PH26825A - Substituted thienobenzodiazepinones and salts thereof - Google Patents
Substituted thienobenzodiazepinones and salts thereof Download PDFInfo
- Publication number
- PH26825A PH26825A PH28462A PH28462A PH26825A PH 26825 A PH26825 A PH 26825A PH 28462 A PH28462 A PH 28462A PH 28462 A PH28462 A PH 28462A PH 26825 A PH26825 A PH 26825A
- Authority
- PH
- Philippines
- Prior art keywords
- methyl
- dihydro
- thieno
- benzodiazepin
- compound
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims description 28
- 239000002253 acid Substances 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 34
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- 230000003000 nontoxic effect Effects 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 230000000026 anti-ulcerogenic effect Effects 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
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- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
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- 230000015572 biosynthetic process Effects 0.000 claims description 3
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Description
’ "26825 : '
SUBSTITUTED THIENOBENZODIAZEFPINONES
AND SALTS THEREOF
This invention relates to novel substituted thienobenzodiazepinones and non-toxic acid addition salts thereof, to methods of preparing these com- pounds, to pharmaceutical compositions containing them as active ingredients, and to a method of using them as anti-ulcerogenics and gastric acid secretion inhibitors.
THE PRIOR ART
German Offenlegungschrift No. 1,795,176 discloses certain dibenzodiazepinones having anti- ulcerogenic and secretion-inhibiting properties.
U. S. Pat. No. 3,953,430 discloses substituted dibenzodiazepines having antidepressant and anal- gesic properties.
U. 8. Pat. No. 4,168,269 discloses substituted thienobenzodiazepinones which are useful as start- ing compounds for the preparation of thienobenzo- diazepines having analgesic properties.
Ld 26825 vo
Published European Patent Application No. EP 0,039,519 discloses thienobenzodiazepinones having antiulcerogenic and secretion-inhibiting properties.
It is an object of the present invention to provide novel aminoacyl-substituted thienobenzodia- zepinones having useful pharmacodynamic properties superior to those of the related compounds disclosed in the prior art.
Other objects and advantages of the invention will become apparent as the description thereof proceeds.
More particularly, the present invention relates to a novel class of aminoacyl-substituted thienoben- zodiazepinones represented by the formula -%=
H 0 Ry a he) 9 10
AN o=o R,
X—R wherein : R is 1-methyl-4-piperidinyl, 4-methylpiperazinyl, or %d- or 3 § -tropanyl, each of which may optionally have another methyl substituent attached to the heterocyclic ring;
R, is hydrogen or alkyl of 1 to 4 carbon atoms;
R, is hydrogen, halogen or alkyl of 1 to 4 carbon atoms; and
X is oxygen, — NH.— or — N(CHz)— ; and non- toxic, pharmacologically acceptable acid addition : : salts thereof.
Examples of alkyl of 1 to 4 carbon atoms are methyl, ethyl, propyl, isopropyl, n-butyl, sec. butyl and tert. butyl, methyl being preferred.
———— ee ———————————————————— . + 26820 .
Examples of halogen are bromine and especially chlorine.
Thus, a preferred subgenus is constituted by those compounds of the formula 1 wherein
R is l1-methyl-4~piperidinyl, 4-methyl-1- piperazinyl, or endo- or exo-8-methyl-8- azabicyclo/3,2,170ct-3-y1 (i.e. 30- or 3p -tropanyl);
Ry is hydrogen or methyl;
R, is chlorine, hydrogen OT methyl; and ’
X is oxygen, — NH— or — N(CHz)— 3 and non-toxic, pharmacologically acceptable acid addition salts thereof.
Specific examples of compounds of the formula 1 are the following: 4,9-Dihydro-t-{/{1-methyl-4-piperidinyl)oxg/car= bonyl) -10H-thieno/3,4-b7/I,57benzodiazepin-10-one, cis-4,9-Dihydro-4- { /T1,2-dimethyl-4-piperidinyl)oxy/-
carbonyl| ~-10H-thieno/3,4-b7/1,5/benzodiazepin- 10-one, trans-4,9-Dihydro-4-{/{1,2-dimethyl-4-piperidinyl)- oxy/carbonyl} ~10H-thieno/3,4-b7/1,5/benzo- diazepin-10-one, cis-4,9-Dihydro-4-{/T1,3-dinethyl-4-piperidinyl)oxy/- carbonyl} -10H-thieno/3,4~b7/1,5/benzodiazepin- 10-one, trans-4,9-Dihydro-4-{/{1,3-dimethyl-4-piperidinyl)- oxy/ carbonyl ~10H-thieno/3,4-b7/T,5/benzo- diazepin-10-one, 4,9-Dihydro-4- {/{1-methyl-4-piperidinyl)amino/car- bonyl} ~10H-thieno/3,4-b7/I,57benzodiazepin-10- one, cis-4,9-Dihydro-4- {/{1,2-dimethyl-4-piperidinyl- )amino/carbonyl{ ~10H-thieno/3,4-b7/I,57benzo- diazepin-10-one, trans-4,9-Dihydro-4- [/{1,2-dimethyl-4-piperadinyl- )amino7carbonyl) ~10H-thieno/3,4-b7/T,3/benzo- diazepin-10-one, cis-4,9-Dihydro-4-{/{1,3-dimethyl-4-piperidinyl-
Yamino/carbonyl}-10H-thieno/3,4-b7/I,57benzo- diazepin-16-one, trans-4,9-Dihydro-4-{/{1,3-dimethyl-4-piperidinyl-
Jamin carbonyl ~10-thieno/3,4-b7/7,57benzod1aze~ pin-10-one, 4,9-Dihydro-1-methyl-4- {/T1-methyl-4-piperidinyl)ox- y/ carbonyl } -10H-thienol/3,4-b//T,5/benzodiazepin- 10-one, 4,9-Bihydro-3-methyl-4~ {/T1-methyl-4-piperidinyl)ox-~ y/ carbonyl3 -10H-thienp/3,4-b//7,5/-benzodiazepin- 10-one, 4,9-Yihydro-1, 3-dimethyl-4— {[T1-methyl-4-piperidinyl-
Joxy7 carbonyl § ~10t-thieno/3,4-b7/7,57venzodiazepin- 10-one 3-Chloro-4,9~dihydro-4- { [{1-methyl-4-piperidinyl)oxy/- carbonyl? ~10li-thieno/3, 4-b7/T,57benzod iazepin~ 10-one, 4,9-Dihydro-1-methyl-4- {/T1-methyl-4-piperidinyl- )amino7 carbonyl} -10H-thieno/3,4-b//7,5/benzodiaze~ pin-10-one, 449-Dihydro-3-methyl-4~ { /T1-mg¥hyl-4-piperidinyl- )aming7 carbonyl ~10H-thieno/3,4-b7/T,5/benzodiaze- pin-10-one, 4,9-Dihydro-1,3-dimethyl-4- {/T1-methyl-4-piperidinyl- )amino7carbonyl 4 -10H-thieno/3, 4-b7/T,57benzodiaze~ pin~10-one, 3~Chloro-4,9~-dihydro-4- { [T1-methyl-4-piperidinyl-
aminoJcarbony b-1on-thienol2,4-b][1,5]benzodiaze- pin-10-one, 4,9-Dihydro-4- {[(4-methyl-1-piperazinyl)amino] carbonyl Y-10H-thienol3,4-b][1,5-]benzodiazepin- 10-one, 4,9-Dihydro-4- {1(3,4-dimeeny1-1-piperazinyl)aminol= carbonyl J -10R-thienol3,4-b1[1,5]benzodiazepin- 10-one, 4,9-Dihydro-4- f[(2,4-dimethyl-1-piperazinyl)amino]- carbonyl) _l0H-thienol[3,4-b)[1,5]benzodiazepin- 10-one 4,9-Dihydro=4= {1 (4-methyl-l-piperazinyl)oxylcar- bonyl Y =10H-thieno[3,4-b]l[1,5]benzodiazepin- 10-one, 4,9-Dihydro-4- {[(3,4-dimethyl-1-piperazinyl)oxyl- carbonyl J _10H-thienol[3,4-b][1,5]benzodiaze- pin-10-one, 4,9-Dihydro-4- {{(2,4-dimethyl-1-piperazinyl)oxy]- carbonyl 3 —10H-thienol[3,4-bl[1,5-benzodiazepin-10- one, 4,9-Dihydro~l-methyl-4- {(4-methyl-1-piperazinyl-
Yamino]carbonyl Y _Jon-thienol3,4-bl[1,5]benzo- diazepin-10-one, 4,9-Dihydro-3-methyl-4- {[(4-methyl-l-piperazinyl- yamigolcarbonyl J ~1OH-thienol3,4-b][1,5]benzo-
diazepin-10-one, 4,9-Dihydro-1,3-dimethyl-4- {i (4-methyl-1-piperazinyl- yaminolcarbonyl J -10H-thienol(3,4-bJ[1,5]benzo- diazepin-10-one, 3-Chloro-4,9-dihydro-4- {Il (4-methyl-1-piperazinyl-
Jamino]carbonyl Y _10H-thieno(3,4-b1[1,5]benzo- diazepin-10-one, 4,9-Dihydro-l-methyl-4-4 [ (4-methyl-l-piperazinyl)ox- ylearbonyl Y ~10H-thienol3,4-b][1,5]benzodiazepin- 10-one, 4 ,9-Dihydro-3-methyl-4- {I (4-methyl-1-piperazinyl)ox- ylcarbonyl J -10H-thienol3,4-b1[1,5]benzodiazepin-
I10~-one, 4,9-Dihydro-1,3-dimethyl-4- {{ (4-methyl-l-piperasinyl-
Joxylcarbonyl Y loH-thienol3,4-b][1,5]benzodiazepin- 10-one, 3=Chloro-4,9-dihydro-4- fl (4-methyl-1-piperazinyl)- oxyl-carbonyl Y _10H-thieno[3,4-b][1,5]benzodiazepin- 10-one, endo-4,9-Dihydro-4- £{(8-methyl-8-azabicyclo[3,2-1]1- oct-3-y1)oxylcarbonyl § -10H-thieno[3,4-b1[1,5]- benzgdiazepin-10-one, exo0-4,9-Dihydro-4- L0(8-methyl-8-azabicyclo[3,2,1] oct-3-yl)oxylcarbonyl J -10H-thieno(3,4-b][1;5]- benzodiazepin-10-one,
endo-4,9-Dihydro-4- {{{(8-methyl-8-azabicyclol3,2- 1Joct-3-y1)aminolcarbonyl } -10H-thieno[3,4- bllt,5)benzodiazepin-10-one, exo-4,9-Dihydro-4- {{(8-methyl-8-azabicyclol3,2,1[- oct-3-yl)aminolcarbonyl J -10H-thieno[3,4-b]~- {1,5)benzodiazepin-10-one, endo-4,9-Dihydro-i-methyl-4- { [(8-methyl-8-azabicy- clol3,2,1]oct-3-yl)oxylcarbonyl Y -10H-thieno- [3,4-b]{1,5]benzodiazepin-10-one, endo-4,9-Dihydro-3-metrhyl-4- f [(8-methyl-8-azabicy- clof3,2,1]oct-3-yl]carbonyl Y-10H-thienol3,4-b- 1[1,5]benzodiazepin-10-one, endo=4 ,9-Dihydro-1,3-dimethyl-4~- {,[(8-methyl-8- : azabicyclo[3,2,1]oct-3-y1)oxyJcarbonyl 4 -10H- thienol3,4-b1[1,5]benzodiazepin-10-one, endo-3-Chloro-4,9-dihydro-4- L[(8-methyl-8-azabi- cyclol3,2,1loct-3-yl)oxylcarbonyl 3 -10H-thieno- [3,4-b[11,5)benzodiazepin-10-one, endo-4,9-Dihydro-l-methyl-4- L [(8-methyl-8-azabi- cyclol3,2,1]oct=-3-yl)aminolcarbonyly -10H-thieno- [3,4-b]J[1,5]benzodiazepin-10-one, endo-4,9-Dihydro-3-methyl-4- GL (8-methyl-8-azabi- cyclo[3,2,1Joct-3-yl)aminolcarbonyl} -10H-thieno- [3,4-b][1,5]benzodiazepin-10-one,
- endo-4,9-Dihydro-1,3-dimethyl-4- { [(8-methyl-8- azabicyclald,2,1loct-3-yl)aminolearbonyly - : lOH-thieno[3,4-bJ[1,5]benzodiazepin=10-one, endo-3-Chloro-4,9-dihydro-4- {{(B-methyl-8-azabicy- 103.2, 1]oct-3-yl)aminolearbonyl -10H- thienol3,4-b1[1,5]benzodiazepin-10-one,, exo-4,9-Dihydro-3-methyl-4- [(B-methyl-8-azabicy- c1o[3.2,1]oct-3-yl)amino)carbonyl § - 10H- thieno[3,4-b1[1,5]benzodiazepin-10-one, 4,9-Dihydro-4- { (N-methyl-N-(1-methyl-4-piperidinyl- yaminoJlcarbonyl Y —\0H-thienol3,4-b1[1,5)benzodiazepin- 10-one, 4,9-Dihydro-l-methyl-4- { (N-methyl-N-(l-methyl-4- piperidinyl)aminolcarbonyl § _\oH-thienol3,4-bl~ [1,5)benzodiazepin-10-one, 4. 9-Dinydro-3-methyl-4-{[N-methyl-N-(l-methyl=4"
Siperidinyl)aminolearbonyly -10H-thienol3,4- bil 1,5)benzodiazepin-10-one, 4,9-Dihydro-1,3-dimethyl-4- {[N-methyl-N-(1-methyl- 4-piperidinyl)aminolcarbonyl Y -10H-thienol3,4-b" 1{1,5]benzodiazepin-10-one, and 3=Chloro-4,9-dihydro-4- L(N-methyl-N-(l-methyl-4- . piperidinyl)aminolearbonyl y -1ou-thienol3,4- b1[1,5)benzodiazepin-10-one.
The present invention further relates to novel acyl-substituted thienobenzodiazepinones of the formula
H “i
I | (1a)
N—C hid
CL YX i Ae R,
Y wherein
R, and R, have the same meanings as in formula I;
Y is halogen, preferably bromine or chlorine, or “OR, and
Ry is unsubstituted or halo-substituted alkyl of | to 5 carbon atoms, phenyl, halo-substituted phenyl, nitro-substituted phenyl, or aralkyl of 7 to 15 carbon atoms; which are useful as intermediates for the preparation of compounds of the formula I.
Examples of Ry are methyl, ethyl, n-butyl, isobutyl, benzyl, 9-fluorenyl-methyl, phanyl, 4-nitrophenyl, 2,2,2-trichloroethyl, 2,4,5-trichloro- phenyl and 2,2,2-trichlrotert. butyl.
—
The compounds of the formula 1 may be prepared by the following methods:
Method A
By reacting A THIENOBENZODIAZEPINONE OF THE formula Ta with a compound of the formula
H-X-R (11) wherein X and R huve the meanings previously defined.
The reaction may be carried out in the absence Or preferably in the presence of an inert solvent, for example water, toluene or alcohols such as methanol, ethanol or isopropanol, but preferably in the presence of an aprotic polar solvent, such as tetrahydrofuran, . l,4-dioxane, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric, acid tri- amide or mixtures thereof, and at temperatures between 0%. and the boiling point of the solvent in question, preferably between 40°C. and 100’c.
It has proved helpful to use additionally an inor- ganic or organic base, for example alkali metal a or alkaline earth metal hydroxides, alkoxides or carbonates, such as sodium hydroxide, sodium me- thoxide, potassium tert.butoxide, sodium carbo- nATE OR POTASSIUM CARBONATE: OR TERTIARY AMINES, such as triethylamine, ethyl diisopropylamine, N,N- dimethylaniline or pyridine; and to perform the eeaction in the presence of an excess of a compound of the formula II.
Method B
By reacting a thienobenzodiazepinone of the formula Ia with a metal compound of the formula
M - X -R Y1la) wherein
X and R have the meanings previously defined, and
M is an alkali metal atom or one equivalent of an alkaline earth metal atom.
A compound of the formula IIa can readily be prepared in situ from a compound of the formula II by reacting it with an alkali metal or alkaline earth methal, for example with sodium, potassium or barium,
or with an alkali metal or alkaline earth metal hydride, for example with sodium, potassium or cBAlcium hydride, or by reacting it with an alkali or alkaline earth orga- nometallic compound, for example with n-butyl lithium or phenyl lithium.
Method C
By reacting a thienobenzodiazepinones of the formula
H o Ki
SPN pd 7 : MN (11) [I 2
H wherein R, and R, have the meanings previously defined, with a chlorocarbonic acid derivative of . the formola- cL -¢C- X-R (v) 0 1 C oo
—— —— or with an isocyanate of the formula 0 =C=0N-R (va) wherein X and R have the meanings previously defined. The reaction is carried out in an inert organic solvent, for example in an aromatic hydrogar-— bon such as toluene, chlorobenzene OT xylene; 1in an ether such as diisopropyl ether, tetrahydrofuran or dioxane; in an acyclic or cyclic aliphatic ketone such as pentan-3-one; in a chlorinated aliphatic 120 hydrocarbon such aa {,2-dichloroethane; or in other solvents such as ace -tonitrile or dimethylformamide, or in mixtures thareof, optionally in the presence of a tertiary organic base such as pyridine, and at temperatures up £O the boiling point o f the reac-
Is tion mixture.
A base of the formula 1 thus obtained can sub- sequently be converted into a non-toxic, pharmaco~ logically acceptable acid addition salt thereof, or any such acid addition salt obtained may be cbnverted into the free base OT another non-toxic, pharmacologically acceptable acid addition salt.
Examples of non-toxic, pharmacologically acceptable acid addition salts arte those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, .methylsulfuric acid, phosphoric acid, tartaric Acid Faris acid, citric acid, maleic acid, succinic acid, glu- conic acid, malic acid, p-toluenesulfonic acid, methanesul fonic acid or amidosulfonic acid.
An acid addition salt is obtained by dissolving the free base in a suitable solvent, for example in water, acetone, an alkanol such as ethanol or isopropanol, or an acyclic or cyclic ether such as diethyl ether or tetrahydrofuran, which contains the desired acid or to which the desired acid is subsequently
Y added. The salt is recovered by filtering, ptecipi- tating with a medium in which the acid addition salt is not soluble, or by evaporating the solvent! The salt may be also be converted into another salt, for example a pharmacologically acceptable acid addition salt, by converting it into the base and reacting the base with another acid.
Some of the thienobenzodiazepinones of the formula I contain one or more asymmetric carbon atoms in the side chain -CO-X-R. These compounds may therefore occur in two diasteroisomeric cis- and trans-forms or as the enantiomersc (+) and (-) forms. The invention includes the individual isomers and the mixtures thereof.
The diasteroisomers may be separated on the bases of their different physico-chemical properties, for instance by fractional recystallization from a suitable solvent.
Racemates of the compounds of the formula I may be separated according to known methods, for example by using an optionally active acid such as (+) -or (-) tartaric acid, or a derivative thereof such as (+) —or (-) diacetyl tartaric acid, (+)- or (-) monomethyl tartrate or (+)- camphorsulfonic acid.
In a conventional method for separating isomers, the racemate of a compound of the ‘ 20 formula I is reacted with an equimolar quantity of one of the above mentioned optically active acids in a solvent, and the crystalline optically active salts obtained are separated on the basis of their different solubilities. This reaction may be carried out in any type of solvent, provided that the salts have sufficiently different solubiu lities in the solvent. Preferably, methanol, ethanol or a mixture thereof, for example in proportions of 50:50 by volume, is used. Then, each of the opti- cally active aalts is dissolved in water, the solution is neutralized with a base such as sodium in carbonate oF potassium carbonate, and/this way the corresponding free base is obtained in the (+) or (-) form.
The intermediate compounds of the formula Ia are obtained by reacting a ‘hienobenzodiazepinone of the formula 0 Fi
N - (111) ~ i
H Rj,
wherein
R, and Ry have the meanings previously defined, with a halocarbonic acid derivative of the formula
Hel = C = ¥ (17) ; wherein lial is bromine or, preferably, chloring, and Y has the meanings previously defined. The reaction is carried out in an inert organic solvent, guch as aromatic hydroearbons, for example toluene, chlorobenzene Or xylene; acyclic or cyclic ethers such as diisopropyl ether, tetrahydrofuran or dioxanej acylic or cyclic aliphatic ketones such as pentan-3-onej chlorinated ali- phatic hydrocarbons, such as 1,2-dichloeo-ethane; or other solvents such as acetonitrile or dimethylformam- jde, or mixtures thereof, in the presence of a tertiary organic base, preferably pyridine, and at temperatures up to, at most, the boiling point of the solvent or mix- ture of solvents, preferably between +30° and +100°
C
The starting compounds of the formula II are known k or may be prepared in analogoy to processes described in the literature. For example, {~hydroxy-4-methyl-pipera~ zine is obtained as described by 5. M. Riba, A. S. Issa and Y. A. Beltagy, Pharmazie 33, 711 (1978)p by react- ing bis /l4(2-chlorocthyl)/-methylamine with hydroxy- lamine hydrochloride in aqueous ethanolic solution and in the presence of potassium carbonate.
The starting compounds of the formula 111 are pre- pared according to U.5. Fat. No. 3,953,430 by reacting o-phenylenediamine with a tetrahydrothiophene car- boxylic acid derivative of the formula 1
Rz00C
Co 8 (v1)
I)
R', i wherein R, has the meanings previously defined, R', hydrogen or alkyl of 1 to 4 carbon atoms, and Rs is hydrogen or alkyl of 1 to 5 carbon atoms. The reaction is effected, for example, in an inert solvent such as toluene at temperatures up to the boiling point of the reaction mixture. A tetrahydrothienobenzodiazepinone of the formula
R
H 0 1
IL XY) (vit) . 1 ( nt } tp is thus obtained, which is subsequently reacted with a dehydrating agent such as N-bromo-succinimide in dimethylformamide to form the corresponding com- pound of the formula RII wherein Rs has the meaning of - , Ryle If it is intended to prepare a compound of the formula IJI wherein n, is balogen , a compound of the formula IIT wherein RB, is hydrogen is halogenated, using conventicnal methods.
In this way, the following starting compounds of the formula III are obtained, for example: 3-Chloro-4,9-dihydro 10l-thieno/3,4~b7/1,5/ben~ zodiazepin+10-one, 4,9-Dih-dro-3-methyls10i~thieno/3,4-b7 [7,57 ben- zodiazepine10-one,
mop. 228° = 230%, (insthanol), 4,9-"ihydro~1,3-dinsthyl+10H~thieno/3,4-b7/T,5/ ben~ zodiazepin-10~-one, m.p. 195° = 196°C,, and 4,9-Dihydro-1-metiyl-10i~-thieno/3, 4-b//T,5/ben~ ~ zodiazepin-10-one, m.p. 274° - 276°C, (n- propanol).
The halocarbonic acid derivatives of the formula
IV are known compounds,
The chlerocarbonic acid derivatives of the formula
V and isocyanates of the formula Va are known compounds or can be obtained by methods described in the litera- ture (ef., for example, I, YY. Hathison et al., J.
Bn I'barm. Sci. 62,158 [196373 i. Hopff and H, Ohlinger,
Angew. Chem. 61, 183 /T9497; W. Bicken, Liebigs Ann.
Chem, 562, 75 /12497; Houbenseyl VIII, 117; Ullmann
V, 72; L. C. Raiford and K. Alexander, J. “rg. Chem, 5, 306 /19407; I. H. Saunders and X, J. Slocombe,
Chem. Rev. 43, 203 /19287; R. J. Slocombe, b. i.
Hardy, J. H. Samders and R. I:Jenkins, J. Amer-
Chem. Soc. 72, 1888 /19507; H. Habad and A. G. ZJeiler,
Chem. lev. 73, 75 19137).
The following examples illustrate the present inven- tion and will enable others s:illed in the art to under- stand it more completely. If should be understood, how- ever, that the invention is not limited solely to the par- ticular examples given below,
Preparation of Starting Compounds of Formula Ta
PEANDIT A
4-Chlorocarbonyl-4,9-dihydro~10H~-thieno/3,4- b//7,5/benzodiazepin-10-one 16.2 gm (0.075 mol) of 4,9-dihydro~10li-thieno/3,4~ b//7,57benzodiazepin-10-phe were admixed with 160 ml of diethylketone and 5.9 gm (0.075 mol) of pyridine at 40°c., and over a period of 20 minutes 75 ml of a 20} solu~ ; tion of phosgene (0.15 mol) in toluene were added : 15 thereto. The reaction mixture was stitred for 2 hours at 40°C. and then for 3 hours at 60°C. After cooling to room temperature, the mixture was stirred with 150 ml of water, then filtered, and the organic phase was separatdd, concentrated by evaporation in vacuo, and the residue was recrystallized from acetonitrile. 4-
Chlorocarbonyl-d,9-dihydro=100~thieno/3,4-7/7,5/ben-
————————— — — } mmm zodiazepin-10-one, m.p. of 244° - 245°C. (decomp. ). was obtained with a yield of 50: of theory.
In analogous manners (a) From 4,9-d ihydro-10H~thieno/3,4-b7/7,5/- benzodiazepin-10-one and methyl chlorocarbonate in a mixture of dioxane znd toluene, 4,9-dihydro-4-methox- yoarbonyl-10li-thieno/3, 4-7/4, 57benzodiazepin-10-one was obtained; (v) From 4,9-dihydro-1-methyl-10i-thieno/3,4= v7 /1,57benzodiazepin-10-one and phosgene in a mixture of dioxane and toluene, 4-chlorocarbonyl-4,9-dihydro-
A-methyl-10i-thieno/3,4-b]/T,57benzod iazepin~-10-one was obtained, m.p. 235° = 236°C. (chloroform); (¢) From 4,9-dihydro-3-methyl-10l-thieno/3, 4= b//7,5/benzodiazepin=-10-one and phosgene in a mixture : of dioxane and toluene, 4-chlorocarbonyl-4,9-dihydro- 5-methyl~10-thieno/3, 4-bB/,37benzod sazepin=10-one was obtained; (a) From 4,9 8ihydro-1,3-dimethyl-10H~thieno/3, 4-
— v7 [7,57 bsnzodiazepin-10-one and phosgene in a doxane toluene mixture, 4-chlorocarbonyl-4,9-dihydro-1,3= dimethyl-10l-thieno/3,4~b//T,5/benzod iazepin-10-one was obtained as an amorphous, foamy product which was further reacted without purifications (e) ¥rom 3-chloro-4,9-dihydro-10t-thieno [354- v//1,5/benzodinzepin-1C-one and phosgene in diethylke- tone, %—chl oro-d-chlorocarbonyl-4p9-dihydro-10i- thieno/3,4-b7/1,5/benzodiaznepin=10-one was obtained, m.p. 238° — 240°C. (ethanol); (£) From 4,9-dihydro-10H-thieno/3,4-b7/,57/- benzodiazepin~10-one and benzyl chlorocarbongte in a dioxane toluene mixture, A-benzyloxycarbonyl-d4,9~dihy= dro-10U-thieno/3,4~b7/1,5/venzcdiazepin-10-one vag obtained. - Preparation of ind Product of Formula I
BLANPIE 2 4,9-Dinydro-4- {/T 1-mothyl-4-piperidinyl )amino/car- bonyl§ ~10H-thieno/3,4-b7/1,5/benzodiazepin=10sone -
A suspension of 3p gm (0.0108 mol) of 4-chlorocar- bonyl~4,9-dihydro-10li-thieno/3,4-b7/1,5/benzodiaze- pin-10-one and 1.2 gm (0.0100 mol) of sodium carbonate in 100 ml of acetonitrile was refluxed, and then a solu- tion of 1.2 gm (0.0108 mol) of A-amino-1-methyl-piperi- - dine in 10 ml of acetonitrile was added dropwise thereto. The mixture was refluxed for 2 hours, then suction+filtered while still hot, and the filtrate was concentrated by evaroration in vacuo. The residue was purified by column chromatography (silica sel, eluant: mathylene chloride + cyclohexane + methanol + ammonia = 102 + 2% + 2% 4 5). The desired fraction was concentrated by evaporation in vacuo, snd the residue was recrystallized from acetonitrile. Needles with an mp. of 206° - 208°C, The yield was 50% of theory.
In analogous manners (a) From A~-chlorocarbonyl=-4,9~-dihydro-10H- thieno/3,4-b//1,5/benzodiazepin-10-one and 1-methyl-4- meéthylaminopiperidine, 4,9-dihydro-4- { [F-methyl-N- (1-methyl-4-piperidinyl)amino/carbonyly -10H=- thieno/3,4-b7/1,57benzodiazepin=-10-one was obtained. ) : (b) trom 4,9-dihydro-4-chlorocarbonyl-10H- }
thieno/3,4~b//1,5/benzodiazepin=10-cne and endo~3- smino-8mme thyl-8-azabicyclo/3,2, Joctene, emdo—~4,9~ dihydro-4- (/8-methyl-8-azabicyclo/3,2,17/-oct-3~ y1)amino7carbonyly - 10H~thieno/3,4-b7/T,5/benzodia-
zepin-10-one was obtained, m.p. 203° -~ 205°C. (acetoni~ trile);
(c) From 4-chlorocarbonyl-4,9-dihydro-1-methyl- 10li~thieno/3,4~b7/1,5/benzodiazepin-10-one and A- amino-1-methylpiperidine, 4,9-dihydro-1-methyl-4- {/C1-
methyl-4-piperidinyl Jamino/ carbonyl y ~10H-thieno-
/[3,4-b7/"1,5/venzod janepin-10-ome was obtained, m.p. 240.5° - 241°C, (from ethyl acetate); (a) From 4-chlorocarbonyl-4,9-dihydro~3-methyl- 10G~thieno/3,4-b//1,5/benzodiazepin-10-one and 4-
1% amino-t-methylpiperidine, 4,9-dihydro~3-nethyl-4f/{1- methyl-4-piperidinyl)amino/carbonyl 5 ~10H~thieno/3,4~ b//7,5/benzodiazepin-10-one was obtained
(e) From A-chlorocarbonyl-4,9-dihydro-1,3-dimethyl 10H-thieno/3,4~b//T1,5/benzodiazepin-10!one and 4- amino~1-methyl-piperidine, 4,9-dihydro-1,3-dimethyl-4- 718 1-methyl-4-piperidinyl )amino7carbonyly ~10H-
thieno/3,4-b//1,5/benzodiazepin-10-one was obtained, mop. 136° = 140°C. (acetonitrile);
(f) From 3-chloro-A4-chlorocarbonyl-4,9-dihydro- 10H-thieno/3,4-b//1,5/benzodiazepin-10-one and 4-amino-
1-methylpiperidine, 3-chloro-4,9-dibydro-4- §/{1-meth= y1-4-piperidinyl )amino/carbonyl § 100-thienc/3,4-b//7,~ §/benzodinzepin-10-one was obtained;
(g) From 4~chlorocarbonyl-4,9-dihydro=-10H~ thieno/3,4~b//7,5/benzodiazepin=-10-one and endo-8-
methyl-3-methylamino-8-azabicyclo/3,2,17octane, en- do-4,9-dihydro~-4- { [-methyl-N-(8- methyl-8-azabicy- clo/3,2,170ct~3-yl)amino/carbonyl I -10Hi~thieno/3, 4~
: v7/7,57benzodiazepin-10-one was obtained, m.p. 259° ~ 260°, (ethanol); (nh) Yrom 4-chlorocarbonyl-4,9-dihydro-10H~ thieno/3,4~b//7,5/benzodiazepin~10~cne and 1-amino- 4-methyl-piperadine, 4,9-dihydro-4- {, [(4-methyl-1- piperazinyl JaminoJcarbonyl J ~10H~thieno/3,4-b7/T,57- benzodiazepin-10-pne was obtained, m.p. 240° - 241°C.
(2-propanol);
ee —————————————— ee ———————————
NL
\/ (i) From A-chlorocarbonyl-i,9-dihydro~1-methyl- 10H-thieno/3,4-b//1,5/benzodiszepin-10-one and 1- amino-4-nethylpiperazine, 4,9-dihydro~1-methyl-4~ { [Ct-notisy)-i-piveraniny) JaningTearbonyl -10H~ thieno/3,4~b7/T,57benzodiazenin=-1C-one was obtained; (i) ¥rom 4-chlorocarbenyl-4,9 dihydro-3-methyl- 10H~thieno/3,4-b7/7,5/benzodiazepin-10-one and I= amino-4-methylpiperazine, 4,9~dihydro-3-methyl-4- {C4 _nothyl-1-piperazinyl Jaminofcarbonyl § -10H-~ thieno/3,4-b/ 1, 5/benzodiazepin-10-one vas obtained; (k) From A-chlorocarb nyl-4,9-dihydro-1,3-dimeth- y1-10H~thieno/3,4-b7 [1,57 benzodiazepin-10-one and 1- amino—4-methyl-piperazine , 4,9-dihydro-1,3-dimethyl- 4- ([Ca-notyl- -piperasinyL)aningfeasbony) 10 = thieno/3,4-b7/1,57 benzodiazepin-10-one was obtained; (1) From %-chloro-4-chlorocarbonyl-4,9-dihydro- 10ti~thieno/3,4~b//T,5/benzod ianepin-10-one and 1- amino-4-methyl-piperazine, 3.chloro-4,9-dihydro-4- { [{ A-rethyl=1-piperaninyl)anino]corbonyl}-10i- thieno/3,4-b/[1,5/venzodinrzepin-10-one was obtained;
(m) ¥rom 4-chlorocarbonyl-4,%-dihydro-10i- thieno/3,4-b//1,5/b nzodiszepin-1C-one and 2X0 ~3=- amino-8-methyl-G-arabicyelo/3,2,1 octane, axo~4, 9= dihydro~4- {/{B-nethy1-8-azabicyelo/3,2, 17-oct=3-
y1)amino/ carbonyl § ~100=thieno/3,4-b7/7,5/venzodia~ zepin-10~one vas obtained, m.p. 235° - 257%, (accto- nitrile);
(n) Trom A=clilorocarbonyl-4,9-dihydro-1-methyl- 10l~thieno/3, 4-b7/7, 57/benzodiazepin-1i-one and endo-
3-amino-8-methyl-t-azabicyelo/3,2,1/octane, endo-4,9- dihydro~i-nethyl-4- { [T8=-methyl-8~azabicyclo/3,2,17~ oct-3-y1)amino/ carbonyl § ~10-thieno/3,4-b7/1,57 - benzodiazepin-1C-one was obtained;
(0) From 4-chlorocarbonyl-i,9-dihydro-3-methyl-
10=-thieno/3,4-b//T,57benzodinzepin-10-one and endo-—
: 3-amino-8-methyl-8-azabicylo/3,2,17oct ne, endo-4,9- dihydro~3-methyl-d- { [{8-methyl-s-azabicyclo/3,2,17~ oct-3-y1 Jamingfcarbonyl ~10l-thieno/3,4yb/[T,57- benzodiazepin-10-cne was obtained;
fp) From A-chilorocarbonyl-4,9-dihydro~1,3=dimoth=
1-10l~thieno/3,4-0//T, 57henuod inzepin-Tu-one and en— dom 3mamino=B-nothyl-t~nmabicyclo/3, 2, 1/octone, endo- 4,9-dihydro-1, Seine by L-d- { [To-notiyl-6-azabi cy=—- clo/3,2, 170ct=3-y1) ming/carbonyl y ~101-thieno/3, 4= 7/7 ,5Penzodiazepin=10-one was obtained; (q) From 3-0 hloro—-A-chlorocarbonyl-4, 9-dihydro=- 10l=thieno/3, 4-07 [1,57 benred inner in=1u-one »nd endo— 3am ino-B-mothyl-B-1znbicyelo/3,2, 1/outane, endo-3- shloromd, 9-dihydro-i- { [{o-metiyl-B-ozebicyclo/3,2- 1700t=3-y1 JaningTenrtonyl i ~1tit-thseno/3,4-b7/T437- benzodiazenin-10-one was obtained, mp. 158° - 161°. (acetonitrile); (r) rom j-chloro=-4-chlorocarbonyl-4,S-dihydro= 10H~thieno/3,4-b7 [1,57 benzodinzepin-10-one and exo->3- amino-8-methyl-f-azabicyelo/3,2, 1 octane, exo=5- chloro-4,2-dihydro—4~ {/T8-nethyl-t-anabicyclo/5,2,- 170ct~3-y1 amino carbonyl} —10li~thieno/3,4-b7 [T,57- benrodinmepin-1t-one was obtained, m.p. 224° - 225°C. (from acetonilrile).
LIANE D
4,2-0ihydro—i~ {/- nethyl=A-riperid iny1)oxy/- apo ORIGINAL ) - 5D = bee carbonyl J — 10H-thieno[3,4-bl[1,5)benzodiazepin-10- one was obtained from 4-chlorocarbonyl-4,9-dihydro-
OH-thienol3,4-b}[1,5]benzodiazepin-10-one and 1- methyl-4-piperidinol, using the procedure described in Example 2. M.p. 189° - 190°C. (from acetonitrile).
Yield: 55% of theory.
The base thus obtained was dissolved in ethgl dcetate, and a solution of hydrogen chloride in dioxane was added. The hydrochloride precipitated thereby was recrystallised from a mimsture of ethanol and diethyl ether (1:1). M.p. 220° zee ¢. (decomp). In analogous manner: ' (a) From 4-chlorocarbonyl-4,9-dihydro-1- methyl-10H-thieno[3,4-bJ[1,5]benzodiazepin-10-one and !-methyl-4-piperidinol, 4,9-dihydro-1-methyl- 4 ~ £08 -mechyl-4-piperidingl oxy )earhonyt]-10u- thienol[3,4-bl[1,5]benzodiazepin-10-one was obtagned, m.p. 201° = 202°C. (ethyl acetate); (b) From 4L-chlorocarbonyl-4,9-dihydro-3-methyl- {OH-thieno[3,4-bl[1,5]benzodiazepin-10-one and 1- methyl-4-piperidinol, 4,9-dihydro-3-methyl-4-
Uf (1-methyl-4-piperidinyl)oxylcarbonyl -10H- thienol3,4-b][1,5)benzodiazepin-10-one was obtained; (¢) From 4-chlorocarbonyl-4.9-dihydro-1,3- dimethyl-10H-thienol[3,4-b1l1,5]benzodiazepin- 10-one dnd l-methyl-4-piperidinol, 4,9-dihydro- l,3-methyl-4- 1 Clomethyl-4-piperidinyl)oxylearbony if {OH-thienol3,4-bl[1,5]benzodiazepin-10-one was obta- : ined, m.p. 198° - 200°C. (ethyl acetate): (d) From J-chloro-4-chlorocarbonyl-4,9- dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10- one and l-methyl-4-piperidinol, 3-ghloro-4,9- dihydro-4- {0 (1-methyl-4-piperidinyl)oxylcarbonyl]- 10H-thienol[3,4-b)}[1,5lbenzndiazepin-10-one was obtained; (e) From 4-chlorocarbonyl-4,9-dihydro-10H- thieno[3,4-bl[1,5]benzodiazepin-10-one and 1- hdroxy-4-methylpiperazine, 4,9-dihydro-4-
Lf (4-methyl-1-piperazinyl)oxylcarbonyld -10H-thieno [3,4-b][1,5)benzodiazepin-10-one was obtained;
(f) From 4-chlorocarbonyl-4,9-dihydro- l-methyl-10H-thienol[3,4-bJ[1,5]benzodiazepin-10-one and l-hydroxy-4-methyl-piperazine, 4,9-dihydro-1I- methyl-4- §[ (4-methyl-l-piperazinyl)oxylcarbonyl}-
10H-thienol3,4-bl[1,5]benzodiazeptn-10-one was obtained; (g) From 4-chlorocarbonyl-4,9-dihydro-10H~- thieno[3,4-bll1,5)lbenzodiazepin-10-one and endo- 8-methyl-8-azabicyclo[3,8,1]loctan-3-0l, ando-4,9- dihydro-4- Rl(8-methyl-8-azabicyclol3,2,310ct 5 11)
carbonyl 4 -10H-thienol3,4-b1[1,5]benzodiazepin=10- one was obtained;
(h) From 4-chlorocarbonyl-4,9-dihydro-1I- methyl-10H-thieno[3,4-b1[1,5]benzodiazepin-10-one and endo-8-methyl-8-azabicyclol3,2,1]octan-3-01,
endo-4,9-dihydro-l-methyl-4- {l(8-methyl-8-azabicyclo-
[3,2,1]oct-3-yl)oxylcarbonyl 4 -10H-thienol3,4-b1- [1,5]benzodiazepin-10-one was obtained; (i) From 4twchlorocarbonyl-4,9-dihydro-3- methyl-10H-thieno[3,4-b}[1,5]benzodiazepin-10-one and endo-8-methyl-8-azabicyclol3,2,1]octan-3-0l, endo 4,9-dihydro-3-methyl-4- {,[ (8-methyl-8-azabicyclo-
[3,2,1]oct-3-yl)oxylcarbonyl by on-thienol3,4-b1- [1,5]lbenzodiazepin-10-one was obtained;
(j) From 4-chlorocARBONYL 4,9-dihydro-1,3- dimethyl-10H-thienol[3,4-b}[1,5]benzodiazepin-10-
one 8nd endo-8-methyl!-8-azabicyclo[3,2,1]Joctan-3-0l. endo 4,9-dihydro-1,3-dimethyl-4- YU (8-methyl-8-azabicyclo [3,2,1]Joct-3-yl)oxylcarbony]l y _1oH-thienol[3,6-b]- [1,5]benzodiazepin-10-one was obtained;
(k) From 3-chloro-4-chlorocarbonyl-4,9-dihydro 10H-thienol3,4-b][1,5lbenzodiazepin-10-one and endo-8-methyl-8-azabicyclol3,2,1]octan-3-0l1, endo- 3-chloro-4,9-dihydro-4- { [(8-merthyl-8-azabicyclo- [3,2,1)oct-3-yl)oxylcarbonyl § ~10H-thienol3,4-b101,5]- benzodiazepin-10-one was obtained;
(1) From 4-chlorocarbonyl-4,9-dibhydro-10H- thienol[3,4-bJ[1,5lbenzodiazepin-10-one and ewma~8r methyl-8-azabicyclol[3,2,1]Joctan-3-01, exo-4,9-dihydro-4- {[(8-methyl-8-azabicyclol3,2,1}oct-3-gl)oxylcarbo- nyl ¥-10H-thienol3,4-b][1,5]benzodiazepin-10one was obtained.
The novel thienobenzodiazepinones of the formula I and their non-toxic, pharmacologically acceptable acid addition salts have useful phar- macodynamic properties. More paricularly, they exhibit anti-ulcerogenic activity, inhibit gastric acid secretion, and have favorABLE EFFECTS ON various disorders of the gastro-intestinal tract, especially irritable colon, in warm-blooded animals.
The above pharmacodynAMIC PROPERTIES OF THE compounds of the formula 'I and their non-toxic acid addi- tion salts were ascertained by the standards test methods described below.
A favorable relation between anti-ulcerogenic and anti-sectetory effects, on the one hand, and the undesirable effects on pupil size and the secretion of tears and saliva, on the other hand, which occurs particularly with therapueticagents having an anti- cholinergic component, is of particular importance in the therapeutic use of the substances. The following tests show that the compounds of the formula I accor- ding to the invention have surprisingly favorable characteristics in this respect.
ee ———————————————————— ieee rere
Tuvestigation of the electivity of the antimuscarinic
Activity
Object
Oxotremorineg, a syeilic avonist for muscarinic re- ceptors, produces lesions in the rmcous membrane of the stomach in rats and ingrease their secretion of sa- liva. This test method was chosen so that any selective activity of an antimuscarinic subslance on the stomach could be identified. lethod
Ten female albino rats (of the Crl: COB3-CD (sD)
BR strain) with a body weight of from 120 to 150 gm were used in each treatment group and were kept with- out food for 24 hours before the start of the test, but given free access {+o drinking water.
In order to determine, in preliminary Ltegts, the nuscarinic effect of oxotremorine on each of the symp- toms studied, a dosage /activity enrve vag drawn up with at least three dodages for each symptom. _ 38 -
EE ————————————————————————————————————————————— eee
When testing the antivuscarinic substances, the dos age of oxotremorine which triggered the symotom in question in 90 to 100.5 of the animals in the prelimimary tests was used.
Lesion in wucous membrane of gtomach: 0.62 ng/kg ive gecretion of saliva: 0.083 mg/g Lev $ach antimuscarinic substance wns administer=zd in- travenously in uniformly craduated doses 15 minutes before the oxotremorine wns administerad. Control groups were given corresnonding quantities of the 301- vent and suspending agent instead of tho test substance.
Immediately after the oxotremorine vas adminis- tered, the animals were placed in a glass cage for 15 minutes, and observed.
The test for the effect on the oxotremorine induced gecretion of saliva was carried out as a blind test, i.e. the tester did not vmow which treatment the animals had been given
The results woie expressed as the percentage inhibi~ tion of the oxotremorine of fect (the percentage of ani-
mals which ¢id not show the symptom in question). The
EDs values were determined using the method de- scribed by LITCHII-ID and WILCOXOW [J Pharmacol,
Bxp. Ther. 96, 49, (174%) 7
The effects on lesions of the mucous membrane of the stomach were evaluated os follows:
The lesions of the gastric mucous membrane were produced by intravenous injection of 0.62 mg/kg of oe I oxotremdérin 30 minutes after the oral administration of LE 1 mg/kg of neostigmine (a chloinesterase inhibitor). 60 minutes after the administration of the neostigmine, the animals were killed, the stomachs were removed, opened and examined for the presence of any lesions in the mucous membrane. The protective effect of the test substances was expressed as the percentage inhibition (percentage of animals without lesions). The EDs and
D6 values were determined using the method of
LITCHFIELD and WILCOXUT (supra).
Hydriasis
The effect of the test substances on the pupil size
— zation. The whole Jeart was cut up with scissors. All the organs werc then homogenized in a Potter appara- tus.
For the bindin;; test, the homogenized organs were diluted as follows:
Smooth muscle of the fundus of the stomach - 1: 100
Whole heart - 1:3 250
Cerebral cortex -— 1:5000
The homogenized orimn preparations were incubated at a specific concentration of thie radioligand and with a series of concentrations of the non-radioactive test substances in an Bppendorf centrifuge tube at 30°C. The re duration of incubation was 45 minutes. 0.3 n molar im 7
H-methylscopolamine (711-113) was used as the radio- ligand. After incubation had been brought to an end by eentrifuging at 14,000 g, the radioactivity in the pellet was determined. It represents the sum of the specific and non-specific binding of mis. The proportion of non-specific binding was defined as the radioactivity which was bound in the presence of Tu molar quinuclidinyl benzylate. Your mensurements were taken in exch case. The IC, values ol the non-labelled test substances vere detormined rajically. They represent the concentration of Lest substance at which the specific binding of Sms to the muscarinic receptors in the various organs was inhibiled by 50%. > The following table shows the results of these tests for a few representative species of the genus represented by formula I, where
A = 4,9-Dihydro-4- { /T1=nethyl-4-pip ridinyloxy/car~ bonyl Y ~10l-thieno/3, 4-b//T,5/benzodiazenin-10-one,
B = 4,9-Yinydro~4- £/T1 methyl-4-pip ridinyl)anino/- carbonyl} ~10i=thieno,3,4-b//1,5/benzod inzepin-10- one, and } C = 4,9! Dihydro~4- { JT 4=me thy1-1-piperazinyl Janino]- carbonyl § ~101-thieno/3,4-b7/T,57venzodiazepin- 10~0ne.,
Ce ———————————————————————— ee —————————— ee re m od : v0 » dg « * at Ra © rs @ rq Iv pa 1
Ha Ta ov va 24
Pi 3 iy
LE tq
Oo
P © 0 $9 oO 9 3 + . oA o nooQ «J © . ori » HN <y 3 vl a rl - - 3 5 or & « o £4 E04 sod oO MM oom & “. bd ® Go
H 3 ' 0 Lu 4 4 « 3 ri <i ar 11 © oO uy Oo 1 ’ © or t bY 3 oo ® ~~ SY } 3 G4 i i! ft 5 «© £ Le t . e t= = f ] tt AN 42? £4 - © (0) o © aD oJ Cin
RY - « £1 0 Q a ©} 0 @ 8 o ~~ o - 2 1 q 1 - , 0) A oy oO © Q qo 5 & £2 8 3 5 «~ HN ol ga — r= 0 4 § 4 3 3 ‘
Ef ol 92] a + + Lu 4 © Q 0 in 5 © © - : et © © Q ont Hi £ <b re ol 0 [Oh] ie] 5 0 rsh =) m © £l 0 tn
The results in Lhe stove table show Lhat the com pounds in question generally have a high affinity for muscarinic receptors. lioreovery the results show that ~ the new compounds of the formula I differentiate be- tween muscarinic receptors in different types of issue.
This is clear fheh the considerably lower Ce values in the tests on prevavations from the cerebral cortex com- pared vith these of the smooth muscle of the stomach and heart.
The pharmacological data in the above inble show in complete agreement with the receotor binding stud- dies- that the formation of oxotremorine~induced lesions in the mucous membrane of the stomach is inhibited by the abovementioned compounds, even at doses at which no diminution of salivation and no mydriasis can be observed,
Thus, the substituted thienobenzmodiazepinines of the formula I and non-toxic acid additien salts there~ of have useful properties which make them commercially viable, and are choarmctlerized in particular by an excellent protective effect on the stomech ond intestines in warm-blooded anim:ls; for example, they inhibit the et laa ORIGINAL IP bee -
formation of gantric ulcers. hioreover, they have a useful therapeutic range, thanks to their low toxicity and the absence of any significant side effects.
The excellent rctivity of the substitnted thienoben- zodiazepinones of the formula 1 and their non-toxic pharmacolosically acceptable acid addition salts makes it possible to use them in both human md veterinary medicine for the treatment and prophylaxis of diseases “due to disorders of the stomach or intestines. They may oo 10 be used, for example, to treat acute ond chronic gastric and duodenal ulcers, gastritis and gastric hyperacidity in humans and animals. f'or pharmaceutical purposes the compounds of the formula I or their non-toxic, phiriaceologically accept- able acid addition salts are sdministered to warm-blooded animals perorally, parontépally or rectally as active ingredients in customary pharmacentical compositions, that is, compositions concisting esgentially of an inert ’ pharmsceutical carrier and an effective amount of the active ingredient, such as tablets, coated nills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, ® suppositories, tea-malking compositions ond the like. The =
BAD ORIGINAL 0
EE ee —— et 3 RE See ee em daily dose for oral ~dministration is generally between C.01 and 5, preferably between 0,02 and 1,5, more particularly between 0.05 and 1.0 wg/ize body weight, sonerally odminiatered in the form of sevoral, nreferably from 1 to 3, individual doses to uwchieve Lhe desired resulls.
If the substituted thiencbeasodiazeninones of the formula I and/or non-loxie, vharmacolo icrlly acceptable acid addition salts thereof are to be used to treat the diseases mentioned above, Lhe pheuvwicenticel preparations ce “10. may also contain one or more vharmacologically active Ce components from other groups of medicaments, such as antacids, for example aluwnimu hydroxide or magnesium aluminate, secretion-inhibitors such as H,- hlockers, for example cimetidine or ranitidine; gastric and intestinal therapeutic agenls, such as metoclopramide, bromoprid and tiaprid; tranquilizers such as bensodiszepines, for example dinwepam nnd oxnzepam; spasmolytics such as bietamiv:rine, camylofine; anti-cholinergics such as oxypnengyclinine and phencarbamide; plucocorticoids such as prednisclone, fluccortolone 2nd bethamecthousone; none steroidal antiphlogistic ngents such az avlocetic acids and arylproplonic neids, hetrron rylacetic acids and heteroarylpropionic acids, banzothinmine carboxamide ‘BAD ORIGINAL J 2 \ . - A] = dioxideg, pyrazolidined-iones or gquinazolinones, for instance ibuprofen, naprofen, dichlofenac, fenbufen, flurbiprofen, indomethacin, lonawolac, sudoxicam, piro- xicam, phenylbutazone, bumadizon-calciwn or proouazones local anesthetics such as tetracaine and procaine; and optionally also enwymes; vitamina, amino ncids, etc.
The following examples illustrate a few rharmaceuti- cal compositions comprising a compound of the formula I wo. teow 210 0 0 as an active ingredient and represent the best modes con= Cen ‘ templated of using the invention, The parts are parts by weight unless otherwise specified.
HAPLE 4
Tablets
The tablets composition is compounded from the following ingredients: > 4,9-Dihydro-4- ¢/T1-methyl-d-piperidingl)- 5.0 parts -oxy/carbonylYy -10l-thieno/3, 4-b//T,5/- benzodiazepin-10-one hydrochloride
Lactose | 148.Q pacts.
Potato starch 65.0 parts liagnesium stearate 2,0 parts 220.0 parts
Preparation
A 104 slurry is prepared from part of the potato starch by heating. "he active ingredient, lactose and remaining potato starch are mixed together and granu-~ lated with the slurry through a screen with a mesh size of 1.5 mm, The gronulate iz dried at 45%. passed through the screen agnin, mixed with magnesium stea- rate and compressed to form 220 mg~tablets, each of qr" =x oro ORIGINAL
TTT TEs -_— which contains 5 mg of the active ingredient,
CKARPTE
Conted Tablets
The tablets prepared according to fixample 4 are coated in conventional manner with a thn shell consist- ing essentially of a mixture of sugar and talcum, The finished coated tabigets are polished with beeswax.
Weight of coated tablet: 300 mg;
CL en Co EXAMPLE. 6 . CL ee -
Injection Solution
The solution is compounded from the following in- gredients: eee eee 4,9-Dihydro-4- {/T1-methyl-4-piperidingl)- 1.0 parts oxy/ carbonyl §-10li~thieno/3,4-b7/7 )57- benzodiazepin-10-one hydrochloride
Sodium chloride 8,0 parts
Distilled water q.s. ad 1000.0 parts by vol,
EE en D gAD ORIG —
ee —————————
Preparation
The active ingredient and the sodinm chloride are dissolved in a sufliciznt svount of distilled water, and the solution is diluted with additional distilled water to the indicated volume and then filtered until free from suspended particles, “he filtrate is filled into 1 ce~ampules which nye then sealed ond sterilized for 20 minutes at 120%. The contents of each ampule are an injectable solution containing 1 mg of the active ingre~ che ee 10 dient ve oo - CT me Te :
SALT
Suppositories
The suppository compodaition is compounded from the following ingredient: ———————— 4,9-" hyd rom-4- {[T1-motbyl-4-piporiding1 )- 5.0 parts oxy7carnonyl § ~10i-thieno/3, 4-b7/7,57- benzodiazepin-10-cne hydrochloride
Suppository base (c.g. gocoa butter) 1,695.0 varts 1,700,0 parts eT 0 epee D
BAD
Precaration
The finely powdered nective ingredient is homoge- neously blonded into the mollen snppository base which fn OL 4 ar . hag been cooled to 407°C, 1,700 wz portions of the com-— - co SO . I. ; J iB) pogition are pourad at 37 C. inte slightly chilled sup- nository molds and allowed Lo hooden Lherein, ach suppository contains 5 mg of the active ingredient,
LANL 8 vr rn SL AE Drop Solution ‘ TT Tees Cr Co
The solution iz compounded from the following in-
Jgredients: 449-Nihydro-4- {/T T—methyl-A4-piporidingl )- 0.5 ports oxy/earbonyl } ~ 10 = thieno/3 ’ 4-b//7 , 57 benzodiazepin-10-one hydrochloride liethyl v-hydroxyhenzoate 0,035 parts
Fropyl p-hydroxybenzoate 0.015 parts
Anise oil 0.05 parts iienthol 0.06 parts
Fure ethanol 10,0 parts
Yano ORIGINAL J
Sodium crelamnic 1.0 narts ulycerol 15.0 parts
Distilled wiier TO0.0 parts hy vol, ee eee eee “reparation
The aclive ingredient ens sodium cyeiomate are dis— solved in about TC arts of distilled water and glycerol is added thereto, “he »~hydrorybensontos, anise oil and methol are disselved in the ethonnl, and nis solution is added to the asuecus solution uhile stirring. "inally, the mixture is made ap to 100 parts by volume with vater and filtered lo remove any suspended particles,
The filtrate is filled into 100 cc=botlles cauipped with a dropping spout. 1 ml (about 20 dropa) of the solution contains 5 mg of the aclive ingre lient, ny one of La olher compounds erbraced by for- mula 1 or a non-lorie, phrormeecologieally accentable acid addition ali thoreef may bz substituted for the “0 particular aclive ingredient in oxamples 4 Lhrourh 8,
Likewise, the amount of zetive ingredient in these illus-
RAD Ae IAT Po) btm - - 5% 4 trative examples may be varied lo achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmociulical carcvier incrodients may be varicd to meel particular requirements, “hile the present inventbn hoes been illustrated with the aid of certain specific embodiments thercof, it will be veondily apoarel to others 3killed in the art that the invention is not limited to these parti- cular embodiments, and that various changes and modifi-~ cations may be made without departing [rom the spirit “ 4 [RU . . . . LI . . , . . ' of the invention or Lhe scope of ihe appended claims, !
BAD ORIGINAL 9 - 54 - ttn re cum.
Claims (7)
- .-— - = — We Claims Te A compound of Lhe formula : Ch i f : Sy Ti 0 ’ He I ~~ A 3 ANY i ~ ZR wherein D It is M4methyl-A-piperidinyl, d-methyl-l1-piperazinyl, or 3 - or Sp-tropanyl, each of which may optionally have another methyl substituent attached to the heterocyclic ring; R, ig hydrogen or alkyl of 1 to 4 carbon atomsy i, is hydrogen, h=loren or aliyl of 1 to 4 carbon atoms; and A is oxygen, ~Mli- or ~l(CH,) = 3 a geometric iso- mer or enantiomer thereof; or a non-toxic, pharmaco~ logically acceptable acid addition salt thereof, 2 A compound of claim 1, wherein f BAD ORIGINAL 9)
- Ris T-mebhyl-d-piperidingl, A-methyl-l-piperazinyl, or endo- or ovo-O-nothyl=0-n whicseln/%,2,17-0ct- 3-313
- 1 is h,drozen or nethyls i, is chlorine, hydrcsen or methyl; and
- A is oxygen, - Hll- or =i) 3 o geometric iso- mer or enantiomer therocly or a non-toxic, pharmaco- logically accesteble acid addition salt thereof.
- 5¢ A compound of claim 1, which is 4,9-dihvdro-4-) 1 {[{1-meghyl-4-piperidiny xy Jearbonyl § -10H~ RE : x , thieno/3,4-b//7,57bennodiazepin-10-one or a non-toxic, pharmacologically accertable acid addition salt thereof,de A compound ol claim 1, which is 4,9-dihydro=4-— {/T1-methyl-4-piveridingd JawinoTen ebony § -10H- thieno/3,4-b7/T, 57benzodiaze nin-10-one or a non-toxic, rharmacolog ically acerptable acid addition salt thereof, 2+ A compound of claim 1, vhich is 4,%-dihydro-4- {/Tamnetingio1=; om ing aminoTear ony § - 104- thieno/3,4~b//T,57benuod insenin=10-one or 3 non-toxic, iharmicolozienlly accenbuble acid oddition salt thereof. - 56 = BAD ORIGINAL 9 VasantCe — ———ii mmm
- 6. A compound of the formula I 0 a — ~~ A vd ’ So N “to IE wo Ce ere C= 0 » CH . ¥ wherein Ry and. 1, have the same meanings as in claim 1¢ Y is halogen Bit; and Ry is ubsubstituted or holo substituted alkyl of 1 to 5 carbon atoms, phenyl, halo substituted phenyl, nitro substituted phenyl, or arallyl of 7 to 15 carbon atoms,10 . : Cn cas
- 7. An anti-ulcervosmmic phormneontical composition consisting essentially of an inert pharmaceutical carrier and an effective anti ulcerogenic amount of a compound of claim 1, BAD ORIGINAL 9 Pro TN raw fry8, ‘The mathod of inhibiting the Formation of gastric ulcers in on wan blooded snimal in need thereof, which comprises perornily, par-nterally or rectally adwinistering to unid animel au offective anti ulcero-~ genic amount of a compound of claim 1, ol fhard singel ‘unther Schmidt Jolfmng cberlein Gunter Trummlitz Adudolf Hammer Tiero Del Soldato, Inventors - 58 - BAD ORIGINA.Ld amd
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PH28462A PH26825A (en) | 1983-02-14 | 1983-02-14 | Substituted thienobenzodiazepinones and salts thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PH28462A PH26825A (en) | 1983-02-14 | 1983-02-14 | Substituted thienobenzodiazepinones and salts thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PH26825A true PH26825A (en) | 1992-11-05 |
Family
ID=19935036
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PH28462A PH26825A (en) | 1983-02-14 | 1983-02-14 | Substituted thienobenzodiazepinones and salts thereof |
Country Status (1)
| Country | Link |
|---|---|
| PH (1) | PH26825A (en) |
-
1983
- 1983-02-14 PH PH28462A patent/PH26825A/en unknown
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