Arylsulfonamide derivative and pharmaceutical compositions and use thereof

TECHNICAL FIELD
The present invention relates to a novel arylsulfonamide derivative having antagonism specific to a thromboxane A.sub.2 receptor and a pharmaceutical composition, particularly, a thromboxane A.sub.2 antagonist, containing said arylsulfonamide derivative as an effective ingredient.
BACKGROUND ART
It is known that thromboxane A.sub.2 (TxA.sub.2) is an autacoid synthesized in cells such as platelets and exhibits a strong platelet agglutination of platelets, constriction of smooth muscle or the like. Accordingly, it is suggested that a TxA.sub.2 receptor antagonist would be effective in the treatment and prevention of diseases relating to TxA.sub.2 action [Japanese Unexamined Patent Publication (Kokai) No. 4-257556, Japanese Examined Patent Publication (Kokoku) No. 57-35910 and so on]. As examples of such diseases, there may be mentioned cardiac infarction, cerebral infarction, pneumobstruction, thrombosis, renal insufficiency, gestational toxemia and asthma due to bronchoconstriction. Efficacy is expected in the treatment and prevention of various diseases as mentioned above, and thus, development of more excellent novel TxA.sub.2 receptor antagonists was desired.
DISCLOSURE OF INVENTION
Under the circumstances, the inventors of the present invention first analyzed and considered the three-dimensional structural elements of TxA.sub.2 and TxA.sub.2 receptor antagonists by means of the techniques of computer graphics and molecular force field calculation. Then, various compounds, which were designed using the techniques of computer graphics and molecular force field calculation, in view of the above results, were synthesized. Further, the physiological activities of various synthesized compounds were evaluated to find novel arylsulfonamide derivatives having TxA.sub.2 receptor antagonism, and the present invention was completed.
Accordingly, the present invention relates to an arylsulfonamide derivative of the general formula (I): ##STR2## wherein R.sup.1 is an unsubstituted phenyl or naphthyl group, or a phenyl group substituted by 1 to 3 (preferably 1 or 2) same or different substituents selected from the group consisting of a halogen atom, alkyl group (preferably straight or branched alkyl group with 1 to 10, more preferably 1 to 3 carbon atoms), nitro group and alkoxy group (preferably straight or branched alkoxy group with 1 to 10, more preferably 1 to 3 carbon atoms), R.sup.2 is a straight, branched, or branched cyclic alkyl group with 1 to 15 (preferably 1 to 8) carbon atoms, phenyl, phenyloxyl group, phenyloxy group substituted by one or more halogen atoms, cycloalkyl group with 5 to 7 carbon atoms (preferably, cyclohexyl group), indolyl group (preferably, 3-indolyl group), alkylthiol group with 1 to 4 (preferably 1 to 2) carbon atoms, hydroxyl group, protected hydroxyl group (for example, tetrahydropyranyloxy, preferably 2-tetrahydropyranyloxy group), imidazolyl group (preferably, 1-imidazolyl group), pyridyloxyl group (preferably, 3-pyridyloxy group), or --OSO.sub.2 R.sup.4 group, R.sup.4 is a straight or branched alkyl group with 1 to 15 (preferably, 1 to 8, more preferably 1 to 3) carbon atoms, or unsubstituted phenyl or thienyl group, or a phenyl or thienyl group substituted by 1 to 3 same or different substituents selected from the group consisting of a halogen atom, alkyl group (preferably straight or branched alkyl group with 1 to 10, more preferably 1 to 3 carbon atoms), nitro group and alkoxy group (preferably straight or branched alkoxy group with 1 to 10, more preferably 1 to 3 carbon atoms), R.sup.3 is a hydrogen atom or straight or branched alkyl group with 1 to 20 (preferably 1 to 5, more preferably 1 to 3) carbon atoms, n is an integer of 0 to 10 (preferably 0 to 2), p is an integer of 0 to 10 (preferably 0 or 1), X is a group of the general formula
--(CH.sub.2)m-A-(CH.sub.2)q-,
m and q are independently an integer of 0 to 8 (preferably 0 to 5), and A is a direct bond or phenylene group (that is, 1,2-, 1,3- or 1,4-phenylene group), or a salt thereof.
Further, the present invention relates to a pharmaceutical composition, particularly an antagonist to thromboxane A.sub.2, characterized by containing an arylsulfonamide derivative of the above-mentioned general formula (I) or pharmaceutically acceptable salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
In the present specification, the straight or branched alkyl group means, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, or the like.
The branched cyclic alkyl group is, for example, an alkyl group with 1 to 9 carbon atoms substituted by a cycloalkyl group with 5 to 7 carbon atoms, for example, 1-cyclopentylmethyl, 2-cyclopentylethyl, 1-cyclohexylmethyl or 2-cyclohexylethyl group. The cycloalkyl group with 5-7 carbon atoms is cyclopentyl, cyclohexyl, or cycloheptyl group.
As the alkoxy group, there may be mentioned, for example, a straight or branched alkoxy group, such as, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy, n-hexanoxy, or the like. The alkylthio group is, for example, methylthiol or ethylthiol group. As the halogen atom, there may be mentioned, for example, fluorine, chlorine, bromine, or iodine atom.
The protected hydroxyl group is, for example, tetrahydropyranyloxy group.
In the above-mentioned general formula (i), phenyl or naphthyl group as the group R.sup.1 may be unsubstituted or mono-, di-, or tri-substituted. The substituents may be the same or different.
The preferable compounds of the above-mentioned general formula (I) are the compounds wherein R.sup.1 is an unsubstituted phenyl or naphthyl group, or a phenyl group substituted by 1 to 3 same or different substituents selected from the group consisting of a halogen atom, straight or branched alkyl group with 1 to 10 carbon atoms, nitro group and straight or branched alkoxy group with 1 to 10 carbon atoms, R.sup.2 is a straight, branched or branched cyclic alkyl group with 1 to 8 carbon atoms, phenyl, phenyloxy, phenyloxy group substituted by one or more halogen atoms, cyclohexyl, indolyl, alkylthiol groups with 1 to 3 carbon atoms, hydroxyl, tetrahydropyranyloxy, imidazolyl, pyridyloxy or --OSO.sub.2 R.sup.4 group, R.sup.4 is a straight or branched alkyl group with 1 to 8 carbon atoms, R.sup.3 is a hydrogen atom or straight or branched alkyl group with 1 to 5 carbon atoms, n is an integer of 0 to 2, p is 0 or 1, X is a group of the general formula
--(CH.sub.2)m-A-(CH.sub.2)q-,
m and q are independently an integer of 0 to 5, and A is a direct bond or 1,2-, 1,3-, or 1,4-phenylene group.
Further, the preferable compounds of the above-mentioned general formula (I) are the compounds in which R.sup.1 is an unsubstituted phenyl or naphthyl group or a phenyl group substituted by 1 or 2 same or different substituents selected from the groups consisting of a halogen atom, straight alkyl group with 1 to 2 carbon atoms, nitro group and straight alkoxy group with 1 to 2 carbon atoms, R.sup.2 is a straight or branched alkyl group with 1 to 6 carbon atoms, phenyl, phenyloxy, phenyloxy group substituted by one or more halogen atoms, cyclohexyl, 3-indolyl, alkylthio group with 1 to 2 carbon atoms, hydroxyl, 2-tetrahydropyranyloxy, 1-imidazolyl, 3-pyridyloxy or --OSO.sub.2 CH.sub.3 group, R.sup.3 is a hydrogen atom or alkyl group with 1 to 3 carbon atoms, n is an integer of 0 to 2, p is 0 or 1, X is a group of the general formula
--(CH.sub.2)m-A-(CH.sub.2)q-,
m and q are independently an integer of 0 to 5, and A is a direct bond or 1,3- or 1,4-phenylene group.
The compound of the formula (I) according to the present invention may be one of geometrical isomers, optical isomers or tautomers. One of the above isomers or a mixture thereof is involved in the scope of present invention.
The salts of the arylsulfonamide derivatives of the present invention are not particularly limited, but are preferably pharmaceutically acceptable salts. When the group R.sup.2 is 1-imidazolyl or 3-pyridyloxy group in the general formula (I), an acid addition salt may be formed, and when the group R.sup.3 is a hydrogen atom, a salt wherein the hydrogen atom is replaced by a metal ion or organic base may be formed.
Pharmaceutically acceptable acid addition salts are, for example, salts containing a pharmaceutically acceptable anion with organic and inorganic acid, such as hydrochloric, hydrobromic, sulfuric, sulfurous, phosphoric, phosphorous, acetic, maleic, fumaric, lactic, tataric, citric, gluconic, succinic, benzoic, or p-toluene sulfonic acid, and the like.
Preferable metal salts are salts of alkali metals such as lithium, sodium or potassium, or alkali earth metals such as calcium or magnesium.
Preferable salts of organic bases are salts of triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, n-butyldimethylamine, tri-n-butylamine, dicyclohexylamine, morpholine, N-methylmorpholine, tromethamine, or the like.
The arylsulfonamide derivative of the general formula (I) of the present invention may be prepared by various methods. A typical process of preparation will be explained hereinafter.
(1) A process wherein a sulfonylaminocarboxylic acid compound of the general formula (II): ##STR3## wherein R.sup.21 is a straight, branched or branched cyclic alkyl group with 1 to 15 carbon atoms, phenyl group, cycloalkyl group with 5 to 7 carbon atoms, indolyl group, alkylthio group with 1 to 4 carbon atoms, protected hydroxyl group, or imidazolyl group, and R.sup.1, n, and p have the same meanings as the above, is used as a starting material.
The sulfonylaminocarboxylic acid compound of the general formula (II) is reacted with an amino acid ester compound of the general formula (III):
H.sub.2 N--X--COO--R.sup.31 (III )
wherein R.sup.31 is a straight or branched alkyl group with 1-20 (preferably 1 to 5, more preferably 1 to 3) carbon atoms, and X has the same meaning as above, for example, in an appropriate solvent (for example, chloroform), in the presence of appropriate condensation agent (for example, pivaloyl chloride, 2-chloro-1-methylpyridinium iodide, N,N'-dicyclohexylcarbodiimide) and appropriate base (for example, triethylamine) to obtain an arylsulfonamide derivative of the general formula (I), wherein R.sup.2 is the group R.sup.21, R.sup.3 is the group R.sup.31, and then, the group R.sup.21 and/or R.sup.31 may be converted into another group R.sup.2 and/or R.sup.3 by a known method.
A sulfonylaminocarboxylic acid compound of the general formula (II) in which R.sup.21 is a protected hydroxyl group may be prepared by protecting the OH group of the --(CH.sub.2)n-OH group of the sulfonylaminocarboxylic acid compound of the general formula (IV): ##STR4## wherein R.sup.1, n and p have the same meanings as the above. The OH group may be protected by a known method. For example, a sulfonylaminohydroxycarboxylic acid of the general formula (IV) may be treated with dihydropyran in an appropriate solvent (for example, chloroform) in the presence of an appropriate acid catalyst (for example, p-toluenesulfonic acid) to convert the OH group of the --(CH.sub.2)n-OH group in the general formula (IV) to tetrahydropyranyl and obtain a sulfonylaminocarboxylic acid compound of the general formula (II) wherein R.sup.21 is 2-tetrahydropyranyloxy group (hereinafter, sometimes referred to as OTHP). The resulting sulfonylaminocarboxylic acid compound may be reacted in the same reaction vessel with an amino acid ester of the general formula (III).
The arylsulfonamide derivative obtained by the above-mentioned method of the general formula (I) wherein R.sup.2 is a protected hydroxyl group (for example, OTHP) may be hydrolyzed in a an appropriate solvent (for example, aqueous ethanol) in the presence of a an appropriate acid catalyst [for example, p-toluenesulfonic acid, pyridinium p-toluenesulfonate (hereinafter referred to as PPTS)], to obtain an arylsulfonamide derivative of the general formula (I) wherein R.sup.2 is hydroxyl group.
Further, the arylsulfonamide derivative obtained by hydrolysis of the general formula (I) wherein R.sup.2 is OH may be sulfonated by treatment with methanesulfonyl chloride in an appropriate solvent (for example, chloroform) in the presence of an appropriate base (for example, pyridine or triethylamine) to obtain an arylsulfonamide derivative of the general formula (I) wherein R.sup.2 is --OSO.sub.2 R.sup.4 (for example, --OSO.sub.2 CH.sub.3).
Further, the arylsulfonamide derivative obtained by sulfonation of the general formula (I) wherein R.sup.2 is --OSO.sub.2 R.sup.4 may be condensed with imidazole in an appropriate solvent [for example, dimethylformamide (hereinafter referred to as DMF)] in the presence of an appropriate base (for example, NaH), to obtain an arylsulfonamide derivative of the general formula (I) wherein R.sup.2 is an imidazolyl group.
Further, the arylsulfonamide derivative obtain by sulfonation of the general formula (I) wherein R.sup.2 is --OSO.sub.2 R.sup.4 may be condensed with 3-hydroxypyridine in an appropriate solvent (for example, DMF) in the presence of an appropriate base (for example, NaH), to obtain an arylsulfonamide derivative of the general formula (I) wherein R.sup.2 is a pyridyloxyl group.
Further, the arylsulfonamide derivative obtained by sulfonation of the general formula (I) wherein R.sup.2 is --OSO.sub.2 R.sup.4 may be condensed with phenol or phenol substituted by one or more halogen atoms in an appropriate solvent (for example, DMF) in the presence of an appropriate base (for example, NaH) to obtain an arylsulfonamide derivative of the general formula (I) wherein R.sup.2 is a phenyloxy group or a phenyloxy group substituted by one or more halogen atoms.
(2) A process wherein the carbonylaminocarboxylic acid compound of the general formula (v): ##STR5## wherein R.sup.5 is a straight or branched alkyl group with 1 to 20 carbon atoms, or unsubstituted benzyl group or a benzyl group substituted by 1 to 3 same or different substituents selected from the group consisting of a halogen atom, alkyl group (preferably, straight or branched alkyl group with 1 to 6 carbon atoms), nitro group, alkoxy group (preferably straight or branched alkoxy group with 1 to 6 carbon atoms) or hydroxyl group, R.sup.21, n and p have the same meanings as above, is used as a starting material.
The carbonylaminocarboxylic acid compound of the general formula (V) may be reacted with the amino acid ester compound of the general formula (III):
H.sub.2 N--X--COO--R.sup.31 (III)
wherein R.sup.31 and X have the same meanings as above, in the presence of, for example, an appropriate condensing agent (for example, pivaloyl chloride, 2-chloro-1-methylpyridinium iodide, N,N'-dicyclohexylcarbodiimide) and an appropriate base (for example, triethylamine) to obtain a carbonylamine derivative of the general formula (VI): ##STR6## wherein R.sup.5, R.sup.21, R.sup.31 and X have the same meanings as above.
Then, the carbonylamine derivative of the general formula (VI) obtained by condensation reaction may be hydrogenolyzed in the presence of, for example, an appropriate catalyst (for example, palladium-carbon) to remove the R.sup.5 --O--CO--group and obtain an amine derivative of the general formula (VII): ##STR7## wherein R.sup.5, R.sup.21, R.sup.31 and X have the same meanings as above, and then, the resulting derivative may be sulfonated with an appropriate sulfonating agent (for example, p-chlorobenzenesulfonyl chloride or toluenesulfonyl chloride) in an appropriate solvent (for example, chloroform) in the presence of an appropriate base (for example, pyridine, triethylamine) to produce an arylsulfonamide derivative of the general formula (I) wherein R.sup.2 is the group R.sup.21 and R.sup.3 is the group R.sup.31, and then, convert the group R.sup.21 and/or R.sup.31 by a known method to another group R.sup.2 and/or R.sup.3.
A carbonylaminocarboxylic acid compound of the general formula (V) wherein R.sup.21 is a protected hydroxyl group may be prepared by protecting the OH group of the --(CH.sub.2)n-OH group of the carbonylaminohydroxycarboxylic acid compound of the general formula (VIII): ##STR8## wherein R.sup.5, n and p have the same meanings as the above. The OH group may be protected by a known method. For example, the carbonylaminohydroxycarboxylic acid compound of the general formula (IV) may be treated with dihydropyran in an appropriate solvent (for example, chloroform) in the presence of an appropriate acid catalyst (for example, p-toluenesulfonic acid) to convert the OH group of the --(CH.sub.2)n-OH group in the general formula (VIII) to tetrahydropyranyl and produce a carbonylaminocarboxylic acid compound of the general formula (V) wherein R.sup.21 is 2-tetrahydropyranyloxy group. The resulting carbonylaminocarboxylic acid compound may be reacted in the same reaction vessel with the amino acid ester of the general formula (III).
If desired, the ester of the arylsulfonamide derivative of the general formula (I) wherein R.sup.3 is an alkyl group may be hydrolyzed, in an appropriate solvent (for example, ethanol or methanol) by treatment with an appropriate base (for example, sodium hydroxide or potassium carbonate), and then, treated by an ordinary method to obtain an arylsulfonamide derivative of the general formula (I) wherein R.sup.3 is a hydrogen atom, that is a derivative having a free carboxyl group. If desired, the arylsulfonamide derivative having the free carboxyl group of the general formula (I) wherein R.sup.3 is H may be treated with one equivalent of an appropriate base (for example, sodium hydroxide, potassium hydroxide, triethylamine, 2-aminobutane, tert-butylamine or diisopropylethylamine) in an appropriate solvent (for example, ethanol or methanol) to obtain a salt of a metal or organic base.
The arylsulfonamide derivative of the general formula (I) according to the present invention was evaluated for physiological activities in the working Examples by the following methods to find remarkable advantages:
(1) measurement of TxA.sub.2 antagonism by binding assay,
(2) measurement of inhibitory activity of vasoconstriction, and
(3) measurement of inhibitory activity of platelet agglutination.
Accordingly, an arylsulfonamide derivative of the general formula (I) according to the present invention exhibits an antagonism specific to a TxA.sub.2 receptor and can be used as an effective ingredient of a pharmaceutical composition on the basis of its TxA.sub.2 receptor antagonism, inhibitory action of vasoconstriction or platelet agglutination. Specifically, for example, there may be mentioned cardiac infarction, cerebral infarction, pneum-obstruction, thrombosis, gestational toxemia, renal insufficiency and asthma due to bronchoconstrictive action. Further, the above derivative is effective for prevention of vasoconstriction followed by subarachnoid hemorrhage, prevention of shock due to TxA.sub.2 after arterial re-perfusion of the circulatory or digestive system, large amount of blood loss, septicemia, trauma, cardiac function failure, endotoxins, acute pancreatitis or burns, or prevention of reduction of platelets in extracorporeal circulation.
The arylsulfonamide derivative of the general formula (I) used as the effective ingredient in the pharmaceutical composition of the present invention includes all pure stereo isomers and a mixture thereof in any ratio, and further include a pharmaceutically acceptable salt thereof.
The pharmaceutical composition of the present invention may be administered oral by or parenterally, for example, intravenously, subcutaneously, per rectum, or percutaneously. Depending on its administration route, the composition may be formulated into an oral agent, injection, inhalant, suppository, and the like. When administered orally, the composition may be used as a normal preparation, for example, solid preparations, such as tablets, dispersions, capsules, or granules, liquid preparations, such as aqueous or oil suspensions, syrups, elixers. When administered parenterally, the composition may be used as aqueous or oil injection, or suppositories.
The pharmaceutical composition of the present invention may contain, in addition to the above-mentioned effective ingredient, a pharmaceutically acceptable diluent or carrier. As the diluent or carrier, for example, any of ordinary excipients, binding agents, lubricants, aqueous solvents, oil solvent, emulsifying agent, suspending agent, or the like may be used. Further, other additives, such as, preservatives or stabilizers may be contained. The dose of the effective ingredient varies with the desired therapeutic effect, the method of administration, age, body weight, or the like, and cannot be determined generally. However, in the case of oral administration, the dose is usually approximately 0.1 mg to approximately 500 mg, preferably approximately 0.5 mg to approximately 2000 mg, per day per 1 kg body weight for adult, and in the case of parenteal administration, the dose is approximately 0.001 mg to approximately 500 mg, preferably approximately 0.5 mg to approximately 100 mg per day per 1 kg body weight for adult. The dose may be divided into 1 to 5 dosages.

EXAMPLES
The present invention now will be illustrated by, but by no means limited to, the following Examples.
Example 1
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide
Dihydropyran (245 .mu.l), p-toluene sulfonic acid (20 mg) and chloroform (5 ml) were successively added to a solution of (S)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (500 mg) in THF (5 ml). The mixture was stirred at room temperature for 4 hours under argon. Triethylamine (327 .mu.l) and pivaloyl chloride (241 .mu.l) were added to the reaction mixture. After stirring for 30 minutes, ethyl p-aminobenzoate (345 mg) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated saline solution, and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure to obtain 1.27 g of a yellow oil. The crude product was purified by column chromatography (silica gel=23 g, hexane/ethyl acetate=5/2) to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (595 mg).
IR .nu.max cm.sup.-1 (KBr): 3359, 3205, 1710, 1693, 1278, 1168
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.38 (3H, t, J=7 Hz), 1.4-1.8 (6H, m), 3.3-4.1 (4H, m), 4.35 (2H, q, J=7 Hz), 4.40 (1H, m), 7.3-7.7 (4H, m), 7.85 (2H, d, J=8.5 Hz), 7.97 (2H, d, J=8.5 Hz)
Fab-MS m/z: 514, 513, 512, 511 (MH.sup.+), 510, 427
Example 2
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (2.7 g) and ethyl p-aminobenzoate (2.13 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (3 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.962 g).
IR .nu.max cm.sup.-1 (KBr): 3359, 1710, 1693, 1278, 1168
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.38 (3H, t, J=7 Hz), 1.4-1.8 (6H, m), 3.3-4.1 (4H, m), 4.35 (2H, q, J=7 Hz), 4.40 (1H, m), 7.3-7.7 (4H, m), 7.85 (2H, d, J=8.5 Hz), 7.97 (2H, d, J=8.5 Hz)
Fab-MS m/z: 514, 513, 512, 511 (MH.sup.+), 510, 427
Example 3
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (1.4 ml) and ethyl p-aminophenyl acetate (2.02 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (2.8 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (3.4 g).
Melting point: 100.degree.-110.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3359, 1734, 1672, 1338, 1168
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.242 (3H, t, J=7.2 Hz), 1.35-1.9 (6H, m), 3.50 (2H, m), 3.569 (2H, s), 3.714 (1H, dd, J=12.8 Hz, J=9.2 Hz), 3.95 (2H, m), 4.137 (2H, q, J=7.2 Hz), 4.40 (1H, m), 7.230 and 7.238 (2H, d, J=8.5 Hz), 7.394 and 7.444 (2H, d, J=8.5 Hz), 7.484 and 7.504 (2H, d, J=8.5 Hz), 7.834 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.13, 20.56 and 20.75, 24.89 and 25.02, 26.98 and 27.09, 30.61 and 30.89, 40.82, 56.39 and 56.65, 60.85, 64.57 and 64.86, 68.31 and 68.71, 101.08 and 101.81, 119.95 and 120.03, 128.74 and 128.91, 129.45 and 129.61, 129.70 and 129.83, 130.54 and 130.61, 136.10, 137.33 and 137.58, 139.76 and 139.86, 166.53 and 166.72, 171.43
Fab-MS m/z: 525 (MH.sup.+), 524(MH.sup.+), 441 (MH.sup.+ -DHP)
Example 4
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (1.4 ml) and methyl p-aminophenylpropionate (2.15 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (2.8 g) to obtain (RS)-2-(4-chloro-benzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.1 g)
Melting point: 102.degree.-107.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3700-2500(br), 3265, 1736, 1662, 1340, 1164
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.3-1.9 (6H, m), 2.598 (2H, t, J=7.7 Hz), 2.911 (2H, t, J=7.7 Hz), 3.50 (2H, m), 3.660 (3H, s), 3.95 (2H, m), 4.16 (1H, m), 4.42 (1H, m), 7.139 and 7.146 (2H, d, J=8.5 Hz), 7.347 and 7.396 (2H, d, J=8.5 Hz), 7.479 and 7.498 (2H, d, J=8.5 Hz), 7.833 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 20.53 and 20.71, 24.89 and 25.02, 30.34, 30.59 and 30.87, 35.63, 51.57, 56.39 and 56.65, 64.51 and 64.81, 68.29 and 68.71, 101.02 and 101.74, 120.05 and 120.14, 128.74 and 128.80, 128.89, 129.46 and 129.59, 135.35, 137.01 and 137.09, 137.34 and 137.60, 139.75 and 139.82, 166.50 and 166.68, 173.17
Fab-MS m/z: 525 (M.sup.+), 524 (M.sup.+), 441 (MH-DHP)
Example 5
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (1.46 ml) and ethyl m-aminobenzoate (2.13 g) were successively reacted with (S)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (3 g) to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.3 g).
IR .nu.max cm.sup.-1 (KBr): 3336, 1716, 1695, 1288, 1168
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.38 (3H, t, J=7.1 Hz), 1.4-1.8 (6H, m), 3.3-4.1 (5H, m), 4.37 (2H, q, J=7.1 Hz), 4.40 (1H, m), 7.2-7.6 (3H, m), 7.7-7.9 (1H, m), 7.85 (2H, d, J=7.6 Hz), 8.01 (2H, d, J=7.1 Hz), 8.83 (2H, d, J=3.4 Hz)
Fab-MS m/z: 511 (MH.sup.+)
Example 6
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (2.7 g) and m-aminobenzoic acid (2.13 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (3 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.725 g).
IR .nu.max cm.sup.-1 (KBr): 3336, 1716, 1695, 1288, 1168
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.38 (3H, t, J=7.1 Hz), 1.4-1.8 (6H, m), 3.3-4.1 (5H, m), 4.37 (2H, q, J=7.1 Hz), 4.40 (1H, m), 7.2-7.6 (3H, m), 7.7-7.9 (1H, m), 7.85 (2H, d, J=7.6 Hz), 8.01 (2H, d, J=7.1 Hz), 8.83 (2H, d, J=3.4 Hz)
Fab-MSm/z: 511 (MH.sup.+)
Example 7
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-(methoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (0.4 ml) and methyl m-aminophenylacetate (604 mg) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (893 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-(methoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (624 mg).
IR .nu.max cm.sup.-1 (neat): 3336, 1723, 1691, 1346, 1167
Fab-MS m/z: 497 (MH.sup.+), 413
Example 8
Preparation of (RS)-2-(4-Chlorobenzenesulfonylamino)-N-(3-(2-methoxycarbonylethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (2.74 ml) and methyl p-aminophenylpropionate (3.94 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (5.59 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-(2-methoxycarbonylethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (7.60 g).
IR .nu.max cm.sup.-1 (neat): 3340, 1733, 1689, 1344, 1165
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.3-1.9 (6H, m), 2.621 (2H, t, J=7.7 Hz), 2.925 (2H, t, J=7.7 Hz), 3.4-3.6 (2H, m), 3.670 (3H, s), 4.15 (1H, m), 4.44 (2H, m), 6.960 (1H, d, J=7.1 Hz), 7.1-7.4 (3H, m), 7.45-7.75 (2H, m), 7.842 (2H, d, J=8.6 Hz), 8.568 (1H, d, J=15.4 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 20.54, 24.89, 30.61, 35.47, 51.59, 56.46, 64.55, 68.29, 101.06, 117.80, 119.70, 124.66, 137.29, 139.75, 141.60, 166.53, 173.12
Fab-MS M/z: 525 (MH.sup.+), 441(MH.sup.+ -DHP), 85
Example 9
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (1.37 ml) and methyl 4-aminobutanate hydrochloride (1.69 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (2.80 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(tetrahydropyran-2-yloxy)propanamide (3.12 g).
IR .nu.max cm.sup.-1 (neat): 3369, 3292, 1736, 1660, 1340, 1167
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.4-1.9 (6H, m), 1.807 (2H, t, J=7.2 Hz), 2.340 (2H, q, J=7.2 Hz), 3.25 (2H, m), 3.45 (2H, m), 3.682 (3H, s), 3.85 (2H, m), 4.35 (1H, m), 4.10 (1H, m), 6.90 (1H, m), 7.503 (2H, d, J=8.3 Hz), 7.813 (2H, d, J=8.3 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.52, 25.00, 27.53, 30.57, 31.05, 38.94, 51.62, 56.39, 64.46, 68.35, 100.91, 128.71, 129.33, 137.44, 139.64, 168.79, 173.45
Fab-MS m/z: 463 (MH.sup.+), 379 (MH.sup.+ -DHP)
Example 10
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-methoxycarbonylbutyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (2.9 ml) and methyl 5-aminopentanate hydrochloride (2.158 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (3 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-methoxycarbonylbutyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.059 g).
IR .nu.max cm.sup.-1 (neat): 3373, 3305, 2945, 1736, 1655, 1439, 1340, 1167, 1124, 1086
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.259 (2H, t, J=7.1 Hz), 1.4-1.9 (8H, m), 2.329 (2H, t, J=7.1 Hz), 3.1-3.3 (2H, m), 3.3-3.5 (2H, m), 3.673 (3H, s), 3.7-3.9 (2H, m), 4.122 (1H, dd, J=14.4 Hz, J=7.1 Hz), 4.3-4.4 (1H, m), 7.4-7.6 (2H, m), 7.7-7.9 (2H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.15, 20.53, 24.93 and 25.00, 28.74, 30.57 and 30.65, 33.40, 39.23, 56.17 and 56.35, 64.42, 68.31, 100.91 and 101.06, 128.71 and 128.93, 137.44 and 137.84, 139.56 and 139.64, 168.46 and 168.68, 173.74
Fab-MS m/z: 477 (MH.sup.+), 393 (MH.sup.+ -THP)
Example 11
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (2.56 ml) and methyl 6-aminohexanate hydrochloride (3.41 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (4.94 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(tetrahydropyran-2-yloxy)propanamide (0.87 g).
Melting point: 59.degree.-60.degree. C.
IR .nu.max cm.sup.-1 (neat): 3377, 3305, 1736, 1662, 1342, 1167, 754
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.9 (12H, m), 2.310 (2H, t, J=7.4 Hz), 3.230 (2H, dd, J=13.3 Hz, J=6.7 Hz), 3.3-4.2 (5H, m), 3.670 (3H, s), 6.90 (1H, m), 7.490 (2H, d, J=8.3 Hz), 7.813 (2H, d, J=8.3 Hz)
Fab-MS m/z: 491 (MH.sup.+), 407
Example 12
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (1.93 ml) and methyl 7-aminoheptanate hydrochloride (1.679 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (2 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-3-(tetrahydropyran-2-yloxy)propanamide (1. 497 g).
IR .nu.max cm.sup.-1 (neat): 3371, 2941, 2866, 1738, 1660, 1441, 1342, 1167, 1124, 1093
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.4 (4H, m), 1.4-1.8 (10H, m), 2.308 (2H, t, J=7.4 Hz), 3.1-3.3 (2H, m), 3.4-3.5 (2H, m), 3.669 (3H, s), 3.7-3.9 (2H, m), 4.0-4.2 (1H, m), 4.3-4.4 (1H, m), 7.495 (2H, dd, J=8.8 Hz, J=3.7 Hz), 7.812 (2H, dd, J=8.8 Hz, J=1.2 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 20.42, 24.71 and 24.93, 26.25, 27.46 and 27.53, 28.59, 29.07, 30.57 and 30.65, 33.87, 39.56, 50.63, 51.44, 56.17 and 56.39, 64.31 and 64.39, 68.27, 100.87, 128.67 and 128.89, 129.33 and 129.48, 137.51 and 137.84, 139.53 and 139.60, 168.46 and 168.64, 174.18
Fab-MS m/z: 505 (MH.sup.+), 421 (MH.sup.+ -THP)
Example 13
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(7-methoxycarbonylheptyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 1 was repeated, except that dihydropyran (2.9 ml) and methyl 6-aminooctanate hydrochloride (2.699 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (3 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(7-methoxycarbonylheptyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.026 g).
IR .nu.max cm.sup.-1 (neat): 3369, 3305, 2939, 1738, 1660, 1441, 1342, 1167, 1122, 1086
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.4 (6H, m), 1.4-1.8 (10H, m), 2.301 (2H, t, J=7.6 Hz), 3.4-3.6 (2H, m), 3.664 (3H, s), 3.7-3.9 (2H, m), 4.0-4.1 (1H, m), 4.3-4.4 (1H, m), 7.484 (2H, d, J=8.6 Hz), 7.812 (2H, d, J=8.6 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 20.38, 24.71 and 24.89, 26.43, 28.70 and 28.85, 29.14, 30.54 and 30.61, 31.89, 33.91, 39.60, 51.37, 56.10 and 56.28, 63.76, 64.24, 68.24, 100.76 and 100.87, 128.67 and 128.85, 129.26 and 129.44, 137.84, 139.45, 168.39 and 168.57, 174.14
Fab-MS m/z: 519 (MH.sup.+), 435 (MH.sup.+ -THP)
Example 14
Preparation of (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
Dihydropyran (2.27 ml) and p-toluenesulfonic acid (500 mg) were added to a suspension of N-benzyloxycarbonyl-DL-serine (5 g) in chloroform, and the mixture was stirred at room temperature overnight under argon. Triethylamine (11.65 ml), ethyl p-aminophenylacetate hydrochloride (4.5 g) and 2-chloro-1-methylpyridinium iodide (6.4 g) were added to the reaction mixture and the whole was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1N HCl, 5% NaHCO.sub.3, and saturated saline solution, and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel=300 g, hexane/ethyl acetate=20/9) to obtain (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (6.847 g).
IR .nu.max cm.sup.-1 (KBr): 3315, 1734, 1685, 1369, 1159
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.241 (3H, t, J=7.08 Hz), 1.4-1.9 (6H, m), 3.567 (2H, s), 3.5-4.0 (3H, m), 4.135 (2H, q, J=7.08 Hz), 4.61 (1H, m), 5.137 (2H, s), 7.225 (2H, d, J=8.30 Hz), 7.35 (5H, m), 7.453 (2H, d, J=8.30 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.16, 19.98, 25.13, 30.52, 40.82, 60.87, 63.34, 67.23, 68.41, 120.07, 128.11, 128.28, 128.57, 129.81, 130.18, 136.08, 136.57, 156.13, 167.96, 171.53
Fab-MS m/z: 458 (MH.sup.+), 401
Example 15
Preparation of (RS)-2-(benzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
10% palladium-carbon (100 mg) was added to a solution of (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (1 g) in methanol (30 ml), and the mixture was stirred under hydrogen at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in pyridine (3 ml). Benzenesulfonyl chloride (521 .mu.l) was added to the solution, and the mixture was stirred at room temperature overnight under argon. The reaction mixture was poured in 1N HCl and extracted with ethyl acetate. The combined ethyl acetate layers were washed with 1N HCl, 5% NaHCO.sub.3, and a saturated saline solution, and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel=25 g, hexane/ethyl acetate=5/4) to obtain (RS)-2-(benzene-sulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (0.96 g).
Melting point: 113.degree.-122.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3350, 3265, 1736, 1666, 1333, 1166, 729, 688
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.239 (3H, t, J=7.08 Hz), 1.3-1.8 (6H, m), 3.4-3.7 (2H, m), 3.562 (2H, s), 3.8-4.05 (3H, m), 4.136 (2H, q, J=7.08 Hz), 4.3-4.5 (1H, m), 7.2-7.7 (7H, m), 7.903 (2H, d, J=8.3 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.15, 20.53, 30.61, 30.76, 40.81, 56.43, 56.76, 60.83, 64.50, 68.31, 101.06, 101.35, 119.94, 120.02, 127.24, 127.39, 129.18, 129.33, 129.77, 130.43, 130.50, 133.18, 133.25, 136.19, 138.79, 139.05, 166.74, 166.92, 171.47
Fab-MS m/z: 490 (M.sup.+), 407
Example 16
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl) phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-fluorobenzenesulfonyl chloride (1.72 g) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (1.59 g).
Melting point: 117.degree.-119.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3338, 3261, 1732, 1657, 1338, 1171, 1155, 1036, 841
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.246 (3H, t, J=7.08 Hz), 1.3-1.9 (6H, m), 3.4-3.6 (2H, m), 3.567 (2H, s), 3.8-4.0 (3H, m), 4.137 (2H, q, J=7.08 Hz), 4.40 (1H, m), 7.1-7.3 (4H, m), 7.3-7.5 (2H, m), 7.918 (2H, dd, J=9.03 Hz, J=4.88 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.15, 20.56, 20.71, 24.89, 25.00, 30.61, 30.87, 40.81, 56.43, 56.65, 60.86, 64.53, 64.83, 68.27, 68.64, 101.06, 101.75, 116.28, 116.42, 116.61, 116.75, 119.94, 120.02, 129.81, 129.99, 130.14, 130.28, 130.58, 134.87, 135.09, 136.12, 163.47, 166.63, 166.81, 167.25, 171.43
Fab-MS m/z: 508 (M.sup.+), 425
Example 17
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy) propanamide (4.34 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-chlorobenzenesulfonyl chloride (3.87 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (3.07 g).
Melting point: 100.degree.-110.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3359, 1734, 1672, 1338, 1168
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.242 (3H, t, J=7.2 Hz), 1.35-1.9 (6H, m), 3.50 (2H, m), 3.569 (2H, s), 3.714 (1H, dd, J=12.8 Hz, J=9.2 Hz), 3.95 (2H, m), 4.137 (2H, q, J=7.2 Hz), 4.40 (1H, m) 7.230 and 7.238 (2H, d, J=8.5 Hz), 7.394 and 7.444 (2H, d, J=8.5 Hz), 7.484 and 7.504 (2H, d, J=8.5 Hz), 7.834 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.13, 20.56 snd 20.75, 24.89 and 25.02, 26.98 and 27.09, 30.61 and 30.89, 40.82, 56.39 and 56.65, 60.85, 64.57 and 64.86, 68.31 and 68.71, 101.08 and 101.81, 119.95 and 120.03, 128.74 and 128.91, 129.45 and 129.61, 129.70 and 129.83, 130.54 and 130.61, 136.10, 137.33 and 137.58, 139.76 and 139.86, 166.53 and 166.72, 171.43
Fab-MS m/z: 525 (MH.sup.+), 524(M.sup.+), 441(MH.sup.+ -DHP)
Example 18
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-bromobenzenesulfonyl chloride (2.08 g) to obtain (RS)-2-(4-bromobenzenesulfonyl-amino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-(tetrahydro-pyran-2-yloxy)propanamide (1.58 g).
Melting point: 115.degree.-126.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3334, 3278, 1734, 1684, 1338, 1167, 742
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.243 (3H, t, J=7.08 Hz), 1.3-1.9 (6H, m), 3.4-4.0 (5H, m), 3.569 (2H, s), 4.137 (2H, q, J=7.08 Hz), 4.42 (1H, m), 7.15-7.5 (4H, m), 7.649 (1H, d, J=8.79 Hz), 7.668 (1H, d, J=8.79 Hz), 7.758 (2H, d, J=8.79 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.15, 20.56, (20.75), 24.89, (25.00), 30.61, (30.87), 56.39, (56.65), 60.86, 64.57, (64.86), 68.31, (68.71), 101.06, (101.79), 119.98, (120.05), 128.27, 128.34, 128.82, 128.96, 129.84, 130.54, 130.61, 132.45, 132.59, 136.08, 137.88, 138.10, 166.52, (166.74), 171.40
Fab-MS m/z: 569 (MH.sup.+ +2), 567 (MH.sup.+)
Example 19
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl) phenyl)-2-(4-iodobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-iodobenzenesulfonyl chloride (1.31 g) to obtain (RS)-N-(4-(ethoxycarbonyl-methyl)phenyl)-2-(4-iodobenzenesulfonylamino)-N-(3-(tetrahydropyran-2-yloxy)propanamide (1.10 g).
Melting point: 146.degree.-147.3.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3278, 1732, 1674, 1338, 1167
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.243 (3H, t, J=7.08 Hz), 1.3-1.9 (6H, m), 3.50 (2H, m), 3.570 (2H, s), 3.6-4.1 (3H, m), 4.137 (2H, q, J=7.08 Hz), 4.40 (1H, m), 7.1-8.0 (8H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.14, 20.53, 20.70, 24.91, 24.99, 30.61, 30.84, 40.80, 56.44, 56.70, 60.87, 64.53, 64.79, 68.27, 68.62, 100.70, 100.76, 101.02, 101.71, 120.02, 120.11, 120.20, 128.52, 128.60, 128.78, 129.84, 130.53, 136.06, 138.42, 138.57, 138.77, 166.59, 166.79, 171.48
Fab-MS m/z: 616 (M.sup.+), 533
Example 20
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl) phenyl)-2-(4-methylbenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy) propanamide (1.0 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-methylbenzenesulfonyl chloride (778 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-methylbenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (540 mg).
Melting point: 119.degree.-128.degree. C.
IR .nu.max cm.sup.-1 (KBr): 1735, 1666, 1333, 1165, 1034, 667, 550
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.241 (3H, t, J=7.08 Hz), 1.3-1.8 (6H, m), 2.404 (3/2H, s), 2.420 (3/2H, s), 3.565 (2H, s), 3.35-3.66 (2H, m), 3.75-4.2 (2H, m), 4.135 (2H, q, J=7.08 Hz), 4.3-4.5 (1H, m), 7.1-7.5 (6H, m), 7.777 (2H, d, J=8.05 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.15, 20.49, 21.52, 24.93, 25.00, 30.61, 30.72, 40.84, 56.46, 56.76, 60.83, 64.42, 68.20, 68.31, 101.02, 101.24, 119.94, 120.02, 127.31, 127.46, 129.77, 129.92, 130.36, 130.43, 135.75, 136.19, 144.15, 144.22, 166.85, 167.03, 171.47
Fab-MS m/z: 504 (M.sup.+), 421
Example 21
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl) phenyl)-2-(4-methoxybenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (0.68 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-methoxybenzenesulfonyl chloride (575 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-methoxybenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (3 19 mg).
Melting point: 113.degree.-115.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3342, 3261, 1730, 1660, 1335, 1160, 1032, 559
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.243 (3H, t, J=7.08 Hz), 1.3-1.9 (6H, m), 3.3-3.7 (2H, m), 3.567 (2H, s), 3.848 (3/2H, s), 3.864 (3/2H, s), 3.8-4.1 (3H, m), 4.137 (2H, q, J=7.08 Hz), 4.2-4.4 (1H, m), 6.9-7.0 (2H, m), 7.15-7.28 (2H, m), 7.4-7.5 (2H, m), 7.825 (2H, d, J=8.79 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.15, 20.53, 25.00, 30.61, 30.79, 40.84, 55.62, 56.46, 56.76, 60.83, 64.46, 68.27, 101.06, 144.37, 144.48, 119.94, 120.02, 129.48, 129.62, 129.77, 130.39, 134.91, 136.26, 160.76, 163.36, 166.88, 167.07, 171.47
Fab-MS m/z: 520 (M.sup.+), 437
Example 22
Preparation of (RS)-2-(4-chloro-3-nitrobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (500 mg) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-chloro-3-nitrobenzenesulfonyl chloride (524 mg) to obtain (RS)-2-(4-chloro-3-nitrobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (198.2 mg).
Melting point: 108.degree.-111.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3275, 1736, 1684, 1659, 1539, 1354, 1174, 1030
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.244 (3H, t, J=7.08 Hz), 1.4-1.9 (6H, m), 3.572 (2H, s), 3.3-3.7 (2H, m), 3.8-4.1 (3H, m), 4.139 (2H, q, J=7.08 Hz), 4.45 (1H, m), 7.23 (2H, m), 7.40 (2H, m), 7.71 (1H, m), 8.05 (1H, m), 8.400 (1H, t, J=1.71 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.19, 20.72, 21.16, 24.90, 25.01, 30.69, 31.06, 40.85, 56.62, 60.95, 64.95, 65.72, 68.32, 69.49, 101.25, 102.75, 119.99, 120.06, 124.65, 124.90, 129.96, 130.81, 130.88, 131.32, 131.54, 132.16, 133.05, 133.16, 135.98, 139.13, 166.09, 166.31, 171.48
Fab-MS m/z: 569 (M.sup.+), 486
Example 24
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl) phenyl)-2-(2-naphthalenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (500 mg) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 2-naphthalenesulfonyl chloride (463 mg) to obtain (RS)-N-(4-(ethoxycarbonyl-methyl)phenyl)-2-(2-naphthalenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (345.7 mg).
Melting point: 132.degree.-136.degree. C.
IR .nu.max cm.sup.-1 (KBr): 1734, 1674, 1336, 1163, 1132, 1074, 1034, 661, 550
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.237 (3H, t, J=7.08 Hz), 1.3-1.9 (6H, m), 3.3-3.5 (2H, m), 3.548 (2H, s), 3.8-4.1 (3H, m), 4.132 (2H, q, J=7.08 Hz), 4.3-4.45 (1H, m), 7.1-8.0 (10H, m), 8.473 (1H, s), 8.641 (1H, d, J=2.19 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.15, 20.53, 24.89, 25.00, 30.61, 30.68, 40.84, 56.54, 56.87, 60.83, 64.53, 68.24, 68.38, 101.09, 101.28, 119.98, 120.05, 122.07, 122.33, 127.72, 127.83, 127.94, 129.00, 129.07, 129.18, 129.26, 129.73, 130.39, 130.47, 132.04, 135.02, 135.46, 136.15, 166.77, 166.99, 171.47
Fab-MS m/z: 540 (M.sup.+), 457
Example 25
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide
A mixture of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy) propanamide (385 mg), PPTS (140 mg) and ethanol (25 ml) was refluxed for 1 hour under argon. The reaction mixture was concentrated under reduced pressure, poured into a saturated saline solution, and extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated saline solution and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure to obtain 339 mg of a yellow oil. The crude product was purified by column chromatography (silica gel=25 g, hexane/ethyl acetate=1/1) to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (145 mg).
Melting point: 157.degree.-159.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3455, 3261, 1708, 1693, 1280, 1168, 1110, 1093
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.40 (3H, t, J=7.1 Hz), 3.63 (1H, dd, J=11.2 Hz, J=5.6 Hz), 3.85 (2H, m), 4.36 (2H, q, J=7.1 Hz), 7.43 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 7.82 (2H, d, J=8.8 Hz), 7.98 (2H, d, J=8.8 Hz)
Fab-MS m/z: 427 (MH.sup.+)
Example 26
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.496 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (1.078 g).
Melting point: 157.degree.-159.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3455, 3261, 1708, 1693, 1280, 1168, 1110, 1093
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.40 (3H, t, J=7.1 Hz), 3.63 (1H, dd, J=11.2 Hz, J=5.6 Hz), 3.85 (2H, m), 4.36 (2H, q, J=7.1 Hz), 7.43 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 7.82 (2H, d, J=8.8 Hz), 7.98 (2H, d, J=8.8 Hz)
Fab-MS m/z: 427 (MH.sup.+)
Example 27
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxypropanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.1 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonyl-methyl)phenyl)-3-hydroxypropanamide (1.36 g),
Melting point: 139.degree.-140.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3506, 3330, 3261, 1718, 1660, 1338, 1166
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6 -d.sub.6): 1.243 (3H, t, J=7.1 Hz), 3.555 (2H, s), 3.66 (1H, m), 3.90 (2H, m), 4.128 (2H, q, J=7.1 Hz), 7.190 (2H, d, J=8.5 Hz), 7.387 (2H, d, J=8.5 Hz), 7.418 (2H, d, J=8.5 Hz), 7.833 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6 -d.sub.6): 14.17, 40.71, 58.88, 60.78, 62.78, 120.05, 128.72, 129.34, 129.63, 130.20, 136.49, 138.23, 139.26, 167.68, 171.48
Fab-MS m/z: 441 (MH.sup.+)
Example 28
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-hydroxypropanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.62 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-hydroxypropanamide (0.99 g).
IR .nu.max cm.sup.-1 (KBr): 3388, 1716, 1674, 1344, 1165
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 2.588 (2H, d, J=7.3 Hz), 2.890 (2H, d, J=7.3 Hz), 3.654 (3H, s), 3.7 to 3.95 (3H, m), 7.097 (2H, d, J=8.4 Hz), 7.21 (1H, d, J=7.3 Hz), 7.329 (2H, d, J=8.4 Hz), 7.400 (2H, d, J=8.6 Hz), 7.831 (2H, d, J=8.6 Hz), 9.038 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 29.91, 30.48, 35.27, 51.13, 58.68, 62.44, 119.67, 128.14, 128.29, 128.84, 135.49, 136.08, 138.08, 138.65, 167.23, 172.71
Fab-MS m/z: 441 (MH.sup.+)
Example 29
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.3 g) to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide (1.49g).
IR .nu.max cm.sup.-1 (KBr): 3482, 3350, 3236, 1718, 1675, 1324, 1087
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.40 (3H, t, J=7.2 Hz), 3.63 (1H, dd, J=11.1 Hz, J=5.1 Hz), 3.88 (1H, dd, J=11.1 Hz, J=5.1 Hz), 3.95 (1H, t, J=5.1 Hz), 4.38 (2H, q, J=7.2 Hz), 7.37 (1H, t, J=7.6 Hz), 7.42 (2H, d, J=8.6 Hz), 7.71 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=7.6 Hz), 7.83 (2H, d, J=8.6 Hz) 7.96 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.07, 58.65, 61.21, 62.25, 120.88, 124.45, 125.63, 128.54, 128.88, 129.32, 130.90, 137.26, 137.93, 166.41, 168.13
Fab-MS m/z: 427 (MH.sup.+)
Example 30
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.224 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide (1.374 g).
Melting point: 142.degree.-144.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3482, 3350, 3236, 1718, 1675, 1324, 1087
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.40 (3H, t, J=7.2 Hz), 3.63 (1H, dd, J=11.1 Hz, J=5.1 Hz), 3.88 (1H, dd, J=11.1 Hz, J=5.1 Hz), 3.95 (1H, t, J=5.1 Hz), 4.38 (2H, q, J=7.2 Hz), 7.37 (1H, t, J=7.6 Hz), 7.42 (2H, d, J=8.6 Hz), 7.71 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=7.6 Hz), 7.83 (2H, d, J=8.6 Hz), 7.96 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.07, 58.65, 61.21, 62.25, 120.88, 124.45, 125.63, 128.54, 128.88, 129.32, 130.90, 137.26, 137.93, 166.41, 168.13
Fab-MS m/z: 427 (MH.sup.+)
Example 31
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(3-methoxycarbonylpropyl)propanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.99 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(3-methoxycarbonylpropyl)propanamide (947 mg).
Melting point: 119.degree.-121.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3479, 3311, 3234, 2946, 1732, 1651, 1628, 1398, 1313, 1163, 1093
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 1.576 (2H, qw, J=7.2 Hz), 2.220 (2H, t, J=7.4 Hz), 2.968 (2H, dd, J=12.7 Hz, J=6.8 Hz), 3.473 (2H, t, J=5.4 Hz), 3.598 (3H, s), 4.590 (1H, t, J=5.6 Hz), 7.550 (2H, d, J=8.4 Hz), 7.798 (2H, d, J=8.4 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 23.92, 27.00, 30.33, 37.59, 58.28, 61.94, 128.10, 128.39, 138.40, 139.65, 163.96, 177.75
Fab-MS m/z: 379 (MH.sup.+)
Example 32
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(4-methoxycarbonylbutyl)propanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-methoxycarbonylbutyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.506 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(4-methoxycarbonylbutyl)propanamide (997 mg).
Melting point: 92.degree.-94.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3296, 2954, 1733, 1637, 1618, 1398, 1313, 1165, 1093
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6 -d.sub.6): 1.2-1.5 (4H, m), 2.248 (2H, t, J=7.3 Hz), 2.887 (2H, dd, J=12.7 Hz, J=6.6 Hz), 3.443 (2H, d, J=5.6 Hz), 3.582 (3H, s), 4.6-4.8 (1H, m), 7.573 (2H, d, J=8.6 Hz), 7.787 (2H, d, J=8.6 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 21.53, 27.18, 27.99, 32.72, 37.96, 50.80, 62.09, 128.32, 128.65, 136.94, 139.91, 168.47, 172.86
Fab-MS m/z: 393 (MH.sup.+)
Example 33
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(5-methoxycarbonylpentyl)propanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.755 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(5-methoxycarbonylpentyl)propanamide (823 mg).
Melting point: 83.degree.-86.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3309, 1736, 1649, 1625, 1315, 1163, 823, 752
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.8 (6H, m), 2.315 (2H, t, J=7.3 Hz), 3.201 (2H, dd, J=12.7 Hz, J=6.6 Hz), 3.403 (1H, dd, J=11.2 Hz, J=5.4 Hz), 3.673 (3H, s), 3.69 (1H, m), 3.896 (1H, dd, J=11.2 Hz, J=3.5 Hz), 6.901 (1H, m), 7.499 (2H, d, J=8.8 Hz), 7.817 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.23, 25.99, 28.70, 33.69, 39.38, 51.59, 57.42, 62.22, 128.60, 129.55, 137.88, 139.67, 169.38, 174.33
Fab-MS m/z: 407 (MH.sup.+)
Example 34
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(6-methoxycarbonylhexyl)propanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.163 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(6-methoxycarbonylhexyl)propanamide (726 mg).
Melting point: 78.degree.-81.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3300, 2935, 1732, 1647, 1622, 1398, 1313, 1163, 1093
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.3 (4H, m), 1.447 (2H, t, J=6.6 Hz), 1.605 (2H, t, J=7.3 Hz), 2.306 (2H, t, J=7.3 Hz), 3.180 (2H, q, J=6.6 Hz), 3.442 (2H, dd, J=11.2 Hz, J=5.4 Hz), 3.670 (3H, s), 3.938 (1H, dd, J=11.2 Hz, J=3.9 Hz), 6.200 (1H, d, J=7.6 Hz), 6.8-6.9 (1H, m), 7.498 (2H, d, J=8.8 Hz), 7.822 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.63, 26.21, 29.48, 28.85, 33.84, 39.63, 51.55, 57.42, 62.44, 128.63, 129.59, 137.84, 139.75, 169.23, 174.40
Fab-MS m/z: 421 (MH.sup.+)
Example 35
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(7-methoxycarbonylheptyl)propanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-2-(4-chlorobenzenesulfonylamino)-N-(7-methoxycarbonylheptyl)-3-(tetrahydropyran-2-yloxy)propanamide (1.835 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(7-methoxycarbonylheptyl)propanamide (815 mg).
Melting point: 88.degree.-92.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3311, 2926, 1734, 1649, 1626, 1398, 1313, 1163, 1093
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.2-1.4 (8H, m), 1.604 (2H, t, J=7.3 Hz), 2.319 (2H, t, J=7.3 Hz), 2.997 (2H, t, J=6.8 Hz), 3.5-3.6 (2H, m), 3.651 (3H, s), 3.776 (1H, t, J=5.6 Hz), 7.546 (2H, d, J=8.8 Hz), 7.838 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 25.90, 27.62, 29.93, 30.00, 30.08, 34.77, 40.42, 51.97, 60.00, 63.74, 129.97, 130.30, 139.95, 140.72, 166.64, 171.45
Fab-MS m/z: 435 (MH.sup.+)
Example 36
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl) phenyl)-2-(4-fluorobenzenesulfonylamino)-3-hydroxy propanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (2.50 g) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-hydroxypropanamide (1.96 g).
Melting point: 148.5.degree.-150.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3506, 3346, 3265, 1712, 1660, 1348, 1169
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.247 (3H, t, J=7.08 Hz), 3.569 (2H, s), 3.60 (1H, m), 3.80-3.95 (2H, m), 4.139 (2H, q, J=7.08 Hz), 7.140 (2H, t, J=8.79 Hz), 7.200 (2H, d, J=8.55 Hz), 7.365 (2H, d, J=8.55 Hz), 7.902 (2H, dd, J=8.79 Hz, J=5.0 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 13.85, 40.63, 58.43, 60.87, 62.20, 62.31, 116.08, 116.39, 120.14, 120.22, 129.55, 129.73, 129.87, 130.39, 135.37, 135.92, 136.00, 167.94, 171.83
Fab-MS m/z: 425 (MH.sup.+)
Example 37
Preparation of (RS)-2-(4-bromobenezenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxy propanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (2.21 g) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxypropanamide (1.33 g).
Melting point: 149.degree.-150.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3506, 3265, 1734, 1670, 1325, 1171, 746
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.247 (3H, t, J=7.08 Hz), 3.48-3.63 (1H, m), 3.570 (2H, s), 3.88 (2H, m), 4.138 (2H, q, J=7.08 Hz), 7.208 (2H, d, J=8.55 Hz), 7.347 (2H, d, J=8.55 Hz), 7.598 (2H, d, J=8.79 Hz), 7.739 (2H, d, J=8.79 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.00, 40.70, 58.22, 60.94, 62.22, 120.20, 120.31, 128.08, 128.60, 129.73, 130.58, 132.45, 135.82, 138.28, 167.65, 171.72
Fab-MS m/z: 487 (M+2), 485 (M.sup.+)
Example 38
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-hydroxy-2-(4-iodobenzenesulfonylamino)propanamide
The procedure described in Example 25 was repeated, except that the THP was removed from the (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonyl-amino)-3-(tetrahydropyran-2-yloxy)propanamide (3.71 g) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxy-2-(4-iodobenzenesulfonylamino)propanamide (2.66 g).
Melting point: 181.degree.-182.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3493, 3342, 3265, 1734, 1668, 1344, 1171, 739
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6 -d.sub.6): 1.243 (3H, t, J=7.1 Hz), 3.551 (2H, s), 3.61-3.73 (1H, m), 3.74-3.88 (1H, m), 3.968 (1H, t, J=5.4 Hz), 4.122 (2H, q, J=7.1 Hz), 7.172 (2H, d, J=8.6 Hz), 7.356 (2H, d, J=8.6 Hz), 7.598 (2H, d, J=8.5 Hz), 7.762 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6 -d.sub.6): 13.52, 40.07, 58.70, 60.02, 62.22, 99.26, 119.36, 127.94, 128.89, 129.26, 136.12, 137.44, 139.38, 167.18, 170.73
Fab-MS m/z: 533 (MH.sup.+)
Example 39
Preparation of (S)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
A mixture of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (200 mg), ethanol (5 ml), and 2N NaOH (2 ml) was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure. It was repeated 3 times in order to remove ethanol completely that a small amount of purified water was added to the residue, and the whole was concentrated under reduced pressure. The residue was acidified with 1N HCl, and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated saline solution and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure to obtain (S)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (147 mg).
Melting point: 139.degree.-221.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3365, 1689, 1319, 1168
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.8 (6H, m), 3.42 (1, m), 3.58 (2H, m), 3.81 (1H, m), 4.167 and 4.173 (0.5H each, t, J=6.6 Hz), 4.49 and 4.59 (0.5H each, m), 7.43 and 7.44 (1H each, d, J=8.8 Hz), 7.40 and 7.49 (1H each, d, J=9.0 Hz), 7.84 (2H, d, J=9.0 Hz), 7.93 (2H, d, J=8.8 Hz)
Fab-MS m/z: 483 (MH.sup.+), 399
Example 40
Preparation of (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy) propanamide (160.8 mg) was hydrolyzed to obtain (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (112 mg).
Melting point: 136.degree.-137.degree. C.
IR .nu.max cm.sup.-1 (neat): 3467, 1691, 1323, 1167
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.2-1.8 (6H, m), 3.42 (1H, m), 3.72 (2H, m), 3.81 (1H, m), 4.17 (1H, m), 4.45 (1H, m), 7.44 (2H, d, J=8.8 Hz), 7.49 (2H, d, J=9.0 Hz), 7.84 (2H, d, J=9.0 Hz), 7.93 (2H, d, J=8.8 Hz)
Fab-MS m/z: 483 (MH.sup.+), 399
Example 41
Preparation of (RS)-N-(4-(carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (200 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (80 mg).
Melting point: 146.degree.-147.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3440 (br), 3253, 1701, 1653, 1338, 1166
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6 -d.sub.6): 1.2-1.7 (6H, m), 3.40 (2H, m), 3.481 (2H, s), 3.65 (2H, m), 4.145 (1H, m), 4.461 and 4.545 (1H, m), 7.157 (2H, d, J=8.5 Hz), 7.329 (2H, d, J=8.5 Hz), 7.525 (2H, d, J=8.6 Hz), 7.815 (2H, d, J=8.6 Hz)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6 -d.sub.6): 18.21 and 18.34, 24.47, 29.47 and 29.51, 39.50, 56.59, 60.77 and 61.01, 66.38 and 66.58, 97.50 and 97.64, 119.26, 128.06, 128.50, 128.94, 130.02, 136.41, 136.92, 139.81, 166.84, 171.89
Fab-MS m/z: 497 (MH.sup.+)
Example 42
Preparation of (RS)-N-(4-(2-carboxyethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (210 mg) was hydrolyzed to obtain (RS)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (130 mg).
Melting point: 150.degree.-151.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3255, 1695, 1658, 1342, 1167
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6 -d.sub.6): 1.2-1.8 (6H, m), 2.489 (2H, t, J=7.5 Hz), 2.785 (2H, t, J=7.5 Hz), 3.3-3.8 (4H, m), 4.133 (1H, t, J=6.4 Hz), 4.460 and 4.542 (1H, m), 7.11 (2H, d, J=8.5 Hz), 7.30 (2H, d, J=8.5 Hz), 7.51 (2H, d, J=8.8 Hz), 7.812 (2H, d, J=8.8 Hz), 9.61 (1H, d, J=11.2 Hz)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6 -d.sub.6): 18.19 and 18.34, 24.47, 29.49, 34.90, 56.59, 66.38 and 66.56, 97.50 and 97.63, 119.33, 127.71 and 127.81, 128.04 and 128.48, 135.84 and 135.87, 135.93, 136.90, 139.80, 166.71 and 166.82, 172.99
Fab-MS m/z: 511 (MH.sup.+), 510 (M.sup.+), 427 (MH.sup.+ -DHP)
Example 43
Preparation of (S)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy) propanamide (130 mg) was hydrolyzed to obtain (S)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (122 mg).
Melting point: 84.degree.-124.degree. C.
IR .nu.max cm.sup.-1 (neat): 3800-2200 (br), 3240, 1702 (br), 1332, 1165
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.2-1.8 (6H, t, m), 3.3-3.9 (4H, m), 4.17 (1H, m), 4.508 and 4.606 (1H, m), 7.379 (1H, t, J=8.1 Hz), 7.443 (1H, d, J=8.6 Hz), 7.448 (1H, d, J=8.6 Hz), 7.61 (1H, m), 7.754 (1H, dt, J=8.1 Hz, J=1.7 Hz) 7.857 (2H, d, J=8.6 Hz), 8.024 (1H, t, J=1.7 Hz)
Fab-MS m/z: 483 (MH.sup.+), 399
Example 44
Preparation of (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy) propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (191 mg) was hydrolyzed to obtain (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (140.4 mg).
Melting point: 165.degree.-166.degree. C.
IR .nu.max cm.sup.-1 (neat): 3800-2200 (br), 3240, 1702 (br), 1332, 1165
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.2-1.8 (6H, m), 3.3-3.9 (4H, m), 4.17 (1H, m), 4.508 and 4.606 (1H, m), 7.379 (1H, t, J=8.1 Hz), 7.443 (1H, d, J=8.6 Hz), 7.448 (1H, d, J=8.6 Hz) 7.61 (1H, m), 7.754 (1H, dt, J=8.1 Hz, J=1.7 Hz) 7.857 (2H, d, J=8.6 Hz), 8.024 (1H, t, J=1.7 Hz)
Fab-MS m/z: 483 (MH.sup.+), 399
Example 45
Preparation of (RS)-N-(3-(carboxymethyl) phenyl)-2-(4chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-(methoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (56 mg) was hydrolyzed to obtain (RS)-N-(3-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (17 mg).
IR .nu.max cm.sup.-1 (KBr): 3263, 1710, 1690, 1338, 1167
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6 -d.sub.6): 1.2-1.8 (6H, m), 3.499 (2H, s), 3.3-3.8 (4H, m), 4.146 (1H, m), 4.461 and 4.541 (0.5H each, m), 6.948 (1H, d, J=7.6 Hz), 7.195 (1H, t, J=7.6 Hz), 7.304 (1H, s), 7.527 (2H d, J=8.8 Hz), 7.813 (2H, d, J=8.8 Hz), 9.684 (1H, m)
Fab-MS m/z: 497 (MH.sup.+)
Example 46
Preparation of (RS)-N-(3-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-(2-methoxycarbonylethyl)phenyl)-3-(tetrahydropyran-2-yloxy) propanamide (525 mg) was hydrolyzed to obtain (RS)-N-(3-(carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (385 mg).
Melting point: 152.degree.-154.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3332, 3251, 1699, 1659, 1338, 1169
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 1.2-1.7 (6H, m), 2.501 (2H, t, J=7.4 Hz), 2.801 (2H, t, 7.4 Hz), 3.4-3.9 (4H, m), 4.15 (1H, m), 4.5 (1H, m), 6.913 (1H, d, J=7.3 Hz), 7.1-7.3 (3H, m), 7.522 (2H, d, J=8.5 Hz), 7.824 (2H, d, J=8.5 Hz), 9.628 (1H, d, J=11.7 Hz)
Fab-MS m/z: 511 (MH.sup.+), 427 (MH.sup.+ -DHP)
Example 47
Preparation of (RS)-N-(3-carboxypropyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(tetrahydropyran-2-yloxy) propanamide (463 mg) was hydrolyzed to obtain (RS)-N-(3-carboxypropyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (424 mg).
Melting point: 96.degree.-101.degree. C.
IR .nu.max cm.sup.-1 (neat): 3369, 1716, 1652, 1338, 1167
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.9 (8H, m), 2.382 (2H, t, J=7.0 Hz), 3.2-3.9 (6H, m), 4.05 (1H, m), 4.35 (1H, m), 6.268 (0.5H, d, J=5.4 Hz), 6.465 (0.5H, d, J=7.1 Hz), 7.014 (1H, dd, J=12.2 Hz, J=6.1 Hz), 7.491 (2H, d, J=8.5 Hz), 7.812 (2H, d, J=8.5 Hz)
Fab-MS m/z: 449 (MH.sup.+), 365 (MH.sup.+ -DHP)
Example 48
Preparation of (RS)-N-(4-carboxybutyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that -(RS)-2-(4-chlorobenzenesulfonyl-amino)-N-(methoxycarbonylbutyl)-3-(tetrahydropyran-2-yloxy)-propanamide (124.8 mg) was hydrolyzed to obtain (RS)-N-(4-carboxybutyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (95.7 mg).
IR .nu.max cm.sup.-1 (neat): 3369, 3307, 2945, 1716, 1653, 1443, 1338, 1167, 1124, 1093
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.258 (2H, t, J=7.1 Hz), 1.4-1.8 (8H, m), 2.360 (2H, t, J=7.0 Hz), 3.1-3.3 (2H, m), 3.4-3.6 (H, m), 3.8-3.9 (2H, m), 4.123 (1H, q, J=7.2 Hz), 4.3-4.4 (1H, m), 6.4-6.6 (1H, m), 6.964 (1H, d, J=5.4 Hz), 7.4-7.5 (2H, m), 7.815 (2H, d, J=8.3 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 20.27, 21.63, 24.89 and 24.96, 28.56, 30.46, 33.29, 39.19, 56.28 and 56.46, 64.06 and 64.13, 68.09 and 68.16, 100.69, 128.67 and 128.85, 129.29 and 129.44, 137.62 and 137.88, 139.45 and 139.53, 168.86 and 169.08, 177.85
Fab-MS m/z: 463 (MH.sup.+), 379 (MH.sup.+ -THP)
Example 49
Preparation of (RS)-N-(5-carboxypentyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(tetrahydropyran-2-yloxy) propanamide (103.7 mg) was hydrolyzed to obtain (RS)-N-(5-carboxypentyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (79.4 mg).
IR .nu.max cm.sup.-1 (neat): 3500-3000 (br), 2941, 1711, 1653, 1396, 1340, 1167
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.3-1.7 (12H, m), 2.343 (2H, t, J=7.2 Hz), 3.226 (2H, t, J=6.4 Hz), 3.4-3.5 (2H, m), 3.8-3.9 (2H, m), 4.3-4.4 (1H, m), 6.886 (1H, q, J=5.9 Hz), 7.483 (2H, dd, J=8.8 Hz, J=1.2 Hz), 7.7-7.9 (2H, m)
Fab-MS m/z: 477 (MH.sup.+), 393 (MH.sup.+ -THP)
Example 50
Preparation of (RS)-N-(6-carboxyhexyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-3-(tetrahydropyran-2-yloxy) propanamide (107.3 mg) was hydrolyzed to obtain (RS)-N-(6-carboxyhexyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (83.2 mg).
Melting point: 86.degree.-88.degree. C.
IR .nu.max cm.sup.-1 (neat): 3383, 2943, 2864, 1713, 1659, 1443, 1338, 1167, 1124, 1028
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.4 (4H, m), 1.4-1.8 (10H, m), 2.341 (2H, t, J=7.3 Hz), 3.1-3.3 (2H, m), 3.4-3.5 (2H, m), 3.7-3.9 (2H, m), 4.008 (1H, dd, J=10.5 Hz, J=3.4 Hz), 4.3-4.4 (1H, m), 6.536 (1H, d, J=7.1 Hz), 6.865 (1H, d, J=4.6 Hz), 7.483 (2H, d, J=8.8 Hz), 7.811 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 20.31 and 20.38, 24.41, 24.93 and 25.00, 26.21, 28.48, 28.92, 30.57, 30.76, 39.60, 56.24 and 56.43, 64.20 and 64.31, 68.13 and 68.24, 100.80, 128.71 and 128.89, 129.33 and 129.48, 137.58 and 137.88, 139.53 and 139.60, 168.75 and 168.97, 178.43
Fab-MS m/z: 491 (MH.sup.+), 407 (MH.sup.+ -THP)
Example 51
Preparation of (RS)-N-(7-carboxyheptyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(7-methoxycarbonylheptyl)-3-(tetrahydropyran-2-yloxy) propanamide (108 mg) was hydrolyzed to obtain (RS)-N-(7-carboxyheptyl)-2-(4-chlorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (72.6 mg).
IR .nu.max cm.sup.-1 (neat): 3271, 3151, 2939, 1711, 1659, 1443, 1342, 1167, 1126, 1093
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.8 (16H, m), 2.337 (2H, t, J=7.5 Hz), 3.1-3.3 (2H, m), 3.4-3.6 (2H, m), 3.7-3.9 (2H, m), 3.9-4.2 (1H, m), 4.3-4.4 (1H, m), 6.796 (1H, d, J=4.9 Hz), 7.495 (2H, d, J=8.5 Hz), 7.809 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 20.34, 24.49, 25.04, 26.39, 28.67 and 28.81, 29.11, 30.61, 33.84, 39.63, 56.17, 56.39, 64.20 and 64.28, 68.20, 100.80, 128.71 and 128.89, 129.33 and 129.48, 137.58, 139.53 and 139.60, 168.64 and 168.83, 178.62
Fab-MS m/z: 505 (MH.sup.+), 421 (MH.sup.+ -THP)
Example 52
Preparation of (RS)-2-(benzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-(tetrahydropyran-2-yloxy) propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(benzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy) propanamide (100 mg) was hydrolyzed to obtain (RS)-2-(benzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (92.7 mg).
Melting point: 128.5.degree.-135.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3265, 1707, 1327, 1165, 1093, 1030, 688, 588
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.3-1.8 (6H, m), 3.4-3.7 (2H, m), 3.575 (2H, s), 3.8-4.1 (3H, m), 4.42 (1H, m), 7.2-7.6 (7H, m), 7.898 (2H, d, J=7.33 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 13.82, 19.83, 24.85, 40.40, 56.61, 56.90, 67.61, 67.83, 100.18, 100.32, 119.98, 120.05, 126.91, 127.02, 128.96, 129.07, 129.59, 130.54, 132.92, 135.86, 139.05, 167.18, 173.89
Fab-MS m/z: 462 (M.sup.+), 379
Example 53
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy) propanamide (223.9 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-fluorobenzenesulfonyl amino)-3-(tetrahydropyran-2-yloxy)propanamide (94.7 mg).
Melting point: 156.degree.-157.2.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3435, 1685, 1325, 1294, 1157, 841
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.3-1.9 (6H, m), 3.576 (2H, s), 3.3-4.2 (5H, m), 7.174 (2H, t, J=8.7 Hz), 7.239 (2H, d, J=8.4 Hz), 7.404 (2H, d, J=8.4 Hz), 7.920 (2H, dd, J=8.7 Hz, J=5.0 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 19.92, 19.99, 25.27, 30.63, 40.86, 57.21, 57.47, 63.63, 63.74, 68.11, 100.30, 100.38, 116.33, 116.40, 116.66, 116.73, 120.44, 120.51, 129.86, 130.04, 130.15, 130.30, 131.15, 136.40, 167.41, 174.42
Fab-MS m/z: 481(MH.sup.+), 480 (M.sup.+), 397
Example 54
Preparation of (RS)-2-(4-bromobenzenesulfonylamino-N-(4-(carboxymethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (348.2 mg) was hydrolyzed to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl) phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (132.1 mg).
Melting point: 155.5.degree.-158.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3348, 1689, 1336, 1167, 741, 611
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.35-1.9 (6H, m), 3.4-4.2 (5H, m), 3.572 (2H, s), 4.52 (1H, m), 7.239 (2H, d, J=8.54 Hz), 7.333 (1H, d, J=8.54 Hz), 7.355 (1H, d, J=8.54 Hz), 7.620 (2H, d, J=8.54 Hz), 7.768 (2H, d, J=8.30 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 19.77, (19.92), 25.60, 30.77, 41.23, 57.66, (57.85), 63.23, (63.49), 68.11, (68.22), 100.01, (100.16), 120.80, 128.28, 129.27, 130.23, 131.55, 132.83, 136.68, 139.65, 168.33, 174.93
Fab-MS m/z: 543 (M+3), 542 (M+2), 541 (M+1), 540 (M.sup.+)
Example 55
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4- iodobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy) propanamide (266.5 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (254.5 mg).
Melting point: 163.degree.-165.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3505, 3265, 1735, 1670, 1344, 1324, 1171
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.9 (6H, m), 3.3-4.1 (5H, m), 3.577 (2H, s), 4.45 (1H, m), 7.239 (2H, d, J=8.7 Hz), 7.35 (2H, d, J=8.7 Hz), 7.595 (2H, d, J=8.85 Hz), 7.832 (2H, d, J=8.55 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 19.87, 24.89, 30.35, 40.48, 56.65, 63.76, 67.80, 100.36, 120.02, 128.45, 129.70, 130.58, 135.82, 138.17, 138.23, 138.90, 167.03, 173.92
Fab-MS m/z: 589 (MH.sup.+), 505
Example 56
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-methylbenzensulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-methylbenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy) propanamide (100 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-methylbenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (69.0 mg).
Melting point: 115.degree.-171.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3325, 1668, 1323, 1163, 1092, 814, 667, 552
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.3-1.8 (6H, m), 2.322 (3H, s), 3.3-3.7 (2H, m), 3.8-4.1 (3H, m), 4.390 (1H, m), 7.1-7.6 (6H, m), 7.752 (2H, d, J=8.30 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 19.90, 20.01, 21.30, 24.82, 24.89, 30.39, 40.40, 56.90, 58.30, 62.15, 63.95, 67.69, 67.98, 100.36, 119.98, 120.05, 120.16, 120.27, 127.02, 127.09, 127.20, 129.66, 129.73, 130.39, 130.50, 135.86, 135.93, 136.08, 144.04, 167.98, 174.14
Fab-MS m/z: 477 (MH.sup.+), 393
Example 57
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-methoxybenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-methoxy-benzenesulfonylamino)-3-(tetrahydropyran-2-yloxy) propanamide (101.6 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-methoxybenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (95.1 mg).
Melting point: 135.degree.-141.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3251, 1684, 1325, 1161, 1026, 835, 804, 569
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.3-1.9 (6H, m), 3.4-3.6 (2H, m), 3.599 (2H, s), 3.7-4.0 (3H, m), 3.819 (3/2H, s), 3.838 (3/2H, s), 4.3-4.5 (1H, m), 6.9-7.0 (2H, m), 7.16-7.24 (2H, m), 7.36-7.48 (2H, m), 7.813 (2H, d, J=8.78 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 20.38, 20.45, 24.93, 25.00, 30.57, 30.68, 40.29, 55.62, 56.57, 56.87, 64.28, 64.35, 68.05, 68.31, 100.98, 114.37, 114.48, 120.09, 129.22, 129.44, 129.59, 129.66, 129.73, 129.88, 130.17, 130.39, 136.37, 163.33, 167.10, 167.32, 176.20
Fab-MS m/z: 493 (MH.sup.+), 492 (M.sup.+), 409
Example 58
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chloro-3-nitrobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chloro-3-nitrobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (102.1 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chloro-3-nitrobenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy) propanamide (100.3 mg).
Melting point: 131.degree.-140.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3442, 1684, 1539, 1352, 1173, 1032
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 1.3-1.9 (6H, m), 3.483 (2H, s), 3.4-3.6 (2H, m), 3.6-3.8 (2H, m), 4.1-4.3 (1H, m), 4.4-4.6 (1H, m), 7.148 (2H, d, J=8.55 Hz), 7.26-7.36 (2H, m), 7.849 (1H, d, J=8.54 Hz), 8.0-8.1 (1H, m), 8.40-8.46 (1H, m)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 18.34, 18.52, 29.64, 56.81, 60.95, 61.21, 66.64, 97.63, 97.77, 119.15, 123.74, 129.16, 130.19, 131.18, 132.46, 136.39, 141.23, 146.88, 166.60, 172.14
Fab-MS m/z: 542 (MH.sup.+), 541 (M.sup.+), 458
Example 60
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-N-(4-(carboxymethyl)phenyl)-2-(2-naphthalenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(2-naphthalenesulfonylamino)-3-(tetrahydropyran-2-yloxy) propanamide (82.6 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-N-(4-(carboxymethyl)phenyl)-2-(2-naphthalenesulfonylamino)-3-(tetrahydropyran-2-yloxy) propanamide (78.8 mg).
Melting point: 130.degree.-140.degree. C.
IR .nu.max cm.sup.-1 (KBr): 1709, 1684, 1327, 1161, 1132, 1074, 1032, 661
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.2-1.8 (6H, m), 3.3-3.6 (2H, m), 3.6-4.2 (3H, m), 4.3-4.5 (1H, m), 7.0-7.3 (4H, m), 7.5-7.7 (2H, m), 7.8-8.0 (4H, m), 8.452 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 19.69, 19.91, 25.82, 30.88, 41.26, 58.02, 58.20, 63.04, 63.30, 68.21, 99.97, 100.04, 120.91, 123.00, 128.20, 128.53, 129.12, 129.52, 129.82, 130.19, 131.54, 132.97, 135.80, 136.93, 137.63, 168.91, 169.02, 175.03
Fab-MS m/z: 513 (MH.sup.+), 512 (M.sup.+), 429
Example 61
Preparation of (S)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanamide
The procedure described in Example 39 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (120 mg) was hydrolyzed to obtain (S)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanamide (111 mg).
Melting point: 231.degree.-234.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3440, 3273, 1678, 1319, 1169
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 3.71 (2H, m), 4.01 (1H, t, J=6 Hz), 7.41 (2H, d, J=8.8 Hz), 7.46 (2H, d, J=9.0 Hz), 7.82 (2H, d, J=8.8 Hz), 7.92 (2H, d, J=9.0 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 60.49, 63.74, 120.19, 127.30, 129.95, 130.23, 131.65, 140.06, 140.49, 143.37, 169.37, 170.12
Fab-MS m/z: 399 (MH.sup.+)
Example 62
Preparation of (S)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanamide
The procedure described in Example 39 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide (100 mg) was hydrolyzed to obtain (S)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanamide (93 mg).
Melting point: 220.degree.-224.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3454, 3249, 1697, 1326, 1164
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 3.72 (2H, m), 3.998 (1H, t, J=6 Hz), 7.356 (1H, t, J=7.5 Hz), 7.413 (2H, d, J=8.8 Hz), 7.577 (1H, m), 7.727 (1H, dt, J=7.5 Hz, J=1.5 Hz), 7.831 (2H, d, J=8.8 Hz), 7.991 (1H, t, J=1.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 60.49, 63.77, 122.37, 125.46, 126.58, 129.78, 129.98, 130.26, 139.28, 140.55, 169.43, 170.00
Fab-MS m/z: 399 (MH.sup.+)
Example 63
Preparation of (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide (983 mg) was hydrolyzed to obtain (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanamide (633 mg).
IR .nu.max cm.sup.-1 (KBr): 3454, 3249, 1697, 1326, 1164
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 3.72 (2H, m), 3.998 (1H, t, J=6 Hz), 7.356 (1H, t, J=7.5 Hz), 7.413 (2H, d, J=8.8 Hz), 7.577 (1H, m), 7.727 (1H, dt, J=7.5 Hz, J=1.5 Hz), 7.831 (2H, d, J=8.8 Hz), 7.991 (1H, t, J=1.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 60.49, 63.77, 122.37, 125.46, 126.58, 129.78, 129.98, 130.26, 139.28, 140.55, 169.43, 170.00
Fab-MS m/z: 399 (MH.sup.+)
Example 64
Preparation of (RS)-N-(5-carboxypentyl)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-hydroxypropanamide (28 mg) was hydrolyzed to obtain (RS)-N-(5-carboxypentyl)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanamide (24 mg).
IR .nu.max cm.sup.-1 (KBr): 3700-2400 (br), 3131, 3190, 1706, 1635, 1340, 1164, 1093, 756
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 1.15-1.35 (4H, m), 1.479 (2H, qu, J=7.3 Hz), 2.162 (2H, t, J=7.3 Hz), 2.889 (2H, dd, J=12.5 Hz, J=6.4 Hz), 3.456 (2H, d, J=5.9 Hz), 3.715 (1H, t, J=5.9 Hz), 7.556 (1H, m), 7.572 (2H, d, J=8.6 Hz), 7.790 (2H, d, J=8.6 Hz)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 23.77, 25.46, 28.06, 33.30, 38.11, 58.35, 61.98, 128.17, 128.47, 168.25, 173.68
Fab-MS m/z: 393 (MH.sup.+)
Example 65
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl-3-methanesulfonyloxypropanamide
Methanesulfonyl chloride (hereinafter referred to as mesyl chloride) (96 .mu.l) was added to a solution of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (132 mg) in pyridine (2.5 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated saline solution, 1N HCl, and a saturated saline solution, and dried over Na.sub.2 SO.sub.4. Then, the solvent was evaporated under reduced pressure to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (133 mg).
IR .nu.max cm.sup.-1 (KBr): 3363, 3259, 1710, 1679, 1348, 1274, 1168, 1114, 1091
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.40 (3H, t, J=7.1 Hz), 3.02 (3H, s), 4.34 (3H, m), 4.37 (2H, q, J=7.1 Hz), 7.43 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz), 7.83 (2H, d, J=8.8 Hz), 7.98 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 13.76, 36.76, 55.91, 60.81, 68.18, 118.95, 126.06, 128.22, 129.14, 130.27, 138.04, 139.34, 141.09, 165.80, 166.20
Fab-MS m/z: 505 (MH.sup.+)
Example 66
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (1 g) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (943 mg). CHCl.sub.3 was used for recrystallization.
Melting point: 153.degree.-158.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3346, 3240, 1709, 1689, 1355, 1176
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.407 (3H, t, J=7.2 Hz), 3.029 (3H, s), 4.3-4.5 (3H, m), 4.370 (2H, q, J=7.2 Hz), 7.433 (2H, d, J=8.5 Hz), 7.504 (2H, d, J=8.8 Hz), 7.836 (2H, d, J=8.5 Hz), 7.976 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.47, 37.48, 56.86, 61.67, 69.10, 119.87, 126.87, 129.17, 129.95, 131.10, 139.25, 140.08, 142.24, 166.89, 167.18
Fab-MS m/z: 505 (MH.sup.+)
Example 67
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxypropanamide (1.32 g) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (1.04 g).
Melting point: 142.degree.-143.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3332, 1732, 1676, 1348, 1180
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.251 (3H, t, J=7.1 Hz), 2.992 (3H, s), 3.560 (2H, s), 4.132 (2H, q, J=7.1 Hz), 4.36 (2H, m), 4.45 (1H, m), 7.192 (2H, d, J=8.5 Hz), 7.346 (2H, d, J=8.5 Hz), 7.392 (2H, d, J=8.8 Hz), 7.827 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.76, 37.05, 40.35, 56.15, 60.37, 68.90, 119.59, 128.12, 128.87, 129.24, 130.01, 135.97, 138.39, 138.74, 164.96, 170.99
Fab-MS m/z: 519 (MH.sup.+)
Example 68
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-hydroxypropanamide (882 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (246 mg).
IR .nu.max cm.sup.-1 (KBr): 3307, 3242, 1736, 1664, 1356, 1167
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 2.596 (2H, t, J=7.5 Hz), 2.898 (2H, t, J=7.5 Hz), 2.990 (3H, s), 3.663 (3H, s), 4.36 (2H, m), 4.45 (1H, m), 7.108 (2H, d, J=8.4 Hz), 7.295 (2H, d, J=8.4 Hz), 7.387 (2H, d, J=8.8 Hz), 7.827 (2H, d, J=8.8 Hz), 7.933 (1H, d, J=8.5 Hz), 9.328 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 29.93, 30.52, 35.23, 51.17, 56.19, 68.95, 119.59, 128.16, 128.27, 128.89, 135.24, 136.52, 138.89, 138.79, 164.88, 172.73
Fab-MS m/z: 519 (MH.sup.+)
Example 69
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide
The procedure described in Example 65 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide (1.38 g) was reacted with mesyl chloride to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (915 mg).
IR .nu.max cm.sup.-1 (KBr): 3342, 3260, 1708, 1680, 1355, 1290, 1172
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.41 (3H, t, J=7.1 Hz), 3.00 (3H, s), 4.28 (2H, m), 4.39 (2H, q, J=7.1 Hz), 4.48 (1H, dd, J=12.2 Hz, J=7.1 Hz), 7.39 (1H, m), 7.45 (2H, d, J=8.8 Hz), 7.7-7.8 (2H, m), 7.84 (2H, d, J=8.8 Hz), 7.97 (1H, t, J=1 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.07, 37.14, 56.03, 61.27, 68.33, 120.88, 124.42, 125.92, 128.45, 129.00, 129.46, 131.04, 137.06, 137.98, 139.71, 165.69, 166.29
Fab-MS m/z: 505 (MH.sup.+)
Example 70
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-hydroxypropanamide (1 g) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (763 mg). Recrystallization from CHCl.sub.3 was carried out.
Melting point: 170.degree.-173.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3466, 3346, 1720, 1689, 1356, 1176
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.49 (3H, t, J=7.1 Hz), 3.035 (3H, s), 4.33 (2H, m), 4.392 (2H, q, J=7.1 Hz), 4.45 (1H, m), 7.398 (1H, t, J=7.8 Hz), 7.433 (2H, d, J=8.8 Hz), 7.664 (1H, ddd, J=7.8 Hz, J=2 Hz, J=1 Hz), 7.797 (1H, dt, J=7.8 Hz, J=1 Hz), 7.884 (2H, d, J=8.8 Hz), 7.99 (1H, t, J=2 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.59, 37.45, 57.38, 62.19, 69.59, 121.97, 125.46, 126.52, 129.75, 129.89, 130.24, 130.30, 132.14, 140.20, 167.41
Fab-MS m/z: 505 (MH.sup.+)
Example 71
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(3-methoxycarbonylpropyl) propanamide
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(3-methoxycarbonylpropyl)propanamide (504 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(3-methoxycarbonylpropyl)propanamide (497.8 mg).
Melting point: 95.degree.-99.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3371, 3251, 3039, 1736, 1670, 1348, 1325, 1167, 1095
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.794 (2H, qw, J=7.0 Hz), 2.347 (2H, q, J=7.0 Hz), 2.999 (3H, s), 3.269 (2H, q, J=6.3 Hz), 3.681 (3H, s), 4.0-4.2 (2H, m), 4.503 (1H, dd, J=10.5 Hz, J=4.4 Hz), 6.386 (1H, d, J=8.1 Hz), 7.065 (1H, t, J=5.6 Hz), 7.517 (2H, d, J=8.7 Hz), 7.841 (2H, d, J=8.7 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.19, 31.16, 37.32, 39.38, 51.81, 55.66, 68.49, 128.71, 129.70, 137.66, 140.00, 167.03, 173.70
Fab-MS m/z: 457 (MH.sup.+)
Example 72
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-methoxycarbonylbutyl) propanamide
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(4-methoxycarbonylbutyl)propanamide (507 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-methoxycarbonylbutyl)propanamide (409.7 mg).
Melting point: 95.degree.-97.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3375, 3250, 2951, 1736, 1672, 1350, 1327, 1171, 1092
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.4-1.7 (4H, m), 2.328 (2H, t, J=7.0 Hz), 3.007 (3H, s), 3.232 (2H, q, J=6.4 Hz), 3.674 (3H, s), 4.0-4.2 (2H, m), 4.518 (1H, dd, J=10.5 Hz, J=4.2 Hz), 6.160 (1H, d, J=8.1 Hz), 6.7-6.9 (1H, m), 7.523 (2H, d, J=8.8 Hz), 7.788 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 21.77, 28.52, 33.29, 37.36, 39.49, 51.62, 55.55, 68.35, 128.74, 129.73, 137.58, 140.08, 166.74, 173.92
Fab-MS m/z: 471 (MH.sup.+)
Example 73
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(5-methoxycarbonylpentyl) propanamide
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(5-methoxycarbonylpentyl)propanamide (507 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(5-methoxycarbonylpentyl)propanamide (483.5 mg).
Melting point: 81.degree.-84.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3273, 3234, 2941, 1734, 1660, 1354, 1331, 1182, 1099
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.3-1.7 (6H, m), 2.318 (2H, t, J=7.2 Hz), 2.992 (3H, s), 3.235 (2H, q, J=6.6 Hz), 3.679 (3H, s), 4.0-4.2 (2H, m), 4.521 (1H, dd, J=10.9 Hz, J=4.3 Hz), 6.020 (1H, d, J=8.1 Hz), 7.525 (2H, d, J=8.3 Hz), 7.831 (2H, d, J=8.3 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.16, 25.95, 28.56, 33.69, 37.43, 39.63, 51.62, 55.58, 68.31, 128.74, 129.81, 137.58, 140.15, 166.59, 174.18
Fab-MS m/z: 485 (MH.sup.+)
Example 74
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(6-methoxycarbonylhexyl) propanamide
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(6-methoxycarbonylhexyl)propanamide (502 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(6-methoxycarbonylhexyl)propanamide (453.1 mg).
Melting point: 77.degree.-82.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3273, 3223, 2937, 1734, 1660, 1354, 1331, 1184, 1097
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.4 (4H, m), 1.4-1.5 (2H, m), 1.5-1.7 (2H, m), 2.312 (2H, t, J=7.3 Hz), 2.995 (3H, s), 3.202 (2H, dd, J=12.9 Hz, J=6.8 Hz), 3.673 (3H, s), 4.0-4.2 (2H, m), 4.512 (1H, dd, J=10.5 Hz, J=4.4 Hz), 6.207 (1H, d, J=8.1 Hz), 6.7-6.8 (1H, m), 7.523 (2H, d, J=8.8 Hz), 7.837 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.60, 26.21, 28.48, 28.81, 33.80, 37.36, 39.89, 51.51, 55.55, 68.38, 128.71, 129.73, 137.62, 140.04, 166.63, 174.25
Fab-MS m/z: 499 (MH.sup.+)
Example 75
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(7-methoxycarbonylheptyl) propanamide
The procedure described in Example 65 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxy-N-(7-methoxycarbonylheptyl)propanamide (504 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(7-methoxycarbonylheptyl)propanamide (503.2 mg).
Melting point: 90.degree.-95.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3275, 3224, 2935, 1740, 1660, 1354, 1331, 1184, 1099
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.3 (6H, m), 1.4-1.5 (2H, m), 1.6-1.7 (2H, m), 2.307 (2H, t, J=7.5 Hz), 2.991 (3H, s), 3.205 (2H, q, J=6.6 Hz), 3.671 (3H, s), 4.101 (2H, dd, J=10.5 Hz, J=4.6 Hz), 4.514 (1H, dd, J=10.5 Hz, J=4.4 Hz), 6.107 (1H, d, J=8.1 Hz), 6.7-6.7 (1H, m), 7.524 (2H, d, J=8.8 Hz), 7.836 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.63, 26.28, 28.89, 28.74, 29.00, 33.91, 37.36, 39.96, 51.48, 55.55, 68.31, 128.71, 129.77, 137.55, 140.11, 166.59, 174.36
Fab-MS m/z: 513 (MH.sup.+)
Example 76
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl) phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide
The procedure described in Example 65 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-hydroxypropanamide (1.88 g) was reacted with mesyl chloride to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (1.70 g).
Melting point: 81.degree.-82.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3342, 3261, 1732, 1655, 1355, 1178
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.250 (3H, t, J=7.08 Hz), 2.969 (3H, s), 3.569 (2H, s), 4.144 (2H, q, J=7.08 Hz), 4.15-4.30 (2H, m), 4.557 (1H, dd, J=10.50 Hz, J=4.20 Hz), 6.331 (1H, d, J=8.06 Hz), 7.20 (4H, m), 7.364 (2H, d, J=8.30 Hz), 7.926 (2H, dd, J=8.79 Hz, J=4.88 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.11, 37.40, 40.70, 56.10, 60.97, 68.13, 116.64, 116.97, 120.38, 129.92, 130.06, 130.21, 131.16, 135.57, 165.16, 171.61
Fab-MS m/z: 503 (MH.sup.+)
Example 77
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide
The procedure described in Example 65 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxypropanamide (674.0 mg) was reacted with mesyl chloride to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxy-propanamide (582.16 mg).
Melting point: 155.degree.-156.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3332, 1732, 1676, 1348, 1180, 769
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 1.180 (3H, t, J=7.1 Hz), 3.110 (3H, s), 3.575 (2H, s), 4.075 (2H, q, J=7.1 Hz), 4.2-4.5 (3H, m), 7.172 (2H, d, J=8.6 Hz), 7.302 (2H, d, J=8.6 Hz), 7.661 (2H, d, J=8.8 Hz), 7.736 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6); 13.76, 36.75, 39.68, 55.67, 59.89, 68.54, 119.52, 126.08, 128.28, 129.13, 129.86, 131.73, 136.31, 139.87, 165.06, 170.67
Fab-MS m/z: 566, 565, 564, 53 (MH.sup.+), 562 (M.sup.+)
Example 78
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl) phenyl)-2-(4-iodo-benzenesulfonylamino)-3-methanesulfonyloxypropanamide
The procedure described in Example 65 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-hydroxy-2-(4-iodobenzenesulfonylamino)propanamide (2.60 g) was reacted with mesyl chloride to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (2.69 g).
Melting point: 160.degree.-162.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3334, 1728, 1676, 1348, 1180, 737
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.233 (3H, t, J=7.1 Hz), 3.010 (3H, s), 3.546 (2H, s), 4.113 (2H, q, J=7.1 Hz), 4.3-4.5 (3H, m), 7.171 (2H, d, J=8.3 Hz), 7.330 (2H, d, J=8.3 Hz), 7.593 (2H, d, J=8.6 Hz), 7.763 (2H, d, J=8.6 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.54, 36.82, 39.98, 55.82, 59.85, 68.47, 99.17, 119.44, 127.84, 128.87, 129.64, 136.02, 137.41, 139.98, 164.81, 170.42
Fab-MS m/z: 611 (MH.sup.+)
Example 79
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl) propanamide
Sodium hydride (60% dispersion in mineral oil, 15.84 mg) was washed with hexane, and suspended in DMF (500 .mu.l) under argon and cooled to 0.degree. C. After imidazole (33.7 mg) was added, the whole was stirred for 15 minutes. Then, a solution of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (100 mg) in DMF (500 .mu.l) was added and the whole was stirred for 4 hours. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na.sub.2 SO.sub.4. Then, the solvent was evaporated and the residue was purified by column chromatography (silica gel=25 g, ethyl acetate/ethanol=20/1) to obtain the desired (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (4 mg) together with a less polar by-product. The by-product was not investigated further.
IR .nu.max cm.sup.-1 (neat): 3249, 1716, 1278, 1164, 1106
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 1.38 (3H, t, J=7.2 Hz), 4.17 (1H, m), 4.36 (2H, q, J=7 Hz), 4.48 (2H, m), 6.80 (1H, m), 6.85 (1H, m), 7.37 (2H, d, J=6.8 Hz), 7.40 (2H, d, J=6.8 Hz), 7.55 (1H, m), 7.72 (1H, m), 7.80 (2H, d, J=8.8 Hz), 7.96 (2H, d, J=8.8 Hz), 9.64 (1H, m)
Fab-MS m/z: 477 (MH.sup.+)
Example 80
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (600 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (115.5 mg) together with a by-product having lower polarity. The by-product was not investigated further.
IR .nu.max cm.sup.-1 (KBr): 3251, 1705, 1680, 1354, 1280, 1167
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.398 (3H, t, J=7.1 Hz), 4.3-4.4 (3H, m), 4.361 (2H, q, J=7.1 Hz), 6.924 (1H, s), 7.024 (1H, s), 7.340 (2H, d, J=8.8 Hz), 7.423 (2H, d, J=8.8 Hz), 7.621 (1H, s), 7.701 (2H, d, J=8.8 Hz), 7.945 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.50, 58.62, 61.70, 119.81, 120.59, 126.90, 128.62, 129.06, 129.89, 131.13, 138.24, 139.34, 139.91, 142.30, 167.21, 167.84
Fab-MS m/z: 477 (MH.sup.+)
Example 81
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (311 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide (86 mg) together with a less polar by-product. The by-product was not investigated further.
Melting point: 164.degree.-165.degree. C.
IR .nu.max cm.sup.-1 (neat): 3250, 1732, 1695, 1335, 1163
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.252 (3H, t, J=7.1 Hz), 3.555 (3H, s), 4.122 (3H, t, J=7.1 Hz), 4.15-4.4 (3H, m), 6.877 (1H, s), 6.941 (1H, s), 7.137 (2H, d, J=8.3 Hz), 7.314 (2H, d, J=8.3 Hz), 7.317 (2H, d, J=8.5 Hz), 7.643 (2H, d, J=8.5 Hz), 7.660 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 13.25, 39.72, 47.44, 57.20, 59.69, 118.60, 119.03, 127.28, 128.08, 128.62, 129.20, 135.69, 136.87, 137.56, 138.24, 165.73, 170.33
Fab-MS m/z: 491 (MH.sup.+)
Example 82
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (208 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (111 mg) together with a less polar by-product. The by-product was not investigated further.
Melting point: 79.degree.-82.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3280, 1734, 1691, 1330, 1162
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 2.569 (2H, t, J=7.3 Hz), 2.874 (2H, t, J=7.3 Hz), 3.654 (3H, s), 4.20 (1H, m), 4.42 (2H, m), 6.7-7.9 (12H, m), 9.256 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 30.28, 35.49, 48.87, 51.62, 57.97, 118.11, 120.24, 128.27, 128.78, 129.55, 134.98, 135.60, 137.33, 137.44, 138.21, 139.38, 166.15, 173.23
Fab-MS m/z: 491 (MH.sup.+)
Example 83
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide
The procedure described in Example 79 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (100 mg) was reacted with imidazole to obtain the desired (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (19.9 mg) together with a less polar by-product. The by-product was not investigated further.
IR .nu.max cm.sup.-1 (neat): 3471, 1716, 1690, 1288, 1165
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.414 (3H, t, J=7.1 Hz), 4.2-4.4 (3H, m), 4.388 (2H, q, J=7.1 Hz), 6.955 (1H, s), 7.022 (1H, s), 7.3-7.9 (3H, m), 7.350 (2H, d, J=8.8 Hz), 7.706 (2H, d, J=8.8 Hz), 7.924 (1H, t, J=2 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.34, 58.05, 61.63, 119.49, 120.40, 121.15, 124.72, 126.19, 127.63, 128.64, 129.30, 129.61, 131.34, 137.50, 138.48, 139.75, 166.21, 166.40
Fab-MS m/z: 479 (M.sup.+ +2), 477 (MH.sup.+)
Example 84
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (163.3 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (63.5 mg) together with a less polar by-product. The by-product was not investigated further.
IR .nu.max cm.sup.-1 (neat): 3471, 1716, 1690, 1288, 1165
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.414 (3H, t, J=7.1 Hz), 4.2-4.4 (3H, m), 4.388 (2H, q, J=7.1 Hz), 6.955 (1H, s), 7.022 (1H, s), 7.3-7.9 (3H, m), 7.350 (2H, d, J=8.8 Hz), 7.706 (2H, d, J=8.8 Hz), 7.924 (1H, t, J=2 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.34, 58.05, 61.63, 119.49, 120.40, 121.15, 124.72, 126.19, 127.63, 128.64, 129.30, 129.61, 131.34, 137.50, 138.48, 139.75, 166.21, 166.40
Fab-MS m/z: 479 (M.sup.+ +2), 477 (MH.sup.+)
Example 85
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(3-methoxycarbonylpropyl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(3-methoxycarbonylpropyl)propanamide (107.6 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(3-methoxycarbonylpropyl)propanamide (16.3 mg) together with a less polar by-product. The by-product was not investigated further.
IR .nu.max cm.sup.-1 (neat): 3234, 3091, 2929, 1734, 1670, 1394, 1330, 1165, 1086
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.616 (2H, t, J=7.1 Hz), 2.196 (2H, t, J=7.4 Hz), 2.968 (2H, t, J=6.8 Hz), 3.661 (3H, s), 4.1-4.3 (3H, m), 7.4-7.6 (4H, m), 7.706 (2H, d, J=8.8 Hz), 7.799 (1H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 25.38, 31.84, 39.65, 45.59, 52.08, 58.68, 122.53, 129.68, 130.38, 130.52, 139.47, 140.02, 140.61, 167.45, 170.27
Fab-MS m/z: 429 (MH.sup.+)
Example 86
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-methoxycarbonylbutyl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-methoxy carbonylbutyl)propanamide (152.5 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-methoxycarbonylbutyl)propanamide (32.4 mg) together with a less polar by-product. The by-product was not investigated further.
IR .nu.max cm.sup.-1 (neat): 3219, 3118, 2949, 1730, 1666, 1331, 1165, 1086
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.3-1.6 (4H, m), 2.2-2.3 (2H, m), 3.0-3.1 (2H, m), 3.661 (3H, s), 4.242 (2H, t, J=4.6 Hz), 4.3-4.4 (1H, m), 6.836 (1H, s), 7.106 (1H, s), 7.441 (2H, dd, J=6.8 Hz, J=2.0 Hz), 7.7-7.8 (2H, m), 8.0-8.1 (1H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 21.88, 28.45, 33.29, 39.34, 48.80, 51.59, 57.60, 119.91, 121.63, 128.30, 129.55, 135.05, 138.68, 139.38, 168.02, 173.85
Fab-MS m/z: 443 (MH.sup.+)
Example 87
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(1H-imidazol-1-yl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(5-methoxycarbonylpentyl)propanamide (150.3 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(1H-imidazol-1-yl)propanamide (46.8 mg) together with a less polar by-product. The by-product was not investigated further.
IR .nu.max cm.sup.-1 (neat): 3367, 3232, 2942, 1734, 1668, 1396, 1335, 1165, 1093
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.4 (4H, m), 1.567 (2H, qw, J=7.4 Hz), 2.271 (2H, t, J=7.3 Hz), 3.075 (2H, dd, J=12.9 Hz, J=6.8 Hz), 3.660 (3H, s), 4.135 (1H, dd, J=13.8 Hz, J=5.3 Hz), 4.250 (1H, t, J=4.9 Hz), 4.488 (1H, dd, J=13.9 Hz, J=4.6 Hz), 6.800 (2H, d, J=9.8Hz), 7.2-7.3 (1H, m), 7.479 (2H, d, J=8.5 Hz), 7.789 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.23, 26.10, 28.67, 33.69, 39.78, 48.84, 51.70, 57.56, 119.91, 119.98, 128.38, 129.59, 137.55, 138.87, 139.49, 167.84, 174.00
Fab-MS m/z: 457 (MH.sup.+)
Example 88
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(6-methoxycarbonylhexyl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(6-methoxycarbonylhexyl)propanamide (144.6 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(6-methoxycarbonylhexyl)propanamide (50.6 mg) together with a less polar by-product. The by-product was not investigated further.
IR .nu.max cm.sup.-1 (KBr): 3219, 2935, 1734, 1670, 1331, 1232, 1163, 1086
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.4 (6H, m), 1.5-1.6 (2H, m), 2.294 (2H, t, J=7.3 Hz), 3.0-3.1 (1H, m), 3.672 (3H, s), 4.1-4.2 (2H, m), 4.4-4.5 (1H, m), 7.0-7.1 (1H, m), 7.463 (2H, d, J=8.6 Hz), 7.750 (2H, d, J=8.3 Hz), 8.0-8.1 (1H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.60, 26.28, 28.48, 28.78, 33.80, 36.48, 48.65, 51.51, 57.42, 119.72, 121.85, 128.27, 129.59, 135.05, 138.72, 162.56, 167.87, 174.25
Fab-MS m/z: 471 (MH.sup.+)
Example 89
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(7-methoxycarbonylheptyl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(7-methoxycarbonylheptyl)propanamide (152.2 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1yl)-N-(7-methoxycarbonylheptyl)propanamide (53.4 ml) together with a less polar by-product. The by-product was not investigated further.
IR .nu.max cm.sup.-1 (neat): 3221, 2926, 1738, 1682, 1338, 1232, 1165, 1086
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.1-1.4 (8H, m), 1.5-1.7 (2H, m), 2.298 (2H, t, J=7.4 Hz), 3.062 (2H, t, J=6.0 Hz), 3.667 (3H, s), 4.1-4.3 (2H, m), 4.3-4.5 (1H, m), 6.8-6.9 (1H, m), 7.0-7.1 (1H, m), 7.453 (2H, d, J=8.8 Hz), 7.749 (2H, d, J=8.5 Hz), 8.006 (2H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.71, 26.39, 28.81, 31.42, 33.91, 36.44, 39.78, 48.73, 51.44, 57.53, 119.61, 123.32, 128.30, 129.55, 138.61, 139.45, 162.56, 167.84, 174.25
Fab-MS m/z: 485 (MH.sup.+)
Example 90
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl)phenyl-2-(4-fluorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (560 mg) was reacted with imidazole to obtain the desired (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide (152.3 mg) together with a less polar by-product. The by-product was not investigated further.
Melting point: 155.degree.-157.degree. C.
IR .nu.max cm.sup.-1 (KBr): 1732, 1693, 1338, 1294, 1236, 1171, 1155, 1092
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.247 (3H, t, J=7.08 Hz), 3.562 (2H, s), 4.138 (2H, q, J=7.08 Hz), 4.2-4.4 (3H, m), 6.85 (2H, m), 7.07 (2H, m), 7.183 (2H, d, J=8.55 Hz), 7.275 (2H, d, J=8.55 Hz), 7.351 (1H, s), 7.795 (2H, dd, J=8.79 Hz, J=4.88 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.00, 40.66, 48.62, 57.71, 60.90, 116.24, 116.57, 119.87, 120.09, 120.20, 128.41, 129.48, 129.62, 129.73, 130.83, 135.75, 137.51, 166.37, 171.61
Fab-MS m/z: 475 (MH.sup.+)
Example 91
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide
The procedure described in Example 79 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (500 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide (85.0 mg) together with a less polar by-product. The by-product was not investigated further.
Melting point: 201.degree.-202.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3253, 1730, 1691, 1335, 1165, 1032, 741, 609
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 1.242 (3H, t, J=7.08 Hz), 3.577 (2H, s), 4.130 (2H, q, J=7.08 Hz), 4.2-4.4 (3H, m), 6.894 (1H, s), 7.038 (1H, s), 7.527 (2H, d, J=8.79 Hz), 7.645 (2H, d, J=8.79 Hz), 7.824 (1H, s)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 13.65, 47.31, 57.54, 59.74, 119.11, 119.41, 125.86, 127.92, 128.03, 128.94, 129.57, 131.40, 136.28, 137.27, 139.76, 166.24, 170.45
Fab-MS m/z: 537 (MH.sup.+ +2), 535 (MH.sup.+)
Example 92
Preparation of (S)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
2N NaOH (2.6 ml) was added to solution of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (120 mg) in ethanol (10 ml) and the whole was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. A small amount of water was added to the residue, and the whole was concentrated under reduced pressure. The above procedure was repeated 3 times to remove ethanol. The residue was dissolved in 1N HCl (20 ml), and diluted with water (20 ml). Then, the solution was washed 3 times with ethyl acetate (10 ml). The aqueous layer was concentrated under reduced pressure. A small amount of water was added, and the whole was concentrated under reduced pressure. The concentrating steps were repeated 3 times to evaporate excess HCl. The residue was dried under reduced pressure in a desiccator. After ethanol was added, the insoluble materials were removed by filtration. The combined filtrates were concentrated under reduced pressure and dried to obtain (S)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (84 mg).
IR .nu.max cm.sup.-1 (KBr): 1695, 1357, 1173
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 4.4-4.6 (3H, m), 6.926 (1H, d, J=8.5 Hz), 7.365 (2H, d, J=9.1 Hz), 7.399 (2H, d, J=9.1 Hz), 7.767 (2H, d, J=8.8 Hz), 7.857 (1H, J=8.5 Hz), 7.933 (2H, d, J=8.8 Hz), 8.909 (1H, s)
Fab-MS m/z: 449 (MH.sup.+ -HCl)
Example 93
Preparation of (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (61.9 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (44.4 mg).
IR .nu.max cm.sup.-1 (KBr): 1695, 1357, 1173
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 4.4-4.6 (3H, m), 6.926 (1H, d, J=8.5 Hz), 7.365 (2H, d, J=9.1 Hz), 7.399 (2H, d, J=9.1 Hz), 7.767 (2H, d, J=8.8 Hz), 7.857 (1H, J=8.5 Hz), 7.933 (2H, d, J=8.8 Hz), 8.909 (1H, s)
Fab-MS m/z: 449 (MH.sup.+ -HCl)
Example 94
Preparation of (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy)propanamide (50 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (37 mg).
Fab-MS m/z: 463 (MH.sup.+ -HCl)
Example 95
Preparation of (RS)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-(2-methoxycarbonylethyl)phenyl) propanamide (74 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (74 mg).
Melting point: 131.degree.-134.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3700-2200 (br), 3257, 1689, 1330, 1163
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 2.485 (2H, t, J=7.4 Hz), 2.787 (2H, t, J=7.4 Hz), 4.15 (1H, m), 4.30 (2H, m), 6.7-7.9 (12H, m), 10.075 (1H, s)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 29.49, 34.92, 47.24, 57.76, 108.85, 117.72, 119.41, 119.52, 127.81, 127.92, 128.43, 128.80, 135.65, 136.31, 137.01, 165.14
Fab-MS m/z: 477 (MH.sup.+ -HCl)
Example 96
Preparation of (S)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
The procedure described in Example 92 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (53.1 mg) was hydrolyzed, and then reacted with HCl to obtain (S)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (18.03 mg).
IR .nu.max cm.sup.-1 (KBr): 3427, 3145, 1701, 1167
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 4.50 (3H, m), 7.3-7.8 (5H, m), 7.41 (2H, d, J=8.6 Hz), 7.797 (2H, d, J=8.6 Hz), 8.031 (1H, s), 9.009 (1H, s)
Fab-MS m/z: 451 (MH.sup.+ +2-HCl), 449 (MH.sup.+ -HCl)
Example 97
Preparation of (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (35.3 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (25.9 mg).
IR .nu.max cm.sup.-1 (KBr): 3427, 3145, 1701, 1167
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 4.50 (3H, m), 7.3-7.8 (5H, m), 7.41 (2H, d, J=8.6 Hz), 7.797 (2H, d, J=8.6 Hz), 8.031 (1H, s), 9.009 (1H, s)
Fab-MS m/z: 451 (MH.sup.+ +2-HCl), 449 (MH.sup.+ -HCl)
Example 98
Preparation of (RS)-N-(3-carboxypropyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(3-methoxycarbonylpropyl)propanamide (15.8 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(3-carboxypropyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (16.2 mg).
IR .nu.max cm.sup.-1 (neat): 3223, 3084, 1728, 1680, 1335, 1165,
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.615 (2H, qw, J=7.1 Hz), 2.217 (2H, t, J=7.5 Hz), 3.0-3.1 (2H, m), 4.3-4.4 (2H, m), 4.609 (1H, t, J=4.8 Hz), 7.5-7.7 (5H, m), 7.7-7.9 (2H, m)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 25.46, 31.91, 39.76, 52.08, 57.91, 120.47, 120.91, 124.07, 129.82, 130.52, 130.63, 140.31, 168.73, 172.00
Fab-MS m/z: 416 (M+2-HCl)
Example 99
Preparation of (RS)-N-(4-carboxybutyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(4-methoxycarbonylbutyl)propanamide (16.8 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-carboxybutyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (17.2 mg).
IR .nu.max cm.sup.-1 (neat): 3412, 3149, 2968, 1670, 1331, 1165, 1095
.sup.1 H-NMR .delta. ppm (D.sub.2 O): 1.2-1.6 (4H, m), 2.462 (2H, t, J=7.1 Hz), 3.0-3.1 (2H, m), 4.3-4.7 (3H, m), 7.5-7.6 (2H, m), 7.7-7.8 (2H, m), 7.8-7.9 (2H, m), 8.806 (1H, s), 8.886 (1H, t, J=1.5 Hz)
.sup.13 C-NMR .delta. ppm (D.sub.2 O): 24.27, 30.32, 36.04, 41.91, 52.99, 59.26, 122.88, 125.16, 131.21, 132.64, 138.25, 139.60, 142.61, 170.81, 181.19
Fab-MS m/z: 429 (MH.sup.+ -HCl)
Example 100
Preparation of (RS)-N-(5-carboxypentyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(1H-imidazol-1-yl)propanamide (23.9 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(5-carboxypentyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (24.8 mg).
IR .nu.max cm.sup.-1 (neat): 3223, 3142, 2943, 1718, 1672, 1342, 1165, 1093
.sup.1 H-NMR .delta. ppm (D.sub.2 O): 1.0-1.2 (4H, m), 1.3-1.5 (2H, m), 2.1-2.2 (2H, m), 2.7-2.8 (2H, m), 3.9-4.0 (1H, m), 4.1-4.3 (2H, m), 7.2-7.3 (2H, m), 7.4-7.5 (2H, m), 7.5-7.6 (3H, m), 8.6-8.7 (1H, m)
.sup.13 C-NMR .delta. ppm (D.sub.2 O): 26.52, 28.05, 30.32, 36.49, 41.96, 52.84, 59.12, 122.73, 125.01, 131.05, 132.49, 138.11, 139.52, 142.43, 170.56, 179.69
Fab-MS m/z: 444 (M+2-HCl)
Example 101
Preparation of (RS)-N-(6-carboxyhexyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(6-methoxycarbonylhexyl)propanamide (36.3 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(6-carboxyhexyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (29.3 mg).
IR .nu.max cm.sup.-1 (neat): 2929, 2860, 1711, 1674, 1333, 1165, 1093
.sup.1 H-NMR .delta. ppm (D.sub.2 O): 1.2-1.5 (6H, m), 1.684 (2H, qw, J=7.4 Hz), 2.502 (2H, t, J=7.3 Hz), 3.0-3.1 (2H, m), 4.4-4.6 (2H, m), 4.707 (1H, dd, J=14.0 Hz, J=4.8 Hz), 7.5-7.7 (3H, m), 7.725 (2H, d, J=8.8 Hz), 7.874 (2H, d, J=8.8 Hz), 8.905 (1H, s)
.sup.13 C-NMR .delta. ppm (D.sub.2 O): 26.95, 28.38, 30.58, 30.65, 36.59, 42.28, 53.06, 59.29, 121.78, 122.92, 125.19, 131.24, 132.67, 138.28, 142.65, 170.70, 181.92
Fab-MS m/z: 457 (MH.sup.+ -HCl)
Example 102
Preparation of (RS)-N-(7-carboxyheptyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)-N-(7-methoxycarbonylheptyl)propanamide (25.6 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(7-carboxyheptyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (24.9 mg).
IR .nu.max cm.sup.-1 (neat): 3402, 2943, 1664, 1659, 1331, 1165, 1093
.sup.1 H-NMR .delta. ppm (D.sub.2 O): 1.2-1.5 (8H, m), 1.6-1.8 (2H, m), 2.507 (2H, t, J=7.3 Hz), 3.0-3.1 (2H, m), 3.769 (1H, q, J=7.1 Hz), 4.274 (1H, q, J=7.1 Hz), 4.4-4.5 (1H, m), 7.600 (2H, d, J=9.0 Hz), 7.727 (2H, d, J=8.8 Hz), 7.876 (2H, d, J=8.5 Hz), 8.898 (1H, s)
.sup.13 C-NMR .delta. ppm (D.sub.2 O): 27.04, 28.48, 30.64, 30.70, 30.84, 36.63, 42.30, 53.04, 59.29, 122.88, 125.15, 131.20, 132.67, 138.28, 139.66, 142.63, 168.84, 170.68
Fab-MS m/z: 471 (MH.sup.+ -HCl)
Example 103
Preparation of (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide
2N NaOH (1.085 ml) was added to a solution of (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonyl-amino)-3-(1H-imidazol-1-yl)propanamide (103 mg) in ethanol (5 ml) and the whole was stirred for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, washed with ethyl acetate 3 times, neutralized by 2N HCl (1.085 ml), and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide (34.3 mg).
Melting point: 162.5.degree.-165.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3442, 3234, 1689, 1170, 1155, 1092, 841
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 3.558 (2H, s), 4.2-4.6 (3H, m), 7.198 (2H, d, J=8.54 Hz), 7.292 (2H, d, J=8.54 Hz), 7.829 (2H, dd, J=8.79 Hz, J=5.13 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 41.30, 50.80, 58.80, 116.92, 117.25, 121.06, 130.60, 130.71, 130.82, 132.39, 137.09, 137.31, 167.08
Fab-MS m/z: 447 (MH.sup.+)
Example 104
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide
The procedure described in Example 103 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide (36.8 mg) was hydrolyzed to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide (30.0 mg).
Melting point: 131.degree.-140.degree. C.
IR .nu.max cm.sup.-1 (KBr): 1687, 1545, 1331, 1165, 1070, 742, 613
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 3.492 (2H, s), 4.1-4.5 (3H, m), 7.166 (2H, d, J=8.30 Hz), 7.315 (2H, d, J=8.30 Hz), 7.555 (2H, d, J=8.54 Hz), 7.593 (2H, d, J=8.54 Hz), 10.067 (1H, s)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 24.91, 57.43, 66.82, 119.41, 126.08, 127.99, 129.13, 130.34, 131.55, 136.17, 139.65, 165.94, 172.18
Fab-MS m/z: 509 (MH.sup.+ +2), 507 (MH.sup.+)
Example 105
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4- ethoxycarbonylphenyl)-3-(pyridin-3-yloxy)propanamide
Sodium hydride (60 % dispersion in mineral oil, 15.84 mg) was washed with hexane, suspended in DMF (1 ml) under argon and cooled to 0.degree. C. 3-Hydroxypyridine (37.67 mg) was added and the whole was stirred for 15 minutes. Then, a solution of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (100 mg) in DMF (500 .mu.l) was added and the whole was stirred for 2 hours. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na.sub.2 SO.sub.4, and the solvent was evaporated to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4- ethoxycarbonylphenyl)-3-(pyridin-3-yloxy)propanamide (94.9 mg).
Melting point: 119.degree.-124.degree. C.
IR .nu.max cm.sup.-1 (neat): 3261, 1700, 1668, 1338, 1161
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.405 (3H, t, J=7.1 Hz), 4.15-4.5 (3H, m), 4.369 (2H, q, J=7.1 Hz), 7.2-8.2 (4H, m), 7.406 (2H, d, J=8.3 Hz), 7.551 (2H, d, J=8.6 Hz), 7.842 (2H, d, J=8.3 Hz), 7.986 (2H, d, J=8.6 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.16, 56.58, 61.01, 67.78, 119.09, 121.66, 123.27, 127.65, 128.48, 129.14, 129.37, 130.58, 137.26, 137.35, 140.00, 142.27, 154.17, 166.29, 166.87
Fab-MS m/z: 504 (MH.sup.+)
Example 106
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy)propanamide
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (101.7 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy)propanamide (62.5 mg).
Melting point: 136.degree.-139.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3335, 3269, 1734, 1678, 1338, 1162
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.261 (3H, q, J=7.1 Hz), 3.591 (2H, s), 4.148 (2H, q, J=7.7 Hz), 4.2-4.4 (3H, m), 7.1-7.3 (1H, m), 7.233 (2H, d, J=8.5 Hz), 7.392 (2H, d, J=8.5 Hz), 7.418 (2H, d, J=8.8 Hz), 7.836 (2H, d, J=8.8 Hz), 8.0-8.3 (3H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.21, 41.07, 56.93, 61.37, 68.45, 120.63, 122.21, 124.68, 128.86, 129.67, 130.04, 130.96, 136.47, 137.70, 138.86, 139.79, 142.38, 154.87, 167.13, 172.43
Fab-MS m/z: 518 (MH.sup.+)
Example 107
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(pyridin-3-yloxy)propanamide (100 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (93.0 mg).
Melting point: 125.degree.-129.degree. C.
IR .nu.max cm.sup.-1 (neat): 3257, 1712, 1680 (sh), 1363, 1165
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.369 (3H, t, J=7.1 Hz), 4.10 (1H, m), 4.351 (2H, q, J=7.1 Hz), 4.3-4.5 (2H, m), 7.402 (2H, d, J=8.5 Hz), 7.826 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.30, 56.60, 61.33, 67.63, 121.05, 121.43, 124.22, 124.48, 126.06, 128.71, 129.17, 129.66, 131.30, 137.12, 137.70, 140.03, 142.68, 153.97, 166.12, 166.49
Fab-MS m/z: 504 (MH.sup.+)
Example 108
Preparation of (RS)-2-(4chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(pyridin-3-yloxy)propanamide
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(3-methoxycarbonylpropyl)propanamide (102.2 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(pyridin-3-yloxy)propanamide (92.8 mg).
IR .nu.max cm.sup.-1 (neat): 3271, 3089, 2931, 1734, 1668, 1389, 1338, 1167, 1095
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.785 (2H, t, J=7.0 Hz), 2.319 (2H, t, J=7.2 Hz), 3.261 (2H, q, J=6.5 Hz), 3.662 (3H, s), 4.0-4.3 (2H, m), 7.0-7.1 (1H, m), 7.1-7.3 (2H, m), 7.448 (2H, d, J=8.8 Hz), 7.819 (2H, d, J=8.8 Hz), 8.1-8.2 (2H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.30, 31.38, 36.40, 39.05, 51.62, 56.10, 120.90, 122.91, 123.87, 128.60, 129.33, 137.95, 138.17, 142.61, 153.97, 162.52, 173.48
Fab-MS m/z: 456 (MH.sup.+)
Example 109
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-methoxycarbonylbutyl)-3-(pyridin-3-yloxy)propanamide
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(4-methoxycarbonylbutyl)propanamide (65.7 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-methoxycarbonylbutyl)-3-(pyridin-3-yloxy)propanamide (64.3 mg).
IR .nu.max cm.sup.-1 (neat): 3248, 3089, 2953, 1732, 1668, 1338, 1165, 1095
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.4-1.7 (4H, m), 2.2-2.4 (2H, m), 3.2-3.3 (2H, m), 3.664 (3H, s), 4.059 (2H, t, J=4.2 Hz), 4.3-4.4 (1H, m), 7.463 (2H, d, J=8.6 Hz), 7.818 (2H, d, J=8.8 Hz), 8.0-8.3 (3H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 21.74, 28.89, 33.29, 36.51, 39.38, 51.66, 55.80, 121.01, 123.21, 124.01, 128.67, 129.55, 137.80, 138.98, 142.86, 153.86, 162.59, 173.74
Fab-MS m/z: 470 (MH.sup.+)
Example 110
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-pyridin-3-yloxy)propanamide
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(5-methoxycarbonylpentyl)propanamide (95.4 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(pyridin-3-yloxy)propanamide (91.3 mg).
IR .nu.max cm.sup.-1 (neat): 3307, 3089, 1726, 1662, 1441, 1279, 1159, 1093
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.7 (6H, m), 2.2-2.4 (2H, m), 3.1-3.3 (2H, m), 3.666 (3H, s), 4.0-4.4 (3H, m), 7.0-7.1 (1H, m), 7.1-7.2 (2H, m), 7.3-7.5 (2H, m), 7.692 (1H, d, J=8.5 Hz), 7.814 (1H, d, J=8.6 Hz), 8.0-8.1 (1H, m), 8.271 (1H, d, J=2.2 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.23, 28.74, 31.49, 33.73, 36.48, 36.55, 51.51, 56.50, 123.46, 124.38, 128.63, 128.89, 129.44, 137.77, 138.50, 140.00, 154.38, 162.63, 176.86
Fab-MS m/z: 484 (MH.sup.+)
Example 111
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-9-(pyridin-3-yloxy)propanamide
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(6-methoxycarbonylhexyl)propanamide (70.0 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-3-(pyridin-3-yloxy)propanamide (30.3 mg).
IR .nu.max cm.sup.-1 (neat): 2929, 2858, 1730, 1664, 1477, 1277, 1165, 1095
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.7 (8H, m), 2.2-2.4 (2H, m), 3.1-3.3 (2H, m), 3.665 (3H, s), 3.9-4.4 (3H, m), 7.2-7.3 (2H, m), 7.4-7.5 (2H, m), 7.7-7.9 (1H, m), 8.0-8.1 (2H, m), 8.1-8.2 (1H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.63, 26.25, 28.48, 28.92, 31.49, 33.84, 36.51, 51.44, 55.80, 124.20, 124.67, 127.90, 128.63, 129.29, 129.55, 137.07, 139.60, 142.72, 162.63, 173.85
Fab-MS m/z: 498 (MH.sup.+)
Example 112
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(7-methoxycarbonylheptyl)-3-(pyridin-3-yloxy)propanamide
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(7-methoxycarbonylheptyl)propanamide (69.0 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(7-methoxycarbonylheptyl)-3-(pyridin-3-yloxy)propanamide (36.7 mg).
IR .nu.max cm.sup.-1 (KBr): 3244, 2933, 1733, 1662, 1477, 1277, 1165, 1101
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.2-1.6 (10H, m), 2.292 (2H, t, J=7.4 Hz), 3.202 (2H, q, J=6.6 Hz), 3.662 (3H, s), 4.0-4.1 (2H, m), 4.3-4.4 (1H, m), 7.453 (2H, d, J=8.8 Hz), 7.811 (2H, d, J=8.8 Hz), 8.0-8.3 (4H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.67, 28.63, 28.78, 29.07, 31.45, 33.91, 36.51, 39.82, 51.44, 55.88, 121.08, 123.35, 128.60, 129.48, 137.88, 139.67, 140.26, 142.72, 162.63, 167.80, 172.93
Fab-MS m/z: 512 (MH.sup.+)
Example 113
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide
The procedure described in Example 105 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (250 mg) was reacted with 3-hydroxypyridine to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide (112.6 mg).
Melting point: 149.5.degree.-151.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3496, 3265, 1734, 1687, 1662, 1338, 1167, 1157, 1092, 571, 550
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.223 (3H, t, J=7.08 Hz), 3.541 (2H, s), 4.103 (2H, q, J=7.08 Hz), 4.223 (2H, d, J=5.86 Hz), 4.482 (1H, t, J=5.86 Hz), 7.0-7.2 (6H, m), 7.402 (2H, d, J=8.32 Hz), 7.911 (2H, dd, J=9.03 Hz, J=5.13 Hz), 8.1-8.2 (2H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.50, 56.30, 59.74, 68.18, 115.08, 115.41, 119.33, 120.80, 123.22, 128.80, 129.20, 129.20, 136.42, 137.71, 141.85, 153.84, 166.05, 170.38
Fab-MS m/z: 502 (MH.sup.+)
Example 114
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy)propanamide
The procedure described in Example 105 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (307 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy)propanamide (90.4 mg).
Melting point: 168.5.degree.-171.degree. C.
IR .nu.max cm.sup.-1 (KBr): 1730, 1689, 1338, 1277, 1165, 740, 611, 565
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD-DMSO-d.sub.6): 1.224 (3H, t, J=7.08 Hz), 3.579 (2H, s), 4.115 (2H, q, J=7.08 Hz), 4.244 (2H, d, J=5.86 Hz), 4.402 (1H, t, J=5.86 Hz), 7.200 (2H, d, J=8.5 Hz), 7.29 (2H, m), 7.359 (2H, d, J=8.5 Hz), 7.608 (2H, d, J=8.79 Hz), 7.786 (2H, d, J=8.79 Hz), 8.13 (2H, m)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD-DMSO-d.sub.6): 14.75, 41.37, 57.95, 61.73, 69.57, 121.24, 123.15, 125.53, 128.21, 129.93, 130.71, 130.82, 131.81, 133.31, 137.89, 138.85, 141.30, 143.25, 155.97, 168.07, 172.84
Fab-MS m/z: 562 (MH.sup.+), 564 (MH.sup.+ 2)
Example 115
Preparation of (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride
2N NaOH (143 .mu.l) was added to a solution of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(pyridin-3-yloxy)propanamide (48.1 mg) in ethanol (5 ml), and the whole was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. A small amount of purified water was added to the residue, and the mixture was concentrated under reduced pressured. The concentration step was repeated 3 times to remove ethanol. The residue was dissolved in 1N HCl (20 ml), diluted with water (20 ml), and then washed 3 times with ethyl acetate (10 ml). The aqueous layer was concentrated under reduced pressure. A small amount of purified water was added, and the mixture was concentrated under reduced pressure. The concentrating step was repeated 3 times to evaporate excess HCl. The residue was dried under reduced pressure in a desiccator, and ethanol was added. The insoluble materials were removed by filtration. The combined filtrates were concentrated and dried under reduced pressure to obtain (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (21.8 mg).
Melting point: 150.degree.-155.degree. C.
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 4.4-4.9 (3H, m), 7.41 (1H, m), 7.8-8.4 (11H, m)
Fab-MS m/z: 476 (MH.sup.+ -HCl)
Example 116
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-pyridin-3-yloxy)propanamide hydrochloride
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy) propanamide (38.1 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (29.7 mg).
Melting point: 162.degree.-165.degree. C.
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 3.569 (2H, s), 3.5-3.7 (2H, m), 4.15 (1H, m), 7.217 (2H, d, J=8 Hz), 7.383 (2H, d, J=8 Hz), 7.432 (2H, d, J=8 Hz), 7.872 (2H, d, J=8 Hz), 7.9-8.7 (4H, m)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 41.04, 56.88, 70.64, 120.77, 128.83, 129.20, 129.93, 130.23, 139.91, 157.73, 166.72, 174.60
Fab-MS m/z: 490 (MH.sup.+ -HCl)
Example 117
Preparation of (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(pyridin-3-yloxy)propanamide (41.7 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (23.3 mg).
Melting point: 165.degree.-167.degree. C.
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 4.50 (1H, m), 4.6-4.9 (2H, m), 7.42 (1H, m), 7.8-8.4 (11H, m)
Fab-MS m/z: 476 (MH.sup.+ -HCl)
Example 118
Preparation of (RS)-N-(3-carboxypropyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(pyridin-3-yloxy)propanamide (39.6 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(3-carboxypropyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (31.4 mg).
IR .nu.max cm.sup.-1 (neat): 3700-2400 (br), 1734, 1684, 1394, 1344, 1163, 1086
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.698 (2H, t, J=7.2 Hz), 2.292 (2H, dd, J=7.3 Hz, J=2.4 Hz), 3.126 (2H, t, J=6.8 Hz), 4.101 (1H, t, J=7.1 Hz), 4.2-4.4 (2H, m), 7.554 (2H, d, J=8.8 Hz), 7.876 (2H, d, J=8.5 Hz), 8.1-8.6 (4H, m)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 25.57, 31.91, 39.80, 57.18, 71.00, 129.46, 129.97, 130.49, 130.93, 133.71, 135.77, 140.13, 140.72, 159.20, 165.73, 169.87
Fab-MS m/z: 442 (MH.sup.+ -HCl)
Example 119
Preparation of (RS)-N-(4-carboxybutyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-methoxycarbonylbutyl)-3-(pyridin-3-yloxy)propanamide (41.4 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-carboxybutyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (29.6 mg).
IR .nu.max cm.sup.-1 (neat): 3394, 3080, 2953, 1713, 1666, 1396, 1335, 1165, 1093
.sup.1 H-NMR .delta. ppm (D.sub.2 O): 1.3-1.6 (4H, m), 2.370 (2H, t, J=7.1 Hz), 3.0-3.1 (2H, m), 4.3-4.5 (3H, m), 7.576 (2H, d, J=8.8 Hz), 7.6-7.7 (1H, m), 7.843 (2H, d, J=8.5 Hz), 8.050 (1H, d, J=7.3 Hz), 8.2-8.4 (2H, m)
.sup.13 C-NMR .delta. ppm DD.sub.2 O): 24.25, 30.44, 36.08, 41.90, 58.34, 71.50, 130.85, 131.00, 131.37, 132.55, 132.70, 135.00, 136.18, 139.90, 142.43, 163.11, 172.12
Fab-MS m/z: 456 (MH.sup.+ -HCl)
Example 120
Preparation of (RS)-N-(5-carboxypentyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-3-yloxy)propanamide hydrochloride
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(pyridin-3-yloxy)propanamide (46.6 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(5-carboxypentyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (30.7 mg).
IR .nu.max cm.sup.-1 (neat): 3369, 3234, 2933, 1709, 1664, 1558, 1396, 1315, 1164, 1093
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.2-1.7 (6H, m), 2.302 (2H, t, J=7.3 Hz), 3.064 (2H, t, J=6.8 Hz), 3.622 (1H, t, J=7.1 Hz), 4.2-4.5 (2H, m), 7.569 (1H, t, J=8.3 Hz), 7.8-8.1 (4H, m), 8.3-8.4 (2H, m)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 25.53, 27.26, 29.79, 34.63, 40.79, 57.18, 71.09, 129.46, 130.01, 130.47, 130.61, 133.61, 134.18, 135.74, 140.08, 158.72, 164.88, 175.76
Fab-MS m/z: 470 (MH.sup.+ -HCl)
Example 121
Preparation of (RS)-N-(6-carboxyhexyl)-3-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-3-(pyridin-3-yloxy)propanamide (12.3 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(6-carboxyhexyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (12.5 mg).
IR .nu.max cm.sup.-1 (neat): 3369, 3080, 2931, 1722, 1664, 1552, 1392, 1282, 1165, 1088
.sup.1 H-NMR .delta. ppm (D.sub.2 O): 1.2-1.8 (8H, m), 2.3-2.5 (2H, m), 3.0-3.4 (2H, m), 3.645 (1H, t, J=4.4 Hz), 3.7-3.8 (1H, m), 4.1-4.4 (1H, m), 7.878 (2H, d, J=8.8 Hz), 8.047 (2H, d, J=8.8 Hz), 8.2-8.5 (3H, m)
Fab-MS m/z: 485 (M.sup.+ 2-HCl)
Example 122
Preparation of (RS)-N-(7-carboxyheptyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(7-methoxycarbonylheptyl)-3-(pyridin-3-yloxy)propanamide (16.5 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(7-carboxyheptyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (17.0 mg).
Melting point: 73.degree.-74.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3427, 3078, 2929, 1720, 1664, 1554, 1396, 1305, 1165, 1093
.sup.1 H-NMR .delta. ppm (D.sub.2 O): 1.2-1.7 (10H, m), 2.360 (2H, t, J=7.4 Hz), 3.060 (2H, t, J=6.6 Hz), 4.3-4.4 (2H, m), 4.444 (1H, d, J=7.3 Hz), 7.585 (2H, d, J=8.5 Hz), 7.846 (2H, d, J=8.5 Hz), 8.0-8.1 (2H, m), 8.3-8.4 (2H, m)
Fab-MS m/z: 498 (MH.sup.+ -HCl)
Example 123
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide
The procedure described in Example 103 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide (160.0 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide (138.9 mg).
Melting point: 152.degree.-153.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3269, 1691 (br), 1332, 1155
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.489 (2H, s), 4.217 (2H, d, J=5.86 Hz), 4.408 (1H, t, J=5.86 Hz), 7.0-7.2 (6H, m), 7.388 (2H, d, J=8.55 Hz), 7.8-8.0 (2H, m), 7.913 (2H, dd, J=8.79 Hz, J=5.13 Hz)
Fab-MS m/z: 474 (MH.sup.+)
Example 124
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-(pyridin-3-yloxy)propanamide
The procedure described in Example 103 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(pyridin-3-yloxy) propanamide (65.0 mg) was hydrolyzed to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-(pyridin-3-yloxy)propanamide (43.0 mg).
Melting point: 205.degree.-207.degree. C.
IR .nu.max cm.sup.-1 (KBr): 1687 (br), 1333, 1277, 1238, 1092, 741, 609
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD-DMSO-d.sub.6): 3.563 (2H, s), 4.269 (2H, d, J=5.9 Hz), 4.452 (1H, t, J=5.9 Hz), 7.238 (2H, d, J=8.54 Hz), 7.31 (2H, m), 7.405 (2H, d, J=8.54 Hz), 7.676 (2H, d, J=7.9 Hz), 7.826 (2H, d, J=7.9 Hz), 8.188 (2H, m)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD-DMSO-d.sub.6): 56.92, 68.69, 120.10, 121.90, 124.32, 128.03, 128.91, 129.71, 131.07, 132.13, 132.21, 136.83, 138.15, 140.57, 142.51, 166.79, 166.79, 172.91
Fab-MS m/z: 534 (MH.sup.+), 536 (MH.sup.+ +2)
Example 125
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenoxypropanamide
Sodium hydride (60%dispersion in mineral oil, 73.6 mg) was washed with hexane, then suspended in DMF (0.5 ml) under argon and cooled to 0.degree. C. A solution of phenol (138.5 mg) in DMF (1 ml) was added and the mixture was stirred for 15 minutes. Then, a solution of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxy-propanamide (382 mg) in DMF (1.5 ml) was added and the mixture was stirred for 1.5 hours. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na.sub.2 SO.sub.4. The solvent was evaporated, and then, the residue was recrystallized from a mixture of hexane/ethyl acetate to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-phenoxypropanamide (309 mg).
Melting point: 145.degree.-146.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3365, 1732, 1670, 1331, 1244, 1167, 831, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.236 (3H, t, J=7.08 Hz), 3.543 (2H, s), 4.1-4.2 (2H, m), 4.1-4.2 (2H, m), 4.2 (1H, m), 6.761 (2H, d, J=7.5 Hz), 6.920 (1H, t, J=7.5 Hz), 7.218 (2H, t, J=7.5 Hz), 7.177 (2H, d, J=8.5 Hz), 7.364 (2H, d, J=8.55 Hz), 7.393 (2H, d, J=8.5 Hz), 7.837 (2H, d, J=8.55 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.38, 56.46, 59.87, 67.47, 77.48, 113.93, 119.32, 120.64, 127.87, 128.30, 128.67, 128.74, 128.96, 129.37, 136.01, 137.95, 138.50, 157.24, 166.19, 170.59
Fab-MS m/z: 517 (MH.sup.+)
Example 126
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(4-chlorophenoxy)propanamide
The procedure described in Example 125 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (360 mg) was reacted with 4-chlorophenol (178.3 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(4-chlorophenoxy) propanamide (248 mg).
Melting point: 136.degree.-137.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3429, 1734, 1649, 1340, 1244, 1169, 827, 758
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.235 (3H, t, J=7.08 Hz), 3.541 (2H, s), 4.144 (2H, q, J=7.08 Hz), 4.15 (2H, m), 4.361 (1H, t, J=5.62 Hz), 6.726 (1H, d, J=9.040 Hz), 7.14-7.2 (4H, m), 7.366 (2H, d, J=8.8 Hz), 7.384 (2H, d, J=8.55 Hz), 7.612 (1H, d, J=9.3 Hz), 7.828 (1H, d, J=8.8 Hz), 7.943 (1H, d, J=9.3 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.50, 26.70, 56.37, 68.14, 82.11, 115.74, 119.33, 127.92, 128.32, 128.58, 128.76, 129.02, 129.38, 129.79, 137.63, 156.23, 166.09, 170.38
Fab-MS m/z: 551 (MH.sup.+)
Example 127
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide
The procedure described in Example 125 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (401 mg) was reacted with 3-chlorophenol (198.7 mg) and was recrystallized from hexane-ethyl acetate to obtain (RS)-2-(4-chlorobenzenesulfonyl-amino)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (363.2 mg).
Melting point: 173.degree.-174.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3356, 1728, 1670, 1331, 1230, 1165, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.246 (3H, t, J=7.2 Hz), 3.560 (2H, s), 4.126 (2H, q, J=7.2 Hz), 4.16-4.24 (2H, m), 4.359 (1H, t, J=5.4 Hz), 6.649 (1H, dd, J=8.3 Hz, J=2.3 Hz), 6.739 (1H, t, J=2.3 Hz), 6.912 (1H, bd, J=8.1 Hz), 7.160 (1H, dd, J=8.3 Hz, J=8.1 Hz), 7.194 (2H, d, J=8.5 Hz), 7.373 (2H, d, J=8.8 Hz), 7.403 (2H, d, J=8.5 Hz), 7.836 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.60, 40.22, 56.54, 60.13, 67.98, 112.50, 114.81, 119.54, 121.01, 128.05, 128.60, 129.04, 129.77, 134.17, 136.08, 138.35, 138.61, 158.23, 166.08, 170.77
Fab-MS m/z: 551 (MH.sup.+)
Example 128
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-(2-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide
The procedure described in Example 125 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (403 mg) was reacted with 2-chlorophenol (390.2 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-(2-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (390.2 mg).
Melting point: 141.degree.-142.5.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3334, 3244, 1734, 1657, 1340, 1250, 1169, 829
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.242 (3H, t, J=7.2 Hz), 3.562 (2H, s), 4.09-4.18 (1H, m), 4.133 (2H, q, J=7.2 Hz), 4.239 (1H, m), 4.441 (1H, dd, J=9.2 Hz, J=4.5 Hz), 6.86-6.98 (2H, m), 7.15-7.45 (8H, m), 7.848 (2H, d, J=8.8 Hz), 8.886 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.65, 40.28, 56.47, 60.18, 69.00, 113.66, 119.73, 121.89, 122.41, 127.42, 128.11, 128.72, 129.06, 129.78, 136.12, 138.31, 138.51, 152.97, 166.13, 170.85
Fab-MS m/z: 551 (MH.sup.+)
Example 129
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-phenoxypropanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenoxypropanamide (178.9 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-phenoxypropanamide (106.5 mg).
Melting point: 190.5.degree.-192.5.degree. C. (recrystallized from ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3358, 1695, 1670, 1331, 1242, 1165, 829, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.515 (2H, s), 4.2 (1H, m), 4.3 (2H, m), 6.754 (2H, d, J=7.5 Hz), 6.919 (1H, t, J=7.5 Hz), 7.212 (2H, t, J=7.5 Hz), 7.918 (2H, d, J=8.5 Hz), 7.364 (2H, d, J=8.79 Hz), 7.378 (2H, d, J=8.5 Hz), 7.833 (2H, d, J=8.79 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 40.17, 56.67, 67.84, 114.23, 119.50, 120.86, 128.00, 128.83, 129.04, 130.25, 135.98, 138.22, 138.77, 157.49, 166.21, 172.52
Fab-MS m/z: 489 (MH.sup.+)
Example 130
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(4-chlorophenoxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(4-chlorophenoxy)propanamide (180 mg) was hydrolyzed and recrystallized from hexane/ethyl acetate to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(4-chlorophenoxy)propanamide (49.7 mg).
Melting point: 205.degree.-207.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3400, 1670, 1606, 1329, 1242, 1165, 825, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 4.1-4.2 (2H, m), 4.33 (1H, m), 6.692 (2H, d, J=9.0 Hz), 7.171 (2H, d, J=9.0 Hz), 7.202 (2H, d, J=8.6 Hz), 7.367 (2H, d, J=8.6 Hz), 7.380 (2H, d, J=8.5 Hz), 7.826 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 40.18, 56.50, 68.02, 115.40, 115.51, 119.47, 128.01, 128.86, 128.71, 129.15, 130.21, 135.86, 138.39, 138.54, 156.06, 166.08, 172.86
Fab-MS m/z: 523 (MH.sup.+)
Example 131
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(3-chlorophenoxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide (200 mg) was hydrolyzed and recrystallized from ethyl acetate to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(3-chlorophenoxy)propanamide (38.11 mg).
Melting point: 219.5.degree.-221.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3400 (br), 3323, 1716, 1655, 1344, 1230, 1167, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.494 (2H, s), 4.083 (1H, dd, J=9.9 Hz, J=7.2 Hz), 4.152 (1H, dd, J=9.9 Hz, J=5.5 Hz), 4.31-4.44 (1H, m), 6.738 (1H, dd, J=8.3 Hz, J=1.7 Hz), 6.786 (1H, t, J=2.2 Hz), 6.949 (1H, dd, J=8.0 Hz, J=2.0 Hz), 7.169 (2H, d, J=8.5 Hz), 7.233 (1H, t, J=8.1 Hz), 7.381 (2H, d, J=8.5 Hz), 7.494 (2H, d, J=8.5 Hz), 7.837 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 39.98, 56.22, 68.07, 113.14, 114.68, 119.30, 120.73, 128.06, 128.50, 128.69, 129.02, 130.15, 133.56, 136.39, 137.19, 139.72, 158.46, 166.05, 172.03,
Fab-MS m/z: 523 (MH.sup.+)
Example 132
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(2-chlorophenoxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-(2-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide (200 mg) was hydrolyzed and recrystallized from hexane/ethyl acetate to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(2-chlorophenoxy)propanamide (62.5 mg).
Melting point: 190.degree.-191.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3435, 3329, 3259, 1705, 1660, 1336, 1248, 1167, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.484 (2H, s), 4.189 (2H, d, J=6.3 Hz), 4.429 (1H, t, J=6.3 Hz), 6.932 (1H, td, J==7.9 Hz, J=1.3 Hz), 7.040 (1H, dd, J=7.9 Hz, J=1.3 Hz), 7.158 (2H, d, J=8.5 Hz), 7.228 (1H, td, J=7.9 Hz, J=1.6 Hz), 7.321 (1H, dd, J=7.9 Hz, J=1.6 Hz), 7.357 (2H, d, J=8.5 Hz), 7.454 (2H, d, J=8.4 Hz), 7.846 (2H, d, J=8.4 Hz), 9.895 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 40.01, 56.19, 68.73, 114.13, 119.41, 121.79, 127.70, 128.10, 128.54, 128.98, 129.60, 130.12, 136.42, 137.23, 139.58, 153.15, 166.20, 172.07
Fab-MS m/z: 523 (MH.sup.+)
Example 133
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-phenoxypropanamide
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzene-sulfonylamino)-3-methanesulfonyloxypropanamide (500 mg) was reacted with phenol (187 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-phenoxypropanamide (400.58 mg).
Melting point: 122.2.degree.-123.5.degree. C. (recrystallized from ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3367, 1732, 1670, 1331, 1244, 1167, 565
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.239 (3H, t, J=7.08 Hz), 3.551 (2H, s), 4.126 (2H, q, J=7.08 Hz), 4.2-4.4 (3H, m), 6.758 (2H, d, J=7.81 Hz), 6.928 (1H, t, J=7.4 Hz), 7.076 (2H, t, J=8.5 Hz), 7.14-7.28 (4H, m), 7.409 (1H, d, J=8.5 Hz), 7.917 (2H, dd, J=8.5 Hz, J=5.0 Hz), 9.267 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.67, 40.29, 56.72, 60.24, 67.76, 114.19, 115.43, 115.76, 119.61, 120.97, 129.00, 129.11, 129.48, 129.77, 136.01, 136.15, 157.46, 162.59, 166.33, 166.44, 170.95
Fab-MS m/z: 501 (MH.sup.+)
Example 194
Preparation of (RS)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)propanamide
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (300 mg) was reacted with 4-chlorophenol (153 mg) to obtain (RS)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)propanamide (236.25 mg).
Melting point: 132.degree.-134.5.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3350, 3223, 1732, 1666, 1333, 1295, 1241, 1155
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.246 (3H, t, J=7.08 Hz), 4.133 (2H, q, J=7.08 Hz), 4.2-4.35 (3H, m), 6.698 (2H, d, J=9.1 Hz), 7.096 (2H, t, J=8.8 Hz), 7.180 (2H, d, J=9.1 Hz), 7.202 (2H, d, J=8.1 Hz), 7.406 (2H, d, J=8.1 Hz), 7.914 (2H, dd, J=8.8 Hz, J=5.13 Hz), 9.156 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.52, 40.40, 56.46, 60.09, 68.09, 115.29, 115.58, 119.50, 125.63, 128.67, 128.96, 129.18, 129.33, 129.62, 136.08, 156.10, 162.41, 166.19, 170.77
Fab-MS m/z: 535 (MH.sup.+)
Example 135
Preparation of (RS)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)propanamide
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (310 mg) was reacted with 3-chlorophenol (125 .mu.l) to obtain (RS)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)propanamide (257.24 mg).
Melting point: 164.degree.-165.3.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3321, 1738, 1652, 1340, 1176, 1090
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.233 (3H, t, J=7.1 Hz), 3.542 (2H, s), 4.118 (2H, q, J=7.1 Hz), 4.18 (2H, m), 4.369 (1H, t, J=5.5 Hz), 6.699 (1H, dd, J=8.3 Hz, J=2.2 Hz), 6.778 (1H, t, J=2.2 Hz), 6.903 (1H, d, J=8.3 Hz), 7.101 (2H, t, J=8.5 Hz), 7.164 (1H, t, J=8.3 Hz), 7.169 (2H, d, J=8.8 Hz), 7.406 (2H, 8.8 Hz), 7.914 (2H, dd, J=8.5 Hz, J=5.1 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.19, 39.71, 56.01, 59.69, 67.58, 112.25, 114.38, 114.90, 115.24, 119.13, 120.48, 128.88, 128.81, 128.95, 129.21, 129.44, 133.59, 135.86, 135.98, 157.89, 161.98, 165.87, 170.42
Fab-MS m/z: 535 (MH.sup.+)
Example 136
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-fluorobenzenesulfonylamino)-3-phenoxypropanamide
The procedure described in Example 39 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-phenoxypropanamide (180.9 mg) was hydrolyzed to obtain -(RS)-N-(4-carboxymethyl)-phenyl)-2-(4-fluorobenzenesulfonylamino)-3-phenoxypropanamide (115.69 mg).
Melting point: 173.4.degree.-175.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3340, 1700, 1670, 1331, 1294, 1240, 1155, 1092
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.495 (2H, s), 4.168 (2H, m), 4.368 (2H, t, J=5.74 Hz), 6.775 (2H, d, J=7.8 Hz), 6.910 (1H, t, J=7.3 Hz), 7.111 (2H, t, J=8.8 Hz), 7.187 (4H, m), 7.393 (2H, d, J=8.5 Hz), 7.917 (2H, dd, J=9.03 Hz, J=5.13 Hz), 9.555 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 40.12, 56.52, 67.88, 114.27, 115.15, 115.48, 119.41, 120.76, 128.94, 129.27, 130.12, 136.24, 136.68, 157.58, 162.24, 166.38, 172.29
Fab-MS m/z: 473 (MH.sup.+)
Example 137
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-3-(4-chlorophenoxy)-2-(4-fluorobenzenesulfonylamino)propanamide
The procedure described in Example 39 was repeated, except that (RS)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)propanamide (160 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-3-(4-chlorophenoxy)-2-(4-fluorobenzenesulfonylamino)propanamide (47.25 mg).
Melting point: 183.5.degree.-186.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3338, 1697, 1315, 1241, 1171, 1155
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.527 (2H, s), 4.1-4.4 (3H, m), 6.720 (2H, d, J=9.3 Hz), 7.097 (2H, t, J=9.1 Hz), 7.1-7.3 (4H, m), 7.419 (2H, d, J=8.6 Hz), 7.913 (2H, dd, J=9.1 Hz, J=5.1 Hz), 9.362 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 39.71, 56.43, 68.09, 115.58, 119.47, 119.58, 119.87, 127.09, 128.67, 129.18, 129.29, 129.36, 135.90, 156.10, 166.15, 172.35
Fab-MS m/z: 507 (MH.sup.+)
Example 138
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-3-(3-chlorophenoxy)-3-(4-fluorobenzenesulfonylamino)propanamide
The procedure described in Example 39 was repeated, except that (RS)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)propanamide (184.9 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-3-(3-chlorophenoxy)-2-(4-fluorobenzenesulfonylamino)propanamide (104.94 mg).
Melting point: 195.degree.-197.degree. C. (recrystallized from ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3300 (br), 1710, 1684, 1333, 1240, 1155, 839
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.536 (2H, s), 4.1-4.4 (3H, m), 6.660 (1H, ddd, J=8.3 Hz, J=2.5 Hz, J=1.0 Hz), 6.755 (1H, t, J=2.5 Hz), 6.913 (1H, ddd, J=8.1 Hz, J=1.8 Hz, J=0.7 Hz), 7.0-7.3 (3H, m), 7.210 (2H, d, J=8.5 Hz), 7.40 (2H, d, J=8.5 Hz), 7.913 (2H, dd, J=8.8 Hz, J=5.1 Hz), 9.228 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6); 40.40, 56.65, 68.13, 112.68, 115.07, 115.62, 115.95, 119.80, 121.26, 127.39, 129.37, 129.59, 129.95, 130.58, 134.39, 136.04, 136.15, 158.37, 162.78, 166.33, 173.12
Fab-MS m/z: 507 (MH.sup.+)
Example 139
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenoxypropanamide
The procedure described in Example 125 was repeated, except that ((RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (500 mg) was reacted with phenol (167 mg) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenoxypropanamide (425.22 mg).
Melting point: 150.5.degree.-153.degree. (recrystallized from ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3369, 3161, 1734, 1670, 1331, 1244, 1167, 557
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.244 (3H, t, J=7.1 Hz), 3.555 (2H, s), 4.125 (2H, q, J=7.1 Hz), 4.20 (2H, m), 4.345 (1H, t, J=5.2 Hz), 6.744 (2H, d, J=8.0 Hz), 6.930 (1H, t, J=7.3 Hz), 7.1-7.3 (4H, m), 7.390 (2H, d, J=8.0 Hz), 7.524 (2H, d, J=8.6 Hz), 7.762 (2H, d, J=8.6 Hz), 9.332 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.63, 40.22, 56.65, 60.17, 67.65, 114.11, 119.43, 119.54, 120.86, 126.87, 128.16, 128.93, 129.04, 129.62, 131.57, 139.01, 157.38, 166.30, 170.84
Fab-MS m/z: 563 (MH.sup.+ +2), 561 (MH.sup.+)
Example 140
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide
The procedure described in Example 125 was repeated, except that ((RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (420 mg) was reacted with 4-chlorophenol (191.6 .mu.l) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (242.12 mg).
Melting point: 154.5.degree.-156.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3342, 3250, 1732, 1672, 1333, 1242, 1165, 823, 742
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.243 (3H, t, J=7.1 Hz), 3.553 (2H, s), 4.118 (2H, q, J=7.1 Hz), 4.14 (2H, m), 4.368 (1H, t, J=5.7 Hz), 6.713 (2H, d, J=9.0 Hz), 7.179 (2H, d, 8.6 Hz), 7.181 (2H, d, J=9.0 Hz), 7.388 (2H, d, J=8.6 Hz), 7.526 (2H, d, J=8.6 Hz), 7.759 (2H, d, J=8.6 Hz), 9.578 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.19, 39.63, 55.91, 59.62, 67.50, 115.10, 118.95, 124.89, 126.10, 127.64, 128.23, 128.82, 129.00, 130.98, 135.79, 138.90, 155.62, 165.67, 170.29
Fab-MS m/z: 595 (MH.sup.+)
Example 141
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl) phenyl)propanamide
The procedure described in Example 125 was repeated, except that ((RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (315 mg) was reacted with 3-chlorophenol (113.2 .mu.l) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (214.48 mg).
Melting point: 59.5.degree.-161.degree. C. (recrystallized from chloroform/hexane)
IR .nu.max cm.sup.-1 (KBr): 3323, 1740, 1653, 1342, 1232, 1167, 746
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.244 (3H, t, J=7.1 Hz), 3.557 (2H, s), 4.128 (2H, q, J=7.1 Hz), 4.15-4.25 (2H, m), 4.348 (1H, t, J=5.2 Hz), 6.647 (1H, dd, J=8.1 Hz, J=2.4 Hz), 6.748 (1H, t, J=2.2 Hz), 6.915 (1H, dd, J=8.1 Hz, J=1.0 Hz), 7.156 (1H, t, J=8.1 Hz), 7.199 (2H, d, J=8.5 Hz), 7.396 (2H, d, J=8.5 Hz), 7.539 (2H, d, J=8.8 Hz), 7.759 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.60, 40.18, 56.46, 60.17, 67.80, 112.39, 114.66, 119.50, 120.93, 126.87, 128.08, 129.04, 129.62, 129.77, 131.57, 134.10, 136.10, 138.98, 158.08, 166.04, 170.88
Fab-MS m/z: 595 (MH.sup.+)
Example 142
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-phenoxypropanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenoxypropanamide (200 mg) was hydrolyzed to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-phenoxypropanamide (147.9 mg).
Melting point: 201.degree.-204.degree. C. (recrystallized from ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3475, 3352, 3259, 1695, 1670, 1329, 1242, 1165, 752
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.526 (2H, s), 4.175 (2H, m), 4.361 (1H, m), 6.745 (2H, d, J=8.6 Hz), 6.928 (1H, t, J=7.5 Hz), 7.1-7.3 (4H, m), 7.387 (2H, d, J=8.6 Hz), 7.528 (2H, d, J=8.5 Hz), 7.767 (2H, d, J=8.5 Hz), 9.496 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 39.96, 56.35, 67.36, 113.78, 114.92, 119.17, 120.53, 126.43, 127.86, 128.63, 128.85, 129.84, 131.24, 135.79, 138.94, 157.13, 166.00, 172.57
Fab-MS m/z: 535 (MH.sup.+ +2), 533 (MH.sup.+)
Example 143
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-(4-chlorophenoxy) propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide (164 mg) was hydrolyzed to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-(4-chlorophenoxy)propanamide (86.85 mg).
Melting point: 217.5.degree.-219.5.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3300 (br), 1666, 1325, 1244, 1165, 822
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.513 (2H, s), 4.165 (2H, m), 4.357 (1H, t, J=5.5 Hz), 6.716 (2H, d, J=9.0 Hz), 7.175 (2H, d, J=9.0 Hz), 7.193 (2H, d, J=8.5 Hz), 7.373 (2H, d, J=8.5 Hz), 7.534 (2H, d, J=8.7 Hz), 7.755 (2H, d, J=8.7 Hz), 9.395 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 39.93, 56.28, 67.94, 115.47, 119.25, 125.26, 126.32, 127.83, 128.41, 128.74, 129.99, 131.20, 135.75, 139.23, 155.95, 165.82, 172.16
Fab-MS m/z: 569 (MH.sup.+ +2), 567 (MH.sup.+)
Example 144
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-(3-chlorophenoxy) propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (154 mg) was hydrolyzed to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-(3-chlorophenoxy)propanamide (81.02 mg).
Melting point: 225.degree.-227.5.degree. C. (recrystallized from ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3300 (br), 1664, 1327, 1232, 1165, 742
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.508 (2H, s), 4.182 (2H, m), 4.372 (1H, t, J=5.6 Hz), 6.677 (1H, dd, J=8.3 Hz, J=2.5 Hz), 6.764 (1H, t, J=2.5 Hz), 6.908 (1H, ddd, J=7.8 Hz, J=2.0 Hz, J=0.7 Hz), 7.166 (1H, t, J=8.3 Hz), 7.190 (2H, d, J=8.5 Hz), 7.380 (2H, d, J=8.5 Hz), 7.545 (2H, d, J=8.8 Hz), 7.762 (2H, d, J=8.8 Hz), 9.483 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 39.82, 56.13, 67.72, 112.35, 14.48, 119.14, 120.53, 126.18, 127.72, 128.63, 129.40, 129.88, 131.09, 133.66, 135.71, 139.23, 157.97, 165.67, 172.02
Fab-MS m/z: 569 (MH.sup.+ +2), 567 (MH.sup.+)
Example 145
Preparation of (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-phenoxypropanamide
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(carbethoxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (400 mg) was reacted with phenol (123 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-phenoxypropanamide (252.62 mg).
Melting point: 177.5.degree.-180.5.degree. C. (recrystallized from ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3358, 3271, 1732, 1670, 1331, 1242, 1165, 756, 735
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.235 (3H, t, J=7.1 Hz), 3.546 (2H, s), 4.116 (2H, q, J=7.1 Hz), 4.16 (2H, m), 4.363 (1H, t, J=5.7 Hz), 6.752 (2H, d, J=8.3 Hz), 6.85-7.30 (5H, m), 7.379 (2H, d, J=8.3 Hz), 7.603 (2H, d, J=8.6 Hz), 7.742 (2H, d, J=8.6 Hz), 9.473 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.50, 44.27, 56.59, 59.85, 67.74, 98.98, 114.20, 115.26, 119.44, 119.77, 120.73, 121.57, 127.66, 127.88, 128.83, 128.94, 129.42, 136.24, 137.34, 140.13, 157.47, 166.20, 170.45
Fab-MS m/z: 609 (MH.sup.+)
Example 146
Preparation of (RS)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)propanamide
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(carbethoxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (380 mg) was reacted with 4-chlorophenol (160 .mu.l) to obtain (RS)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl) phenyl)-2-(4-iodobenzenesulfonylamino)propanamide (297.11 mg).
Melting point: 161.5.degree.-163.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3346, 1732, 1670, 1333, 1244, 1165, 822, 733
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.240 (3H, t, J=7.1 Hz), 3.551 (2H, s), 4.125 (2H, q, J=7.1 Hz), 4.15 (2H, m), 4.347 (1H, t, J=5.5 Hz), 6.702 (2H, d, J=9.0 Hz), 7.177 (2H, d, J=9.0 Hz), 7.186 (2H, d, J=8.5 Hz), 7.376 (2H, d, J=8.5 Hz), 7.594 (2H, d, J=8.8 Hz), 7.744 (2H, d, J=8.8 Hz), 9,325 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 14.00, 40.59, 56.90, 60.53, 68.38, 99.74, 115.91, 119.91, 125.92, 128.34, 129.11, 129.44, 129.99, 136.45, 137.88, 140.15, 156.47, 166.52, 171.17
Fab-MS m/z: 643 (MH.sup.+)
Example 147
Preparation of (RS)-3-(3chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)propanamide
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(carbethoxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (380 mg) was reacted with 3-chlorophenol (160 mg) to obtain (RS)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)propanamide (267.88 mg).
Melting point: 168.8.degree.-170.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3323, 1736, 1653, 1342, 1232, 1167, 737
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.245 (3H, t, J=7.1 Hz), 3.560 (2H, s), 4.128 (2H, q, J=7.1 Hz), 4.15-4.25 (2H, m), 4.348 (1H, t, J=5.4 Hz), 6.641 (1H, ddd, J=8.1 Hz, J=2.4 Hz, J=1.0 Hz), 6.748 (1H, t, J=2.1 Hz), 6.918 (1H, ddd, J=8.1 Hz, J=2.0 Hz, J=0.9 Hz), 7.162 (1H, t, J=8.1 Hz), 7.200 (2H, d, J=8.8 Hz), 7.388 (2H, d, J=8.8 Hz), 7.601 (2H, d, J=8.8 Hz), 8.755 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.63, 40.22, 56.46, 60.17, 67.80, 99.41, 112.43, 114.66, 119.50, 120.97, 127.94, 129.07, 129.62, 129.77, 136.01, 137.51, 139.60, 158.08, 166.04, 170.88
Fab-MS m/z: 643 (MH.sup.+)
Example 148
Preparation of (RS)-3-(2-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4- iodobenzenesulfonylamino)propanamide
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(carbethoxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (430 mg) was reacted with 2-chlorophenol (163 mg) to obtain (RS)-3-(2-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)propanamide (285.8 mg).
Melting point: 140.5.degree.-142.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3498, 3348, 3259, 1734, 1670, 1338, 1250, 1167, 818
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.237 (3H, t, J=7.1 Hz), 3.544 (2H, s), 4.123 (2H, q, J=7.1 Hz), 4.15-4.34 (2H, m), 4.387 (1H, t, J=5.4 Hz), 6.86-6.95 (2H, m), 7.162 (1H, dd, J=8.1 Hz, J=1.7 Hz), 7.180 (2H, d, J=8.6 Hz), 7.298 (1H, dd, J=8.1 Hz, J=1.7 Hz), 7.375 (2H, d, J=8.6 Hz), 7.607 (2H, d, J=8.5 Hz), 7.730 (2H, d, J=8.5 Hz), 9.299 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.49, 40.11, 56.43, 59.91, 69.01, 99.15, 113.82, 119.61, 121.74, 122.40, 127.24, 127.86, 128.85, 129.55, 129.62, 136.12, 137.47, 139.71, 152.98, 165.97, 170.51
Fab-MS m/z: 643 (MH.sup.+)
Example 149
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-iodobenzenesulfonylamino)-3-phenoxypropanamide
The procedure described in Example 39 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-phenoxypropanamide (153 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-iodobenzenesulfonylamino)-3-phenoxypropanamide (73.99 mg).
Melting point: 223.5.degree.-225.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3300 (br), 1695, 1670, 1331, 1242, 1165, 756, 733
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.515 (2H, s), 4.153 (2H, d, J=5.9 Hz), 4.364 (1H, t, J=5.9 Hz), 6.743 (2H, d, J=8.2 Hz), 6.924 (1H, t, J=8.2 Hz), 7.191 (2H, d, J=8.6 Hz), 7.226 (2H, d, J=8.2 Hz), 7.375 (2H, d, J=8.6 Hz), 7.607 (2H, d, J=8.3 Hz), 7.742 (2H, d, J=8.3 Hz), 9.589 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 39.71, 56.02, 67.10, 98.75, 113.56, 118.88, 120.24, 127.42, 128.38, 128.56, 129.51, 135.60, 136.85, 139.45, 156.87, 165.75, 172.09
Fab-MS m/z: 581 (MH.sup.+)
Example 150
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-3-(4-chlorophenoxy)-2-(4-iodobenzenesulfonylamino)propanamide
The procedure described in Example 39 was repeated, except that (RS)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)propanamide (170 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-3-(4-chlorophenoxy)-2-(4-iodobenzenesulfonylamino)propanamide (47.57 mg).
Melting point: 196.degree.-198.degree. C. (recrystallized from hexane/ethyl acetate)
IR .nu.max cm.sup.-1 (KBr): 3400 (br), 3354, 3251, 1701, 1670, 1327, 1242, 1163, 820, 733
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.523 (2H, s), 4.149 (2H, m), 4.353 (1H, t, J=5.5 Hz), 6.701 (2H, d, J=9.0 Hz), 7.182 (2H, d, J=9.0 Hz), 7.202 (2H, d, J=8.6 Hz), 7.373 (2H, d, J=8.6 Hz), 7.598 (2H, d, J=8.8 Hz), 7.744 (2H, d, J=8.8 Hz), 9.471 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 39.93, 56.17, 67.72, 98.97, 115.29, 119.14, 125.15, 127.61, 128.38, 128.78, 129.84, 135.71, 137.14, 139.64, 155.81, 165.78, 172.35
Fab-MS m/z: 615 (MH.sup.+)
Example 151
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-3-(3-chlorophenoxy)-2-(4-iodobenzenesulfonylamino) propanamide
The procedure described in Example 39 was repeated, except that (RS)-3-(3-chlorophenoxy)-N-(4-(ethoxycarbonyl-methyl)phenyl)-2-(4-iodobenzenesulfonylamino)propanamide (183 mg) was hydrolyzed and recrystallized from hexane/ethyl acetate to obtain (RS)-N-(4-(carboxymethyl)phenyl)-3-(3-chlorophenoxy)-2-(4-iodobenzenesulfonylamino)propanamide (109.37 mg).
Melting point: 225.degree.-226.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3321, 3300 (br), 1713, 1655, 1340, 1230, 1165, 735
.sup.1 H NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.521 (2H, s), 4.1-4.2 (2H, m), 4.362 (1H, t, J=5.5 Hz), 6.658 (1H, dd, J=8.0 Hz, J=2.44 Hz), 6.751 (1H, t, J=2.2 Hz), 6.911 (1H, d, J=8.0 Hz), 7.173 (1H, t, J=8.2 Hz), 7.202 (2H, t, J=8.4 Hz), 7.378 (2H, d, J=8.4 Hz), 7.603 (2H, d, J=8.5 Hz), 7.755 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 39.93, 56.13, 67.61, 98.97, 112.28, 114.41, 119.17, 119.65, 120.60, 127.61, 128.78, 128.96, 129.51, 129.84, 133.69, 135.71, 137.14, 139.64, 157.93, 165.75, 172.35
Fab-MS m/z: 615 (MH.sup.+)
Example 152
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-3-(2chlorophenoxy)-2-(4-iodobenzenesulfonylamino) propanamide
The procedure described in Example 39 was repeated, except that (RS)-3-(2-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-iodobenzenesulfonylamino)propanamide (165 mg) was hydrolyzed and recrystallized from hexane/ethyl acetate to obtain (RS)-N-(4-(carboxymethyl) phenyl)-3-(2-chlorophenoxy)-2-(4-iodobenzenesulfonylamino)propanamide (55.95 mg).
Melting point: 198.5.degree.-200.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3344, 3280, 3200 (br), 1697 (br), 1338, 1246, 1165
.sup.1 H NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 3.520 (2H, s), 4.15-4.45 (3H, m), 6.87-6.95 (2H, m), 7.163 (1H, dd, J=8.1 Hz, J=1.7 Hz), 7.203 (2H, d, J=8.6 Hz), 7.301 (1H, dd, J=8.1 Hz, J=1.7 Hz), 7.367 (2H, d, J=8.6 Hz), 7.606 (2H, d, J=8.6 Hz), 7.735 (2H, d, J=8.6 Hz), 9.238 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 39.97, 56.09, 68.65, 98.80, 113.57, 119.22, 119.59, 121.40, 126.53, 126.96, 127.54, 128.60, 128.69, 128.83, 129.27, 129.76, 135.75, 137.10, 139.58, 152.71, 165.69, 171.97
Fab-MS m/z: 615 (MH.sup.+)
Example 153
Preparation of (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide
60% NaH (2.4 g) was suspended in THF (100 ml), and dimethyl malonate (6.9 ml) was added dropwise at 0.degree. C. The mixture was stirred at room temperature for 30 minutes, and then benzylchloromethylether (8.3 ml) in THF (20 ml) was added dropwise. The mixture was stirred at room temperature for further 1 hour. Then, the reaction mixture was cooled to 0.degree. C. and a suspension of 60% NaH (3.36 g) in THF (20 ml) was added dropwise. The whole was stirred for 30 minutes, and then THF (20 ml) and benzylchloromethylether (11.7 ml) were added dropwise. The mixture was stirred at room temperature for 1.5 hours. An excess NaH was decomposed with methanol, and the product was diluted with ethyl acetate, rinsed, dried over Na.sub.2 SO.sub.4, and concentrated. The resulting residue was recrystallized from isopropyl alcohol to give dimethyl (RS)-2,2-bis-(benzyloxymethyl)-1,3-propanedioic acid (11.8 g).
Dimethyl (RS)-2,2-bis-(benzyloxymethyl)-1,3-propanedioic acid (1.05 g) was dissolved in ethanol and 10% KOH, and the mixture was stirred at room temperature for 6 hours, and then at 50.degree. C. for 17 hours. The mixture was acidified to pH1 with 2N HCl and was extracted with ethyl acetate. The organic layer was washed with a saline solution, dried over Na.sub.2 SO.sub.4 and concentrated. Toluene (30 ml) was added to the resulting residue, and the mixture was heated under reflux for 17 hours. The reaction mixture was concentrated under reduced pressure to give crude (RS)-3-benzyloxy-2-benzyloxy-methylpropanoic acid (850 mg) as a colorless syrup. The syrup (850 mg) was dissolved in methylene chloride, and then ethyl 4-aminobenzoate (650 mg) and triethylamine (0.92 ml) were added thereto. The mixture was added to a suspension of 2-chloro-1-methylpyridinium iodide (1.7 g) in methylene chloride (15 ml), and the mixture was heated under reflux under argon for 15 hours. The reaction mixture was washed with 2N HCl, saturated NaHCO.sub.3, and saturated NaCl, dried over Na.sub.2 SO.sub.4, and concentrated. The resulting residue was purified by silica gel column chromatography (Wakogel C-200, ethyl acetate/toluene=1/15) to give (RS)-3-benzyloxy-2-benzyloxymethyl-N-(4-ethoxycarbonylphenyl)propanamide (930 mg). The resulting (RS)-3-benzyloxy-2-benzyloxymethyl-N-(4-ethoxycarbonyl-phenyl)propanamide (930 mg) was suspended in methanol (20ml) and 10%Pd-C (200 mg) was added thereto. The mixture was stirred under hydrogen for 20 hours. The reaction mixture was filtered through Cellite, and the filtrate was concentrated. The resulting residue was recrystallized from toluene to obtain (RS)-N-(4-ethoxycarbonylphenyl)-3-hydroxy-2-hydroxymethylpropanamide (354 mg).
(RS)-N-(4-ethoxycarbonylphenyl)-3-hydroxy-2-hydroxymethylpropanamide (261 mg) and PPTS (74 mg) were dissolved in THF (10 ml), and dihydropyrane (134 .mu.l) was added thereto under argon. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO.sub.3 and saturated NaCl, dried over Na.sub.2 SO.sub.4 and concentrated. The resulting residue was purified by silica gel column chromatography (Wakogel C-200, methylethylketone/toluene=1/2) to give (RS)-N-(4-ethoxycarbonylphenyl)-2-hydroxymethyl-3-(tetrahydropyran-2-yloxy)propanamide (201 mg).
(RS)-N-(4-ethoxycarbonylphenyl)-2-hydroxymethyl-3-(tetrahydropyran-2-yloxy)propanamide (30.5 mg) was dissolved in pyridine, and tosyl chloride (33 mg) was added thereto. The whole was stirred at room temperature overnight. Methanol was added to the reaction mixture to decompose the excess reagents. Then, the mixture was concentrated under reduced pressure. The residue was dissolved with ethyl acetate, washed with water, 2N HCl, saturated NaHCO.sub.3 and saturated NaCl, dried over Na.sub.2 SO.sub.4 and concentrated. The resulting residue and sodium azide (28 mg) were dissolved in a mixture (DMSO-d.sub.6 :H.sub.2 O=4:1) (1 ml) and the solution was stirred at 100.degree. C. for 2 hours. The reaction mixture was poured in ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over Na.sub.2 SO.sub.4 and concentrated. The resulting residue was dissolved in ethanol (1 ml), and 10% Pd--C (5 mg) was added. The whole was stirred under a hydrogen atmosphere for 30 minutes. The reaction mixture was filtered through Cellite. The filtrate was concentrated, and the residue was dissolved in pyridine (0.5 ml). After 4-chlorobenzenesulfonyl chloride (27 mg) was added, and the whole was stirred at room temperature for 3 hours. Methanol was added to the reaction mixture to decompose the excess reagents. Then, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-300, ethyl acetate/hexane=1/3) to obtain (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (13.1 mg).
.sup.1 H NMR .delta. ppm (CDCl.sub.3): 1.390 (3H, t, J=7.08 Hz), 1.48-1.92 (6H, m), 2.78-3.04 (1H, m), 3.10-3.35 (2H, m), 3.46-3.63 (1H, m), 3.68-4.17 (3H, m), 4.362 (2H, q, J=7.08 Hz), 4.53-4.67 (1H, m), 5.48-5.60 (1H, m), 7.46-7.58 (4H, m), 7.797 (2H, d, J=8.7 Hz), 8.006 (2H, d, J=8.7 Hz), 8.73 (0.5H, br.s), 8.78 (0.5H, br.s)
Fab-MS m/z: 524 (M.sup.+), 441
Example 154
Preparation of (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylaminomethyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (7.7 mg) was hydrolyzed to obtain (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylaminomethyl)-3-(tetrahydropyran-2-yloxy)propanamide (7.2 mg).
Fab-MS m/z: 497 (MH.sup.+)
Example 155
Preparation of (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide
After (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (10.8 mg) was dissolved in methanol (5 ml), the mixture was acidified with p-toluenesulfonic acid to pH less than 4, and the whole was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with saturated NaHCO.sub.3 and saturated NaCl and dried over Na.sub.2 SO.sub.4 and concentrated to give (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (8.1 mg).
.sup.1 H NMR .delta. ppm (CD.sub.3 OD): 1.387 (3H, t, J=7.08 Hz), 2.80-2.90 (1H, m), 3.123 (1H, dd, J=5.61 Hz, J=13.55 Hz), 3.221 (1H, dd, J=8.30 Hz, J=13.55 Hz), 3.678 (1H, dd, J=5.86 Hz, J=10.99 Hz), 3.762 (1H, dd, J=6.84 Hz, J=10.99 Hz), 4.344 (2H, q, J=7.08 Hz), 7.10-7.24 (1H, m), 7.513 (2H, d, J=8.79 Hz), 7.670 (2H, d, J=9.03 Hz), 7.815 (2H, d, J=8.79 Hz), 7.880 (1H, s), 7.954 (2H, d, J=9.03 Hz)
Fab-MS m/z: 441 (MH.sup.+)
Example 156
Preparation of (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylaminomethyl)-3-hydroxypropanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (8.1 mg) was hydrolyzed to obtain (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylaminomethyl)-3-hydroxypropanamide (7.5 mg).
Fab-MS m/z: 413 (MH.sup.+)
Example 157
Preparation of (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The crude (RS)-3-benzyloxy-2-benzyloxymethylpropanoic acid (1.56 g) obtained by the same manner as the method described in Example 153 was dissolved in methylene chloride, and then ethyl 4-aminophenylacetate (2.24 g) and triethylamine (2.2 ml) were added. The mixture was added under argon to a suspension of 2-chloro-1-methylpyridinium iodide (2.65 g) suspended in methylene chloride (20 ml) and the whole was heated under reflux for 24 hours. The reaction mixture was washed with 2N HCl, saturated NaHCO.sub.3 and saturated NaCl, dried over Na.sub.2 SO.sub.4 and concentrated. The resulting residue was purified by silica gel column chromatography (Wakogel C-200, ethyl acetate/hexane=1/4) to give (RS)-3-benzyloxy-2-benzyloxymethyl-N-(4-(ethoxycarbonylmethyl)-phenyl)propanamide (655 mg). The functional group in the resulting (RS)-3-benzyloxy-2-benzyloxymethyl-N-(4-(ethoxycarbonylmethyl)phenyl) propanamide (520 mg) was converted in the same manner as in Example 153 to obtain (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (140 mg).
IR .nu.max cm.sup.-1 (KBr): 3512, 3305, 2943, 1732, 1666, 1604, 1415, 1333, 1161, 1030, 754, 619
.sup.1 H NMR .delta. ppm (CDCl.sub.3): 1.246 (3H, t, J=7.18 Hz), 1.43-1.93 (6H, m), 2.88-2.92 (1H, m), 3.16-3.27 (2H, m), 3.572 (2H, s), 3.51-4.07 (4H, m), 4.141 (2H, q, J=7.18 Hz), 4.584 (1H, bs), 5.710 (1H, t, J=6.45 Hz), 7.20-7.24 (2H, m), 7.38-7.48 (4H, m), 7.76-7.82 (2H, m), 8.509 (1H, d, 10.50 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.15, 20.01, 20.34, 25.11, 30.61, 30.90, 40.81, 42.20, 42.35, 46.31, 46.38, 60.86, 63.40, 64.06, 66.51, 67.47, 99.74, 100.91, 119.94, 120.09, 128.45, 129.44, 129.84, 130.25, 136.56, 138.32, 139.12, 170.44, 171.54
Fab-MS m/z: 538 (M.sup.+), 455 (M.sup.+)
Example 158
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylaminomethyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (32 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylaminomethyl)-3-(tetrahydropyran-2-yloxy)propanamide (30 mg).
IR .nu.max cm.sup.-1 (KBr): 3466, 2945, 1713, 1662, 1533, 1329, 1159, 1093, 1028, 482
.sup.1 H NMR .delta. ppm (CD.sub.3 OD): 1.30-2.02 (6H, m), 2.95-4.10 (9H, m), 4.674 (1H, bd, J=11.72 Hz), 7.20-7.42 (2H, m), 7.46-7.73 (4H, m), 7.78-8.01 (2H, m)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 19.99, 20.40, 26.37, 31.43, 31.54, 41.52, 42.95, 62.90, 63.45, 67.41, 67.74, 99.72, 100.56, 121.35, 121.87, 129.60, 130.38, 130.63, 130.82, 131.99, 138.30, 139.80, 140.42, 172.44, 172.58, 175.66
Fab-MS m/z: 511 (MH.sup.+)
Example 159
Preparation of (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide
The crude (RS)-3-benzyloxy-2-benzyloxymethylpropanoic acid (1.52 g) obtained in the same manner as the method described in Example 153 was dissolved in methylene chloride, and then, ethyl 3-aminobenzoate (1.51 g) and triethylamine (1.4 ml) were added. The reaction mixture was added to a suspension of 2-chloro-1-methylpyridinium iodide (2.59 g) suspended in methylene chloride (20 ml) under argon and heated under reflux for 24 hours. The reaction mixture was washed with 2N HCl, saturated NaHCO.sub.3 and saturated NaCl, dried over Na.sub.2 SO.sub.4 and concentrated. The resulting residue was purified by silica gel column chromatography (Wakogel C-200, ethyl acetate/toluene=1/15) to obtain (RS)-3-benzyloxy-2-benzyloxymethyl-N-(3-ethoxycarbonylphenyl)-propanamide (1.31 g). The functional group of (RS)-3-benzyloxy-2-benzyloxymethyl-N-(3-ethoxycarbonylphenyl)propanamide (1.17 g) was converted in the same manner as Example 153 to obtain (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (267 mg).
IR .nu.max cm.sup.-1 (KBr): 3325, 2943, 1718, 1552, 1288, 1162, 1028, 754
1H-NMR .delta. ppm (CDCl.sub.3): 1.390 (3H, t, J=7.18 Hz), 1.46-1.91 (6H, m), 2.83-3.01 (1H, m), 3.12-3.35 (2H, m), 3.05-3.45 (1H, m), 3.69-4.07 (3H, m), 4.373 (2H, q, J=7.18 Hz), 4.603 (1H, bs), 5.693 (1H, bs), 7.35-7.48 (3H, m), 7.77-7.85 (4H, m), 8.014 (1H, s), 8.735 (1H, d, J=4.39 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.29, 20.16, 20.49, 25.07, 30.68, 30.98, 42.16, 42.31, 46.27, 46.49, 61.12, 63.69, 64.31, 66.51, 67.39, 99.92, 101.17, 120.57, 120.71, 124.05, 124.23, 125.41, 128.45, 129.07, 129.44, 131.27, 137.84, 138.32, 139.16, 161.11, 170.66, 170.73
Fab-MS m/z: 524 (M.sup.+), 441
Example 160
Preparation of (RS)-N-(3-carboxyphenyl)-3-(4-chlorobenzenesulfonylaminomethyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(3-ethoxycarbonylphenyl)-3-(tetrahydropyran-2-yloxy)propanamide (46 mg) was hydrolyzed to obtain (RS)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylaminomethyl)-3-(tetrahydropyran-2-yloxy)propanamide (44 mg).
IR .nu.max cm.sup.-1 (KBr): 3278, 2945, 1695, 1593, 1552, 1325, 1161, 1093, 1086, 1026, 754, 482
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.32-1.88 (6H, m), 2.94-3.02 (1H, m), 3.08-3.31 (2H, m), 3.37-3.65 (2H, m), 3.69-3.92 (2H, m), 4.587 (1H, bd, J=13.42 Hz) 7.37-7.55 (3H, m), 7.74-7.85 (4H, m), 8.19-8.23 (1H, m)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 19.99, 20.40, 26.37, 31.43, 31.54, 42.88, 45.11, 62.90, 63.49, 67.37, 67.70, 99.72, 100.56, 122.09, 122.45, 122.93, 125.53, 126.08, 126.34, 126.52, 129.60, 129.79, 130.38, 132.54, 139.80, 140.50, 169.47, 172.73, 172.84
Fab-MS m/z: 497 (MH.sup.+)
Example 161
Preparation of (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-methoxycarbonylbutyl)-3-(tetrahydropyran-2-yloxy)propanamide
The crude (RS)-3-benzyloxy-2-benzyloxymethylpropanoic acid (948 mg) obtained in the same manner as the method described in Example 153 was dissolved in methylene chloride, and then, methyl 5-aminopentanoate (1.06 g) and triethylamine (2.2 ml) were added. The reaction mixture was added to a suspension of 2-chloro-1-methylpyridinium iodide (1.61 g) suspended in methylene chloride (20 ml) under argon, and the whole was heated under reflux for 15 hours. The reaction mixture was washed with 2N HCl, saturated NaHCO.sub.3 and saturated NaCl, dried over Na.sub.2 SO.sub.4 and concentrated. The resulting residue was purified by silica gel column chromatography (Wakogel C-200, ethyl acetate/hexane=1/4) to obtain (RS)-3-benzyloxy-2-benzyloxymethyl-N-(4-methoxycarbonylbutyl)propanamide (935 mg). The functional group of the resulting (RS)-3-benzyloxy-2-benzyloxymethyl-N-(4-methoxycarbonylbutyl)propanamide (914 mg) was converted in the same manner as Example 153 to obtain (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-methoxycarbonyl-butyl)-3-(tetrahydropyran -2-yloxy)propanamide (127 mg).
IR .nu.max cm.sup.-1 (KBr): 3377, 2937, 1736, 1651, 1335, 1165, 1095, 754, 619, 484
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.52-1.74 (10H, m), 2.331 (2H, t, J=7.20 Hz), 2.70-2.76 (1H, m), 3.10-3.27 (4H, m), 3.47-3.64 (2H, m), 3.662 (3H, s), 3.79-3.92 (2H, m), 4.523 (1H, d, J=5.61 Hz), 6.074 (1H, t, J=6.35 Hz), 6.636 (1H, bs), 7.479 (2H, d, J=8.67 Hz), 7.800 (2H, d, J=8.67 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 19.65, 19.87, 21.85, 25.04, 28.59, 28.85, 30.35, 30.50, 33.25, 38.75, 42.27, 45.72, 45.83, 51.37, 62.81, 63.21, 66.29, 66.88, 99.26, 99.96, 128.34, 128.67, 129.18, 129.62, 138.32, 138.79, 171.94, 173.67
Fab-MS m/z: 491 (MH.sup.+)
Example 162
Preparation of (RS)-N-(4-carboxybutyl)-2-(4-chlorobenzenesulfonylaminomethyl)-3-(tetrahydropyran-2-yloxy)propanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-methoxycarbonylbutyl)-3-(tetrahydropyran-2-yloxy)propanamide (12 mg) was hydrolyzed to obtain (RS)-N-(4-carboxybutyl)-2-(4-chlorobenzenesulfonylaminomethyl)-3-(tetrahydropyran-2-yloxy)propanamide (10 mg).
IR .nu.max cm.sup.-1 (KBr): 3305, 2943, 1711, 1651, 1556, 1333, 1163, 1095, 1028, 754, 619, 482
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.49-1.73 (10H, m), 2.359 (2H, t, J=6.96 Hz), 2.72-2.81 (1H, m), 3.133 (2H, q, J=6.43 Hz), 3.22-3.28 (2H, m), 3.47-3.64 (2H, m), 3.77-3.93 (2H, m), 4.536 (1H, bs), 6.123 (1H, bs), 6.750 (1H, bs), 7.472 (2H, d, J=8.66 Hz), 7.794 (2H, d, J=8.66 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.11, 19.72, 19.90, 20.93, 21.77, 25.11, 28.56, 30.46, 30.57, 33.29, 38.97, 42.20, 46.09, 46.20, 60.35, 63.03, 63.32, 66.40, 66.88, 99.44, 99.99, 128.45, 129.29, 138.39, 138.94, 172.38, 172.46, 177.37
Fab-MS m/z: 477 (MH.sup.+), 393 (MH.sup.+)
Example 163
Preparation of (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide
(RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-hydroxypropanamide (13.0 mg) obtained in the same manner as the method described in Example 153 was dissolved in pyridine, and tosyl chloride (10 mg) was added. The whole was stirred at room temperature overnight. Methanol was added to the reaction mixture to decompose the excess reagents. The product was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, 2N HCl, saturated NaHCO.sub.3 and saturated NaCl, dried over Na.sub.2 SO.sub.4 and concentrated. The resulting residue was purified by silica gel column chromatography (Wakogel C-200, ethyl acetate/toluene=1/2) to obtain (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-toluenesulfonyloxypropanamide (12 mg).
A solution of imidazole (6.9 mg) in DMF (0.5 ml) was added to a 60% NaH (4.0 mg) suspension in anhydrous DMF (0.5 ml) prepared at 0.degree. C., under argon. After stirring for 20 minutes, a DMF solution of (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-toluenesulfonyloxypropanamide (12 mg) was added. The whole was stirred at 0.degree. C. to room temperature overnight. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na.sub.2 SO.sub.4. The solvent was evaporated, and the residue was purified by column chromatography (6% water-containing silica gel, chloroform/methanol=5/1) to obtain the desired (RS)-2-(4-chlorobenzenesulfonylaminomethyl)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (7 mg).
IR .nu.max cm.sup.-1 (KBr): 3151, 2927, 1699, 1605, 1279, 1176, 1095, 771, 691
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.351 (3H, t, J=7.08 Hz), 2.645 (1H, m), 3.05-3.28 (3H, m), 3.413 (1H, dd, J=6.47 Hz, J=13.55 Hz), 4.281 (2H, q, J=7.08 Hz), 6.554 (2H, d, J=8.67 Hz), 7.143 (2H, bs), 7.446 (2H, d, J=8.67 Hz), 7.743 (2H, d, J=4.89 Hz), 7.775 (2H, d, J=4.89 Hz), 7.879 (1H, bs)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD):
Fab-MS m/z: 491 (MH.sup.+)
Example 164
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-4-butanolide
(RS)-2-amino-4-hydroxybutanoic acid (2.0438 g) was dissolved in water (20 ml). The solution was cooled to 0.degree. C., and potassium carbonate (5.217 g) and ethyl acetate (20 ml) were added. Then, p-chlorobenzenesulfonyl chloride (9.0536 g) and THF (2 ml) were added, and the whole was stirred overnight. After the reaction was completed, the ethyl acetate layer was separated. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The combined ethyl acetate layers were concentrated to give a crude product. The crude product was purified by silica gel column chromatography (silica gel 50 g, hexane/ethyl acetate=2/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-4-butanolide (2.8674 g).
Melting point: 113.degree.-115.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3255, 1776, 1407, 1336, 1188, 1169, 1091, 756
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 2.0-2.2 (1H, m), 2.4-2.5 (2H, m), 4.1-4.3 (1H, m), 4.2-4.4 (2H, m), 7.561 (2H, d, J=8.8 Hz), 7.897 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 31.73, 53.22, 67.12, 130.05, 130.60, 140.24, 141.52, 176.58
Fab-MS m/z: 276 (MH.sup.+)
Example 165
Preparation of methyl (RS)-2-(4-chlorobenzenesulfonylamino)-4-hydroxybutanoate
(RS)-2-(4-chlorobenzenesulfonylamino)-4-butanolide (1.0084 g) was dissolved in methanol (50 ml). To the resulting solution, triethylamine hydrochloride (1.007 g) and triethylamine (0.370 g) were added, and the whole was stirred at room temperature overnight. The reaction mixture was concentrated. Ethyl acetate and saturated saline solution were added to the residue. After the mixture was shaken, 2 layers were separated. The ethyl acetate layer was washed with 2N HCl and then water, then dried over Na.sub.2 SO.sub.4 and concentrated to give a crude product. The crude product was purified by column chromatography (silica gel 50 g, hexane/ethyl acetate=1/1) to obtain methyl (RS)-2-(4-chlorobenzenesulfonylamino)-4-hydroxybutanoate (787.3 mg).
Melting point: 91.degree.-92.degree. C.
IR .nu.max cm.sup.-1 (neat): 3275, 3093, 2954, 1740, 1587, 1477, 1340, 1162, 1088, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.8-1.9 (1H, m), 2.0-2.1 (1H, m), 3.538 (3H, s), 3.7-3.8 (2H, m), 4.127 (1H, dt, J=8.5 Hz, J=4.6 Hz), 6.215 (1H, d, J=9.0 Hz), 7.478 (2H, d, J=8.3 Hz), 7.807 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 35.08, 52.50, 53.13, 57.97, 128.86, 129.22, 138.10, 139.23, 172.09
Fab-MS m/z: 308 (MH.sup.+)
Example 166
Preparation of methyl (RS)-2-(4-chlorobenzenesulfonylamino)-4-(tetrahydropyran-2-yloxy)butanoate
Methyl (RS)-2-(4-chlorobenzenesulfonylamino)-4-hydroxybutanoate (743.3 mg) was dissolved in dichloromethane (4.4 ml). Further, dihydropyrane (4.06 g) and PPTS (52.8 mg) were added under argon and the whole was stirred at room temperature overnight. The reaction solution was poured into a saturated saline solution, and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over Na.sub.2 SO.sub.4 and concentrated to give methyl (RS)-2-(4-chlorobenzenesulfonylamino)-4-(tetrahydropyran-2-yloxy) butanoate (933.5 mg).
Melting point: 93.degree.-94.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3161, 2954, 1743, 1479, 1344, 1167, 1086, 1016, 754
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.5-1.9 (6H, m), 2.0-2.1 (2H, m), 3.4-3.5 (2H, m), 3.560 (3H, s), 3.7-3.9 (2H, m), 4.4-4.6 (1H, m), 5.767 (1H, d, J=8.6 Hz), 7.474 (2H, d, J=8.6 Hz), 7.798 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 19.54, 19.65, 25.26 and 25.37, 30.61, 30.87, 32.48 and 32.74, 52.36, 62.77, 98.34, 128.60, 129.15, 138.50, 139.12, 171.65 and 171.83
Fab-MS m/z: 392 (MH.sup.+), 308 (MH.sup.+ -THP)
Example 167
Preparation of (RS)-2-(4chlorobenzenesulfonylamino)-4-(tetrahydropyran-2-yloxy)butanoic acid
The procedure described in Example 39 was repeated, except that methyl (RS)-2-(4-chlorobenzenesulfonylamino)-4-(tetrahydropyran-2-yloxy)butanoate (552.8 mg) was hydrolyzed to give (RS)-2-(4-chlorobenzenesulfonylamino)-(RS)-2-(4-chlorobenzenesulfonylamino)-4-(tetrahydropyran-2-yloxy)butanoic acid (519.8 mg).
Melting point: 110.degree.-111.degree. C.
IR .nu.max cm.sup.-1 (neat): 3271, 2945, 1732, 1477, 1340, 1165, 1093, 1024, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.4-1.8 (6H, m), 2.0-2.1 (2H, m), 3.4-3.5 (2H, m), 3.7-3.9 (2H, m), 4.509 (1H, d, J=25.9 Hz), 5.918 (1H, d, J=8.3 Hz), 7.466 (2H, d, J=8.3 Hz), 7.809 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.11, 20.97, 25.18, 30.21 and 30.39, 32.59, 53.60, 60.46, 99.44, 128.63, 129.26, 138.50, 139.23, 174.51, 174.73
Fab-MS m/z: 378 (MH.sup.+), 294 (MH.sup.+ -THP)
Example 168
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-(tetrahydropyran-2-yloxy)butanamide
(RS)-2-(4-chlorobenzenesulfonylamino)-(RS)-2-(4-chlorobenzenesulfonylamino)-4-(tetrahydropyran-2-yloxy) butanoic acid (1.8464 g) was dissolved in 30 ml of THF, and triethylamine (642.8 mg) and pivaloyl chloride (648.1 mg) were added under argon. The whole was stirred at room temperature. After 2 hours, triethylamine (642.8 mg) and pivaloyl chloride (294.6 mg) were added, and the whole was stirred for 1.5 hours. To the resulting solution, ethyl p-aminophenylacetate hydrochloride (1.265 g) and triethylamine (642.8 mg) were added, and then the whole was stirred at room temperature overnight. The reaction solution was poured into a saturated saline solution, extracted 3 times with ethyl acetate, washed with a saline solution, dried over Na.sub.2 SO.sub.4, and then concentrated to give a crude product. The crude was purified by column chromatography (silica gel 180g, hexane/ethyl acetate=2/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-(tetrahydropyran-2-yloxy) butanamide (1.0727 g).
IR .nu.max cm.sup.-1 (KBr): 3275, 2939, 1734, 1684, 1539, 1416, 1340, 1165, 1040, 1093, 1034, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.247 (3H, t, J=7.1 Hz), 1.5-1.9 (8H, m), 2.1-2.2 (1H, m), 3.4-3.6 (2H, m), 3.575 (2H, s), 3.7-4.0 (2H, m), 4.142 (2H, q, J=7.1 Hz), 4.4-4.5 (1H, m), 7.2-7.3 (2H, m), 7.407 (2H, t, J=8.7 Hz), 7.484 (2H, dd, J=8.7 Hz, J=5.7 Hz), 7.831 (2H, dd, J=8.8 Hz, J=2.0 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.18, 20.09, 20.53, 25.11, 30.79, 40.88, 43.52, 56.02, 60.90, 63.51, 100.73, 120.13, 128.82, 129.59, 129.84, 130.65, 136.08, 138.43, 141.07, 168.28, 171.47
Fab-MS m/z: 539 (MH.sup.+)
Example 169
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-(tetrahydropyran-2-yloxy)butanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-(tetrahydropyran-2-yloxy) butanamide (23.2 mg) was hydrolyzed to give (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-4-(tetrahydropyran-2-yloxy)butanamide (20.1 mg).
Melting point: 158.degree.-162.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3278, 2937, 1684, 1608, 1541, 1416, 1325, 1165, 1093, 1024, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.4-1.6 (6H, m), 1.7-1.9 (2H, m), 2.0-2.2 (1H, m), 3.4-3.6 (2H, m), 3.618 (2H, s), 3.7-3.9 (2H, m), 3.9-4.1 (1H, m), 4.4-4.5 (1H, m), 7.219 (2H, dd, J=8.5 Hz, J=2.4 Hz), 7.3-7.5 (4H, m), 7.813 (2H, dd, J=8.8 Hz, J=1.2 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 20.49, 25.11, 29.22, 30.90, 40.22, 42.64, 63.54, 64.94, 99.99, 120.27, 120.35, 128.78, 129.51, 129.92, 134.10, 137.80, 139.75, 175.50, 179.42
Fab-MS m/z: 511 (MH.sup.+), 509 (MH.sup.+ -2)
Example 170
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-hydroxybutanamide
The procedure described in Example 25 was repeated, except that the THP was removed from (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-(tetrahydropyran-2-yloxy)butanamide (981.2 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-hydroxybutanamide (745.7 mg).
Melting point: 164.degree.-167.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3527, 3277, 2895, 1716, 1664, 1603, 1547, 1414, 1325, 1171, 1082, 1024, 754
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.234 (3H, t, J=7.2 Hz), 1.8-1.9 (2H, m), 3.572 (2H, s), 3.6-3.7 (2H, m), 4.0-4.1 (1H, m), 4.125 (2H, q, J=7.2 Hz), 7.172 (2H, d, J=8.8 Hz), 7.243 (2H, d, J=8.8 Hz), 7.392 (2H, d, J=8.8 Hz), 7.806 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 14.46, 36.94, 41.48, 55.97, 58.94, 61.91, 121.32, 129.90, 130.16, 130.56, 137.82, 139.91, 140.50, 171.12, 173.43
Fab-MS m/z: 455 (MH.sup.+)
Example 171
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide
The procedure described in Example 179 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-phenylbutanoic acid (252.0 mg) and ethyl 4-aminophenylacetate hydrochloride (184.3 mg) were condensed in THF (4 ml) in the presence of triethylamine (384.9 .mu.l) and pivaloyl chloride (140.4 .mu.l), and then the resulting crude product was purified by column chromatography (silica gel 50 g, hexane/ethyl acetate=3/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide (170.5 mg).
Melting point: 114.degree.-115.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3201, 2970, 1733, 1637, 1539, 1516, 1416, 1327, 1163, 1093, 1032, 829, 754, 700
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.234 (3H, t, J=7.1 Hz), 1.8-2.0 (1H, m), 2.1-2.3 (1H, m), 2.5-2.7 (2H, m), 3.556 (2H, s), 4.130 (2H, q, J=7.1 Hz), 4.7-4.8 (1H, m), 6.595 (1H, d, J=8.3 Hz), 7.012 (1H, d, J=6.4 Hz), 7.1-7.2 (4H, m), 7.223 (2H, dd, J=9.8 Hz, J=8.3 Hz), 7.319 (2H, d, J=8.8 Hz), 7.509 (2H, d, J=8.5 Hz), 7.735 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.11, 27.38, 33.84, 40.73, 53.38, 60.83, 120.09, 120.24, 126.14, 126.29, 128.27, 128.52, 128.71, 129.40, 129.73, 130.14, 136.74, 140.08, 170.00, 179.20
Fab-MS m/z: 515 (MH.sup.+)
Example 172
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-phenylbutanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide (118.7 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-4-phenylbutanamide (109.2 mg).
Melting point: 163.degree.-167.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3327, 2933, 1710, 1674, 1606, 1516, 1416, 1321, 1163, 1093, 830, 756, 700
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 2.0-2.2 (2H, m), 2.6-2.8 (2H, m), 3.559 (2H, s), 4.5-4.6 (1H, m), 7.1-7.2 (4H, m), 7.209 (2H, d, J=8.1 Hz), 7.226 (2H, d, J=8.8 Hz), 7.370 (1H, d, J=8.8 Hz), 7.504 (2H, d, J=8.8 Hz), 7.797 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 27.76, 33.12, 34.99, 55.12, 121.35, 127.07, 129.42, 129.49, 129.86, 130.19, 130.63, 130.74, 132.02, 132.13, 138.14, 142.32, 172.54, 175.47
Fab-MS m/z: 487 (MH.sup.+)
Example 173
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-phenylbutanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-phenylbutanoic acid (270.3 mg) and methyl 4-aminophenylpropionate hydrochloride (167.8 mg) were condensed in chloroform (10 ml) in the presence of triethylamine (360 .mu.l) and 1-methyl-2-chloropyridinium iodide (243.2 mg), and then the resulting crude product was purified by column chromatography (silica gel 50 g, hexane/ethyl acetate=2/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-phenylbutanamide (43.2 mg) as a colorless oil.
IR .nu.max cm.sup.-1 (KBr): 3267, 2929, 1736, 1713, 1604, 1518, 1352, 1165, 1093, 827, 756, 700
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.9-2.1 (2H, m), 2.5-2.7 (4H, m), 2.879 (2H, dd, J=15.6 Hz, J=7.6 Hz), 3.658 (3H, s), 4.1-4.2 (1H, m), 7.0-7.3 (7H, m), 7.348 (2H, d, J=8.5 Hz), 7.732 (2H, d, J=8.5 Hz), 7.844 (1H, d, J=8.8 Hz), 8.060 (1H, d, J=9.0 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 30.32, 31.27, 34.50, 35.60, 51.62, 57.01, 120.31, 126.43, 128.27, 128.34, 128.60, 128.82, 129.15, 129.22, 129.37, 129.48, 134.98, 137.95, 168.57, 173.19
Fab-MS m/z: 515 (MH.sup.+)
Example 174
Preparation of (RS)-N-(4-(2-carboxyethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-phenylbutanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-phenylbutanamide (41.5 mg) was hydrolyzed to obtain (RS)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-4-phenylbutaneamide (27.7 mg) as a colorless oil.
IR .nu.max cm.sup.-1 (KBr): 3388, 2926, 1711, 1666, 1539, 1414, 1325, 1163, 1093, 827, 756, 700
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.8-2.0 (2H, m), 2.5-2.7 (4H, m), 2.863 (2H, t, J=7.6 Hz), 3.8-3.9 (1H, m), 7.0-7.3 (7H, m), 7.382 (2H, d, J=8.8 Hz), 7.515 (2H, d, J=8.8 Hz), 7.796 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 20.73, 31.36, 32.72, 56.52, 58.24, 121.43, 127.04, 129.42, 129.53, 129.86, 130.16, 130.38, 130.52, 136.90, 139.91, 140.50, 142.04, 171.04, 175.11
Fab-MS m/z: 501 (MH.sup.+)
Example 175
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide
The procedure described in Example 179 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-4-phenylbutanoic acid (310.3 mg) and ethyl 4-aminophenylacetate hydrochloride (201.6 mg) were condensed in THF (5 ml) in the presence of triethylamine (421.2 .mu.l) and pivaloyl chloride (153.6 .mu.l), and then the resulting crude product was purified by column chromatography (silica gel 50 g, hexane/ethyl acetate=3/1) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide (117.6 mg).
Melting point: 130.degree.-131.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3350, 3255, 2974, 1740, 1664, 1637, 1551, 1520, 1419, 1221, 1169, 1030, 835, 700
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.237 (3H, t, J=7.1 Hz), 2.0-2.1 (1H, m), 2.1-2.3 (1H, m), 2.6-2.7 (2H, m), 3.561 (2H, s), 4.133 (2H, q, J=7.1 Hz), 4.7-4.8 (1H, m), 6.5-6.6 (1H, m), 7.0-7.2 (5H, m), 7.211 (2H, d, J=7.3 Hz), 7.244 (2H, d, J=6.6 Hz), 7.502 (2H, dd, J=12.0 Hz, J=8.6 Hz), 7.651 (1H, d, J=8.6 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.15, 31.67, 33.91, 53.38, 60.83, 115.25, 120.13, 120.24, 126.14, 126.32, 128.30, 128.52, 129.73, 130.10, 132.41, 136.85, 140.81, 170.04, 179.13
Fab-MS m/z: 561 (MH.sup.+ +2), 559 (MH.sup.+)
Example 176
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-4-phenylbutanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-phenylbutanamide (56.3 mg) was hydrolyzed to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-4-phenylbutanamide (54.7 mg).
Melting point: 155.degree.-160.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3317, 2964, 1713, 1639, 1516, 1417, 1254, 1163, 1068, 812, 741, 700
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 2.0-2.2 (2H, m), 2.6-2.8 (2H, m), 3.559 (2H, s), 4.5-4.6 (1H, m), 7.1-7.2 (6H, m), 7.214 (2H, d, J=8.1 Hz), 7.229 (2H, d, J=8.5 Hz), 7.519 (2H, t, J=8.5 Hz), 7.718 (1H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 27.73, 33.12, 34.99, 55.09, 121.32, 127.07, 129.38, 129.46, 129.93, 130.63, 130.74, 132.03, 132.10, 133.24, 138.15, 142.33, 172.55, 175.44
Fab-MS m/z: 533 (MH.sup.+ +2), 531 (MH.sup.+)
Example 177
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)butanamide
Triethylamine (1.99 ml), ethyl 4-aminophenylacetate hydrochloride (699 mg), and 1-methyl-2-chloropyridinium iodide (1.1 g) were added to a solution of (RS)-2-(4-chlorobenzenesulfonylamino)butanoic acid (1 g) in chloroform (30 ml), and the whole was heated under reflux for 2 hours under argon. The reaction mixture was concentrated under reduced pressure. After adding 1N HCl, the residue was extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 70 g, hexane/ethyl acetate=2/1) to give (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)butanamide (237 mg).
Melting point: 150.degree.-152.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3367, 1734, 1676, 1331, 1171, 831, 754
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 0.928 (3H, t, J=7.3 Hz), 1.260 (3H, t, J=7.1 Hz), 1.71 (2H, m), 3.57 (2H, s), 3.801 (1H, t, J=7.0 Hz), 4.146 (2H, q, J=7.1 Hz), 7.195 (2H, d, J=8.5 Hz), 7.281 (2H, d, J=8.5 Hz), 7.378 (2H, d, J=8.8 Hz), 7.789 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 10.13, 14.27, 27.00, 41.19, 59.31, 61.50, 120.69, 129.02, 129.64, 130.04, 130.74, 136.83, 139.14, 139.58, 170.42, 172.73
Fab-MS m/z: 439 (MH.sup.+)
Example 178
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)pentanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)pentanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (665 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.9 ml) and 1-methyl-2-chloropyridinium iodide (1.05 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)pentanamide (387 mg).
Melting point: 93.degree.-95.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3327, 3257, 1732, 1660, 1340, 1167, 829, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 0.798 (3H, t, J=7.33 Hz), 1.2 (2H, m), 1.252 (3H, t, J=7.08 Hz), 1.5-1.7 (2H, m), 3.56 (2H, s), 3.88 (1H, m), 4.14 (2H, q, J=7.08 Hz), 7.16 (2H, d, J=8.55 Hz), 7.259 (2H, d, J=8.55 Hz), 7.37 (2H, d, J=8.79 Hz), 7.79 (2H, d, J=8.79 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 13.41, 14.11, 18.47, 35.12, 57.49, 60.97, 120.31, 127.83, 128.56, 129.37, 129.73, 130.03, 130.54, 135.90, 137.99, 139.56, 169.27, 171.72
Fab-MS m/z: 453 (MH.sup.+)
Example 179
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide
Triethylamine (2.28 ml) and pivaloyl chloride (443 .mu.l) were added to a solution of (RS)-2-(4-chlorobenzenesulfonylamino)hexanoic acid (1 g) in THF (20 ml), and the whole was stirred for 2 hours under argon. Then, ethyl 4-aminophenylacetate hydrochloride (829 mg) was added, and the whole was stirred at room temperature overnight. The reaction mixture was poured into a saturated saline solution, and extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure, and 1.31 g of a yellow oil was obtained. The product was purified by column chromatography (silica gel 60 g, hexane/ethyl acetate=3/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (395 mg).
Melting point: 100.degree.-103.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3354, 3251, 1736, 1676, 1329, 1167, 831, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 0.786 (3H, t, J=7.08 Hz), 0.9 (2H, m), 1.2 (2H, m), 1.252 (3H, t, J=7.1 Hz), 1.6-1.7 (2H, m), 3.56 (2H, s), 4.15 (2H, q, J=7.1 Hz), 7.17 (2H, d, J=8.6 Hz), 7.27 (2H, d, J=8.6 Hz), 7.38 (2H, d, J=8.6 Hz), 7.79 (2H, d, 8.6 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 13.71, 14.15, 22.10, 27.27, 32.85, 40.77, 57.71, 60.94, 117.38, 120.27, 128.60, 128.85, 129.40, 129.77, 130.58, 130.83, 135.93, 138.10, 139.60, 169.16, 171.65
Fab-MS m/z: 467 (MH.sup.+)
Example 180
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide
(S)-2-(4-chlorobenzenesulfonylamino)hexanoic acid (3 g) and ethyl 4-aminophenylacetate (2.116 g) were dissolved in dichloromethane (50 ml). To the solution, N,N'-dicyclohexylcarbodiimide (2.43 g) was added, and then the whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated, poured in a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure, and the resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (1.493 g).
[.alpha.].sub.D.sup.24 -52.5.degree. (c 0.85, CHCl.sub.3)
Melting point: 157.degree.-158.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 179.
Example 181
Preparation of (R)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide
The procedure described in Example 177 was repeated, except that (R)-2-(4-chlorobenzenesulfonylamino)hexanoic acid (3 g) and ethyl 4-aminophenylacetate hydrochloride (1.9 g) were condensed in chloroform (100 ml) in the presence of triethylamine (5.4 ml) and 1-methyl-2-chloropyridinium iodide (3.01 g) to obtain as a colorless oily substance (R)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (3.58 g).
[.alpha.].sub.D.sup.24 +52.3.degree. (c 0.70, CHCl.sub.3)
Melting point: 157.degree.-158.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 179.
Example 182
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)hexanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)hexanoic acid (3.024 g) and methyl 4-aminophenylpropionate (1.86 g) were condensed in dichloromethane (70 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.44 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from toluene to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)hexanamide (3.28 g).
[.alpha.].sub.D.sup.27 -45.3.degree. (c 0.950, CHCl.sub.3)
Melting point: 106.degree.-108.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 179.
Example 183
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)hexanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (554.2 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.6 ml) and 1-methyl-2-chloropyridinium iodide (875.4 mg) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (123.8 mg).
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 0.810 (3H, t, J=6.8 Hz), 1.20-1.70 (4H, m), 1.254 (3H, t, J=7.2 Hz), 1.52-1.85 (2H, m), 3.571 (2H, s), 3.838 (1H, bd, J=5.4 Hz), 4.149 (2H, q, J=7.2 Hz), 5.669 (1H, bd, J=7.8 Hz), 7.189 (2H, d, J=8.7 Hz), 7.273 (2H, d, J=8.7 Hz), 7.561 (2H, d, J=8.8 Hz), 7.721 (2H, d, J=8.8 Hz), 8.020 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 13.74, 14.45, 22.14, 27.27, 32.88, 40.81, 57.71, 60.94, 120.24, 128.16, 128.71, 129.81, 130.61, 132.45, 135.86, 168.94, 171.61
Fab-MS m/z: 511
Example 184
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)hexanoic acid (3.50 g) and ethyl 4-aminophenylacetate (1.61 g) were condensed in dichloromethane (40 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.47 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from isopropyl alcohol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (3.36 g).
[.alpha.].sub.D.sup.28 -42.9.degree. (c 1.08, CHCl.sub.3)
Melting point: 157.degree.-159.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 183.
Example 185
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)hexanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)hexanoic acid (3.50 g) and methyl 4-aminophenylpropionate (1.61 g) were condensed in dichloromethane (40 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.47 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from isopropyl alcohol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)hexaneamide (3.47 g).
[.alpha.].sub.D.sup.28 -28.1.degree. (c 1.02, CHCl.sub.3)
Melting point: 112.degree.-116.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3263, 1738, 1662, 1535, 1329, 1167, 1092, 741, 613, 567
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 0.796 (3H, t, J=7.0 Hz), 1.03-1.97 (6H, m), 2.594 (2H, t, J=7.7 Hz), 2.900 (2H, t, J=7.7 Hz), 3.666 (3H, s), 3.81-3.95 (1H, m), 5.95 (1H, bs), 7.092 (2H, d, J=8.6 Hz), 7.231 (2H, d, J=8.6 Hz), 7.528 (2H, d, J=8.7 Hz), 7.722 (2H, d, J=8.7 Hz), 8.202 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 13.74, 22.14, 27.31, 30.32, 32.92, 35.63, 51.66, 57.78, 120.13, 120.38, 128.05, 128.71, 132.37, 135.20, 137.11, 138.61, 169.12, 173.26
Fab-MS m/z: 511 (MH.sup.+)
Example 186
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)hexanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino) hexanoic acid (3.64 g) and ethyl 3-aminobenzoate (1.47 ml) were condensed in dichloromethane (40 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.57 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from toluene to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)hexanamide (1.85 g).
[.alpha.].sub.D.sup.28 -36.9.degree. (c 0.271, CHCl.sub.3)
Melting point: 122.degree.-125.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3329, 1724, 1657, 1311, 1245, 1090, 640
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 0.851 (3H, t, J=7.3 Hz), 1.413 (3H, t, J=7.1 Hz), 1.0-1.95 (6H, m), 3.852 (1H, dd, J=8.0 Hz, J=5.9 Hz), 7.368 (1H, t, J=8.1 Hz), 7.513 (2H, d, J=8.8 Hz), 7.68 (1H, m), 7.707 (2H, d, J=8.8 Hz), 7.768 (1H, dt, J=7.6 Hz, J=1.5 Hz), 7.855 (1H, t, J=1.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 13.60, 14.11, 22.03, 27.35, 32.81, 57.56, 61.23, 120.60, 124.31, 125.41, 127.72, 128.60, 130.87, 132.12, 137.55, 138.83, 157.60, 166.52, 169.85
Fab-MS m/z: 499 (MH.sup.+ +2), 497 (MH.sup.+)
Example 187
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)octanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)octanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (581 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.66 ml) and 1-methyl-2-chloropyridinium iodide (918 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)octanamide (350 mg).
Melting point: 110.degree.-112.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3304, 3228, 1740, 1662, 1331, 1163, 833, 758
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 0.825 (3H, t, J=6.8 Hz), 1.1-1.3 (8H, m), 1.25 (3H, t, J=7.1 Hz), 3.56 (2H, s), 3.8 (1H, m), 4.15 (2H, q, J=7.1 Hz), 7.16 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 7.38 (2H, d, J=8.6 Hz), 7.8 (2H, d, J=8.6 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 13.97, 14.19, 22.48, 25.23, 28.75, 31.54, 33.19, 40.82, 57.80, 61.02, 120.36, 128.68, 129.45, 129.82, 130.00, 130.59, 136.02, 138.11, 139.65, 169.31, 171.81,
Fab-MS m/z: 495 (MH.sup.+)
Example 188
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methylbutanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methylbutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (665 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.9 ml) and 1-methyl-2-chloropyridinium iodide (1.05 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-methylbutanamide (542 mg).
Melting point: 100.degree.-102.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3319, 3265, 1732, 1655, 1335, 1167, 829, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 0.887 (3H, d, J=6.6 Hz), 0.911 (3H, d, J=6.4 Hz), 1.25 (3H, t, J=7.1 Hz), 2.1 (1H, m), 3.5 (2H, s), 3.6 (1H, m), 4.15 (2H, q, J=7.1 Hz) 7.17 (2H, d, J=8.6 Hz), 7.23 (2H, d, J=8.6 Hz), 7.36 (2H, d, J=8.79 Hz), 7.47 (2H, d, J=8.79 Hz), 7.79 (2H, d, J=8.6 Hz), 7.86 (2H, d, J=8.6 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.19, 17.60, 19.14, 31.54, 40.81, 61.02, 63.08, 120.43, 127.95, 128.72, 129.19, 129.41, 129.63, 129.82, 130.04, 130.77, 135.76, 138.00, 139.65, 168.65, 171.70
Fab-MS m/z: 453 (MH.sup.+)
Example 189
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylpentanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (635 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.82 ml) and 1-methyl-2-chloropyridinium iodide (1 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-4-methylpentanamide (455 mg).
Melting point: 117.degree.-120.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3365, 3273, 1728, 1672, 1342, 1165, 829, 754
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 0.73 (3H, d, J=6.0 Hz), 0.85 (3H, d, J=6.0 Hz), 1.25 (3H, t, J=7.1 Hz), 1.5-1.6 (2H, m), 3.56 (2H, s), 3.9 (1H, m), 4.15 (2H, q, J=7.1 Hz), 7.15 (2H, d, J=8.5 Hz), 7.23 (2H, d, J=8.5 Hz), 7.35 (2H, d, J=8.5 Hz), 7.79 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.19, 21.42, 22.85, 24.42, 40.82, 42.06, 56.36, 61.02, 115.37, 120.40, 128.72, 128.94, 129.41, 128.59, 129.78, 130.11, 130.59, 135.98, 138.11, 139.61, 169.72, 171.81
Fab-MS m/z: 467 (MH.sup.+)
Example 190
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (599 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.72 ml) and 1-methyl-2-chloropyridinium iodide (946.8 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (306.3 mg).
Melting point: 121.degree.-123.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3336, 3271, 1736, 1726, 1664, 1336, 1165, 758, 561
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.253 (3H, t, J=7.08 Hz), 1.94-2.05 (2H, m), 2.036 (3H, s), 2.40-2.57 (2H, m), 3.574 (2H, s), 4.03-4.13 (1H, m), 4.149 (2H, q, J=7.08 Hz), 6.071 (1H, bs), 7.207 (2H, d, J=8.55 Hz), 7.30 (2H, d, J=8.55 Hz), 7.429 (2H, d, J=8.54 Hz), 7.818 (2H, d, J=8.54 Hz), 8.160 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.19, 15.22, 30.11, 31.50, 40.82, 56.55, 60.99, 120.25, 128.72, 129.60, 129.93, 130.88, 135.80, 137.92, 139.83, 168.32, 171.62
Fab-MS m/z: 485 (MH.sup.+)
Example 191
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (8 g) and ethyl 4-aminophenyl acetate (4.43 g) were condensed in dichloromethane (60 ml) in the presence of N,N'-dicyclohexylcarbodiimide (6.12 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (4.14 g).
Melting point: 144.degree.-145.5.degree. C.
[.alpha.].sub.D.sup.26 -42.2.degree. (c 1.00, CHCl.sub.3)
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 190.
Example 192
Preparation of (R)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide
The procedure described in Example 180 was repeated, except that (R)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (715 mg) and ethyl 4-aminophenylacetate (430 mg) were condensed in dichloromethane (15 ml) in the presence of N,N'-dicyclohexylcarbodiimide (546 mg). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from hexanechloroform to obtain (R)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (22.9 mg).
Melting point: 138.degree.-140.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 190.
Example 193
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-methylthiobutanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (1.03 g) and methyl 4-aminophenylpropionate hydrochloride (617.4 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.76 ml) and 1-methyl-2-chloropyridinium iodide (975.2 mg) to obtain as a colorless oil (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-methylthiobutanamide (177.1 mg).
Melting point: 115.5.degree.-117.5.degree. C.
The various spectra (IR, .sup.1 H-NMR, Fab-MS) were found to be identical to those of the S-form of Example 194.
Example 194
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-methylthiobutanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (14.79 g) and methyl 4-aminophenylpropionate (7.98 g) were condensed in dichloromethane (150 ml) in the presence of N,N'-dicyclohexylcarbodiimide (11.3 g)-The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from methanolethyl acetate to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-methylthiobutanamide (5.66 g).
[.alpha.].sub.D.sup.27 -39.5.degree. (c 1.00, CHCl.sub.3)
Melting point: 116.5.degree.-117.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3350, 3250, 1736, 1664, 1327, 1165, 758,
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.95-2.01 (2H, m), 2.036 (3H, s), 2.437 (1H, dd, J=13.8 Hz, J=6.3 Hz), 2.539 (1H, dd, J=13.8 Hz, J=6.8 Hz), 2.600 (2H, t, J=7.7 Hz), 2.910 (2H, t, J=7.7 Hz), 3.666 (3H, s), 4.077 (1H, q, J=7.2 Hz), 6.059 (1H, d, J=8.5 Hz), 7.123 (2H, d, J=8.3 Hz), 7.263 (2H, d, J=8.3 Hz), 7.424 (2H, d, J=8.8 Hz), 7.822 (2H, d, J=8.8 Hz), 8.085 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 15.17, 30.06, 30.32, 31.42, 35.60, 51.62, 56.50, 120.27, 128.67, 128.85, 129.55, 134.94, 137.36, 137.88, 139.78, 168.17, 173.19
Fab-MS m/z: 485 (MH.sup.+)
Example 195
Preparation of (S)-2-(4chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-4-methylthiobutanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (10 g) and ethyl 3-aminobenzoate (4.1 g) were condensed in dichloromethane (80 ml) in the presence of N,N'-dicyclohexylcarbodiimide (7.65 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from methanol-ethyl acetate to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-4-methylthiobutanamide (2.13 g).
[.alpha.].sub.D.sup.28 -52.34.degree. (c 1.01, CHCl.sub.3)
Melting point: 150.5.degree.-151.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3273, 1724, 1660, 1545, 1439, 1292, 1163, 756, 565
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.406 (3H, t, J=7.1 Hz), 1.84-2.13 (2H, m), 2.051 (3H, s), 2.42-2.64 (2H, m), 4.088 (1H, d, J=5.1 Hz, J=8.9 Hz), 4.380 (2H, q, J=7.1 Hz), 7.023 (1H, d, J=9.0 Hz), 7.30-7.38 (4H, m), 7.73-7.88 (4H, m), 9.307 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 13.79, 14.71, 29.40, 32.11, 56.27, 60.38, 119.91, 123.42, 124.40, 128.00, 128.23, 128.43, 130.27, 137.56, 138.22, 138.37, 165.49, 168.60
Fab-MS m/z: 471 (MH.sup.+)
Example 196
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-4-methylthiobutanoic acid (7.86 g) and ethyl 4-aminophenylacetate (3.64 g) were condensed in dichloromethane (80 ml) in the presence of N,N'-dicyclohexylcarbodiimide (5.28 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (1.67 g).
[.alpha.].sub.D.sup.29 -34.3.degree. (c 0.93, CHCl.sub.3)
Melting point: 160.degree.-161.degree. C.
IR .nu.max cm.sup.-1 (KCl-Solid): 3250, 1734, 1662, 1331, 1165, 742, 565
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.255 (3H, t, J=7.1 Hz), 1.90-2.08 (2H, m), 2.031 (3H, s), 2.21-2.54 (2H, m), 3.576 (2H, s), 4.076 (1H, dd, J=8.7 Hz, J=5.5 Hz), 4.151 (2H, q, J=7.1 Hz), 6.150 (1H, d, J=8.5 Hz), 7.197 (2H, d, J=8.3 Hz), 7.282 (2H, d, J=8.3 Hz), 7.577 (2H, d, J=8.8 Hz), 7.740 (2H, d, J=8.8 Hz), 8.215 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.15, 15.21, 30.02, 31.60, 40.77, 56.50, 60.97, 120.24, 128.23, 128.74, 129.88, 130.76, 132.52, 135.75, 138.46, 168.31, 171.61
Fab-MS m/z: 529 (MH.sup.+)
Example 197
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-methylthiobutanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-4-methylthiobutanoic acid (10.72 g) and methyl 4-aminophenylpropionate (4.96 g) were condensed in dichloromethane (100 ml) in the presence of N,N'-dicyclohexylcarbodiimide (7.21 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-methylthiobutanamide (2.6 g).
[.alpha.].sub.D.sup.28 -28.8.degree. (c 1.01, CHCl.sub.3)
Melting point: 124.degree.-125.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3244, 1736, 1662, 1327, 1165, 823, 742, 611, 611, 567
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.92-2.09 (2H, m), 2.009 (3H, s), 2.475 (2H, t, J=6.8 Hz), 2.596 (2H, t, J=7.7 Hz), 2.902 (2H, t, J=7.8 Hz), 3.665 (3H, s), 4.090 (1H, m), 6.411 (1H, bs), 7.100 (2H, d, J=8.3 Hz), 7.235 (2H, d, J=8.3 Hz), 7.537 (2H, d, J=8.5 Hz), 7.732 (2H, d, J=8.5 Hz), 8.400 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 15.17, 29.99, 30.28, 33.76, 35.60, 51.59, 56.57, 120.35, 128.08, 128.74, 129.37, 132.41, 135.05, 137.18, 138.54, 168.50, 173.23
Fab-MS m/z: 531 (MH.sup.+ +2)
Example 198
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-4-methylthiobutanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-4-methylthiobutanoic acid (2.99 g) and ethyl 3-aminobenzoate (1.34 g) were condensed in dichloromethane (100 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.01 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-4-methylthiobutanamide (2.018 g).
[.alpha.].sub.D.sup.27 -36.3.degree. (c 1.00, CHCl.sub.3)
Melting point: 157.degree.-158.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3327, 3269, 2927, 2850, 1724, 1659, 1628, 1576, 1338, 1290, 1163, 1088, 829, 750
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.406 (3H, t, J=7.1 Hz), 1.9-2.0 (2H, m), 2.050 (3H, s), 2.4-2.6 (2H, m), 4.0-4.1 (1H, m), 4.378 (2H, q, J=7.1 Hz), 7.345 (1H, t, J=8.1 Hz), 7.494 (2H, d, J=8.5 Hz), 7.730 (4H, d, J=8.5 Hz), 7.889 (1H, s), 9.448 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.05, 24.59, 29.72, 33.63, 56.64, 60.70, 120.22, 123.77, 124.83, 127.22, 128.40, 128.58, 130.65, 131.80, 137.70, 138.94, 165.84, 168.86
Fab-MS m/z: 517 (MH.sup.+ +2), 515(MH.sup.+)
Example 199
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (574.6 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.64 ml) and 1-methyl-2-chloropyridinium iodide (907.5 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (113 mg).
Melting point: 70.degree.-73.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3331, 3250, 1734, 1664, 1340, 1165, 756, 625
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.194 (3H, t, J=7.32 Hz), 1.249 (3H, t, J=7.08 Hz), 1.91-2.00 (2H, m), 2.40-2.53 (2H, m), 2.452 (2H, q, J=7.32 Hz), 3.567 (2H, s), 4.08-4.17 (1H, m), 4.141 (2H, q, J=7.08 Hz), 6.189 (1H, m), 7.186 (2H, d, J=8.54 Hz), 7.288 (2H, d, J=8.54 Hz), 7.404 (2H, d, J=8.79 Hz), 7.810 (2H, d, J=8.79 Hz), 8.272 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.19, 14.56, 25.82, 27.47, 32.16, 40.82, 56.62, 61.02, 120.32, 128.72, 129.38, 129.52, 129.89, 130.81, 135.83, 137.96, 139.76, 168.58, 171.70
Fab-MS m/z: 499 (MH.sup.+)
Example 200
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanoic acid (695.2 mg) and ethyl 4-aminophenylacetate (380 mg) were condensed in dichloromethane (30 ml) in the presence of N,N'-dicyclohexylcarbodiimide (509.5 mg). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (321.5 mg).
[.alpha.].sub.D.sup.23 -34.8.degree. (c 0.76, CHCl.sub.3)
Melting point: 143.5.degree.-144.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 199.
Example 201
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-ethylthiobutanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanoic acid (1.0 g) and methyl 4-aminophenylpropionate hydrochloride (638.4 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.4 ml) and 1-methyl-2-chloropyridinium iodide (907.5 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-ethylthiobutanamide (374 mg).
Melting point: 87.degree.-89.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3354, 3234, 1738, 1672, 1327, 1165, 829, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.183 (3H, t, J=7.3 Hz), 1.94-2.00 (2H, m), 2.39-2.50 (4H, m), 2.594 (2H, t, J=7.7 Hz), 2.899 (2H, t, J=7.8 Hz), 3.663 (3H, s), 4.02-4.17 (1H, m), 6.366 (1H, d, J=8.3 Hz), 7.100 (2H, d, J=8.4 Hz), 7.258 (2H, d, J=8.4 Hz), 7.390 (2H, d, J=8.7 Hz), 7.819 (2H, d, J=8.7 Hz), 8.298 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.48, 25.71, 27.41, 30.26, 32.14, 35.56, 51.57, 56.58, 120.34, 128.63, 128.75, 129.44, 135.03, 137.24, 137.99, 139.60, 168.52, 173.21
Fab-MS m/z: 499 (MH.sup.+)
Example 202
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-4-ethylthiobutanoic acid (199 mg) and ethyl 4-aminophenylacetate (95.7 mg) were condensed in dichloromethane (2 ml) in the presence of N,N'-dicyclohexylcarbodiimide (139.1 mg). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (117.3 mg).
[.alpha.].sub.D.sup.30 -29.699.degree. (c 1.00, CHCl.sub.3)
Melting point: 154.degree.-155.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3253, 1732, 1656, 1338, 1157, 742, 563
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.203 (3H, t, J=7.4 Hz), 1.234 (3H, t, J=7.1 Hz), 1.82-1.97 (2H, m), 2.41-2.66 (2H, m), 2.486 (2H, q, J=7.4 Hz), 3.577 (2H, s), 4.027 (1H, dd, J=8.5 Hz, J=5.6 Hz), 4.125 (2H, q, J=7.1 Hz), 7.179 (2H, d, J=8.7 Hz), 7.251 (2H, d, J=8.7 Hz), 7.561 (2H, d, J=8.8 Hz), 7.736 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 14.46, 15.04, 26.52, 28.24, 34.33, 41.48, 57.80, 61.91, 121.39, 128.36, 129.97, 130.63, 131.81, 133.27, 137.75, 141.05, 170.82, 173.43
Fab-MS m/z: 545 (MH.sup.+ +2)
Example 203
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-4-ethylthio-N-(4-(2-methoxycarbonylethyl)phenyl)butanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-4-ethylthiobutanoic acid (224 mg) and methyl 4-aminophenylpropionate (102 mg) were condensed in dichloromethane (20 ml) in the presence of N,N'-dicyclohexylcarbodiimide (157 mg). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-4-ethylthio-N-(4-(2-methoxycarbonylethyl)phenyl)butanamide (105 mg).
[.alpha.].sub.D.sup.29 -24.4.degree. (c 0.97, CHCl.sub.3)
Melting point: 113.5.degree.-115.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3350, 3250, 1736, 1660, 1329, 1167, 1090, 1070, 825, 746, 567
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.224 (3H, t, J=7.3 Hz), 1.981 (2H, q, J=7.3 Hz), 2.4-2.5 (4H, m), 2.603 (2H, t, J=7.7 Hz), 2.914 (2H, t, J=7.7 Hz), 3.668 (3H, s), 4.060 (1H, dd, J=14.9 Hz, J=6.6 Hz), 6.041 (1H, d, J=8.3 Hz), 7.134 (2H, d, J=8.5 Hz), 7.257 (2H, d, J=8.5 Hz), 7.594 (2H, d, J=8.8 Hz), 7.743 (2H, d, J=8.8 Hz), 8.055 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.51, 25.81, 27.49, 30.32, 31.86, 35.60, 51.62, 56.61, 120.27, 128.27, 128.78, 128.89, 132.52, 134.94, 137.36, 138.39, 168.09, 173.19
Fab-MS m/z: 545 (MH.sup.+ +2), 543 (MH.sup.+)
Example 204
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 177 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (571 mg) were condensed in chloroform (35 ml) in the presence of triethylamine (1.64 ml) and 1-methyl-2-chloropyridinium iodide (902 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)-3-phenylpropanamide (442.3 mg).
Melting point: 148.degree.-150.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3342, 1736, 1678, 1319, 1163, 829, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.25 (3H, t, J=7.2 Hz), 2.953 (1H, dd, J=13.9 Hz, J=8.0 Hz), 3.095 (1H, dd, J=13.9 Hz, J=6.1 Hz), 3.57 (2H, s), 4.14 (2H, q, J=7.08 Hz), 6.6-7.4 (5H, m), 6.97 (2H, d, J=8.3 Hz), 7.06 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.19, 38.69, 40.85, 58.82, 60.95, 115.30, 120.39, 127.47, 127.99, 128.39, 128.53, 128.75, 129.52, 129.85, 130.11, 130.84, 135.76, 137.04, 139.72, 168.07, 171.55
Fab-MS m/z: 501 (MH.sup.+)
Example 205
Preparation of (S)-2-(4chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanoic acid (2.92 g) and ethyl 4-aminophenylacetate (1.54 mg) were condensed in dichloromethane (40 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.0 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (722.3 mg).
[.alpha.].sub.D.sup.26 -80.9.degree. (c 1.05, CHCl.sub.3)
Melting point: 165.degree.-165.5.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 204.
Example 206
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide
Triethylamine (480 .mu.l) and pivaloyl chloride (175 .mu.l) were added to a solution of (RS)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanoic acid (301.7 mg) in THF (5 ml), and the whole was stirred for 2 hours. After methyl 4-aminophenylpropionate hydrochloride (229.8 mg) was added, the whole was stirred at room temperature overnight. The reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure to obtain a yellow oil. The product was purified by column chromatography (silica gel 50 g, hexane/ethyl acetate=3/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl) phenyl)-3-phenylpropanamide (40.4 mg).
IR .nu.max cm.sup.-1 (KBr): 3329, 1734, 1676, 1362, 1160, 1088, 754, 627
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 2.596 (2H, t, J=7.8 Hz), 2.906 (2H, t, J=7.8 Hz), 3.104 (2H, dd, J=14.0 Hz, J=6.8 Hz), 3.662 (3H, s), 4.346 (1H, t, J=6.8 Hz), 6.980 (2H, d, J=7.3 Hz), 7.1-7.3 (5H, m), 7.305 (2H, d, J=8.6 Hz), 7.467 (1H, d, J=8.6 Hz), 7.553 (2H, d, J=8.6 Hz), 7.856 (1H, d, J=8.6 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 30.35, 35.60, 38.68, 51.62, 58.81, 120.39, 127.46, 128.49, 128.78, 129.07, 129.44, 134.98, 135.27, 137.07, 139.06, 168.60, 173.19
Fab-MS m/z: 501 (MH.sup.+)
Example 207
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanoic acid (3.10 g) and methyl 4-aminophenylpropionate (1.90 g) were condensed in dichloromethane (40 ml) in the presence of N,N'-dicyclohexylcarbodiimide (2.19 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-(RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide (2.65 g).
[.alpha.].sub.D.sup.29 -49.5.degree. (c 0.786, CHCl.sub.3)
Melting point: 145.degree.-145.5.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 206.
Example 208
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 179 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (300.2 mg) and ethyl 4-aminophenylacetate hydrochloride (202.2 mg) were condensed in THF (5 ml) in the presence of triethylamine (422.4 .mu.l) and pivaloyl chloride (153.9 .mu.l), and then the resulting crude product was recrystallized from ethanol to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (35.1 mg).
IR .nu.max cm.sup.-1 (KBr): 3263, 1730, 1655, 1531, 1338, 1165, 744, 555
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.249 (3H, t, J=7.2 Hz), 2.939 (1H, dd, J=14.0 Hz, J=8.2 Hz), 3.107 (1H, dd, J=14.0 Hz, J=6.0 Hz), 3.567 (2H, s), 3.987 (1H, m), 4.141 (2H, q, J=7.1 Hz), 5.399 (1H, d, J=7.1 Hz), 6.969 (2H, dd, J=7.7 Hz, J=1.6 Hz), 7.11-7.32 (7H, m), 7.466 (4H, s), 8.002 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.19, 38.69, 40.85, 58.86, 60.99, 120.43, 127.47, 128.24, 128.57, 129.12, 129.85, 130.81, 132.50, 135.25, 135.76, 137.56, 168.10, 171.59
Fab-MS m/z: 547
Example 209
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (5.83 g) and ethyl 4-aminophenylacetate (2.58 g) were condensed in dichloromethane (70 ml) in the presence of N,N'-dicyclohexylcarbodiimide (3.76 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (3.20 g).
[.alpha.].sub.D.sup.29 -71.6.degree. (c 1.03, CHCl.sub.3)
Melting point: 170.5.degree.-171.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 208.
Example 210
Preparation of (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 180 was repeated, except that (R)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (3.0 g) and ethyl 4-aminophenylacetate (1.40 g) were condensed in dichloromethane (30 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.93 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (3.34 g).
[.alpha.].sub.D.sup.29 +71.2.degree. (c 1.01, CHCl.sub.3)
Melting point: 171.degree.-171.5.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 208.
Example 211
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (5.17 g) and methyl 4-aminophenylpropionate (2.29 g) were condensed in dichloromethane (60 ml) in the presence of N,N'-dicyclohexylcarbodiimide (3.33 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide (3.73 g).
[.alpha.].sub.D.sup.27 -68.5.degree. (c 0.97, CHCl.sub.3)
Melting point: 142.degree.-143.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3159, 1738, 1670, 1545, 1317, 1155, 744, 613
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 2.584 (2H, t, J=7.7 Hz), 2.894 (2H, t, J=7.7 Hz), 2.83-2.96 (1H, m), 3.116 (1H, dd, J=13.9 Hz, J=5.9 Hz), 3.656 (3H, s), 4.031 (1H, bq, J=7.1 Hz), 5.647 (1H, d, J=6.6 Hz), 6.969 (2H, d, J=6.6 Hz), 7.10-7.21 (7H, m), 7.409 (2H, d, J=9.0 Hz), 7.466 (2H, d, J=9.0 Hz), 8.099 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 30.28, 35.56, 38.68, 51.62, 58.88, 120.53, 127.24, 128.05, 128.45, 128.74, 128.89, 129.04, 132.37, 134.94, 135.27, 137.22, 137.66, 168.31, 173.23
Fab-MS m/z: 547 (MH.sup.+ +2)
Example 212
Preparation of (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 180 was repeated, except that (R)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (3 g) and methyl 4-aminophenylpropionate (2.58 g) were condensed in dichloromethane (30 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.93 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide (3.09 g).
[.alpha.].sub.D.sup.29 +70.2.degree. (c 1.04, CHCl.sub.3)
Melting point: 143.degree.-144.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the R form of Example 211.
Example 213
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-phenylpropanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (2 g) and ethyl 4-aminobenzoate were condensed in dichloromethane (100 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.29 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from a mixture of carbon tetrachloride and ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-phenylpropanamide (623 mg).
[.alpha.].sub.D.sup.28 49.7.degree. (c 0.90, THF)
Melting point: 176.degree.-177.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3356, 1687, 1601, 1535, 1410, 1313, 1279, 1167, 1109, 741
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.374 (3H, t, J=7.1 Hz), 2.878 (1H, dd, J=13.6 Hz, J=8.3 Hz), 3.038 (1H, dd, J=13.6 Hz, J=7.0 Hz), 4.133 (1H, t, J=7.6 Hz), 4.339 (2H, q, J=7.1 Hz), 7.13-7.18 (5H, m), 7.377 (2H, d, J=8.8 Hz), 7.452 (2H, d, J=8.8 Hz), 7.572 (2H, d, J=8.8 Hz), 7.906 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 14.60, 40.16, 60.30, 61.98, 120.29, 127.04, 127.88, 128.17, 129.46, 129.79, 130.41, 131.37, 133.13, 137.53, 141.01, 143.39, 167.63, 171.26
Fab-MS m/z: 531 (MH.sup.+)
Example 214
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-phenylpropanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-3-phenylpropanoic acid (2 g) and ethyl 3-aminobenzoate were condensed in dichloromethane (100 ml) in the presence of N,N'-dicyclohexylcarbodiimide (1.29 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-phenylpropanamide (812 mg).
[.alpha.].sub.D.sup.28 -74.4.degree. (c 0.84, CHCl.sub.3)
Melting point: 173.degree.-173.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3257, 1724, 1695, 1552, 1165, 746, 619
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.486 (3H, t, J=7.1 Hz), 3.034 (1H, dd, J=13.9 Hz, J=8.3 Hz), 3.238 (1H, dd, J=13.9 Hz, J=5.9 Hz), 4.11-4.20 (1H, m), 4.458 (2H, q, J=7.1 Hz), 5.646 (1H, d, J=7.3 Hz), 7.065 (2H, d, J=6.3 Hz), 7.21-7.37 (3H, m), 7.468 (1H, t, J=7.9 Hz), 7.534 (2H, d, J=9.0 Hz), 7.587 (2H, d, J=9.0 Hz), 7.839 (1H, d, J=9.3 Hz), 7.897 (1H, d, J=7.8 Hz), 8.014 (1H, s), 8.438 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.29, 38.16, 58.99, 61.27, 121.04, 124.60, 125.88, 127.35, 128.19, 128.52, 129.00, 129.11, 131.20, 132.45, 135.09, 137.11, 137.47, 166.15, 168.57
Fab-MS m/z: 533 (MH+2), 531 (MH.sup.+)
Example 215
Preparation of (S)-2-(4chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(3-indolyl) propanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl) propanoic acid (5 g) and ethyl 4-aminophenylacetate (2.36 g) were condensed in a mixed solvent of dichloromethane (100 ml) and acetonitrile (10 ml) in the presence of N,N'-dicyclohexylcarbodiimide (3.27 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol/acetonitrile (10/1) to obtain (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(3-indolyl)propanamide (4.86 g).
[.alpha.].sub.D.sup.29 -12.4.degree. (c 0.99, MeCN)
Melting point: 182.degree.-183.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3251, 1720, 1648, 1533, 1340, 1165, 750
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 1.202 (3H, t, J=7.1 Hz), 2.953 (1H, dd, J=14.5 Hz, J=8.2 Hz), 3.545 (2H, s), 4.086 (2H, q, J=7.1 Hz), 4.14-4.20 (1H, m), 6.89-7.57 (13H, m), 9.689 (1H, s), 10.538 (1H, s)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 13.67, 28.39, 39.79, 57.58, 59.77, 108.79, 110.94, 117.88, 119.41, 120.48, 123.64, 126.84, 127.68, 128.05, 128.86, 129.07, 135.83, 136.75, 136.83, 139.37, 169.03, 170.55
Fab-MS m/z: 540 (MH.sup.+)
Example 216
Preparation of (S)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl)-N-(4-(2-methoxycarbonylethyl)phenyl) propanamide
The procedure described in Example 180 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl) propanoic acid (4.80 g) and methyl 4-aminophenylpropionate (2.73 g) were condensed in a mixture of dichloromethane (80 ml) and acetonitrile (13 ml) in the presence of N,N'-dicyclohexylcarbodiimide (3.14 g). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from hexane/ethyl acetate (13/16) to obtain (S)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl)-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (3.60 g).
[.alpha.].sub.D.sup.28 -13.3.degree. (c 0.99, MeCN)
Melting point: 182.degree.-183.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3404, 1732, 1670, 1531, 1414, 1338, 1165, 754
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 2.577 (2H, t, J=7.5 Hz), 2.834 (2H, t, J=7.5 Hz), 2.952 (1H, dd, J=14.5 Hz, J=8.4 Hz), 3.130 (1H, dd, J=14.5 Hz, J=6.0 Hz), 3.612 (3H, s), 4.10-4.22 (1H, m), 6.938 (1H, t, J=7.0 Hz), 6.99-7.09 (4H, m), 7.136 (2H, d, J=8.7 Hz), 7.305 (3H, t, J=9.0 Hz), 7.481 (1H, d, J=8.9 Hz), 7.514 (2H, d, J=8.7 Hz), 8.126 (1H, d, J=9.2 Hz), 9.742 (1H, s), 10.545 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 28.43, 29.67, 34.99, 50.94, 57.58, 108.81, 111.05, 117.98, 119.41, 120.58, 123.70, 126.82, 127.92, 127.99, 135.32, 135.84, 136.24, 136.94, 139.14, 169.06, 172.25
Fab-MS m/z: 540 (MH.sup.+)
Example 217
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanoic acid
(RS)-phenylalanine (500.2 mg) was dissolved in H.sub.2 O (50 ml) and 2N NaOH (1.5 ml). Rh/Al.sub.2 O.sub.3 catalyst (500.5 mg) was added, and the whole was stirred overnight under a hydrogen atmosphere at atmospheric pressure. After the reaction was completed, Rh/Al.sub.2 O.sub.3 was separated by filtration. The filtrate was concentrated to give crude (RS)-2-amino-3-cyclohexylpropanoic acid. Then, the crude (RS)-2-amino-3-cyclohexylpropanoic acid was dissolved in 2N NaOH (15.08 ml). THF (15 ml) and then 4-chlorobenzenesulfonyl chloride (3.196 g) were added, and the whole was stirred at room temperature overnight under argon. The reaction mixture was diluted with water, washed with ethyl acetate, acidified with 2N HCl and extracted 3 times with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na.sub.2 SO.sub.4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 80 g, ethyl acetate) and then by preparative TLC to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanoic acid (200.9 mg).
Melting point: 127.degree.-129.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3309, 2922, 2850, 1718, 1693, 1450, 1344, 1169, 1095, 825, 754
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 0.8-1.0 (2H, m), 1.1-1.4 (2H, m), 1.4-1.5 (2H, m), 1.6-1.7 (5H, m), 3.315 (2H, dd, J=3.2 Hz, J=1.7 Hz), 3.8-3.9 (1H, m), 7.534 (2H, d, J=8.8 Hz), 7.819 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 27.00, 27.25, 27.40, 32.94, 34.63, 34.77, 41.34, 54.83, 129.79, 130.12, 139.69, 141.01, 175.41
Fab-MS m/z: 346 (MH.sup.+)
Example 218
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexyl-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide
The procedure described in Example 179 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanoic acid (118.9 mg) and ethyl 4-aminophenylacetate hydrochloride (88.98 mg) were condensed in THF (3 ml) in the presence of triethylamine (135.67 mg) and pivaloyl chloride (66.33 mg), and then the resulting crude product was purified by column chromatography (silica gel 20 g, hexane/ethyl acetate=3/1) to obtain as a colorless oil (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexyl-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide (66.2 mg).
IR .nu.max cm.sup.-1 (neat): 3369, 2981, 2927, 2852, 1730, 1628, 1518, 1416, 1369, 1163, 1093, 1032, 829, 754
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 0.7-1.1 (4H, m), 1.1-1.4 (2H, m), 1.238 (3H, t, J=7.1 Hz), 1.3-1.7 (5H, m), 3.4-3.5 (2H, m), 3.562 (2H, s), 3.8-3.9 (1H, m), 4.128 (2H, q, J=7.1 Hz), 6.628 (2H, d, J=8.3 Hz), 7.055 (2H, d, J=8.3 Hz), 7.178 (1H, d, J=8.3 Hz), 7.268 (1H, d, J=8.5 Hz), 7.370 (1H, d, J=8.5 Hz), 7.771 (1H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.11, 25.77, 26.06, 26.17, 32.00, 33.51, 40.51, 40.77, 55.47, 60.64, 60.86, 115.21, 120.24, 123.98, 128.63, 129.37, 129.70, 130.03, 145.32, 169.60, 171.58
Fab-MS m/z: 507 (MH.sup.+)
Example 219
Preparation of (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexyl-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide
The procedure described in Example 180 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanoic acid (200 mg) and methyl 4-aminophenylpropionate (103.64 mg) were condensed in dichloromethane (5 ml) in the presence of N,N'-dicyclohexylcarbodiimide (143.18 mg). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was purified by column chromatography (silica gel 20 g, hexane/ethyl acetate=3/1) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexyl-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (165.2 mg).
Melting point: 64.degree.-65.degree. C.
IR .nu.max cm.sup.-1 (neat): 3271, 2926, 2852, 1738, 1666, 1605, 1535, 1414, 1323, 1163, 1093, 825, 754
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 0.7-1.0 (2H, m), 1.0-1.4 (4H, m), 1.4-1.7 (5H, m), 2.598 (2H, t, J=7.7 Hz), 2.905 (2H, t, J=7.7 Hz), 3.4-3.6 (2H, m), 3.670 (3H, s), 3.8-3.9 (1H, m), 5.783 (1H, d, J=7.8 Hz), 7.106 (2H, d, J=8.3 Hz), 7.263 (2H, d, J=8.5 Hz), 7.399 (2H, d, J=8.5 Hz), 7.814 (2H, d, J=8.5 Hz), 8.138 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 24.82, 25.81, 26.06, 30.32, 32.11, 33.58, 33.84, 35.63, 40.59, 51.62, 55.62, 120.35, 128.74, 128.93, 129.44, 135.24, 137.11, 137.88, 139.67, 169.52, 173.26
Fab-MS m/z: 507 (MH.sup.+)
Example 220
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-3-(4-chlorobenzenesulfonylamino)butanamide
A mixture of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)butanamide (114.2 mg), ethanol (8 ml), and 2N NaOH (650 ml) was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure. It was repeated 3 times in order to remove ethanol completely that a small amount of purified water was added to the residue, and then the product was concentrated under reduced pressure. The residue was dissolved in purified water and washed with ethyl acetate. The aqueous layer was acidified with 1N HCl and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na.sub.2 SO.sub.4. Then, the solvent was evaporated under reduced pressure to obtain (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino) butanamide (91.1 mg).
Melting point: 185.degree.-186.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3250, 1710, 1325, 1165, 829, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD-DMSO-d.sub.6): 0.915 (3H, t, J=7.45 Hz), 1.5-1.8 (2H, m), 3.54 (2H, s), 3.822 (1H, t, J=7.0 Hz), 7.18 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.425 (2H, d, J=8.5 Hz), 7.815 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD-DMSO-d.sub.6): 10.64, 27.55, 41.31, 59.97, 121.14, 129.80, 130.12, 130.64, 131.91, 137.81, 139.54, 140.75, 170.95, 174.61
Fab-MS m/z: 411 (MH.sup.+)
Example 221
Preparation of (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)pentanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)pentanamide (122.4 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)pentanamide (103.6 mg).
Melting point: 202.degree.-204.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3331, 3263, 1705, 1660, 1333, 1165, 829, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD-DMSO-d.sub.6): 0.833 (3H, t, J=7.32 Hz), 1.2-1.5 (2H, m), 1.5 (2H, m), 3.49 (2H, s), 3.6-3.8 (1H, m), 7.15 (2H, d, J=8.54 Hz), 7.29 (2H, d, J=8.54 Hz), 7.48 (2H, d, J=8.7 Hz), 7.79 (2H, d, J=8.7 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD-DMSO-d.sub.6): 13.17, 18.23, 34.77, 39.50, 56.77, 119.52, 119.59, 127.59, 128.43, 128.80, 129.27, 130.23, 136.68, 136.79, 137.34, 139.87, 169.32, 172.51
Fab-MS m/z: 425 (MH.sup.+)
Example 222
Preparation of (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)hexanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (113.3 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)hexanamide (96.1 mg).
Melting point: 192.degree.-194.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3259, 1709, 1666, 1327, 1165, 829, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 0.87 (3H, t, J=7.0 Hz), 1.2 (2H, m), 1.3 (2H, m), 1.6 (2H, m), 3.3 (2H, s), 3.5-3.6 (1H, m), 7.22 (2H, d, J=8.3 Hz), 7.40 (2H, d, J=8.3 Hz), 7.52 (2H, d, J=8.8 Hz), 7.80 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 14.13, 23.03, 28.64, 33.91, 41.34, 58.89, 121.28, 129.75, 130.09, 130.55, 131.99, 137.55, 139.88, 140.37, 171.44, 175.27
Fab-MS m/z: 439 (MH.sup.+)
Example 223
Preparation of (S)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)hexanamide
The procedure described in Example 39 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (1.88 g) was hydrolyzed to obtain (S)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)hexanamide (1.552 g).
[.alpha.].sub.D.sup.28 -11.3.degree. (c 0.92, THF)
Melting point: 212.degree.-214.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 222.
Example 224
Preparation of (R)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)hexanamide
The procedure described in Example 39 was repeated, except that (R)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (126.4 mg) was hydrolyzed to obtain (R)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)hexanamide (87.0 mg).
Melting point: 165.degree.-167.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 222.
Example 225
Preparation of (S)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)hexanamide
(S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (2.717 g) was dissolved in methanol (50 ml), 2N NaOH (8.72 ml) was added and the whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure to remove methanol. The concentrate was poured in 6N HCl while cooling with ice. The precipitated crystals were filtered and recrystallized from acetonitrile to obtain (S)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)hexanamide (1.629 g).
[.alpha.].sub.D.sup.28 -11.4.degree. (c 0.901, THF)
Melting point: 178.degree.-179.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 222.
Example 226
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)hexanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (123.8 mg) was hydrolyzed to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)hexanamide (50.4 mg).
Melting point: 180.degree.-182.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3332, 3253, 1707, 1670, 1329, 1165, 742
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 0.820 (3H, t, J=7.0 Hz), 1.15-1.33 (4H, m), 1.52-1.63 (2H, m), 3.473 (2H, s), 3.873 (1H, bd, J=6.8 Hz), 7.137 (2H, d, J=8.5 Hz), 7.295 (2H, d, J=8.5 Hz), 7.589 (2H, d, J=8.8 Hz), 7.713 (2H, d, J=8.8 Hz), 7.870 (1H, d, J=8.5 Hz), 9.616 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.61, 15.37, 21.67, 27.21, 32.53, 57.17, 119.62, 126.11, 128.53, 129.30, 130.15, 131.73, 136.93, 140.56, 169.24, 172.43
Fab-MS m/z: 485 (MH.sup.+ +2)
Example 227
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)hexanamide
The procedure described in Example 225 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (3.0 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl) phenyl)hexanamide (2.23 g).
[.alpha.].sub.D.sup.29 -22.5.degree. (c 0.99, MeOH)
Melting point: 199.5.degree.-201.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab -MS) were found to be identical to those of the racemate of Example 225.
Example 228
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-carboxyethyl)phenyl)hexanamide
The procedure described in Example 225 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)hexanamide (3.0 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-carboxyethyl)phenyl)hexanamide (1.36 g).
[.alpha.].sub.D.sup.29 -20.1.degree. (c 1.02, MeOH)
Melting point: 183.degree.-185.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3255, 1707, 1657, 1539, 1336, 1165, 741, 611
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 0.798 (3H, t, J=6.8 Hz), 1.12-1.30 (4H, m), 1.47-1.65 (2H, m), 2.488 (2H, t, J=7.4 Hz), 2.775 (2H, t, J=7.6 Hz), 3.81-3.90 (1H, m), 7.098 (2H, d, J=8.5 Hz), 7.251 (2H, d, J=8.5 Hz), 7.628 (2H, d, J=8.9 Hz), 7.703 (2H, d, J=8.9 Hz), 7.983 (2H, d, J=9.0 Hz), 9.648 (1H, s), 11.873 (1H, s)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 13.32, 21.27, 26.89, 29.60, 32.09, 35.06, 38.58, 56.74, 119.37, 125.75, 127.95, 128.28, 131.55, 135.84, 136.06, 168.80, 173.24
Fab-MS m/z: 497 (MH.sup.+)
Example 229
Preparation of (S)-3-(4-bromobenzenesulfonylamino)-N-(3-carboxyphenyl)hexanamide
The procedure described in Example 225 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)hexanamide (1.85 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(3-carboxyphenyl)hexanamide (1.21 g).
[.alpha.].sub.D.sup.29 -9.36.degree. (c 0.94, THF)
Melting point: 235.degree.-236.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3248, 1699, 1552, 1327, 1165, 742, 617
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 0.808 (3H, t, J=7.0 Hz), 1.14-1.34 (4H, m), 1.50-1.68 (2H, m), 3.82-3.92 (1H, m), 7.369 (1H, t, J=7.8 Hz), 7.59-7.69 (2H, m), 7.619 (2H, d, J=8.5 Hz), 7.711 (2H, d, J=8.5 Hz), 8.001 (1H, t, J=1.7 Hz), 8.024 (1H, d, J=8.8 Hz), 9.908 (1H, s), 12.668 (1H, s)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 13.27, 21.21, 26.86, 31.90, 56.78, 119.99, 123.15, 124.02, 125.78, 128.25, 128.40, 131.07, 131.48, 138.22, 140.12, 166.67, 169.20
Fab-MS m/z: 469 (MH.sup.+)
Example 230
Preparation of (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)octanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)octanamide (123.6 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)octanamide (112,5 mg).
Melting point: 192.degree.-193.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3452, 3263, 1701, 1655, 1335, 1165, 829, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 0.84 (3H, t, J=6.7 Hz), 1.1-1.3 (6H, m), 1.5 (4H, m), 3.0-3.8 (4H, m), 7.15 (2H, d, J=8.54 Hz), 7.30 (2H, d, J=8.54 Hz), 7.48 (2H, d, J=8.55 Hz), 7.79 (2H, d, J=8.55 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 13.57, 21.71, 24.76, 27.91, 30.88, 32.53, 40.12, 56.92, 119.44, 128.28, 128.65, 129.13, 130.04, 136.68, 137.19, 139.83, 139.17, 172.33
Fab-MS m/z: 467 (MH.sup.+)
Example 231
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-methylbutanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methylbutanamide (121.7 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-methylbutanamide (93.4 mg).
Melting point: 228.degree.-230.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3280, 1705, 1660, 1329, 1165, 829, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 0.895 (3H, d, J=6.4 Hz), 0.872 (3H, d, J=6.4 Hz), 1.9 (1H, m), 3.47 (2H, s), 3.6-3.7 (1H, m), 7.13 (2H, d, J=8.3 Hz), 7.25 (2H, d, J=8.3 Hz), 7.45 (2H, d, J=8.55 Hz), 7.59 (2H, d, J=8.55 Hz), 7.77 (2H, d, J=8.55 Hz), 7.83 (2H, d, J=8.55 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 18.08, 18.62, 30.66, 40.13, 62.42, 119.34, 127.33, 128.19, 128.48, 129.03, 129.92, 136.46, 136.92, 139.77, 168.37, 172.17
Fab-MS m/z: 425 (MH.sup.+)
Example 232
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylpentanamide (111.4 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanamide (99.0 mg).
Melting point: 208.degree.-209.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3273, 1711, 1674, 1325, 1165, 827, 754
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 0.818 (3H, d, J=6.6 Hz), 0.882 (3H, d, J=6.6 Hz), 1.2 (1H, m), 1.4-1.5 (2H, m), 3.5 (2H, s), 3.7-3.9 (1H, m), 7.14 (2H, d, J=8.5 Hz), 7.28 (2H, d, J=8.5 Hz), 7.45 (2H, d, J=8.1 Hz), 7.79 (2H, d, J=8.1 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 22.52, 23.87, 40.12, 41.48, 55.60, 119.48, 128.28, 128.61, 129.09, 130.01, 136.68, 137.19, 139.76, 169.35, 172.29
Fab-MS m/z: 439 (MH.sup.+)
Example 233
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (119.4 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide (109.4 mg).
Melting point: 169.5.degree.-177.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3261, 1705, 1659, 1335, 1163, 1093, 1086, 756, 625
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 1.79-1.91 (2H, m), 1.994 (3H, s), 2.30-2.52 (4H, m), 3.477 (2H, s), 3.89-4.07 (1H, m), 7.144 (2H, d, J=8.54 Hz), 7.311 (2H, d, J=8.54 Hz), 7.475 (2H, d, J=8.55 Hz), 7.792 (2H, d, J=8.54 Hz), 8.024 (1H, bs), 9.708 (1H, s),
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.38, 29.16, 32.24, 39.98, 55.97, 119.30, 128.06, 128.47, 128.91, 129.90, 136.46, 137.12, 139.58, 168.29, 172.03
Fab-MS m/z: 457 (MH.sup.+)
Example 234
Preparation of (S)-N-(4-(carboxymethyl) phenyl)-2-(4chlorobenzenesulfonylamino)-4-methylthiobutanamide
A solution of K.sub.2 CO.sub.3 (3.2 g) in water (40 ml) was added to a solution of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (3.75 g) in methanol (80 ml), and the whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure. It was repeated 3 times in order to remove methanol completely that a small amount of purified water was added to the residue, and then the product was concentrated under reduced pressure. The residue was dissolved in purified water and washed with ethyl acetate. The aqueous layer was acidified with 1N HCl, and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na.sub.2 SO.sub.4. Then, the solvent was evaporated under reduced pressure, and the resulting crude product was recrystallized from acetonitrile to obtain (S)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide (2.84 g).
Melting point: 192.5.degree.-193.5.degree. C.
[.alpha.].sub.D.sup.27 -26.8.degree. (c 1.17, THF)
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 233.
Example 235
Preparation of (R)-N-(4-(carboxymethyl) phenyl)-2-4-chlorobenzenesulfonylamino)-4-methylthiobutanamide
The procedure described in Example 39 was repeated, except that (R)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (19.5 mg) was hydrolyzed to obtain (R)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide (12.0 mg).
Melting point: 169.degree.-170.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 233.
Example 236
Preparation of (RS)-N-(4-(2-carboxyethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-methylthiobutanamide (82.3 mg) was hydrolyzed to obtain (RS)-N-(4-(2-carboxyethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide (58.7 mg).
Melting point: 143.degree.-145.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the S-form of Example 237.
Example 237
Preparation of (S)-N-(4-(2-carboxyethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide
The procedure described in Example 234 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-methylthiobutanamide (4.29 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide (3.48 g).
[.alpha.].sub.D.sup.27 -25.6.degree. (c 0.91, MeOH)
Melting point: 167.5.degree.-169.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3400 (br), 3338, 3259, 1701, 1662, 1335, 1163, 758
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 1.81-2.02 (2H, m), 2.034 (3H, s), 2.40-2.57 (2H, m), 2.564 (2H, t, J=7.8 Hz), 2.891 (2H, t, J=7.8 Hz), 4.02-4.08 (1H, m), 7.112 (2H, d, J=8.5 Hz), 7.256 (2H, d, J=8.5 Hz), 7.351 (2H, d, J=8.8 Hz), 7.797 (2H, d, J=8.8 Hz), 9.098 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 14.95, 29.69, 30.06, 32.33, 35.45, 56.43, 119.72, 128.27, 128.67, 128.85, 135.42, 136.63, 138.43, 138.68, 168.46, 174.58
Fab-MS m/z: 471 (MH.sup.+)
Example 238
Preparation of (S)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide
The procedure described in Example 39 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-4-methylthiobutanamide (2 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-N-(3-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide (1.60 g).
[.alpha.].sub.D.sup.27 -15.75.degree. (c 1.003, THF)
Melting point: 225.degree.-225.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3246, 2920, 1699, 1593, 1437, 1327, 1163, 1093, 829, 756
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 1.8-2.0 (2H, m), 2.002 (3H, s), 2.3-2.5 (2H, m), 4.0-4.1 (1H, m), 7.370 (1H, t, J=8.3 Hz), 7.480 (2H, d, J=8.8 Hz), 7.628 (2H, d, J=8.3 Hz), 7.794 (2H, d, J=8.8 Hz), 8.014 (1H, s)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 18.16, 29.16, 32.09, 56.04, 120.18, 123.30, 124.14, 128.17, 128.36, 128.61, 131.11, 137.08, 138.18, 139.58, 166.68, 168.69
Fab-MS m/z: 443 (MH.sup.+)
Example 239
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-4-methylthiobutanamide
A solution of K.sub.2 CO.sub.3 (962 mg) in water (15 ml) was added to a solution of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (1.23 g) in ethanol (50 ml). The whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure. It was repeated 3 times in order to remove ethanol completely that a small amount of purified water was added to the residue, and then the mixture was concentrated under reduced pressure. The residue was dissolved in purified water and washed with ethyl acetate. The aqueous layer was acidified with 1N HCl, and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na.sub.2 SO.sub.4. Then, the solvent was evaporated under reduced pressure and the crude product was recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-4-methylthiobutanamide (800 mg).
[.alpha.].sub.D.sup.29 -22.71.degree. (c 1.048, MeOH)
Melting point: 188.5.degree.-189.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3086 (br), 1709, 1665, 1338, 1161, 823, 742, 613, 565
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.82-2.04 (2H, m), 2.043 (3H, s), 2.39-2.63 (2H, m), 3.552 (2H, s), 4.036 (1H, dd, J=8.7 Hz, J=5.5 Hz), 7.192 (2H, d, J=8.7 Hz), 7.251 (2H, d, J=8.7 Hz), 7.566 (2H, d, J=8.8 Hz), 7.735 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 15.26, 30.92, 33.86, 41.37, 57.73, 121.39, 128.39, 130.01, 130.71, 132.25, 133.31, 137.67, 141.05, 170.90, 175.44
Fab-MS m/z: 501 (MH.sup.+)
Example 240
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-carboxyethyl)phenyl)-4-methylthiobutanamide
The procedure described in Example 234 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-methylthiobutanamide (2.6 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-carboxyethyl)phenyl)-4-methylthiobutanamide (1.7 g).
[.alpha.].sub.D.sup.26 -20.3.degree. (c 1.09, MeOH)
Melting point: 183.degree.-184.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3259, 1701, 1662, 1335, 1161, 742, 609
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.80-2.02 (2H, m), 2.045 (3H, s), 2.39-2.65 (2H, m), 2.574 (2H, t, J=7.3 Hz), 2.868 (2H, t, J=7.6 Hz), 4.025 (1H, dd, J=8.5 Hz, J=5.6 Hz), 7.129 (2H, d, J=8.8 Hz), 7.195 (2H, d, J=8.8 Hz), 7.555 (2H, d, J=8.7 Hz), 7.731 (2H, d, J=8.7 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 15.26, 30.88, 31.40, 33.82, 36.64, 57.66, 121.50, 128.39, 129.60, 129.97, 133.24, 136.90, 138.48, 140.97, 170.75, 176.58
Fab-MS m/z: 514 (M.sup.+)
Example 241
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(3-carboxyphenyl)-4-methylthiobutanamide
The procedure described in Example 225 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-N-(3-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (1.946 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzene-sulfonylamino)-N-(3-carboxyphenyl)-4-methylthiobutanamide (895 mg).
[.alpha.].sub.D.sup.30 -12.5.degree. (c 0.80, THF)
Melting point: 229.degree.-229.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3246, 2920, 1697, 1616, 1595, 1554, 1437, 1327, 1161, 1090, 823, 742
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.8-2.0 (2H, m), 2.048 (3H, s), 2.4-2.6 (2H, m), 4.0-4.1 (1H, m), 7.363 (1H, t, J=7.9 Hz), 7.543 (2H, d, J=8.5 Hz), 7.55-7.6 (1H, m), 7.7-7.75 (1H, m), 7.741 (2H, d, J=8.5 Hz), 8.003 (1H, t, J=2.0 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 16.52, 30.51, 33.36, 58.33, 120.50, 122.95, 126.03, 128.31, 130.78, 131.56, 132.11, 134.07, 140.43, 140.55, 168.56, 170.23
Fab-MS m/z: 489 (MH.sup.+ +2), 487 (MH.sup.+)
Example 242
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (47.5 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanamide (36.4 mg).
Melting point: 152.degree.-154.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3423, 1709, 1606, 1537, 1325, 1163, 1093, 756, 624
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -CD.sub.3 OD): 1.159 (3H, t, J=7.32 Hz), 1.77-1.95 (2H, m), 2.34-2.58 (2H, m), 2.448 (2H, q, J=7.32 Hz), 3.502 (2H, s), 7.165 (2H, d, J=8.30 Hz), 7.317 (2H, d, J=8.30 Hz), 7.474 (2H, d, J=8.55 Hz), 7.811 (2H, d, J=8.55 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 14.49, 25.24, 27.07, 33.27, 56.55, 119.85, 128.65, 129.02, 129.49, 130.59, 137.85, 139.98, 168.88, 172.69
Fab-MS m/z: 471 (MH.sup.+)
Example 243
Preparation of (S)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanamide
The procedure described in Example 234 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (105.6 mg) was hydrolyzed to obtain (S)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanamide (95.1 mg).
[.alpha.].sub.D.sup.30 -8.00.degree. (c 0.250, THF)
Melting point: 199.degree.-200.5.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 242.
Example 244
Preparation of (RS)-N-(4-(2-carboxyethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-ethylthiobutanamide (370 mg) was hydrolyzed to obtain (RS)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-4-ethylthiobutanamide (297.6 mg).
Melting point: 145.degree.-146.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3338, 3259, 1707, 1660, 1335, 1163, 756
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 1.134 (3H, t, J=7.3 Hz), 1.820 (2H, qw, J=7.2 Hz), 2.30-2.52 (6H, m), 2.781 (2H, t, J=7.6 Hz), 3.988 (1H, bq, J=7.6 Hz), 7.105 (2H, d, J=8.5 Hz), 7.275 (2H, d, J=8.5 Hz), 7.501 (2H, d, J=8.7 Hz), 7.789 (2H, d, J=8.7 Hz), 8.088 (1H, d, J=9.0 Hz), 9.688 (1H, s)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 14.38, 24.80, 26.63, 29.67, 32.86, 35.14, 38.91, 56.19, 119.37, 119.52, 127.99, 128.50, 128.69, 136.02, 137.16, 139.72, 168.33, 173.32
Fab-MS m/z: 485 (MH.sup.+)
Example 245
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-4-ethylthiobutanamide
The procedure described in Example 234 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (30.8 mg) was hydrolyzed to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-4-ethylthiobutanamide (26.7 mg).
Melting point: 193.5.degree.-195.degree. C.
[.alpha.].sub.D.sup.29 -19.04.degree. (c 0.961, MeOH)
IR .nu.max cm.sup.-1 (KBr): 3265 (br), 1705, 1657, 1538, 1335, 1163, 741, 613
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.205 (3H, t, J=7.4 Hz), 1.82-2.05 (2H, m), 2.42-2.66 (2H, m), 2.489 (2H, q, J=7.4 Hz), 3.552 (2H, s), 4.028 (1H, dd, J=8.5 Hz, J=5.6 Hz), 7.193 (2H, d, J=8.9 Hz), 7.254 (2H, d, J=8.9 Hz), 7.568 (2H, d, J=8.8 Hz), 7.737 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 15.05, 26.51, 28.21, 34.34, 41.40, 57.78, 121.37, 128.36, 129.95, 130.67, 132.19, 133.26, 137.61, 141.01, 170.81, 175.42
Fab-MS m/z: 516 (MH.sup.+ +1)
Example 246
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-carboxyethyl)phenyl)-4-ethylthio-butanamide
The procedure described in Example 225 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-4-ethylthiobutanamide (7.8 mg) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-carboxyethyl)phenyl)-4-ethylthiobutanamide (7 mg).
Melting point: 174.5.degree.-175.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3253, 1703, 1657, 1336, 1164, 1089, 1070, 825, 742
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 1.196 (3H, t, J=7.3 Hz), 1.8-2.0 (2H, m), 2.477 (2H, q, J=7.3 Hz), 2.576 (2H, t, J=7.6 Hz), 2.867 (2H, t, J=7.6 Hz), 4.023 (1H, m), 7.132 (2H, d, J=8.8 Hz), 7.197 (2H, d, J=8.8 Hz), 7.555 (2H, d, J=8.8 Hz), 7.735 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 15.08, 26.52, 28.24, 31.40, 34.37, 36.64, 57.80, 121.54, 128.43, 129.60, 129.97, 133.27, 136.90, 138.48, 140.97, 170.75, 176.58
Fab-MS m/z: 531 (MH.sup.+ +2), 529 (MH.sup.+)
Example 247
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (122.5 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanamide (99.9 mg).
Melting point: 204.degree.-206.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3342, 1709, 1676, 1321, 1163, 829, 754
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 2.795 (1H, dd, J=13.7 Hz, J=7.3 Hz), 2.966 (1H, dd, J=13.7 Hz, J=7.3 Hz), 8.49 (2H, s), 4.1 (1H, m), 7.1-7.3 (5H, m), 7.15 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.55 Hz), 7.61 (2H, d, J=8.55 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 30.37, 40.12, 58.31, 111.41, 119.52, 119.77, 126.23, 126.52, 127.40, 127.84, 128.06, 128.25, 128.58, 129.09, 129.16, 129.38, 129.68, 130.15, 136.61, 136.97, 139.69, 168.62, 172.32
Fab-MS m/z: 473 (MH.sup.+)
Example 248
Preparation of (S)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanamide
The procedure described in Example 234 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (2.52 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanamide (2.22 g).
[.alpha.].sub.D.sup.28 +49.37.degree. (c 1.03, THF)
Melting point: 218.degree.-218.8.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 247.
Example 249
Preparation of (RS)-N-(4-(2-carboxyethyl) phenyl)-2-(4chlorobenzenesulfonylamino)-3-phenylpropanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide (36.7 mg) was hydrolyzed and recrystallized from acetonitrile to obtain (RS)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanamide (28.0 mg).
Melting point: 214.degree.-215.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3325, 1709, 1674, 1321, 1161, 1089, 754, 628
.sup.1 H-NMR .delta. ppm (CDCl.sub.3): 2.563 (2H, t, J=7.6 Hz), 2.855 (2H, t, J=7.6 Hz), 3.025 (2H, dd, J=13.6 Hz, J=7.0 Hz), 4.108 (1H, t, J=7.6 Hz), 7.1-7.2 (7H, m), 7.305 (2H, d, J=8.8 Hz), 7.542 (1H, d, J=8.8 Hz), 7.653 (2H, d, J=8.8 Hz), 7.872 (1H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3): 31.40, 36.68, 40.27, 60.22, 121.65, 127.84, 128.87, 129.46, 129.53, 129.71, 130.12, 130.41, 136.87, 137.64, 138.52, 140.53, 170.82, 176.58
Fab-MS m/z: 487 (MH.sup.+)
Example 250
Preparation of (S)-N-(4-(2-carboxyethyl) phenyl)-3-(4chlorobenzenesulfonylamino)-3-phenylpropanamide
The procedure described in Example 234 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide (2.50 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-phenylpropanamide (2.09 g).
[.alpha.].sub.D.sup.29 +52.47.degree. (c 0.97, THF)
Melting point: 194.degree.-194.5.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the racemate of Example 249.
Example 251
Preparation of (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (33.7 mg) was hydrolyzed and recrystallized from acetonitrile to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-phenylpropanamide (29.8 mg).
Melting point: 184.degree.-185.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the S-form of Example 252.
Example 252
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-phenylpropanamide
(S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (17.0 g) was dissolved in methanol (200 ml) and cooled to 0.degree. C. After 2N NaOH (46.8 ml) was added, the whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure to remove methanol. The concentrate was poured to 6N HCl while cooling with ice. The precipitated crystal was filtered and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-phenylpropanamide (1.10 g).
[.alpha.].sub.D.sup.27 +52.4.degree. (c 0.38, THF)
Melting point: 224.degree.-224.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3361, 1716, 1684, 1525, 1322, 1167, 739, 613
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 2.785 (1H, dd, J=13.8 Hz, J=8.9 Hz), 2.953 (1H, dd, J=13.8 Hz, J=5.7 Hz), 3.486 (2H, s), 3.603 (1H, dd, J=5.7 Hz, J=8.9 Hz), 7.08-7.30 (9H, m), 7.527 (4H, s), 9.757 (1H, s)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 38.88, 39.99, 58.19, 119.38, 124.62, 125.63, 126.12, 127.76, 128.05, 129.00, 129.12, 130.04, 131.48, 136.57, 140.14, 168.48, 172.20
Fab-MS m/z: 517 (MH.sup.+)
Example 253
Preparation of (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 225 was repeated, except that (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-phenylpropanamide (398 mg) was hydrolyzed and recrystallized from acetonitrile to obtain (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(carboxymethyl)phenyl)-3-phenylpropanamide (344 mg).
[.alpha.].sub.D.sup.26 -51.4.degree. (c 1.06, THF)
Melting point: 223.5.degree.-224.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the S-form of Example 252.
Example 254
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-carboxyethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 225 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide (19.4 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-carboxyethyl)phenyl)-3-phenylpropanamide (17.1 g).
[.alpha.].sub.D.sup.28 +52.4.degree. (c 0.38, THF)
Melting point: 208.degree.-209.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3331, 3267, 1703, 1655, 1527, 1338, 1165, 748, 613
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 2.745 (2H, d, J=3.0 Hz), 2.786 (2H, d, J=3.0 Hz), 2.791 (1H, dd, J=13.7 Hz, J=4.9 Hz), 2.949 (1H, dd, J=13.7 Hz, J=5.9 Hz), 4.151 (1H, q, J=6.8 Hz), 7.04-7.28 (9H, m), 7.515 (4H, s), 9.699 (1H, s)
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 29.60, 35.06, 38.22, 58.17, 119.44, 124.58, 125.61, 126.08, 127.73, 127.95, 128.03, 128.98, 131.40, 135.91, 136.57, 140.09, 168.33, 173.24
Fab-MS m/z: 531 (MH.sup.+)
Example 255
Preparation of (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-carboxyethyl)phenyl)-3-phenylpropanamide
The procedure described in Example 225 was repeated, except that (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-methoxycarbonylethyl)phenyl)-3-phenylpropanamide (407 mg) was hydrolyzed and recrystallized from acetonitrile to obtain (R)-2-(4-bromobenzenesulfonylamino)-N-(4-(2-carboxyethyl)phenyl)-3-phenylpropanamide (367 mg).
[.alpha.].sub.D.sup.26 -54.7.degree. (c 1.02, THF)
Melting point: 212.degree.-212.5.degree. C.
The various spectra (IR, .sup.1 H-NMR, .sup.13 C-NMR, Fab-MS) were found to be identical to those of the S-form of Example 254.
Example 256
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(4-carboxyphenyl)-3-phenylpropanamide
The procedure described in Example 225 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-phenylpropanamide (2 13 mg) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-carboxyphenyl)-3-phenylpropanamide (170 mg).
[.alpha.].sub.D.sup.28 58.3.degree. (c 0.63, THF)
Melting point: 300.degree. C. (decomposition)
IR .nu.max cm.sup.-1 (KBr): 3352, 1689, 1601, 1531, 1410, 1317, 1163, 1090, 741
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 2.881 (1H, dd, J=13.5 Hz, J=8.2 Hz), 3.040 (1H, dd, J=13.5 Hz, J=6.8 Hz), 4.11-4.17 (1H, m), 7.13-7.24 (5H, m), 7.366 (2H, d, J=8.8 Hz), 7.455 (2H, d, J=8.8 Hz), 7.576 (2H, d, J=8.7 Hz), 7.915 (2H, d, J=8.7 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 40.16, 60.30, 120.29, 127.33, 127.88, 128.17, 129.46, 129.79, 130.41, 131.66, 133.16, 137.53, 140.97, 143.28, 169.36, 171.23
Fab-MS m/z: 503 (MH.sup.+)
Example 257
Preparation of (S)-2-(4-bromobenzenesulfonylamino)-N-(3-carboxyphenyl)-3-phenylpropanamide
The procedure described in Example 225 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-phenylpropanamide (300 mg) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(3-carboxyphenyl)-3-phenylpropanamide (145 mg).
[.alpha.].sub.D.sup.29 38.9.degree. (c 1.07, THF)
Melting point: 234.5.degree.-235.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3338, 1697, 1552, 1323, 1161, 742, 615
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 2.895 (1H, dd, J=13.7 Hz, J=7.6 Hz), 3.044 (1H, dd, J=13.7 Hz, J=7.6 Hz), 4.122 (1H, t, J=7.6 Hz), 7.14-7.23 (5H, m), 7.343 (1H, t, J=7.9 Hz), 7.43-7.50 (1H, m), 7.456 (2H, d, J=8.8 Hz), 7.595 (2H, d, J=8.8 Hz), 7.730 (1H, dt, J=8.1 Hz, J=1.4 Hz), 7.898 (1H, t, J=1.7 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 39.87, 59.89, 122.16, 125.24, 126.30, 127.51, 127.88, 129.13, 129.46, 130.05, 132.17, 132.80, 137.20, 138.7, 140.61, 168.99, 170.68, 177.98
Fab-MS m/z: 503 (MH.sup.+)
Example 258
Preparation of (S)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl) propanamide
The procedure described in Example 225 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(3-indolyl)propanamide (4.01 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl)propanamide (3.22 mg).
[.alpha.].sub.D.sup.27 -12.6.degree. (c 0.61, MeCN)
Melting point: 182.degree.-183.5.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3282, 1714, 1697, 1533, 1417, 1317, 1161, 750
.sup.1 H-NMR .delta. ppm (DMSO-d.sub.6): 3.014 (1H, dd, J=14.4 Hz, J=8.1 Hz), 3.195 (1H, dd, J=14.4 Hz, J=6.0 Hz), 3.489 (2H, s), 4.13-4.23 (1H, m), 6.943 (1H, t, J=7.4 Hz), 7.02-7.54 (12H, m), 7.662 (1H, bs), 9.449 (1H, s),
.sup.13 C-NMR .delta. ppm (DMSO-d.sub.6): 28.46, 4012, 57.69, 108.70, 110.90, 117.76, 117.98, 119.33, 120.54, 123.44, 126.74, 127.48, 127.88, 128.87, 129.71, 135.80, 136.46, 137.16, 138.81, 168.95, 172.36
Fab-MS m/z: 512 (MH.sup.+)
Example 259
Preparation of (S)-N-(4-(2-carboxyethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl) propanamide
The procedure described in Example 225 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl)-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (3.00 g) was hydrolyzed and recrystallized from acetonitrile to obtain (S)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-(3-indolyl)propanamide (2.68 g).
[.alpha.].sub.D.sup.30 +83.9.degree. (c 0.70, THF)
Melting point: 231.5.degree.-232.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3405, 1707, 1659, 1531, 1416, 1165, 1093, 756
.sup.1 H-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 2.501 (2H, t, J=7.6 Hz), 2.807 (2H, t, J=7.6 Hz), 2.943 (1H, dd, J=14.5 Hz, J=8.4 Hz), 3.123 (1H, dd, J=14.5 Hz, J=5.9 Hz), 4.10-4.21 (1H, m), 6.937 (1H, t, J=7.2 Hz), 7.00-7.12 (4H, m), 7.157 (2H, d, J=8.9 Hz), 7.299 (3H, t, J=8.4 Hz), 7.478 (1H, d, J=8.5 Hz), 7.520 (1H, d, J=8.5 Hz), 8.163 (2H, d, J=8.9 Hz), 9.765 (1H, s), 10.579 (1H, s)
.sup.13 C-NMR .delta. ppm (CDCl.sub.3 -DMSO-d.sub.6): 28.46, 29.78, 35.32, 57.58, 108.55, 111.12, 118.05, 119.48, 120.65, 123.77, 126.85, 127.70, 127.99, 128.10, 135.87, 136.17, 136.94, 139.25, 169.10, 173.65
Fab-MS m/z: 526 (MH.sup.+)
Example 260
Preparation of (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexyl-N-(4-(ethoxycarbonylmethyl)phenyl)propanamide (62.4 mg) was hydrolyzed to obtain (RS)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanamide (30.0 mg).
Melting point: 179.degree.-181.degree. C.
IR .nu.max cm.sup.-1 (KBr): 3236, 2924, 2852, 1711, 1668, 1606, 1518, 1416, 1325, 1163, 1093, 827, 754
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 0.8-1.0 (2H, m), 1.0-1.4 (4H, m), 1.4-1.5 (1H, m), 1.5-1.7 (4H, m), 3.2-3.4 (2H, m), 3.551 (2H, s), 3.951 (1H, dd, J=9.0 Hz, J=5.9 Hz), 7.190 (2H, d, J=8.8 Hz), 7.256 (2H, d, J=8.8 Hz), 7.409 (2H, d, J=8.8 Hz), 7.808 (2H, d, J=8.8 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 27.07, 27.33, 27.44, 33.16, 34.77, 34.88, 41.34, 41.59, 56.44, 121.39, 121.50, 129.90, 130.63, 132.14, 139.91, 140.61, 172.07, 175.41
Fab-MS m/z: 479 (MH.sup.+)
Example 261
Preparation of (RS)-N-(4-(2-carboxyethyl) phenyl)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanamide
The procedure described in Example 39 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexyl-N-(4-(2-methoxycarbonylethyl)phenyl)propanamide (135.3 mg) was hydrolyzed to obtain (RS)-N-(4-(2-carboxyethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanamide (112.2 mg).
Melting point: 197.degree.-198.degree. C.
IR .nu.max cm.sup.-1 (neat): 3338, 2926, 2850, 1709, 1668, 1606, 1539, 1414, 1325, 1163, 1093, 1014, 827, 754
.sup.1 H-NMR .delta. ppm (CD.sub.3 OD): 0.8-1.0 (2H, m), 1.1-1.4 (4H, m), 1.5-1.6 (1H, m), 1.6-1.7 (4H, m), 2.574 (2H, t, J=7.6 Hz), 2.875 (2H, t, J=7.6 Hz), 3.3-3.4 (2H, m), 3.9-4.0 (1H, m), 4.103 (1H, q, J=7.1 Hz), 7.131 (2H, d, J=8.5 Hz), 7.211 (2H, d, J=8.5 Hz), 7.405 (2H, d, J=8.5 Hz), 7.808 (2H, d, J=8.5 Hz)
.sup.13 C-NMR .delta. ppm (CD.sub.3 OD): 20.73, 27.07, 27.29, 27.44, 31.36, 33.16, 34.85, 36.64, 41.56, 56.41, 121.50, 129.53, 129.86, 130.16, 137.01, 138.37, 139.87, 140.53, 171.96, 176.54
Fab-MS m/z: 493 (MH.sup.+)
Pharmacological Examples
The biological activity of the arylsulfonamide derivative of the general formula (I) of the present invention was evaluated as follows, using as a control substance 4-[2-(4-chlorobenzenesulfonylamino) ethyl ]-phenoxy acetic acid [Japanese Examined Patent Publication (Kokoku) No. 57-35910].
(1) TxA.sub.2 antagonist action by binding assay
Guinea pigs (Hartley; male; body weight=approximately 500 g) were anesthetized with ether, and the blood was collected into sodium citrate (final concentration=0.38%). The preparation of platelets was carried out at room temperature. The platelet rich plasma was obtained by centrifugation at 980 rpm for 10 minutes. One tenth (1/10) amount of 77 mM-EDTA-Na (pH 7.4) was added to the platelet rich plasma, and the mixture was centrifuged for 10 minutes at 3000 rpm. The precipitate was suspended in a washing buffer (1) shown in Table 1. The suspension was again centrifuged at 3000 rpm for 10 minutes. The precipitate was further resuspended in a suspension buffer (2) shown in Table 2 to obtain washed platelets. The number of platelets was counted by an automatic blood cell counter (Sysmex Microcellcounter F-800) and the sample was diluted with the suspension buffer to 4.times.10.sup.8 cells/ml.
The platelets, sample solution and labeled compounds were placed into plastic tubes in amounts (volumes) shown in the following Table 3, incubated for 45 minutes at 25.degree. C., and then the mixture was filtered using a cell harvester (Brandel cell harvester M-24R) by a glass fiber filter (Whatman GF/B). After the filter was sufficiently dried, the scintillation was counted by a scintillation counter (Beckman LS5000TD). IC.sub.50 was calculated from (binding)/(control binding) ratio in the presence of an antagonist.
TABLE 1______________________________________ (1) Washing buffer (pH 7.2)______________________________________ 135 mM NaCl 5 mM KCl 8 mM Na2HPO4 2 mM NaH2PO4 10 mM EDTA______________________________________
TABLE 2______________________________________ (2) Suspension buffer (pH 7.5)______________________________________ 135 mM NaCl 5 mM MgCl 1 mM EGTA 25 mM Tris-HCl______________________________________
TABLE 3______________________________________Control binding 1 nM [.sup.3 H]-SQ29, 548 10 .mu.l Suspension buffer 10 .mu.l Washed platelets 980 .mu.lBinding in the presence of 1 nM [.sup.3 H]-SQ29, 548 10 .mu.lantagonist Sample 10 .mu.l Washed platelets 980 .mu.l______________________________________
(2) Inhibitory Activity of Vasoconstriction of Isolated Rat Artery
Rats (Wistar; male; body weight=250-300 g) were stunned by a blow to the head and exsanguinated. Then, the thoracic aorta was quickly removed, and the connective tissue and the endothelium were gently cleaned and then ring preparation was cut. The preparations were suspended in a 25 ml organ bath which was maintained at 37.degree. C. under an aeration of 95% O.sub.2 -5% CO.sub.2. An initial tension of 1.5 g was applied and preincubation was performed for 60 minutes. The organ bath was filled with Krebs-Henselait solution (NaCl=118, KCl=4.7, CaCl.sub.2 2.55, MgSO.sub.4 =1.18, KH.sub.2 PO.sub.4 =1.18, NaHCO.sub.3 =24.88, glucose=11.1). The constriction of the samples was ionotropicaly measured using an isometric transducer (UL-10GR, Minebea) and an amplifier (6M92, NEC SANEI) and recorded by a recticorder (RECTI-HORIZ-8K, NEC SANEI).
(3) Inhibitory Activity of Aggregation in Rat Platelet
The abdomen of etherized rat was open, and blood was taken from the abdominal arteries, using a sodium citrate solution (final concentration was 0.38%). The blood was centrifuged at 1100 rpm for 10 minutes, and the supernatent was separated as the platelet rich plasma. The plasma was further centrifuged at 2000 rpm for 15 minutes to obtain the supernatent as a platelet poor plasma. The platelet rich plasma (280 .mu.l) was placed in a measuring cuvette and preincubated for 1 minute at 37.degree. C. Then, a sample solution (10 .mu.l) was added. After 2 minutes, an arachidonic acid solution (final concentration=0.5 mM) (10 .mu.l) was added as an inducer. The change in light transmission was recorded for 5 minutes. The results are shown in the following Table 4.
TABLE 4______________________________________Compound to be tested A B C______________________________________Control Compound 2.0 6.90 1.7Compound of Example 39 0.20 7.90 --Compound of Example 40 0.50 7.54 0.52Compound of Example 41 0.057 8.16 0.18Compound of Example 42 0.088 7.89 0.54Compound of Example 43 -- 7.38 --Compound of Example 44 0.40 7.49 0.30Compound of Example 45 0.42 -- 3.6Compound of Example 46 0.11 -- 1.7Compound of Example 47 -- -- 1.5Compound of Example 48 -- -- 1.7Compound of Example 49 1.7 -- 0.40Compound of Example 50 1.0 -- 1.75Compound of Example 52 2.2 -- 1.7Compound of Example 53 0.2 -- 0.53Compound of Example 54 0.033 8.23 0.17Compound of Example 55 0.016 8.42 0.53Compound of Example 56 0.3 -- 1.7Compound of Example 57 0.15 -- 0.53Compound of Example 58 1.4 -- 5.3Compound of Example 59 1.6 -- 1.7Compound of Example 60 0.23 -- 5.3Compound of Example 94 0.86 -- 1.7Compound of Example 95 1.5 -- 1.79Compound of Example 100 -- -- 1.7Compound of Example 101 0.41 -- 1.7Compound of Example 103 1.9 -- 1.7Compound of Example 104 0.18 -- 1.7Compound of Example 116 0.50 -- 0.95Compound of Example 119 -- -- 1.7Compound of Example 123 2.0 -- 0.31Compound of Example 124 0.13 -- 0.31Compound of Example 129 0.72 -- 0.54Compound of Example 130 0.16 -- 1.7Compound of Example 131 0.047 -- 1.7Compound of Example 132 0.023 -- 1.7Compound of Example 136 0.15 -- 0.55Compound of Example 137 0.10 -- 1.7Compound of Example 138 0.10 -- 0.53Compound of Example 142 0.024 -- 0.53Compound of Example 143 0.037 -- 1.7Compound of Example 144 0.051 -- 0.53Compound of Example 149 0.017 -- 0.17Compound of Example 150 0.019 -- 5.4Compound of Example 151 0.019 -- 1.7Compound of Example 152 0.074 -- 1.7Compound of Example 169 0.69 -- 1.7Compound of Example 172 0.072 -- 1.7Compound of Example 174 0.17 -- 5.3Compound of Example 220 -- -- 0.53Compound of Example 221 -- -- 0.53Compound of Example 222 -- -- 0.17Compound of Example 223 0.13 -- 0.17Compound of Example 224 48.2 -- 3.4Compound of Example 225 -- -- 0.56Compound of Example 226 0.072 -- 0.53Compound of Example 227 0.045 -- --Compound of Example 228 0.057 -- --Compound of Example 230 -- -- 0.55Compound of Example 231 -- -- 1.7Compound of Example 232 0.16 -- 1.7Compound of Example 233 0.17 -- 0.17Compound of Example 234 0.052 -- 0.17Compound of Example 235 22.0 -- 17.1Compound of Example 236 0.42 -- --Compound of Example 237 0.15 -- 0.3Compound of Example 239 0.026 -- 0.055Compound of Example 240 0.099 -- 0.17Compound of Example 241 0.014 -- 0.053Compound of Example 242 0.032 -- 0.16Compound of Example 243 -- -- 0.17Compound of Example 244 0.29 -- 1.6Compound of Example 245 -- -- 0.055Compound of Example 246 0.034 -- --Compound of Example 247 0.046 -- 0.54Compound of Example 248 0.012 -- 0.053Compound of Example 249 0.024 -- 0.18Compound of Example 250 0.029 -- 0.17Compound of Example 251 0.012 -- 0.17Compound of Example 252 0.0071 -- 0.055Compound of Example 253 1.3 -- --Compound of Example 254 0.005 -- 0.051Compound of Example 256 -- -- 0.17Compound of Example 257 0.0087 -- 0.17Compound of Example 258 -- -- 0.53Compound of Example 260 0.06 -- 0.89Compound of Example 261 -- -- 2.3______________________________________
In Table 4, A, B, and C have the following meanings:
A: TXA.sub.2 antagonist action by binding assay (IC.sub.50 ; .mu.M)
B: Inhibitory activity of vasoconstriction (rat artery) (pA.sub.2)
C: Inhibitory activity of aggregation in rat platelet (IC.sub.50 ; .mu.M)
INDUSTRIAL APPLICABILITY
The arylsulfonamide derivative of the general formula (I) of the present invention exhibits an antagonism specific to a thromboxane A.sub.2 (TxA.sub.2) receptor, and may be used as an effective ingredient in a pharmaceutical composition based on thromboxane A.sub.2 receptor antagonism, inhibitory activity of vasoconstriction and inhibitory activity of agglutinating platelets.
The reaction routes described in the above Examples will be shown schematically hereinafter by chemical structural formulas. In the following reaction routes, Me is a methyl group, Et is an ethyl group, DHP is a dihydropyran, TsOH is a toluenesulfonic acid, OTHP is a tetrahydroxypyranyloxyl group, Ph is a phenyl group, and OMs is a methanesulfonyloxyl group. ##STR9##

Number	Date	Country
5-189236	Jul 1993	JPX
5-351660	Dec 1993	JPX
6-067792	Mar 1994	JPX
6-069031	Mar 1994	JPX

Arylsulfonamide derivative and pharmaceutical compositions and use thereof

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Chemical Abstracts, vol. 97, abstract 6774e (1982).
Chemical Abstracts, vol. 120, abstract 299279r (1994).