CA1207777A - Pyrrole-2-acetylamino acid derivatives - Google Patents
Pyrrole-2-acetylamino acid derivativesInfo
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- CA1207777A CA1207777A CA000443449A CA443449A CA1207777A CA 1207777 A CA1207777 A CA 1207777A CA 000443449 A CA000443449 A CA 000443449A CA 443449 A CA443449 A CA 443449A CA 1207777 A CA1207777 A CA 1207777A
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- Prior art keywords
- methyl
- pyrrol
- acetyl
- methylbenzoyl
- salts
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT
Novel pyrrole-2-acetylamino compounds of the formula
Novel pyrrole-2-acetylamino compounds of the formula
Description
77~7 ~he present invention comprises novel acylamino acids and their salts wherein the acyl group is [l-methyl-5-(4-methylbenzoyl3-lH~pyrrol-2-yl~-acetyl, having the general formula 4 below, and also amide esters of said acids having the general formula 3 below, which are used as intermediates to make the acids of general formula 4.
Tolmetin (general formula 1 below) is the generic name for the compound: [l-methyl 5 (4-methylbenzoyl)-lH-pyrrol-2-yl]-acetic acid; which can also be named as l-methyl-5-(4-methylbenzoyl)-lH-pyrrole-2-acetic acid, which has anti-inflammatory activity, and which is commercially available as tolmetin sodium dihydrate for use as a nonsteroidal, anti-inflammatory agent. Tolmetin is a safe and effective drug, but is administered at relatively large doses~
It has now been unexpectedly found that the potency of tolmetin can be substantially enhanced and the dosage re~uired substantially reduced by means of the novel compounds of the present invention having general formula 4 below, so that the tolmetin is administered in the form of its amide with an amino acid.
The particular amino acid derivatives o tolmetin are the following: glycine, alanine, methionine, glutamic acid, aspartic acid, lysine, and glutamine, and the resultant compounds of the present inventions have general formula 4 below, and may be in either optically active or racemic form. They may be administered in the form of their free acids or in the form of their pharmaceutically-acceptable salts, for example, as salts of alkali metals, preferably sodium or potassium, or alkaline earth metals, preferably calcium, or salts of organic amines, preferably 2-amino-2-(hydroxymethyl)-1,3-propanediol (tromethamine). The amino acid derivatives of tolmetin may be prepared by the following reaction scheme (A):
MN-39~
, j, ~2~`77~7 3~CO~LC~2C02 ~Na~, H N(alkyl)3]-c~3 CH3~CO~LCH7cOx C~3
Tolmetin (general formula 1 below) is the generic name for the compound: [l-methyl 5 (4-methylbenzoyl)-lH-pyrrol-2-yl]-acetic acid; which can also be named as l-methyl-5-(4-methylbenzoyl)-lH-pyrrole-2-acetic acid, which has anti-inflammatory activity, and which is commercially available as tolmetin sodium dihydrate for use as a nonsteroidal, anti-inflammatory agent. Tolmetin is a safe and effective drug, but is administered at relatively large doses~
It has now been unexpectedly found that the potency of tolmetin can be substantially enhanced and the dosage re~uired substantially reduced by means of the novel compounds of the present invention having general formula 4 below, so that the tolmetin is administered in the form of its amide with an amino acid.
The particular amino acid derivatives o tolmetin are the following: glycine, alanine, methionine, glutamic acid, aspartic acid, lysine, and glutamine, and the resultant compounds of the present inventions have general formula 4 below, and may be in either optically active or racemic form. They may be administered in the form of their free acids or in the form of their pharmaceutically-acceptable salts, for example, as salts of alkali metals, preferably sodium or potassium, or alkaline earth metals, preferably calcium, or salts of organic amines, preferably 2-amino-2-(hydroxymethyl)-1,3-propanediol (tromethamine). The amino acid derivatives of tolmetin may be prepared by the following reaction scheme (A):
MN-39~
, j, ~2~`77~7 3~CO~LC~2C02 ~Na~, H N(alkyl)3]-c~3 CH3~CO~LCH7cOx C~3
2 R
0 ~ R
C~3~3 Co~L CH2CONillUC02R
0 ~ R
C~3~3 Co~L CH2CONillUC02R
3~3CO¢;~LCH2CONHC!ICO2H
In the above formulae:
X = halide [particularly Cl or Br], -OCH2CN, or -OCOO
alkyl R ~ alkyl~ (CH2)ncO2R I CH2CH2SCH3, (CH2)4NHCbZ, or ( CH 2 ) 2CONE~ 2 n = 1 or 2 R' = alkyl or benzyl R" = H~ alkyl ~C~2)nCO2H~ CH~C~2SCH3, ~CH2)4N~2, or ~CH2)2cONH2 When the term l'alkyl" is used~ it is intended to include Cl-C6 alkyls, which can be straight or branched chain, primary, secondary or tertiary, such as methyl, isopropyl, isobutyl, sec-butyl, hexyl, and the like alkyls.
Compounds of type 4 may be prepared by the illustrated three-step procedures (1- >4). Tolmetin (1) is first 7~
converted to an activated derivative 12). Three different types of activated derivatives may be used, namely, the acid halide (2, X - halide), the activated ester (2, X ~
OCH2CN), or the mixed carbonic anhydride O
l2, X = O-C-O-alkyl). Preparation of acid halides has been previously described [J. R. Carson, U.S. Patent No. 3,752,826 (1973)~. The activated ester (2, X =
OCH2CNj may be prepared by reaction of a tolmetin salt with chloroacetoni~rile in a dipolar aprotic solvent (such as, for example, DMSO, DMF, acetonitrile or acetone) at o 20 to 80C. The mixed anhydrides (2, X = -o C-O-alkyl) may be prepared by reaction of a tolmetin salt (for example, triethylammonium or N-methylmorpholinium) with an alkyl chloroformate (for example, ethyl chloroformate or isobutyl chloroformate) in an iner~ apro~ic solvent (such as THF or methylene chloride) at -50 to -70C.
In the second step, amino acid esters (NH2-CH-CO2R') are acylated by the action o an activated tolmetin derivative (2) to give amide esters (3). The amino acid esters may be liberated from their corresponding salts by treatment with an organic tertiary amine such as triethylamine or an inorganic weak base such as an alkali metal bicarbonate or carbonate. Acylations of the amino acid esters using tolmetin acyl halides are carried out in the presence of a hydrogen halide acceptor such as a tertiary amine (e.g., triethylamine) in an inert aprotic solvent at 0 to 80C.
The acylation procedures using the activated esters (2, X = OCH2CN) are carried out in an iner~ aprotic solvent (for example, THF or dioxane) at elevated ~7~'7 temperature (50 to 100C), preferably in the presence of a wea~ organic acid catalyst such as acetic acid. The amino acid esters are used in excess. The acylation reactions utilizing the mixed anhydride O
reagents (2, X = -O-l-O-alkyl) are carried out in inert aprotic solvents, preferably in the same solution in which the reagent i5 prepared. The temperature range for carry-ing out acylations using mixed anhydrides is 0 to -75C.
When the amino acid ester being used is a glutamic acid ester, the mixed anhydride route is preferred, and the activated ester route is not used.
The conversion of amide esters 3 to amide acids 4 may be carried out by conventional saponification using about one equivalent of an alkali metal hydroxide in aqueous or mixed aqueous organic solution (e.~., ethanol-water) over a temperature of 25 to 100C. When R' is benzyl, the generation of ~ may be carried out by catalytic debenzyla-tion using hydrogen and a noble metal catalyst (for example, palladium or platinum~ in an organic solvent such as a lower alkanol or acetic acid.
When R i9 ~CH2)4NHCbZ, ~CbZ = benzyloxycarbonyl) the removal of the CbZ blocking group is carried out by catalytic debenzylation or preEerably by treatment with boron tribromide.
When R is tertiary alkyl the conversion of 3 to 4 may be carried out by the action of an aprotic acid, for example, by refluxing trifluoroacetic acid.
Alternatively, compounds of type 4 may be prepared by Schotten-Baumann reaction of the acid halide (2, x =
halide) with the amino acid in the presence of a weak ~-392 LZ~
base, preferably sodium or potassium bicarbonate, in aqueous solu~ion as in the following reaction scheme (B):
},n CH3~Co~CH2CO halide ~ N~12OEIC02H
~ , NaHC03 The salts of the compounds of general formula ~ may be prepared by the conventional method of reacting the acid compounds 4 with the desired base, or by cation exchange.
The anti-inflammatory activity of the compounds of the instant invention was measured in the rat adjuvant arthri-tis test ~S. Wong et al~, J. Pharmacol. and Exp. Ther.185, 127 (1973)]. Female Wistar/Lewis rats were given an injection of heat-killed Mycobacterium butyricum in light mineral oil. After eleven days, the animals which had developed an arthritic condi~ion were selected and given daily oral doses of test drug for seventeen days. The compound tested was administered either as aqueous solution of sodium salt (Admin. Form "a") or as aqueous suspension of free acid in n.os~ methyl cellulose (Admin.
Form "b"). Paw volumes were measured and the percent inhibition of swelling of the noninjected hind paw as compared to controls was calculated for the fourth and seventeenth day after initiation of dosing. The test results are set forth in Table I and are expressed as ED50 ~mg/kg~day).
gL~ 7~
TABLE I*
Compound Admin. ED50 E~50 Form (4 daYs) (17 days) __ _ _ Tolmetin a 47.7 19.8
In the above formulae:
X = halide [particularly Cl or Br], -OCH2CN, or -OCOO
alkyl R ~ alkyl~ (CH2)ncO2R I CH2CH2SCH3, (CH2)4NHCbZ, or ( CH 2 ) 2CONE~ 2 n = 1 or 2 R' = alkyl or benzyl R" = H~ alkyl ~C~2)nCO2H~ CH~C~2SCH3, ~CH2)4N~2, or ~CH2)2cONH2 When the term l'alkyl" is used~ it is intended to include Cl-C6 alkyls, which can be straight or branched chain, primary, secondary or tertiary, such as methyl, isopropyl, isobutyl, sec-butyl, hexyl, and the like alkyls.
Compounds of type 4 may be prepared by the illustrated three-step procedures (1- >4). Tolmetin (1) is first 7~
converted to an activated derivative 12). Three different types of activated derivatives may be used, namely, the acid halide (2, X - halide), the activated ester (2, X ~
OCH2CN), or the mixed carbonic anhydride O
l2, X = O-C-O-alkyl). Preparation of acid halides has been previously described [J. R. Carson, U.S. Patent No. 3,752,826 (1973)~. The activated ester (2, X =
OCH2CNj may be prepared by reaction of a tolmetin salt with chloroacetoni~rile in a dipolar aprotic solvent (such as, for example, DMSO, DMF, acetonitrile or acetone) at o 20 to 80C. The mixed anhydrides (2, X = -o C-O-alkyl) may be prepared by reaction of a tolmetin salt (for example, triethylammonium or N-methylmorpholinium) with an alkyl chloroformate (for example, ethyl chloroformate or isobutyl chloroformate) in an iner~ apro~ic solvent (such as THF or methylene chloride) at -50 to -70C.
In the second step, amino acid esters (NH2-CH-CO2R') are acylated by the action o an activated tolmetin derivative (2) to give amide esters (3). The amino acid esters may be liberated from their corresponding salts by treatment with an organic tertiary amine such as triethylamine or an inorganic weak base such as an alkali metal bicarbonate or carbonate. Acylations of the amino acid esters using tolmetin acyl halides are carried out in the presence of a hydrogen halide acceptor such as a tertiary amine (e.g., triethylamine) in an inert aprotic solvent at 0 to 80C.
The acylation procedures using the activated esters (2, X = OCH2CN) are carried out in an iner~ aprotic solvent (for example, THF or dioxane) at elevated ~7~'7 temperature (50 to 100C), preferably in the presence of a wea~ organic acid catalyst such as acetic acid. The amino acid esters are used in excess. The acylation reactions utilizing the mixed anhydride O
reagents (2, X = -O-l-O-alkyl) are carried out in inert aprotic solvents, preferably in the same solution in which the reagent i5 prepared. The temperature range for carry-ing out acylations using mixed anhydrides is 0 to -75C.
When the amino acid ester being used is a glutamic acid ester, the mixed anhydride route is preferred, and the activated ester route is not used.
The conversion of amide esters 3 to amide acids 4 may be carried out by conventional saponification using about one equivalent of an alkali metal hydroxide in aqueous or mixed aqueous organic solution (e.~., ethanol-water) over a temperature of 25 to 100C. When R' is benzyl, the generation of ~ may be carried out by catalytic debenzyla-tion using hydrogen and a noble metal catalyst (for example, palladium or platinum~ in an organic solvent such as a lower alkanol or acetic acid.
When R i9 ~CH2)4NHCbZ, ~CbZ = benzyloxycarbonyl) the removal of the CbZ blocking group is carried out by catalytic debenzylation or preEerably by treatment with boron tribromide.
When R is tertiary alkyl the conversion of 3 to 4 may be carried out by the action of an aprotic acid, for example, by refluxing trifluoroacetic acid.
Alternatively, compounds of type 4 may be prepared by Schotten-Baumann reaction of the acid halide (2, x =
halide) with the amino acid in the presence of a weak ~-392 LZ~
base, preferably sodium or potassium bicarbonate, in aqueous solu~ion as in the following reaction scheme (B):
},n CH3~Co~CH2CO halide ~ N~12OEIC02H
~ , NaHC03 The salts of the compounds of general formula ~ may be prepared by the conventional method of reacting the acid compounds 4 with the desired base, or by cation exchange.
The anti-inflammatory activity of the compounds of the instant invention was measured in the rat adjuvant arthri-tis test ~S. Wong et al~, J. Pharmacol. and Exp. Ther.185, 127 (1973)]. Female Wistar/Lewis rats were given an injection of heat-killed Mycobacterium butyricum in light mineral oil. After eleven days, the animals which had developed an arthritic condi~ion were selected and given daily oral doses of test drug for seventeen days. The compound tested was administered either as aqueous solution of sodium salt (Admin. Form "a") or as aqueous suspension of free acid in n.os~ methyl cellulose (Admin.
Form "b"). Paw volumes were measured and the percent inhibition of swelling of the noninjected hind paw as compared to controls was calculated for the fourth and seventeenth day after initiation of dosing. The test results are set forth in Table I and are expressed as ED50 ~mg/kg~day).
gL~ 7~
TABLE I*
Compound Admin. ED50 E~50 Form (4 daYs) (17 days) __ _ _ Tolmetin a 47.7 19.8
4~ R" - H b 24.75 3.10 4, R" = CH3 b 28.86 9.68 4, R" = ~CH2)2SCH3 b 22.07 8.66 4, R" = CH2CO2H a 28.Ç5 7.71 4, R" ~ (C~2)2CO2H a 24.56 7.69 4, R ~ ~CH232CoNH2 a 31.1 11.4 4, R" = (CH2)4NH2 a 27.16 *A11 test compounds were significantly different from Tolmetin, p < 0.05~
In addition ~o their anti-inflammatory activity, the com-pounds of the instant invention were evaluated for their ability to induce gastric ulceration since gastric irritation is the most significant side effect following administration of nonsteroidal anti-inflammatory agents.
The compound tested was administered either as aqueous solution of sodium salt (Admin. Form "a") or as aqueous suspension of free acid in 0.05% methyl cellulose (Admin.
Form "b"). As described by Wong et al., the dose tUD50.
mg/kg/day) required to produce 50 percent ulcerogenic response following 4 days of oral dosing with the test drug was determined. A therapeutic index in respect to gastric ulceration, the "Anti-in1ammatory Index" (AII) was calculated.
AII = -The test results are set forth in Table II.
-~`7~t77 TABLE I I *
Admin.
Com~ound Form AII
Tolmetin a 4.7 4, R" = H b 30~41 4, R" = CH3 b 13.09 4, R" - (CH2)2SC~3 b 25.31 4, R'l = CH2CO~H a >34.89 4, R" = ICH~)2CO2H a >32.57 4, R" - ~CH~)2CONH2 a 43.06 *A11 test compounds were significantly different from Tolmetin, p < 0.05.
As can be seen, in addition to greater potency than tolme-tin, the compounds of the instant invention also display a more favorable therapeutic index than the parent drug. In common with other nonsteriodal anti-inflammatory agents, compounds of type 4 also pOS5eSS analgesic activity.
The compounds of formula 4 may be administered to humans in the same general manner as tolmetin, except that, since the compounds are more potent, the amount of active drug 2S per unit dose will be less, on the order of 25 mg ~o 200 mg~
The ollowing examples are intended to illustrate, but not to limit~ the scope of the present invention.
Cyanometh~ Methyl-5-l4-methylbenæoyl)-lH-pyrrol-2-yl]
acetate A 132.9 g ~1.76 mole) sample of chloroacetonitrile was added to a suspension of 44608 g (1.6 mole~ of dry sodium Ll-methyl-5 (4-methylbenzoyl)-lH-pyrrol-2-yl] acetate in one liter of DMF. The mixture was heated at 55C for ~-392 .
2~1;7~7 4 hour~. The reaction was cooled and water was added~
The precipitate was collected and air dried to give 436 g of cyanomethyl [l-methyl-5-(~-methylbenzoyl)-1~-pyrrol-2-yl]-acetate (92% yield), m.p. 132-5Co ace~ylLglycinate A mixture of 5.6 g (0.019 mole) of cyanomethyl [l-methyl-
In addition ~o their anti-inflammatory activity, the com-pounds of the instant invention were evaluated for their ability to induce gastric ulceration since gastric irritation is the most significant side effect following administration of nonsteroidal anti-inflammatory agents.
The compound tested was administered either as aqueous solution of sodium salt (Admin. Form "a") or as aqueous suspension of free acid in 0.05% methyl cellulose (Admin.
Form "b"). As described by Wong et al., the dose tUD50.
mg/kg/day) required to produce 50 percent ulcerogenic response following 4 days of oral dosing with the test drug was determined. A therapeutic index in respect to gastric ulceration, the "Anti-in1ammatory Index" (AII) was calculated.
AII = -The test results are set forth in Table II.
-~`7~t77 TABLE I I *
Admin.
Com~ound Form AII
Tolmetin a 4.7 4, R" = H b 30~41 4, R" = CH3 b 13.09 4, R" - (CH2)2SC~3 b 25.31 4, R'l = CH2CO~H a >34.89 4, R" = ICH~)2CO2H a >32.57 4, R" - ~CH~)2CONH2 a 43.06 *A11 test compounds were significantly different from Tolmetin, p < 0.05.
As can be seen, in addition to greater potency than tolme-tin, the compounds of the instant invention also display a more favorable therapeutic index than the parent drug. In common with other nonsteriodal anti-inflammatory agents, compounds of type 4 also pOS5eSS analgesic activity.
The compounds of formula 4 may be administered to humans in the same general manner as tolmetin, except that, since the compounds are more potent, the amount of active drug 2S per unit dose will be less, on the order of 25 mg ~o 200 mg~
The ollowing examples are intended to illustrate, but not to limit~ the scope of the present invention.
Cyanometh~ Methyl-5-l4-methylbenæoyl)-lH-pyrrol-2-yl]
acetate A 132.9 g ~1.76 mole) sample of chloroacetonitrile was added to a suspension of 44608 g (1.6 mole~ of dry sodium Ll-methyl-5 (4-methylbenzoyl)-lH-pyrrol-2-yl] acetate in one liter of DMF. The mixture was heated at 55C for ~-392 .
2~1;7~7 4 hour~. The reaction was cooled and water was added~
The precipitate was collected and air dried to give 436 g of cyanomethyl [l-methyl-5-(~-methylbenzoyl)-1~-pyrrol-2-yl]-acetate (92% yield), m.p. 132-5Co ace~ylLglycinate A mixture of 5.6 g (0.019 mole) of cyanomethyl [l-methyl-
5-(4-methylbenzoyl)-1~-pyrrol-2-yl]-acetate, 2.34 g (0.019 mole) of glycine methyl ester hydrochloride, 2.6 ml (0.019 mole) of triethylamine, and 0.2 ml of glacial ace-tic acid in 15 ml of THF was heatPd under reflux for 3 hours. ~ second addition of 1.17 g (0.0095 mole) of glycine methyl ester hydrochloride and 1.3 ml (O~OO9S mole) of ~riethylamine was made. ~he reaction was heated under reflux for 2 hours. A third addition of 1.17 g of glycine methyl ester hydrochloride and 1.3 ml of triethylamine was made. The reaction was heated under reflux for 1 hour~ It was cooled and poured into water. The solid was collected and dried to give 6.0 g of white crystalline methyl N-{[l-methyl 5-(4-methylbenzoyl)]-lH-pyrrol-2-yl]-acetyl}-glycinate (97% yield) m.p. 149-150C.
H nmr (CDC13) ~7.7 (d, J=9), 2H; 7.2 (d, J=9), lH, 6.7 (d, J=4), lH; ~.3 ~m) t lH; 6.15 (d, J-4), lH, 4.0 (m), 2H; 3.9 (~), 3Ht 3~71 ~s) 3H, 3.68 (s), 2H; 2.4 (s), ~Ho EXAMPLE III
Using the procedure o~ Example II, employing the following amino acid ester salts in place of glycine methyl ester hydrochloride, and allowing them to react with cyanomethyl [1-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetate in the presence of triethylamine, the respective [l-methyl-5-(4-methylben30yl)-lH-pyrrol-2-yl]-acetyl derivatives of the amino acid esters were prepared:
~-392 ~7~
a ~1 ~ c~
~ ~ ~ ~1 ~
oP ~ r~ ~ ~ Ln co C
O h ~ ~ U~
U ~ -~
~3 ~ S
rl -~ S > Zl~ E ~
~ ~ o a) ~
n ~ ua I ,, ~ _4 U ~ I
~5 ~0 ~ o X ~ -!
O
~ Q, 13 '1 N _ C) ~ 1~ m I ~ ~
I Z 1~
Zl^ JJ Zl~ ZIS ~ $
~1 a~ _I s ~1 N
~ '~ ~ ~ O ~1 0 ~ C
S N f. S N .~:: N I Ll ~1 N 11) Gl N la 1:: ~ ~ C ~ ~ C ~ ~ C ~2, a~ J c u~ ~ O $ ~ .a ~
s ~ a) ~ O ~ 0 a) v ~ a s~ ~ ~ ,~ o ~J
JJ ~ I X N rl O O U ~a 0 5~ ~ ~ O ~ SJ 0 h 0 0 E~ O '~ O ~ o ~ .LI
f' a~ S 1 ~C N ,~: .rl ~ Q, .~ f U O C) .~1 0 rl O a) c o S~ t~ m-,-l h 0 a) 0 a ~ ~ v ~:5 1 m '15 ~JJ
C/~ ~ S ~ .~:: Zl-l S
~77~7 EXAMPLE IV
Following the procedure of Example II, employing the following amino acid esters, causing them to react with cyanomethyl [1-methyl-5-(4-methylbenzoyl1-lH-pyrrol-2-yl]-acetate in the presence of triethylamine, the correspond-ing [l-me~hyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl amino acid esters may be prepared respectively:
10 Amino Acid Ester Product L-Valine methyl ester Methyl -{[l-methyl-5-(4-methyl-hydrochloride benzoyl~]-lH-pyrrol-2-yl]acetyl}-valinate L~Leucine methyl ester Methyl N-{[l-methyl-5-(4-methyl-hydrochloride benzoyl)]-lH-pyrrol-2-yl]~
acetyl}-leucinate 20 L-Isoleucine methyl Methyl N-{[l-methyl-5-(4-methyl-ester hydrochloride benzoyl)]-lH-pyrrol-2-yl]-acetyl}-isoleùcinate EXAMPLE V
Dimethyl N-~l-Methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]
acetvlalutamate v To a suspension o 45.10 g (0.152 mole) [1-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetic acid in 230 ml dry 30 ~HF was added 16.47 ml (0.15 mole) of N-methylmorpholine.
The mixture was cooled to -65C. A 14 ml (0.152 moles) sample of ethyl chloroformate in 50 ml dry THF was added dropwise to the reaction mixture while maintaining the temperature at -65~C. The mixture was stirred for one~
half hour after the addition was completedO
7~'7 Meanwhile, 40.0 g (0.20 mole) L-glutamic acid dimethyl ester hydrochloride was partitioned between 175 ml of cold 20% potassium carbona~e and 310 ml of T~F. The THF was washed with brine, dried over 4A sieves and anhydrous sodium sulfate. (Elapsed time ~10 minutes).
The L-glutamic acid dimethyl ester solution was added to the reaction mixture as quickly as possible maintaining the temperature at -65C. It was stirred an additional 4 hours. The reaction mix~ure was poured into 3N hydro-chloric acid, extracted into chloroform, washed with sodium bicarbonate solution, water, brine and dried over anhydrous magnesiwm sulfate. The solvent was removed in vacuo giving a tan solid which upon recrystallization from 2-propanol gave 40.5 g of dimethyl N-~[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-glutamate (65%
yield), m.p. 109-111C, nmr: 7.70, d, ~J=8), 2H; 7.25, d, (J-8), 2H; 6.68, d, (J=4), lH; 6.52, m, lH; 6.15, d, (J=4), lH; 4.55, m, lH, 3.95, s, 2H; 3.74, S, 3H; 3.66, 2s, (coincidental), 6H; 2.2, m, 4~.
EXAMPLE_VI
N-~[l-Methyl-5-(4-methylbenzoyl) 1~-pyrrol-2-yl;-acetyl}-glycine A solution of 64 ml (0.032 mole) of 0.5 N sodium hydroxide was added dropwise over 2 hours to a refluxing solution of 10.49 g (0.0318 mole) of methyl N-{[l-methyl-5-(4-methyl-benzoyl]~ pyrrol~2-yl]-acetyl}-glycinate in 100 ml o~
methanol. The methanol was evaporated in vacuo. The solution was added to cold 3N HCl. The solid was collected and air dried. It was recrystallized from 2-propanol to give 7.3 g of white crystalline N-{[l-methyl-5-(4 methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-glycine (72%
yield), m.p. 197-199C.
AnalO Calc'd. for Cl7Hl8N24 C, 64.9 ;
Found: C, 64.98; H, 5.~4.
EXAMPLE VII
-- _ Following the procedure of Example VI, employing the N-i[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~
derivatives of the aminoacid methyl esters from Examples III and V in place of methyl N-{[l-methyl-5-(4-methylbenzoyl)-1~1-pyrrol-2-yl]-acetyl}-glycinate and employing one equivalent of sodium hydroxide for each saponifiable ester group, the following N-i[l-me~hyl-5-(4-benzoyl)-lH-pyrrol-2-yl]-acetyl} derivatives of amino acids were prepared respectively:
Compound 4 R'l % m.p.
~ Yield N- t [l-methyl-5-(4-methyl-benzoyl)-lH-pyrrol-2-yl~-acetyl}-alanine CH3 67 181-2 N-{~l methyl-5-(4-methyl-benzoyl)-lH-pyrrol-2-yl]-acetyl~-methionine (CH~)2SC~3 92 162-4 N-{[l-methyl-5-(4-mathyl-benzoyl)-lH-pyrrol-2-yll-acetyl~glutamic acid (CH2)2CO~H 21 178-80 N-{[l-methyl-5-~4methyl-benzoyl)-lH-pyrrol-2-yl]-acetyl~aspartic acid CH~CO~H 52 190d EXAMPLE VIII
Following the procedure of Example VI and employing the N-{[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~
amino acid methyl esters from Example IV, the ollowing products may be obtained respectively:
~7~7 Ni[1-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}~
valine N-{[l-methyl-5-(4-methylbenzoyl)-lH pyrrol-2-yl]-acetyl~-leucine N-t[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-isoleucine EXAMP~E IX
N- t [l-Methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}
_ _ _ aspartic acid A solution of 13.3 g (0.024 mole) of dibenzyl N l[l-methyl-5-(4-methylbenzoyl)~l~-pyrrol-2-yl]-acetyl}-aspartate in 150 ml of glacial acetic acid was hydrogena-ted over 1.3 g of 10% palladium on charcoal for 2-1/4 hours at room temperature under 50 psi of hydrogen. The solvent was evaporated ln vacuo. The residue was recrys-tallized from ethanol-water to give 8.4 g of a gummy red solid. The solid was placed in the thimble of a Soxhlet extractor and continuously extracted with moist ether.
The solid was collected from the extract and dried. There was obtained 5.1 g of pink N {[l-methyl-5-(4-methyl-benzoyl)-l_ pyrrol-2-ylJ-acetyl~-aspartic acid (63%
yield), m.p. 158-60~.
Anal. Calcd. for ClgHzoN2O6: C, 61.2~; H, 5.41; N, 7.52 Found: C, 61.18; H, 5.45; N, 7.52 ~Z~777~
EXAMPLE X
_2_ t ~1-Methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~
lysine hydrate t2~
A 1702 g (0.028 mole) sample of N6-benæyloxycarbonyl N2-{[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-lysine benzyl ester was dissolved in 170 ml of methylene chloride and the solution cooled to -70C in a dry ice bath under a nitrogen atmosphere. Then 227 ml of 1 Molar boron tribrcmide solution in methylene chloride was added dropwise, keeping the temperature of the reaction mixture below -50C. The reaction was mechanically ~tirred for 3 hours at -50C, then allowed to warm to 22C over a one-hour period. Water was then added dropwise with vigorous stirring. The methylene chloride was evaporated in vacuo, and the aqueous mixture basified to pH 12 with sodium hydroxide solution, ~hen treated with 3N hydrochloric acid to pH 7.5. The solid precipitate was filtered cold, then d ried using an evaporating dish.
The solid residue was washed several times with hot acetonitrile, then recrystallized from ethanol-water to give N~-~[l-methyl 5-(4~methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-lysine hydrate (2:1), m.p. 231-233C d as a light tan solid; the yield was 10~ of theoretical.
.
nmr (CD3OD/D~O~: ~7.9-7.0 (q, 4H, J-14 Hz~; 6.8-6.6 ~d, ; lH, J-4Hz); 6.3-6.1 (d, lH, J-4Hz~; 3.85 ts, 3H0; 3.75 (s, 2H); 3.4-3.15 (m, lH~S 3.1-2.6 (m, 2H); 2.4 (2, 3~; 2.1-1.0 tm, 6H).
EXAMPLE XN2-{[l-Methyl-5-(4-methylbenzoyl~-lH pyrrol-2-yl] acetyl}
glutamine A 20 9 sample ~0.073 mole) of [l~methyl-5-t4-methyl-benzoyl)-lH-pyrrol~2-yl]-acetyl chloride was added to a ~-392 7'~'7 solution of 11.5 g (0.079 mole) of glutamine and 29.3 g (0.32 mole) of sodium bicarbonate in 300 ml of water. The solution was stirred for 3 hours. The solid was filtered and discarded. The filtrate was acidified with 3N HCl.
The solid was filtered and washed wi~h water. The solid was dissolved in acetone-water (50:50), treated with charcoal and the solvent evaporated in vacuo. The solid was extracted with boiling acetone to give 4.3 g of white crystalline N2-{[l-methyl-5-(~-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl} glutamine hydrate (lO:l) m.p. 194-6, yield 15.4%.
Anal. calcd. for C20H23N30s-0.1 H~0:
C, 62.04; H, 6.4; H20, 0.45 Found: C, 62.08; H, 6.01; H20, 0029 EXAMPLE XII
Methyl N- t [ l-Methyl-5-~4-methylbenzoyl~-lH-pyrrol-2-yl]-acetyl~-~lycinate 2~
A solution of 14.0 g (0.139 mole) of triethylamine in 350 ml of ethanol free chloroform was added to a suspen-sion of 8.3 g (0.066 mole) of glycine methyl ester hydro-chloride in 500 ml of chloroform. The mixture was cooled to 0 and a solution of 16~83 g (0.061 mole) of [l-methyl-5-(4-methylbenzyl)-lH-pyrrol-2-yl]-acetyl chloride in 300 ml of chloroform added. The mixture was stirred at room temperature for 90 minutes. The solution was then washed successively with dilute HCl, sodium bicarbonate solution, water and brine. The solution was dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The solid was dissolved in chloroform-ethyl acetate and filtered through silica gel, The solvent was evaporated and the residue recrystallized twice from ethyl acetate to give 14.9 g (68% yield) of methyl N-{~l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl3-acetyl~-glycinate, m.p. 149-150C.
el~AMPLE Xl:tI
~G ~a~
(A) A solution of 361 g ~l.l mole) of methyl N-ltl-methyl-5-(4-me~hylben~oyl)-.Lt~-pyrrol-2-yll-acc~yl~-glycinate ln 2 l Oe cth~noL and ~20 ml 5N N~O~ wa0 heated under reflux ~or 4S mLnu~ trhe mlxtur~ wa9 coolad ~nd the solid collected and clried to give 303 g of sodium N-l[l-methyl-5-(4-methylbenzoyL-l~-pyrrol-2-yl]-acetyl~-glycinate, m.p. 2~1-2~4C (d).
(B) A solution from 12 g (0.038 mole) of ~T-l[l-methyl-5-(4-methylben~oyl)-lH-pyrrol-2-yl]-acetyl~-glycine and 4.6 g of 2-amino-2-(hydroxymethyl-1,3-propanediol in 300 ml 2-propanol wa~ concentrated in vacuo and the solid collected and dried. There was obtained 6.0 g o 2-ammonium-2-(hydroxymethyl)-1,3 propanediol ?J-t[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~-glycinate hydrate 1:1.65, m.p. 6~-73C.
(C) ~o a solution of Ç.73 9 of 2-ammonium-2-~hydroxy-methyl)-1,3-propanediol N-t[l-methyl-5-(methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~-glycinate in 50 ml of water was added a saturated solution of 22.64 g of CaCl2 in water. The solid was collected, washed with water and air dried to give calcium N-{[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-glycinate hydrate [1:0.5:1.6], m.p. 267-270C
(d).
EXAMPLE XIV
Following the procedure~ of the eor~going Example X~I and substitutlng the appropriate N-tl-mekhyl-5-~-meth~l-benzoyl)-L~I-p~rrol-2-yll-acetyl aminoacLcl der;Lvatlve th~
following salt~ may be obtained;
~-39~
77~7 Sodium N-{[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~-alaninate Sodium N-{[l-methyl-5-(4-methylbenzoyl3-lH-pyrrol-2-yl]-acetyl~-lysinate 2-Ammonium-2-(hydroxymethyl)-1,3-propanediol N-t[l-methyl-5~(4-methylbenzoyl3-lH-pyrrol-2-yl] acetyl~-methioninate Calcium N- t [l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~-aspartate [1:1]
MN-3g2
H nmr (CDC13) ~7.7 (d, J=9), 2H; 7.2 (d, J=9), lH, 6.7 (d, J=4), lH; ~.3 ~m) t lH; 6.15 (d, J-4), lH, 4.0 (m), 2H; 3.9 (~), 3Ht 3~71 ~s) 3H, 3.68 (s), 2H; 2.4 (s), ~Ho EXAMPLE III
Using the procedure o~ Example II, employing the following amino acid ester salts in place of glycine methyl ester hydrochloride, and allowing them to react with cyanomethyl [1-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetate in the presence of triethylamine, the respective [l-methyl-5-(4-methylben30yl)-lH-pyrrol-2-yl]-acetyl derivatives of the amino acid esters were prepared:
~-392 ~7~
a ~1 ~ c~
~ ~ ~ ~1 ~
oP ~ r~ ~ ~ Ln co C
O h ~ ~ U~
U ~ -~
~3 ~ S
rl -~ S > Zl~ E ~
~ ~ o a) ~
n ~ ua I ,, ~ _4 U ~ I
~5 ~0 ~ o X ~ -!
O
~ Q, 13 '1 N _ C) ~ 1~ m I ~ ~
I Z 1~
Zl^ JJ Zl~ ZIS ~ $
~1 a~ _I s ~1 N
~ '~ ~ ~ O ~1 0 ~ C
S N f. S N .~:: N I Ll ~1 N 11) Gl N la 1:: ~ ~ C ~ ~ C ~ ~ C ~2, a~ J c u~ ~ O $ ~ .a ~
s ~ a) ~ O ~ 0 a) v ~ a s~ ~ ~ ,~ o ~J
JJ ~ I X N rl O O U ~a 0 5~ ~ ~ O ~ SJ 0 h 0 0 E~ O '~ O ~ o ~ .LI
f' a~ S 1 ~C N ,~: .rl ~ Q, .~ f U O C) .~1 0 rl O a) c o S~ t~ m-,-l h 0 a) 0 a ~ ~ v ~:5 1 m '15 ~JJ
C/~ ~ S ~ .~:: Zl-l S
~77~7 EXAMPLE IV
Following the procedure of Example II, employing the following amino acid esters, causing them to react with cyanomethyl [1-methyl-5-(4-methylbenzoyl1-lH-pyrrol-2-yl]-acetate in the presence of triethylamine, the correspond-ing [l-me~hyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl amino acid esters may be prepared respectively:
10 Amino Acid Ester Product L-Valine methyl ester Methyl -{[l-methyl-5-(4-methyl-hydrochloride benzoyl~]-lH-pyrrol-2-yl]acetyl}-valinate L~Leucine methyl ester Methyl N-{[l-methyl-5-(4-methyl-hydrochloride benzoyl)]-lH-pyrrol-2-yl]~
acetyl}-leucinate 20 L-Isoleucine methyl Methyl N-{[l-methyl-5-(4-methyl-ester hydrochloride benzoyl)]-lH-pyrrol-2-yl]-acetyl}-isoleùcinate EXAMPLE V
Dimethyl N-~l-Methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]
acetvlalutamate v To a suspension o 45.10 g (0.152 mole) [1-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetic acid in 230 ml dry 30 ~HF was added 16.47 ml (0.15 mole) of N-methylmorpholine.
The mixture was cooled to -65C. A 14 ml (0.152 moles) sample of ethyl chloroformate in 50 ml dry THF was added dropwise to the reaction mixture while maintaining the temperature at -65~C. The mixture was stirred for one~
half hour after the addition was completedO
7~'7 Meanwhile, 40.0 g (0.20 mole) L-glutamic acid dimethyl ester hydrochloride was partitioned between 175 ml of cold 20% potassium carbona~e and 310 ml of T~F. The THF was washed with brine, dried over 4A sieves and anhydrous sodium sulfate. (Elapsed time ~10 minutes).
The L-glutamic acid dimethyl ester solution was added to the reaction mixture as quickly as possible maintaining the temperature at -65C. It was stirred an additional 4 hours. The reaction mix~ure was poured into 3N hydro-chloric acid, extracted into chloroform, washed with sodium bicarbonate solution, water, brine and dried over anhydrous magnesiwm sulfate. The solvent was removed in vacuo giving a tan solid which upon recrystallization from 2-propanol gave 40.5 g of dimethyl N-~[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-glutamate (65%
yield), m.p. 109-111C, nmr: 7.70, d, ~J=8), 2H; 7.25, d, (J-8), 2H; 6.68, d, (J=4), lH; 6.52, m, lH; 6.15, d, (J=4), lH; 4.55, m, lH, 3.95, s, 2H; 3.74, S, 3H; 3.66, 2s, (coincidental), 6H; 2.2, m, 4~.
EXAMPLE_VI
N-~[l-Methyl-5-(4-methylbenzoyl) 1~-pyrrol-2-yl;-acetyl}-glycine A solution of 64 ml (0.032 mole) of 0.5 N sodium hydroxide was added dropwise over 2 hours to a refluxing solution of 10.49 g (0.0318 mole) of methyl N-{[l-methyl-5-(4-methyl-benzoyl]~ pyrrol~2-yl]-acetyl}-glycinate in 100 ml o~
methanol. The methanol was evaporated in vacuo. The solution was added to cold 3N HCl. The solid was collected and air dried. It was recrystallized from 2-propanol to give 7.3 g of white crystalline N-{[l-methyl-5-(4 methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-glycine (72%
yield), m.p. 197-199C.
AnalO Calc'd. for Cl7Hl8N24 C, 64.9 ;
Found: C, 64.98; H, 5.~4.
EXAMPLE VII
-- _ Following the procedure of Example VI, employing the N-i[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~
derivatives of the aminoacid methyl esters from Examples III and V in place of methyl N-{[l-methyl-5-(4-methylbenzoyl)-1~1-pyrrol-2-yl]-acetyl}-glycinate and employing one equivalent of sodium hydroxide for each saponifiable ester group, the following N-i[l-me~hyl-5-(4-benzoyl)-lH-pyrrol-2-yl]-acetyl} derivatives of amino acids were prepared respectively:
Compound 4 R'l % m.p.
~ Yield N- t [l-methyl-5-(4-methyl-benzoyl)-lH-pyrrol-2-yl~-acetyl}-alanine CH3 67 181-2 N-{~l methyl-5-(4-methyl-benzoyl)-lH-pyrrol-2-yl]-acetyl~-methionine (CH~)2SC~3 92 162-4 N-{[l-methyl-5-(4-mathyl-benzoyl)-lH-pyrrol-2-yll-acetyl~glutamic acid (CH2)2CO~H 21 178-80 N-{[l-methyl-5-~4methyl-benzoyl)-lH-pyrrol-2-yl]-acetyl~aspartic acid CH~CO~H 52 190d EXAMPLE VIII
Following the procedure of Example VI and employing the N-{[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~
amino acid methyl esters from Example IV, the ollowing products may be obtained respectively:
~7~7 Ni[1-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}~
valine N-{[l-methyl-5-(4-methylbenzoyl)-lH pyrrol-2-yl]-acetyl~-leucine N-t[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-isoleucine EXAMP~E IX
N- t [l-Methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}
_ _ _ aspartic acid A solution of 13.3 g (0.024 mole) of dibenzyl N l[l-methyl-5-(4-methylbenzoyl)~l~-pyrrol-2-yl]-acetyl}-aspartate in 150 ml of glacial acetic acid was hydrogena-ted over 1.3 g of 10% palladium on charcoal for 2-1/4 hours at room temperature under 50 psi of hydrogen. The solvent was evaporated ln vacuo. The residue was recrys-tallized from ethanol-water to give 8.4 g of a gummy red solid. The solid was placed in the thimble of a Soxhlet extractor and continuously extracted with moist ether.
The solid was collected from the extract and dried. There was obtained 5.1 g of pink N {[l-methyl-5-(4-methyl-benzoyl)-l_ pyrrol-2-ylJ-acetyl~-aspartic acid (63%
yield), m.p. 158-60~.
Anal. Calcd. for ClgHzoN2O6: C, 61.2~; H, 5.41; N, 7.52 Found: C, 61.18; H, 5.45; N, 7.52 ~Z~777~
EXAMPLE X
_2_ t ~1-Methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~
lysine hydrate t2~
A 1702 g (0.028 mole) sample of N6-benæyloxycarbonyl N2-{[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-lysine benzyl ester was dissolved in 170 ml of methylene chloride and the solution cooled to -70C in a dry ice bath under a nitrogen atmosphere. Then 227 ml of 1 Molar boron tribrcmide solution in methylene chloride was added dropwise, keeping the temperature of the reaction mixture below -50C. The reaction was mechanically ~tirred for 3 hours at -50C, then allowed to warm to 22C over a one-hour period. Water was then added dropwise with vigorous stirring. The methylene chloride was evaporated in vacuo, and the aqueous mixture basified to pH 12 with sodium hydroxide solution, ~hen treated with 3N hydrochloric acid to pH 7.5. The solid precipitate was filtered cold, then d ried using an evaporating dish.
The solid residue was washed several times with hot acetonitrile, then recrystallized from ethanol-water to give N~-~[l-methyl 5-(4~methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-lysine hydrate (2:1), m.p. 231-233C d as a light tan solid; the yield was 10~ of theoretical.
.
nmr (CD3OD/D~O~: ~7.9-7.0 (q, 4H, J-14 Hz~; 6.8-6.6 ~d, ; lH, J-4Hz); 6.3-6.1 (d, lH, J-4Hz~; 3.85 ts, 3H0; 3.75 (s, 2H); 3.4-3.15 (m, lH~S 3.1-2.6 (m, 2H); 2.4 (2, 3~; 2.1-1.0 tm, 6H).
EXAMPLE XN2-{[l-Methyl-5-(4-methylbenzoyl~-lH pyrrol-2-yl] acetyl}
glutamine A 20 9 sample ~0.073 mole) of [l~methyl-5-t4-methyl-benzoyl)-lH-pyrrol~2-yl]-acetyl chloride was added to a ~-392 7'~'7 solution of 11.5 g (0.079 mole) of glutamine and 29.3 g (0.32 mole) of sodium bicarbonate in 300 ml of water. The solution was stirred for 3 hours. The solid was filtered and discarded. The filtrate was acidified with 3N HCl.
The solid was filtered and washed wi~h water. The solid was dissolved in acetone-water (50:50), treated with charcoal and the solvent evaporated in vacuo. The solid was extracted with boiling acetone to give 4.3 g of white crystalline N2-{[l-methyl-5-(~-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl} glutamine hydrate (lO:l) m.p. 194-6, yield 15.4%.
Anal. calcd. for C20H23N30s-0.1 H~0:
C, 62.04; H, 6.4; H20, 0.45 Found: C, 62.08; H, 6.01; H20, 0029 EXAMPLE XII
Methyl N- t [ l-Methyl-5-~4-methylbenzoyl~-lH-pyrrol-2-yl]-acetyl~-~lycinate 2~
A solution of 14.0 g (0.139 mole) of triethylamine in 350 ml of ethanol free chloroform was added to a suspen-sion of 8.3 g (0.066 mole) of glycine methyl ester hydro-chloride in 500 ml of chloroform. The mixture was cooled to 0 and a solution of 16~83 g (0.061 mole) of [l-methyl-5-(4-methylbenzyl)-lH-pyrrol-2-yl]-acetyl chloride in 300 ml of chloroform added. The mixture was stirred at room temperature for 90 minutes. The solution was then washed successively with dilute HCl, sodium bicarbonate solution, water and brine. The solution was dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The solid was dissolved in chloroform-ethyl acetate and filtered through silica gel, The solvent was evaporated and the residue recrystallized twice from ethyl acetate to give 14.9 g (68% yield) of methyl N-{~l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl3-acetyl~-glycinate, m.p. 149-150C.
el~AMPLE Xl:tI
~G ~a~
(A) A solution of 361 g ~l.l mole) of methyl N-ltl-methyl-5-(4-me~hylben~oyl)-.Lt~-pyrrol-2-yll-acc~yl~-glycinate ln 2 l Oe cth~noL and ~20 ml 5N N~O~ wa0 heated under reflux ~or 4S mLnu~ trhe mlxtur~ wa9 coolad ~nd the solid collected and clried to give 303 g of sodium N-l[l-methyl-5-(4-methylbenzoyL-l~-pyrrol-2-yl]-acetyl~-glycinate, m.p. 2~1-2~4C (d).
(B) A solution from 12 g (0.038 mole) of ~T-l[l-methyl-5-(4-methylben~oyl)-lH-pyrrol-2-yl]-acetyl~-glycine and 4.6 g of 2-amino-2-(hydroxymethyl-1,3-propanediol in 300 ml 2-propanol wa~ concentrated in vacuo and the solid collected and dried. There was obtained 6.0 g o 2-ammonium-2-(hydroxymethyl)-1,3 propanediol ?J-t[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~-glycinate hydrate 1:1.65, m.p. 6~-73C.
(C) ~o a solution of Ç.73 9 of 2-ammonium-2-~hydroxy-methyl)-1,3-propanediol N-t[l-methyl-5-(methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~-glycinate in 50 ml of water was added a saturated solution of 22.64 g of CaCl2 in water. The solid was collected, washed with water and air dried to give calcium N-{[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl}-glycinate hydrate [1:0.5:1.6], m.p. 267-270C
(d).
EXAMPLE XIV
Following the procedure~ of the eor~going Example X~I and substitutlng the appropriate N-tl-mekhyl-5-~-meth~l-benzoyl)-L~I-p~rrol-2-yll-acetyl aminoacLcl der;Lvatlve th~
following salt~ may be obtained;
~-39~
77~7 Sodium N-{[l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~-alaninate Sodium N-{[l-methyl-5-(4-methylbenzoyl3-lH-pyrrol-2-yl]-acetyl~-lysinate 2-Ammonium-2-(hydroxymethyl)-1,3-propanediol N-t[l-methyl-5~(4-methylbenzoyl3-lH-pyrrol-2-yl] acetyl~-methioninate Calcium N- t [l-methyl-5-(4-methylbenzoyl)-lH-pyrrol-2-yl]-acetyl~-aspartate [1:1]
MN-3g2
Claims (15)
1. A process for the preparation of a compound of the formula or a pharmaceutically acceptable salt thereof wherein R" is H, C1-6 alkyl, (CH2)nCO2H,CH2CH2SCH, (CH2)4NH2 or (CH2)2CONH2; and n is 1 or 2 which comprises a) saponification of an ester of the formula wherein R' is an alkyl; or b) debenzylating an ester of the formula of a) wherein R' is benzyl.
2. A process for the preparation of N= {[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-glycine and salts thereof which comprises saponification of methyl N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-glycinate.
3. A process for the preparation of N-{[1-methyl-4-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-alanine and salts thereof which comprises saponification of methyl N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-alaninate.
4. A process for the preparation of N-{[1-methyl-4-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-methioninate and salts thereof which comprises saponification of methyl N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl -acetyl}-methioninate.
5. A process for the preparation of N-{[1-methyl-4-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-aspartic acid and salts thereof which comprises saponification of methyl N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyxrol-2-yl]-acetyl}-aspartate.
6. A process for the preparation of N-{[1-methyl-4-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-glutaminc acid and salts thereof which comprises saponification of methyl N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-glutamate.
7. A process for the preparation of N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-aspartic acid and salts thereof which comprises debenzylation of dibenzyl N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-aspartate.
8. A process for the preparation of N2-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-lysine and salts thereof which comprises debenzylation of N6-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-lysinate.
9. A compound of the formula or a pharmaceutically acceptable salt thereof wherein R" is H, C1-6 alkyl, (CH2)nCO2H, CH2CH2SCH3, (CH2)4NH2 or (CH2)2CONH2; and n is 1 or 2 whenever prepared or produced by the process of claim 1 or by any obvious chemical equivalent thereof.
10. N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-glycine and salts thereof whenever prepared or produced by the process of claim 2 or by any obvious chemical equivalent thereof.
11. N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-alaninate and salts thereof whenever prepared or produced by the process of claim 3 or by any obvious chemical equivalent thereof.
12. N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-methionine and salts thereof whenever prepared or produced by the process of claim 4 or by any obvious chemical equivalent thereof.
13. N-{[1-methyl-5 (4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-aspartic acid and salts thereof whenever prepared or produced by the process of claims 5 or 7 or by any obvious chemical equivalent thereof.
14. N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-glutamic acid and salts thereof whenever prepared or produced by the process of claim 6 or by any obvious chemical equivalent thereof.
15. N-{[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-acetyl}-lysine and salts thereof whenever prepared or produced by the process of claim 8 or by any obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US46104783A | 1983-01-26 | 1983-01-26 | |
| US461,047 | 1983-01-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1207777A true CA1207777A (en) | 1986-07-15 |
Family
ID=23831020
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000443449A Expired CA1207777A (en) | 1983-01-26 | 1983-12-15 | Pyrrole-2-acetylamino acid derivatives |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS59141560A (en) |
| KR (1) | KR840007584A (en) |
| CA (1) | CA1207777A (en) |
| PH (1) | PH19284A (en) |
| ZA (1) | ZA84583B (en) |
-
1983
- 1983-12-15 CA CA000443449A patent/CA1207777A/en not_active Expired
-
1984
- 1984-01-24 JP JP59009606A patent/JPS59141560A/en active Pending
- 1984-01-25 PH PH30160A patent/PH19284A/en unknown
- 1984-01-25 KR KR1019840000322A patent/KR840007584A/en not_active Application Discontinuation
- 1984-01-25 ZA ZA84583A patent/ZA84583B/en unknown
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| Publication number | Publication date |
|---|---|
| PH19284A (en) | 1986-03-04 |
| KR840007584A (en) | 1984-12-08 |
| JPS59141560A (en) | 1984-08-14 |
| ZA84583B (en) | 1985-09-25 |
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