CA2117075A1 - Quinazoline derivatives and their preparation - Google Patents
Quinazoline derivatives and their preparationInfo
- Publication number
- CA2117075A1 CA2117075A1 CA002117075A CA2117075A CA2117075A1 CA 2117075 A1 CA2117075 A1 CA 2117075A1 CA 002117075 A CA002117075 A CA 002117075A CA 2117075 A CA2117075 A CA 2117075A CA 2117075 A1 CA2117075 A1 CA 2117075A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- salts
- alkyl
- formula
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
A compound of formula (I) in which R1 is substituted heterocyclic-(lower)alkyl, and R2 is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy, mercapto, optionally substituted heterocyclic-carbonyl, optionally substituted heterocyclic-(lower)alkyl, lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl, R3 is aryl which may have suitable substituent(s), and A is lower alkylene, or pharmaceutically acceptable salts thereof, useful as a dopamine receptor agonist, 5-HT
receptor antagonist or .alpha.1 receptor antagonist.
receptor antagonist or .alpha.1 receptor antagonist.
Description
WO 93/0503 ~ 2 1 1 7 0 7 ~pCr/J"92fO1117 DESCRIPTION
QUINAZOLINE DERIVA~IVES AND THEI~ PREPARA~ION
~ he pre~ent in~ntion rel~te~ to no~el quinazoline deriv~ti~e~ and ph~rmaceutically ~cceptable salts thereof.
MorQ particularly, it relate~ to novel quinazoline deri~ati~es and pharmaceutic~lly ncceptable salts thereof, which display effects on the peripheral or central nervou~
~ystem, to processe~ for the preparation thereof, to a ph~rm~ceutic~l compo~ition comprising th~ 8ame, to a u~e of the s2me a~ a medicament ~nd to a method of the t~erapeuti~ tre~tment of di~e~se~ in a human beinq or ~nimal~
INDUSTRIAI, APPl ICAB~LIT~r A~cordingly, one o~ect of the pre~ent invention is to provide no~rel ~inazoline deriYative~ anc'.
pharm~ceutically acceptable ~alts thereof, w~ich di~play ::
effect~ on the peripheral or centr~l nervous system, in particulhr on the peripheral nervous sy~tem.
~nother ob~ect of the present invention is to pro~ide ~:
processe~ for the preparation of novel quin~zoline deri~atives and ~lts the~eof.
A further ob~ect of the present invention is to pro~ide a ph~rmaceutical composition comprisin~, as an . ~cti~e ingred~ent, said quinazoline deri~ative~ and :
Wo93/oso3s - 2 - pCT/JP92/01117 ~ 211707~
pharmaceutically accept~ble ~alts thereof.
Still further object of the present in~ention i5 to pro~ide ~ use of said quinazoline deri~ati~e~ and phnrmaceutlcally accept~ble salt~ thereof as a dopamine recep~or ~gonist, 5-HT recQptor antagoni~t, e~pecially 5-HT2 receptor antagonist; ~1 receptor antagoni~t; ~nd the like and a method of the therapeutic treatment of dopAm~ne receptor; 5-HT receptor, espec~ally 5-HT2 receptor;
~l-receptor; mediated diseases, particularly hyperten~ion, c~rd~ovascular disorder ( Q . g . angina pectori~) myocardial infarctlon, etc.), Parkin~onism, ~nd the like, in a human .
being or animal.
lS DISCLOSURE OF INVENTION
The ob~ect quinazoline derivati~es are no~el and can bs represented by the following general formula:
Rl O A-N~
~,~ ( I ) ~
in which Rl is ~ub~tituted heterocyclic-(lower~alkyl, and -~2 i~ hydrogen, h~logen, nitro, A~;no, protected amino, hydroxy~mino, lower alkyl, hydroxy, protected hydroxy, ~ulfamoyl, carboxy, protected carboxy, mercapto, option~ ubstituted heterocyclic-carbonyl, optionally 2 1 1 7 ~ 7 5 pcT/Jps2/o~
substituted heterocyclic-~lower)alkyl, lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower~alkyl, R3 is aryl which may have suitable .
substituentls), an~
A is lower alkylene, ~-:
and pharmaceutically acceptable salts thereof. .
Suitable salts of the object compound (I) are pharmaceutlcally acceptable~ conventional non-toxic salts and may include a salt with a base such as an inorganic :~
base salt, for-example, an alkali me~al salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt le.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine sa~t (e.g. triethylamine salt, pyr~dine salt, picoline salt, ethanolamine salt, triethanol~m~ne salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); a salt with an acid such as inorganic acid addition salt (e.~. hydrochloride, hydrobromi~e, sulfa~e, -~
phosphate, etc.), an organic acid addition salt (e.g. :.
formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, etc.);
a salt with a basic or acidlc amino acid (e.g. arginine, :~
aspartic acid, glutamic acid, etc.); and the like.
According to the present invention, the ob;ect compound (I) or pharmaceutically acceptable salts thereof can be prepared.by the processes as illustrated by the foll~w~ny reAction scXemes.
w093/0503~ - 4 - pCT/JP92/01117 ~ 211707~
Process l :
CO(X)2 R3 (III) ; 0 A-N
~II) (I) :~
or salts thereof or salts thereof Process 2 :
Reduction of nitro ~ R3 group of 3 1 O A-N ~ Ra R A-N
a ~
~I-a) (I-b) or salts thereof or salts thereof Process 3 :
Introduction R3 of the R3 l o / -N ~ amino- RI o A-N~
~ ~ N protective ~ ~ ~ /
~ ~ N ~ o , ~ N~o c d c) ~I-d) 35or salts thereof or sa1ts thereo~
W~g3/0503~ 5 2 11 70 7,~ pcT/JP92/01117 Process 4 -1 ~ N~ A N ~ ~
R2 R2 H ;
(I~) tI) -:
or salts thereof or salts thereof Process 5 :
~, ~
Removal of the 1~ , ~ R3 hydroxy- ,R3 ~-1 o A-N ~ :ot ceive ~; o A-N
(I-e) (I-f) or salts thereof or salts thereof Process 6 :
Removal R3 of t~e Rl O A-N ~ carboxy- ~l o A-N
~ N protective ~\rJ~ N
g grO r in ~ N~ O
g) ' (I-h) 3S or salts thereof or salts thereof W093/0s03~ - 6 - PCT/JP92101117 ` 21l707~
wherein Rl, R2, R3 and A are eac~ as defined above, R2 is nitro, ~ is hydroxyamino or amino, Rc is am~no, - Rd is protected amino, Re is protected hydroxy or protec~ed hydroxy- ~:
(lowerJalkyl, R~ is hydroxy or hydroxy(~ower)a~kyl, ;~
Rg is protected carboxy, ~ is car~o~y~ ;
R i~ esterified carboxy, and X isa leavmg group.
The compounds (II~ and (I~) used in the Processes l and 4 are new and can be prepared, for example, by the following methods or a conventional manner.
Method A :
.
21;) ~R3 H2N-A N~
Rl O Rl O R3 \~0 (VI ) ~ ~
2 N~o or salts 2 2 :-R thereof R
~V) ~II) or salts thereof or salts thereof ~ -`
w093/0503~ 2 1 1 7 0 7 ~ pCT/Jpg2/o~
Method B :
Reduction :~
l o R3 of the R1 o R
S ~ \~ g: o~
(VII) ~II) or salts thereof or salts thereof ' Method C :
H2N-A-N/~ ~.
1 O ~ R1 O R3 R ~ ~ ~ N~-A-N
NH-R4or salts NR-R~
R2 thereof R~
IVIII) (IV) or its reactive derivative or salt~ thereof at the carboxy group, or salts thereof Method D :
R3 ~:
H2N-A-N ~ 1 o R3 NH-A-N
NO2 or salts NO2 R thereof R2 ~IX) ~VII) or its reactive derivative or salts thereof at the carboxY group, or salts thereof w043~0~03~ 8 PCT/JP92/01117 in whieh Rl, R2, R3, R4 and A are ea~h as de~ined above.
some of the starting materials of ~he abo~e Method A ~:~
~re new and can be prepared, for example, accordin~ to the me~hod of Preparation a~ mentioned below, or in a convent~onal manner.
In the above and subsequent de criptio~s of the present spe~ificat~on, suitable examp~es and illustrations of the various definitions whlch the present invention includes within the scope thereof are explained in detail ~s follow~.
The ter~ "lower" is intended to mean 1 to 6 carbon atom(s), preferably l to 4 carbon atom(s), unless 1~ otherwise indicated.
Suitable "lower alkyl" m~y include strai~ht or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like.
Su~table "lower alkoxy" may include straight or branched one such as metho~y, ethoxy, propoxy, isopropoxy, :
butoxy, t-butoxy, pentyloxy, hexyloxy, and the ~ike.
Suitable "aryl which may have suitable :::
substituent~s)" may include phenyl, tolyl, xylyl, cumenyl, mesity~, naphthyl, and the li~e, each of which may be .
subst~tute~ by one or more, preferably one or two subst~tuent(s) such as halogen te.g. fluorine, chlorine, bromine, iodine), ~ower alkyl as mentioned above te.g. ~-met~yl, etc.), and the like, in which more preferred example ma~ be phenyl which is substituted or unsubstituted by a group ~onsisting of halogen and lower :~
alkyl, and the most preferred one may be phenyl.
Suitable "protected carboxy" may include carbamoyl, esterified carboxy wherein "e~terified carboxy" ~an be referred to the ones as mentioned below, and the like.
~5 Su~-table examples of the ester moiety of an 211707~
wos3~0so3~ _ 9 _ PCT/JP92~0tl17 esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, iso~utyl ester, t-~utyl ester, pentyl ester, hexyl ester, etc.) which may have at -least one suitable substituent(s), for example, lower alkanoyloxyllower)alkyl ester te.g. acetoxymethyl ester, propionyloxymethyl ester, but~ryloxymethyl ester, ~-~
valeryloxymethyl estèr, piva~oyloxymethyl ester, hexanoyloxymethyl ester, }-(or 2-)acetoxyethyl ester, 1-~or 2- or 3-)acetoxypropyl ester, l-~or 2- or 3- or 4-)acetoxybutyl ester, l-(or 2-)pro~ionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, l-(or 2-)piv~-~oyloxyethyl ester, 1-(or 1~ 2-)hexanoyloxyethyl ester, iso~utyryloxymethyl ester, 2-ethyIbutyryloxymethyl ester, 3,3~dimethy~butyryloxymethy} ester, l-(or 2-)pentanoy~oxyethy~ ester, etc.1, lower alkanesulfonylllower)alkyl ester (e.g. 2-mesylethyl ester, etc.), monolor dl or-tri)halo~lower)alkyl ester (e.g.
2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
lower alkoxycarbonyloxyllower)alkyl ester ~e.g.
methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycar~onyloxymethyl ester, 1-tor 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or 2-)isopropoxycarbonyloxyethyl ester, etc.~, phthalidylidene(lower)alkyl ester, or (5-lower alkyl-2-oxo~ dioxol-4-yl)~lower)alkyl ester te.g.
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (S-ethyl-2-oxo-~,3-dtoxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.];
lower alkenyl ester ~e~g. vinyl ester, allyl ester, etc.);
3~ lower alkynyl ester (e.g. ethynyl ester, propynyl ester, WO 93/0503~ - 10 - PCI`/JP92/01117 211707~
ete.); arllower)alkyl ester [e-g- mono- or di- or :
triphenyl(lower)alkyl ester, ete.] which may have at least .
one sultable substituent(s) (e.g. lower alkoxy, nitro, ..
hydroxy, lower alkyl, ete.), for example, mono- or di- or S triphenyl(lower)alkyl ester which may have (lower~alkoxy le.g. benzyl ester, benzhydryl ester, trityl ester, 0 phenethyl ester, 4-methoxybenzyl ester, 3,4-dLmethoxybenzyl ester, bis(methoxyphenyl)methyl ester, ete.], nitrophenyl(lower)alkyl ester (e.g. 4-nitro~enzyl ester, ete.), [hydroxyl-(lower)alkylphenylllower)alkyl ester ~e.~. 4-hydroxy-~,5-di-t-butylbenzyl ester, etc~);
aryl ester whieh may h~ve at least one suita~le substituent(s) (e.g. phenyl ester, 4-ehlorophenyl ester, ~.
tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, eumenyl ester, ete.); phthalidyl ester; and the like.
More preferable example of the proteeted earboxy thus defined may be earb~moyl and lower alkoxyearbonyl.
Suitable "proteeted amino" may inelude amino proteeted.. by a eonventional amino-protective ~roup as -~
mentioned below.
Suitable "amino-proteetive group" may inelude aeyl sueh as aliphatie aeyl, aromatie aeyl, heteroeyelic aeyl 2~ and aliphatie aeyl substituted with aromatie or heteroeye~le ~roup(s) derived from earboxylie, earbonic, sulfonie ~nd earbamic aeids. .................................... .
The aliphatie ae~l may include saturated or ~.
unsaturated, aeyelie or eyelie ones, for example, alkanoyl -.
~0 sueh as lower alkanoyl le.g. formyl, aeetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, :::
hexanoyl, ete.), alkylsulfonyl sueh as lower alkylsulfonyl (e.~. mesyl, ethylsulfonyl, propylsulfonyl, .
lsopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, 3S pentylsulfonyl, hexylsulfonyl, ete.), earbamoyl, 211707~
w093/0503~ - 11 - PCT/JP92/0lll7 N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxyca~bonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g.
vinyloxycarbonyl, allyloxycarbonyl, etc.), alkehoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.3, cycloalkanecarbonyl such as cyclo~lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyc~opentanecar~onyl, cyclohexanecarbonyl, etc.), and the like.
The aliphatic acyl substituted with aromatic group~s) may ~nclude aralkoxycarbonyl such as phenyl~lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.
These acyl groups may be further substituted with one or more suitable subst~tuent~s) such as nitro, halogen as menttoned below, and the like, and preferable acyl having such subst~tuent(s) may be nitroaralkoxycar~onyl (e.g.
nitrobenzyloxycarbonyl, etc.), trihalo~lower)alkyl ~e.g. -trifluoroacetyl, etc.), and the like.
Pref erable example of amino-pro~ecti~e group thus defined may be :
- lower alkanoyl (e.g. acetyl, etc.); -- trihalo(lower)aIkanoyl such as trifluoro(lower~-alkanoyl (e.g. trifluoroacetyl, etc.);
- lower alkoxycarbonyl (e.g. ethoxycarbonyl, etc.);
'0 - carbamoyl;
- N-(lower)alkylcarbamoyl (e.g. N-ethylcarbamoyl, etc.);
- lower alkylsulf onyl ( e . ~ . mesyl, ethylsulfonyl, etc.); and the like.
~5 W093/0503~ - 12 PCT/JP92/01117 21170~5 "Protected hydroxy" means a hydroxy group protected by a convent~onal hydroxy-protective group, and suitable "hydroxy-protective group" may include lower alkyl as defined above, acy~ as defined above, ar(lower)alkyl such as mono-, di- or tr~phenyl(lower)alkyl ~e~g. trityl, etc.), preferably lower alkyl and triphenyl(lower~alkyl.
Suitable heterocyclic group in "optionally substituted heterocyclic-carbonyl", "optionally substituted heterocyclic-(lower)alkyl" and "substituted heterocyclic-(lower)alky~" may include 3 to 10, preferably 5 or 6-membered heterocycllc group, prefera~ly heteromonocyclic group containing at least one hetero ato~
such as oxygen atom, nitrogen atom and sulfur atom (e.g.
morphollno, etc.), and the like.
1~ Particularly such "heterocyclic group" means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom an~ the like. --~
More preferable heterocyclic group may be heterocyclic group such as :
-unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitroqen atom~s), for example, pyrrolyl, pyrrolînyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyr~dazinyl, triazolyl (e.g., -4H-1,2,4-triazolyl, lH-1,2,3-triazolyl, --~
2~-1,2,3-triazolyl, etc.), tetrazolyl (e.g., l~-tetrazolyl, 2~-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dlhydro-1,2,4-triazinyl, 2,g-dihydro-1,2,4-tr~azin~l, etc.), etc.;
-saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic ~roup ~ontaining 1 to 4 nitrogen atom~s), for example, azetidinyl, pyrrol~dinyl, ~5 ~midazolidinyl, piperidinyl, ~Lazolidinyl, piperazinyl, w093/05035 - 13 - PCT/JP92/01117 ete.;
-unsaturated condensed 7 to 12-membered heteroeyelic group containing 1 to 5 nitrogen atomts), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl ~e.g., tetrazolo[1,~-blpyridazinyl, ete.), dihydrotriazolopyridazinyl, et~.;
-unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonoeyelie ~roup eontaining 1 to 2 oxygen atom~s) and 1 to 3 n~trogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, ~e.g., 1,2,4-oxadiazolyl, ~,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
lS -saturated 3 to 8-membered, preferably ~ or 6-membered heteromonocyclic group eontaining 1 to 2 oxygen atom(s) and L to 3 nitrogen atom~s), for example, morpholinyl, ete.' -unsaturated eondensed 7 to 12-membered heteroey~lie group eontaininq 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atomts), for example, benzoxazolyl, benzoxadiazolyl, ete.;
wherein said heteroeyelie group may be substituted by one or more, preferably one or two suitable substituent(s) sueh as lower alkyl as mentioned above, l~wer alkoxy as 2~ mentioned above, in whieh more preferable example may be saturated 5 or 6-membered heteromonoeyelie group eontaining 1 to 4 nitrogen atom(s), ~r containing 1 to 2 oxygen atomts) and 1 to 3 nitrogen atomls), optional~y substituted by lower alkyl.
$uitab1e lower alkyl group in "heteroeyelie-(lower)alkyl`' ean be referred to the ones as mentioned - above.
More preferable example of substituted heteroeyelie-tlower)alkyl thus defined may be lower alkylpiperazinyl(lower)alkyl and morpholinyl(lower)alkyl, WO 93/0~035 - 14 - PCr/JP92~01117 ~11707~
and the most preferable one may be 4-methylpiperazin-1-ylmethyl.
More preferable example of heterocyclic-carbonyl thus defi~ed may be lower alkylpiperazinylcarbonyl and morpholinylcarbonyl.
Suita~le "halogen" may be fluorine, chlorine, bromine, iodine, and more preferred example may be chlorine.
Suitable "lower alkylene'l may include straight or branche~ one such as methylene~ ethylene, tri~ethylene, tetramethylene, pentamethylene, hexamethylene, -methylmethylene, ethylethylene, propylene, and the like, in which the most preferred one may be tetramethylene.
Suitab~e "leaving group" may include imidazole, lower i5 alkylimidazole ~e.g. 2-methylImidazole, etc.), an acid residue such as halogen as mentioned above (e.g. chlorine, etc.), and the like. -~
Suitable "lower alkylth~o" may include straight or branched one such as methylthio, ethylthio, propylth~o, isopropylth~o, butylthio, t-butylthio, pentylthio, --hexylthio, and the like.
Suitable "esterified carboxy" means the same ones as mentioned in the exp~anation of protected carboxy, in which more preferable ex~mple may be lower alkoxycarbonyl.
Su~table "hydroxy(lower)alkyl" may include hydroxymethyl, hydroxyethyl, hydroxypro~yl, hydsoxyhexyl, ~-~
and the like.
Suitable "protecte~ hydroxy~lower)alkyl" means hydroxy(lower)al~yl protected by a conventional hydroxy-protective group as mentioned in the explanat~on of "protected hydroxy", in which more preferable example may be lower aIXoxy~lower)alkyl and -~
triphenyl(lower)alkoxy(lower)alkyl.
~5 ~11707~
WO 93/0~03~ - 15 - pCr/JP42~01117 ThQ processes for the preparat$on of the ob~ect compound (I) of the prQ~nt inventlon ar~ explained in det~il $n the following. -~.
QUINAZOLINE DERIVA~IVES AND THEI~ PREPARA~ION
~ he pre~ent in~ntion rel~te~ to no~el quinazoline deriv~ti~e~ and ph~rmaceutically ~cceptable salts thereof.
MorQ particularly, it relate~ to novel quinazoline deri~ati~es and pharmaceutic~lly ncceptable salts thereof, which display effects on the peripheral or central nervou~
~ystem, to processe~ for the preparation thereof, to a ph~rm~ceutic~l compo~ition comprising th~ 8ame, to a u~e of the s2me a~ a medicament ~nd to a method of the t~erapeuti~ tre~tment of di~e~se~ in a human beinq or ~nimal~
INDUSTRIAI, APPl ICAB~LIT~r A~cordingly, one o~ect of the pre~ent invention is to provide no~rel ~inazoline deriYative~ anc'.
pharm~ceutically acceptable ~alts thereof, w~ich di~play ::
effect~ on the peripheral or centr~l nervous system, in particulhr on the peripheral nervous sy~tem.
~nother ob~ect of the present invention is to pro~ide ~:
processe~ for the preparation of novel quin~zoline deri~atives and ~lts the~eof.
A further ob~ect of the present invention is to pro~ide a ph~rmaceutical composition comprisin~, as an . ~cti~e ingred~ent, said quinazoline deri~ative~ and :
Wo93/oso3s - 2 - pCT/JP92/01117 ~ 211707~
pharmaceutically accept~ble ~alts thereof.
Still further object of the present in~ention i5 to pro~ide ~ use of said quinazoline deri~ati~e~ and phnrmaceutlcally accept~ble salt~ thereof as a dopamine recep~or ~gonist, 5-HT recQptor antagoni~t, e~pecially 5-HT2 receptor antagonist; ~1 receptor antagoni~t; ~nd the like and a method of the therapeutic treatment of dopAm~ne receptor; 5-HT receptor, espec~ally 5-HT2 receptor;
~l-receptor; mediated diseases, particularly hyperten~ion, c~rd~ovascular disorder ( Q . g . angina pectori~) myocardial infarctlon, etc.), Parkin~onism, ~nd the like, in a human .
being or animal.
lS DISCLOSURE OF INVENTION
The ob~ect quinazoline derivati~es are no~el and can bs represented by the following general formula:
Rl O A-N~
~,~ ( I ) ~
in which Rl is ~ub~tituted heterocyclic-(lower~alkyl, and -~2 i~ hydrogen, h~logen, nitro, A~;no, protected amino, hydroxy~mino, lower alkyl, hydroxy, protected hydroxy, ~ulfamoyl, carboxy, protected carboxy, mercapto, option~ ubstituted heterocyclic-carbonyl, optionally 2 1 1 7 ~ 7 5 pcT/Jps2/o~
substituted heterocyclic-~lower)alkyl, lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower~alkyl, R3 is aryl which may have suitable .
substituentls), an~
A is lower alkylene, ~-:
and pharmaceutically acceptable salts thereof. .
Suitable salts of the object compound (I) are pharmaceutlcally acceptable~ conventional non-toxic salts and may include a salt with a base such as an inorganic :~
base salt, for-example, an alkali me~al salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt le.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine sa~t (e.g. triethylamine salt, pyr~dine salt, picoline salt, ethanolamine salt, triethanol~m~ne salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); a salt with an acid such as inorganic acid addition salt (e.~. hydrochloride, hydrobromi~e, sulfa~e, -~
phosphate, etc.), an organic acid addition salt (e.g. :.
formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, etc.);
a salt with a basic or acidlc amino acid (e.g. arginine, :~
aspartic acid, glutamic acid, etc.); and the like.
According to the present invention, the ob;ect compound (I) or pharmaceutically acceptable salts thereof can be prepared.by the processes as illustrated by the foll~w~ny reAction scXemes.
w093/0503~ - 4 - pCT/JP92/01117 ~ 211707~
Process l :
CO(X)2 R3 (III) ; 0 A-N
~II) (I) :~
or salts thereof or salts thereof Process 2 :
Reduction of nitro ~ R3 group of 3 1 O A-N ~ Ra R A-N
a ~
~I-a) (I-b) or salts thereof or salts thereof Process 3 :
Introduction R3 of the R3 l o / -N ~ amino- RI o A-N~
~ ~ N protective ~ ~ ~ /
~ ~ N ~ o , ~ N~o c d c) ~I-d) 35or salts thereof or sa1ts thereo~
W~g3/0503~ 5 2 11 70 7,~ pcT/JP92/01117 Process 4 -1 ~ N~ A N ~ ~
R2 R2 H ;
(I~) tI) -:
or salts thereof or salts thereof Process 5 :
~, ~
Removal of the 1~ , ~ R3 hydroxy- ,R3 ~-1 o A-N ~ :ot ceive ~; o A-N
(I-e) (I-f) or salts thereof or salts thereof Process 6 :
Removal R3 of t~e Rl O A-N ~ carboxy- ~l o A-N
~ N protective ~\rJ~ N
g grO r in ~ N~ O
g) ' (I-h) 3S or salts thereof or salts thereof W093/0s03~ - 6 - PCT/JP92101117 ` 21l707~
wherein Rl, R2, R3 and A are eac~ as defined above, R2 is nitro, ~ is hydroxyamino or amino, Rc is am~no, - Rd is protected amino, Re is protected hydroxy or protec~ed hydroxy- ~:
(lowerJalkyl, R~ is hydroxy or hydroxy(~ower)a~kyl, ;~
Rg is protected carboxy, ~ is car~o~y~ ;
R i~ esterified carboxy, and X isa leavmg group.
The compounds (II~ and (I~) used in the Processes l and 4 are new and can be prepared, for example, by the following methods or a conventional manner.
Method A :
.
21;) ~R3 H2N-A N~
Rl O Rl O R3 \~0 (VI ) ~ ~
2 N~o or salts 2 2 :-R thereof R
~V) ~II) or salts thereof or salts thereof ~ -`
w093/0503~ 2 1 1 7 0 7 ~ pCT/Jpg2/o~
Method B :
Reduction :~
l o R3 of the R1 o R
S ~ \~ g: o~
(VII) ~II) or salts thereof or salts thereof ' Method C :
H2N-A-N/~ ~.
1 O ~ R1 O R3 R ~ ~ ~ N~-A-N
NH-R4or salts NR-R~
R2 thereof R~
IVIII) (IV) or its reactive derivative or salt~ thereof at the carboxy group, or salts thereof Method D :
R3 ~:
H2N-A-N ~ 1 o R3 NH-A-N
NO2 or salts NO2 R thereof R2 ~IX) ~VII) or its reactive derivative or salts thereof at the carboxY group, or salts thereof w043~0~03~ 8 PCT/JP92/01117 in whieh Rl, R2, R3, R4 and A are ea~h as de~ined above.
some of the starting materials of ~he abo~e Method A ~:~
~re new and can be prepared, for example, accordin~ to the me~hod of Preparation a~ mentioned below, or in a convent~onal manner.
In the above and subsequent de criptio~s of the present spe~ificat~on, suitable examp~es and illustrations of the various definitions whlch the present invention includes within the scope thereof are explained in detail ~s follow~.
The ter~ "lower" is intended to mean 1 to 6 carbon atom(s), preferably l to 4 carbon atom(s), unless 1~ otherwise indicated.
Suitable "lower alkyl" m~y include strai~ht or branched one such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like.
Su~table "lower alkoxy" may include straight or branched one such as metho~y, ethoxy, propoxy, isopropoxy, :
butoxy, t-butoxy, pentyloxy, hexyloxy, and the ~ike.
Suitable "aryl which may have suitable :::
substituent~s)" may include phenyl, tolyl, xylyl, cumenyl, mesity~, naphthyl, and the li~e, each of which may be .
subst~tute~ by one or more, preferably one or two subst~tuent(s) such as halogen te.g. fluorine, chlorine, bromine, iodine), ~ower alkyl as mentioned above te.g. ~-met~yl, etc.), and the like, in which more preferred example ma~ be phenyl which is substituted or unsubstituted by a group ~onsisting of halogen and lower :~
alkyl, and the most preferred one may be phenyl.
Suitable "protected carboxy" may include carbamoyl, esterified carboxy wherein "e~terified carboxy" ~an be referred to the ones as mentioned below, and the like.
~5 Su~-table examples of the ester moiety of an 211707~
wos3~0so3~ _ 9 _ PCT/JP92~0tl17 esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, iso~utyl ester, t-~utyl ester, pentyl ester, hexyl ester, etc.) which may have at -least one suitable substituent(s), for example, lower alkanoyloxyllower)alkyl ester te.g. acetoxymethyl ester, propionyloxymethyl ester, but~ryloxymethyl ester, ~-~
valeryloxymethyl estèr, piva~oyloxymethyl ester, hexanoyloxymethyl ester, }-(or 2-)acetoxyethyl ester, 1-~or 2- or 3-)acetoxypropyl ester, l-~or 2- or 3- or 4-)acetoxybutyl ester, l-(or 2-)pro~ionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, l-(or 2-)piv~-~oyloxyethyl ester, 1-(or 1~ 2-)hexanoyloxyethyl ester, iso~utyryloxymethyl ester, 2-ethyIbutyryloxymethyl ester, 3,3~dimethy~butyryloxymethy} ester, l-(or 2-)pentanoy~oxyethy~ ester, etc.1, lower alkanesulfonylllower)alkyl ester (e.g. 2-mesylethyl ester, etc.), monolor dl or-tri)halo~lower)alkyl ester (e.g.
2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
lower alkoxycarbonyloxyllower)alkyl ester ~e.g.
methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycar~onyloxymethyl ester, 1-tor 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or 2-)isopropoxycarbonyloxyethyl ester, etc.~, phthalidylidene(lower)alkyl ester, or (5-lower alkyl-2-oxo~ dioxol-4-yl)~lower)alkyl ester te.g.
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (S-ethyl-2-oxo-~,3-dtoxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.];
lower alkenyl ester ~e~g. vinyl ester, allyl ester, etc.);
3~ lower alkynyl ester (e.g. ethynyl ester, propynyl ester, WO 93/0503~ - 10 - PCI`/JP92/01117 211707~
ete.); arllower)alkyl ester [e-g- mono- or di- or :
triphenyl(lower)alkyl ester, ete.] which may have at least .
one sultable substituent(s) (e.g. lower alkoxy, nitro, ..
hydroxy, lower alkyl, ete.), for example, mono- or di- or S triphenyl(lower)alkyl ester which may have (lower~alkoxy le.g. benzyl ester, benzhydryl ester, trityl ester, 0 phenethyl ester, 4-methoxybenzyl ester, 3,4-dLmethoxybenzyl ester, bis(methoxyphenyl)methyl ester, ete.], nitrophenyl(lower)alkyl ester (e.g. 4-nitro~enzyl ester, ete.), [hydroxyl-(lower)alkylphenylllower)alkyl ester ~e.~. 4-hydroxy-~,5-di-t-butylbenzyl ester, etc~);
aryl ester whieh may h~ve at least one suita~le substituent(s) (e.g. phenyl ester, 4-ehlorophenyl ester, ~.
tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, eumenyl ester, ete.); phthalidyl ester; and the like.
More preferable example of the proteeted earboxy thus defined may be earb~moyl and lower alkoxyearbonyl.
Suitable "proteeted amino" may inelude amino proteeted.. by a eonventional amino-protective ~roup as -~
mentioned below.
Suitable "amino-proteetive group" may inelude aeyl sueh as aliphatie aeyl, aromatie aeyl, heteroeyelic aeyl 2~ and aliphatie aeyl substituted with aromatie or heteroeye~le ~roup(s) derived from earboxylie, earbonic, sulfonie ~nd earbamic aeids. .................................... .
The aliphatie ae~l may include saturated or ~.
unsaturated, aeyelie or eyelie ones, for example, alkanoyl -.
~0 sueh as lower alkanoyl le.g. formyl, aeetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, :::
hexanoyl, ete.), alkylsulfonyl sueh as lower alkylsulfonyl (e.~. mesyl, ethylsulfonyl, propylsulfonyl, .
lsopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, 3S pentylsulfonyl, hexylsulfonyl, ete.), earbamoyl, 211707~
w093/0503~ - 11 - PCT/JP92/0lll7 N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxyca~bonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g.
vinyloxycarbonyl, allyloxycarbonyl, etc.), alkehoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.3, cycloalkanecarbonyl such as cyclo~lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyc~opentanecar~onyl, cyclohexanecarbonyl, etc.), and the like.
The aliphatic acyl substituted with aromatic group~s) may ~nclude aralkoxycarbonyl such as phenyl~lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.
These acyl groups may be further substituted with one or more suitable subst~tuent~s) such as nitro, halogen as menttoned below, and the like, and preferable acyl having such subst~tuent(s) may be nitroaralkoxycar~onyl (e.g.
nitrobenzyloxycarbonyl, etc.), trihalo~lower)alkyl ~e.g. -trifluoroacetyl, etc.), and the like.
Pref erable example of amino-pro~ecti~e group thus defined may be :
- lower alkanoyl (e.g. acetyl, etc.); -- trihalo(lower)aIkanoyl such as trifluoro(lower~-alkanoyl (e.g. trifluoroacetyl, etc.);
- lower alkoxycarbonyl (e.g. ethoxycarbonyl, etc.);
'0 - carbamoyl;
- N-(lower)alkylcarbamoyl (e.g. N-ethylcarbamoyl, etc.);
- lower alkylsulf onyl ( e . ~ . mesyl, ethylsulfonyl, etc.); and the like.
~5 W093/0503~ - 12 PCT/JP92/01117 21170~5 "Protected hydroxy" means a hydroxy group protected by a convent~onal hydroxy-protective group, and suitable "hydroxy-protective group" may include lower alkyl as defined above, acy~ as defined above, ar(lower)alkyl such as mono-, di- or tr~phenyl(lower)alkyl ~e~g. trityl, etc.), preferably lower alkyl and triphenyl(lower~alkyl.
Suitable heterocyclic group in "optionally substituted heterocyclic-carbonyl", "optionally substituted heterocyclic-(lower)alkyl" and "substituted heterocyclic-(lower)alky~" may include 3 to 10, preferably 5 or 6-membered heterocycllc group, prefera~ly heteromonocyclic group containing at least one hetero ato~
such as oxygen atom, nitrogen atom and sulfur atom (e.g.
morphollno, etc.), and the like.
1~ Particularly such "heterocyclic group" means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom an~ the like. --~
More preferable heterocyclic group may be heterocyclic group such as :
-unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitroqen atom~s), for example, pyrrolyl, pyrrolînyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyr~dazinyl, triazolyl (e.g., -4H-1,2,4-triazolyl, lH-1,2,3-triazolyl, --~
2~-1,2,3-triazolyl, etc.), tetrazolyl (e.g., l~-tetrazolyl, 2~-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dlhydro-1,2,4-triazinyl, 2,g-dihydro-1,2,4-tr~azin~l, etc.), etc.;
-saturated 3 to 8-membered, preferably 5 or 6-membered heteromonocyclic ~roup ~ontaining 1 to 4 nitrogen atom~s), for example, azetidinyl, pyrrol~dinyl, ~5 ~midazolidinyl, piperidinyl, ~Lazolidinyl, piperazinyl, w093/05035 - 13 - PCT/JP92/01117 ete.;
-unsaturated condensed 7 to 12-membered heteroeyelic group containing 1 to 5 nitrogen atomts), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl ~e.g., tetrazolo[1,~-blpyridazinyl, ete.), dihydrotriazolopyridazinyl, et~.;
-unsaturated 3 to 8-membered, preferably 5 or 6-membered heteromonoeyelie ~roup eontaining 1 to 2 oxygen atom~s) and 1 to 3 n~trogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, ~e.g., 1,2,4-oxadiazolyl, ~,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
lS -saturated 3 to 8-membered, preferably ~ or 6-membered heteromonocyclic group eontaining 1 to 2 oxygen atom(s) and L to 3 nitrogen atom~s), for example, morpholinyl, ete.' -unsaturated eondensed 7 to 12-membered heteroey~lie group eontaininq 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atomts), for example, benzoxazolyl, benzoxadiazolyl, ete.;
wherein said heteroeyelie group may be substituted by one or more, preferably one or two suitable substituent(s) sueh as lower alkyl as mentioned above, l~wer alkoxy as 2~ mentioned above, in whieh more preferable example may be saturated 5 or 6-membered heteromonoeyelie group eontaining 1 to 4 nitrogen atom(s), ~r containing 1 to 2 oxygen atomts) and 1 to 3 nitrogen atomls), optional~y substituted by lower alkyl.
$uitab1e lower alkyl group in "heteroeyelie-(lower)alkyl`' ean be referred to the ones as mentioned - above.
More preferable example of substituted heteroeyelie-tlower)alkyl thus defined may be lower alkylpiperazinyl(lower)alkyl and morpholinyl(lower)alkyl, WO 93/0~035 - 14 - PCr/JP92~01117 ~11707~
and the most preferable one may be 4-methylpiperazin-1-ylmethyl.
More preferable example of heterocyclic-carbonyl thus defi~ed may be lower alkylpiperazinylcarbonyl and morpholinylcarbonyl.
Suita~le "halogen" may be fluorine, chlorine, bromine, iodine, and more preferred example may be chlorine.
Suitable "lower alkylene'l may include straight or branche~ one such as methylene~ ethylene, tri~ethylene, tetramethylene, pentamethylene, hexamethylene, -methylmethylene, ethylethylene, propylene, and the like, in which the most preferred one may be tetramethylene.
Suitab~e "leaving group" may include imidazole, lower i5 alkylimidazole ~e.g. 2-methylImidazole, etc.), an acid residue such as halogen as mentioned above (e.g. chlorine, etc.), and the like. -~
Suitable "lower alkylth~o" may include straight or branched one such as methylthio, ethylthio, propylth~o, isopropylth~o, butylthio, t-butylthio, pentylthio, --hexylthio, and the like.
Suitable "esterified carboxy" means the same ones as mentioned in the exp~anation of protected carboxy, in which more preferable ex~mple may be lower alkoxycarbonyl.
Su~table "hydroxy(lower)alkyl" may include hydroxymethyl, hydroxyethyl, hydroxypro~yl, hydsoxyhexyl, ~-~
and the like.
Suitable "protecte~ hydroxy~lower)alkyl" means hydroxy(lower)al~yl protected by a conventional hydroxy-protective group as mentioned in the explanat~on of "protected hydroxy", in which more preferable example may be lower aIXoxy~lower)alkyl and -~
triphenyl(lower)alkoxy(lower)alkyl.
~5 ~11707~
WO 93/0~03~ - 15 - pCr/JP42~01117 ThQ processes for the preparat$on of the ob~ect compound (I) of the prQ~nt inventlon ar~ explained in det~il $n the following. -~.
5 (1) Proc~
The compound (I) or ~alts thereof c~n be prspared by reacting the compo~nd (II) or salts thereof wi~h the compound (III).
Suit~ble ~alt~ of the compound tII) mny be acid add~tion salts such as those ~i~en for the compound ~
Suitsble ex~mple of the compound (III) may include N,N'-c~rbonyldiim$dazole, ~,N'-ca bonylbis(2-methyl-imid~zol~), phosgene or its reactive equi~alent (e.g.
d~mer or trimer thereof, etr. ), and the llke.
lS Thi~ re~ction can be carried out in a conventional solvent which doe~ not ~dversely influence the react~on such a8 dichloromethane, pyridine, N,N-dimethylformam~de, 4-methyl-2-pent~none, tetrahydrofur~n, etc., or a mixture therQof .
The reaction temper~ture is not critical ~nd the re~ction iJ usually carr-ed out under from w~rming to he~ting.
t2) Process 2 :
The compound (I-b) or salts thereof c~n be prepared by ~ub~ecting the compound tI-a) or salts thereof to reduction of n~tso group of R~.
Su~table salts of the compounds (I-a) and (I-b) may be the ~me ~ those for the compound (I).
The pre~ent renction i~ uYually carri~d out by a con~ent~onal method a~ ment~oned below.
Reduction method :
The reduction method applicable for this reaction may include con~ent~onal ones which are capable of converting WO 93/0503~ - 1 6 - PCr/JP92/01 1 17 211707~
a nitro group to ~ hydroxyamino or amino group, for ex~mple, reduction using tin(II) chloride or zinc powder;
reduction u~ing a combination of a metal (e.g~ zinc, zinc ~m~lgam, QtC. ) or a ~alt of chrome compound (e.g. chromous ~-~
chloride, chromous acetate, QtC. ) and an organ~c or ~ inorganic ~cld (e.g. ~cetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.3 oonventional catAlyt$c reduction in the presence of a conventional metallic c~taly~t such a~ palladium catalysts (e.g. ~pongy palladium, pAlladium bl~ck, palladium oxide, palladium on carbon, collo~dal palladium, p~lladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on c~rbon, etc.), nlckel cataly~ts (e.g. reduced nickel, ntckel oxide, Raney nickel, etc.), platinum cataly~ts (e.g. pl~tinum plate, sRongy platinum, platinum bl~ck, colloid~l plat~num, pl~tinum oxide, platinum wire, etc.);
reduction using aluminum am~lgam, electrolytic reduction;
and the like.
Tn case that the c~talytic reduction i-~ applied, the reaction i~ preferably carried out around neutral condition. -Th$~ reaction i8 u~ually carried out in a conventional sol~ent which does not ad~er~ely influence ths reaction such a~ water, alcohol (e.g. methanol, -~
eth~nol, prop~nol, etc.), diox~ne, tetrahydrofuran, ~cetic ~cid, buffer ~olutlon (e.g. phosphate buffer, acetate buffer, etc.-), ~nd the like, or a mixture thereof.
The re~ction temperature i8 not critical ~nd the re~ction i~ u~u~lly carried out under from warming to heating.
(3) Proce~s 3 :
The compound (I-d) or salts thereof can be prepared by introducing ~n ~mino-protecti~e group into the compound (~-c) or salt~ thereof.
211707~
W093/05035 - ~7 - PCT/JP92/01117 Su~table salts of the eompounds (I-e) and tI-d) may ~-be the same as those for the eompo~nd (I).
Su~table introdueing Aqent of the amino-protective ~roup used in this reaetion may be a conventional one whieh is eapable of introdueing the a~ino-proteetive group sueh as aeyl as mentioned before, for example, lower alkyl isoeyanate (e.g. ethyl isoeyanate, ete.);
alkali metal eyanate (e.g. potassium eyanate, ete.);
lower alkyl halo(lower)alkanate le.~. ethyl ehloroform~te, ete.); earboxylie aeid, earbonie aeid, sulfonie aeid and their reaetive derivative (e.g. an aeid halide, an acid anhydride, an aetivated amide, an aetivated ester, ete.);
and the like. Preferable e~ample of sueh reaetiYe derivative may inelude lower alkanoic aeid halide (e.g.
L5 aeetyl ehloride, ete.); lower alkanesulfonyl halide ~e.g.
mesyl ehloride, ethanesulfonyl ehloride, ete.); a mixed aeid anhydride with an aeid sueh as substi~uted phosphorie aeid ~e.g. dialkylphosphorie aeid, phenylphosphorie aeid, diphenylphosp~orie ae~d, dibenzylphosphorie aeid, ~0 halogenated phosphorie aeid, ete.), dialXylphosphorous aeid, sulfurous aeid, thiosulfur~e aeid, sulfurie aeid sulfonie aeid (e.g. methanesulfonie aeid, toluenesulfonie acid, ete.), mono(lower)alkyl ester of carbonie aeid, aliphatie earboxylie aeid (e.g. pivalie aeid, pentanoic aeid, isopentanoie a~id, 2-ethylbutyrie aeid, txiehloroaeetie aeid, ete.), aromatie earboxylie acid le.g. benzoie aeid, ete.); a symmetrieal aeid anhydride sueh as lower alkanoic 2nhydride (e.g. acetie anhydride, ~-ete.), tr~halo~lower)alkanoie anhydride (e.g.
trifluoroaeetie anhydrlde, ete.~; an aetiYated aeid amide with a heteroeyelie eompound eontaining imino funet~on sueh as imidazole, 4-substituted imid~zole, dimethylpyrazole, triazole and tetrazole; an activated ester ~e.g. p-nitrophenyl ester, 2,4-dinitrophenyl ester, triehlorophenyl ester, pentaehlorophenyl ester, WO 93/0503~ - 18 - PCI`/JP92/01117 ~
21170~5 ~
mesylphenyl ester, phenylazophenyl ester~ phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyridyl ester, p~peridinyl ester, 8-quinolyl thioester, or an ester with a N-hydroxy compound such as N,N-dimethylhydroxylamine, l-hydroxy-2-(lH)-p~ridone, N-hydroxysuccinimLde, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.); and the li~e.
This reaction can be carried out in the presence of a base or an acid according to the tntroducing agent of the ;-~mino-protectiYe group to be used.
Suitable base may include an organic or inorganic base such as alkal~ metal ~e.g. lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride le.g. sodiu~ hydride, etc.), alkaline earth metal hydr~de (e.g. calcium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide,potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicar~onate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), aIkali metal alkoxide (e.~. sodium --methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkyl~mine (e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lut~dine, picoline, 4-dimethylaminopyridine, etc.), guinoline, and the like.
Suitable acid m~y include an organic actd (e.g.
formic acld, acetic-acid, propionic acid, trif~uoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid,~ etc.) and an inorganic acid (e.g. ~ydrochloric acid, hydrobromic acld, sulfuric acid, phosphoric acid, etc.).
In case that the introducing agent of the a~no-protective group used in a free fonm or its salt in this reaction, the reaction is preferably carried out 211707~
w093/0~03~ - 19 - pCT/JP92/oll17 in the presence of a condensing agent such as a car~odi~mide compound le.g. N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,~'-diet~ylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-~3-dimethylaminopropyl)carbodiimide, etc.~, a ketenimine compound ~e.g. N,N'-carbonyLbis-(2-methy-imidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ether compounds (e.g. ethoxyacet~lcne, ~0 ~-chlorovinylethyl ether), a sulfonic acid ester sf N-hydroxy~enzotriazole derivative le.g.
1-(4-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole, etc.], a combination of trialkylphosphite or triphenylphosphine and carbon tetrachloride, disulfide or diazenedicarboxylate (e.g. diethyl diazenedicarboxylate, etc.), a phosphorus compound (e.~. ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride, etc.), t~ionyl chloride, oxalyl chloride, N-ethylbenzlsoxazolium salt, N-ethyl-~-phenylisoxazolium-3-sulfonate, a reagent (referred to a so-called ~'Vilsmeier reagent") formed by the reaction of an amide compound such as N,N-di(lower)alkylformamide (e.g. dimethylformamide, etc.), ~-methylformamide or the like with a halogen compound such as thionyl chloride, phosphoryl chloride, phosgene or the like.
The react~on is usually carried out in a conventional solvent w~ich does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g.
methanol, ethanol, etc.), tetrahyd ofuran, pyridine, :
N,N-dimethylformamide, etc., or a mixture thereof, and further in case that the amino-introducing agent is in l~quid, it can also be used as a solvent. ~-The reaction temperature is not critical and the reaction is usually carried out under from coolin~ to 3~ heating.
w093/0503~ z O PCT/JP92/olll7 - 21170~
~4) Process 4 :
The compound ~I~ or salts ~hereof can be prepared by -~
re~cting the compound (IV) or sa~ts thereof with a base. ::
Suitable salts of the compound (IV) may be the ~ame ~-~
as those fsr the compound (I).
Suitable base used in this reaction may be the same as those siven in the explanation of Process 3.
Thls reaction is usually carried out in a conventtonal sol~ent which does not adversely influence the react~on such as tetra~ydrofuran, dioxane, water, methano~, et~a~ol, etc., or a mixture thereof.
The reaction temF~rature is not critical, and the reaction is usually carried out under from warming to heating.
:
(~) Process ~ :
The compound (I-f) or salts thereof can be prepared by sub~ecting the co~pound (I-e) or salts thereof to a removal reaction of the hydroxy protecti~e ~roup in R2. -Suitable salts of the compounds (I-e) a~d (I-f) may be the same as those for the compound (1).
The present reaction is usually carried out by a con~entional method such as hydro~ysis, reduction, and the like. :-li)- Hydrolysis :
The hydrolysis is preferably carried out ~n the presence of a base or an acid. Suitable base may include an alkali metal hydsoxide (e.g. sodium hydroxide, potassium ~ydroxide, etc.)~ an alkaline easth met~l hydroxide (e.g. magnesium hydroxide, calci~m hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride ~e.g. calcium hydride, etc.), alkali metal alkoxide (e.g.
3~ sodium methoxide, sodium ethoxide, potassium t-butox~de, W093/0503~ 2 1 1707~ pCT/JP92t0l1t7 etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), and alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkall metal ~icarbonate (e.g~ sodium ~iearbonate, potassium bicarbonate, etc.), and the liXe.
Sultable aeid may include an organir aeid (e.g.
formic aeid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic aeid, p-toluenesulfonic aeid, etc.) and an inorganic acid (e.q. hydrochloric acid, hydrobromie acid, sulfuric acid, phosphoric acid, etc.). The acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trappir.g agen~ (e.g.
phenol~ anisole, ete.).
This reaction is usually carried out in a conventional solvent which does not adversely influence the reaetion sueh as water, dlchloromethane, aleohol (e.g.
methanol, ethanol, ete.), tetrahyarofuran, dioxane, acetone, etc., or a mix~ure thereof. A liquid base or aeid ean be also used as the solvent.
The reaetion temperature is not eritieal and the reaction is usually carried out unaer from coolin~ to -~
heatin~.
lii) Reduet~on :
~5 The reduction method applicable for this removal ~-reaetion may inelude, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) of a salt of ehrome compound (e.g. chromous chloride, chromuos acetate, etc.) and an organic or inor~anic acid (e.g. acetie acid, propionic acid, hydrochloric acid, sulfurie acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as pal~adium eatalysts (e.g. spongy palladium, palladium blac~, palladium oxide, palladium on earbon, colloidal palladium, palladium on barlum sulfate, palladium on w093/0503~ ~2 PCT/JP92/01117 ` 2I17075 barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, ni~kel oxide, Raney nickel, etc.), platinum catalysts ~e.g. platinum pla~e, spongy p~atinum, platinum black, colloidal platinum, p~atinum oxide, platinum wire, etc.), and the like.
In case that the catalytic reduction is applied, the reaction is preferably carried out around neutral --conditlon.
Th~s reaction is usually carried out in a conventional solvent wh~ch does not adversely influence ~-the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), d~oxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the li~e, or a mixture thereof.
lS The re~ction temperature is not critical and the reaction is usually carried out under from cooling to warming.
The removal reaction can be selected according to the ~0 kind of hydroxy-protective group to be removed.
~ .
The compound (I) or ~alts thereof c~n be prspared by reacting the compo~nd (II) or salts thereof wi~h the compound (III).
Suit~ble ~alt~ of the compound tII) mny be acid add~tion salts such as those ~i~en for the compound ~
Suitsble ex~mple of the compound (III) may include N,N'-c~rbonyldiim$dazole, ~,N'-ca bonylbis(2-methyl-imid~zol~), phosgene or its reactive equi~alent (e.g.
d~mer or trimer thereof, etr. ), and the llke.
lS Thi~ re~ction can be carried out in a conventional solvent which doe~ not ~dversely influence the react~on such a8 dichloromethane, pyridine, N,N-dimethylformam~de, 4-methyl-2-pent~none, tetrahydrofur~n, etc., or a mixture therQof .
The reaction temper~ture is not critical ~nd the re~ction iJ usually carr-ed out under from w~rming to he~ting.
t2) Process 2 :
The compound (I-b) or salts thereof c~n be prepared by ~ub~ecting the compound tI-a) or salts thereof to reduction of n~tso group of R~.
Su~table salts of the compounds (I-a) and (I-b) may be the ~me ~ those for the compound (I).
The pre~ent renction i~ uYually carri~d out by a con~ent~onal method a~ ment~oned below.
Reduction method :
The reduction method applicable for this reaction may include con~ent~onal ones which are capable of converting WO 93/0503~ - 1 6 - PCr/JP92/01 1 17 211707~
a nitro group to ~ hydroxyamino or amino group, for ex~mple, reduction using tin(II) chloride or zinc powder;
reduction u~ing a combination of a metal (e.g~ zinc, zinc ~m~lgam, QtC. ) or a ~alt of chrome compound (e.g. chromous ~-~
chloride, chromous acetate, QtC. ) and an organ~c or ~ inorganic ~cld (e.g. ~cetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.3 oonventional catAlyt$c reduction in the presence of a conventional metallic c~taly~t such a~ palladium catalysts (e.g. ~pongy palladium, pAlladium bl~ck, palladium oxide, palladium on carbon, collo~dal palladium, p~lladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on c~rbon, etc.), nlckel cataly~ts (e.g. reduced nickel, ntckel oxide, Raney nickel, etc.), platinum cataly~ts (e.g. pl~tinum plate, sRongy platinum, platinum bl~ck, colloid~l plat~num, pl~tinum oxide, platinum wire, etc.);
reduction using aluminum am~lgam, electrolytic reduction;
and the like.
Tn case that the c~talytic reduction i-~ applied, the reaction i~ preferably carried out around neutral condition. -Th$~ reaction i8 u~ually carried out in a conventional sol~ent which does not ad~er~ely influence ths reaction such a~ water, alcohol (e.g. methanol, -~
eth~nol, prop~nol, etc.), diox~ne, tetrahydrofuran, ~cetic ~cid, buffer ~olutlon (e.g. phosphate buffer, acetate buffer, etc.-), ~nd the like, or a mixture thereof.
The re~ction temperature i8 not critical ~nd the re~ction i~ u~u~lly carried out under from warming to heating.
(3) Proce~s 3 :
The compound (I-d) or salts thereof can be prepared by introducing ~n ~mino-protecti~e group into the compound (~-c) or salt~ thereof.
211707~
W093/05035 - ~7 - PCT/JP92/01117 Su~table salts of the eompounds (I-e) and tI-d) may ~-be the same as those for the eompo~nd (I).
Su~table introdueing Aqent of the amino-protective ~roup used in this reaetion may be a conventional one whieh is eapable of introdueing the a~ino-proteetive group sueh as aeyl as mentioned before, for example, lower alkyl isoeyanate (e.g. ethyl isoeyanate, ete.);
alkali metal eyanate (e.g. potassium eyanate, ete.);
lower alkyl halo(lower)alkanate le.~. ethyl ehloroform~te, ete.); earboxylie aeid, earbonie aeid, sulfonie aeid and their reaetive derivative (e.g. an aeid halide, an acid anhydride, an aetivated amide, an aetivated ester, ete.);
and the like. Preferable e~ample of sueh reaetiYe derivative may inelude lower alkanoic aeid halide (e.g.
L5 aeetyl ehloride, ete.); lower alkanesulfonyl halide ~e.g.
mesyl ehloride, ethanesulfonyl ehloride, ete.); a mixed aeid anhydride with an aeid sueh as substi~uted phosphorie aeid ~e.g. dialkylphosphorie aeid, phenylphosphorie aeid, diphenylphosp~orie ae~d, dibenzylphosphorie aeid, ~0 halogenated phosphorie aeid, ete.), dialXylphosphorous aeid, sulfurous aeid, thiosulfur~e aeid, sulfurie aeid sulfonie aeid (e.g. methanesulfonie aeid, toluenesulfonie acid, ete.), mono(lower)alkyl ester of carbonie aeid, aliphatie earboxylie aeid (e.g. pivalie aeid, pentanoic aeid, isopentanoie a~id, 2-ethylbutyrie aeid, txiehloroaeetie aeid, ete.), aromatie earboxylie acid le.g. benzoie aeid, ete.); a symmetrieal aeid anhydride sueh as lower alkanoic 2nhydride (e.g. acetie anhydride, ~-ete.), tr~halo~lower)alkanoie anhydride (e.g.
trifluoroaeetie anhydrlde, ete.~; an aetiYated aeid amide with a heteroeyelie eompound eontaining imino funet~on sueh as imidazole, 4-substituted imid~zole, dimethylpyrazole, triazole and tetrazole; an activated ester ~e.g. p-nitrophenyl ester, 2,4-dinitrophenyl ester, triehlorophenyl ester, pentaehlorophenyl ester, WO 93/0503~ - 18 - PCI`/JP92/01117 ~
21170~5 ~
mesylphenyl ester, phenylazophenyl ester~ phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyridyl ester, p~peridinyl ester, 8-quinolyl thioester, or an ester with a N-hydroxy compound such as N,N-dimethylhydroxylamine, l-hydroxy-2-(lH)-p~ridone, N-hydroxysuccinimLde, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chlorobenzotriazole, etc.); and the li~e.
This reaction can be carried out in the presence of a base or an acid according to the tntroducing agent of the ;-~mino-protectiYe group to be used.
Suitable base may include an organic or inorganic base such as alkal~ metal ~e.g. lithium, sodium, potassium, etc.), alkaline earth metal (e.g. calcium, etc.), alkali metal hydride le.g. sodiu~ hydride, etc.), alkaline earth metal hydr~de (e.g. calcium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide,potassium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal bicar~onate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), aIkali metal alkoxide (e.~. sodium --methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g. sodium acetate, etc.), trialkyl~mine (e.g. triethylamine, etc.), pyridine compound (e.g. pyridine, lut~dine, picoline, 4-dimethylaminopyridine, etc.), guinoline, and the like.
Suitable acid m~y include an organic actd (e.g.
formic acld, acetic-acid, propionic acid, trif~uoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid,~ etc.) and an inorganic acid (e.g. ~ydrochloric acid, hydrobromic acld, sulfuric acid, phosphoric acid, etc.).
In case that the introducing agent of the a~no-protective group used in a free fonm or its salt in this reaction, the reaction is preferably carried out 211707~
w093/0~03~ - 19 - pCT/JP92/oll17 in the presence of a condensing agent such as a car~odi~mide compound le.g. N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,~'-diet~ylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-~3-dimethylaminopropyl)carbodiimide, etc.~, a ketenimine compound ~e.g. N,N'-carbonyLbis-(2-methy-imidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ether compounds (e.g. ethoxyacet~lcne, ~0 ~-chlorovinylethyl ether), a sulfonic acid ester sf N-hydroxy~enzotriazole derivative le.g.
1-(4-chlorobenzenesulfonyloxy)-6-chloro-lH-benzotriazole, etc.], a combination of trialkylphosphite or triphenylphosphine and carbon tetrachloride, disulfide or diazenedicarboxylate (e.g. diethyl diazenedicarboxylate, etc.), a phosphorus compound (e.~. ethyl polyphosphate, isopropyl polyphosphate, phosphoryl chloride, phosphorus trichloride, etc.), t~ionyl chloride, oxalyl chloride, N-ethylbenzlsoxazolium salt, N-ethyl-~-phenylisoxazolium-3-sulfonate, a reagent (referred to a so-called ~'Vilsmeier reagent") formed by the reaction of an amide compound such as N,N-di(lower)alkylformamide (e.g. dimethylformamide, etc.), ~-methylformamide or the like with a halogen compound such as thionyl chloride, phosphoryl chloride, phosgene or the like.
The react~on is usually carried out in a conventional solvent w~ich does not adversely influence the reaction such as water, acetone, dichloromethane, alcohol (e.g.
methanol, ethanol, etc.), tetrahyd ofuran, pyridine, :
N,N-dimethylformamide, etc., or a mixture thereof, and further in case that the amino-introducing agent is in l~quid, it can also be used as a solvent. ~-The reaction temperature is not critical and the reaction is usually carried out under from coolin~ to 3~ heating.
w093/0503~ z O PCT/JP92/olll7 - 21170~
~4) Process 4 :
The compound ~I~ or salts ~hereof can be prepared by -~
re~cting the compound (IV) or sa~ts thereof with a base. ::
Suitable salts of the compound (IV) may be the ~ame ~-~
as those fsr the compound (I).
Suitable base used in this reaction may be the same as those siven in the explanation of Process 3.
Thls reaction is usually carried out in a conventtonal sol~ent which does not adversely influence the react~on such as tetra~ydrofuran, dioxane, water, methano~, et~a~ol, etc., or a mixture thereof.
The reaction temF~rature is not critical, and the reaction is usually carried out under from warming to heating.
:
(~) Process ~ :
The compound (I-f) or salts thereof can be prepared by sub~ecting the co~pound (I-e) or salts thereof to a removal reaction of the hydroxy protecti~e ~roup in R2. -Suitable salts of the compounds (I-e) a~d (I-f) may be the same as those for the compound (1).
The present reaction is usually carried out by a con~entional method such as hydro~ysis, reduction, and the like. :-li)- Hydrolysis :
The hydrolysis is preferably carried out ~n the presence of a base or an acid. Suitable base may include an alkali metal hydsoxide (e.g. sodium hydroxide, potassium ~ydroxide, etc.)~ an alkaline easth met~l hydroxide (e.g. magnesium hydroxide, calci~m hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride ~e.g. calcium hydride, etc.), alkali metal alkoxide (e.g.
3~ sodium methoxide, sodium ethoxide, potassium t-butox~de, W093/0503~ 2 1 1707~ pCT/JP92t0l1t7 etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), and alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkall metal ~icarbonate (e.g~ sodium ~iearbonate, potassium bicarbonate, etc.), and the liXe.
Sultable aeid may include an organir aeid (e.g.
formic aeid, acetic acid, propionic acid, trifluoroacetic acid, benzenesulfonic aeid, p-toluenesulfonic aeid, etc.) and an inorganic acid (e.q. hydrochloric acid, hydrobromie acid, sulfuric acid, phosphoric acid, etc.). The acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trappir.g agen~ (e.g.
phenol~ anisole, ete.).
This reaction is usually carried out in a conventional solvent which does not adversely influence the reaetion sueh as water, dlchloromethane, aleohol (e.g.
methanol, ethanol, ete.), tetrahyarofuran, dioxane, acetone, etc., or a mix~ure thereof. A liquid base or aeid ean be also used as the solvent.
The reaetion temperature is not eritieal and the reaction is usually carried out unaer from coolin~ to -~
heatin~.
lii) Reduet~on :
~5 The reduction method applicable for this removal ~-reaetion may inelude, for example, reduction by using a combination of a metal (e.g. zinc, zinc amalgam, etc.) of a salt of ehrome compound (e.g. chromous chloride, chromuos acetate, etc.) and an organic or inor~anic acid (e.g. acetie acid, propionic acid, hydrochloric acid, sulfurie acid, etc.); and conventional catalytic reduction in the presence of a conventional metallic catalyst such as pal~adium eatalysts (e.g. spongy palladium, palladium blac~, palladium oxide, palladium on earbon, colloidal palladium, palladium on barlum sulfate, palladium on w093/0503~ ~2 PCT/JP92/01117 ` 2I17075 barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, ni~kel oxide, Raney nickel, etc.), platinum catalysts ~e.g. platinum pla~e, spongy p~atinum, platinum black, colloidal platinum, p~atinum oxide, platinum wire, etc.), and the like.
In case that the catalytic reduction is applied, the reaction is preferably carried out around neutral --conditlon.
Th~s reaction is usually carried out in a conventional solvent wh~ch does not adversely influence ~-the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), d~oxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the li~e, or a mixture thereof.
lS The re~ction temperature is not critical and the reaction is usually carried out under from cooling to warming.
The removal reaction can be selected according to the ~0 kind of hydroxy-protective group to be removed.
~ .
(6) Process 6 :
The compound (I-h) or salts thereof can be prepared by sub~ect~ng the compound ~I-g) or salts thereof to a 2S removal reaction of the carboxy-pro~ec~ive group in R2.
Suitable salts of the comyounds (I-g) and (I-h) may be the same as those for the compound (I).
This reaction is usually carried out by a conventional metho~ such as ~ydro~ysis, reduction and the like.
The method of hydrolysis and reduction, and the reaction condit~ons (e.g. reaction temperature, solvent etc.) are substantially the same as those illustrated for removal re~ction of the hydroxy-protective group of the compound (I-a) in ~rocess 5, and therefore are to be W0~3/Q~035 2 1 1 7 ~ p~cT/Jp92/olll7 referred to ~aid e~plnnAtion.
The ob~ect compound (I) obt~ined Accord~ng to the Proce~es 1 to 6 c~n be i~olat~d and purified in a con~ention~l manner, for example, extraction, precipitation, fr~ction~l crystall~z~tion, recryst~lliz~tion, chromatography, and the like.
Method A to C for prep~ring the new ~tarting compound~ (II) ~nd (IV) or ~lts thereof Are explained ~n detail in the following.
~,'.
(A) Method A :
The compound (II) or ~a~t~ thereof can be prepared ~y re~cting the compound (V) or salt~ thereof with the compound (VI) or 8alt3 thereof.
Su~t~b}e salts of the compound (~) may be s~lts with bases ~uch as tho~e gi~en for the compound (I).
Suitable salts of the compound (VI) may be the ~2me acid addition sAlts as tho~e for the co~pound (I).
This re~ction is usuAlly carried out in con~ention~l sol~ent which does not adversely influence the reactlon ~uch a~ dichloromethane, pyridine, N,N-d~methylform~mide, 4-methyl-2-pentanone, tetrahydrofur~n, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction i8 u~ually carried out under from warming to heating.
(B) Met~od B :
The compound ~II) or ~alts thereof can be prepared ~y reducing the nitro group of the compound (YII) or salts thereof.
Suitable salts of the compound (YII~ may be the ~ame a~ those for the compound (I).
The method of reduction ~nd the reaction conditions 35 (Q.g. reaction temperature, sol~ent, etc.) are WO 93/0503~ - 24 - PCI`/JP92/01117 21171: ~
sub~tantially the s~me a~ thosQ illu~trAted in Proce~s 2, ::
and therefore ~re to be referred to ~aid explanation.
(c) Method C s T~e compound (IV) or 8~1t~ thereof c~n be prep~red ~y react~nq the co~pound ~VIII) or it~ re~cti~e deri~Ati~e at the cnrboxy group, or 8alt~ thereof with tho compound tVI) or salt~ thereof.
Suitable salt~ of the compound (VIII) may be the ~ame a~ tho~e for the compound (I).
Su~table r~active der~ati~e of the compo~nd (VIII) may ~nclude an acid halide, an acid anhydride, an acSl~ated amide, an acti~sted eYter, And the like.
The suitable example may be an acid chloride; an ac~d ~`
azide; a mixed acid anhydride with an acid such as sub~tituted pho~phoric acid (Q.g. dialkylphosphoric ac~d, phenylpho~phoric acld, diphenylpho~phoric ac~d, :~
dibenzylphosphoric acid, halogen~ted phosphoric acid etc.), di~lkylphosphorou~ acid, lower alkanesulfonic acid (e.g. meth~ne~ulfonic acid, ethanesulfonic acid, etc.), ~ulforou~ ac~d, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g.
pi~alic acid, pentano~c acid, i~opentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.) or arom~tic c~rboxylic ~cid (e.g. benzoic ACid, etc.);
8 ~ymmetrical ~cid ~nhydride; ~n ~cti~ated amide with imid~zol~, 4-~ub~tituted imidazole, dimethylpyr~zole, tri~zole or tetr~zole; or ~n ~cti~ated ester (e.g.
cyanomethyl e~ter, methoxymethyl e~ter, dimQthyliminomethyl [(cH3)2h~cH-] ester, ~inyl ester, propargyl ester, p-nitrophenyl e~ter, 2,4-dinitrophenyl e~ter, trichlorophenyl ester, pent~chlorophenyl e~ter, me~ylphenyl ester, phenyl~zophenyl e~ter, phenyl thioe~ter, p-nitrophenyl thioeQter, p-cresyl thioester, c~rboxymethyl th~oester, pyr~nyl e~ter, pyridyl ester, w~93/0503~ 2 1 1 7 0 7 SpCT/JP92/01.]7 piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hyaroxy compound (e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide, N-hydro~yphthalimide, 1-hydroxy-6-chloro-lH-benzotriazole, ;:
etc.), and the l~ke. These reactive deri~ati~es can optlonal~y be selected from them according to the kind of the compound ~V~II) to be used.
When the compaund (VIII) is used in free acid form or its salt for~ in the reaction, the reaction is preferably 1~ carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylc~rbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide; ~;~
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; ~:
N,N'-d~ethylcarbodlimide, N,N'-diisopropylc~rbodiimide;
~S N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
N,N-carbonylb~s-12-methylimid~zole); pentamethyleneketene-N-cy~lohexylimtne; d~phenylketene-N-cyclohexylimine;
ethoxyacetylene; 1~ oxy-1-chloroethylene; triaIkyl phosphlte; ethyl polyphosphate; isopropyl polyphosphate;
phosphorus oxychlor~de (phosphoryl chloride); phosp~orus trichlor~de; thionyl chloriae; oxalyl chloride;
triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;
2-ethyl-5-lm-sulfop~enyl)isoxazolium hydroxide intramo~ecular salt; l-(p-chlorobenzenesulfonyloxy)-6-2~ chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-~imethylformamide with th~onyl chloride, phosgene, phosphorus oxychlroide, etc.;
or the like.
The reaction may also be carried out in the presence of an inorgan~c or organic base such as those g~ven in the explanat~on of Process 3.
The reaction is usually carried out in a conventional solvent whlch does not adversely influence the reaction such as water, methanol, ethanol, acetone, dioxane, acetonitsile, chloroform, methylene chloride, ethylene W093/0503s - ~6 - PCT/JP92/01117 ` 2~1707~
chloride, tetrahydrofuran, ethyl acetate, N,N-d~methylformamide, pyridine, etc. or a mixture thereof.
The react~on temperature is not critical, and ~he S reaction is usually c~rried out under warming to ~eating.
~D) Method D :
The compound (VII) or salts thereof can be prepared by reacting the compound ~IX) or its react~ve derivativs at the carbo~y group, or salts thereof with the compound (VI) or salts thereof.
Suitable salts and reactive derivative of the compound (IX) may be the same as those for the compound (V~$~
T~e method of reaction and the reaction cond~tions te.g. reaction temperature, so~vent, etc.) are substa~tially the same as those illustrated in Method C, and therefore are to be referred to said explanat$on.
The object guinazoline derivatives ~I) stLmulate presynaptic(neuronal) and~or postsynapti~(vascular) dop~mine receptors that mediate inh~b~tion of neurogenic release of catecholamine and/or dilatation of renal vasculature and remission of Parkinsonism, respectively~
Quinazol~ne deri~atives (I) effect ~n the cardiovascular system as a conseguence of its ~nteraction with dop2minerglc ~nd adrenergic receptors.
The ob~ect compound (I) and ~har~aceutically accep~able salts thereof of the present invention are novel and display dopamine receptor stimulating effects;
5-HT receptor antagonism, especially 5-HT2 receptor antagonisms al receptor antagonism; and the like, and are useful as a dopam~ne receptor agonist; 5-~ receptor an~agonist, especlally S-HT2 receptor antagonist; ~1 receptor antagonist; and the like, for treating or preventing hypertension such as essential hypertension, W093/0503~ ?7 PCT/JP92/01117 renal hypertension, pulmonary hypertension, and other :~-earaiovaseular disorders (e.g. angina peetoris, eongestive heart failure, myocardial infaretion, etc.); Par~insoniSm; -~' hyperprolae~inemia; disorders of peripheral perfusion s~eh as Raynaud's phenomenon, 8ruger's diseases, and intermittent claudieation; thrombotie an~/or smooth muscle eell proliferative disease sueh as restenosis after perculaneous trans~.uminal eoronary an~ioplasty;
hypereholesterolemia, hyperlipemia; urinary disturvanee; .
eardiac hypertrophy; nephropAey sueh as nephritis, renal failure, ete.; arterioselerosis obliterans; obstruetive "
~hrombus; arterial embolus; Burger-Gruts syndsome;
aeroeyanosis; eh~l~lain; frost~ite; pro1aetin-producing ovulation d~sorder; prolaetin-produeing pituitary tumor;
puerperal galaetosehesia; galaetorrhea; distal hypertrophys pituitary gigantism; mental illness such as melaneholia, anxiety, sehizophrenia, ete.; eerebrovaseular diseases sueh as eerebral ~nfaretion, cerebral cireulation insuff~eieney; taehyeardia aeeompanied by sympathetic hypertoni~; hyperaldosteronism; diabetie eomplieation sueh as diabetie hypertriglyeeromia, and the like. '' And further, the objeet eompound II) has vasodilating aetivity, b~ood fl~w inereasing aetivity sueh as renal .
blood flow inereasing aetiv1ty, and the li~e. ~-2~ The eompound (I) and pharmaeeutieally aeeeptable ~' salts thereof may be also useful as an adrenolyt~e, tran~uilizer', se~at~ve, anti-emetie, hypothermic, skeletal ~.
musele relaxant, anti-inflammatory, hypoglyeemie, ':
anti-viral agent.
~0 Now in order to show the usefulness of the obje~t --eompound l~) and pharmaeeutically aeeeptable salts, the :~.
pharmaeologieal test data of the representative eompound of the eompound (I) of this invention are shown in the :
following.
.
WO 93/0503~ - 28 - PCr/JP92/01117 ~
2117075 ~
Test ComPound : r Co~pound A r The product of Example 1]
Test 1 Dopamine receptor ~DA2 receptor) blnding assay Test Metho~ 1 :
The affinlty for DA2 receptor of a Test Compound was determined following in vitro receptor binding assays.
Male rats weighing 150-300g were decapita~ed and the stratum were dissected from their brains. The tissue was homogenized in 40 volumes of buffer which consisted of 50 mM Tri~-HCl (p~ 7.~ ~t 25C), ~ mM tetraethylenediamine tetraacetic acid,5 m~ potassium chloride, 2 mM calcium chloride, and 1 mM maqnesium chloride. The homogenate was centrifuged at 50,000 g for 1~ minutes. The pellet was resuspended in 80 ~olumes of the buffer. The tissue suspension was centrifuged and suspended again in the same w~y. 3 Incubation tubes received 100 ~l of t2-N-~2,3(n)- H~-propyl-N-(2-thiofuranyl)-2'-ethylamino)-5-hydroxy-1,?.,3,4-tetrahydronaphtha~ene, 10 ~1 of the Test Compound and 0.89 ml of tissue suspension during binding assays. The concentration of (2-N-[2,3(n)-3H~propyl-N-~2-thiofuranyl)-2'-ethylamino)-5-hydroxy-1,2,3,4-tetrahydrona~hthalene, was 1.5 nM. The final tissue concentration of rat stratum was 160 ~g/ml. The ~ubes were incubated at 25C
for 4S minutes, and then filtered under vacuum through Whatman GF/B filters and washed three times wi~h 3 ml of ice-cold buffer. The filters were counted by liguid scintillat~on counter.
Speciflc binding of ~he (2-N-I2~3(n)-3H~propyl-(N-t2 thiofuranyl)-2'-ethylam~no)-5-hydroxy-1,2,3,4-tetrahydro-naphtha~ene was determined in the presence of 1 yN
apomorphine. The IC50 value of the Test Compound was 3~ calculated from the data of (2-N-12,3(n)-3H~propyl-N-(2-w093/05035 2 1 1 7 0 7 ~ pCT/Jpg2/olll7 thiofuranyl) 2'-ethylamino)-5-hydroxy-1,2,3,4-tetrahydro- :
naphthalene~ binding in the presence of 10 9M, 10 8M, 10 7M and 10 6M Test Compound.
Test Result 1 :
Test compound IC50 ~M) .. . , . ~ . .
Compound A 2~1 x 10 lû
Te~t 2 ~Inh~bition of reserpine-induced DOPA
accumulation] . :~
.:
Test Method 2 :
lS Male SD rats weighin~ 300-400 g were used in this test. ~ats were pretreated with reserpine (1 mg/kg, S.C.) 17-19 hours before sacrif~ce and then fasted. Test Compound w~s given orally to the rats 2 hours before -sacrifi~e. I~-~YdroxYbenzYlhYdrazine (100 mg/k~ p.) was given 30 mlnutes before sacri~ice.~ E~ch rat was exposed to miarowaves using a head-focus microwa~e applicator for 1.5 seconds. The whole brain was removed and further separated tnto the striatum. ::
DOPA was determined as follows; the striatum was :
homogenized in 9 volumes o~ O.lN perchloric acid solution :;
tO.4% EDTA-2Na). The homo~enate was centr~fuged at 10,000 rpm for 1 minute. The supernatant was appl~ed to high performance liquid chromatography~
:, ~ Test Result 2 . _ _ :
. Test Compound (mg~kg) Inhibit~on (%) .-Compound A ~.2 WO 93~0503~ o _ PCI`/JP92/01117 21170~
Test 3 l5-HT2 Bindinq Assay~
Test Method 3 :
The affinity for Serotonin 2 receptor of a test compound was detenmined following in vitro receptor b~ nding ~ssays.
Male Wistar rats weighin~ 150-300 g were decapitated and the frontal cortex were dissected fr~m their brains.
The tissue was homogenized in 1~ volumes of ice-cold buffer which consisted of 0.32 M Sucrose, 50 mM Tris-HCl (p~ 7.5 at 25C). The homogenate was centrifuged at 3,300 rpm at 4C for 10 minutes. The supernatant was -centrifuged at 2~,000 rpm for 20 minutes. The pellet was resuspended again in the same way, and incubated at ~7~C
for 15 minutes. The tissue suspension was centriAfuged at 20,000 rpm for 20 minutes. The final pellet was resuspended in 15 ~olumes of ice-cold assay buffer (50 mM
Tris~HCl, 4 mM CaC12, 0.1% Ascorb~c acid, 10 yM pargyline, pH7.7 at 25-C).
Incubation tubes received 100 ~l of [ethylen-3Hl-ketanserin, 10 ~l of the test compound and 0.2 ml of tissue suspension, and 0.69 ml assay buffer during binding assays. The f~nal concentration of ~ethylen-3H~-ketanserin was 0.05 nM. The tubes were incubated at 37~C
for 30 minutes, and then filtered under vacuum through Whatman GF/B f~lters and washed three times wi~h ~ ml of ice-cold buffer (50 m~ tris/HCl, pH 7.5 at 25C). The fllters were counted by liquid scintillation counter.
S~ecific b~nding of [ethylen-3H~-ketanserin was determined ln the presence of 1 ~M mianserin. The~ICSO
value of the test compound was calculated from the data of [ethylen-3H~-ketanserin ~inding in the presence of 10 9M, 10 8M, 10 7M, and lO 6M test compound.
3~
2:~171)75 W0~3/0503~ - 31 - PCT/JP92/01117 3~:
..... .......
Test Compound ICsO (M) Compound A 3.5 x l0-8 For ther~peutic admini3tration, the ob~ect compound (I) ~nd the phar~aceutically acceptable ~alt~ thereof of the pres~nt in~ention are used in the form of con~ention~l ph~rmac~utical prep~ration whirh contains said compound, as ~n acti~ ingredient, in admixture with :-pharmaceutically ~ccept~ble carriers such as an organic or inorganic sol~d or liquid excipient which is suit~ble for-oral, p~renteral and external admini~tration. :~
The pharmaceutical prepar tion~ m~y be in ~olid form such a~ t~blet, gr~nule, powder, capsule, or liguid form such ~ ~olution, ~u~pension, ~yrup, emul5 ~on, le nade, ~nd the like.
If neaded, there may be included in the abo~e preparation~ auxiliary sub~t~nces, ~tabilizing agents, wettlng ~gents and other commonly u~ed add~tives ~uch a~
lactose, stearic acid, magne~ium stearate, terra alba, ~ucrose, eorn ~t rch, talc, gelatin, ~gar, pect~n, peanut oll, ol~e oil, cacao butter, ethylene glycol, tartaric ~cid, citric cld, f~mar~c ~c~d, and the like.
While the do~ge of the compound (I) m~y v~ry from and ~l~o depend upon the age, conditionQ of the patien~, a kind of di~ea~es, a kind of tho compound (I) to be ~pplied, etc. In general, amount between about O.OOl mg and ~bout 300 mg, prefer~bly about O.l mg to about 50 mg per d~y may be admini~tered to a patient. An averaqe :~
single do~ of about O.OOl mg, O.Ol mg, 0.03 mg, O.l mg, 0.3 mg, 0.6 mq, l.0 mg, 3.0 mg, lO.0 mg, 50.0 mg, lO0.0 W093/05035 - 32 - pCT/JP92~01117 ` 2117075 m~, of th~ o~ect compound (I) of tho pre~ent ~n~ntion may be used as adrsnolytic, hypotens~e, cardio~a~cul~r, tran~uilizer, sedative, anti-2met~c, hypothermic, skelet~l mu~clQ rel~xant, antl-inflamm tory, and anti-~iral agent~.
The followtng Prep~rat~on~ ~nd Example~ are gi~en for the purpo8~ of illustrating this in~ention in more detail.
Prepar~tion, 1~
To a stirred m~xture of 4~ methylpiperazln-l-ylmethyl)-2-nitrobenzoic ~id (0.28 g), hydroxybenzotriazole (0.14 g) and dry dime~hylform~mide (5 ml) Wa8 ~dded dicyclohexylcarbodiim~de (O.2l g), and the mixture W~8 ~tirred for 1 hour At room temper~ture. Then 4-(4-phenyl-l,2,3,6-tetrahydropyridin-l-yl)butylam~ne hydrochloride IO.27 g) ~nd triethylamine (O.20 g) were ~dded and the stirring wa~ cont~nued for add~tion~l 1 hour. ~N H~drochloric acid (2 ml) and water (20 ml) were added and the mixture was wa~hed with ethyl acetate, ad~usted to pH 8 with Aqueou~ ~odium bicarbonate solution and extracted with ethyl acetate tx2). The combined organic extracts were dried ~er mngnesium sulfate and sol~ent wa~ e~aporated to give 4-(4-methylpiperazin-l-ylmethyl)-2-nitro-N-14-(4-phenyl-l,2,3,6-tetrahydro-25 pyri~n-l-yl )butyl]benzamide (O.2l g).
NMR (CDC13, ~) s l.78 (4~, m3, 2.23 (2H, m), 2.30 (3H, ~, 2.43 (8H, m), 2.52 ~2H, m), 2.62 (2H, m), 3.00 (2H, m), 3.28 ~2H, s~, 3.49 (2H, m), 5.75 (lH, m), 7.1-7.4 (7H, m), 7.75 (lH, s), 8.78 (lH, m) Preparation 1-2) To ~ st~rred ~ixture of 4-(4-methylp~perazin-l-ylmethyl)-2-nitro-N-~4-(4-phenyl-l,2,3,6-tetr~hydropyrid~n-l-yl)butyl]benzamide (0.21 g), ethanol 211707~ :
W093jos03~ - 33 - PCT/~JP92/Otll7 (5 ml) and d~y te~rahydrofur~n (10 ml) was added tin (II) -~
chlorid~ (0.33 g) and the mixtur~ wa3 refluxed for 1 hour. ~-~fter cooling, chloroform (15 ml) and lN ~odium hydroxide (25 ml) w~re added ~nd the mixtur~ wa~ stirred. The --~
org~nic layer was ~ep~rated and the remained aqueous l~yer wa~ ~xtracted with chloroform. The org~nic layer ~nd extract were combined and dried o~er mAgne~ium ~ulf~te and evaporated to gi~e 2-amino-4-(4-methylpiperazin-1-ylmethyl)-N-t4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]benzam~de (O.25 g).
NMR (C~C13, 6) : 1.72 (4~, m), 2.31 (3H, fi), 2.50 (lOH, m), 2.71 (2H, m), 3.15 ~2H, m), 3.33 ~2H, ~), 3.45 (2H, m), 3.75 (2H, m), 5.50 (2H, br ~
6.0~ , m), 6.49 (lH, dd, J-8, lHz), 6.65 (lH, ::
d, J=l~z), 6~41 (lH, m3, 7.2-7.45 (6H, m) -Ex~mple 1 A mixture of 2-~mino-4-(4-methylpiperazin-1- :~
y~methyl)-N-t4-(4-phenyl-1,2,3,6-tetr~hydropyridin-1-yl)butyl~benz~mide (0.25 ~ arbonyldilmidazole (0.45 g) and dry tetrahydrofuran (10 ml) wa~ stirred under reflux for 14 hour~. After evapor~tion of the sol~ent, the crude re~idue wa~ taken up with ethyl acetate, washed with w~ter, dried o~er ma~ne~ium sulfate ~nd e~apora~ed to gi~e crystal~. Recrystallization from ethanol afforded 7-(4-methylpiperaz~n-1-ylmethyl)-3-[4-(4-phenyl-1,2,3,6-tetrahydropyrid~n-l-yl)buty~ 2~3~4- ~;
tetrahydroquinazoline-2,4-dione (0.16 g). :-mp : 167-168C
IR (Nu~ol) : 1700, 1660, 1~20, 1590 cm-l NMR (CDC~3, ~) : 1.75 (4H, m), 2.30 (3H, s), 2.50 (12H, m), 2.~2 (2H, m), 3.18 (2H, m), 3.56 (2H, :~
~), 4.12 (2H, m), 6.05 (lH, m), 7.00 (lH, s), 7.1S-7.40 (6H, m), 8.03 (lH, d, J~8Hz), 9.28 (lH, br 8 )
The compound (I-h) or salts thereof can be prepared by sub~ect~ng the compound ~I-g) or salts thereof to a 2S removal reaction of the carboxy-pro~ec~ive group in R2.
Suitable salts of the comyounds (I-g) and (I-h) may be the same as those for the compound (I).
This reaction is usually carried out by a conventional metho~ such as ~ydro~ysis, reduction and the like.
The method of hydrolysis and reduction, and the reaction condit~ons (e.g. reaction temperature, solvent etc.) are substantially the same as those illustrated for removal re~ction of the hydroxy-protective group of the compound (I-a) in ~rocess 5, and therefore are to be W0~3/Q~035 2 1 1 7 ~ p~cT/Jp92/olll7 referred to ~aid e~plnnAtion.
The ob~ect compound (I) obt~ined Accord~ng to the Proce~es 1 to 6 c~n be i~olat~d and purified in a con~ention~l manner, for example, extraction, precipitation, fr~ction~l crystall~z~tion, recryst~lliz~tion, chromatography, and the like.
Method A to C for prep~ring the new ~tarting compound~ (II) ~nd (IV) or ~lts thereof Are explained ~n detail in the following.
~,'.
(A) Method A :
The compound (II) or ~a~t~ thereof can be prepared ~y re~cting the compound (V) or salt~ thereof with the compound (VI) or 8alt3 thereof.
Su~t~b}e salts of the compound (~) may be s~lts with bases ~uch as tho~e gi~en for the compound (I).
Suitable salts of the compound (VI) may be the ~2me acid addition sAlts as tho~e for the co~pound (I).
This re~ction is usuAlly carried out in con~ention~l sol~ent which does not adversely influence the reactlon ~uch a~ dichloromethane, pyridine, N,N-d~methylform~mide, 4-methyl-2-pentanone, tetrahydrofur~n, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction i8 u~ually carried out under from warming to heating.
(B) Met~od B :
The compound ~II) or ~alts thereof can be prepared ~y reducing the nitro group of the compound (YII) or salts thereof.
Suitable salts of the compound (YII~ may be the ~ame a~ those for the compound (I).
The method of reduction ~nd the reaction conditions 35 (Q.g. reaction temperature, sol~ent, etc.) are WO 93/0503~ - 24 - PCI`/JP92/01117 21171: ~
sub~tantially the s~me a~ thosQ illu~trAted in Proce~s 2, ::
and therefore ~re to be referred to ~aid explanation.
(c) Method C s T~e compound (IV) or 8~1t~ thereof c~n be prep~red ~y react~nq the co~pound ~VIII) or it~ re~cti~e deri~Ati~e at the cnrboxy group, or 8alt~ thereof with tho compound tVI) or salt~ thereof.
Suitable salt~ of the compound (VIII) may be the ~ame a~ tho~e for the compound (I).
Su~table r~active der~ati~e of the compo~nd (VIII) may ~nclude an acid halide, an acid anhydride, an acSl~ated amide, an acti~sted eYter, And the like.
The suitable example may be an acid chloride; an ac~d ~`
azide; a mixed acid anhydride with an acid such as sub~tituted pho~phoric acid (Q.g. dialkylphosphoric ac~d, phenylpho~phoric acld, diphenylpho~phoric ac~d, :~
dibenzylphosphoric acid, halogen~ted phosphoric acid etc.), di~lkylphosphorou~ acid, lower alkanesulfonic acid (e.g. meth~ne~ulfonic acid, ethanesulfonic acid, etc.), ~ulforou~ ac~d, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g.
pi~alic acid, pentano~c acid, i~opentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.) or arom~tic c~rboxylic ~cid (e.g. benzoic ACid, etc.);
8 ~ymmetrical ~cid ~nhydride; ~n ~cti~ated amide with imid~zol~, 4-~ub~tituted imidazole, dimethylpyr~zole, tri~zole or tetr~zole; or ~n ~cti~ated ester (e.g.
cyanomethyl e~ter, methoxymethyl e~ter, dimQthyliminomethyl [(cH3)2h~cH-] ester, ~inyl ester, propargyl ester, p-nitrophenyl e~ter, 2,4-dinitrophenyl e~ter, trichlorophenyl ester, pent~chlorophenyl e~ter, me~ylphenyl ester, phenyl~zophenyl e~ter, phenyl thioe~ter, p-nitrophenyl thioeQter, p-cresyl thioester, c~rboxymethyl th~oester, pyr~nyl e~ter, pyridyl ester, w~93/0503~ 2 1 1 7 0 7 SpCT/JP92/01.]7 piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hyaroxy compound (e.g. N,N-dimethylhydroxylamine, 1-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide, N-hydro~yphthalimide, 1-hydroxy-6-chloro-lH-benzotriazole, ;:
etc.), and the l~ke. These reactive deri~ati~es can optlonal~y be selected from them according to the kind of the compound ~V~II) to be used.
When the compaund (VIII) is used in free acid form or its salt for~ in the reaction, the reaction is preferably 1~ carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylc~rbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide; ~;~
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; ~:
N,N'-d~ethylcarbodlimide, N,N'-diisopropylc~rbodiimide;
~S N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
N,N-carbonylb~s-12-methylimid~zole); pentamethyleneketene-N-cy~lohexylimtne; d~phenylketene-N-cyclohexylimine;
ethoxyacetylene; 1~ oxy-1-chloroethylene; triaIkyl phosphlte; ethyl polyphosphate; isopropyl polyphosphate;
phosphorus oxychlor~de (phosphoryl chloride); phosp~orus trichlor~de; thionyl chloriae; oxalyl chloride;
triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;
2-ethyl-5-lm-sulfop~enyl)isoxazolium hydroxide intramo~ecular salt; l-(p-chlorobenzenesulfonyloxy)-6-2~ chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-~imethylformamide with th~onyl chloride, phosgene, phosphorus oxychlroide, etc.;
or the like.
The reaction may also be carried out in the presence of an inorgan~c or organic base such as those g~ven in the explanat~on of Process 3.
The reaction is usually carried out in a conventional solvent whlch does not adversely influence the reaction such as water, methanol, ethanol, acetone, dioxane, acetonitsile, chloroform, methylene chloride, ethylene W093/0503s - ~6 - PCT/JP92/01117 ` 2~1707~
chloride, tetrahydrofuran, ethyl acetate, N,N-d~methylformamide, pyridine, etc. or a mixture thereof.
The react~on temperature is not critical, and ~he S reaction is usually c~rried out under warming to ~eating.
~D) Method D :
The compound (VII) or salts thereof can be prepared by reacting the compound ~IX) or its react~ve derivativs at the carbo~y group, or salts thereof with the compound (VI) or salts thereof.
Suitable salts and reactive derivative of the compound (IX) may be the same as those for the compound (V~$~
T~e method of reaction and the reaction cond~tions te.g. reaction temperature, so~vent, etc.) are substa~tially the same as those illustrated in Method C, and therefore are to be referred to said explanat$on.
The object guinazoline derivatives ~I) stLmulate presynaptic(neuronal) and~or postsynapti~(vascular) dop~mine receptors that mediate inh~b~tion of neurogenic release of catecholamine and/or dilatation of renal vasculature and remission of Parkinsonism, respectively~
Quinazol~ne deri~atives (I) effect ~n the cardiovascular system as a conseguence of its ~nteraction with dop2minerglc ~nd adrenergic receptors.
The ob~ect compound (I) and ~har~aceutically accep~able salts thereof of the present invention are novel and display dopamine receptor stimulating effects;
5-HT receptor antagonism, especially 5-HT2 receptor antagonisms al receptor antagonism; and the like, and are useful as a dopam~ne receptor agonist; 5-~ receptor an~agonist, especlally S-HT2 receptor antagonist; ~1 receptor antagonist; and the like, for treating or preventing hypertension such as essential hypertension, W093/0503~ ?7 PCT/JP92/01117 renal hypertension, pulmonary hypertension, and other :~-earaiovaseular disorders (e.g. angina peetoris, eongestive heart failure, myocardial infaretion, etc.); Par~insoniSm; -~' hyperprolae~inemia; disorders of peripheral perfusion s~eh as Raynaud's phenomenon, 8ruger's diseases, and intermittent claudieation; thrombotie an~/or smooth muscle eell proliferative disease sueh as restenosis after perculaneous trans~.uminal eoronary an~ioplasty;
hypereholesterolemia, hyperlipemia; urinary disturvanee; .
eardiac hypertrophy; nephropAey sueh as nephritis, renal failure, ete.; arterioselerosis obliterans; obstruetive "
~hrombus; arterial embolus; Burger-Gruts syndsome;
aeroeyanosis; eh~l~lain; frost~ite; pro1aetin-producing ovulation d~sorder; prolaetin-produeing pituitary tumor;
puerperal galaetosehesia; galaetorrhea; distal hypertrophys pituitary gigantism; mental illness such as melaneholia, anxiety, sehizophrenia, ete.; eerebrovaseular diseases sueh as eerebral ~nfaretion, cerebral cireulation insuff~eieney; taehyeardia aeeompanied by sympathetic hypertoni~; hyperaldosteronism; diabetie eomplieation sueh as diabetie hypertriglyeeromia, and the like. '' And further, the objeet eompound II) has vasodilating aetivity, b~ood fl~w inereasing aetivity sueh as renal .
blood flow inereasing aetiv1ty, and the li~e. ~-2~ The eompound (I) and pharmaeeutieally aeeeptable ~' salts thereof may be also useful as an adrenolyt~e, tran~uilizer', se~at~ve, anti-emetie, hypothermic, skeletal ~.
musele relaxant, anti-inflammatory, hypoglyeemie, ':
anti-viral agent.
~0 Now in order to show the usefulness of the obje~t --eompound l~) and pharmaeeutically aeeeptable salts, the :~.
pharmaeologieal test data of the representative eompound of the eompound (I) of this invention are shown in the :
following.
.
WO 93/0503~ - 28 - PCr/JP92/01117 ~
2117075 ~
Test ComPound : r Co~pound A r The product of Example 1]
Test 1 Dopamine receptor ~DA2 receptor) blnding assay Test Metho~ 1 :
The affinlty for DA2 receptor of a Test Compound was determined following in vitro receptor binding assays.
Male rats weighing 150-300g were decapita~ed and the stratum were dissected from their brains. The tissue was homogenized in 40 volumes of buffer which consisted of 50 mM Tri~-HCl (p~ 7.~ ~t 25C), ~ mM tetraethylenediamine tetraacetic acid,5 m~ potassium chloride, 2 mM calcium chloride, and 1 mM maqnesium chloride. The homogenate was centrifuged at 50,000 g for 1~ minutes. The pellet was resuspended in 80 ~olumes of the buffer. The tissue suspension was centrifuged and suspended again in the same w~y. 3 Incubation tubes received 100 ~l of t2-N-~2,3(n)- H~-propyl-N-(2-thiofuranyl)-2'-ethylamino)-5-hydroxy-1,?.,3,4-tetrahydronaphtha~ene, 10 ~1 of the Test Compound and 0.89 ml of tissue suspension during binding assays. The concentration of (2-N-[2,3(n)-3H~propyl-N-~2-thiofuranyl)-2'-ethylamino)-5-hydroxy-1,2,3,4-tetrahydrona~hthalene, was 1.5 nM. The final tissue concentration of rat stratum was 160 ~g/ml. The ~ubes were incubated at 25C
for 4S minutes, and then filtered under vacuum through Whatman GF/B filters and washed three times wi~h 3 ml of ice-cold buffer. The filters were counted by liguid scintillat~on counter.
Speciflc binding of ~he (2-N-I2~3(n)-3H~propyl-(N-t2 thiofuranyl)-2'-ethylam~no)-5-hydroxy-1,2,3,4-tetrahydro-naphtha~ene was determined in the presence of 1 yN
apomorphine. The IC50 value of the Test Compound was 3~ calculated from the data of (2-N-12,3(n)-3H~propyl-N-(2-w093/05035 2 1 1 7 0 7 ~ pCT/Jpg2/olll7 thiofuranyl) 2'-ethylamino)-5-hydroxy-1,2,3,4-tetrahydro- :
naphthalene~ binding in the presence of 10 9M, 10 8M, 10 7M and 10 6M Test Compound.
Test Result 1 :
Test compound IC50 ~M) .. . , . ~ . .
Compound A 2~1 x 10 lû
Te~t 2 ~Inh~bition of reserpine-induced DOPA
accumulation] . :~
.:
Test Method 2 :
lS Male SD rats weighin~ 300-400 g were used in this test. ~ats were pretreated with reserpine (1 mg/kg, S.C.) 17-19 hours before sacrif~ce and then fasted. Test Compound w~s given orally to the rats 2 hours before -sacrifi~e. I~-~YdroxYbenzYlhYdrazine (100 mg/k~ p.) was given 30 mlnutes before sacri~ice.~ E~ch rat was exposed to miarowaves using a head-focus microwa~e applicator for 1.5 seconds. The whole brain was removed and further separated tnto the striatum. ::
DOPA was determined as follows; the striatum was :
homogenized in 9 volumes o~ O.lN perchloric acid solution :;
tO.4% EDTA-2Na). The homo~enate was centr~fuged at 10,000 rpm for 1 minute. The supernatant was appl~ed to high performance liquid chromatography~
:, ~ Test Result 2 . _ _ :
. Test Compound (mg~kg) Inhibit~on (%) .-Compound A ~.2 WO 93~0503~ o _ PCI`/JP92/01117 21170~
Test 3 l5-HT2 Bindinq Assay~
Test Method 3 :
The affinity for Serotonin 2 receptor of a test compound was detenmined following in vitro receptor b~ nding ~ssays.
Male Wistar rats weighin~ 150-300 g were decapitated and the frontal cortex were dissected fr~m their brains.
The tissue was homogenized in 1~ volumes of ice-cold buffer which consisted of 0.32 M Sucrose, 50 mM Tris-HCl (p~ 7.5 at 25C). The homogenate was centrifuged at 3,300 rpm at 4C for 10 minutes. The supernatant was -centrifuged at 2~,000 rpm for 20 minutes. The pellet was resuspended again in the same way, and incubated at ~7~C
for 15 minutes. The tissue suspension was centriAfuged at 20,000 rpm for 20 minutes. The final pellet was resuspended in 15 ~olumes of ice-cold assay buffer (50 mM
Tris~HCl, 4 mM CaC12, 0.1% Ascorb~c acid, 10 yM pargyline, pH7.7 at 25-C).
Incubation tubes received 100 ~l of [ethylen-3Hl-ketanserin, 10 ~l of the test compound and 0.2 ml of tissue suspension, and 0.69 ml assay buffer during binding assays. The f~nal concentration of ~ethylen-3H~-ketanserin was 0.05 nM. The tubes were incubated at 37~C
for 30 minutes, and then filtered under vacuum through Whatman GF/B f~lters and washed three times wi~h ~ ml of ice-cold buffer (50 m~ tris/HCl, pH 7.5 at 25C). The fllters were counted by liquid scintillation counter.
S~ecific b~nding of [ethylen-3H~-ketanserin was determined ln the presence of 1 ~M mianserin. The~ICSO
value of the test compound was calculated from the data of [ethylen-3H~-ketanserin ~inding in the presence of 10 9M, 10 8M, 10 7M, and lO 6M test compound.
3~
2:~171)75 W0~3/0503~ - 31 - PCT/JP92/01117 3~:
..... .......
Test Compound ICsO (M) Compound A 3.5 x l0-8 For ther~peutic admini3tration, the ob~ect compound (I) ~nd the phar~aceutically acceptable ~alt~ thereof of the pres~nt in~ention are used in the form of con~ention~l ph~rmac~utical prep~ration whirh contains said compound, as ~n acti~ ingredient, in admixture with :-pharmaceutically ~ccept~ble carriers such as an organic or inorganic sol~d or liquid excipient which is suit~ble for-oral, p~renteral and external admini~tration. :~
The pharmaceutical prepar tion~ m~y be in ~olid form such a~ t~blet, gr~nule, powder, capsule, or liguid form such ~ ~olution, ~u~pension, ~yrup, emul5 ~on, le nade, ~nd the like.
If neaded, there may be included in the abo~e preparation~ auxiliary sub~t~nces, ~tabilizing agents, wettlng ~gents and other commonly u~ed add~tives ~uch a~
lactose, stearic acid, magne~ium stearate, terra alba, ~ucrose, eorn ~t rch, talc, gelatin, ~gar, pect~n, peanut oll, ol~e oil, cacao butter, ethylene glycol, tartaric ~cid, citric cld, f~mar~c ~c~d, and the like.
While the do~ge of the compound (I) m~y v~ry from and ~l~o depend upon the age, conditionQ of the patien~, a kind of di~ea~es, a kind of tho compound (I) to be ~pplied, etc. In general, amount between about O.OOl mg and ~bout 300 mg, prefer~bly about O.l mg to about 50 mg per d~y may be admini~tered to a patient. An averaqe :~
single do~ of about O.OOl mg, O.Ol mg, 0.03 mg, O.l mg, 0.3 mg, 0.6 mq, l.0 mg, 3.0 mg, lO.0 mg, 50.0 mg, lO0.0 W093/05035 - 32 - pCT/JP92~01117 ` 2117075 m~, of th~ o~ect compound (I) of tho pre~ent ~n~ntion may be used as adrsnolytic, hypotens~e, cardio~a~cul~r, tran~uilizer, sedative, anti-2met~c, hypothermic, skelet~l mu~clQ rel~xant, antl-inflamm tory, and anti-~iral agent~.
The followtng Prep~rat~on~ ~nd Example~ are gi~en for the purpo8~ of illustrating this in~ention in more detail.
Prepar~tion, 1~
To a stirred m~xture of 4~ methylpiperazln-l-ylmethyl)-2-nitrobenzoic ~id (0.28 g), hydroxybenzotriazole (0.14 g) and dry dime~hylform~mide (5 ml) Wa8 ~dded dicyclohexylcarbodiim~de (O.2l g), and the mixture W~8 ~tirred for 1 hour At room temper~ture. Then 4-(4-phenyl-l,2,3,6-tetrahydropyridin-l-yl)butylam~ne hydrochloride IO.27 g) ~nd triethylamine (O.20 g) were ~dded and the stirring wa~ cont~nued for add~tion~l 1 hour. ~N H~drochloric acid (2 ml) and water (20 ml) were added and the mixture was wa~hed with ethyl acetate, ad~usted to pH 8 with Aqueou~ ~odium bicarbonate solution and extracted with ethyl acetate tx2). The combined organic extracts were dried ~er mngnesium sulfate and sol~ent wa~ e~aporated to give 4-(4-methylpiperazin-l-ylmethyl)-2-nitro-N-14-(4-phenyl-l,2,3,6-tetrahydro-25 pyri~n-l-yl )butyl]benzamide (O.2l g).
NMR (CDC13, ~) s l.78 (4~, m3, 2.23 (2H, m), 2.30 (3H, ~, 2.43 (8H, m), 2.52 ~2H, m), 2.62 (2H, m), 3.00 (2H, m), 3.28 ~2H, s~, 3.49 (2H, m), 5.75 (lH, m), 7.1-7.4 (7H, m), 7.75 (lH, s), 8.78 (lH, m) Preparation 1-2) To ~ st~rred ~ixture of 4-(4-methylp~perazin-l-ylmethyl)-2-nitro-N-~4-(4-phenyl-l,2,3,6-tetr~hydropyrid~n-l-yl)butyl]benzamide (0.21 g), ethanol 211707~ :
W093jos03~ - 33 - PCT/~JP92/Otll7 (5 ml) and d~y te~rahydrofur~n (10 ml) was added tin (II) -~
chlorid~ (0.33 g) and the mixtur~ wa3 refluxed for 1 hour. ~-~fter cooling, chloroform (15 ml) and lN ~odium hydroxide (25 ml) w~re added ~nd the mixtur~ wa~ stirred. The --~
org~nic layer was ~ep~rated and the remained aqueous l~yer wa~ ~xtracted with chloroform. The org~nic layer ~nd extract were combined and dried o~er mAgne~ium ~ulf~te and evaporated to gi~e 2-amino-4-(4-methylpiperazin-1-ylmethyl)-N-t4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]benzam~de (O.25 g).
NMR (C~C13, 6) : 1.72 (4~, m), 2.31 (3H, fi), 2.50 (lOH, m), 2.71 (2H, m), 3.15 ~2H, m), 3.33 ~2H, ~), 3.45 (2H, m), 3.75 (2H, m), 5.50 (2H, br ~
6.0~ , m), 6.49 (lH, dd, J-8, lHz), 6.65 (lH, ::
d, J=l~z), 6~41 (lH, m3, 7.2-7.45 (6H, m) -Ex~mple 1 A mixture of 2-~mino-4-(4-methylpiperazin-1- :~
y~methyl)-N-t4-(4-phenyl-1,2,3,6-tetr~hydropyridin-1-yl)butyl~benz~mide (0.25 ~ arbonyldilmidazole (0.45 g) and dry tetrahydrofuran (10 ml) wa~ stirred under reflux for 14 hour~. After evapor~tion of the sol~ent, the crude re~idue wa~ taken up with ethyl acetate, washed with w~ter, dried o~er ma~ne~ium sulfate ~nd e~apora~ed to gi~e crystal~. Recrystallization from ethanol afforded 7-(4-methylpiperaz~n-1-ylmethyl)-3-[4-(4-phenyl-1,2,3,6-tetrahydropyrid~n-l-yl)buty~ 2~3~4- ~;
tetrahydroquinazoline-2,4-dione (0.16 g). :-mp : 167-168C
IR (Nu~ol) : 1700, 1660, 1~20, 1590 cm-l NMR (CDC~3, ~) : 1.75 (4H, m), 2.30 (3H, s), 2.50 (12H, m), 2.~2 (2H, m), 3.18 (2H, m), 3.56 (2H, :~
~), 4.12 (2H, m), 6.05 (lH, m), 7.00 (lH, s), 7.1S-7.40 (6H, m), 8.03 (lH, d, J~8Hz), 9.28 (lH, br 8 )
Claims (11)
1. A compound of the formula :
in which R1 is substituted heterocyclic-(lower)alkyl, and R2 is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy, mercapto, optionally substituted heterocyclic-carbonyl, optionally substituted heterocyclic-(lower)alkyl, lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl, R3 is aryl which may have suitable substituent(s), and A is lower alkylene, or pharmaceutically acceptable salts thereof.
in which R1 is substituted heterocyclic-(lower)alkyl, and R2 is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkyl, hydroxy, protected hydroxy, sulfamoyl, carboxy, protected carboxy, mercapto, optionally substituted heterocyclic-carbonyl, optionally substituted heterocyclic-(lower)alkyl, lower alkylthio, hydroxy(lower)alkyl or protected hydroxy(lower)alkyl, R3 is aryl which may have suitable substituent(s), and A is lower alkylene, or pharmaceutically acceptable salts thereof.
2. The compound of Claim 1, wherein R is hydrogen.
3. The compound of Claim 2, wherein R1 is unsaturated 3 to 8 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, which is substituted by lower alkyl or lower alkoxy, and R3 is phenyl optionally substituted by halogen or lower alkyl.
4. The compound of Claim 3, wherein R1 is pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl or dihydrotriazinyl, each of which is substituted by lower alkyl or lower alkoxy.
5. The compound of Claim 4, wherein R1 is lower alkylpiperazinyl(lower)alkyl, and R3 is phenyl.
6. The compound of Claim 5, which is 7-(4-methylpiperazin-1-ylmethyl)-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione.
7. A process for the preparation of a compound of the formula :
in which R1, R2, R3 and A are each as defined in Claim 1, or salts thereof, which comprises (a) reacting a compound of the formula :
or salts thereof, with a compound of the formula :
CO(X)2 to give a compound of the formula :
or salts thereof; or (b) reducing the nitro group of R2 of a compound of the formula :
or salts thereof, to give a compound of the formula :
or salts thereof; or (c) introducing the amino-protective group into a compound of the formula :
or salts thereof, to give a compound of the formula :
or salts thereof; or (d) reacting a compound of the formula :
or salts thereof, with a base to give a compound of the formula :
or salts thereof; or (e) subjecting a compound of the formula :
or salts thereof, to a removal reaction of the hydroxy-protective group in R?, to give a compound of the formula :
or salts thereof; or (f) subjecting a compound of the formula :
or salts thereof, to a removal reaction of the carboxy-protective group in R?, to give ? compound of the formula :
or salts thereof;
wherein R1, R2, R3 and A are each as defined above, R? is nitro, R? is hydroxyamino or amino, R? s amino, R? is protected amino, R? is protected hydroxy ox protected hydroxy-(lower)alkyl, R? is hydroxy or hydroxy(lower)alkyl, R? is protected carboxy, R? is carboxy, R4 is esterified carboxy, and X is a leaving group.
in which R1, R2, R3 and A are each as defined in Claim 1, or salts thereof, which comprises (a) reacting a compound of the formula :
or salts thereof, with a compound of the formula :
CO(X)2 to give a compound of the formula :
or salts thereof; or (b) reducing the nitro group of R2 of a compound of the formula :
or salts thereof, to give a compound of the formula :
or salts thereof; or (c) introducing the amino-protective group into a compound of the formula :
or salts thereof, to give a compound of the formula :
or salts thereof; or (d) reacting a compound of the formula :
or salts thereof, with a base to give a compound of the formula :
or salts thereof; or (e) subjecting a compound of the formula :
or salts thereof, to a removal reaction of the hydroxy-protective group in R?, to give a compound of the formula :
or salts thereof; or (f) subjecting a compound of the formula :
or salts thereof, to a removal reaction of the carboxy-protective group in R?, to give ? compound of the formula :
or salts thereof;
wherein R1, R2, R3 and A are each as defined above, R? is nitro, R? is hydroxyamino or amino, R? s amino, R? is protected amino, R? is protected hydroxy ox protected hydroxy-(lower)alkyl, R? is hydroxy or hydroxy(lower)alkyl, R? is protected carboxy, R? is carboxy, R4 is esterified carboxy, and X is a leaving group.
8. A pharmaceutical composition comprising, as an active ingredient, a compound of Claim 1 in admixture with a pharmaceutically acceptable carrier or excipient.
9. Use of a compound of Claim 1 as a medicament.
10. Use of a compound of Claim 1 as a dopamine receptor agonist, 5-HT receptor antagonist or .alpha.1 receptor antagonist.
11. A method for the treatment of dopamine receptor mediated diseases, 5-HT receptor mediated diseases or .alpha.1 receptor mediated diseases which comprises administering a compound of Claim 1 to a human being or animal.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP07/755,747 | 1991-09-06 | ||
| US07/755,747 US5296487A (en) | 1990-01-02 | 1991-09-06 | Quinazoline derivatives and their preparation |
| PCT/JP1992/001117 WO1993005035A1 (en) | 1991-09-06 | 1992-09-02 | Quinazoline derivatives and their preparation |
| CN93102096A CN1092067A (en) | 1991-09-06 | 1993-03-05 | Quinazoline derivant and preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2117075A1 true CA2117075A1 (en) | 1993-03-18 |
Family
ID=36808717
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002117075A Abandoned CA2117075A1 (en) | 1991-09-06 | 1992-09-02 | Quinazoline derivatives and their preparation |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0602125A1 (en) |
| JP (1) | JPH06510538A (en) |
| CN (1) | CN1092067A (en) |
| AU (1) | AU2500992A (en) |
| CA (1) | CA2117075A1 (en) |
| WO (1) | WO1993005035A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9205702D0 (en) * | 1992-03-16 | 1992-04-29 | Fujisawa Pharmaceutical Co | A new use of a quinazoline derivative |
| US5565454A (en) * | 1995-05-31 | 1996-10-15 | Ergo Science, Incorporated | Method for preventing intervention-associated stenosis and other symptoms associated with stenosis of blood vessels following non-bypass, invasive interventions |
| US6521630B1 (en) * | 1999-08-31 | 2003-02-18 | Pfizer Inc. | Tetrahydroquinazoline-2,4-diones and therapeutic uses thereof |
| BRPI0613693A2 (en) * | 2005-06-27 | 2011-01-25 | Hoffmann La Roche | 8-alkoxy-4-methyl-3,4-dihydro-quinazolin-2-yl amines and their uses as 5-ht5a receptor binders |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE126796T1 (en) * | 1990-01-02 | 1995-09-15 | Fujisawa Pharmaceutical Co | QUINAZOLINE DERIVATIVES AND THEIR PRODUCTION. |
-
1992
- 1992-09-02 WO PCT/JP1992/001117 patent/WO1993005035A1/en not_active Application Discontinuation
- 1992-09-02 AU AU25009/92A patent/AU2500992A/en not_active Abandoned
- 1992-09-02 EP EP92918711A patent/EP0602125A1/en not_active Withdrawn
- 1992-09-02 JP JP5505101A patent/JPH06510538A/en active Pending
- 1992-09-02 CA CA002117075A patent/CA2117075A1/en not_active Abandoned
-
1993
- 1993-03-05 CN CN93102096A patent/CN1092067A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU2500992A (en) | 1993-04-05 |
| CN1092067A (en) | 1994-09-14 |
| JPH06510538A (en) | 1994-11-24 |
| EP0602125A1 (en) | 1994-06-22 |
| WO1993005035A1 (en) | 1993-03-18 |
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