JPS5910589A - Antiinflammatory and analgesic novel 5-(pyrrol-2-oyl)-1,2-dihydro-3h-pyrrolo(1,2-a) pyrrole derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel substituted 5-(pyrrole-2-oil)-1
, 2-dihydro-3H-pyrrolo(1,2-a)pyrrole derivatives and their corresponding salts, esters, nitrinoamides and substituted amides. U.S. Pat. No. 4,097,57 limited to 5-unsubstituted pyryl derivatives
The novel alkyl, 5-N-alkyl, 5-0 of the present invention different from the known pyrrolo[1,2-a]pyrrole derivative of No. 1
- has a 5-pyryl group substituted with a variety of groups including -alkyl or 5-pyryl. It is very well known that such petero-substituted viroles are difficult to prepare due to the sensitive nature of the pyrrole system. Furthermore, it is found that the compounds of the present invention have higher analgesic/anti-inflammatory effects than prior art compounds, but exhibit much lower ulcer gene stimulation. For chronic diseases, such as arthritis, it is critical that anti-inflammatory/analgesic drugs be regularly and regularly administered in effective doses without causing gastric irritation or ulcers.

Therefore, the objects of the present invention are (1) to provide a novel non-steroidal anti-inflammatory and analgesic agent with high potency as well as lower ulcerogenic side effects; (2) novel 5-(substituted pyrrole-2-oil) -1,
Develop a method for producing 2-dihydro-3H-pyrrolo(1゜2-a)pyrrole derivatives: (3) Develop a method for applying the novel compounds in the treatment of inflammatory diseases, alleviation of pain and fever or inhibition of platelet aggregation. (4) Pharmaceutical compositions and formulations for administering these novel compounds are provided.

The present invention provides novel 5-(substituted pyrrole-2-oil)-1 having the structure:
, 2-dihydro-3H-pyrrolo[l,2-a]pyrrolyl derivatives or pharmaceutically usable salts, esters or amides thereof.

(b) lower alkyl, especially straight-chain or branched alkyl, such as methyl, ethinopropyl, isopropyl, t-butyl, pentyl and hexyl; (c) lower cyclo Alkyl, especially C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl: (d) Lower (cycloalkyl-alkyl), especially C4-8 (cycloalkyl), such as cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cyclohexylethyl. (e) lower alkenyl, especially C2-8 alkenyl, such as 2-propyl, 2-methyl-2-butenyl and 3-ethyl-2-pentenyl; (f) halo-lower alkyl, especially chloromethyl, trifluoromethyl , 1-chloroethyl and 2,2-difluorobutyl; still (g) phenyl-still substituted phenyl-lower alkyl, especially of benzyl, 4-chlorobenzyl, 2-fluoropencyl and phenylpropyl. phenyl-C1-3 alkyl.

The above groups (a) to (g) are unsubstituted or still lower alkyl, lower alkoxy, halo, cyano, carboxy,
substituted amino, haloalkyl, such as sulfonamino, carbamoyl, sulfonyl, sulfinyl, azide, amino, lower alkylamino or di-lower alkylamino;
Carboxyalkyl, carbamoylalkyl, N-substituted rubamoylalkyl or the like. are replaced by a combination of these.

R1 is hydrogen, halo-lower alkyl or lower alkyl, especially auto-6 alkyl as defined above.

R”Z can be in any available ring position
R2 is R as defined above.

n is 1-3.

R3 is (,) hydroxy; (b) lower alkoxy, especially auto-6 as defined above
alkoxy; (c) amino; (d) lower alkylamino, especially C1-6 alkylamino such as cyclohexylamino, methylamino, isopropylamino, n-butylamino or t-butylamino; (e) di-lower alkylamino, di(c,-s alkyl)amino, especially diethylamino or dimethylamino; (f) morpholinyl; (g) bis(hydroxy lower alkino)amino, especially bis(hydroxyethyno)amino, such as bis(hydroxyethyno)amino; -6alkyl)amino: (h) lower alkylcyclohexylamino, especially self-6alkylcyclohexylamino such as methylcyclohexyamino; or (i) gelcosamino: (j) lower (alkanoyloxyamino) ), especially 1-(pivaloyloxy)ethoxy or 1-(acetoxy)ethoxy, (k) aroyloxy lower ajyloxy, especially 1-(benzoxy); ) Ethoxy; (1) Lower (alkoxycarbonyloxydialkoxy)
, especially C1-5(alkoxycarbonyloxydialkoxy) such as 1-(ethoxycarbonyloxy)ethoxy
) aryloxycarbonyloxy lower alkoxy,
Aryloxycarbonyl Cl-6 flukoxy, especially 1-(benzyloxycarbonyloxy)ethoxy; (n) tri(lower alkylamino) lower alkoxy, especially tri(C1-a alkylamino) Ct-a, such as cholineoxy Alkoxy; (,) lower (alkanoylaminoalkoxy), especially CZ-S (alkanoylaminoalkoxy), such as acetamidoethoxy; (p) imide lower alkoxy, especially imide C1-6, such as 1-(succinimido)ethoxy; alkoxy; (q) heterocyclyloxy, such as phthalidyloxy or 2-biridyloxy; (r) hydroxy lower alkoxy, especially hydroxy Ct-6 alkoxy, such as hydroxypropoxy; (s) lower alkoxy alkoxy, especially methoxyethoxy, ethoxy Cl-6 (alkoxyalkoxy) such as ethoxy or methoxymethoxy; (1) di(lower alkylamino) lower alkoxy, especially di(cue alkylamino) Cl such as dimethylaminoethoxy, dimethylaminopropoxy or diethylaminopropoxy; -6 alkoxy; (u) N-pyrrolidinyl lower alkoxy, %-KN-
(v) N-piperidinyl lower alkoxy, especially N-piperidinyl ethoxy; (w) N-morphorinyl lower alkoxy, especially N-
N-morphorinyl self-6 alkoxy or (x) 4-methyl-1-piperazinyl lower alkoxy of morphorinylethoxy,
In particular 4-methyl-1-piperazinyl C1-6 alkoxy such as 4-methyl-1-piperazinylethoxy.

Y is oxygen, sulfur, sulfinyl, sulfonyl, CH2
-'! is hydrogen. However, when Y is hydrogen, R is absent, and 2 is 10-1-s-1-8O-15O2-1-NH-1
-CH2- or halo, especially fluoro, chloro or bromo. However, when 2 is halo, R2 does not exist.

A preferred embodiment of the present invention includes compounds having formula (1), where R is (a) hydrogen or C1-6 alkyl as defined above; (b) 2-propenyl or C2-4 alkenyl such as propenylmethyl; (c) I\rho C1-6 alkyl as defined above;
or (d) phenyl-CI-s alkyl, such as benzyl.

R1 is hydrogen or Cl-6 alkyl; R2Z is at the 5 position or adjacent to N, and R2 is R as defined above.

n is 1; R3 is hydroxy, c, -6 alkoxy or lower (alkanoylaminoalkoxy), especially CI -6 flukanoylaminoalkoxy, such as acetamidoethoxy.

Y is oxygen, sulfur, CH2-H when R is not present yet
and 2 is -S -1CH2- or halo when R2 is absent.

A most preferred embodiment of the invention includes compounds having the structure (1), where R is C1-3 alkyl, especially methyl or present; R1 is hydrogen or methyl; R2z is 5 R2 is hydrogen, methyl or absent; n is 1; R3 is hydroxy 9, c, 6 alkoxy or acetamidoethoxy; Y is oxygen, CH2- or H; However, when Y is H, R is absent and 2 is -S-1-CH2- or halo. However, when 2 is halo, R2 does not exist.

Typical f compounds of the present invention include (1) 5-(5-methylthio-2-pyroyl)-1,2
-dihydro-6-methyl-3H-pyrrolo[1,2-a]
Pyrrole-1-carboxylic acid: (2) Ethyl 5-(5-methylthio-2-pyroyl)-
1,2-dihydro-6-methyl-3H-pyrrolo[1,2
-8] Pyrrole-1-carboxylate; (3) 5-(5-chloro-2-pyroyl)-1゜2-dihydro-6-methyl-3H-pyrrolo(1,2-a)pyrrole-1-carvone acid; or (4) ethyl 5-(5-chloro-2-pyroyl)-1,
2-dihydro-6-methyl-3H-pyrrolo[1,2-a
] Pyrrole-1-carboxylate; (5) 5-(5-isopropyl-2-pyroyl)-1,
2-dihydro-6-methyl-3H-pyrrolo[1,2-a
] Pyrrole-1-carboxylic acid; (6) Ethyl 5-(5-isopropyl-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[
1,2-a]pyrrole-1-carboxylate or (7) 5-(1-methyl-5-methylthio-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[
1,2-a,:l pyrrole-1-carboxylic acid; (8) ethyl 5-(1-methyl-5-methylthio-2-
Pyroinoly 1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate: (9) 5-(1-methyl-5-chloro-2-pyroyl)
-1,2-dihydro-6-methyl-3H-pyrrolo[1,
2-a] pyrrole-1-carboxylic acid; (10) ethyl 5-(1-methyl-5-chloro-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a ) Pyrrole-1-carboxylate; (11) 5-(1-methyl-5-isopropyl-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a) pyrrole-1 -carboxylic acid; (12) ethyl 5-(1-methyl-5-isopropyl-
2-pyroyl)-1,2-dihydro-6-methyl-3H
-pyrrolo[1,2-a)pyrrole-1-carboxylate; (13) 5-(1-methyl-5-ethylthio-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1 ,2-a]pyrrole-1-carboxylic acid; (14) 5-(1-methyl-5-n-propylthio-2
-pyroyl)-1,2-dihydro-6-methyl-3H-
Pyrrolo[1,2-a]pyrrole-1-carboxylic acid: (15) 5-(1-methyl-5-methoxy-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo(
1,2-a'J pyrrole-1-carboxylic acid; (16) 5-(1-methyl-5-ethoxy-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[
1,2-a) Pyrrole-1-carboxylic acid, (17) 5-(1-methyl-5-n-propyloxy-
2-pyroyl)-1,2-dihydro-6-methyl-3H
-Pirolo[:1. ．． 2-a:]]pyrrole-1-carboxylic acid (18) 5-(1-trifluoromethyl-5-methylthio-2-pyroyl)-1,2'-dihydro-6-methyl-3H-pyrrolo[1,2 -a] pyrrole-1-carboxylic acid, (19) ethyl 5-(1-methyl-5-ethylthio-2
-pyroyl)-1,2-dihydro-6-methyl-3H-
Pyrrolo[:1.2-a:]]pyrrole-1-poxylate (20) Ethyl 5-(1-methyl-5-n-propylthio-2-pyroyl)-1,2-dihydro-6-methyl-
3H-Pyrrolo[1,2-a)pyrrole-1-carboxylate, (21) Ethyl 5-(1-methyl-5-methoxy-2-pyroyl)-1,2-dihydro-6-methyl-
3H-pyrrolo[1,2-a:] is a possible protecting group.

According to the above scheme, (1) a is decarboxylated under neutral, acidic or basic conditions. When the decarboxylation is carried out under basic conditions, the precursor of formula Ha is typically heated in a suitable solvent at about 50-250°C, preferably about 90-150°C, for about 0.5-48 hours or until decarboxylation is substantially complete. Heat with base (Table ■) until

The most commonly utilized solvents are (1) water; (2) Cs-5 alkanols, especially methanol, ethanol, isopropanol, and t-butyl alcohol; (3) lower ketones, such as acetone and methyl ethyl ketone; (4) 1 .Lower ethers including 2-dimethoxyethane, tetrahydrofuran (THF), dioxane and diglyme; (5) Includes mixtures of at least two of the solvents described in (1) to (4), especially aqueous solutions thereof.

Table ■ When applied to acidic decarboxylation of tri(lower alkyl)amines, such as triethylamine pyrrolidine pyridine, ncolidine, specifically refluxing la with trifluoroacetic acid to generate 1m, followed by hydrolysis (R4
is not H), it is subjected to various known modifications such as ammonialysis, transesterification, etc. to produce (1). Other acids can also be used. Specifically, they are listed in Table H below.

Table ■ 6 Acid having R' -C-C0OH 8 where R6 and R8 are each hydrogen or halo such as iodo, bromo, chloro or fluoro, preferably chloro or fluoro; and R7 is H,C ! -6 alkyl, halo especially chloro or fluoro or halo C16 alkyl such as trifluoromethyl, trichloromethyl, 1,1-difluoroethyl or 1-chloro-1-fluoropropyl.

(2) Suitable Acids: Acetic Acid Chloroacetic Acid Chlorodifluoroacetic Acid Dichloroacetic Acid Difluoroacetic Acid Trifluoroacetic Acid Trichloroacetic Acid Pentafluoropropionic Acid Acidic decarboxylation can be carried out in an acid or in an inert solvent containing the acid. Examples of frequently used solvents are shown in Table 1 below.

Table 1 Toluene Benzene Xylene Atrahydrofuran 1.2-Dimethoxy-ethane dioxane Methylene chloride Acetic acid The degree of decarboxylation can vary depending on the acid or solvent used. Typical temperatures range from about 30°C to about 120°C.

Under optimal conditions, ie, refluxing trifluoroacetic acid in the presence or absence of a solvent, the temperature ranges from about 35 to about 75°C.

Generally, decarboxylation is substantially complete after heating at a suitable temperature for about 1 to about 20 hours, or under more favorable conditions for about 0.5 to about 5 hours.

Precursors of formula 11a are readily prepared by condensation of a pyrrolo[1,2-,L]pyrrole moiety with a substituted pyrrole derivative as shown in scheme (a) below.

Scheme (a) (1va) 1 where RXR1, R2, R4, R5, Y and 2 are as defined above.

On the other hand, when 2 is -5-1-〇- or -NH-, [a
can be obtained via the following diagram (b).

Scheme (b) (mb) (IVb) Starting material (n
la and l1lb) are known and published on May 3, 1982.
Co-pending application number 373,69 filed on the 1st
No. 2 and US Pat. No. 4,097,579. These two disclosures are incorporated herein by reference.

Pharmaceutically acceptable salts of acids of formula I are readily prepared by conventional procedures known in the art. Specifically, the acid of formula (1) is combined with an alkali or alkaline earth metal hydroxide, a base such as hydroxide, or an organic compound such as an amine such as triethylamine, lysine, dibenzylethylenediamine, piperidine, pyrrolidine, benzylamine, etc. Treat with appropriate amount of base.

Pharmaceutically acceptable esters of acids of structure (1) are prepared by conventional methods. Specifically, (1) the compound of formula (1) was mixed with sulfuric acid, hydrochloric acid and the above table (
An acid such as any one or a combination of the acids exemplified under n) is treated with a lower alkanol or phenol in the presence of an ion exchange resin.

(2) The compound of formula (1) is treated with a halogen agent such as thionyl chloride or phosphorous pentachloride, and then reacted with an alcohol or phenol to form an acid chloride or an acid such as bromide. Converts to halide. 1. T. Harrison (lar
rison) etc. Riley-Interscience 2nd
72 pages (1971) "'Outline of Organic Synthesis Methods'".

Ji'Compendium of Organic
Other well-known methods can also be used, such as those covered by ``5ynthetic Methods'').

Similarly, pharmaceutically usable amides of acids of formula (1) are readily prepared by conventional methods.

Specifically, the acid halide of formula (1) can be treated with ammonia or a substituted amine such as ethylamine, benzylamine or glucosamine to produce the corresponding amide. Other methods can also be used, including treating the acid with an amine in the presence of a catalyst such as DDC or tosyl chloride.

The following examples are presented to illustrate the invention without limiting its scope.

Example 1 Step A: 1-Methyl-2-thiocyanopyrrot Br220 dissolved in methanol 45- to a mixture of 25 g of KSCN in 60- dry methanol at -78°C under nitrogen atmosphere!
i' was added.

The resulting yellow solution was stirred for 5-10 minutes and 1-methylpyrrole 10.1. ! i' was added at once.

The mixture was allowed to warm to room temperature and stirred for an additional hour. Pour the mixture into 600 ml of ice water and add 200 ml of methylene chloride.
Extracted twice with me. The salt f-hymethylene layer was washed, dried, and then concentrated to yield 161 g of a light yellow oil that turned reddish on standing.

Step B: Preparation of 1-methyl-2-methylthiopyrrole Addition of 5.4.9 g of sodium methoxide to a mixture of 6.9 g of 1-methyl-2-thiocyanopyrrole and 14.2 g of CH3I at -30° C. under nitrogen atmosphere and set the temperature to 0.
The temperature was raised to ℃. The reaction mixture boiled (exothermic reaction).

Stirring was continued for 3 hours at ambient temperature. The r liquid was desolvated under reduced pressure to produce 5.75 g of pale yellow oil. This product (NM
R (pure) could be distilled under vacuum at T40°C and stored over 2CO3 at 0°C.

Step C: 1-Methyl-5-methylthiopyrroh 100 m7 of dry ether stirred at 0°C under nitrogen atmosphere! 11 g of phosgene dissolved in 20 ml of ether were added to a solution of 12y7 g of 1-methyl-2-methylthiovirol. This mixture was heated at 0°C for 4 hours and at ambient temperature for 1 hour.
Stirred for 4 hours. Residual phosgene was removed with N27 and the solvent was evaporated. The resulting solid product was recrystallized with hexane to produce pink needle-shaped crystals m, p, 67-70°C.

Step D: Ethyl 1-(2-hydroxyethyl)-3-carboethoxy-4-methyl - 150 ml of ethanolamine in 1250 rnl of water at 20°C.
Diethyl 1,3-acetonedicarboxylate 505I was added to 0 ml of the solution 1, the mixture was stirred at 0°C for 125 minutes and then treated with 1-chloroacetone 237y.

The reaction mixture was maintained below 10°C. After further stirring at room temperature for 5 hours, the mixture was poured into Hα21-ice 6#, and
/ Stirred for 2 hours. The mixture was filtered and the residue was thoroughly washed with H2O and then with hexane to give 200 g, m, of a white product.
p, 133-135°C.

Step FJ: Ethyl 1-(2-mesyloxyethyl)-3
-carboethoxy-4-methyl = 800 methylene chloride dry at 10°C - ethyl in 1
-(2-hydroxyethyl)-3-carboethoxy-4
-Methylvirol-2-acetate (101.7 g) was treated with triethylamine 56- and then methanesulfonyl chloride 31- was added dropwise. After stirring for 30 minutes at room temperature, 250 rnl of water were added, the organic layer was separated and water (3
Ethyl 1-(2-mesyloxyethyl)-3-carboethoxy-4-methylpyrrole-2- was obtained as white crystals from ethyl acetate-hexane, washed with Acetate 121. :19 was generated, rrL p.

66-68℃.

Step F: Preparation of ethyl 1-(2-iodoethyl)=3-carboethoxy-4-methylpyrrole-2-acetate Ethyl 1-(2-mesyloxyethyl)-3-carboethoxy-4-methylpyrrole-2- Acetate (11,
6F) and NaI 27I in acetonitrile 1 for 1 hour.
The mixture was heated to reflux at 50 m/min. removing the solvent by distillation;
The residue was diluted with water. The insoluble product was separated by filtration, air dried, and crystallized from methylene chloride/hexane to give ethyl 1-(2-iodoethyl)-3-carboethoxy-4-methylpyrrole-2-acetate 14.
9. ! 9 was produced as a white solid.

Step G Nidiethyl 1,2-dihydro-6-methyl-3H
-pyrrolo-(1,2-a) pyrrole-1,7-dicarpoxylate Ethyl 1-(2-iodoethyl)-3-carboethoxy-4-methylpyrrole-2-acetate in dry dimethylformamide 65- 60%) 1.6g
and stirred at room temperature for 60 minutes. The mixture was quenched with 100ml of water and extracted with ethyl acetate (3x100ml). The ethyl acetate layer was washed with water, dried over MgSO4,
The crude diethyl 1°2-dihydro-6-methyl-3H was filtered and evaporated to dryness to be used in the next step without further purification.
-pyrrolo-(i,2-a)virol-1,7-cica, 6.4 g of lupoxylate was produced.

Step I (-diethyl5-(1-methyl-5-methylthio-2-pyroyl)-1,2-dihydro-6-methyl-3
Production of H-pyrrolo-[1゜2-a]pyrrole-1,7-dicarboxylate Diethyl 1,2-dihydro-3H-pyrrolo-[1,2-
a) -6-Methylpyrrole-1°7-dicarboxylate (22,2N) and 16.9% of 1-methyl-5-methylthiovirol-2-acid chloride are dissolved in 250 me of methylene chloride at 0°C, Next, methylene chloride 45-S
Dropwise treatment was performed with nα<22ml. After stirring for an additional 3 hours at ambient temperature, 3NHα250- was added and then stirred for 1 hour. Separate the organic layer, wash with water and dilute with Na2SO4
dried, filtered over silica and mixed the PK with an equal volume of hexane, distilled to remove most of the methylene chloride and cooled to give diethyl 5-(1-methyl-5-methylthio-2 -pyroyl)-1゜2-dihydro-6-methyl-3H-pyrrolo-(1',2-a)virol-1,
7-Dicarboxylate 30.5.9 was produced as white crystals, m, p, 142-3°C.

Step I: 5-(1-Methyl-5-methylthio-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]-diethyl 5-(
1-Methyl-5-methylthio-2-pyroyl)-1,2
-dihydro-6-methyl-3H-pyrrolo(1,2-a)
Pyrrole-1,7-dicarboxylate (25,!9)
, H2O, and 25 g of KOH were heated under reflux for 8 hours. The resulting mixture was treated with 200 mg of saturated Naα and distilled to remove methanol. The mixture was acidified with 6NHα with stirring and then cooled.

The resulting crystalline material was separated by filtration, air dried, and recrystallized from ethyl acetate-ethanol to give 5-(1-methyl-5-methylthio,-2-pyroyl)-1,2-dihydro-6- Methyl-3H-pyrrolo-[1,2-a]-pyrrole-1,7-dicarboxylic acid 2117Xm, p.

It produced 212-3°C.

Step J: Ethyl 5-(1-methyl-5-methylthio-2
-pyroyl)-1,2-dihydro-6-methyl-3H-
Preparation of pyrrolo-[1,2-a) pyrrole-1-carboxylate-7-carboxylic acid 5-(1-methyl-5
-methylthio-2-pyroyl)-1゜2-dihydro-6
-methyl-3H-pyrrolo(1,2-a)pyrrole-1,
7-dicarboxylic acid (20g) and resin (BioRad A
G50W-XB, 20-50m'/S:l) 20
solution of jj until the reaction is complete by TLC (6
time) heated to reflux. The solution was filtered hot 7 and the resulting crystalline product was collected by a second filtration to obtain ethyl 5-(1
-Methyl-5-methylthio-2-pyroyl)-1,2-
dihydro-6-methyl-3H-pyrrolo-[1,2-a]
-pyrrole-1-carboxylate-7-carboxylic acid 1
7.5. j9Xm, p, 209-211°C.

Step: Ethyl 5-(1-methyl-5-methylthio-2
-pyroyl)-1,2-dihydro-6-methyl-3H-
Pyrrolo-(1,2-a)pyrroethyl 5-(1-methyl-5-methylthio-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-
1-Carboxylate-7-carboxylic acid (1,65g neat) was heated at 240<0>C until the CO2 bubbling stopped (30 minutes). The resulting residue was then dissolved in 30 rnl of methylene chloride and passed through a short column of silica. The r solution was mixed with an equal volume of hexane and then distilled to the original volume. Upon cooling, ethyl 5-(1-methyl-5-methylthio-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylate 1
．． II was obtained as white crystals, m, p, 101-2°C.

5-(1-methyl-5-methylthio-2
-pyroyl)-1,2-dihydro-6-methyl-3H-
Substantially the same procedure was repeated except that pyrrolo[1,2-alpyrrole-1,7-dicarboxylic acid was used.
5-methylthio-2-pyroyl)-1,2-dihydro-
6-Methyl-3H-pyrrolo[1,2--)pyrrole-1
-carboxylic acid was obtained.

Example 2 5-(1-methyl-5-methylthio-2-pyroyl)-
1,2-dihydro-6-methyl-3H-pyrrolo-[:1
．． 2-a] Pyrrole-1ethyl 5-(1-methyl-5-
Methylthio-2-pyroyl)-1,2-dihydro-6-
Methyl-3H-pyrrolo(1,2-a)pyrrole-1-carboxylate (500 mg) in 10 ml of methanol and 10 ml of 10% NaOH! and stirred for 2 hours. Two hundred grams of saturated sodium chloride solution was added to the resulting mixture, and methanol was distilled off under reduced pressure. The aqueous solution was acidified with 3 NHC/3 with stirring, cooled and the precipitate formed was collected by filtration. The residue was washed with water, air dried and recrystallized from ethyl acetate-hexane to give 5-(1-methyl-5-methylthio-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo( 1,2-a]pyrrole-1-carboxylic acid 450 mg, m, p.

It produced 182-184°C.

On the other hand, the corresponding diacid 5-(1-methyl-5-methylthio-2-pyrrole)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2 -a] The title compound is prepared by decarboxylating pyrrole-1,7-dicarboxylic acid until the reaction is substantially complete. The mixture was quenched with water, extracted with salt fhimethylene, and the methylene chloride layer was diluted with 5% NaHCO3.
Wash several times with aqueous solution, dry and evaporate to give 5-(1-methyl-
5-methylthio-2-pyroyl)-1,2-dihydro-
6-Methyl-3H-pyrrolo-[1,2-a]pyrrole-
1-carboxylic acid was produced.

Example 3 Ethyl 5-(1-methyl-5-chloro-2-pyroyl)
-1,2-dihydro-6-methyl-3H-pyro Step A Nidiethyl 5-(1-methyl-5-chloro-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-(
1,2al pyrrole diethyl ethyl ether, 2-dihydro-3H-pyrrole (1,2a)-6- in 100 ml of methylene chloride
A solution of 16 g of methylpyrrole-1,7-dicarpoxylate-5-acid chloride and 6 J of 1-methyl-5-chloropyrrole was treated with 3nC2415- at =35°C, stirred for 4 hours at room temperature and Example 1, Step Proceeding as described under H yielded 14 g of a crude product consisting of two compounds (α and β isomers).

Silica gel as the solid support and 40% as the moving phase
The α isomer was separated by column chromatography using :60 (ethyl acetate:hexane). The diester was crystallized from methylene chloride-hexane to give diethyl 5-(1
m , p, 124-6°C.

Step B: 6,0 g of 5-(1-methyl-5-chloro-2-pyroyl)--1,2-dihydro-6-methyl-3H-pyrrole-[1,2a]pyrrole-diester in Example 1 , hydrolyzed as in step ① to give 5-(1-methyl-5-chloro-2-pyroyl)-1,2-dihydro-6
-Methyl-3H-pyrrole-(1,2-a]pyrrole-
1,7-dicarboxylic acid was obtained.

Step C: Ethyl 5-(1-methyl-5-chloro-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrole-[1,2-a)pyrrole-1-carboxylate-7- Manufacture of carboxylic acid Ethanol 100rnI! , 5-(1-methyl-5-
Chloro-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo-[1,2-a)]]pyrrole-1.
A solution of 7-dicarboxylic acid 5 was treated with resin 5I and monoesterified as in Example 1, Step J to give ethyl 5-(1-methyl-5-chloro-2-pyroyl)-1,
2-dihydro-6-methyl-311-pyrrole-[1,
2-a] Pyrrole-1-carboxylate-7-carboxylic acid3. sy.

m, p, 18.5-187°C.

Step D: Ethyl 5-(1-methyl-5-prolow 2-
pyroyl)-1,2-dihydro-6-methyl-3H-pyrrole[1,2-a:]]birrole-ethyl5-1-methyl-5-chloro-2-pyroyl)-1,2-dihydro-6 -Methyl-3H-pyrrolo[:1.2-a]pyrrole-1-carboxylate-7-carboxylic acid (35I) was decarboxylated at 200°C. Repeat the same operation to obtain ethyl 5-(1-
Methyl-5-chloro-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrole [1,2-alpyrrole-1-carboxylate 2.5! ! Also generates.

Example 4 N-acetylaminoethyl 5-(1-methyl-5-chloro-2-pyroyl)-1,2-dihydro-6-methyl-
311-Pyrrole-[1,2-a]pyrrole-1-5-(1-methyl-5-chloro-
2-pyroyl)-1,2-dihydro-6-methyl-3H
-pyrrole [ll2-a) pyrrole-1-carvone fi
o,5'i,N-acetylaminoethanol 0.269
A solution of 05 g of XDCC and 0.11.5' of N,N-dimethylaminopyridine was stirred at room temperature for 16 hours.

The generated dicyclohexyl urea was removed, and the residue was dissolved in ether, water, 5% acetic acid 3 x 50me, 5% NaHC.
Washed with O:+, dried and evaporated. N-acetylaminoethyl 5-(1-methyl-5-chloro-2-pyroyl)-1,2-dihydro-6 was crystallized with ethyl acetate.
-Methyl-3H-pyrrolo-[1,2-alpyrrole-1
-carboxylate 40.1 = 9, m, p.

A temperature of 156-157°C was obtained.

Example 5 5-(1-methyl-5-methylthio-2-pyroyl)-
1,2-dihydro-6-methyl-3H-pyrrole-[1
5-(1-Methyl-5-methylthio-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrole[1°2-a]pyrrole-1-carboxylic acid o, sg in 20 ml of methanol and 0.24 jj of lysine were stirred at 40°C for 1 hour, then cooled and ether was slowly added. The generated precipitate was collected by filtration and lysine salt 0.70
7 was generated.

Mass number rrv'e (M H2O), 446 Example 6 5-(1-Methyl-5-methylsulfinyl-2-pyroyl)-1,2-dihydro-6-methyl-3H-5- in pichloroform 22- (1-methyl-5-methylthio-
2-pyroyl)-1,2-dihydro-6-methyl-3H
A solution of 0.2 g of -pyrrolo-[1°2-a]-pyrrole-1-carboxylic acid and 2.3 drops of dimethyl sulfoxide was added to 0.1 m-chloroperbenzoic acid (MCPBA),
! i! and stirred overnight. Then, 5-(1-methyl-5-methylsulfinyl-2-pyroyl)-1,2-dihydro-6 -Methyl-
195 m9 of 3H-pyrrolo-[1,2-a)pyrrole-1-carboxylic acid were obtained. rrV/e334° Similarly, the corresponding sulfone is prepared by a similar operation using 0.2 g of (MCPBA). - After refluxing overnight, 5-(1-
Methyl-5-methylsulfonyl-2-pyroyl)-1,
2-dihydro-6-methyl-3K-pyrrolo-[1,2-
a] Obtain virol-4-carboxylic acid.

The novel compounds of the present invention can be used to treat a wide variety of conditions manifested by one or more symptoms of pain or inflammation, such as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis, rheumatic fever, and pain symptoms associated with other diseases. It is an anti-inflammatory and analgesic agent that has utility in the treatment of. Moreover, at similar dosage levels prior art compounds (U.S. Pat. No. 3,95
No. 2,012) is unexpectedly found to be more effective, but with a very low incidence of undesirable gastric side effects. These results are illustrated by parallel comparative data as shown in Table 1 below.

Table ■ RZ=H10130 RZ=CI-I3S 15--R'=H RZ--CH3S 90 RZ-α 15 R' = H2,1 a Gastric hemorrhage 2 The GHLF test is performed according to the following procedure.

Rat (Spraquada Ray, Jift, 120-1
80V), and the subjects were fasted overnight and administered orally a drug suspended in 0.5% methylcellulose. Each animal has 1. Om
e: / 100,! Drug concentrations were adjusted to accommodate i' body weight. After 4 hours, the animals were killed by asphyxiation with carbon dioxide, and the stomachs were removed, dissected, and everted. The mucosal lining was washed and examined at 3x magnification. Lesions are often identified as perforations in the gastric mucosa that perforate the stomach wall at right angles.

Results are expressed in two ways, mean number of lesions per stomach and number of animals in croup showing at least one lesion.

b, phenylbenzquinone (PBQ) 1 in mice
Groups of 0 male mice (C, B, L, CDt
, 18-22I) were fasted the night before the experiment. Test substances suspended or dissolved in 1% methylcellulose were added to PBQ (
2.0 m/lq intraperitoneal) throw! -14Qi1 was administered orally (0, i mp/10 g body weight) at various times. Place mice on individual bonoxes for 10 minutes (PBQ
(after 5-15 minutes) Observe. For each animal,
The number of abdominal contractions, lordosis, and hindlimb extensions was recorded and the group mean and standard error were calculated. The mean obtained from the croup-treated drug was compared to the excipient control mean and the percent inhibition of writhing was calculated as follows.

] Testing was performed according to procedures well known in the art (C.A. Winter, Arthr.

Rheum Vol. 9, pp. 394-404 (1966)
reference).

For inflammation, fever or pain, the compounds of this invention can be administered orally, topically, parenterally, by inhalation spray or in dosage unit formulations enriched with conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients. Can be administered rectally. The parenteral techniques used in the present invention include subcutaneous, intravenous, intramuscular, intrasternal, and infusion techniques. In addition to the treatment of animals such as mice, rats, horses, dogs, cats, etc., the compounds of the present invention are useful in the treatment of humans.

Pharmaceutical compositions containing the active ingredients can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. It can be in any form suitable for its use. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may be prepared without sweetening agents to provide a pharmaceutically elegant and palatable preparation. , flavoring agents, coloring agents, and preservatives. Tablets contain the active ingredients in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch. , gelatin or gum arabic and lubricants, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby prolong the action over a longer period of time. By way of example, a time delay agent such as glyceryl monostearate or glyceryl distearate may be used.

Formulations for oral use can also be made in hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules mixed with active nut oil, liquid paraffin or olive oil. It can be made to exist as.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.

Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents are natural phosphatides such as lecithin, or alkylene oxides. Condensation products of ethylene oxide and fatty acids, such as polyoxyethylene stearate or ethylene oxide and long-chain aliphatic alcohols, such as heptadecaethylene oxycetanol or polyoxyethylene sorbitol monooleate. It may be a condensation product of a partial ester derived from hexitol or a condensation product of ethylene oxide and a fatty acid with a partial ester derived from hexitol anhydride, such as polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, such as ethyl or n-propyl, p-hydroxybenzoate,
It may contain one or more coloring agents, one or more sweetening agents such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.

Oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of anti-acid agents such as ascorbic acid.

Dispersible powders and granules suitable for preparing aqueous suspensions by the addition of water provide the active ingredient in admixture with dispersing or wetting agents, suspending agents and one or more preservatives.

Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.

In addition, excipients such as flavoring agents and coloring agents can also be present.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers are natural gums such as gum acacia or dragantocomb, natural phosphatides such as soybean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydride;
For example, sorbitan monooleate and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate, may be used. The 4 emulsions also contain flavoring and weighting agents. be able to.

Syrups and elixirs can be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a detoxifying agent, preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Excipients and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as the suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of the present invention can also be administered rectally in the form of herbal medicines. These compositions can be prepared by mixing the drug with suitable nonirritating excipients that are solid at normal temperatures but liquid at rectal temperatures and therefore melt in the rectum and release the drug. can.

Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions containing anti-inflammatory agents are used.

Dose levels of about 0.2 to 14 omy/114 body weight per day are useful in treating the symptoms indicated above (f/patient/day, V). For example, by administering about 0.5 to 50 g of the compound per body weight per day (25 to 3.5 g per patient per day), inflammation can be effectively treated and antipyretic and analgesic effects can be achieved. Advantageously, about 2 to 20 rn9 per 111 body weight per day gives very effective results (50 to 1 g per patient per day).

The number of active ingredients that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a formulation intended for oral administration in humans may contain 5 my to 5 g of active agent, formulated with a suitable and conventional amount of carrier material, which can vary from about 5 to about 95% of the total composition. can. Dispensable unit forms generally contain between about 25 and about 500 active ingredients.

However, the specific dosage level for any particular patient will depend on the activity of the particular compound used, age, body weight, general health, sex, diet, frequency of administration, route of administration, rate of excretion, etc.
It is understood that this will depend on a variety of factors, including the drug combination and the severity of the particular disease being treated.

Claims (1)

[Claims] l A compound having the structural formula: (1) or a pharmaceutically usable salt, ester or amide thereof [wherein R is (,) hydrogen; (b) lower alkyl; (c) lower cycloalkyl; (d) lower (cycloalkyl-alkyl); (e) lower alkenyl; (f) halo lower alkyl; or (g) phenyl or substituted phenyl lower alkyl; ) is unsubstituted or still lower alkyl, lower alkoxy, halo, cyano, carboxy, sulfonamido, carbamoyl, sulfonyl, sulfinyl, azide, amino, substituted amino, halo lower alkyl, carboxy lower alkyl, carbamoyl lower alkyl, N-substituted R is hydrogen; lower alkyl; or haloalkyl; R can be in any available position and R is R as defined above: n is 1 to 3; R3 is (a) hydroxy; (b) lower alkoxy; (c) amino; (d) lower alkylamino; (e) di(lower alkyl) amino; (f) morpholinyl; (g ) bis(hydroxy-lower alkyl)amino; (h) lower alkylcyclohexylamino; (i) gelcosamino; (j) lower (alkanoyloxy-dialkoxy); (k) aroyloxy-lower alkoxy; (1) lower (alkoxycarbonyl-oxy) alkoxy); to) aryloxycarbonyloxy lower alkoxy; (n) tri(lower alkylamino) lower alkoxy; (0) lower (alkanoylamino alkoxy); (p) imido lower alkoxy; (q) heterocyclyl-oxy; r) Hydroxy lower alkoxy; (,) Lower alkoxy alkoxy; (1) Di(lower alkylamino-) lower alkoxy; (u) N-pyrrolidinyl lower alkoxy; (v) N
-piperidinyl lower alkoxy; (W) N-morphorinyl lower alkoxy or (X) 4-methyl-1-piperidinyl lower alkoxy; Y is oxygen, sulfur, sulfinyl, sulfonyl, CH2
or H, provided that when Y is H, R is absent; Z is 10-1-S-1-8O-1-so2-1-NH-
1-CR2 or 8 days, but does not exist when 2 is 8 days. ] 2 R is (a) H or C0-6 alkyl; (b) C
2-4 alkenyl; (c) halo C1-6 alkyl: or (d) phenyl-C1-3 alkyl; if R1 is hydrogen or Cl-6
is alkyl; R2Z is in the 5 position; R2 is R as defined above; n is 1; R3 is hydroxy, C1-6 alkoxy or lower (alkanoylaminoalkoxy); Y is Oxygen, sulfur, CH2- or H, provided that when Y is H, R is not present; and 2 is -S-1-CR2- or halo, provided that when 2 is halo, R2 is not present. A compound according to claim 1. 3 R is Cl-3 alkyl or absent; R1 is hydrogen or methyl; R2Z is in position 5 and R2 is R as defined above; n is 1; R3 is is hydroxy, cl-6 flukoxy or acetamidoethoxy; Y is oxygen, CH2- or H, provided that when Y is H
2. The compound according to claim 1, wherein R2 is absent; and 2 is -8-1-CH2- or halo, provided that Y is eight days and R2 is absent. 4 Structural formula (na) ([1a) (wherein R, Y, R1, R2 and 2 are as defined below; R4 is hydrogen or lower alkyl; and R5 is hydrogen, t-butyl, penthydryl (1) wherein R is (,) hydrogen; (b) lower alkyl; (c) lower cyclo alkyl; (d) lower (cycloalkyl-alkyl); (,) lower alkenyl; (f) halo-lower alkyl; or (g) phenyl-but substituted phenyl-lower alkyl; g) is unsubstituted or lower alkyl, lower alkoxy, halo, cyano, carboxy, sulfonamido, carbamoyl, sulfonyl, sulfinyl, azide, amino, substituted amino, halo lower alkyl1. carboxy lower alkyl,
carbamoyl lower alkyl, N-substituted carbamoyl lower alkyl, or a combination thereof; R1 is hydrogen or lower alkyl; R2 can be in any available position; R2 is R as previously defined; n is 1 to 3; R3 is (,) hydroxy; (b) lower alkoxy; (c) amino; (d) lower alkylamino; (e) di(lower alkyl) amino; (f) morpholinyl ; (g) bis(hydroxy lower alkyl (carbonyloxycarbonyloxy); ni) aryloxycarbonyloxy lower alkoxy; (n) tri(lower alkylamino) lower alkoxy; (,) lower (alkanoylamino alkoxy); (p) imide lower alkoxy; (q) heterocyclyl- Oxy; (r) Hydroxy lower alkoxy; (S) Lower alkoxyalkoxy: (1) Di(lower alkylamino) lower alkoxy; (u) N-pyrrolidinyl lower alkoxy; (v) N
-piperidinyl lower alkoxy; (w) N-morphorinyl lower alkoxy; (X) 4-methyl-1-piperazinyl lower alkoxy;
or (y) lower alkyl; Y is oxygen, sulfur, sulfini/L, sulfonyl, CH
2′! ! or H, provided that when Y is H, R is absent; Z is 10-1-s-1-8O-1-so2-1-NH-
1-CH2- or halo, provided that when 2 is halo,
R does not exist] A method for producing a compound having the following. 5. A non-toxic pharmaceutical carrier and a compound having the structural formula: for the treatment of inflammation, fever and pain in mammals, characterized in that it includes an effective amount of a pharmaceutically usable salt, ester or amide thereof. The pharmaceutical composition of the drug, [wherein R is -(,) hydrogen; (b) lower alkyl; (c) lower cycloalkyl; (d) lower (cycloalkyl-alkyl); (,) lower alkenyl; ) halo lower alkyl; is (g) phenyl- or substituted phenyl-lower alkyl; the above groups (,) to (g) are unsubstituted or lower alkyl, lower alkoxy, halo, cyano, carboxy, substituted by sulfamino, carbamoyl, sulfonyl, sulfinyl, azide, amino, substituted amino, halo-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl, N-substituted rubamoyl-lower alkyl or combinations thereof; R1 is hydrogen or lower alkyl R''Z can be in any available position; R2 is R as previously defined; n is 1-3; R3 is (,) hydroxy; (b) lower alkoxy ; (c) amino; (d) lower alkylamino; (,) di(lower alkyl) amino; (f) morphorinyl; (g) bis(hydroxy lower alkyl) amino; (h) lower alkylcyclohexylamino; (i ) gelcosamino; (j) lower (alkanoyloxy-dialkoxy); (k) aroyloxy-lower alkoxy; (1) lower (alkoxycarbonyloxy-dialkoxy): (c) aryloxycarbonyloxy-lower alkoxy; (n) tri(lower alkyl) (amino) lower superalkoxy; (,) lower (alkanoylaminoalkoxy): (p) imido lower alkoxy: (q) heterocyclyl-oxy; (r) hydroxy lower alkoxy; (s) lower alkoxyalkoxy; (t) cy( (lower alkylamino) lower alkoxy; (u) N-pyrrolidinyl lower alkoxy; (v) N
-piperidinyl lower alkoxy; (w) N-morphorinyl lower alkoxy; (x) 4-methyl-1-piperazinyl lower alkoxy;
or (y) lower alkyl; Y is oxygen, sulfur, sulfinyl, sulfonyl, CH2
or H, provided that when Y is H, R is absent; 2 is -0-1-5-1-S 0-1-8O2-1-NH
-1-CH2- or 8 days, provided that 2 is halo,
R exists and is a person. [6] Treatment of inflammation, fever and pain characterized by administering an effective amount of a compound having structural formula (1) or a pharmaceutically usable salt, ester or amide thereof to a mammal in need of treatment. Treatment method [wherein R is (a) hydrogen; (b) lower alkyl; (c) lower cycloalkyl; (d) lower (cycloalkyl-alkyl); (e) lower alkenyl; (f) halo lower alkyl; or (g) phenyl- or substituted phenyl-lower alkyl; the groups (a) to (g) above are unsubstituted or lower alkyl, lower alkoxy, halo, cyano, carboxy, sulfonamide, carbamoyl, sulfonyl, sulfinyl, Substituted by azide, amino, substituted amino, lower alkyl, carboxy lower alkyl, carbamoyl lower alkyl, N-substituted carbamoyl lower alkyl or combinations thereof: R1 is hydrogen or lower alkyl; can be in any position; R2 is R as defined above; n is 1-3; R3 is (,) hydroxy; (b) lower alkoxy; (c) amino; (d) lower alkylamino (e) di(lower alkyl)amino; (f) morphorinyl; (g) bis(hydroxylower alkyl)amino; (h) lower alkylcyclohexylamino; (i) gelcosamino; (j) lower (alkanoyloxydialkoxy ); (k) Aroyloxy lower alkoxy; (1) Lower (alkoxycarbonyloxydialkoxy); (n) Tri(lower alkylamino) lower alkoxy; (,) Lower (alkanoylaminoalkoxy) ); (p) Imide lower alkoxy: (q) heterocyclyl-oxy; (r) hydroxy lower alkoxy; (,) lower alkoxyalkoxy; (1) di(lower alkylamino) lower alkoxy; (u) N-pyrrolidinyl lower Alkoxy; (v) N
-piperidinyl lower alkoxy; (w) N-morphorinyl lower alkoxy; (X) 4-methyl-1-piperazinyl lower alkoxy;
or (y) lower alkyl; Y is oxygen, sulfur, sulfinyl, sulfonyl, CH2
or H, provided that when YfJ''-H, R is absent: 2 is -0-1-8-1-8o-1-802-1-NH-
1-CH2-4 is halo, but when 2 is halo, R
does not exist. ] 7 The compound is (1) 5-(5-methylthio-2-pyroyl)-1
,2-dihydro-6-methyl-3H-pyrrolo(1,2-
8) Virol-1-carboxylic acid; (2) Ethyl 5-(5-methylthio-2-pyroyl)-
1,2-dihydro-6-methyl-31(-pyrrolo(1,
2-, K) Pyrrole-1-carboxylate; (3) 5-(5-chloro-2-pyroyl)-1゜2
-dihydro-6-methyl-3H-pyrrolo[1,2-a]
Pyrrole-1-carboxylic acid; (4) ethyl 5-(5-chloro-2-pyrrole)-1
,2-dihydro-6-methyl-3H-virolo[,2-a
) Pyrrole-1-carboxylate; (5) s-(5-isopropyl-2-pyroyl)-
1,2-dihydro-6-methyl-3■-pyrrolo(1,2
-a) Pyrrole-1-carboxylic acid; (6) Ethyl 5-(5-isopropyl-2-pyroyl)
-1,2-dihydro-6-methyl-3H-pyrrolo(1,
2-a) Pyrrole-1-carboxylate: Madadah (7) 5. - (1-methyl-5-methylthio-2-
(8) Ethyl 5-(1-methyl-5-methylthio-2-
Pyroyl-1,2-dihydro-6-methyl-3H-pyrrolo(1,2-a)pyrrole-1-carboxylate; (9) 5- < 1-methyl-5-chloro-2-pyroyl)-1, 2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid; θO ethyl 5-(1-methyl-5-chloro-2-pyroyl)-1,2-dihydro-6 -Methyl-3■-pyrrolo(
1,2-a) Pyrrole-1-carboxylate: aυ5-(1-methyl-5-isopropyl-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo(
1,2-a) Pyrrole-1-carboxylic acid: θcanityl 5-(1-methyl-5-isopropyl-2-
pyrrole)-1,2-dihydro-6-methyl-3■-pyrrolo[1,2-a) pyrrole-1-carboxylate;
a field 5-(1-methyl-5-ethyl J rethio-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolof
lu, z-a) pyrrole-1-carboxylic acid; Q→5-(1-methyl-5-n-propyJ and thio-2-
pyrrole)-1,2-dihydro-6-methyl-3H-pyrrolo(1,2-a]pyrrole-1-carboxylic acid; α-5-(1-methyl-5-methoxy-2-pyroyl)
-1,2-dihydro-6-methyl-3H-pyrrolo[1,
2-a) Pyrrole-1-carboxylic acid; (a) 5-(1-methyl-5-ethoxy-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo(1
, 2-a) Pyrrole-1-carboxylic acid; α7) 5-(1-methyl-5-n-propyloxy-2
-pyroyl)-1,2-dihydro-6-methyl-3H-
Pyrrolo[1,2-a)pyrrole-1-carboxylic acid; α1195-(1-trifluoromethyl-5-methylthio-2-pyroyl)-1,2-dihydro-6-methyl-
3H-pyrrolo[1゜2-a]pyrrole-1-carboxylic acid; Q1 ethyl-5-(1-methyl-5-ethylthio-2-
pyrrole)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a) pyrrole-1-carboxylate;
Kan ethyl 5-(1-methyl-5-n-propylthio-2
-pyroyl)-1,2-dihydro-6-methyl-3H-
Pyrrolo[1゜2-a]pyrrole-1-carboxylate: Qυethyl 5-(1-methyl-5-methoxy-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2 -a] Pyrrole-1-carboxylate; (a) Ethyl 5-(1-methyl-5-ethoxy-2-pyroyl)-1,2-dihydro-6-methyl-3H-pyrrolo(1,2a)pyrrole- 1-carboxylate; (c) Ethyl 5-(1-methyl-5-n-propyloxy-2-pyroyl)-1,2-dihydro-6-methyl-
3H-pyrrolo(1,2-a)pyrrole-1-carboxylate; ■Ethyl 5-(1-trifluoromethyl-5-methylthio-2-pyroyl)-1゜2-dihydro-6-methyl-
3H-PyrroloCI, 2-a) Pyrrole-1-carboxylate or the lysine salt thereof. 8. The compound according to claim 1, wherein the compound is a t-4 or d-isomer.