CA1312863C - Carbamic acid esters of benzazepines - Google Patents
Carbamic acid esters of benzazepinesInfo
- Publication number
- CA1312863C CA1312863C CA000590992A CA590992A CA1312863C CA 1312863 C CA1312863 C CA 1312863C CA 000590992 A CA000590992 A CA 000590992A CA 590992 A CA590992 A CA 590992A CA 1312863 C CA1312863 C CA 1312863C
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- tetrahydro
- benzazepine
- chloro
- alkyl
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
ABSTRACT
Compounds having the formula (I) wherein R1 is H, halogen, or C1-4 alkyl R2 is halogen, CF3, CN
R4 is H, or halogen R5 is furyl, thienyl, pyridyl, or ring systems consisting of phenyl ortho condensed with a benzen, cyclo-hexan, cyclohexen, cyclopentan or cyclopenten ring in which rings one of the carbon atoms may be exchanged with oxygen, sulphur or nitrogen, and each of these ring systems option-ally are substituted with halogen, hydroxy or alkoxy with or not more than 4 carbon atoms, R6 is H or CH3 R7 is H or C1-4 alkyl R8 is H, alkyl, aralkyl, cycloalkyl, or aryl R9 is H, or R9 together with R8 form a piperidino, pyrrolidinyl, morpholino, or piperazinyl ring or a ring with the formula or R9 can be alkyl or alkoxycarbonyl with the formula CHR11 - ? - OR13 where R11 is H, CH3, (CH3)2CH, CH2CH(CH3)2, and R13 is H, alkyl, cycloalkyl, aralkyl, or a 2-acetamide group with the formula where R15 is H, CH3, C2H5, C3H8, or CH(CH3)2, and R14 is H, CH3, C2H5, C3H8 or CH(CH3)2 , and pharmaceutical-acceptable salts thereof.
The compounds are useful as prodrugs for compounds active for the treatment of mental disorders.
Compounds having the formula (I) wherein R1 is H, halogen, or C1-4 alkyl R2 is halogen, CF3, CN
R4 is H, or halogen R5 is furyl, thienyl, pyridyl, or ring systems consisting of phenyl ortho condensed with a benzen, cyclo-hexan, cyclohexen, cyclopentan or cyclopenten ring in which rings one of the carbon atoms may be exchanged with oxygen, sulphur or nitrogen, and each of these ring systems option-ally are substituted with halogen, hydroxy or alkoxy with or not more than 4 carbon atoms, R6 is H or CH3 R7 is H or C1-4 alkyl R8 is H, alkyl, aralkyl, cycloalkyl, or aryl R9 is H, or R9 together with R8 form a piperidino, pyrrolidinyl, morpholino, or piperazinyl ring or a ring with the formula or R9 can be alkyl or alkoxycarbonyl with the formula CHR11 - ? - OR13 where R11 is H, CH3, (CH3)2CH, CH2CH(CH3)2, and R13 is H, alkyl, cycloalkyl, aralkyl, or a 2-acetamide group with the formula where R15 is H, CH3, C2H5, C3H8, or CH(CH3)2, and R14 is H, CH3, C2H5, C3H8 or CH(CH3)2 , and pharmaceutical-acceptable salts thereof.
The compounds are useful as prodrugs for compounds active for the treatment of mental disorders.
Description
` 1 ~31 2~
This invention relates to novel carbamic ac~d esters of sub-stituted 7-hydroxy-2,3,4,5-tetrahydro-lH-3- benzazepines which are useful prodrugs for treatment of mental disorders.
As used in this speciflcation the texm "prodrugn $s defined as a derivative of a biologically active compound, which derivative, when absorbed into the blood stream o~ animals and humans, decomposes in such manner as to release the ac-tive substance and permits the latter to attain a hlgher bioavailability than that which would be obtained i~ the active substance, per se, was adm~nistered perorally. Thus, the active substancs san be admi~istared without problems intravenously; however, peroral admlnistration is usually preferred for obvious reasons. Peroral administration of the active substance ls often unsatisfactory, as it ls de-composed in the gastrointestinal tract and during the firstpass through the liver; b~t peroral administration of the prodrug has both the advantage of an easy administration and a high bioavailabili~y.
Applicant's European patent application No. 86303001 (published November 5, 1986), describes 2,3,4,5-tetrahydro-lH-3-benzazepines useful in the trea~ment of mental disor-ders. If administered intravenously, these benzazepines are very useful in the treatment of mental disorders, as described in the European Patent application; however, if administered orally they suffer from the disadvantage tha~
very large doses have to be given in ordar to obtain the wanted ef~ect.
Thus, a need exists for a measure, by means of which the benzazepines described in European patent application No.
863Q3001 can be administered orally in much smallar doses and yet generate the wanted effect.
Now, according to the invention it has been found that a selected category of the benzazepines described in European patent application No. 86303001 (published November 5, 1986), i.e. the category carrying a (phenolic) hydroxy yroup at the position No. 7 in the ",,~ ~
~j - 13~2~
benzazepin~ nucleus (corresponding to the case o~ R3 being hydroxy in the terminology of the European patent applica-tion) can be converted ~o useful prodrugs, lf certain select-ed carbamic acid esters are formed of the members belo~ging to this selected category of benzazepines.
Thus, the carbamic acid esters of substituted 7-hydroxy-2,3,4,5-tetrahydro-lH-3-benzazepines according to the inven-tion have the general formula I
Rl R ~ - R 7 R~ R R4 15 wherein Rl is H, halogen, or Cl 4 alkyl R ls halogen, CF3, CN
R4 is H, or halogen R5 is furyl, thienyl, pyridyl, or ring systems consisting of phenyl ortho condensed with a benzen, cyclo-hexan, cyclohexen, cyclopentan or cyclopenten ring in which rings one of the carbon atoms may be exchanged with oxygen, sulphur or nitrogen, and each of thsse ring systems option-ally are substituted with halogen, hydroxy or alkoxy with or not more than 4 carbon atoms, R6 is H o~ CH3 R is H or Cl_4 alkyl R ls H, alkyl, aralkyl, cycloalkyl, or aryl R9 is Hr or R9 together with R~ form a piperidino, pyrrolidinyl, morphollno, or pipera~inyl ring or a ring with the formula N
/ ~ C
~o~13 3 ~31~
or R9 can b~ alkyl or alkoxycarbonyl with the formula CHR~ _ oR13 where R is H, CH3, (CH3)2CH, CH2CH(CH3)2, -CH - CH2 - CH3~ -CH2 CH2 3 --C112 {~
and R13 is H, alkyl, cycloalkyl, aralkyl, or a 2-acetamide group with the formula ~5 Rl 4 where R is H~ CH3~ ~2H5, C3H8, or CH~cH332~ and 3 2 5 3 8 or CH(CH3)2 , and pharmacsutical-acceptable salts thereof.
:In a preferred embodiement of the eætars according to the : invention R represants hydrogen. Such 2stsrs are easily synthesized.
In a preferred embodiment of tha esters according to the in-35 vontion R2 is halogen, preferabIy chloro or fl~loro. The cor-responding parent substance exhibits a very high affinity : to tho receptor.
8 ~ ~
In a preferred embodiment of the esters according to the in-vention R4 is hydrogen. Such esters are easily synthesized.
In a preferred embod~ment of ths esters according to the in-vention R5 is phenyl ortho condensed with a benzen, cyclo-hexan, cyclohexen, cyclopentan or cyclopenten ring which may be s~bstituted with halogen, hydroxy or methoxy. Due to the big and lipophile R5 moieties the pharmacological effect is very potent.
In a preferred smbodiment of the esters according to the in-vention R5 is benzofuranyl or 2,3-dihydrobenzo-furanyl. Due to the big and lipophile R5 moieties the pharmacological effect is very potent.
In a preferred embodiment of the esters according to the in-vention R5 is benzothienyl or ~,3-dihydrobenzothienyl. Due to the big and lipophile R5 moietiss the pharmacological effect is very potent.
In a preferred embodiment of the esters according to the in-vention R5 is ~uryl, thienyl or py~idyl. Due to the big and lipophile R5 moieties the pharmacological effect ~s very po-tent.
In a preferred embodiment of the esters according to the in-vention R5 is chromanyl or ohromenyl. Due to the big and lipophile R5 moieties the pharmacological effect is very po-tent.
~n a preferred embodimant of the esters according to the in-vention R5 is lndolyl or indolinyl. Due to the big and lipo-phile R5 moieties the pharmacological effect is very potent.
~5 In a preferr~d embodiment ~f the esters according to the in-vention R5 is quinolinyl. Due to the bi~ and lipophile R5 moieties the pharmacologic~l effect is very potent.
~3~2~
In a preferred embodiment of the esters according to the in-vention R6 represents hydrogen. Such esters are easily s~n-thesized.
In a preferred embodiment of the est~rs according to the in-vention R is hydrogen, methyl, or cyclopropyl. Such esters exhibit a potent pharmacological ef*ect, In a preferred embodimsnt of the esters according to the in-vention R8 is alkyl and R9 is H, alkyl, or alkoxy carbonyl.
In a preferred embodiment of the esters according to the in-vention R8 and R9 together form a ring with the formula o ~ \~C~
where R13 is alkyl, preferably Cl-C5-alkyl, or an N,N-di (Cl 5-alkyl)2-acetamide group C1_5alkY
/
-CH~-C-N
Il \
O Cl_5~1kyl Also, the invention comprises a pharmaoeutical composition r-ontaining an ester of formula I according to tha invention or a salt thereof, in solid form for oral administration.
The pharmaceutical composition is usually prepared as a tab-let or a capsule, preferably as an enteric coated tablet.
s ~ 3 ~
Also, the invention comprises a use of a composition accord-ing to the invention as a nPurolepticum.
In a preferred embodiment of the use of a composition accord-ing to the invention the use is for the treatment of schlzo-phrenia, other psychoses, and manio-depressive disorders.
Also, the inventlon comprises a process for preparing esters : of formula I or salts thereof, characterized by reacting a benzazepine compound of the general formula II
p~l HO-¦~N_R7 (II) with an activated carbamic acid (III) o* the formula R8 o \ 11 N-C-OH (III) R9 .
prefer2bly tha acid halide ~8 \ 11 N-C-X (IV) . R9 where X is a halogen, preferably chlorids, 7 i ~ ~ 1 2 g ~ 3 or with one or two isocyanates V
RB-N=C=O and/or R9-N=C=o (V) whereafter (I) is isolated and lf want~d converted to a alt.
As appears from the above, several active centers can be pre-sent in the carbamic ac~d esters according to the lnvention.
It is to be understood that the invention comprises both racematas and all optical lsomers.
~he new compounds may be synthesized by est2rification of the 7-hydroxy-benzazepine with an actlv2 carbamic acid deri-vative. In order to synthesize the ~ew compounds also ~ari-ous new intermediates have been synthes~zed according to methods publ~shed ln the literature. Thus, carbamoyl chlo-rides o~ N-substituted amino pro-moieties are prepared by reacting the actual N-substituted amino compound ~n its base ~orm with phosgene in a suitable organic solvent (vide e.g.
J.Org~Chem., 51, 1986, 3494-3498), and isocyanates of unsub-stituted amino pro-moietias are generally prepared by react-ing the amino compound in lts base form with the diphosgene reagent trichloromethyl chloroformate (TCF, e.g. J.Org.Chem.
2S 41, 1976, 2070-71: Org~Synth., 59, 1979, 195-201~. The id~n-tity of these pro-moiety intermediates are confirmed by micro-analysis, IR, and lH MMR spectroscopy.
In European patent application NoO 170 090 (published February 5, 1986~, it is stated in the paragraph bridging pages 4 and 5 that there is no way to accurately predict which prodrug structure will be suitable for a particular drug, and that a derivative which will work well for one drug may not do so for another, s differences in absorp-tion, metabolism, distribution, and excretion among drugs do not permit generalizations to be made about prodrug design. Also, from page 34 in this European patent appli-cation No. 170 090 it appears that different (but related) parent substances wlth the same prodrug moie-ty exhibit widely vary$ng relative bioavailabilities, which confirms the above finding that there is no way to accura-tely predict which prodrug structure will be suitable ~or a 5 particular drug, even if a similar drug is known to exhibit a satisfactory relative bioavailability with a specific pro-~rug structure.
Thus, even i it appears from Us patent No. 4,284,555 that a certain class of benzazepines can be esterified with car-bamic acld esters to form prodrugs with improved relative bioavailability, the parent substances ln this i~vention (the previously described subgroup of the benzazepines des-cribed in European pa~ent application No. 86303001, pub-lished November 5, 1986) differ significantly from the benzazepines described in US patent No. 4,284,555, and thus there would be no accurate way to predic~ which kind of prodrug structure would be suitable for the parent sub-stances in the invention.
The prodrug effect is mea~ured as the ratio between the area undPr the curve reprasenting the concentration of the parent substance in the blood stream versus t~me in case of oral administration of the prodrug and the corresponding area ~n case of intravenous administration of an equimolar ~mount of the corresponding parent compound. In the sense of this ~nvention the parent compound corresponding to a certain prodrug is a compound related to the prodrug, the only d~f-ferenca being that the position No. 7 in the parent compound carries the unesterified phenolic hydroxy group only. It has been found that mainly the parent compound is found in the blood stream if the prodrug i~ administered orally.
For more detailed information ln regard to prodrug defini-tion reference can be made to A.A. Sinkula and S.~. Yalkow-: sky; J.Pharm.Sci., 64, 1975, lB3-210, H. Bundgaard (ed.~
(1985), Design of Prodrugs, Elsevier~ Amsterdam, E.B. Roche ~ed.) 1977, Design of Biopharmaceutical Properties through ,~ .
J ~
.. ..
9 ~12~
Prodrugs and Analogs, American Pharmaceutical Association, Washington D.C.
More precisely, the prodrug effect of the bioavailability is measured in the following manner.
The prodrug is administered perorally to a test animal and in a total dose designated "dosep ~ ". The concentration of the parent substance in the blood in mg of parent substance/-ml of plasma is measured at regular time intervals afteradministration, and a curve reprssenting this concentration varsus time, e.g. in hours, is drawn up. The area under the curve (AUCp O ) in (mg/ml) x minutes is calculated.
Similarly the parent substance is administered intravenous-ly in a total dosis designated "dosei v " A similar curve is drawn up, and the area below this curve is similarly i . V .
Now, the bioavailability F is calculatad according to the formula AUCp O /dosep O
F = 100%
25AUCi v /dOsei.V.
More specifically, in relation to this invention the bioavail-ability of the prodrugs is measured in dogs.
In a cross-over ætudy parent substance and corresponding pro-drug are administsred with an interval of one week, the pa-rent substance as an intravenous bolus and tha oorresponding prodrug as an oral solutlon, respectively.
By maans o solid phase extraction of the plasma samples and HPLC the plasma concentration of both parent substance and prodrug is estimated up to 24 hours after administration.
; ~3~28~
After the examples illustrating the ~ynthesig of the prodrugs findings in regard to the bioavailability of some of the ex-emplified prodrugs and some prodrugs chemically related ther~-to will be presented.
s The invention will be further illustrated by the following examples .
~ 8-chloro-7[(N,N-dimethylamino~carbonyloxy]-5-(7-benzo-furanyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, HCl.
1.O g ~3.04 mmol~ of the parent substance ((+)-8-chloro-7-hydroxy-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine) was dlssolved in 20 ml of dry pyridine. To this solution was added in a single operation 0.56 ml (6.08 mmol) of N,N-dimethyl carbamoyl chloride. The thus obtained mixture was placed on an oil bath and refluxed for 24 hours.
Pyrldine was evaporated ~n vacuo together with excess of re-agent. The residual material was dissolved in 30.0 ml of dry ether and precipitated with a 1.0 N HCl solution in ether.
The whlte preclpitate was washed with 2 x 10 ml of dry ether.
Drying in the prasence of P205 was performed for 24 hours at 0.2 mm Hg.
The purity of the product in this example and in Examples 2-6 was determined by means of a HPLC method, see below.
The ~ynthesized compound was chromatographed on a Nucleosil RP C-18 silica support ~mean particle siza 5 ~m) column by means of a stPp gradient procedure~ The eluent program was initiated with a mixture of 25% of acetonitrils and 75% of a O.lM ammonium sulphate buffer of pH 3Ø By means of two steps the acetonitrile volume fraction of the eluent was rai~ed to 55%. Detection of the column outflow was performed by means of W absorbance.
i 1 3~2~
Purity according to HPLC > 98~. The product peak corresponds to a retention time of 16.0 minutas.
lH-NMR,~ppm. (CDC13, TMS): 2.36 3H~s~; 3.00 6H(s), 2.70-3.30 6H(m); 4.60 lH(t) 6.10 lH(s): 6.70-7.55 6H(m);
(+)-8-chloro-7-~(N,N-diethylamino)carbonyloxy~5-(7-benzo-furanyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, ~Cl.
0.5 g (1.52 mmol3 of ((+)-8-chloro-7-hydroxy-5-(7-benzofura-nyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine) was dis-solved in 20 ml dry pyridine. To this solution was added in one operation 0.39 ml (3.04 mmol) N,N-diethyl carbamoyl chloride. The thus obtained mixture was placed on an oil bath and refluxed for 24 hours. Pyridine was evaporated in vacuo together with e~cess of reagent. ~he residual material was dissolved in 20 ml of dry ether and precipitated with a 10%
excess of lN HCl solution in ether. The white precipitate was washed with 2xlO ml of dry ether. Drying with P205 was performed for 24 hours at 0.2 mm Hg.
Purity according to HPLC > 98%. The product peak corresponds to a retention time of 24.0 minutes.
H-NMR,~ppm. (CDC13, TMS): 1.15 6H(m); 2.84 3H(s~: 2.9-4.2 6H(m) 3.30 4H(m); 5.48 lH( ); 6.30 lH(~); 6.84-7.70 6H(m~;
2.9-4.2 6H(m). '-~ 8-chloro-7-[(N-methyl-N-ethoxycarbonyl)amino carbonyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzaze-pine, HCl.
0.98 g (3.0 mmol) of (+) 8-chloro-7-hydroxy-5-(7-benzofura-12 ~ 3 1 2 g~ ~
nyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzaz2pine was dis-solved in 10 ml dry pyridine. This solution was added drop-wise and at room temperature to a solution of 1.5 g (9 mmol) of N- methyl-N-chloroformyl ethyl carbamate in 5 ml of dry pyridine. The thus obtained mixture was placed on an oil bath and refluxed for 16 hours. Pyridine was evaporated in vacuo together with excess of reagent. The rscldual material was dissolved in 20 ml of dry ether and precipitated with 10%
excess of lN HCl dissolved in ether. The white precipitate was washed twice with 10 ml of dry ether.
Purity according to HPLC ~ 98~. The product peak corresponds to a retention time of 15.8 minutes.
~S~
H-NMR, ppm. (CDC13, TMS): 1.30 3H(t); 2.96 3H(s); 3.28 3H(s~;
This invention relates to novel carbamic ac~d esters of sub-stituted 7-hydroxy-2,3,4,5-tetrahydro-lH-3- benzazepines which are useful prodrugs for treatment of mental disorders.
As used in this speciflcation the texm "prodrugn $s defined as a derivative of a biologically active compound, which derivative, when absorbed into the blood stream o~ animals and humans, decomposes in such manner as to release the ac-tive substance and permits the latter to attain a hlgher bioavailability than that which would be obtained i~ the active substance, per se, was adm~nistered perorally. Thus, the active substancs san be admi~istared without problems intravenously; however, peroral admlnistration is usually preferred for obvious reasons. Peroral administration of the active substance ls often unsatisfactory, as it ls de-composed in the gastrointestinal tract and during the firstpass through the liver; b~t peroral administration of the prodrug has both the advantage of an easy administration and a high bioavailabili~y.
Applicant's European patent application No. 86303001 (published November 5, 1986), describes 2,3,4,5-tetrahydro-lH-3-benzazepines useful in the trea~ment of mental disor-ders. If administered intravenously, these benzazepines are very useful in the treatment of mental disorders, as described in the European Patent application; however, if administered orally they suffer from the disadvantage tha~
very large doses have to be given in ordar to obtain the wanted ef~ect.
Thus, a need exists for a measure, by means of which the benzazepines described in European patent application No.
863Q3001 can be administered orally in much smallar doses and yet generate the wanted effect.
Now, according to the invention it has been found that a selected category of the benzazepines described in European patent application No. 86303001 (published November 5, 1986), i.e. the category carrying a (phenolic) hydroxy yroup at the position No. 7 in the ",,~ ~
~j - 13~2~
benzazepin~ nucleus (corresponding to the case o~ R3 being hydroxy in the terminology of the European patent applica-tion) can be converted ~o useful prodrugs, lf certain select-ed carbamic acid esters are formed of the members belo~ging to this selected category of benzazepines.
Thus, the carbamic acid esters of substituted 7-hydroxy-2,3,4,5-tetrahydro-lH-3-benzazepines according to the inven-tion have the general formula I
Rl R ~ - R 7 R~ R R4 15 wherein Rl is H, halogen, or Cl 4 alkyl R ls halogen, CF3, CN
R4 is H, or halogen R5 is furyl, thienyl, pyridyl, or ring systems consisting of phenyl ortho condensed with a benzen, cyclo-hexan, cyclohexen, cyclopentan or cyclopenten ring in which rings one of the carbon atoms may be exchanged with oxygen, sulphur or nitrogen, and each of thsse ring systems option-ally are substituted with halogen, hydroxy or alkoxy with or not more than 4 carbon atoms, R6 is H o~ CH3 R is H or Cl_4 alkyl R ls H, alkyl, aralkyl, cycloalkyl, or aryl R9 is Hr or R9 together with R~ form a piperidino, pyrrolidinyl, morphollno, or pipera~inyl ring or a ring with the formula N
/ ~ C
~o~13 3 ~31~
or R9 can b~ alkyl or alkoxycarbonyl with the formula CHR~ _ oR13 where R is H, CH3, (CH3)2CH, CH2CH(CH3)2, -CH - CH2 - CH3~ -CH2 CH2 3 --C112 {~
and R13 is H, alkyl, cycloalkyl, aralkyl, or a 2-acetamide group with the formula ~5 Rl 4 where R is H~ CH3~ ~2H5, C3H8, or CH~cH332~ and 3 2 5 3 8 or CH(CH3)2 , and pharmacsutical-acceptable salts thereof.
:In a preferred embodiement of the eætars according to the : invention R represants hydrogen. Such 2stsrs are easily synthesized.
In a preferred embodiment of tha esters according to the in-35 vontion R2 is halogen, preferabIy chloro or fl~loro. The cor-responding parent substance exhibits a very high affinity : to tho receptor.
8 ~ ~
In a preferred embodiment of the esters according to the in-vention R4 is hydrogen. Such esters are easily synthesized.
In a preferred embod~ment of ths esters according to the in-vention R5 is phenyl ortho condensed with a benzen, cyclo-hexan, cyclohexen, cyclopentan or cyclopenten ring which may be s~bstituted with halogen, hydroxy or methoxy. Due to the big and lipophile R5 moieties the pharmacological effect is very potent.
In a preferred smbodiment of the esters according to the in-vention R5 is benzofuranyl or 2,3-dihydrobenzo-furanyl. Due to the big and lipophile R5 moieties the pharmacological effect is very potent.
In a preferred embodiment of the esters according to the in-vention R5 is benzothienyl or ~,3-dihydrobenzothienyl. Due to the big and lipophile R5 moietiss the pharmacological effect is very potent.
In a preferred embodiment of the esters according to the in-vention R5 is ~uryl, thienyl or py~idyl. Due to the big and lipophile R5 moieties the pharmacological effect ~s very po-tent.
In a preferred embodiment of the esters according to the in-vention R5 is chromanyl or ohromenyl. Due to the big and lipophile R5 moieties the pharmacological effect is very po-tent.
~n a preferred embodimant of the esters according to the in-vention R5 is lndolyl or indolinyl. Due to the big and lipo-phile R5 moieties the pharmacological effect is very potent.
~5 In a preferr~d embodiment ~f the esters according to the in-vention R5 is quinolinyl. Due to the bi~ and lipophile R5 moieties the pharmacologic~l effect is very potent.
~3~2~
In a preferred embodiment of the esters according to the in-vention R6 represents hydrogen. Such esters are easily s~n-thesized.
In a preferred embodiment of the est~rs according to the in-vention R is hydrogen, methyl, or cyclopropyl. Such esters exhibit a potent pharmacological ef*ect, In a preferred embodimsnt of the esters according to the in-vention R8 is alkyl and R9 is H, alkyl, or alkoxy carbonyl.
In a preferred embodiment of the esters according to the in-vention R8 and R9 together form a ring with the formula o ~ \~C~
where R13 is alkyl, preferably Cl-C5-alkyl, or an N,N-di (Cl 5-alkyl)2-acetamide group C1_5alkY
/
-CH~-C-N
Il \
O Cl_5~1kyl Also, the invention comprises a pharmaoeutical composition r-ontaining an ester of formula I according to tha invention or a salt thereof, in solid form for oral administration.
The pharmaceutical composition is usually prepared as a tab-let or a capsule, preferably as an enteric coated tablet.
s ~ 3 ~
Also, the invention comprises a use of a composition accord-ing to the invention as a nPurolepticum.
In a preferred embodiment of the use of a composition accord-ing to the invention the use is for the treatment of schlzo-phrenia, other psychoses, and manio-depressive disorders.
Also, the inventlon comprises a process for preparing esters : of formula I or salts thereof, characterized by reacting a benzazepine compound of the general formula II
p~l HO-¦~N_R7 (II) with an activated carbamic acid (III) o* the formula R8 o \ 11 N-C-OH (III) R9 .
prefer2bly tha acid halide ~8 \ 11 N-C-X (IV) . R9 where X is a halogen, preferably chlorids, 7 i ~ ~ 1 2 g ~ 3 or with one or two isocyanates V
RB-N=C=O and/or R9-N=C=o (V) whereafter (I) is isolated and lf want~d converted to a alt.
As appears from the above, several active centers can be pre-sent in the carbamic ac~d esters according to the lnvention.
It is to be understood that the invention comprises both racematas and all optical lsomers.
~he new compounds may be synthesized by est2rification of the 7-hydroxy-benzazepine with an actlv2 carbamic acid deri-vative. In order to synthesize the ~ew compounds also ~ari-ous new intermediates have been synthes~zed according to methods publ~shed ln the literature. Thus, carbamoyl chlo-rides o~ N-substituted amino pro-moieties are prepared by reacting the actual N-substituted amino compound ~n its base ~orm with phosgene in a suitable organic solvent (vide e.g.
J.Org~Chem., 51, 1986, 3494-3498), and isocyanates of unsub-stituted amino pro-moietias are generally prepared by react-ing the amino compound in lts base form with the diphosgene reagent trichloromethyl chloroformate (TCF, e.g. J.Org.Chem.
2S 41, 1976, 2070-71: Org~Synth., 59, 1979, 195-201~. The id~n-tity of these pro-moiety intermediates are confirmed by micro-analysis, IR, and lH MMR spectroscopy.
In European patent application NoO 170 090 (published February 5, 1986~, it is stated in the paragraph bridging pages 4 and 5 that there is no way to accurately predict which prodrug structure will be suitable for a particular drug, and that a derivative which will work well for one drug may not do so for another, s differences in absorp-tion, metabolism, distribution, and excretion among drugs do not permit generalizations to be made about prodrug design. Also, from page 34 in this European patent appli-cation No. 170 090 it appears that different (but related) parent substances wlth the same prodrug moie-ty exhibit widely vary$ng relative bioavailabilities, which confirms the above finding that there is no way to accura-tely predict which prodrug structure will be suitable ~or a 5 particular drug, even if a similar drug is known to exhibit a satisfactory relative bioavailability with a specific pro-~rug structure.
Thus, even i it appears from Us patent No. 4,284,555 that a certain class of benzazepines can be esterified with car-bamic acld esters to form prodrugs with improved relative bioavailability, the parent substances ln this i~vention (the previously described subgroup of the benzazepines des-cribed in European pa~ent application No. 86303001, pub-lished November 5, 1986) differ significantly from the benzazepines described in US patent No. 4,284,555, and thus there would be no accurate way to predic~ which kind of prodrug structure would be suitable for the parent sub-stances in the invention.
The prodrug effect is mea~ured as the ratio between the area undPr the curve reprasenting the concentration of the parent substance in the blood stream versus t~me in case of oral administration of the prodrug and the corresponding area ~n case of intravenous administration of an equimolar ~mount of the corresponding parent compound. In the sense of this ~nvention the parent compound corresponding to a certain prodrug is a compound related to the prodrug, the only d~f-ferenca being that the position No. 7 in the parent compound carries the unesterified phenolic hydroxy group only. It has been found that mainly the parent compound is found in the blood stream if the prodrug i~ administered orally.
For more detailed information ln regard to prodrug defini-tion reference can be made to A.A. Sinkula and S.~. Yalkow-: sky; J.Pharm.Sci., 64, 1975, lB3-210, H. Bundgaard (ed.~
(1985), Design of Prodrugs, Elsevier~ Amsterdam, E.B. Roche ~ed.) 1977, Design of Biopharmaceutical Properties through ,~ .
J ~
.. ..
9 ~12~
Prodrugs and Analogs, American Pharmaceutical Association, Washington D.C.
More precisely, the prodrug effect of the bioavailability is measured in the following manner.
The prodrug is administered perorally to a test animal and in a total dose designated "dosep ~ ". The concentration of the parent substance in the blood in mg of parent substance/-ml of plasma is measured at regular time intervals afteradministration, and a curve reprssenting this concentration varsus time, e.g. in hours, is drawn up. The area under the curve (AUCp O ) in (mg/ml) x minutes is calculated.
Similarly the parent substance is administered intravenous-ly in a total dosis designated "dosei v " A similar curve is drawn up, and the area below this curve is similarly i . V .
Now, the bioavailability F is calculatad according to the formula AUCp O /dosep O
F = 100%
25AUCi v /dOsei.V.
More specifically, in relation to this invention the bioavail-ability of the prodrugs is measured in dogs.
In a cross-over ætudy parent substance and corresponding pro-drug are administsred with an interval of one week, the pa-rent substance as an intravenous bolus and tha oorresponding prodrug as an oral solutlon, respectively.
By maans o solid phase extraction of the plasma samples and HPLC the plasma concentration of both parent substance and prodrug is estimated up to 24 hours after administration.
; ~3~28~
After the examples illustrating the ~ynthesig of the prodrugs findings in regard to the bioavailability of some of the ex-emplified prodrugs and some prodrugs chemically related ther~-to will be presented.
s The invention will be further illustrated by the following examples .
~ 8-chloro-7[(N,N-dimethylamino~carbonyloxy]-5-(7-benzo-furanyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, HCl.
1.O g ~3.04 mmol~ of the parent substance ((+)-8-chloro-7-hydroxy-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine) was dlssolved in 20 ml of dry pyridine. To this solution was added in a single operation 0.56 ml (6.08 mmol) of N,N-dimethyl carbamoyl chloride. The thus obtained mixture was placed on an oil bath and refluxed for 24 hours.
Pyrldine was evaporated ~n vacuo together with excess of re-agent. The residual material was dissolved in 30.0 ml of dry ether and precipitated with a 1.0 N HCl solution in ether.
The whlte preclpitate was washed with 2 x 10 ml of dry ether.
Drying in the prasence of P205 was performed for 24 hours at 0.2 mm Hg.
The purity of the product in this example and in Examples 2-6 was determined by means of a HPLC method, see below.
The ~ynthesized compound was chromatographed on a Nucleosil RP C-18 silica support ~mean particle siza 5 ~m) column by means of a stPp gradient procedure~ The eluent program was initiated with a mixture of 25% of acetonitrils and 75% of a O.lM ammonium sulphate buffer of pH 3Ø By means of two steps the acetonitrile volume fraction of the eluent was rai~ed to 55%. Detection of the column outflow was performed by means of W absorbance.
i 1 3~2~
Purity according to HPLC > 98~. The product peak corresponds to a retention time of 16.0 minutas.
lH-NMR,~ppm. (CDC13, TMS): 2.36 3H~s~; 3.00 6H(s), 2.70-3.30 6H(m); 4.60 lH(t) 6.10 lH(s): 6.70-7.55 6H(m);
(+)-8-chloro-7-~(N,N-diethylamino)carbonyloxy~5-(7-benzo-furanyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, ~Cl.
0.5 g (1.52 mmol3 of ((+)-8-chloro-7-hydroxy-5-(7-benzofura-nyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine) was dis-solved in 20 ml dry pyridine. To this solution was added in one operation 0.39 ml (3.04 mmol) N,N-diethyl carbamoyl chloride. The thus obtained mixture was placed on an oil bath and refluxed for 24 hours. Pyridine was evaporated in vacuo together with e~cess of reagent. ~he residual material was dissolved in 20 ml of dry ether and precipitated with a 10%
excess of lN HCl solution in ether. The white precipitate was washed with 2xlO ml of dry ether. Drying with P205 was performed for 24 hours at 0.2 mm Hg.
Purity according to HPLC > 98%. The product peak corresponds to a retention time of 24.0 minutes.
H-NMR,~ppm. (CDC13, TMS): 1.15 6H(m); 2.84 3H(s~: 2.9-4.2 6H(m) 3.30 4H(m); 5.48 lH( ); 6.30 lH(~); 6.84-7.70 6H(m~;
2.9-4.2 6H(m). '-~ 8-chloro-7-[(N-methyl-N-ethoxycarbonyl)amino carbonyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzaze-pine, HCl.
0.98 g (3.0 mmol) of (+) 8-chloro-7-hydroxy-5-(7-benzofura-12 ~ 3 1 2 g~ ~
nyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzaz2pine was dis-solved in 10 ml dry pyridine. This solution was added drop-wise and at room temperature to a solution of 1.5 g (9 mmol) of N- methyl-N-chloroformyl ethyl carbamate in 5 ml of dry pyridine. The thus obtained mixture was placed on an oil bath and refluxed for 16 hours. Pyridine was evaporated in vacuo together with excess of reagent. The rscldual material was dissolved in 20 ml of dry ether and precipitated with 10%
excess of lN HCl dissolved in ether. The white precipitate was washed twice with 10 ml of dry ether.
Purity according to HPLC ~ 98~. The product peak corresponds to a retention time of 15.8 minutes.
~S~
H-NMR, ppm. (CDC13, TMS): 1.30 3H(t); 2.96 3H(s); 3.28 3H(s~;
4.25 2H(q); 2.9-4.2 6H(m), 5.50 lH(s); 6.30 lH(s); 6.85-7.70 6H(m).
(~)-8-chloro-7-[(R,S)-N-(l-methoxycarbonyl-l-ethyl~amino carbonyloxy]-5-(7-benzofuranyl~-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine.
0.40 g (3.05 mmol) of N-carbonyl D,L alanine methyl ester is dissolved in 5 ml acetonitrila. This solution was added dropwise to a refluxing solution of 0.50 g (1.52 mmol) of (+)-8-chloro-7-hydro~y-5-(7~benzofuranyl)-2,3,4,5-tetra-hydro-lH-3-methyl-3-benzazepine in 20 ml of acetonitrile, and reflux is continued for further 8 hours. Acetonitrile and excess of reagent was evaporated in vacuo, leaving a yellow oil, which was easily purified by flash chromatography on a ilica column and evaporated in vacuo to a white crys-talline compound.
Purity according to HPLC > 98~. The product peak corresponds to a retention time of 14.3 minutes.
.
13 ~ ~ ~2~
H-NMR,~ppm- lCD3-SO-CD3, TMS): 1.25 3H(8d): 2.28 3H(s);
2.80-4.20 8H(m); 3.56 3H(s); 4.80 lH(d); 6.30 lH(s); 7.0-8.0 6H(m).
EXAMPLE_5 ~ 8-chloro-7~[(S)(2-methoxycarbonyl)-1-pyrrolidinyl-carbo-nyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine.
A solution of 0.58 g (3.05 mmol) of N-chlorocarbonyl L-pro-line methyl ester in 10 ml of dry pyridine was dropwise added to 0.5 g (1.52 mmol) of (~)-8-chloro-7-hydroxy-5-(7-benzo-furanyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine in 10 ml of dry pyridine. When the addition was complete, the mixture was placed on an oil bath for 16 hours with reflux.
Pyridine and excess of reagent was evaporated in vacuo, and the residual material was taken into 50 ml of ether, and washed with 5% NaHC03, saturated NaCl and H20. The ether 20 phase was dried over MgS04 and evaporated to an oil. The re- -sidual oil was purified on a silica column by means of flash chromatography, and after vacuum evaporation of the eluent a white crystalline compound was obtained.
Purity according to HPLC > 98~. The product peak corresponds to a retention time of 18.5 minutes.
l~_NM~, ppm. (CDC13, TMS): 1.50-4.50 l9H~m,complex); 4.80 lH(d): 6.40 lH(d); 6.80-7.70 6H(m).
EX~MPLE 6 ~ 8-chloro-7-(isopropylamino carbonyloxy)-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine ; To a refluxing mixture of 0.5 g(l.5~ mmol) of ~)-8-chloro-7-hydroxy-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-msthyl-3-benzazepin in 20 ml acetonitrile was dropwise added 0.30 ml (3.04 mmol~ isopropyl isoeyanate. The mixtur~ was re~luxed for additional 6 hours, and then the acstonitrile was removed by evaporation in vacuo. The residual material was obtained as analytically pure crystals from hot isopropanol.
Purity according to HPLC > 98~. The product peak corresponds to a retention time of 17.5 minutes.
1H-NMR,~ppm. (CD3SOCD3, TMS): 1.00 6H(d); 2.20 3H(~); 2.10-3.50 8H(m); 4.80 lH(s); 6.25 lH(s); 6.8-7.9 6H(m).
In analogy with the preparation described in example 6 the following compounds w~re synthesized: -~XAMPLE 7 ~ 8-chloro-7-(allylamino carbonyloxy)-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-msthyl-3-benzazepine ~0 lH-NMR,~ppm. ~CDCl3, TMS): 2.35, 3H(s); 2.4-3.3 6H(m); 3.8 2H(t); 4.8 lH(t); 5.0-5.2 3H(m); 5.8 lH(m); 6.4 lH(s); 6.78 lH(s~; 7.05 lH(d); 7.25 2H(m); 7~55 2H(m).
~ 8-chloro-7-(benzylamino carbonyloxy)-5-(7-benzofur~nyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by heating to 70C in toluene with 0.5 equiv. of N-methyl-piperidine as catalyst.
d' H-NMR, ppm. (CDCl3, TMS): 2.3 3Hts); 2~4-3.4 6H(m); 4.85 lH~d), 5~1-5.3 3H(m); 6.5 lH(s); 6.8 lH~s); 7.0-7.6 lOH(m).
~ 3~28~
E~AMPLE 9 (+)-8-chloro-7-(n-butylamino carbonyloxy)-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by haating to 70C in toluene with 0.2 equiv. of N-methylpi-peridine as catalyst.
lH-NMR,~ppm. (CDC13, TMS): 1.2 7H(m); 2.3 3H(s); 2.4-3.3 6H(m);
4.7 lH(d); 5.0-5.2 3H(m); 6.4 lH(s); 6.8 lH(d); 7.05 lH(d);
7.25 2H(m); 7.6 2H(m).
(~)-8-chloro-7-(cyclohexylamino carbonyloxy)-5-(7-benzofu-ranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxing 24 h in methylenechloride with 1 equ~v. of tri-ethylamine as catalyst.
H-NMR,~ppm. (CD3SOCD3, TMS): 1.0-1.8 10H(m~; 2.15 lH(m);
2.25 3H(s); 2.6-3.2 5H(m); 3.7 lH(m); 4.6 lH(d); 6.2 lH(s);
(~)-8-chloro-7-[(R,S)-N-(l-methoxycarbonyl-l-ethyl~amino carbonyloxy]-5-(7-benzofuranyl~-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine.
0.40 g (3.05 mmol) of N-carbonyl D,L alanine methyl ester is dissolved in 5 ml acetonitrila. This solution was added dropwise to a refluxing solution of 0.50 g (1.52 mmol) of (+)-8-chloro-7-hydro~y-5-(7~benzofuranyl)-2,3,4,5-tetra-hydro-lH-3-methyl-3-benzazepine in 20 ml of acetonitrile, and reflux is continued for further 8 hours. Acetonitrile and excess of reagent was evaporated in vacuo, leaving a yellow oil, which was easily purified by flash chromatography on a ilica column and evaporated in vacuo to a white crys-talline compound.
Purity according to HPLC > 98~. The product peak corresponds to a retention time of 14.3 minutes.
.
13 ~ ~ ~2~
H-NMR,~ppm- lCD3-SO-CD3, TMS): 1.25 3H(8d): 2.28 3H(s);
2.80-4.20 8H(m); 3.56 3H(s); 4.80 lH(d); 6.30 lH(s); 7.0-8.0 6H(m).
EXAMPLE_5 ~ 8-chloro-7~[(S)(2-methoxycarbonyl)-1-pyrrolidinyl-carbo-nyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine.
A solution of 0.58 g (3.05 mmol) of N-chlorocarbonyl L-pro-line methyl ester in 10 ml of dry pyridine was dropwise added to 0.5 g (1.52 mmol) of (~)-8-chloro-7-hydroxy-5-(7-benzo-furanyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine in 10 ml of dry pyridine. When the addition was complete, the mixture was placed on an oil bath for 16 hours with reflux.
Pyridine and excess of reagent was evaporated in vacuo, and the residual material was taken into 50 ml of ether, and washed with 5% NaHC03, saturated NaCl and H20. The ether 20 phase was dried over MgS04 and evaporated to an oil. The re- -sidual oil was purified on a silica column by means of flash chromatography, and after vacuum evaporation of the eluent a white crystalline compound was obtained.
Purity according to HPLC > 98~. The product peak corresponds to a retention time of 18.5 minutes.
l~_NM~, ppm. (CDC13, TMS): 1.50-4.50 l9H~m,complex); 4.80 lH(d): 6.40 lH(d); 6.80-7.70 6H(m).
EX~MPLE 6 ~ 8-chloro-7-(isopropylamino carbonyloxy)-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine ; To a refluxing mixture of 0.5 g(l.5~ mmol) of ~)-8-chloro-7-hydroxy-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-msthyl-3-benzazepin in 20 ml acetonitrile was dropwise added 0.30 ml (3.04 mmol~ isopropyl isoeyanate. The mixtur~ was re~luxed for additional 6 hours, and then the acstonitrile was removed by evaporation in vacuo. The residual material was obtained as analytically pure crystals from hot isopropanol.
Purity according to HPLC > 98~. The product peak corresponds to a retention time of 17.5 minutes.
1H-NMR,~ppm. (CD3SOCD3, TMS): 1.00 6H(d); 2.20 3H(~); 2.10-3.50 8H(m); 4.80 lH(s); 6.25 lH(s); 6.8-7.9 6H(m).
In analogy with the preparation described in example 6 the following compounds w~re synthesized: -~XAMPLE 7 ~ 8-chloro-7-(allylamino carbonyloxy)-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-msthyl-3-benzazepine ~0 lH-NMR,~ppm. ~CDCl3, TMS): 2.35, 3H(s); 2.4-3.3 6H(m); 3.8 2H(t); 4.8 lH(t); 5.0-5.2 3H(m); 5.8 lH(m); 6.4 lH(s); 6.78 lH(s~; 7.05 lH(d); 7.25 2H(m); 7~55 2H(m).
~ 8-chloro-7-(benzylamino carbonyloxy)-5-(7-benzofur~nyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by heating to 70C in toluene with 0.5 equiv. of N-methyl-piperidine as catalyst.
d' H-NMR, ppm. (CDCl3, TMS): 2.3 3Hts); 2~4-3.4 6H(m); 4.85 lH~d), 5~1-5.3 3H(m); 6.5 lH(s); 6.8 lH~s); 7.0-7.6 lOH(m).
~ 3~28~
E~AMPLE 9 (+)-8-chloro-7-(n-butylamino carbonyloxy)-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by haating to 70C in toluene with 0.2 equiv. of N-methylpi-peridine as catalyst.
lH-NMR,~ppm. (CDC13, TMS): 1.2 7H(m); 2.3 3H(s); 2.4-3.3 6H(m);
4.7 lH(d); 5.0-5.2 3H(m); 6.4 lH(s); 6.8 lH(d); 7.05 lH(d);
7.25 2H(m); 7.6 2H(m).
(~)-8-chloro-7-(cyclohexylamino carbonyloxy)-5-(7-benzofu-ranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxing 24 h in methylenechloride with 1 equ~v. of tri-ethylamine as catalyst.
H-NMR,~ppm. (CD3SOCD3, TMS): 1.0-1.8 10H(m~; 2.15 lH(m);
2.25 3H(s); 2.6-3.2 5H(m); 3.7 lH(m); 4.6 lH(d); 6.2 lH(s);
5.8 2H(m); 7.15 2H(m); 7.6 2H(m).
In analogy with the preparation described in example 4 the following compounds were synthesized:
(+)-8 chloro-7-[(S3-N-(1-methoxycarbonyl-phenethyl)amino carbonyloxy~-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine lH-NMR,~ppm. (CDC13, TMS): 2.25 3H~s); 2.4-3.2 6H(m~; 3.8-4.1 4H(s,m); 4.55 lH(d); 5.1 2H(m), 6.3 lH(s); 6.75 2H(m);
7.15 2H(m); 7.55 2H(m).
~31~
~ 8-chloro-7-t(S)-N-(1-methoxycarbonyl-2-methyl-butyl)amino carbonyloxy]-5~(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine H-NMR,~ppm. (CDC13, TMS): 1.2-1.5 9H(m); 2.3 3H(s); 2.4-3.2 6H(m); 3.8-4.3 4H(s,m); 4.55 lH(d); 5.2 2H(m); 6.3 lH(s);
In analogy with the preparation described in example 4 the following compounds were synthesized:
(+)-8 chloro-7-[(S3-N-(1-methoxycarbonyl-phenethyl)amino carbonyloxy~-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine lH-NMR,~ppm. (CDC13, TMS): 2.25 3H~s); 2.4-3.2 6H(m~; 3.8-4.1 4H(s,m); 4.55 lH(d); 5.1 2H(m), 6.3 lH(s); 6.75 2H(m);
7.15 2H(m); 7.55 2H(m).
~31~
~ 8-chloro-7-t(S)-N-(1-methoxycarbonyl-2-methyl-butyl)amino carbonyloxy]-5~(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine H-NMR,~ppm. (CDC13, TMS): 1.2-1.5 9H(m); 2.3 3H(s); 2.4-3.2 6H(m); 3.8-4.3 4H(s,m); 4.55 lH(d); 5.2 2H(m); 6.3 lH(s);
6.7 2H(m); 7.3 2H(m), 7.6 2H(m).
EXAMPL~ 13 (+)-8-chloro-7-[(R,S)-N-(l-methoxycarbonyl-3-methyl-butyl)-amino carbonyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine H-NMR,~ppm. (CDC13, TMS): 1.2-1.5 9H(m); 2.3 3H(s); 2.4-3.2 6H(m), 3.8-4.3 4H(s,m); 4.6 lH(dl; 5.3 2H(m); 6.5 lH(s); 6.7 2H(m); 7.3 2H(m~; 7.7 2H(m).
2~
In analogy with the preparation described in example 2 the following compounds were synthesized:
8-chloro-7~[(N,N-dimethylamino~carbonyloxy]-5-(2,3-di-hydrobenzofuran-7-ylj-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, HCl ~ ~`
H-NMR, ppm. free base ~CD3SOCD3, TMS3: 2.2 lH(t): 2.3 3H(s): 2.85 3H(s): 3.0 3H(s), 2.6-303 7H(m); 4.35 lH(d);
4.4 2H(t) 6.38 lH(s); 6.95 2H(m); 7.2 2H(m).
17 ~312~3 (+)-8-chloro-7-C(N,N-diethylamino)carbonyloxy]-5-(2,3-dihy-dro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-bsn-zazepine, HCl H-NMR,~ppm. (CD3SOCD3, TMS): 1.15 6H(double t~; 2.85 3H(s);
3.0-3.8 12H(m); 4.5 2H(m); 4.85 lH(d3; 6.3 lH(s); 7.0 2H(m);
EXAMPL~ 13 (+)-8-chloro-7-[(R,S)-N-(l-methoxycarbonyl-3-methyl-butyl)-amino carbonyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine H-NMR,~ppm. (CDC13, TMS): 1.2-1.5 9H(m); 2.3 3H(s); 2.4-3.2 6H(m), 3.8-4.3 4H(s,m); 4.6 lH(dl; 5.3 2H(m); 6.5 lH(s); 6.7 2H(m); 7.3 2H(m~; 7.7 2H(m).
2~
In analogy with the preparation described in example 2 the following compounds were synthesized:
8-chloro-7~[(N,N-dimethylamino~carbonyloxy]-5-(2,3-di-hydrobenzofuran-7-ylj-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, HCl ~ ~`
H-NMR, ppm. free base ~CD3SOCD3, TMS3: 2.2 lH(t): 2.3 3H(s): 2.85 3H(s): 3.0 3H(s), 2.6-303 7H(m); 4.35 lH(d);
4.4 2H(t) 6.38 lH(s); 6.95 2H(m); 7.2 2H(m).
17 ~312~3 (+)-8-chloro-7-C(N,N-diethylamino)carbonyloxy]-5-(2,3-dihy-dro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-bsn-zazepine, HCl H-NMR,~ppm. (CD3SOCD3, TMS): 1.15 6H(double t~; 2.85 3H(s);
3.0-3.8 12H(m); 4.5 2H(m); 4.85 lH(d3; 6.3 lH(s); 7.0 2H(m);
7.3 2H(d);
(+)-8-chloro-7-[(N-methyl-N-cyclohexyl)amino carbonyloxy]-5-(2,3-dihydro-banzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, HCl by refluxing 4 h in pyridine.
lH-NMR,~ppm. free base (CD3SOCD3, TMS): 1.0-1.8 lOH(m); 2.15 lH(t); 2.2 3H(s); 2.7-3.7 llH(m), 4.35 lH(d); 4.45 2H(t):
6.35 lH(s); 6.9 2H(m); 7.2 lH(d) 7.35 lH(s).
(+)-8-chloro-7-[(N-methyl-N-ethyl)amino carbonyloxy]-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, HCl by refluxing 8 h in pyridine.
lH-NMR,~ppm. free base (CD3SOCD3, TMS): 1.0-1.15 3H(double t, after heating to 90C lt appears as ~ne t~; 2.15 lH(t);
2.25 3~ ; 2.7-3.4 12H(m); 4.4 lH(d): 4.45 2H(t): 6.35 lH(broad 9) 6.9 2H(m); 7.2 2H(d).
18 ~3:~3~
(+)-8-chloro-7-[(N-methyl-N-isopropyl)amino carbonyloxy]-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro- lH-3 -methyl-3-benzazepine, HCl by refluxing 8 h in ~yrldine.
:1 ~
H-NMR, ppm. free base (CD3$OCD3, TMS~: 1.0-1.2 6H(double d); 2.15 lH(t); 2.25 3H(s); 2.7-3.25 llH(m3; 4.4 lH(d);
4.45 2H(t); 6.3 lEI(s); 6.9 2H(m); 7.2 lH(d), 7.4 lH(s).
.
(+)-8-chloro-7-[(N-methyl-N-benzyl)amino carbonyloxy~-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-b~nzazepine, HCl lH-NMR, ~ pm. free base (CD3SOCD3, ~MS): 2.25 lH(t); 2.3 3H(s); 2.7-3.3 10H(m); 4.3-4.6 5H(m); 6.3 lH(d); 6.9 2H(m);
7.2-7.5 7H(m).
'~
In analogy with the preparation described in example 5 the following compounds were synthesized:
(+)-8-chloro-7-[(S)-(2-benzyloxycarbonyl)-1-pyrrolidinyl-carbonyloxy~-5-~2,3-dih~dro-benzofuran-7-yl)-2,3,4,5-tetra-hydro-lH-3-methyl-3-benzazepine by refluxing 4 h ~n ~yridine.
1H-NMR,~ppm. ~CD3SOCD3, TMS): 1.8-2.0 3H(m): 2.2 2H(s), 2.3 3H(s); 2.8-3.7 10H(m), 4~4-4O55 3H(m); 4.95-5.2 2H(m); 6.45 lH(d); 6.7 lH(s); S.9 2H(m); 7~2 lH(m); 7.25-7.4 5H(m~.
19 i ~12~3 (+)-8-chloro-7- r ( R)-(2-benzyloxycarbonyl)-l-pyrrolidinyl-carbonyloxy]-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetra-S hydro-lH-3-methyl-3-benzazepine by refluxing 4 h in pyridine.
lH-NMR,~ppm. (CD3SOCD3, D2O, TMS): 1.8-2.0 3H(m), 2.2 2H(s);
2.3 3H(s); Z.8-3.7 lOH(m~; 4.4-4.55 3H(m); 4.g5-5.2 2H(m);
6.45 lH(d); 6.7 lH(s); 6.9 2H(m); 7.2 lH(m); 7.25-7.4 5H(m).
(+)-8-chloro-7-[(S3-(2 N,N-diethylaminocarbonyl-methyloxy-carbonyl)-l-pyrrolidinyl-carbonyloxy]-5-(2,3-dihydro-benzo-furan-7-yl~-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxing 4 h in pyridine.
H-NMR,~ppm. lCD3SOCD3, D20, TMS): 1.0-1.1 6H~double t, after heating to 90C it appear~ as one t), 1.9 ZH(m): 2.1-2.3 6H(s,m), 2.6-3.6 13H(m); 4.3-4.55 4H(m~; 4.6-4.85 2H(m);
6.35 lH(d); 6~9 2H(m); 7.2 2H(m); 7.4 lH(d).
(~)-8-chloro-7-[(R)-(2-N,N-diethylaminocarbonyl-methyloxy-carbonyl)-l-pyrrolidinyl-carbonyloxy]-5-~2,3-dihydro-benzo-furan-7 yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxing 4 h in pyrldine.
d-H-MMR, ppm. (CD3SOCD3, D20, TMS). 1.0-1.1 6H(double t, after heating to 90 C it appears as one t); 1.9 2H(m); 2.1-2.3 6H(s,m); 2.6-3.6 13H(m); 4.3-4.55 4H(m); 4.6-4.85 2H(m);
6.35 lH(d); 6.9 2H(m), 7.2 2H(m); 7.4 lH(d).
' 1~28~
(+)-8-chloro-7-t(S)-(2-carboxy)-1-pyrrolidinyl-carbonyloxy]-5~(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine 113 mg (0.2 mmol) of (+)-8-chloro-7-[(S)-(2-benzyloxycarbo-nyl)-1-pyrrolidinyl-carbonyloxy]-5-~2,3-dihydro-benzofuran-7-yl)-2,3,4,5~tetrahydro-lH-3-methyl-3-benzazepine (example 22~ were dissolved in 20 ml tetrahydrofuran. 10 mg palladium/-cell~te (10%) was added and the suspenslon was hydrogenated at room temperature and 1 atm. for 45 min. Further 20 mg of palladium/carbon (10%) was added, and the mixture was hydro-genated for 3 h. The catalyst was removed by filtration, and the solvent was evaporated in vacuo. The residual material was dissolved in a few ml of methanol/tetrahydrofuran, water was added and the product was obtained by lyophilyzation.
1H-NMR, ppm- (CD3SOCD3, D20, TMS): 1.8-2.0 3H(m); 2.1-2.3 lH(m) 2.25 3H(s); 2.9-4.6 22H(m); ~.45 lH(s); 6.9 2H(d);
7.2 lH(broad s); 7.4 lH(d).
(+)-8-chloro-7-[(N-methyl-N-cyclohexyl)amino carbonyloxy]-5-(2,3-dihydro-banzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, HCl by refluxing 4 h in pyridine.
lH-NMR,~ppm. free base (CD3SOCD3, TMS): 1.0-1.8 lOH(m); 2.15 lH(t); 2.2 3H(s); 2.7-3.7 llH(m), 4.35 lH(d); 4.45 2H(t):
6.35 lH(s); 6.9 2H(m); 7.2 lH(d) 7.35 lH(s).
(+)-8-chloro-7-[(N-methyl-N-ethyl)amino carbonyloxy]-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, HCl by refluxing 8 h in pyridine.
lH-NMR,~ppm. free base (CD3SOCD3, TMS): 1.0-1.15 3H(double t, after heating to 90C lt appears as ~ne t~; 2.15 lH(t);
2.25 3~ ; 2.7-3.4 12H(m); 4.4 lH(d): 4.45 2H(t): 6.35 lH(broad 9) 6.9 2H(m); 7.2 2H(d).
18 ~3:~3~
(+)-8-chloro-7-[(N-methyl-N-isopropyl)amino carbonyloxy]-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro- lH-3 -methyl-3-benzazepine, HCl by refluxing 8 h in ~yrldine.
:1 ~
H-NMR, ppm. free base (CD3$OCD3, TMS~: 1.0-1.2 6H(double d); 2.15 lH(t); 2.25 3H(s); 2.7-3.25 llH(m3; 4.4 lH(d);
4.45 2H(t); 6.3 lEI(s); 6.9 2H(m); 7.2 lH(d), 7.4 lH(s).
.
(+)-8-chloro-7-[(N-methyl-N-benzyl)amino carbonyloxy~-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-b~nzazepine, HCl lH-NMR, ~ pm. free base (CD3SOCD3, ~MS): 2.25 lH(t); 2.3 3H(s); 2.7-3.3 10H(m); 4.3-4.6 5H(m); 6.3 lH(d); 6.9 2H(m);
7.2-7.5 7H(m).
'~
In analogy with the preparation described in example 5 the following compounds were synthesized:
(+)-8-chloro-7-[(S)-(2-benzyloxycarbonyl)-1-pyrrolidinyl-carbonyloxy~-5-~2,3-dih~dro-benzofuran-7-yl)-2,3,4,5-tetra-hydro-lH-3-methyl-3-benzazepine by refluxing 4 h ~n ~yridine.
1H-NMR,~ppm. ~CD3SOCD3, TMS): 1.8-2.0 3H(m): 2.2 2H(s), 2.3 3H(s); 2.8-3.7 10H(m), 4~4-4O55 3H(m); 4.95-5.2 2H(m); 6.45 lH(d); 6.7 lH(s); S.9 2H(m); 7~2 lH(m); 7.25-7.4 5H(m~.
19 i ~12~3 (+)-8-chloro-7- r ( R)-(2-benzyloxycarbonyl)-l-pyrrolidinyl-carbonyloxy]-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetra-S hydro-lH-3-methyl-3-benzazepine by refluxing 4 h in pyridine.
lH-NMR,~ppm. (CD3SOCD3, D2O, TMS): 1.8-2.0 3H(m), 2.2 2H(s);
2.3 3H(s); Z.8-3.7 lOH(m~; 4.4-4.55 3H(m); 4.g5-5.2 2H(m);
6.45 lH(d); 6.7 lH(s); 6.9 2H(m); 7.2 lH(m); 7.25-7.4 5H(m).
(+)-8-chloro-7-[(S3-(2 N,N-diethylaminocarbonyl-methyloxy-carbonyl)-l-pyrrolidinyl-carbonyloxy]-5-(2,3-dihydro-benzo-furan-7-yl~-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxing 4 h in pyridine.
H-NMR,~ppm. lCD3SOCD3, D20, TMS): 1.0-1.1 6H~double t, after heating to 90C it appear~ as one t), 1.9 ZH(m): 2.1-2.3 6H(s,m), 2.6-3.6 13H(m); 4.3-4.55 4H(m~; 4.6-4.85 2H(m);
6.35 lH(d); 6~9 2H(m); 7.2 2H(m); 7.4 lH(d).
(~)-8-chloro-7-[(R)-(2-N,N-diethylaminocarbonyl-methyloxy-carbonyl)-l-pyrrolidinyl-carbonyloxy]-5-~2,3-dihydro-benzo-furan-7 yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxing 4 h in pyrldine.
d-H-MMR, ppm. (CD3SOCD3, D20, TMS). 1.0-1.1 6H(double t, after heating to 90 C it appears as one t); 1.9 2H(m); 2.1-2.3 6H(s,m); 2.6-3.6 13H(m); 4.3-4.55 4H(m); 4.6-4.85 2H(m);
6.35 lH(d); 6.9 2H(m), 7.2 2H(m); 7.4 lH(d).
' 1~28~
(+)-8-chloro-7-t(S)-(2-carboxy)-1-pyrrolidinyl-carbonyloxy]-5~(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine 113 mg (0.2 mmol) of (+)-8-chloro-7-[(S)-(2-benzyloxycarbo-nyl)-1-pyrrolidinyl-carbonyloxy]-5-~2,3-dihydro-benzofuran-7-yl)-2,3,4,5~tetrahydro-lH-3-methyl-3-benzazepine (example 22~ were dissolved in 20 ml tetrahydrofuran. 10 mg palladium/-cell~te (10%) was added and the suspenslon was hydrogenated at room temperature and 1 atm. for 45 min. Further 20 mg of palladium/carbon (10%) was added, and the mixture was hydro-genated for 3 h. The catalyst was removed by filtration, and the solvent was evaporated in vacuo. The residual material was dissolved in a few ml of methanol/tetrahydrofuran, water was added and the product was obtained by lyophilyzation.
1H-NMR, ppm- (CD3SOCD3, D20, TMS): 1.8-2.0 3H(m); 2.1-2.3 lH(m) 2.25 3H(s); 2.9-4.6 22H(m); ~.45 lH(s); 6.9 2H(d);
7.2 lH(broad s); 7.4 lH(d).
8-chloro-7-[(R)-(2-carboxy)-1-pyrrolidinyl-carbonyloxy]-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine ~he compound was prepared in analogy with the preparation des-cribed in example 24.
H-MMR, ~ pm- (CD3SOCD3, H20, TMS): 1.8-2.0 3H(m~; 2.1-2.3 lH(m): 2.25 3H(s); ~.9-4.6 22~(m), 6.45 lH(s); 6.9 2H(d);
~5 7.2 lH(broad s); 7.4 lH~d).
21 131 2~3 In analogy with the preparation described in example 5 the following compounds were synthesized:
~ 8-chloro-7-[(S)-(N-methyl-N~ methoxycarbonyl-1-phen-ethyl))amino carbonyloxy]-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxing 4 h in pyridine.
~-NMR,~ppm. (CD3SOCD3, D20, TMS): 2.1-2.2 4H(s,t), 2.6-3.2 12H(m); 3.6 3H(d, after heaiing to 90C it appears as s);
4.3-4.5 3H(m); 4.8 lH(m), 6.4 l~(d, after heating to 90C
it appears as a sinylet) ; 6.85 2H(m); 7.15-7.35 7H(m).
(~)-8-chloro-7- r ( s ~ -N-methyl-N-(l~N',N'-diethylaminocarbonyl-methyloxycarbonyl-1-phenethyl3amino carbonyloxy~-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxing 5 h in pyridine.
H-NMR,~ppm. (CD3SOCD3, TMS): 0.9-1.1 6H(d~uble t); 2.7-5.1 26H(m); 6.1 l~(s); 6.9-7.5 9H(m).
~ 8-chloro-7-[(S)-N-methyl-N~ methoxycarbonyl-l-ethyl)-amino carb~nyloxy]-5-(2,3-dthydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxiny 6 h in pyridine.
~2~
lH-NMR,~ppm. (CD3SOCD3, TMS): 1.4 3H(double d); 2.2 lH(t);
2.25 3H(s); 2.7-3.3 lOH(m); 3.6 3H(double s); 4.4 lH(d);
4.5 2H(t); 4.6 lH(m); 6.4 lH(d~; 6.9 2H(m); 7.2 lH(d); 7.4 lH(d).
S
(~)-8-chloro-7 [N-methyl-N-(benzyloxycarbonyl-methyl)amino carbonyloxy]~5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetra-hydro-lH-3-methyl-3-benzazepina lH-MMR ~ppm. (CD3$0CD3, TMS): 2.1 lH(t); 2,15 3H(s); 2-7-3-4 9H(m): 4.1-4.3 2H(d, after heating to 90C it appears as ~
singlet); 4.4 lH(t); 4.S 2H(t); 5.15 2H(m); 6.4 lH(d); 6.85 2H(m); 7.15 lH(t); 7.35 6H(m).
-~ 8-chloro-7-[N-methyl-~-(methoxycarbonyl-methyl)amino carbonyloxy]-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-ielra-hydro-lH-~-methyl-3-benzazepine H-NMR,~ppm- (~D3SOCD3, TMS): 2.2 lH(t); 2.3 3H(s); 2.8-3.3 lOH(m); 3.65 3H(d); 4.15 2H(d); 4.4 lH(t): 4.5 2H(t); 6.4 lH(d); 6.9 2H(m); 7.2 lH(d); 7.4 lH(d).
~XAMPLE 31 (+)-8-chloro-7-[(R,S)-N-methyl-N-(l-methoxycarbonyl-l-ethyl)-amino carbonyloxy~-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by ref luxing 6 h i n pyrididne.
lH-MMR, ~ppm. (CD350CD3, TMS); 1.4 3H(double d~; 2.2 lH(t);
2.3 3H(s); 2.8-3.4 lOH(m): 3.6 3H(t), 4.4 lH(d), 4.5 2H(t);
4.6 1~(~); 6.4 lH(d), 6.9 2H(m), 7.2 lH(d); 7.4 lH(d).
23 3 ~ 2 ~ ~ ?~;
EXA~PLE 32 (+)-8~chloro-7-[(N-methyl-N-carboxymethyl)amino carbonyloxy~-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, HCl The compound was prepared in analogy with the preparation described in example 26 by hydrogenation for 10 h using the hydrochlorida salt of (*)-8-chloro-7-~N-methyl-N-~benzyl-oxycarbonyl-methyl)amino carhonyloxy~-5 (2,3-dihydro-benzo-furan-7-yl)-2,3,4,5-tetrahydro-1~-3-methyl-3-benzazepine H-NMR, ppm. (CD3SOCD3, TMS): 2.75 3H(s); 2.8-3.0 3H(2s~;
3.1-3.6 8.H(m); 3.9-4.1 2H~2s); 4.5 2H(m); 4.8 lH(s); 6.35 lH(s~; 6.9 2H(d); 7.3 lH(d) 7.5 lH(d3.
Tablets are prepared by methods known to professionals skill-ed in the art, the composition of each tablet being:
Formulation, tablets mg/tablet 25 Benzazepine ~0 Lactose 120 .vicel (PH 101) 40 Kollidon~ K25 5 Talcum 4 ~0 Magnesium stearate .
Tablet weight 220 - _ _ .
The bioavailability of the prodruys described in Examples 1-32, measured ln mongrel dogs in accordance with the previ-ously indicated method, are presented in the below indicated table.
24 ~3~ 2~
TABLE
Absolute bioavailability, F ( % ) 5 Example No .R5 ~-- R~ ~ F ( ~ ) .... _ . .. .
Example 1 ~ -CH3 -CH3 20 O
Example 4 ~ -H -CH --C-OCH3 40 20 3xample 6~ 3 ¦- CN~ ¦ 15 Example 7 (~ -H -CH2-CH=CH2 24 Example 8 ~ -H -C~2 ~ 5 Example 10 (~ -H {~ 6 ~; , .
~128~3 Example 11 ~ <U - -OCH3 ~ -CH-C- OCH
Hxample 12 ~ -H CH2 11 Exam le 13 I ~ ,CH
H-MMR, ~ pm- (CD3SOCD3, H20, TMS): 1.8-2.0 3H(m~; 2.1-2.3 lH(m): 2.25 3H(s); ~.9-4.6 22~(m), 6.45 lH(s); 6.9 2H(d);
~5 7.2 lH(broad s); 7.4 lH~d).
21 131 2~3 In analogy with the preparation described in example 5 the following compounds were synthesized:
~ 8-chloro-7-[(S)-(N-methyl-N~ methoxycarbonyl-1-phen-ethyl))amino carbonyloxy]-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxing 4 h in pyridine.
~-NMR,~ppm. (CD3SOCD3, D20, TMS): 2.1-2.2 4H(s,t), 2.6-3.2 12H(m); 3.6 3H(d, after heaiing to 90C it appears as s);
4.3-4.5 3H(m); 4.8 lH(m), 6.4 l~(d, after heating to 90C
it appears as a sinylet) ; 6.85 2H(m); 7.15-7.35 7H(m).
(~)-8-chloro-7- r ( s ~ -N-methyl-N-(l~N',N'-diethylaminocarbonyl-methyloxycarbonyl-1-phenethyl3amino carbonyloxy~-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxing 5 h in pyridine.
H-NMR,~ppm. (CD3SOCD3, TMS): 0.9-1.1 6H(d~uble t); 2.7-5.1 26H(m); 6.1 l~(s); 6.9-7.5 9H(m).
~ 8-chloro-7-[(S)-N-methyl-N~ methoxycarbonyl-l-ethyl)-amino carb~nyloxy]-5-(2,3-dthydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by refluxiny 6 h in pyridine.
~2~
lH-NMR,~ppm. (CD3SOCD3, TMS): 1.4 3H(double d); 2.2 lH(t);
2.25 3H(s); 2.7-3.3 lOH(m); 3.6 3H(double s); 4.4 lH(d);
4.5 2H(t); 4.6 lH(m); 6.4 lH(d~; 6.9 2H(m); 7.2 lH(d); 7.4 lH(d).
S
(~)-8-chloro-7 [N-methyl-N-(benzyloxycarbonyl-methyl)amino carbonyloxy]~5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetra-hydro-lH-3-methyl-3-benzazepina lH-MMR ~ppm. (CD3$0CD3, TMS): 2.1 lH(t); 2,15 3H(s); 2-7-3-4 9H(m): 4.1-4.3 2H(d, after heating to 90C it appears as ~
singlet); 4.4 lH(t); 4.S 2H(t); 5.15 2H(m); 6.4 lH(d); 6.85 2H(m); 7.15 lH(t); 7.35 6H(m).
-~ 8-chloro-7-[N-methyl-~-(methoxycarbonyl-methyl)amino carbonyloxy]-5-(2,3-dihydrobenzofuran-7-yl)-2,3,4,5-ielra-hydro-lH-~-methyl-3-benzazepine H-NMR,~ppm- (~D3SOCD3, TMS): 2.2 lH(t); 2.3 3H(s); 2.8-3.3 lOH(m); 3.65 3H(d); 4.15 2H(d); 4.4 lH(t): 4.5 2H(t); 6.4 lH(d); 6.9 2H(m); 7.2 lH(d); 7.4 lH(d).
~XAMPLE 31 (+)-8-chloro-7-[(R,S)-N-methyl-N-(l-methoxycarbonyl-l-ethyl)-amino carbonyloxy~-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine by ref luxing 6 h i n pyrididne.
lH-MMR, ~ppm. (CD350CD3, TMS); 1.4 3H(double d~; 2.2 lH(t);
2.3 3H(s); 2.8-3.4 lOH(m): 3.6 3H(t), 4.4 lH(d), 4.5 2H(t);
4.6 1~(~); 6.4 lH(d), 6.9 2H(m), 7.2 lH(d); 7.4 lH(d).
23 3 ~ 2 ~ ~ ?~;
EXA~PLE 32 (+)-8~chloro-7-[(N-methyl-N-carboxymethyl)amino carbonyloxy~-5-(2,3-dihydro-benzofuran-7-yl)-2,3,4,5-tetrahydro-lH-3-methyl-3-benzazepine, HCl The compound was prepared in analogy with the preparation described in example 26 by hydrogenation for 10 h using the hydrochlorida salt of (*)-8-chloro-7-~N-methyl-N-~benzyl-oxycarbonyl-methyl)amino carhonyloxy~-5 (2,3-dihydro-benzo-furan-7-yl)-2,3,4,5-tetrahydro-1~-3-methyl-3-benzazepine H-NMR, ppm. (CD3SOCD3, TMS): 2.75 3H(s); 2.8-3.0 3H(2s~;
3.1-3.6 8.H(m); 3.9-4.1 2H~2s); 4.5 2H(m); 4.8 lH(s); 6.35 lH(s~; 6.9 2H(d); 7.3 lH(d) 7.5 lH(d3.
Tablets are prepared by methods known to professionals skill-ed in the art, the composition of each tablet being:
Formulation, tablets mg/tablet 25 Benzazepine ~0 Lactose 120 .vicel (PH 101) 40 Kollidon~ K25 5 Talcum 4 ~0 Magnesium stearate .
Tablet weight 220 - _ _ .
The bioavailability of the prodruys described in Examples 1-32, measured ln mongrel dogs in accordance with the previ-ously indicated method, are presented in the below indicated table.
24 ~3~ 2~
TABLE
Absolute bioavailability, F ( % ) 5 Example No .R5 ~-- R~ ~ F ( ~ ) .... _ . .. .
Example 1 ~ -CH3 -CH3 20 O
Example 4 ~ -H -CH --C-OCH3 40 20 3xample 6~ 3 ¦- CN~ ¦ 15 Example 7 (~ -H -CH2-CH=CH2 24 Example 8 ~ -H -C~2 ~ 5 Example 10 (~ -H {~ 6 ~; , .
~128~3 Example 11 ~ <U - -OCH3 ~ -CH-C- OCH
Hxample 12 ~ -H CH2 11 Exam le 13 I ~ ,CH
Claims (10)
1. Carbamic acid esters selected from 7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepines having the general formula I
(I) wherein R1 is H, halogen, or C14 alkyl R2 is halogen, CF3, CN
R4 is H, or halogen R5 is selected from the group consisting of benzofuranyl and 2,3-dihydrobenzofuranyl, R6 is H or CH3 R7 is H or C14 alkyl R8 is H, alkyl, alkenyl, phenylalkyl, cycloalkyl, or phenyl R9 is H, or R9 together with R8 forms the remainder of piperidino, pyrrolidinyl, morpholino, piperazinyl, or radical or R9 can be alkyl or alkoxycarbonyl with the formula CHR11n - ? - OR13 wherein n is 0 or 1, where R11 is H, CH3, (CH3)2CH, CH2CH(3)2, and R13 is H, alkyl, cycloalkyl, aralkyl, or a 2-acetamide group with the formula where R15 is H, CH3, C2H5, C3H8, or CH(CH3)2, and R14 is H, CH3, C2H5, C3H8 or CH(CH3)2 , and pharmaceutically-acceptable salts thereof, provided that R8 cannot be benzyl when R9 is hydrogen.
(I) wherein R1 is H, halogen, or C14 alkyl R2 is halogen, CF3, CN
R4 is H, or halogen R5 is selected from the group consisting of benzofuranyl and 2,3-dihydrobenzofuranyl, R6 is H or CH3 R7 is H or C14 alkyl R8 is H, alkyl, alkenyl, phenylalkyl, cycloalkyl, or phenyl R9 is H, or R9 together with R8 forms the remainder of piperidino, pyrrolidinyl, morpholino, piperazinyl, or radical or R9 can be alkyl or alkoxycarbonyl with the formula CHR11n - ? - OR13 wherein n is 0 or 1, where R11 is H, CH3, (CH3)2CH, CH2CH(3)2, and R13 is H, alkyl, cycloalkyl, aralkyl, or a 2-acetamide group with the formula where R15 is H, CH3, C2H5, C3H8, or CH(CH3)2, and R14 is H, CH3, C2H5, C3H8 or CH(CH3)2 , and pharmaceutically-acceptable salts thereof, provided that R8 cannot be benzyl when R9 is hydrogen.
2. A compound of Claim 1, wherein the substituent R5 is b nzofuranyl.
3. A compound according to claim 1, which ls (+)-8-chloro-7[(N,N-dimethylamino)carbonyloxy]-5-(7-benzofuranyl) 2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine.
4. A compound according to claim 1, which is (+)-8-chloro-7-[(R,S)-N-(1-methoxycarbonyl-1-ethyl)amino carbonyloxy]-
5-(7-benzofuranyl)-2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine.
5. A compound according to claim 1, which is (+)-8-chloro-7-[(S)-N-(1-methoxycarbonyl-2-methyl-butyl)aminocarbo-nyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine.
5. A compound according to claim 1, which is (+)-8-chloro-7-[(S)-N-(1-methoxycarbonyl-2-methyl-butyl)aminocarbo-nyloxy]-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine.
6. A compound according to claim 1, which is (+)-8-chloro-
7-(allylaminocarbonyloxy)-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine.
7. A compound according to claim 1, which is (+)-8-chloro-7-(isopropylaminocarbonyloxy)-5-(7-benzofuranyl) 2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine.
7. A compound according to claim 1, which is (+)-8-chloro-7-(isopropylaminocarbonyloxy)-5-(7-benzofuranyl) 2,3,4,5-tetrahydro-1H-3-methyl-3-benzazepine.
8. A pharmaceutical composition suitable for use in the treatment of a mental disorder comprising an amount of a compound of claim 1 which is effective for the allevi-ation of such disorder together with a pharmaceutically-acceptable carrier or diluent.
9. A method for preparing a pharmaceutical composition suit-able for treating a mental disorder in a subject in need of such treatment comprising the step of admixing an amount of a compound of claim 1, which is effective for the allevia-tion of such ailment, together with a pharmaceutically-acceptable carrier or diluent.
10. A process for preparing an ester of formula I as defined in Claim 1, or a salt thereof, characterized by reacting a benzazepine compound of the general formula II.
(II) with an activated carbamic acid (III) of the formula (III) wherein R8 and R9 have the meanings set forth in Claim 1, or with one or two isocyanates selected from those of formula V
R8-N=C=O or R9-N=C=O (V) wherein R8 and R9 have the meanings set forth in Claim 1.
(II) with an activated carbamic acid (III) of the formula (III) wherein R8 and R9 have the meanings set forth in Claim 1, or with one or two isocyanates selected from those of formula V
R8-N=C=O or R9-N=C=O (V) wherein R8 and R9 have the meanings set forth in Claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK1076/88 | 1988-03-01 | ||
| DK107688A DK107688D0 (en) | 1988-03-01 | 1988-03-01 | CARBAMIC ACID ESTERS OF SUBSTITUTED 7-HYDROXY-2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1312863C true CA1312863C (en) | 1993-01-19 |
Family
ID=8100728
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000590992A Expired - Fee Related CA1312863C (en) | 1988-03-01 | 1989-02-14 | Carbamic acid esters of benzazepines |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5017571A (en) |
| EP (1) | EP0331130B1 (en) |
| JP (1) | JPH01254679A (en) |
| KR (1) | KR0126473B1 (en) |
| AT (1) | ATE95179T1 (en) |
| AU (1) | AU613716B2 (en) |
| CA (1) | CA1312863C (en) |
| DE (1) | DE68909448T2 (en) |
| DK (1) | DK107688D0 (en) |
| ES (1) | ES2059592T3 (en) |
| FI (1) | FI94955C (en) |
| IE (1) | IE64247B1 (en) |
| IL (1) | IL89207A0 (en) |
| NO (1) | NO173825C (en) |
| NZ (1) | NZ228151A (en) |
| PH (1) | PH26368A (en) |
| PT (1) | PT89887B (en) |
| ZA (1) | ZA891537B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK67489D0 (en) * | 1989-02-14 | 1989-02-14 | Novo Industri As | NEW BENZAZEPINE DERIVATIVES |
| US5939412A (en) * | 1992-06-26 | 1999-08-17 | Smithkline Beecham Corporation | Bicyclic fibrinogen antagonists |
| PT100631B (en) * | 1991-06-28 | 1999-06-30 | Smithkline Beecham Corp | BICYCLE FIBRINOGENIC ANTAGONISTS, ITS USE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM |
| US5470850A (en) * | 1992-02-24 | 1995-11-28 | Novo Nordisk A/S | 2,3,4,5-tetrahydro-1H-3-benzazepines |
| MA23420A1 (en) * | 1994-01-07 | 1995-10-01 | Smithkline Beecham Corp | BICYCLIC FIBRINOGEN ANTAGONISTS. |
| US6458784B1 (en) | 1994-06-29 | 2002-10-01 | Smithkline Beecham Corporation | Vitronectin receptor antagonists |
| US5977101A (en) * | 1995-06-29 | 1999-11-02 | Smithkline Beecham Corporation | Benzimidazoles/Imidazoles Linked to a Fibrinogen Receptor Antagonist Template Having Vitronectin Receptor Antagonist Activity |
| US20030125317A1 (en) * | 1996-10-02 | 2003-07-03 | Smithkline Beecham Corporation | Vitronectin receptor antagonists |
| NZ578503A (en) | 2003-06-17 | 2011-02-25 | Arena Pharm Inc | Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases |
| US20080009478A1 (en) * | 2003-10-22 | 2008-01-10 | Arena Pharmaceuticals, Inc. | Benzazepine Derivatives and Methods of Prophylaxis or Treatment of 5Ht2c Receptor Associated Diseases |
| SI1833473T1 (en) | 2004-12-23 | 2010-01-29 | Arena Pharm Inc | 5ht2c receptor modulator compositions and methods of use |
| EP2288585A1 (en) | 2008-03-04 | 2011-03-02 | Arena Pharmaceuticals, Inc. | Processes for the preparation of intermediates related to the 5-ht2c agonist (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine |
| KR20130112848A (en) | 2010-06-02 | 2013-10-14 | 아레나 파마슈티칼스, 인크. | Processes for the preparation of 5-ht2c receptor agonists |
| US8999970B2 (en) | 2010-09-01 | 2015-04-07 | Arena Pharmaceuticals, Inc. | Administration of an anti-obesity compound to individuals with renal impairment |
| EP2611782A1 (en) | 2010-09-01 | 2013-07-10 | Arena Pharmaceuticals, Inc. | Salts of lorcaserin with optically active acids |
| EP2611427B1 (en) | 2010-09-01 | 2018-10-17 | Arena Pharmaceuticals, Inc. | Modified-release dosage forms of 5-ht2c agonists useful for weight management |
| US9365521B2 (en) | 2010-09-01 | 2016-06-14 | Arena Pharmaceuticals, Inc. | Non-hygroscopic salts of 5-HT2C agonists |
| CA2886875A1 (en) | 2012-10-09 | 2014-04-17 | Arena Pharmaceuticals, Inc. | Method of weight management |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3393192A (en) * | 1965-04-26 | 1968-07-16 | Schering Corp | Novel benzazepines |
| US3609138A (en) * | 1967-12-22 | 1971-09-28 | Ciba Geigy Corp | 1-aryl-3-benzazepines |
| US4011319A (en) * | 1975-07-02 | 1977-03-08 | Smithkline Corporation | Pharmaceutical compositions and methods involving benzazepine derivatives |
| ZA792044B (en) * | 1978-05-08 | 1980-05-28 | Scherico Ltd | Substituted 1-phenyl-2,3,4,5-tetrahydro-1h-3-benzazepines,process for the preparation thereof,and pharmaceutical compositions containing them |
| US4284555A (en) * | 1979-04-27 | 1981-08-18 | Schering Corporation | 7-Chloro-8(substituted amino carbonyloxy)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines |
| US4668685A (en) * | 1984-07-05 | 1987-05-26 | E.I. Du Pont De Nemours And Company | Substituted benzoate ester prodrug derivatives of 3-hydroxymorphinans, which are analgesics or narcotic antagonists |
| DK180485D0 (en) * | 1985-04-22 | 1985-04-23 | Novo Industri As | NITROGEN CONTAINING COMPOUNDS |
| PH27337A (en) * | 1987-03-27 | 1993-06-08 | Schering Corp | Substituted benzazepines their preparation and pharmaceutical compositions containing them |
-
1988
- 1988-03-01 DK DK107688A patent/DK107688D0/en not_active Application Discontinuation
-
1989
- 1989-02-07 IL IL89207A patent/IL89207A0/en not_active IP Right Cessation
- 1989-02-10 IE IE42089A patent/IE64247B1/en not_active IP Right Cessation
- 1989-02-14 CA CA000590992A patent/CA1312863C/en not_active Expired - Fee Related
- 1989-02-20 PH PH38219A patent/PH26368A/en unknown
- 1989-02-22 FI FI890841A patent/FI94955C/en not_active IP Right Cessation
- 1989-02-25 KR KR1019890002236A patent/KR0126473B1/en not_active IP Right Cessation
- 1989-02-27 NZ NZ228151A patent/NZ228151A/en unknown
- 1989-02-28 DE DE89103531T patent/DE68909448T2/en not_active Expired - Lifetime
- 1989-02-28 ZA ZA891537A patent/ZA891537B/en unknown
- 1989-02-28 NO NO890857A patent/NO173825C/en unknown
- 1989-02-28 ES ES89103531T patent/ES2059592T3/en not_active Expired - Lifetime
- 1989-02-28 US US07/317,016 patent/US5017571A/en not_active Expired - Fee Related
- 1989-02-28 AT AT89103531T patent/ATE95179T1/en not_active IP Right Cessation
- 1989-02-28 EP EP89103531A patent/EP0331130B1/en not_active Expired - Lifetime
- 1989-03-01 PT PT89887A patent/PT89887B/en not_active IP Right Cessation
- 1989-03-01 AU AU30907/89A patent/AU613716B2/en not_active Ceased
- 1989-03-01 JP JP1046695A patent/JPH01254679A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| PT89887B (en) | 1994-05-31 |
| NO890857L (en) | 1989-09-04 |
| FI890841A0 (en) | 1989-02-22 |
| IL89207A0 (en) | 1989-09-10 |
| JPH01254679A (en) | 1989-10-11 |
| DK107688D0 (en) | 1988-03-01 |
| AU3090789A (en) | 1989-09-07 |
| ZA891537B (en) | 1989-11-29 |
| PT89887A (en) | 1989-11-10 |
| NO890857D0 (en) | 1989-02-28 |
| DE68909448T2 (en) | 1994-02-10 |
| AU613716B2 (en) | 1991-08-08 |
| FI94955C (en) | 1995-11-27 |
| NZ228151A (en) | 1991-08-27 |
| KR890014494A (en) | 1989-10-24 |
| ATE95179T1 (en) | 1993-10-15 |
| KR0126473B1 (en) | 1997-12-24 |
| NO173825C (en) | 1994-02-09 |
| IE64247B1 (en) | 1995-07-26 |
| ES2059592T3 (en) | 1994-11-16 |
| EP0331130A1 (en) | 1989-09-06 |
| NO173825B (en) | 1993-11-01 |
| US5017571A (en) | 1991-05-21 |
| FI890841A (en) | 1989-09-02 |
| EP0331130B1 (en) | 1993-09-29 |
| PH26368A (en) | 1992-06-01 |
| FI94955B (en) | 1995-08-15 |
| IE890420L (en) | 1989-09-01 |
| DE68909448D1 (en) | 1993-11-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1312863C (en) | Carbamic acid esters of benzazepines | |
| KR910006138B1 (en) | Cyclic amine derivatives | |
| CA1255670A (en) | 2-substituted 4-amino-6,7-dimethoxyquinolines | |
| EP0161877A2 (en) | 1,4-dihydropyridine derivatives, methods for their production and pharmaceutical compositions comprising the same | |
| KR20080043840A (en) | 2-aminopyrimidine derivatives as modulators of the histamine h4 receptor activity | |
| US4695568A (en) | Thieno[2,3-d]pyrimidine derivatives and salts thereof | |
| JPH0566953B2 (en) | ||
| DE69814685T2 (en) | Indole derivatives as PKC inhibitors | |
| JP3683911B2 (en) | Quinazolinyl-amino derivatives having α-antagonistic activity | |
| US4600715A (en) | Benzodiazepine antagonistic β-carboline derivatives and compositions thereof | |
| DeWald et al. | Synthesis and Potential Antipsychotic Activity of 1H-Imidazo [1, 2-c] pyrazolo [3, 4-e] pyrimidines | |
| DE4239440A1 (en) | ||
| US6610717B2 (en) | Dihydropyridine derivatives | |
| CN112608316B (en) | Pyrazolotriazine adenosine receptor antagonist | |
| WO2020241638A1 (en) | Drp1-FILAMIN COMPLEX FORMATION INHIBITORS | |
| PL168617B1 (en) | Method of obtaining derivatives of 4-pyrimidones | |
| WO2007014023A1 (en) | Thiazolidinones, oxazolidinones, and pyrrolidinones for hbv | |
| US5177069A (en) | Naphthysulfonylalkanoic acid compounds and pharmaceutical compositions thereof | |
| SU1731049A3 (en) | Method for synthesis of symmetric ester of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylic acid or its physiologically acceptable salt | |
| DD281385A5 (en) | PROCESS FOR THE PREPARATION OF A 1,3-DIOXY NALKANSAEUREDERIVATE | |
| SK113399A3 (en) | Quinoxalinediones | |
| US4772602A (en) | N-substituted 3,4-dihydropyrimidine derivatives as agents for treating disorders of cardiovascular system | |
| EP0816359B1 (en) | 4-Amino-2-ureido-pyrimidine-5-carboxamides, processes for their preparation, medicaments containing these compounds, and their use | |
| DK162228B (en) | Substituted 7-aminocarbonyloxy-2,3,4,5-tetrahydro-1H-3- benzazepines, their preparation and pharmaceutical preparations which comprise the compounds | |
| JP2875605B2 (en) | 3-exomethylenepyrrolo [2,1-b] thiazole derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |