1 H), 8.90 (s, 2 H), 9.28 (s, 1 H), 11.62 (s, 1 H). MS (APCI):
380, 382.
EXAMPLE 61:
3-Chloro-4-hydroxybenzoic acid (2-hydroxv-. 1-nar~hthylmethvlene)~hydrazide I
O
.N ~ ~ i HO ~ I ~ OH
CI
1 H NMR (DMSO-d6): b 7.18 (d, 1 H), 7.30 (d, 1 H), 7.50 (dd, 1 H), 7.68 (dd, 1 H), 7.88 (d, 1 H), 7.95 (m, 2 H), 8.08 (s, 1 H), 8.29 {d, 1 H), 9.51 (s, 1 H), 11.12 (s, 1 H), 12.12 (s, 1 H).
MS (APCI): 341, 343.
EXAMPLE 62:
~Chloro-4-hvdroxvbenzoic aci i~{2 3-met ylenedioxvbenz~~idene~vdrazide ~--O
O
O
.N~ I i w I _ HO
CI
1 H NMR (DMSO-d6): 8 6.06 (s, 2 H), 6.86 (dd, 1 H), 6.90 (dd, 1 H), 7.01 (d, 1 H), 7.25 {d, 1 H), 7.71 (dd, 1 H), 7.92 (s, 1 H), 8.49 (s, 1 H), 10.93 (s, 1 H), 11.70 (s, 1 H). MS (APCI):
319, 321.
EXAMPLE 63:
3-Chloro-4-hvdroxvbenzoic acid [~4-metho enoxy) Pnzyfidene]hydr- a~idg O ~ ~ ~ ~ O
,N ~ i O
HO
CI
1 H NMR (DMSO-d6}: b 3.98 (s, 3 H), 7.38 (m, 6 H), 7.48 (s, 1 H}, 7.72 (m, 2 H), 7.97 (d, 1 H), 8.19 (s, 1 H), 8.64 (s, 1 H), 11.93 (s, 1 H). MS (APCI): 397, 399.
EXAMPLE 64:
3-Chloro-4-hvdroxybenzoic acid l9-Qhenanthrenylmethylene}h drazidg O
N.N ~ w ~ i H~
HO
CI
1 H NMR (DMSO-d6): 8 7.02 (d, 1 H), 7.52 - 7.83 (rn, 5 H), 7.99 (d, 1 H), 8.08 (d, 1 H), 8.21 (s, 1 H), 8.82 (d, 1 H), 8.89 (dd, 1 H), 8.96 (dd, 1 H), 9.06 (s, 1 H), 10.96 (s, 1 H), 11.82 (s, 1 H). MS (APCI): 375, 377.
EXAMPLE 65:
3-Chloro-4-hvdroxvbenzoic acid [4-(2~y roxyethoxy) 1 na~hthylmethylene]hvdrazide O I ~ OOH
/ .N ~ /
~I
HO
Ci 1 H NMR (DMSO-d6): 8 3.81 (t, J = 4.8 Hz, 2 H), 4.16 (t, J = 4.8 Hz, 2 H), 6.46 (d, J = 8.5 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 1 H), 7.51 - 7.61 (m, 3 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.82 (d, J = 2.1 Hz, 1 H), 8.30 (d, J = 8.2 Hz, 1 H), 8.85 (s, 1 H), 8.87 (d, J = 8.5 Hz, 1 H), 11.38 (s, 1 H).
MS (APCI): 385, 387.
EXAMPLE 66:
3-Bromo-4-hydroxvbenzoic acid (4-h~rdroxy-1-na~htE~lmethvlene)hXdr zid O ~ OH
.N, I /
HO
1 H NMR (DMSO-d6): 8 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = J' _ 8.0 Hz, 1 H), 7.58 (dd, J = J " = 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.77 (dd, J = 2.0, 8.0 Hz, 1 H), 8.08 (d, J = 2.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J = 8.0 Hz, 1 H), 10.73 (s, 1 H}, 11.53 (s, 1 H). MS (APCI): 385, 387.
EXAMPLE 67:
Nicotinic acid 4-[(3-chloro-4-hydro~rbenzok~hvdrazonomethyl] 1 naphthyl ester w y o I ~ o I ~N
/ N.N ~ I / O
H
HO
CI
1 H NMR (DMSO-d6): 8 7.04 (d, J = 8.5 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.64 - 7.69 (m, 4 H), 7.74 - 8.02 (m, 3 H), 8.56 (dd, J = 2.0, 8.0 Hz, 1 H), 8.91 (m, 2 H), 9.05 (s, 1 H), 8.35 (d, J = 1.8 Hz, 1 H), 10.96 (s, 1 H), 11.84 (s, 1 H). MS (APCI): 446, 448.
EXAMPLE 68:
3-Chloro-4-hvdroxvbenzoic acid f4-l1 3-dioxo 1 3 dihydroisoindol 2ylmethoxy) 1 na .~hth~rl metf~lene]hydrazide O
O W O~N
.N ~ I / O
HO
1p CI
~ H NMR (DMSO-d6): 8 5.78 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.37 (d, J =
8.2 Hz, 1 H), 7.48 (m, 1 H), 7.61 (m, 1 H), 7.73 - 7.81 (m, 8 H), 8.90 {m, 2 H}, 10.91 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 500, 502.
EXAMPLE 69:
h ro-4-h rox n i 'd 4- I x f -1- hth Im h I n h dr O ~ ~ O
.N ~ /
HO
CI
1 H NMR (DMSO-d6): 8 1.08 - 1.19 (m, 4 H), 1.66 - 1.72 (m, 3 H), 1.83 - 1.92 (m, 3 H), 3.21 (m, 1 H), 3.95 (m, 2 H), 6.99 (d, J = 8.1 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.53 (dd, J = J' = 7.4 Hz, 1 H), 7.62 (dd, J = J ' = 7.5 Hz, 1 H), 7.72 -7.93 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.22 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.94 (s, 1 H), 11.60 (s, 1 H). MS (APCI): 437, 439.
EXAMPLE 70:
3-Chloro-4-hydroxybenzoic acid [4-~(tetrahydro-2-pyranylmethoxy}-1-naphthylmethyienP,~
hydrazide O I ~ O O
.N ~ i HO
C!
1 H NMR {DMSO-d6): b 1.35 (m, 3 H), 1.60 - 1.71 (m, 2 H), 3.15 - 3.38 (m, 2 H), 3.64 (m, 1 H), 3.78 (m, 1 H), 4.02 (m, 2 H), 6.94 (d, J = 8.5 Hz, 2 H), 7.46 (dd, J = J' = 7.4 Hz, 1 H), 7.54 (dd, J = J ' = 8.2 Hz, 1 H), 7.66 (m, 2 H), 7.86 (d, J = 2.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.78 (s, 1 H), 8.83 (d, J = 8.5 Hz, 1 H), 10.83 (s, 1 H), 11.52 (s, 1 H).
MS (APCI): 439, 441.
EXAMPLE 71:
3-Chloro-4-hydroxybenzoic acid [4-(3-yrridylmethoxy)-1-naphthylmethylene]hydrazide ~ o ~ ~N
.N
HO
1 H NMR (DMSO-d6): 8 5.28 (m, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 7.10 (d, J =
8.5 Hz, 1 H), 7.34 (dd, J = 4.8, 7.8 Hz, 1 H), 7.45 (dd, J = J' = 7.6 Hz, 1 H), 7.54 (dd, J
= J ' = 7.5 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 7.86 (m, 2 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.45 (dd, J =1.5, 4.8 Hz, 1 H), 8.65 (s, 1 H), 8.81 (m, 2 H), 10.90 (s, 1 H), 11.56 (s, 1 H). MS
(APCI): 432, 434.
EXAMPLE 72:
4- h r -4-h ro nzo f h r om t I -1-na hth lox c ti a i et I r O
O I w O~O~CHs .N ~ /
I
HO
CI
1 H NMR (DMSO-d6): 8 1.25 (t, J = 7.0 Hz, 3 H), 4.25 (q, J = 7.0 Hz, 2 H), 5.11 (s, 2 H}, 7.06 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.64 -7.70 (m, 2 H), 7.76 (d, J = 8.2 Hz, 2 H), 8.04 (d, J = 2.1 Hz, 1 H), 8.36 (d, J = 8.2 Hz, 1 H), 8.97 (s, 1 H), 9.02 (d, J = 8.5 Hz, 1 H), 11.01 (s, 1 H}, 11.74 (s, 1 H). MS (APCI): 427, 429.
EXAMPLE 73:
3-Chloro-4-hydroxybenzoic acid~3-nitrobenzylidene)hydrazide Ov .~O_ N
O
/ N.N ~ ( /
H
HO
CI
1 H NMR (DMSO-d6): 8 7.13 (d, J = 8.5 Hz, 1 H), 7.79 -7.86 (m, 2 H), 8.03 (d, J = 2.1 Hz, 1 H), 8.18 (d, J = 7.5 Hz, 1 H}, 8.30 (d, J = 8.0 Hz, 1 H), 8.58 (s, 2 H), 11.08 (s, 1 H), 12.05 (s, 1 H). MS (APCI): 320, 322.
EXAMPLE 74:
3-Chloro-4-hydroxvbenzoic acid (2 4-dichlorobenzv lidene)hydrazide O CI ~ CI
.N
w I _H
HO
CI
1 H NMR (DMSO-d6): 8 7.02 (d, J = 8.5 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.66 (s, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.95 (m, 2 H), 8.71 (s, 1 H), 11.97 (s, 1 H), 11.94 (s, 1 H). MS
(APCI):345.
EXAMPLE 75:
3-Chloro-4-hydroxybenzoic acid l4-fluoro-1-nar~hthylmethylene)hydrazide O ~ F
.N ~ ( /
HO
CI
1 H NMR (DMSO-d6): 8 7.00 (d, J = 8.5 Hz, 1 H), 7.33 (dd, J = 8.2, 10.3 Hz, 1 H), 7.62 - 7.72 (m, 3 H), 7.82 (m, 1 H), 7.91 (d, J = 1.9 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 8.09 (m, 1 H), 8.91 (s, 1 H), 10.81 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 343.
EXAMPLE 76:
0-4- i -h ht t I h I
O ~ OH
.N ~ I i HO
F
1 H NMR (DMSO-d6): b 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (t, J = 8.6 Hz, 1 H), 7.44 - 7.72 (m, 6 H), 8.17 (d, J = 8.6 Hz, 1 H), 8.84 (s, 1 H), 8.89 (d, J = 8.5 Hz, 1 H), 10.60 {s, 1 H), 11.50 (s, 1 H). MS (APCI): 325.
EXAMPLE 77:
3-Chl ro-4-h rox 'c id 4- 2 4-difl or en I -1-n th Im t I ne h dr i w F I w F
.N w I i I
HO
CI
1 H NMR (DMSO-d6): 8 5.33 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (m, 1 H), 7.21 (d, J = 8.2 Hz, 1 H), 7.31 (m, 1 H), 7.52 (m, 1 H), 7.54 (m, 9 H}, 7.69 - 7.80 (m, 3 H), 7.94 (s, 1 H), 8.16 (d, J = 8.2 Hz, 1 H), 8.90 (m, 2 H), 10.91 (s, 1 H}, 11.63 (s, 1 H). MS
(APCI): 467, 469.
EXAMPLE 78:
3-Fluoro-4-hydroxybenzoic acid (1-nahhthylmethv ne)hydrazide I
o I w _N ~ i ~I
HO
1~ F
MS (APCI): 309.
EXAMPLE 79:
I r -4-h r of 4- -m h x ben x -1-n hth I th I n h r O I ~ O I i .CH3 O
I~
HO
CI
1 H NMR (DMSO-d6): b 3.71 (s, 3 H), 5.29 (s, 2 H), 6.87 (d, J = 8.5 Hz, 1 H), 7.00 - 7.14 (m, 4 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.55 (m, 1 H), 7.68 (m, 1 H), 7.75 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 11.00 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461.
EXAMPLE 80:
r -4- r i i 4- 4-fl r I -n ht I th I n a i I
o~
N.N ~ I
H
HO
CI
1 H NMR (DMSO-d6): 8 5.30 (s, 2 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.13 - 7.25 (m, 3 H), 7.53 7.60 (m, 4 H), 7.79 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 449, 451.
EXAMPLE 81:
3- hl r -4- r 'c i 4- -t tr r f r I th -1- a hth Im th h_ydrazide I
o ~ O
i .N. I i w I
HO
C!
1 H NMR (DMSO-d6): b 1.77 - 2.04 (m, 4 H), 3.68 (m, 1 H), 3.78 (m, 1 H), 4.12 -4.16 (m, 2 H), 4.26 (m, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.53 (m, 1 H), 7.62 (m, 1 H), 7.74 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.61 (s, 1 H). MS (APCI): 425, 427.
EXAMPLE 82:
3-Chloro-4-hvdroxvbenzoic acid l3-bromo-4-methox -1-na hit yfmeth~ene~h_ydrazide O ~ w O.CHs H.N ~ ~ gr HO \
CI
1 H NMR (DMSO-d6): 8 3.91 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.65 - 7.76 (m, 3 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.02 {s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.71 (d, J = 8.0 Hz, 1 H), 8.95 (s, 1 H), 10.96 (s, 1 H), 11.85 {s, 1 H). MS (APCI): 433, 435.
EXAMPLE 83:
~Chloro-4-hydroxvbenzoic acid (4-(3-tetrahydrofuranylmetho -1-na~ht~lmethylenel h~rdrazide o ~o N.N w H
HO
CI
1 H NMR (DMSO-d6): 8 1.92 (m, 1 H), 2.10 (m, 1 H), 2.77 (m, 1 H), 3.28 - 3.88 (m, 4 H), 4.12 (m, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.55 (m, 1 H), 7.62 (m, 1 H), 7.74 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.94 {d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.88 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI):
425, 427.
EXAMPLE 84:
4~4-[3-Chloro-4-hydroxvbenzoyl)hydrazonomethyl)-1-naphth~loxymet~rllbenzoic acid methyl ester O
O I ~ O I / CH3 / ~.Nw HO
CI
1 H NMR (DMSO-d6): 8 3.80 (s, 3 H), 5.43 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 7.54 (m, 1 H), 7.57 (d, J = 8.0 Hz, 4 H), 7.93 - 7.99 (m, 3 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H).
MS (APCI): 489, 491.
EXAMPLE 85:
3-Chloro-4-hydroxybenzoic acid [3.5-dimethoxy-4-{4-trifluoromethoxybenzyloxy)benzyi-dene]hydrazide H3C.0 ~ O F
O ~ / ~F
/ N.N ~ I / O.CH3 H( HO
CI
1 H NMR (DMSO-d6): 8 3.76 (s, 6 H), 4.91 (s, 2 H), 6.95 - 7.00 (m, 3 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 2.0, 8.5 Hz, 1 H), 7.88 (s, 1 H), 8.29 (s, 1 H), 10.91 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 525, 527.
EXAMPLE 86:
3-Chloro-4-hydroxybenzoic acid [4-{4-trifluoromethoxybenzytoxy)-1-naphthylmethylene]-h_ydrazide O\ /F
O I ~ O I ~ F~ F
I ~.N .
HO \
CI
1 H NMR (DMSO-d6): b 5.36 (s, 2 H), 7.02 (d, J = 8.4 Hz, 1 H), 7.14 {d, J =
8.2 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 2 H), 7.56 (m, 1 H), 7.62 (m, 3 H), 7.76 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.26 (d, J = 8.3 Hz, 1 H), 8.88 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 515, 517.
EXAMPLE 87:
3-Chloro-4-hvdroxvbenzoic acid j4-(2-methoxvbenzyloxy) 1 na~ht_hylmethylene]h_ razide Iw Iw o ~ o ~N ~ I ~ o~CH
I
HO
CI
1 H NMR (DMSO-d6}: 8 3.79 (s, 3 H), 5.27 {s, 2 H), 6.95 (m, 1 H), 7.03 (d, J =
8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.31 {m, 1 H}, 7.46 -7.53 (m, 2 H), 7.61 (m, 1 H), 7.76 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.22 (d, J = 8.3 Hz, 1 H}, 8.88 (s, 1 H}, 8.92 (d, J = 8.5 Hz, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461, 463.
EXAMPLE 88:
3-Chforo-4-hydroxybenzoic acid [4-(2-fluorobenzvlo~l-1 napht~lmethyiene]hydrazide o ~ o ".N w ~ / F
I
HO
Ci 1 H NMR (DMSO-d6): 8 5.36 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.19 - 7.28 (m, 3 H), 7.39 (m, 1 .H), 7.53 (m, 1 H), 7.63 (m, 2 H), 7.72 - 7.80 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.19 (d, J =
8.3 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.90 {s, 1 H), 11.64 (s, 1 H). MS
(APCI): 449, 451.
EXAMPLE 89:
hl -4- dr x i 4- 'fl r b -1- ht Imeth n h r F I w O ~ O i .N ~ I / F
HO
CI
1 H NMR (DMSO-d6): 8 5.34 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.16 (d, J =
8.2 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.51 (m, 2 H), 7.72 (m, 1 H), 7.74 (d, J =
8.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.03 (d, J
= 8.3 Hz, 1 H), 8.89 (s, 1 H), 8.91 (d, J = 8.5 Hz, 1 H), 10.97 {s, 1 H), 11.65 (s, 1 H). MS
(APCI): 467, 469.
EXAMPLE 90:
4- x - t x n 'd - im -4- m t 7 r -na h!~ th-1-ylm~thoxy,~benzylidene)hy~lrazide 1 H NMR (DMSO-d6): 8 1.2 (s, 12H), 1.63 (s, 4H), 3.82 (s, 6H), 3.85 (s, 3H), 4.90 (s, 2H), 6.88 (d, 1 H), 7.01 (s, 2H), 7.18 (d, 1 H), 7.29 (d, 1 H), 7.38 (s, 1 H), 7.44 (d, 1 H), 7.48 (s, 1 H), 8.40 (brd s, 1 H), 11.62 (s 1 H); MS (APCI): 547.1.
EXAMPLE 91:
3-Fluoro-4-by dr ro -xybenzoic acid [4-~(4-iso~ro~ylben~~rlo~cy)-3 5 dimetho~ybenzylidene],~,~
drazide 1 H NMR (DMSO-d6): 8 1.05 (d, 6H), 2.67 (m, 1 H), 3.61 (s, 6H}, 4.69 (s, 2H), 6.79 (s, 2H), 6.86 (t, 1 H), 7.01 (d, 2H), 7.24 (d, 1 H), 7.44 (dd, 1 H), 7.51 (d, 1 H), 8.10 (brd s, 1 H), 10.32 (s, 1 H), 11.41 (s, 1 H); MS (APCI): 467.19.
EXAMPLE 92:
3-Chloro-4-hydroxybenzoic acid [4-(4-tert-butylbenz~rloxy~~ 3 5 dimethylbenzyfidene]hv drazide Hs / ~ wCHa / O \
O
\ NiN \ \ CH3 H
HO
CI
1 H NMR (DMSO-d6): b 1.06 (s, 9H), 1.99 (s, 6H), 4.55 (s, 2H}, 6.83 (d, 1 H), 7.19 (s, 6H), 7.52 (d, 1 H), 7.73 (s, 1 H), 8.09 (s, 1 H), 10.74 (brd s, 1 H), 11.44 (s, 1 H); MS (FAB): 465.6.
EXAMPLE 93:
3-Chloro-4-hydroxybenzoic acid [3-bromo-5-metho~~4-trifluoromethoxybenzyl oxy~ben~rfidene]~hydrazide 1 H NMR (DMSO-d6): 8 3.92 (s, 3H), 5.07 (s, 2H), 7.07 (d, 1 H), 7.40 (m, 3H), 7.52 (s, 1 H), 7.63 (d, 2H), 7.77 (dd, 1 H), 7.97 (d, 1 H), 8.35 (s, 1 H), 11.00 (brd s, 1 H), 11.86 (s, 1 H); MS
(FAB):575.0 EXAMPLE 94:
-H dr x n i 4- 4-' I I - im li h i 1 H NMR (DMSO-d6): 8 1.05 (d, 6H), 2.71 (m, 1 H), 3.67 (s, 6H), 4.75 (s, 2H), 6.70 (d, 2H), 6.85 (s, 2H), 7.14 (d, 2H), 7.21 (d, 2H), 7.64 (d, 2H), 8.21 (brd s, 1 H), 9.97 (brd s, 1 H), 11.47 (s, 1 H); MS (APCI): 448.9.
EXAMPLE 95:
hl r -4-h dr n 4- r - i th x n n OCH3 / ~ ~C
O
O
\ NON \ \ OCH3 H
HO CI
'H NMR (DMSO-D6): d 1.18 (d, 6H}, 2.87 (septet, 1 H), [3.68 (s, 1 H) + 3.81 (s, 5H), 6H], [4.83 (s, 0.5H} + 4.90 (s, 1.5H), 2HJ, [6.76 (s, 0.5H) + 7.01 (s, 1.5 H), 2H], [6.80 (dd, 1 H) +
6.88 (d, 1 H), 2H], 7.23 (d, 2H), 7.35 (d, 2H), 7.38 (m, 1 H), [7.91 (s, 0.3H) + 8.18 (s, 0.7H), 2HJ, 10.17 (s, 0.7H) + 11.73 (s, 0.3H), 1 HJ; MS (APCI): 483Ø
EXAMPLE 96:
3-Chloro-4-hydroxybenzoic acid [~(4-isol~pylbenz~yloxXl 4 5 dimethox benzylidPneJ~"~
drazide 1 H NMR (DMSO-d6): 8 1.05 (d, 6H), 2.70 (m, 1 H), 3.54 (s, 3H), 3.66 (s, 3H), 4.94 (s, 2H), 6.87 (m, 3H), 7.08 (d, 2H), 7.20 (d, 2H), 7.56 (dd, 1 H), 7.77 (s, 1 H), 8.15 (s, 1 H), 10.76 (s, 1 H), 11.52 (s, 1 H); MS (APCI): 483.7.
EXAMPLE 97:
Chloro-4-h) d/ fOXVbenzoic acid [3-(4-isooropylbenzyloxv)-2 4-dimethoxybenzylide~
ne]hydrazide O
~N ~ \
\ ~H O ~ \
HO ~ OCH3 / CH3 1 H NMR (DMSO-d6): 8 1.20 (d, 6H), 2.89 (m, 1 H), 3.85 (s, 6H), 4.95 (s, 2H), 6.95 (d, 1 H), 7.07 (d, 1 H), 7.22 (d, 2H), 7.40 (d, 2H), 7.64 (d, 1 H), 7.78 (dd, 1 H), 7.97 (d, 1 H), 8.62 (s, 1 H), 11.68 (s, 1 H); MS (APCI): 483.8.
EXAMPLE 98:
3-Chloro-4-hydroxybenzoic acid [~3-trifluoromethoxybenzy~y)naphth 1 ylmet~lene]'hydrazide O OCF~
,N
'N
H
HO
CI
1 H NMR (DMSO-d6): 8 5.46 (s, 2H), 7.10 (d, 1 H), 7.20 (d, 1 H), 7.37 (d, 1 H), 7.65 (m, 5H), 7.82 (m, 2H), 8.01 (s, 1 H), 8.32 (d, 1 H), 8.97 (m, 2H), 11.70 (s, 1 H); MS
(APCI): 514.8 EXAMPLE 99:
r i I n I th I
ylmethylene]-hydrazide ~CH3 O / O
CI ~ .N W
-N
HO I ~ H H3C.0 w 4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (2 g, 9.9 mmol) was dissolved in DMF (25 mL). To this mixture potassium carbonate (6.8 g, 50 mmol) and 4-isopropylbenzylchloride (1.8 g, 10.4 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the resulting mixture was extracted with diethyl ether (3 x 100 mL). The combined organic extracts were washed with saturated sodium chlo-ride (100 mL), dried (MgSO,) and evaporated in vacuo to afford 3.0 g crude product. This was purified using column chromatography on silica gel (300 mL) eluting with a mixture of ethyl acetate and heptane (1:4). This afforded 2.57 g (81%) of 4-isopropylbenzyloxy-8-methoxynaphthalene-1-carbaldehyde.
Calculated for C~H~03:
C, 79.02%; H, 6.63%. Found:
C, 79.10%, H, 6.69%, C, 79.17%, H, 6.69%.
3-Chforo-4-hydroxybenzoic acid hydrazide (205 mg, 1.1 mmol) was dissolved in DMSO (2 mL) and the above 4-isopropylbenzyloxy-8-methoxynaphthalene-1-carbaldehyde (365 mg, 1.1 mmol) and glacial acetic acid (5 drops) were added and the resulting mixture was stirred at room temperature for 20 minutes. More DMSO (2 mL) was added and the mixture was stirred at room temperature for 16 hours. The solid was collected by filtration and washed successively with DMSO and ethyl acetate to afford 330 mg (66%) of the title comp ~~r~
M.p.: > 250 °C.
EXAMPLE 100:
OMe i I CH3 O ~O
H.N . ('~~ I OMe HO
NOZ
'H NMR ( DMSO-ds ) 8 1.13 (d, 6H), 2.82 (sept, 1 H), 3.77 (s, 6H), 4.8 (s, 2H), 7.15 (s, 1 H), 7.18 (s, 2H), 7.30 (d, 2H), 8.00 (dd, 1 H), 8.30 (s, 1 H), 8.44 (s, 1 H), 11.84 (s, 1 H);. MS
(APCI): 494.0 EXAMPLE 101:
i i CF3 O ~ I O ~ I
.N . w I
I~ H
HO
CI
'H NMR ( DMSO-d6 ) 8 5.38 (s, 2H), 6.95 (d, 1 H), 7.06 (d, 1 H), 7.49 (t, 1 H), 7.56 (t, 1 H), 7.65-7.71 (m, 6H), 7.87 (d, 1 H), 8.22 (d, 1 H), 8.80 (s, 1 H), 8.86 (d, 1 H), 10.82 (s, 1 H), 11.55 (s, 1 H); MS (FAB): 499 EXAMPLE 102:
o w o~
H.N . w I I ~ OCF
a HO
CI
'H NMR ( DMSO-ds } 8 5.85 (s, 2H), 7.05 (t, 2H), 7.52-7.63 (m, 4H), 7.73 (m, 2H), 7.95 (s, 1 H), 8.16 (d, 2H), 8.33 (d, 1 H), 8.90 (s, 1 H), 893 (s, 1 H), 10.90 {brd s, 1 H), 11.63 (s, 1 H);
MS (FAB): 543 EXAMPLE 103:
-4- r n i id - 4- r x th - i th ne}hydrazide OCH3 / Br O / O~O \
,N ~
\ ~H OCH3 HO
CI
1 H NMR (DMSO-d6): b 3.78 (s, 6H), 4.21 (m, 4H), 6.87 (d, 2H), 7.00 (s, 2H}, 7.05 (d, 1 H), 7.44 {d, 2H), 7.75 (dd, 1 H), 7.96 (s, 1 H), 8.36 (s, 1 H), 10.95 (brd s, 1 H), 11.66 (s, 1 H);
MS(APCI): 548.8.
EXAMPLE 104:
3-Chloro-4-hydroxybenzoiC acid ~4~3-methoxy 3 (4 me ~rloheny~ nrop~rloxy)n h~-th 1 ylmeth l~ene]hydrazide EXAMPLE 105:
2- t I h n I r m i a i - 4- I ro-4- r x I h r m h I -n t - -yloxy}ethyl ester cl 1 H NMR (CDCI3): b 1.12 {t, 3H), 2.50 (qt, 2H), 3.69 (t, 2H), 4.39 (t, 2H), 5.20 (t, 1 H), 6.57 (t, 1 H), 6.74 (d, 1 H), 6.97 (d, 1 H), 7.08 (m, 3H), 7.57 (t, 1 H), 7.67 (t, 1 H), 7.81 (t, 2H), 8.01 (s, 1 H), 8.35 (d, 1 H), 8.95 (m, 2H), 11.67 (s, 1 H).
EXAMPLE 106:
3-Chloro-4-I~ydr~~benzoic acic~(3-ally~4 iso rohylbenzylQ~y}~
methoxyben~ylidene]hydrazide CHZ / ~ ~C
O \
O
\ N
HO
CI
MS (APCI): 502.9 1 H NMR (DMSO-d6) : 8 1.13 (d, 6H), 2.80 (m, 1 H), 3.20 (m, 2H), 3.85 (s, 3H), 4.82 (s, 2H), 5.00 (d, 2H), 5.70 (m, 1 H), 6.96 (s, 1 H), 7.05 (s, 1 H), 7.20 (d, 2H), 7.30 (d, 2H), 7.70 (d, 1 H), 7.89 (s, 1 H), 8.28 (s, 1 H), 10.80 (brd s, 1 H), 11.61 (s, 1 H); MS (APCI):
493.1.
Similarly, the following compounds were made:
EXAMPLE 107:
N.N.
HO~ H I i CHI
'H NMR (DMSO-Ds): 8 0.99 (d, 6H), 2.68 (septet, 1H), 4.89 (s, 2H), 6.84 (d, 2H), 7.06 (m, 2H), 7.16 (m, 3H), 7.55 (d, 1 H), 7.75 (s, 1 H), 8.18 (s, 1 H), 10.75 (s, 1 H), 11.52 (s, 1 H); MS
(APCI): 423.7, 425.6.
EXAMPLE 108:
CI i I CHI
O ~O w .N~ (~' I~ H
HO
CI
'H NMR (DMSO-D6): 8 1.18 (d, 1 H), 2.88 (septet, 1 H), 5.20 (s, 2H), 7.04 (d, 1 H), 7.28 (t, 2H), 7.30 (s, 1 H), 7.38 (d, 2H), 7.62 (d, 1 H), 7.73 (dd, 1 H), 7.79 (s, 1 H), 7.94 (d, 1 H), 8.32 (s, 1 H), 11.94 (s, 1 H), 11.72 (s, 1 H); MS (APCI}: 457.4, 459.1.
EXAMPLE 109:
CH5 ~ I CHI
O ~O w I ~ H.N ~ ('~~ I CH
HO
'H NMR (DMSO-D6): 8 1.1 (d, 6H), 2.2 (s, 6H), 2.8 (septet, 1 H), 4.7 (s, 2H), 7.0 (d, 1 H), 7.2 (d, 2H), 7.4 (d, 4H), 7.7 (d, 1 H), 7.9 (s, 1 H), 8.2 (s, 1 H), 10.9 (s, 1 H), 11.6 (s, 1 H); MS
(APCI): 451.6, 453.3.
EXAMPLE 110:
~CH~
O / 1 0 \'/~~ I
~ .N. w I~ H
HO
CI
'H NMR (DMSO-DB): 8 1.1 (d, 6H), 2.8 (septet, 1 H), 3.3 (d, 1 H), 5.0 (d, 1 H), 5.1 (d, 1 H), 5.2 (s, 2H), 5.9 (m, 1 H), 7.0 (d, 1 H), 7.1 (d, 1 H), 7.2 (d, 2H), 7.3 (d, 2H), 7.4 (d, 1 H), 7.5 (s, 1 H), 7.7 (dd, 1 H), 7.9 (d, 1 H), 8.3 (s, 1 H), 10.9 (bid s, 1 H), 11.5 (s, 1 H);
MS (APCI): 463.5, 465.1.
EXAMPLE 111:
o w I O.~O w I
.N~
I~ H
HO
CI
'H NMR (DMSO-D6): b 4.47 (t, 2H), 4.54 (t, 2H), 7.01 (d, 2H), 7.07 (d, 1 H), 7.14 (d, 1 H), 7.45 (d, 2H), 7.53 (t, 1 H), 7.27 (d, 1 H), 7.79 (m, 2H), 7.96 (d, 1 H), 8.17 (d, 1 H), 8.91 (s, 1 H), 8.94 (d, 1 H), 10.92 (s, 1 H), 11.64 (s, 1 H), MS (APCI): 539.3, 541.1, 543.1.
EXAMPLE 112:
O. CHs ~ I CHs O ~0 w I \ H.N. ('~~ I O.CH~
HO ~ CI
CI
'H NMR (DMSO-D6): 8 1.18 (d, 6H), 2.87 (septet, 1 H), [3.67 (s, 1.5H) + 3.81 (s, 4.5H), 6H], [4.83 (s, 0.5H) + 4.90 (s, 1.5H), 2H], 6.73 {s, 0.5H) + [7.02 (m, 2.5H), +
7.27 {m, 2.5H) +
7.37 (m, 2.5H), 8H], [7.92 (s, 0.3H) + 8.17 (s, 0.7H), 1 H], [10.96 (s, 0.3H) + 11.12 (s, 0.7H), 1 H], [11.82 (s, 0.7H) + 11.95 (s, 0.3H), 1 H]; MS (APCI): 517.6, 519.2.
EXAMPLE 113:
O.CH~ , I CHI
O ~O w CI ~ N.N w f~~'w ILLO.CH~
I~ H
HO CI
'H NMR (DMSO-D6): 8 1.19 (d, 6H), 2.89 (septet, 1 H), [3.68 (s, 1.5H) + 3.82 (s, 4.5H), 6H], [4.84 (s, 0.5H) + 4.89 (s, 1.5H), 2H], [6.76 (s, 0.5H) + 7.02 (m, 2.5H), 3H], 7.20 (m, 2H), 7.34 (m, 2H), [7.50 (s, 0.3H) + 7.62 (s, 0.7H}, 1 H], 7.92 (s, 0.3H) + 8.18 (s, 0.7H), 1 H], 11.17 (brd s, 1 H), 11.81 (s, 0.7H) + 11.96 (s, 0.3H), 1 H]; MS (APCI): 517.7, 519.2.
EXAMPLE 114:
CHI
O. CHI , ' CHa O ~ O
.N~ w I .CHS
O
HO
NHZ
'H NMR (DMSO-D6): 8 1.20 (d, 6H), 2.87 (septet, 1H), 3.82 (s, 6H), 4.89 (s, 2H), 6.69 (d, 1 H), 6.98 (m, 3H), 7.21 (m, 3H), 7.36 (d, 2H), 8.32 (s, 1 H), 9.8 (brd s, 1 H), 11.50 (s, 1 H}; MS
(APCI):464.7.
EXAMPLE 115:
O.CH3 / I CHI
O ~ O
.N~ w I .CH3 I H
HO ~ F
F
'H NMR (DMSO-D6): 8 1.19 (d, 6H), 2.30 (septet, 1 H), [3.71 (s) + 3.82 (s), 6H], 4.90 (s, 2H), [6.81 (m, 1.5H) + 6.88 (s, 1.5H), 3H], [7.24 (s, 0.2H) + 8.24 (s, 0.8H), 1 H], 11.05 (brd, 1 H), 11.69 (s, 0.75H) + 11.94 (s, 0.25H), 1 H]; MS (APCI): 485.5, 486.3.
EXAMPLE 116:
CHI
O.CH~ , I CHI
O ~O w ~ H.N ~ r'~~ I O.CH~
HO
'H NMR (DMSO-DB): b 1.19 (d, 6H), 2.88 (septet, 1 H), 3.83 (s, 6H), 4.90 (s, 2H), 6.87 (d, 1 H), 7.03 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.53 (m, 3h), 8.26 (m, 3H), 10.73 (s, 1 H), 11.82 (s, 1 H); MS (APC(): 499.8.
EXAMPLE 117:
CHI
O.CH3 , I CH3 O ~O w ~ H.N. \ I~ I O.CH~
HO
II
N
'H NMR {DMSO-D6): 8 1.20 (d, J = 6.9, 6H), 2.89 {sept, J = 6.9, 1 H), 3.84 (s, 6H), 4.91 (s, 2H), 7.03 (br s, 2H), 7.12 (d, J = 8.8, 1 H), 7.23 (d, J = 8.0, 2H), 7.37 (d, J = 8.0, 2H), 8.04 (dd, J = 2.2, 8.8, 1 H), 8.21 (br s, 1 H), 8.35 (br s, 1 H), 11.78 (s, 1 H), 11.89 (br s, 1 H); MS
(APCI, neg): 472.
Preparation of acyl-hydrazones of 4-(2-hydroxyethyl)-1-naphthaldehyde:
General procedure for synthesis of compounds of the general formula X' A~N.NHZ ~ I ~ (CHZ)b~OH ~ O ~ ~ (CHz)o\
H II OH
H i A~N.N ~
O H
formula X
wherein b is 1, 2, 3 or 4 Preparation of 4-l2-hydroxyethyl}-1-nal~ahthaldehyde~
Br Br O H
Br O H
\ \ \ \
~ \ \
\ \ ~ ~ ~ ~ ~ ~ i i Me0 HO O O O O i i p Ho 1-Bromo-4-(2-hydroxyethyllnaphthalene~
To a solution of methyl 4-bromo naphthalene acetate (2.0 g, 7.16 mmol} in anhydrous THF
(15 mL) was added drop wise at 0°C 1 M lithium aluminum hydride in THF
(4 mL). The mix-ture was stirred at room temperature for 16 h, diluted with water (5 ml), acidified with conc.
hydrochloric acid, and extracted with ethyl acetate (3 x 20 mL). The combined organic ex-tracts were dried (MgS04), and concentrated to provide a 1.71 g (95%) colorless oil (1.71 g, 95%). A similar synthetic reference is described in A. A. Kiprianov, A. A.
Shulezhko. Zh.
Org. Khim. 2 (1966), 1852, English translation: J. Org. Chem. (USSR) 2 (1966) 1820].
'H NMR (CDC13) 8 = 2.36 (s, 1H), 3.33 (t, J = 6.7 Hz, 2H), 3.99 (t, J = 6.7 Hz, 2H), 7.24 (d, J
= 7.3 Hz, 1 H), 7.58 - 7.63 (m, 2H), 7.73 (d, J = 7.6 Hz, 1 H), 7.61 (m, 1 H), 8.31 (dd, J = 1.1, 8.0 Hz, 1 H). GCMS (pos.) 250, 252.
1-Bromo-4-(2-tetrahydrop~,anyloxygthyl)naphthalene~
To a solution of 1-bromo-4-(2-hydroxyethyl)naphthalene (1.71 g, 6.8 mmol) in dichloro-methane (20 mL) was added 3,4-dihydro-2H-pyrane (1 mL, 0.92 g, 11.0 mmol) and p-toluene sulfonic acid (80 mg). The mixture was stirred at room temperature for 90 min, dilu-ted with dichloromethane (20 mL), washed with satd. NaHC03 sof. (20 mL), dried (MgS04), and concentrated. Flash chromatography using hexane/ethyl acetate 9:1 as eluent provided 1.69 g (75%) of a colorless oil.
'H NMR (CDCI3) 8 = 1.51 -1.60 m (6H), 3.37 (t , J = 7.2 Hz, 2H), 3.39 - 3.47 (m, 1 H), 3.74 (t, J = 7.2 Hz, 2H), 4.08 (dd, J = 2.4, 7.5 Hz, 1 H), 4.60 (m, 1 H), 7.25 (d, J =
7.3 Hz, 1 H), 7.56 -7.61 (m, 2H), 7.72 (d, J = 7.6 Hz, 1 H}, 8.09 - 8.12 (m, 1 H), 8.29 {dd, J =
2.5, 7.1 Hz, 1 H).
GCMS (pos), 334, 336.
1-Formyl-4-~2-tetrahydropyranvioxyethyl)naphthalene:
A solution of 1-bromo-4-(2-tetrahydropyranyloxyethyl)naphthalene in anhydrous THF (15 mL) under nitrogen was cooled to -78°C. n-Butyl lithium (1.4 mL of a 2.5 M solution in hexa-ne) was added via syringe, and the mixture was stirred at the same temperature for 30 min.
DMF (1.1 mL) was added, and the mixture was allowed to reach room temperature.
It was diluted with satd. NH,CI solution (10 mL), extracted with ether (3 x 10 ml), dried (MgS04) and 1o concentrated. Flash chromatography using hexanelethyl acetate 5:1 as eluent provided 408 mg (54%) of a colorless oil.
'H NMR (CDCI3) 8 = 1.48 -1.69 m (6H), 3.45 - 3.50 (m, 3H), 3.69 - 3.85 (m, 2H), 4.07 - 4.17 (m, 1 H), 4.61 (m, 1 H), 7.58 {d, J = 7.3 Hz, 1 H), 7.62 -7.73 (m, 2H), 7.92 (d, J = 7.3 Hz, 1 H), 8.20 (d, J = 1.0, 8.1 Hz, 1 H), 10.36 (s, 1 H). GCMS: 284 1-Formyl-4=(2~hydroxvethyl}naphthalene:
1-Formyl-4-(2-tetrahydropyranyloxyethyl)naphthalene (400 mg, 1.40 mmol) was dissolved in methanol (15 mL), and p-toluene sulfonic acid (45 mg) was added. The mixture was stirred at room temperature for 16 h, and concentrated. The residue was dissolved in ethyl acetate (3 x 10 mL), washed with satd. NaHC03 (20 mL), dried (MgS04) and concentrated.
Purifica-tion by flash chromatography using hexanelethyl acetate 3:1 as eluent provided 182 mg (65%) of a colorless oil .
'H NMR (CDCI3) 8 = 2.09 (s, 1 H), 3.40 (t, J = 6.6 Hz, 2H}, 4.02 (t, J = 6.6 Hz, 2H), 7.54 {d, J
= 7.3 Hz, 1 H), 7.61- 7.71 (m, 2H), 7.88 (d, J =7.3 Hz, 1 H), 8.13 (dd, J =
1.3, 8.0 Hz, 1 H), 9.29 (dd, J = 1.3, 8.0 Hz, 1 H), 10.28 (s, 1 H). GCMS: 200 The following compounds were prepared according to the general procedure for the synthe-sis of alkylidene hydrazones from the condensation of 1-formyl-4-(2-hydroxyethyl) naphtha-lene (from step D) with 4-hydroxy benzoic acid hydrazides.
EXAMPLE 118:
o w I off I~ H
HO
CI
'H NMR (DMSO-D6) 8 = 3.25 (t, J = 6.5 Hz, 2H), 3.73 (dt, J =J'=6.5 Hz, 2H}, 4.84 (t, J = 6.5 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 7.49 (d, J = 7.4 Hz, 1 H}, 7.60 - 7.68 (m, 2H), 7.80 (dd, J =
1.8, 7.4 Hz, 1 H), 7.84 (d, J = 7.3 Hz, 1 H), 8.00 (d, J = 1.8 Hz, 1 H), 9.19 (d, J = 6.7 Hz, 1 H), 8.85 (d, J = 7.7 Hz, 1 H), 9.05 (s, 1 H), 10.98 {s, 1 H), 11.76 (s, 1 H); MS
(APCI, pos.): 369.4, 371.2.
EXAMPLE 119:
o ~ I off .N. w I
I ~ 'H
HO ~ C7 CI
'H NMR (DMSO-D6) 8 = 3.18 (t, J = 7.0 Hz, 1 H), 3.25 (t, J = 7.0 Hz, 1 H), 3.65 (dd, J = 7.0 Hz, 1 H), 3.74 (dd, J = 5.3, 7.0 Hz, 1 H), 4.74 (t, J = 5.3 Hz, 0.5H}, 4.79 (t, J = 5.3 Hz, 0.5H), 7.04 (d, J = 8.3 Hz, 0.5H), 7.05 (d, J = 8.3 Hz, 0.5H), 7.25 (d, J = 8.3 Hz, 0.5H), 7.28 (d, J =
8.3 Hz, 0.5H}, 7.38 (d, J = 7.4 Hz, 0.5H), 7.43 (d, J = 8.4 Hz, 0.5H), 7.47 -7.57 (m, 1.5H), 7.61-7.72 (m, 1 H), 7.82 (d, J = 7.2 Hz, 0.5H), 8.10 (d, J = 8.6 Hz, 0.5H), 8.19 (dd, J = 2.2, 7.2 Hz, 0.5H), 8.45 (d, J = 8.6 Hz, 0.5H), 8.48 (s, 0.5H), 8.85 (s, 0.5H), 8.87 (dd, J = 2.2, 6.5 Hz, 0.5H), 11.00 (s, 0.5H), 11.15 (s, 0.5H), 11.86 (s, 0.5H), 11.92 (s, 0.5H);
MS (APCI, pos.): 403.4, 405.2, 406.1.
Preparation of acylhydrazones of 4-hydroxymethylnaphthaldehyde:
O OH OH O H
A ~ ~ B
I ~ ~ ---~ I ~
HO ~O HO HO
Step A:
The 1,4-Naphthalenedicarboxylic acid (25 g, 116 mmol) was dripped into a mixture of Lithi-um Aluminum Hydride (15 g, 395 mmol) in 600 mL of anhydrous THF and refluxed for two 1o days. The mixture was cooled in an ice bath and excess LAH was decomposed by the slow addition of methanol followed by ice chips. THF was removed under vacuum and the residue was acidified with 1 N HCI. The product was extracted with ethyl acetate (3x), washed with aqueous sodium bicarbonate (3x), water, brine, and dried over magnesium sulfate. 1,4-Bishydroxymethyfnaphthalene (70%) was obtained as a solid after evaporation of the solvent ~ 5 and can be used in the subsequent oxidation step without further purification. A portion of the material was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) for characterization purposes.
'H NMR (DMSO-D6): 8 5.19 (s, 4H), 7.77 (m, 4H), 8.32 (m, 2H).
Step B:
To a solution of 1,4-bishydroxymethylnaphthalene (12 g, 65 mmol) in ethyl acetate (300 ml) was added manganese dioxide ( 28 g, 325 mmol). After stirring for 45 minutes most of the starting material had disappeared and two new spots (mono aldehyde and dialdehyde) were seen on TLC. The upper spot corresponds to the dialdehyde. The mixture was passed through a bed of Celite and eluted with additional volumes of ethyl acetate.
The solvent was evaporated and 4-hydroxymethylnaphthaldehyde was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) in 50% yield.
H NMR (DMSO-D6): 8 5.19 (s, 2H), 5.71 (brd s, 1 H}, 7.73 (t, 1 H), 7.78 (t, 1 H), 7.95 (d, 1 H), 8.26 (m, 2H), 9.34 (d, 1 H), 10.46 (s, 1 H).
Examples of products employing the above aldehyde:
EXAMPLE 120:
I
o ~ I off .N~ ~
I ~ 'H
HO
N
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-cyano-hydroxybenzoic acid hydrazide.
'H NMR {DMSO-D6): 8 5.02 (s, 2H), 5.44 (s, 1 H), 7.14 (d, 1 H), 7.69 (m, 3H), 7.91 (d, 1 H), 8.10 (d, 1 H), 8.14 (d, 1 H), 8.27 {s, 1 H), 8.87 (d, 1 H), 9.06 (s, 1 H), 11.84 (brd s, 2H); MS
(ACPI): 346.3, 347.2.
EXAMPLE 121:
I
o ~ I off .N~ ~
I , H
HO
CI
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-chloro-4 hydroxybenzoic acid hydrazide.
'H NMR (DMSO-D6): b 5.02 (s, 2H), 5.43 (t, 1 H), 7.10 (d, 1 H), 7.66 (m, 3H}, 7.80 (d, 1 H), 7.90 (d, 1 H), 8.02 (s, 1 H), 8.15 (d, 1 H), 8.87 (d, 1 H), 9.08 (s, 1 H), 10.98 (s, 1 H), 11. 79 (s, 1 H); MS (APCI): 355.5 EXAMPLE 122:
I
o ~ I off .N. w I ~ H
HO
F
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-fluoro-4-hydroxybenzoic acid hydrazide.
'H NMR (DMSO-Ds): d4.84 (s, 2H), 6.91 (t, 1 H), 7.43-7.53 (m, 4H), 7.62 (d, 1 H), 7.72 (d, 1 H), 7.96 (d, 1 H), 8.68 (d, 1 H), 8.98 (s, 1 H), 11.71 (brd s, 1 H); MS
(APCI): 339.4, 340.3.
The compounds of formula II can also be prepared by parallel synthesis using the protocol mentioned above in a combinatorial approach. Thousands of compounds of formula II can thus be prepared by this combinatorial approach which can be semi- or fully automated. The auto-mation of this protocol can be performed using solution phase combinatorial chemistry in e.g. a 96 well setup using an automated synthesizer device. In the first step of the synthesis the al-dehydes or ketones may be prepared according to Scheme II by a combination of a selected number of aldehydes or ketones with a selected number of alkylating reagents.
In the second step the formed aldehydes/ketones can be combined with a selected number of the hydrazides (which may be synthesized according to Scheme I) thereby generating a predetermined very large number of compounds as single entities.
The synthesized compounds mentioned above are examples of such compounds that can be prepared using this combinatorial methodology.
By application of the above methodology, the following compounds may also be synthesized:
EXAMPLE 123:
OMe HO / \ O / \
C7 HTN / \ O \ / OCF3 H
EXAMPLE 124:
HO / \ O / \
CI H ~ / \ O \ / OCF3 H
EXAMPLE 125:
F
HO / \ O / \
v CI H N / \ O \ / OCF3 H
EXAMPLE 126:
CI
HO / \ O / \
CI H N / \ O \ / OCF
H
EXAMPLE 127:
O
HO ~ ~ CI CH3 CI H N ~ ~ O ~ ~ CH3 H
Cl EXAMPLE 128:
O
HO ~ ~ CH3 CH3 CI H ~ ~ ~ O \ / CH
H
EXAMPLE 129:
O
HO ~ ~ C02H CH3 CI H N ~ ~ O \ / CH
H
EXAMPLE 130:
HO ~ ~ OJ CH3 N-N
CI H ~ ~ ~ O \ / CH
H
EXAMPLE 131:
O H
HO / \ CH3 N-CI H \ / CH3 O-~
COZH
EXAMPLE 132:
O
HO / \ Me0 CH3 CI~ H \ ~ ~ O ~ ~ CH3 H
CI
EXAMPLE 133:
O
CHFZ ~ ~ OMe CH3 H N ~ ~ O \ / CH
H
OMe EXAMPLE 134:
O
N / ~ OMe CH3 Me0 H N ~ ~ O \ / CH
H
OMe EXAMPLE 135:
O
N
Me0 H \ ~ ~ O
H
EXAMPLE 136:
N O
Me0 ~ \ OMe CH3 H N ~ ~ O \ / CH
H
OMe EXAMPLE 137:
i O
OMe CH3 H N / ~ O \ / CN
H
OMe EXAMPLE 138:
O
HO / ~ OMe CH3 H \ / ~ O ~ / CH
H
OMe EXAMPLE 139:
CHFZ / ~ O
H' \ / ~ O ~ / OCF3 H
EXAMPLE 140:
HO / ~ O ~ O
CI H N / ~ O ~ / OCF3 H
EXAMPLE 141:
HO / ~ o /
f'N"I N / ~ O ~ / OCF3 H
EXAMPLE 142:
HO ~ ~ O
v Cl H N ~ ~ O ~ ~ N(Et)z H
General procedure for the synthesis of further derivatized hvdrazides of formula II' The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme 111, that is, by converting an alkylidene hydrazide {prepared according to the general method shown in Scheme I, and more specifically as in example 8) into a further derivatized alkylidene hydraz-ide. Thus, by reacting an amine with an alkylidene hydrazide that contains a leaving group X~
(Scheme III) a new alkylidene hydrazide containing an amine in the group K of formula II can be formed.
SCHEME III
O Rsa ,r,~~H-N~(CHz)~ B-O--(CHZ}e CHR3a (CHZ)a X~ ~-(CHz)a D
Ra solvent, base O Rsa A~N-N~(CHz)~ B-O-(CHZ)b CHR3a (CHZ)a N-(CH )-p H R, 2 d wherein A, B, D, n, R° , R3a a, b and d are as defined for formula I
and R5a is lower alkyl.
Specific examples illustrating the preparation of further derivatized hydrazides of formula II are provided below:
EXAMPLE 143:
~Chloro-4-hyrdroxyrbenzoic acid ~4-(2-[~2-N.N-diethylaminoethyl)-N'-(4-trifluoromethoxv-benzyrlamino)]]ethoxy -1-naph_th_ylmethylene)hydrazide o / ~ o~N
\ N~N \ \ I / OCF
/ H \ N
HO
N,N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine:
N~N~CH3 ~CH3 A solution of (4-trifluoromethoxy)benzaldehyde (1.9 g, 10 mmoles), N,N-diethylethylene-diamine (1.16 g, 10 mmoles), zinc chloride (1.36 g, 10 mmoles) and sodium cyanoborohy-dride (1.26 g, 20 mmoies) in methanol (10 mL) in a dry 100 mL round- bottom flask was stirred at room temperature for 8 hours. Water (20 mL) was then added and most of the methanol was removed in vacuo. The residue was distributed between ethyl acetate and 1 N
HCI. The acidic aqueous phase was basified with excess of sodium hydroxide.
Crude N,N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine was obtained. The crude product was used in the following reaction without further purification.
MS (Ci): 291. 'H NMR (CDC13): 8 7.4 (m, 2H), 7.2 (m, 2H), 3.9 (bs, 2H), 3.1-2.6 (m, 9H), 1.4-1.1 (t, 6H).
To a flask containing N,N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine (0.29 g, 1 2o mmole) in DMF (5 mL) was added [1-(4-chloroethoxy)naphthyl](3-chloro-4-hydroxy)benzoic acid hydrazide (0.41 g, 1 mmole) and triethylamine (0.1 g, 1 mmole). The resulting solution was heated at 80°C overnight. Removal of most of the solvent 6n vacuQ
followed by flash chromatography (10:1 CHCl3/MeOH) on silica gel provided the title compound as a brown solid.
'HNMR (DMSO-ds): 8 11.7 (1 H), 9.0 bs, 2H), 8.4-7.0 (m, 12 H), 4.75 (bs, 1 H), 4.65 (bs, 1 H), 4.55 (t, 1 H), 4.35 (t, 1 H), 4.15 (t, 1 H), 3.9 (bs, 1 H), 3.5 (q, 4H), 3.05 (t, 1 H), 1.3 (t, 3H), 0.95 (t, 3H). M.p.: 134-136°C. MS (CI): 657, 659.
EXAMPLE 144:
3-Chloro-4-hvdroxvbenzoic acid f4-f2-(4-trifluoromethoxy ben laminoethoxv]-1-naphthyl methylene}hydrazide O
H
N H-N
HO / /
CI ~ /
~NH
O
To a flask containing 4-trifluoromethoxybenzylamine (0.29 g, 1 mmole) in DMF
(5 mL) was added 3-chloro-4-hydroxybenzoic acid [4-(2-chloroethoxy}-1-naphthyfmethylene]hydrazide (0.403g, 1 mmole) and triethylamine (0.1 g, 1 mmole). The resulting solution was heated at 80°C for 16 hours. Removal of most of the solvent in vacuo, followed by flash chromatogra-phy (10:1 CHCI~/MeOH) on silica gel provided the title confound as a brown solid.
'HNMR (DMSO-ds): 8 11.6 (s, 1 H}, 9.0 (m 2H), 8.3 (m 1 H), 8.0 (m,1 H), 7.8 (s, 2H), 7.7 (m,1 H), 7.6 (m, 1 H), 7.5 (m, 3H), 7.3 (m, 2H), 7.1 (m, 2H), 4.3 (t, 2H), 3.9 (s, 2H), 3.0 (t, 2H).
MS (CI): 557, 559.
By application of the above methodology the following compounds of the invention were syn-thesized:
EXAMPLE 145:
3-Chloro-4.-h roxybenzoic acid {3 5-dimethoxy-4-[2~4-trifluoromethoxybenzylaminol-1 H NMR (CD30D): 8 2.90 (brd t, 2H), 3.75 (s, 6H), 3.89 (s, 2H), 4.08 (brd t, 2H), 6.87 (d, 1 H), 7.10 (s, 2H), 7.20 {d, 2H), 7.43 (d, 2H), 7.65 (m, 1 H), 7.82 (m, 1 H), 8.11 (brd s, 1 H); MS
(APCI): 567.9.
EXAMPLE 146:
3 Chloro-4 hxdroxy,4enzoic acid {4-f2-(2-Qir~eridin-1-yl-ethyl~)ethox~rh hn th-1 H NMR (DMSO-de): 8 1.53 (m, 2H), 1.74 (m, 4H), 3.12 {m, 2H), 3.40 (m, 2H), 3.54 (m, 2H), 3.63 (m, 4H), 4.52 (s, 2H), 7.10 (d,1 H), 7.14 (d, 1 H), 7.60 (t, 1 H), 7.71 (m,1 H), 7.80 (dd, 1 H), 7.83 (d, 1 H), 8.00 (d,1 H), 8.51 (d, 1 H), 8.95 (d, 1 H), 8.98 (s, 1 H), 11.69 (s,1 H); MS (APCI):
495.0 EXAMPLE 147:
'~ Chloro-4 h~rdro enzoic acid ~;4 f2-(3-diethylaminooroQyl~mino)ethoxy]na hn th-1-ylmethylen ~hvdrazide tho benzylidene~ r ' a yimeth~rlen~hvdrazide O ~ \ O\/\H~N~CH~
\ N ' \ _CH3 / /
HO
CI
1 H NMR (DMSO-ds): b 1.21 (t, 6H), 2.10 (m, 2H), 3.14 (m, 10H), 4.52 (t, 2H), 7.10 (d, 1 H), 7.14 (d, 1 H), 7.63 (t, 1 H), 7.73 (m, 1 H), 7.80 (dd, 1 H), 7.84 (d, 1 H), 8.00 (d, 1 H), 8.46 (d,1 H), 8.93 (s,1 H), 8.98 (m, 1 H), 9.20 (m, 2H), 9.69 (m, 1 H), 11.00 (s, 1 H), 11.69 (s, 1 H);
MS (APCI): 497Ø
EXAMPLE 148:
1-l2-{4-[~(3-Chloro-4-hydroxybenzoyl)l7,ydrazonomethyllr~~ th-1-v I,Ly}ethyl)-~ henytamino~~~iiceridine-4-carboxyrlic acid amide 1 H NMR (DMSO-ds): 8 1.16 (m, 2 H), 1.88 (m, 2H), 2.03 (m, 2H), 2.80 (m, 2H), 2.92 (m, 2H), 4.37 (m, 2 H), 4.40 (brd s, 2H), 4.44 (s, 1 H), 6.55 - 6.62 (m, 3 H), 6.96 (s,1 H), 7.03 7.16 (m, 5H), 7.61 (dd, 1 H), 7.68 (dd,1 H), 8.00 (d, 1 H), 8.27 (d, 1 H), 8.94 (s,1 H), 8.97 (s, 1 H), 11.63 (s, 1 H); MS (APCI): 586.4 EXAMPLE 149:
4-(2-{4-[(3-Chloro-4-h dY rox)rbenzoyllhvdrazonomethyl]na hp th-1-v I~y}ethylamino~piperidine 1-carboxylic acid ethyl ester 1H NMR (DMSO-ds): 81,10 (t, 3H), 1.15- 1.23 (m, 2H), 1.86 (m, 2H}, 2.79 (m, 3H), 3.30 (m, 2H), 3.87 (m, 2H), 3.94 (q, 2H), 4.28 (m, 2H), 7.03 (d,1 H), 7.05 (m, 1 H), 7.51 - 7.63 (m, 3H), 7.13 (d, 1 H), 7.75 (m,1 H), 7.93 (d, 1 H), 8.29 (d,1 H), 8.87 (m,2 H), 11.55 (s, 1 H); MS
(APCI): 539.1, 541Ø
EXAMPLE 150:
o -4-h n of a i 4-t tr dron hth-1- f i th x - ht -1-ylmethylene}hvdrazide 1 H NMR (DMSO-ds): 8 1.76 (m, 1 H), 2.04 (m, 1 H), 2.17 (m, 2H), 2.75 - 2.94 (m, 2H), 3.61 (m, 2H), 4.55 (m,2H), 4.71 (s, 1 H), 7.11 (d, 1 H), 7.13 (d, 1 H), 7.23 - 7.35 (m, 3H), 7.61 {d, 1 H), 7.67 (d,1 H), 7.71 (dd, 1 H), 7.81 (dd, 1 H), 7.86 (d, 1 H), 8.01 (d, 1 H), 8.48 (d, 1 H), 8.94 (m, 1 H), 8.99 (m, 1 H), 9.22 (m, 2H), 11.00 (s,1 H), 11.64 (s,1 H); MS
(APCI): 514.0, 516.0 EXAMPLE 151:
1- 2- 4- hl r -h r I h az n th I na hth-1- lox th I i ri i -4-carbox~ic acid amide o \ ~N
\ Ni ~ I \ NHs H
/ I / O
HO
CI
MS (APCI): 495.0 EXAMPLE 152:
-Chl r -h r i 4- th I i o - th -1-n th I-methylene~hydrazide O
HO / \ / \ N OCF3 CI \H N /
H
EXAMPLE 153:
3-Chloro-4-hydroxybenzoic acid {4-f2-(4-morpholinylethv lamino)ethoxyj-1-naphthKmethylenPl-hydrazide HO / ~ O /
H_N ~ O
ci \ / \ p H
By application of the above methodology the following compounds may also be synthezised:
EXAMPLE 154:
O H
HO / ~ / ~ ~N \ / CF3 CI \H N /
H
EXAMPLE 155:
~N(Et)Z
/\O
HO / \ / \ N \~/ CF3 H N / \
CI O
H
EXAMPLE 156:
~N(Et)2 HO / \ p / \ N
CI \H N / \ / \
H
EXAMPLE 157:
~~~tt~2 HO / \ O / \ N
CI \H \ / \ / \
H
EXAMPLE 158:
~N(Et)Z
/\O
HO / \ OMe v CI H ~ / \ C
H
OMe CH3 EXAMPLE 159:
~N(Et)2 \/O
HO ~ \ OMe N
F \H
H
OMe OCF3 EXAMPLE 160:
O
HO / \ OMe N
CI \H
O
H
OMe CH3 General procedures for the ~rer~aration of all~vlidene ark Isr ulfon~l hydrazides according to the invention The compounds of general formula I are prepared according to one embodiment of the inven-tion, the alkylidene arylsulfonyl hydrazides of general formula III, that is, by converting an aryl-sulfonyl halide, for example chloride or bromide to the corresponding hydrazide derivative and further reacting the product arylsulfonyl hydrazide compound with a substituted aldehydes or ketones to yield alkylidene arylsulfonyl hydrazide derivatives as illustrated in Scheme IV.
SCHEME IV
~O NHNHZ
A-S\ CI + NH2NH2 A-S~ O
O O
O
R~(CH2)" B (K)m D HN-N- (CHZ)~ B-(K)m D
A-Sv0 R4 solvent, reflux O
wherein A, B, K, D, m, n and R° are as defined for formula 1.
The synthesis of the arylsulfonylhydrazide precursors is performed by application of general methodology, for example as described by Friedman, L.; Litle, R.L; Reichle, W.
R, in Org.
Synth. Coll. Vol. V, 1973, 1055-1057, by slowly adding the arylsulfonyl chloride either neat, or in a solution in an inert solvent such as tetrahydrofuran, dimethyl ether, dioxane or diethyl ether to an excess of hydrazine, either neat or in solution in the one of the above solvents or a mix-0 ture of these at -20°C to 100°C, preferably between 0°C
to 60°C. When the reaction is judged to be completed, the excess of solvent and volatile reagents is removed by distillation either at atmospheric pressure or in vacuo. The residual product can be further purified by recrystalli-zation from a solvent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, water, toluene, acetic acid, dioxane, tetrahydrofuran or a mixture of two or more of the above solvents when ~ 5 compatible.
Alternatively, the product can be purified by column chromatography using dichloromethane/-methanol or chlorofom~/methanol or isopropyl alcohol as eluent. The corresponding fractions are concentrated either at atmospheric pressure or in vacuo to provide the pure arylsulfonyl 20 hydrazide.
By use of the above methodology the following compounds can be prepared:
EXAMPLE 161:
25 3-Chloro-4-hydroxybenzenesulfonic acid (benzylidene~t vdrazide O N~N- H
O
HO
C!
3-Chloro-4-hydroxybenzenesulfonyl hydrazide:
A solution of 4.82 g (21.2 mmol) 3-chloro-4-hydroxy-benzenesulfonyl chloride, (prepared ac-s cording to the procedure described by Popoff, I. C.; Frank, J. R.; Whitaker R. L.; Miller H. J., Demaree K. D. J. Agr. Food Chem. 1969, 77, 810.) in 15 ml THF was added dropwise with stirring to 3.4 ml 50% hydrazine hydrate (54.4 mmol, 2.5 eq.) at such a rate that the tem-perature is maintained below 10°C. A precipitate formed after the addition was completed.
The mixture was stirred for an additional 30 min, and cooled to 0 °C.
The solid was collected in a Buchner funnel, washed several times with distilled water, and air dried.
Recrystalliza-tion from methanol provided 1.20 g 3-chloro-4-hydroxybenzenesulfonyl hydrazide as a white solid.
H NMR (DMSO-d6): 8 4.78 (bs, 4 H), 6.72 (d, J = 8.6 Hz, 1 H), 7.35 (dd, J =
2.3, 8.6 Hz, 1 H), 5.55 ( J = 2.2 Hz, 1 H); MS(Cl): m/z 223, 221.
To a solution of 105 mg (0.48 mmol) of the above 3-chloro-4-hydroxybenzenesulfonyl hy-drazide in 5 ml methanol was added 0.05 ml {52 mg, 0.49 mmol) benzaldehyde and one drop of acetic acid. After 30 min the mixture was concentrated. Flash chromatography (silica gel, 2:1 hexane/ethylacetate) provided 67 mg (45%) of the title com ound as a solid.
1 H (DMSO-d6): 8 7.10 (d, J = 8.6 Hz, 1 H), 7.38 (m, 3 H), 7.55 (dd, J = 2.3, 6.0 Hz, 2 H), 7.66 (d, J = 2.2, 8.6 Hz, 1 H), 7.76 (d, J = 2.2 Hz, 1 H), 7.90 (s, 1 H), 11.3 (m, 2 H). MS(CI):
m/z 311.
EXAMPLE 162:
3-Chloro-4-hydroxy-benzenesulfonic acid j4-(4-trifluoromethoxvbenzyl~)-1-na~hthylmethXl_ene]hvdrazide HO / ~ S O /
O ~H-N / \ ~ / OCF3 CI O
H
To a solution of 3-chloro-4-hydroxy-benzene sulfonyl hydrazide (105 mg, 0.48 mmol) in 5 ml methanol was added 4-trifluoromethoxybenzyloxy-1-naphthaldehyde (163 mg, 0.49 mmol) and a catalytical amount of glacial acetic acid (5 drops). The reaction mixture was stirred overnight, and filtered. The filtrate was concentrated under vacuo to give the crude product. Flash chro-matography (silica gel, 1:1 hexane/ethylacetate) provided 145 mg (56%) of the title corn o~und_ as a solid.
'H NMR (DMSO-dfi) 8 5.27 (s, 2 H), 6.06 (s, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 2 H), 7.50 - 7.60 (m, 5 H), 7.80 (s, 1 H), 7.85 (dd, J = 3.0, 8.2 Hz, 1 H), 8.08 (d, J = 2.1 Hz, 1 H), 8.26 (s, 1 H), 8.36 (d, J = 7.76 Hz, 1 H), 8.67 (d, J = 8.5 Hz, 1 H).
CIMS m/z: 551, 553.
By using the above methodology, the following compounds may be prepared:
EXAMPLE 163:
HO / \ S O / \ CF3 ii ~
CI o H \ / ~ O
EXAMPLE 164:
HO / ~ S O /
_ ii ~
F ~ H N / ~ O ~ / CI
H
EXAMPLE 165:
O
HO / ~ S~ OMe ii ~
CI O H N ~ ~ O ~ / OCF3 H
OMe EXAMPLE 166:
O
HO / \ ~S\ OMe CI O H \ ~ ~ O ~ ~ CH
H
OMe S~rnthesis of alkylhKdrazides according to the invention' The alkylidene hydrazide derivatives given above can be reduced to the dihydroderivatives by the method given in Scheme V:
SCHEME V
H _ N N--~(CH2)" B (K)m NaBH3CN N H~(CH2)~ B-(K)m D
A \\ R ~ A \\ R4 O CF3C02H p where A, R4, B, K, D, m and n are as defined for formula I.
The alkylhydrazide derivatives can be prepared by reduction (i.e. Lane, C.F.(1975}, Synthesis, p.135) of the corresponding aikylidene hydrazides using a metal hydride, such as sodium bo-rohydride or sodium cyanoborohydride. The alkylidene hydrazide derivative is treated with between 1-10 equivalents, preferentially 1-3 equivalents, of sodium cyanoborohydride in a sol-vent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran, dioxane, water or a compatible mixture of two or more solvents. Optionally a small amount of an acid is used as a catalyst such as hydrochloric acid, trifluoroacetic acid, acetic acid, or sulfuric acid. The reac-tions are performed at 0°C to 60°C, preferably at 10°C to 30°C. When the reaction is complete as judged by HPLC or TLC (silica gel, 1 % methanol in dichloromethane as eluent) the sol-vents) are removed and the residue is chromatographed on a silica gel column using 1 methanol in dichloromethane or chloroform as an eluent. The corresponding fractions are con-1 o centrated to give the desired product. Specific examples illustrating the preparation of alkylhy-drazides according to the invention are provided below.
EXAMPLE 167:
4-hydroxvbenzoic acid (1-na~hthylmethyl)hydrazide /I
H
N
I ~ wHi HO
4-Hydroxybenzoic acid (1-naphthylmethylene)hydrazide (100 mg, 0.34 mmol) was dissolved in methanol (10 mL) and treated with sodium cyanoborohydride (236 mg, 4.1 mmol) followed by two drops of trifluoroacetic acid. After stirring the reaction solution for three hours at room temperature, the solvent was evaporated in vacuo. The residue was introduced into a silica gel column and eluted with dichloromethanelmethanol (9911 ). Evaporation of the corresponding fractions in vacuo gave the title compound in 30% yield. MS (ESI) m/z 293 (M+H)'.
Using the same methodology as described above the following compound was prepared:
EXAMPLE 168:
3-Chloro-4-h,~rdroxybenzoic acid N-[4-(4-iso r~o~ I~benzyloxy)-3.5-dimethoxybenzy]hydra-zide O
H
\ N/N
H
HO
C!
1 H NMR (DMSO-dfi): 8 1.18 (d, 6H), 2.87 {m, 1 H), 3.75 (s, 6H), 3.90 (m, 2H), 4.80 (s, 2H), 5.43 (brd s, 1 H), 6.68 (s, 2H), 6.98 (d, 1 H), 7.20 (d, 2H), 7.34 (d, 2H), 7.64 (dd, 1 H), 7.87 (d, 1 H), 9.89 (brd s, 1 H), 10.80 (s, 1 H); MS (APCI): 485.2.
Furthermore, the following compounds may also be prepared:
EXAMPLE 169:
HO / ~ O /
_H
CI H N / ~ O ~ / OCF3 EXAMPLE 170:
HO / ~ O H / ~ C
CI H N / ~ O \ / CH
EXAMPLE 171:
HO / ~ O H / ~ C
CI H N / ~ O \ / CH
EXAMPLE 172:
O
HO / ~ H OCH3 CI H N / ~ O ~ / OCF3 EXAMPLE 173:
HO / ~ H OCH3 CI H N / ~ O
General procedure for s~rnthesis of comrJOUnds of the general formula XI' O~B~OH ~- B~OCH3 ~ O Bw0 OCH3 step A ~ ~ step B
H O H O
O
A" ~NHz O
O~B~ ~ /OH
O ~~N B~ OH
H O step C A H ~ O
H I IO
O
NHRxR~
~ N B NRscRsa A"
step D
O
formula XI
A and B are as defined for formula I and -NRS'RS° is R''a Raa Reb -N-(CHZ)'~(CHZ)d D where Rsa, R<a, R4b, c, q, d and D are as defined for for-mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The reaction is known and is generally performed by stirring hydroxy benzaldehyde, hydroxy naphthaldehyde or the like together with a bromo acetic acid ester (either methyl, ethyl or other lower alkyl ester) in the presence of a base such as lithium, sodium, potassium or ce-sium carbonate in a solvent such as acetone, 2-methyl-3-pentanone, tetrahydrofuran, dioxane, DMSO, DMF, ethylene glycol, benzene, toluene or a mixture of the above solvents. The reac-tions are performed between 0°C to 130°C, preferably between 20°C to 100°C, most prefera-bly at or about the reflux temperature of the solvent. The reactions are preferably conducted under an inert atmosphere such as NZ or Ar. When the reaction is complete as judged by dis-appearance of the starting ester by TLC or HPLC, the solvent may be removed by concentra-tion at atmospheric or reduced pressure. The product can be further purified by either recrys-tallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xy-lene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloro-methane/methanol or chloroformlmethanoi or isopropyl alcohol as eluent.
Step B: The resulting derivative of acetic ester is then saponified using methods well-known to those skilled in the art such as dissolving the compound in an appropriate solvent such as a lower alcohol (e.g methanol, ethanol or isopropanol), DMF, dioxane or DMSO and adding an aqueous base like lithium, sodium or potassium hydroxide. The reactions are performed be-tween 0°C to 130°C, preferably between 20°C to 100°C. When the reaction is complete as judged by disappearance of the staring ester by TLC or HPLC, the solvent may be removed by concentration at atmospheric or reduced pressure. The product can then be isolated by pour-ing the residue into water or cooled water and acidifying the mixture using an inorganic acid such as hydrochloric acid or sulfuric acid. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure.
The product can be further purified by either recrystallization from a solvent such as ethyl alco-hol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethanelmethanol or chloroformlmethanol or isopropyl alcohol as eluent .
Step C: The resulting carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tent-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, di-chloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethy-lorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further re-crystallized if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture iLvacuo, followed by col-umn chromatography on silica gel using a solvent system such as chloroform/methanol or di-chloromethanelmethanol or chloroformlethyl acetate.
Step D: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an an-hydride or an acid halide that can then react with the amine to give a compound of formula XI.
Step D can also be done combinatorially with a selected number of amines. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, tolu-ene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hex-ane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloro-methanelmethanol or chloroformlmethanol or isopropyl alcohol as eluent giving a compound of formula XI.
Specific examples illustrating the preparation of compounds of the general formula XI ac-cording to the invention are provided below.
EXAMPLE 174:
2-{4-(f3-Chloro-4-hydroxy-benzoyl)~ydrazonomethy]na~ht~rl-1~loxy}~4 chloro phen_yl)acetamide cl ~ ~ / I
O / O~N \
H
,N ~ \
H
\ \N
HO / \
CI
Step A: Hydroxynaphthaldehyde (10 g, 58 mmol), potassium carbonate (16 g, 110 mmol), and methyl bromoacetate (16 g, 100 mmof) were refluxed in acetone (120 mL) overnight.
The reaction mixture was poured into an Erlenmeyer flask containing approximately 500 mL
of ice chips. The mixture was stirred until all of the ice was melted. (4-Formylnaphth-1-yloxy) 1o acetic acid methyl ester (13 g, 50 mmol) was filtered and dried in vacuo overnight.
1 H NMR (CDCi3): 8 3.86 (s, 3H), 4.93 (s, 2H), 6.80 (d, 1 H), 7.61 (t, 1 H), 7.72 (t, 1 H), 7.90 (d, 1 H), 8.42 (d, 1 H), 9.29 (d, 1 H), 10.22 (s, 1 H).
Step B: The above ester (13 g, 50 mmol) was dissolved in methanol (100 mL) and NaOH (40 mL) was added. The reaction solution was stirred overnight and concentrated to approximately 100 mL under vacuo. The residue was poured into approximately 500 mL of ice chips and the mixture was acidified (by pH paper) with the addition of 3N
HCI. The mix-ture was stirred until afl of the ice was melted. (4-Formyinaphth-1-yloxy) acetic acid was filtered and washed with water.
Step C: To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (2g, 10.7 mmol) in DMSO (20 mL) was added the above (4-formylnaphth-1-yloxy) acetic acid (3g, 13 mmol) and a catalytic amount of acetic acid (10 drops). The solution was stirred overnight and diluted with ethyl acetate. The solution was washed with water (3x), brine, and dried over MgS04.
The volume was reduced to approximately 100 mL and placed in an ice-bath. The resulting solid was filtered and washed with cold ethyl acetate to afford {4-[(3-chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphth-1-yloxy) acetic acid.
1 H NMR (DMSO-ds): 8 4.91 (s, 2H), 6.95 (d, 1 H), 7.02 (d, 1 H), 7.55 (t, 1 H), 7.64 (t, 1 H), 7.74 (d, 1 H), 7.92 (d, 1 H), 8.27 (d, 1 H), 8.90 (m, 2H), 10.92 (brd s, 1 H), 11.63 (s, 1 H), 13.14 (brd s, 1 H).
Step D: To a solution of the hydrazone-carboxylic acid {50 mmol) in anhydrous DMSO was added a solution of carbonyldiimidazole (55 mmol) in anhydrous DMSO. After the evolution of gases ceased (approximately 3-4 minutes), the amine was added and the reaction mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate and washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent afforded the crude material, which was purified by reverse phase HPLC chromatography to give the title com-,~ oa und.
1 H NMR (DMSO-d6): 8 4.99 (s, 2H), 7.04 (m, 2H), 7.36 (d, 2H}, 7.65 (m, 4H), 7.79 (t, 2H), 7.99 (s, 1 H), 8.40 (d, 1 H), 8.72 (s, 1 H), 8.92 (d, 1 H), 10.42 (s, 1 H), 10.96 (s, 1 H), 11.69 (s, 1 H); MS (APCI): 507.9.
By using the same methodology, the following compounds were prepared:
2o EXAMPLE 175:
1~(1-Benz vrrolidip-3-yl}-2-{4-[(3-chloro-4-hydroxy-benzoyl)h~rdrazonomethyllna hp th-1-O / I H
\ N~N ~ \
H
/ \
HO
CI
1 H NMR (DMSO-ds): 8 1.96 (m, 2H), 2.32 (m, 5H), 4.58 (s, 2H), 6.78 (d, 1 H), 6.92 (d, 1 H), 7.15 (m, 5H), 7.47 (t, 1 H), 7.52 {t, 1 H), 7.62 (d, 2H), 7.82 (d, 1 H), 8.18 (m, ZH), 8.78 (d, 2H), 10.75 (brd s, 1 H), 11.52 (s, 1 H); MS (APCI): 556.9.
EXAMPLE 176:
- 4- hl -4.-h r o I h z m th I n hth-1- I x -N-in -1- I- t id 1 H NMR (DMSO-d6): b 1.94 (m, 1 H), 2.40 (m, 1 H), 2.80-3.07 (m, 3H), 4.87 (s, 2H), 7.04 (d, 1 H), 7.10 (d, 1 H), 7.21 (m, 4H), 7.61 (t, 1 H), 7.69 (t, 1 H), 7.80 (t, 2H), 8.10 (s, 1 H), 8.42 (d, 1 H), 8.64 (d, 1 H), 8.98 (m, 2H), 11.00 (brd s, 1 H), 11.68 (s, 1 H); MS
(APCI): 514, 516.
EXAMPLE 177:
2-d4-fl3-Chloro-4-hydroxybenzoyl)hxdrazonomethyi]naphth 1 yloxy} N~1 2 3 4 tetrahy~o_ n_a~phthalen-1-yl)acPtamide 1H NMR (DMSO-ds): 8 1.75 (m, 2H), 1.92 (m, 2H), 2.74 (m, 2H), 4.87 (m, 2H), 5.12 (m, 1H), 7.12 (m, 6H), 7.61 (t, 1 H), 7.74 (t, 1 H), 7.84 (m, 2H), 8.01 (s, 1 H), 8.40 (d, 1 H), 8.62 (d, 1 H), 8.97 (m, 2H), 11.72 (s, 1 H); MS (APCI): 528, 530.
EXAMPLE 178:
2-{4-[(3-Chloro-4-hxdroxv bi enzoyl)hydrazonomethylj~~ h~ th-1-yloxy;~-N-(2-(4 chloro enyl)ethyl~acetamide 1 H NMR {DMSO-dfi): 8 2.40 (t, 2H), 2.79 (t, 2H), 4.74 (s, 2H), 6.96 (d, 1 H), 7.10 (d, 1 H), 7.63 (t, 1 H), 7.69 {t, 1 H), 7.72 (m, 2H), 7.81 (s, 1 H), 8.01 (m, 2H), 8.23 (t, 1 H), 8.40 (d, 1 H), 8.95 (s, 1 H), 9.01 (d, 1 H), 10.98 (brd s, 1 H), 11.70 (s, 1 H); MS (APCI) 538.8, 537.8.
EXAMPLE 179:
- 4- h r b n 1 -1- I -N- I i r zin-1-yl)I~ro~yl]acetamidg O ~ O~N~N
H
N\ \
\ N/ ~ wCHs H
HO
1 H NMR (DMSO-de): b 1.50 (m, 2H), 2.26 (m, 2H), 2.48 (m, 5H), 3.01 (m, 8H), 4.53 (s, 2H), 6.78 (d, 1 H), 6.89 (d, 1 H), 7.38 (t, 1 H), 7.47 (t, 1 H), 7.5 (t, 2H), 7.76 (d, 1 H), 8.01 (t, 1 H), 8.22 (d, 1 H), 8.68 (d, 1 H), 8.74 (s, 1 H), 10.74 (brd s, 1 H), 11.45 (s, 1 H); MS (APCI): 538Ø
EXAMPLE 180:
3-Chloro-4-hydroxybenzoic acid ~[4-[2-~1 2 3 4-tetrahydroiso~uinolin-2-yIZ2-oxoethoxv'd~
naphth-1 ~rtmethylene~h vdrazide 1 H NMR (DMSO-ds): b 2.90 (d, 2H), 2.75 (m, 2H), 4.70 (d, 2H), 5.24 (s, 2H), 6.90 (t, 2H), 7.10 (m, 4H), 7.66 (m, 4H), 8.01 (s, 1 H), 8.34 (t, 1 H), 8.95 (m, 2H), 10.97 (brd s, 1 H), 11.68 (brd s, 1 H); MS (APCI): 514.2.
EXAMPLE 181:
2-~4-f(3-Chloro-4-hvdroxv-benzoyl)hydrazonomethyl]n~ h 1 loxy) N~3 trifluoromethox~rbenzyl)acetamide ,N
N
H
HO
CI
~ H NMR (DMSO-ds): 8 4.49 (d, 2H), 4.90 (s, 2H), 7.13 (m, 2H), 7.42 (m, 4H), 7.59 (dd, 1 H), 7.68 (dd, 1 H), 7.78 (m, 2H), 8.03 (s, 1 H), 8.51 (d, 1 H), 8.79 (t, 1 H), 9.0 (m, 2H), 10.85 (brd s, 1 H), 11.72 (s, 1 H); MS (APCI): 572.1.
EXAMPLE 182:
3-Chloro-4-hvdroxvbenzoic acid (4-~2-[4-(4-bromo hen~rl,Lhydrox~rp~eridin 1 yl] 2 oxoethoxy)naphth-1_ylmethylene~~dra~ide o~
o ~ I N
~N ~ \ OH
\ ~N
H \ ~ ~ \
HO
CI Br MS (APCI): 636, 638.
EXAMPLE 183:
2-{4-[(3-Chloro-4-hydroxvbenzoyl)hydrazonomethylJnal ht~ h-1-yloxy}-N~4-triffuoromethylsulfanylbenzyl)acetamide ci 1H NMR (DMSO-ds): 8 4.48 (d, 2H}, 4.88 (s, 2H), 7.08 (m, 2H), 7.45 (d, 2H), 7.68 (m, 4H}, 7.82 (m, 2H), 8.01 (d, 1 H), 8.52 (d, 1 H), 8.87 (t, 1 H), 8.96 (s, 1 H), 9.01 (d, 1 H), 10.98 (brd s, 1 H), 11.72 (s, 1 H}; MS (APCI): 588.2 dichlorobenz~,.[~acetamide EXAMPLE 184:
2-~~4-[(3-Chloro-4-hydroxy-benzoyl)hydrazonometh~rl]nai ht~ h-1-y~xy}-N (3 4 O / O~N \ CI
H
\ N/N \ \ ~ ~ ~ CI
H
i \
HO
CI
1 H NMR (DMSO-d6): 8 4.42 (d, 2H), 4.91 (s, 2H), 7.08 (d, 1 H), 7.11 (d, 1 H), 7.22 (d, 1 H), 7.48 - 7.76 (m, 4H), 7.82 (d, 2H), 8.04 (d, 1 H), 8.51 (dd, 1 H), 8.83 (m, 1 H), 8.91 (s, 1 H), 10.02 (d, 1 H), 11.00 (brd s, 1 H), 11.73 (s, 1 H); MS (APCI): 556.0 EXAMPLE 185:
O \ I O~N
.N. w I ~N~CH3 -N
HO I ~ H CH3 CI
'H NMR (DMSO-D6): 8 0.97 (d, 6H), 2.42 (m, 2H), 2.50 (m, 2H), 2.68 (septet, 1 H), 3.49 (m, 4H), 5.12 (s, 2H), 7.03 (d, 1 H), 7.08 (d, 1 H), 7.60 (t, 1 H), 7.68 (t, 1 H), 7.80 (d, 2H), 8.01 (d, 1 H), 8.33 (d, 1 H), 8.94 (s, 1 H), 9.00 (d, 1 H), 11.68 (s, 1 H); MS (APCI, neg.): 507.1, 509.1.
EXAMPLE 186:
O w ~ O~N~N_CH3 .N~ \ I CHI
I H
HO
CI
'H NMR (DMSO-D6): b 1.75 (m, 2H), 2.25 (m, 2H), 2.24 (d, 3H), 2.39 (quintet, 1 H), 3.26 (m, 2H), [2.84 (s, 1.5H) + 3.04 (s, 1.5H), 3HJ, 5.16 (d, 2H), 6.72 (t, 1 H), 7.07 (d, 1 H), 7.62 (t, 1 H), 7.68 (t, 1 H), 7.78 (dd, 2H), 8.00 (d, 1 H), 8.34 (m, 1 H), 8.94 (s, 1 H}, 9.00 (d, 1 H), 11.65 (brd s, 1,H); MS (APCI): 495.2, 497.2.
EXAMPLE 187:
0'I
0 ~ I O~N
N.N ~ ~ I ~CH
I~ H
HO
CI
'H NMR (DMSO-DB): 8 0.86 (s, 3H), 1.48 (m, 4H), 2.38 (t, 1 H), 2.72 (m, 1 H), 3.09 (t, 1 H), 3.84 (t, 1 H), 4.18 (t, 1 H), 5.09 (m, 2H), 7.03 (d, 1 H), 7.11 (d, 1 H), 7.59 (t, 1 H), 7.64 (t, 1 H), 7.82 (d, 2H), 8.01 (s, 1 H), 8.33 (d, 1 H}, 8.94 (s, 1 H), 9.00 (d, 1 H), 11.0 (brd, 1 H), 11.69 (brd s, 1 H); MS {APCI): 480.1, 482.1.
EXAMPLE 188:
o ~ I o~N ,N I
.N ~ W I CH3 I~ H
HO
CI
'H NMR (DMSO-De): 8 2.88 (s, 1.5H) + (s, 1.5H), 3H], 2.95 (t, 1 H}, 3.01 (s, 1.5H), 3.10 (s, 1.5H), 3.10 (t, 1 H), 3.69 (t, 1 H), 3.81 (t, 1 H), 5.05 (d, 2H), [6.66 + 6.95 (d), 1 H], 7.10 (d, 1 H), [7.20 + 7.38 (d), 1 H], 7.29 (d, 1 H), 7.67 (m, 5H), 8.01 (s, 1 H), 8.30 (t, 1 H), 8.53 (dd, 1 H), 8.97 (m, 2H), 11.67 (brd s, 1 H); MS (APCI): 517.3, 519.2.
EXAMPLE 189:
OMe O~ \ I OH
0 ~ ( H CI
H~N' \ OMe HO
CI
'H NMR (DMSO-D6): b 3.88 (s, 6H), 4.75 (s, 2H), 6.93 (d, 1 H), 7.08 (m, 3H), 7.34 (dd, 1 H), 7.74 (dd, 1 H), 7.79 (d, 1 H), 7.95 (s, 1 H), 8.37 (s, 1 H), 9.74 (s, 1 H), 10.03 (m, 1 H), 10.96 (brd s, 1 H), 11.76 (brd s, 1 H); MS (APCI): 534.4, 536.2.
EXAMPLE 190:
O ~ CH3 O Me0 ~ O~N w I
.N~ ~ I H
I , H
HO
CI
'H NMR (DMSO-D6): 8 1.18 (d, 6H), 2.85 (m, 1 H), 3.87 (s, 3H), 4.76 (s, 2H), 6.71 (d, 1 H), 6.78 (d, 1 H), 7.06 (d, 1 H), 7.20 (d, 2H), 7.58 (d, 2H), 7.78 (dd, 1 H), 7.82 (d, 1 H), 7.99 (d, 1 H), 8.70 (s, 1 H), 10.04 (s, 1 H), 10.92 (brd s, 1 H), 11.62 (brd s, 1 H);
MS (APCI): 496.5, 498.2.
EXAMPLE 191:
o ~ ocF, o w I o.~ N w I
.N. w I H
I ~ 'H
HO
CI
'H NMR (DMSO-D6): 8 4.88 (s, 2H), 6.93 (t, 2H), 7.23 (d, 2H), 7.47 - 7.70 (m, 6H), 7.86 (d, 1 H), 8.30 (d, 1 H), 8.80 (s, 1 H), 8.87 (d, 1 H), 10.34 (s, 1 H), 10.82 (brd s, 1 H), 11.55 (brd s, 1 H); MS (APC1): 558.5, 560Ø
EXAMPLE 192:
cl r~o o~ w I
o ~ i ~ Cr .N.
I H
HO
CI
'H NMR (DMSO-D6): b 4.06 (s, 3H), 4.94 (s, 2H), 6.81 (d, 1 H), 6.89 (s, 1 H), 7.19 (d, 1 H), 7.45 (s, 1 H), 7.90 (m, 3H), 8.10 (s, 1 H}, 8.82 (s, 1 H), 10.62 (s, 1 H), 11.07 (brd s, 1 H), 11.75 (s, 1 H); MS (APCI): 523.3, 524.8, 526.6.
EXAMPLE 193:
O w I O~N~N I i .N~ ~ I H
I ~ 'H
HO
Cr 'H NMR (DMSO-D6): 8 1.68 (m, 2H), 2.01 (m, 2H), 3.05 (m, 2H), 3.35 (m, 2H), 3.86 (m, 1 H), 4.26 (s, 2h), 4.81 (s, 2H), 6.95 (d, 1 H}, 7.09 (d, 1 H), 7.46 (s, 5H), 7.59 (m, 1 H}, 7.66 (t, 1 H), 7.77 (d, 1 H), 7.98 (d, 1 H), 8.34 (d, 1 H), 8.41 (d, 1 H), 8.92 (m, 2H), 9.65 (brd s, 1 H), 11.02 (brd s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 571.3, 572.3, 573.3.
EXAMPLE 194:
O ~ I O~N ~ I CI
.N~ ~ I H
I ~ 'H
HO
CI
'H NMR (DMSO-D6): 8 2.79 (t, 2H), 3.43 (qt, 2H), 4.71 (s, 2H), 6.95 (d, 1H), 7.08 (d, 1H), 7.17 (m, 1 H), 7.26 - 7.30 (m, 3H), 7.61 (t, 1 H), 7.67 (t, 1 H), 7.76 (m, 2H), 7.99 (d, 1 H), 8.24 (t, 1 H), 8.38 (d, 1 H), 8.91 (s, 1 H), 8.98 (d, 1 H), 10.94 (s, 1 H), 11.67 (s, 1 H); MS (APCI):
536.3, 538.2, 539.1.
EXAMPLE 195:
o ci w o ~l .N. w ~ H I , HO
Ci 'H NMR (DMSO-D6): 8 4.42 (d, 2H), 4.87 (s, 2H), 7.06 (m, 2H), 7.38 (d, 2H), 7.60 (t, 1H), 7.63 (m, 1 H), 7.80 (t, 1 H), 7.99 (d, 1 H), 8.49 (d, 1 H), 8.79 (t, 1 HJ), 8.93 (s, 1 H), 8.98 (d, 1 H), 10.95 (s, 1 H), 11.68 (s, 1 H); MS (APCI): 558.2, 560.1.
EXAMPLE 196:
4- 4-br m n I- 4- i i I t mi n ht -1- th i e- - hl r -4-by roxvbenzoic arid hvdrazone t o.
O H.N~ ~ i N
HO ~ I
Br Ruction scheme' C
H
N N N
OH ~ '' A OH B I w C
I I
i gr gr Br i O ,i O
w I I O.~N I --~ O w I I O~~N I
p ~ N.N. w 'H~ '' I ~ I ~ H
Br HO ~ Br CI
4-{4-bromophenyl~-4-Rneridinol chloroacetamide (mgt ,per:
To a solution of 4-(4-bromophenyl)-4-piperidinol (5 g, 19.5 mmol) and diisopropylethylamine (2.8 g, 21.5 mmol) in DMF (30 mL) was added dropwise chloroacetylchloride ( 2.2 g, 21.5 mmol). After stirring the mixture for one hour, the mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate (2x), 1 N HCI (3x), water, brine, and dried over MgS04. The solution was concentrated and chromatographed over silica gel with ethyl ace-tate to give the product as a brown solid (4 g, 62 %).
'H NMR (DMSO-D6): 8 1.21 (d, 2H), 1.71 (t. 1 H), 1.96 (t, 1 H), 2.71 (t, 1 H), 3.37 (t, 1 H), 3.70 (d, 1 H), 4.27 (d, 1 H), 4.54 (s, 2H), 5.26 (s, 1 H), 7.42 (d, 2H), 7.51 (d, 2H).
~4-bromo~yl~3.4-dih~rdro~oeridine chloroacetamide (ste~Bl:
To a solution of 4-(4-bromophenyl)-4-piperidinol chloroacetamide (4 g, 12 mmol) and diiso-propylethylamine (4.6 mL, 26 mmol) in THF (40 mL) cooled in an ice-bath was added methanesulfonyl chloride (2 mL, 26 mmol) and the mixture was refluxed for 16 hours under a nitrogen blanket. The reaction mixture was diluted with ethyl acetate and washed with 1 N
HCI (2x), aqueous NaHC03 (2x), brine (2x), and dried over MgS04. The solvent was evapo-rated and the product was chromotographed over silica gel with ethyl acetatelhexane (416).
The product was obtained as a yellow solid (1.5 g, 32%).
'H NMR (DMSO-Ds): 8 2.44 (t, 2H), 3.62 (m, 2H}, 4.14 (dd, 2H), 4.42 (d, 2H), 6.21 (s, 1H), 7.36 (m, 2H), 7.51 (d, 2H).
~-4-bromoohenyl-3 4-dihydro~~eradinylacetamideox)~naphthaldehyd~P (,~~:
A mixture of 4-(4-bromophenyl)-3,4-dihydropiperidine chloroacetamide (1.5 g, 4.8 mmol~, 4-hydroxynapthaldehyde (1.2 g , 7 mmol), and powdered potassium carbonate (1 g, 7.2 mmol) in acetonitrile (50 mL) was refluxed for 16 hours. The mixture was diluted with ethyl acetate 0 and washed with brine (3x), dried over MgS04, and concentrated. Silica gel chromatography with ethyl acetate/hexane (1/1 ) provided the product {1.4 g, 65%).
'H NMR (DMSO-D6): b 2.27-2.32 (m, 2H), 3.49-3.55 (m, 2H), 3.94 (brd s, 1H), 4.06 (brd s, 1 H), 5.08 (s, 1 H), 5.13 (s, 1 H), 6.05 (s, 1 H}, 6.97 (t, 1 H), 7.20 (t, 1 H), 7.34 (d, 2H), 7.42-7.47 (m, 1 H), 7.52-7.57 (m, 1 H), 7.92 (d, 1 H), 8.16 (d, 1 H), 9.01 (d, 1 H), 9.97 (s, 1 H).
4(-4-bromophenyl-3,4-dihydropiperadinylacetamideoxy)naphth-1-yl methylene-3-chloro-4-hydroxybenzoic acid hydrazone (step D):
The title compound was prepared according to the general procedure for the synthesis of alkylidene hydrazides from the condensation of 3-chloro-4-hydroxybenzoic acid hydrazide and 4-(4-bromophenyl-3,4-dihydropiperadinylacetamideoxy)naphthaldehyde:
'H NMR {DMSO-DB): 8 2.47-2.58 (m, 2H), 3.72 (br s, 2H), 4.13 (s, 1 H), 4.26 (s, 1 H), 5.14 (s, 1 H), 5.18 (s, 1 H), 6.23 (s, 1 H), 6.50-6.53 (m, 1 H), 7.03-7.06 (m, 1 H), 7.35-7.38 (m, 2H), 7.52 (d, 2H), 7.58 (d, 2H), 7.59-7.67 (m, 1 H), 7.75 (d, 1 H), 7.84 (s, 1 H), 8.32 (d, 1 H), 8.89 (s, 1 H), 8.92 (s, 1H), 11.41 (s, 1H); MS (APCI): 618.1, 620.1, 621.1, 622.1 EXAMPLE 197: EXAMPLE 202:
i oII ~ I o O \ I O~N N-CH O \ I O~N
H.N~ w ~ ~ N.N~ W N
i H
HO ~ HO ~ CHI
CI CI
EXAMPLE 198: 20 EXAMPLE 203:
0I' O ~ I O~N / 0 I -' I j~
N.N~ w ~N ~ I O ~ O~N~ / CI
I H .N. w I N I
HO H I , H
CI HO
CI
EXAMPLE 199:
EXAMPLE 204:
0 ~I ~o 0 \ i O~N OMe O \ I O " N OH
N.N~ ~ I \ I ~ H.N~ ~
H I ~ HO ~
HO CI
p~ 25 EXAMPLE 205:
EXAMPLE 200: ~ o I 'I
I p O ~ I O~N OH
N.N~ ~
O .N.v I O~N~ OMe I ~ H I
N ~ HO CI
H I ~ CI
HO
CI
EXAMPLE 201: EXAMPLE 206:
o ~i oI[
0 w I O~N O w I O~N I w .N~ w I ~ N.N~ w ~CH3 N ~ I H
HO I ~ H I ~ CF HO / N-CH3 15 CI ' CI
EXAMPLE 207: 15 EXAMPLE 212:
~ p I~ ~ oII
O w I O~ Q O ~ I O~N ~ CI
N.N~ w I N N~ ~ N.N~ W I H I , I ~ H
HO I ~ H O H HO
CI CI
EXAMPLE 208: EXAMPLE 213:
p ~I o O ~ I O~N N O ~ OV 'N
N.N~ ~ I I ~ ~ ~ N.N~ ~ I HOJ I ~ CI
I / H I , H
HO HO
CI CI
EXAMPLE 209: EXAMPLE 214:
p ~I o p ~ I O~N O ~ O~N
N.Nw w I ~ N.~Iw W I CHy \N
I , 'H N I ~ H
HO HO
CI
CI
EXAMPLE 210: EXAMPLE 215:
0 N.CHz ~ I OII
O W I O~N~ O W I O~N~ O
N.Nw w I CHI ~ N.N~ ~ CH~
I , H I , H
HO HO
EXAMPLE 211:
EXAMPLE 216:
O W I O~N.N~ , O
.N ~ w I H w I O~ O
~N O N
HO I ~ H ~ N.N. ~ I H C
CI HO I ~ H
CI
EXAMPLE 217: EXAMPLE 222:
OI O~NHzi i I OII
O ~ I O~N : ~ I O ~ I O~N
H.N~ w I H % N.N~ W ~Nw/.CH
N I H z HO ~' HO
CI Ct EXAMPLE 218:
EXAMPLE 223:
O ~ I O~N ~ I I ~ OMe O I
.N~ W I H O i O~N~N
H , N ~ ~ ( H CHa HO ~ I ~ -H
5 CI Ho Ct EXAMPLE 224:
EXAMPLE 219:
0'~
I O~ ~O O ~ I O~N ~ I CFA
O ~ I ~N~CHa ~ N.N. ~ I H
N. N . ~ CHI I , H
I H HO
Ho ~ 25 Ct CI
EXAMPLE 220: EXAMPLE 225:
I O'I ~ I i O CH3 O \ O~N~N~ O ~ I O~N w I H ' N.N~ W CN3 .N. w I H I , I H I ~ H CH, HO
HO
CI CI
15 EXAMPLE 221: EXAMPLE 226:
I ~
0 CFA \ I O~ CHI
o I H I ~
N.N. w i ~ O .N~ ~ I H I , I , H I , H
HO HO
CI Ct EXAMPLE 227: EXAMPLE 232:
~I ~I o O O \ O \ O V 'N
O \ I OV 'N \ \ N.N~ \ I
\ .N~ \ I H I , I , H
I H CI HO
HO ~ C1 CI
EXAMPLE 233:
EXAMPLE 228: ~ o O \ I O~N
O CHI \ .N. \ I ~N
O \ I O.~N \ I ~ H I , I H ~ HO
I \ H-N ~ \ ~ CH3 20 CI
HO
CI
EXAMPLE 234:
EXAMPLE 229: ~ I O HOC CH
\ O
O N i I CHI
O \ I O o N CH3 \ N.N ~ \ I ~N \
I H
\ .N. \ I H HO
I H CI
HO
CI
EXAMPLE 235:
EXAMPLE 230:
O ~ N
O O CH3 O \ I O~N \ I
\ O .N ~ \ I H I , I \ H.N. \ I CH3 I / H CI HO
HO CI
C!
EXAMPLE 231:
EXAMPLE 236:
\ I O~ O \ I O~N~ NOz \ O N.N ~ \ I H I i CF I \ H.N. \ I ~N ( \
I H
HO
Ho 30 cl EXAMPLE 237: EXAMPLE 242:
NH
00 % i I ' O
O ~ I O~N ~ I O \ O~N~ CH3 H.N. w I H I ~ H.N~ W I ~N~N~CH
HO
HO
CI CI
EXAMPLE 238:
20 EXAMPLE 243:
O \ I O - N O .N~v I O~H I ~ F
.N~ ~ I O ~ N F
W N I ~ H
H O HO
HO CI
CI
EXAMPLE 239:
EXAMPLE 244:
o cH, O O w I O~N~,N.CH
O ' I O~N~ CHI ~ N.N~ w ( H
N.N. ~ ~N ~ CH3 I H
i H I , HO
HO ~ CI
CI
EXAMPLE 245:
EXAMPLE 240: ~ I o OMe O O ~ I O~N
O ~ O~N~ CH ~ N.N~ ~ O
.N~ ~ I ~N CH I / H HC O
N OMe ~ ~ HO
H I , CI
HO
CI
EXAMPLE 246:
CI
15 EXAMPLE 241: ~ I O~ \ I
o I H CI
O ~ N.N~ ~
O w ~ O~N~CH~ I ~, H
HO
H~N. ~ I ~N I ~ CHI 3p CI
HO
CI
EXAMPLE 247: 15 EXAMPLE 252:
i 0 i 0 O w I I O~N~CH3 O ~ I I O~N
-N~ W ~N -N. w ~1N
I ~ 'H E ~ I ~ H
HO CH3 HO I ~ NO
CI CI
EXAMPLE 248: EXAMPLE 253:
O O CH3 i I OII
O~N
O -N ~ w I N O -N ~ w I ~ O
N
HO I ~ H HO I ~ 'H HsCyO
CI CI H~C'ICH3 EXAMPLE 249: EXAMPLE 254:
I' ~ o O ~ O~N~ ~ I 0~ CH
I H-N~ w I ~N ~ O -N~ ~ I N~
HO ~ I / I , H
F HO
CI CI
10 EXAMPLE 250:
EXAMPLE 255:
O OMe O ~ I O~N ~ I O
N.N~ w I O \ I O~N~ CF3 I H ~ -N ~ ~
HO ~ I ~ H ~N N i CI HO
CI
EXAMPLE 251:
EXAMPLE 256:
O~ O~CH3 ~ O
O N-N. ~ I N ICH\' CH3 O \ I I O N
I H ~ -N ~ w ~N
HO ~ I ~ H N i CI
EXAMPLE 257: 15 EXAMPLE 262:
~I p ~I p O ~ Ov _N O ~ Ov"N
.N. ~ I .N ~ ~ I I , -N ~ ~N
HO I ~ H H~C~O 0 HO , ~ H H~C'N'CH~
CI CI
EXAMPLE 258: EXAMPLE 263:
O F ~ O
p .N,v I o~N I ° \ I I °~N I J
J ~ .N.
N H3C ~ N I ~ ~0 I , H I , H N
HO ~ HO
CI CI
EXAMPLE 259: EXAMPLE 264:
I .~ ~ ( O.
I ° I w w o N'' O .N~ w N / i ~ N.N~ W I ~N~O ~ I
N I H
HO I ~ H H'C.N.CH3 HO Ci O
CI
10 EXAMPLE 260: EXAMPLE 265:
p CI ~ I ~ I ~ Noz O ~ p~N~g~ O ~ I O N I w I H ~ .N ~ ~
N.N~ ~ F I H
HO I ~ H HO ~ H~C'N'CH~
EXAMPLE 261: EXAMPLE: 266 O i O CH i O \ I O" N CHI O ~ I O~N ~ I
I
H,N. ~ H C I ~ H.N~ ~
i i ~N
HO Y HO Y
CI CI
EXAMPLE 267: EXAMPLE 272:
o~ I ~ I o.
O N. N ~ w I CHs I , O N
I
I H I ~ H.N
HO
CI HO
CI
EXAMPLE 268: 20 EXAMPLE 273:
I O II ~.--CHI i I O
~~- N ~ O ~ ~ .CHs O N.N. w I N~ CH3 ~ O .N. w I H~N'CH
I , H I H sC ~
HO
CI HO
CI
EXAMPLE 269: EXAMPLE 274:
o'I ~ o'I
O ~ I I O~N~ F O ~ I O~N
.N~ ~ ~N .N~ ~ I OH
I~ H I~ I~ H
HO HO ~ /
Ct CI
EXAMPLE 270: EXAMPLE 275:
OII ~ 0 CHs O w I O~N~N w CHs O W I O~N~tJ.CH~
N.N~ ~ I H CJ I ~ ~ N.N~ ~ I ~CH
I H ' I H ' HO ~ HO
CI CI
EXAMPLE 276:
EXAMPLE 271:
O w I O~N w / O N
I ~ H
N.N~ ~ I H I i O ~ I O N
I , H ~ N.N
HO I H
CI HO
CI
EXAMPLE 277: EXAMPLE 282:
o ~ o O ~ I O~N / O ~ I O~N~CH~
N.N~ w I W I ~ N.N~ w I ~N' w I H I H
HO ~ HO ~ ~ CI
CI CI
5 EXAMPLE 278: EXAMPLE 283:
oII ~ oII
0 ~ I O~N~ O ~ I I O~N~
N.N~ w I ~.N ~ ~ N.N. W~O
HO I ~ H I i CHI HO I ~ 'H - ~N'Hz CI O CI
EXAMPLE 284:
EXAMPLE 279:
0 0 ~ I I o.~N
O ~ O~N ~ CFA ~ N.N~ ~ ~~ ~ CFA
N.N ~ ~ I H I i CI HO I ~ H
HO ( ~ H 25 CI
10 pl EXAMPLE 285:
EXAMPLE 280:
o CI
I1 O W I O~N
O
O~ ~ .N. W I CH3 I
O N.N~ w I I r I , H
HO
HO I ~ H H3C. N. CH3 CI
cl EXAMPLE 286:
15 EXAMPLE 281: o ~ I °~N'~
~ N.N~ w I ~N w w I
I o~ I ~ H
HO
I ~ O H. N w w I N I / 3~ CI
HO ~ O O
CI 'CH
EXAMPLE 287: EXAMPLE 291:
O ~N
O w O~N~CH3 H.N. w I O w I p_ ~
~N F
HO ~ CHz ~ . N ~ ~ I
N Iw CI HO I i H i CI
EXAMPLE 288: 15 EXAMPLE 292:
p ~ o O ~ I O~N~ O ~ I O~N ~ Cl N.N ~ w I CHI ~ N.N ~ w I H I i CH
I H I ~ H 5 HO HO
CI C!
EXAMPLE 293:
EXAMPLE 289:
I~ ,I ~ Ii 0~
O w O
O .N~v I p~H I \ ~ O N.Nw W I H
i I H ~ HO I ~ H
HO
CI
CI
EXAMPLE 294:
10 EXAMPLE 290:
~ o cH, I N O ~ I O.~N I
.N~ W I H I
o ~ o.~N L ~
.N ~ ~ I HO
N ~ CI
HO I ~ H I i CHI
CI CHs EXAMPLE 295: EXAMPLE 299:
o1. ~ o O w I O~N . N O w I O~N ~ N
N.N. w I / I i ~ N.N. w I ~ I i H I ~ H
HO ~ HO
CI C!
EXAMPLE 296: EXAMPLE 300:
OII ~ O /~~N
O ~ I O~N O ~ I O~N
N.N ~ ~ I H CJ I ~ CH ~ N.N. ~ I
I ~ H ' ~ I ~ H
EXAMPLE 297: EXAMPLE 301:
il o ~I
w o Jl w O N.N. ~ I H I ~ O ~ I I O~N~ CHI
HO ~ H ~ .N~ ~ ~O
CI HO I ~ ~ TCH~
90 EXAMPLE 298:
0'I
O \ ~ O~N~ OI ~
.N. w ~N~
[[[[N
HO I ~ H O
CI
EXAMPLE 302: 15 EXAMPLE 307:
I oII
O ~ O N
O ~ I O~N Nw N.N~ w I ~~ vCH~ ~ .N. w I
HO I ' H I ~ H I N
HO Y
C! C7 EXAMPLE 303: EXAMPLE 308:
' o ~I o O ~ I O~N~OMe O w O~N O
H.N~ w ~ N.N~ w I CH~
HO ' OMe HO I ~ H
CI CI
EXAMPLE 304: EXAMPLE 309:
I II V
p ~ O~N~N~ H~ ~CH~ O w I O~N OMe I H i!'-O ~
~.N. W O ~ N.N ~ w I CHs OMe HO ' I ~ H
HO
CI CI
10 EXAMPLE 305:
EXAMPLE 310:
w I o.~ N ~ I o w oil O N.N~ ~ I I , O I N
N.N~ ~ ~N N\
I~ H
HO ~ ( H I 1 C. HO ' ~N~
CI
EXAMPLE 306:
EXAMPLE 311:
I II
O .N~\~ I O~N I i O \ I O~LN
N CHI . N ~ ~ ( CH
I H w N a HO ' N I ~ H
CI ~O HO
CI
EXAMPLE 312: 15 EXAMPLE 317:
OMe OMe O
~ I ~ ~ I oil 0 ~ I O N ~ OMe O .N. ~ ( ( ~ H.N ~ w CHI I ~ H OMe ~ I
i HO
HO ~ CI
CI CI
EXAMPLE 313: EXAMPLE 318:
o ~I oI' 0 ~ I O~N 'N 0 ~ I O~N I \
N.N. w I ~ I i I ~ H.N. W
I \ H I i HO ~ ~ HO
CI I CI
EXAMPLE 319:
EXAMPLE 314:
I p p ~ I p~N ~ I
O ~ O~N~ ~ .N. ~ I
N.N ~ w I ~N ~ I ~ H
I H ~ HO O
HO ~ ~ CI CI
CI
10 EXAMPLE 315: EXAMPLE 320:
o ~i oI' 0 w I O~N w I O w I O~N~ CHs .N~ w I O ~ N.N~ w ~N
I ~ H I ~ L i H I i HO HO ~ CHI
EXAMPLE 321:
EXAMPLE 316:
i oII
O w I O~N CHI O .N~\~ I O~N I i N.N~ ~ I I , H
I H HO
HO ~ CI N
CI
EXAMPLE 322: 15 EXAMPLE 327:
o ~ o O \ I O~N~ O \ I O~N
H.N~ ~ ~N.CH ~ .Nw W ( ~~
a N v -N
I ~ H
HO HO
CI CI
EXAMPLE 323: EXAMPLE 328:
O O ~ .CHa O ~ I Ov 'N I w w O~ ~S w ~ .N. w O H.N~ ~ ( H HO I i H
HO ~ CI
cl 20 EXAMPLE 324:
EXAMPLE 329:
cH, ~ I o o I ~ I o w I o~~N~
O ~ O~N~~~ ~ N.N~ ~ ~N ~ CI
H.N ~ w I ~ HO I / 'H I
I ~ cl HO
CI
EXAMPLE 325: 25 EXAMPLE 330:
o I
O ~ I O~N O ~ O~N~CH~
TI
N.N. ~ I ~N ~ ~ N.N~ ~ ~N~
H I ~ HO I i H '~('~~~ OMe HO
CI CI
EXAMPLE 326:
EXAMPLE 331:
o w I o~LN cH~ ~ I o N.N~ w I O \ I O~N~ C1 .N~ ~ ~N
HO I ~ 'H CHI I , H I , C! HO ~' 30 cl EXAMPLE 332: EXAMPLE 337:
~I o ~ o I' I II
O ~ I O~N~ O ~N
N.N~ w ~N ~ CHI ~ N.N~v I 0 ~~~N~CH2 I H I H
HO ~ HOC ~ HO
CI CI I
CHZ
EXAMPLE 333: 20 EXAMPLE 338:
O \ I 0 N~ O ~ I O~N~OEt N.N~ ~ ~N ~ .N. ~ I
N
HO I ~ 'H I ~ HO I i H OEt CI CI
EXAMPLE 339:
EXAMPLE 334:
O ~ I O~N'~ O i i I O ~ N.N~ w IN ~ I
O \ I O~N~ CI HO I ~ H CHI
H.N. w N I w CI
HO ~ CI ~ N
25 EXAMPLE 340:
EXAMPLE 335: o w I o~N ~ I
N.N~ ~ I ~OEt TO
0 w I O~N p HO I i H OEt N.N~ ~ I CI
I H
HO ~ II
CI N
EXAMPLE 341:
EXAMPLE 336: o ~ I o Jl N
i I O I % H.N . ~\ I HO I
0 w O~N~ HO CI
CI
.N. ~ I ~N CI
I ~ 'H I ~
HO CI
CI
EXAMPLE 342:
o ~l N.N. w , J N I N
HO ~ H ~ '~' N
Ct General procedure for synthesis of compounds of the qenPral formula XII
O NH
O B\ A~ i Z O O
_OH
step A A" ~ \ B v 'OH
H
O O
NHR~R~ ~~
A J,l / \ B~ / Rsc N
step B ~ Rsa formula XII
A and B are as defined for formula I and -NRS'Rsa is R~ Raa Rat -N-(CHZ)~---~a-(CHZ)d o where Rsa, R'a, R4b, c, q, d and D are as defined for for-mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent.
The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tent-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloro-methane, DMSO, acetic acid, water or a compatible mixture of two or more of the above sol-vents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylort-hofom~ate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C
to 140°C, preferably between 10°C to 80°C. fn many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli-zed if necessary from a solvent such as the above described reaction solvents.
The product can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloro-methane/methanol or chloroform/ethyl acetate.
Step B: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an an-y hydride or an acid halide that can then react with the amine to give a compound of formula Xll.
Step B was also done combinatorially with a preactivated acid and a selection of amines. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purifed by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XII.
Specific examples illustrating the preparation of compounds of the general formula XI! accor-ding to the invention are provided below.
Preparation of 4-formyl-1-naphthylacetic acid:
This compound was prepared from the reduction of 4-cyano-1-naphthylacetic acid in the presence of 85% formic acid and Raney alloy as described in the literature.
References : 1 ) A.A. Shulezhko and A.I. Kiprianov, J. org. Chem., (USSR) English translation, 4, 1968, p.1052. 2) Zh. Org. Khim., 4, 1968, p. 1089.
Preparation of 4-[3-Chloro-4-hydroxybenzoyl}-hydrazonomethyl~-1-naphthylacetic acid (step A):
This compound was prepared according to the general procedure for the synthesis of alkyli-dene hydrazides from the condensation of 4-formyl-1-naphthylacetic acid above and 3-chloro-4-hydroxybenzoic acid hydrazide.
'H NMR (DMSO-Ds): 8 4.1 (s, 2H), 7.1 (d, 1 H), 7.5 (d, 1 H), 7.7 (qt, 2H), 7.8 (d, 1 H), 7.9 (d, 1 H), 8.0 (s, 1 H), 8.1 (d, 1 H), 8.8 (d, 1 H), 9.1 (s, 1 H), 11.0 (brd s, 1 H), 11.8 (s, 1 H), 12.2 (brd s, 1 H); MS (APCI): 383.4, 385.2.
Preparation of (3-formylindoiyl)acetic acid:
Ethyl (3-formylindolyl)acetate:
3-Formylindole (10.0 g, 69 mmoles) was dissolved in DMF (100 ml). Under NZ was a 60%
suspension of NaH in mineral oil (3.0 g) added in portions with cooling (temp < 15 °C). At <
15 °C was a solution of ethyl bromoacetate (8.4 mf) in DMF (15 ml) added drop wise over 30 minutes. The resulting mixture was stirred at room temperature for 16 hours and evaporated in vacuo. The residue was added water (300 ml) and extracted with ethyl acetate (2 x 150 ml), the combined organic extracts were washed with satd. NH4CI, dried (MgS04) and con-centrated to afford 15.9 g ethyl (3-formylindolyl)acetate.
'H NMR ( CDC13 ) 8 1.26 (t, 3H), 4.22 (q, 2H), 4.90 (s, 2H), 7.21 - 7.35 (m, 3H), 7.72 (s, 1 H), 8.30 (d, 1 H), 10.0 (s, 1 H).
(3-formylindolyl)acetic acid:
Ethyl (3-formylindolyl)acetate (15.9 g) was dissolved in 1,4-dioxane (100 ml) and added 36%
aq. NaOH (10 ml). The resulting mixture was stirred at room temperature for 4 days. Water (500 ml) was added and the mixture was washed with diethyl ether (150 ml). The aqueous phase was made acidic with 5N HCI and extracted with ethyl acetate (250 + 150 ml). The combined organic extracts were dried (MgS04) and evaporated in vacuo to afford 10.3 g (73 % over two steps) of (3-formylindolyl)acetic acid.
'H NMR ( DMSO-de ) 8 4.94 (s, 2H), 7.27 - 7.36 (m, 3H), 7.98 (s, 1 H), 8.25 (d, 1 H), 10.0 (s, 1 H), 12.5 (bs, 1 H).
Preparation of (4-Formylindolyl)acetic acid:
4-Formyfindole:
This compound was synthesized according to F. Yamada, M. Somei, Heterocycles (1987) 1173.
'H NMR ( CDCI 3 ) 8 7.28 - 7.36 (m, 2H), 7.41 (t, J = 3.0 Hz, 1 H), 7.60 -7.70 (m, 2H), 8.62 (brd s, 1 H), 10.20 (s, 1 H). GC-MS (pos.): 146 Ethyl (4-formylindolyl)acetate:
This compound was synthesized according to the general procedure for N-alkylation of in-doles.
'H NMR (CDCI,) 8 1.13 {t, J = 6.9 Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H), 4.86 (s, 2H), 7.22 - 7.35 (m, 3H), 7.49 (d, J = 8.6 Hz, 1 H), 7.60 (d, J = 7.3 Hz, 1 H), 10.20 (s, 1 H).
(4-Formylindolyl)acetic acid:
This compound was synthesized according to the general procedure for saponification of esters.
'H NMR ( DMSO-de ) b 5.15 (s, 2H), 7.12 (d, J = 3.0 Hz, 1 H), 7.36 (d, J = 7.9 Hz, 1 H), 7.61 (d, J = 3.1 Hz, 1 H), 7.71 {d, J = 7.3 Hz, 1 H), 7.82 (d, J = 8.2 Hz, 1 H), 10.20 (s, 1 H), 12.94 (brd s, 1 H).
Preparation of (5-formylindolyl)acetic acid:
5-Cyano-N-tosyiindole:
In a 100 mL round-bottom flask was placed NaH (0.4 g, 60% dipersion in mineral oil, 10 mmol) and anhydrous THF (10 mL) was added. To the suspension was added a solution of 5-cyanoindole (1.0 g, 7 mmol) in anhydrous THF (10 mL) by syringe at 0°C. The mixture was stirred for 10 min, and tosyl chloride (1.6 g, 8.4 mmol) was added. After stirring at room temperature for 2 h, water (100 mL) was added. The mixture was extracted with ethyl ace-3o tate (3x50 mL), dried (MgSO,), and concentrated. The residue was purified by column chro-matography using hexane: ethyl acetate = 2:1 as eluent to yield 1.86 g (92%) of the desired product.
'H NMR ( CDC13) b 2:32 (s, 3H), 6.65 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H ), 7.41 (d, J = 8.6 Hz, 1 H), 7.57 (d, J = 3.6 Hz, 1 H), 7.63 (s, 1 H), 7.75 ( d, J = 8.3 Hz, 1 H), 7.99 (d, J =
8.6 Hz, 1 H).
5-Formyl-N-tosylindole:
To a solution of 5-cyano-N-tosylindole (0.66 g, 2.2 mmol) in anhydrous THF (20 mL}, was added 1 M DIBAL in hexane (4 mL, 4 mmol) via syringe at 0°C. The mixture was stirred at room temperature for 16 h, poured into ice-cooled 1 N hydrochloric acid (50 mL), extracted 1 o with ethyl acetate (3 x 80 mL). The combined organic extracts were dried (MgS04), and concentrated to give an oil. After a short column chromatography using hexanelethyl acetate 2: 1 as eluent 0.62 g (95%) pure 5-formyl-N-tosylindole was obtained.
'H NMR (CDCI3) 8 2.29 (s, 3H), 6.74 (d, J = 3.7 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 2H), 7.65 (d, J
= 3.7 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 2H), 7.82 (dd, J = 1.4, 8.6 Hz, 1 H), 8.02 (d, J = 1.1 Hz, 1 H), 8.09 (d, J = 8.6 Hz, 1 H ), 9.99 (s, 1 H).
5-Formylindole:
5-formyl-N-tosylindole (0.5 g, 1.7 mmol) was dissolved in a mixture of methanol (10 mL) containing 5% aqueous KOH solution (5 mL). The mixture was refluxed for 3-h, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (3x50 mL). The combined organic extracts were dried (MgSO,), and concentrated. The residue was purified by short column chromatography to provide 240 mg (97%) of the desired product.
'H NMR (CDCI3) b 6.70 (t, J = 2.1 Hz, 1 H), 7.32 (t, J = 2.3 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.78 ( dd, J = 1.5, 8.6 Hz, 1 H), 8.19 (s, 1 H), 9.45 (b, 1 H), 10.15 (s, 1 H). GC-MS (pos.): 146.
Ethyl (5-formylindolyl)acetate:
This compound was synthesized according to the general procedure for N-alkylation of in-3o doles.
'H NMR (CDC13) 8 1.27 (t, J = 6.8 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 4.87 (s, 2H), 6.70 (d, J =
3.4 Hz, 1 H), 7.18 (d, J = 3.0 Hz, 1 H), 7.36 (d, J = 8.7 Hz, 1 H), 7.78 (d, J
= 8.3 Hz, 1 H), 8.14 (s, 1 H), 10.01 (s, 1 H).
(5-Formylindolyl)acetic acid:
this compound was synthesized according to the general procedure for saponification of esters.
'H NMR (DMSO-de) S 5.10 (s, 2H), 6.66 (d, J = 3.0 Hz, 1 H), 7.48 (d, J = 3.0 Hz, 1 H), 7.56 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 8.17 (s, 1 H), 9.97 (s, 1 H), 12.9 (brd s, 1 H).
General procedure for preparation of [{3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acids:
These compounds were prepared according to the general procedure for the synthesis of alkylidene hydrazones by condensation of the various formylindolylacetic acids with 3-chloro-4-hydroxy benzoic acid hydrazide.
3-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid:
'H NMR (DMSO-DB): 8 2.81 (t, J = 6.5, 2H), 4.43 (t, J = 6.5, 2H), 7.06 (d, J =
8.5, 1 H), 7.15-7.28 (m, 2H), 7.56 (d, J = 8.1, 1 H), 7.75 (d, J = 8.5, 1 H), 7.83 (s, 1 H), 7.95 (s, 1 H), 8.27 (d, J
= 7.65, 1 H), 8.54 (s, 1 H), 10.88 (br s, 1 H), 11.41 (s, 1 H). LRMS calcd for C,9 H,e CI, N3 04 (M - H) 384, found 384Ø
4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid:
'H NMR ( DMSO-d6 ) 8 5.09 (s, 2H), 7.09 (d, J = 8.6 Hz, 1 H), 7.16 - 7.25 (m, 2H), 7.32 (d, J
= 7.2 Hz, 1 H), 7.45 - 7.55 (m, 2H), 7.81 (d, J = 8.2 Hz, 1 H), 8.01 (d, J =
1.8 Hz, 1 H), 8.68 (s, 1 H), 10.96 (s, 1 H), 11.71 (s, 1 H), 12.90 {b, 1 H). MS ( APCI, neg.): 370.
5-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid:
'H NMR (DMSO-d fi) 85.09 (s, 2H), 6.35 (d, J = 2.9 Hz, 1 H), 7.06 (d, J = 8.6 Hz, 1 H), 7.39 (d, J = 3.1 Hz, 1 H), 7.47 (d, J = 8.6 Hz, 1 H), 7.61 (d, J = 8.6 Hz, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.83 (s, 1 H), 7.97 (s, 1 H), 8.48 (s, 1 H), 10.93 (s, 1 H), 11.58 (s, 1 H), 12.90 (brd s, 1 H). MS
(APCI, neg. ): 370.
[3-Chioro-4-hy~~oxybenzoyl~:_hydrazonomethyrl]-1-naphthylacetamides and the various indolacetamides lste~:
1o General librar~production procedures To solutions of 4-[(3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]naphthylacetic acid and the various indolylacetic acids in DMSO was added carbonyldiimidazole (1.2 eq).
The solution was agitated for 5 minutes and diluted with DMSO to a concentration of 50 mM.
The soluti-on was then dispensed into 88 deep well plates containing solutions of amines in DMSO (50 mM). The plates were covered and agitated for 16 hours. The products were purified by HPLC.
Examples of compounds of the formula XII:
EXAMPLE 343:
r cH, O w I NvCH~
II
.N~ ~ I o I~ H
HO
CI
'H NMR (DMSO-D6): b 1.06 (t, 3H), 1.17 (t, 3H), 3.31 (qt, 2H), 3.50 (qt, 2H), 4.19 (s, 2H), 7.10 (d, 1 H), 7.45 (d, 1 H}, 7.64 (quintet, 2H), 7.83 (d, 1 H), 7.88 (d, 1 H), 7.98 (m, 2H), 8.87 (d, 1 H), 9.09 (s, 1 H), 10.99 (brd s, 1 H}, 11.80 (brd s, 1 H); ms (APCI);
438.1, 440.1.
EXAMPLE 344:
o ~ I N '~
_ I ~ ''N
.N~ ~ O
I~ H
HO
CI
'H NMR (DMSO-Dg): 8 0.98 {d, 4H), 2.76 {t, 2H), 3.02 (quintet, 1 H), 3.59 (t, 2H), 4.40 (s, 2H), 7.10 (d, 1 H), 7.48 (d, 1 H), 7.48 (d, 1 H), 7.59 (qt, 1 H), 7.67 (t, 1 H), 7.81 (d, 1 H), 7.89 (d, 1 H), 7.97 (d, 1 H), 8.02 (s, 1 H), 8.84 (d, 1 H), 9.09 (s, 1 H), 10.99 (brd s, 1 H) 11.80 (brd s, 1 H); MS (APCI, neg.): 473.1, 475.1.
EXAMPLE 345:
O ~ I N '~
I ~ ''N
.N~ ~ O
f~
HO
CI
'H NMR (DMSO-Dg): 8 2.50 (2H), 2.68 (t, 2H), 4.00 (s, 2H), 7.10 (d, 1 H), 7.53 (d, 1 H), 7.65 (tt, 2H), 7.80 (dd, 1 H), 7.90 {d, 1 H), 8.02 (d, 1 H), 8.14 (d, 1 H), 8.62 (t, 1 H), 8.84 (d, 1 H), 9.09 (s, 1 H), 11.0 (brd s, 1 H) 11.80 (s, 1 H); MS (APCI): 433.1, 435.1 EXAMPLE 346:
o ~ I N '~
I ~ ''N
.N~ ~ O
I ~ 'H
HO
CI
'H NMR (DMSO-D6): 8 1.08 (m, 4H), 1.54 (m, 6H), 2.70 (t, 2H), 3.45 (t, 2H), 3.76 (m, 1H), 4.30 (s, 2H), 7.06 (d, 1 H), 7.49 (d, 1 H), 7.64 (m, 2H), 7.80 (d, 1 H), 7.88 (d, 1 H), 8.01 {s, 1 H}, 8.07 (d, 1 H), 8.83 (d, 1 H), 9.09 (s, 1 H), 10.5 (brd d, 1 H), 11.78 {brd s, 1 H); MS (APCI, neg.}:
515.2.
EXAMPLE 347:
N
O ~ I N
II
.N~ ~ I O
I
HO
CI
'H NMR (DMSO-D6): b 1.26 (m, 2H), 1.37 (m, 4H), 1.67 (m, 2H), 2.43 (m, 4H), 2.62 (m, 3H), 3.10 (t, 2H), 3.90 (d, 1 H), 4.32 (s, 2H), 4.48 (d, 1 H), 7.10 (d, 1 H), 7.31 (d, 1 H), 7.48 (m, 2H), 7.81 (d, 1 H), 7.88 (d, 1 H), 8.03 (m, 2H), 8.85 (d, 1 H), 9.08 (brd s, 1 H), 11.76 (brd s, 1 H): MS
(APCI): 533.2.
EXAMPLE 348:
~N
p ~I NJ
II
.N. ~ I o I~ H
HO
~I
'H NMR (DMSO-DB): 8 3.03 (m, 4H), 3.68 (t, 2H), 3.79 (t, 2H), 4.30 (s, 2H), 7.14 (m, 5H), 7.47 (d, 1 H), 7.66 (quintet, 2H), 7.82 (d, 1 H), 7.88 (d, 1 H), 8.02 (d, 1 H), 8.07 (d, 1 H), 8.87 (d, 1 H), 9.10 (s, 1 H), 10.99 (s, 1 H), 11.80 (s, 1 H); MS (ACPI): 545.6.
EXAMPLE 349:
~F
N ('~~I
p ~I NJ
Ii .N. ~ I o I ~ 'H
HO
CI
'H NMR {DMSO-DB): 8 3.10 (d, 4H), 3.67 {d, 4H), 4.30 (s, 2H}, 7.00 (m, 2H), 7.09 (m, 3H), 7.47 {d, 1 H), 7.62 (quintet, 2H), 7.82 (d, 1 H}, 7.88 (d, 1 H), 8.03 (s, 1 H), 8.06 (d, 1 H), 8.85 (d, 1 H), 9.10 (s, 1 H), 10.99 (s, 1 H), 11.80 (s, 1 H); MS (ACPI): 544.5, 545.3.
EXAMPLE 350:
CHI
~N~N.CH' o ~I NJ
il .N~ ~ I O
I~
HO
CI
'H NMR (DMSO-DB): 8 2.15 (s, 6H), 2.39 (m, 8H), 3.51 (d, 4H), 4.22 (s, 2H), 7.03 (d, 1 H), 7.43 {d, 1 H), 7.64 (quintet, 2H), 7.77 (d, 1 H), 7.87 (d, 1 H), 7.99 (s, 1 H), 8.02 (d, 1 H), 8.83 (d, 1 H), 9.08 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 522.2.
EXAMPLE 351:
Hz i O ~ I I N~CHz .N~ ~ O
I ~ 'H
HO
CI
'H NMR (DMSO-Ds): 8 3.93 (d, 2H), 4.10 (d, 2H}, 4.23 (s, 2H), 5.20 (m, 4H), 5.79 (m, 1H), 5.94 (m, 1 H), 7.10 (d, 1 H), 7.78 (d, 1 H), 7.63 (m, 2H), 7.80 (d, 1 H), 7.83 (d, 1 H), 7.95 (d, 1 H), 8.02 (d, 1 H), 8.85 (d, 1 H), 9.10 (s, 1 H), 11 (brd s, 1 H), 11.80 (brd s, 1 H); MS (ACPI):
462.2 EXAMPLE 352:
0 ~ I N~N
II
.N. ~ I O
I , H
HO
CI
'H NMR (DMSO-Dg): 8 0.9 (t, 3H}, 1.30 (sextet, 2H), 1.54 (sextet, 2H), 3.56 (t, 2H), 4.31 (s, 2H), 4.39 (s, 2H), 7.06 (d, 1 H) 7.48 (d, 1 H), 7.65 (quintet, 2H), 7.79 (dd, 1 H), 7.87 (d, 1 H), 7.97 (d, 1 H), 8.01 (d, 1 H), 8.85 (d, 1 H), 9.09 (s, 1 H), 11.79 (s, 1 H); MS
(APCI): 477.01, 479.2.
EXAMPLE 353:
H,c o ~I
a .N. w I o I~ H
HO
CI
'H NMR (DMSO-De): 8 1.17 (m, 4H), 1.54 (m, 4H), 2.68 (m, 1 H), 3.77 (d, 1 H), 4.18 (s, 2H), 4.33 (m, 1 H), 4.76 (bid, 1 H), 7.10 (d, 1 H), 7.43 {m, 1 H), 7.65 (quintet, 2H), 7.81 (d, 1 H), 7.88 (d, 1 H), 8.02 (s, 1 H), 8.04 (d, 1 H), 8.84 (d, 1 H), 9.09 (s, 1 H), 11.79 (s, 1 H); MS (APCI):
464.1, 466.2.
EXAMPLE 354:
H~
i I N N
O
N.N~ w I O I i I H
HO
CI
'H NMR (DMSO-D6): 8 0.85 (qt, 3H), 1.53 (m, 2H), 3.00 (dt, 2H), 3.29 (quintet, 2H), 3.77 (dt, 2H), 4.13 (d, 2H), 7.05 (d, 1 H), 7.26 (m, 2H), 7.36 (d, 1 H), 7.52 (qt, 1 H), 7.69 (m, 2H), 7.87 (m, 2H), 7.95 (d, 1 H), 8.00 (s, 1 H), 7.87 (dd, 1 H), 8.84 (t, 1 H), 9.07 (brd, 1 H), 11.76 (brd s, 1 H);. MS (APCI): 529.2, 529.7, 531.2.
EXAMPLE 355:
CHI
i O
.N~ ~ I O
I~ H
HO
Ci 'H NMR (DMSO-D$): 8 0.85 (qt, 3H), 1.33 (m, 1 H), 1.65 (m, 7H), 2.60 (t, 0.5H), 3.10 (t, 0.5H) 3.80 (m, 1 H), 4.21 (s, 2H), 4.24 (m, 1 H), 7.11 (d, 1 H), 7.45 (t, 1 H), 7.65 (m, 2H), 7.75 (d, 1 H), 7.89 (d, 1 H), 8.01 (d, 1 H), 8.05 (d, 1 H), 8.83 (d, 1 H), 9.09 (s, 1 H), 11.80 (s, 1 H); MS
(APCI): 478.4, 480.3.
EXAMPLE 356:
~.N~.CH2 o ~I NJ
.N~ ~ I O
I ~ 'H
HO
C!
'H NMR (DMSO-DB): 8 2.36 (m, 4H), 2.97 (d, 2H), 3.50 (m, 2H), 3.60 (m, 2H), 4.23 (s, 2H), 5.17 (t, 2H), 5.86 (m, 1 H), 7.08 (d, 1 H), 7.43 (d, 1 H), 7.64 (quintet, 2H), 7.79 (dd, 1 H), 7.87 (d, 1 H), 8.01 (s, 1 H), 8.04 (d, 1 H), 8.83 (d, 1 H), 9.09 (d, 1 H), 11.79 (brd s, 1 H); MS (APCI):
4.91.2, 493.2.
EXAMPLE 357:
I
o w N~
.N. ~ I O \\N
I~ H
HO
CI
'H NMR (DMSO-Ds): 8 1.50 (m, 1 H), 1.90 (m, 2H), 1.95 (m, 1 H), 2.72 (t, 1 H), 2.95 (t, 1 H), 3.30 (m, 1 H), 3.55 (m, 1 H), 3.65 (t, 2H), 3.75 (m, 1 H), 3.92 (t, 1 H), 4.12 (t, 1 H) 4.35 (d, 2H), 7.11 (d, 1 H), 7.48 (m, 1 H), 7.65 (t, 1 H), 7.68 (t, 1 H), 7.8 (dd, 1 H}, 7.87 (d, 1 H), 8.00 {d, 1 H), 8.03 (d, 1 H), 8.83 (d, 1 H}, 9.10 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI):
519.5, 521.2, 522.2.
EXAMPLE 358:
~N.CH~
o ~ I NJ
I.
.N. ~ I O
I , H
HO
'H NMR (DMSO-D6): 8 2.19 (s, 3H}, 2.30 (m, 4 H), 3.50 (T, 2H), 3.58 (T, 2H), 4.22 (S, 2H), 7.03 (D, 1 H), 7.43 (D, 1 H), 7.64 (quint, 2H) 7.77 (dd, 1 H), 7.87 (d, 1 H), 7.99 (d, 1 H}, 8.04 (s, 1 H), 8.83 (d, 1 H), 9.09 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 465.2, 467.3.
EXAMPLE 359:
N
~I ~J I~
.N. ~ I O
I H
HO
CI
'H NMR (DMSO-De): 8 2.38 (m, 4H), 3.51 (s, 4H), 3.61 (t, 2H), 4.22 (s, 2H), 7.08 (d, 1H), 7.31 (m, 5H), 7.43 (d, 1 H), 7.61 (quintet, 2H), 7.82 (dd, 1 H), 7.88 (d, 1 H), 8.00 (s, 1 H), 8.02 (d, 1 H), 8.85 (d, 1 H), 9.10 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 541.4, 543.1.
EXAMPLE 360:
CHI OH
O ~ I N w . N w w I O CHI I i I~ H
HO
CI
'H NMR (DMSO-Ds): b 1.33 (dd, 3H), 2.76 (s, 1.5H), 2.96 (s, 1.5H), 3.61 (d, 1 H), 4.14 (quintet, 1 H), 4.65 (m, 2H), 7.10 (m, 2H), 7.33 (s, 3H), 7.42 (m, 3H), 7.54 (m, 2H), 8.02 (t, 1 H), 8.80 (m, 1 H), 9.07 (brd, 1 H), 11.80 (brd s, 7 H); MS (APCI): 530.2, 532.2.
EXAMPLE 361:
cH, off o ~I N w .N, ~ ~ o I~ H
HO
CI
'H NMR (DMSO-D6): s[2.94 (s, 1.5H) + 3.10 (s, 1.5H), 3H], 3.54 (m, 2H), 4.00 (d, 1H), 4.28 (d, 1 H), 4.81 (t, 1 H}, 4.96 (t, 1 H), 7.09 (d, 1 H), 7.35 (m, 3H), 7.43 (m, 3H), 7.61 (m, 2H), 7.83 (m, 3H), 8.04 (s, 1 H), 8.85 (t, 1 H), 9.11 (d, 1 H), 11.80 (brd s, 1 H); MS
(APCI): 516.3, 518.2.
EXAMPLE 362:
to o w N
.N. ~ I O 'N
HO
CI
'H NMR (DMSO-D6): 8 2.75 (t, 1 H), 2.95 (t, 1 H), 3.59 (t, 1 H), 3.80 (t, 1 H), 4.38 (brd s, 3H), 4.61 (s, 1 H), 4.84 (s, 1 H), 6.40 (d, 1 H), 6.53 (d, 1 H), 7.05 (d, 1 H), 7.45 (t, 1 H), 7.58 (m, 3H), 7.81 (m, 3H), 8.00 (brd, 2H), 8.83 (d, 1 H), 9.10 (s, 1 H), 11.78 (brd s, 1 H); MS (APCI, neg.):
513.3, 514.2.
WO 99!01423 PCT/DK98/00287 EXAMPLE 363:
NHZ
O ~ I N
II
.N. ~ I O
~ H
HO
CI
'H NMR (DMSO-D6): 8 1.50 (m, 2H), 1.68, (d, 2H), 2.28 (t, 1 H), 2.59 (t, 1 H), 3.05 (t, 1 H), 3.96 (d, 1 H), 4.16 (s, 2H), 4.32 (d, 1 H), 6.74 (brd s, 1 H), 6.95 (d, 1 H), 7.22 (brd s, 1 H), 7.36 (d, 1 H), 7.57 (quintet, 2H), 7.71 (dd, 1 H), 7.79 (d, 1 H), 7.92 (dd, 1 H), 7.96 (d, 1 H), 8.76 (d, 1 H), 9.01 (s, 1 H), 11.80 (brd s, 1 H); MS (ACPI): 493.1, 495.2.
EXAMPLE 364:
cH, O w I N~N.CH~
II
.N. w I O CHI
I~ H
HO
'H NMR (DMSO-D6): 8 2.10 (s, 3H), 2.15 (s, 3H), 2.29 (t, 1 H), 2.40 (t, 1 H), 2.80 (s, 1 H), 3.05 (s, 2H), 3.36 (t, 1 H), 3.46 (t, 1 H}, 4.16 (d, 2H), 7.01 (d, 1 H), 7.38 (t, 1 H), 7.56 (m, 2H), 7.72 (dd, 1 H), 7.79 (d, 1 H), 7.94 (m, 2H), 8.77 (d, 1 H), 9.02 (s, 1 H), 11.71 (brd s, 1 H); MS (ACPI):
467.3, 469.1.
EXAMPLE 365:
O w I N~N.CH~
II
.N ~ ~ I O CHs i~
HO
CI
'H NMR (DMSO-De): 8 2.11 (s, 3H}, 2.14 (s, 3H), 2.33 (t, 1 H), 2.39 (t, 1 H), 3.37 (t, 1 H), 3.46 (t, 1 H), 4.14 (s, 1 H), 4.32 (s, 1 H), 4.55 (s, 1 H), 4.74 (s, 1 H), 7.05 (d, 1 H), 7.23 (d, 1 H), 7.29 (m, 3H), 7.38 (t, 1 H), 7.43 (d, 1 H), 7.57 (m, 2H), 7.81 (m, 2H), 7.97 (s, 1 H), 8.06 (d, 1 H), 8.79 (t, 1 H), 9.05 (s, 1 H}, 11.75 (brd s, 1 H); MS (APCI): 543.2, 545.2.
EXAMPLE 366: EXAMPLE 371:
OH ~ CHI i O ~ I N ~ O ~ I N ~ I
.N~ ~ I O CHI I / .N~ ~ I O
I ~ 'H I ~ H
HO ~ HO
CI CI
EXAMPLE 367: EXAMPLE 372:
CHI
I i N.N~ w I 0 F O \ I N~N
I H ~ .N~ w O
HO ~ I , H
CI HO
CI
EXAMPLE 368:
cH, ~ 5 EXAMPLE 373:
O ~ CHz 0 w N w N.N~ ~ I O ~ ~ I N
O
HO I ~ H I ~ ~ N.N ~ W I O N
CI I , H
HO
EXAMPLE 369: CI
cl EXAMPLE 374:
~N
~I NJ ,I
O I / (~N~
N.N~ ~ O ~ I NJ CI
O
HO I ~ H ~ N.N~ w I O
CI I , H
HO
EXAMPLE 370: CI
i cH~ ~ I EXAMPLE 375:
O w N
i N.N~ w I O CI
I H ~ ~N CHI
HO ~ ~ I NJ' 1 O CI I ~ O H. N . W I O CHI
HO
20 cl EXAMPLE 376: EXAMPLE 381:
cl H
i ~N ~ O ~ N
O w I NJ OMe ~ .N~ w I O I i I H CI
H.N. w I O HO
HO ~ 15 Cf CI
EXAMPLE 382:
EXAMPLE 377: cH, o ~I N\
~N~CH ~ N.N . w O ~ CH
O w I NJ CHa a HO I i H w I
I I
.Nw W I O CI
I~ H
HO
cl 20 EXAMPLE 383:
H
EXAMPLE 378: o ~ N
I n .N. ~ O
I HO I ~ H ~ I
~N
O ~ I N J CI
.N. w I o EXAMPLE 384:
I
HO ~ CH3 CI O ~ N
N.N . ~ I O
EXAMPLE 379: I ~ H
CI CI
a w I N w I cl EXAMPLE 385:
II
.N~ ~ I O N
II
HO
CI I
N
EXAMPLE 380: \ c_ N. N , ~ ( o I ~ H
I H HO
o ~ ~ 25 C1 H.N~ ~ I o I ~ C!
HO
CI
EXAMPLE 386: EXAMPLE 390:
~N w I ~.NJLO
O , N J O ~ I N H C-'T CHa N.N. w I O ~ N.N. w O CHz H \ I Ho I ~ H I
HO
CI CI
EXAMPLE 387:
H,c 1 EXAMPLE 391:
N
~O~~~
O i N ./u I ~~ ~ N.
N.N . w O O I ~ CH, I H I ~ .N . ~ O
HO ~ \ I / H
CI HO
EXAMPLE 388:
EXAMPLE 392:
H
N F OH
O i N
I
N.N. w O O
ii I-fO I~ H ~I ~ N.N. ~) 0 CI HO I i H
CI
EXAMPLE 389:
cH, 2o EXAMPLE 393:
J
~0 ~ N
O i I N ~ N.N. w I O
I ~ H.N. w I O O O HO I ~ H ~ N
HO ~ ~ 'CH, CI U
CI
EXAMPLE 394: EXAMPLE 398:
~N~o 0 ~ I ~ O / N ~HaC J
n I ~ H.N . ~ I O ~ .N . ~ I O
I~ H ~I
HO HO
CI Ci EXAMPLE 395: EXAMPLE 399:
O ~ CH3 o ~I
N J " N ~ CH3 i O I ~ HOC
N.N. ~ O
I , H \ I O , NH
ii HO ~ N.N . ~ I O
S CI I ~ H ~ I
HO
Ct EXAMPLE 396:
O N
N.N. W I O , N H F
I ~ H ~ I ~ I O .N. w I Or HO CI O J HO I ~ H
10 EXAMPLE 397:
EXAMPLE 401:
cH, N N H
O i I NON I w O ~ I ~ N.N. ~ O
.N . w O I H I
I H I Hp HO CI
CI
N EXAMPLE 400:
EXAMPLE 402: EXAMPLE 406:
I
~N ~ ~ I
O i I NJ N O i I N~0 N.N. w 0 ~ N.N. w 0 r0 HO I ~ H I HO I i H ~ I CHI
CI CI
EXAMPLE 403: EXAMPLE 407:
/ F CHI
O / NON \ I 0 ~ I N
.N . w I O H ~ N.N . w O
H ~ ~ ~ H ~ I CH3 HO ~ ~ HO
EXAMPLE 404: EXAMPLE 408:
0 N ~ I 0 ~ I N - III
N.N . w I I O Cl I ~ H.N ~ y ( O N
HO I ~ H HO
CI 2~ CI
10 EXAMPLE 405: EXAMPLE 409:
F
I O .i N p~F
H ~ ~ N.N ~ ~ I p 0 ~ N HO I i H ~ I I i a I ~ H.N . ~ ( 0 O NHZ CI
HO
CI
EXAMPLE 410: 15 EXAMPLE 415:
i F CHI
O , N ~ I O ~ N
N.N . w I O I I ~ N.N ~ w I O ~N.CH3 I , H ~ I N HO ~ H
HO
CI CI
EXAMPLE 471: EXAMPLE 416:
O ~N
N H
O ~( z ~N
I NH O
.N . ~ o ~ I
I H I I I ~ H.N . w ( 0 HO
CI HO
CI
EXAMPLE 412: EXAMPLE 417:
CHz N H
O I ~ , N
N.N. ~ O ~ OH 0 I
I H ~ I HO I ~ ~ .N . w 0 ~N.CH~
HO
CI HO
CI
10 EXAMPLE 413:
EXAMPLE 418:
H F
N ~ O
O ~( .N. ~ I O FF ~ IOI
I H ~ O , N
HO ~ ~ I n CI ~ N.N . ~ O
I~ H ~I
HO
CI
EXAMPLE 414:
H EXAMPLE 419:
N
O i I N~ O
I ~ H.N. w I O F~ ~ \
HO ~ F O N \
CI I ~ H.N ~ w ~N I
HO ~ O H
CI
EXAMPLE 420: EXAMPLE 425:
/ v / v 0 0 / \
N.N~ ~ ~ ~ N.N. w N //-N O N~-N
HO 1 ~ H 0 H HO I ~ H O ~._/N
CI CI
EXAMPLE 421: EXAMPLE 426:
/ ~ / ~ / \
O : HJ N_ O
N.N~ ~ N~- N~~ / ~ .N~ w N~ N
I , H p H N~ I H
HO CFA HO ~ O
CI 2~ CI
EXAMPLE 422: EXAMPLE 427:
N ' ~ v v I
N.N. w N ~ .N~ w N OH
H O N
HO ~H I , H ~ \ /
HO
CI CI
EXAMPLE 423: 25 EXAMPLE 428:
l 0 ~ 0 NHi O ~ _ N.N~ ~ N \ / ~ .N. ~ N-\
H N I H
HO HO i O / \
CI CI
EXAMPLE 424: EXAMPLE 429:
/ v / v 0 ~ N S 0 .,.
.N~ ~ ~ \ I .N~ ~ N
N
HO I ~ H O H HO I ~ 'H O H / \
CI CI
EXAMPLE 430:
/ \
O _ H3C
N_ N-CH, N. N ~ ~ \ll//--~~
N _ HO I ~ H O
\ /
CI
EXAMPLE 431:
20 EXAMPLE 435:
/ \ I ~
NH ~ H
O
.N~ w N O
H ~ ~ N.N~ I i N
HO I H N
CI HO
CI
EXAMPLE 432:
EXAMPLE 436:
/ \ cH, O ~ O ~ ~N
.N~ ~ N .N~ I i N ~ N~ I ~ H N
I , H O ~N \ / F HO
HO
CI CI
75 EXAMPLE 433: EXAMPLE 437:
\ O ~ J N
p ~ N~ ~ N.N~ I i I H N
N N OH
I H ~N N HO
HO ~ O ~ \ / CI
CI
EXAMPLE 438:
EXAMPLE 434:
O N
O I w O NCH, ~ N.N ~ I i N O
H.N~ / N I , 'H 0 HO
HO ~ 30 CI H,C
EXAMPLE 439: EXAMPLE 444:
~CHz w 0 ~H~
O I J N /
O ~ 0 ~ N.N
I N I H N N
N'N ~ ~ N ~~ HO
HO I ~ H N CI
CI
EXAMPLE 445:
EXAMPLE 440: o I ~ ~N / \
O I \ O ~ I % H.N ~ / ~JN
.N~ i HO
HO
CI
EXAMPLE 446:
EXAMPLE 441: o ~ o N N
CH3 OH ~ N.N ~ ( / N ~ / \
O I ~N I ~ H
.N. i ~J HO
H / \ CI
HO
CI
25 EXAMPLE 447:
EXAMPLE 442: o w o N /
NCH f ~ N.N~ I / N N
O I N I , H
N.N. / N~ \ I HO
CI
HO I ~ H F
CI
EXAMPLE 448:
EXAMPLE 443: o I ~ o ~", - / o OH ~ N.N. ~ N
I , H
O ~ O ~ HO
I H.N' I / N N CI
HO
CI
EXAMPLE 449: EXAMPLE 452:
H,c N-CH, O I w O ~ ~ O N.N~ I i H.N. ~ N~ \ / HO I , H N N/
HO ~ Ct CI
EXAMPLE 450:
EXAMPLE 453:
o w o _ N
N.N ~ I / N O \ O ~ \ ~ CI
HO I ~ H OH ~ N.N w I
N
CI HO ( , H
Ct EXAMPLE 451:
EXAMPLE 454:
~cHz cH, w o ~ o O ~N I N
H.N. I / N NCH I % H.Nw / N
i HO ~ HO
rPneral procedure for synthesis of comr~ounds of the general formula XIII:
A~ ,NHz O
o\\ /B\ /oH
N B OH
H O step A p, H O
O R5°
NHRxR~ ~ ~N B N/
step B A
H O
formula XIII
A and B are as defined far formula I and -NRxRSd is Rsa Rna R4b -N-(CHZ)~~(CHZ)a O where Rsa, R4a, R4b, c, q, d and D are as defined for for-mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent.
The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tent-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloro-methane, DMSO, acetic acid, water or a compatible mixture of two or more of the above sol-vents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylort-hoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C
to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli-zed if necessary from a solvent such as the above described reaction solvents.
The product can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroformlmethanol or dichloro-methanelmethanol or chloroformlethyl acetate.
Step B: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an an-y hydride or an acid halide that can then react with the amine to give a compound of formula XIII.
The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XIII.
Specific examples illustrating the preparation of compounds of the general formula XIII accor-ding to the invention are provided below.
Preparation of 4-formylnaphthoic acid is depicted below:
O OH O OH O OH O OMe CHI Br'CHZ HO'CH2 HO'CHZ
O OMe O OH
i i i i H O H O
4-Bromomethylnaphthoic acid:
A mixture of 4-methylnaphthoic acid (10 g, 54 mmol), N-bromosuccinimide (10 g, 56 mmol) and AIBN (100 mg) in CC14 (250 mL) was refluxed for 3 hr. The reaction mixture was con-centrated and dissolved in ethyl acetate. The organic layer was washed with water, brine and dried over MgS04. Evaporation of the solvent gave the desired product (16 g, 80%).
'H NMR (DMSO-D6): 8 5.24 (s, 2H), 7.73 (m, 3H), 8.03 (d, 1 H), 8.28 (d, 1 H), 8.86 (d, 1 H), 13.29 (brd s, 1 H).
4-Hydroxymethylnaphthoic acid:
4-Bromomethylnaphthoic acid (16 g, 60 mmol) in an aqueous solution of KzC03 (10%, 100 mL) was stirred at 70 °C for 30 minutes. The reaction mixture was cooled and made acidic with conc. HCI. The resulting precipitate was filtered and dried to give the desired product as a yellow solid in quantitative yield.
'H NMR (DMSO-Ds) ; 8 5.01 (s, 2H), 5.96 (s, 1 H), 7.70 (m, 3H), 8.10 (m, 2H), 8.90 (d, 1 H).
Methyl 4-hydroxymethylnaphthoate:
A mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 mL), and conc.
HZS04 {2 mL) was refluxed overnight. The insolubles were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHC03 (2x), brine, dried over MgSO,, and concentrated to give a yellow oil. Silica gel column chro-matography using ethyl acetate/hexane (113) gave the desired product as a yellow oil (3.3 g, 35%).
'H NMR (CDCI3): 8 2.05 (t, 1H), 4.01 (s, 3H), 5.22 (s, 2H), 7.66 (m, 3H), 8.09 (d, 1H), 8.16 (d, 1 H), 8.96 (d, 1 H).
Methyl 4-formylnaphthoate:
To a solution of methyl 4-hydroxymethylnaphthoate above (3.3 g, 15.3 mmol) in dichloro-methane (20 mL) was added Mn02 (6.6 g, 76 mmol). After stirring the dark mixture for 16 hours, the insolubles were filtered through a bed of Celite. Evaporation of the solvent gave the desired product as a white solid in quantitative yield.
'H NMR (CDC13): b 4.06 (S, 3H), 7.75 (m, 2H}, 8.03 (d, 1H), 8.20 (d, 1H), 8.80 (d, 1H), 9.27 (d, 1 H), 10.50 (s, 1 H).
4-Formylnaphthoic acid:
A mixture of the methyl 4-formylnaphthoate above (2.3 g, 1 mmol) and Na2C03 (1.25 g, 12 mmol) in water (30 mL) was heated in a water bath for approximately 2 hr until a clear soluti-on was obtained. The solution was cooled and filtered. The filtrate was acidified with conc.
HCI to give a yellow precipitate. The solids were collected and dried over night to give the desired product (1.86 g, 87%).
'H NMR (DMSO-D6): 8 7.76 (m, 2H), 8.22 (m, 2H), 8.71 (d, 1 H), 9.20 (d, 1 H), 10.49 (s, 1 H}.
4-[(3-Chloro-4-hydroxybenzoy~}hvdrazonomethyl]n~nhthoic acid~step A~:
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (1.53 g, 8.23 mmol) in DMSO (20 15 mL) was added a solution of 4-formylnaphthoic acid (1.65 g, 8.23 mmol) in DMSO (2 mL).
After stirring the solution for 16 hr, the reaction was diluted with ethyl acetate (30 mL) and water (30 mL). A precipitate formed. The precipitate was collected washed with hexane and dried to give the product as a white solid in quantitative yield.
20 'H NMR (DMSO-Ds): 8 4.70 (d, 1 H), 7.70 (m, 2H), 7.83 (d, 1 H), 8.03 (m, 2H), 8.18 (d, 1 H), 8.72 (s, 1 H), 8.90 (d, 1 H), 9.17 (s, 1 H), 11.0 {brd s, 1 H), 11.94 (s, 1 H), 13.4 (brd s, 1 H); MS
(APCI, neg): 368.5, 370.2).
General procedure 25 Derivatives of 4-[l3-Chloro-4-hydroxybenzoyl)hydrazonamethy]naphthamides ~ste~B):
To a solution of a derivative of4-[(4-hydroxybenzoyl)-hydrazonomethylJnaphthoic acid in DMSO was added carbonyldiimidazole (1.2 eq). The solution was agitated for 5 minutes and diluted with DMSO to a concentration of 50 mM. The solution was then dispensed inta 88 30 deep well plates containing solutions of amines in DMSO (50 mM}. The plates were covered and agitated for 16 hours. The products were purified by HPLC.
The following compounds of formula XIII were prepared:
EXAMPLE 455:
ct o ~ I oN ~ I
I ~ H~N~ ~ I H
HO
CI
'H NMR (DMSO-DB): 8 2.91 (t, 2H), 3.67 (t, 2H), 7.12 (d, 1 H), 7.38 (qt, 4H), 7.58 (t, 2H), 7.70 (t, 1 H), 7.50 (d, 1 H}, 7.95 (d, 2H), 8.03 (s, 1 H), 8.69 (brd t. 1 H), 8.81 (d. 1 H), 9.12 (s, 1 H), 11.02 (s, 1 H), 11.89 (s, 1 H); MS {APCI): 507.3, 508.5.
EXAMPLE 456:
o ~ I N ~ cl N.N. w I w I
I~ H
HO
CI
'H NMR (DMSO-DB): 8 2.20 (brd m, 1 H), 2.30 (brd m, 1 H), 2.55 (m, 2H), 3.10 (brd m, 2H), 3.50 (s, 2H), 3.72 (brd m, 1 H), 3.85 (brd m, 1 H), 7.10 (d, 1 H), 7.36 (qt, 4H), 7.53 (d, 1 H), 7.70 (m, 2H); 7.82 (m, 2H), 7.95 (d, 1 H), 8.03 (s, 1 H), 8.88 (d, 1 H), 9.11 (s, 1 H), 11.00 (brd s, 1 H), 11.89 (s, 1 H); MS (APCI, neg.): 559.2, 561.2.
EXAMPLE 457: 15 EXAMPLE 462:
\ I o ~N I ~ ~ I o O I ~ O \ N~ O.CH~
H.N~ \ I \ H.Nw \ I N I \
HO HO
CI CI
EXAMPLE 458: EXAMPLE 463:
O \ I O N OH \ I CI ~ O CF3 \I
I H
\ N.N. \ \ O .N w \ I H I , I~ H I~ H
HO HO
CI CI
EXAMPLE 459: EXAMPLE 464:
\ I o ~N ~ I o ~ I
o I H o \ N
\ N.N~ \ ~ ~ \ .N~ \ I H F
I i H I i H
HO HO
CI CI
10 EXAMPLE 460: EXAMPLE 465:
o F ' I p ~ I
O N
\ O .N~ \ I H I ~ .Nw \ I H CI
HO I ~ H
HO
EXAMPLE 461: EXAMPLE 466:
o ~ I o \ o ~ N
\ O N.N w ~ I H I i CI \ N.N w \ I \ I
H I ~ H
HO HO
CI CI
EXAMPLE 467: EXAMPLE 472:
~ I o ~ I o ~ ~ o ~ N''~
O N.N~ w I H I ~ ~ N.N~ w I ~N w H I H
HO H3C~N~CH3 HO ~ ~ F
CI CI
EXAMPLE 468: EXAMPLE 473:
~ I o ~ I o O ~ I N~ O ~ I N~ F
.N ~ ~ ~N .N ~ ~ ~N
I~ H I~ I~ H I~
HO Y HO
cl 20 CI
EXAMPLE 469: EXAMPLE 474:
~ I o ~ 1 0 O w N~CH3 O \ I
I ~ H.N ~ W I ~N I ~ CH3 I \ H-N ~ w N~CF~
i HO ~ ~ 'fO
HO
C CI
EXAMPLE 470: 25 EXAMPLE 475:
~ I o ~ I CI ~ I o o \ I H ~ o \ I H I ~
N.N ~ W I ~ ~.N ~ w ~ CN
I ~ H
HO HO
CI CI
EXAMPLE 471: EXAMPLE 476:
~ i o ~ o cl o w N ~ CI o ~ I N ~ I
N.N~ ~ I H I i CI ~ N.N~ ~ I 'H CI
I , H I / H
HO HO
CI CI
EXAMPLE 477: EXAMPLE 482:
~ I o O ~ I N~CN
O N
.N ~ ~ I CHs .N ~ ~ I
I H I W' '~. cHZ
HO Y HO
CI CI
EXAMPLE 478: EXAMPLE 483:
I I
i O O ~ N
CFs O ~ N NHZ ~ . N ~ ~ I H
H.N~ w I H O I ~ H
HO
Ho ~ 20 cl CI
EXAMPLE 484:
EXAMPLE 479:
i I O O w N~CFs O ~ I N ~ N.N~ ~ I H I i F
N.N ~ ~ ~OvCHs HO I ~ H
HO I ~ H [O~ CI
CI
25 EXAMPLE 485:
EXAMPLE 480:
~ I o o w I N
O ~ I N~ HsC ~ N.N ~ W N I w I H N \ ~N~O~CHs I / H
HO CI
HO ~ O CHs CI
CI
EXAMPLE 486:
EXAMPLE 481:
o ~ ~ N'~ cl .N~ ~ ~N
O N
N.N ~ ~ I ~N ~ I ~ H I , 'H HO
HO I ~ CI
of 30 EXAMPLE 487: EXAMPLE 492:
O F ~ O CN
I
I
o \ I H I ~ F o ~ N
.N~ W i ~ .N~ ~ I H I , H I 'H F
HO ~ HO
CI CI
EXAMPLE 488: EXAMPLE 493:
~ I o -' I F ~ I o O \ I H \ O \ I H~N~CHs N.N~ ~ ~ N.N~
I H I H
HO ~ HO ~ HOC
EXAMPLE 489: EXAMPLE 494:
O OCF
O CI I
O ~ I N ~ O ~ N
I ' I ~ .N~ ~ I H i ~
.N~ ~ CHI i N
I ,H I / H
HO ~ HO
CI CI
EXAMPLE 490: 25 EXAMPLE 495:
I o F ~ I I ~
O N
O .N~ ~ I H I , ~ N.N~ ~ I CHI I
N I H
HO I ~ H HO
CI CI
EXAMPLE 491: EXAMPLE 496:
i I o ~ I o ~ I
O NON
O N. N ~ ~ I N CN I ~ H.N w w I H CH3 I / H HO i HO ~ CHa CI
CI
EXAMPLE 497: EXAMPLE 502:
~ I o _I
O H.N~ ~ I H O ~ I N N I
HO ~ ~ N.N~ w I H O I i CI HO I , H
CI
EXAMPLE 498:
EXAMPLE 503:
~I o ~I
O ~ N ~ i O i H. N ~ w I CHs OH O ~ I N
~OH
HO ~ ~ N.N ~ y I CHI OH
CI HO I / H
EXAMPLE 499:
EXAMPLE 504:
O ~ I N~OH ~ I O CI
N.Nw W O ~ N W
I / H .N~ ~ ~ H I , HO ~ 'N F
CI O ~ ~ H
CI
EXAMPLE 500:
25 EXAMPLE 505:
~ I o ~ I
O \ N ~ ~ O
N.Nw W I H r0 O w I N N
HO I ~ H CHa ~ N.N w W I CHI
CI HO I , H
Cl EXAMPLE 501:
off EXAMPLE 506:
o w I o N~s w I o N-N ~ ~ I H O i NH F
I
I , H ~ N.N. ~
F
HO I H I I ~ F
CI HO Y F
zs7 EXAMPLE 507:
cl I
O i N
N.N. ~ I OH
I , H
HO
CI
General procedure for synthesis of compounds of the general formula XIV
Rs' O B OH NNR~R~ O B N.RSa step A
O O
O
iNHz A
step B
O Rs' I
B N ~ Rsa H O
formula XIV
A and B are as defined for formula I and -NR5'Rs° is R~ Raa R4e -N-(CHZ)~~(CHZ)d Q where Rsa, R°a, R4b, c, q, d and D are as defined for for-mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
~ 5 Step A: The acid is coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an anhydride or WO 99/01423 PC'f/DK98/00287 an acid halide that can then react with the amine to give a compound of formula XIV. The pro-duct can then be isolated either by fltration or by extraction using a solvent such as ethyl ace-tate, toluene, dichloromethane or diethylether and the solvent may then be removed by con-centration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dich-loromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a com-pound of formula XIV.
Step B: The carbonyl compounds are then treated with an acylhydrazide in a solvent. The sol-vent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, butyl al-cohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dich-loromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethy-lorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recry-stallized if necessary from a solvent such as the above described reaction solvents. The pro-duct can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloro-methane/methanol or chloroform/ethyl acetate.
Specific examples illustrating the preparation of compounds of the general formula XIV accor-ding to the invention are provided below.
The preparation of 3-(4-formylnaphthalene)propanoic acid is depicted below:
DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST lE TOME ~ DE~
NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLlCATI4NSIPATENTS
THiS SECTION OF THE APPL.ICATION/PATENT CONTAINS MORE
THAN ONE VOLUME
THIS IS VOLUME ~/ OF Z
f f t NOTE:.For additional voiumes~piease cantact'the Canadian Patent Office
.. 5 wherein R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is R3a R3b R4a R4b (L) (CH -\~ CH M
2)b P ( 2)a ( )f (CHZ)~ (CH2)d wherein:
R3a, R3b, R4a and R'b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF,, 15 -NO2, -ORZ<a, -NRzoaR2sa, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SRZ°a, -CHF2, -OCHF2, -OCFZCHF2.-OSOZCF3, -CONRz4aR2sa, -CHZCONRz4aRzsa, _OCHZCONRz4aR2sa,-CHZOR24a, -CHZNRZ°aRzsa -OCOR2°a or -COzRz4a;
wherein RZ'a and Rzsa independently are hydrogen, -COR2sa, -SOZRzsa, lower alkyl, aryl or 20 aryl-lower alkyl;
wherein RZSa is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
or R3a and R3b, R4a and R4b, or R'a and R4b together form a bridge -(CHZ); ;
Wherein i is 1, 2, 3 or 4;
a, b, c and d independently are 0, 1, 2, 3 or 4;
e, f and p independently are 0 or 1;
q is 0, 1 or 2; and 5 L and M independently are -O-, -S-, -CH=CH-, -C--_C-, -NRSa-, -CHZNRsa-, -CO-, -OCO-, -COO-, -CONRSa-, -CONRSe-, -NRSaCO-, -SO-, -SOZ-, -OSOZ-, -SOzNRSa-, -NRSaS02-, -NRSaCONRSb-, -CONRSaNRSb-, -NRSaCSNRS°-, -OCONRS°-, -CHzCONRSb-, -OCHZCONRsb-, -G"
-P(O)(ORSa)O-, -NRSaC(O)O- Or ~R~.
wherein Rsa and R5b independently are hydrogen, lower alkyl, -OH, -(CHZ)k-ORsa, -CORsa, -(CHz)k-CH(ORsa)z, -(CHZ)k-CN, -(CHZ)k-NRsaR6b, aryl, aryl-lower alkyl, -(CHZ)9 COOR43 or _ (CHZ)9 CF3i wherein k is 1, 2, 3 or 4;
R6a and Rsb independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
g is 0, 1, 2, 3 or 4;
R43 is hydrogen or lower alkyl;
G" is -OCHZCO-, -CHZCO-, -CO- or a valence bond; and E" is -CHZ , -CHZCHZ-, -CH=CH-, -CHzNH- or -CHzCHZNH-;
D is hydrogen, R ~~" w~~~~r Rzr w ' it Ra \ w :-fit- za W
Rza V'~~ , a / V''Z, ~ ~ ~%Z' , V' Z' , Rz Rz~
R~' w~Q' Rz~ w,iQ~ Rz' ,,W' ' w ~ ~Y, ~ ° Y,. ~ I w'1~
r . , ~ .
Rza Rze R (CHz)' V, ~, it y Rza w ~ w Rz~
w~-z~ I w '~ Y\\ , ~ \ a ze R (CHz~V.%Z~ , Z -V ~~ ~ ~ R Z'-V' ~ .
Rz' Rrr ze W~ \z)s . ~E ~ \F' RE~CHF)s ~ Rza 'f-G Rz~ . ~ , F I /' Q - ~G
Rza R ~ R~
(CH )~E~~Rz~ /E F E~(C~z)s~U)~
z s CH ~~ F' G ( 2)s ~. w ~~ .
Q,y,.~ ' V'~Z~Rze R28 \
(CHz)s E~ \ '(Cyz)S/(G),w ;(C~i).
~.y~~ R~~~Rz' Rza~Rz~
E F' F F .
R~
Rza RZ ~CHz), G
E E Rza or G I E, I ~ Rza ~~ cHz), F,~ I I
F ~E~V';Z
wherein:
ris0orl;
I
s is 0, 1, 2 or 3;
E, E', F, G and G' independently are -CHR38-, >C=O, >NR39, -O- or -S-;
F' is >CR38- or >N-;
Y' is -N= or -CR32=;
Z' is -N= or -CR33=;
V' is -N= or -CR~'=;
W' is -N= or -CR35=; and Q' is -NR36-, -O- or -S-;
wherein:
Rz', Rze, R32, R33, R~ and R35 independently are hydrogen, halogen, -CN, -CF3, -O{CH2)yCF3, -(CHz)yNHCOCF3, -NOZ, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR29, -CHF2, -OCHF2, -OCFZCHFz, -OSOZRZ9, -OSOZCF3, -(CHZ)YCONRZ9R3°, -O(CHz)yCONR29R3°, -(CHz)yOR2s, -(CHZ)YNRZ9R3°, -OCORz9, -CORz9 or -COZR~;
or RZ'and R28, R32 and R33, R33 and R°', or Rte' and R35 together form a bridge -O(CH2)YO-;
wherein y is 0, 1, 2, 3 or 4; and R29 and R3° independently are hydrogen, -COR3', -COZR3', -SOZR3', lower alkyl, aryl or aryl-lower alkyl;
wherein R" is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R'6 and R'9 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
and R38 is hydrogen, -OR°°, -NR°°R", lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR°°, -CHF2, -OCHF2, -OCFZCHF2, -CONR°°R", -(CHZ)xCONR°°R", -O(CHZ)XCONR°°R°', -{CHZ)xOR°°, -(CHZ)XNR°°R°,, -OCOR4° or -COZR°°;
wherein x is 1, 2, 3 or 4;
R'° and R" independently are hydrogen, -COR42, -SOZR°z, lower alkyl, aryl or aryl-lower aI-kyl;
wherein R'2 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
Where the formulae for B make it possible, R'9, R~°, Rz', R~ and Rte' may alternatively be re-placed by R" or R'S, respectively. In such case eg W may be selected from -N=, -CR'9- and _CR,4_ Similarly, where the fom~ulae for D make it possible, R3z, R", R'°, Rte, R36, R~° and R'9 may al-ternatively be replaced by RZ' or R28, respectively. In such case eg E may be selected from -CHR'~-, >C=O, >NR39, -O-, -S-, -CHRZ'- and >NRZ'.
In a preferred embodiment the invention relates to compounds of the following general formula O
A~N~N~ (CH2}~ .B-{Kj~ D (II) R R
wherein A, B, K, D, R', R', n and m are as defined for formula I.
In another preferred embodiment the invention relates to compounds of the following general formula III:
O
I I
A~S~N~N (CH2~B-(K~D (III) O Rs Ra wherein A, B, K, D, R3, R4, n and m are as defined for formula I.
In still another preferred embodiment the invention relates to compounds of the following formula IV:
O
H
A N~N~~~H2~" B (K)m D
R3 Ra wherein A, B, K, D, R3, R°, n and m are as defined for formula I.
In the compounds of the above formulae I to IV the following substituents are preferred:
R3 is preferably hydrogen.
R' is preferably hydrogen.
A is preferably selected from the group consisting of:
R~ R~ R~
N
Re Rg \ RB
/ /
Rs . Rs .
Rs I ~ Rio R~~ Rio Rio I
N.N N R~ ~N R~
R~,%' Re ~ and N
R Rs~ Rs Re wherein R', R8, R9 and R'° are as defined for formula I.
A is more preferably R' Rs 5 wherein R', R8 and R9 are as defined for formula I.
In the above embodiments of A, R' is preferably halogen, lower alkyl, -OH, -NO2, -CN, -COZH, -O-lower alkyl, aryl, aryl-lower alkyl, -COzCH3, -CONH2, -OCHZCONH2, -NH2, -N(CH3)2, -SOZNH2, -OCHFZ, -CF3 or -OCF3.
Preferably, R8 and R9 are independently hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, and R'° is hydrogen, lower alkyl or phenyl.
More preferably, R8 and R9 are independently selected from hydrogen, halogen such as -F and -CI, -O-lower alkyl such as methoxy and ethoxy, -NH2, -CN or -NO2, and R'° is hydrogen.
In a particularly preferred embodiment A is Rs HO
Rs wherein R8 and R9 independently are hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCHzCF3, -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, preferably hydrogen, halogen such as -F and -CI, -O-lower alkyl such as methoxy and ethoxy, -NH2, -CN or -NO2.
In a further particularly preferred embodiment A is \
HO ~ R9 wherein R8 is hydrogen, halogen such as -F or -CI, -O-lower alkyl such as -OCH3 or -OCzHs, -NHz, -CN or -NO2; and R9 is hydrogen or halogen such as -F or -CI.
In a preferred embodiment R8 is halogen and R9 is hydrogen.
In still a preferred embodiment the invention relates to compounds of the following formula V:
R$ O
\ NiN~B \K)fn D M
HO
1 o wherein R°, B, K, D and m are as defined for formula I and R8 and R9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.
B is preferably:
Ris W~, \ W 1. W
-i--%Z / /
V ' ~s V ' ~s V
R R R" R ~ ~e Q W Q W
R ( ~ R \ ~ ~ -CRu'CR~s / V~ , / ~ . .
Ru R's V
a .Q R .D Rie \ Q Ru Rub I ~ '~I
Y Y R,s , W I
Rya Ru W W~~Q
~R" ~~ R,a~R,s / V ~Z
wherein V, W, Z, Y and Q are as defined for formula I; and R'4 and R'S independently are hydrogen, halogen, -CF3, -OCF3, -OR'6, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -OSOzCF3, -CONR'gR", -CH20R'e, -CH2NR'6R", -OCOR'6 or -COZR'8;
or R'4 and R'S together form a bridge -OCHzO- or -(CHZ),-;
wherein I, R'6, R" and R'8 are as defined for formula I.
Q is preferably -O- or -NH-.
Particularly preferred compounds are those in which B is R,a \ \ R~s Rya R~s (~J~
/ / ~ , R,.~~~ ,s R~s R~s R,s R,s / R,a Ru / /
\ w+R~4 , O / , NH ~r NH
V~~ \
R~s wherein V, W, Z, Y and Q are as defined for formula !; and R'4and R'S independently are hydrogen, halogen, -CF3, -OCF3, -OR'B, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -OSOZCF3, -CONR'6R", -CHZOR'e, -CH2NR'6R", -OCOR'6 or -COZR'e;
or R" and R'S together form a bridge -OCH20- or -(CHZ)r;
wherein I, R'6, R" and R'8 are as defined for formula I.
Still more preferred are compounds of the following formula Vl:
Rya \ N. N w \ (K)m ~ (VI ) H R1s HO ~R9 as well as compounds of the following formula VII:
Rya R$ O
(K)rt, D (VII) H
HO
R R
as well as compounds of the general formulae Vllla or Vlllb:
Rs O ~ ~ 1K)fIi D
(Villa) or HO ,a R9 R R,s R'°
RB R,s O
~~N ~ \ ~NH(K)m D ~Illb) HO ~R ~s wherein R"and R'S independently are hydrogen, halogen, -CF3. -OCF3, -OR'6, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -OSOzCF3,-CONR'sR", -CHZOR'6, -CHZNR'sR", -OCOR'6 or -COZR'8; or R" and R'S together form a bridge -OCH20- or -(CHZ),-;
wherein I, R'6, R" and R'8 are as defined for formula I;
K, D and m are as defined for formula I; and R8 and R9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.
In the above formulae VI, VII and VIII, R'° and R'S are preferably independently hydrogen, halogen, lower alkyl, aryl such as phenyl, or -O-lower alkyl such as methoxy.
In the above formulae VI and VII, K is preferably bound in para-position and in the above for-mulae Vllla and Vlllb, K is preferably bound at the nitrogen atom of the indole group.
K is preferably selected from the group consisting of:
-(CHZ)p O-(CHz)a , -(CHz)b S-(CHZ)d , --(CHZ)p CH-CH-(CHZ)d-~ , O
-(CHZ)b (CHZ)a- , -(CHZ)b N-(CHz}d ~ -(CHZ?-~.L-.O-(CHZ)d , R~
sa O Rsa R~ Rao -(CH )~N-(CH )~(CH ) , -(CH ) N--~ CH ~ -(CHz)b O; N- CH
2 b 2 c 2 d 2 b I ( 2)d v O ( 2)a R~
O O
II II O
-(CHZ)b O-(CHz)d , -(CHZ)b S-(CHZ)d , -(CHZ}b O-IL-(CHz)d , O
I I
-O-O-(CH2)a , -(CHZ}a , O-(CHZ)p N~ (CH2)a , R
O
O-(CHZ)b CHR~ (CHz)a N (CHZ}d , -O-(CHZr-~I-N-(CHZ)d ' sa R~
O O
-O-(CHZ)b N~(CHZ~e-- , -O-(CHZr-I~-O-(CHz)d , R~
O
-O-H O-(CH2~ , -O-(CHZ p ~~(CHz)d O
O
-O-(CHz)ti O-(CHZ)a , -O-(CHZ~CHR~- , -O-(CHz}d O--~- i -(CHZ~ , Rso Raa Rdb -O-(CHz)b-N-(CH2)~~(CHz)a , -O-(CH2)p S-(CHZ)a R5a O
Raa Rat Raa Rad -(CHZ)p N-(CHZ)~~(CHz)a- , -(CHZ)d SO-(CHZ)~\~(CHZ)d , R~
Raa Rab O Raa Rao -(CHZ)e SOz (CHZ)~ \~(CHZ)d , -(CHZ)ti P-O-~(CHZ)a , ORS
O Raa Ran O
-O-(CH2)b P-O-~-(CHZ)o , - CHz b~(CH
ORS' ( ) Z)a , O Ray R3b O
-~-N-(CHz)b-O-(CHZ)a , -(CHZ)b~(CHZ)a~N-(CHZ)d , R~
O Rsa O Rsa -O-CHZ~N~~ ~ -O-CH~N~
OII R~ O Rs~
-O-CHZ~N~ -(CHz)C , -O-CHZ~N~-CHZ , O R~ O R~
O CH~..~-N'~(CHZ)b N-(CHZ)a , -O-CHI-~-N , R~
O R~ O O Rsa -O-CH2~ ~ -(CHZ)~- , -CHZ-~L- ~ -(CHz)e , O R~ O Rs~
-O-CHz~N~ -(CHZ)b i -(CHZ)d , --LLN~ -(CHZ)b R~
O R~ O
-CHZ--LL-N~~(CHZ)o , -O-CHZ~N~~/N-R~ , OI' OII ~
-CHz~N~ R~ , ~N~ Rsa O O
-O-CHz~-Rse (CHz)b S-(CHz)d , -CHz~-N-(CHz)b O-(CHz)d .
R~
Raa Rae .
-(CHz)b N-(CHz)~~(CHz)d -CHz N-(CHz)b N-(CHz)d , Rst Rsa Raa Rao -O-(CHz)ti N-(CHz)~~(CHz)d . N-(CHz)p N-(CHz)d .
Rsa Rso Rsa O R~ R3b O
-O"CH~R~ (CHz)~N-(CHz)a , -N-LL-(CHz)p O-(CHz)a R~ R~
O Raa Rae Raa Ran O R~
~~ ~~ R3o -Chlz'~N-(CHz)p~(CHz)~~(CHz)a , -LL--N-(CH2)~(CHz)~ S-(CHz)a Rso R~ , R~ R3b -CH N- CH -~- O Rte' Rte' O
z R~ ( z)d a (CH2)c O-(CHz)d ~ ---~Nsb (CHz)~(CHz)-~-N-(CHz)d R Rsa R3a Rab Raa Rao O
-CHZ R~ (CHz)-~-(CHz)~~-(CHz)d and -CHz~--.N~ (CHz)b N-(CHz)d R R~
wherein R3a, R3b, Raa~ R4b Rsa~ RSb, a, b, c, d, p and q are as defined for formula I.
More preferably, K is selected from the group consisting of:
-(CHz)b O-(CHZ)a ~ -(CHZ)b N-(CHZ)d ~ O-(CHZ)b N-(CHz)a , R~ R~
O
O-(CHz)b CHR~ (CHz)a N (CHz)d , -O-(CHZ~N-(CHZ)d , sa R~
O O
-O-(CH2~0-(CHZ)a , , -O-(CHz~(CHZ)d O O
-O-S-(CHZ)d , -(CHZ)a - , -O-(CHZ)e -O-~-N-(CHZ)d- , O Rsb O
-O-(CHz)b-CHR3a- , -(CHz)D O~(CHZ)a -(CHZ)b g-(CH2)d , p Rsa ~~ Raa~ Reb -(CHZ)--u-N-(CH2)~(CHZ)a , -4-(CHZ)b-N-(CHZ)~~(CHZ)a , R5a Raa Rnb Raa Rab -(CHZ)b N-(CHZ)~\~(CHZ)a - , -(CH2)b SO-(CH2)~ \~(CHZ)a R~
R;a R4b p Rqa R4b -(CHz)ti SOZ (CHZ)~ \~(CHz)d , -(CHZ)d P=O~(CHz)d , ORS
O R°a R°° O
-O-(CHZ)b P-O~(CH2)d , - CH
( z)b (CH2)d , ORS
O R3a R3b O
--~L-N-(CHZ)b-O-(CHZ)d , -(CHZ)b~(CHZ)a~N-(CHz)d R~
5a OII R~ OII Rs~
-O-CH~N\~ , -O-CH~N\' OII R~ O R~
-O-CH~N~ -(CHZ)b , -O-CN~N~-CHz , O Rs~
-O-CH ~~ O R~
~N'~~(CHZ)b N-(CH2)d , -O-CHI-~-N .
R~
R~'' -O-CH~N~RCHz)b-IL- , -C~--~-N~-(CHZ)6 .
U
O Rsa O Rsa O CHZ~ ~ (CHZ)b N-(CHZ)d , ~N~-(CHZ)b R~
O R~ O
-CH--~N~~(CHz)b , -O-CH~ ~ R~
O O
-CH~ U Rsa , ~N~ R~ .
U
O
-O-CH2-~-N-(CHZ)p S-(CH2)a , -O-(CH2~ O-(CHZ)d , Rse O R~ Rao O
-(CHZ)~-N-(CHZ)~~(CHZ)d , -CH~N_(CHZ)b N-(CHZ)d , R~ Rx' R~
O Raa Rae O
-O-(CH2)-~N-(CHZ)~- '~(CHz)d ~ ~NWCHZ)o N-(CHz)a , R~ R~' R~
O R~' R3e O
-O-CHZ~N-(CHZ)~N-(CH2)d , -N-~-(CH2)p O-(CHz)a , Rs° R~ R~
O R~ R3u Raa Rae O R3a R3e -CH2-~LN-(CFiz)b--~-~-}p (CHz)~(CHZ)a , -~L-.-N-(CHZ)~(CHz)~ S-(CHZ)d , Rse Rsa R~ R3e O R~ R~ O
-CHz N-(CHZ)--~-(CHz)~ O-(CHZ)d , -IL-N-(CHZ)~-(CHz)-~-N-(CHZ)a R~ Rse Rsa R3a R3e Raa Rae O
-CHz N~ (CHz)e-~--(CHz)~-~-(CHZ)d , -CH2-II--N-(CHZ)b N-(CH2)d R Rse Rsa O
and -CH2-~-N-(CHZ)b O-(CHz)a Rso wherein R'a, R3b, Raa~ Rat Rsa~ RSb~ a, b, c, d, p and q are as defined for formula I.
5 In a further preferred embodiment K is selected from the group consisting of:
i -(CH2)ti O-(CHZ)d , -(CHz}p N-(CHz)a- , -O-(CHZ)Z N-(CHZ)d , R~ R~
R5a O
-O-CHz CHR~ CHZ N-(CHZ)a ~ -O-CH--~-N-(CHz)d , I~
R
O
-O-CH---~O-(CHZ)z , -(CHZ)b S-(CHz)d , O O
I I
-O-5- . a valence bond , -O-(CHZ)-p-~-~- , O
O O
-O-(CHZ)b CHR3a , -O--~CHz -O-CH2--~- , ~RSa R4a R4b Raa R4b ~~I.I!
-(CHz)b N-(CH2)~(CHZ)a , -O-(CH2)2-H-(CHZ)~ \~(CHZ)a , -(CHZ)b H-CHR°a CHZ -CHZ SO-CR'aRa°-O Raa Rab -CHZ SOZ CR'aR°b- -(CHz)b IP-O~(CHz)d ORS
O Raa Rob O
-O-(CHZ)b P p~(CHZ)d . -(CHZ)°~(CHZ)d , OR
O O
-LLN-(CHZ)°-O-(CHZ)a , ~HR3°~N-(CHZ)d , R~
5a O
--CH2 , -CHZ N--LL-CR'aR°b O Rsa O R~
-O-CH2~N\~ , -O-CHz~N\'-~ , OI R~ OI Rs~
-O-CH~ ~ -(CHZ)b . -O-CH~N~-CHz , R~ O Rsa CH N~~(CHZ)b N-(CH2)a -O-CHZ-~-N~ .
R~
OI R~ O Rs~
-O-CH~ ~ -(CHZ)b~L- , -CHZ-~L ~ -(CHz)b , O Rsa O Rsa -O-CHz~N~ -(CHz)~ i -(CHz)a ~ ~ ~ -(CHZ)b .
R~
OII R~ O~~
-CHz~N\~(CHZ)p , -O-CH~N~~JN-R~ , OII OII ~
CH~ ~ R~ , ~N~ R~ , U
O
-O-CHZ--LL-N-(CHZ)b S-(CHZ)d , -O-(CHZ)b O-(CHZ)a , Rsb O Raa Rab O
-{CHZ)--~-R~ (CHZ)~-~(CH2)d . -CH~Rsb(CHZ)o R~ (CHz)d .
Raa Rab -O-(CHZ)b N-(CHZ)~~(CHz)d . N-(CHz)e N-(CHZ)d , Rsa Rsb Rsa O R~ R3b O
-O-CHZ-LI-Rsb (CHZ)~P--N-(CH2)d , -N-~(CHZ)b O-(CHZ)a , R~ R~
O R~ Rsb R~ Rab O
~~ \/ R~~ R
-CHz R~ (CHZ)b~(CHZ)~~(CHZ)d , ~--N-(CHZ)~(CHZ)~ S-(CH2)a R~
Ray Rsb O R~ R3o O
-CHi R~ (CHZ)b~(CHZ)~ O-(CHz}d , --IL-Nsb (CHZ}~(CHZ).-II-N-(CH2)d Rsa R3a Rsn Raa Rab O
CHZ N~ (CHz}b-~(CHZ)~-~--(CHZ)d , -CHZ~L--N-(CHZ)b N-(CHz)a R Rsb Rsa O
and -CHz-ll-N-(CHZ)b O-(CHZ)a Rso wherein R3a, R3b, Raa, Rab, Rea, Rsn, b, c, d, p and q are as defined for formula I.
In the above embodiments of K, Rsa and RS° are preferably independently hydrogen, lower alkyl, -OH, -{CHZ)kORsa, aryl, aryl-lower alkyl, -CHZCF3, -(CHz)g COORa3, -COORa3, -(CHZ)k-CN or -(CHz)k-NR6aRfib wherein g, k, Ra', Rfia and Rsb are as defined for formula I.
Preferably, g and k are independently 1, 2 or 3, and Rfia and Rsb are independently hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl, In the above embodiments of K, R3a and R3b are preferably independently hydrogen, halo-gen, -OH, -O-lower alkyl, -COO-lower alkyl, lower alkyl or aryl-lower alkyl.
In the above embodiments of K, R°a and R4b are preferably independently hydrogen, -CN, -CONH2, -(CHZ)-N(CH3)2, -O-lower alkyl, -CHZOH, -CH20-aryl, -N(CH3}2, -OH, -C02-lower alkyl or lower alkyl.
D is preferably hydrogen, r-z' Rz~ ~:~,' Q /(~z), W,/
,'Y' W' F
za ,:Z' ~ ~V'-Z ' ~,\Rz' , R V Rze R~ /
Rz' Rz' Rza F I ~
\ W':~ E/(C F)s 2s / V~~' ~ ~'~R2' ' R Rza z~
\ E~R W~Q' R~ G ~ Rz~
(CH~)s ~~ j"-za ~ Y~ , ' F R ~ Rza .-,28 E F
cH ~ ~~
( z)5 G /(~z)s (CH~)a E~,_(G~ W'. , / \ , , .Y. E F'...(G)r ~W' 29 ~ ~'~1 ~~ 29 R R2e Rz~ R V,_Z' R
CH ~E~~R~ Rz~
( z)5 G , Q~~ E ~~Rza o~ ~ E' W ,1,, t Rze G~F~(cHT)s /'E V'-~Z
R2a wherein s, r, R2', R2a, V', Y', Q', Z', W', E, E', F, F', G and G' are as defined for formula 1.
In still a further preferred embodiment D is hydrogen, I
Rrr ~: Y~ ~Q' Rz~
I W .Y. E
28 :Z' 1\ //
R V' ' v'-Z' ' ~ ~~C"2)' , F~ Rza Rz' W''Y' E/(C"~)S E Rze F F
R28 V, ~ ~~ Rz~ . G , R28 Rz~
E7~
CH ~
G / ~ ~ a)s E F~-(G)r w'. /~\Z)' I
I , I .~ , E F,~(G)r _W' 2a R V'~, ~ ~~y za R R2e Rz~ R V._z, R
E Rz' CH ~ ~~ W' z)s G W~cQ~ R~ Q,i Rz~
r w Q' i , Y'~Z' R2e Rze Rza Rz~
~CHz)S
Rz~
E E Rza or G I E, I ~Rza G\ cH2)S F~
F ~E~V,:Z
wherein s, r, R2', RZa, V', Y', Z', Q', Z', W', E, E', F, F', G and G' are as defined for formula I.
D is more preferably hydrogen, Rz' W, Q. Rv , !Y' ~ E~ (/
R28 _/ . ~._Z. . ~ / (CHZ)s / F
Rza n E ( ~2F E Rze R
I
~~ Rz~ . Rm . Rza / V; Z.
R
E
(CHs)/ /( \z)s w E F._(G). W, /(\~)s j :~ ~ E F'-(G)r Z
za Rz~ V~ , \ Rza R Rze Rn E RZ' (CHZ)/ W~cn' R2~ Q,iW Rzr ~ v\ / Y,- 't Q,. I Y, ~ , .
~Y, Z ~ Rza Rze ze RZ'~CHZ)s ~E R2~ R2~
E~E Rza ~ G ~ or G I E, I ~Rze G\ cH~), F Rza ~E V''Z, wherein E and E' independently are >CHR38, >NR39 or -O-; F, G and G' independently are >CHR38, >C=O or >NR39; F' is >CR38- or >N-; and s, r, RZ', R28, R38, R3s, V', Y', Z', Q' and W' are as defined for formula I.
RZ' and RZa are preferably independently hydrogen; halogen such as -CI, -Br or -F; -CF3;
-OCF3: -OCHF2; -OCHzCF3; -(CHZ)YNHCOCF3; -NHCOCF3; -CN; -NO2; -CORz9, -COORZ9, -(CHZ)yORz9 or -ORZ9 wherein Rz9 is hydrogen, aryl or lower alkyl and y is 1, 2, 3 or 4; lower alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl;
lower alkylthio;
-SCF3; aryl such as phenyl; -(CHZ)yNR29R'° or -NRZ9Rso wherein R29 and R3° independently are hydrogen, -COO-lower alkyl or lower alkyl and y is 1, 2, 3 or 4; or -CONH2; or RZ'and RZa together form a bridge -OCH20-; R38 is hydrogen; -OCHF2; -OR"° wherein R'° is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; Eower alkylthio; -SCF3;
-CHZOH; -COO-lower alkyl or -CONHz; and R39 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
In a further embodiment the invention relates to the compounds of the formula I wherein:
R' and Rz independently are hydrogen or lower alkyl or together form a valence bond;
R3 and R' independently are hydrogen or lower alkyl;
X is >C=O, >C=S, >C=NRS or >SO2;
n is 0, 1, 2 or 3;
mis0or1;
R5 is hydrogen, lower alkyl, aryl-lower alkyl, or -OR6;
wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
A is R' R' R' R' Ra \ Ra Nw Ra~Nw Ra \
/ / N /
Rs ' Rs ~ Rs . Rs I \ Rio R~ Rio Re \ N R~
Rs I \ Rt° , R
R~° Rio Rio Rio N R~ N R~ N N
Ra I Ra~ I Ra~ R ~ ~---N . N , N~ .
Ra Ra '-_ Rs Ra Rio Re O R~ O R~ S R
Rs Ra r..- Rs ~- Ra . N , , ~ .
Ra N / I Ra I Ra Rio Rio a S R R ~ I ~ t R~ ~N R N N R N R
\'N I N\ I Re I Ra I N
. , Rs Ra Ra ~ Ra ~ Rs _-Rio Rio N R7 N R7 a N~ R7 a R7 \ Nw Re I . Ra I . R ~ ~ R
Rs , Rs ~ N Ri°
Rs ' N Rs N
s R'°
Ra R' \ N\ Rio a R' N R~N~ R Ra N
\
R
i s ~ i N ~ a / i N N ~ Rto R s R Rio Ra ~ R
S O O O
Ra---~~ , Ra-. Ra N~ or Ra-~~
N
Ra Rs Rs Rs wherein R' is hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NO2, -OR", -NR"R'2, lower al-kyl, aryl, -SCF3, -SR", -CHF2, -OCHFz, -OSOZR", -CONR"R'2, -CHZOR", -CHZNR"R'Z, -OCOR", -COZR'3, -OSOZCF3;
5 R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NOz, -OR", -NR"R'z, lower alkyl, aryl, -SCF3, -SR", -CHF2, -OCHF2, -OS02R", -CONR"R'Z, -CHZOR", -CHZNR"R'Z, -OCOR", -COZR'3, -OSOZCF3, or Re and R9 together form a bridge -OCHZO-;
R" and R'2 independently are hydrogen, -COR'3, -SOZR", lower alkyl or aryl;
R'3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
R'° is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B is Rt5 W~Y \ w~.l' \ w -+- ( -~-- I +-R~4 ' V~ ' Rt5 / V~ta ~ R'S / V~ t4 R R
w. WQ R W,Q Rt4 R'S \Y R,4 Y ~ ~ ~ t5 ~'J~'\7' R , Rts \ Q W 1r Rt4~ -~v...RtS R'° I -+-Y . Yf Z /
Rts Rts Rts R,4 Q W..Y I ~ ~
\ WAY ,4 -CRt4=CR's ~~z . I t R ;
R~5 V / V
or a valence bond; preferably R,s W'' Y \ W 1' \ w'1r .~.- y R,a V ' Ru V~~a ' R1s / V~ ,a R
D W Q W
R,a \ I -y--- R,a \ I
v~ , ~ -CR''~CR's R,s R's .(~ R .Q R,a ~Q R,s R,a~
Y Y R,s R,a R" and R'S independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CHZ),CF3, -NOz, -OR's, -NR'6R", lower alkyl, aryl, -SCF3, -SR'6, -CHF2, -OCHFz, -OCFZCHFz, -OSOzCF3, 5 -CONR'6R", -(CHZ),CONR'6R", -O(CHZ),CONR'sR", -(CH2),COR'6, -O(CHZ),COR'S, -(CHZ)~OR'6, -O{CHZOOR's, -(CHZONR'6R", -O(CHZONR'6R", _OCOR'6, -COZR'8 , -O(CHZ),CN, -O(CH2),CI, or R" and R'S together form a bridge -O-CH2-O-;
R'4 and R'S preferably independently representing hydrogen, halogen, -CF3, -OCF3, 10 -OR'6, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -OSOZCF3, -CONR'6R", -CHZOR'6, -CHzNR'eR", -OCOR'S or -COzR'8; or together forming a bridge -OCH20-;
I is 9 , 2, 3 or 4;
15 R'6 and R" independently are hydrogen, -COR'8, -SOZR'8, lower alkyl, aryl, or R'6 and R" together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
R'e is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
W is -N= or -CR'9=;
Y is -N= or -CRZ°=;
Z is -N= or -CRZ'=
V is -N= or -CRS=;
Q is -NR23-, -O- or -S-;
wherein:
R'9, R~°, RZ' and R'~ independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NOZ, -OR24, -NRZ°R25, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SRZ°, -CHF2, -OCHF2, OCFzCHF2,-OSOZCF3, -CONR2°R25, -CHZCONRZ'R25, -OCHZCONR24R2s,-CHZORz4, -CHZNR24Rz5, -OCORZ° or -COZR24, or R'9and RZ°, R2° and RZ'or RZ' and R~ together form a bridge -OCH20-;
~ 5 R2° and R25 independently are hydrogen, -CORZ6, -SOZRZe, lower alkyl, aryl or aryl-lower alkyl;
R26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is R3a R3b R4a R4b L CH -\~ CH M CH CH
2~b P ~ y~a ~ ~f ~ 2~~ ~ y~d wherein:
Rsa, R3b, R<a and R'b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NOz, -ORz4a, -NR24aRzsa, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SRZ°a, -CHFz, -OCHF2, -OCFZCHF2,-OSOZCF3, -CONRZ°aR2sa -CHZCONR24aRzsa -OCHZCONR2aaR2sa -CH20RZ'a, -CHZNRZ'aRzsa -pCORzaa pr -COZRZaa;
wherein Rz4a and R25a independently are hydrogen, -CORzsa, -SOZRZSa, lower alkyl, aryl or aryl-lower alkyl;
RZSa is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or R'a and R3b, R4a and R4b or R3a and R'b together form a bridge -(CHZ); , wherein iis1,2,3or4;
1 o a, b, c and d independently are 0, 1, 2, 3 or 4;
e, f, p and q independently are 0 or 7 ;
L and M independently are -O-, -S-, -CH=CH-, -C--__C-, -NRSa-, -COO-, -CONRSa-, -NRSaCO-, -SO-, -SOz , -OSOZ-, -SOZ-NRSa-, -NRSaS02-, -NRSaCONRsb-, -NRSaCSNRSb-, -OCONRS°- Or -NRSaC(O)O_ wherein Rsa and Rsb independently are hydrogen, lower alkyl, -(CHz)k-OH, -(CHZ)k-NRsaRsb, aryl or aryl-lower alkyl;
wherein k is 2, 3 or 4;
Rsa and Rsb independently are hydrogen, lower alkyl or aryl-lower alkyl;
K preferably representing -(CHz)b 0-(CHz)a , -(CHz)b CH-CH-(CHz)d- , -(CHz)b (CHz)d- , -(CHz)p N-(CHz)a , R~
O O
-(CHz)d O-ll-(CHz)d , -O-g-(CHz)a O-(CH )-N-(CH ) , II ~ 2 b I 2 C
O R~
O-(CHz)p CHR~''-(CHz)a N (CHz)d 0 -O-(CHzr-LI-N-(CHz)a , R~
O
O
-O-(CHz)b R-ll-(CHz)a- , -p-(CHz~O-(CHz)d , O
-O-H 0-(CHz~ or -O-(CHz p ~i-- ~ -(CHz)~
O
D is hydrogen or Rz7 \ W. "\Q, ~W,~Rr I / W ~~ Rza \ Z, W~V,- ~~~
V Rza ' R2e V' ' ' z7 V' ~ ' Z , R
Rza Rv W~C1' R2~ W,iQ' R27 W~~ W,Y' I ~Y, I Rz7 ( V,:Z' , I ~ .
(CH2)r R28 R28 ~ R28 , (C~"~2)r W V' Rzr W'_ W
,/ ./
Rze ' , Y\\ /
Rze 2'-V' Rz7 / Rze Rz7 W~(CH2)$ ' E~(\~2)5 RE~(~F2)5 ~ Rza 2~ or F
Q~ ~ R R G z7 ~ze R / R
R ~/
preferably hydrogen, W' s W, __~~ Rr , ,~~ R27 ' \ z7 R
Rza Rza I / ~ , V" za R
/
~(CH2)S \ ,E
~Rz7 ~ / R2e or NF I ~ R27 Rza Rza 5 wherein:
r and s independently are 1 or 2;
E, F and G independently are -CHR38-, >C=O, >NR39, -O- or -S-;
Y' is -N= or -CR32=;
Z' is -N= or -CRS=;
V' is -N= or -CR~°=;
W' is -N= or -CR'S=;
Q' is -NR38-, -O- or -S-;
wherein Rz', RZe, Rs2, Rs3, R34a~d R35 are independently hydrogen, halogen, -CN, -CF3, -OCF3, O(CH2)yCF3, -NO2, -OR29, -NRZ9R3°, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SRZS, -CHFZ, -OCHFz, -OCFZCHF2, -OSOZRz9, -OSOZCF3, -CONRz9R3°, -(CHZ)yCONR~'R~°, -O(CHZ)yCONR29Rs°,-(CHZ)yOR29, -(CHz)yNR29Rs°, -OCOR29, -COZR29~
or RZ'and R28, R32 and R33, Rs3 and R'~ or Rte' and R'S together form a bridge -OCHZO-;
Rz' and RZa preferably independently representing hydrogen, halogen,-CF3, -OCF3, -OCHZCF3, -ORz9, lower alkyl, aryl or aryl-lower alkyl, or together forming a bridge -OCHZO-;
y is 1, 2, 3 or 4;
R29 and R3° independently are hydrogen, -COR", -SOZR3', lower alkyl, aryl or aryl-lower alkyl;
R3'is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R3$ is hydrogen, -OR'°, -NR'°R4', lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR4°, -CHFz, -OCHFz, -OCFZCHFz, -CONR°°R~,, -(CHZ)xCONR4°R"', -O(CHZ)xCONR°°R°', -(CHZ)xOR°°, -(CHz)xNR'°R4', -OCOR'° Or -COZR'°;
xis1,2,3or4;
R'° and R" independently are hydrogen, -COR42, -SOZR'2, lower alkyl, aryl or aryl-lower alkyl; and R°z is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
In a further embodiment the invention relates to the compounds of the formula I wherein:
R' and RZ independently are hydrogen or lower alkyl or together form a valence bond;
R3 and R4 independently are hydrogen or lower alkyl;
nis0,1,2or3;
mis0or1;
X is >C=O, >C=S, >C=NRS or >SO2;
wherein R5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR6;
wherein R6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
A is R' R' R' R' Ra \ Ra Nw Ra~Nw Ra \
/ / N /
Rs ' ' Rs ~ Rs . Rs I \ Rio , R' Rio I
Ra \ N R R~
~N
Rs I \ Rio , Ra N Ra Rs ' R~o~
Re Rio Rio Rio Rio N R~ I R~ I I
N N ,N
Ra / Ra~ / R~~ R7 N
Rs ' Rs Ra Re R,o Ra O R~ O R~ S R
R~ N/ / Ra / Ra / .-.'' , ~ , a , Ra Rs Rs R
° Rio Rio a S R R ~ I ~ I
R~ ~N R N N R N R
'N ~ ~- . N~ ~ . Ra ~ , Ra ~ N , Rs Ra s Rs Re R
Rio Rio N R7 N R7 N~ R7 R7 \ Nw Ra ~ . Re ~ X . Ra~ ~ Re ~ , N Rs , Rs / N Rio .Ra ~N .Rs NJ
s R'°
RaR' \ N\ R,o R' N R~N~ R N
a \
Rs / i N ~ R s / i N N / . Rio ' R'___.~
R ' l'~~ Ja Rio Re R
S O ~O ~O
R~ , R'__ ~~ , R'~ o~ R~
N
Ra Ra Ra Re wherein:
R' is hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NO2, -OR", -NR"R'z, lower al-kyl, aryl, -SCF3, -SR", -CHFz, -OCHF2, -OSOZR", -CONR"R'2, -CHZOR", -CHZNR"R'2, -OCOR", -COZR'3 or -OS02CF3;
Re and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NOz, -OR", -NR"R'2, lower alkyl, aryl, -SCF3, -SR", -CHF2, -OCHF2, -OS02R", -CONR"R'2, -CHZOR", -CHzNR"R'2, -OCOR", -COZR"or -OSOZCF3, or R8 and R9 together form a bridge -OCH20- or - OCHZCHzO-;
wherein R" and R'Z independently are hydrogen, -COR'3, -SOZR'3, lower alkyl or aryl;
wherein R'3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and R'° is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
B is R,s W~ ~ ~ W~~ ~ ~ W 1' i R14 V ' R,s V~~4 ~ R1s / V~ ,a R R
W .Q R .~l 14 R's \ ~ R,a~ ~ W / R
/ Y ~ R,s V , ~ .
,4 R1s ~Q~ Q W 1' ,<~- ~R,S R'4 Y . . R / Z . ~ v~
R14 R,s ' R,s Q W, ,4 I
~Z . I \ W~-~-R'° . -CR'~CR's R1s V~ / V~Z
or a valence bond; preferably R,s ~ ~ R,s , R~a R,s R,a R~s \
~ W ~ or -~--R,a O /
/ V' R,s wherein:
5 R'4 and R'S independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CHz),CF3, -NOz, -OR'6, -NR'BR", lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR's, -CHFz, -OCHFz, -OCFZCHFz, -OSOZCF3, -CONR'BR", -(CHz),CONR'sR", -O(CHz),CONR'eR", -(CHz)iCOR'6, -(CHz),COR'6, -(CHzOOR'6~ -O(CHz)iOR's, -(CHz)iNR'eR,~~ -O(Cl..~z)iNR'sRn~
-OCOR's, -COZR'8 , -O(CHz),COzR'8, -O(CHz),CN, -O(CHz),CI, or R'4 and R'S
together 10 form a bridge -OCH20-;
R" andR'S preferably independently representing hydrogen, halogen, -CF,, -OCF3, -OR'6, -NR'6R", lower alkyl, aryl, aryl-lower alkyl, -OS02CF3, -CONR'6R", -CHzOR'6, -CHZNR'sR", -OCOR'6 or -COzR'8; or together forming a bridge -OCH20-;
wherein I is 1, 2, 3 or 4;
R'6 and R" independently are hydrogen, -COR'8, -SOZR'8, lower alkyl, aryl, or R'e and R" together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms;
wherein R'8 is hydrogen, Power alkyl, aryl or aryl-lower alkyl;
W is -N= or -CR'9=
Y is -N= or -CRzo=;
Z is -N= or -CRz'=;
V is -N= or -CRzz=; and Q is -NRz3-, -O- or -S-;
wherein:
R'9, Rz°, Rz' and Rzz independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NOz, -ORz', -NRz'Rzs, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SRz4, -CHFz, -OCHFz, -OCFZCHFz, -OSOzCF3, -CONRz4Rzs _CHzCONRz'Rzs, -OCHzCONRz°Rzs, -CHZORz4 -CHZNRz4Rzs, _OCORz4 or -COZRz", or R'9and Rz°, Rz° and Rz'or Rz' and Rzz together form a bridge -OCH20-;
wherein Rz° and Rzs independently are hydrogen, -CORzs, -SO2Rz6, lower alkyl, aryl or aryl-lower alkyl;
wherein Rzs is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and Rz3 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
K is R3a R3b R4a R4b L1 (CH -~ CH M CH CH -( le 2~b P ( z~a ( ~( ( z~~
wherein:
R3a, R3b R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCHZCF3, -NOz, -ORz4a, -NRzaaRzsa, lower alkyl, aryl, aryl-lower alkyl, SCF3, -SRz'a, -CHFz, -OCHFz, -OCFZCHFz,-OSOZCF3, -CONRzaaRzsa _CHzCONRz4aR2sa -OCH2CONRzaaRzsa -CHZORzaa -CHZNRzaaRzsa -OCORz4a or -C02Rzaa;
wherein RZ'a and RZSa independently are hydrogen, -CORZ6a, -SOZRzsa, lower alkyl, aryl or aryl-lower alkyl;
wherein Rya is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
Or R'a and R3b, R'a and R°b or R3a and R°b together form a bridge -(CHZ);-;
wherein i is 1, 2, 3 or 4;
a, b, c and d independently are 0, 1, 2, 3 or 4;
e, f and p independently are 0 or 1;
q is 0,1 or 2; and L and M independently are -O-, -S-, -CH=CH-, -C=C-, -NRsa-, -CO-, -OCO-, -COO-, -CONRSa-, -NR5aC0-, -SO-, -SOZ , -OSOZ , -SOZ NRsa-, -NRSaS02-, -NRSaCONRSb-, -NRSaCSNRSb-, -OCONRsb- or -NRSaC(O)O-;
wherein Rsa and Rsb independently are hydrogen, lower alkyl, -(CH2)k-OH, -(CHZ)k-NR6aRsb, aryl or aryl-lower alkyl;
wherein k is 2, 3 or 4; and Rsa and Rfib independently are hydrogen, lower alkyl or aryl-lower alkyl;
K preferably representing -O-(CHZ)d . - - , -O-(CHZ)Z N-(CHZ)d , R~' O
-O-CHz CHR~ CHZ H-CHZ . -O-CHZ--~--N-(CHZ)a , I~
R
O O
-O-CH-ll-O-(CHz)z , -O-CH--~
O O
-O-S- , a valence bond , -O-(CHZ)2-p-~-H- , O
O
O-CHR~ , -O~CHz R'~ R'°
-(CHZ)b N-(CHz)a and -O-(CHz)2-H-(CHZ)~\~(CHZ)~
D is hydrogen, Rz~ Rz~
~' Y' \ ~' Y' \
i -t- Rza ~~ ~ ~G, ~Y' za ~/~'Z~ , ~ ~ V.'-Z~ , ~ ,Z' V'-Z' R R Rz7 V' , , Rza Rzi W~cQ' Rz~ W ~Q' R2~ W:-r W:Y.
z~ i ~~., I , R (cHz)r V''Z, ~ Rza (cH ) .=Z~ , ~~ V
Rza Rza Y'-Z' W ~ ~V' z~
W'- W' R
Y\~ -v ~ Rza ' ~ Y\\ ~ ~ / , Rze Z'-V' Rz~ / Rza Rz~
za RW"\ ~Z)~ , E OAF RE~~"F~ ~ RZe F ~Rz~ . Rz~ , F
~'Q' '~i--z'e G~ ' ' za R / Rrr R \~/
(cH )~E~~Rz~ /E F E~(cH2):WG)r z . CH ~, F
G ( Z)' G of G~~~ \ ze Y' ~ ~ \ R
~Rza ~ Rz~
Rza /(\ ~).
~G)r R~' 1 Rza preferably hydrogen, Rz~
~Q' Rz~
wN ~%~ \
R28 / , b'-Z , ~ ~(CHz)f , G~R2e /(CHz)s E R2a E I \ \
Rz' z~
R28 R ' Rz~ ' /
Rza E
(CHz)~ /(~ z)s (CH ) E F,~~G~r / ~ z s ~'~ Wr , Rza , _.
Rza R2~ \ Rz~ \ Rza R2r or E Rz' (CHz)~
QvY ~Z, Rze wherein:
r and s independently are 0, 1 or 2;
E, F and G independently are -CHR38-, >C=O, >NR39, -O- or -S-;
10 F' is >CR38- or >N-;
Y' is -N= or -CR32=;
Z' is -N= or -CR33=;
V' is -N= or -CR~'=;
W' is -N= or -CR'S=; and Q' is -NR36-, -O- or -S-;
wherein:
RZ', Rze,Rsz, R33, R~and R35 are independently hydrogen, halogen, -CN, -CF3, -OCF3, -O(CHZ)yCF3, -NOz, -ORZg, -NR~'R3°, lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR29, -CHFZ, -OCHF2, -OCFZCHF2, -OSOZR29, -OSOZCF3, -CONRZ9R3o, -(CHz)YCONR~''R3°, -O(CHz)YCONRZ9R'°, -(CHZ)yORz9, -(CHZ)yNR29R3o, _OCORZ9 or -C02RZS;
or R2'and R28, R32 and R3', R33 and R~ or Rte' and R35 together form a bridge -OCH20-;
RZ' and R28 preferably independently representing hydrogen; halogen such as -CI or -F;
-CF3; -OCF3; -OCHFz; -OCHzCF3; -ORz9 wherein Rz9 is hydrogen or lower alkyl;
lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF3; -CHzOH;
-COO-lower alkyl; aryl or -CONH2; or together forming a bridge -OCH20-;
wherein y is 1, 2, 3 or 4; and R29 and R3° independently are hydrogen, -COR3', -SOzR", lower alkyl, aryl or aryl-lower alkyl;
wherein R3' is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R36 and R39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl;
and R38 is hydrogen, -OR°°, -NR°°R°', lower alkyl, aryl, aryl-lower alkyl, -SCF3, -SR°°, -CHF2, -OCHF2, -OCFZCHF2, -CONK'°R", -(CHz)XCONR4°R", -O(CHZ)xCONR4°R", -(CHZ)XOR'°, -(CHZ)XNR°°R°', -OCOR°° or -COZR°°;
wherein x is 1, 2, 3 or 4;
R°° and R4' independently are hydrogen, -COR42, -SO2R"2, lower alkyl, aryl or aryl-lower alkyl; and wherein R'2 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
Examples of specific compounds represented by the above general formula V are the follow-ing:
CHI CHI
I CHI O C\ ~ i CHI
O CH O~O w ~0 w H.N w i CI ' ~ H.N w ~ CI
HO ~ HO
CI CI
3-Chloro-4-hydroxybenzoic acid [5-chloro-2- 3-Chloro-4-hydroxybenzoic acid [3,5-dichloro-methoxy-4-(4-isopropylbenzyloxy)- 4-(4-isopropylbenzyloxy)benzylideneJhydrazide benzylidene]hydrazide CHI CHI
0 \ i I CHI O i I CHl O ~ O
H.N ~ I i pCH I ~ H.N ~ I i CI
HO ~ OCH~ ~ HO / CI
CI CI
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [2,3-dichloro-[2,3-dimethoxy-4-(4-isopropylbenzyloxy)- 4-(4-isopropylbenzyloxy)benzylidene]hydrazide benzylidene]hydrazide HOC CHl ~CH3 0 ~ 0 I \ H'N \ I / OCH3 HO
CI
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [3-isopropyl-4-[2,3-dimethyl-4-{4-isopropylbenzyloxy)- {4-isopropylbenzyloxy)-5-benzylidene]hydrazide methoxybenzylidene]hydrazide H3C CH3 , N
CHs ~ CH, O \ O \ O ~ i CH3 \ N.N w I i CH p I ~ o w H 3 ~ N~N ~ ~ OCH
HO ~ HO I ~ H
C) CI
3-Chloro-4-hydroxybenzoic acid [3-isopropyl- 3-Chloro-4-hydroxybenzoic acid 4-(4-isopropylbenzyloxy)-5- {3-[2-{ 1-pyrrolid ino)ethoxy)]-4-(4-methylbenzylidene)hydrazide isopropylbenzyloxy)-5-methoxybenzyiidene}hydrazide CH3 H3C~N~CH3 CH3 CH3 ~ I CH3 O ~ I ~CH3 C \ O \
o \ I
O N~N ~ ~ ~ OCH I \ H.N ~ ~ pCH3 HO CI
CI
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [3-(2-diethylaminoethoxy)-4-{4-isopropyl- [3-(2-diethylaminoethyl)-4-(4-benzyloxy)-5-methoxybenzy(idene]hydrazide isopropylbenzyloxy)-5-methoxybenzylidene]hydrazide ~---CH3 CH COZH CH3 H3C~N ~ I CH3 OJ i I CH3 O~~ ~ O \
O I O
H.N ~ ~ OCH~ I ~ H.N ~ ~ pCH3 HO ~ HO
CI CI
3-Chloro-4-hydroxybenzoic acid 5-[(3-Chloro-4-hydroxybenzoyl)hydrazono-[3-diethylaminomethyl-4-(4-isopropylbenzyl- methyl]-3-methoxy-2-(4-isopropylbenzyloxy)-oxy)-5-methoxybenzylidene]hydrazide phenoxyacetic acid OOH , I CH3 OOH , CH
O J \ O ~ O \ O \ ~ s H.N ~ ~ pCH3 I j H-N ~ ~ OOH
HO C HO
CI
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [3-(2-hydroxyethoxy)-4-(4-isopropyl- [3,5-bis-(2-hydroxyethoxy}-4-(4-benzyloxy)-5-methoxybenzylidene]hydrazide isopropylbenzyloxy)benzylideneJhydrazide CH3 OCH3 i CH3 O\ H O \ i CH3 O
O
N.N w ( ~ OCH ~ \ ~.N w ~ OCH3 HO I ~ H OCH3 HO
CI
CI
3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [2,3,5-trimethoxy-4-(4-isopropylbenzyloxy)- [3,5-dimethoxy-4.-(4-n-propylbenzyloxy)-benzylidene]hydrazide benzyiidene]hydrazide OCH3 i I OvCH3 CH3 O I \ O \ OCH3 i I CH3 \ N.N w i OCH p \ O \
HO I ~ H I ~ H.N w I i OCH3 CI HO
F
3-Chloro-4-hydroxybenzoic acid 3-Fluoro-4-hydroxybenzoic acid [3,5-dimethoxy-4-{4-ethoxybenzyloxy)- [3,5-dimethoxy-4-(4-isopropylbenzyloxy)-benzylidene]hydrazide benzylidene]hydrazide OCH3 ~ I ~CFi3 OCH3 ~ CHs O ~ O w O ~ O
H.N ~ I i pCH3 ~ N.N ~ I ~ OCH
H ' HO HO
NOZ COZH
3-Nitro-4-hydroxybenzoic acid 3-Carboxy-4.-hydroxybenzoic acid [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- ben-benzylidene]hydrazide zylidene]hydrazide OCH3 ~ I CH3 OCHy ~ I CHI
O ~ O ~ O ~O
H.N ~ I i OCH i ~ H.N ~ (i ii' OCH
HO ~ HO
CONHZ CN
3-Carbamoyl-4-hydroxybenzoic acid 3-Cyano-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-isopropylbenzyloxy)- [3,5-dimethoxy-4-(4-isopropylbenzyloxy)-benzylidene]hydrazide benzylidene]hydrazide OCH3 i I Ol OCH3 i OCF3 O ~ O ~ ICF3 O ~ O
CI
~.N ~ ~ OCH3 I ~ H.N ~ ~ OCH3 HO ~ HO
CI CI
3-Chloro-4-hydroxybenzoic acid 3-Chioro-4-hydroxybenzoic acid {3,5-dimethoxy-4-[4-(2,2,2-trifluoroethoxy}- [3,5-dimethoxy-4-(3-chloro-4-benzyloxy]-benzylidene}hydrazide trifluoromethoxybenzyloxy)benzylid-ene]hydrazide O w O w O w O w N.N ~ I / I / CI ~ N.N ~ I i I i CH3 H OCH3 ( H OCH3 HO ~ HO ~ CH3 CI CI
3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-chlorophenoxy) benzylid- dimethoxy-4-(4-isopropylphenoxy) benzylid-ene]hydrazide eneJhydrazide OCH N ~ CF3 OCH3 CH3 w O w ~ O w O CH3 O N.N ~ I ~ OCH I ~ H.N ~ I ~ OCH3 HO I ~ H HO
CI CI
3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-trifluoromethyl-2- dimethoxy-4-(6-methylheptyloxy) benzylid-pyridylmethoxy)- benzylidene]hydrazide ene)hydrazide O ~ O ~r~~
O I O ~ \ CHa H.N w ~ OCH3 I I ~ H.N ~ ~ OCH3 H3C CH3 HO ~ CHZ HO
CI Ci 3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(5-hexenyloxy) benzylid- dimethoxy-4-(5,5-dimethyl-3-hexynyloxy) ene]hydrazide benzylidene]hydrazide \ \
O ~ ( \ O ~ \ O ~ \ O \
\ .N w ~ \ .N w I i I i CH3 N OCF3 ~ N
HO I ~ H HO I ~ H CH3 3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(4-trifluoromethoxyphenoxy)-1- isopropylphenoxy)-1-naphthylmethylene]hydrazide naphthylmethylene]hydrazide OCH3 i CF3 O ~ \ w \ ~ H3 \ H~N ~ ~ OCH3 O
HO ~ ~ N.N
C1 ~ , H ' HO
Ci 3-Chloro-4-hydroxybenzoic acid {3,5- 3-Chloro-4-hydroxybenzoic acid {3,5-di-dimethoxy-4-[2-{4-E-trifluoromethylphenyl}- methoxy-4-[(4-isopropylphenyl)-ethenyl]benzylidene}hydrazide ethynyl]benzylidene}hydrazide O ~ \ / ~ \ H.N H3 \ N~N ~ ~ OCH3 HO
HO I ~ H CI CH3 CI
3-Chloro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3-(2-dimethoxy-4- methoxy-4-methytphenyl)ethynyl-5-(cyclohexylethynyl)benzyfidene]hydrazide methoxybenzylidene]hydrazide I ~ F F F
O ~ OH
N.N ~ I ~ I \ I
H O I ~ O
HO .N ~ ~ F
CI \ I
HO
CI
3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1- 3-chloro-4-hydroxybenzoic acid [4-(3,5-bis-naphthylmethylene)hydrazide trifluoromethylbenzyloxy)-1-naphthylmethyleneJhydrazide o i I °~°I
_ ,N ~ w °
/ H ~ ~ , N.N w HO ~ I H
CI HO
3-chloro-4-hydroxybenzoic acid [4-(2- 4-Hydroxy-3-methoxybenzoic acid (2-chloroethoxy)-1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide O I I ~ OCH3 O CH
N.N w / , N.N w I ~ CH3 ~ I H ~ I H
HO HO
4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxy-3-methoxybenzoic acid (4-tert-methoxy-1-naphthylmethylene)hydrazide butylbenzylidene)hydrazide O I ~ CH3 N.N ~ / O
H , .N ~ I /
HO \ I H
OCH3 HO \
4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxy-3-methoxybenzoic acid (4-isopropylbenzylidene)hydrazide trifluoromethoxybenzylidene)hydrazide WO 99/01423 PCTlDK98/00287 ( ~ ~ Hs O I NH O I ~ N~CH3 ( ~.N w ~ , N.N ~
H
HO HO
4-Hydroxy-3-methoxybenzoic acid (1 H-indol-3- 4-Hydroxy-3-methoxybenzoic acid (4-ylmethylene)hydrazide dimethylamino-1-naphthylmethylene)hydrazide o ~~ ~ o H.N ~ i ~ N.N ~ i I H
HO HO
4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxybenzoic acid (1-phenylbenzylidene)hydrazide naphthylmethylene)hydrazide O I ~ OCH3 O I
.N~ / ,N~ I /
~ I 'H
HO ~ HO \
HO
4-Hydroxybenzoic acid (4-methoxy-1- 3,4-Dihydroxybenzoic acid (1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide ~ F F F
O
.N ~ I i HO
.N ~
L H
HO
4-Hydroxy-3-methoxybenzoic acid (1- 4-Hydroxy-3-methoxybenzoic acid [3-(3-tri-naphthyimethylene)hydrazide fluoromethylphenoxy)benzylidene]hydrazide FY F
I' F
O I ~N O~F
N.N ~ / O \
HO \ I H , N.N w ( /
OCH3 HO \ I H
4-Hydroxy-3-methoxybenzoic acid {4- 4-Hydroxybenzoic acid [3-(1,1,2,2-quinolinyimethylene)hydrazide tetrafluoroethoxy)benzylidene]hydrazide CH3 \
\ OH
o N.N w \ I ~ \CH' , O N.N w I /
HO \ I H CH HO \ I H
4-Hydroxybenzoic acid [3-(4-tert-butylphenyl)- 4-Hydroxy-3-methoxybenzoic acid (4-E-but-2-enylidenejhydrazide hydroxy-1-naphthyimethyiene)hydrazide O \ \
_ ,N~ I ~
o \
HO \ I ~ , N.N ~
I H
HO \
4-Hydroxybenzoic acid (benzylidene)hydrazide 4-Hydroxybenzoic acid {1-naphthylmethylene)hydrazide \ i \
o I \ o I \ off .N ~ / .N ~
~ I ~ ~ I ' HO ~ HO \
NHZ NHz 3-Amino-4-hydroxybenzoic acid (1- naphthyl- 3-Amino-4-hydroxybenzoic acid (4-hydroxy-methylene)hydrazide 1- naphthylmethylene)hydrazide O ~ F
N~N ~ I / O / F
~ I H ~ I O I ~
HO / N.N ~ /
H
HO
CI
4-Hydroxybenzoic acid [3-(3-trifluoro- 3-Chloro-4-hydroxybenzoic acid (1-methylbenzyloxy)benzylidene]hydrazide naphthylmethylene)hydrazide OH O I ~ OH
° Iw .N ~ / / .N ~ /
I I
HO
HO
CI
3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1- 4-Hydroxybenzoic acid (4-hydroxy-naphthylmethylene)hydrazide naphthylmethylene)hydrazide F F O HN-N
O I W O / I F / N.N w W /
/ .N ~ / ~ ~ I H
I ~ HO
HO
4-Hydroxybenzoic acid [4-{3- 4-Hydroxybenzoic acid (5-phenyl-3-trifluoromethylphenoxy)benzylidene]hydrazide pyrazolylmethylene)hydrazide I
I off O I ~ o -N~ ~ / .N~ /
I _ I 'H
HO ~ OH HO
f _.N.
O ~O
2,4-Dihydroxybenzoic acid (4-hydroxy-1- 4-Hydroxy-3-nitrobenzoic acid (1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide O I ~ OH O I ~ OH
/ N.N w I / / N,N ~ I /
H I H
HO \ HO
O-~N~O HO
4-Hydroxy-3-nitrobenzoic acid (4-hydroxy-1- 3,4-Dihydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide O I / O I ~ OH
/ N.N w I / CI / N,N ~ I /
H J H
HO ~ HO
CI
4-Hydroxybenzoic acid (6-methoxy-2- 3,5-Dichloro-4-hydroxybenzoic acid (4-naphthyimethylene)hydrazide hydroxy-1-naphthylmethylene)hydrazide CI
/ I H.N ~ O
O ~ N
/ I H'N \ / OCH3 HO
4-Hydroxy-3-methoxyberizoic acid (9-ethyl-9H- 4-Hydroxy-3-methoxybenzoic acid [5-{3-3-carbazolylmethylene)hydrazide chlorophenyl)-2-furanylmethylene]hydrazide o I~ I
/ I H.N ~ ~ / O ~ O
CHz HO ~ / 'N ~ I /
CI HO ~ I
CI
3-Chloro-4-hydroxybenzoic acid (3-phenyl-E- 3-Chloro-4-hydroxybenzoic acid (4-allyloxy-1-allylidene)hydrazide naphtylmethylene)hydrazide I y O~ I y O I /
/ O N.N w I / , O N.N w ( /
H I H
HO \ HO
CI CI
3-Chloro-4-hydroxybenzoic acid (4- 3-Chloro-4.-hydroxybenzoic acid (4-ethynylmethoxy-1- benzyloxy-1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide O
O I W O~NHz O I W CH3 .N ~ I / / N.N ~ I /
I _ I _H
HO ~ HO
CI CI
2-(4-[(3-Chloro-4-hydroxyben zoyl)hydra- zo- 3-Chloro-4-hydroxybenzoic acid (4-methyl-1-nomethyl]-1-naphthyloxy)acetamide naphthylmethylene)hydrazide O I ~ O I ~ OCH3 / .N ~ / / N.N ~
HO ~ I ~ OH HO ~ I 'H
CI CI
3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1- 3-Chloro-4-hydroxybenzoic acid (4-methoxy-naphthylmethylene)hydrazide 1-naphthylmethylene)hydrazide o o .NON I / O HO I
I ~ H ~ v / .N w I /
HO
C! I / Ho ~ I
CI
N-(2-[(3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid (1-hydroxy-hydroxybenzoyl)hydrazono]ethyl)-2,2- 2-naphthyimethyfene)hydrazide diphenylacetamide ~I
O W O I
° I~
-N w I H-N w ~ OCH3 'H ~ I w HO C HO
CI
3-Chloro-4-hydroxybenzoic acid (2,2- 3-Chloro-4-hydroxybenzoic acid (4-diphenylethylidene)hydrazide benzyloxy-3,5-dimethoxybenzylidene)hydrazide I W \CH O W CHs O ~ ~ .N~ I /
O I _ HO
-N ~ I / CI
~ I H
HO
CI
3-Chioro-4-hydroxybenzoic acid [3-(4-tert- 3-Chloro-4-hydroxybenzoic acid {4-methyl-1-butylphenoxy)benzylidene]hydrazide naphthylmethylene)hydrazide O I ~ OH O I ~ O~CH3 H-N ~ ~ Br / -N ~ I i II0 H
HO HO
CI CI
3-Chloro-4-hydroxybenzoic acid (3-bromo-4- Acetic acid 4-[(3-Chioro-4-hydroxy-1-naphthylmethylene)hydrazide hydroxybenzoyl)hydrazonomethyl]-1-naphthyf ester p~N I
o I~ p N-N ~ / / _ -N ~ I /
HO ~ I H HO ~ I ~ OH
CI CI
3-Chloro-4-hydroxybenzoic acid (4- 3-Chloro-4-hydroxybenzoic acid (2-hydroxy-cyanomethoxy-1- 1-naphthylmethylene)hydrazide naphthylmethylene)hydrazide O
O ~ ~ OCH3 O I ~ , N.N~ I ~ I
N-N ~ ~ ~ I H o 'H HO
HO ~ CI
CI
3-Chforo-4-hydroxybenzoic acid (2,3- 3-Chloro-4-hydroxybenzoic acid [3-(4-methylenedioxybenzyiidene)hydrazide methoxyphenoxy)benzylidene]hydrazide I p o ~ o ~ o~'oH
I H'N~ ~ I ~ / -N~ I /
HO ~ ~ I
HO
CI CI
3-Chloro-4-hydroxybenzoic acid (9- 3-Chloro-4-hydroxybenzoic acid [4-(2-phenanthrenylmethylene)hydrazide hydroxyethoxy)-1-naphthylmethyiene]hydrazide O ~ OH O ~ O ~N
I
I H'N \ / / I ~-N \ I ~ O
HO ~ HO
Br CI
3-Bromo-4-hydroxybenzoic acid (4-hydroxy-1- Nicotinic acid 4-[(3-chloro-4-naphthylmethylene)hydrazide hydroxybenzoyl)hydrazonomethyl]-1-naphthyl ester o I ~ \ / I o O ~ OVN O
I
-N ~ I r O / I ~-N ~
I ~ HO
HO
C CI
3-Chioro-4-hydroxybenzoic acid [4-(1,3-dioxo- 3-Chloro-4-hydroxybenzoic acid [4-1,3-dihydroisoindol-2-ylmethoxy)-1-naphthyl- (cyclohexyfmethoxy)-1-methylene]hydrazide naphthyfmethylene]hydrazide O ~,.~N
O I O O I
.N w ~ .N w ~ I '~ ~ I ' HO ~ HO
CI CI
3-Chloro-4-hydroxybenzoic acid [4- 3-Chloro-4-hydroxybenzoic acid [4-(3-(tetrahydro-2-pyranylmethoxy)-1-naphthyl- pyridylmethoxy)-1-methylene]hydrazide naphthylmethyfene]hydrazide O Oy N,iO_ O I \ O~O~CH3 w .N ~ / O
/ N.N w I /
HO ~ ~ I H
CI HO
CI
4-[(3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid (3-hydroxybenzoyl)hydrazonomethyl]-1- nitrobenzylidene)hydrazide naphthyloxy)acetic acid ethyl ester O CI ~ CI
.N ~ I / I F
_N O W
HO \ I H , .N ~ I
CI HO ~
CI
3-Chloro-4-hydroxybenzoic acid (2,4- 3-Chloro-4-hydroxybenzoic acid (4-fluoro-dichlorobenzylidene)hydrazide naphthyfmethylene)hydrazide F I ~ F
O ~ OH O
.N ~ I / / N.N ~ I /
/ I '~ I H
HO
HO
F Cf 3-Fluoro-4-hydroxybenzoic acid (4-hydroxy-1- 3-Chloro-4-hydroxybenzoic acid [4-(2,4-naphthylmethylene)hydrazide difluorobenzyloxy)-1-naphthylmethylene]hydrazide I
Q ~ o ~ o .N ~ I / N.N ~ I /
' / I ,H
HO ~ HO
F Cl 3-Fluoro-4-hydroxybenzoic acid (1- 3-Chloro-4-hydroxybenzoic acid [4-(3-naphthylmethylene)hydrazide methoxybenzyloxy)-1-naphthylmethyiene]hydrazide ~ F ~ O
I ~ Q I / I o O O
/ N.N ~ I / / N.N ~ I /
H \ I H
HO \ HO
CI CI
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(2-fluorobenzyloxy)-1- tetrahydrofuranylmethoxy)-1-naphthyimethylene]hydrazide naphthylmethylene]hydrazide O ( \ OCH3 O I \ O O
\ \
/ N.N w I / Br / N.N w ( /
H I H
HO \ HO \
CI CI
3-Chloro-4-hydroxybenzoic acid (3-bromo-4- 3-Chloro-4-hydroxybenzoic acid [4-(3-methoxy-1-naphthylmethylene)hydrazide tetrahydrofuranylmethoxy)-1-naphthylmethyleneJhydrazide O O F
OCH3 \ ~
\ \ OCH3 O \ O I / ~F
O I ~ O I / / N.N w N,N \ I / \ I ~H OCH3 /
I 'H HO
HO \ CI
C!
4-(4-[3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid [3,5-hydroxybenzoyl)hydrazonomethyl]-1- dimethoxy-4-(4-trifluoromethoxybenzyloxy)-naphthyloxymethyl)benzoic acid methyl ester benzylidene]hydrazide \ \ O~ F I \ I \
O I \ O ~ / F' F O /
I p \
/ ~N \ / / N~N ~ I / CH
HO \ I ~ \ I H
CI HO
C
3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(2-trifluoromethoxybenzyloxy)-1- methoxybenzyloxy)-1-naphthylmethylene]hydrazide naphthylmethylene]hydrazide WO 99/01423 PCTlDK98/00287 W W W FW
O ~ O i O ~ O i .N w I / F , N.N w I ~ F
'H
HO ~ HO
CI CI
3-Chioro-4-hydroxybenzoic acid [4-(2- 3-Chloro-4-hydroxybenzoic acid [4-(2,6-fluorobenzyloxy)-1- difluorobenzyioxy)-1-naphthyimethylene]hydrazide naphthylmethylene]hydrazide OMe CHI
HO / ~ O / ~ _ HO / ~ O / ~ _ CI H \ / ~ O ~ / OCF~ CI H \ / ~ O ~ / OCF~
H H a CI O
O HO / ~ O-CHI CH, / ~ / ~ _ _ HO -N ~ / OCF3 CI H / ~ O \ / CH
Cl \ / ~ O~ H
H O-CHa O O
HO-~ CI - CHI HO ~ ~ CH3 CH, C! H \ ~ ~ O \ ~ CHI CI H N ~ ~ O \ ~ CH
H ~ I H ~ Ha HO ~ ~ COZH CHI HO ~ ~ O-~ CHI
H N ~ ~ N N
CI \ ~ ~ O~CH~ CI H \ ~ ~ 0 ~ ~ CH
H H ~_ a Ha CHa HO ~ ~ O HO ~ ~ 0 ~ O
N- ~N-N OCF~
CI H CI H \ ~ ~ 0 H
HO~~ ~~ ~~ O ~ ~ HO ~ ~ O
~N-N OCF~ N-N
H \ ~ ~ O \ / CI H \ ~ ~ O \ / N(Et)z H H a 0 / O\/~N~ O H
\ NON w \ ~ ~ / \ NH-N
H I OCF3 ~ / / \
HO
HO ~ CI \ I /
CI CHI CH3 O ~NH
OCF~
HO ~ ~ 0 ~ ~ N OCFy HO ~ ~ O I
CI H N ~ ~ ~ ~ CI H \ ~ ~ NUO
H H
O H i--N(Et)z HO ~ ~ ~ ~ \N ~ ~ CFA CO
CI H ~ ~ HO ~ ~ N ~ ~ N ~ ~ CF' H ~ CI H
H
N(Et)z ~N(Et)2 HO / ~ O / ~ HO / ~ /O
H-N -_~N
CI \ / ~ O / ~ CFA CI H
H
CFA CHI
~N(Et)Z i--N(Et)2 0 / ~ ~O
HO / ~ OMe ~N ~ HO--~~~ OMe N
CI H \ / ~ O / ~ F H N /
H H
OMe CHI OMe OCF~
HOC
O
HO / \ OMe N
CI H N / \ /
H
OMe CHI
The most preferred specific compounds represented by the above general formula 111 are the following:
HO / ~ SO / ~ CFA
NON- H / -i N-N
O CI H \ /
/ ~ ~ H CFA
HO
CI
HO / ~ S O / ~ HO / ~ S O /
O~ ~N-N OCF3 O N-N CI
H
CI \ / ~ O F H \ /
H H \- /
O O
HO / ~ ~S\ OMe - HO / ~ ~S\ OMe CH3 CI O H \ / ~ O ~ / OCF~ CI O H \ / ~ O ~ / CH
H H s Me OMe The most preferred specific compounds represented by the above general formula IV are the following:
Ho / \ o / \ _ H / \ O \ / OCF~
CI
OCH~ O
HO / \ O / \ CH, HO / \ N / \ CH
__~~H-N / \ / CI H / \ O \ / C
CI ~J~'/ ~ \ O~CH3 O / \ O CFA
HO / \ H OCH~ HO--~~~ OCH~ _ N-N OCF N-N
CI H / \ O \ / ~ CI H / \ O \ /
CFA
OCH~ OCH3 O
HO / \ N-N OCH~ CHI
CI H / \ O \ /
OCH~
Preferred specific compounds represented by the formulae VI and VII are the following:
Me0 O
O ~ I ~N O Me0 ~ O~N ~ CI
N.N~ W ~ / S ~ N.N~ ~ I H I i I
I H ~ I H c HO ~ CI ~ HO
CI CI
O Me0 ~ O ~
N
N.N~ w I ~ I O Me0 ~ O~
N
HO I ~ 'H ~ N.N~ w I H
C1 HO I i H
~CI CI
O Ne0 \ I O~H~['~ I O Me0 , O~ OH
N
N.N~ W I
N ~ W
I i H I H ~I /~
HO HO ~ v 'CI
CI CI
Me0 0 N O ~O , p ~ N
O N.Nw W I ~H I ~ CI ~ N.Nw ~ I ~~ ~ CI
I / H I H ~I
HO HO ~ v 'Cl Cl CI
Me0 O N O Me0 ~ O ~ N
O N.N ~ w I ~ ~~ ~ ~ N.N ~ w I ~~ ~ OMe I , ,H I H
HO ~ CI HO
CI
CI
OH
O Me0 , O~N \ I I i OMe \ N.Nw \ I H OH ~ ~I
I / H O ~ O~N
HO CI I H N \ \ I OMe H
HO
~Br O Me0 , O ~ ~[' I C!
N,N\ \ I H
I , H I
HO
CI
O ~ O~N \
CI .N~ \ I H
O M~ / O~N \ I CI I H OMe ~ F
H HO
( \ H.Nw \ CI
HO
cl I
Me0 O
\ O N.N~ \ I ~H I / O.CF3 \ O .N~ \ I O~H I i I , H I N O~ ~CI
HO~ r H
CI HO
CI
OMe ~ I CI
O ~ O~N~CI ( \ .N. \ I H
I H CI O ~ O
HO \ N.N ~ \ I OMe N \
CI
OMe HO I ~ H
C!
O ~ O~N \ CI
\ .N~ \ I H I i .CF \
N CI ~O ' I
H i HO
CI O .Nw \ ( O~H I \ C!
( \ I \ H OMe ~ CI
HO
O ~ O~N / CI
\ N. N w \ I OMe \ I I \
I~ H
HO
CI O / I O
\l I \ I \ H.N~ \
OMe OMe HO
O / O~N \ I CI
OMe I \ H.N ~ \ I OMe CH3 HO
CI
I I
i CI
i O ~ O~N~ O ~ O~N \ I CI
I I H
\ H.N ' \ OMe N I ~ CI I ~ .N ' \
N OMe HO
CI HO
CI CI
\ \
I~ S
0 / I O'/~N~ O / I 0'/'H~\/
I \ H.N ' \ OMe vN I \ OMe I ~ N.N ' \ OMe HO ~ ~ HO
CI CI
I\ I~
O'/'N \
O , I O~N I ~ OMe ~ O N.N' \ I OMe H I i O,CF3 N,N ' \ O~ l~~ I ~ H
I , 'H OMe HO
CI
HO
CI I \
I
OH
I O / I O~H I \
O i O~N~ ~ N.N ' \ pMe i NHZ
I \ H.N' \ I OMe H OH I ~ H
HO
HO ~ CI
CI
\ O \ I O~N
I ~ ~ B~ \ .N' \ I
N \ / S
O ~ O~N \ I HO I ~ H Cl I i I H
( \ H.N ' \ OMe CI
HO
I
CI \ O N \ I O~ ~~ \ I O
\ .N' \ N
I / OH , CI HO I ~ H
O ~ O'/~N ~ I CI
I H
I H N ' \ OMe OH
HO
I
CI O \ O~N \
I \ H.N ' \ I H i ~
HO
CI
N \ i , OMe O \ I O.~~ N ~ I ~ O \ I °.~ N \ I
I \ .N~ \ I H \ .Na \ I H
I~ H
HO HO
CI CI
I
O .N~\\ I O~N \ I O .N~\ I I O~H I \
\ N \ N
I i H I H F
HO HO
CI CI
I
O \ O~N \ O \ I O~ N
N
\ N.N~ \ I I i \ N.N~ \ I H
i~ H I~ H U
HO HO
CI CI
I
O \ I O~N I \ \ I O
\ N.N w \ \ O N.N w \ I ~H I , I i H OH I / H
HO HO
CI CI
CI
O \ I O~N \ I O \ I O~N \
I H
I \ H.N~ \ I % H.N~ \ I H I , CF' HO ~ HO
CI CI
I ~I
I H N
\ O N.N~v O~N ~ OMe \ O N.N~v I O~H
I , H I H CI
HO HO
CI CI
OMe ° \ I I °'~N \ I oMe o \ I I °~'N~
H.N~ \ CHI I \ H.N~ ~ N I \
HO HO ~ v 'CI
CI CI
I
\ O~ ~CI
\ I o O N \
O ~N \ \ N.Nw \ I H I i \ N.N~ \ I I , I ~ H CI
HO
HO I H H~C~N~CH3 CI
CI
I cHy ~ I
O ~ O~N~ O w O~N
N.N~ w I H I i CI ~ N.N~ W ( ~N
~ H HO~ H I i CHI
HO
CI CI O
O ~ I O~N
I
N.N~ w I H w I O ~ I O'~N
( / H ~ N.N~ W
HO I , H I
CI HO
CI
O w I O.~N w I / I
N.N ~ ~ I H OH O ~ O~N ~ OMe H ~ N.N~ ~ I I ~ OMe HO I , H
CI HO
CI
w I 0~ ~ OH ~
o ~~ I
N.Nw w I N w I O ~ O~N
I 'H .N ~ W I H OH
HO ~ I \ H
CI HO
CI
I
O ~ O~N OH I
N.N w w I ~ O w O~N
I , H I , ~ N.N~ ~ I H I ~N
HO Cl I , H
CI HO
CI
o ~ I p~N \ ~ , Br .N ~ w I H I , O w I O~N W I
I / H NHZ ~ N.N ~ ~ I H
HO I / H
CI HO
CI
I O / OH / CI
O ~N~ I
N.N~ w I ~N ~ Cl O W O~N w HO I ~ H I ~ CI W N.N ~ W I H
I / H
CI HO
CI
~' CI
O N.N~ ~ I ~N ~ OMe O ~ I I O~H~r'~ I CI
I / H I , ~ N.Nw HO I / H
C!
i I S ~ OMe p \ I 0~~ O i I O~N
.N~ \ \ .N~ \ N
I \ H I H OMe ~ \ CI
HO ~ HO / I ~ CI
i I OMe ~ I Br 0 \ O~N \ O / O~N \
.N~ \ I H I \ .N~ \ I H
\ N ~O.CFa I H OMe I , H HO
HO
CI CI
OMe I O ~0 0 \ I 0~ ~~ ~ I CI \ N.N\~~/~\ I OMe H I ~ CHa \ N.N~ \ N \ I H
HO I ~ H HO~ CHaHa CI
CI
CI
OMe I
O \ I 0 0 ~ ~N \ CI
\ .N ~ \ I ~H I , CH N N ' \ I O~N
I H a I , H
HO ~ H C CHa HO
a CI
CI
O ~OMe O \ I 0~ I % H.N ~ \ I O~N I \
\ . N ~ \ I H I , NH HO " Br I N ~ z CI
H
HO ~ OMe CI O , 0~N \ CI
CI \ .N~ \ I H I i I N Br ~Cl \ , H
I , HO
OMe Ci 0 ~ I O~N I ~ OMe CHa I \ H.N ~ \ OMe S, 0 i I O~H I \
HO ~ ~ N.N~ \
Br CI
CI HO I , H
OMe CI
O
0 i ~N \ OMe \ .N~ \ I H I ~ ~ O~
I N OMe ~CI 0 N \
i H .N~ \ I H I
HO \ N Br ~ NH
CI I ~ H z HO
OMe CI
O ~ 0~N \ CI
\ .N~ \ I H I i I N OMe ~CI
H
HO
CI
OMe I \ I \ F
O / O~N~ o I \ p /
. N ~ \ I ~ N CI / 'N~ /
I \ H gr I \ \ I q HO
CI
I\ o o / NON I \ o ~N I /
I H I / q \
Ho \ \ I
Ho CI G
\ H,°,° ~o~F
I ~(I / F
p ~ O I \
/I
/ f N \
H
\ a G
F
I \ F~F
o I \ o I\ I\ °o / iN / O \ ° /
I q / .~, I /
HO \ \ I p G w a Ct p CEO 5 I\
O I \ ~ O \ O
/ I
/ I q'~ / .~ p \ I .q Ho G
G
\ o \ \ °YF
O I \ 0~0/\QS O I \ O / F
/ ,\ I / / I H,~ /
\ I ~~H
HO
a G
G
G
\ \
O ~ \ O I \ O I /
/ N~ \ I
H /I
F CI
\ F \ F \ G \ G
O I \ O I / O I \ O I /
/ q~. I / / I q.H\ I /
H~ \ I Ho G G
\ \ \ °
° I \ ° I / °-~ ° \ ° /
/ ,H I / / "~I I / \ I o hHi ~ I ~
HO F~F
a a F
\
o I \ o I / \
/ 'N~ I / ° I \ ° I /
Ho \ I _~ / I H~ \ I /
Ho w F
F FI _F
\ \ F \ x O~F
° I \ ° I / O ~ \ °\/\
H
/ ~~ I / / N~N\ I / \ I
\ ~ H
wI
a I \ I \ F
O \ ° / \ b I I o I/
/ F F F O I \
\ I / I ~N\ /
f~
CI H° \
CI
F
F F I \ I \
\ \ 0 \ 0 /
O I \ O I / F / H N~ ~ /
/ N ~ / F F
~H~ \ HO
FIO \
CI
a F
F F H~O~O \ O"F
I \ I \ O I \ O I / ~'FX__F
\ O / IJw O I I H
/ w HD \
I
a HO
a I \ ~c.o I \
o I \ o~s ° o /
n / o \
/ N O
I H \ G / HiN\ / BF
\ I H O
CI
CI
I \
\ \
O ~0~ GO
N I / 0 / I 0 I I \ 0 I /
\ I p'\ ° / ~\ / O 0 HD
CI F~F HO \
CI
\ F
o p/ \ I I \ ~\/\ / I l~lrC~O ~ F
0 I \ O
Hp \
F
a F / H N Oi~a \ I
CI
F F F F
\ F \ F \
o I \ o ~ / O I \ o I /
,N I I
/ iN /
\ /
\ I ~ \ I H
HO rp I a ot, I \
~o~o I \ ~ o I \ °w/\N~'v°5 o I \ o / I N I
N
~N~N~ / o~aS No \ \ o N ~
\ I a F~F
a 0 I \ °
p I \ O N/\~ o I ° N
I / N. ~ / ~N
/ .N\ / w I N
\ I a Na I \
No ~ a /
G /
I o o \ o \
I \\ o I / a \ .N. \ I L I /N
o I ~p / ~\ / w /
a Ho G
\ r 'o \
I 0 I / o I /
0 N I / o I \ ~c N.N\ / o.~
N
O
/ O~
O \ I O~N
I \ \ O I / \ . \ \ I ~N
p ~ Y
/ ~N\ I / ~ I / ~ /
a No w G
I \ o c \ ~~
N' 'o a5 o I \ o\J\ _ o I \ ° / / I r~-~ / \ /
. o.aS ~ \
/
I e~
No o' ~o 'Sc~o 0II
o~ o.~ / I OS
N~ ~ I / o~~ \ I o 0 0 \
NO \ F'F'F I \ ~ N~ \ O~da a ~p /
F
p °' J~
O 'N I / O~N~ \ O N/N\ \ I O'~I\N/\./\N
\/J[~ ~,'/~V/J1' " J
I N ~ Na / I N \ O.~S ~ \
~N
\ OI
HO
a c F
I \ °N \ r O\/\~/\/N
O N/
\ O\/~N / I
O 'NV I / \ H~N\ \ I
~N
"° a a / O~N \ O~F
° / °~~ / \ N \ I N I / Ff~C~F
\ ~ \ \ \ I / w \ I
a \ I Ho v N~O~
O / ~~/'~ ~ o / I 0 I \ N N \ i I I \ ~. \ \ I / I
\ ~ / \
O I
N~a I O~ ~S O
\ ° ~H \ I H FS° Oy ° H \
H \ \ \
H
"° I / I / \ I
HO
a a ~S
aS / I ~ o~a'4 / I aS
o / I ° \ ° / o \
I \ H' \ p~ I \ H'H\ \ I OW~
HD
H°
a O~F CFt~
O ~ O I 'F
I \ ~ N\ \ I °.~ I \ H~ \ \ I I / CI
~ /
a CI
0 0 / 0 Ni O / °.~ N \ I
\ ~~ \I I \ H ~ / I
I / b \ I NS ~ / \
HD
CI CI
CI
/
I ~ /
o \ o\/\ \ I
' I I / I H
I \ o b.N\ \ ! I~o Ho I / H . \ a5 / a HO
CI
0~~
o\/\ / o~~
\ o .H~ \ I b I / s o ~ \ I o\/\H / \
b ~ .N I
ro I / \ I F' I 'f I \ ~ \
F /
a Hp a o ~05 ° / I °~H ~ 0 / \ / I O\/\N I \
yFI
\ If \ \ I \ N \ O / O~f H
I / \ I / "o /
\ I
O
°'~
° / \
° \ I o \ o ~~N\ \ I I
° /I
N'N\ \ °'d, ~ /
I H
HO /
a ~ 0~~
F
° \\ I o \ I °kF o I \
N \ \ ~ \
\ ~ I/ I/
/ HD
F
a \ I o~ ° \
\ O N\ /\ I O N I / I I ~
\ ~ \
I H ~I/ I/
YO
a a o / I ° ° I \ °\/\N I \
° / ~N a / H.N
° I H I H
I \ N'~ "°~
~H a no /
a °'aS o \ / I °~'p I \ F
° \ N \ /
O~ ' / I y ~~ i0 F F
J[ N N\ \ O HD / HOC
I H CI
a I / ~, 0~ \
o . / I ~ I /
\ N \ \ 0 H
I / '0 \ O / O
S° I / ~ I \ ~ N\ \ I
c-o cl «I \
I/
/ I o \ I ° ~\ \ I °~" I .
\ N \ \ °'aS
H I \ H
Ho / a ro . aS
a a o / ~ \ a ° ° I \ °~N I \
N / /
I \ b'N\ \ I I / I \
/ CI
F
CI
a O~aS aS ° - \ / I °\/\N I \
° \ I \ N \ /
O / I I p O
' ~ HJ
\ N- ~O
H a HD / F
F
The most preferred specific compounds of formula f wherein A is a heterocyclic and/or bicyclic moiety are the following:
CF3 , CF3 O ~ O \ I 0 \ I
O \
I I
I \ H.N ~ I \ N~ I \ ~.N w I \
'N ~ i H
Indole-5-carboxylic acid [4-(4- Indazole-5-carboxylic acid [4-(4-trifluoromethylbenzyloxy)-1- trifluoromethyibenzyloxy)-1-naphthylmethylene]hydrazide naphthylmethylene]hydrazide O \ O \ I O \ I
O
.N ~ I
H I \ ~ H.N w I \
-N
N HO N i H
Pyrazole-3-carboxylic acid [4-(4- 3-Hydroxyisoxazole-5-carboxylic acid[4-(4-trifluoromethylbenzyloxy)-1- trifluoromethylbenzyloxy)-1-naphthylmethyleneJhydrazide naphthylmethyleneJhydrazide O
N~ ~ OMe CHI ~ O
- OMe _ CHI
Me0 H ~ ~ O ~ ~ CH H ~ ~ ~ O ~ ~ CH
OMe H
OMe O
N~
>~' N-N OCFs Me0 H
H /
OMe N O
Me0 ~ ~ OMe CHI
--~~N-N O I ~ OH
H \ ~_~ O ~ ~ cH I
H ' / / -N ~ i OMe HO ~ \ I
CHs CHs OMe ~ I CHs ~ I CH
O \ O \ s O ~ \ O ~ \
N
\ H~ ~ OMe N N ~ \ 'N ~
/ ~N / /
H
Especially preferred according to the present invention are the following compounds which show a particularly high affinity to the human glucagon receptor:
CH3 F~F
H C.O I \ CH T3 O I \ O , I \ O I \ O
.N~ .CHI O \
HO \ I H ' O / I H ~ N\
O~'O HO \
CI
CHI
\ O
H~C.O O I % CH O I I \ O
O \ ~N r \ I
/ .N ( i .CHI I H O
\
I H O HO
HO \ CI F F F
C!
I\ o'' I\
O I W O~N~ O~N~N
I H.N N / O ~N I , H
I H ' ~ /
HO \ ~ HO
CI I i CI
O
OJ
CI F
~CI F
\ \ \ \ F
O I \ O I / I 0 I ~
I ° I\
i I H~N~ ~ , N.N\
\ \ ~ H
HO HO
CI CI
F F F F F F
\ \ \ \
p I \ O I i F O I \ O I i I H N\ I / F F ~ ~N I
I H
HO HO
CI CI
I I \
o N.N~ I ~ o'o~ ~ o I ~ o~H ~ I
H \ I o ~ N.N~ / \
I H ~o HO \
HO \ F-F'F
CI F F CI
F F ~ ~CI
I ~ o i ~ p I I ~ o iI
O I ~ / N.N
. N ~r~ I H
I ,H ~ HO W
HO \ CI
CI
~CH~ w w I ~ p iI ~ I O I
0 0 ~ CI
N.N\ I i / .N I i I H I H
HO \ HO
CI CI
p 0 I w O I ~ O ~ I O~O~N W
I I H
I H.N' / I ~ H.N\
CH
HO ~ HO
CI CI
CHI
.CHI
O 0 ' I CH3 O , I O~H , I
O
.N ~ I .CH I ~ H.N\ ~ I
I , 'H ~ O ~ HO
HO CI
F
O jj N ~ I O
O .N w I OH O ~ I OV 'N I
H \ I ~ N~N
HO ~ ~ I I / H
CI ~ HO
CI
O.CHs , I CHI O.CH~ , I CHI
O W / O
0 .N w I .CHI 0 .N y I .CH
W s I H O I 'H O
HO ~ CI HO ~ F
CI F
0. CHH F F ~ I
N 0 ~ O
p .N ~ I I / F .N ~ I i ~ CH
~N ~ O ~ ~N ~
HO I ~ H CHa HO I ~ H CHI
CI CI
O
I W H~N~ ~ I ~ O .N y I N I
I _H w I
HO HO
CI Br CI
O''I-I~C CHI ~ i ~ Br O ~ ( O~N ~ I O ~ I O~0 ~ I
I ~ H.N\ ~ I CH3 \ .N
I 'H
HO
HO
CI CI
O w I O~N~N I w i I
N.N' ~ I H \ O .N \ ~ I H I , I ~ H I H ~ cl HO HO
CI CI
r CH3 i N CH I
O I F
N.N\ ~ O v ~ ~ O N.N' \ ~ I O I ~ F
I H I H O~F
HO ~ HO
CI CI
CHI
O.CHs ~CH I
0 \ I\ I 3 p ~ N~ ~ CI
O .N w I .CH \ N N~ I N I
I / H \ O ~ HO I ~ H
HO
CI
N
OH H ~ I OH H
0 ~ I O~N O ~ O~N
N.N' ~ I \ _ .N
I ~ H I H
HO HO
CI CI
~I oII
O ~ I OH O w O~N
H-N~ ~ I ~ .Nw ~ I ~N-CHI
I~ H
HO HO
CI CI
0 i 0 o ~~ ~ I
-- N _.
0 N.N ~ ~ I N~N ~ ~ ~ O N.N w ~ I ~N
I H I H
HO ~ p H HO ~ 0 CI CI
0 0 ~ ( O
O I ~N~ OMe O ~ I °~N~ OMe H.Nw W ~N I ~ I ~ H.Nw ~ N
I i HO HO
OMe CI CI
° ° ~ I o '~ ~ °~N
° N.N~ W ( W ~ 0 N.N~ W I W
I H ~I I H
HO ~ v ' CF3 HO ~ CH3 CI CI
O ~ O
° \ I O _ N ~ CI 0 \ I °v _N OH
N.Nw W I ~ I ~ N.Nw W I W
I ~ _H I ~ H I
HO HO
CI CI
O~ O i I O
O I v 'N OH O \ I °~N I
H.N ~ W ~ ~ N.N ~ W ~CH3 I H
HO ~ CI HO ~ N-CH3 CI CI
i OII I ~ i OI' W I O~ ~ 0 W I O~N N
0 N.N~ W I N N, ~ N.N~ W I ( H H HO I ~ H
HO ~ O
CI CI
i I 0'I CI i I O'' O w I O~H I w O w I O~N
H.N ~ ~ ~ CI ~ N.N ~
I~ H
HO HO
CI CI
0 N.CH~ , 0 O W I O~N~ O W I O~N.N
.N~ w I CHI ~ .N~ w I H
I H I 'H
HO ~ HO
CI CI
O ~ O N w O ~ I I O~N~CH~ O w I O~N~ I i N.N w W ~O ~ .N w ~ I H
I H T -N
HO CH' HO I ~ H
CI CI
O / O
O ' I O~N ~ CI O \ I Ov _N
N.N w W I H I , ~ N.N w ~ I HOJ I
I , H I H CI
HO HO
CI CI
~ ~O ~I OII
O \ I I O~N~N O ~ O~N O
I H~Nw W CHI ~ N.N~ ~ I CH~
I ~ H
HO ~ HO
CI CI
/ OfI / I OII CHa O W ( O~N~~O O W I O~H~N.CHa H.N ~ ~ I H C- vNH ~ .N ~
HO HO
CI CI
O O O~NHz/ I
O N p ~ ~ ~ i N.N~ ~ I H ~ N,N~ ~ ~ H
H
HO I ~ 'H HO
CI
CI
o ~I o O w I O~N~CHa O ~ p~N~N ~ I
H.N ~ W CH3 I ~ H.N ~ ~ I H CHI
HO ~ HO
Cl CI
i O,' i OII
O w I O~N~ ~ CFa O ~ I I O~N
I H II
N.Nw W ~/ ~ .Nw W N
I / H I _H ~CHz HO HO
CI CI
OMe ~ ~ ~ I ~ I ~ I
0 i 0 N N ~ 0 ~ O N CFA
.N. \ I H CHI .N~ \ I H
'H OMe I \ 'H
HO ~ HO
CI CI
0I CHI ~ O'' CHI
O \ ( O~N \ O \ I O~N \
.N~ \ I H I ~ .N~ \ I H I , \ \
I H CHI I H
HO ~ HO
CI CI
I / I .~ CH~
O O ~ O ~ 0 N
O ~ I O~N \ ~ N.N ~ \ ( H/~ I // CH3 ,N~ ~ I H I ~ I ~ H
N Cl HO
HO I ~ H CI
CI
0 CHI ~ O CH3 O ~ I O~N O ~ I OV 'N \
.N~ \ I H .N~ \ I H I , \ \
I H I H CI
HO ~ HO
CI CI
O ~ O
O \ I O~N \ 0 ~ I O~N~N-CH~
N.N. \ I H I / CF \ N.N~ \ I CHI
HO ~ HO
CI CI
O ~ O
O \ I O~N 0 \ I O~N
N.N. \ I ~ N.N~ \ I N y HO I ~ 'H HO I ~ 'H I ~ N
CI CI
\ 0 ' \ 0 p I N~ ~ ~ CHI 0 I N
\ N.N~ \ ~N \ .N~ \
H I ~ H CHI
HO ~ HO
CI CI
O / N / OII
0 \ I O~N \ I O \ I
I ~~ NOz I \ H.N~ \ I CHI \ .N~ \ N
N \
HO I ~ H
HO
CI CI
0 NHz 0Ii i i OII
O \ I O~N \ I O \ ( O~N
\ N.N w \ I H \ N,N w \ I
I H I H p HO ~ HO
CI CI
i I O OMe O
0 \ O~N~ CH 0 ~ ( O~N~ CH3 H.N~ \ I ~N I \3 CHy I % H.N~ \ p~ ~N I % CHI
i HO
HO
CI CI
i O i O
O~ CH O w I O
O I N~ a ~N
I \ H.N w \ ~N \ CH3 I ~ H.N w \ I ~~ ~NH3 a CH
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O I ~ OH ~ N.Nw W I ~~ ~ CI
I H I
/ I H~N~ / HO / /
CI
HO ~ CI
CI
I 0 .N~\~ I O~N~ / I 0 O / O~N~ ~ CI w N N~0 I H 'I I / 'H
H.N ~ ~ 0~ ~/ CI HO
/ CI
HO
CI
O ~ I O~N / 0 ~ I O~N
N.N~ ~ I ~ I ~ N.N~ ~ I I /
I H I H
HO / HO /
CI Ci CI
0 ~ I O~N \ 0 ~ I O~N
N.Nw ~ I I / ~ N.Nw ~ I H
HO I / H OH HO I / H
OMe p ~ I p~N \ p ~ I p~N ~ I
.N~ ~ I H I / OMe ~ N.N~ ~ I H
I H I H
HO / HO /
CI CI
i I
O \ O.~' N \ \ I O
\ N.N~ \ I H I ~ F \ O_N.N~ \ I ~H I / p) HO I ~ H I i H O
HO
CI CI
O \ O~N \ \ I O
\ N.N~ \ I H I i CFA W O N.N~ \ I ~H I , I H I H CI
HO ~ HO
CI CI
i /I
\ O~ I
O N O \ O~N ~ CI
I \ H.N~ \ I ~N I ~ I \ .N~ \ I H I / CI
N
HO ~ ~CI HO ~ H
CI CI
CHI i p .N v\ I p~H I ~ p .N v I I p~H ~ I
\
I N CI I \ H \
HO
HO
CI CI
I
O \ O~N \ I O \ I O~N
I \ H.N w \ I H OH \ N.N ~ \ I ~~ ~ CI
HO ~ HO I ~ H I
CI CI
CI
O \ O~N~ O \ I O~N
I
I \ H.N' \ ~N \ OMe \ .N~ \ I
I~ I~ H I~
HO HO
CI CI
i I i ~er O \ O~N ~ OMe O \ I O~ '- j~\ I
i I
\ .N~ \
I H ~ OMe I \ H.N ~ \
HO ~ HO
CI CI
O/~CI , / CI
O \ I O~N \ I O \ I O~N \ I CI
N.N~ w I H ~ .N~ ~ I H
I H I H
HO ~ HO
CI CI
p _ / \
O ~ O~N ~ HO / \ i \ /
.N ~ ~ I H I , CH N-N N
H '~~CH 3 CI H \ / H CH3 HO ~ HaC ' CI
O - O
HO / \ ~ \ / HO / \ ~ \ /
N-N N N-N N
CI H \ / / \ CI H \ / ~ / \
HO
O - / \ HO / \ O - HO
HO / \ i \ / _ N-N~ \ / N
H N CI H \ / H / \
CI \ / H C 'CH
O - O
HO / \ i \ / HO / \ i \ /
N-N N N-N N
CI H \ / H / \ CI H \ /
F HO
F F
HO / \ N-N \ / S~ ~~ HO / \ N-N \ / S~N'N
CI H \ / S CH3 CI H \ / N N
HOC
HO / \ H-N \ / H F HO / \ H-Ni \ /
CI \ / ~ CI \ / / \
CHI
HaC CH3 O
HO / \ O ' \ / \-_/ HO / \ N-N/ \ / N
~H N N CI H \ / H
CI \ / H \..J / \
F
O O
HO / \ i \ / HO / \
N_N ~N N-N \ I N
Cl H \ I ~ / \ CI H \ / /
CHb ~ \
HOC
O
Ho / \ -/ \ N-N~ \ / N HO N-N~ \ / ~H~
CI H H N _ \ I \ ~ O CI H \ I H \ /
Ho Ho / \ o - / \ o _ \ / N_CHs HON-N \ / N
CI \ / ~OH CI~/ ~H \ / H3C / \
O
HO / \ CI
N-Ni \ / N -CI H \ / H ~ CHs HO~\ / \/~' ~J~O \ /
~N_Ni \ / N
H
CI \ / H CHs HO / \ N-N \ / S~N~N HO / \ O-N \ /
CI H N ~ N
\ / NHz CI H \ / ~N
HO / \ O -~-Ni \ / H / \
CI _ \ / HO ~/ \ ~O O
\ / ~N-Ni \ / N--HsC 0 CI J'= ' H \ / H CHs / \ O -HO
H-Ni \ / H HO / \
CI \ / / \ F H-N \ /
CI \ /
/ \ O O - HO
HO H-N~ \ / H HO / \ N-N~ \ / N
CI \ / \ ~ O C! H \ / H C CHs CHs s O-CHs O
HO / \ N-N \ / S~S~ HO /_\ N_N~ \ / N
CI H N ~H
\ / CI \ / H
\ /
NHz / \ O
HO / \ O ~ N HO N_N \ / N
~N-N \ / ~ CI H
CI H \ / I / \ / / \
~H -HO / \ O i \ / / \
O
/ \
CI H N \ / H NH2 HO N-N~ \ / N
\ / CI H \ / H O
HO / \ O i \ / HO / \ O _ N-N N N-N~ \ / N
CI H \ / H // 'S CI H \ / H / 0 CHI
HO / \ O / \ / HO / \ O ~ \ / OH
N-N N N-N N
C1 H \ / H \ / CI H \ / H
HO~ / \ O i H~ N HO / \ O i N
~N-N \ / S~' ~ ~H-N \
CIr H \ / N CI \ / N
The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included in the scope of the invention.
Furthermore, one or more carbon-carbon or carbon-nitrogen double bonds may be present in the compounds which brings about geometric isomers. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the invention.
Furthermore, the compounds of the present invention may exist in different tautomeric forms, eg the following tautomeric forms:
A N~N~ CH -B-(K) -D A~N\N~(CH2)~ B-(K)m-D
( 2)n 'm ~ O .
O H
It is intended that any tautameric forms which the compounds are able to form are included in the scope of the present invention.
Owing to their efficacy in antagonizing the glucagon receptor the present compounds may be suitable for the treatment and/or prevention of any glucagon-mediated conditions and dis-eases.
Accordingly, the present compounds may be applicable for the treatment of hyperglycemia as-sociated with diabetes of any cause or associated with other diseases and conditions, eg im-paired glucose tolerance, insulin resistance syndromes, syndrome X, type l diabetes, type II
diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas, acute pancreatitis, cardiovascular diseases, cardiac hypertrophy, gastrointestinal disorders, diabetes as a conse-quence of obesity etc. Furthermore, they may be applicable as diagnostic agents for identifying patients having a defect in the glucagon receptor, as a therapy to increase gastric acid secre-tions, to reverse intestinal hypomobility due to glucagon administration, to reverse catabolism and nitrogen loss in states of negative nitrogen balance and protein wasting including all causes of type I and type II diabetes, fasting, AIDS, cancer, anorexia, aging and other condi-tions, for the treatment of any of the above conditions or diseases post-operative or during surgery and for decreasing saitety and increasing energy intake. Thus, in a further aspect the present invention relates to a pharmaceutical composition comprising, as an active ingredi-ent, at least one compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients.
The present invention furthermore relates to methods of treating type I or type If diabetes or hyperglycemia which methods comprise administering to a subject in need thereof an effec-tive amount of a compound according to the invention.
Moreover, the present invention relates to a method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to the invention.
The present invention is also concerned with the use of a compound according to the inven-tion for the manufacture of a medicament for treating type I or type If diabetes or hypergly-cemia, or for lowering blood glucose in a mammal.
Pharmaceutical formulations and administration methods The compounds according to the invention, which may also be referred to as an active ingredi-ent, may be administered for therapy by any suitable route including oral, rectal, nasal, pul-monal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal), the oral route being preferred. It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen active ingredient.
The compounds of the invention are effective over a wide dosage range. A
typical dosage is 1o in the range of from 0.05 to about 1000 mg, preferably of from about 0.1 to about 500 mg, such as of from about 0.5 mg to about 250 mg for administration one or more times per day such as 1 to 3 times per day. It should be understood that the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant 15 diseases to be treated as well as other factors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art.
2o For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administra-tion, typically doses are on the order of about 1/2 the dose employed for oral administration.
The compounds of this invention are generally utilized as the free substance or as a pharma-ceutically acceptable salt thereof. One example is an acid addition salt of a compound having 25 the utility of a free base. When a compound of formula I contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of for-mula I with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids, for example: malefic, fumaric, benzoic, ascorbic, pamoic, succinic, bis-methylene salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, sali-3o cylic, citric, pyruvic, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluensulfonic, hydro-chloric, hydrobromic, sulfuric, phosphoric or nitric acids. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable ration such as sodium or ammonium ion.
The compounds of the invention may be administered alone or in combination with pharma-ceutically acceptable carriers, in either single or multiple doses.
For parenteral administration, solutions of the novel compounds of formula i in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cy-clodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage fom~s suitable for the disclosed routes of ad-ministration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as dis-crete units such as capsules or tablets, each containing a predetemlined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet which may be prepared by conventional tabletting techniques may contain:
Core:
Active compound (as free compound or salt 100 mg thereof) Colloidal silicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst. (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium stearate Coating:
HPMC approx. g mg *Mywacett 9-40 T approx. 0.9 mg 1o *Acylated monoglyceride used as plasticizer for film coating.
For nasal administration, the preparation may contain a compound of formula I
dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
Optionally, the pharmaceutical composition of the invention may comprise a compound of formula ! combined with one or more other pharmacologically active compounds, e.g. an an-tidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pato-physiological mechanism. Suitable antidiabetics comprise insulin, GLP-1 derivatives such as those disclosed in WO 98/08871 (Novo Nordisk A/S) which is incorporated herein by refer-ence as well as orally active hypoglycaemic agents such as sulphonyfureas, e.g. glibencla-mide and glipizide; biguanides, e.g. metformin; benzoic acid derivatives, e.g.
repaglinide;
and thiazolidinediones, e.g. troglitazone and ciglitazone, as well as PPAR and RXR agonists.
EXPERIMENTAL
Giucagon binding In the following section binding assays as well as functional assays useful for evaluating the efficacy of the compounds of the invention are described.
Glucagon Binding Assa~r (Il 1o Binding of compounds to the glucagon receptor was determined in a competition binding as-say using the cloned human glucagon receptor.
In the screening setup, antagonism was determined as the ability of the compounds to inhibit the amount of cAMP formed in the presence of 5 nM glucagon.
For full characterization, antagonism was determined in a functional assay, measured as the ability of the compounds to right-shift the glucagon dose-response curve.
Using at least 3 different antagonist concentrations, the K; was calculated from a Schild plot.
Receptor binding was assayed using cloned human receptor (Lok et al, Gene 140, (1994)). The receptor inserted in the pLJ6' expression vector using EcoRl/SSt1 restriction sites (Lok et al) was expressed in a baby hamster kidney cell line (A3 BHK 570-25).
Clones were selected in the presence of 0.5 mg/ml G-418 and were shown to be stable for more than 40 passages. The Ka was shown to be 0.1 nM.
Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM
NaCI, 1 mM dithiothreitol, 5 mg/I leupeptin (Sigma), 5 mg/l pepstatin (Sigma), 100 mg/I baci-tracin (Sigma) and 15 mg/I recombinant aprotinin (Novo Nordisk)), homogenization by two 10-s bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation upon a layer of 41 w/v% sucrose at 95.000 * g for 75 min. The white band located between the two layers was diluted in buffer and centrifuged at 40.000 * g for 45 min. The precipitate containing the plasma membranes was suspended in buffer and stored at -80°C until required.
Glucagon was iodinated according to the chloramine T method (Hunter and Greenwood, Na-tune 194, 495 (1962)) and purified using anion exchange chromatography (Jorgensen et al, Hormone and Metab. Res. 4, 223-224 (1972). The specific activity was 460 uCi/p,g on day of iodination. Tracer was stored at -18°C in aliquots and were used immediately after thawing.
Binding assays were carried out in triplicate in filter microtiter plates (MADV N65, Millipore).
The buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1 % human serum albu-min (Sigma, grade V). Glucagon was dissolved in 0.05 M HCI, added equal amounts(w/w) of HSA and freeze-dried. On the day of use, it was dissolved in water and diluted in buffer to the desired concentrations.
175 ~I of sample (glucagon or test compounds) was added to each well. Tracer (50.000 cpm) was diluted in buffer and 15 p,l was added to each well. 0.5 ~g freshly thawed plasma mem-brave protein diluted in buffer was then added in 15 ~I to each well. Plates were incubated at 25°C for 2 hours. Non specific binding was determined with 10~ M
glucagon. Bound and un-bound tracer were then separated by vacuum filtration (Millipore vacuum manifold). The plates were washed once with 150 p.l buffer/ well. The plates were air dried for a couple of hours, whereafter filters were separated from the plates using a Millipore Puncher.
The filters were counted in a y counter.
Functional Assav 111 The functional assay was carried out in 96 well microtiter plates (tissue culture plates, Nunc).
The resulting buffer concentrations in the assay were 50 mM tris/HCI, 1 mM
EGTA, 1.5 mM
MgS04, 1.7 mM ATP, 20 ~M GTP, 2 mM /BMX, 0.02% tween-20 and 0.1 % HSA. pH was 7.4 Glucagon and proposed antagonist were added in 35 ~cl diluted in 50 mM
tris/HCI, 1 mM
EGTA, 1.85 mM MgS04, 0.0222 % tween-20 and 0.111 % HSA, pH 7.4. 20 ~I of 50 mM
trisIHCI, 1 mM EGTA, 1.5 mM MgS04, 11.8 mM ATP, 0.14 mM GTP, 14 mM iso-buthyl-methyl-xanthine (/BMX) and 0.1% HSA, pH 7.4 was added. GTP was dissolved immediately before the assay.
50 pl containing 5 pg plasma membrane protein was added in a tris/HCI, EGTA, MgS04, HSA
buffer (the actual concentrations were dependent upon the concentration of protein in the stored plasma membranes).
The total assay volume was 140 ~I. The assay was incubated for 2 hours at 37°C with continu-ous shaking. Reaction was terminated by addition of 25 X10.5 N HCI. cAMP was measured by the use of a scintillation proximity kit (Amersham).
GIUC24on Binding Assay (II1 Receptor binding was assayed using the cloned human receptor (Lok et al, Gene 140, 203-209 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/SSt1 restriction sites (Lok et ai) was expressed in a baby hamster kidney cell line (A3 BHK 570-25). Clones were selected in the presence of 0.5 mg/ml G-418 and were shown to be stable for more than 40 passages. The Kd was shown to be 0.1 nM.
Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tr7s/HCl), pH 7.4 containing 30 mM
NaCI, 1 mM dithiothreitol, 5 mg/I leupeptin Sigma), 5 mg/i pepstatin (Sigma), 100 mg/I baci-tracin (Sigma} and 15 mg/I recombinant aprotinin {Novo Nordisk)), homogenization by two 10-s 2o bursts using a Polytron PT 10-35 homogenizer (Kinematics), and centrifugation. The ho-mogenate was resuspended and centrifuged again. The final precipitate containing the plasma membranes was suspended in buffer and stored at -80°C until required.
Binding assays were carried out in duplicate in polypropylene tubes or microtiter plates. The buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1 % bovine serum albumin (Sigma, fraction V). Sample (glucagon {Sachem CA) or test compounds) was added to each tube or well. Tracer (- 25000 cpm) was diluted in buffer and was added to each tube or well.
0.5 p,g freshly thawed plasma membrane protein diluted in buffer was then added in aliquots to each tube or well. Tubes or plates were incubated at 37°C for 1 hour.
Non specific binding was determined with 10'' M glucagon. Bound and unbound tracer were then separated by vacuum filtration (Brandel). The tubes or wells were washed twice with buffer. The filters or plates were counted in a gamma counter.
Functional Assav (Ill The functional assay determined the ability of the compounds to antagonize glucagon-stimulated formation of cAMP in a whole-cell assay. The assay was carried out in borosilicate glass 12 x 75 tubes. The buffer concentrations in the assay were 10 mM HEPES, 1 mM EGTA, 1.4 mM MgCl2, 0.1 mM IBMX, 30 mM NaCI, 4.7 mM KCI, 2.5 mM NaH2P04, 3mM glucose and 0.2% BSA. The pH was 7.4. Loose whole cells (0.5 ml, 106/ml) were pretreated with various concentrations of compounds for 10 min at 37°C, then challenged with glucagon for 20 min.
Some aliquots (500 pL) of cells were treated with test compounds (55 uL) alone to test for 1 o agonist activity. The reactions were terminated by centrifugation, followed by cell lysis with the addition of 500 p.l 0.1 % HCI. Cellular debris was pelleted and the supernatant containing CAMP
evaporated to dryness. CAMP was measured by the use of an RIA kit (NEN, NEK-033). Some assays were carried out utilizing the adenylate cyclase FIashPlate system from NEN.
Synthesis methods The following synthesis protocols refer to intermediate compounds and final products identi-fied in the specification and in the synthetic schemes. The preparation of the compounds of the present invention is described in detail using the following examples, but the chemical reactions described are disclosed in terms of their general applicability to the preparation of the glucagon antagonists of the invention. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifica-tions known to those skilled in the art, that is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions.
Alternatively, other reactions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative meth-ods, all starting materials are known or readily preparable from known starting materials. All temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight when referring to yields and all parts are by volume when refer-ring to solvents and eluents.
General procedures for the r~erJaration of alkylidene hydrazides:
The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme l, that is, by converting an ester of a carboxylic acid, for example, an aromatic acid to a hydrazide derivative and further reacting that product compound with a substituted aldehyde or ketone to yield a substituted alkylidene hydrazide.
SCHEME/
O-Ra solvent NHNHZ
A + NH2NH2 ---,- A--reflux O
O
4~--(CHz)~ B-(K)m D
R HN-N-~-(CHZ)~ B-(K)m D
A-~ R
solvent, reflux O
wherein A, B, K, D, m, n and R4 are as defined for formula I and Ra is lower alkyl.
Seneral procedure for the synthesis of rp ecur.SOr hydrazides ABC=O)-NHNH
The reaction is known (Org. Syn., Coll. Vol. li, A.H.BIatt, ed., John Wiley &
Sons, New York, 1943, p. 85; Org. Syn., Coll. Vol. IV, N. Rabjohn, ed., John Wiley & Sons, New York, 1963, p.
819) and is generally performed by stirring the corresponding ester (either methyl, ethyl or other lower alkyl ester) with 2-10 molar excess of hydrazine in the presence of a solvent such 2o as ethyl alcohol, methyl alcohol, isopropyl or tert-butyl alcohol or tetrahydrofuran, dioxane, DMSO, ethylene glycol, ethylene glycol dimethyl ester, benzene, toluene or a mixture of the above solvents or, in the absence of a solvent where excess of hydrazine acts as a solvent.
The reactions are performed between 0°C to 130°C, preferably between 20°C to 100°C, most preferably at or about the reflux temperature of the solvent. The reactions are preferably con-ducted under an inert atmosphere such as NZ or Ar. When the reaction is complete as judged by disappearance of the starting ester by TLC or HPLC, the solvent may be removed by con-centration at atmospheric or reduced pressure.
The product can be further purified by either recrystallization from a solvent such as ethyl alco-hol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent. The corresponding fractions are concentrated either at atmos-pheric pressure or in vacuo to provide the pure aroyl hydrazide.
Preparation of aromatic acid hydrazi ~Pw The methyl or ethyl ester of the corresponding aromatic acid, such as for example a substi-tuted benzoic acid ester, is dissolved in ethanol and hydrazine (5 eq) is added. The reaction is refluxed overnight under nitrogen. Upon cooling the substituted hydrazide derivative usually precipitates. After filtration the product is usually recrystallized from hot methanol, ethanol or isopropyl alcohol. In cases where the hydrazide does not precipitate, the reaction is concen-trated under vacuo and chromatographed over silica gel using dichloromethane/methanol as the eluent. Specific examples illustrating the preparation of aromatic hydrazides are provided below.
Precaration of 5-hydrox~rindole 2 carbo~rlic a i v razid To a sample of ethyl 5-hydroxyindole-2-carboxylate {5g, 24 mmol), dissolved in ethanol (250 mL) was added hydrazine (4 mt_, 121 mmol). The reaction was refluxed overnight under ni-trogen. Upon cooling the reaction vessel, the desired product crystallized.
The white solid was isolated by filtration. Recrystallization from hot ethanol gave the 5-hydroxyindole-3-carboxylic acid hydrazide in 85% yield.
HO
N
H
O
1 H NMR (DMSO-dg): 8 4.38 (s, 2H); 6.62 (dd, 1 H); 6.76 (dd, 2H); 7.13 (d, 1 H); 8.70 (s, 1 H);
9.57 (s, 1 H}; 11.21 (s, 1 H); MS (FAB): m/z 192 (M+H)+.
Per paration of 3-chloro-4-hvdroxybenzoic acid hvdrazide:
To a sample of methyl 3-chloro-4-hydroxybenzoate (2 g) dissolved in ethanol (50 mL) was added hydrazine (1.8 mL). The reaction was refluxed overnight under nitrogen.
Upon cooling the reaction vessel, the desired product crystallized out of solution. The white solid was iso-lated by filtration. Recrystallization from hot ethanol gave the 3-chloro-4-hydroxybenzoic acid hydrazide in 60% yield.
NHNHZ
HO
CI
1 H NMR (DMSO-d6): 8 4.49 (broad s, 2H), 7.05 (dd, 1 H), 7.71 (dd, 1 H), 7.89 (d, 1 H), 9.669 (s, 1 H), 10.72 (broad s, 1 H).
By use of the above methodology, other hydrazides useful as intermediates in preparing the compounds of the invention are prepared, for example:
HO
Br 3-Bromo-4-hydroxybenzoic acid hydrazide 1 H NMR (DMSO-d6): 8 9.95 (s, 1 H), 9.65 (d, 1 H), 9.61 (broad s, 1 H), 6.95 (d, 1 H), 4.40 (broad s, 2H); MS m/z 233.1.
O
~NHNH2 HO
3-Nitro-4-hydroxybenzoic acid hydrazide 1 H NMR (DMSO-dg): 8 9.28 (broad s,1 H), 8.28 (s, 1 H), 7.52 (d, 1 H), 6.41 (d, 1 H). MS m/z 198.
HO
F
3-Fluoro-4-hydroxybenzoic acid hydrazide 1 H NMR (DMSO-dg): 8 9.45 (broad s, 1 H), 7.5 (d, 1 H), 7.43 (d, 1 H), 6.85 (t, 1 H), 5.55 (broad s, 3H).
Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide, 2,3-dichloro-4-hydroxybenzoic acid hydrazide and 2,5-dichloro-4-hydroxybenzoic acid hydrazide.
B O
OH ~ I ~ OH ~ w OMe p ~ . NHZ
i HZN CI HO ~ CI HO I ~ CI ~ I , H
HO CI
i O O O O
I ~ H.NHz p I w O~ + CI ~ OMe p Cl ~ .NHS
HO ~ CI HO ~ Cl I i ~ I H
CI CI HO CI HO
Preparation of 2-chloro-4-hydroxyrbenzoic acid hyrdrazide Step A:
4-amino-2-chlorobenzoic acid (10 g, 58 mmol) was dissolved in H2S04 (12 N, 120 mL) with heating. After cooling the solution in an ice-bath aqueous NaN02 (2.5 M, 25 mL) was added 2o dropwise such that the internal temperature remained at 5 °C. Urea was added to the mixtu-re for after stirring for 15 minutes to destroy excess NaNOz (monitored by starch iodine test).
CuSO, (100-200 mg) was added and the mixture was heated to 90 °C until evolution of gas stopped. After cooling, the mixture was extracted with ethyl ether (3x). The combined orga-nic fractions were extracted with 3N NaOH (3x). The combined aqueous layer was acidified with conc. HCI and the product was extracted with ethyl ether (3x). The organic fractions were washed with water, brine, and dried over MgS04. The crude product was introduced into a silica gel column and eluted with ethyl acetate/hexane (1I1) to afford 2-chloro-4-hydroxybenzoic acid.
'H NMR (DMSO-D6): 8 6.97 (dd, 1 H), 7.05 (d, 1 H), 7.95 (d, 1 H), 10.90 (brd s, 1 H).
Step B:
To a solution 2-chloro-4-hydroxybenzoic acid in anhydrous methanol was added thionyl chlo-ride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgS04 and concentrated in vacuo to give methyl 2-chloro-4-hydroxybenzoate.
Step C:
To a solution of methyl 2-chioro-4-hydroxybenzoate (13.6 g, 73.1 mmol) in acetic acid (300 mL) was added N-chlorosuccinimide (9.8 g, 73.7 mmol). The solution was refluxed for 24 h and the solvent was evaporated under vasuo. The residue was taken up in chloroform, washed with water, brine, dried over magnesium sulfate, filtered and concentrated. Methyl 2,3-dichloro-4-hydroxybenzoate precipitated out of ethyl acetate.
Chromatography of the re-sidue using ethyl acetate/hexane (1l9 to 3/7) afforded methyl 2,5-dichloro-4-hydroxybenzoate (1.4 g, 60%) as well as an additional batch of methyl 2,3-dichloro-4-hydroxybenzoate isomer (total of 8.4 g, 10%).
Methyl 2,3-dichloro-4-hydroxybenzoate:
'H NMR (DMSO-D6) 8 3.81 (s, 3H), 7.02 (d, 1 H), 7.70 (d 1 H), 11.52 (s, 1 H);
MS (APCI):
221, 223.
Methyl 2,5-dichloro-4-hydroxybenzoate:
' H NMR (CDC13): 8 3.90 (s, 3H), 6.00 (s, 1 H), 7.14 (s, 1 H), 7.27 (s, 1 H), 7.96 (s, 1 H); MS
(APCI): 221.9.
Step D:
The title comb o~ and was prepared according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNHz.
'H NMR (DMSO-D6): 8 6.82 (dd, 1 H), 6.90 (d, 1 H), 7.79 (d, 1 H, 10.68 (brd s, 1 H).
Preparation of 2.3-Dichloro-4-hvdroxvbenzoic acid hy~drazide and 2 5 dichloro-hvdroxybenzoic acid hyrdrazide ~(stelp DO
The 2,3-dichloro-4-hydroxybenzoic acid hydrazide was prepared from the methyl 2,3-dichloro-4-hydroxybenzoate above according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNHZ with the exception that pentanol was the solvent of choice. The product was purified via silica gel column chromatography using CH2C12/MeOH
( 95/5 to 80/20), yield = 50%.
2,5-dichloro-4-hydroxybenzoic acid hydrazide was prepared in a similar way starting from 2,5-dichloro-4-hydroxybenzoate.
2.3-Dichloro-4-hydroxybenzoic acid hydrazide:
'H NMR (DMSO-D6) 8 4.41 (brd s, 2H), 6.99 (1, 1 H), 7.37 (s, 1 H), 9.46 (s, 1 H), 11.04 (s, 1 H).
2.5-Dichloro-4-h~ droxybenzoic acid hydrazide~
'H NMR (DMSO-D6) 8 4.48 (brd s, 3H), 6.92 (d, 2H), 7.18 (d, 2H), 9.45 (brd s, 1 H).
Preaaration of 2 3-difluoro-4-hydroxyrbenzoic acid h~drazide:
~~N O O O
A
I ~ ~ ~ OH B I ~ OMe C a ~ ~ H.NHZ
HO F HO ~ F HO ~ F HO ~ F
F F F F
Step A:
A mixture of 2,3-difluoro-4-cyanophenol (1 g, 6.45 mmol) in water (8 mL), HZS04 (8 mL), and acetic acid (8 mL) was refluxed for 48 hours. The solvents were removed by rotary evapo-ration to give a slurry which was poured onto ice. The product precipitated out of solution and filtered. The solid was washed with water and dried to give 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 71 %).
'H NMR (DMSO-Ds): 8 6.87 (t, 1 H), 7.60 (t, 1 H), 11.28 (s, 1 H), 12.53 (brd s, 1 H).
Step B:
To the 2,3-ditluoro-4-hydroxybenzoic acid (800 mg, 5.1 mmol) dissolved in anhydrous methanol {50 mL) was added thionyl chloride (0.55 mL, 7.3 mmol). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgS04 to give methyl 2,3-difluoro-4-hydroxybenzoate (540 mg, 62%).
'H NMR (CDCI3): S 3.92 (s, 3H), 6.34 (brd s, 1 H), 6.82 (dt, 1 H), 7.68 (dt, 1 H).
Step C:
The 2,3-difluoro-4-hydroxybenzoic acid hydrazide was prepared from the methyl 2,3-difluoro-4-hydroxybenzoate above according to the general procedure for the synthesis of precursor hydrazides A-{C=O)-NHNH2. The product was purified via silica gel column chromatography using CH2CI2/MeOH ( 95/5 to 80/20) to afford the title com op und.
'H NMR (DMSO-D6): 8 4.48 (s, 2H), 6.80 (m, 1 H), 7.22 (m, 1 H), 9.36 (s, 1 H), 10.89 (s, 1 H);
MS (APCI): 189.
Preparation of 3-cyano-4-hyrdroxybenzoic acid hydrazide trifluoroacetate:
OMe A i ~ OMe g I % 'O~ D I ~ OH
--a HO ~ ---~ HO ---~ HO
HO
N N
D
H-NHZ E N.N~O
HO ~ ~ HO I i H O
II II
N N
Step A:
Methyl-4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of warm (65 °C) acetic acid. A solution of iodine monochloride (37.8 g, 0.233 mol) in 50 mL of acetic acid was added slowly (40 minutes) to the methyl-4.-hydroxybenzoate solution, while maintaining a temperature of 65 °C and vigorous stirring. The product crystallizes from solution upon 1 o cooling to room temperature and standing overnight. The crystals were collected on a filter, washed with water, then dried under vacuum. Methyl-4-hydroxy-3-iodobenzoate was obtai-ned as white crystals (28.6 g, 44%).
'H NMR (DMSO-D6): 8 3.79 (s, 3H), 6.95 (d, J = 8.3, 1 H), 7.81 (dd, J = 8.3, 2.2, 1 H), 8.22 (d, J = 2.2, 1 H); '3C NMR (DMSO- D6) 8 52.8, 85.2, 115.5, 123.0, 132.0, 141.0, 161.9, 165.6.;
MS (APCI, peg): 277.
Step B:
Methyl-4-hydroxy-3-iodobenzoate (2.00 g, 7.2 mmol) was dissolved into 5 mL of dry DMF.
Copper(!) cyanide (0.72 g, 8.0 mmol) and a small crystal of sodium cyanide was added. The mixture was flushed with nitrogen, placed in an oil heating bath (100-110 °C), and stirred overnight. TLC indicated nearly complete reaction. The mixture was cooled and the solids removed by filtration. The solids were extracted with DMF (3 mL). The filtrate and washings were taken up in 100 mL of ethyl acetate, then washed with 3 portions of saturated sodium chloride solution. The solids and aqueous washings were combined, and shaken with a mixture of 50 mL of ethyl acetate and a ferric chloride solution (4 g of hydrated ferric chloride in 7 mL of conc. hydrochloric acid). The ethyl acetate layers were combined, washed with brine containing sodium metabisulfite, dried over sodium sulfate, filtered, and the solvent removed in vacuo. The resulting solids were purred by flash chromatography on silica gel (20% ethyl acetate/ hexane) to afford methyl-3-cyano-4-hydroxybenzoate, 0.93g (73%).
'H NMR (DMSO- Ds): 8 3.79 (s, 3H), 7.07 (d, J = 8.7, 1 H), 8.02 (dd, J = 8.7, 1.9, 1 H), 8.10 (d, J = 1.9, 1 H).
1 o Step C:
Methyl-3-cyano-4-hydroxybenzoate (2.71g, 15.3 mmol) was dissolved in 50 mL of THF. The solution was chilled in an ice bath, and 2.OM potassium hydroxide (17 mL, 34 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. TLC in-dicated complete reaction. The THF was removed by rotary evaporation. The aqueous re-sidue was acidified with aqueous trifluoroacetic acid and purified by reverse-phase HPLC (C-18, 0.1 % TFA in water and acetonitrile). 3-Cyano-4-hydroxybenzoic acid was obtained as a white powder (2.1 g, 84%) after lyophilization.
'H NMR (DMSO- DB): 8 7.09 (d, J = 9.0, 1 H), 8.00 (dd, J = 9.0, 2.3, 1 H), 8.07 (d, J = 2.3, 1 H) 12.50 (br s, 2H); MS (APCI, neg): 162. IR: 2252 cm-', CN.
Step D:
3-Cyano-4-hydroxybenzoic acid (1.888, 11.5 mmol) was dissolved in 20 mL of methylene chloride/DMF (1/1 ) and chilled in an ice-bath. Diisopropylethylamine (12 mL, 69 mmol), t-butyl carbazate (1.76g, 13.3 mmol), and PyBroP (bromo-tris-pyrrolidino-phosphonium he-xafluorophosphate, 6g, 12.9 mmol} were added, and the mixture was stirred to form a clear solution. The solution stood in the refrigerator overnight. TLC indicated that the reaction was not complete, so additional diisopropylethylamine (22 mL, 127 mmol), t-butyl carbazate (0.85g, 6.4 mmol) and PyBroP (3.Og, 6.4 mmol) were added. After 8 more hours at 0 °C, the 3o reaction was worked up as follows. The solution was reduced by rotary evaporation. The remaining DMF solution was diluted with 100 mL of ethyl acetate, and washed with several portions of 0.1 M HCI (until the wash remained acidic to litmus paper). The ethyl acetate layer was further washed with 3 portions of brine, dried over magnesium sulfate, filtered, and reduced to an oil in vacuo. The oil was purified by chromatography on silica gel (6:4 hexa-ne:ethyl acetate) to afford tert-butyioxycarbonyl (3-cyano-4-hydroxy)benzoic acid hydrazide as a white solid (1.8g, 56%).
'H NMR (DMSO- D6): b 1.42 (s, 9H), 7.09 (d, J = 8.7, 1 H), 7.98 (m, 1 H), 8.11 (br s, 1 H), 8.92 (s, 1 H), 10.15 (s, 1 H), 11.73 (br s, 1 H); MS (APCI, peg): 276; IR:
cm-', CN.
Step E:
The Boc-hydrazide (1.8g, 6.5 mmol) was suspended in 50 mL of chloroform and cooled in an ice-bath. Trifluoroacetic acid was added with stirring, and the resulting solution stood for 4 hours at 0 °C. TLC indicated complete reaction. Solvent and excess TFA
were removed by rotary evaporation. The remaining oii was purified by reverse-phase liquid chromatography (Aquasil C-18 column, water/acetonitrile/0.1 % TFA). The title comb and was obtained as a white solid (0.24 g, 13%).
'H NMR (DMSO- D6): 8 7.16 (d, J = 9.0, 1 H), 8.00 (dd, J = 1.5, 9.0, 1 H), 8.14 (d, J = 1.5, 1 H), 10.47 (br s, 5H); MS (APCI, peg): 176.
Preparation of 4-hydroxyn~phthoic acid by azid~
O H O OH O OMe O N, NH
i i -' ~ ---~ I W W C
i i i i ~ 1 i i OH OH OH
OH
Step A:
Silver nitrate (17 g, 0.1 moi) was dissolved in water (10 mL) and treated with 1 N NaOH (300 mL, 0.3 mol). The brown precipitate which was formed was stirred for 30 minutes and the supernatant was decanted. The brown silver oxide was washed with additional volumes of water (3x).
To the silver oxide above was added 1 N NaOH (150 mL) and 4-hydroxynaphthaldehyde (1 g, 6 mmol)). The mixture was heated to 70 °C for 10 minutes after which additional amounts of 4-hydroxynaphthaldehyde (5.5 g, 32 mmol) was added in portions. The mixture was kept at 80 °C for 16 hours. TLC analysis indicated incomplete conversion. An additional portion of silver oxide was prepared as above and added to the reaction mixture. After heating the mixture for an additional 6 hours, the mixture was cooled and acidified with 1 N HCI. The aqueous layer was extracted with ethyl acetate (3x) and upon concentration 4-hydroxynaphthoic acid precipitated (3.7 g, 60%) out of solution.
' H NMR (DMSO-D6): b 6.69 (d, 1 H), 7.28 (t, 1 H), 7.39 (t, 1 H), 7.93 (d, 1 H), 8.03 (d, 1 H), 8.82 (d, 1 H), 10.82 (s, 1 H), 12.29 (s, 1 H).
Step B:
To a solution 4-hydroxynaphthoic acid in anhydrous methanol at 0 °C was added thionyl chloride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgS04 to give methyl hydroxynaphthoate.
'H NMR (DMSO-D6): 8 3.87 (s, 3H), 6.92 (d, 1 H), 7.53 (t, 1 H), 7.65 (t, 1 H), 8.13 (d, 1 H), 8.26 (d, 1 H), 8.93 (d, 1 H), 11.16 (s, 1 H).
Step C:
The title com ound was prepared from methyl 4-hydroxynaphthoate according to the proce-dure for the synthesis of precursor hydrazides A-(C=O)-NHNHZ.
'H NMR (DMSO-D6): 8 6.60 (d, 1 H), 7.28 (m, 3H), 7.95 (d, 1 H), 8.07 (d, 1 H), 9.25 (brd s, 1 H).
Moreover, by use of the above methodology, the following hydrazides useful as intermediates in preparing the compounds of the invention may be prepared:
I
F ~NHNH2 HO ~ ~ NHNH2 HO
F
NHNHZ I ~ ~NHNH2 I ~ ~NHNH2 HO HO ~ HO
CI CI CI
OCH O
I 3 I I ~CH3 OCH O
~NHNH2 3 I ~ NHNH2 HO ~ I ~ ~NHNH2 HO
CI HO ~ F CI
~NHNH2 ~ ~NHNH2 NHNH2 HO ~ HO ~ HO
O O
CI Me0 NHNH2 i w ~NHNH2 I ~ ~NHNH2 HO HO ~ HO
CI CI
CI O
~ ~NHNH2 NHNHZ ~ NHNH2 HO ~ F HO OCH3 OH
HO
CI ~ NHNH2 I ~ ~NHNH2 O
O
~NHNH2 ~ NHNH2 ~NHNHZ
HO HO / F HO
OH
CI
O O
F ~ NHNH2 I ~ ~NHNH2 / HO /
HO
C OMe General procedure for the syrnthesis of ether-substituted aryl-aldehydes~
The ether-linked aldehydes may be prepared by 0-alkylation of the corresponding phenolic compounds using various electrophilic alkylating agents that introduce the -(K)m D moiety as 1 o defined above in a reaction generally known as Williamson ether synthesis (H. Fever, J. Hooz in The Chemistry of the Ether Linkage, S. Patai Ed., Wiley, New York 1967, p.
446-460).
SCHEME II
H R3a Rsb R4a R4b R'4 O
Lx-(CH2)b ~ (CH2)a-(M)f (CH2)~ q (CH ) D
2d R'S OH Base, solvent H
R' 4 O
R3a R3b R4a 4b R
R~5 O-(CH2)b p (CHZ)a-(M)f (CH2)~ q (CH2)d D
wherein Lx is a leaving group such as -CI, -Br, -I, -OSOZCH3, -OSOZp-tolyl or -OSOZCF3;
and R3e , R3b, R4a , R4b, a, b, c, d, f, p, q, D, M, R'4 and R'S are as defined for formula I.
According to Scheme II an ether-substituted aryl-aldehyde can be prepared by stirring hy-droxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as acetone, meth-ylethyl ketone, dimethylformamide, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above sol-vents with an equimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the pres-ence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxide, ethoxide or grt-butoxide, sodium, potas-sium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6-collidine or benzyldimethyl-ammonium methoxide or hydroxide. The reaction can be performed at 0°C to 150°C, preferably at 20°C to 100°C and preferably in an inert atmosphere of NZ or Ar. When the reaction is complete the mixture is filtered, concentrated in vacuo and the resulting product optionally purified by column chromatography on silica gel using ethyl acetatelhexane as eluent. The compound can also (when appropriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of ether-substituted aryl-aldehydes are provided below.
PrPnaration of 4-l2-tetrahydropyranylmethoxy)-1-naahthaldehyde:
A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 2-bromomethyl tetrahydropyran (1 g, 5.8 mmol) and powdered KZC03 (1.2 g, 8.7 mmol) in dimethyl formamide was stirred at 60°C
overnight. The mixture was taken up in water and ethyl acetate. The organic layer was sepa-rated and washed with water, brine, dried over MgSO,, filtered, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate/hexane.
H O
\ \
O
-O
'H NMR (DMSO-de): 8 1.48 (m, 4H), 1.74 (d, 1 H), 1.84 (m, 1 H), 3.44 (m, 1 H), 3.78 (m, 1 H), 3.92 (d, 1 H), 4.23 (m, 2H), 7.17 (d, 1 H), 7.64 (t, 1 H), 7.74 (t, 1 H), 8.11 (d, 1 H), 8.27 (d, 1 H), 9.22 (d, 1 H), 10.17 (s,1 H).
Preparation of 4-[(3.5-bis-trifluoromethyl benzylox~~]-1-naphthaldehyde:
A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 3,5-bis-trifluoromethylbenzyfbromide (1.8 g, 5.8 mmol), and powdered KZC03 (1.2 g, 8.7 mmol) was stirred in acetone (40 mL) over-night. The mixture was poured onto 200 mL of ice-chips and stirred until the ice melted. The yellow precipitate, 4-{(3,5-bis-trifluoromethyl)benzyloxy)-1-naphthaldehyde, was collected and 2o dried.
H O
\ \
O
CF3 \ CF3 'H NMR (DMSO-ds): 8 5.58 (s, 2H), 7.07 (d, 1 H), 7.22 (d, 1 H), 7.63 (t, 1 H), 7.69 (t, 1 H), 7.79 (d, 1 H), 7.86 (d, 1 H), 7.99 (s, 1 H), 8.14 (s, 1 H), 8.30 (s, 3H), 8.94 (s, 1 H), 8.97 (d, 1 H), 11.0 (broad s, 1H), 11.69 (s,1H); MS (ESI) m/z 675.2 (M+H)'.
Prej~aration of 4-(2-chloroethoxv -1-na htha ehyde~
To a solution of 4-hydroxy-1-naphthaldehyde (8.6 g, 50 mmoles) and potassium carbonate (13.8 g, 100 mmoles) in N,N-dimethylformamide (DMF)(40 mL) was added 1-bromo-2-chloroethane (7.4 g, 50 mmoles). The mixture was heated at 60°C
overnight. The solution was diluted with ethyl acetate (500 mL), extracted with water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated to obtain 12.1 g product (52 % yield).
O H
/ I \
\ /
O
SCI
MS (C(): 403, 405, 407. 'H NMR (CDCI3): 8 10.2 (s, 1 H), 9.3 (d, 1 H) 8.35 (d, 1 H), 7.85 (d, 1 H), 7.65 (m, 1 H), 7.5 (m, 1 H), 7.1 (d, 1 H), 4.35 (t, 2H), 4.15 (t, 2H).
The products were used as such in further transformations.
By application of the above methodology the following substituted aldehyde intermediates were synthesized:
/ \ OMe / \
O O \
/ \ O O / \ O
H H
4-carbomethoxymethoxy-1-naphthaldehyde 4-benzyioxy-1-naphthaldehyde m.p.: 115-116°C
/ \ / \
O / \ o \ / ~I o H ~/ H
4-(4-chlorobenzyloxy)-1-naphthaldehyde 4-allyloxy-1-naphthaldehyde CH
/ \ / \
O / \ \ / OCF3 O
O / \ O
H H ~J
4-(4-trifluoromethoxybenzyloxy}-1- 4-propargyloxy-1-naphthaldehyde naphthaldehyde / \ / \ NH2 O \ / CF3 O
/ \ O U O O
H ~-=J H
4-(4-trifluoromethylbenzyloxy)-1- 2-[(4-carboxaldehydo)-1 naphthaldehyde naphthyloxy]acetamide m.p. 174-175°C
\ CF3 OCF3 \ ~ ~ ~ \
O
H O
O O
4-(3-trifluoromethylbenzyloxy)-1-naphthaldehyde 4-(2-(4-trifluoromethoxyphenyl)-2-oxo-ethoxy)-1-naphthaldehyde m.p. 112-114°C
OMe O ~ \ \ ~ OCF3 ~ ~ O -N
O
H O ~ ~ O
OMe 4-(4-trifluoromethoxybenzyloxy)-3,5- Nicotinic acid 4-formyl-1-naphthyl ester dimethoxybenzaldehyde m. p. 142-143°C
OMe CHs O / \ O \ / ~H o 0 ° w OMe 4-(4-isopropylbenzyloxy)-3,5-4-(1,3-dioxo-1,3-dihydroisoindol-2-dimethoxybenzaldehyde yimethoxy)-1-naphthaldehyde (oil) m.p. 191-192°C
O O
O O
H H U
4-(4-isopropylbenzyloxy)-1-naphthaldehyde 4-(tetrahydro-2-pyranylmethoxy)-1-naphthaldehyde / \ F
H ~ F
4-(3,5-difluorobenzyloxy)-1-naphthaldehyde m. p. 100-101 °C
Preparation of 3-AIIXI-4-hydroxyr-5-methoxy-benzaldehude:
OH
--a -.r H
To a solution of vanillin (1.0 g, 6.57 mmol) in acetone (30 mL) was added potassium carbon-ate (4.50 g, 32.8 mmol) and allyl bromide (0.62 mL, 7.3 mmol). The mixture was heated un-der reflux for 6 h. TLC showed appearance of a new spot. Potassium salts were removed by filtration and the filtrate was concentrated to a syrup. A small sample was purified using prep TLC using hexane/ethyl acetate 7:3 as developing solvent. 1 H NMR (CDCI3) 8 =
3.94 (s, 3H), 4.67 - 4.83 (m, 2H), 5.30 - 5.55 (m, 2H), 6.01 - 6.21 (m, 1 H), 6.98 (d, J = 9 Hz, 1 H), 7.40 - 7.56 (m, 2H), 9.85 (s, 1 H); MS (APCI): 193.6 The crude syrup was heated neat in an oil bath at 200 °C for 6 h. The crude material was dissolved in chloroform and filtered through a pack of silica gel. The crude product (yield 72%) was used as is in the next step for O-alkylation. A small portion was purified using prep-TLC to give a pure sample of 3-allyl-4-hydroxy-5-methoxy-benzaldehyde. 1 H NMR
(CDC13) b = 3.46 (d, J = 6 Hz, 2 H), 3.96 (s, 3H), 5.02 - 5.22 (m, 2H), 5.94 -6.11 (m, 1 H), 6.30 (s, 1 H), 7.45 (s, 2H), 9.80 (s, 1 H); MS (APCI}: 193.3.
Preparation of 3-Allvl-4-(4-isonroovlbenzvloxv) 5 methoxyh~Pn~aldeh~~g The crude 3-allyl-4-hydroxy-5-methoxy-benzaldehyde was taken up in acetone and treated with 4-isopropylbenzyl chloride in the presence of potassium carbonate to give the desired product.
1 H NMR (CDCi3) b = 1.2fi (d, J = 7 Hz, 6 H), 2.92 (m, 1 H), 3.38 (d, J = 7 Hz, 2H), 3.95 (s, 3H), 4.98 - 5.12 (m, 4H), 5.93 - 5.75 (m, 1 H), 7.20 - 7.43 (m, 6H), 9.87 (s, 1 H).
General~rocedure for the synthesis of compounds of formulae IXa and IXb:
QH
CI N OHC~ IB
D~NH2 -~. CI~ -.. Cp \p -step A
0 O step B
H a \ NiNHx O H
O~B\O~N\D Ho a H a ~ N~N~B\O~N~D
H O R R HH
O
step D HO R9 Formula IXa step C ICZCO~
\ N~NHx O
R° H
Ho , ~ N~N~/B\N~D
O~B~N,D R Ra H H
H
H step D HO Rs Formula IXb In the above formulae 8, D, R8 and R9 have the same meanings as defined for formula I.
Step A:
To a solution of aniline (or an aniline derivative) (1 eq.) in THF was added dropwise chloroacetyl chloride (1.2 eq.). After stirring at room temperature overnight, 100 mL water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with dilute hydrochloric acid, twice with water, dried over MgSO, and then con-centrated to give pure product.
Step B:
To a solution of chloroacetanilide (or a derivative thereof) (1.2 eq.) and 2-methoxy-4-hydroxy benzaldehyde (or another aromatic aldehyde substituted with a hydroxy group) (1 eq.) in DMSO was added potassium carbonate (1.5 eq.). After stirring overnight at room temperature, 100 ml water was added. The mixture was extracted with ethyl acetate, the or-ganic extracts were washed twice with a satd. sodium bicarbonate solution, twice with water, and dried over MgS04. After concentration in vacuo, the product was obtained.
The following two aldehydes were prepared as examples of compounds that can be pre-pared using this methodology:
N-l4-Chloroohenvl)-2-l4-formv! ~ r"Ptho p noxy~acetamide C!
O / I
Me0 O
\N
H
O
H
'H NMR (CDC13 ): 8 4.28 (s, 3H), 5.01 (s, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.97 ( dd, J = 8.6, 2.1 Hz, 1 H), 7.67 ( d, J = 8.9Hz , 2H), 7.89 (d, J = 8.8 Hz, 2H), 8.20 (d, J =
8.6Hz, 1 H), 8.51 (s, 1 H), 10.66 ( s, 1 H); MS ( APCI ): 319.9 .
N- 4-iso r h n r I- -m th h n x cet mi O ~ I ~CH3 Me0 \ O
~ \N
O / H
H
'H NMR ( DMSO-D6): 8 2.07 (d, J = 6.9 Hz , 6H), 2.70 (m, J = 6.9 Hz, 1H), 3.77 (s, 3H), 4.68 (s, 2H), 6.56 (dd, J = 8.7, 2.1 Hz, 1 H), 6.66 ( d, J = 2.1 Hz, 1 H), 7.06 (d, J = 8.5Hz, 2H), 7.39 ( d, J = 8.50 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1 H), 9.93 (s, 1 H), 10.05 (s, 1 H); MS (APCI ): 328.
This type of aidehydes can be coupled to hydrazides using the methodology as described in step D to give a compound of formula IXa. Alternatively these compounds can undergo re-arrangement by treatment with base as described below (step C), followed by coupling to a hydrazide (step D) to give a compound of formula IXb.
WO 99/01423 PCT/DK98/0828'l Step C:
The mixture of aldehyde (1 eq.) and potassium carbonate (1.5 eq.) in acetonitrile was re-fluxed. The reaction was monitored by TLC (hexane : ethyl acetate = 2:1 ).
When TLC
showed almost complete conversion (about 48 h), 100 ml water was added. The mixture was extracted with ethyl acetate, the organic extracts were dried over MgSO,, and concen-trated to give the desired product which can be further purified by column chromatography, or used directly for the next step.
1 o The following two aldehydes were prepared as examples of compounds that can be pre-pared using this methodology:
4-~4-Chlorophenylamino)-2-methoxybenzaldehyde:
Prepared from N-(4-chlorophenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide using the pro-cedure described in step C above.
WO 99/01423 PCT/DK98/0028?
H
Me0 N
\ \
O ~ / ~ /
CI
H
'H NMR (CDC13 ): b 3.84 (s, 3 H), 6.14 (s, 1 H), 6.45 (d, J = 2.0 Hz, 1 H), 6.54 ( dd, J = 8.4, 1.BHz, 1 H), 7.14 (d, J = 8.7Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.74 (d, J =
8.5Hz, 1 H), 10.22 (s, 1 H); MS (APCI ): 261.9.
4-(4-Isopropyl henylamino}-2-methoxybenzal~Ph, Prepared from N-(4-isopropylphenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide using the procedure described in step C above.
H
Me0 N
\ ~ \
'H NMR (CDCI3) b 1.26 (d, J = 6.9Hz, 6H), 2.88 (m, J = 6.9Hz, 1 H), 3.84 (s, 3H), 6.50 (d, J =
1.9Hz, 1 H), 6.55 (dd, J = 8.6, 1.8Hz, 1 H), 6.96 (s, 1 H), 7.15 (d, 2H, J =
8.5Hz, 2H), 7.22 (d, J
= 8.5Hz, 2H), 7.69 (d, J = 8.5Hz, 1 H), 10.18 (s, 1 H); MS (APCI ): 269.
Step D:
The resulting carbonyl compounds are treated with the corresponding acylhydrazide in a sol-vent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, -butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloro-form, dichloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction sol-vents. The product can also be isolated by concentration of the reaction mixture in vacuo, fol-lowed by column chromatography on silica gel using a solvent system such as chioro-form/methanol or dichloromethane/methanol or chloroform/ethyl acetate to give a compound of formula IXb.
The following compounds of formulae IXa or IXb according to the invention were prepared as examples of compounds that can be prepared using this methodology:
EXAMPLE 1:
3-Chloro-4-hydr~benzoic acid (4-(4-chloro~herJ~rlamin~,l-2-methoxybenzylidene]hydra-zide 'H NMR ( DMSO-D6 ): b 3.81 (s, 3H), 6.72-6.67 (m, 2H), 7.04 (d, J = 8.5Hz, 1 H), 7.17 ( d, J
= 8.7Hz, 2H) 7.31 (d, J = 8.7Hz, 2H), 7.77- 7.70 (m, 2H), 7.96 (d, J = 1.6Hz, 1 H), 8.65 {s, 1 H), 8.70 (s, 1 H), 10.87 (s, 1 H), 11.51 (s, 1 H); MS (APCI ): 430.
EXAMPLE 2:
3-Chloro-4-hxdroxubenzoic acid (~4-isopro~ylphenylamino}-2-methoxybenzylidene]h~
drazide 1 H NMR (DMSO-D6): 8 1.18 (2s, 6H), 2.86 (m, 1 H), 3.79 (s, 3H), 6.65 (m, 2H), 7.03 (d, 1 H), 7.11 (d, 2H), 7.19 (d, 2H), 7.70 (d, 1 H), 7.75 (dd, 1 H), 7.97 (s, 1 H), 8.49 (s, 1 H), 8.64 (s, 1 H}, 10.88 (s, 1 H), 11.48 (s, 1 H); MS {FAB): 438.16.
EXAMPLE 3:
2-~4-f(3-Chloro-4-hvdroxybenzoy)hydrazonomethyl] 3 methoxy~ henoxy} N~4 chloro~~henyl}acetamide cl o / I
o lw H
H
HO
CI
1 H NMR (DMSO-D6): 8 3.66 (s, 3H}, 4.57 (s, 2H), 6.48 (d, 1 H), 6.55 (s, 1 H), 6.83 (d, 1 H), 7.20 (d, 2H), 7.48 (d, 2H), 7.56 (dd, 1 H), 7.58 (d, 1 H), 7.77 (d, 1 H), 8.48 (s, 1 H), 10.05 (s, 1 H), 10.72 (brd s, 1 H}, 11.40 (s, 1 H); MS (APCI): 487.8.
EXAMPLE 4:
2-~4-f(3-Chloro-4.-hydroxybenzoyl~h~rdrazonomethyl]i 3 methoxv h noxy~ N~4 1 H NMR (DMSO-D6): b 1.17 (2 s, 6H), 2.85 (m, 1 H), 3.87 (s, 3H), 4.76 (s, 2H), 6.70 (d, 1 H), 6.76 (d, 1 H), 7.05 (d, 1 H), 7.20 (d, 2H), 7.55 (d, 2H), 7.77 (dd, 1 H), 7.80 (d, 1 H}, 7.98 (s, 1 H), 8.70 (s, 1 H), 10.03 (s, 1 H), 10.92 (s, 1 H), 11.62 (s, 1 H); MS (FAB):
496.16.
~prol~ylpheny)acetamide EXAMPLE 5:
~~4-j(~3-Chloro-4-hydro~cybenzoy~hvdrazonomethyl]-3-methoxyphenox~~3 5-dichlorophenyl)acetamide I
CH~O \ O~N \ CI
O I H
\ Ni ~ /
H
HO
CI
~ H NMR (DMSO-D6): 8 4.06 (s, 3H), 4.94 (s, 2H), 6.8 (d, 1 H), 6.88 (s, 1 H), 7.20 (d, 1 H), 7.45 (s, 1 H), 7.90 (m, 3H), 8.10 (s, 1 H), 8.82 (s, 1 H), 10.62 (s, 1 H), 11.07 (brd s, 1 H), 11.75 (s, 1 H); MS (APCI): 524.8.
General i~rocedure for the synthesis of alkylidene hydrazides of formula fl accordin4 to the 1 o invention:
The acylhydrazides are treated with the corresponding carbonyl compounds, such as aldehy-des or ketones, in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloromethane, DMSO, acetic acid, water or a compatible ~ 5 mixture of two or more of the above solvents. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystal-lized if necessary from a solvent such as the above described reaction solvents. The product 2o can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/-methanol or di-chloromethanelmethanol or chlorofom~/ethy! acetate. The product is isolated by concentration in vacuo of the appropriate fractions. Specific examples illustrating the preparation of com-pounds according to the invention are provided below.
EXAMPLE 6:
3-Chloro-4-hvdroxvbenzoic acid (4-hvdroxy-1-naphth ly methylene)hydr 7id~P
OH
O I
/ .N ~ /
HO
CI
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 7.1 mmol) in DMSO (2 ml) was added 4-hydroxynaphthafdehyde and a catalytic amount of glacial acetic acid (5 drops).
The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine, and dried over MgS04. The or-ganic volume was concentrated in vacuo to give the crude product. The product was purified by silica gel column chromatography using CHzCh/MeOH as the mobile phase.
'H NMR (DMSO-d6): 8 6.89 (d, 2H), 7.02 (d, 1 H), 7.47 (t, 1 H), 7.58 (t, 1 H), 7.66 (d, 1 H), 7.73 (d, 1 H), 7.93 (s, 1 H), 8.17 (d, 1 H), 8.84 (s, 1 H), 8.88 (d, 1 H), 10.73 (s, 1 H), 10.88 (s, 1 H), 11.54 (s, 3 H); MS (ES1): m/z 341.04 (M+H)'.
EXAMPLE 7:
3-chloro-4-hvdroxvbenzoic acid f4-(3 5-bis-trifluoromethvlbenzyloxxl 1 naoht~lmethvl~~nP1 hydrazide F F F
O I ~ O I i F
/ N.N ~ I / F F
H
HO
CI
To a solution of 3-chloTO-4.-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 mL) was added 4-(3,5-bis-trifluoromethylbenzyloxy)-1-naphthaldehyde (440 mg, 1.1 mmol) and a catalytic amount of glacial acetic acid (5 drops). The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicar-bonate, water, brine, and dried over MgS04. The organic volume was concentrated under vacuo to give the crude product. The product was purified by silica gel column chromatogra-phy using CH2Ch/MeOH as the mobile phase.
'H NMR (DMSO-ds): 8 3.77 (s, 6H), 4.91 (s, 2H), 6.95 (s, 2H), 6.99 (d, 1 H), 7.30 (d, 2H), 7.52 (d, 2H), 7.68 (m, 1 H), 7.89 (s, 1 H), 8.29 (s, 1 H), 10.90 (broad s, 1 H), 11.69 (s, 1 H); MS (ESI):
mlz 525.37 (M+H)+.
EXAMPLE 8:
3-chloro-4-hydroxybenzoic acid G4-(2-chloroethox~,-1-naphthv li methylene]hy razid o / I O~CI
\ .Nw \
_H \
HO
A solution of 1-(4-chloroethoxy)naphthaldehyde (2.35 g, 10 mmoles), 3-chloro-4-hydroxy benzoic acid hydrazide (1.87g, 10 mmoles), glacial acetic acid (0.2 mL) and dimethylsulfox-ide (DMSO)(15 mL) was stirred at room temperature overnight. Ethyl acetate (100 mL) was added. The solution was extracted with water and brine which induced precipitation. The product (3.1 g, 77% yield) was obtained by suction filtration. The product was purified by recrystallization from ethyl acetate.
MS (CI): 235. 'H NMR (DMSO-de): 8 11.5 (s, 1 H), 10.7 (s, 1 H), 8.7 (bs, 2H), 8.1 (m, 1 H), 7.8 (s, 1 H), 7.6-7.3 (m, 2H), 7.0 (m, 2H), 4.3 (t, 2H), 3.7 (t, 2H).
2o By application of the above methodology the following compounds of the invention are synthe-sized employing the following general procedure:
To a solution of 1 mmol of an arylcarboxylic acid hydrazide in 2 ml of anhydrous DMSO was added 1 mmol of the carbonyl compound (an aldehyde or ketone), followed by a catalytic amount of glacial acetic acid. The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO,. Upon partial concentration of the solvent in vacuo, the alkyiene hydrazides usually precipitated. The alkylene hydrazides were further purified by recrystafliza-tion from hot ethanol or ethyl acetate, or chromatographed using CHZCh/MeOH as an eluent.
EXAMPLE 9:
4-Hvdroxv-3-methoxybenzoic acid l2-naphtt~lmetf~ylene}hv razi ~P
I
O
.N. I i HO
H3C.0 'H NMR (DMSO-ds) 8 3.66 (s, 3 H), 6.67 (d, J = 8.2 Hz, 1 H), 7.32 - 7.47 (m, 5 H), 7.74 (d, J
= 7.2 Hz, 1 H), 7.79 (d, J = 8.2 Hz, 2 H), 8.60 (d, J = 8.2 Hz, 1 H}, 9.11 (s, 1 H), 11.80 (s, 1 H).
APCI m/z: 321 EXAMPLE 10:
4-Hvdroxv-3-methoxvbenzoic acid l4-methoxy-1-nar~hthylmethylene}hvdra7ide O ~ O
N.N ~ I
H
HO
H3C.0 1H NMR (CDC13): 8 4.80 (s, 3 H), 3.86 (s, 3 H), 6.00 (s, 1 H), 6.59 (d, 1 H), 6.83 (d, 1 H), 7.39 (m, 3 H), 7.52 (s, 1 H), 7.73 (s, 1 H), 8.18 (d, 1 H), 8.58 {d, 1 H), 8.88 (s, 1 H), 9.95 (s,1 H). MS (APCI): 351.
EXAMPLE 11:
4-HydroxX 3-metho~benzoic acid (4-tert-but~rlbenzylidene)hydrazide O
N' N w I / CH3 ~ I 'H
HO
H3C'O
1 H NMR (CDC13): b 1.30 (s, 9 H), 3.91 (s, 3 H), 6.16 (s, 1 H), 6.88 (d, 1 H), 7.23 - 7.78 (m, 6 H), 8.28 (s, 1 H), 9.58 (s, 1 H). MS (APCI): 327.
EXAMPLE 12:
4-Hydroxy-3-methoxvbenzoic acid l4-iso ro~ylbenzylidene)hydrazide O I ~ ~CH3 'N ~ i H
HO
H3C'O
1 H NMR (CDC13) 8 1.29 (d, 6 H), 2.94 (q, 1 H), 3.98 (s, 3 H), 6.13 (s, 1 H), 6.97 (d, 1 H), 7.20 - 7.80 (m, 6 H), 8.29 (s, 1 H), 9.38 (s, 1 H). MS (APCI): 313 EXAMPLE 13:
4-Hvdroxv-3-methoxvbenzoic amid (4-trifluoromethoxvbenzylidene}hydrazide F~F
TO
O
.N ~ ~ /
HO
H3C.0 1 H NMR (DMSO-dg): 8 4.01 (s, 3 H), 7.04 (d, J = 8.1 Hz, 1 H}, 7.60 - 7.65 (m, 4 H), 8.01 (d, J = 8.4 Hz, 2 H), 8.63 (s, 1 H), 9.92 (s, 1 H), 11.89 (s, 1 H). MS (APCI):
355, 313, 222, 205.
EXAMPLE 14:
4-Hvdroxv-3-methoxvbenzoic acid (1 H indol 3 ylmeth I ne hydra id / \
O ' / ,N \ ~ NH
H
HO
H3C.0 1 H NMR (DMSO-dg) b 3.79 (s, 3 H), 6.80 (d, J = 8.2 Hz, 1 H), 7.11 (m, 2 H), 7.38 (m, 3 H), 7.73 (d, J = 2.0 Hz, 1 H), 8.53 (d, J = 7.5 Hz, 1 H), 8.53 (s, 1 H), 9.58 (s, 1 H), 11.23 (s, 1 H), 11.49 (s, 1 H). MS (APCI): 310.
EXAMPLE 15:
4-Hydroxy-3-methoxXbenzoic acid (4-dimethylarnino-1-naph~~ylmethyleneUf ,ydrazide I W CHs O I ~ N.CHs / .N w /
w I _H
HO
H3C.0 1 H NMR (DMSO-d6): 8 3.05 (s, 6 H), 4.03 (s, 3 H), 7.06 (d, J = 8.1 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.63 - 7.80 (m, 4 H), 7.97 (d, J = 8.0 Hz, 1 H), 8.38 (d, J = 7.9 Hz, 1 H), 9.10 (d, J
= 8.4 Hz, 1 H), 9.15 (s, 1 H), 9.90 (s, 1 H), 11.73 (s, 1 H). MS {APCI): 364.
EXAMPLE 16:
4-Hysiro~y-3-methoxvlbenzoic acid~4-phenylbenzylidene)h~rdrazide I
O ~ /
/ .N ~ I /
~I
HO
H3C.0 1 H NMR (DMSO-d6): 8 4.02 (s, 3 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.63 - 7.68 (m, 5 H), 7.88 -7.96 (m, 6 H), 8.64 (s, 1 H), 9.91 (s, 1 H), 11.83 (s, 1 H). MS (APCI): 347.
EXAMPLE 17:
4-Hydroxybenzoic acid (1-nab hit iylmeth~rlene,)t~y ra id W
O
.N ~ I i HO
1 H NMR (DMSO-d6): 8 6.82 (d, J = 8.2 Hz, 2 H), 7.48 - 7.68 (m, 3 H), 7.72 -7.88 (m, 3 H), 7.95 (d, J = 8.2 Hz, 2 H), 8.80 (d, 1 H), 9.04 (s, 1 H), 10.14 (s, 1 H). MS
{APCI): 291.
EXAMPLE 18:
4-Hydroxybenzoic acid~4-methoxy-1-naphthylmet ylene)hy drazid I ~ CH3 O I ~ O
.N ~ r ~ I H
HO
1 H NMR (DMSO-d6): 8 3.97 (s, 3 H), 6.82 (d, J = 8.6 Hz, 2 H), 7.04 (d, J =
8.2 Hz, 1 H), 7.52 (dd, J = 7.3, 7.7 Hz, 1 H), 7.62 (dd, J = 6.8, 7.7 Hz, 1 H}, 7.77 (d, J = 8.5 Hz, 3 H}, 8.19 (d, J
= 8.2 Hz, 1 H), 8.89 (m, 2 H), 10.06 (s, 1 H). MS {APCt): 321.
EXAMPLE 19:
3 4-Dihvdroxvbenzoic acid w(1-na~ht yfme t~ylene)hydrazide O
~ .N ~ I i HO
HO
~ H NMR (DMSO-d6): 8 6.64 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.19 (d, J = 2.0 Hz, 1 H), 7.36 - 7.42 {m, 3 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.80 (d, J = 8.2 Hz, 2 H), 8.65 (d, J =
8.2 Hz, 1 H), 8.88 (s, 1 H), 9.07 (s, 1 H), 9.46 (s, 1 H), 11.45 (s, 1 H). MS
(APCI): 307.
EXAMPLE 20:
4-~iydro~-3-methoxyrbenzoic acid ~1-na~hthyrlmethylene)hyr razide O
.N ~ ~ i HO
H3C.0 ~ H NMR (DMSO-dg) 8 3.94 (s, 3H), 6.74 (d, 1 H), 7.37-7.52 (m, 6H), 7.77 (d, 1 H), 7.89 (d, 2H), 8.67 (d, 1 H), 9.93 (s, 1 H), 10.90 (s, 1 H). MS (APCI): 321.
EXAMPLE 21:
4-Hydroxv-3-methoxvbenzoic a .iri ~~ i~-triffuoromethyl~ no y)benzylidene)ihy r zide F F F
I
O
O I
.N ~ /
HO
H3C.0 1 H NMR (DMSO-d6) 8 3.83 (s, 3H), 6.85 (d, 1 H), 7.16 (dd, 1 H), 7.36 (m, 5H), 7.44 (m, 3H), 7.61 (t, 1 H), 8.43 (s, 1 H), 1.75 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 431.
EXAMPLE 22:
4_-Hvdroxv-3-methoxvbenzoic acid (4~- ~uinoli~ met y ene)~drazide I
O ( ~' N
.N ~ i _H
HO
H3C.0 1 H NMR (DMSO-d6): 8 3.58 (s, 3 H), 6.52 (d, J = 8.0 Hz, 1 H), 7.28 (d, J =
7.8 Hz, 2 H), 7.47 (dd, J = J' = 8.1 Hz, 1 H), 7.59 (m, 2 H), 7.86 (d, J = 8.4 Hz, 1 H), 8.50 (d, J = 8.4 Hz, 1 H), 8.73 (d, J = 4.5 Hz, 1 H), 8.94 (s, 1 H). MS (APCI): 322.
EXAMPLE 23:
4-Hyr is roxybenzoic acid [~(1 1 2 2-tetrafluoroetho~y~be~~ylidene~hvdrazide F\ /F
TXF
O F
O
N.N w I /
H
HO
1 H NMR (DMSO-dg) 8 6.49-6.78 (m, 3H), 7.10 (d, 1 H), 7.32 (t, 1 H), 7.41 (m, 2H), 7.57 (d, 2H), 8.23 (s, 1 H), 10.01 (s, 1 H), 11.59 (s, 1 H). MS (APCI): 357.
EXAMPLE 24:
4-Hydroxybenzoic acid j3-l4-tert-butylr~henyl)but-2-enylidene]hydrazide O
\CH3 N.N ~ ~
HO ~ I H CH3 1 H NMR (DMSO-dg) 8 1.15 (s, 9H), 1.99 (s, 3H), 6.64 (s, 1 H), 6.17 (d, 2H), 7.29 (s, 4H), 7.64 (d, 2H), 8.06 (s, 1 H), 9.98 (s, 1 H), 11.36 (s, 1 H). MS (APCI): 337.
EXAMPLE 25:
4-Hvdroxy-3-methoxybenzoic acid l4-hydroxy-1-nahhthylmethylene}I~ydrazide off o ,N
w HO
H3C.0 1 H NMR (DMSO-d6): 8 3.90 (s, 3 H), 6.89 (d, 1 H), 6.99 (d, 1 H), 7.19 (d, 1 H), 7.45 - 7.80 (m, 5 H), 8.22 (d, 1 H), 8.90 (s, 2 H), 9.62 (s, 1 H), 10.68 (s, 1 H). MS
(APCI): 337.
EXAMPLE 26:
4-Hy roxybenzoic acid (benzylidene~hvdrazide O
.N ~ I ~
HO
1 H NMR (DMSO-d6): b 6.86 (d, 2 H), 7.41 - 7.52 (m, 3 H), 7.72 (m, 2 H), 7.82 (d, 2 H), 8.41 (s, 1 H}, 10.14 (s, 1 H). MS (APCI): 241.
EXAMPLE 27:
3-Amino-4-hydroxybenzoic acid {1-naohth_ytmethv li en_e)~hydrazide O
.N ~ ~ i HO
N HZ
1 H NMR {DMSO-d6): b 4.71 (bs, 2 H), 6.68 (d, J = 8.1 Hz, 1 H), 7.01 (dd, J =
2.0, 8.2 Hz, 1 H),7.17(d,J=2.OHz,1H),7.51-7.62(m,3H), 7.84(d,J=7.2Hz,1H),7.94(d,J=8.0 Hz, 2 H), 8.75 (d, J = 7.6 Hz, 1 H), 9.01 (s, 1 H), 9.70 (s, 1 H), 11.54 (s, 1 H). MS (APCI):
306.
EXAMPLE 28:
3-Amino-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethv li ene)hydrazide O ~ OH
N.N ~ I /
H
HO
NHZ
1 H NMR (DMSO-d6): 8 4.68 (bs, 2 H), 6.67 (d, J = 8.2 Hz, 1 H), 6.91 {d, J =
7.3 Hz, 1 H), 7.03 (d, J = 8.2 Hz, 1 H), 7.15 (s, 1 H), 7.43 - 7.65 (m, 3 H), 8.16 (d, J =
8.2 Hz, 1 H), 8.83 (m, 2 H), 10.71 (s, 1 H), 11.34 (s, 1 H). MS (APCI): 322.
EXAMPLE 29:
4-Hvdroxybenzoic acid f3-l3-trifluoromethv I nz I y)b n~ylid neJhydrazide O .N ~ I i F F
H O ~~ ~ F
HO I
1 H NMR (DMSO-d6): 8 5.28 (s, 2 H), 6.88 (d, 2 H}, 7.12 (m, 1 H), 7.24 - 7.50 (m, 3 H), 7.55 - 7.92 (m, 6 H), 8.41 (s, 1 H), 10.16 (s, 1 H), 10.86 (s, 1 H). MS (APCI):
415.
EXAMPLE 30:
3-Chloro-4-hvdroxybenzoic acid (1-naphthylmethyl neLy r ~idP
I
O
.N ~ I i ~I
HO
CI
1 H NMR (DMSO-d6): 8 7.03 (d, J = 8.2 Hz, 1 H), 7.52 - 7.62 (m, 3 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.86 (d, J =7.0 Hz, 1 H), 7.96 (m, 3 H), 8.79 (d, J = 8.2 Hz, 1 H), 9.01 (s, 1 H), 10.94 (s, 1 H), 11.76 (s, 1 H). MS (APCI): 325.
EXAMPLE 31:
3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)t~ydrazide i~
O ~ OH
/ .N ~ I /
HO
CI
1 H NMR (DMSO-d6): 8 6.90 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.50 (dd, J = J' _ 7.8 Hz, 1 H), 7.58 (dd, J = 7.1, 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 7.93 (s, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J =8.5 Hz, 1 H), 10.73 (s, 1 H), 10.88 (s, 1 H), 11.54 (s, 1 H). MS (APCI): 343, 341.
EXAMPLE 32:
4-H~rdroxybenzoic acid~4-hydroxy-1-naJZylmethylene)hydrazide O ~ OH
/ .N
HO
1 H NMR (DMSO-d6): 8 6.88 (d, 2 H), 6.98 (d, 1 H), 7.55 (dd, 1 H), 7.64 (dd, 1 H), 7.71 (d, 1 H), 7.82 (d, 2 H), 8.22 (d, 1 H), 8.94 (m, 2 H), 10.11 (s, 1 H), 10.77 (s, 1 H). MS (APCI):
307.
EXAMPLE 33:
4-Hydroxybenzoic acid (4 (3-trifluoromethyll henoxv)benzylid~Pn~]hvdrazide F F
O ~ O i F
i .N~ I ~ ~ I
HO
1 H NMR (DMSO-d6): 8 6.81 (d, 2 H), 6.98 (d, 1 H), 7.13 (dd, 1 H), 7.30 - 7.48 (m, 3 H), 7.48 - 7.60 (m, 3 H), 7.68 (dd, 1 H), 7.81 (d, 2 H), 8.41 (s, 1 H). MS (APCI): 401.
EXAMPLE 34:
4-Hvdroxybenzoic acid (5-phenyl-3-Ryrazo~rlmethylene)~hydrazide O HN-N
.N
HO
1 H NMR (DMSO-d6): 8 6.81 (d, 2 H), 7.40 - 7.62 (m, 5 H), 7.78 (d, 2 H), 8.09 (s, 1 H), 8.50 (s, 1 H). MS (APCI): 307.
EXAMPLE 35:
2 4-Dihydroxybenzoic acid l4-hydroxy-1-na~h~rlmethKlene)hydrazide I
O ~ OH
N.N ~ I /
H
HO ~ OH
1 H NMR (DMSO-d6): 6.35 (s, 1 H), 6.39 (d, 1 H), 6.99 (d, 1 H), 7.51 (dd, 1 H), 7.65 (dd, 1 H), 7.73 (d, 1 H), 7.82 (d, 1 H), 8.26 (d, 1 H), 8.88 (s, 1 H}, 8.98 (d, 1 H), 10.0 - 11.0 (m, 4 H). MS (APCI): 323.
EXAMPLE 36:
4-Hydroxy-3-nitrobenzoic acid l1-nap~hyimethylen~hvdrazide I
O
N.N ~ I /
H
HO
_,N ~
O ~O
1 H NMR (DMSO-d6): 8 6.15 (d, J = 9.3 Hz, 1 H), 7.37 - 7.48 (m, 4 H), 6.70 (d, J = 7.1 Hz, 1 H), 7.78 - 7.82 (m, 2 H), 8.29 (s, 1 H), 8.43 (d, J = 8.5 Hz, 1 H), 8.85 (s, 1 H).
EXAMPLE 37:
4-H.ydrox~3-nitrobenzoic acid l4-h~rdrox~r-1-na~hthylmeth I~~hydrazide I ~ off N.N ~
H
HO \
O_.N~~O
1 H NMR (DMSO-d6): b 6.24 (d, J = 9.3 Hz, 1 H), 6.83 (d, J = 8.0 Hz, 1 H), 7.37 -7.52 (m, 3 H), 7.57 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 8.34 (s, 1 H), 8.76 (s, 1 H), 8.79 (s, 1 H), 10.57 (s, 1 H), 11.17 (m, 1 H).
EXAMPLE 38:
3 4-DihydroxKbenzoic acid (4-hydroxv -r 1na~hthylmethylene)hydrazide I ~ OH
O I
.N ~ i w I _H
HO
HO
1 H NMR (DMSO-d6): 8 6.86 (d, 1 H), 6.98 (d, 1 H), 7.32 (d, 1 H), 7.42 (s, 1 H), 7.56 (dd, 1 H), 7.63 (dd, 1 H}, 7.71 (d, 1 H), 8.24 (d, 1 H), 8.88 (s, 1 H), 8.92 (m, 2 H), 9.26 (s, 1 H), 9.54 (s, 1 H), 10.75 (s, 1 H). MS (APCI): 323.
EXAMPLE 39:
4-Hydroxybenzoic acid (6-methox~r-2-naohthylmethylene)hydrazid~P
I ~ O
O
N.N w I /
~ l H
HO
1 H NMR (DMSO-d6): b 3.89 (s, 3 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.22 (dd, J =
2.3, 8.9 Hz, 1 H), 7.37 (d, J = 2.3 Hz, 1 H), 7.80 - 7.93 (m, 6 H), 8.04 (s, 1 H), 8.53 (s, 1 H), 11.67 (s, 1 H}.
MS (APCI): 321.
EXAMPLE 40:
3 5-Dichloro-4-hvdroxvbenzoic acid (4-hydroxy 1 naphthylmethyleneLydr z' O ~ OH
CI / ".N w HO
CI
1 H NMR (DMSO-d6): 8 6.98 (d, 1 H), 7.58 (dd, 1 H), 7.68 (dd, 1 H), 7.78 (d, 1 H), 8.02 (s, 2 H), 8.27 (d, 1 H), 8.90 (s, 1 H), 8.96 (d, 1 H), 10.81 (s, 1 H), 10.98 (s, 1 H), 11.67 (s, 1 H).
MS (APCI): 375, 377.
EXAMPLE 41:
6-Hvdroxy-2-naphthoic acid~4-hydroxy 1 na~hthylmethylene~~_hydrazide O ~ OH
N.N w HO ~ ~ hiI
1 H NMR (DMSO-d6): 8 6.04 (d, 2 H), 6.33 (m, 1 H), 6.62 (dd, 2 H), 6.79 (dd, 2 H), 7.06 (d, 2 H), 7.44 (d, 2 H), 8.27 (d, 2 H), 8.39 (s, 2 H).
EXAMPLE 42:
4H~droxv-3-methoxvbenzoic acid l9-ethyl-9H-3-carha~o~,Imetflylene)hydrazide / \
N
O .N ~ ~ ~ CH3 HO
H3C_O
'H NMR (DMSO-dB) S 1.34 (t, J = 7.0 Hz, 3 H), 3.88 (s, 3 H), 4.47 (q, J = 7.0 Hz, 2 H), 6.90 (d, J = 8.0 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.47 - 7.54 (m, 3 H), 7.64 (d, J = 8.2 Hz, 1 H}, 7.69 (d, J = 8.5 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 8.24 (d, J = 7.7 Hz, 1 H), 8.45 (s, 1 H), 8.62 (s, 1 H) 9.62 (s, 1 H), 11.51 (s, 1 H). MS (APCI): 388.
EXAMPLE 43:
4-H ox - -meth x b n of id - 3- hl r n I - -furan (meth I n h r CI
O
i H~N \ O
HO
H3C.0 1 H NMR (DMSO-d6): ~ 3.93 (s, 3 H), 6.97 (d, J = 8.2 Hz, 1 H), 7.14 (d, J =
3.5 Hz, 1 H), 7.37 (d, J = 3.5 Hz, 1 H), 7.48 - 7.63 (m, 4 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.93 (s, 1 H), 8.47 (s, 1 H), 9.85 (s, 1 H), 11.75 (s, 1 H). MS (APCI): 371.
EXAMPLE 44:
3-Chloro-4-hvdroxybenzoic acid~~~~~lallylidene)hydr i O I
.N ~ ~ i HO
CI
1 H NMR (DMSO-d6): 8 7.00 (m, 3 H), 7.22 - 7.40 (m, 3 H), 7.57 (d, 2 H), 7.69 (d, 1 H), 7.89 (s, 1 H), 8.12 (d, 1 H), 11.0 (s, 1 H), 12.0 (s, 1 H). MS (APCI}: 301.
EXAMPLE 45:
3-Chloro-4-hvdroxvbenzoic acid l4-allyhx_y 1 na~ht I"~methylene)hydrazide O I ~ O~CH
/ .N ~ I /
HO
CI
1 H NMR (DMSO-d6): 8 4.68 (m, 2 H), 5.21 (d, 1 H), 5.38 (d, 1 H), 5.90 -6.10 (m, 1 H), 6.86 (dd, 2 H), 7.42 (dd, 1 H), 7.53 (dd, 1 H), 7.67 (dd, 2 H), 7.86 (s, 1 H), 8.18 (d, 1 H), 8.78 (s, 1 H), 8.82 (d, 1 H), 10.9 (s, 1 H), 12.0 (s, 1 H). MS (APCI): 381.
EXAMPLE 46:
3-Chloro-4-hydroxybenzoic acid l4-ethynylmethoxy-1-na~hthylmeth~riene)hydrazide O
O
/ N.N ~
H
HO \
CI
1 H NMR (DMSO-d6): 8 3.60 (s, 1 H), 5.06 (s, 2 H), 6.99 (d, 1 H), 7.12 (d, 1 H), 7.55 (t, 1 H), 7.66 (t, 1 H), 7.73 (t, 1 H), 7.93 (s, 1 H), 8.02 (d, 1 H), 8.16 (t, 1 H), 8.86 (d, 1 H), 9.27 (d, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 378.
EXAMPLE 47:
3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-1-naphthylmethvlenP,~ hvdrazide O I /
O .N ~ ~ /
HO \
CI
1 H NMR (DMSO-d6): 8 5.40 (s, 2 H), 7.08 (d, 1 H), 7.08 (s, 1 H), 7.39 (d, 1 H), 7.43 (m, 3 H), 7.70 (m, 5 H), 8.00 (s, 1 H), 8.01 (d, 1 H), 8.33 (t, 1 H), 8.94 (d, 1 H), 9.35 (d, 1 H), 10.98 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 431, 433.
EXAMPLE 48:
~-(4-f(3-Chloro-4-hvdroxybenzoyl)hydrazonomethyl] 1 naphthylox~~acPtamiclg I \ O
O I \ O~NHz / .N ~ /
\
HO
CI
1 H NMR (DMSO-d6): 8 4.68 (d, 2 H), 6.94 (d, 1 H), 6.98 (dd, 1 H), 7.40 - 7.86 (m, 5 H), 8.00 (m, 1 H), 8.48 (dd, 1 H), 8.93 (m, 1 H), 9.38 (m, 1 H). MS (APCI): 398.
EXAMPLE 49:
3-Chloro-4-hydroxubenzoic acid (4-methyl-1-naphthv Ir methyl neLydrazide I ~ CH3 O I
.N ~ /
HO
CI
1 H NMR (DMSO-d6): 8 2.70 (s, 3 H), 7.10 (d, 1 H}, 7.49 (d, 1 H), 7.67 (m, 2 H), 7.81 (m, 2 H), 8.00 (s, 1 H), 8.11 (d, 1 H), 8.88 (d, 1 H), 9.07 (s, 1 H), 11.0 (s, 1 H).
MS (APCI): 339, 341.
EXAMPLE 50:
3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1-na~hthylmethyiene)hXdrazide O
/ .N ~ I /
HO ~ I ~ OH
CI
1 H NMR (DMSO-d6): 8 6.98 (d, 1 H), 7.98 (d, 1 H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.69 {d, 1 H), 7.78 (dd, 2 H), 7.90 (s, 1 H), 8.06 (d, 1 H), 9.32 (s, 1 H), 11.00 (s, 1 H). MS (APCI):
341.
EXAMPLE 51:
3-Chloro-4-hydroxybenzoic acid {4-metho~y-1 naphthylmethyfene)hy razide I
O I ~ O.CH3 .N ~ /
w HO
CI
1 H NMR (DMSO-d6): b 4.05 (s, 3 H), 7.06 (m, 2 H), 7.59 (dd, 1 H), 7.70 (dd, 1 H), 7.81 (d, 1 H), 7.86 (d, 1 H), 8.00 (s, 1 H), 8.27 (d, 1 H), 8.93 (s, 1 H), 8.99 (d, 1 H), 11.00 (s, 1 H). MS
(APCI): 341, 339.
EXAMPLE 52:
~2-[(3-Chloro-4 hydroxybenzoyl)hydra~on2]ethyl) 2 2 di henylacet~imide 0 o I
I ~.N~~ /
HO
CI I
~ H NMR (DMSO-d6) 8 3.85 (t, 2 H), 4.93 (s, 2 H), 7.16 - 7.25 (m, 10 H), 7.26 (m, 1 H), 7.62 (d, 1 H), 7.82 (s, 1 H), 8.89 (t, 1 H), 10.85 (s, 1 H), 11.39 (s, 1 H). MS
(APCf): 422 EXAMPLE 53:
3-Chloro-4-hvdroxvbenzoic acid l1-h dro y-2-nahhthylmeth feneZh~drazide o Ho I
,N ' ~I
HO
CI
1 H NMR (DMSO-d6): b 6.99 (d, 1 H), 7.22 (d, 1 H), 7.37 -7.56 (m, 4 H), 7.68 (dd, 1 H), 7.77 (d, 1 H), 7.90 (s, 1 H), 8.19 (d, 1 H), 8.58 (s, 1 H), 11.00 (s, 1 H). MS
(APCI): 341.
EXAMPLE 54:
3-Chloro-4-hydroxybenzoic acid (2 2-di henylethvlidene~vdrazide i I
O
i 'N ' i Ho ~ I ~ ~
CI
1 H NMR {DMSO-d6): s 4.94 (d, 1 H), 6.98 (d, 1 H), 7.11 - 7.22 (m, 5 H), 7.22 -7.34 (m, 4 H), 7.68 (d, 1 H), 7.82 (s, 1 H), 8.19 (d, 1 H), 11.00 (s, 1 H). MS (APCI): 365, 367.
EXAMPLE 55:
3-Chloro-4-hydroxybenzoic acid l4-benzyloxy-3 5-dimethoxvbenzylidene)h~idrazide H3C.0 O
O
.N ~ I i O.CH3 HO
CI
1 H NMR (DMSO-d6): 8 3.86 (s, 6 H), 4.98 (s, 2 H), 7.03 (s, 2 H), 7.09 (d, 1 H), 7.25 - 7.33 (m, 3 H), 7.48 (m, 2 H), 7.89 (dd, 1 H), 7.99 (s, 1 H), 8.32 (s, 1 H), 11.00 (s, 1 H). MS
(APCI): 441.
EXAMPLE 56:
3-Chloro-4-hydroxybPnzioc did,j3-{4-tert-butvlahenoxy)benzylidene~hvdrazide l w ~cH3 N.N ~
l H
HO \
CI
1 H NMR (DMSO-d6): 8 1.05 (s, 9 H), 6.90 (m, 3 H), 7.09 (d, 1 H), 7.30 (t, 1 H), 7.40 (m, 3 H), 7.69 (m, 2 H), 7.88 {s, 1 H), 8.44 (s, 1 H), 10.60 (s, 1 H), 11.55 (s, 1 H). MS (APCI): 423.
EXAMPLE 57:
3-Chloro-4-hydroxybenzoic acid l4-methyl-1-nar~hthylmeth~ene)hydrazide O
N.N
H
HO
CI
1 H NMR (DMSO-d6): 8 2.64 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.41 (d, J =
7.4 Hz, 1 H), 7.58 (m, 2 H}, 7.78 (m, 2 H}, 7.95 (d, J = 2.0 Hz, 1 H), 8.06 (dd, J = 2.0, 8.0 Hz, 1 H), 8.82 (d, J =
8.0 Hz, 1 H), 9.07 (s, 1 H}, 10.93 (s, 1 H), 11.71 (s, 1 H). MS (APCI): 337.
339.
EXAMPLE 58:
3- r -4- r x nz is ci 3- -4- r -1- a th im h I n r i I
o I ~ off .N ~ ~ gr HO
CI
1 H NMR (CDC13): 8 7.02 (d, J = 8.5 Hz, 1 H), 7.51 - 7.62 (m, 4 H), 7.80 (dd, J = 2.0, 8.5 Hz, 1 H), 8.00 (d, J = 2.0 Hz, 1 H), 8.21 (s, 1 H), 8.59 (d, J = 8.5 Hz, 1 H), 8.91 (s, 1 H). MS
(APCi): 421, 423.
EXAMPLE 59:
Acetic acid 4-f(3-Chioro-4-hydroxybenzoyiLydrazonomethyl] 1 naphthyl ester I
O ~ O~CH3 N.N ~ I i IIO
H
HO
CI
1 H NMR (DMSO-d6): 8 2.63 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.36 (d, J =
8.0 Hz, 1 H), 7.60 (dd, J = 7.0, 7.5 Hz, 1 H), 7.68 (dd, J = 7.0, 8.0 Hz, 1 H), 7.75 (dd, J
= 1.4, 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H), 8.85 (d, J = 8.5 Hz, 1 H), 9.08 (s, 1 H), 11.0 (s, 1 H), 11.78 (s, 1 H). MS (APCI): 383.
EXAMPLE 60:
3-Chloro-4-hydroxybenzoic acid (4-cyanomethoxv-1-na~hthylmethv li eneLydrazi~g I o~N
.N. I i ~I
HO
CI
1 H NMR (DMSO-d6): 8 5.40 {s, 2 H), 7.00 (d, 1 H), 7.21 (d, 1 H), 7.58 - 7.80 (m, 3 H), 7.82 (d, 1 H), 7.96 (s, 1 H), 8.18 (d, 1 H), 8.90 (s, 2 H), 9.28 (s, 1 H), 11.62 (s, 1 H). MS (APCI):
380, 382.
EXAMPLE 61:
3-Chloro-4-hydroxybenzoic acid (2-hydroxv-. 1-nar~hthylmethvlene)~hydrazide I
O
.N ~ ~ i HO ~ I ~ OH
CI
1 H NMR (DMSO-d6): b 7.18 (d, 1 H), 7.30 (d, 1 H), 7.50 (dd, 1 H), 7.68 (dd, 1 H), 7.88 (d, 1 H), 7.95 (m, 2 H), 8.08 (s, 1 H), 8.29 {d, 1 H), 9.51 (s, 1 H), 11.12 (s, 1 H), 12.12 (s, 1 H).
MS (APCI): 341, 343.
EXAMPLE 62:
~Chloro-4-hvdroxvbenzoic aci i~{2 3-met ylenedioxvbenz~~idene~vdrazide ~--O
O
O
.N~ I i w I _ HO
CI
1 H NMR (DMSO-d6): 8 6.06 (s, 2 H), 6.86 (dd, 1 H), 6.90 (dd, 1 H), 7.01 (d, 1 H), 7.25 {d, 1 H), 7.71 (dd, 1 H), 7.92 (s, 1 H), 8.49 (s, 1 H), 10.93 (s, 1 H), 11.70 (s, 1 H). MS (APCI):
319, 321.
EXAMPLE 63:
3-Chloro-4-hvdroxvbenzoic acid [~4-metho enoxy) Pnzyfidene]hydr- a~idg O ~ ~ ~ ~ O
,N ~ i O
HO
CI
1 H NMR (DMSO-d6}: b 3.98 (s, 3 H), 7.38 (m, 6 H), 7.48 (s, 1 H}, 7.72 (m, 2 H), 7.97 (d, 1 H), 8.19 (s, 1 H), 8.64 (s, 1 H), 11.93 (s, 1 H). MS (APCI): 397, 399.
EXAMPLE 64:
3-Chloro-4-hvdroxybenzoic acid l9-Qhenanthrenylmethylene}h drazidg O
N.N ~ w ~ i H~
HO
CI
1 H NMR (DMSO-d6): 8 7.02 (d, 1 H), 7.52 - 7.83 (rn, 5 H), 7.99 (d, 1 H), 8.08 (d, 1 H), 8.21 (s, 1 H), 8.82 (d, 1 H), 8.89 (dd, 1 H), 8.96 (dd, 1 H), 9.06 (s, 1 H), 10.96 (s, 1 H), 11.82 (s, 1 H). MS (APCI): 375, 377.
EXAMPLE 65:
3-Chloro-4-hvdroxvbenzoic acid [4-(2~y roxyethoxy) 1 na~hthylmethylene]hvdrazide O I ~ OOH
/ .N ~ /
~I
HO
Ci 1 H NMR (DMSO-d6): 8 3.81 (t, J = 4.8 Hz, 2 H), 4.16 (t, J = 4.8 Hz, 2 H), 6.46 (d, J = 8.5 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 1 H), 7.51 - 7.61 (m, 3 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.82 (d, J = 2.1 Hz, 1 H), 8.30 (d, J = 8.2 Hz, 1 H), 8.85 (s, 1 H), 8.87 (d, J = 8.5 Hz, 1 H), 11.38 (s, 1 H).
MS (APCI): 385, 387.
EXAMPLE 66:
3-Bromo-4-hydroxvbenzoic acid (4-h~rdroxy-1-na~htE~lmethvlene)hXdr zid O ~ OH
.N, I /
HO
1 H NMR (DMSO-d6): 8 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = J' _ 8.0 Hz, 1 H), 7.58 (dd, J = J " = 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.77 (dd, J = 2.0, 8.0 Hz, 1 H), 8.08 (d, J = 2.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 8.83 (s, 1 H), 8.88 (d, J = 8.0 Hz, 1 H), 10.73 (s, 1 H}, 11.53 (s, 1 H). MS (APCI): 385, 387.
EXAMPLE 67:
Nicotinic acid 4-[(3-chloro-4-hydro~rbenzok~hvdrazonomethyl] 1 naphthyl ester w y o I ~ o I ~N
/ N.N ~ I / O
H
HO
CI
1 H NMR (DMSO-d6): 8 7.04 (d, J = 8.5 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.64 - 7.69 (m, 4 H), 7.74 - 8.02 (m, 3 H), 8.56 (dd, J = 2.0, 8.0 Hz, 1 H), 8.91 (m, 2 H), 9.05 (s, 1 H), 8.35 (d, J = 1.8 Hz, 1 H), 10.96 (s, 1 H), 11.84 (s, 1 H). MS (APCI): 446, 448.
EXAMPLE 68:
3-Chloro-4-hvdroxvbenzoic acid f4-l1 3-dioxo 1 3 dihydroisoindol 2ylmethoxy) 1 na .~hth~rl metf~lene]hydrazide O
O W O~N
.N ~ I / O
HO
1p CI
~ H NMR (DMSO-d6): 8 5.78 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.37 (d, J =
8.2 Hz, 1 H), 7.48 (m, 1 H), 7.61 (m, 1 H), 7.73 - 7.81 (m, 8 H), 8.90 {m, 2 H}, 10.91 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 500, 502.
EXAMPLE 69:
h ro-4-h rox n i 'd 4- I x f -1- hth Im h I n h dr O ~ ~ O
.N ~ /
HO
CI
1 H NMR (DMSO-d6): 8 1.08 - 1.19 (m, 4 H), 1.66 - 1.72 (m, 3 H), 1.83 - 1.92 (m, 3 H), 3.21 (m, 1 H), 3.95 (m, 2 H), 6.99 (d, J = 8.1 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.53 (dd, J = J' = 7.4 Hz, 1 H), 7.62 (dd, J = J ' = 7.5 Hz, 1 H), 7.72 -7.93 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.22 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.94 (s, 1 H), 11.60 (s, 1 H). MS (APCI): 437, 439.
EXAMPLE 70:
3-Chloro-4-hydroxybenzoic acid [4-~(tetrahydro-2-pyranylmethoxy}-1-naphthylmethyienP,~
hydrazide O I ~ O O
.N ~ i HO
C!
1 H NMR {DMSO-d6): b 1.35 (m, 3 H), 1.60 - 1.71 (m, 2 H), 3.15 - 3.38 (m, 2 H), 3.64 (m, 1 H), 3.78 (m, 1 H), 4.02 (m, 2 H), 6.94 (d, J = 8.5 Hz, 2 H), 7.46 (dd, J = J' = 7.4 Hz, 1 H), 7.54 (dd, J = J ' = 8.2 Hz, 1 H), 7.66 (m, 2 H), 7.86 (d, J = 2.1 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H), 8.78 (s, 1 H), 8.83 (d, J = 8.5 Hz, 1 H), 10.83 (s, 1 H), 11.52 (s, 1 H).
MS (APCI): 439, 441.
EXAMPLE 71:
3-Chloro-4-hydroxybenzoic acid [4-(3-yrridylmethoxy)-1-naphthylmethylene]hydrazide ~ o ~ ~N
.N
HO
1 H NMR (DMSO-d6): 8 5.28 (m, 2 H), 6.94 (d, J = 8.5 Hz, 1 H), 7.10 (d, J =
8.5 Hz, 1 H), 7.34 (dd, J = 4.8, 7.8 Hz, 1 H), 7.45 (dd, J = J' = 7.6 Hz, 1 H), 7.54 (dd, J
= J ' = 7.5 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.70 (d, J = 8.2 Hz, 1 H), 7.86 (m, 2 H), 8.15 (d, J = 8.0 Hz, 1 H), 8.45 (dd, J =1.5, 4.8 Hz, 1 H), 8.65 (s, 1 H), 8.81 (m, 2 H), 10.90 (s, 1 H), 11.56 (s, 1 H). MS
(APCI): 432, 434.
EXAMPLE 72:
4- h r -4-h ro nzo f h r om t I -1-na hth lox c ti a i et I r O
O I w O~O~CHs .N ~ /
I
HO
CI
1 H NMR (DMSO-d6): 8 1.25 (t, J = 7.0 Hz, 3 H), 4.25 (q, J = 7.0 Hz, 2 H), 5.11 (s, 2 H}, 7.06 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.64 -7.70 (m, 2 H), 7.76 (d, J = 8.2 Hz, 2 H), 8.04 (d, J = 2.1 Hz, 1 H), 8.36 (d, J = 8.2 Hz, 1 H), 8.97 (s, 1 H), 9.02 (d, J = 8.5 Hz, 1 H), 11.01 (s, 1 H}, 11.74 (s, 1 H). MS (APCI): 427, 429.
EXAMPLE 73:
3-Chloro-4-hydroxybenzoic acid~3-nitrobenzylidene)hydrazide Ov .~O_ N
O
/ N.N ~ ( /
H
HO
CI
1 H NMR (DMSO-d6): 8 7.13 (d, J = 8.5 Hz, 1 H), 7.79 -7.86 (m, 2 H), 8.03 (d, J = 2.1 Hz, 1 H), 8.18 (d, J = 7.5 Hz, 1 H}, 8.30 (d, J = 8.0 Hz, 1 H), 8.58 (s, 2 H), 11.08 (s, 1 H), 12.05 (s, 1 H). MS (APCI): 320, 322.
EXAMPLE 74:
3-Chloro-4-hydroxvbenzoic acid (2 4-dichlorobenzv lidene)hydrazide O CI ~ CI
.N
w I _H
HO
CI
1 H NMR (DMSO-d6): 8 7.02 (d, J = 8.5 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 1 H), 7.66 (s, 1 H), 7.73 (d, J = 8.2 Hz, 1 H), 7.95 (m, 2 H), 8.71 (s, 1 H), 11.97 (s, 1 H), 11.94 (s, 1 H). MS
(APCI):345.
EXAMPLE 75:
3-Chloro-4-hydroxybenzoic acid l4-fluoro-1-nar~hthylmethylene)hydrazide O ~ F
.N ~ ( /
HO
CI
1 H NMR (DMSO-d6): 8 7.00 (d, J = 8.5 Hz, 1 H), 7.33 (dd, J = 8.2, 10.3 Hz, 1 H), 7.62 - 7.72 (m, 3 H), 7.82 (m, 1 H), 7.91 (d, J = 1.9 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 8.09 (m, 1 H), 8.91 (s, 1 H), 10.81 (s, 1 H), 11.67 (s, 1 H). MS (APCI): 343.
EXAMPLE 76:
0-4- i -h ht t I h I
O ~ OH
.N ~ I i HO
F
1 H NMR (DMSO-d6): b 6.90 (d, J = 8.0 Hz, 1 H), 7.00 (t, J = 8.6 Hz, 1 H), 7.44 - 7.72 (m, 6 H), 8.17 (d, J = 8.6 Hz, 1 H), 8.84 (s, 1 H), 8.89 (d, J = 8.5 Hz, 1 H), 10.60 {s, 1 H), 11.50 (s, 1 H). MS (APCI): 325.
EXAMPLE 77:
3-Chl ro-4-h rox 'c id 4- 2 4-difl or en I -1-n th Im t I ne h dr i w F I w F
.N w I i I
HO
CI
1 H NMR (DMSO-d6): 8 5.33 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (m, 1 H), 7.21 (d, J = 8.2 Hz, 1 H), 7.31 (m, 1 H), 7.52 (m, 1 H), 7.54 (m, 9 H}, 7.69 - 7.80 (m, 3 H), 7.94 (s, 1 H), 8.16 (d, J = 8.2 Hz, 1 H), 8.90 (m, 2 H), 10.91 (s, 1 H}, 11.63 (s, 1 H). MS
(APCI): 467, 469.
EXAMPLE 78:
3-Fluoro-4-hydroxybenzoic acid (1-nahhthylmethv ne)hydrazide I
o I w _N ~ i ~I
HO
1~ F
MS (APCI): 309.
EXAMPLE 79:
I r -4-h r of 4- -m h x ben x -1-n hth I th I n h r O I ~ O I i .CH3 O
I~
HO
CI
1 H NMR (DMSO-d6): b 3.71 (s, 3 H), 5.29 (s, 2 H), 6.87 (d, J = 8.5 Hz, 1 H), 7.00 - 7.14 (m, 4 H), 7.29 (t, J = 8.0 Hz, 1 H), 7.55 (m, 1 H), 7.68 (m, 1 H), 7.75 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 11.00 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461.
EXAMPLE 80:
r -4- r i i 4- 4-fl r I -n ht I th I n a i I
o~
N.N ~ I
H
HO
CI
1 H NMR (DMSO-d6): 8 5.30 (s, 2 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.13 - 7.25 (m, 3 H), 7.53 7.60 (m, 4 H), 7.79 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 449, 451.
EXAMPLE 81:
3- hl r -4- r 'c i 4- -t tr r f r I th -1- a hth Im th h_ydrazide I
o ~ O
i .N. I i w I
HO
C!
1 H NMR (DMSO-d6): b 1.77 - 2.04 (m, 4 H), 3.68 (m, 1 H), 3.78 (m, 1 H), 4.12 -4.16 (m, 2 H), 4.26 (m, 1 H), 7.02 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.53 (m, 1 H), 7.62 (m, 1 H), 7.74 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.2 Hz, 1 H), 8.87 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.93 (s, 1 H), 11.61 (s, 1 H). MS (APCI): 425, 427.
EXAMPLE 82:
3-Chloro-4-hvdroxvbenzoic acid l3-bromo-4-methox -1-na hit yfmeth~ene~h_ydrazide O ~ w O.CHs H.N ~ ~ gr HO \
CI
1 H NMR (DMSO-d6): 8 3.91 (s, 3 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.65 - 7.76 (m, 3 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.02 {s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.71 (d, J = 8.0 Hz, 1 H), 8.95 (s, 1 H), 10.96 (s, 1 H), 11.85 {s, 1 H). MS (APCI): 433, 435.
EXAMPLE 83:
~Chloro-4-hydroxvbenzoic acid (4-(3-tetrahydrofuranylmetho -1-na~ht~lmethylenel h~rdrazide o ~o N.N w H
HO
CI
1 H NMR (DMSO-d6): 8 1.92 (m, 1 H), 2.10 (m, 1 H), 2.77 (m, 1 H), 3.28 - 3.88 (m, 4 H), 4.12 (m, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.55 (m, 1 H), 7.62 (m, 1 H), 7.74 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.94 {d, J = 2.0 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), 8.88 (s, 1 H), 8.90 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI):
425, 427.
EXAMPLE 84:
4~4-[3-Chloro-4-hydroxvbenzoyl)hydrazonomethyl)-1-naphth~loxymet~rllbenzoic acid methyl ester O
O I ~ O I / CH3 / ~.Nw HO
CI
1 H NMR (DMSO-d6): 8 3.80 (s, 3 H), 5.43 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1 H), 7.54 (m, 1 H), 7.57 (d, J = 8.0 Hz, 4 H), 7.93 - 7.99 (m, 3 H), 8.30 (d, J = 8.0 Hz, 1 H), 8.87 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H).
MS (APCI): 489, 491.
EXAMPLE 85:
3-Chloro-4-hydroxybenzoic acid [3.5-dimethoxy-4-{4-trifluoromethoxybenzyloxy)benzyi-dene]hydrazide H3C.0 ~ O F
O ~ / ~F
/ N.N ~ I / O.CH3 H( HO
CI
1 H NMR (DMSO-d6): 8 3.76 (s, 6 H), 4.91 (s, 2 H), 6.95 - 7.00 (m, 3 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.68 (d, J = 2.0, 8.5 Hz, 1 H), 7.88 (s, 1 H), 8.29 (s, 1 H), 10.91 (s, 1 H), 11.69 (s, 1 H). MS (APCI): 525, 527.
EXAMPLE 86:
3-Chloro-4-hydroxybenzoic acid [4-{4-trifluoromethoxybenzytoxy)-1-naphthylmethylene]-h_ydrazide O\ /F
O I ~ O I ~ F~ F
I ~.N .
HO \
CI
1 H NMR (DMSO-d6): b 5.36 (s, 2 H), 7.02 (d, J = 8.4 Hz, 1 H), 7.14 {d, J =
8.2 Hz, 1 H), 7.39 (d, J = 8.2 Hz, 2 H), 7.56 (m, 1 H), 7.62 (m, 3 H), 7.76 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.26 (d, J = 8.3 Hz, 1 H), 8.88 (s, 1 H), 8.93 (d, J = 8.5 Hz, 1 H), 10.91 (s, 1 H), 11.63 (s, 1 H). MS (APCI): 515, 517.
EXAMPLE 87:
3-Chloro-4-hvdroxvbenzoic acid j4-(2-methoxvbenzyloxy) 1 na~ht_hylmethylene]h_ razide Iw Iw o ~ o ~N ~ I ~ o~CH
I
HO
CI
1 H NMR (DMSO-d6}: 8 3.79 (s, 3 H), 5.27 {s, 2 H), 6.95 (m, 1 H), 7.03 (d, J =
8.5 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 7.31 {m, 1 H}, 7.46 -7.53 (m, 2 H), 7.61 (m, 1 H), 7.76 (m, 2 H), 7.94 (d, J = 2.0 Hz, 1 H), 8.22 (d, J = 8.3 Hz, 1 H}, 8.88 (s, 1 H}, 8.92 (d, J = 8.5 Hz, 1 H), 10.90 (s, 1 H), 11.62 (s, 1 H). MS (APCI): 461, 463.
EXAMPLE 88:
3-Chforo-4-hydroxybenzoic acid [4-(2-fluorobenzvlo~l-1 napht~lmethyiene]hydrazide o ~ o ".N w ~ / F
I
HO
Ci 1 H NMR (DMSO-d6): 8 5.36 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.19 - 7.28 (m, 3 H), 7.39 (m, 1 .H), 7.53 (m, 1 H), 7.63 (m, 2 H), 7.72 - 7.80 (m, 2 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.19 (d, J =
8.3 Hz, 1 H), 8.88 (s, 1 H), 8.92 (d, J = 8.5 Hz, 1 H), 10.90 {s, 1 H), 11.64 (s, 1 H). MS
(APCI): 449, 451.
EXAMPLE 89:
hl -4- dr x i 4- 'fl r b -1- ht Imeth n h r F I w O ~ O i .N ~ I / F
HO
CI
1 H NMR (DMSO-d6): 8 5.34 (s, 2 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.16 (d, J =
8.2 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.51 (m, 2 H), 7.72 (m, 1 H), 7.74 (d, J =
8.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 2.1 Hz, 1 H), 8.03 (d, J
= 8.3 Hz, 1 H), 8.89 (s, 1 H), 8.91 (d, J = 8.5 Hz, 1 H), 10.97 {s, 1 H), 11.65 (s, 1 H). MS
(APCI): 467, 469.
EXAMPLE 90:
4- x - t x n 'd - im -4- m t 7 r -na h!~ th-1-ylm~thoxy,~benzylidene)hy~lrazide 1 H NMR (DMSO-d6): 8 1.2 (s, 12H), 1.63 (s, 4H), 3.82 (s, 6H), 3.85 (s, 3H), 4.90 (s, 2H), 6.88 (d, 1 H), 7.01 (s, 2H), 7.18 (d, 1 H), 7.29 (d, 1 H), 7.38 (s, 1 H), 7.44 (d, 1 H), 7.48 (s, 1 H), 8.40 (brd s, 1 H), 11.62 (s 1 H); MS (APCI): 547.1.
EXAMPLE 91:
3-Fluoro-4-by dr ro -xybenzoic acid [4-~(4-iso~ro~ylben~~rlo~cy)-3 5 dimetho~ybenzylidene],~,~
drazide 1 H NMR (DMSO-d6): 8 1.05 (d, 6H), 2.67 (m, 1 H), 3.61 (s, 6H}, 4.69 (s, 2H), 6.79 (s, 2H), 6.86 (t, 1 H), 7.01 (d, 2H), 7.24 (d, 1 H), 7.44 (dd, 1 H), 7.51 (d, 1 H), 8.10 (brd s, 1 H), 10.32 (s, 1 H), 11.41 (s, 1 H); MS (APCI): 467.19.
EXAMPLE 92:
3-Chloro-4-hydroxybenzoic acid [4-(4-tert-butylbenz~rloxy~~ 3 5 dimethylbenzyfidene]hv drazide Hs / ~ wCHa / O \
O
\ NiN \ \ CH3 H
HO
CI
1 H NMR (DMSO-d6): b 1.06 (s, 9H), 1.99 (s, 6H), 4.55 (s, 2H}, 6.83 (d, 1 H), 7.19 (s, 6H), 7.52 (d, 1 H), 7.73 (s, 1 H), 8.09 (s, 1 H), 10.74 (brd s, 1 H), 11.44 (s, 1 H); MS (FAB): 465.6.
EXAMPLE 93:
3-Chloro-4-hydroxybenzoic acid [3-bromo-5-metho~~4-trifluoromethoxybenzyl oxy~ben~rfidene]~hydrazide 1 H NMR (DMSO-d6): 8 3.92 (s, 3H), 5.07 (s, 2H), 7.07 (d, 1 H), 7.40 (m, 3H), 7.52 (s, 1 H), 7.63 (d, 2H), 7.77 (dd, 1 H), 7.97 (d, 1 H), 8.35 (s, 1 H), 11.00 (brd s, 1 H), 11.86 (s, 1 H); MS
(FAB):575.0 EXAMPLE 94:
-H dr x n i 4- 4-' I I - im li h i 1 H NMR (DMSO-d6): 8 1.05 (d, 6H), 2.71 (m, 1 H), 3.67 (s, 6H), 4.75 (s, 2H), 6.70 (d, 2H), 6.85 (s, 2H), 7.14 (d, 2H), 7.21 (d, 2H), 7.64 (d, 2H), 8.21 (brd s, 1 H), 9.97 (brd s, 1 H), 11.47 (s, 1 H); MS (APCI): 448.9.
EXAMPLE 95:
hl r -4-h dr n 4- r - i th x n n OCH3 / ~ ~C
O
O
\ NON \ \ OCH3 H
HO CI
'H NMR (DMSO-D6): d 1.18 (d, 6H}, 2.87 (septet, 1 H), [3.68 (s, 1 H) + 3.81 (s, 5H), 6H], [4.83 (s, 0.5H} + 4.90 (s, 1.5H), 2HJ, [6.76 (s, 0.5H) + 7.01 (s, 1.5 H), 2H], [6.80 (dd, 1 H) +
6.88 (d, 1 H), 2H], 7.23 (d, 2H), 7.35 (d, 2H), 7.38 (m, 1 H), [7.91 (s, 0.3H) + 8.18 (s, 0.7H), 2HJ, 10.17 (s, 0.7H) + 11.73 (s, 0.3H), 1 HJ; MS (APCI): 483Ø
EXAMPLE 96:
3-Chloro-4-hydroxybenzoic acid [~(4-isol~pylbenz~yloxXl 4 5 dimethox benzylidPneJ~"~
drazide 1 H NMR (DMSO-d6): 8 1.05 (d, 6H), 2.70 (m, 1 H), 3.54 (s, 3H), 3.66 (s, 3H), 4.94 (s, 2H), 6.87 (m, 3H), 7.08 (d, 2H), 7.20 (d, 2H), 7.56 (dd, 1 H), 7.77 (s, 1 H), 8.15 (s, 1 H), 10.76 (s, 1 H), 11.52 (s, 1 H); MS (APCI): 483.7.
EXAMPLE 97:
Chloro-4-h) d/ fOXVbenzoic acid [3-(4-isooropylbenzyloxv)-2 4-dimethoxybenzylide~
ne]hydrazide O
~N ~ \
\ ~H O ~ \
HO ~ OCH3 / CH3 1 H NMR (DMSO-d6): 8 1.20 (d, 6H), 2.89 (m, 1 H), 3.85 (s, 6H), 4.95 (s, 2H), 6.95 (d, 1 H), 7.07 (d, 1 H), 7.22 (d, 2H), 7.40 (d, 2H), 7.64 (d, 1 H), 7.78 (dd, 1 H), 7.97 (d, 1 H), 8.62 (s, 1 H), 11.68 (s, 1 H); MS (APCI): 483.8.
EXAMPLE 98:
3-Chloro-4-hydroxybenzoic acid [~3-trifluoromethoxybenzy~y)naphth 1 ylmet~lene]'hydrazide O OCF~
,N
'N
H
HO
CI
1 H NMR (DMSO-d6): 8 5.46 (s, 2H), 7.10 (d, 1 H), 7.20 (d, 1 H), 7.37 (d, 1 H), 7.65 (m, 5H), 7.82 (m, 2H), 8.01 (s, 1 H), 8.32 (d, 1 H), 8.97 (m, 2H), 11.70 (s, 1 H); MS
(APCI): 514.8 EXAMPLE 99:
r i I n I th I
ylmethylene]-hydrazide ~CH3 O / O
CI ~ .N W
-N
HO I ~ H H3C.0 w 4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (2 g, 9.9 mmol) was dissolved in DMF (25 mL). To this mixture potassium carbonate (6.8 g, 50 mmol) and 4-isopropylbenzylchloride (1.8 g, 10.4 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the resulting mixture was extracted with diethyl ether (3 x 100 mL). The combined organic extracts were washed with saturated sodium chlo-ride (100 mL), dried (MgSO,) and evaporated in vacuo to afford 3.0 g crude product. This was purified using column chromatography on silica gel (300 mL) eluting with a mixture of ethyl acetate and heptane (1:4). This afforded 2.57 g (81%) of 4-isopropylbenzyloxy-8-methoxynaphthalene-1-carbaldehyde.
Calculated for C~H~03:
C, 79.02%; H, 6.63%. Found:
C, 79.10%, H, 6.69%, C, 79.17%, H, 6.69%.
3-Chforo-4-hydroxybenzoic acid hydrazide (205 mg, 1.1 mmol) was dissolved in DMSO (2 mL) and the above 4-isopropylbenzyloxy-8-methoxynaphthalene-1-carbaldehyde (365 mg, 1.1 mmol) and glacial acetic acid (5 drops) were added and the resulting mixture was stirred at room temperature for 20 minutes. More DMSO (2 mL) was added and the mixture was stirred at room temperature for 16 hours. The solid was collected by filtration and washed successively with DMSO and ethyl acetate to afford 330 mg (66%) of the title comp ~~r~
M.p.: > 250 °C.
EXAMPLE 100:
OMe i I CH3 O ~O
H.N . ('~~ I OMe HO
NOZ
'H NMR ( DMSO-ds ) 8 1.13 (d, 6H), 2.82 (sept, 1 H), 3.77 (s, 6H), 4.8 (s, 2H), 7.15 (s, 1 H), 7.18 (s, 2H), 7.30 (d, 2H), 8.00 (dd, 1 H), 8.30 (s, 1 H), 8.44 (s, 1 H), 11.84 (s, 1 H);. MS
(APCI): 494.0 EXAMPLE 101:
i i CF3 O ~ I O ~ I
.N . w I
I~ H
HO
CI
'H NMR ( DMSO-d6 ) 8 5.38 (s, 2H), 6.95 (d, 1 H), 7.06 (d, 1 H), 7.49 (t, 1 H), 7.56 (t, 1 H), 7.65-7.71 (m, 6H), 7.87 (d, 1 H), 8.22 (d, 1 H), 8.80 (s, 1 H), 8.86 (d, 1 H), 10.82 (s, 1 H), 11.55 (s, 1 H); MS (FAB): 499 EXAMPLE 102:
o w o~
H.N . w I I ~ OCF
a HO
CI
'H NMR ( DMSO-ds } 8 5.85 (s, 2H), 7.05 (t, 2H), 7.52-7.63 (m, 4H), 7.73 (m, 2H), 7.95 (s, 1 H), 8.16 (d, 2H), 8.33 (d, 1 H), 8.90 (s, 1 H), 893 (s, 1 H), 10.90 {brd s, 1 H), 11.63 (s, 1 H);
MS (FAB): 543 EXAMPLE 103:
-4- r n i id - 4- r x th - i th ne}hydrazide OCH3 / Br O / O~O \
,N ~
\ ~H OCH3 HO
CI
1 H NMR (DMSO-d6): b 3.78 (s, 6H), 4.21 (m, 4H), 6.87 (d, 2H), 7.00 (s, 2H}, 7.05 (d, 1 H), 7.44 {d, 2H), 7.75 (dd, 1 H), 7.96 (s, 1 H), 8.36 (s, 1 H), 10.95 (brd s, 1 H), 11.66 (s, 1 H);
MS(APCI): 548.8.
EXAMPLE 104:
3-Chloro-4-hydroxybenzoiC acid ~4~3-methoxy 3 (4 me ~rloheny~ nrop~rloxy)n h~-th 1 ylmeth l~ene]hydrazide EXAMPLE 105:
2- t I h n I r m i a i - 4- I ro-4- r x I h r m h I -n t - -yloxy}ethyl ester cl 1 H NMR (CDCI3): b 1.12 {t, 3H), 2.50 (qt, 2H), 3.69 (t, 2H), 4.39 (t, 2H), 5.20 (t, 1 H), 6.57 (t, 1 H), 6.74 (d, 1 H), 6.97 (d, 1 H), 7.08 (m, 3H), 7.57 (t, 1 H), 7.67 (t, 1 H), 7.81 (t, 2H), 8.01 (s, 1 H), 8.35 (d, 1 H), 8.95 (m, 2H), 11.67 (s, 1 H).
EXAMPLE 106:
3-Chloro-4-I~ydr~~benzoic acic~(3-ally~4 iso rohylbenzylQ~y}~
methoxyben~ylidene]hydrazide CHZ / ~ ~C
O \
O
\ N
HO
CI
MS (APCI): 502.9 1 H NMR (DMSO-d6) : 8 1.13 (d, 6H), 2.80 (m, 1 H), 3.20 (m, 2H), 3.85 (s, 3H), 4.82 (s, 2H), 5.00 (d, 2H), 5.70 (m, 1 H), 6.96 (s, 1 H), 7.05 (s, 1 H), 7.20 (d, 2H), 7.30 (d, 2H), 7.70 (d, 1 H), 7.89 (s, 1 H), 8.28 (s, 1 H), 10.80 (brd s, 1 H), 11.61 (s, 1 H); MS (APCI):
493.1.
Similarly, the following compounds were made:
EXAMPLE 107:
N.N.
HO~ H I i CHI
'H NMR (DMSO-Ds): 8 0.99 (d, 6H), 2.68 (septet, 1H), 4.89 (s, 2H), 6.84 (d, 2H), 7.06 (m, 2H), 7.16 (m, 3H), 7.55 (d, 1 H), 7.75 (s, 1 H), 8.18 (s, 1 H), 10.75 (s, 1 H), 11.52 (s, 1 H); MS
(APCI): 423.7, 425.6.
EXAMPLE 108:
CI i I CHI
O ~O w .N~ (~' I~ H
HO
CI
'H NMR (DMSO-D6): 8 1.18 (d, 1 H), 2.88 (septet, 1 H), 5.20 (s, 2H), 7.04 (d, 1 H), 7.28 (t, 2H), 7.30 (s, 1 H), 7.38 (d, 2H), 7.62 (d, 1 H), 7.73 (dd, 1 H), 7.79 (s, 1 H), 7.94 (d, 1 H), 8.32 (s, 1 H), 11.94 (s, 1 H), 11.72 (s, 1 H); MS (APCI}: 457.4, 459.1.
EXAMPLE 109:
CH5 ~ I CHI
O ~O w I ~ H.N ~ ('~~ I CH
HO
'H NMR (DMSO-D6): 8 1.1 (d, 6H), 2.2 (s, 6H), 2.8 (septet, 1 H), 4.7 (s, 2H), 7.0 (d, 1 H), 7.2 (d, 2H), 7.4 (d, 4H), 7.7 (d, 1 H), 7.9 (s, 1 H), 8.2 (s, 1 H), 10.9 (s, 1 H), 11.6 (s, 1 H); MS
(APCI): 451.6, 453.3.
EXAMPLE 110:
~CH~
O / 1 0 \'/~~ I
~ .N. w I~ H
HO
CI
'H NMR (DMSO-DB): 8 1.1 (d, 6H), 2.8 (septet, 1 H), 3.3 (d, 1 H), 5.0 (d, 1 H), 5.1 (d, 1 H), 5.2 (s, 2H), 5.9 (m, 1 H), 7.0 (d, 1 H), 7.1 (d, 1 H), 7.2 (d, 2H), 7.3 (d, 2H), 7.4 (d, 1 H), 7.5 (s, 1 H), 7.7 (dd, 1 H), 7.9 (d, 1 H), 8.3 (s, 1 H), 10.9 (bid s, 1 H), 11.5 (s, 1 H);
MS (APCI): 463.5, 465.1.
EXAMPLE 111:
o w I O.~O w I
.N~
I~ H
HO
CI
'H NMR (DMSO-D6): b 4.47 (t, 2H), 4.54 (t, 2H), 7.01 (d, 2H), 7.07 (d, 1 H), 7.14 (d, 1 H), 7.45 (d, 2H), 7.53 (t, 1 H), 7.27 (d, 1 H), 7.79 (m, 2H), 7.96 (d, 1 H), 8.17 (d, 1 H), 8.91 (s, 1 H), 8.94 (d, 1 H), 10.92 (s, 1 H), 11.64 (s, 1 H), MS (APCI): 539.3, 541.1, 543.1.
EXAMPLE 112:
O. CHs ~ I CHs O ~0 w I \ H.N. ('~~ I O.CH~
HO ~ CI
CI
'H NMR (DMSO-D6): 8 1.18 (d, 6H), 2.87 (septet, 1 H), [3.67 (s, 1.5H) + 3.81 (s, 4.5H), 6H], [4.83 (s, 0.5H) + 4.90 (s, 1.5H), 2H], 6.73 {s, 0.5H) + [7.02 (m, 2.5H), +
7.27 {m, 2.5H) +
7.37 (m, 2.5H), 8H], [7.92 (s, 0.3H) + 8.17 (s, 0.7H), 1 H], [10.96 (s, 0.3H) + 11.12 (s, 0.7H), 1 H], [11.82 (s, 0.7H) + 11.95 (s, 0.3H), 1 H]; MS (APCI): 517.6, 519.2.
EXAMPLE 113:
O.CH~ , I CHI
O ~O w CI ~ N.N w f~~'w ILLO.CH~
I~ H
HO CI
'H NMR (DMSO-D6): 8 1.19 (d, 6H), 2.89 (septet, 1 H), [3.68 (s, 1.5H) + 3.82 (s, 4.5H), 6H], [4.84 (s, 0.5H) + 4.89 (s, 1.5H), 2H], [6.76 (s, 0.5H) + 7.02 (m, 2.5H), 3H], 7.20 (m, 2H), 7.34 (m, 2H), [7.50 (s, 0.3H) + 7.62 (s, 0.7H}, 1 H], 7.92 (s, 0.3H) + 8.18 (s, 0.7H), 1 H], 11.17 (brd s, 1 H), 11.81 (s, 0.7H) + 11.96 (s, 0.3H), 1 H]; MS (APCI): 517.7, 519.2.
EXAMPLE 114:
CHI
O. CHI , ' CHa O ~ O
.N~ w I .CHS
O
HO
NHZ
'H NMR (DMSO-D6): 8 1.20 (d, 6H), 2.87 (septet, 1H), 3.82 (s, 6H), 4.89 (s, 2H), 6.69 (d, 1 H), 6.98 (m, 3H), 7.21 (m, 3H), 7.36 (d, 2H), 8.32 (s, 1 H), 9.8 (brd s, 1 H), 11.50 (s, 1 H}; MS
(APCI):464.7.
EXAMPLE 115:
O.CH3 / I CHI
O ~ O
.N~ w I .CH3 I H
HO ~ F
F
'H NMR (DMSO-D6): 8 1.19 (d, 6H), 2.30 (septet, 1 H), [3.71 (s) + 3.82 (s), 6H], 4.90 (s, 2H), [6.81 (m, 1.5H) + 6.88 (s, 1.5H), 3H], [7.24 (s, 0.2H) + 8.24 (s, 0.8H), 1 H], 11.05 (brd, 1 H), 11.69 (s, 0.75H) + 11.94 (s, 0.25H), 1 H]; MS (APCI): 485.5, 486.3.
EXAMPLE 116:
CHI
O.CH~ , I CHI
O ~O w ~ H.N ~ r'~~ I O.CH~
HO
'H NMR (DMSO-DB): b 1.19 (d, 6H), 2.88 (septet, 1 H), 3.83 (s, 6H), 4.90 (s, 2H), 6.87 (d, 1 H), 7.03 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.53 (m, 3h), 8.26 (m, 3H), 10.73 (s, 1 H), 11.82 (s, 1 H); MS (APC(): 499.8.
EXAMPLE 117:
CHI
O.CH3 , I CH3 O ~O w ~ H.N. \ I~ I O.CH~
HO
II
N
'H NMR {DMSO-D6): 8 1.20 (d, J = 6.9, 6H), 2.89 {sept, J = 6.9, 1 H), 3.84 (s, 6H), 4.91 (s, 2H), 7.03 (br s, 2H), 7.12 (d, J = 8.8, 1 H), 7.23 (d, J = 8.0, 2H), 7.37 (d, J = 8.0, 2H), 8.04 (dd, J = 2.2, 8.8, 1 H), 8.21 (br s, 1 H), 8.35 (br s, 1 H), 11.78 (s, 1 H), 11.89 (br s, 1 H); MS
(APCI, neg): 472.
Preparation of acyl-hydrazones of 4-(2-hydroxyethyl)-1-naphthaldehyde:
General procedure for synthesis of compounds of the general formula X' A~N.NHZ ~ I ~ (CHZ)b~OH ~ O ~ ~ (CHz)o\
H II OH
H i A~N.N ~
O H
formula X
wherein b is 1, 2, 3 or 4 Preparation of 4-l2-hydroxyethyl}-1-nal~ahthaldehyde~
Br Br O H
Br O H
\ \ \ \
~ \ \
\ \ ~ ~ ~ ~ ~ ~ i i Me0 HO O O O O i i p Ho 1-Bromo-4-(2-hydroxyethyllnaphthalene~
To a solution of methyl 4-bromo naphthalene acetate (2.0 g, 7.16 mmol} in anhydrous THF
(15 mL) was added drop wise at 0°C 1 M lithium aluminum hydride in THF
(4 mL). The mix-ture was stirred at room temperature for 16 h, diluted with water (5 ml), acidified with conc.
hydrochloric acid, and extracted with ethyl acetate (3 x 20 mL). The combined organic ex-tracts were dried (MgS04), and concentrated to provide a 1.71 g (95%) colorless oil (1.71 g, 95%). A similar synthetic reference is described in A. A. Kiprianov, A. A.
Shulezhko. Zh.
Org. Khim. 2 (1966), 1852, English translation: J. Org. Chem. (USSR) 2 (1966) 1820].
'H NMR (CDC13) 8 = 2.36 (s, 1H), 3.33 (t, J = 6.7 Hz, 2H), 3.99 (t, J = 6.7 Hz, 2H), 7.24 (d, J
= 7.3 Hz, 1 H), 7.58 - 7.63 (m, 2H), 7.73 (d, J = 7.6 Hz, 1 H), 7.61 (m, 1 H), 8.31 (dd, J = 1.1, 8.0 Hz, 1 H). GCMS (pos.) 250, 252.
1-Bromo-4-(2-tetrahydrop~,anyloxygthyl)naphthalene~
To a solution of 1-bromo-4-(2-hydroxyethyl)naphthalene (1.71 g, 6.8 mmol) in dichloro-methane (20 mL) was added 3,4-dihydro-2H-pyrane (1 mL, 0.92 g, 11.0 mmol) and p-toluene sulfonic acid (80 mg). The mixture was stirred at room temperature for 90 min, dilu-ted with dichloromethane (20 mL), washed with satd. NaHC03 sof. (20 mL), dried (MgS04), and concentrated. Flash chromatography using hexane/ethyl acetate 9:1 as eluent provided 1.69 g (75%) of a colorless oil.
'H NMR (CDCI3) 8 = 1.51 -1.60 m (6H), 3.37 (t , J = 7.2 Hz, 2H), 3.39 - 3.47 (m, 1 H), 3.74 (t, J = 7.2 Hz, 2H), 4.08 (dd, J = 2.4, 7.5 Hz, 1 H), 4.60 (m, 1 H), 7.25 (d, J =
7.3 Hz, 1 H), 7.56 -7.61 (m, 2H), 7.72 (d, J = 7.6 Hz, 1 H}, 8.09 - 8.12 (m, 1 H), 8.29 {dd, J =
2.5, 7.1 Hz, 1 H).
GCMS (pos), 334, 336.
1-Formyl-4-~2-tetrahydropyranvioxyethyl)naphthalene:
A solution of 1-bromo-4-(2-tetrahydropyranyloxyethyl)naphthalene in anhydrous THF (15 mL) under nitrogen was cooled to -78°C. n-Butyl lithium (1.4 mL of a 2.5 M solution in hexa-ne) was added via syringe, and the mixture was stirred at the same temperature for 30 min.
DMF (1.1 mL) was added, and the mixture was allowed to reach room temperature.
It was diluted with satd. NH,CI solution (10 mL), extracted with ether (3 x 10 ml), dried (MgS04) and 1o concentrated. Flash chromatography using hexanelethyl acetate 5:1 as eluent provided 408 mg (54%) of a colorless oil.
'H NMR (CDCI3) 8 = 1.48 -1.69 m (6H), 3.45 - 3.50 (m, 3H), 3.69 - 3.85 (m, 2H), 4.07 - 4.17 (m, 1 H), 4.61 (m, 1 H), 7.58 {d, J = 7.3 Hz, 1 H), 7.62 -7.73 (m, 2H), 7.92 (d, J = 7.3 Hz, 1 H), 8.20 (d, J = 1.0, 8.1 Hz, 1 H), 10.36 (s, 1 H). GCMS: 284 1-Formyl-4=(2~hydroxvethyl}naphthalene:
1-Formyl-4-(2-tetrahydropyranyloxyethyl)naphthalene (400 mg, 1.40 mmol) was dissolved in methanol (15 mL), and p-toluene sulfonic acid (45 mg) was added. The mixture was stirred at room temperature for 16 h, and concentrated. The residue was dissolved in ethyl acetate (3 x 10 mL), washed with satd. NaHC03 (20 mL), dried (MgS04) and concentrated.
Purifica-tion by flash chromatography using hexanelethyl acetate 3:1 as eluent provided 182 mg (65%) of a colorless oil .
'H NMR (CDCI3) 8 = 2.09 (s, 1 H), 3.40 (t, J = 6.6 Hz, 2H}, 4.02 (t, J = 6.6 Hz, 2H), 7.54 {d, J
= 7.3 Hz, 1 H), 7.61- 7.71 (m, 2H), 7.88 (d, J =7.3 Hz, 1 H), 8.13 (dd, J =
1.3, 8.0 Hz, 1 H), 9.29 (dd, J = 1.3, 8.0 Hz, 1 H), 10.28 (s, 1 H). GCMS: 200 The following compounds were prepared according to the general procedure for the synthe-sis of alkylidene hydrazones from the condensation of 1-formyl-4-(2-hydroxyethyl) naphtha-lene (from step D) with 4-hydroxy benzoic acid hydrazides.
EXAMPLE 118:
o w I off I~ H
HO
CI
'H NMR (DMSO-D6) 8 = 3.25 (t, J = 6.5 Hz, 2H), 3.73 (dt, J =J'=6.5 Hz, 2H}, 4.84 (t, J = 6.5 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 7.49 (d, J = 7.4 Hz, 1 H}, 7.60 - 7.68 (m, 2H), 7.80 (dd, J =
1.8, 7.4 Hz, 1 H), 7.84 (d, J = 7.3 Hz, 1 H), 8.00 (d, J = 1.8 Hz, 1 H), 9.19 (d, J = 6.7 Hz, 1 H), 8.85 (d, J = 7.7 Hz, 1 H), 9.05 (s, 1 H), 10.98 {s, 1 H), 11.76 (s, 1 H); MS
(APCI, pos.): 369.4, 371.2.
EXAMPLE 119:
o ~ I off .N. w I
I ~ 'H
HO ~ C7 CI
'H NMR (DMSO-D6) 8 = 3.18 (t, J = 7.0 Hz, 1 H), 3.25 (t, J = 7.0 Hz, 1 H), 3.65 (dd, J = 7.0 Hz, 1 H), 3.74 (dd, J = 5.3, 7.0 Hz, 1 H), 4.74 (t, J = 5.3 Hz, 0.5H}, 4.79 (t, J = 5.3 Hz, 0.5H), 7.04 (d, J = 8.3 Hz, 0.5H), 7.05 (d, J = 8.3 Hz, 0.5H), 7.25 (d, J = 8.3 Hz, 0.5H), 7.28 (d, J =
8.3 Hz, 0.5H}, 7.38 (d, J = 7.4 Hz, 0.5H), 7.43 (d, J = 8.4 Hz, 0.5H), 7.47 -7.57 (m, 1.5H), 7.61-7.72 (m, 1 H), 7.82 (d, J = 7.2 Hz, 0.5H), 8.10 (d, J = 8.6 Hz, 0.5H), 8.19 (dd, J = 2.2, 7.2 Hz, 0.5H), 8.45 (d, J = 8.6 Hz, 0.5H), 8.48 (s, 0.5H), 8.85 (s, 0.5H), 8.87 (dd, J = 2.2, 6.5 Hz, 0.5H), 11.00 (s, 0.5H), 11.15 (s, 0.5H), 11.86 (s, 0.5H), 11.92 (s, 0.5H);
MS (APCI, pos.): 403.4, 405.2, 406.1.
Preparation of acylhydrazones of 4-hydroxymethylnaphthaldehyde:
O OH OH O H
A ~ ~ B
I ~ ~ ---~ I ~
HO ~O HO HO
Step A:
The 1,4-Naphthalenedicarboxylic acid (25 g, 116 mmol) was dripped into a mixture of Lithi-um Aluminum Hydride (15 g, 395 mmol) in 600 mL of anhydrous THF and refluxed for two 1o days. The mixture was cooled in an ice bath and excess LAH was decomposed by the slow addition of methanol followed by ice chips. THF was removed under vacuum and the residue was acidified with 1 N HCI. The product was extracted with ethyl acetate (3x), washed with aqueous sodium bicarbonate (3x), water, brine, and dried over magnesium sulfate. 1,4-Bishydroxymethyfnaphthalene (70%) was obtained as a solid after evaporation of the solvent ~ 5 and can be used in the subsequent oxidation step without further purification. A portion of the material was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) for characterization purposes.
'H NMR (DMSO-D6): 8 5.19 (s, 4H), 7.77 (m, 4H), 8.32 (m, 2H).
Step B:
To a solution of 1,4-bishydroxymethylnaphthalene (12 g, 65 mmol) in ethyl acetate (300 ml) was added manganese dioxide ( 28 g, 325 mmol). After stirring for 45 minutes most of the starting material had disappeared and two new spots (mono aldehyde and dialdehyde) were seen on TLC. The upper spot corresponds to the dialdehyde. The mixture was passed through a bed of Celite and eluted with additional volumes of ethyl acetate.
The solvent was evaporated and 4-hydroxymethylnaphthaldehyde was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) in 50% yield.
H NMR (DMSO-D6): 8 5.19 (s, 2H), 5.71 (brd s, 1 H}, 7.73 (t, 1 H), 7.78 (t, 1 H), 7.95 (d, 1 H), 8.26 (m, 2H), 9.34 (d, 1 H), 10.46 (s, 1 H).
Examples of products employing the above aldehyde:
EXAMPLE 120:
I
o ~ I off .N~ ~
I ~ 'H
HO
N
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-cyano-hydroxybenzoic acid hydrazide.
'H NMR {DMSO-D6): 8 5.02 (s, 2H), 5.44 (s, 1 H), 7.14 (d, 1 H), 7.69 (m, 3H), 7.91 (d, 1 H), 8.10 (d, 1 H), 8.14 (d, 1 H), 8.27 {s, 1 H), 8.87 (d, 1 H), 9.06 (s, 1 H), 11.84 (brd s, 2H); MS
(ACPI): 346.3, 347.2.
EXAMPLE 121:
I
o ~ I off .N~ ~
I , H
HO
CI
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-chloro-4 hydroxybenzoic acid hydrazide.
'H NMR (DMSO-D6): b 5.02 (s, 2H), 5.43 (t, 1 H), 7.10 (d, 1 H), 7.66 (m, 3H}, 7.80 (d, 1 H), 7.90 (d, 1 H), 8.02 (s, 1 H), 8.15 (d, 1 H), 8.87 (d, 1 H), 9.08 (s, 1 H), 10.98 (s, 1 H), 11. 79 (s, 1 H); MS (APCI): 355.5 EXAMPLE 122:
I
o ~ I off .N. w I ~ H
HO
F
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-fluoro-4-hydroxybenzoic acid hydrazide.
'H NMR (DMSO-Ds): d4.84 (s, 2H), 6.91 (t, 1 H), 7.43-7.53 (m, 4H), 7.62 (d, 1 H), 7.72 (d, 1 H), 7.96 (d, 1 H), 8.68 (d, 1 H), 8.98 (s, 1 H), 11.71 (brd s, 1 H); MS
(APCI): 339.4, 340.3.
The compounds of formula II can also be prepared by parallel synthesis using the protocol mentioned above in a combinatorial approach. Thousands of compounds of formula II can thus be prepared by this combinatorial approach which can be semi- or fully automated. The auto-mation of this protocol can be performed using solution phase combinatorial chemistry in e.g. a 96 well setup using an automated synthesizer device. In the first step of the synthesis the al-dehydes or ketones may be prepared according to Scheme II by a combination of a selected number of aldehydes or ketones with a selected number of alkylating reagents.
In the second step the formed aldehydes/ketones can be combined with a selected number of the hydrazides (which may be synthesized according to Scheme I) thereby generating a predetermined very large number of compounds as single entities.
The synthesized compounds mentioned above are examples of such compounds that can be prepared using this combinatorial methodology.
By application of the above methodology, the following compounds may also be synthesized:
EXAMPLE 123:
OMe HO / \ O / \
C7 HTN / \ O \ / OCF3 H
EXAMPLE 124:
HO / \ O / \
CI H ~ / \ O \ / OCF3 H
EXAMPLE 125:
F
HO / \ O / \
v CI H N / \ O \ / OCF3 H
EXAMPLE 126:
CI
HO / \ O / \
CI H N / \ O \ / OCF
H
EXAMPLE 127:
O
HO ~ ~ CI CH3 CI H N ~ ~ O ~ ~ CH3 H
Cl EXAMPLE 128:
O
HO ~ ~ CH3 CH3 CI H ~ ~ ~ O \ / CH
H
EXAMPLE 129:
O
HO ~ ~ C02H CH3 CI H N ~ ~ O \ / CH
H
EXAMPLE 130:
HO ~ ~ OJ CH3 N-N
CI H ~ ~ ~ O \ / CH
H
EXAMPLE 131:
O H
HO / \ CH3 N-CI H \ / CH3 O-~
COZH
EXAMPLE 132:
O
HO / \ Me0 CH3 CI~ H \ ~ ~ O ~ ~ CH3 H
CI
EXAMPLE 133:
O
CHFZ ~ ~ OMe CH3 H N ~ ~ O \ / CH
H
OMe EXAMPLE 134:
O
N / ~ OMe CH3 Me0 H N ~ ~ O \ / CH
H
OMe EXAMPLE 135:
O
N
Me0 H \ ~ ~ O
H
EXAMPLE 136:
N O
Me0 ~ \ OMe CH3 H N ~ ~ O \ / CH
H
OMe EXAMPLE 137:
i O
OMe CH3 H N / ~ O \ / CN
H
OMe EXAMPLE 138:
O
HO / ~ OMe CH3 H \ / ~ O ~ / CH
H
OMe EXAMPLE 139:
CHFZ / ~ O
H' \ / ~ O ~ / OCF3 H
EXAMPLE 140:
HO / ~ O ~ O
CI H N / ~ O ~ / OCF3 H
EXAMPLE 141:
HO / ~ o /
f'N"I N / ~ O ~ / OCF3 H
EXAMPLE 142:
HO ~ ~ O
v Cl H N ~ ~ O ~ ~ N(Et)z H
General procedure for the synthesis of further derivatized hvdrazides of formula II' The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme 111, that is, by converting an alkylidene hydrazide {prepared according to the general method shown in Scheme I, and more specifically as in example 8) into a further derivatized alkylidene hydraz-ide. Thus, by reacting an amine with an alkylidene hydrazide that contains a leaving group X~
(Scheme III) a new alkylidene hydrazide containing an amine in the group K of formula II can be formed.
SCHEME III
O Rsa ,r,~~H-N~(CHz)~ B-O--(CHZ}e CHR3a (CHZ)a X~ ~-(CHz)a D
Ra solvent, base O Rsa A~N-N~(CHz)~ B-O-(CHZ)b CHR3a (CHZ)a N-(CH )-p H R, 2 d wherein A, B, D, n, R° , R3a a, b and d are as defined for formula I
and R5a is lower alkyl.
Specific examples illustrating the preparation of further derivatized hydrazides of formula II are provided below:
EXAMPLE 143:
~Chloro-4-hyrdroxyrbenzoic acid ~4-(2-[~2-N.N-diethylaminoethyl)-N'-(4-trifluoromethoxv-benzyrlamino)]]ethoxy -1-naph_th_ylmethylene)hydrazide o / ~ o~N
\ N~N \ \ I / OCF
/ H \ N
HO
N,N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine:
N~N~CH3 ~CH3 A solution of (4-trifluoromethoxy)benzaldehyde (1.9 g, 10 mmoles), N,N-diethylethylene-diamine (1.16 g, 10 mmoles), zinc chloride (1.36 g, 10 mmoles) and sodium cyanoborohy-dride (1.26 g, 20 mmoies) in methanol (10 mL) in a dry 100 mL round- bottom flask was stirred at room temperature for 8 hours. Water (20 mL) was then added and most of the methanol was removed in vacuo. The residue was distributed between ethyl acetate and 1 N
HCI. The acidic aqueous phase was basified with excess of sodium hydroxide.
Crude N,N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine was obtained. The crude product was used in the following reaction without further purification.
MS (Ci): 291. 'H NMR (CDC13): 8 7.4 (m, 2H), 7.2 (m, 2H), 3.9 (bs, 2H), 3.1-2.6 (m, 9H), 1.4-1.1 (t, 6H).
To a flask containing N,N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine (0.29 g, 1 2o mmole) in DMF (5 mL) was added [1-(4-chloroethoxy)naphthyl](3-chloro-4-hydroxy)benzoic acid hydrazide (0.41 g, 1 mmole) and triethylamine (0.1 g, 1 mmole). The resulting solution was heated at 80°C overnight. Removal of most of the solvent 6n vacuQ
followed by flash chromatography (10:1 CHCl3/MeOH) on silica gel provided the title compound as a brown solid.
'HNMR (DMSO-ds): 8 11.7 (1 H), 9.0 bs, 2H), 8.4-7.0 (m, 12 H), 4.75 (bs, 1 H), 4.65 (bs, 1 H), 4.55 (t, 1 H), 4.35 (t, 1 H), 4.15 (t, 1 H), 3.9 (bs, 1 H), 3.5 (q, 4H), 3.05 (t, 1 H), 1.3 (t, 3H), 0.95 (t, 3H). M.p.: 134-136°C. MS (CI): 657, 659.
EXAMPLE 144:
3-Chloro-4-hvdroxvbenzoic acid f4-f2-(4-trifluoromethoxy ben laminoethoxv]-1-naphthyl methylene}hydrazide O
H
N H-N
HO / /
CI ~ /
~NH
O
To a flask containing 4-trifluoromethoxybenzylamine (0.29 g, 1 mmole) in DMF
(5 mL) was added 3-chloro-4-hydroxybenzoic acid [4-(2-chloroethoxy}-1-naphthyfmethylene]hydrazide (0.403g, 1 mmole) and triethylamine (0.1 g, 1 mmole). The resulting solution was heated at 80°C for 16 hours. Removal of most of the solvent in vacuo, followed by flash chromatogra-phy (10:1 CHCI~/MeOH) on silica gel provided the title confound as a brown solid.
'HNMR (DMSO-ds): 8 11.6 (s, 1 H}, 9.0 (m 2H), 8.3 (m 1 H), 8.0 (m,1 H), 7.8 (s, 2H), 7.7 (m,1 H), 7.6 (m, 1 H), 7.5 (m, 3H), 7.3 (m, 2H), 7.1 (m, 2H), 4.3 (t, 2H), 3.9 (s, 2H), 3.0 (t, 2H).
MS (CI): 557, 559.
By application of the above methodology the following compounds of the invention were syn-thesized:
EXAMPLE 145:
3-Chloro-4.-h roxybenzoic acid {3 5-dimethoxy-4-[2~4-trifluoromethoxybenzylaminol-1 H NMR (CD30D): 8 2.90 (brd t, 2H), 3.75 (s, 6H), 3.89 (s, 2H), 4.08 (brd t, 2H), 6.87 (d, 1 H), 7.10 (s, 2H), 7.20 {d, 2H), 7.43 (d, 2H), 7.65 (m, 1 H), 7.82 (m, 1 H), 8.11 (brd s, 1 H); MS
(APCI): 567.9.
EXAMPLE 146:
3 Chloro-4 hxdroxy,4enzoic acid {4-f2-(2-Qir~eridin-1-yl-ethyl~)ethox~rh hn th-1 H NMR (DMSO-de): 8 1.53 (m, 2H), 1.74 (m, 4H), 3.12 {m, 2H), 3.40 (m, 2H), 3.54 (m, 2H), 3.63 (m, 4H), 4.52 (s, 2H), 7.10 (d,1 H), 7.14 (d, 1 H), 7.60 (t, 1 H), 7.71 (m,1 H), 7.80 (dd, 1 H), 7.83 (d, 1 H), 8.00 (d,1 H), 8.51 (d, 1 H), 8.95 (d, 1 H), 8.98 (s, 1 H), 11.69 (s,1 H); MS (APCI):
495.0 EXAMPLE 147:
'~ Chloro-4 h~rdro enzoic acid ~;4 f2-(3-diethylaminooroQyl~mino)ethoxy]na hn th-1-ylmethylen ~hvdrazide tho benzylidene~ r ' a yimeth~rlen~hvdrazide O ~ \ O\/\H~N~CH~
\ N ' \ _CH3 / /
HO
CI
1 H NMR (DMSO-ds): b 1.21 (t, 6H), 2.10 (m, 2H), 3.14 (m, 10H), 4.52 (t, 2H), 7.10 (d, 1 H), 7.14 (d, 1 H), 7.63 (t, 1 H), 7.73 (m, 1 H), 7.80 (dd, 1 H), 7.84 (d, 1 H), 8.00 (d, 1 H), 8.46 (d,1 H), 8.93 (s,1 H), 8.98 (m, 1 H), 9.20 (m, 2H), 9.69 (m, 1 H), 11.00 (s, 1 H), 11.69 (s, 1 H);
MS (APCI): 497Ø
EXAMPLE 148:
1-l2-{4-[~(3-Chloro-4-hydroxybenzoyl)l7,ydrazonomethyllr~~ th-1-v I,Ly}ethyl)-~ henytamino~~~iiceridine-4-carboxyrlic acid amide 1 H NMR (DMSO-ds): 8 1.16 (m, 2 H), 1.88 (m, 2H), 2.03 (m, 2H), 2.80 (m, 2H), 2.92 (m, 2H), 4.37 (m, 2 H), 4.40 (brd s, 2H), 4.44 (s, 1 H), 6.55 - 6.62 (m, 3 H), 6.96 (s,1 H), 7.03 7.16 (m, 5H), 7.61 (dd, 1 H), 7.68 (dd,1 H), 8.00 (d, 1 H), 8.27 (d, 1 H), 8.94 (s,1 H), 8.97 (s, 1 H), 11.63 (s, 1 H); MS (APCI): 586.4 EXAMPLE 149:
4-(2-{4-[(3-Chloro-4-h dY rox)rbenzoyllhvdrazonomethyl]na hp th-1-v I~y}ethylamino~piperidine 1-carboxylic acid ethyl ester 1H NMR (DMSO-ds): 81,10 (t, 3H), 1.15- 1.23 (m, 2H), 1.86 (m, 2H}, 2.79 (m, 3H), 3.30 (m, 2H), 3.87 (m, 2H), 3.94 (q, 2H), 4.28 (m, 2H), 7.03 (d,1 H), 7.05 (m, 1 H), 7.51 - 7.63 (m, 3H), 7.13 (d, 1 H), 7.75 (m,1 H), 7.93 (d, 1 H), 8.29 (d,1 H), 8.87 (m,2 H), 11.55 (s, 1 H); MS
(APCI): 539.1, 541Ø
EXAMPLE 150:
o -4-h n of a i 4-t tr dron hth-1- f i th x - ht -1-ylmethylene}hvdrazide 1 H NMR (DMSO-ds): 8 1.76 (m, 1 H), 2.04 (m, 1 H), 2.17 (m, 2H), 2.75 - 2.94 (m, 2H), 3.61 (m, 2H), 4.55 (m,2H), 4.71 (s, 1 H), 7.11 (d, 1 H), 7.13 (d, 1 H), 7.23 - 7.35 (m, 3H), 7.61 {d, 1 H), 7.67 (d,1 H), 7.71 (dd, 1 H), 7.81 (dd, 1 H), 7.86 (d, 1 H), 8.01 (d, 1 H), 8.48 (d, 1 H), 8.94 (m, 1 H), 8.99 (m, 1 H), 9.22 (m, 2H), 11.00 (s,1 H), 11.64 (s,1 H); MS
(APCI): 514.0, 516.0 EXAMPLE 151:
1- 2- 4- hl r -h r I h az n th I na hth-1- lox th I i ri i -4-carbox~ic acid amide o \ ~N
\ Ni ~ I \ NHs H
/ I / O
HO
CI
MS (APCI): 495.0 EXAMPLE 152:
-Chl r -h r i 4- th I i o - th -1-n th I-methylene~hydrazide O
HO / \ / \ N OCF3 CI \H N /
H
EXAMPLE 153:
3-Chloro-4-hydroxybenzoic acid {4-f2-(4-morpholinylethv lamino)ethoxyj-1-naphthKmethylenPl-hydrazide HO / ~ O /
H_N ~ O
ci \ / \ p H
By application of the above methodology the following compounds may also be synthezised:
EXAMPLE 154:
O H
HO / ~ / ~ ~N \ / CF3 CI \H N /
H
EXAMPLE 155:
~N(Et)Z
/\O
HO / \ / \ N \~/ CF3 H N / \
CI O
H
EXAMPLE 156:
~N(Et)2 HO / \ p / \ N
CI \H N / \ / \
H
EXAMPLE 157:
~~~tt~2 HO / \ O / \ N
CI \H \ / \ / \
H
EXAMPLE 158:
~N(Et)Z
/\O
HO / \ OMe v CI H ~ / \ C
H
OMe CH3 EXAMPLE 159:
~N(Et)2 \/O
HO ~ \ OMe N
F \H
H
OMe OCF3 EXAMPLE 160:
O
HO / \ OMe N
CI \H
O
H
OMe CH3 General procedures for the ~rer~aration of all~vlidene ark Isr ulfon~l hydrazides according to the invention The compounds of general formula I are prepared according to one embodiment of the inven-tion, the alkylidene arylsulfonyl hydrazides of general formula III, that is, by converting an aryl-sulfonyl halide, for example chloride or bromide to the corresponding hydrazide derivative and further reacting the product arylsulfonyl hydrazide compound with a substituted aldehydes or ketones to yield alkylidene arylsulfonyl hydrazide derivatives as illustrated in Scheme IV.
SCHEME IV
~O NHNHZ
A-S\ CI + NH2NH2 A-S~ O
O O
O
R~(CH2)" B (K)m D HN-N- (CHZ)~ B-(K)m D
A-Sv0 R4 solvent, reflux O
wherein A, B, K, D, m, n and R° are as defined for formula 1.
The synthesis of the arylsulfonylhydrazide precursors is performed by application of general methodology, for example as described by Friedman, L.; Litle, R.L; Reichle, W.
R, in Org.
Synth. Coll. Vol. V, 1973, 1055-1057, by slowly adding the arylsulfonyl chloride either neat, or in a solution in an inert solvent such as tetrahydrofuran, dimethyl ether, dioxane or diethyl ether to an excess of hydrazine, either neat or in solution in the one of the above solvents or a mix-0 ture of these at -20°C to 100°C, preferably between 0°C
to 60°C. When the reaction is judged to be completed, the excess of solvent and volatile reagents is removed by distillation either at atmospheric pressure or in vacuo. The residual product can be further purified by recrystalli-zation from a solvent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, water, toluene, acetic acid, dioxane, tetrahydrofuran or a mixture of two or more of the above solvents when ~ 5 compatible.
Alternatively, the product can be purified by column chromatography using dichloromethane/-methanol or chlorofom~/methanol or isopropyl alcohol as eluent. The corresponding fractions are concentrated either at atmospheric pressure or in vacuo to provide the pure arylsulfonyl 20 hydrazide.
By use of the above methodology the following compounds can be prepared:
EXAMPLE 161:
25 3-Chloro-4-hydroxybenzenesulfonic acid (benzylidene~t vdrazide O N~N- H
O
HO
C!
3-Chloro-4-hydroxybenzenesulfonyl hydrazide:
A solution of 4.82 g (21.2 mmol) 3-chloro-4-hydroxy-benzenesulfonyl chloride, (prepared ac-s cording to the procedure described by Popoff, I. C.; Frank, J. R.; Whitaker R. L.; Miller H. J., Demaree K. D. J. Agr. Food Chem. 1969, 77, 810.) in 15 ml THF was added dropwise with stirring to 3.4 ml 50% hydrazine hydrate (54.4 mmol, 2.5 eq.) at such a rate that the tem-perature is maintained below 10°C. A precipitate formed after the addition was completed.
The mixture was stirred for an additional 30 min, and cooled to 0 °C.
The solid was collected in a Buchner funnel, washed several times with distilled water, and air dried.
Recrystalliza-tion from methanol provided 1.20 g 3-chloro-4-hydroxybenzenesulfonyl hydrazide as a white solid.
H NMR (DMSO-d6): 8 4.78 (bs, 4 H), 6.72 (d, J = 8.6 Hz, 1 H), 7.35 (dd, J =
2.3, 8.6 Hz, 1 H), 5.55 ( J = 2.2 Hz, 1 H); MS(Cl): m/z 223, 221.
To a solution of 105 mg (0.48 mmol) of the above 3-chloro-4-hydroxybenzenesulfonyl hy-drazide in 5 ml methanol was added 0.05 ml {52 mg, 0.49 mmol) benzaldehyde and one drop of acetic acid. After 30 min the mixture was concentrated. Flash chromatography (silica gel, 2:1 hexane/ethylacetate) provided 67 mg (45%) of the title com ound as a solid.
1 H (DMSO-d6): 8 7.10 (d, J = 8.6 Hz, 1 H), 7.38 (m, 3 H), 7.55 (dd, J = 2.3, 6.0 Hz, 2 H), 7.66 (d, J = 2.2, 8.6 Hz, 1 H), 7.76 (d, J = 2.2 Hz, 1 H), 7.90 (s, 1 H), 11.3 (m, 2 H). MS(CI):
m/z 311.
EXAMPLE 162:
3-Chloro-4-hydroxy-benzenesulfonic acid j4-(4-trifluoromethoxvbenzyl~)-1-na~hthylmethXl_ene]hvdrazide HO / ~ S O /
O ~H-N / \ ~ / OCF3 CI O
H
To a solution of 3-chloro-4-hydroxy-benzene sulfonyl hydrazide (105 mg, 0.48 mmol) in 5 ml methanol was added 4-trifluoromethoxybenzyloxy-1-naphthaldehyde (163 mg, 0.49 mmol) and a catalytical amount of glacial acetic acid (5 drops). The reaction mixture was stirred overnight, and filtered. The filtrate was concentrated under vacuo to give the crude product. Flash chro-matography (silica gel, 1:1 hexane/ethylacetate) provided 145 mg (56%) of the title corn o~und_ as a solid.
'H NMR (DMSO-dfi) 8 5.27 (s, 2 H), 6.06 (s, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 2 H), 7.50 - 7.60 (m, 5 H), 7.80 (s, 1 H), 7.85 (dd, J = 3.0, 8.2 Hz, 1 H), 8.08 (d, J = 2.1 Hz, 1 H), 8.26 (s, 1 H), 8.36 (d, J = 7.76 Hz, 1 H), 8.67 (d, J = 8.5 Hz, 1 H).
CIMS m/z: 551, 553.
By using the above methodology, the following compounds may be prepared:
EXAMPLE 163:
HO / \ S O / \ CF3 ii ~
CI o H \ / ~ O
EXAMPLE 164:
HO / ~ S O /
_ ii ~
F ~ H N / ~ O ~ / CI
H
EXAMPLE 165:
O
HO / ~ S~ OMe ii ~
CI O H N ~ ~ O ~ / OCF3 H
OMe EXAMPLE 166:
O
HO / \ ~S\ OMe CI O H \ ~ ~ O ~ ~ CH
H
OMe S~rnthesis of alkylhKdrazides according to the invention' The alkylidene hydrazide derivatives given above can be reduced to the dihydroderivatives by the method given in Scheme V:
SCHEME V
H _ N N--~(CH2)" B (K)m NaBH3CN N H~(CH2)~ B-(K)m D
A \\ R ~ A \\ R4 O CF3C02H p where A, R4, B, K, D, m and n are as defined for formula I.
The alkylhydrazide derivatives can be prepared by reduction (i.e. Lane, C.F.(1975}, Synthesis, p.135) of the corresponding aikylidene hydrazides using a metal hydride, such as sodium bo-rohydride or sodium cyanoborohydride. The alkylidene hydrazide derivative is treated with between 1-10 equivalents, preferentially 1-3 equivalents, of sodium cyanoborohydride in a sol-vent such as methyl alcohol, ethyl alcohol, isopropyl alcohol, tetrahydrofuran, dioxane, water or a compatible mixture of two or more solvents. Optionally a small amount of an acid is used as a catalyst such as hydrochloric acid, trifluoroacetic acid, acetic acid, or sulfuric acid. The reac-tions are performed at 0°C to 60°C, preferably at 10°C to 30°C. When the reaction is complete as judged by HPLC or TLC (silica gel, 1 % methanol in dichloromethane as eluent) the sol-vents) are removed and the residue is chromatographed on a silica gel column using 1 methanol in dichloromethane or chloroform as an eluent. The corresponding fractions are con-1 o centrated to give the desired product. Specific examples illustrating the preparation of alkylhy-drazides according to the invention are provided below.
EXAMPLE 167:
4-hydroxvbenzoic acid (1-na~hthylmethyl)hydrazide /I
H
N
I ~ wHi HO
4-Hydroxybenzoic acid (1-naphthylmethylene)hydrazide (100 mg, 0.34 mmol) was dissolved in methanol (10 mL) and treated with sodium cyanoborohydride (236 mg, 4.1 mmol) followed by two drops of trifluoroacetic acid. After stirring the reaction solution for three hours at room temperature, the solvent was evaporated in vacuo. The residue was introduced into a silica gel column and eluted with dichloromethanelmethanol (9911 ). Evaporation of the corresponding fractions in vacuo gave the title compound in 30% yield. MS (ESI) m/z 293 (M+H)'.
Using the same methodology as described above the following compound was prepared:
EXAMPLE 168:
3-Chloro-4-h,~rdroxybenzoic acid N-[4-(4-iso r~o~ I~benzyloxy)-3.5-dimethoxybenzy]hydra-zide O
H
\ N/N
H
HO
C!
1 H NMR (DMSO-dfi): 8 1.18 (d, 6H), 2.87 {m, 1 H), 3.75 (s, 6H), 3.90 (m, 2H), 4.80 (s, 2H), 5.43 (brd s, 1 H), 6.68 (s, 2H), 6.98 (d, 1 H), 7.20 (d, 2H), 7.34 (d, 2H), 7.64 (dd, 1 H), 7.87 (d, 1 H), 9.89 (brd s, 1 H), 10.80 (s, 1 H); MS (APCI): 485.2.
Furthermore, the following compounds may also be prepared:
EXAMPLE 169:
HO / ~ O /
_H
CI H N / ~ O ~ / OCF3 EXAMPLE 170:
HO / ~ O H / ~ C
CI H N / ~ O \ / CH
EXAMPLE 171:
HO / ~ O H / ~ C
CI H N / ~ O \ / CH
EXAMPLE 172:
O
HO / ~ H OCH3 CI H N / ~ O ~ / OCF3 EXAMPLE 173:
HO / ~ H OCH3 CI H N / ~ O
General procedure for s~rnthesis of comrJOUnds of the general formula XI' O~B~OH ~- B~OCH3 ~ O Bw0 OCH3 step A ~ ~ step B
H O H O
O
A" ~NHz O
O~B~ ~ /OH
O ~~N B~ OH
H O step C A H ~ O
H I IO
O
NHRxR~
~ N B NRscRsa A"
step D
O
formula XI
A and B are as defined for formula I and -NRS'RS° is R''a Raa Reb -N-(CHZ)'~(CHZ)d D where Rsa, R<a, R4b, c, q, d and D are as defined for for-mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The reaction is known and is generally performed by stirring hydroxy benzaldehyde, hydroxy naphthaldehyde or the like together with a bromo acetic acid ester (either methyl, ethyl or other lower alkyl ester) in the presence of a base such as lithium, sodium, potassium or ce-sium carbonate in a solvent such as acetone, 2-methyl-3-pentanone, tetrahydrofuran, dioxane, DMSO, DMF, ethylene glycol, benzene, toluene or a mixture of the above solvents. The reac-tions are performed between 0°C to 130°C, preferably between 20°C to 100°C, most prefera-bly at or about the reflux temperature of the solvent. The reactions are preferably conducted under an inert atmosphere such as NZ or Ar. When the reaction is complete as judged by dis-appearance of the starting ester by TLC or HPLC, the solvent may be removed by concentra-tion at atmospheric or reduced pressure. The product can be further purified by either recrys-tallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xy-lene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloro-methane/methanol or chloroformlmethanoi or isopropyl alcohol as eluent.
Step B: The resulting derivative of acetic ester is then saponified using methods well-known to those skilled in the art such as dissolving the compound in an appropriate solvent such as a lower alcohol (e.g methanol, ethanol or isopropanol), DMF, dioxane or DMSO and adding an aqueous base like lithium, sodium or potassium hydroxide. The reactions are performed be-tween 0°C to 130°C, preferably between 20°C to 100°C. When the reaction is complete as judged by disappearance of the staring ester by TLC or HPLC, the solvent may be removed by concentration at atmospheric or reduced pressure. The product can then be isolated by pour-ing the residue into water or cooled water and acidifying the mixture using an inorganic acid such as hydrochloric acid or sulfuric acid. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure.
The product can be further purified by either recrystallization from a solvent such as ethyl alco-hol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethanelmethanol or chloroformlmethanol or isopropyl alcohol as eluent .
Step C: The resulting carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tent-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, di-chloromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethy-lorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further re-crystallized if necessary from a solvent such as the above described reaction solvents. The product can also be isolated by concentration of the reaction mixture iLvacuo, followed by col-umn chromatography on silica gel using a solvent system such as chloroform/methanol or di-chloromethanelmethanol or chloroformlethyl acetate.
Step D: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an an-hydride or an acid halide that can then react with the amine to give a compound of formula XI.
Step D can also be done combinatorially with a selected number of amines. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, tolu-ene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hex-ane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloro-methanelmethanol or chloroformlmethanol or isopropyl alcohol as eluent giving a compound of formula XI.
Specific examples illustrating the preparation of compounds of the general formula XI ac-cording to the invention are provided below.
EXAMPLE 174:
2-{4-(f3-Chloro-4-hydroxy-benzoyl)~ydrazonomethy]na~ht~rl-1~loxy}~4 chloro phen_yl)acetamide cl ~ ~ / I
O / O~N \
H
,N ~ \
H
\ \N
HO / \
CI
Step A: Hydroxynaphthaldehyde (10 g, 58 mmol), potassium carbonate (16 g, 110 mmol), and methyl bromoacetate (16 g, 100 mmof) were refluxed in acetone (120 mL) overnight.
The reaction mixture was poured into an Erlenmeyer flask containing approximately 500 mL
of ice chips. The mixture was stirred until all of the ice was melted. (4-Formylnaphth-1-yloxy) 1o acetic acid methyl ester (13 g, 50 mmol) was filtered and dried in vacuo overnight.
1 H NMR (CDCi3): 8 3.86 (s, 3H), 4.93 (s, 2H), 6.80 (d, 1 H), 7.61 (t, 1 H), 7.72 (t, 1 H), 7.90 (d, 1 H), 8.42 (d, 1 H), 9.29 (d, 1 H), 10.22 (s, 1 H).
Step B: The above ester (13 g, 50 mmol) was dissolved in methanol (100 mL) and NaOH (40 mL) was added. The reaction solution was stirred overnight and concentrated to approximately 100 mL under vacuo. The residue was poured into approximately 500 mL of ice chips and the mixture was acidified (by pH paper) with the addition of 3N
HCI. The mix-ture was stirred until afl of the ice was melted. (4-Formyinaphth-1-yloxy) acetic acid was filtered and washed with water.
Step C: To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (2g, 10.7 mmol) in DMSO (20 mL) was added the above (4-formylnaphth-1-yloxy) acetic acid (3g, 13 mmol) and a catalytic amount of acetic acid (10 drops). The solution was stirred overnight and diluted with ethyl acetate. The solution was washed with water (3x), brine, and dried over MgS04.
The volume was reduced to approximately 100 mL and placed in an ice-bath. The resulting solid was filtered and washed with cold ethyl acetate to afford {4-[(3-chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphth-1-yloxy) acetic acid.
1 H NMR (DMSO-ds): 8 4.91 (s, 2H), 6.95 (d, 1 H), 7.02 (d, 1 H), 7.55 (t, 1 H), 7.64 (t, 1 H), 7.74 (d, 1 H), 7.92 (d, 1 H), 8.27 (d, 1 H), 8.90 (m, 2H), 10.92 (brd s, 1 H), 11.63 (s, 1 H), 13.14 (brd s, 1 H).
Step D: To a solution of the hydrazone-carboxylic acid {50 mmol) in anhydrous DMSO was added a solution of carbonyldiimidazole (55 mmol) in anhydrous DMSO. After the evolution of gases ceased (approximately 3-4 minutes), the amine was added and the reaction mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate and washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent afforded the crude material, which was purified by reverse phase HPLC chromatography to give the title com-,~ oa und.
1 H NMR (DMSO-d6): 8 4.99 (s, 2H), 7.04 (m, 2H), 7.36 (d, 2H}, 7.65 (m, 4H), 7.79 (t, 2H), 7.99 (s, 1 H), 8.40 (d, 1 H), 8.72 (s, 1 H), 8.92 (d, 1 H), 10.42 (s, 1 H), 10.96 (s, 1 H), 11.69 (s, 1 H); MS (APCI): 507.9.
By using the same methodology, the following compounds were prepared:
2o EXAMPLE 175:
1~(1-Benz vrrolidip-3-yl}-2-{4-[(3-chloro-4-hydroxy-benzoyl)h~rdrazonomethyllna hp th-1-O / I H
\ N~N ~ \
H
/ \
HO
CI
1 H NMR (DMSO-ds): 8 1.96 (m, 2H), 2.32 (m, 5H), 4.58 (s, 2H), 6.78 (d, 1 H), 6.92 (d, 1 H), 7.15 (m, 5H), 7.47 (t, 1 H), 7.52 {t, 1 H), 7.62 (d, 2H), 7.82 (d, 1 H), 8.18 (m, ZH), 8.78 (d, 2H), 10.75 (brd s, 1 H), 11.52 (s, 1 H); MS (APCI): 556.9.
EXAMPLE 176:
- 4- hl -4.-h r o I h z m th I n hth-1- I x -N-in -1- I- t id 1 H NMR (DMSO-d6): b 1.94 (m, 1 H), 2.40 (m, 1 H), 2.80-3.07 (m, 3H), 4.87 (s, 2H), 7.04 (d, 1 H), 7.10 (d, 1 H), 7.21 (m, 4H), 7.61 (t, 1 H), 7.69 (t, 1 H), 7.80 (t, 2H), 8.10 (s, 1 H), 8.42 (d, 1 H), 8.64 (d, 1 H), 8.98 (m, 2H), 11.00 (brd s, 1 H), 11.68 (s, 1 H); MS
(APCI): 514, 516.
EXAMPLE 177:
2-d4-fl3-Chloro-4-hydroxybenzoyl)hxdrazonomethyi]naphth 1 yloxy} N~1 2 3 4 tetrahy~o_ n_a~phthalen-1-yl)acPtamide 1H NMR (DMSO-ds): 8 1.75 (m, 2H), 1.92 (m, 2H), 2.74 (m, 2H), 4.87 (m, 2H), 5.12 (m, 1H), 7.12 (m, 6H), 7.61 (t, 1 H), 7.74 (t, 1 H), 7.84 (m, 2H), 8.01 (s, 1 H), 8.40 (d, 1 H), 8.62 (d, 1 H), 8.97 (m, 2H), 11.72 (s, 1 H); MS (APCI): 528, 530.
EXAMPLE 178:
2-{4-[(3-Chloro-4-hxdroxv bi enzoyl)hydrazonomethylj~~ h~ th-1-yloxy;~-N-(2-(4 chloro enyl)ethyl~acetamide 1 H NMR {DMSO-dfi): 8 2.40 (t, 2H), 2.79 (t, 2H), 4.74 (s, 2H), 6.96 (d, 1 H), 7.10 (d, 1 H), 7.63 (t, 1 H), 7.69 {t, 1 H), 7.72 (m, 2H), 7.81 (s, 1 H), 8.01 (m, 2H), 8.23 (t, 1 H), 8.40 (d, 1 H), 8.95 (s, 1 H), 9.01 (d, 1 H), 10.98 (brd s, 1 H), 11.70 (s, 1 H); MS (APCI) 538.8, 537.8.
EXAMPLE 179:
- 4- h r b n 1 -1- I -N- I i r zin-1-yl)I~ro~yl]acetamidg O ~ O~N~N
H
N\ \
\ N/ ~ wCHs H
HO
1 H NMR (DMSO-de): b 1.50 (m, 2H), 2.26 (m, 2H), 2.48 (m, 5H), 3.01 (m, 8H), 4.53 (s, 2H), 6.78 (d, 1 H), 6.89 (d, 1 H), 7.38 (t, 1 H), 7.47 (t, 1 H), 7.5 (t, 2H), 7.76 (d, 1 H), 8.01 (t, 1 H), 8.22 (d, 1 H), 8.68 (d, 1 H), 8.74 (s, 1 H), 10.74 (brd s, 1 H), 11.45 (s, 1 H); MS (APCI): 538Ø
EXAMPLE 180:
3-Chloro-4-hydroxybenzoic acid ~[4-[2-~1 2 3 4-tetrahydroiso~uinolin-2-yIZ2-oxoethoxv'd~
naphth-1 ~rtmethylene~h vdrazide 1 H NMR (DMSO-ds): b 2.90 (d, 2H), 2.75 (m, 2H), 4.70 (d, 2H), 5.24 (s, 2H), 6.90 (t, 2H), 7.10 (m, 4H), 7.66 (m, 4H), 8.01 (s, 1 H), 8.34 (t, 1 H), 8.95 (m, 2H), 10.97 (brd s, 1 H), 11.68 (brd s, 1 H); MS (APCI): 514.2.
EXAMPLE 181:
2-~4-f(3-Chloro-4-hvdroxv-benzoyl)hydrazonomethyl]n~ h 1 loxy) N~3 trifluoromethox~rbenzyl)acetamide ,N
N
H
HO
CI
~ H NMR (DMSO-ds): 8 4.49 (d, 2H), 4.90 (s, 2H), 7.13 (m, 2H), 7.42 (m, 4H), 7.59 (dd, 1 H), 7.68 (dd, 1 H), 7.78 (m, 2H), 8.03 (s, 1 H), 8.51 (d, 1 H), 8.79 (t, 1 H), 9.0 (m, 2H), 10.85 (brd s, 1 H), 11.72 (s, 1 H); MS (APCI): 572.1.
EXAMPLE 182:
3-Chloro-4-hvdroxvbenzoic acid (4-~2-[4-(4-bromo hen~rl,Lhydrox~rp~eridin 1 yl] 2 oxoethoxy)naphth-1_ylmethylene~~dra~ide o~
o ~ I N
~N ~ \ OH
\ ~N
H \ ~ ~ \
HO
CI Br MS (APCI): 636, 638.
EXAMPLE 183:
2-{4-[(3-Chloro-4-hydroxvbenzoyl)hydrazonomethylJnal ht~ h-1-yloxy}-N~4-triffuoromethylsulfanylbenzyl)acetamide ci 1H NMR (DMSO-ds): 8 4.48 (d, 2H}, 4.88 (s, 2H), 7.08 (m, 2H), 7.45 (d, 2H), 7.68 (m, 4H}, 7.82 (m, 2H), 8.01 (d, 1 H), 8.52 (d, 1 H), 8.87 (t, 1 H), 8.96 (s, 1 H), 9.01 (d, 1 H), 10.98 (brd s, 1 H), 11.72 (s, 1 H}; MS (APCI): 588.2 dichlorobenz~,.[~acetamide EXAMPLE 184:
2-~~4-[(3-Chloro-4-hydroxy-benzoyl)hydrazonometh~rl]nai ht~ h-1-y~xy}-N (3 4 O / O~N \ CI
H
\ N/N \ \ ~ ~ ~ CI
H
i \
HO
CI
1 H NMR (DMSO-d6): 8 4.42 (d, 2H), 4.91 (s, 2H), 7.08 (d, 1 H), 7.11 (d, 1 H), 7.22 (d, 1 H), 7.48 - 7.76 (m, 4H), 7.82 (d, 2H), 8.04 (d, 1 H), 8.51 (dd, 1 H), 8.83 (m, 1 H), 8.91 (s, 1 H), 10.02 (d, 1 H), 11.00 (brd s, 1 H), 11.73 (s, 1 H); MS (APCI): 556.0 EXAMPLE 185:
O \ I O~N
.N. w I ~N~CH3 -N
HO I ~ H CH3 CI
'H NMR (DMSO-D6): 8 0.97 (d, 6H), 2.42 (m, 2H), 2.50 (m, 2H), 2.68 (septet, 1 H), 3.49 (m, 4H), 5.12 (s, 2H), 7.03 (d, 1 H), 7.08 (d, 1 H), 7.60 (t, 1 H), 7.68 (t, 1 H), 7.80 (d, 2H), 8.01 (d, 1 H), 8.33 (d, 1 H), 8.94 (s, 1 H), 9.00 (d, 1 H), 11.68 (s, 1 H); MS (APCI, neg.): 507.1, 509.1.
EXAMPLE 186:
O w ~ O~N~N_CH3 .N~ \ I CHI
I H
HO
CI
'H NMR (DMSO-D6): b 1.75 (m, 2H), 2.25 (m, 2H), 2.24 (d, 3H), 2.39 (quintet, 1 H), 3.26 (m, 2H), [2.84 (s, 1.5H) + 3.04 (s, 1.5H), 3HJ, 5.16 (d, 2H), 6.72 (t, 1 H), 7.07 (d, 1 H), 7.62 (t, 1 H), 7.68 (t, 1 H), 7.78 (dd, 2H), 8.00 (d, 1 H), 8.34 (m, 1 H), 8.94 (s, 1 H}, 9.00 (d, 1 H), 11.65 (brd s, 1,H); MS (APCI): 495.2, 497.2.
EXAMPLE 187:
0'I
0 ~ I O~N
N.N ~ ~ I ~CH
I~ H
HO
CI
'H NMR (DMSO-DB): 8 0.86 (s, 3H), 1.48 (m, 4H), 2.38 (t, 1 H), 2.72 (m, 1 H), 3.09 (t, 1 H), 3.84 (t, 1 H), 4.18 (t, 1 H), 5.09 (m, 2H), 7.03 (d, 1 H), 7.11 (d, 1 H), 7.59 (t, 1 H), 7.64 (t, 1 H), 7.82 (d, 2H), 8.01 (s, 1 H), 8.33 (d, 1 H}, 8.94 (s, 1 H), 9.00 (d, 1 H), 11.0 (brd, 1 H), 11.69 (brd s, 1 H); MS {APCI): 480.1, 482.1.
EXAMPLE 188:
o ~ I o~N ,N I
.N ~ W I CH3 I~ H
HO
CI
'H NMR (DMSO-De): 8 2.88 (s, 1.5H) + (s, 1.5H), 3H], 2.95 (t, 1 H}, 3.01 (s, 1.5H), 3.10 (s, 1.5H), 3.10 (t, 1 H), 3.69 (t, 1 H), 3.81 (t, 1 H), 5.05 (d, 2H), [6.66 + 6.95 (d), 1 H], 7.10 (d, 1 H), [7.20 + 7.38 (d), 1 H], 7.29 (d, 1 H), 7.67 (m, 5H), 8.01 (s, 1 H), 8.30 (t, 1 H), 8.53 (dd, 1 H), 8.97 (m, 2H), 11.67 (brd s, 1 H); MS (APCI): 517.3, 519.2.
EXAMPLE 189:
OMe O~ \ I OH
0 ~ ( H CI
H~N' \ OMe HO
CI
'H NMR (DMSO-D6): b 3.88 (s, 6H), 4.75 (s, 2H), 6.93 (d, 1 H), 7.08 (m, 3H), 7.34 (dd, 1 H), 7.74 (dd, 1 H), 7.79 (d, 1 H), 7.95 (s, 1 H), 8.37 (s, 1 H), 9.74 (s, 1 H), 10.03 (m, 1 H), 10.96 (brd s, 1 H), 11.76 (brd s, 1 H); MS (APCI): 534.4, 536.2.
EXAMPLE 190:
O ~ CH3 O Me0 ~ O~N w I
.N~ ~ I H
I , H
HO
CI
'H NMR (DMSO-D6): 8 1.18 (d, 6H), 2.85 (m, 1 H), 3.87 (s, 3H), 4.76 (s, 2H), 6.71 (d, 1 H), 6.78 (d, 1 H), 7.06 (d, 1 H), 7.20 (d, 2H), 7.58 (d, 2H), 7.78 (dd, 1 H), 7.82 (d, 1 H), 7.99 (d, 1 H), 8.70 (s, 1 H), 10.04 (s, 1 H), 10.92 (brd s, 1 H), 11.62 (brd s, 1 H);
MS (APCI): 496.5, 498.2.
EXAMPLE 191:
o ~ ocF, o w I o.~ N w I
.N. w I H
I ~ 'H
HO
CI
'H NMR (DMSO-D6): 8 4.88 (s, 2H), 6.93 (t, 2H), 7.23 (d, 2H), 7.47 - 7.70 (m, 6H), 7.86 (d, 1 H), 8.30 (d, 1 H), 8.80 (s, 1 H), 8.87 (d, 1 H), 10.34 (s, 1 H), 10.82 (brd s, 1 H), 11.55 (brd s, 1 H); MS (APC1): 558.5, 560Ø
EXAMPLE 192:
cl r~o o~ w I
o ~ i ~ Cr .N.
I H
HO
CI
'H NMR (DMSO-D6): b 4.06 (s, 3H), 4.94 (s, 2H), 6.81 (d, 1 H), 6.89 (s, 1 H), 7.19 (d, 1 H), 7.45 (s, 1 H), 7.90 (m, 3H), 8.10 (s, 1 H}, 8.82 (s, 1 H), 10.62 (s, 1 H), 11.07 (brd s, 1 H), 11.75 (s, 1 H); MS (APCI): 523.3, 524.8, 526.6.
EXAMPLE 193:
O w I O~N~N I i .N~ ~ I H
I ~ 'H
HO
Cr 'H NMR (DMSO-D6): 8 1.68 (m, 2H), 2.01 (m, 2H), 3.05 (m, 2H), 3.35 (m, 2H), 3.86 (m, 1 H), 4.26 (s, 2h), 4.81 (s, 2H), 6.95 (d, 1 H}, 7.09 (d, 1 H), 7.46 (s, 5H), 7.59 (m, 1 H}, 7.66 (t, 1 H), 7.77 (d, 1 H), 7.98 (d, 1 H), 8.34 (d, 1 H), 8.41 (d, 1 H), 8.92 (m, 2H), 9.65 (brd s, 1 H), 11.02 (brd s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 571.3, 572.3, 573.3.
EXAMPLE 194:
O ~ I O~N ~ I CI
.N~ ~ I H
I ~ 'H
HO
CI
'H NMR (DMSO-D6): 8 2.79 (t, 2H), 3.43 (qt, 2H), 4.71 (s, 2H), 6.95 (d, 1H), 7.08 (d, 1H), 7.17 (m, 1 H), 7.26 - 7.30 (m, 3H), 7.61 (t, 1 H), 7.67 (t, 1 H), 7.76 (m, 2H), 7.99 (d, 1 H), 8.24 (t, 1 H), 8.38 (d, 1 H), 8.91 (s, 1 H), 8.98 (d, 1 H), 10.94 (s, 1 H), 11.67 (s, 1 H); MS (APCI):
536.3, 538.2, 539.1.
EXAMPLE 195:
o ci w o ~l .N. w ~ H I , HO
Ci 'H NMR (DMSO-D6): 8 4.42 (d, 2H), 4.87 (s, 2H), 7.06 (m, 2H), 7.38 (d, 2H), 7.60 (t, 1H), 7.63 (m, 1 H), 7.80 (t, 1 H), 7.99 (d, 1 H), 8.49 (d, 1 H), 8.79 (t, 1 HJ), 8.93 (s, 1 H), 8.98 (d, 1 H), 10.95 (s, 1 H), 11.68 (s, 1 H); MS (APCI): 558.2, 560.1.
EXAMPLE 196:
4- 4-br m n I- 4- i i I t mi n ht -1- th i e- - hl r -4-by roxvbenzoic arid hvdrazone t o.
O H.N~ ~ i N
HO ~ I
Br Ruction scheme' C
H
N N N
OH ~ '' A OH B I w C
I I
i gr gr Br i O ,i O
w I I O.~N I --~ O w I I O~~N I
p ~ N.N. w 'H~ '' I ~ I ~ H
Br HO ~ Br CI
4-{4-bromophenyl~-4-Rneridinol chloroacetamide (mgt ,per:
To a solution of 4-(4-bromophenyl)-4-piperidinol (5 g, 19.5 mmol) and diisopropylethylamine (2.8 g, 21.5 mmol) in DMF (30 mL) was added dropwise chloroacetylchloride ( 2.2 g, 21.5 mmol). After stirring the mixture for one hour, the mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate (2x), 1 N HCI (3x), water, brine, and dried over MgS04. The solution was concentrated and chromatographed over silica gel with ethyl ace-tate to give the product as a brown solid (4 g, 62 %).
'H NMR (DMSO-D6): 8 1.21 (d, 2H), 1.71 (t. 1 H), 1.96 (t, 1 H), 2.71 (t, 1 H), 3.37 (t, 1 H), 3.70 (d, 1 H), 4.27 (d, 1 H), 4.54 (s, 2H), 5.26 (s, 1 H), 7.42 (d, 2H), 7.51 (d, 2H).
~4-bromo~yl~3.4-dih~rdro~oeridine chloroacetamide (ste~Bl:
To a solution of 4-(4-bromophenyl)-4-piperidinol chloroacetamide (4 g, 12 mmol) and diiso-propylethylamine (4.6 mL, 26 mmol) in THF (40 mL) cooled in an ice-bath was added methanesulfonyl chloride (2 mL, 26 mmol) and the mixture was refluxed for 16 hours under a nitrogen blanket. The reaction mixture was diluted with ethyl acetate and washed with 1 N
HCI (2x), aqueous NaHC03 (2x), brine (2x), and dried over MgS04. The solvent was evapo-rated and the product was chromotographed over silica gel with ethyl acetatelhexane (416).
The product was obtained as a yellow solid (1.5 g, 32%).
'H NMR (DMSO-Ds): 8 2.44 (t, 2H), 3.62 (m, 2H}, 4.14 (dd, 2H), 4.42 (d, 2H), 6.21 (s, 1H), 7.36 (m, 2H), 7.51 (d, 2H).
~-4-bromoohenyl-3 4-dihydro~~eradinylacetamideox)~naphthaldehyd~P (,~~:
A mixture of 4-(4-bromophenyl)-3,4-dihydropiperidine chloroacetamide (1.5 g, 4.8 mmol~, 4-hydroxynapthaldehyde (1.2 g , 7 mmol), and powdered potassium carbonate (1 g, 7.2 mmol) in acetonitrile (50 mL) was refluxed for 16 hours. The mixture was diluted with ethyl acetate 0 and washed with brine (3x), dried over MgS04, and concentrated. Silica gel chromatography with ethyl acetate/hexane (1/1 ) provided the product {1.4 g, 65%).
'H NMR (DMSO-D6): b 2.27-2.32 (m, 2H), 3.49-3.55 (m, 2H), 3.94 (brd s, 1H), 4.06 (brd s, 1 H), 5.08 (s, 1 H), 5.13 (s, 1 H), 6.05 (s, 1 H}, 6.97 (t, 1 H), 7.20 (t, 1 H), 7.34 (d, 2H), 7.42-7.47 (m, 1 H), 7.52-7.57 (m, 1 H), 7.92 (d, 1 H), 8.16 (d, 1 H), 9.01 (d, 1 H), 9.97 (s, 1 H).
4(-4-bromophenyl-3,4-dihydropiperadinylacetamideoxy)naphth-1-yl methylene-3-chloro-4-hydroxybenzoic acid hydrazone (step D):
The title compound was prepared according to the general procedure for the synthesis of alkylidene hydrazides from the condensation of 3-chloro-4-hydroxybenzoic acid hydrazide and 4-(4-bromophenyl-3,4-dihydropiperadinylacetamideoxy)naphthaldehyde:
'H NMR {DMSO-DB): 8 2.47-2.58 (m, 2H), 3.72 (br s, 2H), 4.13 (s, 1 H), 4.26 (s, 1 H), 5.14 (s, 1 H), 5.18 (s, 1 H), 6.23 (s, 1 H), 6.50-6.53 (m, 1 H), 7.03-7.06 (m, 1 H), 7.35-7.38 (m, 2H), 7.52 (d, 2H), 7.58 (d, 2H), 7.59-7.67 (m, 1 H), 7.75 (d, 1 H), 7.84 (s, 1 H), 8.32 (d, 1 H), 8.89 (s, 1 H), 8.92 (s, 1H), 11.41 (s, 1H); MS (APCI): 618.1, 620.1, 621.1, 622.1 EXAMPLE 197: EXAMPLE 202:
i oII ~ I o O \ I O~N N-CH O \ I O~N
H.N~ w ~ ~ N.N~ W N
i H
HO ~ HO ~ CHI
CI CI
EXAMPLE 198: 20 EXAMPLE 203:
0I' O ~ I O~N / 0 I -' I j~
N.N~ w ~N ~ I O ~ O~N~ / CI
I H .N. w I N I
HO H I , H
CI HO
CI
EXAMPLE 199:
EXAMPLE 204:
0 ~I ~o 0 \ i O~N OMe O \ I O " N OH
N.N~ ~ I \ I ~ H.N~ ~
H I ~ HO ~
HO CI
p~ 25 EXAMPLE 205:
EXAMPLE 200: ~ o I 'I
I p O ~ I O~N OH
N.N~ ~
O .N.v I O~N~ OMe I ~ H I
N ~ HO CI
H I ~ CI
HO
CI
EXAMPLE 201: EXAMPLE 206:
o ~i oI[
0 w I O~N O w I O~N I w .N~ w I ~ N.N~ w ~CH3 N ~ I H
HO I ~ H I ~ CF HO / N-CH3 15 CI ' CI
EXAMPLE 207: 15 EXAMPLE 212:
~ p I~ ~ oII
O w I O~ Q O ~ I O~N ~ CI
N.N~ w I N N~ ~ N.N~ W I H I , I ~ H
HO I ~ H O H HO
CI CI
EXAMPLE 208: EXAMPLE 213:
p ~I o O ~ I O~N N O ~ OV 'N
N.N~ ~ I I ~ ~ ~ N.N~ ~ I HOJ I ~ CI
I / H I , H
HO HO
CI CI
EXAMPLE 209: EXAMPLE 214:
p ~I o p ~ I O~N O ~ O~N
N.Nw w I ~ N.~Iw W I CHy \N
I , 'H N I ~ H
HO HO
CI
CI
EXAMPLE 210: EXAMPLE 215:
0 N.CHz ~ I OII
O W I O~N~ O W I O~N~ O
N.Nw w I CHI ~ N.N~ ~ CH~
I , H I , H
HO HO
EXAMPLE 211:
EXAMPLE 216:
O W I O~N.N~ , O
.N ~ w I H w I O~ O
~N O N
HO I ~ H ~ N.N. ~ I H C
CI HO I ~ H
CI
EXAMPLE 217: EXAMPLE 222:
OI O~NHzi i I OII
O ~ I O~N : ~ I O ~ I O~N
H.N~ w I H % N.N~ W ~Nw/.CH
N I H z HO ~' HO
CI Ct EXAMPLE 218:
EXAMPLE 223:
O ~ I O~N ~ I I ~ OMe O I
.N~ W I H O i O~N~N
H , N ~ ~ ( H CHa HO ~ I ~ -H
5 CI Ho Ct EXAMPLE 224:
EXAMPLE 219:
0'~
I O~ ~O O ~ I O~N ~ I CFA
O ~ I ~N~CHa ~ N.N. ~ I H
N. N . ~ CHI I , H
I H HO
Ho ~ 25 Ct CI
EXAMPLE 220: EXAMPLE 225:
I O'I ~ I i O CH3 O \ O~N~N~ O ~ I O~N w I H ' N.N~ W CN3 .N. w I H I , I H I ~ H CH, HO
HO
CI CI
15 EXAMPLE 221: EXAMPLE 226:
I ~
0 CFA \ I O~ CHI
o I H I ~
N.N. w i ~ O .N~ ~ I H I , I , H I , H
HO HO
CI Ct EXAMPLE 227: EXAMPLE 232:
~I ~I o O O \ O \ O V 'N
O \ I OV 'N \ \ N.N~ \ I
\ .N~ \ I H I , I , H
I H CI HO
HO ~ C1 CI
EXAMPLE 233:
EXAMPLE 228: ~ o O \ I O~N
O CHI \ .N. \ I ~N
O \ I O.~N \ I ~ H I , I H ~ HO
I \ H-N ~ \ ~ CH3 20 CI
HO
CI
EXAMPLE 234:
EXAMPLE 229: ~ I O HOC CH
\ O
O N i I CHI
O \ I O o N CH3 \ N.N ~ \ I ~N \
I H
\ .N. \ I H HO
I H CI
HO
CI
EXAMPLE 235:
EXAMPLE 230:
O ~ N
O O CH3 O \ I O~N \ I
\ O .N ~ \ I H I , I \ H.N. \ I CH3 I / H CI HO
HO CI
C!
EXAMPLE 231:
EXAMPLE 236:
\ I O~ O \ I O~N~ NOz \ O N.N ~ \ I H I i CF I \ H.N. \ I ~N ( \
I H
HO
Ho 30 cl EXAMPLE 237: EXAMPLE 242:
NH
00 % i I ' O
O ~ I O~N ~ I O \ O~N~ CH3 H.N. w I H I ~ H.N~ W I ~N~N~CH
HO
HO
CI CI
EXAMPLE 238:
20 EXAMPLE 243:
O \ I O - N O .N~v I O~H I ~ F
.N~ ~ I O ~ N F
W N I ~ H
H O HO
HO CI
CI
EXAMPLE 239:
EXAMPLE 244:
o cH, O O w I O~N~,N.CH
O ' I O~N~ CHI ~ N.N~ w ( H
N.N. ~ ~N ~ CH3 I H
i H I , HO
HO ~ CI
CI
EXAMPLE 245:
EXAMPLE 240: ~ I o OMe O O ~ I O~N
O ~ O~N~ CH ~ N.N~ ~ O
.N~ ~ I ~N CH I / H HC O
N OMe ~ ~ HO
H I , CI
HO
CI
EXAMPLE 246:
CI
15 EXAMPLE 241: ~ I O~ \ I
o I H CI
O ~ N.N~ ~
O w ~ O~N~CH~ I ~, H
HO
H~N. ~ I ~N I ~ CHI 3p CI
HO
CI
EXAMPLE 247: 15 EXAMPLE 252:
i 0 i 0 O w I I O~N~CH3 O ~ I I O~N
-N~ W ~N -N. w ~1N
I ~ 'H E ~ I ~ H
HO CH3 HO I ~ NO
CI CI
EXAMPLE 248: EXAMPLE 253:
O O CH3 i I OII
O~N
O -N ~ w I N O -N ~ w I ~ O
N
HO I ~ H HO I ~ 'H HsCyO
CI CI H~C'ICH3 EXAMPLE 249: EXAMPLE 254:
I' ~ o O ~ O~N~ ~ I 0~ CH
I H-N~ w I ~N ~ O -N~ ~ I N~
HO ~ I / I , H
F HO
CI CI
10 EXAMPLE 250:
EXAMPLE 255:
O OMe O ~ I O~N ~ I O
N.N~ w I O \ I O~N~ CF3 I H ~ -N ~ ~
HO ~ I ~ H ~N N i CI HO
CI
EXAMPLE 251:
EXAMPLE 256:
O~ O~CH3 ~ O
O N-N. ~ I N ICH\' CH3 O \ I I O N
I H ~ -N ~ w ~N
HO ~ I ~ H N i CI
EXAMPLE 257: 15 EXAMPLE 262:
~I p ~I p O ~ Ov _N O ~ Ov"N
.N. ~ I .N ~ ~ I I , -N ~ ~N
HO I ~ H H~C~O 0 HO , ~ H H~C'N'CH~
CI CI
EXAMPLE 258: EXAMPLE 263:
O F ~ O
p .N,v I o~N I ° \ I I °~N I J
J ~ .N.
N H3C ~ N I ~ ~0 I , H I , H N
HO ~ HO
CI CI
EXAMPLE 259: EXAMPLE 264:
I .~ ~ ( O.
I ° I w w o N'' O .N~ w N / i ~ N.N~ W I ~N~O ~ I
N I H
HO I ~ H H'C.N.CH3 HO Ci O
CI
10 EXAMPLE 260: EXAMPLE 265:
p CI ~ I ~ I ~ Noz O ~ p~N~g~ O ~ I O N I w I H ~ .N ~ ~
N.N~ ~ F I H
HO I ~ H HO ~ H~C'N'CH~
EXAMPLE 261: EXAMPLE: 266 O i O CH i O \ I O" N CHI O ~ I O~N ~ I
I
H,N. ~ H C I ~ H.N~ ~
i i ~N
HO Y HO Y
CI CI
EXAMPLE 267: EXAMPLE 272:
o~ I ~ I o.
O N. N ~ w I CHs I , O N
I
I H I ~ H.N
HO
CI HO
CI
EXAMPLE 268: 20 EXAMPLE 273:
I O II ~.--CHI i I O
~~- N ~ O ~ ~ .CHs O N.N. w I N~ CH3 ~ O .N. w I H~N'CH
I , H I H sC ~
HO
CI HO
CI
EXAMPLE 269: EXAMPLE 274:
o'I ~ o'I
O ~ I I O~N~ F O ~ I O~N
.N~ ~ ~N .N~ ~ I OH
I~ H I~ I~ H
HO HO ~ /
Ct CI
EXAMPLE 270: EXAMPLE 275:
OII ~ 0 CHs O w I O~N~N w CHs O W I O~N~tJ.CH~
N.N~ ~ I H CJ I ~ ~ N.N~ ~ I ~CH
I H ' I H ' HO ~ HO
CI CI
EXAMPLE 276:
EXAMPLE 271:
O w I O~N w / O N
I ~ H
N.N~ ~ I H I i O ~ I O N
I , H ~ N.N
HO I H
CI HO
CI
EXAMPLE 277: EXAMPLE 282:
o ~ o O ~ I O~N / O ~ I O~N~CH~
N.N~ w I W I ~ N.N~ w I ~N' w I H I H
HO ~ HO ~ ~ CI
CI CI
5 EXAMPLE 278: EXAMPLE 283:
oII ~ oII
0 ~ I O~N~ O ~ I I O~N~
N.N~ w I ~.N ~ ~ N.N. W~O
HO I ~ H I i CHI HO I ~ 'H - ~N'Hz CI O CI
EXAMPLE 284:
EXAMPLE 279:
0 0 ~ I I o.~N
O ~ O~N ~ CFA ~ N.N~ ~ ~~ ~ CFA
N.N ~ ~ I H I i CI HO I ~ H
HO ( ~ H 25 CI
10 pl EXAMPLE 285:
EXAMPLE 280:
o CI
I1 O W I O~N
O
O~ ~ .N. W I CH3 I
O N.N~ w I I r I , H
HO
HO I ~ H H3C. N. CH3 CI
cl EXAMPLE 286:
15 EXAMPLE 281: o ~ I °~N'~
~ N.N~ w I ~N w w I
I o~ I ~ H
HO
I ~ O H. N w w I N I / 3~ CI
HO ~ O O
CI 'CH
EXAMPLE 287: EXAMPLE 291:
O ~N
O w O~N~CH3 H.N. w I O w I p_ ~
~N F
HO ~ CHz ~ . N ~ ~ I
N Iw CI HO I i H i CI
EXAMPLE 288: 15 EXAMPLE 292:
p ~ o O ~ I O~N~ O ~ I O~N ~ Cl N.N ~ w I CHI ~ N.N ~ w I H I i CH
I H I ~ H 5 HO HO
CI C!
EXAMPLE 293:
EXAMPLE 289:
I~ ,I ~ Ii 0~
O w O
O .N~v I p~H I \ ~ O N.Nw W I H
i I H ~ HO I ~ H
HO
CI
CI
EXAMPLE 294:
10 EXAMPLE 290:
~ o cH, I N O ~ I O.~N I
.N~ W I H I
o ~ o.~N L ~
.N ~ ~ I HO
N ~ CI
HO I ~ H I i CHI
CI CHs EXAMPLE 295: EXAMPLE 299:
o1. ~ o O w I O~N . N O w I O~N ~ N
N.N. w I / I i ~ N.N. w I ~ I i H I ~ H
HO ~ HO
CI C!
EXAMPLE 296: EXAMPLE 300:
OII ~ O /~~N
O ~ I O~N O ~ I O~N
N.N ~ ~ I H CJ I ~ CH ~ N.N. ~ I
I ~ H ' ~ I ~ H
EXAMPLE 297: EXAMPLE 301:
il o ~I
w o Jl w O N.N. ~ I H I ~ O ~ I I O~N~ CHI
HO ~ H ~ .N~ ~ ~O
CI HO I ~ ~ TCH~
90 EXAMPLE 298:
0'I
O \ ~ O~N~ OI ~
.N. w ~N~
[[[[N
HO I ~ H O
CI
EXAMPLE 302: 15 EXAMPLE 307:
I oII
O ~ O N
O ~ I O~N Nw N.N~ w I ~~ vCH~ ~ .N. w I
HO I ' H I ~ H I N
HO Y
C! C7 EXAMPLE 303: EXAMPLE 308:
' o ~I o O ~ I O~N~OMe O w O~N O
H.N~ w ~ N.N~ w I CH~
HO ' OMe HO I ~ H
CI CI
EXAMPLE 304: EXAMPLE 309:
I II V
p ~ O~N~N~ H~ ~CH~ O w I O~N OMe I H i!'-O ~
~.N. W O ~ N.N ~ w I CHs OMe HO ' I ~ H
HO
CI CI
10 EXAMPLE 305:
EXAMPLE 310:
w I o.~ N ~ I o w oil O N.N~ ~ I I , O I N
N.N~ ~ ~N N\
I~ H
HO ~ ( H I 1 C. HO ' ~N~
CI
EXAMPLE 306:
EXAMPLE 311:
I II
O .N~\~ I O~N I i O \ I O~LN
N CHI . N ~ ~ ( CH
I H w N a HO ' N I ~ H
CI ~O HO
CI
EXAMPLE 312: 15 EXAMPLE 317:
OMe OMe O
~ I ~ ~ I oil 0 ~ I O N ~ OMe O .N. ~ ( ( ~ H.N ~ w CHI I ~ H OMe ~ I
i HO
HO ~ CI
CI CI
EXAMPLE 313: EXAMPLE 318:
o ~I oI' 0 ~ I O~N 'N 0 ~ I O~N I \
N.N. w I ~ I i I ~ H.N. W
I \ H I i HO ~ ~ HO
CI I CI
EXAMPLE 319:
EXAMPLE 314:
I p p ~ I p~N ~ I
O ~ O~N~ ~ .N. ~ I
N.N ~ w I ~N ~ I ~ H
I H ~ HO O
HO ~ ~ CI CI
CI
10 EXAMPLE 315: EXAMPLE 320:
o ~i oI' 0 w I O~N w I O w I O~N~ CHs .N~ w I O ~ N.N~ w ~N
I ~ H I ~ L i H I i HO HO ~ CHI
EXAMPLE 321:
EXAMPLE 316:
i oII
O w I O~N CHI O .N~\~ I O~N I i N.N~ ~ I I , H
I H HO
HO ~ CI N
CI
EXAMPLE 322: 15 EXAMPLE 327:
o ~ o O \ I O~N~ O \ I O~N
H.N~ ~ ~N.CH ~ .Nw W ( ~~
a N v -N
I ~ H
HO HO
CI CI
EXAMPLE 323: EXAMPLE 328:
O O ~ .CHa O ~ I Ov 'N I w w O~ ~S w ~ .N. w O H.N~ ~ ( H HO I i H
HO ~ CI
cl 20 EXAMPLE 324:
EXAMPLE 329:
cH, ~ I o o I ~ I o w I o~~N~
O ~ O~N~~~ ~ N.N~ ~ ~N ~ CI
H.N ~ w I ~ HO I / 'H I
I ~ cl HO
CI
EXAMPLE 325: 25 EXAMPLE 330:
o I
O ~ I O~N O ~ O~N~CH~
TI
N.N. ~ I ~N ~ ~ N.N~ ~ ~N~
H I ~ HO I i H '~('~~~ OMe HO
CI CI
EXAMPLE 326:
EXAMPLE 331:
o w I o~LN cH~ ~ I o N.N~ w I O \ I O~N~ C1 .N~ ~ ~N
HO I ~ 'H CHI I , H I , C! HO ~' 30 cl EXAMPLE 332: EXAMPLE 337:
~I o ~ o I' I II
O ~ I O~N~ O ~N
N.N~ w ~N ~ CHI ~ N.N~v I 0 ~~~N~CH2 I H I H
HO ~ HOC ~ HO
CI CI I
CHZ
EXAMPLE 333: 20 EXAMPLE 338:
O \ I 0 N~ O ~ I O~N~OEt N.N~ ~ ~N ~ .N. ~ I
N
HO I ~ 'H I ~ HO I i H OEt CI CI
EXAMPLE 339:
EXAMPLE 334:
O ~ I O~N'~ O i i I O ~ N.N~ w IN ~ I
O \ I O~N~ CI HO I ~ H CHI
H.N. w N I w CI
HO ~ CI ~ N
25 EXAMPLE 340:
EXAMPLE 335: o w I o~N ~ I
N.N~ ~ I ~OEt TO
0 w I O~N p HO I i H OEt N.N~ ~ I CI
I H
HO ~ II
CI N
EXAMPLE 341:
EXAMPLE 336: o ~ I o Jl N
i I O I % H.N . ~\ I HO I
0 w O~N~ HO CI
CI
.N. ~ I ~N CI
I ~ 'H I ~
HO CI
CI
EXAMPLE 342:
o ~l N.N. w , J N I N
HO ~ H ~ '~' N
Ct General procedure for synthesis of compounds of the qenPral formula XII
O NH
O B\ A~ i Z O O
_OH
step A A" ~ \ B v 'OH
H
O O
NHR~R~ ~~
A J,l / \ B~ / Rsc N
step B ~ Rsa formula XII
A and B are as defined for formula I and -NRS'Rsa is R~ Raa Rat -N-(CHZ)~---~a-(CHZ)d o where Rsa, R'a, R4b, c, q, d and D are as defined for for-mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent.
The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tent-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloro-methane, DMSO, acetic acid, water or a compatible mixture of two or more of the above sol-vents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylort-hofom~ate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C
to 140°C, preferably between 10°C to 80°C. fn many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli-zed if necessary from a solvent such as the above described reaction solvents.
The product can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloro-methane/methanol or chloroform/ethyl acetate.
Step B: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an an-y hydride or an acid halide that can then react with the amine to give a compound of formula Xll.
Step B was also done combinatorially with a preactivated acid and a selection of amines. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purifed by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XII.
Specific examples illustrating the preparation of compounds of the general formula XI! accor-ding to the invention are provided below.
Preparation of 4-formyl-1-naphthylacetic acid:
This compound was prepared from the reduction of 4-cyano-1-naphthylacetic acid in the presence of 85% formic acid and Raney alloy as described in the literature.
References : 1 ) A.A. Shulezhko and A.I. Kiprianov, J. org. Chem., (USSR) English translation, 4, 1968, p.1052. 2) Zh. Org. Khim., 4, 1968, p. 1089.
Preparation of 4-[3-Chloro-4-hydroxybenzoyl}-hydrazonomethyl~-1-naphthylacetic acid (step A):
This compound was prepared according to the general procedure for the synthesis of alkyli-dene hydrazides from the condensation of 4-formyl-1-naphthylacetic acid above and 3-chloro-4-hydroxybenzoic acid hydrazide.
'H NMR (DMSO-Ds): 8 4.1 (s, 2H), 7.1 (d, 1 H), 7.5 (d, 1 H), 7.7 (qt, 2H), 7.8 (d, 1 H), 7.9 (d, 1 H), 8.0 (s, 1 H), 8.1 (d, 1 H), 8.8 (d, 1 H), 9.1 (s, 1 H), 11.0 (brd s, 1 H), 11.8 (s, 1 H), 12.2 (brd s, 1 H); MS (APCI): 383.4, 385.2.
Preparation of (3-formylindoiyl)acetic acid:
Ethyl (3-formylindolyl)acetate:
3-Formylindole (10.0 g, 69 mmoles) was dissolved in DMF (100 ml). Under NZ was a 60%
suspension of NaH in mineral oil (3.0 g) added in portions with cooling (temp < 15 °C). At <
15 °C was a solution of ethyl bromoacetate (8.4 mf) in DMF (15 ml) added drop wise over 30 minutes. The resulting mixture was stirred at room temperature for 16 hours and evaporated in vacuo. The residue was added water (300 ml) and extracted with ethyl acetate (2 x 150 ml), the combined organic extracts were washed with satd. NH4CI, dried (MgS04) and con-centrated to afford 15.9 g ethyl (3-formylindolyl)acetate.
'H NMR ( CDC13 ) 8 1.26 (t, 3H), 4.22 (q, 2H), 4.90 (s, 2H), 7.21 - 7.35 (m, 3H), 7.72 (s, 1 H), 8.30 (d, 1 H), 10.0 (s, 1 H).
(3-formylindolyl)acetic acid:
Ethyl (3-formylindolyl)acetate (15.9 g) was dissolved in 1,4-dioxane (100 ml) and added 36%
aq. NaOH (10 ml). The resulting mixture was stirred at room temperature for 4 days. Water (500 ml) was added and the mixture was washed with diethyl ether (150 ml). The aqueous phase was made acidic with 5N HCI and extracted with ethyl acetate (250 + 150 ml). The combined organic extracts were dried (MgS04) and evaporated in vacuo to afford 10.3 g (73 % over two steps) of (3-formylindolyl)acetic acid.
'H NMR ( DMSO-de ) 8 4.94 (s, 2H), 7.27 - 7.36 (m, 3H), 7.98 (s, 1 H), 8.25 (d, 1 H), 10.0 (s, 1 H), 12.5 (bs, 1 H).
Preparation of (4-Formylindolyl)acetic acid:
4-Formyfindole:
This compound was synthesized according to F. Yamada, M. Somei, Heterocycles (1987) 1173.
'H NMR ( CDCI 3 ) 8 7.28 - 7.36 (m, 2H), 7.41 (t, J = 3.0 Hz, 1 H), 7.60 -7.70 (m, 2H), 8.62 (brd s, 1 H), 10.20 (s, 1 H). GC-MS (pos.): 146 Ethyl (4-formylindolyl)acetate:
This compound was synthesized according to the general procedure for N-alkylation of in-doles.
'H NMR (CDCI,) 8 1.13 {t, J = 6.9 Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H), 4.86 (s, 2H), 7.22 - 7.35 (m, 3H), 7.49 (d, J = 8.6 Hz, 1 H), 7.60 (d, J = 7.3 Hz, 1 H), 10.20 (s, 1 H).
(4-Formylindolyl)acetic acid:
This compound was synthesized according to the general procedure for saponification of esters.
'H NMR ( DMSO-de ) b 5.15 (s, 2H), 7.12 (d, J = 3.0 Hz, 1 H), 7.36 (d, J = 7.9 Hz, 1 H), 7.61 (d, J = 3.1 Hz, 1 H), 7.71 {d, J = 7.3 Hz, 1 H), 7.82 (d, J = 8.2 Hz, 1 H), 10.20 (s, 1 H), 12.94 (brd s, 1 H).
Preparation of (5-formylindolyl)acetic acid:
5-Cyano-N-tosyiindole:
In a 100 mL round-bottom flask was placed NaH (0.4 g, 60% dipersion in mineral oil, 10 mmol) and anhydrous THF (10 mL) was added. To the suspension was added a solution of 5-cyanoindole (1.0 g, 7 mmol) in anhydrous THF (10 mL) by syringe at 0°C. The mixture was stirred for 10 min, and tosyl chloride (1.6 g, 8.4 mmol) was added. After stirring at room temperature for 2 h, water (100 mL) was added. The mixture was extracted with ethyl ace-3o tate (3x50 mL), dried (MgSO,), and concentrated. The residue was purified by column chro-matography using hexane: ethyl acetate = 2:1 as eluent to yield 1.86 g (92%) of the desired product.
'H NMR ( CDC13) b 2:32 (s, 3H), 6.65 (d, J = 3.6 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H ), 7.41 (d, J = 8.6 Hz, 1 H), 7.57 (d, J = 3.6 Hz, 1 H), 7.63 (s, 1 H), 7.75 ( d, J = 8.3 Hz, 1 H), 7.99 (d, J =
8.6 Hz, 1 H).
5-Formyl-N-tosylindole:
To a solution of 5-cyano-N-tosylindole (0.66 g, 2.2 mmol) in anhydrous THF (20 mL}, was added 1 M DIBAL in hexane (4 mL, 4 mmol) via syringe at 0°C. The mixture was stirred at room temperature for 16 h, poured into ice-cooled 1 N hydrochloric acid (50 mL), extracted 1 o with ethyl acetate (3 x 80 mL). The combined organic extracts were dried (MgS04), and concentrated to give an oil. After a short column chromatography using hexanelethyl acetate 2: 1 as eluent 0.62 g (95%) pure 5-formyl-N-tosylindole was obtained.
'H NMR (CDCI3) 8 2.29 (s, 3H), 6.74 (d, J = 3.7 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 2H), 7.65 (d, J
= 3.7 Hz, 1 H), 7.77 (d, J = 8.4 Hz, 2H), 7.82 (dd, J = 1.4, 8.6 Hz, 1 H), 8.02 (d, J = 1.1 Hz, 1 H), 8.09 (d, J = 8.6 Hz, 1 H ), 9.99 (s, 1 H).
5-Formylindole:
5-formyl-N-tosylindole (0.5 g, 1.7 mmol) was dissolved in a mixture of methanol (10 mL) containing 5% aqueous KOH solution (5 mL). The mixture was refluxed for 3-h, neutralized with 1 N hydrochloric acid, and extracted with ethyl acetate (3x50 mL). The combined organic extracts were dried (MgSO,), and concentrated. The residue was purified by short column chromatography to provide 240 mg (97%) of the desired product.
'H NMR (CDCI3) b 6.70 (t, J = 2.1 Hz, 1 H), 7.32 (t, J = 2.3 Hz, 1 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.78 ( dd, J = 1.5, 8.6 Hz, 1 H), 8.19 (s, 1 H), 9.45 (b, 1 H), 10.15 (s, 1 H). GC-MS (pos.): 146.
Ethyl (5-formylindolyl)acetate:
This compound was synthesized according to the general procedure for N-alkylation of in-3o doles.
'H NMR (CDC13) 8 1.27 (t, J = 6.8 Hz, 3H), 4.22 (q, J = 7.2 Hz, 2H), 4.87 (s, 2H), 6.70 (d, J =
3.4 Hz, 1 H), 7.18 (d, J = 3.0 Hz, 1 H), 7.36 (d, J = 8.7 Hz, 1 H), 7.78 (d, J
= 8.3 Hz, 1 H), 8.14 (s, 1 H), 10.01 (s, 1 H).
(5-Formylindolyl)acetic acid:
this compound was synthesized according to the general procedure for saponification of esters.
'H NMR (DMSO-de) S 5.10 (s, 2H), 6.66 (d, J = 3.0 Hz, 1 H), 7.48 (d, J = 3.0 Hz, 1 H), 7.56 (d, J = 8.7 Hz, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 8.17 (s, 1 H), 9.97 (s, 1 H), 12.9 (brd s, 1 H).
General procedure for preparation of [{3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acids:
These compounds were prepared according to the general procedure for the synthesis of alkylidene hydrazones by condensation of the various formylindolylacetic acids with 3-chloro-4-hydroxy benzoic acid hydrazide.
3-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid:
'H NMR (DMSO-DB): 8 2.81 (t, J = 6.5, 2H), 4.43 (t, J = 6.5, 2H), 7.06 (d, J =
8.5, 1 H), 7.15-7.28 (m, 2H), 7.56 (d, J = 8.1, 1 H), 7.75 (d, J = 8.5, 1 H), 7.83 (s, 1 H), 7.95 (s, 1 H), 8.27 (d, J
= 7.65, 1 H), 8.54 (s, 1 H), 10.88 (br s, 1 H), 11.41 (s, 1 H). LRMS calcd for C,9 H,e CI, N3 04 (M - H) 384, found 384Ø
4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid:
'H NMR ( DMSO-d6 ) 8 5.09 (s, 2H), 7.09 (d, J = 8.6 Hz, 1 H), 7.16 - 7.25 (m, 2H), 7.32 (d, J
= 7.2 Hz, 1 H), 7.45 - 7.55 (m, 2H), 7.81 (d, J = 8.2 Hz, 1 H), 8.01 (d, J =
1.8 Hz, 1 H), 8.68 (s, 1 H), 10.96 (s, 1 H), 11.71 (s, 1 H), 12.90 {b, 1 H). MS ( APCI, neg.): 370.
5-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acid:
'H NMR (DMSO-d fi) 85.09 (s, 2H), 6.35 (d, J = 2.9 Hz, 1 H), 7.06 (d, J = 8.6 Hz, 1 H), 7.39 (d, J = 3.1 Hz, 1 H), 7.47 (d, J = 8.6 Hz, 1 H), 7.61 (d, J = 8.6 Hz, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.83 (s, 1 H), 7.97 (s, 1 H), 8.48 (s, 1 H), 10.93 (s, 1 H), 11.58 (s, 1 H), 12.90 (brd s, 1 H). MS
(APCI, neg. ): 370.
[3-Chioro-4-hy~~oxybenzoyl~:_hydrazonomethyrl]-1-naphthylacetamides and the various indolacetamides lste~:
1o General librar~production procedures To solutions of 4-[(3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]naphthylacetic acid and the various indolylacetic acids in DMSO was added carbonyldiimidazole (1.2 eq).
The solution was agitated for 5 minutes and diluted with DMSO to a concentration of 50 mM.
The soluti-on was then dispensed into 88 deep well plates containing solutions of amines in DMSO (50 mM). The plates were covered and agitated for 16 hours. The products were purified by HPLC.
Examples of compounds of the formula XII:
EXAMPLE 343:
r cH, O w I NvCH~
II
.N~ ~ I o I~ H
HO
CI
'H NMR (DMSO-D6): b 1.06 (t, 3H), 1.17 (t, 3H), 3.31 (qt, 2H), 3.50 (qt, 2H), 4.19 (s, 2H), 7.10 (d, 1 H), 7.45 (d, 1 H}, 7.64 (quintet, 2H), 7.83 (d, 1 H), 7.88 (d, 1 H), 7.98 (m, 2H), 8.87 (d, 1 H), 9.09 (s, 1 H), 10.99 (brd s, 1 H}, 11.80 (brd s, 1 H); ms (APCI);
438.1, 440.1.
EXAMPLE 344:
o ~ I N '~
_ I ~ ''N
.N~ ~ O
I~ H
HO
CI
'H NMR (DMSO-Dg): 8 0.98 {d, 4H), 2.76 {t, 2H), 3.02 (quintet, 1 H), 3.59 (t, 2H), 4.40 (s, 2H), 7.10 (d, 1 H), 7.48 (d, 1 H), 7.48 (d, 1 H), 7.59 (qt, 1 H), 7.67 (t, 1 H), 7.81 (d, 1 H), 7.89 (d, 1 H), 7.97 (d, 1 H), 8.02 (s, 1 H), 8.84 (d, 1 H), 9.09 (s, 1 H), 10.99 (brd s, 1 H) 11.80 (brd s, 1 H); MS (APCI, neg.): 473.1, 475.1.
EXAMPLE 345:
O ~ I N '~
I ~ ''N
.N~ ~ O
f~
HO
CI
'H NMR (DMSO-Dg): 8 2.50 (2H), 2.68 (t, 2H), 4.00 (s, 2H), 7.10 (d, 1 H), 7.53 (d, 1 H), 7.65 (tt, 2H), 7.80 (dd, 1 H), 7.90 {d, 1 H), 8.02 (d, 1 H), 8.14 (d, 1 H), 8.62 (t, 1 H), 8.84 (d, 1 H), 9.09 (s, 1 H), 11.0 (brd s, 1 H) 11.80 (s, 1 H); MS (APCI): 433.1, 435.1 EXAMPLE 346:
o ~ I N '~
I ~ ''N
.N~ ~ O
I ~ 'H
HO
CI
'H NMR (DMSO-D6): 8 1.08 (m, 4H), 1.54 (m, 6H), 2.70 (t, 2H), 3.45 (t, 2H), 3.76 (m, 1H), 4.30 (s, 2H), 7.06 (d, 1 H), 7.49 (d, 1 H), 7.64 (m, 2H), 7.80 (d, 1 H), 7.88 (d, 1 H), 8.01 {s, 1 H}, 8.07 (d, 1 H), 8.83 (d, 1 H), 9.09 (s, 1 H), 10.5 (brd d, 1 H), 11.78 {brd s, 1 H); MS (APCI, neg.}:
515.2.
EXAMPLE 347:
N
O ~ I N
II
.N~ ~ I O
I
HO
CI
'H NMR (DMSO-D6): b 1.26 (m, 2H), 1.37 (m, 4H), 1.67 (m, 2H), 2.43 (m, 4H), 2.62 (m, 3H), 3.10 (t, 2H), 3.90 (d, 1 H), 4.32 (s, 2H), 4.48 (d, 1 H), 7.10 (d, 1 H), 7.31 (d, 1 H), 7.48 (m, 2H), 7.81 (d, 1 H), 7.88 (d, 1 H), 8.03 (m, 2H), 8.85 (d, 1 H), 9.08 (brd s, 1 H), 11.76 (brd s, 1 H): MS
(APCI): 533.2.
EXAMPLE 348:
~N
p ~I NJ
II
.N. ~ I o I~ H
HO
~I
'H NMR (DMSO-DB): 8 3.03 (m, 4H), 3.68 (t, 2H), 3.79 (t, 2H), 4.30 (s, 2H), 7.14 (m, 5H), 7.47 (d, 1 H), 7.66 (quintet, 2H), 7.82 (d, 1 H), 7.88 (d, 1 H), 8.02 (d, 1 H), 8.07 (d, 1 H), 8.87 (d, 1 H), 9.10 (s, 1 H), 10.99 (s, 1 H), 11.80 (s, 1 H); MS (ACPI): 545.6.
EXAMPLE 349:
~F
N ('~~I
p ~I NJ
Ii .N. ~ I o I ~ 'H
HO
CI
'H NMR {DMSO-DB): 8 3.10 (d, 4H), 3.67 {d, 4H), 4.30 (s, 2H}, 7.00 (m, 2H), 7.09 (m, 3H), 7.47 {d, 1 H), 7.62 (quintet, 2H), 7.82 (d, 1 H}, 7.88 (d, 1 H), 8.03 (s, 1 H), 8.06 (d, 1 H), 8.85 (d, 1 H), 9.10 (s, 1 H), 10.99 (s, 1 H), 11.80 (s, 1 H); MS (ACPI): 544.5, 545.3.
EXAMPLE 350:
CHI
~N~N.CH' o ~I NJ
il .N~ ~ I O
I~
HO
CI
'H NMR (DMSO-DB): 8 2.15 (s, 6H), 2.39 (m, 8H), 3.51 (d, 4H), 4.22 (s, 2H), 7.03 (d, 1 H), 7.43 {d, 1 H), 7.64 (quintet, 2H), 7.77 (d, 1 H), 7.87 (d, 1 H), 7.99 (s, 1 H), 8.02 (d, 1 H), 8.83 (d, 1 H), 9.08 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 522.2.
EXAMPLE 351:
Hz i O ~ I I N~CHz .N~ ~ O
I ~ 'H
HO
CI
'H NMR (DMSO-Ds): 8 3.93 (d, 2H), 4.10 (d, 2H}, 4.23 (s, 2H), 5.20 (m, 4H), 5.79 (m, 1H), 5.94 (m, 1 H), 7.10 (d, 1 H), 7.78 (d, 1 H), 7.63 (m, 2H), 7.80 (d, 1 H), 7.83 (d, 1 H), 7.95 (d, 1 H), 8.02 (d, 1 H), 8.85 (d, 1 H), 9.10 (s, 1 H), 11 (brd s, 1 H), 11.80 (brd s, 1 H); MS (ACPI):
462.2 EXAMPLE 352:
0 ~ I N~N
II
.N. ~ I O
I , H
HO
CI
'H NMR (DMSO-Dg): 8 0.9 (t, 3H}, 1.30 (sextet, 2H), 1.54 (sextet, 2H), 3.56 (t, 2H), 4.31 (s, 2H), 4.39 (s, 2H), 7.06 (d, 1 H) 7.48 (d, 1 H), 7.65 (quintet, 2H), 7.79 (dd, 1 H), 7.87 (d, 1 H), 7.97 (d, 1 H), 8.01 (d, 1 H), 8.85 (d, 1 H), 9.09 (s, 1 H), 11.79 (s, 1 H); MS
(APCI): 477.01, 479.2.
EXAMPLE 353:
H,c o ~I
a .N. w I o I~ H
HO
CI
'H NMR (DMSO-De): 8 1.17 (m, 4H), 1.54 (m, 4H), 2.68 (m, 1 H), 3.77 (d, 1 H), 4.18 (s, 2H), 4.33 (m, 1 H), 4.76 (bid, 1 H), 7.10 (d, 1 H), 7.43 {m, 1 H), 7.65 (quintet, 2H), 7.81 (d, 1 H), 7.88 (d, 1 H), 8.02 (s, 1 H), 8.04 (d, 1 H), 8.84 (d, 1 H), 9.09 (s, 1 H), 11.79 (s, 1 H); MS (APCI):
464.1, 466.2.
EXAMPLE 354:
H~
i I N N
O
N.N~ w I O I i I H
HO
CI
'H NMR (DMSO-D6): 8 0.85 (qt, 3H), 1.53 (m, 2H), 3.00 (dt, 2H), 3.29 (quintet, 2H), 3.77 (dt, 2H), 4.13 (d, 2H), 7.05 (d, 1 H), 7.26 (m, 2H), 7.36 (d, 1 H), 7.52 (qt, 1 H), 7.69 (m, 2H), 7.87 (m, 2H), 7.95 (d, 1 H), 8.00 (s, 1 H), 7.87 (dd, 1 H), 8.84 (t, 1 H), 9.07 (brd, 1 H), 11.76 (brd s, 1 H);. MS (APCI): 529.2, 529.7, 531.2.
EXAMPLE 355:
CHI
i O
.N~ ~ I O
I~ H
HO
Ci 'H NMR (DMSO-D$): 8 0.85 (qt, 3H), 1.33 (m, 1 H), 1.65 (m, 7H), 2.60 (t, 0.5H), 3.10 (t, 0.5H) 3.80 (m, 1 H), 4.21 (s, 2H), 4.24 (m, 1 H), 7.11 (d, 1 H), 7.45 (t, 1 H), 7.65 (m, 2H), 7.75 (d, 1 H), 7.89 (d, 1 H), 8.01 (d, 1 H), 8.05 (d, 1 H), 8.83 (d, 1 H), 9.09 (s, 1 H), 11.80 (s, 1 H); MS
(APCI): 478.4, 480.3.
EXAMPLE 356:
~.N~.CH2 o ~I NJ
.N~ ~ I O
I ~ 'H
HO
C!
'H NMR (DMSO-DB): 8 2.36 (m, 4H), 2.97 (d, 2H), 3.50 (m, 2H), 3.60 (m, 2H), 4.23 (s, 2H), 5.17 (t, 2H), 5.86 (m, 1 H), 7.08 (d, 1 H), 7.43 (d, 1 H), 7.64 (quintet, 2H), 7.79 (dd, 1 H), 7.87 (d, 1 H), 8.01 (s, 1 H), 8.04 (d, 1 H), 8.83 (d, 1 H), 9.09 (d, 1 H), 11.79 (brd s, 1 H); MS (APCI):
4.91.2, 493.2.
EXAMPLE 357:
I
o w N~
.N. ~ I O \\N
I~ H
HO
CI
'H NMR (DMSO-Ds): 8 1.50 (m, 1 H), 1.90 (m, 2H), 1.95 (m, 1 H), 2.72 (t, 1 H), 2.95 (t, 1 H), 3.30 (m, 1 H), 3.55 (m, 1 H), 3.65 (t, 2H), 3.75 (m, 1 H), 3.92 (t, 1 H), 4.12 (t, 1 H) 4.35 (d, 2H), 7.11 (d, 1 H), 7.48 (m, 1 H), 7.65 (t, 1 H), 7.68 (t, 1 H), 7.8 (dd, 1 H}, 7.87 (d, 1 H), 8.00 {d, 1 H), 8.03 (d, 1 H), 8.83 (d, 1 H}, 9.10 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI):
519.5, 521.2, 522.2.
EXAMPLE 358:
~N.CH~
o ~ I NJ
I.
.N. ~ I O
I , H
HO
'H NMR (DMSO-D6): 8 2.19 (s, 3H}, 2.30 (m, 4 H), 3.50 (T, 2H), 3.58 (T, 2H), 4.22 (S, 2H), 7.03 (D, 1 H), 7.43 (D, 1 H), 7.64 (quint, 2H) 7.77 (dd, 1 H), 7.87 (d, 1 H), 7.99 (d, 1 H}, 8.04 (s, 1 H), 8.83 (d, 1 H), 9.09 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 465.2, 467.3.
EXAMPLE 359:
N
~I ~J I~
.N. ~ I O
I H
HO
CI
'H NMR (DMSO-De): 8 2.38 (m, 4H), 3.51 (s, 4H), 3.61 (t, 2H), 4.22 (s, 2H), 7.08 (d, 1H), 7.31 (m, 5H), 7.43 (d, 1 H), 7.61 (quintet, 2H), 7.82 (dd, 1 H), 7.88 (d, 1 H), 8.00 (s, 1 H), 8.02 (d, 1 H), 8.85 (d, 1 H), 9.10 (s, 1 H), 11.80 (brd s, 1 H); MS (APCI): 541.4, 543.1.
EXAMPLE 360:
CHI OH
O ~ I N w . N w w I O CHI I i I~ H
HO
CI
'H NMR (DMSO-Ds): b 1.33 (dd, 3H), 2.76 (s, 1.5H), 2.96 (s, 1.5H), 3.61 (d, 1 H), 4.14 (quintet, 1 H), 4.65 (m, 2H), 7.10 (m, 2H), 7.33 (s, 3H), 7.42 (m, 3H), 7.54 (m, 2H), 8.02 (t, 1 H), 8.80 (m, 1 H), 9.07 (brd, 1 H), 11.80 (brd s, 7 H); MS (APCI): 530.2, 532.2.
EXAMPLE 361:
cH, off o ~I N w .N, ~ ~ o I~ H
HO
CI
'H NMR (DMSO-D6): s[2.94 (s, 1.5H) + 3.10 (s, 1.5H), 3H], 3.54 (m, 2H), 4.00 (d, 1H), 4.28 (d, 1 H), 4.81 (t, 1 H}, 4.96 (t, 1 H), 7.09 (d, 1 H), 7.35 (m, 3H), 7.43 (m, 3H), 7.61 (m, 2H), 7.83 (m, 3H), 8.04 (s, 1 H), 8.85 (t, 1 H), 9.11 (d, 1 H), 11.80 (brd s, 1 H); MS
(APCI): 516.3, 518.2.
EXAMPLE 362:
to o w N
.N. ~ I O 'N
HO
CI
'H NMR (DMSO-D6): 8 2.75 (t, 1 H), 2.95 (t, 1 H), 3.59 (t, 1 H), 3.80 (t, 1 H), 4.38 (brd s, 3H), 4.61 (s, 1 H), 4.84 (s, 1 H), 6.40 (d, 1 H), 6.53 (d, 1 H), 7.05 (d, 1 H), 7.45 (t, 1 H), 7.58 (m, 3H), 7.81 (m, 3H), 8.00 (brd, 2H), 8.83 (d, 1 H), 9.10 (s, 1 H), 11.78 (brd s, 1 H); MS (APCI, neg.):
513.3, 514.2.
WO 99!01423 PCT/DK98/00287 EXAMPLE 363:
NHZ
O ~ I N
II
.N. ~ I O
~ H
HO
CI
'H NMR (DMSO-D6): 8 1.50 (m, 2H), 1.68, (d, 2H), 2.28 (t, 1 H), 2.59 (t, 1 H), 3.05 (t, 1 H), 3.96 (d, 1 H), 4.16 (s, 2H), 4.32 (d, 1 H), 6.74 (brd s, 1 H), 6.95 (d, 1 H), 7.22 (brd s, 1 H), 7.36 (d, 1 H), 7.57 (quintet, 2H), 7.71 (dd, 1 H), 7.79 (d, 1 H), 7.92 (dd, 1 H), 7.96 (d, 1 H), 8.76 (d, 1 H), 9.01 (s, 1 H), 11.80 (brd s, 1 H); MS (ACPI): 493.1, 495.2.
EXAMPLE 364:
cH, O w I N~N.CH~
II
.N. w I O CHI
I~ H
HO
'H NMR (DMSO-D6): 8 2.10 (s, 3H), 2.15 (s, 3H), 2.29 (t, 1 H), 2.40 (t, 1 H), 2.80 (s, 1 H), 3.05 (s, 2H), 3.36 (t, 1 H), 3.46 (t, 1 H}, 4.16 (d, 2H), 7.01 (d, 1 H), 7.38 (t, 1 H), 7.56 (m, 2H), 7.72 (dd, 1 H), 7.79 (d, 1 H), 7.94 (m, 2H), 8.77 (d, 1 H), 9.02 (s, 1 H), 11.71 (brd s, 1 H); MS (ACPI):
467.3, 469.1.
EXAMPLE 365:
O w I N~N.CH~
II
.N ~ ~ I O CHs i~
HO
CI
'H NMR (DMSO-De): 8 2.11 (s, 3H}, 2.14 (s, 3H), 2.33 (t, 1 H), 2.39 (t, 1 H), 3.37 (t, 1 H), 3.46 (t, 1 H), 4.14 (s, 1 H), 4.32 (s, 1 H), 4.55 (s, 1 H), 4.74 (s, 1 H), 7.05 (d, 1 H), 7.23 (d, 1 H), 7.29 (m, 3H), 7.38 (t, 1 H), 7.43 (d, 1 H), 7.57 (m, 2H), 7.81 (m, 2H), 7.97 (s, 1 H), 8.06 (d, 1 H), 8.79 (t, 1 H), 9.05 (s, 1 H}, 11.75 (brd s, 1 H); MS (APCI): 543.2, 545.2.
EXAMPLE 366: EXAMPLE 371:
OH ~ CHI i O ~ I N ~ O ~ I N ~ I
.N~ ~ I O CHI I / .N~ ~ I O
I ~ 'H I ~ H
HO ~ HO
CI CI
EXAMPLE 367: EXAMPLE 372:
CHI
I i N.N~ w I 0 F O \ I N~N
I H ~ .N~ w O
HO ~ I , H
CI HO
CI
EXAMPLE 368:
cH, ~ 5 EXAMPLE 373:
O ~ CHz 0 w N w N.N~ ~ I O ~ ~ I N
O
HO I ~ H I ~ ~ N.N ~ W I O N
CI I , H
HO
EXAMPLE 369: CI
cl EXAMPLE 374:
~N
~I NJ ,I
O I / (~N~
N.N~ ~ O ~ I NJ CI
O
HO I ~ H ~ N.N~ w I O
CI I , H
HO
EXAMPLE 370: CI
i cH~ ~ I EXAMPLE 375:
O w N
i N.N~ w I O CI
I H ~ ~N CHI
HO ~ ~ I NJ' 1 O CI I ~ O H. N . W I O CHI
HO
20 cl EXAMPLE 376: EXAMPLE 381:
cl H
i ~N ~ O ~ N
O w I NJ OMe ~ .N~ w I O I i I H CI
H.N. w I O HO
HO ~ 15 Cf CI
EXAMPLE 382:
EXAMPLE 377: cH, o ~I N\
~N~CH ~ N.N . w O ~ CH
O w I NJ CHa a HO I i H w I
I I
.Nw W I O CI
I~ H
HO
cl 20 EXAMPLE 383:
H
EXAMPLE 378: o ~ N
I n .N. ~ O
I HO I ~ H ~ I
~N
O ~ I N J CI
.N. w I o EXAMPLE 384:
I
HO ~ CH3 CI O ~ N
N.N . ~ I O
EXAMPLE 379: I ~ H
CI CI
a w I N w I cl EXAMPLE 385:
II
.N~ ~ I O N
II
HO
CI I
N
EXAMPLE 380: \ c_ N. N , ~ ( o I ~ H
I H HO
o ~ ~ 25 C1 H.N~ ~ I o I ~ C!
HO
CI
EXAMPLE 386: EXAMPLE 390:
~N w I ~.NJLO
O , N J O ~ I N H C-'T CHa N.N. w I O ~ N.N. w O CHz H \ I Ho I ~ H I
HO
CI CI
EXAMPLE 387:
H,c 1 EXAMPLE 391:
N
~O~~~
O i N ./u I ~~ ~ N.
N.N . w O O I ~ CH, I H I ~ .N . ~ O
HO ~ \ I / H
CI HO
EXAMPLE 388:
EXAMPLE 392:
H
N F OH
O i N
I
N.N. w O O
ii I-fO I~ H ~I ~ N.N. ~) 0 CI HO I i H
CI
EXAMPLE 389:
cH, 2o EXAMPLE 393:
J
~0 ~ N
O i I N ~ N.N. w I O
I ~ H.N. w I O O O HO I ~ H ~ N
HO ~ ~ 'CH, CI U
CI
EXAMPLE 394: EXAMPLE 398:
~N~o 0 ~ I ~ O / N ~HaC J
n I ~ H.N . ~ I O ~ .N . ~ I O
I~ H ~I
HO HO
CI Ci EXAMPLE 395: EXAMPLE 399:
O ~ CH3 o ~I
N J " N ~ CH3 i O I ~ HOC
N.N. ~ O
I , H \ I O , NH
ii HO ~ N.N . ~ I O
S CI I ~ H ~ I
HO
Ct EXAMPLE 396:
O N
N.N. W I O , N H F
I ~ H ~ I ~ I O .N. w I Or HO CI O J HO I ~ H
10 EXAMPLE 397:
EXAMPLE 401:
cH, N N H
O i I NON I w O ~ I ~ N.N. ~ O
.N . w O I H I
I H I Hp HO CI
CI
N EXAMPLE 400:
EXAMPLE 402: EXAMPLE 406:
I
~N ~ ~ I
O i I NJ N O i I N~0 N.N. w 0 ~ N.N. w 0 r0 HO I ~ H I HO I i H ~ I CHI
CI CI
EXAMPLE 403: EXAMPLE 407:
/ F CHI
O / NON \ I 0 ~ I N
.N . w I O H ~ N.N . w O
H ~ ~ ~ H ~ I CH3 HO ~ ~ HO
EXAMPLE 404: EXAMPLE 408:
0 N ~ I 0 ~ I N - III
N.N . w I I O Cl I ~ H.N ~ y ( O N
HO I ~ H HO
CI 2~ CI
10 EXAMPLE 405: EXAMPLE 409:
F
I O .i N p~F
H ~ ~ N.N ~ ~ I p 0 ~ N HO I i H ~ I I i a I ~ H.N . ~ ( 0 O NHZ CI
HO
CI
EXAMPLE 410: 15 EXAMPLE 415:
i F CHI
O , N ~ I O ~ N
N.N . w I O I I ~ N.N ~ w I O ~N.CH3 I , H ~ I N HO ~ H
HO
CI CI
EXAMPLE 471: EXAMPLE 416:
O ~N
N H
O ~( z ~N
I NH O
.N . ~ o ~ I
I H I I I ~ H.N . w ( 0 HO
CI HO
CI
EXAMPLE 412: EXAMPLE 417:
CHz N H
O I ~ , N
N.N. ~ O ~ OH 0 I
I H ~ I HO I ~ ~ .N . w 0 ~N.CH~
HO
CI HO
CI
10 EXAMPLE 413:
EXAMPLE 418:
H F
N ~ O
O ~( .N. ~ I O FF ~ IOI
I H ~ O , N
HO ~ ~ I n CI ~ N.N . ~ O
I~ H ~I
HO
CI
EXAMPLE 414:
H EXAMPLE 419:
N
O i I N~ O
I ~ H.N. w I O F~ ~ \
HO ~ F O N \
CI I ~ H.N ~ w ~N I
HO ~ O H
CI
EXAMPLE 420: EXAMPLE 425:
/ v / v 0 0 / \
N.N~ ~ ~ ~ N.N. w N //-N O N~-N
HO 1 ~ H 0 H HO I ~ H O ~._/N
CI CI
EXAMPLE 421: EXAMPLE 426:
/ ~ / ~ / \
O : HJ N_ O
N.N~ ~ N~- N~~ / ~ .N~ w N~ N
I , H p H N~ I H
HO CFA HO ~ O
CI 2~ CI
EXAMPLE 422: EXAMPLE 427:
N ' ~ v v I
N.N. w N ~ .N~ w N OH
H O N
HO ~H I , H ~ \ /
HO
CI CI
EXAMPLE 423: 25 EXAMPLE 428:
l 0 ~ 0 NHi O ~ _ N.N~ ~ N \ / ~ .N. ~ N-\
H N I H
HO HO i O / \
CI CI
EXAMPLE 424: EXAMPLE 429:
/ v / v 0 ~ N S 0 .,.
.N~ ~ ~ \ I .N~ ~ N
N
HO I ~ H O H HO I ~ 'H O H / \
CI CI
EXAMPLE 430:
/ \
O _ H3C
N_ N-CH, N. N ~ ~ \ll//--~~
N _ HO I ~ H O
\ /
CI
EXAMPLE 431:
20 EXAMPLE 435:
/ \ I ~
NH ~ H
O
.N~ w N O
H ~ ~ N.N~ I i N
HO I H N
CI HO
CI
EXAMPLE 432:
EXAMPLE 436:
/ \ cH, O ~ O ~ ~N
.N~ ~ N .N~ I i N ~ N~ I ~ H N
I , H O ~N \ / F HO
HO
CI CI
75 EXAMPLE 433: EXAMPLE 437:
\ O ~ J N
p ~ N~ ~ N.N~ I i I H N
N N OH
I H ~N N HO
HO ~ O ~ \ / CI
CI
EXAMPLE 438:
EXAMPLE 434:
O N
O I w O NCH, ~ N.N ~ I i N O
H.N~ / N I , 'H 0 HO
HO ~ 30 CI H,C
EXAMPLE 439: EXAMPLE 444:
~CHz w 0 ~H~
O I J N /
O ~ 0 ~ N.N
I N I H N N
N'N ~ ~ N ~~ HO
HO I ~ H N CI
CI
EXAMPLE 445:
EXAMPLE 440: o I ~ ~N / \
O I \ O ~ I % H.N ~ / ~JN
.N~ i HO
HO
CI
EXAMPLE 446:
EXAMPLE 441: o ~ o N N
CH3 OH ~ N.N ~ ( / N ~ / \
O I ~N I ~ H
.N. i ~J HO
H / \ CI
HO
CI
25 EXAMPLE 447:
EXAMPLE 442: o w o N /
NCH f ~ N.N~ I / N N
O I N I , H
N.N. / N~ \ I HO
CI
HO I ~ H F
CI
EXAMPLE 448:
EXAMPLE 443: o I ~ o ~", - / o OH ~ N.N. ~ N
I , H
O ~ O ~ HO
I H.N' I / N N CI
HO
CI
EXAMPLE 449: EXAMPLE 452:
H,c N-CH, O I w O ~ ~ O N.N~ I i H.N. ~ N~ \ / HO I , H N N/
HO ~ Ct CI
EXAMPLE 450:
EXAMPLE 453:
o w o _ N
N.N ~ I / N O \ O ~ \ ~ CI
HO I ~ H OH ~ N.N w I
N
CI HO ( , H
Ct EXAMPLE 451:
EXAMPLE 454:
~cHz cH, w o ~ o O ~N I N
H.N. I / N NCH I % H.Nw / N
i HO ~ HO
rPneral procedure for synthesis of comr~ounds of the general formula XIII:
A~ ,NHz O
o\\ /B\ /oH
N B OH
H O step A p, H O
O R5°
NHRxR~ ~ ~N B N/
step B A
H O
formula XIII
A and B are as defined far formula I and -NRxRSd is Rsa Rna R4b -N-(CHZ)~~(CHZ)a O where Rsa, R4a, R4b, c, q, d and D are as defined for for-mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent.
The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tent-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloro-methane, DMSO, acetic acid, water or a compatible mixture of two or more of the above sol-vents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethylort-hoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C
to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli-zed if necessary from a solvent such as the above described reaction solvents.
The product can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroformlmethanol or dichloro-methanelmethanol or chloroformlethyl acetate.
Step B: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an an-y hydride or an acid halide that can then react with the amine to give a compound of formula XIII.
The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XIII.
Specific examples illustrating the preparation of compounds of the general formula XIII accor-ding to the invention are provided below.
Preparation of 4-formylnaphthoic acid is depicted below:
O OH O OH O OH O OMe CHI Br'CHZ HO'CH2 HO'CHZ
O OMe O OH
i i i i H O H O
4-Bromomethylnaphthoic acid:
A mixture of 4-methylnaphthoic acid (10 g, 54 mmol), N-bromosuccinimide (10 g, 56 mmol) and AIBN (100 mg) in CC14 (250 mL) was refluxed for 3 hr. The reaction mixture was con-centrated and dissolved in ethyl acetate. The organic layer was washed with water, brine and dried over MgS04. Evaporation of the solvent gave the desired product (16 g, 80%).
'H NMR (DMSO-D6): 8 5.24 (s, 2H), 7.73 (m, 3H), 8.03 (d, 1 H), 8.28 (d, 1 H), 8.86 (d, 1 H), 13.29 (brd s, 1 H).
4-Hydroxymethylnaphthoic acid:
4-Bromomethylnaphthoic acid (16 g, 60 mmol) in an aqueous solution of KzC03 (10%, 100 mL) was stirred at 70 °C for 30 minutes. The reaction mixture was cooled and made acidic with conc. HCI. The resulting precipitate was filtered and dried to give the desired product as a yellow solid in quantitative yield.
'H NMR (DMSO-Ds) ; 8 5.01 (s, 2H), 5.96 (s, 1 H), 7.70 (m, 3H), 8.10 (m, 2H), 8.90 (d, 1 H).
Methyl 4-hydroxymethylnaphthoate:
A mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 mL), and conc.
HZS04 {2 mL) was refluxed overnight. The insolubles were filtered off and the filtrate was concentrated. The residue was taken up in ethyl acetate and washed with aqueous NaHC03 (2x), brine, dried over MgSO,, and concentrated to give a yellow oil. Silica gel column chro-matography using ethyl acetate/hexane (113) gave the desired product as a yellow oil (3.3 g, 35%).
'H NMR (CDCI3): 8 2.05 (t, 1H), 4.01 (s, 3H), 5.22 (s, 2H), 7.66 (m, 3H), 8.09 (d, 1H), 8.16 (d, 1 H), 8.96 (d, 1 H).
Methyl 4-formylnaphthoate:
To a solution of methyl 4-hydroxymethylnaphthoate above (3.3 g, 15.3 mmol) in dichloro-methane (20 mL) was added Mn02 (6.6 g, 76 mmol). After stirring the dark mixture for 16 hours, the insolubles were filtered through a bed of Celite. Evaporation of the solvent gave the desired product as a white solid in quantitative yield.
'H NMR (CDC13): b 4.06 (S, 3H), 7.75 (m, 2H}, 8.03 (d, 1H), 8.20 (d, 1H), 8.80 (d, 1H), 9.27 (d, 1 H), 10.50 (s, 1 H).
4-Formylnaphthoic acid:
A mixture of the methyl 4-formylnaphthoate above (2.3 g, 1 mmol) and Na2C03 (1.25 g, 12 mmol) in water (30 mL) was heated in a water bath for approximately 2 hr until a clear soluti-on was obtained. The solution was cooled and filtered. The filtrate was acidified with conc.
HCI to give a yellow precipitate. The solids were collected and dried over night to give the desired product (1.86 g, 87%).
'H NMR (DMSO-D6): 8 7.76 (m, 2H), 8.22 (m, 2H), 8.71 (d, 1 H), 9.20 (d, 1 H), 10.49 (s, 1 H}.
4-[(3-Chloro-4-hydroxybenzoy~}hvdrazonomethyl]n~nhthoic acid~step A~:
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (1.53 g, 8.23 mmol) in DMSO (20 15 mL) was added a solution of 4-formylnaphthoic acid (1.65 g, 8.23 mmol) in DMSO (2 mL).
After stirring the solution for 16 hr, the reaction was diluted with ethyl acetate (30 mL) and water (30 mL). A precipitate formed. The precipitate was collected washed with hexane and dried to give the product as a white solid in quantitative yield.
20 'H NMR (DMSO-Ds): 8 4.70 (d, 1 H), 7.70 (m, 2H), 7.83 (d, 1 H), 8.03 (m, 2H), 8.18 (d, 1 H), 8.72 (s, 1 H), 8.90 (d, 1 H), 9.17 (s, 1 H), 11.0 {brd s, 1 H), 11.94 (s, 1 H), 13.4 (brd s, 1 H); MS
(APCI, neg): 368.5, 370.2).
General procedure 25 Derivatives of 4-[l3-Chloro-4-hydroxybenzoyl)hydrazonamethy]naphthamides ~ste~B):
To a solution of a derivative of4-[(4-hydroxybenzoyl)-hydrazonomethylJnaphthoic acid in DMSO was added carbonyldiimidazole (1.2 eq). The solution was agitated for 5 minutes and diluted with DMSO to a concentration of 50 mM. The solution was then dispensed inta 88 30 deep well plates containing solutions of amines in DMSO (50 mM}. The plates were covered and agitated for 16 hours. The products were purified by HPLC.
The following compounds of formula XIII were prepared:
EXAMPLE 455:
ct o ~ I oN ~ I
I ~ H~N~ ~ I H
HO
CI
'H NMR (DMSO-DB): 8 2.91 (t, 2H), 3.67 (t, 2H), 7.12 (d, 1 H), 7.38 (qt, 4H), 7.58 (t, 2H), 7.70 (t, 1 H), 7.50 (d, 1 H}, 7.95 (d, 2H), 8.03 (s, 1 H), 8.69 (brd t. 1 H), 8.81 (d. 1 H), 9.12 (s, 1 H), 11.02 (s, 1 H), 11.89 (s, 1 H); MS {APCI): 507.3, 508.5.
EXAMPLE 456:
o ~ I N ~ cl N.N. w I w I
I~ H
HO
CI
'H NMR (DMSO-DB): 8 2.20 (brd m, 1 H), 2.30 (brd m, 1 H), 2.55 (m, 2H), 3.10 (brd m, 2H), 3.50 (s, 2H), 3.72 (brd m, 1 H), 3.85 (brd m, 1 H), 7.10 (d, 1 H), 7.36 (qt, 4H), 7.53 (d, 1 H), 7.70 (m, 2H); 7.82 (m, 2H), 7.95 (d, 1 H), 8.03 (s, 1 H), 8.88 (d, 1 H), 9.11 (s, 1 H), 11.00 (brd s, 1 H), 11.89 (s, 1 H); MS (APCI, neg.): 559.2, 561.2.
EXAMPLE 457: 15 EXAMPLE 462:
\ I o ~N I ~ ~ I o O I ~ O \ N~ O.CH~
H.N~ \ I \ H.Nw \ I N I \
HO HO
CI CI
EXAMPLE 458: EXAMPLE 463:
O \ I O N OH \ I CI ~ O CF3 \I
I H
\ N.N. \ \ O .N w \ I H I , I~ H I~ H
HO HO
CI CI
EXAMPLE 459: EXAMPLE 464:
\ I o ~N ~ I o ~ I
o I H o \ N
\ N.N~ \ ~ ~ \ .N~ \ I H F
I i H I i H
HO HO
CI CI
10 EXAMPLE 460: EXAMPLE 465:
o F ' I p ~ I
O N
\ O .N~ \ I H I ~ .Nw \ I H CI
HO I ~ H
HO
EXAMPLE 461: EXAMPLE 466:
o ~ I o \ o ~ N
\ O N.N w ~ I H I i CI \ N.N w \ I \ I
H I ~ H
HO HO
CI CI
EXAMPLE 467: EXAMPLE 472:
~ I o ~ I o ~ ~ o ~ N''~
O N.N~ w I H I ~ ~ N.N~ w I ~N w H I H
HO H3C~N~CH3 HO ~ ~ F
CI CI
EXAMPLE 468: EXAMPLE 473:
~ I o ~ I o O ~ I N~ O ~ I N~ F
.N ~ ~ ~N .N ~ ~ ~N
I~ H I~ I~ H I~
HO Y HO
cl 20 CI
EXAMPLE 469: EXAMPLE 474:
~ I o ~ 1 0 O w N~CH3 O \ I
I ~ H.N ~ W I ~N I ~ CH3 I \ H-N ~ w N~CF~
i HO ~ ~ 'fO
HO
C CI
EXAMPLE 470: 25 EXAMPLE 475:
~ I o ~ I CI ~ I o o \ I H ~ o \ I H I ~
N.N ~ W I ~ ~.N ~ w ~ CN
I ~ H
HO HO
CI CI
EXAMPLE 471: EXAMPLE 476:
~ i o ~ o cl o w N ~ CI o ~ I N ~ I
N.N~ ~ I H I i CI ~ N.N~ ~ I 'H CI
I , H I / H
HO HO
CI CI
EXAMPLE 477: EXAMPLE 482:
~ I o O ~ I N~CN
O N
.N ~ ~ I CHs .N ~ ~ I
I H I W' '~. cHZ
HO Y HO
CI CI
EXAMPLE 478: EXAMPLE 483:
I I
i O O ~ N
CFs O ~ N NHZ ~ . N ~ ~ I H
H.N~ w I H O I ~ H
HO
Ho ~ 20 cl CI
EXAMPLE 484:
EXAMPLE 479:
i I O O w N~CFs O ~ I N ~ N.N~ ~ I H I i F
N.N ~ ~ ~OvCHs HO I ~ H
HO I ~ H [O~ CI
CI
25 EXAMPLE 485:
EXAMPLE 480:
~ I o o w I N
O ~ I N~ HsC ~ N.N ~ W N I w I H N \ ~N~O~CHs I / H
HO CI
HO ~ O CHs CI
CI
EXAMPLE 486:
EXAMPLE 481:
o ~ ~ N'~ cl .N~ ~ ~N
O N
N.N ~ ~ I ~N ~ I ~ H I , 'H HO
HO I ~ CI
of 30 EXAMPLE 487: EXAMPLE 492:
O F ~ O CN
I
I
o \ I H I ~ F o ~ N
.N~ W i ~ .N~ ~ I H I , H I 'H F
HO ~ HO
CI CI
EXAMPLE 488: EXAMPLE 493:
~ I o -' I F ~ I o O \ I H \ O \ I H~N~CHs N.N~ ~ ~ N.N~
I H I H
HO ~ HO ~ HOC
EXAMPLE 489: EXAMPLE 494:
O OCF
O CI I
O ~ I N ~ O ~ N
I ' I ~ .N~ ~ I H i ~
.N~ ~ CHI i N
I ,H I / H
HO ~ HO
CI CI
EXAMPLE 490: 25 EXAMPLE 495:
I o F ~ I I ~
O N
O .N~ ~ I H I , ~ N.N~ ~ I CHI I
N I H
HO I ~ H HO
CI CI
EXAMPLE 491: EXAMPLE 496:
i I o ~ I o ~ I
O NON
O N. N ~ ~ I N CN I ~ H.N w w I H CH3 I / H HO i HO ~ CHa CI
CI
EXAMPLE 497: EXAMPLE 502:
~ I o _I
O H.N~ ~ I H O ~ I N N I
HO ~ ~ N.N~ w I H O I i CI HO I , H
CI
EXAMPLE 498:
EXAMPLE 503:
~I o ~I
O ~ N ~ i O i H. N ~ w I CHs OH O ~ I N
~OH
HO ~ ~ N.N ~ y I CHI OH
CI HO I / H
EXAMPLE 499:
EXAMPLE 504:
O ~ I N~OH ~ I O CI
N.Nw W O ~ N W
I / H .N~ ~ ~ H I , HO ~ 'N F
CI O ~ ~ H
CI
EXAMPLE 500:
25 EXAMPLE 505:
~ I o ~ I
O \ N ~ ~ O
N.Nw W I H r0 O w I N N
HO I ~ H CHa ~ N.N w W I CHI
CI HO I , H
Cl EXAMPLE 501:
off EXAMPLE 506:
o w I o N~s w I o N-N ~ ~ I H O i NH F
I
I , H ~ N.N. ~
F
HO I H I I ~ F
CI HO Y F
zs7 EXAMPLE 507:
cl I
O i N
N.N. ~ I OH
I , H
HO
CI
General procedure for synthesis of compounds of the general formula XIV
Rs' O B OH NNR~R~ O B N.RSa step A
O O
O
iNHz A
step B
O Rs' I
B N ~ Rsa H O
formula XIV
A and B are as defined for formula I and -NR5'Rs° is R~ Raa R4e -N-(CHZ)~~(CHZ)d Q where Rsa, R°a, R4b, c, q, d and D are as defined for for-mula I or -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
~ 5 Step A: The acid is coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an anhydride or WO 99/01423 PC'f/DK98/00287 an acid halide that can then react with the amine to give a compound of formula XIV. The pro-duct can then be isolated either by fltration or by extraction using a solvent such as ethyl ace-tate, toluene, dichloromethane or diethylether and the solvent may then be removed by con-centration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dich-loromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a com-pound of formula XIV.
Step B: The carbonyl compounds are then treated with an acylhydrazide in a solvent. The sol-vent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, butyl al-cohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dich-loromethane, DMSO, acetic acid, water or a compatible mixture of two or more of the above solvents. A catalyst such as acetic acid can be added. A dehydrating reagent such as triethy-lorthoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of NZ or Ar at temperatures between 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recry-stallized if necessary from a solvent such as the above described reaction solvents. The pro-duct can also be isolated by concentration of the reaction mixture in vacuo, followed by column chromatography on silica gel using a solvent system such as chloroform/methanol or dichloro-methane/methanol or chloroform/ethyl acetate.
Specific examples illustrating the preparation of compounds of the general formula XIV accor-ding to the invention are provided below.
The preparation of 3-(4-formylnaphthalene)propanoic acid is depicted below:
DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDS OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST lE TOME ~ DE~
NOTE: Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLlCATI4NSIPATENTS
THiS SECTION OF THE APPL.ICATION/PATENT CONTAINS MORE
THAN ONE VOLUME
THIS IS VOLUME ~/ OF Z
f f t NOTE:.For additional voiumes~piease cantact'the Canadian Patent Office
Claims (39)
1. A compound of the general formula (I):
wherein R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, C1-5-alkyl, aryl, -SCF3, -SR11, -CHF3, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13 or -OSO2CF3, or R8 and R9 together form a bridge -OCH2O- or -OCH2CH2O-, R11 and R12 independently are hydrogen, -COR13, -SO2R13, C1-6-alkyl or aryl, R13 is hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or aryl, R4 is hydrogen or C1-6-alkyl, B is R14 and R15 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CH2)1CF3, -NO2, -OR16, -NR16R17, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)1CONR16R17, -O(CH2)1CONR16R17, -(CH2)1COR16, -(CH2)1COR15, -(CH2)1OR18, -O(CH2)1OR16, -(CH2)1NR16R17, -O(CH2)1NR16R17, -OCOR16, -CO2R18, -O(CH2)1CO2R18, -O(CH2)1CN or -O(CH2)1Cl, or R14 and R15 together form a bridge -O(CH2)1O- or -(CH2)1-, I is 1, 2, 3 or 4, R16 and R17 independently are hydrogen, -COR18, -SO2R18, C1-6-alkyl or aryl, or R16 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms, R18 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, W is -N= or -CR19=, Y is -N= or -CR20=, Z is -N= or -CR21=, V is -N= or -CR22=, R19, R20, R21 and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR24R25, -OCOR24 or -CO2R24, or R19 and R20, R20 and R21, or R21 and R22 together form a bridge -OCH2O-, R24 and R25 independently are hydrogen, -COR28, -SO2R26, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R26 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, K is R3a, R3b, R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a or -CO2R24a, R24a and R25a independently are hydrogen, -COR25a, -SO2R26a, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R26a is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, or R3a and R3b, R4a and R4b, or R3a and R4b together form a bridge -(CH2)i-, i is 1, 2, 3 or 4, a, b, c and d independently are 0, 1, 2, 3 or 4, e, f and p independently are 0 or 1, q is 0, 1 or 2, L and M independently are -O-, -S-, -CH=CH-, -C=C-, -NR5a-, -CH2NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -CONR5b-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2NR5a-, -NR5a SO2-, -NR5a CONR5b-, -CONR5a NR5b-, -NR5a CSNR5b-, -OCONR5b-, -CH2CONR5b-, -OCH2CONR5b-, -P(O)(OR5a)O-, -NR5aC(O)O- Or R5a and R5b independently are hydrogen, C1-5-alkyl, -OH, -(CH2)k-OR6a, -COR6a, -(CH2)k-CH(OR6a)2, -(CH2)k-CN, -(CH2)k-NR6aR6b, aryl, aryl-C1-6-alkyl, -(CH2)9-COOR43 or -(CH2)g-CF3, k xis 1, 2, 3 or 4, R6a and R6b independently are hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, g is 0, 1, 2, 3 or 4, R43 is hydrogen or C1-6-alkyl, G" is -OCH2CO-, -CH2CO-, -CO- or a valence bond, E" is -CH2-, -CH2CH2-, -CH=CH-, -CH2NH- or -CH2CH2NH-, m is 0 or 1.
D is hydrogen, r is 0 or 1, s is 0, 1, 2, 3, R38 is hydrogen, -OR40, -NR40R41, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)xCONR40R41, -O(CH2)X CONR40R41, -(CH2)XOR40, -(CH2)X NR40R41, -OCOR40 or -CO2R40, x is 1, 2, 3 or 4, R40 and R41 independently are hydrogen, -COR42, -SO2R42, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R42 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, except for the following compounds:
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
wherein R8 and R9 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, C1-5-alkyl, aryl, -SCF3, -SR11, -CHF3, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13 or -OSO2CF3, or R8 and R9 together form a bridge -OCH2O- or -OCH2CH2O-, R11 and R12 independently are hydrogen, -COR13, -SO2R13, C1-6-alkyl or aryl, R13 is hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or aryl, R4 is hydrogen or C1-6-alkyl, B is R14 and R15 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CH2)1CF3, -NO2, -OR16, -NR16R17, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)1CONR16R17, -O(CH2)1CONR16R17, -(CH2)1COR16, -(CH2)1COR15, -(CH2)1OR18, -O(CH2)1OR16, -(CH2)1NR16R17, -O(CH2)1NR16R17, -OCOR16, -CO2R18, -O(CH2)1CO2R18, -O(CH2)1CN or -O(CH2)1Cl, or R14 and R15 together form a bridge -O(CH2)1O- or -(CH2)1-, I is 1, 2, 3 or 4, R16 and R17 independently are hydrogen, -COR18, -SO2R18, C1-6-alkyl or aryl, or R16 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms, R18 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, W is -N= or -CR19=, Y is -N= or -CR20=, Z is -N= or -CR21=, V is -N= or -CR22=, R19, R20, R21 and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR24R25, -OCOR24 or -CO2R24, or R19 and R20, R20 and R21, or R21 and R22 together form a bridge -OCH2O-, R24 and R25 independently are hydrogen, -COR28, -SO2R26, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R26 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, K is R3a, R3b, R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24aR25a, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a, -CH2CONR24aR25a, -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24aR25a, -OCOR24a or -CO2R24a, R24a and R25a independently are hydrogen, -COR25a, -SO2R26a, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R26a is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, or R3a and R3b, R4a and R4b, or R3a and R4b together form a bridge -(CH2)i-, i is 1, 2, 3 or 4, a, b, c and d independently are 0, 1, 2, 3 or 4, e, f and p independently are 0 or 1, q is 0, 1 or 2, L and M independently are -O-, -S-, -CH=CH-, -C=C-, -NR5a-, -CH2NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -CONR5b-, -NR5aCO-, -SO-, -SO2-, -OSO2-, -SO2NR5a-, -NR5a SO2-, -NR5a CONR5b-, -CONR5a NR5b-, -NR5a CSNR5b-, -OCONR5b-, -CH2CONR5b-, -OCH2CONR5b-, -P(O)(OR5a)O-, -NR5aC(O)O- Or R5a and R5b independently are hydrogen, C1-5-alkyl, -OH, -(CH2)k-OR6a, -COR6a, -(CH2)k-CH(OR6a)2, -(CH2)k-CN, -(CH2)k-NR6aR6b, aryl, aryl-C1-6-alkyl, -(CH2)9-COOR43 or -(CH2)g-CF3, k xis 1, 2, 3 or 4, R6a and R6b independently are hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, g is 0, 1, 2, 3 or 4, R43 is hydrogen or C1-6-alkyl, G" is -OCH2CO-, -CH2CO-, -CO- or a valence bond, E" is -CH2-, -CH2CH2-, -CH=CH-, -CH2NH- or -CH2CH2NH-, m is 0 or 1.
D is hydrogen, r is 0 or 1, s is 0, 1, 2, 3, R38 is hydrogen, -OR40, -NR40R41, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)xCONR40R41, -O(CH2)X CONR40R41, -(CH2)XOR40, -(CH2)X NR40R41, -OCOR40 or -CO2R40, x is 1, 2, 3 or 4, R40 and R41 independently are hydrogen, -COR42, -SO2R42, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R42 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, except for the following compounds:
as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R8 and R9 independently are hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, -O-C1-6-alkyl, C1-6-alkyl or phenyl.
3. A compound according to claim 2, wherein R8 and R9 independently are hydrogen, halogen, -O-C1-6-alkyl, -NH2, -CN or -NO2.
4. A compound according to claim 1 of the general formula (II):
wherein R8 is hydrogen, halogen, -O-C1-6-alkyl, -NH2, -CN or -NO2, and R9 is hydrogen or halogen.
wherein R8 is hydrogen, halogen, -O-C1-6-alkyl, -NH2, -CN or -NO2, and R9 is hydrogen or halogen.
5. A compound according to any one of the claims 1 to 4, wherein R4 is hydrogen.
6. A compound according to claim 1 of the formula (III):
wherein R8, R9, R14, R15, K, D and m are as defined in claim 1.
wherein R8, R9, R14, R15, K, D and m are as defined in claim 1.
7. A compound according to claim 1 of the formula (IV):
wherein R8 is halogen, and R9, R14, R15, K, D and m are as defined in claim 1.
wherein R8 is halogen, and R9, R14, R15, K, D and m are as defined in claim 1.
8. A compound according to claim 1 of the formula (V):
wherein R8, R9, R14, R15, K, D and m are as defined in claim 1.
wherein R8, R9, R14, R15, K, D and m are as defined in claim 1.
9. A compound according to claim 1 of the formula (VI):
wherein R8 is halogen, and R9, R14, R15, K, D and m are as defined in claim 1.
wherein R8 is halogen, and R9, R14, R15, K, D and m are as defined in claim 1.
10. A compound according to claim 1 of the formulae (V11a) or (V11b):
or Wherein R8, R9, R14, R15, K, D and m are as defined in claim 1.
or Wherein R8, R9, R14, R15, K, D and m are as defined in claim 1.
11. A compound according to claim 1 of the formulae (VIIIa) or (VIIIb):
R8 is halogen, and R9, R14, R15, K, D and m are as defined in claim 1.
R8 is halogen, and R9, R14, R15, K, D and m are as defined in claim 1.
12. A compound according to any one of the claims 6, 8 and 10, wherein R8 and in-dependently are hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, -O-C1-6-alkyl, C1-6-alkyl or phenyl.
13. A compound according to claim 12, wherein R8 and R9 independently are hydrogen, halogen, -O-C1-6-alkyl, -NH2, -CN or -NO2.
14. A compound according to any one of the claims 7, 9 and 11, wherein R9 is hydrogen, halogen, -OH, -NO2, -NH2, -CN, -OCF3, -SCF3, -CF3, -OCH2CF3, -O-C1-6-alkyl, C1-6-alkyl or phenyl.
15. A compound according to claim 14, wherein R9 is hydrogen, halogen, -O-C1-6-alkyl, -NH2, -CN or -NO2.
16. A compound according to any one of the claims 1 to 15, wherein R14 and R15 independently are hydrogen, halogen, -CF3, -OCF3, -OR16, -NR16R17, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -OSO2CF3, -CONR16R17, -CH2OR16, -CH2NR16R17, -OCOR16 or -CO2R18, or R14 and R15 together form a bridge -OCH2O- or -(CH2)~-, I is 1, 2, 3 or 4, R16 and R17 independently are hydrogen, -COR18, -SO2R18, C1-6-alkyl or aryl, or R16 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms, R18 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl.
17. A compound according to claim 16, wherein R14 and R15 independently are hydrogen, halogen, C1-6-alkyl, -O-C1-6-alkyl or aryl.
18. A compound according to any one of the preceding claims, wherein K is selected from the group consisting of wherein R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p and q are as defined in claim 1.
19. A compound according to claim 18, wherein K is selected from the group consisting of wherein R3a, R3b, R4a, R4b, R5a, R5b, a, b, c, d, p and q are as defined in claim 1.
20. A compound according to claim 19, wherein K is selected from the group consisting of wherein R3a, R3b R4a, R4b, R5a, R5b, b, c, d, p and q are as defined in claim 1.
21. A compound according to any one of the claims 18 to 20, wherein R5a and R5b independently are hydrogen, C1-6-alkyl, -OH, -(CH2)k OR6a, aryl, aryl-C1-6-alkyl, -CH2CF3, -(CH2)g-COOR43, -COOR43, -(CH2)k-CN or -(CH2)k-NR6a R6b, g, k, R43, R6a and R6b are as defined in claim 1.
22. A compound according to claim 21, wherein g and k independently are 1, 2 or 3, R6a and R6b independently are hydrogen, C1-6-alkyl such as methyl or ethyl, or aryl such as phenyl.
23. A compound according to any one of the claims 18 to 22, wherein R3a and R3b independently are hydrogen, halogen, -OH, -O-C1-6-alkyl, -COO-C1-6-alkyl, C1-6-alkyl or aryl-C1-6-alkyl.
24. A compound according to any one of the claims 18 to 23, wherein R4a and R4b independently are hydrogen, -CN, -CONH2, -(CH2)-N(CH3)2, -O-C1-6-alkyl, -CH2OH, -CH2O-aryl, -N(CH3)2, -OH, -COO-C1-6-alkyl or C1-6-alkyl.
25. A compound according to any one of the preceding claims, wherein D is hydrogen, wherein s, r, R27, R28, V', Y', Q', Z', W', E, E', F, F', G and G' are as defined in claim 1.
26. A compound according to claim 25, wherein D is hydrogen, wherein s, r, R27, R28, V', Y', Z', Q', Z', W', E, E', F, F', G and G' are as defined in claim 1.
27. A compound according to claim 26, wherein D is hydrogen, wherein E and E' independently are >CHR38, >NR39 or -O-, F, G and G' independently are >CHR38, >C=O or >NR39, F' is >CR38- or >N-, and s, r, R27, R28, R38, R39, V', Y', Z', Q' and W' are as defined in claim 1.
28. A compound according to any one of the claims 25 to 27, wherein R27 and R28 independently are hydrogen, halogen such as -Cl, -Br or -F, -CF3, -OCF3, -OCHF2, -OCH2CF3, -(CH2)y NHCOCF3, -NHCOCF3, -CN, -NO2, -COR29, -COOR29, -CH2)y OR29 or -OR29 wherein R29 is hydrogen, aryl or C1-6-alkyl and y is 1, 2, 3 or 4, C1-6-alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl, C1-6-alkylthio, -SCF3, aryl such as phenyl, -(CH2)y NR29R30 or -NR29R30 wherein R29 and R30 independently are hydrogen, -COO-C1-6-alkyl or C1-6-alkyl and y is 1, 2, 3 or 4, or -CONH2, or R27and R28 together form a bridge -OCH2O-, R38 is hydrogen, -OCHF2, -OR40 wherein R40 is hydrogen or C1-6-alkyl, C1-6-alkyl such as methyl, isopropyl or tert-butyl, C1-6-alkylthio, -SCF3, -CH2OH, -COO-C1-6-alkyl or -CONH2, R39 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl.
29. A compound according to any one of the claims 1 to 28, characterized by having a glucagon antagonistic activity as determined by the Glucagon Binding Assay I
or Glucagon Binding Assay II disclosed herein corresponding to an IC50 value of less than 1 µM, preferably of less than 500 nM and even more preferred of less than 100 nM.
or Glucagon Binding Assay II disclosed herein corresponding to an IC50 value of less than 1 µM, preferably of less than 500 nM and even more preferred of less than 100 nM.
30. A compound according to any one of the claims 1 to 29 for use as a medicament.
31. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 1 to 29 together with one or more pharmaceutically acceptable carriers or excipients.
32. A pharmaceutical composition according to claim 31 in unit dosage form, comprising from about 0.05 mg to about 1000 mg, preferably of from about 0.1 mg to about 500 mg such as of from about 0.5 mg to about 250 mg of the compound according to any one of the claims 1 to 29.
33. A method of treating type I or type II diabetes, comprising administering to a subject in need thereof an effective amount of A compound of the general formula (I):
wherein R8 and R9 independently are hydrogen, halogen; -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, C1-6-alkyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13 or -OSO2CF3, or R8 and R9 together form a bridge -OCH2O- or -OCH2CH2O-, R11 and R12 independently are hydrogen, -COR13, -SO2R13, C1-6-alkyl or aryl, R13 is hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or aryl, R4 is hydrogen or C1-6-alkyl, B is R14 and R15 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CH2),CF3, -NO2, -OR16, -NR16R17, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)l CONR16R17, -O(CH2)l CONR16R17, -(CH2)l COR16, -(CH2)l COR16, -(CH2)l OR16, -O(CH2)l OR16, -(CH2)l NR16R17, -O(CH2)l NR16R17, -OCOR16, -CO2R18, -O(CH2)l CO2R18, -O(CH2)l CN or -O(CH2)l Cl, or R14 and R15 together form a bridge -O(CH2)l O- or -(CH2)l -, l is 1, 2, 3 or 4, R16 and R17 independently are hydrogen, -COR18, -SO2R18, C1-6 alkyl or aryl, or R16 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms, R18 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, W is -N= or -CR19=, Y is -N= or -CR20=, Z is -N= or -CR21=, V is -N= or -CR22=, R19, R20, R21 and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, C1-6alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR24R25, -OCOR24 or -CO2R24, or R19 and R20, R21 and R21, or R21 and R22 together form a bridge -OCH2O-, R24 and R25 independently are hydrogen, -COR26, -SO2R26, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R26 is hydrogen, C1-6 alkyl, aryl or aryl-C1-6 alkyl, K is R3a, R3b, R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24a R25a, C1-8-alkyl, aryl, aryl-C1-8-alkyl, -SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a -CH2CONR24aR25a -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24a R25a, -OCOR24a or -CO2R24a, R24a and R25a independently are hydrogen, -COR26a, -SO2R26a, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R26a is hydrogen, C1-6-alkyl, aryl or aryl-C1-8-alkyl, or R3a and R3b, R4a and R4b, or R3a and R4b together form a bridge -(CH2)i-, i is 1, 2, 3 or 4, a, b, c and d independently are 0, 1, 2, 3 or 4, e, f and p independently are 0 or 1, q is 0, 1 or 2, L and M independently are -O-, -S-, -CH=CH-, -C~C-, -NR5a-, -CH2NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -CONR5b-, -NR5a O-, -SO-, -SO2-, -OSO2-, -SO2NR5a-, -NR5a SO2-, -NR5a CONR5b-, -CONR5a NR5b-, -NR5a CSNR5b-, -OCONR5b-, -CH2CONR5b-, -OCH2CONR5b-, -P(O)(OR5a)O-, -NR5aC(O)O- or R5a and R5b independently are hydrogen, C1-6-alkyl, -OH, -(CH2)k-OR6a, -COR6a, -(CH2)k-CH(OR6a)2, -(CH2)k-CN, -(CH2)k-NR6a R6b, aryl, aryl-C1-6-alkyl, -(CH2)g-COOR43 or -(CH2)g-CF3, k is 1, 2, 3 or 4, R6a and R6b independently are hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, g is 0, 1, 2, 3 or 4, R43 is hydrogen or C1-6-alkyl, G" is -OCH2CO-, -CH2CO-, -CO- or a valence bond, E" is -CH2-, -CH2CH2-, -CH=CH-, -CH2NH- or -CH2CH2NH-, m is 0 or 1, D is hydrogen, r is 0 or 1, s is 0, 1, 2 or 3, E, E', F, G and G' independently are -CHR38-, >C=O, >NR39, -O- or -S-, F' is >CR38- or >N-, Y' is -N= or -CR32=, Z' is -N= or -CR33=, V' is -N= or -CR34=, W' is -N= or -CR35=, Q' is -NR36-, -O- or -S-, R27, R28, R32, R33, R34 and R35 independently are hydrogen, halogen, -CN, -CF3, -O(CH2)y CF3, -(CH2)y NHCOCF3, -NO2, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -(CH2)y CONR29R30, -O(CH2)y CONR29R30, -(CH2)y OR29, -(CH2)y NR29R30, -OCOR29, -COR29 or -CO2R29, or R27 and R28, R32 and R33, R33 and R34, or R34 and R35 together form a bridge -O(CH2)y O-, y is 0, 1, 2, 3 or 4, R29 and R30 independently are hydrogen, -COR31, -CO2R31, -SO2R31, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R31 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R36 and R39 independently are hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R36 is hydrogen, -OR40, -NR10R41, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)x CONR40R41, -O(CH2)x CONR40R41, -(CH2)x OR40, -(CH2)x NR40R41, -OCOR40 or -CO2R40, x is 1, 2, 3 or 4, R40 and R41 independently are hydrogen, -COR42, -SO2R42, C1-8-alkyl, aryl or aryl-C1-8-alkyl, R42 is hydrogen, C1-8-alkyl, aryl or aryl-C1-6-alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a compound according to any one of the claims 1 to 29.
wherein R8 and R9 independently are hydrogen, halogen; -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR11, -NR11R12, C1-6-alkyl, aryl, -SCF3, -SR11, -CHF2, -OCHF2, -OSO2R11, -CONR11R12, -CH2OR11, -CH2NR11R12, -OCOR11, -CO2R13 or -OSO2CF3, or R8 and R9 together form a bridge -OCH2O- or -OCH2CH2O-, R11 and R12 independently are hydrogen, -COR13, -SO2R13, C1-6-alkyl or aryl, R13 is hydrogen, C1-6-alkyl, aryl-C1-6-alkyl or aryl, R4 is hydrogen or C1-6-alkyl, B is R14 and R15 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -O(CH2),CF3, -NO2, -OR16, -NR16R17, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR16, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR16R17, -(CH2)l CONR16R17, -O(CH2)l CONR16R17, -(CH2)l COR16, -(CH2)l COR16, -(CH2)l OR16, -O(CH2)l OR16, -(CH2)l NR16R17, -O(CH2)l NR16R17, -OCOR16, -CO2R18, -O(CH2)l CO2R18, -O(CH2)l CN or -O(CH2)l Cl, or R14 and R15 together form a bridge -O(CH2)l O- or -(CH2)l -, l is 1, 2, 3 or 4, R16 and R17 independently are hydrogen, -COR18, -SO2R18, C1-6 alkyl or aryl, or R16 and R17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms, R18 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, W is -N= or -CR19=, Y is -N= or -CR20=, Z is -N= or -CR21=, V is -N= or -CR22=, R19, R20, R21 and R22 independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24, -NR24R25, C1-6alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR24, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24R25, -CH2CONR24R25, -OCH2CONR24R25, -CH2OR24, -CH2NR24R25, -OCOR24 or -CO2R24, or R19 and R20, R21 and R21, or R21 and R22 together form a bridge -OCH2O-, R24 and R25 independently are hydrogen, -COR26, -SO2R26, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R26 is hydrogen, C1-6 alkyl, aryl or aryl-C1-6 alkyl, K is R3a, R3b, R4a and R4b independently are hydrogen, halogen, -CN, -CF3, -OCF3, -OCH2CF3, -NO2, -OR24a, -NR24a R25a, C1-8-alkyl, aryl, aryl-C1-8-alkyl, -SCF3, -SR24a, -CHF2, -OCHF2, -OCF2CHF2, -OSO2CF3, -CONR24aR25a -CH2CONR24aR25a -OCH2CONR24aR25a, -CH2OR24a, -CH2NR24a R25a, -OCOR24a or -CO2R24a, R24a and R25a independently are hydrogen, -COR26a, -SO2R26a, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R26a is hydrogen, C1-6-alkyl, aryl or aryl-C1-8-alkyl, or R3a and R3b, R4a and R4b, or R3a and R4b together form a bridge -(CH2)i-, i is 1, 2, 3 or 4, a, b, c and d independently are 0, 1, 2, 3 or 4, e, f and p independently are 0 or 1, q is 0, 1 or 2, L and M independently are -O-, -S-, -CH=CH-, -C~C-, -NR5a-, -CH2NR5a-, -CO-, -OCO-, -COO-, -CONR5a-, -CONR5b-, -NR5a O-, -SO-, -SO2-, -OSO2-, -SO2NR5a-, -NR5a SO2-, -NR5a CONR5b-, -CONR5a NR5b-, -NR5a CSNR5b-, -OCONR5b-, -CH2CONR5b-, -OCH2CONR5b-, -P(O)(OR5a)O-, -NR5aC(O)O- or R5a and R5b independently are hydrogen, C1-6-alkyl, -OH, -(CH2)k-OR6a, -COR6a, -(CH2)k-CH(OR6a)2, -(CH2)k-CN, -(CH2)k-NR6a R6b, aryl, aryl-C1-6-alkyl, -(CH2)g-COOR43 or -(CH2)g-CF3, k is 1, 2, 3 or 4, R6a and R6b independently are hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, g is 0, 1, 2, 3 or 4, R43 is hydrogen or C1-6-alkyl, G" is -OCH2CO-, -CH2CO-, -CO- or a valence bond, E" is -CH2-, -CH2CH2-, -CH=CH-, -CH2NH- or -CH2CH2NH-, m is 0 or 1, D is hydrogen, r is 0 or 1, s is 0, 1, 2 or 3, E, E', F, G and G' independently are -CHR38-, >C=O, >NR39, -O- or -S-, F' is >CR38- or >N-, Y' is -N= or -CR32=, Z' is -N= or -CR33=, V' is -N= or -CR34=, W' is -N= or -CR35=, Q' is -NR36-, -O- or -S-, R27, R28, R32, R33, R34 and R35 independently are hydrogen, halogen, -CN, -CF3, -O(CH2)y CF3, -(CH2)y NHCOCF3, -NO2, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR29, -CHF2, -OCHF2, -OCF2CHF2, -OSO2R29, -OSO2CF3, -(CH2)y CONR29R30, -O(CH2)y CONR29R30, -(CH2)y OR29, -(CH2)y NR29R30, -OCOR29, -COR29 or -CO2R29, or R27 and R28, R32 and R33, R33 and R34, or R34 and R35 together form a bridge -O(CH2)y O-, y is 0, 1, 2, 3 or 4, R29 and R30 independently are hydrogen, -COR31, -CO2R31, -SO2R31, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R31 is hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R36 and R39 independently are hydrogen, C1-6-alkyl, aryl or aryl-C1-6-alkyl, R36 is hydrogen, -OR40, -NR10R41, C1-6-alkyl, aryl, aryl-C1-6-alkyl, -SCF3, -SR40, -CHF2, -OCHF2, -OCF2CHF2, -CONR40R41, -(CH2)x CONR40R41, -O(CH2)x CONR40R41, -(CH2)x OR40, -(CH2)x NR40R41, -OCOR40 or -CO2R40, x is 1, 2, 3 or 4, R40 and R41 independently are hydrogen, -COR42, -SO2R42, C1-8-alkyl, aryl or aryl-C1-8-alkyl, R42 is hydrogen, C1-8-alkyl, aryl or aryl-C1-6-alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a compound according to any one of the claims 1 to 29.
34. A method of treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound as defined in claim 33.
35. A method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound as defined in claim 33.
36. The method according to any one of the claims 33 to 35 comprising administering to a subject in need thereof an amount of the compound as defined in claim 33 in the range of from about 0.05 mg to about 1000 mg, preferably of from about 0.1 mg to about 500 mg such as of from about 0.5 mg to about 250 mg one or more times per day such as 1 to 3 times per day.
37. Use of a compound as defined in claim 33 for the manufacture of a medicament for treating type I or type II diabetes.
38. Use of a compound as defined in claim 33 for the manufacture of a medicament for treating hyperglycemia.
39. Use of a compound as defined in claim 33 for the manufacture of a medicament for lowering blood glucose in a mammal.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US88678597A | 1997-07-01 | 1997-07-01 | |
| US08/886,785 | 1997-07-01 | ||
| US3251698A | 1998-02-27 | 1998-02-27 | |
| US09/032,516 | 1998-02-27 | ||
| PCT/DK1998/000287 WO1999001423A1 (en) | 1997-07-01 | 1998-06-30 | Glucagon antagonists/inverse agonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2294046A1 true CA2294046A1 (en) | 1999-01-14 |
Family
ID=31891731
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002294046A Abandoned CA2294046A1 (en) | 1997-07-01 | 1998-06-30 | Glucagon antagonists/inverse agonists |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2294046A1 (en) |
-
1998
- 1998-06-30 CA CA002294046A patent/CA2294046A1/en not_active Abandoned
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