Tricyclic compounds and TXA.sub.2 antagonistic compositions thereof

BACKGROUND OF THE INVENTION
The present invention relates to novel tricyclic compounds which strongly antagonize an action of thromboxane A.sub.2 (hereafter referred to as TXA.sub.2).
It is hitherto known that TXA.sub.2 strongly aggregates platelets and is a potent vasoconstrictor [cf. Arachidonic Acid Cascade and Drugs, edited by Shozo Yamamoto, Gendai Iryo Publishing Co., Ltd. (1958)]. Further TXA.sub.2 is a powerful vasoconstrictor against bronchus and bronchial smooth muscle. Therefore, TXA.sub.2 is considered to take part in pathological conditions over a wide range. The following diseases can be exemplified.
(1) Ischemic disease
For example, myocardial infarction, angina pectoris, and thrombosis
(2) Cerebro-vascular disease
For example, transient ischemic attack, migraine, cerebral hemorrhage, and cerebral infarction,
(3) Peripheral vascular diseases and disease caused by unbalanced lipid.
For example, atherosclerosis, capillary convulsion, peripheral circulation disorders, hypertension, and pulmonary embolism
(4) Inflammatory and allergic diseases
For example, bronchial asthma, bronchitis, pneumonia, nephritis, and hepatitis
(5) Shock
(6) Cancer metastasis
Accordingly, compounds that antagonize the action of TXA.sub.2 are expected to have therapeutic effects in preventing or treating one or more of the diseases described above or other diseases involving TXA.sub.2. Further where in drugs used for medical purposes heretofore, application thereof is limited due to side effects mediated by TXA.sub.2 or assumed to be mediated by TXA.sub.2, it is expected to alleviate the side effects by the use of compounds which antagonize the action of TXA.sub.2.
As an antagonist of TXA.sub.2, representative compounds are exemplified in Thrombosis Research, 44, 377 (1986). Furthermore, an indole compound having the following structure: ##STR2## etc. is disclosed in Japanese Published Unexamined Patent Application No. 249960/1986 [West German Patent Application (DE) No. 3,514,696] and a compound having the following structure: ##STR3## is disclosed in Japanese Published Unexamined Patent Application No. 212552/1986 [West German Patent Application (DE) No. 3,508,692]. These compounds are derivatives having a phenylsulfonamide group and exhibit an activity of antagonizing TXA.sub.2.
On the other hand, among tricyclic compounds represented by the following formula: ##STR4## wherein L is --CH.dbd.CH--, R.sup.o as a substituent on the aromatic ring has carboxyl or a derivative thereof (for example, an ester, an amide, etc.; hereafter collectively referred to as carboxylic acid group) directly or via an alkylene chain, etc. and W.sup.o is hydrogen or a substituent such as oxo (.dbd.0), methylene (.dbd.CH.sub.2), hydroxyl, alkoxyl, etc., oxepine derivatives wherein X.sub.1 --X.sub.2 .dbd.--CH.sub.2 O-- are known to show antiinflammatory, antiallergic activities, etc. [J. Med. Chem., 19, 941 (1976); ibid., 20, 1499 (1977); ibid, 21, 633 (1978); U.S. Patent No. 4,282,36(Japanese Published Unexamined Patent Application No. 21679/1983); U.S. Pat. No. 4,585,788; Japanese Published Unexamined Patent Application Nos. 152673/1986; 152674/1986 and 152675/1986]. Further, it is also known that oxepine derivatives wherein R.sup.o is hydrogen or a substituent other than the carboxylic acid group, such as alkyl, alkoxyl, halogen, etc. and W.sup.o has an alkylaminoalkyl chain via hetero atom (--NH--, --O--, --S--, etc.) show antihistaminic, antiallergic, antiasthmatic, activities, etc. [Japanese Published Unexamined Patent Application Nos. 150083/1981 (U.S. Pat. Nos. 4,396,550 and 4,465,835); 139073/1982; 126883/1983 (EP 0085870A) and 227879/1984]. It is also known that derivatives such as oxepine or thiepine (wherein X.sub.1 --X.sub.2 is --CH.sub.2 S--) wherein W.sup.o is alkylaminoalkylidene show an antidepressant action, etc. [U.S. Pat. Nos. 3,354,155 and 3,420,851; Drugs, 13, 161 (1977), Arz.-Forsch., 13, 1039 (1963); ibid.,14, 100 (1964)]. Furthermore, it is known that derivatives such as cycloheptene (wherein X.sub.1 --X.sub.2 is --CH.dbd.CH--) or thiepine wherein W.sup.o has an alkyl chain substituted with an alicyclic nitrogen-containing heterocyclic group such as piperazine, etc. at the terminal thereof via --NHCO-- have a calcium antagonizing activity [Japanese Published Unexamined Patent Application Nos. 47466/1986 (USP 4,749,703) and 153280/1987].
Further oxepine derivatives having an antiallergic activity wherein R.sup.o has carboxylic acid group and W.sup.o has an alkylaminoalkyl chain via a hetero atom are known [Japanese Published Unexamined Patent Application Nos. 28972/1985 (U.S. Pat. No. 4,596,804); 152669/1986; 152670/1986; 152671/1986; 152672/1986 (all of them correspond to EP 188802 A); 152676/1986 and 257981/1986]. Furthermore, oxepine or cycloheptene (wherein X.sub.1 --X.sub.2 .dbd.--CH.sub.2 CH.sub.2 --) derivatives showing an antihistaminic activity wherein W.sup.o is alkylaminoalkylidene are known [Japanese Published Unexamined Patent Application No. 45557/1987 (EP 2l4779A)].
In addition, thienobenzoxepine and thiepine derivatives showing an antiinflammatory activity wherein L is --S--, R.sup.o has carboxylic acid group and W.sup.o is oxo are disclosed in J. Med. Chem., 21, 633 (1978) supra.
SUMMARY OF THE INVENTION
Novel and useful TXA.sub.2 antagonists are expected to have preventive and therapeutic effects on various diseases, and are in demand.
An object of the present invention is to provide novel tricyclic compounds having a TXA.sub.2 -antagonizing activity by containing side chains in combination, wherein aforementioned R.sup.o is the carboxylic acid group and W.sup.o is an aminoalkyl chain or aminoalkylidene substituted with an acyl group such as carbonyl, sulfonyl, etc. via a hetero atom.
The present invention relates to a tricyclic compound [hereafter referred to as Compound (I); terms like this shall apply to other compounds]represented by formula (I): ##STR5## wherein X.sub.1 --X.sub.2 represents --CH.sub.2 O--, ##STR6## (wherein l represents 0, 1 or 2), --CH.sub.2 --CH.sub.2 -- or --CH.dbd.CH--;
L represents --CH.dbd.CH-- or --S--;
represents a single bond or a double bond;
W represents --S--, --O--, --NH--, --CH--, --NHCO-- or .dbd.CH-- (wherein the left side of each formula is bound to the mother nucleus); n is 0, 1, 2 or 3; Z represents --NR.sup.1 CO--, NR.sup.1 SO.sub.2 --, NR.sup.1 CONH--, --NR.sup.1 CSNH--, --NR.sup.1 NHCONH--,--NR.sup.1 NHCSNH--,--NR1COO-- or --NR1COS--(wherein R.sup.1 represents hydrogen or lower alkyl, in which the right side of each formula is bound to Q);
Q represents straight or branched alkyl having 1 to 18 carbon atoms, alicyclic alkyl having 3 to 6 carbon atoms, lower alkenyl having 2 to 6 carbon atoms, or optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aromatic heterocyclic group [the group represents furyl, thienyl, N-substituted or unsubstituted pyrrolyl (the N-substituent is selected from lower alkyl, phenyl and benzyl), pyridyl, quinolyl or isoquinolyl]or coumarinyl; wherein the substitution means that with 1 to 3 substituents onto the aromatic ring and the substituent is independently selected from lower alkyl, phenyl, benzyl, halogen, trifluoromethyl, nitro, OR.sup.2 and SR.sup.2 (wherein R.sup.2 represents hydrogen, lower alkyl, phenyl or benzyl); one of R.sup.A and R.sup.B represents hydrogen and the other represents --Y--M [wherein Y represents single bond, --CR.sup.3 R.sup.4 --(CH.sub.2)m-- or --CR.sup.3 .dbd.CR.sup.4 --(CH )m-- (wherein each of R.sup.3 and R.sup.4 independently represents hydrogen or lower alkyl and m represents 0, 1, 2, 3 or 4, in which the left side of each formula is bound to the mother nucleus); M represents --COOR.sup.5 (wherein R.sup.5 represents hydrogen or lower alkyl), --CONR.sup.5a R.sup.5b (wherein each of R.sup.5a and R.sup.5b independently has the same significance for R.sup.5 as described above) or tetrazolyl]; each of G.sup.A and G.sup.B independently represents lower alkyl, halogen or OR.sup.6 (wherein R.sup.6 represents hydrogen, lower alkyl, phenyl or benzyl);
each of g.sup.A and g.sup.B independently represents 0, 1, 2 or 3; and a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
In the definition of Q in formula (I), examples of the straight or branched alkyl having 1 to 18 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl and octadecyl, etc.; and examples of the alicyclic alkyl having 3 to 6 carbon atoms include cyclopropyl, cyclopentyl and cyclohexyl, etc. Examples of the lower alkenyl having 2 to 6 carbon atoms include vinyl, allyl, propenyl, butenyl and hexenyl, etc. The aryl is exemplified by phenyl and naphthyl having 6 to 10 carbon atoms, etc.; the aralkyl, by benzyl, phenethyl and benzhydryl having 7 to 15 carbon atoms, etc.; and the aralkenyl by styryl and cinnamyl having 8 to 18 carbon atoms, etc.
Further in the definition of each group in formula (I), examples of the lower alkyl include the straight or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. and of the alicyclic alkyl having 3 to 6 carbon atoms such as cyclopropyl, cyclopentyl and cyclohexyl, etc.; and examples of the halogen atom include fluorine, chlorine, bromine and iodine.
The pharmaceutically acceptable salt of Compound (I) includes an acid addition salt, a metal salt, an ammonium salt, an organic amine addition salt, an amino acid addition salt, etc. which are pharmaceutically acceptable.
As the pharmaceutically acceptable acid addition salt of Compound (I), mention may be made of the inorganic acid salt such as hydrochloride, sulfate, phosphate, etc. and the organic acid salt such as acetate, maleate, fumarate, tartarate, citrate, etc. As the pharmaceutically acceptable metal salt, the alkali metal salt such sodium salt, potassium salt, etc.; alkaline earth metal salt such as magnesium salt, calcium salt, etc. and further the aluminum salt and the zinc salt are appropriate. As the ammonium salt, mention may be made of a salt of ammonium, tetramethylammonium, etc. As the pharmaceutically acceptable organic amine addition salt, mention may be made of an addition salt of morpholine, piperidine, etc. As the pharmaceutically acceptable amino acid addition salt, an addition salt of lysine, glycine, phenylalanine or the like are mentioned.
Compounds represented by formula (II) can be used as the starting material in the process for producing Compound (I): ##STR7## (wherein X.sub.1 --X.sub.2, L, R.sup.A , R.sup.B , G.sup.A G.sup.B , g.sup.A and g.sup.B have the same significances as described above).
Compounds (II) are either described in J. Med. Chem., 19, 941 (1976);ibid., 21, 1035 (1978); ibid., 20, 1557 (1977);ibid., 20, 1499 (1977); ibid., 29, 2347 (1986); ibid., 21, 633 (1978); ibid., 20, 456 (1977); U.S. Pat. Nos. 4,172,949 and 4,282,365; Japanese Published Unexamined Patent Application Nos. 21679/1983; 28972/1985; 152669/1986; 152672/1986; 152675/1986 and 10784/1988, etc. or can be synthesized according to methods described in these publications.
Hereafter processes for producing Compound (I) are described below but the production of Compound (I) is not deemed to be restricted thereto. Further in various processes, reaction conditions can be appropriately chosen from those described below.
A reaction solvent may be chosen from water or an organic solvent which does not participate in the reaction and can be used alone or in combination. Examples of the organic solvent include an alcohol such as methanol, ethanol, propanol, isopropanol, etc.; an ether such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether or ethylene glycol dimethyl ether, etc.; a hydrocarbon such as benzene, toluene, xylene, hexane, cyclohexane, petroleum ether, ligroin, decaline, etc.; a ketone such as acetone, methyl ethyl ketone, etc.; an amide such as formamide, dimethylformamide, hexamethylphosphoric triamide, etc.; acetonitrile, ethyl acetate, dimethylsulfoxide or a halogenated hydrocarbon such as methylene chloride, dichloroethane, tetrachloroethane, chloroform, carbon tetrachloride, etc. Further in case that bases or acids later described are liquid, they may also be used as a solvent.
As the appropriate base, an inorganic or organic base can be used. These bases include an alkali metal hydroxide, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate, for example, sodium carbonate, sodium hydrogencarbonate or potassium carbonate; an alkali metal acetate, for example, sodium acetate or potassium acetate; an alkali metal alkoxide, for example, sodium methoxide, sodium ethoxide or potassium tert-butoxide; or an organic metal compound, for example, sodium hydride, n-butyl lithium, sec-butyl lithium; and an organic amine, for example, triethylamine, tri-n-butylamine, pyridine, N,N-dimethylamino-pyridine, picoline, lutidine, N,N-dimethylaniline, dicyclohexylmethylamine, N-methylpiperidine, morpholine, diazabicyclooctane, diazabicycloundecene or N-benzyltrimethylammonium hydroxide (Triton B), etc.
As the appropriate acid, an inorganic or organic acid or Lewis acid can be used. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, hypochloric acid, sulfurous acid or nitrous acid, etc. Examples of the organic acid are formic acid, acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid or methanesulfonic acid, etc. Examples of the Lewis acid include aluminum chloride, zinc chloride, tin chloride, boron trifluoride, boron trifluoride diethyl ether complex, titanium tetrachloride, etc.
A reaction temperature is generally from -80.degree. C. to a boiling point of a solvent It is also possible to heat in the absence of any solvent The reaction may generally be carried out under normal pressure but it is also possible to apply pressure In this case, the reaction temperature may be raised to a temperature higher than the boiling point of a solvent.
A reaction time is generally in a range of 1 minute to a week.
In the following description, preferred reaction conditions are given.
Further in the following description, the tricyclic moiety that does not directly participate in the reaction: ##STR8## wherein , X.sub.1 --X.sub.2, L, R.sup.A , R.sup.B , G.sup.A , G.sup.B , g.sup.A and g.sup.B have the same significances as described above; is sometimes referred to as: ##STR9##
Method 1-1
Synthesis of Compound (Ia) in Compound (I), wherein W is W.sub.a and Z is --NR.sup.1 SO.sub.2 -- (part 1) ##STR10## wherein W.sub.a represents --S--, --O-- or --NH--; and X.sub.1 --X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above.
Firstly, the carbonyl group of Compound (II) is converted into Compound (IIIa), (IIIb) or (IIIc) according to the following reaction equations: ##STR11## wherein ##STR12## has the same significance as described above;
R.sup.7 represents lower alkyl and Hal represents halogen. Herein the definitions of the lower alkyl and halogen are the same as in the definitions of the lower alkyl and halogen for the respective groups in formula (I).
Compound (II) and 0.5 to 5 molar equivalents of sodium borohydride are reacted in an alcohol, for example, methanol, at a temperature from 0.degree. C. to room temperature for 1 to 24 hours to obtain Compound (IIIa).
Compound (IIIb) can be obtained by reacting Compound (IIIa) with an alcohol shown by R.sup.7 --OH in the presence of an appropriate acid catalyst, for example, p-toluenesulfonic acid, etc. at between room temperature and a boiling point of the alcohol for 1 to 24 hours.
Compound (IIIc) can be obtained by reacting Compound (IIIa) with 1 to 5 molar equivalents of a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus tribromide, etc. as they are, or, in an inert solvent such as methylene chloride, chloroform, etc., at a temperature from 0.degree. C. to room for 1 to 24 hours.
Further, the thus obtained Compound (IIIc) is led to Compound (IIIb) by reacting Compound (IIIc) with an alcohol shown by R.sup.7 --OH, if necessary and desired, in the presence of a base such as pyridine, etc., at between room temperature and a boiling point of the alcohol for 1 to 24 hours.
The thus obtained Compounds (IIIa), (IIIb) and (IIIc) are converted into Compound (Va) according to the following reaction step. ##STR13## wherein A.sup.1 represents OH, OR.sup.7 or Hal, and ##STR14## W.sub.a, R.sup.1, R.sup.7, Hal and n have the same significances as described above.
Compound (Va) or acid addition salts thereof can be obtained by reacting Compound (IIIa) with 1 to 5 molar equivalents of an appropriate dehydrating and condensing agent, for example, trifluoroacetic anhydride, in an inert solvent such as methylene chloride, chloroform, etc., at a temperature of from 0.degree. C. to room temperature for 1 to 24 hours, then adding 1 to 5 molar equivalents of Compound (IV) or acid addition salts thereof (for example, hydrochloride, hydrobromide, acetate, trifluoroacetate and p-toluenesulfonate; in the following description, the acid addition salts also mean these salts) to this reaction solution and carrying out the reaction at between 0.degree. C. and a boiling point of the solvent, if necessary and desired, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex, for 1 to 24 hours, according to the method disclosed in Japanese Published Unexamined Patent Application No. 152676/1986.
Compound (Va) or acid addition salts thereof can also be obtained by reacting Compound (IIIb) with 1 to 5 molar equivalents of Compound (IV) or acid addition salts thereof in an inert solvent such as methylene chloride, chloroform, etc., at between 0.degree. C. and a boiling point of the solvent, if necessary and desired, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex, for 1 to 24 hours.
Compound (Va) or acid addition salts thereof can also be obtained by reacting Compound (IIIc) with 1 to 10 molar equivalents of Compound (IV) or acid addition salts thereof in an inert solvent such as methylene chloride, chloroform, etc., between at 0.degree. C. and a boiling point of the solvent, if necessary and desired, in the presence of a base such as triethylamine, etc. for 1 to 24 hours.
Then, Compound (Va) is converted into Compound (Ia) according to the following reaction step. ##STR15## wherein ##STR16## W.sub.a, n, R.sup.1 , Hal and Q have the same significances as described above.
Compound (Ia) can be obtained by reacting Compound (Va) or acid addition salts thereof with 1 to 5 molar equivalents of a sulfonyl halide (VI) or a sulfonic anhydride (VII) in an inert solvent such as methylene chloride, chloroform, etc., in the presence of a base such as pyridine, etc. or in a basic organic solvent such as pyridine, triethylamine, etc., at a temperature of from 0.degree. C. to room temperature for 1 to 24 hours.
Method 1-2
Synthesis of Compound (Ia) (part 2)
Compound (IXb) or (IXc) can be obtained from (IIIa), (IIIb) and (IIIc) shown in Method 1-1 according to the following reaction steps. ##STR17## wherein ##STR18## A.sup.1, W.sub.a, Hal and n have the same significances as described above; and R.sup.8 represents a group capable of being split as OR.sup.8.
Herein, R.sup.8 means alkylsulfonyl such as methanesulfonyl, trifluoromethanesulfonyl, etc. and arylsulfonyl such as phenylsulfonyl, p-toluenesulfonyl, etc.
The corresponding Compound (IXa) or (IXc) can be obtained by reacting Compound (IIIa) with 1 to 5 molar equivalents of an appropriate dehydrating and condensing agent, for example, trifluoroacetic anhydride, in an inert solvent such as methylene chloride, chloroform, etc., at a temperature of from 0.degree. C. to room temperature for 1 to 24 hours, then adding 1 to 10 molar equivalents of an alcohol (VIIIa) or its halide (VIIIb) to this reaction solution and carrying out the reaction at between room temperature and a boiling point of the solvent, if necessary and desired, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex, for 1 to 24 hours.
Compound (IXa) or (IXc) can also be obtained by reacting Compound (IIIb) or (IIIc) with 1 to 10 molar equivalents of an alcohol (VIIIa) or its halide (VIIIb) in an inert solvent such as methylene chloride, chloroform, etc., at between room temperature and a boiling point of the solvent, if necessary and desired, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex, for 1 to 24 hours.
Further the thus obtained Compound (IXa) may be reacted with 1 to 5 molar equivalents of Hal--R.sup.8 or (R.sup.8).sub.2 O (wherein R.sup.8 has the same significance as described above) in an inert solvent such as methylene chloride, chloroform, etc. if necessary and desired, in the presence of a base such as pyridine, etc. at a temperature of from -50.degree. C. to room temperature for 1 to 24 hours to give Compound (IXb).
Furthermore, Compound (IXa) may be reacted either with 1 to 5 molar equivalents of a halogenating agent, for example, thionyl chloride, in an inert solvent such as methylene chloride, chloroform, etc., if necessary and desired, in the presence of a base such as pyridine, etc., at a temperature of from 0.degree. C. to room temperature for 1 to 24 hours to give Compound (IXc), or with 1 to 10 molar equivalents of a halogenating agent such as methanesulfonyl chloride, etc. in dimethylformamide in the presence of 1 to 10 molar equivalents of a salt such as lithium chloride at a temperature of from -20.degree. C. to 100.degree. C. for 1 to 24 hours.
Where Compound (IXc) is the chloride (Hal.dbd. Cl) or bromide (Hal.dbd. Br), the compound may be reacted further with an iodide, for example, sodium iodide, in a polar solvent such as acetonitrile to give the iodide (Hal.dbd. I). Compound (IXb) can be converted into Compound (IXc) under similar conditions.
The thus obtained Compound (IXb) or Compound (IXc) can be converted into Compound (Va), wherein routes for the conversion are different depending upon the species of R.sup.1. That is, in case that R.sup.1 is H, Route A [Gariel synthesis: Merk Index, 10th edition, page ONR-34 (1983)] is advantageously applied; in case that R.sup.1 is not H, Route B is applied. ##STR19## wherein A.sup.2 represents OR.sup.8 or Hal; R.sup.1a represents R.sup.1 except for hydrogen; R.sup.8, Hal and R.sup.1 have the same significances as described above; and ##STR20## Wa and n have also the same significances as described above.
Route A
Compound (IXb) or Compound (IXc) is reacted with 1 to 10 molar equivalents of potassium phthalimide in a polar solvent, for example, N,N-dimethylformamide, between at room temperature and a boiling point of the solvent for 1 to 48 hours, followed by dephthaloylation. The reaction may be completed by reacting with hydrazine in an alcoholic solvent such as methanol, at between room temperature and a boiling point of the solvent for 1 to 48 hours to give dephthaloyled Compound (Va-1).
Route B
Compound (Va-2) can be obtained by reacting Compound (IXb) or Compound (IXc) with 1 molar equivalent to a largely excessive amount of an amine (Xa) or acid addition salts thereof in an inert solvent such as ethanol, dioxane, etc., at a temperature of from 0.degree. C. to a boiling point of the solvent, for 1 to 48 hours.
Compound (Va) [(Va-1) and/or (Va-2)] or acid addition salts thereof can be converted into Compound (Ia) in a manner similar to Method 1-1.
Method 2
Synthesis of Compound (Ib) in Compound (I), wherein W is --NHCO-- and Z is --NR.sup.1 SO.sub.2 ##STR21## wherein X.sub.1 --X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above.
Compound (IIIc) described in Method 1-1 is converted into Compound (Vb) according to the following reaction steps: ##STR22## wherein ##STR23## R.sup.1 , n and Hal have the same significances as described above.
Compound (XI) can be obtained by reacting Compound (IIIc) with a molar equivalent to a largely excessive amount of ammonia in an inert solvent such as methylene chloride, chloroform, etc., at a temperature from -78.degree. C. to room temperature, for 1 to 24 hours.
Next, Compound (XI) or acid addition salts thereof are reacted with 1 to 5 molar equivalents of an acid halide (XII) in an inert solvent such as methylene chloride, chloroform, etc., if necessary and desired, in the presence of a base such as pyridine, etc., at a temperature of from 0.degree. C. to room temperature for 1 to 24 hours to give Compound (IXd).
The thus obtained Compound (IXd) is reacted with a molar equivalent to a largely excessive amount of an amine (Xb) or acid addition salts thereof in an inert solvent such as methylene chloride, chloroform, etc , if necessary and desired, in the presence of a base such as triethylamine, etc., between at 0.degree. C. and a boiling point of the solvent for 1 to 24 hours to give Compound (Vb).
Compound (Ib) can be obtained from Compound (Vb) or acid addition salts thereof according to the following reaction steps. ##STR24## wherein ##STR25## R.sup.1, n, Hal and Q have the same significances as described above.
The reaction can be performed in a manner similar to the method for converting Compound (Va) into Compound (Ia) in Method 1-1.
Method 3-1
Synthesis of Compound (Ic) in Compound (I), wherein W is .dbd.CH-- and Z is --NR.sup.1 SO.sub.2 -- ##STR26## wherein X.sub.1 --X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above.
Firstly, the carbonyl group of Compound (II) is converted into Compound (IXf) according to the following reaction steps: ##STR27## wherein ##STR28## and n have the same significances as described above, R.sup.9 represents a protective group of hydroxyl and Ph represents phenyl.
Herein, as the protective group for hydroxyl, groups generally used as protective groups for an alcoholic hydroxyl may be used; preferably used is, for example, tetrahydropyranyl or the like.
An ylide (XIII) in which hydroxyl is protected by an appropriate protective group (for example, tetrahydropyranyl, etc.) is formed in an inert solvent, for example, tetrahydrofuran [J. Org. Chem., 44, 3760 (1979)].
Then, the formed ylide (XIII) is reacted with 0.2 to 1 molar equivalent of Compound (II) based on Compound (XIII) at a temperature from -78.degree. C. to a boiling point of the solvent for 1 to 48 hours to give Compound (IXe).
The protective group is removed from Compound (IXe) to give Compound (IXf) The removal of protective group can be conducted in a conventional manner; in the case of using, for example, tetrahydropyranyl group as a protective group, Compound (IXe) is reacted in a suitable hydrated solvent such as hydrated dioxane, hydrated tetrahydrofuran, etc., in the presence of an acid catalyst such as p-toluenesulfonic acid, hydrochloric acid, etc., at between 0.degree. C. and a boiling point of the solvent for 1 to 24 hours to give Compound (IXf).
Compound (IXf) can be led to Compound (IXg) or Compound (IXh) by the following reaction steps. ##STR29## wherein ##STR30## R.sup.8, Hal and n have the same significances as described above.
The reactions can be performed in a manner similar to the method for leading from Compound (IXa) to Compound (IXb) and Compound (IXc) and from Compound (IXb) to Compound (IXc), described in Method 1-2.
Compound (Vc) [Vc-1) and/or (Vc-2)] can be obtained from Compound (IXg) and Compound (IXh) according to the following reaction equation. ##STR31## wherein ##STR32## A.sup.2, Hal, R.sup.8, R.sup.1, R.sup.1a and n have the same significances as described above.
The reactions can be performed in a manner similar to the method for converting Compound (IXb) and Compound (IXc) into Compound (Va) in Method 1-2.
Compound (Vc) or acid addition salts thereof can be converted into Compound (Ic) in a manner similar to the method for converting Compound (Va) into Compound (Ic) in Method 1-1. ##STR33## wherein ##STR34## R.sup.1, Q, Hal and n have the same significances as described above.
Method 3-2
Synthesis of Compound (Ic-1) in Compound (Ic), wherein n is 1 ##STR35## wherein X.sub.1 --X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above.
Firstly, the carbonyl group of Compound (II) is converted into Compound (XV) according to the following reaction steps: ##STR36## wherein ##STR37## and Ph have the same significances as described above.
Compound (II) is reacted with 1 to 5 molar equivalents of an ylide (XIV) in an inert solvent such as tetrahydrofuran, etc., at a temperature of from 0.degree. C. to room temperature for 1-48 hours to give Compound (XV).
Compound (XV) can be converted into Compound (IXg-1) [in Compound (IXg), n is 1 and Hal is chlorine ] according to the following reaction steps. ##STR38## wherein ##STR39## has the same significance as described above; each of R.sup.12 and R.sup.13 independently represents lower alkyl or may be combined to nitrogen adjacent thereto to form a heterocyclic ring.
Herein, lower alkyl has the same significance as previously described for lower alkyl in formula (I). As the heterocyclic ring formed, mention may be made of pyrrolidine, piperdine, N-methylpiperazine, morpholine, N-methylhomopiperazine and the like.
Compound (XV) is reacted with 1 to 10 molar equivalents of formaldehyde and/or a formaldehyde polymer, for example, paraformaldehyde, in hydrochloric acid or an inert solvent, for example, dioxane, saturated with hydrogen chloride and, if necessary and desired, in the presence of a strong acid such as sulfuric acid or trifluoroacetic acid, between at room temperature and a boiling point of the solvent, for 1 to 24 hours to give Compound (IXg-1).
Further Compound (IXg-1) can also be obtained as follows. That is, Compound (XV) is reacted with 1 to 2 molar equivalents of formaldehyde and/or a formaldehyde polymer, for example, paraformaldehyde, and 1 to 3 molar equivalents of a secondary amine (XVI) and trifluoroacetic acid, in an inert solvent such as methylene chloride, dichloroethane, chloroform, etc , if necessary and desired, in the presence of acetic acid, between at room temperature and a boiling point of the solvent, for 1 to 48 hours to give Compound (XVII) This compound is reacted with 1 to 10 molar equivalents of ethyl chloroformate in an inert solvent such as methylene chloride, chloroform, etc., between at 0.degree. C. and a boiling point of the solvent for 1 to 48 hours to give Compound (IXg-1).
The thus obtained Compound (IXg-1) can be converted into Compound (Ic-1) via Compound (Vc-3) according to the following reaction steps, in a manner similar to the method for converting Compound (IXg) into Compound (Ic) in
Method 3-1. ##STR40## wherein ##STR41## R.sup.1, Q and Hal have the same significances as described above.
Herein, Route A and Route B can be carrier out according to Method 3-1.
Method 4
Synthesis of Compound (Id) in Compound (I), wherein W is Wb and Z --NR.sup.1 CO-- ##STR42## wherein Wb represents --S--, --O--, --NH--, --NHCO-- or .dbd.CH--; and , X --X.sub.2, L, R.sup.A , R.sup.B , G.sup.A , G.sup.B , R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above.
Compound (Id) can be obtained from Compound (Va), (Vb) or (Vc) according to the following reaction steps. ##STR43## wherein ##STR44## Wa, Wb, R.sup.1 , Q and n have the same significances as described above.
Compound (Id) can be obtained by reacting Compound (Va), (Vb) or (Vc) or acid addition salts thereof with 1 to 5 molar equivalents of a carboxylic .acid (XVIII) or reactive derivatives thereof, either in an inert solvent such as methylene chloride, chloroform, etc., if necessary and desired, in the presence of a base such as pyridine, etc. or in a basic solvent such as pyridine, between at 0.degree. C. and a boiling point of the solvent for 1 to 48 hours.
Herein, the carboxylic acid reactive derivative include an acid halide such as acid chloride, acid bromide, etc., an acid anhydride such as acid anhydride formed with a dehydrating condensing agent such as N,N'-dicyclohexylcarbodiimide, etc., in the reaction system, commercially available acid anhydrides, etc.), an activated ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester), a mixed acid anhydride such as monoethyl carbonate, monoisobutyl carbonate, etc. and the like.
Method 5
Synthesis of Compound (Ie) in Compound (I), wherein W is Wb and Z is ##STR45## wherein , X.sub.1 --X.sub.2, L, R.sup.A, R.sup.B , G.sup.A , G.sup.B, Wb, R.sup.1, Q, n, g.sup.A and g.sup.B have the same significances as described above and E represents oxygen or sulfur.
Compound (Ie) can be obtained from Compound (Va), (Vb) or (Vc) according to the following reaction steps. ##STR46## wherein ##STR47## Wa, Wb, R.sup.1, Q, E and n have the same significances as described above.
Compound (Ie) can be obtained by reacting Compound (Va), (Vb) or (Vc) or acid addition salts thereof with 1 to 5 molar equivalents of an isocyanate (XIX wherein E=O) or an isothiocyanate (XIX wherein E=S), in an inert solvent, for example, toluene, if necessary and desired, in the presence of a base such as pyridine, etc. between at 0.degree. C. and a boiling point of the solvent for 1 to 24 hours.
Method 6
Synthesis of Compound (If) in Compound (I), wherein W is Wb and Z is ##STR48## wherein , X.sub.1 --X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, Wb, R.sup.1, E, Q, n g.sup.A and g.sup.B have the same significances as described above.
Compound (If) can be obtained according to the following reaction steps. ##STR49## wherein ##STR50## Wa, Wb, A.sub.2, R.sup.1 , R.sup.8, Hal, Q, E and n have the same significances as described above.
Compound (XXI) can be obtained by reacting Compound (IXb), (IXc), (IXd), (IXg) or (IXh) with a molar equivalent to a largely excessive amount of a hydrazine (XX) or acid addition salts thereof, in an inert solvent such as ethanol, etc., if necessary and desired, in the presence of a base such as triethylamine, etc. between at 0.degree. C. and a boiling point of the solvent for 1 to 24 hours.
Next, Compound (XXI) or acid addition salts thereof are reacted with 1 to 5 molar equivalents of an isocyanate (XIX wherein E=0) or an isothiocyanate (XIX wherein E=S), in an inert solvent, for example, tetrahydrofuran, etc., if necessary and desired, in the presence of a base such as pyridine, etc. between at 0.degree. C. and a boiling point of the solvent for 1 to 24 hours to give Compound (If).
Alternatively, Compound (XXI) or acid addition salts thereof are reacted with 1 to 5 molar equivalents of an urea (XXII: E is 0) or a thiourea (XXII: E is S), in an inert solvent, for example, water, etc., if necessary and desired, in the presence of a base such as sodium bicarbonate, etc. between at 0.degree. C. and a boiling point of the solvent for 1 to 24 hours to give Compound (If).
Method 7
Synthesis of Compound (Ig) in Compound (I), wherein W is Wb and Z is ##STR51## wherein , X.sub.1 --X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, Wb, R.sup.1, E, Q, n, g.sup.A and g.sup.B have the same significances as described above.
Compound (Ig) can be obtained according to the following reaction steps. ##STR52## wherein ##STR53## Wa, Wb, R.sup.1, E, Q, Hal and n have the same significances as described above. Compound (Ig) can be obtained by reacting Compound (Va), (Vb) or (Vc) or acid addition salts thereof with 1 to 5 molar equivalents of a haloformate (XXIII), in an inert solvent, for example, pyridine, between at 0.degree. C. and a boiling point of the solvent for 1 to 24 hours.
Method 8
Synthesis of Compound (Ih) in Compound (I), wherein W is --CH.sub.2 -- ##STR54## wherein X.sub.1 --X.sub.2, L, R.sup.A, R.sup.B, G.sup.A, G.sup.B, Z, Q, n, g.sup.A and g.sup.B have the same significances as described above.
Compound (Ih) can be obtained according to the following reaction steps. ##STR55## wherein ##STR56## Z, Q, R.sup.1, E and n have the same significances as described above.
Compound (Ih) wherein W is --CH.sub.2 -- can be obtained by subjecting Compound (Ic-2), (Id-1), (Ie-1), (If-1) or (Ig-1) wherein W is .dbd.CH-- to a suitable reduction process, for example, hydrogenation using as a catalyst, for example, palladium-carbon, platinum oxide, Raney nickel, nickel boride or cobalt boride, etc., if necessary and desired, in the co-presence of an acid such as hydrochloric acid, in an inert solvent, for example, ethanol, acetic acid, etc. between at 0.degree. C. and a boiling point of the solvent for 1 to 48 hours, under from normal pressure to under pressure.
Method 9-1
In the methods for production shown by Methods 1 through 8, where groups defined in Compound (I) change under reaction conditions for practicing the method or are inappropriate for practicing the method, the groups may be subjected to conventional means used in organic synthesis chemistry, for example, means for protecting functional groups, removing protection, etc. [for example, cf., Protective Groups in Organic Synthesis, Green, John Wiley & Sons Incorporated (1981)], methods for oxidation, reduction, hydrolysis, etc. [for example, cf., SHIN-JIKKEN KAGAKU KOZA, vols. 14 & 15, Maruzen (1977)]. For example, in case that M is --COOH, a desired compound can be obtained either by hydrolyzing the corresponding ester (cf., Method 9-2 later described) or by hydrolyzing (removing protection of) a compound obtained according to Methods 1 through 8, etc. in which the group corresponding to --Y--M is --Y'--CH.sub.2 OD [wherein Y' represents a group obtained by removing CH from Y and D represents a protective group of hydroxyl (e.g., acetyl, etc.)] and oxidizing the resulting --Y'--CH.sub.2 OH.
Method 9-2
Synthesis of Compound (I-1) in Compound (I), wherein M is --COOH ##STR57## wherein one of R.sup.A1 and R.sup.B1 represents --Y--COOH and the other represents hydrogen; and , X.sub.1 --X.sub.2, L, G.sup.A , G.sup.B , Y, W, Z, Q, n, g.sup.A and g.sup.B have the same significances as described above.
Compound (I-1) can be obtained according to the following reaction steps. ##STR58## wherein one of R.sup.A2 and R.sup.B2 represents --Y--COOR.sup.14 and the other represents hydrogen; and , X.sub.1 --X.sub.2, L, G.sup.A, G.sup.B, Y, W, Z, Q, R.sup.A1 , R.sup.B1 n, g.sup.A and g.sup.B have the same significances as described above and R.sup.14 represents lower alkyl.
Herein, the lower alkyl is the same as defined for the lower alkyl of each group in formula (I).
Compound (I-2) synthesized by applying Methods 1 to 8 is subjected to an appropriate hydrolysis, for example, reacted with a molar equivalent to a largely excessive amount of sodium hydroxide or potassium hydroxide, etc. in a solvent mixture of a lower alcohol such as methanol, ethanol, etc. and water, between at room temperature and a boiling point of the solvent, for 1 to 48 hours to give Compound (I-1).
The intermediates and desired compounds in the respective methods described above can be isolated and purified by purification methods conventionally used in organic synthesis chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various column chromatographies, etc. Further the intermediates may also be provided in the subsequent reaction, without being particularly purified.
In Compound (I) obtained by the foregoing methods, compounds wherein W is .dbd.CH-- include geometrical isomers of E-form and Z-form with respect to stereochemistry. In general, the methods described above give a mixture of these isomers. Isolation and purification of these isomers can be made in a conventional manner used in organic synthesis chemistry, for example, column chromatography, recrystallization, etc.
It is also possible to isolate the isomers at stages of intermediates (IXe to IXh), (Vc) and (XVII), by the aforesaid various methods.
Further, if desired, E- and Z-forms may be isomerized from each other. This isomerization can be made by treating each isomer under reflux in e.g., acetic acid, for 1 to 24 hours, in the presence of an appropriate acid catalyst such as p-toluenesulfonic acid, etc.
In the present invention, Compound (I) includes not only the E/Z isomers described above but also all possible stereoisomers and a mixture thereof.
In case that salts of Compound (I) are desired to obtain, when Compound (I) is obtained in the form of a salt, Compound (I) may be purified as it is. Further in case that Compound (I) is obtained in a free form, salts may be formed in a conventional manner. Furthermore, Compound (I) and pharmaceutically acceptable salts thereof may also be present in the form of addition products to water or various solvents; in these adducts including the pharmaceutically acceptable salts are also included in the present invention.
Specific examples of Compound (I) obtained by various methods are shown in Table 1.
Numbering of substitution positions in Table 1 and Table 5 later described does not necessarily harmonize with the correct nomenclature [cf. see (NOTE) below]; but for purpose of simplicity, numbering of the substitution positions is systematically made as illustrated below, wherein positional numbering within parenthesis indicates the case where L is --S--. ##STR59##
NOTE
In cycloheptene derivatives (wherein L is --CH.dbd.CH--; and X.sub.1 --X.sub.2 is --CH.sub.2 CH.sub.2 --or --CH.dbd.CH--), despite the positional number in the general formula above, for example, a substituent on the carbon at the 2-position in the formula above is correctly given as a substituent at the 3-position. However, in the tables, according to the positional numbering in the formula described above, --COOH on the carbon at the 2-position is indicated to be 2--COOH (correctly 3-COOH).
Further in thienobenzo derivatives (wherein L is --S--), for example, --COOH which should correctly be a substituent on the 8 -position is likewise indicated as 2-COOH in the tables.
TABLE 1__________________________________________________________________________ Com- L X.sub.1X.sub.2 (G.sup.A)g.sup.A /(G.sup.B)g.sup.B ##STR60## Q R.sup.A /R.sup.B No.pound__________________________________________________________________________CHCH CH.sub.2O none ##STR61## ##STR62## 2-COOCH.sub.3 1a" " " " " 2-COOH 1b" " " " " 2-CH.sub.2 COOCH.sub.3 2a" " " " " 2-CH.sub.2 COOH 2b" " " " " 3-COOCH.sub.3 3a" " " " " 3-COOH 3b" " " " " 9-COOCH.sub.3 4a" " " " " 9-COOH 4b" " " ##STR63## " 2-COOCH.sub.3 5a" " " " " 2-COOH 5bCHCH CH.sub.2O 9-Br ##STR64## ##STR65## 2-COOCH.sub.3 6a" " " " " 2-COOH 6b" " none " ##STR66## 2-COOCH.sub.3 7a" " " " " 2-COOH 7b" " " " ##STR67## 2-COOCH.sub.3 8a" " " " " 2-COOH 8b" " " " ##STR68## 2-COOCH.sub.3 9a" " " " " 2-COOH 9b" " " " ##STR69## 2-COOCH.sub.3 10a" " " " " 2-COOH 10bCHCH CH.sub.2O none ##STR70## ##STR71## 2-COOCH.sub.3 11a" " " " " 2-COOH 11b" " " " ##STR72## 2-COOCH.sub.3 12a" " " " " 2-COOH 12b" " " " ##STR73## 2-COOCH.sub.3 13a" " " " " 2-COOH 13b" " " " ##STR74## 2-COOCH.sub.3 14a" " " " " 2-COOH 14b" " " " ##STR75## 2-COOCH.sub.3 15a" " " " " 2-COOH 15bCHCH CH.sub.2O none ##STR76## ##STR77## 2-COOCH.sub.3 16a" " " " " 2-COOH 16b" " " " ##STR78## 2-COOCH.sub.3 17a" " " " " 2-COOH 17b" " " " ##STR79## 2-COOCH.sub.3 18a" " " " " 2-COOH 18b" " " " ##STR80## 2-COOCH.sub.3 19a" " " " " 2-COOH 19b" " " " ##STR81## 2-COOCH.sub.3 20a" " " " " 2-COOH 20bCHCH CH.sub.2O none ##STR82## ##STR83## 2-COOCH.sub.3 21a" " " " " 2-COOH 21b" " " " ##STR84## 2-COOCH.sub.3 22a" " " " " 2-COOH 22b" " " " ##STR85## 2-COOCH.sub.3 23a" " " " " 2-COOH 23b" " " ##STR86## ##STR87## 2-COOC.sub.2 H.sub.5 24a" " " " " 2-COOH 24b" " " ##STR88## " 2-COOCH.sub.3 25a" " " " " 2-COOH 25bCHCH CH.sub.2O none ##STR89## ##STR90## 2-COOCH.sub.3 26a" " " " " 2-COOH 26b" " " ##STR91## " 2-COOCH.sub.3 27a" " " " " 2-COOH 27b" " " ##STR92## " 2-COOCH.sub.3 28a" " " " " 2-COOH 28b" " " " " 2-CH.sub.2 COOCH.sub.3 29a" " " " " 2-CH.sub.2 COOH 29b" " " ##STR93## " 2-COOCH.sub.3 30a" " " " " 2-COOH 30bCHCH CH.sub.2O none ##STR94## ##STR95## 2-COOCH.sub.3 31a" " " " " 2-COOH 31b" " " ##STR96## " 2-COOCH.sub.3 32a" " " " " 2-COOH 32b" " " " ##STR97## 2-COOCH.sub.3 33a" " " " " 2-COOH 33b" " " " ##STR98## 2-COOCH.sub.3 34a" " " " " 2-COOH 34b" " " " ##STR99## 2-COOCH.sub.3 35a" " " " " 2-COOH 35bCHCH CH.sub.2O none ##STR100## ##STR101## 2-COOCH.sub.3 36a" " " " " 2-COOH 36b" " " " ##STR102## 2-COOCH.sub.3 37a" " " " " 2-COOH 37b" " " " ##STR103## 2-COOCH.sub.3 38a" " " " " 2-COOH 38b" " " " ##STR104## 2-COOCH.sub.3 39a" " " " " 2-COOH 39b" " " " (CH.sub.2).sub.5 CH.sub.3 2-COOCH.sub.3 40a" " " " " 2-COOH 40bCHCH CH.sub.2O none ##STR105## ##STR106## 2-CH.sub.2 COOCH.sub.3 41a" " " " " 2-CH.sub.2 COOH 41b" " " " ##STR107## 2-CH.sub.2 COOCH.sub.3 42a" " " " " 2-CH.sub.2 COOH 42b" " " ##STR108## ##STR109## 2-COOCH.sub.3 43a" " " " " 2-COOH 43b" " " ##STR110## " 2-COOCH.sub.3 44a" " " " " 2-COOH 44b" " " " " 2-CH.sub.2 COOCH.sub.3 45a" " " " " 2-CH.sub.2 COOH 45bCHCH CH.sub.2O none ##STR111## ##STR112## 2-COOCH.sub.3 46a" " " " " 2-COOH 46b" " " ##STR113## " 2-COOCH.sub.3 47a" " " " " 2-COOH 47b" " " ##STR114## " 2-COOCH.sub.3 48a" " " " " 2-COOH 48b" " " ##STR115## " 2-COOCH.sub.3 49a" " " " " 2-COOH 49b" " " ##STR116## " 2-COOCH.sub.3 50a" " " " " 2-COOH 50bCHCH CH.sub.2O none ##STR117## ##STR118## 2-COOCH.sub.3 51a" " " " " 2-COOH 51b" " " ##STR119## " 2-COOCH.sub.3 52a" " " " " 2-COOH 52b" " " ##STR120## " 2-COOCH.sub.3 53a" " " " " 2-COOH 53b" " " ##STR121## " 2-COOCH.sub.3 54a" " " " " 2-COOH 54b" CH.sub.2S " ##STR122## " 2-COOCH.sub.3 55a" " " " " 2-COOH 55bCHCH CH.sub.2S none ##STR123## ##STR124## 2-COOCH.sub.3 56a" " " " " 2-COOH 56b" " " ##STR125## ##STR126## 2-COOCH.sub.3 57a" " " " " 2-COOH 57b" " " ##STR127## ##STR128## 2-COOCH.sub.3 58a" " " " " 2-COOH 58b" CH.sub.2CH.sub.2 " ##STR129## " 2-COOCH.sub.3 59a" " " " " 2-COOH 59b" " " " ##STR130## 2-COOCH.sub.3 60a" " " " " 2-COOH 60bCHCH CH.sub.2CH.sub.2 none ##STR131## ##STR132## 2-COOCH.sub.3 61a" " " " " 2-COOH 61b" " " ##STR133## " 2-COOCH.sub.3 62a" " " " " 2-COOH 62b" " " ##STR134## " 2-COOCH.sub.3 63a" " " " " 2-COOH 63b" CHCH " ##STR135## " 2-COOCH.sub.3 64a" " " " " 2-COOH 64b" " " " ##STR136## 2-COOCH.sub.3 65a" " " " " 2-COOH 65bCHCH CHCH none ##STR137## ##STR138## 2-COOCH.sub.3 66a" " " " " 2-COOH 66bS CH.sub.2O " ##STR139## " 2-CH.sub.2 COOCH.sub.3 67a" " " " " 2-CH.sub.2 COOH 67b__________________________________________________________________________ Chemical
The thus produced Compound (I) has a strongly antagonizing activity against TXA.sub.2. Among Compound (I), Compound (I-1) having the following structure: ##STR140## wherein , X.sub.1 --X.sub.2, L, R.sup.A1, R.sup.B1, G.sup.A, G.sup.B, Z, W, Q, n, g.sup.A and g.sup.B have the same significances as described above are particularly preferred.
Specific examples of Compound (I-1) are shown in Table 2 .
Furthermore, specific examples of particularly preferred Compound (I-1) are shown in Table 3.
Names of the compounds in Table 2, Table 3, Reference Examples and Examples harmonize with the formal nomenclature.
TABLE 2______________________________________ Com- poundCompound No.______________________________________11-[2-[(Phenylsulfonyl)amino]ethyl]thio-6,11- 1bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(Phenylsulfonyl)amino]ethyl]thio-6,11- 2bdihydrodibenz[b,e]oxepin-2-acetic acid9-Bromo-11-[2-[(phenylsulfonyl)amino]ethyl]thio- 6b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2-Nitrophenylsulfonyl)amino]ethyl]thio- 7b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(3-Nitrophenylsulfonyl)amino]ethyl]thio- 8b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Nitrophenylsulfonyl)amino]ethyl]thio- 9b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Fluorophenylsulfonyl)amino]ethyl]thio- 10b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Chlorophenylsulfonyl)amino]ethyl]thio- 11b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Methylphenylsulfonyl)amino]ethyl]thio- 12b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Methoxyphenylsulfonyl)amino]ethyl]thio- 13b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2-Thienylsulfonyl)amino]ethyl]thio- 15b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(3-Pyridylsulfonyl)amino]ethyl]thio- 17b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(Styrylsulfonyl)amino]ethyl]thio-6,11- 18bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2,5-Dimethoxyphenylsulfonyl)amino]ethyl]thio- 20b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(3,4-Dimethoxyphenylsulfonyl)amino]ethyl]thio- 21b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Trifluoromethylphenylsulfonyl)amino]ethyl]- 23bthio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid11-[2-[(Phenylsulfonyl)amino]ethyl] amino-6,11- 24bdihydrodibenz[b,e]oxepin-2-carboxylic acid(E)-11-[3-(Phenylsulfonyl)amino]propylidene-6,11- E-28bdihydrodibenz[b,e]oxepin-2-carboxylic acid(E)-11-[2-(Phenylsulfonyl)amino]ethylidene-6,11- E-30bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(Benzoyl)amino]ethyl]thio-6,11-dihydro- 32bdibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2-Methoxybenzoyl)amino]ethyl]thio-6,11- 33bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2-Hydroxybenzoyl)amino]ethyl]thio-6,11- 34bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2,6-Dimethoxybenzoyl)amino]ethyl]thio-6,11- 35bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(3,4,5-Trimethoxybenzoyl)amino]ethyl]thio- 36b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2,3,4-Trimethoxybenzoyl)amino]ethyl]thio- 37b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2-Methylthenoyl)amino]ethyl]thio-6,11- 38bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(Cinnamoyl)amino]ethyl]thio-6,11- 41bdihydrodibenz[b,e]oxepin-2-acetic acid11-[2-[[Coumarin-3-yl)carbonyl]amino]ethyl]thio- 42b6,11-dihydrodibenz[b,e]oxepin-2-acetic acid11-[2-[(3-Phenylureido)ethyl]thio-6,11- 44bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(3-Benzyl)thioureido)ethyl]thio-6,11- 46bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11- 55bdihydrodibenzo[b,e]thiepin-2-carboxylic acid5-[2-[(phenylsulfonyl)amino]ethyl]thio-10,11- 59bdihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic acid5-[2-[(Styrylsulfonyl)amino]ethyl]thio-10,11- 60bdihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic acid5-[2-[(phenylsulfonyl)amino]ethyl]thio- 64b5H-dibenzo[a,d]cyclohepten-3-carboxylic acid5-[2-[(Styrylsulfonyl)amino] 9 ethyl]thio-5H- 65bdibenzo[a,d]cyclohepten-3-carboxylic acid______________________________________
TABLE 3______________________________________11-[2-[(Phenylsulfonyl)amino]ethyl]thio-6,11- 1bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(Phenylsulfonyl)amino]ethyl]thio-6,11- 2bdihydrodibenz[b,e]oxepin-2-acetic acid9-Bromo-11-[2-[(phenylsulfonyl)amino]ethyl]thio- 6b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2-Nitrophenylsulfonyl)amino]ethyl]thio- 7b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(3-Nitrophenylsulfonyl)amino]ethyl]thio- 8b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Nitrophenylsulfonyl)amino]ethyl]thio- 9b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Fluorophenylsulfonyl)amino]ethyl]thio- 10b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Chlorophenylsulfonyl)amino]ethyl]thio- 11b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Methylphenylsulfonyl)amino]ethyl]thio- 12b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Methoxyphenylsulfonyl)amino]ethyl]thio- 13b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2-Thienylsulfonyl)amino]ethyl]thio- 15b6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(Styrylsulfonyl)amino]ethyl]thio-6,11- 18bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(4-Trifluoromethylphenylsulfonyl)amino]ethyl]- 23bthio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylicacid(E)-11-[2-(Phenylsulfonyl)amino]ethylidene-6,11- E-30bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2-Methoxybenzoyl)amino]ethyl]thio-6,11- 33bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(2-Hydroxybenzoyl)amino]ethyl]thio-6,11- 34bdihydrodibenz[b,e]oxepin-2-carboxylic acid11-[2-[(Phenylsulfonyl)amino]ethyl]thio-6,11- 55bdihydrodibenzo[b,e]thiepin-2-carboxylic acid5-[2-[(Phenylsulfonyl)amino] 9 ethyl]thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3- 59bcarboxylic acid5-[2-[(Styrylsulfonyl)amino]ethyl]thio-10,11- 60bdihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic acid5-[2-[(Phenylsulfonyl)amino]ethyl]thio- 64b5H-dibenzo[a,d]cyclohepten-3-carboxylic acid5-[2-[(Styrylsulfonyl)amino]ethyl]thio-5H- 65bdibenzo[a,d]cyclohepten-3-carboxylic acid______________________________________
Next, TXA.sub.2 antagonizing activity of Compound (I) is described below.
Test on anti-platelet activity (TXA.sub.2 antagonizing test)
Using guinea pig platelet, influence of the compounds in accordance with the present invention on platelet aggregation induced by U-46619 (9,11-dideoxy-9.alpha.,11a-methanoepoxyprostaglandin F.sub.2 .alpha.; manufactured by Cayman Chemica Co., Ltd.) which was a TXA.sub.2 /prostaglandin H.sub.2 receptor stimulant was examined.
Male guinea pig (Hartley strain; body weight, 300 to 600 g) was anesthesized by intraperitoneal administration of sodium pentobarbital (30 mg/kg) and blood was collected from the descending aorta of the abdomen with a 1/10 volume of sodium citrate. By centrifugation (KC-70: manufactured by Kubota Co., Ltd.) at 800 rpm for 10 minutes, platelet rich plasma (PRP) was collected. Platelet aggregation induced by U-46619 (0.5- 1 .mu.M) was determined by photometry [Born, G. V. R. et al., Nature (London), 194, 927-929 (1962)]. A test compound was pretreated before 3 minutes and an ability of inhibiting aggregation was measured. The minimum concentration of inhibiting platelet aggregation by 30% or more was defined as the minimum effective concentration (MEC) of the test compound.
The results are shown in Table 4.
Acute toxicity test
Using three dd strain male mice weighing 20.+-.1 g, a test compound was orally (po; 300 mg/kg) or intraperiotoneally (ip; 100 mg/kg) administered. MLD (the minimum lethal dose) was determined by observing the mortality for seven days after administration.
The results are shown in Table 4.
TABLE 4______________________________________ Acute Toxicity TXA.sub.2 Antagonizing (MLD) mg/kg Activity (MEC)Compound No.** po ip .mu.g/ml______________________________________1b >300 >100 0.31b' >300 >100 0.36b >300 >100 0.0310b >300 >100 0.315b >300 >100 0.316b >300 >100 324b >300 >100 3E-29b >300 >100 133b >300 >100 0.355b >300 >100 3BM13177* >300 >100 3(reference compound)______________________________________ ##STR141## **In Compound No., symbol ' indicates an addition product of the corresponding compound in Tables 1 through 3 to a salt or solvent and, symbols E and Z represent Eform and Zform, respectively (hereafter the symbols have the same significances).
As demonstrated in Table 4, Compound (I) and pharmaceutically acceptable salts thereof possess a TXA.sub.2 antagonizing activity.
Compound (I) and pharmaceutically acceptable salts thereof may be administered singly as they are, but in general, it is preferably administered as various medical preparations. These medical preparations are used for animals and human beings.
The medical preparation in accordance with the present invention may contain, as an active ingredient, Compound (I) or pharmaceutically acceptable salts thereof singly or as admixture with other optional effective components for different treatment. Further these medical preparations can be produced by optional procedures well known in the pharmaceutical field, by mixing the active ingredient together with one or more pharmaceutically acceptable carriers.
Herein, as the optional effective components for different treatment contained togethwer with Compound (I) or pharmaceutically acceptable salts thereof, mention may be made of, for example, a steroid, a non-steroid antiinflammatory agent, a peripheral analgesic, a leucotriene antagonist, a leucotriene biosynthesis inhibitor, an H.sub.2 receptor antagonist, an antihistaminic agent, a histamine release inhibitor, a bronchodilator, an angiotensin converting enzyme inhibitor, a thromboxane A.sub.2 biosynthesis inhibitor, an H+-K+ATPase inhibitor, a coronary dilator, a calcium antagonist, a diuretic, a xanthine oxidase inhibitor, a cerebral circulation improving agent, a celebral metabolism activator, a cerebral protecting agent, an antiplatelet agent, a thrombolytic agent, an adrenaline .alpha. receptor antagonist, an adrenergic .beta. receptor agent, an adrenaline .beta. receptor antagonist, a serotonine antagonist, a platelet activation factor (PAF) antagonist, adenosine receptor antagonist, antihyperlipidemic agent, cholesterol biosynthesis inhibitor, immunostimulating agent, immunosuppressive agent, anticancer agent, etc.
It is preferred that the most effective route for treatment be selected as a route for administration. Oral or parenteral administration such as intrarectal, topical, intranasal, intraocular, intrabuccal, subcutaneous, intramuscular and intravenous routes, etc. are mentioned.
As the form of administration, there are a capsule, a tablet, a granule, a powder, a syrup, an emulsion, a suppository, an ointment, an eyedrop, a nosedrop, a troche, an aerosol, an injection, etc.
A liquid preparation suited for oral administration, for example, an emulsion and a syrup can be prepared using water; sugars such as sucrose, sorbitol, fructose, etc.; glycols such as polyethylene glycol, propylene glycol, etc.; oils such as sesame oil, olive oil, soybean oil, etc.; antiseptics such as a p-hydroxybenzoic acid ester, etc.; flavors such as strawberry flavor, pepper mint, etc. Further a capsule, a tablet, a powder and a granule, etc. can be prepared using an excipient such as lactose, glucose, sucrose, mannitol, etc.; a disintegrator such as starch, sodium alginate, etc.; a lubricant such as magnesium stearate, talc, etc.; a binder such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, etc.; a surfactant such as an aliphatic ester, etc.; a plasticizer such as glycerine, etc.
A preparation suited for parenteral administration is composed of a sterile aqueous preparation containing active compounds which are preferably isotonic to blood of recipient. For example, with an injection, a solution for injection is prepared using carriers composed of a saline solution, a glucose solution or a mixture of saline water and glucose solution.
A nasal spray preparation is comprised of a purified aqueous solution of the active compounds which contains an antiseptic and an isotonic agent. Such a preparation is adjusted to pH compatible with nasal membrane and to an isotonic state.
An ocular preparation is prepared in a manner similar to the nasal spray, except that pH and isotonic factors are controlled so as to fit those of eyes.
A topical preparation is prepared by dissolving or suspending the active compound in one or more media, for example, a mineral oil, petroleum, a polyvalent alcohol or other bases used for topical medical preparations.
A preparation for rectal administration is provided as a suppository using conventional carriers, for example, cacao fat, hydrogenated fat or hydrogenated fat carboxylic acid, etc.
Further these parenteral preparations may also be added with one or more auxiliary components such as a diluent, a fragrance, an antiseptic (including an antioxidant), an excipient, a disintegrator, a lubricant, a binder, a surfactant, a plasticizer and the like.
Effective dose and number of administration of Compound (I) or pharmaceutically acceptable salts thereof vary depending upon mode of administration, age and body weight of the patient and properties or severity of conditions to be treated. In general, daily dose is 0.01 to 1000 mg/person and number in administration is once a day, or the dosage may be divided into several ones.
Hereafter, the present invention is described by referring to Reference Examples and Examples below.
Intermediates obtained in the following Reference Examples are shown in Table 5.
TABLE 5__________________________________________________________________________ ##STR142##Compound (Reference Example) L X.sub.1X.sub.2 (G.sup.A)g.sup.A /G.sup.B)g.sup.B R.sup.A /R.sup.B ##STR143##__________________________________________________________________________a (1) CHCH CH.sub.2O none 2-COOCH.sub.3 Ob (2) " " " " OHc (3) " " " 2-COOC.sub.2 H.sub.5 "d (4) " " " 2-CH.sub.2 COOCH.sub.3 Oe (5) " " " " OHf (6) " " " 2-COOCH.sub.3 SCH.sub.2 CH.sub.2 NH.sub.2g (7) " " " 2-COOC.sub.2 H.sub.5 NHCH.sub.2 CH.sub.2 NH.sub.2h (8) " " " 2-COOCH.sub.3 NH(CH.sub.2).sub.3 NH.sub.2i (9) " " " " CHCH.sub.2 CH.sub.2 NH.sub.2j (10) CHCH CH.sub.2O none 2-CH.sub.2 COOCH.sub.3 CHCH.sub.2 CH.sub.2 NH.sub.2k (11) " " " 2-COOCH.sub.3 CHCH.sub.2 NH.sub.2l (12) " " 9-Br " SCH.sub.2 CH.sub.2 NH.sub.2m (13) " " none 3-COOCH.sub.3 "n (14) " " " 9-COOCH.sub.3 "o (15) " " " 2-CH.sub.2 COOCH.sub.3 "p (16) " " " 2-COOCH.sub.3 SCH.sub.2 CH.sub.2 NHCH.sub.3q (17) " CH.sub. 2S " " OCH.sub.3r (18) " " " " SCH.sub.2 CH.sub.2 NH.sub.2s (19) " CH.sub.2 CH.sub.2 " " "t (20) " CHCH " " "u (21) S CH.sub.2O " 2-CH.sub.2 COOCH.sub.3 "__________________________________________________________________________

REFERENCE EXAMPLE 1
Methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate(Compound a)
A mixture of 348.9 g of methyl p-hydroxybenzoate sodium salt, 402.4 g of phthalide and 200 g of sodium chloride was stirred at 150.degree. C. for 6 hours. After completion of the reaction, the mixture was cooled to room temperature and 4 liters of 10% acetic acid aqueous solution were added thereto. The mixture was allowed to stand at room temperature overnight. After stirring at room temperature for 3 hours, crystals were filtered. To the crystals was added 6 liters of water. After stirring at room temperature for 30 minutes, the crystals were taken out by filtration. To the crystals was added 3 liters of toluene. The mixture was stirred at room temperature for an hour. The crystals were taken out by filtration and dried by heating under reduced pressure to give 393.9 g of 2-(4-methoxycarbonylphenoxy)methyl benzoate.
IR(KBr tablet, cm-1):3400, 1700, 1610, 1260, 1235
In 5.0 liters of methylene chloride was suspended 392.7 g of the thus obtained 2-(4-methoxycarbonylphenoxy)methyl benzoate and, 266.0 g of trifluoroacetic anhydride was added to the suspension. After stirring at room temperature for an hour, 19.4 g of boron trifluoride ethyl ether complex was added to the mixture followed by stirring at room temperature for 2 hours. The reaction solution was poured into ice water. The organic layer was washed with a diluted sodium hydoxide aqueous solution and then with water and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 335.3 g of the desired compound as white crystals.
Melting point:128-129.degree. C.
Elemental analysis: as C.sub.16 H.sub.12 O.sub.4
______________________________________ C H______________________________________Found (%) 71.55 4.48Calcd. (%) 71.63 4.51______________________________________
NMR (CDCl.sub.3, .delta., ppm): 3.84 (s, 3H), 5.14 (s, 2H), 6.87-8.93 (m, 7H)
IR (KBr tablet, cm-1): 1710, 1650, 1610, 1250, 1010
REFERENCE EXAMPLE 2
Methyl 11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound b):
Compound a, 50 g, obtained in Reference Example 1 was suspended in 300 ml of methanol and 6.3 g of sodium borohydride was added to the suspension. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, 10 ml of acetic acid and 300 ml of water were added thereto followed by stirring for 30 minutes. Insoluble matters were taken out by filtration and washed with methanol and then with water. By drying with heating under reduced pressure, 40 g of the desired compound was obtained.
NMR (CDCl.sub.3, .delta., ppm): 2.16 (s, 6H), 2.30-2.76 (m, 4H), 3.83 (s, 3H), 4.83 and 6.40 (ABq, J=l2.6Hz, 2H), 5.01 (s, 1H), 6.79-7.93 (m, 7H)
IR (neat, cm.sup.-1) : 2950, 1710, 1240, 1015
REFERENCE EXAMPLE 3
Ethyl 11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound c)
The corresponding starting material was used and treated in a manner similar to Reference Example 1 and Reference Example 2 to give the desired compound as colorless oil.
NMR (CDCl.sub.3, .delta., ppm): 1.31 (t, J=7Hz, 3H), 3.60 (d, J=3Hz, 1H), 4.25 (q, J=7Hz, 2H), 4.91 and 5.95 (ABq, J=l2.5Hz, 2H), 5.61 (d, J=3Hz, 1H), 6.69-8.12 (m, 7H)
IR (neat, cm.sup.-1): 3430, 1675, 1610, 1480, 1250
REFERENCE EXAMPLE 4
Methyl 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound d)
The corresponding starting material was used and treated in a manner similar to Reference Example 1 to give the objective compound as light yellow crystals (recrystallized from methanol).
Melting point:75.degree.-76.degree. C.
REFERENCE EXAMPLE 5
Methyl 11-hydroxy-6,11-dihydrodibenz[b,e]oxepin-2-acetate (Compound e)
The objective compound was obtained as light yellow crystals (recrystallized from diethyl ether) from Compound d obtained in Reference Example 4 in a manner similar to Reference Example 2.
Melting point:85-87.degree. C.
NMR (CDCl.sub.3, .delta., ppm): 2.08 (s, 3H), 3.49 (s, 2H), 3.59 (s, 3H), 4.89 and 5.75 (ABq, J=l3Hz, 2H), 5.54 (bs, 1H), 6.7-7.4 (m, 7H)
REFERENCE EXAMPLE 6
Methyl 11-(2-aminoethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound f)
In 300 ml of methylene chloride was dissolved 30.0 g of Compound b obtained in Reference Example 2. Under ice cooling, 10 ml of thionyl chloride was dropwise added to the solution. After stirring for further 2 hours under ice cooling, the reaction mixture was concentrated under reduced pressure. To the resulting residue, 500 ml of methanol and 20 ml of triethylamine were added and the mixture was stirred at room temperature for an hour. The solvent was distilled off under reduced pressure and the residue was extracted with 1 liter of ethyl acetate. The extract was washed in sequence with saturated aqueous sodium bicarbonate solution and then saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from isopropyl ether to give 19.0 g of white crystalline methyl 11-methoxy-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate.
NMR (CDCl.sub.3, .delta., ppm): 3.27 (s, 3H), 3.82 (s, 3H), 4.84 and 6.08 (ABq, J=12.1 Hz, 2H), 4.99 (s, 1H), 6.73-8.16 (m, 7H)
The aforesaid compound, 18.6 g, and 8.92 g of 2-aminoethanethiol hydrochloride were suspended in 300 ml of methylene chloride and 5 ml of boron trifluoride diethyl ether complex was added to the suspension. The mixture was stirred at room temperature for a day. The solvent was distilled off under reduced pressure and 200 ml of water was added to the residue. Further 1 N sodium hydroxide aqueous solution was added thereto to adjust pH to 13. Furthermore, 100 ml of ether was added and the mixture was stirred at room temperature for 10 minutes. Insoluble matters were taken out by filtration and washed with ether. By drying with heating under reduced pressure, 16.6 g of the objective compound was obtained as colorless syrup.
NMR (CDCl.sub.3, .delta., ppm): 1.30 (s, 2H), 2.23-2.97 (m, 4H), 3.79 (s, 3H), 4.79 and 6.32 (ABq, J=l2.5Hz, 2H), 4.93 (s, 1H), 6.72-7.83 (m, 7H)
IR (neat, cm.sup.-1): 3370, 1710, 1240, 1115
REFERENCE EXAMPLE 7
Ethyl 11-(2-aminoethyl)amino-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound g):
In 200 ml of methylene chloride was dissolved 10.0 g of Compound c obtained in Reference Example 3. Under ice cooling, 4 ml of thionyl chloride was dropwise added to the solution. After stirring for further 2 hours under ice cooling, the solvent was distilled off under reduced pressure. The residue was dissolved in 200 ml of methylene chloride. The solution was dropwise added to a solution of 50 ml of ethylenediamine in 500 ml of methylene chloride under ice cooling. After stirring for further 5 hours under ice cooling, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was diStilled off under reduced pressure to give 11.0 g of the objective compound.
NMR (CDCl.sub.3, .delta., ppm): 1.34 (t, J=7.8Hz, 3H), 2.37-2.87 (m, 4H), 4.27 (q, J=7.8Hz, 2H), 4.59 (s, 1H), 4.75 and 6.54 (ABq, J=l2.2Hz, 2H), 6.64-8.01 (m, 7H)
REFERENCE EXAMPLE 8
Methyl 11-(2-aminopropyl)amino-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound h)
The corresponding starting material was used and treated in a manner similar to Reference Example 7 to give the objective compound as yellow syrup.
NMR (CDCl.sub.3, .delta., ppm): 1.37-1.86 (m, 2H), 2.28-2.92 (m, 4H), 2.93 (bs, 2H), 3.77 (s, 3H), 4.57 (s, 1H), 4.75 and 6.52 (ABq, J=11.8Hz, 2H), 6.76 (d, J=8.5Hz, 1H), 7.02-7.39 (m, 4H), 7.72 (dd, J=2.2, 8.5Hz, 1H), 7.87 (d, J=2.2Hz, 1H)
IR (CHCl.sub.3, cm.sup.-1): 3662, 3064, 2952, 1713, 1612,
1289, 1133, 1004
REFERENCE EXAMPLE 9
Methyl (E,Z)-11-(3-aminopropylidene)-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound i)
In 250 ml of tetrahydrofuran was suspended 40.0 g of [3-[(tetrahydro-2H-pyran-2-yl)oxy]propyl]triphenylphosphonium bromide. In a nitrogen atmosphere, the suspension was ice cooled and 50 ml of n-butyl lithium/hexane solution (1.6 normal) was dropwise added thereto. After stirring at room temperature for further an hour, 15.0 g of Compound a obtained in Reference Example 1 was added thereto followed by stirring at room temperature for 12 hours. 50 ml of water was added to the reaction mixture followed by extraction with 1 liter of ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution 3 times. After drying over anhydrous sodium sulfate, the obtained residue was dissolved in 500 ml of dioxane and, 200 ml of water and 1.0 g of p-toluenesulfonic acid were added to the solution. The mixture was heated under reflux for an hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was extracted with 1 liter of ethyl acetate. The extract was washed in sequence with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluting solvent; toluene:ethyl acetate= 1:1 ) to give 9.8 g of methyl (E,Z)-11-(3-hydroxy)propylidene-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate. A ratio of E/Z was approximately 3:7 according to NMR analysis.
The thus obtained product, 4.8 g, mainly composed of the Z-form and 10.0 g of p-toluenesulfonic acid were stirred at 100.degree. C. for 42 hours in 250 ml of acetic acid. After completion of the reaction, the solvent was distilled off under reduced pressure and 200 ml of methanol was added to the residue. The mixture was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure and the residue was extracted with 500 ml of ethyl acetate. The extract was washed with saturated sodium bicarbonate aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=1:1) to give 4.5 g of the product having an E/Z ratio of about 7:3.
NMR (CDCl.sub.3, .delta., ppm): 2.17-2.72 (m, 2H), 3.37-3.76 (m, 2H), 3.77 (s, 3H), 4.68-5.43 (m, 1H), 5.70 (t, J=7.4Hz, 0.9H; Z-form), 6.40 (t, J=6.9Hz, 2.1H; E-form), 6.52-8.12 (m, 7H)
The aforesaid compound having the E/Z of about 7:3, 3.5 g, was dissolved in 50 ml of pyridine and 1.7 ml of methanesulfonyl chloride was dropwise added to the solution under ice cooling. After stirring for further an hour under ice cooling, the solvent was distilled off under reduced pressure. The residue was extracted with 200 ml of ethyl acetate and the extract was washed in sequence with 1 N hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and then saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure thereby to give 4.3 g of methyl (E,Z)-11-[3-(methylsulfonyl)oxy]propylidene-6,11-dihydrodibenz[b,e]oxepin- 2-carboxylate as colorless oil.
NMR (CDCl.sub.3, .delta., ppm): --SO.sub.2 CH3; 2.93 (s, 2.1H; E-form), 3.00 (s, 0.9H; Z-form)
The aforesaid compound, 4.3 g, having an E/Z ratio of approximately 7:3 and 2.5 g of potassium phthalimide were stirred at room temperature for 2 days in 100 ml of dimethylformamide. The solvent was distilled off under reduced pressure and the residue was extracted with 300 ml of methylene chloride. The extract was washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure The obtained crude product was recrystallized from toluene to give 1.6 g of (E,Z)-N-[3-(2-methoxycarbonyl-6,11-dihydrodibenz-[b,e]oxepin-11-ylidene)propyl]-phthalimide. A ratio of E/Z was approximately 7:3.
Elemental analysis: as C.sub.27 H.sub.21 NO.sub.5
______________________________________ C H N______________________________________Found (%) 73.66 4.91 3.25Calcd. (%) 73.79 4.82 3.19______________________________________
The aforesaid compound, 1.5 g, having an E/Z ratio of approximately 7:3 was heated under reflux for 7 hours in 100 ml of methanol, together with 0.2 ml of anhydrous hydrazine. The solvent was distilled off under reduced pressure to give 1.0 g of the crude desired compound as colorless oil. The compound was used for the subsequent reaction without further purification.
REFERENCE EXAMPLE 10
Methyl (E,Z)-11-(3-aminopropylidene)-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound j)
The corresponding starting material was used and treated in a manner similar to Reference Example 9 to give the desired compound as white solid (E/Z ratio: about 3:7).
NMR (CDCl.sub.3, .delta., ppm): 2.30-3.19 (m, 4H), 3.52 (s, 2H), 3.65 (s, 3H), 5.18 (bs, 2H), 5.70 (t, J=7.5Hz, 1H; Z-form), 6.75 (t, J=7.5Hz, 1H; E-form), 6.67-7.51 (m, 7H)
REFERENCE EXAMPLE 11
Methyl (E)-11-(2-aminoethylidene)-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound k)
The corresponding starting material was used and treated in a manner similar to Reference Example 9 to give the desired compound.
This compound was difficult to purify so that after the reaction solution was concentrated under reduced pressure, the concentrate was used for the next step, without performing purification.
MS (m/Z): 176 (M.sup.+)
REFERENCE EXAMPLE 12
Methyl 9-bromo-11-(2-aminoethyl)thio-6,11-dihydrodibenz[ b,e]oxepin-2-carboxylate (Compound l)
The corresponding starting material was used and treated in a manner similar to Reference Example 6 to give the objective compound as yellow oil.
NMR (CDCl.sub.3, .delta., ppm): 1.42 (s, 2H), 2.5-2.7 (m, 2H), 2.7-2.95 (m, 2H), 3.88 (s, 3H), 4.86 and 6.36 (ABq, J=13.0Hz, 2H), 4.95 (s, 3H), 6.85 (d, J=8.6Hz, 1H), 7.1-7.5 (m, 3H), 7.81 (dd, J=8.6, 2.2Hz, 1H), 7.93 (d, J=2.2Hz, 1H)
MS (m/Z): 408 (M.sup.+)
REFERENCE EXAMPLE 13
Methyl 11-(2-aminoethyl)thio-6,11-dihydrodibenz-[b,e]oxepin-3-carboxylate (Compound m)
The corresponding starting material was used and treated in a manner similar to Reference Example 6 to give the objective compound as yellow brown oil.
NMR (CDCl.sub.3, .delta., ppm): 1.69 (bs, 2H), 2.31-3.00 (m, 4H), 3.82 (s, 3H), 4.84 and 6.23 (ABq, J=12.9Hz, 2H), 4.94 (s, 1H), 6.92-7.64 (m, 7H)
IR (CHCl.sub.3, Cm.sup.-1): 2954, 1720, 1282, 1097, 1033
REFERENCE EXAMPLE 14
Methyl 11-(2-aminoethyl)thio-6,11-dihydrodibenz-[b,e]oxepin-9-carboxylate (Compound n)
The corresponding starting material was used and treated in a manner similar to Reference Example 6 to give the yellow amorphous desired compound.
MS (m/Z): 329 (M.sup.+)
REFERENCE EXAMPLE 15
Methyl 11-(2-aminoethyl)thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound o)
Compound e obtained in Reference Example 5 was used and treated in a manner similar to Reference Example 6 to give the desired compound as light red oil.
NMR (CDCl.sub.3, .delta., ppm): 2.6-3.1 (m, 4H), 3.55 (s, 2H), 3.65 (s, 3H), 4.86 and 6.17 (ABq, J=13.1 Hz, 2H), 5.12 (s, 1H), 6.77 (d, J=8.4Hz, 1H), 6.95-7.40 (m, 7H)
REFERENCE EXAMPLE 16
Methyl 11-[2-(methylamino)ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound p)
The corresponding starting material was used and treated in a manner similar to Reference Example 6 to give the desired compound.
NMR (CDCl.sub.3, .delta., ppm): 2.15 (bs, 3H), 2.38-2.78 (m, 4H), 3.86 (s, 3H), 4.86 and 6.42 (ABq, J=12.7Hz, 2H), 5.00 (s, 1H), 6.81 (d, J=8.5Hz, 1H), 7.20-7.39 (m, 4H), 7.75 (dd, J=2.2, 8.5Hz, 1H), 7.93 (d, J=2.2Hz, 1H)
REFERENCE EXAMPLE 17
Methyl 11-methoxy-6,11-dihydrodibenzo[b,e]thiepin-2-carboxolate.
(Compound q)
In 150 ml of methanol was suspended 50.0 g of p-bromothiophenol and, 14.9 g of sodium methoxide was added to the suspension. The mixture was stirred at 50.degree. C. for an hour. The solvent was distilled off under reduced pressure and 35.5 g of phthalide was added to the residue followed by stirring at 180.degree. C. for 3 hours. After cooling to room temperature, 200 ml of water was added to the reaction mixture, and dissolution was carried out by heating. After allowing to cool, pH was adjusted to 1.5 with conc. hydrochloric acid. The crystallized crude product was taken out by filtration. After drying, the crystals were recrystallized from toluene to give 56.3 g of 2-[(4-bromophenyl)thio]methylbenzoic acid.
Melting point:139.degree.-140.degree. C.
The compound described above, 12.0 g, was stirred at 90.degree. C. for 10 hours, together with 120.0 g of polyphosphoric acid. The reaction solution was poured into 1 liter of ice. The mixture was stirred for further an hour and the crystallized crude product was taken out by filtration. After drying, the crystals were recrystallized from toluene to give 9.0 g of 2-bromo-11-oxo-6,11-dihydrodibenzo[b,e]thiepine.
Melting point:151.degree.-152.degree. C.
The aforesaid compound, 20.0 g, was suspended in a solvent mixture of 500 ml of methanol and 300 ml of tetrahydrofuran and, 4.5 g of sodium borohydride was added to the suspension followed by stirring at room temperature for an hour. The solvent was distilled off under reduced pressure and the resulting residue was recrystallized from methanol to give 12.0 g of 2-bromo-11-hydroxy-6,11-dihydrodibenzo[b,e]thiepine.
Melting point:169.degree.-170.degree. C.
The aforesaid compound, 8.6 g, was suspended in 180 ml of methanol and, 0.5 g of p-toluenesulfonic acid was added to the suspension. The mixture was heated for an hour under reflux. The solvent was distilled off under reduced pressure and the residue was extracted with 200 ml of ethyl acetate. The extract was washed in sequence with saturated sodium chloride aqueous solution and then with saturated sodium bicarbonate aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from hexane to give 7.8 g of 2-bromo-11-methoxy-6,11-dihydrodibenzo[b,e]thiepine.
Melting point:68.degree.-71.degree. C.
The aforesaid compound, 19.0 g, and 8.0 g of cuprous cyanide were heated in 100 ml of dimethylformamide for 8 hours under reflux. After allowing to cool, 25 ml of ethylenediamine was added to the mixture. The mixture was stirred at 60.degree. C. for 30 minutes and 100 ml of water was further added thereto followed by stirring at 60.degree. C. for 30 minutes. After allowing to cool, the reaction mixture was extracted with 500 ml of ethyl acetate Insoluble matters were filtered off followed by washing 3 times with saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=1:1). Further recrystallization from ethanol gave 11.3 g of 11-methoxy-2-cyano-6,11-dihydrodibenzo[b,e]thiepine.
Melting point:117.degree.-118.degree. C.
The aforesaid compound, 7.3 g, was heated in a solvent mixture of 300 ml of conc. hydrochloric acid and 200 ml of acetic acid under reflux for 8 hours. The solvent was distilled off under reduced pressure and 200 ml of methanol and 0.5 g of p-toluenesulfonic acid were added to the resulting residue. The mixture was heated under reflux for 3 hours. After allowing to cool, the solvent was distilled off under reduced pressure The resulting residue was extracted with 500 ml of ethyl acetate. The extract was washed in sequence with saturated sodium chloride aqueous solution and then with saturated sodium bicarbonate aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate =5:1) to give 4.5 g of the light yellow amorphous desired compound.
IR (CHCl.sub.3, cm.sup.-1): 2994, 2952, 1715, 1437, 1301, 1120
REFERENCE EXAMPLE 18
Methyl 11-(2-aminoethyl)thio-6,11-dihydrodibenzo[b,e]-thiepin-2-carboxylate (Compound r)
Compound q obtained in Reference Example 17 was used and treated in a manner similar to Reference Example 6 to give the colorless amorphous desired compound.
IR (CHCl.sub.3, cm.sup.-1): 2998, 1715, 1596, 1299, 1275, 1122
REFERENCE EXAMPLE 19
Methyl 5-(2-aminoethyl)thio-10,11-dihydro-5H-dibenz-[a,d]-cyclohepten-3-carboxylate (Compound s)
In 1.0 liter of tetrahydrofuran was suspended 60 g of (2-methoxycarbonylbenzyl)triphenylphosphonium bromide and, 3.2 g of sodium hydride was added to the suspension followed by stirring at room temperature for 3 hours. Then, 18 g of 4-bromobenzaldehyde was added and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 500 ml of water, 200 ml of methanol and 100 ml of 0.1 N hydrochloric acid aqueous solution were added thereto and the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate. After washing in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure The resulting residue was recrystallized from methanol to give 17 g of methyl 2-(4-bromostyryl)benzoate as white needles.
Melting point:104.degree.-106.degree. C.
The aforesaid compound, 23 g, was dissolved in a solvent mixture of 470 ml of ethanol and 160 ml of acetic acid, 0.39 g of platinum dioxide was suspended therein. The suspension was stirred at 50.degree. C. for 4 hours under hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure to give 24 g of light yellow amorphous methyl [2-(4-bromophenyl)ethyl]benzoate.
NMR (CDCl.sub.3, .delta., ppm): 2.7-3.0 (m, 2H), 3.1-3.4 (m, 2H), 3.84 (s, 3H), 6.9-7.4 (m, 7H), 7.86 (dd, 1H)
The aforesaid compound, 24 g, was dissolved in 490 ml of isopropanol, 160 ml of water and 160 ml of dioxane and, 19 ml of 10 N sodium hydroxide aqueous solution was added to the solution followed by stirring at 70.degree. C. for an hour. After allowing to cool, pH was adjusted to 7.0 with 4 N hydrochloric acid aqueous solution. The solvent was distilled off under reduced pressure, and the aqueous layer was extracted with 200 ml of ethyl acetate. After washing with saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 23 g of [2-(4-bromophenyl)ethyl]benzoic acid as white crystals.
Melting point:103.degree.-107.degree. C. acetate=
A mixture of 27 g of the aforesaid compound, 270 g of polyphosphoric acid and 130 ml of sulfolane was stirred at 160.degree. C. for 2 hours. The reaction solution was poured into 500 ml of ice water and extracted with 500 ml of ethyl acetate. After washing in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate =4:1) to give 9.6 g of brown amorphous 3-bromo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptane.
NMR (CDCl.sub.3, .delta., ppm): 3.15 (s, 4H), 7.0-7.6 (m, 5H), 7.9-8.1 (m, 1H), 8.10 (d, 1H)
The aforesaid compound, 9.0 g, and 5.6 g of cuprous cyanide were heated under reflux for 6 hours in 90 ml of dimethylformamide. After cooling to 50.degree. C., 42 ml of anhydrous ethylenediamine was added to the reaction mixture followed by stirring at 50.degree. C. for 30 minutes. Water, 200 ml, was added to the mixture and extracted with 200 ml of ethyl acetate. After washing with saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate= 4:1) to give 3.8 g of 3-cyano-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptane.
IR (CHCl.sub.3, cm.sup.-1): 2232, 1644
The aforesaid compound, 2.0 g, was heated under reflux for 16 hours in a solvent mixture of 12 ml of conc. hydrochloric acid and 20 ml of acetic acid. The solvent was distilled off under reduced pressure and 20 ml of methanol and 1.7 ml of 10 N sodium hydroxide aqueous solution were added to the resulting residue. The mixture was heated under reflux for 30 minutes. After allowing to cool, pH was adjusted to 6.9 with 4 N hydrochloric acid aqueous solution and the solvent was distilled off under reduced pressure The resulting residue was recrystallized from isopropanol to give 1.8 g of 5-oxo-10,11-dihydro-5H-dibenzo[ a,d]cycloheptan-3-carboxylic acid as yellow crystals.
Melting point:211.degree.-215.degree. C.
To a solution of 4.5 g of the compound described above in 90 ml of methanol was added 5.0 ml of conc. sulfuric acid. The mixture was heated under reflux for 3 hours. After allowing to cool, the solvent was distilled off under reduced pressure and 100 ml of water wa added thereto. The mixture was extracted with 100 ml of ethyl acetate. After washing in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 4.5 g of colorless amorphous methyl 5-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-3-carboxylate.
NMR (CDCl.sub.3, .delta., ppm): 3.18 (s 4H) 3.90 (s. 3H), 7.1-7.6 (m, 4H), 7.9-8.2 (m, 2H), 8.61 (d, 1H)
IR (CHCl.sub.3, cm.sup.-1):1714, 1651
The compound described above was used and treated in a manner similar to Example 2 to give methyl 5-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate as colorless oil.
NMR (CDCl.sub.3, .delta., ppm): 2.82-2.93 (m, 1H), 3.02-3.42 (m, 4H), 3.85 (s, 3H), 5.96 (bs, 1H), 7.09-7.42 (m, 5H), 7.80 (dd, J=1.8, 7.9Hz, 1H), 8.12 (d, J=1.5 Hz, 1H)
The compound described above was used and treated in a manner similar to Reference Example 6 to give the desired compound as light yellow oil.
NMR (CDCl.sub.3, .delta., ppm): 1.27 (s, 2H), 2.59 (dd, 2H, J=5.4, 17.7Hz), 2.4-3.1 (m, 4H), 3.6-4.0 (m, 2H), 3.86 (s, 3H), 5.10 (s, 1H), 7.0-7.4 (m, 5H), 7.81 (dd, 1H, J=1.9, 7.8Hz), 7.92 (d, 1H, J=1.8 Hz)
REFERENCE EXAMPLE 20
Methyl 5-(2-aminoethyl)thio-5H-dibenzo[a,d]cyclohepten-3-carboxylate (Compound t)
In 100 ml of carbon tetrachloride was dissolved 3.30 g of methyl 5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate obtained in Reference Example 19, 1.21 g of N-bromosuccinimide and 10 mg of benzoyl peroxide were added to the solution. The mixture was heated under reflux for an hour. To the reaction mixture was added 1.21 g of N-bromosuccinimide. The mixture was heated under reflux for further an hour. After allowing to cool to room temperature, the reaction mixture was filtered and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 60 ml of dimethylformamide and 2.4 ml of 1,8-diazabicyclo[5.4.0]-7-undecene was added to the solution. The mixture was stirred at 80.degree. C. for an hour. After allowing to cool to room temperature, 100 ml of water was added and the precipitated crystals were filtered to give 3.16 g of methyl 5-oxo-5H-dibenz-[a,d]cyclohepten-3-carboxylate as white crystals.
Melting point:118.degree.-120.degree. C.
NMR (CDCl.sub.3, .delta., ppm): 3.96 (s, 3H), 7.09 (s, 1H), 7.11 (s, 1H), 7.5-7.7 (m, 4H), 8.1-8.3 (m, 2H), 8.85 (d, 1H, J=17Hz)
The compound described above was used and treated in a manner similar to Reference Example 2 to give methyl 5- hydroxy-5H-dibenz-[a,d]cyclohepten-3-carboxylate as colorless oil.
NMR (CDCl.sub.3, .delta., ppm): 2.76-2.93 (m, 1H), 3.86 (s, 3H), 5.31 (s, 1H), 7.05 (s, 1H), 7.08 (s, 1H), 7.15-7.48 (m, 4H), 7.67 (d, J=7.0Hz, 1H), 7.84 (dd, J=1.8, 7.9Hz, 1H), 8.31 (d, J=1.5 Hz, 1H)
The compound described above was used and treated in a manner similar to Reference Example 6 to give the desired compound as light yellow oil.
NMR (CDCl.sub.3, .delta., ppm): 1.25 (s, 2H), 2.1-2.8 (m, 4H), 3.87 (s, 3H), 5.20 (s, 1H), 6.97 (s, 2H), 7.0-7.5 (m, 5H), 7.8-8.0 (m, 2H)
REFERENCE EXAMPLE 21
Methyl 10-(2-aminoethyl)thio-4,10 -dihydrothieno[3,2-c][1]benzoxepin-8-acetate (Compound u)
4,10-Dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid, 25.5 g, synthesized according to the method of D.E. Aultz, et al. [J. Med. Chem., 20, 456 (1977)] and 0.9 g of p-toluenesulfonic acid monohydrate were heated under reflux for 3 hours in 600 ml of methanol. The solvent was distilled off under reduced pressure and the resulting residue was extracted with 500 ml of ethyl acetate. After washing in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate= 3:1) to give 24.9 g of methyl 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetate as light yellow solids.
NMR (CDCl.sub.3, .delta., ppm): 3.59 (s, 2H), 3.62 (s, 3H), 5.12 (s, 2H), 6.91 (d, J=5.2Hz, 1H), 7.01 (d, J=8.3Hz, 1H), 7.36 (dd, J=2.4, 8.3Hz, 1H), 7.55 (d, J=5.2Hz, 1H), 7.95 (d, J=2.4Hz, 1H)
The compound described above was used and treatead in a manner similar to Reference Example 2 to give methyl 10-hydroxy-4,10 -dihydrothieno[3,2-c][1]benzoxepin-8-acetate as colorless syrup.
NMR (CDCl.sub.3, .delta., ppm): 3.48 (s, 2H), 3.56 (s, 3H), 5.02 (s, 2H), 5.86 (d, J=7.6Hz, 1H), 6.57 (d, J=4.8Hz, 1H), 6.95-7.4 (m, 4H)
The compound described above was used and treatead in a manner similar to Reference Example 6 to give the desired compound as light yellow oil.
MS (m/Z):329 (M.sup.+)
EXAMPLE 1
Methyl 11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 1a)
In 100 ml of pyridine was dissolved 9.00 g of methyl 11-(2-aminoethyl)thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound f) obtained in Reference Example 6. Under ice cooling, 4.2 ml of benzenesulfonyl chloride was dropwise added to the solution and the mixture was stirred at room temperature overnight. Pieces of ice were added to the mixture. After stirring for further an hour, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate and the extract was washed in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=7:3) to give 9.90 g of the desired compound.
In Examples 2 through 5 described below, the desired compound was prepared in a manner similar to Example 1, using the corresponding 11-(2-aminoethyl)thio-6,11-dihydrodibenz-[b,e]oxepine derivative (Compound 1, m, n or o).
EXAMPLE 2
Methyl 11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 2a)
EXAMPLE 3
Methyl 11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-3-carboxylate (Compound 3a)
EXAMPLE 4
Methyl 11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-9-carboxylate (Compound 4a)
EXAMPLE 5
Methyl 9-bromo-11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 6a):
In Examples 6 through 20 described below, the objective compound was prepared in a manner similar to Example 1 except that benzenesulfonyl chloride in Example 1 was changed to the corresponding sulfonyl chloride compound.
EXAMPLE 6
Methyl 11-[2-[(2-nitrophenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz[ b,e]oxepin-2-acetate (Compound 7a)
EXAMPLE 7
Methyl 11-[2-[(3-nitrophenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 8a)
EXAMPLE 8
Methyl 11-[2-[(4-nitrophenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 9a)
EXAMPLE 9
Methyl 11-[2-[(4-fluorophenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 10a)
EXAMPLE 10
Methyl 11-[2-[(4-chlorophenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 11a)
EXAMPLE 11
Methyl 11-[2-[(4-methylphenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 12a)
EXAMPLE 12
Methyl 11-[2-[(4-methoxyphenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 13a)
EXAMPLE 13
Methyl 11-[2-[(2-naphthylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 14a)
EXAMPLE 14
Methyl 11-[2-[(2-thienylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 15a)
EXAMPLE 15
Methyl 11-[2-[(8-quinolylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 16a)
EXAMPLE 16
Methyl 11-[2-[(3-pyridylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 17a)
EXAMPLE 17
Methyl 11-[2-[(styrylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 18a)
EXAMPLE 18
Methyl 11-[2-[(2,5-dimethoxysulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 20a)
EXAMPLE 19
Methyl 11-[2-[(3,4-dimethoxysulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 21a)
EXAMPLE 20
Methyl 11-[2-[(4-trifluoromethylphenylsulfonyl)amino]ethyl]-thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 23a)
Physicochemical properties of the compounds obtained in Examples 1 through 20 are shown in Table 6-1.
In Tables 6-1 through 6-11, * at the shoulder of solvent for recrystallization means solidification by trituration.
TABLE 6-1__________________________________________________________________________ mp (.degree.C.) [solvent ElementalExample No. for re- Analysis (%)(Compound crystal- NMR IR MS upper column: foundNo. Appearance lization] (solvent) .delta., ppm (method) cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.1 (1a) Colorless -- (CDCl.sub.3) 2.28-2.71 (m,2H), 2.73- (CHCl.sub.3) 3275, -- -- oil 3.12 (m,2H), 3.81 (s,3H), 4.88 1710, 1612, (s,1H), 5.28 (t,J = 6.3 Hz,1H), 1324, 1162, 4.79 and 6.28 (ABq,J = 12.5 Hz,2H) 1118 6.67-8.03 (m,12H)2 (2a) Pale -- (CDCl.sub.3) 2.31-2.74 (m,2H), 2.72 (CHCl.sub.3) 3280, -- -- yellow 3.14 (m,2H), 3.49 (s,2H), 3.65 1732, 1328, amorphous (s,3H), 4.76 and 6.11 (ABq,J = 1161, 585 13.3 Hz,2H), 5.04-5.45 (m,1H), 6.65-7.96 (m,12H)3 (3a) Yellow -- (CDCl.sub.3) 2.33-2.75 (m,2H), 2.76- (CHCl.sub.3) 3250, -- -- amorphous 3.20 (m,2H), 3.80 (s,3H), 4.79 1719, 1615, and 6.10 (ABq,J = 12.7 Hz,2H), 1322, 1297, 5.44 (m,1H), 6.92-7.99 (m,12H) 1161, 10974 (4a) Colorless -- (CDCl.sub.3) 2.29-2.68 (m,2H), 2.76- (neat) 469 -- oil 3.16 (m,2H), 3.85 (s,3H), 4.86 3496, 3296, (M.sup.+) and 6.07 (ABq,J = 13.6 Hz,2H), 1719, 1157, 4.91 (s,1H), 5.21 (t,J = 5.4 Hz, 1013 (1H), 6.65-8.08 (m,12H)5 (6a) Colorless -- (CDCl.sub.3) 2.36-2.70 (m,2H), 2.80- (neat) -- -- oil 3.21 (m,2H), 3.82 (s,3H), 4.78 1705, 1609, and 6.21 (ABq,J = 12.9 Hz,2H), 1313, 1157 4.82 (s,1H), 5.25 (t, J = 6.2 Hz, 1H), 6.67-8.07 (m,11H)6 (7a) Colorless Unclear (CDCl.sub.3) 2.32-2.78 (m,2H), 2.83 (KBr tablet) 514 -- amorphous [ether]* 3.36 (m,2H), 3.81 (s,3H), 4.87 3312, 1719, (M.sup.+) and 6.26 (ABq,J = 13.2 Hz,2H), 1612, 1531, 5.18 (s,1H), 6.78 (d,J = 9.0 Hz), 1323, 1250 1H), 7.13-7.42 (m,4H), 7.53-8.13 1168, 1119 (m,6H)7 (8a) Pale -- (CDCl.sub.3) 2.41-2.79 (m,2H), 2.83- (KBr tablet) 514 -- yellow 3.23 (m,2H), 3.85 (s,3H), 4.85 1710, 1610 (M.sup.+) oil and 6.29 (ABq,J = 12.8 Hz,2H), 1533, 1353, 5.47-5.83 (m,1H), 6.81 (d,J = 1250, 1163, 8.5 Hz,1H), 7.10-8.70 (m,10H) 11278 (9a) Light 144.5- (CDCl.sub.3 + DMSO-d.sub.6) 2.30-2.71 (KBr tablet) -- -- yellow 145.5 (m,2H), 2.70-3.15 (m,2H), 3.84 3260, 1712, crystal [iso- (s,3H), 4.84 and 6.30 (ABq,J = 1611, 1524, propa- 13.3 Hz,2H), 5.02 (s,1H), 6.78 1351, 1242, nol] (d,J = 8.5 Hz,1H), 7.00-8.45 (m, 1159 10H)9 (10a) Colorless -- (CDCl.sub.3) 2.38-2.71 (m,2H), 2.80- (neat) -- -- oil 3.12 (m,2H), 3.83 (s,3H), 4.83 3278, 1716, and 6.28 (ABq,J = 12.9 Hz,2H), 4.94 1609, 1329, (s,1H), 5.29 (t,J = 6.5 Hz,1H), 1229 6.72-7.99 (m,11H)10 (11a) White 133.5- (CDCl.sub.3) 2.3-2.71 (m,2H), 2.76- (KBr tablet) 504 C.sub.24 H.sub.22 ClNO.sub.5 S.sub.2 solid 134 3.14 (m,2H), 3.82 (s,3H), 4.81 3296, 1716, (M.sup.+) C H N [iso- and 6.24 (ABq,J = 12.2 Hz,2H), 1332, 1251, 57.10 4.55 2.86 propyl 4.91 (s,1H), 5.27 (t,J = 5.9 Hz, 1159, 1119, 57.19 4.40 2.78 ether] 1H), 6.77 (d,J = 8.6 Hz,1H), 1003 6.97-7.95 (m,10H)11 (12a) White 127- (CDCl.sub.3) 2.39 (s,3H), 2.26- (KBr tablet) 483 C.sub.25 H.sub.25 NO.sub.5 S.sub.2 solid 128 2.27 (m,2H), 2.76-3.21 (m,2H) 3292, 1714, (M.sup.+) C H N [iso- 3.84 (s,3H), 4.83 and 6.30 1609, 1326, 62.01 5.35 3.10 propyl (ABq,J = 12.7 Hz,2H), 4.91 (s,1H) 1250, 1156, 62.09 5.21 2.90 ether]* 5.18 (t,J = 6.5 Hz,1H), 6.80 (d, 1119, 1005 J = 8.0 Hz,1H), 6.93-7.97 (m,10H)12 (13a) White 132- (CDCl.sub.3) 2.34-2.75 (m,2H), (KBr tablet) 499 C.sub.25 H.sub.25 NO.sub.6 S.sub.2 solid 133 2.75-3.17 (m,2H), 3.82 (s,3H) 3272, 1707, (M.sup.+) C H N [tolu- 3.86 (s,3H), 4.84 and 6.32 (ABq, 1498, 1327, 60.15 5.30 2.55 ene] J = 13.3 Hz,2H), 4.94 (s,1H) 1253, 1155, 60.10 5.04 2.80 4.93-5.25 (m,1H), 6.73-7.99 1120, 1010 (m,11H)13 (14a) Colorless -- (CDCl.sub.3) 2.30-2.71 (m,2H), 2.71- (KBr tablet) 487 -- amorphous 3.22 (m,2H), 3.78 (s,3H), 4.73 3258, 1715, (M.sup.+) and 6.2 (ABq,J = 12.9 Hz,2H), 4.87 1610, 1435, (s,1H), 5.46 (t,J = 6.3 Hz,1H), 1324, 1244, 6.72 (d,J = 8.0 Hz,1H), 6.80-8.03 1156, 1131, (m,12H), 8.32 (bs,1H) 100714 (15a) White 115-116 (CDCl.sub.3) 2.38-2.74 (m,2H), 2.84- (KBr tablet) -- C.sub.22 H.sub.21 NO.sub.5 S.sub.3 crystal [iso- 3.30 (m,2H), 3.86 (s,3H), 4.85 3270, 1717, C H N propyl and 6.32 (ABq,J = 12.1 Hz,2H) 1611, 1330, 55.49 4.50 3.00 ether] 4.95 (s,1H), 5.29 (t,J = 6.2 Hz, 1295, 1249, 55.56 4.45 2.95 1H), 6.71-8.03 (m,10H) 1149, 100815 (16a) White 135-136 (CDCl.sub.3) 2.37-2.75 (m,2H), (KBr tablet) 520 C.sub.27 H.sub.24 N.sub.2 O.sub.5 S.sub.2 crystal [ethyl 2.82-3.19 (m,2H), 3.94 (s,3H), 3252, 1704, (M.sup.+) C H N acetate] 4.81 and 6.33 (ABq,J = 13.4 Hz, 1328, 1251, 62.00 4.78 5.18 2H, 4.97 (s,1H), 6.65-9.27 1163, 1006 62.29 4.65 5.38 (m,13H)16 (17a) White -- (CDCl.sub.3) 2.4-3.8 (m,4H), 3.88 KBr tablet) 470 -- amorphous (s,3H), 4.89 and 6.36 (ABq,J = 3068, 1713, (M.sup.+) 13.0 Hz,2H), 5.05 (s,1H), 6.83 1610, 1327, (d,J = 8.6 Hz,1H), 7.2-8.3 1257, 1165, (m,10H) 1111, 101117 (18a) Colorless -- (CDCl.sub.3) 2.50-2.90 (m,2H), 2.95- (KBr tablet) 495 -- oil 3.39 (m,2H), 3.85 (s,3H), 4.88 3256, 1704, (M.sup.+) and 6.37 (ABq,J = 12.8 Hz,2H), 1610, 1434, 5.05 (s,1H), 5.13 (t,J = 7.4 Hz, 1322, 1244, 1H), 6.70 (d,J = 8.6 Hz,1H), 6.86- 1143 7.66 (m,11H), 7.78 (dd,J = 2.4, 8.6 Hz,1H), 7.98 (d,J = 2.4 Hz, 1H)18 (20a) Colorless -- (CDCl.sub.3) 2.30-2.71 (m,2H), 2.80- (KBr tablet) 529 -- oil 3.22 (m,2H), 3.82 (s,3H), 3.89 2836, 1714, (M.sup.+) (s,6H), 4.84 and 6.31 (ABq,J = 1610, 1496, 12.4 Hz,2H), 4.94 (s,1H), 5.45 1325, 1275, (t,J = 6.1 Hz,1H), 6.81 (d,J = 1244, 1156, 8.4 Hz,1H), 6.99-7.48 (m,8H), 1007 7.65-7.98 (m,2H)19 (21a) White 153-154 (CDCl.sub.3) 2.26-3.16 (m,4H), 3.82 (KBr tablet) 529 C.sub.26 H.sub.27 NO.sub.7 S.sub.2 solid [toluene] (s,3H), 3.84 (s,3H), 3.86 (s, 3240, 1714, (M.sup.+) C H N 3H), 4.90 and 6.31 (ABq,J = 1610, 1574, 58.81 5.40 2.50 11.9 Hz,2H), 5.25 (s,1H), 6.82 1325, 1296, 58.96 5.14 2.64 (d,J = 8.5 Hz,1H), 6.99-7.56 (m, 1275, 1244, 7H), 7.73 (dd,J = 1.9,8.5 Hz,1H), 1156, 1131, 7.99 (d,J = 1.9 Hz,1H) 100720 (23a) Colorless -- (CDCl.sub.3) 2.39-2.83 (m,2H), -- 537 -- oil 2.84-3.25 (m,2H), 3.86 (s,3H), (M.sup. +) 4.84 and 6.30 (ABq,J = 12.8 Hz, 2H), 4.97 (s,1H), 5.59 (t,J = 6.0 Hz,1H), 6.82 (d,J = 8.6 Hz, 1H), 7.58-8.25 (m,10H)__________________________________________________________________________
EXAMPLE 21
11-[2-[(Phenylsulfonyl)amino]ethyl]thio-6,11-(dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 1b)
Compound 1a, 9.90 g, obtained in Example 1 was dissolved in a solvent mixture of 200 ml of methanol and 20 ml of water and 2.70 g of sodium hydoxide was added to the solution. The mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure and the resulting residue was dissolved in 200 ml of water. A pH was adjusted to 1.5 with 4 N hydrochloric acid aqueous solution. The crystallized crude product was taken out by filtration and dried. The crude product was recrystallized from 300 ml of isopropanol to give 6.44 g of the desired compound.
In Examples 22 through 40 described below, the desired compound was obtained in a manner similar to Example 21, by hydrolyzing an ester of the corresponding oxepine derivative.
EXAMPLE 22
11-[2-[(Phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetic acid (Compound 2b)
EXAMPLE 23
11-[2-[(Phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-3-carboxylic acid (Compound 3b)
EXAMPLE 24
11-[2-[(Phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-9-carboxylic acid (Compound 4b)
EXAMPLE 25
9-Bromo-11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 6b)
EXAMPLE 26
11-[2-[(2-Nitrophenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.0.2 hydrate (Compound 7b')
EXAMPLE 27
11-2-{3-Nitrophenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.0.5 isopropanol.0.5 hydrate (Compound 8b')
EXAMPLE 28
11-[2-[(4-Nitrophenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 9b)
EXAMPLE 29
11-[2-[(4-Fluorophenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 10b)
EXAMPLE 30
11-[2-[(4-Chlorophenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 11b)
EXAMPLE 31
11-[2-[(4-Methylphenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 12b)
EXAMPLE 32
11-[2-[(4-Methoxyphenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 13b)
EXAMPLE 33
11-[2-[(2-Naphthylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.0.3 hydrate (Compound 14b')
EXAMPLE 34
11-[2-[(2-Thienylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid (Compound 15b)
EXAMPLE 35
11-[2-[(8-Quinolylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 16b)
EXAMPLE 36
11-[2-[(3-Pyridylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.monohydrate (Compound 17b')
EXAMPLE 37
11-[2-[(Styrylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid 0.2 hydrate (Compound 18b')
EXAMPLE 38
11-[2-[(2,5-Dimethoxyphenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 20b)
EXAMPLE 39
11-[2-[(3,4-Dimethoxyphenylsulfonyl)amino]ethyl]thio-6,11 -dihydrodibenz-[b,e]oxepin-2-carboxylic acid 0.2 hydrate (Compound 21b')
EXAMPLE 40
11-[2-[(4-Trifluoromethylphenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 23b)
EXAMPLE 41
Sodium 11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrobenzo[b,e]oxepin-2-carboxylate monohydrate (Compound 1b')
Compound 1b, 3.3 g, obtained in Example 21 was suspended in 100 ml of methanol and sodium methoxide was added to the solution followed by stirring for about an hour. The solvent was distilled off under reduced pressure and the resulting crude product was solidified by isopropyl ether to give 2.3 g of the desired compound.
EXAMPLE 42
Sodium 11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 2b')
The desired compound was prepared in a manner similar to Example 41, using Compound 2b obtained in Example 22.
Physicochemical properties of the compounds obtained in Examples 21 through 42 are shown in Table 6-2.
TABLE 6-2__________________________________________________________________________ mp (.degree.C.) [solventExample No. for re- IR Elemental Analysis (%)(Compound crystal- (method) MS upper column: foundNo.) Appearance lization] NMR (solvent) .delta., ppm cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.21 (1b) White 184-186 (DMSO-d.sub.6) 2.46-2.51 (m, 2H), (KBr tablet) -- C.sub.23 H.sub.21 NO.sub.5 S.sub.2 crystal [isopro- 2.71-2.94 (m, 2H), 5.42 (s, 1H), 3274, 1680, C H N panol] 5.02 and 6.20 (ABq, J=12.8Hz, 1610, 1324, 60.65 4.62 2.99 2H), 6.84-7.98 (m, 12H), 12.76 1243, 1158 60.64 4.65 3.07 (bs, 1H)22 (2b) Colorless -- (DMSO-d.sub.6) 2.42-2.51 (m, 2H), -- 469 -- oil 2.58-2.87 (m, 2H), 3.13 (s, 1H), (M.sup.+) 4.83 and 6.04 (ABq, J=13.0Hz, 2H), 5.19 (s, 1H), 6.61-7.82 m, 12H)23 (3b) Yellow 85 (DMSO-d.sub.6) 2.46-2.52 (m, 2H), (KBr tablet) -- C.sub.28 H.sub.21 NO.sub.5 S.sub.2.0.2C.su b.6 H.sub.14 O amorphous (un- 2.81-2.92 (m, 2H), 4.98 and 6.03 1685, 1566, C H N clear) (ABq, J=12.9Hz, 2H), 5.33 (s, 1423, 1322, 60.87 5.00 2.61 [iso- 1H), 7.31-7.87 (m, 12H), 12.89 1156, 1092, 61.07 5.04 2.94 propyl (bs, 1H) 1028, 751 ether]24 (4b) White 156-160 (DMSO-d.sub.6) 2.45-2.55 (m, 2H), (KBr tablet) 455 C.sub.23 H.sub.21 NO.sub.5 S.sub.2 crystal [tolu- 2.75-2.90 (m, 2H), 4.99 and 6.07 3450, 3275, (M.sup.+) C H N ene] (ABq, J=13.4Hz, 1H), 5.32 (s, 1693, 1310, 60.97 4.56 2.74 1H), 6.84 (d, J=8.1Hz, 1H), 6.95 1154, 753 60.64 4.65 3.07 (t, J=7.3Hz, 1H), 7.15-7.35 (m, 2H), 7.48 (d, J=7.7Hz, 1H), 7.6- 7.95 (m, 8H)25 (6b) White 183-185 (DMSO-d.sub.6) 2.30-2.58 (m, 2H), (KBr tablet) -- C.sub.23 H.sub.20 BrNO.sub.5 S.sub.2 crystal [tolu- 2.80-2.94 (m, 2H), 5.04 and 6.13 3298, 1682, C H N ene] (ABq, J=12.8Hz, 2H), 5.44 (s, 1607, 1328, 51.78 3.64 2.58 1H), 6.85-7.93 (m, 1H) 1254, 1158 51.69 3.77 2.6226 (7b') Light 211-212.5 (DMSO-d.sub.6) 2.5-2.6 (m, 2H), (KBr tablet) 500 C.sub.23 H.sub.20 N.sub.2 O.sub.7 S.sub.2.0.2H.sub.2 O yellow [isopro- 2.85-3.20 (m, 2H), 5.01 and 6.19 3328, 1682, (M.sup.+) C H N crystal panol] (ABq, J=12.7Hz, 1H), 5.43 (s, 1H) 1609, 1537, 54.74 3.68 5.35 6.86 (d, J=8.5H, 1H), 7.3-7.45 1346, 1255, 54.80 4.08 5.56 (m, 4H), 7.71 (dd, J=2.2, 8.5Hz, 1176 1H), 7.83-8.0 (m, 5H), 8.23 (t, J=5.6Hz, 1H), 12.75 (bs, 1H)27 (8b') White 190-191 (DMSO-d.sub.6) 2.45-2.6 (m, 2H), (KBr tablet) 500 C.sub.23 H.sub.20 N.sub.2 O.sub.7 S.sub.2.0.5C.sub.3 H.sub.8 O. crystal (decom- 2.75-3.05 (m, 2H), 4.98 and 6.16 3450, 1685, (M.sup.+) 0.5H.sub.2 O posed) (ABq, J=12.6Hz, 2H), 5.41 (s, 1609, 1532, C H N [isopro- 1H), 6.82 (d, J=8.6Hz, 1H), 7.3- 1352, 1234, 54.78 4.35 5.06 panol- 7.45 (m, 4H), 7.68 (dd, J=2.2, 1166 54.53 4.67 5.19 iso- 8.6Hz, 1H), 7.85-7.95 (m, 2H), propyl 8.15-8.35 (m, 2H), 8.45-8.50 (m, ether] 2H)28 (9b) White 235-237 (DMSO-d.sub.6) 2.45-2.55 (m, 2H), (KBr tablet) 500 C.sub.23 H.sub.20 N.sub.2 O.sub.7 S.sub.2 crystal [ethyl 2.75-3.1 (m, 2H), 5.01 and 6.18 3348, 1683, (M.sup.+) C H N acetate] (ABq, J=12.7Hz, 2H), 5.43 (s, 1607, 1527, 55.02 3.98 5.42 1H), 6.85 (d, J=8.5Hz, 1H), 7.35- 1348, 1247, 55.19 4.03 5.60 7.45 (m, 4H), 7.70 (dd, J=2.2, 1157 8.5Hz, 1H), 7.97 (d, J=2.2Hz, 1H), 8.01 (d, J=9.0Hz, 2H), 8.24 (t, J=5.7Hz, 1H), 8.41 (d, J=9.0Hz, 2H), 12.7 (bs, 1H),29 (10b) White 100 (DMSO-d.sub.6) 2.43-2.52 (m, 2H), (KBr tablet) -- C.sub.23 H.sub.20 FNO.sub.5 S.sub.2 crystal (un- 2.71-2.96 (m, 2H), 4.91 and 6.10 1612, 1560, C H N clear) (ABq, J=12.7Hz, 2H), 5.27 (s, 1387 58.06 3.99 2.91 [isopro- 1H), 6.66-8.32 (m, 1H) 58.34 4.26 2.96 panol]30 (11b) White 188-189 (DMSO-d.sub.6) 2.45-2.55 (m, 2H), (KBr tablet) -- C.sub.23 H.sub.20 ClNO.sub.5 S.sub.2 crystal [isopro- 2.70-3.00 (m, 2H), 5.01 and 6.20 3300, 1679, C H N panol] (ABq, J=12.7Hz, 2H), 5.42 (s, 1H) 1609, 1427, 56.30 4.03 2.63 6.86 (d, J=8.5H, 1H), 7.3-7.5 1233, 1155, 56.38 4.11 2.86 (m, 4H), 7.6-7.8 (m, 5H), 7.93 1091 (t, J=5.6Hz, 1H), 7.98 (d, J=1.9 Hz, 1H)31 (12b) White 181.5-182 (DMSO-d.sub.6) 2.4-2.55 (m, 2H), (KBr tablet) 469 C.sub.24 H.sub.23 NO.sub.5 S.sub.2 crystal [isopro- 2.70-2.95 (m, 2H), 5.01 and 6.20 3256, 1680, (M.sup.+) C H N panol] (ABq, J=12.7Hz, 2H), 5.40 (s, 1610, 1323, 61.19 4.90 2.77 1H), 6.86 (d, J=8.5Hz, 1H), 7.3- 1254, 1156 61.39 4.94 2.98 7.5 (m, 6H), 7.6-7.8 (m, 4H), 7.97 (d, J=1.9Hz, 1H)32 (13b) White 189-190 (DMSO-d.sub.6) 2.4-2.55 (m, 2H), (KBr tablet) 485 C.sub.24 H.sub.23 NO.sub.6 S.sub.2 crystal [aceto- 2.65-2.90 (m, 2H), 3.85 (s, 3H), 3284, 1679, (M.sup.+) C H N nitrile] 5.01 and 6.20 (ABq, J=12.8Hz, 1599, 1324, 59.07 4.63 2.57 2H), 5.41 (s, 1H), 6.86 (d, J=8.5 1254, 1152 59.37 4.77 2.88 Hz, 1H), 7.10 (d, J=8.8Hz, 2H), 7.3-7.45 (m, 4H), 7.65-7.75 (m, 4H), 7.97 (d, J=1.9Hz, 1H)33 (14b') White 150 (DMSO-d.sub.6) 2.4-2.6 (m, 2H), (KBr tablet) -- C.sub.27 H.sub.23 NO.sub.5 S.sub.2.0.3H.su b.2 O crystal (decom- 2.7-3.0 (m, 2H), 4.93 and 6.13 3450, 1684, C H N posed) (ABq, J=12.6Hz, 2H), 5.37 (s, 1608, 1322, 63.39 4.64 2.71 [isopro- 1H), 6.80 (d, J=8.6Hz, 1H), 7.15 1155 63.46 4.65 2.74 pyl 7.35 (m, 4H), 6.5-7.8 (m, 4H), ether] 7.95 (bs, 1H), 8.05-8.2 (m, 4H), 8.40 (bs, 1H)34 (15b) White 100 (DMSO-d.sub.6) 2.49-2.54 (m, 2H), (KBr tablet) -- C.sub.21 H.sub.19 NO.sub.5 S.sub.3 crystal (un- 2.84-2.99 (m, 2H), 5.02 and 6.21 3240, 1683, C H N clear) (ABq, J=12.7Hz, 2H), 5.43 (s, 1609, 1325, 54.52 3.81 2.96 [isopro- 1H), 6.84-8.02 (m, 10H) 1234, 1154 54.65 4.15 3.03 panol]35 (16b) White 191-193 (DMSO-d.sub.6) 2.41-2.51 (m, 2H), (KBr tablet) 506 C.sub.26 H.sub.22 N.sub.2 O.sub.5 S.sub.2 crystal [isopro- 2.85-2.96 (m, 2H), 4.89 and 6.03 3258, 1694, (M.sup.+) C H N panol] (ABq, J=12.7Hz, 2H), 5.30 (s, 1604, 1317, 61.55 4.46 5.16 1H), 6.80-9.07 (m, 13H) 1231 61.64 4.38 5.5336 (17b') White 172-174 (DMSO-d.sub.6) 2.4-2.6 (m, 2H), 2.75- (KBr tablet) 442 C.sub.22 H.sub.20 N.sub.2 O.sub.5 S.sub.2.H.sub.2 O crystal [isopro- 3.05 (m, 2H), 5.01 and 6.19 (ABq, 3450, 3278, (M.sup.+) C H N panol- J=12.8Hz, 2H), 5.44 (s, 1H), 6.86 1699, 1610, 57.52 4.50 6.09 water] (d, J=8.5Hz, 1H), 7.4-7.5 (m, 3H), 1322, 1251, 57.38 4.82 6.08 7.6-7.75 (m, 2H), 8.05-8.20 (m, 1165 2H), 7.98 (bs, 1H), 8.83 (bs, 1H), 8.93 (bs, 1H)37 (18b') White 176-178 (DMSO-d.sub.6) 2.5-2.65 (m, 2H), (KBr tablet) -- C.sub.25 H.sub.23 NO.sub.5 S.sub.2.0.2H.su b.2 O crystal [tolu- 2.85-3.20 (m, 2H), 5.01 and 6.22 3475, 1696, C H N ene] (ABq, J=12.7Hz, 2H), 5.45 (s, 1611, 1321, 61.93 4.76 2.86 1H), 6.86 (d, J=8.5Hz, 1H), 7.15 1254, 1142 61.89 4.86 2.89 7.55 (m, 11H), 7.65-7.75 (m, 2H), 8.01 (d, J=1.8Hz, 1H), 12.75 (bs, 1H)38 (20b) White 168-172 (DMSO-d.sub.6) 2.4-2.55 (m, 2H), (KBr tablet) 515 C.sub.25 H.sub.25 NO.sub.7 S.sub.2 crystal [isopro- 2.75-3.05 (m, 2H), 3.76 (s, 3H), 3450, 1674, (M.sup.+) C H N panol] 3.80 (s, 3H), 5.00 and 6.17 (ABq, 1609, 1496, 58.23 4.95 2.44 J=12.7Hz, 2H), 5.37 (s, 1H), 6.85 1324, 1235, 58.24 4.89 2.72 (d, J=8.6Hz, 1H), 7.15-7.45 (m, 1158 8H), 7.70 (dd, J=2.0, 8.6Hz, 1H), 7.96 (d, J=2.0Hz, 1H)39 (21b') White 136-138 (DMSO-d.sub.6) 2.4-2.55 (m, 2H), (KBr tablet) 515 C.sub.25 H.sub.25 NO.sub.7 S.sub.2.0.2H.su b.2 O crystal [aceto- 2.65-2.95 (m, 2H), 3.80 (s, 3H), 3450, 3270, (M.sup.+) C H N nitrile] 3.85 (s, 3H), 5.00 and 6.19 (ABq, 1700, 1508, 57.77 4.91 2.48 J=12.7Hz, 2H), 5.40 (s, 1H), 6.85 1314, 1263, 57.83 4.93 2.70 (d, J=8.5Hz, 1H), 7.11 (d, J=8.5) 1237, 1138 Hz, 1H), 7.25-7.45 (m, 6H), 7.63 (t, J=5.7Hz, 1H), 7.70 (dd, J=2.0, 8.5Hz, 1H), 7.97 (d, J=2.0Hz, 1H)40 (23b) White 207-208 (DMSO-d.sub.6) 2.4-2.6 (m, 2H), 2.75- (KBr tablet) -- C.sub.24 H.sub.20 F.sub.3 NO.sub.5 S.sub.2 crystal [tolu- 3.05 (m, 2H), 5.00 and 6.19 (ABq, 3450, 3280, C H N ene]* J=12.7Hz, 2H), 5.43 (s, 1H), 6.85 1684, 1608, 55.20 3.99 2.50 (d, J=8.5Hz, 1H), 7.30-7.45 (m, 1323, 1161, 55.06 3.85 2.68 4H), 7.70 (dd, J=2.2, 8.5Hz, 1H), 1131 7.95-8.05 (m, 5H), 8.12 (t, J=5.5 Hz, 1H)41 (1b') Pale Impossible -- -- -- C.sub.23 H.sub.20 NO.sub.5 S.sub.2 Na.H.sub.2 O yellow to measure C H N amor- due to 55.32 4.25 2.88 phous hygroscopic 55.47 4.48 2.83 nature [iso- propyl ether]*42 (2b') Pale Impossible -- -- 491 C.sub.24 H.sub.22 NO.sub.5 S.sub.2 Na yellow to measure (M.sup.+) C H N amor- due to 58.40 4.57 2.56 phous hygroscopic 58.64 4.51 2.85 nature [iso- propyl ether]*__________________________________________________________________________
EXAMPLE 43
Methyl N-methyl-11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 5a)
The desired compound was prepared in a manner similar to Example 1, using Compound p obtained in Reference Example 16.
EXAMPLE 44
N-Methyl-11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 5b)
The desired compound was prepared by hydrolyzing Compound 5a obtained in Reference Example 43 in a manner similar to Example 21.
Physicochemical properties of the compounds obtained in Examples 43 and 44 are shown in Table 6-3.
TABLE 6-3__________________________________________________________________________Example No. mp (.degree.C.) Elemental Analysis (%)(Compound [solvent for IR MS upper column: foundNo.) Appearance recrystallization] NMR (solvent) .delta., ppm (method) cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.43 (5a) Colorless -- (CDCl.sub.3) 2.68 (s, 3H), 2.27- (CHCl.sub.3) 3066, 483 -- oil 3.39 (m, 4H), 3.85 (s, 3H), 4.88 1712, 1611, (M.sup.+) and 6.39 (ABq, J=13.1Hz, 2H), 1342, 1244, 5.07 (s, 1H), 6.83 (d, J=8.5Hz, 1163, 1119, 1H), 7.14-8.06 (m, 11H) 100744 (5b) White 180-181 (DMSO-d.sub.6) 2.49-2.52 (m, 2H), (KBr tablet) 469 C.sub.24 H.sub.23 NO.sub.5 S.sub.2 crystal [isopropanol] 2.63 (s, 3H), 2.85-3.20 (m, 2H), 3372, 1680, (M.sup.+) C H N 5.04 and 6.25 (ABq, J=12.8Hz, 1607, 1336, 61.00 4.94 2.90 2H), 5.49 (s, 1H), 6.87 (d, J= 1236, 1163, 61.39 4.94 2.98 8.5Hz, 1H), 7.36-7.58 (m, 4H), 996 7.60-7.75 (m, 6H), 8.00 (d, J=2.2Hz, 1H), 12.73 (bs, 1H)__________________________________________________________________________
EXAMPLE 45
Ethyl 11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 24a)
The desired compound was prepared in a manner similar to Example 1, using Compound g obtained in Reference Example 7.
EXAMPLE 46
Methyl 11-[2-[(phenylsulfonyl)amino]propyl]amino-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 25a)
The desired compound was prepared in a manner similar to Example 1, using Compound h obtained in Reference Example 8.
In Examples 47 and 48 described below, the desired compound was obtained by hydrolyzing an ester of the corresponding oxepine derivative in a manner similar to Example 21.
EXAMPLE 47
11-[2-[(Phenylsulfonyl)amino]ethyl]amino-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.0.25 hydrate (Compound 24b')
EXAMPLE 48
11-[2-[(Phenylsulfonyl)amino]propyl]amino-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.0.5 hydrate (Compound 25b')
Physicochemical properties of the compounds obtained in Examples 45 through 48 are shown in Table 6-4.
TABLE 6-4__________________________________________________________________________Example No. mp (.degree.C.) IR Elemental Analysis (%)(Compound [solvent for (method) MS upper column: foundNo.) Appearance recrystallization] NMR (solvent) .delta., ppm cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.45 (24a) White 118-119 (CDCl.sub.3) 1.38 (t, J=7.1Hz, 3H), (KBr tablet) 466 C.sub.25 H.sub.26 N.sub.2 O.sub.5 S crystal [isopropyl ether] 1.87 (bs, 1H), 2.51-2.60 (m, 1H), 3264, 1705, (M.sup.+) C H N 2.69-2.78 (m, 1H), 2.95 (bs, 2H), 1570, 1243 64.21 5.65 5.94 4.33 (q, J=7.1Hz, 2H), 4.54 (s, 64.36 5.62 6.00 1H), 4.81 and 6.39 (ABq, J=12.4 Hz, 2H), 5.01 (bs, 1H), 6.84-7.87 (m, 12H)46 (25a) White 126-128 (CDCl.sub.3) 1.22-1.77 (m, 2H), 2.24- (CHCl.sub.3) 3280, 466 C.sub.25 H.sub.26 N.sub.2 O.sub.5 S crystal [methanol] 3.06 (m, 5H), 3.80 (s, 3H), 4.52 1708, 1613, (M.sup.+) C H N (s, 1H), 4.79 and 6.36 (ABq, J= 1311, 1159, 64.38 5.62 5.62 12.6, 2H), 6.80 (d, J=9.4Hz, 1H), 1121, 1094, 64.36 5.62 6.00 6.98-7.95 (m, 11H) 100547 (24b') White 130 (DMSO-d.sub.6) 2.30-2.57 (m, 2H), (KBr tablet) -- C.sub.23 H.sub.22 N.sub.2 O.sub.5 S.0.5H.sub.2 O crystal (unclear) 2.79-2.83 (m, 2H), 4.65 (s, 1H), 1610, 1378, (M.sup.+) C H N [ethyl acetate- 4.90 and 6.45 (ABq, J=11.7Hz, 1324, 1158 62.10 5.04 6.20 hexane] 2H), 6.77-7.86 (m, 12H) 61.98 5.16 6.2848 (25b') White 251-254 (DMSO-d.sub.6) 1.46-1.52 (m, 2H), (KBr tablet) 452 C.sub.24 H.sub.24 N.sub.2 O.sub.5 S.0.5H.sub.2 O crystal (decomposed) 2.25-2.8 (m, 5H), 4.69 (s, 1H) 3050, 1619, (M.sup.+) C H N [isopropanol] 4.93 and 6.48 (ABq, J=11.8Hz, 1538, 1384, 62.78 5.27 5.68 2H), 6.81 (d, J=8.5Hz, 1H), 7.3- 1322, 1159, 62.46 5.46 6.07 718 (m, 11H), 7.89 (d, J=2.2Hz, 1006 1H)__________________________________________________________________________
EXAMPLE 49
Methyl (E,Z)-11-[3-(phenylsulfonyl)amino]propylidene-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound E/Z-28a)
The desired compound was obtained in a manner similar to Example 1, using Compound i obtained in Reference Example 9. The ratio of E/Z was approximately 7:3.
EXAMPLE 50
Methyl (E,Z)-11-[3-(phenylsulfonyl)amino]propylidene-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound E/Z-29a)
The desired compound was prepared in a manner similar to Example 1, using Compound j obtained in Reference Example 10. The ratio of E/Z was approximately 3:7.
EXAMPLE 51
Methyl (E)-11-[2-(phenylsulfonyl)amino]ethylidene-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound E-30a)
The desired compound was prepared in a manner similar to Example 1, using Compound k obtained in Reference Example 11.
EXAMPLE 52
(E)-11-[3-(Phenylsulfonyl)amino]propylidene-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound E-28b) and (Z)-11-[3-(phenylsulfonyl)amino]propylidene-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.0.5 isopropanol (Compound Z-28b')
Compound E/Z-28a (1.0 g) obtained in Example 49 was hydrolyzed in a manner similar to Example 21 to prepare Compound E/Z-28b. The obtained crude product rich in E-form was recrystallized from isopropanol-isopropyl ether to obtain 0.2 g of E-form (Compound E-28b). Further Z-form (Compound Z-28b') solidified with isopropyl ether was obtained from the filtrate rich in Z-form.
EXAMPLE 53
(Z)-11-[3-(Phenylsulfonyl)amino]propylidene-6,11-dihydrodibenz-[b,e]oxepin-2-acetic acid.0.5 methanol.0.25 hydrate (Compound Z-29b')
Compound E/Z-29a obtained in Example 50 was hydrolyzed in a manner similar to Example 21 to prepare (Z)-11-[3-(phenylsulfonyl)amino]propylidene-6,11-dihydrodibenz-[b,e]oxepin-2-acetic acid (Compound Z-29b) which contained 93% of Z-form. This compound was treated in a manner similar to Example 41 to give the sodium salt.
EXAMPLE 54
(E)-11-[2-(Phenylsulfonyl)amino]ethylidene-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.0.25 hydrate (Compound E-30b')
Compound E-30a obtained in Example 51 was hydrolyzed in a manner similar to Example 21 to prepare the desired compound.
Physicochemical properties of the compounds obtained in Examples 49 through 54 are shown in Table 6-5.
TABLE 6-5__________________________________________________________________________ mp (.degree.C.) [solventExample No. for re- IR Elemental Analysis (%)(Compound crystal- (method) MS upper column: foundNo.) Appearance lization] NMR (solvent) .delta., ppm cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.49 (E/Z-28a) Colorless -- (CDCl.sub.3) 2.22-2.62 (m, 2H), -- 449 -- oil 2.82-3.26 (m, 2H), 3.81 (s, 3H), (M.sup.+) 4.95-5.57 (m, 2H), 5.91 (t, J=6.9 Hz, 1H), 6.71 (d, J=9.0Hz, 1H), 7.05-8.05 (m, 12H) (E-form)50 (E/Z-29a) Colorless -- (CDCl.sub.3) 2.26-2.70 (m, 2H), (neat) 463 -- oil 2.89-3.23 (m, 2H), 3.45 (s, 2H), 3282, 1735, (M.sup.+) 3.61 (s, 3H), 5.07 (s, 2H), 5.49 1488, 1327, (t, J=7.7Hz, 1H), 6.63-7.29 (m, 1226, 1159, 13H) (Z-form) 101051 (E-30a) Colorless -- (CDCl.sub. 3) 3.40-3.57 (m, 2H), -- 435 -- oil 3.78 (s, 3H), 5.11 (bs, 2H), 5.91 (M.sup.+) (t, J=7.4Hz, 1H), 6.65 (d, J=9.6 Hz, 1H), 6.90-7.98 (m, 12H)52 (E-28b) White 211-212 (DMSO-d.sub.6) 2.25-2.50 (m, 2H), (KBr tablet) 435 C.sub.24 H.sub.21 NO.sub.5 S crystal [isopro- 2.88-2.95 (m, 2H), 4.95 (bs, 1H), 3278, 1682, (M.sup.+) C H N panol] 5.50 (bs, 1H), 6.00 (t, J=7.2Hz, 1604, 1313, 66.03 4.76 3.16 [iso- 1H), 6.78-7.87 (m, 12H), 12.71 1247, 1154 66.19 4.86 3.22 propyl (bs, 1H) ether]52 (Z-28b') Colorless 130 (DMSO-d.sub.6) 2.42-2.50 (m, 2H), (KBr tablet) 435 C.sub.24 H.sub.21 NO.sub.5 S.0.5C.sub.3 H.sub.8 O amorphous (un- 2.92-2.97 (m, 2H), 5.26 (bs, 2H), 3228, 1674, (M.sup.+) C H N clear) 5.59 (t, J=7.0Hz, 1H), 6.87 (d, 1607, 1409, 65.84 5.55 2.87 [isopropyl J=8.5Hz, 1H), 7.30-7.80 (m, 11H), 1308, 1249, 65.79 5.41 3.01 ether]* 12.70 (bs, 1H) 1157, 1094, 100553 (Z-29b') White Impossible -- (KBr tablet) -- C.sub.25 H.sub.22 NO.sub.5 SNa.0.5CH.sub.4 O. solid to measure 3400, 1574, 0.25H.sub.2 O due to 1487, 1389, C H N hygroscopic 1307, 1159, 62.39 5.36 2.67 nature 1093, 1012 62.25 5.02 2.85 [isopropyl ether]*54 (E-30b') White 254-257 (DMSO-d.sub.6) 3.5 (bs, 2H), 4.96 (bs, (KBr tablet) 421 C.sub.23 H.sub.19 NO.sub.5 S.0.25H.sub.2 O solid (decom- 1H), 5.39 (bs, 1H), 5.91 (t, J= 3270, 1680, (M.sup.+) C H N posed) 7.2Hz, 1H), 6.80 (d, J=8.5Hz, 1605, 1311, 64.92 4.40 3.52 [aceto- 1H), 7.14 (d, J=7.3Hz, 1H), 7.25- 1247, 1154 64.85 4.61 3.29 nitrile] 7.75 (m, 9H), 7.80 (d, J=2.2Hz, 1H), 7.93 (t, J=5.2Hz, 1H)__________________________________________________________________________
In Examples 55 through 60 described below, the desired compound was prepared in a manner similar to Example 1, using the corresponding starting material (Compound r, s, t or u) and sulfonyl compounds.
EXAMPLE 55
Methyl 11-[2-[(phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenzo[b,e]thiepin-2-carboxylate (Compound 55a)
EXAMPLE 56
Methyl 5-[2-[(phenylsulfonyl)amino]ethyl]thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate (Compound 59a)
EXAMPLE 57
Methyl 5-[2-[(styrylsulfonyl)amino]ethyl]thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylate (Compound 60a)
EXAMPLE 58
Methyl 5-[2-[(phenylsulfonyl)amino]ethyl]thio-5H-dibenzo-[a,d]cyclohepten-3-carboxylate (Compound 64a)
EXAMPLE 59
Methyl 5-[2-[(styrylsulfonyl)amino]ethyl]thio-5H-dibenzo-[a,d]cyclohepten-3-carboxylate (Compound 65a)
EXAMPLE 60
Methyl 10-[2-[(phenylsulfonyl)amino]ethyl]thio-4,10 -dihydrothieno[3,2-c][1]benzoxepin-8-acetate (Compound 67a)
Physicochemical properties of the compounds obtained in Examples 55 through 60 are shown in Table 6-6. 62
EXAMPLE
b)
64
b)
65
b)
66
4,10
TABLE 6-6__________________________________________________________________________Ex. No. M. P. (.degree.C.) Elemental Analysis (%)(Compound (solvent for IR MS upper column: foundNo.) Appearance recrystallization) NMR (solvent) .delta., ppm (method) cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.55 Pale -- (CDCl.sub.3) 2.38-2.73(m, 2H), 2.82- (CHCl.sub.3) -- --(55a) yellow 3.22(m, 2H), 3.63 and 5.62(ABq, 1715, 1591, amorphous J=15Hz, 2H), 3.86(s, 3H), 5.11 1328, 1299, (s, 1H), 7.01-8.10(m, 12H) 116056 Colorless -- (CDCl.sub.3) 2.30-2.60(m, 2H), 2.70- (CHCl.sub.3) -- --(59a) oil 3.10(m, 4H), 3.60-4.00(m, 2H), 1712, 1636, 3.89(s, 3H), 4.98(s, 1H), 4.90- 1280, 1105 5.24(m, 1H), 6.92-7.92(m, 12H)57 Colorless -- (CDCl.sub.3) 2.61(t, 2H, J=6.48Hz), -- -- --(60a) oil 2.70-3.22(m, 4H), 3.60-4.00(m, 2H), 3.88(s, 3H), 4.86(t, 1H, J=6.04Hz), 5.11(s, 1H), 6.70(d, 1H, J=15.4Hz), 6.90-7.54(m, 11H), 7.81(dd, 1H, J=1.54, 7.91Hz), 7.90(s, 1H)58 Colorless -- (CDCl.sub.3) 2.30-2.50(m, 2H), 2.72- (CHCl.sub.3) -- --(64a) oil 3.00(m, 2H), 3.92(s, 3H), 4.74- 1716, 1601, 4.96(m, 1H), 5.14(s, 1H), 6.99 1280, 1162 (s, 1H), 7.00(s, 1H), 6.98-7.58 (m, 10H), 7.80(dd, 1H, J=2.20, 7.50Hz), 7.94(d, 1H, J=2.20Hz)59 Colorless -- (CDCl.sub.3) 2.28-2.62(m, 2H), 2.80- (CHCl.sub.3) -- --(65a) oil 3.06(m, 2H), 3.91(s, 3H), 3.50- 1716, 1602, 3.80(m, 1H), 5.26(s, 1H), 6.64 1279, 1142, (d, 1H, J=15.4Hz), 7.01(s, 1H), 971 7.03(s, 1H), 7.10-7.48(m, 11H), 7.80-8.00(m, 2H)60 Colorless -- (CDCl.sub.3) 2.35-3.06(m, 4H), 3.49 -- 489 (M.sup.+) --(67a) oil (s, 2H), 3.61(s, 3H), 4.75 and 5.31(ABq, J=15.0Hz, 2H), 4.92 (s, 1H), 5.14-5.34(m, 1H), 6.53 (d, J= 5.8Hz, 1H), 6.91-7.87(m, 9H)__________________________________________________________________________
In Examples 61 through 66 described below, the desired compound was prepared in a manner similar to Example 21, using the corresponding ester.
EXAMPLE 61
11-[2-[(Phenylsulfonyl)amino]ethyl]thio-6,11-dihydrodibenzo-[b,e]thiepin-2-carboxylic acid (Compound 55b)
EXAMPLE 62
5-[2-[(Phenylsulfonyl)amino]ethyl]thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic acid (Compound 59b) Example 63
5-[2-[(Styrylsulfonyl)amino]ethyl]thio-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic acid (Compound 60b)
EXAMPLE 64
5-[2-[(Phenylsulfonyl)amino]ethyl]thio-5H-dibenzo[a,d]-cyclohepten-3-carboxylic acid (Compound 64b)
EXAMPLE 65
5-[2-[(Styrylsulfonyl)amino]ethyl]thio-5H-dibenzo[a,d]-cyclohepten-3-carboxylic acid (Compound 65b)
EXAMPLE 66
10-[2-[(Phenylsulfonyl)amino]ethyl]thio-4,10-dihydrothieno-[3,2-c][1]benzoxepin-8-acetic acid (Compound 67b)
Physicochemical properties of the compounds obtained in Examples 61 through 66 are shown in Table 6-7.
TABLE 6-7__________________________________________________________________________Ex. No. M.P. (.degree.C.)(Com- (solvent for Elemental Analysis (%)pound recrystal- NMR IR MS upper column: foundNo.) Appearance lization) (solvent) .delta., ppm (method) cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.61 Pale 98 (DMSO-d.sub.6) 2.46-2.51(m, 2H), (KBr tablet) -- C.sub.23 H.sub.21 NO.sub.4 S.sub.3(55b) yellow (decomposed) 2.83-2.91(m, 2H), 3.32(bs, 1H), 3278, 1681, C H N crystal [isopropyl 5.55(bs, 1H), 5.74(bs, 1H), 1594, 1310, 58.42 4.86 2.91 ether] 7.13-8.01(m, 12H), 12.89(bs, 1156 58.58 4.49 2.97 1H)62 Pale 141-144 (DMSO-d.sub.6) 2.39-2.51(m, 2H), (KBr tablet) -- C.sub.24 H.sub.23 NO.sub.4 S.sub.2.0.2C.su b.3 H.sub.8 O(59b) yellow [ethyl 2.77-2.92(m, 4H), 3.66-3.75(m, 3282, 1693, C H N crystal acetate- 2H), 5.38(s, 1H), 7.11-7.31(m, 1446, 1328, 63.18 5.34 2.97 hexane] 4H), 7.54-7.64(m, 3H), 7.73- 1154 63.46 5.33 3.01 7.81(m, 4H), 7.93(s, 1H)63 Pale 158-161 (DMSO-d.sub.6) 2.53(t, 2H, J=7.53Hz), (KBr tablet) -- C.sub.26 H.sub.25 NO.sub.4 S.sub.2(60b) yellow [isopropyl 2.84-3.02(m, 4H), 3.69-3.78(m, 3278, 1690, C H N crystal ether] 2H), 5.44(s, 1H), 7.06-7.50(m, 1419, 1318, 64.98 5.19 2.90 10H), 7.67-7.77(m, 3H), 7.98 1285, 1142, 65.11 5.25 2.92 (d, 1H), J=1.71Hz) 97364 Pale 167-170 (DMSO-d.sub.6) 2.20-2.27(m, 2H), (KBr tablet) -- C.sub.24 H.sub.21 NO.sub.4 S.sub.2.0.1C.su b.3 H.sub.8 O(64b) yellow [aceto- 2.69-2.74(m, 2H), 5.57(s, 1H), 3270, 1635, C H N crystal nitrile] 7.04 and 7.08(ABq, 2H, J=12.2Hz), 1446, 1309, 63.61 4.51 3.21 7.32- 7.75(m, 10H), 7.85(dd, 1H, 1155 63.78 4.80 3.06 J=1.70, 7.82Hz), 8.07(d, 1H, J=1.51Hz)65 Pale 120 (DMSO-d.sub.6) 2.32-2.40(m, 2H), 2.80- (KBr tablet) -- C.sub.26 H.sub.23 NO.sub.4 S.sub.2(65b) yellow (decomposed) 3.08(m, 2H), 5.47(s, 1H), 6.97 3400, 3058, C H N crystal [isopro- (s, 2H), 7.13(d, 1H, J=15.4Hz), 1584, 1537, 65.64 4.69 2.92 panol] 7.25-7.48(m, 8H), 7.67-7.72(m, 1404, 1382, 65.39 4.85 2.93 3H), 7.80(dd, 1H, J=1.46, 7.81 1143, 970 Hz), 8.00(d, 1H, J=1.22Hz)66 Pale 186-187 (DMSO-d.sub.6) 2.50-2.60(m, 2H), 2.75- (KBr tablet) 475(M.sup.+) C.sub.22 H.sub.21 NO.sub.5 S.sub.3(67b) yellow (decomposed) 2.95(m, 2H), 3.52(s, 2H), 4.80 3450, 3240, C H N crystal [methanol] and 5.40(ABq, J=15.4Hz, 2H), 1709, 1499, 55.46 4.39 3.11 5.30(s, 1H), 6.76(d, J=5.1Hz, 1327, 1160 55.56 4.45 2.95 1H), 7.02(d, J=7.8Hz, 1H), 7.14- 7.18(m, 2H), 7.39(d, J=5.1Hz, 1H), 7.56-7.80(m, 6H), 12.35 (bs, 1H)__________________________________________________________________________
In Examples 67 through 76 described below, the desired compound was prepared, using the corresponding 11-(2-aminoethyl)thio-6,11-dihydrodibenz-[b,e]oxepine derivative (Compound f or o), either by changing the benzenesulfonyl chloride in Example 1 to the corresponding acid chloride or acid anhydride, or in a manner similar to Example 1.
EXAMPLE 67
Methyl 11-[2-[(benzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 32a)
EXAMPLE 68
Methyl 11-[2-[(2-methoxybenzoyl)amino]ethyl]thio-6,11-dihydro-dibenz[b,e]oxepin-2-carboxylate (Compound 33a)
EXAMPLE 69
Methyl 11-[2-[(2,6-dimethoxybenzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 35a)
EXAMPLE 70
Methyl 11-[2-[(3,4,5-trimethoxybenzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate.0.3 hydrate (Compound 36a')
EXAMPLE 71
Methyl11-[2-(2,3,4-trimethoxybenzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 37a)
EXAMPLE 72
Methyl 11-[2-[(2-methylthenoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 38a)
EXAMPLE 73
Methyl 11-[2-[(cyclohexanecarbonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 39a)
EXAMPLE 74
Methyl 11-[2-[(hexanoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 40a)
EXAMPLE 75
Methyl 11-[2-[(cinnamoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 41a)
EXAMPLE 76
Methyl 11-[2-[[(coumarin-3-yl)carbonyl]amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetylate (Compound 42a)
EXAMPLE 77
Methyl 11-[2-[(2-hydroxybenzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 34a)
Compound 33a, 2.1 g, obtained in Example 68 was dissolved in 100 ml of methylene chloride and 0.6 ml of boron trifluoride was dropwise added to the solution at -78.degree. C. under a nitrogen atmosphere. After stirring for further 2.5 hours, pieces of ice were added to the reaction mixture to decompose an excess of the reagent. Then, extraction was performed with 200 ml of methylene chloride. After washing with water, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=1:1) to give 1.5 g of the desired compound.
Physicochemical properties of the compounds obtained in Examples 67 through 77 are shown in Table 6-8.
TABLE 6-8__________________________________________________________________________Ex. No. M.P. (.degree.C.)(Com- (solvent for Elemental Analysis (%)pound recrystal- NMR IR MS upper column: foundNo.) Appearance lization) (solvent) .delta., ppm (method) cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.67 White 150-151 (CDCl.sub.3) 2.38-2.86(m, 2H), 3.34- (KBr tablet) 433(M.sup.+) C.sub.25 H.sub.23 NO.sub.4 S(32a) crystal [isopropyl 3.75(m, 2H), 3.80(s, 3H), 4.84 3336, 1718, C H N ether] and 6.36(ABq, J=12.6Hz, 2H), 1635, 1527, 69.21 5.27 3.33 5.06(s, 1H), 6.81(d, J=9.0Hz, 1295, 1253, 69.26 5.35 3.23 1H), 7.10-8.11(m, 12H) 1120, 100968 White 123-125 (CDCl.sub.3) 2.50-2.89(m, 2H), 3.40- (KBr tablet) -- C.sub.26 H.sub.25 NO.sub.3 S(33a) crystal [isopropyl 3.79(m, 2H), 3.76(s, 3H), 3.83 3372, 1708, C H N ether] (s, 3H), 4.82 and 6.35(ABq, 1645, 1602, 67.37 5.44 3.02 J=12.9Hz, 2H), 5.05(s, 1H), 1533, 1295, 67.42 5.61 3.03 6.67-8.47(m, 11H) 1253, 76869 White 163-164 (CDCl.sub.3 + DMSO-d.sub.6) 2.41-2.83(m, (KBr tablet) 493(M.sup.+) C.sub.27 H.sub.27 NO.sub.6 S(35a) crystal [toluene] 3.16-3.54(m, 2H), 3.66(s, 3H), 3400, 2948, C H N 3.74(s, 6H), 4.90 and 6.33(ABq, 1718, 1636, 65.50 5.80 2.71 J=12.4Hz, 2H), 5.23(s, 1H), 6.51 1597, 1241, 65.70 5.51 2.84 (d, J=8.0Hz, 2H), 6.78(d, J= 1112 8.6Hz, 1H), 7.02-7.40(m, 5H), 7.67(dd, J=2.5, 8.6Hz, 1H), 7.82 (bs, 1H), 7.95(d, J=2.5Hz, 1H)70 Colorless 78-81 (CDCl.sub.3) 2.51-2.83(m, 2H), 3.27- (KBr tablet) 523(M.sup.+) --(36a') amorphous (unclear) 3.78(m, 2H), 3.84(s, 12H), 4.85 3400, 2934, [isopropyl and 6.34(ABq, J=12.8Hz, 2H), 1715, 1633, ether]* 5.04(s, 1H), 6.80(d, J=8.5Hz, 1610, 1582, 1H), 7.01(s, 2H), 7.12-7.37(m, 1498, 1332, 4H), 7.73(dd, J=2.4, 8.5Hz, 1H), 1239, 1127, 7.93(d, J=2.4Hz, 1H) 100571 Colorless -- (CDCl.sub.3) 2.51-2.87(m, 2H), 3.40- (KBr tablet) 523(M.sup.+) --(37a) amorphous 3.86(m, 2H), 3.78(s, 6H), 3.83 3380, 2940, (s, 3H), 3.86(s, 3H), 4.87 and 1711, 1655 6.41(ABq, J=12.9Hz, 2H), 5.11(s, 1596, 1279, 1H), 6.70(d, J=5.0Hz, 1H), 6.85 1093, 1006 (d, J=5.4Hz, 1H), 7.12-7.40(m, 4H), 7.64-8.04(m, 3H), 8.12-8.45 (m, 1H)72 Colorless -- (CDCl.sub.3) 2.42(s, 3H), 2.42-2.88(m, (KBr tablet) 453(M.sup.+) --(38a) amorphous 2H), 3.31-3.78(m, 2H), 3.81(s, 3300, 2946, 3H), 4.85 and 6.36(ABq, J=12.6Hz, 1720, 1617, 2H), 5.07(s, 1H), 6.35(bs, 1H), 1234, 1118, 6.71-6.98(m, 2H), 7.14-7.44(m, 1009 5H), 7.74(dd, J=2.0, 8.8Hz, 1H), 7.95(d, J=2.0Hz, 1H)73 Colorless -- (CDCl.sub.3) 1.1-2.2(m, 11H), 2.4-2.7 (KBr tablet) -- --(39a) amorphous (m, 2H), 3.25-3.55(m, 2H), 3.89 3312, 1717, (s, 3H), 4.91 and 6.41(ABq, J= 1641, 1530, 12.9Hz, 2H), 5.05(s, 1H), 5.71 1250, 1117, (bs, 1H), 6.86(d, J=8.4Hz, 1H), 1007 7.1-7.5(m, 4H), 7.7-8.0(m, 2H)74 Colorless -- (CDCl.sub.3) 0.8-2.0(m, 9H), 2.4-2.9 (KBr tablet) -- --(40a) amorphous (m, 4H), 3.3-3.5(m, 2H), 3.89(s, 3310, 1703, 3H), 4.91 and 6.40(ABq, J=12.7 1632, 1548, Hz, 2H), 6.86(d, J=8.6Hz, 1H), 1281, 1250, 7.25-7.39(m, 4H), 7.80(dd, J= 1115, 1008 2.2 and 8.6Hz, 1H), 7.96(d, J= 2.2Hz, 1H)75 Pale -- (CDCl.sub.3) 2.43-2.83(m, 2H), 3.26- (CHCl.sub.3) 473(M.sup.+) --(41a) yellow 3.72(m, 2H), 3.49(s, 2H), 3.61 3384, 1733, amorphous (s, 3H), 4.78 and 6.19(ABq, J= 1667, 1627, 13.1Hz, 2H), 4.97(s, 1H), 6.38 1500, 1123, (d, J=15.6Hz, 1H), 6.61-7.56(m, 1014 12H), 7.59(d, J=15.6Hz, 1H)76 Light red -- (CDCl.sub.3) 2.47-2.90(m, 2H), 3.22- (CHCl.sub.3) 515(M.sup.+) --(42a) amorphous 3.69(m, 2H), 3.52(s, 2H), 3.61 3344, 1720, (s, 3H), 4.80 and 6.25(ABq, J= 1710, 1655, 12.6Hz, 2H), 5.04(s, 1H), 6.74 1611, 1570, (d, J=8.0Hz, 1H), 6.91-7.71(m, 1540, 1161, 10H), 8.80(s, 1H), 8.73-9.09 1122, 1011 (m, 1H)77 Colorless 149-151 (CDCl.sub.3) 2.47-2.86(m, 2H), 3.32- (CHCl.sub.3) 449(M.sup.+) --(34a) amorphous [isopropyl 3.71(m, 2H), 3.83(s, 3H), 4.84 1716, 1646, ether]* and 6.34(ABq, J=13.1Hz, 2H), 5.03 1599, 1297, (s, 1H), 6.81(d, J=8.4Hz, 1H), 1252, 1120, 6.83-7.55(m, 8H), 7.76(dd, J= 1008 2.2, 8.4Hz, 1H), 7.98(d, J=2.2Hz, 1H), 12.22(bs, 1H)__________________________________________________________________________
In Examples 78 through 88 described below, the desired compound was prepared by hydrolyzing an ester of the corresponding oxepin derivative in a manner almost similar to Example 21.
EXAMPLE 78
11-[2-[(Benzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 32b)
EXAMPLE 79
11-[2-[(2-Methoxybenzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 33b)
EXAMPLE 80
11-[2-[(2,6-Dimethoxybenzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.0.2 hydrate (Compound 35b')
EXAMPLE 81
11-[2-[(3,4,5-Trimethoxybenzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 36b)
EXAMPLE 82
11-[2-[(2,3,4-Trimethoxybenzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 37b)
EXAMPLE 83
11-[2-[(2-Methylthenoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 38b)
EXAMPLE 84
11-[2-[(Cyclohexanecarbonyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid (Compound 39b)
EXAMPLE 85
11-[2-[(Hexanoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]-oxepin-2-carboxylic acid (Compound 40b)
EXAMPLE 86
11-[2-[(Cinnamoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]-oxepin-2-carboxylic acid.0.25 hydrate (Compound 41b')
EXAMPLE 87
11-[2-[[(Coumarin-3-yl)carbonyl]amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetic acid.0.5 hydrate (Compound 42b')
EXAMPLE 88
11-[2-[(2-Hydroxybenzoyl)amino]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.0.5 hydrate (Compound 34b')
Physicochemical properties of the compounds obtained in Examples 78 through 88 are shown in Table 6-9.
TABLE 6-9__________________________________________________________________________Ex. No. M.P. (.degree.C.)(Com- (solvent for Elemental Analysis (%)pound recrystal- NMR IR MS upper column: foundNo.) Appearance lization) (solvent) .delta., ppm (method) cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.78 White 193-194 (DMSO-d.sub.6) 2.5-2.75(m, 2H), 3.2- (KBr tablet) 419(M.sup.+) C.sub.24 H.sub.21 NO.sub.4 S(32b) crystal [isopro- 3.6(m, 2H), 5.00 and 6.25(ABq, 3322, 1683, C H N panol] J=12.4Hz, 2H), 5.44(s, 1H), 6.83 1630, 1607, 68.67 5.23 3.36 (d, J=8.6Hz, 1H), 7.2-7.9(m, 1537, 1254, 68.72 5.05 3.34 11H), 8.5(m, 1H) 1112, 101279 White 198-200 (DMSO-d.sub.6) 2.50-2.62(m, 2H), (KBr tablet -- C.sub.25 H.sub.23 NO.sub.5 S(33b) crystal [isopro- 3.46-3.54(m, 2H), 3.88(s, 3H), 3340, 1699, C H N panol] 5.06 and 6.27(ABq, J=12.7Hz, 2H), 1608, 1553, 66.85 5.12 3.21 5.49(s, 1H), 6.86-8.42(m, 11H), 1232, 1120, 66.80 5.16 3.12 12.8(bs, 1H) 75980 White 232-234 (DMSO-d.sub.6) 2.45-2.7(m, 2H), 3.2- (KBr tablet) 479(M.sup.+) C.sub.26 H.sub.25 NO.sub.6 S.0.2H.sub.2 O(35b') crystal [isopro- 3.4(m, 2H), 3.68(s, 6H), 5.06 and 3388, 3262, C H N panol] 6.28(ABq, J=12.7Hz, 2H), 5.47(s, 1701, 1607, 64.67 5.36 2.83 1H), 6.65(d, J=8.4Hz, 2H), 6.88 1474, 1254, 64.64 5.30 2.90 (d, J=8.5Hz, 1H), 7.27(t, J=8.4 1231, 1115, Hz, 1H), 7.35-7.5(m, 4H), 7.72 1005 (dd, J=2.2, 8.5Hz, 1H), 8.02(d, J=2.2Hz), 8.20(t, J=5.6Hz, 1H), 12.75(bs, 1H)81 White 215-217 (DMSO-d.sub.6) 2.55-2.7(m, 2H), 3.4- (KBr tablet) 509(M.sup.+) C.sub.27 H.sub.27 NO.sub. 7 S(36b) crystal [toluene] 3.55(m, 2H), 3.70(s, 3H), 3.83 3320, 2932, C H N (s, 6H), 5.05 and 6.28(ABq, J= 1686, 1639, 63.60 5.36 2.68 12.6Hz, 2H), 5.47(s, 1H), 6.87 1613, 1580, 63.64 5.34 2.75 (d, J=8.6Hz, 1H), 7.19(s, 2H), 1498, 1335, 7.35-7.5(m, 4H), 7.71(dd, J=2.2, 1232, 1133, 8.6Hz, 1H), 8.05(d, J=2.2Hz, 1H), 1001 8.59(t, J=5.6Hz, 1H), 12.75(bs, 1H)82 White 214-215.5 (DMSO-d.sub.6) 2.64(t, J=6.6Hz, 2H), (KBr tablet) 509(M.sup.+) C.sub.27 H.sub.27 NO.sub.7 S(37b) crystal [isopro- 3.3-3.6(m, 2H), 3.76(s, 3H), 3354, 1679, C H N panol] 3.83(s, 3H), 3.84(s, 3H), 5.06 1646, 1613, 63.45 5.39 2.65 and 6.26(ABq, J=12.7Hz, 2H), 1525, 1234, 63.64 5.34 2.75 5.50(s, 1H), 6.88(8, J=8.5Hz, 1091,1001 1H), 6.90(d, J=8.9Hz, 1H), 7.35- 7.50(m, 4H), 7.55(d, J=8.9Hz, 1H), 7.71(dd, J=2.2, 8.5Hz, 1H), 8.05(d, J=2.2Hz, 1H), 8.33(t, J=5.9Hz, 1H)83 White 170-172 (DMSO-d.sub.6) 2.40(s, 3H), 2.5-2.7(m, (KBr tablet) 439(M.sup.+) C.sub.23 H.sub.21 NO.sub.4 S.sub.2(38b) crystal [isopro- 2H), 3.3-3.5(m, 2H), 5.05 and 3294, 1684, C H N panol] 6.27(ABq, J=12.7Hz, 2H), 5.45(s, 1628, 1609, 62.99 4.92 3.19 1H), 6.87(d, J=8.5Hz, 1H), 6.95 1255, 1232, 62.85 4.82 3.19 (d, J=4.9Hz, 1H), 7.35-7.50(m, 1111, 1008 4H), 7.55(d, J=4.9Hz, 1H), 7.71 (dd, J=2.2, 8.5Hz, 1H), 8.0-8.1 (m, 2H), 12.75(bs, 1H)84 White 181-182 (DMSO-d.sub.6) 1.14-1.67(m, 10H), (KBr tablet) -- C.sub.24 H.sub.27 NO.sub.4 S(39b) crystal [Aceto- 2.03-2.11(m, 1H), 2.41-2.50(m, 3336, 1674, C H N nitrile] 2H), 3.15-3.25(m, 2H), 5.04 and 1608, 1548, 67.51 6.32 3.26 6.26(ABq, J=12.6Hz, 2H), 5.39(s, 1395, 1319, 67.74 6.40 3.29 1H), 6.86(d, J=8.5Hz, 1H), 7.35- 1231, 1001 7.49(m, 4H), 7.70(dd, J=2.2 and 8.5Hz, 1H), 7.80(t, J=5.5Hz, 1H), 7.99(d, J=2.2Hz, 1H)85 White 123-125 (DMSO-d.sub.6) 0.83(t, J=7.0Hz, 3H), (KBr tablet) -- C.sub.23 H.sub.27 NO.sub.4 S(40b) crystal [Isopro- 1.18-1.29(m, 4H), 1.43-1.54(m, 3344, 1671, C H N panol] 2H), 2.05(t, J=7.4Hz, 2H), 2.42- 1606, 1540, 66.56 6.81 3.18 2.54(m, 2H), 3.15-3.33(m, 2H), 1226, 1204, 66.80 6.58 3.39 5.04 and 6.26(ABq, J=12.6Hz, 2H), 1109, 1004 5.41(s, 1H), 6.87(d, J=8.5Hz, 1H), 7.33-7.47(m, 4H), 7.71(dd, J=2.2 and 8.5Hz, 1H), 7.91(t, J=5.7Hz, 1H), 7.99(d, J=2.2Hz, 1H)86 Pale Unclear -- (KBr tablet) 459(M.sup.+) C.sub.27 H.sub.25 NO.sub.4 S.0.2H.sub.2 O(41b') yellow [isopropyl 3400, 1700, C H N amorphous ether] 1652, 1608, 69.66 5.80 2.83 1498, 1228, 69.88 5.54 3.02 101387 Colorless 165 (DMSO-d.sub.6) 2.64(t, J=6.8Hz, 2H), (KBr tablet) 501(M.sup.+) C.sub.28 H.sub.23 NO.sub.6 S.0.5H.sub.2 O(42b') amorphous (decomposed) 3.3-3.5(m, 2H), 3.49(s, 2H), 2916, 1704, C H N [Isopropyl 4.95 and 6.11(ABq, J=12.9Hz, 2H), 1608, 1498, 65.95 4.54 2.72 ether] 5.28(s, 1H), 6.75(d, J=8.3Hz, 1229, 1122, 65.87 4.74 2.74 1H), 7.06(dd, J=2.2, 8.3Hz, 1H), 1010 7.26(d, J=2.2Hz, 1H), 7.3-7.55 (m, 7H), 7.73-7.79(m, 1H), 8.00 (dd, J=1.6, 7.8Hz, 1H), 8.91(s, 1H), 12.3(bs, 1H)88 White 125 (DMSO-d.sub.6) 2.6-2.8(m, 2H), 3.45- (KBr tablet) 435(M.sup.+) C.sub.24 H.sub.21 NO.sub.5 S.0.5H.sub.2 O(34b') crystal (unclear) 3.55(m, 2H), 5.04 and 6.25(ABq, 3350, 1682, C H N [Isopropyl J=12.6Hz, 2H), 5.46(s, 1H), 6.86 1635, 1597, 64.78 4.74 3.02 ether] (d, J=8.5Hz, 1H), 6.92(d, J= 1538, 1493, 64.85 4.99 3.15 4.6Hz, 1H), 6.8-6.9(m, 1H), 7.3- 1235, 1112, 7.5(m, 5H), 7.71(dd, J=2.0, 8.5 1007 Hz, 1H), 7.84(dd, J=1.5, 7.8Hz, 1H), 8.05(d, J=2.0Hz, 1H), 8.99 (bs, 1H), 12.7(bs, 1H__________________________________________________________________________
EXAMPLE 89
Methyl 11-[2-(3-phenylureido)ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylate (Compound 44a)
Compound f, 2.0 g, obtained in Reference Example 6 was dissolved in 100 ml of methylene chloride and 0.7 ml of phenyl isocyanate was added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was extracted with 200 ml of ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=2:1) to give 2.2 g of the desired compound.
In Examples 90 to 92 described below, the desired compound was prepared in a manner similar to Example 89 except for using the corresponding 11-(2-aminoethyl)thio-6,11-dihydrodibenz-[b,e]oxepin derivative (Compound f or o) and an isocyanate, isothiocyanate or chloroformate.
EXAMPLE 90
11-[2-(3-phenylureido)ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-acetate (Compound 45a)
EXAMPLE 91
Methyl 11-[2-[(3-benzyl)thioureido]ethyl]thio-6,11-dihydrodibenz-[ b,e]oxepin-2-carboxylate (Compound 46a)
EXAMPLE 92
Methyl 11-[2[[(benzyloxy)carbonyl]amino]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound 53a)
Physicochemical properties of the compounds obtained in Examples 89 through 92 are shown in Table 6-10.
TABLE 6-10__________________________________________________________________________Ex. No. M.P. (.degree.C.)(Com- (solvent for Elemental Analysis (%)pound recrystal- NMR IR MS upper column: foundNo.) Appearance lization) (solvent) .delta., ppm (method) cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.89 Colorless -- (CDCl.sub.3) 2.33-2.70(m, 2H), 3.03- (KBr tablet) 448(M.sup.+) --(44a) amorphous 3.52(m, 2H), 3.81(s, 3H), 4.86 1715, 1498, and 6.33(ABq, J=13.3Hz, 2H), 4.99 1435, 1237 (s, 1H), 5.78-6.15(m, 1H), 6.80 1117, 1007 (d, J=8.2Hz, 1H), 6.91-7.42(m, 9H), 7.65-7.84(m, 2H), 7.94(d, J=2.0Hz, 1H)90 Colorless -- (CDCl.sub.3) 2.37-2.66(m, 2H), 3.12- (KBr tablet) 462(M.sup.+) C.sub.26 H.sub.26 N.sub.2 O.sub.4 S(45a) amorphous 3.34(m, 2H), 3.43(s, 2H), 3.56 3340, 1731, C H N (s, 3H), 4.74 and 6.17(ABq, J= 1647, 1597, 67.76 5.80 5.89 13.8Hz, 2H), 6.68(d, J=9.0Hz, 1550, 1498, 67.51 5.67 6.06 1H), 6.73-7.56(m, 11H), 8.13(bs, 1309, 1230, 1H) 1163, 101191 Colorless -- (CDCl.sub.3) 2.41-2.74(m, 2H), 3.43- (KBr tablet) 478(M.sup.+) --(46a) amorphous 3.78(m, 2H), 3.75(s, 3H), 4.56 3400, 1717, (d, J=4.0Hz, 2H), 4.80 and 6.25 1610, 1533, (ABq, J=12.8Hz, 2H), 5.02(s, 1H), 1242, 1118, 6.30-6.68(m, 1H), 6.76(d, J=8.6 1005 Hz, 1H), 7.01-7.34(m, 9H), 7.69 (dd, J=2.2, 8.6Hz, 1H), 7.90(d, J=2.2Hz, 1H)92 Colorless -- (CDCl.sub.3) 2.34-2.73(m, 2H), 3.05- (KBr tablet) 463(M.sup.+) --(53a) amorphous 3.48(m, 2H), 3.83(s, 3H), 4.85 1700. 1609, and 6.38(ABq, J=11.4Hz, 2H), 5.01 1567, 1532, (s, 1H), 5.09(s, 2H), 6.83(d, J= 1431, 1300, 8.5Hz, 1H), 7.04-7.48(m, 9H), 1121, 1013 7.77(dd, J=2.0, 8.5Hz, 1H), 7.96(d, J=2.0Hz, 1H)__________________________________________________________________________
In Examples 93 through 96 described below, the desired compound was prepared by hydrolyzing an ester of the corresponding dibenzoxepine derivative in a manner similar to Example 21.
EXAMPLE 93
11-[2-(3-Phenylureido)ethyl]thio-6,11-dihydrodibenzo-[b,e]-oxepin-2-carboxylic acid (Compound 44b)
EXAMPLE 94
11-[2-(3-Phenylureido)ethyl]thio-6,11-dihydrodibenzo-[b,e]-oxepin-2-acetic acid.0.25 hydrate (Compound 45b')
EXAMPLE 95
11-2-[(3-Benzyl)thioureido]ethyl]thio-6,11-dihydrodibenz-[b,e]oxepin-2-carboxylic acid.0.6 toluene monohydrate (Compound 46b')
EXAMPLE 96
11-[2-[[(Benzyloxy)carbonyl]amino]ethyl]thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid (Compound 53b)
Physicochemical properties of the compounds obtained in Examples 93 through 96 are shown in Table 6-11.
TABLE 6-11__________________________________________________________________________Ex. No. M.P. (.degree.C.)(Com- (solvent for Elemental Analysis (%)pound recrystal- NMR IR MS upper column: foundNo.) Appearance lization) (solvent) .delta., ppm (method) cm.sup.-1 m/z lower column:__________________________________________________________________________ calcd.93 White 160-162 (DMSO-d.sub.6) 2.4-2.65(m, 2H), 3.2- (KBr tablet) 434(M.sup.+) C.sub.24 H.sub.22 N.sub.2 O.sub.4 S(44b) crystal [toluene]* 3.35(m, 2H), 5.05 and 6.27(ABq, 3398, 1693, C H N J=12.8Hz, 2H), 5.46(s, 1H), 6.41 1668, 1610, 66.31 5.05 5.97 (t, J=5.6Hz, 1H), 6.87(d, J=8.5 1553, 1498, 66.34 5.10 6.45 Hz, 1H), 7.21(t, J=7.8Hz, 2H), 1299, 1254, 7.35-7.50(m, 6H), 7.72(dd, J=2.0, 1232, 1112, 8.5Hz, 1H), 8.03(d, J=2.0Hz, 1H), 1010 8.65(s, 1H)94 White 108-110 (DMSO-d.sub.6) 2.45-2.6(m, 2H), 3.3- (KBr tablet) 448(M.sup.+) C.sub.25 H.sub.24 N.sub.2 O.sub.4 S.0.25H.s ub.2 O(45b') crystal [water]* 3.4(m, 2H), 3.47(s, 2H), 4.94 and 3450, 1714, C H N 6.12(ABq, J=12.8Hz, 2H), 5.25(s, 1673, 1613, 66.13 5.36 6.21 1H), 6.28(t, J=5.9Hz, 1H), 6.75 1486, 1439, 66.28 5.56 6.18 (d, J=8.5Hz, 1H), 6.89(t, J=7.3 1201, 1133, Hz, 1H), 7.06(dd, J=2.2, 8.5Hz, 1005 1H), 7.2-7.5(m, 9H), 8.58(s, 1H), 12.3(bs, 1H)95 White 135-136 (DMSO-d.sub.6) 2.55-2.7(m, 2H), 3.5- (KBr tablet) 464(M.sup.+) C.sub.25 H.sub.24 N.sub.2 O.sub.3 S.sub.2.0 .6(46b') crystal [toluene] 3.8(m, 2H), 4.66(bs, 2H), 5.05 3275, 1685, C.sub.7 H.sub.8.H.sub.2 O and 6.23(ABq, J=12.7Hz, 2H), 5.46 1606, 1553, C H N (s, 1H), 6.88(d, J=8.6Hz, 1H), 1291, 1252, 65.21 5.50 6.25 7.1-7.5(m, 10H), 7.66(bs, 1H), 1236, 1111, 65.20 5.77 5.21 7.72(dd, J=2.0, 8.6Hz, 1H), 8.02 1008 (d, J=2.0Hz, 1H),96 Colorless -- (DMSO-d.sub.6) 2.45-2.55(m, 2H), 3.1- (KBr tablet) 449(M.sup.+) C.sub.25 H.sub.23 NO.sub.5 S(53b) amorphous 3.25(m, 2H), 5.03 and 6.25(ABq, 3450, 1685, C H N J=11.1Hz, 2H), 5.05(s, 2H), 5.42 1609, 1542 66.52 5.23 2.96 (s, 1H), 6.87(d, J=8.6Hz, 1H), 1272, 1254, 66.80 5.16 3.12 7.15-7.5(m, 10H), 7.71(dd, J=2.0, 1231, 1111, 8.6Hz, 1H), 8.03(d, J=2.0Hz, 1H), 1009 12.72(bs, 1H)__________________________________________________________________________
______________________________________Pharmaceutical Preparation 1 Tablet______________________________________
A tablet having the following composition is prepared in a conventional manner.
______________________________________Compound lb 200 mgLactose 60 mgPotato starch 30 mgPolyvinyl alcohol 2 mgMagnesium stearate 1 mgTar pigment tracePharmaceutical Preparation 2 Powder______________________________________
Powders having the following composition are prepared in a conventional manner.
______________________________________Compound E-28b 200 mgLactose 270 mgPharmaceutical Preparation 3 Syrup______________________________________
Syrup having the following composition is prepared in a conventional manner.
______________________________________Compound lb 200 mgRefined sugar 40 gEthyl p-hydroxybenzoate 40 mgPropyl p-hydroxybenzoate 10 mgStrawberry flavor 0.1 cc______________________________________
Water is added to make the whole volume 100 cc.
According to the present invention, Compound (I) and pharmaceutically acceptable salts thereof possess a thromboxane A.sub.2 (TXA.sub.2)-antagonizing activity and are expected to exhibit preventive and therapeutic effects against diseases over a wide range.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Number	Name	Date
3354155	Tretter	Nov 1967
3420851	Bloom et al.	Jan 1969
3905972	Dostert et al.	Sep 1975
4282365	Rokach et al.	Aug 1981
4396550	Takizawa et al.	Aug 1983
4465835	Takizawa et al.	Aug 1984
4585788	Helsley et al.	Apr 1986
4596804	Takizawa et al.	Jun 1986
4749703	Uno et al.	Jun 1988

Number	Date	Country
0085870	Aug 1983	EPX
188802	Jul 1986	EPX
214779	Mar 1987	EPX
0235796	Sep 1987	EPX
139073	Aug 1983	JPX
227879	Dec 1984	JPX
152673	Jul 1986	JPX
152674	Jul 1986	JPX
152675	Jul 1986	JPX
152676	Jul 1986	JPX
257981	Nov 1986	JPX
153280	Aug 1987	JPX
1167263	Feb 1967	GBX
8705014	Feb 1987	WOX

Tricyclic compounds and TXA.sub.2 antagonistic compositions thereof

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

Priority Claims (1)

Parent Case Info

US Referenced Citations (9)

Foreign Referenced Citations (14)

Non-Patent Literature Citations (8)

Divisions (1)

Entry
Chemical Abstracts, vol. 105 (1986), abst. No. 60549g.
Chemical Abstracts, vol. 96 (1982), abst. No. 68848v.
J. Med. Chem. 19, 941 (1976), Ueno et al.
J. Med. Chem. 20, 1499, Aultz et al.
J. Med. Chem. 21, 633 (1978), Yoshioka et al.
Drugs, 13, 161 (1977), Pinder et al.
Arz.--Forsch., 13, 1039 (1963), Metvsova et al.
Arz.--Forsch., 14, 100 (1964), Benesova et al.