Deprecated: The each() function is deprecated. This message will be suppressed on further calls in /home/zhenxiangba/zhenxiangba.com/public_html/phproxy-improved-master/index.php on line 456
AU781849B2 - Inhibitors of IL-12 production - Google Patents
[go: Go Back, main page]

AU781849B2 - Inhibitors of IL-12 production - Google Patents

Inhibitors of IL-12 production Download PDF

Info

Publication number
AU781849B2
AU781849B2 AU56074/00A AU5607400A AU781849B2 AU 781849 B2 AU781849 B2 AU 781849B2 AU 56074/00 A AU56074/00 A AU 56074/00A AU 5607400 A AU5607400 A AU 5607400A AU 781849 B2 AU781849 B2 AU 781849B2
Authority
AU
Australia
Prior art keywords
compound
heteroaryl
aryl
alkyl
halo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU56074/00A
Other versions
AU781849C (en
AU5607400A (en
Inventor
Beatrice Brunkhorst
Stephen Gillies
Mitsunori Ono
Nha Huu Vo
Yumiko Wada
Tadeusz Warchol
Wojciech Wrona
Dan Zhou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synta Phamaceuticals Corp
Original Assignee
Synta Phamaceuticals Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synta Phamaceuticals Corp filed Critical Synta Phamaceuticals Corp
Publication of AU5607400A publication Critical patent/AU5607400A/en
Assigned to SYNTA PHARMACEUTICALS CORP. reassignment SYNTA PHARMACEUTICALS CORP. Alteration of Name(s) of Applicant(s) under S113 Assignors: SHIONOGI BIORESEARCH CORP.
Publication of AU781849B2 publication Critical patent/AU781849B2/en
Application granted granted Critical
Publication of AU781849C publication Critical patent/AU781849C/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
    • C07D251/52—Two nitrogen atoms with an oxygen or sulfur atom attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Oncology (AREA)
  • Psychiatry (AREA)
  • Communicable Diseases (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

INHIBITORS OF IL-12 PRODUCTION 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.
Cytokines such as interleukin-12 (IL-12) mediate the acute phase response to inflammatory stimuli, enhance the microbicidal functions of macrophages and other cells, o* 10 and promote specific lymphocyte responses. See, Fearon and Locksley, Science 272:50(1996).
Recently, in vivo studies revealed that inhibition of IL-12 production has therapeutic effects against inflammatory disorders such as sepsis (Zisman et al., Eur. J. Immunol.
27:2994 (1997)), collagen induced arthritis (Malfait et al., Clin. Exp. Immunol. 111:377 15 (1998)), established colitis Patent No. 5,853,697), experimental autoimmune 9 encephalomyelitis (Leonard et al., J. Exp. Med. 181:381 (1995)), experimental autoimmune uveoretinitis (Yokoi et al., Eur. J. Immunol. 27:641 (1997)), psoriasis (Turka et al., Mol.
Med. 1:690 (1995)), and cyclophosphamide induced diabetes (Rothe et al., Diabetologia 40:641 (1997)).
Production of IL-12 can be inhibited by anti-IL-12 antibodies. However, long term treatments of chronic diseases with such antibodies are expensive. Also, antibodies can be unstable after administration. Thus, there exists a need for use of small non-protein compounds instead of anti-IL-12 antibodies to inhibit the production of IL-12.
WO 00178757 WO 0078757PCT/USOO/16094 Sumrmary of the Invention An aspect of this invention relates to a compound of formula M:) Cz~ X is triazinyl. LI is in which is (C or -N (Rb) and is (CH (Rc) or a bond. Each of Ra and Rc, independently, is hydrogen, al~kyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. R b is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. Each of m and n, independently, is 1-8. W is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which being optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy. L 2 is in which A2 is a bond, -N or (R2 and B2 is a bond, -N=C(R 4 C (Rs) C (R 6 =C (M 7 -N (R 8 _N (R 9 -N (RIO) C (R11) (R12)- -0-C (R 4 CO0-C (R1 (R1 6 CO -N (R 7 -N (R 9
-CO-,
-2 wo oon8757 WO 00/8757 CiIUSOOii 6094
-S-C(R
9
(R
2 0 -CS-C(R 21
(R
22
-CS-
N (R 23 -N (R 2 -CS- -So 2 provided that -A 2
-B
2 cannot be a bond. -A 2
-B
2 together is (cH 2 q-0- r- (NR5 (C O) or (R16) (R 2 Each of R 1 R 2
R
3 R4, Rs, R 6
R
7 R8, R 9 RIO, R1 2
R
13
R
1 4 R's, R 16 1 R 17
R'
8
R
19 1 R 2 0
R
2 1, R 22
R
23
R
24
R
25
R
26 and R 27 independently, is hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Each of p, q, r, S, t, u, and v, independently, is 1, 2, or 3. Y is wherein RI is a bond, or cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which optionally being substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonyl amino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, or alkoxycarbonylimino. L' is a bond,
-N(R
28 f -N (R 2 9 -CO- -CO-N (R 3 0 -CO-0- or -0- CO-. Each of R 28
R
29 and R 30 independently, is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. R" is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which being optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, forrnyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy. Z is morpholinyl which is optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, -3 WO 00/78757 WO 0078757PC'T/USOO/16094 amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy.
Another aspect of this invention relates to a method of inhibiting IL-12 production, which includes administering to a patient in need thereof an effective amount of a compound of formula MI, supr-a- X is triazinyl. Li is in which is (CH(Ra))~ or -N (Rb) and -Bl- is (CH or a bond.
Each of Ra and Rc, independently, is hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thicalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. Rb is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. Each of m and n, independently, is 1-8. W is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, each of which being optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy. L2 is -A 2
-B
2 in which A 2 is a bond, or (R 2
(R
3 and B 2 is a bond, -C CRs) -CR6) -C CR7) -N (RB) =N CR 9 -N CR"0)-C CR") CR1 2 -0-C CR' 3 CR4) -CO-C CR1 5 -CO-N CR"7) -N (RIB) -co-, -CO-S-,I -S-C (R' 9
(R
20 -CS-C (R 21
CR
22 -4 wo oon8757 WO 0078757PCT/USOOII6O94 -CS-N (R 23 -N (R 24 -CS- -CS- -S provided that -A 2 -B3 2 cannot be a bond. -A 2
-B
2 together is (CH 2 q- (R 2 5) -(CH or
(R
26 (CH 2
)-NCR
27 Each of RI, R 2
R
3
R
4 R5, R 6
R
7 R8, R 9 RID, R 11 R1 2
R
1 3, R1 4 R1 5
R
16
R
17
R
18 R1 9
R
20 R21, R 22
R
23
R
24
R
2 5, R 26 and R 27 independently, is hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Each of p, q, r, s, t, u, and v, independently, is 1, 2, or 3. Y is wherein RI is a bond, or cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, or alkoxycarbonylimino. L' is a bond, -NCR 28
-N(R
2 9
-CO-N(R
30 or Each of R 28
R
29 and R'3 0 independently, is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. R" is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, each of which optionally being substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy. Z is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which being optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, -6thioalkyl, cyano, nitro, alkylcarbonylamino, alkylam-inocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy.
According to a first aspect, the present invention provides a compound of the following formula: w Lx z wherein X is 1,3,5-triazinyl; L' is -A in which is -(CH(R or -N(R and -B3 is or a bond, each of R a and independently, being hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, am-inoalkyl, thio, mercaptoalkyl, *cyano, nitro, alkylcarbonylam-ino, alkylam-inocarbonyl, formyl, alkylcarbonyl, *alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, cycloalkyl, heterocycloalkyl, aryl, 15 aralkyl, heteroaryl, or heteroaralkyl; R b being hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and each of m and n, independently, being W is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, 20 mercaptoalkyl, cyano, nitro, alkylcarbonylan-ino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; L L 2 is -A 2 -13 2 in which A 2 is a bond, or 2 and B2 is a bond, 4 -C(R 5 -C(R -N(R 8 -N(R 0 -O-C(R 3 14
-CO-C(R'
5 -N(R -S-C(-kR' 9
)(R
20 2
)(R
2 -4(R 23
-(R
24
-C-
-S02-, provided that -A 2-B 2_ cannot be a bond; or -A 2-B 2_ is N(R 2)-(CH 2 or 26
)-(CH
2 each of R1, R 2, R 3, R 4, R 5, R 6, R 7,R8 9 10 11 12 13 14 15 16 17 IS 19 20 21 22 23 24 25 26 R9,R R R R R R ,R ,R ,R8,R R R R R R R R 6 and R 27 independently, being hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and each of p, q, r, s, t, u, and v, independently, being 1, 2, or 3; 6a Y is wherein R' is a bond, or cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, or alkoxycarbonylimino; L' is a bond, -N(R28)-, -N(R29)-CO-, -CO-N(R30)-, or each of R 28
R
29 and R' 30 independently, being hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and R" is heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; and Z is morpholinyl optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; or a salt thereof.
According to a second aspect, the present invention provides a method of inhibiting IL-12 production, comprising administering to a patient in need thereof an effective amount of a compound of the following formula: I I L
L
W X Y
Z
wherein X is 1,3,5-triazinyl; L' is in which is or and is (CH(Rc))n- or a bond, each of Ra and RC, independently, being hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, aikylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Rb is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and each of m and n, independently, is 1-8; 6b W is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylc arbonyl amino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; L' is -A -B 2 in which A 2is a bond, or 2
)(R
3 and B 2is a bond, 4
-C(R
5 -C(R 6
)=C(R
7
-N(R
8 9
-N(R'
0 )-C(Rl 1)(R 12 -O-C(R 3 1 4 -CO-C(R 1)(R 1 6
-CO-N(R'
7 -N(R -S-C(R -CS-C(R 21 2 2 -CS-N(R 2 -N(R 24 -S02-, provided that -A 2-B 2_ cannot be a bond; or -A 2-B 2_ *is -(0O(CH2)qO)r-, (N(R )-(CH 2 )sCO-)t, or 2)-(CH 2 each *2 3 4 5 6 7 8 9 1 I 12 13 14 15 16 17 18 19 20 21 of R, R R ,R ,R ,R R ,R R ,R ,R 22 23 24 2 2 :R R R k25 R 26 andR R, independently, being hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, am-inoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and each of p, q, r, s, t, u, and v, independently, being 2, or 3; Y is wherein R' is a bond, or cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, :alkoxycarbonyl, alkylcarbonyloxy, or alkoxycarbonylimino; L' is a bond, -N(R 2 -N(R -CO-N(R or each of R 2, R 29, and R" independently, being hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or hleteroaralkyi; and R" is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, araikyl, or heteroaralkyl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; and Z is morpholinyl optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptooalkyl, cyano, nitro, -6c alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; or a salt thereof.
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".
Set forth below are exemplary of compounds of this invention: [52
.H
o Y O N
N
*o u o* gJQH,
N
f
'.-IN
OCH
wo 00178757 CIS I 69 PCT/USOO/16094 0 S, 9 0
H-
c 0
N
NN
cl H InHICq.OCH 0 I0 N0 (0 7- 8- N
Y
0 0 H 61 0? (0 H
N
N
N 0ol H l l 00 C-t, N H (0
N
0O)CH KN2 H~ NN 00 N N Lr N N
H
V6O91IOOSflLJ LLUOO LSLSLIOO OM -6 IHD)o I N -N N N~ N
NN
N N N< 0 N LZ C-0
N
t'6O91IOOSflJJd LLUOO LSLSLIOO om WO 00/78757 PCT/US00/16094 A pharmaceutically acceptable salt of a compound of formula is also within the scope of this invention.
For example, a salt can be formed between a negatively charged substituent such as carboxylate and a positively charged counterion such as an alkali metal ion a sodium ion or a potassium ion); an alkaline earth metal ion a magnesium ion or a calcium ion); an ammonium ion or an organic ammonium group such as tetramethylammonium ion or diisopropylethyl-ammonium ion.
As another example, if an amino substituent can form a salt with a negatively charged counterion. Suitable counterions include, but are not limited to, chloride, hydrochloride, bromide, iodide, sulfate, nitrate, phosphate, or acetate.
As used herein, alkyl is a straight or branched hydrocarbon chain containing 1 to 12 carbon atoms.
Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tert-butyl, n-pentyl, 2-methylhexyl, 3-ethyloctyl, and 4-ethyldecyl.
The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2 to 12 carbon atoms and one or more 1-6) double bonds. The term "alkynyl" also refers to such a hydrocarbon chain, except that the chain contains one or more triple bonds instead of double bonds. Some examples of alkenyl and alkynyl are allyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-butynyl, 2-pentynyl and 2-hexynyl.
By cycloalkyl is meant a cyclic alkyl group containing 3 to 8 carbon atoms. Some examples of cycloalkyl are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl. Heterocycloalkyl is a cycloalkyl group containing 1-3 heteroatoms such as 10 WO 00/78757 PCT/US00/16094 nitrogen, oxygen, or sulfur. Examples of heterocycloalkyl include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, and morpholinyl.
Cycloalkenyl is a cycloalkyl group containing one or more 1-3) double bonds. Examples of such a group include cyclopentenyl, 1,4-cyclohexadienyl, cycloheptenyl, and cyclooctenyl groups. By the same token, heterocycloalkenyl is a heterocycloalkyl group containing one or more double bonds.
As used herein, aryl is an aromatic group containing 6-12 ring atoms and can contain fused rings, which may be saturated, unsaturated, or aromatic. Examples of an aryl group include phenyl, naphthyl, biphenyl, phenanthryl, and anthracyl. Heteroaryl is aryl containing 1-3 heteroatoms such as nitrogen, oxygen, or sulfur and can contain fused rings. Some examples of heteroaryl are pyridyl, furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, and benzthiazolyl.
A cyclic moiety can be cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl.
A
tricyclic moiety is a fused ring formed from three of the just-mentioned moieties. An example of a tricyclic moiety is dibenzocycloheptenyl. Heteroatoms such as nitrogen, oxygen, and sulfur can be included in the cyclic moiety.
An amino group can be unsubstituted, monosubstituted, or di-substituted. It can be substituted with groups such as alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Halo refers to fluoro, chloro, bromo, or iodo.
Compounds of this invention show an unexpected high level of potency in inhibiting the production of IL-12.
11 I WO oon78757 PCT/US00/16094 Other features or advantages of the present invention will be apparent from the following detailed description of several embodiments, and also from the appending claims.
Detailed Description of the Invention A compound of formula can be prepared in a stepwise manner by using cyanuric chloride as a starting material. Cyanuric chloride is commercially available.
The three chloro groups of cyanuric chloride can be successively displaced by various nucleophilic substituents. The order of displacement is not of particular importance. For example, a chloro group of cyanuric chloride can be substituted with a nucleophile W-BI-A'-H wherein A 1 is or and W and BI have been defined above, thus forming an ether linkage. Below is an example of a displacement reaction in which the nucleophile is phenethyl alcohol A' is B 1 is -CH 2
-CH
2 and W is phenyl):
C
1
OH
Cl CI N N N N N N,N-Dimethylacetamide C1 N Cl CH 2
CI
2 reflux CI N O A compound of formula wherein A' is (Ra and m have been defined above) can be prepared by first converting cyanuric chloride to an organometallic compound of group IA or IIA metal, a Grignard reagent. The organometallic compound acts as a 12 WO 00/78757 PCTIUSOO016094 nucleophile and reacts with a compound with a good leaving group, an alkyl halide, to form a carboncarbon linkage.
A chloro group of cyanuric chloride can also be displaced by a nucleophile ZH (Z has been defined above), morpholine, to form a morpholinyl triazine compound as shown in the following reaction (see, Step (2) of Example 1 for details): C1 H CI
N
C N C C N N CI N Cl DIEA, CH2O°C ,A* A chloro group of cyanuric chloride can undergo yet another displacement reaction with a nucleophile H-A 2
-B
2
-Y
wherein A 2 is an amine and B 2 is a bond to form an amino linkage between the triazine ring and the nucleophile.
Some examples of such an amine include 3-aminocarbazole, 6-aminobenzofuran, and 4-(3-methylphenyl)aniline. See, Step of Example 5. On the other hand, as shown in the following reaction, if the desired linkage -A-Bis -NH-N=CH-, the chloro group can be first displaced by hydrazine, and the primary amine of the coupled hydrazine moiety can then react with an aldehyde to form an imine linkage: 13 WO 00/78757 PCT/US00/16094
CI
N N CI N
NH
2
NH,
EtOH
H
CHO
EtOH, HOAc, reflux
CI
N^N
Cl N NHNH 2 Cl N N Cl' N
N
A compound of formula wherein the linkage -A 2
-B
2 is a carbon-carbon linkage can be formed, via an organometallic intermediate described above and further reacting such an intermediate with a nucleophile.
Other types of linkages can be prepared by similar nucleophilic reactions. Sensitive moieties on both the triazinyl intermediates and the nucleophiles can be protected prior to coupling. For suitable protecting groups, see, Greene, T. Protective Groups in Organic Synthesis, John Wiley Sons, Inc., New York (1981).
A compound of formula prepared by the methods shown above can be purified by flash column chromatography, preparative high performance liquid chromatography, or crystallization.
A pharmaceutical composition containing an effective amount of one or more compounds of this invention for 14 WO 00/78757 PCT/USOO/16094 inhibiting IL-12 production or treating an IL-12 mediated disorders is also within the.scope of this invention.
Some examples of IL-12 mediated disorders include sepsis and autoimmune disorders, rheumatoid arthritis, Crohn's disease, psorasis, and multiple sclerosis. The use of a compound of this invention or a salt thereof for the manufacture of a medicament for inhibiting IL-12 production or treating the above-mentioned IL-12-mediated disorders is also within the scope of this invention.
Still another aspect of this invention is a method of treating an IL-12-mediated disorder, sepsis, by administering to a patient a pharmaceutical composition containing an effective amount of a compound of this invention or a salt thereof. An effective amount is defined as the amount which is required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep. 1966, 50, 219. Body surface area may be approximately determined from height and weight of the patient. See, Scientific Tables, Geigy Pharmaceuticals, Ardley, New York, 1970, 537. An effective amount of a compound of this invention can range from about 0.1 mg/kg to about 100 mg/kg. Effective doses will also vary, as recognized by those skilled in the art, dependant on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments such as the use of other antiinflammatory agents.
The pharmaceutical composition may be administered via the parenteral route, including orally, topically, 15 WO 00/78757 PCTIUS00/16094 subcutaneously, intraperitoneally, intramuscularly, and intravenously. Examples of parenteral dosage forms include aqueous solutions, isotonic saline or 5% glucose of the active agent, or other well-known pharmaceutically acceptable excipient. Solubilizing agents such as cyclodextrins, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compounds.
A compound of this invention can be formulated into dosage forms for other routes of administration utilizing conventional methods. For example, it can be formulated in a capsule, a gel seal, or a tablet for oral administration. Capsules may contain any standard pharmaceutically acceptable materials such as gelatin or cellulose. Tablets may be formulated in accordance with conventional procedures by compressing mixtures of a compound of this invention with a solid carrier and a lubricant. Examples of solid carriers include starch and sugar bentonite. A compound of this invention can also be administered in a form of a hard shell tablet or a capsule containing a binder, lactose or mannitol, a conventional filler, and a tableting agent.
The biological activities of a compound of this invention can be evaluated by a number of cell-based assays. One of such assays can be conducted using mononuclear cells from human peripheral blood (PBMC).
Human Interferon gamma (IFN-y) and lipopolysaccharide are added to the cell-containing solutions to induce IL-12 production. A solution containing a compound of this invention is added to each well. The level of inhibition of IL-12 production can be measured by determining the amount of P70 IL-12) by using a sandwich ELISA 16 WO 00/78757 PCT/US00/16094 assay with anti-human IL-12 antibodies. ICS 0 of each test compound can then be determined and potent compounds are selected for further testing.
The selected compounds can be further assayed in parallel on two types of cells, PBMC and human leukemia mononuclear cell line (THP-1), for verification. More specifically, each test compound is added to a well of stimulated PBMC or THF-1 cells. PBMC are stimulated by a combination of IFN-y and LPS, and THP-1 cells are stimulated by a combination of IFN-y and pansorbin. The amount of P70 present in each well is then measured using a sandwich ELISA with anti-human IL-12 antibodies and IC 0 is determined for each test compound.
The cytotoxity of the test compounds of this invention can be determined by using a bioreductive assay. Specifically, PBMC and THP-1 cells are incubated with the test compounds. Viability are evaluated by the ability of mitochondrial dehydrogenases of the incubated cells to reduce 3-(4,5-dimethylthiazole-2-yl)-5-(3carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) in the presence of phenazine methosulfate (PMS).
Compounds of this invention can also be evaluated by animal studies. One of such studies involves the ability of a test compound to inhibit septic shock. Animals are injected with LPS to induce septic shock. Mortality rate of the induced animals is monitored after administering to the animals a test compound and compared with that of a control experiment in which the induced animals are not treated.
The following specific examples, which describe syntheses and biological testings of compounds of this invention, are to be construed as merely illustrative, 17 WO 00/78757 PCT/US00/16094 and not limitative of the remainder of the disclosure in any way whatsoever.
In the following examples, 1 H nuclear magnetic resonance spectra were recorded on a Varian Mercury 300 MHz spectrometer. ES mass spectra were recorded on a Finnigan Navigator mass spectrometer.
Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. The following specific examples, which described syntheses, screening, and biological testing of various compounds of this invention, are therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications recited herein, including patents, are hereby incorporated by reference in their entirety.
Example 1 Preparation of compound 1 Step Cyanuric chloride (18.7 g, 0.10 mol) was added to a solution of methylene chloride (100 mL). Phenethyl alcohol (12.2 g, 0.10 mol) and N,N-dimethyacetamide (26.1 g, 0.30 mol) were then added after cyanuric chloride was dissolved. The reaction mixture was refluxed for hours, cooled to room temperature, diluted with methylene chloride (100 ml), washed with water (100 ml, 3 times), dried over MgSO and then filtered.
Step Morpholine (8.70 g, 0.10 mol) and diisopropylethylamine (12.9 g, 0.10 mol) were dissolved in 20 ml methylene chloride and added dropwise into the filtrate from step at 0oC. The reaction was 18 WO 00/78757 PCTIUS00/16094 monitored by TLC (EtOAc:Hexane, After the product was formed, the reaction mixture was washed with IN HC1 ml, 3 times), saturated NaHCO 3 (50 ml), brine (50 ml), then dried over MgSO The solvent was removed under reduced pressure. The crude residue was recrystallized from acetone/water solution to give 20.5 g of the desired triazine monochloride intermediate.
Step (3) The triazine monochloride intermediate (20.0 g, 0.062 mol) was dissolved in 100 ml ethanol and added dropwise to a solution of hydrazine monohydrate (25.0 g, 0.62 mol) in ethanol (50 ml). The mixture was stirred at room temperature for 30 minutes before 20 ml water was added. Excess ethanol was then removed under reduced pressure and the desired triazinyl hydrazine precipitated out which was collected by filtration and washed with water.
Triazinyl hydrazine (316 mg, 1.0 mmol) and indole 3carboxylaldehyde (145 mg, 1.0 mmol) were added to 5 ml methanol and warmed to form a homogeneous solution. Two drops of glacial acetic acid was then added. After the reaction mixture was allowed to stand at room temperature for 10 hours, the product precipitated which was then filtered, washed with methanol, and dried under reduced pressure to yield compound 1 (395 mg, 'H NMR
(CD
3 COCD 8.34 (bd, 1, 8.28 7.60 1), 7.39 1, j= 8 2 7.34-7.69 4.60 2, j 3.90-3.86 3.79-3.75 3.30 2, MS (ESI): m/z 444 Example 2 Preparation of compound 2 19 WO 00/78757 PCT/US00/16094 Steps and of the preparation were prepared in an identical manner described in Example 1 except that 2-(4-methoxyphenyl)ethanol was used instead of phenethyl alcohol.
Step Triazinyl monochloride (330 mg, 1.0 mmol) was added to 10 ml of 1,4-dioxane, followed by the addition of 3aminocarbazole (182 mg, 1.0 mmol) and diisopropylethylamine (129 mg, 1.0 mmol). The reaction mixture was heated to 100°C for 8 hours, cooled to room temperature, diluted with ethyl acetate (50 ml), washed with water and brine, dried over MgSO., filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica; EtOAc/hexane 3/7) to yield 270 mg of compound 2 (58% yield). ESMS: calculated for C2H 2N60: 496.5; found: 497.2 'H NMR (DMSO) 2.92 2H, 3.63-3.69 8H), 3.71 3H), 4.41 2H, 6.82 (br, s, 2H), 6.87 1H, j=7.
8 7.08 (br, s, 1H), 7.17 (br, s, 2H), 7.24 1H, 7.31-7.45 5H), 7.49 (br, s, 1H), 7.88 (br, s, 1H), 8.24 1H), 9.49 1H), 11.12 1H).
Example 3 Preparation of compound 3 Step Cyanuric chloride (2 g, 10.8 mmol) and 4-hydroxy-3methoxyphenethyl alcohol (1.6 g, 10.8 mmol) were dissolved in CH 2 Cl 2 (25 ml). N,N-dimethylacetamide (2.8 g, 32.5 mmol) was then added. The reaction mixture was refluxed for 3 hours, washed with water (3 times), and then dried over MgSO The dried solution was 20 WO 00/78757 PCT/US00/16094 concentrated under reduced pressure to yield the desired triazine dichloride intermediate.
Step The triazine dichloride intermediate (3.0 g, mmol) was dissolved in acetone (30 ml). After the acetone solution was cooled to 0°C, a 10 ml aqueous solution of sodium bicarbonate (0.842 g, 10 mmol) was added to the acetone solution with stirring. Morpholine (0.87 ml, 10 mmol) was added dropwise to mixture and white precipitate was formed within 10 minutes. The precipitate was filtered and washed with water (3 times) and dried under vacuum to yield the desired triazine monochloride intermediate (4.0 g, as a white solid.
Step The triazine monochloride intermediate (3.5 g, 9.98 mmol) was dissolved in 20 ml of THF, followed by the addition of a solution of hydrazine (3.2 ml, 99 mmol) in ethanol (20 ml). The mixture was allowed to react until a white precipitate was formed (in about 10 minutes).
The solid was filtered washed 3 times with water, and dried under vacuum to afford 3.1 g of the triazine hydrazine intermediate as a white solid.
The triazine hydrazine (0.50 g, 1.44 mmol) was dissolved in methanol (10 ml) and stirred at room temperature. Indole-3-carboxyaldehyde (0.21 g, 1.44 mmol) was added to the solution, followed by the addition of two drops of acetic acid. The reaction mixture was refluxed for 5 minutes, and the product precipitated upon cooling. The precipitate was filtered, washed 3 times with water, and dried under vacuum to afford compound 3 (0.45 g, 66%) as a pale yellow solid. 'H NMR (CDC1 3 3.02(t, 2H, j= 7 2 3.74 4H), 3.82 4H), 3.90 (s, -OCH, 3H), 4.13 2H), 4.56 2H, 6.71 (d, 21 WO 00/78757 PCT/US00/16094 1H), 6.83 2H), 7.19 3H), 7.38 1H, j= 8 4 7.52 (sharp d, 1H, 8.38 1H, 8.50 (s, 1H). ESMS calculated for C H NO4: 489.53; found: 490.0 Example 4 Preparation of compound 4 Step Cyanuric chloride (13.66 g, 74 mmol) was dissolved in methylene chloride (100 ml) at -78 0 C, followed by the addition of diisopropylethylamine (12.9 ml, 74 mmol).
The reaction mixture was stirred for 5 minutes.
Morpholine (6.46 ml, 74 mmol) was added dropwise into the reaction mixture in 10 minutes. The resulting white precipitate was filtered, washed with water, and dried to afford the desired intermediate in quantitative yield (17 g, 100%).
Step 2-(2-Hydroxyethyl)pyridine (2 g, 16.2 mmol) was dissolved in THF (20 ml) at 0°C. 6.5 ml of 2.5 M n-butyl lithium (16.2 mmol) was into the pyridine solution dropwise in 5 minutes. The resulting solution was then added dropwise via cannula to a triazine dichloride solution (3.8 g, 16.2 mmol, in THF) at -78°C. The reaction was allowed to warm to room temperature for overnight to yield the triazine monochloride intermediate (2.8 g, 54%) as a white powder.
Step Hydrazine (0.5 ml, 15.5 mmol, 5 eq.) was dissolved in 10 ml ethanol at room temperature. The triazine monochloride intermediate (1 g, 3.11 mmol) was added to a solution of ethanol (20 ml) and heated to 60 0 C before adding into the hydrazine solution. After stirring for 22 WO 00/78757 PCT/US00/16094 minutes, white crystals precipitated, which were then filtered, washed with water and air dried to yield the triazine hydrazine intermediate (781 mg, 78%) as a white powder.
Indole-3-aldehyde (1.05 g, 7.25 mmol) and the triazine hydrazine intermediate (2.3 g, 7.25 mmol) were added to 30 ml of methanol at room temperature. 5 ml of acetic acid was added to the reaction mixture and was refluxed for 5 minutes. Upon cooling, a white precipitate was formed, which was filtered and washed with water to yield compound 4 as a white powder (1.7 g, 'H NMR (CDC1,) 3.28 2H, 3.7 (broad s, 4H), 3.86 (broad s, 4H), 4.73 (broad t, 2H), 7.14-7.24 2H), 7.27-7.30 3H), 7.37 1H, 7.45 (d, 1H, j= 2 7.59 1H, j= 7 8.14 1H), 8.42 (d, 1H, j=7.
8 8.49 1H), 8.56 1H, ESMS calculated for C H NO 444.49; found: 445.2 23 24 8 2 Example Preparation of compound Steps and of the preparation were prepared in an identical manner described in Example 3 except that (3,4-dimethoxyphenyl)ethanol was used instead of 4hydroxy-3-methoxyphenethyl alcohol.
Step The triazine monochloride intermediate (760 mg, mmol) was dissolved in 10 ml DMF. methoxyphenyl)amino)aniline (429 mg, 2.0 mmol) and DIEA (387 mg, 3.0 mmol) were then added to the DMF solution.
The reaction mixture was allowed to react at 100 0 C for hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 ml), washed with HO0 (3 X 25 ml), brine (25 ml), dried over MgSO filtered, and 23 WO 00/78757 PCTIUS00/16094 concentrated under reduced pressure. The resulting crude residue was further purified by crystallization from acetone/water to give 970 mg of compound 5 'H NMR
(CDCI
3 7.36 (bd, 2, 7.02 2, 6.92-6.78 5.44 4.47 2, J= 7 4 3.86 3), 3.85 3.84 3.83-3.78 3.74-3.69 (m, 3.02 2, j= 7 MS (ESI): m/z 559 Example 6 Preparation of compound 6 Steps and of the preparation were identical to the corresponding steps described in Example Step Triazine monochloride intermediate (0.3 thienyl-2-aminothiophene (0.143 anhydrous K 2
CO
3 (0.545 g) were added to 10 ml of DMSO. The reaction mixture was heated at 100-120°C and stirred for overnight. After cooling to room temperature, water was added and then extracted by CHC1 3 The extract was dried over MgSO. and evaporated. Residue was purified by column chromatography with a mixture of hexane:ethyl acetate as an eluent. Yield 257 mg 'H NMR (300 MHz, CDC 3 7.61 1H); 7.17-7.15 1H); 7.10-6.92 2H); 6.91 j=3.9 Hz, 1H); 6.86-6.76 3 H) 6.48 j= 3 9 Hz, 1H); 4.50 j=7.2 Hz, 2H); 3.97-3.68 (m, 8H); 3.86 6H); 3.06 j= 7 2 Hz, 2H); MS m/z: 526 24 WO OOr78757 WO 0078757PCT/USOO/16094 Example 7 Preparation of Compound 7 Compound 7 was prepared in a similar manner as described in Example 2. ESMS: calculated for C 30
H
31 4 526; found: 527.4 IH-NMR (DMSO) 2.93 Ct, 2H, j-- 6 9 3.63-3.69 Cm, 14H), 4.44 2H, 6.78 Cbr s, 2H), 6.89 1H1), 7.1 (br s, IH), 7.33-7.44 1H1), 7.8-7.95 (br s, 1H), 8.45 Cs, 1H), 9.49 Cs, 1H1), 11.1 1H).
Example 8 Preparation of Compound 8 Compound 8 was prepared in a similar manner as described in Example 2. ESMS Calculated for C 2211 2 9 N 7 0 2 495.0; found: 496.2 CM-sH) IH NNR (DMSO) 1.16 3H, 2.58 2H1, 3.12 Ct, 2H1, 3.63-3.72 (in, 8H1), 4.62 Ct, 2H1, j-- 7 2 7.08 Cm, 1H), 7.24 (mn, 1H), 7.31-7.44 (mn, 5H), 7.53 Cm, 8.36 (s, 1H), 8.42 1H1), 9.49 Cs, 1H), 11.10 1H-).
Example 9 Preparation of Compound 9 Compound 9 was prepared in a similar manner as described in Example 6. 'H NMR (300 MHz, CDC 3 9.80 Cs, 1H1); 7.39-7.33 Cm, 2H); 7.10-7.04 Cm, 2H); 6.86-6.7B Cm, 3H1); 4.60-4.53 411); 3.96-3.58 (mn, 8H); 3.87 Cs, 611); 3.08 t, J=7.5 Hz, 2H); 1.51 Ct, J=7.2 Hz, 3 MS in/z: 582 CM+H)*: 25 WO OOn8757 WO 0078757PCTLJSOO/I 6094 Example Preparation of Compound Compound 10 was prepared in a similar manner as described in Example 2. 2H NMR (300 MHz, CDCl,3) 3.7-3.9 Cm, 8H) 4.25 Ct, j--5.4 Hz, 2H) 4.58 r--5.4 Hz, 2H1), 7.1 (brs, lH), 7.19-7.23 Cm, 1H1), 7.36 (d, j= 7 .5Hz, 1H1), 7.41-7.48 (in, 4H1), 7.97 Cd, j=-7.5Hz, 1H1), B.18 1H) 8.22 (brs, 1H1). MS 525.2 CM+H).
1o Example 11 Preparation of Compound 11 Compound 11 was prepared in a similar manner as described in Example 2. ESMS: calculated for C 29H 2 9 N 0: 527.5; found: 528.2 1H NMR (DMSO) 2.94 2H, 3.64-3.70 Cm, 14H), 4.46 Ct, 2H1, 6.79 (q, 2H, 6.90 Cs, 111), 7.33 (in, 1H), 7.49 Ct, 1H, 7.61 Cm, 2H1), 7.85 Cbr s, 1H), 8.49 1H1), 9.70 Cs, 1H).
Exampl2e 12 Preparation of Compound 12 Compound 12 was prepared in a similar manner as described in Example 3. ESMS: calculated for C2512 503; found: 504.2 CM+H) 'H NMR (DMS0) 2.95 Cbr s, 2H), 3.63-3.72 Cm, 1411), 3.85 Cbr s, 1H), 4.41-4.52 Cm, 2H), 6. 79 91 Cm, 4H1), 7. 13 Cbr s, 211), 7. 37 111, 7.68 Cd, 111, j= 2 8.27 Cs, 111), 8.36 (br s, 1H) 10. 88 Cs, 1H), 11.40 1H1).
26 WO OOn8757 WO 0078757PCT/USOO116094 Example 13 Preparation of Compound 13 Compound 13 was prepared in a similar manner as described in Example 3. IH NNR CDMSO-d 6 5 1.95 Cm, 2H), 53.24 Cm, 2H), 3.6-3.8 Cm, 8H), 4.0-4.1 Cm, 4H), 6.88 (s, 1H) 6. 97 (brs, 1H) 7. 07 Ct, j-- 7 2 Hz, 1H) 7. 15 (d, 1H), 7.19 (in, lH), 7.39 j--7.5Hz, 1H), 7.64 2H) 8.35 (in, 1H) 8.44 (in, iN) 11.36 1H). MS m/e 447 CM+H) Example 14 Preparation of Compound 14 Compound 14 was prepared in a similar marnner as described in Example 2. ESMS Calculated for C,,H 27N40 6 515. 5; found: 515.2 CM+H) 'H-NNR (CDC1,) 1. 85 Cm, 4H) 2.62 Ct, 2H), 2.71 Ct, 2H), 2.93 Ct, 2H, 3.66 Cm, 8H), 3.78 Cs, 3H), 3.82 3H), 4.40 Ct, 2H-, j--7.
2 6.60-6.71 Cm, 3H), 6.86 (dd, 1H, j=- 2 7 7.18-7.21 Cm, 2H), 7.69 Cs, 1H).
Example Preparation of Compound Compound 15 was prepared in a similar manner as described in Example 1. 'H NMR CCDC1 3 8.48-8.35 3H), 8.04 Cs, 1H), 7.66 1H), 7.44-7.25 Cm, 4.58 Ct, 2H, 3.90-3.86 Cm, 4H), 3.82-3.78 Cm, 4H), 3.13 2H-, 2.67 3H) MS (ESI) m/z 486 CM-iH).
Example 16 Preparation of Compound 16 Compound 16 was prepared in a similar manner as described in Example 4. ESMS: calculated for C, H2N NO 495.0; found: 496.2 CM+H) 'H NR CDMSO) 1.16 Ct, 3H, 27 WO 00/78757 WO 0078757PCT/USOO/16094 7.5) 2. 58 2H, 5) 3. 12 Ct, 2H1, r-- 7 3.63-3.72 8H), 4.62 2H, 7.08 Cm, 114), 7.24 (in, 1H), 7.31-7.44 (in, 5H), 7.53 (in, 1H), 8.36 Cs, 1H), 8.42 1H), 9.49 Cs, 1H), 11.10 Cs, 111).
Example 17 Preparation of Compound 17 Compound 17 was prepared in a similar manner as described in Example 6. 2H NMR (300 MHz, DMSO-d 6 7.45 1H); 6.83-6.75 Cm, 3H); 6.60 (br s, IH); 6.54 (in, 2H); 5.95 1H); 4.52 j--7.2 Hz, 2 3.90-3.67 (mn, 8H); 3.89,3.87 (2s, 6H); 3.00 Ct, j--7.
2 Hz, 2H); MS in/z: 494 Example 18 Preparation of Compound 18 Compound 18 was prepared in a similar manner as described in Example 6. 'H NMR (300 MHz, CuDC 3 ppm: 7.75 1H); 6.80-6.70 (in, 3H); 5.26 (br.s. 1H); 4.50 J--7.1 HZ, 2H); 4.36 j--7.0 Hz, 211); 3.83, 3.81 (2s, 6H); 3.71-3.60 (in, 8H); 3.98 Ct, Hz, 2H); 1.24 j-- 7 .0 Hz, 3H); MS in/z: 582 CM+Na).
Example 19 Preparation of Compound 19 Compound 19 was prepared in a similar manner as described in Example 6. 1H NMR (CDC1 3 8.74-8.66 1H), 8.11 1H), 7.38-7.24 (mn, 9H1), 4.63 t, 211, j-- 7 7 3.90-3.86 4H), 3.81 311), 3.81-3.77 Cm, 411), 3.65 311), 3.17 Ct, 2H, j- 7 7 MS (ESI): m/z 472 CM+H).
Example Preparation of Compound 28 wo oon8757 WO 00l8757PCTIUSOO/16094 Compound 20 was prepared in a similar manner as described in Example 1. 111 NMR (CDC 3 10.1 1H1), 9.27 Cbs, 1H1), 8.19 1H), 7.94 1H), 7.40-7.21 (in, 7H), 6.89-6.8S (in, 1H1), 4.52 t, 211, 3.89-3.85 (m, 4H1), 3.73 311), 3.81-3.77 (in, 4H), 3.09 211, ,7= 7 4 MS (ESI) m/z 474 (Mi-H) Example 22.
Preparation of Compound 21 Compound 21 was prepoared in a similar manner as described in Example 6. ESMS Calculated for C 28H 2N4 06 515.5; found: 515.2 'H-NMR (CDClj) 1.85 (mn, 411), 2.62 t, 211), 2.71 t, 2H1), 2.93 211, j-- 7 3.66 (m, 8H1), 3.78 311), 3.82 311), 4.40 Ct, 211, j=7.2), 156.60-6.71 (mn, 311), 6. 86 (dd, 1H1, 7) 7.18-7.21 (in, 211), 7.69 1H).
Example 22 Preparation of compound 22 Compound 22 was prepared in a similar manner as described in Example 6. ESMS Calculated for C 27 H 3 N 6 04: 504.5; found: 505.2 (Mi-H) 1H1 NMR (DMSO) 2.05 (br s, 311), 2.26 311), 2.91 t, 2H, j-- 7 2 3.61-3.70 Cm, 1411), 4.41 2H1, 6.67-6.9 Cm, 411), 7.08 Cs, 211), 7.76 (in, 111), 9.26 Cs, 111), 10.49 111).
Example 23 Preparation of Compound 23 Compound 23 was prepared in a similar manner as described in Example 6. '11 NNR (CDC1 3 7.95 111), 7.85-7.20 Cseries of m, 1111), 7.08 (bs, 111), 4.53 2H1,
,T-
7 4 3.85-3.81 Cm, 411), 3.79-3.75 411), 3.11 (t, 2H1, 7 MS CESI) i/z 480 CM+H).
29 WO 00/78757 WO 0078757PCTIUSOO/16094 Example 24 Preparation of Compound 24 Compound 24 was prepared in a similar manner as in Example 6. ESMS Calculated for C 27 H 3 1
N
5 0 4
S
521.6; found: 522.2 1 H NMR CDMSO) 2.42 Cs, 211), 2.93 2H, j--7.
2 3.64-3.71 Cm, 14H), 4.44 Ct, 2H, j-- 7 6.75 Cd, 1H1, 6.84 1H, 6.88 Cs, 1H), 7.38 Cd, lH, 7.68 Cd, 1H, j-- 8 7 8.21 Cs, 111), 9.63 Cs, 1H).
Example Preparation of Compound Compound 25 was prepared in a similar manner as 1described in Example 6. 'H NMR (300 MHz, DMSO 5-6) 10.50, 9.80 (2 hr s, 1iH) 7.43 111); 7.59-7-29 Cm, 211); 7.18-7.02 (in, 1H); 6.96-6.73 (mn, 3H); 6.30 (hr s, 1H1); 4.43 j--7.2 Hz, 211); 3.78-3.58 811); 3.71 6H1); 2.94 j--7.2 HZ); MS in/z: 510 Example 26 Preparation of Compound 26 Compound 26 was prepared in a similar manner as described in Example 5. 'H NMR (CD 3 OD) 8.17 Cddd, 1H, 1.7, 7.92 (ddd, 2H, j 1.7, 1.7), 7.76-7.46 Cm, 911), 7.33-7.18 211), 4.55 Ct, 211, 3.85-3.81 (mn, 4H), 3.78-3.74 Cm, 411), 3.08 Ct, 211, j-- 7 2 MS (ESI) m/z 497 CM-N).
Example 27 Preparation of Compound 27 Compound 27 was prepared in a similar manner as described in Example 5. LH NNR (CDCI 3) 7.36 Cbd, 2H, 30 WO 00/78757 PCT/US00/16094 7.35-7.22 5H), 7.03 (ddd, 2H, j=9.0, 2,2), 6.90 (ddd, 2H, j=8.8, 2 2 6.85 (ddd, 2H, j=9.0, 2, 2), 6.75 (bs, 1H), 5.43 1H), 4.50 2H, j=7.7), 3.84-3.79 4H), 3.80 3H), 3.75-3.70 4H), 3.09 2H, j= 7 7 MS (ESI) m/z 499 (M+H) Example 28 Preparation of Compound 28 Compound 28 was prepared in a similar manner as described in Example 6. 'H NMR (300 MHz, CDCl 3 ppm: 8.37-8.24 1H); 8.10-7.95 2H); 6.88-6.67 4H); 6.61 (br s, 1H); 4.51 j=6.9 Hz, 2H); 3.90-3.66 (m, 8H); 3.86 6H); 3.02 j= 6 9 Hz, 2H); MS m/z: 544 Example 29 Mononuclear cells from human peripheral blood (PBMC) were harvested from a leukopak using standard procedures and diluted to three million per ml with RPMI. Also present in the RPMI solution were fetal calf serum penicillin, streptomycin and L-glutamate. Human Interferon gamma (IFN-y) was added to the solution containing the cells at the concentration of 60 units/ml (obtained from Boehringer Mannheim; catalog no. 1040596).
100 pl of this solution was then added to each well in a 96 well plate with U-shaped bottoms. The plate was then incubated overnight under a 7% CO 2 atmosphere at 370C. A RPMI stock solution (4X) was prepared for each test compound of this invention. Each test compound was added to a well of the 96 well plate with a final concentration of 1 pg/ml, followed by the addition of a RPMI stock solution (4X concentration) containing lipopolysaccharide (LPS; obtained from Serratia Marscencens Sigma; catalog 31 WO 0078757 PCT/US00/16094 no. L-4766) with a final concentration of 1 ug/ml. The plate was gently vortexed and incubated for 16 hours under a 7% CO 2 atmosphere at 370C. After harvesting the supernatant from each well, the amount of P70 in the supernatant was measured using a sandwich ELISA with anti-human IL-12 antibodies (obtained from R&D systems; catalog no. mAb 611 and catalog no. BAF219). A number of the test compounds of this invention demonstrated a level of above 70% in inhibiting IL-12 production when compared to the data obtained from a control experiment in which no compound was added. Nine compounds were selected for further testing described in the following example.
Example The specificity of the nine selected compound (see Example 29) was tested on PBMC and human leukemia mononuclear cell line THP-1 in parallel to verify results.
PBMC were plated in wells of a 96-well plate at a concentration of 500,000 cells per well and stimulated by adding IFN-y (200 U/mL) and LPS (1 pg/mL). THP-1 cells were plated in wells of a 96-well plate at a concentration of 800,000 cells per well (100 pl). Human IFN-y was added at 2000 U/ml. The plate was incubated overnight under a 7% CO 2 atmosphere at 370C. Each selected test compound (in 4X RPMI solution) was then added to a well of the 96 well plate with a final concentration of 1 pg/ml, which was then followed by the addition of Staph Aureus Cowan I (SAC or Pansorbin; obtained from Calbiochem; Lot B15921) with a final concentration of 0.05%. The plate was then gently vortexed and incubated for 16 hours under a 7% C02 atmosphere at 37 0 C. Supernatant was harvested and was 32 WO 00/78757 PCT/US00/16094 assayed for the amount of P70 present by using a sandwich ELISA with anti-human IL-12 antibodies (obtained from R&D systems; catalog no. mAb 611 and catalog no. BAF219).
The nine selected test compounds all showed similar biological activities towards both PBMC and THP-1 cells.
Among these selected compounds, one showed an IC 5 0 of about 30 nM for the PBMC cell line and an IC of about 200 nM for the THP-1 cell line; six showed an IC50 of between 1-3 nM for the PBMC cell line and an IC of between 8-20 nM for the THP-1 cell line; and two compounds unexpectedly showed an IC50 of about 0.1 nM for the PBMC cell line and an ICs of about 0.8 nM for the THP-1 cell line. The two most potent compounds showed a increase in inhibiting IL-12 production over a known anti-inflammatory compound, dexamethazone.
33 WO 00/78757 PCT/US00116094 Example 31 The nine selected compounds (see Example 29) were also assayed for cytotoxicity using a Cell Titer 96 Aqueous Non-radioactive kit (obtained from Promega, order no. G5421). Phenazine methosulfate (obtained from Sigma; catalog no. P 5812) was added as an electron donor to wells containing PBMC (500,000 cells per well) and test compounds (final concentration of test compounds 1 pg/ml). 3-(4,5-Dimethylthiazole-2-yl)-5-(3carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) was then added. Cells were incubated for 2 hours under a 7% CO atmosphere at 37 0 C. Supernatant was harvested and its absorbance at 490 nm was recorded.
Cell viability data was obtained from the level of bioreduction of MTS by mitochondrial dehydrogenases. The data was then compared to that obtained from a control experiment in which no test compound was added to the cells. The cytotoxicity assay was also carried out with THP-1 cells. A test compound is considered cytotoxic if the absorbance is under 70% of that of the control.
The nine test compounds all showed similar trend in cytotoxity toward the two cell lines. For the PBMC cell line, one compound showed a CCs 0 of under 1 pM; five compounds showed a CC 50 of between 2-10 pM; and three compounds showed a CC 50 of 20 pM or above. For the THP-1 cell line, one compound showed a CC 5 0 of about 2 pM; five compounds showed a CC.
0 of about 20 pM; and three compounds showed a CC 0 of above 20 pM. Compared with an assay in which dexamethazone was added, four compounds showed a lower cytotoxity toward the PBMC cell line, and three compounds showed a lower cytotoxity toward the THP- 1 cell line.
34 WO 00/78757 PCT/US00/16094 Example 32 Three compounds of this invention were tested in an animal study using Balb/c mice. The mice were divided into groups of five. Septic shock was induced in each of them by single intradermal injection of LPS (1 pg/mL) in the foot pad. After 24 hours, a group of mice received no treatment; another group received vehicle only DMSO and 18% Cremophor RH40); or three groups received test compounds. More specifically, each group received a different test compound at a dosage of 10-20 mg/kg. The mice were dosed daily for three days and the mortality rate in each group was then recorded.
The mice all died in the groups that received no treatment or vehicle only. Among the groups that received test compounds, two had a survival rate of and Other Embodiments From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the claims.
What is claimed is: 35

Claims (31)

1. A compound of the following formula: 2 L, ILI" w x Y I wherein X is 1,3,5-triazinyl; L' is in which is -(CH or N(R b) and is each of R" and RC, independently, being hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R bbeing hdoeakl yoalkyl, heterocycloalkyl,ayl aralkyl, heteroaryl, or heteroaralkyl; and each of m and n, independently, being 1-8; W is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; L' is -A 2 -B 2 in which A 2 is a bond, -N or-( C and B 2 i s a bond, N CCW) N 9 C(R'6) C (R7) -N NC(R 9 -NC(R' 0 -C -0-C CR')- -CO-CC(R') CR") -CO-N (R'1 7 -CO-S-, -S-CCR' 9 CR 20 CS CC(R") CR 2 -CS-NCR 2 3 -NCR 24 -Cs-, -502-, provided that -A 2 -B 2 cannot be a bond; or _B2_ is -0- 2 or CNCR 2 6) NC(R 27 each of R4, R 5 R6, R 7 R', W 9 R' 0 R1 2 R' R 4 R's, R16, R"s, R19, R 20 R 21 R 22 R 23 R 2 1, R 2 s, R 26 and R" 7 independently, being hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroar-yl, aralkyl, or heteroaralkyl; and each of p, q, r, s, t, u, and v, independently, being 1, 2, or 3; Y is -RI-LI-R' wherein RI is a bond, or cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, 36 AMENDED SHEET 37 optionally substituted with alkyl, alkoxy, hydiroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, or alkoxycarbonylimrino; L' is a bond, -N(R 2 8 -N(R CO-N(R 3 0 or each of R 28 R 29 and R 30 independently, being hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and R" is heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted with alkyl, atkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; and Zis morpholinyl optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, amninoalkyl, thio, mercaptoalkyl, cyano, itro, alkylcarbonylamidno, alkylamninocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; or a salt thereof.
2. The compound of claim 1, wherein R" is a tricyclic fused aryl or heteroaryl. 32 2 3The comfpound of claim 2, wherein A is and B is abond. The compound of claim 3, wherein -A-l is or to 0 0* 00 -38-
6. The compound of claim 2, wherein A 2 is and B 2 is a bond, or -A 2 -B 2 is
7. The compound of claim 6, wherein A 2 is and B 2 is a bond, R' being hydrogen or alkyl.
8. The compound of claim 7, wherein R" is aryl or heteroaryl.
9. The compound of claim 8, wherein L' is or -N(R 29 each of R 28 and R 29 independently, being hydrogen or alkyl.
10. The compound of claim 9, wherein is or -(CH(Ra))m in which Ra is o hydrogen and m is 1-3, and W is aryl or heteroaryl, optionally substituted with alkyl, 10 alkoxy, hydroxyl, or halo.
11. The compound of claim 10, where the compound is *H O** 0
12. The compound of claim 6, wherein -A2-B2 is
13. The compound of claim 12, wherein R" is aryl or heteroaryl. N N 12. The compound of claim 6, wherein -A 2 -B 2 is 13. The compound of claim 12, wherein R" is aryl or heteroaryl. -39-
14. The compound of claim 13, wherein L' is or -N(R 29 each of R 28 and R 2 9 independently, being hydrogen or alkyl. The compound of claim 14, wherein is or -(CH(Ra))m in which Ra is hydrogen and m is 1-3, and W is aryl or heteroaryl, optionally substituted with alkyl, alkoxy, hydroxyl, or halo.
16. The compound of claim 15, where the compound is compound 21 as follows: H 3 CO 0 N 0 H 3 CO N O
17. The compound of claim 2, wherein A2 is -N(R and B2 is -N-C(R4 C(R5)-N- -C(R6)-C(R or
18. The compound of claim 17, wherein A2 iS and B2 is each of R1 and R4, independently, being hydrogen or alkyl.
19. The compound of claim 18, wherein R" is aryl or heteroaryl. The compound of claim 19, wherein is or in which Ra is hydrogen and m is 1-3, and W is aryl or heteroaryl, optionally substituted with alkyl, alkoxy, hydroxyl, or halo. 2 1. The compound of claim 20, where the compound is H O Y TN NH N -N H 3 CO (N 1 OH 0 0 y^Ny.N .N_ I 0 H 0 N. Y, Y N NH N N N (N) 0 H yNyN_ N NH N" N N ~N2V 0 (C0 0000 OS 0 0 0 0 **00 0 0 0 400~ @0 0 0 000 S S. S S 00 0 0 *0.S 0 0.0* 00 *.0 0 0 *OOS 0 0400 4.0 0 0 4. 0, S 0005
22. The compound of claim 17, wherein A 2 is and B 2 is -C(R 6 )C(R 7 1 6 15 each of R 1 R 6 and R 7 independently, being hydrogen or alkyl.
23. The compound of claim 22, wherein R" is aryl or heteroaryl.
24. The compound of claim 23, wherein -A'-B 1 is or in which Ra is hydrogen and m is 1-3, and W is aryl or heteroaryl, optionally substituted with alkyl, alkoxy, hydroxyl, or halo.
25. The compound of claim 24, where the compound is N T ONYN NI 0
26. A method of inhibiting IL-12 production, comprising administering to a patient in need thereof an effective amount of a compound of the following formula: 41 wherein X is 1,3,5-triazinyl; L' is -A in which is or -N(R and -Bl- is (CH(Rc))n- or a bond, each of R a and Rc, independently, being hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Rb being hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and each of m and n, independently, being 1-8; W is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, 15 mercaptoalkyl, cyano, nitro, alkylcarbonylarrino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; is in which A 2 is a bond, -N(R or and B 2 is a bond, -N=C(R 4 -C(R 5 -C(R 6 )=C(R 7 -N(R 8 )=N(R 9 -N(R' 0 )-C(Rl l)(R 1 2 -0-C(R' 3 4 -CO-C(R' 5 6 -CO-N(R' 7 -N(R' 8 -S-C(R 9)(R -CS-C(R 2 1 2 2 -CS-N(R 1 3 -N(R 2 4 -S02-, provided that -A 2-B 2_ cannot be a bond; or -A 2-B 2_ is (0(CH2)q0O)r-, 5 )-(CH 2 or 6 )-(CH 2 each 2 2 13 14 15 16 17 18 19 20 21 ofRl,R,R,R,R',R,R,R,R 9 ,R 1 0 ,RI,R R ,R ,R ,R R ,R ,R9,R ,R R2, k23, R 24 R 2 1 R 2 and R 27 independently, being hydrogen, alkyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and each of p, q, r, s, t, u, and v, independently, being 1, 2, or 3; -42- Y is wherein R' is a bond, or cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkylcarbonyloxy, or alkoxycarbonylimino; L' is a bond, -N(R 2 8 -CO-N(R30)-, or 28 29 each of R28, R29, and R 30 independently, being hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and R" is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl, optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, **thioalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; and Z is morpholinyl optionally substituted with alkyl, alkoxy, hydroxyl, hydroxylalkyl, carboxyl, halo, haloalkyl, amino, aminoalkyl, thio, mercaptoalkyl, cyano, nitro, alkylcarbonylamino, alkylaminocarbonyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, or alkylcarbonyloxy; or a salt thereof.
27. The method of claim 26, wherein Z is heterocycloalkyl.
28. The method of claim 27, wherein Z is morpholinyl. 20 29. The method of claim 28, wherein W is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl. The method of claim 29, wherein W is aryl or heteroaryl, optionally substituted with alkyl, alkoxy, hydroxyl, or halo.
31. The method of claim 28, wherein R" is a tricyclic fused aryl or heteroaryl.
32. The method of claim 31, wherein W is aryl or heteroaryl, optionally substituted with alkyl, alkoxy, hydroxyl, or halo. -43-
33. The method of claim 28, wherein A 2 is and B 2 is -NC(R 4 7 or -N(R )N(R 9
34. The method of claim 33, wherein W is aryl or heteroaryl, optionally substituted with alkyl, alkoxy, hydroxyl, or halo.
35. The compound of claim 21, wherein the compound is H O NN N N H
36. The method of claim 26, wherein the compound is H 7 N NY N 0
37. Use ofa compound according to any one of claims 1 to 25, or claim 35 in the manufacture of a medicament for inhibiting I1-12 production.
38. A method of inhibiting IL-12 production according to claim 26, and substantially as herein described with reference to any one of the examples but excluding comparative examples.
39. A compound according to claim 1, and substantially as herein described with reference to any one of the examples but excluding comparative examples. -44- DATED this 8 th day of March 2005 Shelston IP Attorneys for: Shionogi Bioresearch Corp. o* e** oo oooo S* oo ooo
AU56074/00A 1999-06-17 2000-06-12 Inhibitors of IL-12 production Ceased AU781849C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US13962399P 1999-06-17 1999-06-17
US60/139623 1999-06-17
PCT/US2000/016094 WO2000078757A1 (en) 1999-06-17 2000-06-12 Inhibitors of il-12 production

Publications (3)

Publication Number Publication Date
AU5607400A AU5607400A (en) 2001-01-09
AU781849B2 true AU781849B2 (en) 2005-06-16
AU781849C AU781849C (en) 2006-03-02

Family

ID=22487544

Family Applications (1)

Application Number Title Priority Date Filing Date
AU56074/00A Ceased AU781849C (en) 1999-06-17 2000-06-12 Inhibitors of IL-12 production

Country Status (5)

Country Link
EP (1) EP1185528A4 (en)
JP (1) JP2003502424A (en)
AU (1) AU781849C (en)
TW (1) TWI265929B (en)
WO (1) WO2000078757A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002231166B2 (en) * 2000-12-21 2008-02-21 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7473691B2 (en) 2000-09-15 2009-01-06 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US6660731B2 (en) 2000-09-15 2003-12-09 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
WO2002022605A1 (en) 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors
US6462078B1 (en) * 2001-01-29 2002-10-08 Shionogi Bioresearch Corp. Epoxyvibsanin B
MY141867A (en) 2002-06-20 2010-07-16 Vertex Pharma Substituted pyrimidines useful as protein kinase inhibitors
CN1319968C (en) 2002-08-02 2007-06-06 沃泰克斯药物股份有限公司 Pyrazole compositions useful as inhibitors of GSK-3
JP4768265B2 (en) 2002-10-15 2011-09-07 シンタ ファーマシューティカルズ コーポレーション New compounds
WO2005000404A2 (en) * 2003-05-29 2005-01-06 Synta Pharmaceuticals, Corp. Heterocyclic compounds for preventing and treating disorders associated with excessive bone loss
AU2004289303A1 (en) 2003-11-10 2005-05-26 Synta Pharmaceuticals, Corp. Fused heterocyclic compounds
AU2004289304A1 (en) * 2003-11-10 2005-05-26 Synta Pharmaceuticals, Corp. Pyridine compounds
EP1689403A4 (en) * 2003-11-10 2007-09-05 Synta Pharmaceuticals Corp Heteroaryl-hydrazone compounds
TWI380816B (en) * 2004-04-13 2013-01-01 Synta Pharmaceuticals Corp Disalt inhibitors of il-12 production
WO2006007532A2 (en) * 2004-07-01 2006-01-19 Synta Pharmaceuticals Corp. 2-substituted heteroaryl compounds
WO2006053227A2 (en) * 2004-11-10 2006-05-18 Synta Pharmaceuticals Corp. Il-12 modulatory compounds
TW200628463A (en) 2004-11-10 2006-08-16 Synta Pharmaceuticals Corp Heteroaryl compounds
US7923557B2 (en) 2004-11-10 2011-04-12 Synta Pharmaceuticals Corporation Process for preparing trisubstituted pyrimidine compounds
US7851466B2 (en) 2004-11-19 2010-12-14 Synta Pharmaceuticals Corp. Pyrimidine compounds and uses thereof
MX2008005814A (en) 2005-11-03 2008-10-15 Vertex Pharma Aminopyrimidines useful as kinase inhibitors.
NZ582879A (en) 2007-07-31 2012-03-30 Vertex Pharma Process for preparing 5-fluoro-1h-pyrazolo [3, 4-b] pyridin-3-amine and derivatives thereof
WO2009048750A2 (en) 2007-10-09 2009-04-16 Dow Agrosciences Llc Insecticidal (1,3,5)-triazinyl phenyl hydrazones
WO2009109613A2 (en) 2008-03-07 2009-09-11 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Novel 1-benzyl-3-hydroxymethylindazole derivatives and use thereof in the treatment of diseases based on the expression of mcp-1, cx3cr1 and p40
HRP20191953T8 (en) 2008-03-07 2021-06-25 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. 1-benzyl-3-hydroxymethylindazole derivatives and use thereof in the treatment of diseases based on the expression of mcp-1, cx3cr1 and p40
JP2012529512A (en) * 2009-06-08 2012-11-22 アブラクシス バイオサイエンス リミテッド ライアビリティー カンパニー Triazine derivatives and their therapeutic applications
JP5785940B2 (en) * 2009-06-09 2015-09-30 アブラクシス バイオサイエンス， エルエルシー Triazine derivatives and their therapeutic applications
EP2440055B1 (en) * 2009-06-09 2015-03-11 California Capital Equity, LLC Styryl-triazine derivatives and their therapeutical applications
US9321735B2 (en) 2010-07-20 2016-04-26 Vestaron Corporation Insecticidal triazines and pyrimidines
US12589097B2 (en) 2018-02-21 2026-03-31 OrphAl Therapeutics Inc. Apilimod compositions and methods of use
TW202000205A (en) 2018-02-21 2020-01-01 美商Ａｉ治療公司 Combination therapy with apilimod and glutamatergic agents
TWI885039B (en) 2020-01-13 2025-06-01 美商邊際分析公司 Substituted pyrazolo-pyrimidines and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0356412A1 (en) * 1988-08-16 1990-02-28 U C B, S.A. Use of 2-amino-4-morpholino-6-propyl-1,3,5-triazines in the preparation of a medicament for the treatment of cognitive and mental disorders
EP0527117A1 (en) * 1991-07-25 1993-02-10 U C B, S.A. Substituted cyclopropylamino-1,3,5-triazines

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1231369B (en) * 1964-03-05 1966-12-29 Basf Ag Process for the production of anthraquinone dyes
US5593992A (en) * 1993-07-16 1997-01-14 Smithkline Beecham Corporation Compounds
AU1924699A (en) * 1997-12-19 1999-07-12 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositionsand uses

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0356412A1 (en) * 1988-08-16 1990-02-28 U C B, S.A. Use of 2-amino-4-morpholino-6-propyl-1,3,5-triazines in the preparation of a medicament for the treatment of cognitive and mental disorders
EP0527117A1 (en) * 1991-07-25 1993-02-10 U C B, S.A. Substituted cyclopropylamino-1,3,5-triazines

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002231166B2 (en) * 2000-12-21 2008-02-21 Vertex Pharmaceuticals Incorporated Pyrazole compounds useful as protein kinase inhibitors

Also Published As

Publication number Publication date
WO2000078757A1 (en) 2000-12-28
JP2003502424A (en) 2003-01-21
EP1185528A4 (en) 2003-03-26
AU781849C (en) 2006-03-02
TWI265929B (en) 2006-11-11
AU5607400A (en) 2001-01-09
EP1185528A1 (en) 2002-03-13

Similar Documents

Publication Publication Date Title
AU781849B2 (en) Inhibitors of IL-12 production
US6384032B1 (en) Inhibitors of IL-12 production
ES2358988T3 (en) BENZAMIDE AND HETEROARILAMIDE AS ANTAGONISTS OF THE P2X7 RECEIVER.
EP0747368B1 (en) Derivatives of monocyclic polyamines, their preparation, and their use as antiviral agents
AU2016317521B2 (en) Novel pyrazolo[3,4-d]pyrimidine compound or salt thereof
KR100663147B1 (en) Condensed Pyridazine Derivative Compounds and Pharmaceuticals Containing the Same as Active Ingredients
KR102885432B1 (en) Methods and compositions for targeting Tregs with CCR8 inhibitors
AU2005278962B2 (en) Isoindolin-1-one derivatives
AU707751B2 (en) Substituted 2,4-imidazolidinedione compounds as pharmaceutical active ingredients
ES2971909T3 (en) Pharmaceutical composition comprising: 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid
JPH07504654A (en) Amine derivatives of oxo- and hydroxy-substituted hydrocarbons
JPH07503718A (en) Novel amidine derivatives, their preparation and use as LTB↓4 antagonists
JPH04506222A (en) N-substituted heterocyclic derivative and method for producing the same
HU211237A9 (en) Ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds
ES2578290T3 (en) Oxazoline and isoxazoline derivatives as CRAC modulators
US6544981B2 (en) Lactam inhibitors of factor Xa and method
US7125997B2 (en) Differential tumor cytotoxicity compounds and compositions
CA3081564A1 (en) Double-headed protease inhibitor
US5109011A (en) P-acylaminophenoxycarbamates and derivatives
JPH0322394B2 (en)
US6258806B1 (en) Amine derivatives of oxo- and hydroxy- substituted hydrocarbons
JPH11180952A (en) 2-oxindole derivative
CN120230148A (en) STAT inhibitor compounds and their applications
CN120230147A (en) Signal transduction and transcription activator protein inhibitor compounds and their applications
CN121085992A (en) Signal transduction and transcriptional activator 6 selective degradation agent compounds