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Title:
MONOFLUOROALKYL DERIVATIVES
Document Type and Number:
WIPO Patent Application WO/2000/066546
Kind Code:
A2
Abstract:
The present invention provides monofluoroalkyl derivatives of the formula (I) wherein: A represents SO¿2?, CO¿2? or CONH; R?a¿ represents (1-6C)alkyl, (2-6C)alkenyl, -(1-4C)alkyl(3-8C)cycloalkyl, or (1-4C)alkylaromatic; R?b¿ represents H, (1-6C)alkyl, (2-6C)alkenyl, -(1-4C)alkyl(3-8C)cycloalkyl, or (1-4C)alkylaromatic; or R?a¿ and R?b¿ together with the carbon atoms to which they are attached form a (3-8C) saturated carbocyclic ring, a (3-8C) saturated carbocyclic ring containing a heteroatom selected from the group consisting of sulfur or oxygen, or a (5-8C) carbocyclic ring containing one double bond; R?1¿ represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heteroaromatic group, or an unsubstituted or substituted (5-8C)cycloalkyl group; R?2¿ represents (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)fluoroalkyl, (1-6C)chloroalkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or when A represents SO¿2?, a group of formula R?3¿R?4¿N in which R?3¿ and R?4¿ each independently represents (1-4C)alkyl or , together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a pharmaceutically acceptable salt thereof, useful for potentiating glutamate receptor function in a mammal and thereof, useful for treating a wide variety of condutions, such as psychiatric and neurological disorder.

Inventors:
BENDER DAVID MICHAEL (US)
CANTRELL BUDDY EUGENE (US)
FRAY ANDREW HENDLEY (US)
JONES WINTON DENNIS (US)
MILLER WILLIAM DAVID (US)
MITCHELL DAVID (US)
SIMON RICHARD LEE (US)
ZARRINMAYEH HAMIDEH (US)
ZIMMERMAN DENNIS MICHAEL (US)
Application Number:
PCT/US2000/008734
Publication Date:
November 09, 2000
Filing Date:
April 17, 2000
Export Citation:
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Assignee:
LILLY CO ELI (US)
BENDER DAVID MICHAEL (US)
CANTRELL BUDDY EUGENE (US)
FRAY ANDREW HENDLEY (US)
JONES WINTON DENNIS (US)
MILLER WILLIAM DAVID (US)
MITCHELL DAVID (US)
SIMON RICHARD LEE (US)
ZARRINMAYEH HAMIDEH (US)
ZIMMERMAN DENNIS MICHAEL (US)
International Classes:
A61K31/18; C07D295/18; A61K31/192; A61K31/195; A61K31/216; A61K31/27; A61K31/277; A61K31/381; A61K31/40; A61K31/404; A61K31/42; A61K31/4418; A61K31/455; A61P25/00; A61P25/18; A61P25/20; A61P25/28; A61P25/30; C07C307/06; C07C311/03; C07C311/04; C07C311/05; C07C311/06; C07C311/08; C07C311/09; C07C311/37; C07C311/39; C07D209/34; C07D213/38; C07D213/42; C07D213/61; C07D213/81; C07D213/82; C07D261/18; C07D295/192; C07D333/16; C07D333/20; C07D333/38; (IPC1-7): C07C311/00
Domestic Patent References:
WO1998033496A11998-08-06
WO1996018615A11996-06-20
Foreign References:
US4186129A1980-01-29
Other References:
G.M. ALVERNHE ET AL: J. ORG. CHEM., vol. 46, no. 24, 1981, pages 4938-4948, XP002155661
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; STN, CAPLUS accession no. 1993:56667, XP002155667 & A. HIRASHIMA ET AL: COMP. AGRIC. CHEM., C: COMP. PHARMACOL. TOXICOL. , vol. 103c, no. 2, 1992, pages 321-325,
H.O. HOUSE ET AL: J. AM. CHEM. SOC., vol. 81, 1959, pages 4733-4737, XP002155662
K.A. VAN HOUTEN ET AL: J. AM. CHEM. SOC. , vol. 120, no. 24, 1998, pages 5864-5872, XP002155663
I. FLEMING ET AL: J. CHEM. SOC. PERKIN TRANS. I, 1979, pages 829-837, XP002155664
H. BRUNNER ET AL: CHEM. BER., vol. 123, no. 5, 1990, pages 1029-1038, XP002155665
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; STN, CAPLUS accession no. 1988:569967, XP002155668 & A. ALBEROLA ET AL: AN. QUIM., SER. C, vol. 83, no. 2, 1987, pages 175-178,
G. DREFAHL ET AL: CHEM. BER., vol. 94, 1961, pages 915-922, XP002155666
Attorney, Agent or Firm:
Lentz, Nelsen L. (IN, US)
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Claims:
WE CLAIM:
1. A compound of the formula: wherein: A represents S02, C02, or CONH; Ra represents (16C) alkyl, (26C) alkenyl, (14C) alkyl (38C) cycloalkyl, or (14C) alkylaromatic; Rb represents H, (16C) alkyl, (26C) alkenyl, (14C) alkyl (38C) cycloalkyl, or (14C) alkylaromatic; or Ra and Rb together with the carbon atoms to which they are attached form a (3 8C) saturated carbocyclic ring, a (38C) saturated carbocyclic ring containing a heteroatom selected from the group consisting of sulfur or oxygen, or a (58C) carbocyclic ring containing one double bond; R'represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heteroaromatic group, or an unsubstituted or substituted (5 8C) cycloalkyl group; R2 represents (16C) alkyl, (36C) cycloalkyl, (16C) fluoroalkyl, (16C) chloroalkyl, (26C) alkenyl, (14C) alkoxy (14C) alkyl, phenyl which is unsubstituted or substituted by halogen, (14C) alkyl or (14C) alkoxy, or when A represents S02, a group of formula R3R4N in which R3 and R4 each independently represents (1 4C) alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein A is S02.
3. A compound according to claim 1 wherein A represents C02.
4. A compound according to claim 1 wherein A represents CONH.
5. A compound according to claim 2 wherein R'represents a naphthyl group or a phenyl, furyl, thienyl or pyridyl group which is unsubstituted or substituted by one or two substituents selected independently from halogen; nitro; cyano; hydroxyimino; (110C) alkyl; (210C) alkenyl; (210C) alkynyl; (3 8C) cycloalkyl; hydroxy (38C) cycloalkyl; oxo (38C) cycloalkyl; halo (110C) alkyl; (CH2) yX1 R9 in which y is 0 or an integer of from 1 to 4, X'represents O, S, NRl 0, CO, COO, OCO, CONR11, NR12CO, NR12COCOO or OCONR13, R9 represents hydrogen, (110C) alkyl, (310C) alkenyl, (310C) alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (38C) cycloalkyl and R1 pi R11, R12 and R13 each independently represents hydrogen or (110C) alkyl, or R9 and R1 R11, R12 or R13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N (14C) alkylpiperazinyl; Nphenyl (14C) alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (1 4C) alkoxycarbonyldihydrothiazolyl; (14C) alkoxycarbonyidimethyidihydro thiazoty); tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R14 (La) nX2 (Lb) m in which X2 represents a bond, O, NH, S, SO, S02, CO, CH (OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH or CH=CH, La and Lb each represent (14C) alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, nitro, cyano, hydroxyimino, (210C)alkenyl,(210C)alkynyl,(38C)cycloalkyl,4(1,1(110C)alkyl, dioxotetrahydro1,2thiazinyl), halo (110C) alkyl, cyano (210C) alkenyl, phenyl, and (CH2) zX3R1 5 in which z is 0 or an integer of from 1 to 4, X3 represents O, S, NR16, CO, CH (OH), COO, OCO, CONR17, NR18CO, NHS02, S02NH, NHSo2NR17, NHCONH, OCONR19 or NR19COO, R15 represents hydrogen, (110C) alkyl, phenyl (14C) alkyl, halo (110C) alkyl, (14C) alkoxycarbonyl (1 4C) alkyl, (14C) alkylsulfonylamino (14C) alkyl, (N (14C) alkoxycarbonyl) (1 4C) alkylsulfonylamino (14C) alkyl, (310C) alkenyl, (310C) alkynyl, (38C) cycloalkyl, camphoryl or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (14C) alkyl, halo (1 4C) alkyl, di (14C) alkylamino and (14C) alkoxy and R16, R17, R18 and R19 each independently represents hydrogen or (110C) alkyl, or R15 and R16, R1, R18 or Rl 9 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
6. A compound according to claim 5 wherein R2 represents (16C) alkyl, (36C) cycloalkyl, fluoro (16C) alkyl, chloro (16C) alkyl, (26C) alkenyl 1 4C) alkoxy (14C) alkyl, heteroaromatic, or phenyl which is unsubstituted or substituted by halogen, (14C) alkyl or (14C) alkoxy.
7. A compound according to claim 6 wherein R2 represents (16C) alkyl, (36C) cycloalkyl or heteroaromatic, or phenyl which is unsubstituted or substituted by halogen, (14C) alkyl or (14C) alkoxy.
8. A compound according to claim 7 wherein R2 represents methyl, ethyl, isopropyl, tbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, isovaleryl, phenyl, benzyl, 2furyl, 2thienyl, 5oxazoyl, 2pyridyl, 3pyridyl, or 4pryidyl.
9. A compound according to claim 8 wherein Ra represents (16C) alkyl or (26C) alkenyl.
10. A compound according to claim 9 wherein Ra represents methyl, ethyl, propyl, nbutyl, secbutyl, tertbutyl, pentyl or hexyl.
11. A compound according to claim 10 wherein Ra represents methyl.
12. A compound as claimed in any one of claims 1 to 11 wherein Rb represents H, (16C) alkyl, or (26C) alkenyl.
13. A compound as claimed in any one of claims 1 to 11 wherein Rb represents H.
14. A compound as claimed in any one of claims 1 to 13 wherein R1 is selected from the group consisting of:.
15. A compound selected from the group consisting of: [2fluoro2 (4iodophenyl) propyl] [ (methylethyl) sulfonyl]amine; [2fluoro2(4phenylphenyl)propyl][(methylethyl)sulfonyl]amine; <BR> <BR> <BR> <BR> 4 [4 (lfluorolmethyl2<BR> <BR> <BR> <BR> <BR> <BR> <BR> {[(methylethyl) sulfonyl] amino} ethyl) phenyl] benzenecarbonitrile; 4[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzoicacid; {2[4(3aminophenyl)phenyl]2fluoropropyl}[(methylethyl)sulfonyl]amine; [2fluoro2 (4 {3 [(methylsulfonyl) amino] phenyl} phenyl) propyl] [(methylethyl) sulfonyl] amine; [2fluoro2(4(3thienyl)phenyl)propyl][(methylethyl)sulfonyl]amine; [2fluoro2(4(3pyridyl)phenyl)propyl][(methylethyl)sulfonyl]amine; <BR> <BR> <BR> <BR> 2 {4 [4 (lfluorolmethyl2<BR> <BR> <BR> <BR> <BR> <BR> {[(methylethyl) sulfonyl] amino} ethyl) phenyl] phenyl} ethanenitrile; 4[4(1fluoro1methyl2 {[(methylethyl) su If onyl] amino} ethyl) phenyl] benzaldehyde; {4[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}N methylcarboxamide; {4[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}N,N dimethylcarboxamide; Nethyl{4 [4 (lfluoro1methyl2 {[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}carboxamide; 4[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl pyrrolidinylketone; <BR> <BR> <BR> N {3 [4 ( 1fluoro1methyl2<BR> <BR> <BR> <BR> <BR> {[(methylethyl) sulfonyl] amino} ethyl) phenyl] phenyl} acetamide;<BR> <BR> <BR> <BR> N {3 [4 (1fluoro1methyl2 {[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}propanamide; N{3[4(1fluoro1methyl2 {[(methylethyl) sulfonyl] amino} ethyl) phenyl] phenyl} butanamide; aminoN {3 [4 (1fluoro1methyl2 {[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}amide; N[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzamide; (3cyanophenyl)N [4 (1fluoro1methyl2 {[(methylethyl) sulfonyl] amino} ethyl) phenyl] carboxamide; N[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]4 pyridylcarboxamide; N[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]{4[2 (methoxycarbonylamino)ethyl]phenyl}carboxamide; (2 {4 [ (3, 5difluorophenyl) methoxy] phenyl}2 fluoropropyl) [(methylethyl) sulfonyl]amine; {2fluoro2[4(4{2 [(methylsulfonyl) amino] ethyl} phenyl) phenyl] propyl} [(methylethyl) sulfonyl] amine; (4chlorophenyl)N[4(1fluoro1methyl2 {[(methylethyl) sulfonyl] amino} ethyl) phenyl] carboxamide; (6chloro (3pyridyl))N [4 (lfluoro1methyl2 {[(methylethyl) su If onyl] amino} ethyl) phenyl]carboxamide; (4cyanophenyl)N [4 (1fluoro1methyl2 {[(methylethyl) sulfonyl] amino} ethyl) phenyl] carboxamide; ethoxyN [4 (lfluoro1methyl2 {[(methylethyl) sulfonyl] amino} ethyl) phenyl] carboxamide; N[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]isoxazol5 ylcarboxamide; 4(dimethylamino)N[4(1fluoro1methyl2 {[(methylethyl) sulfonyl] amino} ethyl) phenyl] butanamide; N[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]3 thienylcarboxamide; {2fluoro2 [4 (phenylmethoxy) phenyl] propyl} [ (methylethyl) sulfonyl]amine; 2{[4(1fluoro1methyl2 { [ (methylethyl) sulfonyl] amino} ethyl) phenoxy] methyl} benzenecarbonitrile; [2fluoro2(4methoxyphenyl)propyl][(methylethyl)sulfonyl]amine; {2[4(3,5difluorophenyl)phenyl]2fluoropropyl}[(methylethyl)sulfonyl]amine; [(dimethylamino)sulfonyl][2fluoro2(4iodophenyl)propyl]amine; 4[4(2{[(dimethylamino)sulfonyl]amino}1fluoro isopropyl) phenyl] benzenecarbonitrile; {2[4(3aminophenyl)phenyl]2fluoropropyl}[(dimethylamino)sulfonyl]amine; [ (dimethylamino) sulfonyl] [2fluoro2 (4 {3 [(methylsulfonyl) amino] phenyl} phenyl) propyl] amine; [(dimethylamino)sulfonyl]{2fluoro2[4(3 {[(methylethyl) sulfonyl] amino} phenyl) phenyl] propyl} amine; 4 [4 (lfluoro1methyl2 {[(methylethyl)sulfonyl]amino}ethyl)phenyl]benzenesulfonamide; <BR> <BR> <BR> N (2 {3fluoro4' [1fluoro1methyl2 (propane2 sulfonylamino)ethyl]biphenyl<BR> <BR> <BR> <BR> <BR> 4yl}ethyl)isobutyramide;<BR> <BR> <BR> <BR> N (2 {3fluoro4' [1fluoro1methyl2 (propane2sulfonylamino)ethyl]biphenyl<BR> <BR> <BR> <BR> 4yl}ethyl)acetamide;<BR> <BR> <BR> <BR> N {2 (2fluoro2 [3'fluoro4' (2methanesulfonylamino)ethyl)biphenyl4 yl] propyl}2propane sulfonamide; N{2(2fluoro2[3'fluoro4'(2(propane2sulfonylamino)ethyl)biphenyl4 <BR> <BR> <BR> yl] propyl}2propane sulfonamide.<BR> <BR> <BR> <BR> <P>N (2 {3'fluoro4' [2 (propane2sulfonylamino)ethyl]biphenyl4yl}2hydroxy propyl)2propane sulfonamide; N {2Fluoro2 [4 (2oxo2, 3dihydro1 Hindol6yl)phenyl]propyl)2 propanesulfonamide; (+)[2fluoro2(4iodophenyl)propyl][(methylethyl)sulfonyl]amine; ()[2fluoro2(4iodophenyl)propyl][(methylethyl)sulfonyl]amine; [2fluoro2 (4 {3 [(methylsulfonyl)amino]phenyl}phenyl)propyl][(methylethyl)sulfonyl]amine (enantiomer 1); [2fluoro2 (4 {3 [(methylsulfonyl) amino] phenyl} phenyl) propyl] [(methylethyl) sulfonyl] amine (enantiomer 2); {4[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}N methylcarboxamide (enantiomer 1); and {4[4(1fluoro1methyl2{[(methylethyl)sulfonyl]amino}ethyl)phenyl]phenyl}N methylcarboxamide (enantiomer 2); and the pharmaceutically acceptable salts thereof.
16. A compound of the formula: wherein R'represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heteroaromatic group, or an unsubstituted or substituted (58C) cycloalkyl group; or a pharmaceutically acceptable salt thereof.
17. A compound according to claim 16 wherein R'represents a substituted aromatic group.
18. A compound according to claim 17 wherein the substituted aromatic group is a substituted phenyl.
19. A compound according to claim 18 wherein the substituted phenyl is substituted with halogen; nitro; cyano; hydroxyimino; (110C) alkyl; (2 10C) alkenyl; (210C) alkynyl; (38C) cycloalkyl; hydroxy (38C) cycloalkyl; oxo (3 8C) cycloalkyl; halo (110C) alkyl; (CH2) yX1 R9 in which y is 0 or an integer of from 1 to 4, Xl represents O, S, NRl 0, CO, COO, OCO, CONR11, NR12CO, NR12COCOO, OCONR13, R9 represents hydrogen, (110C) alkyl, (3 10C) alkenyl, (310C) alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3 8C) cycloalkyl and R1 0, R1 1, R12 and R13 each independently represents hydrogen or (110C)alkyl, or R9 and Rl 0. Rl 1. Rl 2 or R13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N (14C) alkylpiperazinyl; Nphenyl (1 4C) alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazoty); imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (14C) alkoxycarbonyl dihydrothiazolyl; (14C) alkoxycarbonyl dimethyldihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl ; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R14 (La) nX2 (Lb) m in which X2 represents a bond, O, NH, S, SO, S02, CO, CH (OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH, or CH=CH, La and Lb each represent (14C) alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (110C) alkyl; (21OC) alkenyl; (21OC) alkynyl; (38C) cycloalkyl; 4 (1,1dioxotetrahydro1,2 thiazinyl); halo (110C) alkyl; cyano (210C) alkenyl; phenyl; and (CH2) zX3R15 in which z is 0 or an integer of from 1 to 4, X3 represents O, S, NR16, CO, CH (OH), COO, OCO, CONR17, NRl8CO, NHS02, S02NH, NHS02NR1, OCONR19 or representshydrogen,(110C)alkyl,phenyl(14C)alkyl,halo(1NR19COO,R15 10C)alkyl, (14C) alkoxycarbonyl (14C) alkyl, (14C) alkylsulfonylamino (14C) alkyl, N (14C) alkoxycarbonyl) (14C) alkylsulfonylamino (14C) alkyl, (310C) alkenyl, (3 10C) alkynyl, (38C) cycloalkyl, camphoryl, or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (14C) alkyl, halo (14C) alkyl, di (14C) alkylamino and (14C) alkoxy, and R16, R17, R18 and independentlyrepresentshydrogenor(110C)alkyl,orR15andR16,R19each R17, R18 or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
20. A compound according to claim 19 wherein the substituted phenyl is substituted with a group of formula R14 (La) nX2 (Lb) m in which X2 represents a bond, O, NH, S, SO, S02, CO, CH (OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH, or CH=CH, La and Lb each represent (14C) alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (110C) alkyl; (210C) alkenyl; (210C) alkynyl; (3 8C) cycloalkyl; 4 (1,1dioxotetrahydro1,2thiazinyl); halo (110C) alkyl; cyano (2 1 OC) alkenyl; phenyl; and (CH2) zX3R1 5 in which z is 0 or an integer of from 1 to 4, X3 represents O, S, NR16, CO, CH (OH), COO, OCO, CONR17, NR18CO, NHS02, S02NH, NHSO2NR17, OCONR19 or NR19COO, R15 represents hydrogen, (110C) alkyl, phenyl (14C) alkyl, halo (110C) alkyl, (1 4C) alkoxycarbonyl(14C)alkyl, (14C) alkylsulfonylamino (14C) alkyl, N (1 4C) alkoxycarbonyl) (14C) alkylsulfonylamino (14C) alkyl, (310C) alkenyl, (3 10C)alkynyl, (38C) cycloalkyl, camphoryl, or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (14C) alkyl, halo (14C) alkyl, di (14C) alkylamino and (14C) alkoxy, and R16, R17, R18 and R19 each independently represents hydrogen or (110C) alkyl, or R15 and R16, p17 R18 or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
21. A compound according to claim 20 wherein (La) nX2 (Lb) m represents a bond, CONH, or CH2O,.
22. A compound according to claim 21 wherein R14 represents a phenyl which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (1 1 OC) alkyl; (21 OC) alkenyl; (21 OC) alkynyl; (38C) cycloalkyl; 4 (1,1 halo (110C) alkyl; cyano (210C) alkenyl; phenyl; and (CH2) zX3R15 in which z is 0 or an integer of from 1 to 4, X3 represents O, S, NR16, CO, CH (OH), COO, OCO, CONR17, NR18CO, NHS02, S02NH, orNR19COO,R15representshydrogen,(110C)alkyl,NHSO2NR17,OCONR19 phenyl (14C) alkyl, halo (110C) alkyl, (14C) alkoxycarbonyl (14C) alkyl, (1 4C) alkylsulfonylamino (14C) alkyl, N (14C) alkoxycarbonyl) (1 4C) alkylsulfonylamino (14C) alkyl, (310C) alkenyl, (310C) alkynyl, (3 8C) cycloalkyl, camphoryl, or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (14C) alkyl, halo(1 4C) alkyl, di (14C) alkylamino and (14C) alkoxy, and R16, R17, R18 and R19 each independently represent hydrogen or (110C) alkyl, or R15 and R16, R17, R18 or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
23. A compound according to claim 21 wherein phenyl is substituted by one or two of halogen; nitro; cyano; (110C) alkyl; halo (110C) alkyl; and (CH2) zX3R15 in which z is 0,1 or 2, X3 represents O, NR16, CO, COO, NHSO2,SO2NH,NHSO2NR17,OCONR19orNR19COO,CONR17,NR18CO, R15 represents hydrogen, (110C)alkyl, phenyl(14C)alkyl, halo(110C)alkyl, or (310C)alkenyl, and R16, R17 R18 and R19 each independently represent hydrogen or (110C) alkyl.
24. A compound according to claim 21 wherein phenyl is substituted by one or two of fluoro; chloro, cyano; (14C) alkyl ; trifluoromethyl; and (CH2) zX3R15 in which z is 0, or 2, X3 represents NR16, CO, COO, CONRl 7, NR18CO, NHS02, R15 represents hydrogen, (14C) alkyl, phenyl (14C) alkyl, or halo (1 4C) alkyl, and R16, R17, R18 and R19 each independently represent hydrogen or (14C) alkyl.
25. A compound according to claim 21 wherein phenyl is substituted by one of fluoro; chloro, cyano; (14C) alkyl; trifluoromethyl; and (CH2) zX3R15 in which z is 0, or 2, X3 represents NR16, CO, COO, CONR17, NR18CO, NHSO2, R15 represents hydrogen, (14C) alkyl, phenyl (14C) alkyl, or halo (14C) alkyl, and R16, R17 R18 and R19 each independently represent hydrogen or (14C) alkyl.
26. A compound of the formula: wherein Ra represents (16C) alkyl, (26C) alkenyl, (14C) alkyl (38C) cycloalkyl, or (14C) alkylaromatic; Rb represents H, (16C) alkyl, (26C) alkenyl, (14C) alkyl (38C) cycloalkyl, or (14C) alkylaromatic; or Ra and Rb together with the carbon atoms to which they are attached form a (3 8C) saturated carbocyclic ring, a (38C) saturated carbocyclic ring containing a heteroatom selected from the group consisting of sulfur or oxygen, or a (58C) carbocyclic ring containing one double bond; R1 represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heteroaromatic group, or an unsubstituted or substituted (5 8C) cycloalkyl group; or a pharmaceutically acceptable salt thereof; with the proviso that when Ra is methyl, then R'is other than 4bromophenyl.
27. A compound of the formula: wherein R'represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heteroaromatic group, or an unsubstituted or substituted (58C) cycloalkyl group; or a pharmaceutically acceptable salt thereof.
28. A compound according to claim 27 wherein R'represents a substituted aromatic group.
29. A compound according to claim 28 wherein the substituted aromatic group is a substituted phenyl.
30. A compound according to claim 29 wherein the substituted phenyl is substituted with halogen; nitro; cyano; hydroxyimino; (110C) alkyl; (2 10C) alkenyl; (210C) alkynyl; (38C) cycloalkyl; hydroxy (38C) cycloalkyl; oxo (3 8C) cycloalkyl; halo (110C) alkyl; (CH2) yX1 R9 in which y is 0 or an integer of from 1 to 4, Xl represents O, S, NR10, CO, COO, OCO, CONR11, NR12CO, NR12COCOO, OCONR13, R9 represents hydrogen, (110C) alkyl, (3 10C) alkenyl, (310C) alkynyl, pyrrolidinyl, tetrahydrofuryl, morpholino or (3 8C) cycloalkyl and R1 pi R12 and R13 each independently represents hydrogen or (110C)alkyl, or R9 and Rl 0. Rl 1. Rl 2 or R13 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group; N (14C) alkylpiperazinyl; Nphenyl(1 4C) alkylpiperazinyl; thienyl; furyl; oxazolyl; isoxazolyl; pyrazolyl; imidazolyl; thiazolyl; pyridyl; pyridazinyl; pyrimidinyl; dihydrothienyl; dihydrofuryl; dihydrothiopyranyl; dihydropyranyl; dihydrothiazolyl; (14C) alkoxycarbonyl dihydrothiazolyl; (14C) alkoxycarbonyl dimethyldihydrothiazolyl; tetrahydrothienyl; tetrahydrofuryl; tetrahydrothiopyranyl; tetrahydropyranyl ; indolyl; benzofuryl; benzothienyl; benzimidazolyl; and a group of formula R14 (La) nX2 (Lb) m in which X2 represents a bond, O, NH, S, SO, S02, CO, CH (OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH, or CH=CH, La and Lb each represent (14C) alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (110C) alkyl; (210C) alkenyl; (210C) alkynyl; (38C) cycloalkyl; 4 (1,1dioxotetrahydro1,2 thiazinyl); halo (110C) alkyl; cyano (210C) alkenyl; phenyl; and (CH2) zX3R15 in which z is 0 or an integer of from 1 to 4, X3 represents O, S, NR16, CO, CH (OH), COO, OCO, CONR17, NR18CO, NHSO2, SO2NH, NHSO2NR17, OCONR19 or NR19COO, R15 represents hydrogen, (110C) alkyl, phenyl (14C) alkyl, halo (1 (14C)alkylsulfonylamino(14C)alkyl,10C)alkyl,(14C)alkoxycarbonyl(14C)alkyl, N(14C)alkoxycarbonyl) (14C) alkylsulfonylamino (14C) alkyl, (310C) alkenyl, (3 10C)alkynyl, (38C) cycloalkyl, camphoryl, or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (14C) alkyl, halo (14C) alkyl, di (14C) alkylamino and (14C) alkoxy, and R16, R17, R18 and R19 each independently represents hydrogen or (110C) alkyl, or R15 and R16, R1 7, R18 or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
31. A compound according to claim 30 wherein the substituted phenyl is substituted with a group of formula R14 (La) nX2 (Lb) m in which X2 represents a bond, O, NH, S, SO, S02, CO, CH (OH), CONH, NHCO, NHCONH, NHCOO, COCONH, OCH2CONH, or CH=CH, La and Lb each represent (14C) alkylene, one of n and m is 0 or 1 and the other is 0, and R14 represents a phenyl or heteroaromatic group which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (110C) alkyl; (210C) alkenyl; (210C) alkynyl; (3 8C) cycloalkyl; 4 (1,1dioxotetrahydro1,2thiazinyl); halo (110C) alkyl; cyano (2 1 OC) alkenyl; phenyl; and (CH2) zX3R1 5 in which z is 0 or an integer of from 1 to 4, X3 represents O, S, NR16, CO, CH (OH), COO, OCO, CONR17, NR18CO, NHS02, S02NH, NHSo2NR17 OCONR19 or NR19COO, R15 represents hydrogen, (110C) alkyl, phenyl (14C) alkyl, halo (110C) alkyl, (1 4C) alkoxycarbonyl (14C) alkyl, (14C) alkylsulfonylamino (14C) alkyl, N (1 4C) alkoxycarbonyl) (14C) alkylsulfonylamino (14C) alkyl, (310C) alkenyl, (3 10C)alkynyl, (38C) cycloalkyl, camphoryl, or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (14C) alkyl, halo (14C) alkyl, di (14C) alkylamino and (14C) alkoxy, and R16, R17, R18 and R19 each independently represents hydrogen or (110C) alkyl, or Rl and R16, R1 Rl8 or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
32. A compound according to claim 31 wherein (La) nX2 (Lb) m represents a bond, CONH, or CH20.
33. A compound according to claim 32 wherein R14 represents a phenyl which is unsubstituted or substituted by one or two of halogen; nitro; cyano; (1 1 OC) alkyl; (21 OC) alkenyl; (21 OC) alkynyl; (38C) cycloalkyl; 4 (1,1 halo (110C) alkyl; cyano (210C) alkenyl; phenyl; and (CH2) zX3R1 5 in which z is 0 or an integer of from 1 to 4, X3 represents O, S, NR16, CO, CH (OH), COO, OCO, CONR17, NR18CO, NHS02, S02NH, orNR19COO,R15representshydrogen,(110C)alkyl,NHSO2NR17,OCONR19 phenyl (14C) alkyl, halo (110C) alkyl, (14C) alkoxycarbonyl(14C)alkyl, (1 4C) alkylsulfonylamino (14C) alkyl, N (14C) alkoxycarbonyl) (1 4C) alkylsulfonylamino (14C) alkyl, (310C) alkenyl, (310C) alkynyl, (3 8C) cycloalkyl, camphoryl, or an aromatic or heteroaromatic group which is unsubstituted or substituted by one or two of halogen, (14C) alkyl, halo(1 4C) alkyl, di (14C) alkylamino and (14C) alkoxy, and R16, R17, R18 and R19 each independently represent hydrogen or (11 OC) alkyl, or R15 and R16, R17 R18 or R19 together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl or morpholino group.
34. A compound according to claim 32 wherein phenyl is substituted by one or two of halogen; nitro; cyano; (110C) alkyl; halo (110C) alkyl; and (CH2) zX3R1 5 in which z is 0,1 or 2, X3 represents O, NR16, CO, COO, NHSO2,SO2NH,NHSO2NR17,OCONR19orNR19COO,CONR17,NR18CO, hydrogen,(110C)alkyl,phenyl(14C)alkyl,halo(110C)alkyl,orR15represents (310C) alkenyl, and R16, R17, R18 and R19 each independently represent hydrogen or (110C)alkyl.
35. A compound according to claim 32 wherein phenyl is substituted by one or two of fluoro; chloro, cyano; (14C) alkyl; trifluoromethyl; and (CH2) zX3R15 in which z is 0, or 2, X3 represents NR16, CO, COO, CONR1 7, NR18CO, NHS02, R15 represents hydrogen, (14C) alkyl, phenyl (14C) alkyl, or halo(1 4C) alkyl, and R16 R17 R18 and R19 each independently represent hydrogen or (14C)alkyl.
36. A compound according to claim 32 wherein phenyl is substituted by one of fluoro; chloro, cyano; (14C) alkyl; trifluoromethyl; and (CH2) zX3R15 in which z is 0, or 2, X3 represents NR16, CO, COO, CONRl 7, NRl 8CO, NHS02, Rl represents hydrogen, (14C) alkyl, phenyl (14C) alkyl, or halo (14C) alkyl, and R16, R17, R18 and R19 each independently represent hydrogen or (14C) alkyl.
37. A compound according to claim 26 wherein R'is selected from the group consisting of:.
38. A pharmaceutical composition, which comprises a compound as claimed in claim 1 and a pharmaceutically acceptable diluent or carrier.
39. A method of potentiating glutamate receptor function in a patient, which comprises administering to said patient an effective amount of a compound of formula: wherein A represents S02, C02, or CONH; Ra represents (16C) alkyl, (26C) alkenyl, (14C) alkyl (38C) cycloalkyl, or (14C) alkylaromatic; Rb represents H, (16C) alkyl, (26C) alkenyl, (14C) alkyl (38C) cycloalkyl, or (14C) alkylaromatic; or Ra and Rb together with the carbon atoms to which they are attached form a (3 8C) saturated carbocyclic ring, a (38C) saturated carbocyclic ring containing a heteroatom selected from the group consisting of sulfur or oxygen, or a (58C) carbocyclic ring containing one double bond; R1 represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heteroaromatic group, or an unsubstituted or substituted (5 8C) cycloalkyl group; R2 represents (16C) alkyl, (36C) cycloalkyl, (16C) fluoroalkyl, (16C) chloroalkyl, (26C) alkenyl, (14C) alkoxy (14C) alkyl, phenyl which is unsubstituted or substituted by halogen, (14C) alkyl or (14C) alkoxy, or when A represents SO2, a group of formula R3R4N in which R3 and R4 each independently represents (1 4C) alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a pharmaceutically acceptable salt thereof.
40. A method of treating a cognitive disorder; a neurodegenerative disorder; agerelated dementia; ageinduced memory impairment; movement disorder; reversal of a druginduced state; depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis; or druginduced psychosis in a patient, which comprises administering to a patient in need thereof an effective amount of a compound of formula: wherein A represents S02, C02, or CONH; Ra represents (16C) alkyl, (26C) alkenyl, (14C) alkyl (38C) cycloalkyl, or (14C) alkylaromatic; Rb represents H, (16C) alkyl, (26C) alkenyl, (14C) alkyl (38C) cycloalkyl, or (14C) alkylaromatic; or Ra and Rb together with the carbon atoms to which they are attached form a (3 8C) saturated carbocyclic ring, a (38C) saturated carbocyclic ring containing a heteroatom selected from the group consisting of sulfur or oxygen, or a (58C) carbocyclic ring containing one double bond; R1 represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heteroaromatic group, or an unsubstituted or substituted (5 8C) cycloalkyl group; R2 represents (16C) alkyl, (36C) cycloalkyl, (16C) fluoroalkyl, (16C) chloroalkyl, (26C) alkenyl, (14C) alkoxy (14C) alkyl, phenyl which is unsubstituted or substituted by halogen, (14C) alkyl or (14C) alkoxy, or when A represents S02, a group of formula R3R4N in which R3 and R4 each independently represents (1 4C) alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a pharmaceutically acceptable salt thereof.
41. A method for improving memory or learning ability in a patient, which comprises administering to a patient in need thereof an effective amount of a compound of formula: wherein A represents S02, C02, or CONH; Ra represents (16C) alkyl, (26C) alkenyl, (14C) alkyl (38C) cycloalkyl, or (14C) alkylaromatic; Rb represents H, (16C) alkyl, (26C) alkenyl, (14C) alkyl (38C) cycloalkyl, or (14C) alkylaromatic; or Ra and Rb together with the carbon atoms to which they are attached form a (3 8C) saturated carbocyclic ring, a (38C) saturated carbocyclic ring containing a heteroatom selected from the group consisting of sulfur or oxygen, or a (58C) carbocyclic ring containing one double bond; R1 represents an unsubstituted or substituted aromatic group, an unsubstituted or substituted heteroaromatic group, or an unsubstituted or substituted (5 8C) cycloalkyl group; R2 represents (16C) alkyl, (36C) cycloalkyl, (16C) fluoroalkyl, (16C) chloroalkyl, (26C) alkenyl, (14C) alkoxy (14C) alkyl, phenyl which is unsubstituted or substituted by halogen, (14C) alkyl or (14C) alkoxy, or when A represents SO2, a group of formula R3R4N in which R3 and R4 each independently represents (1 4C) alkyl or, together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a pharmaceutically acceptable salt thereof.
42. A compound according to any of Claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.
43. The use of a compound according to any of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for potentiating glutamate receptor function.
44. The use of a compound according to any of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cognitive disorder; a neurodegenerative disorder; agerelated dementia; ageinduced memory impairment; movement disorder; reversa of a druginduced state; depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis; or druginduced psychosis in a patient.
Description:
INTERNATIONAL SEARCH j--------------) Intern ial Application No PCT/US 00/08734 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X H. O. HOUSE ET AL : J. AM. CHEM. SOC., 26 vol. 81,1959, pages 4733-4737, XP002155662 page 4734, scheme compounds IIa-d X K. A. VAN HOUTEN ET AL: J. AM. CHEM. SOC., 26 vol. 120, no. 24,1998, pages 5864-5872, XP002155663 page 5866, column 1, compound 6 X US 4 186 129 A (A. HUTH ET AL) 26 29 January 1980 (1980-01-29) column 12, line 35; example 14 X I. FLEMING ET AL: J. CHEM. SOC. PERKIN 26 TRANS. I, 1979, pages 829-837, XP002155664 scheme 1, compounds 4a, c-e, h X H. BRUNNER ET AL : CHEM. BER., 26 vol. 123, no. 5,1990, pages 1029-1038, XP002155665 scheme 4, compound 33 X DATABASE CHEMABS'Online ! 26 CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO,US; STN, CAPLUS accession no. 1988: 569967, XP002155668 abstract; RN 116936-67-5 &A. ALBEROLA ET AL: AN. QUIM., SER. C, vol. 83, no. 2,1987, pages 175-178, X G. DREFAHL ET AL: CHEM. BER., 26 vol. 94,1961, pages 915-922, XP002155666 page 920, formulae A WO 98 33496 A (ELI LILLY AND CO) 1,2,16, 6 August 1998 (1998-08-06) 38-44 cited in the application page 5, line 1-page 6, line 24; examples A WO 96 18615 A (RHONE-POULENC RORER 26 PHARMACEUTICALS INC) 20 June 1996 (1996-06-20) preparation 19 1 INTERNATIONAL SEARCH = lal Applicabon No mformation on patent family members PCT/US 00/08734 Patent document Publication Patent family Publication cited in search report date member (s) date US 4186129 A 29-01-1980 DE 2655369 A 08-06-1978 AT 357529 B 10-07-1980 AT 868677 A 15-12-1979 AU 519994 B 07-01-1982 AU 3117577 A 07-06-1979 BE 861451 A 02-06-1978 CA 1097657 A 17-03-1981 CH 635578 A 15-04-1983 CS 199694 B 31-07-1980 DD 133667 A 17-01-1979 DK 536677 A, B, 04-06-1978 ES 464963 A 01-08-1978 FR 2372814 A 30-06-1978 GB 1588639 A 29-04-1981 GR 64964 A 10-06-1980 HU 175676 B 28-09-1980 IE 46435 B 15-06-1983 IL 53520 A 31-07-1981 IT 1089341 B 18-06-1985 JP 1385250 C 26-06-1987 JP 53082777 A 21-07-1978 JP 61054792 B 25-11-1986 LU 78616 A 20-04-1978 NL 7713153 A 06-06-1978 SE 441446 B 07-10-1985 SE 7713635 A 04-06-1978 SU 888821 A 07-12-1981 WO 9833496 A 06-08-1998 AU 6259598 A 25-08-1998 BR 9807297 A 18-04-2000 CN 1251523 T 26-04-2000 EP 0860428 A 26-08-1998 NO 993667 A 20-09-1999 PL 334963 A 27-03-2000 WO 9618615 A 20-06-1996 US 5556990 A 17-09-1996 AU 695852 B 27-08-1998 AU 4369896 A 03-07-1996 CA 2207429 A 20-06-1996 EP 0801644 A 22-10-1997 JP 10511084 T 27-10-1998



 
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