WO1986005779A1 - Phenylene derivatives - Google Patents
Phenylene derivatives Download PDFInfo
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- WO1986005779A1 WO1986005779A1 PCT/JP1986/000155 JP8600155W WO8605779A1 WO 1986005779 A1 WO1986005779 A1 WO 1986005779A1 JP 8600155 W JP8600155 W JP 8600155W WO 8605779 A1 WO8605779 A1 WO 8605779A1
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- group
- lower alkyl
- alkyl group
- general formula
- hydrogen atom
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- 0 *=*c1ccccc1[N+]([O-])=O Chemical compound *=*c1ccccc1[N+]([O-])=O 0.000 description 18
- CZMPSRPZJZPIHQ-UHFFFAOYSA-N C/C(/NC)=N/NN Chemical compound C/C(/NC)=N/NN CZMPSRPZJZPIHQ-UHFFFAOYSA-N 0.000 description 1
- WOXIQVRJTAROCD-DWJQMLCTSA-N CC(S/C(/C)=N\C)=N Chemical compound CC(S/C(/C)=N\C)=N WOXIQVRJTAROCD-DWJQMLCTSA-N 0.000 description 1
- ZAEBZZFQAHRPAI-UHFFFAOYSA-N CC1=NN=C(C)S1C Chemical compound CC1=NN=C(C)S1C ZAEBZZFQAHRPAI-UHFFFAOYSA-N 0.000 description 1
- WEPVMHQGQNWQMB-HSZRJFAPSA-N CCOC(COc(ccc(C)c1)c1N[C@H](C)C(c(cc1)ccc1OCCCCc1ccccc1)=O)=O Chemical compound CCOC(COc(ccc(C)c1)c1N[C@H](C)C(c(cc1)ccc1OCCCCc1ccccc1)=O)=O WEPVMHQGQNWQMB-HSZRJFAPSA-N 0.000 description 1
- AJAPXEIMCRETTP-UHFFFAOYSA-N CCOC(CS(C)(c(cccc1)c1NCc(cc1)ccc1OCCCCc1ccccc1)=C)=O Chemical compound CCOC(CS(C)(c(cccc1)c1NCc(cc1)ccc1OCCCCc1ccccc1)=C)=O AJAPXEIMCRETTP-UHFFFAOYSA-N 0.000 description 1
- ZNKKYYNWFKHNHZ-SSDOTTSWSA-N C[C@@H]1C=CC=CC1 Chemical compound C[C@@H]1C=CC=CC1 ZNKKYYNWFKHNHZ-SSDOTTSWSA-N 0.000 description 1
- LETPSQYGJVZQFQ-UHFFFAOYSA-N Cc(c(CCl)ccc1)c1O Chemical compound Cc(c(CCl)ccc1)c1O LETPSQYGJVZQFQ-UHFFFAOYSA-N 0.000 description 1
- JXQGICFGPUAVLJ-UHFFFAOYSA-N Cc1nnc(C)[s]1 Chemical compound Cc1nnc(C)[s]1 JXQGICFGPUAVLJ-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
- C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
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- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
- C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
- C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
- C07C59/70—Ethers of hydroxy-acetic acid, e.g. substitutes on the ring
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- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
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- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
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- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
- C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
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- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
Definitions
- the present invention relates to novel phenylene derivatives useful as drugs, particularly SRS-A (slow reacting substance of anaphylaxis) antagonists. (Means for solving the problems)
- the compounds of the present invention are phenylene derivatives represented by general formula (I) described below.
- A a hydrogen atom, a phenyl group or a phenoxy group
- n an integer of 3 to 10
- R 1 a hydrogen atom or a lower alkoxy group
- B a group represented by:
- R 2 a hydrogen atom, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a carboxy group, a cyano group, an oxaloamido group (-NHCOCOOH), a lower alkoxycarbonyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxy-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio- lower alkyl group, a halo-lower alkyl
- R 4 and R 5 which may be the same or different, each represents a hydrogen atom, a lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group or a mono- or di-lower alkylaminocarbonyl group), R 3 : a hydrogen atom, a hydroxy group or a lower alkoxy group,
- the "lower alkyl group” includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, etc.
- lower alkoxy and “lower alkoxy group” include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group, an isohexyloxy group, etc.
- alkylene group having 1 to 6 carbon atoms which may be intervened with a sulfur atom for Y 4 includes a methylene group, an ethylene group and the aforesaid alkylene group having 3 to 6 carbon atoms; in addition thereto, includes these alkylene groups intervened by one sulfur atom at an optional position thereof, specifically -CH 2 -S-CH 2 -, -(CH 2 ) 2 -S-CH 2 -, -(CH 2 ) 3 -S-CH 2 -, - (CH 2 ) 4 -S-CH 2 -,
- X 1 Specific examples of the "group shown by formula: -CH 2 -Y 1 - or -Y 1 -CH 2 -" for X 1 include a methyleneoxy group (-CH 2 -O-), a methylenethio group (-CH 2 -S-), a methylenimino group (-CH 2 - -NH-), an oxymethylene group (-O-CH 2 -), a thiomethylene group (-S-CH 2 -), an iminomethylene group (-NH-CH 2 -), etc.
- X 1 Specific examples of the "group shown by formula: -CO-Y 2 - or -Y 2 -CO-" for X 1 include a carbonylimino group (-CONH-), a carbonylmethyleneoxy group (-COCH 2 -O-), a carbonylmethylenethio group (-COCH 2 -S-), a carbonylmethyleneimino group (-COCH 2 -NH-), an iminocarbonyl group (-NHCO-), a methyleneoxycarbonyl group (-CH 2 -O-CO-), a methylenethiocarbonyl group (-CH 2 -S-CO-), a methyleneiminocarbonyl group (-CH 2 -NH-CO-), an oxymethylenecarbonyl group (-O-CH 2 -CO-), a thiomethylenecarbonyl group (-S-CH 2 -CO-), an iminomethylenecarbonyl group (-NH-CH 2 -CO-), a carbon
- R 2 , R 4 or R 5 include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, etc.; specific examples of the "substituted phenyl-lower alkoxycarbonyl-lower alkanoyl group” include p-methoxybenzyloxycarbonylacetyl group, etc.; and specific examples of the "lower alkoxalyl group” include a methoxalyl group, an ethoxalyl group, etc.
- the compounds of general formula (I) described above include optical isomers based on the presence of an asymmetric carbon and cis- and trans-stereoisomers based on the presence of the alkenyl group, etc.
- the compounds of the present invention are encompassed to include isolated isomers thereof and mixtures thereof.
- the present invention also includes salts of the compounds of general formula (I) described above.
- examples of such salts are salts with inorganic bases such as sodium, potassium, etc.; salts with organic bases such as ethylamine, propylamine, diethylamine, triethylamine, morpholine, piperidine, N-ethylpiperidine, diethanolamine, cyclohexylamine, etc.; salts with basic amino acids such as lysine, ornithine, etc.; ammonium salts; salts with mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc. (Prior art)
- the desired compounds of the present invention exhibit a potent antagonistic action on SRS-A.
- SRS-A is known as a slow reactive and long acting chemical mediator while histamine is a rapid acting and short acting chemical mediator. It has recently been clarified that SRS-A is a mixture of Leukotrienes C 4 , D 4 and E 4 , the structure of which have been determined by Samuelsson.
- SRS-A namely, Leukotrienes are metabolites of polyvalent unsaturated fatty acids (in particular, arachidonic acid) with lipoxygenase and it has been reported that SRS-A has various activities such as acceleration of mucus secretion, reduction of mucociliary movement, coronary artery contraction, reduction of cardiac contraction, etc., in addition to the aforesaid action as chemical mediator in immediate hypersensitivity reactions. Accordingly, it has been desired to develop medicaments capable of inhibiting the production and release of SRS-A or antagonizing the. effects of SRS-A.
- the present inventors have extensively investigated medicaments capable of inhibiting the production and release of SRS-A or medicaments capable of antagonizing the effects of SRS-A. As a result, they have found that the compounds (I) of the present invention strongly antagonize SRS-A and have accomplished the present invention. (Effects of the invention)
- the compounds (I) of the present invention are useful as prophylaxis and treatment for various allergic diseases
- bronchial asthma for example, bronchial asthma, allergic rhinitis, urticaria
- ischemic heart diseases inflammation, etc. induced by
- SRS-A since the compounds strongly antagonize SRS-A as described above. Further some of the compounds of the present invention exhibit an activity similar to that of SRS-A. It can be expected that such compounds having the SRS-A agonist activity can be used in treatment for intestinal tube paralysis and also effective as reagents for investigations of anti-SRS-A agents or SRS-A antagonists, in place of Leukotrienes that have been heretofore difficult to acquire in a stable form.
- the compounds (I) of the present invention can be orally or perenterally administered safely as medical compositions [for example, tablets, capsules, powders, granules, pills, ointments, syrups, injections, inhalation, sapositories] as they are, or by mixing with known pharmaceutically acceptable carries, excipients, etc.
- Dose may vary depending upon object to be administered, route for administration, condition, etc. but daily dose is generally 0.1 to 500 mg, preferably 1 to 200 mg, for adult.
- the dose is orally or perenterally administered twice or three times a day. (Processes)
- the compounds of the present invention can be prepared, for example, by processes shown by the following reaction equations:
- M 1 a hydrogen atom or an alkali metal atom when Y 1 is an oxygen atom or a sulfur atom and when Y 1 is an imino group, a hydrogen atom;
- Z 1 a halogen atom or a sulfonyloxy group
- Y 5 a methylene group or a methylenecarbonyl group (-CH 2 CO-); Y : a methylene group or a carbonylmeth lene group
- R fi a phenyl group or a butyl group
- R_ a lower alkyl group or a lower alkoxyphenyl-lower alkyl group
- Y_ an oxygen atom or a sulfur atom
- M_ a hydrogen atom or an alkali metal atom.
- Examples of the alkali metal atom shown by , or M_ include a sodium atom, a potassium atom.
- Examples of the halogen atom shown by Z, or Z_ include an iodine atom, a bromine atom, a chlorine atom, etc.
- As the sulfonyloxy group, a toluenesulfon loxy group, a benzenesulfonyloxy group, etc. are preferably ' used.
- Compound (la) wherein X, is a carbonylimino group (-CONH-) is prepared by reacting a substituted benzoic acid shown by general formula (II) or a reactive derivative -thereof with an amino compound shown by general formula (III).
- acid halides such as acid chlorides, acid bromides, etc.; acid azides; activated esters with N-hydroxybenztriazole or N-hydroxysuccinimide; symmetric acid anhydrides; alkyl carbonate mixed acid anhydride, mixed acid anhydrides with p-toluenesulfonic acid; etc.
- the reaction is performed using Compound (II) or a reactive derivative thereof and Compound (III) in an almost equimolar amount or in a slightly excessive amount in one of them, in an organic solvent inert to the reaction, for example, pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, ethyl acetate, acetonitrile, or the like.
- an organic solvent inert for example, pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, ethyl acetate, acetonitrile, or the like.
- a base such as triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline, potassium carbonate, sodium hydroxide, etc.
- Pyridine can also be used as the solvent.
- the reaction temperature may vary depending upon kind of the reactive derivative but is not particularly limited.
- Process 2 is not particularly limited.
- Compound (lb) wherein X 1 is an iminocarbonyl group (-NHCO-) is prepared by reacting a substituted aniline shown by general formula (IV) with a carboxylic acid shown by general formula (V) or a reactive derivative thereof.
- the group of Compounds (Ic) wherein X 1 is -Y 1 -CH 2 - i.e., -O-CH 2 -, -S-CH 2 - or -NH-CH 2 - can be produced by reacting a substituted phenol or substituted phenylmercaptane or an alkali metal-substituted compoud thereof or a substituted aniline shown by general formula (VI) with a halogen compound or a sulfonate compound shown by general formula (VII). The reaction is performed using Compound (VI) and
- Compound (VII) in an almost equimolar amount or in an excess amount of either compound in an organic solvent such as dimethylformamide, dimethylsulfcxide, methanol, ethanol, propanol, acetone, methyl ethyl ketone, tetrahydrofuran, chloroform, dioxane, benzene, to.uene, xylene, dichloromethane, dichloroethane, etc.
- organic solvent such as dimethylformamide, dimethylsulfcxide, methanol, ethanol, propanol, acetone, methyl ethyl ketone, tetrahydrofuran, chloroform, dioxane, benzene, to.uene, xylene, dichloromethane, dichloroethane, etc.
- the reaction is conducted, if necessary, in the presence of a base.
- bases include potassium carbonate, Triton B, potassium hydroxide, sodium hydride, sodium carbonate, pyridine, picoline, N,N-dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine, etc.
- the reaction temperature is not particularly limited but generally set at room temperature or heating temperature.
- the group of Compound (Id) wherein X, is -CH 2 -Y 1 -, i.e., -CH 2 O-, -CH 2 S-, or -CH 2 NH- can be produced by reacting a halogen compound or sulfonate compound shown by general formula (VIII) with a hydroxy- or mercaptan-compound or an alkali metal-substituted compound or an amine compound shown by general formula (IX).
- a base such as n-butyl lithium, an alkali metal amide, an alkali metal alkoxide, methylsulfinylmethylide sodium salt, etc.
- the reaction at the former stage may proceed in the absence of any solvent but generally performed in an organic solvent such as benzene, toluene, xylene, etc.
- the reaction temperature is not particularly limited.
- the reaction at the latter stage is performed in the organic solvent used in the reaction at the former stage or in a solvent such as tetrahydrofuran, ether, dimethoxyethane, dimethylsulfoxide, alcohol, etc.
- the reaction temperature is not particularly limited.
- Compound (Ig) wherein D is a carboxy group can be produced by removing an ester residue from the corresponding ester shown by general formula (If).
- compound (Ih) wherein X 2 is -Y 7 -Y 4 -, i.e., -O-Y 4 - or -S-Y 4 - can be produced by reacting a hydroxy- or mercapto- compound or an alkali metal-substituted compound shown by general formula (XIII) with a substituted alkyl halide shown by general formula (XIV).
- the reaction conditions are almost identical with those of Processes 3 and 4.
- the comounds of the. present invention can be produced by reacting a hydroxy compound or a metal-substituted compound shown by general formula (XVII) with a substituted alkyl halide shown by general formula (XVIII).
- the reaction conditions are almost identical with those of Processes 3 and 4.
- the vinylene group can also be reduced to the corresponding alkyl group by catalytic reduction using palladium-carbon, etc. in a conventional manner.
- a compound wherein R 2 is: wherein R 4 and R 5 both are not a hydrogen atom, can be obtained by alkylation, acylation, etc. of a compound wherein R 2 is an amino group; a compound wherein R 2 is a halo-lower alkyl group by halogenation of a compound wherein R 2 is a hydroxy-lower alkyl group; a compound wherein R 2 is a hydroxymethyl group by reduction of a compound wherein
- R 2 is a formyl group; a compound wherein R 2 is a lower alkoxylower alkyl group by lower alkoxylation of a compound wherein R 2 is a halo-lower alkyl group; a compound wherein R 2 is a lower alkoxycarbonyl-lower alkylthio-lower alkyl group by lower alkoxycarbonyl-lower alkylsulfenylation of a compound wherein R 2 is a halo-lower alkyl group.
- the compounds of the present invention produced by these various processes can be isolated and purified by applying thereto chemical procedures generally used in the art such as extraction, recrsytallization, column chromatography, etc.
- Example 2 In a manner similar to Example 1, Compounds of Examples 7 and 10 described hereafter were obtained.
- Example 2 In a manner similar to Example 1, Compounds of Examples 7 and 10 described hereafter were obtained.
- Example 2 In a manner similar to Example 1, Compounds of Examples 7 and 10 described hereafter were obtained.
- Example 2
- Example 3 In a manner similar to Example 2, Compounds of Examples 5, 6 and 8 described hereafter were obtained.
- Example 3 In a manner similar to Example 2, Compounds of Examples 5, 6 and 8 described hereafter were obtained.
- Example 5 Compounds obtained in Examples 5 to 10 and their physical properties are shown below.
- Example 5 Compounds obtained in Examples 5 to 10 and their physical properties are shown below.
- Example 21 Desired compound:
- a mixture of 1.6 g of sodium hydrodie (60%, oil) in 60 ml of dimethylsulfoxide was stirred at 55 ⁇ 60°C for l hour. fter lowering to room temperature, a solution of 9 g of (4-carboxybutyl)triphenyl phosphonium bromide in 20 ml of dimethylsulfoxide was added to the mixture. After stirring at room temperature for 30 minutes, a solution of 3 g of o-nitrobenzaldehyde in 10 ml of dimethylsulfoxide was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into cold diluted hydrochloric acid followed by extraction with ether.
- This acid chloride was dissolved in 15 ml of methylene chloride and the resulting solution was added to a solution of 0.93 g of ethyl 3-amino-4 hydroxybenzoate in 8 ml of pyridine and 10 ml of methylene chloride under ice cooling. The mixture was stirred for 1.5. hours. The reaction mixture was poured into 10% hydrochloric acid at 0°C and the product was extracted with ethyl acetate. After washing with a saturated sodium hydrogen carbonate solution, water and then a saturated saline aqueous solution in this order, the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystalline residue was recrystallized from hexane-ethyl acetate to obtain 1.47 g of ethyl 3-hydroxy-4-[p-(4-phenylbutoxy)benzamido]benzoate.
- a catalytic amount of tetra-n-butylammonium bromide was added to a mixture of 0.62 g of 4-hydroxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid obtained in Example 78, 0.46 g of anhydrous potassium carbonate, 2.47 g of methyl iodide and 10 ml of 2-butanone followed by stirring at 60°C for 20 hours.
- the reaction mixture was diluted with ethyl acetate and insoluble materials were filtered off. After the filtrate was washed in order with a 0.02N aqueous sodium hydroxide solution and water and dried over anhydrous magnesium sulfate, the solvent was distilled off.
- a catalytic amount of tetra-n-butylammonium bromide was added to a mixture of 0.64 g of 4-hydroxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid obtained in Example 78, 0.50 g of anhydrous potassium carbonate, 0.60 g of ethyl bromoacetate and 8 ml of 2-butanone followed by stirring at 60°C for 4 hours.
- the reaction mixture was diluted with ethyl acetate and insoluble materials were filtered off. After the filtrate was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off.
- Example 95 In 25 ml of 90% methanol was suspended 0.54 g of methyl 4-methoxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 95. To the suspension wad added 10 ml of a 1N sodium hydroxide aqueous solution followed by stirring at 60°C for 2 hours. The reaction mixture was diluted with 50 ml of water and the system was rendered acidic with 7 ml of 2N hydrochloric acid. Extraction was performed with ethyl acetate. After the organic layer was washed water and dried over anhydrous magnesium sulfate, the solvent was distilled off.
- Example 96 Ethyl [[4-ethoxycarbonymethoxy-2-[p-(4-phenylbutoxy)benzamido]phenoxy]acetoxy]acetate, 0.77 g, obtained in Example 96 was used as a starting compound and treated in a manner similar to Example 97 to obtain 0.57 g of [2-[p-(4-phenylbutoxy)benzamido]-1,4-phenylenedioxy]diacetic acid.
- Example 100 1-hydroxy-4-(p-heptyloxybenzyloxy)-2-indaneacetate obtained in Example 100 and, 2.5 ml of a 5% sodium hydroxide solution was added thereto followed by stirring at room temperature for 8 hours.
- the system was rendered acidic with 20% hydrochloric acid and extracted with ethyl acetate.
- the ethyl acetate layer was washed subsequently with water and then a saturated saline aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
- Example 104 After uniformly mixing 30 g of Compound of Example 40, 104 g of lactose and 57 g of corn starch, 40 ml of a 10% (w/w) aqueous solution of hydroxypropyl cellulose was added to the mixture and the resulting mixture was granulated by a wet granulation method. The granules thus obtained were mixed with 4 g of calcium carboxymethyl cellulose and 1 g of magnesium stearate and the mixture was press-tabletted into tablet (200 mg per tablet).
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Abstract
Novel phenylene derivatives shown by general formula (I) wherein A represents a hydrogen atom, a phenyl group or a phenoxy group, n represents an integer of 3 to 10, R1 represents a hydrogen atom or a lower alkoxy group, X1 represents -CH2CH2-, -CH=CH-, -CONH-, etc., B represents (II) (wherein R2 represents a hydrogen atom, a halogen atom, a nitro group, etc.), (III) or (IV) (wherein R3 represents a hydrogen atom, a hydroxyl group or a lower alkoxy group), X2 represents -CH=CH-, -CH2CH2-, etc. and D represents a carboxy group, a lower alkoxycarbonyl group or (V); which are useful as drugs, particularly SRS-A (slow reacting substance of anaphylaxis) antagonist, i.e. they are useful as prophylaxis and treatment for various allergic diseases (e.g. bronchial asthma, allergic rhinitis, urticaria) or, ischemic heart diseases, inflammation, etc. induced by SRS-A.
Description
DESCRIPTION TITLE OF THE INVENTION Phenylene derivatives
DETAILED DESCRIPTION OF THE INVENTION (Industrially applicable field) The present invention relates to novel phenylene derivatives useful as drugs, particularly SRS-A (slow reacting substance of anaphylaxis) antagonists. (Means for solving the problems)
The compounds of the present invention are phenylene derivatives represented by general formula (I) described below.
Compounds represented by general formula (I) or pharmaceutically acceptable salts thereof:
wherein symbols represent:
A: a hydrogen atom, a phenyl group or a phenoxy group, n: an integer of 3 to 10
R1: a hydrogen atom or a lower alkoxy group, X1: a group shown by -CH2CH2-, -CH=CH-, -CH2-Y1- (wherein Y1
-O-, -S- or -NH-), -Y1-CH2-, -CO-Y2- (wherein Y2:
-NH-, -CH2-Y1- or -Y1-CH2-) or -Y2-CO-. Ⓑ: a group represented by:
[wherein:
R2: a hydrogen atom, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a carboxy group, a cyano group, an oxaloamido group (-NHCOCOOH), a lower alkoxycarbonyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxy-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio- lower alkyl group, a halo-lower alkyl
group, a carboxyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group or a group represented by
formula:
(wherein R4 and R5, which may be the same or different, each represents a hydrogen atom, a lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group or a mono- or di-lower alkylaminocarbonyl group), R3 : a hydrogen atom, a hydroxy group or a lower alkoxy group,
X2: a group represented by -CH=CH- or -Y3-Y4- (wherein Y3: a single bond, -O-, -S- or -NH-; Y4 : an alkylene group having 1 to 6 carbon atoms which may be intervened by a sulfur atom), D: a carboxy group, a lower alkoxycarbonyl group or a group represented by:
provided that Ⓑ is
Definitions of the aforesaid general formula (I) and general formulae later described and preferred specific examples thereof are described in detail below.
The term "lower" as used throughout the present specification refers to a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise indicated.
Accordingly, the "lower alkyl group" includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, etc. Also the "lower alkoxy" and "lower alkoxy group" include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group,
a pentyloxy group, an isopentyloxy group, a hexyloxy group, an isohexyloxy group, etc.
The "alkylene group having 1 to 6 carbon atoms which may be intervened with a sulfur atom" for Y4 includes a methylene group, an ethylene group and the aforesaid alkylene group having 3 to 6 carbon atoms; in addition thereto, includes these alkylene groups intervened by one sulfur atom at an optional position thereof, specifically -CH2-S-CH2-, -(CH2)2-S-CH2-, -(CH2)3-S-CH2-, - (CH2)4-S-CH2-,
-(CH2)2-S-(CH2)3-, -CH2-S-(CH2)4-, -CH2-CH(CH3)-CH2-S-CH2-, etc.
Specific examples of the "group shown by formula: -CH2-Y1- or -Y1-CH2-" for X1 include a methyleneoxy group (-CH2-O-), a methylenethio group (-CH2-S-), a methylenimino group (-CH2- -NH-), an oxymethylene group (-O-CH2-), a thiomethylene group (-S-CH2-), an iminomethylene group (-NH-CH2-), etc.
Specific examples of the "group shown by formula: -CO-Y2- or -Y2-CO-" for X1 include a carbonylimino group (-CONH-), a carbonylmethyleneoxy group (-COCH2-O-), a carbonylmethylenethio group (-COCH2-S-), a carbonylmethyleneimino group (-COCH2-NH-), an iminocarbonyl group (-NHCO-), a methyleneoxycarbonyl group (-CH2-O-CO-), a methylenethiocarbonyl group (-CH2-S-CO-), a methyleneiminocarbonyl group (-CH2-NH-CO-), an oxymethylenecarbonyl group (-O-CH2-CO-), a
thiomethylenecarbonyl group (-S-CH2-CO-), an iminomethylenecarbonyl group (-NH-CH2-CO-), a carbonyloxy group (-CO-O-), a carbonylthio group (-CO-S-), an oxycarbonyl group (-O-CO-), a thiocarbonyl group (-S-CO-), etc. Specific examples of the "lower alkanoyl group" for
R2, R4 or R5 include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, etc.; specific examples of the "substituted phenyl-lower alkoxycarbonyl-lower alkanoyl group" include p-methoxybenzyloxycarbonylacetyl group, etc.; and specific examples of the "lower alkoxalyl group" include a methoxalyl group, an ethoxalyl group, etc.
Specific examples of the "group shown by formula: -Y3-Y4-" for X2 include a methylene group (-CH2-), an ethylene group (-CH2-CH2-), a tetramethylene group
(-(CH2)4-), a pentamethylene group (-(CH2)5-), a methylenethiomethylene group (-CH2-S-CH2-), an oxymethylens group (-OCH2-), an oxyethylene group (-O-CH2CH2-) , an oxypropylene group (-O-CH2-CH2-CH2-), an oxypropylenethiomethylene group (-O-CH2CH2CH2-S-CH2-), a thiomethylene group (-S-CH2-), a thioethylene group (-S-CH2CH2-), a thiopropylene group (-S-CH2CH2CH2-), a thioethylenethiomethylene group (-S-CH2CH2-S-CH2-), an iminomethylene group (-NHCH2-), an iminoethylene group (-NHCH2CH2-) , an iminoethylenethio
ethylene group (-NH-CH2CH2-S-CH2CH2-), etc.
The compounds of general formula (I) described above include optical isomers based on the presence of an asymmetric carbon and cis- and trans-stereoisomers based on the presence of the alkenyl group, etc. The compounds of the present invention are encompassed to include isolated isomers thereof and mixtures thereof.
Some of the compounds of the present invention form salts thereof. The present invention also includes salts of the compounds of general formula (I) described above. Examples of such salts are salts with inorganic bases such as sodium, potassium, etc.; salts with organic bases such as ethylamine, propylamine, diethylamine, triethylamine, morpholine, piperidine, N-ethylpiperidine, diethanolamine, cyclohexylamine, etc.; salts with basic amino acids such as lysine, ornithine, etc.; ammonium salts; salts with mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc. (Prior art) The desired compounds of the present invention exhibit a potent antagonistic action on SRS-A.
It is generally considered that in allergic asthma and other atopic diseases of human or anaphylactic shock in animals, various chemical mediators are released from the
lung and other tissues and cause difficulties in the living body, such as contraction of smooth muscles, e.g., bronchi, pulmonary artery, etc., and enhancement of vascular permeability in the skin. As such chemical mediators, there are histamine and SRS-A. Histamine plays an important role in guinea pig anaphylactic shock but no in allergic asthma in human [Eiser, Pharmacol. Ther., 17, 239-250 (1982)]; whereas a number of evidences suggest that SRS-A is the most important chemical mediator of allergic asthma in human [Brocklehurst, J. Physiol., 151, 416-435 (1960); Austen and Orange, Am. Rev. Resp. Dis., 112, 423-436 (1975); Adams and Lichtenstein , J. Immunol., 122, 555-562 (1979)].
The development of medicaments for prophylaxis, elimination and alleviation of hypersensitive reactions was performed, aiming at inhibiting the production and release of such chemical mediators or antagonizing the action of these chemical mediators. As an inhibitor of histamine release, disodium cromoglycate is well known and as an inhibitor of actions induced by histamine, various anti-histaminics are commercially available. On the other hand, SRS-A is known as a slow reactive and long acting chemical mediator while histamine is a rapid acting and short acting chemical mediator. It has recently been clarified that SRS-A is a mixture of Leukotrienes C4, D4 and E4, the structure of which
have been determined by Samuelsson. SRS-A, namely, Leukotrienes are metabolites of polyvalent unsaturated fatty acids (in particular, arachidonic acid) with lipoxygenase and it has been reported that SRS-A has various activities such as acceleration of mucus secretion, reduction of mucociliary movement, coronary artery contraction, reduction of cardiac contraction, etc., in addition to the aforesaid action as chemical mediator in immediate hypersensitivity reactions. Accordingly, it has been desired to develop medicaments capable of inhibiting the production and release of SRS-A or antagonizing the. effects of SRS-A.
The present inventors have extensively investigated medicaments capable of inhibiting the production and release of SRS-A or medicaments capable of antagonizing the effects of SRS-A. As a result, they have found that the compounds (I) of the present invention strongly antagonize SRS-A and have accomplished the present invention. (Effects of the invention)
The compounds (I) of the present invention are useful as prophylaxis and treatment for various allergic diseases
(for example, bronchial asthma, allergic rhinitis, urticaria) or, ischemic heart diseases, inflammation, etc. induced by
SRS-A since the compounds strongly antagonize SRS-A as described above.
Further some of the compounds of the present invention exhibit an activity similar to that of SRS-A. It can be expected that such compounds having the SRS-A agonist activity can be used in treatment for intestinal tube paralysis and also effective as reagents for investigations of anti-SRS-A agents or SRS-A antagonists, in place of Leukotrienes that have been heretofore difficult to acquire in a stable form.
The compounds (I) of the present invention can be orally or perenterally administered safely as medical compositions [for example, tablets, capsules, powders, granules, pills, ointments, syrups, injections, inhalation, sapositories] as they are, or by mixing with known pharmaceutically acceptable carries, excipients, etc. Dose may vary depending upon object to be administered, route for administration, condition, etc. but daily dose is generally 0.1 to 500 mg, preferably 1 to 200 mg, for adult. The dose is orally or perenterally administered twice or three times a day. (Processes)
The compounds of the present invention can be prepared, for example, by processes shown by the following reaction equations:
wherein A, n, R1, X1, X2, Y1, and D have the same
significances as described hereinabove and other symbols represents the following significances:
M1 : a hydrogen atom or an alkali metal atom when Y1 is an oxygen atom or a sulfur atom and when Y1 is an imino group, a hydrogen atom;
Z1: a halogen atom or a sulfonyloxy group;
Y5: a methylene group or a methylenecarbonyl group (-CH2CO-);
Y : a methylene group or a carbonylmeth lene group
(-COCH2-); Z-: a halogen atom;
Rfi: a phenyl group or a butyl group; R_ : a lower alkyl group or a lower alkoxyphenyl-lower alkyl group; Y_ : an oxygen atom or a sulfur atom; M_ : a hydrogen atom or an alkali metal atom.
Examples of the alkali metal atom shown by , or M_ include a sodium atom, a potassium atom. Examples of the halogen atom shown by Z, or Z_ include an iodine atom, a bromine atom, a chlorine atom, etc. As the sulfonyloxy group, a toluenesulfon loxy group, a benzenesulfonyloxy group, etc. are preferably 'used.
Process 1:
In the compounds of the pre≤ent invention, Compound (la) wherein X, is a carbonylimino group (-CONH-) is prepared by reacting a substituted benzoic acid shown by general formula (II) or a reactive derivative -thereof with an amino compound shown by general formula (III).
As ' the reactive derivatives of Compound (II), there are acid halides such as acid chlorides, acid bromides, etc.; acid azides; activated esters with N-hydroxybenztriazole or
N-hydroxysuccinimide; symmetric acid anhydrides; alkyl carbonate mixed acid anhydride, mixed acid anhydrides with p-toluenesulfonic acid; etc.
In case that Compound (II) is reacted with a free carboxylic acid, it is advantageous to perform the reaction in the presence of a condensing agent such as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, etc.
The reaction is performed using Compound (II) or a reactive derivative thereof and Compound (III) in an almost equimolar amount or in a slightly excessive amount in one of them, in an organic solvent inert to the reaction, for example, pyridine, tetrahydrofuran, dioxane, ether, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, dimethylformamide, ethyl acetate, acetonitrile, or the like.
Depending upon kind of the reactive derivative, it is sometimes advantageous for smooth performance of the reaction to add a base such as triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline, potassium carbonate, sodium hydroxide, etc. Pyridine can also be used as the solvent.
The reaction temperature may vary depending upon kind of the reactive derivative but is not particularly limited. Process 2:
In the comounds of the present invention, Compound
(lb) wherein X1 is an iminocarbonyl group (-NHCO-) is prepared by reacting a substituted aniline shown by general formula (IV) with a carboxylic acid shown by general formula (V) or a reactive derivative thereof.
The reaction conditions are almost the same as in Process 1. Process 3:
In the compounds of the present invention, the group of Compounds (Ic) wherein X1 is -Y1-CH2- i.e., -O-CH2-, -S-CH2- or -NH-CH2- can be produced by reacting a substituted phenol or substituted phenylmercaptane or an alkali metal-substituted compoud thereof or a substituted aniline shown by general formula (VI) with a halogen compound or a sulfonate compound shown by general formula (VII). The reaction is performed using Compound (VI) and
Compound (VII) in an almost equimolar amount or in an excess amount of either compound in an organic solvent such as dimethylformamide, dimethylsulfcxide, methanol, ethanol, propanol, acetone, methyl ethyl ketone, tetrahydrofuran, chloroform, dioxane, benzene, to.uene, xylene, dichloromethane, dichloroethane, etc.
The reaction is conducted, if necessary, in the presence of a base. Preferred examples of such bases include potassium carbonate, Triton B, potassium hydroxide, sodium
hydride, sodium carbonate, pyridine, picoline, N,N-dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine, etc.
The reaction temperature is not particularly limited but generally set at room temperature or heating temperature. Process 4:
In the compounds of the present invention, the group of Compound (Id) wherein X, is -CH2-Y1-, i.e., -CH2O-, -CH2S-, or -CH2NH- can be produced by reacting a halogen compound or sulfonate compound shown by general formula (VIII) with a hydroxy- or mercaptan-compound or an alkali metal-substituted compound or an amine compound shown by general formula (IX).
The reaction conditions are almost identical with those of Process 3. Process 5:
In the compounds of the present invention, Compound (Ie) wherein X, is a vinylene group (-CH=CH-) can be produced by reacting a substituted benzyl halide shown by general formula (X) with triphenyl(or tributyl)phosphine, then reacting the resulting substituted benzyltriphenylphosphonium halide with a base such as n-butyl lithium, an alkali metal amide, an alkali metal alkoxide, methylsulfinylmethylide sodium salt, etc., and finally reacting the resulting
substituted benzyltriphenylphosphorane with an aldehyde shown by general formula (XII).
The reaction at the former stage may proceed in the absence of any solvent but generally performed in an organic solvent such as benzene, toluene, xylene, etc. The reaction temperature is not particularly limited.
The reaction at the latter stage is performed in the organic solvent used in the reaction at the former stage or in a solvent such as tetrahydrofuran, ether, dimethoxyethane, dimethylsulfoxide, alcohol, etc. The reaction temperature is not particularly limited. Process 6:
In the compounds of the present invention, Compound (Ig) wherein D is a carboxy group can be produced by removing an ester residue from the corresponding ester shown by general formula (If).
In the reaction, a conventional manner of either hydrolyzing in the presence of a base such as sodium carbonate, sodium hydroxide, etc., or treating with an acid such as trifluoroacetic acid, hydrochloric acid, etc. is applicable. Process 7:
In the compounds of the present invention, compound (Ih) wherein X2 is -Y7-Y4-, i.e., -O-Y4- or
-S-Y4- can be produced by reacting a hydroxy- or mercapto- compound or an alkali metal-substituted compound shown by general formula (XIII) with a substituted alkyl halide shown by general formula (XIV). The reaction conditions are almost identical with those of Processes 3 and 4. Process 8:
In the compounds of the present invention, Compound
(Ii) wherein D is a 1H-1,2,3,4-tetrazol-2-yl group can be produced by reacting a nitrile compound shown by general formula (XV) with sodium azide in the presence of ammonium chloride.
The reaction is performed with heating in an organic solvent such as dimethylformamide, dimethylsulfoxide, etc. Process 9:
The comounds of the. present invention can be produced by reacting a hydroxy compound or a metal-substituted compound shown by general formula (XVII) with a substituted alkyl halide shown by general formula (XVIII). The reaction conditions are almost identical with those of Processes 3 and 4.
In case that Compound (I) contains a vinylene group, the vinylene group can also be reduced to the corresponding alkyl group by catalytic reduction using palladium-carbon,
etc. in a conventional manner.
Ⓑ of aimed compounds is , and the compound
wherein R2 is a formyl group can be obtained by elimination of the protecting group of a compound wherein R2 is:
(protecting group).
Further conversion of one product into another product can be performed in a conventional manner. For example, a compound wherein R2 is:
wherein R4 and R5 both are not a hydrogen atom, can be obtained by alkylation, acylation, etc. of a compound wherein R2 is an amino group; a compound wherein R2 is a halo-lower alkyl group by halogenation of a compound wherein R2 is a hydroxy-lower alkyl group; a compound wherein R2 is a hydroxymethyl group by reduction of a compound wherein
R2 is a formyl group; a compound wherein R2 is a lower alkoxylower alkyl group by lower alkoxylation of a compound wherein R2 is a halo-lower alkyl group; a compound wherein R2 is a lower alkoxycarbonyl-lower alkylthio-lower alkyl group by lower alkoxycarbonyl-lower alkylsulfenylation of a compound wherein R2 is a halo-lower alkyl group. These conversion
modes are described in the examples later in detail.
The compounds of the present invention produced by these various processes can be isolated and purified by applying thereto chemical procedures generally used in the art such as extraction, recrsytallization, column chromatography, etc.
(1) Inhibition of SRS-A- and LTD4-induced contractions of guinea-pig ileum and trachea
Method: Male Hartley quinea- pigs, weighing 500 to 700 g were sacrificed by a blow on the head. The ileum and tracheal strips prepared according to the method of Constantine (1965) were suspended with 1.0 g tention in an organ bath containing 10 ml of Tyrode solution equilibrated with a mixture of 95% O2 and 5% CO2 at 37°C. The tissues were equilibrated for 60 minutes; during this period the Tyrode solution was replaced every 15 minutes and the loading tention was adjusted, to 1.0 g. The developed tention of the tissues was measured isometrically with a strain gauge transducer, and recorded on a Recticorder. Both the contractile response of the ileum to submaximal concentration of SRS-A (derived from guinea-pig lung) and tracheal response to 10 -8 M LTD4 were recorded in the absence and then the presence of various concentrations of test compounds. The incubation time of the compounds was 20 minutes.
Results: The compounds of the present invention, e.g., compounds of Examples 23, 10, 18, 42, 40, 41 and 39, showed potent anti-SRS-A activity in isolated guinea-pig ileum (Table 1) . Further, compounds of Examples 23, 40 and 39 inhibited the contractions induced by LTD in isolated guinea-pig trachea (Table 1) .
Table 1. Anti-SRS-A and anti-LTD4 effects of representative compounds of this invention in isolated guinea-pig ileum and trachea
Example No. of IC 50 (M) compound Ileum Trachea a-SRS-A a-LTD4
Ex. 23 4.4 x 10 -8 4.0 x 10-7
Ex. 10 1.8 x 10 -8 -
Ex. 18 3.3 x 10 -8 -
Ex. 42 8.1 x 10 -8 -
Ex. 40 3.6 x 10-9 5.7 x 10 -8
Ex. 41 7.4 x 10 -9 -
Ex. 39 7.3 x 10 -9 2.5 x 10-7
Method: Male Hartley guinea-pigs weighing 270 to 305, starved for 16 hours, were intradermally injected 5 ng LTD4 in a volume of 0.1 ml into two sites on the shaved back. In addition, 0.1 ml of vehicle was injected intradermally in each animal to see non-specific irritation. One ml of saline containing 1% Evans value was intravenously injected 2 minutes before LTD4 injection. The leaked dye at the site of LTD4 or vehicle injection was extracted according to the method of Harada et al. (1971) and measured photometrically at 620 nm. The LTD4-induced skin reaction was expressed as a difference in the amount of dye between LTD4 and vehicle. Test compounds were orally administered 30 minutes before LTD4 injection.
Results : Compounds of Examples 23, 39 and 40 dose-dependently inhibited the LTD4-enhanced vascular permeability in guinea-pigs; their ED50 were 22.8, 36.1 and 5.5 mg/kg p.o., respectively. These results indicate that Compounds of Examples 23, 39 and 40 show potent anti-Leukotriene effect by oral route.
(3) Acute toxicity in rats
Male Fischer 344 rats 7 week old were used. Compounds of Examples 39 and 40 at 1000 mg/kg p.o. caused no toxic
effect upon the rats during the observation period of 7 days. References:
Constantine, J.W., J. Pharm. Pharmacol., 17, 384
(1965)
Harada, M. et al., ibid., 23, 218 (1971)
Hereafter the present invention will be described in detail with reference to the examples below.
Reference Example 1
To a mixture of 3.9 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 4.2 g of potassium carbonate and 50 ml of ethanol was gradually added 5 g of ethyl bromoacetate under ice cooling. Then, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 200 ml of water followed by extraction with ethyl acetate. After washing with water, the extract was dried over anhydrous magensium sulfate and the solvent was distilled off. The solid obtained was washed with toluene and dried to obtain 2.7 g of ethyl [(5-amino-1,3,4-thiadiazol-2-yl)thio]-
acetate.
Nuclear magnetic resonance spectra (CDCl3, TMS, ppm)
1.25 (3H, t, -CH3), 3.90 (2H, s, -CH2-) , 4.19(2H, q, -CH2)
Reference Example 2
To a solution of 9.92 g of sodium hydroxide in 160 ml of methanol-water (10:1) was added 37.2 g of 2,5-dimercapto-1,3,4-thiadiazole to dissolve. Then 40 g of ethyl bromobutyrate was added to the solution followed by stirring for 3 hours. The reaction mixture was settled overnight. The formed solid was taken by filtration, washed with methanolwater (10:1) and dried under reduced pressure to obtain 41.5 g of ethyl 3-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]butyrate. Melting point: 107 - 108°C Reference Example 3
A mixture of 2.2g of reduced iron, 0.5 ml of cone. hydrochloric acid and 2.5 ml of water was added to a solution of 2.2 g of ethyl o-nitrocinnamate in 30 ml of ethanol. After heating under reflux for 1 hour, insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. An aqueous sqdium hydrogen carbonate solution was added to the residue followed by extraction with toluene. After the extract was washed with water and dried, the solvent was distilled off to obtain 1.6 g of ethyl o-aminocinnamate as yellow crystals. Nuclear magnetic resonance spectra (CDCl3, TMS, ppm)
1.30 (3H, t, -CH3), 4.23 (2H, q, -OCH2-) , 6.30(1H, d),
6.50-7.50(4H, m), 7.80(1H, d)
Reference Example 4
In a manner similar to Reference Example 4, the following compounds were obtained.
m-Heptyloxy-N-(o-hydroxyphenyl)benzamide
Melting point: 108 ~ 109 °C
Reference Example 6
p-Heptyloxy-N-(m-hydroxyphenyl)benzamide
Melting point: 182 ~ 184 °C
Reference Example 7
m-Heptyloxy-N-(m-hydroxyphenyl)benzamide
Melting point: 115 ~ 117 °C
Reference Example 8
A mixture of 1.6 g of m-heptyloxy-N-(o-hydroxyphenyl)-benzamide obtained in Reference Example 5, 0.5 g of chloroacetonitrile, 0.8 g of anhydrous potassium carbonate, 0.1 g of potassium iodide, 0.1 g of tetra-n-butyl ammonium bromide and 20 ml of methyl ethyl ketone was vigorously stirred at 80°C for 1 hour. After cooling, 100 ml of ethyl acetate was added to the reaction mixture. The mixture was washed with water, dried over anhydrous magensium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 1.4 g of m-heptyloxy-N-(o-cyanomethoxyphenyl)benzamide. Melting point: 105 ~ 106°C Reference Examples 9 to 11
The following compounds were obtained in a manner similar to Reference Example 8.
Reference Example 9
p-Heptyloxy-N-(m-cyanomethoxyphenyl)benzamide
Melting point: 119 ~ 120°C
Starting Compound:
Reference Example 6
Reference Example 10
p-Heptyloxy-N-(o-cyanomethoxyphenyl)benzamide
Melting point: 97 ~ 98°C
Starting Compound:
Reference Example 4
Reference Example 11
m-Heptyloxy-N-(m-cyanomethoxyphenyl)benzamide
Melting point: 105 ~ 106°C
Starting Compound:
Reference Example 7
Example 1
In 10 ml of pyridine were stirred 0.5 g of ethyl
[(5-amino-1,3,4-thiadiazol-2-yl)thio]acetate obtained in Reference Example 1, 0.7 g of m-heptyloxybenzoic acid, 0.7 g of dicyclohexylcarbodiimide and 2 to 3 mg of p-toluenesulfonic acid at room temperature for 2 hours. After completion of the reaction, insoluble matters were filtered off and the filtrate was concentrated under reduced pressure.
The residue was extracted with ethyl acetate. After washing the extract with water and drying, the solvent was removed by distillation to obtain a solid material. The solid material was washed with a mixture of toluene-n-hexane (2:1) and dried to obtain 1.0 g of ethyl [[5-(m-heptyloxybenzamido)-1,3,4- thiadiazol-2-yl]thio]acetate. Melting point: 114 ~ 116°C.
Elemental analysis for C20H27N3O4S2
C% H% N%
Calcd. 54.90 6.22 9.60
Found 55.20 6.29 9.77
In a manner similar to Example 1, Compounds of Examples 7 and 10 described hereafter were obtained. Example 2
A solution of 0.4 g of ethyl o-aminocinnamate obtained in Reference Example 3 in 4 ml of pyridine was cooled to lower than -20°C and 0.7 g of p-(4-phenyIbutoxy)benzoyl chloride obtained by thionylchlorination of p-(4-phenylbutoxy)benzoic acid in benzene using dimethylformamide as a catalyst was added thereto followed by stirring at room temperature for 30 minutes. To the reaction mixture was
added 30 ml of water. The mixture was extracted with ethyl acetate. After washing with water, a 5% aqueous hydrochloric acid solution and water in this order, the extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation to obtain a solid material. The solid material was dissolved in 10 ml of toluene with heating and 2 ml of n-hexane was added to the solution. After cooling, precipitated crystals were taken by filtration and dried to obtain 0.8 g of ethyl o-[p-(4-phenyIbutoxy)benzamido]cinnamate.
Melting point: 129 ~ 131°C. Elemental analysis for C28H29NO4
C% H% N% Calcd. 75.82 6.59 3.16 Found 75.83 6.53 3.14
In a manner similar to Example 2, Compounds of Examples 5, 6 and 8 described hereafter were obtained. Example 3
A mixture of 0.6 g of p-heptyloxy-2-bromoacetophenone, 0.6 g of ethyl [(5-mercapto-1,3,4-thiadiazol-2-yl)thio]butyrate and 0.4 g of potassium carbonate was heated under reflux for 30 minutes together with 20 ml of acetone. After cooling, insoluble materials were filtered off and the filtrate was concentrated under reduced pressure and the filtrate was concentrated under reduced pressure. The thus obtained solid material was washed with ethanol and dried to obtain 1.0 g of 4-[[5-[(p-heptyloxyphenacyl)thio]-1,3,4-thiadiazol-2-yl]thio]- butyrate. Melting point: 72 ~ 73 °C. Elemental analysis for C23H32N2O4S3
C% H% N%
Calcd. 55.62 6.49 5.64
Found 55.54 6.52 55.2 In a manner similar to Example 3, Compound of Example 9 described hereafter were obtained. Example 4
In 2 ml of dimethylformamide were dissolved 190 mg of ethyl 5-hydroxy-1-methoxyindane-2-acetate and 220 mg of p-heptyloxybenzyl chloride. To the solution was added 180 mg of potassium carbonate. The mixture was stirred at 60°C overnight. After allowing to cool, water and ethyl acetate were added to the mixture. By thoroughly shaking the mixture, the organic layer was separated. After washing with water, drying and concentrating the organic layer, the residue obtained was purified by flash chromatography (eluant: toluene/ethyl acetate (25/1)) to obtain 220 mg of ethyl 5-(p-heptyloxybenzyloxy)-1-methoxy-2-indaneacetate as a colorless oily product.
Nuclear magnetic resonance spectra (CDCl3, TMS, ppm) : 1.89(3H, br), 1.23(3H, t, J=7Hz) , 1.2 - 1.9(10H), 2.3 - 3.4(5H), 3.41(3H, s), 3.96 (2H, t, J-=7Hz), 4.17 (2H, q, J=7Hz), 4.48 (1H, d, J=3.5Hz), 4.96 (2H, s),
6.8 - 7.4(7H)
Desired compound:
Ethyl [[5-(p-heptyloxybenzamido)-1,3,4-thiadiazol2-yl]thio]acetate Physicochemical properties: i) Melting point: 159~ 160°C ii) Elemental analysis for C20H27N3O4S2
C% H% N% Calcd. 54.90 6.22 9.60 Found 55.18 6.39 9.63 Starting compound:
+ Compound of Reference Example 1 Example 6
Desired compound:
Ethyl [[5-[p-(4-phenylbutoxy)benzamido]- 1,3,4-thiadiazol-2-yl]thio]acetate Physicochemical properties: i) Melting point: 147~ 148 °C ii) Elemental analysis for C23H25N3O4S2
C% H% N% Calcd. 58.58 5.34 8.91 Found 58.37 5.23 8.89
Starting compound:
Example 7
Desired compound:
Ethyl [[5-(m-(4-phenylbutoxy)benzamido]-1,3,4- thiadiazol-2-yl]thio]acetate
Physicochemical properties : i) Melting point: 124 - 126°C ii) Elemental analysis for C23H25N3O4S2
C% H% N%
Calcd. 58.58 5.34 8.91
Found 58.80 5.36 8.83
Starting compound:
Desired compound:
Ethyl o-[p-(4-phenylbutoxy)benzamido]cinnamate
Physicochemical properties: i) Melting point: 129 ~ 131°C ii) Elemental analysis for C28H29NO4
C% H% N%
Calcd. 75.82 6.59 3.16
Found 75.83 6.53 3.14 Starting compound:
Desired compound:
Ethyl 4-[[5-(p-heptyloxybenzyl)thio-1,3,4- thiadiazol-2-yl]thio]butyrate Physicochemical properties: i) Melting point: 56 ~ 57°C ii) Elemental analysis for C22H32N2O3S3
C% H% N% Calcd. 56.38 6.88 5.98 Found 56.32 7.08 5.87 Starting compound:
+ Compound of Reference Example 2
Example 10
Desired compound:
Ethyl 3-[o-[p-(4-phenylbutoxy)benzamido]- phenyl]propionate
Physicochemical properties : i) oily substance ii) Nuclear magnetic resonance spectra (CDCl3, TMS, ppm): 1.10(3H,t), 1.5 - 2.0(4H), 2.4 - 3.0(6H), 3.8 - 4.3(4H), 6.8 - 8.2(13H)
Starting compound:
Ethyl o-[p-(4-phenylbutoxy)benzamido]cinnamate, 0.5 g, obtained in Example 2 was heated under reflux for 10 minutes together with 2 ml of 50% potassitim hydroxide and 20 ml of methanol.
After 20 ml of water was added to the reaction mixture, 10% hydrochloric acid was added to render the system acidic. The precipitated crystals were taken by filtration, washed with water and ethanol and dried to obtain 0.15 g of o-[p-(4-phenylbutoxy)benzamido]cinnamic acid.
Melting point: 129 ~ 131°C (recrystallized from ethanol). Elemental analysis for C28H29NO4
C% H% N% Calcd. 75.82 6.59 3.16 Found 75.83 6.53 3.14 In a manner similar to Example 11, Compounds of
Examples 12 to 18 described below were obtained. Example 12
Desired compound:
[[5-(p-Heptyloxybenzamido)-1,3,4-thiadiazol- 2-yl]thio]acetic acid Physicochemical properties: i) Melting point: 246 ~ 248°C ii) Elemental analysis for C18H23N3O4S2
C% H% N%
Calcd. 52.79 5.66 10.26
Found 52.93 5.75 10.19
Starting compound: Compound of Example 5 Example 13
Desired compound:
[[5-[P-(4-Phenylbutoxy)benzamido]-1,3,4-thiadiazol- 2-yl]thio]acetic acid Physicochemical properties : i) Melting point: 244 ~ 245°C ii) Elemental analysis for C21H21N3O4S2
C% H% N% S%
Calcd. 56.87 4.77 9.47 14.46
Found 56.68 4.57 9.43 14.31 Starting compound: Compound of Example 6 Example 14
Desired compound:
[[5-[m-(4-Phenylbutoxy)benzamido]-1,3,4-thiadiazol- 2-yl]thio]acetic acid
Physicochemical properties: i) Melting point: 182 ~ 183°C ii) Elemental analysis for C21H21N3O4S2
C% H% N% S%
Calcd. 56.87 4.77 9.47 14.46
Found 56.93 4.62 9.37 14.30
Starting compound: Compound of Example 7 Example 15
Desired compound:
[[5-(m-Heptyloxybenzamido)-1,3,4-thiadiazol- 2-yl] thio]acetic acid Physicochemical properties: i) Melting point: 196 ~ 198ºC ii) Elemental analysis for C18H23N3O4S2
C% H% N%
Calcd. 52.79 5.66 10.26
Found 52.78 5.58 10.14
Starting compound: Compound of Example 1 Example 16
Desired compound:
4-[[5-[(p-Heptyloxyphenacyl)thio]-1,3,4-thiadiazol- 2-yl]thio]butyric acid Physicochemical properties: i) Melting point: 116 ~ 117°C ii) Elemental analysis for C21H28N2O4S3
C% H% N%
Calcd. 53.82 6.02 5.98
Found 53.60 6.05 5.87
Starting compound: Compound of Example 3 Example 17
Desired compoun:d:
4-[[5-[(p-Heptyloxybenzyl)thio]-1,3,4-thiadiazol- 2-yl]thio]butyric acid Physicochemical properties : i) Melting point: 106 ~ 107°C ii) Elemental analysis for C20H28N2O3S3
C% H% N%
Calcd. 54.51 6.40 6.36
Found 54.49 6.54 6.36
Starting compound: Compound of Example 9 Example 18
Desired compound:
C% H% N%
Calcd. 74.80 6.52 3.35
Found 74.48 6.87 3.63
Starting compound: Compound of Example 10 Example 19
In 1 ml of tetrahydrofuran and 8 ml of methanol were dissolved 220 mg of ethyl 5-(p-heptyloxybenzyloxy)-1-methoxy-
2-indaneacetate obtained in Example 4. After 1 ml of a 5% aqueous sodium hydroxide solution was added to the solution, the mixture was stirred at room temperature for 8 hours. After diluting with water, the system was rendered acidic with hydrochloric acid followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated. The obtained crystalline residue was recrystallized from ether-pentane to obtain 150 mg of 5-(p-heptyloxybenzyloxy)-1-methoxy-2-indaneacetic acid. Melting point:: 80 ~ 82°C.
Elemental analysis for C26H34O5
C% H%
Calcd. 73.21 8.03
Found 73.20 8.26 e 20
A mixture of 500 mg of p-heptyloxy-N-(o-cyanomethoxy
phenyl)benzamide obtained in Reference Example 10, 116 mg of sodium azide, 95 mg of ammonium chloride and 10 ml of dimethylformamide was stirred at 140 to 150°C overnight. After cooling, 50 ml of water was added to the reaction mixture followed by washing with ethyl acetate. The aqueous layer was rendered acidic with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 300 mg of 4-heptyloxy-2'-(5-tetrazolylmethoxy)benzanilide.
Melting point: 148 ~ 150°C. Elemental analysis for C22H27N5O3
C% H% N% Calcd. 64.53 6.65 17.10
Found 64.65 6.70 17.13 In a manner similar to Example 20, Compounds of Examples 21 to 23 described hereafter were obtained. Example 21 Desired compound:
C% H%
Calcd. 64.53 6.65
Found 64.64 6.81
Starting compound: Compound of Reference Example 9 Example 22
Desired compound:
3-Heptyloxy-3'-(5-tetrazolylmethoxy)- benzanilide
Physicochemical properties: i) Melting point: 149 ~ 150 °C ii) Elemental analysis for C22H27N5O3
C% H% N%
Calcd. 64.53 6.65 17.10
Found 64.55 6.77 17.02
Starting compound: Compound of Reference Example 11 Example 23
Desired compound:
3-Heptyloxy-2'-(5-tetrazolylmethoxy)- benzanilide Physicochemical properties: i) Melting point: 108 ~ 110°C ii) Elemental analysis for C22H27N5O3
C% H% N%
Calcd. 64.53 6.65 17.10
Found 64.59 6.77 17.13
Starting compound: Compound of Reference Example 8 Reference Example 12
One drop of N,N-dimethylformamide was added to a solution of 1 g of p-(4-phenylbutoxy)benzoic acid in 5 ml of methylene chloride and 2 ml of oxalyl chloride was added to the mixture at -30°C or lower. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain crude p-(4-phenylbutoxy)benzoyl chloride. This substance was dissolved in 5 ml of methylene chloride and the resulting solution was added to a solution of 1 g of 2-amino-4-methylphenol in 5 ml of pyridine under ice cooling followed by stirring at room temperature for 3 hours. The reaction mixture was poured into cone. hydrochloric acid-ice and then extracted with ethyl acetate. The extract was washed subsequently with water, an aqueous solution of sodium hydrogen carbonate and again water. After drying over anhydrous magnesium sulfate, the system was concentrated under reduced pressure to obtain 1.4 g of 2'-hydroxy-5'-methyl-4-(4-phenylbutoxy)benzanilide. Melting point: 138 ~ 140°C.
Reference Example 13
In a manner similar to Reference Example 12 except for using 1 g of 2-amino-4-chlorophenol as a starting material, 1.42 g of 5'-chloro-2'-hydroxy-4-(4-phenylbutoxy)benzanilide was obtained.
Melting point: 137 ~ 139°C. Reference Example 14
In a manner similar to Reference Example 12 except for using 400 mg of 2-amino-4-nitrophenol as a starting material, 450 mg of 2'-hydroxy-5'-nitro-4-(4-phenylbutoxy)benzanilide was obtained.
Melting point: 174 ~ 176°C.
Reference Example 15
In a manner similar to Reference Example 12 except for using 400 mg of 2-aminophenol as a starting material, 630 mg of 2'-hydroxy-4-(4-phenylbutoxy)benzanilide was obtained. Melting point: 116 ~ 117°C. Reference Example 16
In a manner similar to Reference Example 12 except for using 1 g of ethyl 3-(3-amino-4-hydroxyphenyl)propionate hydrochloride as a starting material, 1.6 g of ethyl 3-[4-hydroxy-3-[p-(4-phenylbutoxy)benzoyl]amidophenyl]-propionate was obtained.
Melting point: 94 ~ 99°C.
Reference Example 17
A mixture of 1.6 g of sodium hydrodie (60%, oil) in 60 ml of dimethylsulfoxide was stirred at 55 ~ 60°C for l hour. fter lowering to room temperature, a solution of 9 g of (4-carboxybutyl)triphenyl phosphonium bromide in 20 ml of dimethylsulfoxide was added to the mixture. After stirring at room temperature for 30 minutes, a solution of 3 g of o-nitrobenzaldehyde in 10 ml of dimethylsulfoxide was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into cold diluted hydrochloric acid followed by extraction with ether. After washing with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain oily 6- (o-nitrophenyl)-5-hexenic acid. This substance was added to a mixture of 20 ml of ethanol and 4 ml of cone. surfuric acid. The resulting mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue
followed by extracting with toluene. The extract was washed with water, a diluted aqueous sodium hydrogen carbonate and water, in order. After drying over anhydrous magnesium sulfate, the system was concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with toluene to obtain 0.73 g of ethyl 6-(o-nitrophenyl)-5-hexenate.
This substance was dissolved in 10 ml of ethanol and 0.1 g of 10% palladium-carbon was added to the solution. Catalytic reduction was performed until absorption of hydrogen was discontinued. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 0.6 g of ethyl 6-(o-aminophenyl)hexanate.
Nuclear magnetic resonance spectra (CDCl3, TMS internal standard, ppm) :
1.24 (t, 3H) , 1.0 - 2.0(m, 6H) , 2.30(t, 2H) , 2.49(t,2H), 2.8 -3.8(2H), 4.10(q, 2H), 6.5 - 7.2(m,4H)
Reference Example 18
Cl(CH2)3SCH2COOC2H5
A mixture of 2.0 g of ethyl mercaptoacetate, 3.13 g of 1-bromo-3-chloropropane, 2.29 g of anhyrous potassium carbonate and 10 ml of dimethylformamide was stirred at room temperature for 3 hours. The reaction mixture was diluted with toluene and insoluble matters were filtered off. The filtrate was washed with an aqueous sodium hydroxide and water in order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with a mixture of hexane-ethyl acetate (15:1) to obtain 2.65 g of oily ethyl [(3-chloropropyl)thio]acetate.
Nuclear magnetic resonance spectra (CDCl3,
TMS internal standard, ppm):
1.28(t, 3H) , 1.9 - 2.2(2H), 2.7-2.9(2H), 3.20(s, 3H), 3.64 (t, 2H) , 4.19 (q, 2H)
Mass spectrum m/z: 196 (M+)
Reference Example 20
A mixture of 860 mg of vaniline, 1.00 g of 4-bromobutylbenzene, 1.00 g of potassium carbonate and 8 ml of 2-butanone was heated under reflux for 3 hours. The reaction mixture was poured into water and the product was extracted with ether. The ethereal layer was washed with water, dried and concentrated. The obtained residue was applied to silica gel column chromatography and eluted with toluene to obtain 500 mg of 4-(4-phenylbutoxy)-3-methoxybenzaldehyde. Nuclear magnetic resonance spectra (CDCl3, TMS internal standard, ppm):
1.8-2.0(4H), 2.71(t, 2H, J=7Hz), 3.89(s, 3H), 4.08(t,2H, J=7Hz), 6.92 (d, 1H, J=9.5Hz), 7.15-7.50 (7H), 9.85 (s, 1H)
Reference Example 21
In 5 ml of methanol was dissolved 660 mg of 4-(4-phenylbutoxy)-3-methoxybenzamide obtained in Reference Example 20 and, 200 mg of sodium borohydride was gradually added to the solution at 0°C. After stirring for 1 hour, water and ethyl acetate were added to the mixture followed by vigorously stirring. The ethyl acetate layer obtained by separation was washed subsequently with water and an aqueous saline solution and then concentrated. The residue was applied to silica gel column chromatography and eluted with toluene : ethyl acetate (10:1) to obtain 430 mg of 4-(4-phenylbutoxy)-3-methoxybenzyl alcohol.
Nuclear magnetic resonance spectra (CDCl3, TMS internal standard, ppm):
1.7-1.9 (4H) , 2.68(t, 2H, J=7Hz), 3.87(s, 3H), 4.00(t, 2H, J=7Hz), 4.60(d, 1H, J=5.5Hz, s,after addition of D2O) , 6.8-6.95 (3H), 7.15-7.3
Reference Example 22
To a solution of 410 mg of 4-(4-phenylbutoxy)- 3-methoxybenzyl alcohol obtained in Reference Example 21 in 0.5 ml of toluene and 2 ml of benzene was added 0.5 ml of thionyl chloride at 0°C. The mixture was stirred for 20 minutes and a saturated sodium bicarbonate aqueous solution was added thereto. The reaction mixture was separated. After washing with water and a saline aqueous solution, the organic layer was concentrated. The residue was applied to silica gel column chromatography and eluted with toluene : heaxane : ethyl acetate (20:15:1) to obtain 300 mg of 4-chloromethyl-2-methoxy-1-(4-phenylbutoxy)-benzene.
Nuclear magnetic resonance spectra (CDCl3, TMS internal standard, ppm) :
1.75~1.95 (4H),2.68(t,2H,J=7Hz),3,87(s,3H),4.01 (d,2H.
J=7Hz) ,4.52(s,2H),6.80~6.90(3H),7.15~7.25(5H)
The product described above was dissolved in 2 ml of xylene and the solution was treated together with 304 mg of triphenyl phosphine at a reflux temperature for 1.5 hours. After cooling, the precipitated colorless crystals were collected by suction and dried under reduced pressure to obtain 260 mg of [4-(4-phenylbutoxy)-2-methoxybenzyl]triphenylphosphonium chloride. Melting point: 119 ~ 128°C Mass spectrum m/z: 531 (M+-Cl) Reference Example 23
In a manner similar to Reference Examples 20 to 22 except for using salicylaldehyde as a starting material, o-(4-phenylbutoxy)benzyltriphenylphosphonium chloride was obtained. Melting point: 214 ~ 216°C.
Reference Example 24
In 1.5 ml of N,N-dimethylformamide were stirred 390 mg of 4-chloromethyl-1-(4-phenylbutoxy)benzene, 180 mg of catechol and 270 mg of potassium carbonate at room temperature overnight. The reaction mixture was dispersed in water and ethyl acetate and the dispersion was separated. The ethyl acetate layer washed subsequently with water and an aqueous saline solution, dried and concentrated. The obtained residue was applied to silica gel column chromatography and eluted with toluene to obtain 240 mg of o-[p-(4-phenylbutoxy)benzyloxy]phenol.
Nuclear magnetic resonance spectra (CDCl3, TMS internal standard, ppm):
1.7-2.0(4H), 2.5-2.8(2H), 3.8-4.1(2H), 4.95(s, 2H), 5.63 (s, 1H, vanishing after addition of D2O)
Reference Example 25
o-[[p-(4-Phenylbutoxy)benzyl]thio] aniline was obtained from 4-chloromethyl-1-(4-phenylbutoxy) benzene and o-aminothiophenol in a manner similar to Reference Example 24.
Nuclear magnetic resonance spectra (CDCl3, TMS internal standard, ppm) : 1.7-1.9:(4H), 2.6-2.8(2H), 3.85(s, 2H), 3.8-4.0(2H),
4.2 (broad, 2H, vanishing after addition of D2O), 6.5-7.3 (13H)
Example 24
Physicochemical properties:
1) Melting point: 79 ~ 80°C.
2) Elemental analysis for C28H31NO5
C% H% N%
Calcd. 72.86 6.77 3.03
Found 72.80 6.68 2.87
Compounds of Examples 25 through 32 were obtained in a manner similar to Example 24.
Example 25
Ethyl 4-chloro-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate Physicochemical properties: 1) Melting point: 81 ~ 84°C.
2) Elemental analysis for C27H20ClNNO5 C% H% N% Cl%
Calcd. 67.28 5.86 2.91 7.36
Found 67.33 5.87 2.82 7.31
Starting compound:
Compound of Reference Example 13 + BrCK2COOC2H5
Example 26
Ethyl 4-nitro-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate Physicochemical properties:
1) Melting point: 113°C. 2) Elemental analysis for C27H28N2O7
N% Calcd. 5.09 Found 5.39 Starting compound:
Compound of Reference Example 14 + BrCH2COOC2H5
Example 27
Ethyl o-[p-(4-phenylbutoxy)benzamido]phenoxyacetate Physicochemical properties: 1) Oily product 2) Elemental analysis for C27H29NO5
C% H% N% Calcd. 72.46 6.53 3.13 Found 72.22 6.53 3.05
Starting compound:
Compound of Reference Example 15 + BrCH2COOC2H5
Example 28
Ethyl 3-[4-ethoxycarbonylmethoxy-3-[p-(4-phenylbutoxy)benzamido]phenyl]propionate
Physicochemical properties:
1) Melting point: 61 ~ 62°C. 2) Elemental analysis for C32H37NO7
C% H% N% Calcd. 70.18 6.81 2.56
Found 70.13 6.73 2.47 Starting compound:
Compound of Reference Example 16 + BrCH2COOC2H55
Example 29
Ethyl [[3-[4-chloro-2-[p-(4-phenylbutoxy)- benzamido]phenoxy]propyl]thio]acetate Physicochemical properties:
1) Melting point: 70 ~ 73 °C. 2) Elemental analysis for C30H34NO5SCl
N% Calcd. 2.52 Found 2.71 Starting compound:
Compound of Reference Example 13 + Compound of Reference Example 19 Example 30
Ethyl o-[N-[p-(4-phenylbutoxy)phenyl]carbamoyl]-phenoxy]acetate Physicochemical properties :
1) Melting point: 86 ~ 88ºC. 2) Elemental analysis for C27H29NO5
C% H% N% Calcd. 72.46 6.53 3.13 Found 72.54 6.62 3.10
Starting compound:
Compound of Reference Example 18 + Br(CH2)4Ph
Example 31
Physicochemical properties:
1) Oily product 2) Nuclear magnetic resonance spectra: (CDCl3, TMS internal standard, ppm)
1.24(t,3H),1.6~1.8(4H),2.5~2.7(2H),3.8~4.0(6H),4.16 (q,2H) ,4.61 (s,2H),5.02(s,2H),6.7~7.3(13H)
Starting compound:
Compound of Reference Example 24 + BrCH2COOC2H5
Example 32
Ethyl N-[o-[[p-(4-phenylbutoxy)benzyl]thio]-phenyl]glycine
Physicochemical properties:
1 ) Oily product 2) Nuclear magnetic resonance spectra: (CDCl3, TMS internal standard, ppm)
1.28 (t,3H),1.7~1.9(4H),2.6~2.8(2H),3.8~4.0(6H),4.27 (q,2H),5.64(1H),6.6~7.3(13H)
Starting compound: Compound of Reference Example 25 + BrCH2COOC2H5
Example 33
A solution of p-(4-phenylbutoxy)benzoyl chloride prepared from 1 g of p-(phenylbutoxy)benzoic acid and 2 ml of
oxalyl chloride in methylene chloride was added to a solution of 0.6 g of ethyl 6-(o-aminophenyl)hexanate obtained in Reference Example 17 in
10 ml of pyridine at temperature less than -30°C. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. Toluene was added to the residue. The mixture was washed with diluted hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The systems was concentrated under reduced pressure to obtain 1.0 g of oily ethyl 6-[o-[p-(4-phenylbutoxy)benzamido]phenyl]-hexanate.
Physicochemical properties:
1) Melting point: Oily product 2) Nuclear magnetic resonance spectra: (CDCl3, TMS internal standard, ppm)
1.20(t,3H),1.0~2.0(m,10H),2.26(t,2H),2.4~2.δ(m,4H),
4.02(t,2H),4.08(q,2H),6.8~8.2(m,13H)
3) Mass spectrum m/z: 487 (M+) Example 34
Ethyl o-[p(3-phenoxypropoxy)benazmido]cinnamate, 0.52 g, was obtained in a manner similar to Example 31 except that (3-phenoxypropoxy)benzoyl chloride prepared from 0.5 g of (3-phenoxypropoxy)benzoic acid and 1 ml of oxalyl chlorde and 0.3 g of ethyl o-aminocinnamate were used as starting compounds.
Physicochemical properties:
1) Melting point: 155 ~ 157°C. 2) Elemental analysis for C27H27NO5
C% H% N%
Calcd. 72.79 6.11 3.14
Found 72.69 6.10 3.15
Example 35
To a solution of 250 mg of ethyl o-[p-(3-phenoxypropoxy)benzamido]cinnamate obtained in Example 34 in 10 ml of methanol and 20 ml of ethyl acetate was added 10% palladium-carbon. Catalytic reduction was performed until absorption of hydrogen was discontinued. The catalyst was filtered off and the residue was recrystallized from isopropyl alcohol to obtain 200 mg of ethyl 3-[o-[p-(3-phenoxypropoxy)benzamido]phenyl]propionate. Physicochemical properties:
1) Melting point: 89 ~ 90°C. 2) Elemental analysis for C27H29NO5
C% H% N% Calcd. 72.46 6.53 3.13 Found 72.27 6.54 3.12
To a suspension of 260 mg of [4-(4-phenylbutoxy)-2-methoxybenzyl]triphenylphosphonium choride obtained in Reference Example 22 in 2.5 ml of tetrahydrofuran was dropwise added 0.36 ml of a 1.42M n-butyl lithium/hexane solution. The mixture was stirred for 10 minutes to form a dark red solution. The solution was dropwise added to a solution of 114 mg of ethyl o-formylphenoxyacetate in 1 ml of tetrahydrofuran at 0°C using an injection tube. After stirring for 20 minutes, a saturated ammonium chloride aqueous solution was added thereto. The product was extracted with ether. After washing with water and then an aqueous saline solution, the ethereal layer was dried and concentrated. The crude product was fractionated and separated by TLC (developer; hexane : methylene chloride : acetone = 8:2:1) to obtain 170 mg of ethyl o-[3-methoxy-4-(4-phenylbutoxy)styryl]phenoxyacetate.
Physicochemical properties:
1) Nuclear magnetic resonance spectra: (CDCl3, TMS internal standard, ppm) 1.27, 1.29 ( each of them is t, 3H by joining, J=7.2Hz), 1.75-1.9(4H), 2.6-2.75(2H), 3.52(s, 3H) , 3.95-4.40. (4H) , 4.61, 4.66 (each of them is s, 2H by joining) 6.6-7.6 (14H)
Example 37
To a suspension of 230 mg of o-(4-phenylbutoxy)benzyltriphenylphosphonium chloride obtained in Reference Example 23 in 2 ml of tetrahydrofuran was dropwise added a 1.4M n-butyl lithiun/hexane solution at 0°C. After stirring for 20 minutes, this deep scarlet solution was dropwise added to a solution of 100 mg of ethyl o-formylphenoxyacetate in 1 ml
of tetrahydrofuran at 0ºC. After stirring for 50 minutes, a saturated ammonium chloride aqueous solution was added and the product was extracted with ethyl acetate. After washing with water twice and then with a saturated saline aqueous solution, the ethyl acetate layer was dried and concentrated under reduced pressure. The obtained residue, 380 mg, was purified by silica gel fractionation thin layer chromatography to obtain 180 mg of o-[o-(4-phenylbutoxy)styryl]-phenoxyacetate as a colorless oily substance. Physicochemical properties:
1) Oily product 2) Nuclear magnetic resonance spectra: (CDCl3, TMS internal standard, ppm)
1.2-1.4 (3H), 1.7-1.9 (4H), 2.6-2.8(2H), 3.9-4.4(4H), 4.61 and 4.63(each of them is s, 2H by joining),
6.6-7.7(15H)
Example 38
Physicochemical properties:
1) Melting point: 88 ~90 °C. 2) Nuclear magnetic resonance spectra: (CDCl3, TMS internal standard, ppm) 1.26(t,3H), 1.5-2.0 (m, 4H) , 2.4-2.8(m, 2H) , 3.8-4.2
(m, 2H) , 4.22 (q, 2H) , 4.60 (s, 2H) , 6.0-7.0 (m, 12H)
Example 39
1) Melting point: 122 ~ 123°C. 2) Elemental analysis for C26H27NO5
C% H% N% Calcd. 72.04 6.28 3.23 Found 71.79 6.23 3.20
Compounds of Examples 40 through 52 were prepared in a manner similar to Example 39.
4-Chloro-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid Physicochemical properties:
1) Melting point: 139 ~ 140°C. 2) Elemental analysis for C25H24NO5Cl
C% H% N%
Calcd. 66.15 5.33 3.09
Found 66.01 5.34 3.16
Starting compound: Compound of Example 25 Example 41
1) Melting point: 168 ~ 170ºC. 2) Elemental analysis for C25H24N2O7
C% H% N%
Calcd. 64.65 5.21 6.03
Found 64.47 5.29 5.89
Starting compound: Compound of Example 26 Example 42
o-[p-(4-Phenylbutoxy)benzamido]phenoxyacetic acid Physicochemical properties :
1) Melting point: 135 ~ 137°C. 2) Elemental analysis for C25H25NO5
C% H% N%
Calcd. 71.58 6.01 3.34
Found 71.54 5.98 3.35
Starting compound: Compound of Example 27 Example 43
3-[4-Carbomethoxy-3-[p-(4-phenylbutoxy)benzamido]phenyl]- propionic acid
Physicochemical properties: 1) Melting point: 218 ~ 220°C. 2) Elemental analysis for C28H29NO7
C% H% N% Calcd. 68.42 5.95 2.85 Found 68.27 6.00 2.90 Starting compound: Compound of Example 28
[[3-[4-Chloro-2-]p-(4-phenylbutoxy)benzamido]phenoxy]propyl]-thio]acetic acid
Physicochemical properties:
1) Melting point: 94 ~ 96°C. 2) Elemental analysis for C28H30NO5SCl
C% H% N%
Calcd. 63.69 5.73 2.65
Found 63.54 5.78 2.56
Starting compound: Compound of Example 29 Example 45
o-[N-[p-(4-Phenylbutoxy)phenyl]carbamoyl]phenoxyacetic acid Physicochemical properties:
1) Melting point: 150 ~ 152°C. 2) Elemental analysis for C25H25NO5
C% H% N%
Calcd. 71.58 6.01 3.34
Found 71.41 6.12 3.43
Starting compound: Compound of Example 30 Example 46
1) Melting point: 125 ~ 127°C. 2) Elemental analysis for C29H33NO4
C% H% N%
Calcd. 75.79 7.24 3.05
Found 75.61 7.27 3.01
Starting compound: Compound of Example 33 Example 47
3-[o-[p-(3-Phenoxypropoxy)benzamido]phenyl]propionic acid Physicochemical properties:
1) Melting point: 161 ~ 163°C. 2) Elemental analysis for C25H25NO5
C% H% N%
Calcd. 71.58 6.01 3.34
Found 71.49 6.05 3.50
Starting compound: Compound of Example 35 Example 48
4-Amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid Physicochemical properties:
1) Melting point: 178 ~ 180°C. 2) Elemental analysis for C25H26N2O5
N% Calcd. 6.45 Found 6.32 Starting compound: Compound of Example 38 Example 49
1) Oily product 2) Elemental analysis for C25H20O5
C% H%
Calcd. 73.78 6.45
Found 73.65 6.47
Starting compound: Compound of Example 31 Example 50
N-[o-[[p-(4-Phenylbutoxy)benzyl]thio]phenyl]glycine Physicochemical properties: 1) Melting point: 135 ~ 137°C. 2) Elemental analysis for C25H27NO3S
C% H% N% S%
Calcd. 71.23 6.46 3.32 7.61
Found 71.01 6.43 3.32 7.73
Starting compound: Compound of Example 32 Example 51
o-[3-Methoxy-4-(4-phenylbutoxy)styryl]phenoxyacetic acid was obtained from Compound of Example 36 except that the product was purified by silica gel column chromatography (eluate = chloroform : methanol (12:1)) in lieu of recrystallization.
Physicochemical properties:
1 ) Oily product 2) Nuclear magnetic resonance spectra: (CDCl3, TMS internal standard, ppm)
1.7-1.9(4H), 2.6-2.8(2H), 3.63(s, 3H) , 3.9-4.1(2H), 4.60, 4.74 (each of them is s, 2H by joining), 5.35 (broad, vanishing after addition of D2O)
Example 52
o-[o-(4-phenylbutoxy)styryl]phenoxyacetic acid Physicochemical properties: 1) Oily product 2) Nuclear magnetic resonance spectra: (CDCl3, TMS internal standard, ppm)
1.7-2.0(4H), 2.6-2.8(2H), 3.9-4.1(2H), 4.54 and 4.69 (each of them is s, 2H by joining), 6.1 (broad, vanishing after addition of D2O) , 6.6-7.7
Starting compound: Compound of Example 37 Reference Example 26
In 30 ml of tetrahydrofuran and 130 ml of ethanol was dissolved 3.32 g of ethyl 3-hydroxy-4-nitrocinnamate. To the solution was added 100 mg of 10% palladium-carbon. The mixture was stirred under normal pressure in a hydrogen flow until absorption of hydrogen was discontinued. The catalyst was filtered off by suction and the filtrate was concentrated under reduced pressure to obtain 3.10 g of crude ethyl 4-amino-3-hydroxybenzenepropionate as an oily substance. Nuclear magnetic resonance spectra: (CDCl3, TMS internal standard, ppm):
1.22(3H, t), 2.4-2.8(2H), 3.5-3.8(2H), 4.10(2H, q),
6.60(3H),
One drop of N,N-dimethylformamide was added to a solution of 1.41 g of p-(4-phenylbutoxy)benzoic acid in 35 ml of methylene chloride and 1.5 ml of oxalyl chloride was further added to the mixture under ice cooling. The mixture was stirred for 30 minutes and at room temperature for further 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude p-(4-phenylbutoxy)benzoyl chloride. This acid chloride was dissolved in 15 ml of methylene chloride and the resulting solution was added to a solution of 0.93 g of ethyl 3-amino-4 hydroxybenzoate in 8 ml of pyridine and 10 ml of methylene chloride under ice cooling. The mixture was stirred for 1.5. hours. The reaction mixture was poured into 10% hydrochloric acid at 0°C and the product was extracted with ethyl acetate. After washing with a saturated sodium hydrogen carbonate solution, water and then a saturated saline aqueous solution in this order, the ethyl
acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystalline residue was recrystallized from hexane-ethyl acetate to obtain 1.47 g of ethyl 3-hydroxy-4-[p-(4-phenylbutoxy)benzamido]benzoate.
Melting point: 156 - 158°C
Elemental analysis for C26H27NO5
C% H% N%
Calcd. 72.04 6.28 3.24
Found 71.79 6.26 3.16
Compounds of Reference Examples 28 through 36 were produced in a similar manner. Reference Example 28 Desired compound:
5'-Bromo-2'-hydroxy-4-(4-phenylbutoxy)benzanilide Physicochemical properties: i) Melting point: 145 - 147°C ii) Elemental analysis for C23H22BrNO3
C% H% N% Br%
Calcd. 62.74 5.04 3.18 18.15
Found 62.57 5.01 3.05 18.21
Starting compound:
Reference Example 29 Desired compound:
2'-Hydroxy-4-(4-phenylbutoxy)-5'-phenylsulfonyloxybenzanilide Physicochemical properties : i) Melting point: 169 - 171°C ii) Elemental analysis for C29H27NO6S
C% H% N% S%
Calcd. 67.29 5.26 2.71 6.20
Found 67.08 5.32 2.59 6.26 Starting compound:
Reference Example 30
Desired compound:
5'-Ethyl-2'-hydroxy-4-(4-phenylbutoxy)benzanilide
Physicochemical properties: i) Melting point: 122 - 124°C ii) Elemental analysis for C25H27NO3
C% H% N%
Calcd. 77.09 6.99 3.60
Found 77.00 7.14 3.62
Starting compound:
Reference Example 31
Desired compound:
2'-Hydroxy-4-(4-phenylbutoxy)-5'-propylbenzanilide Physicochemical properties: i) Melting point: 125 - 128°C ii) Elemental analysis for C26H29NO3
C% H% N%
Calcd. 77.39 7.24 3.47
Found 77.55 7.24 3.44
Starting compound:
Reference Example 32 Desired compound:
5'-Cyano-2'-hydroxy-4-(4-phenylbutoxy)benzanilide
Physicochemical properties: i) Melting point: 153 - 154 °C ii) Elemental analysis for C24H22N2O3
C% H% N%
Calcd. 74.59 5.73 7.25
Found 74.69 5.79 7.21
Starting compound:
Reference Example 33 Desired compound:
Ethyl 4-hydroxy-3-[p-(4-phenylbutoxy)benzamido]pheny¬- acetate i) Oily product ii) Nuclear magnetic resonance spectra: (CDCl2, internal standard: TMS, ppm)
1.23(3H, t), 1.7-2.0 (4H), 2.6-2.8(2H), 3.45(2H, s),
3.9-4.2(2H), 4.08(2H, q), 6.8-8.2(12H)
Starting compound:
Reference Example 34 Desired compound:
Ethyl 3-hydroxy-4-[p-(4-phenylbutoxy)benzamide]- benzoate Physicochemical properties: i) Melting point: 148 - 149°C ii) Elemental analysis for C26H27NO5
C% H% N%
Calcd. 72.04 6.28 3.23
Found 71.81 6.37 3.60
Starting compound:
Reference Example 35 Desired compound:
2'-Hydroxy-5'-isopropyl-4-(4-phenylbutoxy)benzanilide Physicochemical properties: i) Melting point: 105 - 107°C ii) Elemental analysis for C26H29NO3
C% H% N%
Calcd. 77.39 7.24 3.47
Found 77.47 7.23 3.35
Starting compound:
Reference Example 36 Desired compound:
Ethyl 3-[3-hydroxy-4-[p-(4-phenylbutoxy)benzamido]phenyl]propionate Physicochemical properties: i) 'Melting point: 105 - 107°C ii) Elemental analysis for X28H31NO5
C% H% N%
Calcd. 72.86 6.77 3.03 Found 72.71 6.81 2.91 Starting compound: Reference Example 26 +
Reference Example 37
A mixture of 8 g of 4-hydroxy-3-nitrobenzaldehyde, 16 g of 1,3-propanediol, a catalytic amount of pyridinium p-toluenesulfonic acid and 250 ml of toluene was azeotropicaily dehydrated with heating under reflux. The reaction mixture was cooled, washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from toluene-n-hexane to obtain
9.2 g of 4-(1,3-dioxan-2-yl)-2-nitrophenol.
Melting point: 70 - 71°C Reference Example 38
In a manner similar to Reference Example 37, 2.8 g of 4-(1-methyl-1,3-dioxan-2-yl)-2-nitrophenol was obtained using 3 g of 4'-hydroxy-3'-nitroacetophenone as a starting compound.
Melting point: 109 - 111°C Reference Example 39
A solution of 4 g of 4-(1,3-dioxan-2-yl)-2-nitrophenpl obtained in Reference Example 37 was catalytically reduced at
room temperature until absorption of hydrogen was discontinued. The catalyst was filtered off and 5 ml of pyridine was added to the mother liquor. The mixture was cooled to temperatures lower than -20°C. To the mixture was added p-(4-phenylbutoxy)benzoyl chloride prepared from 4.8 g of p-(4-phenylbutoxy)benzoic acid in a manner similar to Reference Example 27 . The mixture was stirred at room temperature for 2 hours and 200 ml of ethyl acetate was added thereto. After washing with diluted hydrochloric acid, water, a diluted sodium hydrogen carbonate aqueous solution and then water in this order, the system was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 7.5 g of 5'-(1,3-dioxan-2-yl)-2'-hydroxy- (4-phenylbutoxy)benzanilide. Melting point: 122 - 123°C
Elemental analysis for C27H29NO5
C% H% N%
Calcd. 72.46 6.53 3.13
Found 72.50 6.60 3.06
Reference Example 40
In a manner similar to Reference Example 39 , 2.5 g of
5'-acetyl-2'-hydroxy-(4-phenylbutoxy)benzanilide was obtained except that 1.5 g of 4-(1-methyl-1,3-dioxan-2-yl)-2-nitrophenol obtained in Reference Example 38 was used as a starting compound.
Melting point: 134 - 135°C Elemental analysis for C25H25NO4
C% H% N% Calcd. 74.42 6.25 3.47
Found 74.20 6.27 3.43 Reference Example 41
Melting point: 73°C
Elemental analysis for C31H35NO7
C% H% N%
Calcd. 69.78 6.61 2.62
Found 69.68 6.58 2.49
Reference Example 42
Melting point: 85- 87°C
Elemental analysis for C33H33NO8S
C% H% N% S%
Calcd. 65.66 5.51 2.32 5.31
Found 65.45 5.45 2.23 5.48
Reference Example 43
In 15 ml of 2-butanone were heated under reflux 2.27 g of ethyl 4-hydroxyindan-1-one-2-acetate, 2.10 g of p-heptyloxybenzyl chloride and 2.00 g of potassium carbonate overnight. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with a saturated saline aqueous solution and dried over anhydrous magnesium sulfa.te.
Volatile matters were removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluant: toluene-ethyl acetate (20:1)) to obtain 2.17 g of ethyl 4-(p-heptyloxybenzyloxy)indan-1-one-2-acetate. i) Oily product ii) Nuclear magnetic resonance spectra: (CDCl3, internal standard: TMS, ppm)
0.8-0.95(3H), 1.21(3H, t), 1.2-1.4 (8H), 1.7-1.9(2H), 2.3-3.1(4H), 3.44 (1H, dd), 3.96(2H, t) 4.14(2H, q), 5.08(2H, s), 6.93(2H, d), 7.0-7.4 (5H).
Reference Example 44
To a solution of 730 mg of p-heptyloxybenzoic acid in 5 ml of methylene chloride were added 10 μl of N,N-dimethylformamide and 410 μl of oxalyl chloride. The mixture was
stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude p-heptyloxybenzoyl chloride. A solution of p-heptyloxybenzoyl chloride described above in 2 ml of methylene chloride was dropwise added to a solution of 380 mg of
3-(m-aminophenyl)propionitrile in 1.5 ml of pyridine and 4 ml of methylene chloride at -30°C. The mixture was gradually warmed to room temperature and stirred for 3 hours. Water was added and the product was extracted with ethyl acetate. After washing with 5% hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution, water and then a saturated saline aqueous solution in this order, the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purifed by silica gel column chromatography (eluant: toluene-ethyl acetate (10:1)) to obtain 830 mg of 3-[m-[(p-heptyloxy)benzamido]phenyl]propionitrile. i) Melting point: 129 - 131°C ii) Nuclear magnetic resonance spectra: (CDCl3, internal standard: TMS, ppm)
0.8-1.0(3H), 1.3-1.6(8H), 1.7-1.9(2H), 2.55-2.75 (2H), 2.90-3.10(2H), 4.03(2H, t), 6.9-7.9(8H).
A mixture of 2.5 g of 5'-acetyl-2'-hydroxy-4-(4-phenylbutoxy)benzanilide obtained in Reference Example 40, 1.3 g of ethyl bromoacetate, 1.2 g of anhydrous potassium carbonate, a catalytic amount of tetra-n-butylammonium bromide and 30 ml of 2-butanone was stirred at 60 to 70°C for 6 hours. To the reaction mixture was added 50 ml of toluene. The mixture was washed with a diluted sodium hydroxide aqueous solution and then with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 2.4 g of ethyl 4-acetyl-2-[p-(4-phenylbutoxy}benzamido]phenoxyacetate.
Melting point: 105 - 107°C
Elemental analysis for C29H31NO66
C% H% N%
Calcd. 71.15 6.38 2.86
Found 70.92 6.39 2.77
Compounds of Examples 54 through 63 were obtained in a similar manner. Example 54
Desired compound:
Ethyl 4-bromo-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate
Physicochemical properties: i) Melting point: 85 - 86°C ii) Elemntal analysis for C27H28NO5Br
C% H% N% Br% Calcd. 61.60 5.36 2.66 15.18
Found 61.58 5.35 2.61 15.20 Starting compound: Compound of Reference Example 28 +
BrCH2COOC2H55
Example 55
Desired compound:
Ethyl 4-ethyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate Physicochemical properties : i) Melting point: 58 - 59°C ii) Elemental analysis for C29H33NO5
C% H% N% Calcd. 73.24 6.99 2.95 Found 73.14 6.85 2.69 Starting compound: Compound of Reference Example 30 +
BrCH2COOC2H5
Example 56
Desired compound:
Ethyl 2-[p-(4-phenylbutoxy)benzamido]-4-propylphenoxyacetate Physicochemical properties: i) Melting point: 57 - 58°C ii) Elemental analysis for C30H35NO5
C% H% N% Calcd. 73.60 7.21 2.86 Found 73.47 7.39 2.84 Starting compound: Compound of Reference Example 31 +
BrCH2COOC2H5
Example 57
Desired compound:
C% H% N% Calcd. 73.60 7.21 2.86 Found 73.64 7.31 2.82 Starting compound: Compound of Reference Example 35 + BrCH2COOC2H5 xample 58
Desired compound:
Ethyl 4-cyano-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate Physicochemical properties: i) Melting point: 115 - 116°C
ii) Elemental analysis for C28H28N2O5
C% H% N% Calcd. 71.17 5.97 5.93 Found 71.15 6.01 5.85 Starting compound: Compound of Reference Example 32 +
BrCH2COOC2H5
Example 59
Desired compound:
Ethyl 4-ethoxycarbonylmethoxy-3-[p-(4-phenylbutoxy)- benzamido]benzoate Physicochemical properties: i) Melting point: 93 - 94°C ii) Elemental analysis for C30H33NO7
C% H% N%
Calcd. 69.35 6.40 2.70 Found 69.30 6.45 2.63 Starting compound: Compound of Reference Example 27 +
BrCH2COOC2H5
Example 60
Desired compound:
Ethyl 4-ethoxycarbonylmethyl-2-[p-(4-phenylbutoxy)- benzamido]phenoxyacetate Physicochemical properties: i) Oily product ii) Elemental analysis for C31H35NO7
N% Calcd. 2.62
Found 2.54 Starting compound: Compound of Reference Example 33 +
BrCH2COOC2H5
Example 61
Desired compound:
C% H% N% Calcd. 69.35 6.40 2.70 Found 69.19 6.53 2.75 Starting compound: Compound of Reference Example 34 + BrCH2COOC2H5
Example 62
Desired compound:
Ethyl 5-(2-ethoxycarbonyl)ethyl-2-[p-(4-phenylbutoxy)- benzamido]phenoxyacetate Physicochemical properties: i) Melting point: 86 - 88°C
ii) Elemental analysis for C32H37NO7
C% H% N% Calcd. 70.18 6.81 2.56 Found 70.19 6.87 2.57 Starting compound: Compound of Reference Example 36 +
BrCH2COOC2H5
Example 63
Desired compound:
Ethyl 4-[4-chloro-2-[p-(4-phenylbutoxy)benzamido]- phenoxybutyrate Physicochemical properties: i) Melting point: 87 - 88°C ii) Elemental analysis for C29H32NO5Cl
C% H% N% Calcd. 68.29 6.32 2.75 Found 68.06 6.30 2.75
Starting compound:
Example 64
In 200 ml of acetone was dissolved 8.69 g of ethyl 4-(1,3-dioxan-2-yl)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Reference Example 41. To the solution was added 6 ml of 6% hydrochloric acid. The mixture was stirred at room temperature for 2 hours. After adding 30 ml of water thereto, the mixture was cooled and the precipitated crystals were taken by filtration, washed with 50% acetone to obtain 6.0 g of ethyl 4-formyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Melting point: 109 - 110°C
Elemental analysis for C28H28NO6
C% H% N% Calcd. 70.72 6.15 2.95 Found 70.77 6.05 2.93 Example 65
Under ice cooling 0.2 g of sodium borohydride was added to a mixture of 2.8 g of ethyl 4-formyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Reference Example 64 and 30 ml of ethanol. The mixture was stirred for 2 hours and 50 ml of ethyl acetate was added thereto. The mixture was rendered acidic with diluted hydrochloric acid. The ethyl acetate layer was fractionated, washed with water, dried over anhydrous magnesium sulfate and. concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 2.06 g of ethyl 4-hydroxymethyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate. Melting point: 101 - 104°C
Elemental analysis for C28H31NO6
C% H% M
Calcd. 70.42 6.54 2.93
Found 70.25 6.51 2.85
Example 66
Under ice cooling 260 mg of thionyl chloride was added to a solution of 1 g of ethyl 4-hydroxymethyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Reference Example 65 in 20 ml of benzene and 20 ml of methylene chloride. After stirring at room temperature for 30 minutes, 60 ml of toluene was added to the reaction mixture. The mixture was washed with chilled water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from toluene-n-hexane to obtain 0.76 mg of ethyl 4-chloroxymethyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Melting point: 115 - 117°C Elemental analysis for C28H30NO5Cl
H% N% Cl%
Calcd. 67.80 6.10 2.82 7.15
Found 67.87 6.13 2.79 7.27
Example 67
A mixture of 200 mg of ethyl 4-chloroxymethyl-2-[p-(4- phenyIbutoxy)benzamido]phenoxyacetate obtained in Reference Example 66, 50 mg of ethyl thioacetate, 60 mg of anhydrous potassium carbonate and 5 ml of N,N-dimethylformamide was stirred at room temperature for 1hour. After adding 20 ml of toluene thereto, the mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel; 30 ml), eluted with a toluene-ethylacetate (9:1) mixture to obtain 170 mg of ethyl 4-[(ethoxycarbonylmethylthio)methyl]-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Melting point: 56 - 57°C
Elemental analysis for C32H37NO7S
C% H% N% Calcd. 66.30 6.43 2.42 Found 66.04 6.43 2.31 Example 68
To a mixture of 200 mg of ethyl 4-amino-2-Cp-(4-phenyIbutoxy)benzamido]phenoxyacetate hydrochloride and 3 ml of pyridine was added 1 ml of formic acid-acetic anhydride (3:5 v/v) mixture followed by stirring at room temperature overnight. To the reaction mixture was added 40 ml of ethyl acetate. The mixture was rendered acidic with diluted hydrochloric acid and then separated. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from isopropyl alcohol to obtain 130 mg of ethyl 4-formylamido-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Melting point: 112 - 114°C
Elemental analysis for C28H30N2O6
C% H% N% Calcd. 68.56. 6.16 5.71 Found 68.43 6.31 5.62 Example 69
Under ice cooling 1 ml of acetic anhydride was added to a mixture of 200 mg of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride and 5 ml of pyridine followed by stirring at room temperature overnight. The reaction mixture was treated similarly to Example 68 to obtain 150 mg of ethyl 4-acetamido-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Melting point: 130 - 132°C
Elemental analysis for C29H32N2O6
C% H% N%
Calcd. 69.03 6.39 5.55
Found 68.89 6.37 5.43
Example 700
To a mixture of 200 mg of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride, 40.5 mg of triethylamine and 5 ml of methylene chloride was added 30 mg of ethyl isocyanate followed by stirring at room temperature overnight. The reaction mixture was treated in a manner similar to Example 68 to obtain 130 mg of ethyl 4-(3-ethylureido)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Melting point: 170 - 172°C Elemental analysis for C30H35N3O6
C% H% N%
Calcd. 67.53 6.61 7.87
Found 67.59 6.63 7.80 Example 71
Nuclear magnetic resonance spectra: (CDCl3, internal standard: TMS, ppm)
1.1-1.6 (m, 6H) , 1.6-2.0 (m, 4H) , 2.5-2.8 (m, 2H), 3.8-4.1
(m, 2H), 4.1-4.5 (m, 4H), 4.58(s, 2H), 6.6-7.8(12H) Example 72
To a mixture of 200 mg of ethyl 4-amino-2-[p-(4-
phenylbutoxy)benzamido]phenoxyacetate hydrochloride, 107 mg of mono-p-methoxybenzyl malonate and 5 ml of pyridine was added 90 mg of dicyclohexylcarbodiimide. The mixture was stirred at room temperature overnight. The reaction mixture was treated in a manner similar to Example 68. Thereafter the system was applied to silica gel column chromatography and eluted with a toluene-ethyl acetate (4:1) mixture to obtain 110 mg of caramel-like ethyl 4-(p-methoxybenzyloxycarbonyl)acetamido-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Nuclear magnetic resonance spectra: (CDCl3, internal standard: TMS, ppm)
1.18(t,3H), 1.5-2.0 (m, 4H), 2.5-2.8(m, 2H), 3.46.(s, 2H), 3.72(s, 3H), 4.9-4.2(m, 2H), 4.16(q, 2H), 4.82(s, 2H), 5.06(s, 2H), 6.8-8.3(16H) Example 73
Melting point: 61 - 63°C
Elemental analysis for C31H36N2O7
C% H% N%
Calcd. 67.87 6.61 5.11 Found 67.74 6.56 5.11 Example 74
Melting point: 186 - 188°C
Elemental analysis for C27H27NO6
C% H% N%
Calcd. 70.27 5.90 3.03
Found 70.07 5.73 3.02
Compounds of Examples 75 through 92 were obtained following the same procedure.
Desired compound:
4-Ethyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid Physicochemical Properties: i) Melting point: 129 ~ 132°C ii) Elemental analysis for C27H29NO5
C% H% N%
Calcd. 72.46 6.53 3.13
Found 72.33 6.65 3.09
Starting Compound: Compound of Example 55 Example 76
Desired compound:
2-[p-(4-phenylbutoxy)benzamido]-4-propylphenoxyacetic
acid Physicochemical Properties: i) Melting point: 109 ~ 112°C ii) Elemental analysis for C28H31NO5
N% Calcd. 3.03 Found 3.01 iii) Nuclear magnetic resonance spectra (CDCl3, TMS internal standard, ppm): 0.90 (t,3H), 1.4-2.0 (6H) , 2.4- 2.8(4H), 3.8-4.1(2H), 4.70(s, 2H), 6.7-7.0(4H), 7.0-7.4(5H), 7.8-8.0(2H), 8.15 (d, 1H), 8.62(s, 1H) , 8.91(s, 1H) Starting Compoumd: Compound of Example 56 Example 77
Desired compound:
C% H% N% Calcd. 72.86 6.77 3.03 Found 73.05 6.91 3.04
Starting Compound: Compound of Example 57 Example 78
Desired compound:
4-Hydroxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid Physicochemical Properties: i) Melting point: 198 ~ 199°C ii) Elemental analysis for C25H25NO6
C% H% N%
Calcd. 68.95 5.79 3.22
Found 69.01 5.99 3.13
Starting Compound: Compound of Example 42 Example 79
Desired compound:
N% Calcd. 6.06 Found 5.99 Starting Compound: Compound of Example 68 Example 80
Desired compound:
4-Acetamido-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid Physicochemical Properties: i) Melting point: 184 ~ 186°C ii) Elemental analysis for C27H28N2O6
C% H% N%
Calcd. 68.05 5.92 5.88
Found 67.77 5.96 5.79
Starting Compound: Compound of Example 69 Example 81
Desired compound:
4-Oxalamido-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid
Physicochemical Properties: i) Melting point: 206 ~ 207°C (decomposed) ii) Elemental analysis for C27H26N2O8.1/2H2O
C% H% N%
Calcd. 63.57 5.22 5.49
Found 63.63 5.21 5.44
Starting Compound: Compound of Example 71 Example 82
Desired compound:
4-(2-Carboxyacetamido)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid
Physicochemical Properties: i) Melting point: 179 ~ 181°C (decomposed) ii) Elemental analysis for C28H28N2O8
C% H% N%
Calcd. 64.61 5.42 5.38
Found 64.67 5.39 5.32
Starting Compound: Compound of Example 72 Example 83
Desired compound:
4-Carboxy-2-[p-(4-phenyIbutoxy)benzamido]phenoxyacetic acid Physicochemical Properties: i) Melting point: 244 ~ 246°C ii) Elemental analysis for C26H25NO7
C% H% N%
Calcd. 67.38 5.44 3.02
Found 67.33 5.48 3.03
Starting Compound: Compound of Example 59
Example 84
Desired compound:
4-Carboxymethyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid Physicochemical Properties: i) Melting point: 210 ~ 213°C ii) Elemental analysis for C27H27NO7
C% H% N% Calcd. 67.91 5.70 2.93 Found 67.45 5.69 2.92
Starting Compound: Compound of Example 60 Example 85
Desired compound:
4-Formyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid
Physicochemical Properties: i) Melting point: 151 ~ 152°C ii) Elemental analysis for C26H25NO6
C% H% N%
Calcd. 69.79 5.63 3.13
Found 69.79 5.54 3.11
Starting Compound: Compound of Example 64 Example 86
Desired compound:
4-Hydroxymethyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid Physicochemical Properties: i) Melting point: 138 - 139°C ii) Elemental analysis for C26H27NO6
C% H% N%
Calcd. 69.47 6.05 3.12
Found 69.34 5.81 3.05
Starting Compound: Compound of Example 65
Example 87
Desired compound:
4-Carboxymethylthiomethyl-2-[p-(4-phenylbutoxy) benzamido]phenoxyacetic acid Physicochemical Properties: i) Melting point: 139 ~ 141°C ii) Elemental analysis for C28H29NO7S
N% Calcd. 2.68 Found 2.57 Starting Compound: Compound of Example 67 Example 88
Desired compound:
4-Cyano-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid
Physicochemical Properties: i) Melting point: 148 ~ 149 °C ii) Elemental analysis for C2gH24N2O5
C% H% N%
Calcd. 70.26 5.44 6.30
Found 70.14 5.44 6.12
Starting Compound: Compound of Example 58 Example 89
Desired compound:
4-Bromo-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid Physicochemical Properties: i) Melting point: 163 ~ 165 °C ii) Elemental analysis for C25H24NO5Br C% H% N% Br%
Calcd. 60.25 4.85 2.81 16.03 Found 60.15 4.99 2.75 16.02 Starting Compound: Compound of Example 54
Example 90
Desired compound:
5-Carboxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid Physicochemical Properties: i) Melting point: 235 ~ 237.5°C ii) Elemental analysis for C26H25NO7
C% H% N%
Calcd. 67.38 5.44 3.02
Found 67.06 5.53 3.10
Starting Compound: Compound of Example 61 Example 91
Desired compound:
C% H% N%
Calcd. 67.68 6.00 2.82
Found 67.60 6.19 2.64
Starting Compound: Compound of Example 62 Example 92
Desired compound:
4-[4-Chloro-2-[p-(4-phenylbutoxy)benzamido]phenoxy]- butyric acid Physicochemical Properties: i) Melting point: 118 ~ 119°C ii) Elemental analysis for C27H28NO5Cl
C% H% N%
Calcd. 67.28 5.86 2.91
Found 67.13 5.77 2.82
Starting Compound: Compound of Example 63 Example 93
Desired compound:
4-Carboxymethylamino-2-[p-(4-phenylbutoxy)benzamido]- phenoxyacetic acid
Physicochemical Properties: i) Melting point: 129 ~ 132°C ii) Elemental analysis for C27H28N2O7. 1/2H2O
C% H% N% Calcd. 64.66 5.83 5.59
Found 64.69 5.92 5.46
Starting Compound: Compound of Example 73
Example 94
Desired compound:
4-(3-Ethylureido)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid
Physicochemical Properties: i) Melting point: 156°C ii) Elemental analysis for C28H31N3O6
C% H% N%
Calcd. 66.52 6.18 8.31 Found 66.18 6.15 8.13
Starting Compound: Compound of Example 70 Example 95
A catalytic amount of tetra-n-butylammonium bromide was added to a mixture of 0.62 g of 4-hydroxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid obtained in Example 78, 0.46 g of anhydrous potassium carbonate, 2.47 g of methyl iodide and 10 ml of 2-butanone followed by stirring at 60°C for 20 hours. The reaction mixture was diluted with ethyl acetate and insoluble materials were filtered off. After the filtrate was washed in order with a 0.02N aqueous sodium hydroxide solution and water and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained solid
was recrystallized from ethanol to obtain 0.59 g of methyl 4-methoxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyaeetate. Melting point: 91 ~ 93 °C ii) Elemental analysis for C27H29NO6
N%
Calcd. 3.02 Found 2.98 Example 96
A catalytic amount of tetra-n-butylammonium bromide was added to a mixture of 0.64 g of 4-hydroxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid obtained in Example 78, 0.50 g of anhydrous potassium carbonate, 0.60 g of ethyl bromoacetate and 8 ml of 2-butanone followed by stirring at 60°C for 4 hours. The reaction mixture was diluted with ethyl acetate and insoluble materials were filtered off. After the filtrate was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained solid was recrystallized from ethanol to obtain 0.83 g of ethyl [[4-ethoxycarbonylmethoxy-2-[p-(4-phenyl
butoxy)benzamido]phenoxy]acetoxy]acetate. Melting point: 64 °C Elemental analysis for C33H37NO10
C% H% N%
Calcd. 65.23 6.14 2.31 Found 65.00 5.96 2.23 Example 97
In 25 ml of 90% methanol was suspended 0.54 g of methyl 4-methoxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 95. To the suspension wad added 10 ml of a 1N sodium hydroxide aqueous solution followed by stirring at 60°C for 2 hours. The reaction mixture was diluted with 50 ml of water and the system was rendered acidic with 7 ml of 2N hydrochloric acid. Extraction was performed with ethyl acetate. After the organic layer was washed water and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained solid was recrystallized from isopropyl alcohl to obtain 0.4 g of 4-methoxy-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid.
Melting point: 139 ~ 141°C ii) Elemental analysis for C26H27NO6
C% H% N%
Calcd. 69.47 6.05 3.12
Found 69.33 6.13 3.03
Example 98
Ethyl [[4-ethoxycarbonymethoxy-2-[p-(4-phenylbutoxy)benzamido]phenoxy]acetoxy]acetate, 0.77 g, obtained in Example 96 was used as a starting compound and treated in a manner similar to Example 97 to obtain 0.57 g of [2-[p-(4-phenylbutoxy)benzamido]-1,4-phenylenedioxy]diacetic acid.
Melting point: 211 ~ 214 °C ii) Elemental analysis for C27H27NO8 C% H% N%
Calcd. 65.71 5.51 2.84 Found 65.74 5.51 2.77 Example 99
To a sodium methoxide-methanol solution obtained from 100 mg of metallic sodium and 5 ml of methanol was added 200 mg of ethyl 4-chloromethyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 66. The mixture was stirred at room temperature overnight. To the reaction mixture was added 1 ml of water and stirred for 1 hour. After rendering acidic with diluted hydrochloric acid, the system was concentrated under reduced pressure. To the residue was added 10 ml of water. The formed crystals were filtered and recrystallized from isopropyl alcohol to obtain 100 mg of 4-methoxymethyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid. Melting point: 126 ~ 129°C ii) Elemental analysis for C26H25NO6
C% H% N%
Calcd. 69.79 5.63 3.13 Found 69.79 5.54 3.11 Example 100
To a solution of 30 mg of cerous chloride heptahydrate in 8 ml of methanol was dossolved 350 mg of ethyl
4-(p-heptyloxybenzyloxy)-indan-1-one-2-acetate obtained in Reference Example 43. The mixture was cooled to -10°C.
Thereto was added 300 mg of sodium borohydride followed by stirring for 30 minutes. Water was aded and the temperature was elevated to room temperature. The product was extracted with ethyl acetate. The ethyl acetate layer was washed twice with a saturated saline aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 390 mg of ethyl 1-hydroxy-4-(p-heptyloxybenzyloxy)indan-2-acetate. i) Oily product ii) Nuclear magnetic resonance spectra (CDCl3, internal standard; TMS, ppm)
0.8-1.0 (3H), 1.25, 1.28 (3H by joining, each of them is t), 1.2-1.45(8H), 1.6-1.9 (2H), 2.3-4.4(5H), 3.96 (2H, t), 4.15, 4.21 (2H by joining, each of them is q, 7:4), 5.00(2H, s), 5.20(1H, w/2=11Hz), 6.8-7.4(7H).
Example 101
1-hydroxy-4-(p-heptyloxybenzyloxy)-2-indaneacetate obtained in Example 100 and, 2.5 ml of a 5% sodium hydroxide solution was added thereto followed by stirring at room temperature for 8 hours. The system was rendered acidic with 20% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed subsequently with water and then a saturated saline aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was recrystallized from ethyl acetate-hexane to obtain 230 mg of 1-hydroxy-4-(p-heptyloxybenzyloxy)-2-indaneacetic acid, i) Melting point: 180°C ii) Elemental analysis for C25H32O5
C% H% Calcd. 72.79 7.82
Found 72.66 7.98 Example 102
In 5 ml of N,N-dimethylformamide was dissolved 630 mg of 3-[m-[p-heρtyloxy)benzamido]phenyl]ρropionitrile obtained in Example 44. To the solution were added 340 mg of sodium azide and 280 mg of ammonium chloride. The mixture was heated at 130°C. Four hours and 16 hours after, the same amounts of sodium azide and ammonium chloride were added to the system followed by heating 20 hours. Water was added to the reaction mixture and the formed crystalline solid was collected by suction. After washing with water and drying, the solid was recrystallized from methanol-ethyl acetate to obtain 540 mg of 4-heptyloxy-3'-[2-(5-tetrazolyl)ethyl]benzanilide. i) Melting point : 164 ~ 165 °C ii) Elemental analysis for C23H29N5O2
C% H% N%
Calcd. 67.79 7.17 17.19
Found 67.96 7.13 16.91
Example 103
(Tablet)
Compound of Example 40 30 mg
Lactose 104 mg
Corn starch 57 mg
Hydroxypropyl cellulose 4 mg
Calcium carboxymethyl cellulose 4mg
Magnesium stearate 1 mg total 200 mg
After uniformly mixing 30 g of Compound of Example 40, 104 g of lactose and 57 g of corn starch, 40 ml of a 10% (w/w) aqueous solution of hydroxypropyl cellulose was added to the mixture and the resulting mixture was granulated by a wet granulation method. The granules thus obtained were mixed with 4 g of calcium carboxymethyl cellulose and 1 g of magnesium stearate and the mixture was press-tabletted into tablet (200 mg per tablet). Example 104 (capsule)
Compound of Example 40 30 mg
Crystalline cellulose 40 mg
Crystalline lactone 129 mg
Magnesium stearate 1 mg total 200 mg
The above components each in an amount 1000 times the foregoing amount were mixed and then filled in gelatin capsule to provide capsules (200 mg per capsule). Example 105 (Inhalation)
After dissolving 0.1 g of Compound of Example 40 in about 90 ml of a mixture of ethanol, propylene glycol and purified water (30:10:60 in weight ratio), the volume of the solution was adjusted to 100 ml using the aforesaid mixture and 10 ml each of the solution was filled in a definite container followed by sealing to provide an inhalation.
Claims
1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
wherein symbols represent:
A: hydrogen atom, a phenyl group or a phenoxy group, n: an integer of 3 to 10
R1: hydrogen atom or a lower alkoxy group, X1 : a group shown by -CH2CH2-, -CH=CH-, -CH2-Y1- (wherein Y1 : -O-, -S- or -NH-), -Y1-CH2-, -CO-Y2- (wherein Y2 : -NH-, -CH2-Y1- or -Y1-CH2-) or -Y2-CO-, Ⓑ : a group represented by:
group, a carboxyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group or a group represented by formula:
(wherein R4 and R5, which may be the same or different, each represents a hydrogen atom, a lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group or a mono- or di-lower alkylaminocarbonyl group), R3: a hydrogen atom, a hydroxy group or a lower alkoxy group, X2 a group represented by -CH=CH- or -Y3-Y4- (wherein Y3: a single bond, -O-, -S- or -NH-; Y4: an alkylene group having 1 to 6 carbon atoms which may be intervened by a sulfur atom),
D: a carboxy group, a lower alkoxycarbonyl group or a group represented by:
2. A compound as claimed in Claim 1 wherein A represents a hydrogen atom or a phenyl group, n is an integer of 4 to 7, R1 is a hydrogen atom, X1 is -CO-Y2- (wherein Y2 is -NH-), B is :
(wherein R2 is a hydrogen atom, a halogen atom, a nitro group, a lower alkyl group or a carboxy-lower alkyl group) or: 
X2 is -CH=CH- or -Y3-Y4- (wherein Y3 represents a single bond, -O- or -S-, and Y4 is an alkylene group having 1 to 6 carbon atoms which may be intervented by a sulfur atom) and D is a carboxy group or:
3. A compound as claimed in Claim 1 which is 4-chloro-2-[(4-phenylbutoxy)benzamido]phenoxyacetic acid.
4. A compound as claimed in Claim 1 which is 3-[o-[p-(4-phenylbutoxy)benzamido]phenyl]propionic acid.
5. A compound as claimed in Claim 1 which is o-[p-(4-phenylbutoxy)benzamido]cinnamic acid.
6. A compound as claimed in Claim 1 which is o-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid.
7. A compound as claimed in Claim 1 which is 4-nitro-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid.
8. A compound as claimed in Claim 1 which is 4-methyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid.
9. A compound as claimed in Claim 1 which is 4-heptyloxy-2'-(5-tetrazolylmeth.oxy)benzanilide.
10. A process for the production of a phenylene derivative represented by the general formula (I) :
{wherein A stands for a hydrogen atom, a phenyl group, or a phenoxy group; n for an integer of the value of 3 to 10; R1
for a hydrogen atom or a lower alkoxy group; X1 for a group represented by -CH2CH2-, -CH=CH-, -CH2-Y1- (whereinY1 stands for -O-, -S-, or -NH-), -Y1-CH2-, -CO-Y2- (wherein Y2 stands for -NH-, -CH2-Y1-, or -Y1-CH2-), or -Y2-CO-; Ⓑ for a group represented by
[wherein R2 stands for a hydrogen atom, a halogen atom, a nitro group, a hydroxy! group, a lower alkoxy group, a carboxy group, a cyano group, an oxaloamide group (-NHCOCOOH) , a lower alkoxycarbonyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxy-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio-lower alkyl group, a halo-lower alkyl group, a carboxy- lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl-lower alkoxy group, a lower alkoxycarbonyl- lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of (wherein R4 and R5, which may be 
the same or different, each stands for a hydrogen atom, a lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group, or a mono- or di-lower alkylamino-carbonyl group); R3 for a hydrogen atom, a hydroxyl group, or a lower alkoxy group]; X2 for a group represented by -CH=CH- or -Y3-Y4- (wherein Y3 stands for a single bond, -O-, -S-, or -NH- and Y4 for an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom), and D for a carboxyl group, a lower alkoxy-carbonyl group, or a group represented by , prividing that when A is 
a hydrogen atom, Ⓑis
characterized by: 
(a) reacting a carboxylic acid represented by the general formula
(II) :
(wherein A, n, and R1 have the same meanings as defined above) or a reactive derivative thereof with an amino compound represented by the general formula (III): 
(wherein Ⓑ, X2, and D have the same meanings as defined above) or (b) reacting an amino compound represented by the general formula (IV):
(wherein A, n, and R1 have the same meanings as defined above) with a carboxylic acid represented by the general formula (V) : 
(wherein Ⓑ, X2, and D have the same meanings as defined above) or a reactive derivative thereof, or (c) reacting a compound represented by the general formula (VI):
(wherein A, n, R1, Y1 have the same meanings as defined above, M1 stands for a hydrogen atom or an alkali metal atom when Y1 is an oxygen atom or a sulfur atom, or for a hydrogen atom when Y1 is an imino group) with a compound represented by the general formula (VII) : 
[wherein Ⓑ, X2, and D have the same meanings as defined above, Z1 stands for a halogen atom or a sulfonate residue, and Y5 for a methylene group or a methylenecarbonyl group (-CH2CO-) ] , or (d) reacting a compound represented by the general formula (VIII) :
(wherein A, n, and R1 have the same meanings as defined above and Z2 stands for a halogen atom) with triphenyl phosphine or tributyl phosphine thereby producing a compound represented by the general formula (XI):
(wherein A, n, R1, and R2 have the same meanings as defined above and R6 stands for a phenyl group or a butyl group), then converting said compound of said general formula (XI) with a base into a substituted benzyl triphenyl (or tributyl) phosphoran, and reacting a compound represented by the general formula (XII): 
(wherein Ⓑ, X2, and D have the same meanings as defined above) upon said substituted benzyl triphenyl (or tributyl) phosphoran, or
(f) removing an ester residue from the corresponding ester represented by the general formula (If):
(wherein A, n, R1, Ⓑ, X1, and X2 have the same meanings as defined above, and R7 stands for a lower alkyl group or a lower alkoxypheriyl-lower alkyl group), or (g) reacting a compound represented by the general formula (XIII):
(wherein A, n, R1, X1, and Ⓑ have the same meanings as defined above, Y7 stands for an oxygen atom or a sulfur atom, and M2 for a hydrogen atom or an alkali metal atom) with a compound represented by the general formula (XIV) . 
(wherein Z2, Y4, and D have the same meanings as defined above), or
(h) reacting sodium azide with a compound represented by the general formula (XV) : 
(wherein A, n, R1, X1, Ⓑ, and X2 have the same meanings as defined above), or (i) racting a compound represented by the general formula (XVII):
(wherein M2, R1, X1, Ⓑ, X2, and D have the same meanings as defined above) with a substituted alkyl halide represented by the general formula (XVIII) :
(wherein A, n, and Z2 have the same meanings as defined above).
11. A process for the production of a phenylene derivative represented by the general formula (I) :
[wherein R2 stands for a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a lower alkoxy group, a carboxyl group, a cyano group, an oxaloamide group (-NHCOCOOH) , a lower alkoxycarbonyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio-lower alkyl group, a halo-lower alkyl group, a carboxy- lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of ( wherein R4 and R5, which may be the same 
or different, each stands for a hydrogen atom, a lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group, or a mono- or di-lower alkylaminocarbonyl group); R3 for a hydrogen atom, a hydroxyl group, or a lower alkoxy group]; X2 for a group represented by -CH=CH- or -Y3-Y4- (wherein Y3 stands for a single bond, -O-, -S-, or -NH- and Y4 for an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom), and D for a carboxyl group, a lower alkoxycarbonyl group, or 9. &roup represented by , providing that 
when A is a hydrogen atom, Ⓑ is or a salt thereof, which process 
is characterized by:
(a) reacting a carboxylic acid represented by the gneral formula
(II):
(wherein A, n, and R1 have the same meanings as defiend above) or a reactive derivative thereof with an amino compound represented by the general formula (III):
(wherein Ⓑ, X2, and D have the same meanings as defined above,
or (b) reacting an amino compound represented by the general formula
(IV):
(wherein A, n, and R1 have the same meaning as defined above) with a caroboxylic acid represented by the general
formula (V): 
(wherein Ⓑ, X2, and D have the same meanings as defined above) or a reactive derivative thereof, or (c) reacting a compound represented by the general formula (VI)
(wherein A, n, R1, Y1 have the meanings as defiend above, M1 stands for a hydrogen atom or an alkali metal atom where Y1 is an oxygen atom or a sulfur atom,or for a hydrogen atom where Y1 is an imino group) with a compound represented by the general formula (VII): 
[wherein Ⓑ, X2, and D have the same meanings as defined above, Z1 stands for a halogen atom or a sulfonate residue, and Y5 for a methylene group or a methylenecarbonyl group (-CH2CO-)], or (d) reacting a compound represented by the general formula (VIII):
[wherein A, n, R1, and Z1 have the same meanings as definad above, and Y6 stands for a methylene group or a carbonyl- methylene group (-COCH2-)] with a compound represented by the general formula (IX): 
(wherein M1, Y1, Ⓑ , and D have the same meanings as defined above), or (e) reacting a halogen compound represented by the general formula (X) :
(wherein A, n, and R1 have the same meanings as defined above and Z2 stands for a halogen atom) triphenyl phosphine or tributyl phosphine thereby producing a compound represented by the general formula (XI):
(wherein A, n, R1, and R2 have the same meanings as defined above and R6 stands for a phenyl group or a butyl group), then converting said compound of said general formula (XI) with a base into a substituted benzyl triphenyl (or tributyl) phosphoran, and causing a compound represented by the general formula (XII): 
(wherein (B) , X2, and D have the same meanings as defined above) to react upon said substituted benzyl triphenyl (or tributyl) phosphoran, or
(f) removing an ester residue from the corresponding ester represented by the general formula(If):
(wherein A, n, R1, X1, and Ⓑ have the same meanings as defined above, Y7 stands for an oxygen atom or a sulfur atom, and M2 for a hydrogen atom or an alkali metal atom) with a compound represented by the general formula (XIV) : 
(wherein Z2, Y4, and D have the same meanings as defiend above), or
(h) reacting sodium azide with a compound represented by the general formula (XV):
(wherein A, n, R1, X1, Ⓑ, and X2 have the same meanings as defined above), or (i) reacting a compound represented by the general formula (XVII):
(wherein A, n, and Z2 have the same meanings as defined above), thereby obtaining said phenylene derivative or a salt thereof, and then optionally
(j) reducing said compound of the general formula (I) by an ordinary method thereby converting said compound into a corresponding compound (I) possessing an ethylene group when said compound (I) possesses a vinylene group, (k) alkylating or acylating said compound of the general formula
(I) by an ordinary method thereby converting said compound into a corresponding compound (I) possessing an alkylamino group or an acylamino group when R2 in said compound (I) is an amino group,
(l) halogenating said compound of the general formula (I) by an ordinary method thereby converting said compound into a corresponding compound (I) possessing a halo-lower alkyl group whem R2 in said compound (I) is a hydroxy-lower alkyl group, (m) reducing said compound of the general formula (I) by an ordinary method thereby converting said compound into a corresponding compound (I) possessing a hydroxymethyl group when R2 in said compound (I) is a fromyl group, , (n) lower alkoxylating said compound of the general formula (I) by an ordinary method thereby converting said compound into a corresponding compound (I) possessing a lower alkoxy-lower alkyl group when R2 in said compound (I) is a halo-lower alkyl group, or
(o) lower alkoxycarbonyl-lower alkylsulfenylating said compdund of the general formula (I) thereby converting said compound into a corresponding compound (I) possessing a lower alkoxycarbonyl- lower alkylthio-lower alkyl group when R2 in said compound (I) is a halo-lower alkyl group.
12. A process for the production of a compound represented by the general formula (la):
I wherein A stands for a hydrogen atom, a phenyl group, or a phenoxy group; n for an integer of the value of 3 to 10; R1 for a hydrogen atom or a lower alkoxy group; (B) fur a group represented by
[wherein R2 stands for a. hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a lower alkoxy group, a carboxy group, a cyano group, an oxaloamide group (-NHCOCOOH) , a lower alkoxycarbonyl group, a lower alkyl group, a hydroxy-lowr alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxy-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio-lower alkyl group, a halo-lower alkyl group, a carboxy-lower alkoxy group, a lower alkoxycarbonyl-lowr alkoxy group, a lower alkanoyl-lower alkoxy group, a lower alkoxycarbonyl-lowr alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of (wherein R4 and R5 , which may be the same 
or different, each stands for a hydrogen atom, a lower alkyl group, a carbony-lower
alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group, or a mono- or di-lower alkylaminocarbonyl group); R3 for a hydrogen atom, a hydroxyl group, or a lower alkoxy group]; X2 for a group represented by -CH=CH- or -Y3-Y4- ( wharein Y3 stands for a single bond, -O-, -S-, or -NH- and Y4 for an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom midway in the length thereof), and D for a carboxy group, a lower alkoxycarbonyl group, or a group represented by which process is characterized 
by reacting a carboxylic acid represented by the general formula (II):
(wherein Ⓑ, X2, and D have the same meanings as defined above) providing that when A in the general formula (II) is a hydrogen atom,
13. A process for the production of a compound represented by the general formula (lb) :
[wherein R2 stands for a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a lower alkoxy group, a carboxy group, a cyano group, an oxaloamide group (-NHCOCOOH) , a lower alkoxycarbonyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxy-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio-lower alkyl group, a halo-lower alkyl group, a carboxy- lowr alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a lowr lakanoyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of (wherein R4 and R5 , which may be the same or 
different, each stands for a hydrogen atom, a lower alkyl gorup, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group, or a mono- or di-lower alkylaminocarbonyl group) ; R3 for a hydrogen atom, a hydroxyl group, or a lower alkoxy group]; X2 for a group represented by -CH=CH- or -Y3-Y4- (wherein Y stands for a single bond, -O-, -S-, or -NH- and Y4 for an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom); and D for a carboxy group, a lower alkoxycarbonyl group, or a group represented by , which process is characterized by 
reacting an amino compound represented by the general formula (IV) :
providing that when A in the general formula (IV ) is a hydrogen atom, Ⓑ is or or 
D is 
or a reactive derivative thereof
14. A process for the production of a compound represented by the general formula (Ic) :
[ wherein R2 stands for a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a lower alkoxy group, a carboxy group, a cyano group, an oxaloamide group (-NHCOCOOH), a lower alkoxycarbonyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio-lower
alkyl group, a halo-lower alkyl group, a carboxy-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of (wherein R4 and R5 , which may be the same or different, each 
stands for a hydrogen atom, a lower alkyl gorup, a carboxy-lower alkyl group a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycabonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group, or a mono- or di-lower alkylaminocarbonyl group); R3 for a hydrogen atom, a hydroxyl group, or a lower alkoxy group]; X2 for a group represented by -CH=CH- or -Y3-Y4- (where Y3 stands for a single bond, -O-, -S-, or -NH- and Y4 for an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom ); and
D for a carboxyl group, a lower alkoxycarbonyl group, or a group represented by which process is characterized by reacting 
a compound represented by the general formula (VI) :
(wherein A, n, R1, Y1 have the same meanings as. defined above, and M1 stands for a hydrogen atom or an alkali metal atom when Y1 is an oxygen atom or a sulfur atom, or for a hdyrogen atom when Y1 is an imino group) with a compound represented by the general formula (VII): 
(wherein Z1 stands for a halogen atom or a sulfonate residue, Y5, Ⓑ, X2, and D have the same meaning as defined above)
providing that when A in the general formula (VI ) is a hydrogen atom, Ⓑ is or , or 
D is 
15. A process for the production of a compound represented by the general formula (Id) :
{wherein A stands for a hydrogen atom, a phenyl group, or a phenoxy group; n for an integer of the value of 3 to 10; R1 for a hydrogen atom or a lower alkoxy group; Y6 for a methylene group or a carbonylmethylene group (-CONH2-), Ⓑ for a group represented by
alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of (wherein R4 and R5, which may be the same or 
different, each stands for a hydrogen atom, a lower alkyl gorup, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group, or a mono- or di-lower alkyl- aminocarbonyl group); R3 for a hydrogen atom, a hydroxyl group, or a lower alkoxy group] ; X2 for a group represented by -CH=CH- or -Y3-Y4- ( wherein Y3 stands for a single bond, -O-, -S-, or -NH- and Y4 for an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom); and D for a carboxyl group, a lower alkoxycarbonyl group, or a group represented by , which process is characterized by reacting 
a compound represented by the general formula (VIII):
(wherein A, n, R1, and R6 have the same meanings as defined above, and Z1 stands for a halogen atom or a sulfonate residue) with a compotind represented by the general formula (IX):
(wherein M1 stands for a hydrogen atom or an alkali metal atom when Y1 is an oxygen atom or a sulfur atom, or for a hydrogen atom when Y1 is an imino group, and Ⓑ, X2, and D have the same meanings as defined above)
providing that when A in the general formula (VIII ) is a hydrogen atom, Ⓑ is or or 
D is 
16. A process for the production of a compound represented by the general formula (Ie) :
{wherein A stands for a hydrogen atom, a phenyl group, or a phenoxy group; n for an integer of the value of 3 to 10; R1 for a hdyrogen atom or a lower alkoxy group; Ⓑ for a group represented by
[ wherein R2 stands for a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a lower alkoxy group, a carboxy group, a carboxyl group, a cyano group, an oxaloamide group (-NHCOCOOH) , a lower alkoxycarbonyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxyl-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio-lower alkyl group a halo-lower alkyl group, a carboxy-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a lower alkanpyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of (wherein R4 and R5 , which may be the same 
or different, each stands for a hydrogen ato, a lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lowor alkoxalyl group, or a mono- or di-lower alkylaminocarbonyl group); R3 for a hydrogen atom, a hydroxyl group, or a lower alkoxy group]; X2 for a group represented by -CH=CH- or -Y3-Y4- (wherein Y3 stands for a single bond, -O-, -S-, or -NH- and Y4 for an alkylene group of 1 to 6 carbon atoms which may be interrupted by asulfur atom), and D for a carboxyl group, a lower alkoxycarbonyl group, or a group represented by which process is characterized by 
reacting a compound represented by the general formula (X) :
(wherein A, n, and R1 have the same meanings as defined above and Z 2 stands for a halogen atom) with triphenyl phosphine or tributyl phosphine thereby producing a compound represented by the general formula (XI) :
(wherein Ⓑ, X2, and D have the same meanings as defined above)
providing that when A in the general formula ( X ) is a hydrogen atom, Ⓑ is or or 
D is 
to react upon said substituted benzyl triphenyl (or tributyl) phosphoran.
17. A process for the production of a compound represented by the general formula (Ig) :
{wherein A stands for a hydrogen atom, a phenyl group, or a phenoxy group; n for an integer of the value of 3 to 10; R1 for a hydrogen atom or a lower alkoxy group; X1 for a group represented by -CH2CH2-, -CH=CH-, -CH2-Y1- ( wherein Y1 stands for -O-, -S-, or -NH-) , -Y1-CH2-, -CO-Y2- (wherein Y2 stands for
-NH-, -CH2-Y1-, or -Y1-CH2-), or -Y2-CO-; Ⓑ for a group represented by
a cyano group, an oxaloamide group (-NHCOCOOH) , a lower alkoxycarbonyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxy-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio-lower alkyl group, a halo-lower alkyl group, a carboxy-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of (wherein R4 and R5 , which may be the same or different, each stands f 
or a hydrogen atom, a lower alkyl gorup, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lowr alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group, or a mono- or di-lower alkylaminocarbonyl group); R3 for a hydrogen atom, a hydroxyl group, or a lower alkoxy group]; and X2 for a group represented by -CH=CH- or -Y3-Y4- (wherein Y3 stands for a single bond, -O-, -S-, or -NH- and Y4 for an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom )}; or a salt thereof, which process is characterized by removing an ester residue fcσm the corresponding ester represented by the general formula (If):
(wherein A, n, R1, X1, B , and X2 have the same meanings as defined above and R7 stands for a lower alkyl group or a lower alkoxyphenyl-lower alkyl group).
18. A process for the production of a compound represented by the general formula (Ih):
{wherein A stands for a hydrogen atom, a phenyl group, or a phenoxy group; n for an integer of the value of 3 to 10; R1 for a hydrogen atom or a lower alkoxy group; X1 for a group represented by -CH2CH2-, -CH=CH-, -CH2-Y1- ( wherein Y1 stands for -O-, -S-, or -NH-) , -Y1-CH2-, -CO-Y2- (wherein Y2 stands for -NH-, -CH2-Y1, or -Y1-CH2-), or -Y2-CO- ; Ⓑ for a group represented by
a lower alkanoyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of (wherein R4 and R5, which may be the same or 
different, each stands for a hydrogen atom, a lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group, or a mono- or di-lower alkyl- aminocarbonyl group); R3 for a hydrogen atom, a hydroxyl group, or a lower alkoxy group]; Y7 for an oxygen atom of a sulfur atom,
Y4 for an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom midway along the length thereof, and D for a carboxyl group, a lower alkoxycarbonyl group, or a group represented by which process is charaterized by 
reacting a compound represented by the general formula (XIII):
providing that when A in the general formula (XIII) is a hydrogen atom, Ⓑ is or or 
D is 
with a compound represented by the general formula (XIV):
Z2-Y4-D (XIV)
(wherein Z2 stands for a halogen atom and Y4 and D have the same meanings as defined above).
19. A process for the production of a compound represented by the general formula (Ii):
{wherein A stands for a hydrogen atom, a phenyl group, or a phenoxy group; n for an integer of the value of 3 to 10; R1 for a hydrogen atom or a lower alkoxy group; X1 for a group represented by -CH2CH2-, -CH=CH-, -CH2-Y1- ( wherein Y1 stands for -O-, -S-, or -NH-), -Y1-CH2-, -CO-Y2- (wherein Y2 stands for -NH-, -CH2-Y1-, or -Y1-CH2-), or -Y2-CO-, Ⓑ for a group represented by
[where R2 stands for a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a lower alkoxy group, a carboxy group, a cyano group, an oxaloamide group (-NHCOCOOH) , a lower alkoxy-carbonyl group, a lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxy-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio-lower alkyl group, a halo-lower alkyl group, a carboxy-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of (wherein R4 and R5, which may be the same or different, 
each stands for a hydrogen atom, a lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group, or a mono- or di-lower alkylaminocarbonyl group)
R3 for a hydrogen atom, a hydroxyl group, or a lower alkoxy group]
X2 for a group represented by -CH=CH- or -Y3-Y4- (wherein Y3 stands for a single bond, -O-, -S-, or -NH- and Y for an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom , which process is characterized by reacting sodium axide with a compound represented by the general formula (XV) :
(wherein A, n, R1, X1, Ⓑ, and X2 have the same meanings as defined above).
20. A process for the production of a compound represented by the general formula (I) :
[ wherein R2 stands for a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a lower alkoxy group, a carboxyl group, a cyano group, an oxaloamide group (-NHCOCOOH) , a lower alkoxycarbonyl group, a lower alkyl group, a hydroxyl-lower alkyl group, a lower alkoxy-lower alkyl group, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a carboxy-lower alkylthio-lower alkyl group, a lower alkoxycarbonyl-lower alkylthio-lower alkyl group, a halo-lower alkyl group, a carboxy- lower alkoxy group, a lower alkoxycarbonyl-lower alioxy group, a lower alkanoyl-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxycarbonyl-lower alkoxy group, a lower alkanoyl group, or a group of the formula of (wherein R4 and R5, which may be the same or 
different, each stands for a hydrogen atom, a lower alkyl gorup, a carboxy-lower alkyl group, a lower alkoxycarbonyl-lower alkyl group, a lower alkanoyl group, a carboxy-lower alkanoyl group, a lower alkoxycarbonyl-lower alkanoyl group, a substituted or unsubstituted phenyl-lower alkoxycarbonyl-lower alkanoyl group, a carbamoyl group, a lower alkoxalyl group, or a mono- or di-lower alkyl- aminocarbonyl group) ; R3 for a hydrogen atom, a hyroxyl group, or a lower alkoxy group]; X2 for a group represented by -CH=CH- or -Y3-Y4- ( wherein Y3 stands for a single bond, -O-, -S-, or -NH- and Y4 for an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom) and D for a carboxyl group, a lower alkoxycarbonyl group, or a group represented by which process is characterized by 
reacting a compound represented by the general formula (XVII) :
(wherein M2 stands for a hydrogen atom or an alkali metal atom,R1, X1, Ⓑ, X2, and D have the same meanings as defined above) with a substituted alkyl halide represented by the general formula (XVIII):
A-(CH2)n-Z2 (XVIII)
(wherein A and n have the same meanings as defined above and Z2 stands for a halogen atom)
providing that when A in the general formula (XVIII) is a hydrogen atom, Ⓑ is 
D is 
21. A process according to Claim 8, wherein A is a hydrogen atom or a phenyl group; n is an integer of the value of 4 to 7, R1 is a hydrogen atom, X1 is -CO-Y2- (wherein Y2 is -NH-) , Ⓑ is
(wherein R2 is a hydrogen atom, a halogen atom, a nitro 
group, a lower alkyl group, or a carboxy-lower alkyl group) or
X2 is -CH=CH- or -Y3-Y4- (wherein Y3 is a single bond, 
-O-, or -S- and Y4 is an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom); and R7 is a lower alkyl group.
22. A process according to Claim 10, wherein A is a hdyrogen atom or a phenyl group ; n is an integer of the value of 4 to 7; R1 is a hydrogen atom; X1 is -CO-Y2- (wherein Y2 is -NH-) ; Ⓑ is
(wherein R2 is a hydrogen atom, a halogen atom, a nitro 
group, or a lower alkyl group) and X2 is -Y3-Y4- (wherein Y3 is a single bond, -O- or -S-, Y4 is an alkylene group of 1 to 6 carbon atoms which may be interrupted by a sulfur atom).
23. A process according to Claim 8, wherein said compound of the general formula (If) is ethyl-4-chloro-2-[p-(4-phenylbutoxy)- benzamide]-phenoxyacetate.
24. A process according to Claim 8, wherein said compound of the general formula (If) is ethyl-3-[o-{p-(4-phenylbutoxy)benzamide}- phenyl]propionate.
25. A process according to Claim 8, wherein said compound of the general formual (If) is ethyl-o-[p-(4-phenylbutoxy)benzamide]- cinnamate.
26. A process according to Claim 8, wherein said compound of the general formula (If) is ethyl-o-[p-(4-phenylbutoxy)benzamide]- phenoxyacetate.
27. A process according to Claim 8, wherein said compound of the general formula (If) is ethyl-4-nitro-2-[p-(4-phenylbutoxy)-benzmide]phenoxyacetate.
28. A process according to Claim 8, wherein said compound of the general formula (If) is ethyl-4-methy1-2[p-(4-phenylbutoxy)-benzamide]-phenoxyacetate.
29. A process according to Claim 10, wherein said compound of the general formula (XV) is p-heptyloxy-N-(o-cyanomethoxyphenyl)-benzamide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR860700851A KR870700064A (en) | 1985-04-03 | 1986-12-01 | Phenylene derivatives |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60/70566 | 1985-04-03 | ||
| JP7056685 | 1985-04-03 | ||
| JP29709685 | 1985-12-26 | ||
| JP60/297096 | 1985-12-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1986005779A1 true WO1986005779A1 (en) | 1986-10-09 |
Family
ID=26411704
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1986/000155 WO1986005779A1 (en) | 1985-04-03 | 1986-03-31 | Phenylene derivatives |
Country Status (5)
| Country | Link |
|---|---|
| US (2) | US4994479A (en) |
| EP (1) | EP0218728A1 (en) |
| KR (1) | KR870700064A (en) |
| CA (1) | CA1273940A (en) |
| WO (1) | WO1986005779A1 (en) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0294035A2 (en) * | 1987-06-04 | 1988-12-07 | Ono Pharmaceutical Co., Ltd. | Benzoylaminophenoxybutanoic acid derivatives |
| AP83A (en) * | 1987-10-19 | 1990-05-01 | Pfizer | Substituted tetralins, chromans and related compounds in the treatment of asthma, arthtitits and related diseases. |
| US5159097A (en) * | 1988-05-13 | 1992-10-27 | Bayer Aktiengesellschaft | Alkenoic acid derivatives |
| WO1993016053A1 (en) * | 1992-02-13 | 1993-08-19 | Rotta Research Laboratorium S.P.A. | Novel bistetrazol derivatives having an antiallergic and cytoprotective activity |
| US5446058A (en) * | 1984-08-20 | 1995-08-29 | Ono Pharmaceutical Co., Ltd. | (Fused) benz(thio)amides |
| WO1999007357A1 (en) * | 1997-08-08 | 1999-02-18 | Ono Pharmaceutical Co., Ltd. | η-TYPE REGULATORS FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR |
| WO2001000566A2 (en) * | 1999-06-25 | 2001-01-04 | The Institutes For Pharmaceutical Discovery, Llc | Substituted phenoxyacetic acids |
| US6462069B2 (en) | 2000-04-18 | 2002-10-08 | Agouron Pharmaceuticals, Inc. | Compounds, pharmaceutical compositions, and methods for inhibiting protein kinases |
| US6531491B1 (en) | 1999-07-02 | 2003-03-11 | Agouron Pharamaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| US6620828B2 (en) | 1999-06-04 | 2003-09-16 | Agouron Pharmaceuticals, Inc. | Thiazole compounds and pharmaceutical compositions for inhibiting protein kinases and methods for their use |
| WO2003078409A1 (en) * | 2002-03-19 | 2003-09-25 | Ono Pharmaceutical Co., Ltd. | Carboxyoic acid compounds and drugs containing the compounds as the active ingredient |
| WO2005028455A1 (en) * | 2003-09-17 | 2005-03-31 | Ono Pharmaceutical Co., Ltd. | Carboxylic acid compounds and medicinal compositions containing the same as the active ingredient |
| US7141581B2 (en) | 1999-07-02 | 2006-11-28 | Agouron Pharmaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| KR101152495B1 (en) * | 2003-09-17 | 2012-06-01 | 오노 야꾸힝 고교 가부시키가이샤 | Carboxylic Acid Compounds and Pharmaceutical Compositions Containing These As Active Ingredients |
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| US12016860B2 (en) | 2021-04-08 | 2024-06-25 | Nurix Therapeutics, Inc. | Combination therapies with Cbl-b inhibitor compounds |
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| DE4227878A1 (en) * | 1992-08-22 | 1994-02-24 | Philips Patentverwaltung | Shielding cover for SQUID magnetometer against electromagnetic interference fields |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5446058A (en) * | 1984-08-20 | 1995-08-29 | Ono Pharmaceutical Co., Ltd. | (Fused) benz(thio)amides |
| US5459134A (en) * | 1984-08-20 | 1995-10-17 | Ono Pharmaceutical Co., Ltd. | (Fused) benz (thio) amides |
| EP0294035A2 (en) * | 1987-06-04 | 1988-12-07 | Ono Pharmaceutical Co., Ltd. | Benzoylaminophenoxybutanoic acid derivatives |
| EP0294035A3 (en) * | 1987-06-04 | 1990-02-28 | Ono Pharmaceutical Co., Ltd. | Benzoylaminophenoxybutanoic acid derivatives |
| AP83A (en) * | 1987-10-19 | 1990-05-01 | Pfizer | Substituted tetralins, chromans and related compounds in the treatment of asthma, arthtitits and related diseases. |
| US5159097A (en) * | 1988-05-13 | 1992-10-27 | Bayer Aktiengesellschaft | Alkenoic acid derivatives |
| WO1993016053A1 (en) * | 1992-02-13 | 1993-08-19 | Rotta Research Laboratorium S.P.A. | Novel bistetrazol derivatives having an antiallergic and cytoprotective activity |
| WO1999007357A1 (en) * | 1997-08-08 | 1999-02-18 | Ono Pharmaceutical Co., Ltd. | η-TYPE REGULATORS FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR |
| US6620828B2 (en) | 1999-06-04 | 2003-09-16 | Agouron Pharmaceuticals, Inc. | Thiazole compounds and pharmaceutical compositions for inhibiting protein kinases and methods for their use |
| WO2001000566A3 (en) * | 1999-06-25 | 2002-02-07 | Inst For Pharm Discovery Inc | Substituted phenoxyacetic acids |
| US6420426B1 (en) | 1999-06-25 | 2002-07-16 | The Institute For Pharmaceutical Discovery Llc | Substituted phenoxyacetic acids |
| JP2003503381A (en) * | 1999-06-25 | 2003-01-28 | ザ インスティテューツ フォア ファーマスーティカル ディスカヴァリー エルエルシー | Substituted phenoxyacetic acid |
| WO2001000566A2 (en) * | 1999-06-25 | 2001-01-04 | The Institutes For Pharmaceutical Discovery, Llc | Substituted phenoxyacetic acids |
| US6531491B1 (en) | 1999-07-02 | 2003-03-11 | Agouron Pharamaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| US6534524B1 (en) | 1999-07-02 | 2003-03-18 | Agouron Pharmaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| US7141587B2 (en) | 1999-07-02 | 2006-11-28 | Agouron Pharmaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| US7141581B2 (en) | 1999-07-02 | 2006-11-28 | Agouron Pharmaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| US6884890B2 (en) | 1999-07-02 | 2005-04-26 | Agouron Pharmaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| US6891044B2 (en) | 1999-07-02 | 2005-05-10 | Agouron Pharmaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for Inhibiting protein kinases, and methods for their use |
| US6462069B2 (en) | 2000-04-18 | 2002-10-08 | Agouron Pharmaceuticals, Inc. | Compounds, pharmaceutical compositions, and methods for inhibiting protein kinases |
| WO2003078409A1 (en) * | 2002-03-19 | 2003-09-25 | Ono Pharmaceutical Co., Ltd. | Carboxyoic acid compounds and drugs containing the compounds as the active ingredient |
| JP2010189431A (en) * | 2002-03-19 | 2010-09-02 | Ono Pharmaceut Co Ltd | Carboxylic acid compound and drug containing the compound as active ingredient |
| JPWO2003078409A1 (en) * | 2002-03-19 | 2005-07-14 | 小野薬品工業株式会社 | Carboxylic acid compound and drug containing the compound as an active ingredient |
| US7351705B2 (en) | 2002-03-19 | 2008-04-01 | Ono Pharmaceutical Co., Ltd. | Carboxylic acid compounds and a pharmaceutical agent comprising the compound as the active ingredient |
| JP4547913B2 (en) * | 2002-03-19 | 2010-09-22 | 小野薬品工業株式会社 | Carboxylic acid compound and drug containing the compound as an active ingredient |
| US8138335B2 (en) | 2003-09-17 | 2012-03-20 | Ono Pharmaceutical Co., Ltd | Carboxylic acid compounds and medicinal compositions containing the same as the active ingredient |
| US7601712B2 (en) | 2003-09-17 | 2009-10-13 | Ono Pharmaceutical Co., Ltd. | Carboxylic acid compounds and medicinal compositions containing the same as the active ingredient |
| WO2005028455A1 (en) * | 2003-09-17 | 2005-03-31 | Ono Pharmaceutical Co., Ltd. | Carboxylic acid compounds and medicinal compositions containing the same as the active ingredient |
| KR101152495B1 (en) * | 2003-09-17 | 2012-06-01 | 오노 야꾸힝 고교 가부시키가이샤 | Carboxylic Acid Compounds and Pharmaceutical Compositions Containing These As Active Ingredients |
| CN107922353A (en) * | 2015-06-26 | 2018-04-17 | 百时美施贵宝公司 | IDO inhibitor |
| US20190002402A1 (en) * | 2015-06-26 | 2019-01-03 | Bristol-Myers Squibb Company | Ido inhibitors |
| US10689331B2 (en) * | 2015-06-26 | 2020-06-23 | Bristol-Myers Squibb Company | IDO inhibitors |
| US20220324835A1 (en) * | 2018-01-26 | 2022-10-13 | Nurix Therapeutics, Inc. | Inhibitors of cbl-b and methods of use thereof |
| WO2020262603A1 (en) | 2019-06-28 | 2020-12-30 | 小野薬品工業株式会社 | Ep2 antagonist |
| US12016860B2 (en) | 2021-04-08 | 2024-06-25 | Nurix Therapeutics, Inc. | Combination therapies with Cbl-b inhibitor compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| CA1273940A (en) | 1990-09-11 |
| EP0218728A1 (en) | 1987-04-22 |
| KR870700064A (en) | 1987-02-28 |
| US4994479A (en) | 1991-02-19 |
| US5116853A (en) | 1992-05-26 |
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