AU749271B2 - Glucagon antagonists/inverse agonists - Google Patents
Glucagon antagonists/inverse agonists Download PDFInfo
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- AU749271B2 AU749271B2 AU79083/98A AU7908398A AU749271B2 AU 749271 B2 AU749271 B2 AU 749271B2 AU 79083/98 A AU79083/98 A AU 79083/98A AU 7908398 A AU7908398 A AU 7908398A AU 749271 B2 AU749271 B2 AU 749271B2
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- 0 NNC1=*c2c1ccc(O)c2F Chemical compound NNC1=*c2c1ccc(O)c2F 0.000 description 6
- ZRJUTEDOQWPTOI-UHFFFAOYSA-N COC(CC(C=C1Cl)C(NN)=O)=C1O Chemical compound COC(CC(C=C1Cl)C(NN)=O)=C1O ZRJUTEDOQWPTOI-UHFFFAOYSA-N 0.000 description 1
- YHTXQNJUUSZPST-UHFFFAOYSA-N COc(c(O)c1)cc(C(NN)=O)c1Cl Chemical compound COc(c(O)c1)cc(C(NN)=O)c1Cl YHTXQNJUUSZPST-UHFFFAOYSA-N 0.000 description 1
- GUMQDUFQQBSSJJ-UHFFFAOYSA-N Cc(c(C(NN)=O)c1)cc(O)c1Cl Chemical compound Cc(c(C(NN)=O)c1)cc(O)c1Cl GUMQDUFQQBSSJJ-UHFFFAOYSA-N 0.000 description 1
- WEGMYYNETSPDPZ-UHFFFAOYSA-N NNC(C(CC(Cl)=C1O)C=C1Cl)=O Chemical compound NNC(C(CC(Cl)=C1O)C=C1Cl)=O WEGMYYNETSPDPZ-UHFFFAOYSA-N 0.000 description 1
- OCNQWVGUIJRXEV-UHFFFAOYSA-N NNC(c(c(Br)c1)cc(Cl)c1O)=O Chemical compound NNC(c(c(Br)c1)cc(Cl)c1O)=O OCNQWVGUIJRXEV-UHFFFAOYSA-N 0.000 description 1
- NXNFBXPVCBGQGL-UHFFFAOYSA-N NNC(c(c(C(F)(F)F)c1)cc(Cl)c1O)=O Chemical compound NNC(c(c(C(F)(F)F)c1)cc(Cl)c1O)=O NXNFBXPVCBGQGL-UHFFFAOYSA-N 0.000 description 1
- ZSRSCZRTCRHCBR-UHFFFAOYSA-N NNC(c(cc(c(O)c1)Cl)c1F)=O Chemical compound NNC(c(cc(c(O)c1)Cl)c1F)=O ZSRSCZRTCRHCBR-UHFFFAOYSA-N 0.000 description 1
- DPMBBSJEIZGVBF-UHFFFAOYSA-N NNC(c(cc1OC(F)(F)F)ccc1O)=O Chemical compound NNC(c(cc1OC(F)(F)F)ccc1O)=O DPMBBSJEIZGVBF-UHFFFAOYSA-N 0.000 description 1
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Description
-1- GLUCAGON ANTAGONISTS/INVERSE AGONISTS Field of the Invention The present invention relates to agents that act to antagonize the action of the glucagon peptide hormone. It relates particularly to non-peptide glucagon antagonists or inverse agonists.
Background of the Invention Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
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 glucagon is opposed by insulin which stimulates cells to take up and store glucose whenever blood glucose levels rise. Both glucagon and insulin are peptide hormones.
Glucagon is produced in the alpha islet cells and insulin in the beta islet cells of the .pancreas. Diabetes mellitus, the common disorder of glucose metabolism, is characterized by hyperglycemia, and can present as type I, insulin-dependent, or type II, 20 a form that is non-insulin-dependent in character. Subjects with type I diabetes are hyperglycemic and hypoinsulinemic, and the conventional treatment for this form of the disease is to provide insulin. However, in some patients with type I or II diabetes, absolute or relative elevated glucagon levels have been shown to contribute to the hyperglycemic state. Both in healthy animals as well as in animal models of type I and II, removal of circulating glucagon with selective and specific antibodies has resulted in reduction of the glycemic level (Brand et al. Diabetologia 37, 985 (1994); Diabetes 43, [suppl 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 antihyperglycemia treatment of diabetes. The action of glucagon can be -lasuppressed by providing an antagonist or an inverse agonist, substances that inhibit or prevent glucagon induced response. The antagonist can be peptide or non-peptide in nature. Native glucagon is a 29 amino acid-containing peptide having the sequence: o*oo o* o 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-GIn-Asp- Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH 2 Glucagon exerts its action by binding to and activating its receptor, which is part of the Glucagon-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.
Several publications disclose peptide antagonists. Probably, the most thoroughly characterized antagonist is DesHis'[Glu 9 ]-glucagon amide (Unson et al., Peptides 10, 1171 (1989); Post et al., Proc. Natl. Acad. Sci. USA 90, 1662 (1993)). Other antagonists are eg DesHis',Phe 6 [Glu]-glucagon amide (Azizh et al., Bioorganic Medicinal Chem. Lett. 16, 1849 (1995)) or NLeu,Ala"' 16 -glucagon amide (Unson et al., J. Biol. Chem. 269(17), 12548 (1994)).
Peptide antagonists of peptide hormones are often quite potent; however, they are defective as drugs because of degradation by physiological enzymes, and poor biodistribution. Therefore, non-peptide antagonists of the peptide hormones are preferred. Among the non-peptide glucagon antagonists, a quinoxaline derivative, (2-styryl-3-[3-(dimethylamino)propylmethylamino]-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.
Anderson, U.S. Patent No. 4,359,474 discloses the glucagon antagonistic properties of 1phenyl pyrazole derivatives. Barcza, U.S. Patent No. 4,374,130, discloses substituted disilacyclohexanes as glucagon antagonists. WO 98/04528 (Bayer Corporation) discloses substituted pyridines and biphenyls as glucagon antagonists. Furthermore, WO 97/16442 (Merck Co., Inc.) discloses substituted pyridyl pyrroles as glucagon antagonists and WO 98/21957 (Merck Co., Inc.) discloses 2,4-diaryl-5-pyridylimidazoles as glucagon antagonists. These glucagon antagonists differ structurally from the present compounds.
2a Summary of the Invention According to a first aspect, the present invention provides a compound of the general (1) R 8 0 NN B 0DI
H
wherein R' and R' independently are hydrogen, halogen, -ON, -OF 3 -00F 3
-OCH
2
CF
3
-NO
2
-OR"
1 9.9-NR 1 R 12
O
1 -6-alkyl, aryl, -SOF., -SR 11
-CHF
2
-OCHF
2
-OSO
2
R
1
-CONR
1 R 12 -0H 2 0)R
-OH
2 NR"R 1 2 -000R 1
-CO
2 R or -0S0 2
CF
3 or R' and R 9 together form a bridge -OOH 2
O-
or -OCH 2
OH
2 0- *99R1 1 and R 12 independently are hydrogen, -00R 3 -S0 2 R 1 3 Cl 1 ,-alkyl or aryl,
R
3 is hydrogen, Cl 1 ,-alkyl, aryl-C,,-alkyl or aryl, R' is hydrogen or Cl 1 ,-alkyl, -2b- B is R Ri Oa 1 R14 R1i R 14,- R is 9 9* a..
9* 9 *9 9*a* *9*aa* a
R
R is
R"
4 and independently are hydrogen, halogen, -ON, -OFI, -OCF 3 -O(0H 2
),C
3
N
-OR's, -NR'GR 17 C,,-alkyl, aryl, aryl-0 1 .,-alkyl, -SOF,, -SR" 6 -CHF 2
-OCHF
2
-OCF
2
CHF
2 -0S0 2 0F 3
-CONR
16 R'1 7 -(CH CN'R 1 7
-O(CH
2 1 00NR'OR 1 7
-(CH
2 1 00R'a, -(CH 2
)CR
8
-(CH
2 )O -O(0H 2 -(CH 2 )NRiaR' 7 -O(CH7)jN R' 6
-OCOR'
6
-CO
2
R'
8 -O(0H 2 )0C0 2
R
1 8, -O(0H 2 )OCN or -O(0H 2 or R 1 4 and R 15 together form a bridge -O(CH 2 10 or -(OH 2 1 I is 1, 2, 3 or 4,
R"
6 and R' 7 independently are hydrogen, -OOR' 8
-SO
2
R'
8 0 14 6-alkyl or aryl, or R" 6 and R'7 15 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms, R" is hydrogen, Ci, 4 -alkyl, aryl or aryl-C 1 -,-alkyl, W is or -OR' 9 Y is or -R= Z is or -CR 21 V is or -2 c-
R
19 R 20 R 21 and R' independently are hydrogen, halogen, -ON, -OF 3 -00F 3 -00H,0F 3
-NO
2 -OR 24 -NR 2 "R 2
O
1 alkyI, aryl, aryl-O 1 ,-alkyl, -SCF 3 -SR 2 4
-OHF
2
-OOHF
2
-OOF
2
OHF
2 -0S0 2 0F 3 -0NR 24
R
25 -0H 2 00NR 24
R
25 -0CH 2 00NR 2 Rz 5 -0H 2 OR 2 4
-CH
2 NR 24 R25, -O00R 24 or -00 2 R 24 or R 19 and R 2 1, R 2 1 and R 21 or R 2 'and R 2 together form a bridge -OCH 2
O-,
R 2 4 and R25 independently are hydrogen, -C0R 2 1, -SO 2
R'
6
C,
1 alkyl, aryl or aryl-O 1 ,-alkyl, R 2 1is hydrogen, 0 1 .,-alkyl, aryl or aryl-0 14 a-alkyl, K is R 3 a R 3 b 4 R 4 b (H p C 2
(CH
2 )T (CH 2 R 3a, R 3 b R 4 a andR R 4 b independently are hydrogen, halogen, -ON, -OF 3 -00F 3
-OOH
2
CF
3
-NO
2 -OR 24 -NR 24 aR 2 5a, 0 14 ,-alkyl, aryl, aryl-C, 1 ,-alkyl, -SOF., -SR 24 2, -OHF 2
-OOHF
2
-OOF
2 CH F 2 ,-0S0 2 0F 3
-OONR
4 'RZa -0H 2 00 NR 2
-OOH
2
OONR
4 2R3 '-H 2 ORz,
-OH
2 NRZ aR S, -000 R 2 or C2
:R
24 ~and R 25 independently are hydrogen, -SO 2 RI", O 1 ,-alkyl, aryl or aryl-0 1 6 -alkyl, 2 6a is* hydrogen, 0 1 4 6-alkyl, aryl or aryl-O 1 .,-alkyl, or R~a and R 3 b R 4 and R 4 b, or R~ 3and R 4 b together form a bridge 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, -2dq is 0, 1 or 2, L and M independently are -CH=CH-, -NR la_, -CH 2 NR la_, -000-, -COO-, -CONR 5 -CONR Ib_, -NR 5aCO_,
-SO
2 -OS02-, -S0 2 -NR"aS0 2
-NR
5 aCO N R 5 -CONR~aNR 5 -NR 5 aCSN 5sb_, -OCONR 5
-CH
2 00N Rslb, -OCH 2 CONR Ib_, 2" -P(O)(OR 5a)O-, -NR"aC(O)0- or *0 o 0E 6 0* 0 S 00 6* 0*
S
*0 6S we 0
S
*5
S
0 00 04 4 0 4 a rot..
4 S#6.
0 .0000 4 Rsa and R 5 b independently are hydrogen, 0 14 ,-alkyl, -OH, -(CH 2 -)k-OR 6 a, -COR 6
-(CH
2 )k-CH(ORa) 2 -(0H 2 )k-CN, -(CH2)k-NR R6aR 1b, aryl, aryl-0 14 6-alkyl, -(CH,2)g-COO R 43 or
-(CH
2 ),gOF3, k is 1, 2, 3 or 4, R la and R Ib independently are hydrogen, C, 1 ,-alkyl, aryl or aryl-.,-alkyl, g is 0, 1,2, 3 or 4, R 1 is hydrogen or C,,-alkyl, .20 G" is -00H 2 00-, -0H 2 00-, -00- or a valence bond, E" is -OH 2 -0H 2 0H 2 -CH=CH-, -CH 2 NH- or -CH 2
CH
2
NH-,
m is 0 or 1, -2eo is hydrogen, 27
R
2 7 2r R
R.ZY
'Z
w. *y ii z-v.
0 0 0 0 R 2 7 (CH) C 2 RR2 2 GZ (CH), E F E R27
(CH
2 G R 1 7 R
Z
(C H 2
(CH
2 e- R R RV F R2
E
r is 0or 1, s is 0, 1, 2 or 3, -2f- E, F, G and G' independently are -CHR 38 or F is >CR- 1 or Y1 is or Z' is or -CR 3=, V is-N=or
-CR-=
W' is or' -CRw=, Q' is -N R or R, R28, R R and R' independently are hydrogen, halogen, -ON, -0(CH 2 ),CF3,
,NHCOCF
3
-NO
2
C
1 .,-alkyl, aryf, aryi-C 14 -alkyl, -SCF 3 -SRI, -CHF 2
-OCHF
2
*-OCF
2 CHF,, -OS07 2 g, -OS0 2
CF
3
-(CH
2 )YCONRZ2R 3 O. -O(CHz)yCONR~mR 3
-(OH
2 0RF; 9
-(CH
2 )vNR2uR'Ic -OCORI, -C0R" or -C0 2
R'
or
R
7 and R2A, R-'2and RI and R' 4 or R' and FR~ together form a bridge!-0(CH,O-, yis0, 1, 2, 3or4, 000.. R2 and Fe" independently are hydrogen, -OR-l, -C0 2
W"
1 _S0 2
R
3
C,
4 8alky[, aryl or aryl- C,,-alkyl, RS' is hydrogen,
C,
1 ,-aikyI, aryl or aryl-C,.
8 -alVy, R' and R11 independently are hydrogen,
C
1 ,-alkyl, aryl or aryI-0 14 ,-afkyl,
R
38 is hydrogen, -CR' 0 -NR 40
R
4 0 14 -aikyl, aryl, aryi-C 1 -,-alkyl, -SCF 3 -SR O, -CHF 2
-OCHF
2
-OCF
2
CHF
2
-CONR
40
R
41
-(CH
2
).CCNR
4 0
R
4 1 -0(CH 2 )xCCNR OR 41
-(CH
2 C,bzQ
(CH
2
).NR
4
OR
4 -00CR 0 or -CC 2
,R
4 x is 1, 21'3 or 4,
FR
4 and R 41 independently are hydrogen, -OR 42 -S0 2
R
2 C,,-alkyi, aryl or aryl-C, 4 6-akyl, R 4 1 is hydrogen, C, 14 -alkyl, aryl or aryi-C 1 -,-aikyl, except for the following compounds:
S
S..
*S*S
0 N
I
HO0 O COOCA
HO&
oF
N,
CN
0 as well as any optical or geometric isomer or tautcrrner4 form thereof including mixtures of these or a pharmaceutically acceptable salt thereof 2h- According to a second aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, at least one compound according to the first aspect, together with one or more pharmaceutically acceptable carriers or excipients.
According to a third aspect, the present invention provides a method of treating type I or type II diabetes, comprising administering to a subject in need thereof an effective amount of a compound of the general formula R 8 0
HO
HO H B D (I) *0 wherein -2 i- R' and R' independently are hydrogen, halogen, -ON, -OF 3 0CF 3 -00H 2 0F 3
-NO
2
-OR"
1 -NR"R 1 2 Ol,-alkyI, aryl, -SOF 3
-OHF
2
-OOHF
2 -O0 2
R
1
-OONRIR'
2
-OH
2
OR'
1
-OH
2
NR
11
R'
2
-OOOR
11 -C0 2 R1 3 or -OSO 2
OF
3 or R 8 and R 9 together form a bridge -00H.0or -00 H,0H 2 0-, R" and R' 2 independently are hydrogen, -OOR' 3
-SO
2 R 13 O,.,-alkyl or aryl,
R'
3 is hydrogen, O, 4 ,-alkyl, aryI-C,.,-alkyl or aryl, R 4 is hydrogen or O,,-alkyl, B is
S
R 14 R.0 R is R 1 4 and R" 5 independently are hydrogen, halogen, -ON, -OF 3 -00F 3 -O(0H 2 )I0F 3
-NO
2
-OR'
6 -NR1 6 R 1 7 C,6-alkyI, aryl, aryl-O 1 -6-alkyl, -SOF., -SR" 6
-OHF
2
-OOHF
2
-OOF
2
OHF
2
-OSO
2
OF
3 -OONR1 6 R 1 7 -(0H 2
)OCONR'
6 R'1 7 -O(0H 2 )ICONR'sR 1 7 -(0H 2 ),OOR'3, -(0H 2
)OCOR'S,
-(0H 2
),OR'
6 -O(0H 2
),OR'
6 -(0H 2 ),NR1 6
R'
7
-O(OH,)INR'
6
R,-OR
6
-OR"
8 -O(0H,)00O 2
R'
8 -O(0H.)OCN or -O(0H 2 )OlI, orR 1 4 and R1 5 together form a bridge -O(0H 2 1 0or is 1, 2, 3 or 4,
R
16 and R 1 7 independently are hydrogen, -OOR' 6
-SO,R
6 O,-,-alkyl or aryl, or R' 6 and R 1 7 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms, -2j
R
18 is hydrogen, 0 1 .,-alkyl, aryl or aryf-O 1 alkyl, W is or -OR 9 Y is or -CR 2 Z is or -R= V is or C'=
R'
9
R
20 R 2 and RI independently are hydrogen, halogen, -ON, -OF 3
-OCF
3 -00H 2 0F 3 -NO2, -OR 24 -NR 24
R
25
O
1 -,-alkyl, aryl, aryl-O 1 -,-alkyl, -SCF 3
-CHF
2
-OOHF
2
~-OCF
2
CHF
2 -0S0 2 0F,, -C0NR "R 25
-CH
2 00NR 4
R
2 -00H 2 00NR 4 R, -CH 2 0R.
4 15 -0H 2 NR 24
R
25 -000R 24 or -00 2 R 24 or R 19 and R 2 1, R 20 and R 21 or R 2 1 and R 2 together form a bridge -00H 2 0-,
R
4 and R" 5 independently are hydrogen, -00R 2 1, -S0 2 R 2 1, O 1 ,-alkyl, aryl or aryl-O 1 ,-alky1, 20 R 2 is hydrogen, O 1 -,-alkyl, aryl or aryl-O 1 -,-alkyl, K is a -4a 3~a 3 b R 4 b (L -CH2b4 4 2 )c 7 (CH 2 R 3 a R 3 b, R 4 a and R 4 b independently are hydrogen, halogen, -ON, -OF 3 -00F 3 -00H 2 0F 3
-NO
2 -OR 24 -NR 24 .R 2 C,,-alkyl, aryl, aryl-O 1 alkyl, -SOF,, -SR 24
-OHF
2
-OOHF
2
-OOF
2
OHF
2 -0S0 2 0F 3 -OONR 'Ra -OH 2 OONR 4 R S, -OOH 2 OONR aR -H 2
OR
2 a -O H 2 NR RR, -OCOR or -CO 2
R
2 R 24 a and R 2 5a independently are hydrogen, -OOR 2 1a, -S0 2 R 26 a, C,,-alkyl, ary] or aryl-C, 1 ,-alkyl,
R
2 1, is hydrogen, O 1 -,-alkyl, aryl or aryl-0 1 6 -alkyl, -2kor R" and R"b, R" 2 and R"b, or and R Ab together form a bridge is 1, 2,3 or 4, a, b, c and d independently are 0, 1, 2, 3 or 4, e, f and p independently are 0 or 1, q is 0, 1 or 2, L and M independently are -CH=CH-, -NRsa-, -CH 2
NR
5 -000-, 15 -COO-, -CONR~a-, -CONR b -NR~aCO-, -SO 2 -0S0 2 -S0 2 NR 5a_, -NR -NR~aCONR 5 -CONRaNRlb_, -NR 5aCSNR 5b_, -OCONR Ib_, -CH 2 CON R Sb, -OCH 2 C0NR Sb_, 9 9 52 -NR"aC(0)O- or
R
5 8 and R-b independently are hydrogen, 0 14 alkyl, -00R" 20 -(CH 2 )k-CH (OR6a) 2
-(CH
2 )k-CN, k-N RaR~b, aryl, aryl-C, 1 ,-alkyl, -(CH,)g-COOR 43 or
-(CH
2 ),gCF 3 k is 1, 2, 3 or 4, Ra' and R independently are hydrogen, 0 14 -alkyl, aryl or aryl-0 1 alkyl, g is 0, 1, 2,3 or 4, R 4 is hydrogen or C, 16 -alkyl, G" is -00H 2 00-, -0H 2 C0-, -C0- or a valence bond, -21- E" is -OH 2
-CH
2 -CH=CH-, -CH 2 NH- or -CH 2
CH
2
NH-,
m is 0ori1, is hydrogen, R 28 Q, 21~?
W..
R
'FZ27 wR a a..
a..
a. a a a a.
a a a. a.
a a a a a
G~~
2
RP
R 27 E FR 2 R 28 /(CH 7)
G
2 8
FCGW.
27 P,
Y
E F F RPa 8 R7 R R 2 R27 E
,Y
F"
II
E 2mr is 0 or 1, s is 0, 1, 2 or'3, E, F, G and G' independently are -0HR 3 8 >00O, or F' is >OR" 8 or Y' is or-0R, Zis or -CR33=, V is or -0R 34 Wis or -CR 3 5 Q' is -NR 3 or 20 R 27 R 2 8, R 32 R3 3 R 34 and R 3 5 independently are hydr ogen, halogen, -ON, -OF 3
-C(CH
2 )yOF 3 -(OH2)vNHCOCF,
-NC
2 C,6-alkyl, aryl, aryl-0 14 -alkyl, -SCF 3
-SR
29
-OHF
2
-CHF
2
-CF,OHF
2 -O0 2 R 29 -C S0D 2 0F 3
-(CH
2 yONR 2 9 R 30 -0(OH 2
)ONR
2 9
R
30 O, -(CHz)yCR 29
-(OH
2 )yN R 2 9
R
3 0 -00COR, -OR 2 1 or -00 2
RI
9 25 or R 27 and R 2 1 R 3 2 and R 3 3 R33and R34, or and R' together form a bridge -0(OH 2 Y is 0, 1,2, 3 or 4, R2' and R 30 independently are hydrogen, 0 2
R-'
1
-SC
2
R
31 O~a-alkyl, aryl or aryl-
O
1 a-alkyl,
R
3 1 is hydrogen, 0 ,6-aikyl, aryl or anA[-C, 1 -alkyl, 2n
R
3 6 and R" independently are hydrogen, C,4-alkyl, aryl or aryl-C,-alkyl, R" is hydrogen, -NR'oR", C, -alkyl, aryl, aryl-C,-alkyl, -SCF,, -SR' 0 -CHF, -OCHF
-OCF
2
CHF
2
-CONR'OR
1 -(CH),CONR"R',
-O(CH
2 )CONR'R -(CH),OR 0 1
-OCOR
40 or -COR xis 1, 2, 3 or4,
R'
0 and R" independently are hydrogen, -COR 42
-SO
2
R"
2 C.,-alkyl, aryl or aryl-C,,-alkyl,
R
2 is hydrogen, C,,-alkyl, aryl or aryl-C,.-alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these of a pharmaceutically acceptable salt thereof or a compound according to the 10 first aspect.
According to a fourth aspect, the present invention provides a method of treating hyperglycemia, comprising administering to subject in need thereof an effective amount Sof a compound according to the third aspect.
According to a fifth aspect, the present invention provides a method of lowering blood .glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to the third aspect.
According to a sixth aspect, the present invention provides use of a compound according to the third aspect for the manufacture of a medicament for treating type I or type II diabetes.
According to a seventh aspect, the present invention provides use of a compound according to the third aspect for the manufacture of a medicament for treating hyperglycemia.
According to an eighth aspect, the present invention provides use of a compound according to the third aspect for the manufacture of a medicament for lowering blood glucose in a mammal.
-2o- Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".
a a. a a a *a 4a a a a a a 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 invention: "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 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, 2hexynyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, cyclooctyl, 4-cyclohexylbutyl, and the like.
Further non-limiting examples are sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, nhexyl, isohexyl, n-heptyl, n-nonyl, n-decyl, vinyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-i -propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 2,4-heptadienyl, 1-octenyl, 2,4octadienyl, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3pentyny, 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, 1cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cyclopropylethyl, cyclobutylmethyl, 2cyclobutylethyl, cyclohexenylmethyl, 4-cyclohexyl-2-butenyl, 4-(1 -cyclohexenyl)-vinyl and the like.
The term "lower alkyl" designates a hydrocarbon moiety specified above, of from 1 to 6 carbon atoms.
"Aryl" means an aromatic ring moiety, for example: phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazoly, 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, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydrobenzofuryl, triazolyl, pyranyl, thiadiazinyl, isoindolyl, indazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, benzothienyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinolizinyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidinyl, piperidinyl and the like.
The aryl moieties are optionally substituted by one or more substituents, for example selected from the group consisting of F, CI, I, and Br; lower alkyl; lower alkanoyl such as formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl and the like; -OH; -CN; -COH; -O-lower alkyl; aryl; aryl-lower alkyl; -COCH 3
-CONH
2
-OCH
2
CONH
2
-NH
2
-N(CH
3
-SO
2 NH,; -OCHF 2
-CF
3 -OCF and the like. A further non-limiting example is Such aryl moieties may also be substituted by two substituents forming a bridge, for example "Aryl-lower alkyl" means a lower alkyl as defined above, substituted by an aryl, for example: The aryl group is optionally substituted as described above.
Description of the invention The present invention is based on the unexpected observation that compounds having a selected nitrogen-bearing central motif and the general structural features disclosed below antagonize the action of glucagon.
WO 99/01423 PCT/DK98/00287 Accordingly, the invention is concemed with compounds of the general formula I:
R
1
I
AX, NN (CH2) B-(K) D R3 R 2
R
wherein:
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; n is 0, 1, 2 or 3; mis 0 or 1; X is
>C=NR
5 or >SO 2 wherein R 5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR 6 wherein R is hydrogen, lower alkyl, aryl or aryl-lower alkyl; A is WO 99/01423 PCT/DK98/00287
R
8
R
R 7 R NR 10
S
R
8 0
RR
R 8 R7N or 8
R
wherein: WO 99/01423 WO 9901423PCT/DK98/00287 7 Ris hydrogen, halogen, -CN, -OF 3
-OCF
3
-OCH
2
CF
3
-NO
2
-OR"
1
-NR
1 1
R'
2 lower alkyl, aryl1, aryl-lower alkyl, -SCF 3 -S0 2
NR
1 R 12
-SR'
1
-CHF
2
-OCHF
2 -0S0 2
R
1
-CONR
11 R 12 -00H 2 C0NR 1 R R 12
-CH
2 0R 1 1
-CH
2 NR'1 1R 2 -000R 1 -C0 2 R 1 3 or -0S0 2 0F 3 R" and R 9 independently are hydrogen, halogen, -ON, -OF 3 -00F 3
-OCH
2
CF
3
-NO
2
-OR",
-NR
1 R 12 lower alkyl, aryl, -SCF 3
-SR"
1
-CHF
2
-OCHF
2
-OSO
2
RI
1 -00N 11
R
1 2
-CH
2 0R 1 -0H 2
NR
1 R 12 -000k' 1 -00 2 R 13 or -OSO 2
CF
3 or R 8 and R' together form a bridge -OCH 2
O-
or -OCH 2
CH
2 0-; wherein R 1 1 and R 1 2 independently are hydrogen, -00k' 3 -S0 2 lower alkyl or aryl; wherein R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and Rio is hydrogen, lower alkyl, aryl-lower alkyl or aryl; B is R Is w
R
W, Q R14 Y -i C Q 1 4 14_ WI v 15 V -CR -CRL or a valence bond; WO 99/01423 WO 9901423PCT/DK98/00287 8 wherein:
R'
4 and R" 5 independently are hydrogen, halogen, -CN, -CF 3
-OCF
3
-O(CH
21
CF
3
-NO
2 -OR'1 6
-NR'
6 R 1 7 lower alkyl, aryl, aryl-lower alkyl, -SCF 3
-SR
16
-CHF
2
-OCHF
2
-OCF
2
CHF
2
-OSO
2
CF
3
-CONR'
6 R, -(CH 2
)ICONR
16
-O(CH
2 1
CONR
6 R, -(CH 2 )IC0R 16
-(CHA)
1 0R' 6
-(CH
2 ),OR 1 6
-O(CH
2 )OR 16
-(CH
2 ),NR 16 R 1 7
-O(CH
2 )jNR1 6 R 1 7
-OCOR'
6
-CO
2
R'
8
-O(CH
2 )IC0 2 R'B, -O(CH 2 1 CN, -O(CH 2 )C1, or R" 4 and R 5 together form a bridge -O(CH 2 1 0- or wherein I is 1, 2, 3 or 4;
R"
6 and R 1 7 independently are hydrogen, -COR', -S0 2
R
8 lower alkyl, aryl, or R" 6 and R 17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms; wherein R' 8 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; W is or -R= Y is or -CR 20 Z is or -R2 V is or -CR 2 and Q is -NR 23 or wherein:
R
19 R 20
R
2 1 and R22 independently are hydrogen, halogen, -CN, -CF 3
-OCF
3
-OCH
2
CF
3
-NO
2 -OR 24 -NR 24 R 2 lower alkyl, aryl, aryl-lower alkyl, -SCF 3 -SR 2 1, -CHF 2
-OCHF
2
-OCF
2
CHF
2
-OSO
2
CF
3 -C0NR 4
R
2
-CH
2
CONR
4
R
2
-OCH
2
CONR
4
R
2
-CH
2 0R 4
-CH
2 NR 24
R
25 -0C0R 24 or -C0 2 R 24 or R' 9 and R 20 R 20 and R 21 or R 2 and RI together form a bridge -OCH 2
O-;
WO 99/01423 WO 9901423PCT/DK98/00287 9 wherein R 24 and R 2 -9 independently are hydrogen, -CORI 6
-SO
2 lower alkyl, aryl or aryllower alkyl; wherein R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and R 2 1 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K is 38 3b4a (HR 3 'R 3b(HR 4 b e 2)bCH__ P 2 (CH 2 )c (CH 2 )jd wherein: R 3 a, Rlb R 4 2 and R 4 b independently are hydrogen, halogen, -ON, -CE 3
-OCF
3
-OCH
2
CF
3
-NO
2
-OR
24 -NR 24 a R 2 5 a, lower alkyl, aryl, aryl-lower alkyl, -SCF., -SR 24 a, -CHF 2
-OCHF
2
-OCF
2
CHF
2
-OSO
2
CF
3 -CONR 24 aR 2
-CH
2 CONR 24 'R 2 5a, .OCH 2
CONR
2 4 R~ 25 CH 2
OR
24 i-,
-CH
2 NR 24 aR 2 5a, -000 R 2 4 a or -CO 2
R
2 4 a; wherein R 24 1 and R 25 a independently are hydrogen, -C0R 26 a, _S0 2 R 26 a, lower alkyl, aryl or aryl-lower alkyl; wherein R 26 a is hydrogen,- lower alkyl, aryl or aryl-lower alkyl; or R 3 'and Rlb R 4 a and R 4 1, 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; WO 99/01423 WO 9901423PCT/DK98/00287 e, f and p independently are 0 or 1; q is 0, 1 or 2; and L and M independently are -CH=CH-, -NR 5
-CH
2 NR 5a_, -OCO-, -COO-, -CONR 5 -CONR 5 b_, _S2_ -OSO2-, -SO 2
NR
5 -N R5S0 2 -NR aCON R CONR 'N Rb, -NR 5 aCSNRs5b_, -OCONR 5
-CH
2 CONR-9b_, -OCH 2 CONR 5 b_,
-P(O)(OR
5
-NR
5 aC(O)O- or wherein R"a and Rb independently are hydrogen, lower alkyl, -OH, -(CH 2 )k-OR a, -COR~a
-(CH
2 )k-CH(OR 6 a 2
-(CH
2 )k-CN, -(CH 2 )k-NR 6 aryl, aryl-lower alkyl, -(CH 2 )g-COOR 43 or-
(CH
2 )g-CF3; wherein k is 1, 2, 3 or 4; and Rsb independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; g is 0, 1, 2, 3 or4; R 4 1 is hydrogen or lower alkyl; G" is -OCH 2 CO-, -CH 2 CO-, -CO- or a valence bond; and E" is -OH 2
-CH
2
CH
2 -CH=CH-, -CH 2 NH- or -CH 2
CH
2
NH-;
D is hydrogen,
L
WO 99/01423 PCT/DK98/00287 FF,
W'
1 1 R 28 R 2- R28- R2 eR V\
II
,.,,a27 W R
Y
28 27XCH\
RCH
2 3 rx
F
R 28 27 28 (C H 2
)W
Z-\
Y Z-V Fe /(CH2).
W88 (CH
E/
G;
W8 R 28 E "F
F
RR28 R2,v KeJKR 27 E R 2 G, E'
W
or G 1R
E
wherein: r is 0 or 1; WO 99/01423 PTD9/08 PCT/DK98/00287 12 s is 0, 1, 2 or 3; E, F, G and Gindependlently are.-CHR 3 11_ >NR 39 or F is >CR 3 1_ or Y' is or -R3= Z' is or -R= V is or -R= W is or -CR 3 and Q' is -NR 36 or wherein: R 27 R 28 R 32 R 33 RI and R 3 1 independently are hydrogen, halogen, -CN, -CF 3 -0(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 CH F 2 -0S0 2 R 29
-OSO
2
CF
3
-(CH
2 )YCONR 29 R 30
-O(CH
2 )yCONR 29 R 30
-(CH
2
)YOR
2 9
-(CH
2 )yNR 29
R
30 -000R 29 -C0R 29 or -C0 2 R29; or R 2 'and R 28 R 32 and R 33 R 33 and or R34 and R 35 together form a bridge -O(CH 2 )yO-; wherein y is 0, 1, 2, 3 or 4; and
R
2 9 and R 3 independently are hydrogen, -C0R 1 -C0 2 1RII, -S0 2
R
1 lower alkyl, aryl or aryl-lower alkyl; WO 99/01423 PCT/DK98/00287 13 wherein R 3 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
R
38 is hydrogen, -OR 40
-NR
4 0
R
41 lower alkyl, aryl, aryl-lower alkyl, -SCF 3
-SR
40
-CHF
2
-OCHF
2
-OCF
2
CHF
2
-CONR
4 0
R
41
-(CH
2
CONR
4 0
R
41
-O(CH
2 )xCONR 4 0
R
41
-(CH
2
).OR
40
-(CH
2 )xNR 4 0
R
41
-OCOR
4 0 or -C0 2
R
4 0 wherein x is 1, 2, 3 or 4;
R
4 0 and R 4 independently are hydrogen, -COR 42 -S0 2
R
42 lower alkyl, aryl or aryl-lower alkyl; 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 these or a pharmaceutically acceptable salt thereof.
Where the formulae for B make it possible, R 19
R
21 R' and R 2 may alternatively be replaced by R 1 4 or R 1 5 respectively. In such case eg W may be selected from -CR 19 and
-CR
1 4 Similarly, where the formulae for D make it possible, R 32
R
3 3
R
3 4
R
5 R, R 3 and R 9 may alternatively be replaced by RI or R 2 respectively. In such case eg E may be selected from -CHR-, >NR 39
-CHR
2 7 and >NR 2 In a preferred embodiment the invention relates to compounds of the following general formula
II:
0 A- N N- (CH2)B (K D (11) A 3 4
SR
4 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 IIl: 0
II
AIS. N N (CH2)-B-(K-D l l l 0 13 4 R R 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 A N N (CH 2
(IV)
R3
R
4 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.
R
4 is preferably hydrogen.
A is preferably selected from the group consisting of:
R
7 R R 7 R R R R L and I I I R
R
8 ",a WO 99/01423 PCT/DK98/00287 wherein R 7
R
8
R
9 and R' 1 are as defined for formula I.
A is more preferably
R
7 8
R
wherein R 7
R
8 and R 9 are as defined for formula I.
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, -CO 2
CH
3
-CONH
2
-OCH
2
CONH
2
-NH
2
-N(CH
3 2
-SO
2
NH
2
-OCHF
2
-CF
3 or -OCF 3 Preferably, R 8 and R 9 are independently hydrogen, halogen, -OH, -NO 2
-NH
2 -CN, -OCF 3
-SCF
3
-CF
3
-OCH
2
CF
3 -O-lower alkyl such as methoxy and ethoxy, lower alkyl such as methyl and ethyl, or phenyl, and R' is hydrogen, lower alkyl or phenyl.
More preferably, R 8 and R 9 are independently selected from hydrogen, halogen such as -F and -Cl, -O-lower alkyl such as methoxy and ethoxy, -NH 2 -CN or -NO 2 and R 10 is hydrogen.
In a particularly preferred embodiment A is
R
8
HO
R
9 wherein R 8 and R 9 independently are hydrogen, halogen, -OH, -NO 2
-NH
2 -CN, -OCF 3
-SCF
3
-CF
3
-OCHCF
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 -CI, -O-lower alkyl such as methoxy and ethoxy, -NH 2 -CN or -NO In a further particularly preferred embodiment A is WO 99/01423 PCT/DK98/00287 16
HOR
9
R
8 wherein R 8 is hydrogen, halogen such as -F or -Cl, -O-lower alkyl such as -OCH 3 or -OC 2 Hs,
-NH
2 -CN or -NO 2 and R 9 is hydrogen or halogen such as -F or -Cl.
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: N, N B
HO-
R
9 wherein R 4 B, 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 of A above.
B is preferably: RW R i s W 14 I Rs R
R
RRI
w
R
R
N I R 1 or WO 99/01423 WO 9901423PCT/DK98/00287 17 wherein V, W, Z, Y and Q are as defined for formula 1; and
R'
4 and R" 5 independently are hydrogen, halogen, -CF 3
-OCF
3
-OR'
6
-NR'
6 lower alkyl, aryl, aryl-lower alkyl, -OSO 2
CF
3
-CONR
6
R
1
-CH
2
OR'
6
-CH
2 NR1 6 R 1 7 -OCOR" or -C0 2
W
6 or R 1 4 and R 1 5 together form a bridge -OCH 2 O- or -(CH 21 wherein 1, R' 6
R"
7 and R 1 8 are as defined for formula 1.
Q is preferably or -NH-.
Particularly preferred compounds are those in which B is 14 R 1 5 or 4S R 1 wherein V, W, Z, Y and Q are as defined for formula 1; and R1 4 and R" 5 independently are hydrogen, halogen, -CF 3
-OCF
3
-OR'
6
-NR'
6 lower alkyl, aryl, aryl-lower alkyl, -OSO 2
CF
3
-CONR'
6 R 1 7
-CH
2
ORI
6
-CH
2 NR1 6 R 1 7 -000W 6 or -C0 2
R";
or R 1 4 and R1 5 together form a bridge -OCH 2 O- or -(CH 21 wherein 1, RI 6 R 1 7 and R' 8 are as defined for formula 1.
Still more preferred are compounds of the following formula VI: WO 99/01423 WO 9901423PCT/DK98/00287 R 8 0 I H R1 HO R 9 as well as compounds of the following formula VI I: R 8 0 I H HO R R 1 as well as compounds of the general formulae Vllla or Vlib:
(VI)
(VII)
(Villa) (Vllib) wherein R' and independently are hydrogen, halogen, -CF 3
-OCF
3
-OR
16
-NR
1 6
R
17 lower alkyl, aryl, aryl-lower alkyl, -OSO 2
CF
3 -C0NR 1 6 R 17
-CH
2 0R'II, -CH 2
NR
1 6 RI 7 -000R 16 or -C0 2
R'
8 or R 14 and R" 5 together form a bridge -OCH 2 O- or -(OH 21 wherein 1, R 16
R"
7 and R 18 are as defined for formula 1; WO 99/01423 PCT/DK98/00287 19 K, D and m are as defined for formula I; and
R
8 and R 9 are as defined for formula I and preferably as defined for the preferred embodiments of A above.
In the above formulae VI, VII and VIII, R 1 4 and R 1 5 are preferably independently hydrogen, halogen, lower alkyl, aryl such as phenyl, or -O-lower alkyl such as methoxy.
In the above formulae VI and VII, K is preferably bound in para-position and in the above formulae Villa and VIllb, K is preferably bound at the nitrogen atom of the indole group.
K is preferably selected from the group consisting of: WO 99/01423 WO 9901423PCT/DK98/00287 (CH )-CH=CH-(CH 2 (CIH 2 b (CH2)d- 0 H) -N H H)a1 -C 2j 0 R~a WaR4 0 0 R s -P 1 (HI (H 7 -C 2b2c q 2j2 1 sa 26 0 2)
R
0 11 0 0 11 0 0 11 0 0 I sa
R
-0 2 )b 11((HHA) I sa
RR
-0 -R y 0-C 2) 0 0 -0 (C -L 00 I 5 b R 4 a R 4b 0 I I 0 WO 99/01423 WO 9901423PCT/DK98/00287 21 R 4 R 4 b 04a R)4 -(CH
-(CH
2 )(CS0-(CH2).
Rn~ R 4 b -0-CH AL\C.I -0- 20)CH-PN"7K qC 2 )d- N-(CHALN-j.(CH)N-C 2 a 15a 2),i
RR
0 Rsa 0 -0-H2 1 N-X -(CA o Rq 0Rsa 0 0 *-O-CHALN2 0 a -CHrJ 2 1N/
-(CH
2 )b
R
0 -CH 2 N QN-RH 2 0 0 N/L N -R v~I WO 99/01423 PTD9/08 PCT/DK98/00287 0
-O-CH
2 11 N-(CH 2 2 R
S
0 R~a R 4
-O-(CH
2 )b 1 5-C28 q C2j
R
0 R 3 R 3 b R R' 0 \,R3b R 4 b 2 15 b P/
R
0 0 5b 0 0
N-AL(CH
2 )0-O(CH 2 o R 3 R 3b o 3a 3b' 0 1 5b 0 wherein R la, R 3 b, R 4 a R 4 b R 5 a, R5b a, b, c, d, p and q are as defined for formula 1.
More preferably, K is selected from the group consisting of: WO 99/01 423 PTD9/08 PCT/DK98/00287 23 0 I sa
RR
0 0 1
-(C
I I 0 -0 CRa -(H2
-(CH
2 11 NI(CH 4
'(CH
2 0 0
IR
5 b 0 4a o4b
-O-(CH
2 )b-N-(CH 2 4 4-(CH 2 o5a Ra R 4 b R 4 a 04b
-(CH
2
R
O R 4 R4 I sa
OR
0 I sa
R
O R~a 4b ORa 0
(CH
2 )il(CH R3a 3 b 0 1
-C
WO 99/01423 WO 9901423PCT/DK98/00287 CH2 11 0 O--CH2 11 N(3i -0-CH2 11 N/ XN 2
(CH
2 )6- 0 -0-CHA-LN2jhL(CH)N
-(CH
2
R-
-O-CH7-LN2c -0-CH2JLN/2SN(CH 2 )dJL 0C2 N-X-C 0I 0
R
0 -~CH iL" i~ -0-CHIL-N~< 0
X
WO 99/01423 PCTIDK98/00287 0 -0-CH2 11 N-(CH)-S-(CHA-- I R' Rb 11 N-(CHCH 2)F
R'
0 R QR 4 0 R R3aR 3 b RSb -0-CN-(CH) 4
-(CH
2
)EO-(CH
2 R' b
R
O R3a 0R~ 4a 0/4b -CN CH2)- 1q (CH2)-- R3a R 3b -CHF-(CH) C2EO(H2F 32 ~3b R Q R 4b~
R~R
0 -CH-JLN -(CH2rN-(C 5b 2 R 0 LN-(CHA-N-(CH 2)F I 5b I~ R AU 0 -N 11(CH 2 )6-0(CH 2 )r- 0 R 3a R 3bb 11 N- (CH 4p saa 0 R 3a 3b 0 NIN -(CH A f S4p (CH IN-(CH-- 0 R R 0 and -CH1 H- 2 wherein R 3 R b, R 4 a, R 4
R
5 R b, a, b, c, d, p and q are as defined for formula i.
In a further preferred embodiment K is selected from the group consisting of: WO 99/01423 WO 9901423PCT/DK98/00287 26 I~a R -0-CHT-CHR CHj-2- NC 2 d 0 0 0 11 -0-Sa valence bond 0 0 0OR RC 4 a 0 4 b -(CH2)b 11 NI~-O-(CH 2 ).(CHT 0-H2 -(H)-NCRECi2 -CHy-SO- 00 0 R4a R4b 2-N-(CH 2
C
CRaRb 0 1R~a 4b Iq'q ORsa 0 L -C WO 99/01423 WO 9901423PCT/DK98/00287 -0O-CH 11 NO 0 -0-CH 2 0 O0CHALN2
LCH
2 )6-N -(CH 2 -O-CHrf7 4
CHF
0 Ra0 s -~0-CH2-LN/rY4
-(CH
2 )g-N -(CH 2 Nr
R
0 R I 0 -0-CHA1Jf2 (x Sa 2 ilN/ Q<-R WO 99/01423 WO 9901423PCT/DK98/00287 0 'Sb 0 R R I Sa
R
0 R~ R a 4
R
0 R 3aR 3bR~\ CH2 N-(CH 2
N(H
2
(CH
2 3 a 3 b 04a 4b -0(C H 2 (C H 2 d_ 0 -CH2 11N-(CH 2 5b R-
R
0
SN(CH
2 )g -1CH 2 )a_ Rb 0 N 11(CH)b01CH 2 )ga o R 3 R 3
*IN-(CH)
4 (CH)ES(CH)j R'Sa Rb 0
RRS
0 and H21 -C wherein R 3 R b, R 4 R~b R 5 3, R b, b, c, d, p and q are as defined for formula I.
In the above embodiments of K, R 5 and R 5b are preferably independently hydrogen, lower alkyl, -OH, -(CH 2 XOR"a, aryl, aryl-lower alkyl, -CH 2 CF,, -(CH 2 )gC00R 4 1, -C00R 4 1, -(CH 2 )k- ON or -(CH 2 )k-NR"aR b wherein g, k, R1 3
R
6 a and R lb are as defined for formula I.
Preferably, g and k are independently 1, 2 or 3, and R 6a and R lb are independently hydrogen, 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, halogen, -OH, -0-lower alkyl, -COO-lower alkyl, lower alkyl or aryl-lower alkyl.
WO 99/01423 WO 9901423PCT/DK98/00287 29 In the above embodiments of K, Rn" and R 4 b are preferably independently hydrogen, -CN,
-CONH
2
-(CH
2
)-N(CH
3 2 -0-lower alkyl, -CH 2 OH, -CH 2 O-aryl, -N(CH 3 2 -OH, -C0 2 -lower alkyl or lower alkyl.
D is preferably hydrogen, R w27 w, y* w, F e$o I-ACH )3 E 2
F
G 21 R 28
R
E 27 f~C
(CHA)
IE/F
(CH
2 E F-(G)r R 2 R227 E';E -R 2 GF (H) or R2
EV
wherein s, r, R 27 R 28 Y, E, F, F, G and G' are as defined for formula 1.
In still a further preferred embodiment D is hydrogen, WO 99/01423 WO 9901423PCT/DK98/00287 rxK R% 28\-s V'W EK &CH2)s
,ACH
2 E NGR21 R 28 R 2 8
RV
E F'-(G)r
RR
R 28 'L-E
R
28 F,(CH2 R2 E' W or IG R2 F E
V
wherein s, r, R 27 R 2 1, V, E, F, F, G and G' are as defined for formula 1.
D is more preferably hydrogen, WO 99/01423 WO 9901423PCT/DK98/00287 n27
(CHA)
E F
RV
R 2 8 z
R
28 R 27 E E R 28 G~ R 2 E' W or G R 2 XE Vwherein E and E' independently are >CHRI, >NR 39 or F, G and G' independently are >CHR 38 >C=O or >NR 39 F is >CR 3 1_ or and s, r, R 27
R"
8 R 3 11, R 39 V" Y, Q' and W' are as defined for formula 1.
R 2 7 and R' 8 are preferably independently hydrogen; halogen such as -CI, -Br or -CF 3 0OCF 3
-OCHF
2
-OCH
2
CF
3
-(CH
2 )yNHCOCF 3
-NHCOCF
3 -CN; -NO 2 -C0R 2 1, -C00R 2 1
-(CH
2 )YOR 2 1 or -OR 2 1 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 2 'R 3 1 or -NR 2 'R 3 1 wherein R' 9 and R" 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 1 together form a bridge -OCH 2 R 3 1 is hydrogen; -OCHF 2 -OR 4 1 wherein R" 0 is hydrogen or WO 99/01423 PCT/DK98/00287 lower alkyl; lower alkyl such as methyl, isopropyl or tert-butyl; lower alkylthio; -SCF 3
-CH
2 0H; -COO-lower alkyl or -CONH 2 and R' 9 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;
R
3 and R 4 independently are hydrogen or lower alkyl; X is >C=NR 5 or >SO 2 n is 0, 1,2 or 3; m is 0 or 1;
R
5 is hydrogen, lower alkyl, aryl-lower alkyl, or -OR 6 wherein R 6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; A is WO 99/01423 WO 99/1 423PCT/DK98/00287
R
7 W
N
N 1
R
8 R' R R 1
S
R
8 0 R 9 wherein WO 99/01423 WO 9901423PCT/DK98/00287 Ris hydrogen, halogen, -CN, -CF 3
-OCF
3
-OCH
2
CF
3
-NO
2
-OR"
1
-NR
11
R
1 lower alkyl, aryl, -SCF 3
-SR
1
-CHF
2
-OCHF
2 -0S0 2
R
1 -C0NR 1
R
1
-CH
2 0R 11
-CH
2
NR
11
R
12 000OR, _C0 2 R 13 0OS0 2
CF
3 RI and R' independently are hydrogen, halogen, -CN, -CF 3
-OCF
3
-OCH
2
CF
3
-NO
2
-OR"
1 -NR1R 1 2 lower alkyl, aryl, -SCF 3 -SRI', -CHF 2
-OCHF
2
-OSO
2
R'
1 -C0NRI 1 R 12
-CH
2 0R11, -CH 2
NR
11 R 1 2 -0C0R 1 1
-CO
2 R 1 3 -OS0 2
CF
3 or R" and R 9 together form a bridge -OCH 2
O-;
R"
1 and R 12 independently are hydrogen, -C0R 13
-SO
2
R
13 lower alkyl or aryl; R 13 is hydrogen, lower alkyl, aryl-lower alkyl or aryl;
R
10 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; R Is
W
R'V
14 wR Y 1 -V is
Q,
w \1v 1
R
14 3-_77R R 1
'N.W,
Y 14
V
-CR 14CR'or a valence bond; preferably WO 99/01423 WO 9901423PCT/DK98/00287 36 W/ w R 15
VV
14
R
1 R R R. V~ II -ZCR-CRI
R
WOC 2 C, RO( is) 1 r R 1 4
R
1 t g he fo m a b igs O CH I~o is,23o4
R
1 4 and R'5 independently are hydrogen, -Cloge, -S0R, lower alky, aryl,F, o- 1 Nd, -R 1 6 s 16 hyroe, lower alkyl, aryl, or aryl-SwR alkyl; OCF,-OFCH2_SOC W7 is -N7 or 16R16 Y is or -CR 20 WO 99/01423 WO 9901423PCTIDK98/00287 37 Z is or -R= V is or -R= Q is -NR 23 or wherein:
R
19 R 2 and R22 independently are hydrogen, halogen, -ON, -OF 3 -00F 3
-OCH
2
OF
3
-NO
2
-OR
2 4 -NR 24 R 2 lower alkyl, aryl, aryl-lower alkyl, SCF 3 -SR 24
-CHF
2
-OCHF
2
OOF
2
CHF
2 -0S0 2
CF
3 -CONR 24
R
25
-CH
2 00NR 24
R
25
-OCH
2 C0NR 24
R
25
-CH
2
OR
24
CH
2 NR 24
R
25 ,1 -OCOR 24 or 0 2 R 24 or R 19 and R 2 1, R 2 0 and R 21 or R 21 and R' together form a bridge -OCH 2
O-;
R 2 and R 2 1 independently are hydrogen, -COR 2 1, -S0 2
R
2 lower alkyl, aryl or aryl-lower alkyl;
R"
6 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; R 2 3 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K is R 3 a R 3 b R Rab wherein: R 3 a, R 3 b R 4 and R'b independently are hydrogen, halogen, -ON, -OF 3 -00F 3 -00H 2 0F 3
-NO
2 -OR 24 -NR 4 R 2 1, lower alkyl, aryl, aryl-lower alkyl, SOF,, -SR 24 -OH F 2 -OOH F 2
-OOF
2
OHF
2 ,-0S0 2 0F 3 -OON R 24
-R
25
-OH
2 OONR 4 Ra
-OCH
2 OONR 24 a R 25 a, -CH 2 0R 24 a, -CH 2 NR 24 a R 25 a, -OOOR 24 or -C0 2 R 24 1; WO 99/01423 WO 9901423PCT/DK98/00287 38 wherein R 24 I and independently are hydrogen, -COR B, _S0 2 R 6 lower alkyl, aryl or aryl-lower alkyl; R 2 1a is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or and R"b, R 4 and R"b or R" and R 4 1 together form a bridge -(CH 2 wherein is 1, 2, 3 or 4; 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 _S0 2 -NR 5 -NR 5 aS0 2 -NR 5 CNR 5b_, .NR 5 aCSNR 5 -OC0NR 5 b_ or -NR- 5 aC(0)0wherein Rsa and R 5 b independently are hydrogen, lower alkyl, -(CH 2 )k-OH, -(CH 2 )k- NRla RIb aryl or aryl-lower alkyl; wherein k is 2, 3 or 4; R la and R eb independ .ently are hydrogen, lower alkyl or aryl-lower alkyl; K preferably representing WO 99/01423 WO 9901423PCTIDK98/00287 -(CH2)
I
-(CH2) (CH 2)d- R
S
0 0 11 -0-S-C2j I I 0 0
R-
R
0 -0
R
0 0 0 D is hydrogen or WO 99/01423 WO 9901423PCT/DK98/00287 4v28 R27 R
R
2 1r
*R
7
(CH
2 ),VrV 71 w -V 28 (H 2 E
\F
R 2 or _E 111- R28 or 2 preferably hydrogen,
'S
R 27~ I r R 2 28 or 28 wherein: r and s independently are 1 or 2; E, F and G independently are -CHR 38 >NR 39 or Y' is or -0R 32 WO 99/01423 WO 9901423PCT/DK98/00287 41 Zis or C V is or -R= W' is or -R= Q' is -NR 36 or wherein R 2 7 R 28 R 32 R 33 R34and R 35 are independently hydrogen, halogen, -ON, -CE 3
-OCF
3
_O(CH
2 )yCF 3
-NO
2 -OR29, -NR 29 R 30 lower alkyl, aryl, aryl-lower alkyl, -SCF 3
-SRI,.
-CHF
2
-OCHF
2
-OCF
2
CHF
2 -0SO 2
R
29
-OSO
2
CF
3 -CONR 2 9 R 30
-(CH
2 )yCONR 29R
-O(CH
2 )yCONR 2 9 R 30
-(CH
2 )yOR 29
-(CH
2
)YNR
2 9 R 30 -OCOR 29
-CO
2
R
29 or R 2 'and R 2 1, R 3 2 and R 33
R
33 and R34 or R34 and together form a bridge -OCH 2
O-;
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
-OCH
2
O-;
y is 1, 2, 3 or 4; R 2 and R 3 1 independently are hydrogen, -COR 31 -S0 2 R 31 lower alkyl, aryl or aryl-lower alkyl; R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; R 3 1 and R 3 1 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; R 38 is hydrogen, -OR 40 -NR 40 R 41 lower alkyl, aryl, aryl-lower alkyl, -SCF 3 -SR 4 1, -CHF 2
OCHF
2
-OCF
2
CHF
2 -C0NR OR 41
-(CH
2 )xCONR OR 1
-O(CH
2 ),,CONR OR 1 -C2)
-(CH
2 )XNR 40 R 41 -000R 4 1 or -00 2 R 40 WO 99/01423 PCT/DK98/00287 42 x is 1, 2, 3 or 4;
R
4 0 and R 41 independently are hydrogen, -COR 42 -S0 2
R
42 lower alkyl, aryl or aryl-lower 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: R 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; n is 0,1, 2 or 3; m is 0 or 1; X is >C=NR 5 or >SO 2 wherein R 5 is hydrogen, lower alkyl, aryl-lower alkyl or -OR 6 wherein R is hydrogen, lower alkyl, aryl or aryl-lower alkyl; A is WO 99/01423 WO 9901423PCT/DK98/00287 R 7 8fN R N)a-'
R
RO~
t 9
NR
10
S
R
8 0
R
7 N or R 8 wherein: WO 99/01423 PTD9/08 PCT/DK98/00287 44
R
7 is hydrogen, halogen, -ON, -OF 3 -00F 3
-OCH
2
CF
3
-NO
2
-OR"
1
-NR
11 R'1 2 lower alkyl, aryl, -SCF 3 -SRI', -CHF 2
-OCHF
2
-OSO
2 R"I, -OONR"R 2
-CH
2 ORII, -CH 2
NR
1
R
1 -OCOR", -C0 2 R1 3 or 0OS0 2
CF
3 R' and R" independently are hydrogen, halogen, -ON, -CE 3
-OCF
3
-OCH
2
CF
3
-NO
2
-OR"
1 -NR1R 1 2 lower alkyl, aryl, -SCF 3
-CHF
2
-OCHF
2 -0S0 2 RII, -OONRIR 1 2 -0H 2 0R 1 1
-OH
2 NR"R 1 2 -000R 1
_CO
2 R1 3 or -0S0 2 0F 3 or R' and R' together form a bridge -00H 2 0- or OCH 2
CH
2 0-; wherein R11 and R' independently are hydrogen, -00R R, -S0 2
R
13 lower alkyl or aryl; wherein R 1 3 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; and R 0 is hydrogen, lower alkyl, aryl-lower alkyl or aryl; B is 1Z 15 4 V!RA14 R1 R R R11 Wl 14 14R R H R 14 1 R CR or a valence bond; preferably WO 99/01423 WO 9901423PCT/DK98/00287 R U _0R 15 R 111O R wherein:
R'
4 and R' 5 independently are hydrogen, halogen, -CN, -CF 3
-OCF
3
-O(CH
21
CF
3
-NO
2
-OR'
6 -NR 16
R
17 lower alkyl, aryl, aryl-lower alkyl, -SCF 3
-SR'
6
-CHF
2
-OCHF
2
-OCF
2
CHF
2
-OSO
2
CF
3
-CONR'
6
-(CH
2 ),CONR R -O(CH 2 )IC0NR 6
R
7
-(CH
2
)COR'
6
-(CH
2 ),C0R 1 6
-(CH
2
)OR'
6
-O(CH
2
),OR'
6
-(CH
2 ),NR 6
R
17
-O(CH
2
),NR
16
R'
-OCOR'1 6
-CO
2 R 1 8 -O(0H 2
)ICO
2
R'
8
-O(CH
2 )ICN, -O(CH 2 )C1, or R'1 4 and R15 together form a bridge -OCH 2
O-;
R"
4 andR' 5 preferably independently representing hydrogen, halogen, -CF 3
-OCF
3 -OR 1 6 -NR1 6 R 1 7 lower alkyl, aryl, aryl-lower alkyl, -OSO 2
CF
3
-CONR'
7
-CH
2
OR'
6
-CH
2 NR1 6 R 17 -OCOR 16 or -CO 2
R'
8 or together forming a bridge -OCH 2
O-;
wherein I is 1, 2, 3 cr4;
R'
6 and R1 7 independently are hydrogen, -COR 8
-SO
2
R'
8 lower alkyl, aryl, or R' 6 and R 17 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms; wherein R" 8 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; W is or -CR Y is or C2= WO 99/01423 WO 9901423PCT/DK98/00287 46 Z is or -CR 21 V is or and Q is -NR 23 or wherein:
R
19
R
2 1, R 2 1 and R' independentiy are hydrogen, halogen, -CN, -CF 3
-OCF
3
-OCH
2
CF
3
-NO
2 -OR 24
-NR
2 4 R 25 lower alkyl, aryl, aryl-lower alkyl, SCF 3 -SR 24
-CHF
2
-OCHF
2
-OCF
2
CHF
2
-OSO
2
CF
3 -C0NR 2 4 R 25
-CH
2 C0NR 24
R
25
-OCH
2 CONR 24
R
25
-CH
2
OR
24
-CH
2 NR 24
R
25
-OCOR
24 or _CO224, or R 19 and R' 0 R 2 0 and R 21 or R 2 1 and R' together form a bridge -OCH 2
O-;
wherein R' 4 and R 2 independently are hydrogen, -COR 26 -S0 2
R
6 lower alkyl, aryl or aryl-lower alkyl; wherein R 26 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; and R 23 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; K is R 3a R 3b R 4 a R 4 b
VCH
2 2
(CH
2 wherein:
R
3 a, R3b R 4 a and R 4 b independently are hydrogen, halogen, -ON, -OF 3 -00F 3 -00H 2 0F 3
-NO
2 -OR 24
-NR
24 a R 25 a, lower alkyl, aryl, aryl-lower alkyl, SOF 3
-SR
24 a,
-CHF
2
-OCHF
2
-OCF
2
OHF
2 -0S0 2 0F 3
-CONR
4 aR 5
-CH
2
OONR
4
R,
-OOH
2 OONR 24 -R 25 a, -CH 2 0R 24
-OH
2 NR 24 a R 25 OOOR 24 a or _CO 2 R 24 a; WO 99/01423 WO 9901423PCT/DK98/00287 47 wherein R 2 4 a and R 2 1a independently are hydrogen, -C0R 26 a, -SO 2 R 2 6a lower alkyl, aryl or aryl-lower alkyl; wherein R 2 1, is hydrogen, lower alkyl, aryl or aryl-lower alkyl; or R 3 and R 3 1, R 4 a and R 4 1 or R 3 and R 4 1 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; e, f and p independently are 0 or 1; q is 0, 1 or 2; and L and M independently are -CH=CH-, -NR 5 -OCO-, -COO-, -CONR 5 -NR 5aCO_, -So-, -S02-, -0502-, -SO 2 -NR 5 -NR R 5
SO
2 -N R 5 a CONR 5
-NR
5 aCSN R 5 -0CC N R 5 b_ or -NR laC(O)O_; wherein R la and R 5 1 independently are hydrogen, lower alkyl, -(CH 2 )k-OH, -(CH 2 )k- NRla R"b, aryl or aryl-lower alkyl; wherein k is 2, 3 or 4; and
R
6 and R Ib independently are hydrogen, lower alkyl or aryl-lower alkyl; K preferably representing WO 99/01423 WO 9901423PCT/DK98/00287
H
0
-O-CH
2 CHR-0Cj--N-C-j---- 1 a
R
0 0
H
0 11 -0-s- 11 0 a valence bond 0 -(CH and -0-(CH 2 2
-(C
2DH 2 CH2j- D is hydrogen, WO 99/01423 WO 9901423PCT/DK98/00287 R27 v R 28 v1z R 2 aj R 21Z w. y
Y
>RY'N2 R 28k 1 *R (CM 2 R 27
X(CH
IN
F
R 28 E 27~
G
(CH,
2 E F 2 7
R
2 E/4 (CH/
G~
7 R 28
R
ERe 6\R 28 preferably hydrogen, WO 99/01423 WO 9901423PCT/DK98/00287 R27 WR2 28 32
RR
HA 28
VV'
2 s
E
.R 27 -2-7-bR
R
28
R
E
(C H F (G 2 F28 F'-(G)r e 27 or E R 2
(CHA)
Q,\
wherein: r and s independently are 0, 1 or 2; E, F and G independently are -CHR 3 11, >C0O, >NR 3 1, or Fis >CR 38 or Y' s o -C 32 Y' is or -CR V is or -R= WO 99/01423 PTD9/08 PCT/DK98/00287 51 W' is or and Q' is -NR 36 or wherein: R 27 R 28
R
3 2 R 33 R'and R 3 are independently hydrogen, halogen, -CN, -CF 3
-OCF
3
-O(CH
2
)C
3
-NO
2 -OR 29 -NR 29
R
30 lower alkyl, aryl, aryl-lower alkyl, -SCF 3
-SR',
-CHF
2
-OCHF
2
-OCF
2
CHF
2 -0S0 2 R 29
-OSO
2
CF
3 -C0NR 2 9 R 30
-(CH
2 )yCONR29R -0(CH 2 )YCONR 2 9
R
3 0
-(CH
2 )YOR 29
-(CH
2 )yNR 2 9 R 30 -OCOR 29 or -CO 2 R29; or
R
2 7 and R 2 8 R 32 and R 3 3 R 3 3 and R34 or R34 and R 35 together form a bridge -OCH 2
O-;
R 2 and R 2 1 preferably independently representing hydrogen; halogen such as -Cl or -F;
-CE
3 0OCF 3
-OCHF
2
-OCH
2
CF
3 -OR 2 1 wherein R' 9 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
O-;
wherein y is 1, 2, 3 or 4; and R 2 and R 3 1 independently are hydrogen, -C0R 31 -S0 2 R 31 lower alkyl, aryl or aryl-lower alkyl; wherein R 31 is hydrogen, lower alkyl, aryl or aryl-lower alkyl; R 3 and R 3 1 independently are hydrogen, lower alkyl, aryl or aryl-lower alkyl; and R 3 11is hydrogen, -OR 40 -NR 4 1R 41 lower alkyl, aryl, aryl-lower alkyl, -SCF 3
-SR
40
-CHF
2
-OCHF
2
-OCF
2 CH F 2 -C0NR OR 41
-(CH
2 ),,CONR OR 41
-O(CH
2 ),,CONR OR 1
-(CH
2
)"OR
40
-(CH
2 40 R 41 -0COR 4 1 or C241 WO 99/01423 PCTIDK98/00287 52 wherein x is 1, 2, 3 or 4;
R
4 0 and R 4 1 independently are hydrogen, -C0R 42 -S0 2 R 42 lower alkyl, aryl or aryl-lower alkyl; and wherein R 42 is hydrogen, lower alkyl, aryl or aryl-lower alkyl.
WO 99/01423 WO 9901423PCT/DK98/00287 53 Examples of specific compounds represented by the above general formula V are the following:
CH
3 OCH~)~J~j
CH
3 HO H 0 ci.
3-Chloro-4-hydroxybenzoic acid [5-chloro-2methoxy-4-(4-isopropylbenzyloxy)benzylidene~hydrazide
CH
3 CH3 N N OCH, HO' H OCH 3 C1 3-Chloro-4-hydroxybenzoic acid [2,3-d imethoxy-4-(4-isopropylbenzyloxy)benzylidene]hydrazide CH 3
CH
3 ON 0 N'H
CH
3 HOP H o 3 C1 3-Chloro-4-hydroxybenzoic acid [2,3-dimethyl-4-(4-isopropylbenzyoxy)benzylidene]hydrazide
CH
3 C1
CH
3 O0 0
N-.
N(3 N' C1
HO
ci 3-Ch loro-4-hydroxybenzoic acid 4 4 -isopropylbenzyioxy)benzylidenelhydrazide
CH
3
CH
3 0 0 N N C I HOJ:A -CI 3-Chloro-4-hydroxybenzoic acid [2,3-dichioro- 4-(4-isopropylbenzyloxy)benzylidene]hydrazide
CH
3 H&C CHO
CH
3 HO N' N OCH 3 ci 3-Chloro-4-hydroxybenzoic acid [3-isopropyl-4methoxybenzylidene]hydrazide WO 99/01423 WO 9901423PT/DK98/OO287 -CH 3 S CH 3 'OCH 3 3-Chloro-4-hydroxybenzoic acid t3-isopropyl- 3-Chloro-4-hydroxybenzoic acid 4-(4-isopropylbenzyloxy)-5- -pyrrolidino)ethoxy)]-4-(4methylbenzylidene]hydrazide methoxybenzylidene}hydrazide KCH3 H3C fN,,CH 3
CH
3
CH
3 0CH0 0 N ACH 3
HHO
H
3-Chloro-4-hydroxybenzoic acid [3-(2-diethylaminoethoxy)-4-(4-isopropyl- 3-Chloro-4-hydroxybenzoic acid [3-(2-diethylaminoethyl methoxybenzylidene]hydrazide C0 2 H CH 3
-J-
N
CH
3 HO N NOH ci 5-[(3-Chloro-4-hyd roxybenzoyt)hydrazonomethyl]-3-methoxy-2-(4-isopropylbenzyloxy)phenoxyacetic acid
OCH
3 3-Chloro-4-hydroxybenzoic acid [3-diethylaminomethyl-4-(4-isopropylbenzy- WO 99/01423 WO 9901423PCT/DK98/00287 CH 3
CH
3 0 CH 3 0 0H 0 0 :0 0 0O N N OCH 3 N' 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-hydroxyethoxy)-4-(4isopropylbenzyloxy)benzylidenelhydrazide
OCH
3
CH
3
N
0
OCH
3
OCH
3 3-Chloro-4-hydroxybenzoic acid [2,3 .5-trimethoxy-4-(4-isopropylbenzyloxy)benzylidenejhydrazide 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-n-propylbenzyloxy)benzylidenelhydrazide
'CH
3 3-Chloro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-ethoxybenzyloxy)benzylidene]hydrazide 3-Fluoro-4-hydroxybenzoic acid [3 ,5-dimethoxy-4-(4-isopropylbenzyloxy)benzylidene]hydrazicje WO 99/01423 WO 9901423PCTIDK98/00287 OCH 3 N0 2 3-Nitro-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-isopropylbenzyloxy)benzylidene]hydrazide 3-Carboxy-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-isopropylbenzyoxy)- benzylideneihydrazide
OH
3 0CM 3 C H 3 00 N
OCH
3
HOH
ON
3-Cyano-4-hydroxybenzoic acid (3,5-di methoxy-4-(4-isopropylbenzyloxy)benzylidene]hydrazide CONH 2 3-Carbamoyl-4-hydroxybenzoic acid [3,5-dimethoxy-4-(4-isopropylbenzyloxy)benzylidene]hydrazide 3 -P,1 0 C F 3 'CH 3 3-Chloro-4-hydroxybenzoic acid {3 ,5-dimethoxy-4-[4-(2,2,2-trifluoroethoxy)benzyloxy]-benzylidenelhydrazide 3-Chloro-4-hydroxybenzoic acid [3 ,5-dimethoxy-4-(3-chloro-4trifluoromethoxybenzyioxy)benzylideneihydrazide WO 99/01423 WO 9901423PCT/DK98/00287
OCH
3 3-Chloro-4-hydroxybenzoic acid [3,5dimethoxy-4-(4-chlorophenoxy) benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid dimethoxy-4-(4-isopropylphenoxy) benzylidene]hydrazide 33
'OCH
3 3-Chloro-4-hydroxybenzoic acid [3,5dimethoxy-4-(4-trifluoromethyl-2pyridylmethoxy)- benzylidene]hydrazide
OCH
3 3-Chloro-4-hyd roxybenzoic acid dimethoxy-4-(6-methyheptyloxy) benzylideneihydrazide 3-Chloro-4-hydroxybenzoic acid [3,5benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid dimethoxy-4-(5,5-dimethy-3-hexynyloxy) benzylidene]hydrazide WO 99/01423 WO 9901423PCT/DK98/00287 .0 z
OCF
3 C H 3
CH
3 3-Chloro-4-hydroxybenzoic acid trifluoromethoxyphenoxy)-1 naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid isopropylphenoxy)-1 naphthylmethylene]hydrazide
'OCH
3 3-Chloro-4-hydroxybenzoic acid {3,5dimethoxy-4-[2-(4-E-trifluoromethylphenyl)ethenyllbenzylidene~hydrazide 3-Chloro-4-hydroxybenzoic acid methoxy-4-[(4-isopropylphenyl)ethynyl]benzylidene)hydrazide
PCH
3 3-Chloro-4-hydroxybenzoic acid (3,5dimethoxy-4- (cyclohexylethynyl)benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid methoxy-4-methylphenyl methoxybenzylidene]hyd razide WO 99/01423 WO 9901423PCT/DK98/00287 3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1 naphthylmethylene)hydrazide 3-chloro-4-hydroxybenzoic acid [4-(3,5-bistrifluoromethylbenzyloxy)-l naphthylmethylene]hydrazide
OCH
3 3-chloro-4-hydroxybenzoic acid chloroethoxy)-1 -naphthyimethylene]hydrazide 4-Hydroxy-3-methoxybenzoic acid (2naphthylmethylene)hydrazide CH 3
OCH
3 OCH 3 4-Hydroxy-3-methoxybenzoic acid (4methoxy-1 -naphthylmethylene)hydrazide 4-Hydroxy-3-methoxybenzoic acid (4-tertbutylbenzylidene)hydrazide
FFF
0
N
0
N
n H
CH
3
OCH
3 4-Hydroxy-3-methoxybenzoic acid (4isopropylbenzylidene)hydrazide 4-Hydroxy-3-methoxybenzoic acid (4trifluoromethoxybenzylidene)hydrazide WO 99/01423 WO 9901423PCT/DK98/00287
CH
3 3
OCH
3 4-Hydroxy-3-methoxybenzoic acid (1 H-indol-3ylmethylene)hydrazide 4-Hydroxy-3-methoxybenzoic acid (4dimethylamino-1 naphthylmethylene)hydrazide
N
N
OCH
3 4-Hydroxy-3-methoxybenzoic acid (4phenylbenzylidene)hydrazide O
NOCH
3 I
H
HO
4-Hydroxybenzoic acid (4-methoxy-1 naphthylmethylene)hydrazide
NN
HONQ
H
OCH
3 4-Hydroxy-3-methoxybenzoic acid (1naphthylmethylene)hydrazide 4-Hydroxybenzoic acid (1naphthytmethyiene)hydrazide 0
HO
3,4-Dihydroxybenzoic acid (1nap hthyl methylene)hyd razide FF F 00 N' N I H HO N
OCH
3 4-Hydroxy-3-methoxybenzoic acid [3-(3-trifluoromethylphenoxy)benzylidene] hyd razide WO 99/01423 WO 9901423PCT/DK98/00287
FIF
XF
O F
OCH
3 4-Hydroxy-3-methoxybenzoic acid (4q uinolinylmethylene)hydrazide 4-Hydroxybenzoic acid ,1,2,2tetrafluoroethoxy)benzylidenelhydrazide
CH
3 CH 3
OCH
3 4-Hydroxybenzoic acid [3-(4-tert-butylphenyl)- E-but-2-enylidene]hydrazide 4-Hydroxy-3-methoxybenzoic acid (4hydroxy- 1 -naphthylmethylene)hydrazide N.t 4-Hydroxybenzoic acid (benzylidene)hydrazide 4-Hydroxybenzoic acid (1naphthylmethylene)hydrazide 3-Amino-4-hydroxybenzoic acid naphthylmethylene)hyd razide 3-Amino-4-hydroxybenzoic acid (4-hydroxy- 1- naphthylmethylene)hydrazide WO 99/01423 WO 9901423PCT/DK98/00287 4-Hydroxyberizoic acid [3-(3-trifluoromethylbenzyloxy)benzylidene]hydrazide 3-Chloro-4-hydroxybenzoic acid (1naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (4-hydroxy-1 naphthylmethylene)hydrazide
F
0
F
0 F H-
N
4-Hydroxybenzoic acid trifluoromethylphenoxy)benzylidene]hydrazide 4-Hydroxybenzoic acid (4-hydroxy-1 nap hthyl methylene)hyd razide 0 HN-N
WNN
4-Hydroxybenzoic acid (5-phenyl-3pyrazolylmethylene)hydrazide 0 N
N
HON
4-Hydroxy-3-nitrobenzoic acid (1naphthylmethylene)hydrazide 2,4-Dihydroxybenzoic acid (4-hydroxy-1 naphthylmethylene)hyd razide WO 99/01423 WO 9901423PCT/DK98/00287
H_
4-Hydroxy-3-nitrobenzoic acid (4-hydroxy- 1nap hthylmethyle ne)hyd razide 3,4-Dihydroxybenzoic acid (4-hydroxy-1naphthylmethylene)hydrazide 4-Hydroxybenzoic acid (6-methoxy-2nap hthyl methylene)hyd razide 0
N
N CH 3
HO
OCH
3 3,5-Dichloro-4-hydroxybenzoic acid (4hydroxy-1 -nap hthylmethylene)hyd razide
CI
0 N N 0 OCH 3 4-Hydroxy-3-methoxybenzoic acid (9-ethyl-9H- 4-Hydroxy-3-methoxybenzoic acid 3-carbazolylmethylene)hydrazide chlorophenyl)-2-furanylmethylene]hydrazide
NN~
HON
C I
'~CH
2 3-Chloro-4-hydroxybenzoic acid (3-phenyl-Eallylidene)hydrazide 3-Oh Ioro-4-hyd roxybenzoic acid (4-allyloxy-1 naphtylmethylene)hydrazide WO 99/01423 WO 9901423PCT/DK98/00287 .0
HO'
CI
3-Chloro-4-hydroxybenzoic acid (4benzyloxy-1 -naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (4ethynyimethoxy-1 naphthylmethylene)hydrazide 2-(4-[(3-Chloro-4-hydroxyben zoyl)hydra- zonomethyl]- 1 -naphthyloxy)acetamide 3-Chloro-4-hydroxybenzoic acid (4-methyl-inaphthylmethylene)hyd razide 3-Chloro-4-hydroxybenzoic acid (2-hydroxy- 1naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (4-methoxy- 1 -naphthylmethylene)hydrazide N-(2-[(3-Chloro-4hydroxybenzoyl )hydrazono]ethyl)-2,2diphenylacetamide 3-Chloro-4-hydroxybenzoic acid (1 -hydroxy- 2-naphthyimethylene)hydrazide WO 99/01423 WO 9901423PCT/DK98/00287
'OCH
3 3-Chloro-4-hydroxybenzoic acid (2,2diphenylethylidene)hydrazide
CH
3 N CH 3 OI
CH
3 00 N'
N,
HON
CI
3-Chloro-4-hydroxybenzoic acid [3-(4-tertbutylphenoxy)benzylidene]hydrazide
CI
3-Chloro-4-hydroxybenzoic acid (4d imethoxybenzylidene)hydrazide 3-Chloro-4-hydroxybenzoic acid (4-methyl-i naphthylmethylene)hydrazide O0 CH3 0 3-Chloro-4-hydroxybenzoic acid (3-bromo-4hydroxy- 1 -naphthylmethylene)hyd razide Acetic acid 4-[(3-Chloro-4hydroxybenzoyl)hydrazonomethyl]- 1 -naphthyl ester 3-Chloro-4-hydroxybenzoic acid (4cyanomethoxy-1 naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid (2-hydroxy- 1 -naphthylmethylene)hydrazide WO 99/01423 WO 9901423PCTIDK98/00287 0 CH 3 HO'C H
CI
3-Chloro-4-hydroxybenzoic acid methoxyphenoxy)benzyfidenelhydrazide 3-Chloro-4-hydroxybenzoic acid (2,3methylenedioxybenzylidene)hydrazide 3-Chloro-4-hydroxybenzoic acid (9phenanthrenylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid hydroxyethoxy)-1 naphthylmethylene]hydrazide 3-Bromo-4-hydroxybenzoic acid (4-hydroxy-1 naphthylmethylene)hydrazide Nicotinic acid 4-[(3-chloro-4hydroxybenzoyl)hydrazonomethyl]-l -naphthyl ester 3-Chloro-4-hyd roxybenzoic acid 1,3-dioxo- 1 ,3-dihydroisoindol-2-ylmethoxy)-1 -naphthylmethylene]hydrazide 3-Chioro-4-hydroxybenzoic acid [4- (cyclohexylmethoxy)-1 naphthylmethylene]hydrazide WO 99/01423 WO 9901423PCT/DK98/00287 3-Chloro-4-hydroxybenzoic acid [4- (tetrahydro-2-pyranylmethoxy)-1 -naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid pyridylmethoxy)-1 naphthylmethylene]hydrazide N N..
HON.
C1 3-Chloro-4-hydroxybenzoic acid (3nitrobenzylidene)hydrazide 4-[(3-Chloro-4hydroxybenzoyl)hydrazonomethyl]-1 naphthyloxy)acetic acid ethyl ester 0 Cl 1; C N
HOH
C1 3-Chloro-4-hydroxybenzoic acid (2,4dichlorobenzylidene)hydrazide 3-Chloro-4-hydroxybenzoic acid (4-fluoro-1naphthylmethylene)hydrazide WO 99/01423 WO 9901423PCT/DK98/00287
F)CF
I
3-Fluoro-4-hydroxybenzoic acid (4-hydroxy-1 naphthytmethylene)hydrazide 0
N
HO
F
3-Fluoro-4-hydroxybenzoic acid (1naphthylmethyiene)hydrazide 3-Chloro-4-hydroxybenzoic acid difluorobenzyfoxy)-1 naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid methoxybenzyloxy)-1 naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid fluorobenzyloxy)-l naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid tetrahydrofuranylmethoxy)-1 naphthyimethylene]hydrazide WO 99/01423 WO 9901423PCT/DK98/00287
.OCH
3 3-Chloro-4-hydroxybenzoic acid (3-bromo-4methoxy-1 -naphthylmethylene)hydrazide 3-Chloro-4-hydroxybenzoic acid tetra hyd rofura nyl methoxy)- 1 naphthylmethylene]hydrazide
OCH
3 0F N N:
OCH
3 4-(4-[3-Chloro-4hydroxybenzoyl)hydrazonomethyq]-l naphthyloxymethyl)benzoic acid methyl ester 3-Chloro-4-hydroxybenzoic acid dimethoxy-4-(4-trifluoromethoxybenzyloxy)benzylidenelhydrazide 0 F
)<F
'0 F 3-Chloro-4-hydroxybenzoic acid trifluoromethoxybenzyloxy)-l naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid methoxybenzyloxy)-1 naphthylmethylenelhyd razide WO 99/01423 PCT/DK98/00287 3-Chloro-4-hydroxybenzoic acid j4-(2fluorobenzyloxy)-1 naphthylmethylene]hydrazide 3-Chloro-4-hydroxybenzoic acid difluorobenzyloxy)-1 naphthylmethylene]hydrazide WO 99/01423 WO 9901423PCT/DK98/00287 71 0 0 HO H ci
CH
3 HO CH~
CH
3 N-N
N-N
ci
CH
3 ci H\ /0
CH,
H
H
ci
CH
3 HO /\CO H CH, HO
CHCH,
N-N H\ oH c
CH
3
CH
3 CH 3 HO0 C02H 0 H N-N -N-N ra C clH -3 c H H C0 2
H
WO 99/01423 WO 9901423PCT/DK98/00287 CN(Et), 0C Ho \OM- N- J N-N F 0\
HI
OMe
OCF,
The most preferred specific compounds represented by the above general formula Ill are the following: 0 N-N
OF
H 4'S/ OMe -i 0 H OMe HO
CF,
0N-N
H\/
H -CF 3 0 N-N C H
I,
0N-N 0l -CH 3 H OMe The most preferred specific compounds represented by the above general formula IV are the following: WO 99/01423 WO 9901423PCT/DK98/00287 73
H
H
N-
H ~OCF 3 HO H- CH
O
C1H 0 CF
OCH
3 HOH OCH,
CH
3
N-N
HiL-
CH,
OCH
3 HO0
CF
3 HOH
OCH
3
N-N
-P-H
OCH 3 Preferred specific compounds represented by the formulae VI and VII are the following: MeO 0 -N0 MeO c H I OfI H
C
HOq cI
HO
CI
CI
0 MeO 0
N'
H
HO
CI
0 MeO, 0 MeO 0 N N" H
C
HO' cI KN~ci N e S C
I
WO 99/01423 WO 9901423PCTIDK98/00287
HOH
Br
H
c:P OMe
H
'OMe N c
H
0MeO 'q- 0 ,N
C
e H0
HO
cI OMe Il H HOq
H
CI
OO
N O~ HO
NH
N NN' OMe Hl
HC
HOJ( A Ci 0 N N0 Me H ZLI OMe 6H
HOH
HO
WO 99/01423 WO 9901423PCT/DK98/00287 0 0 N NNS N OKN ~ci HO cx CIll 0
NN'
HO"(
H
cI .0
N-'
H
'OMe ome 0%
N
N NOMe O .CF 3 IOJ
H
HO
HO -f 0 j
NX
I H
HO
CI
Br
N
H
HO'P
H
C!
0 N
H
HOJP
H
CI
x m a: m T x I: 0 0 0 0 0 0 0 0.0 0 0 0 0 0 0 0 0 0 z z IZ xIZ IZ I Z zo 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0)A 0 0 0 0 0 0 0 0 mxz z zz z b1$ IZ- LZ IZI x 0) 0 WO 99/01423 WO 9901423PCT/DK98/00287
CH
3 0N N' Ho-(
H
HO
0 N N 0 N H O HO'
H
cl
ON
0 N N.
I H
HO-
cI '1 N H" a
H
HO
HOJ;
)A
CI
0N. 2
H
HO
CI
NN
HH
HOH
11 H 0 N( A
N.
I H
HOA
CI
WO 99/01423 WO 9901423PCT/DK98/00287 O
N
N
H OMe HO H OMe N' N'k.
H
HOH Oe-
CH,
HO
CH
3 Ci N N IO(
H
O H OH N H HO 30H CH 3 0N H N5 H ,NH 2
HOA
CI
C,
H
Br OMe N N N'Br HO
(AH
OMe CH 3 N Br C HO j Cl OMe N OMe Ni HO"
H
Cl OMe 0 N H"
C
N OMe A 0 1 HO
(A
cI 04 0 0 2j zT
Z=I
0 m z
ZI
0
U.
2 0 0 0 0 2 LI. 0 0 0 9 0+ t-
C
000 0%0 0 0 h ~z-x 0 0 0/ a 0 0 0 0 =4 0 0 o 0 ol 02 2 2 2 2 2 2 2 0 00 0 0 /Z z z C/ c 0 0 a 0 0z to 0 0 0 2:z x2 0 00 X~o 0 0 0 2 V CO 00 0 0 0 0 xzx z
"Z
p0 0 0 99 0 0 oo 0 0 0 00 'b/ 0- 0' 00 G-0 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: 0 N
N~
HH
acid trifluoromethylbenzyloxy)-1 naphthylmethylene]hydrazide 0 N 0
NN
H
Pyrazole-3-carboxylic acid trifluoromethylbenzyloxy)-1 naphthylmethylenelhydrazide o4 N A
H
Indazole-5-carboxylic acid trifluoromethylbenzyoxy)-l naphthylmethylene]hydrazide
C
0 N 0
N
0- N
N
HO 0
HI
3-Hydroxyisoxazole-5-carboxylic acid[4-(4trifluoromethylbenzyloxy)-1 naphthylmethylene]hydrazide WO 99/01423 WO 9901423PCT/DK98/00287 0 N' OMe
CH
3
-N
MeO H, 00 IN NNCF MeO H\ 0\ OF
H
N 0 MeO OMe
CH
3 H OMe
CH
3 OMe
-~CH
3 0 lp N OMe NI H %N e
H
N 0 H 0Me CH 3 0
C
3
H
OMe HO e 0
CH,
N-N
H OMe 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: CH F F HoC.
0 CH 3
F
0 0 0 HOci
CH
3 N. C H 3 O 0 0 HON H
CI
F
F
F
WO 99/01423 WO 9901423PCT/DK98/00287 87 0 NN*Y HN N
H
HO HO CH 3 CI N. q 1 CH 3 I N* Yz H A HO" H HON H~l ~BrII O 0 A N' N N H HO N H I H CH 3 HO ~HO
AP
CH
3 N N H JP H HO AN HO Al
F
NN OH 0 0,,N H N N HO _qHO
A
Br
CI
OH
3 CH 3 A CH 3 CH 3 A OH C H 3 0 N o H 3 N NzbN OH3 N N,&JJCH3 HO I A H IA H HO CI HO F CI
F
WO 99/01423 WO 9901423PCT/DK98/00287 6H 3 00 N
H
HOJP
H
cI p, Br 0 1J HOJ
H
0
NH
N~ 5y-
N
H
HO
-P
0 N 'F N NF
H
HO-P
cI r OH 3 'NcI Q.Na
OHH
N.0
H
HO
CI
0
OH
N'
H
HO
CI
OHH
0
ICHH
HO
cI WO 99/01423 WO 9901423PCTIDK98/00287 0 "q
N
HOA
CI
OMe 0 N OMe HO 6OMe HO H 0 00 HOCF3 HO A HCH 3 CI Ci 0
NN'
HOP
H
HO
No HI;A
H
HO
WO 99/01423 WO 9901423PCT/DK98/00287 00
N
I H HO cI
HO
cl N' H~
H
3 C- N HO"
H
cI Nt HO c 0 CH 3 N
H
HO
CI
0OJN WO 99/01423 WO 9901423PCT/DK98/00287 91 OMe 00 ZI H H, HO H HH N H 3 N N N N HO'J H HO -P 0 ~i HO 3: 0H 3H HO N.N*HI Q C N.N% CN HO*( HO C0 CI 0 NOU N' N3S a H I HCF H HO HO' O 0 0 0N'.N0 IA N 'N N Q ~CI HO H
H-;AH
0~ 0 N CN- O:N. %CH 3 N K- 0N'A
HH
HO" HO WO 99/01423 WO 9901423PCT/DK98/00287 0NN
CH,
H
o
NH
2 0 KH 0 N
N,.
I H HO -Pl
CI
~%~NCH3 0
N
HO
0 N'0 IO(P H H 3 C -,O cl 00 N N"9 HO' cI -0 CH3 N O -N N. CH N5
H
0 CH 3 0 OMe WO 99/01423 WO 9901423PCT/DK98/00287 93 N N N N ON 0 0
N
y
H
H3C 0
O(P
H3 CH3 cI OJNh CF 3 0 oN- ONN N N HO -f(P H rCF3 00
F
N N NH
H
3 C 0 0
HO--P
0 0c 'A)IN 0 U' S N NN
F
I H
H
3 C N CH 3
HO
H
3 JA NN I HN HO
H
3 C, CH 3
CI
000 0 0 WO 99/01423 WO 9901423PCT/DK98/00287 94 0 0 N HH N HNC 3 HO HO -P HO
-?H
O 0 N N N HO'? H HO
H
N H NNNr~ N. S H N HO -PIH H 0 0 CH3 0 N" N'H AN C
NH
3 C OH 3
OH
3 N'NH 3 HO'P HO 0 N0
N'OH
HN
HO H
HO
0 N"U 0 "f V NN~ NR N L, HO(? H HO H CI NCH3 ci Ci 0 WO 99/01423 WO 9901423PCTIDK98/00287 N OlA c -N~ 3 0 NN N H NiI HO-O A HO'( AH 3 C CH 3 00 NNI Q2 OU ,JNYH 3 HO-P H HO H ci CH3cI 0 0 N 0, N HO" H
NH
2 HO-P HN~c H' N
H,
H H HO HO N N o-,CH 3 0 0 'J ;Ol N *KN N NH K. H H I H HO C3 HO cI Cl
NN
0O'. N 0 .JN N
N
HO HHO of HL yCH 3 CI CI
CH
3 WO 99/01423 WO 9901423PCT/DK98/00287 00 0N N H 3 C ~CH 3
HOJP
CI
0 N HO
J-
cl 0 CH3 0 N
N,
I H
HO-
CI
0 N NN I H
HO
0 NCH3 0 OMe
'N
WO 99/01423 WO 9901423PCT/DK98/00287 97 0 N H I H 6 HO -HO
N
N 0 1 N 0~ N N N 6H, N~ N N N N HO'i;IH HO-P H- 0 0 o O A 0 -,t N *N63N 6H3 HO~ -H 6 HO j 0 K N0 oN\ H HO HO JP O
OI
0o)N~I WO 99/01423 WO 9901423PCT/DK98/00287 3
PH
3
N
0 0 CH 3 N H
HO-
0 .0
N
1 1 lk;z 01-11 0
N
I H
HO
cI 0 A
N-
I H
HO
cI N0 WO 99/01423 WO 9901423PCT/DK98/00287 0
SN'
I H HO cI 0 N N N HO J;
H
cI
CH
2 H
HH
HO
N
HOP
H
(CH
0
N
N NNt 0 HOI
H
0 N Np N' NN N 0 CI IOjl)
H
HO
H
3 C. N 'CH 3 N N R 0o I H HO -I
CI
0
N,)
NA NN 2N 0
H
HO
WO 99/01423 WO 9901423PCT/DK98/00287 100
CH
3
AN,
N I N N N*NN N R0 N* NN, N 4 HO J? HHO-P (N CI NaC 0I 0 l0-
CH
3 S N'N N 0 Hd H Io? H
N'
0
N,
0 OMe N N 0'Y
HH
HO A HCI
CH
3 A' N 1 PfCH3
N
0 CH 3
N
N NNN 0 N 'NN.
HO'A H HO-Pl H 0oN N, N N .~oN) HO (AH HO-P A A (r'N 9
AAC
0oN N F 0 N r H I H HO ;A HO A CI
CI
WO 99/01423 WO 9901423PCT/DK98/00287 N' N 0I IOP
H
HO
H
0 N.N 0
N,,C
0 N -C N
N
HH
HO
N
NN.. N 0 CHY
H
HO N
CIH
N NN
CH
0 N
N
IH
HO
cI O N N :6Y HO H 0 N.N N 0 l CH, O N 0 OH 3 N J: 0
HON
cI 0 N
N
HIQr
H
HO
N
0 j:6,rcN N N.N N 0
IHI
HON
CI
WO 99/01423 WO 99/1 423PCT/DK98/00287 0
N
HO
cI 0 CH 3 N
N
HO
J
oN
P
N N 0 HO
NA
HOQ(NN~. N 0 cI 0 N CH 3 N N0
IHI
HOIQ YON
CI
0 N N I H
HO
cI 0
N)
N
NN
HO -N cI
F
N Ica OH3 0 NN 0
HON
CI
N N
H
HO
CI
0 N 0 N.N 0 H HO N
CI
WO 99/01423 WO 9901423PCT/DK98/00287
H
3
CI
0 0 N N.N N 0
HO
cI 0 N
NN
HIA
H
HO
NH F
F
0 N N I H
HO-
cI N F
C
0 0 N N N.N% H OH I HI HO -N
OH
3 0 0 0 -Y N C24 N NNN 0 3 C I HI 0 HO -N
OH
3 c 0 HO
CI
N'0 y
OH
HO N NJ
HOH
HO 00 N
NNO
I H
HO
CI
WO 99/01423 WO 9901423PCT/DK98/00287 N
HOJP
cI N
NN
H
HO0 0
HON
N NN N 0
HOH
HO A H 0 0 N N 0 HO A YO
C!
0 O A O..2N H I HO
A
HO A NCI Np" NN HO N
N
~N N 0 A: NNN N 0 H oH Q&rCH
H
O A NH N NN
HOAN
(N
0
NII
11rII-- C?
I
0 0 NN N N Q HO 0 H cOH WO 99/01423 WO 9901423PCT/DK98/00287 0 HOP-l N 0O0NH2
CH
3
N
N.k N' N 0 N HO A; H
N.H
cI NN%; 0 HO H N CH 3
CI
CH
3 N. NN.N
N
HoP H I:F 0 NN NN I H
HOA
Cl
F
NH 0 F 0 NN. NN I H
HOA
CI
H 0 0. N.N 1( HO I
CI
H
CH
3 0 N
N~-
N N 0 I H HO AN
CIH
N 0 HH H A6 H HO A N.P A N N 0. N.N 0. 0 HO AN
CI
H
F
F
N. N N HO A N.
H
3 cI WO 99/01423 WO 9901423PCT/DK98/00287
N
HO 0" qH 3 N N HO'
H
H
N N'N N0 HO P H NY Cl
H
N *N 0
IH
HO N Cl 0 00N.ND N H HO'?
H
CI
0 OANK No""I
NH
2 N N.N N 0 HO N Cl 9H 3 0
N
N N N N 0
H
)(CHN
0 O Al NA> N NN N 0 HO H N~y N
H
H
HO A
CI
F
H' aCj 0 N
N,
H
HOA
CI
WO 99/01423 WO 9901423PCT/DK98/00287 0 0 HOI
H
HO
H c
H
N'-c I H C
HO
0 0 N N N F HO
A
A0 N N
R)N
HOf
H
HO
0 0-
H
N. NN F
H
HO A1 0
CI
0J&0 ~C I WO 99/01423 WO 9901423PCT/DK98/00287 6H3
IK-CH
3 0 0 N) N N*N~ N KN~N 0 H
CF
3 N N N HOi?
H
CI
0 0 N N H IJ H c 00 N F F O N
)AF
IO
H
0 )A
C
N N
C~
IO"
H
HO
KN~CH2 NNZICF3 H
F
H
WO 99/01423 WO 9901423PCT/DK98/00287 O Il CN N N HO' AH
CH
3
CI
1 0 OCF 3 .N H
HO
cI
OH
OH
3 0OH
HO'P
0 TaOH A N R)ACH 3
OH
NI H HO _q 0 CI N N N N H HIL NjN N
F
HO
CI
WO 99/01423 WO 9901423PCT/DK98/00287
H
0
NN'
I H
HO
0 J N N
HOH
HO
0 N~ NN I H
HO
0 N N4 HO H cI 1-VNQ 0 H NNN HO0 0 N' NN I H
HO
Ci 0 N
N.
H
HO
CI
H
J)N 0 WO 99/01423 WO 9901423PCT/DK98/00287 0 NO -CH 3 o N0 PH 3 O I
H
HO H r N
NY
HO-I;f
H
cI 3
OH
N'
NN*AQJNY
HO
-(A
CI
0
N
HO -H OH r
CH
3
OH
0 0-N HO(?
H
HO
2Y f2 HO'( cI
HO
F1N N.N% 3 H N i 0
N
N NN
A
IH -z HO -;A
CI
WO 99/01423 WO 9901423PCT/DK98/00287
NN
HO _f OH cI 0 r N Nr HO
N
CI
O 0 PH 3
N'N
HOj
CI
1
CH
2
CH
2 0 0( O\ Nac l N NN HO(?
H
HO
Br
H
0 N cl N IO(P
H
FF
0 N HO -H 3 Co N N HO -H 3 Co cI 'o 'N *a 00 HO 6~H H3 0
H
0 0 C I' N'
H
HO~
WO 99/01423 WO 9901423PCT/DK98/00287
H
NN
H
HO H 3 Co F F cI 0 iii N 0 OMe c I H
HO
CI
0 NN N I H HO A; cI
N'
HO-(
H
0
N
IOP
H
0 0 NC' N N N IOP
H
It mH
OH
0 N N- H: A O- e
HO
CI
WO 99/01423 WO 9901423PCT/DK98/00287 114 0 o' 0 a ;k O HO H I- H:P)N
HOHO
0 O 0 NHC 3 N H HO';A H
HO'J
0~ N HD N HOHH HO -P H
HO(-
Cl CI
OH
3 O N 0 N N NN H ClI. H HO HO N OH N N N c HO AH-f--
CI
0 6 N' N"S (N OMe j;A "z HOJP Nc HO H 0 0 N kOe0 N Nj)OMe N.
WO 99/01423 PTD9/08 PCT/DK98/00287 .115 0N N H HO'? H
F-
CI
H
C
cl
H
HO N
H
3 0 OH 3 HO \Q4 ci H H F
F
F
HO
N-N
cl H S OH 3 HO Q c HH F F HO Cl HH
HOQ/\/
C!
H
HOH
HHO
HH
HO H -Q N /N N6 c H H HO \Q /r N-N N c H h cl Hh N N H3 WO 99/01423 WO 9901423PCT/DK98/00287
N-
H H 0- S/ N-OH 3 H
HO
ci H N HO N N--"H 0N-N S cl H N NH 2
HOH
H
3
C-O
HO ci H H HO 7i~'
N
ci H H -0CH, 0- OH 3 HO ci HN
HON~
ci H 116 HO ~N N7
ICH
H O HO
H
C H ci HO 0 H-
N-
cl hH
OH
3
HHO
0 0 HO H l H H OH 3
HOH
N
-N
clHH
OH
0 HO0 HO -p~i H3
HNH
HH
WO 99/01423 PCT/DK98/00287 N-N N-
HO
N-N N- 6 Cl H H S H SH H/ N c l
H
0
N
fi^ 0
HO(
N-
Cl
H
CI H
H
HCHO
HO -N N-
S
H
H
HO N.- N N Cl The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included in the scope of the invention.
Furthermore, one or more carbon-carbon or carbon-nitrogen double bonds may be present in the compounds which brings about geometric isomers. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are included in the scope of the invention.
Furthermore, the compounds of the present invention may exist in different tautomeric forms, eg the following tautomeric forms:
H
S 'N (CH2)n-B-(K)m-D
O
A. N (CH,)n-B-(K)m-D
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 diseases.
Accordingly, the present compounds may be applicable for the treatment of hyperglycemia associated with diabetes of any cause or associated with other diseases and conditions, eg impaired glucose tolerance, insulin resistance syndromes, syndrome X, type I diabetes, type II diabetes, hyperlipidemia, dyslipidemia, hypertriglyceridemia, glucagonomas, acute pancreatitis, cardiovascular diseases, cardiac hypertrophy, gastrointestinal disorders, diabetes as a consequence 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 secretions, to reverse intestinal hypomobility due to glucagon administration, to reverse catabolism and nitrogen loss in states of negative nitrogen balance and protein wasting including all causes of type I and type II diabetes, fasting, AIDS, cancer, anorexia, aging and other conditions, 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 ingredient, at least one compound according to the present invention together with one or more pharmaceutically acceptable carriers or excipients.
The present invention furthermore relates to methods of treating type I or type II diabetes or hyperglycemia which methods comprise administering to a subject in need thereof an effective amount of a compound according to the invention.
Moreover, the present invention relates to a method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound according to the invention.
The present invention is also concerned with the use of a compound according to the invention for the manufacture of a medicament for treating type I or type II diabetes or hyperglycemia, 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 ingredient, may be administered for therapy by any suitable route including oral, rectal, nasal, pulmonal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal), the oral route being preferred. It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the condition to be treated, and the chosen active ingredient.
The compounds of the invention are effective over a wide dosage range. A typical dosage is 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 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.
For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, 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 pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having 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 formula I with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids, for example: maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene salicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, pyruvic, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluensulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric or nitric acids. Physiologically acceptable salts of a WO 99/01423 PCTIDK98/00287 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 pharmaceutically acceptable carriers, in either single or multiple doses.
For parenteral administration, solutions of the novel compounds of formula I in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of formula I and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
Formulations of the present invention suitable for oral administration may be presented as discrete 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.
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.
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 *Acylated monoglyceride used as plasticizer for film coating.
For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
Optionally, the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more other pharmacologically active compounds, e.g. an antidiabetic or other pharmacologically active material, including compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the patophysiological 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 reference 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
Glucaaon 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.
Glucaaon Binding Assay (1) Binding of compounds to the glucagon receptor was determined in a competition binding assay using the cloned human glucagon receptor.
In the screening setup, antagonism was determined as the ability of the compounds to inhibit the amount of cAMP formed in the presence of 5 nM glucagon.
For full characterization, antagonism was determined in a functional assay, measured as the ability of the compounds to right-shift the glucagon dose-response curve. Using at least 3 different antagonist concentrations, the K, was calculated from a Schild plot.
Receptor binding was assayed using cloned human receptor (Lok et al, Gene 140, 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 passages. The Kd was shown to be 0.1 nM.
Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM NaCI, 1 mM dithiothreitol, 5 mg/I leupeptin (Sigma), 5 mg/I pepstatin (Sigma), 100 mg/I bacitracin (Sigma) and 15 mg/I recombinant aprotinin (Novo Nordisk)), homogenization by two bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation upon a layer of 41 w/v% sucrose at 95.000 g for 75 min. The white band located between the two layers was 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 0 C until required.
Glucagon was iodinated according to the chloramine T method (Hunter and Greenwood, Nature 194, 495 (1962)) and purified using anion exchange chromatography (Jergensen et al, Hormone and Metab. Res. 4, 223-224 (1972). The specific activity was 460 pCi/g on day of iodination. Tracer was stored at -18 0 C in aliquots and were used immediately after thawing.
Binding assays were carried out in triplicate in filter microtiter plates (MADV N65, Millipore).
The buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1% human serum albumin (Sigma, grade 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) was diluted in buffer and 15 pl was added to each well. 0.5 jg freshly thawed plasma membrane protein diluted in buffer was then added in 15 p. to each well. Plates were incubated at 0 C for 2 hours. Non specific binding was determined with 10 6 M glucagon. Bound and unbound tracer were then separated by vacuum filtration (Millipore vacuum manifold). The plates were washed once with 150 p.l buffer/ well. The plates were air dried for a couple of hours, whereafter filters were separated from the plates using a Millipore Puncher. The filters were counted in a y counter.
Functional Assay (I) The functional assay was carried out in 96 well microtiter plates (tissue culture plates, Nunc).
The resulting buffer concentrations in the assay were 50 mM tris/HCI, 1 mM EGTA, 1.5 mM 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 p.I 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-methylxanthine (IBMX) and 0.1% HSA, pH 7.4 was added. GTP was dissolved immediately before the assay.
WO 99/01423 PCT/DK98/00287 124 0d containing 5 tg 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).
The total assay volume was 140 pl. The assay was incubated for 2 hours at 37 0 C with continuous shaking. Reaction was terminated by addition of 25 pl 0.5 N HCI. cAMP was measured by the use of a scintillation proximity kit (Amersham).
Glucaaon Binding Assay (II) 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 passages. The Kd was shown to be 0.1 nM.
Plasma membranes were prepared by growing cells to confluence, detaching them from the surface and resuspending the cells in cold buffer (10 mM tris/HCI), pH 7.4 containing 30 mM NaCI, 1 mM dithiothreitol, 5 mg/I leupeptin Sigma), 5 mg/I pepstatin (Sigma), 100 mg/I bacitracin (Sigma) and 15 mg/I recombinant aprotinin (Novo Nordisk)), homogenization by two bursts using a Polytron PT 10-35 homogenizer (Kinematica), and centrifugation. The homogenate was resuspended and centrifuged again. The final precipitate containing the plasma membranes was suspended in buffer and stored at -80 0 C until required.
Binding assays were carried out in duplicate in polypropylene tubes or microtiter plates. The buffer used in this assay was 25 mM HEPES pH 7.4 containing 0.1% bovine serum albumin (Sigma, fraction 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.
u g freshly thawed plasma membrane protein diluted in buffer was then added in aliquots to each tube or well. Tubes or plates were incubated at 37 0 C for 1 hour. Non specific binding was 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 (II) The functional assay determined the ability of the compounds to antagonize glucagonstimulated formation of cAMP in a whole-cell assay. The assay was carried out in borosilicate glass 12 x 75 tubes. The buffer concentrations in the assay were 10 mM HEPES, 1 mM EGTA, 1.4 mM MgCI 2 0.1 mM IBMX, 30 mM NaCI, 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 8 /ml) were pretreated with various concentrations of compounds for 10 min at 37 0 C, then challenged with glucagon for 20 min.
Some aliquots (500 p.L) of cells were treated with test compounds (55 uL) alone to test for 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 identified in the specification and in the synthetic schemes. The preparation of the compounds of the present invention is described in detail using the following examples, but the chemical reactions described are disclosed in terms of their general applicability to the preparation of the glucagon antagonists of the invention. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications 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 methods, all starting materials are known or readily preparable from known starting materials. All temperatures are set forth in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight when referring to yields and all parts are by volume when referring to solvents and eluents.
WO 99/01423 PCT/DK98/00287 127 General procedures for the preparation of alkvlidene hydrazides: The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme I, that is, by converting an ester of a carboxylic acid, for example, an aromatic acid to a hydrazide derivative and further reacting that product compound with a substituted aldehyde or ketone to yield a substituted alkylidene hydrazide.
SCHEME I O-Ra
NHNH
A-
NH
2
NH
2 solvent A-4 O reflux O 0 R-(CH2)-
B-(K)-D
R A-
R
4 solvent, reflux O wherein A, B, K, D, m, n and R 4 are as defined for formula I and R a is lower alkyl.
General procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH: 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 as ethyl alcohol, methyl alcohol, isopropyl or tert-butyl alcohol or tetrahydrofuran, dioxane, DMSO, ethylene glycol, ethylene glycol dimethyl ester, benzene, toluene or a mixture of the above solvents or, in the absence of a solvent where excess of hydrazine acts as a solvent.
The reactions are performed between 0°C to 130 0 C, preferably between 20 0 C to 100 0 C, most preferably 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 disappearance of the starting ester by TLC or HPLC, the solvent may be removed by concentration 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 alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Altematively, 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 aroyl hydrazide.
Preparation of aromatic acid hydrazides: The methyl or ethyl ester of the corresponding aromatic acid, such as for example a substituted benzoic acid ester, is dissolved in ethanol and hydrazine (5 eq) is added. The reaction is refluxed ovemight 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 concentrated 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: 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 nitrogen. Upon cooling the reaction vessel, the desired product crystallized. The white solid was isolated by filtration. Recrystallization from hot ethanol gave the 5-hydroxyindole-3carboxylic acid hydrazide in 85% yield.
HO
HOI NHNH2
N
H
H NMR (DMSO-d6): 4.3 2H); 6.62 (dd, 1H); 6.76 (dd, 2H); 7.13 1H); 8.70 1H); 1 H NMR (DMSO-d6): 5 4.38 2H); 6.62 (dd, 1H); 6.76 (dd, 2H); 7.13 1H); 8.70 1H); 9.57 1H); 11.21 1H); MS (FAB): m/z 192 (M+H) WO 99/01423 PCT/DK98/00287 129 Preparation of 3-chloro-4-hvdroxybenzoic acid hydrazide: To a sample of methyl 3-chloro-4-hydroxybenzoate (2 g) dissolved in ethanol (50 mL) was added hydrazine (1.8 mL). The reaction was refluxed overnight under nitrogen. Upon cooling the reaction vessel, the desired product crystallized out of solution. The white solid was isolated by filtration. Recrystallization from hot ethanol gave the 3-chloro-4-hydroxybenzoic acid hydrazide in 60% yield.
O
NHNH
2
HO'
Cl 1 H NMR (DMSO-d6): 5 4.49 (broad s, 2H), 7.05 (dd, 1H), 7.71 (dd, 1H), 7.89 1H), 9.669 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
Br 3-Bromo-4-hydroxybenzoic acid hydrazide 1 H NMR (DMSO-d6): 8 9.95 1H), 9.65 1H), 9.61 (broad s, 1H), 6.95 1H), 4.40 (broad s, 2H); MS m/z 233.1.
O
NHNH
2
HO'
WO 99/01423 WO 9901423PCT/DK98/00287 130 3-Nitro-4-hydroxybenzoic acid hydrazide 1 H NMVR (DMSO-d6): 589.28 (broad s,1 8.28 1IH), 7.52 1 6.41 1 MS mlz 198.
0 N
NHNH
2 HO
F
3-Fluoro-4-hydroxybenzoic acid hydrazide 1 HNMVR (DMSO-d6): 5 9.45 (broad s, 1 7.5 1 7.43 1 6.85 1 5.55 (broad s, 3H).
Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide, 2,3-dichloro-4hydroxybenzoic acid hydrazide and 2,5-dichloro-4-hydroxybenzoic acid hydrazide.
0 A0 B 0 OHOH r~AOMe D0N NH2 H KO 1 _H
H
2 N' C HOC HO' C1 Ic HO
C
O 00 N H D N~ D~ CK<,A N H0 HOH HO J:]CI OMe CI 1HO CI F. HO C1 Preparation of 2-chloro-4-hydroxybenzoic acid hydrazide: Step A: 4-amino-2-chlorobenzoic acid (10 g, 58 mmol) was dissolved in H 2 S0 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 dropwise such that the internal temperature remained at 5 0 C. Urea was added to the mixture 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 OC until evolution of gas stopped. After cooling, the mixture was extracted with ethyl ether The combined organic fractions were extracted with 3N NaOH The combined aqueous layer was acidified with conc. HCI and the product was extracted with ethyl ether The organic fractions 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 to afford 2-chloro-4hydroxybenzoic acid.
'H NMR (DMSO-D6): 8 6.97 (dd, 1H), 7.05 1H), 7.95 1H), 10.90 (brd s, 1H).
Step B: To a solution 2-chloro-4-hydroxybenzoic acid in anhydrous methanol was added thionyl chloride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over 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 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 residue using ethyl acetate/hexane (1/9 to 3/7) afforded methyl 2,5-dichloro-4hydroxybenzoate (1.4 g, 60%) as well as an additional batch of methyl 2,3-dichloro-4hydroxybenzoate isomer (total of 8.4 g, Methyl 2,3-dichloro-4-hydroxybenzoate: 'H NMR (DMSO-D6) 5 3.81 3H), 7.02 1H), 7.70 (d 1H), 11.52 1H); MS (APCI): 221,223.
Methyl 2,5-dichloro-4-hydroxybenzoate: WO 99/01423 WO 9901423PCT/DK98/00287 132 'H NMVR (CDCI 3 583.90 3H), 6.00 1 7.14 1 7.27 1 7.96 1 MS (APOI): 221.9.
Step 0: The title compound was prepared according to the general procedure for the synthesis of precursor hydrazides A-(C0)-NH
NH
2 'H NMR (DMSO-D6): 8 6.82 (dd, 1 6.90 1 7.79 1 H, 10.68 (brd s, 1 H).
Preparation of 2.3-Dichloro-4-hydroxybenzoic acid hydrazide and 2.5-dichloro-4hydroxybenzoic acid hydrazide (step D): The 2,3-dichloro-4-hydroxybenzoic acid hydrazide was prepared from the methyl 2,3dichloro-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 CH2CI2/MeOH 95/5 to 80/20), yield 2,5-dichloro..4-hydroxybenzoic acid hydrazide was prepared in a similar way starting from 2,5-dichloro-4-hydroxybenzoate.
2.3-Dichloro-4-hydroxybenzoic acid hydrazide: 'H NMR (DMSO-D6) 8 4.41 (brd s, 2H), 6.99 1 7.37 1 9.46 1 11.04 (s, 1 H).
2.5-Dichloro-4-hydroxybenzoic acid hydrazide: 'H NMR (DMSO-D6) 584.48 (brd s, 3H), 6.92 2H), 7.18 2H), 9.45 (brd s, 1IH).
Preparation of 2.3-difluoro-4-hydroxybenzoic acid hydrazide: WO 99/01423 PCT/DK98/00287 133 N 00 0
ANBNH
S
A OH B HOOMe C .N H2 HO HO HO- HO F H F F F F
F
Step A: 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 evaporation 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-4hydroxybenzoic acid (800 mg, 71%).
'H NMR (DMSO-D 6 5 6.87 1H), 7.60 1H), 11.28 1H), 12.53 (brd s, 1H).
Step B: To the 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 5.1 mmol) dissolved in anhydrous methanol (50 mL) was added thionyl chloride (0.55 mL, 7.3 mmol). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO 4 to give methyl 2,3-difluoro-4-hydroxybenzoate (540 mg, 62%).
'H NMR (CDCI 3 5 3.92 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 hydrazides A-(C=O)-NHNH 2 The product was purified via silica gel column chromatography using CH2Cl2/MeOH 95/5 to 80/20) to afford the title compound.
'H NMR (DMSO-D 6 8 4.48 2H), 6.80 1H), 7.22 1H), 9.36 1H), 10.89 1H); MS (APCI): 189.
WO 99/01423 PCT/DK98/00287 134 Preparation of 3-cyano-4-hydroxvbenzoic acid hydrazide. trifluoroacetate: W- A- OMe B N OMe OH HOj O HO O- HO HO HO N
N
I
D
0 o HO y .H HO' 0 N
N
Step A: Methyl-4-hydroxybenzoate (35.5 g, 0.233 mol) was dissolved in 200 mL of warm (65 °C) acetic acid. A solution of iodine monochloride (37.8 g, 0.233 mol) in 50 mL of acetic acid was added slowly (40 minutes) to the methyl-4-hydroxybenzoate solution, while maintaining a temperature of 65 OC and vigorous stirring. The product crystallizes from solution upon 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 obtained as white crystals (28.6 g, 44%).
'H NMR (DMSO-D 6 5 3.79 3H), 6.95 J 8.3, 1H), 7.81 (dd, J 8.3, 2.2, 1H), 8.22 (d, J 2.2, 1H); "C 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.
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 and stirred overnight. TLC indicated nearly complete reaction. The mixture was cooled and the solids removed by filtration. The solids were extracted with DMF (3 mL). The filtrate and washings were taken up in 100 mL of ethyl acetate, then washed with 3 portions of saturated sodium chloride solution. The solids and aqueous washings were combined, and shaken with a 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 (20% ethyl acetate/ hexane) to afford methyl-3-cyano-4-hydroxybenzoate, 0.93g 1 H NMR (DMSO- De): 8 3.79 3H), 7.07 J 8.7, 1H), 8.02 (dd, J 8.7, 1.9, 1H), 8.10 J 1.9, 1H).
Step C: Methyl-3-cyano-4-hydroxybenzoate (2.71g, 15.3 mmol) was dissolved in 50 mL of THF. The solution was chilled in an ice bath, and 2.0M potassium hydroxide (17 mL, 34 mmol) was added dropwise. The resulting mixture was stirred at room temperature overnight. TLC indicated complete reaction. The THF was removed by rotary evaporation. The aqueous residue 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- D 6 5 7.09 J 9.0, 1H), 8.00 (dd, J 9.0, 2.3, 1H), 8.07 J 2.3, 1H) 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 and chilled in an ice-bath. Diisopropylethylamine (12 mL, 69 mmol), tbutyl carbazate (1.76g, 13.3 mmol), and PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, 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 the reaction was worked up as follows. The solution was reduced by rotary evaporation. The remaining DMF solution was diluted with 100 mL of ethyl acetate, and washed with several portions of 0.1 M HCI (until the wash remained acidic to litmus paper). The ethyl acetate layer was further washed with 3 portions of brine, dried over magnesium sulfate, filtered, and WO 99/01423 PCT/DK98/00287 136 reduced to an oil in vacuo. The oil was purified by chromatography on silica gel (6:4 hexane:ethyl acetate) to afford tert-butyloxycarbonyl 3 -cyano-4-hydroxy)benzoic acid hydrazide as a white solid (1.8g, 56%).
1 H NMR (DMSO- De): 8 1.42 9H), 7.09 J 8.7, 1H), 7.98 1H), 8.11 (brs, 1H), 8.92 1H), 10.15 1H), 11.73 (brs, 1H); MS (APCI, neg): 276; IR: 2232 cm- 1
CN.
Step E: The Boc-hydrazide (1.8g, 6.5 mmol) was suspended in 50 mL of chloroform and cooled in an ice-bath. Trifluoroacetic acid was added with stirring, and the resulting solution stood for 4 hours at 0 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 white solid (0.24 g, 13%).
'H NMR (DMSO- D6): 8 7.16 J 9.0, 1H), 8.00 (dd, J 1.5, 9.0, 1H), 8.14 J 1H), 10.47 (brs, 5H); MS (APCI, neg): 176.
Preparation of 4-hydroxynaphthoic acid hydrazide: O H A OH O OMe o H A B NH2 OH OH OH
OH
Step A: 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 OC 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 OC for 16 hours. TLC analysis indicated incomplete conversion. An additional portion of silver oxide was prepared as above and added to the reaction mixture. After heating the mixture for an additional 6 hours, the mixture was cooled and acidified with 1N HCI. The aqueous layer was extracted with ethyl acetate (3x) and upon concentration 4hydroxynaphthoic acid precipitated (3.7 g, 60%) out of solution.
1H NMR (DMSO-D6): 5 6.69 1H), 7.28 1H), 7.39 1H), 7.93 1H), 8.03 1H), 8.82 1H), 10.82 1H), 12.29 1H).
Step B: To a solution 4-hydroxynaphthoic acid in anhydrous methanol at 0 OC was added thionyl chloride (1.5 eq). After stirring the solution at room temperature for 16 hours, the solvent was evaporated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate, water, brine, and dried over MgSO 4 to give methyl 4hydroxynaphthoate.
'H NMR (DMSO-D6): 5 3.87 3H), 6.92 1H), 7.53 1H), 7.65 1H), 8.13 1H), 8.26 1H), 8.93 1H), 11.16 1H).
Step C: The title compound was prepared from methyl 4-hydroxynaphthoate according to the procedure for the synthesis of precursor hydrazides A-(C=O)-NHNH 2 'H NMR (DMSO-D6): 5 6.60 1H), 7.28 3H), 7.95 1H), 8.07 1H), 9.25 (brd s, 1 H).
Moreover, by use of the above methodology, the following hydrazides useful as intermediates in preparing the compounds of the invention may be prepared: WO 99/01423 WO 9901423PCT/DK98/00287
NHNH
2
OCH
3 0 F NHNH2
HO
OCH
3 0
NHNH
2 HO f
OCF
3
CF
3 0
NHNH
2
HOI
CI
OCH
3 0 N. NHNH 2
HO
CI
OCH
3 0
NHNH
2
HO
OCH
3 Br 0 N. NHNH 2
HO--
F 0 N. NHNH 2 HO4
CI
NHNH 2
NHNH
2
NHNH
2
HO'
HO'
Cil
HO'
NHNH
2
NHNH
2 0 N.
NHNH
2
HO"
OCH
2
CF
3 0 Me
NHNH
H.
WO 99/01423 PCT/DK98/00287 F O N NHNH 2 HO F 0 j T NHNH 2 Cl
OH
0
NHNH
2
HO
OCH
3
O
INHNH
2 HO
OCH
3 CIl
NHNH
2
OH
NHNH
2
NHNH
2
NHNH
2 0
F
NHNH
2
HO
Cl 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 moiety as defined above in a reaction generally known as Williamson ether synthesis 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 SCHEME II 3a 3b 4a R3 R R4a R 4 b RiO Lx-(CH 2
(CH
2
(M)(CH
2
(CH
2
D
Ri 5 OH Base, solvent
H
R 1 4 0 R3a R 3 b R4 R 4 b 0
-(CH
2 )b (CH 2 wherein Lx is a leaving group such as -Cl, -Br, -OSO 2
CH
3
-OSO
2 p-tolyl or -OSO 2
CF
3 and R3a, Rb, R 4a
R
4 b, a, b, c, d, f, p, q, D, M, R 14 and R 1 5 are as defined for formula I.
According to Scheme II an ether-substituted aryl-aldehyde can be prepared by stirring hydroxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as acetone, 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 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 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 hydroxide. The reaction can be performed at 0°C to 150 0 C, preferably at 20 0 C to 100 0 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 WO 9901423PCT/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-tetrahydropyranyimethoxy)-1 -naphthaidehd: A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 mmol), 2-bromomethyl tetrahydropyran (1 g, 5.8 mmol) and powdered K 2 C0 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 separated 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 0- 0 6 1 H NMVR (DMSO-d 6 5 1.48 (in, 4H), 1.74 1 1.84 (in, 1 3.44 (in, 1 3.78 (in, 1 H), 3.92 1 4.23 (mn, 2H), 7.17 1IH), 7.64 1IH), 7.74 1 8.11 1 8.27 1IH), 9.22 1 10. 17 1H).
Preparation of 4-[(3.5-bis-trifluoromethyl)benzloy]-1-naphthaldehyde: A mixture of 4-hydroxynaphthaldehyde (1 g, 5.8 inmol), (1.8 g, 5.8 inmol), and powdered K 2 C0 3 (1.2 g, 8.7 inmol) was stirred in acetone (40 mL) overnight. 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 dried.
WO 99/01423 WO 9901423PCT/DK98/00287 142 H 0 0 CF 3 CF 3 1 H NMVR (DMSO-d 6 5 5.58 2H), 7.07 1 7.22 1 7.63 1 7.69 1IH), 7.79 1 7.86 1IH), 7.99 1IH), 8.14 1 8.30 3H), 8.94 1 8.97 1 11.0 (broad s, 1 11.69 1H); MS (ESI) m/z 675.2 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-2chloroethane (7.4 g, 50 mmoles). The mixture was heated at 60*C overnight. The solution was diluted with ethyl acetate (500 mL), extracted with water and brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated to obtain 12.1 g product (52 yield).
0 H MS 403, 405, 407. 'H NMR (CDCI 3 8 10.2 1 9.3 1 H) 8.35 1 7.85 (d, 1 7.65 (in, 1 7.5 (mn, 1IH), 7.1 1 4.35 2H), 4.15 2H).
The products were used as such in further transformations.
WO 99/01423 WO 9901423PCT/DK98/00287 143 By application of the above methodology the following substituted aldehyde intermediates were synthesized: OMe, 0 0 4-carbomethoxymethoxy-1 -naphthaldehyde 4-benzyloxy- 1 -naphthaldehyde 4-(4-chlorobenzyloxy)-1 -naphthaldehyde 0~ /C H 2
H-
4-allyloxy-1 -naphthaldehyde
CH
0
H-
4-propargyloxy-1 -naphthaldehyde 4-(4-trifluoromethoxybenzyloxy)-1 naphthaldehyde 4-(4-trifluoromethylbenzyloxy)-1 naphthaldehyde 2-[(4-carboxaldehydo)-1 naphthyloxy]acetamide m.p. 174-1750C WO 99/01423 WO 9901423PCT/DK98/00287 4-(3-trifluoromethylbenzyloxy)-1 naphthaldehyde OMe 0
OCF
3 H OMe 4-(4-trifluoromethoxybenzyloxy)-3,5dimethoxybenzaldehyde 4-(2-(4-trifluoromethoxyphenyl)2oxoethoxy)-1 -naphthaldehyde m.p. 112-114 0
C
Nicotinic acid 4-formyl-1 -naphthyl ester m.p. 142-143 0
C
OMe 4-(4-isopropylbenzyloxy)-3,5dimethoxybenzaldehyde (oil) 4-(1 ,3-dioxo-1 ,3-dihydroisoindol-2ylmethoxy)- 1 -nap hthatdehyde m.p. 191-192 0
C
0 HI0 0 4-(tetrahydro-2-pyranylmethoxy)-1 naphthaldehyde 4-(4-isopropybenzyoxy)-1 -naphthaldehyde WO 99/01423 PCT/DK98/00287 145
F
0 H
F
4-(3,5-difluorobenzyloxy)-1-naphthaldehyde m.p. 100-101°C Preparation of 3-Allyl-4-hydroxy-5-methoxy-benzaldehyde: HC-
\CH
2 OH 0
OH
OCH,
OCH
3 OCH 3 H H H To a solution of vanillin (1.0 g, 6.57 mmol) in acetone (30 mL) was added potassium carbonate (4.50 g, 32.8 mmol) and allyl bromide (0.62 mL, 7.3 mmol). The mixture was heated under reflux for 6 h. TLC showed appearance of a new spot. Potassium salts were removed by filtration and the filtrate was concentrated to a syrup. A small sample was purified using prep TLC using hexane/ethyl acetate 7:3 as developing solvent. 1 H NMR (CDCl 3 8 3.94 (s, 3H), 4.67 4.83 2H), 5.30 5.55 2H), 6.01 6.21 1H), 6.98 J 9 Hz, 1H), 7.40 7.56 2H), 9.85 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 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 (CDC3) 6 3.46 J 6 Hz, 2 3.96 3H), 5.02 5.22 2H), 5.94- 6.11 1H), 6.30 1H), 7.45 2H), 9.80 1 MS (APCI): 193.3.
WO 99/01423 WO 9901423PCT/DK98/00287 146 Preparation of 3-Aily-4-(4-isopropylbenzyloxy)-5-methoxybenzaldehyde: The crude 3-allyI-4-hydroxy-5-methoxy-benzaldehyde was taken up in acetone and treated with 4-isopropylbenzyl chloride in the presence of potassium carbonate to give the desired product.
1 H NMVR (CDCI,) 5 1.26 J 7 Hz, 6 2.92 (in, 1 3.38 J 7 Hz, 2H), 3.95 (s, 3H), 4.98 -5.12 (in, 4H), 5.93 5.75 (mn, 1 7.20 -7.43 (mn, 6H), 9.87 1 H).
WO 99/01423 PCT/DK98/00287 147 General procedure for the synthesis of compounds of formulae IXa and IXb- D INH 2 c 0
H
step A Cl
D
0
TH
OHCB
step B
H
O BO NND step C K 2
CO,
H
a
NINH,
t-e
H
HOstp step D
H
HO RO
R"
Formula IXa N NNH, HO- v R step D step D R H H HO R Formula IXb In the above formulae B, D, R 8 and R 9 have the same meanings as defined for formula I.
Step A: To a solution of aniline (or an aniline derivative) (1 eq.) in THF was added dropwise chloroacetyl chloride (1.2 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 concentrated to give pure product.
Step B: To a solution of chloroacetanilide (or a derivative thereof) (1.2 eq.) and 2-methoxy-4hydroxy benzaldehyde (or another aromatic aldehyde substituted with a hydroxy group) (1 eq.) in DMSO was added potassium carbonate (1.5 After stirring overnight at room temperature, 100 ml water was added. The mixture was extracted with ethyl acetate, the organic 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 WO 9901423PCT/DK98/00287 148 The following two aldehydes were prepared as examples of compounds that can be prepared using this methodology: N-(4-Chlorophenyl)-2-(4-formyl-3-methoxyphenoxy~acetamide: 'H NMR (CDCI, 5 4.28 3H), 5.01 2H), 6.90 J 2.2 Hz, 1 6.97 dd, J 8.6, 2.1 Hz, 1 7.67 d, J 8.9Hz 2H), 7.89 J 8.8 Hz, 2H), 8.20 J 8.6Hz, 1 8.51 (s, 1 10.66 1 MS APCI 319.9.
N-(4-isopropylphenyfl-2-(4-formyl-3-methoxyohenoxv)acetamide: H NMR DMSO-D6): 8 2.07 J 6.9 Hz 2.70 (in, J 6.9 Hz, 1 3.77 3H), 4.68 2H), 6.56 (dd, J 8.7, 2.1 Hz, 1 6.66 J 2.1 Hz, 1 7.06 J 8.5 Hz, 2H), 7.39 J 8.50 Hz, 2H), 7.55 J 8.7 Hz, 1 9.93 1 10.05 1 MS (APCI 328.
This type of aldehydes can be coupled to hydrazides using the methodology as described in step D to give a compound of formula V~a. Alternatively these compounds can undergo rearrangement by treatment with base as described below (step followed by coupling to a hydrazide (step D) to give a compound of formula lXb.
WO 99/01423 PCT/DK98/00287 149 Step C: The mixture of aldehyde (1 eq.) and potassium carbonate (1.5 eq.) in acetonitrile was refluxed. The reaction was monitored by TLC (hexane ethyl acetate When TLC showed almost complete conversion (about 48 100 ml water was added. The mixture was extracted with ethyl acetate, the organic extracts were dried over MgSO 4 and concentrated to give the desired product which can be further purified by column chromatography, or used directly for the next step.
The following two aldehydes were prepared as examples of compounds that can be prepared using this methodology: 4-(4-Chlorophenylamino)-2-methoxybenzaldehyde: Prepared from N-(4-chlorophenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide using the procedure described in step C above.
WO 99/01423 PCT/DK98/00287 150
H
MeO NC 0
H
'H NMR (CDCI 3 6 3.84 3 6.14 1H), 6.45 J 2.0 Hz, 1H), 6.54 dd, J 8.4, 1.8Hz, 1H), 7.14 J 8.7Hz, 2H), 7.33 J 8.7 Hz, 2H), 7.74 J 8.5Hz, 1H), 10.22 1H); MS (APCI): 261.9.
4-(4-lsopropylphenylamino)-2-methoxybenzaldehyde: Prepared from N-(4-isopropylphenyl)-2-(4-formyl-3-methoxyphenoxy)acetamide using the procedure described in step C above.
H
MeO N H
CH
3 'H NMR (CDCI) 5 1.26 J 6.9Hz, 6H), 2.88 J 6.9Hz, 1H), 3.84 3H), 6.50 J 1.9Hz, 1H), 6.55 (dd, J 8.6, 1.8Hz, 1H), 6.96 1H), 7.15 2H, J 8.5Hz, 2H), 7.22 J 8.5Hz, 2H), 7.69 J 8.5Hz, 1H), 10.18 1H); MS (APCI): 269.
Step D: The resulting carbonyl compounds are treated with the corresponding 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, 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 0°C to 140°C, preferably between 10°C to 80*C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction sol- WO 99/01423 WO 9901423PCT/DK98/00287 151 vents. 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 dichloromethane/methanol or chloroform/ethyl acetate to give a compound of formula lXb.
The following compounds of formulae IVa or lXb according to the invention were prepared as examples of compounds that can be prepared using this methodology: EXAMPLE 1: a-Chloro-4-hydroxybenzoic acid 4 4 -chlorophenylamino)-2-methoxybenzylidenelhydrp-zide 'H NMR DMSO-D6 5 3.81 3H), 6.72-6.67 (in, 2H), 7.04 J 8.5Hz, 1IH), 7.17 d, J 8.7Hz, 2H) 7.31 J 8.7Hz, 2H), 7.77- 7.70 (in, 2H), 7.96 J 1.6Hz, 1 8.65 (s, 1 8.70 1 10.87 1 11 .51 1 MS (APOI 430.
EXAMPLE 2: 3-Chloro-4-hydroxybenzoic acid f 4 4 -isoprOpylphenylamino)-2-methoxybenzylidenelhydrazid 1 H NMR (DMSO-D6): 8 1.18 (2s, 6H), 2.86 (in, 1 3.79 3H), 6.65 (mn, 2H), 7.03 1 H), 7.11 2H), 7.19 2H), 7.70 1 7.75 (dd, 1IH), 7.97 1 8.49 1IH), 8.64 (s, 1 10.88 1 11.48 1 MS (FAB): 438.16.
WO 99/01423 WO 9901423PCT/DK98/00287 152 EXAMPLE 3: 2-4r3Clr--yrxbnolhdaznmtyl3mtov~eov--4 chlorophenvlhacetamide 1 H NMR (DMSO-D6): 5 3.66 3H), 4.57 2H), 6.48 1 6.55 1 6.83 1IH), 7.20 2H), 7.48 2H), 7.56 (dd, 1 7.58 1 7.77 1IH), 8.48 1 10.05 (s, 1H), 10.72 (brd s, 1H), 11.40 1H); MS (APCI): 487.8.
EXAMPLE 4: 2 3 -Choro-4-hydroyenzoyl)hydrazonomethI1-3-methOXDhenox,1.N-(4isoprolvlhenvflacetamide 1 H NMR (DMSO-D6): 8 1.17 (2 s, 6H), 2.85 (in, 1 3.87 3H), 4.76 2H), 6.70 1 H), 6.76 1 7.05 1IH), 7.20 2H), 7.55 2H), 7.77 (dd, 1 7.80 1 7.98 (s, 1 8.70 1 10.03 1 10.92 1 11.62 1 MS (FAB): 496.16.
WO 99/01423 PCT/DK98/00287 153 EXAMPLE 2-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-3-methoxvphenoxy}-N-(3.5dichlorophenyl)acetamide o N cI
H
HO"
CI
1H NMR (DMSO-D6): 5 4.06 3H), 4.94 2H), 6.8 1H), 6.88 1H), 7.20 1H), 7.45 1H), 7.90 3H), 8.10 1H), 8.82 1H), 10.62 1H), 11.07 (brd s, 1H), 11.75 1H); MS (APCI): 524.8.
General procedure for the synthesis of alkylidene hydrazides of formula II according to the invention: The acylhydrazides are treated with the corresponding carbonyl compounds, such as aldehydes 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 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 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 recrystallized 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 dichloromethane/methanol or chloroform/ethyl acetate. The product is isolated by concentration in vacuo of the appropriate fractions. Specific examples illustrating the preparation of compounds according to the invention are provided below.
WO 99/01423 PCT/DK98/00287 154 EXAMPLE 6: 3-Chloro-4-hydroxybenzoic acid (4-hydroxy- -naphthylmethylene)hydrazide To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 ml) 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 organic volume was concentrated in vacuo to give the crude product. The product was purified by silica gel column chromatography using CH 2 Cl/MeOH as the mobile phase.
'H NMR (DMSO-d6): 5 6.89 2H), 7.02 1H), 7.47 1H), 7.58 1H), 7.66 1H), 7.73 1H), 7.93 1H), 8.17 1H), 8.84 1H), 8.88 1H), 10.73 1H), 10.88 1H), 11.54 1H); MS (ESI): m/z 341.04 EXAMPLE 7: 3-chloro-4-hvdroxvbenzoic acid [4-(3.5-bis-trifluoromethvlbenzvloxv-1 -naDhthvlmethvlenelhydrazide 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 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 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 chromatography using CH 2 Cl 2 /MeOH as the mobile phase.
'H NMR (DMSO-d 6 8 3.77 6H), 4.91 2H), 6.95 2H), 6.99 1H), 7.30 2H), 7.52 2H), 7.68 1H), 7.89 1H), 8.29 1H), 10.90 (broad s, 1H), 11.69 1H); MS (ESI): m/z 525.37 EXAMPLE 8: 3-chloro-4-hvdroxybenzoic acid [4-(2-chloroethoxy)-1 -naphthylmethylenelhydrazide o N O-'-CI
HO
CI
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 dimethylsulfoxide (DMSO)(15 mL) was stirred at room temperature overnight. Ethyl acetate (100 mL) was added. The solution was extracted with water and brine which induced precipitation. The product (3.1 g, 77% yield) was obtained by suction filtration. The product was purified by recrystallization from ethyl acetate.
MS 235. 'H NMR (DMSO-de): 8 11.5 1H), 10.7 1H), 8.7 (bs, 2H), 8.1 1H), 7.8 1H), 7.6-7.3 2H), 7.0 2H), 4.3 2H), 3.7 2H).
By application of the above methodology the following compounds of the invention are synthesized employing the following general procedure: To a solution of 1 mmol of an arylcarboxylic acid hydrazide in 2 ml of anhydrous DMSO was added 1 mmol of the carbonyl compound (an aldehyde or ketone), followed by a catalytic amount of glacial acetic acid. The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO 4 Upon partial concentration of the solvent in vacuo, the alkylene WO 99/01423 WO 9901423PCT/DK98/00287 156 hydrazides usually precipitated. The alkylene hydrazides were further purified by recrystallization from hot ethanol or ethyl acetate, or chromatographed using CH 2
CI
2 IMeOH as an eluent.
EXAMPLE 9: 4-Hydroxy-3-methoxybenzoic acid (2-naphthylmethylene)hydrazide 'H NMR (DMSO-d 6 8 3.66 3 6.67 J 8.2 Hz, 1 7.32 7.47 (in, 5 7.74 J 7.2 Hz, 1 7.79 J 8.2 Hz, 2 8.60 J 8.2 Hz, 1 9.11 1 11.80 1
H).
APCI m/z: 321 EXAMPLE 4-Hydroxy-3-methoxybenzoic acid (4-methoy- 1 -naphthylmethylene)hyd razide 1 H NMR (CDC13): 864.80 3 3.86 3 6.00 1 6.59 1 6.83 1 H), 7.39 (in, 3 7.52 1 7.73 1 8.18 1 8.58 1 8.88 1 9.95 (S,1 MS (APOI): 351.
WO 99/01423 PTD9/08 PCT/DK98/00287 157 EXAMPLE 11: 4-HydroLxy-3-methoxybenzoic acid (4-tert-butylbenzlidene'hydrazide
CH
3 1 H NMR (CDCI3): 5 1.30 9 3.91 3 6.16 1 6.88 1 7.23 7.78 (in, 6 8.28 1 9.58 1 MS (APCI): 327.
EXAMPLE 12: 4-Hydroxy-3-methoxybenzoic acid (4-isopropylbenzylidene)hvdrazide 1 H NMR (CDCI3) 5 1.29 6 2.94 1 3.98 3 6.13 1 6.97 1 H), 7.20 7.80 (in, 6 8.29 1 9.38 1 MS (APCI): 313 WO 99/01423 WO 99/1 423PCT/DK98/00287 158 EXAMPLE 13: 4-Hydroxy-3-methoxybenzoic acid (4-trifluoromethoxybenzylidene)hyd razide
FFF
0 N HO
N
1 H NMR (DMSO-d6): 584.01 3 7.04 J 8.1 Hz, 1 7.60 7.65 (in, 4 8.01 J 8.4 Hz, 2 8.63 1 9.92 1 11.89 1 MS (APOI): 355, 313, 222, 205.
EXAMPLE 14: 4-Hyd roxy-3-methoxybenzoic acid (1 H-indol-3-ylmethylene)hydrazide 0 -j
HON
H
3 C, 0 1 H NMR (DMSO-d6) 8 3.79 3 6.80 J 8.2 Hz, 1 7.11 (in, 2 7.38 (in, 3 H), 7.73 J 2.0 Hz, 1 8.53 J 7.5 Hz, 1 8.53 1 9.58 1 11.23 1 11.49 1 MS (APCI): 310.
WO 99/01423 WO 9901423PCT/DK98/00287 159 EXAMPLE 4-Hydroxy-3-methoxybenzoic acid (4-dimethylamino-1 -naphthylmethyleneJhvdrazide 1 H NMR (DMSO-d6): 8 3.05 6 4.03 3 7.06 J 8.1 Hz, 1 7.33 J Hz, 1 7.63 7.80 (in, 4 7.97 J 8.0 Hz, 1 8.38 J 7.9 Hz, 1 9.10 J -8.4 Hz, 1 9.15 1 9.90 1 11.73 1 MS (APCI): 364.
EXAMPLE 16: 4-Hydroxy-3-methoxybenzoic acid (4-phenylbenzylidene)hydrazide 1 H NMR (DMSO-d6): 8 4.02 3 7.04 J 8.2 Hz, 1 7.63 7.68 (in, 5 7.88 7.96 (in, 6 8.64 1 9.91 1 11.83 1 MS (APCI): 347.
WO 99/01423 WO 9901423PCT/DK98/00287 160 EXAMPLE 17: 4-Hyd roxybenzoic acid (1 -naphthytmethytene~hydrazide 1 HNMR (DMSO-d6): 8 6.82 J 8.2 Hz, 2 7.48 7.68 (in, 3 7.72 7.88 (in, 3 H), 7.95 J 8.2 Hz, 2 8.80 1 9.04 1 10.14 1 MS (APCI): 291.
EXAMPLE 18: 4-Hydroxybenzoic acid (4-methoxy-1 -naphthylmethylene)hvdrazide C H '0 1 H NMR (DMSO-d6): 8 3.97 3 6.82 J 8.6 Hz, 2 7.04 J 8.2 Hz, 1 7.52 (dd, J 7.3, 7.7 Hz, 1 7.62 (dd, J 6.8, 7.7 Hz, 1 7.77 J 8.5 Hz, 3 8.19 J 8.2 Hz, 1 8.89 (in, 2 10.06 1 MS (APCI): 321.
WO 99/01423 WO 9901423PCT/DK98/00287 161 EXAMPLE 19: 3 .4-Dihydroxybenzoic acid (1 -naphthylmethylene)hvd razide 1 H NMR (DMSO-d6): 8 6.64 J 8.6 Hz, 1 7.13 J 8.2 Hz, 1 7.19 J Hz, 1 7.36 7.42 (in, 3 7.68 J 8.2 Hz, 1 7.80 J 8.2 Hz, 2 8.65 J 8.2 Hz, 1 8.88 1 9.07 1 9.46 1H), 11.45 1 MS (APCI): 307.
EXAMPLE 4-Hydroxy-3-methoxybenzoic acid (1 -naphthylmethlene)hydrpzide 1 H NMR (DMSO-d6) 8 3.94 3H), 6.74 1 7.37-7.52 (in, 6H), 7.77 1 7.89 (d, 2H), 8.67 1 9.93 1IH), 10.90 1 MS (APCI): 321.
WO 99/01423 WO 9901423PCT/DK98/00287 162 EXAMPLE 21: 4-Hydroxy-3-methoxybe-nzoic acid [3-(3-trifluoromethylphenoxy)benzygidenel hvd razide 1 H NMR (DMSO-d6) 583.83 3H), 6.85 1 7.16 (dd, 1 7.36 (in, 5H), 7.44 (in, 3H), 7.61 1 8.43 1 1.75 1IH), 11.69 1 MS (APCI): 431.
EXAMPLE 22: 4-Hydr-oxy-3-methoxybenz-oic acid (4-g-uinolinylmethylenemhvdrpzide
HO-
H
3
C,
1 H NMR (DMSO-d6): 8 3.58 3 6.52 J 8.0 Hz, 1 7.28 J 7.8 Hz, 2 7.47 (dd, J T= 8.1 Hz, 1 7.59 (in, 2 7.86 J 8.4 Hz, 1 8.50 J =8.4 Hz, 1 H), 8.73 J 4.5 Hz, 1 8.94 1 MS (APCI): 322.
WO 99/01423 WO 9901423PCT/DK98/00287 163 EXAMPLE 23: 4-Hydroxybenzoic acid 1.1 .2.2-tetrafluoroethoxy)benzylidenelhydrazide F: F N' N HOe
H
1 1 H NMR (DMSO-d6) 8 6.49-6.78 (in, 3H), 7.10 1 7.32 1IH), 7.41 (in, 2H), 7.57 (d, 2H), 8.23 1 10.01 1 11 .59 1 MS (APOI): 357.
EXAMPLE 24: 4-Hyd roxyWbenzoic acid [3-(4-tert-butylp~henyl)but-2-enylidenelhydrazide 1 H NMR (DMSO-d6) 8 1.15 9H), 1.99 3H), 6.64 1 6.17 2H), 7.29 4H), 7.64 2H), 8.06 1H), 9.98 1H), 11.36 1H). MS (APOI): 337.
WO 99/01423 WO 9901423PCT/DK98/00287 164 EXAMPLE 4-Hvdroxv-3-methoxvbenzoic acid (4-hydroxy-1 -nalhthylmethylene'hvdrazide ~H NMR (DMSO-d6): 8 3.90 3 6.89 1 6.99 1 7.19 1 7.45 -7.80 (in, 5 8.22 1 8.90 2 9.62 1 10.68 1 MS (APCI): 337.
EXAMPLE 26: 4-Hydroxybenzoic acid (benzylidene)hydrazide 100 1 H NMR (DMSO-d6): 8 6.86 2 7.41 7.52 (in, 3 7.72 (in, 2 7.82 2 8.41 1 10.14 I MS (APOI): 241.
WO 99/01423 WO 9901423PCTIIDK98/00287 165 EXAMPLE 27: 3-Amino-4-hyd roxybenzoic acid (1 -naphthylmethylene)hydrazide 1 H NMR (DMSO-d6): 854.71 (bs, 2 6.68 J 8.1 Hz, 1 7.01 (dd, J 2.0, 8.2 Hz, 1 7.17 J 2.0 Hz, 1 7.51 7.62 (in, 3 7.84 J 7.2 Hz, 1 7.94 J Hz, 2 8.75 J 7.6 Hz, 1 9.01 1 9.70 1 11.54 1 MS (APCI): 306.
EXAMPLE 28: 3-Amino-4-hydroxybenzoic acid (4-hydroxy-1 -naphthyimethyjene~hvdrazide 1HNMR (DMSO-d6): 6 4.68 (bs, 2 6.67 J 8.2 Hz, 1 6.91 J 7.3 Hz, 1 H), 7.03 J 8.2 Hz, 1 7.15 1 7.43 7.65 (in, 3 8.16 J 8.2 Hz, 1 8.83 (in, 2 10.71 1 11.34 1 MS (APCI): 322.
WO 99/01423 WO 9901423PCT/DK98/00287 166 EXAMPLE 29: 4-Hydroxybenzoic acid 3 3 -trifluoromethylbenzyloxy)benzylidenelhydrpzide 'H NMR (DMSO-d6): 5 5.28 2 6.88 2 7.12 (in, 1 7.24 7.50 (in, 3 7.55 -7.92 (in, 6 8.41 1 10.16 1 10.86 1 MS (APCI): 415.
EXAMPLE a-Chloro-4-hydroxybenzoic acid (1 -naphthylinethylenemiyd razide 0
N
HO"'N.
CI
1 H NMR (DMSO-d6): 5 7.03 J 8.2 Hz, 1 7.52 7.62 (in, 3 7.74 J 8.2 Hz, 1 7.86 J =7.0 Hz, 1 7.96 (in, 3 8.79 J 8.2 Hz, 1 9.01 1 10.94 (s, 1 11.76 1 MS (APCI): 325.
WO 99/01423 WO 9901423PCT/DK98/00287 167 EXAMPLE 31: 3-Chloro-4-hyd roxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydrazide 1 H NMR (DMSO-d6): 8 6.90 J 8.0 Hz, 1 7.02 J 8.5 Hz, 1 7.50 (dd, J J= 7.8 Hz, 1 7.58 (dd, J 7.1, 8.0 Hz, 1 7.65 J 8.0 Hz, 1 7.72 J 8.5 Hz, 1 7.93 1 8.17 J 8.2 Hz, 1 8.83 1 8.88 J =8.5 Hz, 1 10.73 1 10.88 1 11.54 1 MS (APOI): 343, 341.
EXAMPLE 32: 4-Hydroxybenzoic acid (4-hydroxy- 1-naphthylmethylene~hvdrazide 1 H NMR (DMSO-d6): 8 6.88 2 6.98 1 7.55 (dd, 1 7.64 (dd, 1 7.71 1 7.82 2 8.22 1 8.94 (in, 2 10. 11 1 10.77 1 MS (APCI): 307.
WO 99/01423 WO 9901423PC2T/DK98/00287 168 EXAMPLE 33: 4-Hydroxybenzoic acid [4-(3-trifluoromethylphenoxy)benzylidenelhydrazide
FF
0 F N 0 HON N-.
1 H NMR (DMSO-d6): 5 6.81 2 6.98 1 7.13 (dd, 1 7.30 -7.48 (i,3 7.48 -7.60 (in, 3 7.68 (dd, 1 7.81 2 8.41 1 MS (APCI): 401.
EXAMPLE 34: 4-Hyd roxybenzoic acid (5-phenyl-3-pyrazolylmethylene)hydrazide 0 HNq-N 1 H NMR (DMSO-d6): 8 6.81 2 7.40 7.62 (in, 5 7.78 2 8.09 1 8.50 1 MS (APOI): 307.
EXAMPLE 2 .4-Dihydroxybenzoic acid (4-hydroxy-1 -naphthylmethylene)hydr-azide
NOH
0
NN
HOJ: OH 1 H NMR (DMSO-d6): 6.35 1 6.39 1 6.99 1 7.51 (dd, 1 7.65 (dd, 1 7.73 1 7.82 1 8.26 1 8.88 1 8.98 1 10.0 -11.0 (in, 4 MS (APCI): 323.
WO 99/01423 WO 9901423PCT/DK98/00287 169 EXAMPLE 36: 4-Hyd roxv-3-nitrobenzoic acid (1 -naphthvlmethylene)hvd razide 1 H NMR (DMSO-d6): 586.15 J 9.3 Hz, 1 7.37 7.48 (in, 4 6.70 J 7.1 Hz, 1 7.78 7.82 (in, 2 8.29 1 8.43 J 8.5 Hz, 1 8.85 1 H).
EXAMPLE 37: 4-Hyd roxy-3-nitrobenzoic acid (4-hyd roxy- 1 -naphthylmethylene)hydrazide 1 HNMR (DMSO-d6): 8 6.24 J 9.3 Hz, 1 6.83 J 8.0 Hz, 1 7.37 -7.52 (in, 3 7.57 J 8.0 Hz, 1 8.10 J 8.0 Hz, 1 8.34 1 8.76 1 8.79 1 10.57 1 11.17 (in, 1 H).
WO 99/01423 WO 9901423PCT/DK98/00287 170 EXAMPLE 38: 3.4-Dihydroxybenzoic acid (4-hydroxy-l1-naphthyl methylene)hyd razide 0
NOH
I H
HO
1 H NMR (DMSO-d6): 586.86 1 6.98 1 7.32 1 7.42 1 7.56 (dd, 1 7.63 (dd, 1 7.71 1 8.24 1 8.88 1 8.92 (in, 2 9.26 1 H), 9.54 1 10.75 1 MS (APCI): 323.
EXAMPLE 39: 4-Hydroxybenzoic acid (6-methoxy-2-naphthylmethylene)hydrazide C H 3
N
0 0
HONO
1 H NMR (DMSO-d6): 8 3.89 3 6.86 J 8.6 Hz, 2 7.22 (dd, J 8.9 Hz, 1 7.37 J 2.3 Hz, 1 7.80 7.93 (in, 6 8.04 1 8.53 1 11.67 1 H).
MS (APCI): 321.
WO 99/01423 WO 9901423PCT/DK98/00287 171 EXAMPLE 3. 5-Dichloro-4-hydroxybenzoic acid (4-hydroxy- 1 -naphthylmethylene)hydrazide 1 H NMR (DMSO-d6): 8 6.98 1 7.58 (dd, 1 7.68 (dd, 1 7.78 1 8.02 2 8.27 1 8.90 1 8.96 1 10.81 1 10.98 1 11.67 1 H).
MS (APCI): 375, 377.
EXAMPLE 41: 6-Hydroxy-2-naphthoic acid (4-hyd'roxy- 1 -naphthylmethylen-e)hytdrazide 0
~OH
HO
1 H NMR (DMSO-d6): 8 6.04 2 6.33 (in, 1 6.62 (dd, 2 6.79 (dd, 2 7.06 2 7.44 2 8.27 2 8.39 2 H).
EXAMPLE 42: 4-Hydroxv-3-methoxybenzoic acid 9 -ety-H-cabzymeyenhypzd
H
3
C
WO 99/01423 WO 9901423PCT/DK98/00287 172 'H NMR (DMSO-d6) 5 1.34 J 7.0 Hz, 3 3.88 3 4.47 J 7.0 Hz, 2 6.90 J =8.0 Hz, 1 7.25 J 7.5 Hz, 1 7.47 7.54 (in, 3 7.64 J 8.2 Hz, 1 H), 7.69 J 8.5 Hz, 1 7.89 J 8.5 Hz, 1 8.24 J 7.7 Hz, 1 8.45 1 H), 8.62 1 H) 9.62 1 11. 51 1IH). M S (APOI1): 388.
EXAMPLE 43: 4-Hydroxy-3-methoxybenzoic acid 3 -chloroph nyl)-2-furanylmethylenelhydrpzide
CI
0 N I 0
HO"~
HC
1 H NMR (DMSO-d6): 8 3.93 3 6.97 J 8.2 Hz, 1 7.14 J 3.5 Hz, 1 H), 7.37 J 3.5 Hz, 1 7.48 7.63 (in, 4 7.84 J 8.0 Hz, 1 7.93 1 8.47 1 9.85 1 11.75 1 MS (APOI): 371.
EXAMPLE 44: 3-Chlomo4-hydroxybenzpic acid Q3phnylalylidene)hydrazide
HON;)
1 NMR (DMSO-d 6 8 7.00 (mn, 3 7.22 7.40 (in, 3 7.57 2 7.69 1 7.89 1 8.12 1 11.0 1 12.0 1 MS (APOI): 301.
EXAMPLE 3-Chloro-4-hydroxybenzoic acid (4-allyloxy- 1 -naohtvlmethylene)hvdrazide WO 99/01423 WO 9901423PCT/DK98/00287 1 H NMR (DMSO-d6): 8 4.68 (in, 2 5.21 1 5.38 1 5.90 -6.10 (in, 1 6.86 (dd, 2 7.42 (dd, 1 7.53 (dd, 1 7.67 (dd, 2 7.86 1 8.18 1 8.78 (s, 1 8.82 1 10.9 1 12.0 1 MS (APCI): 381.
EXAMPLE 46: 3-Chloro-4-hydroxybenzoic acid (4-ethynylmethoxy-1 -nap~hthylmethylenemhydrazide 1 H NMR (DMSO-d6): 8 3.60 1 5.06 2 6.99 1 7.12 1 7.55 1 H), 7.66 1 7.73 1 7.93 1 8.02 1 8.16 1 8.86 1 9.27 1 10.90 1 11.62 1 MS (APCI): 378.
EXAMPLE 47: 3-Chloro-4-hydroxybenzoic acid (4-benzyloxy- 1 -naphthylmethylene)hydrazide .0 WO 99/01423 PTD9/08 PCT/DK98/00287 '74 1 H NMR (DMSO-d6): 5 5.40 2 7.08 1 7.08 1 7.39 1 7.43 (in, 3 7.70 (in, 5 8.00 1 8.01 1 8.33 I 8.94 1 9.35 1 10.98 1 11.69 1 MS (APOI): 431, 433.
EXAMPLE 48: 2-(4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-1 -naphthyloxy)acetamide 1 H NMR (DMSO-d6): 8 4.68 2 6.94 1 6.98 (dd, 1 7.40 -7.86 (in, 5 8.00 (in, 1 8.48 (dd, 1 8.93 (in, 1 9.38 (in, 1 MS (APCI): 398.
EXAMPLE 49: 3-Chloro-4-hydrozybenzoic acid (4-methyl-i -nalhthvlmethylene'hvdrazide
CH
3 1 H NM R (DMSO-d6): 5 2.70 3 7.10 1 7.49 1 7.67 (mn, 2 7.81 (mn, 2 8.00 1 8.11 1 8.88 1 9.07 1 11.0 1 MS (APCI): 339, 341.
EXAMPLE 3-Chloro-4-hyd roxybenzoic acid (2-hydroxv-1 -naphthylmethylene~hyd razide WO 99/01423 WO 9901423PCT/DK98/00287 1 H NMR (DMSO-d6): 8 6.98 1 7.98 1 7.29 (dd, 1 7.48 (dd, 1 7.69 1 7.78 (dd, 2 7.90 1 8.06 1 9.32 1 11.00 1 MS (APCI): 341.
EXAMPLE 51: 3-Chloro-4-hyd roxybenzoic acid (4-methoxy-1 -naphthyl methylene~hydrazide 0, 0
CH
3 HO )A cI H NMR (DMSO-d6): 8 4.05 3 7.06 (in, 2 7.59 (dd, 1 7.70 (dd, 1 7.81 1 7.86 1 8.00 1 8.27 1 8.93 1 8.99 1 11.00 1 MS (APCI): 341, 339.
EXAMPLE 52:
N-(
2 3 -Chloro-4-hydroxybenzoyl)hydrazonolethyl)-.2..diphenylacetainide WO 99/01423 WO 9901423PCT/DK98/00287 176 1 H NMR (DMSO-d6) 8 3.85 2 4.93 2 7.16 7.25 (in, 10 7.26 (in, 1 7.62 1. 7.82 1 8.69 1 10.85 1 11.39 1 MS (APCI): 422 EXAMPLE 53: 3-Chloro-4-hydroxybenzoic acid (1 -hydroxy-2-naphthylmethylene)hydrazide 1 H NMR (DMSO-d6): 8 6.99 1 7.22 1 7.37 -7.56 (in, 4 7.68 (dd, 1 7.77 1 7.90 1 8.19 1 8.58 1 11.00 1 MS (APCI): 341.
EXAMPLE 54: 3-Chloro-4-hydroxybenzoic acid (2.2-diphenylethylidene)hyd razide 1 HNMR (DMSO-d6): 8 4.94 1 6.98 1 7.11 7.22 (mn, 5 7.22 -7.34 (mn, 4 H), 7.68 1 7.82 1 8.19 1 11.00 1 MS (APCI): 365, 367.
EXAMPLE 3-Chloro-4-hydroxybenzoic acid (4-benzyloxy-3-5-dimethoxvbenzylidene)hvd razide WO 99/01423 WO 9901423PCT/DK98/00287 177 .0CH 1 H NMR (DMSO-d6): 5 3.86 6 4.98 2 7.03 2 7.09 1 7.25 7.33 (in, 3 7.48 (in, 2 7.89 (dd, 1 7.99 1 8.32 1 11.00 1 MS (APCI): 441.
EXAMPLE 56: 3-Chloro-4-hydroxybenzioc acid [3-(4-tert-butyl Dhenoxy~benzylidenelhyd razide
'CH
3 1 H NMR (DMSO-d 6 8 1.05 9 6.90 (in, 3 7.09 1 7.30 1 7.40 (in, 3 7.69 (in, 2 7.88 1 8.44 1 10.60 1 11.55 1 MS (APOI): 423.
EXAMPLE 57: 3-Chloro-4-hydroxybenzoic acid (4-methyl-I -naphthylinethylene)hyd razide WO 99/01423 WO 9901423PCT/DK98/00287 178 1 H NMR (DMSO-d6): 5 2.64 3 7.03 J 8.5 Hz, 1 7.41 J 7.4 Hz, 1 7.58 (in, 2 7.78 (in, 2 7.95 J 2.0 Hz, 1 8.06 (dd, J 2.0, 8.0 Hz, 1 8.82 J= Hz, 1 9.07 1 10.93 1 11.71 1 MS (APCI): 337. 339.
EXAMPLE 58: 3-Chloro-4-hydroxybenzoic acid (3-bromo-4-hydroxy-1 -naphthytmethylene)hyd razide 1 H NMR (CDCI3): 5 7.02 J 8.5 Hz, 1 7.51 7.62 (mn, 4 7.80 (dd, J 2.0, 8.5 Hz, 1 8.00 J 2.0 Hz, 1 8.21 1 8.59 J 8.5 Hz, 1 8.91 1 MS (APCI): 421, 423.
EXAMPLE 59: Acetic acid 4-U3-Chioro-4-hydroxybenzoyl)hydr-azonomethyll- -naphthvl ester o0 CH3 0 1 NMR (DMSO-d 6 5 2.63 3 7.03 J 8.5 Hz, 1 7.36 J =8.0 Hz, 1 H), 7.60 (dd, J 7.0, 7.5 Hz, 1 7.68 (dd, J 7.0, 8.0 Hz, 1 7.75 (dd, J 8.0 Hz, 1 H), 7.89 J 8.0 Hz, 1 7.97 J 8.0 Hz, 2 8.85 J 8.5 Hz, 1 9.08 1 H), 11.0 1 11.78 1 MS (APOI): 383.
WO 99/01423 WO 9901423PCTIDK98/00287 179 EXAMPLE 3-Chloro-4-hydrozybenzoic acid (4-cyanomethoxy-1 -naphthylmethyleneghydrpazd-e 1 H NMR (DMSO-d6): 8 5.40 2 7.00 1 7.21 1 7.58 7.80 (in, 3 7.82 1 7.96 1 8.1.8 1 8.90 2 9.28 1 11.62 1 MS (APCI): 380, 382.
EXAMPLE 61: 3-Chloro-4-hydroxybenzoic acid (2-hydroxy-1 -naphthylmethylene)hydrazide 1 H NMR (DMSO-d6): 867.18 1 7.30 1 7.50 (dd, 1 7.68 (dd, 1 7.88 1 7.95 (in, 2 8.08 1 8.29 1 9.51 1 11.12 1 12.12 1 H).
MS (APCI): 341, 343.
EXAMPLE 62: 3-Chloro-4-hydroxybenzoic acid (23-methylenied ioxybenzylidene~hvd razide 0
H"
cI WO 99/01423 WO 9901423PCT/DK98/00287 180 1 H NMR (DMSO-c16): 586.06 2 6.86 (dd, 1 6.90 (dd, 1 7.01 1 7.25 1 7.71 (dd, 1 7.92 1 8.49 1 10.93 1 11.70 1 MS (APCI): 319,321.
EXAMPLE 63: 3-Chloro-4-hydroxybenzoic acid 3 4 -methoxyphenoxy)ben yfidenehy-drpzide C H3 O 0
HON
1 H NMR (DMSO-d6): 8 3.98 3 7.38 (in, 6 7.48 1 7.72 (in, 2 7.97 1 8.19 1 8.64 1 11.93 1 MS (APCI): 397, 399.
EXAMPLE 64: 3-Chloro-4-hydroxybenzoic acid (9-phenanthrenylmethylene)hydrazide 1 N 4 0 N
HON
c 1 H NMR (DMSO-d6): 5 7.02 1 7.52 7.83 (in, 5 7.99 1 8.08 1 8.21 1 8.82 1 8.89 (dd, 1 8.96 (dd, 1 9.06 1 10.96 1 11.82 1 MS (APOI): 375, 377.
EXAMPLE 3-Ch Ioro-4-hydroxybenzoic acid 4-(2-hydroxyethoxy)- 1-naphthylmethylenelhydrazide WO 99/01423 WO 9901423PCT/DK98/00287 181
HON
cI 1 H NMR (DMSO-d6): 8 3.81 J 4.8 Hz, 2 4.16 J 4.8 Hz, 2 6.46 J 8.5 Hz, 1 7.01 J 8.5 Hz, 1 7.51 7.61 (in, 3 7.72 J 8.2 Hz, 1 7.82 J 2.1 Hz, 1 8.30 J 8.2 Hz, 1 8.85 1 8.87 J 8.5 Hz, 1 11.38 1 H).
MS (APCI): 385, 387.
EXAMPLE 66: 3-Bromo-4-hydroxybenzoic acid (4-hydroxy-l1-naphthylmethylene)hydrazide o NOH
HON
Br 1 H NMR (DMSO-d6): 5 6.90 J 8.0 Hz, 1 7.00 J 8.0 Hz, 1 7.47 (dd, J =J= Hz, 1 7.58 (dd, J J 8.0 Hz, 1 7.66 J 8.0 Hz, 1 7.77 (dd, J 2.0, Hz, 1 8.08 J 2.0 Hz, 1 8.17 J 8.0 Hz, 1 8.83 1 8.88 J Hz, 1 10.73 1 11.53 1 MS (APCI): 385, 387.
EXAMPLE 67: Nicotin ic acid 4-(3-chloro-4-hydroxybenzoyl )hydrazonomethyll-l1-naphthyl ester WO 99/01423 WO 9901423PCT/DK98/00287 182 1H NMR (DMSO-d6): 8 7.04 J 8.5 Hz, 1 7.58 J 8.0 Hz, 1 7.64 7.69 (in, 4 7.74 8.02 (in, 3 8.56 (dd, J 2.0, 8.0 Hz, 1 8.91 (in, 2 9.05 1 8.35 (d, J 1.8 Hz, 1 10.96 1 11.84 1 MS (APCI): 446, 448.
EXAMPLE 68: 3-Chloro-4-hydroxybenzoic acid 1. 3-dioxo- 1.3-dihvdroisoi dgl-2-vimethoxvl-l -nanhthvimethylenelhydraz'de 0 HO N: A N 1 H NMR (DMSO-d6): 585.78 2 7.03 J 8.5 Hz, 1 7.37 J 8.2 Hz, 1 H), 7.48 (in, 1 7.61 (in, 1 7.73 7.81 (in, 8 8.90 (in, 2 10.91 1 11.67 1 MS (APCI): 500, 502.
EXAMPLE 69: 3-Chloro-4-hydroxvbenzoic acid [4-(cyclohexylmetho Y)-1 -naphthylmethylenelhydrazide 1 H NMR (DMSO-d6): 5 1.08 -1.19 (in, 4 1.66 1.72 (in, 3 1.83 1.92 (in, 3 3.21 (in, 1 3.95 (in, 2 6.99 J 8.1 Hz, 1 7.03 J 8.5 Hz, 1 7.53 (dd, J =T WO 99/01423 WO 9901423PCT/DK98/00287 183 =7.4 Hz, 1 7.62 (dd, J =J '7.5 Hz, 1 7.72 -7.93 (in, 2 7.94 J 2.1 Hz, 1 H), 8.22 J 8.0 Hz, 1 8.87 1 8.90 J 8.5 Hz, 1 10.94 1 11 .60 1 MS (APOI): 437, 439.
EXAMPLE 3-Chloro-4-hydroxybenzoic acid 4-(tetrahvdro-2-pyranvlmethoxv)-1 -naohthvmethvL--nt-lhydrazide 1 H NMR (DMSO-d6): 5 1.35 (in, 3 1.60 -1.71 (in, 2 3.15 -3.38 (in, 2 3.64 (in, 1 3.78 (in, 1 4.02 (in, 2 6.94 J 8.5 Hz, 2 7.46 (dd, J J' 7.4 Hz, 1 H), 7.54 (dd, J J =8.2 Hz, 1 7.66 (in, 2 7.86 J =2.1 Hz, 1 8.13 J 8.0 Hz, 1 8.78 1 8.83 J 8.5 Hz, 1 10.83 1 11.52 1 MS (APCI): 439, 441.
EXAMPLE 71: 3-Chloro-4-hydroxybenzoic acid r4-(3-pyridylinethoxy)-1 -naphthylmethylene] hyd razide 1 H NMR (DMSO-d6): 8 5.28 (in, 2 6.94 J 8.5 Hz, 1 7.10 J =8.5 Hz, 1 H), 7.34 (dd, J 4.8, 7.8 Hz, 1 7.45 (dd, J J= 7.6 Hz, 1 7.54 (dd, J 7.5 Hz, 1 H), 7.66 J 8.5 Hz, 1 7.70 J 8.2 Hz, 1 7.86 (in, 2 8.15 J 8.0 Hz, 1 H), WO 99/01423 WO 99/1 423PCT/DK98/00287 184 8.45 (dd, J 4.8 Hz, 1 8.65 1 8.81 (in, 2 10.90 1 11.56 1 MS (APCI): 432, 434.
EXAMPLE 72: 4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl- 1 -naphthytoxy)acetic acid ethyl ester 0 O- CH 3 1 H NMR (DMSO-d6): 8 1.25 J 7.0 Hz, 3 4.25 J 7.0 Hz, 2 5.11 2 7.06 J 8.2 Hz, 1 7.13 J 8.5 Hz, 1 7.64 -7.70 (in, 2 7.76 J 8.2 Hz, 2 H), 8.04 J 2.1 Hz, 1 8.36 J 8.2 Hz, 1 8.97 1 9.02 J 8.5 Hz, 1 H), 11.01 1 11.74 1 MS (APCI): 427, 429.
EXAMPLE 73: 3-Chloro-4-hydroxybenzoic acid (3-nitrobenzylidene)hyd razide 0l-+, 1 H NMR (DMSO-d6): 8 7.13 J 8.5 Hz, 1 7.79 -7.86 (in, 2 8.03 J 2.1 Hz, 1 8.18 J 7.5 Hz, 1 8.30 J 8.0 Hz, 1 8.58 2 11.08 1 12.05 (s, 1 MS (APCI): 320, 322.
EXAMPLE 74: 3-Chloro-4-hydroxybenzoic acid (2.4-dichlorobenzytidene~hvdrazide WO 99/01423 WO 99/1 423PCT/DK98/00287 1 H NMR (DMSO-d6): 5 7.02 J 8.5 Hz, 1 7.46 J 8.2 Hz, 1 7.66 1 H), 7.73 J 8.2 Hz, 1 7.95 (in, 2 8.71 1 11.97 1 11.94 1 MS (APCI): 345.
EXAMPLE 3-Chloro-4-hydroxybenzoic acid (4-fluoro-1 -naphthylmethylene)hvdrpzide 1 H NMR (DMSO-d6): 587.00 J 8.5 Hz, 1 7.33 (dd, J 8.2, 10.3 Hz, 1 7.62 -7.72 (in, 3 7.82 (in, 1 7.91 J 1.9 Hz, 1 8.04 J 8.1 Hz, 1 8.09 (in, I H), 8.91 1 10.81 1 11.67 1 MS (APCI): 343.
EXAMPLE 76: a-Fluoro-4-hydroxyb-enzoic acid (4-hydroxy-1 -naphthylinethylene)hydrazide WO 99/01423 WO 99/1 423PCT/DK98/00287 186 1 H NMR (DMSO-d6): 5 6.90 J 8.0 Hz, 1 7.00 J 8.6 Hz, 1 7.44 7.72 (in, 6 8.17 J 8.6 Hz, 1 8.84 1 8.89 J 8.5 Hz, 1 10.60 1 11.50 (s, 1 MS (APCI): 325.
EXAMPLE 77: 3-Chloro-4-hydroxybenzoic acid [4-(2.4-difluorobenzyoxv)-l1-naphthylmethylenelhydrazide
FF
'0 1 H NMR (DMSO-d6): 5 5.33 2 7.03 J 8.5 Hz, 1 7.12 (in, 1 7.21 J 8.2 Hz, 1 7.31 (in, 1 7.52 (in, 1 7.54 (mn, 1 7.69 7.80 (in, 3 7.94 1 8.16 J 8.2 Hz, 1 8.90 (in, 2 10.91 1 11.63 1 MS (APCI): 467, 469.
EXAMPLE 78: 3-Fluoro-4-hydroxybenzoic acid (1 -naphthylmethylene~hydrazide MS (APCI): 309.
EXAMPLE 79: 3 -Chloro-4-hydroxybenzoic acid [4--(3-methoxybenzyloxv)-1 -nao~hthvlmethylenelhvd razide WO 99/01423 WO 9901423PCT/DK98/00287 187 Q 0 15 CH 3 ll 1 H NMR (DMSO-d6): 583.71 3 5.29 2 6.87 J 8.5 Hz, 1 7.00 7.14 (in, 4 7.29 J 8.0 Hz, 1 7.55 (in, 1 7.68 (in, 1 7.75 (in, 2 7.94 J Hz, 1 8.25 J 8.0 Hz, 1 8.87 1 8.92 J 8.5 Hz, 1 11.00 1 H), 11.62 1 MS (APCI): 461.
EXAMPLE 3-Chloro-4-hydrozybenzoic acid 4-(4-fluorobenzyloxy)-- -naphthylmethylenelhydrazide N NF o N 0 0 NN- HON HA
CI
1 H NMR (DMSO-d6): 8 5.30 2 7.02 J 8.5 Hz, 1 7.13 7.25 (in, 3 7.53 7.60 (in, 4 7.79 (in, 2 7.94 J 2.0 Hz, 1 8.23 J 8.0 Hz, 1 8.88 1 8.92 J 8.5 Hz, 1 10.93 1 11.63 1 MS (APCI): 449, 451.
EXAMPLE 81: 3-Chloro-4-hydroxybenzoic acid 4 (2-tetraydof ranylmethoxy)-1 -naphthylmethylene]hydrazide 0 N WO 99/01423 WO 9901423PCT/DK98/00287 188 1 H NMR (DMSO-d6): 8 1.77 -2.04 (in, 4 3.68 (in, 1 3.78 (in, 1 4.12 -4.16 (in, 2 4.26 (in, 1 7.02 J 8.5 Hz, 1 7.04 J 8.2 Hz, 1 7.53 (mn, 1 7.62 (in, 1 7.74 (in, 2 7.94 J 2.0 Hz, 1 8.20 J 8.2 Hz, 1 8.87 1 8.90 (d, J 8.5 Hz, 1 10.93 1 11.61 1 MS (APCI): 425, 427.
EXAMPLE 82: 3-Chloro-4-hydroxybenzoic acid (3-broino-4-inethoxy-1 -naphthylmethylene)hydrazide 0 0,CH 3 NN 2 Br I H 1 H NMR (DMSO-d6): 583.91 3 7.03 J 8.5 Hz, 1 7.65 7.76 (in, 3 7.94 (d, J 2.0 Hz, 1 8.02 1 8.12 J 8.0 Hz, 1 8.71 J 8.0 Hz, 1 8.95 1 10.96 1 11.85 1 MS (APCI): 433, 435.
EXAMPLE 83: 3-Chloro-4-hyd roxybenzoic acid I'4-(3-tetrahydrofuranylmethoxy)-l1-naphthylmethylene]-
NN.
HOJPA
CI
1 H NMR (DMSO-d6): 8 1.92 (mn, 1 2. 10 (in, 1 2.77 (in, 1 3.28 3.88 (in, 4 4.12 (mn, 2 7.03 J 8.5 Hz, 1 7.04 J 8.2 Hz, 1 7.55 (in, 1 7.62 (mn, 1 H), 20 7.74 J 8.5 Hz, 1 7.76 J 8.0 Hz, 1 7.94 J 2.0 Hz, 1 8.20 J Hz, 1 8.88 1 8.90 J =8.5 Hz, 1 10.91 1 11.63 1 MS (APCi): 425, 427.
WO 99/01423 WO 9901423PCT/DK98/00287 189 EXAMPLE 84: 4-(4-[3-Chloro-4-hydroxybenzoyl~hydrazonomethyll-1 -naphthyloxymethyl)benzoic acid methyl ester 1 H NMR (DMSO-d6): 6 3.80 3 5.43 2 7.03 J 8.5 Hz, 1 7.12 J 8.2 Hz, 1 7.54 (in, 1 7.57 J 8.0 Hz, 4 7.93 7.99 (in, 3 8.30 J 8.0 Hz, 1 8.87 1 8.93 J 8.5 Hz, 1 10.91 1 11.63 1 MS (APCI): 489, 491.
EXAMPLE 3-Chlnrn-4-hvd rnyvhenzOir acid r3 5-d impthoxv-4-(4-trifli 1rnmpthnyvhen7vcwvAhp-n7VIidenelhydrazide 1 H NMR (DMSO-d6): 8 3.76 6 4.91 2 6.95 7.00 (in, 3 7.30 J 8.2 Hz, 2 7.52 J 8.5 Hz, 2 7.68 J 2.0, 8.5 Hz, 1 7.88 1 8.29 1 H), 10.91 1 11.69 1 MS (APCI): 525, 527.
EXAMPLE 86: 3-Chloro-4-hyd roxybenzoic acid r4-(4-trifluoromethoxybenzyoxy)-1 -naphthylmethylenelhydrzid WO 99/01423 WO 9901423PCT/DK98/00287 190
N
HO"
1 H NMR (DMSO-d6): 8 5.36 2 7.02 J 8.4 Hz, 1 7.14 J 8.2 Hz, 1 H), 7.39 J 8.2 Hz, 2 7.56 (in, 1 7.62 (in, 3 7.76 (in, 2 7.94 J 2.0 Hz, 1 8.26 J 8.3 Hz, 1 8.88 1 8.93 J 8.5 Hz, 1 10.91 1 11.63 (s, 1 MS (APCI): 515, 517.
EXAMPLE 87: 3-Chloro-4-hydroxvbenzoic acid [4-(2-methoxybenzyoxy)-l1-naphthyl m-ethylenelhydrazide 0 NN 0
CH
3
HON
CI
1 H NMR (DMSO-d6): 8 3.79 3 5.27 2 6.95 (mn, 1 7.03 J 8.5 Hz, 1 H), 7.04 J 8.2 Hz, 1 7.13 J 8.5 Hz, 1 7.31 (in, 1 7.46 7.53 (in, 2 7.61 (in, I 7.76 (in, 2 7.94 J 2.0 Hz, 1 8.22 J 8.3 Hz, 1 8.88 1 H), 8.92 J =8.5 Hz, 1 10.90 1 11.62 1 MS (APCI): 461, 463.
EXAMPLE 88: 3-Chloro-4-hydroxybenzoic acid [4-(2-fluorobenzyoxy)-lI-naphthvlmethvlenelhvdrazide WO 99/01423 WO 9901423PCT/DK98/00287 191 1 H NMR (DMSO-d6): 8 5.36 2 7.03 J 8.5 Hz, 1 7.19 -7.28 (in, 3 7.39 (in, 7.53 (in, 1 7.63 (in, 2 7.72 7.80 (in, 2 7.94 J 2.1 Hz, 1 8.19 J 8.3 Hz, 1 8.88 1 8.92 J 8.5 Hz, 1 10.90 1 11.64 1 MS (APCI): 449,451.
EXAMPLE 89: 3-Chloro-4-hydroxvbenzoic acid ifluorobenzyloxy)-1 -naphthylmethylenelhydrazi- 1 H NMR (DMSO-d6): 8 5.34 2 7.03 J 8.5 Hz, I 7.16 J 8.2 Hz, 1 H), 7.18 J 8.0 Hz, 1 7.27 J 8.2 Hz, 1 7.51 (in, 2 7.72 (in, 1 7.74 J= Hz, 1 7.78 J =8.0 Hz, 1 7.94 J 2.1 Hz, 1 8.03 J 8.3 Hz, 1 H), 8.89 1 8.91 J =8.5 Hz, 1 10.97 1 11.65 1 MS (APCI): 467, 469.
EXAMPLE 4-Hydroxy-3-methoxybenzoic acid 5-dimethoxy-4-(5.5 8-tetramethyl-5.6 .7.8-tetrahydronaphth=--ylmethoxy)benzylidenelhvdrazide
OCH
3 1 H NMR (DMSO-d6): 8 1.2 12H), 1.63 4H), 3.82 6H), 3.85 3H), 4.90 2H), 6.88 1 7.01 2H), 7.18 1 7.29 1 7.38 1 7.44 1 7.48 1 H), 8.40 (brd s, 1H), 11.62 (s 1H); MS (APOI): 547.1.
WO 99/01423 WO 9901423PCT/DK98/00287 192 EXAMPLE 91: 3-Fluoro-4-hydrozybenzoic acid [4-(4-isopropylbenzyloxy)-3. 1 H NMR (DMSO-d6): 5 1.05 6H), 2.67 (in, 1 3.61 6H), 4.69 2H), 6.79 2H), 6.86 1 7.01 2H), 7.24 1 7.44 (dd, 1 7.51 1 8. 10 (brd s, 1IH), 10.32 (s, 1 11.41 1 MS (APOI): 467.19.
EXAMPLE 92: 3-Chloro-4-hvdroxvbenzoic acid 4-(4-tert-butvtbenzvloxy3 1 H NMR (DMSO-d6): 851.06 9H), 1.99 6H), 4.55 2H), 6.83 1 7.19 6H), 7.52 1 7.73 1 8.09 1 10.74 (brd s, 1 11.44 1 MS (FAB): 465.6.
EXAMPLE 93: 3-Chloro-4-hyd roxybenzoic acid- [3-bromo-5-methoxy-4-(4-trifluoromethoxybenzoxy)bgnzylidenelhydrazide WO 99/01423 WO 99/1 423PCT/DK98/00287 1 H NMR (DMSO-d6): 863.92 3H), 5.07 2H), 7.07 1 7.40 (in, 3H), 7.52 1 H), 7.63 2H), 7.77 (dd, 1 7.97 1IH), 8.35 1 11.00 (brd s, 1IH), 11.86 1 MS (FAB): 575.0 EXAMPLE 94: 4-Hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidenelhydrazide 1 H NMR (DMSO-d6): 8 1.05 6H), 2.71 (mn, 1 3.67 6H), 4.75 2H), 6.70 2H), 6.85 2H), 7.14 2H), 7.21 2H), 7.64 2H), 8.21 (brd s, 1 9.97 (brd s, 1 11.47 1 MS (APCI): 448.9.
EXAMPLE 2-Chloro-4-hydroxybenzoic acid E4-(4-isopropytbenzyloxy)-3 drazde WO 99/01423 WO 9901423PCT/DK98/00287 194 'H.NMR (DMSO-D6): d 1. 18 6H), 2.87 (septet, 1 [3.68 1 H) 3.81 5H), 6H], [4.83 0.5H) 4.90 1.5H), 2H], [6.76 0.5H) 7.01 1.5 2H], [6.80 (dd, 1 H) 6.88 1 2H], 7.23 2H), 7.35 2H), 7.38 (in, 1 [7.91 0.3H) 8.18 0.7H), 2H], 10.17 0.7H) 11.73 0.3H), 1H]; MS (APCI): 483.0.
EXAMPLE 96: 3-Chloro-4-hydroxybenzoic aced [3-(4-isopropylbenzyloxy')-4.5-dimethoxybenzylidenelhy-
CH
3 0~
OCH
3
CH
3
HO:
clCH 3 1 H NMR (DMSO-d6): 8 1.05 6H), 2.70 (in, 1 3.54 3H), 3.66 3H), 4.94 2H), 6.87 (in, 3H), 7.08 2H), 7.20 2H), 7.56 (dd, 1IH), 7.77 1 8.15 1 10.76 (s, 1 11.52 1 MS (APCI): 483.7.
EXAMPLE 97: 3-Chloro-4-hydroxybenzoic acid [3-(4-isopropybenzyloxy)-2 .4-dimethoxybenzylidenelhydraide 1 H NMR (DMSO-d6): 8 1.20 6H), 2.89 (mn, 1 3.85 6H), 4.95 2H), 6.95 1 H), 7.07 1 7.22 2H), 7.40 2H), 7.64 1 7.78 (dd, 1 7.97 1 8.62 (s, 1 11.68 1 MS (APCI): 483.8.
EXAMPLE 98: WO 99/01423 WO 9901423PCT/DK98/00287 195 3-Chloro-4-hydroxybenzoic acid 4 -(3-trifluoromethoxybenzyloxy)npphth-lylmethylenelhydr-azide 0 0 N.
H
HOIq
CI
1 H NMR (DMSO-d6): 8 5.46 2H), 7. 10 1 7.20 1 7.37 1IH), 7.65 (in, 7.82 (in, 2H), 8.01 1H), 8.32 1H), 8.97 (in, 2H), 11.70 1H); MS (APOI): 514.8 EXAMPLE 99: 3-Chloro-4-hydroXy-benzoic acid 4 4 -isoprooylbenzyloxy'-8-methoxynaphthalen1ylmethylene]-hydrazide
CH
3 CH 3 C N N N HO H 4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (2 g, 9.9 mmol) was dissolved in DMF mL). To this mixture potassium carbonate (6.8 g, 50 mmol) and 4-isopropylbenzylchloride (1.8 g, 10.4 minol) 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 chloride (100 mL), dried (MgSO 4 and evaporated in acu to afford 3.0 g crude product. This was purified using column chromatography on silica gel (300 mL) eluting with a mixture of ethyl acetate and heptane This afforded 2.57 g of 4-isopropylbenzyloxy-8methoxynaphthalene-1 -carbaldehyde.
Calculated for C22H22 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 mL) and the above 4 -isopropylbenzyloxy- 8 -methoxynaphthalene-1-carbaldehyde (365 mg, 1.1 mmol) and glacial acetic acid (5 drops) were added and the resulting mixture was stirred at room temperature for 20 minutes. More DMSO (2 mL) was added and the mixture was stirred at room temperature for 16 hours. The solid was collected by filtration and washed successively with DMSO and ethyl acetate to afford 330 mg of the title compound.
250 °C.
EXAMPLE 100:
CH
OMe CH 3 0
OC
N N OMe
HH
NO
2 'H NMR DMSO-de 5 1.13 6H), 2.82 (sept, 1H), 3.77 6H), 4.8 2H), 7.15 1H), 7.18 2H), 7.30 2H), 8.00 (dd, 1H), 8.30 1H), 8.44 1H), 11.84 MS (APCI): 494.0 EXAMPLE 101: o H HO
O
Cl 'H NMR DMSO-d 6 5.38 2H), 6.95 1H), 7.06 1H), 7.49 1H), 7.56 1H), 7.65-7.71 6H), 7.87 1H), 8.22 1H), 8.80 1H), 8.86 1H), 10.82 1H), 11.55 1H); MS (FAB): 499 WO 99/01423 WO 9901423PCT/DK98/00287 197 EXAMPLE 102: 00 N' NN
C
HO _Q H
OF
1 H NMR DMSO-d 6 5.85 2H), 7.05 2H), 7.52-7.63 (in, 4H), 7.73 (in, 2H), 7.95 (s, 1 8.16 2H), 8.33 1 8.90 1 893 1 10.90 (brd s, 1 11.63 1IH); MS (FAB): 543 EXAMPLE 103: 3-Chloro-4-hydroXybenzoic acid {4-[2-(4-bromophenoxy)ethoxyl-3 .5-d imethoxybenzvlide-
OCH
3 Br OCH3
H
HO'*
1 H NMR (DMSQ-d6): 8 3.78 6H), 4.21 (in, 4H), 6.87 2H), 7.00 2H), 7.05 1 H), 7.44 2H), 7.75 (dd, 1 7.96 1 8.36 1 10. 95 (brd s, 1 11.66 1IH); MS(APCI): 548.8.
EXAMPLE 104: 3-Chloro-4-hydroxybenzoic acid E 4 -(3-methoxy-3-(4-methylphenyl )-propyloxy~naphth-1 ylinethylenelhydrazide WO 99/01423 WO 9901423PCT/DK98/00287 MS (APCI): 502.9 EXAMPLE 105: (2-Ethylphenyflcarbamic acid 2 4 -[(3-chloro-4-hydroxybenzoyl)hydraznomethyllnpphth-l yloxylethyl ester 1 H NMR (CDC13): 5 1.12 3H), 2.50 (qt, 2H), 3.69 2H), 4.39 2H), 5.20 1 6.57 (t, 1 6.74 1IH), 6.97 1 7.08 (in, 3H), 7.57 1 7.67 1 7.81 2H), 8. 01 (s, 1 8.35 1 8.95 (in, 2H), 11.67 1 H).
EXAMPLE 106: 3-Chloro-4-hydroxybenzoic acid f3-allyi-4-(4-isopropylbenzyloxy)-5methoxybenzvlidenelhvdrazide WO 99/01423 PCT/DK98/00287 1 H NMR (DMSO-d 6 5 1.13 6H), 2.80 (in, 1 3.20 (in, 2H), 3.85 3H), 4.82 2H), 5.00 2H), 5.70 (in, 1 6.96 1 7.05 1 7.20 2H), 7.30 2H), 7.70 1 H), 7.89 1 8.28 1 10.80 (brd s, 1 11.61 1 MS (APCI): 493. 1.
WO 99/01423 PCT/DK98/00287 200 Similarly, the following compounds were made: EXAMPLE 107: HO N N N~ 2
L
H H' HO.-
CH
3 cI
CH
3 1 H NMR (DMSO-D 6 5 0.99 6H), 2.68 (septet, 1 4.89 2H), 6.84 2H), 7.06 (in, 2H), 7.16 (in, 3H), 7.55 1IH), 7.75 1 8.18 1 10.75 1 11.52 1 MS (APOI): 423.7, 425.6.
EXAMPLE 108:
CH
3 CI
CH
3 o N
N
H
HO0 1 H NMR (DMSO-D 6 5 1. 18 I1H), 2.88 (septet, 1 5.20 2H), 7.04 1 7.28 (t, 2H), 7.30 1 7.38 2H), 7.62 1 7.73 (dd, 1 7.79 1 7.94 1 8.32 1H), 11.94 1H), 11.72 1H); MS (APCI): 457.4, 459.1.
EXAMPLE 109:
CH
3
CH
3
C
CCH
3 HO'
H
(APCI): 451.6, 453.3.
WO 99/01423 PCT/DK98/00287 201 EXAMPLE 110:
CH
2 CH 3
SCH
3
H
HOJ
1 H NMR (DMSO-Do): 8 1. 1 6H), 2.8 (septet, 1 3.3 1 5.0 1 5.1 1 5.2 2H), 5.9 (in, 1 7.0 1 7.1 1 7.2 2H), 7.3 2H), 7.4 1 7.5 1 H), 7.7 (dd, 1 7.9 1 8.3 1 10.9 (brd s, 1 11.5 1 MS (APCI): 463.5, 465. 1.
EXAMPLE 111:
HO
cI 'H NMR (DMSO-D 6 864.47 2H), 4.54 2H), 7.01 2H), 7.07 1 7.14 1 7.45 2H), 7.53 1 7.27 1 7.79 (mn, 2H), 7.96 1 8.17 1 8.91 1 8.94 1 10.92 1 11.64 1 MS (APCI): 539.3, 541.1, 543. 1.
EXAMPLE 112: C H
OCH
3 0 1CH CH3
CH
O 0 HOP
CIH
I N 1 H NMR (DMSO-D 6 8 1.18 6H), 2.87 (septet, 1 [3.67 1.5H) 3.81 4.5H), 6H], [4.83 0.5H) 4.90 1.5H), 2H], 6.73 0.5H) [7.02 (mn, 2.5H), 7.27 (mn, 2.5H) 7.37 (mn, 2.5H), 8H], [7.92 0.3H) 8.17 0.7H), 1iH], [10.96 0.3H) 11. 12 0.7H), 1H], [11.82 0.7H) 11.95 0.3H), 1iH]; MS (APCI): 517.6, 519.2.
WO 99/01423 PCT/DK98/00287 202 EXAMPLE 113:
CH
3 c- N,,H 3
CH
N*
1 H NMR (DMSQ-D6): 8 1.19 6H), 2.89 (septet, 1H), [3.68 1.5H) 3.82 4.5H), 6H], [4.84 0.5H) 4.89 1.5H), 2H], [6.76 0.5H) 7.02 (in, 2.5H), 3H], 7.20 (in, 2H), 7.34 (in, 2H), [7.50 0.3H) 7.62 0.7H), 1 7.92 0.3H) 8.18 0.7H), 1iH], 11. 17 (brd s, 1H), 11.81 0.7H) 11.96 0.3H), 1H]; MS (APCi): 517.7, 519.2.
EXAMPLE 114:
CH
3
CH
3 I HH HO H
NH
2 'H NMR (DMSO-D 6 5 1.20 6H), 2.87 (septet, 1 3.82 6H), 4.89 2H), 6.69 (d, 1H), 6.98 (mn, 3H), 7.21 (mn, 3H), 7.36 2H), 8.32 1 9.8 (brd s, 1IH), 11.50 1 MS (APCI): 464.7.
EXAMPLE 115:
OH
3 0- OH IOq
H
HO F
F
1 H NMR (DMSO-D 6 8 1.19 6H), 2.30 (septet, 1 [3.71 3.82 6H], 4.90 2H), [6.81 (in, 1.5H) 6.88 1.5H), 3H], [7.24 0.2H) 8.24 0.8H), 1 11.05 (brd, 1 H), 11 .69 0.75H) 11.94 0.25H), 1iH]; MS (APCI): 485.5, 486.3.
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 116: 1 H NMR (DMSO-D 6 8 1.19 6H), 2.88 (septet, 1H), 3.83 6H), 4.90 2H), 6.87 (d, 1 7.03 2H), 7.23 2H), 7.36 2H), 7.53 (in, 3h), 8.26 (in, 3H), 10.73 1IH), 11.82 1 MS (APOI): 499.8.
EXAMPLE 117: I H NMR (DMSO-D 6 5 1.20 J 6.9, 6H), 2.89 (sept, J 6.9, 1 3.84 6H), 4.91 (s, 2H), 7.03 (br s, 2H), 7.12 J 8.8, 1 7.23 J 8.0, 2H), 7.37 J 8.0, 2H), 8.04 (dd, J 2.2, 8.8, 1 8.21 (br s, 1 8.35 (br s, 1 11.78 1 11.89 (br s, 1 MS (APCI, neg): 472.
Preparation of acyl-hydrazones of 4-(2-hydroxyethyl )-l1-naphthaldehyde: General procedure for synthesis of comp~ounds of the general formula X: A NH2
H
H a_(HbOH 0 1 1. (CH 2
,OH
A N N~ "RN 0 H formula X WO 99/01423 PCT/DK98/00287 204 wherein b is 1, 2, 3 or 4 Preparation of 4-(2-hvdroxyethyl)-l-naphthaldehyde: Br BrBr H Mo 1-Bromo-4-(2-hydroxvethyl)naphthalene: To a solution of methyl 4-bromo naphthalene acetate (2.0 g, 7.16 mmol) in anhydrous THF mL) was added drop wise at 0°C 1 M lithium aluminum hydride in THF (4 mL). The mixture 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 extracts were dried (MgSO 4 and concentrated to provide a 1.71 g colorless oil (1.71 g, A similar synthetic reference is described in A. A. Kiprianov, A. A. Shulezhko. Zh.
Org. Khim. 2 (1966), 1852, English translation: J. Org. Chem. (USSR) 2 (1966) 1820].
H NMR (CDCI 3 5 2.36 1H), 3.33 J 6.7 Hz, 2H), 3.99 J 6.7 Hz, 2H), 7.24 J 7.3 Hz, 1H), 7.58 7.63 2H), 7.73 J 7.6 Hz, 1H), 7.61 1H), 8.31 (dd, J 1.1, Hz, 1H). GCMS (pos.) 250, 252.
1-Bromo-4-(2-tetrahydropyranyloxvethvl)naDhthalene: To a solution of 1-bromo-4-(2-hydroxyethyl)naphthalene (1.71 g, 6.8 mmol) in dichloromethane (20 mL) was added 3,4-dihydro-2H-pyrane (1 mL, 0.92 g, 11.0 mmol) and ptoluene sulfonic acid (80 mg). The mixture was stirred at room temperature for 90 min, diluted with dichloromethane (20 mL), washed with satd. NaHCO 3 sol. (20 mL), dried (MgSO 4 and concentrated. Flash chromatography using hexane/ethyl acetate 9:1 as eluent provided 1.69 g of a colorless oil.
1H NMR (CDCl 3 5 1.51 -1.60 m 3.37 J 7.2 Hz, 2H), 3.39 3.47 1H), 3.74 (t, J 7.2 Hz, 2H), 4.08 (dd, J 2.4, 7.5 Hz, 1H), 4.60 1H), 7.25 J 7.3 Hz, 1H), 7.56 WO 99/01423 PCT/DK98/00287 205 7.61 2H), 7.72 J 7.6 Hz, 1H), 8.09 8.12 1H), 8.29 (dd, J 2.5, 7.1 Hz, 1H).
GCMS (pos), 334, 336.
1-Formyl-4-(2-tetrahydroDvranyloxvethyl)naphthalene: A solution of 1-bromo-4-(2-tetrahydropyranyloxyethyl)naphthalene in anhydrous THF mL) under nitrogen was cooled to -780C. n-Butyl lithium (1.4 mL of a 2.5 M solution in hexane) 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 concentrated. Flash chromatography using hexane/ethyl acetate 5:1 as eluent provided 408 mg of a colorless oil.
H NMR (CDCI) 5 1.48 -1.69 m 3.45 3.50 3H), 3.69 3.85 2H), 4.07 -4.17 1H), 4.61 1H), 7.58 J 7.3 Hz, 1H), 7.62 -7.73 2H), 7.92 J 7.3 Hz, 1H), 8.20 J 1.0, 8.1 Hz, 1H), 10.36 1H). GCMS: 284 1-Formyl-4-(2-hydroxvethyl)naphthalene: 1-Formyl-4-(2-tetrahydropyranyloxyethyl)naphthalene (400 mg, 1.40 mmol) was dissolved in methanol (15 mL), and p-toluene sulfonic acid (45 mg) was added. The mixture was stirred at room temperature for 16 h, and concentrated. The residue was dissolved in ethyl acetate (3 x 10 mL), washed with satd. NaHCO 3 (20 mL), dried (MgSO 4 and concentrated. Purification by flash chromatography using hexane/ethyl acetate 3:1 as eluent provided 182 mg of a colorless oil.
H NMR (CDCI 3 5 2.09 1 3.40 J 6.6 Hz, 2H), 4.02 J 6.6 Hz, 2H), 7.54 J 7.3 Hz, 1H), 7.61- 7.71 2H), 7.88 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 1H). GCMS: 200 The following compounds were prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 1-formyl-4-(2-hydroxyethyl) naphthalene (from step D) with 4-hydroxy benzoic acid hydrazides.
WO 99/01423 PCT/DK98/00287 206 EXAMPLE 118:
OH
0 I H
HO
cI H NMR (DMSO-De) 5 3.25 J 6.5 Hz, 2H), 3.73 (dt, J Hz, 2H), 4.84 J Hz, 1 7.08 J 8.5 Hz, 1 7.49 J 7.4 Hz, 1 7.60 7.68 (in, 2H), 7.80 (dd, J 1. 8, 7.4 Hz, 1 7.84 J 7.3 Hz, 1 8.00 J 1. 8 Hz, 1 9.19 J 6.7 Hz, 1 H), 8.85 J 7.7 Hz, 1 9.05 1 10.98 1 11.76 1 MS (APCI, pos.): 369.4, 371.2.
EXAMPLE 119: 0
OH
N*
N
HO'( Cl
CI
H NMR (DMSO-D6) 6 3.18 J 7.0 Hz, 1 3.25 J 7.0 Hz, 1 3.65 (dd, J Hz, 1 3.74 (dd, J 5.3, 7. 0 Hz, 1 4.74 J 5.3 Hz, 0. 5H), 4.79 J 5.3 Hz, 0. 7.04 J 8.3 Hz, 0.5H), 7.05 J 8.3 Hz, 0.5H), 7.25 J 8.3 Hz, 0.5H), 7.28 J= 8.3 Hz, 0.5H), 7.38 J 7.4 Hz, 0.5H), 7.43 J 8.4 Hz, 0.5H), 7.47 7.57 (in, 7.61-7.72 (mn, 1 7.82 J 7.2 Hz, 0.5H), 8.10 J =8.6 Hz, 0.5H), 8.19 (dd, J 2.2, 7.2 Hz, 0.5H), 8.45 J 8.6 Hz, 0.5H), 8.48 0.5H), 8.85 0.5H), 8.87 (dd, J 2.2, Hz, 0.5H), 11.00 0.5H), 11.15 0.5H), 11.86 0.5H), 11.92 0.5H); MS (APCI, pos.): 403.4, 405.2, 406.1.
WO 99/01423 PCT/DK98/00287 207 Preparation of acylhydrazones of 4-hydroxymethylnaphthaldehyde: 0 OH OH O H A B HO 0 HO HO Step A: The 1,4-Naphthalenedicarboxylic acid (25 g, 116 mmol) was dripped into a mixture of Lithium Aluminum Hydride (15 g, 395 mmol) in 600 mL of anhydrous THF and refluxed for two 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 1N HCI. The product was extracted with ethyl acetate washed with aqueous sodium bicarbonate water, brine, and dried over magnesium sulfate. 1,4- Bishydroxymethylnaphthalene was obtained as a solid after evaporation of the solvent 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 4H), 7.77 4H), 8.32 2H).
Step B: To a solution of 1,4-bishydroxymethylnaphthalene (12 g, 65 mmol) in ethyl acetate (300 ml) was added manganese dioxide 28 g, 325 mmol). After stirring for 45 minutes most of the starting material had disappeared and two new spots (mono aldehyde and dialdehyde) were seen on TLC. The upper spot corresponds to the dialdehyde. The mixture was passed through a bed of Celite and eluted with additional volumes of ethyl acetate. The solvent was evaporated and 4-hydroxymethylnaphthaldehyde was purified by column chromatography using hexane/ethyl acetate (80/20 to 75/25) in 50% yield.
H NMR (DMSO-D6): 8 5.19 2H), 5.71 (brd s, 1H), 7.73 1H), 7.78 1H), 7.95 1H), 8.26 2H), 9.34 1H), 10.46 1H).
WO 99/01423 PCT/DK98/00287 208 Examples of products employing the above aldehyde: EXAMPLE 120: o N OH
H
HO
N
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-cyano-4hydroxybenzoic acid hydrazide.
1 H NMR (DMSO-De): 5 5.02 2H), 5.44 1H), 7.14 1H), 7.69 3H), 7.91 1H), 8.10 1H), 8.14 1H), 8.27 1H), 8.87 1H), 9.06 1H), 11.84 (brd s, 2H); MS (ACPI): 346.3, 347.2.
EXAMPLE 121: 0 NN OH
CI
ci The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-chloro-4hydroxybenzoic acid hydrazide.
'H NMR (DMSO-D 6 8 5.02 2H), 5.43 1H), 7.10 1H), 7.66 3H), 7.80 1H), 7.90 1H), 8.02 1H), 8.15 1H), 8.87 1H), 9.08 1H), 10.98 1H), 11.79 (s, 1H); MS (APCI): 355.5 WO 99/01423 PCT/DK98/00287 209 EXAMPLE 122: 0 OH HO
H
F
The above compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of the above aldehyde with 3-fluoro-4hydroxybenzoic acid hydrazide.
'H NMR (DMSO-D 6 d4.84 2H), 6.91 1H), 7.43-7.53 4H), 7.62 1H), 7.72 (d, 1H), 7.96 1H), 8.68 1H), 8.98 1H), 11.71 (brd s, 1H); MS (APCI): 339.4, 340.3.
The compounds of formula II can also be prepared by parallel synthesis using the protocol mentioned above in a combinatorial approach. Thousands of compounds of formula II can thus be prepared by this combinatorial approach which can be semi- or fully automated. The automation 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 aldehydes or ketones may be prepared according to Scheme II by a combination of a selected number of aldehydes or ketones with a selected number of alkylating reagents. In the second step the formed aldehydes/ketones can be combined with a selected number of the hydrazides (which may be synthesized according to Scheme I) thereby generating a predetermined very large number of compounds as single entities.
The synthesized compounds mentioned above are examples of such compounds that can be prepared using this combinatorial methodology.
By application of the above methodology, the following compounds may also be synthesized: WO 99/01423 210 EXAMPLE 123: OMe H :H IN/
OCF
3
H
EXAMPLE 124:
CH
3 HO 0 N-N
OF
ci H 0 /OF
H-
EXAMPLE 125:
F
HO
IN-N OCF3 H EXAMPLE 126:
CI
HO~~ 0 N-N
OF
H PCT/DK98/00287 WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 127:
CH
3 EXAMPLE 128:
CH
3 EXAMPLE 129:
/CH
3
OH
3 EXAMPLE 130: EXAMPLE 131: WO 99/01423 WO 9901423PCT/DK98/00287 212 EXAMPLE 132: EXAMPLE 133:
CHF
2
N-
H
EXAMPLE 134: MeC OMe EXAMPLE 135: *0 OCF3 MeO EXAMPLE 136: OMe WO 99/01423 WO 9901423PCT/DK98/00287 213 EXAMPLE 137:
CH
3 EXAMPLE 138: HO- OMe
CH
3 EXAMPLE 139:
CHF
2 EXAMPLE 140: HO0 N-N
OCF
3 H N" EXAMPLE 141: H-C X N-N a
OCF
3 H 3 WO 99/01423 PCT/DK98/00287 214 EXAMPLE 142:
HO'
N-N
C) 0 N(Et),
H
General procedure for the synthesis of further derivatized hydrazides of formula II: The compounds of general formula I may be prepared according to one embodiment of the invention, the alkylidene hydrazides of general formula II, as indicated in Scheme III, that is, by converting an alkylidene hydrazide (prepared according to the general method shown in Scheme I, and more specifically as in example 8) into a further derivatized alkylidene hydrazide. Thus, by reacting an amine with an alkylidene hydrazide that contains a leaving group X, (Scheme III) a new alkylidene hydrazide containing an amine in the group K of formula II can be formed.
SCHEME III 0
R
5a
I
A -N H-B-O(CH 2
)-CHR
3
(C
2 2 d D solvent, base 0 A N-N= (CH2)B- O-(CH,)-(CR 3 a
R
wherein A, B, D, n, R 4
R
3 aa, b and d are as defined for formula I and RS a is lower alkyl.
Specific examples illustrating the preparation of further derivatized hydrazides of formula II are provided below: EXAMPLE 143: WO 99/01423 PCT/DK98/00287 215 3-Chloro-4-hydroxybenzoic acid .N-diethylaminoethyl-N '-(4-trifluoromethoxybenzylamino)l]ethoxy -1 -naphthylmethylenelhydrazide 0 N~ 0N- N N NC II H OC HO N N ClCH 3 CH 3 N, N-diethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine: H
/"-CH
3 N
\CH
3
OCF
3 A solution of (4-trifluoromethoxy)benzaldehyde (1.9 g, 10 mmotes), N,N-diethylethylenediamine (1.16 g, 10 mmoles), zinc chloride (1.36 g, 10 mmoles) and sodium cyanoborohydride (1.26 g, 20 mmoles) in methanol (10 ml-) in a dry 100 mL round- bottom flask was stirred at room temperature for 8 hours. Water (20 mL) was then added and most of the methanol was removed invco The residue was distributed between ethyl acetate and 1 N HCI. The acidic aqueous phase was basified with excess of sodium hydroxide. Crude N,Ndiethyl-N'-(4-trifluoromethoxybenzyl)ethylenediamine was obtained. The crude product was used in the following reaction without further purification.
MS 291. 'H NMVR (CDC1 3 587.4 (in, 2H), 7.2 (in, 2H), 3.9 (bs, 2H), 3.1-2.6 (mn, 9H), 1.4- 1.1 6H).
To a flask containing N, N-diethyl-N'-(4-trifl uoromethoxybenzyl)ethylenediainine (0.29 g, 1 minole) in 0 MF (5 mL) was added [1 -(4-chloroethoxy)naphthyl] (3-chloro-4-hydroxy)benzoic acid hydrazide (0.41g, 1 minole) and triethylainine (0.1 g, iiniole). The resulting solution was heated at 8000 overnight. Removal of most of the solvent in vacuo followed by flash chromatography (10: 1 CHC1 3 /MeOH) on silica gel provided the title compoound as a brown solid.
WO 99/01423 PCT/DK98/00287 216 'HNMR (DMSO-d 6 8 11.7 (1 9.0 bs, 2H), 8.4-7.0 (in, 12 4.75 (bs, 1 4.65 (bs, 1 H), 4.55 1IH), 4.35 1 4.15 1 3.9 (bs, 1 3.5 4H), 3.05 1 1.3 3H), 0.95 3H). 134-136'C. MS 657, 659.
EXAMPLE 144: 3-Chloro-4-hvdroxvbenzoic acid f4-[2-(4-trifluoromethoxvAbenz laminnthnxv1-1 -nnrnhthvI methylenelhydrazide 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 1 g, 1immole). The resulting solution was heated at for 16 hours. Removal of most of the solvent in vacuo, followed by flash chromatography (10:1 CHCI 3 IMeOH) on silica gel provided the title compound as a brown solid.
1 HNMR (DMSO-d, 6 5 11.6 1H), 9.0 (m 2H), 8.3 (in 1H), 8.0 7.8 2H), 7.7 (mn,1 7.6 (in, 1 7.5 3H), 7.3 (in, 2H), 7.1 (in, 2H), 4.3 2H), 3.9 2H), 3.0 2H).
MS 557, 559.
By application of the above methodology the following compounds of the invention were synthesized: EXAMPLE 145: WO 99/01423 PCT/DK98/00287 217 3-Chloro-4-hydroxybenzoic acid (3 .5-dimethoxy-4-[2-(4-trifluoromethoxybenzylamino)ethoxvlbenzylidenelhydrazide 1 HNMR (CD 3 OD): 8 2.90 (brd t, 2H), 3.75 6H), 3.89 2H), 4.08 (brd t, 2H), 6.87 (d, 1 7. 10 2H), 7.20 2H), 7.43 2H), 7.65 (in, 1 7.82 (in, 1 8.11 (brd s, 1 MS (APOI): 567.9.
EXAMPLE 146: 3-Chloro-4-hydroxybenzoic acid L4-[2-(2-p2iperidin-1 -yl-ethylamino)ethoxyjnaphth-1ylmethylenelhydrazide 1 H NMR (DMSO-d 6 8 1.53 (in, 2H), 1.74 (in, 4H), 3.12 (mj, 2H), 3.40 (mn, 2H), 3.54 (mn, 2H), 3.63 (mn, 4H), 4.52 2H), 7.10 1H), 7.14 1 7.60 1 7.71 1H), 7.80 (dd, 1 H), 7.83 1H), 8.00 8.51 1H), 8.95 1H), 8.98 1H), 11.69 MS (APCI): 495.0 EXAMPLE 147: 3-Chloro-4-hydroxybenzoic acid {4-[2-(3-diethylamino-propylamino)ethoxylnaphth-1ylmethylenelhydrazide WO 99/01423 PCT/DK98/00287 218 N CH 3
H
HOJ
cI 1 H NMR (DMSO-d 6 8 1.21 6H), 2.10 (in, 2H), 3.14 (in, 1 OH), 4.52 2H), 7.10 1 H), 7.14 1IH), 7.63 1IH), 7.73 (in, 1IH), 7.80 (dd, 1 7.84 1 8.00 1 8.46 8.93 8.98 (in, 1H), 9.20 (in, 2H), 9.69 (in, 1H), 11.00 1H), 11.69 1H); MS (APCI): 497.0.
EXAMPLE 148: 1 (3-Chloro-4-hydroxybenzoyl)hyd razonomethyllnaphth-1 -ylo-xylethyl)-4- Dhenvlaminopiperidine-4-carboxylic acid amide 1 H NMR (DMSO-de): 581.16 (mn, 2 1.88 (in, 2H), 2.03 (in, 2H), 2.80 (in, 2H), 2.92 (in, 2H), 4.37 (in, 2 4.40 (brd s, 2H), 4.44 1 6.55 6.62 (mn, 3 6.96 (s,1 7.03- 7.16 (mn, 5H), 7.61 (dd, 1 7.68 (dd, 1 8.00 1 8.27 1 8.94 1 8.97 (s, 1 11.63 1 MS (APCI): 586.4 EXAMPLE 149: 4-(2-{4-r(3-Chloro-4-hydroxybenzoyl)hyd razonomethyllnaphth-1 -yloxylethylamino)piperidi ne- 1 -carboxylic acid ethyl ester WO 99/01423 WO 9901423PCT/DK98/00287 1 H NMR (DMSO-d,): 561,10 3H), 1.15 -1.23 (in, 2H), 1.86 (in, 2H), 2.79 (in, 3H), 3.30 (in, 2H), 3.87 (in, 2H), 3.94 2H), 4.28 (mn, 2H), 7.03 1H), 7.05 (mn, 1 7.51 7.63 (in, 3H), 7.13 1 7.75 1 7.93 1 8.29 1 8.87 (m,2 11.55 1 MS (APCI): 539.1, 541 .0.
EXAMPLE 150: 3-Chloro-4-hydroxybenzoic acid A4-[2-(1 .2.3.4-tetrahydronaphth-1 -ylamino)ethoxy]-naphth-1 ylmethylenelhydrazide 1 H NMR (DMSO-ds): 6 1.76 (in, 1 2.04 (mn, 1 2.17 (mn, 2H), 2.75 -2.94 (mn, 2H), 3.61 (mn, 2H), 4.55 4.71 1 7.11 1 7.13 1 7.23 -7.35 (in, 3H), 7.61 (d, 1 7.67 1H), 7.71 (dd, 1 7.81 (dd, 1 7.86 1 8.01 I1H), 8.48 1IH), 8.94 (mn, 1H), 8.99 (in, 1H), 9.22 (in, 2H), 11.00 (s,1 11.64 MS (APCI): 514.0, 516.0 EXAMPLE 151: 1 -(2-{4-[(3-Chloro-4-hyd roxybenzoyLI)hyd razonoinethyl] naphth- 1 -yloxylethyl ~piperidine-4carboxylic acid amnide WO 99/01423 WO 9901423PCT/DK98/00287 MS (APCI): 495.0 EXAMPLE 152: 3-Chloro-4-hvdroxvbenzoic acid f4-r2-(2-trifluoromethoxvbpn7v:;min'-pthwv-1 -nnnhthvI.
methylenelhydrazide 0 EXAMPLE 153: 3-Chloro-4-hydroxybenzoic acid f4-r2-(4-morpholinylethylamino)ethoxyl-1 -naphthylmethylene)- By application of the above methodology the following compounds may also be synthezised: EXAMPLE 154:
H
N
CF
3 WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 155: EXAMPLE 156: N(Et) 2 EXAMPLE 157: HOr EXAMPLE 158: WO 99/01423 PCT/DK98/0087 222 EXAMPLE 159: /N(Et) 2 0 HO- OMe N
N-N
H OMe
OCF
3 EXAMPLE 160: O H HO-- 4- OMe
N-
H
OMe CH 3
HC
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 invention, the alkylidene arylsulfonyl hydrazides of general formula III, that is, by converting an arylsulfonyl halide, for example chloride or bromide to the corresponding hydrazide derivative and further reacting the product arylsulfonyl hydrazide compound with a substituted aldehydes or ketones to yield alkylidene arylsulfonyl hydrazide derivatives as illustrated in Scheme IV.
SCHEME IV WO 99/01423 PCT/DK98/00287 223 O NHNH 2 A-S-Cl NH 2
NH
2 A-S O O O 0 0 O\ (CH2)-B-(K)-D R HN-N= A-S O R 4 solvent, reflux
O
wherein A, B, K, D, m, n and R 4 are as defined for formula I.
The synthesis of the arylsulfonylhydrazide precursors is performed by application of general methodology, for example as described by Friedman, 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 mixture of these at -20°C to 100°C, preferably between 0°C 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 recrystallization 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 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 hydrazide.
By use of the above methodology the following compounds can be prepared: EXAMPLE 161: 3-Chloro-4-hvdroxvbenzenesulfonic acid (benzvlidene)hvdrazide WO 99/01423 PCT/DK98/00287 224
SH
IOI N, H c" N ;b
HO
CI
3-Chloro-4-hydroxybenzenesulfonyl hydrazide: A solution of 4.82 g (21.2 mmol) 3-chloro-4-hydroxy-benzenesulfonyl chloride, (prepared according to the procedure described by Popoff, I. Frank, J. Whitaker R. 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 temperature is maintained below 10 0 C. A precipitate formed after the addition was completed.
The mixture was stirred for an additional 30 min, and cooled to 0 OC. The solid was collected in a Buchner funnel, washed several times with distilled water, and air dried. Recrystallization from methanol provided 1.20 g 3-chloro-4-hydroxybenzenesulfonyl hydrazide as a white solid.
H NMR (DMSO-d6): 5 4.78 (bs, 4 6.72 J 8.6 Hz, 1 7.35 (dd, J 2.3, 8.6 Hz, 1 5.55 (J 2.2 Hz, 1 MS(CI): m/z 223, 221.
To a solution of 105 mg (0.48 mmol) of the above 3-chloro-4-hydroxybenzenesulfonyl hydrazide in 5 ml methanol was added 0.05 ml (52 mg, 0.49 mmol) benzaldehyde and one drop of acetic acid. After 30 min the mixture was concentrated. Flash chromatography (silica gel, 2:1 hexane/ethylacetate) provided 67 mg of the title compound as a solid.
1 H (DMSO-d6): 8 7.10 J 8.6 Hz, 1 7.38 3 7.55 (dd, J 2.3, 6.0 Hz, 2 H), 7.66 J 2.2, 8.6 Hz, 1 7.76 J 2.2 Hz, 1 7.90 1 11.3 2 MS(CI): m/z 311.
EXAMPLE 162: WO 99/01423 PCT/DK98/00287 225 3-Chloro-4-hvdroxy-benzenesulfonic acid [4-(4-trifluoromethoxybenzylox)-1 naphthvlmethylene]hydrazide HO SN O O N-N
OCF
H To a solution of 3-chloro-4-hydroxy-benzene sulfonyl hydrazide (105 mg, 0.48 mmol) in 5 ml methanol was added 4-trifluoromethoxybenzyloxy-l-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 chromatography (silica gel, 1:1 hexane/ethylacetate) provided 145 mg of the title compound as a solid.
'H NMR (DMSO-d 6 5 5.27 2 6.06 1 6.83 J 8.1 Hz, 1 7.10 J 8.1 Hz, 1 7.26 J 7.3 Hz, 2 7.50 7.60 5 7.80 1 7.85 (dd, J 3.0, 8.2 Hz, 1 8.08 J 2.1 Hz, 1 8.26 1 8.36 J 7.76 Hz, 1 8.67 J 8.5 Hz, 1 H).
CIMS m/z: 551, 553.
By using the above methodology, the following compounds may be prepared: EXAMPLE 163: HO /O CF3 HO S O N-N Cl H\ O H
CF
3 EXAMPLE 164: WO 99/01423 PCT/DK98/00287 226 EXAMPLE 165: HO S OMe o/N-N OCF 3
CI
H
OMe EXAMPLE 166: HO S OMe CH O0 N-N
C
l H o H 3
H
OMe 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: SCHEME V H
H
N-N (CH2) NaBHC N N-N -D A R A R 4 O CF 3
CO
2 H O where A, R 4 B, K, D, m and n are as defined for formula I.
The alkylhydrazide derivatives can be prepared by reduction Lane, C.F.(1975), Synthesis, p.135) of the corresponding alkylidene hydrazides using a metal hydride, such as sodium borohydride or sodium cyanoborohydride. The alkylidene hydrazide derivative is treated with between 1-10 equivalents, preferentially 1-3 equivalents, of sodium cyanoborohydride in a solvent 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 a catalyst such as hydrochloric acid, trifluoroacetic acid, acetic acid, or sulfuric acid. The reactions are performed at 0°C to 60 0 C, preferably at 10°C to 30 0 C. When the reaction is complete as judged by HPLC or TLC (silica gel, 1% methanol in dichloromethane as eluent) the solvent(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 concentrated to give the desired product. Specific examples illustrating the preparation of alkylhydrazides according to the invention are provided below.
EXAMPLE 167: 4-hydroxybenzoic acid (1-naphthylmethyl)hydrazide
H
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 temperature, the solvent was evaporated in vacuo. The residue was introduced into a silica gel column and eluted with dichloromethane/methanol Evaporation of the corresponding fractions in vacuo gave the title compound in 30% yield. MS (ESI) m/z 293 Using the same methodology as described above the following compound was prepared: EXAMPLE 168: 3-Chloro-4-hydroxybenzoic acid N-[4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzyllhydra-zide WO 99/01423 WO 9901423PCT/DK98/00287 1 H NMR (DMSO-d 6 8 1.18 6H), 2.87 (in, 1 3.75 6H), 3.90 (in, 2H), 4.80 2H), 5.43 (brd s, 1 6.68 2H), 6.98 1IH), 7.20 2H), 7.34 2H), 7.64 (dd, 1 7.87 (d, 1 9.89 (brd s, 1 10.80 1 MIS (APOI): 485.2.
Furthermore, the following compounds may also be prepared: EXAMPLE 169:
I/-/&OCF
3 EXAMPLE 170: EXAMPLE 171: WO 99/01423 WO 9901423PCT/DK98/00287 229 EXAMPLE 172:
HO-P
CI
EXAMPLE 173: HOF General procedure for synthesis of compounds of the general formula Xl: 0 11H Br OCH 3 stpA 0 Y BI-0-' OCH 3 H H 0 step B 0 Y OH H 0 step D 0 Ap 11kN
NH
2 step C formula XI A and B are as defined for formula I and -NRscR 5d is R 5 R4a 4b q (CH)~-Dwhere R 5
R
4 R b, c, q, d and D are as defined for formulalIor where 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 cesium carbonate in a solvent such as acetone, 2-methyl-3-pentanone, tetrahydrofuran, dioxane, DMSO, DMF, ethylene glycol, benzene, toluene or a mixture of the above solvents. The reactions are performed between 0°C to 130°C, preferably between 20°C to 100°C, most preferably at or about the reflux temperature of the solvent. The reactions are preferably conducted 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 concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent.
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 between 0°C to 130°C, preferably between 20°C to 100°C. When the reaction is complete as judged by disappearance of the staring ester by TLC or HPLC, the solvent may be removed by concentration at atmospheric or reduced pressure. The product can then be isolated by pouring the residue into water or cooled water and acidifying the mixture using an inorganic acid such as hydrochloric acid or sulfuric acid. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure.
The product can be further purified by either recrystallization from a solvent such as ethyl 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.
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, 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 0°C to 140*C, preferably between 10 0 C to 80"C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction 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 dichloromethane/methanol or chloroform/ethyl acetate.
Step D: The resulting acid is then coupled to a primary or secondary amine using one of the methods well-known to those skilled in the art. This coupling can be performed using one of the standard amide or peptide synthesis procedures such as by generating an active ester, an anhydride or an acid halide that can then react with the amine to give a compound of formula XI.
Step D can also be done combinatorially with a selected number of amines. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XI.
Specific examples illustrating the preparation of compounds of the general formula XI according 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-chlorophenvl)acetamide 0o N
H
H
HO
CI
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-l-yloxy) acetic acid methyl ester (13 g, 50 mmol) was filtered and dried in vacuo overnight.
1 H NMR (CDCI3): 5 3.86 3H), 4.93 2H), 6.80 1H), 7.61 1H), 7.72 1H), 7.90 (d, 1H), 8.42 1H), 9.29 1H), 10.22 1H).
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 HCI. The mixture was stirred until all of the ice was melted. (4-Formylnaphth-l-yloxy) acetic acid was filtered and washed with water.
Step C: To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (2g, 10.7 mmol) in DMSO (20 mL) was added the above (4-formylnaphth-l-yloxy) acetic acid (3g, 13 mmol) and a catalytic amount of acetic acid (10 drops). The solution was stirred overnight and diluted with ethyl acetate. The solution was washed with water 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-hydroxybenzoyl)hydrazonomethyl]naphth-1-yloxy} acetic acid.
WO 99/01423 PCT/DK98/00287 233 1 H NMR (DMSO-d,): 8 4.91 2H), 6.95 1H), 7.02 1H), 7.55 1H), 7.64 1H), 7.74 1H), 7.92 1H), 8.27 1H), 8.90 2H), 10.92 (brd s, 1H), 11.63 1H), 13.14 (brd s, 1H).
Step D: To a solution of the hydrazone-carboxylic acid (50 mmol) in anhydrous DMSO was added a solution of carbonyldiimidazole (55 mmol) in anhydrous DMSO. After the evolution of gases ceased (approximately 3-4 minutes), the amine was added and the reaction mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate and washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent afforded the crude material, which was purified by reverse phase HPLC chromatography to give the title compound.
1H NMR (DMSO-de): 8 4.99 2H), 7.04 2H), 7.36 2H), 7.65 4H), 7.79 2H), 7.99 1H), 8.40 1H), 8.72 1H), 8.92 1H), 10.42 1H), 10.96 1H), 11.69 (s, 1H); MS (APCI): 507.9.
By using the same methodology, the following compounds were prepared: EXAMPLE 175: N-(1-Benzylpyrrolidin-3-vl)-2-{4-[(3-chloro-4-hydroxy-benzoyl)hydrazonomethyl]naphth-1vloxvyacetamide WO 99/01423 PCT/DK98/00287 234 1 H NMR (DMSO-d,): 8 1.96 (in, 2H), 2.32 (in, 5H), 4.58 2H), 6.78 1 6.92 1IH), 7.15 (in, 5H), 7.47 1 7.52 1 7.62 2H), 7.82 1 8.18 (mn, 2H), 8.78 2H), 75 (brd s, 1 11. 52 1IH); M S (APCI1): 556.9.
EXAMPLE 176: 2-44-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyllnaphth-1 -yloxyb-N-indan- 1-yI-acetamide 1 H NMR (DMSO-d 6 5 1.94 (in, 1IH), 2.40 (mn, 1 2.80-3.07 (mn, 3H), 4.87 2H), 7.04 (d, 1 7. 10 1 7.21 (in, 4H), 7.61 1 7.69 I1H), 7.80 2H), 8.10 1 8.42 (d, 1H), 8.64 1 8.98 (in, 2H), 11.00 (brd s, 1 11.68 1 MS (APCI): 514, 516.
EXAMPLE 177: 2-f4-[(3-Chloro-4-hydroxvberlzoflhydrazonomethvllnaDhth-1 -vloxvl-N-(l 12.3 .4-tetrahvdronaphthalen-1 -yI)acetamide 1 H NMR (DMSO-d, 5 5 1.75 (in, 2H), 1.92 (in, 2H), 2.74 (mn, 2H), 4.87 (mn, 2H), 5.12 (mn, 1 H), 7.12 (in, 6H), 7.61 1 7.74 1 7.84 (mn, 2H), 8.01 1 8.40 1 8.62 1 H), 8.97 (mn, 2H), 11.72 1 MS (APCI): 528, 530.
WO 99/01423 PCT/DK98/00287 235 EXAMPLE 178: 2-{4-[(3-Chloro-4-hydroxybenzoyl )hydrazonomethyllnaghth-1 -yloxyl--2-(4-chlorpahenyflethyllacetamide 1 H NMR (DMSO-d.): 5 2.40 2H), 2.79 2H), 4.74 2H), 6.96 1 7.10 1IH), 7.63 1 7.69 1 7.72 (in, 2H), 7.81 1 8. 01 (in, 2H), 8.23 1 8.40 1 8.95 1 9.01 1 10.98 (brd s, 1 11.70 1 MS (APOI) 538.8, 537.8.
EXAMPLE 179: 2-44-f (3-Chloro-4-hydroxybenzoyl)hydrazonomethyllnahth-1 -yloxy}-N-[3-(4-methylliperazin- 1 -yflpropyllacetamide 1 H NMR (DMSO-d 6 8 1.50 (in, 2H), 2.26 (mn, 2H), 2.48 (mn, 5H), 3.01 (in, 8H), 4.53 2H), 6.78 1 6.89 1 7.38 1 7.47 1 7.5 2H), 7.76 1 8.01 I1H), 8.22 1 8.68 1 8.74 1 10.74 (brd s, 1 11.45 1 MS (APOI): 538.0.
EXAMPLE 180: 3-Chloro-4-hydroxybenzoic acid 1.2. 3.4-tetrahyd roisoguinolin-2-yI )-2-oxoethoxylnaphth-1 -ylmethylenelhydrazide WO 99/01423 WO 9901423PCT/DK98/00287 1 H NMR (DMSO-d 6 8 2.90 2H), 2.75 (in, 2H), 4.70 2H), 5.24 2H), 6.90 2H), 7.10 (in, 4H), 7.66 (in, 4H), 8.01 1H), 8.34 1H), 8.95 (in, 2H), 10.97 (brd s, 1H), 11.68 (brd s, 1H); MS (APCI): 514.2.
EXAMPLE 181: 2- 4-r(-Chloro-4-hy r xy-benzoI hydraonoin hInaohtth-1 -vioxvl-N-('3trifluoromethoxvbenzvflpcetpmide 1 H NMR (DMSO-d 6 8 4.49 2H), 4.90 2H), 7.13 (in, 2H), 7.42 (in, 4H), 7.59 (dd, 1 H), 7.68 (dd, 1 7.78 (in, 2H), 8.03 1 8.51 1 8.79 1 9.0 (in, 2H), 10.85 (brd s, 1 11.72 1 MS (APOI): 572. 1.
EXAMPLE 182: 3-Chloro-4-hydroxybenzoic acid 4 -{2-[4-(4-bromophenyl-4-hydroxypiperidin-1 -yUl-2oxoethoxylnarohth- 1 -vlmethylene~hvdrazide WO 99/01423 WO 9901423PCTIDK98/00287 MS (APCI): 636, 638.
EXAMPLE 183: 2-f4-F(3-Chloro-4-hydroxvbenzovfhdrazonomethvllnarhth- I -vioxvl-N-(4trifluoromethylsulfa nytbenzyl)acetamide 1 H NMR (DMSO-d 8 5 4.48 2H), 4.88 2H), 7.08 (in, 2H), 7.45 2H), 7.68 (in, 4H), 7.82 (in, 2H), 8.01 1 8.52 I 8.87 1 8.96 1 9.01 1 10. 98 (brd s, 1 11.72 1 MS (APCI): 588.2 WO 99/01423 PCT/DK98/00287 238 EXAMPLE 184: 2-44-[(3-Chloro-4-hydroxy-benzoyl)hydrazonomethyllnaphth-1 -Yloxyl-N-(3 .4dichlorobenzyl)acetammde 1 H NMR (DMSO-d 6 8 4.42 2H), 4.91 2H), 7.08 1 7.11 1 7.22 I1H), 7.48 -7.76 (in, 4 7.82 2H), 8.04 1 8.51 (dd, 1 8.83 (mn, 1 8.91 1 H), 10.02 1 11.00 (brd s, 1 11.73 1 MS (APCI): 556.0 EXAMPLE 185: 'H NMR (DMSO-De): 5 0.97 6H), 2.42 (in, 2H), 2.50 (mn, 2H), 2.68 (septet, 1H), 3.49 (in, 4H), 5.12 2H), 7.03 1 7.08 1IH), 7.60 I1H), 7.68 1 7.80 2H), 8.01 (d, 1 8.33 1 8.94 1 9.00 1 11.68 1 MS (APCI, neg.): 507.1, 509. 1.
EXAMPLE 186: 1 0 CN.. CH 3
HOH
'H NMR (DMSO-D 6 8 1.75 (mn, 2H), 2.25 (in, 2H), 2.24 3H), 2.39 (quintet, 1 3.26 (in, 2H), [2.84 1.5H) 3.04 1.5H), 3H], 5.16 2H), 6.72 1 7.07 1 7.62 1 H), WO 99/01423 PCT/DK98/00287 239 7.68 1 7.78 (dd, 2H), 8.00 1 8.34 (in, 1 8.94 1 9.00 1 11.65 (brd s, 1H); MS (APOI): 495.2, 497.2.
EXAMPLE 187: 00 HO I
CH
3 cI 'H NMR (DMSO-D 6 8 0.86 3H), 1.48 (in, 4H), 2.38 1 2.72 (mn, 1 3.09 I1H), 3.84 1 4.18 1 5.09 (mn, 2H), 7.03 1 7.11 1 7.59 1 7.64 1 H), 7.82 2H), 8.01 1 8.33 1IH), 8.94 1 9.00 1 11.0 (brd, 1 11.69 (brd s, 1H); MS (APCI): 480.1,482.1.
EXAMPLE 188: 1- 0 0 N N
HO(AH
'H NMR (DMSO-De): 582.88 1.5H) 1.5H), 3H], 2.95 1 3.01 1.5H), 3.10 (s, 3. 10 1IH), 3.69 1 3.81 1IH), 5.05 2H), [6.66 6.95 1 7.10 1 H), (7.20 7.38 1iH], 7.29 1 7.67 (mn, 5H), 8.01 1 8.30 1 8.53 (dd, 1IH), 8.97 (in, 2H), 11.67 (brd s, 1 MS (APCI): 517.3, 519.2.
EXAMPLE 189: 0e 0 H H N NN. OMeH HO
(A
cI WO 99/01423 PCT/DK98/00287 240 H NMR (DMSO-D 6 583.88 6H), 4.75 2H), 6.93 1 7.08 (in, 3H), 7.34 (dd, 1 H), 7.74 (dd, 1 7.79 1 7.95 1 8.37 1 9.74 1 10.03 (in, 1 10.96 (brd s, 1lH), 11. 76 (brd s, 1 M S (APOI1): 534.4, 536.2.
EXAMPLE 190:
CH
3 0
CH
3 MeO 0
H
N' H
HOH
'H NMR (DMSO-D 6 8 1.18 6H), 2.85 (mn, 1H), 3.87 3H), 4.76 2H), 6.71 1H), 6.78 1 7.06 1 7.20 2H), 7.58 2H), 7.78 (dd, 1 7.82 1 7.99 (d, 1 8.70 1 10.04 1IH), 10.92 (brd s, 1 11.62 (brd s, 1 MS (APOI): 496.5, 498.2.
EXAMPLE 191: 0 <OCF 3 0H
HOH
HO
'H NMR (DMSO-D 6 8 4.88 2H), 6.93 2H), 7.23 2H), 7.47 7.70 (mn, 6H), 7.86 (d, 1 8.30 I1H), 8.80 1 8.87 1 10.34 1 10.82 (brd s, I1H), 11.55 (brd s, 1 MS (APCI): 558.5, 560.0.
WO 99/01423 PCT/DK98/00287 241 EXAMPLE 192: cI N i
H
HO(
H
'H NMR (DMSO-D 6 4.06 3H), 4.94 2H), 6.81 1H), 6.89 1H), 7.19 1H), 7.45 1 7.90 (in, 3H), 8.10 I1H), 8.82 1 10.62 1 11.07 (brd s, 1 11.75 1IH); MS (APCI): 523.3, 524.8, 526.6.
EXAMPLE 193: 0 0 N
H
HO
Cl 'H NMR (DMSO-D 6 5 1.68 (mn, 2H), 2.01 (mn, 2H), 3.05 (mn, 2H), 3.35 (mn, 2H), 3.86 (mn, 1IH), 4.26 2h), 4.81 2H), 6.95 1 7.09 1 7.46 5H), 7.59 (in, 1 7.66 1 H), 7.77 1IH), 7.98 1 8.34 1 8.41 1 8.92 (in, 2H), 9.65 (brd s, 1 11.02 (brd s, 1IH), 11.80 (brd s, 1 MS (APCI): 571.3, 572.3, 573.3.
EXAMPLE 194:
H
HO
CI
'H NMR (DMSO-Dr): 5 2.79 2H), 3.43 (qt, 2H), 4.71 2H), 6.95 1H), 7.08 1H), 7.17 (in, 1 7.26 -7.30 (mn, 3H), 7.61 1 7.67 1 7.76 (in, 2H), 7.99 1 8.24 WO 99/01423 PCT/DK98/00287 242 1 8.38 I 8.91 1 8.98 1H), 10.94 1H), 11.67 1H); MS (APCI): 53 6.3, 538.2, 539.1.
EXAMPLE 195: 'H NMR (DMSO-D 6 84.42 2H), 4.87 2H), 7.06 (in, 2H), 7.38 2H), 7.60 1 H), 7.63 (mn, 1 7.80 1 7.99 1lH), 8.49 1 8.79 1 HJ), 8.93 1 8.98 1 H), 10.95 1 11.68 1lH); MS (APCI): 558.2, 560. 1.
EXAMPLE 196: 4-(4-bromophenyl-3 .4-dihydropiperadinylacetamideoxy)naphth-1 -yI inethylene-3-chloro-4hydroxybenzoic acid hydrazone Reaction scheme: WO 99/01423 PCT/DK98/00287 243 cl c i CI
CI
o o
H
NN
N
H A OH B C Br Br Br 0 0 0 6 0 Na a D 0 D N N H Br HOP H N Br
CI
4-(4-bromophenvl-4-piperidinol chloroacetamide (step A): To a solution of 4-(4-bromophenyl)-4-piperidinol (5 g, 19.5 mmol) and diisopropylethylamine (2.8 g, 21.5 mmol) in DMF (30 mL) was added dropwise chloroacetylchloride 2.2 g, 21.5 mmol). After stirring the mixture for one hour, the mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate 1 N HCI water, brine, and dried over MgSO4. The solution was concentrated and chromatographed over silica gel with ethyl acetate to give the product as a brown solid (4 g, 62 1 H NMR (DMSO-D 6 5 1.21 2H), 1.71 1H), 1.96 1H), 2.71 1H), 3.37 1H), 3.70 1H), 4.27 1H), 4.54 2H), 5.26 1H), 7.42 2H), 7.51 2H).
4-(4-bromophenyl)-3.4-dihydropiperidine chloroacetamide (step B): To a solution of 4-(4-bromophenyl)-4-piperidinol chloroacetamide (4 g, 12 mmol) and diisopropylethylamine (4.6 mL, 26 mmol) in THF (40 mL) cooled in an ice-bath was added methanesulfonyl chloride (2 mL, 26 mmol) and the mixture was refluxed for 16 hours under a nitrogen blanket. The reaction mixture was diluted with ethyl acetate and washed with 1 N HCI aqueous NaHCO 3 brine and dried over MgSO 4 The solvent was evaporated and the product was chromotographed over silica gel with ethyl acetate/hexane 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 2H), 3.62 (in, 2H), 4.14 (dd, 2H), 4.42 2H), 6.21 1 H), 7.36 (in, 2H), 7.51 2H).
4(-4-bromophenyl-3.4-dihydropiperadinylacetamideoxy'naphthaldehyde (step. C): A mixture of 4-(4-bromophenyl)-3,4-dihydropiperidine chloroacetamide (1.5 g, 4.8 mmolL4hydroxynapthaldehyde (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 and washed with brine dried over MgSO,, and concentrated. Silica gel chromatography with ethyl acetate/hexane provided the product (1.4 g, 1H NMVR (DMSO-D 6 8 2.27-2.32 (in, 2H), 3.49-3.55 (mn, 2H), 3.94 (brd s, 1IH), 4.06 (brd s, 1 5.08 1 5.13 I1H), 6.05 1 6.97 1 7.20 1IH), 7.34 2H), 7.42-7.47 (in, 1 7.52-7.57 (in, 1 7.92 1 8.16 1 9.01 1 9.97 1IH).
4(-4-broinophenyl-3,4-dihydropiperadinyiacetamideoxy)naphth-1 -yl methylene-3-chloro-4hydroxybenzoic acid hydrazone (step D): The title compound was prepared according to the general procedure for the synthesis of alkylidene hydrazides from the condensation of 3-chloro-4-hydroxybenzoic acid hydrazide and 4-(4-broinophenyl-3,4-dihydropiperad inylacetainideoxy)naphthaldehyde: 'H NMVR (DMSO-D 6 8 2.47-2.58 (in, 2H), 3.72 (br s, 2H), 4.13 1 4.26 1 5.14 (s, 1IH), 5.18 1 6.23 1 6.50-6.53 (in, 1IH), 7.03-7.06 (in, 1 7.35-7.38 (in, 2H), 7.52 2H), 7.58 2H), 7.59-7.67 (in, 1 7.75 1 7.84 1IH), 8.32 1 8.89 1 H), 8.92 1 11.41 1IH); MS (APCI): 618.1, 620.1, 621.1, 622.1 WO 99/01423 WO 9901423PCTIDK98/00287 EXAMPLE 197: EXAMPLE 202: 00
N*
HO(?
H
EXAMPLE 198:
CH
3 EXAMPLE 203: 0OH IH HO
-P
cI EXAMPLE 199: EXAMPLE 204: N( OMe EXAMPLE 205: EXAMPLE 200: EXAMPLE 206: EXAMPLE 201: WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 207: 0 Nz, I H
HO
cI EXAMPLE 208: 15 EXAMPLE 212: 0 EXAMPLE 213: 0 HO )ci EXAMPLE 209: EXAMPLE 214: EXAMPLE 210: EXAMPLE 215:
H
3
HO
cI N' H HO fi:-A cI EXAMPLE 211: 0N'
IH
HO-
CI
EXAMPLE 216: 0
,NN
HO-
cI WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 217: EXAMPLE 222: N CH 2 EXAMPLE 218: EXAMPLE 223: W~e 0 0,)
HOH
,(AC e
C
EXAMPLE 224: EXAMPLE 219: 0 OK11
,CF
3
HO
Ci EXAMPLE 225: EXAMPLE 220: EXAMPLE 221: EXAMPLE 226:
N
HOJ;
H
CI
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 227: 0 0 Ok
HOJ()
EXAMPLE 228: 0C3 H NHa CH 3 20
HOH
HO
EXAMPLE 229: 0 CH 3 N H
HO"I
CI
EXAMPLE 230: EXAMPLE 232: EXAMPLE 233: 0 N Nt I H
HO
CI
EXAMPLE 234: 0
H
3 C H 0 N)
CH
3 N NN
CH
3 HI(P
H
HO
EXAMPLE 235: 0 O0 A 'N
I
6H3 EXAMPLE 236: EXAMPLE 231: WO 99/01423 WO 9901423PCT/DI(98/00287 EXAMPLE 237: EXAMPLE 242: 0 NH 2 HO oo cI EXAMPLE 243: EXAMPLE 238: 0
N,
N N
H
HO
cI EXAMPLE 239: 00 0 N'I H F HO'
H
cI EXAMPLE 244: 0 H3
N
HO(?
H
HO
EXAMPLE 245: EXAMPLE 240: 0
N.
I H
HO
CI
_0
H
3 C %11 0 EXAMPLE 246: EXAMPLE 241: 00c
N
HOJ('l
CI
WO 99/01423 PCT/DK98/00287 250 EXAMPLE 247: 15 EXAMPLE 252: O 0 N.N II_ N' N N(NI HOJ(T Ha CH 3 HO' H EXAMPLE 248: EXAMPLE 253: CH3 0 O N' 2, N
N
I H I JH y HO" HO H3C 0 cI cI H 3
CCH
EXAMPLE 249: EXAMPLE 254: 1 0H 0 O..l)t 0 0 ,CH 3 .N N N4 N NN' H HI I H ci ci EXAMPLE 250: EXAMPLE 255: 0 0 SOMe0 o N okNN .N.N 0 0--N CI NN
N
I HN HOJ?
HN,,
cl HO"? cl EXAMPLE 251: EXAMPLE 256: N 0 0 O\<3 -0 0 OIJN )<H NN.N CH 3 I N N N HO'P HO H WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 257: 0
HO
EXAMPLE 258: 15 EXAMPLE 262: 0 F 0 N Nk H H 3
C
HO Q
H
cI EXAMPLE 263: 0
N.
I H
HO
CI
EXAMPLE 264: EXAMPLE 259: 0
HO
EXAMPLE 260: 0 N(
NN
I H
HO
CI
EXAMPLE 261: 0 0 EXAMPLE 265: EXAMPLE: 266 Ik N WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 267: EXAMPLE 272: .N'7 EXAMPLE 268: 20 EXAMPLE 273:
-CH
3
-N
CH
3 0
H
3 C CH 3 CH3 EXAMPLE 269: 0 I H
HO
cl EXAMPLE 270: EXAMPLE 274: 0 I H
HO
CI
EXAMPLE 275: 0 0 0 0 N NNZ H N N H 3
C
IO(
H
EXAMPLE 271: 0 0 I HN I H
HO'Q
cI 0 Cl-I o N.
N H N CH 3 HOi? EXAMPLE 276: WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 277: EXAMPLE 282: 00
N
HO;
)H
EXAMPLE 278: 0
N-~
I H
HO
cI EXAMPLE 283: 00
NH
2 EXAMPLE 284: EXAMPLE 279: 0 .0 "fly CF3 H acI EXAMPLE 285: EXAMPLE 280: 0 O~k0 HO 3C N CH 3 Cl 0 Ci N C-3 IO-
H
EXAMPLE 286: EXAMPLE 281: 0
N
I H
HO
cI WO 99/01423 WO 9901423PCT/DK98/00287 254 EXAMPLE 287: EXAMPLE 291: o
N
HO NN 0)NY HO C H 3 cI
HO
EXAMPLE 288: 15 EXAMPLE 292.
N N N* NH H HC
N'H
HO jj- HO c
CI
EXAMPLE 293: EXAMPLE 289: H N
NN
OO N Cl EXAMPLE 294: EXAMPLE 290: 00 0 N N N c N H
H
HO PA b rCH 3
C
CI CM WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 295: 0 fN HO N-H EXAMPLE 296: EXAMPLE 299:
N
EXAMPLE 300: 00
CI
0
N
CH3 EXAMPLE 297: EXAMPLE 301: 0 N NN NNH HO
J-
cI 0 HOq
A
cI EXAMPLE 298: ~N h 0\ 0 WO 99/01423 PTD9/08 PCT/DK98/00287 EXAMPLE 302: 15 EXAMPLE 307: 0* Q N
H
EXAMPLE 303: EXAMPLE 308: N0 I H HO(? OMe cI EXAMPLE 304: EXAMPLE 309: EXAMPLE 305: EXAMPLE 310: 0 0 o) N N.N N
.NTN'
HO(? H N
CI
EXAMPLE 306: 0 Nj
NN:
H
HO
cI EXAMPLE 311: WO 99/01423 WO 9901423PCT/DK98/00287 257 EXAMPLE 312: 15 EXAMPLE 317: 6H 3 EXAMPLE 318: EXAMPLE 313: 0 I H
HO
CI
EXAMPLE 314: EXAMPLE 319: EXAMPLE 320: EXAMPLE 315: EXAMPLE 316: 0
HOH
EXAMPLE 321: 0 0 N N
N
HO
N
WO 99/01423 WO 9901423PCTIDK98/00287 EXAMPLE 322: 15 EXAMPLE 327: I H
HO
C,
EXAMPLE 328: EXAMPLE 323: EXAMPLE 329: EXAMPLE 324: 0
N-
HOH
HO
25 EXAMPLE 330: EXAMPLE 325: 0N.N2'kN HO'I
H
EXAMPLE 326: A 0 0 OANLCH3 HO(? H CH 3
HO
EXAMPLE 331:
C'
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 332: EAPE37 0 NN Nt
H
HO
cI EXAMPLE 333: 20 EXAMPLE 338:
NN
EXAMPLE 339: EXAMPLE 334: 0 AN
N,.
HO
CI
EXAMPLE 335: 0 N N.
H
HO
CI
EXAMPLE 336: 0
N
H
HO
C,
25 EXAMPLE 340: 00 N( N N yOEt HO H OEt
HO
EXAMPLE 341: 0 0
N
N NN
H
HO'f H H cI WO 99/01423 PCT/DK98/00287 EXAMPLE 342:
N
0OH WO 99/01423 PCT/DK98/00287 261 General procedure for synthesis of compounds of the general formula XII: 0 O B A NH2 O step A A H
H
0
O
stepB A H R formula XII A and B are as defined for formula I and -NRR 5 d is
R
5
R
4 a R 4 b P4-2 c (CH,)-D
(CH
2 )D where Rs R 4a
R
4 b, c, q, d and D are as defined for formula I or where is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, 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 0"C to 140"C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction 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 dichloromethane/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 anhydride 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 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. Altematively, 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.
Specific examples illustrating the preparation of compounds of the general formula XII according to the invention are provided below.
Preparation of 4-formyl-1-naphthylacetic acid: This compound was prepared from the reduction of 4-cyano-1-naphthylacetic acid in the presence of 85% formic acid and Raney alloy as described in the literature. References 1) A.A. Shulezhko and A.I. Kiprianov, J. org. Chem., (USSR) English translation, 4, 1968, p.1052. 2) Zh. Org. Khim., 4, 1968, p. 1089.
Preparation of 4-[3-Chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylacetic acid (step
A):
This compound was prepared according to the general procedure for the synthesis of alkylidene hydrazides from the condensation of 4-formyl-1-naphthylacetic acid above and 3chloro-4-hydroxybenzoic acid hydrazide.
WO 99/01423 PCT/DK98/00287 263 'H NMR (DMSO-D 6 8 4.1 2H), 7.1 1H), 7.5 1H), 7.7 (qt, 2H), 7.8 1H), 7.9 (d, 1H), 8.0 1H), 8.1 1H), 8.8 1H), 9.1 1H), 11.0 (brd s, 1H), 11.8 1H), 12.2 (brd s, 1H); MS (APCI): 383.4, 385.2.
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 suspension of NaH in mineral oil (3.0 g) added in portions with cooling (temp 15 At 15 *C was a solution of ethyl bromoacetate (8.4 ml) in DMF (15 ml) added drop wise over minutes. The resulting mixture was stirred at room temperature for 16 hours and evaporated invacuo. 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 concentrated to afford 15.9 g ethyl (3-formylindolyl)acetate.
'H NMR CDCI 3 1.26 3H), 4.22 2H), 4.90 2H), 7.21 7.35 3H), 7.72 1H), 8.30 1H), 10.0 1H).
(3-formylindolyl)acetic acid: Ethyl (3-formylindolyl)acetate (15.9 g) was dissolved in 1,4-dioxane (100 ml) and added 36% aq. NaOH (10 ml). The resulting mixture was stirred at room temperature for 4 days. Water (500 ml) was added and the mixture was washed with diethyl ether (150 ml). The aqueous phase was made acidic with 5N HCI and extracted with ethyl acetate (250 150 ml). The combined organic extracts were dried (MgSO 4 and evaporated in vacuo to afford 10.3 g (73 over two steps) of (3-formylindolyl)acetic acid.
'H NMR DMSO-d 5 4.94 2H), 7.27 7.36 3H), 7.98 1H), 8.25 1H), 10.0 (s, 1H), 12.5 (bs, 1H).
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 CDCI 3 5 7.28 7.36 2H), 7.41 J 3.0 Hz, 1H), 7.60 7.70 2H), 8.62 (brd s, 1H), 10.20 1H). GC-MS 146 Ethyl (4-formylindolyl)acetate: This compound was synthesized according to the general procedure for N-alkylation of indoles.
'H NMR (CDCI 3 8 1.13 J 6.9 Hz, 3H), 4.15 J 7.2 Hz, 2H), 4.86 2H), 7.22 7.35 3H), 7.49 J 8.6 Hz, 1H), 7.60 J 7.3 Hz, 1H), 10.20 1H).
(4-Formylindolyl)acetic acid: This compound was synthesized according to the general procedure for saponification of esters.
'H NMR DMSO-d 6 55.15 2H), 7.12 J 3.0 Hz, 1H), 7.36 J 7.9 Hz, 1H), 7.61 J 3.1 Hz, 1H), 7.71 J 7.3 Hz, 1H), 7.82 J 8.2 Hz, 1H), 10.20 1H), 12.94 (brd s, 1H).
Preparation of (5-formylindolyl)acetic acid: In a 100 mL round-bottom flask was placed NaH (0.4 g, 60% dipersion in mineral oil, mmol) and anhydrous THF (10 mL) was added. To the suspension was added a solution of (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 acetate (3x50 mL), dried (MgSO 4 and concentrated. The residue was purified by column chromatography using hexane: ethyl acetate 2:1 as eluent to yield 1.86 g of the desired product.
WO 99/01423 PCT/DK98/00287 265 'H NMR (CDC3) 5 2.32 3H), 6.65 J 3.6 Hz, 1H), 7.19 J 7.9 Hz, 2H 7.41 (d, J 8.6 Hz, 1H), 7.57 J 3.6 Hz, 1H), 7.63 1H), 7.75 d, J 8.3 Hz, 1H), 7.99 J 8.6 Hz, 1H).
To a solution of 5-cyano-N-tosylindole (0.66 g, 2.2 mmol) in anhydrous THF (20 mL), was added 1M DIBAL in hexane (4 mL, 4 mmol) via syringe at 0°C. The mixture was stirred at room temperature for 16 h, poured into ice-cooled 1 N hydrochloric acid (50 mL), extracted 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 pure 5-formyl-N-tosylindole was obtained.
'H NMR (CDCIl) 8 2.29 3H), 6.74 J 3.7 Hz, 1H), 7.21 J 8.3 Hz, 2H), 7.65 J 3.7 Hz, 1H), 7.77 J 8.4 Hz, 2H), 7.82 (dd, J 1.4, 8.6 Hz, 1H), 8.02 J 1.1 Hz, 1H), 8.09 J 8.6 Hz, 1H 9.99 1H).
(0.5 g, 1.7 mmol) was dissolved in a mixture of methanol (10 mL) containing 5% aqueous KOH solution (5 mL). The mixture was refluxed for 3_h, neutralized with 1N 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 of the desired product.
'H NMR (CDCl 3 5 6.70 J 2.1 Hz, 1H), 7.32 J 2.3 Hz, 1H), 7.49 J 8.4 Hz, 1H), 7.78 dd, J 1.5, 8.6 Hz, 1H), 8.19 1H), 9.45 1H), 10.15 1H). GC-MS 146.
Ethyl This compound was synthesized according to the general procedure for N-alkylation of indoles.
WO 99/01423 PCT/DK98/00287 266 1H NMVR (CDC'I 3 5 1.27 J 6.8 Hz, 3H), 4.22 J 7.2 Hz, 2H), 4.87 2H), 6.70 J 3.4,Hz, 1 7.18 J 3.0 Hz, 1 7.36 J 8.7 Hz, 1 7.78 J 8.3 Hz, 1 8.14 1 10. 01 1 H).
(5-Formylindolyl)acetic acid: this compound was synthesized according to the general procedure for saponification of esters.
1H NMR (DMSO-de) 5 5.10 2H), 6.66 J 3.0 Hz, 1 7.48 J 3.0 Hz, 1 7.56 (d, J 8.7 Hz, 1 7.66 J 8.3 Hz, 1 8.17 1 9.97 I 12.9 (brd s, 1 H).
General procedure for preparation of [(3-chloro-4-hydroxybenzoyl)hyd razonomethyllindolyl acetic acids: These compounds were prepared according to the general procedure for the synthesis of alkylidene hydrazones by condensation of the various formylindolylacetic acids with 3-chioro- 4-hydroxy benzoic acid hydrazide.
3-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]indoly acetic acid: 'H NMR (DMSO-Ds): 8 2.81 J 6.5, 2H), 4.43 J 6.5, 2H), 7.06 J 8.5, 1 7.15- 7.28 (in, 2H), 7.56 J 8. 1, 1 7.75 J 8.5, 1 7.83 1 7.95 1 8.27 J 7.65, 1 8.54 1 10.88 (br s, 1 11.41 1 LRMS calcd for H, 8 Cl, N 3 04, (M H) 384, found 384.0.
4-f (3-chloro-4-hydroxybenzoyl )hydrazonomethyl]indoly acetic acid: 'H NMR DMSO-d 6 5 5.09 2H), 7.09 J 8.6 Hz, 1 7.16 7.25 (in, 2H), 7.32 J 7.2 Hz, 1 7.45 -7.55 (mn, 2H), 7.81 J 8.2 Hz, 1 8.01 J 1.8 Hz, 1 8.68 (s, 1 10.96 1 11.71 1IH), 12.90 1 MS APOI, neg.): 370.
5-[(3-Chloro-4-hydroxybenzoyl )hydrazonomethylindolyI acetic acid: WO 99/01423 PCT/DK98/00287 267 1 H NMR (DMSO-d 6 855.09 2H), 6.35 J 2.9 Hz, 1 7.06 J 8.6 Hz, 1 7.39 (d, J =3.1 Hz, 1 7.47 J 8.6 Hz, 1 7.61 J 8.6 Hz, 1 7.76 J 8.5 Hz, 1 H), 7.83 I 7.97 1 8.48 1 10.93 1 11.58 1 12.90 (brd s, 1 MS (APOI, neg. 370.
4-[3-Chloro-4-hydroxybenzoyl)-hydrazonomethyll-1 -naphthylacetamides and the various indolacetamides (steWLB: 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 DM50S to a concentration of 50 mM. The solution was then dispensed into 88 deep well plates containing solutions of amines in DM50S mM). The plates were covered and agitated for 16 hours. The products were purified by
HPLC.
Examples of compounds of the formula XII: EXAMPLE 343:
CH,
0 NNl' I r NN 4, 0
HO'(
ci 1 H NMR (DMSO-D 6 5 1.06 3H), 1.17 3H), 3.31 (qt, 2H), 3.50 (qt, 2H), 4.19 2H), 7.10 1 7.45 1 7.64 (quintet, 2H), 7.83 1 7.88 1 7.98 (in, 2H), 8.87 1 9.09 1 10.99 (brd s, 1 11 .80 (brd s, 1 ms (APOI); 438.1, 440. 1.
WO 99/01423 PCT/DK98/00287 268 EXAMPLE 344: 0.
N
HO
JA
'H NMR (DMSO-D 6 5 0.98 4H), 2.76 2H), 3.02 (quintet, 1H), 3.59 2H), 4.40 (s, 2H), 7. 10 1 7.48 1lH), 7.48 1lH), 7.59 (qt, 1lH), 7.67 1lH), 7.81 1 7.89 (d, 1lH), 7.97 1lH), 8.02 1lH), 8.84 1 9.09 1lH), 10.99 (brd s, 1 H) 11.80 (brd s, 1 MS (APCI, neg.): 473.1, 475.1.
EXAMPLE 345:
H
0 N' N 0 'N HOQj
H
CI
'H NMR (DMSQ-De): 582.50 2.68 2H), 4.00 2H), 7.10 1 7.53 1 7.65 (tt, 2H), 7.80 (dd, 1 7.90 1 8.02 1 8.14 1 8.62 1 8.84 1 9.09 1 11.0 (brd s, 1 H) 11.80 1 MS (APCI): 433.1, 435.1 EXAMPLE 346:
N
1 H H 'H NMR (DMSO-D, 6 8 1.08 (in, 4H), 1.54 (mn, 6H), 2.70 2H), 3.45 2H), 3.76 (mn, 1 H), 4.30 2H), 7.06 1 7.49 1 7.64 (mn, 2H), 7.80 1IH), 7.88 1 8.01 1 H), 8.07 1 8.83 1 9.09 1 10.5 (brd d, 1 11.78 (brd s, 1 MS (APOI, neg.): 515.2.
WO 99/01423 PCT/DK98/00287 269 EXAMPLE 347:
NO
O' NnOf
HOJ
cl 'H NMR (DMSO-D 6 8 1.26 (in, 2H), 1.37 (in, 4H), 1.67 (in, 2H), 2.43 (in, 4H), 2.62 (in, 3H), 3.10 2H), 3.90 1 4.32 2H), 4.48 1 7.10 1 7.31 1 7.48 (in, 2H), 7.81 1 7.88 1 8.03 (in, 2H), 8.85 1 9.08 (brd s, 1 11.76 (brd s, 1 MS (APCI): 533.2.
EXAMPLE 348: N N N
HO'P
cl 'H NMR (DMSO-De,): 8 3.03 (in, 4H), 3.68 2H), 3.79 2H), 4.30 2H), 7.14 (in, 7.47 1 7.66 (quintet, 2H), 7.82 1 7.88 1 8.02 1 8.07 1 8.87 (d, 1 9.10 1 10.99 1 11.80 1 MS (ACPI): 545.6.
EXAMPLE 349: 0
N..
N' H
HOH
Cl WO 99/01423 PCT/DK98/00287 270 IH NMR (DMSO-0 8 5 3.10 4H), 3.67 4H), 4.30 2H), 7.00 (in, 2H), 7.09 (in, 3H), 7.47 1 7.62 (quintet, 2H), 7.82 1 7.88 1 8.03 1 8.06 1 8.85 (d, 1iH), 9. 10 1 10.99 1 11.80 1 MS (ACPI): 544.5, 545.3.
EXAMPLE 350: YH3 N I sN. CH 3 0 N' N2 0 HO
A
'H NMR (DMSO-De): 582.15 6H), 2.39 (mn, 8H), 3.51 4H), 4.22 2H), 7.03 1 H), 7.43 1 7.64 (quintet, 2H), 7.77 1 7.87 1 7.99 1 8.02 1 8.83 (d, 1 9.08 1IH), 11.80 (brd s, 1 MS (APCI): 522.2.
EXAMPLE 351:
CH
2 0
OH
2 N*NN N 0 HO
A
Cl 'H NMR (DMSO-Da): 8 3.93 2H), 4.10 2H), 4.23 2H), 5.20 (mn, 4H), 5.79 (in, 1 H), 5.94 (in, 1 7. 10 1 7.78 1 7.63 (in, 2H), 7.80 1 7.83 1 7.95 (d, 1 8.02 1 8.85 1 9.10 1 11 (brd s, 1 11.80 (brd s, 1 MS (ACPI): 462.2 WO 99/01423 PCT/DK98/00287 271 EXAMPLE 352:
CH
3
NN
0
N.~
I H
HOPI
'H NMR (DMSO-D 6 5 0.9 3H), 1.30 (sextet, 2H), 1.54 (sextet, 2H), 3.56 2H), 4.31 (s, 2H), 4.39 2H), 7.06 1 H) 7.48 1 7.65 (quintet, 2H), 7.79 (dd, 1 7.87 1IH), 7.97 1 8.01 1 8.85 1 9.09 1 11.79 1 MS (APCI): 477.01, 479.2.
EXAMPLE 353: 0 H3
HO"PJH
CI
'H NMR (DMSO-D 6 8 1.17 (in, 4H), 1.54 (in, 4H), 2.68 (mn, 1 3.77 1 4.18 2H), 4.33 (mn, 1 4.76 (brd, 1 7. 10 1 7.43 (mn, 1 7.65 (quintet, 2H), 7.81 1 7.88 1 8.02 1 8.04 1 8.84 1 9.09 1IH), 11.79 1 MS (APCI): 464.1, 466.2.
EXAMPLE 354: 'H NMR (DMSO-D 6 8 0.85 (qt, 3H), 1.53 (in, 2H), 3.00 (dit, 2H), 3.29 (quintet, 2H), 3.77 (dt, 2H), 4.13 2H), 7.05 1 7.26 (mn, 2H), 7.36 1 7.52 (qt, 1 7.69 (mn, 2H), 7.87 WO 99/01423 PCT/DK98/00287 272 7.95 1 8.00 1 7.87 (dd, 1 8.84 1 9.07 (brd, 1 11.76 (brd s, 1H);,MS (APOI): 529.2, 529.7, 531.2.
EXAMPLE 355:
CH
3 0 H
HOH
cI 'H NMR (DMSO-De): 5 0.85 (qt, 3H), 1.33 (in, 1 1.65 (mn, 7H), 2.60 0.5H), 3.10 3.80 (in, 1IH). 4.21 2H), 4.24 (mn, I1H), 7.11 1 7.45 1IH), 7.65 (in, 2H), 7.75 (d, 1 7.89 1 8.01 1 8.05 1 8.83 1 9.09 1 11.80 1 MS (APCI): 478.4, 480.3.
EXAMPLE 356: N.N N 0N)
HO'*
cl 'H NMR (DMSO-Dtl): 5 2.36 (in, 4H), 2.97 2H), 3.50 (mn, 2H), 3.60 (in, 2H), 4.23 2H), 5.17 2H), 5.86 (mn, 1 7.08 1 7.43 1 7.64 (quintet, 2H), 7.79 (dd, 1 7.87 1 8.01 1 8.04 1 8.83 1 9.09 1 11.79 (brd s, 1 MS (APCI): 4.91.2, 493.2.
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 357:
PO
'H NMR (DMSO-D 6 5 1.50 (i 1 1.90 (in, 2H), 1.95 (in, 1 2.72 1 2.95 1 H), 3.30 (in, 1 3.55 (in, 1 3.65 2H), 3.75 (in, 1 3.92 1 4.12 1 H) 4.35 2H), 7.11 1 7.48 (mn, 1 7.65 1 7.68 1 7.8 (dd, 1 7.87 1IH), 8.00 1 H), 8.03 1 8.83 1 9.10 1 11.80 (brd s, 1 MS (APCI): 519.5, 521.2, 522.2.
EXAMPLE 358:
DNCH,
0 N- 1
N
HO'*
cl 'H NMR 5 2.19 3H), 2.30 (mn, 4 3.50 2H), 3.58 2H), 4.22 2H), 7.03 1 7.43 1IH), 7.64 (quint, 2H) 7.77 (dd, 1 7.87 1 7.99 1 8.04 (s, 1 8.83 1 9.09 1IH), 11.80 (brd s, 1 MS (APCI): 465.2, 467.3.
EXAMPLE 359: 0
N,,
N N 0
H
CI
'H NMR (DMSO-D 6 8 2.38 (mn, 4H), 3.51 4H), 3.61 2H), 4.22 2H), 7.08 1 H), 7.31 (mn, 5H), 7.43 1 7.61 (quintet, 2H), 7.82 (dd, 1 7.88 1 8.00 1 8.02 1 8.85 1 9.10 1 11 .80 (brd s, 1 M S (APC 541.4, 543. 1.
WO 99/01423 PCT/DK98/00287 274 EXAMPLE 360:
YH
3
OH
0 N
N'
N' NNS 0 CH,
HO'*
1 H NMR (DMSO-De): 8 1.33 (dd, 3H), 2.76 1.5H), 2.96 1.5H), 3.61 1H), 4.14 (quintet, 1 4.65 (in, 2H), 7.10 (mn, 2H), 7.33 3H), 7.42 (in, 3H), 7.54 (in, 2H), 8.02 (t, 1 8.80 (in, 1 9.07 (brd, 1 11.80 (brd s, 1 MS (APOI): 530.2, 532.2.
EXAMPLE 361:
CH
3
OH
0
N
O
N
HOPA
'H NMR (DMSO-Ds): 5[2.94 1.5H) 3. 10 1.5H), 3H], 3.54 (mn, 2H), 4.00 1 4.28 1 4.81 1 4.96 1 7.09 1 7.35 (in, 3H), 7.43 (in, 3H), 7.61 (in, 2H), 7.83 (mn, 3H), 8.04 1 8.85 1 9.11 1 11.80 (brd s, 1 MS (APCI): 516.3, 518.2.
EXAMPLE 362: o no 0 N N N 0
N
HO(?
H
CI
'H NMR (DMSO-DG): 8 2.75 1 2.95 1 3.59 1 3.80 1 4.38 (brd s, 3H), 4.61 1 4.84 1 6.40 1 6.53 1 7.05 1 7.45 1 7.58 (mn, 3H), 7.81 (in, 3H), 8.00 (brd, 2H), 8.83 1 9.10 1 11.78 (brd s, 1 MS (APCI, neg.): 513.3. 514.2.
WO 99/01423 PCT/DK98/00287 275 EXAMPLE 363: 0 0 *Nn-N:
NH
2 HI(?
H
'H NMR (DMSO-D 6 8 1.50 (in, 2H), 1.68, 2H), 2.28 1 2.59 1 3.05 1 H), 3.96 1 4.16 2H), 4.32 1 6.74 (brd s, 1lH), 6.95 1IH), 7.22 (brd s, 1 7.36 1lH), 7.57 (quintet, 2H), 7.71 (dd, 1 7.79 1lH), 7.92 (dd, 1lH), 7.96 1lH), 8.76 (d, 1 9.01 1 11.80 (brd s, 1 MS (ACPI1): 493.1, 495.2.
EXAMPLE 364: 0
CH,
N' NN. 0 6H 3 HO
(A
CI
'H NMR (DMSO-Ds): 8 2.10 3H), 2.15 3H), 2.29 1 2.40 1 2.80 1 3.05 2H), 3.36 1 3.46 1 4.16 2H), 7.01 1 7.38 1 7.56 (in, 2H), 7.72 (dd, 1 7.79 1 7.94 (mi, 2H), 8.77 1 9.02 1 11.71 (brd s, 1 MS (ACPI): 467.3, 469.1.
EXAMPLE 365: WO 99/01423 PCTIDK98/00287 276 'H NMR (DMSO-D 6 5 2.11 3H), 2.14 3H), 2.33 1 2.39 1IH), 3.37 1 3.46 1H), 4.14 1IH), 4.32 1 4.55 1 4.74 1IH), 7.05 1 7.23 1 7.29 (in, 3H), 7.38 1 7.43 1 7.57 (in, 2H), 7.81 (mn, 2H), 7.97 1 8.06 1 H), 8.79 1 9.05 1 11.75 (brd s, 1 MS (APCI): 543.2, 545.2.
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 366: EXAMPLE 371: H
OH
N N, CH, I H
HO
EXAMPLE 367: EXAMPLE 372: 0
NN-
I H
HOA
Cl EXAMPLE 368: 0 Nj; N
H
HO
CI
EXAMPLE 369: 0 Cl EXAMPLE 370: EXAMPLE 373: EXAMPLE 374: 0 NN NN I H
HOA
CI
EXAMPLE 375: 0
NN
I H
HOA
Cl
CH
3
A
N N WO 99/01423 WO 99/1 423PCT/DK98/00287 EXAMPLE 376: EXAMPLE 381: 0 N N
N
N C N I H C
HO
cI EXAMPLE 377: rN P- ACH 3 0 CH, N NN4 0
HO(?
CI
EXAMPLE 378: o ~N 0 N N 0R O EXAMPLE 379:
H
0 y N 0 ac HO'?
H
EXAMPLE 380:
H
0 N N
N
HOH
HO
EXAMPLE 382: 0 HO cI 20 EXAMPLE 383:
H
0
N
N N 0
H
HON
CI
EXAMPLE 384: N N 0 HO N EXAMPLE 385: NN N. N 0Y
HOH
25
CI
WO 99/01423 WO 9901423PCTIDK98/00287 EXAMPLE 386: EXAMPLE 390: 0 N N'N NJ: 0 HO N ci 0
<NO
0
NCCH
N N 0 3 CH- 3 HO EXAMPLE 387:
H
3
C)
0A 0 N N
N,
I H
HO
ci EXAMPLE 388: 0 N N N,
HO'I;)
EXAMPLE 389: EXAMPLE 391: O N CH 3 N K N .N N 0
HO
Ci EXAMPLE 392:
OH
0 N 0 N HO Ci CH3 0
N
N o)S0 HO H N~o H Cl-I 20 EXAMPLE 393: 0 NN N I H
HO
Cl
N
Q9 WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 394: 0 I H
HO
EXAMPLE 398: &0-cN H 3 c EXAMPLE 395: EXAMPLE 399: 0 0 -H 3
C
N N' 0 HO H c! o)rCH3 N~ N.N N N H
HO
CI
EXAMPLE 396:
N
O N N N HO 0 EXAMPLE 397:
KNN
O N N 0
HO-N
CI
EXAMPLE 400: 0 NTH FF EXAMPLE 401: 0
NN
I H
HO
CI
CH
3
N_
WO 99/01423 PTD9/08 PCT/DK98/00287 EXAMPLE 402: EXAMPLE 406:
N
0
N
N
N.
HO A( H N-1 y cI 0 A 1 l N 0 N. 0 0 NN Ia or HO AN CH 3 cI EXAMPLE 403: 0 N N.
HOH
HO
EXAMPLE 407: EXAMPLE 404:
F
j N
N
HO H N~y EXAMPLE 405: 0
N
HOH
O N 0 0 Nn NN N.N* HO A H
CH
3 EXAMPLE 408:
CH
3 Q A N N NN
N
HOH
EXAM PLE 409:
F
H F.
N O F WO 99/01423 WO 9901423PCT/DK98/00287 282 EXAMPLE 410: 15 EXAMPLE 415: HN
F
N
CH
A N 0 N NC N CH
HH
HO
cI EXAMPLE 416: EXAMPLE 411: 0
N
I H
HOA
EXAMPLE 417: EXAMPLE 412: EXAMPLE 413:
HF
0 AlF N NN HO H YO
H
O A N 0 N0 N 0, HO
AN
CI
EXAMPLE 418: 0 N N 0 HO
CI
EXAMPLE 419: EXAMPLE 414: 0 ,Qr
N.,N
H
HO
CI
0
F
F
0 Nj:
NN
AH
HO0
CI
H
WO 99/01423 WO 9901423PCT/DK98/00287 283 EXAMPLE 420: 0
N,.
N-
I H
HO
CI
EXAMPLE 421: 0 N N
H
HO
CI
EXAMPLE 422: 0 I H
HO
CI
EXAM PLE 423: EXAMPLE 425: 0 HO NN N N HO J[ H 0 cI EXAMPLE 426: 0
HO
20
CI
EXAM PLE 427: N'0
H
OH
25 EXAMPLE 428: EXAMPLE 424: EXAMPLE 429: I H H HO0
CI
WO 99/01423 WO 9901423PCTIDK98/00287 EXAMPLE 430: 0 j N H~qN-CH 3 N HO(? Ho EXAMPLE 431: 0
N-~
I H
HO
c EXAMPLE 432: 0
N-~
I H
HO
cI EXAMPLE 433: 0
NN'
H
HO
CI
EXAMPLE 434: EXAMPLE 435:
OH
0
N
HO N EXAMPLE 436: 0 N N H HO NO I H-
CI
N
EXAMPLE 437: 0
N
OH
EXAMPLE 438: f N ly 0
H
3
C
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 439: EXAMPLE 444:
CH
3 N
N
0 0 1 N' N,
HO
cI EXAMPLE 445: EXAMPLE 440: 0o J..N-j EXAMPLE 446: EXAMPLE 441: 0 0- C OH
N-N
HO HcI EXAMPLE 442:
F
O N, 0 r
HO--[P
EXAMPLE 447: 0 N N HO EXAMPLE 448: 0 0 0 H N N HO'f? cI EXAMPLE 443:
OH
0 -N0
HOH
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 449: EXAMPLE 452: 0 1
HOH
HO
EXAMPLE 450:0 0 N-* HO N.z N'
N
HO
?A
EXAMPLE 453: 0N?
OH
0 H N- l HOJ()
H
CI
EXAMPLE 454: EXAMPLE 451: /CH2 0 N N% N
CH
2 I H L-
HO"-
cI WO 99/01423 PCT/DK98/00287 287 General procedure for synthesis of compounds of the general formula XIII: 0 0 B NH 2 O B OH step A A N B OH H 0 H 0 0
R
5 c step B A B N
R
H O formula XIII A and B are as defined for formula I and -NRRd is R R4 R 4 4 b
-N-(CH
2 q (CH 2 where R R 4a
R
4 b, c, q, d and D are as defined for formula I or where is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, 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 0°C to 140 0 C, preferably between 10"C to 80 0 C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction 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 dichloromethane/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 anhydride or an acid halide that can then react with the amine to give a compound of formula XIII.
The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Alternatively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XIII.
Specific examples illustrating the preparation of compounds of the general formula XIII according to the invention are provided below.
Preparation of 4-formylnaphthoic acid is depicted below: O OH 0 OH 0 OH 0 OMe
CH
3 Br-CH 2 Ho.CH 2
HO.CHZ
O OMe O OH HO HO 4-Bromomethyinaphthoic acid: A mixture of 4-methylnaphthoic acid (10 g, 54 mmol), N-bromosuccinimide (10 g, 56 mmol) and AIBN (100 mg) in CCl4 (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 MgS04. Evaporation of the solvent gave the desired product (16 g, 'H NMR (DMSO-D 6 8 5.24 2H), 7.73 3H), 8.03 1H), 8.28 1H), 8.86 1H), 13.29 (brd s, 1H).
4-Hydroxymethylnaphthoic acid: 4-Bromomethylnaphthoic acid (16 g, 60 mmol) in an aqueous solution of K 2 CO3 100 mL) was stirred at 70 OC for 30 minutes. The reaction mixture was cooled and made acidic with conc. HCI. The resulting precipitate was filtered and dried to give the desired product as a yellow solid in quantitative yield.
'H NMR (DMSO-D) 8 5.01 2H), 5.96 1H), 7.70 3H), 8.10 2H), 8.90 1H).
Methyl 4-hydroxymethylnaphthoate: A mixture of 4-hydroxymethylnaphthoic acid (10 g, 50 mmol), methanol (300 mL), and conc.
H
2 SO4 (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 brine, dried over MgSO 4 and concentrated to give a yellow oil. Silica gel column chromatography using ethyl acetate/hexane gave the desired product as a yellow oil (3.3 g, 'H NMR (CDCIl): 5 2.05 1H), 4.01 3H), 5.22 2H), 7.66 3H), 8.09 1H), 8.16 1H), 8.96 1H).
Methyl 4-formylnaphthoate: To a solution of methyl 4-hydroxymethylnaphthoate above (3.3 g, 15.3 mmol) in dichloromethane (20 mL) was added MnO 2 (6.6 g, 76 mmol). After stirring the dark mixture for 16 hours, the insolubles were filtered through a bed of Celite. Evaporation of the solvent gave the desired product as a white solid in quantitative yield.
WO 99/01423 PCT/DK98/00287 290 'H NMR (CDCI): 5 4.06 3H), 7.75 2H), 8.03 1H), 8.20 1H), 8.80 1H), 9.27 10.50 1H).
4-Formylnaphthoic acid: A mixture of the methyl 4-formylnaphthoate above (2.3 g, 1 mmol) and Na 2 CO, (1.25 g, 12 mmol) in water (30 mL) was heated in a water bath for approximately 2 hr until a clear solution was obtained. The solution was cooled and filtered. The filtrate was acidified with conc.
HCI to give a yellow precipitate. The solids were collected and dried over night to give the desired product (1.86 g, 87%).
'H NMR (DMSO-D6): 8 7.76 2H), 8.22 2H), 8.71 1H), 9.20 1H), 10.49 1H).
4-[(3-Chloro-4-hydroxvbenzoyl)hydrazonomethyl]naphthoic acid (step A): To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (1.53 g, 8.23 mmol) in DMSO 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.
'H NMR (DMSO-D 6 8 4.70 1H), 7.70 2H), 7.83 1H), 8.03 2H), 8.18 1H), 8.72 1H), 8.90 1H), 9.17 1H), 11.0 (brd s, 1H), 11.94 1H), 13.4 (brd s, 1H); MS (APCI, neg): 368.5, 370.2).
General procedure Derivatives of 4-[(3-Chloro-4-hydroxvbenzoyl)hydrazonomethylnaphthamides (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 deep well plates containing solutions of amines in DMSO (50 mM). The plates were covered and agitated for 16 hours. The products were purified by HPLC.
The following compounds of formula XIII were prepared: WO 99/01423 PCT/DK98/00287 291 EXAMPLE 455: 0~
CI
N* N )A
H
HOJ
CI
'H NMR (DMSO-D6): 8 2.91 2H), 3.67 2H), 7.12 1 7.38 (qt, 4H), 7.58 2H), 7.70 1 7.50 1 7.95 2H), 8.03 1 8.69 (brd t. 1 8.81 1 9.12 1IH), 11.02 1IH), 11.89 1 MS (APCI): 507.3, 508.5.
EXAMPLE 456: 0 N
N-.
HOJI
Cl 'H NMR (DMSO-D 6 582.20 (brd m, 1IH), 2.30 (brd m, 1 2.55 (in, 2H), 3. 10 (brd m, 2H), 3.50 2H), 3.72 (brd m, 1 3.85 (brd m, 1 7. 10 1 7.36 (qt, 4H), 7.53 1 H), 7.70 (in, 2H), 7.82 (mn, 2H), 7.95 1 8.03 1 8.88 1 9.11 1 11.00 (brd s, 1 11.89 1 MS (APCI, neg.): 559.2, 561.2.
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 457: 15 EXAMPLE 462: 0 NH N N
H
HO:?
H
CI
0,CH3 EXAMPLE 458: EXAMPLE 463: 0 I H N H HO"
H
CI
1 0 CF 3 0 N N N
HI
HO
CI
EXAMPLE 459: 0 j::N
N'
I H
HO
CI
EXAMPLE 460: EXAMPLE 464: *N
N-
H
F
EXAMPLE 465: 0 H c EXAMPLE 461: EXAMPLE 466: 0 0N
NH
N N Cl I H HO
CI
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 467: 0 N I H
HOA
cI EXAMPLE 468: EXAMPLE 472:
F
EXAMPLE 473: 0 0 N N NN
NN~
I H
HO'I
cI EXAMPLE 469: HO' p N N N (CH3
C
N N EXAMPLE 474: 0
N
I H
HO
CI
EXAMPLE 470: 25 EXAMPLE 475: 0 0l N H HOI?
H
CI
A 0 IHil 'PIN. N
NCN
HOA
CI
EXAMPLE 471: EXAMPLE 476: A 0l N H HO;'
A
CI
N-DpN H c WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 477: EXAMPLE 482: 'Nh ON CH 2 EXAMPLE 478: EXAMPLE 483: 1 0 ro 0 NH 2 N' H 0 HOC?
H
CI
1 01 0 N.NN N t
HCF
3 I H
HO
Cs EXAMPLE 484: EXAMPLE 479: 0 qN
NN
H
HO-
CI
0 AN NP A .N HN'N
F
HOH
HO
EXAMPLE 485: EXAMPLE 480: 0 N
H
3
C
N' N- N H I H 0 CH HOJP
H
Cl EXAMPLE 481: 0 o N I H HO 9
CI
1 0 N N 1 N) HO J 'NR A EXAMPLE 486: WO 99/01423 WO 9901423PCT/DK98/00287 295 EXAMPLE 487: EXAMPLE 492: 0 CN 0 N I H
HO'J
cI EXAMPLE 493: EXAMPLE 488: N N OH 3
H
3
C
EXAMPLE 494: EXAMPLE 489:
CI
H
3 0 OCF 3 0 NN N4 I H HO'?
H
cl EXAMPLE 490: 25 EXAMPLE 495: 0 F N' N
H
HO'I
HI
N .l 0 0N *N NH7 IOJJ
H
HO
EXAMPLE 491: EXAMPLE 496: H IH C3 WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 497: EXAMPLE 502: 0 N N H HO"l
H
cI EXAMPLE 498: 0 0' N N-T N NNN CH 3
OH
HO'I
H
cI EXAMPLE 503: N OH 6H 3
OH
EXAMPLE 499: 0 N~A
HO-
CI
EXAMPLE 500: EXAMPLE 504: 0 Ci 0 N N N N. N HF
HO'*
25 EXAMPLE 505: N' N"R)CH 3 HOq
H
Cl 0
N
Hp
CH
3 EXAMPLE 501: 0
OH
0 N N H HO
CI
EXAMPLE 506: 0 N N *Nz, I H
HO
CI
NH F
NF
I F WO 99/01423 PCT/DK98/00287 297 EXAMPLE 507: 0 N
OH
HO H Cl General procedure for synthesis of compounds of the general formula XIV:
R
5
C
O Y B OH NHRR 0 B N 5 d H stepA H 0 A NII step B H 0 formula XIV A and B are as defined for formula I and -NRcR 5 d is Rs R4a 4b I
V,
N (CH 2 where R, R, R, c, q, d and D are as defined for for mula I or where is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The acid is coupled to a primary or secondary amine using one of the methods wellknown 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 product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Altematively, the product can be purified by column chromatography using dichloromethane/methanol or chloroform/methanol or isopropyl alcohol as eluent giving a compound of formula XIV.
Step B: The carbonyl compounds are then treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, Ler-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, 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 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction 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 dichloromethane/methanol or chloroform/ethyl acetate.
Specific examples illustrating the preparation of compounds of the general formula XIV according to the invention are provided below.
The preparation of 3-(4-formylnaphthalene)propanoic acid is depicted below: WO 99/01423 PCT/DK98/00287
OH
OH
O H 0 0 F F Ir 00 0 0 sS0 F F EtO O
F
f-- O O EtO O0 OH OH EtO O HO O 4-Trifluoromethylsulfonyloxy naphthaldehyde: To a solution of 4-hydroxy naphthaldehyde (34.4 g, 0.20 mol) in dichloromethane (200 mL) and pyridine (19 mL, 18.58 g, 0.23 mol) was added dropwise at 0°C trifluoromethane sulfonic anhydride (46.75 g, 0.16 mol). The mixture was stirred at 0°C for 2 hr and at room temperature 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.
1 H NMR (CDC 3 8 7.89 7.97 3H), 8.09 (dd, J 2.8, 6.5 Hz, 1H), 8.33 J 8.0 Hz, 1H), 9.24 (dd, J 2.8, 6.5 Hz, 1H), 10.45 1H).
2-(4-Trifluoromethylsulfonyloxy naphthyl) dioxolane: A solution of 4-trifluoromethylsulfonyloxy naphthaldehyde (4.09 g, 13.4 mmol), ethylene glycol (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).
'H NMR (CDCI 3 5 4.19 4H), 6.47 1H), 7.47 J 8.0 Hz, 1H), 7.66- 7.70 2H), 7.81 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 PCTDK98/00287 300 GCMS: 348.
2-[4-(2-ethoxycarbonylvinyl)naphthyl]dioxolane: Nitrogen was passed through a solution of 2-(4-trifluoromethylsulfonyloxynaphthyl) dioxolane (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 added. The well stirred solution was heated at 90 0 C for 8 hr, and concentrated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (2x 50 mL), dried (Na 2
SO
4 and concentrated. Purification by flash chromatography using hexane /ethyl acetate 9:1 as eluent provided a yellow solid (1.13 g, 53%).
1H NMR (CDCI 3 8 1.38 J 7.0 Hz, 3H), 3.74 4.22 4H), 8.65 J 7.0 Hz, 2H), 6.50 1H), 6.53 J 15.7 Hz, 1H), 7.58-7.62 2H), 7.74 J 7.5 Hz, 1H), 7.80 J Hz, 1H), 8.21-8.28 2H), 8.52 J 15.2 Hz, 1H).
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 on BaCO3, 51 mg). The mixture was stirred under a hydrogen atmosphere for 16 hr, filtered by suction through Celite and concentrated to provide 689 mg of a colorless oil.
H NMR (CDCI 3 5 1.25 J 7.0 Hz, 3H), 2.75 J 8.0 Hz, 2H), 3.43 J 8.0 Hz, 2H), 4.12- 4.22 6H), 6.46 1H), 7.37 J 7.3 Hz, 1H), 7.54 7.70 2H), 7.70 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).
Ethyl 3-(4-formylnaphthalene)propanoic acid: To a solution of 2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxolane (689 mg, 2.29 mmol) in THF 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 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 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 precipitate 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%).
1H NMR (DMSO-Ds) 8 2.69 J 7.0 Hz, 2H), 3.39 J 7.0 Hz, 2H), 7.66-7.77 2H), 8.10 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 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) 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 temperature for 16 hr, the mixture was diluted with ethylacetate (5 mL), extracted with water 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.
Examples of amides: N CH 3 CH3 0 H NMR (CDCI 3 5 1.06 J 7.0 Hz, 3H),1.12 J 7.0 Hz, 3H), 2.79 J 8.0 Hz, 2H), 3.50 J 8.0 Hz, 2H), 4.12 J 7.1 Hz, 2H), 7.54 J 7.3 Hz, 1 7.64 7.71 (m, 2H), 7.92 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 1H). MS (APCI, pos.) 284.1 WO 99/01423 PCT/DK98/00287 302 N H 14 0 H NMR (CDCI 3 8 0.77 J 7.0 Hz, 3 0.86 J 7.0 Hz, 3 1. 15 -1.82 (in, 8 H), 2.58 (dt, 0.5 2.65 2.88 (in, 2H), 2.92 (dt, 0.5H), 3.39 3.60 (in, 2.5H), 3.62- 3.73 (in, 0.5H), 4.58 (dd, 0.5H), 4.73 (in, 0.5H), 7.56 J 7.3 Hz, 1 7.91 J 7.3 Hz, 1 H), 7.61 7.72 (in, 2H), 8.16 J 8.3 Hz, 1 9.33 J 8.0 Hz, 1 10.34 1IH). MS (APCI, pos.) 325.2 Derivatives of 4-[(4-hyd roxybenzoyl)hyd razonomethyll na phthylp ropanam ides (step B3): These compounds were prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl-1 -naphthyl propanainides (from step A) and 4-hydroxybenzoic acid hydrazide derivatives.
EXAMPLE 508: 0 0~ N'CH N N
CH
3 HO ci H NMR (DMSO-D 8 8 0.95 1.02 (mn, 6H), 2.69 J 7.3 Hz, 2H), 3.19 J 7.0 Hz, 2H), 3.25 J 7.0 Hz, 2H), 3.33 J 7.3 Hz, 2H), 7.08 J 8.5 Hz, 1 7.49 J Hz, 1 7.65 (mn, 2H), 7.81 (mn, 2H), 8.00 J 2.0 Hz, 1 9.17 (dd, J 2.4, 6.5 Hz, 1IH), 8.87 J 7.6 Hz, 1 9.05 1 11.00 1 11.77 1 MS (APCI, pos. 452.2, 454.2 WO 99/01423 PCT/DK98/00287 303 EXAMPLE 509: 0 CH 3 0 N Ns HO(?
H
ci H NMR (DMSO-D 6 5 0.68 J =7.5 Hz, 3H), 0.75 J 7.5 Hz, 3H), 0.76 (dd, 0.5 0.90 (dd, 0.5 1.02 1.68 (in, 8H), 2.49 (in. 2.75 (in, 2H), 2.90 J 14.0 Hz, 3.33 (in, 2H), 3.61 J 12.0, Hz, 3.75 (in, 4.36 J 12.0 Hz, 0.51H), 4.53 (in, 7.08 J 8.5 Hz, 1 7.50 J 7.5 Hz, 1 7.64 -7.66 (in, 2H), 7.80 (dd, J 1.9, 8.5 Hz, 1 7.83 J =7.5 Hz, 1 8.00 J 1.9, Hz, 1 8.17 (in, 1 8.88 J 7.5 Hz, 7.25 1 11.0 1 11.76 1 MS (APOI, pos.): 492.1, 494.1 EXAMPLE 510: Ethyl 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyll naphthyl propanate 0 H 0 0 CH
SN
1
H
HO-P
ci The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of ethyl 4-formyl-1 -naphthylpropanate (from step E) and 3-chloro-4-hydroxy benzoic acid hydrazide.
IHNMR (DMSO-D 6 5 1.14 J 7.0 Hz, 3H), 2.73 J 7.5 Hz, 2H), 3.35 J =7.5 Hz, 2H), 4.02 J 7.0 Hz, 2H), 7.08 J 8.6 Hz, 1 7.66 (in, 2H), 7.79 (dd, J 8.6 Hz, 1 7.86 J 7.5 Hz, 1 8.85 J 7.7 Hz, 1 9.05 1 11.0 (brd s, 1 H), 11. 78 1 M S (APCI1, pos.): 425.5, 427.3 WO 99/01423 PCT/DK98/00287 304 EXAMPLE 511: 3-Chloro-4-hydroxy benzoic acid (4-trifi uoromethylsulfonyloxy naphthylideneahydrazide 0
N'
HO,
A
ci The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-trifluoromethylsulfonyloxy naphthaidehyde 3chloro-4-hydroxy benzoic acid hydrazide.
IHNMR (DMSO-D 6 5 7.09 J 8.7 Hz, 1 7.68 7.95 (in, 4H), 8.00 8.10 (in, 3H), 8.90 1 9.10 1 11.02 1 11.96 1 MS (APCI, pos.): 473.2, 475.1 WO 99/01423 PCT/DK98/00287 305 General procedure for synthesis of compounds of the general formula XV: 0 A NH 2
O
H 0 step A step B 0 A B.
/R
5 c A N B O N OH R' formula XV A and B are as defined for formula I and -NRsCR 5 d is R R4a R4b (CH)D where Rs, R 4
R
4 b, c, q, d and D are as defined for formula I or where is defined as a subset of -D that contains a primary or secondary amine that can react as a nucleophile.
Step A: The carbonyl compounds are treated with an acylhydrazide in a solvent. The solvent may be one of the following: ethyl alcohol, methyl alcohol, isopropyl alcohol, tert-butyl alcohol, dioxane, tetrahydrofuran, toluene, chlorobenzene, anisole, benzene, chloroform, 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 0°C to 140°C, preferably between 10°C to 80°C. In many cases the product simply crystallizes out when the reaction is completed and is isolated by suction filtration. It can be further recrystallized if necessary from a solvent such as the above described reaction 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 dichloromethane/methanol or chloroform/ethyl acetate.
Step B: The epoxide is then ring opened by a primary or secondary amine using one of the 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, dichloromethane, DMSO, DMF, NMP, water or a compatible mixture of two or more of the above solvents. The product can then be isolated either by filtration or by extraction using a solvent such as ethyl acetate, toluene, dichloromethane or diethylether and the solvent may then be removed by concentration at atmospheric or reduced pressure. The product can be further purified by either recrystallization from a solvent such as ethyl alcohol, methyl alcohol, isopropyl alcohol, toluene, xylene, hexane, tetrahydrofuran, diethyl ether, dibutyl ether, water or a mixture of two or more of the above. Altematively, the product can be purified by column chromatography 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 according to the invention are provided below.
The preparation of 4-(2,3-epoxypropanoxy)-1-naphthaldehyde is depicted below: O H O H OH O j 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%).
1 H NMR (CDCI 3 8 2.88 (dd, J 2.6, 4.8 Hz, 1H), 3.02 (dd, J 4.0, 4.6 Hz, 1H), 3.51 3.57 1H), 4.22 (dd, J 5.8, 11.1 Hz, 1H), 4.55 (dd, J 2.8, 11.1 Hz, 1H), 6.94 J 8.1 Hz, 1H), 7.60 J 7.2 Hz, 1H), 7.71 J 7.7 Hz, 1H), 7.92 J 8.0 Hz, 1H), 8.89 J 8.4 Hz, 1H), 9.31 J 8.6 Hz, 1H), 10.22 1H).
General Procedure: 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 alkylidene hydrazones from the condensation of the above epoxy-aldehyde with 4-hydroxy benzoic acid hydrazide derivatives.
'H NMR (DMSO-d 6 8 2.84 (dd, J 2.2, 4.9 Hz, 1H), 2.92 (dd, J 4.5, 4.5 Hz, 1H), 3.45 3.57 1H), 4.11 (dd, J 6.4, 11.3 Hz, 1H), 4.60 J 11.3 Hz, 1H), 7.02 7.18 2H), 7.55 7.90 4H), 7.99 J 1.9 Hz, 1H), 8.29 J 8.3 Hz, 1H), 8.90 9.05 2H), 10.94 1H), 11.66 1H). MS (APCI, negative 395.
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.
Examples of compounds of formula XV: EXAMPLE 512: x CH 3
CO,H
WO 99/01423 PCT/DK98/00287 308 'H NMR (DMSO-d 6 60.95 J 6.9 Hz, 6H), 1.90 3H), 2.50, 2.62 (2q, J 6.6 Hz, 4H), 2.70 (dd, J 6.6, 13.0 Hz, 1lH), 2.88 (dd, J 7.0, 14.2 Hz, 1 3.95 4.35 (in, 3H), 7.02 (d, J 8.7 Hz, 1 7.06 J 8.3 Hz, 1 7.55 -7.85 (in, 4H), 7.96 J 1.9 Hz, 1 8.36 J 8.3 Hz, 1H), 8.85 -9.05 2H), 11.60 1H); MS (APCI, pos.): 470.
EXAMPLE 513: HO r HO cl Hx
CH
3
CO
2
H
'H NMR (DMSO-d 6 6 1.67 (brd s, 4H), 1.88 3H), 2.50 2.85 (mn, 6H), 4.0 4.3 (in, 3H), 7.00 -7.12 2H), 7.55 7.85 (mn, 4H), 7.97 1IH), 8.36 J 8.3 Hz, 1 8.85 -9.05 (d, 2H), 11.63 1 MS (APCI, pos.): 468.
EXAMPLE 514: OH r 0oN N o.Q1. N..
HOJ( x CH 3
CO
2
H
cI 'H NMR (DMSO-d6) 6 1.30 -1.55 (in, 6H), 1.88 3H), 2.35 -2.60 (in, 6H), 4.05 4.30 (in, 3H), 7.04 J 8.5 Hz, 1 7.12 J 8.3 Hz, 1 7.55 7.85 (mn, 4H), 7.97 J 2.1 Hz, 1 8.36 J 8.2 Hz, 1 8.85 -9.05 2H), 11.62 1 MS (APCI, pos.): 470.
EXAMPLE 515: OH
H
0
N
N ,2 O x CH 3
CO
2
H
WO 99/01423 PCT/DK98/00287 309 'H NMR (DMSO-d 6 5 1.25 -1.82 (in, 8H), 1.88 3H), 2.68 -2.90 (in, 2H), 3.08 1 m1H), 4.25 (in, 3H), 7.03 J 8.6 Hz, 1 7.07 J 8.3 Hz, 1 7.52 7.85 (i,4H), 7.97 J 1.4 Hz, 1IH), 8.34 J 8.4 Hz, 1 8.85 -9.0 2H), 11.61 1 MS (APCI, pos.): 482.
EXAMPLE 516:
OHH
HOH
HO clx CH 3 00 2
H
'H NMR (DMSO-d 6 5 0.95 -1.80 m, 1 OH 1.88 3H 2.45 (mn, 1 H 2.70 -2.90 (in, 2H, 3.98-4.30 (in, 3H), 7.02 J 8.52 Hz, 1 7.07 J 8.2 Hz, H 7.52 7.75 (in, 4H), 7.97 J 2.05 Hz, I 8.34 J 8.33 Hz, 1 8.87 -9.00 (in, 2H), 11.61 1 MS( APCI, pos.): 496.
EXAMPLE 517: 3-Chloro-4-hydroxybenzoic acid 4-(3-hyd roxypropyl)naphthylmethylene hyd razide f r-\0 H 0 0 0 0 N 0 OH A BC I H
HO
CO Et OHOH cl 2-[4-(3-Hydroxypropyl)naphthylldioxolane (step A): To a solution of 2-[4-(2-ethoxycarbonylethyl)naphthyl]dioxolane (210 mg, 0.70 mmol) in anhydrous THF (5 mL) was added at 0 0 C 1 M lithium aluminum hydride in THF (0.5 mnL). THE inL) 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,), and concentrated. The residue was purified by flash chromatography using hexane/ethyl acetate 2:1 as eluent to provide 67 mng (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 (in, 2H), 3.19 J 7.4 Hz, 2H), 3.75 J= 6.3 Hz, 2H), 4.16 4.22 (in, 4H), 6.47 1 7.35 J 7.3 Hz, 1 7.52 7.70 (in, 2H), 7.70 J 7.3 Hz, 1 8.11 J 9.8 Hz, 1 8.25 J 9.8 Hz, 1 GCMS: 258 1 -Formyl-4-(3-hydroxypropyl)naphthalene (step B3): To a solution of 2-[4-(3-hydroxypropyl)naphthyl]dioxolane (67 mg, 0.26 mmol) in anhydrous THE (5 mL) was added 1IN hydrochloric acid (1 mL). The mixture was stirred at room temperature for 48 hr, diluted with ethyl ether (20 mL), washed with satd. NaHCO 3 solution (2x mL), dried (MgSO 4 concentrated and coevaporated with CHC1 3 (3 x 10 mL) to yield 40 mg of a colorless oil.
'H NMR (CDC 3 5 1.56 (brd s, 1 2.02 -2.08 (in, 2H), 3.27 J 7.5 Hz, 2H), 3.78 J 6.4 Hz, 2H), 7.53 J 7.3 Hz, 7.62 -7.70 (mn, 2H), 7.92 J 7.3 Hz, 1 9.17 J= 8.3 Hz, 1 9.34 J 8.6 Hz, 1IH), 10.34 1 H).
3-Chloro-4-hydroxybenzoic acid 4-(3-hydroxypropyl)naphthylinethylene hydrazide (step C): This compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones by condensation of 1 -forinyl-4-(3-hydroxypropyl) naphthalene from step B and 3-chloro-4-hydroxy benzoic acid hydrazide.
1 H NMR DMSO-D 6 8 1.83 (mn, 2H), 3.12 J 7.5 Hz, 2H), 3.51 (dt, J 4.9, 7.0 Hz, 2H), 7.09 J 8.5 Hz, 1 7.47 J 7.5 Hz, 1 7.65 (in, 2H), 7.80 (dd, J 2.0, 8.5 Hz, 1 7.86 J 7.5 Hz, 1IH), 8.00 J 2.0 Hz, I1H),8.19 (dd, J 2.5, 7.0 Hz, 1 8.84 (d, J 8.4 Hz, 1 9.05 1 10.98 1 11.76 1 H).
MS (APCI, pos.): 383.1, 385.1.
EXAMPLE 518: 4-((3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl diethylacrylamide WO 99/01423 PCT/DK98/00287 311 t H-OCOt-- COEt OCO 2
H
HO! A HO B 0 C 0 H H N 0 D O
.CH
3 E H C H
O
H
C
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).
The mixture was stirred at 0 C 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 step.
'H NMR (CDCI 3 6 1.37 J 7.1 Hz, 3H), 1.86 (brd s, 1H), 4.32 J 7.1 Hz, 2H), 5.17 2H), 6.50 J 15.7 Hz, 1H), 7.54 7.62 2H), 7.70 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 J 15.7 Hz, 1H).
Ethyl 4-formylnaphthalene acrylate (step B): The crude material (900 mg) from step A was dissolved in chloroform (10 mL), and manganese 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.
Flash chromatography using hexane/ethyl acetate 5:1 provided 491 mg (60% over 2 steps) of a colorless oil.
1 H NMR (CDCl 3 8 1.39 J 7.1 Hz, 3H), 1.86 (brd s, 1H), 4.34 J 7.1 Hz, 2H), 6.60 J 15.7 Hz, 1H), 7.68 7.75 2H), 7.85 J 7.4 Hz, 1H), 8.00 J 7.4 Hz, 1H), 8.25 J 8.1 Hz, 1H), 8.50 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, 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.
'H NMR (DMSO-D6) 5 6.72 J 15.7 Hz, 1H), 7.71 7.75 2H), 8.12 J 7.45Hz, 1H), 8.20 J 7.5 Hz, 1H), 8.30 J 8.0 Hz, 1H), 8.40 J 15.7 Hz, 1H), 9.21 J 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 temperature 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 (MgSO4) and concentrated. After flash chromatography using hexane/ethylacetate 1 1, 115 mg of a yellow oil was obtained.
'H NMR (CDCI 3 1.25 J 7.1 Hz, 3H), 1.30 J 7.1 Hz, 3H), 3.55 4H), 6.97 J 15.7 Hz, 1H), 7.63 -7.76 2 7.80 J 7.4 Hz, 1H), 7.99 J 7.4 Hz, 1H), 8.29 J 8.3 Hz, 1H), 8.51 J 15.7 Hz, 1H), 9.30 J 8.3 Hz, 1H), 10.43 1H).
4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl diethylacrylamide (step E): The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl-l-naphthyl diethylacrylamide (from step D) and 3-chloro-4-hydroxy benzoic acid hydrazide.
'H NMR (DMSO-D) 8 1.11 J 7.0 Hz, 3H), 1.18 J 7.0 Hz, 3H), 3.42 J 7.0 Hz, 1H), 3.56 J 7.0 Hz, 2H), 7.10 J 8.5 Hz, 1H), 7.22 J 15.1 Hz, 1H), 7.67 7.72 2H), 7.81 J 8.3 Hz, 1H), 7.96-8.03 2H), 8.06 J 7.7 Hz, 1H), 8.26 (dd, J WO 99/01423 PCT/DK98/00287 313 2.1, 7.2 Hz, 1 8.32 J 15.1 Hz, 1 8.83 J 7.0 Hz, 1 9.13 1IH), 11.00 (s, 1 11.86 1 MS (APCI, pos.): 450.3 EXAMPLE 519: Ethyl 4-f(3-Chloro-4-hydroxybenzoyl) h-ydrazonomethyl] naphthyl acrylate 0 HO(?
H
ci The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of ethyl 4-formyl-1-naphthyl acrylate (from step B) and 3-chloro-4-hydroxy benzoic acid hydrazide.
1 1- NMR (DMSO-D 6 5 1.29 J 7.1 Hz, 3H), 4.25 J 7.1 Hz, 2H), 6.75 J 15.7 Hz, 1 7.10 J 8.5 Hz, 1 7.71 (in, 2H), 7.92 J 8.5 Hz, I 8.01 (in, 2H), 8.07 J 8.0 Hz, 1 8.46 J 15.7 Hz, 1 8.81 J 7.1 Hz, 1IH), 9.13 1IH), 11.00 1 H), 11.89 1 MS (APCI, pos.): 421.1, 423.0 EXAMPLE 520: 4-[(3-Chloro-4-hydroxybenzoyl) hydrazonomethyl] naphthyl acrylate O OH HO'?
H
ci The compound was prepared according to the general procedure for the synthesis of alkylidene hydrazones from the condensation of 4-formyl -1 -naphthyl acrylate (from step C) and 3-chloro-4-hydroxy benzoic acid hydrazide.
WO 99/01423 PCT/DK98/00287 314 'H NMR (DMSO-D6) 5 6.65 J 15.6 Hz, 1H), 7.09 J 8.5 Hz, 1H), 7.66 7.74 (m, 2H), 7.81 J 8.5 Hz, 1H), 7.97 8.05 3H), 8.29 (dd, J 2.2, 7.1 Hz, 1H), 8.41 J 15.6 Hz, 1H), 8.82 J 7.6 Hz, 1 9.12 1 10.92 1 11.89 1H), 12.62 (s, 1H). MS (APCI, pos.): 394.1, 395.3 General procedure for the synthesis of substituted piperazine-arvl-aldehydes followed by hydrazone formation: The substituted piperazine-aryl-aldehydes may be prepared by N-alkylation of the corresponding unsubstituted piperazine-aryl-aldehydes using various electrophilic alkylating agents that introduce the moiety as defined above.
WO 99/01423 PCT/DK98/00287 315 O H R R 3 R R4
R
1 x-(CH2)b (CH 2 )a-(M)F(CH 2 )c q(CH 2
D
R
is Base, solvent
N
N
H
R
14 R 3b R R4b H 13a R3b 4a N N-(CH 2 )b q( -(M(CH2 f 2 c q (CH2)d- D
R
1
H
N-NH,
O=2
A
f R3a R3b R R4b H V R\ H N N-(CH 2 )b (p (CH 2
(M)-(CH
2
(CH
2 d- D o=
R
1
A
wherein Lx is a leaving group such as -Cl, -Br, -OSO 2
CH
3
-OSO
2 p-tolyl or -OSO 2
CF
3 and A, R 3a
R
3 b, R 4a
R
4 b, a, b, c, d, f, p, q, D, M, R' 4 and R 15 are as defined for formula I.
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 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 tertbutoxide, 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 benzyldimethyl- ammonium methoxide or hydroxide. The reaction can be performed at 0°C to 150C, preferably at 20°C 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 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, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture. Specific examples illustrating the preparation of unsubstituted piperazinearyl-aldehydes are provided below.
The following step, the hydrazone formation is described above in general and below in detail.
Preparation of 4-piperazinyl-2.5-dimethylbenzaldehyde: 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 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 The product (21 g, 71%) was obtained as an oil.
1 H NMR (CDCl 3 2.24 3H), 2.29 3H), 2.60 (brd s, 4H), 2.92 (brd s, 4H), 3.55 2H), 6.78 1H), 6.84 1H), 7.04 1H), 7.30 4-(2,5-dimethyl-4-formylphenyl)-1-benzylpiperazine: The 4-(2,5-dimethylphenyl)-1-benzylpiperazine (10 g, 36 mmol) was dissolved in anhydrous 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 OC 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 with ethyl acetate The organic layer was washed with water brine, dried over magnesium sulfate and purified by silica gel column chromatography using gradient hexane/ethyl acetate (10/0 to The product (9 g, 81%) was obtained as an oil.
1 H NMR (CDCI) 5 2.29 3H), 2.28 (s t, 7H), 3.03 4H), 3.59 2H), 6.75 1H), 7.31 5H), 7.58 1H), 10.12 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 anhydrous 1,2-dichloroethane (100 mL) and 1-chloroethyl chloroformate (4.5 g, 31.5 mmol) 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 starting material by TLC using hexane/EtOAc 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.
1 H NMR (CDCI) 8 1.84 3H), 2.32 3H), 2.61 3H), 2.99 (brd m, 4H), 3.70 (brd m, 4H), 6.62 (qt, 1H), 6.76 1H), 7.62 1H), 10.14 1H).
4-piperazinyl-2,5-dimethylbenzaldehyde: To a solution of the dimethylphenylpiperazinylcarbamate above (6 g, 18.5 mmol) in THF mL) was added 1 N HCI (50 mL, 50 mmol). The mixture was warmed to approximately 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%).
'H NMR (DMSO-D 6 5 2.2 3H), 2.50 3H), 3.13 (brd s, 8H), 6.85 1H), 7.54 1H), 9.49 (brd s, 2H), 10.02 1H).
WO 99/01423 PCT/DK98/00287 318 4-piperazinyl-2.3-dimethylbenzaldehvde: 4-Piperazinyl-2,3-dimethylbenzaldehyde was prepared in the same fashion as above. Formylation 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.
'H NMR (DMSO-D 8 8 2.15 3H), 2.47 3H), 3.07 (brd m, 4H), 3.17 (brd m, 4H), 5.90 (brd s, 1H, NH), 7.02 1H), 7.50 1H), 9.54 (brd s, 2H, NH2), 10.10 1H).
4-piperazinyl-3.5-dimethylbenzaldehyde: 4-Piperazinyl-3,5-dimethylbenzaldehyde was prepared in the same manner as above.
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 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 derivative (1 eq) in DMSO and a solution of acetic acid (catalytic) in DMSO were added into each well. The reaction mixtures were agitated for 16 hours to give the crude products which were purified by HPLC.
Examples of products: EXAMPLE 521 WO 99/01423 PCT/DK98/00287 319
CH
3 $--*NS''NOc N N I H
HO
cl 'H NMR (DMSO-D 6 5 2.26 3H), 2.38 3H), 2.65 (brd s, 4H), 2.73 2H), 2.89 (brd s, 4H), 4.07 2H), 6.03 2H), 6.84 2H), 7.02 1 7.13 1 7.72 1 7.82 (dd, 1 8.01 1 8.86 (brd s, 1 11.68 (brd s, 1 MS (APOI): 480.7, 482.3.
EXAMPLE 522: CH3 $l->Q 0 NZ&
,)U
N'
OH
3
H
'H NMR (DMSO-D 6 8 2.49 6H), 2.68 (brd s 4H), 3.22 (brd s, 4H), 3.72 2H), 7.22 (d, 1 7.44 (in, 1 7.52 (in, 6 7.92 (dd, 1 8.13 1 8.46 1 11. 12 (brd s, 1IH), 11. 80 1 M S (APOI1): 477.5, 479.2.
EXAMPLE 523:
CH
3
N
O H 3 C. N C. H 3
HOH
HO
'H NMR (DMSO-D,): 8 1.25 3H), 1.27 3H), 2.26 3H), 2.38 3H), 2.57 (brd s, 4H), 2.95 (brd s, 4H), 3.56 2H), 7.02 1 7.12 1 7.30 (qt, 4H), 7.72 1 7.82 (d, 1 8.01 1 8.83 1 11.0 (brd s, 1 11. 1 1 MS (APCI): 519.7, 521.5.
WO 99/01423 PCT/DK98/00287 320 EXAMPLE 524:
CH
3 r
H
OO
IH NMR (DMSO-D 6 5 2.22 3H), 2.33 3H), 3.17 (brd s, 4H), 3.23 (in, 2H), 3.36 (in, 2H), 4.41 2H), 6.98 1IH), 7. 10 1IH), 7.48 (mn, 3H), 7.68 (in, 3H), 7.71 1 7.97 1 8.83 1 11.00 1 11.02 (brd s, 1IH), 11.69 I MS (APCI): 477.4, 479.2.
EXAMPLE 525: OH0CH 3 rNN0 I H
HO
c 'H NMR (DMSO-D 6 8 2.20 3H), 2.31 3H), 2.59 4H), 2.87 4H), 3.69 2H), 6.98 1 7.02 1 7.64 (in, 2H), 7.75 (dd, 1IH), 7.82 1 7.94 1 8.12 (dd, 1 8.19 1 8.74 1 10.94 (brd s, 1IH), 11.54 1 MS (APCI): 522.2, 524.3.
EXAMPLE 526:
CH
3
,'NN
0
N:C
N N I H
HO
CI
'H NMR (DMSO-D 6 5 2.20 3H), 2.31 3H), 2.62 (brd s, 4H), 2.87 (brd s, 4H), 3.68 (s, 2H), 6.98 1 7.04 1 7.55 1 7.61 1 7.74 (dd, 1 7.91 1 7.92 1 8.01 1IH), 8.74 1 10.93 (brd s, 1 11.54 1 MS (APOI): 519.2, 521.3.
WO 99/01423 PCT/DK98/00287 321 EXAMPLE 527: ,AN H
CH
3 HOJ
H
ci 'H NMR (DMSO-D, 6 8 2.21 3H), 2.37 3H), 2.66 (brd s, 4H), 2.91 (brd s, 4H), 3.76 (s, 2H), 6.83 1 7.05 1 7.62 1 7.69 1 7.75 (dd, 1 7.86 2H), 7.94 (s, 1 8.15 2H), 8.60 1 10.92 (brd s, 1 11.55 1 MS (APCI): 628.3, 630.2, 631.2.
General procedure for the synthesis of N-substituted indole aldehydes followed by hydrazone formain: The N-substituted indole aldehydes may be prepared by N-alkylation of the corresponding unsubstituted indole aldehydes using various electrophilic alkylating agents that introduce the (K)mD moiety as defined above.
WO 99/01423 PCT/DK98/00287 0 H
R
1 5
H
R 3 R 3 b
R
4 a R Lx-(CH A X CH 2 2 CH 2 Base, solvent STEP A
-NH
2
A
STEP B wherein Lx is a leaving group such as -CI, -Br, -OSO 2
CH
3
-OSO
2 p-tolyl or -OSO 2
CF
3 and A, R 3a R3b, R4a, R 4 b, a, b, c, d, f, p, q, D, M, R 14 and R 15 are as defined for formula I.
According to the above scheme the N-substituted indole aldehydes can be prepared by stirring formylindoles 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 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 equivalents (preferably 1 to 5 equivalents) of a base such as sodium hydride, potassium hydride, 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 hydroxide. The reaction can be performed at 0°C to 150"C, preferably at 20*C 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 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, ethyl 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.
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.
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 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: Amber glass vials (for preparing stock solutions) were dried for at least four hours at 110 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 format).
WO 99/01423 PCT/DK98/00287 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 deep-well plates. The plates were vortexed briefly to mix, then allowed to react for two hours.
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 volume of 10.0 mL. 100 pL of the 1.0 M acid hydrazide TFA salt solution was added to each 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 eluent.
The following compounds were prepared: EXAMPLE 528: 1 H NMR (DMSO-De): 8 5.46 2H), 7.10 J 8.7, 2H), 7.20 2H), 7.28 5H), 7.51 J 7.53, 1H), 7.79 J 7.9, 1H), 7.99 1H), 8.01 1H) 8.33 J 6.96, 1H), 8.62 1H), 10.9 1H), 11.5 1H); LRMS calcd for C26 H 24 C, N 3 02 (M H) 402, found 402.1.
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 529: 0
N~
I H
HO
'H NMR (DMSO-D 6 8 1.14 J 6.8, 6H), 2.81 (sept, J 6.9, 1H), 5.41 2H), 7.07 J 8.3, 1 7.20 (in, 6 7.54 J 7.6, 1 7.77 J 7.9, 1 7.97 1 8. 01 (s, 1 8.29 J 7.2, 1 8.59 1 10.88 1 11.44 1 LRMS calcd for C 26
H
24 Cl, N 3 02 (M H) 445, found 445.9 EXAMPLE 530:
F
N.N
HO A c 'H NMR (DMSO-D6): 8 5.47 2H), 7.08, J 8.7, 1H), 7.13-7.25 (in, 5H), 7.18 J= 74.2, 1 7.35 J 8.7, 1 7.54 J 7.9, 1 7.77 (dd, J 8.7, 1.7, 1 7.97 J= 1.7, 1IH), 8.02 1 8.30 J 1 8.59 1IH), 10.89 1IH), 11.45 1IH). LRMS calcd for C 24
H
1 8 Cl, F 2
N
3 03 (M 468, found 468. 1.
EXAMPLE 531: 0
CH
3 N
C
3
HO'
cI 1 H NMR (DMSO-D 6 850.94 J 6.2, 6H), 1.54 (sept, J 6.2, 1H), 1.66-1.73 (in, 2H), 4.23 J 7.0, 2H), 7.08 J 8.7, 1 7.16-7.29 (mn, 2H), 7.54 J 7.95, 1 7.77 (d, WO 99/01423 PCT/DK98/00287 326 J 8.7, 1 7.88 1 7.97 1 8.29 J 7.5, 1 8.57 1 10.88 1 H).
11.42 1 LRMS calcd for C 2 1 H22Cl, N 3 02 (M H) 384, found 384.2.
EXAMPLE 532: N0NN H
N
HO:AH
cI 'H NMR (DMSO-D 6 8 7.06 J 8.5, 1 7.12-7.26 7.46-7.49 7.78 J 8.1, 1 7.99 1 11.33 1 11.65 1 LRMS calcd for C 1 6
H,
2 0C, N 3 02 (M- H) 312, found 312.0.
General procedure for the synthesis of alkyl/aryl-sulfonyloxy aryl-aldehydes followed by hydrazone formation: The alkyl/aryl-sulfonyloxy aryl-aldehydes may be prepared by 0-sulfonylation of the corresponding phenolic compounds using various electrophilic sulfonylating agents that introduce the -(K)mD moiety as defined above.
WO 99/01423 PCT/DK98/00287 327 H R ~3a R3bR4a Rb R RXSi (H R (CHR~
R
1 4 LXSfC b k )p H 2 )a_(M)j-(CH 2 )c q (CHA)-D R is OH Base, solvent
H
I\R 3 R 3 b 4a R 4 b
R
5 OS02-(ACH 2 )b p (C 2 )ai(M)j 1 (0H 2 )c q AC 2 A- 0 0X
N,=NH
HH
R 14
\H
3a R 3 b Ra R4b FR(H )a(M)j-(CH _(CH OS2-CH)b p 2c q A)d wherein Lx is a leaving group such as -Cl, -Br, -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 14 and R 15 are as defined for formula I.
According to the above scheme an alkyl/aryl-sulfonyloxyaryl aldehyde can be prepared by stirring hydroxybenzaldehydes or hydroxynaphthaldehydes in an organic solvent such as acetone, 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, aryisulfonyl halide or an aryl-lower alkyl sulfonyihalide 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 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 performed at 0°C to 150*C, preferably at 20*C 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 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, ethyl acetate, isopropyl alcohol, water, hexane, toluene or their compatible mixture.
The following hydrazone formation step is described above in general.
Examples of compounds synthesized using the methodology described are given below: EXAMPLE 533: ci o O.s J HN4-2T 0. 0 0
H
Cl 'H NMR (DMSO-D 6 5 7.03 1H), 7.28 1H), 7.39 1H), 7.61 1H), 7.67 1H), 7.75 2H), 7.87 2H), 7.95 1H), 8.75 1H), 9.02 1H), 11.00 1H), 11.88 1H); MS (APCI): 521.0, 523.0.
EXAMPLE 534: S
CH
3 0
CH
3 N' N 0 0 HO.
H
HO-"
Cl 'H NMR (DMSO-D 6 8 1.38 6H), 3.91 (septet, 1H), 6.97 1H), 7.46 1H), 7.61 (m, 2H), 7.71 1H), 7.81 1H), 7.89 1H), 8.01 1H), 8.69 1H), 9.11 1H), 11.00 (brd s, 1H), 11.98 1H); MS (APCI, neg.): 445.0, 487.0, 339 iprso 2 WO 99/01423 PCT/DK98/00287 329 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 [Building block 2] Resin- [Building block [Building block [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 [Building block [Building block [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, 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 were all prepared as described below.
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 following scheme: 0 CI N. B--Lea Resin f Oe'' [Building block 3]
R
Pd catalyst 0 Resin
N
0 Resin-[Building block 1]-[Building block 2] R" Lea R" where B-Lea is 4R Lea or Ris R RI Resin-[Building block 1]-[Building block 2]-[Building block 3] wherein Lea is a leaving group and preferably is selected from bromo, iodo and trifluoromethanesulfonyloxy, and R 14 and R 15 are as defined for formula I.
The following resin, here depicted as Resin-[Building block 1] was used: o ci
NH
2 Yo where PS is polystyrene. In the following "Resin" is the PS polystyrene resin with the Wang linker.
where Op C Resin WO 99/01423 WO 9901423PCT/DK98/00287 The following building blocks were used: [Buiding block 21: 3,4-dimethoxy-5-iodobenzaldehyde O, H 3-Bromobenzaldehyde OH
B
4-Bromobenzaldehyde Br Trifluoromethanesulfonic acid 4-formyl-1 naphthyl ester O H F'kF WO 99/01423 WO 9901423PCT/DK98/00287 [Building block 31: 1 -Ethynylcyclohexylamine
H
2 N-Methyl-N-propargylbenzylamine H CH l N, N-Diethylpropargylamine
<~N'CH
3 H
CHI
3-Phenyl-1 -propyne 2-Amino-4-pentynoic acid 0
OH
H NH 2 Propargylamine
NH
2 Phenyl propargyl ether
H
Ethynyl p-tolyl sulfone WO 99/01423 WO 9901423PCTIDK98/00287 1 -Ch loro-4-ethynyl benzene 5-Phenyl-1 -pentyne
H
5-Phenyl-2-(2-propynylamino)-2-oxazolin-4one 3-Ethynyiphenol 'e-a
OH
2-Ethynylpyridine H
N
tert-Butyl propiolate, O CH CH 3 0 OH 3 tert-Butyl 1 -methyl-2-propynyl ether
OHCH
3 C3J<CH 3 0 CH 3 4-Pentynoic acid 0
OH
WO 99/01423 PCT/DK98/00287 334 3-Butyn-l-ol 5-Hexyn-3-ol OH
CH
3 H H OH O-Trimethylsilylpropargyl alcohol 3-(2,6-Dichlorophenoxy)prop-1 -yne
CH
3 CI l I ,CH, 0 'CH3° H H CI By combination of these building blocks in a fully combinatorial way 1x4x20 80 compounds were prepared.
Preparation of [Building block 21: Preparation of 3,4-dimethoxy-5-iodobenzaldehyde: lodomethane (2.5 mL, 40 mmoles) was added to a mixture of 5-iodovanillin (10 g, 36 mmoles), potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture 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 of 3,4-dimethoxy-5-iodobenzaldehyde, m.p. 58-63 OC.
Preparation of trifluoromethanesulfonic acid 4-formyl-l-naphthyl ester: 4-Hydroxy-l-naphthaldehyde (10 g, 58 mmoles) was dissolved in pyridine (50 ml) and the mixture was cooled to 0 OC. Trifluoromethanesulfonic anhydride (11.7 mL, 70 mmoles) was added dropwise while maintaining the temperature below 5 OC. When the addition was completed 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 hydrochloric acid (200 mL), and saturated NaCI (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 Pure fractions WO 99/01423 PCT/DK98/00287 335 eluting with R, 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 OC.
The other [Building block 2]'s (3-Bromobenzaldehyde and 4-bromobenzaldehyde) are commercially available.
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 Cl 2 (80 mL) and diisopropylethylamine (60 mL) was added. The mixture was cooled to 0 C and methanesulfonyl chloride (5.8 mL) dissolved in CH 2 Cl2 (30 mL) was added drop wise while maintaining the temperature below 5 When addition was complete the mixture was stirred at 0 OC for 30 minutes and at room temperature for 30 minutes. The resin was successively washed with CH 2 Cl 2 (3 x 80 mL) and N-methylpyrrollidone (NMP) (3 x 80 mL). This 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 oC 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 hydroxide (2.6 g) was added and the mixture was stirred at 60 OC under N 2 for 16 hours. After cooling the resin was successively washed with DMF (3 x 80 mL), CH 2
CI
2 (3 x 80 mL) and methanol (80 mL) and dried in vacuo at 50 OC for 3 days.
The above resin (3.0 g) was suspended in CH 2
CI
2 (20 mL) and 1-hydroxybenzotriazole (0.6 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 hydrate (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 CHCI, (3 x 20 mL) to afford resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (Resin-[Building block 11).
Preparation of Resin-[Building block 11-[Building block 21: Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (3,4-dimethoxy-5-iodobenzylidene)hydrazide: WO 99/01423 PCT/DK98/00287 336 The above resin (Resin-[Building block (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 successively washed with DMF (4 x 40 mL) and CH 2
C
2 (6 x 40 mL), and dried in vau at 50 0
C
for 16 hours to afford resin bound 3-chloro-4-hydroxybenzoic acid (3,4-dimethoxy-5iodobenzylidene)hydrazide.
Preparation of resin bound trifluoromethanesulfonic acid 4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]naphthalen-1 -yl ester: Similarly as described above but using trifluoromethanesulfonic acid 4-formyl-1 -naphthyl ester instead of 3,4-dimethoxy-5-iodobenzaldehyde resin bound was trifluoromethanesulfonic acid 4-I(3-chloro-4-hydroxybenzoyI)hydrazonomethyl]naphthalen-1 -yI ester obtained.
Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide: Similarly as described above but using 3-bromobenzaldehyde instead of 3,4-dimethoxy-5iodobenzaldehyde resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide) was obtained.
Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (4-bromobenzylidene)hyd razide: Similarly as described above but using 4-bromobenzaldehyde instead of 3,4-dimethoxy-5iodobenzaldehyde resin bound 3-chloro-4-hydroxybenzoic acid (4-bromobenzylidene)hydrazide) was obtained.
WO 99/01423 PCT/DK98/00287 337 EXAMPLE 535: O.CH3 O r^ CH HO H Cl 3-Chloro-4-hydroxybenzoic acid hydrazide To the resin bound 3-chloro-4-hydroxybenzoic acid (3-bromobenzylidene)hydrazide (0.05 mmoles) was added copper 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 solution of 1-ethynylcyclohexylamine ([Building block 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, 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
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
CI
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 LC-MS (molecular mass).
The RP-HPLC analysis was performed on a Waters HPLC system consisting of WatersM 600S Controller, WatersTM 996 Photodiode Array Detector, Waters T 717 Autosampler, WatersTM 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% acetonitrile/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 WatersT 3 mm x 150 mm 3.5 p C-18 Symmetry column and positive ionspray with a flow rate at 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 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 1 Empty RB_Heating_AIl_1to36 for 2.000 minute(s) 2 REM Addition of DIPEA 3 Transfer 2 0 0pl from Monomers_1to36 [25] to RB_Heating_AIl_1to96 [1-80] using DCE 4 Mix for 1.00 minutes at 600 rpm(s) REM Addition of Ph3P in NMP 6 Transfer 500pl from Monomers_1to36 [21] to RB Heating_All_1to96 [1-80] using DCE 7 REM Addition of Bu4NCI in water 8 Transfer 300pl from Monomers_1to36 [22] to RB Heating_AIl_1to96 [1-80] using DCE 9 Mix for 1.00 minutes at 600 rpm(s) REM Addition of Pd(OAc)2 in NMP 11 Transfer 250pl from Monomers_1to36 [22] to RB_Heating_All_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_Heating_AIl_1to96 rack 14 Set Temperature to 90.0 degrees Celsius Mix for 15.00 minutes at 600 rpm(s) 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) Wait for 15.000 minute(s) 21 Repeat from step 19, 7 times 22 Empty RB_Heating_All_1to96 for 2.000 minute(s) 23 Dispense System Fluid NMP1 1500pl to RB_CleavageAll_1to96 [1-80] 24 Mix for 3.00 minutes at 600 rpm(s) Empty RB_Heating_AII_1to96 for 2.000 minute(s) 26 Repeat from step 23, 2 times 27 REM Wash with 50% WO 99/01423 PCT/DK98/00287 339 28 Transfer 1500pl from Reagent_3 to RB_Heating_AllI to96 [1-80] using NMP1 29 Mix for 3.00 minutes at 600 rpm(s) Empty RB_Heating_All_1to96 for 2.000 minute(s) 31 Repeat from step 28, 2 times 32 Dispense System Fluid NMP1 1500pl to RB_Cleavage_AII_1to96 [1-80] 33 Mix for 3.00 minutes at 600 rpm(s) 34 Empty RB_Heating_All_1to96 for 2.000 minute(s) Repeat from step 32, 1 times 36 REM Wash with Sodium diethylaminodithiocarbamate 37 Transfer 1500pl from Reagent_3 to RB_Heating_All_1to96 [1-80] using NMP1 38 Mix for 3.00 minutes at 600 rpm(s) 39 Empty RB_Heating All_1to96 for 2.000 minute(s) Repeat from step 37, 2 times 41 Transfer 1500pl from REAGENT_4 to RB_Heating All_1to96 [1-80] using NMP1 42 Mix for 3.00 minutes at 600 rpm(s) 43 Empty RB_Heating_All_1to96 for 2.000 minute(s) 44 Repeat from step 41, 2 times Transfer 1500pl from REAGENT_5 to RB_Heating_All_1to96 [1-80] using NMP1 46 Mix for 2.00 minutes at 600 rpm(s) 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 RB_Cleavage_AIl_1to96 [1-80] Mix for 3.00 minutes at 600 rpm(s) 51 Empty RB_Heating_All_1to96 for 2.000 minute(s) 52 Repeat from step 49, 4 times 53 Dispense System Fluid DCE1 1500pl to RB_Cleavage_All_1to96 [1-80] 54 Mix for 3.00 minutes at 600 rpm(s) Empty RB_Heating_All_1to96 for 2.000 minute(s) 56 Repeat from step 53, 5 times 57 REM Cleavage from Resin 58 REM with 50% TFA/DCM 59 Transfer 1500pl from Reagent _3 to RB_Cleavage_All_1to96 [1-80] using DCM1 Mix for 45.00 minutes at 600 rpm(s) 61 Empty RB_Cleavage_All_1to96 for 1.000 minute(s) 62 Dispense System Fluid DCM1 500pl to RB_Cleavage_All_1to96 [1-80] 63 Mix for 1.00 minutes at 300 rpm(s) 64 Empty RB_Cleavage_All_1to96 for 1.000 minute(s) 66 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 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 WO 9901423PCT/DK98/00287 EXAMPLE 536: 2-Amino-5-{5-[(3-chloro-4hydroxybenzoyl)hydrazonomethyl]-2,3dimethoxyphenyl}-4-pentynoic acid EXAMPLE 537: 3-Chloro-4-hydroxybenzoic acid diethylamino-1 dimethoxybenzylidene]hydrazide 0
.CH
3 0 0.C
.CH
3 0. CH 3 0 HO
CI
HO'
'NH
2 EXAMPLE 538: 3-Chloro-4-hydroxybenzoic acid{3-[3- (benzylmethylamino)-1 -propynyl]-.4,5dimethoxybenzylidenelhydrazide EXAMPLE 539: 3-Chloro-4-hydroxybenzoic acid [3,4dimethoxy-5-(3-phenyl-1 propynyl)benzylidene]hydrazide 0*H 0 0. CH 3
HO'
CI
0
HOJ(
CI
H
3 cvN_,o EXAMPLE 540: 3-Chloro-4-hydroxybenzoic acid [3-(3-amino-1 EXAMPLE 541: 3-Chloro-4-hydroxybenzoic acid [3,4dimethoxy-5-(3-phenoxy-1 propynyl)benzylideneljhydrazide O*.H3 09-H 0 HO H
CI
N'
I H
HO-
CI
NH
2 0 WO 99/01423 WO 99/1 423PCT/DK98/00287 EXAMPLE 542: 3-Chloro-4-hydroxybenzoic acid [3,4dimethoxy-5-(toluene-4-sulfonylethynyl)benzylidene]hydrazide O 0
.CH
3 N N
N~
HO H
CI
HOC
EXAMPLE 544: 3-Chloro-4-hydroxybenzoic acid chlorophenylethynyl)-4, 5d imethoxybenzyiidene]hydrazide 0. OH 3 O .C 11rI Y EXAMPLE 543: 3-Chloro-4-hydroxybenzoic acid dimethoxyberlzylidene]hydrazide 0 H 01 0 OHr
OH
EXAMPLE 545: 3-Chloro-4-hydroxybenzoic acid [3,4dimethoxy-5-(2-pyridylethynyl]benzylidene]hydrazide
HO'
EXAMPLE 546: 3-Ohloro-4-hydroxybenzoic acid [3,4dimethoxy-5-(5-phenyl-1 pentynyl)benzylidene]hydrazide oOH 3 0 0. C0H WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 547: 3-Chloro-4-hydroxybenzoic acid {3,4dimethoxy-5-[3-(4-oxo-5-phenyl-4,5-dihydro- 2-oxazolylamino)-1 -propynyl]benzylidene~hydrazide O. CH 3 0 0. CH3
HOH
HO 0 EXAMPLE 549: 5-{5-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-2,3-dimethoxyphenyl)-4pentynoic acid 3 EXAMPLE 548: {5-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-2, 3-dimethoxyphenyllpropynoic acid EXAMPLE 550: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 benzylidene]hydrazide O' CH 3
HO
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 551: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -butynyl)-4,5-dimethoxybenzylidene]hydrazide 0CH3 0 0 CF
H
HOJP
CI
EXAMPLE 553: 3-Chloro-4-hydroxybenzoic acid hyd roxy-l1-propynyl)-4,5-dimethoxybenzylidene]hyd razide CY CH 3 EXAMPLE 552: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 benzylidene]hyd razide CI HO' EXAMPLE 554: 3-Chloro-4-hydroxybenzoic acid dichlorophenoxy)-1 dimethoxybenzylidenelhydrazide 0 H Y- 0 CH 3
HO'
EXAMPLE 555: 3-Chloro-4-hydroxybenzoic acid aminocyclohexylethynyl)-1 naphthylmethylene]hydrazide
H
2
N
0 N N N
HO
WO 99/01423 WO 9901423PCTIDK98/00287 EXAMPLE 556: 3-Ohloro-4-hydroxy benzoic acid benzylmethytamino-1 -propynyl)-1 naphthylmethylerie] hydrazide 3N N N
N
HO
C I EXAMPLE 558: 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyll-1 -naphthyl)-4-pentynoic acid EXAMPLE 557: 3-Chloro-4-hydroxybenzoic acid f4-(3-amino- 1 -propynyl)-1 -naphthylmethylenelhyd razide EXAMPLE 559: 3-Chloro-4-hydroxybenzoic acid[4-(3d iethylamino-1 -propynyl)-1 -naphthylmethylenelhydrazide OH3 HO N
HO'
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 560: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 1 -propynyl)-1 -naphthylmethylene]hydrazide EXAMPLE 561: 3-Chloro-4-hydroxybenzoic acid [4-(toluene- 4-sulfonylethynyl)-1 naphthylmethylene]hydrazide EXAMPLE 562: 3-Chloro-4-hydroxybenzoic acid phenoxy-1 -propynyl)-1 -naphthylmethylene]hydrazide EXAMPLE 563: 3-Chloro-4-hydroxybenzoic acid chlorophenylethynyl)-1 -naphthylmethylene]hyd razide '0c0
HO'
HO'
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 564: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 1 -pentynyl)-1 -nap hthylmethylene] hyd razide 0 H NN HO-f?
H
CI
EXAMPLE 566: 3-Chloro-4-hydroxybenzoic acid hydroxyphenylethynyl)-1 -naphthylmethylene]hydrazide EXAMPLE 565: 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- 5-phenyl-4, 5-dihydro-(2-oxazolylamino)-1 propynyl]-1 -naphthylmethylene~hydrazide 0
N-
HNAlO 0 N
N
Hd H H
CI
EXAMPLE 567: 5-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-1 -naphthyl}-4-pentoic acid 0
'OH
HO'
WO 99/01423 WO 9901423PCTIDK98/00287 348 EXAMPLE 568: 3-Chloro-4-hydroxybenzoic acid pyridyl)ethynyl-1 -naphthylmethylene)hydrazide N N
HO
CI
EXAMPLE 570: 3-Chloro-4-hydroxybenzoic acid hyd roxy-1 -butynyl)-1 -naphthylmethylene]hydrazide EXAMPLE 569: {4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]l--naphthyl)propynoic acid 0
OH
O' N A
CI
EXAMPLE 571: 3-Chloro-4-hydroxybenzoic acid hyd roxy-1 -propynyl)-1 -naphthylmethylene]hydrazide
OH
0 NN
HO
CI
EXAMPLE 573: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -hexynyl)-1 -riaphthylmethylene]hydrazide
CI
EXAMPLE 572: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -butynyl)-1 -naphthylmethylene]hydrazide
,OH
H
3
C-
HO'
WO 99/01423 WO 9901423PCTIDK98/00287 EXAMPLE 574: 3-Chloro-4-hydroxybenzoic acid dichlorophenoxy)-1 -propynyl]-1naphthylmethylenelhydrazide Ci
CI
EXAMPLE 576: 3-Chloro-4-hydroxybenzoic acid aminocyclohexylethynyl)benzyiidene]hydrazide EXAMPLE 575: 2-Amino-5-{3-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl~phenyl}-4pentynoic acid 0 HO
CI
EXAMPLE 577: 3-Chloro-4-hydroxybenzoic acid (benzylmethylamino)-1 propynyllbenzyiidenelhydrazide 0 N PH3
N'H
HO Q
CI
EXAMPLE 578: 3-Chloro-4-hydroxybenzoic acid [3-(3-amino- 1 -propynyl)benzylidene]hydrazide 0 N
NN
I H NH 2
CI
WO 99/01423 PTD9/08 PCT/DK98/00287 EXAMPLE 579: 3-Chloro-4-hydroxybenzoic acid diethylamino- I -propynyl)benzylidene]hydrazide 0 NN CH.3 HO H NCH 3
CI
EXAMPLE 580: 3-Chloro-4-hydroxybenzoic acid [3-(toluene- 4-sulfonylethynyl)benzylidenelhydrazide EXAMPLE 581: EXAMPLE 582: 3-Chloro-4-hydroxybenzoic acid [3-(3-phenyl- 3-Chloro-4-hyd roxybenzoic acid 1 -propynyl)benzylidene]hydrazide chlorophenylethynyl)benzylidene]hydrazide 0 0 jN NN N H" 0 H HO C HOC EXAMPLE 583: 3-Chloro-4-hydroxybenzoic acid phenoxy-1 -propynyl)benzylidene]hydrazide EXAMPLE 584: 3-Chloro-4-hydroxybenzoic acid 1 -pentynyl)benzylidene]hydrazide WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 585: 3-Chloro-4-hydroxybenzoic acid hydroxyphenylethynyl)benzylidene]hydrazide 0
CI
EXAMPLE 587: 3-Chloro-4-hydroxybenzoic acid pyridylethynyl)benzylidene]hydrazide EXAMPLE 586: 5-{3-[(3-Chloro-4-hydroxybenzoyl)-hydrazonomethyllphenyl}-4-pentynoic acid
CI
EXAMPLE 588: {3-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]phenyl)propynoic acid N N HO'
,OH
EXAMPLE 589: 3-Chloro-4-hydroxybenzoic acid {3-[3-(4-oxo- 5-phenyl-4,5-dihydro-(2-oxazolylamino))- 1propynyl]benzylidene~hydrazide 0
N'N
N
CI
EXAMPLE 590: 3-Chloro-4-hydroxybenzoic acid hydroxy- 1 -butynyl)benzylidene]hydrazide N
NN
0 '>OH WO 99/01423 WO 9901423PCTIDK98/00287 EXAMPLE 591: 3-Chtoro-4-hydroxybenzoic acid hydroxy-lI-butynyl)benzylidene]hydrazide EXAMPLE 592: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -hexynyl)benzylidene]hydrazide HO A OH EXAMPLE 594: 3-Chioro-4-hydroxybenzoic acid dichlorophenoxy)-1 -propynyflbenzylidene}hydrazide EXAMPLE 593: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -propynyl)benzylidene]hydrazide 0N
NN
I H ANOH HO A
CI
EXAMPLE 595: 3-Chloro-4-hydroxybenzoic acid aminocyclohexylethynyl)benzylidene]hydrazide EXAMPLE 596: 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]phenyl}-4-pentynoic acid 0 -11-
OH
NH
2 WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 597: 3-Chloro-4-hydroxybenzoic acid (benzylmethylamino)-1 -propynyl]benzylidene~hydrazide
NN
6H 3
K
EXAMPLE 598: 3-Chloro-4-hydroxybenzoic acid [4-(3-amino- 1 -propynyl)benzylidene]hydrazide SNH 2 0 j
H
HO
CI
EXAMPLE 600: 3-Chioro-4-hydroxybenzoic acid phenoxy-1 -propynyllbenzylidene]hydrazide EXAMPLE 599: 3-Chloro-4-hydroxybenzoic acid diethylamino-1 -propynyl)benzylidene]hyd razide N CH 3 0 HH HO 0 C I EXAMPLE 601: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 1 -propynyl)benzylidene]hydrazide 0N N N
N
HOQT
H
0 0
CI
EXAMPLE 602: 3-Chloro-4-hydroxybenzoic acid [4-(toluene- 4-sulfonylethynyl)benzylidene]hydrazide 9 O H 3 WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 603: 3-Chloro-4-hydroxybenzoic acid chlorophenylethynyl)benzylidene]hydrazide
C
0 oj
N
HO H EXAMPLE 604: 3-Chloro-4-hydroxybenzoic acid hydroxyphenylethynyl)benzylidene] hydrazide 0 OH EXAMPLE 605: EXAMPLE 606: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 3-Chloro-4-hydroxybenzoic acid 1 -pentynyl)benzylidene]hydrazide pyridylethynyl)benzylidene]hyd razide EXAMPLE 607: 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1 propynyl] benzylidene~hydrazide 0 N 0
<N
HI(?
H
CI
EXAMPLE 608: {4-[(3-Chloro-4hydroxybenzoyl)hydrazonomethy]phenylipropynoic acid
OH
<0
O
K N N HO0 WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 609: 5-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]phenyl}-4-pentynoic acid
OH
CI
EXAMPLE 611: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -butynyl)benzylidene]hydrazide EXAMPLE 610: 3-Chloro-4-hydroxybenzoic acid hydroxy- 1 -butynyl)benzylidene]hydrazide
CH
3
OH
HO
CI
EXAMPLE 612: -Chloro-4-hydroxybenzoic acid hydroxy-1 -hexynyl)benzylidene]hydrazide
CH
3 O0 OH I H
HO"
CI
EXAMPLE 614: 3-Chloro-4-hydroxybenzoic acid dichlorophenoxy)-1 -propynyl]benzylidene)hydrazide Ck 0 -CI EXAMPLE 613: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -propynyl)benzylidene]hydrazide
HO'
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.
The compounds were prepared according to the following equation: Resin- [Building block 1] Resin- [Building block [Building block 2] Resin- [Building block [Building block [Building block 3] and were simultaneously cleaved (and deprotected when protected) from the resin with trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula: [Building block [Building block [Building block 3].
The starting resins, Resin-[Building block 1]-[Building block were all prepared as described above.
The resin used was a polystyrene resin loaded with a Wang linker and the substitution capacity 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 following scheme.
WO 99/01423 PCT/DK98/00287 357 [Building block 3] Catecholborane 0 s NCI N.N- 8 -Lea Resin. H Resin-[Building block 1]-[Building block 2] 09 Pd catalyst R Pd catalyst 0 Resin Resin. Resin-[Building block 1]-[Building block 2]-[Building block 3] where B-Lea is Lea Lea R 4
R"
1 wherein Lea is a leaving group and R 14 and R 1 5 are as defined for formula I.
The starting materials used were the same as those use in examples 535 to 614, i.e.
Resin-[Building block [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-hydroxvbenzoic acid f3-f2-(1-aminocyclohexylvinyll-4.5-dimethoxvbenzylidenelhydrazide
H
2
N
O O'CH3 HO sN-N o.CH 3 C H Cl Preparation of a 1,4-dioxanefTHF solution of 1-(2-Benzo[1,3,2]dioxaborol-2-ylvinyl)cyclohexylamine: To a solution of 1-ethynylcyclohexylamine ([Building block 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 60 OC 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 triphenylphosphine and tetrabutylammonium chloride in NMP (both 0.4 M, 0.5 mL), a solution of palladium (II) acetate in NMP (0.16 M, 0.25 mL), was mixed and the solution of 1-(2benzo[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 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 mL, 2 times), 1% sodium diethylaminodithiocarbamate trihydrate (1.5 mL, 9 times), NMP mL, 5 times) and CH 2
CI
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
CI
2 (1.5 mL). The mixture was filtered and the resin was extracted with CH 2
CI
2 (0.5 mL). The combined CH 2
CI
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 CI (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 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, WatersTM 616 Pump, WatersTM 3 mm x 150 mm 3.5 p C-18 Symmetry column and Millenium QuickSet Control Ver. 2.15 using UV detection at 214 nm. A gradient of 5% to 90% acetonitrile/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 pL/minute.
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 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 RB_Heating_All_1to96 for 2.000 minute(s) 2 3 REM Addition of Cs2C03 in water 4 Transfer 200pl from Monomers_1to36 [25] to RB_HeatingAllI_to96 [1-80] using DCE 6 Mix for 1.00 minutes at 600 rpm(s) 7 8 REM Addition of Ph3P Bu4NCI in NMP 9 Transfer 500pl from Monomers_1to36 [21] to RB_HeatingAll_1to96 [1-80] using DCE 11 Mix for 1.00 minutes at 600 rpm(s) 12 13 REM Addition of Pd(OAc)2 in NMP 14 Transfer 5001I from Monomers_1to36 [22] to RB_Heating_All_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_Heating_All 1to96 rack 18 Set Temperature to 70.0 degrees Celsius 19 Mix for 15.00 minutes at 600 rpm(s) 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) 25 Repeat from step 23, 7 times 26 Empty RB_Heating_All 1to96 for 2.000 minute(s) 27 Dispense System Fluid NMP1 1500pI to RB_Cleavage_All_1to96 [1-80] 28 Mix for 3.00 minutes at 600 rpm(s) 29 Empty RB_Heating_All_1to96 for 2.000 minute(s) 30 Repeat from step 27, 2 times 31 32 REM Wash with 50% 33 34 Transfer 1500pl from Reagent _3 to RB_Heating_All_1to96 [1-80] using NMP1 35 Mix for 3.00 minutes at 600 rpm(s) 36 Empty RB_Heating_All_1to96 for 2.000 minute(s) 37 Repeat from step 34, 2 times 38 Dispense System Fluid NMP1 1500pl to RB_CleavageAll_1to96 [1-80] 39 Mix for 3.00 minutes at 600 rpm(s) 40 Empty RB_Heating_All_1to96 for 2.000 minute(s) 41 Repeat from step 38, I times 42 43 REM Wash with Sodium diethylaminodithiocarbamate 44 45 Transfer 1500pl from Reagent_3 to RB_Heating_All_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 to RB_HeatingAll_1to96 [1-80] using NMP1 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 REAGENT_5 to RB_Heating_All_1to96[ 1-80] using NMP1 54 Mix for 2.00 minutes at 600 rpm(s) 55 Empty RB_Heating_All_1to96 for 2.000 minute(s) 56 Repeat from step 53, 2 times 57 Dispense System Fluid NMP1 1500pl to RB_Cleavage_All_1to96 [1-80] 58 Mix for 3.00 minutes at 600 rpm(s) 59 Empty RB_Heating_All_1to96 for 2.000 minute(s) 60 Repeat from step 57, 4 times 61 Dispense System Fluid DCE1 1500pl to RB_Cleavage All_1to96 [1-80] 62 Mix for 3.00 minutes at 600 rpm(s) 63 Empty RB_Heating_All_1to96 for 2.000 minute(s) 64 Repeat from step 61, 5 times WO 99/01423 PCT/DK98/00287 361 66 REM Cleavage from Resin 67 REM with 50% TFA/DCM 68 69 Transfer 1500pl from Reagent_3 to RB_Cleavage_All_1to96 [1-80] using DCM1 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 RB_Cleavage_All_1to96 [1-80] 73 Mix for 1.00 minutes at 300 rpm(s) 74 Empty RB_Cleavage_All_1to96 for 1.000 minute(s) 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] 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: 2-Amino-.5-{5-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-2,3-dimethoxyphenyl}-4pentenoic acid NH 2 EXAMPLE 617: 3-Chloro-4-hydroxybenzoic acid amino-I benzylidenejhydrazide EXAMPLE 618: 3-Chloro-4-hydroxybenzoic acid dimethoxybenzylidene~hydrazide 91H 3 WO 99/01423 WO 9901423PCT/DK98/00287 363 EXAMPLE 619: 3-Chloro-4-hydroxybenzoic acid diethylamino-1 -propenyl)-4,5dimethoxybenzylidene]hydrazide r CH 3
NCH
3 0 0. CH3 S Nw NN., OH 3 I H
HO
CI
EXAMPLE 621: 3-Chloro-4-hydroxybenzoic acid [3,4dimethoxy-5-(3-phenyl-1 -propenyl)benzylidene]hyd razide EXAMPLE 620: 3-Chloro-4-hydroxybenzoic acid [3,4dimethoxy-5-(3-phenoxy-1 -propenyl)benzylidene]hydrazide 0, 0 0. CH3 N Nl, *CH3 H0"
H
CI
EXAMPLE 622: 3-Chloro-4-hydroxybenzoic acid (3,4dimethoxy-5-[2-(toluene-4-sufonyl)vinyl]benzylidene~hydrazide
OH
3 WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 623: 3-Chloro-4-hydroxybenzoic acid dimethoxybenzylidene~hydrazide
CI
EXAMPLE 624: 3-Chloro-4-hydroxybenzoic acid benzylidene~hydrazide EXAMPLE 625: 3-Chloro-4-hydroxybenzoic acid [3,4dimethoxy-5-(5-phenyl-1 -pentenyt)benzylidene]hydrazide 0 0. 0
CH
0*3
HO
EXAMPLE 626: 3-Chloro-4-hydroxybenzoic acid [3,4dimethoxy-5-(2-(2-pyridyl)vinyl)benzylidene]hydrazide WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 627: 3-Chloro-4-hydroxybenzoic acid {3,4dimethoxy-5-[3-(4-oxo-5-phenyl-4,5-dihydro-2oxazolylamino)-1 -propenyl]benzylidene~hydrazide 0
NH
N HH
HOH
Cl EXAMPLE 629: 5-{5-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-2,3-dimethoxyphenyl}-4pentenoic acid O OH 0 0. 0 CH3 'NNN 'N OH 3 H IJ('
H
EXAMPLE 628: 3-{5-[(3-Chloro-4-hydroxybenzoyl hydrazonomethyl]-2,3-dimethoxyphenyl}acrylic acid O OH 0 0. 0 CH3 0
CH
3
HOH
CI
EXAMPLE 630: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 benzylidene]hydrazide H 3 C OH N N N
CH
HO
WO 99/01423 PTD9/08 PCT/DK98/00287 EXAMPLE 631: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -butenyl)-4,5-dimethoxybenzylidene]hydrazide EXAMPLE 632: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 benzylidene]hydrazide
CH
3
OH
~CH
3 0' CH 3 CI
CI
EXAMPLE 633: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -propenyl)-4,5-dimethoxybenzylidene]hydrazide EXAMPLE 634: 3-Chloro-4-hydroxybenzoic acid dichlorophenoxy)-1 dimethoxybenzylidenelhydrazide CI"* CI '~0
HO'
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 635: 3-chloro-4-hydroxybenzoic acid aminocyclohexyl)vinyl]-1 -naphthylmethytene~hydrazide EXAMPLE 636: 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]-1 -naphthyl}-4-pentenoic acid ,N2 EXAMPLE 637: 3-Chloro-4-hydroxybenzoic acid (benzylmethylamino)propenyl]-l naphthylmethylenelhydrazide 0N N N* HO H H
CI
EXAMPLE 639: 3-Chloro-4-hydroxybenzoic acid[4-(3diethylamino-1 -propenyl)-1 -naphthylmethylene]hydrazide O0 N N N" N N
HOQAN
EXAMPLE 638: 3-Chloro-4-hydroxybenzoic acid [4-(3-amino- 1 -propenyl)-1 -naphthylmethylene]hydrazide EXAMPLE 640: 3-Chloro-4-hydroxybenzoic acid phenoxy-l1-propenyl)-l1-naphthylmethylene]hydrazide WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 641: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyl- 1 -propenyl)-1 -naphthylmethylene]hydrazide EXAMPLE 642: 3-Chloro-4-hydroxybenzoic acid (toluene-4-sulfonyl)vinyl]-1 naphthylmethylene)hydrazide 0
'&S
j N
N
I HN
HO
CI
EXAMPLE 644: 3-Chloro-4-hyd roxybenzoic acid hydroxyphenyl)vinyl]-1 -naphthylmethyleneihydrazide EXAMPLE 643: 3-Chloro-4-hydroxybenzoic acid chlorophenyl)vinyl]-1 -naphthylmethylene}hydrazide EXAMPLE 645: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 1 -pentenyl)-1 -naphthytmethylene]hydrazide EXAMPLE 646: 3-Chtoro-4-hydroxy-benzoic acid pyridyl)vinyl)-1 -naphthylmethylene]hydrazide WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 647: 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1 propenyl]- 1 -naphthylmethylene~hydrazide 0 N' N NI
H
HO N
CI
EXAMPLE 649: 5-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-1 -naphthyl}-4-pentenoic acid EXAMPLE 648: 3-{4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-l1-naphthyl}acrylic acid EXAMPLE 650: 3-Chioro-4-hydroxybenzoic acid hydroxy- I -butenyl)-1 -naphthylmethyiene]hydrazide EXAMPLE 651: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -butenyl)-1 -naphthylmethylene]hydrazide EXAMPLE 652: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -hexenyl)-1 -naphthylmethylenelhydrazide WO 99/01423 WO 9901423PCT/DK98/00287 370 EXAMPLE 653: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -propenyl)-1 naphthylmethylene]hydrazide EXAMPLE 654: 3-Chloro-4-hydroxybenzoic acid dichlorophenoxy)-1 -propenyl]-1 naphthytmethylenelhydrazide CI-p 'N-1 CI EXAMPLE 655: 3-Chloro-4-hydroxybenzoic acid 1aminocyclohexyl)vinyl]benzylidene~hydrazide EXAMPLE 656: 2-Amino-5-{3-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]phenyl}-4pentenoic acid
H
2
N-
0
N'
HOQI
H
CI
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 657: 3-Chloro-4-hydroxybenzoic acid (benzylmethylamino)-1 -propenyl]benzylidene~hydrazide
CH
3 N 0
H
CI
EXAMPLE 659: 3-Chloro-4-hydroxybenzoic acid diethylamino-1 -propenyl)benzylidene]hydrazide EXAMPLE 658: 3-Chloro-4-hydroxybenzoic acid [3-(3-amino- 1 -propenyl)benzylidene]hydrazide NH 2 0 H I-
H
CI
EXAMPLE 660: 3-Chloro-4-hydroxybenzoic acid phenoxy-1 -propenyl)benzylidene]hydrazide r
H
3 NCH 3
HO'
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 661: 3-Chloro-4-hydroxybenzoic acid [3-(3-phenyl- 1 -propenyl)benzylidene]hydrazide EXAMPLE 662: 3-Chloro-4-hydroxybenzoic acid (toluene-4-sulfonyl)vinyf]benzylidene}hydrazide
HO'
EXAMPLE 663: 3-Chloro-4-hydroxybenzoic acid chlorophenyl)vinyl]benzylidene}hydrazide EXAMPLE 664: 3-Chloro-4-hydroxybenzoic acid hydroxyphenyl)vinyl]benzylidenelhydrazide -O H
HO'
WO 99/01423 WO 9901423PCTIDK98/00287 EXAMPLE 665: 3-Chloro-4-hydroxybenzoic acid [3-(5-phenyl- 1 -pentenyl)benzylidene]hydrazide 0 C I EXAMPLE 667: 3-Chloro-4-hydroxybenzoic acid {3-[3-(4-oxo- 5-phenyl-4,5-dihydro-(2-oxazolylamino))-l propenyl]benzylidene)hydrazide EXAMPLE 666: 3-Chloro-4-hydroxybenzoic acid pyridyl)vinyl)benzylidene]hydrazide EXAMPLE 668: 3-{3-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]phenyl~acrylic acid 0OOH 0
N
I H
HO
HO'
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 669: 5-{3-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]phenyl}-4-pentenoic acid 0 0
HOO
CII
EXAMPLE 671: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -butenyl)benzylidene]hydrazide
OH
EXAMPLE 670: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -butenyl)benzylidene]hydrazide HOC OH 0NN I H
HO
CI
EXAMPLE 672: 3-Chloro-4-hydroxybenzoic acid 13-(4hydroxy-l1-hexenyl)benzylidene]hydrazide
OCH
3
'OH
HO'
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 673: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -propenyl)benzylidenelhydrazide EXAMPLE 674: 3-Chloro-4-hydroxybenzoic acid dichlorophenoxy)-1 -propenyl]benzylidene~hydrazide
,OH
HO'
EXAMPLE 675: 3-Chloro-4-hydroxybenzoic acid aminocyclohexyl)vinyl]benzylidene}hydrazide
H
2
N
0 N
N
HO q
CI
EXAMPLE 676: 2-Amino-5-{4-[(3-chloro-4-hydroxybenzoyl)hydrazonomethyl]phenyl}-4-pentenoic acid 0 NH 2 N N OH EXAMPLE 677: EXAMPLE 678: 3-Ch Ioro-4-hydroxybenzoic acid ben- 3-Chioro-4-hydroxybenzoic acid [4-(3-aminozylmethylamino)- 1 -propenyl]- 1 -propenyl)benzylidene]hydrazide benzylidene~hydrazide
N
Hd
H
CI
WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 679: 3-Chloro-4-hydroxybenzoic acid diethylaminopropenyl)benzylidene]hydrazide 0 11
~C
N
OH
I 3 EXAMPLE 681: 3-Chloro-4-hydroxybenzoic acid [4-(3-phenyt- 1 -propenyl)benzylidene]hydrazide 0 N
N
Ho
H
CI
EXAMPLE 683: 3-Chloro-4-hydroxybenzoic acid chlorophenyl)vinyqbenzylidenelhydrazide
CI
O0 EXAMPLE 680: 3-Chloro-4-hydroxybenzoic acid phenoxy-1 -propenyl]benzylidene]hydrazide O
N
0 N NNN,
ZN'
HO( H l
CI
EXAMPLE 682: 3-Chloro-4-hydroxybenzoic acid (toluene-4-sulfonyl)vinyl]benzylidene}hydrazide 0 s N f&-CH 3 HOC
H
CI
EXAMPLE 684: 3-Chloro-4-hydroxybenzoic acid hydroxyphenyl)vinyl]benzylidene~hydrazide Q OH WO 99/01423 WO 9901423PCT/DK98/00287 EXAMPLE 685: 3-Chloro-4-hydroxybenzoic acid [4-(5-phenyl- 1 -pentenyl)benzylidene]hydrazide N HO
H
CI
EXAMPLE 687: 3-Chloro-4-hydroxybenzoic acid {4-[3-(4-oxo- 5-phenyl-4,5-dihydro-(2-oxazolylamino)-1 propenyl]benzylidene~hydrazide 0 0 NN' N H H0~ H Ci EXAMPLE 689: 5-{4-[(3-.Chloro-4-hydroxybenzoyl)hydrazonomethyl]phenyl}-4-pentenoic acid 0 0 -OH Kl EXAMPLE 686: 3-Chloro-4-hydroxybenzoic acid pyrid inyl)virlyl]benzylidenelhydrazide EXAMPLE 688: {4-[(3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]phenyl~acrylic acid 0 0
N.
H. 0.N N.-1 EXAMPLE 690: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -hexenyl)benzylidene]hydrazide 0 N NO CH3 H0 H
CI
WO 99/01423 WO 9901423PCTIDK98/00287 EXAMPLE 691: 3-Chloro-4-hydroxybenzoic acid hydroxy-1 -butenyl)benzylidenelhydrazide O
OH
I H
HO
CI
EXAMPLE 693: 3-Chloro-4-hydroxybenzoic acid hyd roxy-l1-butenyl)benzylidene]hydrazide
OH
3 O0- OH Ho
H
CI
EXAMPLE 692: 3-Chloro-4-hydroxybenzoic acid hyd roxy- 1 -propenyl)benzylidene]hydrazide
HO
CI
EXAMPLE 694: 3-Chloro-4-hydroxybenzoic acid dichlorophenoxy)-l1-propenyl]benzylidene)hydrazide.
N N
CI
H0 H
CI
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 [Building block 2] Resin- [Building block [Building block [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 [Building block [Building block [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 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 was prepared as described above.
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 according to the following formulae, which are included in the general formula II: WO 99/01423 WO 9901423PCT/DK98/00287 0 Cl
N'NH
Resin'
H
Resin-f Building block 1] H Ya 0 [Building block 2] Ir 0 f ~~Br Cl
NLN\J
Resin. 0 K( H Resin-f Building block 1]-[Building block 2] I HNRscRsd (Building block 3] Resin .HR Resin-[Building block 1]-fBuilding block 2]-[Building block 3] (Building block I]-Building block 2]-(Building block 3] and 0 Cl':j N.NH 2 Resin '0H Resin-[Building block 1]
H.
[Building block 2] 0 0 NlBr Cl I: N .N Resin R 1 Resin-[Building block 1]-(Building block 2] S [Building block 3] [Building block I]-[Building block 2]-[Building block 3] Resin-[Building block I]-[Building block 2]-[Building block 3) wherein R 1 4 R's are as defined for formula I and -NRScR~ is where R 5 a, R 4
,R
4 b, c, q, d, and D are as defined for formula I or WO 99/01423 PCT/DK98/00287 381 where 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: o CI^
.NH,
o where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker: P 0 O Resin The following building blocks were used: WO 99/01423 WO 9901423PCT/DK98/00287 (Building block 2]: 4-(2-bromoethoxy)-2-methoxybenzaldehyde 4-(2-bromoethoxy)-3-methoxybenzaldehyde Br Br 0Q90 0 0 3
H
3 C 3 4-(2-bromoethoxy)-3-chloro-5- 4-(2-bromoethoxy)-1 -naphthaldehyde methoxybenzaldehyde Br Br cl0 H3C-O 4-(2-bromoethoxy)-3,5- 4-(2-bromoethoxy)-3,5dimethylbenzaldehyde dibromobenzaldehyde Br H 3 C Br Br H O/ H HOC Br 4-(2-bromoethoxy)-3-methoxy-5- 4-(2-bromoethoxy)-3,5phenylbenzaldehyde dimethoxybenzaldehyde Br Meo Br 0~
,H
H
3 0-O WO 99/01423 WO 9901423PCT/DK98/00287 4-(2-,bromoethoxy)-3-bromo-5- 3-(2-bromoethoxy)-4-methoxybenzaldehyde methoxybenzaldehyde H 3 C 0 Br BrH
H
H
3
C-O
2-(2-bromoethoxy)-1 -naphthaldehyde 4-(2-bromoethoxy)-3-methoxyacetophenone O H Br 0 Br0 MaO CH WO 99/01423 WO 9901423PCT/DK98/00287 [Building block 31: N-isopropylbenzylamine 4-amino-I -benzylpipeddine 1 -(4-methoxyphenyl)piperazine H3CN y HN N-
CH
3 C~
CH
3 N-benzyl-ethanolamine 4-methoxybenzylamine N'-benzyl-N ,N-
H
2 N -J 02 CH dimethylethylenediamine
H
3 c. N 6H 3 1 -(4-acetylphenyl)- 1 -benzylpiperazine 2-phenyl pipe ridi ne piperazine N) N HN N h
CH
3 1 3-benzylaminopyrrolidine 2-amino-2-phenylethanol methylenedioxyphenyl)piperazine N Ji23jJ
H
2 HN N H0H 0 WO 99/01423 WO 99/1 423PCT/DK98/00287 1,2,3t4- 1 4-chloro-atetrahydroisoquinoline methylenedioxybenzyl)- methylbenzylamine l-nI-piperazine c HNHN) r- H 2 Nya C NI Z4-. >CH 3 4-(trifluoromethyl)- 4-(4-chlorophenyl)-4,5,6,7- 4-(4-chlorophenyl)-4benzylamnine tetrahydro- hydroxypiperidine FF thieno[3,2-clpyridine H
H
2 N 's
H
3,4-d ichlorophenethyla mine 3 ,4-dichlorobenzylamine 4-methoxyphenethyiamine 4-aminobenzylamine 4-chiorophenethylamine 4-bromophenethylamine efNH 2
NH
2
NH
2
H
2 N clBr 2-amino-i -phenylethanol 2-amino-3-(4-chlorophenyl)- 2-amino-i -phenyl-1 ,3- OH 1 -propanol propanediol N NH 2 NH2 OH NHO -l OH WO 99/01423 WO 9901423PCT/DK98/00287 4-fluorobenzylamine 1 -(4-chlorophenyl)-piperazine 2-(2-thienyl)ethylamine
[~~NH
2 c NH s5N.. NH 2
F'(
4-chlorobenzylamnine 1 -(3-methoxyphenyl)- 6,7-dimethoxy-1 3,4- CjI N2 piperazine tetrahydroisoquinoline CI~~ 9 NNH r(X~I 0 MeO 4-trifluoromethoxybenzyl- 4-benzylpiperidine 2-(3,4-dimethoxyphenyl)-Namine Hmethylethylamine
NHH
N H OI 2 MeO 1 Nz 'CH 3 MeO) r 1 ,2,3,4-tetrahydro-1 1 -(3,4-dichlorophenyl)- 1 ,4-bis(aminomethyl)naphthylamnine piperazine benzene Nl
H
2 I NH 2
NHN
NH
2 4-(aminomethyl)pyridine INkIP' NH 2 Preparation of resin-['Building block 11: This resin was prepared as described above.
Preparation of [Building block 2L: Preparation of 4-(2-bromoethoxy)-2-methoxybenzaldehyde: I ,2-Dibromoethane (57 mL, 0.66 moles) was added to a mixture of 4-hydroxy-2methoxybenzaldehyde (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 of 4-(2-bromoethoxy)-2methoxybenzaldehyde, 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-3methoxybenzaldehyde (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 of 4-(2bromoethoxy)-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-5methoxybenzaldehyde (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, and evaporated in vacuo to afford 9.33 g of 4-(2-bromoethoxy)-3chloro-5-methoxybenzaldehyde. M.p. 52 54 OC.
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-4hydroxybenzaldehyde (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 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 afford 8.2 g of 4-(2-bromoethoxy)-3,5-dimethylbenzaldehyde as an oil.
1 H-NMR (300 MHz, CDCI 3 8 2.33 (6H, 3.83 (2H, 4.18 (2H, 7.60 (2H, 9.88 (1H, 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-4hydroxybenzaldehyde (10 g, 36 mmoles) and potassium carbonate (25 g, 180 mmoles) in DMF (100 ml) and the resulting mixture was stirred vigorously at 70 OC 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 chloride (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, washing with 60% ethanol and drying 10.7 g of 4-(2-bromoethoxy)-3,5dibromobenzaldehyde was isolated in two crops. M.p. 84 85 °C.
Preparation of 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde: A mixture of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (20 g, 72 mmoles), ethylene glycol 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 and washed with saturated sodium hydrogencarbonate (3 x 200 mL). The combined aqueous phases were extracted with dichloromethane (3 x 150 mL). The combined organic extracts were washed with saturated sodium chloride (200 mL), dried over MgSO 4 and evaporated in vacuo to afford 22.1 g of 4-[1,3]dioxolan-2-yl-2-iodo-6-methoxy-phenol. M.p.
120- 121 °C.
Under N 2 tetrakis-triphenylphosphinepalladium(0) was added to a mixture of the above dioxolane (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 hydrochloric 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 chromatography over silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:2) to afford 5.49 g 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- (5.49 g, 24 mmoles) and potassium carbonate (17 g, 123 mmoles) in DMF (80 ml) and the resulting mixture was stirred vigorously at room temperature 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-(2as an oil.
'H-NMR (300 MHz, DMSO-d 6 8 3.50 (2H, 3.96 (3H, 4.19 (2H, 7.4-7.6 (11H, m).
Preparation of 4-(2-bromoethoxy)-1-naphthaldehyde: 1,2-Dibromoethane (30 mL, 0.35 moles) was added to a mixture of 4-hydroxy-1naphthaldehyde (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 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 to afford 8.5 g of 4-(2-bromoethoxy)-1-naphthaldehyde as a solid. 83 84 *C.
Calculated for C, 1 H,,BrO 2 C, 55.94%; H, 3.97%.
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, 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 phases were washed with saturated sodium chloride (500 mL), dried over MgSO 4 and evaporated in vacuo to afford 3.44 g of 4-(2-bromoethoxy)-3,5dimethoxybenzaldehyde.
'H-NMR (300 MHz, DMSO-d 6 5 3.70 (2H, 3.88 (3H, 4.27 (2H, 7.27 (2H, s).
Preparation of 3-(2-bromoethoxy)-4-methoxybenzaldehyde: 1,2-Dibromoethane (56 mL, 0.66 moles) was added to a mixture of 3-hydroxy-4methoxybenzaldehyde (10 g, 66 mmoles) and potassium carbonate (45 g, 328 mmoles) in 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 chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane to afford 9.8 g of 3-(2-bromoethoxy)-4-methoxybenzaldehyde.
'H-NMR (300 MHz, DMSO-d): 5 3.82 (2H, 3.90 (3H, 4.40 (2H, 7.22 (1H, 7.44 (1H, 7.59 (1H, dd).
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 stirring 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 sodium chloride (300 mL), dried over MgSO 4 and evaporated in vacuo to afford 13.7 g of 4-(2-bromoethoxy)-3-bromo-5-methoxybenzaldehyde.
WO 99/01423 PCT/DK98/00287 391 1 H-NMR (300 MHz, DMSO-d 6 5 3.79 (2H, 3.93 (3H, 4.40 (2H, 7.55 (1H, 7.79 (1H, d).
EXAMPLE 695: Preparation of 3-Chloro-4-hydroxvbenzoic acid {4-12-(1.2.3.4-tetrahydroisoauinolin-2vl)ethoxy]-2-methoxvbenzylidene}hydrazide
CH
3 N .O O
N
H
HO-
ci The resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building blockl]) (3 g, ~3 mmoles) was swelled in DMF (35 mL) for 30 minutes. Then 4-(2-bromoethoxy)-2methoxybenzaldehyde (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 in DMF (35 ml, 4 times), CH 2
CI
2 (35 mL, 6 times) and N-methyl-2-pyrrolidinone (NMP) mL, 2 times) and filtered. The resin was swelled in NMP (40 mL) and 1,2,3,4tetrahydroisoquinoline (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 Cl 2 (40 mL, 10 times) and filtered. 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
CI
2 (40 mL). The mixture was filtered and the resin was extracted with CH 2
CI
2 (40 mL, 2 times). The combined CH 2
CI
2 extracts were concentrated in vacuo. The residue was dissolved in CH 2
CI
2 (40 mL) and concentrated in vacuo. The residue was dissolved in methanol (40 mL) and concentrated in vacuo. The residue was partitioned 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, and concentrated in vacuo. The residue was purified by coloumn chromatography over silica gel (200 mL) eluting with a mixture of CH 2
CI
2 and methanol This afforded 280 mg of the title compound.
WO 99/01423 PCT/DK98/00287 392 H PLC-MS (METHOD R, 8.44 min; mlz 480 1).
1 H-NMR (300 MHz, DMSO-d 6 )8S= 2.80 (4H, in), 2.90 (2H, 3.69 (2H, 3.86 (3H, 4.25 (2H, 6.68 (2H, in), 7.04 (1 H, 7.07-7.14 (5H, in), 7.75 (1IH, dd), 7.80 (1H, bs), 7.96 (1 H, 8.58 (1 H, 11.6 (1 H, s).
HR-MS: Calcd. for C 2
,H
26 C1N 3 0 4 479.1611; Found: 479.1604.
EXAMPLE 696: 3-Chloro-4-hydroxybenzoic acid (2-methoxy-4-f2-(4-trifluoromethylbenzylamino)ethoxybenzylidenelhydrazode 9H3 0 0 TrN N F HO
F
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block (2 g, -2 minoles), 4-(2-broinoethoxy)-2-methoxybenzaldehyde ([building block 2]) (0.73 g, 1.5 equivs.), and 4-trifluoromethylbenzylamine ([building block (3.3 g, equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1 g) was purified by column chromatography on silica gel (20 g) eluting with a mixture of 25% aq. ammonia, ethanol and dichloroinethane (1 :9:115). This afforded 130 mg of the title compo-und.
HPLC-MS (METHOD Rt 9.4 min; in/z 522 EXAMPLE 697: 3-Chloro-4-hvd roxvbenzoic acid 14-[2-(4-benzvloioerazin-1 -vl)ethoxy]-2inethoxybenzylidenelhydrazide WO 99/01423 PCT/DK98/00287 393
CH
3 o 0 N CI .N O O N
HO'
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block (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 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.4 g) was dissolved in 2-propanol ml) and concentrated to 20 ml. The mixture was allowed to stand at 5 *C for 1 h and filtered.
The mother liquor was concentrated in vacuo and the residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of methanol and dichloromethane This afforded 0.98 g of the title compound.
'H-NMR (400 MHz, DMSO-de): 8H 2.4 (2H, bs), 2.55 (2H, bs), 2.62 (2H, bs), 3.50 (2H, bs), 3.85 (3H, 4.15 (2H, 6.62 (2H, 7.05 (1H, 7.30 (5H, 7.75 (2H, 7.97 (1H, s), 8.67 (1H, 11 (1H, bs), 11.5 (1H, s).
HPLC-MS (METHOD R, 7.7 min; m/z 523 EXAMPLE 698: 3-Chloro-4-hydroxybenzoic acid {2-methoxy-4-[2-(2-phenylpiperidin-1 yl)ethoxy]benzylidene}hyd razide
CH
3 CI NN 0
HO
This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block (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 (3.0 g, 10 equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was purified by column chromatography on silica gel (28 g) eluting with a mixture of methanol and dichloromethane (1:13).
This afforded 0.24 g of the title compound.
1 H-NMR (400 MHz, DMSO-d6): 8H 1.4 (2H, 1.65 (4H, 2.25 (2H, 2.75 (1H, m), 3.16 (1H, 3.25 (2H, 3.83 (3H, 4.0 (2H, 6.50 (1H, 6.54 (1H, 7.07 (1H, d), 7.23 (1H, 7.35 (4H, 7.73 (1H, 7.77 (1H, dd), 7.96 (1H, 8.65 (1H, 10.9 (1H, 11.6 (1H, s).
HPLC-MS (METHOD R, 9.1 min; m/z 508 EXAMPLE 699: 3-Chloro-4-hydroxvbenzoic acid {3-chloro-4-r2-(1.2.3.4-tetrahydro-isoauinolin-2-yl)ethoxy]-5methoxybenzylidene}hydrazide o.CH, o H HO-
N
Cl This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block (2 g, -2 mmoles), 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde ([building block (0.81 g, 1.5 equivs.), and 1,2,3,4-tetrahydroisoquinoline ([building block (2.5 g, equivs.). After cleavage with 50% trifluoroacetic acid, the residue (1.0 g) was dissolved in 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 dichloromethane This afforded 0.11 g of the title compound.
WO 99/01423 PCT/DK98/00287 395 'H-NMR (400 MHz, DMSO-d 6 8 H 1.9 (1 H, 2.18 (1 H, 2.90 (2H, 3.70 (2H, 3.90 (3H, 4.19 (2H, 7.05 (5H, in), 7.37 (2H, 7.78 (1 H, 7.95 (1 H, 8.33 (1 H, 11 (1 H, bs), 11. 8 (1 H, s).
HPLC-MS (METHOD R, 9.0 min; mlz 514 EXAMPLE 700: 3-Chloro-4-hydroxybenzoic acid 1.2.3 .4-tetrahydro-isoguinolin-2-YI)ethoxy]-5methoxybiphenyl-3-ylmethylenelhydrazide o' CH 3 HO N' N N I H ci This compound was prepared analogously to the compound described in the previous example starting from resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block (2 g, -2 mmoles), 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde ([building block (0.93 g, 1.5 equivs.), and 1 ,2,3,4-tetrahydroisoquinoline ([building block (2.5 g, 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 column chromatography on silica gel (25 g) eluting with a mixture of methanol and dichloromethane This afforded 0.31 g of the title compod.
'H-NMR (400 MHz, DMSO-de 6 5H 2.60 (4H, in), 2.70 (2H, in), 3.48 (2H, 3.92 (3H, s), 3.96 (2H, 6.98 (1 H, in), 7.10 (4H, in), 7.22 (1 H, 7.40 (4H, in), 7.55 (2H, 7.78 (1 H, 8.00 (1 H, 8.40 (1 H, 11 (1 H, bs), 11.7 (1 H, s).
HPLC-MS (METHOD R, 9.6 min; m/z 557 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 9o 10 N HO H Cl Cl A solution of 4-(2-bromoethoxy)-3,5-dibromobenzaldehyde ([building block in DMF (0.6 M, 1 mL) was added to the resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin- [building block (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
CI
2 (1.5 mL, 2 times) and NMP (1.5 mL, 2 times) for 5 minutes and filtered. The resulting resin (resin-[building block 1]-[building block was added a solution 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
CI
2 (1.5 mL, 6 times) for 2 minutes and filtered.
The compound was cleaved off the resin by shaking for 1 hour at room temperature with a solution of trifluoroacetic acid in CH 2 Cl2 (1.5 mL). The mixture was filtered and the resin was extracted with CH 2
CI
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 residue was dissolved in a 1:1 mixture of methanol and CH 2 Cl2 (1 mL) and concentrated in vacuo to give the title compound.
HPLC-MS (METHOD R, 15.02 min; m/z 671.
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 [building block 2] and [building block was 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. The compounds are all expected to be present in the respective wells.
The resin bound 3-chloro-4-hydroxybenzoic acid hydrazide (resin-[building block is equally distributed in the wells in the synthesizer prior to the initialization of the device.
ChemFile C:\ACT_1328\90250012.CHM: 1 REM Filtration of resin 2 Empty RB1_1to96 for 5.000 minute(s) 3 Empty RB2_1to96 for 5.000 minute(s) 4 Empty RB3_1to96 for 5.000 minute(s) Empty RB4_1to96 for 5.000 minute(s) 6 Pause 7 8 REM Washing of resin 9 Dispense System Fluid Disdul_4* 1500ul to RB1 _to96[1-96] 11 Dispense System Fluid Disdul_4* 1500ul to RB2_1to96[1-96] 12 Dispense System Fluid Disdul_4* 1500ul to RB3_1to96[1-96] 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.
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.
18 Wait for 25.000 minute(s) 19 Repeat from step 14, 1000 times 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) 23 Empty RB4_1to96 for 5.000 minute(s) 24 Pause 26 REM Coupling with aldehydes 27 28 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96] 29 Dispense System Fluid Disdu2_3* 1500ul to RB2_1to96[1-96] Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96] 31 Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[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.
Mix "RB4_1to96" for 5.00 minutes at 600 rpm(s) and wait.
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) Pause 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 Start mixing "RB1_1to96" for 2.00 minutes at 600 rpm(s) and continue.
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.
Mix "RB3_1to96" for 2.00 minutes at 600 rpm(s) and wait.
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.
Mix "RB4_1to96" for 2.00 minutes at 600 rpm(s) and wait.
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.
Start mixing "RB2_1to96" for 5.00 minutes at 600 rpm(s) and continue.
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 Empty RB1_1to96 for 5.000 minute(s) 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 71 REM Wash after coupling with aldehydes 72 73 Flush Arm1 with Flush Diluteri and Flush Diluter 2 Arm2 with Flush Diluter 74 Dispense System Fluid Disdu2_3* 1500ul to RB1_1to96[1-96] Dispense System Fluid Disdu2 3* 1500ul to RB2_1to96[1-96] 76 Dispense System Fluid Disdu2_3* 1500ul to RB3 1to96[1-96] 77 Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[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.
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) 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_1to96[1-96] 90 Dispense System Fluid Disdul_4* 1500ul to RB3_1to96[1-96] 91 Dispense System Fluid Disdul_4* 1500ul to RB4_1to96[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.
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) 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_1to96[1-96] 103 Dispense System Fluid Disdu2_3* 1500ul to RB3_1to96[1-96] 104 Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[1-96] 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) 110 Repeat from step 105, 1000 times 111 Pause 112 Empty RB1_1to96 for 5.000 minute(s) 113 Empty RB2_1to96 for 5.000 minute(s) 114 Empty RB3_1to96 for 5.000 minute(s) 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* 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.
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.
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 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.
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.
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 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) 159 Empty RB4_1to96 for 5.000 minute(s) 160 161 162 REM Wash after coupling with amines 163 164 Flush Arm1 with Flush Diluteri 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_1to96[1-96] 168 Dispense System Fluid Disdu2_3* 1500ul to RB3_lto96[1-96] 169 Dispense System Fluid Disdu2_3* 1500ul to RB4_1to96[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.
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_1to96[1-96] 182 Dispense System Fluid Disdul_4* 1500ul to RB3_1to96[1-96] 183 Dispense System Fluid Disdul_4* 1500ul to RB4_1to96[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.
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) 192 193 Repeat from step 180, 5 times 194 195 Dispense System Fluid Disdul_4* 1500ul to RB1_1to96[1-96] 196 Dispense System Fluid Disdul_4* 1500ul to RB2_1to96[1-96] 197 Dispense System Fluid Disdul_4* 1500ul to RB3_1to96[1-96] 198 Dispense System Fluid Disdul_4* 1500ul to RB4_1to96[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.
203 Wait for 25.000 minute(s) 204 Repeat from step 199, 1000 times 205 206 Flush Arm1 with Flush Diluteri and Flush Diluter 2 Arm2 with Flush Diluter 3 207 Empty RB4_1to96 for 5.000 minute(s) 208 Pause 209 210 REM Clevage (50%TFA/DCM manually added, one rack at a time) 211 Flush Arm1 with Flush Diluterl, Arm2 with Flush Diluter 4 212 Mix "RB1_1to96" for 5.00 minutes at 600 rpm(s) and wait.
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 218 Empty RB1_1to96 for 5.000 minute(s) 219 220 Dispense System Fluid Disdul_4* 500ul to RB1_1to96[1-96] 221 Wait for 1.000 minute(s) 222 Empty RB1_1to96 for 1 second(s) 223 Wait for 4 second(s) 224 Repeat from step 17, 25 times 225 Empty RB1_lto96 for 5.000 minute(s) 226 WO 99/01423 PCT/DK98/00287 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 combinatorial addition of the amines into the 4 reaction blocks each containing 96 wells in the syntheziser.
The library containing the following compounds was synthesized, and the products were characterised by HPLC-MS (molecular mass retention time).
WO 99/01423 WO 9901423PCTIDK98/00287 Ex Structure HPLC..MS HPLC-MS No. (METHOD B) (METHOD B3) mlZ R (minutes) 702 0MeO 0I~ 0 596 15.9 N s HO( H I S 703 Me 522 8.82 704 CI502 6.62 0MeO 0 0
N
N N.N'
H
HOqI
H
705 MeO 0 488 6.68 N C H I H
HO
CI
706 0MeO 543 10.93 HO CI
CI
707 0MeO CI 522 9.40 N* CI IO(?
H
708 494 7.87 0MeO 0 0 -N N .N 'NN
HO'J
CI
SUBSTITUTE SHEET (RULE 26) WO 99/01423 WO 9901423PCT/DK98/00287 5558 5.37 4 577 13.50 7110 S N' rk H 4 539 7.43 712 OH 214 2.05 0MeO 0 ~o NN>>
OH
I H
HO
CI
713 Br 548 7.10 MeO A N
H
I H
HO
CI
714 OH CI 532 5.38 0 MeO 0 N
N
H
HO
CI
715 M f: ci 536 8.43
HOH
HO
716 0 e N 538 9.05 H0
HO
CI
SUBSTITUTE SHEET (RULE 26) WO 99/01423 WO 9901423PCT/DK98/00287 717 OMe ci 572 9.93 N' N~ H I H
HO
cI 718 OMe 572 10.78 O I H CF3 I H
HO
CI
719 N598 11.47 NNNN O9 e
IH
HO
cI 720 N618 7.35 A OMe N O Ce H(A 0
HO
CI
721 574 7.27 OMe 0 H Nj N.N N OMe
HOH
722 N548 8.50 N .N OMeF I H
HO
CI
SUBSTITUTE SHEET (RULE 26) WO 99/01423 WO 9901423PCT/DK98/00287 11.38 iii .OMe N-"ci 619 QMe
O
cI 0
N'
HO'P
cI 0 jj N N4 I H
HO
CI
SUBSTITUTE SHEET (RULE 26) WO 99/01423 WO 9901423PCT/DK98/00287 729 N655 16.35 N N, 0 'cNl N "g ome KN~C HO C Cl 730 615 12.15
OO
731 N616 8.30 O O NI OMe N N OMe OM e IO(?
H
732 N590 5.30
OH
0 N N N H OH H N" N OMe
HO
CI
73 624 10.90 Br N N*N N OMe HO
"(P
734 N608 8.95
H
N N N OMe HO
'(P
CI
SUBSTITUTE SHEET (RULE 26) WO 99/01423 WO 9901423PCT/DK98/00287 735 -~612 12.65 cI 0 H N' N OMe HO
'P
CI
736 N550 7.88 0 N S
IH
NN~ N OMe IOfC
H
HO
737 N614 13.07 N HI C N N oMe F 3 I H
HO
738 N559 2.33 O0 0
N
.N-N HI NH 2 N N OMe2 I H
HO
CI
739 616 17.98 0o
NN
N~ N.0
HO'(PH
CI
SUBSTITUTE SHEET (RULE 26) WO 99/01423 WO 9901423PCT/DK98/00287 409 0 OH N
H~N
0HH
HOH
0 H N NN
H
H
HO A
CI
N0NA N N.N NK.-
H
HOH
HO A
N
H OH
HOA
CI
0I H N N.NN 5 NO~
HO
CI
6.57 518 SUBSTITUTE SHEET (RULE 26) WO 99/01423 WO 9901423PCT/DK98/00287 748 OMe 562 7.35 0 N' OMe N. N CH, HO cI 749 -545 7.54 0 N N
IH
HO HC H
CI
750 492 517.52 N F"" I H
HO
CI
751 42 7.57 0 1 -N I N N N5 Nl I H
HO
CI
7523 Nf 543 6.13 I H
HO
CI
753 518 6.3 NNN. NF HO
(A
CI
SUBSTITUTE SHEET (RULE 26) WO 99/01423 WO 9901423PCT/DK98/00287 755 508 10.32 NN
H~~
Hill
HOJP
cI 756 563 14.17 N N H LiI HOJ c I
CI
757 544 13.07 N c
HOJ?
CI
758 CH 3 522 12.65
N
N NN- ci
HO
cI 759 -514 12.03 0 I H
N'
H
HO
CI
760 -504 4.57 0 N H r' H OH
NN
IO(?
H
761 543 9.30 N' NN 0 IO(
H
HO
SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 762 578 7.77 HIJ H c HO c
CI
763 489 2.23 0 N N H NH 2
HO'
C,
764 597 15.73 HS KN~ YCI HO Ci
CI
765 559 11.25 0 N H K..NN OMe
HO'P
cI 766 571 8.38 0 N N
N
HO H -l CH 3 CI 0 767 528 15.38 j N N S NN
H
HO
CI
768 0 1 560 8.00 N O..."NNK3 IIIIe N' OMe
HO
CI
SUBSTITUTE SHEET (RULE 26) WO 99/01423 WO 9901423PCT/DK98/00287 769 -OH 5.34 3.33 0 H N
OH
HO'?
H
cI 770 475 2.23 0I H N' NN
H
HO'f
CI
771 Br 568 10.07 0 H NN NN IO(?
H
772 N OH ci 552 6.93 0 Nf H I H
HOH
773 ci556 12.02 NN NN I H
HO
CI
74S494 7.12 0 0 N N 0H
HOH
HO
775 558 12.58 0 N NN.N N T 1 3C I H
HO
CI
SUBSTITUTE SHEET (RULE 26) WO 99/01423 PTD9/08 PCT/DK98/00287 O~Nl 0 N NN I H
HO
cI 0 0 N N H N H 2
HO
cI 15.23 OMe N N OMe
CI
IH
HO
CI
OMe N N'N N OMe c
HO
CI
SUBSTITUTE SHEET (RULE 26) WO 99/01423 WO 9901423PCTIDK98/00287 SUBSTITUTE SHEET (RULE 26) WO 99/01423 PCT/DK98/00287 790 OMe 549 1.70 o
H
HO
J' J:Br H -NH 2
CI
791 OMe 549 15.33 HO N f Br N
CI
Cl EXAMPLE 792: 3-Amino-4-hydroxybenzoic acid f4-[2-(1.2.3.4-tetrahydro-isoquinolin-2-yl)ethoxy]-2methoxybenzylidene}hydrazide CH3 o 0 N"'
H
2 N .N N O
HO
The above 4-(2-bromoethoxy)-2-methoxybenzaldehyde (16.8 g, 65 mmol) ([building block was dissolved in acetone (300 ml) and potassium carbonate (44.9 g, 0.33 mol), potassium iodide (2 g) were added followed by addition of 1,2,3,4tetrahydroisoquinoline (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 inorganic 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 washed with water (2 x 20 ml) saturated sodium chloride (20 ml), dried over MgSO, 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 2 liters) then with a mixture of ethyl acetate and heptane 5 liters) to afford 12 g of 4- [2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde as a solid. M.p.: 69 71 °C.
Calculated for C 1
,H
2 zNO.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 reflux temperature for 16 hours. After cooling the mixture was filtered and solid was washed with ethanol to afford after drying 1.4 g of 3-amino-4-hydroxybenzoic acid hydrazide as a solid. 242 243 "C.
Calculated for C 7
HN
3 0 2 C, 50.30%; H, 5.43%; N, 25.14%.
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 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 of the title compound as a solid. 162 164 "C.
HPLC -MS (METHOD Rt 6.50 minutes. m/z 461.
EXAMPLE 793: 3-Amino-4-hydroxybenzoic acid [4-(4-isopropylbenzyloxy)-3.5-dimethoxybenzylidenelhvdrazide
CH,
OOH
CH
3
H
2 N N OCH3 C3 2N NJN OCHz HO3" 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).
The combined organic extracts were washed with water (100 ml), saturated NaCI (100 ml), WO 99/01423 PCT/DK98/00287 418 dried (MgSO 4 treated with activated carbon, filtered and concentrated in vacuo to afford g (100%) of 4-(4-isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde as an oil.
'H-NMR (400 MHz, DMSO-de): 5H 1.20 (9H, 2.89 (1H, 3.86 (6H, 4.98 (2H, s), 7.23 (2H, 7.27 (2H, 7.36 (2H, d).
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-(4isopropylbenzyloxy)-3,5-dimethoxybenzaldehyde(93 mg, 0.3 mmol) were dissolved in 2propanol (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 4 ml) and dried by suction to afford 144 mg (100%) of the title compound as a solid. 174 175 °C.
HPLC-MS (METHOD R, 10.40 minutes. m/z 464.
EXAMPLE 794: (R)-2-{4-[(3-Amino-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenoxy}-N-(1benzylpvrrolidin-3-yl)acetamide
H
3 0 O
N
H
2 N_ A .N ,J H 0 H S H
(R)
HO:C
(R)-(-)-1-Benzyl-3-aminopyrrolidine (5 g, 28 mmol) was dissolved in dichloromethane ml). To this solution, a solution of bromoacetyl chloride (4.55 g, 28 mmol) in dichloromethane 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 of (3R)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid 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 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 vacup. The residue was crystallized from diethyl ether to afford 2.11 g (R)-N-(1-benzylpyrrolidin-3-yl)- 2-(4-formyl-3-methoxyphenoxy)acetamide as a solid. 98 101 *C.
Calculated for C 21
H
24
N
2 0 4 .0.5H 2 0: C, 66.83%; H, 6.68%; N, 7.42%.
Found: 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 N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (110 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 (2 x 3 ml) and dried by suction to afford 109 mg of the title compound as a solid. 157 160 "C.
HPLC-MS (METHOD Rt 3.10 minutes. m/z 518.
EXAMPLE 795: (R)-2-{4-[(3-Amino-4-hvdroxvbenzoyl)hydrazonomethyllnaDhthvl-1 -vloxvy-N-(1 benzvlDvrrolidin-3-yl)acetamide 0 N JO NH (R) Ho 4-Hydroxy-l-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 Benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.0 g, 9 mmol) in DMF (16 ml). The 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 mi) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2 x 20 mi) and the combined organic extracts were washed with saturated sodium chloride (3 x 15 mi), dried (MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (110 g) eluting with ethyl acetate to afford 1.7 g -benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide as a solid.
105 107 *C.
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, 73.81%; 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 N-(1 -benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1 -yloxy)acetamide (116 mg, 0.3 mmol) were dissolved in 2-propanol (4 mi) 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 mi) and dried by suction to afford 140 mg of the title compound as a solid. 187 192 0
C.
HPLC-MS (METHOD R, 5.72 minutes. m/z 538.
EXAMPLE 796: (S)-2-{4-[(3-Amino-4-hydroxybenzoyl)-hydrazonomethyll-3-methoxyphenoxy}-N-( 1benzylpyrrolidin-3-yl)acetamide S CH (S)
HO
(S)-(+)-1-Benzyl-3-aminopyrrolidine (6 g, 34 mmol) was dissolved in dichloromethane (12 mi). To this solution, a solution of bromoacetyl chloride (5.46 g, 34 mmol) in dichloromethane WO 99/01423 PCT/DK98/00287 421 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 of (3S)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step.
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 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 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 (4 g) was crystallised from a mixture of diethyl ether and heptane, filtered and dried in vacuo to afford 2.7 g (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide as a solid. 96 100 *C.
Calculated for C 21
H
24
N
2 0 4 .0.25H 2 0: C, 67.63%; H, 6.62%; N, 7.51%.
Found: 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 N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)acetamide (110 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 109 mg of the title compound as a solid. 139 141 °C.
HPLC-MS (METHOD R, 3.15 minutes. m/z 518.
EXAMPLE 797: WO 99/01423 PCT/DK98/00287 422 (S)-2-{4-[(3-Amino-4-hydroxvbenzovylhydrazonomethyl]naDhthyl-1-yloxy benzylpyrrolidin-3-ylvacetamide
SN
H N .N
H
HO
4-Hydroxy-l-naphthaldehyde (2.71 g, 16 mmol) was dissolved in DMF (10 ml) and potassium 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 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 (4 g) was purified by column chromatography on silica gel (110 g) eluting with ethyl acetate to give an oil (2 which was crystallized from a mixture of diethyl ether and heptane to afford 1.8 g (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide as a solid. 96 97 *C.
Calculated for C 2 4
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%; 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 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 (3 x 3 ml) and dried by suction to afford 143 mg of the title compound as a solid. 192 193 "C.
HPLC-MS (METHOD Rt 5.18 minutes. m/z 538.
WO 99/01423 PCT/DK98/00287 423 EXAMPLE 798: (S)-2-f4-(3-Fluoro-4-hydroxvbenzoylvhydrazonomethyllnaphthyl-1-vloxy}-N-(1benzylpyrrolidin-3-yl)acetamide JL'7 I H(S) HO- 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-4hydroxybenzoic acid hydrazide. Thus, methyl 3-fluoro-4-hydroxybenzoate was attached to the resin. Hydrolysis of the methyl ester (aq. LiOH, dioxane, 60 followed by reaction with hydrazine (PyBOP, hydrazine, DMF) afforded resin bound 3-fluoro-4-hydroxybenzoic acid 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 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 successively 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 methanol and dichloromethanne (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 column chromatography on silica gel (40 g) eluting first with a mixture of dichloromethane, ethanol and 25% aq. ammonia then with (85:13.5:1.5) and finally with (80:18:2).
Pure fractions were pooled and concentrated in vacuo to afford 0.15 g of the title compound.
HPLC-MS (METHOD R t 8.82 minutes. m/z 541.
Calculated for C3,H 2 9
N
4 0 4 F.0.25CH 2
C
2 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-hydroxybenzoyflhydrazonomethyllnaphthyl-1 -yloxy}-N-( 1benzyl pyrrolidin-3-yl)aceta mid e Fe 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 (1-benzylpyrrolidin-3-yl)-2-(4-formylnaphthyl-1-yloxy)acetamide (0.4 g, 0.94 mmol). After cleavage the compound was purified by column chromatography to afford 0.14 g of the itle compoud.
HPLC-MS (METHOD B3): Rt 9.02 minutes. mlz 541.
Calculated for C 3 1 H2NOF.0.25CH 2
C
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%.
EXAMPLE 800: (S)-2-{4-[(3-Fluoro-4-hydroxybenzoyl'~hydrazonomethyll-3-methoxyphenoxy-N-( 1benzyipyrrolidin-3-yflacetamide
H
3 0 OF N' N
(S)H
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 (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 comnpound.
HPLC-MS (METHOD B3): R, 3.68 minutes. mlz =521.
Calculated for C 28
H
29
N
4 0 5 F.0.25CH 2 C1 2 C; 62.63%; H, 5.49%; N, 10.34%.
Found: C, 62.92%; H, 5.83%; N, 10.15%; C, 62.71 H, 5.81 N, 10. 16%.
EXAMPLE 801: (R)-2-{4-[(3-Fluoro-4-hydroxybenzoyl)-hydrazonomethyll-3-methoxyphenoxy-N-( 1benzylpyrrolidin-3-yl)acetamide I"J H (R) HO 14 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 (1 -benzylpyrrolidin-3-yI)-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 compound.
HPLC-MVS (METHOD B3): R, 4.18 minutes. ml/z 521.
Calculated for C 28
H
29
N
4 0 5 F.0.25CH 2
C
2 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%.
EXAMPLE 802: WO 99/01423 PCT/DK98/00287 426 3-Fluoro-4-hydroxybenzoic acid {4-[2-(1.2.3.4-tetrahydro-isoquinolin-2-yl)ethoxy]-2methoxybenzylidene}hydrazide
CH
3 HO 0 O
N
HO H 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 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.
HPLC-MS (METHOD Rt 7.60 minutes. m/z 464.
Calculated for C 26
H
26
N
3 0 4 F.0.5CH 2
CI
2 C, 62.91%; H, 5.38%; N, 8.30%.
Found: 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 System using a WatersTM 3 mm x 150 mm 3.5 p C-18 Symmetry column and positive ionspray 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 1 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 described above, the only difference being the eluent. The column was eluted with a linear gradient 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-hvdroxy-benzoic acid {4-[2-(1.2.3.4-tetrahydro-isoquinolin-2-yl)-ethoxy]-8methoxy-naphthalen-1 -ylmethylene}-hydrazide CIa N N H;C HO 4-hydroxy-8-methoxynaphthalene-1-carbaldehyde (1 g, 5 mmol) was dissolved in DMF mL). To this mixture potassium carbonate (3.4 g, 25 mmol) and 1,2-dibromoethane (4 mL, 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 (100 mL), dried (MgSO 4 and evaporated in vacuo to afford 1.13 g of 4-(2bromoethoxy)-8-methoxynaphthalene-1-carbaldehyde.
HPLC-MS (Method R, 14.1 minutes. m/z 309.
1 H-NMR (300 MHz, DMSO-de): 8H 3.99 (3H, 7.00 (1H, 7.20 (1H, 7.47 (1H, 7.88 (2H, 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)-8methoxynaphthalene-1-carbaldehyde (1.7 g, 5.4 mmol) was added followed by triethyl orthoformate (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 mL) was added followed by potassium iodide (0.6 g) and 1,2,3,4-tetrahydro-isoquinoline (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 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 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 ethyl acetate (2 x 80 mL) and the combined organic extracts were dried (MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (200 mL) eluting with a mixture of dichloromethane and methanol This afforded 217 mg of the title compound.
HPLC-MS (Method R, 9.14 minutes. m/z 530.
WO 99/01423 PCT/K98/00287 429 General Procedure for Examples 804 to 824: The compounds were prepared as single entities according to the following equation Resin- [Building block 1] Resin- [Building block [Building block 2] Resin- [Building block [Building block [Building block 3] and were simultaneously deprotected (when required) and cleaved from the resin with trifluoroacetic acid in dichloromethane to give the desired compounds as individual entities according to the following formula [Building block [Building block [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 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 was prepared as described above.
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, which are included in the general formula II: WO 99/01423 WO 9901423PCT/DK98/00287 Resi.Ob1 .H2 +4 R 0 Resin-[Building block 1] [Building block 21 (Building block 3]
R
Resin. o R9 Resin-iBuilding block lJ-(BUllding block 2] Resin-[Building block 1l]-[Building block 2]-(Building block 3]
(CH
2 k (CH 2 2Y.C1z)4.CH 2
O
[Building block 1 ]-[Building block 21.(Building block 31 wherein R 8
R
14
R"
5 and R3a R 3 b R a 4 -(CI-12)4p 7q CH 2 )d D as defined for formula 1.
The following resin, here depicted as Resin-[Building block 1] was used: 0 Ci I N NH 2
H
PS
where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker: 0 Resin WO 99/01423 WO 9901423PCT/DK98/00287 The following building blocks were used: [Building block 21: (4-Formyl-3-methoxyphenyl)carbamic acid (4-Forrnyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: 9H-fluoren-9-ylmethyl ester NHFmoc NHFmoc H
H
CH 3
HC
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 0 NHFmoc HQ H
H
TBDMSO
WO 99/01423 PCT/DK98/00287 fBuilding block 31: WO 99/01423 WO 9901423PCT/DK98/00287 Foc-beta-(3-pyridyl)-D-Ala- Methanesulfonylacetic acid Fmoc-Trp(Boc)-OH OH 0.
0 CH3 OH
OH
3 P.HN y0
N
N H IH 3 C-L{ H Fmoc-L-Methionine 5-Methoxy- 1 -indanone-3- 4-Hydroxycinnamic acid H 3CSacetic acid 0\ OH O.,<NH OH 0O 0 CH 3
HO
0 Fmoc-Arg(Boc)-2-OH 5-Oxopryrrolidine-2- 4-Bromo-2,5-dimethyl-1 -Hcarboxylic acid pyrrole-3-carboxylic acid 0 HO- H Br OH 0 NH 0 I OH H 3 C N OH3 r O
H
HN N 0 CH H 3 %OyNH OH 3 C CH 3 H 3 C CHD Acetic acid Hippuric acid 2-M ethyip rope noic acid OH 0O 3 0(HHO~O OH 3 0 WO 99/01423 WO 9901423PCT/DK98/00287 434 Cyano-acetic acid 0-Anisic acid 4-Acetamidobenzoic acid
H
3
H
HO
0 1O
NO
H
Trifluoroacetic acid 2-Amino-4-thiazole acetic p-Anisic acid F F 0 acid
XCH
3
HHO
0 s OH
OH
Quln-2-croxeylicacid Benzoyfurn2croyic acid onmeth mac onat ,C OH 0 S 0OH
OOH
3-Cynoenic aci(-yrdlcylic acid Cyclopentanecarboxylic acid omehlaont OH cH ~0 OH
N
WO 99/01423 WO 9901423PCT/DK98/00287 N-Acetylglycine DL-Glyceric acid 2-Chloro-3- S0OH HO methoxythiophene-4- H 3 0 carboxylic acid 3 HHO OH 0 H 3 C-O
OH
5-Fluoroindole-2-carboxylic 3-(4,5-Methylenedioxy-2- 3- Acid nitrophenyl)acrylic acid (Formylaminomethyl)benzoic F o acid I OH ~N OH .0 HO 0 0 0 5-Bromo-2-furoic Acid 3-Methylthiophene-2- Methylmalonic acid Br 0 OH carboxylic acid PH
HOY'X
HCH
3 4-Thioureido-benzoic acid (4-Trifluoromethoxy)phenoxy (4-Chlorophenoxy)acetic acid
NH
2 0 acetic acid
OH
H Fa
F
0
CV
Isoquinoline-1 -carboxylic a- 6-Methylnicotinic acid 3H-Indene-1-carboxylic acid cid H 3 CZ OH OH IaO OH 0 6 I 0"Y WO 99/01423 WO 9901423PCT/DK98/00287 Benzo[bjthien-3-yl acetic a- 2-methyl-2-phenoxypropionic 3-Benzo[1 cid acid acrylic acid O 0 OH -OH OH SCHCH3 3-(3-Trifluoromethylphenyl) 2-Fluoro-3-phenylacrylic acid 2-Oxo-3-phenylpropionic acid acrylic acid F OH 01OH F F OH F -I 3-Methoxybenzo[b]thio- Benzo[b]thiophene-2- Fmoc-phenylalanine phene-2-carboxylic acid carboxylic acid 0 0 0 OH OHN
O
N
HO
CH
3 0 (2,4-Dichlorophenoxy)acetic 3-(4-Trifluoromethylphenyl)- (3-Trifluoromethyiphenyl)acid propionic acid acetic acid H H FEF 00 F
-YOH
caci F0
F
Preparation of resin-[Building block 11: This resin was prepared as described above.
WO 99/01423 PCT/DK98/00287 437 Preparation of [Building block 21: (4-Formyl-3-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: 0 O H NHFmoc
H
0 CH3 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 320 mL) at reflux for 16 hr. The reaction 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 hydrochloric acid (200 mL), 0.2 N hydrochloric acid (200 mL), water (200 mL) and a 20 saturated 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 solution of diisobutylaluminium hydride (90 mL, 1.2 M in toluene) was dropwise added at 0-5 0
C.
The reaction mixture was stirred at 200C for 16 hr and quenched by dropwise addition of water (58 mL) at 0-5 OC. 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 dichloromethane (400 mL) and manganese dioxide (15.6 g, 180 mmol) was added. The mixture was stirred for 16 hr at 200C and filtered. The filtrate was concentrated in vacuo to give 5.1 g of the title compound.
m.p. 187-1880C HPLC-MS (METHOD R, 15.1 min, m/z= 374.
Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% 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 \NHFmoc
H.
HHC
Thionylchloride (12.8 g, 108 mmol) was dropwise added to an ice cold suspension of 4amino-3-methoxybenzoic acid (12.3 g, 72 mmol) in methanol (250 mL). The reaction mixture was stirred at 20 0 C for 16 hr and concentrated in vacuo. Ethyl acetate (250 mL) and a saturated 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 240 mL) at 90 0
C
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.
m.p. 96-98 0
C
HPLC (Method 1) 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% 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 0-5 0 C. The reaction mixture was stirred at 20 0 C for 16 hr and quenched by dropwise addition of water (58 mL) at 0-50C. The reaction mixture was stirred at 20 0 C for 3 hr and filtered.
The filtrate was concentrated in vacuo to give 5.5 g of product 169-171 0 The product (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 20 0 C and filtered. The filtrate was concentrated in vacuo to give 3.5 g of the title compound. Recrystallization from ethyl acetate.
WO 99/01423 PCTDK98/00287 439 m.p. 150-1520C HPLC (Method 1) R, 30.6 min Micro analysis: calculated: C, 73.98; H, 5.13; N, 3.75% 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
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 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 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) added. The organic phase was isolated and washed with water (2x50 mL), a saturated solution 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 as eluent.
The product was recrystallized from methanol to give 4-(9H-fluoren-9ylmethoxycarbonylamino)-2-hydroxybenzoic acid methyl ester.
m.p.156-9 0
C
HPLC (Method 1) R, 31.7 min Micro analysis: calculated: C, 70.94; H, 4.92; N, 3.60% 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 (10 mL) was dropwise added and the reaction mixture was stirred at 200C for 16 hr. The reaction 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 (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 mixture was stirred at 200C for 3.5 hr, and quenched by dropwise addition of water at 0-50C. After 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 as eluent. The isolated 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 0°C 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.
HPLC (Method 1) R, 30.7 min and 36.8 min (5-Formyl-2-methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester: NHFmoc H
CH,
Thionylchloride (10.3 g, 85 mmol) was dropwise added to an ice cold suspension of 3amino-4-methoxybenzoic acid (9.48 g, 56.7 mmol) in methanol (180 mL). The reaction mixture was stirred at 200C for 16 hr and concentrated in vacuo. Ethyl acetate (100 mL) and a 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 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.
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- The reaction mixture was stirred at 200C for 16 hr and quenched by dropwise addition of water (23 mL) at 0-5 0 C. The reaction mixture was stirred at 200C for 1.5 hr and filtered. The 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 20 0 C and filtered. The filtrate was concentrated in vacuo to give 4.3 g crude product that was purified on silica (150 g) using ethyl acetate and n-heptane as eluent to give 1.9 g of the title compound.
m.p. 139-1420C HPLC (Method 1) Rt 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% EXAMPLE 804: N-(4-[3-Chloro-4-hydroxybenzoyl)hydrazonomethyl]-3-methoxyphenyl)-2-(4trifluoromethoxyphenoxy)acetamide F F ^.o0 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-3methoxyphenyl)carbamic acid 9H-fluoren-9-ylmethyl ester, 0.5 g, 1.36 mmol) dissolved in dimethylformamide (3 mL) was added followed by addition of triethylorthoformate (1.5 mL).
The mixture was shaken for 16 hr at 20 0 C and drained. The resin was washed with dimethylformamide (5x4 mL), dichloromethane (5x4 mL) and dimethylformamide (5x4 mL).
The coupling of the aldehyde was repeated twice.
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), Nmethylpyrrolidinone (5x4 mL) and dimethylformamide (5x4 mL).
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 dimethylformamide (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 added. After shaking for 1 hr the resin was drained. The eluent was collected and concentrated in vacuo. The residue was crystallized from methanol to give 0.2 g of the title compound.
m.p. 235-236.5 0
C
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 [building block 2] and [building block was 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. The compounds 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- (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 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 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 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 automated synthesizer using the following ChemFile to control the device.
ChemFile: C:\DATA\90250017.CHM 1 Empty RB1to96 for 2.000 minute(s) 2 Flush Arml with NMParml and DCMarml 3 4 REM Adding acids 1 to 36 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) 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) 16 Pause 17 18 REM Adding DIC 19 20 Transfer 300ul from Monomerlto36[12]() to RB1to96[2-48] using NMParml 21 Mix for 2.00 minutes at 600 rpm(s) 22 Transfer 300ul from Monomerlto36[13]() to RB1to96[50-96] using NMParml 23 Mix for 10.00 minutes at 600 rpm(s) 24 25 REM Adding DMAP 26 27 Transfer 200ul from Monomerlto36[14]() to RB1to96[2-48] using NMParml 28 Transfer 200ul from Monomerlto36[14]() to RB1to96[50-96] using NMParml 29 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 36 REM wash 37 38 Empty RB1to96 for 2.000 minute(s) 39 Dispense System Fluid NMPdualarms* 1000ul to RB1to96[1-96] 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 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) 50 Empty RB49to72 for 2.000 minute(s) 51 Pause 52 53 REM wash 54 Dispense System Fluid NMPdualarms* 1000ul to RB1to96[1-96] WO 99/01423 PCT/DK98/00287 445 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 59 Dispense System Fluid DCMdualarm* 1000ul to RB1to96[1-96] 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 64 REM TFA CLEAVAGE 66 Mix for 1.00 minutes at 300 rpm(s) 67 Transfer 1000ul from Reagent2[1]() to RBcleavagelto96[1-96] using DCMarml 68 Mix for 1.00 hours at 600 rpm(s) 69 Empty RBcleavagelto96 for 30 second(s) Dispense System Fluid DCMdualarm* 500ul to RBcleavagelto96[1-96] 71 Mix for 5.00 minutes at 300 rpm(s) 72 Empty RBcleavagelto96 for 30 second(s) 73 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 retention time) and includes: EXAMPLE 805: Quinoline-2-carboxylic acid {4-[(3-chloro-4-hydroxybenzovlhydrazonomethyl]-3methoxyphenyllamide
H
H H HO" H 3
C
Cl m.p. 236-238°C HPLC (Method 1) R=26.2 min EXAMPLE 806: WO 99/01423 PCT/DK98/00287 446 N-44-[(3-chloro-4-hydroxybenzoy)hydrazonomethyll-2-methoyrhenyll-2Z(4trifluoromethoxyphenov~acetamide
F
F
HO 'N 5d 3 m.p. 216-218 0
C
HPLC (Method 1) R,=26.6 min EAMPE 807: Quinoline-2-carboxylic acid {4-[(3-chloro-4-hyd roxybenzoyl)hydrazonomethyt]-2methoxyphenylla mode
H
HO3 m.p. 159-162 0
C
HPLC (Method 1) R,=27.7 min EAMPLE 808 N-{4-F(3-Chloro-4-hydroxybenzoy)hyd razonomethyll-3-methoxyphenyl}-2-(4chlorophenoxy)acetamide m.p. 216-218*C HPLC-MS (METHOD A) R,=1 3.4 min, mlz=488 WO 99/01423 PCT/DK98/00287 447 EXAMPLE 809: N-f4-U(3-Chloro-4-hydroxybenzpflhydrazonomethvll-3-methoxvrhenvlmethylnicotinamide HPLC-MS (METHOD A) Rt=8.2 min, m/z=439 EXAMPLE 810: N-144r(3-ChInrn-4-hvfroyvhnzvlhvi-71 tvl-'-otnvhnvl211 trifluoromethylphenyflacetamide HPLC-MS (METHOD A) Rt= 13.4 min, mlz=506 EXAMPLE 811: N-4[3Clr--yr~ezy~y rznmtvl3mtovhni--24 dichlorophenoxy)acetamide WO 99/01423 WO 9901423PCT/DK98/00287 HPLC-MS (METHOD A) 14.3 min, m/z=524 EXAMPLE812: N-{4-1(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-3-methoxyphenyl}-3-(4trifluoromethvtp~henyl)p2ropionamide HPLC-MS (METHOD A) 14.0 min, mlz=520 EXAMPLE813: Isoguinoline-1 -carboxylic acid {4-r(3-chloro-4-hyd roxybenzoyl)hydrazonomethyl]-3methoxyphenyliamide HPLC-MS (METHOD A) R,=13.0 min, m/z=475 WO 99/01423 PCT/DK98/00287 449 EXAMPLE 814: 7-Ethozybenzofuran-2-carboxylic acid 4-[(3-chloro-4-hydroxybenzoyI)hydrazonomethyi1-3methoxyphenyllamide
HO
0 1 HPLC-MS (METHOD A) Rt=13.3 min, mlz=508 N-{4-f(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-3-methoxyphenyl}-2-(toluene-4 sulonyflacetamide H 0
N
N -N 00 HO H Hc 0 CH3 HPLC-MS (METHOD A) R,=10.8 min, mlz=517 EXAMPLE 816: Benzofuran-2-carboxylic acid (4-[(3-Chloro-4-hyd roxybenzoyflhydrazonomethy]methoxyphenyll-amide WO 99/01423 WO 9901423PCT/DK98/00287 450 H PLC-MS (METHOD A) 12.3 min, mlz=465 EXAMPLE 817: N-{4-(3-Chloro-4-hydroxybenzoyl)hydrazonomethyll-3-methoxyphenyl}-3-cyanobenzamide HPLC-MS (METHOD A) Rt= 10.8 min, mlz=450 EXAMPLE 818: 5-Chloro-4-methoxythiophene-3-carboxylic acid {4-[(3-Chloro-4hydroxybenzoyl)hydrazonomethyll-3-methoxyphenyllamide HPLC-MS (METHOD A) Rt=9.8 min, mlz=495 WO 99/01423 PCT/DK98/00287 451 EXAMPLE 819: 5-Brnmofiirnn-2-crrnylic acid f4-[(3-Chloro-4-hvdroxvbenzov 'hvdra~onmethvI1-lmethoxyphenyllamide HPLC-MS (METHOD A) Rt=1 1.4 min, m/z=494 EXAMPLE 820: 2-Benzofblthien-3-yl-N-44-f(3-chloro-4-hydroxybenzoyl)hydrazonomethyll-2methoxyphenyllacetamide HPLC-MS (METHOD A) R,=13.4 min, m/z=494 EXAMPLE 821: N-44-[(3-Chloro-4-hydroxybenzoyl )hyd razonomethyll-2-methoxyphenyl}-2-(4-chlorophenoxy) 2-methylpropionamide HPLC-MS (METHOD A) R,=14.7 min, m/z=516 WO 99/01423 PCT/DK98/00287 452 EXAMPLE 822: N-{4-[(3-Chloro-4-hydr-oxbenzoyflhydrazon omethyll-2-methoxyphenyll-3-(3 trifluoromethylphenvl ~acrvlamide HPLC-MS (METHOD A) R,=14.3 min, m/z=518 EXAMPLE 823: N-44-r(3-Chloro-4-hvdroxvbenzovflhvd razonomthvIl-2-methnxvnhnvll-2-flujorn-3-I pnlaJrlamde HPLC-MS (METHOD A) R,=14.3 min, mlz=468 EXAMPLE 824: 2-Ren7nrhlth ipnep2rrnv i id 14-r('A-rh Inr-4-hvd rnyvhtmnznvflhvd rnzonomthvIl-2methoxyphenyllamide WO 99/01423 PCT/DK98/00287 453 H /p N' 9 0 Hr H
CH
3 Cl HPLC-MS (METHOD A) R,=13.8 min, m/z=480 HPLC Method 1.
The RP-HPLC analysis was performed using UV detection at 254 nm and a Merck Hibar LiChrosorb RP-18 (5 pm) 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 II: 0.1% Trifluoroacetic acid in water.
The column was equilibrated with a mixture composed of 20% of solvent system I and 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 minutes.
General Procedure for Examples 825 to 875: The compounds were prepared as single entities according to the following equation Resin- [Building block 1] Resin- [Building block [Building block 2] Resin- [Building block [Building block [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 WO 99/01423 PCT/DK98/00287 454 [Building block [Building block [Building block 3].
The following 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, 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 was prepared as described above.
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 according to the following formulae, which are included in the general formula II: WO 99/01423 WO 9901423PCT/DK98/00287 455 0 Resinr3IIf"' NH Resin-[Building block 1]
R'
C1 0 N'NOH Resin R Resin-[Building block IH.Building block 2] (Building black 2] CI- S- CH 3 0 HNR~cRs [Building block 3] (Building block 1]-[Building block 2]-[Building block 3] Resin-[Building block 1M-Building block 2]-[Building block 3] and WO 99/01423 WO 9901423PCTIDK98/00287 0 Res Nk N*K NH 2 Resin-f Building block 1] [Building block 2] Resin-[Building block 1]-[Building block 2] 0 CI- S-H 3 0 HSR~c [Building block 3] R 5 c R
SC
[Building block 1 ]-[Building block 2]-[Building block 3] Resin-[Building block 1]-[Building block 2]-[Building block 3] wherein R 15 are as defined for formula I and -NR 5 cR~d is R Sa R4a 0b where R51, R 4 1, R b, c, q, d, and D are as defined for formula I or where is defined as a subset of -D that contains a primary or a secondary amine that can react as a nucleophile; and -SR 5 c is WO 99/01423 PCT/DK98/00287 457 4a 4b where R b, c, q, d, and D are as defined for formula I or where is defined as a subset of -D that contains a thiol that can react as a nucleophile.
The following resin, here depicted as Resin-[Building block 1] was used: where PS is polystyrene. In the following "Resin" is the polystyrene resin with the Wang linker: PS cr" Resin The following building blocks were used: 4-Hydroxymethylnaphthalene-1 carbaldehyde
O
[Building block 31: (1 ,4'-Bipiperidine)- 2-Thiophenemethylamine 5-Methyl-2-fu ran methyla mine 4'carboxamide s H 3Z'>3 0 3
~KH
N
ONH
2 WO 99/01423 WO 9901423PCT/DK98/00287 458 1 -Pyrrolidinocarbonylmethyl)- 1 -(2-Furoyl)piperazine 2-Amino-2-phenylethanol piperazine HN>~ NH 2 HN'N) 0
ON
L-Methionine ethyl ester DL-Serine methyl ester 4-Acetyl-4-phenylpiperidine
NH
2 NH 2
N
H
4-Piperidinopiperidine N-Ethylpiperazine 1 -Acetylpiperazine HI -oHN C H 3 (N)
N
H
3 C -il0 Piperazine 2-(Aminomethyl)pyridine 4-(Aminomethyl)piperidine 'NH H N~
HN\,NH
2 1 ,3-Diaminocyclohexane Pyrrolidline
H
2 Na 0
'NH
2 4-(2-Aminoethyl)pyridime 4-(Hydroxymethyl)piperidine Thiomorpholine OH OH N- -NH 2 6N
H
2-(2-Methylaminoethyl)- (s)-2-Amino-3-cyclohexyl- 1- 3-isopropylamino-npyridine propanol propylamine NN' NOH H CH. CH3 WO 99/01423 WO 9901423PCT/DK98/00287 459 L-Prolinol 4-Hydroxypiperidine 1 -Amino-2-propanol OH IHfNJO-OHHO -N
H
Furfurylamine 2-Methoxyisopropylamine L-lsoleucinol 0 2 H2NNO
CH
3
H
2
N
3-Aminopentane 2-Piperidineethanol 3-Amino-i ,2-propanediol
H
H
3 Ch OH 3 N HO"-rNH 2 NF DOH Cyclopropylamine Ethylenediamine 1 -Benzyl-3-Aminopyrrolidine
H
2
H
2 Nn 3-Pyrrolidinol 2-Aminocyclohexanol Morpholine HNc
NHOH
3-Mercaptopropionic acid Glycine tert butylester 3-Mercaptopropionic. acid HO o H 3 C CH 3 ethyl ester HS9 0 HS -yO,_,H3
INH
2 0 Ethylamine Methylamine 2-Aminoethanol
<OH
3
H
3 C. H
OH
NHNH?
NH
2
H
2
N
Isopropylamine Isopentylamine Dimethylamine 083
H
3
C,
H2N OCH 3
H
2 N- O'H 3
HGCN
OH
3 WO 99/01423 WO 9901423PCT/DK98/00287 Propylamine Cyclopentylamine 2-Furanylmethylamine ri -6NY
H
2 N
NH,
2-Methylimidazole 3-Amino-5-mercapto-1 Captopril N ~triazole0 N N O H
H
3 2,2-Dimethyipropylamine N ,N-Dimethylethylene- 2,4-Dimethylimidazole CH H2 diamine
H
3
CN
H
3 C HCN.>pH 3-Mercapto-1 H-i .2,4-triazol Cyclopropylmethylamine Cyclobutylamine N1SH L NHq 4-Mercaptopyridine Thiazolidine Isopropylmercaptane SH SH 61S -NH H3C )lCH 3 4-(4-Trifluoromethylphenyl)- 4-(2-Thienyl)-4-piperidinol 4-(3-Trifluoromethylphenyl)- 4-piperidinol HO3-piperidinol N F H
F
F
COH
OH
H
N
H
WO 99/01423 WO 9901423PCT/DK98/00287 Glutamic Acid di Ilrt butyle- 2,2,2-Trifluoroethylamine S-1-amino-2-propanol sterF NHHO'r^2 HCH 0FF CH 3 0 0
H
3 C
-CH
3 4-(Aminomethyl)-piperidine D-Valinol Thiophene-2-ethylamine N
~H
2 N C3C LNH2 Tetrahydro-3-thiophenamine 1,1-dioxide 2,3-Dimethoxybenzylamine Alfa-methylbenzylamine 1,2,3,4- H2NI >-Tetrahydroisoquinoline cH 3 1 ,2,3,4-Tetrahydro-1 N-Benzylethanolamine 4-Methoxybenzylamine naphthylamine H H 2
~~CH
3
NH
2 WO 99/01423 WO 9901423PCT/DK98/00287 N'-Benzyl-N,Nn- 2-Benzylamino-1 -propanol d imethylethylened ia mineH
H
3 C. HHOF N1- N-1Isopropyl benzyla mine 1 ,2-Dimethylpropylamine D-(-)-apha-Phenylglycinol N~<~HNJ1 HO-NJo H
H
3 C CH 3 H 2
N
4-Fluorobenzylamine N-Ethylbenzylamine N-(n-propyl) Benzylamnine F~ HH3 NiiY 2-Amino-2-methyl-1 -propanol Piperonylamnine 4-(Trifluoromethyl)benzyl- H2N <'OH0 Lamine
H
3 C CH 0
HN
(-)-Norephedrine 2-Methylaminoethanol 2-Butylamine H -I HN
H
3 H2-I HO
IO
Benzytmethylamine Diisobutylamnine Cyclohexylamnine a>H 3 C N p HN. CH 3 HCNH 2 N-Benzylhydroxylamine Methylamninoacetonitril N, N-Diethyl nipecotamide OHCH
CH
3 Hr NH H 3
CN)
H
WO 99/01423 WO 9901423PCT/DK98/00287 4-Aminocyclohexanol 2-isopropylaminoethanol 1 .3-Dimethytbutanamine
NH
2
H'
3 C(
H
3
C'N
H~
H
3 C NH,
OH
4-Methyicyclohexylamine Alfa-methyl-4-chlorobenzyl- 4-Methoxybenzylhydroxyl- H a Hamine Qiamine
C
2. 3
NH
2 H0 Ci~ 3 HO' 2-Phenylglycinonitrile 3-(Benzylamino)propionitrile 3-Methoxybenzyla mine
NH
2 H93
NH
2 1 -Methyl-2- 3-Fluorobe nzyla mine 1 -Aminoindan phenoxyethylamnine
NH
2 K
NH
2 0
F
N2 3-Piperidinemethanol 3,4-Dimethoxybenzylamine OH CHmethyithiadiazole 0 H2N HS N. N H
S
1 -Methyl-5-mercaptotetra- 3-Methylaminopropionitril Isopropylmethylamiiie zole HC /N H 3 C H HS-.N. H H 3 C CH3
N-N
H
3
C
2-Mercaptothiazole 2-Amino-i -propanol exo-2-Aminoflorborlafle N
~H
3 C -l.<,OH s NH ztzNH 2 WO 99/01423 WO 9901423PCTIDK98/00287 4-Aminobenzylamine 2-Mercaptoimidazol 2-Mercapto-1 -methylimidazol H 2 N <N4 SH N SH
NN
H
'H
3-Mercapto-4-methyl-1 2-Methyl-4-amino-5- 2-Phenylpiperidine triazol aminomethylpyrimidine N- l N Y, H 3 N' (NA SH 2-I*NH H6N 3
N
3-benzylamino- 1 -propanol 4-Aminomethylpyridine 3-Aminomethylpyridine NH2
NH
2 R-2-Amino-1 -propanol 4-(Ethylaminomethyl)pyridine 4-Trifluoromethoxybenzyl- NH2',F rN"klr I-,CH amine F rNZ NH 2 F 0~- 4-lg-Butylbenzylamine 3-Aminobenzylamine 3-(Methylaminomethyl)-
NH
2
NH
2 pyridine
H
3 C
N'CH
HOC
CH3 Cl H3
NH
2
N
OL-Phenylalanine methyl ester
H
2 Nj 0-H 3 0 WO 99/01423 WO 9901423PCT/DK98/00287 465 Preparation of resin-l'Building block 11: This resin was prepared as described above.
Preparation of 4-hydroxymethyinaphtaldehyde ([Building block 21) The preparation of this compound is described above.
Preparation of resin-[Building block 11-[Buildina block Preparation of resin bound 3-chloro-4-hydroxybenzoic acid (4hydroxymethylnaphthylmethylene)hydrazide: aS 0' Resin-[Building block 1] (4 g) was suspended in DMF (40 mL) and was allowed to swell for min. and then washed with DMF (2 x 40 mL), DCM (3 x 40 mL) and DMVSO (2 x 40 mL).
The solvent was removed by filtration. 1.488 g (8 mmol) 4-hydroxymethylnaphtaldehyde was dissolved in 40 mL DMVSO and was added to the resin followed by 4 mL glacial acetic acid.
The suspension was shaken for 16 hours at 25 IC. The resin was successively washed with DMSQ (2 x 40 mL), THF (3 x 40 mL), CH 3 0H (40 mL), CH 2
CI
2 (40 mL), CH 3 0H (40 mL),
CH
2
CI
2 (40 mL) and dried in vacuo at 40 IC for 16 hours to afford resin bound 3-chloro-4hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide.
EXAMPLE 825: 3-chloro-4-hydroxybenzoic acid H-i .2.4-Triazol-3-ylsulfanylmethyl)naphthylmethylene)hydrazide WO 99/01423 PCT/DK98/00287 466
N-\
NH
HNH
H O N.NS
N
HO Cl The resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide (resin-[Building block 1]-[Building block (2 g, 2 mmoles) was swelled in
CH
2
CI
2 (20 mL) for 15 min, then washed twice with CH 2 Cl 2 (20 mL). 8 mL CH 2 Cl 2 and 8 ml diisopropylethylamine was subsequently added and the suspension was cooled to 0 OC.
Methanesulfonylchloride (2 mL) was dissolved in CH 2
CI
2 (6 mL) and added to the suspension. The mixture was allowed to react at 0 °C for 30 min, then at 25 OC for 1 hour. The resin was isolated by filtration and washed with CH 2
CI
2 (2 x 20 mL) and N-methyl-2-pyrrolidone (2 x 20 mL). 1 H-1,2,4-Triazole-3-thiol (0.8 g) and KI (0.4 g) was dissolved in a mixture of 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 OC for 2 days. The solvent was removed by suction and the resin was washed with N-methyl-2-pyrrolidone (3 x mL) THF (3 x 20 mL), CH 3 OH (20 mL), CH 2
CI
2 (20 mL), CH 3 OH (20 mL), CH 2
CI
2 (4 x mL). The compound was cleaved from the resin by shaking for 1 hour at 25 OC with a solution of trifluoroacetic acid in CH 2
CI
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 concentrated in vacuo. The residue was treated with CH 3 OH (4 mL) at 25 OC providing an offwhite precipitate which was isolated by filtration. The solid was washed with CHOH (3 x 2 mL) and dried in vacuo at 40 °C.
This afforded 275 mg of the title compound.
HPLC-MS (METHOD Rt 2.48 min; m/z 438 1 H-NMR (300 MHz, DMSO-d 6 8 4.9 (2H, 7.1 (1H, d),7.5-7.9 (5H, 8.0 (1H, 8.25 (1H, 8.9 (1H, 9.1 (1H, 11.0 (1H, 11.8 (1H, s) EXAMPLE 826: 3-Chloro-4-hydroxybenzoic acid (4-(isobutylaminomethyl)naphthvlmethylene)hydrazide WO 99/01423 PCT/DK98/00287 467 0 NH I H: cH
HOCH
CI
The resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide (resin-[Building block 1]-[Building block (50 mg, 0.05 mmoles) was swelled in CH 2
CI
2 (1 mL) for 15 min, then washed with CH 2
CI
2 (2 x 0.5 mL). 0.4 mL
CH
2
CI
2 and 0.4 mL diisopropylethylamine was subsequently added and the suspension was cooled to 0 OC. Methanesulfonylchloride (0.1 mL) was dissolved in CH 2
CI
2 (0.3 mL) and added to the suspension. The mixture was allowed to react at 0 OC for 30 min, then at 25 OC for 1 hour. The resin was isolated by filtration and washed with CH 2
CI
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 diisopropylethylamine. The mixture was shaken at 25 OC for 16 hours, filtered and washed successively with DMSO (2 x 0.5 mL), THF (3 x 0.5 mL), CH 3 OH (0.5 mL), CH 2 Cl2 (0.5 mL),
CH
3 OH (0.5 mL), CH 2
CI
2 (4 x 0.5 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 OC with a 50% solution of trifluoroacetic acid in CH 2
CI
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 concentrated in vacuo to give the title compound.
HPLC-MS (METHOD R, 4.20 min; m/z 410 (M+1) EXAMPLE 826: 3-Chloro-4-hydroxybenzoic acid ((4-(4-trifluoromethoxybenzylamino)methylnaphthylmethylene)hydrazide 0 NH
N*
IOjj H I F HO N.N NO F Cl
F
Resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide: (resin-[building block 1]-[building block (50 mg) was swelled in a 1:1 mixture of CH 2 C1 2 and N-methyl-2-pyrrolidone (0.5 mL) for 15 minutes and then washed with CH 2
CI
2 (3 x mL). 800 pL of a 1:1 mixture of CH 2
C
2 and diisopropylethylamine was added to the resin WO 99/01423 PCT/DK98/00287 468 which subsequently was cooled to -3 A solution of 100 pL methanesulfonylchloride dissolved in 300 pL was added and allowed to react at -3 OC for 30 minutes then at 25 OC for 1 hour. Filtration of the resin was followed by washing with CH 2
CI
2 (2 x 1 mL) and N-methyl-2pyrrolidone (2 x 0.5 mL). 600 pL of a solution of 4-trifluoromethoxybenzylamine (45.8 mg, 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 °C for 16 hours. The resin was isolated by filtration and washed successively with N-methyl-2-pyrrolidone (5 x mL), THF (3 x 0.8 mL), CH 3 OH (0.8 mL), CH 2
CI
2 (0.8 mL), CHOH (0.8 mL) and CH 2
CI
2 (3 x 0.8 mL). The compound was cleaved from the resin by shaking 1 hour at 25 °C with a solution of 50% trifluoroacetic acid in CH 2
CI
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 concentrated in vacuo to give the title compound.
HPLC-MS (METHOD R, 10.07 min; m/z 528 (M+1) EXAMPLES 828 TO 875: A library of compounds of all the possible combinations of the above listed building blocks ([building block [building block 2] and [building block was 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. The compounds are all expected to be present in the respective wells.
A suspension of the resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide: (resin-[building block 1]-[building block (50 mg) in a 1:1 mixture of CH 2
CI
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 1 REM Nucleophilic displacement of benzylic alcohol WO 99/01423 PCT/K98/00287 469 2 REM via mesylation 3 4 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 9 REM Adjust pressure REM Add 100 mL DIEA/DCM 1:1 mixture to Reagenti 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 16 Pause 17 REM Initialising...
18 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 23 Flush Arm1 with Flush Diluteri and Flush Diluter 2 Arm2 with Flush Diluter 3 and with Flush Diluter 4 24 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 Emptyl_72_3min 29 Go to ChemFile MTY72_3M.CHM, line 1 Repeat from step 26, 2 times 31 32 REM Adding DCM/DIEA mixture from Reagenti 33 Transfer 800ul from REAGENT 1[1](DCM/DIEA) to RB1_1to96[1-72] using Flush Diluteri 34 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
Set Temperature of rack "RB1_1to96" to -3.0 degrees Celsius and wait for Tempererature to reach setpoint 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 REM Adding mesylchloride 41 Transfer 400ul from REAGENT_2[1](MsCI/DCM) to RB1_1to96[1-72] using Flush Diluteri 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) 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 "RB1_1to96" to 25.0 degrees Celsius and wait for Tempererature to reach setpoint 49 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
Wait for 4.000 minute(s) 51 Repeat from step 46, 11 times 52 53 REM Subroutine Empty1_72_3min 54 Go to ChemFile MTY72_3M.CHM, line 1 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.
59 Go to ChemFile MTY72_3M.CHM, line 1 Repeat from step 57, 1 times 61 62 REM NMP wash 63 64 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72] 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 69 Repeat from step 64, 1 times 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 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 81 REM End of reaction 82 Go to ChemFile MTY72_3M.CHM, line 1 83 Go to ChemFile MTY72_3M.CHM, line 1 84 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 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 Pause 96 97 Flush Arm1 with Flush Diluteri 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 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 1 103 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.
108 Go to ChemFile MTY72_3M.CHM, line 1 109 110 Dispense System Fluid Disdul_4* 800ul to RB1_1to96[1-72] 111 Mix "RB1_1to96" for 10.00 minutes at 300 rpm(s) and wait.
112 Go to ChemFile MTY72_3M.CHM, line 1 113 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 RB1_1to96[1-72] 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 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 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 Diluterl 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! 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 Diluteri 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 146 The following chemfile is called to empty the wells of the reaction block.: ChemFile C:\ACT_1328\MTY72_3M.CHM 1 REM Subroutine Empty1_72_3min 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 vials containing the final product in a controlled manner.
ChemFile C:\ACT_1328\PULSEMP1.CHM 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) Return 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.
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 WO 99/01423 PCT/DK98/00287 474 WO 99/01423 PCT/DK98/00287 843 0 468 6.25
N-N
CI H S CH 3 844 0 453 4.87 u N.N CI H z N-N 845 H 437 2.68 FiCl HiN_ 846 0 436 7.88 Cl H
F
847 500 14.12 CI H H
CH
3 HC CH3 Ex No. Structure HPLC-MS HPLC-MS (METHOD (METHOD A) A) m/z Rt (minutes) 848 484 9.80 Fi 0 -W N N N CI H H 849 0 462 9.38 H N-N~ N CI H H
F
WO 99/01423 WO 99/1 423PCT/DK98/00287 476 850 0 472 9.37 Fi
N-NI
CI H3 851 0 486 9.55 Fi cl N-N 3 CI
H
852 0 488 9.18 853 0 CH 488 9.37 N /N N CI HH
HO~
854 0 412 7.83 H#NN /r N-CH 3 CI H 0
H
855 458 9.30 856 0-~-4I -450 9.62 Fi 0 N-N/ N- C1 CI HH 857 ci 492 10,03 Ff
N
CI Hi H CH 3 858 0 453 8.90 Ci Hl N -P -I4
NH
2 WO 99/01423 WO 9901423PCT/DK98/00287 859 0~N- 497 10.73 ci HN 860 0 474 9.15 ci H
H/
HC-0 861 488 9.55 cI H HCH 862 0 462 9.27 cl" H N 6 -N H 863 470 9.43 H-F\)N CI
HH
864 0 504 8.98
CH
3 0-CH 3 865 -0H 440 8.35 Fi -P 4 N/ N CI H !qH -C3 H3C 866 454 12.90 0I
HS
WO 99/01423 WO 9901423PCT/DK98/00287 867 0 J 459 7.63 I-i N-N' N cI H 7~
NH
2 868 0H 3 C 451 8.45 Fi -p 4
N
CI H ND 869
H
3 q 452 9.31 N-N/ S-4 CI Fi N'N 870 498 9.65 871 0502 9.03 IFi 872 0 459 7.60 CI H .H
-H
873 516 9.33 0N Xi H H 0 cl 0
'CH
3 EXAMPLE 874: WO 99/01423 PCT/DK98/00287 479 'H NMR (DMSO-D6) d 2.37 8H), 3.44 2H), 3.90 2H), 7.10 J 8.5 Hz, 1H), 7.30 J 8.5 Hz, 2H), 7.37 J 8.5 Hz, 2H), 7.55 J 7.4 Hz, 1H), 7.67 2H), 7.81 J 8.7 Hz, 1H), 7.86 J 7.3 Hz, 1H), 8.02 J 1.8 Hz, 1H), 8.36 (dd, J 1.7, Hz, 1H), 8.83 J 8.0 Hz, 1H), 9.08 1H), 10.99 1H), 11.78 1H). MS (APCI, pos.): 547.1, 550.1 EXAMPLE 875: 0N cl 1 H NMR (DMSO-D 6 d 2.66 2.75 4H), 3.69 2H), 4.06 2H), 6.36 1H), 6.40 (m, 1H), 7.06 J 8.5 Hz, 1H), 7.51 7.66 4H), 7.77 J 8.0 Hz, 1H), 7.83 J 7.1 Hz, 1H), 7.98 1H), 8.26 J 8.5 Hz, 1H), 8.80 J 8.5 Hz, 1H), 9.04 1H), 10.94 1H), 11.77 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 Resin-[Building block 1] Resin-[Building block 1]-[Building block 2] Resin-[Building block 1]-[Building block [Building block 3] Resin-[Building block 1]-[Building block [Building block [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 following formula WO 99/01423 PCT/DK98/00287 480 [Building block [Building block [Building block [Building block 4].
The following 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, whereas the attachment of [Building block 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 was prepared as described above.
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 followed by an acylation reaction attaching [Building block 4] according to the following formulae, which are included in the general formula II: WO 99/01423 WO 99/1 423PCT/DK98/00287 0 CN' N NH, Resin,) I H Resin-[Building block 1] 0 Resin. 00 [Building block 2] Resin-[Building black 1]-fBuilding block 2] 0
CI-S-CH
6 HNRS8 (Building block 3] 0 Nl:~ N N.
Resin.
H
0o 0 0 S-CH 3 0 Resin-[Building block I]-[Building block 2]-[Building block 3] 0 R[B I Lea [uilding black 4] Resin-[Building black 1 ]-[Building black 2H[Building block 3].[Building black 4] [Building black 1])-[Building black 2]-[Building black 3].[Building black 41 wherein R 55
R
14
R"
5 are as defined for formula I and R'C is R4a R4b where Rla, ROb, c, q, d, and D are as defined for formula I or where is defined as a subset of -D that contains an activated carboxylic acid capable of reacting as an electrophile and Lea is a leaving group such as chioro, bromo, iodo, carboxylate, WO 99/01423 PCT/DK98/00287 482 0- 0 0 NS ~JN 0:N The following resin, here depicted as Resin-[Building block 1] was used: 0 N NH 2 0 where PS is polystyrene. In the following "Resin" O~ r is the polystyrene resin with the Wang linker: o =Resin The following building blocks were used: [Building block 21: 4-Hydroxymethylnaphthalene-1 carbaldehyde
OH
0't WO 99/01423 PTD9/08 PCT/DK98/00287 ['Building block 31: 2-Thiophenemethylamine 5-Methyl-2-furanmethylamine L-Methionine ethyl ester s -170 HN'- 0\ Hc 0 Z<AH,
H
3 C's-ro -CH
NH
2 2-(Aminomethyl)pyridine 4-(2-Aminoethyl)pyridine 3-Aminopentane H2 0 C NH 2 NH 2 Furfurylamine 2-Methoxyisopropylamine Cyclopropyla mine 0
~H
2 N "r O- a-iHN- Glycine 2-Furanylmethylamine N,N-Dimethylethylenedio OH NH 2 amine
NH
2 93 HaC-N NH2 Ethylamine Methylamine Propylamine <a-i 3
H
3 C.N2C r-1
NH
2 H 2
N
Isopropylamine Isopentytamine Cyclopentylamine
CH
3 1 -i H H 2
N"-CH
3
H
cH 3 Cyclopropylmethylamine Cyclobutylamine Thiophene-2-ethylamine
&INH
2 NH/ NH 2 N2 Glutamic Acid di tert butyte- 2,2,2-Trifluoroethylamine Tetra hyd ro-3-th iophena mine CHOr F F(NH 2,-ixd
CH
3 L 0 'D NH 2 H C 0N H 2 2 H3C Co a-0 WO 99/01423 WO 9901423PCT/DK98/00287 [Building block 41: Acetic anhy- N-Led Butoxycarbonyldride proline anhydride HCf 0 CH k YT§P CH.
H3Ck Oo_-oO+CH3 0 CH 3
CH,
Prearation of resin-[Building block 1]: This resin was prepared as described above.
Preparation of resin-["Building block 11-f Buildina block 21: This resin was prepared as described above.
EXAMPLE 876: N-{4-[(3-Chloro-4-hyd roxybenzoyl)-hyd razonomethyll na phthymethyl}-N -isobutylp2ro lina mid e 0
HO_(
ci The resin bound 3-chloro-4-hyd roxybenzoic acid (4-hyd roxymethyl nap hthylmethylene)hydrazide (resin-[Building block 1]-[Building block (50 mg, 50 p.moles) was swelled in CH 2
CI
2 (0.5 mL) for 15 min, then washed twice with CH 2
C
2 (0.5 mL). 0.4 mL
CH
2
CI
2 and 0.4 mL diisopropylethylamine were subsequently added and the suspension was cooled to 0 OC. Methanesulfonylchloride (0.1 mL) was dissolved in CH 2
CI
2 (0.3 mL) and added to the suspension. The mixture was allowed to react at 0 OC for 30 min, then at 25 OC for 1 hour. The resin was isolated by filtration and washed with CH 2
C
2 (2 x 0.5 mL) and DMVSO (0.5 mL). 0.5 mL DMVSO 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 OC for 16 hours. The solvent 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 mL) was added diisopropylcarbodiimide (16 pL, 0.2 mmol). This solution was allowed to react at 25 OC for 10 minutes and then added to the resin. The suspension was shaken at OC for 16 hours after which the resin was isolated by suction and washed with THF (3 x mL), DMF (3 x 0.5 mL) THF (3 x 0.5 mL), CH 3 OH (0.5 mL), CH 2
CI
2 (0.5 mL), CH 3 OH mL), CH 2 Cl 2 (4 x 0.5 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 OC with a 50% solution of trifluoroacetic acid in CH 2
CI
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 mL) and concentrated in vacuo to give the title compound.
HPLC-MS (METHOD R, 3.90 min; m/z 507 EXAMPLE 877: 3-Chloro-4-hydroxybenzoic acid ((4-(4-trifluoromethoxybenzylamino)methyl)naphthylmethylene)hydrazide i H -N N C Resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide (resin-[building block 1]-[building block (50 mg) was swelled in a 1:1 mixture of CH 2
CI
2 and N-methyl-2-pyrrolidone (0.5 mL) for 15 minutes and then washed with CH 2
CI
2 (3 x mL). 800 pL of a 1:1 mixture of CH 2
CI
2 and diisopropylethylamine was added to the resin which subsequently was cooled to -3 OC. A solution of 100 pL methanesulfonylchloride dissolved in 300 pL was added and allowed to react at -3 OC for 30 minutes then at 25 OC for 1 hour. Filtration of the resin was followed by washing with CH 2
CI
2 (2 x 1 mL) and N-methyl-2pyrrolidone (2 x 0.5 mL). 600 pL of a solution of 4-trifluoromethoxybenzylamine (45.8 mg, 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 OC for 16 hours. The resin was isolated by filtration and washed successively with N-methyl-2-pyrrolidone (5 x 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 OC for 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 OH (0.8 mL) and CH 2
CI
2 (3 x 0.8 mL). The compound was cleaved from the resin by shaking for 1 hour at 25 °C with a solution of 50% trifluoroacetic acid in
CH
2
CI
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 concentrated in vacuo to give the title compound.
HPLC-MS (METHOD Rt 6.42 min; m/z 492 (M+1) EXAMPLES 878 TO 881: A library of compounds of all the possible combinations of the above listed building blocks ([building block [building block [building block 3] and acetic anhydride as [building block was 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. The compounds are all expected to be present in the respective wells.
A suspension of the resin bound 3-chloro-4-hydroxybenzoic acid (4-hydroxymethylnaphthylmethylene)hydrazide (resin-[building block 1]-[building block (50 mg) in a 1:1 mixture of CH 2
CI
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 1 REM Nucleophilic displacement of benzylic alcohol 2 REM via mesylation 3 WO 99/01423 PCT/DK98/00287 487 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 9 REM Adjust pressure REM Add 100 mL DIEA/DCM 1:1 mixture to Reagenti 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 16 Pause 17 REM Initialising...
18 19 REM Subroutine Empty1_72_3min is called twice to remove DCM/NMP from dispensed resin Go to ChemFile MTY72_3M.CHM, line 1 21 Go to ChemFile MTY72_3M.CHM, line 1 22 23 Flush Arm1 with Flush Diluteri and Flush Diluter 2 Arm2 with Flush Diluter 3 and with Flush Diluter 4 24 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 Empty1_72_3min 29 Go to ChemFile MTY72_3M.CHM, line 1 Repeat from step 26, 2 times 31 32 REM Adding DCM/DIEA mixture from Reagenti 33 Transfer 800ul from REAGENT_1[1](DCM/DIEA) to RBl_1to96[1-72] using Flush Diluteri 34 Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
Set Temperature of rack "RB1_1to96" to -3.0 degrees Celsius and wait for Temperature to reach setpoint 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 REM Adding mesylchloride 41 Transfer 400ul from REAGENT_2[1](MsCI/DCM) to RB1_lto96[1-72] using Flush Diluteri 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) Repeat from step 43, 5 times 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 Wait for 4.000 minute(s) 51 Repeat from step 46, 11 times 52 53 REM Subroutine Emptyl 72_3min 54 Go to ChemFile MTY72_3M.CHM, line 1 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.
59 Go to ChemFile MTY72 3M.CHM, line 1 Repeat from step 57, 1 times 61 62 REM NMP wash 63 64 Dispense System Fluid Disdu2_3* 500ul to RB1_1to96[1-72] 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 69 Repeat from step 64, 1 times 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 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 81 REM End of nucleophilic substitution reaction 82 Go to ChemFile MTY72_3M.CHM, line 1 83 Go to ChemFile MTY72_3M.CHM, line 1 84 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.
88 Go to ChemFile MTY72 3M.CHM, line 1 89 Go to ChemFile MTY72_3M.CHM, line 1 Repeat from step 86, 4 times 91 92 REM Change systemfluids: 93 REM Diluter2: THF 94 REM Diluter3: MeOH 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] 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 1 105 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: 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 3 REM Diluter2: THF 4 REM Addition of acylation reagent 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) 8 Repeat from step 6, 60 times 9 Go to ChemFile MTY72_3M.CHM, line 1 Go to ChemFile MTY72_3M.CHM, line 1 11 Return The following chemfile is called to wash the resin bound products: ChemFile C:\ACT_1328\WASH.CHM 1 REM Washing procedure 2 REM Systemfluids: 3 4 REM Diluter2: THF REM Diluter3: MeOH 6 7 Flush Arm1 with Flush Diluteri 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] 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 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 20 Dispense System Fluid Disdul_4* 800ul to RB1_1to96[1-72] 21 Mix "RB1_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 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 30 Repeat from step 117, 1 times 31 32 REM Washing procedure has ended 33 Return The following chemfile is called to cleave the products from the resin: ChemFile C:\ACT_1328\Cleavage.CHM 1 REM Setup for cleavage: 2 REM Cleavage vials 3 REM Lower pressure 4 REM Add 100 mL TFA/DCM 1:1 mixture to Reagent3 REM Add 100 mL CH3CN to Reagent4 6 Pause 7 8 REM Adding cleavage solution, 1hr 9 Transfer 1000ul from REAGENT_3[1](TFA/DCM) to RB1_1to96[1-72] using Flush Diluteri Mix "RB1_1to96" for 1.00 minutes at 300 rpm(s) and wait.
11 Wait for 4.000 minute(s) 12 Repeat from step 133, 11 times 13 REM PULSE EMPTY! 14 Go to ChemFile PULSEMP1.CHM, line 1 16 REM Washing with CH3CN 17 Transfer 500ul from REAGENT_4[1](CH3CN) to RB1_1to96[1-72] using Flush Diluteri 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! Go to ChemFile PULSEMP1.CHM, line 1 21 Return 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 Empty1_72_3min 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 vials containing the final product in a controlled manner.
ChemFile C:\ACT_1328\PULSEMP1.CHM Page 1 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) Return Dispense sequence C:\ACT_1328\R2-A.DSP is a subroutines that control the combinatorial 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.
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 WO 9901423PCT/DK98/00287 Ex No. Structure HPLC-MS HPLC-MS (METHOD (METHOD B) B) m/z R (minutes) 878 CH3 490 6.22 cl H 1 879 H *0 .0 0 ,CH 3 454 1.05
N
CI H 0 880 H 0~ 464 6.33 ci H N/ eCH 3 881 H O CH-i3 450 5.30 CI H \t WO 99/01423 PCT/DK98/00287 493 EXAMPLE 882: N-{4-[3-chloro-4-hydroxybenzoyl)-hydrazonemethyl]-1 -naohthyllmethyl iso-Dropyl amiide o O )N.CHz N N.N H
CH,
HO j Cl 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 "C and stirred for 30 min.
Solution turned orange. The reaction was filtered and the clear solution was concentrated to 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.
Column chromatography eluted with ethyl acetate afforded the amide. Deprotection of diethyleneacetal was achieved by 10% HCI in THF to give the title compound (50 mg).
1 H NMR (CDCI 3 d 1.2 6H), 2.4 1H), 4.9 2H), 6.1 1H), 7.5 1H), 7.6 2H), 7.8 1H), 8.0 1H), 9.2 1H), 10.3 1H).
The title compound was prepared similarly as described above.
'H NMR (DMSO-D 6 d 1.0 6H), 2.4 1H), 4.7 2H), 7.0 1H), 7.4 1H), 7.6 (m, 2H), 7.7 1H), 7.8 1H), 7.9 1H), 8.1 1H), 8.3 1H), 8.8 1H), 9.0 1H), 10.9 1H), 11.7 1H); ms (APCI negative); 422.
EXAMPLE 883: 4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyll-1-naphthylmethyl iso-propylsulfoxide WO 99/01423 PCT/DK98/00287 494 CH
H
HO H Cl 4-Ethyleneacetal-4-formyl-naphthylmethyl iso-propylthioether: A mixture of 4-bromomethyl naphthaldehyde ethyleneacetal (232 mg, 0.79 mmol) and isopropyl thioalcohol (0.08 mL, 0.81 mmol) and 0.12 mL of triethylamine was left at room temperature for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography eluted with ethyl acetate /hexane to afford 93 mg of the desired product as pale radish oil.
'H NMR (CDCI 3 d 1.3 6H), 2.9 1H), 4.2 6H), 6.5 1H), 7.4 1H), 7.6 2H), 7.7 1H), 8.2 1H).
4-Ethyleneacetal-naphthylmethyl iso-propylsulfoxide: To a mixture of the above 4-ethyleneacetal-naphthylmethyl iso-propylthioether (79 mg, 0.27 mmol) in 5 mL of dichioromethane at -78 *C was added m-chloro perbenzoic acid (82 mg, 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 to yield 56 mg of desired product as an oil.
1 H NMR (CDCIl): d 1.3 3H), 1.4 3H), 2.7 1H), 4.2 4H), 4.4 (dd, 2H), 6.5 (s, 1H), 7.5 1H), 7.6 2H), 7.7 1H), 8.1 1H), 8.2 1H). This compound was hydrolyzed in aqueous 10% HCI in THF for 1 hr to give the corresponding aldehyde.
4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyl]-1-naphthylmethyl iso-propylsulfoxide: The title compound was prepared similarly as described above.
WO 99/01423 WO 9901423PCT/DK98/00287 495 IH NMR (DMSO-D 6 d 1.3 (dd, 6H), 3.0 (in, I1H), 4.3 1 4.7 1 7.1 1IH), 7.6 (n 3H), 7.8 1IH), 7.9 1 8.0 1 8.2 1 8.8 1 9.1 1 11.0 1 H), 11.8 1 ms (APC I negative); 427, 337.
EXAMPLE 884: 4-[3-chloro-4-hydroxybenzoyl)-hydrazonomethyll-lI-naphthylmethyI iso-propylsulfone Similarly, the title compound was prepared.
'H NMR (DMSO-D6): d 1.3 6H), 3.4 (in, 1 5.0 2H), 7.0 1 7.6 (mn, 3H), 7.7 (d, 1 7.9 2H), 8.2 1 8.7 1 9.0 1 10.9 1 11.8 1 ms (APCI negative); 443, 336.
EXAMPLE 885: 4-[3-chloro-4-hyd roxybenzoyl)-hy-drazonomethvll-1 -naphthyl methyl iso-propylsulfide
CH
3 0 N' NS ),CH3
HO"(
ci Similarly, the title compound was prepared.
WO 99/01423 WO 9901423PCT/DK98/00287 496 Further examples of the invention are the following compounds: EXAMPLE 886: 0 F HO'j:;rj cI EXAMPLE 887: OH3 0 N. 0 OH 3 N Nz. 0 HO'Q
J
EXAMPLE 888:
OH
3 N f 6 0 HOQ H H 3 0 ci EXAMPLE 889: O
H
3 N0 N HO" H
HOC
cI WO 99/01423 WO 9901423PCT/DK98/00287 497 EXAMPLE 890:
CH
3
QFCH
3
H
3
C
891: N N5, o 00
HOJ~"
CI
EXAMPLE 892: 0
CH
3 I "A ,N 0 0o ,1 EXAMPLE 893: EXAMPLE 894: 0 N 'N 0 0-, HO'jH
CI
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 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 respects only as illustrative and not restrictive, and the scope of the invention is, therefore, indicated 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.
Claims (31)
- 6-alkyl, W is or -R= Y is or -R= Z is or -0R 21 Vi-=or C2= AMENDED SHEET 5004 SUBSTITUTE SHEET 501 R1 9 R 20 R 21 and R22 independently are hydrogen, halogen, -ON, -OF 3 -OOF 3 -OOH 2 CF 3 -NO 2 -CR 24 -NR 24 R 25 O 1 -6-alkyl, aryl, aryi-O 1 -6-alkyI, -SOF 3 -SR 24 -OH F 2 -OCHF 2 -OOF 2 OHF 2 -0S0 2 0F 3 -00NR 24 R 25 -0H 2 00NR 24 R 25 -00H 2 00NR 24 R 25 -0H 2 0R 24 -0H 2 NR 24 R 2 -00CR 24 or -0 2 R 24 or R 19 and R 20 R 2 0 and R 21 or R 21 and R 2 together form a bridge -00H 2 0-, R 24 and R 2 5 independently are hydrogen, -OR 2 1, -S0 2 R 2 1, 0 _'-alkyl, aryl or aryl-O 1 _,-alkyl, R 2 1 is hydrogen, C 1 .6-alkyl, aryl or aryl-Cl-6-alkyI, K is R 3 R 3 b R 4 a\ R 4 b (L)ea (CH 2 )b /P (CH 2 (CH 2 (CH 2 )d R 3 a, Rlb R 4 a and R~b independently are hydrogen, halogen, -ON, -OF 3 -CF 3 -CH 2 OF 3 -NC 2 -OR 24 -NR 24 a R 25 a, 0 14 ,-alkyl, aryl, aryl-CO 1 l-alkyl, -SOF 3 -SR 24 a, -OHF 2 -CHF 2 -OOF 2 OHF 2 -0S0 2 0F 3 CONR 4 R 2 -OH 2 ONR 4 R 5 CH 2 OONR 4 aR S, -CH 2 0R 2 a -OH 2 NR 4 R 5 -OOR 4 or C0 2 R 2 a R 24 a and R Ila independently are hydrogen, COR 2 _SO 2 R 2 6 C 1 alkyl, aryl or aryl-0 14 -alkyl, R 2 Ila is hydrogen, 0 1 .6-alkyl, aryl or aryi--O 1 6-alkyl, or R 3 a and R 3 b R 4 a and R 4 b, or R 3 and R 4 b together form a bridge -(OH 2 i is 1, 2, 3 or 4, a, b, c and d independently are 0, 1, 2, 3 or 4, p independently are 0 or 1, AMEIDED SHEET SUBSTITUTE SHEET 502 q isO0, 1 or 2, L and M independently are -CH=CH-, -CH 2 NR 5a_, _C0_ -oco-, -COO-, -CONR 5a_, .CONR 5 -NR5aCO-, -S02-, -0502-, -SO 2 NR 5a_, -NR5a S0 2 RCONR -CONR R-NR b, -NR aSNR b, -OCONR b, -CH 2 00NR Rb, -OCH 2 00 NRb, R -P(O)(OR 5 -NR 5 or R la and R lb independently are hydrogen, Cl-6-alkyl, -OH, -(CH 2 )k-OR Ia, -COR 6a, -(CH 2 )k-CH(OR 6 a) 2 -(CH 2 )k-CN, -(CH 2 )k-NRaR 6b aryl, aryI-Cl-6-alkyl, -(CH 2 )g-C00R 43 or -(CH 2 )g-CF 3 k is 1, 2, 3 or 4, and R 6 b independently are hydrogen, C,.,-alkyl, aryl or aryi--C 14 -alkyl, g isO0, 1, 2, 3or 4, R 4 1 is hydrogen or Cl- 6 -alkyl, G" is -OCH 2 00-, -CH 2 00-, -00- or a valence bond, E" is -OH 2 -CH 2 CH 2 -CH=CH-, -CH 2 NH- or -CH 2 CH 2 N H-, m is 0 or 1, L"I'HEET 5004 SUBSTITUTE 'SHEET' 503 D is hydrogen, R 2 7 R~ 28 c Y Z R 28 R w. -Iy R27 I W (CH 2 W 7 w. 027 R (C;H 2 R 27 VV(C H 2 S "F W.- 28 E FV R28 F\ (CH 2 R 28 I(CH) E (CH G) 2)N E RFP or RG2 E V r is 0ori1, 4650, Wl ,2 or 3, AMENDED SHEET 504 E, F, G and G' independently are -CHRkm-, or F' Is 'CR 3 or >PN-, Z s or -CR33=, is-N=or _CR31, W Is or -CR, Q'is -0-or R 2 R 38 W4 and- R' 8 independently are hydrogen, halogen, -CN, "O(CHa,i. -(CH2),,NHCOCF 3 -NO 2 Cw 4 alkyl.- aryl, aiyI-Cl-a~kyl, -SCF., -SR 29, -CHF 2 -OCHF 2 -OCFzCHF2, -OSO 2 R0. -0S0 2 CF 3 -(CH2) 7 C0NRw 3 -O(CH2)C0N fRo -(Cllz 0R21. -(CHI NRR.O -OCOR'O, -COR2n or -C0 2 RO. or 2i and RO, R 2andl R 3 R 38 and or R" and R 38 together frm a bridg 265 Yis 0,l,.Z 3 or 4, R2R and WD independently *are hydrogen, -COR2', -C60R~ 1 -so 2 c,.-adky, aryl or aryf- R* Is hydrogen, C...-alkcyi. aryl or aryl-C,.,-alkI, R and Ru independently are hydrogen, C,-alk-A, aryl or aryI-C-akyi, -505- R' is hydrogen, -NR'R 4 1 C,,-aikyl, aryl, ayi-O.-aikyl, -SCF., -SFR -CHF 2 -OCHF, -OCF 2 CHF 2 -CONR4R 4 1 -(CH)0,C ON RR4', CHCONR 40 R4", -(CH 2 ),OR *.CH 2 ),NR R 4 1 -OCOR4 or -C 2 R 40 x is 1, 2, 3 or 4, R40 and R 4 1 independently are hydrogen, -CR42, -S0 2 R 4 2 C,-akyl, aryl or aryl-C 1 4 -aikyl, R4 2 is hydrogen, C- 1 -alkyl, aryl or aryl-C 14 -alkyl, except for the following compounds: N 080 HO H 9Hoe HO& 9A 0 HO 90 0F 9 HO a si...f hci 2eaaa 0 9 ii Il B HO HJ F Y HHO as well as any optical or geometric isomer or tautomr'c form thereof including mixtures of these or a pharmaceuticaly acceptable salt thereo. SUBSTITUTE SHEET 506 2. A compound according to claim 1, wherein R 8 and R 9 independently are hydrogen, halogen, -OH, -NO 2 -NH 2 -CN, -OCF 3 -SCF 3 -CF, -OCH 2 CF 3 -O-C.6-alkyl, C 1 alkyl or phenyl. 3. A compound according to claim 2, wherein R 8 and R 9 independently are hydrogen, halogen, -O-Cl.-alkyl, -NH 2 -CN or -NO 2 4. A compound according to claim 1 of the general formula (II): HO' wherein R 8 is hydrogen, halogen, -O-C-.-alkyl, -NH 2 -CN or -NO 2 and R 9 is hydrogen or halogen. A compound according to any one of the claims 1 to 4, wherein R 4 is hydrogen. 6. A compound according to claim 1 of the formula (III): (Ill) wherein R 8 R 9 R 1 4 R 1 5 K, D and m are as defined in claim 1. SHEET SUBSTITUTE SHEET 507
- 7. A compound according to claim 1 of the formula (IV): ,,14 (IV) wherein R 8 is halogen, and R 9 R 1 4 R 1 5 K, D and m are as defined in claim 1.
- 8. A compound according to claim 1 of the formula wherein R 8 R 9 R 1 4 R 15 K, D and m are as defined in claim 1.
- 9. A compound according to claim 1 of the formula (VI): (VI) HO' wherein R 8 is halogen, and R 9 R 1 4 R' 5 K, D and m are as defined in claim 1. Al~li- cK37 SrLE SUBSTITUTE SHEET 508 A compound according to claim 1 of the formulae (Vlla) or (Vllb): (Vlla) (Vllb) HO' wherein R 8 R 9 R 1 4 R 15 K, D and m are as defined in claim 1. SUBSTITUTE SHEET 509
- 11. A compound according to claim 1 of the formulae (Villa) or (Vlllb): (Villa) (Vlllb) -D -HO R 8 is halogen, and R 9 R 1 4 R 1 5 K, D and m are as defined in claim 1.
- 12. A compound according to any one of the claims 6, 8 and 10, wherein R 8 and R 9 in- dependently are hydrogen, halogen, -OH, -NO 2 -NH 2 -CN, -OCFa, -SCF 3 -CF 3 ,-OCHCF 3 -O-C,-e-alkyl, C,. 6 -alkyl or phenyl.
- 13. A compound according to claim 12, wherein R' and R 9 independently are hydrogen, halogen, -O-C 1 .,-alkyl, -NH 2 -CN or -NO 2
- 14. A compound according to any one of the claims 7, 9 and 11, wherein R 9 is hydro- gen, halogen, -OH, -NO 2 -CN, -OCF 3 -SCF 3 -CF 3 -OCH 2 CF 3 -O-C,-alkyl, Cl.e-alkyl or phenyl. A compound according to claim 14, wherein R 9 is hydrogen, halogen, -O-CI.-alkyl, -NH 2 -CN or -NO 2 SA compound according to any one of the claims 1 to 15, wherein AMENDED SHEf 5004 SUBSTITUTE SHEET 510 R 1 4 and R 1 5 independently are hydrogen, halogen, -CF 3 -OCF 3 -OR 16 -NR1 6 R 17 Cl-6-alkyI, aryl, aryl-C,.-alkyI, -OSO 2 CF 3 -CONR 16 R 7 -CH 2 0R 1 6 -CH 2 NR 16 R'1 7 -OCOR'1 6 or -C0 2 R1 8 or R 1 4 and R 1 5 together form a bridge -OCH 2 O- or -(OH 2 I is 1, 2, 3 or 4, R 1 6 and R 1 7 independently are hydrogen, -OR 1 -S0 2 R 18 O 1 -6-alkyl or aryl, or R 16 and R 1 7 together form a cyclic alkyl bridge containing from 2 to 7 carbon atoms, R' 8 is hydrogen, C 1 .6-alkyl, aryl or aryl-Cl-6-alkyl.
- 17. A compound according to claim 16, wherein R 1 4 and R 15 independently are hydro- gen, halogen, C 1 ,-alkyl, -0-Cl-6-aikyl or aryl. AMENDED SHEE f SUBSTITUTE SHEET 511
- 18. A compound according to any one of the preceding claims, wherein K is selected from the group consisting of 0-(CH2)j-- (CH 2 )b (CH 2 -(CH 2 (CH)- I a d 0 0OR 5 a 4a 4 b o 0 R s 1 0 0 I I 0 0 11 0 0 11 0 -(CH2)j-- -N-(CH 0-(CH 2)b I Sa 2) R 0 -0-(CHA-LN-(CH2)d I 0 0 0 0-(cHA bH2T 0 -0-(CH Ab-0-(CH)d- -0-(CH 2 )-CHR' 0(H2 I A R~b (CH)A -N-(cH 2 )r C RI 5a 0 11 -0-(CH2) -S-(CH2)j- I I 0 AMEN\DED ISHELE-if 5004 SUBSTITUTE SHEET 512 I 5a 2)1- H 2 )b-SO-(CH 2 R 4a R 4 -(CH 2 SO(CH 2 C 004 -0IN~-(CH 2 -0 -(CH 2 Iisa OR 0 N 2) -0-CH)d O- C I sa RR 0 -sa H 2 N -(CH 2 6 -2 0 R~R CHI--ILN2 (CH 2 oR u CH 2 11 N_ (C R 2 (C 2J6 o R41 R 4b OR 5 a 0 (CH 2 CcH )d Ra 0 3 b 0 NaN- 0 W CH-LN2 0 R s IL2 1N/ CH -j 0 )-CH 11LN/ N-R a N- R 5 a AMENDED SHEET 5004 SUBSTITUTE SHEET 513 0 I R 2 1 N CH 2 (C H 2 RI 0 R~ 4a -0 CH2 b I SB C RR RR 0 Rb 0 -CH 11LN-(CH 2 )NcH R b R s 0 RRS 0 0 R3 11LN(CH) 6 (CH (CH). 0 S R a 3 R' 3a R 3 b R 4 R Q -CH-N(CH \)/4(CH 2 )4\(CH 2 and -H N(H2E--C 1Isa 25 b p C q d R Rb R wherein R a Rlb R 4 a, RWb, R a Rlb a, b, c, d, pand qare as defined in claim 1. AMENDED SHEET SUBSTITUTE SHEET 514
- 19. A compound according to claim 18, wherein K is selected from the group consisting of RR 0 R 0 0 11 -o-S-(CH 2 2 )d I I 0 -O--(CH 2 )b-CHR' R Rb -(CH 2 )bo-( 2 )Cr(H)- R -JN-(CH 2 2 IIsa OR 0 0 ISb R 0 R4a 4b 0-(CHA)-s-(cH r.(H) R RS a RR 4a R4 AMENDED SHEET 5004 SUBSTITUTE SHEET 515 CHLN -0-CH 2 1LN o e 0 Rs -0-CrL3 (H N CH--L N'CH)7- -O(CHL 2 R 0 0 a0 -CH 11 N -Ru2) H 1 N 5004 SUBSTITUTE SHEET 516 0 -0-CH2 11 R51 0 R 4a R 4b -(-(CH(CHb 1 2)L- /q (CH 0 R4a R4b -0O-(C b -(CH )C1 i (C 2) Sb RR 0 R 3aR R 3b -0CH- 11 -(CH 2 b- -CH R R R 3aR R 3b R a -CH 1N -(OH \-(CH 2 R 3a R R3b -CHj-N~-(CH 2)b ts~p(CH 2)c OFH), R 3a R R3b R 4a R R4b CHF-N- -(CH2)b /Plf~- (CH2)C j (CH OF- 0 CH2 11 -(CH2)b NN R5b I sa R R 0 N-(CH) N-(CH2)d Sb 0 -N 11 R' a o R R 3 b N-LN-(CH, t fi-- (CH SaS 0 R3a R ~b 0 11 C~~(CH2)b jlC 1 N-(CH) 0 -CH2 N-(CH2) -N-(CH2Rj-a R5b I sa 0 and -CH 2 11 N-(CH 26-- -(CH2)d S b R wherein R 3 a, R 3 b, R4a, R 4 b, RBa, R5b, a, b, c, d, p and q are as defined in claim 1. AMENDED SHEET 5004 SUBSTITUTE SHEET 517 A compound according to claim 19, wherein K is selected from the group consisting I a R H 2 CHR-CHT--N -(CH 2 0 R s 0 0 11 0 a valence bond 0 0 (CH2)2---O I I N- -0-(CHOE--CHR!- 0 0 -0-H 2 0 a R4a R4b O RC R R H -CHF-SO-CR4aR4-b OR~ 0 IN-(CH)-0(CH). OR~ 0 -(CH 2 )bJ-(CH 2 0 1 R 0 -CH2 AMENDED SHEET 5004 SUBSTITUTE SH~EET 0 R a 0Q s -N-CH- o-H- N/ X -C2bN N (H oI a R 0 0 -CH-i liN N-R N-R' AMENcEqD SHEET 5004 SUBSTITUTE SHEE T 519 0 O- 11 NI~ -0H),-CH 2 1 5b 2)E--S-(CH 2,IL O,6 -(C4 R 0 R4 R 4b 0 oX (CH 2)b N -C2 LN-(CH 2)F 5b S RR RR 3 b -0 ('H2 f CH) -N(CH 2)E-N-(CH 24 b b R R R 0 R3 R 3 b 0 Ra R CH"---(CH2)b 1P N-(CHN -N 1 (CH2cE,),CH2lF R~'Sa I 5b I b Ra R 3 b Ra RR o -CH 11 CH2(CH CH2 C N-(C 2)b (CH-S(H2d 'Sa I5b R Rb R 0 and -CH2 11 N-(CH -0-(CH2)d wherein R 3 R 3 b, R 4 R 4 b, R 5 R b, b, C, dp and q are as defined in claim 1.
- 21. A compound according to any one of the claims 18 to 20, wherein R 5 a and R5b independently are hydrogen, C 1 alkyl, -OH, -(CH 2 )kOR 6 a, aryl, aryl-C 1 4 -alkyl, -CH 2 CF 3 -(CH 2 )g-COOR 43 -COOR 43 -(CH 2 )k-CN or -(CH 2 )k-NR 6 aaR6b, g, k, R 43 R" and R6b are as defined in claim 1.
- 22. A compound according to claim 21, wherein g and k independently are 1, 2 or 3, AMENDED SHEET 5004 SUBSTITUTE SHEET 520 and R"b independently are hydrogen, C, 14 -alkyl such as methyl or ethyl, or aryl such as phenyl.
- 23. A compound according to any one of the claims 18 to 22, wherein R 3 a and R 3 b inde- pendently are hydrogen, halogen, -OH, -O-C 1 -6-alkyl, -COO-C, 1 6-alkyl, C 1 -6-alkyl or
- 24. A compound according to any one of the claims 18 to 23, wherein R 4 a and R 4 b inde- pendently are hydrogen, -CN, -CONH 2 -(CH 2 )-N(CH 3 2 -O-Cl-6-alkyl, -CH 2 OH, -CH 2 O-aryl, -N(CH 3 2 -OH, -COO-C 1 .,-alkyl or C 1 _6-alkyl. AMENDED SHEET 5004 SUBSTITUTE SHEET 521 A compound according to any one of the preceding claims, wherein D is hydrogen, R w Y II (CM 2 W F -2'-R2 Rk 28 R w, R28 R 27 R 2 8 R 2 EX R2 F W 28 7 EF G RCH27 R 28 E F-(G)r V y111R28 28 E E R G, ,(CH 2 R' 27 or G28 E l wherein s, r, R 2 7 R 2 11, Q1' E, EF, F, F, G and G' are as defined in claim 1. AMENDED SHEET 5004 SUBSTITUTE SHEET 522
- 26. A compound according to claim 25, wherein D is hydrogen, R v w. Y' E 27 R 2 (CH 2 E F- (G)r V W. R27 R2 R 2 8 F ,(CH 2 R27 or IG R2 F E wherein s, r, R 2 1, R 2 1, Z' E, EF, F, F, G and G' are as defined in claim 1. SUBSTITUTE SHEET 523
- 27. A compound according to claim 26, wherein D is hydrogen, 27 R~ (CH 2 W Q.-I w. Y pR7 X.(CH 2 F R 28 5 R 2 7 R 2 R 28 V E F-(G)r 2 8 G W 28 or G 8 I F E wherein E and E' independently are >0HR 38 >NR 39 or F, G and G' independently are >CHR 38 >0=0 or F' is >CR 38 or and s, r, R 27 R 28 R 3 8 R 39 Q' and W' are as defined in claim 1.
- 28. A compound according to any one of the claims 25 to 27, wherein 0 R' 7 and R 2 independently are hydrogen, halogen such as -CI, -Br or -0CF 3 -0CHF 2 -OCH 2 CF 3 -(CH 2 )YNHC0CF 3 -NHCOCF 3 -ON, -NO 2 -C0R 2 9 -000R 29 -CH 2 )yOR 2 1 or -OR29 wherein R 2 9 is hydrogen, aryl or Cl 1 ,-alkyl and y is 1, 2, 3 or 4, C 1 -6-alkyl such as methyl, ethyl, 2-propenyl, isopropyl, tert-butyl or cyclohexyl, C 1 -,-alkylthio, -SCF 3 Isuch as phenyl, -(CH 2 )yNR'R 3 1 or -NR 9 R 3 1 wherein R 2 and R 3 1 independently are hy- AMEN'DED SHEET 5004 SUBSTITUTE SHEET 524 drogen, -COO-Cl.6-alkyl or C 1 alkyl and y is 1, 2, 3 or 4, or -CONH 2 or R 27 and R 28 together form a bridge R 38 is hydrogen, -OCHF 2 -OR 4 0 wherein R 4 0 is hydrogen or C,.-alkyl, C 1 alkyl such as methyl, isopropyl or tert-butyl, Cl.-alkylthio, -SCF 3 -CH 2 OH, -COO-C.6,-alkyl or -CONH 2 R 39 is hydrogen, Cl. -alkyl, aryl or aryl-C.-alkyl.
- 29. A compound according to any one of the claims 1 to 28, characterized by having a glucagon antagonistic activity as determined by the Glucagon Binding Assay I or Glucagon Binding Assay II disclosed herein corresponding to an ICo value of less than 1 piM, prefera- bly of less than 500 nM and even more preferred of less than 100 nM. A compound according to any one of the claims 1 to 29 for use as a medicament.
- 31. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 1 to 29 together with one or more pharmaceu- tically acceptable carriers or excipients.
- 32. A pharmaceutical composition according to claim 31 in unit dosage form, compris- ing from about 0.05 mg to about 1000 mg, preferably of from about 0.1 mg to about 500 mg such as of from about 0.5 mg to about 250 mg of the compound according to any one of the claims 1 to 29.
- 33. A method of treating type I or type II diabetes, comprising administering to a subject in need thereof an effective amount of A compound of the general formula R8 0 SN B D (I) HO R HO AMENDED SHEET 5004 SUBSTITUTE SHEET 525 R" and R 9 independentiy are hydrogen, halogen, -ON, -CE 3 -CCF 3 -CH 2 OF 3 -NC 2 -CR", -NR"R 1 2 C,-6-alkyl, aryl, -SOF 3 -OHF 2 -CCHF 2 -CSC 2 R"1, -CONR"R' 2 -CH 2 CRI", -OH 2 NR"R 1 2 -00CR", -00 2 R1 3 or -CS0COF 3 or R' and R 9 together form a bridge -OCH 2 O- or -OCH 2 CH 2 C-, R" and R'1 2 independently are hydrogen, -OR' 3 -SC 2 R'1 3 C, alkyI or aryl, R 13 is hydrogen, O,-,-alkyl, aryl-0 14 6-alkyl or aryl, R' is hydrogen or C,,-alkyl, B is R14 15 i R 1~ R 1 or R 1 4 and R' 5 independently are hydrogen, halogen, -ON, -CF 3 -OCH 2 )]0F 3 -NC 2 -CR'1 6 -NR1 6 R 1 7 Ol,-alkyl, aryl, aryl-CO 1 alkyl, -SOF 3 -SR 1 6 -OHF 2 -CHF 2 -CF 2 OHF 2 -CS0COF 3 -ONR1 6 R 1 7 -(0H 2 )ICCNR1 6 R 17 -OCH 2 )ICCNR1 6 R 1 7 -(CH 2 ),CCR 1 6 -(0H 2 ),CCR' 6 -(0HA) 1 -OCH 2 )COR'8, -(0H 2 ),NR' 6 R 7 -OCH 2 1 NR 6 R 1 7 -CCR 6 -CC 2 -OCH 2 )0 2 R 1 8 -OCH 2 ),0N or -OCH 21 01, or R'1 4 and R' 5 together form a bridge -OCH 2 1 C- or -(OH 2 I is 1, 2, 3 or 4, R1 6 and R 1 7 independently are hydrogen, -OR, -SC 2 R, ,C,-alkyl or a ryl, or R' 6 and R 17 ~te form a cyclic alkyl bridge containing from 2 to 7 carbon atoms, AMENDED SHEET SUBSTITUTE SHEET 526 R" 8 is hydrogen, Cl 1 ,-alkyI, aryl or aryI-C 1 -,-alkyl, W is or C9= Y is or -R= Z is or -R1 V is or R 19 R 20 R 2 1 and R22 independently are hydrogen, halogen, -CN, -OF 3 -OCF 3 -OCH 2 CF 3 -NO 2 -OR 24 -NR 2 Cl 1 ,-alkyI, aryl, aryl-Cl-6-alkyl, -SCF 3 -SR 2 1, -CHF 2 -OCHF 2 -OCF 2 CHF 2 -OSO 2 CF 3 -00NR 4 R 2 -0H 2 00NR 4 R, -00H 2 00NR 4 R, -CH 2 0R 24 -CH 2 NR 24 R 25 -00CR 24 or -C0 2 R 24 or R 19 and R 2 1, R 20 and R 21 or R 21 and R' together form a bridge -OCH 2 O-, R 2 4 and R 25 independently are hydrogen, -C0R 26 -S0 2 R 2 1, C 1_-alkyl, aryl or aryl-C 14 ,-alkyl, R 2 is hydrogen, C,6-alkyl, aryl or aryl-C, 1 alkyl, K is R 3 2 R 3 b R V e 1 (CH 2 (0H 2 )C (CH 2 )d R 3 a, R 3 b, R 4 a and R 4 b independently are hydrogen, halogen, -ON, -OF 3 -OCF,, -OCH 2 CF 3 -NO 2 -OR 24 a, NR 24 a R 25 a, C, 1 6-alkyl, aryl, aryl-C, 14 -alkyl, -SCF 3 -SR 24 -CHF 2 -OCHF 2 -OCF 2 CHF 2 -OSO 2 CF 3 -CONR 4 R 2 -CH 2 CONR 4 R 2 -OCH 2 C0NR 4 R 5 -CH 2 0R 2 a CHN 24 aR 25 a, -0 24 or a R 24 a and R 2 5a independently are hydrogen, -COR 26 a 1 -SO 2 R 2 6a, C 1 -6-alkyl, aryl or aryl-Cl-6-alkyl, k,2 is hydrogen, 0 14 6-alkyl, aryl or aryl-C 14 6-alkyl, z Tt 5004 SUBSTITUTE SHEET 527 or R 3 a and R 3 1, R 4 a and R 4 1, or R 3 and R 4 1 together form a bridge -(OH 2 1 is 1, 2, 3 or 4, a, b, c and d independently are 0, 1, 2, 3 or 4, e, f and p independently are 0 or 1, q is 0, 1 or 2, L and M independently are -CH=CH-, -CC- -NRla_, CH 2 NRla_, -000-, -COO-, -CONR 5a_, .CONR 5b_ -NR 1aCO_, -SO 2 _OS02_, _SO 2 NR Sa_, -NR5a S0 2 -NR 5 aCONR 5 CONR 5 aNR 5b_ -NR 5 aCSNR 5 -OCONR 5 -CH 2 CONR 5b_, -OCH 2 CONR 5 b_, R -NR 5 aC(O)O_ or and R lb independently are hydrogen, C 1 -6-alkyI, -OH, -(CH 2 )k-OR~a, -COR 6 a, -(CH 2 )k-CH(OR 6 a) 2 -(CH 2 )k-CN, -(CH 2 )k-NR 6 'R 6 b aryl, aryI-Cl-6-alkyl, -(CH 2 )g-COOR 4 1 or -(CH 2 )g-CF 3 k is 1, 2, 3 or 4, R 6 a and R 6b independently are hydrogen, C 1 -,-alkyl, aryl or aryl-C 14 ,-alkyl, g isO0, 1, 2, 3 or 4, R 4 1 is hydrogen or C 1 -6-alkyl, G" is -OCH 2 00-, -CH 2 00-, -CO- or a valence bond, AMENDED SHEET 5004 SUBSTITUTE SHEETi 528 E" is -OH 2 -CH 2 CH 2 -CH=CH-, -CH 2 NH- or -CH 2 CH 2 N H-, m is 0 or 1, D is hydrogen, R 27 28 r R RFe w\,Q.Yl (CH 25 Y 28 R 2 FE: R C27 E FV R 2 8 Q, G EF RG2 E FP R 28 R' 27 or G 2 E VI AMENDED SHEET SUBSTITUTE SHEET 529 r is 0 or 1, s is 0, 1, 2 or 3, E, F, G and G' independentiy are -CHR 38 >NR 39 or F is >CR 3 1_ or Y' is or -0R 32 Z' is or -0R 3 V is or -R= Wis or -0R 35 Q' is -N R 3 or R 27 R 28 R 32 R 33 R34and R' independently are hydrogen, halogen, -ON, -OF 3 -0(CH 2 )yCF 3 -(CH 2 )YNHC0OF 3 -NO 2 C, 1 ,-alkyl, aryl, aryl-O 1 -6-alkyl, -SCF 3 -SR 29 -CHF 2 -OCHF 2 -OCF 2 CHF 2 -0S0 2 R 9 -0S0 2 CF 3 -(OH 2 )yOONR 29 R 30 -O(OH 2 )yCONR 9 R 30 -(CH 2 )yOR 29 -(OH 2 )yNR 29 R 30 -OCOR', -00R 2 1 or -C0 2 R' 9 or R 27 and R 2 1, R 32 and R 33 RI and or R' and R 3 1 together form a bridge -O(CH 2 )YO-, y is 0, 1, 2, 3or 4, R 2'and R 3 1 independently are hydrogen, -00R 31 -C0 2 R 31 -S0 2 R 31 O 1 ,-alkyl, aryl or aryl- C 1 -6-alkyl, hydrogen, C, 1 6-alkyl, aryl or aryi-C0 14 -alkyl, AMENDPD SHEET SUBSTITUTE SHEET 530 R 3 6 and R 3 9 independently are hydrogen, C, -alkyl, aryl or aryl-Cl-alkyl, R 38 is hydrogen, -OR 40 -NR 4 0 R 41 C 1 alkyl, aryl, aryl-C 1 alkyl, -SCF,, -SR 4 0 -CHF 2 -OCHF 2 -OCF 2 CHF 2 -CONR 4 0 R 41 -(CH 2 )xCONR 40 R 41 -O(CH 2 )xCONR 40 R 41 -(CH 2 )xOR 4 0 -(CH 2 )xNR 4 0 R 41 -OCOR 4 0 or -C0 2 R 4 0 x is 1, 2, 3 or 4, R 4 0 and R 41 independently are hydrogen, -COR 42 -S0 2 R 42 C1 -alkyl, aryl or aryl-C,--alkyl, R 4 2 is hydrogen, C 1 alkyl, aryl or aryl-C,--alkyl, as well as any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof or a compound according to any one of the claims 1 to 29
- 34. A method of treating hyperglycemia, comprising administering to a subject in need thereof an effective amount of a compound as defined in claim 33. A method of lowering blood glucose in a mammal, comprising administering to said mammal an effective amount of a compound as defined in claim 33.
- 36. The method according to any one of the claims 33 to 35 comprising administering to a subject in need thereof an amount of the compound as defined in claim 33 in the range of from about 0.05 mg to about 1000 mg, preferably of from about 0.1 mg to about 500 mg such as of from about 0.5 mg to about 250 mg one or more times per day such as 1 to 3 times per day.
- 37. Use of a compound as defined in claim 33 for the manufacture of a medicament for treating type I or type II diabetes. a Use of a compound as defined in claim 33 for the manufacture of a medicament for o -531
- 39. Use of a compound as defined in claim 33 for the manufacture of a medicament for lowering blood glucose in a mammal. A compound of general formula O 8 R N B (K)m D (I) H k HOH H• ,R 9 substantially as herein described with reference to any one of the examples but excluding comparative examples.
- 41. A pharmaceutical composition comprising, as an active ingredient, at least one 5. compound according to any one of the claims 1 to 29 together with one or more pharmaceutically acceptable carriers or excipients, substantially as herein described with S reference to any one of the examples but excluding comparative examples.
- 42. A method of treating type I or type II diabetes, substantially as herein described with reference to any one of the examples but excluding comparative examples. SO too*
- 43. A method of treating hyperglycemia, substantially as herein described with ease o° reference to any one of the examples but excluding comparative examples. 0 00o@ 15 44. A method of lowering blood glucose in a mammal, substantially as herein e..o e: described with reference to any one of the examples but excluding comparative 4*0&0 examples. Use of a compound as defined in claim 33 for the manufacture of a medicament for treating type I or type II diabetes, substantially as herein described with reference to any one of the examples but excluding comparative examples.
- 46. Use of a compound as defined in claim 33 for the manufacture of a medicament for treating hyperglycemia, substantially as herein described with reference to any one of the examples but excluding comparative examples. -532-
- 47. Use of a compound as defined in claim 33 for the manufacture of a medicament for lowering blood glucose in a mammal, substantially as herein described with reference to any one of the examples but excluding comparative examples. DATED this 14 th Day of March 2002 NOVO NORDISK A/S and AGOURON PHARMACEUTICALS, INC. Attorney: JACINTA FLATTERY-O'BRIEN Registered Patent Attorney of The Institute of Patent and Trade Mark Attorneys of Australia of BALDWIN SHELSTON WATERS
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| US08/886785 | 1997-07-01 | ||
| US3251698A | 1998-02-27 | 1998-02-27 | |
| US09/032516 | 1998-02-27 | ||
| PCT/DK1998/000287 WO1999001423A1 (en) | 1997-07-01 | 1998-06-30 | Glucagon antagonists/inverse agonists |
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| AU7908398A AU7908398A (en) | 1999-01-25 |
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| US3836580A (en) * | 1971-07-01 | 1974-09-17 | American Home Prod | 2,6-dichlorobenzylidenehydrazides |
| US3746703A (en) * | 1971-07-01 | 1973-07-17 | American Home Prod | 2,6-dichlorobenzylidenehydrazides |
| US3859281A (en) * | 1971-07-01 | 1975-01-07 | American Home Prod | 2,6-dichlorobenzylidenehydrazides |
| US4334015A (en) * | 1979-05-23 | 1982-06-08 | Minnesota Mining And Manufacturing Company | Imaging compositions |
| DE4033808A1 (en) * | 1990-04-11 | 1991-10-17 | Bayer Ag | NAPHTHALINE DERIVATIVES |
| JPH04121717A (en) * | 1990-09-12 | 1992-04-22 | Fuji Photo Film Co Ltd | Novel organic nonlinear optical material and method for converting light wavelength by using this material |
| JP3529491B2 (en) * | 1995-05-16 | 2004-05-24 | 旭電化工業株式会社 | Thermal recording material |
| AU702887B2 (en) * | 1995-10-31 | 1999-03-11 | Merck & Co., Inc. | Substituted pyridyl pyrroles, compositions containing such compounds and methods of use |
-
1998
- 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
- 1998-06-30 JP JP50616099A patent/JP2003514508A/en active Pending
- 1998-06-30 AU AU79083/98A patent/AU749271B2/en not_active Ceased
- 1998-07-01 CN CN98808125A patent/CN1267281A/en active Pending
- 1998-07-01 PL PL98337781A patent/PL337781A1/en unknown
- 1998-07-01 KR KR1019997012562A patent/KR20010020590A/en not_active Application Discontinuation
- 1998-07-01 IL IL13337798A patent/IL133377A0/en unknown
- 1998-07-01 HU HU0002373A patent/HUP0002373A3/en unknown
- 1998-07-01 EP EP98929244A patent/EP0994848A1/en not_active Withdrawn
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1999
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| EP0994848A1 (en) | 2000-04-26 |
| NO996550L (en) | 2000-02-29 |
| HUP0002373A2 (en) | 2000-10-28 |
| HUP0002373A3 (en) | 2000-11-28 |
| WO1999001423A8 (en) | 1999-05-14 |
| KR20010020590A (en) | 2001-03-15 |
| JP2003514508A (en) | 2003-04-15 |
| WO1999001423A1 (en) | 1999-01-14 |
| CN1267281A (en) | 2000-09-20 |
| AU7908398A (en) | 1999-01-25 |
| PL337781A1 (en) | 2000-09-11 |
| IL133377A0 (en) | 2001-04-30 |
| NO996550D0 (en) | 1999-12-29 |
| BR9810378A (en) | 2000-08-29 |
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