US005837705A

United States Patent

Bare et al.

[19]

[il] [45]

Patent Number: Date of Patent:

5,837,705
Nov. 17,1998

[54] ALPHA-SUBSTITUTED PYRIDAZINO QUINOLINE COMPOUNDS [75] Inventors: Thomas Michael Bare, West Chester, Pa.; James Roy Empfield, Bear, Del.; Janet Marie Forst; Keith John Herzog, both of Wilmington, Del.; Richard Bruce Sparks, Linwood, Pa. [73] Assignee: Zeneca Limited, London, United Kingdom [21] Appl. No.: 617,728 [22] Filed:

Godard et al., Bull. Soc. Chim. Fr., 1588-1592, (1972) Ried et al., Chem. Ber., 85, 204-216, (1952). Tominaga et al., J. Heterocyclic Chem. 30,267-273 (1993). Kurasawa and Takada, Hetercycles, 14(3), 267-270 (1980). Primavy Examinev4mily Bernhardt Attorney, Agent, or F i v m a i c h a e l D. Alexander; Paul R. Darkes [571

ABSTRACT

Apr. 1, 1996

PO1
[51] Int.

The invention relates to alpha-substituted pyridazinoquinoline compounds of the formula 1:

Apr. 7, 1995 [GB]

Foreign Application Priority Data United Kingdom ................... 9507318

........................ A61K 31/50; C07D 471104;

C07D 471114; C07D 491114 [52] U.S. Cl. .......................... 5141248; 5441234; 5461114; 5461116; 5461123; 5461156 [58] Field of Search ..................................... 5441230, 234; 5141248 ~561
5,604,227

References Cited
U.S. PATENT DOCUMENTS
211997 Bare et al.

.............................. 5141248

FOREIGN PATENT DOCUMENTS

512817 1111992 European Pat. Off. 516297 1211992 European Pat. Off. WO 95111244 411995 WIPO .

OTHER PUBLICATIONS Choi, Neuvon 1, pp. 623-634 (1988). Koh et al, Bvain Reseavch, 533, pp. 315-320 (1990). Trujillo et al, Science 251 pp. 85-87 (1991). Luo and Castle, J. Heterocyclic Chem., 28,205-208, (1991). Kurasawa and Takada, Chem. Pharm. Bull. 28(12), 3457-3465 (1980).

wherein Ring A i s chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring; R1 is selected from a variety of substituents including halogen, (1-4C) alkyl and nitro; R' is selected from a group of the formula R2', R2" or R2"' wherein R2' is -CHR~(CH,),C(O)NR~R~; R2" is -cHR~(cH,),R~ and R2"' is -CHR~(CH,),L wherein n is &6; R' is aryl or substituted aryl; R6 is (1-6C)alkyl or hydrogen; R~ is (1-6C)alkyl, (0-6C) alkylCF, or (0-6C)alkylCOORt; R4 is (1-6C)alkyl, (2-6C) alkyl containing a double or triple bond, or (O-6C)alkylaryl; L is a variety of substituents including phenyl, heteroaryl and C02Rt; R' is hydrogen or (14C)alkyl; Z is selected H,H-, H, (1-6C)alkyl or (1-6C) from 0x0, -OH, alkylaryl; and R7 is hydrogen or -(CO)Rs wherein Rs is a variety of substituents including hydrogen and (1-12C) alkyl.

3 Claims, No Drawings

5,837,705

1
ALPHA-SUBSTITUTED PYRIDAZINO QUINOLINE COMPOUNDS
This invention relates to pyridazinedione compounds useful in the treatment of neurological disorders generally in mammals such as man. More specifically, the compounds are useful in the treatment of strokes andior other neurodegenerative disorders such as hypoglycemia, cerebral palsy, transient cerebral ischemic attack, perinatal asphyxia, epilepsy, psychosis, Huntington's chorea, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Olivo-pontocerebellar atrophy, viral-induced neurodegeneration such as in acquired immunodeficiency syndrome and its associated dementia, anoxia such as from drowning, spinal cord and brain trauma, and chronic pain, for the prevention of drug and alcohol withdrawal symptoms, and for the inhibition of tolerance and dependence to opiate analgesics. The invention particularly relates to novel pyridazinedione compounds useful in reducing neurological degeneration such as can be induced by a stroke and the associated functional impairment which can result. Treatment using a compound of the invention can be remedial or therapeutic as by administering a compound following an ischemic event to mitigate the effects of that event. Treatment can also be prophylactic or prospective by administering a compound in anticipation that an ischemic event may occur, for example in a patient who is prone to stroke. It is known that ischemic events can trigger a dramatic increase in extracellular concentrations of the excitatory amino acids glutamate and aspartate which can, in turn, cause prolonged neuronal excitation leading to a massive influx of calcium from extracellular to intracellular sites in brain neural cells. Acalcium overload can thereby be created which leads to a cascade of events leading to ce11 catabolism and eventually resulting in ceIl death, The N-rnethyl-Daspartate (NMDA) receptor complex is believed to play a significant role in the cascade of events leading to ce11 necrosis following an ischemic event. The compounds provided by this invention may be useful in a variety of neurodegenerative disorders because they function as excitatory amino acid antagonists. They rnay do so indirectly, via allosteric modulation of the glutamate binding site, specifically by acting as antagonists of the strychnine-insensitive glycine receptor on the NMDAreceptor complex. They may also do so directly, by binding to the glutamate site itself on the NMDA receptor complex. A compound of formula 1:
5

2
R' is selected from a cycloalkyl moiety of 3-7 carbon atoms; or R2 is selected from a group of the formula R2', R2" or R2"' wherein R2' is -CHR3(CH2)fiC(0)NR5R6; R2" is -CHR3(CH2),R4 and R2"' is -CHR3(CH2),L wherein, for a group of formula R2"', L is M or W , M is phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1 , 2 , 3 or 4 groups chosen from -O-(1-4C)alkyl, -O-(24C)alkenyl, -0(2-4C)alkynyl, -O(CO-C6alkyl)phenyl, -OH, -halo, -NO2, -CN, -CF,, -(l-4C)alkylCF3, -NH(CO)Rt, -(l-4C)alkyl, -NRtR", -C02Rt, -CONRtR", -SOmRt, -S02NRtR", (Cl-C6) alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6) alkyloxy-, oxy(1-6C)alkyloxy which rnay form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(l-4C)alkyl, (C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6) alkyloxy-, hydroxy(C1-C6)alkyloxy(Cl-C6) alkyloxy-, -O(Cl-C6alkyl)NRtR", -NRt (Cl-C6alkyl)NRtR", -(Cl-C6alkyl)NRtR", -0(1-4C)perfluroalkyl, -(l-4Cperfluroalky1, -NRt (Cl-C6alkyloxy), -NRt(C1-C6alkylhydroxy), -(Cl-4alkyl)oxy(Cl-4alkyl), -O(Cl-4alkyl) COOR', +CH),NRtR"COOR' wherein n is 1-4, -(C14alkyl)NRtRtt, -(Cl-4alkyl)ORt, -NRt(CH2), COOR', -S(O),(Cl-4alkyl)oxy(Cl-4alkyl), -S(O),(Cl-4alkyl)oxy(Cl-4alkyl)oxy (Cl-4alkyl), -NRt(C1-4alkyl)oxy(Cl-4alkyl), -NR'(C1-4alkyl)oxy(Cl-4alkyl)oxy(C1-4alkyl); heterocycle wherein heterocycle is selected fr0m a fiveandior six- andior seven-membered heteroc~clicring containing 1 , 2 , or 3 heteroatoms chosen from O, N, or S, or aryl or heteroaryl benz derivatives thereof, wherein the N on the heterocycle is optionally substituted with R' and a carbon or nitrogen atom on the heteroc~cle maY be substituted with R or R' or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with O to form a carbonyl group or sulfonyl group (S(O),) with the proviso that a heterocyclic nitrogen maY Dot be attached to a nitrogen on the tric~clic ring system of formula 1; heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivathose thereof including pyridyl, thienyl, furanyl, or tives groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole or isothiazole (and oxidized versions thereof selected from S(O), wherein m is 0-2), pyridazine, pyrimidine, pyrazine or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or triazine, or those groups containing four heteroatoms such as tetrazole, wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic substituents include typical aromatic substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to +CH2), via a carbon atom or a heteroatom on the heteroaryl group; W is selected from OH, OR', OCOR', S(0),Rt, S(O), NR'R", halo, CF,, NR'R" or W is COR', NR'COR", OCONR', N R t C 0 2 R " , (C3-6)cycloalkyl, NRCONR'R", C02Rt, or CONRR';

lo

lS

20

2s

30

3s

40

4s

RLdz=*> yR2
I

so

=y
OR'

is claimed as a glycine receptor antagonist useful in the 5s treatment and prevention of neurological disorders and a pharmaceutically acceptable salt thereof wherein, Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, furyl, pyrrolyl or thienyl either unsub- 60 stituted or multi-substituted at a ring carbon atom with R1 wherein R1 is independently selected from the group consisting of halo, (1-4C)alkyl, NO,, CN, (Cl-3) perfluoroalkyl, OH, OCF,, (24C)-alkenyl, (2-4C) alkynyl, 0(14C)alkyl, NR'R", S02NRtR", SO,Rt, a 65 heterocyclic group, NR'COR", COR", NRtC02R", C02Rt, or CONR'R";

5,837,705

n is chosen from &6; The present invention also relates to a compound of formula 1: Z is selected from 0x0, -OH, H,H-, H,(1-6C)alkyl or (1-6C)alkylaryl wherein aryl rnay be substituted with a I substituent or substituents selected from halogen, s Cl-6alkyl or other typical aromatic substituents; R3 is selected from (1-6C)alkyl, (O-6C)alkylCF3, (&6C) alkyl-COOH; N R7 is selected from hydrogen or +CO)Rs wherein Rs is OR' selected from (1) hydrogen, (2) (1-12C)alkyl which rnay contain a double or triple bond, and which rnay or pharmaceutically acceptable salts thereof wherein: bear a group selected from (a) CN, and Ring A is chosen from an ortho fused aromatic or hetwherein Re is selected from hydrogen, (1-4C)alkyl, eroaromatic five- or six-membered ring selected from and phenyl and phenyl(1-4C)alkyl, the phenyl rings of phenyl, pyridyl, furyl, pyrrolyl or thienyl either unsubwhich can be substituted with from &3 substituents stituted or multi-substituted at a ring carbon atom with selected from halo, amino, hydroxy, cyano, nitro, 15 R1 wherein R1 is independently selected from the group (1-4C)alkyl, and (1-4C)alkoxy; (b) NR~,and CONR~, consisting of halo, (1-4C)alkyl, NO,, CN, (Cl-3) wherein each R~is independently selected (1) from R ~ , perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (2-4C) COR^, and CO OR^ when the said group is NR~,and (2) alkynyl, 0(14C)alkyl, NR'R", S02NRtR",or SOmRt, a from the values of R~ when the said group is CONR~,, heterOc~clic grouP3 wherein R~ can have any of the values stated above for O ' NR'COR", COR", NRtC02R", C02Rt, CONR'R"; Re, or wherein, for either of the said groups, the two R~ values, together with the nitrogen to which they are R2 iS Selected from -CHR3(CH2),L wherein L is M or attached, form a saturated 4- to 7-membered ring, (3) W., NRg2 wherein each Rg can independently have any of M is the values stated above for Re, or wherein the two Rg phenyl or benz derivatives thereof and is either unsubgroups together with the nitrogen to which are are stituted or substituted with 1 , 2 , 3 or 4 groups chosen attached form a saturated 4- to 7-membered ring, (4) -O-(24C)alkenyl, -0from -O-(1-4C)alkyl, pyridyl, pyridyl(1-12C)alkyl, (5) phenyl, and phenyl (2-4C)alkynyl, -O(CO-C6alkyl)phenyl, -OH, (1-4C)alkyl wherein the phenyl rings can be substi-halo, -NO,, -CN, -CF,, -(l-4C)alkylCF3, tuted with from 0-3 substituents selected from halo, 30 -NH(CO)Rt, -(l-4C)alkyl, -NRtR", -C02Rt, amino, hydroxy, cyano, nitro, (1-4C)alkyl, and (1-4C) -CONRtR", -SOmRt, -SO,NRtR", (Cl-C6) alkoxy; alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6) R is selected from H or (14C)alkyl; alkyloxy-, oxy(1-6C)alkyloxy which may form a R' and R" are independently selected from H, (14C)alkyl 3s cyclic ring attached to the phenyl ring in an ortho wherein alkyl includes alkenyl(C2-C4) and alkynyl manner, aryloxy(1-4C)alkyloxy(l-4C)alkyl, (C2-C4); (3-6C)cycloalkyl, Phenyl(0-4C)alkyl-, (C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6) heterocycle(0-4C)alkyl- or heteroaryl(0-4C)alkylalkyloxy-, hydroxy(C1-C6)alkyloxy(Cl-C6) wherein phenyl or heterocycle or heteroaryl is as alkyloxy-, -O(Cl-C6alkyl)NRtR", -NRt defined above and any of the above is optionally 40 (Cl-C6alkyl)NRtR", -(Cl-C6alkyl)NRtR", -0substituted at one or more carbon atoms with halo, H, (1-4C)perfluroalkyl, -(l-4Cperfluroalky1, -NRt (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, NO,, CN, CF,, (Cl-C6alkyloxy), -NRt(C1-C6alkylhydroxy), OH, O-(14C)alkyl, NR'R" S(0),Rt or S02NRtR" -(Cl-4alkyl)oxy(Cl-4alkyl), -O(Cl-4alkyl) wherein NR'R" may optionally form an N-alkyl(C1-3) COOR', +CH),NRtR"COOR' wherein n is 1-4, oxyalkyl(C2-3) ring with N; and 45 -(C14alkyl)NRtRtt, -(Cl-4alkyl)ORt, -NRt(CH2), For a group of formula R2', R' is selected from aryl COOR', -S(0)m(C1-4alkyl)oxy(C1-4alkyl), wherein the aryl group may be unsubstituted or mono-S(0)m(C1-4alkyl)oxy(C1-4alkyl)oxy or multisubstitued with a typical aromatic substituent (Cl-4alkyl), -NRt(C1-4alkyl)oxy(Cl-4alkyl), selected from halogen, (14C)alkyl, NO,, CN, (Cl-3) -NR'(C1-4alkyl)oxy(Cl-4alkyl)oxy(C1-4alkyl); perfluoroalk~l, OH, OCF3, (2-4C)alken~l~(2-4C) 50 heterocycle wherein heterocycle is selected from a fivealkynyl, O(1-4C)alkyl, NR'R", S02NRtR", SOmRt, andior six- andior seven-membered heterocyclic ring NR'COR", COR", NRtC02R", C02Rt, or CONR'R"; containing 1 , 2 , or 3 heteroatoms chosen from O, N, or and R6 is chosen from (1-6C)alkyl or hydrogen; S, or aryl or heteroaryl benz derivatives thereof, wherein the N on the heterocycle is optionally substiFor a group of formula R2", R~ is selected from (1-6C) alkyl or (O-6C)alkylaryl wherein the aryl moiety rnay 5s tuted with R' and a carbon or nitrogen atom on the be unsubstituted or substituted or multisubstituted with heterocycle may be substituted with R or R' or a carbon a typical aromatic substituent selected from halogen, atom may be disubstituted to form a C5-C7 spiral (1-4C)alkyl, NO,, CN, (Cl-3)perfluoroalkyl, OH, group or a carbon atom or sulfur atom may be substiOCF,, (24C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, tuted with O to form a carbonyl group or sulfonyl group NR'R", S02NRtR", SOmRt; or NR'COR", COR", 60 (S(O),) with the proviso that a heterocyclic nitrogen NRtC02R", C02Rt, or CONR'R"; may not be attached to a nitrogen or the tricyclic ring system of formula 1; . . . means a C-C, C-N or C-O double bond is optionally present with the provis0 that the proper heteroaryl wherein heteroaryl is selected from unsubsticarbon or nitrogen valency may not be exceeded; a tuted or substituted aromatic species and benz derivawavy line means a designatecl group is optionally 6s tives thereof including pyridyl, thienyl, furanyl, or present; those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, m is chosen from 0-2.

RLdz= yR2 =y

''

5,837,705
5
oxazole, thiazole or isothiazole (and oxidized versions thereof selected from S(O), wherein m is 0-2), pyridazine, pyrimidine, pyrazine or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or triazine, or those groups s containing four heteroatoms such as tetrazole, wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic substituents include typical aromatic substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl 10 group is attached to +CH,), via a carbon atom or a heteroatom on the heteroaryl group; W is selected from OH, OR', OCOR', S(0),Rt, S(O), NR'R", halo, CF,, NR'R"; or W is COR', NR'COR", O C O N R ' , N R t C 0 2 R " , ( C 3 - 6 ) c y c l o a l k y l , 1s NRCONR'R", C02Rt, or CONRR' and n is chosen from &6; R3 is selected from (1-6C)alkyl, (O-6C)alkylCF3 or (0-6C)alkylCOOH; 20 R~ is selected from H or -c(o)R' wherein R' is selected from (1-12C)alkyl which may contain a double or triple bond; R is selected from H or (14C)alkyl; R' and R" are independently selected from H, (14C)alkyl 25 wherein alkyl includes alkenyl(C2-C4) and alkynyl (C2-C4); (3-6C)cycloalkyl, Phenyl(0-4C)alkyl-, heterocycle(0-4C)alkyl- or heteroaryl(0-4C)alkylwherein phenyl or heterocycle or heteroaryl is as defined above and any of the above is optionally 30 substituted at one or more carbon atoms with halo, H, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, NO,, CN, CF,, OH, O-(14C)alkyl, NR'R" S(0),Rt or S02NRtR" wherein NR'R" rnay optionally form an N-alkyl(C1-3) oxyalkyl(C2-3) ring with N; 35 m is chosen from 0-2. The present invention further relates to a compound of formula 1:
1 40

6
-CONRtR", -SOmRt, -SO,NRtR", (Cl-C6) alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6) alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(l-4C)alkyl,

(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)
alkyloxy-, hydroxy(C1-C6)alkyloxy(Cl-C6) alkyloxy-, -O(Cl-C6alkyl)NRtR", -NRt (Cl-C6alkyl)NRtR", -(Cl-C6alkyl)NRtR", -0(1-4C)perfluroalkyl, -(l-4Cperfluroalky1, -NRt (Cl-C6alkyloxy), -NRt(C1-C6alkylhydroxy), -(Cl-4alkyl)oxy(Cl-4alkyl), -O(Cl-4alkyl) COOR', +CH),NRtR"COOR' wherein n is 1-4, -(C14alkyl)NRtRtt, -(C14alkyl)ORt, -NR (CH,), COOR', -S(O),(Cl-4alkyl)oxy(Cl-4alkyl), -S(O),(Cl-4alkyl)oxy(Cl-4alkyl)oxy (Cl-4alkyl), -NRt(C1-4alkyl)oxy(Cl-4alkyl),

-NR'(C1-4alkyl)oxy(Cl-4alkyl)oxy(C1-4alkyl);
heterocycle wherein heterocycle is selected from a fiveandior six- andior seven-membered heterocyclic ring containing 1 , 2 , or 3 heteroatoms chosen from O, N, or S wherein the N on the heterocycle is optionally substituted with R' and a carbon or nitrogen atom on the heterocycle may be substituted with R or R' or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with O to form a carbonyl group or sulfonyl group (S(O),); wherein the heterocyclic groups may be selected from, for example, 2-pyrolidinone, piperazine, oxazolidone, 2,5oxazolidinedione, 2,4-imidazollidinedione, 2,4thiazolidinedione or succinimide; aryl or benz or heteroarylbenz derivatives thereof (3,4pyridinedicarboximide, -1-pthalimido, isatoic anhydride, orthobenzoicsulfimide) either unsubstituted or mono, bi or tri-substituted with alkyl or aromatic substituents including -halo, -Cl-C6alky1, -OH, Cl-Coalkoxy, phenyl, OCF,, CF,, NO,, CN, NH,, SO,Rt, NH(C1-4alkyl), or N(C1-C4alkyl),; heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, selected or those groups such as pyrazole, imidazole, furanyl, from N, O or S containing two heteroatoms

isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups 45 OR^ containing 4 heteroatoms such as tetrazole wherein and pharmaceutically acceptable salts thereof wherein: Ring the N on the heteroaryl group is optionally substiA i s chosen from an ortho fused aromatic or heteroaromatic tuted with R and the substituted aromatic substitufive- or six-membered ring selected from phenyl, pyridyl, ents include typical aromatic substituents selected pyrrolyl or thienyl either unsubstituted or substituted at one so from hydroxy, alkoxy, halo or cyano and the hetor more ring carbon atoms with R' wherein R' is indepeneroaryl group is attached to +CH,), via a carbon dently selected from the group consisting of hydrogen, halo, atom or a heteroatom on the heteroaryl group; (1-4C)alkyl, NO,, CN, (Cl-3)perfluoroalkyl, OH, OCF,, n is 0-3; R, R,, R ~R', RI, R" and m are as previously , (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR'R", defined. S02NRtR",or SO,Rt; ss The present invention further relates to a compound of formula 1: R' is -CHR,(CH,),L wherein L is chosen from: -O(Cl-C4alkyl)aryl, I -OH, -O(Cl-C4alkyl), (Cl-C4alkyl)COORt, OCOR', S(0),Rt, NR'R" with the proviso that NR'R", NR'COR", OCONR', 60 R' NRtC02R", NRCONR'R", C02Rt, or CONRR'; phenyl or benz derivatives thereof and is either unsubN stituted or substituted with 1 , 2 , 3 or 4 groups chosen OR^ from -O-(1-4C)alkyl, -O-(24C)alkenyl, -0(2-4C)alkynyl, -O(CO-C6alkyl)phenyl, -OH, 6s and pharmaceutically acceptable salts thereof wherein: -CN, -CF,, -(l-4C)alkylCF3, Ring A is chosen from an ortho fused aromatic or het-halo, -NO,, -NH(CO)Rt, -(l-4C)alkyl, -NRtR", -C02Rt, eroaromatic five- or six-membered ring selected from
N

R1dz=*s yR2
=y

dZ--.s rR2 =y

5,837,705

7
phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted atone or more ring carbon atoms with R1 wherein is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO,, CN, (Cl-3)perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, s (2-4c)alkynyl, O(l-4C)alkyl, NR'R", S02NRtR", or SO,Rt; R' is -CHR,(CH,),L wherein L is chosen from: phenyl or benz derivatives thereof and is either 10 unsubstituted or substituted with 1, 2, 3 or 4 -0groups chosen from -O-(1-4C)alkyl, (2-4C)alkenyl, -O-(2-4C)alkynyl, -O(CCLC6alkyl)phenyl, -OH, -halo, -NO,, -CN, -CF,, -(l-4C)alkylCF3, -NH(CO)Rt, 1s -(l-4C)alkyl, -NRtR", -C02Rt, -CONRtR", -SOmRt, -SO,NRtR", (Cl-C6)alkyloxy (Cl-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, 20 aryloxy(1-4C)alkyloxy(l-4C)alkyl, (Cl-C6)

8
wherein is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO,, CN, (Cl-3)perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (2-4C)alkynyl, 0(14C)alkyl, NR'R", S02NRtR", or SO,R'; ~2 iS -CHR~(CH,),N wherein L is chosen from: -OH, -O(Cl-C4alkyl), CF,-O(C1-C4alkyl) aryl, (Cl-C4alkyl)COORt, OCOR', S(0),Rt, NR'R", NR'COR", OCONR', N R t C 0 2 R " , NRCONR'R", C02Rt, or CONRR'; phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1 , 2 , 3 or 4 groups chosen from -O-(1-4C)alkyl, -O-(24C)alkenyl, -0(2-4C)alkynyl, -O(CO-C6alkyl)phenyl, -OH, -halo, -NO,, -CN, -CF,, -(l-4C)alkylCF3, -NH(CO)Rt, -(l-4C)alkyl, -NRtR", -C02Rt, -CONRtR", -SOmRt, -SO,NRtR", (Cl-C6) alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6) alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(l-4C)alkyl,

alkyloxy(C1-C6)alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6)alkyloxy(C1-C6)alkyloxy-,
-O(Cl-C6a1kyl)NR1R1, -NRt(C1-C6alkyl) NR'R", -(Cl-C6alkyl)NRtR", -0-(1-4C) 2s perfluroalkyl, -(l-4C)perfluroalkyl, -NRt (Cl-C6alkyloxy), -NRt(C1-C6alkylhydroxy), -(Cl-4alkyl)oxy(Cl-4alkyl), -O(Cl-4alkyl) COOR', +CH),NRtR"COOR' wherein n is 1-4, -(Cl-4alkyl)NRtR", -(Cl-4alkyl)ORt, -NRt 30 (CH2),COORt, -S(O),(Cl-4alkyl)oxy (Cl-4alkyl), -S(O),(Cl4alkyl)oxy(Cl4alkyl) oxy(C1-4alkyl), -NRt(C1-4alkyl)oxy (Cl-4alkyl), -NRt(C1-4alkyl)oxy(Cl-4alkyl) oxy(C1-4alkyl); 35 heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, 40 isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroaryl group is optionally substi- 4s tuted with R and the substituted aromatic substituents include typical aromatic substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to +CH,), via a carbon so atom or a heteroatom on the heteroaryl group; n is O; R, R3, R7, Rs, RI, R" and m are as defined previously. In addition, the invention relates to a compound of formula 1:

(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)
alkyloxy-, hydroxy(C1-C6)alkyloxy(Cl-C6) alkyloxy-, -O(Cl-C6alkyl)NRtR", -NRt (Cl-C6alkyl)NRtR", -(Cl-C6alkyl)NRtR", -0(1-4C)perfluroalkyl, -(l-4Cperfluroalky1, -NRt (Cl-C6alkyloxy), -NRt(C1-C6alkylhydroxy), -(Cl-4alkyl)oxy(Cl-4alkyl), -O(Cl-4alkyl) COOR', +CH),NRtR"COOR' wherein n is 1-4, -(C14alkyl)NRtRtt, -(Cl-4alkyl)ORt, -NRt(CH2), COOR', -S(O),(Cl-4alkyl)oxy(Cl-4alkyl), -S(O),(Cl-4alkyl)oxy(Cl-4alkyl)oxy (Cl-4alkyl), -NRt(C1-4alkyl)oxy(Cl-4alkyl),

-NR'(C1-4alkyl)oxy(Cl-4alkyl)oxy(C1-4alkyl);
heterocycle wherein heterocycle is selected from a fiveandior six- andior seven-membered heterocyclic ring containing 1 , 2 , or 3 heteroatoms chosen from O, N, or S wherein the N on the heterocycle is optionally substituted with R' and a carbon or nitrogen atom on the heterocycle may be substituted with R or R' or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with O to form a carbonyl group or sulfonyl group (S(O),); wherein the heterocyclic groups may be selected from, for example, 2-pyrolidinone, piperazine, oxazolidone, 2,5oxazolidinedione, 2,4-imidazollidinedione, 2,4thiazolidinedione or succinimide; aryl or benz or heteroarylbenz derivatives thereof (3,4pyridinedicarboximide, -1-pthalimido, isatoic anhydride, orthobenzoicsulfimide) either unsubstituted or mono, bi or tri-substituted with alkyl or aromatic substituents including -halo, -Cl-C6alky1, -OH, Cl-Coalkoxy, phenyl, OCF,, CF,, NO,, CN, NH,, SO,Rt, NH(C1-4alkyl), or N(C1-C4alkyl),; heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic substitu-

R'

dZ=J rR2
I

ss

=y
OR'

60

or a pharmaceutically acceptable salt thereof wherein: Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted atone or more ring carbon atoms with R1

65

5,837,705

9
ents include typical aromatic substituents selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to +CH,), via a carbon atom or a heteroatom on the heteroaryl group; n is 1; R, R,, R ~R', RI, R" and m are as previously s , defined. The invention also relates to a compound of formula 1:
I

10
2-pyrolidinone, piperazine, oxazolidone, 2,5oxazolidinedione, 2,4-imidazollidinedione, 2,4thiazolidinedione or succinimide; aryl or benz or heteroarylbenz derivatives thereof (3,4pyridinedicarboximide, -1-pthalimido, isatoic anhydride, orthobenzoicsulfimide) either unsubstituted or mono, bi or tri-substituted with alkyl or aromatic substituents including -halo, -Cl-C6alky1, -OH, Cl-Coalkoxy, phenyl, OCF,, CF,, NO,, CN, NH,, SO,Rt, NH(C1-4alkyl), or N(C1-C4alkyl),; heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole, isothiazole, or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or those groups containing 4 heteroatoms such as tetrazole wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic substituents include typical aromatic substituents selected from hydroxy, alkoxy, halo or cyano and the hetvia a carbon eroaryl group is attached to +CH,), atom or a heteroatom on the heteroaryl group; n is 2; R, R3, R7, Rs, RI, R" and m are as previously
-

IO

15

or pharmaceutically acceptable salts thereof wherein: Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, pyrrolyl or thienyl either unsubstituted or substituted atone or more ring carbon atoms with R1 a wherein is independently selected from the group consisting of hydrogen, halo, (1-4C)alkyl, NO,, CN, (Cl-3)perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR'R", S02NRtR", or SO,Rt; R' is -CHR,(CH,),N wherein L is chosen from: -OH, -O(Cl-C4alkyl), CF,-O(C1-C4alkyl) aryl, (Cl-C4alkyl)C02Rt, OCOR', S(0),Rt, NR'R". NR'COR". OCONR'. NRtCO,R"., ' . NRCONR'R", C02Rt, or CONRR'; phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1 , 2 , 3 or 4 groups chosen from -O-(l-4C)alk~l, -O-(2-4C)alkenyl9 -0-(2-4C) a l k ~ n ~-0(CeC6a1k~1)~hen~1~ -OH, l, -CN, -(1-4C)alky1CF33 -NH (CO)Rt, -(l-4C)alkyl, -NRtR", -C02Rt, 40mR" 402NR'R"' alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6) alkyloxy-, oxy(l-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho manner, aryloxy(1-4C)alkyloxy(l-4C)alkyl,

20

25

30

35

40

(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)
alkyloxy-, hydroxy(C1-C6)alkyloxy(Cl-C6) alkyloxy-, -O(Cl-C6alkyl)NRtR", -NRt 45 (Cl-C6alkyl)NRtR", -(Cl-C6alkyl)NRtR", -0(1-4C)perfluroalkyl, -(l-4C)perfluroalkyl, -NRt (Cl-C6alkyloxy), -NRt(C1-C6alkylhydroxy), -(Cl-4alkyl)oxy(Cl-4alkyl), -O(Cl-4alkyl) COOR', +CH),NRtR"COOR' wherein n is 1-4, so -(Cl-4alkyl)NRtR", -(Cl-4alkyl)ORt, -NRt (CH2),COORt, -S(O),(Cl-4alkyl)oxy (Cl-4alkyl), -S(O),(Cl4alkyl)oxy(Cl4alkyl) oxy(C1-4alkyl), -NRt(C1-4alkyl)oxy (Cl-4alkyl), -NRt(C1-4alkyl)oxy(Cl-4alkyl) ss oxy(C1-4alkyl); heterocycle wherein heterocycle is selected from a fiveandior six- andior seven-membered heterocyclic ring containing 1 , 2 , or 3 heteroatoms chosen from O, N, or S wherein the N on the heterocycle is optionally 60 substituted with R' and a carbon or nitrogen atom on the heterocycle may be substituted with R or R' or a carbon atom may be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom may be substituted with O to form a carbonyl group or 65 sulfonyl group (S(O),); wherein the heterocyclic groups may be selected from, for example,

defined. The N-2 substituted derivatives recited above are readily prepared by reacting the appropriate BOC-protected -CHR3(CH2),L (as R2) hydrazine as shown generally below with the appropriate 2-pyrrolidinocarbamide-3carboxylic acid precurser. The general reaction between the R2-substituted hydrazine and the 2-pyrrolidinocarbamide-3carboxylic acid (reacted with DCC) can be used to selectively produce the N-2 R' substituted PQD derivative from any of the groups recited wherein R2 may be above in the definition R2. The present invention preferably relates to a compound of formula 1 or Ia-Id:
I

R1dz=.s *'y
N/R2

"

R'

R'

w w
\
N
/

OR^

OR^

rR2

N
y,R2

H I

OR^

5,837,705

11
-continued
IC

12
R' is selected from a cycloalkyl moiety of 3-7 carbon atoms; . . . means a C-C, C-N or C-O double bond is optionally present with the proviso that the proper carbon or nitrogen valency may not be exceeded; a s wavy line means a designated group is optionally present; Z is selected from H, -OH, 0x0 or H,H; m is chosen from 0-2. The present invention also relates to a compound of 10 formula Ia-Id:

R'

q
H
O

OR^

Id

VRZ

OR^

1s

R'

or a pharmaceutically acceptable salt thereof and tautomers thereof wherein: Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from 20 phenyl, pyridyl, furyl, pyrrolyl or thienyl either unsubstituted or multi-substituted at a ring carbon atom with R1 wherein R1 is independently selected from the group consisting of halo, (1-4C)alkyl, NO,, CN, (Cl-3) perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (2-4C) 2s alkynyl, O(1-4C)alkyl, NR'R", S02NRtR", SOmRt; NR'COR", COR", NRtC02R", C02Rt, CONR'R"; R2 is selected from a group of the formula R2' or RZii

R'

w w
\
N
/

Ia

H I

OR^

N H I

OR^ y / R z

UT/R6
R2' 30

R5

OR^

wherein, n is 0-2; I R, is selected from (1-6C)alkyl, (O-6C)alkylCF3, 40 OR^ (0-6C)alkylCOOH; or pharmaceutically acceptable salts thereof: F~~ a group of formula ~ 2 ! ~5 iS Selected from aryl , wherein: wherein the aryl group rnay be unsubstituted or R1 is an aromatic substituent on the phenyl A ring of the mono- or multi-substituted with a typical aromatic A-B-C tric~licring SYstem wherein the phenyl ring substituent selected from halogen, (1-4C)alkyl, 4s may be unsubstituted or mono-, bi-, tri- or tetrasubstiNO,, CN, (Cl-3)perfluoroalkyl, OH, OCF,, (2-4C) tuted with R1 wherein R1 is selected from halogen, alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR'R", (1-4C)alkyl, NO,, CN, (Cl-3)perfluoroalkyl, OH, S02NRtR",or SOmRt; OCF,, (2-4C)alkenyl, (24C)alkynyl, O(1-4C)alkyl, NR'COR", COR", NRtC02R", C02Rt, CONR'R"; and so NR'R", S02NRtR", or SOmRt; NR'COR", COR", R~ is chosen from (1-6C)alkyl or hydrogen; NRtCO,R", C02Rt, CONR'R"; For a group of formula R2", R4 is selected from R2 is selected from a group of the formula R2' or RZii (l-6C)alkyl or (O-6C)alkylaryl wherein the aryl moiety rnay be unsubstituted or substituted or mulR2' tisubstituted with a typical aromatic substituent selected from halogen, (1-4C)alkyl, NO,, CN, ss (Cl-3)perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (24C)alkynyl, O(1-4C)alkyl, NR'R", S02NRtR",or R5 SOmRt; NR'COR", COR", NRtC02R", C02Rt, CONR'R"; R' and R" are independently selected from H, (1-4C) 60 alkyl wherein alkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); or (3-6C)cycloalkyl; or Phenyl wherein, (04C)alkyl- wherein the phenyl ring rnay be unsubn is 0-2; stituted or substituted with a typical aromatic subR, is selected from (1-6C)alkyl, (O-6C)alkylCF3, 65 stituent as recited above; (Cb6C)alkylCOOH; R~ is selected from H or (1-6C)C(O)-; For a group of formula R2', R' is selected from aryl or wherein the aryl group rnay be unsubstituted or

UT,R6

5,837,705

13
mono- or multisubstitued with a typical aromatic substituent selected from halogen, (1-4C)alkyl, NO,, CN, (Cl-3)perfluoroalkyl, OH, OCF,, (2-4C) alkenyl, (2-4C)alkynyl, O(1-4C)alkyl, NR'R", S 0 2 N R t R " , or SOmRt; NR'COR", COR", 5 NRtC02R", C02Rt, CONR'R"; and R6 is chosen from (1-6C)alkyl or hydrogen; For a group of formula R2", R4 is selected from (1-6C)alkyl or (O-6C)alkylaryl wherein the aryl moiety may be unsubstituted or substituted or mul- lo tisubstituted with a typcial aromatic substituent selected from halogen, (1-4C)alkyl, NO,, CN, (Cl-3)perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (24C)alkynyl, O(1-4C)alkyl, NR'R", S02NRtR",or SOmRt; NR'COR", COR", NRtC02R", C02Rt, l5 CONR'R"; R' and R" are independently selected from H, (1-4C) alkyl wherein alkyl includes alkenyl(C2-C4) and alkynyl(C2-C4); or (3-6C)cycloalkyl; or Phenyl (04C)alkyl- wherein the phenyl ring rnay be unsub- 20 stituted or substituted with a typical aromatic substituent as recited above; R~ is selected from H or (1-3C)alkylC(O)-; or

14
manner, aryloxy(1-4C)alkyloxy(l-4C)alkyl,

(C1-C6)alkyloxy(C1-C6)alkyloxy(C1-C6)
alkyloxy-, hydroxy(C1-C6)alkyloxy(Cl-C6) alkyloxy-, -O(Cl-C6alkyl)NRtR", -NRt (Cl-C6alkyl)NRtR", -(Cl-C6alkyl)NRtR", -0(1-4C)perfluroalkyl, -(l-4C)perfluroalkyl, -NRt (Cl-C6alkyloxy), -NRt(C1-C6alkylhydroxy), -(Cl-4alkyl)oxy(Cl-4alkyl), -O(Cl-4alkyl) COOR', +CH),NRtR"COOR' wherein n is 1-4, -(C14alkyl)NRtRtt,-(Cl-4alkyl)ORt, -NRt(CH2) ,COORt, -S(0)m(Cl-4alkyl)oxy(Cl-4alkyl), -S(0)m(C1-4alkyl)oxy(C1-4alkyl)oxy (Cl-4alkyl), -NRt(C1-4alkyl)oxy(Cl-4alkyl),

-NR'(C1-4alkyl)oxy(Cl-4alkyl)oxy(C1-4alkyl);
heterocycle wherein heterocycle is selected from a fiveandior six- andior seven-membered heterocyclic ring containing 1 , 2 , or 3 heteroatoms chosen from O, N, or S, or aryl or heteroaryl benz derivatives thereof, wherein the N on the heterocycle is optionally substituted with R' and a carbon or nitrogen atom on the heterocycle rnay be substituted with R or R' or a carbon atom rnay be disubstituted to form a C5-C7 spiral group or a carbon atom or sulfur atom rnay be substituted with O to form a carbonyl group or sulfonyl group @(O),) with the proViso that a heterocyclic nitrogen rnay not be attached to a nitrogen on the tricyclic ring system of formula 1; heteroaryl wherein heteroaryl is selected from unsubstituted or substituted aromatic species and benz derivatives thereof including pyridyl, thienyl, furanyl, or those groups containing two heteroatoms selected from N, O or S such as pyrazole, imidazole, isoxazole, oxazole, thiazole or isothiazole (and oxidized versions thereof selected from S(O), wherein m is 0-2), pyridazine, pyrimidine, pyrazine or those groups containing three heteroatoms chosen from N, O or S such as triazole or oxadiazole or triazine, or those groups containing four heteroatoms such as tetrazole, wherein the N on the heteroaryl group is optionally substituted with R and the substituted aromatic substituents are selected from hydroxy, alkoxy, halo or cyano and the heteroaryl group is attached to +CH,), via a carbon atom or a heteroatom on the heteroaryl group; is from OH, OR', OCoR'~ S(0)mR', S(0)m NR'R", halo, CF,, NR'R" or W is COR', NR'COR", OCONR', N R t C 0 2 R " , (C3-6)cycloalkyl, NRCONR'R", C02Rt, or CONRR'; n is chosen from 0-6; Z is selected from 0x0, -OH, H,H-, H, (1-6C)alkyl or (1-6C)alkylaryl wherein aryl may be substituted with a substituent or substituents selected from halogen or Cl-6alkyl; R3 is selected from (1-6C)alkyl, (&6C)alkylCF3, (&6C) alkylCOORt; R~ is selected from hydrogen or +CO)R' wherein R' is selected from (1) hydrogen, (2) (1-12C)alkyl which may contain a double or triple bond, and which may bear a group selected from (a) CN, ORe, and C02Re, wherein Re is selected from hydrogen, (1-4C)alkyl, and phenyl and phenyl(l4C)alkyl, the phenyl rings of which can be substituted with from &3 substituents selected from halo, amino, hydroxy, cyano, nitro, (1-4C)alkyl, and (1-4C)alkoxy; (b) NR~,and CONR~, wherein each R~is independently selected (1) from R ~ , COR^, and CO OR^ when the said group is NR~,and (2) from the values of R~ when the said group is CONR~,,

R2 is from a c ~ c l o a l k moi et^ of 3-7 carbon ~l atoms; m is chosen from 0-2. The present invention further relates to compounds of the Formula 1:

25

RI

dZ--.$ rR2
I 30

=y
OR'

35

or a pharmaceutically acceptable salt thereof; andior a tautomer thereof andior a solvate thereof; andior a hydrate thereof; andior a stereoisomer thereof; wherein: 40 Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring selected from phenyl, pyridyl, furyl, pyrrolyl or thienyl either unsubstituted or multi-substituted at a ring carbon atom with R1 wherein R1 is independently selected from the group 45 consisting of halo, (1-4C)alkyl, NO,, CN, (Cl-3) perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (2-4C) alkynyl, 0(14C)alkyl, NR'R", S02NRtR", SOmRt,a heterocyclic group, NR'COR", COR", NRtC02R", C02Rt, or CONR'R"; 50 R' is selected from a cycloalkyl moiety of 3-7 carbon atoms; or R2 is selected from a group of the formula R2', R2" or R2"' wherein R2' is -cHR~(cH,),c(o) NR'R~; R2" is -cHR,(cH,),R~ and R2"' is -CHR, (CH,),L wherein, for a group of formula R2"', L is M 5s or W , M is phenyl or benz derivatives thereof and is either unsubstituted or substituted with 1 , 2 , 3 or 4 groups chosen from -O-(1-4C)alkyl, -O-(24C)alkenyl, -060 (2-4C)alkynyl, -O(CO-C6alkyl)phenyl, -OH, -halo, -NO,, -CN, -CF,, -(l-4C)alkylCF3, -NH(CO)Rt, -(l-4C)alkyl, -NRtR", -C02Rt, -CONRtR", -SOmRt, -SO,NRtR", (Cl-C6) alkyloxy(C1-C6)alkyloxy-, hydroxy(C1-C6) 65 alkyloxy-, oxy(1-6C)alkyloxy which may form a cyclic ring attached to the phenyl ring in an ortho

5,837,705 15

16

wherein Rh can have any of the values stated above for alkyl or hydrogen; R4 is selected from (1-3C)alkyl or (O-3C)alkylphenyl wherein the phenyl moiety is Re, or wherein, for either of the said groups, the two Rf values, together with the nitrogen to which they are unsubstituted or substituted with a substituent selected attached, form a saturated 4- to 7-membered ring, (3) from halogen, (1-4C)alkyl, NO,, CN, (Cl-3) perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (2-4C) NRg2 wherein each Rg can independently have any of s alkynyl, or O(1-4C)alkyl; L is phenyl, or C02Rt the values stated above for Re, or wherein the two Rg groups together with the nitrogen to which are attached wherein R' is hydrogen or (1-4C)alkyl; form a saturated 4- to 7-membered ring, (4) pyridyl, R7 is selected from hydrogen or (1-3C)alkyl C(0)- and pyridyl(1-12C)alkyl, (5) phenyl, and phenyl(1-4C) R3 is as defined directly above. a l k ~wherein the phenyl rings cari be substituted with 10 l Particularly preferred compounds of the Formula Ia above from 0-3 substituents selected from halo, amino, are those wherein: h ~ d r O xcyanO, ~, (14C)a1k~1, and (1-4C)alk0x~; the ring A phenyl ring is mono-substituted with R1 R is selected from H or (14C)alkyl; wherein R1 is halo; R' and R" areinde~endentl~ selected from H, ( 1 4 C ) a l k ~ l R2 is cyclohexyl, or R2 is selected from a group of the wherein alkyl includes alkenyl(C2-C4) and alkynyl lS ~~~~~l~~ ~ 2 1 ~ 2 or ~ 2 "wherein is 0-2; , " ' (C2-C4); (3-6C)cycloalkyl, Phenyl(0-4C)alkyl-, R5 is phenyl wherein the phenyl group is unsubstituted; heterocycle(0-4C)alkyl- or heteroaryl(0-4C)alkylR4 is (1-3C)alkyl or (O-3C)alkylphenyl wherein the wherein phenyl or heterocycle or heteroaryl is as phenyl moiety is unsubstituted; L is phenyl or C02Rt defined above and any of the above is optionally wherein R' is hydrogen or (1-4C)alkyl; substituted at one or more carbon atoms with halo, H, 20 R7 is hydrogen and R3 and R6 are as defined directly (1-4C)alkyl, (3-6C)cycloalkyl, phenyl, NO,, CN, CF,, above. OH' 0-(14C)a1ky1' NR'R" S(0)mR' Or S02NR'R" Especially particularly preferred compounds of the Forwherein NR'R" may optionally form an N-alkyl(C1-3) mula Ia above are those wherein: oxyalkyl(C2-3) ring with N; the Ring A phenyl ring is mono-substituted with R1 for a group of formula R2!, R~ is selected from aryl 2s wherein R1 is chloro; wherein the aryl group may be unsubstituted or monoR2 is cyclohexyl, or R2 is selected from a group of the or multisubstituted with a substituent selected from formula R2', R2" or R2"' wherein n is 0-2; R5 is halogen, (14C)alkyl, NO,, CN, (Cl-3)perfluoroalkyl, phenyl; R6 is hydrogen or methyl; R4 is methyl, OH, OCF,, (24C)alkenyl, (24C)alkynyl, O(1-4C) isopropyl, or phenyl; L is phenyl or C02Rt wherein R' alkyl, NR'RII, SO,NR~RII, SO,R~, NR'CORII, COR", 30 is hydrogen or methyl; NRtC02R", C02Rt, or CONR'R"; and R6 is chosen R7 is hydrogen; and from (1-6C)alkyl or hydrogen; R3 is methyl, trifluoromethyl, C02H or C02CH3. for a group of formula R2", R4 is selected from (1-6C) Preferred species of the Formula Ia are those selected alkyl, (2-6C)alkyl containing a double or triple bond, or (O-6C)alkylaryl wherein the aryl moiety rnay be 3s from the group consisting of: unsubstituted or substituted or multisubstituted with a 7-chloro-4-hydroxy-2-[1-(N-phenylcarbamoyl)ethyl]-1, substituent selected from halogen, (1-4C)alkyl, NO,, 2,5,10-tetrahydropyridazino[4,5-b]quinoline-l,10CN, (Cl-3)perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, dione, (2-4C)alkynyl, O(1-4C)alkyl, NR'R", S02NRtR", 7-chloro-4-hydroxy-2-cyclohexyl-1,2,5,10SO,R', NR'COR", COR", NR'CO,R", CO,R', or 40 tetrahydropyridazino[4,5-blquinoline-1,lO-dione, CONR'R"; and 7-chloro-4-hydroxy-2-(l-methylbenzyl)-l,2,5,10m is chosen from 0-2. tetrahydropyridazino[4,5-blquinoline-1,lO-dione, Com~oundswithintheambitofFormulaIabovearethose 7-c~~oro-4-~y~roxy-2-(-~-met~y~~uty of the Formula Ia: 4s tetrahydropyridazino[4,5-blquinoline-1,lO-dione, Ia 7-chloro-4-hydroxy-2-(l-methyl-2-phenylethyl)-l,2,5, l0-tetrahydropyridazino[4,5-b]quinoline-l,lO-dione, 7-chloro-4-hydroxy-2-(-1,3-dimethylbutyl)-l,2,5,10RI tetrahydropyridazino[4,5-blquinoline-1,lO-dione,

wherein R1, R2 and R7 are as described directly above. Preferred compounds of the Formula Ia above are those ss wherein: theRingAphenylringismono,diortrisubstitutedwith R1 wherein R1 is selected from halo, (1-4C)alkyl or nitro; R2 is selected from a cycloalkyl moiety of 5-7 carbon 60 atoms, or R2 is selected from a group of the Formulas R2', R2" or R2"' wherein n is chosen from 0-2; R5 is phenyl wherein the phenyl group is unsubstituted or mono- or multisubstituted with a substituent selected from halogen, (1-4C)alkyl, NO,, CN, (Cl-3) 6s perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (2-4C) alkynyl, or O(1-4C)alkyl; R6 is chosen from (1-3C)

w
\
N
/

7-chloro-4-hydroxy-2-[(R)-l-(methyloxy-carbonyl)ethyl] -1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-l,10rR2

H I

OR'

dione, 7-chloro-4-hydroxy-2-[l-(methyloxycarbonyl)benzyl]-l, 2,5,l0-tetrah~dro~~ridazino[4,5-blquinoline-l~lodione, 7-chlor0-4-h~drox~-2-[l-(N-~hen~l-Nmethylcarbamoyl)ethy1]-1,2,5,l0-tetrahydropyridazino [4,5-blquinoline-1,lO-dione, 7-chloro-4-h~drox~-2-[l-meth~l-2-(N-~hen~l~arbam0~1) -ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline1,lO-dione, 7-chloro-4-hydroxy-2-[1-methyl-2-(N-phenyl-Nmethylcarbamoyl)ethyl]l,2,5,1O-tetrahydropyridazino [4,5-blquinoline-1,lO-dione, 7-chloro-4-hydroxy-2-(1-trifluoromethylbenzy1)-1,2,5, l0-tetrahydropyridazino[4,5-b]quinoline-l,lO-dione,

5,837,705

17
7-chloro-4-hydroxy-2-(l-carboxybenzyl)-l,2,5,10tetrahydropyridazino[4,5-blquinoline-l,10-dione, and 7-chloro-4-hydroxy-2-[(R)-l-carboxyethyl]-l,2,5,10tetrahydropyridazino[4,5-blquinoline-1,lO-dione. s The present invention also relates to a pharmaceutical composition comprising a compound of formula 1 or Ia-Id with the-variables recited above and a pharmaceutically acceptable excipient or diluent. 10 The invention further relates to a method for the treatment of neurological disorders comprising administering to a patient in need of such treatment an effective amount of a compound of the Formula 1, or Ia-Id. The present invention also relates to a method of treating 15 or preventing ischemic damage in a patient in need of such treatment comprising administering a pharmaceutically effective amount of a compound of formula 1 or Ia-Id with the variables as recited above to said patient. 20 The invention further relates to a method of treating or preventing neurological damage associated with excitatory amino acids in a patient in need of such treatment comprising administering a pharmaceutically effective amount of a 25 compound of formula 1 or Ia-Id to said patient. The invention also relates to a method of treating stroke or epileptic convulsions or diseases or disorders associated with excessive calcium influx in the brain caused by excitatory amino acids comprising administering to a patient in 30 need of treatment thereof a pharmaceutically effective amount of a compound of formula 1 or Ia-Id. The invention further relates to a process for producing a compound of formula 1 or Ia-Id, comprising:
35

18
(a) reacting a compound of the Formula IV:

OH O

O
with a hydrazine of the formula:

7
R~-s&

O O

to produce a compound of the Formula II

jII
c. ' .". o
O

and (b) reacting said compound of the Formula II with an acid to afford the compounds of the Formula 1. The invention also relates to the use of a compound of formula 1 or Ia-Id in medicine and to diseases or disorders associated with excitatory amino acids. The invention further relates to the use of a compound of 40 the Formula 1 or Ia-Id for the preparation of a medicament for the treatment of neurological disorders. The invention also relates to the use of a compound of formula 1 or Ia-Id for the treatment or prevention of stroke 45 epileptic conwlsions or disorders or conditions associated with excessive influx of calcium ions in the brain. None any unto(a) 7-chloro-4-hydroxy-2-[l-(phenylcarbamoy~)ey], of the compounds recited herein have ~roduced 2,5,10-tetrahydropyridazino[4,5-b]quinoline-l,10ward effects. The present invention also relates to compounds which dione; are useful as key intermediates in the production of glycine (b) 7-chloro-4-hydroxy-2-cyclohexyl-1,2,5,10- receptor antagonists. Key intermediates include 3-carboxylic acid quinoline 2-pyrrolidineamide compounds tetrahydropyridazino[4,5-blquinoline-l,10-dione; which are utilized to react with BOC-protected substituted 7-ch10r0-4-h~dr0x~-2-(a1~ha-meth~1benz~112510 hydrazines to form, after coupling with dicyclohexyldiimide tetrah~dro~~ridazino[4,5-b]quinoline-l,10-dione; 55 or diisopropVldiimide or 1-cyclohexyl-3-(2-morpholinyl-. (d) 7-chloro-4-hydroxy-2-(l-methylbutyl)-1,2,, ethy1)-carbodiimide, in a solGent 'such a s THF, methanol, diethylether, dioxane, CH2C12, CH3CN or DMF tetrahydropyridazino[4,5-blquinoline-l,10-dione; and an acid ( e . g . C H 3 S 0 3 H ) to p r o d u c e (e) 7-chloro-4-hydroxy-2-(alpha-methylphenet- a - p y r r o l i d i i o c a r b a m i d e 3 c a r b o x y l i c a c i d - N - 1 l0-tetrahydropyridazino[4,5-blquinoline-,10-dione; R2-substituted hydrazide, which after deprotection or 60 and removal of the BOC or other bulk N-vrotection prouv, leads selectively to the N-2 substituted PQD. (seeuscherne 1, ( f ) 7-chloro-4-hydroxy-2-(1,3-dimethylbutyl)l,2,5,10formula II and III) wherein R' is defined as recited herein. tetrahydropyridazino[4,5-blquinoline-1,lO-dione. The pyrrolidine may be substituted with an equivalent amine The invention further relates to a process for producing a 65 which produces an amide with limited steric hindrance and compound of the Formula 1 which comprises: which acts as an appropriate leaving group. treating any of the compounds of formula Ia produced in SteP (a) recited in the following Pages with a reducing agent under suitable conditions to form a compound of formula Ib and further treating a compound of formula Ib with a reducing agent under the appropriate conditions to form a comvound of formula Ic. The invention further relates to a process for producing a com~oundof Or Ia-Id according to certain recited above or as shown in the examples wherein the compounds are selected from:

'

SCHEME 1

DCC or other equivalent reagent

>

R'

MSA

H
III

O
1

la, R7 = H

1) NaBH41CH3COzH THF (for lb) and Hz/ metal for lb to lc lb or lc

EPO publication number O 516 297 A l describes certain 35 R2 is selected from a group of the formula R2' or R2" pyridazinediones. In addition, the compounds (1) thieno[2', 3':5,6]pyrido[2,3-d]pyridazine-5,8,9(4H,6H,7H)-trione and R2' (2) thieno[3',2':5,6]pyrido[2,3-d]pyridazine-4,5,8(6H,7H, 9H)-trione are known, for example from J. Heterocyclic 40 R y '6 Chem., 28, 205, (1991). R5 Other pyridazinedione compounds are known from, for example, Beilstein's Handbuch der Organischen Chemie; R2" Godard et. al., Bull. Soc. Chim. Fr., 1588, (1972); and Reid R4 et. al., Chem. Ber., 85, 204, (1952). The compounds of the present invention, on the other hand, relate to novel 45 wherein, 2-substituted pyridazinediones or tautomers thereof as n is 0-2; shown above in formula 1 or Ia-Id with the variables as R, is selected from (1-6C)alkyl, (&6C)alkylCF3, (&6C) recited above. alkylCOOH; Particular subgroups within the above broadly defined a grouP R2', R5 is frOm a r ~ l group of compounds include those compounds having the 50 wherein the aryl group may be unsubstituted or monospecific formulae 1 wherein: or multi-substituted with a typical aromatic substituent selected from halogen, (1-c)alkyl, NO,, CN, (Cl-3) perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (2-4C) alkynyl, O(1-4C)alkyl, NR'R", S02NRtR",or SOmRt; NR'COR", COR", NRtC02R", C02Rt, CONR'R"; and R6 is chosen from (1-6C)alkyl or hydrogen; For a group of formula R2", R~ is selected from (1-6C) alkyl or (&6C)alkylaryl wherein the aryl moiety may be unsubstituted or substituted or multisubstituted with Ring A i s chosen from an ortho fused aromatic or heteroaro- 60 a typical aromatic substituent selected from halogen, matic five- or six-membered ring selected from phenyl, (1-4C)alkyl, NO,, CN, (Cl-3)perfluoroalkyl, OH, pyridyl, pyrrolyl or thienyl either unsubstituted or substiOCF,, (2-4C)alkenyl, (24C)alkynyl, O(1-4C)alkyl, tuted at one or more ring carbon atoms with R1 wherein R1 NR'R", S02NRtR", or SOmRt; NR'COR", COR", is independently selected from the group consisting of NRtCO,R", C02Rt, CONR'R"; hydrogen, halo, (1-4C)alkyl, NO,, CN, (Cl-3) 65 perfluoroalkyl, OH, OCF,, (2-4C)alkenyl, (2-4C)alkynyl, R' and R" are independently selected from H, (14C)alkyl O(1-4C)alkyl, NR'R", S02NRtR", or SOmRt; wherein alkyl includes alkenyl(C2-C4) and alkynyl

5,837,705

21
(C2-C4); or (3-6C)cycloalkyl; or Phenyl(0-4C)alkylwherein the phenyl ring rnay be unsubstituted or substituted with a typical aromatic substituent as recited above;

22

R' 5 or \ 0 N R2 is selected from a cycloalkyl moiety of 3-7 carbon H 1 OR^ r R 2 atoms; . . . means a C-C, C-N Or C-O is or pharmaceutically acceptable salts thereof wherein the o ~ t i o n a l lPresent with the provis0 that the ProPer 10 phenyl ring unsubstituted or substituted and is selected from ~ carbon or nitrogen valency rnay not be exceeded; a phenyl, 7-chlorophenyl, 7,9-dichlorophenyl, 7-chloro-9wavy line means a designated group is optionally methylphenyl, 7-methyl, 9-chlorophenyl, 7,9present; dimethylphenyl, 7-chloro-8-nitrophenyl, 7,9-dichloro-8n i t r o ~ h e n ~7-ch10r0-9-eth~1~hen~1 l, wherein the Ilumeric is chosen from 0-2; and pharmaceutically acceptable salts thereof, The present invention also relates to 15 designations refer to the position on the final pyridazino quinoline ring system; R2 is selected from cyclohexyl, pharmaceutical compositions of a compound of foralpha-methylbenzyl, 1-methylbutyl, 1-(phenylcarbamoyl) mula 1 as defined above and a pharmaceutically acceptethyl, alpha-methylphenethyl or 1,3-dimethylbutyl; R7 is able excipient. In addition, the present invention relates selected from or acetyl, When R7 iS acetyl, the compounds t" intermediates which are usehl in the 20 may act as a and hydrolyze under physiological synthesis of a compound of formula 1. conditions to the active parent compound or may be active particular subgrOu~s inchde those cOm~Ounds havper se as the mono-acetylated derivative. The most preferred ing the specific formulae Ia or Ib, R1 substituent is 7-chloro. The preferred group for R5 is phenyl; and for R6 is methyl or hydrogen. The preferred Ia 25 group for R4 is a C3-6 straight or branded chain hydrocarbon (depending upon the value for n) or a phenyl ring (e.g. OCalkylphenyl). R' The present invention also relates to pharmaceutical comN positions containing a preferred compound of formula Ia as N 30 shown above and a pharmaceutically acceptable carrier. OR^ H It will be appreciated that the formulae described herein can be drawn in various tautomeric and positional isomeric ~b forms, as discussed below. The present invention includes such alternate forms unless otherwise indicated, also R' 35 includes salts thereof, especially the pharmaceutically N acceptable addition salts. N It will be appreciated that some of the compounds disOR^ H closed herein can exist and be drawn in various true tautomeric forms (i.e., imine to enamine conversion in the B wherein 40 ring).

It will further be appreciated by those skilled in the art that the phenyl ring is mono, di or tri-substituted with R" certain compounds of formula 1 rnay contain an asymmetriwherein RH is selected from halo, nitro or simple cally substituted carbon atom, and accordingly may exist in, Cl-C4alkyl including methyl, ethyl or propyl; and be isolated in, optically-active and racemic forms. Some R2 is selected from R2' or R2" as shown above wherein, 45 compounds rnay exhibit polymorphism. It is to be undern is 0-2; stood that the present invention encompasses any racemic, R3 is selected from (1-3C)alkyl, CF, or COOH; optically-active, polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful in For a group of formula R2', R5 is selected from phenyl the treatment of neurodegenerative disorders, it being well wherein the phenyl group rnay be unsubstituted or mono- or multi-substitued with a typical aromatic sub- 50 known in the art how to prepare optically-active forms (for example, by resolution of the racemic form or by s~nthesis stituent selected from halogen, (1-4C)alkyl, NO,, CN, ( ~ 1 - 3 ) ~ ~ ~ f l OH, ~ ~ ~ l ( k ~ 4 ~ ) ~ l k ~ ~ from, optically-active starting materials) and how to deter~ ~ OCF,, 2- l , ~l ( 2 - 4 ~ ) ~ l k o (~l - 4l ~ ) ~ l k ~ l ; ~6 iS choSen from ~ ~ , and mine neuroprotective properties by the standard tests (1-3C)alkyl or hydrogen; described hereinafter. 55 The invention further provides a method for the treatment a group R2", R4 is frOm (1-3C) of neurological disorders, comprising administering to a a l k ~ Or (0-3C)a1k~1~hen~1 l wherein the phenyl moi et^ rnammal in need of treatment an effective amount of a may be unsubstituted or substituted or multisubstituted compound according to the invention as defined above, or a with a typcial aromatic substituent from pharmaceutically acceptable salt thereof, or a composition (14C)alky12 CN, (C1-3)perflu0r0alky12 60 as defined above. The invention also encompasses a method OH, OCF3? (24C)a1keny12 (24C)alkyny12 of antagonizing an NMDA receptor in mammals comprising alkyl; administering a pharmaceutically effective amount of the or compound or its salt as claimed herein or a pharmaceutical R2 is selected from a cycloalkyl moiety of 5-7 carbon composition as recited herein to a patient in need of treatatoms. 65 ment thereof. The preferred therapeutic treatment area is Preferably, the present invention relates to compounds of prevention andior treatment of stroke. A pharmaceutically formula Ia: effective amount of a compound as claimed and disclosed in

5,837,705

23

24

the present invention may be administered immediately after dihalophenyl, 2-methyl-4-fluorophenyl, or 2,3 or 4 an ischemic event to prevent ce11 damage andior ce11 death. (CONRtR")phenyl. The present is also directed to a method of Particular values of phenyl(l-4C)alkyl substituted with preventing treating damage induced b~ the excitatory from 0-4 substituents may include benzyl, phenylethyl, amino acids such as L-glutamate. The invention also relates s phenylpropyl, phenylbutyl; 2-, 3-, and 5-halobenzyl; 2-, 3to a method of preventing the excessive influx of calcium and 4- CF3-benzyl, 2-, 3-, and 4-aminobenzyl; 2-, 3-, and ions in central neurons. The invention relates to a method of 4-cyanobenzyl, 2-, 3-, and 4-nitrobenzyl, 2-, 3-, and preventing ischemic neuronal injury following transient 4-meth~1benz~1; 3-, and 4-eth~1benz~1; 3-, and 2-, 2-, global ischemia and a rnethod of reducing infarct volume following focal ischemic insults by treating a patient in need 10 4 - ~ r o ~ ~ 1 b e n 2-, 1 ; and 4 - h ~ d r o x ~ b e n z 2-, ;3-, and z ~ 3-, ~1 4-methox~benz~l; 3-3 and 4-ethoxybenzyl; 2-3 3-3 and 2-3 of treatment thereof with a pharmaceutically effective 4-~'o~oxYbe"zYl; and 3,5-dihalobenzYl, 3-halo-4amount of a compound of formula Ia wherein the variables hYdroxYbenzY1, 395-diCF3benzYl and 335-dihalo-4for R' and R' are as defined herein. In addition to being hYdroxYbenzY1 or 2,3,4,5,6-~entahalobenzYl; and phenyl useful in the treatment of acute stroke patients, the compounds and compositions of the invention may be extremely 1s (1-4C)alkyl substituted with methoxyethyloxy, beneficial in preventing neurological morbidity during carmethoxyethyloxyethyloxy, N,N-dimethylethyloxy, and diac resuscitation or administered as cerebral prophylatics N,N-dimethylethylaminyl; 3,4-dimethoxy; 3,4-dihydroxy; during high-risk surgery. 3,5-dimethoxy; 3,5-dihydroxy or 2,3,4-SMe or 2,3,4-SH. In this specification the terms "alkyl" and "alkoxy" More particular values of halo include chloro and bromo. include both straight and branched chain radicals, but it is to 20 More particular values of (l-3C)perfluoroalkyl include be understood that references to individual radicals such as trifluoromethyl and pentafluoroethyl. "propyl" or "propoxy" embrace only the straight chain More particular values of 4- to 7-membered rings con("normal'') radical, branched chain isomers as "isoprotaining nitrogen include piperidino, piperazinyl and pyrropyl" or "isopropoxy" being referred to specifically. The term "halo" is inclusive of fluoro, chloro, bromo, and 2s lidinyl. iodo unless noted otherwise. More particular values of (l-3C)alkyl substituted with a The term c ~ c l O a l k moi et^ ~l 3-7 carbon atoms means trifluoromethyl group include trifluoromethylmethyl and c y c l o ~ r o ~ y cyclobutyl, cyclo~entyl,cyclohexyl and l, 2-trifluoromethylethyl. cycloheptyl, preferably cyclohexyl. More particular values of m include &2. Particular values of (l-3C)alkyl include methyl, ethyl, 30 More particular values of n include 0-2. propyl, isopropyl. Particular values of (2-4C)alkyl containing a double or More particular values of phenyl substituted with from triple bond include vinyl, 2-propenyl (i.e. allyl), 2-propynyl, 0-3 substituents may include phenyl; 2- and 4-halophenyl; (i.e. propargyl), 2-butenyl, and 3-butenyl. 2- and 4-aminophenyl; 2-, 3- and 4-hydroxyphenyl; 2-, 3Particular values of (1-4C)alkoxY include methox~,35 and 4-methoxyphenyl; 2,4-dihalophenyl; 3,5-dihalophenyl; ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and 2,6-dihalo-4-hydroxyphenyl, 2-halo-4-methylphenyl; t-butoxy. 2-methoxy-4-methylphenyl; 2-methyl-4-methoxyphenyl; Particular values of (1-6C)alkYl include methyl, ethYl, 3-hydroxy-4-methylphenyl; 2-hydroxy-4-methyl phenyl, P ~ O P Yi ~ ,o ~ r o ~butYl, isobutyl, sec-but~l,tert-but~l, 2-methyl-4-chlorophenyl, 2,4-dimethylphenyl, 3,4s ~l, pentyl, isopentyl, neopentyl, hexyl, isohexyl. 40 dimethoxyphenyl, 2-methyl-4-methoxyphenyl, 3,4(2-6C)a1k~l containing a double or dihydroxyphenyl or 2,4-dimethylphenyl; and includes those triple bond include vinYl, 2-~ro~enYl(i.e. allYl), 2-~ro~YnYl, values specifically exemplified in the examples. (i'e' P ~ ~ P ~ but-2-en~1,2 - ,~ e n t e n ~ 1 ,- ~ e n t e n ~ 1 , ~ ~ Y ~ ) 3 More particular values of phenyl(C1-C4)alkyl substituted 4-pentenyl, 4-pentynyl, 5-hexenyl, 5-hexynyl. with 0-3 substituents may include benzyl; phenylethyl; 2Particular values of phenyl substituted with from 0-4 4s and 4-halobenzyl; 2- and 4-cyanobenzyl; 2- and substituents may but are limited t0 phenyl; 2-, 3-, 4-nitrobenzyl; 2- and 4-methoxybenzyl; 2,4-dihalobenzyl, and 4-ha10~heny1; 3-3 and 4-amin0~hen~1; 3-3 and 2-, 2-, 3,5-dihalobenzyl; and 2,6-dihalo-4-hydroxybenzyl, corThe 4 - h ~ d r o x ~ ~ h e 2-, 1 ; and 4 - c ~ a n 0 ~ h e n ~ 1 ; 3-, and n ~ 3-, 2-, responding phenethyl isomers may also be included, 4-nitrophenyl; 2-, 3-, and 4-methylphenyl; 2-, 3-, and Preferred com~ounds having 4-ethylphenyl; 2-, 3-, and 4-propylphenyl; 2,3 or so 4-isopropylphenyl; 2-, 3-, and 4-methoxyphenyl; 2-, 3-, and (a) 7-chloro-4-hydroxy-2-[l-(phenylcarbamoyl)ethyl]-l, 4-ethoxyphenyl; 2-, 3-, and 4-propoxyphenyl; and 3,52,5,10-tetrahydropyridazino[4,5-b]quinoline-l,10dihalophenyl, 3-halo-4-hydroxyphenyl, and 3,5-dihalo-4dione; hydroxyphenyl and phenyl substituted at 1, 2 or 3 carbon (b) 7-chloro-4-hydroxy-2-cyclohexyl-1,2,5,10atoms with methoxYethYloxY, methoxYethYloxYethYloxY, 5s tetrahydropyridazino[4,5-blquinoline-1 ,IO-dione; N,N-dimeth~leth~lox~, N,N-dimeth~leth~lamin~l; and 3,4(c) 7~chloro-4-hydroxy-2-(alpha-methylbenzyl)~~,~,~,~~~ dimethoxy; 3,4-dihydroxy; 3,5-dimethoxy; 3,5-dihydroxy or tetrahydropyridazino[4,5-blquinoline-1,lO-dione; 2,3,4-SMe or 2,3,4-SH and further includes groups selected from 4-(S02CH3)phenyl, 2-methyl-4-chlorophenyl, 2,47-ch10ro-4-h~drox~-2-(1-meth~1but~1)-1,2~5~10d i h a l o h e y 1, 4 ( t e t a 1e ) h e y 1, 3 , 5 - 60 tetrah~dr0~~ridazin0[4,5-b]quin01ine-1,10-di0ne; trifluoromethylphenyl, 2,4-dimethylphenyl, 3-halo-4(e) 7-~hloro-4-h~droxY-2-(al~ha-methYl~henethYl)-l,2,5, methylphenyl, 4-trifluoromethylphenyl, 3,4l0-tetra-hydropyridazino[4,5-b]quinoline-l,lO-dione; dimethylphenyl, 2-methyl-4-methoxyphenyl, 2-methoxy-4and (f) 7-chloro-4-hydroxy-2-(1,3-dimethylbutyl)l,2,5,10halophenyl, 2-methyl-4-hydroxyphenyl, 2,3dimethylphenyl, 2,4-dimethoxyphenyl, 2,5-6s tetrahydropyridazino[4,5-b]quinoline-l,lO-dione.Of dimethoxyphenyl, 2,5-dimethylphenyl, 4(benyloxy)phenyl, course, because of the convenient and easy preparation 4-(ethoxy)phenyl, 2,5-dihydroxyphenyl, 4-vinylphenyl, 2,5of the starting Nt-R2 substituted BOC protected

'

5,837,705 25
hydrazines, the above compounds are non-limiting and include any of the compounds within the generic scope as recited previously. Pvridazinediones of formula 1 (or other formulae as recited herein) can be made bv arocesses which include 5 , processes known in the chemical arts for the production of structurally analogous compounds. The preparation of compounds wherein Z is H on certain starting materials described herein can be affected by chlorinating the hydroxy 10 group of the dialkyl 4-OH quinoline-2,3-dicarboxylate (starting material) using phosphorous oxychloride. This chlorine is then reduced using tetrakistriphenylphosphine Pd(0) and sodium formate to provide dimethyl quinoline2,3-dicarboxylate which is then processed through the 15 remaining chemical steps (e.g. adding the hydrazine etc.) The processes for the manufacture of a starting pyridazinedione of formula 1 as defined above are provided to show the preparation of the preferred starting materials utilized in the present invention and are illustrated by the following pro- 20 cedures in which the meanings of generic radicals are as given above unless othenvise qualified. Such a process can be effected, generally, (a) to obtain a compound of formula 1 via a process as described herein is achieved according to the general 25 procedure described in Scheme 1 and specifically exemplified in non-limiting examples 1-14. A 2-pyrrolidinocarbamide quinoline 3 carboxylic acid, prepared from hydrolysis of the corresponding 30 3-methyl ester which is prepared by reacting the corresponding 3 carbomethoxy quinoline 2 carboxylic acid with dicyclohexylcarbodimide or other appropriate diimide coupling reagent such as diisopropyl carbodiimide and pyrollidine, is reacted with an N-t- 35 b u t o ~ ~ c a r b o n ~ l - ~ ' - 2 - ~ ~ ~ ~L( with ~ ) (or replace ~ ~ -R4 or -c(o)NR~R~) (n=0-4) hydrazine (prepared from the reaction of either (a) t-butylcarbazate and the desired Cl-C4 alkvlarvl or a substituted alkvl arvl or , , , , an alkoxy alkyl compound wherein the terminal alkyl 40 carbon has a suitable leaving group selected from halo (X) or triflate in a solvent such as DMF, CH2C12 or CH3CN or equivalent and a base such as NEt, or, other groups which may readily react with t-butylcarbazate to form a starting disubstituted hydrazine t-butylO(C0) 45 -N-N-R2 include any alkylaryl, aryloxyalkyl, alkyloxyalkyl, alkyloxyalkyloxy or alkylheteroaryl recited herein wherein the alkyl group has a suitable leaving group. For n=0-4, a suitable aryl or substituted aryl aldehyde or substituted alkylaldehyde with so t-butylcarbazate in refluxing hexanes or equivalent organic solvent to form the corresponding imine which is then reduced with a reducing agent (e.g. BH, THF or LMH,) to obtain a key intermediate hydrazide which is cvclized in CH,SO,HITHF or eauivalent solvent to ss selectively form 2-sibstituted <cR~H)(cH,), aryl or +cR~H)(cH,)~ alkyl aryl PQD or +CR~H) (CH2)n substituted alkyl PQD. This process may generally be utilized to selectively form a compound of formula 1. t-butylcarbazate is commercially available and the R2-substituted t-butyl carbonate hydrazines are readily prepared. As described in the examples, there are at least three ways to prepare the starting substituted hydrazines-methods X, Y and Z (See Scheme 2). As is readily apparent from Scheme 2, the starting halides, aldehydes or alcohol are easily prepared or are commercially available.
L

26
Scheme 2 Hydrazine Preparation: Method X
H

1
4 (5 equiv.) 50" C. Et3N

>

~ preparation: ~ d H

~~ Y

~~

~~

di

AH
6

Hexanes, reflux

>

, ~
Hydrazine Preparation: Method
OH

Rz

1. TFZO, CHZC~Z 2.6-lutidine, O n C. H

>

2~hNy0F
O

O" C. R1 or RZ= COZR' 35" C. RI or R~ # COZR'

A compound of formula 1 wherein L is a heterocyclic moiety such as a 4-(Cl-C6)substituted piperazine or 4-arylsubstituted piperazine or a phthalimido or another commercially available nucleophilic heterocycle may be formed by reacting the heterocyclic nucleophilic species with a 2-halo(CH2),CR3alkyl pyridazino[4,5-b]quinolines of formula 1, the latter of which is prepared from the corresponding hydroxy species. As the following examples will show, compounds within the scope of the present invention are prepared by a variety of chemical synthetic steps or procedures. Compounds of formula 1 wherein Z is (Cl-6)alkyl or (Cl-6)alkylaryl may be prepared from the

carboxylic acids, carbonyl halides, esters, amides, or tetracorresponding compound of formula 1with Z as 0x0 by alkyl or alkylaryl addition to the B-ring carbonyl of the PQD zoles. As indicated previously, anion displacement systems. Grignard reactions using ZMgX or coupling sys(nucleophilic displacement) is utilized to produce various tems with alkyl lithium anions (e.g. ZLi or ZM) or a Wittig heterocyclic compounds or benz or heteroaryl benz derivareaction using Ph3P-C(RRt) rnay be utilized to form a s tives thereof which are glycine receptor antagonists. An N-2 halo(C14) alkyl PQD is reacted with the selected nucleoprecursor to a compound of formula 1 which is subsequently reduced or modified and reduced to form a compound of phile (heterocyclic or heteroaryl) to form the corresponding formula 1 wherein Z is alkyl or alkyl aryl. N-2 Nucleophile-(Cl-4) alkyl PQD. In the case of alkylation or benzylation of the B-ring If not commercially available, the necessary starting carbonyl, it rnay be necessary to perform the reaction on a 10 materials for the procedures such as that described above pre-coupled precusor which is also nitrogen-protected. This rnay be made by procedures which are selected from stanwould avoid unselective alkylation at the C-ring carbonyls. dard organic chemical techniques, techniques which are However, it rnay also be possible to protect the C-ring analogous to the synthesis of known, stmcturally similar carbonyl(s) before alkylating (with ZM) the B-ring carbocompounds, or techniques which are analogous to the above nyl. 15 described procedure or the procedures described in the In general, Schemes 1 and 2 describe how some of the examples. Examples of suitable pharmaceutically acceptable salts compounds within the scope of the present invention or intermediates are prepared. The preferred compounds are are salts formed with bases which form a physiologically those of formula Ia. The preferred process for producing acceptable cation, such as alkali metal (especially lithium, compounds of formula Ia involves (i) preparing an interme- 20 sodium and potassium), alkaline earth metal (especially diate PQD of formula II and III which is then cyclized to a calcium and magnesium), aluminum and ammonium salts, . as well as salts made with appropriate organic bases such as compound of formula Ia ( R 7 = ~ )This compound rnay be reduced to a compound of formula Ib or Ic under the choline hydroxide, triethylamine, morpholine, piperidine, conditions as described below (see Scheme 1). The preferred ethylenediamine, lysine, ethanolamine, diethanolamine, reduction conditions involve suspending a compound of 25 triethanolamine, N-methyl-D-glucamine (meglumine), formula Ia (specifically prepared as shown in examples 1-6) arginine, and tris(hydroxymethy1)aminomethane. Choline, meglumine, sodium and potassium salts are preferred. in an organic solvent selected from, but not limited to, THF with subsequent addition of trifluoroacetic acid (significant Choline, sodium and potassium salts are especially premolar excess). This suspension is cooled to about O" C. and ferred. sodium borohydride is added in molar excess (5x or less). 30 When used to intervene therapeutically following a stroke, a pyridazinedione of formula 1 or Ia-Id generally is The reduction is then allowed to proceed at 0' C. for about administered as an appropriate pharmaceutical composition 15 minutes and then warmed to room temperature and stirred for about 3 hours. Upon work-up and after triturating which comprises a compound according to the invention as defined hereinbefore together with a pharmaceutically and filtering (2x), the title compounds are readily obtained. The preferred group for Z on a compound of formula 1 is 35 acceptable diluent or carrier, the composition being adapted for the particular route of administration chosen. Such oxygen. Z, in a compound of formula 1, rnay also be hydrogen, OH SH or NHR or as othenvise described herein. compositions are provided as a further feature of the invenKey intermediates are shown in the Schemes or described in tion. They rnay be obtained employing conventional procethe text. dures and excipients and binders and may be in a variety of As exemplified in a non-limiting manner in the examples, 40 dosage forms. For example, they rnay be in the form of tablets, capsules, solutions or suspensions for oral adminisa key process for selectively producing N-~-(cHR~)(cH,), aryl, -(CHR3)(CH2), heteroaryl, substituted alkyl or other tration; in the form of suppositories for rectal administration; species prepared from any N-2 intermediates involves the in the form of sterile solutions or suspensions for administration by intravenous or intramuscular injection or infusion; initial production of a 2-pyrrolidinoamido substituted quinoline which is formed from the corresponding 2-carboxy 45 and in the form of powders together with pharmaceutically acceptable inert solid diluents such as lactose for adminis3-carboalkoxy quinoline. This compound or analogous compounds (e.g. with groups equivalent to pyrrolidinoamido) is tration by insufflation. hydrolyzed to form the corresponding 2-pyrrolidinoamidoThe dose of a compound according to the invention which 3-carboxy quinoline (IV) which is then coupled with the is administered will necessarily be varied according to selected R 2 - ~ - ~ - ~ ( O ) O - t - b u t ~ l hydrazine using a so principles well known in the art taking account of the route of administration, the severity of the postischemic disorder, selected dimide (e.g. DCC or equivalent) to form a hydrazide intermediate-e.g. 2-pyrrolidinoamido-3and the size and age of the patient. In general, a compound of according to the invention will be administered to a warm carboxylic ~c~~-NR'-N(Boc) hydrazide which, under the cyclization conditions, forms the N-2 substituted PQD withblooded animal (such as man) so that an effective dose is out any N-3 substituted PQD formed. For example, the alpha ss received, generally a dose in the range of about 0.01 to about methyl benzyl or substituted benzyl compounds described 100 mgikg body weight. For example, if the compound is herein are readily and conveniently prepared from the approadministered intravenously, it is administered in the range of priate 2-pyrrolidinoamido 3-carboxylic acid and the about 0.01 to about 10 mgikg body weight. If it is adminN-alphamethylbenzylNt-t-butyl carboxy hydrazine which istered orally, it is administered in the range of about 0.5 to was actually prepared from the corresponding alkylhalide 60 about 100 m g k g body weight. and t-butyl carbazate. t-Butylcarbazate reacts readily to It will be apparent to those skilled in the art that a displacethehalideoralcoholsuchastriflatetoformthe c o m p o u n d a c c o r d i n g to the i n v e n t i o n c a n be desired hydrazine. CO-administered with other therapeutic or prophylactic Another intermediate and glycine receptor antagonist agents andior medicaments that are not medically incomincludes N-2-alpha substituted (1-6C)alkylaryl PQDs of 65 patible therewith. In general, representative compounds of formula 1 substituted with a cyano substitutent or substituthe instant invention do not show any indication of signifients. This moiety (CN) can be further manipulated to form ciant toxicity in laboratory test animals.

5,8: 705

29
The actions of compounds according to the invention as antagonists at the glycine receptor of the NMDA receptor complex can be shown by one or more standard tests such as the [3~]-glycine binding assay (Test A) and by tests in vivo such as the red nucleus test (Test B) and the Rat Middle Cerebral Artery test (Test C). These tests confirm that compounds of the invention are NMDAreceptor antagonists in vitro and in vivo. Certain compounds of the invention are potent NMDA receptor antagonists. Test A In the [3~]-glycinebinding assay, neuronal synaptic membranes are prepared from adult (about 250 g) male Sprague-Dawley rats. Freshly dissected cortices and hippocampi are homogenized in 0.32M sucrose (110 mg1mL). Synaptosomes are isolated by centrifugation (1000xg, 10 min), the supernatant is pelleted (20,00Oxg, 20 min) and resuspended in double-distilled water. The suspension was centrifuged for 20 minutes at 8,000xg. The resulting supernatant and buffy coat are washed twice (48,00Oxg, 10 mins, resuspension in double-deionized water). The final pellet is quickly frozen (dry icelethanol bath) under doubledeionized water and stored at -70' C. On the day of the experiment, thawed synaptic membranes are homogenized with a Brinkmann Polytron (tm, Brinkmann Instruments, Westbury, N.Y.) tissue homogenizer in 50 millimolar tris(hydroxymethy1)aminomethane citrate, pH 7.1. The membranes are incubated with 0.04% Sufact-AMPS XlOO (tm, Pierce, Rockford, Ill.) in buffer for 20 minutes at 37' C. and washed six times by centrifugation (48,00Oxg, 10 min) and resuspended in buffer. The final pellet is homogenized at 200 mg wet weightImL of the buffer for the binding assay. For [3H]-glycine binding at the N-methyl-D-aspartate (4&60 Cilmmol, New receptor, 20 nanomolar [3~]-glycine England Nuclear, Boston, Mass.) is incubated with the membranes suspended in 5 0 millimolar tris (hydroxymethy1)aminomethane citrate, pH 7.1 for 30 minutes at 4' C. Glycine, 1 millimolar, is used to define the nonspecific binding. Bound [3~]-glycineis isolated from free using a Brandel (Biomedical Research and Development Laboratories, Gaithersburg, Md.) ce11 harvester for vacuum filtration over glass fiber filters (Whatman GF/B from Brandel, Gaithersburg, Md.) presoaked in 0.025% polyethylenimine. The samples retained on the glass fiber filters are rinsed 3 times with a total of 2.5 mL ice cold buffer. Radioactivity is estimated by liquid scintillation counting. IC,, values are obtained from a least-squares regression of a logit-log transformation of the data. Typical IC,, values for compounds of the invention are usually less than 50 pM (micromolar) and are illustrated by the compound of Examples 1-6 (Ex. 1, 2.4x10-~;Ex. 2, l . 2 x l 0 - ~ ; Ex. 3, 3 . 7 ~ 1 0 - ~ ; 4, 2 . 4 ~ 1 0 - ~ ; 5, 3 . 0 ~ 1 0 - ~ ; 6, Ex. Ex. Ex. 2.9~10-~~). Test B Red Nucleus Test The purpose of this test is to determine the effects of intravenously administered glycine antagonists on the NMDA-induced excitatory response of red nucleus cells. HA-966 (racemic) and CGP 37849 are reference agents that have been shown active in this test (ID5Os of 7.9 and 1.7 m g k g iv, respectively). The procedure for the red nucleus test is as follows. Rats are anesthetized with chloral hydrate (400 m g k g ip) and the femoral vein is catheterized for iv drug administration. Five-barre1 micropipettes are stereotaxically positioned in the red nucleus. Typically, three to four of the five barrels are filled as follows: the recording barrel with 2M potassium

30
citrate, the current balancing barrel with 4M NaCl, the drug barrel with 25 mM NMDA, and another dmg barrel with 2.5 mM quisqualic acid (QAis only used in selectivity studies). NMDA is iontophoretically applied with an ejection current that is adjusted depending on the sensitivity of each individual red nucleus cell. The NMDA is cycled on and off (usually 30-60 sec. on and 60-120 sec. ofi) and the firing rate of the ce11 during each period is recorded. Once the baseline firing rate of the ce11 has been established, the test-drug is administered iv. The effect of the dmg on the NMDA-induced excitatory response of the red nucleus ce11 can be both qualitatively and quantitatively evaluated from the recordings and the raw data accumulated. Compounds of the invention exhibited a antagonist response. For example, the compound of example 4 as the meglumine salt (N=3) had an ID50 of 3.770. Test C Rat Middle Cerebral Artery Test Male SHR rats weighing 280-320 g are used for these studies. The method used for permanent middle cerebral artery (MCA) occlusion is as described by Brint et a1 (1988). Briefly, focal ischemia is produced by occluding first the left common carotid artery and then the left middle cerebral artery just superior to the rhinal fissure. Following occlusions, dmgs are administered intravenously via jugular catheter. Twenty-four hours after MCA/common carotid artery occlusion, the animals are sacrificed and their brains quickly removed. Coronal sections of 1 mm thickness are cut using a vibratome and stained with 2,3,5-triphenyl-2Htetrazolium chloride (TTC) dye. Following staining, necrotic tissue is readily distinguished from the intact brain and the area of infarcted cortex can be traced on an image analyzer. The infarct volume for each section is quantified with an image analyzer, and the total infarct volume is calculated with a program that summed al1 interval volume. See S. Brint et al. J. Cerebral Blood Flow 8:474485 (1988). The statistical analysis of the difference between the volume of ischemic damage in the vehicle control and drug-treated animals is analyzed by student's-t-test. Al1 data are presented as the mean2S.E. of the mean for n animals. compounds of the invention reduced ischemic damage. For example, the compound of example 4 at an I.V. dose of 20 mgslkglhr caused an infarct % volume change of -22%. The invention will now be illustrated by the following non-limiting examples. In the Examples, unless stated othenvise: (i) temperatures are given in degrees Celsius (OC.); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18"-25" C.; (ii) evaporation of solvent was carried out using a rotary evaporator under reduced pressure (6004000 Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60' C.; (iii) flash chromatography was carried out on Merck Kieselgel (Art 9385) and column chromatography on Merck Kieselgel 60 (Art 7734); [these materials were obtained from E. Merck, Darmstadt, W. Germany]; thin layer chromatography (TLC) was carried out on Analtech 0.25 mm silica gel GHLF plates (Art 21521), obtainable from Analtech, Newark, Del., USA, (iv) in general, the course of reactions was followed by TLC or HPLC and reaction times are given for illustration only; (v) melting points are uncorrected and (d) indicates decomposition; the melting points given are those obtained for the materials prepared as described; poly-

5,837,705

31
morphism may result in isolation of materials with different melting points in some preparations; (vi) al1 final products were essentially pure by TLC or HPLC and had satisfactory n~clear magnetic reSOnanCe (NMR) spectra (300 MHz 'H NMR in D-DMSO unless 5 otherwise specified) and microanalytical data; (vii) yields are given for illustration only; (viii) chemical symbols have their usual meanings; the following abbreviations have been usedl 10 (weight); mp (melting point), [liter(~)l, mL mM g mg [milligram(s)], min (minutes), h (hour); and (ix) solvent ratios are given in volume: volume (vlv) terms. 1s As the examples and in vitro or in vivo results indicate, the present invention or the compounds and glycine receptor antagonists recited herein are useful as in vitro tools for determining relative glycine antagonist properties and as in vivo compounds or compositions which are useful as in vivo 20 tools for determining relative antagonist properties and as compounds or compositions which antagonize the glycine receptor in animals or humans in need of treatment thereof. The present invention, therefore, also relates to a method of in vitro antagonism of a mammalian glycine receptor com- 25 prising administering an antagonist effective amount of a cornPound of formula 1 or 1a-1d wherein the respective variables (RI-R') are as recited previously. The invention further relates to a method of in vivo antagonism of a mammalian, including human, glycine receptor comprising administering a pharmacologically effective amount of a compound of formula 1 or Ia-Id to a mammal or a human wherein the variables for are as previously defined. EXAMPLE 1
35

32
J=8.0, lH,), 7.66 (d, J=8.2,2H,), 7.92 (s, lH), 8.10 (d, J=8.5, lH), 10.08 (s, lH), 11.88 (s,lH, ex), 12.65 (s,lH, ex). s h e ,tarting ~-pyrrolidinocarbamide-7-chloro-4-

hydroxyquinoline-3-carboxylic acid was prepared in the

following mariner: To a s u s p e n s i o n o f 3 - c a r b o m e t h o x y - 2 pyrrolidinocarbamide-7-chloro-4-hydroxyquinoline (2.528, 7.5 mm) in de-ionized water (40 m ~ was added dropwise ) a solution (20 mL) of an aqueous potassium hydroxide (882 mg, 15.75 mM). Upon complete addition, the reaction was warmed to 60' C. Mter 3 hours, the reaction was filtered to remove a small amount of insoluble material. The filtrate was then acidified to pH=l which yielded a white precipitate. The solid was isolated by vacuum filtration, washed with water, and dried at 30' C. under vacuum for 16 hours. This provided the desired title compound (1.5 g, 64%) as a white solid, mp=225"4" C.; MS (CI): 321 (M+H)
300 lH NMR (DMS0-d6): '.12 (d2J=8.7 7.60 (d, lH, j=1.8 Hz), 7.47 (dd, lH, J=8.8,2.0 Hz), 3.69 (s, 3H), 3.40-3.49 (m, 2H), 3.27-3.33 (m, 2H), 1.80-1.96 (m, 4H).

The starting 3-carbomethoxy-2-pyrrolidinocarbamide-7chloro-4-hydroxyquinolinewas prepared in the following manner: To a suspension of 3-carbomethoxy-7-chloro-4hydroxyquinoline-2-carboxylic acid (2.25 g, 8.0 mM) in tetrahydrofuran (20 mL) at ambient temperature under a N, atmosphere was added dicyclohexylcarbodiimide (1.65 g, 8.0 mM) and pyrrolidine (0.596 g, 8.4 mM). The reaction was stirred room temperature for 15 hours after which time the bvvroduct urea was removed via filtration. The desired product was purified via flash column chromatography employing 5% methanol in chloroform to provide the title compound (2.52 g, 94.3%) as a tan solid, mp+215" C.; MS (CI): 335 (M+H).
- A

7-chloro-4-hydroxy-2-[l-(phenylcarbamoyl)ethyl]-l, 2,5,10-tetrahydropyridazino[4,5-b]quinoline-l,10dione
To a stirred suspension of 2-pyrrolidinocarbamide-7chloro-4-hydroxyquinoline-3-carboxylic acid (0.908 g, 2.8 mm) in tetrahydrofuran (36 mL) at ambient temperature was added dicyclohexylcarbodiimide(0.875 g, 4.2 mM). A tetrahydrofuransolution(18mL)ofN-t-butoxycarbonyl-N'[1-(phenylcarbamoyl)ethyl]-hydrazine (1.18 g, 4.2 mM, pre- 45 pared by Method X described below) was immediately added to the above suspension. The reaction mixture was stirred at room temperature for four hours. Upon completion of the coupling, the byproduct urea was removed via 50 vacuum filtration. Partial purification by flash column chromatography employing 5% methano1 in chloroform provided the semi-pure hydrazide in nearly quantitative yield. To the hydrazide suspended in tetrahydrofuran (55 mL) was added methanesulfonic acid (6.0 mL, 93 mM). The reaction 55 was stirred at room temperature for 15 hours, concentrated in vacuo, and then poured into ice water (600 mL). The resulting precipitate was isolated, dried, and trituratedl sonicated with methanol(20 mL) and isolated to yield after dr~ing under vacuum at 50' C. 0.827 g (71%) of the title 60 compound as an orange solid, mP >259" C. 0.827 g (71%) ofthetitlecom~oundasanorangesolid,mP>250"C.;MS (CI): 411 (M+H). Analysis for C,,H,,N,O,Cl: Calculated: C, 58.47; H, 3.68; N, 13.64; Found: C, 58.20; H, 3.84; N, 13.43; 300 65 MHz 'H NMR (DMSO-d,): 1.52 (d, J=6.9, 3H), 5.54-5.64 (m, lH), 7.03 (t, J=7.4, lH), 7.24-7.36 (m,2H), 7.41 (d,
40

300 MHz 'H NMR (DMSO-d,): 8.12 (d, J=8.7 Hz, lH), 7.60 (d, lH, J=1.8 Hz), 7.47 (dd, lH, J=8.8,2.0 Hz), 3.69 (s, 3H), 3.40-3.49 (m, 2H), 3.27-3.33 (m, 2H), 1.80-1.96 (m, 4H). Hydrazine Preparation Method X

The starting N - t - b u t O x ~ c a r b O n ~ l - N ' - [ l (phen~lcarbamo~l)-eth~ll-h~drazine ~ r e ~ a r ein the was d follOwing mariner: A mixture of t-butylcarbazate (2.87 g, 21.7 mM) and 2-bromo-N-phenylpropionamide (1.07 g, 4.69 mM) in dimethyl formamide (6 mL) was warmed to 50' C. To this mixture was added triethylamine (1.3 mL, 9.33 mM). Mter stirring at 100' C. for 3 hours, the reaction mixture was poured into water (70 mL) and extracted with methylene chloride. The combined organic extracts were washed with water and brine, dried over MgSO,, and concentrated in vacuo. The crude product was purified by flash column chromatography employing 3:l diethyl ether:hexanes and 100% ether as eluants. This provided the title compound. (1.18 g, 90%) as a white solid; MS (CI): 280 (M+H). 300 MHz 'H NMR (DMSO-d,): 9.95 (br s, lH), 8.50 (br s, lH), 7.64 (d, J=7.6,2H), 7.27-7.37 (m, 2H), 7.00-7.10(m, 1H),5.15(brs,1H),3.38-3.50(m,2H),1.36(s,9H),1.19 (d, J=7.0, 3H). N-t-BOC-Nt-2-methylbenzylhydrazine, N-t-BOC-Nt-1methylbutylhydrazine and N-t-BOC-Nt-1,3dimethylbutylhydrazine were also prepared according to this method.

TABLE 1-continued
The following Examples were made generally as set forth in Example 1 using appropriate corresponding precursors to make the compounds listed. 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimidemetho-p-toluenesulfonate was emploved in place of dicvclohexvlcarbodiimide in examples 2. 3. and 5-12. Analysis (cal'dlfound)

EX. # Name

Yield 62

m.p. 2424

MS(C1) 412(M

NMR (DMSO -de) 3.71 (s, 3H), 6.60(s, lH), 7.30-7.49 (m, 6H), 8.04 (d, J=1.4, lH), 8.15, d, J= 8.67, lH), 12.01 (brs, lH, ex), 12.71(brs, lH, ex) 1.29-1.40 (m, 3H), 3.16 (s, 3H)5.23-5.46 (m, lH), 7.15-7.50 (m, 6H), 8.02(s, lH), 8.11 (d, J=8.6, lH), 11.87@rs, lH, ex), 12.58 @rs, lH, ex) 1.31 (d, J=6.6. 3H), 2.65-2.86 (m, 2H) 5.37-5.54 (m, ZH), 7.01 (t, J=7.3, lH), 7.22-7.32 (m, ZH), 7.42 (d, J=8.5, lH), 7.55 (d, J=7.7, ZH), 8.01 (s, lH), 8.14(d, J=8.6, lH), 9.99 (s, lH), 11.88@rs, lH), 12.45 @rs, 1H) 1.16 (d, J=4.9, 3H), 2.43 (brs, ZH), 3.13 (s, 3H) 5.42(q, J=6.5, lH), 7.28-7.55(m, 6H), 8.01 (s, lH), 8.14 (d, J=8.5, lH), 11.85 @rs, lH), 12.38 (brs, 1H) 1.91 (q, J=8.7, lH), 7.42-7.50 (m, 4H), 7.62-7.72 (m, ZH), 8.05 (s, lH), 8.14 (d, J=8.7, lH), 12.08 (s, lH), 12.90 (s, 1H)

+ H)

7-chloro-4-hydroxy-2-[l-(N-phenyl-Nmethyl carbamoyl)ethyl]-l,2,5,10tetrahydropyridazinof4,S-blquinoline1,lO-dione.

170-80

425(M

+ H)

10

7-chloro-4-hydroxy-2-[l-methyl-2-(Nphenyl carbamoyl)ethyl]-1,2,5,10tetrahydro pyridazino[4,5-blquinoline1,lO-dione.

61

>250

425(M

+ H)

13

218-9

439(M

+ H)

237-8

422(M

+ H)

30

EXAMPLE 13

7-chloro-4-hydroxy-2-[(R)-l-carboxyethyl]-l,2,5l0-tetrahydropyridazino[4,5-b]quinoline-l,lO-dione To 7-chloro-4-hydroxy-2-[(R)-1-(methyloxycarbonyl) 35 ethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-l,10dione (500 mg, 1.43 mM) in 20 ml of water with added potasskm hydroxide (240 mg, 4.28 mM). The remnants were washed into the reaction vesse1 with about 2 ml of water. The reaction mixture formed a white slurry. This 40 mixture was then refluxed for 30 minutes, causing the reaction to become clear, at which point 98% of the ester had been converted to the acid as analyzed by HPLC. The reaction was then cooled to 0' C. in an ice bath. Hydrochloric acid (IN, approximately 15 ml) was then added

filtered to yield after drying under vacuum at 40' C. 455 mg (95%) of the title compound as a white solid, mp>275" C. MS (Cl): 236 (M+H). Analysis for C,,H,,N,O,Cl 1.0 H20: Calculated: C, 47.54; H, 3.42: N, 11.88; Found: C, 47.89; H, 3.73; N, 11.42; 300 MHz 'H NMR (DMSO-d,): 1.51 (d, J=7.1,3H), 5.42 (dd, J=7.1, 14.8, 1H) 7.43 (dd, J=2.0, 14.8, 1H), 8.03 (d, J=2.0, lH), 8.15 (d, J=8.7, lH), 12.67 (br s, lH). Following a procedure similar to that described in Example 13, the following compounds of the Formula 1 illustrated in Table 2 were prepared.

TABLE 2
The following Examples were made generally as set forth in Example 13 using appropriate corresponding precursors to make the compounds isted. Analysis (cal'dlfound) C2,H15N404C1: C=58.47158.20, H=3.6813.84, N=13.64113.43

EX. # Name 14 7-chloro-4-hydroxy-2-(1-carboxybenzy1)-1,2,5,10-tetrahydro pyridazino[4,5-blquinoline 1,lO-dione.

Yield 71

m.p. >250

MS(C1) 411(M

NMR (DMSO -d6) 1.52 (d, J=6.9, 3H), 5.54-5.64 (m, lH), 7.03 (t, J=7.4, lH), 7.24-7.36(m, ZH), 7.41 (d,J=8.0,1H,),7.66 (d,J=8.2, ZH,), 7.92 (s, lH), 8.10 (d, J=8.5, lH), 10.08 (s, lH), 11.88 (s, lH, ex), 12.65 (s, 1H, ex)

+ H)

60

dropwise until the pHe7. A white solid gradually fell out of solution over a 30 minute period. This solid was isolated, dried and trituratedlsonicated with methanol (10 ml) and

The appropriate R2-substituted hydrazines which are required for the synthesis of the compounds of the Formula 1 can be prepared as shown in Tables 3 and 4.

37
TABLE 3
The following BOC-protected hydrazines were made generally as set forth in Method X, using appropriate corresponding precursors to make the compounds listed. Preparation # Name
1

Yield 90

MS(C1) 280(M

NMR (DMSO-d,) 1.19 (d, J=7.0, 3H), 1.36 (s, 9H), 3.38-3.50 (m, 2H), 5.15 (br s, lH), 7.00-7.10 (m, lH), 7.27-7.37 (m, 2H), 7.64 (d, J=7.6, 2H), 8.50 (br s, lH), 9.95 (br s, 1H). 1.16 (d, J=6.5, 3H), 1.35 (s, 9H), 4.07 (br s, lH), 4.53-4.59 (m, lH), 7.05-7.35 (m, SH), 8.16 @r s, 1H). 0.83-0.93 (m, 6H), 1.00-1.43 (br m, 4H), 1.38 @r s, 9H), 2.73-2.87 (br s, lH), 4.11 @r s, lH), 8.18 (br s, 1H). 0.82 (d, J=6.6, 3H), 0.87 (d, J=6.6, 6H), 0.921.06 (m, 2H), 1.17-1.29 (m, lH), 1.38 @r s, 9H), 1.57-1.74(m, lH),7,42(dd, J=8.6, 1.7, lH), 8.02 (s, lH), 2.79-2.97 (m, lH), 4.11 (br s, lH), 8.20 (br s, 1H). 0.93 (d, J=6.2, 3H), 1.36 (s, 9H), 3.15(s, 3H), 3.34-3.46 (br s, lH), 4.32-4.43 (br s, lH), 7.28(d, J=7.6, 2H), 732-7.50 (m, 3H), 7.938.14 @r s, 1H).

N-t-butoxycarbonyl-N'-[l-(Nphenylcarbamoyl) ethyllhydrazine

+ H)

N-t-butoxycarbonyl-N'-1methylbenzyl-hydrazine N-t-butoxycarbonyl-N'-1methylbutyl-hydrazine

80

237(M

+ H)

68

203(M + H)

N-1-butoxycarbonyl-N'-1,3dimethyl-butylhydrazine

22

217(M

+ H)

83

294(M

+ H)

TABLE 4
The following BOC-protected hydrazines were made generally as set forth in Method Z, using appropriate corresponding precursors to niake the compounds listed. Preparation # Name 6
N-t-butoxycarbonyl-N'-[(R)1-(methyloxycarbony1)ethyllhydrazine N-t-butoxycarbonyl-N-[ 1-(methyloxycarbonyl)benzyl]hydrazine

Yield 94

MS(C1) 219(M

NMR (DMSO-d,) 1.11 (d, J=7.0, 3H), 1.36 (s, 9H), 3.503.60 (m, lH), 3.60 (s, 3H), 4.70 @rs, lH, ex), 8.21 (brs, lH, ex).

+ H)

83

225 (M-tBu)

N-t-butoxycarbonyl-N'-[l-methyl2-(N-phenyl
carbamoyl)ethyl]hydrazine

N-t-butoxycarbonyl-N'-[l-methyl2-(N-phenyl-Nmelhylcarbamoyl)ethyl]-hydrazine
N-t-butoxycarbonyl-N'-1trifluoromethylbenzylhydrazine

57

308(M

+ H)

10

73

0.82 (d, J=5.8, 3H), 1.36 (s, 9H), 1.77-1.93 (m, lH), 2.07-2.23 (m, lH), 3.14 (s, 3H), 4.32 @rs, lH), 7.27-7.52 (m, SH), 8.07 (br s>1H) 1.35 (s, 9H), 4.594.75 (m, lH), 5.34 (s, lH), 7.36-7.50 (m, SH), 8.49 (s, 1H)

The following illustrate representative pharmaceutical dosage forms containing a compound of formula 1 or Ia-Id, or a pharmaceutically acceptable salt thereof, for example as illustrated in Examples 1-14 (hereinafter referred to as "compound X"), for therapeutic or prophylactic use in humans:

-continued
50 (b) Capsule Compound X Mannitol. USP Croscarmellose sodium Magnesium stearate 10.0 488.5 mgitablet

55

EXAMPLE 15
mgitablet (a) Tablet Compound X Mannitol, USP Croscarmellose sodium Maize starch Hydroxypropylmethylcellulose (HPMC), USP Magnesium stearate 50.0 223.75 6.0 15.0 2.25 3.0
bu

,_

The above formulations may be obtained by conventional vrocedures well known in the vharmaceutical art. The tablets -may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. EXAMPLE 16

65

This is an example of a formulation suitable for parenteral use made with the compound of Example 4:

Parenteral Formulation: Compound Meglumine Dextrose, anhydrous Sterile Water for Injection

me/mL
10.0 19.5 39.5 qs ad 1 mL

R'

The solution was prepared by conventional measures well known in the pharmaceutical field. General formulations for this class of compounds and their salts, other than for acylated compounds, rnay be prepared by solubilizing the active compound in an aqueous meglumine (N-methylglucamine) solution containing an equimolar, or if solubilization is difficult, a molar excess of meglumine relative to Compound. Choline salts are preferred for use in making formulations. Excipients such has dextrose may be added to adjust the osmolality of the formulation. Water for Injection is added to bring the solution to final volume. Alternately, other amine bases such as tromethamine or 1-arginine rnay be used to solubilize the active compound. EXAMPLE 17 A formulation is made as in Example 16, except that the choline salt of Compound X is used in place of the compound of Example 4. EXAMPLE 18 A formulation is made comprising a 5% aqueous solution of dextrose made to 10 mg/mL in the choline salt of Compound X. The previous examples are considered to be non-limiting and thus, the compounds of formula 1 or Ia-Id and pharmaceutical compositions containing same rnay be used to treat andior prevent stroke and the other diseases as related herein. Schemes 1 and 2 presented hereinbefore and the following formulae are presented to clarify how to make the compounds of the invention. Table 1 shows compounds of the invention. The formula pages describe formula 1, groups R2'-R2"', and formula Ia-Id. Scheme 1 describes how compounds of the invention were or may be prepared. Scheme 2 describes how the starting BOC-protected hydrazines may be prepared.
FORMULAE

R'
l5

w w
-continued
FORMULAE

yz R . N

OR^

H I

OR^

20

N 25
H

OR^
O

iz
N
30

OR^
35

What is claimed is: 1, A compound selected from the group consisting of:

40

7-chloro-4-h~drox~-2-[1-(N-~hen~lcarbamo~l)eth~ll-1, 2,5,10-tetrahydropyridazino-[4,5-b]quinoline-l,10dione, 7 -, h 1o r - 4- h y d y - 2 - y l o h y 1- 1 , 2 , 5 , 1 0 tetrahydropyridazino[4,5-b]-quinoline-l,lO-dione, 7-chloro-4-hydroxy-2-(l-methylbenzyl)-l,2,5,10tetrahydropyridazino[4,5-b]-quinoline-l,lO-dione, 7-chloro-4-hydroxy-2-(l-methylbutyl)-1,2,5,10tetrahydropyridazino[4,5-b]-quinoline-l,lO-dione, 7-chloro-4-hydroxy-2-(l-methyl-2-phenylethyl)-l,2,5, l0-tetrahydropyridazino[4,5-b]-quinoline-l,lO-dione, and

45

R'

dz-.*~ yRZ .-*y

O
I

so

OR^
R2, 55

J J L N . R 6 R5

J,(&

R2" 60

R4 ~2"'
65

7-chloro-4-hydroxy-2-(1,3-dimethylbutyl)-l,2,5,10tetrahydropyridazino[4,5-b]-quinoline-1,lO-dione or a pharmaceutically acceptable salt thereof andior a tautomer thereof, andior a hydrate thereof, andior a solvate thereof, andior a stereoisomer thereof. 2. Apharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient or diluent. 3. A method for the treatment of stroke, hypoglycemia, ischemic attack, anoxia, or epilepsy comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1.

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