AU7908398A - Glucagon antagonists/inverse agonists - Google Patents
Glucagon antagonists/inverse agonists Download PDFInfo
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- AU7908398A AU7908398A AU79083/98A AU7908398A AU7908398A AU 7908398 A AU7908398 A AU 7908398A AU 79083/98 A AU79083/98 A AU 79083/98A AU 7908398 A AU7908398 A AU 7908398A AU 7908398 A AU7908398 A AU 7908398A
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Description
WO 99/01423 PCT/DK98/00287 1 GLUCAGON ANTAGONISTSIINVERSE AGONISTS Field of the invention 5 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 10 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. 15 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 1, insulin-dependent, or type 11, a form that is non-insulin dependent in character. Subjects with type I diabetes are hyperglycemic and hypoinsulinemic, 20 and the conventional treatment for this form of the disease is to provide insulin. However, in some patients with type I or 11 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); 25 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. 30 The antagonist can be peptide or non-peptide in nature. Native glucagon is a 29 amino acid containing peptide having the sequence: WO 99/01423 PCT/DK98/00287 2 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-NH 2 . 5 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 al. Science 259, 1614, (1993)). The receptor functions by activation of the adenylyl cyclase second messenger system and the result is an increase in cAMP levels. 10 Several publications disclose peptide antagonists. Probably, the most thoroughly character ized antagonist is DesHis 1 [Glu"]-glucagon amide (Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. NatI. Acad. Sci. USA 90, 1662 (1993)). Other antagonists are eg DesHis',Phe*[Glu 9 ]-glucagon amide (Azizh et al., Bioorganic & Medicinal Chem. Lett. 16, 1849 (1995)) or NLeu 9 ,Ala 1 16 -glucagon amide (Unson et al., J. Biol. Chem. 269(17), 12548 15 (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 20 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 94/14426 discloses use of skyrin, a natural product comprising a pair of linked 9,10-anthracenedione groups, and its synthetic analogues, as glucagon antagonists. 25 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 WO 98/21957 30 (Merck & Co., Inc.) discloses 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. These glucagon antagonists differ structurally from the present compounds.
WO 99/01423 PCT/DK98/00287 3 Description of the invention Definitions The following is a detailed definition of the terms used to describe the compounds of the inven tion: 5 "Halogen" designates an atom selected from the group consisting of F, Cl, 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 10 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, propargyl, 2 hexynyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclooctyl, 4-cyclohexylbutyl, and the like. 15 Further non-limiting examples are sec-butyl, n-pentyl, isopentyl, neopentyl, tert-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-pentynyl, 2-pentynyl, 3 20 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. 25 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, 30 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, WO 99/01423 PCT/DK98/00287 4 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, 5 1,2,3,4-tetrahydronaphthyl, 2,3-dihydrobenzofuryl, triazolyl, 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. 10 The aryl moieties are optionally substituted by one or more substituents, for example selected from the group consisting of F, Cl, I, and Br; lower alkyl; lower alkanoyl such as formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like; -OH; -NO 2 ; -CN; -CO 2 H; -0-lower alkyl; aryl; aryl-lower alkyl; -C02CH 3 ; -CONH 2 ; -OCH 2
CONH
2 ; -NH 2 ; -N(CH 3
)
2 ; -SO 2
NH
2 ; -OCHF 2 ; -CF 3 ; 15 -OCF 3 and the like. A further non-limiting example is -NH-(C=S)-NH 2 Such aryl moieties may also be substituted by two substituents forming a bridge, for example
-OCH
2 0-. 20 "Aryl-lower alkyl" means a lower alkyl as defined above, substituted by an aryl, for example: S N The aryl group is optionally substituted as described above. 25 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.
WO 99/01423 PCT/DK98/00287 5 Accordingly, the invention is concerned with compounds of the general formula 1: R4 A X, N N (CH 2 )nB-(K)mD (I) 13 ~\4 R R2 R 5 wherein:
R
1 and R 2 independently are hydrogen or lower alkyl or together form a valence bond; 10 R' and R 4 independently are hydrogen or lower alkyl; n is 0, 1, 2 or 3; m is 0 or 1; 15 X is >C=0, >C=S, >C=NR5 or >S0 2 ; wherein R 5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR*; 20 wherein R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; A is WO 99/01423 PCT/DK98/00287 6 R7R 7 7 R 7 8 N 8 N8 8
R
8 8 R N
R
9 7 RR1 R ~ N R R R 10 R 10R9RlO/ R 9 R RR10R 10 R 10 N R 7I N N N N- N
R
8
R
8
R
10 7 R_- R R N N 0/R - 9 R 8 9 ROR 7 R 0R 1 0 R 1 77 7 ,N RN R N R N\ / R / R 8 N 9 R R R N R N R N R R7 N R8R 8
R
9 R N8, R N N g N 8~ R. N N R 1 R 9 R 8 N 5 Reg RR R 8 8 R 8 R 8 R 8 R wherein: WO 99/01423 PCT/DK98/00287 7 R' is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2
CF
3 , -NO 2 , -OR", -NR"R, lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SO 2 NR"R , -SR", -CHF 2 , -OCHF 2 , -OSO 2 R", -CONR"R,
-OCH
2 CONR" R1 2 , -CH 2 OR", -CH 2 NR"R -O 2 , -0CR", -C0 2 R" or -OSO 2
CF
3 ; 5 R' and R' independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2
CF
3 , -NO 2 , -OR", -NR"R1 2 , lower alkyl, aryl, -SCF 3 , -SR 11 , -CHF 2 , -OCHF 2 , -OSO 2 R", -CONR"R1 2 , -CH 2 OR",
-CH
2 NR"R1 2 , -OCOR", -C0 2
R
3 or -OS02CF 3 , or R' and R' together form a bridge -OCH 2 0 or -OCH 2
CH
2 0-; 10 wherein R" and R1 2 independently are hydrogen, -COR 3 , -SO 2 R"1, lower alkyl or aryl; wherein R1 3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and R' is hydrogen, lower alkyl, aryl-lower alkyl or aryl; 15 B is R1 1 R R R14 R R 4 RR R 15 - R 5 R RR 14A /R 14Ry Y V 15 R R Q Q w ,
R'
4 -- -7- V
VRR
14 , -CR CR R Vs or a valence bond; WO 99/01423 PCT/DK98/00287 8 wherein: R1 4 and R" independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O(CH 2
)CF
3 , -NO 2 ,
-OR
16 , -NR1 6
R
1 7 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 16 , -CHF 2 , -OCHF 2 , -OCF 2
CHF
2 , 5 -OS0 2
CF
3 , -CONR1 6
R
1 7 , -(CH 2 )CONR1 6
R
17 , -O(CH 2
)CONR
6
R"
17 , -(CH 2 )iCOR 16 , -(CH 2
),COR
6 ,
-(CH
2
),OR'
6 , -O(CH 2
)IOR
16 , -(CH 2
),NR
16
R
1 7 , -O(CH 2 )iNR 16
R'
7 , -OCOR 16 , -C0 2
R'
8 ,
-O(CH
2
)ICO
2
R
18 , -O(CH 2 )ICN, -O(CH 2 )ICI, or R" and R 15 together form a bridge -O(CH 2
)
1 0- or
-(CH
2
)
1 -; 10 wherein I is 1, 2, 3 or 4;
R'
6 and R 17 independently are hydrogen, -COR", -SO 2 R"', lower alkyl, aryl, or R 1 6 and R 17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms; 15 wherein R" is hydrogen, lower alkyl, aryl or aryl-lower alkyl; W is -N= or -CR4=; Y is -N= or -CR 2 0 = 20 Z is -N= or -CR21 V is -N= or -CR 22 =; and 25 Q is -NR 23 -, -0- or -S-; wherein:
R
19 , R 20 , R21 and R 2 2 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2
CF
3 , 30 -NO 2 , -OR 24 , -NR 24
R
2 5 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 2 4 , -CHF 2 , -OCHF 2 ,
-OCF
2
CHF
2 , -OS02CF 3 , -CONR 2 4
R
2 , -CH 2
CONR
24
R
2 , -OCH 2
CONR
2 4
R
2 , -CH 2 0R 24 ,
-CH
2
NR
24
R
2 5, -OCOR 2 4 or -C0 2
R
2 4 , or R"and R 20 , R 20 and R 21 , or R 21 and R 22 together form a bridge -OCH 2 0-; WO 99/01423 PCT/DK98/00287 9 wherein R 24 and R 2 1 independently are hydrogen, -COR 2 6 , -S0 2
R
2 6 , lower alkyl, aryl or aryl lower alkyl; 5 wherein R 2 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and
R
2 3 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K is 3a R3b R R 4 b 10(L), (CH2)b_ v (CH2) (M), (C2c (CH 2)d wherein:
R
3 a, R 3 b, R 4 a and R 4 b independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2
CF
3 , 15 -NO 2 , -OR" 24 , -NR 24 aR 2 a, lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24 a, -CHF 2 , -OCHF 2 ,
-OCF
2
CHF
2 -OSO2CF 3 , -CONRaR 2 a, -CH 2
CONR
2
"R
25 ", -OCH 2 CONR aR 2 S", -CH 2 ORa,
-CH
2
NR
24 aR 25 a, -OCOR" 24 or -CO 2
R
24 a; wherein R 2 " and R 25 " independently are hydrogen, -COR 2 ea, _SO 2
R
26 ", lower alkyl, aryl or 20 aryl-lower alkyl; wherein R 2 ea is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or 25
R
3 a and R3b, R 4 a and R 4 b, or R 3 a and R 4 b together form a bridge -(CH 2 )i-; wherein i is 1, 2, 3 or 4; 30 a, b, c and d independently are 0, 1, 2, 3 or 4; WO 99/01423 PCT/DK98/00287 10 e, f and p independently are 0 or 1; q is 0, 1 or 2; and 5 L and M independently are -0-, -S-, -CH=CH-, -C=C-, -NR 5 a-, -CH 2 NRS-, -CO-, -OCO-, -COO-, -CONR 5 a-, -CONR 5 b-,
-NR
5 aCO-, - -SO 2 -, -OSO2-, -S0 2
NR
5 -, -NR 5 aSO2-, -NR 5 "CONR5b-, -CONR 5 aNR 5 b-, -NR "CSNR b-, -OCONR b-, -CH 2 CONR b-, -OCH 2 CONRob-, -- G" ,N '
-P(O)(OR
5 a)O-, -NR 5 aC(O)O- or Ra 10 wherein Rs 5and Rsb independently are hydrogen, lower alkyl, -OH, -(CH 2 )k-OR 6 a, -CORea
-(CH
2 )k-CH(OR 6
)
2 , -(CH 2 )k-CN, -(CH 2 )k-NR 6 aR 6 b, aryl, aryl-lower alkyl, -(CH 2 )g-COOR 43 or (CH 2 )g-CF 3 ; 15 wherein k is 1, 2, 3 or 4;
R
6 " and R 6 b independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; g is 0,1,2,3 or4; 20
R
4 3 is hydrogen or lower alkyl; G" is -OCH 2 CO-, -CH 2 CO-, -CO- or a valence bond; and 25 E" is -CH 2 -, -CH 2
CH
2 -, -CH=CH-, -CH 2 NH- or -CH 2
CH
2 NH-; D is hydrogen, WO 99/01423 PCT1DK98/00287 R 27 7 28 7 . 21i R 2 7 : Q ~~R2 , VZ Y~
/R
8 (Ct R28 R28 2 R 28 R R 2 27 8 28\282 % . (CH2)s '(CZ) I\'4 IE R 28 272 27 R2 R 2R Q. (CH 2 G \ ' R - 28 R 2 7 GR272 R -- 6 E/ 28
R
27 f E' W' E'H) ER (rG) 2s GCH 2 )2)F -2' F E wherein 5 > 2 r isO or21 WO 99/01423 PCT/DK98/00287 12 s is 0, 1, 2 or 3; E, E', F, G and G' independently are -CHR 3 a-, >C=0, >NR 3 9 , -0- or -S-; 5 F' is >CRaa- or >N-; Y' is -N= or -CR32 10 Z' is -N= or -CR 3 3 ; V' is -N= or -CRM=; W' is -N= or -CR 3 1=; and 15 Q' is -NR 3 *-, -0- or -S-; wherein: 20 R 27 , R 2 8 , R 32 , R 3 3 , R'and R 3 " independently are hydrogen, halogen, -CN, -CF 3 , -O(CH 2 )yCF 3 ,
-(CH
2 )yNHCOCF 3 , -NO 2 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 , -CHF 2 , -OCHF 2 ,
-OCF
2
CHF
2 , -OS0 2
R
29 , -OS02CF 3 , -(CH 2 )yCONR 29
R
3 , -O(CH 2 )yCONR 2 9
R
3 0 , -(CH 2 )yOR 29 ,
-(CH
2 )yNR 29
R
3 0 , -OCOR 29 , -COR 2 9 or -CO2R29 25 or
R
27 and R 2 8 , R 32 and R 3 3 , R 33 and R', or R 34 and R 3 5 together form a bridge -O(CH 2 )yO-; wherein y is 0, 1, 2, 3 or 4; and 30
R
29 and R 3 independently are hydrogen, -COR 31 , -C0 2
R
31 , -S0 2
R
31 , lower alkyl, aryl or aryl-lower alkyl; WO 99/01423 PCT/DK98/00287 13 wherein R 3 1 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R
36 and R 39 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; and 5 R 3 1 is hydrogen, -OR 4 ", -NR 4
"R
41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 4 0 , -CHF 2 ,
-OCHF
2 , -OCF 2
CHF
2 , -CONR 4
R
4 1 , -(CH 2 )xCONR 4 0
R
4 1 , -O(CH 2 )xCONR 4 0
R
4 1 , -(CH 2 )x0R 40 ,
-(CH
2 )xNR 4 4R 4 1 , -OCOR 4 0 or -C0 2
R
4 *; wherein x is 1, 2, 3 or 4; 10
R
4 0 and R 4 ' independently are hydrogen, -COR 42 , -S0 2
R
4 2 , lower alkyl, aryl or aryl-lower al kyl; wherein R 4 2 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; 15 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 20 , R 21 , R22 and R3 may alternatively be re 20 placed by R 14 or R' 5 , respectively. In such case eg W may be selected from -N=, -CR"- and
-CR'
4 . Similarly, where the formulae for D make it possible, R 32 , R33, R34, R-, R 3 r, R" and R 3 9 may al tematively be replaced by R' or R 2 1, respectively. In such case eg E may be selected from 25 -CHR- 38 , >C=0, >NR 39 , -0-, -S-, -CHR 2 7 - and >NR 2 7 . In a preferred embodiment the invention relates to compounds of the following general formula Hl: 0 A K 4(CH2)-B-(K);D R3 R4 30 wherein A, B, K, D, R 3 , R 4 , n and m are as defined for formula I.
WO 99/01423 PCT/DK98/00287 14 In another preferred embodiment the invention relates to compounds of the following general formula IlI: 0 11 A N (CH2)-B--(K);-D o 13 4 R R 5 wherein A, B, K, D, R 3 , R 4 , n and m are as defined for formula 1. In still another preferred embodiment the invention relates to compounds of the following formula IV: 0 3 AN (CH2)n--B-(K)--D (IV) R 3 R4 10 wherein A, B, K, D, R 3 , R 4 , n and m are as defined for formula I. In the compounds of the above formulae I to IV the following substituents are preferred:
R
3 is preferably hydrogen. 15
R
4 is preferably hydrogen. A is preferably selected from the group consisting of: R R 7 R R 8
R
8 R R 1 0 R 10 R1 N N N
R
7 R and R 20 R' R' WO 99/01423 PCT/DK98/00287 15 wherein R 7 , R 8 , R 9 and R" are as defined for formula 1. A is more preferably R7 R 8 R 9 5 wherein R 7 , R" and R 9 are as defined for formula 1. In the above embodiments of A, R 7 is preferably halogen, lower alkyl, -OH, -NO 2 , -CN,
-CO
2 H, -0-lower alkyl, aryl, aryl-lower alkyl, -O 2
CH
3 , -CONH 2 , -OCH 2
CONH
2 , -NH 2 ,
-N(CH
3
)
2 , -SO 2
NH
2 , -OCHF 2 , -CF, or -OCF 3 . 10 Preferably, Ro and R* are independently hydrogen, halogen, -OH, -NO 2 , -NH 2 , -CN, -OCF 3 ,
-SCF
3 , -CF 3 , -OCH 2
CF
3 , -0-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, and R" is hydrogen, lower alkyl or phenyl. 15 More preferably, R' and R' are independently selected from hydrogen, halogen such as -F and -Cl, -0-lower alkyl such as methoxy and ethoxy, -NH 2 , -CN or -NO 2 , and R" is hydrogen. In a particularly preferred embodiment A is R 8 HO
R
9 20 wherein R" and R 9 independently are hydrogen, halogen, -OH, -NO 2 , -NH 2 , -CN, -OCF 3 ,
-SCF
3 , -CF 3 , -OCH 2
CF
3 , -0-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, preferably hydrogen, halogen such as -F and -Cl, -0-lower alkyl such as methoxy and ethoxy, -NH 2 , -CN or -NO 2 25 In a further particularly preferred embodiment A is WO 99/01423 PCT/DK98/00287 16 HO R9
R
8 wherein R' is hydrogen, halogen such as -F or -Cl, -0-lower alkyl such as -OCH, or -OC 2 H,
-NH
2 , -CN or -NO 2 ; and R' is hydrogen or halogen such as -F or -CI. 5 In a preferred embodiment R' is halogen and R 9 is hydrogen. In still a preferred embodiment the invention relates to compounds of the following formula V: R 0 NN B--(K)m;- D (V B HO RH 10 wherein R 4 , B, K, D and m are as defined for formula I and R and R 9 are as defined for formula I and preferably as defined for the preferred embodiments of A above. B is preferably: R 1 5
R
15 W RR w4 0 W1 v QWW R 14 o R's Ri-- 15 VV "Y R14 or R14, R1 v + - WO 99/01423 PCT/DK98/00287 17 wherein V, W, Z, Y and Q are as defined for formula I; and R1 4 and R 15 independently are hydrogen, halogen, -CF 3 , -OCF 3 , -OR 16 , -NR'"R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2
CF
3 , -CONR"R 7 , -CH 2 0R4, -CH 2
NR
1 6
R
1 7 , -OCOR 6 or -C0 2 RI; 5 or R 1 4 and R" together form a bridge -OCH 2 0- or -(CH 2 )-; wherein I, R 1 ", R 1 7 and R 1 " are as defined for formula 1. Q is preferably -0- or -NH-. 10 Particularly preferred compounds are those in which B is R14 R , R4 -() R 15 'RM
R
1 R R 5R 15 R 1 R R 1 w y ON or NH V z 14 N R 15 wherein V, W, Z, Y and Q are as defined for formula I; and
R
1 and R" independently are hydrogen, halogen, -CF 3 , -OCF 3 , -OR', -NR 1
'R'
7 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2
CF
3 , -CONR"R 7 , -CH 2 OR'", -CH 2
NR
16
R
17 , -OCOR' 6 or -C0 2 R3; or R 1 4 and R 1 5 together form a bridge -OCH 2 0- or -(CH 2 )-; 20 wherein I, R", R 1 7 and R" are as defined for formula 1. Still more preferred are compounds of the following formula VI: WO 99/01423 PCT/DK98/00287 18 R144 R 8 0 (K) -;-D (VI) HR HO R9 as well as compounds of the following formula VII: R 14 NN (K)mT-D (Vll) H HO 9 5R R1 as well as compounds of the general formulae Villa or Villb: R 8 0/ I N (K)m--D (Villa) or HO R 1 R1 R R4 'N NH N (K);-D (Vilib) HO R9 10 wherein R 14 and R 1 5 independently are hydrogen, halogen, -CF 3
-OCF
3 , -OR" 6 , -NR 6
R
17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2
CF
3 , -CONR'*R 17 , -CH 2 0R'", -CH 2 NR'R , -OCOR 6 or -C0 2 R; or R 1 4 and R" together form a bridge -OCH 2 0- or -(CH 2 )-; 15 wherein I, R 1 6 , R 17 and R" are as defined for formula I; WO 99/01423 PCT/DK98/00287 19 K, D and m are as defined for formula I; and R' and R' are as defined for formula I and preferably as defined for the preferred embodiments 5 of A above. In the above formulae VI, VII and VIII, R 14 and R" are preferably independently hydrogen, halogen, lower alkyl, aryl such as phenyl, or -0-lower alkyl such as methoxy. 10 In the above formulae VI and VII, K is preferably bound in para-position and in the above for mulae VIlla and VIlIb, K is preferably bound at the nitrogen atom of the indole group. K is preferably selected from the group consisting of: WO 99/01423 PCTfDK98/00287 20 -(CH260(
C
H 2) -O (HA- S -(CH2j-- - (CH 2 )-CH=CH- (CH 2 )d-, ____ 0 - ( C H 2 b ( C 2) d - - ( C A -- N ( C H C H 2 C 2) j , 5a 2j- - C R 0 aRaR4 0R a (CH)SN( H 00 01 00 -(CHyTS(CH 2 )w- 01 H 2 b(CH 2 )Eo 1 (H2j 0 00 H -O0CH 2 b (CH 2 )jc -(CCH 2 )d II(C N 00 WO 99/01423 PCTIDK98/00287 21 R 4a R 4bRa R4
(
0 HO -N ( H 2 ) d(H -(CH 2 ) -- S0-(CH9 2) (CH 2 )6d R 4a R 4b0 R 4 R4 -(CH9 -S0~--(CH9 q (CH 2 )d t(CH 2 )H P-0 0R~a o R 4 R4 -0-(C0 2R p -,(CO-(CH 2 )bilL-(CH )d 0 R3a R 3 b 0 IR5a R 0a -0-CH 11LN -- CH 1i.LN -0-CH 11LN/ - 2 H 2 )~i2 2 -N CH2E--0-CH 11 N N-CH/\ 0 Ra0 s -0-CH 2 JLN (CH 2 )s-N -(CH 2 )- -0-CHAJ-N 0a0 0 R5 0 0 CHN-R' Nl/XN-rn-5 WO 99/01423 PCT/DK98/00287 22 o 0 00 -- O-CH2 11N- (CH 2)E-~S~(CH 2)a- , -CH2 1 -(CH2-O -(H)~ , RG5a R o R R O0 -(CH2)b 1N-(CH2)c )q (CH2)j- -CH2 N-(CH2)6-N-(CH2)j-~ R RRb 0 R Ra R -- CH2CH2 H2) p N-(CH (H2)j~- -'-H(CH2)O---(CH2)-s RI RI RI OR R3 R R3 3 RM RM R R3b 0 R R O - -CH- -2 ) p (CH2)-O-(CH2)-- , N N-CH1 p(C2CH--(H2 R R5b Isa'5. 26- -(H) R R R 0 R 3 a R 3 b R 4a 4b 0 R3aRb - C H - - -( C H 2 ) P ( CH 2 )c q H2) 2 ) and - -C H2 N - (C H 2 -N (C H2) RR Rs RM R wherein R, R 3 , R 4 , R*, R 5 " RSb, a, b, c, d, p and q are as defined for formula . 5 More preferably, K is selected from the group consisting of: WO 99/01423 PCT/DK98/00287 23 0 bC 2 ~ a l 5as 2)' O 0 -0-(CH 2)-1-L ~ O-(CH 2 ) --- C Ab1-C2 0 0 o
R
5 b 0 -O -(CH),-CHR 3 a_ -(C 2)- 1(H2 -(CH2 S (H2d 0 O~aC4a DO 4a C4b -(CH) 1 Nl-(CH) (CH 0-(CH N-(CH 2 ')-4 ' C 2b 2a c4bA O 2 R 4a R 4bR 4a R4 -(C2),--N(CH) (H2- -(CH 2 ) -SO-(CHA: >4(CH 2 )dF I sa R Ra R 4b0 R 4 4b 2)6 A~~ (CH 2 )d- -C26- 4 ORR 0 R~ R4a R4 ORa WO 99/01423 PCTfDK98/00287 24 -0--H2 1 N - 0-C JLL 2-H 2 )- 0 C 2 2 0 0 R5 -O-CHrlJLLH)F- (C2N -O-CH ,-LN R 0 R 5 a 0 05 -0-IH2 1 N -XN(CH 2 )NCH) - C~- N -N (H) R 0 0 -CH'2 Nr2 NR'a N-R a WO 99/01423 PCT/DK98/00287 25 0 -- O-CH 2 11N-(CH2)b- S-(CH 2)5- , -O-(CH2)6-0O-(CH 2)d- , R 0 R4 R 4 b 0 -- (CH N-(CH g (CH2 -CH21 N-(CH 2 )EN--(CH2~, I a 15b 5 R R R o R 4 a Re O -O--(CH2 A H2)c q (CH2)d- (CH 2
)N-(CH
2 )d 5aI5bI5 Ra Ra R 0 R3 R 3 b O -O--CH 2 N-(CH 2)b N-(CH 24d- , -N 11(CH 2)6-0-(CH2)6-- , I5 I RER O Ra R 3 b R4 R 4 b o 33 36 -CH2L -(CH2 \,/p (CH 2 )c q (CH 2 ) ~ N-(CH2 ) (CH2)c- S
R
5 b Ra R3 R 3 b 0 R3 R 3 b 0 -- CHI~ -(CH2) p (CH);0--(CH2)d-- ,N--(CH2)b dp (C2). N--(CH2)6-~ R R R R R3b R4a R 4 b o -CHz--(CH2 b /p (CH2)c (CH2);~ -CH2 N-(CH 2
)E--N-(CH
2 ) I 5b I 5a RR R 0 and C 21 -C 26- - C 2 R wherein R 3 , R b, R 4 , R b, R 5 , Rsb, a, b, c, d, p and q are as defined for formula 1. 5 In a further preferred embodiment K is selected from the group consisting of: WO 99/01423 PCT/DK98/00287 26
R
5 a 0 15a R 0 0 0 11 -U-0- ~a valence bond - -C 22T--0 0 0 -0 -(CH2),-CHR~a- 0 ]L CH 2 - -H2 1 O R 5a [, 4 a DOb R 4 a R 4 b 0a 4a 4 -CH -O2--C 4b- CH -S 1-_R(C OR~ 0 R 4 1 R 4b
(CH
2 blLcH) ORa 0 0 N -(CH 2 )b O-(CH 2 )d- -- H' -C I 5aa 0 -CI CIN 1C~R WO 99/01423 PCT/DK98/00287 27 -0--H 11N - - O-C 2 2 2' -0-CH 11LN/ (CH)- N (C CH)- - -CH -N o R 0a0 R5 R 0o 5a 0 o0 7 " ' s 0 X -CH2 N/ N-RLN/
-R
WO 99/01423 PCT/DK98/00287 28 0 -- O-CH 2 1N--(CH2)6-S-(CH 2)T , -O--(CH2)E-_0-(CH2)a- R R 4a R 4 b 0 -- (CH2 N-(CH2 c R ( -g(CH2 - , -CH2 N--(CH2E6-N-(CH2~~, R R Rb o Ra Rn4 0 -O--(CH2 A N-(CH2)c q (CH2)j- , N-C2)E- -CH) I 5a I b I158 R R R 0 R3 R 3 b O -- CH2 1 N-(CH2)
N-(CH
2 )a- , -N (CH2)EO-(CH2)- , S5b I s 5 R R R 0 R R 3 1 R "a R 4 0 3a R 3 -CH2 N-(CH2)b p (CH2c q (CH2- N-(CH2) (CH2)-S-~(CH2)j RWb R R3 R 3 b 0 R3 R 3 b O -- CHi- -- (CH2 /p (CH2)-0-(CH2)- N-(CH2) p C2)c N--(CH2)J R R R R3 R 3 b R4 R4b 0
-CH-N-(CH
2 )b p (CH 2 )c ji)q(CH 2 )a- , -CH2 N-(CH2)-N-(CH2)-~ R R 0 and -CH2 N-(CH2)E~O-(CH2)d RM wherein R 3 a, R 3 b, R 4 ", R 4 , Rea, Rlb, b, c, d, p and q are as defined for formula 1. 5 In the above embodiments of K, RS" and RSb are preferably independently hydrogen, lower alkyl, -OH, -(CH 2 )kORea, aryl, aryl-lower alkyl, -CH 2
CF
3 , -(CH 2 )g-COOR 4 3 , -COOR 4 3 , -(CH 2 )k CN or -(CH 2 )k-NReaRSb wherein g, k, R 43 , R 6 a and R6b are as defined for formula 1. Preferably, g and k are independently 1, 2 or 3, and R a and R b are independently hydrogen, 10 lower alkyl such as methyl or ethyl, or aryl such as phenyl, In the above embodiments of K, R 3 a and R 3 b are preferably independently hydrogen, halo gen, -OH, -0-lower alkyl, -COO-lower alkyl, lower alkyl or aryl-lower alkyl.
WO 99/01423 PCT/DK98/00287 29 In the above embodiments of K, R 4 " and R 4 ' are preferably independently hydrogen, -CN,
-CONH
2 , -(CH 2
)-N(CH
3
)
2 , -0-lower alkyl, -CH 2 OH, -CH 2 0-aryl, -N(CH 3
)
2 , -OH, -C0 2 -lower alkyl or lower alkyl. 5 D is preferably hydrogen, R 27W (CH2) w ' '' W' F R2V ,Z R2 7 R - R 2 7 R CR R R 2 7 R2 R Q 2 8 E (CH Er \ 2 RR R~ R 22'--G) R 2'1G F' (C23 F ' 28
(CH
2 ) (C2) E F'-(G). . E F'-(G)r V 108 wheei s, r, R2,R8 ' YQ ,ZW' ,EF ',G adG rea eie frfr ua In s f r r
(CH
2 )(/ G G 2
R
27 G -~~ 28 E E E1R or R Y'28 Y 8GF 7 (CHA) F V
R
2 10 wherein s, r, R 27 R 2 1, V1, y', Q1' Z', W', E, E', F, F, G and G' are as defined for formula I. In still a further preferred embodiment D is hydrogen, WO 99/01423 PCT/DK98/00287 30 n27 ' .R2 R4 V V.Z H2)s R27 W' ER2 R V ' 'VZ' , Z R2 F GH 2 E R 28 '- G R 27 G R 28 :Q 2
(CH
2 )s G/CH2 E F'-(G W H2A E F'-(G) R2 RR R28 27 R .- R2 EF E R27 (CH2 ) 27 W . R2 G. R R R27 SS R 27 CH2 G 27 E 28 o R E' W 28 G~ F(CH 2 )s F E 1 wherein s, r, R, 27
R
2 3, V', Y', Z', Q', Z', W', E, E', F, F', G and G' are as defined for formula 1. 5 D is more preferably hydrogen, WO 99/01423 PCT/DK98/00287 31 R-27 ' E2 7 E R 28 2R E
(CH
2 ) (CH27s E F'-(G)r w R R F(G)r R R8 R 2 E
(CH
2 ) Zw R27 H2 RaR R2 ERa E R" o R ERw R 277 2( R E ' Z R R 28 R22 E' ~ ~ ~ V ERZ\ /o G( ,ACH 2 )W - F F 28 8 wherein E and E' independently are >CHR 3 8 , >NR" 9 or -0-; F, G and G' independently are 5 >CHR 3 8 , >C=0 or >NR 39 ; F' is >CR 3 3- or >N-; and s, r, R 27 , R 2 3, R 38 , R" 9 , V', Y', Z', Q' and W' are as defined for formula 1.
R
27 and R 28 are preferably independently hydrogen; halogen such as -Cl, -Br or -F; -OF 3 ;
-OCF
3 ; -OCHF 2 ; -OCH 2
CF
3 ; -(CH 2 )yNHCOCF 3 ; -NHCOCF 3 ; -ON; -NO 2 ; -COR 9 , -0CR" 9 , 10 -(CH 2 )yOR 29 or -OR 29 wherein R 29 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;
-SCF
3 ; aryl such as phenyl; -(CH 2 )yNR 9
R
3 0 or -NR" 9
R
3 0 wherein R 29 and R 3 0 independently are hydrogen, -COO-lower alkyl or lower alkyl and y is 1, 2, 3 or 4; or -CON H 2 ; or R 27 and R 2 3 together form a bridge -OCH 2 0-; R 3 8 is hydrogen; -OCHF 2 ; -OR 40 wherein R 40 is hydrogen or WO 99/01423 PCT/DK98/00287 32 lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF 3 ;
-CH
2 OH; -COO-lower alkyl or -CONH 2 ; and R 39 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
WO 99/01423 PCT/DK98/00287 33 In a further embodiment the invention relates to the compounds of the formula I wherein:
R
1 and R 2 independently are hydrogen or lower alkyl or together form a valence bond; 5 R 3 and R 4 independently are hydrogen or lower alkyl; X is >C=O, >C=S, >C=NR 5 or >S0 2 ; n is 0, 1, 2 or 3; 10 m is 0 or 1; R' is hydrogen, lower alkyl, aryl-lower alkyl, or -OR'; 15 wherein R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; A is WO 99/01423 PCT/DK98/00287 34 R 7 R 7 R 7R R8:?~ R 8 9R 9 R 9 R 9 R 10 17 8~ IR 9 R R10/ R R 0R 1 0 R 1 I R71 R711 8 N r" NN ,N RB /s-
R
8 -\ R %% RON N- Nt R- R 9 0 7 0 R 7 R
R
8 N N N 7 R 0 R' R 0 Rs01 R 10 N R N R N NN -\ /R 8 R 8 N RO R Rg R R R 10 R 10 7 7 7 C N R N R
F:,R
8 R R 8 R R ' N 9 N N 9
R
9
NR
1 R R N 1 R N 7 9 R 1 0 N RR N R 8 , R ~ N N-R 1 R _r R 9 N tR R
R
8 4 R 8 R N or wherein WO 99/01423 PCT/DK98/00287 35 R' is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2
CF
3 , -NO 2 , -OR", -NR"R 2 , lower al kyl, aryl, -SCF 3 , -SR", -CHF 2 , -OCHF 2 , -OS0 2 R", -CONR"R , -CH 2 OR", -CH 2 NR'"R, -OCOR", -C0 2
R
13 , OSO2CF 3 ; 5 R' and R' independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2
CF
3 , -NO 2 , -OR", -NR"R , lower alkyl, aryl, -SCF 3 , -SR' 1 , -CHF 2 , -OCHF 2 , -OSO 2
R'
1 , -CONR 11 R,
-CH
2
OR
1 , -CH 2
NR'
1 R1 2 , -OCOR", -CO 2
R'
3 , -OSO 2
CF
3 , or R' and R 9 together form a bridge
-OCH
2 0-; 10 R 1 1 and R' independently are hydrogen, -COR , -SO 2 R, lower alkyl or aryl;
R
1 3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; R" is hydrogen, lower alkyl, aryl-lower alkyl or aryl; 15 B is R15 w "Y W R R R14 R R R R V, 1414 QY 15 R R Q R R Q w
R
1 4 ~~CR'CR R V or a valence bond; preferably WO 99/01423 PCT/DK98/00287 36 R V ~ R R4 ' 1 R R1 R1 14 Q R' QI 4 l R
R
1 or R R is R
R'
4 and R' 5 independently are hydrogen, halogen, -ON, -CF 3 , -OCF 3 , -O(CH 2 )iCF 3 , -NO 2 ,
-OR'
6 , -NR" 6
R
17 , lower alkyl, aryl, -SCF 3 , -SR 16 , -CHF 2 , -OCHF 2 , -OCF 2
CHF
2 , -OSO 2
CF
3 , 5 -CONR' 6
R'
7 , -(CH 2
)CONR"
6
R'
7 , -O(CH 2
),CONR
6
R'
7 , -(CH 2
)COR'
6 , -O(CH 2
)COR
6 ,
-(CH
2 )0OR 6 , -O(CH 2
):OR'
6 , -(CH 2 )iNR' 6
R
17 , -O(CH 2
):NR'
6
R'
7 , -OCOR' 6 , -CO 2
R'
8 ,
-O(CH
2 )QCN, -O(CH 2 )CI, or Rand R'together form a bridge -O-CH 2 -0-;
R'
4 and R' 5 preferably independently representing hydrogen, halogen, -CF 3 , -OCF 3 , 10 -OR' 6 , -NR' 6
R'
7 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2
CF
3 , -CONR'' 7 , -CH 2
OR'
6 ,
-CH
2
NR
16 R", -OCOR'" or -C 2
R
8 ; or together forming a bridge -OCH 2 0-; I is 1, 2,3 or4; 15 R 1 4 and R'" independently are hydrogen, -COR1e, -SO 2 R", lower alkyl, aryl, or R' and R'o together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms; R0 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; 20 W is -N= or 4; Y is -N= or -CR20 WO 99/01423 PCT/DK98/00287 37 Z is -N= or -CR21 V is -N= or -CR22 5 Q is -NR 23 -, -0- or -S-; wherein:
R
1 9 , R 2 , R 21 and R 2 2 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2
CF
3 , 10 -NO 2 , -OR 2 4 , -NR 2 4
R
2 ", lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 2 4 , -CHF 2 , -OCHF 2 ,
OCF
2
CHF
2 , -OSO 2
CF
3 , -CONR 24
R
2 5 , -CH 2
CONR
24
R
2 5 , -OCH 2
CONR
2 4
R
2 5 , -CH 2
OR
2 4 , _
CH
2
NR
24
R
2 5 , -OCOR 24 or -CO 2
R
2 4 , or R"and R 2 0 , R 2 0 and R 21 or R 21 and R 2 2 together form a bridge -OCH 2 0-; 15 R 2 4 and R 2 1 independently are hydrogen, -COR 2 6 , -S0 2
R
2 1, lower alkyl, aryl or aryl-lower alkyl;
R
2 1 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; 20 R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K is 4a R3a R3b R
R
4 b (C
(H
2 )a-(M)f
(CH
2 )c (CH 2 )d 25 wherein:
R
3 a, R 3 b, R 4 a and R 4 b independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 ,
-OCH
2
CF
3 , -NO 2 , -OR 2 4 2 , -NR 24
R
25 a, lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24 ,
-CHF
2 , -OCHF 2 , -OCF 2
CHF
2 -OSO2CF 3 , -CONR 24 aR 2 5 a, -CH 2
CONR
24 aR 2 5 , 30 -OCH 2
CONR
24
"R
2 5 a, -CH 2
OR
24 ., -CH 2
NR
24
.R
25 a, -OCOR 24 a or -CO2R24a WO 99/01423 PCT/DK98/00287 38 wherein R 24 " and R 25 " independently are hydrogen, -COR 2 6 a, -SO 2
R
2 ", lower alkyl, aryl or aryl-lower alkyl;
R
2 6 , is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or 5
R
3 a and R 3 b, R 4 " and R 4 b or R 3 a and R 4 b together form a bridge -(CH 2 )i-, wherein i is 1, 2, 3 or 4; 10 a, b, c and d independently are 0, 1, 2, 3 or 4; e, f, p and q independently are 0 or 1; L and M independently are 15 -O-, -S-, -CH=CH-, -C=C-, -NRS-a, -COO-, -CONR 5 a-, -NRSaCO-, -SO-, -SO2-, -OSO2-,
-SO
2
-NR
5 a-, -NR 5 aSO 2 r, -NR 5 aCONRb-, -NR 5 aCSNR 5 b-, -OCONR 5 b- or -NRS"C(O)O wherein R 5 a and Rsb independently are hydrogen, lower alkyl, -(CH 2 )k-OH, -(CH 2 )k 20 NR 6 aR 6 b, aryl or aryl-lower alkyl; wherein k is 2, 3 or 4; R** and R6b independently are hydrogen, lower alkyl or aryl-lower alkyl; 25 K preferably representing WO 99/01423 PCTIDK98/00287 39 R S 0 0 - -(CH 2 ) CH~ 2 ) S (H2jN-C --C 0 oa RR o( H b( CH O -(CH or 5a 2 Hj)- l -(CH 2 )- N ( H) 00 D is hydrogen or WO 99/01423 PCT/DK98/00287 40 R R28 WR28 R V ' 27 R Y 228 R2 Z -V' R27 R2 Z'" 227 R (C H2 R (C H 2 )28 2 C2 2 R R R2 I R27 R RV R27 2 o rH N8 /' \ 28 28 F F V W\(C) :Q\CH)2 e F or Y '2 is -N 28 o -C7 preferably hydrogen, R27 E X(CH 2 ) or E~~\ 2 / 7R2 F R2 R 28 2 5 wherein: r and s independently are 1 or 2; E, F and G independently are -CHR 1 8 _, >0=0, >NR 39 , -0- or -S-; 10 Y' is -N= or -CR 1 2
=;
WO 99/01423 PCT/DK98/00287 41 Z' is -N= or -CR 33 =; V' is -N= or -CR'=; 5 W' is -N= or -CR"=; Q' is -NR 3 6 -, -0- or -S-; 10 wherein
R
27 , R 2 8 , R 3 2 , R 3 3 , R1 4 and R 3 5 are independently hydrogen, halogen, -CN, -CF 3 , -OCF 3 ,
_O(CH
2 )yCF 3 , -NO 2 , -OR 29 , -NR 29
R
3 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 ,
-CHF
2 , -OCHF 2 , -OCF 2
CHF
2 , -0S0 2
R
29 , -OS02CF 3 , -CONR 29
R
3 , -(CH 2 )yCONR 29
R
3 4, 15 -O(CH 2 )yCONR 2
R
3 0 , -(CH 2 )yOR 29 , -(CH 2 )yNR 2 9
R
3 0 , -OCOR 29 , -C0 2
R
29 ; or R 2 'and R 2 1, R 3 2 and R 3 3 , R 3 3 and R3 or R3 and R 3 5 together form a bridge -OCH 2 0-;
R
27 and R 2 1 preferably independently representing hydrogen, halogen,-CF 3 , -OCF 3 ,
-OCH
2
CF
3 , -OR 29 , lower alkyl, aryl or aryl-lower alkyl, or together forming a bridge 20
-OCH
2 0-; y is 1,2, 3or4;
R
2 9 and R 3 1 independently are hydrogen, -COR 31 , -S0 2
R
31 , lower alkyl, aryl or aryl-lower 25 alkyl;
R
31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R
3 6 and R 3 9 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; 30
R
3 1is hydrogen, -OR 4 0 , -NR 4 0
R
4 4, lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 4 1, -CHF 2 , OCHF 2 , -OCF 2
CHF
2 , -CONR R 4 4, -(CH 2 )xCONR R 4 4, -O(CH 2 )xCONR 4
*R
41 , -(CH2)x0R
-(CH
2 )xNR 4 0
R
4 1 , -OCOR 4 0 or -CO2R40; WO 99/01423 PCT/DK98/00287 42 x is 1, 2, 3 or 4;
R
4 0 and R 4 1 independently are hydrogen, -COR 42 , -S0 2
R
42 , lower alkyl, aryl or aryl-lower 5 alkyl; and
R
42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl. In a further embodiment the invention relates to the compounds of the formula I wherein: 10
R
1 and R 2 independently are hydrogen or lower alkyl or together form a valence bond;
R
3 and R 4 independently are hydrogen or lower alkyl; 15 nis0,1,2or3; m is 0 or 1; X is >C=0, >C=S, >C=NR' or >S0 2 ; 20 wherein R 5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR"; wherein R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; 25 A is WO 99/01423 PCT/DK98/00287 43
R
7 R R7 R 7 N N 8 N 8 N8 RR R R R R R R R R R R 7 R 10 N R R 7 9 1 R R R RN/ R R R Ra1R0R R 10 10 10 SR R R R N R oR N 8 /N R R8 9 N e I N8 RR R R
R
10 o R T 7s R N N8 - S 7 RN R R8 I I-./I- S ,N R N RN 8 8 9 R' 7 1 RN 10 N 0R1 R 1 R 1 R '
R
7 1 N R N R a N R N
R
9 3 R RR9 RR10 R R 1 7 7 7 N or 7
R
8 R weeN: RN WO 99/01423 PCT/DK98/00287 44 R' is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2
CF
3 , -NO 2 , -OR", -NR"R 2 , lower al kyl, aryl, -SCF 3 , -SR", -CHF 2 , -OCHF 2 , -OSO 2 R", -CONR"R, -CH 2 OR", -CH 2
NR
1 R, -OCOR", -CO 2 R or -OSO 2
CF
3 ; 5 R' and R' independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2
CF
3 , -NO 2 , -OR", -NR"R , lower alkyl, aryl, -SCF 3 , -SR", -CHF 2 , -OCHF 2 , -OSO 2 R", -CONR 1 R,
-CH
2 OR", -CH 2
NR"R
2 , -OCOR , -CO 2 R1 3 or -OSO 2
CF
3 , or R 8 and R 9 together form a bridge -OCH 2 0- or - OCH 2
CH
2 O-; 10 wherein R" and R 2 independently are hydrogen, -COR, -SO 2 R, lower alkyl or aryl; wherein R' 3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and 15 R' is hydrogen, lower alkyl, aryl-lower alkyl or aryl; B is R 15 ww "Y ww RJR; R R5 Vz1 R -+-1 RR R wR 1' 5 R Q R isQQI RQ w w4 Z / , 5R R V1Z 14 a Q vac b R Ii14- 15 14 -t-CR-CR5 or a valence bond; preferably WO 99/01423 PCT/DK98/00287 45 R R4, R R15 R 1
R
15 w or 0 S -P-R V,.-r R 15 wherein: 5 R 14 and R' 5 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O(CH 2
)CF
3 , -NO 2 ,
-OR
16 , -NR 16 R 7 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR' 6 , -CHF 2 , -OCHF 2 ,
-OCF
2
CHF
2 , -OS0 2
CF
3 , -CONR'"R , -(CH 2 )ICON R*R4, -O(CH 2
)ICONR
1 6 R 7 ,
-(CH
2
)ICOR
16 , -(CH 2
)COR
16 , -(CH 2
)OR
16 , -O(CH 2
)OR
16 , -(CH 2
)NR
16
R
17 , -O(CH 2 )iNR 1 6
R'
7 ,
-OCOR
16 , -C0 2
R
1 8 , -O(CH 2 )iC0 2
R
18 , -O(CH 2 )ICN, -O(CH 2 ),CI, or R1 4 and R 1 5 together 10 form a bridge -OCH 2 0-;
R
14 andR" preferably independently representing hydrogen, halogen, -CF 3 , -OCF 3 , -OR", -NR 1 6 R 7 , lower alkyl, aryl, aryl-lower alkyl, -OS02CF 3 , -CONRR 16 1 7 , -CH 2
OR
16 ,
-CH
2
NR
16
R
17 , -OCOR 16 or -C0 2
R
8 ; or together forming a bridge -OCH 2 0-; 15 wherein I is 1, 2, 3 or 4;
R
16 and R 1 7 independently are hydrogen, -COR 18 , -S0 2 R", lower alkyl, aryl, or R" and
R
17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms; 20 wherein R 18 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; W is -N= or -CR= 25 Y is -N= or -CR 2 0
=
WO 99/01423 PCT/DK98/00287 46 Z is -N= or -CR21 V is -N= or -CR 22 =; and 5 Q is -NR 23 -, -0- or -S-; wherein:
R
1 9 , R 20 , R 21 and R 22 independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2
CF
3 , 10 -NO 2 , -OR 24 , -NR 2 4
R
2 1, lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 ,
-OCF
2
CHF
2 , -OSO 2
CF
3 , -CONR 24
R
2 , -CH 2
CONR
24
R
2 , -OCH 2
CONR
24
R
2 , -CH 2 0R 24 ,
-CH
2
NR
24
R
2 5 , -OCOR 2 4 or -C0 2
R
24 , or R 1 and R 2 0 , R 20 and R 21 or R 2 'and R 22 together form a bridge -OCH 2 0-; 15 wherein R 24 and R 25 independently are hydrogen, -COR 2 , -SO 2
R
2 , lower alkyl, aryl or aryl-lower alkyl; wherein R 2 1 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and 20 R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K is Ra R 3 b R R 4 (,-(CH )p (CH 2 )a (M)f (CH 2 )c ' (CH 2 )d 25 wherein:
R
3 a, R 3 b, R 4 " and R 4 b independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 ,
-OCH
2
CF
3 , -NO 2 , -OR 24 , -NR 24
"R
2 5 ", lower alkyl, aryl, aryl-lower alkyl, SCF 3 , -SR 24 ,
-CHF
2 , -OCHF 2 , -OCF 2
CHF
2 .-OS0 2
CF
3 , -CONR 24 aR 2 5 ", -CH 2
CONR
24 aR 2 a 30 -OCH 2
CONR
24 aR 2 5 a, -CH 2 0R 24 ., -CH 2
NR
2 4 aR 2 5 a, -OCOR 24 , or -O 2
R
24 a; WO 99/01423 PCT/DK98/00287 47 wherein R 2 4 " and R 2 " independently are hydrogen, -COR 2 a, _S0 2
R
2 e", lower alkyl, aryl or aryl-lower alkyl; wherein R 2 1, is hydrogen, lower alkyl, aryl or aryl-lower alkyl; 5 or
R
3 " and R 3 ", R 4 ' and R 4 b or R 3 a and R 4 b together form a bridge -(CH 2 )i-; 10 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; 15 q is 0,1 or 2; and L and M independently are 20 -0-, -S-, -CH=CH-, -C=C-, -NR 5 "-, -CO-, -OCO-, -COO-, -CONRa-, -NReaCO-, -SO-, -So 2 -, -OSO 2 -, -S02-NR 5 a-, -NR 5
"SO
2 -, -NR 5 aCONR 5 b-, -NR 5 aCSNR 5 b-, -OCONRb- or
-NR
5 aC(0)0; wherein R 5 a and R b independently are hydrogen, lower alkyl, -(CH 2 )k-OH, -(CH 2 )k 25 NRaR 6 b, aryl or aryl-lower alkyl; wherein k is 2, 3 or 4; and Rea and R b independently are hydrogen, lower alkyl or aryl-lower alkyl; 30 K preferably representing WO 99/01423 PCT/DK98/00287 48 -N- -- C -O-(CH2)g- -- - , --- (CH2)2-N-(C2 A R 0
-O-CH
2 CHR' CH2 N-CH2 , -O-CH2 N-(CH2 2 H 2 S R 0 0 -O--CH2 110--(CH2)2 , -O-CH2 1 o 0 11 -- 0-- , a valence bond -O-(CH2)2--O N il H 0 0 -0-CHR-- ,0 OACH 2 O R R4 R4 |I R
-(CH
2 )b N-(CH 2 )- and O(CH 2
)
2
N(CH
2 ) q (CH2) D is hydrogen, WO 99/01423 PCT/DK98/00287 49 27 27 , R ~ RR
R
28 7_- R ' R28 R R28 R2 - RR R7 27, R 27 (CH2)(CH. R27 (C 2 E FE(2 R\ R2/ R27 RI (C2(CH V E F '--- (G)- I R28 prefea28 hydrogen, R Z - V R
R
2 27 E \2) FE2 /FR 2727F /-Q R
(C
2 (EF R 27 / E(CH 2 ). (G), G (C 2 ). G -or Y, R 2 8 ' R28R 2 8 R272
(CH
2 ), E F'\ (G)r F27 6\2 preferably hydrogen, WO 99/01423 PCT/DK98/00287 50 R 2 7 WW Q I E R 27 R22,27R R/ R C 2 ) E 2)I ( H 2 ) 28 2 '' - R28 R R
(CH
2 )S E8 E
R
27 R 27 R27 E 10 F' i> -E o >N-(G) R27 R-- 2 7 28 R R2 27 R 8 or R27 Y'is-N or RC
(CH
2 )K wherein: 5 r and s independently are 0, 1 or 2; E, F and G independently are -CHR 38 -, >0=0, >NR 39 , -0- or -S-; 10 Fis >0R 3 1_ or >N-; Y' is -N= or -0R 3 = Z' is -N= or -CR 33 =; 15 V is -N= or -R= WO 99/01423 PCT/DK98/00287 51 W' is -N= or -CRas=; and Q' is -NR 36 -, -0- or -S-; 5 wherein:
R
27 , R 2 8
,R
32 , R 33 , R 34 and R 3 ' are independently hydrogen, halogen, -CN, -CF 3 , -OCF.,
-O(CH
2 )yCF 3 , -NO 2 , -OR 29 , -NR 2 9
R
3 0 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 29 ,
-CHF
2 , -OCHF 2 , -OCF 2
CHF
2 , -OS0 2
R
29 , -OS02CF 3 , -CONR 29
R
3 , -(CH 2 )yCONR 2 9
R
3 4, 10 -O(CH 2 )yCONR 2 9
R
3 0 , -(CH 2 )yOR 2 9 , -(CH 2 )yNR 2 9
R
3 0 , -OCOR 29 or -C0 2
R
2 9 ; or
R
27 and R 2 1, R 3 2 and R 3 3 , R 33 and R4 or R3 and R3 5 together form a bridge -OCH 2 0-; 15
R
27 and R 2 1 preferably independently representing hydrogen; halogen such as -Cl or -F;
-CF
3 ; -OCF 3 ; -OCHF 2 ; -OCH 2
CF
3 ; -OR 2 1 wherein R 2 1 is hydrogen or lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF 3 ; -CH 2 OH; -COO-lower alkyl; aryl or -CONH 2 ; or together forming a bridge -OCH 2 0-; 20 wherein y is 1, 2, 3 or 4; and
R
2 9 and R 3 0 independently are hydrogen, -COR 3 1 , -S0 2
R
31 , lower alkyl, aryl or aryl-lower alkyl; 25 wherein R 3 1 is hydrogen, lower alkyl, aryl or aryl-lower alkyl;
R
3 6 and R 3 1 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; and 30 R 38 is hydrogen, -OR 4 0 , -NR 4 1R 4 1 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 4 1, -CHF 2 ,
-OCHF
2 , -OCF 2
CHF
2 , -CONR 4 0
R
41 , -(CH 2 )xCON R 4 0
R
4 1 , -O(CH 2 )xCONR 4 0
R
41 , -(CH2)x0R40,
-(CH
2 )xNR 4 0
R
4 1 , -OCOR 4 0 or -CO2R40; WO 99/01423 PCT/DK98/00287 52 wherein x is 1, 2, 3 or 4;
R
4 ' and R 4 ' independently are hydrogen, -COR 42 , -S0 2
R
42 , lower alkyl, aryl or aryl-lower alkyl; and 5 wherein R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
WO 99/01423 PCT/DK98/00287 53 Examples of specific compounds represented by the above general formula V are the follow ing: CH, CH CH, C1 CH HO HO N CI C1 3-Chloro-4-hydroxybenzoic acid [5-chloro-2- 3-Chloro-4-hydroxybenzoic acid [3,5-dichloro methoxy-4-(4-isopropylbenzyloxy)- 4 -(4-isopropylbenzyloxy)benzylidene]hydrazide benzylidene]hydrazide CH, CH, O CH 3 O
CH
3 O0~ N 0 N 0 N Ij;A H OCH 3 NCH Ho( N 0! HO N OCHa HO N C C1 C1 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 CH,
CH
3
OOCH
3 H H CH, 0 N 0 & N0 HO N CH 3 N HON
OCH
3 Cl C1 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 WO 99/01423 PCT/DK98/00287 54 H 3 C CH 3 . CH 3 OHO 0 N 0 N0 C H 3 0 N H HO I[p HN " 0(CH 3 HO ~HOH ci ci 3-Chloro-4-hydroxybenzoic acid [3-isopropyJ- 3-Chioro-4-hydroxybenzoic acid 4-(4-isopropylbenzyoxy)-5- {3-[2-(lI -pyrrolid ino)ethoxy)]-4-(4 methylbenzylidene] hydrazide isopropylbenzyioxy)-5 methoxybenzylidene}hydrazide
OCH
3 H / N--'H3 C f 3
CH
3 H3 CH CH 3 00 OJ-1 H 3 0 0 NN'OH O' N N NN O- OCH HIJ( H HOH 3 H 3-Chioro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [3-(2-diethylaminoethoxy)-4-(4-isopropyi- [3-(2-d iethylaminoethyi)-4-(4 benzyioxy)-5-methoxybenzylidene] hyd razide isopropyibenzyloxy)-5 methoxybenzylidene] hydrazide H 3 CO O C H O - H 3
OH
3 O0 0 0 N H 00OC3 H C HO -~HO ( N ci ci 3-Chioro-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 WO 99/0 1423 PCT/DK98/00287 55
OH
3 CH 3 O,, O
H
3 0 ,-OH
OH
3 0O N 0 N N N OCH 3 N N,,,& - O HO'H HO'H Ci CI 3-Chloro-4-hydroxybenzoic acid 3-Chloro-4-hydroxybenzoic acid [3-(2-hydroxyethoxy)-4-(4-isopropyl- [3 ,5-bis-(2-hyd roxyethoxy)-4-(4 benzyloxy)-5-methoxybenzylidenelhydrazide isopropylbenzyloxy)benzylidene] hydrazide
OH
3 OCH 3 OH 3
OCH
3 OH3 0Njo, I N' N 0 &,CH O' N 0 NC3 N NN H OCH 3 H H(? 3-Oh Ioro-4-hyd roxybenzoic acid 3-Chioro-4-hydroxybenzoic acid [2,3, 5-trimethoxy-4-(4-isopropylbenzyoxy)- [3, 5-dimethoxy-4-(4-n-propylbenzyloxy) benzyiidenejhydrazide benzylidenejhydrazide
OOH
3 . 0 1-. OH 3 OH 3 0 0 NOH 3 3~O ,l: )N NN
OCH
3 0N 0 N HO HN ' NN OCH 01 HO -? F 3-Chioro-4-hydroxybenzoic acid 3-Fluoro-4-hydroxybenzoic acid [3, 5-dimethoxy-4-(4-ethoxybenzyoxy)- [3, 5-dimethoxy-4-(4-isopropylbenzyoxy) benzylidene]hydrazide benzylidene]hydrazide WO 99/01423 PCT/DK98/00287 56 OH 3 OH
OCH
3 - ~CH 3 OCH 3 CH O 3 O0 0 0 0N 0 N N NN OCH 3 Ij:P N H C I H H OH HO HO N0~2 C0 2 H 3-Nitro-4-hydroxybenzoic acid 3-Carboxy-4-hydroxybenzoic acid [3 ,5-dimethoxy-4-(4-isopropyibenzyloxy)- [3, 5-d imethoxy-4-(4-isopropyl benzyioxy)- ben benzylidene]hydrazide zylidene]hydrazide
CH
3 OH 3
OCH
3 - ~CH 3 OCH 3 - H 3 0OJ 0 0 N Q-1 N 0 N HN N 111 ( ,& O C H 3 HO HO
CONH
2 ON 3-Carbamoyl-4-hyd roxybenzoic acid 3-Cyano-4-hydroxybenzoio acid [3, 5-d imethoxy-4-(4-isopropylbenzyloxy)- [3, 5-di methoxy-4-(4-isopropylbenzyloxy) benzylidene]hydrazide benzylidene]hydrazide OCH 3 0~ 00H 3
OCF
3 O 0 N
CF
3
N
0 H N ci N NN-& 'H N NN OC0H 3 HO jHO 3-Chioro-4-hydroxybenzoic acid 3-Chloro-4-hyd roxybenzoio acid {3 ,5-d imethoxy-4-[4-(2,2,2-trifluoroethoxy)- [3 ,5-di methoxy-4-(3-ohloro-4 benzyloxy]-benzylidene~hyd razide trifluoromethoxybenzyloxy)benzylid ene]hydrazide WO 99/01423 PCT/DK98/00287 57
OCH
3 OCH 3 O N'N, 0C O 0 NC N N l:I N'H Ci N N.' - H 3 ~~~H OCH 3 ? H0CH3)"rC HO HO H OH3 cl cl 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 ene]hydrazide OCH CF 3
OCH
3
CH
3 0I z 0 _-,, - CH 3 N 0 NN-d OH N OCH 3 N OCH HO JC:AHO0 C CIC 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
OCH
3 OCH 3 O 0 0
N
0 HO
.
H
2 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 WO 99/01423 PCTfDK98/00287 58 N CH N N'N ~ OCF N NN - H 3 H I H HOj HOj CH 3 CI CI 3-Chloro-4-hyd roxybenzoic acid [4-(4- 3-Chioro-4-hyd roxybenzoic acid [4-(4 trifluoromethoxyphenoxy)-l - isopropylphenoxy)-1 naphthylmethylene]hydrazide naphthylmethylene]hydrazide OCH 3 CF 3 CH 3 0 N N N -~ CH 3 0OCH 3 j N A.- OC HO N NN OCH HO CI 3-Chloro-4-hydroxybenzoic acid {3,5- 3-Chloro-4-hydroxybenzoic acid {3,5-di dimethoxy-4-[2-(4-E-trifl uoromethylphenyl)- methoxy-4-[(4-isopropylphenyl) ethenyl]benzylidene}hydrazide ethynyl]benzylidene}hydrazide OCH 3 OCH 3 0 A N C O0 N'3 HN N N
OCH
3 HO' HO HCI
OH
3 CI 3-Chioro-4-hydroxybenzoic acid [3,5- 3-Chloro-4-hydroxybenzoic acid [3-(2 dimethoxy-4- methoxy-4-methylphenyl )ethynyl-5 (cyclohexylethynyl)benzylidene~hydrazide methoxybenzylidenelhydrazide WO 99/01423 PCT/DK98/00287 59 O NOH N N H 0 N 0 ~F HONI:: F CC 3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1 - 3-chloro-4-hydroxybenzoic acid [4-(3,5-bis naphthylmethylene)hyd razide trifluoromethyi benzyloxy)-1 naphthylmethylene]hydrazide O CI I H [A ' HO N H CI HO N
OCH
3 3-chloro-4-hydroxybenzoic acid [4-(2- 4-Hydroxy-3-methoxybenzoic acid (2 chloroethoxy)-1 -naphthylmethylene]hydrazide naphthylmethylene)hydrazide ON OCCH HO NH 4-Hydroxy-3-methoxybenzoic acid (4- 4Hdoy3mtoyezi cd(-et methoxy-1 -naphthylmethylene)hydrazide btlezldn~yrzd
OCH
3 O NNN CH 3 HO H H CH HON
OCHOCH
3 4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxy-3-methoxybenzoic acid (4 meshopoylbe-nzphyiden hy ydde trifluoromethobenzylidene)hydrazide HO N HO HO OCHs 4-Hyrox-3-mthoybenoicacid(4-4-Hydroxy-3-methoxybenzoic acid (2 isopropylbenzyldene~hydranahthyfl methyeyiene)hydrazide WO 99/01423 PCT/DK98/00287 60 N OCH 3 0 0 N, NCH3 HO I H H H HO NN HO N
OCH
3
OCH
3 4-Hydroxy-3-methoxybenzoic acid (1 H-indol-3- 4-Hydroxy-3-methoxybenzoic acid (4 ylmethylene)hydrazide dimethylamino-1 naphthylmethylene)hydrazide 0 N HOO N HO N HON H HoN H
OCH
3 4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxybenzoic acid (1 phenylbenzylidene)hydrazide naphthylmethylene)hydrazide O OCH 3 0 HO HO N HO 4-Hydroxybenzoic acid (4-methoxy-1- 3,4-Dihydroxybenzoic acid (1 naphthylmethylene)hydrazide naphthylmethylene)hydrazide N F F H N HO" N'N HON; HH
OCH
3 ,N N HOH
OCH
3 4-Hydroxy-3-methoxybenzoic acid (1- 4-Hydroxy-3-methoxybenzoic acid [3-(3-tri naphthylmethylene)hydrazide fluoromethylphenoxy)benzylidene]hydrazide WO 99/0 1423 PCTLDK98/00287 61 F F o O~F 0 NZNN N' H HO H~ e N.N 00H 3 HON 4-Hydroxy-3-methoxybenzoic acid (4- 4-Hydroxybenzoic acid [3-(1 A ,2,2 quinolinylmethylene)hydrazide tetrafluoroethoxy)benzylidene]hydrazide
CH
3 0
~CH
3 0O Oe N QH NN'H HO H CH 3 HON H
OCH
3 4-Hydroxybenzoic acid [3-(4-tert-butyiphenyl)- 4-Hydroxy-3-methoxybenzoic acid (4 E-but-2-enylidenelhydrazide hydroxy-1 -naphthy~methylene)hydrazide HON WN.. A NN I H 4-Hydroxybenzoic acid (benzylidene)hydrazide 4-Hydroxybenzoic acid (1 naphthylmethylene)hydrazide 0 0 Q OH HO" HO N;
NH
2 NH 2 3-Amino-4-hydroxybenzoic acid (1 - naphthyl- 3-Amino-4-hydroxybenzoic acid (4-hydroxy methylene)hydrazide 1- naphthylmethylene)hydrazide WO 99/01423 PCT/DK98/00287 62 H N F O N'N N' ~F0 Hoe H N - N HON H Cl 4-Hydroxybenzoic acid [3-(3-trifluoro- 3-Chloro-4-hydroxybenzoic acid (1 methylbenzyloxy)benzylidene]hydrazide naphthylmethylene)hydrazide O OH 0 OH HOH HON H CI 3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1- 4-Hydroxybenzoic acid (4-hydroxy- 1 naphthylmethylene)hydrazide naphthylmethylene)hydrazide F F 0 HN-N OoNO O N HON N O 4-Hydroxybenzoic acid [4-(3- 4-Hydroxybenzoic acid (5-phenyl-3 trifluoromethylphenoxy)benzylidene]hydrazide pyrazolylmethylene)hydrazide H N N O N OH O S N s N HON OH HO O, .N O 2,4-Dihydroxybenzoic acid (4-hydroxy-1- 4-Hydroxy-3-nitrobenzoic acid (1 naphthylmethylene)hydrazide naphthylmethylene)hydrazide WO 99/01423 PCTIDK98/00287 63 N N N O HO NO HON HON 0 --N Kz HO 4-Hydroxy-3-nitrobenzoic acid (4-hydroxy-1 - 3,4-Dihydroxybenzoic acid (4-hydroxy-1 naphthylmethylene)hydrazide naphthylmethylene)hydrazide OCH 3 N 0 N l0 NOH HON H HON H CI 4-Hydroxybenzoic acid (6-methoxy-2- 3,5-Dichioro-4-hydroxybenzoic acid (4 naphthylmethylene)hydrazide hydroxy-1 -naphthylmethylene)hydrazide N N 0 0 N\ H ICH 3HON:; HONN
OCH
3 OCH 3 4-Hyd roxy-3-methoxybenzoic acid (9-ethyl-9H- 4-Hyd roxy-3-methoxybenzoic acid [5-(3 3-carbazolylmethylene)hydrazide chloropheny!)-2-furanyimethylenejhydrazide H N HON - NN~ Il H HO )A CI 3-Chloro-4-hydroxybenzoic acid (3-phenyl-E- 3-Chloro-4-hydroxybenzoic acid (4-allyloxy-1 aliylidene)hydrazide naphtylmethylene)hydrazide WO 99/01423 PCT/DK98/00287 64 N N N O' N 0< 0 ' N 0 1 11 HI H HO JHO CI CI 3-Chloro-4-hydroxybenzoic acid (4- 3-Chioro-4-hydroxybenzoic acid (4 ethynylmethoxy-1 - benzyloxy-1 -naphthylmethylene)hydrazide naphthylmethylene)hydrazide O O 0 --A N H 2 0 H HO HO H Cl CI 2-(4-[(3-Chloro-4-hydroxyben zoyl)hydra- zo- 3-Chloro-4-hydroxybenzoic acid (4-methyl-i nomethyl]-1 -naphthyloxy)acetamide naphthylmethylene)hydrazide ,N N O N
NOCH
3 I H HO OH HON CI CI 3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1 - 3-Chioro-4-hydroxybenzoic acid (4-methoxy naphthylmethylene)hydrazide 1 -naphthylmethylene)hydrazide 0 0 NN O HO H H HO N N HO N Cl N-(2-[(3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid (1 -hydroxy hydroxybenzoyl)hydrazono]ethyl)-2,2- 2-naphthylmethylene)hydrazide diphenylacetamide WO 99/01423 PCT/DK98/00287 65
OCH
3 0 N0 N N 0 H O HON NC HON Cl CI 3-Chloro-4-hydroxybenzoic acid (2,2- 3-Chloro-4-hydroxybenzoic acid (4 diphenylethylidene)hydrazide benzyioxy-3,5 dimethoxybenzylidene)hydrazide
CH
3 OO N CH CH H 3 0 0 Ho -C j O N O HOH Cl 3-Chloro-4-hydroxybenzoic acid [3-(4-tert- 3-Chioro-4-hydroxybenzoic acid (4-methyl-i butylphenoxy)benzylidene]hydrazide naphthyimethylene)hydrazide N OH S,N Br N' N 0 HON - H HO H Cl CI 3-Chloro-4-hydroxybenzoic acid (3-bromo-4- Acetic acid 4-[(3-Chloro-4 hydroxy-1 -naphthylmethylene)hydrazide hydroxyberzoyl)hydrazonomethyl-i -naphthyl ester N N HO N HON O OH CI CI 3-Chloro-4-hydroxybenzoic acid (4- 3-Chioro-4-hydroxybenzoic acid (2-hydroxy cyanomethoxy-1 - 1 -naphthylmethylene)hydrazide naphthylmethymene)hydrazide WO 99/01423 PCTIDK98/00287 66 O ~ NOCHa 0 0 N N N N~ NH~ H~NN HO I HON CI ci 3-Chloro-4-hydroxybenzoic acid (2,3- 3-Chloro-4-hydroxybenzoic acid [3-(4 methylenedioxybenzylidene)hydrazide methoxyphenoxy)benzylidenelhydrazide N N HO Cl CI 3-Chloro-4-hydroxybenzoic acid (9- 3-Chloro-4-hydroxybenzoic acid [4-(2 phenanthrenylmethylene)hydrazide hydroxyethoxy)-1 naphthylmethylene]hydrazide "CkNN N N HO HON Br Ci 3-Bromo-4-hydroxybenzoic acid (4-hydroxy-1 - Nicotinic acid 4-[(3-chloro-4 naphthylmethylene)hydrazide hydroxybenzoyl)hydrazonomethyl]-1 -naphthyl ester 0 11 N "l O 0Np 0 N 0 H O N, 0 -H O H OJ:;:)HO"CI CI 3-Chloro-4-hydroxybenzoic acid [4-(1 ,3-dioxo- 3-Chioro-4-hydroxybenzoic acid [4 1 ,3-dihydroisoindol-2-ylmethoxy)-l -naphthyl- (cyclohexylmethoxy)-1 methyiene]hydrazide naphthylmethylene]hydrazide WO 99/01423 PCT/DK98/00287 67 O N 0 0 N HO H HO, Cl CI 3-Chloro-4-hydroxybenzoic acid [4- 3-Chloro-4-hydroxybenzoic acid [4-(3 (tetrahydro-2-pyranylmethoxy)-1 -naphthyl- pyridylmethoxy)-l methylene]hydrazide naphthylmethylene]hydrazide 0 0 N+ O N O O CHN HON N ,N~ HO ,H ClH 4-[(3-Chloro-4- 3-Chloro-4-hydroxybenzoic acid (3 hydroxybenzoyl)hydrazonomethyl]-1 - nitrobenzylidene)hydrazide naphthyloxy)acetic acid ethyl ester N'CI C1 O N N H N HON"[::) H , ,Z CH HON CI 3-Chloro-4-hydroxybenzoic acid (2,4- 3-Chloro-4-hydroxybenzoic acid (4-fluoro-1 dichlorobenzylidene)hydrazide naphthylmethylene)hydrazide WO 99/01423 PCT/DK98/00287 68 N N F N F O OH HO N HON HON HC: F Ci 3-Fluoro-4-hydroxybenzoic acid (4-hydroxy-1- 3-Chioro-4-hydroxybenzoic acid [4-(2,4 naphthylmethylene)hydrazide difluorobenzyloxy)-1 naphthynmethylenehydrazide N N' N NO O F HO HO F C 3-Fluoro-4-hydroxybenzoic acid (1- 3-Chioro-4-hydroxybenzoic acid [4-(3 naphthyfmethylene)hydrazide methoxybenzyloxy)naphthylmethylene]hydrazide 0 0 O NN O OC HO HO H CI Cl 3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(2 fluorobenzyloxy)-l tetrahydrofuranylmethoxy)-1 naphthylmethylene]hydrazide naphthylmethylene]hydrazide WO 99/01423 PCT/DK98/00287 69 0 OCH 3 0 O N Br HO N HON H: HON Cl CI 3-Chloro-4-hydroxybenzoic acid (3-bromo-4- 3-Chloro-4-hydroxybenzoic acid [4-(3 methoxy-1 -naphthylmethylene)hydrazide tetrahydrofuranylmethoxy)-1 naphthylmethylene]hydrazide 00 F N ON OCO F OCH 3 0 N 0 - FE O0N
.N
oj: N OCH 3 HO H HO H HO HO** Cl CI 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 N 0 0 ~ FN HON OOH N
CH
3 HOJ HON H Cl CI 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 PCT/DK98/00287 70 0 0_- 0 0 HO HO N F 3-Chloro-4-hydroxybenzoic acid [4-(2- 3-Chloro-4-hydroxybenzoic acid [4-(2,6 fluorobenzyloxy)-1- difluorobenzyloxy)-1 naphthylmethylene]hydrazide naphthylmethylene]hydrazide OMe CH 3 HO -O HO CC - -- N OCF N-N -CH C H 3 H --- / ci 0 HO /\O-CH, CH, HO - N-N -H \ - /\ OCF 3 H H, H O-CH 5 WO 99/01423 PCT/DK98/00287 71 / 0 HO CH OO -5 H HO CH - N-N N-N H\ /\ -
CH
3 cI H\ I \ H cl 0 3 0CCa H - H ci OH 3 0 ~~~CO2HC 02 HO CO O CH HO / C N-N CH H \ 0 CHO N - CH H - / / 0CCH 3 HH 3 HH O N OHC 0 HO - O CH HOON(Et)2 N-H NN-N H ci H\ -CH 3 ci H\ / 0/ ~ OF H -H 0003 - HO 7 O - 4N-N JOCF HC N-N H\ ~\/ 3 ~ / \ 0N(Et) H -H> 0 0 H N NNaC NH-N H NH HO N N N CH 3
C
3 HO CF 3 H O'~N-- CF 3 HOH - - N-N N 0 H\ 4 /-- N-N P H 0 H 0 H0CP H \ N F N(Et) 2 HOS NN NHC O HO4 N-N N\/CF 3 H \- H\ /I\ HH -l WO 99/01423 PCT/DK98/00287 72 N(Et), N(Et) 2 O 0 Ho'\ N HO "N - -N N-N H H CFO CH, HHC N(Et) 2 -N(Et) 2 / 0 HO OMe N HO OMe N N-N N-N C - H H - H -> _ OMe CH, OMe OCF, HC 0 HO NHO N - N-N C1 H H -4 OMe
CH
3 HCC The most preferred specific compounds represented by the above general formula Ill are the following: 0CF O H HO CF\ 3 ;S/ N- 0N-N S, P 0,H
-
CF HOq F CI HO--P - HO ;S/ - ;S ON-N O O-,N-N H0 /\/ CF 3 F \ / H H OMe /S OMe H 5 The most preferred specific compounds represented by the above general formula IV are the following: WO 99/01423 PCT/DK98/00287 73 H H HO HO-N~ OC OCF
OCH
3 O HO H CH HO - N-NCH HO H N-N Ci '1H H
OCH
3 / 0 F HO / eO OCH 3
-
HO
OCH
3 O N' e O. NO F H H NN H H1 C1
OCF
3 HO-- H CCl H OCH 3 OCH, N N -N H
LO
3 H O M e O , C H3 OCHC Preferred specific compounds represented by the formulae VI and VII are the following: HO H HO 0H 0 H MeO aO C HN'O N O H HO H HO ci H HHO M OC N'O N'l MeO O N C-N HO HO H ci ci O O 0 Me N N~>> 1- N< N N N% C1:C HOq I 1H HO H crO l HO MeO O N OOe CI C N WO 99/01423 PCT/DK98/00287 74 OH NiO O 0e.<O.. N OMe N H OH '' H H HOH Ne O~ cl H HH HOO 0 0 N~N N N H HO 0 ci O MeO O~ H HO' N c .F .N N'Oe HNij HH N ~ CF3N N' - N *i OMe HO C O N N C jj HI NN,& HO .N-. NNH N N N OMe .C cl H O~~e HO ))C 0 - 0 -''N Sz CFCI NI I NN N' N.Ne N O H H HO ci o - 0 N O~e H HO ~e H O~~ 0 ""N N e N~ NO j~ H 6 HO*f H ci WO 99/01423 PCT/DK98/00287 75 O N N C C1 Cf O O e N O N CI Cf N N~ HO OO ON0OMe N.N O. OMe O OMe HO CH CIC O- o O N. OM, NH HO H NOO HO H CI C O OF O O-r HO.NN O - O M e O M e N N NN10- N H 0 O ON NeO HHO HO -CI ci 0N BNN'HN N I. H ( " NN OMe OHI H HO Cf 0 N N N N'N N HO"^ CI HH HOH N' N H HO'P Cf WO 99/01423 PCT/DK98/00287 76 ~ N ~C ~OMe 0 0 N N N HN NN N H HO- l HOH N N' N 0 N K0K-. NN.N I H NI H -) F HO-f: HO' AH 0 0 '-""N - N 'NN H N ' H HOJP HO'?H 0 0 0 -- NN o N jj NN .N N K N N H 0N> HO H OH I H N ' N H N N H 3R "" C HO0 HO* N 0 -''N 0 o N a~ N '.N N HI N" O N'N Nj 1 H OeI H HO HO;A ",_,,,OMe 0 '' N OMe 0 N N N.N N 6H 3 N N N . HJ? H HOI(P H N Nl N' N H N NN. N K I H HO'P HOJ H 3 C CH 3 CI
CI
WO 99/01423 PCT/DK98/00287 77 H
H
3 N . N N N 5 ci No NN~NLN HO ~ O O O N'~ N H 0 N N N N HO H CH HO CIC HON N Cl 0 C N NHO N OH 2 o CI HO O ONOH N NO N N NCII OH N OH HO"O H - CIO N NN N NO N CI HO . Cl N N Br& I* HIz N H N HOO H CI HO - CI OoONN B N N.NNHN .N H Cl 0~ .N-" OBC H N NO NNC HO'? CI HO CI A' A om N'N N 0N O N*' N"l~ HO IA H NN J.OeN NN NH CI HOJP H
CI
WO 99/01423 PCT/DK98/00287 78 SS\ OMe O N 0 NN H - H' "&OMe HN' H HO HO c OMe B 0NNN N' HN H HCF, Ci ci OMe -0 0 N- " Y N' N (?A~~NA N H OH HO.NHH cl O N O OH2 H H H O HOH HO" H HO ci O,,(eOMe O O N H.N 0 'e N H HOH i.HOOM Cr N N.N N H NH 2 HO ciB H HO . OMe cl 0 " N~lCl O Or Br OMe Ci 0HN OMe H 3 NNN N OMe s 0--- N-' N HO' NH N Br c CI H CI HO C OMe cO 0 0 '-H.N OMe N N" & W H IC N N~ O~e -Oe CHN HO N Br C I H BrN 2 Ci HO OMe cO CCl Cl WO 99/01423 PCT/DK98/00287 79 OMe N F N ~ -. N " N N' Br ~ HO-' HcI ci cI OH' HNOP 0 CHN NN 0 - N N N 'NN H H- l HO 'N P cI c F 0 0 H a a cil 0 N 0 N'1 cci N,, 0 F 0 N O HO cI CI, N 0 HON F ci cl N~.N HO HO N cl ci 0 oC 0 N0~~ 0 N ci ci WO 99/01423 PCT/DK98/00287 80 0 m 0 HO NN I FFF F 0 N F 0N 0 N 1 N " I 1: ' HO NC: 00 F N N FIDI F F N N" 0 -, F 00 NF INN F , 0~
-
NII , N -, HO H 0 NN 77 0 m N' H;"C. N, 0 N , HO II y F 0 ' 0"( F~ NN - 0F Hso:;) H 00 0 0SNj IO HO '--C~" 0 ci F 4 'F cH WO 99/01423 PCT/DK98/00287 81 0C%0 O N~~ A HH HO F{'F aF N o 0 0 0 N N"0 3 CH3 H C, 0
N
0 0~ CIHO ,N 0 0 0 NM HC 0-I, HO HO 00 - 0 0 -a HO N1 N Nco HO Nl N 0 - i 1% 0 0 0O N HO F' cl4 N' 7c 'il 0 0 Nt 0 N FAFN H HO FF 0e 0 I O N ~ ,N N II N N H N - 04, L 1 H H, ~ NN N HO WO 99/01423 PCT/DK98/00287 82 0 0N HO O 0 0 ~0 0 H H H IO CH 0CF 001- , N 'N N 'N .,01 HO-- HO 09 , O0 o I 0 N 0 HO 9 01, 0 , 0 H N 0a 0 0 0 HO Hk N N H00 0N .. N, 'NH 0 HO'
CBI
WO 99/01423 PCTfDK98/00287 83 0 0 c 0 aiD Cy' N N " CH DeCH H 0 0 N o- FI 0 N N N0 0 H Ha Ha aF cH, 0 - 0 N o 0 'b a H H HO N N &'- NNC' H al Hal y t Hl CH NH HO N a HH clC 0 0 N N 0 N N4 OS a A a HH .- (? F a a-Fai WO 99/01423 PCT/DK98/00287 84 The most preferred specific compounds of formula I wherein A is a heterocyclic and/or bicyclic moiety are the following:
CF
3
CF
3 0 N N 0 N0 N 0 N HI Ne NH H H Indole-5-carboxylic acid [4-(4- Indazole-5-carboxylic acid [4-(4 trifluoromethylbenzyloxy)-1 - trifluoromethylbenzyloxy)-l naphthylmethylene]hydrazide naphthylmethylene]hydrazide
CF
3 cF 3 0N'N 0 N N N N H H N-N HO N 0 H Pyrazole-3-carboxylic acid [4-(4- 3-Hydroxyisoxazole-5-carboxylic acid[4-(4 trifluoromethylbenzyloxy)-1 - trifluoromethylbenzyloxy)-l naphthylmethylenelhydrazide naphthylmethylene]hydrazide WO 99/01423 PCT/DK98/00287 85 0 NP7OMe HH N' ~ 0 MO~_ H\ Oe- H b/4Oe H ~~OMe C e0
H
3 -N-N Me N OMe H OMe - N N MeO HOH\O f OCF 3 CH H - \ N-N O C O CH H N OMe N 0 MeO / "OMe - CH OH H - CH, ~ OMeHO
OH
3
OH
3 OMe - C H 3 OH 3 0 0" 0 N 0 Np N OMe N N NIH NIH H H WO 99/01423 PCT/DK98/00287 86 Especially preferred according to the present invention are the following compounds which show a particularly high affinity to the human glucagon receptor: CHF O0 CH3 O 0 O O CH H1N O 0 HOO O O' NN HO H HOHO . O OF
CH
3 N0 HO .c 30 N 0N 0 0 0
N
0 NN N 0 N- N.'-3 H OFNF HO .N cci 0 N 0 1 'N 0 'N 0 II1 -t0IJINC ON N H N H H HON:; NoC: ci I HO .N c F ON N N N 0 N N 0 1 N'O O HONA HHO .N c cO HO FF F F F F 0 N 0 F 0 N
N
0 N HONC) HON: H ci ci N N HO N H 0 HO'CN H F+ F ci FF ci WO 99/01423 PCT/DK98/00287 87 ON 0 0!: HO N CI O O CH, HO N CHH C1 HON O CHH 3 N F H N 0 0 c N HO H HON ciO CI HOBr 0 O OC I N 0 0 N0 H NH N N .N O O I H H H 3 HOQ1"HO CH
OH
3 0' CH
OH
3 0 0 N N N N NH N N H N ' ONH 3 I H O.HH HOH HO HO F 0 0 - K 0 NN OH 0 N N N N~ N -9z HO .N O HCH Cl C Br 01
OH
3 OH 3 0 CH O ' H 3 - H 3 0 N 00 N N N , OH N N O H I H HO 01 HO ( F 01 F 0' OH 3 F H F N N NH- N N OH HO H O H 3 HO'P OH 3 01 cI WO 99/01423 PCT/DK98/00287 88 - 0 0 OH 0 N N N N N N B HO N H HON HO NOHO BrC Cl Cl 0N NZ 0 Br,, SNH N H N O'39zN' H O H HO HO Cl Cl 0 HO N OHo N N N N O N N'N . NNCC HO (?A H HO H Cl Cl N 00 N N 0N 0F N N 0_,_ ~~ F H I H HO-P HO(?
H
3 N,, .CH O A HONO NC N ,NN C NN O H N HO'I HO-J~f N H OH HO(? HOPA 01 0? WO 99/0 1423 PCT/DK98/00287 89 0 0 0 N, rO .00)' A N. N.y NL' "z HO N HCX4N OH HO 0 R -01 *) OMe 0 N 'A "' OMe N-.N K.N N-,N N N ' N N N HO-P HtOMe HO'('H 0 0 '-ANh 0 N O..kNh I NN.. j: N.N N Q.N N HO (; H KO<CF3 HO H HH 0 0 01 'N OH CI Cf 0 0 0 N o)k NCKtZJ&C 0 N OU.N O H H 3.~ HO'( Ac HO " H-H3 0 0 H N ' NN N, 1 N NN. N, H N H HO'P 0 CH HO--P - 0 ri'T 0 0 .. ).. "r o~k 0 'A)IN N N .~ .)N NN9a NL HO'P H HOI(rH0 -0 CH3 0 N 6H N H .,. N 3 N'N H CII H HO PAHO-P CI CI WO 99/01423 PCT/DK98/00287 90 0 0a 00-.)kN CH, 0 %J04 H I H HO'* H HO-qP -0 0 N N'~ N* HO c HO'q:P H HO qj H 0 -0 N N O 3.. N NN N OH 3 , NN Nf::; N.N N OH HO" H HOH N O'k N -o - 0 OHN N HN'N H H' 3' H HO HO ) N OJk 6H N'' H NOf[; HIO? H HO c CI C I' 3 0 " N ) OHi N H N, N N CHN HO'AH HO-P II F 0l 0 WO 99/01423 PCT/DK98/00287 91 OMe 0 O O JN NAJ0 N O H OH" O~e 3 I CF 3 H 3 HOH Cl Cl 0 OH 3 0 OH 0 .NA.N C O.A)N 3 NO CH H OHON N.N HO HO C1 0 0 OH 3 0 0,C 0 N O .N COH HO ClA l HJ HO 01 CC -~0 OH 3 A0 OH 3 0 O.J N 0 0Ol)klN N NH N.N O HOA HHO H 0C1 H . O CH HO AHO.NOC 010 1 0 NO O N N-CH3 HO .N.O NHI H N HO-P HA HOJP 00 00 N O .N N HO HO A O Cl
CI
WO 99/01423 PCT/DK98/00287 92 0 -N -0 0 0 NOkN N N N CH N NO 2 _, HO'? H HO H0 N N N, HH 4' , 'NN, H H I H HO Ojc e 00 . ~ H 0 N O.AN~h CH 3
ON
0 0~ ).N) N H 3 N' NNNN CH (IA H C H HO HOH HO N PA ~..H HO NNNPANNAo -~0 -0 O 0 ~ t, N ) " C N NN N j)~ N NN H HO" HHC-1 HOH -0 -0 CI3 0 N 0kN o N ,RyC N 'NN N NN N HOI(P HO : CH 0O Hj: 00 001 0 ~ 0)N)00OH 3 'N N' OH 3 , NN ~ k HOJ(? H -0 HO H cl c3 WO 99/01423 PCT/DK98/00287 93 N~~ 0 ~ CH 3 0 ... O~~ HO'? HO-P H0N 00 0 0 0 AN- 0 o NN , N IN 0 H N ... _(;Y H H3C 0H HO y'HO* ci H 3 C CH 3 CI 0 O..>LNh CF 3 0 "U N N .. ,N j H HO'?H N.. HO H F 0 0 F 0 o N 0 ~ 0 O'JUr' N... N N N H 3 C~ HO-q j H 3 C 1 0 0 HO-q -0 0 0l 0 N' N N 0 N '"" H D N N N N I H I H HO'P H 3 C N CH 3 HO 0 0 O N CH 3 0 NN N H~Ci N NI I H I H HO? HO
H
3 CN CH 3 00 0 N ,U O.kN "N< O 0 ~% .2Nm N NN N N Kj:;-o N N N-... N 0&.__o I H H0 HOI: N HO0 CI CI WO 99/01423 PCTJDK98/00287 94 0 NO 2 -0 CH< 0 N " N 0 N N N NJ HO'P
H
3 CN CH 3 HO-P cl cI 0 0 N 0 0 N -H 3 HONN, N 6HNN N CHN HO H HIP H Cl CI N N F 0 0Q"UN N C& -N I HO N N HO H3H N N Cl Cl O NN HO'k H H ci HO 0 -0 OH3 N H C N (NCH CH N 3k~..L N .N H' 3 3 3j N H N CH, HO' H HOH - 0 0 O..kN 9 N.N N OHy ON H oc 0 0)N HO 7'> NLS HO Cl H I H , HOI;AHH0 HO OH 3 Cl Cl 0 WO 99/01423 PCT/DK98/00287 95 -- c 00 HON O J N~CF3 oN O A N'N N N N N HCI O NNO HO HO AO CHH OO CI H 3 C CH 3 -0 0 0 N'I N 0 NII' 0H HN. N N N H NNH HO OHO O O NCH C H N O...A..N 0 SON 0 N NN HKNj N CF 3 HO
NH
2 HOO CI Cl A O N CH HON N C N O O N OHN N F A H ~I H HO A HO N Cl CI 0 O 0 N N CH3 0 N CH N NN.N >N NNR Nl 6H H CHN CH CICICH NN N'H .N 5, OC HO N C1 Hl I H Q CIl
CIH
3 N 0 N ~ 0..J0~ N-. N5 OI N c I H F NNN N HO HH HO A ACI Cl WO 99/01423 PCT/DK98/00287 96 0 OH 3 N 0' O."U.N N N NN H N NN HOI HO'? Hcl -0 0 o 0.N N N N.N N T L'KI CH CH H H H HO A HO A0 A0 -0 A 0 O.)kN 0 N J N0 N' N, H N 'H N O HO A H HO 0O" H-P 0 0- 0 NN 0 N5 0 kN"O' 0 01), KN HH IA H HO (A H HO3 &CI CH 0H 0 -- 3 H N-9a 0N ,NC N 'N- N' 0 HO' HHOj;A -0 0 0 3 H N OJ.)N NO~ 0 N Ol)kNo N N;H I H I N N, NAN NN N, A H O A~ AO IH O H 3 0H A 0I YCIkN" N,00' WO 99/01423 PCT/DK98/00287 97 0 0jk N N 0 N' N 'Q N 3N HO HOH O Ny(OMe ' N 6H 3 OMe N 9 z N, N HO'J HO-P N ci cI 0 0. OMe 0 N >' N 0 N O...>.. N Oe N .~N CH, N.. N H 3 HO ( HHOj H Cl CI -0 0 O N ~N 0 jN N'NN NR QlI- N N N HO -PAK HO c H CI CI -0 -0 0 N ) N 0 . NN 0 ... No r Ca HO'!AH HOH CI CI OMe 0 N'OMe N N.N.. HO cl HOJHH 0 0 0 0 N O KN-') OH 3 N NN"N N.N~KN N HO 0
HO
ciJ O- O-H 3 WO 99/01423 PCT/DK98/00287 98 -0 0 0 0 O.)N 0 ),N N' N'C HO' AHIIHH CIN HO j PH N 0 0 ~~ 0 - o) OHk N 0) 1 eN, "N 0 .. H N NN. H* N HOICAc cCI 0 C N' N N N HO' A HI HOo;' HOH 3 00 0 N NU Naj 0 N O..)l.. N N 'N N NN Nj HO -? H I- H 0 N, NoH300 Nc 0 -. I1 ' 0 (, *V N N CH..N ciJ( H3 C HO 0 N 0j-0 H' N , N NN HO HC~ H HO'P cI'' HO N CI
CI
WO 99/01423 PCT/DK98/00287 99 0 N 0 H .N.- 0N)N ON' N.. N HO N H N N CI HO H C CI C 0 0 At N O N N5 O.N NN-CH HH OH HO" HH H 3 HO I;- H QEt CI C A0 A0A 0 . N AN) 0 0 O), N S N' N-.a N, '--N . -. ,CH, N' N- NKOEt HOH H HOP OI:A OEt CI CHC ci AOH OH H.C.NN CH3 N O O N A o HO O N N .N NN0 N~ O NR4 OH CAC HO A 0~ ~~ HNt 0 O N, CI AN N CH N NN NH0O .NH H HO A HOHO.A O Cl
H
3 AH o NNNCN N0 N 0 N N H N N.N N O HO A ~'Y Al NtH SHO CI HO .NH HO A HO A CI CI WO 99/01423 PCT/DK98/00287 100 9
H
3 0 .N N 0 N N 0 N H O H N' N O N, C1 NN HO HH CI C N O NP CH ON N O CI H N N,, , 0 N NN-N HO HO Cl CI N CHNNJ 0 N 0~ ~ N'. N QO O N NH3 HO HH N .N O N , N N 0 H HO CI N OHF NN.Ns N O . HO HHO HO. N H ~I H H OH O N -H HO. O N N N FON .N O N N.N N 0O NN N N HO - HO CI CI WO 99/01423 PCT/DK98/00287 101 0 aci HO.N % H H H ' 0 Cl c CH HO . N HN N CI c A H C ' I H O N N N H CI N' HN HO HO O CHy ci cl N N CHN HOHO NIC CI
OH
3 CH N 0 HOON. NN C HO PA H 0I " H HO .N N N Cl
H
3 N N N? H IH O . N N <00 C1HO HH H N HO'(A N HO A N C1 N N N NO.N N N NN N 0HI HO A N HO . CI1C WO 99/01423 PCT/DK98/00287 102
HH
3 H3 N , H 0 NN HO .N O CH, H HO .N C0 N O NNH3C H N HO .N Ci N F HO .N N .N CI
CHH
3 N N 0 O N HO . N N H 3
COH
3 CCH HO C I H .NN N C IOI(; H I:,o0 , HO N N CI H H C HHI HO N HO N Cl N NN ~.HO..N 0 N NN N.N N 0 H HI I H C1 N 1HO .N O
CI
WO 99/01423 PCT/DK98/00287 103 HC 0 00 0 NH F O .N F H .N OD N FQ'N HO NNJ N H c H CHO ci H ci N F0O OO NCCH 9 N N 0 N HH HO .N N OH H.HO O N I HN C cI HON C CH3 0 N ~ N I I) N~4CH 0N . N O OH N 10 HO N N '-0 0 N. CH 3 N N'N N 0 H I HO N HO -Nci cI OH ? 0 N O - N~qNN N 0 N N' N NK~ N H J: HO N HO N HH c K cI CH9' CH, OL~ 0 NNNN 0 H: y I O N N 0 HN HO HO NCP HCI cI WO 99/01423 PCT/DK98/00287 104 0 Ci 0-0 N O O 0 N HC HO N 0 FN N 0 CI C HO .N F Cl c O HO .N, ON 0~~ ~~ N'NN0N 01N4 OO N HO NN N o 0HO .PI N 0 H CH 3 N ~ ~ Hu 0I N C NN HO PIN N N 0 N~r NC CHN O -H O . NHN H N H N 0 N HO N HO N.N ~ N HO N F C 0 H .N NO N O N N N N N.N . HO NO C1 CI H H 0 N[- N.N HN 0 Nl HON NN HO 0 HOH cI CI WO 99/01423 PCTIDK98/00287 105 N" O N,0 NOT N .~N 0 N .N N 00 H ONH 2 HN HO N HO
CH
3
OH
3
CH
3 NN N N 0 N N.N N0 N H P H I CH 3 HoIQ HI 0 F FH . F 0 NH 0 F..~ N HII H I N HO -r ci HO PA N H 07 0 N NH HQT N N 0.N N HO HOH ci H
CH
3 0~ N: ,r N N K HI HON
OH
3 H F N N ' F N. N YH 0 j: OH 0NN0 F N N N '0 H I O .I HI HO PA N HO NQl N. N N 0 lCH3 N *N N 3 N'~ N 0 HO'(P NF dH3 HO N~AHc Cl WO 99/01423 PCT/DK98/00287 106 H0 0 4 0N- NH 2 N N I: Y F N HO H .
N N N.C0 cH HO C
CH
3
CH
3 O N 0. O N 0 N N O N 0 HO HO'(' JHO N N ci H H NC N.. ~O~~~NCH, 0~~~~ N.CH H JJ HO H .N cCl NH O .N N H O H CI N' N HO N N CC1 HO C1 O0 . HOO N H.N N 0 CI ~I HI HO N O.CH HOH HO N H CI C1 0 ~ 0 F)0 H o N NH N NN N N) HN H H H HO HO(? Cl CI WO 99/01423 PCT/DK98/00287 107 " 0 CF 3 0 0 N HO HO CI C 0O H N. N O * N CH HO .N .
N C H N, HO HO C1 C Cl 0 0 N-o 00N H.N ) A H CN A 107 _(?O N N. N.~. N ~ NHO~N N.N F H NH HO HHO .NN cl Cl 0 N 0 N' N N H N N. N HO (?A HN C N. CH N. HO q 0 H -- '-y CH H HO HO CI CI o N. CO N 0 .. N. N. 0 N) N. CNN NN N. HO PA H HIP H F1~i - 0 0 CI 0 H HO .N N CF, I. H IN H HO* HO PA0 CI CI #- 0 0 0 l 0 N. 0O N :P N. N'N N. N N N . H ci HO HO .N C1 CI C1 WO 99/01423 PCT/DK98/00287 108 0 N CN HO .N CH, y H NO.N HO N OoCHH H N HO N HO .NNN C 0 HO c 0 0 0 N- 0 N) H 3 C H N, N OCH N C 0 N F R) H H HO HO- 0 CH 3 N0 . N oN N h )A N N N OCH HO HO CI Cl O N CF3 H NO . NN C N N N H N NN N HO'P H HO-P 0 . CF o NN'>O N Nh Ci N .N N HO H Nal H H N 0 N0 .NN HO N N N oN N NR) cl Cl N ' N NI H I .% N' H H H HO- HO Cl C1 WO 99/01423 PCT/DK98/00287 109 N H 0 N O 0 H I H HO CH 3 HO Cl CI - 0 - 0 O0F 3 0 0 N N I H I H N'NN N N N. N HO .NH HO Cl c 0I 0 NN OH NO NN C H' N 0 )A0 N NHOHN H ~I H N oj( O N.N F H HO HO H cl Cl 00 01 N N O 0 N N NR) H N. N CH 3 OH HO PAH HOP .N H .N H HO HO F Cl 01 0 OH0 N N~H 0 N N 0 NN. NN HO HOA OH 3 N Cl C H ~ o OH o0 0 NS 0 NN H3 OH H HO (?A HO N . Cl HO WO 99/01423 PCT/DK98/00287 110 0 N N HO,, N' HOP l N' L, HHN~ cl Cl H .N OH 2 H V HO N HO H N HOO CI ci F 0 H O N NN HO. N N0 CCI H 0 - '- H 0 HO OAOH N HO HON N O HC 01 O N 0 HO OHN O N2N NHO . N 0 O N N N HO-? 0 OH HO(;l OH //\1: N'N NHO N N HO O ON > / H H N H O N0H .HN O N OH H.N N NN HO )A /o H N N~ H C00 H O 0 H0 cl CI WO 99/01423 PCT/DK98/00287 C11 0 r OH H .N N H N 0 HN NO N N. N HO'.N H cI HO(? cC HO. N N . 0- N N-.. - N HOH. NO N H HO HO N OH O.N N N H0 HOH O .N N N HOH OH ci H 3 C HO '? N CI 0 N o0 CH H N NO N N N N HO HO .N N CI C1 CH OH H .N N NO H F N N N N HHO .N? NH HO HO N ( CI O ~ ~~ ~ 0 H,~.i1 \0N N N N-. Y N, N-. .- J "~~ H -qNy \I H - N/ HO HO 0 NO 'N 0 NO r H N HNN OH NN Cl HI ci ~I H- WO 99/01423 PCT/DK98/00287 112 HO N.N NJN N N N 0 H' N-.. P NC CI HO .N N*C I 0 NO N0 HON.N. JN joO HN I i N NN O ' O NNC HO N H Cl c HHO O NO 0 N N H F -~ F F HO HO HC CI C 0 N . . ) N ) 2 \CN B r NH N N N'- N .N H I HN' HO HH C1l HO ON . NN N H.N N'~.O NO FF H I H HO HO HO Ci C F F0 I H H H NN HO O N F F N N 0 c . HO H. OCF CCI cCl O F HH C< N '-N 0 O N O N N O H .N H HO H 3 C HO C OH CC H N CI NO N 0.0N N l 0 H jH H HO H HO H3C'
CI
WO 99/01423 PCT/DK98/00287 113 Nr
HO
0 F FH H O c H C oH O 'H H 3 C , F H I F 0OH 0 NN N_ _ N ,?N __~'. 0 1 H H 0HON H) HO H 3 C, Br CI OHH N. HO c HO'N H c 0 0 O~~ - LIN . I H lTI H j N.N" , OMe "'~ ci HO H Ci HO Ci HO'?H HOJ , 'N N H~N NjN ~~~ N N H HOH OH IO(? H CI cl 0 0--*'N0 0'^N "_", OMe N' NN'N ' HO'P HOJ ci Ci WO 99/01423 PCT/DK98/00287 114 0 0'"' k0N q O N .N O F N N H HO H IO(? H0 HO HOO F CI1C N O N CF N N HO P HHO .N N N' 0-NT N0 HO NH O HOCl H N Cl CI C1H 3 O N HO. N O 0 N HIO N N' N N .NN HO JHO CI C N N HH .HN N CI NN N H N I , H~ OH &N.0 HHO CI CI CI HO.N 0 ~~~ O''N Oe0T '''N NH N N OMe N N HO HO. Cl Cl HO .NO
NHO.NOB
WO 99/01423 PCT/DK98/00287 115 OH c- OI 0 0 I- N or"' c I H H.O~N O N NR NO NNC HO H H Cl c .N H C HO HC HO CI C
HO
0 ~N NH -(Y H OH H a3 C H3 HO HOHFH 0 0 HO N -N S /S C-/ H~~~ HO i7- 0 HHO HO NN-N N ~O NNC 0N-HOi -N O H 0 3 OH /O -fH O - -4 N H N N - N N 1 H H 01 H C F HON FEF 00 \/ ~HO'NN HO HN-N H N-N 01 H S O H 3 01 H H6N -N HO- H / HO 01 H 01 H H
OH
3
H
3 0
OH
3 0 Q HO' HO N \/ -- p N-N' 17 N c H 0HH F 0 0 HO'-p / HO 'P
//
- N-N N - N-NN or ~ CH' H3 WO 99/01423 PCT/DK98/00287 116 0 0 HO -NN CH~/ /Ci1 H H - / \ H H0~ HO ' - NH3 C HN-N N -O H 2- HO -N N -ci 0 H \/ (H HO HO H HO -N /F-~
-H
3 H " HO-N CHH N N 0-CH/ N-N-NN ci H HI H HO8 H 0 -NN H O'' -. ~NHO -N N N HN-N O-N-NC ci H N NHO ci HO-N N HO - -H CH3 \ H 3 HO H H N HO O N-N ~ N(H N-N N 2c H HO0 HO N c H H 0_ 0iHH H
HOH
3 / H3C-ocl HHOH 3 0-0H HO HO-N1"N H cl HH- N -N/ 'N Fi c H H _ 0 0 - N
-
- N-N / /l HHc H NH C - N-N N- \ 7 c c l ONHN WO 99/01423 PCT/DK98/00287 117 ~ / / N0 H H
HO
1 HNHO N-N N /ci H 0 0
CH
3 HO N-N N HON-N N ci H H Hl H / O C1 HO\ HO O NlHH _N cl H N ci H H ND~ ~ HO ' 0 - HN_ _\SN - N-N / s-)- NNs{i cl H N Hi M 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 5 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 10 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: H A N N (CH2)n-B-(K)m-D N (H 2 )nB(K)mD 15 0 H It is intended that any tautomeric forms which the compounds are able to form are included in the scope of the present invention.
WO 99/01423 PCT/DK98/00287 118 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. 5 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 I diabetes, type I diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas, acute pancreatitis, 10 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 15 causes of type I and type I 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 20 pharmaceutically acceptable carriers or excipients. The present invention furthermore relates to methods of treating type I or type 11 diabetes or hyperglycemia which methods comprise administering to a subject in need thereof an effec tive amount of a compound according to the invention. 25 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. 30 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 11 diabetes or hypergly cemia, or for lowering blood glucose in a mammal.
WO 99/01423 PCT/DK98/00287 119 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 5 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 10 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. 20 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: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bis methylene salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, sali 30 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 WO 99/01423 PCT/DK98/00287 120 compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion. The compounds of the invention may be administered alone or in combination with pharma 5 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 10 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 15 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 20 combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms 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. 25 Formulations of the present invention suitable for oral administration may be presented as dis crete units such as capsules or tablets, each containing a predetermined 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. 30 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.
WO 99/01423 PCT/DK98/00287 121 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. 5 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. 9 mg *Mywacett 9-40 T approx. 0.9 mg 10 *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 15 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 20 formula I 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 25 ence as well as orally active hypoglycaemic agents such as sulphonylureas, e.g. glibencla- WO 99/01423 PCT/DK98/00287 122 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 5 Glucagon 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. Glucaqon Binding Assay (1) 10 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. 15 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, 203-209 20 (1994)). The receptor inserted in the pLJ6' expression vector using EcoRI/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 Kd was shown to be 0.1 nM. 25 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 NaCl, 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 bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation upon a layer of 30 41 w/v% sucrose at 95.000 * g for 75 min. The white band located between the two layers was WO 99/01423 PCT/DK98/00287 123 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 5 ture 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 pCi/pg 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). 10 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 pL of sample (glucagon or test compounds) was added to each well. Tracer (50.000 cpm) 15 was diluted in buffer and 15 p1l was added to each well. 0.5 p~g freshly thawed plasma mem brane protein diluted in buffer was then added in 15 gl to each well. Plates were incubated at 250C for 2 hours. Non specific binding was determined with 106 M glucagon. Bound and un bound tracer were then separated by vacuum filtration (Millipore vacuum manifold). The plates were washed once with 150 pl buffer/ well. The plates were air dried for a couple of hours, 20 whereafter filters were separated from the plates using a Millipore Puncher. The filters were counted in a y counter. Functional Assay (I) The functional assay was carried out in 96 well microtiter plates (tissue culture plates, Nunc). 25 The resulting buffer concentrations in the assay were 50 mM tris/HCI, 1 mM EGTA, 1.5 mM MgSO 4 , 1.7 mM ATP, 20 pM GTP, 2 mM IBMX, 0.02% tween-20 and 0.1% HSA. pH was 7.4 Glucagon and proposed antagonist were added in 35 pl diluted in 50 mM tris/HCI, 1 mM EGTA, 1.85 mM MgSO 4 , 0.0222 % tween-20 and 0.111 % HSA, pH 7.4. 20 pl of 50 mM tris/HCI, 1 mM EGTA, 1.5 mM MgSO 4 , 11.8 mM ATP, 0.14 mM GTP, 14 mM iso-buthyl-methyl 30 xanthine (IBMX) and 0.1% HSA, pH 7.4 was added. GTP was dissolved immediately before the assay.
WO 99/01423 PCT/DK98/00287 124 50 Iad containing 5 pg plasma membrane protein was added in a tris/HCI, EGTA, MgSO 4 , HSA buffer (the actual concentrations were dependent upon the concentration of protein in the stored plasma membranes). 5 The total assay volume was 140 pW. The assay was incubated for 2 hours at 370C with continu ous shaking. Reaction was terminated by addition of 25 gl 0.5 N HCI. cAMP was measured by the use of a scintillation proximity kit (Amersham). Glucagon Binding Assay (11) 10 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 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 Kd was shown to be 0.1 nM. 15 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 NaCl, 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 20 bursts using a Polytron PT 10-35 homogenizer (Kinematica), 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 25 buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1 % bovine serum albumin (Sigma, fraction V). Sample (glucagon (Bachem 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 pg freshly thawed plasma membrane protein diluted in buffer was then added in aliquots to each tube or well. Tubes or plates were incubated at 370C for 1 hour. Non specific binding was 30 determined with 10-7 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.
WO 99/01423 PCT/DK98/00287 125 Functional Assay (1l) 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 5 glass 12 x 75 tubes. The buffer concentrations in the assay were 10 mM HEPES, 1 mM EGTA, 1.4 mM MgCl 2 , 0.1 mM IBMX, 30 mM NaCl, 4.7 mM KCI, 2.5 mM NaH 2
PO
4 , 3mM glucose and 0.2% BSA. The pH was 7.4. Loose whole cells (0.5 ml, 10 6 /ml) were pretreated with various concentrations of compounds for 10 min at 370C, then challenged with glucagon for 20 min. Some aliquots (500 pL) of cells were treated with test compounds (55 uL) alone to test for 10 agonist activity. The reactions were terminated by centrifugation, followed by cell lysis with the addition of 500 pl 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 FlashPlate system from NEN.
WO 99/01423 PCT/DK98/00287 126 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 5 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 10 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 15 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.
WO 99/01423 PCT/DK98/00287 127 General procedures for the preparation 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 11, as indicated in Scheme I, that is, by 5 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 I O-Ra NHNH A + NH 2
NH
2 solvent A 10 O reflux 0 R -C nB() HN-N==T(CH2)n-B-(K);-D SA4 R 4 solvent, reflux 0 wherein A, B, K, D, m, n and R 4 are as defined for formula I and R" is lower alkyl. 15 General procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH2 The reaction is known (Org. Syn., Coll. Vol. II, A.H.Blatt, 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 20 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 OC to 1300C, preferably between 200C to 100 C, most preferably at or about the reflux temperature of the solvent. The reactions are preferably con 25 ducted under an inert atmosphere such as N 2 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.
WO 99/01423 PCT/DK98/00287 128 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 5 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 hydrazides: 10 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 15 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. Preparation of 5-hydroxyindole-2-carboxylic acid hydrazide: 20 To a sample of ethyl 5-hydroxyindole-2-carboxylate (5g, 24 mmol), dissolved in ethanol (250 mL) was added hydrazine (4 mL, 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. 25 HO H I NHNH N 2 H 0 1 H NMR (DMSO-d6): 6 4.38 (s, 2H); 6.62 (dd, 1H); 6.76 (dd, 2H); 7.13 (d, 1H); 8.70 (s, 1H); 9.57 (s, 1H); 11.21 (s, 1H); MS (FAB): m/z 192 (M+H)+.
WO 99/01423 PCT/DK98/00287 129 Preparation of 3-chloro-4-hydroxybenzoic acid hydrazide: To a sample of methyl 3-chloro-4-hydroxybenzoate (2 g) dissolved in ethanol (50 mL) was 5 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. 0
NHNH
2 HO CI 10 1 H NMR (DMSO-d6): 8 4.49 (broad s, 2H), 7.05 (dd, 1H), 7.71 (dd, 1H), 7.89 (d, 1H), 9.669 (s, 1H), 10.72 (broad s, 1H). By use of the above methodology, other hydrazides useful as intermediates in preparing the compounds of the invention are prepared, for example: 0
NHNH
2 HO 15 Br 3-Bromo-4-hydroxybenzoic acid hydrazide 1 H NMR (DMSO-d6): 5 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. 0
NHNH
2 HO
NO
2 WO 99/01423 PCT/DK98/00287 130 3-Nitro-4-hydroxybenzoic acid hydrazide 1 H NMR (DMSO-d6): 5 9.28 (broad s,1H), 8.28 (s, 1H), 7.52 (d, 1H), 6.41 (d, 1H). MS m/z 198. 0
NHNH
2 HO 5F 3-Fluoro-4-hydroxybenzoic acid hydrazide 1H NMR (DMSO-d6): 5 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). 10 Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide, 2,3-dichloro-4 hydroxybenzoic acid hydrazide and 2,5-dichloro-4-hydroxybenzoic acid hydrazide. O O O H2 OH A OH B OMe D NH2 HN C1 HO C HO O CI H - HC HO Cl 0 0 0 0 CIC HOj N .NH2 D HO OMe CI OMe D C) .N2 15 Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide: Step A: 4-amino-2-chlorobenzoic acid (10 g, 58 mmol) was dissolved in H 2
SO
4 (12 N, 120 mL) with heating. After cooling the solution in an ice-bath aqueous NaNO 2 (2.5 M, 25 mL) was added 20 dropwise such that the internal temperature remained at 5 0C. Urea was added to the mixtu re for after stirring for 15 minutes to destroy excess NaNO 2 (monitored by starch iodine test).
WO 99/01423 PCT/DK98/00287 131 CuSO 4 (100-200 mg) was added and the mixture was heated to 90 0C 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 5 were washed with water, brine, and dried over MgSO 4 . The crude product was introduced into a silica gel column and eluted with ethyl acetate/hexane (1/1) to afford 2-chloro-4 hydroxybenzoic acid. 'H NMR (DMSO-D6): 5 6.97 (dd, 1H), 7.05 (d, 1H), 7.95 (d, 1H), 10.90 (brd s, 1H). 10 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 15 sodium bicarbonate, water, brine, and dried over MgSO 4 and concentrated in vacuo to give methyl 2-chloro-4-hydroxybenzoate. Step C: To a solution of methyl 2-chloro-4-hydroxybenzoate (13.6 g, 73.1 mmol) in acetic acid (300 20 mL) was added N-chlorosuccinimide (9.8 g, 73.7 mmol). The solution was refluxed for 24 h and the solvent was evaporated under vacuo. 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 (1/9 to 3/7) afforded methyl 2,5-dichloro-4 25 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: 30 1 H NMR (DMSO-D6) 5 3.81 (s, 3H), 7.02 (d, 1H), 7.70 (d 1H), 11.52 (s, 1H); MS (APCI): 221, 223. Methyl 2,5-dichloro-4-hydroxybenzoate: WO 99/01423 PCT/DK98/00287 132 'H NMR (CDCl 3 ): 5 3.90 (s, 3H), 6.00 (s, 1H), 7.14 (s, 1H), 7.27 (s, 1H), 7.96 (s, 1H); MS (APCI): 221.9. 5 Step D: The title compound was prepared according to the general procedure for the synthesis of precursor hydrazides
A-(C=O)-NHNH
2 'H NMR (DMSO-D6): 8 6.82 (dd, 1H), 6.90 (d, 1H), 7.79 (d, 1 H, 10.68 (brd s, 1H). 10 Preparation of 23-Dichloro-4-hydroxybenzoic acid hydrazide and 2.5-dichloro-4 hydroxybenzoic acid hydrazide (step D): The 2,3-dichloro-4-hydroxybenzoic acid hydrazide was prepared from the methyl 2,3 15 dichloro-4-hydroxybenzoate above according to the general procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH 2 with the exception that pentanol was the solvent of choice. The product was purified via silica gel column chromatography using CH2Cl2/MeOH ( 95/5 to 80/20), yield = 50%. 20 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: 25 'H NMR (DMSO-D6) 6 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-hydroxybenzoic acid hydrazide: 30 'H NMR (DMSO-D6) 6 4.48 (brd s, 3H), 6.92 (d, 2H), 7.18 (d, 2H), 9.45 (brd s, 1H). Preparation of 2.3-difluoro-4-hydroxybenzoic acid hydrazide: WO 99/01423 PCT/DK98/00287 133 N OH B OMe C N N HO F Ho oH F HO Fe HO FH F F F F Step A: 5 A mixture of 2,3-difluoro-4-cyanophenol (1 g, 6.45 mmol) in water (8 mL), H 2
SO
4 (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%). 10 1 H NMR (DMSO-D 6 ): 5 6.87 (t, 1H), 7.60 (t, 1H), 11.28 (s, 1H), 12.53 (brd s, 1H). Step B: To the 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 5.1 mmol) dissolved in anhydrous 15 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 MgSO 4 to give methyl 2,3-difluoro-4-hydroxybenzoate (540 mg, 62%). 20 'H NMR (CDCI 3 ): 6 3.92 (s, 3H), 6.34 (brd s, 1H), 6.82 (dt, 1H), 7.68 (dt, 1H). 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 25 hydrazides A-(C=O)-NHNH 2 . The product was purified via silica gel column chromatography using CH2CI2/MeOH ( 95/5 to 80/20) to afford the title compound. 1 H NMR (DMSO-D 6 ): 8 4.48 (s, 2H), 6.80 (m, 1H), 7.22 (m, 1H), 9.36 (s, 1H), 10.89 (s, 1H); MS (APCI): 189. 30 WO 99/01423 PCT/DK98/00287 134 Preparation of 3-cyano-4-hydroxybenzoic acid hydrazide. trifluoroacetate: 0 0 0 0 OMe A HO- OMe B :HO OMe C HO OH -OJO1 HO -:PH N N 0 D NHN N N 5 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 4C and vigorous stirring. The product crystallizes from solution upon 10 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-D 6 ): 5 3.79 (s, 3H), 6.95 (d, J = 8.3, 1H), 7.81 (dd, J = 8.3, 2.2, 1H), 8.22 (d, 15 J = 2.2, 1H); 13C NMR (DMSO- D) 5 52.8, 85.2, 115.5, 123.0, 132.0, 141.0, 161.9, 165.6.; MS (APCI, neg): 277. Step B: Methyl-4-hydroxy-3-iodobenzoate (2.00 g, 7.2 mmol) was dissolved into 5 mL of dry DMF. 20 Copper(l) 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 25 chloride solution. The solids and aqueous washings were combined, and shaken with a WO 99/01423 PCT/DK98/00287 135 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 purified by flash chromatography on silica gel 5 (20% ethyl acetate/ hexane) to afford methyl-3-cyano-4-hydroxybenzoate, 0.93g (73%). 1 H NMR (DMSO- D): 5 3.79 (s, 3H), 7.07 (d, J = 8.7, 1H), 8.02 (dd, J = 8.7, 1.9, 1H), 8.10 (d, J = 1.9, 1H). 10 Step C: Methyl-3-cyano-4-hydroxybenzoate (2.71 g, 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 15 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 (2.1g, 84%) after lyophilization. 1 H NMR (DMSO- D6): 5 7.09 (d, J = 9.0, 1H), 8.00 (dd, J = 9.0, 2.3, 1H), 8.07 (d, J = 2.3, 1H) 20 12.50 (br s, 2H); MS (APCI, neg): 162. IR: 2252 cm 1 , CN. Step D: 3-Cyano-4-hydroxybenzoic acid (1.88g, 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 25 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 (3.0g, 6.4 mmol) were added. After 8 more hours at 0 0C, the 30 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 HCl (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 WO 99/01423 PCT/DK98/00287 136 reduced to an oil in vacuo. The oil was purified by chromatography on silica gel (6:4 hexa ne:ethyl acetate) to afford tert-butyloxycarbonyl
(
3 -cyano-4-hydroxy)benzoic acid hydrazide as a white solid (1.8g, 56%). 5 1 H NMR (DMSO- D 6 ): 5 1.42 (s, 9H), 7.09 (d, J = 8.7, 1H), 7.98 (m, 1H), 8.11 (br s, 1H), 8.92 (s, 1H), 10.15 (s, 1H), 11.73 (br s, 1H); MS (APCI, neg): 276; IR: 2232 cm-', CN. Step E: 10 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 oil was purified by reverse-phase liquid chromatography (Aquasil C-18 column, water/acetonitrile/0.1% TFA). The title compound was obtained as a 15 white solid (0.24 g, 13%). 'H NMR (DMSO- D): 5 7.16 (d, J = 9.0, 1H), 8.00 (dd, J = 1.5, 9.0, 1H), 8.14 (d, J = 1.5, 1H), 10.47 (br s, 5H); MS (APCI, neg): 176. 20 Preparation of 4-hydroxynaphthoic acid hydrazide: o H 0 OH 0 OMe H A B C N.NH2 OH OH OH OH Step A: 25 Silver nitrate (17 g, 0.1 mol) 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).
WO 99/01423 PCT/DK98/00287 137 To the silver oxide above was added 1N NaOH (150 mL) and 4-hydroxynaphthaldehyde (1 g, 6 mmol)). The mixture was heated to 70 0C 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 5 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. 10 'H NMR (DMSO-D6): 5 6.69 (d, 1H), 7.28 (t, 1H), 7.39 (t, 1H), 7.93 (d, 1H), 8.03 (d, 1H), 8.82 (d, 1H), 10.82 (s, 1H), 12.29 (s, 1H). Step B: To a solution 4-hydroxynaphthoic acid in anhydrous methanol at 0 0C was added thionyl 15 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 MgSO 4 to give methyl 4 hydroxynaphthoate. 20 'H NMR (DMSO-D6): 5 3.87 (s, 3H), 6.92 (d, 1H), 7.53 (t, 1H), 7.65 (t, 1H), 8.13 (d, 1H), 8.26 (d, 1H), 8.93 (d, 1H), 11.16 (s, 1H). Step C: The title compound was prepared from methyl 4-hydroxynaphthoate according to the proce 25 dure for the synthesis of precursor hydrazides
A-(C=O)-NHNH
2 'H NMR (DMSO-D6): 8 6.60 (d, 1H), 7.28 (m, 3H), 7.95 (d, 1H), 8.07 (d, 1H), 9.25 (brd s, 1 H). 30 Moreover, by use of the above methodology, the following hydrazides useful as intermediates in preparing the compounds of the invention may be prepared: WO 99/01423 PCT/DK98/00287 138 0
OCH
3 0
NHNH
2 F
OCH
3 0
NHNH
2 HO F
NHNH
2 HO
OCF
3 HO F CF3 O F CH3 0
NHNH
2 NHNH 2 NHNH 2 HO HO HO CI CI CI
OCH
3 0
OCH
3 0
NHNH
2 3 NHNH 2 HO NHNH 2 HO 5 CI HO F C
OCH
3 0 CI 0 0
NHNH
2 NHNH 2 NHNH 2 HO HO HO
OCH
3 OCH 3 OCH 2
CF
3 Br 0 0 0
NHNH
2 Cl NHNH 2 MeO NHNH 2 HO HO HO Cl CI CI WO 99/01423 PCT/DK98/00287 139 Cl 0 F 0 OCH 3 0
NHNH
2
NHNH
2
NHNH
2 HO F HO OCH 3 OH 0
NHNH
2 HO OH O H0 OH HN2 CHF 2 O 0 0
NHNH
2 NHNH 2 NHNH 2 HO HO HOq F OH CI O 0 F
NHNH
2
NHNH
2 HO HO 5 CI OMe General procedure for the synthesis 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 10 defined above in a reaction generally known as Williamson ether synthesis (H. Feuer, J. Hooz in The Chemistry of the Ether Linkage, S. Patai Ed., Wiley, New York 1967, p. 446-460).
WO 99/01423 PCT/DK98/00287 140 SCHEMEII R3a R3b R4a R4b H R4 0 Rx C (CH Lx(CH 2 )b
(CH
2 )a-(M)f-(CH 2 )c q (CH 2 )d D
R
1 OH Base, solvent H R 14 0 R3a R 3 b R4a R4
O-(H
2 )b ( p (CH2(-(M)--(CH 2
)
0 ( (CH2d D 5 wherein Lx is a leaving group such as -Cl, -Br, -1, -OSO 2
CH
3 , -OSO 2 p-tolyl or -OSO 2
CF
3 ; and
R
3 a, R 3 b, R 4 a, R 4 b, a, b, c, d, f, p, q, D, M, R 14 and R" are as defined for formula I. 10 According to Scheme Il 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 15 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 tert-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 00C to 1500C, preferably at 200C to 20 100*C and preferably in an inert atmosphere of N 2 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 acetate/hexane as eluent. The compound can also (when appropriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, WO 99/01423 PCT/DK98/00287 141 ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of ether-substituted aryl-aldehydes are provided below. Preparation of 4-(2-tetrahydropyranylmethoxy)-1-naphthaldehyde: 5 A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 2-bromomethyl tetrahydropyran (1 g, 5.8 mmol) and powdered K 2
CO
3 (1.2 g, 8.7 mmol) in dimethyl formamide was stirred at 60 0 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 4 , filtered, and concentrated. The product was purified by silica gel column chromatography using ethyl acetate/hexane. H 0 10 10 6 'H NMR (DMSO-d 6 ): 6 1.48 (m, 4H), 1.74 (d, 1H), 1.84 (m, 1H), 3.44 (m, 1H), 3.78 (m, 1H), 3.92 (d, 1H), 4.23 (m, 2H), 7.17 (d, 1H), 7.64 (t, 1H), 7.74 (t, 1H), 8.11 (d, 1H), 8.27 (d, 1H), 9.22 (d, 1H), 10.17 (s,1H). 15 Preparation of 4-[(3.5-bis-trifluoromethyl)benzyoxyl-1-naphthaldehyde: A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 3,5-bis-trifluoromethylbenzylbromide (1.8 g, 5.8 mmol), and powdered K 2 C0 3 (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 20 dried.
WO 99/01423 PCT/DK98/00287 142 H 0 0
CF
3 CF 3 'H NMR (DMSO-d 6 ): 8 5.58 (s, 2H), 7.07 (d, 1H), 7.22 (d, 1H), 7.63 (t, 1H), 7.69 (t, 1H), 7.79 (d, 1H), 7.86 (d, 1H), 7.99 (s, 1H), 8.14 (s, 1H), 8.30 (s, 3H), 8.94 (s, 1H), 8.97 (d, 1H), 11.0 (broad s, 1H), 11.69 (s,1H); MS (ESI) m/z 675.2 (M+H)*. 5 Preparation of 4-(2-chloroethoxy)-1 -naphthaldehyde: 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 600C overnight. The solution 10 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). 0 H Cl 15 MS (Cl): 403, 405, 407. 1 H NMR (CDCI 3 ): 6 10.2 (s, 1H), 9.3 (d, 1H) 8.35 (d, 1H), 7.85 (d, 1H), 7.65 (m, 1H), 7.5 (m, 1H), 7.1 (d, 1H), 4.35 (t, 2H), 4.15 (t, 2H). The products were used as such in further transformations.
WO 99/01423 PCT/DK98/00287 143 By application of the above methodology the following substituted aldehyde intermediates were synthesized: \ OMe / \ O O 0 0 0 H ~ H 4-carbomethoxymethoxy-1 -naphthaldehyde 4-benzyloxy-1 -naphthaldehyde m.p.: 115-116*C 0 C0 O
CH
2 H -- H 4-(4-chlorobenzyloxy)-1 -naphthaldehyde 4-allyloxy-1 -naphthaldehyde CH O
OCF
3 O\ H H 4-(4-trifluoromethoxybenzyloxy)-1 - 4-propargyloxy-1 -naphthaldehyde naphthaldehyde / \ NH 2 0
CF
3 0 0 H H~ 4-(4-trifluoromethylbenzyloxy)-1 - 2-[(4-carboxaldehydo)-1 naphthaldehyde naphthyloxy]acetamide m.p. 174-175'C WO 99/01423 PCT/DK98/00287 144 / \CF 3 00F 3 0 H - 0 0 0 4-(3-trifluoromethyibenzyloxy)-1 -H naphthaldehyde 4-(2-(4-trifl uoromethoxyphenyl)-2-oxo ethoxy)-l -naphthaidehyde 0 /\_a 00F 3 0\ , N OMe H 4-(4-trifluoromethoxybenzyloxy)-3,5- N icotin ic acid 4-formyl-l1-naphthyi ester dimethoxybenzaidehyde m.p. 142-1430C W~e
-
H
3 0 0 0 C30 H - H OMe 0 4-(4-isopropylbenzyloxy)-3,5 dimethoxybenzaldehyde 4-(1 ,3-dioxo-1 ,3-dihydroisoindol-2 (oil) ylmethoxy)-1 -naphthaldehyde m.p. 191-1920C
-
H
3 00 O H 3 0 0 0 H -H 4-(4-isopropyibenzyloxy)-1 -naphthaldehyde 4-(tetrahydro-2-pyranylmethoxy)-1 naphthaldehyde WO 99/01423 PCT/DK98/00287 145 F 0 0 H - F 4-(3,5-difluorobenzyloxy)-1 -naphthaldehyde M.P. 100-101*C Preparation of 3-Allyl-4-hydroxy-5-methoxy-benzaldehyde: H2c
NCH
2 OH 0 OH o OCH 3 O OCH 3
OCH
3 H H H 5 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. 1H NMR (CDCl 3 ) 8 = 3.94 (s, 10 3H), 4.67 - 4.83 (m, 2H), 5.30 - 5.55 (m, 2H), 6.01 - 6.21 (m, 1H), 6.98 (d, J = 9 Hz, 1H), 7.40 - 7.56 (m, 2H), 9.85 (s, 1H); 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 15 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. 1H NMR (CDCl 3 ) 8 = 3.46 (d, J = 6 Hz, 2 H), 3.96 (s, 3H), 5.02 - 5.22 (m, 2H), 5.94 - 6.11 (m, 1H), 6.30 (s, 1H), 7.45 (s, 2H), 9.80 (s, 1 H); MS (APCI): 193.3. 20 WO 99/01423 PCT/DK98/00287 146 Preparation of 3-Allyl-4-(4-isopropylbenzyloxy)-5-methoxybenzaldehyde: The crude 3-allyl-4-hydroxy-5-methoxy-benzaidehyde was taken up in acetone and treated with 4-isopropylbenzyl chloride in the presence of potassium carbonate to give the desired 5 product.
H
3 CH2
CH
3 0,0
OCH
3 H 1 H NMR (CDC1S) S = 1.26 (d, J = 7 Hz, 6 H), 2.92 (m, 1H), 3.38 (d, J = 7 Hz, 2H), 3.95 (s, 3H), 4.98 - 5.12 (m, 4H), 5.93 - 5.75 (m, 1H), 7.20 - 7.43 (m, 6H), 9.87 (s, 1H).
WO 99/01423 PCT/DK98/00287 147 General procedure for the synthesis of compounds of formulae IXa and lXb: H D NH 2 + Ci C t cl D OHCB step stepB H ND NH 2 0 H 0 NN H 8 N N 0 H OR R L -. H D step D HO R Formula IXa step c K 2 C0 N NH 2 0 R H D HO N N N D N R R H H YH H step D HO Re Formula iXb In the above formulae B, D, R' and R 9 have the same meanings as defined for formula I. 5 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 4 and then con 10 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 15 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 MgSO 4 . After concentration in vacuo, the product was obtained.
WO 99/01423 PCT/DK98/00287 148 The following two aldehydes were prepared as examples of compounds that can be pre pared using this methodology: N-(4-Chlorophenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide: 5 Cl MeO 0 N4 H H 1 H NMR (CDCl 3 ): 64.28 (s, 3H), 5.01 (s, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.97 (dd, J = 8.6, 2.1 Hz, 1H), 7.67 ( d, J = 8.9Hz , 2H), 7.89 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.6Hz, 1H), 8.51 (s, 10 1H), 10.66 ( s, 1H); MS ( APCI ): 319.9. N-(4-isopropylphenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide:
CH
3 O - CH 3 MeO 0 N H H 15 'H NMR ( DMSO-D6): 6 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, 1H), 6.66 ( d, J = 2.1Hz, 1H), 7.06 (d, J = 8.5Hz, 2H), 7.39 ( d, J = 8.50 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 9.93 (s, 1H), 10.05 (s, 1H); MS (APCI ): 328. 20 This type of aldehydes 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/DK98/00287 149 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 5 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 4 , and concen trated to give the desired product which can be further purified by column chromatography, or used directly for the next step. 10 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 15 cedure described in step C above.
WO 99/01423 PCT/DK98/00287 150 H MeO N CI H 1 H NMR (CDCI 3 ): 5 3.84 (s, 3 H), 6.14 (s, 1H), 6.45 (d, J = 2.0 Hz, 1H), 6.54 ( dd, J = 8.4, 1.8Hz, 1H), 7.14 (d, J = 8.7Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.5Hz, 1H), 10.22 5 (s, 1H); MS (APCI ): 261.9. 4-(4-Isopropylphenylamino)-2-methoxybenzaldehyde: Prepared from N-(4-isopropylphenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide using the procedure described in step C above. H MeO N o
CH
3 10 H
CH
3 1 H NMR (CDC1 3 ) 8 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, 1H), 6.55 (dd, J = 8.6, 1.8Hz, 1H), 6.96 (s, 1H), 7.15 (d, 2H, J = 8.5Hz, 2H), 7.22 (d, J = 8.5Hz, 2H), 7.69 (d, J = 8.5Hz, 1H), 10.18 (s, 1H); MS (APCI ): 269. 15 Step D: The resulting carbonyl compounds are treated with the corresponding acyihydrazide in a sol vent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloro 20 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 N 2 or Ar at temperatures between 00C to 1400C, preferably between 10*C to 800C. In many cases the product simply 25 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- WO 99/01423 PCT/DK98/00287 151 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 chloro form/methanol or dichloromethane/methanol or chloroform/ethyl acetate to give a compound of formula IXb. 5 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: 10 3-Chloro-4-hydroxybenzoic acid [ 4
-(
4 -chlorophenylamino)-2-methoxybenzylidenelhydra-zide H CHO N N 'Nu ci H HO C1 'H NMR ( DMSO-D6 ): 5 3.81 (s, 3H), 6.72-6.67 (m, 2H), 7.04 (d, J = 8.5Hz, 1H), 7.17 ( d, J 15 = 8.7Hz, 2H) 7.31 (d, J = 8.7Hz, 2H), 7.77- 7.70 (m, 2H), 7.96 (d, J = 1.6Hz, 1H), 8.65 (s, 1H), 8.70 (s, 1H), 10.87 (s, 1H), 11.51 (s, 1H); MS (APCI ): 430. EXAMPLE 2: 3-Chloro-4-hydroxybenzoic acid [ 4
-(
4 -isopropylphenylamino)-2-methoxybenzylidene1hy_ 20 drazide H cH 3 HO / CH3 ci 1 H NMR (DMSO-D6): 6 1.18 (2s, 6H), 2.86 (m, 1H), 3.79 (s, 3H), 6.65 (m, 2H), 7.03 (d, 1H), 7.11 (d, 2H), 7.19 (d, 2H), 7.70 (d, 1H), 7.75 (dd, 1H), 7.97 (s, 1H), 8.49 (s, 1H), 8.64 (s, 25 1H), 10.88 (s, 1H), 11.48 (s, 1H); MS (FAB): 438.16.
WO 99/01423 PCT/DK98/00287 152 EXAMPLE 3: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-3-methoxyphenoxy}-N-(4 chlorophenyl)acetamide cI 0 CHO 0 O N H N HO" H 5 CI 1 H NMR (DMSO-D6): 6 3.66 (s, 3H), 4.57 (s, 2H), 6.48 (d, 1H), 6.55 (s, 1H), 6.83 (d, 1H), 7.20 (d, 2H), 7.48 (d, 2H), 7.56 (dd, 1H), 7.58 (d, 1H), 7.77 (d, 1H), 8.48 (s, 1H), 10.05 (s, 1H), 10.72 (brd s, 1H), 11.40 (s, 1H); MS (APCI): 487.8. 10 EXAMPLE 4: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-3-methoxyphenoxy}-N-(4 isopropylphenyl)acetamide
H
3 O CH 3 CH O 0 N N H N H HO' CI 15 1 H NMR (DMSO-D6): 5 1.17 (2 s, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.70 (d, 1H), 6.76 (d, 1H), 7.05 (d, 1H), 7.20 (d, 2H), 7.55 (d, 2H), 7.77 (dd, 1H), 7.80 (d, 1H), 7.98 (s, 1H), 8.70 (s, 1H), 10.03 (s, 1H), 10.92 (s, 1H), 11.62 (s, 1H); MS (FAB): 496.16. 20 WO 99/01423 PCT/DK98/00287 153 EXAMPLE 5: 2-{4-r(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-3-methoxyphenoxy-.N-(3 dichlorophenyl)acetamide 0 CHo 0 0 N N N CI HH N H HOC 5 1H NMR (DMSO-D6): 5 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, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, 1H), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCI): 524.8. General procedure for the synthesis of alkylidene hydrazides of formula If according to the 10 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 15 mixture of two or more of the above solvents. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N 2 or Ar at temperatures between 00C to 1400C, preferably between 100C to 800C. 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 20 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 chloromethane/methanol or chloroform/ethyl 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. 25 WO 99/01423 PCT/DK98/00287 154 EXAMPLE 6: 3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide OOH HO N C1 To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 ml) 5 was added 4-hydroxynaphthaldehyde 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 MgSO 4 . The or ganic volume was concentrated in vacuo to give the crude product. The product was purified by silica gel column chromatography using CH 2 Cl 2 /MeOH as the mobile phase. 10 'H NMR (DMSO-dQ): 8 6.89 (d, 2H), 7.02 (d, 1H), 7.47 (t, 1H), 7.58 (t, 1H), 7.66 (d, 1H), 7.73 (d, 1H), 7.93 (s, 1H), 8.17 (d, 1H), 8.84 (s, 1H), 8.88 (d, 1H), 10.73 (s, 1H), 10.88 (s, 1H), 11.54 (s, 1 H); MS (ESI): m/z 341.04 (M+H)*. EXAMPLE 7: 15 3-chloro-4-hydroxybenzoic acid [4-(3.5-bis-trifluoromethylbenzyloxy)-1-naphthylmethylenel hydrazide F F F F 0 0 F H HO Cl To a solution of 3-chloro-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 20 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 MgSO 4 . The organic volume was concentrated under WO 99/01423 PCT/DK98/00287 155 vacuo to give the crude product. The product was purified by silica gel column chromatogra phy using CH 2
CI
2 /MeOH as the mobile phase. 'H NMR (DMSO-d): 5 3.77 (s, 6H), 4.91 (s, 2H), 6.95 (s, 2H), 6.99 (d, 1H), 7.30 (d, 2H), 7.52 5 (d, 2H), 7.68 (m, 1H), 7.89 (s, 1H), 8.29 (s, 1H), 10.90 (broad s, 1H), 11.69 (s, 1H); MS (ESI): m/z 525.37 (M+H)*. EXAMPLE 8: 3-chloro-4-hydroxybenzoic acid [4-(2-chloroethoxy)-1-naphthylmethylenelhydrazide 0 N 0--C H HO 10 C1 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 15 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-d,): 6 11.5 (s, 1H), 10.7 (s, 1H), 8.7 (bs, 2H), 8.1 (m, 1H), 7.8 (s, 1H), 7.6-7.3 (m, 2H), 7.0 (m, 2H), 4.3 (t, 2H), 3.7 (t, 2H). 20 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 25 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 4 . Upon partial concentration of the solvent in vacuo, the alkylene WO 99/01423 PCT/DK98/00287 156 hydrazides usually precipitated. The alkylene hydrazides were further purified by recrystalliza tion from hot ethanol or ethyl acetate, or chromatographed using CH 2 Cl 2 /MeOH as an eluent. 5 EXAMPLE 9: 4-Hydroxy-3-methoxybenzoic acid (2-naphthylmethylene)hydrazide HO H3C'O 1 H NMR (DMSO-d 6 ) 5 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 10 = 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: 15 4-Hydroxy-3-methoxybenzoic acid (4-methoxy-1 -naphthylmethylene)hydrazide
CH
3 0 N'N H HO H3C' 0 1 H NMR (CDCl3): 5 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 20 H). MS (APCI): 351.
WO 99/01423 PCT/DK98/00287 157 EXAMPLE 11: 4-Hydroxy-3-methoxybenzoic acid (4-tert-butylbenzylidene)hydrazide
CH
3 CH 3 O N OH 3 H HO'O 5 1 H NMR (CDC13): 5 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-methoxybenzoic acid (4-isopropylbenzylidene)hydrazide
CH
3 0 '- H 3 ON' NCs I H HOH 10
H
3 C'O 1 H NMR (CDCl3) 6 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 WO 99/01423 PCT/DK98/00287 158 EXAMPLE 13: 4-Hydroxy-3-methoxybenzoic acid ( 4 -trifluoromethoxybenzvlidene)hydrazide F+F 0 O HO" H3C'O 5 1 H NMR (DMSO-d6): 5 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: 10 4-Hydroxy-3-methoxybenzoic acid (1 H-indol-3-ylmethylene)hydrazide 0 j N NH HON HCH H3C'O 1 H NMR (DMSO-d6) 8 3.79 (s, 3 H), 6.80 (d, J = 8.2 Hz, 1 H), 7.11 (m, 2 H), 7.38 (m, 3 H), 15 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.
WO 99/01423 PCT/DK98/00287 159 EXAMPLE 15: 4-Hydroxy-3-methoxybenzoic acid (4-dimethvlamino-1-naphthylmethylene)hydrazide , OH 3 0 ~ N, CH 3 H
HO*
0 H3C'O 5 1 H NMR (DMSO-d6): 5 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: 10 4-Hydroxy-3-methoxybenzoic acid (4-phenylbenzylidene)hydrazide 0 N,
HO"
0 H3C'O H NMR (DMSO-d6): S 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. 15 WO 99/01423 PCT/DK98/00287 160 EXAMPLE 17: 4-Hydroxybenzoic acid (1-naphthylmethylene)hydrazide 0 HO 5 1H 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: 10 4-Hydroxybenzoic acid (4-methoxy-1-naphthylmethylene)hydrazide CH 3 01 0 O H HO 1 H NMR (DMSO-d6): 6 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 15 = 8.2 Hz, 1 H), 8.89 (m, 2 H), 10.06 (s, 1 H). MS (APCI): 321.
WO 99/01423 PCT/DK98/00287 161 EXAMPLE 19: 3.4-Dihydroxybenzoic acid (1-naphthylmethylene)hydrazide 0 I H HO 5 1 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, 1H), 11.45 (s, 1 H). MS (APCI): 307. EXAMPLE 20: 10 4-Hydroxy-3-methoxybenzoic acid (1-naphthylmethylene)hydrazide 0 HO N H3C'O 1 H NMR (DMSO-d6) 5 3.94 (s, 3H), 6.74 (d, 1H), 7.37-7.52 (m, 6H), 7.77 (d, 1H), 7.89 (d, 2H), 8.67 (d, 1H), 9.93 (s, 1H), 10.90 (s, 1H). MS (APCI): 321. 15 WO 99/01423 PCT/DK98/00287 162 EXAMPLE 21: 4-Hydroxy-3-methoxybenzoic acid [ 3
-(
3 -trifluoromethylphenoxv)benzvlidenelhydrazide F F F N 00 N O ' HON H C'O H3C0 5 1 H NMR (DMSO-d6) 5 3.83 (s, 3H), 6.85 (d, 1H), 7.16 (dd, 1H), 7.36 (m, 5H), 7.44 (m, 3H), 7.61 (t, 1H), 8.43 (s, 1H), 1.75 (s, 1H), 11.69 (s, 1H). MS (APCI): 431. EXAMPLE 22: 4-Hydroxy-3-methoxybenzoic acid (4-guinolinvimethylene)hydrazide 10 N , N N N'N ' HON H HOC H3C'O 1 H NMR (DMSO-d6): 6 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), 15 8.73 (d, J = 4.5 Hz, 1 H), 8.94 (s, 1 H). MS (APCI): 322.
WO 99/01423 PCT/DK98/00287 163 EXAMPLE 23: 4-Hydroxybenzoic acid [3-(1.1.2.2-tetrafluoroethoxy)benzylidenelhydrazide F F F O F o N'N HOe H 5 1 H NMR (DMSO-d6) 5 6.49-6.78 (m, 3H), 7.10 (d, 1H), 7.32 (t, 1H), 7.41 (m, 2H), 7.57 (d, 2H), 8.23 (s, 1H), 10.01 (s, 1H), 11.59 (s, 1H). MS (APCI): 357. EXAMPLE 24: 4-Hydroxybenzoic acid [3-(4-tert-butylphenyl)but-2-enylidene]hydrazide
CH
3
CH
3 10 HO N CH|CH 3 AN. I H
OH
3 10 HN 1 H NMR (DMSO-d6) 5 1.15 (s, 9H), 1.99 (s, 3H), 6.64 (s, 1H), 6.17 (d, 2H), 7.29 (s, 4H), 7.64 (d, 2H), 8.06 (s, 1H), 9.98 (s, 1H), 11.36 (s, 1H). MS (APCI): 337.
WO 99/01423 PCT/DK98/00287 164 EXAMPLE 25: 4-Hydroxy-3-methoxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide OOH HO,N H" H3,' 5 1 H NMR (DMSO-d6): 6 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-Hydroxybenzoic acid (benzylidene)hydrazide NN 10 HO N 1 H NMR (DMSO-d6): 5 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.
WO 99/01423 PCT/DK98/00287 165 EXAMPLE 27: 3-Amino-4-hydroxybenzoic acid (1 -naphthylmethylene)hydrazide N' N / H HO'N
NH
2 5 1 H NMR (DMSO-d6): 5 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 = 2.0 Hz, 1 H), 7.51 - 7.62 (m, 3 H), 7.84 (d, J = 7.2 Hz, 1 H), 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. 10 EXAMPLE 28: 3-Amino-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide 0 OH N'N H HO'N H
NH
2 15 1H NMR (DMSO-d6): 6 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.
WO 99/01423 PCT/DK98/00287 166 EXAMPLE 29: 4-Hydroxybenzoic acid [ 3
-(
3 -trifluoromethylbenz y)benzyidenelhydrazide 0 FF - N 0 -~ F I H HO N 5 iH NMR (DMSO-d6): 5 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-hydroxybenzoic acid (1 -naphthylmethylene)hydrazide ON 0 N HON 10 Cl 1 H NMR (DMSO-d6): 6 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. 15 WO 99/01423 PCT/DK98/00287 167 EXAMPLE 31: 3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide OH ,N / HON CI 5 1H NMR (DMSO-d6): 5 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. 10 EXAMPLE 32: 4-Hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide o NOH H HO 15 1 H NMR (DMSO-d6): 5 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.
WO 99/01423 PCT/DK98/00287 168 EXAMPLE 33: 4-Hydroxybenzoic acid [4-(3-trifluoromethylphenoxy)benzylidenelhydrazide F O F HOH HONO 5 1 H NMR (DMSO-d6): 5 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: 10 4-Hydroxybenzoic acid (5-phenyl-3-pyrazolylmethylene)hydrazide 0 HN-N O N HON 1H NMR (DMSO-d6): 5 6.81 (d, 2 H), 7.40 - 7.62 (m, 5 H), 7.78 (d, 2 H), 8.09 (s, 1 H), 8.50 15 (s, 1 H). MS (APCI): 307. EXAMPLE 35: 2.4-Dihydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide N O ,NOH HO N OH 20 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.
WO 99/01423 PCT/DK98/00287 169 EXAMPLE 36: 4-Hydroxy-3-nitrobenzoic acid (1 -naphthylmethylene)hydrazide 0N O N H HO O 0 5 1 H NMR (DMSO-d6): 5 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: 10 4-Hydroxy-3-nitrobenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide O NOH N'N / H HO O-IN 0 1H NMR (DMSO-d6): 6 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 15 H), 10.57 (s, 1 H), 11.17 (m, 1 H).
WO 99/01423 PCT/DK98/00287 170 EXAMPLE 38: 3.4-Dihydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide OH N' N H HO HO 5 1H NMR (DMSO-d6): 5 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: 10 4-Hydroxybenzoic acid (6-methoxy-2-naphthylmethylene)hydrazide C H OH 3 00 H HO 1 H NMR (DMSO-d6): 5 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). 15 MS (APCI): 321.
WO 99/01423 PCT/DK98/00287 171 EXAMPLE 40: 3.5-Dichloro-4-hydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide O OH Cl N H O~ H Cl 5 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: 10 6-Hydroxy-2-naphthoic acid (4-hydroxy-1 -naphthvimethylenelhydrazide O OH HOI H HO~ N 1 H NMR (DMSO-d6): 5 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). 15 EXAMPLE 42: 4-Hydroxy-3-methoxybenzoic acid (9-ethyl-9H-3-carbazolylmethylenelhydrazide N N
CH
3 HO H3C' 0 WO 99/01423 PCT/DK98/00287 172 'H NMR (DMSO-d 6 ) 5 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), 5 8.62 (s, 1 H) 9.62 (s, 1 H), 11.51 (s, 1H). MS (APCI): 388. EXAMPLE 43: 4-Hydroxy-3-methoxybenzoic acid [5-( 3 -chlorophenyl)-2-furanylmethylenelhydrazide Cl 0 N / \ HO~ H 10 H3C'O 1 H NMR (DMSO-d6): 6 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. 15 EXAMPLE 44: 3-Chloro-4-hydroxybenzoic acid (3-phenylallylidene)hydrazide 0 .NN HON CI 20 1 H NMR (DMSO-d6): 6 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-hydroxybenzoic acid (4-allyloxy-1-naphtylmethylene)hydrazide WO 99/01423 PCT/DK98/00287 173 0 N " CH 2 HO N Cl 1 H NMR (DMSO-d6): 5 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, 5 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 (4-ethynylmethoxy-l-naphthylmethylene)hydrazide 0 I H HOC 10 1 H NMR (DMSO-d6): 5 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. 15 EXAMPLE 47: 3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-1 -naphthylmethylene)hydrazide oj HN HO:JJ
CI
WO 99/01423 PCT/DK98/00287 174 1 H NMR (DMSO-d6): 5 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. 5 EXAMPLE 48: 2-(4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-1 -naphthyloxy)acetamide O O '- NH2 HON. CI 10 iH NMR (DMSO-d6): 5 4.68 (d, 2 H), 6.94 (d, 1 H), 6.98 (dd, 1H), 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-hydroxybenzoic acid (4-methyl-1-naphthylmethylene)hydrazide O
CH
3 HONN 15 1 H NMR (DMSO-d6): 5 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, 1H), 11.0 (s, 1 H). MS (APCI): 339, 341. 20 EXAMPLE 50: 3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1-naphthylmethylene)hydrazide WO 99/01423 PCT/DK98/00287 175 O N N HON. 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): 5 341. EXAMPLE 51: 3-Chloro-4-hydroxybenzoic acid (4-methoxv-1-naphthylmethylene)hydrazide O N. CH 3 HO' N 10 Cl 1 H NMR (DMSO-d6): 5 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. 15 EXAMPLE 52:
N-(
2
-[(
3 -Chloro-4-hydroxybenzoyl)hydrazonolethyl)-2.2-diphenylacetamide 0 0 N HONN Cl 20 WO 99/01423 PCT/DK98/00287 176 1 H NMR (DMSO-d6) 6 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), 8.69 (t, 1 H), 10.85 (s, 1 H), 11.39 (s, 1 H). MS (APCI): 422 EXAMPLE 53: 5 3-Chloro-4-hydroxybenzoic acid (1 -hydroxy-2-naphthylmethylene)hydrazide HO 0 N HON CI 1 H NMR (DMSO-d6): 6 6.99 (d, 1 H), 7.22 (d, 1 H), 7.37 -7.56 (m, 4 H), 7.68 (dd, 1 H), 7.77 10 (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-diphenylethylidene)hydrazide O HON N 15 CI 1H NMR (DMSO-d6): 6 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: 20 3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-3.5-dimethoxybenzylidene)hydrazide WO 99/01423 PCT/DK98/00287 177 H3C'O O N 'N ,)[/ O'CH 3 H HO' CI 1 H NMR (DMSO-d6): 5 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. 5 EXAMPLE 56: 3-Chloro-4-hydroxybenzioc acid r3-(4-tert-butylphenoxy)benzylidenelhydrazide CH 00 N' N H HONN Cl 10 1 H NMR (DMSO-d6): 5 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 (4-methyl-1 -naphthylmethylene)hydrazide O CH 3 NN '3 HO H 15 01 WO 99/01423 PCT/DK98/00287 178 1 H NMR (DMSO-d6): 5 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. 5 EXAMPLE 58: 3-Chloro-4-hydroxybenzoic acid (3-bromo-4-hydroxy-1-naphthylmethylene)hydrazide 0 ~ OH H N~ / Br HO" CI 10 1 H NMR (CDCl3): 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 (APC): 421, 423. EXAMPLE 59: 15 Acetic acid 4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-1-naphthyl ester SO CH 3 N' N s0 H HOH 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), 20 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.
WO 99/01423 PCT/DK98/00287 179 EXAMPLE 60: 3-Chloro-4-hydroxybenzoic acid (4-cyanomethoxy--1-naphthylmethylene)hydrazide HO' N 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 5 (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-hydroxy-1-naphthylmethylene)hydrazide 10 N / HON. OH CI 1 H NMR (DMSO-d6): 5 7.18 (d, 1 H), 7.30 (d, 1 H), 7.50 (dd, 1H), 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. 15 EXAMPLE 62: 3-Chloro-4-hydroxybenzoic acid (2.3-methylenedioxybenzylidene)hydrazide /-0 0 0 N. HON.N
CI
WO 99/01423 PCT/DK98/00287 180 1 H NMR (DMSO-d6): 5 6.06 (s, 2 H), 6.86 (dd, 1 H), 6.90 (dd, 1H), 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. 5 EXAMPLE 63: 3-Chloro-4-hydroxybenzoic acid [3-(4-methoxyhenoxv)benzVlidnmhydrazidri
CH
3 0 N 0 HON Cl 10 1 H NMR (DMSO-d6): 5 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-hydroxybenzoic acid (9-phenanthrenylmethylene)hydrazide 0 NN .N. N 111 HON 15 c 1 H NMR (DMSO-d6): 5 7.02 (d, 1 H), 7.52 - 7.83 (m, 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. 20 EXAMPLE 65: 3-Chloro-4-hydroxybenzoic acid [4-(2-hydroxyethoxv)-1-naphthylmethylenelhydrazide WO 99/01423 PCT/DK98/00287 181 0 0 OH HO N ci 1 H NMR (DMSO-d6): 5 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 5 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-hydroxybenzoic acid (4-hydroxy-1-naphthylmethylene)hydrazide o OH HON 10 Br 1 H NMR (DMSO-d6): 5 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 15 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-hydroxybenzoyl)hydrazonomethyl]-1-naphthyl ester N N N'N N / 0 H HON
CI
WO 99/01423 PCT/DK98/00287 182 1 H NMR (DMSO-d6): 6 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. 5 EXAMPLE 68: 3-Chloro-4-hydroxybenzoic acid r4-(1.3-dioxo-1.3-dihydroisoindoi-2-ylmethoxy)-1-naphthyl methylene]hydrazide 0 0 -~ HO N O 10 1 H NMR (DMSO-d6): 5 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. 15 EXAMPLE 69: 3-Chloro-4-hydroxybenzoic acid [4-(cyclohexylmethoxy)-1-naphthylmethylenelhydrazide O ON HO""N 20 CI 1 H NMR (DMSO-d6): 5 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 WO 99/01423 PCT/DK98/00287 183 = 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. 5 EXAMPLE 70: 3-Chloro-4-hydroxybenzoic acid [4-(tetrahydro-2-pyranylmethoxy)-1-naphthylmethylenel hydrazide 'N N HOH HO CI 10 1 H NMR (DMSO-d6): 5 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, 15 441. EXAMPLE 71: 3-Chloro-4-hydroxybenzoic acid [4-(3-pyridylmethoxy)-1 -naphthylmethylenelhydrazide 0~~ N,! N HON 20 CI 1 H NMR (DMSO-d6): 5 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), WO 99/01423 PCT/DK98/00287 184 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: 5 4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-1-naphthyloxy)acetic acid ethyl ester 0 0 0 ',-AO CH3 N HON Cl 1 H NMR (DMSO-d6): 5 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), 10 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 O 0 ON HON N 15 Cl 1 H NMR (DMSO-d6): 6 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. 20 EXAMPLE 74: 3-Chloro-4-hydroxybenzoic acid (2.4-dichlorobenzylidene)hydrazide WO 99/01423 PCT/DK98/00287 185 N'C CI H HO-c H ci 1 H NMR (DMSO-d6): 5 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 5 (APCI): 345. EXAMPLE 75: 3-Chloro-4-hydroxybenzoic acid (4-fluoro-1-naphthylmethylene)hydrazide O F HN N H0~ H CI 10 1 H NMR (DMSO-d6): 5 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. 15 EXAMPLE 76: 3-Fluoro-4-hydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide 0 OH F ,N WO 99/01423 PCT/DK98/00287 186 1 H NMR (DMSO-d6): 5 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. 5 EXAMPLE 77: 3-Chloro-4-hydroxybenzoic acid [4-(2.4-difluorobenzvioxy)-1-naphthylmethylenelhydrazide F F 0 N 0 0 HON Cl 1 H NMR (DMSO-d6): 5 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 10 Hz, 1 H), 7.31 (m, 1 H), 7.52 (m, 1 H), 7.54 (m, 1H), 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-naphthyimethylene)hydrazide O N ,N HON 15 F MS (APCI): 309. EXAMPLE 79: 3-Chloro-4-hydroxybenzoic acid [4-(3-methoxybenzyloxy)-1-naphthylmethylenelhydrazide WO 99/01423 PCT/DK98/00287 187 O OCH Q , 0 N C HO N Cl 1 H NMR (DMSO-d6): 5 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), 5 11.62 (s, 1 H). MS (APCI): 461. EXAMPLE 80: 3-Chloro-4-hydroxybenzoic acid [4-(4-fluorobenzyloxy)-1-naphthylmethylenelhydrazide O ONF HON H CI 10 1 H NMR (DMSO-d6): 5 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. 15 EXAMPLE 81: 3-Chloro-4-hydroxybenzoic acid 4 -(2-tetrahydrofuranylmethoxy)-1-naphthylmethylene] hydrazide ,N O 0 ON HON
CI
WO 99/01423 PCT/DK98/00287 188 1 H NMR (DMSO-d6): 6 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. 5 EXAMPLE 82: 3-Chloro-4-hydroxybenzoic acid (3-bromo-4-methoxy-1-naphthylmethylene)hydrazide 0o1 0
'CH
3 N S/Br H HO' Cl 10 1 H NMR (DMSO-d6): 5 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: 15 3-Chloro-4-hydroxybenzoic acid [4-(3-tetrahydrofuranylmethoxy)-1-naphthylmethylene] hydrazide H HOH CI 1 H NMR (DMSO-d6): 5 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), 20 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.
WO 99/01423 PCT/DK98/00287 189 EXAMPLE 84: 4-(4-[3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-1 -naphthyloxymethyl)benzoic acid methyl ester 0 00 3 C O O 3 HO N Cl 5 1 H NMR (DMSO-d6): 5 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. 10 EXAMPLE 85: 3-Chloro-4-hydroxybenzoic acid [3.5-dimethoxy-4-(4-trifluoromethoxybenzyloxy)benzyli denelhydrazide 0 0 N. s / O'CH3 HO N CI 1H NMR (DMSO-d6): 5 3.76 (s, 6 H), 4.91 (s, 2 H), 6.95 - 7.00 (m, 3 H), 7.30 (d, J = 8.2 Hz, 15 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-trifluoromethoxybenzyloxy)-1-naphthylmethylenel 20 hydrazide WO 99/01423 PCT/DK98/00287 190 0O0 F HO 'N cI 1 H NMR (DMSO-d6): 5 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, 5 1 H). MS (APCI): 515, 517. EXAMPLE 87: 3-Chloro-4-hydroxybenzoic acid [4-(2-methoxybenzyloxy)-1-naphthylmethylene]hydrazide HOO Cl 10 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. 15 EXAMPLE 88: 3-Chloro-4-hydroxybenzoic acid [4-(2-fluorobenzyloxy)-1-naphthylmethylenelhydrazide -N , F HO'N
CI
WO 99/01423 PCT/DK98/00287 191 1 H NMR (DMSO-d6): 5 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. 5 EXAMPLE 89: 3-Chloro-4-hydroxybenzoic acid [4-(2.6-difluorobenzyloxy)-1-naphthylmethylenelhydrazi HO cI 10 1 H NMR (DMSO-d6): 5 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. 15 EXAMPLE 90: 4-Hydroxy-3-methoxybenzoic acid [ 3 .5-dimethoxy-4-(5.5.8.8-tetramethyl-5.6.7.8-tetrahydro naphth-1 -ylmethoxy)benzylidenelhydrazide O C H 3 H 3 OCH3
CH
3 HN
OCH
3
H
3 HO
OCH
3 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), 20 6.88 (d, 1H), 7.01 (s, 2H), 7.18 (d, 1H), 7.29 (d, 1H), 7.38 (s, 1H), 7.44 (d, 1H), 7.48 (s, 1H), 8.40 (brd s, 1H), 11.62 (s 1H); MS (APCI): 547.1.
WO 99/01423 PCT/DK98/00287 192 EXAMPLE 91: 3-Fluoro-4-hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidenehy drazide
H
3
OCH
3 CH 3 0 O N
OCH
3 HO 5 F 1 H NMR (DMSO-d6): 8 1.05 (d, 6H), 2.67 (m, 1H), 3.61 (s, 6H), 4.69 (s, 2H), 6.79 (s, 2H), 6.86 (t, 1H), 7.01 (d, 2H), 7.24 (d, 1H), 7.44 (dd, 1H), 7.51 (d, 1H), 8.10 (brd s, 1H), 10.32 (s, 1H), 11.41 (s, 1H); MS (APCI): 467.19. 10 EXAMPLE 92: 3-Chloro-4-hydroxybenzoic acid [4-(4-tert-butylbenzyloxy)-3.5-dimethylbenzylidenelhy drazide
H
3
CH
3 3 CH, N N CH H HO ci 1 H NMR (DMSO-d6): 8 1.06 (s, 9H), 1.99 (s, 6H), 4.55 (s, 2H), 6.83 (d, 1H), 7.19 (s, 6H), 15 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-methoxy-4-(4-trifluoromethoxybenzyl oxy)benzylidenelhydrazide WO 99/01423 PCT/DK98/00287 193 O OCF 3 00 N
OCH
3 HO Cf 1 H NMR (DMSO-d6): 8 3.92 (s, 3H), 5.07 (s, 2H), 7.07 (d, 1H), 7.40 (m, 3H), 7.52 (s, 1H), 7.63 (d, 2H), 7.77 (dd, 1H), 7.97 (d, 1H), 8.35 (s, 1H), 11.00 (brd s, 1H), 11.86 (s, 1H); MS 5 (FAB): 575.0 EXAMPLE 94: 4-Hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidene]hydrazide
CH
3 CH 3 OH3 N OCH 3 HO 10 1 H NMR (DMSO-d6): 8 1.05 (d, 6H), 2.71 (m, 1H), 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, 1H), 9.97 (brd s, 1H), 11.47 (s, 1H); MS (APCI): 448.9. EXAMPLE 95: 15 2-Chloro-4-hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidenehy drazide:
H
3
OCH
3 OrH 3 H :& OCH 3 HO cI WO 99/01423 PCT/DK98/00287 194 'H NMR (DMSO-D 6 ): d 1.18 (d, 6H), 2.87 (septet, 1H), [3.68 (s, 1H) + 3.81 (s, 5H), 6H], [4.83 (s, 0.5H) + 4.90 (s, 1.5H), 2H], [6.76 (s, 0.5H) + 7.01 (s, 1.5 H), 2H], [6.80 (dd, 1H) + 6.88 (d, 1H), 2H], 7.23 (d, 2H), 7.35 (d, 2H), 7.38 (m, 1H), [7.91 (s, 0.3H) + 8.18 (s, 0.7H), 5 2H], 10.17 (s, 0.7H) + 11.73 (s, 0.3H), 1H]; MS (APCI): 483.0. EXAMPLE 96: 3-Chloro-4-hydroxybenzoic acid [3-(4-isopropylbenzyloxy)-4.5-dimethoxybenzylidenelhy drazide
OCH
3 O ~OCH 3 NN H3
CH
3 HO'q 10 Cl CH3 1 H NMR (DMSO-d6): 6 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, 1H), 7.77 (s, 1H), 8.15 (s, 1H), 10.76 (s, 1H), 11.52 (s, 1H); MS (APCI): 483.7. 15 EXAMPLE 97: 3-Chloro-4-hydroxybenzoic acid [3-(4-isopropylbenzyloxy)-2.4-dimethoxybenzylide nelhydrazide
OCH
3 HO
OCH
3 O
CH
3 CI
CH
3 1 H NMR (DMSO-d6): 8 1.20 (d, 6H), 2.89 (m, 1H), 3.85 (s, 6H), 4.95 (s, 2H), 6.95 (d, 1H), 20 7.07 (d, 1H), 7.22 (d, 2H), 7.40 (d, 2H), 7.64 (d, 1H), 7.78 (dd, 1H), 7.97 (d, 1H), 8.62 (s, 1H), 11.68 (s, 1H); MS (APCI): 483.8. EXAMPLE 98: WO 99/01423 PCT/DK98/00287 195 3-Chloro-4-hydroxybenzoic acid 4-(3-trifluoromethoxybenzyloxy)naphth-1 ylmethylenelhydrazide 0 /'
OCF
3 NNNNN H HO CI 1 H NMR (DMSO-d6): 5 5.46 (s, 2H), 7.10 (d, 1H), 7.20 (d, 1H), 7.37 (d, 1H), 7.65 (m, 5H), 5 7.82 (m, 2H), 8.01 (s, 1H), 8.32 (d, 1H), 8.97 (m, 2H), 11.70 (s, 1H); MS (APCI): 514.8 EXAMPLE 99: 3-Chloro-4-hydroxy-benzoic acid [ 4
-(
4 -isopropylbenzyloxy)-8-methoxynaphthalenl 10 ylmethylene]-hydrazide CH
CH
3 CI .N HO NN0 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 15 (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 4 ) 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 20 ethyl acetate and heptane (1:4). This afforded 2.57 g (81%) of 4-isopropylbenzyloxy-8 methoxynaphthalene-1 -carbaldehyde. Calculated for C2H2O 3 : C, 79.02%; H, 6.63%. Found: WO 99/01423 PCT/DK98/00287 196 C, 79.10%, H, 6.69%, C, 79.17%, H, 6.69%. 3-Chloro-4-hydroxybenzoic acid hydrazide (205 mg, 1.1 mmol) was dissolved in DMSO (2 5 mL) and the above 4 -isopropylbenzyloxy-8-methoxynaphthalene-l-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 compound. 10 M.P.: > 250 *C. EXAMPLE 100: CH OMe O
CH
3 0 0 N OMe HO
NO
2 15 1 H NMR ( DMSO-d 6 ) 8 1.13 (d, 6H), 2.82 (sept, 1H), 3.77 (s, 6H), 4.8 (s, 2H), 7.15 (s, 1H), 7.18 (s, 2H), 7.30 (d, 2H), 8.00 (dd, 1H), 8.30 (s, 1H), 8.44 (s, 1H), 11.84 (s, 1H);. MS (APC): 494.0 20 EXAMPLE 101: o .
c
F
3 0
.
0N HO .N ci H NMR ( DMSO-d 6 ) 5 5.38 (s, 2H), 6.95 (d, 1H), 7.06 (d, 1H), 7.49 (t, 1H), 7.56 (t, 1H), 7.65-7.71 (m, 6H), 7.87 (d, 1H), 8.22 (d, 1H), 8.80 (s, 1H), 8.86 (d, 1H), 10.82 (s, 1H), 11.55 25 (s, 1H); MS (FAB): 499 WO 99/01423 PCT/DK98/00287 197 EXAMPLE 102: 00 S.N N
OCF
3 HO cl 5 1 H NMR ( DMSO-d 6 ) 5 5.85 (s, 2H), 7.05 (t, 2H), 7.52-7.63 (m, 4H), 7.73 (m, 2H), 7.95 (s, 1H), 8.16 (d, 2H), 8.33 (d, 1H), 8.90 (s, 1H), 893 (s, 1H), 10.90 (brd s, 1H), 11.63 (s, 1H); MS (FAB): 543 EXAMPLE 103: 10 3-Chloro-4-hydroxybenzoic acid { 4
-[
2
-(
4 -bromophenoxy)ethoxy-3.5-dimethoxybenzylide ne}hydrazide Br
OCH
3 N rOCH H HO" 1 ci 1 H NMR (DMSO-d6): S 3.78 (s, 6H), 4.21 (m, 4H), 6.87 (d, 2H), 7.00 (s, 2H), 7.05 (d, 1H), 15 7.44 (d, 2H), 7.75 (dd, 1H), 7.96 (s, 1H), 8.36 (s, 1H), 10.95 (brd s, 1H), 11.66 (s, 1H); MS(APCI): 548.8. EXAMPLE 104: 3-Chloro-4-hydroxvbenzoic acid f 4
-(
3 -methoxv-3-(4-methylphenyl)-propyloxy)naphthl- 20 ylmethylene]hydrazide WO 99/01423 PCT/DK98/00287 198
CH
3 O 0 ' N N
OCH
3 H HO C1 MS (APCI): 502.9 EXAMPLE 105: 5 (2-Ethylphenyl)carbamic acid 2
-{
4 -[(3-chloro-4-hdroxbenzoyl)hydrazonomethyl]-naphth- yloxy}ethyl ester 0 0 N O O N H N N~ N 'C H
CH
3 HO Cl 1 H NMR (CDCl3): 5 1.12 (t, 3H), 2.50 (qt, 2H), 3.69 (t, 2H), 4.39 (t, 2H), 5.20 (t, 1H), 6.57 (t, 10 1H), 6.74 (d, 1H), 6.97 (d, 1H), 7.08 (m, 3H), 7.57 (t, 1H), 7.67 (t, 1H), 7.81 (t, 2H), 8.01 (s, 1H), 8.35 (d, 1H), 8.95 (m, 2H), 11.67 (s, 1H). EXAMPLE 106: 3-Chloro-4-hydroxybenzoic acid [3-allyi-4-(4-isopropylbenzyloxy)-5 15 methoxybenzylidenelhydrazide
H
3 CH2
CH
3 O O N
OCH
3 HO
CI
WO 99/01423 PCT/DK98/00287 199 1 H NMR (DMSO-d,) : 5 1.13 (d, 6H), 2.80 (m, 1H), 3.20 (m, 2H), 3.85 (s, 3H), 4.82 (s, 2H), 5.00 (d, 2H), 5.70 (m, 1H), 6.96 (s, 1H), 7.05 (s, 1H), 7.20 (d, 2H), 7.30 (d, 2H), 7.70 (d, 1H), 7.89 (s, 1H), 8.28 (s, 1H), 10.80 (brd s, 1H), 11.61 (s, 1H); MS (APCI): 493.1. 5 WO 99/01423 PCT/DK98/00287 200 Similarly, the following compounds were made: EXAMPLE 107: 0 ~ N 0 Io _ HO .OCH 3 Ci
CH
3 5 1 H NMR (DMSO-D): 5 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, 1H), 7.75 (s, 1H), 8.18 (s, 1H), 10.75 (s, 1H), 11.52 (s, 1H); MS (APCI): 423.7, 425.6. 10 EXAMPLE 108: CH CO
CH
3 HO CI 'H NMR (DMSO-D 6 ): 5 1.18 (d, 1H), 2.88 (septet, 1H), 5.20 (s, 2H), 7.04 (d, 1H), 7.28 (t, 2H), 7.30 (s, 1H), 7.38 (d, 2H), 7.62 (d, 1H), 7.73 (dd, 1H), 7.79 (s, 1H), 7.94 (d, 1H), 8.32 15 (s, 1H), 11.94 (s, 1H), 11.72 (s, 1H); MS (APCI): 457.4, 459.1. EXAMPLE 109:
CH
3
OH
3 - H 3 O N OHCH H HO N Ci 20 'H NMR (DMSO-D 6 ): 5 1.1 (d, 6H), 2.2 (s, 6H), 2.8 (septet, 1H), 4.7 (s, 2H), 7.0 (d, 1H), 7.2 (d, 2H), 7.4 (d, 4H), 7.7 (d, 1H), 7.9 (s, 1H), 8.2 (s, 1H), 10.9 (s, 1H), 11.6 (s, 1H); MS (APCI): 451.6, 453.3.
WO 99/01423 PCT/DK98/00287 201 EXAMPLE 110:
CH
2 CH 3 OCH3 O 0 N H HO N CI 5 'H NMR (DMSO-D 6 ): 5 1.1 (d, 6H), 2.8 (septet, 1H), 3.3 (d, 1H), 5.0 (d, 1H), 5.1 (d, 1H), 5.2 (s, 2H), 5.9 (m, 1H), 7.0 (d, 1H), 7.1 (d, 1H), 7.2 (d, 2H), 7.3 (d, 2H), 7.4 (d, 1H), 7.5 (s, 1H), 7.7 (dd, 1H), 7.9 (d, 1H), 8.3 (s, 1H), 10.9 (brd s, 1H), 11.5 (s, 1H); MS (APCI): 463.5, 465.1. EXAMPLE 111: O 1 O Br 0 N.Nc N HO 10 Cl 'H NMR (DMSO-D 6 ): 6 4.47 (t, 2H), 4.54 (t, 2H), 7.01 (d, 2H), 7.07 (d, 1H), 7.14 (d, 1H), 7.45 (d, 2H), 7.53 (t, 1H), 7.27 (d, 1H), 7.79 (m, 2H), 7.96 (d, 1H), 8.17 (d, 1H), 8.91 (s, 1H), 8.94 (d, 1H), 10.92 (s, 1H), 11.64 (s, 1H), MS (APCI): 539.3, 541.1, 543.1. 15 EXAMPLE 112:
CH
3
OCH
3 CH3 H HO CI CI 1 H NMR (DMSO-D 6 ): 6 1.18 (d, 6H), 2.87 (septet, 1H), [3.67 (s, 1.5H) + 3.81 (s, 4.5H), 6H], 20 [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), 1H], [10.96 (s, 0.3H) + 11.12 (s, 0.7H), 1H], [11.82 (s, 0.7H) + 11.95 (s, 0.3H), 1HJ; MS (APCI): 517.6, 519.2.
WO 99/01423 PCT/DK98/00287 202 EXAMPLE 113:
CH
3
O.H
3 CH
CH
3 0 0 C N N sN-.. O.CH3 H HO Cl 5 1 H NMR (DMSO-D 6 ): 5 1.19 (d, 6H), 2.89 (septet, 1H), [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), 1H], 7.92 (s, 0.3H) + 8.18 (s, 0.7H), 1H], 11.17 (brd s, 1H), 11.81 (s, 0.7H) + 11.96 (s, 0.3H), 1H]; MS (APCi): 517.7, 519.2. 10 EXAMPLE 114:
CH
3
O.CH
3
CH
3 0 0 N-1 N N N'&
O.CH
3 I H HO
NH
2 'H NMR (DMSO-D6): 5 1.20 (d, 6H), 2.87 (septet, 1H), 3.82 (s, 6H), 4.89 (s, 2H), 6.69 (d, 1H), 6.98 (m, 3H), 7.21 (m, 3H), 7.36 (d, 2H), 8.32 (s, 1H), 9.8 (brd s, 1H), 11.50 (s, 1H); MS 15 (APCI): 464.7. EXAMPLE 115:
CH
3 OO. H3 CH3 N N N 0. 3 H HO F F 20 'H NMR (DMSO-D 6 ): 6 1.19 (d, 6H), 2.30 (septet, 1H), [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), 1H], 11.05 (brd, 1H), 11.69 (s, 0.75H) + 11.94 (s, 0.25H), 1H]; MS (APCI): 485.5, 486.3.
WO 99/01423 PCT/DK98/00287 203 EXAMPLE 116: CH OOH CH 3 CH 3 N N.N~ N .H HH HO 5 1 H NMR (DMSO-D 6 ): 8 1.19 (d, 6H), 2.88 (septet, 1H), 3.83 (s, 6H), 4.90 (s, 2H), 6.87 (d, 1H), 7.03 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.53 (m, 3h), 8.26 (m, 3H), 10.73 (s, 1H), 11.82 (s, 1H); MS (APCI): 499.8. EXAMPLE 117:
CH
3
O.CH
3 :r
CH
3 SN.N O.CH H HO || 10 N 'H NMR (DMSO-D 6 ): 5 1.20 (d, J = 6.9, 6H), 2.89 (sept, J = 6.9, 1H), 3.84 (s, 6H), 4.91 (s, 2H), 7.03 (br s, 2H), 7.12 (d, J = 8.8, 1H), 7.23 (d, J = 8.0, 2H), 7.37 (d, J = 8.0, 2H), 8.04 (dd, J = 2.2, 8.8, 1H), 8.21 (br s, 11H), 8.35 (br s, 1H), 11.78 (s, 1H), 11.89 (br s, 1H); MS 15 (APCI, neg): 472. Preparation of acyl-hydrazones of 4-(2-hydroxyethyl)-1-naphthaldehyde: General procedure for synthesis of compounds of the general formula X: 20 A ~N~ NH2 + I (CH2)bN ,N (CH 2 )N.OH H H I~N N 0 H formula X WO 99/01423 PCT/DK98/00287 204 wherein b is 1, 2, 3 or 4 Preparation of 4-(2-hydroxyethyl)-1-naphthaldehyde: Br Br O H Br-----1 0 H Meo HO O'_ HO 1 -Bromo-4-(2-hydroxyethyl)naphthalene: 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 00C 1 M lithium aluminum hydride in THF (4 mL). The mix 10 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 (MgSO 4 ), 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]. 15 H NMR (CDC1 3 ) 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, 1H), 7.58 - 7.63 (m, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.61 (m, 1H), 8.31 (dd, J = 1.1, 8.0 Hz, 1H). GCMS (pos.) 250, 252. 20 1 -Bromo-4-(2-tetrahydropyranyloxyethyl)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. NaHCO 3 sol. (20 mL), dried (MgSO 4 ), 25 and concentrated. Flash chromatography using hexane/ethyl acetate 9:1 as eluent provided 1.69 g (75%) of a colorless oil. H NMR (CDCi 3 ) 5 = 1.51 -1.60 m (6H), 3.37 (t, J = 7.2 Hz, 2H), 3.39 - 3.47 (m, 1H), 3.74 (t, J = 7.2 Hz, 2H), 4.08 (dd, J = 2.4, 7.5 Hz, 1H), 4.60 (m, 1H), 7.25 (d, J = 7.3 Hz, 1H), 7.56 - WO 99/01423 PCT/DK98/00287 205 7.61 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 8.09 - 8.12 (m, 1H), 8.29 (dd, J = 2.5, 7.1 Hz, 1H). GCMS (pos), 334, 336. 1 -Formyl-4-(2-tetrahydropyranyloxyethyl)naphthalene: 5 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 4 CI solution (10 mL), extracted with ether (3 x 10 ml), dried (MgSO 4 ) and 10 concentrated. Flash chromatography using hexane/ethyl acetate 5:1 as eluent provided 408 mg (54%) of a colorless oil. H NMR (CDCl 3 ) 6 = 1.48 -1.69 m (6H), 3.45 - 3.50 (m, 3H), 3.69 - 3.85 (m, 2H), 4.07 - 4.17 (m, 1H), 4.61 (m, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.62 -7.73 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 15 8.20 (d, J = 1.0, 8.1 Hz, 1H), 10.36 (s, 1H). GCMS: 284 1 -Formyl-4-(2-hydroxyethyl)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 20 at room temperature for 16 h, and concentrated. The residue was dissolved in ethyl acetate (3 x 10 mL), washed with satd. NaHCO 3 (20 mL), dried (MgSO 4 ) and concentrated. Purifica tion by flash chromatography using hexane/ethyl acetate 3:1 as eluent provided 182 mg (65%) of a colorless oil . 25 H NMR (CDC13) 5 = 2.09 (s, 1H), 3.40 (t, J = 6.6 Hz, 2H), 4.02 (t, J = 6.6 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1H), 7.61- 7.71 (m, 2H), 7.88 (d, J =7.3 Hz, 1H), 8.13 (dd, J = 1.3, 8.0 Hz, 1H), 9.29 (dd, J = 1.3, 8.0 Hz, 1H), 10.28 (s, 1H). GCMS: 200 The following compounds were prepared according to the general procedure for the synthe 30 sis of alkylidene hydrazones from the condensation of 1-formyl-4-(2-hydroxyethyl) naphtha lene (from step D) with 4-hydroxy benzoic acid hydrazides.
WO 99/01423 PCT/DK98/00287 206 EXAMPLE 118: N. OH HO H CI 5 H NMR (DMSO-D 6 ) 5 = 3.25 (t, J = 6.5 Hz, 2H), 3.73 (dt, J =J'=6.5 Hz, 2H), 4.84 (t, J = 6.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.60 - 7.68 (m, 2H), 7.80 (dd, J = 1.8, 7.4 Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 9.19 (d, J = 6.7 Hz, 1H), 8.85 (d, J = 7.7 Hz, 1H), 9.05 (s, 1H), 10.98 (s, 1H), 11.76 (s, 1H); MS (APCI, pos.): 369.4, 371.2. 10 EXAMPLE 119: o . OH N' H HO Cl CI 15 H NMR (DMSO-D6) S = 3.18 (t, J = 7.0 Hz, 1H), 3.25 (t, J = 7.0 Hz, 1H), 3.65 (dd, J = 7.0 Hz, 1H), 3.74 (dd, J = 5.3, 7.0 Hz, 1H), 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, 1H), 7.82 (d, J = 7.2 Hz, 0.5H), 8.10 (d, J = 8.6 Hz, 0.5H), 8.19 (dd, J = 2.2, 20 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. 25 WO 99/01423 PCT/DK98/00287 207 Preparation of acyihydrazones of 4-hydroxymethylnaphthaldehyde: 0 OH OH 0 H A B 5 HO 0 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 10 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 Bishydroxymethylnaphthalene (70%) was obtained as a solid after evaporation of the solvent 15 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). 20 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 25 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): 6 5.19 (s, 2H), 5.71 (brd s, 1H), 7.73 (t, 1H), 7.78 (t, 1H), 7.95 (d, 1H), 30 8.26 (m, 2H), 9.34 (d, 1H), 10.46 (s, 1H).
WO 99/01423 PCT/DK98/00287 208 Examples of products employing the above aldehyde: 5 EXAMPLE 120: 0 OH H HO N The above compound was prepared according to the general procedure for the synthesis of 10 alkylidene hydrazones from the condensation of the above aldehyde with 3-cyano-4 hydroxybenzoic acid hydrazide. 1 H NMR (DMSO-D 6 ): 5 5.02 (s, 2H), 5.44 (s, 1H), 7.14 (d, 1H), 7.69 (m, 3H), 7.91 (d, 1H), 8.10 (d, 1H), 8.14 (d, 1H), 8.27 (s, 1H), 8.87 (d, 1H), 9.06 (s, 1H), 11.84 (brd s, 2H); MS 15 (ACPI): 346.3, 347.2. EXAMPLE 121: 0 OH HO l: K H ci 20 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-D 6 ): 5 5.02 (s, 2H), 5.43 (t, 1H), 7.10 (d, 1H), 7.66 (m, 3H), 7.80 (d, 1H), 25 7.90 (d, 1H), 8.02 (s, 1H), 8.15 (d, 1H), 8.87 (d, 1H), 9.08 (s, 1H), 10.98 (s, 1H), 11. 79 (s, 1H); MS (APCI): 355.5 WO 99/01423 PCT/DK98/00287 209 EXAMPLE 122: o N OH HO F 5 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. 10 1 H NMR (DMSO-D 6 ): d4.84 (s, 2H), 6.91 (t, 1H), 7.43-7.53 (m, 4H), 7.62 (d, 1H), 7.72 (d, 1H), 7.96 (d, 1H), 8.68 (d, 1H), 8.98 (s, 1H), 11.71 (brd s, 1H); MS (APCI): 339.4, 340.3. The compounds of formula 11 can also be prepared by parallel synthesis using the protocol mentioned above in a combinatorial approach. Thousands of compounds of formula I can thus 15 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 I by a combination of a selected number of aldehydes or ketones with a selected number of alkylating reagents. In the second 20 step the formed aldehydes/ketones can be combined with a selected number of the hydrazides (which may be synthesized according to Scheme 1) 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 25 prepared using this combinatorial methodology. By application of the above methodology, the following compounds may also be synthesized: WO 99/01423 PCT/DK98/00287 210 EXAMPLE 123: 5 OMe HO N-N OCF 3 H EXAMPLE 124:
CH
3 HO N-N
OCF
3 clH 0 10 EXAMPLE 125: F HO OC0 - N-N OCF 3
H
15 EXAMPLE 126: cl HO 7 NO0 - N-N OCE H - WO 99/01423 PCT/DK98/00287 211 EXAMPLE 127: H - N-N C3 HH
CH
3 H CI EXAMPLE 128: HO C
OH
3
-
3 - N-N
H
CH
3 EXAMPLE 129: HO
HO
2 H
CH
3 -P HN-N /__ ci H\
O
3
H
CH
3 EXAMPLE 130: C02H HO N-NCH H CH 3 10 EXAMPLE 131: O CO H HO N-NCH c H\ CO2H 3 iH 0--\ WO 99/01423 PCT/DK98/00287 212 EXAMPLE 132: HO MeO - CH 3 - N-N H\ 0\ CH 3 H O CI EXAMPLE 133: 0
CHF
2 /ON OMe CH 3 H\ \ 0 CH 3 H 5 OMe EXAMPLE 134: OMe
CH
3 - N-N MeO H\
CH
3
H
OMe EXAMPLE 135: N Me - N-N \ OCF 3 MeO O C0 H 10 EXAMPLE 136: N 0 MeO / O OMe CH 3 - N-N H\ H O CH3 H O OMe WO 99/01423 PCT/DK98/00287 213 EXAMPLE 137: N /\ 0 H OMe CH H CH - N-N H\ /\ CH 3 H OMe 5 EXAMPLE 138: O HO OMe - CH 3 - N-N H\ CH3
H
OMe EXAMPLE 139: 0 C H F 2 /N2O CF\ 1 HN OCF3
H
EXAMPLE 140: HO OCF3 N NN OCE , H\
--
3 10 clH
/
EXAMPLE 141: HO 0 -0N-N OF
H-
WO 99/01423 PCT/DK98/00287 214 EXAMPLE 142: 0
-
r N-N HO O N(Et) 2 H ~ General procedure for the synthesis of further derivatized hydrazides of formula I: 5 The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula 1l, as indicated in Scheme Ill, that is, by converting an alkylidene hydrazide (prepared according to the general method shown in Scheme 1, 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 XL 10 (Scheme Ill) a new alkylidene hydrazide containing an amine in the group K of formula || can be formed. SCHEME III 0 R 5 a A N-N T(CH-2) B--O-(CH 2a2) CHR -(CH2) Xe -C2 R4 solvent, base 0 R 5 a A N- N (CH 2
);-B-O--(CH
2 ) CHR--CH2-N-(CH2)TD R42 15 wherein A, B, D, n, R 4 , R" a, b and d are as defined for formula I and R a is lower alkyl. Specific examples illustrating the preparation of further derivatized hydrazides of formula II are provided below: 20 EXAMPLE 143: WO 99/01423 PCT/DK98/00287 215 3-Chloro-4-hydroxybenzoic acid {4-[2-[N'-(2-N.N-diethylaminoethyl)-N'-(4-trifluoromethoxy benzylamino)]]ethoxy -1 -naphthylmethylene}hydrazide 0 0~ , O N NN
OCF
3 H H N HO Cl
CH
3
CH
3 5 N,N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine: H CH N N 3
CH
3
OCF
3 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 mmoles) in methanol (10 mL) in a dry 100 mL round- bottom flask was 10 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 HCL. 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. 15 MS (Cl): 291. 'H NMR (CDCl 3 ): 5 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 20 mmole) in DMF (5 mL) was added [1-(4-chloroethoxy)naphthyl](3-chloro-4-hydroxy)benzoic acid hydrazide (0.41g, 1 mmole) and triethylamine (0.1 g, 1mmole). The resulting solution was heated at 800C overnight. Removal of most of the solvent in vacuo followed by flash chromatography (10:1 CHCI 3 /MeOH) on silica gel provided the title compound as a brown solid.
WO 99/01423 PCT/DK98/00287 216 'HNMR (DMSO-d 6 ): S 11.7 (1H), 9.0 bs, 2H), 8.4-7.0 (m, 12 H), 4.75 (bs, 1H), 4.65 (bs, 1H), 4.55 (t, 1H), 4.35 (t, 1H), 4.15 (t, 1H), 3.9 (bs, 1H), 3.5 (q, 4H), 3.05 (t, 1H), 1.3 (t, 3H), 0.95 (t, 3H). M.p.: 134-136*C. MS (CI): 657, 659. 5 EXAMPLE 144: 3-Chloro-4-hydroxybenzoic acid {4-[2-(4-trifluoromethoxy)benzylaminoethoxy-1-naphthyl methylene}hydrazide O H Nc NH-N HO C1 ONH
OCF
3 10 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 -naphthylmethylene]hydrazide (0.403g, 1 mmole) and triethylamine (0.1 g, 1mmole). 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 CHCI3/MeOH) on silica gel provided the title compound as a brown solid. 15 'HNMR (DMSO-d,): 6 11.6 (s, 1H), 9.0 (m 2H), 8.3 (m 1H), 8.0 (m,1H), 7.8 (s, 2H), 7.7 (m,1H), 7.6 (m, 1H), 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. 20 By application of the above methodology the following compounds of the invention were syn thesized: EXAMPLE 145: WO 99/01423 PCT/DK98/00287 217 3-Chloro-4-hydroxybenzoic acid {3.5-dimethoxy-4-[2-(4-trifluoromethoxybenzylamino) ethoxylbenzylidene}hydrazide
OCH
3 O H N I- OCHa OCF3 HO CI 1 H NMR (CD 3 OD): 5 2.90 (brd t, 2H), 3.75 (s, 6H), 3.89 (s, 2H), 4.08 (brd t, 2H), 6.87 (d, 5 1H), 7.10 (s, 2H), 7.20 (d, 2H), 7.43 (d, 2H), 7.65 (m, 1H), 7.82 (m, 1H), 8.11 (brd s, 1H); MS (APCI): 567.9. EXAMPLE 146: 10 3-Chloro-4-hydroxybenzoic acid {4-[2-(2-piperidin-1 -yl-ethylamino)ethoxy]naphth-1 ylmethylene}hydrazide 0N No H HO CI 1 H NMR (DMSO-d 6 ): 6 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,1H), 7.14 (d, 1H), 7.60 (t, 1H), 7.71 (m,1H), 7.80 (dd, 1H), 15 7.83 (d, 1H), 8.00 (d,1H), 8.51 (d, 1H), 8.95 (d, 1H), 8.98 (s, 1H), 11.69 (s,1H); MS (APCI): 495.0 EXAMPLE 147: 20 3-Chloro-4-hydroxybenzoic acid {4-[2-(3-diethylaminopropylamino)ethoxylnaphth-1 ylmethylene}hydrazide WO 99/01423 PCT/DK98/00287 218 0 N CH 3 H HO CI 1 H NMR (DMSO-d 6 ): 8 1.21 (t, 6H), 2.10 (m, 2H), 3.14 (m, 10H), 4.52 (t, 2H), 7.10 (d, 1H), 7.14 (d, 1H), 7.63 (t, 1H), 7.73 (m, 1H), 7.80 (dd, 1H), 7.84 (d, 1H), 8.00 (d, 1H), 8.46 (d,1H), 8.93 (s,1H), 8.98 (m, 1H), 9.20 (m, 2H), 9.69 (m, 1H), 11.00 (s, 1H), 11.69 (s, 1H); 5 MS (APCI): 497.0. EXAMPLE 148: 10 1-(2-{4-f(3-Chloro-4-hydroxybenzoyl)hydrazonomethyllnaphth-1 -yloxy}ethyl)-4 phenylaminopiperidine-4-carboxylic acid amide N N N N H H
NH
2 HO?) CI 1 H NMR (DMSO-d): 5 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 15 7.16 (m, 5H), 7.61(dd, 1H), 7.68 (dd,1 H), 8.00 (d, 1H), 8.27 (d, 1H), 8.94 (s,1 H), 8.97 (s, 1H), 11.63 (s, 1H); MS (APCI): 586.4 EXAMPLE 149: 20 4-(2-{4-[(3-Chloro-4-hydroxybenzoyl)hyd razonomethyllnaphth-1 -yloxy}ethylamino)piperidine 1 -carboxylic acid ethyl ester WO 99/01423 PCT/DK98/00287 219 0 IN O 11 CH 3 0~ Nc | H HOO cI 1 H NMR (DMSO-d 6 ): 5 1,10 (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,1H), 7.05 (m, 1H), 7.51 - 7.63 (m, 3H), 7.13 (d, 1H), 7.75 (m,1 H), 7.93 (d, 1H), 8.29 (d,1 H), 8.87 (m,2 H), 11.55 (s, 1H); MS 5 (APCI): 539.1, 541.0. EXAMPLE 150: 3-Chloro-4-hydroxybenzoic acid {4-[2-(1.2.3,4-tetrahydronaphth-1-ylamino)ethoxy]-naphth-1 10 ylmethylene}hydrazide N H H HO ci 1 H NMR (DMSO-d 6 ): 6 1.76 (m, 1H), 2.04 (m, 1H), 2.17 (m, 2H), 2.75 - 2.94 (m, 2H), 3.61 (m, 2H), 4.55 (m,2H), 4.71(s, 1H), 7.11 (d, 1H), 7.13 (d, 1H), 7.23 - 7.35 (m, 3H), 7.61 (d, 1H), 7.67 (d,1H), 7.71 (dd, 1H), 7.81 (dd, 1H), 7.86 (d, 1H), 8.01(d, 1H), 8.48 (d, 1H), 8.94 15 (m, 1H), 8.99 (m, 1H), 9.22 (m, 2H), 11.00 (s,1 H), 11.64 (s,1H); MS (APCI): 514.0, 516.0 EXAMPLE 151: 1-(2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]naphth-1 -yloxy}ethyl)piperidine-4 20 carboxylic acid aide WO 99/01423 PCT/DK98/00287 220 N ' N
NH
2 H C~ HOJC ) ci MS (APCI): 495.0 EXAMPLE 152: 5 3-Chloro-4-hydroxybenzoic acid {4-r2-(2-trifluoromethoxybenzylamino)-ethoxyl-1-naphthyl methylene}hydrazide H HO N OCF 3 - N-N C1 O H 10 EXAMPLE 153: 3-Chloro-4-hydroxybenzoic acid {4-[2-(4-morpholinylethylamino)ethoxy-1-naphthylmethylene} hydrazide H HO N-N N 0 H\ C1 H0 H 15 By application of the above methodology the following compounds may also be synthezised: EXAMPLE 154: 0 H HO11 N CF 3 H\ H 20 WO 99/01423 PCT/DK98/00287 221 EXAMPLE 155: N(Et) 2 HO 0 N C F3 - N-N H\ H EXAMPLE 156: N(Et) 2 HO N - N-N
HCH
3 HH3 5 CF 3 EXAMPLE 157: O N(Et) 2 H HO 00
-
N-N H O CH 3 H3C 10 EXAMPLE 158: (N(Et) 2 H O O M e N - N-0 H OMe O H 3
H
3 0 WO 99/01423 PCT/DK98/00287 222 EXAMPLE 159: N(Et) 2 HO OMe N N-N H F H\> / 0 OMe
OCF
3 5 EXAMPLE 160: H HO OMe N - N-N C1 H0\ H OMe
CH
3
H
3 C 10 General procedures for the preparation of alkylidene arylsulfonyl 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 Ill, that is, by converting an aryl sulfonyl halide, for example chloride or bromide to the corresponding hydrazide derivative and 15 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 WO 99/01423 PCT/DK98/00287 223 O NHNH /2 A-S-Cl + NH 2
NH
2 - A-S O 0 0 0 R/ -(CH2)n-B-(K)m D H-= -C2nB(~ 4I 3 A-S=O R 4 solvent, reflux 0 wherein A, B, K, D, m, n and R 4 are as defined for formula 1. 5 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 10 ture of these at -200C to 100 C, preferably between 0C to 600C. 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 15 compatible. 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 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)hydrazide WO 99/01423 PCT/DK98/00287 224 O H H OH 0N NH HO CI 3-Chloro-4-hydroxybenzenesulfony hydrazide: A solution of 4.82 g (21.2 mmol) 3-chloro-4-hydroxy-benzenesulfony chloride, (prepared ac 5 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, 17, 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 10 in a Bjchner funnel, washed several times with distilled water, and air dried. Recrystalliza tion from methanol provided 1.20 g 3-chloro-4-hydroxybenzenesulfony 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 15 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-hydroxybenzenesulfony 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 20 gel, 2:1 hexane/ethylacetate) provided 67 mg (45%) of the title compound as a solid. 1 H (DMSO-d6): 5 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. 25 EXAMPLE 162: WO 99/01423 PCT/DK98/00287 225 3-Chloro-4-hydroxy-benzenesulfonic acid [4-(4-trifluoromethoxybenzyoxy)-1 naphthylmethylenelhydrazide HO ~ / ON-N
OCF
3 H 5 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 compound 10 as a solid. 'H NMR (DMSO-d 6 ) 6 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). 15 CIMS m/z: 551, 553. By using the above methodology, the following compounds may be prepared: EXAMPLE 163: 00 HO / O/ CFa HO \ O N-N \ 20 H
CF
3 EXAMPLE 164: HO S H0N-N C1 H - WO 99/01423 PCT/DK98/00287 226 EXAMPLE 165: HO S O M e O ON-N :;0&OF 3 H OMe EXAMPLE 166: HO S OMe - CH - 0 N-N H ~ OMe 5 Synthesis of alkylhydrazides according to the invention: The alkylidene hydrazide derivatives given above can be reduced to the dihydroderivatives by the method given in Scheme V: 10 SCHEME V H H N-N (CH 2 )n-B-(K)aD N N (CH2)n-B-(K) D 4 NaBH 3 C N A R A H O CF 3
CO
2 H O 15 where A, R 4 , B, K, D, m and n are as defined for formula 1. The alkyihydrazide derivatives can be prepared by reduction (i.e. Lane, C.F.(1 975), Synthesis, p.135) of the corresponding alkylidene hydrazides using a metal hydride, such as sodium bo 20 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 WO 99/01423 PCT/DK98/00287 227 a compatible mixture of two or more solvents. Optionally a small amount of an acid is used as 5 a catalyst such as hydrochloric acid, trifluoroacetic acid, acetic acid, or sulfuric acid. The reac tions are performed at 0 C to 600C, preferably at 10*C to 300C. When the reaction is complete as judged by HPLC or TLC (silica gel, 1% methanol in dichloromethane as eluent) the sol vent(s) 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 10 centrated to give the desired product. Specific examples illustrating the preparation of alkylhy drazides according to the invention are provided below. EXAMPLE 167: 15 4-hydroxybenzoic acid (1-naphthylmethyl)hydrazide H N' N H 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 20 temperature, the solvent was evaporated in vacuo. The residue was introduced into a silica gel column and eluted with dichloromethane/methanol (99/1). 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: 25 EXAMPLE 168: 3-Chloro-4-hydroxybenzoic acid N-[4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzyllhydra-zide WO 99/01423 PCT/DK98/00287 228
H
3
OCH
3 OH 3 ON OCH3 H HO'* C1 1 H NMR (DMSO-d.): 5 1.18 (d, 6H), 2.87 (m, 1H), 3.75 (s, 6H), 3.90 (m, 2H), 4.80 (s, 2H), 5.43 (brd s, 1H), 6.68 (s, 2H), 6.98 (d, 1H), 7.20 (d, 2H), 7.34 (d, 2H), 7.64 (dd, 1H), 7.87 (d, 1H), 9.89 (brd s, 1H), 10.80 (s, 1H); MS (APCI): 485.2. 5 Furthermore, the following compounds may also be prepared: EXAMPLE 169: HO 0 OC - N-N 00F 3 H 10 EXAMPLE 170:
OCH
3 HO O H -H 3
-
N-N, ClH 0 OH 3 EXAMPLE 171: HO C 5N-N ci H
OH
3 15 WO 99/01423 PCT/DK98/00287 229 EXAMPLE 172: 0 HO OCH O O - N-N OCF 3 ci H
OCH
3 EXAMPLE 173: 0
CF
3 HO H OCH _ N-N CI H /
CF
3
OCH
3 5 General procedure for synthesis of compounds of the general formula XI: O B OH + B
OCH
3 step A O B O
OCH
3 step B H H 0stB 0 O B OH A ste NH 2 0 OOH H 0 step C A N - N H 0 0
NHR
5 cR~d step D0' N rB'O- Rc~ H 0 formula XI A and B are as defined for formula I and -NRscR 5 d is R5a R4a R4b -N--(CH2)c kq (CH2)-D where R 5 ", R 4 ", R 4 b, c, q, d and D are as defined for for 10 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.
WO 99/01423 PCT/DK98/00287 230 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, 5 DMSO, DMF, ethylene glycol, benzene, toluene or a mixture of the above solvents. The reac tions are performed between 00C 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 N 2 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 10 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 chloroform/methanol or isopropyl alcohol as eluent. 15 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 20 tween 00C to 1300C, 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 25 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 30 purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent.
WO 99/01423 PCT/DK98/00287 231 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, tert-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 5 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 N 2 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 10 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 in vacuo, followed by col umn chromatography on silica gel using a solvent system such as chloroform/methanol or di chloromethane/methanol or chloroform/ethyl acetate. 15 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 20 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 25 above. Alternatively, the product can be purified by column chromatography using dichloro methane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula Xl. Specific examples illustrating the preparation of compounds of the general formula XI ac 30 cording to the invention are provided below.
WO 99/01423 PCT/DK98/00287 232 EXAMPLE 174: 2-{4-[(3-Chloro-4-hydroxy-benzoyl)hydrazonomethyllnaphthyl-1 -yloxy}-N-(4-chloro phenyl)acetamide ci 0 0 N C H N N H HO 5 C1 Step A: Hydroxynaphthaldehyde (10 g, 58 mmol), potassium carbonate (16 g, 110 mmol), and methyl bromoacetate (16 g, 100 mmol) 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) 10 acetic acid methyl ester (13 g, 50 mmol) was filtered and dried in vacuo overnight. 1 H NMR (CDCl3): 8 3.86 (s, 3H), 4.93 (s, 2H), 6.80 (d, 1H), 7.61 (t, 1H), 7.72 (t, 1H), 7.90 (d, 1H), 8.42 (d, 1H), 9.29 (d, 1H), 10.22 (s, 1H). 15 Step B: The above ester (13 g, 50 mmol) was dissolved in methanol (100 mL) and 2 M 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 HCl. The mix ture was stirred until all of the ice was melted. (4-Formylnaphth-1-yloxy) acetic acid was 20 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 25 with ethyl acetate. The solution was washed with water (3x), brine, and dried over MgSO4. 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.
WO 99/01423 PCT/DK98/00287 233 1 H NMR (DMSO-d,): 6 4.91 (s, 2H), 6.95 (d, 1H), 7.02 (d, 1H), 7.55 (t, 1H), 7.64 (t, 1H), 7.74 (d, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 8.90 (m, 2H), 10.92 (brd s, 1H), 11.63 (s, 1H), 13.14 (brd s, 1H). 5 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, 10 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 pound. 1 H NMR (DMSO-d,): 8 4.99 (s, 2H), 7.04 (m, 2H), 7.36 (d, 2H), 7.65 (m, 4H), 7.79 (t, 2H), 15 7.99 (s, 1H), 8.40 (d, 1H), 8.72 (s, 1H), 8.92 (d, 1H), 10.42 (s, 1H), 10.96 (s, 1H), 11.69 (s, 1 H); MS (APCI): 507.9. By using the same methodology, the following compounds were prepared: 20 EXAMPLE 175: N-(1-Benzylpyrrolidin-3-yl)-2-{4-[(3-chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphth-1 yloxy}acetamide 0 o N o N H N.. H H2 O c 25 c0 WO 99/01423 PCT/DK98/00287 234 1 H NMR (DMSO-d,): 5 1.96 (m, 2H), 2.32 (m, 5H), 4.58 (s, 2H), 6.78 (d, 1H), 6.92 (d, 1H), 7.15 (m, 5H), 7.47 (t, 1H), 7.52 (t, 1H), 7.62 (d, 2H), 7.82 (d, 1H), 8.18 (m, 2H), 8.78 (d, 2H), 10.75 (brd s, 1H), 11.52 (s, 1H); MS (APCI): 556.9. 5 EXAMPLE 176: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyllnaphth-1-yloxy}-N-indan-1-yI-acetaride 0 N N H HO cl 10 1 H NMR (DMSO-d 6 ): 3 1.94 (m, 1H), 2.40 (m, 1H), 2.80-3.07 (m, 3H), 4.87 (s, 2H), 7.04 (d, 1H), 7.10 (d, 1H), 7.21 (m, 4H), 7.61 (t, 1H), 7.69 (t, 1H), 7.80 (t, 2H), 8.10 (s, 1H), 8.42 (d, 1H), 8.64 (d, 1H), 8.98 (m, 2H), 11.00 (brd s, 1H), 11.68 (s, 1H); MS (APCI): 514, 516. EXAMPLE 177: 15 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyllnaphth-1 -yloxy}-N-(1.2.3.4-tetrahydro naphthalen-1 -yl)acetamide 0 N N HH HoH HO' CI 20 1 H NMR (DMSO-d 6 ): 5 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, 1H), 7.74 (t, 1H), 7.84 (m, 2H), 8.01 (s, 1H), 8.40 (d, 1H), 8.62 (d, 1H), 8.97 (m, 2H), 11.72 (s, 1H); MS (APCI): 528, 530.
WO 99/01423 PCT/DK98/00287 235 EXAMPLE 178: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyllnaphth-1 -yloxy}-N-[2-(4-chloro 5 phenyl)ethyllacetamide N CI N N H
HO
CI 1 H NMR (DMSO-d,): 6 2.40 (t, 2H), 2.79 (t, 2H), 4.74 (s, 2H), 6.96 (d, 1H), 7.10 (d, 1H), 7.63 (t, 1H), 7.69 (t, 1H), 7.72 (m, 2H), 7.81 (s, 1H), 8.01 (m, 2H), 8.23 (t, 1H), 8.40 (d, 1H), 8.95 (s, 1H), 9.01 (d, 1H), 10.98 (brd s, 1H), 11.70 (s, 1H); MS (APCI) 538.8, 537.8. 10 EXAMPLE 179: 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyllnaphth-1-yloxy}-N-[3-(4-methylpiperazin 1 -yl)propyllacetamide 0 N N ", N NNCH3 H
HO-
15 Cl 1 H NMR (DMSO-d,): 8 1.50 (m, 2H), 2.26 (m, 2H), 2.48 (m, 5H), 3.01 (m, 8H), 4.53 (s, 2H), 6.78 (d, 1H), 6.89 (d, 1H), 7.38 (t, 1H), 7.47 (t, 1H), 7.5 (t, 2H), 7.76 (d, 1H), 8.01 (t, 1H), 8.22 (d, 1H), 8.68 (d, 1H), 8.74 (s, 1H), 10.74 (brd s, 1H), 11.45 (s, 1H); MS (APCI): 538.0. 20 EXAMPLE 180: 3-Chloro-4-hydroxybenzoic acid {4-[2-(1.2.3.4-tetrahydroisoquinolin-2-yl)-2-oxoethoxyl naphth-1 -ylmethylene}hydrazide WO 99/01423 PCT/DK98/00287 236 0 0 ON N 'N N N H HO ci 1 H NMR (DMSO-d,): 5 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, 1H), 8.34 (t, 1H), 8.95 (m, 2H), 10.97 (brd s, 1H), 11.68 (brd s, 1H); MS (APCI): 514.2. 5 EXAMPLE 181: 2-{4-[(3-Chloro-4-hydroxy-benzoyl)hydrazonomethylnaphth-1 -yloxy}-N-(3 trifluoromethoxybenzyl)acetamide 0 O- N A OCF3 H N' HO 10 Cl 1 H NMR (DMSO-d): 3 4.49 (d, 2H), 4.90 (s, 2H), 7.13 (m, 2H), 7.42 (m, 4H), 7.59 (dd, 1H), 7.68 (dd, 1H), 7.78 (m, 2H), 8.03 (s, 1H), 8.51 (d, 1H), 8.79 (t, 1H), 9.0 (m, 2H), 10.85 (brd s, 1H), 11.72 (s, 1H); MS (APCI): 572.1. 15 EXAMPLE 182: 3-Chloro-4-hydroxybenzoic acid ( 4 -{2-[4-(4-bromophenyl-4-hydroxypiperidin-1-yll-2 oxoethoxy}naphth-1 -ylmethylene)hydrazide 0 OO - N HO NN HO Cl Br WO 99/01423 PCT/DK98/00287 237 MS (APCI): 636, 638. EXAMPLE 183: 5 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyllnaphth-1 -yloxy}-N-(4 trifluoromethylsulfanylbenzyl)acetamide 0 0 0 -, ON SCF 3 H HO N Cl 1H NMR (DMSO-d,): S 4.48 (d, 2H), 4.88 (s, 2H), 7.08 (m, 2H), 7.45 (d, 2H), 7.68 (m, 4H), 10 7.82 (m, 2H), 8.01 (d, 1H), 8.52 (d, 1H), 8.87 (t, 1H), 8.96 (s, 1H), 9.01 (d, 1H), 10.98 (brd s, 1H), 11.72 (s, 1H); MS (APCI): 588.2 WO 99/01423 PCT/DK98/00287 238 EXAMPLE 184: 2-{4-[(3-Chloro-4-hydroxy-benzoyl)hydrazonomethyllnaphth-1 -yloxy}-N-(3.4 dichlorobenzyl)acetamide 0 0 CI o NC H HO 5 Cl 1 H NMR (DMSO-d): 5 4.42 (d, 2H), 4.91 (s, 2H), 7.08 (d, 1H), 7.11 (d, 1H), 7.22 (d, IH), 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, 1H), 11.00 (brd s, 1H), 11.73 (s, 1H); MS (APCI): 556.0 10 EXAMPLE 185: 0 0 0N O .NI N CH 3 HOH CI 'H NMR (DMSO-D 6 ): 5 0.97 (d, 6H), 2.42 (m, 2H), 2.50 (m, 2H), 2.68 (septet, 1H), 3.49 (m, 4H), 5.12 (s, 2H), 7.03 (d, 1H), 7.08 (d, 1H), 7.60 (t, 1H), 7.68 (t, 1H), 7.80 (d, 2H), 8.01 (d, 15 1H), 8.33 (d, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.68 (s, 1H); MS (APCI, neg.): 507.1, 509.1. EXAMPLE 186: S N CN-CH3 SN.N sN 6H, I H HO Cl 20 1 H NMR (DMSO-D 6 ): 8 1.75 (m, 2H), 2.25 (m, 2H), 2.24 (d, 3H), 2.39 (quintet, 1H), 3.26 (m, 2H), [2.84 (s, 1.5H) + 3.04 (s, 1.5H), 3H], 5.16 (d, 2H), 6.72 (t, 1H), 7.07 (d, 1H), 7.62 (t, 1H), WO 99/01423 PCT/DK98/00287 239 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, 1H); MS (APCI): 495.2, 497.2. EXAMPLE 187: - 0 HN N CH3 HO'* 5 CI 'H NMR (DMSO-D 6 ): 8 0.86 (s, 3H), 1.48 (m, 4H), 2.38 (t, 1H), 2.72 (m, 1H), 3.09 (t, 1H), 3.84 (t, 1H), 4.18 (t, 1H), 5.09 (m, 2H), 7.03 (d, 1H), 7.11 (d, 1H), 7.59 (t, 1H), 7.64 (t, 1H), 7.82 (d, 2H), 8.01 (s, 1H), 8.33 (d, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.0 (brd, 1H), 11.69 (brd 10 s, 1H); MS (APCI): 480.1, 482.1. EXAMPLE 188: 0 0 0 'AJN" N N N H HO Cl 15 'H NMR (DMSO-D 6 ): 5 2.88 (s, 1.5H) + (s, 1.5H), 3H], 2.95 (t, 1H), 3.01 (s, 1.5H), 3.10 (s, 1.5H), 3.10 (t, IH), 3.69 (t, 1H), 3.81 (t, 1H), 5.05 (d, 2H), [6.66 + 6.95 (d), 1H], 7.10 (d, 1H), [7.20 + 7.38 (d), 1H], 7.29 (d, 1H), 7.67 (m, 5H), 8.01 (s, 1H), 8.30 (t, 1H), 8.53 (dd, 1H), 8.97 (m, 2H), 11.67 (brd s, 1H); MS (APCI): 517.3, 519.2. 20 EXAMPLE 189: OMe O OH N N N OMe HO H
CI
WO 99/01423 PCT/DK98/00287 240 'H NMR (DMSO-D 6 ): 5 3.88 (s, 6H), 4.75 (s, 2H), 6.93 (d, 1H), 7.08 (m, 3H), 7.34 (dd, 1H), 7.74 (dd, 1H), 7.79 (d, 1H), 7.95 (s, 1H), 8.37 (s, 1H), 9.74 (s, 1H), 10.03 (m, 1H), 10.96 (brd s, 1H), 11.76 (brd s, 1H); MS (APCI): 534.4, 536.2. 5 EXAMPLE 190: CH, O H MeO O
H
3 N.N H I H HO CI 'H NMR (DMSO-D 6 ): 8 1.18 (d, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.71 (d, 1H), 6.78 (d, 1H), 7.06 (d, 1H), 7.20 (d, 2H), 7.58 (d, 2H), 7.78 (dd, 1H), 7.82 (d, 1H), 7.99 (d, 10 1H), 8.70 (s, 1H), 10.04 (s, 1H), 10.92 (brd s, 1H), 11.62 (brd s, 1H); MS (APCI): 496.5, 498.2. EXAMPLE 191: O0 N OCF N .N H H HO C1 15 'H NMR (DMSO-D 6 ): 5 4.88 (s, 2H), 6.93 (t, 2H), 7.23 (d, 2H), 7.47 - 7.70 (m, 6H), 7.86 (d, 1H), 8.30 (d, 1H), 8.80 (s, 1H), 8.87 (d, 1H), 10.34 (s, 1H), 10.82 (brd s, 1H), 11.55 (brd s, 1H); MS (APCI): 558.5, 560.0. 20 25 WO 99/01423 PCT/DK98/00287 241 EXAMPLE 192: CI OMeO O- NIC 0 ~0 ' N H H HO"Q Cl 5 'H NMR (DMSO-D,): 5 4.06 (s, 3H), 4.94 (s, 2H), 6.81 (d, 1H), 6.89 (s, 1H), 7.19 (d, 1H), 7.45 (s, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, 1H), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCI): 523.3, 524.8, 526.6. EXAMPLE 193: 1 0 K~N~ O N N H HO 10 Cl 'H NMR (DMSO-D 6 ): 5 1.68 (m, 2H), 2.01 (m, 2H), 3.05 (m, 2H), 3.35 (m, 2H), 3.86 (m, 1H), 4.26 (s, 2h), 4.81 (s, 2H), 6.95 (d, 1H), 7.09 (d, 1H), 7.46 (s, 5H), 7.59 (m, 1H), 7.66 (t, 1H), 7.77 (d, 1H), 7.98 (d, 1H), 8.34 (d, 1H), 8.41 (d, 1H), 8.92 (m, 2H), 9.65 (brd s, 1H), 11.02 15 (brd s, 1H), 11.80 (brd s, 1H); MS (APCI): 571.3, 572.3, 573.3. EXAMPLE 194: 0 O O..)Nk ' C N NN 'N HO .N H Cl 20 'H NMR (DMSO-D 6 ): 5 2.79 (t, 2H), 3.43 (qt, 2H), 4.71 (s, 2H), 6.95 (d, 1H), 7.08 (d, 1H), 7.17 (m, 1H), 7.26 - 7.30 (m, 3H), 7.61 (t, 1H), 7.67 (t, 1H), 7.76 (m, 2H), 7.99 (d, 1H), 8.24 WO 99/01423 PCT/DK98/00287 242 (t, 1H), 8.38 (d, 1H), 8.91 (s, 1H), 8.98 (d, 1H), 10.94 (s, 1H), 11.67 (s, 1H); MS (APCI): 536.3, 538.2, 539.1. EXAMPLE 195: 0 ci I HI N .N C I H HO 5 c1 'H NMR (DMSO-D 6 ): 64.42 (d, 2H), 4.87 (s, 2H), 7.06 (m, 2H), 7.38 (d, 2H), 7.60 (t, 1H), 7.63 (m, 1H), 7.80 (t, 1H), 7.99 (d, 1H), 8.49 (d, 1H), 8.79 (t, 1HJ), 8.93 (s, 1H), 8.98 (d, 1H), 10.95 (s, 1H), 11.68 (s, 1H); MS (APCI): 558.2, 560.1. 10 EXAMPLE 196: 15 4-(4-bromophenyl-3.4-dihydropiperadinylacetamideoxy)naphth-1-yl methylene-3-chloro-4 hydroxybenzoic acid hydrazone 0 0 N IO" H HO .NO NBr C: 20 Reaction scheme: WO 99/01423 PCT/DK98/00287 243 cl C1 N N CH A 3OH B c Br Br Br 0 -0 H OBr HO'.N O N Br cBr C1 4-(4-bromophenyl)-4-piperidinol chloroacetamide (step A): To a solution of 4-(4-bromophenyl)-4-piperidinol (5 g, 19.5 mmol) and diisopropylethylamine 5 (2.8 g, 21.5 mmol) in DMF (30 mL) was added dropwise chloroacetychloride (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 MgSO4. The solution was concentrated and chromatographed over silica gel with ethyl ace tate to give the product as a brown solid (4 g, 62 %). 10 'H NMR (DMSO-D 6 ): 5 1.21 (d, 2H), 1.71 (t. 1H), 1.96 (t, 1H), 2.71 (t, 1H), 3.37 (t, 1H), 3.70 (d, 1H), 4.27 (d, 1H), 4.54 (s, 2H), 5.26 (s, 1H), 7.42 (d, 2H), 7.51 (d, 2H). 4-(4-bromophenyl)-3.4-dihydropiperidine chloroacetamide (step B): 15 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 20 HCI (2x), aqueous NaHCO 3 (2x), brine (2x), and dried over MgSO 4 . The solvent was evapo rated and the product was chromotographed over silica gel with ethyl acetate/hexane (4/6). The product was obtained as a yellow solid (1.5 g, 32%).
WO 99/01423 PCT/DK98/00287 244 'H NMR (DMSO-D 6 ): 5 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). 5 4(-4-bromophenyl-3.4-dihydropiperadinylacetamideoxy)naphthaldehyde (step C): A mixture of 4-(4-bromophenyl)-3,4-dihydropiperidine chloroacetamide (1.5 g, 4.8 mmol)A 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 10 and washed with brine (3x), dried over MgSO 4 , and concentrated. Silica gel chromatography with ethyl acetate/hexane (1/1) provided the product (1.4 g, 65%). 'H NMR (DMSO-D 6 ): 5 2.27-2.32 (m, 2H), 3.49-3.55 (m, 2H), 3.94 (brd s, 1H), 4.06 (brd s, 1H), 5.08 (s, 1H), 5.13 (s, 1H), 6.05 (s, 1H), 6.97 (t, 1H), 7.20 (t, 1H), 7.34 (d, 2H), 7.42-7.47 15 (m, 1H), 7.52-7.57 (m, 1H), 7.92 (d, 1H), 8.16 (d, 1H), 9.01 (d, 1H), 9.97 (s, 1H). 4(-4-bromophenyl-3,4-dihydropiperadinylacetamideoxy)naphth-1-yl methylene-3-chloro-4 hydroxybenzoic acid hydrazone (step D): 20 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-D 6 ): 5 2.47-2.58 (m, 2H), 3.72 (br s, 2H), 4.13 (s, 1H), 4.26 (s, 1H), 5.14 (s, 25 1H), 5.18 (s, 1H), 6.23 (s, 1H), 6.50-6.53 (m, 1H), 7.03-7.06 (m, 1H), 7.35-7.38 (m, 2H), 7.52 (d, 2H), 7.58 (d, 2H), 7.59-7.67 (m, 1H), 7.75 (d, 1H), 7.84 (s, 1H), 8.32 (d, 1H), 8.89 (s, 1H), 8.92 (s, 1H), 11.41 (s, 1H); MS (APCI): 618.1, 620.1, 621.1, 622.1 WO 99/01423 PCT/DK98/00287 245 EXAMPLE 197: EXAMPLE 202: 0 -0 O N0H SN-CH3 HO HO H H 3 ci ci EXAMPLE 198: 20 EXAMPLE 203: 0 N N HO O HO JH 5 Cl EXAMPLE 199: EXAMPLE 204: 0 0 N '- N^.) N~ 0 N -A) .N OH N N .N N HO HO;A H OMe O? c5 25 C1 10 EXAMPLE 205: EXAMPLE 200: 2 SO 0 ON om) N OH HO. N~ OMe 25H H N N ,N HON O N Ci HO'(AHc ci 30 EXAMPLE 201: EXAMPLE 206: 0 0I O O N ON O N N N I, H'C H HO(A-C HO.N
CF
3 N 3 15 CI WO 99/01423 PCT/DK98/00287 246 EXAMPLE 207: 15 EXAMPLE 212: 0 0 iii I S.N O N .N O HI I H C NH HOP - 0 H HO EXAMPLE 208: EXAMPLE 213: H.N O N H C1 H c HO HHOJ 5 CI 20 EXAMPLE 209: EXAMPLE 214: M0 0 OI N.CN 0 o~k NC 0 0)" O N .N C NO.. N.NN N H N ' N I H HOP .N HOP 10 EXAMPLE 210: EXAMPLE 215: 0 C30 0 O..)tNLo) 0 N 0 O .N O H N N.N 6 H 3 N H HO HHO ci 25 Cl EXAMPLE 211: EXAMPLE 216: O - N O j : N . I . N~ H 0 HO N'~ N HCJNH HO HO HNHC N CI HO
CI
WO 99/01423 PCT/DK98/00287 247 EXAMPLE 217: EXAMPLE 222: SNH 0 N 0 N o. )N) (;ANN5 I H N N N-~ -. N.-CH HO H HO NH 2 CI Cl 20 EXAMPLE 218: EXAMPLE 223: 0~ ON N O HN H H H H N. OWe CH3 H O H 5 CH Cl EXAMPLE 224: EXAMPLE 219: 0 0 1 0 N CHO.N O N N CF 0 ' 0--iKP.-CH 3 N ~ HCF N. N CH N' H HO HO C 25 Cl Cl 10 EXAMPLE 220: EXAMPLE 225: 0 ~kN.N 2 i 0 OH 3 0 T H N HI0) N ' N
'..,
3 N ' N 0H HO H HO H 30 15 EXAMPLE 221: EXAMPLE 226: H CF 0 OH 3 0 O..)kN 3N OJ.N 0* N HI N'~ N HO H HO' H Cl Cl WO 99/01423 PCT/DK98/00287 248 EXAMPLE 227: EXAMPLE 232: 0 0N N o'), No H H N 'NcI) HO(? HOP H c HO .N C Cl EXAMPLE 233: 5 EXAMPLE 228: 0 N " O CH 3 N N O O N I N H IHO(A "R) N" N H 3 20 CI HO . CI EXAMPLE 234: EXAMPLE 229: E
H
3 C HO 0 . OH 3 -0 OH 3 N-. NN OH 3 I 0 NNN 0 N ON H H I H CI'P HOHON Nb HOJPA HHO CC 25 10 EXAMPLE 235: EXAMPLE 230: - 0 OH 3 0 O.)t.N "'j O N OCHN .N ON N' H HO HO c CI EXAMPLE 236: EXAMPLE 231: 0 0 0 N O N OK 0N ~ O N HI N' I H C 3 HO 1 HO cl30
CI
WO 99/01423 PCT/DK98/00287 249 EXAMPLE 237: EXAMPLE 242: 0OVNH2 0 -z OH N N N CH HO .N H HO N N:N'CH Cl CI 20 EXAMPLE 243: EXAMPLE 238: 0 0F O iiO.~0 O'JNK NF O N NO O . N H F H 0-' HO HO ci 5 CI EXAMPLE 244: EXAMPLE 239: 0 0 CH 3 0 0"'NI CH~ O O NN CH O .NO CH H N N CH 3 HO H HO HO;AHHO CI CI 25 10 EXAMPLE 245: EXAMPLE 240: 0 OMe O O OkN O o N CH NN S .N OMe N CH 3 O H H 3 CO HOe 3CIJ A CI EXAMPLE 246: 15 EXAMPLE 241: 0 N C 0 N N H 0 N ,, O..N'NCH3 IO" H N .N N CH 30 c HOC
CI
WO 99/01423 PCT/DK98/00287 250 EXAMPLE 247: 15 EXAMPLE 252: -0 0 O O, N-N CH 3 O O N N N K~~~ N N 'N N HO N H CH HO NH
NO
2 Cl CI EXAMPLE 248: EXAMPLE 253: 0 lz0 O N ONN O O N-. N HO N NN HNH N NO I H H H HOCA HO'? H3C 'r0 5 cI cI H 3 C CH 20 EXAMPLE 249: EXAMPLE 254: 0 -' N 0o' N ,H Nh N NNO H H H HO .N N F HO .N CI CI 10 EXAMPLE 250: EXAMPLE 255: 0 Ilk e O N N O.eJkN 0 CF N' O....0kN h CF 3 HO H N N N HOJ c HOIC H 25 CI EXAMPLE 251: EXAMPLE 256: 0 OH 0 0 .~ NS Y<CH 3 N OH N O N N N HOCAj H c1 HO
CF
3 Cl WO 99/01423 PCT/DK98/00287 251 EXAMPLE 257: 15 EXAMPLE 262: 0 N 0 N 0 .N O N O0.NN N N N N HHN HO
H
3 C 0 0 HO
H
3 C CH 3 Cl C1 EXAMPLE 258: EXAMPLE 263: -0 F -0 0 N 'N 0 O' 'N NO N' NN, HG3C N NN' N 0 I H I H HO .N O HO N 5 Cl CI 20 EXAMPLE 259: EXAMPLE 264: 0 0 0 0 ')~N ;N 0O..kN Nh N N H N H HO0 HO H 3 C CH 3 ci cI 10 EXAMPLE 260: EXAMPLE 265: 0 II0 0 HON O N"S 25 0 NOC N N, N F N' H HO'P H HO _[_) HH 3 C - CH 3 ci 25 cI EXAMPLE 261: EXAMPLE: 266 0 1 0 C H<. N 0 N CH O NONN N N' HH3 H T HO .N HAC HO N Cl CI WO 99/01423 PCT/DK98/00287 252 EXAMPLE 267: EXAMPLE 272: 0 N'? HO .N O6H HO o.N O. N N H N'NN H O ifH O cl 5 EXAMPLE 268: 20 EXAMPLE 273: OO CH 3 O 0 HO HO- .N H3C) CH CH 3 O N N FO N N. N- NH 3
O
3 H H' N N HC HO H cl ci EXAMPLE 269: EXAMPLE 274: O 0 0 0 - K N FN ' N O N N O N CH3 O N' N OHa HOI H HOC H cl ci 10 25 EXAMPLE 270: EXAMPLE 275: 0 H-, NH N 0 0 0"" CH 3 HO N N ON .N H N HO5 C HO ci cl EXAMPLE 276: EXAMPLE 271: l 0 O')kN NH N H I0 O.I>N HNN HO I H 15 ci HO" cl WO 99/01423 PCT/DK98/00287 253 EXAMPLE 277: EXAMPLE 282: O 0 0 . o..)N 0 0,,kN. H O .N O N O N OC HO HO H cI Cl C1 20 5 EXAMPLE 278: EXAMPLE 283: 0 0 O0 N 0O N N.N 2. N ,N N N.NN . 0 HO H CH 3 HO H NH 2 CI 0 Ci EXAMPLE 284: EXAMPLE 279: 0 O .N O'tN O ~O O A.Nh 0 N .JLN NCF 3 .N N.N CF N.A Cl HO H H(? HO 25 CI 10 Cl EXAMPLE 285: EXAMPLE 280: 0 C1 o ~O O >.N 0. 00.).N O"N N' NN NOH 3 . NN N HOH H HO'? H3CN CH 3 Cl Cl EXAMPLE 286: 15 EXAMPLE 281: . O 0 I H NNN 0 U N HO'HO N OH0 H N ' .N N 30 C' I H HO C 00 Cl KCH3 WO 99/01423 PCT/DK98/00287 254 EXAMPLE 287: EXAMPLE 291: 0 O O N ,CH, 0 N.NO N 0 Q'),NF H O HO H 3 H O . N N EXAMPLE 288: 15 EXAMPLE 292: 0 1 NJD 0 U OH HN. N 6H3 N N OaH 3 HO H HO 5 CI EXAMPLE 293: EXAMPLE 289: HN 10 EXAMPLE)290: O0 NN N I H IN'NN HO .CO CCI HO .N, 20 EXAMPLE 294: 10 EXAMPLE 290: C0
OH
3 NN k N 0 N H 0 9 N.N 0 N'N N - N ci(? HO H- O H 3 C CI
OH
3 WO 99/01423 PCT/DK98/00287 255 EXAMPLE 295: EXAMPLE 299: H N , O / N N HN N s HA & H HO S HO 15 EXAMPLE 296: EXAMPLE 300: O 0 N 0 HO .'NH HO N O N N CN' O' 'N2 CiOA O "z N O H N N C H H 3 C C HH HO"( HOJ A H 5 Cl cl EXAMPLE 297: EXAMPLE 301: 0 N' N O.)R.. H 0 0 j H K HO'( H .NN CI HOq OH, 20 CI 10 EXAMPLE 298: N N HO;'H
CI
WO 99/01423 PCT/DK98/00287 256 EXAMPLE 302: 15 EXAMPLE 307: 0 0 N 0 ~.~~ 0 "'N N H NN NCH HO N N HOJ HO qAH & cl cl EXAMPLE 303: EXAMPLE 308: 0 -0 0 0, ON -,,,OMe 0 OlA c N' N N O NO 3 I H IH HO .O HO.C O 5 Cl CI 20 EXAMPLE 304: EXAMPLE 309: -~ 0 \H H 3 CH 0 N O N O N N HO .N N CH 3 HOP H HOI(' H 10 EXAMPLE 305: EXAMPLE 310: 0 IIk N 0 0 Nfl N)N NN N N~ N NR 1_ N, HO' H IYN'H ci HO (P HN 25 Cl EXAMPLE 306: EXAMPLE 311: 00 0 N J' N N N O.'kN N'1 I H H 3 N 3.~ NC HO-P N ~ IOJ! H c 0 HO WO 99/01423 PCT/DK98/00287 257 EXAMPLE 312: 15 EXAMPLE 317: O' e W~e 0 0 0'N O"a e A N N.~ M~ OH N Ne N N 3 H HO'N H HO N' OeCl HO EXAMPLE 313: EXAMPLE 318: 0 N 0 H 5NH .N~ O N N 20 HHO .N bO N' H HO-j:P H HO CI 5 cl 20 EXAMPLE 319: EXAMPLE 314: 0 0 0 N 0 N HN OkN) N N N .N. N, H H HO? HO'* I CI Cl 10 EXAMPLE 315: EXAMPLE 320: N O N NOO N CH 0, N N'.N0 0 N NN N.N, N R H ' HO .CH 3 ci 25 Cl EXAMPLE 321: EXAMPLE 316: 0 0 0 N d. O N O , N . CH 3 .N N N N H H HO'j: N HO ci
CI
WO 99/01423 PCT/DK98/00287 258 EXAMPLE 322: 15 EXAMPLE 327: 0 -0 0 N OOH N N N N. HO . HO . Cl CI EXAMPLE 323: EXAMPLE 328: OZH: 0 OH 3 0 0 N *OH3 0 N O'>~N HN O - 'N S HO..N O H I H N* NN.. HO(? HO"(Y H01 5 C0 20 EXAMPLE 329: EXAMPLE 324:
OH
3 0 O N N~J O N" O C O N HO 10 E L O NO ONN H HO N HO. 10 EXAMPLE 325: 25 EXAMPLE 330: 3 0 0 OJ-).N) 0 NfN"-rH .N.N N, N' NN N N N I H EXAMPLE 326: EAPE31 00 o N O..)LN OH 3 o; 1 OQ..0.N Thl N N ' N " r N N H CH N.N. HO OH 3 I H ci H 30 cl WO 99/01423 PCT/DK98/00287 259 EXAMPLE 332: EXAMPLE 337: 0 0 HN N CH HO N.N:N N ,NCH2 HO N .N. 3NC H HO ? H N> CIc
CH
2 EXAMPLE 333: 20 EXAMPLE 338: O 0"kN" O O' N -- _OEt -0 o NN N' N H (A HO HO OEt 5 ci ci EXAMPLE 334:EXAMPLE 339: EXAMPLE 334: 0 N HOH N N'N. o NCI HO H
CH
3 O O N HO N NN HO Ci Ci 25 EXAMPLE 340: 10 EEXAMPLE 341: A N'N ~ Ny OEt EXA M PLE' 336 Ot O H O N NONNH CIC HO .N N EXAMPLE 341: 0 EXAMPLE 336: 0 O)-N N .~N No 0 N ''N HO -N Ci N N N~ 30 C H HO Ci 15 c WO 99/01423 PCT/DK98/00287 260 EXAMPLE 342: 5 0 0 HO 0 H Cl WO 99/01423 PCT/DK98/00287 261 General procedure for synthesis of compounds of the general formula XII: 0 0 A NH2 O O OHN H step A A N B OH H o 0 NHRecR d B 5C step B A 5d H R formula XII 5 A and B are as defined for formula I and -NR 5 cRsd is
R
5 a R 4 a R 4 b
-N-(CH
2 )c /q (CH 2 )-D where R 5 ", R 4 , R 4 b, 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. 10 Step A: The carbonyl compounds are treated with an acyihydrazide 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, dichloro methane, DMSO, acetic acid, water or a compatible mixture of two or more of the above sol 15 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 N 2 or Ar at temperatures between 00C 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 20 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.
WO 99/01423 PCT/DK98/00287 262 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 5 hydride or an acid halide that can then react with the amine to give a compound of formula XII. 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 10 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 XII. 15 Specific examples illustrating the preparation of compounds of the general formula XII accor ding to the invention are provided below. Preparation of 4-formyl-1-naphthylacetic acid: 20 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. 25 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 30 dene hydrazides from the condensation of 4-formyl-1 -naphthylacetic acid above and 3 chloro-4-hydroxybenzoic acid hydrazide.
WO 99/01423 PCT/DK98/00287 263 'H NMR (DMSO-D 6 ): 5 4.1 (s, 2H), 7.1 (d, 1H), 7.5 (d, 1H), 7.7 (qt, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 8.0 (s, 1 H), 8.1 (d, 1H), 8.8 (d, 1H), 9.1 (s, 1H), 11.0 (brd s, 1H), 11.8 (s, 1H), 12.2 (brd s, 1H); MS (APCI): 383.4, 385.2. 5 Preparation of (3-formylindolyl)acetic acid: Ethyl (3-formylindolyl)acetate: 3-Formylindole (10.0 g, 69 mmoles) was dissolved in DMF (100 ml). Under N 2 was a 60% suspension of NaH in mineral oil (3.0 g) added in portions with cooling (temp < 15 *C). At < 10 15 *C was a solution of ethyl bromoacetate (8.4 ml) 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. NH 4 CI, dried (MgSO 4 ) and con centrated to afford 15.9 g ethyl (3-formylindolyl)acetate. 15 1 H NMR ( CDCI ) 5 1.26 (t, 3H), 4.22 (q, 2H), 4.90 (s, 2H), 7.21 - 7.35 (m, 3H), 7.72 (s, 1H), 8.30 (d, 1H), 10.0 (s, 1H). (3-formylindolyl)acetic acid: 20 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 (MgSO 4 ) and evaporated in vacuo to afford 10.3 g (73 25 % over two steps) of (3-formylindolyl)acetic acid. 'H NMR ( DMSO-d. ) 5 4.94 (s, 2H), 7.27 - 7.36 (m, 3H), 7.98 (s, 1H), 8.25 (d, 1H), 10.0 (s, 1H), 12.5 (bs, 1H). 30 Preparation of (4-Formylindolyl)acetic acid: 4-Formylindole: WO 99/01423 PCT/DK98/00287 264 This compound was synthesized according to F. Yamada, M. Somei, Heterocycles 26 (1987) 1173. 'H NMR ( CDCl 3 ) 5 7.28 - 7.36 (m, 2H), 7.41 (t, J = 3.0 Hz, 1 H), 7.60 - 7.70 (m, 2H), 8.62 5 (brd s, 1H), 10.20 (s, 1H). GC-MS (pos.): 146 Ethyl (4-formylindolyl)acetate: This compound was synthesized according to the general procedure for N-alkylation of in doles. 10 'H NMR (CDCl 3) 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, 1H), 7.60 (d, J = 7.3 Hz, IH), 10.20 (s, 1H). (4-Formylindolyl)acetic acid: 15 This compound was synthesized according to the general procedure for saponification of esters. 'H NMR ( DMSO-d 6 ) 5 5.15 (s, 2H), 7.12 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 10.20 (s, 1H), 12.94 20 (brd s, 1H). Preparation of (5-formylindolyl)acetic acid: 5-Cyano-N-tosylindole: 25 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 30 tate (3x50 mL), dried (MgSO 4 ), 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.
WO 99/01423 PCT/DK98/00287 265 'H NMR ( CDC 3 ) 5 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, 1H), 7.57 (d, J = 3.6 Hz, 1H), 7.63 (s, 1H), 7.75 ( d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H). 5 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 00C. The mixture was stirred at room temperature for 16 h, poured into ice-cooled 1 N hydrochloric acid (50 mL), extracted 10 with ethyl acetate (3 x 80 mL). The combined organic extracts were dried (MgSO 4 ), and concentrated to give an oil. After a short column chromatography using hexane/ethyl acetate 2: 1 as eluent 0.62 g (95%) pure 5-formyl-N-tosylindole was obtained. 'H NMR (CDCl 3 ) 8 2.29 (s, 3H), 6.74 (d, J = 3.7 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.65 (d, J 15 = 3.7 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.82 (dd, J = 1.4, 8.6 Hz, 1H), 8.02 (d, J = 1.1 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H ), 9.99 (s, 1H). 5-Formylindole: 5-formyl-N-tosylindole (0.5 g, 1.7 mmol) was dissolved in a mixture of methanol (10 mL) 20 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 4 ), and concentrated. The residue was purified by short column chromatography to provide 240 mg (97%) of the desired product. 25 'H NMR (CDCl 3 ) 5 6.70 (t, J = 2.1 Hz, 1H), 7.32 (t, J = 2.3 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.78 ( dd, J = 1.5, 8.6 Hz, 1H), 8.19 (s, 1H), 9.45 (b, 1H), 10.15 (s, 1H). GC-MS (pos.): 146. Ethyl (5-formylindolyl)acetate: This compound was synthesized according to the general procedure for N-alkylation of in 30 doles.
WO 99/01423 PCT/DK98/00287 266 'H NMR (CDC3l) 5 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, 1H), 7.18 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 8.14 (s, 1H), 10.01 (s, 1H). 5 (5-Formylindolyl)acetic acid: this compound was synthesized according to the general procedure for saponification of esters. 1H NMR (DMSO-da) 5 5.10 (s, 2H), 6.66 (d, J = 3.0 Hz, 1H), 7.48 (d, J = 3.0 Hz, 1H), 7.56 (d, 10 J = 8.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 8.17 (s, 1H), 9.97 (s, 1H), 12.9 (brd s, 1H). General procedure for preparation of [(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indolyl acetic acids: 15 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]indoly acetic acid: 20 'H NMR (DMSO-D 6 ): 6 2.81 (t, J = 6.5, 2H), 4.43 (t, J = 6.5, 2H), 7.06 (d, J = 8.5, 1H), 7.15 7.28 (m, 2H), 7.56 (d, J = 8.1, 1H), 7.75 (d, J = 8.5, 1H), 7.83 (s, 1H), 7.95 (s, 1H), 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 H, Cl, N 3 04 (M - H) 384, found 384.0. 25 4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indoly acetic acid: 'H NMR ( DMSO-d 6 ) 6 5.09 (s, 2H), 7.09 (d, J = 8.6 Hz, 1H), 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, 30 1H), 10.96 (s, 1H), 11.71 (s, 1H), 12.90 (b, 1H). MS ( APCI, neg.): 370. 5-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]indoly acetic acid: WO 99/01423 PCT/DK98/00287 267 1 H NMR (DMSO-d 6 ) 535.09 (s, 2H), 6.35 (d, J = 2.9 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 7.39 (d, J 3.1 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.97 (s, 1H), 8.48 (s, 1H), 10.93 (s, 1H), 11.58 (s, 1H), 12.90 (brd s, 1H). MS 5 (APCI, neg. ): 370. 4-r3-Chloro-4-hydroxybenzoyl)-hydrazonomethyll-1-naphthylacetamides and the various indolacetamides (step B): 10 General library 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 15 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: 20 EXAMPLE 343: rCH O N CH3 N.N 0 H I H HO cl 1 H NMR (DMSO-D): 5 1.06 (t, 3H), 1.17 (t, 3H), 3.31 (qt, 2H), 3.50 (qt, 2H), 4.19 (s, 2H), 25 7.10 (d, 1H), 7.45 (d, 1H), 7.64 (quintet, 2H), 7.83 (d, 1H), 7.88 (d, 1H), 7.98 (m, 2H), 8.87 (d, 1H), 9.09 (s, 1H), 10.99 (brd s, 1H), 11.80 (brd s, 1H); ms (APCI); 438.1, 440.1.
WO 99/01423 PCT/DK98/00287 268 EXAMPLE 344: 0 N N HO( HO CI 'H NMR (DMSO-D 6 ): 5 0.98 (d, 4H), 2.76 (t, 2H), 3.02 (quintet, 1H), 3.59 (t, 2H), 4.40 (s, 5 2H), 7.10 (d, 1H), 7.48 (d, 1H), 7.48 (d, 1H), 7.59 (qt, 1H), 7.67 (t, 1H), 7.81 (d, 1H), 7.89 (d, 1H), 7.97 (d, 1H), 8.02 (s, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 10.99 (brd s, 1H) 11.80 (brd s, 1H); MS (APCI, neg.): 473.1, 475.1. EXAMPLE 345: HO 10 cI 'H NMR (DMSO-D 6 ): 5 2.50 (2H), 2.68 (t, 2H), 4.00 (s, 2H), 7.10 (d, 1H), 7.53 (d, 1H), 7.65 (tt, 2H), 7.80 (dd, 1H), 7.90 (d, 1H), 8.02 (d, 1H), 8.14 (d, 1H), 8.62 (t, 1H), 8.84 (d, 1H), 9.09 (s, 1H), 11.0 (brd s, 1H) 11.80 (s, 1H); MS (APCI): 433.1, 435.1 15 EXAMPLE 346: o N N H HO CI 'H NMR (DMSO-D): 5 1.08 (m, 4H), 1.54 (m, 6H), 2.70 (t, 2H), 3.45 (t, 2H), 3.76 (m, 1H), 20 4.30 (s, 2H), 7.06 (d, 1H), 7.49 (d, 1H), 7.64 (m, 2H), 7.80 (d, 1H), 7.88 (d, 1H), 8.01 (s, 1H), 8.07 (d, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 10.5 (brd d, 1H), 11.78 (brd s, 1H); MS (APCI, neg.): 515.2.
WO 99/01423 PCT/DK98/00287 269 EXAMPLE 347: 0 N N N N.N s N H HO Cl 'H NMR (DMSO-Dr): 5 1.26 (m, 2H), 1.37 (m, 4H), 1.67 (m, 2H), 2.43 (m, 4H), 2.62 (m, 3H), 5 3.10 (t, 2H), 3.90 (d, 1H), 4.32 (s, 2H), 4.48 (d, 1H), 7.10 (d, 1H), 7.31 (d, 1H), 7.48 (m, 2H), 7.81 (d, 1H), 7.88 (d, 1H), 8.03 (m, 2H), 8.85 (d, 1H), 9.08 (brd s, 1H), 11.76 (brd s, 1H): MS (APCI): 533.2. EXAMPLE 348: N O N N F N.N 0 H HO 10 Cl 'H NMR (DMSO-D 6 ): 6 3.03 (m, 4H), 3.68 (t, 2H), 3.79 (t, 2H), 4.30 (s, 2H), 7.14 (m, 5H), 7.47 (d, 1H), 7.66 (quintet, 2H), 7.82 (d, 1H), 7.88 (d, 1H), 8.02 (d, 1H), 8.07 (d, 1H), 8.87 (d, 1H), 9.10 (s, 1H), 10.99 (s, 1H), 11.80 (s, 1H); MS (ACPI): 545.6. 15 EXAMPLE 349: F rN ON N) N N.N. N O H HO Cl WO 99/01423 PCT/DK98/00287 270 'H NMR (DMSO-D 6 ): 5 3.10 (d, 4H), 3.67 (d, 4H), 4.30 (s, 2H), 7.00 (m, 2H), 7.09 (m, 3H), 7.47 (d, 1H), 7.62 (quintet, 2H), 7.82 (d, 1H), 7.88 (d, 1H), 8.03 (s, 1H), 8.06 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 10.99 (s, 1H), 11.80 (s, 1H); MS (ACPI): 544.5, 545.3. 5 EXAMPLE 350:
CH
3 N N CH 3 0 Y N_) N N 0 H HO Cl 'H NMR (DMSO-D 6 ): 5 2.15 (s, 6H), 2.39 (m, 8H), 3.51 (d, 4H), 4.22 (s, 2H), 7.03 (d, 1H), 7.43 (d, 1H), 7.64 (quintet, 2H), 7.77 (d, 1H), 7.87 (d, 1H), 7.99 (s, 1H), 8.02 (d, 1H), 8.83 (d, 10 1H), 9.08 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 522.2. EXAMPLE 351:
CH
2 NI 0Y NA CH 2 N N.N 5 0 I H HO C: 15 'H NMR (DMSO-D 6 ): 8 3.93 (d, 2H), 4.10 (d, 2H), 4.23 (s, 2H), 5.20 (m, 4H), 5.79 (m, 1H), 5.94 (m, 1H), 7.10 (d, 1H), 7.78 (d, 1H), 7.63 (m, 2H), 7.80 (d, 1H), 7.83 (d, 1H), 7.95 (d, 1H), 8.02 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 11 (brd s, 1H), 11.80 (brd s, 1H); MS (ACPI): 462.2 WO 99/01423 PCT/DK98/00287 271 EXAMPLE 352:
CH
3 0 N ,N N ' - 0 I H HO cl 'H NMR (DMSO-D 6 ): 6 0.9 (t, 3H), 1.30 (sextet, 2H), 1.54 (sextet, 2H), 3.56 (t, 2H), 4.31 (s, 5 2H), 4.39 (s, 2H), 7.06 (d, 1H) 7.48 (d, 1H), 7.65 (quintet, 2H), 7.79 (dd, 1H), 7.87 (d, 1H), 7.97 (d, 1H), 8.01 (d, 1H), 8.85 (d, 1H), 9.09 (s, 1H), 11.79 (s, 1H); MS (APCI): 477.01, 479.2. EXAMPLE 353: O N N.N.N ~ O I H HO 10 CI 'H NMR (DMSO-D 6 ): 6 1.17 (m, 4H), 1.54 (m, 4H), 2.68 (m, 1H), 3.77 (d, 1H), 4.18 (s, 2H), 4.33 (m, 1H), 4.76 (brd, 1H), 7.10 (d, 1H), 7.43 (m, 1H), 7.65 (quintet, 2H), 7.81 (d, 1H), 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): 15 464.1, 466.2. EXAMPLE 354:
CH
3 O .N N N' N 0 HO Cl 20 'H NMR (DMSO-D): 5 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, 1H), 7.26 (m, 2H), 7.36 (d, 1H), 7.52 (qt, 1H), 7.69 (m, 2H), 7.87 WO 99/01423 PCT/DK98/00287 272 (m, 2H), 7.95 (d, 1H), 8.00 (s, 1H), 7.87 (dd, 1H), 8.84 (t, 1H), 9.07 (brd, 1H), 11.76 (brd s, 1H); MS (APCI): 529.2, 529.7, 531.2. EXAMPLE 355:
CH
3 0 NN N HOO 5 cl 'H NMR (DMSO-D,): 6 0.85 (qt, 3H), 1.33 (m, 1H), 1.65 (m, 7H), 2.60 (t, 0.5H), 3.10 (t, 0.5H) 3.80 (m, 1H), 4.21 (s, 2H), 4.24 (m, 1H), 7.11 (d, 1H), 7.45 (t, 1H), 7.65 (m, 2H), 7.75 (d, 1H), 7.89 (d, 1H), 8.01 (d, 1H), 8.05 (d, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 11.80 (s, 1H); MS 10 (APCI): 478.4, 480.3. EXAMPLE 356: IN --. CH2 O N NNr) N N.N. O. H HO cI 15 'H NMR (DMSO-D): 5 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, 1H), 7.08 (d, 1H), 7.43 (d, 1H), 7.64 (quintet, 2H), 7.79 (dd, 1H), 7.87 (d, 1H), 8.01 (s, 1H), 8.04 (d, 1H), 8.83 (d, 1H), 9.09 (d, 1H), 11.79 (brd s, 1H); MS (APCI): 4.91.2, 493.2. 20 WO 99/01423 PCT/DK98/00287 273 EXAMPLE 357: O .N' N IO" H HO C1 'H NMR (DMSO-D): 5 1.50 (m, 1H), 1.90 (m, 2H), 1.95 (m, 1H), 2.72 (t, 1H), 2.95 (t, 1H), 5 3.30 (m, 1H), 3.55 (m, 1H), 3.65 (t, 2H), 3.75 (m, 1H), 3.92 (t, 1H), 4.12 (t, 1H) 4.35 (d, 2H), 7.11 (d, 1H), 7.48 (m, 1H), 7.65 (t, 1H), 7.68 (t, 1H), 7.8 (dd, 1H), 7.87 (d, 1H), 8.00 (d, 1H), 8.03 (d, 1H), 8.83 (d, 1H), 9.10 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 519.5, 521.2, 522.2. EXAMPLE 358: N.CH, O N) N.N 0 H HO 10 Cl 'H NMR (DMSO-D 6 ): 5 2.19 (s, 3H), 2.30 (m, 4 H), 3.50 (T, 2H), 3.58 (T, 2H), 4.22 (S, 2H), 7.03 (D, 1H), 7.43 (D, 1H), 7.64 (quint, 2H) 7.77 (dd, 1H), 7.87 (d, 1H), 7.99 (d, 1H), 8.04 (s, 1H), 8.83 (d, 1H), 9.09 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 465.2, 467.3. 15 EXAMPLE 359: O N N N N.N , N 0 H HO CI 'H NMR (DMSO-D 6 ): 5 2.38 (m, 4H), 3.51 (s, 4H), 3.61 (t, 2H), 4.22 (s, 2H), 7.08 (d, 1H), 20 7.31 (m, 5H), 7.43 (d, 1H), 7.61 (quintet, 2H), 7.82 (dd, 1H), 7.88 (d, 1H), 8.00 (s, 1H), 8.02 (d, 1H), 8.85 (d, 1H), 9.10 (s, 1H), 11.80 (brd s, 1H); MS (APCI): 541.4, 543.1.
WO 99/01423 PCT/DK98/00287 274 EXAMPLE 360: S CH OH O N N'NN N 0 CH-~ . HO H cl 'H NMR (DMSO-D): 5 1.33 (dd, 3H), 2.76 (s, 1.5H), 2.96 (s, 1.5H), 3.61 (d, 1H), 4.14 5 (quintet, 1H), 4.65 (m, 2H), 7.10 (m, 2H), 7.33 (s, 3H), 7.42 (m, 3H), 7.54 (m, 2H), 8.02 (t, 1H), 8.80 (m, 1H), 9.07 (brd, 1H), 11.80 (brd s, 1H); MS (APCI): 530.2, 532.2. EXAMPLE 361:
CH
3 OH O N.N 0 N'N Nz 0N HO H Cl 10 1 H NMR (DMSO-D 6 ): S[2.94 (s, 1.5H) + 3.10 (s, 1.5H), 3H], 3.54 (m, 2H), 4.00 (d, 1H), 4.28 (d, 1H), 4.81 (t, 1H), 4.96 (t, 1H), 7.09 (d, 1H), 7.35 (m, 3H), 7.43 (m, 3H), 7.61 (m, 2H), 7.83 (m, 3H), 8.04 (s, 1H), 8.85 (t, 1H), 9.11 (d, 1H), 11.80 (brd s, 1H); MS (APCI): 516.3, 518.2. 15 EXAMPLE 362: 0 N' N N N.N ~ O N I H HO CI 1 H NMR (DMSO-D 6 ): 5 2.75 (t, 1H), 2.95 (t, 1H), 3.59 (t, 1H), 3.80 (t, 1H), 4.38 (brd s, 3H), 4.61 (s, 1H), 4.84 (s, 1H), 6.40 (d, 1H), 6.53 (d, 1H), 7.05 (d, 1H), 7.45 (t, 1H), 7.58 (m, 3H), 20 7.81 (m, 3H), 8.00 (brd, 2H), 8.83 (d, 1H), 9.10 (s, 1H), 11.78 (brd s, 1H); MS (APCI, neg.): 513.3, 514.2.
WO 99/01423 PCT/DK98/00287 275 EXAMPLE 363: 0 ON- N H 2 N. N s 0 H HO C1 'H NMR (DMSO-D 6 ): 5 1.50 (m, 2H), 1.68, (d, 2H), 2.28 (t, 1H), 2.59 (t, 1H), 3.05 (t, 1H), 5 3.96 (d, 1H), 4.16 (s, 2H), 4.32 (d, 1H), 6.74 (brd s, 1H), 6.95 (d, 1H), 7.22 (brd s, 1H), 7.36 (d, 1H), 7.57 (quintet, 2H), 7.71 (dd, 1H), 7.79 (d, 1H), 7.92 (dd, 1H), 7.96 (d, 1H), 8.76 (d, 1H), 9.01 (s, 1H), 11.80 (brd s, 1H); MS (ACPI): 493.1, 495.2. 10 EXAMPLE 364: CH, O N N. - N CH, N.N,_ 0 6H3 I" H HO CI 'H NMR (DMSO-D 6 ): 82.10 (s, 3H), 2.15 (s, 3H), 2.29 (t, 1H), 2.40 (t, 1H), 2.80 (s, 1H), 3.05 (s, 2H), 3.36 (t, 1H), 3.46 (t, 1H), 4.16 (d, 2H), 7.01 (d, 1H), 7.38 (t, 1H), 7.56 (m, 2H), 7.72 15 (dd, 1H), 7.79 (d, 1H), 7.94 (m, 2H), 8.77 (d, 1H), 9.02 (s, 1H), 11.71 (brd s, 1H); MS (ACPI): 467.3, 469.1. EXAMPLE 365: N N N.CH3 .N- N 0 6H3 IA H HO A Cl 20 WO 99/01423 PCT/DK98/00287 276 'H NMR (DMSO-D 6 ): 5 2.11 (s, 3H), 2.14 (s, 3H), 2.33 (t, 1H), 2.39 (t, 1H), 3.37 (t, 1H), 3.46 (t, 1H), 4.14 (s, 1H), 4.32 (s, 1H), 4.55 (s, 1H), 4.74 (s, 1H), 7.05 (d, 1H), 7.23 (d, 1H), 7.29 (m, 3H), 7.38 (t, 1H), 7.43 (d, 1H), 7.57 (m, 2H), 7.81 (m, 2H), 7.97 (s, 1H), 8.06 (d, 1H), 8.79 (t, 1 H), 9.05 (s, 1 H), 11.75 (brd s, 1 H); MS (APCI): 543.2, 545.2.
WO 99/01423 PCT/DK98/00287 277 EXAMPLE 366: EXAMPLE 371: H O N N 0 N'NN N 0 CH 3 - N'N N 0 N HO .N HO cl ci EXAMPLE 367: EXAMPLE 372:
CH
3 0N N C N N H N N N HO'j -l IO H HO HOH C1i 5 EXAMPLE 368: c L15 EXAMPLE 373: H H N O NC NO( H N0 N' N 2 y HO N . N H HO H EXAMPLE 369: ci EXAMPLE 374: HN NN HO A EXAMPLE 370: ci
OH
3 1 EXAMPLE 375: H [N HC HO O N N0 N'N~ N ,S0 HOH H O N 20 Ci WO 99/01423 PCT/DK98/00287 278 EXAMPLE 376: EXAMPLE 381: H.N N e 5H H C1 EXAMPLE 382: EXAMPLE 377:
CH
3 0 N O0N N C H.N N O H N N.Ns N 0 C1 N HO HO H 5 C1 20 EXAMPLE 383: H EXAMPLE 378: o - N NNO HN C HO HCH 10 EXMLE 379 HOAPL H83 HOH Cl N , E EXAMPLE 384:: 0 H HO HOOH C N' NC,,,I EXAMPLE 385:
HO
1 * H H EXAMPLE 380: HO N.N' H H H N EXAPL N305: 0 Hl HOJP H ci WO 99/01423 PCT/DK98/00287 279 EXAMPLE 386: EXAMPLE 390: 0 N N O O N 0 N NC CH 3 HO NHO.NC cl 0l CI C EXAMPLE 387: HC EXAMPLE 391: 0'-0 O O N NN HO .N H N. CH H HN' cl HO 5 15 CI EXAMPLE 388: EXAMPLE 392: H NOF OH 0 ?~ H' NN N 0 N0 HO -. H N N cl ~HO'I; C1 EXAMPLE 389: CH 20 EXAMPLE 393: 0 r-,-0 0 N O N N... N ~ I H l~ o H HO HO N H 3 HO 10 0l WO 99/01423 PCT/DK98/00287 280 EXAMPLE 394: EXAMPLE 398: 0 N O21O .N o N,,QHC N'N N'N HO NHON 5 CI C 15 EXAMPLE 395: EXAMPLE 399: 0 H N 0 NJZ CH3 O - H 3 C ? SN NH HO
.
O 5 cl HOJP EXAMPLE 396: EXAMPLE 400: N 0 O N N N N 0O HO N N Y 0 N NN . 0 HO N NNH 20 Cl 10 EXAMPLE 397: EXAMPLE 401: H CH 3 N O N N 0 N,,) N.. N 0 NN N NN N 0~ IC H N HO HHO Cl
CI
WO 99/01423 PCT/DK98/00287 281 EXAMPLE 402: EXAMPLE 406: N N 0N: , N , 0 N y' 0 N NN.NN N N r0 HO .N N HO .N CH 3 Cl C1 15 EXAMPLE 403: EXAMPLE 407:
CH
3 H _rFN O N FN NJ:. N H N N 0 N N HOH CH 2 HO lAH Of3 5 CI C1 EXAMPLE 404: EXAMPLE 408:
FCH.
3 H N ON0N N F N NJ: 0 CI N ' N 0 N I HO HO . O NH2 c1 20 CI 10 EXAMPLE 405: EXAM PLE 409: F N H F* O0 . N O F H 'N N..N 0 N, 0 0 N NJ6 0 NH 2 HOcI j H HON
CI
WO 99/01423 PCT/DK98/00287 282 EXAMPLE 410: 15 EXAMPLE 415:
CHH
3 H N 0N F 0 N N N C HO .N O H H I H HON HO N H ciC EXAMPLE 411: EXAMPLE 416: H 0 HN .NFO N 0 J;y N NH, N. N 00 N H I HO N HO .N 5 c2Cl 20 EXAMPLE 412: EXAMPLE 417:
CH
3 N EH H. N FFH OHO OH 0 N IN N' 0 HOI N ZI 0 KN H IH HO'QN ci HON cl 10 EXAMPLE 413: EXAMPLE 418: H F0 N H 0 N.)F HO N,, HO NQ N . 0 N cl ~HO J 25 CI EXAMPLE 414: N...NI>H EXAMPLE 419: N N F 0 HO N O0N N Q CI jj;rN // N~ H H HO ci WO 99/01423 PCT/DK98/00287 283 EXAMPLE 420: EXAMPLE 425: 0 -0 HON.N N N NNN HO HO - 0H\'(;) 0 cl cl EXAMPLE 421: EXAMPLE 426: 0 -\ 0 N SN-. H H H 0 HO .N N CF 3 HO .N N H 5 cl 20 cl EXAMPLE 422: EXAMPLE 427: 'N 9 N ~jN--\ OH OH HO(? .N N HO .NNH cl cl 10 EXAMPLE 423: 25 EXAMPLE 428: 0 0 NH 2 N N NN N HO'PA H 0\/ HO H H Cl Cl EXAMPLE 424: EXAMPLE 429: 0 -,_2 Sa N_ HO NHON N 15 WO 99/01423 PCT/DK98/00287 284 EXAMPLE 430: 5
H
3 C O N N
N-CH
3 N H N HO o AL EXAMPLE 431: 20 EXAMPLE 435: NH OH 10 ci HO C EXAMPLE 432: EXAMPLE 436: H NN N N NN F O N N "JN' H N H HOH 0 F~ HO( ci ci 25 15 EXAMPLE 433: EXAMPLE 437: O N .N N N HN N N H OH HOPAH0c cE EXAMPLE 438: EXAMPLE 434: OC 3N_,( N\-N 0 z , lj - J N N 0 NN- HO (f A HO
.
30 C H3 O cl WO 99/01423 PCT/DK98/00287 285 EXAMPLE 439: EXAMPLE 444: CH3 H H.N N -N N N.N \CN N HO A HOJ Cc ci EXAMPLE 445: EXAMPLE 440: N 20 HOPAH L-20 c 5 ci EXAMPLE 446: EXAMPLE 441: N 0 C .N, - 'l rNj O N H3O N N NO P H cN H cc 25 EXAMPLE 447: 10 EXAMPLE 442: 0 H ON 0 /-CH3 H 'N q N HO. j N HO N N N N HO-P H F c ci EXAMPLE 448: EXAMPLE 443: - N - 0 OH N N N HO NN 30 c1 15 WO 99/01423 PCT/DK98/00287 286 EXAMPLE 449: EXAMPLE 452: H2CN-CH3 O. N N N NI z NJ H -N H N.N N N 5I EXAMPLE 450:EXAMPLE 453: HOHO OH N N HN CI HO 5 CI EXAMPLE 451: EXAMPLE 454: N CCH 2 CH N . NJ HHO N NN HO HHO C1 15 C1 WO 99/01423 PCT/DK98/00287 287 General procedure for synthesis of compounds of the general formula XIII: 0 o B OH A 0NH BOO H 0 step A A N B OH H 0 o RSC NHR5cR sd step B A N R H 0 formula Xlll 5 A and B are as defined for formula I and -NRscRd is Rs R4a R4b - -- (CH2)C kq (CH 2 )D where R 5 a, R 4 ", R 4 b, 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. 10 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, tert-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 15 hoformate can also be added to the reaction mixture. The reaction is performed by stirring the reaction mixture preferably under an inert atmosphere of N 2 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 20 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.
WO 99/01423 PCT/DK98/00287 288 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 5 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, 10 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 X111. 15 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: 20 0 OH 0 OH 0 OH 0 OMe
CH
3 Br'cH2 HO.CH 2
HO.CH
2 o OMe 0 OH H O H O 4-Bromomethylnaphthoic acid: 25 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- WO 99/01423 PCT/DK98/00287 289 centrated and dissolved in ethyl acetate. The organic layer was washed with water, brine and dried over MgSO 4 . Evaporation of the solvent gave the desired product (16 g, 80%). 1 H NMR (DMSO-D): 5 5.24 (s, 2H), 7.73 (m, 3H), 8.03 (d, 1H), 8.28 (d, 1H), 8.86 (d, 1H), 5 13.29 (brd s, 1H). 4-Hydroxymethylnaphthoic acid: 4-Bromomethylnaphthoic acid (16 g, 60 mmol) in an aqueous solution of K 2
CO
3 (10%, 100 10 mL) was stirred at 70 *C for 30 minutes. The reaction mixture was cooled and made acidic with conc. HCl. The resulting precipitate was filtered and dried to give the desired product as a yellow solid in quantitative yield. 'H NMR (DMSO-D 6 ) ; 8 5.01 (s, 2H), 5.96 (s, 1H), 7.70 (m, 3H), 8.10 (m, 2H), 8.90 (d, 1H). 15 Methyl 4-hydroxymethylnaphthoate: A mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 mL), and conc.
H
2
SO
4 (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 NaHCO 3 20 (2x), brine, dried over MgSO 4 , and concentrated to give a yellow oil. Silica gel column chro matography using ethyl acetate/hexane (1/3) gave the desired product as a yellow oil (3.3 g, 35%). 1 H NMR (CDC1 3 ): 5 2.05 (t, 1H), 4.01 (s, 3H), 5.22 (s, 2H), 7.66 (m, 3H), 8.09 (d, 1H), 8.16 25 (d, 1H), 8.96 (d, 1H). Methyl 4-formylnaphthoate: To a solution of methyl 4-hydroxymethylnaphthoate above (3.3 g, 15.3 mmol) in dichloro methane (20 mL) was added MnO 2 (6.6 g, 76 mmol). After stirring the dark mixture for 16 30 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.
WO 99/01423 PCT/DK98/00287 290 'H NMR (CDCl 3 ): 5 4.06 (S, 3H), 7.75 (m, 2H), 8.03 (d, 1H), 8.20 (d, 1H), 8.80 (d, 1H), 9.27 (d, 1H), 10.50 (s, 1H). 4-Formylnaphthoic acid: 5 A mixture of the methyl 4-formylnaphthoate above (2.3 g, 1 mmol) and Na 2
CO
3 (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%). 10 1 H NMR (DMSO-D 6 ): 8 7.76 (m, 2H), 8.22 (m, 2H), 8.71 (d, 1H), 9.20 (d, 1H), 10.49 (s, 1H). 4-{(3-Chloro-4-hydroxybenzoyl)hydrazonomethyllnaphthoic 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 1 H NMR (DMSO-D 6 ): 5 4.70 (d, 1H), 7.70 (m, 2H), 7.83 (d, 1H), 8.03 (m, 2H), 8.18 (d, 1H), 8.72 (s, 1H), 8.90 (d, 1H), 9.17 (s, 1H), 11.0 (brd s, 1H), 11.94 (s, 1H), 13.4 (brd s, 1H); MS (APCI, neg): 368.5, 370.2). General procedure 25 Derivatives of 4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyllnaphthamides (step B): To a solution of a derivative of4-[(4-hydroxybenzoyl)-hydrazonomethyl]naphthoic 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 into 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 XIIl were prepared: WO 99/01423 PCT/DK98/00287 291 EXAMPLE 455: - 0
-
l 0N O .NC I H A HO 5 CI 'H NMR (DMSO-D): 5 2.91 (t, 2H), 3.67 (t, 2H), 7.12 (d, 1H), 7.38 (qt, 4H), 7.58 (t, 2H), 7.70 (t, 1H), 7.50 (d, 1H), 7.95 (d, 2H), 8.03 (s, 1H), 8.69 (brd t. 1H), 8.81 (d. 1H), 9.12 (s, 1H), 11.02 (s, 1H), 11.89 (s, 1H); MS (APCI): 507.3, 508.5. 10 EXAMPLE 456: 0 N CI N N , HOH CI 'H NMR (DMSO-D 6 ): 5 2.20 (brd m, 1H), 2.30 (brd m, 1H), 2.55 (m, 2H), 3.10 (brd m, 2H), 15 3.50 (s, 2H), 3.72 (brd m, 1H), 3.85 (brd m, 1H), 7.10 (d, 1H), 7.36 (qt, 4H), 7.53 (d, 1H), 7.70 (m, 2H), 7.82 (m, 2H), 7.95 (d, 1H), 8.03 (s, 1H), 8.88 (d, 1H), 9.11 (s, 1H), 11.00 (brd s, 1H), 11.89 (s, 1H); MS (APCI, neg.): 559.2, 561.2.
WO 99/01423 PCT/DK98/00287 292 EXAMPLE 457: 15 EXAMPLE 462: 0 O N"4 a, O ' N O N O.CH3 N H N HO .N H HO . CI CI EXAMPLE 458: EXAMPLE 463: O OH CI 0 N N 0 N N IR) H IHi N N.NN NN HO H IOP H HO H 5 CI C 20 EXAMPLE 459: EXAMPLE 464: 0 CN 0 0 N N 0 N S .N N N' F HO H IOJ( H O HO. CI CI 10 EXAMPLE 460: EXAMPLE 465: 0~ 0 N F 0~ 0 N N' N N N N NRAc O N.N~ N O .NNNC IO" H IOJ( H HO HO CI 25 CI EXAMPLE 461: EXAMPLE 466: - 0 - 0 O N N C O .N N0 N' I Hi j N N <NjNI HO HO CI Cl WO 99/01423 PCT/DK98/00287 293 EXAMPLE 467: EXAMPLE 472: - 0 0 0 N' N 0. N0 N H N ',,H HO H 3 C CH 3 HO F CI Cl EXAMPLE 468: EXAMPLE 473: - 0 0 O N0 N) F N N."R N NN-A I H t )I H HOIN HO N 5 CI 20 CI EXAMPLE 469: EXAMPLE 474: 00 O N CH 3 O0N N N N CN CH 3 N , N N CF 3 HO HO O CI CI 10 EXAMPLE 470: 25 EXAMPLE 475: 0 .NCI H 0 0 HI H N*NN N N N.N N CN HO? HOH CI Cl EXAMPLE 471: EXAMPLE 476: -' 0 -l 0 0 N NCI 0 N N N N NI N .N N CI HO HO CI C1 15 30 WO 99/01423 PCT/DK98/00287 294 EXAMPLE 477: EXAMPLE 482: 0 - 0 0 N O NyoCN O N HO NN CH3 HO N N N CH2 H I: H HOI H2 CI CI EXAMPLE 478: EXAMPLE 483: - 0 0 N0 NF 0 NNHH N N N H CF N N H 0 I" H HO(? H 20 CI 5 CI EXAMPLE 484: EXAMPLE 479: C1F 10 EX M L 480 OAN N N N_ O CH HONN F HO(I H 0 ci HO O CaC Cl 25 EXAMPLE 485: 10 EXAMPLE 480: - 0 - 0 0 ~ N) o N N>-' NH N' N. N KNya~ OA N, CH N.N N O 3 HO .N IO; H 0 H 3 c HO C C1 3 EXAMPLE 486: EXAMPLE 481: 0 - 0 0 N)N 0 N) N'N N KNN N' HO (A HO(? H c cl 30 15 WO 99/01423 PCT/DK98/00287 295 EXAMPLE 487: EXAMPLE 492: - 0 F -~ 0 CN 0 N F 0 N SN' I HI N ~ I F I H I H HO HO ci ci EXAMPLE 488: EXAMPLE 493: 0 N 0 O N F OH .NNN CH3 N H N H HO HO H 3 C 5 Ci 20 Ci EXAMPLE 489: EXAMPLE 494: 1 EM 0 OCF 3 ON N 1O H N IH- N' N" ) -t H HO HO'.N CH HO c CI 10 EXAMPLE 490: 25 EXAMPLE 495: 0 0 N F00 N 0 NH N NO N H 0 H I N.'- - N.~ ~ H 0. N.N N H HH I H HO-:A HO" HOCH 15 30 WO 99/01423 PCT/DK98/00287 296 EXAMPLE 497: EXAMPLE 502: 0 N HO0. CHI N N 0 O N O 5 H IH HOi N N'~ N 0 . IlH'? H ci HO 20CI EXAMPLE 498: EXAMPLE 503: - 0 N 0 O N CHOH C OH H OO N N H 3 CI I H 5 clHO'? H 20 c EXAMPLE 499: EXAMPLE 504: - 0 O S N 0 c I' N 0 N N HO HN H Cl 10 EXAMPLE 500: 25 EXAMPLE 505: 0 0 N o* N N N CN O N HO.N CH 3 N N H 3 CI HO:AH Cl EXAMPLE 501: 0 OH -EXAMPLE 506: N ) N S N0 N NN I H 0 - NH F HO H N N F j H I I F HOCI HO N N Ci 15 30 WO 99/01423 PCT/DK98/00287 297 EXAMPLE 507: cl N N H j H HO ci 5 General procedure for synthesis of compounds of the general formula XIV: RSc O B OH NHRR5d O B NRd H O H O 0 A N step B 0 R 5c A N B 5d H 0 formula XIV A and B are as defined for formula I and -NR 5 cRd is R5a R4a R4b Ra R4 R4 10 2N-(CH 2 )c q (CH 2 ) D where R5a , 4 , R 4 b, 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. 15 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 PCT/DK98/00287 298 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 filtration 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 5 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. 10 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, tert-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 15 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 N 2 or Ar at temperatures between 0*C to 1400C, preferably between 10*C to 800C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recry 20 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. 25 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: WO 99/01423 PCT/DK98/00287 299 /--\\ O H O H 00 00 30 OH \ S. 0. F F F F EtO 0 0 0 H O H EtO O EtO 0 HO 0 4-Trifluoromethylsulfonyloxy naphthaldehyde: To a solution of 4-hydroxy naphthaldehyde (34.4 g, 0.20 mol) in dichloromethane (200 mL) 5 and pyridine (19 mL, 18.58 g, 0.23 mol) was added dropwise at 0 0 C trifluoromethane sulfo nic anhydride (46.75 g, 0.16 mol). The mixture was stirred at 00C for 2 hr and at room tem perature for 16 hr. It was poured into water (200 mL), and extracted with ether (3 x 100 mL). The combined organic extracts were washed with water (100 mL), 0.1 N hydrochloric acid (2 x 100 mL), water (100 mL), brine (100 mL), dried (MgSO 4 ), and concentrated. 10 1 H NMR (CDC 3 ) 6 7.89 - 7.97 (m, 3H), 8.09 (dd, J = 2.8, 6.5 Hz, 1 H), 8.33 (d, J = 8.0 Hz, 1H), 9.24 (dd, J = 2.8, 6.5 Hz, 1H), 10.45 (s, 1H). 2-(4-Trifluoromethylsulfonyloxy naphthyl) dioxolane: 15 A solution of 4-trifluoromethylsulfonyloxy naphthaldehyde (4.09 g, 13.4 mmol), ethylene gly col (1.5 mL, 1.67 g, 26.9 mmol), and p-toluene sulfonic acid (250 mg) in toluene (250 mL) was refluxed for 16 hr using a Dean -Stark trap. The solution was allowed to reach room temperature, was washed with satd. NaHCO 3 -sol. (2x 80 mL), brine (80 mL), dried (MgSO 4 ), and concentrated to give a yellow oil (4.79 g, quant). 20 'H NMR (CDC1 3 ) 6 4.19 (m, 4H), 6.47 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.66- 7.70 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 8.13 (dd, J = 3.3, 6.3 Hz, 1H), 8.30 (dd, J = 3.3, 6.3 Hz, 1H).
WO 99/01423 PCT/DK98/00287 300 GCMS: 348. 2-[4-(2-ethoxycarbonylvinyl)naphthyl]dioxolane: Nitrogen was passed through a solution of 2-(4-trifluoromethylsulfonyloxynaphthyl) dioxolane 5 (2.46 g, 7.06 mmol), ethyl acrylate (2.3 mL, 2.1 g, 21.2 mmol), triethylamine (4.3 g, 42.3 mmol) in DMF (6 mL) for 15 min, and bis(triphenylphosphine)palladium dichloride was ad ded. The well stirred solution was heated at 900C for 8 hr, and concentrated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (2x 50 mL), dried (Na 2 SO4), and concentrated. Purification by flash chromatography using hexane /ethyl acetate 9:1 as elu 10 ent provided a yellow solid (1.13 g, 53%). 'H NMR (CDC1 3 ) 5 1.38 (t, J = 7.0 Hz, 3H), 3.74 - 4.22 (m, 4H), 8.65 (q, J = 7.0 Hz, 2H), 6.50 (s, 1H), 6.53 (d, J = 15.7 Hz, 1H), 7.58-7.62 (m, 2H), 7.74 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H), 8.21-8.28 (m, 2H), 8.52 (d, J = 15.2 Hz, 1H). 15 2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxolane: To a solution of 2-[4-(2-ethoxycarbonylvinyl)naphthyl]dioxolane (701 mg, 2.35 mmol) in ethyl acetate (15 mL) was added palladium (5% on BaCO 3 , 51 mg). The mixture was stirred under a hydrogen atmosphere for 16 hr, filtered by suction through Celite and concentrated to pro 20 vide 689 mg (98%) of a colorless oil. 'H NMR (CDC13) 5 1.25 (t, J = 7.0 Hz, 3H), 2.75 (t, J = 8.0 Hz, 2H), 3.43 (t, J = 8.0 Hz, 2H), 4.12- 4.22 (m, 6H), 6.46 (s, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.54 - 7.70 (m, 2H), 7.70 (d, J = 7.3 Hz, 1H), 8.07 (dd, J = 3.3, 6.5 Hz, 1H), 8.26 (dd, J = 3.3, 6.5 Hz, 1H). 25 Ethyl 3-(4-formylnaphthalene)propanoic acid: To a solution of 2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxolane (689 mg, 2.29 mmol) in THF (15 mL) was added 6N hydrochloric acid (2 mL). The mixture was stirred for 16 hr at room temperature, diluted with ethyl acetate (20 mL), washed with satd. NaHCO 3 solution (20 30 mL), dried (MgSO 4 ), and concentrated to give the product as a colorless oil (407 mg, 68%) that crystallized upon sitting.
WO 99/01423 PCT/DK98/00287 301 3-(4-formylnaphthalene)propanoic acid: Ethyl 3-(4-formylnaphthalene)propanoic acid (310 mg, 1.2 mmol) was suspended in water (10 mL), and Na 2
CO
3 (130 mg, 1.2 mmol) was added. The mixture was refluxed for 5 hr, and allowed to cool to room temperature. After acidification with conc. hydrochloric acid, a preci 5 pitate was formed. The precipitate was collected by suction, and dried at 80 0 C in vacuum for 16 hr to give a white solid (300 mg, 73%). H NMR (DMSO-D 6 ) 8 2.69 (t, J = 7.0 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H), 7.66-7.77 (m, 2H), 8.10 (d, J = 7.3 Hz, 1H), 8.23 (dd, J = 1.1, 8.0 Hz, 1H), 9.22 (dd, J = 1.1 , 9.0 Hz, 1H), 10.33 10 (s, 1H), 12.30 (br s, 1H). General procedure (Step A): Preparation of 3-(4-formylnaphthalene)propanamides: To a solution of 3-(4-formylnaphthalene)propanoic acid (100 mg, 0.437 mmol) in DMF (3 mL) 15 was added carbonyl diimidazole (140 mg, 0.863 mmol). The mixture was stirred at room temperature for 1 hr, and amine (1.3 equivalents) was added. After stirring at room tempe rature for 16 hr, the mixture was diluted with ethylacetate (5 mL), extracted with water (5 mL), 1 N hydrochloric acid (5 mL), and water (3 x 5 mL), dried (MgSO 4 ) and concentrated. After flash chromatography using hexane/ethylacetate 1 : 1 pure amide was isolated. 20 Examples of amides: 0 N N CH 3 H CH 0 25 H NMR (CDC1 3 ) 5 1.06 (t, J = 7.0 Hz, 3H),1.12 (t, J = 7.0 Hz, 3H), 2.79 (t, J = 8.0 Hz, 2H), 3.50 (t, J = 8.0 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1 H), 7.64 - 7.71 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 8.18 (dd, J = 1.3, 8.0 Hz, 1H), 9.34 (dd, J = 1.3, 8.0 Hz, 1H), 10.34 (s, 1H). MS (APCI, pos.) 284.1 WO 99/01423 PCT/DK98/00287 302 H N CH, H N 0 H NMR (CDC 3 ) 8 0.77 (t, J = 7.0 Hz, 3 H), 0.86 (t, J = 7.0 Hz, 3 H), 1.15 -1.82 (m, 8 H), 2.58 (dt, 0.5 H), 2.65 - 2.88 (m, 2H), 2.92 (dt, 0.5H), 3.39 - 3.60 (m, 2.5H), 3.62- 3.73 (m, 5 0.5H), 4.58 (dd, 0.5H), 4.73 (m, 0.5H), 7.56 (d, J = 7.3 Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.61 - 7.72 (m, 2H), 8.16 (d, J = 8.3 Hz, 1H), 9.33 (d, J = 8.0 Hz, 1H), 10.34 (s, 1H). MS (APCI, pos.) 325.2 Derivatives of 4-[(4-hydroxybenzoyl)hydrazonomethyl]naphthylpropanamides (step B): 10 These compounds were prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl-1 -naphthyl propanamides (from step A) and 4-hydroxybenzoic acid hydrazide derivatives. 15 EXAMPLE 508: 0 0
N'CH
3 N N cH, HO'P cl H NMR (DMSO-D 6 ) 8 0.95 - 1.02 (m, 6H), 2.69 (t, J = 7.3 Hz, 2H), 3.19 (q, J = 7.0 Hz, 2H), 3.25 (q, J = 7.0 Hz, 2H), 3.33 (t, J = 7.3 Hz, 2H), 7.08 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 7.5 20 Hz, 1H), 7.65 (m, 2H), 7.81 (m, 2H), 8.00 (d, J = 2.0 Hz, 1H), 9.17 (dd, J = 2.4, 6.5 Hz, 1H), 8.87 (d, J = 7.6 Hz, 1H), 9.05 (s, 1H), 11.00 (s, 1H), 11.77 (s, 1H). MS (APCI, pos. ): 452.2, 454.2 25 WO 99/01423 PCT/DK98/00287 303 EXAMPLE 509: SN H, 0.~ N N , * HO C1 5 H NMR (DMSO-D 6 ) 6 0.68 (t, J = 7.5 Hz, 3H), 0.75 (t, J = 7.5 Hz, 3H), 0.76 (dd, 0.5 H), 0.90 (dd, 0.5 H), 1.02 - 1.68 (m, 8H), 2.49 (m. 0.5H), 2.75 (m, 2H), 2.90 (t, J = 14.0 Hz, 0.5H), 3.33 (m, 2H), 3.61 (d, J = 12.0, Hz, 0.5H), 3.75 (m, 0.5H), 4.36 (d, J = 12.0 Hz, 0.5H), 4.53 (m, 0.5H), 7.08 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.64 - 7.66 (m, 2H), 7.80 (dd, J = 1.9, 8.5 Hz, 1 ), 7.83 (d, J =7.5 Hz, 1H), 8.00 (d, J = 1.9, Hz, 1H), 8.17 (m, 1H), 8.88 (d, J 10 = 7.5 Hz, H), 7.25 (s, 1H), 11.0 (s, 1H), 11.76 (s, 1H). MS (APCI, pos.): 492.1, 494.1 EXAMPLE 510: Ethyl 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl propanate 15 0 0 .N0
CH
3 HO ci The compound was prepared according to the general procedure for the synthesis of alkyli dene hydrazones from the condensation of ethyl 4-formyl-1-naphthylpropanate (from step E) 20 and 3-chloro-4-hydroxy benzoic acid hydrazide. H NMR (DMSO-D 6 ) 8 1.14 (t, J = 7.0 Hz, 3H), 2.73 (t, J = 7.5 Hz, 2H), 3.35 (t, J = 7.5 Hz, 2H), 4.02 (q, J = 7.0 Hz, 2H), 7.08 (d, J = 8.6 Hz, 1H), 7.66 (m, 2H), 7.79 (dd, J = 1.8, 8.6 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 8.85 (d, J = 7.7 Hz, 1H), 9.05 (s, 1H), 11.0 (brd s, 1H), 25 11.78 (s, 1H). MS (APCI, pos.): 425.5, 427.3 WO 99/01423 PCT/DK98/00287 304 EXAMPLE 511: 5 3-Chloro-4-hydroxy benzoic acid (4-trifluoromethylsulfonyloxy naphthylidene) hydrazide N. s. s o OF N ' N 0 0 I H HO ci The compound was prepared according to the general procedure for the synthesis of alkyli 10 dene hydrazones from the condensation of 4-trifluoromethylsulfonyloxy naphthaldehyde 3 chloro-4-hydroxy benzoic acid hydrazide. H NMR (DMSO-D 6 ) 5 7.09 (d, J = 8.7 Hz, 1H), 7.68 - 7.95 (m, 4H), 8.00 - 8.10 (m, 3H), 8.90 (s, 1H), 9.10 (s, 1H), 11.02 (s, 1H), 11.96 (s, 1H). MS (APCI, pos.): 473.2, 475.1 15 WO 99/01423 PCT/DK98/00287 305 General procedure for synthesis of compounds of the general formula XV: 0 A NH 2 0 A "_B H 0 step A A o NHR5cR5d step B 0 A N N OH R formula XV 5 A and B are as defined for formula I and -NR5cR5d is R5a R4a R40 RM R R4 -N-(CH
(CH
2 )2)D where Ra, R 4 a, R 4 , 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. 10 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, tert-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 15 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 N 2 or Ar at temperatures between 0*C to 140*C, preferably between 10*C to 800C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystalli 20 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 WO 99/01423 PCT/DK98/00287 306 chromatography on silica gel using a solvent system such as chloroform/methanol or dichloro methane/methanol or chloroform/ethyl acetate. Step B: The epoxide is then ring opened by a primary or secondary amine using one of the 5 methods well-known to those skilled in the art to give a compound of formula XV. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, dichloro methane, DMSO, DMF, NMP, water or a compatible mixture of two or more of the above sol vents. The product can then be isolated either by filtration or by extraction using a solvent such 10 as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be rem oved 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 alco hol, 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 15 using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XV. Specific examples illustrating the preparation of compounds of the general formula XV accor 20 ding to the invention are provided below. The preparation of 4-(2,3-epoxypropanoxy)-1-naphthaldehyde is depicted below: O H O H 0 OH 25 4 -(2,3-epoxypropanoxy)-1 -naphthaldehyde: To a solution of 4-hydroxy-1-naphthaldehyde (1 g, 5.8 mmol) in DMSO (20 mL) was added
K
2
CO
3 (1 g, 7.2 mmol ). The mixture was stirred at room temperature for 30 min, and then 2,3-epoxypropyl bromide (0.96 g, 7 mmol) was added. After stirring for 24 hr, water (100 WO 99/01423 PCT/DK98/00287 307 mL) was added. The mixture was extracted with ethyl acetate (3x80 mL), dried (MgSO 4 ), and concentrated to give a brown solid (1.23 g, 93%). 'H NMR (CDCI 3 ) 5 2.88 (dd, J = 2.6, 4.8 Hz, 1H), 3.02 (dd, J = 4.0, 4.6 Hz, 1H), 3.51 - 3.57 5 (m, 1H), 4.22 (dd, J = 5.8, 11.1 Hz, 1H), 4.55 (dd, J = 2.8, 11.1 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 8.89 (d, J = 8.4 Hz, 1H), 9.31 (d, J = 8.6 Hz, 1H), 10.22 (s, 1H). General Procedure: 10 4-hydroxybenzoic acid 4-(2,3-epoxypropanoxy)-1-naphthylidene hydrazide derivatives (step A): The compound was prepared according to the general procedure for the synthesis of alkyli dene hydrazones from the condensation of the above epoxy-aldehyde with 4-hydroxy ben zoic acid hydrazide derivatives. 15 'H NMR (DMSO-d 6 ) 5 2.84 (dd, J = 2.2, 4.9 Hz, 1H), 2.92 (dd, J = 4.5, 4.5 Hz, 1H), 3.45 3.57 (m, 1H), 4.11 (dd, J = 6.4, 11.3 Hz, 1H), 4.60 (d, J = 11.3 Hz, 1H), 7.02 - 7.18 (m, 2H), 7.55 - 7.90 (m, 4H), 7.99 (d, J = 1.9 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.90 - 9.05 (d, 2H), 10.94 (s, 1H), 11.66 (s, 11H). MS (APCI, negative ): 395. 20 General procedure for epoxide ring opening (step B): A mixture of epoxide (0.2 mmol) and amine (0.3 mmol) in 10 mL ethanol was refluxed for 4 hr. A red oil was obtained after concentration. Products were purified by preparatory HPLC. 25 Examples of compounds of formula XV: EXAMPLE 512: -OH rH o ,O AN HCH 3 HO .N Ci x CH 3 cO 2
H
WO 99/01423 PCT/DK98/00287 308 'H NMR (DMSO-d 6 ) 5 0.95 (t, J = 6.9 Hz, 6H), 1.90 (s, 3H), 2.50, 2.62 (2q, J = 6.6 Hz, 4H), 2.70 (dd, J = 6.6, 13.0 Hz, 1H), 2.88 (dd, J = 7.0, 14.2 Hz, 1H), 3.95 - 4.35 (m, 3H), 7.02 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 7.55 - 7.85 (m, 4H), 7.96 (d, J = 1.9 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1 H), 8.85 - 9.05 (d, 2H), 11.60 (s, 1 H); MS (APCI, pos.): 470. 5 EXAMPLE 513: O OH N 0 N2 N'01 J H HO . CO cx CH CO 2 H 1 H NMR (DMSO-d 6 ) 6 1.67 (brd s, 4H), 1.88 (s, 3H), 2.50 - 2.85 (m, 6H), 4.0 - 4.3 (m, 3H), 10 7.00 - 7.12 (t, 2H), 7.55 - 7.85 (m, 4H), 7.97 (s, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.85 - 9.05 (d, 2H), 11.63 (s, 1H); MS (APCI, pos.): 468. EXAMPLE 514: -~ OH r O Oll- N 'PAN N2 H HO . CO cx CH CO 2 H 15 1 H NMR (DMSO-d 6 ) 6 1.30 -1.55 (m, 6H), 1.88 (s, 3H), 2.35 -2.60 (m, 6H), 4.05 - 4.30 (m, 3H), 7.04 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 7.55 - 7.85 (m, 4H), 7.97 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H), 8.85 - 9.05 (d, 2H), 11.62 (s, 1H); MS (APCI, pos.): 470. 20 EXAMPLE 515: OH OH N N.N O HOH HOC x CH 3 C0 2 H cI WO 99/01423 PCT/DK98/00287 309 1 H NMR (DMSO-d 6 ) 5 1.25 -1.82 (m, 8H), 1.88 (s, 3H), 2.68 -2.90 (m, 2H), 3.08 ( m, 1H), 4.0 - 4.25 (m, 3H), 7.03 (d, J = 8.6 Hz, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 7.52 - 7.85 (m, 4H), 7.97 (d, J = 1.4 Hz, 1 H), 8.34 (d, J = 8.4 Hz, 1 H), 8.85 - 9.0 (d, 2H), 11.61 (s, 1 H); MS (APCI, pos.): 482. 5 EXAMPLE 516: -OHH 0 N.N o N HOH HOc x CH 3 0 2 H 1 H NMR (DMSO-d 6 ) 5 0.95 -1.80 ( m, 1OH ), 1.88 (s, 3H ), 2.45 (m, 1H ), 2.70 -2.90 (m, 2H), 10 3.98-4.30 (m, 3H), 7.02 (d, J = 8.52 Hz, 1H), 7.07 (d, J = 8.2 Hz, H ), 7.52 -- 7.75 (m, 4H), 7.97 (d, J = 2.05 Hz, 1 H), 8.34 (d, J = 8.33 Hz, 1 H), 8.87 - 9.00 (m, 2H), 11.61 (s, 1 H); MS ( APCI, pos.): 496. EXAMPLE 517: 15 3-Chloro-4-hydroxybenzoic acid 4-(3-hydroxypropyl)naphthylmethylene hydrazide 0 OH .- -N N A B C H HO
CO
2 Et OH OH C1 2-[4-(3-Hydroxypropyl)naphthyl]dioxolane (step A): 20 To a solution of 2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxolane (210 mg, 0.70 mmol) in an hydrous THF (5 mL) was added at 00C 1 M lithium aluminum hydride in THF (0.5 mL). THF (5 mL) was added and the mixture was stirred at room temperature for 16 hr, diluted with water (10 mL), acidified with conc. hydrochloric acid, and extracted with ether (3x 10 mL). The combined organic extracts were dried (MgSO 4 ), and concentrated. The residue was pu 25 rifled by flash chromatography using hexane/ethyl acetate 2:1 as eluent to provide 67 mg (37 %) of a colorless oil.
WO 99/01423 PCT/DK98/00287 310 'H NMR (CDC 3 ) 5 1.51 (brd s, 1H), 1.99 - 2.04 (m, 2H), 3.19 (t, J = 7.4 Hz, 2H), 3.75 (t, J = 6.3 Hz, 2H), 4.16 - 4.22 (m, 4H), 6.47 (s, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.52 - 7.70 (m, 2H), 7.70 (d, J = 7.3 Hz, 1H), 8.11 (d, J = 9.8 Hz, 1H), 8.25 (d, J = 9.8 Hz, 1H). GCMS: 258 5 1-Formyl-4-(3-hydroxypropyl)naphthalene (step B): To a solution of 2-[4-(3-hydroxypropyl)naphthyl]dioxolane (67 mg, 0.26 mmol) in anhydrous THF (5 mL) was added 1 N hydrochloric acid (1 mL). The mixture was stirred at room tempe rature for 48 hr, diluted with ethyl ether (20 mL), washed with satd. NaHCO 3 solution (2x 10 10 mL), dried (MgSO 4 ), concentrated and coevaporated with CHCI 3 (3 x 10 mL) to yield 40 mg (72%) of a colorless oil. 1 H NMR (CDC13) 5 1.56 (brd s, 1 H), 2.02 - 2.08 (m, 2H), 3.27 (t, J = 7.5 Hz, 2H), 3.78 (t, J = 6.4 Hz, 2H), 7.53 (d, J = 7.3 Hz, H), 7.62 -7.70 (m, 2H), 7.92 (d, J = 7.3 Hz, 1H), 9.17 (d, J = 15 8.3 Hz, 1H), 9.34 (d, J = 8.6 Hz, 1H), 10.34 (s, 1H). 3-Chloro-4-hydroxybenzoic acid 4-(3-hydroxypropyl)naphthylmethylene hydrazide (step C): This compound was prepared according to the general procedure for the synthesis of alkyli dene hydrazones by condensation of 1-formyl-4-(3-hydroxypropyl) naphthalene from step B 20 and 3-chloro-4-hydroxy benzoic acid hydrazide. 'H NMR DMSO-D 6 ) 5 1.83 (m, 2H), 3.12 (t, J = 7.5 Hz, 2H), 3.51 (dt, J = 4.9, 7.0 Hz, 2H), 7.09 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.65 (m, 2H), 7.80 (dd, J = 2.0, 8.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H),8.19 (dd, J = 2.5, 7.0 Hz, 1H), 8.84 (d, 25 J = 8.4 Hz, 1H), 9.05 (s, 1H), 10.98 (s, 1H), 11.76 (s, 1H). MS (APCI, pos.): 383.1, 385.1. EXAMPLE 518: 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyll naphthyl diethylacrylamide 30 WO 99/01423 PCT/DK98/00287 311 H~~~ ------- NC2t- - CO 2 Et N N C0 2 H HO H A HOC2E B 0 CE C 0 H H OO N O N'CH 3 'CH - --- Nq .- K SN'N
CH
3 D 0 CH 3 E HO I? - H C1 Ethyl (4-hydroxymethyl) naphthalene acrylate (step A): To a suspension of sodium hydride (160 mg, 60% dispersion in mineral oil, 4.00_mmol) in THF (10 mL) at 0 C was added triethylphosphonoacetate (0.77 mL, 670 mg, 3.88 mmol). 5 The mixture was stirred at 00C for 1 hr, and 4-hydroxymethyl naphthaldehyde (600 mg, 3.2 mmol) in THF (5 mL) was added at the same temperature. The mixture was stirred at room temperature for 16 hr, diluted with satd. NH 4 CI-solution (10 mL), and extracted with ethyl acetate (3x 10 mL). The combined organic extracts were dried (MgSO 4 ), and concentrated, to provide 900 mg of a colorless oil, which was used without further purification in the next 10 step. 1 H NMR (CDC 3 ) 5 1.37 (t, J = 7.1 Hz, 3H), 1.86 (brd s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 5.17 (s, 2H), 6.50 (d, J = 15.7 Hz, 1H), 7.54 - 7.62 (m, 2H), 7.70 (d, J = 7.4 Hz, 1H), 8.13 (dd, J = 2.8, 9.8 Hz, 1H), 8.21 (dd, J = 2.8, 9.8 Hz, 1H), 8.49 (d, J = 15.7 Hz, 1H). 15 Ethyl 4-formylnaphthalene acrylate (step B): The crude material (900 mg) from step A was dissolved in chloroform (10 mL), and manga nese dioxide (1.5 g, 17 mmol) was added. After stirring at room temperature for 16 h, the suspension was filtered by suction through Celite, and the filtrate was concentrated. 20 Flash chromatography using hexane/ethyl acetate 5:1 provided 491 mg (60% over 2 steps) of a colorless oil. 1 H NMR (CDC 3 ) 6 1.39 (t, J = 7.1 Hz, 3H), 1.86 (brd s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 6.60 (d, J = 15.7 Hz, 1H), 7.68 - 7.75 (m, 2H), 7.85 (d, J = 7.4 Hz, 1H), 8.00 (d, J = 7.4 Hz, 1H), 25 8.25 (d, J = 8.1 Hz, 1H), 8.50 (d, J = 15.7 Hz, 1H), 9.31 (dd, J = 1.3, 8.1 Hz, 1H), 10.43 (s, 1H). MS (APCI, neg.): 254.1 WO 99/01423 PCT/DK98/00287 312 4-Formylnaphthalene acrylic acid (step C): A suspension of ethyl 4-formylnaphthalene acrylate (391 mg, 1.53 mmol), sodium carbonate (195 mg, 1.84 mmol) in water (10 mL) was refluxed for 16 hr. The cold solution was filtered, 5 and the filtrate was acidified with conc. hydrochloric acid. The precipitate was collected by suction and dried for 48 hr in vacuum to give the product (325 mg, 94%) as a yellow solid. 1 H NMR (DMSO-D 6 ) 5 6.72 (d, J = 15.7 Hz, 1H), 7.71 - 7.75 (m, 2H), 8.12 (d, J = 7.45Hz, 1H), 8.20 (d, J = 7.5 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 15.7 Hz, 1H), 9.21 (d, J = 10 8.0 Hz, 1H), 10.43 (s,1 H). 4-Formylnaphthalene diethyl acrylamide (step D): To a solution of 4-formylnaphthalene acrylic acid (210 mg, 0.92 mmol) in DMF (4 mL) was added carbonyl diimidazole (180 mg, 1.10 mmol). The mixture was stirred at room tempe 15 rature for 1 hr, and diethylamine (0.1 mL, 71 mg, 0.97 mmol) was added. After stirring at room temperature for 16 hr, the mixture was diluted with ethylacetate (5 mL), extracted with water (5 mL), 1 N hydrochloric acid (5 mL), and water (3 x 5 mL), dried (MgSO 4 ) and con centrated. After flash chromatography using hexane/ethylacetate 1 : 1, 115 mg (43%) of a yellow oil was obtained. 20 'H NMR (CDCl 3 ) 5 1.25 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 3.55 (m, 4H), 6.97 (d, J = 15.7 Hz, 1H), 7.63 - 7.76 (m, 2 H), 7.80 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 7.4 Hz, 1H), 8.29 (d, J = 8.3 Hz, 1H), 8.51 (d, J = 15.7 Hz, 1H), 9.30 (d, J = 8.3 Hz, 1H), 10.43 (s, 1H). 25 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl diethylacrylamide (step E): The compound was prepared according to the general procedure for the synthesis of alkyli dene hydrazones from the condensation of 4-formyl-1-naphthyl diethylacrylamide (from step D) and 3-chloro-4-hydroxy benzoic acid hydrazide. 30 1 H NMR (DMSO-D 6 ) 6 1.11 (t, J = 7.0 Hz, 3H), 1.18 (t, J = 7.0 Hz, 3H), 3.42 (q, J = 7.0 Hz, 1H), 3.56 (q, J = 7.0 Hz, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 15.1 Hz, 1H), 7.67 - 7.72 (m, 2H), 7.81 (d, J = 8.3 Hz, 1H), 7.96-8.03 (m, 2H), 8.06 (d, J = 7.7 Hz, 1H), 8.26 (dd, J = WO 99/01423 PCT/DK98/00287 313 2.1, 7.2 Hz, 1H), 8.32 (d, J = 15.1 Hz, 1H), 8.83 (d, J = 7.0 Hz, 1H), 9.13 (s, 1H), 11.00 (s, 1 H), 11.86 (s, 1 H). MS (APC1, pos.): 450.3 EXAMPLE 519: 5 Ethyl 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyll naphthyl acrylate 0 0'CH o N O HO ci The compound was prepared according to the general procedure for the synthesis of alkyli 10 dene hydrazones from the condensation of ethyl 4-formyl-1-naphthyl acrylate (from step B) and 3-chloro-4-hydroxy benzoic acid hydrazide. 1 H NMR (DMSO-D 6 ) S 1.29 (t, J = 7.1 Hz, 3H), 4.25 (q, J = 7.1 Hz, 2H), 6.75 (d, J 15.7 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 7.71 (m, 2H), 7.92 (d, J = 8.5 Hz, 1H), 8.01 (m, 2H), 8.07 (d, J 15 = 8.0 Hz, 1H), 8.46 (d, J = 15.7 Hz, 1H), 8.81 (d, J = 7.1 Hz, 1H), 9.13 (s, 1H), 11.00 (s, 1H), 11.89 (s, 1H). MS (APCI, pos.): 421.1, 423.0 EXAMPLE 520: 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl acrylate 20 0 OH N ' N . N HoH HO(? H ci The compound was prepared according to the general procedure for the synthesis of alkyli dene hydrazones from the condensation of 4-formyl -1-naphthyl acrylate (from step C) and 25 3-chloro-4-hydroxy benzoic acid hydrazide.
WO 99/01423 PCT/DK98/00287 314 'H NMR (DMSO-D6) 5 6.65 (d, J = 15.6 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.66 - 7.74 (m, 2H), 7.81 (d, J = 8.5 Hz, 1H), 7.97 - 8.05 (m, 3H), 8.29 (dd, J = 2.2, 7.1 Hz, 1H), 8.41 (d, J = 15.6 Hz, 1H), 8.82 (d, J = 7.6 Hz, 1 H), 9.12 (s, 1 H), 10.92 (s, 1 H), 11.89 (s, 1H), 12.62 (s, 5 1H). MS (APCI, pos.): 394.1, 395.3 General procedure for the synthesis of substituted piperazine-aryl-aldehydes followed by hy drazone formation: 10 The substituted piperazine-aryl-aldehydes may be prepared by N-alkylation of the correspon ding unsubstituted piperazine-aryl-aldehydes using various electrophilic alkylating agents that introduce the -(K)m-D moiety as defined above.
WO 99/01423 PCT/DK98/00287 315 S H R 3 a R 3 b RA R 4 Lx-(CH 2 )b (CH 2 )a~(M)F(CH 2 ) q (CH 2 )dD
R
1 5 Base, solvent N N H H 4R 3a 4a 4b O N N-(CH 2 )b (CH2)f(M)-(CHc () (CH 2 )d- D
R
15 H N-NH A R 4R R b R4 R 4 b H H / N N-(CH2)b , (CH 2 )-f(M)(CH 2 )( (C N-N O R 15 A wherein Lx is a leaving group such as -Cl, -Br, -1, -OSO 2
CH
3 , -OSO 2 p-tolyl or -OSO 2
CF
3 ; and A, R 3 a, R 3 b, R4a, R 4 b, a, b, c, d, f, p, q, D, M, R1 4 and R' 5 are as defined for formula 1. 5 According to the above scheme the substituted piperazine-aryl-aldehydes can be prepared by stirring piperazinylbenzaldehydes or piperazinylnaphthaldehydes in an organic solvent such as acetone, methylethyl ketone, dimethylformamide, DMSO, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or 10 more of the above solvents with an equimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the presence 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 art butoxide, sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or WO 99/01423 PCT/DK98/00287 316 potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6-collidine or benzyl dimethyl- ammonium methoxide or hydroxide. The reaction can be performed at 00C to 150*C, preferably at 20*C to 100*C and preferably in an inert atmosphere of N 2 or Ar. When the reac tion is complete the mixture is filtered, concentrated in vacuo and the resulting product optio 5 nally purified by column chromatography on silica gel using ethyl acetate/hexane as eluent. The compound can also (when appropriate) be purified by recrystallization from a suitable sol vent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of unsubstituted piperazine aryl-aldehydes are provided below. 10 The following step, the hydrazone formation is described above in general and below in detail. Preparation of 4-piperazinyl-2.5-dimethylbenzaldehyde: 15 4-(2,5-dimethylphenyl)-1 -benzylpiperazine: A solution of 2,5-dimethylphenylpiperazine (20 g, 105 mmol) was prepared in acetonitrile (300 mL) and cooled to 0 OC. Benzyl bromide (19 g, 111 mmol) was added and the reaction mixture was stirred for 15 minutes before potassium carbonate (16 g, 116 mmol) was added. After stirring the mixture for two hours, the acetonitrile was evaporated and the residue taken 20 up in water and ethyl acetate. The organic layer was separated and washed with brine and dried over magnesium sulfate. The benzylated product was purified by silica gel column chromatography using gradient hexane/ethyl acetate (10/0 to 8/2). The product (21 g, 71%) was obtained as an oil. 25 1 H NMR (CDC 3 ) 5 2.24 (s, 3H), 2.29 (s, 3H), 2.60 (brd s, 4H), 2.92 (brd s, 4H), 3.55 (s, 2H), 6.78 (m, 1H), 6.84 (s, 1H), 7.04 (m, 1H), 7.30 (m, 5H). 4-(2,5-dimethyl-4-formylphenyl)-1 -benzylpiperazine: The 4-(2,5-dimethylphenyl)-1-benzylpiperazine (10 g, 36 mmol) was dissolved in anhydrous 30 DMF (30 mL, 390 mmol) and cooled to 0 OC. Fresh POC13 (70 mL, 750 mmol) was added drop wise with stirring. Once the addition was completed the dark mixture was warmed to 75 0C for five hours or until TLC analysis indicated the disappearance of the starting materi- WO 99/01423 PCT/DK98/00287 317 al. The excess phosphorous oxychloride was distilled off and the entire mixture was diluted with ethyl acetate and added slowly to 500 mL of ice-chips. The solution was neutralized and made basic with concentrated NaOH. The neutralization and basification must be done at low temperatures to avoid creating by-products. The formylated product was extracted 5 with ethyl acetate (5x). The organic layer was washed with water (2x), brine, dried over magnesium sulfate and purified by silica gel column chromatography using gradient hexa ne/ethyl acetate (10/0 to 8/2). The product (9 g, 81%) was obtained as an oil. H NMR (CDCl 3 ) 6 2.29 (s, 3H), 2.28 (s + t, 7H), 3.03 (t, 4H), 3.59 (s, 2H), 6.75 (s, 1H), 7.31 10 (m, 5H), 7.58 (s, 1H), 10.12 (s, 1H). 4-(2,5-dimethyl-4-formylphenyl)-1 -(1 -chloroethoxycarbonyl)piperazine: The 4-(2,5-dimethyl-4-formylphenyl)-1-benzylpiperazine (9 g, 29 mmol) was dissolved in an hydrous 1,2-dichloroethane (100 mL) and 1-chloroethyl chloroformate (4.5 g, 31.5 mmol) 15 was added. The solution was refluxed for 30 minutes or until TLC analysis indicated the disappearance of the starting material. The product was just slightly less polar than the star ting material by TLC using hexane/EtOAc (3/1). Dichloroethane was evaporated and the residue was chromatographed using gradient hexane/EtOAc (10/0 to 8/2) to give the product (6 g, 64%) as an oil. 20 1 H NMR (CDCl 3 ) 5 1.84 (d, 3H), 2.32 (s, 3H), 2.61 (s, 3H), 2.99 (brd m, 4H), 3.70 (brd m, 4H), 6.62 (qt, 1H), 6.76 (s, 1H), 7.62 (s, 1H), 10.14 (s, 1H). 4-piperazinyl-2,5-dimethylbenzaldehyde: 25 To a solution of the dimethylphenylpiperazinylcarbamate above (6 g, 18.5 mmol) in THF (50 mL) was added 1 N HCI (50 mL, 50 mmol). The mixture was warmed to approximately 80 OC until the evolution of C02 stopped. Most of the THF was removed by rotary evaporation and the residue was lyophilized to give the product as the dihydrochloride salt (5.5 g, 99%). 30 'H NMR (DMSO-D 6 ) 5 2.2 (s, 3H), 2.50 (s, 3H), 3.13 (brd s, 8H), 6.85 (s, 1H), 7.54 (s, 1H), 9.49 (brd s, 2H), 10.02 (s, 1H).
WO 99/01423 PCT/DK98/00287 318 4-piperazinyl-2.3-dimethylbenzaldehyde: 4-Piperazinyl-2,3-dimethylbenzaldehyde was prepared in the same fashion as above. For 5 mylation of the N-benzyl-piperazinyl-2,3-dimethylbenzene was much slower and required overnight heating at 70 OC. All other steps were otherwise very similar and the yields were comparable. 1 H NMR (DMSO-D 6 ) 5 2.15 (s, 3H), 2.47 (s, 3H), 3.07 (brd m, 4H), 3.17 (brd m, 4H), 5.90 10 (brd s, 1H, NH), 7.02 (d, 1H), 7.50 (d, 1H), 9.54 (brd s, 2H, NH2), 10.10 (s, 1H). 4-piperazinyl-3.5-dimethylbenzaldehyde: 4-Piperazinyl-3,5-dimethylbenzaldehyde was prepared in the same manner as above. 15 General library procedure for N-alkylation and hydrazone formation: To a solution of the unsubstituted piperazinyl-aryl-aldehyde in DMSO dispensed into 88 deep well plates were added solutions of desired alkylating agents (1 eq) in DMSO followed by 20 diisopropylethylamine (5 eq). Solid potasssium carbonate (5 eq) may also be substituted. After stirring the solutions for 16 hours, a solution of 4-hydroxybenzoic acid hydrazide deri vative (1 eq) in DMSO and a solution of acetic acid (catalytic) in DMSO were added into e ach well. The reaction mixtures were agitated for 16 hours to give the crude products which were purified by HPLC. 25 Examples of products: EXAMPLE 521 : WO 99/01423 PCT/DK98/00287 319 O H 3 C : . NI ) 'CN N, a N H HO CI 'H NMR (DMSO-D 6 ): 5 2.26 (s, 3H), 2.38 (s, 3H), 2.65 (brd s, 4H), 2.73 (t, 2H), 2.89 (brd s, 4H), 4.07 (t, 2H), 6.03 (d, 2H), 6.84 (t, 2H), 7.02 (d, 1H), 7.13 (d, 1H), 7.72 (d, 1H), 7.82 (dd, 5 1H), 8.01 (s, 1H), 8.86 (brd s, 1H), 11.68 (brd s, 1H); MS (APCI): 480.7, 482.3. EXAMPLE 522: CH 3rl N 0 NO NN / HO .NCH C1 10 'H NMR (DMSO-D): 8 2.49 (s, 6H), 2.68 (brd s 4H), 3.22 (brd s, 4H), 3.72 (s, 2H), 7.22 (d, 1H), 7.44 (m, 1H), 7.52 (m, 6H), 7.92 (dd, 1H), 8.13 (s, 1H), 8.46 (s, 1H), 11.12 (brd s, 1H), 11.80 (s, 1 H); MS (APCI): 477.5, 479.2. 15 EXAMPLE 523:
CH
3 r' N O H 3 C N/ CH 3 N. N CH 3 H HO CI 'H NMR (DMSO-D 6 ): 5 1.25 (s, 3H), 1.27 (s, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 2.57 (brd s, 4H), 20 2.95 (brd s, 4H), 3.56 (s, 2H), 7.02 (d, 1H), 7.12 (d, 1H), 7.30 (qt, 4H), 7.72 (d, 1H), 7.82 (d, 1H), 8.01 (s, 1H), 8.83 (s, 1H), 11.0 (brd s, 1H), 11.1 (s, 1H); MS (APCI): 519.7, 521.5.
WO 99/01423 PCT/DK98/00287 320 EXAMPLE 524: CH3r' N H:,C N j N .N N O H HO C1 'H NMR (DMSO-D 6 ): 6 2.22 (s, 3H), 2.33 (s, 3H), 3.17 (brd s, 4H), 3.23 (m, 2H), 3.36 (m, 5 2H), 4.41 (s, 2H), 6.98 (d, 1H), 7.10 (d, 1H), 7.48 (m, 3H), 7.68 (m, 3H), 7.71 (d, 1H), 7.97 (s, 1 H), 8.83 (s, 1 H), 11.00 (s, 1 H), 11.02 (brd s, 1 H), 11.69 (s, 1 H); MS (APCI): 477.4, 479.2. EXAMPLE 525:
CH
3 (N NO2 O H 3 C N ' N N. N HO H HO 10 C1 'H NMR (DMSO-D 6 ): 5 2.20 (s, 3H), 2.31 (s, 3H), 2.59 (s, 4H), 2.87 (s, 4H), 3.69 (s, 2H), 6.98 (d, 1H), 7.02 (d, 1H), 7.64 (m, 2H), 7.75 (dd, 1H), 7.82 (d, 1H), 7.94 (d, 1H), 8.12 (dd, 1H), 8.19 (s, 1H), 8.74 (s, 1H), 10.94 (brd s, 1H), 11.54 (s, 1H); MS (APCI): 522.2, 524.3. 15 EXAMPLE 526:
CH
3 N .O N NN.N I H HO CI 'H NMR (DMSO-D 6 ): 6 2.20 (s, 3H), 2.31 (s, 3H), 2.62 (brd s, 4H), 2.87 (brd s, 4H), 3.68 (s, 20 2H), 6.98 (d, 1H), 7.04 (d, 1H), 7.55 (d, 1H), 7.61 (d, 1H), 7.74 (dd, 1H), 7.91 (s, 1H), 7.92 (d, 1H), 8.01 (d, 1H), 8.74 (s, 1H), 10.93 (brd s, 1H), 11.54 (s, 1H); MS (APCI): 519.2, 521.3.
WO 99/01423 PCT/DK98/00287 321 EXAMPLE 527: H N N HO .N CH3 HOH C1 'H NMR (DMSO-D 6 ): 8 2.21 (s, 3H), 2.37 (s, 3H), 2.66 (brd s, 4H), 2.91 (brd s, 4H), 3.76 (s, 5 2H), 6.83 (s, 1H), 7.05 (d, 1H), 7.62 (s, 1H), 7.69 (s, 1H), 7.75 (dd, 1H), 7.86 (d, 2H), 7.94 (s, 1H), 8.15 (d, 2H), 8.60 (s, 1H), 10.92 (brd s, 1H), 11.55 (s, 1H); MS (APCI): 628.3, 630.2, 631.2. General procedure for the synthesis of N-substituted indole aldehydes followed by hydrazo ne formation: 10 The N-substituted indole aldehydes may be prepared by N-alkylation of the corresponding un substituted indole aldehydes using various electrophilic alkylating agents that introduce the (K)m-D moiety as defined above.
WO 99/01423 PCT/DK98/00287 322 3a 3ba R R R 4 a R 4 b 0 H R Lx-(CH 2 )b P (CH 2 )a~(M)F-(CH2) q (CH 2 )d D
R
15 Base, solvent STEP A 0 H 4
R
4 R3a R3b R4a R R13 N-(CH 2 )b p (CH 2 ) (M),-(CH 2 ) q (CH2d D A O-NH 2 STEP B A A I R4-N H R R
R
1 5
N-(CH
2 )b p (CH 2 )a(M)r-(CH 2 )c q (CH 2 )d 0 wherein Lx is a leaving group such as -Cl, -Br, -1, -OSO 2
CH
3 , -OSO 2 p-tolyl or -OS0 2
CF
3 ; and A, R 3 " , R 3 b, R 4 , a, b, c, d, f, p, q, D, M, R 14 and R 5 are as defined for formula 1. 5 According to the above scheme the N-substituted indole aldehydes can be prepared by stir ring formylindoles in an organic solvent such as acetone, methylethyl ketone, dimethylforma mide, DMSO, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, di ethylether, water or a compatible mixture of two or more of the above solvents with an e 10 quimolar amount of an alkyl halide or an aryl-lower alkyl halide and in the presence of 1 to 15 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydri de, sodium or potassium methoxide, ethoxide or tert-butoxide, sodium, potassium 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 hy 15 droxide. The reaction can be performed at O*C to 1500C, preferably at 200C to 100*C and WO 99/01423 PCT/DK98/00287 323 preferably in an inert atmosphere of N 2 or Ar. When the reaction is complete the mixture is fil tered, concentrated in vacuo and the resulting product optionally purified by column chromato graphy on silica gel using ethyl acetate/hexane as eluent. The compound can also (when ap propriate) be purified by recrystallization from a suitable solvent such as ethyl alcohol, ethyl 5 acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. The following step, the hydrazone formation is described above in general and below in detail. 10 Library Procedure for Indole Alkylation (Step A): Preparation of the sodium salt of the indole: Indole-3-carboxaldehyde (1.45 g) was dissolved into 8.6 mL of dry DMF in a dried and cooled 3 100 mL 3-necked roundbottom flask. 15 Evolution of large amounts of hydrogen gas occurs during this step. Care should be taken to keep the flow of inert gas steady and maintain adequate venting to accommodate the hydrogen gas evolution. While maintaining a steady flow of nitrogen or argon through the 3-necked round bottomed 20 flask, 1.1 equivalent of sodium hydride (0.27 g of dry 95% reagent) was transferred to the indole solution. The mixture was stirred for 15 minutes, while maintaining flow of inert gas. Proceeded promptly to the next step. Preparation of the alkyl halide solutions: 25 Amber glass vials (for preparing stock solutions) were dried for at least four hours at 110 0C, then were allowed to cool under an argon atmosphere in a desiccator. Alkyl halides solutions (1.0 M) were prepared in anhydrous DMF in the dried vials. Each alkyl halide solution (100 pL) was added to its corresponding well of a deep-well plate (1 x 88 x 1 for mat). 30 WO 99/01423 PCT/DK98/00287 324 Alkylation of the indole sodium salt: 100 pL of the 1.0 M indole salt solution was quickly delivered to each alkyl halide in the de ep-well plates. The plates were vortexed briefly to mix, then allowed to react for two hours. 5 Library Procedure for Hydrazone Formation (Step B): Acyl Hydrazone formation: 3-Chloro-4-hydroxybenzoic acid hydrazide (1.86 g) was dissolved in 5 mL of dry DMSO, followed by trifluoroacetic acid (0.77mL). The resulting solution was diluted to a final volu me of 10.0 mL. 100 pL of the 1.0 M acid hydrazide TFA salt solution was added to each 10 well of the deep-well plate. The plate was vortexed for one minute to mix, then allowed to react for 30 minutes. The products were purified by chromatography on silica gel with ethyl acetate/hexane elu ent. 15 The following compounds were prepared: EXAMPLE 528: 0 NJ_ o .NN H cl 20 1 H NMR (DMSO-D 6 ): 6 5.46 (s, 2H), 7.10 (d, J = 8.7, 2H), 7.20 (m, 2H), 7.28 (m, 5H), 7.51 (d, J = 7.53, 1H), 7.79 (d, J = 7.9, 1H), 7.99 (s, 1H), 8.01 (s, 1H) 8.33 (d, J = 6.96, 1H), 8.62 (s, 1 H), 10.9 (s, 1 H), 11.5 (s, 1 H); LRMS calcd for C26 H 2 4 Cl, N 3 02 (M - H) 402, found 402.1. 25 WO 99/01423 PCT/DK98/00287 325 EXAMPLE 529:
H
3 C
CH
3 0 HO . Cl 'H NMR (DMSO-D 6 ): 6 1.14 (d, J = 6.8, 6H), 2.81 (sept, J = 6.9, 1H), 5.41 (s, 2H), 7.07 (d, J 5 = 8.3, 1H), 7.20 (m, 6H), 7.54 (d, J = 7.6, 1H), 7.77 (d, J = 7.9, 1H), 7.97 (s, 1H), 8.01 (s, 1 H), 8.29 (d, J = 7.2, 1 H), 8.59 (s, 1 H), 10.88 (s, 1 H), 11.44 (s, 1 H). LRMS calcd for C2, H 2 4 Cl1 N 3 02 (M - H) 445, found 445.9 EXAMPLE 530: F 0--- H HO 10 C1 'H NMR (DMSO-D 6 ): 6 5.47 (s, 2H), 7.08, (d, J = 8.7, 1H), 7.13-7.25 (m, 5H), 7.18 (t, J = 74.2, 1H), 7.35 (d, J = 8.7, 1H), 7.54 (d, J = 7.9, 1H), 7.77 (dd, J = 8.7, 1.7, 1H), 7.97 (d, J = 1.7, 1H), 8.02 (s, 1H), 8.30 (d, J = 7.2, 1H), 8.59 (s, 1H), 10.89 (s, 1H), 11.45 (s, 1H). LRMS 15 calcd for C24 H 1 8 Cl1 F 2
N
3 03 (M - H) 468, found 468.1. EXAMPLE 531:
CH
3 0 N N.N
CH
3 HOH Cl 20 1 H NMR (DMSO-D 6 ): 6 0.94 (d, J = 6.2, 6H), 1.54 (sept, J = 6.2, 1H), 1.66-1.73 (m, 2H), 4.23 (t, J = 7.0, 2H), 7.08 (d, J = 8.7, 1H), 7.16-7.29 (m, 2H), 7.54 (d, J = 7.95, 1H), 7.77 (d, WO 99/01423 PCT/DK98/00287 326 J = 8.7, 1H), 7.88 (s, 1H), 7.97 (s, 1H), 8.29 (d, J = 7.5, 1H), 8.57 (s, 1H), 10.88 (s, 1H). 11.42 (s, 1 H). LRMS calcd for C21 H22 Cl, N 3 02 (M + H) 384, found 384.2. EXAMPLE 532: 0 H .N NH IO:? H 5 ci 'H NMR (DMSO-D 6 ): 8 7.06 (d, J = 8.5, 1H), 7.12-7.26 (m,3H), 7.46-7.49 (M,2H), 7.78 (d, J = 8.1, 1 H), 7.99 (s, 1 H), 11.33 (s, 1 H), 11.65 (s, 1 H). LRMS calcd for C1. H 1 2 C1, N 3 02 (M H) 312, found 312.0. 10 General procedure for the synthesis of alkyl/aryl-sulfonyloxy aryl-aldehydes followed by hy drazone formation: The alkyl/aryl-sulfonyloxy aryl-aldehydes may be prepared by 0-sulfonylation of the corre 15 sponding phenolic compounds using various electrophilic sulfonylating agents that introduce the -(K)m-D moiety as defined above.
WO 99/01423 PCT/DK98/00287 327 R3a R3b4a Rb H R' R3 R~ R 4 b 1 4 O R Lx-SO2- (CH2A )p (CH 2 )a~(M)F-(CH2)c q (CH 2 )d-D R OH Base, solvent H R3 R 3 b R 4 b OSO2-(CH 2 )b p (CH 2 )a-(M)F-(CH 2 )c ) (CH 2 )d D AOj A-_ A O
'NH
2 N, N
R
14 \ H R3 R 3 b R4a R4 R 1 OSO2-(CH 2 )b p(C H 2 )a-(M)-(CH 2 )1 ( (CH2d wherein Lx is a leaving group such as -CI, -Br, -1, -OSO 2
CH
3 , -OSO 2 p-tolyl or -OSO 2
CF
3 ; and A, R 3 a, R 3 b, R 4 a, R 4 b, a, b, c, d, f, p, q, D, M, R 1 4 and R 1 5 are as defined for formula 1. 5 According to the above scheme an alkyl/aryl-sulfonyloxyaryl aldehyde can be prepared by stir ring hydroxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as aceto ne, methylethyl ketone, dimethylformamide, dioxane, tetrahydrofuran, toluene, ethylene glycol dimethyl ether, sulfolane, diethylether, water or a compatible mixture of two or more of the above solvents with an equimolar amount of an alkylsulfonylhalide, arylsulfonylhalide or an a 10 ryl-lower alkyl sulfonylhalide and in the presence of 1 to 15 equivalents (preferably 1 to 5 equi valents) of a base such as sodium hydride, potassium hydride, sodium or potassium methoxi de, ethoxide or tert-butoxide, sodium, potassium or cesium carbonate, potassium or cesium fluoride, sodium or potassium hydroxide or organic bases such as diisopropylethylamine, 2,4,6- WO 99/01423 PCT/DK98/00287 328 collidine or benzyldimethyl- ammonium methoxide or hydroxide. The reaction can be perfor med at 0*C to 150*C, preferably at 200C to 100*C and preferably in an inert atmosphere of N 2 or Ar. When the reaction is complete the mixture is filtered, concentrated in vacuo and the re sulting product optionally purified by column chromatography on silica gel using ethyl aceta 5 te/hexane as eluent. The compound can also (when appropriate) be purified by recrystallizati on from a suitable solvent such as ethyl alcohol, ethyl acetate, isopropyl alcohol, water, hexa ne, toluene or their compatible mixture. The following hydrazone formation step is described above in general. 10 Examples of compounds synthesized using the methodology described are given below: EXAMPLE 533: ci 0 s N N.N O H HO ci 15 1 H NMR (DMSO-D 6 ): 6 7.03 (d, 1H), 7.28 (d, 1H), 7.39 (d, 1H), 7.61 (t, 1H), 7.67 (t, 1H), 7.75 (m, 2H), 7.87 (d, 2H), 7.95 (s, 1H), 8.75 (d, 1H), 9.02 (s, 1H), 11.00 (s, 1H), 11.88 (s, 1H); MS (APCI): 521.0, 523.0. 20 EXAMPLE 534: cH 3 0 s CH 3 N.N N 0 0 I H HO cl 'H NMR (DMSO-D): 5 1.38 (d, 6H), 3.91 (septet, 1H), 6.97 (d, 1H), 7.46 (d, 1H), 7.61 (m, 2H), 7.71 (d, 1H), 7.81 (d, 1H), 7.89 (s, 1H), 8.01 (d, 1H), 8.69 (d, 1H), 9.11 (s, 1H), 11.00 25 (brd s, 1H), 11.98 (s, 1H); MS (APCI, neg.): 445.0, 487.0, 339 - iprso 2
.
WO 99/01423 PCT/DK98/00287 329 5 General procedures for the preparation of alkylidene hydrazides according to the invention involving parallel synthesis on a solid support: The compounds of Examples 535 to 614 were prepared according to the following equation Resin [Building block 1] Resin [Building block 1]- [Building block 2] 10 Resin [Building block 1]- [Building block 2]- [Building block 3] and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula 15 [Building block 1]- [Building block 2]- [Building block 3]. The following 80 compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block 1]-[Building block 2] was done manually, 20 whereas the attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS. The starting resins, Resin-[Building block 1]-[Building block 2], were all prepared as de scribed below. 25 The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g.
WO 99/01423 PCT/DK98/00287 330 All 80 compounds are based on attachment of [Building block 3] to Resin-[Building block 1] [Building block 2] in a fully combinatorial way using a Heck reaction according to the follow ing scheme: [Building block 3] 0-R c 0 N~B~ cil N,.. B-Lea CI ,NFt B -~ R Rein .- Resin, .-5 i03 Pd catalyst Resin-[Building block 1]-[Building block 2] Resin-[Building block 1]-[Building block 2]-[Building block 3] R Lea R1 where B-Lea is )i M Lea or RJc 5 wherein Lea is a leaving group and preferably is selected from bromo, iodo and trifluoromethanesulfonyloxy, and R 1 4 and R" are as defined for formula I. The following resin, here depicted as Resin-[Building block 1] was used: 0 where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker: where = Resin WO 99/01423 PCT/DK98/00287 331 The following building blocks were used: [Building block 21: 3,4-dimethoxy-5-iodobenzaldehyde 3-Bromobenzaldehyde O H O H CH30 I Br
OCH
3 Trifluoromethanesulfonic acid 4-formyl-1- 4-Bromobenzaldehyde naphthyl ester 0 H O H Br 0
-
0 o s, F'4 F WO 99/01423 PCT/DK98/00287 332 [Buildina block 31: 1 -Ethynylcyclohexylamine 2-Amino-4-pentynoic acid H 0
NH
2 OH H NH 2 N-Methyl-N-propargylbenzylamine Propargylamine N _
NH
2 H CH, H N, N-Diethylpropargylamine Phenyl propargyl ether H 5 NCH3 H 3-Phenyl-1 -propyne Ethynyl p-tolyl sulfone 0 0 CH HH S~ CH WO 99/01423 PCT/DK98/00287 333 1 -Chloro-4-ethynylbenzene 3-Ethynylphenol HCI H O aOH 5-Phenyl-1-pentyne 2-Ethynylpyridine H H 5-Phenyl-2-(2-propynylamino)-2-oxazolin-4- tert-Butyl propiolate one 0 I O H 3 H 0 H N N O H H 4-Pentynoic acid tert-Butyl 1-methyl-2-propynyl ether OH
CH<H
3 H 0 <H 3 H H C WO 99/01423 PCT/DK98/00287 334 3-Butyn-1 -ol 5-Hexyn-3-ol OH CH3 H H OH 0-Trimethylsilylpropargyl alcohol 3-(2,6-Dichlorophenoxy)prop-1 -yne
CH
3 I CH 3 0' siCH 0 H H ci By combination of these building blocks in a fully combinatorial way 1x4x20 = 80 compounds were prepared. 5 Preparation of [Building block 2]: Preparation of 3,4-dimethoxy-5-iodobenzaldehyde: lodomethane (2.5 mL, 40 mmoles) was added to a mixture of 5-iodovanillin (10 g, 36 10 mmoles), potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mix ture was stirred at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with water (200 mL), dried over MgSO 4 and evaporated in vacuo to afford 9.78 g (93%) of 3,4-dimethoxy-5-iodobenzaldehyde, m.p. 58-63 *C. 15 Preparation of trifluoromethanesulfonic acid 4-formyl-1-naphthyl ester: 4-Hydroxy-1-naphthaldehyde (10 g, 58 mmoles) was dissolved in pyridine (50 ml) and the mixture was cooled to 0 *C. Trifluoromethanesulfonic anhydride (11.7 mL, 70 mmoles) was added dropwise while maintaining the temperature below 5 0C. When the addition was com 20 pleted the mixture was stirred at room temperature for 30 minutes. Diethyl ether (200 mL) was added and the mixture was successively washed with water (2 x 250 mL), 3 N hydro chloric acid (200 mL), and saturated NaCl (200 mL). The organic phase was dried over MgSO 4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:4). Pure fractions WO 99/01423 PCT/DK98/00287 335 eluting with Rf = 0.46 were pooled and evaporated in vacuo to afford 8.35 g (47 %) of trifluoromethanesulfonic acid 4-formyl-1-naphthyl ester, m.p. 44-47 *C. The other [Building block 2]'s (3-Bromobenzaldehyde and 4-bromobenzaldehyde) are com mercially available. 5 Preparation of Resin-[Building block 1]: (Resin bound 3-chloro-4-hydroxybenzoic acid hydrazide) Polystyrene resin (15 g) loaded with the Wang linker (0.92 mmoles/g), was successively washed with DMF (3 x 40 mL) and CH 2 Cl 2 (3 x 40 mL). The resin was suspended in CH 2 C1 2 10 (80 mL) and diisopropylethylamine (60 mL) was added. The mixture was cooled to OC and methanesulfonyl chloride (5.8 mL) dissolved in CH 2 Cl 2 (30 mL) was added drop wise while maintaining the temperature below 5 0C. When addition was complete the mixture was stirred at 0 0C for 30 minutes and at room temperature for 30 minutes. The resin was suc cessively washed with CH 2 Cl 2 (3 x 80 mL) and N-methylpyrrollidone (NMP) (3 x 80 mL). This 15 resin and cesium carbonate (12.3 g) were added to ethyl 3-chloro-4-hydroxybenzoate (15 g) dissolved in NMP (200 mL) and the mixture was stirred at 80 0C for 4 hours. After cooling the resin was successively washed with NMP (3 x 80 mL) and methanol (3 x 80 mL). The above resin was suspended in 1,4-dioxane (150 mL) and water (36 mL). Lithium hy 20 droxide (2.6 g) was added and the mixture was stirred at 60 0C under N 2 for 16 hours. After cooling the resin was successively washed with DMF (3 x 80 mL), CH 2 Cl 2 (3 x 80 mL) and methanol (80 mL) and dried in vacuo at 50 0C for 3 days. The above resin (3.0 g) was suspended in CH 2 Cl 2 (20 mL) and 1-hydroxybenzotriazole (0.6 25 g), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, hydrochloride (0.9 g) and DMF (10 mL) were added. The mixture was shaken at room temperature for 45 minutes, hydrazine hy drate (300 pL) was added, and the mixture was shaken overnight at room temperature. The resin was successively washed with DMF (3 x 20 mL) and CH 2 Cl 2 (3 x 20 mL) to afford resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (Resin-[Buildinq block 1]). 30 Preparation of Resin-[Building block 11-[Building block 2]: Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (3,4-dimethoxy-5-iodobenzyli dene)hydrazide: WO 99/01423 PCT/DK98/00287 336 The above resin (Resin-[Building block 1]) (4 g) was suspended in DMF (50 mL) and 3,4-dimethoxy-5-iodobenzaldehyde (5.8 g) and triethyl orthoformate (25 mL) were added and the mixture was shaken for 16 hours at room temperature. The resin was suc cessively washed with DMF (4 x 40 mL) and CH 2 Cl 2 (6 x 40 mL), and dried in vacuo at 50 0C 5 for 16 hours to afford resin bound 3-chloro-4-hydroxybenzoic acid (3,4-dimethoxy-5 iodobenzylidene)hydrazide. Preparation of resin bound trifluoromethanesulfonic acid 4-[(3-chloro-4-hydroxybenzoyl) hydrazonomethyl]naphthalen-1-yl ester: 10 Similarly as described above but using trifluoromethanesulfonic acid 4-formyl-1-naphthyl ester instead of 3,4-dimethoxy-5-iodobenzaldehyde resin bound was trifluoromethanesulfo nic acid 4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]naphthalen-1 -yl ester obtained. Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide: 15 Similarly as described above but using 3-bromobenzaldehyde instead of 3,4-dimethoxy-5 iodobenzaldehyde resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydra zide) was obtained. Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (4-bromobenzylidene)hydrazide: 20 Similarly as described above but using 4-bromobenzaldehyde instead of 3,4-dimethoxy-5 iodobenzaldehyde resin bound 3-chloro-4-hydroxybenzoic acid (4-bromobenzylidene) hydrazide) was obtained.
WO 99/01423 PCT/DK98/00287 337 EXAMPLE 535: O. CH3 0 / C H3 H HO CI H 2 N 3-Chloro-4-hydroxybenzoic acid [3-(1 -aminocyclohexylethynyl)-4.5-dimethoxybenzylidenel hydrazide 5 To the resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide (0.05 mmoles) was added copper (1) iodide (10 mg). Diisopropylethylamine (0.2 mL), a solution of triphenylphosphine in NMP (0.4 M, 0.5 mL), a solution of tetrabutylammonium chloride in water (0.66 M, 0.3 mL), a solution of palladium (II) acetate in NMP (0.16 M, 0.25 mL) and a 10 solution of 1-ethynylcyclohexylamine ([Building block 3]) in NMP (1 M, 0.5 mL) were added successively, and the mixture was shaken at 90 OC for 15 hours. The resin was repeatedly washed with NMP (1.5 mL, 3 times), 50% water in DMF (1.5 mL, 3 times), NMP (1.5 mL, 2 times), 1% sodium diethylaminodithiocarbamate trihydrate (1.5 mL, 9 times), NMP (1.5 mL, 5 times), and CH 2 Cl 2 (1.5 mL, 6 times) for 2 minutes and filtered. 15 The compound was cleaved off the resin by shaking for 45 minutes at room temperature with a 50% solution of trifluoroacetic acid in CH 2
CI
2 (1.5 mL). The mixture was filtered and the resin was extracted with CH 2 Cl 2 (0.5 mL). The combined CH 2
CI
2 extracts were concentrated in vacuo. The residue was dissolved in a 1:1 mixture of methanol and CH 2 Cl 2 (1 mL) and 20 concentrated in vacuo to give the title compound. The final product obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass). 25 The RP-HPLC analysis was performed on a Waters HPLC system consisting of WatersTM 600S Controller, WaterSTM 996 Photodiode Array Detector, WatersTM 717 Autosampler, Wa tersTM 616 Pump, WatersTM 3 mm x 150 mm 3.5 p C-18 Symmetry column and Millenium WO 99/01423 PCT/DK98/00287 338 QuickSet Control Ver. 2.15 using UV detection at 214 nm. A gradient of 5% to 90% acetoni trile/0.1% trifluoroacetic acid/water during 15 minutes at 1 mL/minute. The LC-MS analysis was performed on a PE Sciex API 100 LC/MS System using a WatersTM 5 3 mm x 150 mm 3.5 p C-18 Symmetry column and positive ionspray with a flow rate at 20 pL/minute. Examples 536 to 614: A library of the following 79 compounds can be prepared in parallel as individual entities analogously to example 535 on an Advanced ChemTech Model 384 HTS using the following 10 ChemFile to control the operation of the synthesizer. The 4 resins of type Resin-[Building block 1]-[Building block 2] are equally distributed in the 80 wells in the syntheziser prior to the initialization of the device. ChemFile C:\ACT\90250004.CHM Page 1 15 1 Empty RBHeatingAll_1to36 for 2.000 minute(s) 2 REM Addition of DIPEA 3 Transfer 200pl from Monomers_1to36 [25] ()to RBHeating_All_1to96 [1-80] using DCE 4 Mix for 1.00 minutes at 600 rpm(s) 5 REM Addition of Ph3P in NMP 20 6 Transfer 500pl from Monomers_1to36 [21] ( to RB HeatingAll_1to96 [1-80] using DCE 7 REM Addition of Bu4NCI in water 8 Transfer 300pl from Monomers 1to36 [22] 0 to RB Heating_All_1to96 [1-80] using DCE 9 Mix for 1.00 minutes at 600 rpm(s) 10 REM Addition of Pd(OAc)2 in NMP 25 11 Transfer 250pl from Monomers_1to36 [22] () to RB_HeatingAll_1to96 [1-80] using DCE 12 Mix for 2.00 minutes at 600 rpm(s) 13 Dispense Sequence C:\ACT\ALKYNES.DSP with 500pl to RB_HeatingAll_1to96 rack 14 Set Temperature to 90.0 degrees Celsius 15 Mix for 15.00 minutes at 600 rpm(s) 30 16 Wait for 15.000 minute(s) 17 Repeat from step 15, 47 times 18 Turn Temperature Controller Off 19 Mix for 15.00 minutes at 600 rpm(s) 20 Wait for 15.000 minute(s) 35 21 Repeat from step 19, 7 times 22 Empty RB Heating_All_1to96 for 2.000 minute(s) 23 Dispense System Fluid NMP1 1500pI to RB_CleavageAll_1to96 [1-80] 24 Mix for 3.00 minutes at 600 rpm(s) 25 Empty RBHeating_All_1to96 for 2.000 minute(s) 40 26 Repeat from step 23, 2 times 27 REM Wash with 50% H20/NMP WO 99/01423 PCT/DK98/00287 339 28 Transfer 1500pl from Reagent 3 [1] () to RB_HeatingAll_1to96 [1-80] using NMP1 29 Mix for 3.00 minutes at 600 rpm(s) 30 Empty RBHeating_All_1to96 for 2.000 minute(s) 31 Repeat from step 28, 2 times 5 32 Dispense System Fluid NMP1 1500pl to RBCleavageAll_1to96 [1-80] 33 Mix for 3.00 minutes at 600 rpm(s) 34 Empty RBHeating_All_1to96 for 2.000 minute(s) 35 Repeat from step 32, 1 times 36 REM Wash with Sodium diethylaminodithiocarbamate 10 37 Transfer 1500pl from Reagent 3 [1] () to RB_HeatingAll_1to96 [1-80] using NMP1 38 Mix for 3.00 minutes at 600 rpm(s) 39 Empty RBHeating_All_1to96 for 2.000 minute(s) 40 Repeat from step 37, 2 times 41 Transfer 1500pl from REAGENT_4 [1] () to RBHeatingAll_1to96 [1-80] using NMP1 15 42 Mix for 3.00 minutes at 600 rpm(s) 43 Empty RBHeating_All_1to96 for 2.000 minute(s) 44 Repeat from step 41, 2 times 45 Transfer 1500pl from REAGENT_5 [1] () to RBHeatingAll_1to96 [1-80] using NMP1 46 Mix for 2.00 minutes at 600 rpm(s) 20 47 Empty RB Heating_All_1to96 for 2.000 minute(s) 48 Repeat from step 45, 2 times 49 Dispense System Fluid NMP1 1500pl to RBCleavageAll_1to96 [1-80] 50 Mix for 3.00 minutes at 600 rpm(s) 51 Empty RBHeating_All_1to96 for 2.000 minute(s) 25 52 Repeat from step 49, 4 times 53 Dispense System Fluid DCE1 1500pl to RBCleavageAll_1to96 [1-80] 54 Mix for 3.00 minutes at 600 rpm(s) 55 Empty RBHeating_All_1to96 for 2.000 minute(s) 56 Repeat from step 53, 5 times 30 57 REM Cleavage from Resin 58 REM with 50% TFA/DCM 59 Transfer 1500pl from Reagent _3 [1] ( to RB_CleavageAll_1to96 [1-80] using DCM1 60 Mix for 45.00 minutes at 600 rpm(s) 61 Empty RBCleavageAll1to96 for 1.000 minute(s) 35 62 Dispense System Fluid DCM1 500pl to RBCleavageAll_1to96 [1-80] 63 Mix for 1.00 minutes at 300 rpm(s) 64 Empty RB_CleavageAll_1to96 for 1.000 minute(s) 65 66 40 Dispense Sequence C:\ACT\ALKYNES.DSP is a subroutine that controls the combinatorial addition of the solutions of the 20 alkynes of type [Building block 3] into the 80 wells in the synthesizer.
WO 99/01423 PCT/DK98/00287 340 The library containing the compounds listed below was synthesized. A subset of the library obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass).
WO 99/01423 PCT/DK98/00287 341 EXAMPLE 536: EXAMPLE 537: 2-Amino-5-{5-[(3-chloro-4- 3-Chloro-4-hydroxybenzoic acid [3-(3 hydroxybenzoyl)hydrazonomethyl]-2,3- diethylamino-1 -propynyl)-4,5 dimethoxyphenyl}-4-pentynoic acid dimethoxybenzyiidene]hydrazide 0 , 0H 3 0. OH 3 0 N CH 3 0 O H HO HO CI NH 2 H 3 CN OH
OH
3 EXAMPLE 538: EXAMPLE 539: 3-Chloro-4-hydroxybenzoic acid{3-[3- 3-Chioro-4-hydroxybenzoic acid [3,4 (benzylmethylamino)-1 -propynyl]-4,5- dimethoxy-5-(3-phenyl-1 dimethoxybenzylidene}hydrazide propynyl)benzylidene]hydrazide O. OH 3 O. CH 3 O 0. 0 CH 0 0 CH IHOI 3 C H HO ,C HOq' H33 EXAMPLE 540: EXAMPLE 541: 3-Chloro-4-hydroxybenzoic acid [3-(3-amino-1-. 3-Chloro-4-hydroxybenzoic acid [3,4 propynyl)-4,5-dimethoxybenzylidene]hydrazide dimethoxy-5-(3-phenoxy-1 propynyl)benzylidene]hydrazide , OH 3 ~ O.CH 3 O 0. 0
CH
3 0 0. C3 ,N -N ~ C HO .N HO .N, ci N 2 ci WO 99/01423 PCT/DK98/00287 342 EXAMPLE 542: EXAMPLE 543: 3-Chloro-4-hydroxybenzoic acid [3,4- 3-Chloro-4-hydroxybenzoic acid [3-(3 dimethoxy-5-(toluene-4-sulfonylethynyl)- hydroxyphenyiethynyl)-4,5 benzylidene]hydrazide dimethoxybenzyfidene]hydrazide O . H 3 0 0 CH , NNN NJ HO l . H
S'
0 HO H Cl CO
H
3 C EXAMPLE 544: EXAMPLE 545: 3-Chloro-4-hydroxybenzoic acid [3-(4- 3-Chioro-4-hydroxybenzoic acid [3,4 chlorophenylethynyl)-4,5- dimethoxy-5-(2-pyridylethynyl] dimethoxybenzylidene]hydrazide benzylidene]hydrazide O. CH 3 0* OH 3 o CH 3 0 0. OH N.N N NN N'~ N HO H C I 1C1 II EXAMPLE 546: 3-Chloro-4-hydroxybenzoic acid [3,4 dimethoxy-5-(5-phenyh-1 pentynyl)benzymidene]hydrazide 0' OH 3 0 O OCH. NOO
CC
WO 99/01423 PCT/DK98/00287 343 EXAMPLE 547: EXAMPLE 548: 3-Chloro-4-hydroxybenzoic acid {3,4- {5-[(3-Chloro-4-hydroxybenzoyl) dimethoxy-5-[3-(4-oxo-5-phenyl-4,5-dihydro- hydrazonomethyl]-2,3-dimethoxy 2-oxazolylamino)-1 -propynyl]- phenyl}propynoic acid benzylidene}hydrazide SCH3 O CH3 O N.0 OCH 3 O H JN N N HO CI OH EXAMPLE 549: EXAMPLE 550: 5-{5-[(3-Chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid [3-(3 hydrazonomethyl]-2,3-dimethoxyphenyl}-4- hydroxy-1 -butynyl)-4,5-dimethoxy pentynoic acid benzylidene]hydrazide O. CH3 0 H 0. 0. 0 30CH 0
OH
3 HO HO 01 0 01 OH
OH
WO 99/01423 PCT/DK98/00287 344 EXAMPLE 551: EXAMPLE 552: 3-Chloro-4-hydroxybenzoic acid [3-(4- 3-Chloro-4-hydroxybenzoic acid [3-(4 hydroxy-1 -butynyl)-4,5-dimethoxy- hydroxy-1 -hexynyl)-4,5-dimethoxy benzylidene]hydrazide benzylidene]hydrazide 0'CH . 'CH3 'C O O. CH 3 0 0H N NO H HOJH HO HNK O0~ "K HO CI HO Cl OH
CH
3 EXAMPLE 553: EXAMPLE 554: 3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid {3-[3-(2,6 hydroxy-1 -propynyl)-4,5-dimethoxy- dichlorophenoxy)-1 -propynyl]-4,5 benzylidene]hydrazide dimethoxybenzylidene}hydrazide O .CH3 0 CH 3 A N ".N 0 /H'C O H O'C HO . HO N Cl Cl OH CI 0 CI EXAMPLE 555: 3-Chloro-4-hydroxybenzoic acid [4-(1 aminocyclohexylethynyl)-1 naphthylmethylene]hydrazide
H
2 N 0 N NH HO
CI
WO 99/01423 PCT/DK98/00287 345 EXAMPLE 556: EXAMPLE 557: 3-Chloro-4-hydroxy benzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid [4-(3-amino benzylmethylamino-1 -propynyl)-1 - 1 -propynyl)-1 -naphthylmethylene]hydrazide naphthylmethylene] hydrazide
NH
2
H
3 C'N HN 00 H H HO HO CI CI EXAMPLE 558: EXAMPLE 559: 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid[4-(3 hydrazonomethyl]-1 -naphthyl}-4-pentynoic diethylamino-1 -propynyl)-1 -naphthyl acid methylene]hydrazide OH
H
2 N 0 OH O3 HON 0 ' 0 H I. H NI 0 HOH HO
CI
WO 99/01423 PCT/DK98/00287 346 EXAMPLE 560: EXAMPLE 561: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid [4-(toiuene 1 -propynyl)-1 -naphthylmethylene]hydrazide 4-sulfonylethynyl)-1 naphthylmethylene]hydrazide o -. HO .N 0 N" 00 f(I OH3 N N '-Z HO H ICI HO Cl EXAMPLE 562: EXAMPLE 563: 3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chioro-4-hydroxybenzoic acid [4-(4 phenoxy-1 -propynyl)-1 -naphthylmethylene]- chlorophenylethynyl)-1 -naphthyl hydrazide methyienehydrazide o C j: N N ' N HO .N -I C I WO 99/01423 PCT/DK98/00287 347 EXAMPLE 564: EXAMPLE 565: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo 1 -pentynyl)-1 -naphthylmethylene]hydrazide 5-phenyi-4,5-dihydro-(2-oxazolylamino)-1 propynyl]- -naphthylmethyeneehydrazide 0
N
HNHO. 00 N N N N~. N HO' AH I H ICi CI EXAMPLE 566: EXAMPLE 567: 3-Chloro-4-hydroxybenzoic acid [4-(3- 5-{4-[(3-Chloro-4-hydroxybenzoyl) hydroxyphenylethynyl)-1 -naphthyl- hydrazonomethyl]- 1 -naphthyl)-4-pentoic acid methylene]hydrazide 0 OH OH O j N N N.0 HO .N N.N. N HO HOl N
C
WO 99/01423 PCT/DK98/00287 348 EXAMPLE 568: EXAMPLE 569: 3-Chloro-4-hydroxybenzoic acid [4-(2- {4-[(3-Chloro-4-hydroxybenzoyl) pyridyl)ethynyl-1 -naphthylmethylene)- hydrazonomethyl]-1-naphthylpropynoic acid hydrazide 0 NI <OH 0~ NN <N 0 N N N ' N N , NN HO H CO C EXAMPLE 570: EXAMPLE 571: 3-Chioro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid [4-(3- hy hydroxy-1 -butynyl)-1 -naphthylmethylene]- droxy-1 -propynyl)-1 -naphthyimethylenel hydrazide hydrazide
OH
3 OH OH OO N N - N HO ~HO N CI CI EXAMPLE 572: EXAMPLE 573: 3-Oh oro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(4 hydroxy-1 -butynyl)-l -naphthylmethylene]- hydroxy-1 -hexynyl)-1 -naphthylmethylene] hydrazide hydrazide OH HO OH O 0 Ol: 0N, N0 N N HO N H Cl CI WO 99/01423 PCT/DK98/00287 349 EXAMPLE 574: EXAMPLE 575: 3-Chloro-4-hydroxybenzoic acid {4-[3-(2,6- 2-Amino-5-{3-[(3-chloro-4-hydroxy dichlorophenoxy)-1 -propynyl]-1 - benzoyl)hydrazonomethyljphenyl}-4 naphthylmethylene}hydrazide pentynoic acid Cl0 0 COH 'o H HO .N CI EXAMPLE 576: EXAMPLE 577: 3-Chloro-4-hydroxybenzoic acid [3-(1- 3-Chloro-4-hydroxybenzoic acid {3-[3 aminocyclohexylethynyl)benzylidene]- (benzylmethylamino)-1 hydrazide propynyl]benzylidene}hydrazide HO .N NH24P Np N NN N.N: N 3 H HO 'T1 H ~ >HHO H ' N CI CI EXAMPLE 578: 3-Chloro-4-hydroxybenzoic acid [3-(3-amino 1 -propynyl)benzylidene]hydrazide 0 HOI H NH2 HO
CCI
WO 99/01423 PCT/DK98/00287 350 EXAMPLE 579: EXAMPLE 580: 3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid [3-(toluene diethylamino-1 -propynyl)benzylidene]- 4-sulfonylethynyl)benzylidene]hydrazide hydrazide S0 N N CH3 N . I HNN, C> N H 3 H ' -'.0 HO ClHO CNCH CI C I ACH3 EXAMPLE 581: EXAMPLE 582: 3-Chloro-4-hydroxybenzoic acid [3-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid [3-(4 1 -propynyl)benzylidene]hydrazide chlorophenylethynyl)benzylidene]hydrazide O .N O .N f( N , N N A N N HO H HO A Cl Cl Cl EXAMPLE 583: EXAMPLE 584: 3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid [3-(5-phenyl phenoxy-1 -propynyl)benzylidene]hydrazide 1 -pentynyl)benzylidene]hydrazide H .N H N j N"
NS
HO A-(?~J O AN CI CI WO 99/01423 PCT/DK98/00287 351 EXAMPLE 585: EXAMPLE 586: 3-Chloro-4-hydroxybenzoic acid [3-(3- 5-{3-[(3-Chloro-4-hydroxybenzoyl)-hydrazo hydroxyphenylethynyl)benzylidene]- nomethyl]phenyl}-4-pentynoic acid hydrazide O 0 O~j N N N HN H N O HO
.
OH HO .N OH Cl CI EXAMPLE 587: EXAMPLE 588: 3-Chloro-4-hydroxybenzoic acid [3-(2- {3-[(3-chloro-4-hydroxybenzoyl) pyridylethynyl)benzylidene]hydrazide hydrazonomethyl]phenyl}propynoic acid O N 0 HO NN - NN O . HO N OH CI0 EXAMPLE 589: EXAMPLE 590: 3-Chloro-4-hydroxybenzoic acid {3-[3-(4-oxo- 3-Chloro-4-hydroxybenzoic acid [3-(3 5-phenyl-4,5-dihydro-(2-oxazolylamino))-1 - hydroxy-1 -butynyl)benzylidene]hydrazide propynyl]benzylidenelhydrazide 0 N' N ~ H 0 NNN I H zz_ N HOJ "r~'t OH N HO 0
OH
3 WO 99/01423 PCT/DK98/00287 352 EXAMPLE 591: EXAMPLE 592: 3-Chloro-4-hydroxybenzoic acid [3-(4- 3-Chloro-4-hydroxybenzoic acid [3-(4 hydroxy-1 -butynyl)benzylidene]hydrazide hydroxy-1 -hexynyl)benzylidene]hydrazide HO NO H HN O H C HO C EXAMPLE 593: EXAMPLE 594: 3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid {3-[3-(2,6 hydroxy-1 -propynyl)benzylidene]hydrazide dichlorophenoxy)-1 -propynyl]benzylidene} hydrazide N N N N N CI O NOH HO N HO Cl HO- A16 Cl CI CI EXAMPLE 595: EXAMPLE 596: 3-Chloro-4-hydroxybenzoic acid [4-(1- 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl) aminocyclohexylethynyl)benzylidene]- hydrazonomethyl]phenyl}-4-pentynoic acid hydrazide 0 OH 0 NH2 0 N OH N ON N N H HOf[ H HO I[;' CI
CI
WO 99/01423 PCT/DK98/00287 353 EXAMPLE 597: EXAMPLE 598: 3-Chloro-4-hydroxybenzoic acid {4-[3- 3-Chloro-4-hydroxybenzoic acid [4-(3-amino (benzylmethylamino)-1 -propynyl]- 1 -propynyl)benzylidene]hydrazide benzylidene}hydrazide O HN - NH 2 HON HHO .N N HO'j: HO0- -1- CI CI EXAMPLE 599: EXAMPLE 600: 3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chioro-4-hydroxybenzoic acid [4-(3 diethylamino-1 -propynyl)benzylidene]- phenoxy-1 -propynyl]benzylidene]hydrazide hydrazide K N CH 3 0 N N
H
3 <0 HO' O H N N ci O- H HOO H C EXAMPLE 601: EXAMPLE 602: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid [4-(toiuene 1 -propynyl)benzylidene]hydrazide 4-sulfonylethynyl)benzylidene]hydrazide NI 00O O N N N.~ N ' HO H ci HO~ H
CI
WO 99/01423 PCT/DK98/00287 354 EXAMPLE 603: EXAMPLE 604: 3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(3 chlorophenylethynyl)benzylidene]hydrazide hydroxyphenylethynyl)benzylidene]hydrazide Cl OH 0 0 OO. N O.NN *O N AN N N N(NPA N H H H HO'(' Cl EXAMPLE 605: EXAMPLE 606: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 3-Chloro-4-hydroxybenzoic acid [4-(2 1 -pentynyl)benzylidene]hydrazide pyridylethynyl)benzylidene]hydrazide NN OO NN HO H N.N N CI HO'Q Cl EXAMPLE 607: EXAMPLE 608: 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- {4-[(3-Chloro-4 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1 - hydroxybenzoyl)hydrazonomethyl] propynyl]benzylidene}hydrazide phenyl}propynoic acid 0 OH N O 00 N N N N.N I H I . H HO HO H Cl
CI
WO 99/01423 PCT/DK98/00287 355 EXAMPLE 609: EXAMPLE 610: 5-{4-[(3-Chloro-4-hydroxybenzoyl)- 3-Chioro-4-hydroxybenzoic acid [4-(3 hydrazonomethyl]phenyl}-4-pentynoic acid hydroxy-1 -butynyi)benzylidenejhydrazide OH OH 3 00 < H O 0 SNN HO H H I: " H HO HO CI CI EXAMPLE 611: EXAMPLE 612: 3-Chloro-4-hydroxybenzoic acid [4-(4- -Chloro-4-hydroxybenzoic acid [4-(4 hydroxy-1 -butynyl)benzylidene]hydrazide hydroxy-1 -hexynyl)benzylidene]hydrazide OH
OH
3 HO H H'IA H HO H Cl CI EXAMPLE 613: EXAMPLE 614: 3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid {4-[3-(2,6 hydroxy-1 -propynyi)benzylidene]hydrazide dichlorophenoxy)-1 -propynyl]benzylidene) hydrazide OH C 1 HO N.N OH, HO j H C H NN OH HOHO H
C
WO 99/01423 PCT/DK98/00287 356 General procedure for the preparation of Examples 615 to 694: The following 80 compounds were prepared as single entities by parallel synthesis on a solid support. The attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS. 5 The compounds were prepared according to the following equation: Resin [Building block 1] IN Resin [Building block 1]- [Building block 2] M Resin [Building block 1]- [Building block 2]- [Building block 3] 10 and were simultaneously cleaved (and deprotected when protected) from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula: [Building block 1]-[Building block 2]-[Building block 3]. 15 The starting resins, Resin-[Building block 1]-[Building block 2], were all prepared as de scribed above. The resin used was a polystyrene resin loaded with a Wang linker and the substitution ca 20 pacity was 0.9 mmol/g. All 80 compounds are based on attachment of [Building block 3] to Resin-[Building block 1] [Building block 2] in a fully combinatorial way using a Suzuki reaction according to the fol lowing scheme.
WO 99/01423 PCT/DK98/00287 357 =-R [Building block 3] Catecholborane O0 Nt LO 'B RO H N Resinc, .N B-Lea Resin, .N B R Pd catalyst O Resin-[Building block 1]-[Building block 2] Resin-[Building block 1]-[Building block 2]-[Building block 3] R14 Lea R where B-Lea is Lea or wherein Lea is a leaving group and R 1 4 and R" are as defined for formula 1. The starting materials used were the same as those use in examples 535 to 614, i.e. 5 Resin-[Building block 1], [Building block 2] and [Building block 3] were the same as those used in examples 535 to 614, the only difference being the products in examples 615 to 694 are having double bonds as compared to the products in examples 535 to 614 having triple bonds.
WO 99/01423 PCT/DK98/00287 358 EXAMPLE 615: 3-Chloro-4-hydroxybenzoic acid {3-[2-(1-aminocyclohexyl)vinyll-4.5-dimethoxybenzylidene} hydrazide
H
2 N 0 0. CH3 N CC OH N" 0* 3 H HO 5 Cl Preparation of a 1,4-dioxane/THF solution of 1-(2-Benzo[1,3,2]dioxaborol-2-ylvinyl)cyclo hexylamine: To a solution of 1-ethynylcyclohexylamine ([Building block 3]) in 1,4-dioxane (1 M, 0.5 mL) was added a solution of catecholborane in THF (1 M, 0.5 mL) and the mixture was heated at 10 60 0C for 4 hours. The solution was cooled to room temperature and used directly in the Suzuki coupling reaction. To the resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide (0.05 mmoles) was added a solution of cesium carbonate in water (1.25 M, 0.2 mL), a solution of 15 triphenylphosphine and tetrabutylammonium chloride in NMP (both 0.4 M, 0.5 mL), a solu tion of palladium (II) acetate in NMP (0.16 M, 0.25 mL), was mixed and the solution of 1-(2 benzo[1,3,2]dioxaborol-2-ylvinyl)cyclohexylamine in 1,4-dioxane/THF (prepared as described above) was added and the mixture was shaken at 70 0C for 15 hours. The resin was repeat edly washed with NMP (1.5 mL, 3 times), 50% water in DMF (1.5 mL, 3 times), NMP (1.5 20 mL, 2 times), 1% sodium diethylaminodithiocarbamate trihydrate (1.5 mL, 9 times), NMP (1.5 mL, 5 times) and CH 2 Cl 2 (1.5 mL, 6 times) for 2 minutes and filtered. The compound was cleaved off the resin by shaking for 45 minutes at room temperature with a 50% solution of trifluoroacetic acid in CH 2 Cl 2 (1.5 mL). The mixture was filtered and the 25 resin was extracted with CH 2 Cl 2 (0.5 mL). The combined CH 2 Cl 2 extracts were concentrated WO 99/01423 PCT/DK98/00287 359 in vacuo. The residue was dissolved in a 1:1 mixture of methanol and CH 2 Cl 2 (1 mL) and concentrated in vacuo to give the title compound. The final product obtained was characterized by analytical RP-HPLC (retention time) and by 5 LC-MS (molecular mass). The RP-HPLC analysis was performed on a Waters HPLC system consisting of WatersTM 600S Controller, WatersTM 996 Photodiode Array Detector, WatersTM 717 Autosampler, Wa tersTM 616 Pump, WatersTM 3 mm x 150 mm 3.5 p C-18 Symmetry column and Millenium 10 QuickSet Control Ver. 2.15 using UV detection at 214 nm. A gradient of 5% to 90% acetoni trile/0.1% trifluoroacetic acid/water at 15 minutes at 1 mL/minute. The LC-MS analysis was performed on a PE Sciex API 100 LC/MS System using a WatersTM 3 mm x 150 mm 3.5 p C-18 Symmetry column and positive ionspray with a flow rate at 20 pL/minute. 15 EXAMPLES 616 to 694: A library of the following 79 compounds can be prepared in parallel as individual entities analogously to example 615 on an Advanced ChemTech Model 496 HTS using the following ChemFile to control the operation of the synthesizer. The 4 resins of type Resin-[Building 20 block 1]-[Building block 2] are equally distributed in the 80 wells in the synthesizer prior to the initialization of device. ChemFile C:\ACT\90250003.CHM Page 1 1 Empty RBHeatingAll_1to96 for 2.000 minute(s) 25 2 3 REM Addition of Cs2CO3 in water 4 5 Transfer 200pl from Monomers_1to36 [25] () to RBHeating_All_Ito96 [1-80] using DCE 6 Mix for 1.00 minutes at 600 rpm(s) 30 7 8 REM Addition of Ph3P + Bu4NCI in NMP 9 10 Transfer 500pl from Monomers_1to36 [21] ( to RB_HeatingAll_1to96 [1-80] using DCE 11 Mix for 1.00 minutes at 600 rpm(s) 35 12 13 REM Addition of Pd(OAc)2 in NMP 14 15 Transfer 500pl from Monomers_1to36 [22] ( to RB_HeatingAll_1to96 [1-80] using DCE WO 99/01423 PCT/DK98/00287 360 16 Mix for 2.00 minutes at 600 rpm(s) 17 Dispense Sequence C:\ACT\ALKYNES.DSP with 500pl to RB_HeatingAll_1to96 rack 18 Set Temperature to 70.0 degrees Celsius 19 Mix for 15.00 minutes at 600 rpm(s) 5 20 Wait for 15.000 minute(s) 21 Repeat from step 19, 29 times 22 Turn Temperature Controller Off 23 Mix for 15.00 minutes at 600 rpm(s) 24 Wait for 15.000 minute(s) 10 25 Repeat from step 23, 7 times 26 Empty RBHeating_All 1to96 for 2.000 minute(s) 27 Dispense System Fluid NMP1 1500pl to RB_CleavageAll_1to96 [1-80] 28 Mix for 3.00 minutes at 600 rpm(s) 29 Empty RB Heating_All_1to96 for 2.000 minute(s) 15 30 Repeat from step 27, 2 times 31 32 REM Wash with 50% H20/NMP 33 34 Transfer 1500pl from Reagent _3 [1] 0 to RB_HeatingAll_1to96 [1-80] using NMP1 20 35 Mix for 3.00 minutes at 600 rpm(s) 36 Empty RBHeating_All_1to96 for 2.000 minute(s) 37 Repeat from step 34, 2 times 38 Dispense System Fluid NMP1 1500pl to RBCleavageAll_1to96 [1-80] 39 Mix for 3.00 minutes at 600 rpm(s) 25 40 Empty RBHeating_All_1to96 for 2.000 minute(s) 41 Repeat from step 38, I times 42 43 REM Wash with Sodium diethylaminodithiocarbamate 44 30 45 Transfer 1500pl from Reagent 3 [1] () to RBHeatingAll_1to96 [1-80] using NMP1 46 Mix for 3.00 minutes at 600 rpm(s) 47 Empty RBHeating_All_1to96 for 2.000 minute(s) 48 Repeat from step 45, 2 times 49 Transfer 1500pl from REAGENT_4 [1] () to RBHeatingAll_1to96 [1-80] using NMP1 35 50 Mix for 3.00 minutes at 600 rpm(s) 51 Empty RBHeating_All_1to96 for 2.000 minute(s) 52 Repeat from step 49, 2 times 53 Transfer 1500pl from REAGENT5 [1] () to RBHeatingAll_1to96[ 1-80] using NMP1 54 Mix for 2.00 minutes at 600 rpm(s) 40 55 Empty RBHeating_All_1to96 for 2.000 minute(s) 56 Repeat from step 53, 2 times 57 Dispense System Fluid NMP1 1500pl to RBCleavageAll_1to96 [1-80] 58 Mix for 3.00 minutes at 600 rpm(s) 59 Empty RBHeating_All_1to96 for 2.000 minute(s) 45 60 Repeat from step 57, 4 times 61 Dispense System Fluid DCE1 1500pl to RB_CleavageAll_1to96 [1-80] 62 Mix for 3.00 minutes at 600 rpm(s) 63 Empty RBHeating_All_1to96 for 2.000 minute(s) 64 Repeat from step 61, 5 times WO 99/01423 PCT/DK98/00287 361 65 66 REM Cleavage from Resin 67 REM with 50% TFA/DCM 68 5 69 Transfer 1500pl from Reagent 3 [1] () to RB_CleavageAll_1to96 [1-80] using DCM1 70 Mix for 45.00 minutes at 600 rpm(s) 71 Empty RB_CleavageAll_1to96 for 1.000 minute(s) 72 Dispense System Fluid DCM1 500pl to RBCleavageAll_1to96 [1-80] 73 Mix for 1.00 minutes at 300 rpm(s) 10 74 Empty RB_CleavageAll_1to96 for 1.000 minute(s) 75 Dispense Sequence C:\ACT\ALKYNES.DSP is a subroutine that controls the combinatorial addition of the solutions of the 20 2-vinyl-benzo[1,3,2]dioxaboroles of type [Building block 3] 15 into the 80 wells in the synthesizer.
WO 99/01423 PCT/DK98/00287 362 The library containing the compounds listed below was synthesized. A subset of the library obtained was characterized by analytical RP-HPLC (retention time) and by LC-MS (molecular mass). EXAMPLE 616: EXAMPLE 617: 2-Amino-5-{5-[(3-chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid [3-(3 hydrazonomethyl]-2,3-dimethoxyphenyl}-4- amino-i -propenyl)-4,5-dimethoxy pentenoic acid benzylidene]hydrazide
NH
2
NH
2 OH 0 . CCH SOCH N H O O .CH HO HO Cl Cl EXAMPLE 618: 3-Chloro-4-hydroxybenzoic acid {3-[3 (benzylmethylamino)propenyl]-4,5 dimethoxybenzylidene}hydrazide H O OCH3 HO . Cl WO 99/01423 PCT/DK98/00287 363 EXAMPLE 619: EXAMPLE 620: 3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid [3,4 diethylamino-1 -propenyl)-4,5- dimethoxy-5-(3-phenoxy-1 -propenyl) dimethoxybenzylidene]hydrazide benzylidene]hydrazide
CH
3 0
N-CH
3 0 0. CH3 0N0.CH0 3 O CH 3 .N, .CHH OC3 HO H CI HO Cl EXAMPLE 621: EXAMPLE 622: 3-Chloro-4-hydroxybenzoic acid [3,4- 3-Chloro-4-hydroxybenzoic acid {3,4 dimethoxy-5-(3-phenyl-1 -propenyl)- dimethoxy-5-[2-(toluene-4-sulfonyl)vinyl] benzylidene]hydrazide benzylidene}hydrazide
CH
3 O O O. CH3 N.N .CH3 O CH HO C H H N O.CH CI HO C
CI
WO 99/01423 PCT/DK98/00287 364 EXAMPLE 623: EXAMPLE 624: 3-Chloro-4-hydroxybenzoic acid {3-[2-(4- 3-Chloro-4-hydroxybenzoic acid {3-[2-(3 chlorophenyl)vinyl]-4,5- hydroxyphenyl)vinyl]-4,5-dimethoxy dimethoxybenzylidene}hydrazide benzylidene}hydrazide CI NOH NO 0. CH 0. 0 -~ O 3 0 C CH 3 N.N O . CH 3 N N N OH NN 3 H H HO H Oj(: CI C I EXAMPLE 625: EXAMPLE 626: 3-Chloro-4-hydroxybenzoic acid [3,4- 3-Chloro-4-hydroxybenzoic acid [3,4 dimethoxy-5-(5-phenyl-1 -pentenyl)- dimethoxy-5-(2-(2-pyridyl)vinyl) benzylidene]hydrazide benzylidene]hydrazide N 0 O.CH3 O CH3 OHCH3 CC H' HO N O.3 HO
CI
WO 99/01423 PCT/DK98/00287 365 EXAMPLE 627: EXAMPLE 628: 3-Chloro-4-hydroxybenzoic acid {3,4- 3-{5-[(3-Chloro-4-hydroxybenzoyl) dimethoxy-5-[3-(4-oxo-5-phenyl-4,5-dihydro-2- hydrazonomethyl]-2,3-dimethoxyphenyl} oxazolylamino)-1 -propenyl]- acrylic acid benzylidene}hydrazide 0 OH
O
N O OCH3 NH HN,
OH
3 HO CI O 0 .CH3 N 0 3 N NN N O.CH 3 H HO CI EXAMPLE 629: EXAMPLE 630: 5-{5-[(3-Chloro-4-hydroxybenzoyl)- 3-OhIoro-4-hydroxybenzoic acid [3-(3 hydrazonomethyl]-2,3-dimethoxyphenyl}-4- hydroxy-1 -butenyl)-4,5-dimethoxy pentenoic acid benzylidene]hydrazide O OH HO OH O0 .HC , N N O CHH HH HO N 0* 3 HO H Cl
CI
WO 99/01423 PCT/DK98/00287 366 EXAMPLE 631: EXAMPLE 632: 3-Chloro-4-hydroxybenzoic acid [3-(4- 3-Chloro-4-hydroxybenzoic acid [3-(4 hydroxy-1 -butenyl)-4,5-dimethoxy- hydroxy-1 -hexenyl)-4,5-dimethoxy benzylidene]hydrazide benzylidene]hydrazide OH
CH
3 OH O
CH
3 OOCH3 CH OCH H H HOH HO H CI C1 EXAMPLE 633: EXAMPLE 634: 3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid {3-[3-(2,6 hydroxy-1 -propenyl)-4,5-dimethoxy- dichlorophenoxy)-1 -propenyl]-4,5 benzylidene]hydrazide dimethoxybenzylidene}hydrazide OH Cl Cl 0 O. CH 3 O N N, OCH I H O HO 0 0. CH 3 CI N.N, O.CH3 H HO
CI
WO 99/01423 PCT/DK98/00287 367 EXAMPLE 635: EXAMPLE 636: 3-chloro-4-hydroxybenzoic acid {4-[2-(1- 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl) aminocyclohexyl)vinyl]-1 -naphthyl- hydrazonomethyl]-1 -naphthyl}-4-pentenoic methylene}hydrazide acid H2N 0
NH
2 OOHN N OH 0(AN N H HNN' HO "N H H I CI EXAMPLE 637: EXAMPLE 638: 3-Chloro-4-hydroxybenzoic acid {4-[3- 3-Chloro-4-hydroxybenzoic acid [4-(3-amino (benzylmethylamino)propenyl]-1 - 1 -propenyl)-1 -naphthylmethylene]hydrazide naphthylmethylene}hydrazide OO.N N N OH 3 .
NH
2 N ' N;,JN N N ' H HC EXAMPLE 639: EXAMPLE 640: 3-Chloro-4-hydroxybenzoic acid[4-(3- 3-Chloro-4-hydroxybenzoic acid [4-(3 diethylamino-1 -propenyl)-1 -naphthyl- phenoxy-1 -propenyl)-1 -naphthyl methylene]hydrazide methylene]hydrazide 0 N N"'0CH 3 0 N 0 N N N N'" N NH HO N 3 HO . Ci Cl WO 99/01423 PCT/DK98/00287 368 EXAMPLE 641: EXAMPLE 642: 3-Chloro-4-hydroxybenzoic acid (4-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid {4-[2 1 -propenyl)-1 -naphthylmethylene]hydrazide (toluene-4-sulfonyl)vinyl]-1 - naphthyl methyleneihydrazide O 0 N N 0 N &S/ H HN N'-'. HO .NHO N H CI C1 EXAMPLE 643: EXAMPLE 644: 3-Chloro-4-hydroxybenzoic acid {4-[2-(4- 3-Chloro-4-hydroxybenzoic acid {4-[2-(3 chlorophenyl)vinyl]-1 -naphthylmethylene}- hydroxyphenyl)vinyl]-1 -naphthyl hydrazide methylene}hydrazide Cl O O OH H l H HO*IC HO N 'HO0 EXAMPLE 645: EXAMPLE 646: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 3-Chloro-4-hydroxy-benzoic acid [4-(2-(2 1 -pentenyl)-1 -naphthylmethylene]hydrazide pyridyl)vinyl)-1 -naphthylmethylene] hydrazide N' N N N HO: H NC NI CI HO qj HN
CI
WO 99/01423 PCT/DK98/00287 369 EXAMPLE 647: EXAMPLE 648: 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- 3-{4-[(3-Chloro-4-hydroxybenzoyl) 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1 - hydrazonomethyl]-l-naphthy}acrylic acid propenyl]-1 -naphthylmethylene}hydrazide 0 0 O OH H N H N, H Cl CI EXAMPLE 649: EXAMPLE 650: 5-{4-[(3-Chloro-4-hydroxybenzoyl)- 3-Chioro-4-hydroxybenzoic acid [4-(3 hydrazonomethyl]-1 -naphthyl}-4-pentenoic hydroxy-1 -butenyl)-1 -naphthyimethyiene] acid hydrazide O CH 3 O OH 0 OH HOq: H HO( H Cl C EXAMPLE 651: EXAMPLE 652: 3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(4 hydroxy-1 -butenyl)-1 -naphthylmethylene]- hydroxy-1 -hexenyl)-1 -naphthyl hydrazide methylene]hydrazide O N OH 0 -
CH
3 N N'O HO H HO-N, H Cl CI WO 99/01423 PCT/DK98/00287 370 EXAMPLE 653: EXAMPLE 654: 3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid {4-[3-(2,6 hydroxy-1 -propenyl)-1 - dichlorophenoxy)-1 -propenyl]-1 naphthylmethylene]hydrazide naphthylmethylene}hydrazide O0 ~ OH Ci N N~ 0-. N~l H Ij: H N N N Ci CH HO H CI EXAMPLE 655: EXAMPLE 656: 3-Chloro-4-hydroxybenzoic acid {3-[2-(1- 2-Amino-5-{3-[(3-chloro-4-hydroxy aminocyclohexyl)vinyl]benzylidene}hydrazide benzoyl)hydrazonomethyl]phenyl}-4 pentenoic acid
NH
2 H2N OH C0 HO'j: H HO-( CI
CI
WO 99/01423 PCT/DK98/00287 371 EXAMPLE 657: EXAMPLE 658: 3-Chloro-4-hydroxybenzoic acid {3-[3- 3-Chloro-4-hydroxybenzoic acid [3-(3-amino (benzylmethylamino)-1 -propenyl]- 1 -propenyl)benzylidene]hydrazide benzylidene}hydrazide OH NH 2 N O O NN N NN H I H HO HO CI Cl EXAMPLE 659: EXAMPLE 660: 3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chloro-4-hydroxybenzoic acid [3-(3 diethylamino-1 -propenyl)benzylidene]- phenoxy-1 -propenyl)benzylidene]hydrazide hydrazide rCH3 0,
NCH
3 O 0 N N N N I H SN H HO'C C
CI
WO 99/01423 PCT/DK98/00287 372 EXAMPLE 661: EXAMPLE 662: 3-Chloro-4-hydroxybenzoic acid [3-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid {3-[2 1 -propenyl)benzylidene]hydrazide (toluene-4-sulfonyl)vinyl]benzylidene} hydrazide CH O O 0 N NN N N N N HO HO . CI CI EXAMPLE 663: EXAMPLE 664: 3-Chloro-4-hydroxybenzoic acid {3-[2-(4- 3-Chloro-4-hydroxybenzoic acid {3-[2-(3 chlorophenyl)vinyl]benzylidene}hydrazide hydroxyphenyl)vinyl]benzylidene}hydrazide Cl OH 0 O N NN.N HOJ H HO I
CC
WO 99/01423 PCT/DK98/00287 373 EXAMPLE 665: EXAMPLE 666: 3-Chloro-4-hydroxybenzoic acid [3-(5-phenyl- 3-Chloro-4-hydroxybenzoic acid [3-(2-(2 1 -pentenyl)benzylidene]hydrazide pyridyl)vinyl)benzylidene]hydrazide N O 0 N NN: . H I[P HO' H HO .N HO .N CI CI EXAMPLE 667: EXAMPLE 668: 3-Chloro-4-hydroxybenzoic acid {3-[3-(4-oxo- 3-{3-[(3-Chloro-4-hydroxybenzoyl) 5-phenyl-4,5-dihydro-(2-oxazolylamino))-1- hydrazonomethyl]phenyl}acrylic acid propenyl]benzylidene}hydrazide 0 -p 0 OH NH 0 0 N N H H H O HO .NC
CI
WO 99/01423 PCT/DK98/00287 374 EXAMPLE 669: EXAMPLE 670: 5-{3-[(3-Chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid [3-(3 hydrazonomethyl]phenyl}-4-pentenoic acid hydroxy-1 -butenyl)benzylidene]hydrazide 0 H3C OH OH O 0 H H HO HO Cl CI EXAMPLE 671: EXAMPLE 672: 3-Chloro-4-hydroxybenzoic acid [3-(4- 3-Chloro-4-hydroxybenzoic acid [3-(4 hydroxy-1 -butenyl)benzylidene]hydrazide hydroxy-1 -hexenyl)benzylidene]hydrazide OH
CH
3 OH O 0 I H N HO N HO. H 01 0! WO 99/01423 PCT/DK98/00287 375 EXAMPLE 673: EXAMPLE 674: 3-Chloro-4-hydroxybenzoic acid [3-(3- 3-Chioro-4-hydroxybenzoic acid {3-[3-(2,6 hydroxy-1 -propenyl)benzylidene]hydrazide dichlorophenoxy)-1 -propenyl] benzylidene}hydrazide OH
.
C O0 N. H HO-f CII EXAMPLE 675: EAPE66 3-Chloro-4-hydroxybenzoic acid {4-[2-(1- 2Aio5{-(-hoo4hdoyezy) aminocyclohexyl)vinyl]benzylidene}hydrazide hdaooehlpey}4pneocai 'NN 0 ~ 'N HO _, H 'N 0N 'N HO H ClI EXAMPLE 677: EXAMPLE 676: 3-Chloro-4-hydroxybenzoic acid {4-[3-( ben- 2-[hloro-4-hydroxybenzo) zylmethylamino)-1 -propenyl]- 1- oenlb zli n]hdrzd nyl hyibenzylidene}hydrazide H NA N *N N H 2 N ' HO . N 'N I H HO EXAMPLE 677:EXAMPLE 678: 3-Choro4-hyroxbenoic cid{4-[-( en- 3-Chloro-4-hydroxybenzoic acid {[-(2-no zylmehyamno)-1-propnyl]ichlrophleoxy-1preny] bbenzylidene~hydrazide HOHO . CI CI WO 99/01423 PCT/DK98/00287 376 EXAMPLE 679: EXAMPLE 680: 3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chloro-4-hydroxybenzoic acid [4-(3 diethylaminopropenyl)benzylidene]hydrazide phenoxy-1 -propenyljbenzylidene]hydrazide O N.N, N CH 0 0 N H N CH 3 N H J-lH 3 HO HO C N CI C EXAMPLE 681: EXAMPLE 682: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 3-Chloro-4-hydroxybenzoic acid {4-[2 1 -propenyl)benzylidene]hydrazide (toluene-4-sulfony)vinyl]benzylidene} hyd razide O N N HO HO H C CI EXAMPLE 683: EXAMPLE 684: 3-Chloro-4-hydroxybenzoic acid {4-[2-(4- 3-Chloro-4-hydroxybenzoic acid {4-[2-(3 chlorophenyl)vinyl]benzylidene}hydrazide hydroxyphenyI)vinyl]benzylidene}hydrazide CI O N.N C NH HO 0 H HO .N CI
CI
WO 99/01423 PCT/DK98/00287 377 EXAMPLE 685: EXAMPLE 686: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 3-Chloro-4-hydroxybenzoic acid {4-[2-(2 1 -pentenyl)benzylidene]hydrazide pyridinyl)vinyl]benzylidene}hydrazide O' N N HO N HO N CI HO(? H CI EXAMPLE 687: EXAMPLE 688: 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- {4-[(3-Chloro-4-hydroxybenzoyl) 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1 - hydrazonomethyl]phenyl}acrylic acid propenyl]benzylidene}hydrazide 0 0 N OH 0 N -J N% \ 0 , OH N N_-NHN NN HO HO Cl Cl EXAMPLE 689: EXAMPLE 690: 5-{4-[(3-Chloro-4-hydroxybenzoyl)- 3-Chloro-4-hydroxybenzoic acid [4-(4 hydrazonomethyl]phenyl}-4-pentenoic acid hydroxy-1 -hexenyl)benzylidene]hydrazide 0 0 CH O OH HN H3 N -. N N HO0 H H HO HO CI Cl WO 99/01423 PCT/DK98/00287 378 EXAMPLE 691: EXAMPLE 692: 3-Chloro-4-hydroxybenzoic acid [4-(4- 3-Chloro-4-hydroxybenzoic acid [4-(3 hydroxy-1 -butenyl)benzylidene]hydrazide hydroxy-1 -propenyl)benzylidene]hydrazide SOH 0 H N Nr\ HO H HO 0 H HO( H Cl CI EXAMPLE 693: EXAMPLE 694: 3-Chloro-4-hydroxybenzoic acid [4-(3- 3-Chioro-4-hydroxybenzoic acid {4-[3-(2,6 hydroxy-1 -butenyl)benzylidene]hydrazide dichlorophenoxy)-1 -propenyl] benzylidene~hydrazide
CH
3 CI O NNOH N N N.~ NO N.NcO I H HO HHO CI Cl WO 99/01423 PCT/DK98/00287 379 General Procedure for Examples 695 to 701: The compounds were prepared as single entities according to the following equation Resin [Building block 1] Resin [Building block 1]- [Building block 2] a 5 Resin [Building block 1]- [Building block 2]- [Building block 3] and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula 10 [Building block 1]-[Building block 2]-[Building block 3]. The following compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block 1] was done manually, whereas the attachment 15 of [Building block 2] and [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS. The starting resin, Resin-[Building block 1], was prepared as described above. 20 The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g. All compounds are based on successive attachment of [Building block 2] and [Building block 3] to Resin-[Building block 1] in a combinatorial way using a nucleophilic substitution reaction 25 according to the following formulae, which are included in the general formula 11: WO 99/01423 PCT/DK98/00287 380 o1 R1 Ci N NH 2
+
0 -H-Br 0 B Resin' H + -e HR 0RI Resin, 0 Resin-[Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] HNR5cR5d [Building block 3] R 1 4 5CR14 S 0___0 N - R 0 c 11i 5 C1 N NN~( RC O' ONQ N'N ORO N. H R 1 s Resin C R [Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3] and
R
1 i R 15 0 | N Br N1 N'NH 2 B, C 0 N . ResinC 0 H2 + H R 1 B ResinC H R 0 0 Resin-[Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] HNR5cR5d [Building block 3] 1R 15 I .N RX ResinC H [Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3] 5 wherein R" 4 , R 1 are as defined for formula I and -NR"RLd is Raa 4a R4b R R4 -- (CH2)c(CH 2 );-D where R", R 4 5 , R 4 b, C, q, d, and D are as defined for formula or WO 99/01423 PCT/DK98/00287 381 -D' where -D' is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile. The following resin, here depicted as Resin-[Building block 1] was used: 5 0 CI NH2 H o where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker: N o =Resin The following building blocks were used: WO 99/01423 PCT/DK98/00287 382 [Building block 21: 4-(2-bromoethoxy)-2-methoxybenzaldehyde 4-(2-bromoethoxy)-3-methoxybenzaldehyde Br Br o o H O\/ H 0 H3C-o HOC 4-(2-bromoethoxy)-3-chloro-5- 4-(2-bromoethoxy)-1 -naphthaldehyde methoxybenzaldehyde Br Br C0 o H H
H
3 C-O 4-(2-bromoethoxy)-3,5- 4-(2-bromoethoxy)-3,5 dimethylbenzaldehyde dibromobenzaldehyde Br H 3 C Br Br H O\ H
H
3 C Br 4-(2-bromoethoxy)-3-methoxy-5- 4-(2-bromoethoxy)-3,5 phenylbenzaldehyde dimethoxybenzaldehyde Br MeO Br O / 0 HMeO H2C-,H
H
3
C-O
WO 99/01423 PCTIDK98/00287 383 4-(2-bromoethoxy)-3-bromo-5- 3-(2-bromoethoxy)-4-methoxybenzaldehyde methoxybenzaldehyde H 3 q 0 Br Br 0\/ H 0 Br- 7
H
3 C-0 2-(2-bromoethoxy)-1 -naphthaldehyde 4-(2-bromoethoxy)-3-methoxyacetophenone 0 H Br \- 0 0B _Q1 / CH 3 MeO WO 99/01423 PCT/DK98/00287 384 [Building block 31: N-isopropylbenzylamine 4-amino-1 -benzylpiperidine 1-(4-methoxyphenyl)
H
2 Npiperazine HC NN
H
3 HN N C N-benzyl-ethanolamine 4-methoxybenzylamine N'-benzyl-N,N H 0- CH 3 dimethylethylenediamine OH H2N 'CH ' ,1 O2H H3C'N N / CH3 1-(4-acetylphenyl)- 1 -benzylpiperazine 2-phenylpiperidine piperazine HN"h N HN N -HCH, 1-(3,4- 3-benzylaminopyrrolidine 2-amino-2-phenylethanol methylenedioxyphenyl) piperazine N H 2 N HN N N HO 0 1 WO 99/01423 PCT/DK98/00287 385 1,2,3,4- 1-(3,4- 4-chloro-a tetrahydroisoquinoline methylenedioxybenzyl)- methylbenzylamine piperazine cl HN,, /, HN ) N H2N c a 4-(trifluoromethyl)- 4-(4-chlorophenyl)-4,5,6,7- 4-(4-chlorophenyl)-4 benzylamine tetrahydro- hydroxypiperidine F thieno[3,2-c]pyridine HO F CI- NNH
H
2 N s N H 3,4-dichiorophenethylamine 3,4-dichlorobenzylamine 4-methoxyphenethylamine CI NH 2 C NH 2 M NH 2 cI'l MeOlc 4-aminobenzylamine 4-chlorophenethylamine 4-bromophenethylamine H2N NH2 N NH 2 Br NH 2
H
2 N'I CI Br 2-amino-1 -phenylethanol 2-amino-3-(4-chlorophenyl)- 2-amino-1 -phenyl-1,3 OH 1-propanol propanediol N.
NH
2 N OH Cli r OH C-OH WO 99/01423 PCT/DK98/00287 386 4-fluorobenzylamine 1-(4-chlorophenyl)-piperazine 2-(2-thienyl)ethylamine F NH 2 ci N /-- NH
NH
2 4-chlorobenzylamine 1-(3-methoxyphenyl)- 6,7-dimethoxy-1,2,3,4 j NH 2 piperazine tetrahydroisoquinoline cl N NH H OMe \...... HN /:: OMe MeO 4-trifluoromethoxybenzyl- 4-benzylpiperidine 2-(3,4-dimethoxyphenyl)-N amine methylethylamine NH H CF , NH 2 Meo CH Me0) ' 1,2,3,4-tetrahydro-1 - 1-(3,4-dichlorophenyl)- 1,4-bis(aminomethyl) naphthylamine piperazine benzene N. cI~
NH
2 CI \ N NH H 2 N
NH
2 4-(aminomethyl)pyridine N NH 2 Preparation of resin-[Building block 11: 5 This resin was prepared as described above. Preparation of [Building block 21: 10 Preparation of 4-(2-bromoethoxy)-2-methoxybenzaldehyde: 1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-2 methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in WO 99/01423 PCT/DK98/00287 387 DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.8 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (400 mL), dried over MgSO 4 and evaporated in vacuo to afford 17.4 g (99%) of 4-(2-bromoethoxy)-2 5 methoxybenzaldehyde, M.p. 78 - 79 *C. Preparation of 4-(2-bromoethoxy)-3-methoxybenzaldehyde: 1,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-3 10 methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 0.33 moles) in DMF (130 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1.2 L) and extracted with ethyl acetate (500 + 4 x 300 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO 4 and evaporated in vacuo to afford 16.3 g (95%) of 4-(2 15 bromoethoxy)-3-methoxybenzaldehyde. M.p. 61 - 64 *C. Preparation of 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde: 1,2-Dibromoethane (46 mL, 0.54 moles) was added to a mixture of 3-chloro-4-hydroxy-5 20 methoxybenzaldehyde (10 g, 54 mmoles) and potassium carbonate (37 g, 0.27 moles) in DMF (180 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over MgSO 4 and evaporated in vacuo to afford 9.33 g (59%) of 4-(2-bromoethoxy)-3 25 chloro-5-methoxybenzaldehyde. M.p. 52 - 54 *C. Preparation of 4-(2-bromoethoxy)-3,5-dimethylbenzaldehyde: 1,2-Dibromoethane (26 mL, 0.3 moles) was added to a mixture of 3,5-dimethyl-4 30 hydroxybenzaldehyde (4.57 g, 30 mmoles) and potassium carbonate (21 g, 150 mmoles) in DMF (90 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.3 L), added saturated sodium chloride (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed WO 99/01423 PCT/DK98/00287 388 with saturated sodium chloride (300 mL), dried over MgSO 4 and evaporated in vacuo to af ford 8.2 g (95%) of 4-(2-bromoethoxy)-3,5-dimethylbenzaldehyde as an oil. 'H-NMR (300 MHz, CDC13): 6 = 2.33 (6H, s), 3.83 (2H, t), 4.18 (2H, t), 7.60 (2H, s), 9.88 (1H, 5 s). Preparation of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde: 1,2-Dibromoethane (62 mL, 0.72 moles) was added to a mixture of 3,5-dibromo-4 10 hydroxybenzaldehyde (10 g, 36 mmoles) and potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred vigorously at 70 0C for 16 hours. After cooling, the mixture was poured into water (300 mL) and extracted with ethyl acetate (400 mL). Water (200 mL) was added to the aqueous phase and this was extracted with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium chlo 15 ride (3 x 150 mL), dried over MgSO 4 and evaporated in vacuo. The residue was dissolved in refluxing 96% ethanol (60 mL). Water (15 mL) was added and after cooling, filtration, wash ing with 60% ethanol and drying 10.7 g (77%) of 4-(2-bromoethoxy)-3,5 dibromobenzaldehyde was isolated in two crops. M.p. 84 - 85 *C. 20 Preparation of 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde: A mixture of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (20 g, 72 mmoles), ethylene glycol (8.0 mL, 144 mmoles), and chlorotrimethylsilane 36.5 mL, 0.29 moles) in dichloromethane (300 mL) was heated at reflux for 16 hours. The mixture was cooled to room temperature 25 and washed with saturated sodium hydrogencarbonate (3 x 200 mL). The combined aque ous phases were extracted with dichloromethane (3 x 150 mL). The combined organic ex tracts were washed with saturated sodium chloride (200 mL), dried over MgSO 4 and evapo rated in vacuo to afford 22.1 g (95%) of 4-[1,3]dioxolan-2-yl-2-iodo-6-methoxy-phenol. M.p. 120 - 121 *C. 30 Under N 2 , tetrakis-triphenylphosphinepalladium(0) was added to a mixture of the above di oxolane (10 g, 31 mmoles), benzeneboronic acid (4.5 g, 37 mmoles), toluene (67 mL), 2 M aqueous sodium carbonate (33 mL) and methanol (20 mL). The resulting mixture was WO 99/01423 PCT/DK98/00287 389 heated at reflux under N 2 for 16 hours. After cooling the mixture was diluted with water (150 mL) and washed with heptane (400 mL) . The aqueous phase was made acidic with 3N hy drochloric acid and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were dried over MgSO 4 and evaporated in vacuo. The residue was purified by column chro 5 matography over silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:2) to afford 5.49 g (77%) of 4-hydroxy-3-methoxy-5-phenylbenzaldehyde. M.p. 107 - 108 *C. 1,2-Dibromoethane (41 mL, 0.48 moles) was added to a mixture of the above 4-hydroxy-3 methoxy-5-phenylbenzaldehyde (5.49 g, 24 mmoles) and potassium carbonate (17 g, 123 10 mmoles) in DMF (80 ml) and the resulting mixture was stirred vigorously at room tempera ture for 16 hours. The mixture was poured into water (1 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (200 mL), dried over MgSO 4 and evaporated in vacuo to afford 8.1 g (100%) of 4-(2 bromoethoxy)-3-methoxy-5-phenylbenzaldehyde as an oil. 15 'H-NMR (300 MHz, DMSO-d,): 8 = 3.50 (2H, t), 3.96 (3H, s), 4.19 (2H, t), 7.4-7.6 (11H, m). Preparation of 4-(2-bromoethoxy)-1-naphthaldehyde: 20 1,2-Dibromoethane (30 mL, 0.35 moles) was added to a mixture of 4-hydroxy-1 naphthaldehyde (6 g, 35 mmoles) and potassium carbonate (24 g, 175 mmoles) in DMF (110 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over 25 MgSO 4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:1) to afford 8.5 g (88%) of 4-(2-bromoethoxy)-1-naphthaldehyde as a solid. M.p.: 83 - 84 *C. Calculated for C 13 H,,BrO 2 : C, 55.94%; H, 3.97%. 30 Found: C, 56.10%; H, 3.98%; C, 56.30%; H, 3.97%. Preparation of 4-(2-bromoethoxy)-3,5-dimethoxybenzaldehyde: WO 99/01423 PCT/DK98/00287 390 1,2-Dibromoethane (47 mL, 0.55 moles) was added to a mixture of syringaldehyde (10 g, 55 mmoles) and potassium carbonate (38 g, 275 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3 x 300 mL). The combined organic 5 phases were washed with saturated sodium chloride (500 mL), dried over MgSO 4 and evaporated in vacuo to afford 3.44 g (22%) of 4-(2-bromoethoxy)-3,5 dimethoxybenzaldehyde. 1 H-NMR (300 MHz, DMSO-d 6 ): S = 3.70 (2H, t), 3.88 (3H, s), 4.27 (2H, t), 7.27 (2H, s). 10 Preparation of 3-(2-bromoethoxy)-4-methoxybenzaldehyde: 1,2-Dibromoethane (56 mL, 0.66 moles) was added to a mixture of 3-hydroxy-4 methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 328 mmoles) in 15 DMF (170 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with saturated sodium chloride (500 mL), dried over MgSO 4 and evaporated in vacuo. The residue was purified by column chromatog raphy on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:1) to af 20 ford 9.8 g (58%) of 3-(2-bromoethoxy)-4-methoxybenzaldehyde. 'H-NMR (300 MHz, DMSO-d 6 ): 5 = 3.82 (2H, t), 3.90 (3H, s), 4.40 (2H, t), 7.22 (1H, d), 7.44 (1H, d), 7.59 (1H, dd). 25 Preparation of 4-(2-bromoethoxy)-3-bromo-5-methoxybenzaldehyde: 1,2-Dibromoethane (37 mL, 0.43 moles) was added to a mixture of 5-bromovanillin (10 g, 43 mmoles) and potassium carbonate (30 g, 216 mmoles) in DMF (150 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours followed by vigorously stir 30 ring at 60 *C for 16 hours. The cooled mixture was poured into water (1 L) and extracted with ethyl acetate (3 x 250 mL). The combined organic phases were washed with saturated so dium chloride (300 mL), dried over MgSO 4 and evaporated in vacuo to afford 13.7 g (94%) of 4-(2-bromoethoxy)-3-bromo-5-methoxybenzaldehyde.
WO 99/01423 PCT/DK98/00287 391 1 H-NMR (300 MHz, DMSO-d 6 ): 8 = 3.79 (2H, t), 3.93 (3H, s), 4.40 (2H, t), 7.55 (1H, d), 7.79 (1H, d). 5 EXAMPLE 695: Preparation of 3-Chloro-4-hydroxybenzoic acid {4-[2-(1.2.3.4-tetrahydroisoquinolin-2 yl)ethoxy]-2-methoxybenzylidene}hydrazide cH 3 N N O N H H HOq ci 10 The resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block1) (3 g, -3 mmoles) was swelled in DMF (35 mL) for 30 minutes. Then 4-(2-bromoethoxy)-2 methoxybenzaldehyde (2.33 g, 9 mmoles) and triethyl orthoformate (18 mL) were added and the mixture was shaken at room temperature for 16 hours. The resin was repeatedly swelled 15 in DMF (35 ml, 4 times), CH 2
CI
2 (35 mL, 6 times) and N-methyl-2-pyrrolidinone (NMP) (35 mL, 2 times) and filtered. The resin was swelled in NMP (40 mL) and 1,2,3,4 tetrahydroisoquinoline (3.75 mL, 30 mmoles) and potassium iodide (1.0 g, 6 mmoles) were added. The resin was shaken at room temperature for 16 hours and filtered. The resin was repeatedly swelled in DMF (40 ml, 5 times), CH 2
C
2 (40 mL, 10 times) and filtered. The com 20 pound was cleaved off the resin by shaking for 1 hour at room temperature with a 50% solu tion of trifluoroacetic acid in CH 2 Cl 2 (40 mL). The mixture was filtered and the resin was ex tracted with CH 2 Cl 2 (40 mL, 2 times). The combined CH 2 Cl 2 extracts were concentrated in vacuo. The residue was dissolved in CH 2 Cl 2 (40 mL) and concentrated in vacuo. The residue was dissolved in methanol (40 mL) and concentrated in vacuo. The residue was partitioned 25 between ethyl acetate (50 mL) and saturated sodium hydrogencarbonate (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL), and the combined organic extracts were dried over MgSO 4 and concentrated in vacuo. The residue was purified by coloumn chromatography over silica gel (200 mL) eluting with a mixture of CH 2 Cl 2 and methanol (9:1). This afforded 280 mg of the title compound.
WO 99/01423 PCT/DK98/00287 392 HPLC-MS (METHOD A): Rt = 8.44 min; m/z = 480 (M+1). 1 H-NMR (300 MHz, DMSO-d 6 ) 5 = 2.80 (4H, m), 2.90 (2H, t), 3.69 (2H, s), 3.86 (3H, s), 4.25 5 (2H, t), 6.68 (2H, m), 7.04 (1H, d), 7.07-7.14 (5H, m), 7.75 (1H, dd), 7.80 (1H, bs), 7.96 (1H, d), 8.58 (1H, s), 11.6 (1H, s). HR-MS: Calcd. for C 2 eH 26
CIN
3 0 4 : 479.1611; Found: 479.1604. 10 EXAMPLE 696: 3-Chloro-4-hydroxybenzoic acid {2-methoxy-4-[2-(4-trifluoromethylbenzylamino)ethoxy] benzylidene}hydrazide
CH
3 0 o'." 0 r~ N H F H N F 15 This compound was prepared analogously to the compound described in the previous ex ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, -2 moless, 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and 4-trifluoromethylbenzylamine ([building block 3]) (3.3 g, 10 20 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1 g) was purified by col umn chromatography on silica gel (20 g) eluting with a mixture of 25% aq. ammonia, ethanol and dichloromethane (1:9:115). This afforded 130 mg of the title compound. HPLC-MS (METHOD A): R, = 9.4 min; m/z = 522 (M+1). 25 EXAMPLE 697: 3-Chloro-4-hydroxybenzoic acid {4-[2-(4-benzylpiperazin-1 -yl)ethoxy]-2 methoxybenzylidene}hydrazide WO 99/01423 PCT/DK98/00287 393
CH
3 0 0 N CI N N N HOH This compound was prepared analogously to the compound described in the previous ex ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building 5 block 1]) (2 g, -2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and 1-benzylpiperazine ([building block 3]) (3.3 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.4 g) was dissolved in 2-propanol (50 ml) and concentrated to 20 ml. The mixture was allowed to stand at 5 0C for 1 h and filtered. The mother liquor was concentrated in vacuo and the residue was purified by column chro 10 matography on silica gel (20 g) eluting with a mixture of methanol and dichloromethane (1:9). This afforded 0.98 g of the title compound. 1 H-NMR (400 MHz, DMSO-d 6 ): SH = 2.4 (2H, bs), 2.55 (2H, bs), 2.62 (2H, bs), 3.50 (2H, bs), 3.85 (3H, s), 4.15 (2H, t), 6.62 (2H, m), 7.05 (1H, d), 7.30 (5H, m), 7.75 (2H, t), 7.97 (1H, s), 15 8.67 (1H, s), 11 (1H, bs), 11.5 (1H, s). HPLC-MS (METHOD A): Rt = 7.7 min; m/z = 523 (M+1). EXAMPLE 698: 20 3-Chloro-4-hydroxybenzoic acid {2-methoxy-4-[2-(2-phenylpiperidin-1 yl)ethoxylbenzylidene}hydrazide
CH
3 H N O N C I H 25 This compound was prepared analogously to the compound described in the previous ex ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, -2 mmoles), 4-(2-bromoethoxy)-2-methoxybenzaldehyde ([building block 2]) WO 99/01423 PCT/DK98/00287 394 (0.73 g, 1.5 equivs.), and 2-phenylpiperidine ([building block 3]) (3.0 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was purified by column chroma tography on silica gel (28 g) eluting with a mixture of methanol and dichloromethane (1:13). This afforded 0.24 g of the title compound. 5 1 H-NMR (400 MHz, DMSO-d 6 ): 5H = 1.4 (2H, m), 1.65 (4H, m), 2.25 (2H, m), 2.75 (1H, m), 3.16 (1H, d), 3.25 (2H, d), 3.83 (3H, s), 4.0 (2H, m), 6.50 (1H, d), 6.54 (1H, s), 7.07 (1H, d), 7.23 (1H, t), 7.35 (4H, m), 7.73 (1H, d), 7.77 (1H, dd), 7.96 (1H, d), 8.65 (1H, s), 10.9 (1H, s), 11.6 (1H, s). 10 HPLC-MS (METHOD A): R, = 9.1 min; m/z = 508 (M+1). EXAMPLE 699: 3-Chloro-4-hydroxybenzoic acid {3-chloro-4-[2-(1.2.3.4-tetrahydro-isoquinolin-2-yl)ethoxyl-5 15 methoxybenzylidene}hydrazide O' CH 3 0 - 'N I H HO cl 20 This compound was prepared analogously to the compound described in the previous ex ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, -2 mmoles), 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde ([building block 2]) (0.81 g, 1.5 equivs.), and 1,2,3,4-tetrahydroisoquinoline ([building block 3]) (2.5 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was dissolved in 25 15 ml of a mixture of 25% aq. ammonia, methanol and dichloromethane (1:9:90) and purified by column chromatography on silica gel (25 g) eluting with a mixture of methanol and di chloromethane (1:12). This afforded 0.11 g of the title compound.
WO 99/01423 PCT/DK98/00287 395 'H-NMR (400 MHz, DMSO-d 6 ): SH = 1.9 (1H, p), 2.18 (1H, t), 2.90 (2H, t), 3.70 (2H, s), 3.90 (3H, s), 4.19 (2H, t), 7.05 (5H, m), 7.37 (2H, s), 7.78 (1H, d), 7.95 (1H, s), 8.33 (1H, s), 11 (1H, bs), 11.8 (1H, s). 5 HPLC-MS (METHOD A): Rt = 9.0 min; m/z = 514 (M+1). EXAMPLE 700: 3-Chloro-4-hydroxybenzoic acid {6-[2-(1.2.3.4-tetrahydro-isoquinolin-2-yI)ethoxy]-5 10 methoxybiphenyl-3-ylmethylene}hydrazide O. CH 3 0 0 HN N HO ci This compound was prepared analogously to the compound described in the previous ex 15 ample starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) (2 g, -2 mmoles), 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde ([building block 2]) (0.93 g, 1.5 equivs.), and 1,2,3,4-tetrahydroisoquinoline ([building block 3]) (2.5 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue was dissolved in 15 ml of a mixture of 25% aq. ammonia, methanol and dichloromethane (1:9:90) and purified by 20 column chromatography on silica gel (25 g) eluting with a mixture of methanol and di chloromethane (1:12). This afforded 0.31 g of the title compound. 1 H-NMR (400 MHz, DMSO-d): 5H = 2.60 (4H, m), 2.70 (2H, m), 3.48 (2H, s), 3.92 (3H, s), 3.96 (2H, t), 6.98 (1H, m), 7.10 (4H, m), 7.22 (1H, s), 7.40 (4H, m), 7.55 (2H, d), 7.78 (1H, 25 d), 8.00 (1H, s), 8.40 (1H, s), 11 (1H, bs), 11.7 (1H, s). HPLC-MS (METHOD A): Rt = 9.6 min; m/z = 557 (M+1). EXAMPLE 701: WO 99/01423 PCT/DK98/00287 396 3-Chloro-4-hydroxybenzoic acid (3.5-dibromo-4-{2-[4-(4-chloropheryl)piperazin-1 -yl] ethoxy}benzylidene)hydrazide Br 0 HO .N Br N CI HO Nci ci 5 A solution of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde ([building block 2]) in DMF (0.6 M, 1 mL) was added to the resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin [building block 1]) (0.05 mmoles) followed by addition of triethyl orthoformate (0.5 mL) and the mixture was shaken at room temperature for 15 hours. The resin was repeatedly swelled in DMF (1.5 mL, 3 times), CH 2 Cl 2 (1.5 mL, 2 times) and NMP (1.5 mL, 2 times) for 5 minutes 10 and filtered. The resulting resin (resin-[building block 1]-[building block 2]) was added a solu tion of 1-(4-chlorophenyl)piperazine (0.4 M, 1 mL) and a solution of potassium iodide in NMP (0.08 M, 0.5 mL) were added and the mixture was shaken at room temperature for 16 hours. The resin was repeatedly swelled in DMF (1.5 mL, 3 times) and CH 2 Cl 2 (1.5 mL, 6 times) for 2 minutes and filtered. 15 The compound was cleaved off the resin by shaking for 1 hour at room temperature with a 50% solution of trifluoroacetic acid in CH 2 Cl 2 (1.5 mL). The mixture was filtered and the resin was extracted with CH 2 Cl 2 (0.5 mL). The combined CH 2 Cl 2 extracts were concentrated in vacuo. The residue was dissolved in methanol (1 mL) and concentrated in vacuo. The resi 20 due was dissolved in a 1:1 mixture of methanol and CH 2 Cl 2 (1 mL) and concentrated in vacuo to give the title compound. HPLC-MS (METHOD B): Rt = 15.02 min; m/z = 671. 25 EXAMPLES 702 TO 791 : The following 90 compounds were prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer.
WO 99/01423 PCT/DK98/00287 397 Further, a library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2] and [building block 3]) was prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 5 384 HTS using the following ChemFile to control the operation of the synthesizer. The com pounds are all expected to be present in the respective wells. The resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block 1]) is equally distributed in the wells in the synthesizer prior to the initialization of the device. 10 ChemFile C:\ACT_1328\90250012.CHM: 1 REM Filtration of resin 2 Empty RB1_1to96 for 5.000 minute(s) 15 3 Empty RB2_1to96 for 5.000 minute(s) 4 Empty RB3_1to96 for 5.000 minute(s) 5 Empty RB4_1to96 for 5.000 minute(s) 6 Pause 7 20 8 REM Washing of resin 9 10 Dispense System Fluid Disdul_4* 1500ul to RBI_to96[1-96] 11 Dispense System Fluid Disdul_4* 1500ul to RB2_1 to96[1-96] 12 Dispense System Fluid Disdul_4* 1500ul to RB3_lto96[1-96] 25 13 Dispense System Fluid Disdul_4* 1500ul to RB4_1to96[1-96] 14 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. 15 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. 16 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 17 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 30 18 Wait for 25.000 minute(s) 19 Repeat from step 14, 1000 times 20 Empty RB1_1to96 for 5.000 minute(s) 21 Empty RB2_1to96 for 5.000 minute(s) 22 Empty RB3_1to96 for 5.000 minute(s) 35 23 Empty RB4_1to96 for 5.000 minute(s) 24 Pause 25 26 REM Coupling with aldehydes 27 40 28 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96] 29 Dispense System Fluid Disdu2_3* 1500ul to RB2_1to96[1-96] 30 Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96] 31 Dispense System Fluid Disdu2_3* 1500ul to RB4_lto96[1-96] WO 99/01423 PCT/DK98/00287 398 32 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. 33 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. 34 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 35 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 5 36 Empty RB1_1to96 for 5.000 minute(s) 37 Empty RB2_1to96 for 5.000 minute(s) 38 Empty RB3_1to96 for 5.000 minute(s) 39 Empty RB4_1to96 for 5.000 minute(s) 40 Pause 10 41 42 Dispense Sequence c:\ACT13_28\R2-A.DSP with 1000ul to RB1_1to96 rack using DMF 43 Mix "RB1_1to96" for 2.00 minutes at 600 rpm(s) and wait. 44 Dispense Sequence c:\ACT13_28\R2-B.DSP with 1000ul to RB2_1to96 rack using DMF 45 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. 15 46 Mix "RB2_1to96" for 2.00 minutes at 600 rpm(s) and wait. 47 Dispense Sequence c:\ACT13_28\R2-C.DSP with 1000ul to RB3_1to96 rack using DMF 48 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. 49 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue. 50 Mix "RB3_1to96" for 2.00 minutes at 600 rpm(s) and wait. 20 51 Dispense Sequence c:\ACT13_28\R2-D.DSP with 1000ul to RB4_1to96 rack using DMF 52 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. 53 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue. 54 Start mixing "RB3_1to96" for 2.00 minutes at 600 rpm(s) and continue. 55 Mix "RB4_1to96" for 2.00 minutes at 600 rpm(s) and wait. 25 56 57 Pause 58 REM Manual addition of CH(OC2H5)3 59 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. 60 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. 30 61 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 62 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 63 Wait for 25.000 minute(s) 64 Repeat from step 59, 200 times 65 Empty RB1_1to96 for 5.000 minute(s) 35 66 Empty RB2_1to96 for 5.000 minute(s) 67 Empty RB3_1to96 for 5.000 minute(s) 68 Empty RB4_1to96 for 5.000 minute(s) 69 Pause 70 40 71 REM Wash after coupling with aldehydes 72 73 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 74 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96] 75 Dispense System Fluid Disdu2_3* 1500ul to RB2_1to96[1-96] 45 76 Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96] 77 Dispense System Fluid Disdu2_3* 1500ul to RB4_lto96[1-96] 78 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. 79 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. 80 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue.
WO 99/01423 PCT/DK98/00287 399 81 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 82 Empty RB1_1to96 for 5.000 minute(s) 83 -Empty RB2_1to96 for 5.000 minute(s) 84 Empty RB3_1to96 for 5.000 minute(s) 5 85 Empty RB4_1to96 for 5.000 minute(s) 86 Repeat from step 74, 2 times 87 Pause 88 Dispense System Fluid Disdul_4* 1500ul to RB1_1to96[1-96] 89 Dispense System Fluid Disdul_4* 1500ul to RB2_lto96[1-96] 10 90 Dispense System Fluid Disdul_4* 1500ul to RB3_lto96[1-96] 91 Dispense System Fluid Disdul_4* 1500ul to RB4lto96[1-96] 92 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. 93 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. 94 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 15 95 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 96 Empty RB1_1to96 for 5.000 minute(s) 97 Empty RB2_1to96 for 5.000 minute(s) 98 Empty RB3_1to96 for 5.000 minute(s) 99 Empty RB4_1to96 for 5.000 minute(s) 20 100 Repeat from step 88, 1 times 101 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96] 102 Dispense System Fluid Disdu2_3* 1500ul to RB2_lto96[1-96] 103 Dispense System Fluid Disdu2_3* 1500ul to RB3_lto96[1-96] 104 Dispense System Fluid Disdu2_3* 1500ul to RB4_lto96[1-96] 25 105 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. 106 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. 107 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 108 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 109 Wait for 25.000 minute(s) 30 110 Repeat from step 105, 1000 times 111 Pause 112 Empty RB1_1to96 for 5.000 minute(s) 113 Empty RB2_1 to96 for 5.000 minute(s) 114 Empty RB3_1to96 for 5.000 minute(s) 35 115 Empty RB4_1to96 for 5.000 minute(s) 116 Repeat from step 101, 1 times 117 118 REM Coupling with amines 119 Flush Arm1 with Disdu2_3*, Arm2 with Disdu2_3* 40 120 Dispense Sequence c:\ACT13_28\R3-A.DSP with 1000ul to RB1_1to96 rack using NMP 121 Mix "RB1_1to96" for 2.00 minutes at 600 rpm(s) and wait. 122 Dispense Sequence c:\ACT13_28\R3-B.DSP with 1000ul to RB2_1to96 rack using NMP 123 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. 124 Mix "RB2_1to96" for 2.00 minutes at 600 rpm(s) and wait. 45 125 Dispense Sequence c:\ACT13_28\R3-C.DSP with 1000ul to RB3_1to96 rack using NMP 126 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. 127 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue. 128 Mix "RB3_1to96" for 2.00 minutes at 600 rpm(s) and wait. 129 Dispense Sequence c:\ACT13_28\R3-D.DSP with 1000ul to RB4_1to96 rack using NMP WO 99/01423 PCT/DK98/00287 400 130 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. 131 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue. 132 Start mixing "RB3_1to96" for 2.00 minutes at 600 rpm(s) and continue. 133 Mix "RB4_1to96" for 2.00 minutes at 600 rpm(s) and wait. 5 134 Pause 135 Transfer 500ul from REAGENT_3[1]() to RB1_1to96[1-96] using NMP 136 Mix "RB1_1to96" for 2.00 minutes at 600 rpm(s) and wait. 137 Pause 138 Transfer 500ul from REAGENT_3[1]() to RB2_1to96[1-96] using NMP 10 139 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. 140 Mix "RB2_1to96" for 2.00 minutes at 600 rpm(s) and wait. 141 Pause 142 Transfer 500ul from REAGENT_3[1]() to RB3_1to96[1-96] using NMP 143 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue. 15 144 Start mixing "RB2_1to96" for 2.00 minutes at 600 rpm(s) and continue. 145 Mix "RB3_1to96" for 2.00 minutes at 600 rpm(s) and wait. 146 Pause 147 Transfer 500ul from REAGENT_3[1]() to RB4_1to96[1-96] using NMP 148 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. 20 149 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. 150 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 151 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 152 Wait for 25.000 minute(s) 153 Repeat from step 148, 200 times 25 154 Pause 155 156 Empty RB1_1to96 for 5.000 minute(s) 157 Empty RB2_1to96 for 5.000 minute(s) 158 Empty RB3_1to96 for 5.000 minute(s) 30 159 Empty RB4_1to96 for 5.000 minute(s) 160 161 162 REM Wash after coupling with amines 163 35 164 Flush Arm1 with Flush Diluter1 and Flush Diluter 2, Arm2 with Flush Diluter 165 166 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96] 167 Dispense System Fluid Disdu2_3* 1500ul to RB2_lto96[1-96] 168 Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96] 40 169 Dispense System Fluid Disdu2_3* 1500ul to RB4_lto96[1-96] 170 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. 171 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. 172 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 173 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 45 174 Empty RB1_1to96 for 5.000 minute(s) 175 Empty RB2_1to96 for 5.000 minute(s) 176 Empty RB3_1to96 for 5.000 minute(s) 177 Empty RB4_1to96 for 5.000 minute(s) 178 Repeat from step 166, 2 times WO 99/01423 PCT/DK98/00287 401 179 Pause 180 Dispense System Fluid Disdul_4* 1500ul to RB1_1to96[1-96] 181 Dispense System Fluid Disdul_4* 1500ul to RB2_lto96[1-96] 182 Dispense System Fluid Disdul_4* 1500ul to RB3_lto96[1-96] 5 183 Dispense System Fluid Disdul_4* 1500ul to RB4_lto96[1-96] 184 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. 185 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. 186 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 187 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 10 188 Empty RB1_1to96 for 5.000 minute(s) 189 Empty RB2_1to96 for 5.000 minute(s) 190 Empty RB3_1to96 for 5.000 minute(s) 191 Empty RB4_1to96 for 5.000 minute(s) 192 15 193 Repeat from step 180, 5 times 194 195 Dispense System Fluid Disdul_4* 1500ul to RBl1to96[1-96] 196 Dispense System Fluid Disdul_4* 1500ul to RB2_lto96[1-96] 197 Dispense System Fluid Disdul_4* 1500ul to RB3_lto96[1-96] 20 198 Dispense System Fluid Disdul_4* 1500ul to RB4_lto96[1-96] 199 Start mixing "RB1_1to96" for 5.00 minutes at 600 rpm(s) and continue. 200 Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue. 201 Start mixing "RB3_1to96" for 5.00 minutes at 600 rpm(s) and continue. 202 Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait. 25 203 Wait for 25.000 minute(s) 204 Repeat from step 199, 1000 times 205 206 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 207 Empty RB4_1to96 for 5.000 minute(s) 30 208 Pause 209 210 REM Clevage (50%TFA/DCM manually added, one rack at a time) 211 Flush Arm1 with Flush Diluter1, Arm2 with Flush Diluter 4 212 Mix "RB1_1to96" for 5.00 minutes at 600 rpm(s) and wait. 35 213 Wait for 5.000 minute(s) 214 Repeat from step 7, 5 times 215 Empty RB1_1to96 for 1 second(s) 216 Wait for 4 second(s) 217 Repeat from step 10, 25 times 40 218 Empty RB1_1to96 for 5.000 minute(s) 219 220 Dispense System Fluid Disdul_4* 500ul to RB1_to96[1-96] 221 Wait for 1.000 minute(s) 222 Empty RB1_1to96 for 1 second(s) 45 223 Wait for 4 second(s) 224 Repeat from step 17, 25 times 225 Empty RB1_1to96 for 5.000 minute(s) 226 WO 99/01423 PCT/DK98/00287 402 Dispense sequence files C:\ACT13_28\R3-A.DSP, C:\ACT13_28\R3-B.DSP, C:\ACT 13_28\R3-C.DSP and C:\ACT13_28\R3-D.DSP are subroutines that control the combinato rial addition of the amines into the 4 reaction blocks each containing 96 wells in the syn theziser. 5 The library containing the following compounds was synthesized, and the products were characterised by HPLC-MS (molecular mass & retention time).
WO 99/01423 PCT/DK98/00287 403 Ex Structure HPLC-MS HPLC-MS No. (METHOD B) (METHOD B) m/z Rt (minutes) 702 0 MeO O N 596 15.9 N H IJ H I1 HO CI CI 703 MeO O N 522 8.82 N HO H CI 704 CI 502 6.62 0MeO 0 "N ' : I H H HO CI 705 MeO O -N 488 6.68 .NsHHC HO CI 706 MeO O N 543 10.93 .N N j H HO CI CI 707 MeO O,-N cl 522 9.40 H N C1 CIC I H HO CI 708 494 7.87 O MeO O N N N I H I H HO Cl SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 404 709 MeO O N 558 5.37 .N OH HO cl CI 710 0 MeO N 577 13.50 NN N Cl IP H HO C1 CI 711 0 MeO O N 539 7.43 N N.N :D N OMe HO H HO CI 712 OH 214 2.05 MeO O N[; 0NN. OH HO H HOH CI 713 NMOBr 548 7.10 0MeO 0 NB N N H HO H HO CI 714 OH NMOc1 532 5.38 HO P H CI 715 C1 536 8.43 N'MeO 0 N Cl j N. N N N HO Cl 716 0 MeO O -'N 538 9.05 N. H O.CF3 HO Cl SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 405 717 OMe CI 572 9.93 O - N N CI HO N Cl 718 OMe 572 10.78 0 . N -. CF HO CI 719 598 11.47 N N OM H H HO 0 CI 720 618 7.35 OMe 0 0 '- N 'N OMe N.~. 'NCH, N' OMe H HO CI 721 574 7.27 OMe O O~ 0 "N CI 722 548 8.50 O N H N.N 'N OMe F H HO Cl SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 406 723 564 11.38 0N .N '9 W OMe cl I H HO ci 724 619 14.47 O O N N. OMe HO C cI 725 598 13.87 O N CI N N OMe Cl H HO CI 726 570 12.50 O N HO.NN OMeH N N m HO( CI 727 560 6.02 OO N O N N..N OMe HOC CI 728 B T634 8.05 N N .N-... N ome N b HO jci Ci SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 407 729 655 16.35 0 0 N N'N OMeCl I; H HO CI cl 730 615 12.15 OO N N OMe ,OIC NN ,, OMe Il I H HO CI 731 616 8.30 O ~ O N OMe ( N OMe OMe HO CI 732 590 5.30 OH I H O H j NN ' OMe OH H HO Cl 733 624 10.90 Br H 0 N Brgome I H HO Cl 734 608 8.95 OH .CI O O - 0 N .Ns OMeH HH HO Cl SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 408 735 612 12.65 O CI CCI N I H N' OMe HO CI 736 550 7.88 00 0 H HO N OMe HO
J
CI 737 614 13.07 O O N N OMe HO.CF3 HO CI 738 559 2.33 O H N OMe - NH 2 HO Cl 739 616 17.98 0~ N N- N. HO N Cl 740 587 7.87 0 .N O N O ~~ N N-". LN ~ N 0 IOCP H HO Cl SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 409 741 OH 504 5.40 0 N N H N N.. N' I H HO 742 N 557 6.57 N , N HO H CI 743 5.42 12.68 N N N I H HO CI 744 500 11.95 0 N HN N I H 745 518 8.83 0N HO N CI 746 ONC522 9.53 N N H HO N Cl 7457~ 518 8.83 NN N H OH " om HOI? C SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 410 748 9. OMe 562 7.35 0 N 0 ,INOMe N..N OH, HO H HO CI 749 545 7.54 0 0 N -'H N-.. N HO 7 H H 3 N CH 3 CI 750 OMe 518 6.52 0 0 N j N N H HO H HO CI 751 492 7.57 0 0 -~N N N O N N ~ HN- ' I H HO CI 752 543 6.13 0 0 N N Np N.N N /H I H HO CI 753 B T518 6.43 0 N' 0 'N N 0 IO? HI 0 N.~ HOH NN CF' 3 H H HO CI SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 411 755 508 10.32 0 N CH 756 563 14.17 O NN N H HO. CI 7567. 563 14.17 N c NNO N N.NH C HO H CI 758 CH 3 522 12.65 HO HO .N CI CI 759 514 12.03 N O N I HI N N N I H HO CI 760 504 4.57 N N H OH HO H HO CI 761 543 9.30 00 H N.N N I H HOH Cl I I SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 412 762 578 7.77 0 0 N OH HO NC Cl 763 489 2.23 0 0 N N .N H H NHH
NH
2 HO'? CI 764 597 15.73 0 N) j N N N ~ Cl H HO CI Cl 765 559 11.25 0 0 N N N.N N N OMe HO H HO CI 766 571 8.38 0 0 N N N HN HO-f;T lc-- CH 3 CI 0 767 528 15.38 0 0 ll- N HON HO0 CI 768 560 8.00 0 ONNN OMe HO Cl SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 413 769 OH 5.34 3.33 O O ON N.N H OH I" H HO CI 770 475 2.23 O N N 'l H HO CI 771 O NBr 568 10.07 0 H N H HO [I H HO CI 772 OH Cl 552 6.93 O N 0 -N 0I H N N IO: H HO. CI 773 Ci 556 12.02 O N 0 -N CN 0 HCI O jN .N CI 774 s494 7.12 0 0 N 't H N H I H HO CI 775 558 12.58 N N .N O CF HO Cl SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 414 776 577 12.68 N' O NN CN HOI H HO C1 777 530 13.23 0 0 "'-N'N HON O CH HO J AHCH 3 3 CI 778 503 1.88 N O NN 0 N.N N H - NH 2 HI[C H HO CI 779 CI 626 15.23 OMe O - QN 0N OMe S HO .NO-A CI 780 OMe 518 5.23 O &- 0
-
-a , N 0 .N O HO N CI 781 OMe 573 8.48 0 N HO . NOMe N OeC 782 OMe 552 7.52 O0 0 "-'- N Na CI 0 .N OMe CI HO HO CI SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 415 783 OMe 607 12.25 0 0 "N H.N' OMe N Cl I H HO c CI 784 OMe Br 578 5.70 HO.
O~
0 "~e C H 785N O 54H79 0 .N OMe HO CH3 CI 785 OMe 540 7.98 O ~ - -~ 0 'N N Y OOMe H CH N N.NN Oe N HO .OH 3 CI 786 K.<CI 577 11.48 7 OMe 60N1.1 N N 'N~ ,,aN "_ HO .N B CI 787 O OMe 548 5.63 HOH N N ,,( 0 - N HO -C Br CI 788 OMe 602 12.13 I,_, O HI N N Br CI HO j CI 789 OMe OH 3 582 11.67 . N~ H"~ N .~N Br Cl I H HO CI SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 416 790 OMe 549 1.70 HO N Br
NH
2 HO'P cl 791 OMe 549 15.33 O 0 N .N-N C1 HON Br N zcI I H HO ci ci EXAMPLE 792: 3-Amino-4-hydroxybenzoic acid {4-[2-(1.2.3,4-tetrahydro-isoquinolin-2-yl)ethoxy-2 methoxybenzylidene}hydrazide 5 cH 3 0 0 0 :: HN N , O 2 I . N 2 H HO The above 4-(2-bromoethoxy)-2-methoxybenzaldehyde (16.8 g, 65 mmol) ([building block 2]) was dissolved in acetone (300 ml) and potassium carbonate (44.9 g, 0.33 10 mol), potassium iodide (2 g) were added followed by addition of 1,2,3,4 tetrahydroisoquinoline (9.07 g, 72 mmol). The resulting mixture was stirred vigorously at reflux temperature for 16 hours. After cooling, the mixture was filtered and the inor ganic precipitate was washed with acetone (100 ml). The combined acetone filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and 15 washed with water (2 x 20 ml) saturated sodium chloride (20 ml), dried over MgSO 4 and concentrated in vacuo. The residue (23 g) was purified by column chromatography on silica gel (400 g) eluting first with a mixture of ethyl acetate and heptane (1:1, 2 liters) then with a mixture of ethyl acetate and heptane (2:1, 5 liters) to afford 12 g (60%) of 4 [2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde as a solid. M.p.: 20 69 - 71 OC. Calculated for C 19
H
21
NO
3 .0.25H 2 0: C, 72.24%; H, 6.86%; N, 4.43%. SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 417 Found: C, 72.79%; H, 6.86%; N, 4.46%; C, 72.65%; H, 6.88%; N, 4.47%. Methyl 3-amino-4-hydroxybenzoate (5.0 g, 30 mmol) was dissolved in ethanol (50 ml) and hydrazine hydrate (4.4 ml, 90 mmol) was added and the resulting mixture was heated at re 5 flux temperature for 16 hours. After cooling the mixture was filtered and solid was washed with ethanol to afford after drying 1.4 g (28%) of 3-amino-4-hydroxybenzoic acid hydrazide as a solid. M.p.: 242 - 243 "C. Calculated for CH 9
NA
2 : C, 50.30%; H, 5.43%; N, 25.14%. 10 Found: C, 50.27%; H, 5.46%; N, 24.35%; C, 50.41%; H, 5.47%; N, 24.38%. The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-[2 (1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde (93 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 15 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 x 4 ml) and dried by suction to afford 66 mg (48%) of the title compound as a solid. M.p.: 162 164 *C. HPLC -MS (METHOD B): Rt = 6.50 minutes. m/z = 461. 20 EXAMPLE 793: 3-Amino-4-hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidene] hydrazide CH, OcH 3 CH 3 0 0
H
2 N N.N sO H HO 25 Syringaldehyde (4-hydroxy-3,5-dimethoxybenzaldehyde) (10.2 g, 55 mmol) was dissolved in DMF (45 ml), and 4-isopropylbenzylchloride (9.7 g, 55 mmol) and potassium carbonate (11.5 g) were added successively. The resulting mixture was heated at 60 *C for 16 hours. After cooling, the mixture was partitioned between water (150 ml) and ethyl acetate (3 x 100 ml). 30 The combined organic extracts were washed with water (100 ml), saturated NaCl (100 ml), WO 99/01423 PCT/DK98/00287 418 dried (MgSO 4 ), treated with activated carbon, filtered and concentrated in vacuo to afford 15 g (100%) of 4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde as an oil. 1 H-NMR (400 MHz, DMSO-d 6 ): 8H = 1.20 (9H, d), 2.89 (1H, h), 3.86 (6H, s), 4.98 (2H, s), 5 7.23 (2H, d), 7.27 (2H, s), 7.36 (2H, d). The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-(4 isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde(93 mg, 0.3 mmol) were dissolved in 2 propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled 10 mixture was filtered and the precipitate was washed with 2-propanol (2 x 4 ml) and dried by suction to afford 144 mg (100%) of the title compound as a solid. M.p.: 174 - 175 *C. HPLC-MS (METHOD B): R, = 10.40 minutes. m/z = 464. 15 EXAMPLE 794: (R)-2-{4-r(3-Amino-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenoxy}-N-(1 benzylpyrrolidin-3-yl)acetamide
CH
3 0
H
2 N ,oNN O,,-N H (R) HO 20 (R)-(-)-1-Benzyl-3-aminopyrrolidine (5 g, 28 mmol) was dissolved in dichloromethane (10 ml). To this solution, a solution of bromoacetyl chloride (4.55 g, 28 mmol) in dichloromethane (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 6.8 g (72%) of (3R)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid 25 which was used directly in the next step. 4-Hydroxy-2-methoxybenzaldehyde (2.05 g, 13 mmol) was dissolved in DMF (7 ml) and potassium carbonate (6.2 g, 45 mmol) was added followed by a suspension of the above (3R)-N-(1-Benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 9 mmol) in DMF (16 30 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was WO 99/01423 PCT/DK98/00287 419 then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO 4 ) and concentrated in vacuo. The resi due was crystallized from diethyl ether to afford 2.11 g (64%) (R)-N-(1-benzylpyrrolidin-3-yl) 5 2-(4-formyl-3-methoxyphenoxy)acetamide as a solid. M.p.: 98 - 101 0C. Calculated for C21H 2 4
N
2 0 4 .0.5H 2 0: C, 66.83%; H, 6.68%; N, 7.42%. Found: 10 C, 67.15%; H, 6.57%; N, 7.75%; C, 66.96%; H, 6.57%; N, 7.77%. The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (R) N-(1 -benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (110 mg, 0.3 mmol) 15 were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2 x 3 ml) and dried by suction to afford 109 mg (70%) of the title compound as a solid. M.p.: 157 160 "C. 20 HPLC-MS (METHOD B): Rt = 3.10 minutes. m/z = 518. EXAMPLE 795: (R)-2-{4-[(3-Amino-4-hydroxybenzoyl)hydrazonomethyllnaphthyl-1 -yloxy}-N-( 1 benzylpyrrolidin-3-yl)acetamide 1 N HNI H H2N .N (R) 25 HO 4-Hydroxy-1-naphthaldehyde (2.32 g, 13 mmol) was dissolved in DMF (7 ml) and potassium carbonate (6.2 g, 45 mmol) was added followed by a suspension of the above (3R)-N-(1 Benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 9 mmol) in DMF (16 ml). The 30 resulting mixture was stirred at room temperature for 16 hours. The mixture was then parti- WO 99/01423 PCT/DK98/00287 420 tioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO 4 ) and concentrated in vacuo. The residue was pu rified by column chromatography on silica gel (110 g) eluting with ethyl acetate to afford 1.7 5 g (49%) (R)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide as a solid. M.p.: 105 - 107 *C. Calculated for C 24
H
24
N
2 0 3 .0.25H 2 0: C, 73.36%; H, 6.28%; N, 7.13%. 10 Found: C, 73.81%; H, 6.22%; N, 7.11%; C, 73.92%; H, 6.23%; N, 7.11%. The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (R) 15 N-(1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide (116 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (6 x 2 ml) and dried by suction to afford 140 mg (87%) of the title compound as a solid. M.p.: 187 192 *C. 20 HPLC-MS (METHOD B): Rt = 5.72 minutes. m/z = 538. EXAMPLE 796: (S)-2-{4-[(3-Amino-4-hydroxybenzoyl)-hydrazonomethyll-3-methoxyphenoxy}-N-(1 25 benzylpyrrolidin-3-yl)acetamide CHo HN& Nz. ~. 2 ON. O N H (S) HO (S)-(+)-1-Benzyl-3-aminopyrrolidine (6 g, 34 mmol) was dissolved in dichloromethane (12 30 ml). To this solution, a solution of bromoacetyl chloride (5.46 g, 34 mmol) in dichloromethane WO 99/01423 PCT/DK98/00287 421 (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 7.3 g (64%) of (3S)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step. 5 4-Hydroxy-2-methoxybenzaldehyde (2.39 g, 16 mmol) was dissolved in DMF (10 ml) and potassium carbonate (7.3 g, 52 mmol) was added followed by a suspension of the above (3S)-N-(1 -benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.5 g, 10 mmol) in DMF (20 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was 10 then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 ml), dried (MgSO 4 ) and concentrated in vacuo. The resi due (4 g) was crystallised from a mixture of diethyl ether and heptane, filtered and dried in vacuo to afford 2.7 g (71%) (S)-N-(1--benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy) 15 acetamide as a solid. M.p.: 96 - 100 *C. Calculated for C 2 1
H
24
N
2 0 4 .0.25H 2 0: C, 67.63%; H, 6.62%; N, 7.51%. Found: 20 C, 67.35%; H, 6.61%; N, 7.85%; C, 67.24%; H, 6.59%; N, 7.82%. The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (S) N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (110 mg, 0.3 mmol) 25 were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (6 x 2 ml) and dried by suction to afford 109 mg (70%) of the title compound as a solid. M.p.: 139 141 "C. 30 HPLC-MS (METHOD B): Rt = 3.15 minutes. m/z = 518. EXAMPLE 797: WO 99/01423 PCT/DK98/00287 422 (S)-2-{4-[(3-Amino-4-hydroxybenzoyl)hydrazonomethyllnaphthyl-1 -yloxy}-N-(1 benzylpyrrolidin-3-yl)acetamide
H
2 N N. N H H (S) HO 4-Hydroxy-1-naphthaldehyde (2.71 g, 16 mmol) was dissolved in DMF (10 ml) and potas 5 sium carbonate (7.25 g, 52 mmol) was added followed by a suspension of the above (3S)-N (1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 10 mmol) in DMF (20 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was ex tracted with ethyl acetate (2 x 20 ml) and the combined organic extracts were washed with 10 saturated sodium chloride (3 x 15 ml), dried (MgSO 4 ) and concentrated in vacuo. The resi due (4 g) was purified by column chromatography on silica gel (110 g) eluting with ethyl acetate to give an oil (2 g), which was crystallized from a mixture of diethyl ether and hep tane to afford 1.8 g (45%) (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy) acetamide as a solid. M.p.: 96 - 97 *C. 15 Calculated for C 24
H
2 4
N
2 0 3 .0.25H 2 0: C, 73.36%; H, 6.28%; N, 7.13%. Found: C, 73.58%; H, 6.28%; N, 7.05%; 20 C, 73.55%; H, 6.27%; N, 7.03%. The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above (S) N-(1 -benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1 -yloxy)acetamide (116 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 25 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (3 x 3 ml) and dried by suction to afford 143 mg (89%) of the title compound as a solid. M.p.: 192 193 *C. HPLC-MS (METHOD B): Rt = 5.18 minutes. m/z = 538. 30 WO 99/01423 PCT/DK98/00287 423 EXAMPLE 798: (S)-2-{4-[(3-Fluoro-4-hydroxybenzoy)hydrazonomethyllnaphthyl-1 -yloxy}-N-( 1 benzylpyrrolidin-3-yl)acetamide 0N. N F ; OH. ON H (S) HO 5 This compound was prepared on solid phase using resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide, prepared similarly as described above for the resin bound 3-chloro-4 hydroxybenzoic acid hydrazide. Thus, methyl 3-fluoro-4-hydroxybenzoate was attached to the resin. Hydrolysis of the methyl ester (aq. LiOH, dioxane, 60 *C) followed by reaction with hydrazine (PyBOP, hydrazine, DMF) afforded resin bound 3-fluoro-4-hydroxybenzoic acid 10 hydrazide. The resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) was swelled in DMF (10 ml) for 30 minutes and filtered. This was repeated once more. DMF (4 ml) and the above (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide (0.4 g, 0.94 15 mmol) were added followed by triethyl orthoformate (1.5 ml) and the resulting mixture was shaken at room temperature for 16 hours. The mixture was filtered and the resin was suc cessively washed with DMF (5 x 4 ml) and dichloromethane (5 x 4 ml). The compound was cleaved off the resin by addition of 50% TFA in dichloromethane (6 ml) and shaking at room temperature for 1 hour. Filtration followed by extraction of the resin with a mixture of metha 20 nol and dichloromethanne (4:6) (2 x 4 ml) followed by extraction with dichloromethane (4 ml). The combined filtrates were concentrated in vacuo, stripped successively with wet methanol, dichloromethane, methanol and dichloromethane. The residue (0.39 g) was purified by col umn chromatography on silica gel (40 g) eluting first with a mixture of dichloromethane, ethanol and 25% aq. ammonia (90:9:1), then with (85:13.5:1.5) and finally with (80:18:2). 25 Pure fractions were pooled and concentrated in vacuo to afford 0.15 g of the title compound. HPLC-MS (METHOD B): Rt = 8.82 minutes. m/z = 541. Calculated for C3H 29
N
4 0 4 F.0.25CH 2 Cl 2 : 30 C, 66.81%; H, 5.29%; N, 9.97%. Found: C, 67.30%; H, 5.48%; N, 10.03%; WO 99/01423 PCT/DK98/00287 424 C, 67.33%; H, 5.49%; N, 10.02%. EXAMPLE 799: (R)-2-{4-[(3-Fluoro-4-hydroxybenzoyl)hydrazonomethyllnaphthyl-1 -yloxy}-N-(1 5 benzylpyrrolidin-3-yl)acetamide F O N ( H H (R) HO This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above (R)-N (1 -benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1 -yloxy)acetamide (0.4 g, 0.94 mmol). After 10 cleavage the compound was purified by column chromatography to afford 0.14 g of the title compound. HPLC-MS (METHOD B): Rt = 9.02 minutes. m/z = 541. 15 Calculated for C3HNN 4 0 4 F.0.25CH 2 Cl 2 : C, 66.81%; H, 5.29%; N, 9.97%. Found: C, 66.77%; H, 5.46%; N, 10.02%; C, 67.14%; H, 5.42%; N, 9.97%. 20 EXAMPLE 800: (S)-2-{4-[(3-Fluoro-4-hydroxybenzoyl)hydrazonomethyll-3-methoxyphenoxy}-N-(1 benzylpyrrolidin-3-yl)acetamide CH O 0H 0- F NO N.N ,. I H I H (S) HO 25 This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above (S)-N (1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (0.4 g, 0.94 mmol). After WO 99/01423 PCT/DK98/00287 425 cleavage the compound was purified by column chromatography to afford 0.13 g of the title compound. HPLC-MS (METHOD B): Rt = 3.68 minutes. m/z = 521. 5 Calculated for C 2 3H 29
N
4 0 5 F.0.25CH 2 Cl 2 : C, 62.63%; H, 5.49%; N, 10.34%. Found: C, 62.92%; H, 5.83%; N, 10.15%; 10 C, 62.71%; H, 5.81%; N, 10.16%. EXAMPLE 801: (R)-2-{4-[(3-Fluoro-4-hydroxybenzoyl)-hydrazonomethyll-3-methoxyphenoxy}-N-(1 benzylpyrrolidin-3-yl)acetamide CH O F N N H I H (R) 15 HO This compound was prepared similarly as described in the previous example starting from resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above (R)-N (1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.16 g of the title 20 compound. HPLC-MS (METHOD B): Rt= 4.18 minutes. m/z = 521. Calculated for C 28
H
29
N
4 0 5 F.0.25CH 2 Cl 2 : 25 C, 62.63%; H, 5.49%; N, 10.34%. Found: C, 62.65%; H, 5.73%; N, 10.31%; C, 62.84%; H, 5.81%; N, 10.30%. 30 EXAMPLE 802: WO 99/01423 PCT/DK98/00287 426 3-Fluoro-4-hydroxybenzoic acid {4-r2-(1.2.3.4-tetrahydro-isoquinolin-2-yl)ethoxy]-2 methoxybenzylidene}hydrazide
CH
3 F N HO I& This compound was prepared similarly as described in the previous example starting from 5 resin bound 3-fluoro-4-hydroxybenzoic acid hydrazide (1 g, 0.94 mmol) and the above 4-[2 (1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.13 g of the title compound. 10 HPLC-MS (METHOD B): Rt = 7.60 minutes. m/z = 464. Calculated for C2 6
H
2 6
N
3
O
4 F.0.5CH 2 Cl 2 : C, 62.91%; H, 5.38%; N, 8.30%. Found: 15 C, 62.68%; H, 5.47%; N, 8.02%; C, 62.48%; H, 5.43%; N, 8.01%. The HPLC-MS (METHOD A) analyses were performed on a PE Sciex API 100 LC/MS Sys tem using a WatersTM 3 mm x 150 mm 3.5 p C-18 Symmetry column and positive ionspray 20 with a flow rate of 20 pL/minute. The column was eluted with a linear gradient of 5-90% A, 85-0% B and 10% C in 15 minutes at a flow rate of I ml/min (solvent A = acetonitrile, solvent B = water and solvent C = 0.1% trifluoroacetic acid in water). The HPLC-MS (METHOD B) analyses were performed on a system identical to the one de 25 scribed above, the only difference being the eluent. The column was eluted with a linear gra dient of 30-80% A, 60-10% B and 10% D in 15 minutes at a flow rate of 1 ml/min (solvent A = acetonitrile, solvent B = water and solvent D =20 mM ammonium acetate in water, pH 7). EXAMPLE 803: WO 99/01423 PCT/DK98/00287 427 3-Chloro-4-hydroxy-benzoic acid {4-[2-(1.2.3.4-tetrahydro-isoquinolin-2-y)-ethoxyl-8 methoxy-naphthalen-1 -ylmethylene}-hydrazide O N C N '' 1 HO HC 5 4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (1 g, 5 mmol) was dissolved in DMF (15 mL). To this mixture potassium carbonate (3.4 g, 25 mmol) and 1,2-dibromoethane (4 mL, 50 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Water (150 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 90 mL). The combined organic extracts were washed with saturated sodium chloride 10 (100 mL), dried (MgSO 4 ) and evaporated in vacuo to afford 1.13 g (74%) of 4-(2 bromoethoxy)-8-methoxynaphthalene-1 -carbaldehyde. HPLC-MS (Method A): Rt = 14.1 minutes. m/z = 309. 15 'H-NMR (300 MHz, DMSO-d 6 ): 8H = 3.99 (3H, s), 7.00 (1H, d), 7.20 (1H, d), 7.47 (1H, t), 7.88 (2H, m), 10.9 (1H, s). The above resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (2 g, 1.8 mmol) was swelled in DMF (25 mL) for 30 minutes and the above 4-(2-bromoethoxy)-8 20 methoxynaphthalene-1-carbaldehyde (1.7 g, 5.4 mmol) was added followed by triethyl ort hoformate (1.2 mL) and the resulting mixture was shaken at room temperature for 16 hours. The mixture was filtered and the resin was successively washed with DMF (3 x 25 mL), dichloromethane (4 x 25 mL) and N-methyl pyrrolidin-2-one (NMP) (2 x 25 mL). NMP (25 mL) was added followed by potassium iodide (0.6 g) and 1,2,3,4-tetrahydro-isoquinoline 25 (2.25 mL, 18 mmol) and the resulting mixture was shaken at room temperature for 16 hours. The mixture was filtered and the resin was successively washed with NMP (2 x 25 mL) and dichloromethane (6 x 25 mL). The compound was cleaved off the resin by addition of 50% TFA in dichloromethane (30 mL) and shaking at room temperature for 1 hour. After filtration followed by extraction of the resin with dichloromethane (2 x 30 mL) the combined filtrates 30 were concentrated in vacuo. The residue was partitioned between ethyl acetate (80 mL) and saturated sodium hydrogen carbonate (100 mL). The aqueous phase was extracted with WO 99/01423 PCT/DK98/00287 428 ethyl acetate (2 x 80 mL) and the combined organic extracts were dried (MgSO 4 ) and con centrated in vacuo. The residue was purified by column chromatography on silica gel (200 mL) eluting with a mixture of dichloromethane and methanol (9:1). This afforded 217 mg of the title compound. 5 HPLC-MS (Method A): R, = 9.14 minutes. m/z = 530.
WO 99/01423 PCT/DK98/00287 429 General Procedure for Examples 804 to 824: The compounds were prepared as single entities according to the following equation Resin [Building block 1] 3 Resin [Building block 1]- [Building block 2] 2 5 Resin [Building block 1]- [Building block 2]- [Building block 3] and were simultaneously deprotected (when required) and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula 10 [Building block 1]-[Building block 2]-[Building block 3]. The following compounds were prepared as single entities by parallel synthesis on a solid support. Preparation of Resin-[Building block 1] and attachment of [Building block 2] was 15 done manually, whereas the attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 496 HTS in several runs. The starting resin, Resin-[Building block 1], was prepared as described above. 20 The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g. All compounds are based on successive attachment of [Building block 2] and [Building block 3] to Resin-[Building block 1] in a combinatorial way according to the following formulae, 25 which are included in the general formula 11: WO 99/01423 PCT/DK98/00287 430 8 0 NHFmoc O N R NH Hj .1 R N ResinO 1 + H 14 Resin R R 0 R Resin-[Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] ~3R 3 b R 3 4a 4 HO-(CH2Rg CH)-(M-(CH,) 1(CH2 -D RR H3Ra Ra3b Ra 4 8 O N (CH-2) CH)M(CH CH2)c Iq g C2);d [Building block 3] R 0 N 2 Resin'.. R 14 R Resin-[Building block I]-[Building block 2]-[Building block 3] 0 R '0 N (CH2) pCH213--(M)f-(CH2Cq (CH2)7D HO R [Building block 1]-[Building block 2]-[Building block 3] wherein R , R 9 , R", R" and Raa
R
3 b R 4a b -(CH)4b( (CH 2 )-(M)r-H ( iCH 2 )-D 5 are as defined for formula 1. The following resin, here depicted as Resin-[Building block 1] was used: 0 Cl .NH 2 I H o where PS is polystyrene. In the following "Resin" o / ris the polystyrene resin with the Wang linker: PS O = Resin
PS
WO 99/01423 PCT/DK98/00287 431 The following building blocks were used: [Buildina block 21: (4-Formyl-3-methoxyphenyl)carbamic acid (4-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: 9H-fluoren-9-ylmethyl ester - NHFmoc NHFmoc H H d 0Q H 3 C
CH
3 3-(tert-Butyldimethylsilanyloxy)-4- (5-Formyl-2-methoxyphenyl)carbamic acid formylphenyl)carbamic acid 9H-fluoren-9- 9H-fluoren-9-ylmethyl ester: ylmethyl ester: NHFmoc 0 0NHFmoc HH 3 H3 TBDMSO 5 WO 99/01423 PCT/DK98/00287 432 [Building block 31: 4-Methoxy-2- N-Methylpyrrole-2-carboxylic Succinylsulfathiazole quinolinecarboxylic acid acid H H HN N /-- N HO 9H 3 0 N O OH 0
H
3 C 7-Ethoxybenzofuran-2- 4-Toluenesulfonylacetic acid 3-(2-Thienoyl)propionic acid carboxylic acid 0 O S ' CH3 0 OHO 000 OH OH
CH
3 Boc-Hyp-OH N-fmoc-O-t-butyl-L-serine Fmoc-His(Boc)-OH HO)KCH H C0/0 HO-... OH H3 C 0 OH HO3 C OH CN 0 NHm O XO CH 3 N HN O
H
3 0 H 3 0 0 WO 99/01423 PCT/DK98/00287 433 Foc-beta-(3-pyridyl)-D-Ala- Methanesulfonylacetic acid Fmoc-Trp(Boc)-OH OH0 CH OH OH NHHH OO
H
3 OHwy I4 N N / H H H3C N H3 HO N3O CH 3 Fmoc-L-Methionine 5-Methoxy-1 -indanone-3- 4-Hydroxycinnamic acid H CH acetic acid 0 OH OOH 0 3H 3 HO HOH 0 \I \/0 0 OHH H Br H ON NH 0 I I3 OH HOrrN NH3 OH H 00 WO 99/01423 PCT/DK98/00287 434 Cyano-acetic acid O-Anisic acid 4-Acetamidobenzoic acid
H
3 cN H HO 0 HOH 0 N H Trifluoroacetic acid 2-Amino-4-thiazole acetic p-Anisic acid F acid
CH
3 FO HO F OH
SNH
2 HO O Alfa-Methoxyphenylacetic Benzoylformic acid Oxamic acid acid H 2 N O
'CH
3 0 HO 0 O OH OH Quinolin-2-carboxylic acid Benzofuran-2-carboxylic acid Monomethyl malonate N,0 D 0 OH H HC ' 0 OH0 OH 3-Cyanobenzoic acid 3-(3-Pyridyl)acrylic acid Cyclopentanecarboxylic acid 0 OH OH SOH
N
WO 99/01423 PCT/DK98/00287 435 N-Acetylglycine DL-Glyceric acid 2-Chloro-3 0 0 OH HO methoxythiophene-4 0 carboxylic acid HO OH 0
H
3 C-O OH Cl g 5-Fluoroindole-2-carboxylic 3-(4,5-Methylenedioxy-2- 3 Acid nitrophenyl)acrylic acid (Formylaminomethyl)benzoic F 0 acid 0 OH OH O HN O ~ N HO 0 0 HN) 0 5-Bromo-2-furoic Acid 3-Methylthiophene-2- Methylmalonic acid B 0 OH carboxylic acid H O H 3 HO O OH
CH
3 S 4-Thioureido-benzoic acid (4-Trifluoromethoxy)phenoxy (4-Chlorophenoxy)acetic acid
NH
2 0 acetic acid H O H O H O H F Isoquinoline-1 -carboxylic a- 6-Methylnicotinic acid 3H-Indene-1-carboxylic acid cid H3C OH OH OH O
A
WO 99/01423 PCT/DK98/00287 436 Benzo[b]thien-3-yl acetic a- 2-methyl-2-phenoxypropionic 3-Benzo[1,3]dioxol-5-yl cid acid acrylic acid O 0 OH O OH OH
CHCH
3 O 3O 3 3-(3-Trifluoromethylphenyl) 2-Fluoro-3-phenylacrylic acid 2-Oxo-3-phenylpropionic acid acrylic acid F OH OH FF OH F' 3-Methoxybenzo[b]thio- Benzo[b]thiophene-2- Fmoc-phenylalanine phene-2-carboxylic acid carboxylic acid OH OH N N \ \z H 9 HO O
CH
3 (2,4-Dichlorophenoxy)acetic 3-(4-Trifluoromethylphenyl)- (3-Trifluoromethylphenyl) acid propionic acid acetic acid HH IFF 0 F F OH F Preparation of resin-[Building block 11: 5 This resin was prepared as described above.
WO 99/01423 PCT/DK98/00287 437 Preparation of [Building block 2]: (4-Formyl-3-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: NHFmoc 0 OH CH3 5 Methyl 4-amino-2-methoxybenzoate (14.7 g, 7.3 mmol) and Fmoc-Osu (26.1 g, 77.3 mmol) were stirred in a mixture of acetonitrile and water (1:1, 320 mL) at reflux for 16 hr. The reac tion mixture was concentrated to half the volume and the precipitate isolated by filtration. The isolated solid was dissolved in ethyl acetate (300 mL) and washed with 0.4 N hydrochlo ric acid (200 mL), 0.2 N hydrochloric acid (200 mL), water (200 mL) and a 20 % saturated 10 solution of sodium chloride (200 mL). After drying (magnesium sulphate) the organic phase was concentrated in vacuo, and the solid residue was washed with methanol and dried. The crude product (12g) was dissolved in dichloromethane (1 L) under nitrogen and a solu tion of diisobutylaluminium hydride (90 mL, 1.2 M in toluene) was dropwise added at 0-5oC. 15 The reaction mixture was stirred at 200C for 16 hr and quenched by dropwise addition of water (58 mL) at 0-5 0C. The reaction mixture was stirred at 200C for 3 hr and filtered. The filtrate was concentrated in vacuo. The crude product (6.8 g) was suspended in di chloromethane (400 mL) and manganese dioxide (15.6 g, 180 mmol) was added. The mix ture was stirred for 16 hr at 200C and filtered. The filtrate was concentrated in vacuo to give 20 5.1 g of the title compound. m.p. 187-1880C HPLC-MS (METHOD A): Rt = 15.1 min, m/z= 374. Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% 25 found: C, 73.44; H, 5.20; N, 3.56% (4-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: WO 99/01423 PCT/DK98/00287 438 HO NHFmoc
H
/O
H
3 C Thionylchloride (12.8 g, 108 mmol) was dropwise added to an ice cold suspension of 4 amino-3-methoxybenzoic acid (12.3 g, 72 mmol) in methanol (250 mL). The reaction mixture 5 was stirred at 200C for 16 hr and concentrated in vacuo. Ethyl acetate (250 mL) and a satu rated solution of sodium hydrogen carbonate (150 mL) were added and the organic phase was washed with saturated solutions of sodium hydrogen carbonate (2x50 mL), dried (magnesium sulphate) and concentrated in vacuo. The crude product (12.5 g) and Fmoc Osu (28 g, 83 mmol) was stirred in a mixture of acetonitrile and water (1:1, 240 mL) at 900C 10 for 16 hr. The reaction mixture was concentrated to half the volume. Ethyl acetate (200 mL) was added together with 0.4N hydrochloric acid (150 mL). The organic phase was washed with 0.2N hydrochloric acid (100 mL), water (100 mL) and a saturated solution of sodium chloride (2x100 mL). After drying (magnesium sulphate) the organic phase was concentrated in vacuo, and the residue was crystallized from methanol and dried. 15 m.p. 96-980C HPLC (Method 1) Rt= 32.4 min Micro analysis: calculated: C, 71.45; H, 5.25; N, 3.47% found: C, 71.32; H, 5.24; N, 3.41% 20 The product (12 g, 29.7 mmol)) was dissolved in dichloromethane (800 mL) under nitrogen and a solution of diisobutylaluminium hydride (90 mL, 1.2M in toluene) was dropwise added at 0-50C. The reaction mixture was stirred at 200C for 16 hr and quenched by dropwise addi 25 tion of water (58 mL) at 0-50C. The reaction mixture was stirred at 200C for 3 hr and filtered. The filtrate was concentrated in vacuo to give 5.5 g of product (m.p. 169-1710C). The prod uct (5.5 g) was suspended in dichloromethane (325 mL) and manganese dioxide (12.8 g, 148 mmol) was added. The mixture was stirred for 16 hr at 200C and filtered. The filtrate was concentrated in vacuo to give 3.5 g of the title compound. Recrystallization from ethyl ace 30 tate.
WO 99/01423 PCT/DK98/00287 439 m.p. 150-1520C HPLC (Method 1) Rt = 30.6 min Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% 5 found: C, 73.54; H, 5.18; N, 3.65% 3-(tert-Butyldimethylsilanyloxy)-4-formylphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: 0 / \NHFmoc H 10 TBDMSO 4-(9H-Fluoren-9-ylmethoxycarbonylamino)-2-hydroxybenzoic acid methyl ester: Thionylchloride (19.4g, 163 mmol) was dropwise added to an ice cold solution of 4-amino 15 salicylic acid (10.0g, 65.3 mmol) in methanol (200 mL). The reaction mixture was hereafter heated to 650C for 6 days. The reaction mixture was concentrated in vacuo and the crude product was dissolved in a mixture of acetonitrile and water (1:1, 220 mL). Fmoc-Osu (22.0 g, 65.3 mmol) was added and the reaction mixture was stirred at 900C for 16 hr. The reaction mixture was concentrated to 100 mL in vacuo, and water (50 mL) and ethyl acetate (250 mL) 20 added. The organic phase was isolated and washed with water (2x50 mL), a saturated solu tion of sodium chloride (2x50 mL), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified on silica (300 g) using ethyl acetate and n-heptane (1:2) as eluent. The product was recrystallized from methanol to give 4-(9H-fluoren-9 25 ylmethoxycarbonylamino)-2-hydroxybenzoic acid methyl ester. m.p.156-9*C HPLC (Method 1) Rt = 31.7 min Micro analysis: calculated: C, 70.94; H, 4.92; N, 3.60% 30 found: C, 70.73; H, 4.98; N, 3.37% WO 99/01423 PCT/DK98/00287 440 4-(9H-Fluoren-9-ylmethoxycarbonylamino)-2-hydroxybenzoic acid methyl ester (4.36 g, 11.2 mmol) was dissolved in dimethylformamide (20 mL) and imidazole (1.92 g, 28 mmol) was added. tert-Butyldimethylsilylchloride (2.09 g, 13.4 mmol) dissolved in dimethylformamide 5 (10 mL) was dropwise added and the reaction mixture was stirred at 200C for 16 hr. The re action mixture was poured into water (160 mL) and extracted with ethyl acetate (4x50 mL). The collected organic phases were washed with a saturated solution of sodium chloride (4x50 mL), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified on silica (150 g) using ethyl acetate and n-heptane (15:85) as eluent. The isolated product 10 (3.10 g, 6.15 mmol) was dissolved in dichloromethane (200 mL) under nitrogen. A solution of diisobutylaluminiumhydride (18.5 mL, 1.2M in toluene) was dropwise added 0-50C. The mix ture was stirred at 200C for 3.5 hr, and quenched by dropwise addition of water at 0-50C. Af ter 2.5 hr at 200C the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on silica using ethyl acetate and n-heptane (1:3) as eluent. The isolated 15 product (2.40 g) was dissolved in dichloromethane (120 mL) and manganese dioxide (4.39 g, 50.5 mmol) was added. The reaction mixture was stirred at 00C for 16 hr and filtered. The filtrate was concentrated in vacuo and the residue purified on silica using ethyl acetate and n-heptane (15:85) as eluent to give 1.0 g of the title compound. 20 HPLC (Method 1) Rt = 30.7 min and 36.8 min (5-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: NHFmoc 00 25 CH3 Thionylchloride (10.3 g, 85 mmol) was dropwise added to an ice cold suspension of 3 amino-4-methoxybenzoic acid (9.48 g, 56.7 mmol) in methanol (180 mL). The reaction mix ture was stirred at 200C for 16 hr and concentrated in vacuo. Ethyl acetate (100 mL) and a 30 saturated solution of sodium hydrogen carbonate (100 mL) were added and the organic phase was washed with saturated solutions of sodium hydrogen carbonate (2x40 mL), dried WO 99/01423 PCT/DK98/00287 441 (magnesium sulphate) and concentrated in vacuo. The crude product (7.7 g) and Fmoc-Osu (12.9 g, 38.2 mmol) were stirred in a mixture of acetonitrile and water (1:1, 75 mL) at 200C for 16 hr, and at reflux for 3.5 hr. The reaction mixture was concentrated to half the volume and the precipitate isolated by filtering the mixture to give 15 g of intermediate crude product. 5 The product (5 g, 12 mmol) was dissolved in dichloromethane (400 mL) under nitrogen and a solution of diisobutylaluminium hydride (38 mL, 1.2M in toluene) was dropwise added at 0 50C. The reaction mixture was stirred at 200C for 16 hr and quenched by dropwise addition of water (23 mL) at 0-54C. The reaction mixture was stirred at 200C for 1.5 hr and filtered. The 10 filtrate was concentrated in vacuo to give 4.9 g of intermediate product. The product (4.9 g) was suspended in dichloromethane (180 mL) and manganese dioxide (11.2 g, 129 mmol) was added. The mixture was stirred for 16 hr at 200C and filtered. The filtrate was concen trated in vacuo to give 4.3 g crude product that was purified on silica (150 g) using ethyl acetate and n-heptane (3:7) as eluent to give 1.9 g of the title compound. 15 m.p. 139-1420C HPLC (Method 1) R, = 29.8 min Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% found: C, 73.45; H, 5.17; N, 3.72% 20 EXAMPLE 804: N-(4-[3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-3-methoxyphenyl)-2-(4 25 trifluoromethoxyphenoxy)acetamide F F H~I 0 H o _O 1 HO HOe H H3C'O0 C1 WO 99/01423 PCT/DK98/00287 442 Step 1: Coupling of aldehyde [building block 2] to resin[buildingblock 1] 0.75 g resin (Wang resin loaded with 3-chloro-4-hydroxybenzoic acid hydrazide) was swelled in dimethylformamide (6 mL) for 30 min and drained. The aldehyde (4-formyl-3 methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester, 0.5 g, 1.36 mmol) dissolved in 5 dimethylformamide (3 mL) was added followed by addition of triethylorthoformate (1.5 mL). The mixture was shaken for 16 hr at 200C and drained. The resin was washed with di methylformamide (5x4 mL), dichloromethane (5x4 mL) and dimethylformamide (5x4 mL). The coupling of the aldehyde was repeated twice. 10 Step 2: Deprotection of aniline The resin was swelled in dimethylformamide (5 mL) and piperidine added (1.25 mL). After shaking for 30 min, the resin was drained and washed with dimethylformamide (5x4 mL), N methylpyrrolidinone (5x4 mL) and dimethylformamide (5x4 mL). 15 Step 3: Coupling of acid [building block 3] to resin[building block 1][building block 2] The resin[building block 1][building block 2] was swelled in dimethylformamide (2.5 mL) and the acid (4-trifluoromethoxy)phenoxy acetic acid (0.64 g, 2.7 mmol) was added together with diisopropylcarbodiimide (0.21 mL). After 5 min of shaking dimethylaminopyridine (0.34 mL) was added and the mixture was shaken for 3 hr and drained. The resin was washed with di 20 methylformamide (5x4 mL), dichloromethane (5x4 mL) and dimethylformamide (5x4 mL). The coupling of the acid was repeated twice, but with 16 hr reaction time for the repetition. Step 4: Cleavage from the resin The resin was swelled in dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL) was 25 added. After shaking for 1 hr the resin was drained. The eluent was collected and concen trated in vacuo. The residue was crystallized from methanol to give 0.2 g of the title com pound. m.p. 235-236.5*C 30 HPLC-MS (METHOD A) R, = 13.5 min m/z = 538 Micro analysis: calculated: C, 53.59; H, 3.56; N, 7.81% found: C, 53.57; H, 3.58; N, 7.51% WO 99/01423 PCT/DK98/00287 443 Further, a library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2] and [building block 3]) was prepared in parallel as individual entities analogously to the previous example on an Advanced ChemTech Model 5 384 HTS using the following ChemFile to control the operation of the synthesizer. The com pounds are all expected to be present in the respective wells. The four [building block 2] aldehydes, (4-Formyl-3-methoxyphenyl)carbamic acid 9H-fluoren 9-ylmethyl ester, (4-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester, 3 10 (tert-Butyldimethylsilanyloxy)-4-formylphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester and (5-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester, were coupled to four individually batches of the resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin [building block 1]) using the same procedure as described for step 1 in the example above. Subsequently the Fmoc deprotection of the anilino group was carried out as described in 15 step 2 in the example above. The four different examples of resin[building block 1][building block 2] thus prepared were equally distributed in the wells in the synthesizer prior to the initialization of the device. The attachment of the array of [building block 3] mentioned above was carried out in a fully 20 combinatorial way with the four types of resin[building block 1][building block 2] using the general procedure as described in step 3 in the example above. The final cleavage was performed using the same general procedure as described in step 4 in the example above. During this cleavage step deprotection of acid sensible protection groups was also taken place. These two steps 3 and 4 were carried out (in several runs) on an ACT 496 HTS 25 automated synthesizer using the following ChemFile to control the device. ChemFile: C:\DATA\90250017.CHM 30 1 Empty RB1to96 for 2.000 minute(s) 2 Flush Arm1 with NMParml and DCMarml 3 4 REM Adding acids 1 to 36 5 WO 99/01423 PCT/DK98/00287 444 6 Dispense Sequence C:\act\ACID1-36.DSP with 1000ul to RB1to96 rack using NMParml 7 Mix for 2.00 minutes at 600 rpm(s) 8 Pause 9 Mix for 2.00 minutes at 600 rpm(s) 5 10 11 REM Adding acids 37 to 48 12 13 Dispense Sequence AC137-48.DSP with 1000ul to RB1to96 rack using NMParml 14 Mix for 2.00 minutes at 600 rpm(s) 10 15 16 Pause 17 18 REM Adding DIC 19 15 20 Transfer 300ul from Monomerlto36[12]() to RBlto96[2-48] using NMParml 21 Mix for 2.00 minutes at 600 rpm(s) 22 Transfer 300ul from Monomerlto36[13]() to RBlto96[50-96] using NMParml 23 Mix for 10.00 minutes at 600 rpm(s) 24 20 25 REM Adding DMAP 26 27 Transfer 200ul from Monomerlto36[14]() to RBlto96[2-48] using NMParml 28 Transfer 200ul from Monomerlto36[14]() to RBlto96[50-96] using NMParml 29 25 30 REM Mixing overnight 31 32 Mix for 10.00 minutes at 600 rpm(s) 33 Wait for 20.000 minute(s) 34 Repeat from step 32, 150 times 30 35 36 REM wash 37 38 Empty RB1to96 for 2.000 minute(s) 39 Dispense System Fluid NMPdualarms* 1000ul to RBlto96[1-96] 35 40 Mix for 3.00 minutes at 600 rpm(s) 41 Empty RB1to96 for 2.000 minute(s) 42 Repeat from step 39, 5 times 43 44 REM de fmoc 40 45 Mix for 3.00 minutes at 600 rpm(s) 46 Dispense Sequence C:\act\DEFMOC.DSP with 1500ul to RB1to96 rack using NMParml 47 Mix for 15.00 minutes at 600 rpm(s) 48 Empty RB1to96 for 3.000 minute(s) 49 Empty RB1to24 for 3.000 minute(s) 45 50 Empty RB49to72 for 2.000 minute(s) 51 Pause 52 53 REM wash 54 Dispense System Fluid NMPdualarms* 1000ul to RBlto96[1-96] WO 99/01423 PCT/DK98/00287 445 55 Mix for 3.00 minutes at 600 rpm(s) 56 Empty RB1to96 for 3.000 minute(s) 57 Repeat from step 54, 2 times 58 Flush Arm1 with NMParml and DCMarml, Arm2 with DCMarm2 5 59 Dispense System Fluid DCMdualarm* 1000ul to RB1to96[1-96] 60 Mix for 3.00 minutes at 600 rpm(s) 61 Empty RB1to96 for 3.000 minute(s) 62 Repeat from step 59, 5 times 63 10 64 REM TFA CLEAVAGE 65 66 Mix for 1.00 minutes at 300 rpm(s) 67 Transfer 1000ul from Reagent2[l]() to RBcleavagelto96[1-96] using DCMarm1 68 Mix for 1.00 hours at 600 rpm(s) 15 69 Empty RBcleavage1to96 for 30 second(s) 70 Dispense System Fluid DCMdualarm* 500ul to RBcleavagelto96[1-96] 71 Mix for 5.00 minutes at 300 rpm(s) 72 Empty RBcleavage1to96 for 30 second(s) 73 20 Dispense sequence files C:\act\ACID1-36.DSP are subroutines that control the combinatorial addition of the amines into the 4 reaction blocks each containing 96 wells in the syntheziser. Examples of compounds from this library were characterized by HPLC-MS (molecular mass 25 & retention time) and includes: EXAMPLE 805: Quinoline-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyll-3 30 methoxyphenyl}amide N't O N 0 N H HO H3C' Cl m.p. 236-238*C HPLC (Method 1) R,=26.2 min 35 EXAMPLE 806: WO 99/01423 PCTIDK98/00287 446 N -{-[(3-ch Ioro-4-hydroxybenzoyl)hyd razonomethyll-2-methoxyphenyl}-2-(4 trifluoromethoxyphenoy)acetamide H I)< 0,1a F HO~ H
CH
3 5 m.p. 216-218 0 C HPLC (Method 1) Rt=26.6 min EXAMPLE 807: 10 Quinoline-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyll-2 methoxyphenyllamide H H H H1 H 3 m.p. 159-1620C HPLC (Method 1) Rt=27.7 min 15 EXAMPLE 808: N-{4-[(3-Ch Ioro-4-hyd roxybenzoyl)hyd razonomethyl]-3-methoxyphenyl}-2-(4 chlorophenoxy)acetamide N N HO H 3HCH 3 0 CI 20 m.p. 216-218 0 C HPLC-MS (METHOD A) R,=13.4 min, mlz=488 WO 99/01423 PCT/DK98/00287 447 5 EXAMPLE 809: N-{4-[(3-Chloro-4-hydroxybenzoyl)hyd razonomethyll-3-.methoxyphenyl}-6 methylnicotinamide H
OH
3 N ~ MNN H H HO' ' H0 0 ' 10 H PLC-MS (METHOD A) Rt=8.2 min, mlz=439 EXAMPLE 810: N-{4-[(3-Chloro-4-hyd roxybenzoyl)hyd razonomethyll-3-methoxypheny}-2-(3 15 trifluoromethylphenyl)acetamide H SNN N N 0 I H F HO HOC F F 0I HPLC-MS (METHOD A) Rt=13.4 min, mlz=506 EXAMPLE 811: 20 N-{4-(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-3-methoxyphenyl}-2-(2.4 dichlorophenoxy)acetamide WO 99/01423 PCT/DK98/00287 448 CI CI H N' N HO H~c HPLC-MS (METHOD A) R,=14.3 min, mlz=524 5 EXAMPLE 812: N-{4-r(3-Chloro-4-hyd roxybenzoyl)hydrazonomethyl]-3-methoxyphenyl}-3-(4 trifluoromethylphenyl)propionamide F H IF N H 0 HOl H~C 0 10 HPLC-MS (METHOD A) R,=14.0 min, mlz=520 EXAMPLE 813: Isoguinoline-1 -carboxylic acid {4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-3 15 methoxyphenyllamide H NN HO'
H
3 'o CI HPLC-MS (METHOD A) R,=13.0 min, mlz=475 WO 99/01423 PCTIDK98/00287 449 EXAMPLE 814: 7-Ethoxybenzofu ran-2-carboxylic acid {4-r(3-ch Ioro-4-hyd roxybenzoyl)hydrazonomethyll-3 methoxyphenyllamide HOC 0 H N 'r0 HO"
H
3 c0 5 1I HPLC-MS (METHOD A) R,=13.3 min, mlz=508 EXAMPLE 815: 10 N-{4-[(3-Chloro-4-hyd roxybenzoyl)hyd razonomethyl]-3-methoxyphenyl}-2-(toluene-4 sulonyl)acetamide H 0 N ' HO I H H 3 c' H CI HPLC-MS (METHOD A) Rt=1O.8 min, mlz=517 15 EXAMPLE 816: Benzofuran-2-carboxylic acid {4-(3-Chloro-4-hydroxybenzoyl)hydrazonomethyImethoxyphenyll-amide WO 99/01423 PCTIDK98/00287 450 H I H 0 HOj H 3 0' GI HPLC-MS (METHOD A) R,=12.3 min, mlz=465 EXAMPLE 817: 5 N-{4- (3-Ch loro-4-hyd roxybenzoyl)hyd razon omethyll-3-methoxyp he nyll-3-Qya nobe nza mid e H HO H C' HPLC-MS (METHOD A) R,=10.8 min, mlz=450 10 EXAMPLE 818: 5-Chloro-4-methoxythiophene-3-carboxylic acid {4-f(3-Chloro-4 hydroxybenzoyl)hydrazonomethyll-3-methoxyphenyllamide H N /Cl HO"H Hc0 C1 15 HPLC-MS (METHOD A) R,=9.8 min, mlz=495 WO 99/01423 PCTIDK98/00287 451 EXAMPLE 819: 5-Bromofuran-2-ca rboXylic acid {4-[(3-Chloro-4-hydroxybenzoyl )hyd razonomethy]-3 methoxyphenyllamide Br H ~ - 0 I Ho HO--;
H
3 C0 5 HPLC-MS (METHOD A) R,=1 1.4 min, m/z=494 EXAMPLE 820: 2-Benzofblthien-3-yi-N4{4-((3-chloro-4-hyd roxvbenzoyl)hyd razonomethy!L-2 methoxyphenyllacetamide 10
H
~. N 0 K' H.' H OH 3 HPLC-MS (METHOD A) Rt=13.4 min, mlz=494 EXAMPLE 821: 15 N-{4-[(3-Chloro-4-hydroxybenzoyl )hyd razonomethyll-2-methoxyphenyl}-2-(4-ch lorophenoxy) 2-methyl prop iona mide
H
3
CH
3 ~ C I N H I[? H OH 3 HPLC-MS (METHOD A) Rt=14.7 min, mlz=516 WO 99/01423 PCTfDK98/00287 452 EXAMPLE 822: N-{4-[r(3-Ch Ioro-4-hyd roxybenzoyl)hydrazonomethyl]-2-methoxyphenyl}-3-(3 trifluoromethylphenyl)acryamide H MzN N F N' 90FF HOe H CH 3 5 cI HPLC-MS (METHOD A) Rt=14.3 min, m/z=518 EXAMPLE 823: 10 N-{4-[(3-Chloro-4-hydroxybenzoyl)hyd razonomethyll-2-methoxyphenyl}-2-fluoro-3 phenylacrylamide H F N' 9 0 HO'l e CI HPLC-MS (METHOD A) Rt=14.3 min, mlz=468 15 EXAMPLE 824: 2-Benzofblthieophene-2-carboxylic acid {4-r(3-chloro-4-hydroxybenzoyl)hydrazonomethyll-2 methoxyphenyllamide WO 99/01423 PCT/DK98/00287 453 H N N' 0 S HO H CH 3 Cl HPLC-MS (METHOD A) R,=13.8 min, m/z=480 5 HPLC Method 1. The RP-HPLC analysis was performed using UV detection at 254 nm and a Merck Hibar LiChrosorb RP-18 (5 im) prepacked column (Cat. No. 50333), which was eluted at 1 mL/minute. Two solvent systems were used: Solvent system I: 0.1% Trifluoroacetic acid in acetonitrile. Solvent system 1l: 0.1% 10 Trifluoroacetic acid in water. The column was equilibrated with a mixture composed of 20% of solvent system I and 80% of solvent system II. After injection of the sample a gradient of 20% to 80% of solvent system I in solvent system II was run over 30 minutes. The gradient was then extended to 100% of solvent system I over 5 minutes followed by isocratic elution with 100% of this system for 6 15 minutes. General Procedure for Examples 825 to 875: The compounds were prepared as single entities according to the following equation 20 Resin [Building block 1] 3 Resin [Building block 1]- [Building block 2] 3 Resin [Building block 1]- [Building block 2]- [Building block 3] and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the 25 following formula WO 99/01423 PCT/DK98/00287 454 [Building block 1]- [Building block 2]--[Building block 3]. The following compounds were prepared as single entities by parallel synthesis on a solid 5 support. Preparation of Resin-[Building block 1]-[Building block 2] was done manually, whereas the attachment of [Building block 3] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS. The starting resin, Resin-[Building block 1], was prepared as described above. 10 The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g. All compounds are based on successive attachment of [Building block 2] and [Building block 15 3] to Resin-[Building block 1] in a combinatorial way using a nucleophilic substitution reaction according to the following formulae, which are included in the general formula fl: WO 99/01423 PCT/DK98/00287 455 R 15
R
15 0 a O OH N N' NH O N N Resin Cl H + H H 1Resin, R 4 Resin-[Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] O CN- S-CH R 1 O O-S-CHa C N N'N N 0 Resin H R" HNR5cR5d [Building block 3] RIS R15 N N . RR 01 N' 0 0N N 5 N HN R Resin HR [Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3] and WO 99/01423 PCT/DK98/00287 456
R
1 s R 15 0 I N OH N .H 2 OH H~ C N N. Resin, .H2 + H OR I 14 0 1 Resin, 0 . R 00 Resin-[Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] O
CI-S-CH
3 R1 5 1 0 O O-S-CH3 CN' N. Resin 'O H R 1 4 0 HSRsc [Building block 3] R 1 5 R CR 15 , 5 0lN. N N I' S.N 'Resin C H R H H4 Resi '0 [Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3] wherein R" 4 , R'S are as defined for formula I and -NR5cR 5 d is R 5a R4a R4b Ra R" R4 5 N-CH2)Nc
(CH
2 )--D where Rea, R 4 a, R 4 , C, q, d, and D are as defined for formula I or -D' where -D' is defined as a subset of -D that contains a primary or a secondary amine that can react as a nucleophile; 10 and -SR'* is WO 99/01423 PCT/DK98/00287 457 R4a R4b -S--(CH2)c q (CH2);-D where R 4 , R 4 b, c, q, d, and D are as defined for formula I or -D' where -D' is defined as a subset of -D that contains a thiol that can react as a nu 5 cleophile. The following resin, here depicted as Resin-[Building block 1] was used: 0 C1 .NH2 I H 0 where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker: Ps 0 =Resin 10 The following building blocks were used: [Building block 21: 4-Hydroxymethylnaphthalene-1 carbaldehyde 'S OH 15 [Building block 31: (1,4'-Bipiperidine)- 2-Thiophenemethylamine 5-Methyl-2-furanmethylamine 4'carboxamide s H H2N/ H3c NH N 0 NH 2 WO 99/01423 PCT/DK98/00287 458 1-Pyrrolidinocarbonylmethyl)- 1-(2-Furoyl)piperazine 2-Amino-2-phenylethanol piperazine HNQ O
NH
2 0 N HN N L-Methionine ethyl ester DL-Serine methyl ester 4-Acetyl-4-phenylpiperidine
H
3 CS'-rO CH, HO - 3 O
NH
2 NH 2 H3C N H 4-Piperidinopiperidine N-Ethylpiperazine 1-Acetylpiperazine -- N H HNQ-N HN' N H 3 N N
H
3 C 0 Piperazine 2-(Aminomethyl)pyridine 4-(Aminomethyl)piperidine r'NH H N HN? NH 2 1,3-Diaminocyclohexane Pyrrolidine
H
2 N NH 2 HNQ 4-(2-Aminoethyl)pyridine 4-(Hydroxymethyl)piperidine Thiomorpholine N- NH2 OH
NHN
2 H 2-(2-Methylaminoethyl)- (s)-2-Amino-3-cyclohexyl-1 - 3-lsopropylamino-n pyridine propanol propylamine N N CH OH H C N-,NH H NHCH 3
CH
3 WO 99/01423 PCT/DK98/00287 459 L-Prolinol 4-Hydroxypiperidine 1 -Amino-2-propanol OH HNO-H
NH
2 N CH 3 Furfurylamine 2-Methoxyisopropylamine L-Isoleucinol O H 2 N
CH
3
H
2 N O33 HO CH
H
2 N 3-Aminopentane 2-Piperidineethanol 3-Amino-1,2-propanediol H
H
3 C'> CH 3 N HO <NH 2
NH
2 HO OH Cyclopropylamine Ethylenediamine 1 -Benzyl-3-Aminopyrrolidine
H
2 N< H 2 N N H 2 N N 3-Pyrrolidinol 2-Aminocyclohexanol Morpholine OH H HN-OH NH H 3-Mercaptopropionic acid Glycine tert butylester 3-Mercaptopropionic acid HO o H 3 C CH 3 ethyl ester HS ' CHa o o HS' "O ,CH3
NH
2 0 Ethylamine Methylamine 2-Aminoethanol
CH
3
H
3 C, OH
NH
2
NH
2 H 2 N Isopropylamine Isopentylamine Dimethylamine
CH
3 H 3 C,
H
2 N> CH 3 H3CNH HN 3
CH
3 WO 99/01423 PCT/DK98/00287 460 Propylamine Cyclopentylamine 2-Furanylmethylamine CH, NH 2
H
2 N
NH
2 2-Methylimidazole 3-Amino-5-mercapto-1,2,4- Captopril -rCH, triazole O H HSY-N H3yoOH H HS NH H3C OO
NH
2 HS 2,2-Dimethylpropylamine N,N-Dimethylethylene- 2,4-Dimethylimidazole
CH
3 NH diamine HC
H
3 C HH 3 N
H
3 C-N NH2 H 3-Mercapto-1 H-1,2,4-triazol Cyclopropylmethylamine Cyclobutylamine N SH NH2 NN NH2 H 4-Mercaptopyridine Thiazolidine Isopropylmercaptane SH /--\ SH S NH H2C CH 4-(4-Trifluoromethylphenyl)- 4-(2-Thienyl)-4-piperidinol 4-(3-Trifluoromethylphenyl) 4-piperidinol 3-piperidinol F FHO F\ FS F IF N F H F F OH OH N H N
H
WO 99/01423 PCT/DK98/00287 461 Glutamic Acid di tert butyle- 2,2,2-Trifluoroethylamine S-1-amino-2-propanol ster F NH2 HO NH2 CH O F F CH3
H
3 C* NH 2
H
2 C 0 0 CH
H
2 C 4-(Aminomethyl)-piperidine D-Valinol Thiophene-2-ethylamine H H s N HO 3 Cj/-. NH 2 N FNC 3 KNH2 Tetrahydro-3-thiophenamine 1,1-dioxide o,,'sD NH2 o-2 2,3-Dimethoxybenzylamine Alfa-methylbenzylamine 1,2,3,4
H
2 N H 2 N Tetrahydroisoquinoline CH3 H3C H H0 1 2
CH
3 1,2,3,4-Tetrahydro-1 - N-Benzylethanoiamine 4-Methoxybenzylamine naphthylamine H - HN _. CH3 NH 2 HO N NH2 WO 99/01423 PCT/DK98/00287 462 N'-Benzyl-N,Nn- 2-Benzylamino-1 -propanol dimethylethylenediamine H
H
3 C. HHOH N1 Ho N
H
3 C N-Isopropylbenzylamine 1,2-Dimethylpropylamine D-(-)-apha-Phenylglycinol H H 2 N H 3
H
3 C
H
3 C GH 3 H 2 N 4-Fluorobenzylamine N-Ethylbenzylamine N-(n-propyl) Benzylamine
H
2 N F H 3 C H HCN)<J 2-Amino-2-methyl-1 -propanol Piperonylamine 4-(Trifluoromethyl)benzyl H2N amine
H
3 C CH O NH 2 F H2N\ F (-)-Norephedrine 2-Methylaminoethanol 2-Butylamine CH CHH 3 C-<CH3
H
2 N. 3 HN C HO OH OH Benzylmethylamine Diisobutylamine CyClohexylamine H3CN HN,CH3 H3C NH 2 N-Benzylhydroxylamine Methylaminoacetonitril N,N-Diethyl nipecotamide OH CH CH3 HNH H C N N
H
WO 99/01423 PCT/DK98/00287 463 4-Aminocyclohexanol 2-Isopropylaminoethanol 1,3-Dimethylbutanamine
CH
3 CH 3 H3C< OH
H
3 C
H
3 C
NH
2 OH 4-Methylcyclohexylamine Alfa-methyl-4-chlorobenzyl- 4-Methoxybenzylhydroxyl H3C amine amine 2 O 3
.H
3 C NH 2 H 0 HO* NNH 2-Phenylglycinonitrile 3-(Benzylamino)propionitrile 3-Methoxybenzylamine
NH
2 CH 3 N N
NH
2 1 -Methyl-2- 3-Fluorobenzylamine 1 -Aminoindan phenoxyethylamine
NH
2
NH
2 (OHF CH3
NH
2 3-Piperidinemethanol 3,4-Dimethoxybenzylamine 2-Mercapto-5 OH CH 3 methylthiadiazole
H
2 N 0 HS NN H
OH
3 4 CHs 1 -Methyl-5-mercaptotetra- 3-Methylaminopropionitril lsopropylmethylamine zole H3C' N H 3 C H HS N. H
H
3 C CH 3 N-N
H
3 C 2-Mercaptothiazole 2-Amino-1-propanol exo-2-Aminonorbornane SH
H
3 Cy-OH SH
NH
2 O zbNH 2 WO 99/01423 PCT/DK98/00287 464 4-Aminobenzylamine 2-Mercaptoimidazol 2-Mercapto-1 -methylimidazol
H
2 N N SH N SH HN\ H H2 ,H 'CH3 H2N6 3-Mercapto-4-methyl-1,2,4- 2-Methyl-4-amino-5- 2-Phenylpiperidine triazol aminomethylpyrimidine N -N N C N NASH H2N -2 H N
NH
2 3-benzylamino-1 -propanol 4-Aminomethylpyridine 3-Aminomethylpyridine ___ N HO,,,N
NH
2
NH
2 R-2-Amino-1 -propanol 4-(Ethylaminomethyl)pyridine 4-Trifluoromethoxybenzyl HON N C amine F NZ NH2 F o0 4-!trt-Butylbenzylamine 3-Aminobenzylamine 3-(Methylaminomethyl)
NH
2
NH
2 pyridine
H
3 C N' 3
NH
2 N DL-Phenylalanine methyl ester H2N OH 3 0 WO 99/01423 PCT/DK98/00287 465 Preparation of resin-[Building block 11: This resin was prepared as described above. 5 Preparation of 4-hydroxymethylnaphtaldehyde ([Building block 2]): The preparation of this compound is described above. Preparation of resin-[Building block 11-rBuildinq block 2]: 10 Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (4 hydroxymethylnaphthylmethylene)hydrazide: 0 OH ci , N .N PS 15 Resin-[Building block 1] (4 g) was suspended in DMF (40 mL) and was allowed to swell for 15 min. and then washed with DMF (2 x 40 mL), DCM (3 x 40 mL) and DMSO (2 x 40 mL). The solvent was removed by filtration. 1.488 g (8 mmol) 4-hydroxymethylnaphtaldehyde was dissolved in 40 mL DMSO and was added to the resin followed by 4 mL glacial acetic acid. 20 The suspension was shaken for 16 hours at 25 *C. The resin was successively washed with DMSO (2 x 40 mL), THF (3 x 40 mL), CH 3 OH (40 mL), CH 2 C1 2 (40 mL), CH 3 0H (40 mL),
CH
2
CI
2 (40 mL) and dried in vacuo at 40 OC for 16 hours to afford resin bound 3-chloro-4 hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide. 25 EXAMPLE 825: 3-chloro-4-hydroxybenzoic acid (4-(1 H-1.2,4-Triazol-3-ylsulfanylmethyl)naphthyl methylene)hydrazide WO 99/01423 PCT/DK98/00287 466 NH o / H HO N ci The resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene) hydrazide (resin-[Building block 1]-[Building block 2]) (2 g, - 2 mmoles) was swelled in
CH
2 Cl 2 (20 mL) for 15 min, then washed twice with CH 2 Cl 2 (20 mL). 8 mL CH 2 C1 2 and 8 ml 5 diisopropylethylamine was subsequently added and the suspension was cooled to 0 0C. Methanesulfonylchloride (2 mL) was dissolved in CH 2 Cl 2 (6 mL) and added to the suspen sion. The mixture was allowed to react at 0 0C for 30 min, then at 25 "C for 1 hour. The resin was isolated by filtration and washed with CH 2
C
2 (2 x 20 mL) and N-methyl-2-pyrrolidone (2 x 20 mL). 1H-1,2,4-Triazole-3-thiol (0.8 g) and KI (0.4 g) was dissolved in a mixture of 10 10 mL N-methyl-2-pyrrolidone and 10 mL dimethylsulfoxide and was added to the resin. Then 4 mL diisopropylethylamine was added and the mixture was shaken at 25 0C for 2 days. The solvent was removed by suction and the resin was washed with N-methyl-2-pyrrolidone (3 x 20 mL) THF (3 x 20 mL), CH 3 OH (20 mL), CH 2 Cl 2 (20 mL), CH 3 OH (20 mL), CH 2 Cl 2 (4 x 20 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 *C with a 50% 15 solution of trifluoroacetic acid in CH 2 Cl 2 (20 mL). The mixture was filtered and the resin was extracted with acetonitrile (20 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH 3 OH (10 mL) and acetonitrile (10 mL) and con centrated in vacuo. The residue was treated with CH 3 0H (4 mL) at 25 0C providing an off white precipitate which was isolated by filtration. The solid was washed with CH 3 OH (3 x 2 20 mL) and dried in vacuo at 40 C. This afforded 275 mg of the title compound. HPLC-MS (METHOD B): Rt = 2.48 min; m/z = 438 (M+1). 25 'H-NMR (300 MHz, DMSO-d 6 ) 6 = 4.9 (2H, s), 7.1 (1H, d),7.5-7.9 (5H, m), 8.0 (1H, s), 8.25 (1H, d), 8.9 (1H, d), 9.1 (1H, s), 11.0 (1H, s), 11.8 (1H, s) EXAMPLE 826: 3-Chloro-4-hydroxybenzoic acid (4-(isobutylaminomethyl)naphthylmethylene)hydrazide WO 99/01423 PCT/DK98/00287 467 0 / NH O N c H 3 I H ci The resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthyl methylene)hydrazide (resin-[Building block 1]-[Building block 2]) (50 mg, - 0.05 mmoles) was swelled in CH 2 Cl 2 (1 mL) for 15 min, then washed with CH 2 Cl 2 (2 x 0.5 mL). 0.4 mL 5 CH 2
C
2 and 0.4 mL diisopropylethylamine was subsequently added and the suspension was cooled to 0 C. Methanesulfonylchloride (0.1 mL) was dissolved in CH 2 Cl 2 (0.3 mL) and added to the suspension. The mixture was allowed to react at 0 0C for 30 min, then at 25 0C for 1 hour. The resin was isolated by filtration and washed with CH 2 Cl 2 (2 x 0.5 mL) and DMSO (0.5 mL). DMSO (0.5 mL) was added followed by 50 pL isobutylamine and 100 pL 10 diisopropylethylamine. The mixture was shaken at 25 0C for 16 hours, filtered and washed successively with DMSO (2 x 0.5 mL), THF (3 x 0.5 mL), CH 3 0H (0.5 mL), CH 2 Cl 2 (0.5 mL),
CH
3 OH (0.5 mL), CH 2 Cl 2 (4 x 0.5 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 *C with a 50% solution of trifluoroacetic acid in CH 2 Cl 2 (1 mL). The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were 15 concentrated in vacuo. The residue was redissolved in a mixture of CH 3 OH (0.5 mL) and acetonitrile (0.5mL) and concentrated in vacuo to give the title compound. HPLC-MS (METHOD B): R, = 4.20 min; m/z = 410 (M+1) 20 EXAMPLE 826: 3-Chloro-4-hydroxybenzoic acid ((4-(4-trifluoromethoxybenzylamino)methyl)naphthyl methylene)hydrazide 0 / NH N IOP H I F HO .N O cl F ci 25 Resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide: (resin-[building block 1]-[building block 2]) (50 mg) was swelled in a 1:1 mixture of CH 2 Cl 2 and N-methyl-2-pyrrolidone (0.5 mL) for 15 minutes and then washed with CH 2 Cl 2 (3 x 0.5 mL). 800 pL of a 1:1 mixture of CH 2 C1 2 and diisopropylethylamine was added to the resin WO 99/01423 PCT/DK98/00287 468 which subsequently was cooled to -3 0C. A solution of 100 pL methanesulfonylchloride dis solved in 300 pL was added and allowed to react at -3 0C for 30 minutes then at 25 0C for 1 hour. Filtration of the resin was followed by washing with CH 2 Cl 2 (2 x 1 mL) and N-methyl-2 pyrrolidone (2 x 0.5 mL). 600 pL of a solution of 4-trifluoromethoxybenzylamine (45.8 mg, 5 0.24 mmol, 0.4M) and KI (10 mg, 0.06 mmol, 0.1M) in N-methyl-2-pyrrolidone (0.5 mL) and diisopropylethylamine (0.1 mL) was added and allowed to react at 25 0C for 16 hours. The resin was isolated by filtration and washed successively with N-methyl-2-pyrrolidone (5 x 0.5 mL), THF (3 x 0.8 mL), CH 3 0H (0.8 mL), CH 2 Cl 2 (0.8 mL), CH 3 OH (0.8 mL) and CH 2
C
2 (3 x 0.8 mL). The compound was cleaved from the resin by shaking 1 hour at 25 0C with a solu 10 tion of 50% trifluoroacetic acid in CH 2 Cl 2 (1 mL) The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mixture of CH 3 OH (0.5 mL) and acetonitrile (0.5mL) and con centrated in vacuo to give the title compound. 15 HPLC-MS (METHOD A): R, = 10.07 min; m/z = 528 (M+1) EXAMPLES 828 TO 875: 20 A library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2] and [building block 3]) was prepared in parallel as indi vidual entities analogously to the previous example on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the operation of the synthesizer. The com pounds are all expected to be present in the respective wells. 25 A suspension of the resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethyl naphthylmethylene)hydrazide: (resin-[building block 1]-[building block 2]) (50 mg) in a 1:1 mixture of CH 2 Cl 2 and N-methyl-2-pyrrolidone (0.5 mL) is equally distributed in the wells in the synthesizer prior to the initialization of the device. 30 ChemFile C:\ACT_1328\MAIN.CHM 1 REM Nucleophilic displacement of benzylic alcohol WO 99/01423 PCT/DK98/00287 469 2 REM via mesylation 3 4 5 REM Dipense resin bound benzylic alchohol to wells 5 6 7 8 REM Setup Diluterl=DCM, D2=NMP (N-methyl-2-pyrrolidone), D3=NMP, D4=DCM 9 REM Adjust pressure 10 REM Add 100 mL DIEA/DCM 1:1 mixture to Reagent1 10 11 REM Add 70 mL MsCI/DCM 1:3 mixture to Reagent2 12 REM Add 100 mL TFA/DCM 1:1 mixture to Reagent3 13 REM Add 100 mL CH3CN to Reagent4 14 REM Nitrogen for cooling 15 15 16 Pause 17 REM Initialising... 18 19 REM Subroutine Emptyl72_3min is called twice to remove DCM/NMP from dispensed resin 20 20 Go to ChemFile MTY72_3M.CHM, line 1 21 Go to ChemFile MTY72_3M.CHM, line 1 22 23 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 and with Flush Diluter 4 25 24 25 REM Washing with DCM, 3 times 26 Dispense System Fluid Disdul_4* 500ul to RB1_1to96[1-72] 27 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait. 28 REM Subroutine Emptyl72_3min 30 29 Go to ChemFile MTY72_3M.CHM, line 1 30 Repeat from step 26, 2 times 31 32 REM Adding DCM/DlEA mixture from Reagent1 33 Transfer 800ul from REAGENT_1[1](DCM/DIEA) to RB1_1to96[1-72] using Flush Diluter1 35 34 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 35 Set Temperature of rack "RB1_1to96" to -3.0 degrees Celsius and wait for Temperera ture to reach setpoint 36 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 37 REM Ensure complete cooling 40 38 Wait for 15.000 minute(s) 39 40 REM Adding mesylchloride 41 Transfer 400ul from REAGENT_2[1](MsCI/DCM) to RB1_1to96[1-72] using Flush Diluter1 42 REM Reacts 30 min @ -3 0C 45 43 Mix "RB1 1to96" for 1.00 minutes at 300 rpm(s) and wait. 44 Wait for 4.000 minute(s) 45 Repeat from step 43, 5 times 46 47 REM Reacts 60 min @ 25 C WO 99/01423 PCT/DK98/00287 470 48 Set Temperature of rack "RB 1_1to96" to 25.0 degrees Celsius and wait for Temperera ture to reach setpoint 49 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 50 Wait for 4.000 minute(s) 5 51 Repeat from step 46, 11 times 52 53 REM Subroutine Emptyl 72_3min 54 Go to ChemFile MTY72_3M.CHM, line 1 55 10 56 REM Initiate washing procedure, 2XDCM 57 Dispense System Fluid Disdul_4* 1000ul to RB1lto96[1-72] 58 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait. 59 Go to ChemFile MTY72_3M.CHM, line 1 60 Repeat from step 57, 1 times 15 61 62 REM NMP wash 63 64 Dispense System Fluid Disdu2_3* 500ul to RB1lto96[1-72] 65 Mix "RB1_1to96" for 5.00 minutes at 300 rpm(s) and wait. 20 66 Go to ChemFile MTY72_3M.CHM, line 1 67 68 Go to ChemFile MTY72_3M.CHM, line 1 69 Repeat from step 64, 1 times 70 25 71 REM Make sure that nucleophiles are dissolved and ready for addition 72 Pause 73 74 Dispense Sequence C:\ACT_1328\R2-A.DSP with 600ul to RB1_1to96 rack using Flush Diluter 2 30 75 REM Nucleophiles react @ 25 C for 16 hr 76 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 77 Wait for 4.000 minute(s) 78 Repeat from step 76, 11 times 79 Repeat from step 76, 15 times 35 80 81 REM End of reaction 82 Go to ChemFile MTY72_3M.CHM, line 1 83 Go to ChemFile MTY72_3M.CHM, line 1 84 40 85 REM Commence final washing procedure 86 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72] 87 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait. 88 Go to ChemFile MTY72 3M.CHM, line 1 89 Go to ChemFile MTY72_3M.CHM, line 1 45 90 Repeat from step 86, 4 times 91 92 REM Change systemfluids: 93 REM * Diluter2: THF 94 REM * Diluter3: MeOH WO 99/01423 PCT/DK98/00287 471 95 Pause 96 97 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 and Flush Diluter 4 5 98 REM THF wash 3 times 99 Dispense System Fluid Flush Diluter 2 800ul to RB1_1to96[1-72] 100 Mix "RB1 1to96" for 10.00 minutes at 300 rpm(s) and wait. 101 Go to ChemFile MTY72_3M.CHM, line 1 102 Go to ChemFile MTY72_3M.CHM, line 1 10 103 Repeat from step 99, 2 times 104 105 REM Alternating MeOH/DCM wash, 2 cycles 106 Dispense System Fluid Flush Diluter 3 800ul to RB1_1to96[1-72] 107 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait. 15 108 Go to ChemFile MTY72_3M.CHM, line 1 109 110 Dispense System Fluid Disdul_4* 800ul to RB11to96[1-72] 111 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait. 112 Go to ChemFile MTY72_3M.CHM, line 1 20 113 Go to ChemFile MTY72_3M.CHM, line 1 114 115 Repeat from step 106, 1 times 116 117 Dispense System Fluid Disdul_4* 800ul to RBl1to96[1-72] 25 118 Mix "RB1 1to96" for 10.00 minutes at 300 rpm(s) and wait. 119 Go to ChemFile MTY72_3M.CHM, line 1 120 Repeat from step 117, 1 times 121 122 REM Washing procedure has ended 30 123 124 REM Setup for cleavage: 125 REM * Cleavage vials 126 REM * Lower pressure 127 REM * Add 100 mL TFA/DCM 1:1 mixture to Reagent3 35 128 REM * Add 100 mL CH3CN to Reagent4 129 Pause 130 131 REM Adding cleavage solution, 1hr 132 Transfer 1000ul from REAGENT_3[1](TFA/DCM) to RB1_1to96[1-72] using Flush Di 40 luter1 133 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 134 Wait for 4.000 minute(s) 135 Repeat from step 133, 11 times 136 REM PULSE EMPTY! 45 137 Go to ChemFile PULSEMP1.CHM, line 1 138 139 REM Washing with CH3CN 140 Transfer 500ul from REAGENT_4[1](CH3CN) to RB1_1to96[1-72] using Flush Diluter1 141 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
WO 99/01423 PCT/DK98/00287 472 142 REM PULSE EMPTY! 143 Go to ChemFile PULSEMP1.CHM, line 1 144 145 REM The End 5 146 The following chemfile is called to empty the wells of the reaction block.: ChemFile C:\ACT_1328\MTY72_3M.CHM 10 1 REM Subroutine Emptyl72_3min 2 Empty RB1_1to96 for 5.000 minute(s) 3 Return 15 The following chemfile is called to empty the wells of the reaction block into the cleavage vi als containing the final product in a controlled manner. ChemFile C:\ACT_1328\PULSEMP1.CHM 20 1 Empty RB1_1to96 for 1 second(s) 2 Wait for 4 second(s) 3 Repeat from step 1, 11 times 4 Empty RB1_1to96 for 5.000 minute(s) 5 Return 25 Dispense sequence C:\ACT_1328\R2-A.DSP is a subroutine that controls the combinatorial addition of the amines into the reaction block in the syntheziser. 30 Examples of compounds from this library were characterised by HPLC-MS (molecular mass & retention time) including the following examples 828 to 875: WO 99/01423 PCT/DK98/00287 473 Ex No. Structure HPLC-MS HPLC-MS (METHOD (METHOD B) B) m/z (M+1) Rt (minutes) 828 N 422 6.10 HOH HOJP I CI 829 0 / NH 410 4.20 N 'N- NOH, HO H CHa cl 830 0 NCH 410 4.93 N N, CH HO [ H cI 831
CH
3 508 13.30 0 OCH,3 O N 3 HO .N Cl 832 O 450 7.87 O H N-N N Ci H 833 0 448 7.07 H. N-N N cH H
OH
3 WO 99/01423 PCT/DK98/00287 474 834 0 474 6.10 O Hi N-N ' N 835 OH 445 3.32 H =- xN -NN 836 458 9.55 H 0 N-N N C1 H HCH 837 0 470 14.13 H N-N N C1 H 838 0 488 9.85 H. N-N N CI H H 839 486 17.00 0/ H N-N N C1
HH
3 C CHj 840 0 HO 474 6.35 H - N-N N CI H 1 841 0 512 12.82
.
-
N-N N
-
F F FEF 842 O 452 3.25 H. N-N N
HO
WO 99/01423 PCT/DK98/00287 475 843 o 468 6.25 o N-N cl H S H 3 844 0 453 4.87 CH H
H
3 C 845 o H 437 2.68 0 N H ~N-NS-( 0l k N 846 o 436 7.88 HO N-N N 847 o 500 14.12 CI H H oi N-N N CH
OH
3 HOC
CH
3 Ex No. Structure HPLC-MS HPLC-MS (METHOD (METHOD A) A) m/z (M+1) Rt (minutes) 848 484 9.80 0 - \, HN -N Nl 01 H H8 849 o 462 9.38 0/ H. N-N N CI H H
F
WO 99/01423 PCT/DK98/00287 476 850 0 472 9.37 HO/~~ .N-N Cl Hi 851 o -486 9.55 HO -l .N -N N3 852 0 488 9.18 C1 HN-N/ N 853 o488 9.37 H1o N-N NCH -PH 855 458 9.3 ol F N-N N-CH3 H -N N 8585 453 8.90 ol FH N-N N
NH
WO 99/01423 PCT/DK98/00287 477 859 0 497 10.73 0 -/ / I\ / H C- H.N-N N 860 0 474 9.15 HO - N-N N C1 H CI H H H3C-O 861 488 9.55 00 0 / H - N-N N cI H H OH3 862 0 462 9.27 H - N-N N CI H H F 863 47N94 864 0 504 8.98 Oi N-N' N O
CH
3 0-CH 3 865 0 HO 440 8.35 H N-N N CI Hf X H CH
H
3 C 866 0 S 454 12.90 /-\ - s i - N cI H N WO 99/01423 PCT/DK98/00287 478 867 o 459 7.63 o - N-N N
NH
2 868 0 H C 451 8.45 0 N i C N-N S-N cI Hi N 869 O H 3 C 452 9.31 0 N C - N-N S_4N CI Hi N'N 870 498 9.65 0 N 871 0 502 9.03 0 C HO N-N N CI HO I-i 872 0 459 7.60 H H N-N N
-
H HI -b -H 873 516 9.33 HO N-N' N cI H H 0 0
CH
3 EXAMPLE 874: 0 .N C N'p N N N K N N ' HO Cl WO 99/01423 PCT/DK98/00287 479 'H NMR (DMSO-D6) d 2.37 (m, 8H), 3.44 (s, 2H), 3.90 (s, 2H), 7.10 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 7.4 Hz, 1H), 7.67 (m, 2H), 7.81 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 7.3 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 8.36 (dd, J = 1.7, 7.0 Hz, 1H), 8.83 (d, J = 8.0 Hz, 1H), 9.08 (s, 1H), 10.99 (s, 1H), 11.78 (s, 1H). MS (APCI, pos.): 5 547.1, 550.1 EXAMPLE 875: o N_ 0 N HO. 10 ci 'H NMR (DMSO-D 6 ) d 2.66 - 2.75 (m, 4H), 3.69 (s, 2H), 4.06 (s, 2H), 6.36 (m, 1H), 6.40 (m, 1H), 7.06 (d, J = 8.5 Hz, 1H), 7.51 - 7.66 (m, 4H), 7.77 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.98 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.80 (d, J = 8.5 Hz, 1H), 9.04 (s, 1H), 10.94 15 (s, 1H), 11.77 (s, 1H). MS (APCI, pos.): 485.1, 487.1 General Procedure for Examples 876 to 877: The compounds were prepared as single entities according to the following equation 20 Resin-[Building block 1] Resin-[Building block 1]-[Building block 2] 3 Resin-[Building block 1]-[Building block 2]- [Building block 3] : Resin-[Building block 1]-[Building block 2]-[Building block 3]-[Building block 4] and were simultaneously deprotected and cleaved from the resin with 50% trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the 25 following formula WO 99/01423 PCT/DK98/00287 480 [Building block 1]- [Building block 2]- [Building block 3]- {Building block 4]. The following compounds were prepared as single entities by parallel synthesis on a solid 5 support. Preparation of Resin-[Building block 1]-[Building block 2] was done manually, whereas the attachment of [Building block 3], attachment of [Building block 4] and cleavage from the resin were performed on an Advanced ChemTech Model 384 HTS. The starting resin, Resin-[Building block 1], was prepared as described above. 10 The resin used was a polystyrene resin with a Wang linker and the substitution capacity was 0.9 mmol/g. All compounds are based on successive attachment of [Building block 2] and [Building block 15 3] to Resin-[Building block 1] in a combinatorial way using a nucleophilic substitution reaction followed by an acylation reaction attaching [Building block 4] according to the following for mulae, which are included in the general formula 11: WO 99/01423 PCT/DK98/00287 481
R
1 5 R1 5 O I OH Resin, H 14 H N R C R Resin C0 R1 Resin-[Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] ICl-S-CHa R's H 2
NR
5 - R1 5 [ B 5 [Building block 3] N N N O-S-CH3 C INH 0 N o Cl N 14 C N.N Resin, H RH I H -~Resin, R Resin-[Building block 1]-[Building block 2]-[Building block 3] I 0 R' Lea ~[Building block 4] R 1 5 R 1 5 R R 5 R --- (CH2) 0 q(C2 14N N N0 Resin, , H R141 '0 H.00R Resin-[Building block 1 ]-[Building block 2]-[Building block 3]-[Building block 4] [Building block 1 ]-[Building block 2]-[Building block 3]-(Building block 4] wherein R 5 a, R1 4 1 R" 5 are as defined for formula I and RSc is 5 4a 4b R R -(CH2)c q (CH 2 )-D where R 4 ", R 4 b, c, q, d, and D are as defined for formula I or -D' where -D' is defined as a subset of -D that contains an activated carboxylic acid capable 10 of reacting as an electrophile and Lea is a leaving group such as chloro, bromo, iodo, carboxylate, WO 99/01423 PCT/DK98/00287 482 o ' 0 0
N
The following resin, here depicted as Resin-[Building block 1] was used: 0 C N N NH2 I H o where PS is polystyrene. In the following "Resin" 0 /is the polystyrene resin with the Wang linker: PS 5O =Resin The following building blocks were used: [Buildina block 21: 4-Hydroxymethylnaphthalene-1 carbaldehyde ON OH 10 WO 99/01423 PCT/DK98/00287 483 [Building block 31: 2-Thiophenemethylamine 5-Methyl-2-furanmethylamine L-Methionine ethyl ester H2N- H3C NH
H
3 C' 0 CH 3
NH
2 2-(Aminomethyl)pyridine 4-(2-Aminoethyl)pyridine 3-Aminopentane H2N N NH2
H
3 C CH 3 Furfurylamine 2-Methoxyisopropylamine Cyclopropylamine 0
H
2 N o-CH3 H2N H2N/- 0\/
CH
3 Glycine 2-Furanylmethylamine N,N-Dimethylethylenedi o OH NH 2 amine
NH
2
OH
3
H
3 C-N NH2 Ethylamine Methylamine Propylamine
CH
3
H
3 C,
CH
3 NH NH2
NH
2
H
2 N Isopropylamine Isopentylamine Cyclopentylamine CH3 ON -<H 3
H
2 N- LCH 3 y
CH
3 Cyclopropylmethylamine Cyclobutylamine Thiophene-2-ethylamine AINH2 C NH2 NH2 Glutamic Acid di tert butyle- 2,2,2-Trifluoroethylamine Tetrahydro-3-thiophenamine ster F NH2 1,1-dioxide
CH
3 O F F
H
3 O,,
H
3 C NH 2 0, NH 2 0 0 H3 /O H3 CH3 WO 99/01423 PCT/DK98/00287 484 [Building block 4]: Acetic anhy- N-tet Butoxycarbonyl dride praline anhydride H~c- 0 C H' 1 >r o...97] C H,
H
3 CHO 00 0ookCH 3 0 CH 3
CH
3 Preparation of resin-[Building block 1]: 5 This resin was prepared as described above. Preparation of resin-[Building block 1]-[Building block 2]: 10 This resin was prepared as described above. EXAMPLE 876: N-{4-[(3-Chloro-4-hydroxybenzoyl)-hydrazonomethyllnaphthylmethyl}-N-isobutylprolinamide 0042 N' N.- N N _H HO N H CH3 15 ci The resin bound 3-chloro-4-hydroxybenzoic acid (4-hyd roxymethylnaphthyl methylene)hydrazide (resin-[Building block 1]-[Building block 2]) (50 mg, - 50 pmoles) was swelled in CH 2 Cl 2 (0.5 mL) for 15 min, then washed twice with CH 2 Cl 2 (0.5 mL). 0.4 mL 20 CH 2 C1 2 and 0.4 mL diisopropylethylamine were subsequently added and the suspension was cooled to 0 *C. Methanesulfonylchloride (0.1 mL) was dissolved in CH 2 Cl 2 (0.3 mL) and added to the suspension. The mixture was allowed to react at 0 "C for 30 min, then at 25 0C for 1 hour. The resin was isolated by filtration and washed with CH 2 Cl 2 (2 x 0.5 mL) and DMSO (0.5 mL). 0.5 mL DMSO was added to the resin followed by isobutylamine (50 pL) WO 99/01423 PCT/DK98/00287 485 and diisopropylethylamine (100 pL). The mixture was shaken at 25 *C for 16 hours. The sol vent was removed by suction and the resin was washed with DMSO (2 x 0.5 mL) andTHF (3 x 0.5 mL). To a solution of N-tert- butoxycarbonyl-proline (46 mg, 0.21 mmol) in THF (0.5 mL) was added diisopropylcarbodiimide (16 pL, 0.2 mmol). This solution was allowed to re 5 act at 25 OC for 10 minutes and then added to the resin. The suspension was shaken at 25 0C for 16 hours after which the resin was isolated by suction and washed with THF (3 x 0.5 mL), DMF (3 x 0.5 mL) THF (3 x 0.5 mL), CH 3 OH (0.5 mL), CH 2 Cl 2 (0.5 mL), CH 3 0H (0.5 mL), CH 2 Cl 2 (4 x 0.5 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 0C with a 50% solution of trifluoroacetic acid in CH 2 Cl 2 (1 mL). The mixture was filtered 10 and the resin was extracted with acetonitrile (1 mL). The combined extracts were concen trated in vacuo. The residue was redissolved in a mixture of CH 3 OH (0.5 mL) and acetonitrile (0.5 mL) and concentrated in vacuo to give the title compound. HPLC-MS (METHOD B): Rt = 3.90 min; m/z = 507 (M+1). 15 EXAMPLE 877: 3-Chloro-4-hydroxybenzoic acid ((4-(4-trifluoromethoxybenzylamino)methyl)naphthyl methylene)hydrazide o - NN-N N CH cl H 20 Resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide (resin-[building block 1]-[building block 2]) (50 mg) was swelled in a 1:1 mixture of CH 2 Cl 2 and N-methyl-2-pyrrolidone (0.5 mL) for 15 minutes and then washed with CH 2 Cl 2 (3 x 0.5 25 mL). 800 pL of a 1:1 mixture of CH 2 Cl 2 and diisopropylethylamine was added to the resin which subsequently was cooled to -3 *C. A solution of 100 pL methanesulfonylchloride dis solved in 300 pL was added and allowed to react at -3 0C for 30 minutes then at 25 0C for 1 hour. Filtration of the resin was followed by washing with CH 2 Cl 2 (2 x 1 mL) and N-methyl-2 pyrrolidone (2 x 0.5 mL). 600 pL of a solution of 4-trifluoromethoxybenzylamine (45.8 mg, 30 0.24 mmol, 0.4M) and KI (10 mg, 0.06 mmol, 0.1M) in N-methyl-2-pyrrolidone (0.5 mL) and WO 99/01423 PCT/DK98/00287 486 diisopropylethylamine (0.1 mL) was added and allowed to react at 25 0C for 16 hours. The resin was isolated by filtration and washed successively with N-methyl-2-pyrrolidone (5 x 0.5 mL) and THF (3 x 0.5 mL). 600 pL of a solution of acetic anhydride (120 pL, 130 mg, 1.27 mmol) in THF (480 pL) was added to the resin. The mixture was allowed to react at 25 0C for 5 16 hr. The resin was filtered and washed successively with THF (2 x 0.8 mL), CH 3 OH (0.8 mL), CH 2
CI
2 (0.8 mL), CH 3 0H (0.8 mL) and CH 2 Cl 2 (3 x 0.8 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 OC with a solution of 50% trifluoroacetic acid in
CH
2 Cl 2 (1 mL). The mixture was filtered and the resin was extracted with acetonitrile (1 mL). The combined extracts were concentrated in vacuo. The residue was redissolved in a mix 10 ture of CH 3 0H (0.5 mL) and acetonitrile (0.5mL) and concentrated in vacuo to give the title compound. HPLC-MS (METHOD B): Rt = 6.42 min; m/z = 492 (M+1) 15 EXAMPLES 878 TO 881: A library of compounds of all the possible combinations of the above listed building blocks ([building block 1], [building block 2], [building block 3] and acetic anhydride as [building block 4]) was prepared in parallel as individual entities analogously to the previous example 20 on an Advanced ChemTech Model 384 HTS using the following ChemFile to control the op eration of the synthesizer. The compounds are all expected to be present in the respective wells. A suspension of the resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethyl 25 naphthylmethylene)hydrazide (resin-[building block 1]-[building block 2]) (50 mg) in a 1:1 mixture of CH 2 Cl 2 and N-methyl-2-pyrrolidone (0.5 mL) is equally distributed in the wells in the synthesizer prior to the initialization of the device. ChemFile C:\ACT_1328\MAIN.CHM 30 1 REM Nucleophilic displacement of benzylic alcohol 2 REM via mesylation 3 4 WO 99/01423 PCT/DK98/00287 487 5 REM Dipense resin bound benzylic alchohol to wells 6 7 8 REM Setup Diluterl=DCM, D2=NMP (N-methyl-2-pyrrolidone), D3=NMP, D4=DCM 5 9 REM Adjust pressure 10 REM Add 100 mL DIEA/DCM 1:1 mixture to Reagent1 11 REM Add 70 mL MsCI/DCM 1:3 mixture to Reagent2 12 REM Add 100 mL TFA/DCM 1:1 mixture to Reagent3 13 REM Add 100 mL CH3CN to Reagent4 10 14 REM Nitrogen for cooling 15 16 Pause 17 REM Initialising... 18 15 19 REM Subroutine Emptyl72_3min is called twice to remove DCM/NMP from dispensed resin 20 Go to ChemFile MTY72_3M.CHM, line 1 21 Go to ChemFile MTY72_3M.CHM, line 1 22 20 23 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 and with Flush Diluter 4 24 25 REM Washing with DCM, 3 times 26 Dispense System Fluid Disdul_4* 500ul to RBl1to96[1-72] 25 27 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait. 28 REM Subroutine Emptyl_72_3min 29 Go to ChemFile MTY72_3M.CHM, line 1 30 Repeat from step 26, 2 times 31 30 32 REM Adding DCM/DIEA mixture from Reagent1 33 Transfer 800ul from REAGENT_1[1](DCM/DIEA) to RB1_1to96[1-72] using Flush Diluter1 34 Mix "RB1 1to96" for 1.00 minutes at 300 rpm(s) and wait. 35 Set Temperature of rack "RB1_1to96" to -3.0 degrees Celsius and wait for Temperature to reach setpoint 35 36 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 37 REM Ensure complete cooling 38 Wait for 15.000 minute(s) 39 40 REM Adding mesylchloride 40 41 Transfer 400ul from REAGENT_2[1](MsCI/DCM) to RB1_1to96[1-72] using Flush Diluter1 42 REM Reacts 30 min @ -3 "C 43 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 44 Wait for 4.000 minute(s) 45 Repeat from step 43, 5 times 45 46 47 REM Reacts 60 min @ 25 C 48 Set Temperature of rack "RB1_1to96" to 25.0 degrees Celsius and wait for Temperature to reach setpoint 49 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
WO 99/01423 PCT/DK98/00287 488 50 Wait for 4.000 minute(s) 51 Repeat from step 46, 11 times 52 53 REM Subroutine Emptyl72_3min 5 54 Go to ChemFile MTY72_3M.CHM, line 1 55 56 REM Initiate washing procedure, 2XDCM 57 Dispense System Fluid Disdul_4* 1000ul to RB1_1to96[1-72] 58 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait. 10 59 Go to ChemFile MTY72_3M.CHM, line 1 60 Repeat from step 57, 1 times 61 62 REM NMP wash 63 15 64 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72] 65 Mix "RB1_1to96" for 5.00 minutes at 300 rpm(s) and wait. 66 Go to ChemFile MTY72_3M.CHM, line 1 67 68 Go to ChemFile MTY72_3M.CHM, line 1 20 69 Repeat from step 64, 1 times 70 71 REM Make sure that nucleophiles are dissolved and ready for addition 72 Pause 73 25 74 Dispense Sequence C:\ACT_1328\R2-A.DSP with 600ul to RB1_1to96 rack using Flush Diluter 2 75 REM Nucleophiles react @ 25 C for 16 hr 76 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 77 Wait for 4.000 minute(s) 30 78 Repeat from step 76, 11 times 79 Repeat from step 76, 15 times 80 81 REM End of nucleophilic substitution reaction 82 Go to ChemFile MTY72_3M.CHM, line 1 35 83 Go to ChemFile MTY72_3M.CHM, line 1 84 85 REM Commence washing procedure 86 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72] 87 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait. 40 88 Go to ChemFile MTY72_3M.CHM, line 1 89 Go to ChemFile MTY72_3M.CHM, line 1 90 Repeat from step 86, 4 times 91 92 REM Change systemfluids: 45 93 REM * Diluter2: THF 94 REM * Diluter3: MeOH 95 Pause 96 WO 99/01423 PCT/DK98/00287 489 97 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 and Flush Diluter 4 98 REM THF wash 3 times 99 Dispense System Fluid Flush Diluter 2 500ul to RB1_1to96[1-72] 5 100 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait. 101 Go to ChemFile MTY72_3M.CHM, line 1 102 Go to ChemFile MTY72_3M.CHM, line 1 103 Repeat from step 99, 2 times 104 Go to ChemFile Acylation.CHM, line 1 10 105 Go to ChemFile WASH.CHM, line 1 106 Go to ChemFile Cleavage.CHM, line 1 107 REM The End The following chemfile is called to acylate the amines: 15 ChemFile C:\ACT_1328\Acetyl.CHM 1 REM Acetylation procedure 2 REM Charge REAGENT_5 with 100 mL Acetic anhydride/THF 1:4 v/v 20 3 REM * Diluter2: THF 4 REM Addition of acylation reagent 5 Dispense Sequence C:\R3-A.DSP with 600 pL to RB1to96 rack using Flush Diluter 2 6 Mix for 1.00 minutes at 300 rpm(s) 7 Wait for 5.000 minute(s) 25 8 Repeat from step 6, 60 times 9 Go to ChemFile MTY72_3M.CHM, line 1 10 Go to ChemFile MTY72_3M.CHM, line 1 11 Return 30 The following chemfile is called to wash the resin bound products: ChemFile C:\ACT_1328\WASH.CHM 1 REM Washing procedure 35 2 REM Systemfluids: 3 4 REM * Diluter2: THF 5 REM * Diluter3: MeOH 6 40 7 Flush Arm1 with Flush Diluter1 and Flush Diluter 2 , Arm2 with Flush Diluter 3 and Flush Diluter 4 8 REM THF wash 3 times 9 Dispense System Fluid Flush Diluter 2 800ul to RB1_1to96[1-72] 10 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
WO 99/01423 PCT/DK98/00287 490 11 Go to ChemFile MTY72_3M.CHM, line 1 12 Go to ChemFile MTY72_3M.CHM, line 1 13 Repeat from step 9, 2 times 14 5 15 REM Alternating MeOH/DCM wash, 2 cycles 16 Dispense System Fluid Flush Diluter 3 800ul to RB1_1to96[1-72] 17 Mix "RB1_1to96" for 3.00 minutes at 300 rpm(s) and wait. 18 Go to ChemFile MTY72_3M.CHM, line 1 19 10 20 Dispense System Fluid Disdul_4* 800ul to RB1_1to96[1-72] 21 Mix "RB1I_1to96" for 10.00 minutes at 300 rpm(s) and wait. 22 Go to ChemFile MTY72_3M.CHM, line 1 23 Go to ChemFile MTY72_3M.CHM, line 1 24 15 25 Repeat from step 16, 1 times 26 27 Dispense System Fluid Disdul_4* 800ul to RB1_1to96[1-72] 28 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait. 29 Go to ChemFile MTY72_3M.CHM, line 1 20 30 Repeat from step 117, 1 times 31 32 REM Washing procedure has ended 33 Return 25 The following chemfile is called to cleave the products from the resin: ChemFile C:\ACT_1328\Cleavage.CHM 1 REM Setup for cleavage: 30 2 REM * Cleavage vials 3 REM * Lower pressure 4 REM * Add 100 mL TFA/DCM 1:1 mixture to Reagent3 5 REM * Add 100 mL CH3CN to Reagent4 6 Pause 35 7 8 REM Adding cleavage solution, 1hr 9 Transfer 1000ul from REAGENT 3[1](TFA/DCM) to RB1_1to96[1-72] using Flush Diluter1 10 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait. 11 Wait for 4.000 minute(s) 40 12 Repeat from step 133, 11 times 13 REM PULSE EMPTY! 14 Go to ChemFile PULSEMP1.CHM, line 1 15 16 REM Washing with CH3CN 45 17 Transfer 500ul from REAGENT 4[1](CH3CN) to RB1_1to96[1-72] using Flush Diluter1 18 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
WO 99/01423 PCT/DK98/00287 491 19 REM PULSE EMPTY! 20 Go to ChemFile PULSEMP1.CHM, line 1 21 Return 5 The following chemfile is called to empty the wells of the reaction block.: ChemFile C:\ACT_1328\MTY72_3M.CHM Page 1 1 REM Subroutine Emptyl_72_3min 10 2 Empty RB1_1to96 for 5.000 minute(s) 3 Return The following chemfile is called to empty the wells of the reaction block into the cleavage vi als containing the final product in a controlled manner. 15 ChemFile CAACT_1328\PULSEMPI.CHM Page 1 1 Empty RB1_1to96 for 1 second(s) 2 Wait for 4 second(s) 20 3 Repeat from step 1, 11 times 4 Empty RB1_1to96 for 5.000 minute(s) 5 Return Dispense sequence C:\ACT_1328\R2-A.DSP is a subroutines that control the combinatorial 25 addition of the amines into the reaction block in the syntheziser. Dispense sequence C:\ACT_1328\R3-A.DSP is a subroutines that control the combinatorial addition of the acylating agents into reaction block in the syntheziser. 30 Examples of compounds from this library were characterised by HPLC-MS (molecular mass & retention time) including the following examples 878 to 881.
WO 99/01423 PCT/DK98/00287 492 Ex No. Structure HPLC-MS HPLC-MS (METHOD (METHOD B) B) m/z (M+1) Rt (minutes) 878 H CH 3 490 6.22 So=(N CI HN- N
CH
3 879 H 0 OCH 454 1.05 N-N\ - N CI H H 880 Ho464 6.33 0 0( C HN-N ci H N \/H 0 881 H 0_, OH 3 450 5.30 0 l WO 99/01423 PCT/DK98/00287 493 EXAMPLE 882: N-{4-[3-chloro-4-hydroxybenzoyl)-hydrazonemethyll-1-naphthyl}methyl iso-propyl amide O ,yCH, 0 NN
CH
3 HH I H HOj ci 5 Preparation of N-4-Formylnaphthylmethyl isopropyl amide: A mixture of 4-bromomethyl-1-naphthaldehyde ethyleneacetal (447 mg, 1.52 mmol) and NaN 3 (221 mg, 3.4 mmol) in 10 mL DMF was warmed up to 100 0C and stirred for 30 min. Solution turned orange. The reaction was filtered and the clear solution was concentrated to 10 391 mg of yellow oil. This oil (249 mg) together with triphenylphosphine (260 mg, 0.99 mmol) was dissolved in 10 mL of THF. The reaction mixture was left overnight followed by the addition of water. Ninhydrin test revealed the formation of an amine. This amine was extracted into ethyl acetate layer, dried to give an oil. This oil was dissolved in CH 2 Cl 2 , EDC, DMAP and 2-methylpropionic acid were added. The reaction mixture was left for 2 days. 15 Column chromatography eluted with ethyl acetate afforded the amide. Deprotection of di ethyleneacetal was achieved by 10% HCI in THF to give the title compound (50 mg). 'H NMR (CDCI 3 ): d 1.2 (d, 6H), 2.4 (m, 1H), 4.9 (d, 2H), 6.1 (b, 1H), 7.5 (d, 1H), 7.6 (m, 2H), 7.8 (d, 1H), 8.0 (d, 1H), 9.2 (d, 1H), 10.3 (s, 1H). 20 The title compound was prepared similarly as described above. 'H NMR (DMSO-D 6 ): d 1.0 (d, 6H), 2.4 (m, 1H), 4.7 (s, 2H), 7.0 (d, 1H), 7.4 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 7.9 (s, 1H), 8.1 (d, 1H), 8.3 (s, 1H), 8.8 (d, 1H), 9.0 (s, 1H), 10.9 25 (s, 1H), 11.7 (s, 1H); ms (APCI negative); 422. EXAMPLE 883: 4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylmethyl iso-propylsulfoxide WO 99/01423 PCT/DK98/00287 494
CH
3 NNS OH 3 H HO ci 4-Ethyleneacetal-4-formyl-naphthylmethyl iso-propylthioether: A mixture of 4-bromomethyl naphthaldehyde ethyleneacetal (232 mg, 0.79 mmol) and iso 5 propyl thioalcohol (0.08 mL, 0.81 mmol) and 0.12 mL of triethylamine was left at room tem perature for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography eluted with ethyl acetate /hexane (1/5) to afford 93 mg of the desi red product as pale radish oil. 10 'H NMR (CDCl 3 ): d 1.3 (d, 6H), 2.9 (m, 1H), 4.2 (m, 6H), 6.5 (s, 1H), 7.4 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 8.2 (m, 1H). 4-Ethyleneacetal-naphthylmethyl iso-propylsulfoxide: To a mixture of the above 4-ethyleneacetal-naphthylmethyl iso-propylthioether (79 mg, 0.27 15 mmol) in 5 mL of dichloromethane at -78 0C was added m-chloro perbenzoic acid (82 mg, 55% purity, 0.28 mmol). The reaction mixture was left for 1 hour and 40 min. Then, NaHSO, solution was added followed by NaHCO 3 . The mixture was extracted with water and dichloromethane. The organic layer was combined and dried over MgSO 4 . Solvent was removed and the residue was purified by column chromatography eluted with ethyl acetate 20 to yield 56 mg of desired product as an oil. 1 H NMR (CDCl 3 ): d 1.3 (d, 3H), 1.4 (d, 3H), 2.7 (m, 1H), 4.2 (m, 4H), 4.4 (dd, 2H), 6.5 (s, 1H), 7.5 (d, 1H), 7.6 (m, 2H), 7.7 (d, 1H), 8.1 (m, 1H), 8.2 (m, 1H). This compound was hy drolyzed in aqueous 10% HCI in THF for 1 hr to give the corresponding aldehyde. 25 4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylmethyl iso-propylsulfoxide: The title compound was prepared similarly as described above.
WO 99/01423 PCT/DK98/00287 495 'H NMR (DMSO-D 6 ): d 1.3 (dd, 6H), 3.0 (m, 1H), 4.3 (d, 1H), 4.7 (d, 1H), 7.1 (d, 1H), 7.6 (m, 3H), 7.8 (d, 1H), 7.9 (d, 1H), 8.0 (s, 1H), 8.2 (d, 1H), 8.8 (d, 1H), 9.1 (s, 1H), 11.0 (s, 1H), 11.8 (s, 1 H); ms (APCI negative); 427, 337. 5 EXAMPLE 884: 4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylmethyl iso-propylsulfone o .NHCH HO HO ' A CI 10 Similarly, the title compound was prepared. 'H NMR (DMSO-D,): d 1.3 (d, 6H), 3.4 (m, 1H), 5.0 (s, 2H), 7.0 (d, 1H), 7.6 (m, 3H), 7.7 (d, 1H), 7.9 (d, 2H), 8.2 (d, 1H), 8.7 (d, 1H), 9.0 (s, 1H), 10.9 (s, 1H), 11.8 (s, 1H); ms (APCI 15 negative); 443, 336. EXAMPLE 885: 4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylmethyl iso-propylsulfide 20 CH3 O NS
CH
3 H HO cl Similarly, the title compound was prepared.
WO 99/01423 PCT/DK98/00287 496 Further examples of the invention are the following compounds: EXAMPLE 886: O .N O F N 'N 00o"S 0 HOH 5 CI EXAMPLE 887: - CH 3 o N N' CH H HO CI 10 EXAMPLE 888: CH3 HO' A H H ) . -^
H
3 C CI 15 EXAMPLE 889:
OCH
3 N5 I C;..0 HO . H 3 C
CI
WO 99/01423 PCT/DK98/00287 497 EXAMPLE 890:
CH
3 O P, CH HO .N H2)-CH3 CI 5 EXAMPLE 891: N N O NO.0 0 HOH CI EXAMPLE 892:
)CH
3 0 N. N o 0 I? H HO 10 CI EXAMPLE 893:
CH
3 0 N.N N o/"O CH 3 H I H HO Cl 15 EXAMPLE 894: N N 00\\ H HO CI 20 WO 99/01423 PCT/DK98/00287 498 It should be apparent from the foregoing that other starting materials and other intermediate compounds can be substituted in the above procedures to prepare all of the compounds of the invention. The methods disclosed herein are based on established chemical techniques, as 5 will be apparent to those skilled in the art, and therefore all of the compounds of the invention are broadly enabled by the preceding disclosure. Accordingly, the invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all re 10 spects only as illustrative and not restrictive, and the scope of the invention is, therefore, indi cated by the appended claims rather than by the foregoing description. All modifications which come within the meaning and range of the lawful equivalency of the claims are to be embraced within their scope. 15
Claims (47)
1. A compound of the general formula 1: R 1 A N'N .I(CH2)n-B-(K)mD) A N _ 5 R3 R 2 R 4 wherein: R 1 and R 2 independently are hydrogen or lower alkyl or together form a valence bond; 10 R 3 and R 4 independently are hydrogen or lower alkyl; n is 0, 1, 2 or 3; 15 m is 0 or 1; X is >C=0, >C=S, >C=NR 5 or >S0 2 ; wherein R 5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR*; 20 wherein R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; A is WO 99/01423 PCT/DK98/00287 500 R 7 R 7 R 7 R R N N 8R 8 R8R R' R R R R R 9 R 9 R R R R 7 R 10 R 7 N RR a R R R8 RRR R Ri R NR Ra1 R10/ R Ra R R R RR 10 7R R R R N8 4 N N N IN 9 k8 RR 9 R R 10 7 R R r Rs w i Rn : R 1 R8-\s)R 8 I 9 R 9 7 _ jF N 8 8 \N/ R8- / R / N FRR'R R 9 R 8 N0 R R 8 N0 N R N N R 9 R N 1 R8 8R R 9 R 8 8' N, RoR R wNeRe8nN WO 99/01423 PCT/DK98/00287 501 R' is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR", -NR"R , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SO 2 NR 11 R1', -SR' 1 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 11 R, -OCH 2 CONR 1 1 R 12 , -CH 2 OR' 1 , -CH 2 NR 1 1 R 12 , -OCOR 1 , -O 2 R 1 'or -OSO 2 CF 3 ; 5 R' and R* independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR", -NR"R' 2 , lower alkyl, aryl, -SCF 3 , -SR 1 1 , -CHF 2 , -OCHF 2 , -OSO 2 R 11 , -CONR 1 1 R 12 , -CH 2 OR", -CH 2 NR"R 12 , -OCOR", -C0 2 R1 3 or -OSO 2 CF 3 , or R' and R 9 together form a bridge -OCH 2 0 or -OCH 2 CH 2 O-; 10 wherein R" and R' independently are hydrogen, -COR , -S0 2 R, lower alkyl or aryl; wherein R 1 3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and R" is hydrogen, lower alkyl, aryl-lower alkyl or aryl; 15 B is R1 5 R R 15R 1 R 1 R 1 RR RR R 15 Y WV w15 R I 1414 R RR R -CR CR or a valence bond; 20 wherein: WO 99/01423 PCT/DK98/00287 502 R" and R" independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -O(CH 2 )CF 3 , -NO 2 , -OR 16 , -NR 16 R 1 7 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 6 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OS02CF 3 , -CONR 1 R 17 , -(CH 2 )0CONR 6 R 17 , -O(CH 2 )ICONR R' 7 , -(CH 2 )ICOR 6 , -(CH 2 )ICOR, 5 -(CH 2 )iOR' 6 , -O(CH 2 )OR 6 , -(CH 2 ),NR R 17 , -O(CH 2 ),NR R 17 , -OCOR 6 , -C02R 6 , -O(CH 2 )IC0 2 R 18 , -O(CH 2 )ICN, -O(CH 2 )CI, or R" and R 1 5 together form a bridge -O(CH 2 ) 1 O- or -(CH 2 ) 1 -; wherein I is 1, 2, 3 or 4; 10 R 1 and R 17 independently are hydrogen, -COR1, -S02R", lower alkyl, aryl, or R" and R 17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms; wherein Ri 8 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; 15 W is -N= or -CR4=; Y is -N= or -CR21 20 Z is -N= or -CR21 V is -N= or -CR 22 =; and Q is -NR 23 -, -0- or -S-; 25 wherein: R 1 9 , R 2 0 , R21 and R' independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 , -NR 24 R 2 5 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 24 , -CHF 2 , -OCHF 2 , 30 -OCF 2 CHF 2 , -OS02CF 3 , -CONR 24 R 2 , -CH 2 CONR 24 R 2 , -OCH 2 CONR 24 R 2 s, -CH 2 0R 24 , -CH 2 NR 2 4 R 2 5 , -OCOR 2 4 or -C0 2 R 2 4 , or R"and R 2 0 , R 2 0 and R 21 , or R 21 and R 22 together form a bridge -OCH 2 0-; WO 99/01423 PCT/DK98/00287 503 wherein R 24 and R 2 independently are hydrogen, -COR 2 , -S0 2 R 2 e, lower alkyl, aryl or aryl lower alkyl; wherein R 2 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and 5 R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K is 3a 3b R4a 4 R R R R 4 (L)a (CH 2 )b p (CH 2 )a (M)f (CH 2 )o I (CH 2 )d 10 wherein: R 3 a, Rab, R 4 a and R 4 b independently are hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -OCH 2 CF 3 , -NO 2 , -OR 24 ., -NR 2 4 aR 2 5 a, lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 2 4 a, -CHF 2 , -OCHF 2 , 15 -OCF 2 CHF 2 , -OS02CF 3 , -CONR 2 4 R 2 S, -CH 2 CONR 24 aR 2 5 a, -OCH 2 CONR 24 aR 2 5 a, -CH 2 OR 2 4 ., -CH 2 NR 24 aR 2 5 a, -OCOR 24 , or -CO 2 R 2 4 a; wherein R 2 4 ' and R 252 independently are hydrogen, -COR 2 ", -S0 2 R 2 2 , lower alkyl, aryl or aryl-lower alkyl; 20 wherein R 2 eais hydrogen, lower alkyl, aryl or aryl-lower alkyl; or 25 Ra and Rab, R 4 a and R 4 b, or R 3 a and R 4 b together form a bridge -(CH 2 )-; wherein i is 1, 2, 3 or 4; a, b, c and d independently are 0, 1, 2, 3 or 4; 30 e, f and p independently are 0 or 1; WO 99/01423 PCT/DK98/00287 504 q is 0, 1 or 2; and L and M independently are -0-, -S-, -CH=CH-, -C=C-, -NR a-, -CH 2 NRS"-, -CO-, -OCO-, -COO-, -CONR a-, -CONR 5 b-, 5 -NR 5 "CO-, -SO-, -S02-, -OS0 2 -, -SO 2 NR 5 -- , -NR5"SO 2 , -NR 5 aCONR 5 b-, -CONR 5 aNR5b-, -NR 5 aCSNR 5 b-, -OCONR5b-, -CH 2 CONR 5 b-, -OCH 2 CONR 5 b-, -P(O)(OR 5 a)O-, -NR 5 "C(O)O- or wherein R" and Rob independently are hydrogen, lower alkyl, -OH, -(CH 2 )k-ORea, -CORea, 10 -(CH 2 )k-CH(OR 6 ) 2 , -(CH 2 )k-CN, -(CH 2 )k-NR 6 aR 6 b, aryl, aryl-lower alkyl, -(CH 2 )g-COOR 4 3 or (CH 2 )g-CF 3 ; wherein k is 1, 2, 3 or 4; 15 Rea and R6b independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; g is 0, 1, 2, 3 or 4; R 4 3 is hydrogen or lower alkyl; 20 G" is -OCH 2 CO-, -CH 2 CO-, -CO- or a valence bond; and E" is -CH 2 -, -CH 2 CH 2 , -CH=CH-, -CH 2 NH- or -CH 2 CH 2 NH-; 25 D is hydrogen, WO 99/01423 PCTIDK98/00287 505 R 2 8 Y, W W 2 -I R ~ I7' R R 2 7 WW2 R 28 R 2 R - R 2 ZY y 8 R Y\ V (CH 2 ) I\/ \ R- 2 8 / Ri'v (c V-; I - 28 C 2 7 )R 28CH 2 ) 3 R R 28 W "F(C, E F -4-R 2 - F QR G/2 R 28 (CH) E R 27 / F'C )_-G 2 S G(CH 2 ) F / R 2 7 Z8R 2 R 2 2zNI/F 2 R 2 (CH 2 ). 2 28 (G) E F. E'Z EoR28 2 R ~ 7 CH) r Rs or G-2 WO 99/01423 PCT/DK98/00287 506 s is 0, 1, 2 or 3; E, E', F, G and G' independently are -CHR 3 8 -, >C=0, >NR 3 9 , -0- or -S-; 5 F' is >CR 3 1- or >N-; Y' is -N= or -CR 3 2 =; Z' is -N= or -CR33 10 V' is -N= or -CR"=; W' is -N= or -CR 3 1=; and 15 Q' is -NR 3 6 -, -0- or -S-; wherein: R 27 , R 28 , R 3 2 , R 33 , R3and R 3 5 independently are hydrogen, halogen, -CN, -CF 3 , -O(CH 2 )yCF 3 , 20 -(CH 2 )yNHCOCF 3 , -NO 2 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 2 9 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -OS0 2 R 2 9 , -OS02CF 3 , -(CH 2 )yCONR 2 9 R 30 , -O(CH 2 )yCONR 2 9 R 3 0 , -(CH 2 )yOR 29 , -(CH 2 )yNR 2 9 R 3 0 , -OCOR 2 9 , -COR 2 1 or -CO2R21 or 25 R 27 and R 2 8 , R 32 and R 33 , R 33 and R', or R3 and R 3 5 together form a bridge -O(CH 2 )yO-; wherein y is 0, 1, 2, 3 or 4; and 30 R 29 and R 3 independently are hydrogen, -COR 3 4, -C0 2 R , -SO2R 31 , lower alkyl, aryl or aryl-lower alkyl; wherein R 3 1 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; WO 99/01423 PCT/DK98/00287 507 R 3 6 and R 3 " independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; and R 3 8 is hydrogen, -OR 4 0 , -NR 40 R 41 , lower alkyl, aryl, aryl-lower alkyl, -SCF 3 , -SR 4 0 , -CHF 2 , -OCHF 2 , -OCF 2 CHF 2 , -CONR 4 R 41 , -(CH 2 )xCONR4R 4 4, -O(CH 2 )xCONR*R 41 , -(CH 2 )x0R 40 , 5 -(CH 2 )xNR 4 0 R 41 , -OCOR 4 0 or -CO2R41; wherein x is 1, 2, 3 or 4; R 4 0 and R 4 1 independently are hydrogen, -COR 42 , -SO 2 R 4 2 , lower alkyl, aryl or aryl-lower al 10 kyl; wherein R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; as well as any optical or geometric isomer or tautomeric form thereof including mixtures of 15 these or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 having the following formula II: 0 A NN (CH2)-B- (K);;-D (I1) R3 20 wherein A, B, K, D, R 3 , R 4 , n and m are as defined in claim 1.
3. A compound according to claim 1 having the following formula Ill: 0 A I N (CH2)B-(K;-D ( 0 3 25 R R wherein A, B, K, D, R 3 , R 4 , n and m are as defined in claim 1. WO 99/01423 PCT/DK98/00287 508
4. A compound according to claim 1 having the following formula IV: 0 N (CH2)n-B-(K)-D (IV) 13 4 R R 5 wherein A, B, K, D, R 3 , R 4 , n and m are as defined in claim 1.
5. A compound according to any one of the preceding claims, wherein R 3 is hydrogen.
6. A compound according to any one of the preceding claims, wherein R 4 is hydrogen. 10
7. A compound according to any one of the preceding claims, wherein A is selected from the group consisting of R 7R R R N_ R RR R R R9R9R 9 R 10 R 0R10 R10 N R 7 7 R 7 ' R a n d R / R 8 - - R 9 andR 15 wherein R 7 , R 8 , R' and R' 0 are as defined in claim 1.
8. A compound according to claim 7, wherein A is R 9 20 WO 99/01423 PCT/DK98/00287 509 wherein R 7 , R 8 and R 9 are as defined in claim 1.
9. A compound according to claim 7 or 8, wherein R 7 is halogen, lower alkyl, -OH, -NO 2 , -CN, -C0 2 H, -0-lower alkyl, aryl, aryl-lower alkyl, -C0 2 CH 3 , -CONH 2 , -OCH 2 CONH 2 , 5 -NH 2 , -N(CH 3 ) 2 , -SO 2 NH 2 , -OCHF 2 , -CF 3 or -OCF 3 .
10. A compound according to any one of the claims 7 to 9, wherein Rand R' inde pendently are hydrogen, halogen, -OH, -NO 2 , -NH 2 , -CN, -OCF 3 , -SCF 3 , -CF 3 , -OCH 2 CF 3 , -0-lower alkyl, lower alkyl or phenyl and R' 1 is hydrogen, lower alkyl or phenyl. 10
11. A compound according to claim 10, wherein R' and R' independently are hydrogen, halogen, -0-lower alkyl, -NH 2 , -CN or -NO 2 and R"O is hydrogen.
12. A compound according to claim 8, wherein A is 15 R 8 HO wherein R' and R* independently are as defined in any one of the claims 10 or 11. 20
13. A compound according to claim 12, wherein A is 9 HO R R 8 wherein Ra is hydrogen, halogen, -0-lower alkyl, -NH 2 , -CN or -NO 2 ; and R 9 is hydrogen or 25 halogen.
14. A compound according to any one of the claims 7 to 13 having the following formula V: WO 99/01423 PCT/DK98/00287 510 R8 0 RR IN B3-(K)T---D (V H R4 HO R 9 wherein R 8 and R 9 are as defined in any one of the claims 1, 10, 11 or 13 and R 4 , B, K, D and m are as defined in claim 1. 5
15. A compound according to any one of the preceding claims, wherein B is R 1 5 RW W4 R 144 R 15 V1 R1415VCR R 15 R RW V W - - R 5 zi W\Q W W 14 Y or 14 ' R R wherein V, W, Z, Y and Q are as defined in claim 1; and R 1 4 and R" independently are hydro gen, halogen, -CF 3 , -OCF 3 , -OR 6 , -NR'"R 17 , lower alkyl, aryl, aryl-lower alkyl, -OSO 2 CF 3 , 10 -CONR 16 R' 7 , -CH 2 0R 16 , -CH 2 NR 16 R 1 7 , -OCOR" or -C0 2 R"; or R 14 and R"' together form a bridge -OCH 2 0- or -(CH 2 )-; wherein I, R'*, R 17 and R 1 " are as defined in claim 1.
16. A compound according to claim 15, wherein Q is -0- or -NH-. WO 99/01423 PCT/DK98/00287 511
17. A compound according to claim 15, wherein B is R14 15 RR1 R1 R R 4 R R 1 5 R1 5 W 4-S or R'-S W-yR O NH NH -- R - -z 14 R wherein R 4 and R" 5 are as defined in claim 15, and V, W, Z and Y are as defined in claim 1. 5
18. A compound according to claim 17 having the following formula VI: R 0 N(K)-D (VI) H R 1 HO R 9 wherein R' 4 and R 1 5 are as defined in claim 15, Rand R' are as defined in any one of the 10 claims 1, 10, 11 or 13, and K, D and m are as defined in claim 1.
19. A compound according to claim 17 having the following formula VII: R 14 R8 0 Ra N N -D (VII) H HO R R R15 15 wherein R 14 and R 1 5 are as defined in claim 15, Rand R' are as defined in any one of the claims 1, 10, 11 or 13, and K, D and m are as defined in claim 1. WO 99/01423 PCT/DK98/00287 512
20. A compound according to claim 17 having the following formulae Villa or Villb: H R0 N -N s (K)-D NN H (Villa) or HO R 14 R R 1 R 1 R8 O R5 ,Ns N NH (Villb) H (K)M D HO R9 5 wherein R 1 4 and R" 5 are as defined in claim 15, R and R 9 are as defined in any one of the claims 1,10, 11 or 13, and K, D and m are as defined in claim 1.
21. A compound according to any one of the claims 15 to 20, wherein R 14 and R 15 inde pendently are hydrogen, halogen, lower alkyl, -0-lower alkyl or aryl. 10
22. A compound according to any one of the preceding claims, wherein K is selected from the group consisting of WO 99/01423 PCT/DK98/00287 513 ____ 0 '5a 0 R 5 a R 4 a R 4 b 0 0 R 5 - (CH 2 )b~LL N(H) 4# (CHO)- (CH 2 ) 6 - N C 2-jCH 2 )6-S 2 N OI5a 0 0R 00 0 0 0 11 11 1 22)F 0 R5 0 -0- (CH 2 ) -H (CH 2 - ACH 2 )- -0-(CH)~L N-(C 0 0 R 0 - 0 -fy0CH 2 )d- -0-(CH 2 b (CH 2 )d 0 0 -O-(CH 2 )b-0-(CH 2 )d~ -- (CH 2 )-CHR 3_,--(Hb0-N (H R 5 b R 0 WO 99/01423 PCTLDK98/00287 514 R a R4b R4a R4b R(C R)-- -C R) RCAS -(CH 2 ) N-(H 2 ) -(C 2)c 2 ) (C q R 4a R4b0a b 2)c (CH 2 ) -(CH) ATIS 01w ORa 0 -o 0H~--+-(CH (CH 2 )--- (CH 2 ).i(H IR 2d-L ( 0 R 3 R 3 b 0 -L(CH 2 )b- C 2) -CH 2 )CH 2 Pa(CH N-(CH 2 115a R -0-CH2 [L(] y-O-CH 2 L1No oOC 0 R5 rLN L(C 2)--N(CH2)j---CHALN2 Isa o 5 0 R, a R 0 0 CH N N-R' 1 NR 5a WO 99/01423 PCT/DK98/00287 515 o 0 -- O-CH2 11N--(CH 2)E-S-(CH 2)5-- ,-CH211N-(CH2)6--O--(CH 2)E-, R R-5 O R R 4 b 0 -- (CIH2 N-(CH2) R () (CH2)~ '-CH2 N-(CH2-N(Hd . -- 2 b N-2)c R (9) (C2; -C2)-N-(CH2)- , 5b ISa R- R R o R~a RO -O-(CH 2 ) N-CH 2 ) N-q (CH 2 )j- - (CH 2 )T--(CH 2 ) R R 0 R 3 R R 3 b -- CH2 N-(CH 2 )b N-(CH 2 ) - (CH2)~, -(CH 2) (C Rb R31 0RR. RR R 0 R R 3 b R0 R 4 " 3a RO -CH-N-(CH2)b p (CH 2 ) q (CH 2 )i- a -N(H 2 p (CH 2 )1--C H R b R15 R R R 3 a R 3 b R 4 4b0 -CH-lNI4(CH) A , %/(CH 2 )j'q+(CH 2 )T and -H -C2 N(H2T Rf Rr wherein R 3 ", Rab, R 4 ", R 4 b, R 55 , Rsb, a, b, c, d, p and q are as defined in claim 1. 5
23. A compound according to claim 22, wherein K is selected from the group consisting of WO 99/01423 PCT/DK98/00287 516 RR 0 R 5aa 0 0 0 0 0Rb 0 -- 0-(CH 2 )b--CHR'- -(CH 2 ) -O--'-(CH 2 )d-- -(CH 2 ) -S- (CH 2 )j 0 R aa 4 b ,4a 4b -H N_(C 4q-(CH -0-(CH )-N-(CH (Hj Ra R 4 b R 4 a R4 -CH 2 )b N-(CH 2 )~ (CH 2 )dl - (C 2 )6 -O-C 2 )c q 2(Hjd R R 4a R 4b0 R 4 R4 I a OR O tDa 4 0 2)E- p0- 2)-- (CH 2 )b[JL(CH 2 )~ OR 0R 3 R 3 b 0 N -(CH 2 )b -O-(CH 2 ) -- -(CH 2 ) /P (CH 2 )A~ N-(CH 2 )- R158 R WO 99/01423 PCTJDK98/00287 517 2 _7'(NCHALN N-CHi -0 Cr N2 N(CH)-N -(Hf7<-O C2-N R 0 0~ 0 Rsa -0- ~~ WO 99/01423 PCT/DK98/00287 518 0 -- O-CH2 N--(CH2)E- S-(CH2)J~-~ -- O-(CH2)6-O--(CH2)d- , Rsb O R4 R 4 b 0 -- (CH2 N-(CH2) ,c (CH2)J- , - N -(CH2 )-N - (CH 2 )F R!-'- R5b R R RR -O-(CH 2 1 N(CH) p (CH 2 )- -N (CH)g-(CH R' R R R 0 R R R O -- C:H2 A N-C2(CH2) CH2) - -N (CH2)J~ ,-(CH2) C25--(H) 5b 5 R R R 3 b 4 R 4 b OR Rb -CHgINC2(CH 2 ) CH2(c-( C H~ 2 ) LN(CH 2 )bI p (CH 2 )SCHN--H)ir R~5a 5b R' R0 RR RRQ -CH N-(CH p (CH2 c q 2) -(CH 2 ) --- (CH 2 ) A I 5b ' 5 R R RR R- 0 and -CH2 N-(CH 2 )~O-(CH 2 ) 5b R' wherein R 3 ", R 3 b, R 4 a, R 4 b, R 5 a, R5b, a, b, c, d, p and q are as defined in claim 1. 5
24. A compound according to claim 23, wherein K is selected from the group consisting of WO 99/0 1423 PCTIDK98/00287 519 -(CH 2) -- O -(CH 2)F- -(CH 2 )b -C2JI'- -CH) -CH 2 )d RR R 5 a 0 R'5a 0 00 11 -O-S- a valence bond - 0-C22 0 0 -0-(CH 2 ) -CHR- -0 1[CT- O-H 1 0OR 5a R 4 a R 4 b R 4 a R 4 b -C C25 -O -(CH )--(CH ) ~(CH)~ -CH2-O---CRR--- -CH 2 ) 1 FP 4 a4- H 2 a O Ra R4b -- CHi)-S--CR O---C 2 a - (CH 2 )b-p- i(24 OROR O1 0 1 6a RR 0 -CHF - -~ i--N41 CR 4b WO 99/01423 PCT/DK98/00287 520 O0CHJ11Nr(H -0 CHJL N-CH 20C~~L C 2 6 N(H~ -0-CH 11 oOC, 01N -C2E R 0 0 ~ -0 CH L /- N(C)-NR -2-N N/(H2 WO 99/01423 PCT/DK98/00287 521 0 -O-CH2 11N--(CH2) _-S-(CH2)5-- ,-O-(CH2) -0--(CH 2)d- RR O R4a R4b 0 -- (CH 2 )Lb -(CH 2 )c R (q) (CH 2 )--- -- -(CH 2 )~N--(CH 2 )d , R0a RRb R4a -O-(CH2b N--(CH2)c q (CH2)T- N-(CH2)6-N-(CH2) , R 58 R5a R' R 0 R3 R 3 b R0 R 4 O R R -CH 2N-(CH 2 )b p (CH 2 )c q (CH 2 )- , N(CH 2 )b p (CH 2 )S--(CH 2 ) 5b 5 RR Rs R R 3 b 4Ra R 3 O 0~ R'5 /RR0 -CH 1-(CH2) P (CH2)- 0-(CH , N-(CH2) p C-S-(CH2)d RR R 3 a R3 R0 RR O c d, -CH-N-(CHy drop (CH2)c a-(CH 2)-~2 N-(CH 2) a -(CH 2 1F 3 , R3a 3b Rsa 4 O and -- CH2 11N-(CH2)g--O-(CH2)d_ wherein Raa, R3 , R43, R4 , R ", R ", b, c, d, p and q are as defined in claim 1. 5
25. A compound according to any one of the claims 22 to 24, wherein R a and R lb inde pendently are hydrogen, lower alkyl, -OH, -(CH2)kORea , aryl, aryl-lower alkyl, -CH2CF3, -(CH 2 )g-COOR 43 , -COOR 43 , -(CH 2 )k-CN or -(CH 2 )k-NR""R b wherein g, k, R 43 , Rea and Reb are as defined in claim 1. 10
26. A compound according to claim 25, wherein g and k independently are 1, 2 or 3, Re" and R"b independently are hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl, WO 99/01423 PCT/DK98/00287 522
27. A compound according to any one of the claims 22 to 26, wherein R 3 a and R 3 b inde pendently are hydrogen, halogen, -OH, -0-lower alkyl, -COO-lower alkyl, lower alkyl or aryl lower alkyl. 5
28. A compound according to any one of the claims 22 to 27, wherein R 4 a and R 4 b inde pendently are hydrogen, -CN, -CONH 2 , -(CH 2 )-N(CH 3 ) 2 , -0-lower alkyl, -CH 2 OH, -CH 2 0-aryl, -N(CH 3 ) 2 , -OH, -C0 2 -lower alkyl or lower alkyl.
29. A compound according to any one of the preceding claims, wherein D is hydrogen, e7 W (CH2). W V' WA F 2 21W' 'Y' W . F e R 28 / R28 R 2 R7 W, W8 28C R27 R2 RRW 10 E W R27 (CH2) E HF W8~~Y E.L F- ---(GG r ~~F2 R~.28\ F RR (CHCE 27 R ), 101 G0 E RR r W R 2 /F (CH 2 )S G /(2j2) G ~ F W (CH2) Z EE F'1(G) I 2 R z R27 Fes R R 2 ' YH,), (CH 2 ) 5 G 28R 27 E' J W ',Y W _E; ER or G \28G, /,ACH 2 ). 7 wherein s, r, R 27 R 2 8 , V, y,, Q,' Z, W', E, E', F, F, G and G' are as defined in claim 1. WO 99/01423 PCT/IDK98/00287 523
30. A compound according to claim 29, wherein D is hydrogen, 27 I E 2 8 V 2 7F (CH 2 )- F E F'-(G)r W~ H2()s I \ 2827 F'-() R2 27 R 8 R R 2 8 RMV-Z (C2/E ,RQ7 2 Q c HG)W R Y'R 2 Ra R 28 R CH2) s ( 2 7 R27 7 A28 E' W'.' E tE R or E 2 G'F2(CH 2 ) F ,EZ' 5 wherein s, r, R 27 , R 28 , V', Y', Z', Q', Z', W', E, E', F, F', G and G' are as defined in claim 1.
31. A compound according to claim 29, wherein D is hydrogen, WO 99/01423 PCT/DK98/00287 524 R27 w' R7 w YE R2110. V.-Z' , |(CH21s F R 28 R 27 ' 27 (CH2) E8W7 W E E'( wR 2 E E '-.Y GR27 R2 VR2R~ 27 28 E (CH 2 )( (CH 2 ) ( \ w2(2)7 E F'-(GX w. E F(G)r 2R7 R 2 8 R2 2 7 E C 2 7 E R27 W R 7 E E/ ~ \Q or R 7 (CH 2 )GR 0' ,, R 2 8 R~~ ~ ~ ~ 27 H2W.,,, 7R2 A- 28 or/ Gr GN E EC) RR GF Z(H) 28 E l wherein E and E' independently are >CHRa 8 , >NR 3 or -0-; F, G and G' independently are 5 >CHR 38 , >C=O or >NR 3 9 ; F' is >CR 38 - or >N-; and s, r, R 27 , R 2 1, R 38 , R 3 9 , V', Y', Z', Q' and W' are as defined in claim 1.
32. A compound according to any one of the claims 29 to 31, wherein R 27 and R 2 ' inde pendently are hydrogen; halogen such as -Cl, -Br or -F; -CF 3 ; -OCF 3 . -OCHF 2 ; -OCH 2 CF 3 ; 10 -(CH 2 )yNHCOCF 3 ; -NHCOCF 3 ; -CN; -NO 2 ; -COR 2 9 , -COOR 29 , -(CH 2 )yOR 2 9 or -OR 2 9 wherein R 2 9 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; -SCF 3 ; aryl such as phenyl; -(CH 2 )yNR 2 'R 3 1 or -NR 2 9 R 3 0 wherein R 2 9 and R 3 1 independently are hydrogen, -COO-lower alkyl or lower alkyl and y is 1, 2, 3 or 4; or -CONH 2 ; or R 2 'and R 2 1 together form a bridge 15 -OCH 2 0-; R 3 1 is hydrogen; -OCHF 2 ; -OR 4 1 wherein R 4 1 is hydrogen or lower alkyl; lower alkyl WO 99/01423 PCT/DK98/00287 525 such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF 3 ; -CH 2 OH; -COO-lower alkyl or -CONH 2 ; and R 3 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
33. A compound according to any one of the claims 1 to 32 for use as a medicament. 5
34. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 1 to 32 together with one or more pharmaceu tically acceptable carriers or excipients. 10
35. A pharmaceutical composition according to claim 34 in unit dosage form, compri sing 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 32. 15
36 A method of treating type I or type I diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to any one of the claims 1 to 32.
37 A method of treating hyperglycemia, comprising administering to a subject in need 20 thereof an effective amount of a compound according to any one of the claims 1 to 32.
38. A method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to any one of the claims 1 to 32. 25
39. The method according to any one of the claims 36 to 38 comprising administering to a subject in need thereof an amount of the compound as defined in claim 1 to 33 in the ran ge 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. 30
40. Use of a compound according to any one of the claims 1 to 32 for the manufacture of a medicament for treating type I or type Il diabetes. WO 99/01423 PCT/DK98/00287 526
41. Use of a compound according to any one of the claims 1 to 32 for the manufacture of a medicament for treating hyperglycemia.
42. Use of a compound according to any one of the claims 1 to 32 for the manufacture 5 of a medicament for lowering blood glucose in a mammal.
43. A compound according to any one of the claims 1 to 32 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 pIM, prefera 10 bly of less than 500 nM and even more preferred of less than 100 nM. WO 99/01423 527 PCTIDK98/00287 AMENDED CLAIMS [received by the International Bureau on 01 December 1998 (01.12.98); original claims 19-43 replaced by new claims 19-47; remaining claims unchanged (18 pages)] 17. A compound according to claim 15, wherein B is R1 R , R14 O R S 'R1 R14 R 1 5 R 5 R 0 H or H z | R1 5 5 wherein R"' and R" are as defined in claim 15, and V, W, Z and Y are as defined in claim 1. 18. A compound according to claim 17 having the following formula VI: R 1 R (K)m-D (VI) R R 15 HO R9 10 wherein R 14 and R 1 5 are as defined in claim 15, R" and R 9 are as defined in any one of the claims 1, 10, 11 or 13, and K, D and m are as defined in claim 1. 19. A compound according to claim 18 except for the following compounds: 15 CH, ,N.0 - 0 HoN N HO cl COOc 2 H, HO N HON WO 99/01423 528 PCT/DK98/00287 SNO2 F HO-I HO& H CN H Cl o N CF.N HO 0 CF, HO& , , 20. A compound according to claim 18 of the formula Vla: R144 0 R O (K)- D (Via) HO R 8 5 wherein R 4 and R" 5 are as defined in claim 15, R' is halogen, R 9 is as defined in any one of the claims 1, 10, 11 or 13, and K, D and m are as defined in claim 1. 21. A compound according to claim 17 having the following formula VII: 10 R144 R 8 0 ( K ) - D ( V I I ) H HOR R 1 wherein R 14 and R 15 are as defined in claim 15, R 8 and R 9 are as defined in any one of the claims 1, 10, 11 or 13, and K, D and m are as defined in claim 1. A MVrnn QUrW W1r I AflTTC P 1 M WO 99/01423 529 PCT/DK98/00287 22. A compound according to claim 21 of the formula Vila: R144 HOR 5 wherein R 1 4 and R' 5 are as defined in claim 15, R' is halogen, R 9 is as defined in any one of the claims 1, 10, 11 or 13, and K, D and m are as defined in claim 1. 23. A compound according to claim 17 having the following formulae Villa or Villb: 10 H R O N (K)m-D H (VIlla) or HO R 14 R14 N NH (Villb) H (K)m-D HO R 9 wherein R 14 and R 1 5 are as defined in claim 15, R and R 9 are as defined in any one of the claims 1,10, 11 or 13, and K, D and m are as defined in claim 1. 15 24. A compound according to claim 17 having the following formulae Vllla' or Villb': A uN41nI1n QTVWwT r(A RTrT. 101 WO 99/01423 530 PCT/DK98/00287 R (K)-D I N M( V I l l a ' ) o r HO R RR1 R 1 5 RR N NH (VIIIb') H (K)--D HO Ra8 wherein R 4 and R" are as defined in claim 15, R' is halogen, R 9 is as defined in any one of the claims 1,10, 11 or 13, and K, D and m are as defined in claim 1. 5 25. A compound according to any one of the claims 15 to 24, wherein R 1 4 and R 1 5 inde pendently are hydrogen, halogen, lower alkyl, -0-lower alkyl or aryl. 26. A compound according to any one of the preceding claims, wherein K is selected 10 from the group consisting of WO 99/01423 531 PCT/DK98/00287 (CH2)EO-(CH2)--- , -- (CH2) S-(CH2)-- , -- (CH 2 ) -CH-CH-(CH 2 )d 0 -- (CH2)u (CH2)d-, -(CH2)6N--(CH2)F- ' -(CH2)6 O-(CH2)d R 5 O Ra R 4 a R 4 b 0 Ra I I , I If I -(CH2) N (CH2)c )4 (CH 2 )d- , -(CH 2 ) -N 1 CH2(CH 2 )- -CH 2 )6-S N - (CH 2 )j 1 0 Rsa 0 -- C2) -S-(CH2)T-~ -(CH2)ES--(CH2)d- , -(CH2-0 (H)' 0 II 00 -O-a-(CH2)j -(CH 2 )4- -O-(CH 2 )-N-(CH 2 )d 11 R) ) 0 R O -O-(CH2)b-CHR3-(CH2)i-N-(CH2)4-- -O-(CH2 N-(CH2) d a 1a R 0 0 -O-(CH2)--N 1(CH 2)d-- . -0-(CH 2 ) O-(CH 2 ) 00 -(O-N O-(CH 2 )- ' -(CH2) (CH2) Y O0 -O--(CH 2)6--O-(CH 2)d~' -- O-(CH2)i--CHRa- , -O-(CH2)E-~-O N--(CH 2 1~ R 5b R 4a R 4b -O (HA {-C2)c ( la (CH2)d,T- -- O-(CH2) - -(CH 2)d , R O A MNNMWn CZT4WWT i A DTCT V 101l WO 99/01423 532 PCTIDK98/00287 R a R4b Ra R 4 R R R 4 a R 4 b ORsa o R 4 a R 4 b -0-(H 2 - PO (CH24-(CH )-L-(CH) I sa 2d OR 0 R 3 R 3 b N-C 0-(CH2 -(CH 2 )b ' iC 2 (CH 2 )a N (CH 2 )j ISa5 RaR 0 R5a 0 R5 0 R 5a 0R -O-H 1N N-(CH)- -O-CH2 11N N-CH 0 Rsa 0 R5 -O-CHrLN- CH-N '(H)- -O-CHzJ-LN2 Is R 0 R sa 0 Qa -O--CH2 1 - N-(CH 2 ) CH-1 N -- H) 0 R 5a R0 I5a R 0 Rsa 0 0 0o / . ICHI-RN N-Rs WO 99/01423 533 PCT/DK98/00287 0 0 -O-CH2 11N-(CH2)b-~S--(CH2)d- , CH2 11N-(CH2)E-O -(CH2)d~~ I 5bb R 5 b R OR 4 4b 0 -- H2) N-(CH2)c R C2a , -CH2 11 (CH2)6-~(CH2) $5a 'b R5 R R o R 4 a R4 0 -- O--(CH2b 11 N--(CH2)c ,)q (CH2)-- , N-(CH)-N--(CH2) I 5a 'R5b R S 0 Ra R 3 o -- O-H2N(CH 2 )b p N(H)- ~ C2;0-C2a 0 R R3 R3b R0 R R' -0CH2 N-(CH2) p (CH2) -N (C2 1 , C2 O N (CH2)j C2)-S(C2l 5 b I a 5 R3 R 3 b OR33 R3b O -CHZ -1N -(C H)b- p (C2cOCH 2- ,O N-CH) P (C2)c- N--Hd R5a ' 5 R R R3 R 3 b R0 R3 0 -CH-N-(CH 2 ) p -,O - (c (CH 2 )~ and -- CH2 N--(CH211-N-(CH2)d R Ra RR wherein R 3 ", R 3 b, R 4 , R 4 b, R 5 ", RSb, a, b, c, d, p and q are as defined in claim 1. 5 27. A compound according to claim 26, wherein K is selected from the group consisting of AMNTWf HWT (ATTHT TC 10 WO 99/01423 54PCTIDK98/00287 0 O-(H 2 ~-CHR'aICH 2 ) 7 N-(CH9W -O-(CH 2 b N-(CH 2 )d~ R Sa R 0 0 -O-(CH 2 y IL -(CH 2 )d ~ -O-(CH 2 b C2) 0 0 -0(CH-)CH 11 R 5b 0 0 -(C2) N-CH A 2j- 0-CH -CH (CHS(H (CH(CA 2 2),-C4R R a R 4 4 b R 4 a R 4 b /I -(CH) - NS-(C) -CO - -CO q (CH 2 )d- (C 2 )-S - H 2 ). (CH 2 )d- R R4a R4b0 R 4 a R 4 b -(CH 2 ) -SO0T(CH 2 )c ( CH 2 )F-~ -(CH92----P- q (C 2 4 I 5a OR O R 4 a 0 4 b0 -O-CH2 -p 0 q 2)dCH 2 )b4JL-c 2 )d OR 0R 3 R 3 b 0 1LN-(CH 2 )b -O-(CH 2 )d-~ -CH 2 ) /P(CH 2 )a 11N CH 2 )j A MW 7V1W n QTV W'T ( A DlTT.F~ 101' WO 99/01423 535 PCTJDK98/00287 -0-CH2JLN \ N(H)--0-CH J R 0 0 a -0-CH211 / N-RC2) - - H 11N/-R(H2 0 5 R5 WO 99/01423 536 PCT/DK98/00287 0 -- O-CH2 1 N--(CH2)E- S-(CH2)5 , -- O-(CH2)6--O--(CH2)j~ S5b R R R RR 4 b 0 R RR RR -O--(CH2) 11 N--(CH2)c a,4 (CH2)T- , 1 N-(CH2 )E-N--(CH2)d , Ro R' RM ~5a ~5b 5 O RM RR O -- O-CH2 -UN-(CH2)u N-(CH2)j~ -N 11(CH2)E-O-(CH2)j- , 155 I 5a R- R Ra 0 R\ R 3 Ra R 4 O R' R' -CH2ALN-(CH 2 ) 5 P (CH2) q (CH 2 )T~ , N-(CH2)I p (CH 2 )E~S-(CH 2 )j~ R-9 R R R 3 b 0 R3 R 3 b 0 -CH2-N-(CH 2 ) p (CH 2 )c-O-(CH 2 )j - N-(CH 2 ) p (CH2)c N--(CH2) 5a'5b ' Sa R R 3 Ra R I Sa '5b 5 R R R 0 and -CH21N-(CH2)6---(CH2)d R' wherein R 3 a, R 3 ", R 4 a, R 4 b, R 5 a, Rsb, a, b, c, d, p and q are as defined in claim 1. 5 28. A compound according to claim 27, wherein K is selected from the group consisting of Au uNflLnTW cu1erVTr f ATOrMWer r 1mQ WO 99/01423 537 PCT/DK98/00287 -(CH 2 )-O- (CH 2 )- - (CH 2 ),- N-(CH 2 )d- '-0-(CH 2 ) N -(CH 2 )d I sa I5a Ra R R 5 a 0 -0-CHi--CHR -CH 2 N-(CH 2 )j-- -O-CH2--i'-N-( 2 )d R~ 0 0 0 11 -O-S I a valence bond - -C22 0 0 -0-(CH)E--CW2- - CHF- -0-CH 2 1 OR 5a R 4a R 4 b R 4 a R 4 b -(CI 2 ) -1-N-(CH 2 ). 4 (C H 2 )- -0-(CH 2 ) 2 -N-(CH 2)c (CH) -(CH26--NCH~i2CH2--CHF-SO-CRe I sa OR 11H b-I-(cH0 0 0 F5a 0 __ F -CHI- 11 4aR~ A MFNflVfl 4ZT-T?1rT fA UlTWTI? 1011 WO 99/01423 538 PCTIDK98/00287 -0-CHI11NO I -0CHH2N lN o 0 -0-CHjI--N">< (CH 2 -N -(0H 2 )a-- -O-~CH 2 ) 1K R 0 s 0 Rs 0 0 a -CH 1 N (CN- -- 2 N - -R 0&H'1f T1~ AT T1 O WO 99/01423 539 PCT/DK98/00287 0 -O-CH2 N----(CH2)E- S-(CH2)d- , 0-(CH2)6_-0-(CH2)j- , R5b OR R 4 b 0 -- (CH2) N-(CH2)c R (4 (CH2 )- -CH 2 N-(CH 2 )-N-(CH2)d , R R" R O R4a R4b 0 -O---(CH2)b 1 N-(CH2)c a'/)q (CH 2 )j- , (CH26-N-(CH2)j , 1 a I I 15b IR5"R 0 R3a R3 0 -0-CH2 1N-(CH 2 )b N-(CH2)d, -N1(CH2)EO-(CH2)' , I5b 5a R R 0 Ra R 3 b R4 R 4 b R3 R3 -CH2-1 N-(CH2) A p (CH2) (CH2)j-, N-(CH2) 14 (CH2) S-(CH2 R R R3a R3b 0 R R 3 b O -CH2-N-(CH2)b 4p (CH2);-0-(CH2)F-~ N-(CH2) p (CH2)c 11N--(CH2)Ed R5a I R'~~ RRR3 4' R3a R b R4 4b0 -CHi--N-(CH2)b p (CH2)c ( q(CH2)F~ , -CH2 N-(CH2 ) -N-(CH24)d R R R R 0 and -CH2 N-(CH2)E--O-(CH2)j- wherein R 3 , R 3 , R 4 , R 4 b, Ra, R b, b, c, d, p and q are as defined in claim 1. 5 29. A compound according to any one of the claims 26 to 28, wherein R 5 " and R b inde pendently are hydrogen, lower alkyl, -OH, -(CH 2 )kOR*a, aryl, aryl-lower alkyl, -CH 2 CF 3 , -(CH 2 )g-COOR 43 , -COOR 43 , -(CH 2 )k-CN or -(CH 2 )k-NR 6 aR 6 b wherein g, k, R 43 , R a and Reb are as defined in claim 1. 10 30. A compound according to claim 29, wherein g and k independently are 1, 2 or 3, R 6 and R 6 b independently are hydrogen, lower alkyl such as methyl or ethyl, or aryl such as phenyl, 31. A compound according to any one of the claims 26 to 30, wherein R 3 ' and R 3 1 inde 15 pendently are hydrogen, halogen, -OH, -0-lower alkyl, -COO-lower alkyl, lower alkyl or aryl lower alkyl. A MVN'nwn QT-TwwT r (A DTTrFT i 1m WO 99/01423 540 PCT/DK98/00287 32. A compound according to any one of the claims 26 to 31, wherein R 4 and R 4 b inde pendently are hydrogen, -CN, -CONH 2 , -(CH 2 )-N(CH 3 ) 2 , -0-lower alkyl, -CH 2 OH, -CH 2 0-aryl, -N(CH 3 ) 2 , -OH, -C0 2 -lower alkyl or lower alkyl. 5 33. A compound according to any one of the preceding claims, wherein D is hydrogen, I \\ / w' V' RN w' \('H2). R 2 8 V' Z R ' / R 28 YR. R 2 - R 2 w C2 E F wF VY' E F' (G R R 28 R2 R-Z (R R 2 27 Ex Q. R 2 7 Q. R ZFC F Z'H RW R F R 2 7 /(CH) 10 Cherei s, rR72,VY, ' ' ' ,EFFGadG r s eie ncam1 GN \ (C 2 W, F C2) FE V R 28 2 7 34. A compound according to claim 33, wherein D is hydrogen, A VNR ART [ DTCIV Q WO 99/01423 541 PCT/DK98/00287 RR 2 E\ . 28 ~ ~ w , YIv'z R ZVR F G k 27 F E F R 8 V. Z 27 Q R2 R 2 8 R2R (CH 2 )s (CH2s R2E F'-(G) W.\2.(G), R 8 R27 V R28 YR R RR e / 2R 27 28 2 E W' R(CH 2 )SR E' E R or R Y 28 G~ F(CH 2 )s Z' wherein s, r, R 27 , R 28 , V', Y', Z', Q', Z', W', E, E', F, F', G and G' are as defined in claim 1. 5 35. A compound according to claim 34, wherein D is hydrogen, R . W'8 27 R w a' G . M R N27 T E RWr G E F/-EV wherein~~~~~~~2 28 rR2 8 "YZQ, ,WE ,F ,GadGaea eie ncam1 R R2 R7 R.\ 1.F2 AM42.l~' V.1'1' (ATC V1 WO 99/01423 542 PCT/DK98/00287 E (cH 2 ) (CH2)s E F -(G), W, E F-(G)r R 28 R 27 R 7 R 2 E R 27 2 (H);/ R2727 W' 27 (CH)/N RR R 27 CH 2 ) E ' W ' 28or E' R2ER \ Gor G,F (CH 2 ), 28 E V wherein E and E' independently are >CHR 3 8 , >NR 3 9 or -0-; F, G and G' independently are >CHR 38 , >C=0 or >NR 3 9 ; F' is >CR 38 - or >N-; and s, r, R 27 , R 28 , R 38 , R 39 , V', Y', Z', Q' and W' 5 are as defined in claim 1. 36. A compound according to any one of the claims 33 to 35, wherein R 27 and R 28 inde pendently are hydrogen; halogen such as -Cl, -Br or -F; -CF 3 ; -OCF 3 ; -OCHF 2 ; -OCH 2 CF 3 ; -(CH 2 )yNHCOCF 3 ; -NHCOCF 3 ; -CN; -NO 2 ; -COR 29 , -COOR 29 , -(CH 2 )yOR 2 1or -OR 29 wherein 10 R 2 1 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; -SCF 3 ; aryl such as phenyl; -(CH 2 )yNR 29 R 3 1 or -NR 29 R 3 0 wherein R 2 9 and R 3 0 independently are hydrogen, -COO-lower alkyl or lower alkyl and y is 1, 2, 3 or 4; or -CONH 2 ; or R 27 and R 28 together form a bridge -OCH 2 0-; R 3 1 is hydrogen; -OCHF 2 ; -OR 4 0 wherein R 40 is hydrogen or lower alkyl; lower alkyl 15 such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF 3 ; -CH 2 OH; -COO-lower alkyl or -CONH 2 ; and R 39 is hydrogen, lower alkyl, aryl or aryl-lower alkyl. 37. A compound according to any one of the claims 1 to 36 for use as a medicament. 20 38. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 1 to 36 together with one or more pharmaceu tically acceptable carriers or excipients. A 41PNRflT QTJ1 T /A DTTT V 1O\ WO 99/01423 543 PCT/DK98/00287 39. A pharmaceutical composition according to claim 38 in unit dosage form, compri sing 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 5 claims 1 to 36. 40. A method of treating type I or type 11 diabetes, comprising administering to a subject in need thereof an effective amount of a compound according to any one of the claims 1 to 36. 10 41. A method of treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound according to any one of the claims 1 to 36. 42. A method of lowering blood glucose in a mammal, comprising administering to said 15 mammal an effective amount of a compound according to any one of the claims 1 to 36. 43. The method according to any one of the claims 40 to 42 comprising administering to a subject in need thereof an amount of the compound as defined in claim 1 to 36 in the ran ge of from about 0.05 mg to about 1000 mg, preferably of from about 0.1 mg to about 500 20 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.
44. Use of a compound according to any one of the claims 1 to 36 for the manufacture of a medicament for treating type I or type I diabetes. 25
45. Use of a compound according to any one of the claims 1 to 36 for the manufacture of a medicament for treating hyperglycemia.
46. Use of a compound according to any one of the claims 1 to 36 for the manufacture 30 of a medicament for lowering blood glucose in a mammal.
47. A compound according to any one of the claims 1 to 36 characterized by having a glucagon antagonistic activity as determined by the Glucagon Binding Assay I or Glucagon A 1NAWI'%Mr"f 4ZTT'1' f(A ODTC'T r I ON~ WO 99/01423 544 PCT/DK98/00287 Binding Assay 11 disclosed herein corresponding to an IC50 value of less than 1 IM, prefera bly of less than 500 nM and even more preferred of less than 100 nM. A MFNfl1fn P.T4W1 T (A DTTfT r 1 o, WO 99/01423 545 PCT/DK98/00287 STATEMENT UNDER ARTICLE 19 In order to delimit the present compounds from the documents cited in the International Search Report a new claim 19 has been added in which 9 disclaimers have been inserted. The compounds disclaimed are known from US 4,334,015, Table 1, Nol1; US No 3,859,281, Example XVII (= US No 3,746,703, Example XVII = US No 3,836,580, Example XVII); and US No 5,229,038, Compounds 3 to 10. Furthermore, new claims 20, 22 and 24, respectively, have been added in which R' has been restricted to halogen in meta-position.
Applications Claiming Priority (5)
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| US09/032516 | 1998-02-27 | ||
| PCT/DK1998/000287 WO1999001423A1 (en) | 1997-07-01 | 1998-06-30 | Glucagon antagonists/inverse agonists |
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| EP (1) | EP0994848A1 (en) |
| JP (1) | JP2003514508A (en) |
| KR (1) | KR20010020590A (en) |
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- 1998-06-30 JP JP50616099A patent/JP2003514508A/en active Pending
- 1998-06-30 BR BR9810378-4A patent/BR9810378A/en not_active IP Right Cessation
- 1998-06-30 WO PCT/DK1998/000287 patent/WO1999001423A1/en not_active Application Discontinuation
- 1998-07-01 KR KR1019997012562A patent/KR20010020590A/en not_active Application Discontinuation
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110229056A (en) * | 2019-06-21 | 2019-09-13 | 天津科技大学 | A kind of novel curcumin analog and its preparation method and application |
| CN110229056B (en) * | 2019-06-21 | 2022-11-08 | 天津科技大学 | Novel curcumin analogue and preparation method and application thereof |
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| NO996550D0 (en) | 1999-12-29 |
| HUP0002373A3 (en) | 2000-11-28 |
| EP0994848A1 (en) | 2000-04-26 |
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| PL337781A1 (en) | 2000-09-11 |
| WO1999001423A1 (en) | 1999-01-14 |
| HUP0002373A2 (en) | 2000-10-28 |
| AU749271B2 (en) | 2002-06-20 |
| IL133377A0 (en) | 2001-04-30 |
| JP2003514508A (en) | 2003-04-15 |
| WO1999001423A8 (en) | 1999-05-14 |
| BR9810378A (en) | 2000-08-29 |
| NO996550L (en) | 2000-02-29 |
| CN1267281A (en) | 2000-09-20 |
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