CA2090023A1 - Benzodiazepine derivatives - Google Patents
Benzodiazepine derivativesInfo
- Publication number
- CA2090023A1 CA2090023A1 CA002090023A CA2090023A CA2090023A1 CA 2090023 A1 CA2090023 A1 CA 2090023A1 CA 002090023 A CA002090023 A CA 002090023A CA 2090023 A CA2090023 A CA 2090023A CA 2090023 A1 CA2090023 A1 CA 2090023A1
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- CA
- Canada
- Prior art keywords
- compound
- salt
- suitable substituent
- formula
- group
- 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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Benzodiazepine derivatives of formula (I), wherein R1 is heterocyclic group which may have one or more suitable substituent(s), or cyano, R2 is hydrogen or halogen, R3 is aryl which may have one or more suitable substituent(s), R4 is aryl which may have one or more suitable substituent(s), etc., and A is lower alkylene, and pharmaceutically acceptable salts thereof which are useful as a medicament.
Description
_ WO92/01683 2 0 9 0 0 2 3 PC~/JP91/0095~
,` -- 1 -- .
DESCRIPTION
BENZODIAZEPINE DERIVATIVES
TECHNICAL FIELD
This inven.ion relates to new benzodia~e~ine derivatives and pharmaceutically acceptable sa1is thereof which are useful as a medicament.
B.~C~GROUND ART
Some benzodiazepine deriva~ives have been known as descri~ed, for example, in European Patent Application Publication No. 349949 and U.S. Patent 4,820,834.
DISCLOSURE OF INVENTION
This invention relates to new benzodiazepine -~
derivatives and pharmaceutically acceptable salts thereof.
More particularly, it relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are cholecystokinin (CCK) antagonists and therefore useful as therapeutical and/or preventive agents for emesis, pancreatitis, disorders of appetite requlatory systems, pain, insulinoma, gastroparesis, carcinoma of pancreas, gallbladder disease (e.g. acute cholecystitis, 2S calculus, etc.), disorders associated with intenstinal smooth muscle hyperactivity (e.g. irritable bowel syndrome, sphincter spasm, etc.), hyperinsulinemia, dyspepsia, nausea, etc.
The benzodiazepine derivatives of this invention can be represented by the following formula (I) : ~-i:
,. . . . . . , ,, ~
- - . . 1:
~g_ . -. .. .. . j - -~ .. . .
. .
,` -- 1 -- .
DESCRIPTION
BENZODIAZEPINE DERIVATIVES
TECHNICAL FIELD
This inven.ion relates to new benzodia~e~ine derivatives and pharmaceutically acceptable sa1is thereof which are useful as a medicament.
B.~C~GROUND ART
Some benzodiazepine deriva~ives have been known as descri~ed, for example, in European Patent Application Publication No. 349949 and U.S. Patent 4,820,834.
DISCLOSURE OF INVENTION
This invention relates to new benzodiazepine -~
derivatives and pharmaceutically acceptable salts thereof.
More particularly, it relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are cholecystokinin (CCK) antagonists and therefore useful as therapeutical and/or preventive agents for emesis, pancreatitis, disorders of appetite requlatory systems, pain, insulinoma, gastroparesis, carcinoma of pancreas, gallbladder disease (e.g. acute cholecystitis, 2S calculus, etc.), disorders associated with intenstinal smooth muscle hyperactivity (e.g. irritable bowel syndrome, sphincter spasm, etc.), hyperinsulinemia, dyspepsia, nausea, etc.
The benzodiazepine derivatives of this invention can be represented by the following formula (I) : ~-i:
,. . . . . . , ,, ~
- - . . 1:
~g_ . -. .. .. . j - -~ .. . .
. .
2 ~ 9 o o ~ C.3 i . PCT/JP91/0095~
2 -- .
_Rl o ~2~ ~ NHCo-R4 !I) ~ N
R
wherein Rl is heterocyclic group which may have one or more suitable substituent(s), or cyano, R2 is hydrogen or halogen, R3 is aryl which may nave one or more sultable substituent(s), R is aryl which may have one or more suitable substituent(s), ar(lower)alkenyl which lS may have one or more suitable substituent(s), arylamino which may have one or more suitable substituent(s), heteromonocyclic group which may have one or more suitable substituent(s), ~uinolyl, isoquinolyl, cinnolinyl, indolyl, or ~uinoxalinyl, and A is lower alkylene, with proviso that when R4 is indolyl, then :
(i) R is tetrazolyl which may have one or more suitable substituent(s) and R3 is halophenyl or : .
Iii~ Rl is imidazolyl which may have one or more :~
suitable substituent(s), R3 is halophenyl and ~.
A is ethylene.
According to the present invention, the new ben~cdi~zepine derivatives (I) can be prepared by the processes which are illustrated in the following scheme.
!:
~ ..
. .. .. . - ' '. .. .. ,, - .. ~ .... . .. , .. .; . ~ ... . . .
W092tO1683 2 0 9 0 O ~ 3 PCT/JP91/00952
2 -- .
_Rl o ~2~ ~ NHCo-R4 !I) ~ N
R
wherein Rl is heterocyclic group which may have one or more suitable substituent(s), or cyano, R2 is hydrogen or halogen, R3 is aryl which may nave one or more sultable substituent(s), R is aryl which may have one or more suitable substituent(s), ar(lower)alkenyl which lS may have one or more suitable substituent(s), arylamino which may have one or more suitable substituent(s), heteromonocyclic group which may have one or more suitable substituent(s), ~uinolyl, isoquinolyl, cinnolinyl, indolyl, or ~uinoxalinyl, and A is lower alkylene, with proviso that when R4 is indolyl, then :
(i) R is tetrazolyl which may have one or more suitable substituent(s) and R3 is halophenyl or : .
Iii~ Rl is imidazolyl which may have one or more :~
suitable substituent(s), R3 is halophenyl and ~.
A is ethylene.
According to the present invention, the new ben~cdi~zepine derivatives (I) can be prepared by the processes which are illustrated in the following scheme.
!:
~ ..
. .. .. . - ' '. .. .. ,, - .. ~ .... . .. , .. .; . ~ ... . . .
W092tO1683 2 0 9 0 O ~ 3 PCT/JP91/00952
- 3 -Process l ~-Rl o N g Ho-c-R4 N /
(III) (II) or its reactive derivative or its reactive derivative, ::.
at the amino group, or a salt thereof or a salt thereof .;.
A-R
, N
R2~/ \) NHCo-R4 ~ N /
(I) or a salt thereof ~-Process 2 : :25 ::
(Ia) ;~ ~~ or a salt thereof :
~: 35 :
W092/01683 2 0 9 0 0 2 ~ ~ . PCT/JP91/00952 Elimination reaction of the imino protective group ¦ b O
R2 ~ N--__ /~ NHCO-R-~ ~ N
. R3 (Ib) ~
or a salt thereof ::
Process 3 A-Rl R ~ C ~ NHCO-Ra ~:
R
(Ic) or a salt thereof .. I . ~". .
Reduction ".
. ~
- ' ' i' "' .. ~,~ 1:
; 35 '~
':
.. ,'' -,, . . . ,i. . i.. .
.. ~ .. ... . ;. . . . . .. ~ . . ..... .. . . . .. .. ..
WO 92tO16832 0 9 0 o 2 ~ - Pc-r/JPgl/00952 ~-Rl R2 ~ ~ ; HCo-R4 (Id) or a salt thereof Process 4 :..
H
O
~ N </
15R2 ~ ~ ~ NHCo-R4 + X_A_Rl :
R3 (V) :
~ .
(IV) or a salt thereof .
. 20or a salt thereof , ' A-~l 'o > R ~$~ ~ ~
~3 30~
or a salt thereof '-: :-~ . .
: ~ 3S~ `
~, ", ~ ~
~, ~
WO92/01683 2 0 9 `~ t~ 2 3: ; ; PCT/JP91/0095~
?rocess 5 A-CN O
S
R (VI) (Ie)or a salt thereof or a salt thereof H
N -N
~\ N /N ~ :
O , -' :.,';
~ R2 ~ ~ NHco-R4 ~ N
R
; . (If) ~.
or a salt thereof wherein R1, R2, R3, R4 and A are each as defined above, I
:~ Ra .is heterocyclic group having a protected imino , .
group of the formula :
~ / , , ' ~::
in which R6 is imino protective R6 groUP) . -.,.. :
in its hetero ring, which may have one or ~
WO92/01683 2 0 9 0 0 2 3 PCT/JPg1/00952 more suitable substituent~s!, Rl is heterocyclic group having an imino group of the formula : - N /
H
in its hetero ring, which may have one or more suitable substituent(s), Ra is ar~lower)alkenyl having a nitro group, Rb is ar(lower)alkenyl having an amino group and X is z~ acid residue. :~
1 0 ~,,, The starting co~ounds (II) and (IV) can be prepared by the following processes.
Process A
A-R O
R2 ~ ~ ~ R7 :
N
~; 20~ .
(VII) or a salt thereof Elimination reaction of ~ the amino protective group A-Rl O
N ~
13~;5~ ~ : or a salt thereof W092/01683 2 0 9 0 ~2 3 `` PC~JP91/00952 ~ ~
P~ocess ~3 R2 ~ NH2 + HO-C-R
R (IIl) or its reactive (VIII) derivative, or its reactive derivative. or a salt thereof -~at the amino group, or a salt thereof H O
N ~ -R ~ ~NHCo-R4 ~ N
(IV) or a salt thereof ::
wherein R1, R2, R3, R4 and A are each as defined above, and R7 is protected amino.
~: :
The starting compound (VII) or a salt thereof can be prepared by the methods disclosed in the Preparations 1-3, ^``
~30 6 and 7 described later or similar manners`thereto. `.
.: .
With regard to the objsct compound (I), in case tha_ the compound ~I-)~has ths group of the .ormula : :
..; WO92101683 2 0 9 0 0~;~3~. ~ ` pcT/Jpg1loo952 q NH
in R , said group can also exist in the tautomeric _orm and such tautomeric equilibrium can be represented by the following scheme.
H
N ___~ N
~
NH N . .
(A) (B) : :
Both of the above tautomeric isomers are included within the scope of the present invention. In the present specification and claim, the compounds including the group of such tautomeric isomers are represented for the convenient sake by one expression of the group of the formula (A). ::
Further, in case that the compound (I) has the group ~.
of the formula :
.
~5 N
:, . \
\ /N
N - N
:in Rl, said group can also exist in the tautomeric form --and suc~ tautomeric equili~rium can be represented by the foIlowing scheme.
~:3~S~
~ ~ .
WO 92/01683 2 0 9 0 0 2~ PCI~/JPgl/009~
. ' i ' ~ ' . 1 0 -- , !
H :
N ~ N
/ \N ~N
\\ /1 \\ / :
N --N N NH
(C) ~D) .
Both of the above tau,omeric isomers are ir.cluded within the scope of the present invention. In the presen.
specification and claim, the compounds including the srou?
o~ such tautomeric isomers are re~resented for the -convenient sake by one expression of the group or the ..
formula (C).
.. .
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g.
sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magne~ium salt, etc.), an ammonium salt~ an organic base salt (e.g. trimethy~amine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetatel etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate~, etc~), a salt with an amino acid (e.g. I
arglnine, aspartic acidj glutamic acid, etc.), and the ~ ;
like.
In the above and subsequent descriptions of the present~specification, suitable examples and illustrations o~ the various definitions which the present invention include within the scope thereof are explained in detail as follows. ~æ~
The term "lower" is intended to mean 1 to 6 carbon .
.....
- , . .~
WO92/01683 2 ~ 9 ~ 0 2 3 PCT/JP9~/009s~
atom5s), unless otherwise indicated.
Suitable "heterocyclic group" may include saturated or unsaturated, monocyclic or polycyclic heterocycllc group contalning at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And es~ecially preferable heterocyclic group ma-~ be heterocyclic group such as unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom~s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and lts N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl ~e.g.
1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl ~e.g., lH-tetrazolyl, 2H-tetr'azolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom~s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;
unsaturated co~densed heterocyclic group containing 1 to 5 nitro~en atom(s), for example, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizynyl, benzimidazolyl, quinolyl, iso~uinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g. tetrazolo-~1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic gxoup containing 1 to 2 oxygen atomts) and 1 to 3 nitrogen atom(s~, for example, oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl, 1,3,4'-oxadiazolyl, 1;2,5-oxadiazolyl, etc.) etc.;
saturated 3 to 8-membered heteromonocyclic ~roup containing l to 2 oxygen atom(s3:and 1 to 3 nitrGge~
atom(s), for example, morpholinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 WO92/01683 2 0 9 0 ~ 2 3 ` PCT/J~1/00952 oxygen atom(s) and 1 to 3 nitrogen atom(s~, for ex~mple, benzoxazolyl, benzoxadlazolyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, 1,3-thiazolyl, 1,2-thiazol~l, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.;
saturated 3 to 8-membered neteromonocyclic grou~
containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazo~idinyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example furyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc. and the like.
Suitable "substituent" in the terms `'heterocyclic group which may have one or more suitable substituent(s)"
and "heteromonocyclic group which may have one or more suitable substituent(s)" may include amino, protected amino as exemplified below, oxo, hydroxy, imino protective group as exemplified below, lower alkyl (e.g., methyl, 2~ ethyl r propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.) and the like.
Suitable "protected amino" may include acylamino and the like.
Suitable "imino protective group" may include acyl, 30 - mono~or di or tri)phenyl(lower)alkyl (e.g. trityl, etc.) :
tetrahydropyranyl and the like.
Suitable:"acyl" and "acyl moiety" in the term "acylamino" may include aliphatic acyl group and ac~l group containing an aromatic or heterocyclic ring.
And, suitable examples of the said acyl may be lower .
~ 13 -alkanoyl ~e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.);
lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, l-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-~utoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.);
lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.);
arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); ~ -aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.);
ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.);
ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.
The acyl moiety as stated above may have at least one suitable substituent(s) such as halogen (e.g. chlorine, bromine, fluorine and iodine), amino, protected amino (e.g. lower alkanoylamino, phenylthioureido, etc.), or the like.
~ ~ Suitable "acid residue" may include halogen and the like.
.
Suitable "halogen" may include chlorine, bromine, - fluorine and iodine.
Suitable "aryl" and "aryl moiety" in the terms "ar(lower)alkenyl" and "arylamino" may~include phenyl, 30~ naphthyl and the like. -suitabIe~"substituent" in the terms "aryl which may have one~or~more sui-table~substituent(s)", artlower)alkeny~ which~may have one ôr more suitabie substituent(s)" and-"arylamino~which may have one~or more 3~5 ~ suitable substituent(s)'i may include hydroxy, protected 2~9~0~3'; ` - 14 -hydroxy as exemplified below, nitro, lower alkoxy (e.g.
methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, etc.), amino, protected amino as exemplified above, lower alkyl (e.g., methyl, ethyl, propyl, isop~opyl, butyl, isobutyl, sec-buty~, t-buty~, pentyl, t-pentyl, hexyl, etc.), halogen as exemplified above, and the like:
- Suit2ble "lower alkenyl moiety" in the term "ar(lower)alkenyl" may include vinyl, allyl, l-propenyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 7 or 3 or 4 or 5-hexenyl and the li~e.
Suitable "heteromonocyclic group" may include saturated or unsaturated heteromonocyclic group contalning at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And, especially preferable heteromonocyclic group may be heteromonocyclic group such as unsaturated 3 to 8-membered heteromonocyclc group containing 1 to 4 nitrogen atom~), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g.
1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, -etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl ~e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5~dihydro-1,2,4-triazinyl, etc.), etc.;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2-oxygen atom(s) and 1 to 3 nitrogen 1`
atom~s), for example, oxazolyl, isoxazolyl, dihydroisoxazol~l, oxadiazolyl, ~e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5~oxadiazolyl, etc.) etc.;
.~
saturated 3 to 8-membered heteromonocyclic group ~ 1... -WO92/01683 2 0 9 0 0 2 3 PCT/JP91/0095~
containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), ~or example, morpholinyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,S-thiadiazoylyl, 1,2,3-thiadiazolyl, etc.;
saturated 3 to 8-membered heteromonocyclic group co~ainina 1 to 2 sulfur atom(s) and 1 to 3 nitrogen.
atom(s), for example, thiazo-liainyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example furyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, ror example, thienyl, etc.;
and the like.
Suitable "lower alkylene" may include straight or branched one having 1 to 6 carbon atom~s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or the like, preferably one having 1 to 4 carbon atom(s).
Preferable "heterocyclic group" in the terms "heterocyclic grou~ having a protected imino group of the formula : ~ N / 6 1 (in which R is imino protective group) in its hetero ring" and "heterocyclic group having an imino group of the formula : \ N ~ in its hetero ring"
H -0 may includeunsaturated 3 to 8~membered h~teromonocyclic group containing l to 4 nitrogen atom(s), for-example, pyrrolyl, Fyrroliny~, imidazolyl, pyrazolyl,~~dihydroDyridazin~
~~~ tetrahydropyridazinyl, triazolyl (e.g. 1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl j.
WO 92/01683 2 0 9 ~ 0 2 3 P~-r/JP91/00952 fe.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,~-dihydro-1,2,4-triazinyl, etc.), etc.;
saturated 3 to 8-membered heteromonocyclic group containing l to 4 nitrogen atomls), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.; and the like.
The preferred embodiments of the object compound (I~
are as follows.
1 0 , R1 is heterocyclic group (more preferably unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), most preferably tetrazolyl or imidazolyl) which may have one to three (more ~-preferably one) suitable substituent(s) [more preferably tetrazolyl or imidazolyl, each of which may have an imino protective group; most preferably tetrazolyl or imidazolyl, each of which may have mono(or di or tri)phenyl(lower)alkyl], or cyano;
R is hydrogen;
R is aryl (more preferably phenyl) which ma~ have one to three (more preferably one) suitable substituent(s) [more preferably phenyl or halophenyl];
R is aryl (more preferably phenyl or naphthyl) which may have one to three (more preferably one or two) suitable substituent(s) [more preferably phenyl or naphthyl, each of which may have one or two `
substituent(s) selected ~rom the group consisting of halogen and amino; most preferably naphthyl, dihalophenyl or phenyl having halogen-and amino], ar(lower)alkenyl (more prefera~lv phenyl(lower)alkenyl)-which may have one to three (more-preferably one) suitable substitu nt(s) Lmore preferably phenyl(lower)alkenyl which may have amino or nitro; most preferably nitrophenyl(lower)alkenyl ,~ :
_. :
WO92/01683 2 0 9 0 0 2 3 pCT/Jp91/~o952 - ,, .
or aminophenyl(lower~alkenyl], arylamino (more preferably phenylamino) which may have one to three (more preferably one) suitable substituent(s) [more preferably phenylamino which may have lower alkyl or halogen; most preferably lower alkylphenylamino or halophenylamino~, heteromonocyclic group (more preferably pyridyl or tetrahydropyridazinyl) which may have one to three (more preferably one) suitable substituent(s) [more pre~erably pyridyl, or tetrahydropyridazinyl which may have an oxo group;
most preferably pyridylr or tetrahyàropyridazinyl having an oxo group~, quinolyl, isoquinolyl, cinnolinyl, indolyl or ~uinoxalinyl, and A is lower alkylene (more preferably Cl-C4 alkylene), 15 with proviso that when R is indolyl, then (i) R1 is tetrazolyl and R3 is halophenyl or ~ii) R1 is imidazolyl which may have mono(or di or tri)-phenyl(lower)alkyl, R3 is halophenyl and A is ethylene.
The processes for pxeparing the object compound ~I) and the starting compounds of the present invention are explained in detail in the following.
:
Process 1 :
The compound (I) or a salt thereof can be prepared by re~cting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereo.. :
~ Suitable reactive derivative- at~the~amino grou~ of the--compound (II) may include Schiff's base type imino or its tautome`ric enamine type isomer-formed by the~reaction of the compound (II) with a carbonyl compound such as : ` :
, .
WO92tO1683 2 ~ 9 0 0 2 3 ; ~ 18 - PCT/JP91/OOgs~ ~
aldehyde, ketone or the like; a silyl derivative Lormed by the reaction of the compound (II) with a silyl co~pound such as N,O-bis(trimethylsilyl~aoetamide, N-trimethylsilylacetamide or the likei a derivative formed by the reaction or the compound (II) with phosphorus trichloride or phosgene and the like.
Suitable salts o~ the compound (Il) and (III) can be referred to the ones as exemplified ~or the compound (I).
Suitable reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activate~ ester, isocyanate and the like. The suitable example may be an acid chlorid~, an acid azidei a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, 1~ phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acïd, alkanesulfonic acid (e.g.
methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g.
pivalic acid, pentanoic acid, isopentanoic acid, -2-ethylbutyric acid, trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g.
cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N=CH-~ ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cres~,l thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine, .. ~ . .
`
. j , . . - .. .
209Q~23 l-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, l-hydroxy-6-chloro-lH-benzotriazole, etc.), isocyanate of the formula : R5-N=C=o (in which R is aryl which may have one or more suitable substituent~s)), and the like.
These reactive derivatives can optionally b~ selected from them according to the kind of the compound (III) to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chlorororm, methylene chlorid~, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.
When the compound (III) is used in free acid form or its salt form in the reaction, the reaction is: preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodlimide;
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
N,N-carbonylbis-(2-methylimidazole);
pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene; -l-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphsphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride;
thionyl chloride; oxalyl chloride; triphenylphosphine;
2-ethyl-7-hydroxybenzisoxazolium salt;
2-ethyl-5-~m-sulroDhenyl)isoxazoiium hydroxide intra-molecuiar saït;
l-(p-chlorobenæenesulfonyloxy)-6-chloro-lH benzotrlazole;
so-called ~ilsmeier reagent prepared by the reaction of .. . . .
' ~... .
... ,, .. .. _ .. ,, .. _ . _ ... ... ... . .. . . ... . .... ..
,; , , , , ., , . . , , -. ., ; . :
WO92/01683 2 0 9 ~ ~ 2 3 PCT/JP91/0095' - 20 - ' ~ .
N;N-dimethylformamide wlt~ thionyl chloride, phosgene, phosphorus oxychloride, etc.;
or the like.
The reaction may also be carried out in the presence o~ an inorganic or organi- base such as an alkali metal bicarbonate, tri~lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N~N-ditlower)alkylbenzylamine~
- or the like. The reaction temperature is not critical, and the reaction is uisiually carried out under cooling to heating.
.
Process 2 The compound ~Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the imino protective group.
Suitable ~ethod of this reaction may include conventional ' one such as hydrolysis, reduction and the like.
(i~ For Hydrolysis :
The hydrolysis is pre~erably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal ~e.g. sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine Ee.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene, 1,4-diazabicycloE2.2.2~octane, 1,8-diazabicyclo[5.4.0~undec-7-ene, or the like.
Suitable acid may include an organic acid ~e.g. -formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid,'etc.] and an inorganic acid ' - - ' ~e.g. hydrochloric''acid, hydrobromic acid, sulfùric a--d, :~' hydrogen chloride, hydrogen bromide, étc.].' Tne eiiminatlon using'Lewis acid such as trihaloacetic acid ~e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or . . ~ .
~ '...
'~ "' ' i ., '., "i, .' '' ',; . ' , the like is pre~erably carried out in the presence of cation trapping agents ~e.g. anisole, phenol, etc.].
The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], N,N-dimethylformamide, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does no~ adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried o-t under cooling to heating.
(ii) For reduction :
Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
~5 Suitable reducing agents to be uised in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g.
platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium ~ -catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, ~ -palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, `~
. . .................................. .
nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g.
reduced cobalt, Raney cobalt, etc.), lron catalysts (e.g.
reduced iron, Raney iron, etcO), copper catalysts (e.g.
.. . . --, . ... .. .
reduced copper, Raney copper, Ullman copper, etc.) and the like. The reduction ls usuaily carried out in a .
conventional solvent wh}ch does not adversely influence '.
. ~ .: .
W0 92/01683 2 0 9 ~ ~ 2 3 " i PCT/JP91/0095~
the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereoI. Additionally, in case that the above-mentioned ~ ~
acids to be used in chemical reduction are in liquid, they ' - "
can also be used as a solvent.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating. ; ' Process 3 The compound (Id) or a salt thereof can be prep2red by subjecting the compound (Ic) or a salt thereof to ' reduction reaction. This reduction reaction can be -referred to that of the aforementioned Process 2. '' Process 4 The compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof. ' '' Suitable salts of the compounds (IV) and (V) can be referred to the ones as exemplified for the compound (I). ':
This reaction is usually carried out in the presence o~ base.
Suitable base may include an inorganic base such as " ' alkali metal hydride (e.g. sodium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium l;
hydroxide, etc.), alkaline earth metal hydroxide (e.g. :
magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.'g. sodium carbonate, potassium' carbonate, etc.), alkaline earth metal carbonate (e.g.
magnesium car~onate,'~calci~m~carb'onate, etc.), ~lkali metal bicarbonaté (e.g. sodi~m bicarbonat3, potassium ' -~~~bicarbonate, etc.),~alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.),''alkaline earth metal ..
!:
1 .;-WO92/01683 2 o 9 o o ~ ~ PCT/JP91/00952 phosphate (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like, and an organic ~ase such as trialkylamine (e.g. trimethylamine, trlethylamine, etc.), picolir.e, N-methy~pyrrolidine, N-methylmorpholine or the like.
This reaction is usually carried out in a solvent such as alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or iO any other solvent which does not adversely affec~ the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. ~ ~-1~ Process 5 The compound (If) or a salt thereof can ~e prepared by reacting the compound (Ie) or a salt thereof with the compound (VI) or a salt thereof.
Suitable salts of the compounds (Ie) and ~If) can be referred to the ones as exemplified for the compound (I).
Suitable salts of the compound ~VI) may include an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and the like.
The reaction is usually carried out in a conventional solvent such as l-methyl-2-pyrrolidinone, N,N-dimethylformamide, dichloromethane, ethylene chloride or any other solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is usually carried out under warming to heating.
, ~ . . . I : .
Process A -The compound (II) or a salt thereof can be prepared by subjecting the compound IVII) or a salt thereof to elimination reaction of the amino protective ~roup.
WO92/01683 2 0 9 ~ ~ 2 3 PCT/JP~1/0095~
Suitable salts of the~compound (~II) can be referred to the ones as exempli~ièd for the compound (I).
The elimination reaction is carried out in accordance with a conventional method such as hydrolysis;
reduction; Edman's method (pnenyl isothiocyanate method);
or the like. The hydrolysis may include a method using an acid or base or hydrazine and the like. These ~ethods may be selected depending on the kind o~ the protective groups to be eliminated.
Among these ~ethods, hydroiysls using an 2Ci~ is one of the most common and preferable method for elimina_ing the protective groups such as substituted or unsubstituted alkoxycarbonyl, for example, tert-pentyloxycarbonyl, iower alkanoyl (e.g. formyl, acetyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl ~e.g. trityl), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like. -Suitable acid includes an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonicacid, p-toluenesulfonic acid, hydrochloric acid and the like, and the most suitable acid is an acid which can easily be removed from the reaction mixture by a conventi~nal manner such as distillation under reduced ~-pressure, for example, formic acid, rifluoroacetic acid, hydrochloric acid, etc. The acids can be selected according to the kind of the protective group to be eliminated. ~-The elimination reaction reaction using - trifluoroacetic acid may be carried out in the presence OI
anisole. The hydrolysis using hydrazine is commonly applied ~or eliminating a phthaloyl, succinyl type amino-protective group. -The elimination using base is uséd for eliminating an acyl group such as trifluoroacetyl. Suitable base may ; ~ , ;, ., .. .. . ... . ~ .~.. . . . . . .. . .
20~0023 WO92/01683 PCT/JPg1/009$2 include an inorganic base and an organic base.
The reductive elimination is generally applied for eliminating the protective group, for example, haloalkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g.
benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc.
Suitable reduction may include, for example, reauction with an alkali ~etal borohydride (e.g. sodium borohydride, etc.), reduction with a combination of a metal (e.g. tin, zinc, iron, etc.) or the said metal toaether with a metal salt compound (e.g. chromous.chloride, chromous acetate, etc.) and an organic or inorganic acid ~e.g. acetic acid, propionic acid, hydroch~oric acid, etc.); and catalytic reduction. Suitable catalyst includes a conventional one, for example, Raney nickel, platinum oxide, palladium on carbo~ and the like.
Among the protective groups, the acyl grou~ can generally be eliminated ~y hydrolysis. Especially, halogen substituted-alkoxycarbonyl and 8-quinolyloxycarbonyl groups are usually eliminated by treating with a heavy me~al such as copper, zinc, or the like.
The reaction is usually carried out in a conventional solvent such as water, chloroform, methylene chloride, alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran or any other organic solvent which does not adversely -influence the reaction.
The reaction temperature is not critical and may suitably be selected in accordance with the kind of the amino protective group and the elimination method as mentioned-above, and the reaction is usually carried out under a mild condition sucn-zs unde. coolins-or at slightly elevated temperature. Among the protective groups, the acyl group derived from -amino acid can be -eliminated by Edman's method.
, _, . . , ,, ... , ..... , . . .. ,, . . ... " . ~, ., ~ .. . . ....
WO92/01683 2 G 9 ~ ~ 2 3 PCT/JP91/00952 Process B
The compound (IV) or a salt thereof can be prepared by reacting the compound (VIII) or its reac~ive derivative at the amino group or a salt thereof with the com~ound (III) or its reactive derivative or 2 salt thereof.
The reaction is carri.ed out by s~ stantially the same ~-method as that of Process 1, and thè~ëfore the reaction method and conditions are to be referred to said Process ~.
1. :
The object compound (1) and pharmaceu_ically acceptable salts thereof are.CCK antagonists and therefore useful as therapeutical agents for emesis, pancreatltis, .
etc.
Further, it is expected that the object compound (I) ..
lS and pharmaceutically acceptable salts thereo have gastric :
antagonism and are useful as therapeutical and/or preventive agents for ulcers, excess gastric secretion, Zollinger-Ellison S~ndrome, etc. -In order to show the utility of the object compound (I), the pharmacological activity of the representative ..
compound thereof is shown in the following. .
[I~ Test Compound : .
(3S)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-[(E)-3-(2-: aminophenyl)propenoylamino]-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one dihydrochloride Ehereinafter referred to as test compound A]
30 ~II] Test-:-- CCK receptor antagonism in isolated.fundic circulax muscle from ~inea Dl stomach - - '-' ' . , . :. ,- ~- . ., ~ Test Method The strip of circular muscle from guinea pig stomach was suspended in 25 ml organ bath containing Krebs' ' . . ., . . . ., .............. . . .. . ~ ~; . . . .
; , , : , : -:
WO92/01683 2 0 9 0 0 2 3 PCT/JP91/0095' bicarbonate solution (NaCl 118mM, KCl 4.8mM, KH2P04 1.2mM, MgSO4 1.2mM, CaCl2 2.5mM, NaHCO3 25mM, glucose llmM and bovine serum albumin 0.1~) maintained at 37C and gassed with 95~ 2 and 5% CO2.
The strip was placed under an initial tension of 0.5 g and equilibrated for 60 minutes during which the bath volume W2S replaCeG every 15 minutes. Isometric contraction was measured using a force transducer. CCK-8 ~3.2 x lO 7M) was added to the bathing solution and the contractile force was measured. After washing out CCK-8, it stood Ior about 15 minutes until contractile force became plateau. Then test compound A (1 x 10 6M) was added. 5 minutes later, CCK-8 was added and the contractile force was recorded. CCK antogonism was calculated by comparing the contractile force induced by CCK in the absence or presence o~ test compound A.
Test Result Inhibition (%) : 89.9 The object compound ~I) or pharmaceutically acceptable salts thereof can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository~or the like, and the most suitable -dosage form is injection.
The pharmaceutical composition o~ this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose, such as excipient (e.g. sucrose, starch, manni " sorbit, lactose, glucose, cellulose, talc, calci~m phosphate calcium carbonate, etc.j, binding agent (cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, ::
WO92/01683 2 0 9 0 0 2 3 PCT/JP91/009S~
gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g. starch, carboxymethyl cellulose, calcium salt of carboxymethyl oellulosP, hydroxypropylstarch, sodlum glyc~le-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), I
lubricant (e.g. magnesium stearate, talc, sodium I-laurylsulfate, etc.), flavoring agent (e.g. citric acid, mentol, glycine, orange powders, etc.), preservative (e.g.
sodium benzoate, sodium bisulrite, methylparaben, propylparaben, etc.), stabilizer ~e.g. citric acid, sodium citrate, acetic acid, etc.),- suspending agent (e.g. methyl cellulose, polyvinylpyrrolidone, aluminum stearate, etc.), dispersing agent, aqueous diluting agent (e.g. water), base wax (e.g. cacao butter, polyethyleneglycol, white petrolatum, etc.).
The effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 50 mg/kg, l to 4 times a day. However, the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.
The following Preparations and Examples are given only for the purpose of illustrating the present invention in more detail.
.. ~ ' , - --, ~ . .-. :
-~
- --,..
~:
: . - .
W092/01683 2 0 9 ~ 0 2 3 PCT/JP91/00952 -; ;
- ?9 -PreParation 1 To a solution of (3RS)-3-phthalimido-5-l2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin 2-one (21.17 g) in N,N-dimethylformamide (400 ml) was added gradually sodium hydride (2.0 g, 60% suspension in ~ineral oil) under cooling in an ice-bath and nitrogen atmosphere.
The mixture was stirred under the same conditions for 0.
hour and at ambient temperature for 1 hour. The mixture was cooled in ice-bath and a solution OI
chloroacetonitrile t3.48 ml) in N,N-dimethylrormamide (~
ml) was added dropwise thereto. The mixture was stirre~
~or 1 hour at the same temperature and at ambient temperature overnight. To the reaction mixture wa~ added acetic acid (3.5 g) under cooling and the resultant mixture was poured into a mixture of ethyl acetate and water under stirring. The mixture was adjusted to pH 7.5 with agueous sodium bicarbonate. The crystals were collected by filtration and washed with cold ethyl acetate to give (3RS)~3-phthalimido-1-cyanomethyl-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (20.9 g).
mp : 260C (dec.) IR (Nujol) : 2160, 1776, 1725, 1700, 1604 cm 1 NMR (DMSO-d6, ~) : 5.15 (2H, ABq, J=24.6Hz, 17.8Hz), 5.83 (lH, s), 7.2-8.1 (12H, m) PreParation 2 A mixture of (3RS)-3-phthalimido-1-cyanomethyl-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (20.0 g), sodium azide (8.43 g) and triethylamine hydrochloride (8.92 g) in N-methyl-2-pyrrolidone (350 ml)~
- was heated at 145C under stirring-for 3.5 hours.-~ After coolins to amb ent temperatu~e, the-mixture :W2S poured into 5% hydrochloric acid (500 ml) and ice. The resultant ~ precipitates were collected by filtration,~ washed with 35 cold water several times and dried over phosphorus -~
. . -...
. ~:
. . . ~ ..
W092/01683 2 0 9 0 ~ 2 3 PCT/JP91/00952 pentoxide under reduced pressure to afford (3RS)-3-phthalimido-l~3-dihydro-5-(2-fluorophenyl)-l-~(lH
tetrazol-5-yl)methyl]-2H-~,4-benzodiazepin-2-one (18.07 g ) . .` ':~.
IR (Nujol) : 1778, 172~, 1693, 1610 cm 1 NMR ~DMSO-d6, ~ .46 (2H, s), 5.85 (lH, s), 7.2-8.0 (13H, m) Pre~aration_3 To a solution of ~3RS)-3-~hthalimido-1,3-dihydro-5-(2-fluorophenyl)-1-~(lH-tetr~zol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (18.07 g) and trityl chloride (10.99 g) in N,N-dimethylformamide (330 ml) was dropwise added a solution o~ triethylamine (4.6 g) in N,N-dimethylformamide (10 ml) under stirring and cooling in an ice-bath. The mixture was stirred for 20 minutes under the same conditions and at ambient temperature overnight. The reaction mixture was poured into an ice-water (500 ml), and the resultant precipitates were collected ~y filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to afford ~3RS)-3-phthalimido-1,3-dihydro-S-(2-fluorophenyl~-1-[(l-trityl-lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (33.41 g) as white powder.
IR INujol) : 1778, 1723, 169S, 1610 cm 1 NMR (DMSO-d6, ~) : 5.i6 (2H, ABq, J-l~.OHz, 52.6Hz), 5.80 (lH, s), 6.8-8.1 ~27H, m) Pre~aration 4 30 - To a suspension of (3RS)-3-phthalimido-1-[(1-trityl-: lH-tetrazol-5-yl)methyl~-5-(2-fluorophenyl)-1,3-dihydro-2~-1,4-benzodiazepin-2-one (33.4 g) in tetrahydrofuran - (SOO ml) was added hydrazine hydrate (1.90 g) under -stirring at ambient temperature. The mixture was stirred for 2 hours-at the same temperature and refluxed under ;:
I',' ' W092/Ot683 2 0 9 0 0 2 3 PCT/JP91/009S2 stirring for 2 hours. The reaction mixture was cooled in an ice-bath and the resultant precipitates were filtered off. The filtrate and the washings were combined and evaporated to afford a residue, which was stirred in ethyl acetate and ~iltered. The filtrate and washings were combined and evaporated to give white powder (14.43 g~ of (3RS)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1~
trityl-lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one.
I~ (Nujol) : 3350, 1686, 1597, 760, 700 cm 1 NMR ~CDC13, ~) : 2.95 (2.~, br s), 4.62 (lH, s), 5.42 (2H, ABq, J=19.6Hz, 15.8Hz), 6.8 7.6 (23H, m) PreParation 5 The rollowing compound was obtained according to a similar manner to that of Preparation 4.
t3Rs)-3-Amino-l~3-dihydro~5-pheny~ (l-trityl-lH
tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one mp : 132-135C
IR (Nujol) : 3375, 1680, 1595, 1575, 1560 cm 1 NMR (CDC13, ~) : 2.72 (2H, s), 4.55 (1~, s), 5.46 ~2~, ABq, J=16Hz, 51Hz), 6.90-6.70 ~6H, m), 7.15-7.50 (18H, m) Preparation 6 To a solution of (3RS)-3-amino-1,3-dihydro-5-~2-fluorophenyl)-l-[(l-trityl-lH-tetrazol-5-yl)methyI]-2H-~1,4-benzodiazepin-2-one (11.54 g) and N-t-butoxycarbonyl-30~ -phenylalanine (5.42 g) in N,N-dimethylformamide (200 ml) were added successivel~ l-hydroxybenzotriazole (2.76 g), - l-ethyl-3-(3-dimPthylaminopropyl)carbodiLmide hydrochloxide~S3.91 g) and triethylamine !2.36 g) ~.aer stirring at ambient temperature. The mixture was stirred under the same conditions for 4.5 hours and then poured ' " :
'.
- 32 ~`
into water (1.5 Q)~3~nder stirring. The mixture was adjusted to pH ~'with an aqueous solution of sodium bicarbonate. The resultant precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give a mixture (16.29 g) of (3R)-3-[((2S)-2-t-butoxycarbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro-5-~2-fluoropnenyl)-1-~(l-trityl-lH-tetrazol-5-yl)methyl)-2H-1,4-benzodiazepin- '' 2-one and (3S)-3-[((2S)-2-t-butoxycarbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro-5-(2-fluoro~henyl)-1-[(l-trityl~ tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one. ' mp : 108-114C
IR (Nujolj : 3330, 1700, 1690, 1675, 1610 cm 1 -~-NMR (DMSO-d6, ~) : 1.28 (9H, s), 2.65-2.9 ~lH, m), 3.0-3.2 (lH, m), 4.40 (lH, m), 5.33-5.41 (2H, ~
m), 5.39, 5.40 (lH, each d, J=8Hz), 5.58 t2H, ' ABq, J-16.8Hz, 82.2Hz), 6.8-7.95 (14H, m), 9.25, 9.37 (lH, each d, J=8Hz) PreParation 7 A mixture of a mixture (16.2 g) of (3R)-3-[((2S)-2-t-butoxycarbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro-5-(2-fluorophenyl)~ tl-trityl-lH-tetrazol-5-yl)methyl]-25~ 2H-1,4-benzodiazepin-2-one and (3S)-3-~((2S)-2-t-butoxy-arbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro-5-2;-fluorophenyl)-1-t(l-trityl-IH-tetrazol-5-yl)methyl]-2H-1,4~-benzodiazepin-2-one and 4N solution of hydrogen chloride~in ethyl acetate (200 ml) was stirred at ambient 39~ temperature~for 5'hours~. The mlxture~was concentrated in vacuo~ito~give~a residue, which was dissolved'in'methanol ;(100 ml)~`and~~neutr'al~zed-with an'ethanolic ammonia. The mix.ure was~concentr'ated in vacuo to dryness.~ The residue . ~~' was'~subj~ected to column chroma~ography on silica-~gel with 35-~ an eluent~(CHO13:~CN3OH~= I0:'1). The fractions containing W092/01683 2 0 9 0 0 2 ~ PCT/JPg1/009~2 the object compound were combined and evaporated to give an amorphous mass, which was suspended in diisopropyl ether and collected by filtration to give (3S)-3-[((2S)-2-~mino-3-phenylpropanoyl)amino]-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (4.57 g).
NMR (DMSO-d6, ~) : 2.91 (lH, dd, J=14.0Hz, 8.4Hz), 3.20 (lH, dd, J=4Hz, 14.0Hz), 4.13 (lH, dd, J=4Hz, 8.4Hz3, 5.26 (2H, AB~, J-15.4Hz, 31.6Hz), 5.39 (lH, d, J=8.0Hz), 7.1-7.35 (lOH, m), 7.52-7.66 (4H, m), 7.96 (lH, d, J=8.4Hz), 9.77 (lH, d, J=8.0Hz) The fractions containing the other object compound were combined and evaporated to give an amorphous mass, which was suspended in diisopropyl ether and collected by filtration to give (3R)-3-~((2S)-2-amino-3-phenyl-propanoyl)amino]-1,3-dihydro 5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (4.76 g).
NMR (DMSO-d6, ~ 3.0-3.17 (lH, m)j 3.57-3.64 (lH, m), 3.0-4.1 (2H, broad), 4.21 (lH, t, J=4.2Hz), 5.19 (2H, ABg, J=15.6Hz, 70.1Hz), 5.38 (lH, d, J=8.3Hz), 7.16-7.4 (lOH, m), 7.51-7.67 t4H, m), 7.97 (lH, d, J=8.2Hz), 9.78 (lH, d, J=8.3Hz) - ~-Preparation 8 To a solution of ~3S)-3-[((2S)-2-amino-3-phenylpropanoyl~amino]-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one ~ -~4.57 g), and triethylamine (0.974 g) in dried tetrahydrofuran (45 ml) was added phenyl isothiocyanate (2.54 g) under stirring at ambient temperature.~
-~- The-mixture was stirred for 2 hours at ambient temperature and~for 1 hour`at 50C.~ To the reaction mixture was added lN-hydrochloric acid-(9.64 ml) under ice cooling.
. . :
WO92/01683 2 0 9 0 0 ~ 3 PCT/JP91/00952 The mixture was concentrated in vacuo to give a residue, which was extracted with ethyl acetate. The extract was washed with water twice and dried over magnesium sulfate.
Removal of the solvent in vacuo afforded an amorphous mass (7.23 g), which was powdered by stirring in diisopropyl ether for 3 hours. The resultant powder was collected by filtration and washed with diisopropyl ether to give (3S)-3-[[(2S)-2-{N'-(phenyl)thioureido}-3-phenyl-propanoyl]amino]-l~3-dihydro-5-(2-fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (5.63 g).
The product obtained above was suspended in tetrahydrofuran (35 ml) and 4N-hydrogen chloride in ethyl acetate (33.5 ml) was added dropwise thereto under ice-cooling. The mixture was stirred for 5 hours and then evaporated in vacuo to give a viscous oil, which was washed with ethyl acetate by stirring for 3 hours. The resultant powder was collected by filtration, a:nd dried under reduced pressure to give (3S)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one hydrochloride (2.91 g).
[a~30 = -36.36 ~C=0.495, CH30H) Preparation 9 The following compound was obtained according to a similar manner to that of Preparation 8.
(3R)-3-Amino-1,3-dihydro-S-(2-fluorophenyl)-1-[~lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one hydrochloride ~ -[a]30 = + 33.46 (C=0.505, CH30H) Pre~aration 10 - ; -To a suspension of ( 3RS)-3-amlno-1,3-dihydro-i~
- -: fluorophenyl)-2H-1,4-benzodiazepin-2-one (2.0 g~ in methylene chloride (30 ml) was added dropwise .
2~9002~
WO92~01683 PCT/JP91/00952 triethylamine ~1.61 g) under stirring and cooling in an ice-bath. To the mixture was added 2-naphthoyl chloride (1.52 g) under the same conditions. The mixture was stirred for 2 hours at the same temperature. The resultant precipitate was collected by filtration and washed with methylene chloride and water successively.
The collected crystals were dried over phosphorus pentoxide under reduced pressure to give ~3RS)-3-(2-naphthoylamino)-5-~2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (2.33 g).
NMR (DMSO-d6, ~) : 5.60 (lH, d, J=7.7Hz), 7.22-7.39 (5H, m), 7.54-7.66 (5H, m), 7.99-8.11 (4H, m), 8.72 (lH, s), 9.74 (lH, d, J=7.7Hz), 11.05 (1~, -m) MASS (m/e) : 423 (M ) Pre~aration 11 The following compounds were obtained according to a similar manner to that of Preparation 10.
(1) (3RS)-3-(3-Quinolylcarbonylamino)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one IR (Nujol) : 3600, 1695, 1670, 1610, 1590, 1515 cm 1 NMR (DMSO-d6, ~) : 5.59 (lH, d, J=7.6Hz), 7.23-7.40 (5H, m), 7.61-7.76 (4H, m), 7.67-7.94 (1~, m), 8.1-8.16 12H, m), 9.09 (lH, s), 9.40 (lH, d, J=2.1Hz), 10.1 (lH, d, J=7.6Hz~, 11.08 (lH, s) -.:, .. .
(2) (3RS)-3-(3,4-Dichlorobenzoylamino~-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one NMR (DMSO-d6, ~) : 5.49 (lP., d, J=7.ÇHz), 7.2-8.02 .-(llH, m), 8.21 (lH, s), 9.93 (1;~, d, J=7.~Hz), 11.03 (lH, s): -MASS (mJe) : ~442 (M+) ..
:~' .
WO92/01683 2 0 9 0 0 2 3 PCT/JP91/009~' .
ExamDle 1 To a solution or (3S)-1,3-dihydro-5-~2-fluorophenyl)-3-amino-1-[(1-tritylimidazol-4-yl)methyl]-2H-1,4-benzodiazepin-2-one (1.0 g) in N,N..dimethylformamide (10 ml) were added successively ~E)-3 (2-nitrophenyl)propenoic acid (330 my~, l-hydroxyDenzo~rIazole (230 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (320 mg) and triethylamine (170 mg) under stirring at ambient temperature. The mixture was stirred for 3 hours and allowed to stand overnight. The reaction mixture was poured into a mi~ture of ethyl acetate and water under stirring. The separated organic layer was washed with water twice and dried. The solvent was removed under reduced pressure to give an amorphous residue, wnich was purified by column chromatography on silica gel with an eluen-t of chloroform. The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying undex reduced pressure gave (35)-1,3-dihydro-1-[tl-tritylimidazol-4-yl)methyl]-3-~(E)-3-~2-nitrophenyl)propenoylamino]-5-12-fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.16 g).
NMR tCDC13, ~) : 5.07 ~2H, br s), 5.66-5.7 (lH, m), 6.49-8.14 (32H, m) Example 2 The following compounds were obtained according to a similar manner to that of Example 1.
~ - - ... . , . ~
(1) (3S)-1,3-Dihydro-l-[(l-tritylimidazol-4~yl)methyl]-3-~(2-amino-4-chlorobenzoyl)amino}-5-t2-fluoroPhenYl)-2H-1~4-benzodiazepin-2-one NMR (CDC13, ~) : 5.06 (2H, d, J=3.7Hz), WO92/016~3 2 0 9 0 0 2 ~ pCT/JP91/00952 5.62-5.68 (3H, m), 6.63-8.04 (29H, m) MASS (m/e) : 502 (M -243) ,... :
(2) (3RS)-1,3-Dihydro-l-[~l-tritylimidazol-4-yl)methyl]-3-[(2,3,4,5-tetrahydro-3-oxopyrid zin-6-yl)-carbonylamino]-5-~2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (3) (3RS)-1,3-Dihydro-1-[(1-tritylimidazol-4-yl)methyl]-3-(3,4-dichlorobenzoylamino)-;-~2-fluorophenyl)-2H-1,4-benzodiazepin-2-one NMR lCDC13, ~) : 5.02 ~lH, d, J=15Hz), 5.12 (lH, d, J=15Hz), 5.67 (lH, d, J=7.8Hz), 6.85-8.04 (29H, m) ~4) (3RS) 1,3-Dihydro-l-[(l-tritylimidazol-4 yl)methyl]-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one NMR (DMSO-d6, ~) : 5.01-5.18 (2H, m), 5.78 (lH, d, J=7.8Hz), 6.87-8.26 (30H, m), 8.72 (lH, d, J=1.9Hz), 9.44 (lH, d, J=2.2Hz) MASS (mle~ ; 504 (M -243), 424 (5) (3RS)-1,3-Dihydro-l-[(l-tritylimiazol-4-yl)methyl]- `
3-(2-quinoxalinylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one '. .
(6) (3RS)-1,3-Dihydro-l-~(l-tritylimidazol-4-yl)methyl~
3-(4-cinnolinylcar~onylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one NMR (CDC13, ~) : 5.09 (2H, s), 5.80 (lH, d,J=7.8Hz), 6.8~-8.09 ~28~, m), 8.49-8.66 (2~, m), 9.54 (lH, . .
~ s) (7) (3RS)-1,3-Dihydro-l-~(l-tritylimidazol-4-yl)methyl~-~: - " ' . . - :
:~ ~ ` ' . :; .
W092/0i683 2 0 9 0 0 2 3 PCTIJP91/00952 ~ 38 - r 3-(1-isoquinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-~enzodiazepin-2-one NMR (CDC13, ~) : 5.11 (2H, s), 5.78 (lH, d, J=8.3Hz), 6.89-7.89 (28H, m), 8.05 (lH, d, J=8.2Hz), 8.59 (lH, d, J~-5;5Hz), 9.52-9.56 (lH, m), 9.93 ~lH, d, J=8.2Hz) . . ~; .
(8) (3RS)-1,3-Dihydro-l~ trltylimidazol~4-yl)methyl]-3-nicotinoylamino-5-~2-fluoropheny~)-2H-1,4-benzodiazepin-2-one NMR (CDC13, ~) : 4.99-.5.16 (4H, m), 5.71 (lH, d, J=7.7Hz), 6.85-9.18 (28H, m) Example 3 To a solution of (3RS)-1,3-dihydro-1-[(1-tritylimidazol-4-yl)methyl]-3-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.0 g) in methylene c~loride (10 ml) were added successively triethylamine (340 mg) and 2-naphthoyl chloride (320 mg). The mixture was stirred for 1.5 hours. The reaction mixture was washed with water and dried. The solvent was removed under rPduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent o~ chloroform.
The fractions containing the desired product were combined and evaporated to afford on oil, which was dried under reduced pressure to~give (3RS)-1,3-dihydro-1-~
tritylimidazol-4-yl)methyl]-3-(2-naphthoylamino~-5-(2-.
- fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.21 g).
NMR (CDC13, ~) : 5.03 (2H, d, J=15Hz), 5.15 (2H, d, J-15Hz), 5.79 ~lH, d, J=8Hz), ~.89-8.07 (29H, m), 8.22 tlH, d, J=8Hz), 8.47 (lH, s) ExamDle 4 To a solution of (3RS)-1,3-dihydro-i-~tl-35 tritylimidazol-4-yl)methyl]-3-amino-5-(2-fluorophenyl)-2H-; ~ ~ , . ' 1,4-benzodiazepin-2-one (1.5 g) in tetrahydrofuran (23 ml) was added m-tolyl isocyanate (0.35 g) under stirring at ambient temperature. The mixture was stirred for 2 hours under the same condition. From the reaciton mixture, the solvent was removedin vacuo to give crude product, which was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to afford pure (3RS)-1,3-dihydro-1-[(1-tritylimidazol-4-yl)methyl]-3-[3-(3-methylphenyl)ureido]-5-(2-flurophenyl)-2H-1,4-benzodiasepin-2-one (1.47 g).
NMR (DMSO-d6, .delta.) : 2.24 (3H, s), 4.85 (1H, d, J=14.8Hz), 5.24-5.33 (2H, m), 6.67-7.68 (29H, m), 7.91 (aH, d, J=8.2Hz), 8.97 (1H, s) Example 5 To a suspended mixture of iron powder (1.1 g) and ammonium chloride (0.13 g) in a mixture of water (2.5 ml) and ethanol (7.5 ml) was added portionwise (3S)-1,3-dihydro-1-[(1-tritylimidazol-4-6l)methyl]-3-[(E)-3-(2-nitrophenyl)propenoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.1 g) under stirring and refluxing.
After ethanol (7.5 ml) and water (2.5 ml) were added, the resultant mixture was refluxed under stirring for 1.5 hours. The reaction mixture was filtered through celite and the filtered mass was washed with hot ethanol several times. From the filtrate and the washings, ethanol was removed under reduced pressure. To the residual mixture was added a saturated aqueous solution of sodium bicarbonate (100 ml) and the mixture was extracted with ethyl acetate (100 ml). After washing with water and drying over magnesium sulfate, the extract was evaporated to give an amorphous reside, which was pulverized with diisopropyl ether and collected by filtration to afford (3S)-1,3-dihydro-1-[(1-tritylimidazol)-4-yl)methyl]-3-[(E)-3-(2-aminophenyl)propenoylamino]-5-(2-fluorophenyl)-WO92/01683 2 0 9 ~ Q 2 3 PCT/JP91/00952 - 40 - ..
2H-1,4-benzodiazepin-2-one (0.98 g).
NMR (CDC13, ~) : 3.71-4.07 ~2H, br d), 5.06 ~2H, s), 5.68 (lH, d, J=8Hz), 6.47.7.93 ~32H, m) MASS (m~e) : 476 (M+-260) L, Exam~le_6 To a solution OL (3S)-1,3-dihydro-1-~
tritylimidazol-4-yl~methyl~-3-[(E)-3-(2-2minophenyl3-propenoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (0.49 g) in N,N-dimethylformamide (4.9 ml! was adde~
6N-hydrochloric acid (3.4 ml~ under stirring and cooling in an ice-bath. The mixture was warmed to 50C and stirred for 1 hour. After cooling to room temperature, to the reaction mixture were added water and ethyl acetate under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium ~ioarbonate. The separated organic layer was washed with water and dried. The .
solvent was removed under reduced pressure to give an amorphous residue, which was pulverized and stirred for several hours.in.diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave (3S)-1,3-dihydro-1-(4-imidazolylmethyl)-3-[(E)-3-(2-aminophenyl)propenoylamino]-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (350 mg).
To a solution of the product obtained above in chloroform ~: ~ (10 ml) was added 20%-hydrogen chloride in ethanol (5 ml) under cooling. The clear yellow solution was evaporated to dryness under reduced pressure. Th~ residue was .
pulverized and stirred for several hours in diisopropyl : ether. Collection by filtration, washing with diisopropyl : .~ ether and drying under reduced:pressure gave yellow-powder (234 mg:) o- (3S~-1,3-dihydro-1-~4-imidazolylmethyl)-3- 1 .~E.)-3-(2-aminophenyl)propenoylamino]-5-(2-rluorophenyl)- 1 :
2H-1,4-benzodiazepin-2-one dihydrochloride. ....................... ¦ .
:~ 35 IR (Nujol) : 3650-3050, 2700-2150, 1660, 1605 cm 1 W092/016X3 Z O ~ O 0 2 3 PCTtJP91/00952 NMR (CDC13, ~) : 3.8-4.8 ~2H, b), 5.15-5.56 (3H, m), 7.04-7.81 (18H, m), 9.03 (lH, s), 9.43 (lH, d, J=8HZ ) MASS (m/e) : 494 (M -73), 476 Exam~le 7 The following compounds were obtained according to a similar manner to that of Example 6.
(1) (3S)-1,3-Dihydro-1-(4-imidazoly~methyl)-3-[(2-amino-
(III) (II) or its reactive derivative or its reactive derivative, ::.
at the amino group, or a salt thereof or a salt thereof .;.
A-R
, N
R2~/ \) NHCo-R4 ~ N /
(I) or a salt thereof ~-Process 2 : :25 ::
(Ia) ;~ ~~ or a salt thereof :
~: 35 :
W092/01683 2 0 9 0 0 2 ~ ~ . PCT/JP91/00952 Elimination reaction of the imino protective group ¦ b O
R2 ~ N--__ /~ NHCO-R-~ ~ N
. R3 (Ib) ~
or a salt thereof ::
Process 3 A-Rl R ~ C ~ NHCO-Ra ~:
R
(Ic) or a salt thereof .. I . ~". .
Reduction ".
. ~
- ' ' i' "' .. ~,~ 1:
; 35 '~
':
.. ,'' -,, . . . ,i. . i.. .
.. ~ .. ... . ;. . . . . .. ~ . . ..... .. . . . .. .. ..
WO 92tO16832 0 9 0 o 2 ~ - Pc-r/JPgl/00952 ~-Rl R2 ~ ~ ; HCo-R4 (Id) or a salt thereof Process 4 :..
H
O
~ N </
15R2 ~ ~ ~ NHCo-R4 + X_A_Rl :
R3 (V) :
~ .
(IV) or a salt thereof .
. 20or a salt thereof , ' A-~l 'o > R ~$~ ~ ~
~3 30~
or a salt thereof '-: :-~ . .
: ~ 3S~ `
~, ", ~ ~
~, ~
WO92/01683 2 0 9 `~ t~ 2 3: ; ; PCT/JP91/0095~
?rocess 5 A-CN O
S
R (VI) (Ie)or a salt thereof or a salt thereof H
N -N
~\ N /N ~ :
O , -' :.,';
~ R2 ~ ~ NHco-R4 ~ N
R
; . (If) ~.
or a salt thereof wherein R1, R2, R3, R4 and A are each as defined above, I
:~ Ra .is heterocyclic group having a protected imino , .
group of the formula :
~ / , , ' ~::
in which R6 is imino protective R6 groUP) . -.,.. :
in its hetero ring, which may have one or ~
WO92/01683 2 0 9 0 0 2 3 PCT/JPg1/00952 more suitable substituent~s!, Rl is heterocyclic group having an imino group of the formula : - N /
H
in its hetero ring, which may have one or more suitable substituent(s), Ra is ar~lower)alkenyl having a nitro group, Rb is ar(lower)alkenyl having an amino group and X is z~ acid residue. :~
1 0 ~,,, The starting co~ounds (II) and (IV) can be prepared by the following processes.
Process A
A-R O
R2 ~ ~ ~ R7 :
N
~; 20~ .
(VII) or a salt thereof Elimination reaction of ~ the amino protective group A-Rl O
N ~
13~;5~ ~ : or a salt thereof W092/01683 2 0 9 0 ~2 3 `` PC~JP91/00952 ~ ~
P~ocess ~3 R2 ~ NH2 + HO-C-R
R (IIl) or its reactive (VIII) derivative, or its reactive derivative. or a salt thereof -~at the amino group, or a salt thereof H O
N ~ -R ~ ~NHCo-R4 ~ N
(IV) or a salt thereof ::
wherein R1, R2, R3, R4 and A are each as defined above, and R7 is protected amino.
~: :
The starting compound (VII) or a salt thereof can be prepared by the methods disclosed in the Preparations 1-3, ^``
~30 6 and 7 described later or similar manners`thereto. `.
.: .
With regard to the objsct compound (I), in case tha_ the compound ~I-)~has ths group of the .ormula : :
..; WO92101683 2 0 9 0 0~;~3~. ~ ` pcT/Jpg1loo952 q NH
in R , said group can also exist in the tautomeric _orm and such tautomeric equilibrium can be represented by the following scheme.
H
N ___~ N
~
NH N . .
(A) (B) : :
Both of the above tautomeric isomers are included within the scope of the present invention. In the present specification and claim, the compounds including the group of such tautomeric isomers are represented for the convenient sake by one expression of the group of the formula (A). ::
Further, in case that the compound (I) has the group ~.
of the formula :
.
~5 N
:, . \
\ /N
N - N
:in Rl, said group can also exist in the tautomeric form --and suc~ tautomeric equili~rium can be represented by the foIlowing scheme.
~:3~S~
~ ~ .
WO 92/01683 2 0 9 0 0 2~ PCI~/JPgl/009~
. ' i ' ~ ' . 1 0 -- , !
H :
N ~ N
/ \N ~N
\\ /1 \\ / :
N --N N NH
(C) ~D) .
Both of the above tau,omeric isomers are ir.cluded within the scope of the present invention. In the presen.
specification and claim, the compounds including the srou?
o~ such tautomeric isomers are re~resented for the -convenient sake by one expression of the group or the ..
formula (C).
.. .
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g.
sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magne~ium salt, etc.), an ammonium salt~ an organic base salt (e.g. trimethy~amine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetatel etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate~, etc~), a salt with an amino acid (e.g. I
arglnine, aspartic acidj glutamic acid, etc.), and the ~ ;
like.
In the above and subsequent descriptions of the present~specification, suitable examples and illustrations o~ the various definitions which the present invention include within the scope thereof are explained in detail as follows. ~æ~
The term "lower" is intended to mean 1 to 6 carbon .
.....
- , . .~
WO92/01683 2 ~ 9 ~ 0 2 3 PCT/JP9~/009s~
atom5s), unless otherwise indicated.
Suitable "heterocyclic group" may include saturated or unsaturated, monocyclic or polycyclic heterocycllc group contalning at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And es~ecially preferable heterocyclic group ma-~ be heterocyclic group such as unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom~s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and lts N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl ~e.g.
1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl ~e.g., lH-tetrazolyl, 2H-tetr'azolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), etc.;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom~s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;
unsaturated co~densed heterocyclic group containing 1 to 5 nitro~en atom(s), for example, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizynyl, benzimidazolyl, quinolyl, iso~uinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g. tetrazolo-~1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic gxoup containing 1 to 2 oxygen atomts) and 1 to 3 nitrogen atom(s~, for example, oxazolyl, isoxazolyl, dihydroisoxazolyl, oxadiazolyl, (e.g., 1,2,4-oxadiazolyl, 1,3,4'-oxadiazolyl, 1;2,5-oxadiazolyl, etc.) etc.;
saturated 3 to 8-membered heteromonocyclic ~roup containing l to 2 oxygen atom(s3:and 1 to 3 nitrGge~
atom(s), for example, morpholinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 WO92/01683 2 0 9 0 ~ 2 3 ` PCT/J~1/00952 oxygen atom(s) and 1 to 3 nitrogen atom(s~, for ex~mple, benzoxazolyl, benzoxadlazolyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, 1,3-thiazolyl, 1,2-thiazol~l, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.;
saturated 3 to 8-membered neteromonocyclic grou~
containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazo~idinyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example furyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc. and the like.
Suitable "substituent" in the terms `'heterocyclic group which may have one or more suitable substituent(s)"
and "heteromonocyclic group which may have one or more suitable substituent(s)" may include amino, protected amino as exemplified below, oxo, hydroxy, imino protective group as exemplified below, lower alkyl (e.g., methyl, 2~ ethyl r propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.) and the like.
Suitable "protected amino" may include acylamino and the like.
Suitable "imino protective group" may include acyl, 30 - mono~or di or tri)phenyl(lower)alkyl (e.g. trityl, etc.) :
tetrahydropyranyl and the like.
Suitable:"acyl" and "acyl moiety" in the term "acylamino" may include aliphatic acyl group and ac~l group containing an aromatic or heterocyclic ring.
And, suitable examples of the said acyl may be lower .
~ 13 -alkanoyl ~e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.);
lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, l-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-~utoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.);
lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.);
arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); ~ -aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.);
ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.);
ar(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.
The acyl moiety as stated above may have at least one suitable substituent(s) such as halogen (e.g. chlorine, bromine, fluorine and iodine), amino, protected amino (e.g. lower alkanoylamino, phenylthioureido, etc.), or the like.
~ ~ Suitable "acid residue" may include halogen and the like.
.
Suitable "halogen" may include chlorine, bromine, - fluorine and iodine.
Suitable "aryl" and "aryl moiety" in the terms "ar(lower)alkenyl" and "arylamino" may~include phenyl, 30~ naphthyl and the like. -suitabIe~"substituent" in the terms "aryl which may have one~or~more sui-table~substituent(s)", artlower)alkeny~ which~may have one ôr more suitabie substituent(s)" and-"arylamino~which may have one~or more 3~5 ~ suitable substituent(s)'i may include hydroxy, protected 2~9~0~3'; ` - 14 -hydroxy as exemplified below, nitro, lower alkoxy (e.g.
methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy, etc.), amino, protected amino as exemplified above, lower alkyl (e.g., methyl, ethyl, propyl, isop~opyl, butyl, isobutyl, sec-buty~, t-buty~, pentyl, t-pentyl, hexyl, etc.), halogen as exemplified above, and the like:
- Suit2ble "lower alkenyl moiety" in the term "ar(lower)alkenyl" may include vinyl, allyl, l-propenyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 7 or 3 or 4 or 5-hexenyl and the li~e.
Suitable "heteromonocyclic group" may include saturated or unsaturated heteromonocyclic group contalning at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And, especially preferable heteromonocyclic group may be heteromonocyclic group such as unsaturated 3 to 8-membered heteromonocyclc group containing 1 to 4 nitrogen atom~), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, triazolyl (e.g.
1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, -etc.), tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl ~e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5~dihydro-1,2,4-triazinyl, etc.), etc.;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2-oxygen atom(s) and 1 to 3 nitrogen 1`
atom~s), for example, oxazolyl, isoxazolyl, dihydroisoxazol~l, oxadiazolyl, ~e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5~oxadiazolyl, etc.) etc.;
.~
saturated 3 to 8-membered heteromonocyclic group ~ 1... -WO92/01683 2 0 9 0 0 2 3 PCT/JP91/0095~
containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), ~or example, morpholinyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,S-thiadiazoylyl, 1,2,3-thiadiazolyl, etc.;
saturated 3 to 8-membered heteromonocyclic group co~ainina 1 to 2 sulfur atom(s) and 1 to 3 nitrogen.
atom(s), for example, thiazo-liainyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example furyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing a sulfur atom, ror example, thienyl, etc.;
and the like.
Suitable "lower alkylene" may include straight or branched one having 1 to 6 carbon atom~s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or the like, preferably one having 1 to 4 carbon atom(s).
Preferable "heterocyclic group" in the terms "heterocyclic grou~ having a protected imino group of the formula : ~ N / 6 1 (in which R is imino protective group) in its hetero ring" and "heterocyclic group having an imino group of the formula : \ N ~ in its hetero ring"
H -0 may includeunsaturated 3 to 8~membered h~teromonocyclic group containing l to 4 nitrogen atom(s), for-example, pyrrolyl, Fyrroliny~, imidazolyl, pyrazolyl,~~dihydroDyridazin~
~~~ tetrahydropyridazinyl, triazolyl (e.g. 1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl j.
WO 92/01683 2 0 9 ~ 0 2 3 P~-r/JP91/00952 fe.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,~-dihydro-1,2,4-triazinyl, etc.), etc.;
saturated 3 to 8-membered heteromonocyclic group containing l to 4 nitrogen atomls), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.; and the like.
The preferred embodiments of the object compound (I~
are as follows.
1 0 , R1 is heterocyclic group (more preferably unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), most preferably tetrazolyl or imidazolyl) which may have one to three (more ~-preferably one) suitable substituent(s) [more preferably tetrazolyl or imidazolyl, each of which may have an imino protective group; most preferably tetrazolyl or imidazolyl, each of which may have mono(or di or tri)phenyl(lower)alkyl], or cyano;
R is hydrogen;
R is aryl (more preferably phenyl) which ma~ have one to three (more preferably one) suitable substituent(s) [more preferably phenyl or halophenyl];
R is aryl (more preferably phenyl or naphthyl) which may have one to three (more preferably one or two) suitable substituent(s) [more preferably phenyl or naphthyl, each of which may have one or two `
substituent(s) selected ~rom the group consisting of halogen and amino; most preferably naphthyl, dihalophenyl or phenyl having halogen-and amino], ar(lower)alkenyl (more prefera~lv phenyl(lower)alkenyl)-which may have one to three (more-preferably one) suitable substitu nt(s) Lmore preferably phenyl(lower)alkenyl which may have amino or nitro; most preferably nitrophenyl(lower)alkenyl ,~ :
_. :
WO92/01683 2 0 9 0 0 2 3 pCT/Jp91/~o952 - ,, .
or aminophenyl(lower~alkenyl], arylamino (more preferably phenylamino) which may have one to three (more preferably one) suitable substituent(s) [more preferably phenylamino which may have lower alkyl or halogen; most preferably lower alkylphenylamino or halophenylamino~, heteromonocyclic group (more preferably pyridyl or tetrahydropyridazinyl) which may have one to three (more preferably one) suitable substituent(s) [more pre~erably pyridyl, or tetrahydropyridazinyl which may have an oxo group;
most preferably pyridylr or tetrahyàropyridazinyl having an oxo group~, quinolyl, isoquinolyl, cinnolinyl, indolyl or ~uinoxalinyl, and A is lower alkylene (more preferably Cl-C4 alkylene), 15 with proviso that when R is indolyl, then (i) R1 is tetrazolyl and R3 is halophenyl or ~ii) R1 is imidazolyl which may have mono(or di or tri)-phenyl(lower)alkyl, R3 is halophenyl and A is ethylene.
The processes for pxeparing the object compound ~I) and the starting compounds of the present invention are explained in detail in the following.
:
Process 1 :
The compound (I) or a salt thereof can be prepared by re~cting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative or a salt thereo.. :
~ Suitable reactive derivative- at~the~amino grou~ of the--compound (II) may include Schiff's base type imino or its tautome`ric enamine type isomer-formed by the~reaction of the compound (II) with a carbonyl compound such as : ` :
, .
WO92tO1683 2 ~ 9 0 0 2 3 ; ~ 18 - PCT/JP91/OOgs~ ~
aldehyde, ketone or the like; a silyl derivative Lormed by the reaction of the compound (II) with a silyl co~pound such as N,O-bis(trimethylsilyl~aoetamide, N-trimethylsilylacetamide or the likei a derivative formed by the reaction or the compound (II) with phosphorus trichloride or phosgene and the like.
Suitable salts o~ the compound (Il) and (III) can be referred to the ones as exemplified ~or the compound (I).
Suitable reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activate~ ester, isocyanate and the like. The suitable example may be an acid chlorid~, an acid azidei a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, 1~ phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acïd, alkanesulfonic acid (e.g.
methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g.
pivalic acid, pentanoic acid, isopentanoic acid, -2-ethylbutyric acid, trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g.
cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N=CH-~ ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cres~,l thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine, .. ~ . .
`
. j , . . - .. .
209Q~23 l-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, l-hydroxy-6-chloro-lH-benzotriazole, etc.), isocyanate of the formula : R5-N=C=o (in which R is aryl which may have one or more suitable substituent~s)), and the like.
These reactive derivatives can optionally b~ selected from them according to the kind of the compound (III) to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chlorororm, methylene chlorid~, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.
When the compound (III) is used in free acid form or its salt form in the reaction, the reaction is: preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodlimide;
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
N,N-carbonylbis-(2-methylimidazole);
pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexylimine; ethoxyacetylene; -l-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphsphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride;
thionyl chloride; oxalyl chloride; triphenylphosphine;
2-ethyl-7-hydroxybenzisoxazolium salt;
2-ethyl-5-~m-sulroDhenyl)isoxazoiium hydroxide intra-molecuiar saït;
l-(p-chlorobenæenesulfonyloxy)-6-chloro-lH benzotrlazole;
so-called ~ilsmeier reagent prepared by the reaction of .. . . .
' ~... .
... ,, .. .. _ .. ,, .. _ . _ ... ... ... . .. . . ... . .... ..
,; , , , , ., , . . , , -. ., ; . :
WO92/01683 2 0 9 ~ ~ 2 3 PCT/JP91/0095' - 20 - ' ~ .
N;N-dimethylformamide wlt~ thionyl chloride, phosgene, phosphorus oxychloride, etc.;
or the like.
The reaction may also be carried out in the presence o~ an inorganic or organi- base such as an alkali metal bicarbonate, tri~lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N~N-ditlower)alkylbenzylamine~
- or the like. The reaction temperature is not critical, and the reaction is uisiually carried out under cooling to heating.
.
Process 2 The compound ~Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to elimination reaction of the imino protective group.
Suitable ~ethod of this reaction may include conventional ' one such as hydrolysis, reduction and the like.
(i~ For Hydrolysis :
The hydrolysis is pre~erably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal ~e.g. sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine Ee.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene, 1,4-diazabicycloE2.2.2~octane, 1,8-diazabicyclo[5.4.0~undec-7-ene, or the like.
Suitable acid may include an organic acid ~e.g. -formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid,'etc.] and an inorganic acid ' - - ' ~e.g. hydrochloric''acid, hydrobromic acid, sulfùric a--d, :~' hydrogen chloride, hydrogen bromide, étc.].' Tne eiiminatlon using'Lewis acid such as trihaloacetic acid ~e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or . . ~ .
~ '...
'~ "' ' i ., '., "i, .' '' ',; . ' , the like is pre~erably carried out in the presence of cation trapping agents ~e.g. anisole, phenol, etc.].
The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], N,N-dimethylformamide, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does no~ adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried o-t under cooling to heating.
(ii) For reduction :
Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
~5 Suitable reducing agents to be uised in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g.
platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium ~ -catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, ~ -palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, `~
. . .................................. .
nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g.
reduced cobalt, Raney cobalt, etc.), lron catalysts (e.g.
reduced iron, Raney iron, etcO), copper catalysts (e.g.
.. . . --, . ... .. .
reduced copper, Raney copper, Ullman copper, etc.) and the like. The reduction ls usuaily carried out in a .
conventional solvent wh}ch does not adversely influence '.
. ~ .: .
W0 92/01683 2 0 9 ~ ~ 2 3 " i PCT/JP91/0095~
the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereoI. Additionally, in case that the above-mentioned ~ ~
acids to be used in chemical reduction are in liquid, they ' - "
can also be used as a solvent.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating. ; ' Process 3 The compound (Id) or a salt thereof can be prep2red by subjecting the compound (Ic) or a salt thereof to ' reduction reaction. This reduction reaction can be -referred to that of the aforementioned Process 2. '' Process 4 The compound (I) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof. ' '' Suitable salts of the compounds (IV) and (V) can be referred to the ones as exemplified for the compound (I). ':
This reaction is usually carried out in the presence o~ base.
Suitable base may include an inorganic base such as " ' alkali metal hydride (e.g. sodium hydride, etc.), alkali metal hydroxide (e.g. sodium hydroxide, potassium l;
hydroxide, etc.), alkaline earth metal hydroxide (e.g. :
magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.'g. sodium carbonate, potassium' carbonate, etc.), alkaline earth metal carbonate (e.g.
magnesium car~onate,'~calci~m~carb'onate, etc.), ~lkali metal bicarbonaté (e.g. sodi~m bicarbonat3, potassium ' -~~~bicarbonate, etc.),~alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.),''alkaline earth metal ..
!:
1 .;-WO92/01683 2 o 9 o o ~ ~ PCT/JP91/00952 phosphate (e.g. magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), or the like, and an organic ~ase such as trialkylamine (e.g. trimethylamine, trlethylamine, etc.), picolir.e, N-methy~pyrrolidine, N-methylmorpholine or the like.
This reaction is usually carried out in a solvent such as alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or iO any other solvent which does not adversely affec~ the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. ~ ~-1~ Process 5 The compound (If) or a salt thereof can ~e prepared by reacting the compound (Ie) or a salt thereof with the compound (VI) or a salt thereof.
Suitable salts of the compounds (Ie) and ~If) can be referred to the ones as exemplified for the compound (I).
Suitable salts of the compound ~VI) may include an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and the like.
The reaction is usually carried out in a conventional solvent such as l-methyl-2-pyrrolidinone, N,N-dimethylformamide, dichloromethane, ethylene chloride or any other solvent which does not adversely influence the reaction.
The reaction temperature is not critical and the reaction is usually carried out under warming to heating.
, ~ . . . I : .
Process A -The compound (II) or a salt thereof can be prepared by subjecting the compound IVII) or a salt thereof to elimination reaction of the amino protective ~roup.
WO92/01683 2 0 9 ~ ~ 2 3 PCT/JP~1/0095~
Suitable salts of the~compound (~II) can be referred to the ones as exempli~ièd for the compound (I).
The elimination reaction is carried out in accordance with a conventional method such as hydrolysis;
reduction; Edman's method (pnenyl isothiocyanate method);
or the like. The hydrolysis may include a method using an acid or base or hydrazine and the like. These ~ethods may be selected depending on the kind o~ the protective groups to be eliminated.
Among these ~ethods, hydroiysls using an 2Ci~ is one of the most common and preferable method for elimina_ing the protective groups such as substituted or unsubstituted alkoxycarbonyl, for example, tert-pentyloxycarbonyl, iower alkanoyl (e.g. formyl, acetyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl ~e.g. trityl), substituted phenylthio, substituted aralkylidene, substituted alkylidene, substituted cycloalkylidene or the like. -Suitable acid includes an organic or inorganic acid such as formic acid, trifluoroacetic acid, benzenesulfonicacid, p-toluenesulfonic acid, hydrochloric acid and the like, and the most suitable acid is an acid which can easily be removed from the reaction mixture by a conventi~nal manner such as distillation under reduced ~-pressure, for example, formic acid, rifluoroacetic acid, hydrochloric acid, etc. The acids can be selected according to the kind of the protective group to be eliminated. ~-The elimination reaction reaction using - trifluoroacetic acid may be carried out in the presence OI
anisole. The hydrolysis using hydrazine is commonly applied ~or eliminating a phthaloyl, succinyl type amino-protective group. -The elimination using base is uséd for eliminating an acyl group such as trifluoroacetyl. Suitable base may ; ~ , ;, ., .. .. . ... . ~ .~.. . . . . . .. . .
20~0023 WO92/01683 PCT/JPg1/009$2 include an inorganic base and an organic base.
The reductive elimination is generally applied for eliminating the protective group, for example, haloalkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g.
benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc.
Suitable reduction may include, for example, reauction with an alkali ~etal borohydride (e.g. sodium borohydride, etc.), reduction with a combination of a metal (e.g. tin, zinc, iron, etc.) or the said metal toaether with a metal salt compound (e.g. chromous.chloride, chromous acetate, etc.) and an organic or inorganic acid ~e.g. acetic acid, propionic acid, hydroch~oric acid, etc.); and catalytic reduction. Suitable catalyst includes a conventional one, for example, Raney nickel, platinum oxide, palladium on carbo~ and the like.
Among the protective groups, the acyl grou~ can generally be eliminated ~y hydrolysis. Especially, halogen substituted-alkoxycarbonyl and 8-quinolyloxycarbonyl groups are usually eliminated by treating with a heavy me~al such as copper, zinc, or the like.
The reaction is usually carried out in a conventional solvent such as water, chloroform, methylene chloride, alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran or any other organic solvent which does not adversely -influence the reaction.
The reaction temperature is not critical and may suitably be selected in accordance with the kind of the amino protective group and the elimination method as mentioned-above, and the reaction is usually carried out under a mild condition sucn-zs unde. coolins-or at slightly elevated temperature. Among the protective groups, the acyl group derived from -amino acid can be -eliminated by Edman's method.
, _, . . , ,, ... , ..... , . . .. ,, . . ... " . ~, ., ~ .. . . ....
WO92/01683 2 G 9 ~ ~ 2 3 PCT/JP91/00952 Process B
The compound (IV) or a salt thereof can be prepared by reacting the compound (VIII) or its reac~ive derivative at the amino group or a salt thereof with the com~ound (III) or its reactive derivative or 2 salt thereof.
The reaction is carri.ed out by s~ stantially the same ~-method as that of Process 1, and thè~ëfore the reaction method and conditions are to be referred to said Process ~.
1. :
The object compound (1) and pharmaceu_ically acceptable salts thereof are.CCK antagonists and therefore useful as therapeutical agents for emesis, pancreatltis, .
etc.
Further, it is expected that the object compound (I) ..
lS and pharmaceutically acceptable salts thereo have gastric :
antagonism and are useful as therapeutical and/or preventive agents for ulcers, excess gastric secretion, Zollinger-Ellison S~ndrome, etc. -In order to show the utility of the object compound (I), the pharmacological activity of the representative ..
compound thereof is shown in the following. .
[I~ Test Compound : .
(3S)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-[(E)-3-(2-: aminophenyl)propenoylamino]-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one dihydrochloride Ehereinafter referred to as test compound A]
30 ~II] Test-:-- CCK receptor antagonism in isolated.fundic circulax muscle from ~inea Dl stomach - - '-' ' . , . :. ,- ~- . ., ~ Test Method The strip of circular muscle from guinea pig stomach was suspended in 25 ml organ bath containing Krebs' ' . . ., . . . ., .............. . . .. . ~ ~; . . . .
; , , : , : -:
WO92/01683 2 0 9 0 0 2 3 PCT/JP91/0095' bicarbonate solution (NaCl 118mM, KCl 4.8mM, KH2P04 1.2mM, MgSO4 1.2mM, CaCl2 2.5mM, NaHCO3 25mM, glucose llmM and bovine serum albumin 0.1~) maintained at 37C and gassed with 95~ 2 and 5% CO2.
The strip was placed under an initial tension of 0.5 g and equilibrated for 60 minutes during which the bath volume W2S replaCeG every 15 minutes. Isometric contraction was measured using a force transducer. CCK-8 ~3.2 x lO 7M) was added to the bathing solution and the contractile force was measured. After washing out CCK-8, it stood Ior about 15 minutes until contractile force became plateau. Then test compound A (1 x 10 6M) was added. 5 minutes later, CCK-8 was added and the contractile force was recorded. CCK antogonism was calculated by comparing the contractile force induced by CCK in the absence or presence o~ test compound A.
Test Result Inhibition (%) : 89.9 The object compound ~I) or pharmaceutically acceptable salts thereof can usually be administered to mammals including human being in the form of a conventional pharmaceutical composition such as capsule, micro-capsule, tablet, granule, powder, troche, syrup, aerosol, inhalation, solution, injection, suspension, emulsion, suppository~or the like, and the most suitable -dosage form is injection.
The pharmaceutical composition o~ this invention can contain various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose, such as excipient (e.g. sucrose, starch, manni " sorbit, lactose, glucose, cellulose, talc, calci~m phosphate calcium carbonate, etc.j, binding agent (cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, ::
WO92/01683 2 0 9 0 0 2 3 PCT/JP91/009S~
gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g. starch, carboxymethyl cellulose, calcium salt of carboxymethyl oellulosP, hydroxypropylstarch, sodlum glyc~le-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), I
lubricant (e.g. magnesium stearate, talc, sodium I-laurylsulfate, etc.), flavoring agent (e.g. citric acid, mentol, glycine, orange powders, etc.), preservative (e.g.
sodium benzoate, sodium bisulrite, methylparaben, propylparaben, etc.), stabilizer ~e.g. citric acid, sodium citrate, acetic acid, etc.),- suspending agent (e.g. methyl cellulose, polyvinylpyrrolidone, aluminum stearate, etc.), dispersing agent, aqueous diluting agent (e.g. water), base wax (e.g. cacao butter, polyethyleneglycol, white petrolatum, etc.).
The effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 50 mg/kg, l to 4 times a day. However, the above dosage may be increased or decreased according to age, weight, conditions of the patient or the administering method.
The following Preparations and Examples are given only for the purpose of illustrating the present invention in more detail.
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W092/01683 2 0 9 ~ 0 2 3 PCT/JP91/00952 -; ;
- ?9 -PreParation 1 To a solution of (3RS)-3-phthalimido-5-l2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin 2-one (21.17 g) in N,N-dimethylformamide (400 ml) was added gradually sodium hydride (2.0 g, 60% suspension in ~ineral oil) under cooling in an ice-bath and nitrogen atmosphere.
The mixture was stirred under the same conditions for 0.
hour and at ambient temperature for 1 hour. The mixture was cooled in ice-bath and a solution OI
chloroacetonitrile t3.48 ml) in N,N-dimethylrormamide (~
ml) was added dropwise thereto. The mixture was stirre~
~or 1 hour at the same temperature and at ambient temperature overnight. To the reaction mixture wa~ added acetic acid (3.5 g) under cooling and the resultant mixture was poured into a mixture of ethyl acetate and water under stirring. The mixture was adjusted to pH 7.5 with agueous sodium bicarbonate. The crystals were collected by filtration and washed with cold ethyl acetate to give (3RS)~3-phthalimido-1-cyanomethyl-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (20.9 g).
mp : 260C (dec.) IR (Nujol) : 2160, 1776, 1725, 1700, 1604 cm 1 NMR (DMSO-d6, ~) : 5.15 (2H, ABq, J=24.6Hz, 17.8Hz), 5.83 (lH, s), 7.2-8.1 (12H, m) PreParation 2 A mixture of (3RS)-3-phthalimido-1-cyanomethyl-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (20.0 g), sodium azide (8.43 g) and triethylamine hydrochloride (8.92 g) in N-methyl-2-pyrrolidone (350 ml)~
- was heated at 145C under stirring-for 3.5 hours.-~ After coolins to amb ent temperatu~e, the-mixture :W2S poured into 5% hydrochloric acid (500 ml) and ice. The resultant ~ precipitates were collected by filtration,~ washed with 35 cold water several times and dried over phosphorus -~
. . -...
. ~:
. . . ~ ..
W092/01683 2 0 9 0 ~ 2 3 PCT/JP91/00952 pentoxide under reduced pressure to afford (3RS)-3-phthalimido-l~3-dihydro-5-(2-fluorophenyl)-l-~(lH
tetrazol-5-yl)methyl]-2H-~,4-benzodiazepin-2-one (18.07 g ) . .` ':~.
IR (Nujol) : 1778, 172~, 1693, 1610 cm 1 NMR ~DMSO-d6, ~ .46 (2H, s), 5.85 (lH, s), 7.2-8.0 (13H, m) Pre~aration_3 To a solution of ~3RS)-3-~hthalimido-1,3-dihydro-5-(2-fluorophenyl)-1-~(lH-tetr~zol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (18.07 g) and trityl chloride (10.99 g) in N,N-dimethylformamide (330 ml) was dropwise added a solution o~ triethylamine (4.6 g) in N,N-dimethylformamide (10 ml) under stirring and cooling in an ice-bath. The mixture was stirred for 20 minutes under the same conditions and at ambient temperature overnight. The reaction mixture was poured into an ice-water (500 ml), and the resultant precipitates were collected ~y filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to afford ~3RS)-3-phthalimido-1,3-dihydro-S-(2-fluorophenyl~-1-[(l-trityl-lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (33.41 g) as white powder.
IR INujol) : 1778, 1723, 169S, 1610 cm 1 NMR (DMSO-d6, ~) : 5.i6 (2H, ABq, J-l~.OHz, 52.6Hz), 5.80 (lH, s), 6.8-8.1 ~27H, m) Pre~aration 4 30 - To a suspension of (3RS)-3-phthalimido-1-[(1-trityl-: lH-tetrazol-5-yl)methyl~-5-(2-fluorophenyl)-1,3-dihydro-2~-1,4-benzodiazepin-2-one (33.4 g) in tetrahydrofuran - (SOO ml) was added hydrazine hydrate (1.90 g) under -stirring at ambient temperature. The mixture was stirred for 2 hours-at the same temperature and refluxed under ;:
I',' ' W092/Ot683 2 0 9 0 0 2 3 PCT/JP91/009S2 stirring for 2 hours. The reaction mixture was cooled in an ice-bath and the resultant precipitates were filtered off. The filtrate and the washings were combined and evaporated to afford a residue, which was stirred in ethyl acetate and ~iltered. The filtrate and washings were combined and evaporated to give white powder (14.43 g~ of (3RS)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1~
trityl-lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one.
I~ (Nujol) : 3350, 1686, 1597, 760, 700 cm 1 NMR ~CDC13, ~) : 2.95 (2.~, br s), 4.62 (lH, s), 5.42 (2H, ABq, J=19.6Hz, 15.8Hz), 6.8 7.6 (23H, m) PreParation 5 The rollowing compound was obtained according to a similar manner to that of Preparation 4.
t3Rs)-3-Amino-l~3-dihydro~5-pheny~ (l-trityl-lH
tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one mp : 132-135C
IR (Nujol) : 3375, 1680, 1595, 1575, 1560 cm 1 NMR (CDC13, ~) : 2.72 (2H, s), 4.55 (1~, s), 5.46 ~2~, ABq, J=16Hz, 51Hz), 6.90-6.70 ~6H, m), 7.15-7.50 (18H, m) Preparation 6 To a solution of (3RS)-3-amino-1,3-dihydro-5-~2-fluorophenyl)-l-[(l-trityl-lH-tetrazol-5-yl)methyI]-2H-~1,4-benzodiazepin-2-one (11.54 g) and N-t-butoxycarbonyl-30~ -phenylalanine (5.42 g) in N,N-dimethylformamide (200 ml) were added successivel~ l-hydroxybenzotriazole (2.76 g), - l-ethyl-3-(3-dimPthylaminopropyl)carbodiLmide hydrochloxide~S3.91 g) and triethylamine !2.36 g) ~.aer stirring at ambient temperature. The mixture was stirred under the same conditions for 4.5 hours and then poured ' " :
'.
- 32 ~`
into water (1.5 Q)~3~nder stirring. The mixture was adjusted to pH ~'with an aqueous solution of sodium bicarbonate. The resultant precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give a mixture (16.29 g) of (3R)-3-[((2S)-2-t-butoxycarbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro-5-~2-fluoropnenyl)-1-~(l-trityl-lH-tetrazol-5-yl)methyl)-2H-1,4-benzodiazepin- '' 2-one and (3S)-3-[((2S)-2-t-butoxycarbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro-5-(2-fluoro~henyl)-1-[(l-trityl~ tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one. ' mp : 108-114C
IR (Nujolj : 3330, 1700, 1690, 1675, 1610 cm 1 -~-NMR (DMSO-d6, ~) : 1.28 (9H, s), 2.65-2.9 ~lH, m), 3.0-3.2 (lH, m), 4.40 (lH, m), 5.33-5.41 (2H, ~
m), 5.39, 5.40 (lH, each d, J=8Hz), 5.58 t2H, ' ABq, J-16.8Hz, 82.2Hz), 6.8-7.95 (14H, m), 9.25, 9.37 (lH, each d, J=8Hz) PreParation 7 A mixture of a mixture (16.2 g) of (3R)-3-[((2S)-2-t-butoxycarbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro-5-(2-fluorophenyl)~ tl-trityl-lH-tetrazol-5-yl)methyl]-25~ 2H-1,4-benzodiazepin-2-one and (3S)-3-~((2S)-2-t-butoxy-arbonylamino-3-phenylpropanoyl)amino]-1,3-dihydro-5-2;-fluorophenyl)-1-t(l-trityl-IH-tetrazol-5-yl)methyl]-2H-1,4~-benzodiazepin-2-one and 4N solution of hydrogen chloride~in ethyl acetate (200 ml) was stirred at ambient 39~ temperature~for 5'hours~. The mlxture~was concentrated in vacuo~ito~give~a residue, which was dissolved'in'methanol ;(100 ml)~`and~~neutr'al~zed-with an'ethanolic ammonia. The mix.ure was~concentr'ated in vacuo to dryness.~ The residue . ~~' was'~subj~ected to column chroma~ography on silica-~gel with 35-~ an eluent~(CHO13:~CN3OH~= I0:'1). The fractions containing W092/01683 2 0 9 0 0 2 ~ PCT/JPg1/009~2 the object compound were combined and evaporated to give an amorphous mass, which was suspended in diisopropyl ether and collected by filtration to give (3S)-3-[((2S)-2-~mino-3-phenylpropanoyl)amino]-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (4.57 g).
NMR (DMSO-d6, ~) : 2.91 (lH, dd, J=14.0Hz, 8.4Hz), 3.20 (lH, dd, J=4Hz, 14.0Hz), 4.13 (lH, dd, J=4Hz, 8.4Hz3, 5.26 (2H, AB~, J-15.4Hz, 31.6Hz), 5.39 (lH, d, J=8.0Hz), 7.1-7.35 (lOH, m), 7.52-7.66 (4H, m), 7.96 (lH, d, J=8.4Hz), 9.77 (lH, d, J=8.0Hz) The fractions containing the other object compound were combined and evaporated to give an amorphous mass, which was suspended in diisopropyl ether and collected by filtration to give (3R)-3-~((2S)-2-amino-3-phenyl-propanoyl)amino]-1,3-dihydro 5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (4.76 g).
NMR (DMSO-d6, ~ 3.0-3.17 (lH, m)j 3.57-3.64 (lH, m), 3.0-4.1 (2H, broad), 4.21 (lH, t, J=4.2Hz), 5.19 (2H, ABg, J=15.6Hz, 70.1Hz), 5.38 (lH, d, J=8.3Hz), 7.16-7.4 (lOH, m), 7.51-7.67 t4H, m), 7.97 (lH, d, J=8.2Hz), 9.78 (lH, d, J=8.3Hz) - ~-Preparation 8 To a solution of ~3S)-3-[((2S)-2-amino-3-phenylpropanoyl~amino]-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one ~ -~4.57 g), and triethylamine (0.974 g) in dried tetrahydrofuran (45 ml) was added phenyl isothiocyanate (2.54 g) under stirring at ambient temperature.~
-~- The-mixture was stirred for 2 hours at ambient temperature and~for 1 hour`at 50C.~ To the reaction mixture was added lN-hydrochloric acid-(9.64 ml) under ice cooling.
. . :
WO92/01683 2 0 9 0 0 ~ 3 PCT/JP91/00952 The mixture was concentrated in vacuo to give a residue, which was extracted with ethyl acetate. The extract was washed with water twice and dried over magnesium sulfate.
Removal of the solvent in vacuo afforded an amorphous mass (7.23 g), which was powdered by stirring in diisopropyl ether for 3 hours. The resultant powder was collected by filtration and washed with diisopropyl ether to give (3S)-3-[[(2S)-2-{N'-(phenyl)thioureido}-3-phenyl-propanoyl]amino]-l~3-dihydro-5-(2-fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (5.63 g).
The product obtained above was suspended in tetrahydrofuran (35 ml) and 4N-hydrogen chloride in ethyl acetate (33.5 ml) was added dropwise thereto under ice-cooling. The mixture was stirred for 5 hours and then evaporated in vacuo to give a viscous oil, which was washed with ethyl acetate by stirring for 3 hours. The resultant powder was collected by filtration, a:nd dried under reduced pressure to give (3S)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one hydrochloride (2.91 g).
[a~30 = -36.36 ~C=0.495, CH30H) Preparation 9 The following compound was obtained according to a similar manner to that of Preparation 8.
(3R)-3-Amino-1,3-dihydro-S-(2-fluorophenyl)-1-[~lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one hydrochloride ~ -[a]30 = + 33.46 (C=0.505, CH30H) Pre~aration 10 - ; -To a suspension of ( 3RS)-3-amlno-1,3-dihydro-i~
- -: fluorophenyl)-2H-1,4-benzodiazepin-2-one (2.0 g~ in methylene chloride (30 ml) was added dropwise .
2~9002~
WO92~01683 PCT/JP91/00952 triethylamine ~1.61 g) under stirring and cooling in an ice-bath. To the mixture was added 2-naphthoyl chloride (1.52 g) under the same conditions. The mixture was stirred for 2 hours at the same temperature. The resultant precipitate was collected by filtration and washed with methylene chloride and water successively.
The collected crystals were dried over phosphorus pentoxide under reduced pressure to give ~3RS)-3-(2-naphthoylamino)-5-~2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (2.33 g).
NMR (DMSO-d6, ~) : 5.60 (lH, d, J=7.7Hz), 7.22-7.39 (5H, m), 7.54-7.66 (5H, m), 7.99-8.11 (4H, m), 8.72 (lH, s), 9.74 (lH, d, J=7.7Hz), 11.05 (1~, -m) MASS (m/e) : 423 (M ) Pre~aration 11 The following compounds were obtained according to a similar manner to that of Preparation 10.
(1) (3RS)-3-(3-Quinolylcarbonylamino)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one IR (Nujol) : 3600, 1695, 1670, 1610, 1590, 1515 cm 1 NMR (DMSO-d6, ~) : 5.59 (lH, d, J=7.6Hz), 7.23-7.40 (5H, m), 7.61-7.76 (4H, m), 7.67-7.94 (1~, m), 8.1-8.16 12H, m), 9.09 (lH, s), 9.40 (lH, d, J=2.1Hz), 10.1 (lH, d, J=7.6Hz~, 11.08 (lH, s) -.:, .. .
(2) (3RS)-3-(3,4-Dichlorobenzoylamino~-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one NMR (DMSO-d6, ~) : 5.49 (lP., d, J=7.ÇHz), 7.2-8.02 .-(llH, m), 8.21 (lH, s), 9.93 (1;~, d, J=7.~Hz), 11.03 (lH, s): -MASS (mJe) : ~442 (M+) ..
:~' .
WO92/01683 2 0 9 0 0 2 3 PCT/JP91/009~' .
ExamDle 1 To a solution or (3S)-1,3-dihydro-5-~2-fluorophenyl)-3-amino-1-[(1-tritylimidazol-4-yl)methyl]-2H-1,4-benzodiazepin-2-one (1.0 g) in N,N..dimethylformamide (10 ml) were added successively ~E)-3 (2-nitrophenyl)propenoic acid (330 my~, l-hydroxyDenzo~rIazole (230 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (320 mg) and triethylamine (170 mg) under stirring at ambient temperature. The mixture was stirred for 3 hours and allowed to stand overnight. The reaction mixture was poured into a mi~ture of ethyl acetate and water under stirring. The separated organic layer was washed with water twice and dried. The solvent was removed under reduced pressure to give an amorphous residue, wnich was purified by column chromatography on silica gel with an eluen-t of chloroform. The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying undex reduced pressure gave (35)-1,3-dihydro-1-[tl-tritylimidazol-4-yl)methyl]-3-~(E)-3-~2-nitrophenyl)propenoylamino]-5-12-fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.16 g).
NMR tCDC13, ~) : 5.07 ~2H, br s), 5.66-5.7 (lH, m), 6.49-8.14 (32H, m) Example 2 The following compounds were obtained according to a similar manner to that of Example 1.
~ - - ... . , . ~
(1) (3S)-1,3-Dihydro-l-[(l-tritylimidazol-4~yl)methyl]-3-~(2-amino-4-chlorobenzoyl)amino}-5-t2-fluoroPhenYl)-2H-1~4-benzodiazepin-2-one NMR (CDC13, ~) : 5.06 (2H, d, J=3.7Hz), WO92/016~3 2 0 9 0 0 2 ~ pCT/JP91/00952 5.62-5.68 (3H, m), 6.63-8.04 (29H, m) MASS (m/e) : 502 (M -243) ,... :
(2) (3RS)-1,3-Dihydro-l-[~l-tritylimidazol-4-yl)methyl]-3-[(2,3,4,5-tetrahydro-3-oxopyrid zin-6-yl)-carbonylamino]-5-~2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (3) (3RS)-1,3-Dihydro-1-[(1-tritylimidazol-4-yl)methyl]-3-(3,4-dichlorobenzoylamino)-;-~2-fluorophenyl)-2H-1,4-benzodiazepin-2-one NMR lCDC13, ~) : 5.02 ~lH, d, J=15Hz), 5.12 (lH, d, J=15Hz), 5.67 (lH, d, J=7.8Hz), 6.85-8.04 (29H, m) ~4) (3RS) 1,3-Dihydro-l-[(l-tritylimidazol-4 yl)methyl]-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one NMR (DMSO-d6, ~) : 5.01-5.18 (2H, m), 5.78 (lH, d, J=7.8Hz), 6.87-8.26 (30H, m), 8.72 (lH, d, J=1.9Hz), 9.44 (lH, d, J=2.2Hz) MASS (mle~ ; 504 (M -243), 424 (5) (3RS)-1,3-Dihydro-l-[(l-tritylimiazol-4-yl)methyl]- `
3-(2-quinoxalinylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one '. .
(6) (3RS)-1,3-Dihydro-l-~(l-tritylimidazol-4-yl)methyl~
3-(4-cinnolinylcar~onylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one NMR (CDC13, ~) : 5.09 (2H, s), 5.80 (lH, d,J=7.8Hz), 6.8~-8.09 ~28~, m), 8.49-8.66 (2~, m), 9.54 (lH, . .
~ s) (7) (3RS)-1,3-Dihydro-l-~(l-tritylimidazol-4-yl)methyl~-~: - " ' . . - :
:~ ~ ` ' . :; .
W092/0i683 2 0 9 0 0 2 3 PCTIJP91/00952 ~ 38 - r 3-(1-isoquinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-~enzodiazepin-2-one NMR (CDC13, ~) : 5.11 (2H, s), 5.78 (lH, d, J=8.3Hz), 6.89-7.89 (28H, m), 8.05 (lH, d, J=8.2Hz), 8.59 (lH, d, J~-5;5Hz), 9.52-9.56 (lH, m), 9.93 ~lH, d, J=8.2Hz) . . ~; .
(8) (3RS)-1,3-Dihydro-l~ trltylimidazol~4-yl)methyl]-3-nicotinoylamino-5-~2-fluoropheny~)-2H-1,4-benzodiazepin-2-one NMR (CDC13, ~) : 4.99-.5.16 (4H, m), 5.71 (lH, d, J=7.7Hz), 6.85-9.18 (28H, m) Example 3 To a solution of (3RS)-1,3-dihydro-1-[(1-tritylimidazol-4-yl)methyl]-3-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.0 g) in methylene c~loride (10 ml) were added successively triethylamine (340 mg) and 2-naphthoyl chloride (320 mg). The mixture was stirred for 1.5 hours. The reaction mixture was washed with water and dried. The solvent was removed under rPduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent o~ chloroform.
The fractions containing the desired product were combined and evaporated to afford on oil, which was dried under reduced pressure to~give (3RS)-1,3-dihydro-1-~
tritylimidazol-4-yl)methyl]-3-(2-naphthoylamino~-5-(2-.
- fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.21 g).
NMR (CDC13, ~) : 5.03 (2H, d, J=15Hz), 5.15 (2H, d, J-15Hz), 5.79 ~lH, d, J=8Hz), ~.89-8.07 (29H, m), 8.22 tlH, d, J=8Hz), 8.47 (lH, s) ExamDle 4 To a solution of (3RS)-1,3-dihydro-i-~tl-35 tritylimidazol-4-yl)methyl]-3-amino-5-(2-fluorophenyl)-2H-; ~ ~ , . ' 1,4-benzodiazepin-2-one (1.5 g) in tetrahydrofuran (23 ml) was added m-tolyl isocyanate (0.35 g) under stirring at ambient temperature. The mixture was stirred for 2 hours under the same condition. From the reaciton mixture, the solvent was removedin vacuo to give crude product, which was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to afford pure (3RS)-1,3-dihydro-1-[(1-tritylimidazol-4-yl)methyl]-3-[3-(3-methylphenyl)ureido]-5-(2-flurophenyl)-2H-1,4-benzodiasepin-2-one (1.47 g).
NMR (DMSO-d6, .delta.) : 2.24 (3H, s), 4.85 (1H, d, J=14.8Hz), 5.24-5.33 (2H, m), 6.67-7.68 (29H, m), 7.91 (aH, d, J=8.2Hz), 8.97 (1H, s) Example 5 To a suspended mixture of iron powder (1.1 g) and ammonium chloride (0.13 g) in a mixture of water (2.5 ml) and ethanol (7.5 ml) was added portionwise (3S)-1,3-dihydro-1-[(1-tritylimidazol-4-6l)methyl]-3-[(E)-3-(2-nitrophenyl)propenoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (1.1 g) under stirring and refluxing.
After ethanol (7.5 ml) and water (2.5 ml) were added, the resultant mixture was refluxed under stirring for 1.5 hours. The reaction mixture was filtered through celite and the filtered mass was washed with hot ethanol several times. From the filtrate and the washings, ethanol was removed under reduced pressure. To the residual mixture was added a saturated aqueous solution of sodium bicarbonate (100 ml) and the mixture was extracted with ethyl acetate (100 ml). After washing with water and drying over magnesium sulfate, the extract was evaporated to give an amorphous reside, which was pulverized with diisopropyl ether and collected by filtration to afford (3S)-1,3-dihydro-1-[(1-tritylimidazol)-4-yl)methyl]-3-[(E)-3-(2-aminophenyl)propenoylamino]-5-(2-fluorophenyl)-WO92/01683 2 0 9 ~ Q 2 3 PCT/JP91/00952 - 40 - ..
2H-1,4-benzodiazepin-2-one (0.98 g).
NMR (CDC13, ~) : 3.71-4.07 ~2H, br d), 5.06 ~2H, s), 5.68 (lH, d, J=8Hz), 6.47.7.93 ~32H, m) MASS (m~e) : 476 (M+-260) L, Exam~le_6 To a solution OL (3S)-1,3-dihydro-1-~
tritylimidazol-4-yl~methyl~-3-[(E)-3-(2-2minophenyl3-propenoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (0.49 g) in N,N-dimethylformamide (4.9 ml! was adde~
6N-hydrochloric acid (3.4 ml~ under stirring and cooling in an ice-bath. The mixture was warmed to 50C and stirred for 1 hour. After cooling to room temperature, to the reaction mixture were added water and ethyl acetate under stirring. The mixture was adjusted to pH 8 with an aqueous solution of sodium ~ioarbonate. The separated organic layer was washed with water and dried. The .
solvent was removed under reduced pressure to give an amorphous residue, which was pulverized and stirred for several hours.in.diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave (3S)-1,3-dihydro-1-(4-imidazolylmethyl)-3-[(E)-3-(2-aminophenyl)propenoylamino]-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (350 mg).
To a solution of the product obtained above in chloroform ~: ~ (10 ml) was added 20%-hydrogen chloride in ethanol (5 ml) under cooling. The clear yellow solution was evaporated to dryness under reduced pressure. Th~ residue was .
pulverized and stirred for several hours in diisopropyl : ether. Collection by filtration, washing with diisopropyl : .~ ether and drying under reduced:pressure gave yellow-powder (234 mg:) o- (3S~-1,3-dihydro-1-~4-imidazolylmethyl)-3- 1 .~E.)-3-(2-aminophenyl)propenoylamino]-5-(2-rluorophenyl)- 1 :
2H-1,4-benzodiazepin-2-one dihydrochloride. ....................... ¦ .
:~ 35 IR (Nujol) : 3650-3050, 2700-2150, 1660, 1605 cm 1 W092/016X3 Z O ~ O 0 2 3 PCTtJP91/00952 NMR (CDC13, ~) : 3.8-4.8 ~2H, b), 5.15-5.56 (3H, m), 7.04-7.81 (18H, m), 9.03 (lH, s), 9.43 (lH, d, J=8HZ ) MASS (m/e) : 494 (M -73), 476 Exam~le 7 The following compounds were obtained according to a similar manner to that of Example 6.
(1) (3S)-1,3-Dihydro-1-(4-imidazoly~methyl)-3-[(2-amino-
4-chlorobenzoyl)amino] 5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one mp : 180-220C (dec.) -IR (Nujol) : 3500-3000, 1675, 1640 cm 1 NMR (CDC13, ~ : 4.93 (lH, d, J=15Hz), 5.20 (lH, d, J=15Hz), 5.25-5.69 (3H, m), 6.62-6.67 (2H, m), 6.98-7.26 (6H, m), 7.40-7.69 (5H, m), 7.89-7.91 (2H, m) MASS (m/e) : 502 (M ) (2) (3RS~-1,3-Dihydro-1-(4- midazolylmethyl)-3-[(2,3,4,5-tetrahydro-3-oxopyridazin-6-yl)carbonylamino~-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one dihydrochloride mp : 230-240C (dec.) IR (Nujol) : 3650-3050, 2650, 2200, 1670, 1610, ' 1500 cm~l - .
NMR (DMSO-d6, ~) : 2.41-2.88 ~4H, m), 5.20 (lH, d, J=16Hz), 5.42 (lH, d, J=16Hz), 5.43 (lH, d, J=7.8Hz), 7.`15-7.78 (9H, m), 8.58 (lH, d, J=7.8Hz), 9.02 (lH, s), 11.31 (lH, s), 14.67 -~ - (lH, br~s~ - -MASS (m/e) : 393 ~M -153) ~35 (3) (3RS)-1,3-Dihydro-1-(4-imidazolylmet~yl)-3-(3,4-. .
W092/01683 2 ~ ~ O 0 2 3 PCT/JP91/009~2 ~ 42 -~, dichlorobenzoylamino)-5-(2-~luorophenyl)-2H-1,4-benzodiazepin-2-one hydrochloride mp : 212-230C (dec.) IR (Nujol) : 3650, 3150, 2650-2000, 1650, 1600, 1510 cm 1 NMR (DMSO-d6, ~) : 5.20 (lH, d, J=16Hz),
NMR (DMSO-d6, ~) : 2.41-2.88 ~4H, m), 5.20 (lH, d, J=16Hz), 5.42 (lH, d, J=16Hz), 5.43 (lH, d, J=7.8Hz), 7.`15-7.78 (9H, m), 8.58 (lH, d, J=7.8Hz), 9.02 (lH, s), 11.31 (lH, s), 14.67 -~ - (lH, br~s~ - -MASS (m/e) : 393 ~M -153) ~35 (3) (3RS)-1,3-Dihydro-1-(4-imidazolylmet~yl)-3-(3,4-. .
W092/01683 2 ~ ~ O 0 2 3 PCT/JP91/009~2 ~ 42 -~, dichlorobenzoylamino)-5-(2-~luorophenyl)-2H-1,4-benzodiazepin-2-one hydrochloride mp : 212-230C (dec.) IR (Nujol) : 3650, 3150, 2650-2000, 1650, 1600, 1510 cm 1 NMR (DMSO-d6, ~) : 5.20 (lH, d, J=16Hz),
5.43 (lH, d, J=l6Hzl~ 5.61 (lH, d, J=7.3Hz), ~-7.19-7.82 ~lOH, m), 7.98 (lH, dd, J=2Hz, 8Hz), 8.30 (lH, d, J=2Hz), 9.02 ~lH, d, J=1.2Hz), 10.0 (~H, d, J=9.4Hz), 14.64 (lH, br s) MASS ~m/e) : 521 (M -3~), 441 (4) (3RS)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-(3-quinolylcar~onylamino)-5 (2-fluorophenyl)-2H-1,4-benzodiazepin-2-one dihydrochloride mp : 230-233C (dec.) IR (Nujol) : 3600-3100, 2700-2100, 1670, 1610, 1510 cm~l , .. .
NMR (DMSO-d6, ~) : 5.24 (lH, d, J=16Hz), 5.47 (lH, d, J=16.1Hz), 5.71 (lH, d, J-7.2Hz), 7.2-8.39 (13H, m), 9.05 (lH, d, J=l.lHz), 9.48 (lH, d, J=1.8Hz), 9.60 (lH, d, J-2Hz), 10.3~ (lH, d, J=7.2Hz), 14.72 (lH, br s) MASS (m/e) : 504 (M -73), 424 ~5) (3RS)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-~2-quinoxalinylcarbonylamino)-5-[2-fluorophenyl)-2H-1,4-benzodiazepin-2-one hydrochloride ~
- mp : 205-220C (dec.) - -IR (Nujol~ : 3600-3050, 2700-2000, 1670, 1600 cm 1 NMR (DMSO-d6, ~ 5.25 (lH, d, J=16.1Hz), - 5.48 (lH, d, J=16.1Hz), 5.68 (lH, d, J=7.8~z), 7.18-B.35 (13H, m), 9.04 (lH, s), 9.53-9.61 (2H, m), 14.63 (lH, m) -; ~35 NASS (m~e) : 505 (M -36), 425 . ~ .
W092/01683 2 0 9 0 0 2 3 Pcr/JP9l/oo9s ' :
NMR (DMSO-d6, ~) : 5.24 (lH, d, J=16Hz), 5.47 (lH, d, J=16.1Hz), 5.71 (lH, d, J-7.2Hz), 7.2-8.39 (13H, m), 9.05 (lH, d, J=l.lHz), 9.48 (lH, d, J=1.8Hz), 9.60 (lH, d, J-2Hz), 10.3~ (lH, d, J=7.2Hz), 14.72 (lH, br s) MASS (m/e) : 504 (M -73), 424 ~5) (3RS)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-~2-quinoxalinylcarbonylamino)-5-[2-fluorophenyl)-2H-1,4-benzodiazepin-2-one hydrochloride ~
- mp : 205-220C (dec.) - -IR (Nujol~ : 3600-3050, 2700-2000, 1670, 1600 cm 1 NMR (DMSO-d6, ~ 5.25 (lH, d, J=16.1Hz), - 5.48 (lH, d, J=16.1Hz), 5.68 (lH, d, J=7.8~z), 7.18-B.35 (13H, m), 9.04 (lH, s), 9.53-9.61 (2H, m), 14.63 (lH, m) -; ~35 NASS (m~e) : 505 (M -36), 425 . ~ .
W092/01683 2 0 9 0 0 2 3 Pcr/JP9l/oo9s ' :
(6) (3RS)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-(4-cinnolinylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one dihydrochloride mp : 215-230C (dec.) -IR (Nujol) : 3600-3100, 2700-2103, 1660, 1610 cm 1 NMR (DMSO-d6, ~) : 5.21-5.72 (3H, m),
7.18-8.61 (13H, m), 9.01 (lH, s), 9.48 (lH, s), 10.46 (lH, d, J=7.1Hz), 14.61 (lH, br s) MASS (m/e) : 505 (M -73), 448 ~ ~ .
(7) (3RS)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-(1-isoauinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one dihydrochloride -mp : 209-220C (dec.) IR (Nujol) : 3600-3200, 2700-2100, 1670, 1610 cm 1 NMR (DMSO d6, 6) : 5.2-5.55 (2H, m), 5.67 (lH, d, J=7.7Hz), 7.23-~.19 (13H, m),
(7) (3RS)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-(1-isoauinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one dihydrochloride -mp : 209-220C (dec.) IR (Nujol) : 3600-3200, 2700-2100, 1670, 1610 cm 1 NMR (DMSO d6, 6) : 5.2-5.55 (2H, m), 5.67 (lH, d, J=7.7Hz), 7.23-~.19 (13H, m),
8.67 (lH, d, J=5.6Hz), 9.03 (lH, s),
9.19 tlH, d, J=8.4Hz), 9.9 (lH, d, J=7.7Hz), 14.62 tlH, br s) MASS (m/e) : 504 (M -73), 424 ~: .
(8) (3RS)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-nicotinoylamino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one dihydrochloride mp : ~220-235C (dec.) NMR (DMSO-d6, ~) : 5.21 (lH, d, J=16.1Hz), 5.45 (lH, d, J=16.1Hz~, 5.64 ~lH, d, J=7.2Hz), 7.2-8.0 (lH, m), 8.76-9.04 (2H, m), 9.32 (lH, --~ s), 10.32 (lH, d, J=7.2Hz), 14.67 (lH, br s) ~ - MASS.-(m/e) : 454 tM -73) .. .. : : . :, , -~ (9) 13RS)-1,3~Dihydro-1-(4-imidazolylmethyl)-3-(2-.
- naphthoylamino)-5-(2-fluorophen~l)-2H-1,4-~: :
.
WO 92/01683 2 0 9 0 0~ 2 3 PCT/JP91~0095 ~ _ - ~4 -benzodlazepin-2-one hydrochloride mp : 220-230c (dec.) IR ~Nujol) : 3600-3050, 2800-2000, 1690, 1660, 1610 cm 1 NMR (DMSO-d6, ~) : 5.22 (lH,;~, J=16Hz), 5.4~ (lH, d, J=16Hz), ~_70 (lH, d, J=7.4Hz), 7.19-8.1 (~5.H, m), 8.;~0 (lH, s), 9.03 (lH, s), - 9.78 (lH, d, J=7.4Xz), 14.61 (lH, br s) MASS tm/e) : 503 (M -37), 427
(8) (3RS)-1,3-Dihydro-1-(4-imidazolylmethyl)-3-nicotinoylamino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one dihydrochloride mp : ~220-235C (dec.) NMR (DMSO-d6, ~) : 5.21 (lH, d, J=16.1Hz), 5.45 (lH, d, J=16.1Hz~, 5.64 ~lH, d, J=7.2Hz), 7.2-8.0 (lH, m), 8.76-9.04 (2H, m), 9.32 (lH, --~ s), 10.32 (lH, d, J=7.2Hz), 14.67 (lH, br s) ~ - MASS.-(m/e) : 454 tM -73) .. .. : : . :, , -~ (9) 13RS)-1,3~Dihydro-1-(4-imidazolylmethyl)-3-(2-.
- naphthoylamino)-5-(2-fluorophen~l)-2H-1,4-~: :
.
WO 92/01683 2 0 9 0 0~ 2 3 PCT/JP91~0095 ~ _ - ~4 -benzodlazepin-2-one hydrochloride mp : 220-230c (dec.) IR ~Nujol) : 3600-3050, 2800-2000, 1690, 1660, 1610 cm 1 NMR (DMSO-d6, ~) : 5.22 (lH,;~, J=16Hz), 5.4~ (lH, d, J=16Hz), ~_70 (lH, d, J=7.4Hz), 7.19-8.1 (~5.H, m), 8.;~0 (lH, s), 9.03 (lH, s), - 9.78 (lH, d, J=7.4Xz), 14.61 (lH, br s) MASS tm/e) : 503 (M -37), 427
(10) (3RS)-1,3-Dihydro 1-(4-imidazolylmethyl)-3-[3-(3-methylphenyl)Ureido]-5-(2-fluorophenyl)-2H-l,d- ~ -benzodiazepin-2-one hydrochloride mp : 210-225C (dec.) IR (Nujol) : 3600-3050, 1680, 1610, 1555 cm 1 NMR (DMSO-d6, ~) : 2.24 (3H, s), 5.06 (2H, s), 5.26 (lH, d, J=8.4Hz), 6.74 (lH, d, J-6.6Hz), 6.87 (lH, s), 7.07-7.71 (l~H, m), 8.02 (lH, d, J=8.0Hz), 8.99 (lH, s) ExamPle 8 To a mixture o~ (3RS)-1,3-dihydro-3-(3-quinolyl-carbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (850 mg) and 1-trityl-4-(2-chloroethyl)imidazole monohydrochloride (900 mg) in N,N-dimethylformamide were added sodium hydride t60~ suspension in mineral oil, 180 mg~ and sodium iodide ~3.98 g) under stirring and cooling at 0C in an ice-salt bath in a stream of nitrogen. The mixture was stirred at room temperature for 1.5 hours and at 60-65C for 6 hours. Acetic acid (2 ml) was added to the reaction mixture. The resultant mixture was poured into a mixture of ethyl acetate (200 ml) and water ~200 ml) under stirring. The mixture was adjusted to pH 8 with ,`
an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water. The solvent was : ~ ' ' .: ' ,' 1 ~ ' WO92/01683 2 0 9 ~ 0 2 3 PCT/JP91/00952 removed under reduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The fractions containing the desired product were comsined and evaporated to afford an amorphous mass, which was dried under reduced pressure to give (3RS)-1,3-dihydro-1-[2-(1-tritylimidazol-4-yl~ethyl~-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one ~750 mg).
NMR (DMSO-d6, ~) : 2.49-2.65 ~2H, m), 3.8-4.6 (2H, m), ~.62 (1'~, d, J=7.48Hz), 6.70 ~lH, s), 7.00-8.1 (2~H, m),-9.05 (lH, s), 9.35 tlH, d, J=2.2Hz), 10.0 (lH, d, J=7.64Hz) Exam~le 9 To a solution of (3RS)-1,3-dihydro-3-(2-naphthoyl-amino)-5-t2-fluorophenyl) 2H-1,4-benzodiazepin-2-one (1.25 g) in N,N-dimethylformamide (31 ml~ was added sodium hydride (60% suspension in mineral oil, 130 mg) under stirring and cooling at 0C in an ice-salt bath in a stream of nitrogen. After the mixture was stlrred at room temperature for 45 minutes, a solution of chloroacetonitrile (270 mg) in N,N-dimethylformamide (5 ml) was added to the mixture at ~C under stirring. The `
resultant mixture was stirred overnight at room temperature. Acetic acid (0.5 g) was added to the reaction mixture. The resultant-mixture was poured into a mixture of ethyl acetate (200 ml) and water (300 ml) under stirring. The mixture was adjusted to pH 8 with an agueous solution of sodium bicarsonate. The separated - organic layer was washed with water. The solvent was removed u~der-reduced pressure to give amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.~ The fractions containing .~....
the desired product were com~ined and evaporated to afford an amorphous mass, which was dried under reduced pressure .
. .
,. ''. ,' ,: ,' .. ; .. . . . . , ', ' . ' , , . ' ~ . '. " " . .~ ' ' . ' WO92/01683 2 0 9 0 ~ 2 3 PCT/JP91/00952 to give (3RS)-1,3-dihydro-1-cyanomethyl-3-(2-naphthoyl-amino)-5-(2-fluorophenyl)-2H 1,4-benzodiazepin-2-one (1.19 g)-NMR (DMSO-d6, ~) : 5.08-5.3~ ~(2H, m), 5.74 (lH, d, J=7.65Hz), 7.25-7.~2 (14H, m), 8.71 (lH, s), 9.95 (lH, d, J=7.68Hz) Example 10 The following compounds we~e obtained according to similar manners to those of Examples 8 and 3.
(1) (3RS)-1,3-Dihydro-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-l-[llH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one mp : 284-285C
IR (Nujol~ : 3400, 1695, 1650, 1600, 1525 cm 1 NMR (DMSO-d6, ~ : 5.4-5.62 (2H, m), 5.76 (lH, d, J=7.74Hz), 7.23-7.39 (4H, m), 7.63-7.79 (4H, m), 7.86-7.93 (2H, m), 8.09-8.32 (2H, m), 9.05 (lH, s), 9.37 (1~, d, J=2.36Hz), 10.12 (lH, d, J=7.78Hz), lS.2-16.0 (lH, br s) MASS (m/e) : 507 ~M ), 424 (M -83) (2) ~3RS)-1,3-Dihydro-3-(3,4-dichlorobenzoylamino)-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one mp : 260-265C (dec.) IR (Nujol) : 3600, 3050, 1650, 1600 cm 1 NMR (DMSO-d6, ~) : 3.83 (lH, br s), 5.2-5.4 --- (2H, m~, 5.63 ~lH-, d, J=7.8Hz), 7.14-7.33 (5H, .- - --m), 7.55-7.67 (4H, m), 7.77 (lH,-d, J=8.4Hz), - 7.97--(2H; d, J=8.4Hz), E.?8 ~lr, d, J=l.9~z), 9.94 (lH, d, J=7.83~z) - NASS (m/e) : 524 (M ), 368 (M+-156) ¦ -~'.,.
' ', ' ,'; .'., "' "', ' ' ' '. ~ "., ' . ,~ "' ', ., ," ." ,' ', ' ' ~,`' ', ., '.', ', ' ' '... ' . '..., , , ,. '., ,... ' . ,', WO9~/01683 pCT/JP91/0095 (3) (3RS)-1,3-Dihydro-3-(2-indolylcarbonylamino)-5-(2-fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl~-2H-1,4-benzodiazepin-2-one mp : 280-290C (dec.) I~ (Nujol) : 3150, 1640, 1540 cm 1 NMR (DMSO-d6, ~) : 5.21-;.3 (2H, m), 5.69 (lH, d, J=8.14Hz), 7.02-7.66 (13H, m), 7.97 (lH, d, J=8.26Hz), 9.52 (lH, d, J=8.18Hz), 11.67 (lH, s) MASS (m/e) : 351 (M -144), 332 (M -162) 1 0 , .
(a) (3RS)-1,3-Dihydro-1-[2-(4-imidazolyl]ethyl]-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one mp : 165-175C (dec.) IR (Nujol) : 3600-3000, 1650, 1600 cm 1 (5) (3S)-3-(2-Indolylcarbonylamino)-1,3-dihydro-;-~2-fluorophenyl)-l-[(lH-tetxazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one NMR (DMSO-d6, ~) : 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 (lH, d, J-8.0Hz), 7.0-7.91 (14H, m), 9.60 (lH, d, J=8.0Hz), 11.65 (lH, s) -ExamPle 11 To a solution of (3RS)-1,3-dihydro-1-~2-(1-trityl- -imidazol-4-yl)ethyl~-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (740 mg) in N,N-dimethylformamide (7.4 ml) was added 6N-hydrochloric acid (5.18 ml) under stirring and cooling in an ice-bath.
The mixture was waxmed to 60-70C and stirred for one - hour. After cooling to room temperature, to-the-:reaction - mixture were added ice water and:ethyl acetate under -.stirrinc. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate-. The separated organic layer was washed with water and dried.
WO9~/01683 2 0 ~ ~ ~ 2 3 PCT/JP91/0095l - 48 - ~ :
The solvent was removed unde~ reduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.
The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in dlisopropyl ether. The precipitate was collec~ed by filtration, washed with diisopropyl ether a~d dried under reduced pressure to give (3RS)-1,3-dihydro-1-[2-(a-imidazolyl)-ethyl]-3-(3-quinolylcarbonylamino)-5-(2--luoro~henyl)-2H-1,4-benzodiazepin-2-one (0.2S g).
mp : 165-175C (dec.) IR (Nujol) : 3600-3000, 1650, 1600 cm ~
NMR (DMSO-d6, ~) : 2.52-2.66 (2H, m), 4.09-4.63 ~2H, m), 5.65 (lH, d, J=7.6Hz), 6.77 (lH, s), 7.24-8.32 (13H, m~, 9.07 (lH, d, J=1.92Hz), 9.39 (lH, d, J=2.2Hz), 10.11 (lH, d, J=7.:6Hz), 11.82 (lH, br s) MASS ~m/e) : 518 (M ) ExamPle 12 To a mixture of (3RS)-1,3-dihydro-3~(3,4-dichloro-benzoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepln-2-one (500 mg) and 1-trityl-4-(2-chloroethyl)imidazole ~5 monohydrochloride (295 mg) in N,N-dimethylformamide (7.5 ml) were added sodium hydride (60% suspensior. in mineral oil, 99.5 mg) and sodium iodide (2.25 g) under stirring and cooling at 0C in an ic~-salt bath in a stream of -nitrogen. After the mixture was stirred at room temperature for 1.5 hours and at 60-65C for 6 hours. To - the reaction-mixture were added acetic acid (l.l ml) and - -6N-hydrochloric acid (5 ml) and the:mixture was-stirred at ~ 60 70c for one hour. The resultant mixture was pourec into a mixture of ethyl~acetate (100 ml) and water (100 ml~ under stirring. The mixture was adjusted to pH 8 with _ WO92~01683 2 0 9 0 0 2 3 PCT/JP91/0095' an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. The solvent was remo~ed under reduced pressure to give an amorphous residue, which was purified by column ~ -chromato~raphy on silica gel with an eluent of chloroform.
The fractions containing the desired product were comDined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave (3RS)-1,3-dihydro-1-[2-(4-imidazolyl)ethyl]-3-(3,4-dichlorobenzoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one 10.18 g).
mp : 149-159C
IR (Nujol) : 3600-3100, 1650, 1600 cm 1 NMR (DMSO-d6, ~) : 2.5-2.59 ~2H, m), 3.95-4.62 (2H, m), 5.5 llH, d, J=7.52Hz), 6.77 ~lH, ~r s), 7.23-8.32 112H, m), 9.99 llH, br s), 11.8 llH, br s) MASS (m/e) : 386 (M -150) Exam~le 13 The following compounds were obtained according to a similar manner to that o~ Example 12.
l --~1) (3RS)-1,3-Dihydro-1-[2-(4-imidazolyl)ethyl~-3-(2-naphthoylamino)-5-(2-fluorophenyl)-2H-1,4- ;~
benzodiazepin-2-one mp : 198-205C (dec.) IR (Nujol) : 3275, 1680, 1630, 530 cm 1 :
NMR (DMSO-d6, ~) : 2.5-2.8 (2H,-m), 4.0-4.6 12H, m), ~ 5.65 (1H,- d, J=7.67Hz), 6.8I (lH, kr s), 7.24-8.09 (15H, m), 8.71 (lH, s), 9.78 llH, d, J=7.7lHz), 11.8 (lH, br s) MASS (m/e) : 518 (M+) i:; :
1 ' WO92/01683 2 0 9 0 0 2 3 50 _ PCT/JP91/00952 _ (2) ~3RS)-1,3-Dihydro-1-~2-(4-imidazolyl)ethyl]-3-(2-indolylcarbonylamino)-5-~2-fluorophenyl)-2H 1,4-benzodiazepin-2-one mp : 18~-205C (dec.) IR (Nujol) : 3550-3100, 1640, 1540 cm 1 NMR (DMSO-d6, ~) : 2.51-2.65 (2H,~m), ~.01-4.0~ (lH, m), 4.50-4.57 (lH, m), 5.6~ (~lH, d, J=7.gHz), 6.56 (lH, s), 6.76-7.81 (14H, m), 9.60 (lH, d, J=7.9Hz), 11.64 (lH, s), 11.81 ~lH, br s) Exam~le 14 (1) A mixture of (3RS)-1,3-dihydro-1-cyanomethyl-3-(2-naphthoylamino)-$-(2-fluorophenyl~-2H-1,4-benzodiazepin-2-one (1.15 g), sodium aæide (480 mg) and triethylamlne monohydrochloride (510 mg) in 1-methyl-2-pyrrolidi~one (20 ml) was stirred at 145C for 3.5 hours. The reaction mixture was poured into 5C hydrochloxic acid (100 ml) under stirring. The resultant precipitates were collected - by filtration, washed with wa~er and purified by column chromatography on silica gel with an eluent of chloroform. -The fractions containing the desired product were combined and evaporated t~ afford a~ amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing wi~h diisopropyl ether and drying under reduced pressure gave (3RS)-1,3-dihydro-3-(2-naphthoylamino)-5-~2-fluorophenyl)-l- E ~lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one ~540 mg).
mp : 265-275C (dec.) IR (Nujol~ : 3570-3100, 1650, 1490 cm 1 NMR (DMSO-d6, ~) : 5.33 (2H, s)j 5.73 ~lH, d, -- J=7.98Hz3, 7.18-8.09 (15H m), 3.69 (lH, s), v 9.72 (lH, d, J-8Hæ) MASS (m/e) : 505 IM ) :
: .
'' :, '~ :
~ WO92/01683 2 ~ 9 0 ~ 2 3 PCT/JP91/00952 The following compound was obtained according to a ~.
similar manner to that of Exi~mple 14(1).
~2) (3S)-3-(2-Indolylcarbonylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one NMR (DMSO-d6, ~ : 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 (lH, d, J=8.0Hz), 7.0-7.91 (14H, m), 9.60 (lH, d, J=8Hz), 11.65 ~lH, s) Exam~le 15 4-Chlorophenyl isocyanate (0.14 g) was added to 2 solution of (3RS~-3-amino-1,3-dihy~ro-5-phenyl-1-[(1-trityl-lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (0.50 g) in dry tetrahydroruran (10 mll at room temperature. After the mixture was stirred for 3 hours, . :
8.4N-ethanolic hydro~en chloride (1.5 ml) was added to the mixture at room temperature and then the mixture was stirred for 3 hours. The solvent was removed under reduced pressure. The residue was suspended with a , . mixture of ethanol and ethyl acetate and the resultant precipitate was collected by filtration to give (3RS)-1,3-~ :
dihydro-3-l3-(4-chlorophenyl~ureido)-5-phenyl-1-[(lY.- ~ :
tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one monohydrochloride (0.40 g).
mp : 205-208C
- IR (Nujol) :. 3325, 3250, 3190,. 2725, 1690, 1600, . 1545 cm 1 NMR (DMSO-d6, ~ 5.30-5.50 (lH, m), 5.46 (2H, ABq, J=17~z, 24Hz.), 7.20-7.85 (15H,. m), 9.0-11.0 (lH, ::
broad~, 9.42 ~lH, s) .-... ~., -ExamD le 16 .
The following compounds were obtained according to a :~ 35 similar manner to that of Example 15.
.
' . ,..,~, .~. .
WO92/01683 2 0 9 0 0 2 3 - 52 - PCT/JPgl/00952 ~1) (3RS)-1,3-Dihydro-3-[3-~4-chlorophenyl)ureido~-5-(2-(fluorophenyl)-l~[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one monohydrochloride mp : 203-205C
IR (Nujol) : 3320, 3250, 3190, 2720, 1695, 1605, 1525 cm-1 NMR (DMSO-d6, ~) : 5.30-5.40 (lH, m), 5.48 (2~, ABq, J=17Hz, 21Hz), 7.20-7.80 (13H, m), 8.0-10.5 (2H, broad), 9.37 (lH, s) (2) (3RS)-1,3-Dihydro-3-[3-~3-methylphenyl)ureido]-~-phenyl-l-[(lH-tetrazol-5-yl)methyl~-2H-1,4-benzodiazepin-2-one monohydrochloride -mp : 188-194C (dec.) IR (Nujol) : 3290, 2720, 2605, 1685, 1610, 1595, 1540 cm 1 NMR tDMSO-d6, ~) : 2.24 13H, s), 5.30-5.48 (lH, m), -5.46 (2H, ABq, J=17Hz, 25Hz), 6.70-6.80 (1~, m), 7.00-7.54 (12H, m), 7.70-7.80 (2H, m), 8.0-10.20 (2H, b~oad), 9.12 (lH, s) .
(3) (3RS)-1,3-Dihydro-5-(2-fluorophenyl)-3-[3-(3-methylphenyl)ureido]-l-~(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one monohydrochloride mp : 181-191C (dec.) ,~
IR (Nujol~ : 3300, 2710, 2610, 1690, 1595, 1550 cm 1 NMR ~DMS~-d6, ~) : 2.24 ~3H, s), 5.35-5.45 (lH, m), 5.48 (2H, ABq, J=llHz, 22H7), 6.70-6.78 (1~, m), 7.05-7.38-(7H, m), 7.50-7.81 (6H, m), 8.0-10.4 - (2H, broad),~ 9.`11 11H, s) .- , ~
Exam~le 17 To a solution o~ ~3S)-1,3-dihydro-1-[(1- --~ tritylimidazol-4-yl)methyl]-3-(3,4-dichlorohenzoylamino)-i5 5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2 one (20.34 g) in W092/01683 2 0 9 ~ 0 2 3 PCT/JP91/00952 N,N-dimethylformamide (204 ml) was added 6N-hydrochloric acid (157 ml) under stirring and cooling in an ice-bath.
The mixture was warmed to 70-80C and stirred for 1 hour.
After cooling to room temperature, to the reaction mixture were added ice water and ethyl acetate under stirring.
The mixture was a~justed to pH 8.0 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. The solvent was removed under reduced pressure to give an amorphous : -residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The Irac.ions containing the desired product were combined and evaporated to afford an amorphous mass, which was dried under reduced pressure to give (3S)-1,3-dihydro-1-(4-imidazolylmethyl)-3-(3,4-dichlorobenzoylamino)-5-(2-fluoropheny~)-2H-1,4-benzodiazepin-2-one. This was dissolved in chloroform (200 ml~ and to the resultant solution was added 20%-hydrogen chloride in ethanol (50 ml) under cooling. The clear yellow solution was evaporated to dryness under reduced pressure to give an amorphous mass, which was lyophirized to give (3S)-1,3-dihydro-l-(4-imidazolylmethyl)-3 (3,4-dichlorobenzoyl-amino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one hydrochloride as yellow powder (12.97 g).
IR ~CHC13) : 3000, 2900-2200, 1660, 1600, 1500 cm 1 NMR (DMSO-d6, ~) : 5.19 (lH, d, J=16Hz), 5.43 (lH, d, J=16Hz), 5.61 tlH, d, J=7.3Hz), 7.19-7.39 (SH, m), 7.56-7.82 (5H, m?, 7.95-8.00 (lH, m), : 8.30 (lH,-d, J=1.9Hz), 9~01 ~lH, s), 9.99 (lH, d, J=7.3Hz~, 14.6 (lH, br s) MASS (m/e) : 521 (M+-37) t ~30 = -24.75 (C=0.832 ! CH3OH) .. . . . . ........... . . . . . . ~ . . : . _ Example 18 `
To a suspension of 2-indolecarboxylic acid (161.2 mg) ... -. I
j.
WO92/01683 2 0 ~ O 0 2 3 - 54 ~ PCT/JP91/00952 in methylene chloride (3.25 ml) was added thionyl chloride (119.0 mg) and one drop of N,N-dimethylformamide under stirring at ambient temperature. The mixture was re.luxed for 1 hour with stirring. To a solution of (3S)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl] 2H-1,4-benzodiazepin-2-one hydrochloride (387.8 mg) and triethylamine (506.0 mg) in methylene chloride (8 ml) was added dropwise the solution of 2-indolylcarbonyl chloride in methylene chloride obtained above under ice-cooling and stirring. The mixture was stirred under the same conditions for 3 hours. ~-To the reaction mixture was added chloroform. The mixture was washed with diluted hydrochloric acid and water successively and dried over magnesium sulfate. Removal of the solvent in vacuo afforded an amorphous mass, which was suspe~ded with stirring in diisopropyl ether. The resultant powder was collected ~y filtration, washed with diisopropyl ether and dried under reduced pressure to give (3S)-3-~2-indolylcarbonylamino)-1,3-dihydro-5-(2- ;
fluorophenyl)-1-[~lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one.
mp : 270-271C (dec.) [~28 5 = -18.87 ~C=0.62, tetrahydrofuran) NMR ~DMSO-d6, ~) : 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 (lH, d, J=8.0Hz), 7.0-7.91 (14H, m), 9.60 (lH, d, J=8.0Hz), 11.65 (lH, s) :~
MASS (m/e) : 494 (M ) ., Example_19 30 ~ the following compound was obtained according to a similar manner to that of Example 18.
(3R)-3-(2-Indolylcar~onylamino)-1,3-dihydro-5-(2-fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodlazepin 2-one ~-J::~ i ' ' I
~WO92/01683 2 0 9 ~ 0 2 3 PCT/JP91/00952 mp : 270-271C (dec~) ~28.5 : +18.72 (C=0.625, tetrahydrofuran) NMR (DMSO-d6, ~) : 5.49 (2H, ABq, J=16.3Hz, 24.7Hz), i.73 (lH, d, J=8.0Hz), 7.0-7.91 (14H, m), 9.60 (lH, d, J=8.0Hz), 11.65 (lH, s) MASS (m/e) : 494 (M ) Example 20 The f o~lowing com~ounds were obtained according to a :
similar manner to tha, of Example 1.
(1) (35)-1,3-Dihydro-l-[(1-tritylimidazol--4-yl)methyl3- - -3~(3,4-dichlorobenzoylamino~-5-(2-~luorophenyl)-2H- ~
1,4-benzodiazepin-2-one NMR (CDC13, ~) : 5.02 (lH, d, J=15Hz), 5.11 (lH, d, J=15Hz), 5.67 (lH, d, J.-7.8Hz), -6.84-8.~4 (29H, m) ~2) t3Rs)-l~3-Dihydro-l-~2-(4-imidazolyl)ethyl~-3-(3 quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one mp : 165-175C (dec.) IR ~Nujol) : 3600-3000, 1650, 1600 cm 1 Example 21 The foll~wi~g compound was obtained according to a similar manner to that of Example 11.
~3S)-3-~2-Thdolylcarbonylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one .
NMR (DMSO-d6, ~) : S.49 (2H, ABq, J=16.4Hz, 2~.8Hz), . . .
. -. J~r 5.73 ~lH, d, J=8.0Hz), ?.0-7.91 (14H, m), r~.60 (lH, d, J=8.0Hz), 11.65 (lH, s) , ., ~ . .
.:: - : ~ . . , :
an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water. The solvent was : ~ ' ' .: ' ,' 1 ~ ' WO92/01683 2 0 9 ~ 0 2 3 PCT/JP91/00952 removed under reduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The fractions containing the desired product were comsined and evaporated to afford an amorphous mass, which was dried under reduced pressure to give (3RS)-1,3-dihydro-1-[2-(1-tritylimidazol-4-yl~ethyl~-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one ~750 mg).
NMR (DMSO-d6, ~) : 2.49-2.65 ~2H, m), 3.8-4.6 (2H, m), ~.62 (1'~, d, J=7.48Hz), 6.70 ~lH, s), 7.00-8.1 (2~H, m),-9.05 (lH, s), 9.35 tlH, d, J=2.2Hz), 10.0 (lH, d, J=7.64Hz) Exam~le 9 To a solution of (3RS)-1,3-dihydro-3-(2-naphthoyl-amino)-5-t2-fluorophenyl) 2H-1,4-benzodiazepin-2-one (1.25 g) in N,N-dimethylformamide (31 ml~ was added sodium hydride (60% suspension in mineral oil, 130 mg) under stirring and cooling at 0C in an ice-salt bath in a stream of nitrogen. After the mixture was stlrred at room temperature for 45 minutes, a solution of chloroacetonitrile (270 mg) in N,N-dimethylformamide (5 ml) was added to the mixture at ~C under stirring. The `
resultant mixture was stirred overnight at room temperature. Acetic acid (0.5 g) was added to the reaction mixture. The resultant-mixture was poured into a mixture of ethyl acetate (200 ml) and water (300 ml) under stirring. The mixture was adjusted to pH 8 with an agueous solution of sodium bicarsonate. The separated - organic layer was washed with water. The solvent was removed u~der-reduced pressure to give amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.~ The fractions containing .~....
the desired product were com~ined and evaporated to afford an amorphous mass, which was dried under reduced pressure .
. .
,. ''. ,' ,: ,' .. ; .. . . . . , ', ' . ' , , . ' ~ . '. " " . .~ ' ' . ' WO92/01683 2 0 9 0 ~ 2 3 PCT/JP91/00952 to give (3RS)-1,3-dihydro-1-cyanomethyl-3-(2-naphthoyl-amino)-5-(2-fluorophenyl)-2H 1,4-benzodiazepin-2-one (1.19 g)-NMR (DMSO-d6, ~) : 5.08-5.3~ ~(2H, m), 5.74 (lH, d, J=7.65Hz), 7.25-7.~2 (14H, m), 8.71 (lH, s), 9.95 (lH, d, J=7.68Hz) Example 10 The following compounds we~e obtained according to similar manners to those of Examples 8 and 3.
(1) (3RS)-1,3-Dihydro-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-l-[llH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one mp : 284-285C
IR (Nujol~ : 3400, 1695, 1650, 1600, 1525 cm 1 NMR (DMSO-d6, ~ : 5.4-5.62 (2H, m), 5.76 (lH, d, J=7.74Hz), 7.23-7.39 (4H, m), 7.63-7.79 (4H, m), 7.86-7.93 (2H, m), 8.09-8.32 (2H, m), 9.05 (lH, s), 9.37 (1~, d, J=2.36Hz), 10.12 (lH, d, J=7.78Hz), lS.2-16.0 (lH, br s) MASS (m/e) : 507 ~M ), 424 (M -83) (2) ~3RS)-1,3-Dihydro-3-(3,4-dichlorobenzoylamino)-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one mp : 260-265C (dec.) IR (Nujol) : 3600, 3050, 1650, 1600 cm 1 NMR (DMSO-d6, ~) : 3.83 (lH, br s), 5.2-5.4 --- (2H, m~, 5.63 ~lH-, d, J=7.8Hz), 7.14-7.33 (5H, .- - --m), 7.55-7.67 (4H, m), 7.77 (lH,-d, J=8.4Hz), - 7.97--(2H; d, J=8.4Hz), E.?8 ~lr, d, J=l.9~z), 9.94 (lH, d, J=7.83~z) - NASS (m/e) : 524 (M ), 368 (M+-156) ¦ -~'.,.
' ', ' ,'; .'., "' "', ' ' ' '. ~ "., ' . ,~ "' ', ., ," ." ,' ', ' ' ~,`' ', ., '.', ', ' ' '... ' . '..., , , ,. '., ,... ' . ,', WO9~/01683 pCT/JP91/0095 (3) (3RS)-1,3-Dihydro-3-(2-indolylcarbonylamino)-5-(2-fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl~-2H-1,4-benzodiazepin-2-one mp : 280-290C (dec.) I~ (Nujol) : 3150, 1640, 1540 cm 1 NMR (DMSO-d6, ~) : 5.21-;.3 (2H, m), 5.69 (lH, d, J=8.14Hz), 7.02-7.66 (13H, m), 7.97 (lH, d, J=8.26Hz), 9.52 (lH, d, J=8.18Hz), 11.67 (lH, s) MASS (m/e) : 351 (M -144), 332 (M -162) 1 0 , .
(a) (3RS)-1,3-Dihydro-1-[2-(4-imidazolyl]ethyl]-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one mp : 165-175C (dec.) IR (Nujol) : 3600-3000, 1650, 1600 cm 1 (5) (3S)-3-(2-Indolylcarbonylamino)-1,3-dihydro-;-~2-fluorophenyl)-l-[(lH-tetxazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one NMR (DMSO-d6, ~) : 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 (lH, d, J-8.0Hz), 7.0-7.91 (14H, m), 9.60 (lH, d, J=8.0Hz), 11.65 (lH, s) -ExamPle 11 To a solution of (3RS)-1,3-dihydro-1-~2-(1-trityl- -imidazol-4-yl)ethyl~-3-(3-quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (740 mg) in N,N-dimethylformamide (7.4 ml) was added 6N-hydrochloric acid (5.18 ml) under stirring and cooling in an ice-bath.
The mixture was waxmed to 60-70C and stirred for one - hour. After cooling to room temperature, to-the-:reaction - mixture were added ice water and:ethyl acetate under -.stirrinc. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate-. The separated organic layer was washed with water and dried.
WO9~/01683 2 0 ~ ~ ~ 2 3 PCT/JP91/0095l - 48 - ~ :
The solvent was removed unde~ reduced pressure to give an amorphous residue, which was purified by column chromatography on silica gel with an eluent of chloroform.
The fractions containing the desired product were combined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in dlisopropyl ether. The precipitate was collec~ed by filtration, washed with diisopropyl ether a~d dried under reduced pressure to give (3RS)-1,3-dihydro-1-[2-(a-imidazolyl)-ethyl]-3-(3-quinolylcarbonylamino)-5-(2--luoro~henyl)-2H-1,4-benzodiazepin-2-one (0.2S g).
mp : 165-175C (dec.) IR (Nujol) : 3600-3000, 1650, 1600 cm ~
NMR (DMSO-d6, ~) : 2.52-2.66 (2H, m), 4.09-4.63 ~2H, m), 5.65 (lH, d, J=7.6Hz), 6.77 (lH, s), 7.24-8.32 (13H, m~, 9.07 (lH, d, J=1.92Hz), 9.39 (lH, d, J=2.2Hz), 10.11 (lH, d, J=7.:6Hz), 11.82 (lH, br s) MASS ~m/e) : 518 (M ) ExamPle 12 To a mixture of (3RS)-1,3-dihydro-3~(3,4-dichloro-benzoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepln-2-one (500 mg) and 1-trityl-4-(2-chloroethyl)imidazole ~5 monohydrochloride (295 mg) in N,N-dimethylformamide (7.5 ml) were added sodium hydride (60% suspensior. in mineral oil, 99.5 mg) and sodium iodide (2.25 g) under stirring and cooling at 0C in an ic~-salt bath in a stream of -nitrogen. After the mixture was stirred at room temperature for 1.5 hours and at 60-65C for 6 hours. To - the reaction-mixture were added acetic acid (l.l ml) and - -6N-hydrochloric acid (5 ml) and the:mixture was-stirred at ~ 60 70c for one hour. The resultant mixture was pourec into a mixture of ethyl~acetate (100 ml) and water (100 ml~ under stirring. The mixture was adjusted to pH 8 with _ WO92~01683 2 0 9 0 0 2 3 PCT/JP91/0095' an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. The solvent was remo~ed under reduced pressure to give an amorphous residue, which was purified by column ~ -chromato~raphy on silica gel with an eluent of chloroform.
The fractions containing the desired product were comDined and evaporated to afford an amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing with diisopropyl ether and drying under reduced pressure gave (3RS)-1,3-dihydro-1-[2-(4-imidazolyl)ethyl]-3-(3,4-dichlorobenzoylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one 10.18 g).
mp : 149-159C
IR (Nujol) : 3600-3100, 1650, 1600 cm 1 NMR (DMSO-d6, ~) : 2.5-2.59 ~2H, m), 3.95-4.62 (2H, m), 5.5 llH, d, J=7.52Hz), 6.77 ~lH, ~r s), 7.23-8.32 112H, m), 9.99 llH, br s), 11.8 llH, br s) MASS (m/e) : 386 (M -150) Exam~le 13 The following compounds were obtained according to a similar manner to that o~ Example 12.
l --~1) (3RS)-1,3-Dihydro-1-[2-(4-imidazolyl)ethyl~-3-(2-naphthoylamino)-5-(2-fluorophenyl)-2H-1,4- ;~
benzodiazepin-2-one mp : 198-205C (dec.) IR (Nujol) : 3275, 1680, 1630, 530 cm 1 :
NMR (DMSO-d6, ~) : 2.5-2.8 (2H,-m), 4.0-4.6 12H, m), ~ 5.65 (1H,- d, J=7.67Hz), 6.8I (lH, kr s), 7.24-8.09 (15H, m), 8.71 (lH, s), 9.78 llH, d, J=7.7lHz), 11.8 (lH, br s) MASS (m/e) : 518 (M+) i:; :
1 ' WO92/01683 2 0 9 0 0 2 3 50 _ PCT/JP91/00952 _ (2) ~3RS)-1,3-Dihydro-1-~2-(4-imidazolyl)ethyl]-3-(2-indolylcarbonylamino)-5-~2-fluorophenyl)-2H 1,4-benzodiazepin-2-one mp : 18~-205C (dec.) IR (Nujol) : 3550-3100, 1640, 1540 cm 1 NMR (DMSO-d6, ~) : 2.51-2.65 (2H,~m), ~.01-4.0~ (lH, m), 4.50-4.57 (lH, m), 5.6~ (~lH, d, J=7.gHz), 6.56 (lH, s), 6.76-7.81 (14H, m), 9.60 (lH, d, J=7.9Hz), 11.64 (lH, s), 11.81 ~lH, br s) Exam~le 14 (1) A mixture of (3RS)-1,3-dihydro-1-cyanomethyl-3-(2-naphthoylamino)-$-(2-fluorophenyl~-2H-1,4-benzodiazepin-2-one (1.15 g), sodium aæide (480 mg) and triethylamlne monohydrochloride (510 mg) in 1-methyl-2-pyrrolidi~one (20 ml) was stirred at 145C for 3.5 hours. The reaction mixture was poured into 5C hydrochloxic acid (100 ml) under stirring. The resultant precipitates were collected - by filtration, washed with wa~er and purified by column chromatography on silica gel with an eluent of chloroform. -The fractions containing the desired product were combined and evaporated t~ afford a~ amorphous mass, which was pulverized and stirred for several hours in diisopropyl ether. Collection by filtration, washing wi~h diisopropyl ether and drying under reduced pressure gave (3RS)-1,3-dihydro-3-(2-naphthoylamino)-5-~2-fluorophenyl)-l- E ~lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one ~540 mg).
mp : 265-275C (dec.) IR (Nujol~ : 3570-3100, 1650, 1490 cm 1 NMR (DMSO-d6, ~) : 5.33 (2H, s)j 5.73 ~lH, d, -- J=7.98Hz3, 7.18-8.09 (15H m), 3.69 (lH, s), v 9.72 (lH, d, J-8Hæ) MASS (m/e) : 505 IM ) :
: .
'' :, '~ :
~ WO92/01683 2 ~ 9 0 ~ 2 3 PCT/JP91/00952 The following compound was obtained according to a ~.
similar manner to that of Exi~mple 14(1).
~2) (3S)-3-(2-Indolylcarbonylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one NMR (DMSO-d6, ~ : 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 (lH, d, J=8.0Hz), 7.0-7.91 (14H, m), 9.60 (lH, d, J=8Hz), 11.65 ~lH, s) Exam~le 15 4-Chlorophenyl isocyanate (0.14 g) was added to 2 solution of (3RS~-3-amino-1,3-dihy~ro-5-phenyl-1-[(1-trityl-lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (0.50 g) in dry tetrahydroruran (10 mll at room temperature. After the mixture was stirred for 3 hours, . :
8.4N-ethanolic hydro~en chloride (1.5 ml) was added to the mixture at room temperature and then the mixture was stirred for 3 hours. The solvent was removed under reduced pressure. The residue was suspended with a , . mixture of ethanol and ethyl acetate and the resultant precipitate was collected by filtration to give (3RS)-1,3-~ :
dihydro-3-l3-(4-chlorophenyl~ureido)-5-phenyl-1-[(lY.- ~ :
tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one monohydrochloride (0.40 g).
mp : 205-208C
- IR (Nujol) :. 3325, 3250, 3190,. 2725, 1690, 1600, . 1545 cm 1 NMR (DMSO-d6, ~ 5.30-5.50 (lH, m), 5.46 (2H, ABq, J=17~z, 24Hz.), 7.20-7.85 (15H,. m), 9.0-11.0 (lH, ::
broad~, 9.42 ~lH, s) .-... ~., -ExamD le 16 .
The following compounds were obtained according to a :~ 35 similar manner to that of Example 15.
.
' . ,..,~, .~. .
WO92/01683 2 0 9 0 0 2 3 - 52 - PCT/JPgl/00952 ~1) (3RS)-1,3-Dihydro-3-[3-~4-chlorophenyl)ureido~-5-(2-(fluorophenyl)-l~[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one monohydrochloride mp : 203-205C
IR (Nujol) : 3320, 3250, 3190, 2720, 1695, 1605, 1525 cm-1 NMR (DMSO-d6, ~) : 5.30-5.40 (lH, m), 5.48 (2~, ABq, J=17Hz, 21Hz), 7.20-7.80 (13H, m), 8.0-10.5 (2H, broad), 9.37 (lH, s) (2) (3RS)-1,3-Dihydro-3-[3-~3-methylphenyl)ureido]-~-phenyl-l-[(lH-tetrazol-5-yl)methyl~-2H-1,4-benzodiazepin-2-one monohydrochloride -mp : 188-194C (dec.) IR (Nujol) : 3290, 2720, 2605, 1685, 1610, 1595, 1540 cm 1 NMR tDMSO-d6, ~) : 2.24 13H, s), 5.30-5.48 (lH, m), -5.46 (2H, ABq, J=17Hz, 25Hz), 6.70-6.80 (1~, m), 7.00-7.54 (12H, m), 7.70-7.80 (2H, m), 8.0-10.20 (2H, b~oad), 9.12 (lH, s) .
(3) (3RS)-1,3-Dihydro-5-(2-fluorophenyl)-3-[3-(3-methylphenyl)ureido]-l-~(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one monohydrochloride mp : 181-191C (dec.) ,~
IR (Nujol~ : 3300, 2710, 2610, 1690, 1595, 1550 cm 1 NMR ~DMS~-d6, ~) : 2.24 ~3H, s), 5.35-5.45 (lH, m), 5.48 (2H, ABq, J=llHz, 22H7), 6.70-6.78 (1~, m), 7.05-7.38-(7H, m), 7.50-7.81 (6H, m), 8.0-10.4 - (2H, broad),~ 9.`11 11H, s) .- , ~
Exam~le 17 To a solution o~ ~3S)-1,3-dihydro-1-[(1- --~ tritylimidazol-4-yl)methyl]-3-(3,4-dichlorohenzoylamino)-i5 5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2 one (20.34 g) in W092/01683 2 0 9 ~ 0 2 3 PCT/JP91/00952 N,N-dimethylformamide (204 ml) was added 6N-hydrochloric acid (157 ml) under stirring and cooling in an ice-bath.
The mixture was warmed to 70-80C and stirred for 1 hour.
After cooling to room temperature, to the reaction mixture were added ice water and ethyl acetate under stirring.
The mixture was a~justed to pH 8.0 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water and dried. The solvent was removed under reduced pressure to give an amorphous : -residue, which was purified by column chromatography on silica gel with an eluent of chloroform. The Irac.ions containing the desired product were combined and evaporated to afford an amorphous mass, which was dried under reduced pressure to give (3S)-1,3-dihydro-1-(4-imidazolylmethyl)-3-(3,4-dichlorobenzoylamino)-5-(2-fluoropheny~)-2H-1,4-benzodiazepin-2-one. This was dissolved in chloroform (200 ml~ and to the resultant solution was added 20%-hydrogen chloride in ethanol (50 ml) under cooling. The clear yellow solution was evaporated to dryness under reduced pressure to give an amorphous mass, which was lyophirized to give (3S)-1,3-dihydro-l-(4-imidazolylmethyl)-3 (3,4-dichlorobenzoyl-amino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one hydrochloride as yellow powder (12.97 g).
IR ~CHC13) : 3000, 2900-2200, 1660, 1600, 1500 cm 1 NMR (DMSO-d6, ~) : 5.19 (lH, d, J=16Hz), 5.43 (lH, d, J=16Hz), 5.61 tlH, d, J=7.3Hz), 7.19-7.39 (SH, m), 7.56-7.82 (5H, m?, 7.95-8.00 (lH, m), : 8.30 (lH,-d, J=1.9Hz), 9~01 ~lH, s), 9.99 (lH, d, J=7.3Hz~, 14.6 (lH, br s) MASS (m/e) : 521 (M+-37) t ~30 = -24.75 (C=0.832 ! CH3OH) .. . . . . ........... . . . . . . ~ . . : . _ Example 18 `
To a suspension of 2-indolecarboxylic acid (161.2 mg) ... -. I
j.
WO92/01683 2 0 ~ O 0 2 3 - 54 ~ PCT/JP91/00952 in methylene chloride (3.25 ml) was added thionyl chloride (119.0 mg) and one drop of N,N-dimethylformamide under stirring at ambient temperature. The mixture was re.luxed for 1 hour with stirring. To a solution of (3S)-3-amino-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl] 2H-1,4-benzodiazepin-2-one hydrochloride (387.8 mg) and triethylamine (506.0 mg) in methylene chloride (8 ml) was added dropwise the solution of 2-indolylcarbonyl chloride in methylene chloride obtained above under ice-cooling and stirring. The mixture was stirred under the same conditions for 3 hours. ~-To the reaction mixture was added chloroform. The mixture was washed with diluted hydrochloric acid and water successively and dried over magnesium sulfate. Removal of the solvent in vacuo afforded an amorphous mass, which was suspe~ded with stirring in diisopropyl ether. The resultant powder was collected ~y filtration, washed with diisopropyl ether and dried under reduced pressure to give (3S)-3-~2-indolylcarbonylamino)-1,3-dihydro-5-(2- ;
fluorophenyl)-1-[~lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one.
mp : 270-271C (dec.) [~28 5 = -18.87 ~C=0.62, tetrahydrofuran) NMR ~DMSO-d6, ~) : 5.49 (2H, ABq, J=16.4Hz, 24.8Hz), 5.73 (lH, d, J=8.0Hz), 7.0-7.91 (14H, m), 9.60 (lH, d, J=8.0Hz), 11.65 (lH, s) :~
MASS (m/e) : 494 (M ) ., Example_19 30 ~ the following compound was obtained according to a similar manner to that of Example 18.
(3R)-3-(2-Indolylcar~onylamino)-1,3-dihydro-5-(2-fluorophenyl)-l-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodlazepin 2-one ~-J::~ i ' ' I
~WO92/01683 2 0 9 ~ 0 2 3 PCT/JP91/00952 mp : 270-271C (dec~) ~28.5 : +18.72 (C=0.625, tetrahydrofuran) NMR (DMSO-d6, ~) : 5.49 (2H, ABq, J=16.3Hz, 24.7Hz), i.73 (lH, d, J=8.0Hz), 7.0-7.91 (14H, m), 9.60 (lH, d, J=8.0Hz), 11.65 (lH, s) MASS (m/e) : 494 (M ) Example 20 The f o~lowing com~ounds were obtained according to a :
similar manner to tha, of Example 1.
(1) (35)-1,3-Dihydro-l-[(1-tritylimidazol--4-yl)methyl3- - -3~(3,4-dichlorobenzoylamino~-5-(2-~luorophenyl)-2H- ~
1,4-benzodiazepin-2-one NMR (CDC13, ~) : 5.02 (lH, d, J=15Hz), 5.11 (lH, d, J=15Hz), 5.67 (lH, d, J.-7.8Hz), -6.84-8.~4 (29H, m) ~2) t3Rs)-l~3-Dihydro-l-~2-(4-imidazolyl)ethyl~-3-(3 quinolylcarbonylamino)-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one mp : 165-175C (dec.) IR ~Nujol) : 3600-3000, 1650, 1600 cm 1 Example 21 The foll~wi~g compound was obtained according to a similar manner to that of Example 11.
~3S)-3-~2-Thdolylcarbonylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-[(lH-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one .
NMR (DMSO-d6, ~) : S.49 (2H, ABq, J=16.4Hz, 2~.8Hz), . . .
. -. J~r 5.73 ~lH, d, J=8.0Hz), ?.0-7.91 (14H, m), r~.60 (lH, d, J=8.0Hz), 11.65 (lH, s) , ., ~ . .
.:: - : ~ . . , :
Claims (12)
1. A compound of the formula :
wherein R1 is heterocyclic group which may have one or more suitable substituent(s), or cyano, R2 is hydrogen or halogen, R3 is aryl which may have one or more suitable substituent(s), R4 is aryl which may have one or more suitable substituent(s), ar(lower)alkenyl which may have one or more suitable substituent(s), arylamino which may have one or more suitable substituent(s), heteromonocyclic group which may have one or more suitable substituent(s), quinolyl, isoquinolyl, cinnolinyl, indolyl, or quinoxalinyl, and A is lower alkylene, with proviso that when R4 is indolyl, then (i) R1 is tetrazolyl which may have one or more suitable substituent(s) and R3 is halophenyl or (ii) R1 is imidazolyl which may have one or more suitable substituent(s), R3 is halophenyl and A is ethylene, and a pharmaceutically acceptable salt thereof.
wherein R1 is heterocyclic group which may have one or more suitable substituent(s), or cyano, R2 is hydrogen or halogen, R3 is aryl which may have one or more suitable substituent(s), R4 is aryl which may have one or more suitable substituent(s), ar(lower)alkenyl which may have one or more suitable substituent(s), arylamino which may have one or more suitable substituent(s), heteromonocyclic group which may have one or more suitable substituent(s), quinolyl, isoquinolyl, cinnolinyl, indolyl, or quinoxalinyl, and A is lower alkylene, with proviso that when R4 is indolyl, then (i) R1 is tetrazolyl which may have one or more suitable substituent(s) and R3 is halophenyl or (ii) R1 is imidazolyl which may have one or more suitable substituent(s), R3 is halophenyl and A is ethylene, and a pharmaceutically acceptable salt thereof.
2. A compound of claim 1, wherein R1 is tetrazolyl which may have an imino protective group, imidazolyl which may have an imino protective group, or cyano, R3 is phenyl or halophenyl, R4 is phenyl or naphthyl, each of which may have one or two substituent(s) selected from the group consisting of halogen and amino;
phenyl(lower)alkenyl which may have amino or nitro; phenylamino which may have lower alkyl or halogen; pyridyl; tetrahydropyridazinyl which may have an oxo group; quinolyl; isoquinolyl;
cinnolinyl; indolyl; or quinoxalinyl.
phenyl(lower)alkenyl which may have amino or nitro; phenylamino which may have lower alkyl or halogen; pyridyl; tetrahydropyridazinyl which may have an oxo group; quinolyl; isoquinolyl;
cinnolinyl; indolyl; or quinoxalinyl.
3. A compound of claim 2, wherein R1 is tetrazolyl which may have mono(or di or tri)-phenyl(lower)alkyl, imidazolyl which may have mono(or di or tri)phenyl(lower)alkyl, or cyano, R4 is naphthyl; dihalophenyl; phenyl having halogen and amino; nitrophenyl(lower)alkenyl;
aminophenyl(lower)alkenyl; lower-alkylphenylamino; halophenylamino; pyridyl;
tetrahydropyridazinyl having an oxo group;
quinolyl; isoquinolyl; cinnolinyl; indolyl; or quinoxalinyl.
aminophenyl(lower)alkenyl; lower-alkylphenylamino; halophenylamino; pyridyl;
tetrahydropyridazinyl having an oxo group;
quinolyl; isoquinolyl; cinnolinyl; indolyl; or quinoxalinyl.
4. A compound of claim 3, wherein R1 is tetrazolyl, R2 is hydrogen, R3 is halophenyl, R4 is indolyl and A is C1-C4 alkylene.
5. A compound of claim 4, which is (3S)-3-(2-indolylcarbonylamino)-1,3-dihydro-5-(2-fluorophenyl)-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one
6. A process for preparing a compound of the formula :
wherein R1 is heterocyclic group which may have one or more suitable substituent(s), or cyano, R2 is hydrogen or halogen, R3 is aryl which may have one or more suitable substituent(s), R4 is aryl which may have one or more suitable substituent(s), ar(lower)alkenyl which may have one or more suitable substituent(s), arylamino which may have one or more suitable substituent(s), heteromonocyclic group which may have one or more suitable substituent(s), quinolyl, isoquinolyl, cinnolinyl, indolyl, or quinoxalinyl, and A is lower alkylene, with proviso that when R4 is indolyl, then (i) R1 is tetrazolyl which may have one or more suitable substituent(s) and R3 is halophenyl or (ii) R1 is imidazolyl which may have one or more suitable substituent(s), R3 is halophenyl and A is ethylene, or a salt thereof, which comprises (1) reacting a compound of the formula :
wherein R1, R2, R3 and A are each as defined above, or its reactive derivative at the amino group, or a salt thereof with a compound of the formula :
wherein R4 is as defined above, or its reactive derivative or a salt thereof to give a compound of the formula :
wherein R1, R2, R3, R4 and A are each as defined above, or a salt thereof, or 2) subjecting a compound of the formula :
wherein R2, R3, R4 and A are each as defined above, and R? is heterocyclic group having a protected imino group of the formula :
(in which R6 is imino protective group) in its hetero ring, which may have one or more suitable substituent(s), or a salt thereof to elimination reaction of the imino protective group to give a compound of the formula :
wherein R2, R3, R4 and A are each as defined above, and R? is heterocyclic group having an imino group of the formula : in its hetero ring, which may have one or more suitable substituent(s), or a salt thereof, or (3) subjecting a compound of the formula :
wherein R1, R2, R3 and A are each as defined above, and R? is ar(lower)alkenyl having a nitro group, or a salt thereof to give a compound of the formula :
wherein R1, R2, R3 and A are each as defined above, and R? is ar(lower)alkenyl having an amino group, or a salt thereof, or (4) reacting a compound of the formula :
wherein R2, R3 and R4 are each as defined above, or a salt thereof with a compound of the formula :
wherein R1 and A are each as defined above, and X is an acid residue, or a salt thereof to give a compound of the formula :
wherein R1, R2, R3, R4 and A are each as defined above, or a salt thereof, or (5) reacting a compound of the formula :
wherein R2, R3, R4 and A are each as defined above, or a salt thereof with a compound of the formula :
or a salt thereof to give a compound of the formula :
wherein R2, R3, R4 and A are each as defined above, or a salt thereof.
wherein R1 is heterocyclic group which may have one or more suitable substituent(s), or cyano, R2 is hydrogen or halogen, R3 is aryl which may have one or more suitable substituent(s), R4 is aryl which may have one or more suitable substituent(s), ar(lower)alkenyl which may have one or more suitable substituent(s), arylamino which may have one or more suitable substituent(s), heteromonocyclic group which may have one or more suitable substituent(s), quinolyl, isoquinolyl, cinnolinyl, indolyl, or quinoxalinyl, and A is lower alkylene, with proviso that when R4 is indolyl, then (i) R1 is tetrazolyl which may have one or more suitable substituent(s) and R3 is halophenyl or (ii) R1 is imidazolyl which may have one or more suitable substituent(s), R3 is halophenyl and A is ethylene, or a salt thereof, which comprises (1) reacting a compound of the formula :
wherein R1, R2, R3 and A are each as defined above, or its reactive derivative at the amino group, or a salt thereof with a compound of the formula :
wherein R4 is as defined above, or its reactive derivative or a salt thereof to give a compound of the formula :
wherein R1, R2, R3, R4 and A are each as defined above, or a salt thereof, or 2) subjecting a compound of the formula :
wherein R2, R3, R4 and A are each as defined above, and R? is heterocyclic group having a protected imino group of the formula :
(in which R6 is imino protective group) in its hetero ring, which may have one or more suitable substituent(s), or a salt thereof to elimination reaction of the imino protective group to give a compound of the formula :
wherein R2, R3, R4 and A are each as defined above, and R? is heterocyclic group having an imino group of the formula : in its hetero ring, which may have one or more suitable substituent(s), or a salt thereof, or (3) subjecting a compound of the formula :
wherein R1, R2, R3 and A are each as defined above, and R? is ar(lower)alkenyl having a nitro group, or a salt thereof to give a compound of the formula :
wherein R1, R2, R3 and A are each as defined above, and R? is ar(lower)alkenyl having an amino group, or a salt thereof, or (4) reacting a compound of the formula :
wherein R2, R3 and R4 are each as defined above, or a salt thereof with a compound of the formula :
wherein R1 and A are each as defined above, and X is an acid residue, or a salt thereof to give a compound of the formula :
wherein R1, R2, R3, R4 and A are each as defined above, or a salt thereof, or (5) reacting a compound of the formula :
wherein R2, R3, R4 and A are each as defined above, or a salt thereof with a compound of the formula :
or a salt thereof to give a compound of the formula :
wherein R2, R3, R4 and A are each as defined above, or a salt thereof.
7. A compound of the formula :
wherein R1 is tetrazolyl which may have one or more -suitable substituent(s), R2 is hydrogen or halogen, R3 is aryl which may have one or more suitable substituent(s), and A is lower alkylene, and a salt thereof.
wherein R1 is tetrazolyl which may have one or more -suitable substituent(s), R2 is hydrogen or halogen, R3 is aryl which may have one or more suitable substituent(s), and A is lower alkylene, and a salt thereof.
8. A process for preparing a compound of the formula :
wherein R1 is tetrazolyl which may have one or more suitable substituent(s), R2 is hydrogen or halogen, R3 is aryl which may have one or more suitable substituent(s), and A is lower alkylene, or a salt thereof, which comprises subjecting a compound of the formula:
wherein R1, R2, R3, and A are each as defined above, and R7 is protected amino, or a salt thereof to elimination reaction of the amino protective group.
wherein R1 is tetrazolyl which may have one or more suitable substituent(s), R2 is hydrogen or halogen, R3 is aryl which may have one or more suitable substituent(s), and A is lower alkylene, or a salt thereof, which comprises subjecting a compound of the formula:
wherein R1, R2, R3, and A are each as defined above, and R7 is protected amino, or a salt thereof to elimination reaction of the amino protective group.
9. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.
10. A use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as a cholecystokinin antagonist.
11. A method for treating or preventing cholecystokinin-mediated diseases which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals.
12. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
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| Application Number | Priority Date | Filing Date | Title |
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| GB9015879.1 | 1990-07-19 | ||
| GB909015879A GB9015879D0 (en) | 1990-07-19 | 1990-07-19 | Benzodiazepine derivatives |
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| CA2090023A1 true CA2090023A1 (en) | 1992-01-20 |
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| CA002090023A Abandoned CA2090023A1 (en) | 1990-07-19 | 1991-07-17 | Benzodiazepine derivatives |
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| EP (1) | EP0539591A1 (en) |
| JP (1) | JPH06502620A (en) |
| CN (1) | CN1059141A (en) |
| AU (1) | AU650034B2 (en) |
| CA (1) | CA2090023A1 (en) |
| GB (1) | GB9015879D0 (en) |
| HU (1) | HUT63627A (en) |
| IE (1) | IE912428A1 (en) |
| IL (1) | IL98873A0 (en) |
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| CA2099672A1 (en) * | 1990-12-25 | 1992-06-26 | Masato Satoh | Benzodiazepine derivatives |
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| US5220018A (en) * | 1991-04-10 | 1993-06-15 | Merck & Co., Inc. | Cholecystokinin antagonists |
| US5220017A (en) * | 1991-04-10 | 1993-06-15 | Merck & Co., Inc. | Cholecystokinin antagonists |
| US5218114A (en) * | 1991-04-10 | 1993-06-08 | Merck & Co., Inc. | Cholecystokinin antagonists |
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| US5378838A (en) * | 1993-01-13 | 1995-01-03 | Merck & Co., Inc. | Benzodiazepine cholecystokinin antagonists |
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| US6509331B1 (en) | 1998-06-22 | 2003-01-21 | Elan Pharmaceuticals, Inc. | Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
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| DE60007960T2 (en) * | 1999-04-30 | 2004-10-21 | Univ Michigan Ann Arbor | Therapeutic applications of pro-apoptotic benzodiazepines |
| GB0221923D0 (en) * | 2002-09-20 | 2002-10-30 | Arrow Therapeutics Ltd | Chemical compounds |
| EP1845996A4 (en) | 2005-01-03 | 2009-04-29 | Univ Michigan | Compositions and methods relating to novel compounds and targets thereof |
| US9126978B2 (en) | 2009-11-17 | 2015-09-08 | The Regents Of The University Of Michigan | 1,4-benzodiazepine-2,5-diones and related compounds with therapeutic properties |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4820834A (en) * | 1984-06-26 | 1989-04-11 | Merck & Co., Inc. | Benzodiazepine analogs |
| US4970207A (en) * | 1988-07-07 | 1990-11-13 | Fujisawa Pharmaceutical Company, Ltd. | Benzodiazepine derivatives |
-
1990
- 1990-07-19 GB GB909015879A patent/GB9015879D0/en active Pending
-
1991
- 1991-07-11 ZA ZA915423A patent/ZA915423B/en unknown
- 1991-07-11 IE IE242891A patent/IE912428A1/en unknown
- 1991-07-17 IL IL98873A patent/IL98873A0/en unknown
- 1991-07-17 HU HU93403A patent/HUT63627A/en unknown
- 1991-07-17 CA CA002090023A patent/CA2090023A1/en not_active Abandoned
- 1991-07-17 AU AU82171/91A patent/AU650034B2/en not_active Ceased
- 1991-07-17 JP JP3512847A patent/JPH06502620A/en active Pending
- 1991-07-17 WO PCT/JP1991/000952 patent/WO1992001683A1/en not_active Application Discontinuation
- 1991-07-17 EP EP91913066A patent/EP0539591A1/en not_active Withdrawn
- 1991-07-18 CN CN91105587A patent/CN1059141A/en active Pending
- 1991-07-18 PT PT98370A patent/PT98370A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CN1059141A (en) | 1992-03-04 |
| WO1992001683A1 (en) | 1992-02-06 |
| HU9300403D0 (en) | 1993-05-28 |
| GB9015879D0 (en) | 1990-09-05 |
| EP0539591A1 (en) | 1993-05-05 |
| AU650034B2 (en) | 1994-06-09 |
| HUT63627A (en) | 1993-09-28 |
| JPH06502620A (en) | 1994-03-24 |
| AU8217191A (en) | 1992-02-18 |
| IL98873A0 (en) | 1992-07-15 |
| ZA915423B (en) | 1992-04-29 |
| IE912428A1 (en) | 1992-01-29 |
| PT98370A (en) | 1992-05-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |